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Lucidi Chimica Organica Superiore 2

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Chemistry creates its subject .This creative ability, similar to that of art, essentially distinguishes Chemistry among the natural sciences.Berthelot, J. 1860

The ultimate goal of Organic Synthesis is to assemble a given organic compound (target molecule ) from readily available starting materials and reagents in the most efficient way. This process usually begins with the design of a synthetic plan (strategy) which calls upon various synthetic reactions to address individual synthetic objectives in a certain sequence. If a transformation or a strategic maneuver required by the synthetic plan has to be demonstrated before, the plan must rely on the development of a suitable synthetic method or tactic to solve the particular problem at hand. Thus, the science of organic synthesis is constantly enriched by new inventions and discoveries pursued deliberately for their own sake or as subgoals within a program directed towards the synthesis of a target molecule. Nicolaou, K. C. Classics in Total Synthesis

Name Reaction !!!!

The Practice of Total SynthesisWith its share of glorious moments, setbacks, and frustrations Total Synthesis can be compared to the game of chess. The object of this game is to capture the opponent's king by a series of allowed moves played out in such a combination and order as outmaneuver the opponent. Similarly, in total synthesis the object is to reach the target molecule by a series of reactions which have to be carried out in the right sequence to outmaneuver natural barriers. Studying and applying the moves (reactions) to capture the king (make the molecule) then becomes the object of total synthesis. The practice and elegance of total synthesis involves and depends of the following stages:1. Selection of the target: natural product or designed molecule2. DESIGN OF THE SYNTHETIC STRATEGY: RETROSYNTHETIC ANALYSIS3. Selection of the reagents and conditions4. Experimental execution

Design is a term that refers to a creative activity within the realm of technology, an activity that, to be sure, can ascend into the domain of great art. The design of a chemical synthesis is not science a priori:it is a fruit of science; its prerequisite is comprehensive matured, and approved scientific knowledge.

Robert Burns Woodward. Architect and Artist in the World of Molecules

Organic Synthesis

Serratosa defined Synthesis as a heuristic activity"According to the Oxford Dictionary, the word heuristic derives from the Greek heurisko ("I find')and it is used as an adjective to describe activities directed towards the act of discovering , including all those reasonings and arguments that are persuasive and plausible without being logically ri gorous ...The heuristic principles, in contrast with the mathematical theorems and the rules of proof, do not pretend to be laws, an only suggest lines of activities “

Serratosa, F. Organic Chemistry in Action.

Organic Synthesis:

The targets can be Natural Products ...

Brevetoxin Bmarine neurotoxin associated with the red tide catastrophes[Nicolaou 1995]

Vancomycinantibiotic of last resort against anti-drug resistant bacteriaEvans 1995]

Swinholide Acytotoxic potent activity against multi-drug-resistant (MDR) carcinoma cell lines[Paterson 1994]

Organic Synthesis:

The targets can be compounds with interesting activities...

Acetylsalicilic acid (Aspirin, Bayer) Fluoxetine (Prozac, Eli Lilly)depressions

Allura red AC (Allied Chem)red pigment

Parathioninsecticide

Crivixan (Merck)anti AIDS Sildenafil (Viagra, Pfizer)

male erection disfunction

Organic Synthesis:

The targets can be compounds with artistic or anthropomorphic attributes...

NanoPutiansTour, J. M. JOC2003, 8750

Classifications of Synthesis: The Power of "Converge nt Synthesis "

The first principle of retrosynthetic planning: convergent strategies are the most efficient strategies for the assembly of complex molecules

Classifications of Synthesis Divergent synthesis :

• A divergent synthesis is a strategy with the aim to improve the efficiency of chemical synthesis. It is often an alternative to convergent synthesis or linear synthesis. In one strategy divergent synthesis aims to generate a library of chemical compounds by first reacting a molecule with a set of reactants. This methodology quickly diverges to large numbers of new compounds

Classifications of SynthesisCombinatorial synthesis :

The characteristic of combinatorial synthesis is that different compounds are generated simultaneously under identical reaction conditions in a systematic manner, so that ideally the products of all possible combinations of a given set of starting materials (termed building blocks) will be obtained at once.

Retrosynthetic (or antithetic) analysis is a problem solving technique for transforming the structure of a synthetic target (TGT) molecule to a sequence of progressively simpler structures along a pathway which ultimately leads to simple or commercially available starting materials for a chemical synthesis. The transformation of a molecule to a synthetic precursor is accomplished by the application of a transform , the exact reverse of a synthetic reaction , to a target structure. Each structure derived antithetically from a TGT then itself becomes a TGT for a further analysis. Repetition of this process eventually produces a tree of intermediates having chemical structures as nodes and pathways from bottom to top corresponding to possible synthetic routes to the TGT.

By the mid 1960's,a different and more systematic approach was developed: Retrosynthetic Analysis

In the beginning until Second World War organic synthesis was based on the Direct Associative Approach (i.e. associative thinking or thinking by analogy was sufficient)With the exception of a minor proportion which clearly depended on a more subtle way to thinking about, the planning syntheses were initially basedon the availability of starting materials that contained a major portion of the final atomic framework and on the knowledge of reaction suitable for forming polycyclic molecules

Organic Synthesis

In The Direct Associative Approach, the chemist directly recognizes within the structure of the target molecule a number of readily available structural subunits, which can be properly joined by using standard reactions with which he is familiar

Organic Synthesis

In the synthesis of peptides, recognition of the constituent aminoacids is almost immediate. However, the realization of the synthesis in the laboratory may be one of the most arduous tasks which the synthetic organic chemist faces

Strategies and Tactics in Organic Synthesis

Retrosynthetic Analysis: The key to the design of efficient syntheses

"The end is where we start from....“T. S. Eliot

". . . the grand thing is to be able to reason backwards. That is a very useful accomplishment, and a very easy one, but people do not practice it much.“ Sherlock Holmes

1 overall plan to achieve the ultimate synthetic target2 Intellectual3 retrosynthetic planning4 TRANSFORMS

Strategy Tactics

1 means by which plan is implemented2 experimental3 synthetic execution4 REACTIONS

Synthetic versus retrosynthetic analysis

tactic Strategy

In pursuit a total synthesis, a chemist tries to foresee the key disconnections which will allow him to reach the target. The set of these main disconnections defines and establishes the strategy.However thoroughly proficient the strategy formulation (the retrosynthetic analysis ) ..., still needs tactical coordination to smooth the progression, otherwise the success will be ardous and unspectacular ... although the demarcation between certain tactics and strategies is difficult to make.

Strategy and Tactic Ho, T.-L.Tactics of Organic Synthesis

Strategies and Tactics in Organic Synthesis

"...even in the earliest stages of the process of simplification of a synthetic problem, the chemist must make use of a particular form of analysis which depends on the interplay between structural features that exist in the target molecule and the types of reactions or synthetic operations available from organic chemistry for the modification or assemblage of structural units. The synthetic chemist has learned by experience to recognize within a target molecule certain units which can be synthesized, modified, or joined by known or conceivable synthetic operations...it is convenient to have a term for such units; the term "synthon" is suggested. These are defined as structural units within a molecule which are related to possible synthetic operations... a synthonmay be almost as large as the molecule or as small as a single hydrogen; the same atoms within a molecule may be constituents of several overlapping synthons...“ from "General Methods for the Construction of Complex Molecules“ E. J. Corey, Pure Appl. Chem. 1969, 14, 19

"Retron : The minimal substructural element in a target structure which keys the direct application of a transform to generate a synthetic precursor.“ from E. J. Corey and X.-M. Cheng, "The Logic of Chemical Synthesis", 1989For instance, in Diels-Alder reaction the retron , a minimal keying element, is 6-membered ring with a π-bond:

E. J. Corey

retron

RetronStructural unit that signals the application of a particular strategy algorithm during retrosynthetic analysis.TransformImaginary retrosynthetic operation transforming a target molecule into a precursor molecule in a manner such that bond(s) can be reformed (or cleaved) by known or reasonable synthetic reactions. The exact reverse of a synthetic reaction; the formation of starting materials from a single product.Strategy AlgorithmStep-by-step instructions for performing a retrosynthetic operation.

Strategies and Tactics in Organic Synthesis

Retrosynthesis analysis is a problem solving technique for transforming the structure of synthetic target molecule (TM) to a sequence of progressively simpler structures along the pathway which ultimately leads to simple or commercially available starting materials for a chemical synthesis. (E.J Corey)

The transformation of a molecule to a synthetic precursor is accomplished by:· Disconnection : the reverse operation to a synthetic reaction. The retrosynthetic step involving the breaking of bond(s) to form two (or more) synthons is referred to as a disconnection .· Functional Group Interconversion (FGI) : is the process of the transformation of one functional group to another to help synthetic planning and to allow disconnections corresponding to appropriate reactions. In planning a synthetic strategy, apart from devising means of constructing the carbon skeleton with the required functionality, there are other factors which must be addressed including the control of regiochemistry and stereochemistry. The converting process transform one functional group into another by substitution, addition, elimination, reduction, or oxidation.

Each structure thus derived from TM then itself becomes a TM for further analysis. Repetition of the process eventually produces a tree of intermediates having chemicalstructures in the nodes and possible chemical transformations as pathways from bottom to TM. One should avoid excessive branching and proliferation of useless pathways. Strategies for control and guidance are of the utmost importance.

Synthetic Strategies : Choosing the way along the retrosynthetic tree or the synthetic planning.Synthetic Tactics : How a specific bond or set of bonds at a given site can be efficiently created.

The central point in this methodology is a rational and penetrating analysis of the structure of TGT. Such analysis leads to a limited logical set of intermediate structures which can be transformed into the original in just one reaction or synthetic step. Every structure generated is then carefully analysed as before to give another set of structures, which can be transformed into the preceding structures in one step. The process is repeated for every intermediate until a "tree“ of such intermediate structure is obtained. By this process a set of possible alternative synthetic pathways is generated which correspond to sequences of synthetic intermdiates structures that go from possible starting materials to TGT: it is the so-called "synthesis tree".

Target molecule: the molecule to be synthetizedRetrosynthetic analysis or retrosynthesisthe process of menthally breaking down a molecule into starting materialTransform: the exact reverse of a synthetic reactionRetron: structural subunit on the target that enables a transform to operateDisconnection: an imaginary bond cleavage corresponding to the reverse of a realreactionSynthon: idealized fragments, usually a cation, anion or radical, resulting from a disconnectionReagent: a real chemical compound used as the equivalent of a synthon

Synthesis tree: set of all the possible disconnections and synthons leading from the target to the starting materials of a synthesis

1. There are many approaches to the synthesis of a TGT.2. All the synthetic routes can be derived through arational and penetrating analysis of the structure of TGT,which should consideri) symmetry, either real or potential,ii) functional group relationships (it is imperative to remove or modify the highly unstable groups)iii) carbon skeleton: chains, rings and appendagesiv) stereochemistry3. Then, the synthetic possibilities derive from the identification of retrons and the application of transforms , which permit the generation of synthons . These synthons are next evaluated.This repeating analysis produces the synthesis tree .4. The best route is the most simple, flexible, and efficient.5. It is desirable that disconnections correspond to known and reliable reactions. It is worth identifying the most difficult steps and to provide alternative routes (flexibility)6. Problems associated to the construction of the skeleton, the manipulation of functional groups, and the introduction of stereochemistry must be considered simultaneously.i) consider alternative disconnections and choose routes that avoid chemo- and regioselectivity problems

ii) use two-group disconnections wherever possible.

Some Useful GuidelinesSome Useful Definitions

Strategies and Tactics in Organic Synthesis

The transformation of a molecule into a synthetic precursor is accomplished by application of a transform (antithesis process) , the exact reverse of a synthetic reaction , to a target structures.

Transform & Retron

In order for a transform to operate on a target structure to generate a synthetic predecessor,theenabling structural subunit or retron for that transform must be present in the target.

It is possible to have partial Diels-Alder retron as in the case of cyclohexane unit

Strategies and Tactics in Organic Synthesis

There are many thousands of transforms which are potentially useful in retrosynthetic analysis just as there are very many known and useful chemical reactions ...One feature of major significance is the overall effect of transform application onmolecular complexity.

Molecular complexity elements are:

(1) Molecular size

(2) Cyclic connectivity or topology

(3) Element or functional group content

(4) Stereocenter content/density

(5) Centers of high chemical reactivity

(6) Kinetic (thermal) stability

Transforms & Molecular Complexity

Strategies and Tactics in Organic Synthesis

moderate complexity

high complexity

Types of Transforms

1. Structurally simplifying transforms effect molecular simplification bydisconnecting molecular skeleton, and/or functional groups and/or stereocenters.

2. There are transforms which bring about no essentially no change in molecular complexity, but which can be useful because they modify a TGT to allow the subsequent application of simplifying transforms. They include rearrangements of molecular skeleton, functional group interchange (FGI) , and inversion/transfer of stereocenters.

3. Opposite to 1, structurally increasing complexity transforms includes addition of rings or stereocenters and addition functional groups (FGA) ,.

Strategies and Tactics in Organic Synthesis

1. Structurally simplifying transforms by disconnecting molecular skeleton and by disconnecting functional groups or stereocenters..

Types of Transforms

Strategies and Tactics in Organic Synthesis

2. Structurally "neutral" transforms ...by rearrangements of molecular skeleton,

Types of Transforms

or functional group interchange (FGI)

Strategies and Tactics in Organic Synthesis

3. Structurally increasing complexity transforms includes addition of rings, functional groups (FGA), or stereocenters.

Types of Transforms

Strategies and Tactics in Organic Synthesis

Guidelines in action: SymmetryA TGT molecule is said to have real symmetry if the structure possesses symmetry elements: axis, plane or centre .Otherwise, it is said to have potential symmetry when, although asymmetrical molecule, may be disconnected to give either a symmetrical structure or two synthetically equivalent structures.The recognition of symmetry in the structure of the TGT may be of paramount importance in the choices of disconnections to simplify the molecular complexity

Paterson, I.JACS 1994, 2615, 9391Tetrahedron1995, 9393–9437

regioselective esterification

See: Two-directional Chain Synthesis . Chem. Scripta 1987, 563; Acc. Chem. Res. 1994, 9; Tetrahedron 1995, 2167; Angew. Chem. Int. Ed 2003, 1096

Strategies and Tactics in Organic Synthesis

Guidelines in action: Symmetry

Robinson, R. J. Chem. Soc. 1917, 762

Bartlett, R. J. Am. Chem. Soc.1984, 5304Fleming, I.J. Chem. Soc. Chem. Commun.1994, 2285

Strategies and Tactics in Organic Synthesis

Guidelines in action: SymmetrySee also these works

Barton, D. H. R. Chem&Ind 1955, 1039; J. Chem. Soc. 1956, 530

Chapman, O. L. J. Am. Chem. Soc. 1971, 93, 6696

Schreiber, S.L. J. Am. Chem. Soc. 1992, 114, 2525

Strategies and Tactics in Organic Synthesis

Guidelines in action: Unstable functional groups?

It is imperative to remove or modify the highly unstable groups:Early strategic disconnections must address this type of problems. If this information is not available, preliminary studies are often required. At the outset of the project, no NMR spectroscopic or chemical stability data are available for the natural product. Since such information is invaluable in the design stages of any complex synthesis plan, both spectroscopic and chemical studies have to be undertaken.Evans, D. A. JACS 1990 7001.

Strategies and Tactics in Organic Synthesis

Taxol

The facile epimerization of taxol at C-7 is well documented, and in this synthesis the authors decide to pursue a synthetic strategy in which this stereocenter would be introduced at an early stage or the synthetic plan and carried throughout most of the synthesis in the absence of the C-9 carbonyl group

Holton, R. A. J. Am. Chem. Soc. 1994, 116, 1597

Guidelines in action: Unstable functional groups?

Strategies and Tactics in Organic Synthesis

Guidelines in action: functional groups relationships

Taking into account that most common synthetic reactions are polar, a bond forming process (and the corresponding transform) can be viewed as a combination of donor, d, and acceptor, a, synthons. Then, it might be useful to consider the carbon framework of any molecule as an ionic aggregate, whose origin relies on the presence of functional groups.

Following this idea, Evans suggested an heuristic (from the Greek heurisko: "I find')classification of functional groups (Attention: only the heteroatom is considered as the functional group)

Strategies and Tactics in Organic Synthesis

Guidelines in action: functional groups relationships

Strategies and Tactics in Organic Synthesis

Guidelines in action : stereochemical issues

The selective removal of stereocenters depends on the availability of stereosimplifying transforms, the establishment of the required retrons (complete with defined stereocenter relationships) and the presence of a favorable spatial environment in the precursor generated by application of such a transform...The most powerful transforms produce an overall simplification on the stereochemistry, the functional group and the skeleton of the target molecules.Remember that stereocontrol can rely on the same molecule (substrate control ) or on external reagents (reacting control ) and that just one or several elementscan play a crucial role (single or double asymmetric reactions, matched and mismatched cases)

Corey, E. J. The Logic of Chemical SynthesisMasamune, S. Angew. Chem. Int. Ed. Eng. 1985, 1Evans, D. A. Chem Rev. 1993,1307

Strategies and Tactics in Organic Synthesis

Synthon

Corey defined synthon in 1967 as: structural units within a molecule which are relate d to possible synthetic operations or units which can be formed and/or assembled by known or conceivable synthetic operations "Corey, E. J. Pure&Appl. Chem. 1967, 14, 19.

... but later, he avoids this term and uses synthetic precursor instead.Corey, E. J. The Logic ...; Angew. Chem. Int. Ed. Eng. 1990, 1320

However, this concept easily rooted in the synthetic language and nowadays is commonly used. Additionally, polar synthons have been classified...Taking into account that the most common synthetic reactions are polar,they can be viewed as combination of a negatively polarized (electronegative) carbon atom,or electron donor, d, of one synthon and a positively polarized (electropositive) carbon atom,or electon acceptor, a, of another synthon. Synthons are numbered (d0, d1, d2,... or a0, a1, a2, ....) with respect to the relative positions of a functional group (FG) and the reacting site

Strategies and Tactics in Organic Synthesis

Synthon

Strategies and Tactics in Organic Synthesis

Donor Synthons

Acceptor Synthons

Synthon

Strategies and Tactics in Organic Synthesis

Synthon

Strategies and Tactics in Organic Synthesis

Some “natural Synthons”

Strategies and Tactics in Organic Synthesis

Strategies and Tactics in Organic Synthesis

Some “Unnatural Synthons”

Strategies and Tactics in Organic SynthesisDisconnections

Other guidelines for retrosynthesis are given below:1. It is better to use convergent approach rather than divergent for many complex molecules.2. Use only disconnections corresponding to disconnect C–C bonds and C–X bonds wherever possible.3. Disconnect to readily recognizable synthons by using only known reactions (transform).4. The synthesis must be short.5. It is better to use those reactions which do not form mixtures.6. The focus is on the removal of stereocentres under stereocontrol. Stereocontrol can be achieved through either mechanistic control or substrate control.

Where should I choose to disconnect?Disconnections very often take place immediately adjacent to, or very close to functionalgroups in the target molecule (i.e. the one being disconnected). This is pretty much inevitable,given that functionality almost invariably arises from the forward reaction.

Strategies and Tactics in Organic Synthesis

DisconnectionsHow do I recognize a good disconnection?A good disconnection visibly simplifies the target molecule. Otherwise, the synthesis challengedoesn’t get any easier!

How do I decide which synthon carries which charge?A good trick here is to consider whether you can draw a resonance form of the synthon whichlooks more like a real reactive intermediate… If it does, you’ve clearly made a good choice ofpolarity, and you’ve most likely gone a long way to identifying the synthetic equivalent!

Strategies and Tactics in Organic Synthesis

Disconnections

Basic Guidelines:1. Use disconnections corresponding to known reliable reactions, choose disconnectioncorresponding to the highest yielding reaction.

synthons

Diazonium salt and propargylic Grignard

phenylGrignard and propargylic halide

reagents

Benzyl-halide and propyne.Grignard

BenzylGrignard and propyne-halide.

2. Disconnect C-C bond according to the present FGsin the molecule:

Strategies and Tactics in Organic Synthesis

Disconnections

a. C-C bond with no neighbouring functional groups

b. C-C bond with one oxygen substituent

c. Allylic C-C bond

d. C-C bond with two oxygen substituents in positions 1,3

Strategies and Tactics in Organic Synthesis

Disconnections

2. Disconnect C-C bond according to the present FGsin the molecule:

e. C-C bond with two heteroatom substituents in posi tions 1,2 or 1,4. Umpolung methods .

3. Aim for simplification:

a) Disconnect C-X bond (RCO-X)

Strategies and Tactics in Organic Synthesis

Disconnections3. Aim for simplification:

b) disconnect in the middle of the molecule

c) disconnect at a branch pointd) use symmetry

Tetrahedron Lett. 1981, 22, 5001

K.C.NicolaouAngew. Chem. Int. Ed.2001, 40, 761

Strategies and Tactics in Organic Synthesis

Disconnections3. Aim for simplification:

e) disconnect rings from chain

f) use rearrangements

Org. Lett.2001, 3, 115

Strategies and Tactics in Organic Synthesis

Disconnections

4. Carbocyclic Rings:

If one or more 6-membered carbocyclic unit present in the molecule consider a set of disconnection available for construction of 6-membered rings: Diels-Alder, Robinson annulation, aldol, Dieckmann, internal SN2, Birch reduction, etc.Some types of Diels-Alder disconnections:

f) use rearrangements

HO HO O

Oxy-Cope

Strategies and Tactics in Organic Synthesis

Disconnections

5. Examples of cleavage of C-C bond as a retrosynthetic reconnection

Via retro [2+2] and ketene formation

More electronrich doublebond ozonolysis

TM

TM

TM

TM

TMTM

TM

Those disconnections leading to two fragments of similar complexity are specially appealing.Alkyl, aryl,... subunits may be considered as building blocks and they should not be disconnectedWhen an heteroatom (X = N, O, S), is embodied in the carbon framework,the C–X bond disconnection uses to be strategic

C–C disconnections far from functional groups or stereocentres are not favored.C=C disconnections are used to be strategic.

Strategies and Tactics in Organic Synthesis

Disconnections

In the case of cyclic systems it is more difficult to elaborate general trends because of the different shapes present in these systems.

But in the case of a monocyclic system ...

Strategies and Tactics in Organic Synthesis

Disconnections

Strategies and Tactics in Organic Synthesis

Disconnections

Disconnection of molecules according to the present FGs in the molecule:

The potential of carbonyl functionality

Latent Polarity

Latent polarity is the imaginary pattern of alternating positive and negative charges used to assist in the choice of disconnections and synthons. Sticking to latent polarity usually gives the best choiceof synthons. However, this is not always possible!

Willis p. 15

According to these ideas, it is possible to identify difunctional relationships (consonant or dissonant ) among the functional groups in a TGT

Consonant relationships usually permit to devise easy disconnections. However, dissonant relationships often require to introduce umpolung tactics, radical or perycyclic reactions

1,2-difunctional dissonant relationship

1,3-difunctional consonant relationship

1,4-difunctional dissonant relationship

1,5-difunctional consonant relationship

Guidelines in action: functional groups relationships

Strategies and Tactics in Organic Synthesis

Disconnections

Guidelines in action: dissonant disconnection examples+

+-

Masked acylanion: unpolung

H

-

Disconnections

Strategies and Tactics in Organic Synthesis

1,2-Difunctional Compounds

1,2-Difunctional Compounds

Guidelines in action: consonant disconnection examples

+ - +

1,5-difunctionalised compounds

+ - + - +

Strategies and Tactics in Organic Synthesis

Disconnections

1,3-Difunctional Compounds

1,4-Difunctional Compounds

1,4-Difunctional Compounds

1,4-Difunctional Compounds

1,5-Difunctional Compounds

1,5-Difunctional Compounds

1,6-Difunctional Compounds

1,6-Difunctional Compounds

1,6-Difunctional Compounds

Disconnection GuidelinesWarren, p. 86-92

Disconnection Guidelines

Disconnection Guidelines

Available Starting Materials

A list of starting materials Warren p.90

Available Starting Materials

Chiral and enanthiopure compounds

Summary of Useful Reactions

Summary of Useful Reactions

Regioselective Enolate Formation

Regioselective Enolate Formation

Regioselective Enolate Formation

Strategies and Tactics in Organic Synthesis

Functional Group Interconversion (FGI):

Classification of functional groups by oxidation state of carbon atoms:

Oxidation state of carbon in alkanes (cycloalkanes ) is usually negative, the carbon in the fragment C-H is approximated as carbanion. The replacement of the hydrogen with a higher electronegative atom (C and heteroatoms) is equivalent to oxidation

Strategies and Tactics in Organic Synthesis

Functional Group Interconversion (FGI):

FGI can be divided into two groups :

Type 1 . Isohypsic transformations with no change to the ox idation level of carbonType 2 . Non-isohypsic transformations, where carbon atom i s either reduced or oxidised .

In general, on the same oxidation level any functional group interconversion can be performed in more or less easy way. However, transformations between levels can be achieved only on certain derivatives.

Very difficult

0+2

simple

0+2 +2

0+2

oxidation

reduction

Strategies and Tactics in Organic Synthesis

Functional Group Interconversion (FGI):

Type 1 (no change in oxidation state), Level 1 . The most common functions resulting from C-C bond construction are alcohol (Grignard addition to carbonyl compounds, aldol reaction, etc) and olefin (Wittig and related processes, croton condensation, olefin methathesis, etc). In addition, FGI of type 2 often lead to alcohols and olefins (reduction of carbonyl compounds, partial hydrogention)

synthons

Conclusion: in practice all functions of oxidation level 1 are synthetically equivalent as theycan be easily transformed into each other.

Strategies and Tactics in Organic Synthesis

Functional Group Interconversion (FGI):

Type 1 (no change in oxidation state), Level 2 . The main functional groups are carbonylcompounds (aldehydes and ketones) and alkynes.

Formation of synthetic equivalents of carbanions:

Formation of vinyl derivatives.

In organic synthesis vinyl halides can play a dual role: as electrophiles in reaction withorganocuprates and as nucleophiles when transformed themselves into organometallicderivatives.

Strategies and Tactics in Organic Synthesis

Functional Group Interconversion (FGI):

Compounds having two functional groups of level 1 which react as a whole belong to level 2(1,2-disubstituted compounds, oxiranes, allylic systems)

Formation of epoxides in a C-C bond forming procedure (apart from epoxidation of olefines):

Formation of allylic systems:

Strategies and Tactics in Organic Synthesis

Functional Group Interconversion (FGI):

Type 1 (no change in oxidation state), Level 3 . The main functional group that allows formation of any other derivative on the same level is acid halide. This is a typical electrophile used to make derivatives of carboxylic acids and in Friedel-Crafts C-C bond forming reactions.

Polyfunctional compounds of level 3 are α,β-unsaturated aldehydes and ketones – good Michael acceptors:

Strategies and Tactics in Organic Synthesis

Functional Group Interconversion (FGI):

Other important kind of transformations – interconversion of nitrogen containing functions.

Conclusions:1. Many functional groups, especially on the same level of oxidation, can be considered as synthetically equivalent so their retrosynthetic interconversions can be planned.2. As any functional group can be removed, retrosynthetically we can put a functional group in any position of alkane or cycloalkane chain and that would allow assembly of a given C-C fragment. Unfortunately, reverse is not achievable as yet.

Type 2 transformations (change in oxidation state) . Availability of methods to go from alcohol to carboxylic acid derivatives and back makes alcohol, carbonyl and carboxyl functions synthetically equivalent.

Strategies and Tactics in Organic Synthesis

Example of FGI and FGA approach

FGA= functional group addition

Strategies and Tactics in Organic Synthesis

Atom economy

The concept of atom economy was developed by B. M. Trost which deals with chemical reactions that do not waste atoms. Atom economy describes the conversion efficiency of a chemical process in terms of all atoms involved. It is widely used to focus on the need to improve the efficiency of chemical reactions.A logical extension10 of B. M. Trost’s concept of atom economy is to calculate the percentage atom economy . This can be done by taking the ratio of the mass of the utilized atoms to the total mass of the atoms of all the reactants and multiplying by 100.

Even if the reaction were to proceed with 100% yield, only 44.14% (by weight) of the atoms of the reactants are incorporated into the desired product, with 55.86% of the reactant atoms ending up as unwanted by-products.

Trost, B. M., Science, 1991, 254, 1471. Trost, B. M., Angew. Chem., Int. Ed. Engl., 1995, 34, 259.

Strategies and Tactics in Organic Synthesis

Atom economy

Other examples: Boots and Hoechst Celanese Corporat ion synthesis of ibuprofen

The total MFW of all the reactants used is 514.5 (C20H42NO10ClN9) and the total MFW of atoms utilized is 206 (ibuprofen; C13H18O2).

new three stage process with an atom economy of 77.4%.

Efficiency and Selectivity in Organic Synthesis

Selectivity:

Stereoselectivity:Formation of one stereoisomer over others

Regioselectivity:Formation of one regioisomer over others

Chemoselectivity:Reaction of one functional groups over others

Specificity :complete selectivity - chemo-, regio-, stereo

Efficiency

Tactical Efficiency:High Yield Atom Economy

Strategic Efficiency:Minimum of StepsConvergence

Protecting groups in organic synthesis

As seen, the selectivity may concern stereo- and regiochemistry, but may also be a question of which functional groups in the molecule are transformed preferentially: the so called chemoselectivity. Sometimes it simply isn't possible to devise a reaction which carries out a desired transformation whilst leaving other functional groups in the molecule untouched. This is often the case in multi-stage syntheses of complex, polyfunctional molecules. When this happens, it is necessary to mask or protect functional groups temporarily, in order that they are not affected by reactions transforming functions in other parts of the molecule. The functional group used to effect this protection is called a protecting group (PG).

Properties of protecting groups.An ideal protecting group has the following properties:1) It must be introduced selectively in the first instance in high yield, using reagents which are readily available, stable and easily handled;2) It must be stable to a wide range of reaction conditions;3) It must be readily removed by a specific, mild reagent, to regenerate the starting functional group;4) It must itself possess a minimum of functionality to avoid the possibility of sidereactions;5) It must be achiral, in order to avoid the formation of diastereomers;6) It must confer solubility, and facilitate purification;7) It must stabilize the whole molecule (e.g. avoids racemisation or epimerisation);8) Participation of the protecting group in any reaction should be either complete or absent.

9) It must be small compared to the mass of what you are trying to make..

Of course, few protecting groups meet all of these criteria, although it is not always necessary for them to do so, and generally a compromise must be found

Comprehensive Synthetic Organic Chemistry, 6, 631-701.Protective Groups in Organic Synthesis 2nd ed. Greene, T.W.; Wuts, P.G.MSynthetic Organic Chemistry Michael B. Smith, 629-672. A very smart discussion.Advanced Organic Chemistry part B: Reactions and Synthesis. Carey,J., capter 13, pp. 677-92

Strategies For Protection

1. None This could be achieved with selective reagents (so called Reagent Control ), but is limited by the availability of such reagents. The next best thing is the use of transient protection.

2. Substrate Control - use of steric bulk to block reactivity;- use of chelation control;- use of negative electron density to repel reagents e.g. via dianions.

3. Multiple protection - Orthogonal Protection (a set of PG whose removal can beaccomplished in any order with reagents and conditions which do not affect other PG);

- Graded Protection (deprotection relies upon differences in relative rates of reaction of various PG under the same reaction conditions);

- Uniform Protection ( use of PG which are all removed under the same conditions)- Convert protecting groups to other functionality4. Protecting groups which block more than one functional group.

Protecting groups in organic synthesis

Some things to consider before you use protecting g roups

1) Know why and when do you need to protect a functional group.2) Don’t just protect a group because you have to go through x number of steps.3) One must use protecting groups when the functionality (you wish to preserve) and the reaction conditions necessary to accomplish a desired transformation are incompatible (non-orthogonal).4) If you can avoid protection of a group in a synthesis, you should5) It is much better to plan ahead and avoid protection6) Protecting groups add extra steps to your synthesis more steps cost time and money. These aspects are often against the efficiency in terms of Tactical Efficiency (i.e. Atom Economy) and Strategic Efficiency (i.e. Minimum of Steps)

Remember the Efficiency: Tactical Efficiency:High Yield Atom Economy: the atom of PGs are not included in the final product.Strategic Efficiency:Minimum of Steps: each PG introduces at least two extra steps to the synthesisConvergence

Protecting groups in organic synthesis

Types of protecting groups (by method of cleavage)- acid labile-base labile- hydrogenolytically labile1) H2 and catalyst2) catalytic transfer hydrogenation (NH4

+ HCOO-) and catalyst;-other conditions –1) Reductive - Zn/HOAc;2) SN2-type cleavage PhSe-, Nu-; F-

3) Organometallic: Pd(0);4) Lewis acid: ZnCl2.5) Oxidative6) Photolytic

Protecting groups in organic synthesis

Protecting groups for a variety of functional group s

heteroatom functional groups, i.e. ROH, carboxylic acid and derivatives, RNH2 and RSH

- carbonyls

- unsaturated carbon-carbon bonds

- α-methylene groups of ketones

- phosphate

Hydroxyl Protecting Groups

Protecting groups in organic synthesis

EthersMethyl ethersR-OH → R-OMe difficult to remove except for on phenolsFormation: - CH2N2 , (J. Chem. Soc., Perkin Trans. 1 1996, 2619).silica or HBF4; NaH, MeI, THF (Org Synth., Collect. Vol. IV 1963, 836).Cleavage: - AlBr3 /EtSH, EtS- (J. Org. Chem. 1977, 42, 1228); PhSe- or Ph2P-

Me3SiI (J. Org. Chem. 1977, 42, 3761); 9-Bromo-9-borabicyclo[3.3.0]nonane, J.Organomet. Chem. 1978,156, 221

Benzyl Ethers (R-OBn)R-OH → R-OCH2Ph, stable to acid and baseFormation: - KH, THF, PhCH2Cl; PhCH2OC(=NH)CCl3, F3CSO3H J. Chem. Soc. P1 1985, 2247Cleavage: H2 / PtO2; Li / NH3

2-Napthylmethyl Ethers (NAP)

formation: 2-chloromethylnapthalene, KH, J. Org. Chem. 1998, 63, 4172cleavage: hydrogenolysisH2 / PtO2

p- Methoxybenzyl Ethers (PMB)Formation: - KH, THF, p-MeOPhCH2Cl p-MeOPhCH2OC(=NH)CCl3, F3CSO3H Tetrahedron Letters 1988, 29 , 4139Cleavage: H2 / PtO2; Li / NH3; DDQ; Ce(NH4)2(NO3)6 (CAN), electrochemically

Hydroxyl Protecting Groups

O-R

Allyl etherFormation CH2=CHCH2OC(=NH)CCl3, H+. For base-sensitive substrates.J. Chem. Soc., Perkin Trans. 1 1985, 2247 and Tetrahedron 1998, 54, 2967.

Pd(Ph3P)4, RSO2Na, CH2Cl2. J. Org. Chem. 1997, 62, 8932

Protecting groups in organic synthesis

o-Nitrobenzyl ethersReview: Synthesis 1980, 1; Organic Photochemistry, 1987, 9 , 225

Hydroxyl Protecting Groups

p-Nitrobenzyl Ether Tetrahedron Letters 1990, 31 , 389-selective removal with DDQ, hydrogenolysis or electrochemically

Cleavage: - photolysis at 320 nm

Protecting groups in organic synthesis

t-Butyldiphenylsilylethyl (TBDPSE) ether formation: The TBDPSE group is stable to 5% TFA/CH2Cl2, 20% piperidine–CH2Cl2, catalytic hydrogenation, n-BuLi, and lead tetraacetate. The TBDPSE group has been cleaved using TBAF (2.0 equiv, 40 °C, overnight) or 50% TFA/CH2Cl2.

J. Org. Chem. 2005, 70, 1467.

9-Phenylxanthyl- (pixyl, px) ,Tetrahedron Letters 1998, 39, 1653

Hydroxyl Protecting GroupsProtecting groups in organic synthesis

Trityl Ethers -CPh3 = TrR-OH → R-OCPh3 - selective for 1°alcoholsremoved with mild acid; base stableformation: - Ph3C-Cl, pyridine, DMAP or Ph3C+ BF4-

Cleavage: - mild acidMethoxytrityl Ethers, JACS 1962, 84 , 430; methoxy group(s) make it easier to remove

Tr-OR < MMTr-OR < DMTr-OR << TMTr-OR

Hydroxyl Protecting Groups

Protecting groups in organic synthesis

Methoxymethyl ether MOMR-OH → R-OCH2OMe stable to base and mild acidFormation: MeOCH2Cl, NaH, THF (on the corresponding Na-alcoholate); MeOCH2Cl, CH2Cl2, iPr2EtN. Sometimes a source of iodide ion is added to enhance the reactivity of the alkylatingreagent. Typical sources include Bu4N

+ I– LiI, or NaI.Cleavage - Me2BBr2 Tetrahedron Letters 1983, 24 , 3969, Bromocatechol borane.

Hydroxyl Protecting Groups Acetals

Protecting groups in organic synthesis

O

O

B Br

Application to Oligonucleotide Synthesis (phosphoramidite method - Lessinger)Tetrahedron 1992, 48 , 2223

Protecting groups in organic synthesis

Methoxyethoxymethyl ethers (MEM)R-OH → R-OCH2OCH2CH2OMe stable to base and mild acidFormation: MeOCH2CH2OCH2Cl, NaH, THF (on Na-alcoholate)- MeOCH2CH2OCH2Cl, CH2Cl2, iPr2EtN Tetrahedron Letters 1976, 809Cleavage : Lewis acids such as ZnBr2, TiCl4, Me2BBr2 . Can also be cleaved in the presence of THP ethers

Methyl Thiomethyl Ethers (MTM)R-OH → R-OCH2SMe Stable to base and mild acidFormation: MeSCH2Cl, NaH, THF( on Na-alcoholate)Cleavage: HgCl2, CH3CN/H2O

AgNO3, THF, H2O , base

Benzyloxymethyl Ethers (BOM)R-OH → R-OCH2OCH2Ph, Stable to acid and baseFormation: PhOCH2Cl, CH2Cl2, iPr2EtN Cleavage: H2/ PtO2 ; Na/ NH3, EtOH

Hydroxyl Protecting GroupsAcetals

Protecting groups in organic synthesis

Bromocatechol borane. This reagent cleaves a number of protective groups in approximately the following order: MOMOR ≈MEMOR > t-BuO2CNHR > BnO2CNHR ≈ t-BuOR > BnOR > allylOR > t-BuO2CR ≈ 2°alkylOR > BnO2CR > 1°alkylOR >> alkylO2CR. Tetrahedron Lett. 1985, 26, 1411.

Tetrahydropyranyl Ether (THP)

Formation: dihydropyran (DHP), pTSA, PhH (azeotropic water removing)Cleavage: AcOH, THF, H2O; Amberlyst H-15, MeOH

Stable to base, acid labileDHP

Hydroxyl Protecting GroupsAcetals

Ethoxyethyl ethers (EE)J. Am. Chem. Soc 1979, 101 , 7104; JACS 1974, 96 , 4745.

base stable, acid labile

Protecting groups in organic synthesis

Silyl EthersR-OH → R-O-SiR3 Synthesis 1985, 817; 1993, 11; 1996, 1031formation: - R3Si-Cl, pyridine, DMAP; J. Am. Chem. Soc. 1972, 94, 6190R3Si-Cl, CH2Cl2 (DMF, CH3CN), imidazole, DMAPR3Si-OTf, iPr2EtN, CH2Cl2 Tetrahedron Lett. 1981, 22, 3455Trimethylsilyl ethers Me3Si-OR TMS-OR- very acid and water labile-useful for transiant protection

Triethylsilyl ethers Et3Si-OR TES-OR-considerably more stable that TMS

can be selectively removed in the presence of more robust silyl ethers with with F-or mild acid

Hydroxyl Protecting Groups

Protecting groups in organic synthesis

Silyl EthersTriisopropylsilyl ethers iPr3Si-OR TIPS-OR- more stabile to hydrolysis than TMSPhenyldimethylsilyl ethers, J. Org. Chem. 1987, 52 , 165t-Butyldimethylsilyl Ether tBuMe2Si-OR TBS-OR TBDMS-OR; JACS 1972, 94 , 6190- Stable to base and mild acid- under controlled condition is selective for 1°alco holst-butyldimethylsilyl triflate tBuMe2Si-OTf; TL 1981, 22 , 3455- very reactive silylating reagent, will silylate 2°al coholscleavage: acid; F- (HF, nBu4NF, CsF, KF)

t-Butyldiphenylsilyl Ether tBuPh2Si-OR TBDPS-OR - stable to acid and base- selective for 1°alcohols- Me3Si- and iPr3Si groups can be selectively removed in the presence of TBS or TBDPS groups.- TBS can be selectively removed in the presence of TBDPS by acid hydrolysis. TL 1989, 30 , 19Cleavage: F-, Fluoride sources: - nBu4NF (TBAF basic reagent), HF / H2O /CH3CN TL 1979, 3981. HF•pyridine Synthesis 1986, 453; other fluoride sources: Triethylamine trihydrofluoride, Et3N•3HF; Tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF); H4N+F–

JOC 1981, 46 ,1506TL 1989, 30 , 19. JACS 1984, 106 , 3748

Protecting groups in organic synthesis

• In general, the stability of silyl ethers towards acidic media increases as indicated:TMS (1) < TES (64) < TBS (20,000) < TIPS (700,000) < TBDPS (5,000,000)

• In general, stability towards basic media increases in the following order:TMS (1) < TES (10-100) < TBS ~ TBDPS (20,000) < TIPS (100,000)

J.Chem. Soc., Perkin Trans . 1 1992, 3043. J. Org. Chem. 1988, 53, 2602

Silyl Ethers: stability

Protecting groups in organic synthesis

Monosilylation of symmetrical diols is possible, and useful

J. Org. Chem. 1986, 51, 3388.

Tetrahedron Lett. 2000, 41, 4281

J. Org. Chem. 1983, 49, 4674

Selective deprotection of silyl ethers is also important, and is also subject to empirical determination

J. Am. Chem. Soc., 1994, 116, 1599.

J. Am. Chem. Soc. 1995, 117, 8106

Silyl EthersProtecting groups in organic synthesis

Protecting groups in organic synthesis

Esters and Carbonates:

Protecting groups in organic synthesis

Ester formation with activated carboxylic functions

carbonyldimidazole

Carbonate formation

Mukaiyama's Reagent, Chem. Lett. 1975, 1045; 1159; 1976, 49; 1977, 575

Corey Reagent

Protecting groups in organic synthesis

Activated esters. These activated esters can be used as acyl transfer agents to alcohols or amines (Nu)

The DMTC group is stable to a variety of reagents and reaction conditions (PCC oxidations, Swern oxidations, chromium reagents, Grignard and alkyllithium reagents, phosphorous ylides, LAH, HF, TBAF, and borane). The protecting group is introduced using imid2CS followed by treatment with dimethylamine, or by reaction with commercially available ClCSN(CH3)2.

In general, the susceptibility of esters to base catalyzed hydrolysis increases with the acidity of the product acid.

Esters are stable to acid and mild base, not compatible with strong base or strong nucleophiles such as organometallic reagents

Protecting groups in organic synthesis

TrifluoroacetatesFormation: trifluoroacetic anhydride or trifluoroacetyl chlorideCleavage: - K2CO3, MeOHPivaloate (t-butyl ester), Fairly selective for primary alcoholsFormation: - tbutylacetyl chloride or t-butylacetic anhydrideCleavage: - removed with mild baseBenzoate (Bz) more stable to hydrolysis than acetates.Formation: benzoyl chloride, benzoic anhydride, benzoyl cyanide (TL 1971, 185) , benzoyltetrazole (TL 1997, 38, 8811)Cleavage: mild base; - KCN, MeOH, reflux

Protecting groups in organic synthesis

Ester function cleavage

Acetate Esters:Several methods cleaving acetate esters have been developed. K2CO3, MeOH, reflux; KCN, EtOH, reflux; NH3, MeOH; LiOH, THF, H2O and enzymatic hydrolysis. Lipases can often be used for the enantioselective hydrolysis of acetate esters (the same enzimes are emploied for forming acetates). The enantioselective hydrolysis of mesodiesters is an important synthetic transformation and racemic esters have been kinetically resolved using lipases.

Tetrahedron Lett. 1986, 27, 1255.

Meso compounds

Chloroacetate: can be selectively cleaved with Zn dust, thiourea or primary amines

H2N SH

NH

J. Am. Chem. Soc. 1998, 120, 5319J. Chem. Soc. CC 1987, 1026

Carbonate function cleavage

Protecting groups in organic synthesis

Methyl Carbonate

9-Fuorenylmethyl Carbonate:

Trichloroethyl Carbonate:

Allyl Carbonate

2-(Trimethylsilyl)ethyl Carbonate:

Benzyl Carbonate:

Dimethylthiocarbamate (DMTC) Carbamate

Tetrahedron Lett. 1978, 19, 1375

J. Chem. Soc., Chem. Comm. 1982, 672

Tetrahedron Lett. 1988, 29, 2227.

Synlett 1993, 680.

Tetrahedron Lett. 1981, 22, 969.

J. Am. Chem. Soc. 1939, 61, 3328

Org. Lett. 2003, 5, 4755

Protection of 1,2- and 1,3- Diols

Protecting groups in organic synthesis

acetals

Silylethers, cleaved with fluoride (HF, CH3CN -or- Bu4NF -or- HF•pyridine), will notfuctionalize a 3°-alcohol

Synthesis 1981, 501 Chem. Rev. 1974, 74, 581

TL 1981, 22 , 4999TL 1988, 29 , 1561

formation (t-Bu)2SiCl2, Et3N, CH3CN, HOBT

FormationiPr2Si(Cl)-O-Si(Cl)iPr2pyridine

General methods used to form acetals and ketals.

Cycloalkylidene Ketals- Cyclopentylidene are slightly easier to cleave than acetonides- Cyclohexylidenes are slightly harder to cleave than acetonides

Acetonides: in competition between 1,2- and 1,3-diols, 1,2-acetonide formation is usually favored- cleaved with mild aqueous acid

Synthesis 1981, 501 Chem. Rev. 1974, 74, 581

Protecting groups in organic synthesis

The relative rates of hydrolysis of 1,2-O-alkylidene-a-glucofuranoses have been studied.

Carbohydr. Res. 1977, 58, 337

J. Am. Chem. Soc. 1984, 108, 2949

Selective Protection: thermodynamic control Selective Protection: kinetic control

Carbohydr. Res. 1974, 35, 87Methods Carbohydr. Chem. 1963, 2, 318

In the case of a 1,2,3-triol, careful analysis must be performed to accurately predict the site of acetonide formation. The more substituted acetonide will be favored in cases where the substituents on the resultant five-membered ring will be trans. If the substituents on the five-membered ring would be oriented cis, then the alternative, less substituted acetonide may be favored.

J. Org. Chem. 1989, 54, 915.

J. Chem. Soc., Perkin Trans. 1 1997, 913

Examples of selectivity in acetal and ketal formation.

Protecting groups in organic synthesis

Benzylidene Acetals in competition between 1,2- and 1,3-diols, 1,3-benzylidene formation for is usually favored- benzylidenes can be removed by acid hydrolysis or hydrogenolysis- benzylidene are usually hydrogenolyzed more slowly than benzyl ethers or olefins

General methods used to form Benzylidenes.

Protecting groups in organic synthesis

Selectivity in benzylidenes formation

Helv. Chim. Acta. 1995, 78, 1837.

Examples of selectivity in benzylidenes formation.

In general, cis-fused 5,6-systems are formed faster than trans-fused 5,6-systems

Acta. Chem. Scand. 1972, 26, 518.

Carbohydr. Res. 1972, 21, 473

No

Note the preference for 1,3-diol protection with the benzylidene acetal. The phenyl group isoriented exclusively as shown, in an equatorial orientation.

Protecting groups in organic synthesis

cis trans

Protecting groups in organic synthesis

Special diol protection groups

Formation of dispiroacetals as a protective group for vicinal trans diequatorial diols

A cheaper alternative has also been developed:

Tetrahedron Lett. 1992, 4767

J. Org. Chem. 1996, 61, 3897

J. Chem. Soc., Perkins Trans. 1 1997, 2023.

Protecting groups in organic synthesis

Generalities concerning the selective removal of ac etals and ketals:Hydrolysis of the less substituted dioxane or dioxolane ring occurs preferentially in substrates bearing two such groups.

Tetrahedron Lett. 1996, 37, 8643

Methods Carbohydr. Chem. 1963, 2, 318.

Carbohydr. Res. 1978, 45, 181

Generalities concerning the selective removal of be nzylidenes:In general, substitution of the ring of a benzylidene acetal with a p-methoxy substituent increases the rate of hydrolysis by about an order of magnitude

Benzylidene acetals can also be cleaved from the diol reductive

J. Am. Chem. Soc. 1962, 84, 430.

Protecting groups in organic synthesis

Can be oxidatively removed with Ce(NH4)2(NO3)6 (CAN)

Protecting groups in organic synthesis

Methods have also been developed to cleave only one carbon-oxygen bond resulting in the formation of a benzyl ether. This reaction has been extensively studied in the context of carbohydrate chemistry

Selective removal of benzylidenes

Tetrahedron Lett. 1995, 5, 669.

Tetrahedron Lett., 1998, 39, 355

Pure. Appl. Chem. 1984, 56, 845.J. Org. Chem. 1993, 58, 3480

Protecting groups in organic synthesis

Other examples of selective removal of benzylidenes

Protecting groups in organic synthesis

Selective removal of benzylidenes

Oxidation of benzylidene and substituted benzylidene acetals:

mechanism

J. Org. Chem. 1969, 34, 1035, 1045, and 1053.

Org. Syn. 1987, 65, 243

Protecting groups in organic synthesis

Selective removal of benzylidenes

Oxidation of benzylidene and substituted benzylidene acetals: Ozonolysis also cleaves acetals to hydroxy esters efficiently. This reaction has been reviewed: Can. J. Chem. 1974, 52, 3651.

J. Org. Chem. 1984, 49, 992

J. Org. Chem. 1996, 61, 2394

2- electron oxidation of 4-methoxybenzyl groups with DDQ is a general reaction.

J. Org. Chem. 1989, 54, 17.

Tetrahedron Lett. 1983, 24, 4037

Protecting groups in organic synthesis

A useful extension of this reaction has been developed to protect diols directly

Protecting groups in organic synthesisCarbonyl protective groups

General order of reactivity of carbonyl groups towa rds nucleophiles:aldehydes (aliphatic > aromatic) > acylic ketones ≈ cyclohexanones > cyclopentanones > α,β-unsaturated ketones ≈ α,α disubstituted ketones >> aromatic ketones.

Preparation of dimethyl acetals and ketals:

1. MeOH, dry HCl. J. Chem. Soc. 1953, 3864.2. MeOH, LaCl3, (MeO)3CH. Acetals are formed efficiently, but ketalization is unpredictable. J. Org. Chem. 1979, 44, 4187.3. Me3SiOCH3, Me3SiOTf, CH2Cl2, –78 °C. Tetrahedron Lett. 1993, 34, 995.4. Sc(OTf)3, (MeO)3CH, toluene, 0 °C. Synlett 1996, 839Other dialkyl acetals are formed similarly.

Cleavage of dimethyl acetals and ketals:TFA, CHCl3, H2O. These conditions cleaved a dimethyl acetal in the presence of a1,3-dithiane and a dioxolane acetal. Tetrahedron Lett. 1975, 499.2. TsOH, acetone. J. Chem. Soc., Chem. Commun. 1971, 858. Trans-ketalization3. 70% H2O2, Cl3CCO2H, CH2Cl2, t-BuOH; dimethyl sulfide. Tetrahedron Lett. 1988, 29, 5609.

Cyclic acetals and ketals:Protecting groups in organic synthesis

Relative rates of ketalization with common diols:

In general, saturated ketones can be selectively protected in the presence of α,β-unsaturated ketones. Generally, methods used for formation of 1,3-dioxolanes are also useful for formation of 1,3-dioxanes

In protecting α,ß-unsaturated ketones, olefin isomerization is common.

Recl. Trav. Chim. Pays-Bas. 1973, 92, 1047.

J. Org. Chem. 1986, 51, 773

Tetrahedron Lett. 1980, 21, 1357.

Cleavage of 1,3-dioxanes and 1,3-dioxolanes (Chem. Rev. 1967, 67 , 427)

1. PPTS, acetone, H2O, heat. J. Chem. Soc., Chem. Commun. 1987, 1351.2. 1M HCl, THF. J. Am. Chem. Soc. 1977, 43, 4178.3. Me2BBr, CH2Cl2, –78 °C. This reagent also cleaves MEM and MOM ethe rs.Tetrahedron Lett. 1983, 24, 3969.4. NaI, CeCl3•7H2O, CH3CN. J. Org. Chem. 1997, 62, 4183. This method is selective for cleavage of ketals in the presence of acetals. It is also selective for ketals of α,ß-unsaturated ketones over ketals of saturated ketones.

Protecting groups in organic synthesis

Basic cleavage

Using fluoride

Using organic bases

Dithioacetals

General methods of formation of S,S''-dialkyl acetals

1. RSH, HCl, 20 °C. Chem. Ber. 1950, 83, 275.2. RSSi(CH3)3, ZnI2, Et2O. J. Am. Chem. Soc. 1977, 99, 5009.3. RSH, BF3•Et2O, CH2Cl2. Marshall, J. A.; Belletire, J. L. Tetrahedron Lett. 1971, 871. Seealso J. Org. Chem. 1978, 43, 4172. α,β-Unsaturated ketones are reported not to isomerizeunder these conditions. However, with any of the above mentioned conditions conjugate addition is a concern.

General methods of cleavage of S,S''-dialkyl acetals .A variety of methods has been developed for the cleavage of S,S''-dialkyl acetals, largelydueto the fact that these functional groups are often difficult to remove.

1. Hg(ClO4)2, MeOH, CHCl3. Tetrahedron Lett. 1989, 30,15.2. CuCl2, CuO, acetone, reflux. Org. Synth. Collect. Vol. 1988, 6, 109.3. m-CPBA; Et3N Ac2O, H2O.. J. Am. Chem. Soc. 1973,95, 6490.4. (CF3CO2)2IPh, H2O, CH3CN. Tetrahedron Lett. 1989, 30, 287.

Protecting groups in organic synthesis

Dithioacetals as useful synthons

In addition to serving as a protective group, S, S'-dialkyl acetals serve as an umpolung synthon (acyl anion equivalent) in the construction the of carbon-carbon bonds.

Org. Lett. 2000, 2, 3127.

Protecting groups in organic synthesis

Carboxylic Acid Protective Groups: Alkyl Esters

Formation: - Fisher esterification (RCOOH +R'OH + H+), or Acid Chloride + R-OH, pyridine t-butyl esters: Isobutylene, H2SO4, Et2O, 25 °C, Org. Synth., Collect. Vol. IV. 1963, 261. t-BuOH, EDC•HCl, DMAP, CH2Cl2, J. Org. Chem. 1982, 47, 1962. i-PrN=C(O-tBu)NH-i-Pr, toluene, 60 °C, Tetrahedron Lett. 1993, 34, 975.

Cleavage: CF3CO2H, CH2Cl2. J. Am. Chem. Soc. 1977, 99, 2353; Bromocatechol borane. Tetrahedron Lett.1985, 26, 1411.methyl esters: MeOH, H2SO4, J. Am. Chem. Soc. 1978, 100, 6536. diazomethane; TMSCHN2, MeOH, benzene, Chem. Pharm. Bull. 1981, 29, 1475. This is considered a safe alternative to using diazomethane;

Protecting groups in organic synthesis

LiOH, MeOH, 5 °C. Tetrahedron Lett. 1977, 3529. Bu2SnO, PhH, reflux (Tetrahedron Lett. 1991, 32, 4239); Pig liver esterase. This enzyme is often effective for the enantioselective cleavage of a meso diester

Tetrahedron Lett. 1984, 25, 2557.Tetrahedron Lett. 1989, 30, 2513

Protecting groups in organic synthesisAllyl esters, Formation: Allyl bromide, Cs2CO3, DMF. Int. J. Pept. Protein Res. 1985, 26, 493. Allyl alcohol, TsOH, benzene, (–H2O). Liebigs Ann. Chem., 1983, 1712

Cleavage: The use of allyl esters in synthesis has been reviewed: Tetrahedron, 1998, 54, 2967; Pd(Ph3P)4, RSO2Na, CH2Cl2. J. Org. Chem. 1997, 62, 8932.

The 1,1-dimethylallyl ester is removed under the same conditions as an allyl ester, but is less susceptible to nucleophilic attack at the acyl carbon. Org. Lett. 2005, 7, 1473.

Benzyl ester: benzyl esters are typically prepared by the methods outlined in the general methodssection

Phenyl esters: Phenyl esters typically prepared by the methods outlined in the general methods section.They have have the advantage of being cleaved under mild, basic conditions

cleavage:1. H2, Pd–C. Org. React. 1953, 7, 263.2. BCl3, CH2Cl2. Synthesis. 1991, 294.3. Na, NH3

Cleavage: H2O2, H2O, DMF, pH = 10.5. J. Am. Chem. Soc. 1972, 94, 3259.

Synthesis, 1980, 547.

Other carboxylic acid activation systems for mild esterification

Protecting groups in organic synthesis

2-(Trimethylsilyl)ethyl Esters J. Am. Chem. Soc. 1984, 106 , 3030 - cleaved with Fluoride ion; 2-Trimethylsilyl)ethoxymethyl Ester (SEM), Helv. Chim. Acta 1977, 60 , 2711. Cleaved with Bu4NF in DMF; MgBr2•OEt2 Tetrahedron Lett. 1991, 32, 3099

Diphenylmethyl Esters, Cleavage: - mild H3O+; H2, Pd/C; BF3•OEt2

o-Nitrobenzyl Esters: selective removed by photolysis

SEM ester

Special Carboxylates, α-Hydroxy and ß-Hydroxy:

Formation:1. Ketone or aldehyde, Sc(NTf2)3, CH2Cl2, MgSO4. Synlett 1996, 839. Pivaldehyde, acid catalyst. Helv. Chim. Acta. 1986,70, 448,

Ortho Esters: The synthesis of simple ortho esters has been reviewed: Synthesis, 1974, 153; Chem. Soc. Rev. 1987, 75. Stable to base; cleaved with mild acid

Alternatively, ortho esters can be prepared from a nitrile:

Helv. Chim. Acta. 1983, 66, 2294.

Tetrahedron Lett. 1983, 24, 5571

Special protecting groups

Protecting groups in organic synthesis

Protection of amines:Protecting groups in organic synthesis

Trifluoroacetamide

TritylamineBenzylamine Allylamine

Amides

Carbamates

Methyl Carbamate Benzyl carbamate (Cbz) Allyl Carbamate (Alloc)2,2,2-Trichloroethyl

Carbamate (Troc)

9-Fluorenylmethyl Carbamate (Fmoc)2-(Trimethylsilyl)ethyl Carbamate (Teoc)

t-Butyl Carbamate (Boc)

Acc. Chem. Res. 1987, 20 , 401

Removable alkyl groups

formamides acetamides

Formation of benzylamines:

If primary amines are the starting materials, dibenzylamines are the products

Formation of allylamines:If primary amines are the starting materials, diallylaminesare the products.

Formation of tritylamines:

Monobenzylated derivatives

J. Org. Chem. 1993, 58, 6109.

Synthesis 1989, 198.

Protecting groups in organic synthesis

Removal : Pd–C, ROH, HCO2NH4. Tetrahedron Lett. 1987, 28, 515; Na, NH3. Synth. Comm. 1990, 20, 1209.

Removal: Pd(Ph3P)4, RSO2Na, CH2Cl2. Most allyl groups are cleaved by this method, including allylethers and esters. J. Org. Chem. 1997, 62, 8932.

Cleavage: 0.2% TFA, 1% H2O, CH2Cl2. Tetrahedron Lett. 1996, 37, 4195.

General preparation of carbamates:

Bases that are typically employed are tertiary amines or aqueous hydroxide.

Tetrahedron Lett. 1986, 27 , 3753

Protecting groups in organic synthesis

Tetrahedron Lett. 1985, 26 , 1411

Cleavage of carbamates

Methyl Carbamate:

TMSI, CH2Cl2. J. Am. Chem. Soc. 1987, 109, 442; MeLi, THF. J. Am. Chem. Soc. 1992, 114 , 5959

9-Fluorenylmethyl Carbamate:

Amine base. The half-lives for the deprotection of Fmoc-ValOH have been studied Atherton, E.; Sheppard R. C. in The Peptides, Udenfriend, S. and Meienhefer Eds., Academic Press: New York, 1987, Vol. 9, p. 1.

Acc. Chem. Res. 1987, 20 , 401

Protecting groups in organic synthesis

Other removal methods: Bu4N+F–, DMF. Tetrahedron Lett. 1987, 28, 6617; Bu4N+F–, n-C8H17SH. Thiols can be used to scavenge liberated fulvene. Chem. Lett. 1993, 721.

2,2,2-Trichloroethyl Carbamate:

Zn, H2O, THF, pH = 4.2. Synthesis, 1976, 457; Cd, AcOH. Tetrahedron Lett. 1982, 23, 249; electrochemically.

2-Trimethylsilylethyl Carbamate:

Bu4N+F–, KF•H2O, CH3CN, 50 °C. J. Chem. Soc., Chem. Commun. 1979, 514; CF3COOH, 0 °C. J.Chem. Soc., Chem. Commun. 1978, 358; Tris(dimethylamino)sulfonium difluorotrimethylsilicate(TASF), DMF. J. Am. Chem. Soc. 1997, 49, 2325.

Tetrahedron Lett. 1986, 27 , 4687

JACS 1979, 101, 7104

Protecting groups in organic synthesisCleavage of carbamates

t-Butyl carbamate

CF3COOH, PhSH. Thiophenol is used to scavenge t-butyl cations. TBS and TBDMS ethers are reported to be stable under these conditions. J . Org. Chem. 1996, 61, 2413; Bromocatecholborane. Tetrahedron Lett. 1985, 26, 1411and Tetrahedron Lett 1985, 26 , 1411; TMS-I

Allyl Carbamate

1. Pd(Ph3P)4, Bu3SnH, AcOH, 70 – 100% yield. J. Org. Chem. 1987, 52, 4984; Pd(Ph3P)4, (CH3)2NTMS, 89 – 100% yield. Tetrahedron Lett. 1992, 33, 477.

Tetrahedron Lett 1986, 27 , 3753

Protecting groups in organic synthesisCleavage of carbamates

Protecting groups in organic synthesis

Cleavage of carbamates

FormamidesCleavage of Amides

removed with strong acid

Acetamides

removed with strong acid

Trifuoroacetamides

base (K2CO3, MeOH, reflux, J. Org. Chem. 1988, 53, 3108);NH3, MeOH

Benzyl Carbamate:H2/Pd–C. Chem. Ber. 1932, 65, 1192; H2/Pd–C, NH3. These conditions cleave the benzyl carbamate in the presence of a benzylether. Tetrahedron Lett. 1995, 36, 3465; BBr3, CH2Cl2. J. Org. Chem. 1974, 39, 1427; Bromocatecholborane. This reagent is reported to cleave benzyl carbamates in the presence of benzyl ethers and TBS ethers. Tetrahedron Lett. 1985, 26, 1411; hν (254 nm); Na/ NH3

or Ac2O/HCOOH

removed by photolysis

J. Org. Chem. 1974, 39 , 192

Protecting groups in organic synthesis

Sulfonamidesp-Toluenesulfonyl (Ts)

Cleavage: - Strong acid; sodium Naphthalide; Na(Hg)

Trifluoromethanesulfonyl (introduced using (CF3SO2)2O)

J. Org. Chem. 1989, 54 , 2992

J. Org. Chem. 1992, 33, 5505

Protecting groups in organic synthesis

Trimethylsilylethanesulfonamide (SES)

Tetrahedron Lett. 1986, 54 , 2990; J. Org. Chem. 1988, 53, 4143; removed with CsF, DMF, 95°C

tert-Butylsulfonyl (Bus) J. Org. Chem. 1997, 62, 8604

Other amine protecting groups

Alkyne protecting groups

Typical silyl groups include TMS, TES, TBS, TIPS, and TBDMS. Many silylacetylenes are commercially available, and are useful acetylene equivalents.

General preparation of silyl acetylenes:Silyl chorides are suitable for smaller silyl groups, but the preparation of more hindered silylacetylenes may require the use of the more reactive silyl triflate.

Protecting groups in organic synthesis

In general, a strong fluoride source such as TBAF is used to cleave silylalkynes. In the caseof trimethylsilylalkynes, milder conditions can be used. Cleavage of trimethysilylalkynes:KF, MeOH, 50 °C. J. Am. Chem. Soc. 1991, 113, 694; AgNO3, 2,6-lutidine. J. Am. Chem Soc. 1995, 117,

8106; K2CO3, MeOH. Helv. Chim. Acta. 1995, 78, 732.

Angew. Chem., Int. Ed. Engl. 2000, 15, 2732.

Alternatively to trialkylsilyl groups, propargylic alcohol can be considered as alkyne protecting group. These are formed by reacting acetilides with ketones (acetone or benzophenones) and removed by treatment with NaOH in MeOH

R R1 R1

O

R1 = Me or Ph

+R1 R1

HO

R

R HNa OH

MeOH

Synthesis plan guide line1. Write the synthetic sequence , including reagents.2. Check for mutually incompatible FGs.3. Check compatibility between FGs and reagents .4. Take into account problems of regioselectivity and chemoselectivity .5. Use protecting groups to resolve these problems.6. Make sure you make the right TM: check for length of carbon chain, size of rings, position of substituents, nature and position of FGs, removal of protecting groups.

computer-assisted synthetic analysis

The computer-assisted synthetic analysis designated OCSS (organic chemical simulation of synthesis) and LHASA (logic and heuristics applied to synthetic analysis) were designed to assist chemists in synthetic analysis by Corey et al. LHASA generates trees of synthetic intermediates from a target molecule by analysis in the retrosyntheticdirection. Other programs: WODCA, EROS (Gasteiger), SYNGEN (Hendrickson) AIPHOS (Sasaki). www.infochem.de, www.spresi.de, [email protected]

Corey, E. J., Wipke, W. T., Cramer, R. D., III and Howe,W. J., J. Am. Chem. Soc., 1972, 94, 421. Corey, E. J., Howe,W. J. and Pensak, D. A., J. Am. Chem. Soc., 1974, 96, 7724

Strategies and Tactics in Organic Synthesis

Basic Concepts of Retrosynthetic Analysis

There are some useful general strategies which do not depend on molecular complexity:

Transform-based strategies rely on the application of powerfully simplifying transforms.Structure-based strategies rely on the recognition of possible starting materialsor key intermediates for a synthesis.Functional group-based strategies identify functional groups as key structural subunits.Topological-based strategies depend on the identification of one or more individual bond disconnections or correlated bond-pair disconnections as strategic.Stereochemical-based strategies remove stereocenters and stereorelationshipsunder control.

Corey, E. J. The Logic of Chemical Synthesis

Strategies and Tactics in Organic Synthesis

Transform -based strategies

Transform-based strategies consist on the identification of a powerful simplifying transform leading to a TGT with certain keying features.

The required retron may be not present in a complex TGT and a number of antithetic (retrosynthetic) steps may be needed to establish it. Such a strategy relies on synthetic and mechanistic knowledge, which can inspire the recognition of a hidden retron (partial retron )

Strategies and Tactics in Organic Synthesis

Transform-based Strategies

Strategies and Tactics in Organic Synthesis

A case: six-membered cyclic motif

Is it possible to envisage any simple transform in these cyclic structures?The answer could be ... Yes.

Transform-based Strategies

In the case of tetrahydropyran a straightforwarddisconnection, based on SN2 or SN1 processes, can be easily envisaged

Angew.Chem. Int. Ed. 2003, 1258

For a similar retrosynthetic analysis based on a SN2 process, see J. Org. Chem. 1997, 5672 and Synlett 2003, 1817

Strategies and Tactics in Organic Synthesis

Transform-based Strategies

It becomes more difficult to identify a similar transform in the cyclohexane case and often FGA transforms are required, in the sense that one or more functional gruop is added to individuate the retron

retron for Diels-Aldercycloaddition or Robinson annulation

1 x FGA

retron for Diels-Alder cycloaddition, Metathesis and Cationic ring formation

retron for Diels-Aldercycloaddition or Birchreduction of a benzene ring with Li

Strategies and Tactics in Organic Synthesis

In all these case a Diels-Alder reaction can be envisage

Transform-based Strategies

The venerable Diels-Alder reaction: a [4π + 2π] cycloaddition

Remember that an alkyne can also partecipate in Diels- Alder process

Strategies and Tactics in Organic Synthesis

Kurt Alder

Otto Diels

Otto Diels and Kurt Alder Justus Liebigs Annalen der Chemie 460, 98 (1928)

Transform-based Strategies

It can be rationalized through Frontier Orbital analysis which permits to predict the regio-, site-and the relative stereochemistry

Strategies and Tactics in Organic Synthesis

Transform-based Strategies

Regioselectivity: orto-para rule

The coefficients of AO of the monosubstituted diene and of the mono-substituted dienophile are not equal at each end

Strategies and Tactics in Organic Synthesis

Site-selectivity

Strategies and Tactics in Organic Synthesis

Transform-based Strategies

For a siteselectivity analysis in unsymmetrical quinones, see JACS 2004, 4800

Relative stereochemistry: endo rule

Transform-based Strategies

Strategies and Tactics in Organic Synthesis

Lewis acid catalysed DA reactions are faster and more stereo and regioselective. All these features can be explained by the effect the Lewis acid has on the LUMO of the dienophile. The Lewis acid coordination with the dienophile lowers the energy of the LUMO, which increases the rate, modifiesthe LUMO coefficient, increasing the regioselectivity and makes the secondaryinteraction greater that in the uncatalysed case which accounts for the greaterendo selectivity

Fleming, I. Frontier Orbitals and Organic Chemical Reactions

Transform-based Strategies

Strategies and Tactics in Organic Synthesis

A classic example: the synthesis of reserpine by Woodward

Transform-based Strategies

Strategies and Tactics in Organic Synthesis

Carpanone

JACS 1971, 6696

Other examples

Strategies and Tactics in Organic Synthesis

The power of tactic combinations: estrone by Vollhardt

Transform-based Strategies

J. Am. Chem. Soc. 1980, 5253

Strategies and Tactics in Organic Synthesis

An asymmetric Diels Alder reaction: colombiasin A synthesis by Nicolaou

Angew. Chem. Int. Eng. 2001, 2482

Strategies and Tactics in Organic Synthesis

Strategies and Tactics in Organic Synthesis

Olefinic Metathesis: an alternative to Diels-Alder cyclohexene retronMetathesis = Meta (change) & thesis (position)

AB + CD AC + BD

Olefin metathesis has come to the fore in recent years owing to the wide range of transformations that are possible with commercially available and easily handled catalysts. Consequently, olefin metathesis is now widely considered as one of the m ost powerful synthetic toolsin organic chemistry.... With the evolution of new catalysts, the selectivity, efficiency, and functional-group compatibility of this reaction have improved to a level that was unimaginable just a few years ago. These advances together with a better understanding of the mechanism have brought us to a stage where more and more researchers are employing cross-metat hesis reactions in multistep procedures and in the synthes is of natural products. Olefin metathesis can be formally described as the intermolecular mutual exchange of alkylidene fragments between two olefins promoted by metal-carbene complexes

Katz 1976 Tebbe 1978 Schrock 1990 Grubbs 1995 Grubbs 1999

Blechert, S. Angew. Chem. Int. Ed. 2003, 1900 Schrock, R. R.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2004, 4592.K. C. Nicolaou, Angew. Chem. Int. Ed. 2005, 44, 4490 – 4527

Strategies and Tactics in Organic Synthesis

Olefinic Metathesis: The perfect reaction:The process is catalytic (1–5 mol%)High yields under mild conditionsHigh levels of chemo-, regio-,and stereoselectivityThe reaction is reversibleThe starting materials are easily preparedThe olefinic products are suitable for further structural elaboration

Three main variations on the metathesis theme

a) Cross–Metathesis

b) Ring-Closing & Ring-Opening Metathesis (RCM & ROM)

c) Enyne metathesis

Strategies and Tactics in Organic Synthesis

Diels-Alder and Ring-Closing-Metathesis (RCM): two transforms for cyclohexene retron

(Catalytic) processInter or intramolecular process

ReversibleUp to four new stereocenters

Carbon- and hetero-Diels-Alder are possible

Catalytic processIntramolecular process

ReversibleNo new stereocenters

Carbon- and hetero-RCM are possible

Olefinic Metathesis

Strategies and Tactics in Organic Synthesis

The power of RCM: laulimalide by Ghosh and Mulzer

Olefinic Metathesis

Laulimalide

Ghosh, A. K. J. Org. Chem. 2001, 8973Mulzer, J. Adv. Synth. Catal. 2002, 573

Strategies and Tactics in Organic Synthesis

Pioneering catalytic transforms: Sch38516 by Hoveyda

Zirconium-Catalyzed Asymmetric Carbomagnesation

Hoveyda, A. J. Am. Chem. Soc. 1993, 6997

Sch38516

J. Am. Chem. Soc. 1997, 10302

Double bonds

Olefinic Metathesis

Strategies and Tactics in Organic Synthesis

The hidden retron: halosaline by Blechert

Olefinic Metathesis

Combined ROM & RCM metathesis

Expected metathesis disconnection(–)-Halosaline

Tetrahedron 1999, 817

>78%

Strategies and Tactics in Organic Synthesis

Domino cyclization mediated by metathesis: Grubbs

Olefinic Metathesis

Grubbs, R. H. J. Org. Chem. 1998, 4291

Strategies and Tactics in Organic Synthesis

A domino reaction is a process involving two or more bond-forming transformations (usually C–C bonds) which take place under the same reaction conditions without adding additional reagents and catalysts, and in which the subsequent reactions result as a consequence of the functionality formed in the previous step. Tietze, L. Chem. Rev. 1996, 115

Domino reactions

With ever-increasing pressure to fashion diverse molecular architectures rapidlythrough efficient and atom-economical processes with high degrees of selectivity,cascade reactions are destined to become an integra l design aspiration of most synthetic endeavors. In order to push the state-of the art of these sequences ...will require increasingly precise mechanistic and kinetic understanding of organic transformations combined with a large dose of intellectual flexibility and creativity.Nicolaou, K. C. Classics in Total Synthesis II

Strategies and Tactics in Organic Synthesis

Domino reaction: Isolated rings

The Baldwin rules often constitute a good starting poin t to analyze thesynthetic possibilities .

Rule 1. Tetra) 3,4,5,6,7-Exo allowedb) 5 i 6-Endo forbidden

Rule 2. Triga) 3,4,5,6,7- Exo allowedb) 3,4,5-Endo forbiddenc) 6,7-Endo allowed

Rule 2. Diga) 3-4- Exo forbiddenb) 5,6,7-Exo allowedc) 3,4,5,6,7-Endo allowed

Strategies and Tactics in Organic Synthesis

Cation π-cyclization.The retron for the cation π-cyclization transform can be defined as a carbocationwith charge β to a ring bond which is to be cleaved.

Radical π-cyclizationIn a similar way, the retron for the radical π-cyclization transform can be definedas a radical with electron β to a ring bond which is to be cleaved, but ...

Strategies and Tactics in Organic Synthesis

K2CO372%

Stereochemical course of the process relies on stereoelectronic issues, according to the Stork-Eschenmoserhypothesis. Three rings and six contiguous stereocenters are created simultaneously

Progesterone, JACS 1971, 4332

Domino reaction: a classic of cation π-cyclization: progesterone by Johnson

Strategies and Tactics in Organic Synthesis

Domino reaction: a nice solution to a daunting problem: aspidophytine by Corey

AspidophytineJ. Am. Chem. Soc. 1999, 6771

Strategies and Tactics in Organic Synthesis

Apparently similar radical π-cyclization

Strategies and Tactics in Organic Synthesis

HirsuteneJACS 1985, 1448

∆9(12)-CapnelleneTL 1985, 4991

Just two classics of radical π-cyclization: hirsutene and ∆9(12)-capnellene by Curran

Strategies and Tactics in Organic Synthesis

Functional group-based Strategies

The concept of functional group provides a valuable framework for understanding reactivity and an useful tool to go deeply into retrosyntheticanalysis

Functional groups

Strategies and Tactics in Organic Synthesis

Functional group-based Strategies

Corey classifies the functional groups, FG, in three families:1st Level: the most important FG

2nd Level: less important FG

3rd Level: peripheral, which are associated with us eful reagents providing activation or control in chemical processes, or combination of more fundamental group

They can also be associated into super-set or super-families depending on their electronic behaviour EWG: CO, CN, SOR, NO2 or EDG: OR, NR

Strategies and Tactics in Organic Synthesis

Functional group-based Strategies

Furthermore, many retrons contain only a single FG, while others consist of a pair of FG's separated by a specific carbon chain path or connection

Functional group-based strategiesThe use of functional group to guide retrosynthetic reduction of molecular complexity. Single FG'sor pairs of FG's, and the interconnecting atom path,can key directly the disconnection of a TGT skeleton to form simpler molecules or signal the application of transforms which replace functional by hydrogen.FGI is a commonly used tactic for generating from a TGT retrons which allow the application of simplifying transforms. FG's may key transforms which stereoselectively remove stereocenters, break strategic bonds or join proximate atoms to form rings.As mentioned early, taking into account that most common synthetic reactions are polar, a bond forming process (and the corresponding transform) can be viewed as a combination of donor, d, and acceptor, a, synthons. Then,obvious rules can apply to arrangement of functionality in the product. For a molecule containing n FG's there are n(n–1)/2 possible pairs …

Consonant relationschip

Strategies and Tactics in Organic SynthesisFunctional group-based Strategies

Functional group-based StrategiesRemember!

Strategies and Tactics in Organic Synthesis

1,2-Difunctional systems: a1 + d1 combination

Moss, N. Synthesis 1997, 32

Strategies and Tactics in Organic Synthesis

1,3-Difunctional systems: a1 + d2 combination

d2 synthons: enol, enolate and synthetic equivalents

a1synthons: aldehydes, ketones and esters

Strategies and Tactics in Organic Synthesis

A benchmark: helminthosporal by Corey

Helminthosporal

JACS 1965, 5728

Strategies and Tactics in Organic Synthesis

Attention:this 1,5-difunctional relationship can evolve throu gh two different pathways

Experimental condition and final result

Strategies and Tactics in Organic Synthesis

Helminthosporal: synthetic protocol

Strategies and Tactics in Organic Synthesis

A polifunctional target: 18-epi-tricyclic core of garsubellin A by Shibasaki

Org. Lett. 2002, 859

Applying the n(n–1)/2

Strategies and Tactics in Organic Synthesis

Retrosynthesis garsubellin A core

Strategies and Tactics in Organic Synthesis

Garsubellin A core: synthetic protocol

More accessible site forderotonation withpotassiumhexamethyldisilylamide(KHDMS) a bulky base

KHDMSNSiMe3Me3Si

K

Strategy leads the way, but tactics accounts for the success: regiocontrol of enolate formation

Kinetic trap of the resulting enolate avoidsregioselective problems

OK OTBS

more stagle but not formes by steric inderance

Strategies and Tactics in Organic Synthesis

Garsubellin A core: synthetic protocol

Strategies and Tactics in Organic Synthesis

Retrosynthetic strategy is based on the following disconnections

Garsubellin A core: synthetic protocol

Strategies and Tactics in Organic Synthesis

Garsubellin A core: final steps

Strategies and Tactics in Organic Synthesis

TRANSITION METAL-MEDIATED PROCESSES: Cross-Coupling reactions

Tsuji Palladium Reagents & Catalysts Wiley 2004 and van Leeuwen Homogenous CatalysisKluwer 2004, K. C. Nicolaou, Angew. Chem. Int. Ed. 2005, 44, 4442 – 4489

Strategies and Tactics in Organic Synthesis

TRANSITION METAL-MEDIATED PROCESSES

Tsuji: Palladium Reagents & Catalysts, ed. Wiley 2004; van Leeuwen: HomogenousCatalysis, ed. Kluwer 2004

LG

Pd0

Pd

Nu

LG:leaving group

Strategies and Tactics in Organic Synthesis

Boronic or other organometallic reagent

Oxidative additionReductive elimination

Palladium mediated cross coupling reaction mechamism

Strategies and Tactics in Organic Synthesis

What should be the analysis in the case of dissonant relationships? Remember of considering the opportunity of:

Seebach, D. Angew. Chem. Int. Ed. Eng 1979, 239Johnson, J. S. Angew. Chem. Int. Ed. 2004, 1326.

Strategies and Tactics in Organic Synthesis

Remember, in a retrosynthetic sense, if a disconnection is identified as strategic but is notpermitted by the particular core functional group present, the replacement of that group by an equivalent which allows or actuates becomes a subgoal objective.Obviously, such an operation requires a synthetic step that permits to invert (umpolung ) the type of synthon, from acceptor to donor or from donor to acceptor

Strategies and Tactics in Organic Synthesis

Carbonyl Umpolung: acylanion

Strategies and Tactics in Organic Synthesis

Enolate Umpolung: α−carbonyl cation

Strategies and Tactics in Organic Synthesis

Michael acceptor Umpolung: β−carbonyl anion

Strategies and Tactics in Organic Synthesis

The Spongistatins: architecturally Complex Natural Products through umpolungconcept

ACIE 2001, 191,195; OL 2002, 783

Strategies and Tactics in Organic Synthesis

Fragment A–B

1,3-Consonant relationships: Aldol reaction could be the answer? It could be, but it wasenvisioned another disconnection

Strategies and Tactics in Organic Synthesis

Fragment C–DFragment C–D

Strategies and Tactics in Organic Synthesis

Fragment A–B

HMPA: hexamethylphosphorotriamide, strong lithium coordinating agent. It is used todisaggregate lithium organometallic reagents improving nucleophilicity and basicity.

P O

Me2N

Me2N

Me2N HMPA

Strategies and Tactics in Organic Synthesis

Organometallic compounds have at least one carbon to metal bond, according to mostdefinitions. This bond can be either a direct carbon to metal bond ( σ bond or sigma bond) or a metal complex bond ( π bond or pi bond). Compounds containing metal to hydrogenbonds as well as some compounds containing nonmetallic ( metalloid ) elements bondedto carbon are sometimes included in this class of compounds. Some common properties of organometallic compounds are relatively low melting points, insolubility in water, solubility in ether and related solvents, toxicity, oxidizability, and high reactivity. An example of an organometallic compound of importance years ago is tetraethyllead (Et 4 4Pb) which is an antiknock agent for gasoline. It is presently banned from use in the UnitedStates. The first metal complex identified as an organometallic compound was a salt, K(C 2 H 4 )PtCl

3 , obtained from reaction of ethylene with platinum (II) chloride by William Zeise in 1825. Itwas not until much later (1951–1952) that the correct structure of Zeise's compound

was reported in connection with the structure of a metallocenecompound known as ferrocene

Organometallic Compounds Strategies and Tactics in Organic Synthesis

Nomenclature:Organometallic compounds are normally named as substituted metals, e.g. alkyl metal or alkyl metal halide. Organomagnesium compounds are generally referred to as Grignard reagents. Examples: CH3Li = methyl lithium, CH3MgBr = methyl magnesium bromide. Physical Properties: Organometallic are usually kept in solution in organic solvents due to their very high reactivity (especially with H2O, O2 etc.) Structure: Organosodium and organopotassium compounds are essentially ionic compounds. Organolithiums and organomagnesiums have a s bond between a C atom and the metal: C-M These are very polar, covalent bonds due to the electropositive character of the metals. Look at the electronegativities of the metals Li, Na, K and Mg compared to C and the other atoms we have seen so far (e.g. N, O, F, Cl etc). See how C is more electronegative than the metal.

H2.1

He

Li 1.0 Be1.5 B2.0 C2.5 N3.0 O3.5 F4.0 Ne

Na0.9 Mg1.2

Al1.5

Si1.8 P2.1 S2.5 Cl3.0 Ar

K0.8 Ca1.0 Sc Ti V Cr Mn Fe Co Ni Cu Zn Ga Ge As Se Br2.8 Kr

Partial Periodic Table with Pauling Electronegativit ies

methyl chloride methyl lithium methyl magnesium bromide

The images show the electrostatic potentials for methyl chloride, methyl lithium and methyl magnesium bromide.The more red an area is, the higher the electron density and the more blue an area is, the lower the electron density

Organometallic CompoundsStrategies and Tactics in Organic Synthesis

In the alkyl halide, the methyl group has lower electron density (blue ), and is an electrophile .In methyl lithium, the methyl group has higher electron density (red ) and is a nucleophile . In methyl magnesium bromide, the methyl group is less electron rich that methyl lithium. Therefore, organometallic compounds react as electron rich or anionic carbon atoms i.e. as carbanions, which means they will function as either bases or nucleophiles . It is reasonable to think of these organometallic compounds as R- M+

Basicity:The following equation represents the loss of a proton from a generic hydrocarbon forming a carbanion:

Organolithium and organomagnesium compounds are strong bases since the negative charge is on carbon. Simple carbanions are strong bases, (see pKa's below) since the C is not very electronegative (compared to N or O). In the presence of weak acids, RLi and RMgXprotonate giving the hydrocarbon.

Implications : RLi or RMgX CANNOT be used in the presence of acidic hydrogens such as -OH, -NH or -SH units.

Organometallic Compounds

Strategies and Tactics in Organic Synthesis

Compound Structure pKa

2-methylpropane

71

ethane 62

methane 60

ethene 45

Benzene 43

ammonia 36

ethyne 25

Ethanol

water

16

15.7

The table shows the pKa's of a selection of representative systems. Note that the hydrocarbons are very weak acids, implying that the carbanions will be strong bases.

Organometallic Compounds

Strategies and Tactics in Organic Synthesis

Preparation of Organolithium Reagents

Reaction type: oxidation - reduction

SummaryOrganolithiums are formed by the reaction of alkyl halides with lithium metal.Typical solvents are normally anhydrous diethyl ether but pentane or hexane can also be used. The alkyl group can be primary, secondary or tertiary. Halide reactivity : I > Br > Cl R can be alkyl, vinyl or aryl Other Group I metals (Na, K) can be used instead of Li.

Organometallic Compounds

Strategies and Tactics in Organic Synthesis

Preparation of Organomagnesium Reagents

Reaction type: oxidation – reduction

SummaryOrganomagesiums are formed by the reaction of alkyl halides with magnesium metal. Typical solvents are normally anhydrous diethyl ether or tetrahydrofuran. The alkyl group can be primary, secondary or tertiary. Halide reactivity : I > Br > Cl R can be alkyl, vinyl or aryl.

Organometallic Compounds Strategies and Tactics in Organic Synthesis

Preparation of Organocopper Reagents

SummaryThe most useful organocopper reagents are lithium dialkylcuprates, R2CuLi . Lithium dialkylcuprates are formed by the reaction of 2 equivalents of an organolithiumwith a copper (I) halide. Typical solvents are normally anhydrous diethyl ether or tetrahydrofuran. The alkyl group is usually primary. Secondary and tertiary are prone to decomposition. R can be alkyl, vinyl or aryl.

Organometallic Compounds

Strategies and Tactics in Organic Synthesis

Preparation of Organozinc Reagents

Reaction type: oxidation – reduction

SummaryOrganozinc reagents, RZnX, are prepared in a fashion analogous to that of organomagnesium reagents RMgX. They are much less reactive than either RLi or RMgX to aldehydes and ketones. The most common application of organozinc reagents is in the Simmons Smith reaction

Organometallic Compounds

Strategies and Tactics in Organic Synthesis

Preparation of Acetylenic Reagents

Reaction type: acid-baseSummaryterminal acetylenes can be deprotonated using sodium amide, NaNH2

Acetylenic Grignard reagents, RC=CMgX, can also be prepared. Rather than starting from the acetylenic halides, they are prepared by an acid-base reaction of the terminal acetylene with a second Grignard reagent. Acetylenic Grignards react in a similar fashion to other Grignard reagents.

Organometallic Compounds Strategies and Tactics in Organic Synthesis

Reactivity of OrganometallicsAs previously said, the carbon attached to the metal is anionic in character, so it reacts as a carbanion, a nucleophilic carbon . In principle there are 3 important groups of reactions where nucleophiles attack electrophilic C atoms. For the organometallic reagents these types of reactions will result in the formation of new C-C bonds.

1. Nucleophilic Substitution: R2CuLi with alkyl halides or tosylates to give alkanes

2. Nucleophilic Addition: RLi or RMgX with aldehydes or ketones to give 2o or 3o alcohols

3. Nucleophilic Acyl Substitution: RLi or RMgX with esters to give 3o alcohols

Limitations: Organolithium, RLi , and organomagnesium, RMgX, reagents are typically too basic to be used in nucleophilic substitution reactions (1) with alkyl halides or tosylates where they tend to cause elimination reactions or other side reactions. Organocuprates, R2CuLi , reagents are less reactive and do not react with aldehydes, ketones or esters but can be reacted with alkyl halides or tosylatesto give alkanes without elimination. Nucleophilic acyl substitution (3) reactions of organolithium, RLi , and organomagnesium, RMgX, reagents are most commonly used with esters.

Organometallic Compounds Strategies and Tactics in Organic Synthesis

Overview of Grignard Reactions: Here is a preview of Grignard reactions. In each case the alkyl group, R', from the original Grignard reagent is indicated in blue and the electrophilic portion in black .

Organometallic Compounds

Strategies and Tactics in Organic Synthesis

Reactions of RLi and RMgX with Aldehydes and Ketones. Reactions performed usually in Et2O or THF followed by H3O+ work-ups

Reactions of RC=CM with Aldehydes and Ketones. Reaction usually in Et2O followed by H3O+ work-up

Reactions of RLi and RMgX with Esters. Reaction usually in Et2O followed by H3O+

work-up. First step Nucleophilic Acyl Substitution then Nucleophilic Addition

Organometallic Compounds

Strategies and Tactics in Organic Synthesis

Alkane synthesis using R2CuLi

Organolithium cuprates, R2CuLi , react with alkyl halides forming a new C-C, giving alkanes. Primary alkyl iodides make the best substrates otherwise elimination can be a problem. The R group of the cuprate can also be aryl or vinyl. The R' group in the halide can also be aryl or vinyl. Although the mechanism looks like a SN2, it is more complex and is currently not well understood.

Conjugate Addition with Organocopper reagents

Other organometallics reagents such as alkyl lithiums tend to undergo direct or 1,2-addition, while Grignard reagents may give mixtures of 1,2- and 1,4-addition depending on the system.

Organometallic Compounds

Strategies and Tactics in Organic Synthesis

Synthesis of Cyclopropanes using RZnX (The Simmons-Smith reaction)

The iodomethyl zinc iodide is usually prepared using Zn activated with Cu. The iodomethyl zinc iodide reacts with an alkene to give a cyclopropane. The reaction is stereospecific with respect to to the alkene (mechanism is concerted). Substituents that are trans in the alkene are trans in the cyclopropane

Organometallic Compounds Strategies and Tactics in Organic Synthesis

Oxymercuration-Demercuration of Alkenes

Overall transformation C=C to H-C-C-OHThis is an alternative method for hydrating alkenes to give alcohols Typical reagents are mercury acetate, Hg(OAc)2 in aqueous THF Unfortunately, mercury compounds are generally quite toxic Regioselectivity predicted by Markovnikov’s rule (most highly substituted alcohol) The reaction is not stereoselectiveReaction proceeds via the formation of a cyclic mercurinium ion (compare with bromination of alkenes)

Organometallic Compounds

Hg

OAc

Nu

+

Nu

HgOAc

NaBH4Nu

H

Strategies and Tactics in Organic Synthesis

Structure-goal strategies

Structure-goal strategies are based on the identification of a potential starting material, building block, retron–containing element or initiating chiral element.In other words, the retrosynthetic analysis is guided by the use of a particular structure corresponding to a potentially available starting material or synthetic intermediate.In many synthetic problems the presence of a certain type of subunit in the target molecule coupled with information on the commercial availability of compounds containing that unit can suggest potential starting materials

Strategies and Tactics in Organic Synthesis

Chiron approach: synthesis of enantiomerically pure compounds. The chiron approach to synthesis involves disconnection of strategic bonds in a target molecule with minimum pertubation of existing stereogenic centers. This generates chirons with a maximum overlap of functional groups, of stereochemical features, and of carbon framework with the target molecule (or a given substructure). Such molecules normally contain one to five or six stereogenic centers and can originate from Nature (terpenes, carbohydrates, α-amino acids, α-hydroxy acids,...), from asymmetric reactions on achiral substrates, from resolution of racemates, and from enzymatic and related sources. By relating a TGT to chiral starting materials as the outset, the scenario for a synthesis plan is established In the chironapproach,it is the type of chiral substructure prese nt in the molecules that will dictate the strategy. The main issue now deal with proceeding in the forward direction using the inherent or newly-created chirality and building from there.Hanessian, S. Total Synthesis of Natural Products: The Chiron ApproachPure & Appl. Chem. 1993, 1189

Sugars

carbon framework asymmetric centres sense of chirality

Acyclic 1–5 (or 6 includes 2n permutations, generall y DCyclic anomeric center)combination3–7 carbon atoms

sequential functionalityα-hydroxy aldehyde, ...α-amino aldehyde, ...polyols, amino alcohols, …

Strategies and Tactics in Organic Synthesis

Sugars as starting chiral materials: some example of retrosynthesis approach

Elaboration of glucose in the synthesis of thromboxane B2

Can. J. Chem. 1977, 562; Can. J. Chem. 1981, 870

Strategies and Tactics in Organic Synthesis

Strategies and Tactics in Organic Synthesis

Tetrahedron Lett. 1984, 1853

D-Mannose

Strategies and Tactics in Organic Synthesis

(+)-Meroquinone by Hanessian

(+)-Meriquenone ,Tetrahedron 1990, 231

It is evident that all the hydroxyl groups in D-glucose must be destroyed en route to the construction of the carbon skeleton of (+)-meroquinone, which can be regarded as a stereochemically wasteful procedure. However, the D-glucose framework is efficiently used to install the two vicinal C-substituents by a sequential stereocontrolled one-step conjugate addition and enolate trapping protocol on a readily available enonePure & Appl. Chem. 1993, 1189

D-Glucose

Strategies and Tactics in Organic Synthesis

Other chiral starting materials: Amino acids, hydroxy acids, terpenes

Strategies and Tactics in Organic Synthesis

Some examples of retrosynthesis individuating aminoacids, terpenes and hydroxyacids

Strategies and Tactics in Organic Synthesis

JACS 1966, 852

A brilliant performance: cephalosporin C by Woodward

Strategies and Tactics in Organic Synthesis

Strategies and Tactics in Organic Synthesis

Topological-based strategies

The existence of alternative bond paths through a molecular skeleton as a consequence of the presence of cyclic subunits gives rise to a topological complexity which is proportional to the degree of internal connectivity. Then, topological strategies are based on the use of a particular bond, pair of bonds, set of bonds, or subunit as eligible for disconnection to guide retrosyntheticanalysis. Conversely, the designation of bonds or cyclic subunits as ineligible for disconnection. The disconnection of a strategic bond simplifies the topological complexit y of a TGT

Guidelines– It is not worth disconnecting aromatic or heteroaromatic systems.– Cycloalkyl subunits bound to the carbon skeleton should not be disconnected– Several options should be considered.

Strategies and Tactics in Organic Synthesis

MetathesisCannon & Blechert.ACIE 2003, 1900

Pauson-KhandGibson&StevenazziACIE 2003, 1800

Strategies and Tactics in Organic Synthesis

Fused and Bridged systemsPrimary rings are those that can not be constructed by the sum of two or more smaller ringsSecondary rings are those that are not primary ringsSynthetically significant rings are 3-7 membered primary or secondary rings

Strategies and Tactics in Organic Synthesis

Strategies and Tactics in Organic Synthesis

Strategies and Tactics in Organic Synthesis

Strategies and Tactics in Organic Synthesis

Strategies and Tactics in Organic Synthesis

Woodward, R. B. Art and Science in the Synthesis of Organic Compounds: Retrospect and Prospect. In Pointers and Pathways in Research, CIBA of India ,1963Corey, E. J. Pure&Appl.Chem. 1967, 14, 19.Corey, E. J.; Wipke, W. T. Science 1969, 166, 178.Corey, E. J. Q. Rev. Chem. Soc. 1971, 25, 455.Seebach, D. Angew. Chem. Int. Ed. Engl. 1990, 29, 1320.Corey, E. J. Angew. Chem. Int. Ed. Engl. 1991, 30, 455.Hanessian, S.; Franco, J.; Larouche, B. Pure&Appl.Chem. 1990, 62, 1887.Tietze, L. F.; Beifuss, U. Angew. Chem. Int. Ed. Engl. 1993, 32, 131.Hanessian, S. Pure&Appl.Chem. 1993, 65, 1189.Trost, B. Angew. Chem. Int. Ed. Engl. 1995, 34, 259.Ihlenfeldt, W-D.; Gasteiger, J. Angew. Chem. Int. Ed. Engl. 1995, 34, 2613.Diverses autors. Frontiers in Organic Synthesis. Chem. Rev. 1996, 96, Vol. 1.Nicolaou, K. C.; Sorensen, E. J.; Winssinger, N. J. Chem. Ed. 1998, 75, 1226.Mukaiyama, T. Tetrahedron 1999, 55, 8609.Nicolaou, K. C.; Vourloumis, D.; Winssinger, N.; Baran, P. S. Angew. Chem. Int. Ed. 2000, 39, 44.Sierra, M. A.; de la Torre, M. C. Angew. Chem. Int. Ed. 2000, 39, 1538.Arya, P.; Chou, D. T. H.; Baek, M.-G- Angew. Chem. Int. Ed. 2001, 40 , 339.Schreiber, S. L. Science 2000, 287, 1964.Nicolaou, K. C.; Baran, P. S. Angew. Chem. Int. Ed. 2002, 41, 2678.Benfey, O. T.; Morris, P. J. T. Robert Burns Woodward. Architect and Artist in the World of Molecules. Chemical Heritage Foundation. Philadelphia, 2003.Burke, M. D.; Schreiber, S. L. Angew. Chem. Int. Ed. 2004, 43 , 46.de la Torre, M. C.; Sierra, M. A. Angew. Chem. Int. Ed. 2004, 43 , 160.

Further readings

Strategies and Tactics in Organic Synthesis

Strategies and Tactics in Organic Synthesis

Stereochemical-based Strategies

Why should we consider stereochemistry?For practical and aesthetic reasons, it is now common practice to plan synthesis in such a way so as to produce an enantiomerically pure (or enriched) TGT.This has become a virtual necessity in pharmaceuthical research laboratories since stereochemistry is the common denominator between chemistry and biology.

Hanessian, S. Pure & Appl. Chem. 1993, 1189.

About 80% of the active compounds that pharmaceutical companies have in the pipeline are chiral, and it is estimated that this fraction will increase, as the development of active compounds continues to be improved ...The authorities responsible for the registration of new active compounds increasingly demandthe targeted synthesis of one stereoisomer...Enantiomerically pure compounds are also being used increasingly in the agrochemicals industry.The targeted synthesis of the active enantiomer can improve the economics of the process and lead to reduced quantities applied and thus to reduced environmental impact.

Hauer, B. Angew. Chem. Int. Ed. 2004, 788There are basically three main strategies to adopt when the synthesis of an enantiomerically pure molecule is considered:1) resolution of a racemic final compound or an intermediate2) use of an enantiomerically pure starting material, which can be obtained by resolution, anasymmetric process or by relying on the "chiral pool"3) through an asymmetric synthesis

Strategies and Tactics in Organic SynthesisThe chirality is a dimensional property in the sense that it is referred to the order of dimension. Object can be chiral in one, two and three dimensional system. A system chiral in a dimension is achiral or prochiral in a higher order dimension.

Nature yields an enormous variety of chiralcompoundsEach enantiomer often have very different effects , properties and usesWe must control stereochemistry

Roughly 1/3 of pharmaceuticals are chiral; 90% of the top 10 selling drugs the active ingredient is chiralA. M. Rouhi, Chem. Eng. News. 2004, June 14, 47 and Sept. 6, 41

The importance of chirality

A B B

AA

AA A

B B

A AB B

C CD DChiral object in monodimensional system. Achiral

in bi or tridimensional systems

Chiral object in bidimensional system. Achiral

or prochiral in tridimensional systems

Chiral object in tridimensional system. Achiral or

prochiral in higher dimensional systems

mirrormirror

mirror

Strategies and Tactics in Organic Synthesis

Strategies and Tactics in Organic Synthesis

Atrovastin or atorvastin

SimvastatinOlanzapine

Amlodipine

LansoprazoleClopidogrel

FlutucasoneSertaline

stereocentre

Strategies and Tactics in Organic Synthesis

Terminology Stereoisomers - Isomers that differ only by the arrangement of substituents in spaceStereogenic element - the origin of stereoisomerism,

be it a stereogenic centre, axis or plane, within the molecule such that the change of two substituentsabout this element leads to different stereoisomersChiral compound - simply a molecule (or object) that cannot be superimposed upon its mirror image. The chirality is a property of the whole object and not of a part of it. Most obvious example is our hands...

Molecule with a single stereocentre or stereounit, it is tolerated the old definition of chiral centre. In a tetrahedral (Xabcd) or trigonal pyramidal (Xabc) structure, the atom X to which the four (or three, respectively) substituents abc(d) are attached. Lone pairs a re considered as sustituents with the lowest prioritystereocentre

The direct goal of stereochemical strategies is the reduction of stereochemical complexityby the retrosynthetic elimination of stereogenic elements in a TGT. Stereocomplexity depen ds on the number of stereogenic elements present in a m olecule and their spatial and topological locations relative to one another. Stereogenic element is the origin of stereoisomerism (stereogenic center, axis, or plane) in a molecule s uch that interchange of two ligands (i.e. 1 and 2) attached to an atom in such a molecule leads to a different stereisomer.

Strategies and Tactics in Organic Synthesis

Stereogenic units other than carbon: Nitrogen, Sulfur and Phosphorous

Defining absolute configuration: Define priorities according to CIPPoint lowest priority (4) away from viewerDraw line from 1 to 3If the way from 1 to 3 is anti-clockwise,the descriptor is (S)

(S)-(4-methoxyphenyl)methylphenyl-phosphineoxide

Nitrogen / amines have the potential to be chiral, but due to the rapid pyramidal inversion normally prevents isolation of either enantiomer. If substituents are constrained in a ring then rigid structure prevents inversion as in the case of Troger’s base.

Strategies and Tactics in Organic Synthesis

Trigonal pyramidal phosphorus(III) is configurationally stable below 200°CTetrahedral phosphorus (V) is configurationally stable

Sulfoxides thiosulfinic esters and sulfinamided have a tetrahedral sulfur atom which possesses a lone pair as substituent!Are configurationally stable at room temperature but, certain anions (chloride ), can cause racemisation (interconversion of the enantiomers)

Strategies and Tactics in Organic Synthesis

Chiral molecules with only first order symmetry elements (simple rotation axis)

C2 axis

C2 axis

Spiro-compounds

atropoisomerism

(S)-2-(diphenylphosphino)-1-(2-(diphenylphosphino)n aphthalen-1-yl)naphthalene

Chiral axis in CIP definitions

Molecules with C2 symmetry, i.e. with only C2 symmetry axis

Strategies and Tactics in Organic Synthesis

Other chiral systems

Helical system: twisted molecules (like a cork-scr ew)Right-handed helix is denoted P (clockwise as you travel away from viewer) and M for Left-handed

Chiral organometallics compounds: chirality resulting from the arrangement of out-of-plane groups with respect to a plane

Planar chirality in CIP definitions

Helical chirality in CIP definitions

Strategies and Tactics in Organic Synthesis

Enantiomers and optical rotation

Each enantiomer has identical physical & chemical properties (in an achira l environment)Only differ by how they rotate plane polarised light (rotate in opposite directions)Enantiomers are said to be optically active

Enantiomeric excess: Optical purity - an outdated measurement of the enan tiomeric excess (amount of two enantiomers) in a solution / mixture. If a solution contains only one enantiomer, the maximum rotation is observed. The observed rotation is proportional to the amount of each enantiomer present

Strategies and Tactics in Organic Synthesis

Enantiomeric excess

Racemate (racemic mixture) - 1 to 1 mixture of enantio mers (50% of each) Racemisation -converting 1 enantiomer to a 1:1 mixture of enantiom ers Polarimeter measures difference in the amount of each enantiomer. New methods more reliable & purity measured in terms of enantiomeric excess (e.e.)

A molecule with 1 stereogenic centre exists as 2 stereoisomers or enantiomersEnantiomers have identical physical properties in an achiral environment) A molecule with 2 or more stereogenic units can exist as 4 or 2 n stereoisomersEnantiomers (mirror images) still have identical physical propertiesDiastereoisomers (non-mirror images) have different properties

Molecules with more than one stereogenic unit

Strategies and Tactics in Organic Synthesis

chiralsolubility 0.1g/100ml EtOH

mesosolubility 3.3g/100ml EtOH

Enantiomers differ only by their absolute stereochemistry (R or S etc) and Diastereoisomers differ by their relative stereochemistry. Relative stereochemistry - defines configuration with respect to any other stereogeneic element within the molecule but does NOT differentiate enantiomersA molecule can only have one enantiomer but any number of diastereoisomers. The different physical properties of diastereoisomers allow us to purify them

Meso CompoundsThe rule 2n gives the maximum number of stereoisomers but in special case as in the case of mesocompounds the number of possible stereoisomers is lower A meso compound is - an achiral member of a set of diastereoisomers that also includes at least one chiral member. Simplistically - a molecule that contains at least one stereogenic unit but has a second order symmetry element (plane of symmetry) and is thus achiral• Meso compounds have a plane of symmetry which split up the molecule in two subunit (each ones are stereocentres) which are one the mirror image of the other with (R) configuration on one side and (S) on the other

SR

Tartaric acid

C2 axismirror

chiralno plane of symmetry non-superimposable on mirror image but due tothe presence of a C2 symmetry axis it isasymmetric molecule

achiralplane of symmetrysuperimposable onmirror image(meso)

Strategies and Tactics in Organic Synthesis

Strategies and Tactics in Organic Synthesis

Difference in diastereomers allows chiral derivatising agents to resolve enantiomers

Remember a good chiral derivatising agent should:Be enantiomerically pure (or it is pointless or useless)Coupling reaction of both enantiomers must reach 100% (if you are measuring ee)Coupling conditions should not epimerize stereogenic centresEnantiomers must contain point of attachmentAbove list probably influenced depending whether you are measuring %ee or preparativelyseparating enantiomers

Strategies and Tactics in Organic Synthesis

Popular derivatising agent for alcohols and amines is α-methoxy-α-trifluoromethylphenylacetic acid (MTPA) or Mosher’s acidTypical difference in chemical shifts in 1H NMR 0.15 ppm and 19F NMR gives one signal for each diastereoisomerNo α-hydrogen so configurationally stableDiastereoisomers can frequently be separatedIn many cases use of both enantiomers of MTPA can be used to determine the absolute configuration of a stereocentre (JACS, 1973, 512, JOC 1973, 2143 and JACS 1991, 4092)

Chiral derivatising agent: Mosher’s acid

Difference in NMR signals between diastereoisomers : 1H NMR ∆δ = 0.08 (Me), 19F NMR ∆δ = 0.17 (CF3)

Strategies and Tactics in Organic Synthesis

No need to covalently attach chiral derivatising group Benefit - normally easier to recover and reuse reagentUse of non-covalent interactions allows other methods of resolving enantiomers

Diastereoisomeric ionic salt formation

Strategies and Tactics in Organic Synthesis

Resolution of enantiomers: chiral column chromatogaphy

Resolution - the separation of enantiomers from either a racemic mixture orenantiomerically enriched mixtureChiral chromatography - Normally HPLC or GCA racemic solution is passed over a chiral stationary phaseCompound has rapid and reversible diastereotopic interaction with stationary phaseHopefully, each complex has a different stability allowing separation

Strategies and Tactics in Organic Synthesis

Measurements of ee by HPLC or GC are quick and accurate (±0.05%)Chiral stationary phase may only work for limited types of compoundsColumns are expensive (>€1500)Need both enantiomers to set-up an accurate method

Resolution of enantiomers: chiral column chromatogaphy

Strategies and Tactics in Organic Synthesis

Chiral paramagnetic lanthanide complexes can bind reversibly to certain chiralmolecules via the metal centre. Compound must contain Lewis basic lone pair (OH, NH2, C=O, CO2H etc). Coordination process faster than NMR timescale and normally observe a downfield shift (higher ppm)Two diastereomeric complexes are formed on coordination; these may have different NMR signalProblems - as complexes are paramagnetic, line broadening is observed (especially on high field machines). Accuracy is only ±2%

NMR spectroscopy: chiral shift reagents

NMR spectroscopy: chiral shift reagents

New reagents are being developed all that time that can overcome some y of these problems1H NMR spectra (400 MHz) of valine (0.06 M, [D]/[L] = 1/2.85) in D2O at pH 9.4 and in the presence of samarium complex

Signal show no paramagnitic broadening. Extimated ratio D/L: 1/ 3.02 vs 1/2.85 experimental

Strategies and Tactics in Organic Synthesis

Strategies and Tactics in Organic Synthesis

From a synthetic point of view, the introduction of new stereogenic centers into a TGT is normally achieved by means of two fundamentally distinct processes: most commonly through addition to one or other stereoheterotopic (enantio- or diastereotopic) faces of a double bond, but also by selective modification or replacement of stereoheterotopic ligands.

Desymmetrisation : process that transforms a symmetric or prochiral object into a non symmetric one or in a chiral one

Chiral in a bidimentionalsystem or prochiral in a tridimentional one

Chiral in a bidimentionalsystem or prochiral in a tridimentional one

Chiral in tridimentional system

Symmetric object containing II order symmetry element (planecontaining 1,2 and carbon

Symmetric object containing II order symmetry element (planecontaining 1, 2, 3 and carbon

carbon

carbon

Strategies and Tactics in Organic SynthesisSubstrate: stereocontrol due to a stereochemical bias in the substrate

The stereochemical outcome of a wide range of reactions is not contolled by mechanistic issues. Otherwise, it depends on the structure of the substrate or rea gent. The generation of a new stereocenter can be controlled by the steric bias of preexisting stereocenters. This kind of stereocontrol is frequent in cyclic structures , conformationally no flexibles. In acyclic systems , the situation is much more complicated Given that the new stereocenters are usually created by addition to a sp2 carbon, high stereocontrol can be achieved if the molecule adopts a definite reactive conformation in which one of the two diastereofaces is efficiently shielded by steric effects of the substituents:1) Passively by steric shielding of one or two diastereotopic faces on the reactive center.2) Actively by binding the reagent in form of non-covalent interactions anddirecting it towards one of the diastereotopic facesSteric and stereoelectronic effects play a crucial role to devise powerful retrosynthetic analysis.

Conformational issues must be considered

Acyclic systems

Cyclic systems

Strategies and Tactics in Organic Synthesis

weak lone pair repulsionMore stable

strong lone pair repulsionLess stable

Stereoelectronic effect: is any effect determining the properties or reactivity of a species that depends on the orientation of filled or unfilled electron orbitals in space. Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry

medium lone pair repulsion

O

O

OO

O

O

What conformation is the most stable? And the most r eactive?

Lewis acid – Lewis base considerations, coordination (chelation ), hydrogen-bonding, must be also considered

Strategies and Tactics in Organic Synthesis

Mechanism: intrinsically stereocontrolled transforms

There are reactions which show stereoselectivity primarily because of mechanism:SN2 processes, hydroboration, epoxidation, OsO4 oxidation of alkenes ect..Those disconnections involving C–C bonds are specially important

The stereochemistry of bis-epoxide controls the final stereochemical outcome

Mulzer, J. ACIEE 1990, 1476

Ireland, R. E. JOC 1991, 4031

Strategies and Tactics in Organic SynthesisStereoselectivity in Organic Synthesis

Stereospecific reactions - a reaction where the mechanism and the stereochemistry of the starting material determine the stereochemistry of the product; there is no choice! e.g. SN2 reactions. Diastereospecificreaction permits only one diastereoisomer to be formed control relative stereochemistry not absolute stereochemistry for example Iodolactonisation Proceeds via an iodonium species followed by intramolecular ring-opening Geometry of alkene controls relative stereochemistry If there is a pre-existing stereogenic centre then reaction can be stereoselective. In such reactions two diastereoisomers could be formed but one is favoured

Stereoselective reactions - a reaction where one stereoisomer of a product is formed preferentially over another. The mechanism does not prevent the formation of two or more stereoisomers but one predominates.Diastereoselective reactions - a stereogenic centre is introduced into a molecule in such a way that diastereoisomers are produced in unequal amounts

Enantioselective reactions - a reaction that produces two enantiomers of a product in unequal amounts

I2

Strategies and Tactics in Organic Synthesis

Stereoselective reactions Nucleophilic addition to C=O and Prochiral Nomenclature

Trigonal carbons that are not stereogenic units but can be transformed into them are called prochiral, t o each carbonyl face is assigned the label Si or Re based on the CIP rules.If the carbonyl function is in a chiral molecule is called prostereogenic unit and the faces are said to be diastereotopicIn the case of achiral molecules the carbonyl faces are named enantiotopic and the addition of nucleophiles to the carbonyl function can occur with enantioselection or the reaction is enantioselective if one prochiral face is attached preferentially over the other.

Reaction of a nucleophile with a carbonyl in a substrate where other sterecentre are present, gives two possible diastereoisomers. Reaction is stereoselective if one diastereoisomerpredominates

Strategies and Tactics in Organic Synthesis

Possible models proposed along the time for nucleophile apprach to the carbonyl function witha stereocentre in α

Nucleophiles attack the carbonyl group along the Bürghi-Dunitz angle of ~107°

Models proposed with a perpendicular approach of Nu to the carbonyl function

the Bürghi-Dunitz (107°) angle is the compromise between electrostatic interaction and optimised orbital overlaps

Later on other models have been proposed with Bürghi-Dunitz trajectory of Nu to the carbonyl function

Strategies and Tactics in Organic Synthesis

Newman projection: two substituents(C=O & Ph) are eclipsed - unfavoured

Other possible conformers: Two favoured as largest substituent (Ph) furthest from O and H

One of the more stable conformer largest substituent(Ph) furthest fromO & H

One of the more stable conformer largest substituent(Ph) furthest fromO & H

Importance of conformational analysis

Explained using Felkin-Ahn model

Si faceRe face

in most stable conformation the favoured approach is close to the smallest substituent (H) when molecule

Strategies and Tactics in Organic Synthesis

General features for the addition to a carbonyl with a α stereocentre: Felkin-Ahn Model

To explain or predict the stereoselectivity of nuclophilic addition to a carbonyl group with an adjacent stereogenic centre, use the Felkin-Ahn model: Draw Newman projection with the largest substituent (L) perpendicular to the C=O; Nucleophile (Nu) will attack along the Bürghi-Dunitztrajectory passed the least sterically demanding (smallest, S) substituent, draw the Newman projection of the product, redraw the molecule in the normal representation. Whilst the Felkin-Ahnmodel predicts the orientation of attack, it does not give any information about the degree of selectivity but only whose will be the predominant stereoisomerThe size of the nucleophile greatly effects the diastereoselectivity of addition: Larger nucleophilesgenerally give rise to greater diastereoselectivities. Choice of metal effects the selectivity as well, although this may just be a steric effect. The size of substituents on the substrate will also effect the diastereoselectivity. Again, larger groups result in greater selectivity. Should be noted that larger substituents normally result in a slower rate of reaction

Strategies and Tactics in Organic Synthesis

The effect of electronegative atom in α to carbonyl function

Steric hinderance is not the only factor that justify the high observed stereoselectivity and faster reaction in the addition of ester enolates to α-amino substituted aldehydes. Other factors, such as electronic factors, can play an important rule as in the case of α-dibenzylamino substituted aldehydes. The Bn2N group must be perpendicular to C=O since in this way there is a better interaction between the C-N and the carbonyl double bond. Applying the Fenkin-Ahn model, the approach of enolate is favoured from the opposite site to Bn2N (electronic repulsion between two electron rich group namely enolate and Bn2N).

When an electronegative group is perpendicular to the C=O it is possible to get an overlap of the π* orbital and the σ* orbital which results in a new, lower energy orbital, more susceptible to nucleophilic attack, thus if electronegative group perpendicular, C=O is more reactive.

Fenkin-Ahn approach

Strategies and Tactics in Organic Synthesis

The effect of electronegative atom and chelation control

If heteroatom (Z) is capable of coordination and a metal capable of chelating 2 heteroatoms is present we observe chelationcontrol. Metal chelates carbonyl and heteroatom together fixing their conformation affording greater selectivity and faster reaction. The chelating metal acts as a Lewis acid and activatesthe carbonyl group to attack. Chelation can reverse selectivity.Chelation controlled additions are easy to predict and normally do not need to draw Newman projection!

Other example of electronic effect control

Strategies and Tactics in Organic Synthesis

Chelation control in the nucleophilc addition to α carbonyl: other examples

The following example shows normal Felkin-Ahn selectivity gives one diastereoisomerElectronegative and bulky phosphorus group in perpendicular position, Chelation control gives opposite diastereoisomer and occurs through 6-membered ring. Lower reaction temperatures are typical in activated chelated carbonyl systems

Strategies and Tactics in Organic Synthesis

Application of Fenkin-Ahn model in total synthesis

An example of the Sakurai reaction (addition of allylsilane to carbonyl) from the synthesis of preswinholide A which is effectively the monomer of swinholide A (the dimmer, isolated from a Red Sea sponge), a compound displaying potent cytotoxic activity Total synthesis by Ian Paterson, Tetrahedron, 1995, 51, 9437

Strategies and Tactics in Organic Synthesis

The synthesis of canadensolide, a fungicidal agent is another example of the Mukaiyama aldol reaction (addition of ester silylenolether to carbonyls• Yung-Son Hon & Cheng-Han Hsieh, Tetrahderon, 2006, 62, 9713

Strategies and Tactics in Organic Synthesis

Stereoselctive reaction of enolates

The stereoselectivity of reactions of enolates is dependent on:Presence of stereogenic centres on R1, R2 and frequently on the geometry of the enolate (but not always)

Geometry of the enolate: The terms cis and trans in relation of the disposition group with highest priority on the α-carbon atom to O–M bond

R1

MO

H

R2

α

C-α si face

C-α re face

R1

MO

R2

C-α si face

C-α re face

Strategies and Tactics in Organic Synthesis

Enolate formation and geometry

Enolate normally formed by deprotonation , this is favoured when the C–H bond is perpendicular to C=O bond as this allows σ orbital to overlap π orbital. σ C–H orbital ultimately becomes p orbital at C-α of the enolate π bond

Deprotonation process and geometry of the enolate

Two possible conformations which allow this:Little steric interaction between R1 and R2Initial conformation (Newman projection) similar to transition stateresults in the formation of cis enolate

Strategies and Tactics in Organic Synthesis

Deprotonation process and geometry of the enolateSecond conformation: C–H perpendicular to C=O which differs by relative position of R1 and R2 and gives trans- enolateThe steric interaction of R1 and R2 results in the cis -enolate normally predominating but the stereoselectivity is influenced by the size of R

Enolate formation and geometry

Strategies and Tactics in Organic Synthesis

Enolate formation and geometry

The selectivity observed can be explained via chair-like transition state of deprotonation stepIn ketones cis -enolate favoured if R is large but trans -enolate favoured if R is small

With esters the R vs OMe interaction is alleviated and 1,3-diaxial interaction controls the geometry of the enolate, hence trans -enolate predominates

Strategies and Tactics in Organic Synthesis

Amides invariably give the cis -enolate ; remember restricted rotation of C–N bond. The previous arguments are good generalisations, many factors effect geometry. Use of the additive HMPA (hexamethylphosphoric triamide) reduces coordination and favours the thermodynamically more stable enolate

Enolate formation and geometry

In ester the reverse is observed

Strategies and Tactics in Organic Synthesis

Addition electrophile to an enolate: Alkylation

It is important to know the trajectory of approach of the enolate and electrophileReaction is the overlap of the enolate HOMO and electrophile LUMOTherefore, new bond is formed more or less perpendicular to carbonyl groupThe example shows a simple SN2 reaction with X = leaving group

Strategies and Tactics in Organic Synthesis

Stereoselective (diastereoselective) alkylation of prochiral enolates.The alkylation of prochiral enolates of acid is normally preformed using chiral derivatives such as chiral amides (Meyer approach, enantiopure aminoalcohol) or imides (Evans approach enantiopure oxazolidinones)

From phenylalanine

Chelation is important for enolate geometry and for the approach of the electrophile. M= Li (JACS 1982, 104, 1737 ) or TiCl3 (JACS 1990, 112, 8215) d.e.>95 to 100%. After removingthe chiral auxiliary the final acid is obatin with high e.e.

Cis- enolate

Evans approach

Myers approach

JACS 1994, 116, 9361; 1995, 117, 8488Cis-enolate

d.e. >94%, yields >80%

Strategies and Tactics in Organic Synthesis

Stereoselective (diastereoselective) alkylation of chiral enolates

Simple alkylation of a chiral enolate usually occurs with very high diastereoselectivitySince the cis -enolate is usually formed with high diastereoselectivity the reactive conformer considering the alkenes A(1,3) strain. Larger the substituent, R, greater the selectivity

minor diastereoisomer probably arises from electrophile approaching from R group site and not reacting with the trans enolate. So its dimension play and important role in determining diastereoselectivity. It is possible to change the diastereoselectivity simply using the proton as electrophile in quenching the enolate of the alkylated final product

The geometry of enolateis not important

Cis-enolate

Strategies and Tactics in Organic Synthesis

Stereoselective (diastereoselective) aldol reaction

The aldol reaction is a valuable C–C forming reaction. In addition it can form two new stereogenic centres in a diastereoselective manner. Most aldol reactions take place via a highly order transition state know as the Zimmerman–Traxler transition state which is a 6-membered, chair-like transition state. Contrary to alkylation, the enolate geometry effects diastereoselectivity

syn aldol

Strategies and Tactics in Organic Synthesis

Stereoselective (diastereoselective) aldol reaction: Zimmerman–Traxler transition state

Enolate substituents are fixed due to the double bond thus the orientation of the aldehyde in relation to the enolate is crucial in determining the final stereoselectivity (diatereo and enantioselectivity) in the aldol reaction Bulky aldehyde substituent should be arranged in pseudo-equatorial position in the Zimmerman–Traxler transition state in order to avoid 1,3-diaxial interactions

Zimmerman–Traxler transition state for cis-enolate

to ‘see’ relative stereochemistry consider the blue carbon sequence on a plane and see which groups are above and which below. Thus in this case Me and OH are farer from observer

re face of enolate attackssi face of aldehyde

si face of enolate attacksre face of aldehyde

Attack via the enantiomeric transition state (re face of aldehyde) gives the enantiomeric aldol product. This differs only by the absolute stereochemistry but the relative stereochemistry is the same Me and OH on the same site

Enantiomeric TS

Me and OH point towards the observer

Strategies and Tactics in Organic Synthesis

Stereoselective (diastereoselective) aldol reaction: Zimmerman–Traxler transition state

Trans-enolate: The opposite stereochemistry of enolate gives opposite relative stereochemistry

In this case the two hydrogens must axial

Strategies and Tactics in Organic Synthesis

With boron enolates we can select the geometry by altering the boron reagent used

In the lithium enolates of ketones the size of the non-enolised substituent, R, is importantGeometry of the enol in ketones is determined by the dimension of R

Stereoselective (diastereoselective) aldol reaction: enolate geometry

The bulky groups on boron force enolate toadopt trans geometry

9-BBN (9-borabicyclononane) looks bulky, but most of it is ‘tied-back’ behind boron thus allowing formation of the cis-enolate

Strategies and Tactics in Organic Synthesis

Substrate control in the total synthesis of oleandomycin aglycon

Cram chelation control

Strategies and Tactics in Organic Synthesis

Aldon reaction: Substrate control in the total synthesis of oleandomycin aglycon

the opportunities offered by the aldol reaction. It creates 1 C–C bond and 2 stereogenic centres per reaction. Ian Paterson,, J. Am. Chem.Soc., 1994,116, 11287

Strategies and Tactics in Organic Synthesis

Aldon reaction: Substrate control in the total synthesis of swinholide A by PatersonTetrahedron 1995, 9393–9467

fragment A

fragment B

Strategies and Tactics in Organic Synthesis

fragment A

fragment B

Strategies and Tactics in Organic SynthesisStereoselective Synthesis; Chiral auxiliary

Chiral auxiliary - allows enantioselective synthesis via diastereoselective reactionAdd chiral unit to substrate to control stereoselective reaction. Can act as a built in resolving agent (if reaction not diastereoselective). Problems - need point of attachment, adds additional steps (atom economy),.cleavage conditions must not damage product!

An ideal chiral auxiliary has to fulfil several criteria:i) it should be cheap, and both enantiomers should be readily availa ble; ii) attachment of the substrate to the auxiliary should proceed in high yield by simpl e methods, applicable to a broad variety of substrates; iii) there should be many different types of reactions to be carried out ; iv) the auxiliary must be stable under the conditions of the diastereoselective reaction; v) there must be a high degree of diastereoselectionvi) the derivatives of the chiral auxiliary should preferabl y be crystalline, allowing easier purification, and removal of diastereoisomeric ans other impurities by simple crystallization; vii) the cleavage of the auxiliary must be possible with high yield under mild conditi ons, and the procedures should be generally applicableviii) the auxiliary should not be destroyed under the con ditions applied for cleavage, thus allowing for recyclingix) isolation of the enantiomerically pure product and recovery of the auxiliary should be possible by simple methods. Seebach, D. Helvetica Chimica Acta 1998, 2093

Strategies and Tactics in Organic Synthesis

Chiral auxiliary and addition to the carbonyl group

We have seen many examples of substrate control in nucleophilic addition to the carbonyl group (Felkin-Ahn & chelation control). If molecule does not contain a stereogenic centre then we can use a chiral auxiliary. The chiral auxiliary can be removed at a later stage

Opposite diastereoisomer can be obtained from reduction of the ketone with lower diastereoselectivity...‘H–’ is smaller

Chiral auxiliary in synthesis

The chiral auxiliary, 8-phenylmenthol, has been utilised to form the pheromone, frontalinAggregation pheromone of the Southern Pine Beetle - the most destructive beetle topine forests in southeastern united states

Strategies and Tactics in Organic Synthesis

Stereoselective synthesis: chiral reagents

Chiral reagent - stereochemistry initially resides on the reagent• Advantages - No coupling / cleavage steps required....................... .Often override substrate control....................... .Can be far milder than chiral auxiliaries• Disadvantages - Need a stoichiometric quantity (not a tom economic).............................Frequently expensive.............................Problematic work-ups

Chiral reagents

Strategies and Tactics in Organic Synthesis

Chiral reagents

Clearly, chiral reagents are preferable to chiral auxiliaries in that they fu nctionindependent of the substrate’s chirality or on prochiral substratesA large number have been developed for the reduction of carbonylsMost involve the addition of a chiral element to one of our standard reagents

selectivity governedby 1,3-diaxialinteractions

Strategies and Tactics in Organic Synthesis

Binol derivative of LiAlH4

Reducing reagent based on BINOL and lithium aluminium hydride• Selectivity is thought to arise from a 6-membered transition state (surprise!!)• Largest substituent (RL) adopts the pseudo-equatorial position and the s mallsubstituent (RS) is axial to minimise 1,3-diaxial interactions

Transition state

Strategies and Tactics in Organic Synthesis

Chiral reagent in total synthesis

(+)-Ipc2BCl is a more reactive, Lewis acidic version of Alpine-borane• Might want to revise the Mitsunobu reaction (step 2)

• M. Srebnik, P.V. Ramachandran & H.C. Brown, J. Org. Chem., 1988, 53, 2916

Strategies and Tactics in Organic Synthesis

Chiral allyl boron reagents

Allyl boron reagents have been used extensively in the synthesis of homoallylic alcohols• Reaction always proceeds via coordination of Lewis basic carbonyl and Lewis acidic boron

• This activates carbonyl as it is more electrophilic and weakens B–C bond, makingthe reagent more nucleophilic• Funnily enough, reaction proceeds by a 6-membered transition state

Aldehyde will place substituent in pseudo-equatorial position (1,3-diaxail strain )• Therefore alkene geometry controls the relative stereochemistry (like aldol rct)

Strategies and Tactics in Organic Synthesis

Chiral allyl boron reagents II

Reagent is synthesized from pinene in two steps• Gives excellent selectivity but can be hard to handle (make prior to reaction)

• Remember pinene controls absolute configurationGeometry of alkene controls relative stereochemistry

Strategies and Tactics in Organic Synthesis

Other boron reagents

A number of alternative boron reagents have been developed for the synthesis ofhomoallylic alcohols• These either give improved enantiomeric excess, diastereoselectivity or ease ofhandling / practicality• Ultimately, chiral reagents are wasteful - they need at least one mole of reagen t foreach mole of substrate• End by looking at chiral catalysts

Strategies and Tactics in Organic Synthesis

Chiral reagent in total synthesis

Silicon reagent developed by J. Leighton• Used in the synthesis of (+)-SCH 351448, a reagent for the activation of low-densitylipoprotein receptor (LDLR) promoter. L. Leighton, Org. Lett., 2005, 7, 3809

Strategies and Tactics in Organic Synthesis

Stereoselective synthesis: chiral catalysisChiral catalysis - ideally a reagent that accelerates a reaction (without being destroyed) in a chiral environment thus permitting one chiral molecule to generate millions of new chiral molecule The reaction is often perfomed on achiral substrates or prochiral ones (as for example carbonyl functions).

Strategies and Tactics in Organic Synthesis

Catalytic enantioselective reduction

An efficient catalyst for the reduction of ketones is Corey-Bakshi-Shibata catalyst (CBS): The reagent is prepared from a proline derivative: diphenylprolinol. Enantioselection is deternatedby the nature of chiral reagent and occurs by the formation of diastereoisomeric transition states with different energies.The reaction utilises ~10% heterocycle and a stoichiometric amount of borane and works most effectively if there is a big difference between each of the substituents on the ketone.

Prochiral carbonyl function

Strategies and Tactics in Organic Synthesis

The mechanism is quite elegant: This catalyst brings a ketone and borane together in a chiralenvironment

Boron Lewis acidiccenter that coordinatescarbonyl oxygen

Catalytic enantioselective nucleophilic addition

There are now many different methods for catalytic enantioselective reactions. Some few examples.Simple amino alcohols are known to catalyse the addition of dialkylzinc reagents toaldehydes with a mechanism involving a bifunctional zinc species where one zinc becomes the Lewis acidic centre and activates the aldehyde and the second equivalent of the zinc reagent actually attacks the aldehyde. Once again a 6-membered ring is involved and 1,3-diaxial interactions govern the observed selectivity

1,3-diaxial interaction

Strategies and Tactics in Organic Synthesis

Lewis acid catalysed allylation / crotylationChiral Lewis acids can be used to activate carbonyl group with impressive results and in the case of allylation works very well with high e.e. However the control of diastereoselectivity is often difficult to achieve. In this reaction the reaction proceeds via an open transition state and this partially explain the relative difficulty in controlling the diastereoselection.

The E or Z nature of stannyl derivative has no influence on diatereoselection but are important the dimention of the group in gamma position to the Sn i.e the differences between the dimention RE

and RZ.

C-Sn Bond is enough polarized and this makes the gamma position particularly nucleophilic

RzRE

Sn

δ−

δ+

nucleophilc site

Strategies and Tactics in Organic Synthesis

Catalytic chiral Lewis base mediated allylation with allyl silicon reagents

Alternatively allylsilyl reagents are emploied in allylation of carbonyls. In this case the use of chiralLewis bases, which activate the crotyl reagent, high er diatereoselection are obeserved. The reaction proceeds via the activation of the allylsilicon reagent by coordination of chiral base and with the generation a hypervalent silicon speciesThis species coordinates and activate the carbonyl function allowing the reaction to proceed by a highly ordered by a closed transition state. As a result good diastereoselectivities are observed and the geometry of nucleophile controls the relative stereochemistry .

Example of base catalysts used in this reactionRE and RZ = Me or H

Strategies and Tactics in Organic Synthesis

Strategies and Tactics in Organic Synthesis

Reactions of alkenes: Stereospecific reactionsAlkenes are versatile functional groups that present plenty of opportunity for the introduction of stereocenters. One possibility is by Hydroboration (the reaction that allows to transform alkenes in alcohols) that permits the stereo-selective introduction of boron. The corresponding borane can undergo a wide-range of stereospecific reactions

The two compounds formed previously, mono-& diisopinocampheylborane are common reagents for the stereoselective hydroborationof alkenes. Ipc 2BH is very effective for cis -

alkenes but less effective for trans. IpcBH 2

gives higher enantiomeric excess with trans and trisubstituted alkenes

Strategies and Tactics in Organic Synthesis

Hydrogenation: is another important reaction that can be carried out enantioselectively under metal catalysis condition. One well known example for its huge importance from industrial point of view, is the catalytic hydrogenation of dehydroaminoacid derivatives (prepared by Knovenagel like reaction on glycine). Diphosphines are used as Rutenium ligand and it is essential that there is a second coordinating group (the amide in the dehydroaminoacid).

On coordination, two diastereoisomeric complexes are formed. The stability / ratio of each of these complexes is unimportant in determining the final stereoselection but the rate of hydrogen coordination.

Re faceSi face

Strategies and Tactics in Organic Synthesis

Mechanism proposed for catalytic hydrogenation

Hydrogen oxidative addition

Hydrogen transfer

Strategies and Tactics in Organic Synthesis

Other systems can be hydrogenated with the same chiral catalyst: industrial synthesis of candoxatril

Used in the synthesis of candoxatril, a potent atrial natriuretic factor (ANF) potentiator(cardiovascular drug developed by Pfizer). Process used on ton-scaleOrg.Process Res. Dev., 2001, 5, 438

Strategies and Tactics in Organic Synthesis

Reactions of alkenes: epoxidation diastereospecific reaction

Diastereospecific - reaction permits only one diastereoisomer to be formedcontrol relative stereochemistry not absolute stereochemistryElectrophilic epoxidation via a concerted process is a good example

Concerted oxygen transfer

Epoxidation is irreversible and the reaction is under kinetic control.

Strategies and Tactics in Organic Synthesis

Conformation are important in determining the observed stereoselection: the lowest energy conformations have greatest separation of bulky substituents. The control of conformation in allyl systems is called allylic strain or A(1,3) strain

allylic strain or A(1,3) strain

Strategies and Tactics in Organic Synthesis

In the trans alkene the differences in energy between the two conformers is sensibly lower and the d.e. is minor (61/39)

Strategies and Tactics in Organic Synthesis

Hydroxyl group can direct epoxidation in acyclic compounds as well• Once again, major product formed from the most stable conformation

• Thus the cis methyl group is very important• The minor product is formed either via non-directed attack or via the less favoured...conformation

Strategies and Tactics in Organic Synthesis

Directed epoxidation: effect of C-2 substituent

The presence of a substituent in the C-2 position (Me) facilitates a highlydiastereoselective reaction• The preferred conformation minimises the interaction between the two Me (& Me)groups• With C-2 substituent (H) there is little energy difference between conform ations• Therefore, get low selectivity

Strategies and Tactics in Organic Synthesis

Directed epoxidation from the synthesis of oleandomycin aglcon• Glycosylated version (R=sugar) is a potent antibiotic from streptomyces antibioticus

• David A. Evans and Annette S. Kim, J. Am. Chem. Soc. 1996, 118, 11323

Substrate control in total synthesis

Strategies and Tactics in Organic Synthesis

A hydroxyl group can reverse normal selectivity and direct epoxidation• Epoxidation with a peracid, such as m-CPBA, is directed by hydrogen bonding andfavours attack from the same face as hydroxyl group• The reaction with a vanadyl reagent results in higher stereoselectivity as it bonds /chelates to the oxygen

Sharpless Asymmetric Epoxidation (SAE) of allylic alcohols Sharpless, K. B. JACS 1980, 5974

• Sharpless asymmetric epoxidation was the first general asymmetric catalyst. There are a large number of practical considerations that we will not discuss. Suffice to say it works for a wide range of compounds in a very predictable manner. Compounds must be allylic alcohols as shown by epoxidation of the diolefin

SAE is highly predictable . To understand where this comes from we must look at the mechanism

Strategies and Tactics in Organic Synthesis

Active species thought to be 2 x Ti bridged by 2 x tartrateReagents normally left to ‘age’ before addition of substrate thusallowing clean formation of dimer

Mechanism of SAE

Strategies and Tactics in Organic Synthesis

SAE works for a wide range of allylic alcohols. Only cis di-substituted alkenes show lesser enantioselection

SAE can over-ride (have the priority) the inherent selectivity of a substrate. Furthermore, it demonstrates the concept of matched & mismatched. When the catalyst & substrate reinforce each other spectacular (or matched) results are achieved

Strategies and Tactics in Organic Synthesis

Use of SAE in synthesis

Fluoxetine is a commercial anti-depressant (better known as Sarafem® or Prozac®). Can be synthesized in a number of methods • One involves the use of the SAE reaction... Y. Gao and K. B. Sharpless, J. Org. Chem., 1988, 53, 4081. Yun Gao, Robert M. Hanson, Janice M. Klunder, Soo Y. Ko, Hiroko Masamune, and K. Barry Sharpless, J. Am. Chem. Soc., 1987, 109, 5165

Strategies and Tactics in Organic Synthesis

Using the same diethyltartrate, both enantiomers should be epoxidised from same face, but rate of epoxidation is different and the differences are sufficient to epoxidise only one enantiomer if the reaction is stopped at 50% conversion. if reaction goes to 100% completion a 1:1 mixture of diastereoisomers is obtained

Kinetic resolutionas racemic mixture

if allylic alcohol is desired: use 0.6eq TBHPif epoxy alcohol is desired: use 0.45eq TBHP

Strategies and Tactics in Organic Synthesis

Kinetic resolutionKinetic resolution normally works efficiently, but the problem with kinetic resolution is that is can only give a maximum yield of 50% in epoxide. Desymmetrisation of a meso compound allows 100% yield. Effectively, the same as two kinetic resolutions, first desymmetrises compound second removes unwanted enantiomer. E.e. of desired product increases with the reaction time (84% ee 3hrs ➔ >97% 140hrs)

Desymmetrisation has been used in many elegant syntheses. As an example in the synthesis of KDO, a key component of the cell wall lipopolysaccharide (LPS) of Gram-negative bacteria forming the necessary linkage between the polysaccharide and lipid A regions. Tetrahedron, 1990, 46, 4793. and J. Am. Chem. Soc.,1987, 109, 1525

Strategies and Tactics in Organic Synthesis

Jacobsen-Katsuki epoxidationSAE is a marvelous reaction but suffers certain limitations: substrate must be an allylic alcohol and cis-disubstituted alkenes are poor substrates. Alternatively (salen)Mn catalysts with bleach (NaOCl) are good in the epoxidation of many olefins.

The Industrial Syntheses of the Central Core Molecules of Indinavir, an HIV protease inhibitor marketed by Merck as Crixivan®, represent an example that demonstrates the industrial potential of such catalytic systems. Chem. Rev., 2006, 106, 2811

Strategies and Tactics in Organic Synthesis

Sharpless Asymmetric Dihydroxylations (SAD)

The active, catalytic, oxidant is K2OsO2(OH)4 . OsO4 is too volatile & toxic, K3Fe(CN)6 is the stoichiometric oxidant K 2CO3 & MeSO2NH2 accelerate the reaction Normally use a biphasic solvent system And the two ligands are

Ligands are pseudo-enantiomers (only blue centres are inverted; red are not). Coordinate to the metal via the green nitrogen...

Strategies and Tactics in Organic Synthesis

Sharpless Asymmetric Dihydroxylation

Reaction works on virtually all alkenes• Exact mechanism not known but it is relatively predictable (but not as predictable as the SAE)

The example shows the power of the SAD reaction in synthesis: exo-Brevicomin is the aggregation pheromone of several timber beetles. Interestingly, endo-brevicomin inhibits the aggregation of the southern pine beetle. Tetrahedron Lett., 1993, 34, 5031

Strategies and Tactics in Organic Synthesis

The Sharpless aminohydroxylation reaction

A variant has now been developed that permits aminohydrodroxylation. It has been employed in the semi-synthesis of paclitaxel (Taxol®), an anti-carcinogen. Acta Chem. Scand., 1996, 50, 649

Strategies and Tactics in Organic Synthesis

Stereoselective Conjugate (1,4-) additionNucleophilic attack on C=C bond normally requires electron deficient alkene as in the case of α−β unsaturated carbonyl derivaties. The reaction is known as 1,4-addition or conjugate Michael addition. After the addition of the nucleophile an enolate is formed this open to the possibility of forming two stereogenic centres. Substrate control - initial nucleophile addition to the least hindered face of enone, the electrophile addition normally occurs from opposite face

First stereocentre

Second stereocentre

Prostaglandins are technically hormones with very strong physiological effects, for example have been utilised to prevent and treat peptic ulcers, as a vasodilator, to treat pulmonary hypertension and induce childbirth / abortion R. Noyori, J. Am. Chem. Soc. 1988, 110, 4718

Application to the synthesis of PGE2

This stereocentre control the addition to the double bond

Strategies and Tactics in Organic Synthesis

Diastereoselective conjugate additionsPossible to use chiral auxiliary to control 1,4-nucleophilic addition. The chelation of amide and sultam oxygens to Mg restricts rotation and favours cis conformation, the nucleophile (Et) addition occurs from most sterically accessible side. Chiral auxiliary readily cleaved (& reused) to give enantiomerically pure compound via diastereoselective reaction

Strategies and Tactics in Organic Synthesis

Chiral auxiliary to control two stereocentres

It possible to utilise 1,4-addition to introduce two stereogenic centres. The first addition (BuMgBr ) occurs as before to generate an enolate. The enolate can then be trapped by an appropriate electrophile. Once again the sultam chiral auxiliary controls the face of addition (of Me)

Strategies and Tactics in Organic Synthesis

Alternative chiral auxiliaries

A second chiral auxiliary is the oxazoline (5-membered ring) of Meyers. It can be prepared from carboxylic acids (normally in 3 steps) or from condensation of the amino alcohol and a nitrile. As can be seen excellent enantiomeric excesses can be achieved via a highly diastereoselectivereaction

Strategies and Tactics in Organic Synthesis

Chiral auxiliary and radical conjugate addition

Radicals once thought to be too reactive to allow diastereoselective reactions.But this is not always true - oxazolidinone auxiliary. Rare-earth Lewis acids give superior results. Use of Et3B & O2 as radical initiator allows the use of low temperatures

Strategies and Tactics in Organic Synthesis

Sulfoxide-based chiral auxiliary (& total synthesis)

Sulfoxide is a good chiral auxiliary; not only does it introduce a stereocentre but itactivates the alkene by addition of an extra electron-withdrawing group. Sulfoxide substituentblocks the bottom face & is readily removed. Simple substrate control instals aryl group on opposite face to substituent (–)-Podorhizon is a member of the anticancer podophyllotoxinfamily of compounds. Tetrahedron Lett. 1984, 25, 2627

Strategies and Tactics in Organic Synthesis

Chiral auxiliaries and total synthesis

L-CCG-I (L-carboxycyclopropylglycine-I) is a conformationally restrained analogue of L-glutamicacid (there are four possible stereoisomers of L-CCG). L-Glutamic acid is the most abundant excitatory neurotransmitter in our bodies; it is thought to be involved in cognitive functions like learning and memory in the brain and possibly with umami, one of the five basic human tastes. J. Org. Chem. 2003, 68,6817

Strategies and Tactics in Organic Synthesis

Enantioselective catalytic conjugate addition

Much effort has been expended trying to develop enantioselective catalysts for conjugate addition. Whilst many are very successful for certain substrates, few are capable of acting on a wide range of compounds. The system above gives excellent enantioselectivities for cyclohexenone but no selectivity for cyclopentenone

Strategies and Tactics in Organic Synthesis

Enantioselective radical conjugate addition

C2 symmetry axis

Once stereoselective conjugate radical additions with auxiliaries had been developed, the enantioselective catalytic variant rapidly has been proposed. The following chiral Lewis acid catalysed reaction. Most work in this area has been pioneered by Sibi

Strategies and Tactics in Organic Synthesis

[3,3]-Sigmatropic rearrangements

A class of pericyclic reactions whose stereochemical outcome is governed by the geometric requirements of the cyclic transition state. Reactions generally proceed via a chair-like transition state in which 1,3-diaxial interactions are minimised. The type of activation (thermal or photochemical) and the stereochemistry can often be predicted by the Woodward-Hoffmann rules which are based on the total number of electrons (those in the π-system + those of single bonds) involved in the rearrangement process: 4n electrons, is photochemically allowed from excited state; 4n + 2 electrons, the migration thermally allowed.Many similarities to the aldol reaction. Absolute stereochemistry - controlled by existing

stereocentre (destroyed in rct).Relative stereochemistry - controlled by alkene / enolategeometry

Both are potential stereogenic unit or prochiral, depend on the nature of a,b,c,d

Strategies and Tactics in Organic Synthesis

Cope rearrangementA very simple example of a substrate controlled [3,3]-sigmatropic rearrangement is the Cope rearrangement. To minimise 1,3-diaxial interactions phenyl group is pseudo-equatorial.

Note: the original stereocentre is destroyed as the new centre is formed. This process is often called ‘chirality transfer’

Strategies and Tactics in Organic Synthesis

Claisen rearrangements

One of the most useful sigmatropic rearrangements is the Claisen rearrangement and all it’s variants. In blue the new formed C-C bond.

Strategies and Tactics in Organic Synthesis

Enantioconvergent’ synthesisBoth enantiomers of initial alcohol can be converted into the same enantiomer of product. This process (Eschenmoser-Claisen) shows the importance of alkene geometry in [3+3] sigmatropicrearrangement

Same configuration

Strategies and Tactics in Organic Synthesis

Enolate geometry controls relative stereochemistry, therefore, the enolisation step controls the stereochemistry of the final product. As we have seen it is relatively easy to control enolategeometry and consequently the final stereochemistry

Ireland-Claisen reaction

Strategies and Tactics in Organic Synthesis

Substrate control in Ireland-Claisen rearrangement

In a similar fashion to the Cope rearrangement, the Ireland-Claisen rearrangement occurs with ‘chirality transfer ’. Initial stereogenic centre governs the conformation of the chair-like transition state: Largest substituent will adopt the pseudo-equatorial position. Once again, the relative stereochemistry between the two new stereocentres is governed by the geometry of the enolate

Strategies and Tactics in Organic Synthesis

Auxiliary controlled rearrangement in total synthesis

The use of chiral and enantiopure auxiliaries it is possible to perform the rearrangement in enantioselective manner. An application in the synthesis of (–)-Malyngolide is an antibiotic isolated from the blue-green marine algae Lyngbya majuscule. This synthesis utilises Enders' RAMP hydrazone as a chiral auxiliary to set up the quarternary centre. Tetrahedron 1996, 52, 5805

Ender’s hydrazine

Strategies and Tactics in Organic Synthesis

Chiral reagent control in the Ireland-Claisen rearrangement

It is possible to carry the reaction out under “reagent” control as in the case of chiral boroenolates.

Although, it could be argued that this is just a form of temporary auxiliary control! Enolate formation(enolate geometry ) governs relative stereochemistry

Strategies and Tactics in Organic Synthesis

The use of a chiral reagent in total synthesis

Dolabellatrienone is a marine diterpenoid isolated from gorgonian octocorals such as Euniceacalyculata and other marine organisms His enantioselective synthesis relies on boron enolatechemistry to establish the stereochemistry of the final molecule J. Am. Chem. Soc. 1996, 118, 1229

Via cis boroenolate

Strategies and Tactics in Organic Synthesis

Chiral catalyst control in the Ireland-Claisen rearrangement

It is also possible to perform the reactions under chiral catalyst control using for example chiralLewis acids. In this case it is reasonable that the Lewis acid coordinates to the oxygen influencing the reactive conformation thus controlling enantioselectivity

Coordination by Lewis acid

Strategies and Tactics in Organic Synthesis

2,3-Wittig rearrangement

The 2,3 Wittig rearrangement is useful for good 'chirality transfer'. Requires the formation of anion and, in turn, acidic proton (Z=electron withdrawing group) or metal-functional group exchange Driving force is stability of alkoxide (although other elements can be used...).Transition state is under debate but it is reasonable the invoke a based on 'envelope' chair model

Largest substituents adopt pseudo-equatorial position

Strategies and Tactics in Organic Synthesis

Enantioselectivity in the 2,3-Wittig rearrangement

Reagent control utilising chiral boron reagent similarly to that seen in Ireland-Claisenrearrangement reactions.

Enammine can be used as anion and the use of chiral amine the reaction show significant enantioselection

Strategies and Tactics in Organic Synthesis

[2,3]-aza-Wittig reaction in total synthesis

Aza-Wittig rearrangement is less common. The relief of ring-strain accelerates reaction. Aza-Wittig rearrangement has been use in the total synthesis of indolizidine 209B from Dendrobatespumilio or the strawberry poison dart frog. Tetrahedron, 1995, 51, 9741

Strained aziridine ring

Strategies and Tactics in Organic Synthesis

Stereoselective Diels-Alder reaction

Diels-Alder (DA) reaction is incredibly valuable method for the synthesis of 6-rings and is highly regioselective. It is controlled by the ‘relative sizes’ of the π-orbitals in the LUMO & HOMO involved or on the value of their orbital coefficients. In the presence of a Lewis acid dienophileis polarised giving higher regioselectivity and a faster reaction

Strategies and Tactics in Organic Synthesis

Endo vs exo selectivityEndo transition state and adduct is more sterically congested thus thermodynamically less stable but it is normally the predominant product. The reason is endo transition state is stabilised by π orbital overlap of the group on C or D with the diene HOMO; an effect called ‘secondary orbital overlap’. The reaction is suprafacial and the geometry of the diene and dienophile is preserved. Finally, remember that the dienophile invariably reacts from the less hindered face

The ‘cube’ method is a nice way to visualise the relative stereochemistry

Strategies and Tactics in Organic Synthesis

Chiral auxiliaries on the dienophile

One diastereoisomer is formed - the endo product, but mixture of enantiomers, If we add a chiral auxiliary then there are two possible endo diastereoisomers, but one predominates, thus we can prepare a single enantiomer

No enantioselection

Enantioselective version using a chiral auxilary

Strategies and Tactics in Organic Synthesis

Origin of diastereoselectivity

Coordination dienophile by the Lewis acid and its activation, The rigidity of the chelate governs reactive conformationc (s-cis) and s-trans (s is referred to the double bond position in relation to carbonyl double bond). For steric reason the s-trans is disfavoured. >The iso-Propyl group blocks bottom face of the double bond so the diene’s approaches from less hindered face and maximises secondary orbital overlap favouring the endo product

Strategies and Tactics in Organic Synthesis

Other auxiliaries can be utilised and most give good diastereoselectivities

Camphor-derived auxiliary

Strategies and Tactics in Organic Synthesis

It is possible to attach the chiral auxiliary to the diene as well

Use of a chiral auxiliary in an intramolecular Diels-Alder reaction (IMDA). An example in the total synthesis of (–)-stenine.• (–)-Stenine is isolated from Stemona family of sub-shrubs (bush) is a constituent of a variety of Eastern folk medicines. Angew. Chem. Int. Ed. Engl., 1996, 35, 904

Strategies and Tactics in Organic Synthesis

Chiral catalysis and the Diels-Alder reaction

The fact the Diels-Alder reaction is mediated or catalysed by Lewis acids means enantioselective variants are readily carried out. The aluminium catalyst, utilised in enolate chemistry (aldol) reaction, is very effective also in this Diels-Alder reaction.

Bis(oxazoline) ligands (Box) are amongst the most versatile and well used ligands known. Simply prepared from amino alcohols (and hence amino acids). Can be used in both DA and the equally useful HDA

Strategies and Tactics in Organic Synthesis

(+)-Ambruticin is an antifungal agent extracted from the myxobacterium Polyangium Cellulsoum, it has shown activity against Coccidioides immitis the cause of coccidioimycosisSynthesis of (+)-ambruticin J. Am.Chem. Soc. 2001, 123, 10772

Catalytic enantioselective HDA in total synthesis

Strategies and Tactics in Organic Synthesis

Stereoselective metal mediated reaction:The Heck reaction is a versatile method for the coupling sp2 hybridised centres

Strategies and Tactics in Organic Synthesis

Alkene isomerisation

β-Hydride elimination is reversible, thus the double bond can ‘walk’ or migrate to give the most stable alkene. Only restriction is every step must be syn

Strategies and Tactics in Organic Synthesis

Enantioselective Heck reaction

With the use of chiral ligands the Heck reaction can be enantioselectiveIntramolecular variant allows the construction of ring systems. The silver salt accelerates the reaction and prevents alkene isomerisation

Strategies and Tactics in Organic Synthesis

Enantioselective Heck reaction in total synthesis

(+)-Xestoquinone was isolated from the Pacific sponge Xestospongia sapra and is a potent irreversible inhibitor of both the oncogenic protein tyrosine kinase pp60V-src encoded by the Roussarcoma virus & the human epidermal growth factor kinase (EGF). The first total synthesis involved two Heck reactions; the first is enantioselective to give a quaternary centre and the second gives a second 6-ring. J. Am.Chem. Soc. 1996, 118, 10766Review of asymmetric Heck: Chem. Rev. 2003, 103, 2945

Strategies and Tactics in Organic Synthesis

Suzuki-Miyuara reaction

The Suzuki-Miyuara reaction is (normally) the palladium catalysed coupling of an alkenyl or aryl halide with an alkenyl or aryl boronic acid. Normally the components should be sp2 hybridised to avoid β-eliminations.

Strategies and Tactics in Organic Synthesis

Enantioselective biaryl formation

Non only molecules that contain stereogenic units such stereocentres can be chiral, also hindered rotation, as in biphenyls, can be in a chiral situation. Two examples of chiral bisaryl compounds. Both ligands are thought to be mono-dentate (in the active species at least, although they may be bidentate in ‘resting state’) via the phosphine

Strategies and Tactics in Organic Synthesis

Enantioselective Pd catalysed allylic substitution

Displacement of good leaving group (OAc, OCO2R, halide, epoxide etc.) normally using soft nucleophile . The reaction does not occur by direct displacement but via a palladium η3

complex

Strategies and Tactics in Organic Synthesis

Pd catalysed allylic substitution: Regio- and stereoselectivity

Palladium initially adds to the opposite face to the leaving group (although possible equilibrium). Soft nucleophiles (large, diffuse charge) usually attack from opposite face to

PdL n. Normally the nucleophile will add to the least hindered end of the allyl system.

Strategies and Tactics in Organic Synthesis

Enantioselectivity

Problem with inducing selectivity is that ligand is on opposite side to nucleophile. Bulky ligandscan overcome this problem and to have stereogenic centre on the substrate or on the nucleophile.

Stereocentre on the nucloephile

Stereocentre on the substrate

Strategies and Tactics in Organic Synthesis

. Allylic substitution in total synthesis

(–)-Swainsonine can be isolated from locoweeds; in cattle it causes symptons similar to mad cow disease (BSE) and hence plants named after the Spanish for crazy. In humans it shows anticancer, antiviral, and immunoregulatory properties. J. Org.Chem. 2002, 67, 4325. On the desymmetrisation see also J. Org. Chem. 1998, 63, 1339

desymmetrisation process

Strategies and Tactics in Organic Synthesis

Other catalytic enantioselective reactions

There are now a huge number of enantioselective reactions with more being invented / developed all the time. It is highly unlikely that this research in this vast, fascinating field will slow in the foreseeable future. It should be possible to develop enantioselective variants of most reactions – even those that do not initially look set-up for such chemistry. An example of a chiralvariant of the Schrock metathesis catalyst. The reaction involves desymmetrisation by selective reaction if one disubstituted alkene

Strategies and Tactics in Organic Synthesis

Summary of methods for stereoselective synthesis

Strategies and Tactics in Organic Synthesis

In organic chemistry, the term Organocatalysis (a concatenation of the terms "organic" and "catalyst") refers to a form of catalysis, whereby the rate of a chemical reaction is increased by an organic catalyst referred to as an "organocatalyst" consisting of carbon, hydrogen, sulfurand other nonmetal elements found in organic compounds. Because of their similarity in composition and description, they are often mistaken as a misnomer for enzymes due to their comparable effects on reaction rates and forms of catalysis involved. Organocatalysts which display secondary amine functionality can be described as performing either enamine catalysis (by forming catalytic quantities of an active enamine nucleophile) or iminium catalysis (by forming catalytic quantities of an activated iminium electrophile). This mechanism is typical for covalent organocatalysis. Covalent binding of substrate normally requires high catalyst loading (for proline-catalysis typically 20-30 mol%). Noncovalent interactions such as hydrogen-bonding facilitates low catalyst loadings (down to 0.001 mol%).Organocatalysis offers several advantages. There is no need for metal-based catalysis thus making a contribution to green chemistry. In this context, simple organic acids have been used as catalyst for the modification of cellulose in water on multi-ton scale. When the organocatalyst is chiral an avenue is opened to asymmetric catalysis, for example the use of proline in aldol reactions,

Berkessel, A., Groeger, H. (2005). Asymmetric Organocatalysis. Weinheim: Wiley-VCH. List, B. (2007). "Organocatalysis". Chem. Rev. 107 (12): 5413–5883. P. I. Dalko, L. Moisan, Angew. Chem. Int. Ed . 2001, 40, 3726 -3748 and Angew. Chem. Int.Ed. 2004, 43, 5138–5175. M.J. Gaunt, C. C.C. Johansson, A. McNally, N.T. Vo, "Enantioselective organocatalysis" DrugDiscovery Today, 2007, 12(1/2), 8-27. D. Enders, C. Grondal, M. R. M. Hüttl, review: "Asymmetric Organocatalytic Domino Reactions", Angew. Chem. Int. Ed. 2007, 46, 1570–1581.

Justus von Liebig's synthesis of oxamide from dicyan and water represents the first organocatalytic reaction, with acetaldehydefurther identified as the first discovered pure "organocatalyst", which act similarly to the then-named "ferments", now known as enzymes. Justus von Liebig, Annalen der Chemie und Pharmacie1860, 113 , 246–247

OrganocatalysisStrategies and Tactics in Organic Synthesis

Organocatalysts for asymmetric synthesis can be grouped in several classes:Biomolecules: notably proline, phenylalanine. Secondary amines in general. The cinchonaalkaloids, certain oligopeptides.Synthetic catalysts derived from biomolecules.Hydrogen bonding catalysts, including TADDOLS, derivatives of BINOL such as NOBIN, and organocatalysts based on thioureasS. Bertelsen, K. A. Jørgensen, Chem. Soc. Rev., 2009, 38, 2178–2189

A certain class of imidazolidinone compounds (also called MacMillan organocatalysts ) are suitable catalysts for many asymmetric reactions such as asymmetric DA reactions. The original such compound was derived from the biomolecule phenylalanine in two chemical steps (amidationwith methylamine followed by condensation reaction with acetone) which leave the chirality intact

Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W.C. J.J. AmAm. . ChemChem. Soc. Soc. 2000; 122; 4243-4244

CHIRAL ORGANOCATALYSIS

Strategies and Tactics in Organic Synthesis

Baylis–Hillman reaction

Regular achiral organocatalysts are based on nitrogen such as piperidine used in the Knoevenagel condensation, DMAP used in esterfications and DABCO used in the Baylis-Hillman reaction. Thiazolium salts are employed in the Stetter reaction. These catalysts and reactions have a long history but current interest in organocatalysis is focused on asymmetric catalysis with chiral catalysts and this particular branch is called asymmetric organocatalysis or enantioselective organocatalysis . A pioneering reaction developed in the 1970s is called the Hajos-Parrish reaction:

Z. G. Hajos, D.R. Parrish J. Org. Chem.; 1974; 39, 1615-1621

Strategies and Tactics in Organic Synthesis

This catalyst works by forming a iminium ion with carbonyl groups of α,β-unsaturated aldehydes (enals) and enones in a rapid chemical equilibrium. This iminium activation is similar to activation of carbonyl groups by a Lewis acid and both catalysts lower the substrates LUMO. G. Lelais and D. W. C. MacMillan Aldrichimica Acta . 2006, 39, 3, 79

Angew. Chem. Int. Ed. 2003,42, 4955-4957

J. Am. Chem. Soc. 2007, 129, 15438-15439

Strategies and Tactics in Organic Synthesis

Organocatalytic hydrogenation

A recent development is the use of small organic molecules to achieve hydrogenation• Inspire by nature

• Based on the formation of a highly reactive iminium ion (this is the basis of manyorganocatalytic reactions)

Strategies and Tactics in Organic Synthesis

Organocatalytic epoxidations

As with most chemical reactions, epoxidation has seen a move towards ‘greener’ chemistry and the use of catalytic systems that do not involve transition metals A number of systems exist, notably the catalysts of Shi & Armstrong. Most are based on the in situ conversion of ketones to the active, dioxirane species, that actually performs the epoxidation

Dioxirane, epoxidation reagent

Tanabe Seiyaku Co. utilise organocatalysis in the synthesis of diltiazem-L®, a blood pressure reducing agent. J. Org. Chem. 2002, 67, 4599

Strategies and Tactics in Organic Synthesis

Organocatalytic epoxidations in the industrial synthesis of Diltiazen-L® by Tanabe Seiyaku Co.a blood pressure reducing agent. T. Furutani, R. Imashiro, M. Hatsuda and M. Seki, J. Org. Chem.

2002, 67, 4599

Cat.

Strategies and Tactics in Organic Synthesis

Lewis acid organocatalysis

Intermolecular hydrogen bond acts as aLewis acid and activates carbonyl, intramolecular hydrogen bond organisesCatalyst. Catalyst derived from simple nature product, tartaric acid. Clean, green and effective

Strategies and Tactics in Organic Synthesis

Organocatalysis in Michael addition

New small molecule organic catalysts are now achieving remarkable results. Enone is activated by formation of the charged iminium species The catalyst also blocks one face of the enone allowing selective attack

Strategies and Tactics in Organic Synthesis

Organocatalysis in Michael addition: electronrich aromatic ring can be emploied in Michael addition

Strategies and Tactics in Organic Synthesis

An interesting reaction is the Stetter reaction - this is the conjugate addition of an acylgroup onto an activated alkene and proceeds via Umpolung chemistry (the reversal of polarity of the carbonyl group)

Organocatalysis in Michael additionStrategies and Tactics in Organic Synthesis

Organocatalysis in Michael addition

The thio(urea) moiety acts as a Lewis acid via two hydrogen bondsThe amine both activates the nucleophile and positions it to allow good selectivity

Strategies and Tactics in Organic Synthesis

Beautiful example of enantioselective conjugate addition in total synthesis. From the synthesis of a marine alkaloid from the Bryozoa, Flustra foliacea by Joel F. Austin, Sung-Gon Kim, Christopher J.Sinz, Wen-Jing Xiao, and David W. C. MacMillan, PNAS 2004, 101, 5482

Organocatalysis in Michael addition

Strategies and Tactics in Organic Synthesis

Catalysis in total synthesis

(R)-Muscone is the primary contributor to the odour of musk, a glandular secretion of the musk deer. •A racemic, synthetic version is used in perfumes. J. Am. Chem. Soc.,1993, 115, 1593

(R)-Muscone

Strategies and Tactics in Organic Synthesis

Organocatalysis and the Diels-Alder reaction

Organic secondary amines can catalyse certain Diels-Alder reactions. The reaction proceeds via the formation of an iminium species. This charged species lowers the energy of the LUMO thus catalysing the reaction In addition one face of dienophile is blocked thus allowing the high selectivity

Application tio the total synthesis of the marine metabolite solanapyrone D, a phytotoxicpolyketide isolated from thefungus Altenaria solani

Strategies and Tactics in Organic Synthesis

An example of a hetero-Diels-Alder reactionThe aldehyde is the dienophile and the counterpart is a very electron rich diene. The amine catalyst acts as a Lewis acid via two hydrogen bonds

Tf= CF3SO2

Another hetero-Diels-Alder reaction. It looks very similar to the previous reaction but ...It is believed that only one hydrogen bond coordinates the aldehyde and the other is used to form a rigid chiral environment for the reaction

Strategies and Tactics in Organic Synthesis

Organic Photochemistry

Introduction:Photophysics, interaction of light with the matter and photostimulated processes.Interaction with atoms and with moleculesPhotophysical processes

Photochemistry:Photochemical processesOrganic photostimulated reactions:

Dissociation into radicalsDissociation into ions or “internal” electron transfer Intramolecular rearrangementPhotoisomerizationHydrogen atom abstraction

Photodimerization or photoadditionPhotosensitized reactionsPhotoionisation reactions

Miscellaneous reactionsPhotoreactivity of aromatic compoundsPhotochemistry of diazo- and azido compoundsPhotocleavable protecting groupsPhotopolimerizationChemoluminescence

4. Technical and experimental aspects.

A B+ A B ‡ products

A

∆heat

hν+ ( A )*

exited state

products

productsB

Thermally stimulated reactions

Photochemically stimulated reactions

transition state

Organic Photochemistry

Differences between thermally and photochemically st imulated reactions:1) Excited state has usually higher energy than transition state.2) Electrons in the excited state are in high energy molecular orbitals, so they are more

prone to react in comparison to that in bounding orbitals3) Different type of excited states are possible with different chemical behavior4) Electrons of different finctionalities can be excited by simple selecting the light

energy, thus specific reactions for specific functionalities are possible

Organic Photochemistry

Organic Photochemistry

Organic Photochemistry

. sen i = c1/c2 sen r

c1/c2=n21 refraction index

The energy of light does not match with the difference in energy between occupied and unoccupied atomic orbitalsor occupied bonding and unoccupied antibondingmolecular orbitals, i.e. there is no absorption of light by the matter. The light is reflected or refracted by the matter and these phenomena are governed by the laws of classic optical physics.

Organic Photochemistry

Irf /I0=(n21-1/ n21+1)2

Organic Photochemistry: photophysics processes

1) The electronic transition between orbitals must generate (absorption) or destroy (emission) a node

2) The transition moment must a determined value i.e.

different from 0 or ∞ 0 means no interaction of light

with electrons, ∞ means ionization process and not transition between orbitals.

Prerequisites for absorption and emission

Interaction of light with atoms

The energy of light matches with the energy gap between bonding and antibonding molecular orbital or atomic orbitals. In this case the energy is called resonant with the frequencies at which electrons oscillate in bonds and around nuclei. Typically these frequencies fall in the range of 10 15-1016 s-1 i.e. 200-700nm (visible and ultraviolet region). The interaction in such a caseforces the electron to oscillate resonantly with the electromagnetic radiation and its motion describes an orbital at higher energy. This process is pictured for a hydrogen atom for a transition of an electron from a 1s orbital to a 2p orbital, which occurs at 121.6 nm

1s

2s and 2p

3s, 3p, 3d

Organic Photochemistry

E

H

E

H

bond axis

σ molecular hydrogen orbital no node

light

light

σ molecular hydrogen orbital no node

bond axis

π -like molecular orbital one node

hν: 121.2nm

hν: 110.9nm

σ∗ molecular orbital one node

direction of light propagation perpendicular to molecular axis

direction of light propagation parallel to molecular axis

Interaction with molecules

photophysics

singlet(spins paired)

electron jumpspin allowed absorption

spin forbidden absorptionelectron jump

and spin flip

electron jump

electron jump

and spin flip

triplet(spins parallel)

singlet(spins paired)

singlet(spins paired)

excited stateground state

hν, fluorescence

hν, phosphorescence

Energy level description of absorption and emission. The arrows indicate electrons and the spin orientation; wavy arrows indicate photons

S0 S1

ψ*

ψ

ψ

ψ*ψ*

ψT1

S1

S0

kST

kICkF kP

S0 T1

kRS

kRT

fluo

resc

enc

e

int e

rnal

con

vers

i on

sing

let-

sing

let

abso

rptio

n

sing

let-

trip

let a

bso

rptio

n

phos

phor

esce

nce

inte

r sys

t em

cr o

ssin

g

i nte

r sys

tem

cro

ssi n

g

sing

let r

eact

i on

tri p

l et r

eact

ion

State energy diagram

Organic Photochemistry

Possible transition Possible processes

photophysics

Organic Photochemistry

Vibrational levelDifferently from single atoms, in molecules atoms in a bond vibrate from their equilibrium position, thus the ground electronic state is splitted into vibrational modes

Bonds are usually described as spring connection atoms. Under this description, the bond energy is related to spring force k by Hooke law E= 1/2kr2

photophysics

Organic Photochemistry

Lennard-Jones curve for real moleculeVibrational level

Eυ = hν (ν +1/2)

photophysics

Intensity of absorption band follows the Franck-Condon principle which states:The electronic transition starts from the

lowest ν0 vibration state and the intensity is related to the sign and value of the function describing the vibrational state in the ground state and the arriving vibrational mode in the excited state.The transitions are describe by vertical lines and this because during the transition, which is very fast, negligible movement of atoms from their equilibrium position is observed

Ground and excited state Lennard-Jones curve

Organic Photochemistry Absorption bands photophysics

Organic Photochemistry

Radiative relaxing processes From the excited state:Fluorescence and phosphorescence

Vibrationalmodes

Radiative processes occur fromThe lowest vibrational state of theexcite state: Kasha rule

photophysics

Organic PhotochemistryAbsorption and emission band structure and energy

In atoms absorption and emission bands have the same energy since only atomic orbital are involved. In molecules due to the presence of vibrational modes and to Kasha rule, the emission is at lower energy with respect to absorption

absorption emission

emissionabsorption

λ

E

distint vibrationalstates in molecules

unresolted vibrationalstates in molecules

emissionabsorption

λ

E

absorption emission

emissionabsorption

λ

E

Atoms

E

λ

a

b

c

a: sharp line absorption and emission spectrum typical of atoms at low pressure vapor phaseb:broad-band absorption and emission spectrum typical of certain rigid molecule at low pressure vapor phase with resolted vibrational bandsc:broad-band absorption and emission spectrum typical of molecule in solution with unresolted vibrational bands

photophysics

Organic Photochemistry

Time scale of photophysical

processes

photophysics

Organic Photochemistry

photophysics

More important Photophysical processes

S0 ground state S0

S2

S0ν'

T1

2nd excited singlet state

1st excited singlet state

1st excited triplet state

quantized rrotational level

quantized ν vibrational level

abso

rptio

n to

2nd

exc

ited

sing

let s

tate

abso

rptio

n to

1st e

xcite

d si

ngle

t sta

te

S1ν

S2ν

IC2

IC1

ISC1

T1ν

S0ν

phosphorescence

fluorescence

Jablonski Diagram: solid lines are radiative transition; wave lines are radiationless processes: vertical are vibratioan and rotational relaxation processes; horizontal IC: internal conversion, ISC: intersystem crossing

Exctited states and photophysical transitions between these states in a "typical" organic molecule

ISC2

S1

Organic Photochemistry

Jablonski Diagram

photophysics

Organic Photochemistry: photochemical processes

Photophysical radiative process (fluorescence and phosphorescence) rates span from 10-15 to 1 sec, so only ultrafast reactions can be observed from singlet states. Fast chemical reaction can be competitive with radiative process from triplet states

Organic Photochemistry: photochemical processes

The first law of photochemistry formulated by Grotthus (1817) and Draper (1843) in the early nineteenth century: Only the light which is absorbed by a molecule can be effective in producing photochemical change in the molecule. This law was then reformulated by Stark (1908-1912) and Einstein (1912-1913):The absorption of light by a molecule is a one-quantum process, so that the sum of all primary process quantum yields φ must be unity, that is ∑φi= 1, where φi is the quantum yield of the ith primary process.

A + hν → B

Φ = Molecules of B formed x unit of volume x unit time/quanta absorbed by A x unit of volume x unit time

Under the validity of photochemistry law proposed by Stark-Bodenstain it is possible to correlate the absorption of light to the characteristics of any absorbing material. This is well expressed by the Beer-Lambert law

T= I/I0 = 10-εεεεcl

Secondary chemical processes are all those started by the intermediates produced in the primary process. As an example in radical halogenation of alkane the primary process is the halogen-halogen bond fission and the subsequent radical halogenationof alkane occurs without light so in the dark. One halogen molecule bond fission produce many halogenated alkane molecules. In this case the quantum yield is>1

photochemistry

A= -log I/I 0 = εεεεcl

ENERGETIC CONSIDERATIONS

S1 T1

kcal/mol

electronic excitation

vibrationalexcitation

10

5

3000 nm

6000 nm

C-H streching

C=O streching

40

60

80

75

110

90

80

70

ketones

300nm

400nm

700nm

visible

ultraviolet

infrared

UV Lamps

Sun Light

violet

red

bond energy

O-O

C-I

C-Br

C-Cl

C-C

C-H

O-H

Organic Photochemistry: photochemical processes

photochemistry

photochemistry

ABC (S1) orABC (T1)

PRIMARY PHOTOCHEMICAL PROCESSES

C Dissociation into radicals

ACB Intramolecular rearrangement

ABC' (S1) orABC' (T1) ABC' (S0)

Photoisomerization

R-H (ABCH) R Hydrogen abstraction

(ABC)2 Photodimerization (photoaddition)ABC

D ABC + products Photosensitized reactions

ABC+ + e-

+

Photoionization

D ABC+ or - D- or ++ "External" electron transfer

AB+ or - C- or ++ "Internal" electron transfer

+

AB

Organic Photochemistry

Dissociation into radicals

Organic Photochemistry

ABC (S1 or T1) →→→→ AB . .C

[X-X]* →→→→ X. + X.; X =Cl or Br

[NO2]* →→→→ NO. + O.

[NOCl] * →→→→ NO. + Cl.

NO-Cl NOhν

+ Cl

H

H

- HCl

HNO

HONN-OH

chloro-chloro or bromo-bromo bond can be homolitically broken by irradiation with mercury or tungsten lamps and the generated halogen radicals are exploited in the halogenation of alkanes, while the nitrosil and chlororadicals photogenerated from excited NOCl are industrially used for transforming cyclohexane into cyclohenanoneoxima, a precursor of e-caprolactam

Photochemical behavior of carbonyl compounds

Dissociation into radicals

Ketones and aldehydes show two principal electronic transitions n→π* (excitation of an electron from oxygen nonbonding orbitalsto antibonding π* orbital) in the 280-330 nm range and π→π* transition (excitation of an electron from π bonding orbital to antibonding π* orbital) usually below 250 nm. The n→π* transitions (~300 nm) are the more convenient to stimulate a photochemical reaction. Singlet excited state photochemistry is generally observed in aliphatic aldehydes or ketones, while in aromatic ketones, such as benzophenone or acetophenone, triplet states are involved. Aromatic ketones are often used as excellent triplet sensitizers.

Organic Photochemistry

There are two main photochemical pathways from an excited carbonyl function:1) α-cleavage reaction, known as Norrish Type I cleavage reaction2) Norrish Type II photoelimination reaction

The Norrish Type I reaction dominates gas phase photochemistry of many aldehydes and ketones and is an homolitic carbon-carbonyl bond scission affording acyl radical and alkyl radical. The acyl radical collapses into carbon monoxide and alkyl radical; this latter reacts with another alkyl radical (generated in the first step) to give hydrocarbons. This process is less common in solution chemistry where hydrogen atom abstraction is usually the predominant process.

R-CHO + hνννν→→→→ R. .CO-H →→→→ H. + C=O + R. →→→→R-HR-CO-R’ + hνννν→→→→ R. .CO-R’ or R’ . .CO-R →→→→ R-R’ + C=O

Ph

Ph

hνPh

Ph-C=OO

diphenylindanone

O

Me

PhMeO2C

CN

Ph

C

O

Me

PhMeO2C

CN

Ph

Me

PhMeO2C

CN

Ph

1) hν

2) α-cleav.

3) -CO

R S R R

e.e. ca 100%d.e.>95%

enantiopure

Enanthioselective Norrish I, solid state reaction

Organic PhotochemistryDissociation into radicals

Norrish Type II photoelimination reaction :

formation of aldehydes and alkenes

R2CH-CR2CR2-CHO + hνννν →→→→ R2C=CR2 + CR2=CH-OH→→→→ CR2H-CHO

R2CH-CR2CR2-CO-R + hνννν →→→→ R2C=CR2 + CR2=CR-OH→→→→ CR2H-CO-R

O O

H

O

Hhν

O

Si(Me)3 H Si(Me)3

Ohν

MeOH

Examples in cyclic ketones

Organic Photochemistry

The a-cleavage reaction occurs also in other carbonyl compounds such as carboxylic acids, anhydrides and esters by irradiation around 220nm. In the case of carboxylic acids the main products are hydrocarbons, CO and CO2; anhydrides give carboxylic acids, ketenes and CO2 while esters afford alcohols, hydrocarbons, CO and CO2. It must be made clear that these processes occur employing high energy radiation so that normally they are absent or negligible in almost all photochemical reactions.

Dissociation into radicals

R CO-O-Hhν

R. +

.CO-O-H CO2 + R-H

R CO-O.

+ .H CO2 + R-H

Photochemistry of Carboxylic acids

R CO-O-R'hν

R. +

.CO-O-R' CO2 + R-R', R-R, R'-R'

R CO-O.

+ .R' CO2+ R-R', R-R, R'-R'

Photochemistry of Esters

Photochemistry of Anhydrides

R2CH-CO-O-CO-R'hν

R2CHCO2. + .

CO-R' CO2 + R2CH-R' + CO

R2C=C=O + R2CHCO2H

More attention must be devoted to molecules containing particular functional groups: E.g. diazo compounds decompose when irradiated at 320nm into carbenes loosing nitrogen (shown later). Alkylnitro compounds decompose into alkyl radical and nitrosyl radical (.NO2) or nitrous acid and alkenes. To avoid the use of nitromethane or nitroethane as photoreaction solvent, differently aromatic nitro derivatives are transformed into nitroso compounds loosing an atom of oxygen (oxene) when irradiated at 350-400 nm. When benzylic hydrogens are present in substituents in the ortho position to the nitro group, the photogenerated oxene inserts itself into the C-H benzylic bond. This latter photochemical process has been exploited in developing a new photolabile protecting group for carbonyl compounds and alcohols (shown later) and to measure (actinometry) the intensity of incident light on the photochemical system. For example, the 2-nitro-benzaldehyde (NBA) is transformed into 2-nitrosobenzoyc acid by irradiation at 350-400nm with 0.5 quantum yield. If the concentration of NBA (called actinometric compound) and the optical pathway of the exposed sample cell are sufficiently high to make the reaction rate approximately of zero order, the intensity of incident light is inversely proportional to the quantum yield (I0 = k0/φ). By plotting [NBA] against time a straight line is usually obtained with k0 slope and therefore it is possible to evaluate the intensity of incident light .(in the range of 350-400nm)

Organic PhotochemistryDissociation into radicals

H

NO2

O

O-H

NO

O

d[Act]

dt- =

NBA

I0 φ fI0= light intensityφ=quantum yieldf=fraction of absorbed light[Act]= concentration of NBA

f= (I0-I)/I0 or =1-I/I0 where I=absorbed light

from Lambert-Beer Lawlog(I0/I)=εl[Act]

f = 1-10-εl[Act] , thus Io=d[Act]

dt- x 1/φ x 1/(1-10-εl[Act] )

under the zero order condition Io=ko/φ, thus plotting [Act] vs a line is usually obtained with ko slope. If φ is known the intensity of incident light Io can be evaluated

Dissociation into ions or “internal” electron transf er

Organic Photochemistry

ABC (S1 or T1) →→→→ AB+ .C-

Two possible pathways can be active: 1) heterolitic bond scission with production of cations and anions:

Any possible reaction is related to the electrophilic or nucleophilic nature of photogenerated ions

2) Internal electron transfer without bond scission.

A typical example of the first type is observed in photolysis of leucocynides (triphenylacetonitriles such as Malachite Green or Crystal violet) in polar solvent where this scission produces triphenylmethyl carbocations and cyanide. Generally, variation of absorbing properties is observed in these processes. This phenomenon is called Photochromism

CN CNhν

R

R'

R"

R'

R

R"

polar solvents

Malachite green leucocianide, R=H, R'=R"=N(Me)2Crystal violet leucocianide, R= R'=R"=N(Me)2

NO

NO

hν1

hν2

colorlesscolored

Other photochromic systems:spiropyran–merocyanine dyes

Used in photochromatic lenses or optical memories

1) heterolitic bond scission with production of cati ons and anions:

Organic Photochemistry

Dissociation into ions or “internal” electron transf er

2) Internal electron transfer without bond scissio n.

This process is observed in olefins. In detail, from the excited S1 state of an olefin two possible pathways can be followed namely a true internal electron transfer giving a zwitterionic excited state (indicated by Z) or the expulsion of an electron affording a radical cation (termed as D±). The zwitterionic excited state can subsequently collapse into a radical cation by expulsion of an electron. Both these excited states, called Rydberg states, can react with nucleophiles or electrophileseventually present in the reaction medium

Z

radical cation excited state

zwitterionic excited state

Rydberg Stateshν

+ e-

S1

D± state needs the presence of electron accepting molecules.

CH CHAr Rhν

R'OHCH CH2Ar R

R'O

CH CHAr R

hνR'OH

R

R R

RR

Rhν

Z

strained trans cycloalkenes

R

R

H

ROH

+ R'O-

R

R

H

R'O

carboniumion

addition product

RH

R"-H+

products from alkyl and hydride migration

skeleton rearrangement

More stable zwitteronic excited state

Organic Photochemistry

2) Internal electron transfer without bond scissio n.

2) Internal electron transfer without bond scissio n.

Organic Photochemistry

Ph

Ph

Ph

Ph

Ph

Ph H

ROH

RO-Ph

Ph H

OR

PhH

Ph

PhH

PhRO-

OR30% 50%

Ph

hν, ROH

Ph-CO-Me

PhOR

via zwitterionic excited state Z

Ph

hν, ROH

Ph-CO-Me H

Ph

no addition product is formed

Intramolecular rearrangement:

Organic Photochemistry

ABC (S1 or T1) →→→→ ACB .

In this process, the excited state evolves by bond formation or breaking followed by internal rearrangement of the molecular skeleton. Electrocyclic reactions and sigmatropic rearrangements represent typical examples of this process. This process is generally observed in conjugated polyunsaturated systems and regulated by Woodward-Hoffman rules. In conjugated polyenes a photochemically stimulated electrocyclic reaction starts from their excited states. The process occurs stereospecifically and determines the observed stereochemistry in the final cycloadducts. When the electrocyclic reaction represents the primary photochemical process, the following selection rules generally hold: Rule1: The stereochemical pathway of photochemical electrocyclic ring opening is the same as for ring closure.Rule 2: photochemical electrocyclic reactions proceed via disrotatory pathways when the number of interacting electrons in the cyclicarray is 4q, where q is an integer.Rule 3: photochemical electrocyclic reactions proceed via conrotatory pathways when the number of interacting electrons in the cyclic array is 4q+2 (q is an integer). Conjugated dienes give cyclobutanes (4 electrons involved = 4q, i.e. q=1) by a disrotatory process while conjugated hexatrienes (6 electrons involved 4q+2, q=1) give cyclohexadienes by a conrotatory process

disrotatory ring closurephotochemically allowed

excited diene π*orbital

trans-trans trans cyclobutene

trans-cis-trans conrotatory ring closurephotochemically allowed

excited triene π*orbital

trans cyclohexadiene

Organic Photochemistry

Intramolecular rearrangement: Electrocyclic reactions

HO HO

HO

Provitamine D3

Vitamine D3

O

O

O

O

O

O

Dewar BenzenePb(OAc)4

Disrotatory ring closure: synthesis of Dewar benzene

Conrotatory ring opening: synthesis of provitamine D3

Organic Photochemistry

Intramolecular rearrangement: sigmatropic rearrangeme nts

These rearrangements or sigmatropic shifts involve a migration of a group or p-bond across an adjacent p-system. The type of activation (thermal or photochemical) and the stereochemistry can often be predicted by the Woodward-Hoffmann rules which are based on the total number of electrons (those in the p-system + those of single bonds) involved in the rearrangement process:4n electrons, the migration via supra-supra with retention is photochemically allowed from excited state (supra-antara, thermally allowed); 4n + 2 electrons, the migration via supra-antara with inversion is allowed from the excited state (supra-supra , thermally allowed).[1,3] supra-supra hydrogen or alkyl migration with retention

R

H1 H

H

H

R

H

H

H H1

4 electrons supra 1,3 shift retention

CN CN

Hhν

[1,5] hydrogen sigmatropic shift

C

H

[1,7] hydrogen sigmatropic shift

HH

6 electrons supra-antara 8 electrons supra-supra

Organic Photochemistry

Intramolecular rearrangement: sigmatropic rearrangeme ntsOther examples: [1,2]-sigmatropic rearrangement

[1,2] sigmatropic rearrangement (also known as di-π-methane rearrangement or Aza-di-π-methane rearrangements discovered by H. Zimmermann in the late sixties) where the migration of different groups from hydrogen is observed. This rearrangement is observed in 4,4-disubstituted cyclohexenones or related derivatives and generally occurs with high stereospecificity.

O

RR

1

2

345

RR

O

54

3

2hν

antarawith inversion

R

R

O

mechamism of migration

R=alkyl

X

ArAr

migration mechamism

Ar

Ar

X

Ar X

RX= O, C(Ph)2

Ph Ph

Ph

PhCO2Me

CO2Me

Ph Ph

Ph PhCO2Me

CO2Me

NPh

Ph O-COPh Ph Ph

N

O-COPh

hν, CH2Cl2

H

PhCO-Me

[1,2]-sigmatropic rearrangement in alicyclic compoun ds

mechamism of migration

Ph

Ph

Ph

Ph

COOMe

COOMe

Organic Photochemistry

Photoisomerization: ABC (S1 or T1) →→→→ ABC’ (S 1 or T1) →→→→ ABC’Excited molecules undergo internal rearrangements without any bond scission and produce a new spatial disposition of molecular constituting units.A classical photoisomeration reaction occurs in the photochemical cis-trans interconversion of alkenes. The formation of the lowest excited singlet state of simple alkenes arises from the allowed π-π* transition. This generally requires short wavelength irradiation extending to about 200 –210 nm. On irradiation, a photochemical steady state is established between the cis and trans isomers and this is usually more enriched in the cis isomer than that in the ground state. The composition of thisphotostationary state is correlated to the absorption properties of the two isomers, i.e. cis→trans and trans→cis quantum yieldsand the εcis and εtrans extinction coefficients, by the equation

εcis

εtrans

cis trans

trans cis

[trans]s[cis]s

=ΦΦ

Generally εtrans > εcis and, assuming the quantum yield of cis→trans ≈ trans→cis, the concentration [cis]s > [trans]s. The double bondisomerization is believed to involve an excited state where the two sp2 carbons are twisted 90° with respect to their position in the ground state. This state is referred to as p (perpendicular) geometry and its energy is settled at a minimum between that for singletand triplet excited states

a

b

a

b

cis

a

b

b

a

trans

a

b

a

bhν hν

p geometry

Ph

trans stilbenePh

H

H Ph

H

H

Ph

p geometry

Ph

Ph

H

Hcis stilbene

hν hν

The cis → trans isomerization plays an important role in vision processes where light promotes the transformation of cis retinal into trans retinal bonded to a lysine residue of opsine by an imine function. The adduct retinal-opsine is called rodopsine and three different rodopsines are present in the rods of the retina which absorb the blue, green and red components of white light enabling color vision

Organic Photochemistry

Photoisomerization:

CH3H3C

CH3

N

CH3

H

CH3H3C

CH3

N

CH3 H

11-cis retinal11-trans retinal

opsinehν

opsine

11-cis retinal + opsine

RODOPSINEvisual signal

11-trans retinal + opsine

isomerasi

Photoisomerization: enantioselective process

Organic Photochemistry

chiral sensitizer H

H H

H

e.e up to 53%

+

COOR*

COOR*R*OOC

R*OOC

chiral sensitizer

Photoisomerization in azo derivatives

N N

R

R

trans azo derivative

N N

R R

∆ N NR

R

cis azo derivative

N N

R

R

N2 + R2

N N

-N2

via singlet excited state

Ph2CON N

∆via triplet excited state

+

Azo group is another unsaturated system that undergoes photochemically induced trans-cis isomerization. Dramatic changes in absorption properties occurs during this isomerization, for example trans diarylazo compounds absorb in the visible region (coloured compounds) while the cis in the UV (white compounds). By thermal treatments, the cis isomer can be reconverted to the trans isomer or undergoes fragmentation with production of radicals which further evolve, losing nitrogen, into hydrocarbons.

XR

XR

Dewar like structure

X

R

X

Rhν

overall process

electrocyclic process [4e]

[1,3] shiftelectrocyclic process [4e]

hν or ∆

R

H X

cyclopropenyl-carbonyl derivative

[1,3] shift

[1,3] shifthν or ∆

Photoisomerization:

Organic Photochemistry

SR S

RS

Rhν

R

H S

or

NO

R

NO

NR

H O

orN

OR

hνR

Aromatic heterocycles undergo electrocyclicphotorearrangements that may be unified under two common primary processes that convert the excited singlet states into: bicyclic isomers via 4q electrocyclic reaction or a cyclopropene derivative via a [1,3] shift. Their subsequent thermal or photochemical rearrangements afford rearranged isomers of the starting heterocycle

For example 2-substituted thiophenes isomerize to 3-substituted ones, while isoxazoles to oxazolesunder irradiation

Photoisomerizations followed by oxidation: Synthesis of Helicenes.

Photoisomerization:

Organic Photochemistry

HH

H

H-H2

trans/cis

isomerization

electrocyclic reaction

oxidation

O2/J2

O2/J2

hexaelicene

phenantrene

dihydro-phenantrene

Application to the synthesis of hexaelicene

trans stilbene

cis stilbene

Hydrogen atom abstraction ABC (S1 o T1) + R-H→→→→ ABC-H + R .

Organic Photochemistry

From molecular singlet or triplet excited states hydrogen atom abstraction reaction can be observed. This reaction is quite common with carbonyl compounds where both singlet and triplet excited states show diradical character and are able to abstract hydrogen atoms either intramolecularly or intermolecularly from molecules possessing weak R-H bonds (called hydrogen donors). After the hydrogen abstraction step, the generated radical species are responsible for the observed chemical reactions.

Intramolecular hydrogen abstraction with the formation of cyclocarbinols (Yang reaction)The intramolecular hydrogen abstraction is very common when hydrogens are present at the g position to form a diradicalintermediate which evolves into cyclobutanols via intramolecular coupling of radical centres. Depending on the multiplicity of the excited state (singlet or triplet) and on the efficiency of intersystem crossing (from singlet to triplet), the diradical intermediate can be singlet or triplet in nature and this reflects on the timing of cyclobutane ring formation: very fast from singlet, slow from triplet

R

O

H

HH R

OH

H

Hhν

R

HO

HH

ROH

HH

singlet or triplet carbonyl excited state hydrogen migration from γ

position

1,4-diradical intermediate

cyclobutanolsradical coupling

R

O

H

R

OH

R

OH

singlet or triplet carbonyl excited state hydrogen migration from γ

position

cyclobutanols

R

OH

R

OHOHR

cyclohexanols

O

CH3

RHO

CH2

R

HO

H2C

Rpregnan-11-one

diradical intermediate

Ph

O

O

H

Ph

OH

O Ph

OH O

Ph

O

Ph

OH

Ph

OH

diradical intemediate

+

diradical intemediate

unstable enol

Ph

O

+

An interesting example of this reaction is reported in stereoid chemistry where a angular methyl is involved in the hydrogen abstraction process which becomes included in a cyclobutane ring. The carbonyl group of ester function can be involved in hydrogen abstraction. In the following example the migration of the double bond is observed after hydrogen abstraction affordingβ,γ-unsaturared esters. The structure of carbonyl compounds strongly influence the course of reaction. In special cases the fragmentation of the molecule represents the main process as in the formation of α-cyclopropyloxyacephenone or decalinederivatives

Organic PhotochemistryIntramolecular hydrogen atom abstraction

OEt

O

H

OEt

OH

OEt

OH

OEt

O

diradicalintermediate

unstable enol

N

S

O

O

O O

COOMe

H

N

S

OH

O

O O

COOMeN

SOH

O

O O

COOMe

N

O

O SCH2H

N

O

O SCH2

N

O

HO SCH2

O

H

CO(CH2)5

O

R

OCO(CH2)5

OH

R

OCO(CH2)5

OH

R

penicillin derivative (β-lactam)diradical

diradical

80%hν

9-membered ring

14-membered ring

diradical

The hydrogen abstraction can occur also at 4 and more carbon atoms far from the carbonyl oxygen atom. In this latter case fused polycyclic derivatives and macrocycles (up to 14-membered rings) can be obtained. Significant examples of these type are reported in the field of steroid, ftalimido and β-lactam derivatives

Organic Photochemistry

H H

O OH

H

OH

H

hν+

42% 10%

In cyclic ketones, the hydrogens in the γ position are physically inaccessible to the carbonyl oxygen thus the abstraction occurs across the ring from a carbon which results in close proximity to the excited carbonyl function. For example the irradiation of cyclodecalone at 254nm affords the isomeric decanols, respectively in 42 and 10% yields

Intramolecular hydrogen atom abstraction: other examples

Organic Photochemistry

Hydrogen abstraction can also be performed a stereoselective manner. For example the enantioselective hydrogen abstraction at the δ in cyclic urea affords via a Norrish-Yang cyclization bicyclicderivatives in good enantio and diastereoselection. The strong hydrogen bonding between the substrate and a chiraltemplate forces the ring closure at the diradical species to occur from the Reface of carbonyl function and cyclic urea ring. The Si face of carbonyl is less favoured by steric interaction with benzoisoxazole moiety of the chiraltemplate

NHN

O

PhOH

NHN

O

PhHONHN

O

Ph OHH

toluene

SR

endo adduct

exo adduct

yields up to 80%e.e up to 60%exo/endo up to 4:1 NHN

O

PhHOH

NHN

O

PhHOH

RS

SS

NHN

O

PhHOHS

S

+

+

N

ON

OH

N

NH

O

Ph

HO

Re face

exo with respect to

N

ON

OH

N

NH

O

Ph

OH

Re face

endo with respect to

Si face

origin of stereoselection

steric intraction

exo adduct endo adduct

N

O

OCOOMe

N

OH

OCOOMe

HN

OH

OCOOMe

hνIf the Norrish type II and Yang reaction are not allowed for structural reasons, as in the case of phtalimmido derivative of valine, a photoreduction of the carbonyl function can be observed.

Stereoselective intramolecular hydrogen atom abstraction

O

Ph

CH2H

OH

Ph

CH2

OH

Ph

CH2 unstable enoldiene trapped by Diels-Alder reaction

HO Ph

COOEt

COOEt

EtOOC COOEt

diradical

In some particular (substituted compounds) for example ortho-methyl benzophenones, the intramolecular hydrogen abstraction can involve the methyl group producing a diene intermediate (via photogenerated diradical) which can be involved in Diels-Alder [4+2]-cycloaddition reaction acetilenic dienophiles to produce dihydronaphtalene derivatives

Organic PhotochemistryIntramolecular hydrogen atom abstraction, particular cases

Organic PhotochemistryIntermolecular hydrogen atom abstraction

Hydrogen abstraction occurs also intermolecularly. In this case the presence of good hydrogen donor molecules is needed or molecules with X-H bond energy lower than the energy of carbonyl excited states (exothermic reaction). A n→π* electronic transition is of about 70-75 kcal/mole thus suitable hydrogen donors are tertiary C-H in the isopropanol, O-H bond of phenols and Sn-H bond in tin hydrides. The energy of aliphatic C-H, aromatic C-H bonds and O-H of aliphatic alcohols is too high to be used as hydrogen donors

∆H<0

∆H>0

O π*

triplet state

H X

70-75 kcal/mol

n π*

OH

+ X

exothermic reaction

endothermic reactionRCH2O

RCH2

O

OH

R3Sn

Qualitative comparison of the energetics for hydrogen abstraction from different hydrogen donors by triplet state of alkyl or aryl ketones

Ph Ph

O

Ph

Ph

HO

Ph

Ph

OH

isopropanol

Ph Ph

O

T1: tripket excited statewith diradical behavior

Ph Ph

OH

dimerizationMe

OH

Me

H

hνPh2C=OH-Donor

Ph

PhOH

CH

NPh R

CH

NPh R +

Ph

PhO

HC

HNPh R+

HC

HNPh R

CH

HNPh R

95%

N NPh

PhHN NH

Ph

Ph

Ph N

N NH

Ph

PhOH

Me

Me

+

O

O

OH

Me

Me

+Ph N

O

OH

Ph N

H

H

IPA

IPA

Isopropanol (IPA) is used as hydrogen source in manyother photoreduction reactions. As an examplephenylazobenzene and nitrobenzene respectivelyundergo reduction to hydrazines and primary amines

Aromatic aldimines undergo a similar photoreductivedimerization reaction. In this case the final product is a 1,2-diamino derivative obtained generally in high yields. Isopropanol is used both as hydrogen source and solvent.

A didactic example of this reaction is the photoreductivedimerization of benzophenone to benzopinacol where the reaction is performed in isopropanol as solvent and as hydrogen donor. The benzopinacol is produced by coupling of two α-hydroxy radicals produced in the hydrogen abstraction step. The reaction is completely inhibited in the presence of catalytic amounts of triplet quencher such as naphthalene

Organic PhotochemistryIntermolecular hydrogen atom abstraction

Organic PhotochemistryHydrogen atom abstraction intermolecular process: p hoto-Friedel-Craft of quinones

For the formation of the acylated photoproducts, two limiting mechanisms have been proposed:in-cage scenario proposed by Schenck and

Maruyamafree-radical mechanism suggested by Moore. This

latter was confirmed by trapping experiments with styrene and 1,1-diphenylethylene. In 1,2-naphthoquinone both in-cage and out-of-cage mechanism operated more or less simultaneously, depending on the specific reaction conditions (temperature, solvent, quinone or aldehydeapplied). In some cases O-acylated products are observed and a possible explanation involve electron transfer processes from acyl radical to quinone with to formation od quinone radical anion and acylcation.

6 7

O

O

O

OH

Ph-C=O

3Q

Photodimerization or photoaddition: ABC (S 1 o T1) →→→→ (ABC) 2

Processes where excited molecules react giving dimericadducts. The [2+2] cycloaddition reaction represents one of the most important examples of photodimerization, it can occur between two C=C bonds and give cyclobutanes or between C=C and a C=O bond to give oxetanes (Paternò-Büchi reaction) . From the Woodward-Hoffmann based orbital symmetry rules, these reactions are only photochemically allowed and it is assumed that the HOMO excited π* orbital symmetry of a double bond matches with that of the LUMO ground state π* orbital of the others

HOMO excited π∗ orbital

LUMO ground state π∗ orbital

cyclobutane

Me

Me

MeMe

φ=0,5

2

2

Me Me

MeMe

Me

MeMe

Me

+φ=0,04

φ=0,04Me Me

MeMe

Me MeMeMe

+

From the HOMO excited π* orbital, trans/cis double bond isomerization is also possible, thus the intermolecular [2+2] cycloadditionreactions occur with a low stereochemical control. In addition, the quantum yield for trans/cis isomezation is often higher than that for [2+2] cycloaddition so the distribution of stereoisomers is random

Ph

Ph

Me

Me

Me

Me

+

Ph

PhMe

Me

Me

Me95%hν

The nature of olefins plays an important role in discriminating the possible photo-adducts. For example from the photoreaction between trans-stilbene and tetramethylethylene affords only the mixed photoadduct in high yields and without trans/cis isomerization

Organic Photochemistry

Topochemical control of [2+2] cycloaddition reactions in solution

The selectivity of [2+2] photocycloaddition reactions can increase if the environment in which the reaction occurs has a specific geometry. A good example is represented by [2+2] photocycloaddition of trans-cinnamic-amide and paracyclophane-diaminewhich affords only one of all the possible stereoisomers. This stereochemical outcome is the result of two synergic effects: 1) the paracyclophane-template keeps the two double bonds of the cimmanic units at a correct distance to react and 2) avoids thetrans/cis isomerization. At the end of photocycloaddition the dimer of cinnamic acid is collected as a single diastereoisomer and the paracyclophane-diamine is collected in high yield and is recyclable

NH2

NH2

COClHN

HN

OC

OC

NH

HN

OC

OC

HOOC

HOOC

HCl

A

+ 2

+ A.2HCl

single diastereoisomer

hν; 78%

98%

Organic Photochemistry

Photodimerization or photoaddition

Topochemical control of [2+2] cycloaddition reactions in the solid state

Organic Photochemistry

Photodimerization or photoaddition

[2+2] cycloaddition reactions can occur in the solid state if the crystal packing is able to bring the distance between the two reacting double bonds below 4 Å. This situation is not easy to find and only limited cases are described in the literature. A representative example is the solid state photodimerization of 2,3,4,5,6,pentafluorofluoro-stilbene where perfluoroarene-areneπ-π interactions in the crystal are strong enough to force the distance of the double bonds below 4 Å. The transformation occurs in high yield (>90%) and with high stereoselection (controlled by crystalline packing forces)

F

F F

FF

H H

HH

H

F

FF

F F

HH

H H

Hperfluoroarene-arene π−π interaction

<4 Å

F

F F

FF

F

FF

F F

hνsolid state

Intramolecular [2+2] cycloaddition reactions

hνbenzene

Si(Me)2 Si(Me)2

65%

O O

OO

O O

OO

hνbenzene

sensitizer:

CN

CN

O O

OO

+

O

O OBz

O

OOBz

O

O R

O

O R

O

O

OBz

hν, 350nm

benzene

hν, 350nm

benzene

O

O

R

87%

R= H, 90%

R= CH2OBz, 92%

When both reacting double bonds are in the same molecule, the [2+2] cycloaddition reaction can occur intramolecularly affording bicyclic or polycyclcic derivatives. No stereocontrolis usually observed.

In some cases, the number of possible stereoisomers can be reduced by structural constrains. For example in furanone derivatives, the length of the side chain containing the double bond controls the regioselectivity of the [2+2] photocycloaddition. In fact, this changes completely by adding only a CH2 in the chain containing the double bond

Organic Photochemistry

Photodimerization or photoaddition

O

O

O

tetronic derivative

O

O

O

H

n

n

Et2O

n=1 yield 74%n=2 yield 71%

hν, 254 nm

[2+2] photocycloaddition can be performed in an enanthioselective manner and an example is reported in scheme 47, where the chiral template a is used to bind reversibly by hydrogen bonding to the substrate. The presence of an excess of chiral template ais needed to bind completely to the substrate to prevent the photochemical [2+2] photocyclization occurring on uncoordinated substrate. The chemical yields are high with enantiomeric excess over 90%. The length of the side chain containing the double bond controls the regioselectivity of the [2+2] photocycloaddition

NO

NO

HNO

NO

H N

H

O

N

H

O+

a 2.6 equiv.

On

On

NH

O

O

HH

NH

O

OH

H

hν, -60° Ctoluene

n = 1, 77%, e.e.>90%

hν, -60° Ctoluene

n = 2, 87%, e.e.>90%

Organic Photochemistry

Photodimerization or photoaddition

OCH2OH

HN

N

O

O

O

PO

O

O-

OCH2OH

O

PO

O

O-

N

NH

O

OO

HOH2C

HN

N

O

O

O

PO

O

O-

OCH2OH

O

PO

O

O-

N

NH

O

O

cyclobutanethymine

UV-damage

Photolyase

The formation of cyclobutane is a reversible reaction. This is extremely important in biological systems. It is known that damage of DNA occurring where dimerization of two thymine residues stimulated by UV light produces a thymine cyclobutane dimer. Photolyases an enzimatic system containing redox cofactor flavin (reduced photochemically at radical anion state), is able to promote stepwise cyclobutane ring opening repairing in this way the damaged DNA

Organic Photochemistry

Photodimerization or photoaddition

Organic Photochemistry

Photodimerization or photoaddition

triplet sensitizer

+

[2+2] adductscis/trans mixture

[4+2] adducts

triplet sensitizer

[2+2] adductscis/trans mixture

[4+2] adducts

+

hνdiantracene2

The photochemical outcome can be different in the presence of triplet sensitizers. Indeed, under this condition, [2+2] or/and [4+2] cycloaddition reactions are observed

Paternó Büchi reaction

Organic Photochemistry

Photodimerization or photoaddition

In this reaction the excited state of the carbonyl function is involved. Two different mechanisms can be followed: 1) the formation of an exciplex (i.e. a complex between the excited carbonyl function and the alkene) which collapses directly into oxetane or via the formation of a diradical species; 2) abstraction of an electron from the alkene with the formation of a radical anion and radical cation which collapse into oxetane via the formation of a diradical species

O*

carbonyl excited state

+

O O O

O*exciplex

diradical species

Organic Photochemistry

Photodimerization or photoaddition

The Paternò-Büchi reaction shows a certain level of regioselectivity. In fact, in the case of reaction of benzophenone with isobutene the isomer with vicinal quaternary carbon atoms is formed in a 9:1 ratio compared to that where the carbon atoms are separated by a CH2. This ratio can be explained considering the major stability of tertiary radicals in the diradical intermediate. Enolethers can be used as alkenes. Cis-trans isomerization goes with the [2+2] photocyclization and a mixture of oxetanes are formed as in the case of the reaction of acetone with a cis-1,2,dialkoxyalkene

Paternó Büchi reaction

Ph

Ph

O

Me

Me

+

OO

PhPh

MeMe

PhPh Me

Me+

Φ= 0.510%

90%

Me

Me

O

OR

+

RO

OOR

OR

OR

RO

mixture of cis and trans oxetane

trans isomer+

Me Me

O

PhPh Me

Me

O

Ph Ph

MeMe

diradical intermediate

diradical more stable than

O

MeOOC H

O

+

O

MeOOC H

O

O

MeOOC H

O

+hν

benzene

Ph

O

O(CH2)9

O

Ph

O

O

O(CH2)9

83%

The Paternò-Büchi reaction can also occur intramolecularly affording polycyclic derivatives

Furanes can be used as enolethers. In this latter case bicyclic derivatives are obtained with high regioselectivity (i.e. only the regioisomer with geminaloxygen is formed)

Organic Photochemistry

Photodimerization or photoaddition Paternó Büchi reaction: other examples

Chiral phenylglioxilic esters or reversible binding of alkene derivative to chiral template allow to perform diastereo and enanthioselective Paternò-Büchi reactions

N

O

OH hν, -10° C

toluene

56%, e.e.>90%

H

O

ON

O

O

HH

O

ONH

O

N

H

O

NO

O

H

HO

O

N

H

O

H

H

+

O

O

OR* O

O+

O

OOR*

O

Ohν

O*RO

O

O

O

+

major diastreoisomer

R*=

Organic Photochemistry

Photodimerization or photoaddition Paternó Büchi reaction: enantio and diastereoselective reactions

Organic Photochemistry

Photodimerization or photoaddition Paternó Büchi reaction of thioketonesThioketones undergo photoreaction analogous to ketones e.g. photoreduction and cycloaddition. A special feature of thioketones is that the reaction can also involve the S2 excited state. The photoreaction can be initiated both from S2 (π→π*) or T1 (n→π*). In absence of reacting substrates the thioketone dimerizes to 1,4-dithietane derivatives, while in the presence of alkenes [2+2] cycloaddition reaction occurs. The cycloaddition is stereospecific but not regiospecific from S2 and regiospecific but not stereospecific from T1. Because of the reactivity of S2 the reaction involving thioketones are wavelength dependent. Electron poor olefins seem more reactive with theS2 excited state affording thietanes, while T1

affords thietanes and 1,4-dithianes

SR

RS

SR

R

R

R

1,4-dithietane

SR

R

thietane

C=C

SPh

Ph hνS

Ph

Ph *

S2

SPh

Ph *

T1

SPh

Ph

S

S PhPh

PhPh

1,4-dithiane

C=C C=C C=C

Photosensitized reactions :ABC (S1 o T1) + D→→→→ ABC + products from excited state of the molecule D

Organic Photochemistry

This reaction is promoted by energy transfer from an excited molecule (sensitizer) to another which undergoes chemical transformation. Examplesof sensitized reactions have been analysed in the photodimerization or photoaddition and photoisomerization sections; here, attention is focused on photosensitized reactions involving the oxygen as reagent. Oxygen exists in nature in a triplet ground state. In this state, the oxygen is not particularly reactive as oxidazing agent or its reaction with molecules occurs with very slow reaction rates. Reactions are faster if oxygen is excited to its singlet state. Two singlet states are possible for oxygen: S1 or 1∆ state as commonly designated spectroscopically, the oxygen molecule is described O=O, while in its S2 or 1Σ state is described as a diradical species with paired electrons on two different π* molecular orbitals (termed πx* and πy* i.e. antibonding π* orbital along x and y axis). The two different singlet oxygen states show different chemical behaviour

πx* πy

*

πx* πy

* πx* πy

*

πx* πy

*

To

S1

S21Σ

1∆

electronicstate

spectroscopicdesignation

O O

O O

O O

diradical characterparamagnetic state

diradical characterparamagnetic state

Lewisstructure

O O

x

y z

O O

πx*

πy*

Singlet oxygen can be generated from triplet oxygen in many solvents by a broad variety of sensitizers and the more common are porphorhyns (usually tetraphenylporphyrine), Bengal rose and 1-cianonaphthalene. Typical organic reactions of singlet oxygen (both in its 1Σ and 1∆ excited state) are:

O O

J

JJ

Na+ -O

J

COO- Na+

Cl

Cl

Cl

Cl

Rosa Bengala sodium salt

HN

N

NH

N

tetraphenylporphyrine

CN

1-cianonaphtalene

1) [2+2] cycloaddition reactions with alkenes giving 1,2-dioxetanes or [4+2] Diels-Alder like reaction, with conjugated dienes such as for example cyclopentadiene, furane, thiophene, pyrroleor 9,10-diphenyl-antracene affording endoperoxides respectively typically from 1∆ singlet excited state (O=O behavior). 1,2-dioxetane derivatives decompose under irradiation or by heating into carbonyl derivatives by C-C scission; one of the carbonyl derivatives is in its excited state

O O

oxygen: 1O 1∆ excited state

O O

1,2 dioxetane

O O+

*

excited carbonyl derivative

hν or ∆

[2+2] cycloaddition

[4+2] cycloaddition

X

X

O

OX = CR2, O, S, N-R

1O2

Ph

Ph

1O2

Ph

Ph

OO;

Organic Photochemistry

Photosensitized reactions: singlet oxygen reactions

Oxygen sensitizers

2) allylic hydroperoxidation to give hydroperoxides; typically from O2 in its 1Σ excited state (diradicaloid nature). The mechanism can be described as an ene-type reaction. In general, the reactivity of an alkene in this reaction increases with alkyl substitution. Terminal alkenes usually do not react. If several allyl positions are present the hydrogen abstraction occurs from the side of the double bond that is more substituted (i.e bearing more alkyl substituents since statistically more allylic hydrogens are present)

Organic Photochemistry

Photosensitized reactions: singlet oxygen reactions

OH

O2, TPP, hν

OH OH

HOO HOO

+

OH

H

OO

oxygen singlet 1Σdiradicaloid character

SS O2, hν

1-cianonaphtalene

SS O

80%

Oxygen singlet is also involved in oxygen atom transfer photoreactions as for example in the oxidation of sulfide to sulfoxides or phosphines to phosphinoxides. The presence of 1-ciano-naphtalene as oxygen sensitizer is required

If singlet oxygen is deleterious for an organic reaction, oxygen must be excluded from the reaction mixture or its production inhibited using singlet oxygen quenchers. Suitable candidates for this aim are tertiary aliphatic amines and in particular 1,4-diazabicyclo[2,2,2]-octane (DABCO). In some cases phenols can be used. N

N

DABCO

Oxygen can also react in its natural triplet state. In this case the sensitizer must transfer its excitation to the substrate by a photoelectron transfer process (PET) into a radical cation. This latter is more prone to react with triplet oxygen (diradical nature). The oxidation potential of the substrate must be lower than that of the sensitizer.

Organic Photochemistry

Photosensitized reactions: triplet oxygen reactions

1Sens + hν → 1Sens* sensitizer excitation 1Sens* + A → Sens.���� +A + photoelectron transfer processA + + 3O2 → A-O-O+ reaction of radical cation of substrate with oxygenA-O-O+.���� + Sens.���� → Sens +AO2 (oxidized substrate)

In some reactions the radical anion of the sensitizer reacts with the triplet oxygen producing superoxide radical anion, which, in turn, reacts with the radical cation of the substrate.

Sens.���� + 3O2 → Sens + O2.- superoxide radical anion production

O2.- + A + → AO2 reaction of radical cation of substrate with superoxide radical anion

In other cases the triplet state of the sensitizer abstracts hydrogen from the substrate and the resulting radical of the substrate reacts with triplet oxygen affording a radical peroxide which can initiate a radical chain reaction.

1Sens + hν → 1Sens* sensitizer excitation1Sens → 3Sens* intersystem crossing process: evolution of singlet to triplet3Sens* + A-H → H-Sens. +A. Starting radical chain process (primary photochemical process)A. + 3O2 → A-O-O. reaction of radical cation of substrate with oxygen to give peroxiradical.A-O-O. A-H → A-O-O-H +A. reaction of peroxiradical with substrate with propagation of the radicalchain.

An example of the latter process is the transformation of benzaldehyde into perbenzoic acid by photolysis in presence of oxygen and benzophenone as triplet sensitizer

Ph2C=O Ph2C Ohν

triplet state

Ph C=O

H

+

Ph2C OH

Ph C=O+

radical chain initiation

Ph C=O

radical chain propagation

+ O2 Ph C=O

O-O

Ph C=O

H

Ph C=O

O-OH

Ph C=O+

radical chain termination

Ph C=O

O-O

+ Ph C=O

O-OH

Ph2C=O+ +

perbenzoic acid

Ph2C OH

Organic Photochemistry

Photosensitized reactions: triplet oxygen reactions

Photoionisation reactions:

Organic Photochemistry

ABC (S1 o T1)→→→→ ABC+ + e-

Process where an electron is removed from the molecule. This process is more common in metal or metal oxides and it is the basis of the photoelectric effect. In molecules this process is less common and requires light of high energy in the range of X or γ-ray. Ionization processes can occur in the stratosphere and it is responsible for the generation of radical chlorofluorohydrocarbons (freons) which are highly effective in removing ozone (triplet oxygen) from the atmosphere. In very electron rich aromatic substrates such as 1,2-dimethoxybenzene the abstraction of an electron is possible by irradiation with formation of an aromatic radical cation. This latter undergoes nucleophilic aromatic substitution in the presence of nucleophiles such as cyanide anion

OMe

OMe

OMe

OMe

OMe

CNhν, CN-

t-ButOH, H2Ohν

, -e

-

Processes where an electron jumps from an excited molecule to another in its ground state are more common. This process can produce both radical cation and a radical anion couple or cation or anion species and are called external electron transfer:

ABC (S1 o T1) + D→→→→ ABC .(+, -) + D.(-, +) radical speciesABC (S1 o T1) + D→→→→ ABC (+, -) + D(-, +)

Ph2C=O +Ar3N →→→→ Ph2C .-O - + Ar3N.+

λλλλmax 620nm λλλλmax 670nm

The external electron transfer between benzophenone and a triarylamine is a typical example. In this reaction the triplet state of the carbonyl compound removes an electron from the lone pair of nitrogen

When tertiary aliphatic amine are used, the ketyl radical anion further evolves by extracting a hydrogen from an alkyl substituent of the amine radical cation affording an α-hydroxybenzyl radical, which evolves into pinacols, and an amino radical and the whole process is the photoreduction of a carbonyl compound like that observed in presence of hydrogen donor

CH3

O

CH3

OH

2

pinacol

hν, (CH3CH2)3N

CH3

O

carbonyl excitedtriplet state

N(CH2CH3)3

electron transfer process

CH3

O H3C CH-NEt2

H

proton transfer process

CH3

OH

radical dimerization

Ohν

N(Et)3/EtOH 8:2

O

79%

Organic Photochemistry

Photoionisation reactions:

the photoinduced electron transfer from sacrificial triethylamine can be exploited in other photoreductive process such as cyclopropane and epoxide reduction

O

OO

OMe O

O OH

OMehν, N(Et)3

CH3CN

Ketyl radical anion

Photoinduced electron transfer reactions can be used to initiate radical reactions of alkenes. Two pathways are possible: oxidative leading to a radical cation, and reductive, leading to a radical anion. More common are oxidative processes (induced by the presence of 1,9-dicianoanthracene as electron acceptor) since alkenes are more easy to oxidize than to reduce

- e-+ e-

CN

CN

CN

CN

+ e-

oxidation process reduction process

electron acceptor

CN

CN

CN

CN

+ e-

electron acceptor

O

SiMe3

COOEt

O

SiMe3

COOEt

- e-

COOEt

O

An example of this type is the photooxidation of enol silylether of cyclopentanone bearing a dimethylbutenylsubstituent in a position. The photogenerated radical of 9,10-diciano-anthracene is intercepted intramolecularlyby the double bond affording a bicyclic derivative

Ph

*olefin excited state

+ R-CNelectron

transfer

Ph

+ [R-CN]

D

ROH

Ph

O

R

H+ [R-CN]

Ph

O

R

H- RCN

Ph

O

R

H

Aromatic nitriles are generally employed to interceptthe zwitterionic S1 excited state of an olefin. The removal of an electron generates a radical cationable to react with nucleophiles such as alcoholsaffording the corresponding addition product. THislatter is different from that obtained from the photolysis in absence of nitrile and involving the D±Rydberg state ionic pair of an excited alkene

Organic PhotochemistryPhotoionisation reactions:

Miscellaneous

Photoreactivity of aromatic compounds

Dewar benzene

hν203 nm

hν254 nm

+

benzvalene fulvalene

Aromatic compounds are usually unreactive under photochemical conditions and normally used as reaction solvent (e.g. toluene or benzene). However for prolonged irradiation in the UV spectrum (200÷254nm where the aromatic compounds show strong absorption bands) certain reactivity can be observed. The reactivity of aromatic compounds arises from changes in the electron distribution in the excited state. For example, if benzene is irradiated with light of 254 nm small amounts of benzvalene and fulvene are formed, while if the irradiation is performed at 203 nm, the formation of Dewar benzene is observed

Some functionalized benzene derivatives show a more prone photoreactivity. For example the 1,4-dimethoxybenzene gives [2+2] cycloaddition in reaction with acrylonitrile affording the corresponding cyclobutane derivatives in high yield

OMe

MeO

CN

+hν, 254nm

low pressureHg lamps

OMe

MeO

CN

95%

Organic Photochemistry

Photoinduced aromatic substitution reactions

The reactivity of aromatic compounds changes dramatically under photochemical conditions. The nucleophilic aromatic substitution follows a different pathway from that occurring under thermal conditions. For example, 3,4-dimethoxy, 1-nitro benzene undergoes, as expected, thermal nucleophilic substitution of the para-methoxy group with OH-, while the methoxy group in meta position is substituted under photochemical condition. This is one of differentiating aspects of photochemical reactivity from thermal reactivity

OMe

NO2

OMe

electron withdrawinggroup

OMe

NO2

OH

OH

NO2

OMe

∆, OH-

hν, OH-

thermal:para-orientation

Photochemical:meta-orientation

The explanation of this different behavior can be found in the zwitterionic nature of the excited state of aromatic compounds when an electron withdrawing group is present. This foresees thelocalization of the negative charge on the carbon bearing the electron withdrawing group and the positive one localised in meta position as described by cyclopropane containing structures generated by a redistribution of π-electrons. In addition, in 3,4-dimethoxy 1-nitro benzene the positive charge in the meta position is stabilized by the electron donating methoxy group. Thus under photochemical conditions the charge distribution on the aromatic ring is the reverse of that of the ground state (where the meta position is less electron rich). The reverse is also observed in the chemical behaviour to nucleophilic substitution

W

electron withdrawinggroup

resonant structures describing the aromatic π∗ excited state

W W

Organic Photochemistry

Photoreactivity of aromatic compounds

Under photochemical conditions it is possible to carry out nucleophilic substitution even on electron rich halogen aromatic compounds. In some cases the reaction occurs by homolitic scission of the C-halogen bond generating an aryl radical which reacts with the nucleophile

OMe

Cl

hν, CN-

electron releasing group

OMe

CNOMe

Cl

CN-

In other cases the nucleophilic substitution follows a different mechanism especially when negative charged nucleophiles are employed. In a first step, the nucloephilicsubstitution is promoted by the photostimulated transfer of an electron from the nucleophile to the aromatic with the formation of an aromatic radical anion. This undergoes C-halogen bond scission with formation of an aryl radical which reacts with the starting nucleophile affording a new aromatic radical anion. The latter subsequently transfers an electron to the starting aromatic substrate propagating the aromatic nucleophilc substitution. This type of aromatic substitution is called monomolecular radical nucleophilcaromatic substitution or SRN1. Bromo and iodo arenes are the suitable substrates and the reaction tolerates alkoxyand acyl substituents. Good nucleophiles in this type of reactions are: ketone enolates, β-diketone enolates, dialkylphosphite anions and thiolates.

X

X = Br, I

+ Nu- hν

X

+ Nu-

NuNuhν, Nu- Ph-X

-X-

Nu-

Organic Photochemistry

Photoreactivity of aromatic compounds

Photoinduced nucleophilic aromatic substitution reactions

In naphtalenic substrates only the nucleophilic substitution at the α-position is observed independently of the nature of substituentspresent on the aromatic nucleus

Organic Photochemistry

Photoreactivity of aromatic compounds

Photoinduced nucleophilic aromatic substitution reactions

O2N

NO2

H

OMe

hν, OH-

O2N

OH

hν, CN-

CN

OMe

100% α-substitution

The photolysis of esters of phenols and amides of anilines produces the cleavage of C-O or C-N bond followed by a [1,3] or [1,5] acyl shift, called photo-Fries reaction, affording ortho or para acylated derivatives

Organic Photochemistry

Miscellaneous

XR

O hν

photo-FriesXH

RO

XHR

O

X= O, NH

hν α-cleavage

XR

O X

O

H

XR

O Hrecombination

+

+

tautomerization

R

If the ortho position is blocked by substituents only the [1,6] acyl rearrangement can be observed. An interesting application of an intramolecular photo-Fries has been devised to generate paracyclophanes

N

O

(CH2)11

Me

Me

N

O

(CH2)11

Me

Me

NHO

(CH2)11

Me

Me

paracyclophane derivative

hν [1,6] shift

Photochemistry of diazo- and azido compounds

Organic Photochemistry

Miscellaneous

The most characteristic photoreaction of diazo and azido compounds is photoelimination of a molecule of N2 followed by reaction of the resulting carbene and nitrene. Using the Wigner spin rule, i.e spin conservation in a elemental chemical step: from a singlet excited state singlet carbene or nitrenes are generated while triplet carbene or nitrene from triplet exited states. Singlet carbene or nitrene show a zwitterionic nature and diradicaloid in their triplet states. The reactivity reflects the singlet or triplet nature of these species. Typical reactions of singlet states are: 1,2 sigmatropic shift with formation of a double bond; stereospecific insertion into σ-bonds; stereospecific insertion into π-bonds; addition of a nucleophile or (less commonly) an electrophile. Typical reaction of triplet states are: atom abstraction reaction with production of radicals; nonstereospecific addition to insertion into π-bonds; addition of radicals or radical-like substrates. The presence of sensitizers (benzophenone) is needed in the photochemical production of triplet excited states of diazo or azido compounds

R

R

N N

R

R

N N

hν R

R

RCR

triplet

RC

R

singlet

R

Rdiradicaloid character

RC

R

zwitterioniccharacter

- N2

R N N N

R N N N

- N2

NR

triplet

NR

singlet

NRzwitterioniccharacter

NR

diradicaloid character

diazo compound

azide

As an example, the reaction of diphenylcarbene (photogenerated from diphenyldiazomethane) in the presence of isopropanol affords different products in relation to its electronic state: diphenyl-isopropylether from singlet state (reaction as zwitterionic character) and diphenyl-methane and acetone from triplet state (diradicaloid state)

Ph

PhN N

PhC

Ph

PhC

Ph

singlet zwitterionic nature

triplet diradicaloid nature

Me

MeHO+

Me

MeOH

PhC

Ph

PhC

Ph Me

MeOH Ph

CHPh Me

MeO

HPh

CHPh

Me

MeOH

Me

MeO

PhCH2

Ph+ +

CH2N2

hνvia singlet carbene

+ via triplet carbene

hν,Ph2CO

Difference in chemical behaviour is also observed in reactions of carbenes with double bonds. For example singlet photogenerated carbene from diazomethane adds in a stereospecific manner to cis2-butene affording a single cyclopropane derivative, while triplet carbene (photoproduced from diazomethane in the presence of benzophenone as triplet sensitiser) affords a mixture of two possible stereoisomers

Organic Photochemistry

Photochemistry of diazo- and azido compounds

Diazoketones are photodecomposed to singlet ketocarbene which, in turn, undergoes Wolff [1,2] rearrangement to ketenes captured by nucleophiles such as alcohols to give esters, while triplet ketocarbene cannot undergo Wolff rearrangement without violation of Wigner spin rule thus normally evolves to methylketone by hydrogen abstraction

CHN2

hν,Ph2CO

PhCO

(Me)2CH-OH

Ph CH

O

Ph CH

O

singlet

tripletdiradicaloid behavior

(Me)2CH-OHPhCO-O-CH(Me)2

PhCOCH3via hydrogen abstraction

PhCH=C=Oketene

[1,2]

Wolffrearr.

Acylazides are photodecomposed to acylnitreneswhich do not undergo Curtius rearrangement to isocianate as occurs under thermal conditions, but give insertion reactions in C-H or in double bonds

H3C

OMe

CO-N3

H3C

OMe

CO-N

CH2

OMe

CO

HN

insertion

acylnitrene

N3

Phhν

NPh

Organic Photochemistry

Photochemistry of diazo- and azido compounds

Photocleavable protecting groups

Organic Photochemistry

Protecting groups are often a necessity in organic synthesis along with all the drawbacks associated with their use as for example the fact that their introduction and cleavage require two synthetic steps and introduce complications to the synthetic plan by theirincompatibility with some organic reagents. The complication increases rapidly with the number of different protecting groups on the same molecule. The conditions necessary for their cleavage have to be very specific for a given group in order to leave intact all the others (the so-called “orthogonality”). Photolabile protecting groups bring an interesting feature: they do not require any reagent for their cleavage, just light. This category of protecting groups opens the possibility of dealing with extremely sensitive molecules, otherwise incompatible with acids or bases.

o-nitrobenzylic derivatives

The most popular photolabile protecting groups are based on o-nitrobenzyl derivatives which undergo a photochemically-induced photoisomerisation into o-nitrosobenzaldehyde. The mechanism is: the excited triplet state of the nitro function abstracts a hydrogen from the ortho benzylic carbon atom, subsequently the so formed diradical species evolves into a cyclic acetal derivative whose hydrolysis yields o-nitrosobenzaldehyde liberating the moiety X bounded (bonded) to the benzylic carbon atom in high or quantitative yields

NO2

X

N

X

O

O

N

X

OH

ON

X

O

OH

N

X

OH

O

N

CHO

O+ X-H

hydrogenabstraction

acetalicfunction hydrolysisN

X

OH

O

Different functionalities can be protected by this group such as for example nitrogen of heterocycles or hydroxy functionalities.The N-(o-nitrobenzyl) protecting group of the imidazole side-chain of histidine is removed quantitative yields giving back histidinewithout any racemisation: The tertButhoxycarbamoyl (BOC) nitrogen protection is stable under photolysis conditions

NO2

N

CHO

Ohν

N

OH

O

N

N

NH-Boc

COOH

imidazole protected histidine

N

N

NH-Boc

COOHN

N

NH-Boc

COOH

H

+100%

The ortho-Nitrobenzyl alcohol derivatives were used for the protection of the phosphate group in nucleotide synthesis. Both protection and deprotection occur very efficiently

NO2

O

phosphate protectedmotiety

P2

O

OH

PCl5NO2

O P2

O

Cl

ThyO

OAc

HO+

NO2

O P2

O

ThyO

OAc

O

>305 nm70%

HO P

O

ThyO

OAc

OHO

Organic Photochemistry

Photocleavable protecting groups

Orthogonal photolabile groups i.e. group which can be removed using light of different wavelength.

Organic Photochemistry

Photocleavable protecting groups

NO2

O

MeO

MeO

HN

O

COOH

R

Nitroveratroyloxycarbonyl protecting group (NVOC)

NO2

OHN

O

COOH

R

Nitrobenzyloxycarbonyl protecting group (NBOC)

hν, 350nm

- CO2

NO2

O

MeO

MeOH2N COOH

R

+H

The 6-nitroveratroyloxycarbonyl group (NVOC) is undisputedly the most popular and used photolabile protecting group for the amino function in amino-acids. The two methoxy groups were introduced to increase the absorbance at wavelengths longer than 320 nm. Under these conditions, even the tryptophan, one of the most light-sensitive compounds, is not affected The simpler ortho-nitro-benzyloxycarbonyl group (NBOC) is normally used with less light sensitive substrates

O2N

R

R

OHO

HOOH

O

OH

R= H, OMe

OHO

HOOH

OH

OH

quant.

hν, 260nm

Both NVOC and NBOC groups can be used for the protection of the hydroxygroups in carbohydrate chemistry. For example, the hemiacetalic form of glucose can be protected as a mixed acetal. Photolysis gives quantitative yields of glucose, with both types of photolabilegroups

Organic Photochemistry

Photocleavable protecting groups

The 1-(2-nitrophenyl)ethylenglicole can be effectively used in the protection of the carbonyl function of ketones.

NO2

OH

OH

R1 R2

O+

TsOH/PhH

- H2O

70-97%

NO2

O

OR2

R1

N

O

OR2

R1

O

OH

hν, 350 nmPhH

31-90%

NO

O

OH

R1 R2

O+

Organic Photochemistry

Photocleavable protecting groups

Benzophenone as photooxidantThe N-(2-acetoxyethyl) group (introduced by alkylation of an amine with 2-acetoxyethyl bromide) can be used as amine protecting photolabile group. The deprotection requires a stoichiometric amount of 4,4 -dimethoxybenzophenone (the electron acceptor), and irradiation at 350 nm. The deprotection follows an external electron transfer process

NR2

R1

O-Ac

O

OMeMeO

+

NR2

R1

O-Ac

O

OMeMeO

hν, 350 nm external electron transfer process

MeCN/H2O

NHR2

R1

OH

OMeMeO

+

Organic Photochemistry

Photocleavable protecting groups

Benzyl alcohol derivatives

R

O

O

HN COO-

R1

R

+

-O

O

HN COO-

R1

hν254 nm

H2O

- CO2

RH3N COO-

R1OH

+

Organic Photochemistry

Photocleavable protecting groups

The N-benzyloxycarbonyl (Cbz) amino protecting group is usually removed by hydrogenolysis but it is found that its cleavage can be performed in significant chemical yields (~ 70%) by a photosolvolysis process upon irradiation at 254 nm. A heterolyticmechanism of C-O bond scission has been proposed with formation of benzylic carbocation and carbammic acid anion. In the presence of water both these intermediates evolve into benzylic alcohol and amine with evolution of CO2. The presence of electron-releasing groups on the aromatic ring or of water in the reaction medium increases the quantum yield of the deprotection reaction

Thiohydroxamate derivatives

Thiohydroxamate derivatives of carboxylic acids can be regarded as protecting groups of a C-H bond. The deprotection reaction requires the use of an external hydrogen donor agent such as Bu3SnH, TMS3SiH or t-BuSH. Thiohydroxamate derivatives are also used as traceless linkers in solid state synthesis

S N

SOH

O

R

MeS N

SO O

RMe

S N

SH

Me

+ CO2 + R-H

hydrogendonor X-H

OH+Couplingreagent

S N

SO

Me

O

NMe

thiohydroxamic acid

Ohν, 350 nm

hydrogendonor

NMeMe

S N

SH

Me

O

+

Organic Photochemistry

Photocleavable protecting groups

Photopolimerization

Organic Photochemistry

O

Me

X

O

Me

X

nphotoinitiator

methaacrylate derivative

polymethylmethacrylate

Ph Ph

O

Ph

OPh

OMeMeO

photoinitiators

benzophenone

2,2-dimethoxy-2-phenyl-acetophenoneDMPA

The generation of radicals by homolitic bond scission or molecular excited states with radical character can be exploited to initiatepolymerization. Under irradiation benzophenone is excited to a triplet state with diradical nature and, as already seen in the previous sections, can stimulate many photochemical processes as well as be exploited as radical photoinitiator of polymerization processes. A recent application of this possibility is the surface modification of polypropylene microporous membranes by means of a polymeric layer with the aim of improving its hydrophilicity, permeation, hemocompatibilty and anti-fouling properties. This has been realized by photopolymerization of suitable methylacrylate induced by catalytic amounts of benzophenone as photoinitiator

Chemoluminescence

Chemoluminescence is a phenomenon that occurs when a sizeable amount of exothermicity (∆G) of a chemical reaction is converted into electronic excitation energy of a reaction product which then relaxes emitting light (hν). The most significant examples of chemoluminescence are:oxidation of luminol by oxygen under alkaline conditions. The treatment of luminal by NaOH transforms it into the corresponding dianion which reacts with oxygen producing an endoperoxide whose decomposition produces N2 and the triplet state of 3-aminopthalate. The light is emitted after intersystem crossing from the triplet state to the singlet

NH

N

NH3 O

Oluminol

N

N

NH2 O

O

N

N

NH2 O

O

O

O

O2

NH2 O

O

O

O

3

triplet excited state

intersystemcrossing

NH2 O

O

O

O

1

singlet excited state3-amino-phtalate3-amino-phtalate

NH2 O

O

O

OLight +

- N2

endoperoxide2 OH-

Organic Photochemistry

Bioluminescence observed in fireflies (Photinus pyralis) represents a particular and well know aspect of chemoluminescence. Bioluminescence requires a lumophore and an enzime system that acts as mediator of chemoluminescence step. The enzyme system (termed luciferase) associated with lumophore is called luciferin. Commonly a molecule of oxygen is also required and aquantum yield of 1 for chemoluminescence process has been measured. The decarboxylation of a peroxolactone is believed to be a key step in producing the excited intermediate whose relaxation occurs radiatively

S

N

HO

N

S

CO-OHH

lumophore

luciferase

ATPS

N

HO

N

S

CO-AMPH

+ P2O7-2

O2

S

N

HO

N

S

O

O

AMP

O

H

S

N

HO

N

S

O O

O

endoperoxide

S

N

HO

N

S

O

- CO2

*

excited lumophore

S

N

HO

N

S

O

+ Light

Organic Photochemistry

Chemoluminescence

One of the most efficient “synthetic” chemoluminescent systems (quantum yield Φ~0.25) involves the reaction of H2O2 with diphenylester of oxalic acid. A peroxydione intermediate (peranhydride of oxalic acid) decomposes into two CO2 molecules, one of which is in the excited state is believed to be at the basis of the chemoluminescence process. The excitation of CO2 is transferred to a suitable energy acceptor as for example Rubrene which, in turn, emits in the visible region (yellow green)

O O

OPhPhOH2O2+

O O

OOperoxydione

C

O

O

C

O

O

*

excited carbondioxydemolecule

+

Ph

Ph Ph

Ph

energy transfer toRubrene

excited Rubrene

*Ph

Ph Ph

Ph

Light +

Rubrene

Rubrene

Organic Photochemistry

Chemoluminescence

Technical and experimental aspects

Organic Photochemistry

In order to perform photochemical reactions correctly, safely, and with success, technical and experimental protocols and indications should be followed.1) Purity of starting materials. This is a prerequisite valid in general for any procedure in organic synthesis, but plays a particular and important role in photochemical reactions since the reactive species are photogenerated at very low concentration and can be captured or quenched by the presence of impurities.2) Before starting a photochemical reaction a UV/vis spectrum of the “photoactive” compound should be recorded. The “photoactive” compound is the electronically excited molecule which undergoes or initiates a primary photochemical process from its excited singlet or triplet state. From UV spectra recorded with different compound concentrations, allows to evaluate the extinction coefficients in the whole range of interest. The extinction coefficient gives an idea of the power of light source to be used: low extinction coefficient need high intense radiation to produce enough excited molecules. UV spectra of all reagents should be recorded to be sure that there is no or little interference in absorption with the “photoactive” compound. If available, a UV spectrum of the product should also be recorded. UV spectra from the reaction mixture may help to identify ground state interactions between the reagents or CT complexes, which can be useful as a guide to individuate the best reaction conditions.3) In principle, photochemical reactions can be performed in the gas phase, in solid state or in solution. For practical reasons most photochemical reactions are performed in solution, therefore the choice of the right solvent is critical. The solvent must be transparent or at least it must show a very low extinction coefficient in comparison with the “photoactive” compound. In fact, if the extinction coefficient of the “photoactive” compound is only 10 times higher than that of the solvent at the irradiation wavelength, a significant solvent filter effect can be observed with the consequence that the reaction is much slower than it could be. The solvent must be free of impurities (ethylendiamine tetracetic acid EDTA can be useful to remove, by complexation, trace metal ions). The solvent must, of course, dissolve the reactants. The polarity of the solvent plays an important role in stabilizing or destabilizing the ground and excited states of a molecule and consequently this reflects on their reactivity and on the energy needed for performing a photochemical reaction. In Table 2 the optical characteristics of some utilized solvents for photochemical reactions are reported, expressed by the cut off wavelength (lcutoff) together with the parameter normally used for valuating the solvent polarity (dielectric constant e and the Dimroth-Reichardt value). At longer wavelength than lcutoff the solvent can be considered completely transparent

Organic Photochemistry

Technical and experimental aspects

Solvent Cut-off wavelength nm εεεεT ET(30)

Water 185 78.30 63.1

acetonitrile 190 35.94 45.6

n-hexane 195 1.88 31.0

Ethanol 204 24.5 51.9

Methanol 205 32.66 55.4

Cyclohexane 215 2.02 30.9

Diethylether 215 4.20 34.5

1,4-dioxane 230 2.21 36.0

Methylene chloride 230 8.93 40.7

Chloroform 245 4.81 39.1

Tetrhydrofurane 245 7.58 37.5

Ethyl acetate 255 6.02 38.1

Acetic acid 250 6.17 51.7

Dimethylsulfoxide 277 46.45 45.1

Benzene 280 2.27 34.3

Toluene 285 2.38 33.9

Pyridine 305 12.91 40.5

Acetone 330 20.56 42.2

Solvent ET (kJ/mol)a Es (kJ/mol)b ΦΦΦΦISCc

Benzene 353 459 0.25

Toluene 346 445 0.53

Methyl benzoate 326 428 -

Acetone 332d 372 0.90/1.00d

Acetophenone 310 330 1.00

Xanthone 310 324 -

Benzaldehyde 301 323 1.00

Triphenylamine 291d 362 0.88

Benzophenone 287 316 1.00

Fluorine 282 397 0.22

Triphenylene 280 349 0.86

Biphenyl 274 418 0.84

Phenanthrene 260 346 0.73

Styrene 258 415 0.40

Naphtalene 253 385 0.75

2-acetylnaphtalene 249 325d 0.85d

biacetyl 236d 267d 1.00

benzil 223 247 0.92

Anthracene 178 318 0.71

Eosine 177 209 0.33

Rose bengala 164 213 0.61

Methylene blue 138 180 0.52

Table 3: Sensitizer and Quencher in non-polar solv ents

Different light sources can be used for photochemical reactions:1a) the sun, useful wavelenghts 300÷1400 nm,1) low-pressure mercury lamp (Hg approx. 10-5 atm), useful wavelenghts: 185, 254 (the most intense), 577÷579 nm. 2) medium pressure Hg lamps (Hg vapor pressure 5 atm), useful wavelengths: 365 (the most intense), 436, 546 and 577÷579 nm,3) high pressure Hg lamps (Hg vapor pressure approx. 100 atm;), useful wavelenghts from 360÷600 nm, (broad emission),4) low- and high pressure sodium lamps, useful wavelenghts 589 nm.Among the different typologies of photoreactors commercialized or homemade, the more used are:1) Apparatus for external irradiation (the simplest case is an irradiated flask) or Raynet a or Immersion-well reactor b in which the lamp is surrounded by the reactions

cooling fan

motor

reflecting walls

UV lamps

photoreactors

a

water inletacqua

water outletacqua

Hg medium pressure bulb

electric supply

cooling walls

b

Organic Photochemistry

Technical and experimental aspects

In all cases the lamp usually needs cooling to avoid its overheating and heating of the reaction solution. Low pressure mercury lamps are commercialized from 1 W to tens of Watts, medium and high pressure mercury lamps are commercialized from 125 up to 500W. Most lamps operate at high temperature (400÷700°C) and at high vapor pressure. Never move or touch lamps during operation. Never switch off the cooling system immediately after switching off the lamp.

200 250 300 350 400λ nm

20

40

60

80

t ras

mi t

t an c

e %

quartz

pyrex

Quartz and Pyrex transmittance, sample thickness 2mm

The material of the reactor depends on the necessary irradiation energy. For irradiation at 254 nm quartz glass (expensive apparatus) is needed. For irradiation at 300 nm pyrex glass is needed, and for irradiation > 350 nm normal lab glass (window glass) is sufficient. The glass acts as a solid filter. Additional solid or liquid optical filters may be used to restrict the irradiation wavelength.

Organic Photochemistry

Technical and experimental aspects


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