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Asymmetric transfer hydrogenation of ketones

Petra, D.G.I.

Publication date1999

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Citation for published version (APA):Petra, D. G. I. (1999). Asymmetric transfer hydrogenation of ketones.

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Download date:22 May 2021

Chapter 1

Introduction

Chapter 1

1.1 General introduction

The central topic of the research described in this thesis is the development of fast

and selective catalysts for the preparation of optically active alcohols. The

phenomena of chirality and optical activity were discovered one and a half centuries

ago by the pioneering work of Pasteur,1 Van 't Hoff2 and Le Bel.3 Once the

significance of optically active compounds was recognised, major efforts were

undertaken to find effective routes to obtain optically pure compounds.

There are many examples where the chirality of a compound has a determining

effect on its interaction with a living organism.4 The L-form of asparagine, one of the

20 natural occurring amino acids, tastes bitter, whereas the (i?)-isomer is sweet. The

(+)-form of estrone is a hormone, whereas the (-)-form has no hormonal activity.

There are barbiturates for which one enantiomer has a narcotic effect and its mirror

image isomer has a carcinogenic effect. Only one isomer of thalidomide, which was

sold as a racemic mixture under the commercial name of Softenon in the

Netherlands, proved to have the desired sedative effect, whereas the opposite

enantiomer caused severe fetal damage.5 These examples illustrate that the two

enantiomers of a racemic mixture can behave very differently in biological systems.

The reason for this is that all living beings contain only single enantiomers of the

constituent amino acids and sugars in their proteins, DNA and glycoproteins. The

uniform chirality in biological systems results in diastereomeric interactions with the

compounds of a racemic mixture. If synthetic compounds are to be used as

pharmaceuticals, agrochemicals, human food additives and animal food

supplements they should be used in their optically pure form to avoid secondary

effects and to ensure that the minimum quantity is sufficient. Examples such as the

use of the sweetener aspartame in soft-drinks, that contains only the L-form of

phenylalanine, and the use of L-lysine in animal feed demonstrate this strategy.

The insight in the effects of chiral compounds on living beings as is described above

has had a major impact on the developments in the fine-chemical industries. Some

years ago most synthetic drugs were sold as racemates, whereas recently they are

more sold as single enantiomers.6 At the moment, two thirds of the drugs in

development are chiral and more than 50% are being developed as single

Introduction

enantiomer drugs.7 Also FDA regulations on the marketing of new drugs have

become stricter in recent years with respect to chiral compounds.7 Any company

wishing to license a new active ingredient as a racemic mixture has to establish the

activity of both enantiomers and show that the unwanted enantiomer does not cause

any adverse effects. In the same report it is estimated that the market for dosage

forms of single enantiomers will increase from $73 billion in 1996 to above $90

billion by the year 2000.

Nowadays there are several well-established routes for obtaining optically pure

compounds (Figure 1.1).8"10 Starting from a racemic mixture the optically pure

compound can be obtained either by diastereomeric salt formation (i) or by

enzymatic or chemical kinetic resolution (ii). A drawback in using these methods is

that the undesired enantiomer is always formed in 50%. This unwanted enantiomer

should be racemised and recycled to obtain high atom efficiencies. The classical

resolution of racemates by diastereomeric crystallisation is, however, still the most

important method applied in industry.11

Racemate

diastereomeric salt formation

Racemate

Optically pure compound

enzymatic or chemical kinetic resolution

synthesis

Naturally occurring compounds

asymmetric catalysis

Prochiral substrate

Figure 1.1 Routes to optically pure compounds

In asymmetric synthesis starting from naturally occurring compounds a

stoichiometric amount of the chiral material is needed for a reaction (iii). As optically

Chapter 1

active material is usually expensive this is not a very economic approach with regard

to the amount of chiral information that is required. Furthermore, the lack of

availability of both enantiomers of most natural compounds is often a limiting

factor.

A more elegant way to prepare chiral compounds is catalytic asymmetric synthesis

starting from a prochiral substrate (iv). In this case the chiral information is part of

an optically active catalyst. Only a minimum amount of expensive chiral material is

required because one chiral catalyst can create up to millions of targeted chiral

product molecules. This concept is called asymmetric catalysis. Its application leads to a

multiplication of the chiral information contained in the catalyst. The subject of this

thesis falls within the field of asymmetric catalysis.

Special attention has been devoted to the topic of asymmetric catalysis during the

last decades. A wide variety of highly successful reactions with enantiomeric

excesses of over 95% have been reported.12"14 In most cases transition metal

complexes are used as the catalyst, preferably generated in situ.

The effectiveness of a homogeneous chiral catalyst, involved in a one step process,

depends on the difference in the Gibbs free energy between the transition states of

the (JR)- and the (S)-enantiomer (i.e. AG^ and AGs*). Starting from a prochiral

substrate the chirality of the product is induced by the catalyst in the

enantioselectivity determining step of the reaction. The interaction between the

substrate and the chiral catalyst results in an enantiomerically enriched product

mixture, or in the ideal situation, an enantiopure compound. The optically active

information present in the catalyst differentiates between front side and back side

attack (the re-face and sî-face of the substrate in Figure 1.2).

The reaction path will proceed by preference via the transition state with the lowest

energy gap, A(AG"':), forming either the (R)- or the (S)-enantiomer in excess. Unless

the reaction products exhibit enantioselectivities in the high 90's, there is only a

small energy difference between these transition states. When the energy gap

between the two diastereomeric transition states becomes more than 3 kcal/mol (at

room temperature) one enantiomer is formed in over 99%. It should be noted that

this value is in the same order of magnitude as the rotation energy of a simple

10

Introduction

molecule such as ethane.15 Predicting product enantioselectivity from the structure

of a postulated catalyst-substrate intermediate species is therefore still extremely

difficult.

Ay pvRu.lX

"re-face" "si-f ace"

OH

(S)-product

»iRu,,0

N X

OH

(R)-product

Figure 1.2 Front side and back side attack of a ruthenium-amino alcohol catalyst.

The first example of homogeneous enantioselective catalysis that appeared in the

literature dates back to 1966. In the reaction of styrene with ethyl diazoacetate cis

and trans isomeric cyclopropane derivatives were formed, each consisting of a pair

of enantiomers. For the trans isomers the observed enantiomeric excess was 6%.16

Most of the early work in the field of enantioselective catalysis centered around the

hydrogénation of prochiral olefins with emphasis on amino acid precursors as

unsaturated substrates. A milestone in the development of enantioselective catalysts

is Kagan's synthesis of the diphosphine DIOP (Figure 1.3).17 In this ligand the

chirality resides in the backbone rather than in the phosphorus atom. This invention

greatly simplified the synthesis of these chiral diphosphines and it became the

cornerstone of a massive worldwide effort to create new diphosphine ligands. With

rhodium complexes of DIOP, hydrogénation of Z-a-acetamidocinnamic acid gave N-

11

Chapter 1

acetylphenylalanine with an enantiomeric excess 95%.

DIP AMP (Figure 1.3) is the basis of the first commercial application of the concept of

enantioselective catalysis.19 L-Dopa, a drug for Parkinson's disease, is produced in

the Monsanto amino acid process by rhodium catalysed hydrogénation of the

corresponding dehydro amino acid.

x rv°cH3 f^ o o SJL,

H H < "̂H P P,

Ph2P PPh2 ^ !/ ^

/? H3CO'J

(R,R)-D\OP (R,R)-D\PAMP

Figure 1.3

Due to the growing demand for optically active compounds the concept of

enantioselective catalysis is nowadays applied to many other reactions. The most

abundant reactions involved are asymmetric reduction, asymmetric oxidation and

asymmetric carbon-carbon bond formation. Asymmetric reduction of carbonyl

functionalities forming chiral alcohols is among the most essential molecular

transformations.8 This thesis describes the development of enantioselective catalysts

for the reduction of unsymmetrical ketones in order to obtain optically active

alcohols. For supplementary information concerning asymmetric organometal

catalysed reactions considering different transformations the interested reader is

referred to the references throughout this Chapter.

1.2 Routes to optically active alcohols via asymmetric catalysis

The synthesis of chiral non-racemic secondary alcohols by catalytic enantioselective

reduction of the corresponding ketone remains a pivotal transformation in organic

12

Introduction

synthesis. Chiral alcohols form an important class of intermediates for the

pharmaceutical, agrochemical, flavour and fragrance industries.8-12 The synthesis of

these types of compounds should proceed in an environmentally benign way.

Efficient and clean enantioselective routes to chiral alcohols are well known but

hardly developed on an industrial scale. The four major catalytic procedures that

have emerged in recent years are: (i) enzymatic catalysed reduction; (ii)

enantioselective hydride reduction; (iii) enantioselective hydrogénation; and (iv)

enantioselective transfer hydrogénation.

In early days, synthesis of enantiomerically pure compounds from prochiral

precursors was considered possible only by using biochemical methods. Enzymes in

man, animals and plants perform the elegant and valuable concept of asymmetric

catalysis to produce all the optically pure substances needed for life. Enzymes are

able to catalyse reactions spectacularly fast, however, mainly with their natural

substrates. Usually, a remarkable drop in enzymatic turnover and enantioselectivity

is observed when different substrates are involved. Furthermore, the use of enzymes

as biocatalysts is often limited to the accessibility of only one stereoisomer and is

frequently accompanied by the use of complicated co-factor systems. The use of

biocatalysts has proven to be economically successful in several cases. However,

most of these examples are limited to hydrolytic enzymes, e.g. aminopeptidases,

amidases, lipases and esterases, that are used for kinetic resolutions in which 50% of

the undesired enantiomer is formed.20

Some of the most successful and general catalysts for hydride reduction are based on

the oxazaborolidine structure, developed by Corey et al.,21> 2 2 following on from

initial work by Itsuno et al..23 Excellent results have been obtained with these

materials, however the high level of rather expensive catalyst that is often required

(typically 10 mol%), and the non-compatibility of borane with certain functional

groups somewhat limits its utility. Furthermore, borane salts are always formed as

waste.

Catalytic reduction using molecular hydrogen can be conducted with a cheap

reducing reagent on a large scale without producing intrinsic byproducts. Great

success has been achieved concerning asymmetric induction and turnover numbers

using e.g. ruthenium-BINAP, ruthenium-DuPHOS and rhodium-DIPAMP

13

Chapter 1

catalysts.26-34 More recently, Noyori and coworkers have described a variant system

which utilises a chiral diamine and KOH in 2-propanol to activate a BINAP-Ru(II)

complex to catalyse the hydrogénation of unfunctionalised aromatic ketones.35

Remaining problems within the field of hydrogénation are related to the high

pressure equipment needed and the often difficult synthesis and handling of the

required chiral diphosphine ligands. Furthermore, not all types of substrates can be

reduced enantioselectively by classical hydrogénation. In this respect

unfunctionalised olefins, simple ketones and imines remained a problem for a long

time.

Better techniques are required to overcome these disadvantages. One of the most

attractive methods for industrial application is transfer hydrogénation of ketones.

Transfer hydrogénation has recently emerged as a powerful, practical and versatile

system for the transformation of prochiral ketones to chiral alcohols, and is

described in detail below.

1.3 History of asymmetric transfer hydrogénation of ketones

General

The reduction of a multiple bond by the aid of a hydrogen donor in the presence of a

catalyst is known as hydrogen transfer or transfer hydrogénation.36- 37 This process

involves hydrogen abstraction from the reagent (hydrogen donor) by means of a

catalyst, followed by (or in concert with) hydrogen addition to the unsaturated

functional group of the substrate (hydrogen acceptor), as is generalised in Scheme

1.1.

In hydrogen transfer reactions the hydrogen source is different from dihydrogen.

The most common reagents employed are 2-propanol and formic acid.37' 38 Other

less frequently used organic molecules are unsaturated hydrocarbons such as

14

Introduction

cyclohexene or cyclohexadiene and primary or secondary alcohols like methanol or

benzyl alcohol.37

DH2 + A • * D + AH2

DH2 = hydrogen donor; A = hydrogen acceptor

Scheme 1.1 Transfer hydrogénation

The use of organic hydrogen donors has some advantages over the use of molecular

hydrogen. It avoids the risks and the constraints associated with H 2 and the reaction

does not require special high-pressure equipment that is necessary for

hydrogénation reactions. Furthermore, the reaction can be favourably affected by

selecting the most appropriate hydrogen donor.

Because of the advantages of this method, much effort has been devoted to the

development of new chiral catalysts tailored to the transfer hydrogénation of various

prochiral substrates. Several substrates have been successfully reduced by transfer

hydrogénation in the presence of both heterogeneous and homogeneous catalysts.

The list of hydrogen acceptors includes ketones, cc,ß-unsaturated acids and esters,

imines and nitro compounds.36' 39~42 While until 1981 the optical yields were not

higher than 20% ee,39 and consequently lower than the ones obtained in catalytic

hydrogénation, more recently enantioselectivities of over 95% have been reached.38

Enantioselective transfer hydrogénation catalysts

Enantioselective transfer hydrogénation reactions have been carried out most

commonly using iridium, rhodium or ruthenium catalysts in combination with

many ligands. In the following a brief summary of the recent developments in

asymmetric transfer hydrogénation is given.

15

Chapter 1

Phosphine ligands in iridium, rhodium and ruthenium catalysed transfer hydrogénation

Chiral phosphines are the most popular ligands in asymmetric catalysis and they

have been employed in transfer hydrogénation since the very beginning in iridium,

rhodium and ruthenium catalysts. Besides a few tertiary monophosphines,43

chelating didentate ligands like DIOP, CHIRAPHOS, NORPHOS, BINAP,

PROPHOS and BPPM have mainly been used (see Figure 1.4). The common feature

of several of these ligands is the C2-symmetry axis.44 '45

Enantioselective transfer hydrogénation of ketones in the presence of the iridium or

rhodium diphosphine catalysts [M(diene)(P-P)]PF6 (P-P = CHIRAPHOS, DIOP or

PROPHOS) resulted in good catalyst activities and enantioselectivities of up to

66%46, 47

H"4 (""H

Ph2P PPh2

(fl,F?)-Diop

H3Q CH3

/ \ Ph2P PPh2

(R,f?)-Chiraphos

•PPh2

PPh2

(fl,R)-Norphos (S)-Binap

H3Q

Ph2P PPh2

(fi)-Prophos

Ph2P

COOrBu I

PPh2

(S,S)-BPPM

Figure 1.4 Phosphine ligands applied in transfer hydrogénation reactions

Very low optical yields (0.3-9.8%) were obtained with [H4Ru4(CO)8(-)-DIOP)2] as

preformed catalyst.48 Better results were obtained by Genêt et al. in the transfer

hydrogénation of acetophenone using a series diphosphineRu(Br)2 catalysts and

16

Introduction

NaOH as promotor.49 After 2-25 minutes enantioselectivities of up to 52%, with a

yield of over 80%, were obtained using CHIRAPHOS, BINAP, PROPHOS or BPPM

as the chiral ligand.

Recently, enantioselectivities of up to 72% were obtained using a ruthenium(II)

complex of the diferrocene derived (S)-(R)-Pigiphos.50

Nitrogen donor ligands iridium, rhodium and ruthenium catalysed transfer hydrogénation

Unlike asymmetric hydrogénation, in the field of asymmetric transfer hydrogénation

the most successful chiral auxiliairies contain nitrogen as the donor atom. This may

be the consequence of higher catalytic activities displayed in early hydrogen transfer

reactions by Rh(I) and Ir(I) complexes containing chelating didentate nitrogen

ligands compared to catalysts containing didentate phosphorus ligands.51-54

Iridium catalysed transfer hydrogénation using nitrogen donor ligands

Iridium(I) complexes with chiral phenanthrolines55 and chiral imines56 (Figure 1.5)

have shown poor to moderate enantioselectivities (i.e. of up to 63%) in the transfer

hydrogénation of acetophenone. More recently, much better results have been

obtained in asymmetric hydrogen transfer reduction of ketones. This is in part a

result of a report by Pfaltz and coworkers in 1991 pointing out that iridium(I)

catalysts containing C2-symmetric 4,4',5,5'-tetrahydro-2,2'-bioxazoles (Figure 1.5)

display a good activity in the hydrogen transfer reduction of ketones in 2-propanol.

Aryl-alkyl ketones were readily reduced, affording the corresponding alcohols in 47-

91% ee, whereas dialkyl ketones were less reactive and gave low yields of racemic

products.57 In 1995, at the starting point of this project, this was still the best result in

the hydrogen transfer reduction of aryl-alkyl ketones that was published in

literature.

The use of iridium(I) as a catalyst precursor is limited in examples. The combination

of iridium(I) and the diamine ligand depicted in Figure 1.5 gave rise to 78 % ee in the

17

Chapter 1

reduction of acetophenone.58 A tosylated diamine ligand developed by Noyori and

coworkers (i.e. TsDPEN) proved to be very useful in iridium(I) catalysed hydrogen

transfer reactions in 2-propanol, resulting in an enantioselectivity of 92% in the

reduction of acetophenone (TsDPEN = N-(p-tolylsulfonyl)-l,2-

diphenylethylenediamine).59 This ligand was initially developed for ruthenium(II)

catalysed transfer hydrogénation reactions giving rise to high enantioselectivities

and reaction rates.60

chiral phenanthrolines

H3Q

Prf -N N- '

chiral imine

R-' N N " \ ,

tetrahyd ro-bioxazoles

Ph An

An

H2N NH2

chiral diamine

Ph / h

/ \ H2N HN—Ts

H-? ^"H H2N HN—Ts

monotosylated diamines

Figure 1.5 Chiral nitrogen donor ligands in iridium catalysed transfer hydrogénation

Very recently, two papers described the use of similar monotosylated diamines in

iridium(III) and rhodium(III) complexes.61"63 The Ir(III) and Rh(III) complexes

contain pentamethylcyclopentadienyl counterions, which make them isoelectronic

with the ruthenium(II)-arene complexes bearing the same monotosylated diamine

ligands. The Ir(III) and Rh(III) complexes catalyse the reduction of acetophenone

affording enantioselectivities of up to 97%.

18

Introduction

Rhodium catalysed transfer hydrogénation using nitrogen donor ligands

In the field of rhodium(I) catalysed transfer hydrogénation chiral alkyl-2,2'-

bipyridines and alkyl-l,10-phenanthrolines (see Figure 1.6) were used by Gladiali et

al. giving rise to ee's of up to 63% for acetophenone reduction.64

Various C2-symmetric chiral diamines have been used as ligands for rhodium

catalysed transfer hydrogénation by Lemaire and coworkers.65"68 In general, the

enantioselectivities obtained were modest, the best (i.e. 67%) being obtained with the

diamine depicted in Figure 1.6. This ligand was incorporated into a polymer

backbone, by preparation of the polyurea derivative, which gave rise to higher

reaction rates and an enantioselectivity of 43% in the rhodium catalysed reduction of

acetophenone.

chiral bipyridines chiral phenanthrolines

Ph Ph

M H3C-NH HIM-CH3

chiral diamines

Ph Ph

V ^ //° /—NH H N ^ PhHN NHPh

chiral diurea

Figure 1.6 Chiral nitrogen donor ligands in rhodium catalysed transfer hydrogénation

Ruthenium catalysed transfer hydrogénation using nitrogen donor ligands

The most frequently used metal for the asymmetric transfer hydrogénation of

ketones is ruthenium(II). Simple racemic ß-amino alcohols have proved to afford

one of the highest levels of acceleration in the ruthenium(II) catalysed transfer

19

Chapter 1

hydrogénation of ketones.35' 69 The use of chiral amino alcohol ligands in

ruthenium(II) catalysed hydrogen transfer reduction of ketones was pioneered by

Noyori and coworkers and further developed by Palmer and Andersson (Figure 1.7).

Enantioselectivities of up to 95% were reached in the transfer hydrogénation of

acetophenone.69-71 A notable feature of the Ru(II)-amino alcohol catalysts is the need

for a primary or secondary amine in the ligands to obtain high activities and

enantioselectivities.

The tridentate "ambox" ligand developed by Zhang and coworkers proved to be a

very good chiral ligand for ruthenium(II) catalysed reduction of aromatic ketones

using RuCl2(PPh3)3 as the catalyst precursor, giving rise to enantioselectivities of up

to 98%.72 The presence of the central amine is considered to be essential for high

reactivity and enantioselectivity.

Didentate, tridentate and tetradentate P,N-containing ligands have been applied

successfully in the ruthenium(II) catalysed transfer hydrogénation of ketones. Zhang

and coworkers prepared and evaluated a series of nitrogen containing phosphine

ligands in Ru(II) catalysed transfer hydrogénation in which notable

enantioselectivities of up to 92% were achieved.73-75 The tetradentate

diphosphine/diamine system, developed by Noyori and coworkers has been

applied in the asymmetric transfer hydrogénation of aromatic ketones furnishing

products in up to 96% ee.76 Helmchen and coworkers have applied Ru(II) complexes

of chiral phosphinooxazolines to the transfer hydrogénation of ketones in 2-

propanol.77 Enantioselectivities of 86% were obtained in the reduction of

acetophenone, whereas aliphatic ketones could be obtained in up to 60% ee.

Recently, Nishibayashi et al. found that the related ruthenium complex RuC^PPb^)-

(oxazolinyl-ferrocenylphosphine) is an effective catalyst for the reduction of ketones

resulting in enantioselectivities of >99%.78 In contrast to the N,0- or N,N-chelates

the P,N-containing ligands do not necessarily need a primary or secondary amine

functionality in order to obtain high activities and enantioselectivities.

20

Introduction

Ph Ph H HO NH2

H -N-

Ph Ph

Ambox

NH

chiral amino alcohols

Ph

-P~

P% ir°s 9-i ïr°s

VN N Y ^ NY Ph Ph

N,P,N-tridentate

NH2

•OH

Ph2P

phosphinooxazolines

N ^R

oxazolinyl-ferrocenylphosphlne

Ph sPh

R2 -NH R R/ HN-R2

chiral thiourea's

Ph Ph

M H2N HN—Ts

TsDPEN

Figure 1.7 Chiral nitrogen donor ligands in rhodium catalysed transfer hydrogénation

The mono- and dithiourea ligands used by Lemaire and coworkers were a little less

successful with ee's of up to 93%,79 just like the ferrocenyl ligands of Knöchel et alß°

Noyori and coworkers developed a highly effective monosubstituted diamine

ligand, i.e. TsDPEN, for ruthenium(II) catalysed transfer hydrogénation using either

formic acid or 2-propanol as a hydrogen donor.60' 81 The monotosylated TsDPEN

ligand can be considered as the most effective and best understood ligand system yet

reported. Three different ruthenium(II)-TsDPEN complexes that are involved in the

catalytic cycle have been characterised by X-ray diffraction. With chemical yields of

up to 100% and enantioselectivities of over 95% in the reduction of most aryl-alkyl

ketones this system is of great use in organic synthesis.

21

Chapter 1

The use of transfer hydrogénation is a valuable and versatile reaction which is now

emerging as one of the very best methods for achieving asymmetric reductions of

C=0 bonds. The combination of practical simplicity, mild reaction conditions,

relatively non-hazardous reagents and high selectivities is unparalleled by most

other processes in synthetic organic chemistry.

Mechanistic aspects

From a mechanistic point of view, two general reaction paths can be envisaged for

hydrogen transfer: a stepwise process, called "hydridic route", and a concerted

process, called "direct hydrogen transfer" (Figure 1.8).37

The "hydridic route" involves the intermediate formation of a metal hydride

derivative by interaction of the catalyst with the hydrogen donor, followed by

hydride transfer from the metal to the substrate. The "direct hydrogen transfer"

implies that hydrogen is transferred to the substrate in a concerted process where

both the H-donor and the H-acceptor are held together in close proximity of the

catalyst. If the "hydridic route" is operative, enantioface differentiating reactions

should be only marginally affected by the use of different hydrogen donors. In

contrast, enantiomer discriminating H-transfer reactions that follow the "direct

hydrogen transfer" could give rise to different enantioselectivities using various

hydrogen donors. It should be noted however, that the hydrogen donor can be a

"noninnocent" spectator ligand in the stereodetermining step of the "hydridic route"

and that it can therefore influence, albeit moderately, the stereochemistry of the

reaction. An example in which the direct hydrogen transfer route is operative is the

Meerwein-Pondorf-Verley reduction, involving aluminium or lanthanide

catalysts.6•£• 82 When transition metal catalysts are involved, however, it is assumed

that the hydridic route is preferred.

In ruthenium(II) catalysed transfer hydrogénation Noyori and coworkers isolated a

ruthenium hydride complex, that was capable of reducing acetophenone to its

corresponding chiral alcohol in high yield and high enantiomeric excess.81 Also,

Lemaire and coworkers postulated that for rhodium(I) catalysed transfer

22

Introduction

hydrogénation the active catalyst is a rhodium hydride complex, based on both

theoretical and experimental data.65

MLX + HO—( Ç H ,

CH,

- base

Path A: "Hydridic route" H3C/,, >CH3

nf^"- ^ Path B: "Direct hydrogen transfer"

QH3

L - M

S V + Substrate

r / ^ C H 3 ^ C / , >CH3

\ — ? H

L-M—H Lx-Mv_J

ÇH3

H 3 C, . c > CH 3 , ^

? > — { L — M - S L x — M - S - H

- acetone | + substrate

n L— M-H

S-H

U—M

Figure 1.8

From these results one could rationalise that for transition metal catalysed transfer

hydrogénation reactions the active catalyst is most likely a metal hydride, as in path

A.

1.4 Source of chirality

The success of the use of optically active catalysts for asymmetric synthesis depends

highly on the availability of chiral ligands. The possibility of efficient fine-tuning of

the ligand systems plays an important role to create selective catalysts.

23

Chapter 1

The optically active catalysts described in this thesis all contain chiral ligands that

are directly or indirectly derived from chiral 1,2-amino alcohols. A relatively large

number of natural products contain an amino alcohol functionality. Amino sugars

can be considered as members of this class of compounds, and nucleosides and

nucleotides also fall within the definition. Three types of 1,2-amino alcohols can be

distinguished, i.e. 1-substituted, 2-substituted and 1,2-disubstituted 2-amino-l-

alcohols (Figure 1.9).

1 -F R. sR'

HO NH2 HO NH2 HO NH2

1-substituted, 2-substituted and 1,2-disubstituted amino alcohols

Figure 1.9

a-Amino alcohols that contain a chiral centre at the 2-position can easily be obtained

from a-amino acids by reduction. oc-Amino acids are natural compounds that are

readily available. Moreover, a wide variety of non-natural amino acids can be

synthesised on large scale using an L-specific aminopeptidase, produced by

Pseudomanos putida, in an enzymatic resolution of a racemic mixture of a-amino acid

amides.83"87- Simple transformations, such as a-amino acid reductions, allow entry

to other classes of compounds that are also useful as chiral source. Various hydride

sources have been used to reduce amino acids to form amino alcohols such as

lithium aluminium hydride, sodium borohydride, lithium borohydride, etc. Recently

other efficient routes from amino acids to amino alcohols have been reported. One

approach uses a sodium borohydride-sulphuric acid system88 while a different route

employs sodium borohydride-iodine.89 The formed 1,2-amino alcohols can serve as

ligands of which the heteroatoms can be used to form an organometal complex, i.e.

the chiral catalyst.

a-Amino alcohols in which the chiral centre is positioned at the 1-position can only

be obtained using a different synthetic strategy, since they can not be derived from

24

Introduction

natural occurring amino acids. The 1-substituted amino alcohols that are described

in this thesis are derived from their corresponding cyanohydrins. An efficient three-

step one-pot synthesis to convert optically active cyanohydrins into 1-substituted

amino alcohols was developed by Brussee and coworkers (see Figure 1.10).90' 91 The

reaction sequence involves a DIBAL reduction of the nitrile to an imine,

transamination to a secondary imine and sodium borohydride reduction to the

corresponding 1-substituted amino alcohols.

hydroxynitrile H lyase

OH

(fî)-cyanohydrin

OH

DIBAL "Al(/-Bu)2

Transamination 1. NH4Br 2. HoN-R'

OH H

R' NaBH4

OH

^ N . .

^

Figure 1.10

Optically active cyanohydrins are generated using hydroxynitrile lyases. They

catalyse the stereoselective addition of hydrocyanic acid to aldehydes and ketones.

Enzymes for the synthesis of either (R)- or (S)-cyanohydrins are available.92 The

hydroxynitrile lyase from almonds, Prunus amygdalus, provides an easy access to (R)-

cyanohydrins. Furthermore, recent advances in cloning and overexpression

techniques have provided (S)-Hydroxynitrile lyase enzymes from Hevea brasiliensis

and Manihot esculenta in sufficient quantity for potential application to industrial

synthesis of (S)-cyanohydrins.

Chiral cyanohydrins can also be converted into 1,2-disubstituted amino alcohols, as

25

Chapter 1

was shown by Krepski et al. and Brussee et al.93-95 Erythro and threo amino alcohols

were synthesised by the addition of a Grignard reagent to the O-protected

cyanohydrins, followed by reduction of the intermediate imine. In this way (1R, 2S)-

norephedrine and (IS, 2R)-2-amino diphenylethanol could be synthesised in good

yields.

Other possible ways to obtain 1,2-amino alcohols containing two stereogenic centres

include either isolation of the natural product from Ephedrae Herba, which contains

norephedrine, ephedrine, pseudoephedrine and methylephedrine, or, among others,

oxime reduction, imine reduction, ketone reduction, etc.96

The optically active 1,2-amino alcohols that are described in this thesis serve directly

or indirectly as chiral auxiliairies in asymmetric transfer hydrogénation reactions to

generate a new stereogenic centre in the final product.

1.5 IOP objectives and justification

The research described in this thesis was financed by the Dutch Ministry of

Economic Affairs via the Innovation Oriented Research Programmes directed towards

Catalysis.

The Innovation Oriented Research Programmes were set up by the Dutch Ministry

of Economic Affairs to promote research in a number of promising fields to improve

the Dutch competitive position in international trade. These IOP's provide Dutch

universities and research institutes with additional funding for research projects that

are specifically aimed at meeting the needs of industry. IOP's are also intended to

encourage stronger relationships between academic research institutes and industry.

Catalysis offers the opportunity to steer chemical conversions in a desired direction.

The central theme of a four year research programme known as IOP Catalysis is

"precision in chemical conversion". This precision is required both to save energy

and feedstocks and to avoid the formation of undesired byproducts and waste.

Catalytic conversions are involved in the manufacture of more than 80% of the total

volume of chemicals. Hence a solid knowledge based on catalysis is of strategic

26

Introduction

interest to the Dutch chemical industry.

Catalysis is extensively applied in petroleum refining and in the manufacture of bulk

chemicals. This is far less the case in the manufacture of fine chemicals where

classical multi-step chemical conversions play a larger role. These classical

procedures often involve lower selectivities, the use of undesirable, toxic, or

corrosive reagents, and the formation of side products and large amounts of waste.

Therefore, it has been decided to direct the efforts of IOP Catalysis in particular to

the introduction of novel catalytic routes in the fine chemical industries.

The work described in this thesis involves the development of novel catalytic routes

to chiral alcohols in the fine chemical industries.

The objective of the project described in this thesis is the development of fast and

selective transfer hydrogénation catalysts for the synthesis of chiral alcohols.

Enantioselective transfer hydrogénation is one the most attractive methods for the

synthesis of chiral alcohols as has been outlined in section 1.2. So far, asymmetric

transfer hydrogénation using various aryl-alkyl ketones has been applied

successfully. However, substrates of industrial interest carry functional groups that,

in general, have a dramatic effect on both the activity and the selectivity of the

catalyst. Therefore, it will be necessary to tailor catalysts for the transfer

hydrogénation of functionalised model substrates (e.g. 1-3).

ci ^ ^ > ^ ^ C I ^ ^ ^ V ° ^ O

3

These substrates have the advantage that successful transfer hydrogénation may

lead directly to commercial application. The product alcohol of chloroacetophenone

(1) can be converted into chiral epoxides. Asymmetric reduction of

chloropropiophenone (2) results in a precursor for the homochiral form of

fluoxetine, an anti-depressant. The product of a-keto-ester 3 is a potential building

block for "Angiotensin Converting Enzyme inhibitors", blood regulating

27

Chapter 1

compounds. The latter product is an oil, which makes purification by crystallisation

impossible. Hence, the enantioselectivity of the reaction needs to be high. Also,

asymmetric reduction of dialkyl ketones, ketones containing an alkyne functionality,

oc-keto esters and a,ß-unsaturated ketones will lead to industrial interesting products

and have therefore also been taken into account in this project.

1.6 Outline of this thesis

The development of fast and selective transfer hydrogénation catalysts for the

synthesis of chiral alcohols was the main objective in the research project of which

the results are described in this thesis. A variety of ruthenium(II)-amino alcohol and

iridium(I)-amino sulf(ox)ide catalysts were studied and used in the asymmetric

transfer hydrogénation of several ketones.

Chapter 2 describes the asymmetric transfer hydrogénation of prochiral ketones

using ruthenium(II)-amino alcohol catalysts and 2-propanol as the hydrogen donor.

The ligand coordination fashion was studied and the amino alcohol structure was

optimised in terms of activity and enantioselectivity.

The enantioselective outcome of the ruthenium(II)-amino alcohol catalysed reaction

was studied in more detail in chapter 3. The actual process of the transfer of a

hydride from the metal to the substrate was calculated on the density functional

level of theory. Comparison of two proposed mechanistic pathways showed that the

pathway of choice proceeds through hydrogen bond formation between the

substrate and the catalyst. The steric interactions between the ketone and the catalyst

were discussed resulting in a better understanding of the observed

enantioselectivities.

A completely different and new catalytic system for the asymmetric transfer

hydrogénation of ketones is described in chapter 4. A series of amino sulf(ox)ides was

synthesised from amino alcohols and was used in the iridium(I) catalysed reduction

of ketones. Both formic acid and 2-propanol were successfully used as hydrogen

donors. Aryl-alkyl ketones were reduced to the corresponding alcohols in high

28

Introduction

enantiomeric excess.

With the active and enantioselective catalysts described in chapters 2-4 the scope of

the reaction was studied in order to synthesise functionalised chiral alcohols. The

results of substrate variations are presented in chapter 5. High chemoselectivities and

moderate to high enantioselectivities were obtained in the reduction of various

substituted ketones.

In chapter 6 a high throughput screening method for the enantioselective transfer

hydrogénation of ketones is presented. On using IR-spectroscopy the performance of

ruthenium(II)-amino alcohol catalysts was determined by monitoring the reverse

reaction.

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33