Lecture 14 APPLICATIONS IN ORGANIC SYNTHESIS

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I. Enantioselective functional group interconversions

ORGANOMET CHEM IN ORGANIC SYNTHESIS

II. Carbon-carbon bond formation via nucleophilic attack on a ligand.

ORGANOMET CHEM IN ORGANIC SYNTHESIS

III. Carbon-carbon bond formation via carbonyl or alkene insertion.

ORGANOMET CHEM IN ORGANIC SYNTHESIS

IV. Carbon-carbon bond formation via transmetallation reactions.

ORGANOMET CHEM IN ORGANIC SYNTHESIS

V. Carbon-carbon bond formation through cyclization reactions.

ORGANOMET CHEM IN ORGANIC SYNTHESIS

The C=C and C=O undergoes transformations to variety of organic compounds (alcohols, alkyl halides, alkanes).

The C=C and C=O are planar and achiral but in their reactions creates one or more stereogenic centers in the reaction product.

Assymetric Hydrogenations

Methods of producing an enantiomer of a chiral compound:

Chemical resolution of a racemateChiral chromatographyUse of a chiral natural products as starting materialStoichiometric use of chiral auxilliariesAsymmetric catalysis

Asymmetric Hydrogenations

Chiral chromatography:

Use of chiral, enantioenriched groups to the solid support

In the chiral environment, the two enantiomers will have diastereomerically different interactions with the columns

ORGANOMET CHEM IN ORGANIC SYNTHESIS

Synthesis of biotin (involved in enzymatic transfer of CO2):

ORGANOMET CHEM IN ORGANIC SYNTHESIS

Use of chiral auxiliaries:

ORGANOMET CHEM IN ORGANIC SYNTHESIS

Asymmetric Catalysis: same approach as the use of chiral auxilliary except that the selectivity occurs catalytically

The most environmentally benign approach to enantioselectivity.

ORGANOMET CHEM IN ORGANIC SYNTHESIS

Wilkinson’s catalyst: LnM+ (M = Rh or Ir)

Assymetric Hydrogenations

Chiral Diphosphine Ligands:

Asymetric Hydrogenation using Rh Catalysts

Mechanism:

Assymetric Hydrogenation using Rh-CHIRAPHOS

Assymetric Hydrogenation

Assymetric Hydrogenation

Assymetric Hydrogenation

Assymetric Hydrogenation of C=C bonds using Ru(II)

Noyori pioneered the development of Ru(II) catalysts showing enantioselective hydrogenation.

ASYMMETRIC HYDROGENATION OF C=C BONDS

ASYMMETRIC HYDROGENATION OF C=C BONDS

ASYMMETRIC HYDROGENATION OF C=C BONDS

Asymmetric Hydrogenation of C=O

ASYMMETRIC HYDROGENATION OF C=O

ASYMMETRIC HYDROGENATION OF C=O

ORGANOMET CHEM IN ORGANIC SYNTHESIS

ORGANOMET CHEM IN ORGANIC SYNTHESIS

Transfer hydrogenation (TH) Asymmetric TH

ASYMMETRIC HYDROGENATION OF C=O

ASYMMETRIC HYDROGENATION OF C=O

Assymetric Hydrogenation Using Ir(I) Catalysts

ORGANOMET CHEM IN ORGANIC SYNTHESIS

ORGANOMET CHEM IN ORGANIC SYNTHESIS

ASYMMETRIC OXIDATION

ORGANOMET CHEM IN ORGANIC SYNTHESIS

Pd-Catalyzed Oxidation of Secondary Alcohols

OXIDATION OF SECONDARY ALCOHOLS

ORGANOMET CHEM IN ORGANIC SYNTHESIS

CARBON – CARBON BOND FORMATION VIA NUCLEOPHILIC ATTACK ON AN 3 - ligand:

THE TSUJI-TROST REACTION

ORGANOMET CHEM IN ORGANIC SYNTHESIS

TSUJI – TROST REACTION

Organic synthesis using allylic substrates:unpredictable stereochemistrypoor control of regioselectivitypossible carbon- skeleton rearrangement.

Leaving groups for Tsuji-Trost Reaction

Tsuji-Trost Reaction:

With hard nucleophiles (pKa of conjugate acid >25) results in an overall inversion of configuration at the allylic site.

With soft nucleophile (pKa of conjugate acid < 25) react to give retention of configuaration.

TSUJI – TROST REACTION

TSUJI – TROST REACTION

TSUJI – TROST REACTION - EXAMPLE

TSUJI – TROST REACTION

Several points in catalytic cycle where asymmetric reaction could occur:

a) enantiomeric faces of the alkeneb) enantiomeric leaving groupsc) enantioface exchange in the 3 allyl complexd) attack at enantiotopic termini of the 3 ally ligande) Attack by different enantifaces of prochiral

nucleophiles.

ASSYMETRIC TSUJI – TROST REACTION

TSUJI-TROST REACTION

TSUJI_TROST REACTION Assymetric Quat center

Tsuji-Trost Reaction – Quat Center

EXAMPLE:

Tsuji-Trost Reaction

ORGANOMET CHEM IN ORGANIC SYNTHESIS

Tsuji Trost Reaction:

C-C Bond formation via CO and alkene

insertion

CARBONYLATIONINSERTIONS

CARBONYL INSERTIONS EXAMPLE

CARBONYL INSERTIONS

C-C Double bond Insertion: The Heck Reaction

Heck Reaction – migratory C=C insertion

Step a ) OA b) alkene coordination c) migratory insertion of C=C d) -elimination

Insertion is key step

R = aryl, alkyl, benzyl or allyl

X = Cl, Br, I, OTf

Rate of reaction and regioselectivity are sensitive to steric hindrance about the C=C bond.

Rate of reaction varies according to:

Heck Reaction:

Example:

Heck Reaction

Heck Reaction

Also know as Cross Coupling Reaction:

C-C Bond Bond formation via Transmetallation Reactions

Transmetallation Reaction

Transmetallation Reaction – a method for introducing a -bonded hydrocarbon ligands Into the coordination sphere transition metals.

The equilibrium is thermodynamically favorable from left to right if the electronegativity of M is greater than that of M’.

TRANSMETALLATION REACTIONS

Via a concerted -bond metathesis

--------transfer of R to M with retention of configuration.

TRANSMETALLATION REACTION MECHANISM

TRANSMETALLATION REACTIONS 4-TYPES

GENERAL REACTION MECHANISM

CROSS-COUPLING REACTION - GENERAL

CROSS-COUPLING REACTION

The use of organotin compound have the advantage that one group will preferentially transfer over the other:

CROSS-COUPLING REACTION

Example:Propose a catalytic cycle for the cross coupling plus carbonylation reaction below

CROSS-COUPLING REACTION

Mechanism:

CROSS-COUPLING REACTION - STILLE

Synthesis Application Example:

CROSS-COUPLING REACTION - STILLE

Sample Problem:

CROSS-COUPLING REACTION - STILLE

Transmetalating Agent is R-B(R’)2 but similar in scope as the Stille.

CROSS-COUPLING REACTION - SUZUKI

Reaction Pathway:

CROSS-COUPLING REACTION - SUZUKI

Synthesis Application: The chemo-, regio-, and stereoselectivity similar to those with Stille. Suzuki more widely used for aryl-aryl coupling.

CROSS-COUPLING REACTION - SUZUKI

Cross coupling between alkynyl and aryl :

CROSS-COUPLING REACTION - Sonogashira

- Requires high loadings of Cu and Pd catalysts, relativelly hight temperatures

- Cu-alkynes are formed in situ and then the alkyne is transferred to Pd.

Mechanism:

CROSS-COUPLING REACTION -

Mechanism:

CROSS-COUPLING REACTION - Sonogashira

Synthesis Applications:

CROSS-COUPLING REACTION - Sonogashira

Method of choice for syhthesis of acrylic, di- and tri- terpenoid systems. Organozinc are often used.

CROSS-COUPLING REACTION - Negishi

Reaction mechanism:

CROSS-COUPLING REACTION - Negishi

Synthesis Applications:

CROSS-COUPLING REACTION – Negishi

Mechanism:Dotz Arene Synthesis

C-C Bond formation: Cyclizations

Cyclization involving Palladium

Mechanism:

CYCLIZATION Pd

Cyclization – Oppolzer’s

Cyclization – Pauson - Kand

CROSS-COUPLING REACTION