EP1809586A1

EP1809586A1 - Process for the de-enrichment of enantiomerically enriched substrates

Info

Publication number: EP1809586A1
Application number: EP05804713A
Authority: EP
Inventors: Andrew John Blacker; Matthew John Stirling
Original assignee: Avecia Pharmaceuticals Ltd
Current assignee: Piramal Healthcare UK Ltd
Priority date: 2004-10-29
Filing date: 2005-10-27
Publication date: 2007-07-25
Also published as: JP2008517990A; GB0424000D0; MX2007005169A; IL182589A0; CA2583821A1; BRPI0517243A; ZA200702979B; CN101052604A; KR20070068428A; WO2006046062A1

Abstract

There is provided a process for the de-enrichment of enantiomerically enriched compositions which comprises reacting an enantiomerically enriched composition comprising at least a first enantiomer or diastereomer of a substrate comprising a carbon-heteroatom bond, wherein the carbon is a chiral centre and the heteroatom is a group VI heteroatom, in the presence of a catalyst system and optionally a reaction promoter to give a product composition comprising first and second enantiomers or diastereomers of the substrate having a carbon-heteroatom bond, the ratio of second to first enantiomer or disatereomer in the product composition being greater than the ratio of second to first enantiomer or disatereomer in the enantiomerically enriched composition. Preferred substrates include compounds of Formula (1) wherein: X represents O, S; R1, R2 each independently represents an optionally substituted hydrocarbyl, a perhalogenated hydrocarbyl, an optionally substituted heterocyclyl group; or R1 & R2 are optionally linked in such a way as to form an optionally substituted ring(s); provided that R1 and R2 are selected such that * is a chiral centre. In a preferred process a compound of Formula : (2) wherein: X represents O, S; R1, R2 each independently represents an optionally substituted hydrocarbyl, a perhalogenated hydrocarbyl, an optionally substituted heterocyclyl group; or R1 & R2 are optionally linked in such a way as to form an optionally substituted ring(s); provided that R1 and R2 are different, may be obtained.

Description

PROCESS FOR THE DE-ENRICHMENT OF ENANTIOMERICALLY ENRICHED

SUBSTRATES

The invention concerns a process for the de-enrichment of enantiomerically enriched substrates, especially alcohols and sulphides.

According to a first aspect of the present invention, there is provided a process for the de-enrichment of enantiomerically enriched compositions which comprises reacting an enantiomerically enriched composition comprising at least a first enantiomer or diastereomer of a substrate comprising a carbon-heteroatom bond, wherein the carbon is a chiral centre and the heteroatom is a group Vl heteroatom, in the presence of a catalyst system and optionally a reaction promoter to give a product composition comprising first and second enantiomers or diastereomers of the substrate having a carbon-heteroatom bond, the ratio of second to first enantiomer or diastereomer in the product composition being greater than the ratio of second to first enantiomer or diastereomer in the enantiomerically enriched composition.

Preferably the product composition is a racemic mixture of the first and second enantiomers of the substrate comprising a carbon-heteroatom bond, wherein the carbon is a chiral centre.

Substrates which may be enantiomerically de-enriched by the process of the present invention include alcohols at a chiral secondary carbon atom and sulphides chiral at a secondary carbon atom.

Preferably, in the process of the present invention, the substrate comprising a carbon-heteroatom bond, the carbon atom being a chiral centre, is a compound of formula (1 ):

wherein:

X represents O, S; R¹, R² each independently represents an optionally substituted hydrocarbyl, a perhalogenated hydrocarbyl, an optionally substituted heterocyclyl group; or R¹ & R² are optionally linked in such a way as to form an optionally substituted ring(s); provided that R¹ and R² are selected such that * is a chiral centre. Hydrocarbyl groups which may be represented by R^1'2 independently include alkyl, alkenyl and aryl groups, and any combination thereof, such as aralkyl and alkaryl, for example benzyl groups.

Alkyl groups which may be represented by R^1"2 include linear and branched alkyl groups comprising up to 20 carbon atoms, particularly from 1 to 7 carbon atoms and preferably from 1 to 5 carbon atoms. When the alkyl groups are branched, the groups often comprising up to 10 branch chain carbon atoms, preferably up to 4 branch chain atoms. In certain embodiments, the alkyl group may be cyclic, commonly comprising from 3 to 10 carbon atoms in the largest ring and optionally featuring one or more bridging rings. Examples of alkyl groups which may be represented by R^1'4 include methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, t-butyl and cyclohexyl groups.

Alkenyl groups which may be represented by R^1"2 include C_2-20, and preferably C_2-6 alkenyl groups. One or more carbon - carbon double bonds may be present. The alkenyl group may carry one or more substituents, particularly phenyl substituents. Examples of alkenyl groups include vinyl, styryl and indenyl groups. When either of R¹ or R² represents an alkenyl group, a carbon - carbon double bond is preferably located at the position β to the C-heteroatom moiety.

Aryl groups which may be represented by R^1"2 may contain 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocyclic rings. Examples of aryl groups which may be represented by R^1"2 include phenyl, tolyl, fluorophenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, anisyl, naphthyl and ferrocenyl groups.

Perhalogenated hydrocarbyl groups which may be represented by R^1'2 independently include perhalogenated alkyl and aryl groups, and any combination thereof, such as aralkyl and alkaryl groups. Examples of perhalogenated alkyl groups which may be represented by R^1'2 include -CF₃ and -C₂F₅.

Heterocyclic groups which may be represented by R^1"2 independently include aromatic, saturated and partially unsaturated ring systems and may constitute 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocyclic rings. The heterocyclic group will contain at least one heterocyclic ring, the largest of which will commonly comprise from 3 to 7 ring atoms in which at least one atom is carbon and at least one atom is any of N, O, S or P. When either of R¹ or R² represents or comprises a heterocyclic group, the atom in R¹ or R² bonded to the C-heteroatom group is preferably a carbon atom. Examples of heterocyclic groups which may be represented by R^1'2 include pyridyl, pyrimidyl, pyrrolyl, thiophenyl, furanyl, indolyl, quinolyl, isoquinolyl, imidazoyl and triazoyl groups.

When any of R^1"2 is a substituted hydrocarbyl or heterocyclic group, the substituent(s) should be such so as not to adversely affect the rate or stereoselectivety of the reaction. Optional substituents include halogen, cyano, nitro, hydroxy, amino, thiol, acyl, hydrocarbyl, perhalogentated hydrocarbyl, heterocyclyl, hydrocarbyloxy, mono or di- hydrocarbylamino, hydrocarbylthio, esters, carbonates, amides, sulphonyl and sulphonamido groups wherein the hydrocarbyl groups are as defined for R¹ above. One or more substituents may be present.

When R¹ & R² are linked in such a way that when taken together with either the carbon atom and/or atom X of the compound of formula (1) that a ring is formed, it is preferred that these be 5, 6 or 7 membered rings and optionally containing one or more ring heteroatoms, preferably O, S or N ring atoms. Examples of such compounds of formula (1) include 2-methylcyclohexanol.

In certain preferred embodiments, R¹ and R² are both different and selected to both be different C_1-6 alkyl groups, both be different aryl groups, particularly where one is a phenyl group, or are selected such that one is aryl, particularly phenyl and one is C_1-6 alkyl. Substituents may be present, particularly substituents para to the C-X group when one or both of R¹ and R² is a substituted phenyl group.

Examples of compounds of formula (1) include 1-phenylethan-1-ol, 1-(2- naphthyl)ethan-1-ol, 1-(1-naphthyl)ethan-1-ol 1-phenylethan-1 -thiol, 1-(2-naphthyl)ethan- 1 -thiol, and 1-(1-naphthyl)ethan-1 -thiol.

The catalyst system preferably comprises a transition metal catalyst and optionally a ligand.

Ligands which optionally may be present include amines, alcohols and sulphides. When a ligand is used, optionally the ligand and the transition metal catalyst may be pre-mixed or pre-coordinated prior to the reaction with the substrate. Examples of such pre-coordinated ligand and the transition metal catalysts include those catalysts disclosed in the International patent applications with publication numbers WO97/20789, WO98/42643, and WO02/44111 , each of which is incorporated herein by reference. Transition metal catalysts include transition metal halides, transition metal halide complexes and transition metal complexes wherein the transition metal is optionally complexed by a displaceable ligand.

Displaceable ligands include phosphines, such as tri-hydrocarbyl phosphines for example Ph₃P, carbenes such as imidazole carbene, nitriles such as acetonitrile, carbon monoxide, triflate, alkenes and dienes. Examples of transition metal complexes wherein the transition metal is optionally complexed by a displaceable ligand include complexes of the formula M_nL₀X_pY_r Wherein

M is a transition metal; L is a displaceable ligand;

X is a halide;

Y is a neutral optionally substituted hydrocarbyl complexing group, a neutral optionally substituted perhalogenated hydrocarbyl complexing group, or an optionally substituted cyclopentadienyl complexing group; and n is an integer; and each of o, p, and r is 0 or an integer provided that o+p+r is an integer. Preferably, the transition metal catalyst is a transition metal halide or transition metal halide complex based on the transition metals in Group VIII of the Periodic Table, especially ruthenium, rhodium or iridium. More preferably, the transition metal catalyst is a transition metal halide complex of the formula M_nX_pY_r Wherein

M is a transition metal; X is a halide;

Y is a neutral optionally substituted hydrocarbyl complexing group, a neutral optionally substituted perhalogenated hydrocarbyl complexing group, or an optionally substituted cyclopentadienyl complexing group; and n, p and r are integers. Although transition metal catalyst is believed to be substantially as represented in the above formula, in some circumstances the transition metal catalyst may also exist as a dimer, trimer or some other polymeric species.

Metals which may be represented by M include metals which are capable of catalysing transfer hydrogenation. Preferred metals include transition metals, more preferably the metals in Group VIII of the Periodic Table, (iron, cobalt, nickel, ruthenium, rhodium, palladium, osmium, iridium and platinum), more preferably ruthenium, rhodium or iridium, most preferably iridium.

Typically, the integers n, p, r are selected such that the transition metal halide complex is overall a neutral species. Therefore, the selection of n, p, r are directly related to the valance state of the metal and the number of halides present and the nature of the complexing group Y. For example, where Y is a negatively charged cyclopentadienyl complexing group, the number of negatively charged halides required to balance the valence state of the metal will be less than when Y is a neutral hydrocarbyl complexing group. When the metal is ruthenium it is preferably present in valence state II. When the metal is rhodium or iridium it is preferably present in valence state I when Y is a neutral optionally substituted hydrocarbyl or a neutral optionally substituted perhalogenated hydrocarbyl ligand, and preferably present in valence state III when Y is an optionally substituted cyclopentadienyl ligand. An especially preferred metal is iridium. The neutral optionally substituted hydrocarbyl or perhalogenated hydrocarbyl complexing group which may be represented by Y includes optionally substituted aryl and alkenyl complexing group.

Optionally substituted aryl complexing groups which may be represented by Y may contain 1 ring or 2 or more fused rings which include cycloalkyl, aryl or heterocyclic rings. Preferably, the complexing group comprises a 6 membered aromatic ring. The ring or rings of the aryl complexing group are often substituted with hydrocarbyl groups. The substitution pattern and the number of substituents will vary and may be influenced by the number of rings present, but often from 1 to 6 substituents are present. Substituents may include halogen, cyano, nitro, hydroxy, amino, thiol, acyl, hydrocarbyl, perhalogentated hydrocarbyl, heterocyclyl, hydrocarbyloxy, mono or di-hydrocarbylamino, hydrocarbylthio, esters, carbonates, amides, sulphonyl and sulphonamido groups wherein the hydrocarbyl groups are as defined for R¹ above. Typically, the 1 to 6 substituents are each independently hydrocarbyl groups, preferably 2, 3 or 6 hydrocarbyl groups and more preferably 6 hydrocarbyl groups. Preferred hydrocarbyl substituents include methyl, ethyl, iso-propyl, menthyl, neomenthyl and phenyl. Particularly when the aryl complexing group is a single ring, the complexing group is preferably benzene or a substituted benzene. When the complexing group is a perhalogenated hydrocarbyl, preferably it is a polyhalogenated benzene such as hexachlorobenzene or hexafluorobenzne. When the hydrocarbyl substitutents contain enantiomeric and/or diastereomeric centres, it is preferred that the enantiomerically and/or diastereomerically purified forms of these are used. Benzene, p-cymyl, mesitylene and hexamethylbenzene are especially preferred complexing group.

Optionally substituted alkenyl complexing groups which may be represented by Y include C_2-30, and preferably C_6-12, alkenes or cycloalkenes with preferably two or more carbon-carbon double bonds, preferably only two carbon-carbon double bonds. The carbon-carbon double bonds may optionally be conjugated to other unsaturated systems which may be present, but are preferably conjugated to each other. The alkenes or cycloalkenes may be substituted preferably with hydrocarbyl substituents. When the alkene has only one double bond, the optionally substituted alkenyl complexing group may comprise two separate alkenes. Preferred hydrocarbyl substituents include methyl, ethyl, iso-propyl and phenyl. Examples of optionally substituted alkenyl complexing groups include cyclo-octa-1 ,5-diene and 2,5-norbornadiene. Cyclo-octa-1 ,5-diene is especially preferred. Optionally substituted cyclopentadienyl complexing groups which may be represented by Y includes cyclopentadienyl groups capable of eta-5 bonding. The cyclopentadienyl group is often substituted with from 1 to 5 substituents. Substituents may include halogen, cyano, nitro, hydroxy, amino, thiol, acyl, hydrocarbyl, perhalogentated hydrocarbyl, heterocyclyl, hydrocarbyloxy, mono or di-hydrocarbylamino, hydrocarbylthio, esters, carbonates, amides, sulphonyl and sulphonamido groups wherein the hydrocarbyl groups are as defined for R¹ above. Preferably, the cyclopentadienyl group is substituted with 1 to 5 hydrocarbyl groups, more preferably with 3 to 5 hydrocarbyl groups and most preferably with 5 hydrocarbyl groups. Preferred hydrocarbyl substituents include methyl, ethyl and phenyl. When the hydrocarbyl substitutents contain enantiomeric and/or diastereomeric centres, it may be advantageous that the enantiomerically and/or diastereomerically purified forms of these are used. Examples of optionally substituted cyclopentadienyl complexing groups include cyclopentadienyl, pentamethyl-cyclopentadienyl, pentaphenylcyclopentadienyl, tetraphenylcyclopentadienyl, ethyltetramethylpentadienyl, menthyltetraphenylcyclopentadienyl, neomenthyl- tetraphenylcyclopentadienyl, menthylcyclopentadienyl, neomenthylcyclopentadienyl, tetrahydroindenyl, menthyltetrahydroindenyl and neomenthyltetrahydroindenyl groups. Pentamethylcyclopentadienyl is especially preferred.

Transition metal halide complexes of the formula M_nX_pY_r wherein M is Rh or Ir, and Y is an optionally substituted cyclopentadienyl group are preferred. Transition metal halide complexes of the formula M_nX_pY_r wherein M is Ir and Y is an optionally substituted cyclopentadienyl group are most preferred.

Examples of transition metal halide complexes include Ru₂CI₄(CyITIyI)₂, Rh₂CI₄(Cp^*)₂, Rh₂Br₄(Cp^*);,_, Rh₂l₄(Cp^*)_2ι lr₂CI₄(Cp^*)_2i Ru₂l₄(cymyl)_2, RhCI₂Cp^* _, RhBr₂Cp^*, RhI₂Cp^* _, and lr₂l₄(Cp^*)₂ wherein Cp^* is a pentamethylcyclopentadienyl group.

In certain preferred embodiments, the catalyst system is preferably a composition obtainable by contacting a transition metal halide complex of the formula M_nX_pY_r wherein M is a transition metal; X is a halide; Y is a neutral optionally substituted hydrocarbyl complexing group, a neutral optionally substituted perhalogenated hydrocarbyl complexing group, or an optionally substituted cyclopentadienyl complexing group; and n, p and r are integers with an alcohol or sulphide ligand of formula (1).

The catalytic system may advantageously be introduced, at least in part, on a solid support or as an encapsulated system. Where the catalytic system is present on a solid support or as an encapsulated system, such supported catalyst systems may be of assistance in performing separation operations which may be required, and may facilitate the ease of cycling of materials between steps, especially when repetitions are envisaged. Examples of solid support or encapsulation technology that may be employed to support or encapsulate the catalytic system are described in WO03/006151 and WO05/016510.

Reaction promoters, which optionally may be present, include halide salts, for example metal halides. Preferred reaction promoters include bromide and especially iodide salts. Highly preferred are potassium iodide and caesium iodide.

Preferably, the process of the present invention is carried out in the presence of a base. Examples of bases include potassium carbonate and sodium carbonate.

In a further aspect of the present invention, the corresponding ketones or thioketones of formula (2)

(2) wherein:

X represents O, S;

R¹, R² each independently represents an optionally substituted hydrocarbyl, a perhalogenated hydrocarbyl, an optionally substituted heterocyclyl group; or

R¹ & R² are optionally linked in such a way as to form an optionally substituted ring(s); provided that R¹ and R² are different, derived by deprotonation of the starting alcohols or sulphides of formula (1) may be produced.

Where it is desired to suppress or promote the production of the corresponding ketones or thioketones of formula (2) derived by deprotonation of the starting alcohols or sulphides of formula (1), the use of hydrogen acceptors and/or hydrogen donors may advantageously be employed.

Hydrogen acceptors which may be present in the process of the present invention include the proton from an acid, oxygen, aldehydes and ketones, imines and imminium salts, readily hydrogenatable hydrocarbons, dyes, clean oxidising agents, carbonates, bicarbonates and any combination thereof.

The proton may emanate from any convenient and compatible acid such as formic acid, acetic acid, hydrogen carbonate, hydrogen sulfate, ammonium salt or alkyl ammonium salt. Conveniently the proton may emanate from the substrate itself. Aldehydes and ketones which may be employed as hydrogen acceptors comprise commonly from 1 to 20 carbon atoms, preferably from 2 to 15 carbon atoms, and more preferably 3 to 5 carbon atoms. Aldehydes and ketones include alkyl, aryl, hetroaryl aldehydes and ketones, and ketones with mixed alkyl, aryl or hetroaryl groups.

Examples of aldehydes and ketones which may be represented as hydrogen acceptors include formaldehyde, acetone, methylethylketone and benzophenone. When the hydrogen donor is an aldehyde or ketone, acetone is especially preferred.

Readily hydrogenatable hydrocarbons which may be employed as hydrogen acceptors comprise hydrocarbons which have a propensity to accept hydrogen or hydrocarbons which have a propensity to form reduced systems. Examples of readily hydrogenatable hydrocarbons which may be employed by as hydrogen donors include quinones, dihydroarenes and tetrahydroarenes.

Clean oxidising agents which may be represented as hydrogen acceptors comprise reducing agents with a high reduction potential, particularly those having an oxidation potential relative to the standard hydrogen electrode of greater than about 0.1eV, often greater than about 0.5eV, and preferably greater than about 1eV. Examples of clean oxidising agents which may be represented as hydrogen acceptors include oxidising metals and oxygen.

Dyes include Rose Bengal, Proflavin, Ethidium Bromide, Eosin and Phenolphthalein. Carbonates and bicarbonates include alkali metal, alkaline earth metal, ammonium and quaternary amine salts of carbonate and bicarbonate.

The most preferred hydrogen acceptors are protons from acids, acetone, oxygen, the substrate amine and carbonate and bicarbonate salts.

Hydrogen donors include hydrogen, primary and secondary alcohols, primary , secondary and tertiary amines, carboxylic acids and their esters and amine salts, readily dehydrogenatable hydrocarbons, clean reducing agents, and any combination thereof.

Primary and secondary alcohols which may be employed as hydrogen donors comprise commonly from 1 to 10 carbon atoms, preferably from 2 to 7 carbon atoms, and more preferably 3 or 4 carbon atoms. Examples of primary and secondary alcohols which may be represented as hydrogen donors include methanol, ethanol, propan-1-ol, propan- 2-ol, butan-1-ol, butan-2-ol, cyclopentanol, cyclohexanol, benzylalcohol, and menthol. When the hydrogen donor is an alcohol, secondary alcohols are preferred, especially propan-2-ol and butan-2-ol. Primary secondary and tertiary amines which may be employed as hydrogen donors comprise commonly from 1 to 20 carbon atoms, preferably from 2 to 14 carbon atoms, and more preferably 3 or 8 carbon atoms. Examples of primary, secondary and tertiary amines which may be represented as hydrogen donors include ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, hexylamine, diethylamine, dipropylamine, di-isopropylamine, dibutylamine, di-isobutylamine, dihexylamine, benzylamine, dibenzylamine, piperidine, (R) or (S) 6,7-dimethoxy-1- methyldihydroisoquinoline, triethylamine. When the hydrogen donor is an amine, primary amines are preferred, especially primary amines comprising a secondary alkyl group, particularly isopropylamine and isobutylamine. Carboxylic acids or their esters or salts which may be employed as hydrogen donors comprise commonly from 1 to 10 carbon atoms, preferably from 1 to 3 carbon atoms. In certain embodiments, the carboxylic acid is advantageously a beta-hydroxy- carboxylic acid. Esters may be derived from the carboxylic acid and a C_1-10 alcohol. Examples of carboxylic acids which may be employed as hydrogen donors include formic acid, lactic acid, ascorbic acid and mandelic acid. When a carboxylic acid is employed as hydrogen donor, at least some of the carboxylic acid is preferably present as a salt. Amine salts may be formed. Amines which may be used to form such salts include both aromatic and non-aromatic amines, also primary, secondary and tertiary amines and comprise typically from 1 to 20 carbon atoms. Tertiary amines, especially trialkylamines, are preferred. Examples of amines which may be used to form salts include trimethylamine, triethylamine, di-isopropylethylamine and pyridine. The most preferred amine is triethylamine. When at least some of the carboxylic acid is present as an amine salt, particularly when a mixture of formic acid and triethylamine is employed, the mole ratio of acid to amine is commonly about 5 : 2. This ratio may be maintained during the course of the reaction by the addition of either component, but usually by the addition of the carboxylic acid. Other preferred salts include sodium, potassium, magnesium

Readily dehydrogenatable hydrocarbons which may be employed as hydrogen donors comprise hydrocarbons which have a propensity to aromatise or hydrocarbons which have a propensity to form highly conjugated systems. Examples of readily dehydrogenatable hydrocarbons which may be employed by as hydrogen donors include cyclohexadiene, cyclohexene, tetralin, dihydrofuran and terpenes.

Clean reducing agents which may be represented as hydrogen donors comprise reducing agents with a high reduction potential, particularly those having a reduction potential relative to the standard hydrogen electrode of greater than about -0.1 eV, often greater than about -0.5eV, and preferably greater than about -1eV. Examples of clean reducing agents which may be represented as hydrogen donors include hydrazine and hydroxylamine.

The most preferred hydrogen donors are (R) or (S) 6,7-dimethoxy-1- methyldihydroisoquinoline propan-2-ol, butan-2-ol, triethylammonium formate, sodium formate, potassium formate and a mixture of triethylammonium formate and formic acid.

Although gaseous hydrogen may be present, the process is normally operated in the absence of gaseous hydrogen since it appears to be unnecessary.

Typically, inert gas sparging may be employed. Suitably the process is carried out at temperatures in the range of from minus 78 to plus 150⁰C, preferably from minus 20 to plus 110⁰C and more preferably from minus 10 to plus 4O⁰C.

The initial concentration of the substrate, a compound of formula (1 ), is suitably in the range 0.05 to 1.0 and, for convenient larger scale operation, can be for example up to 6.0 more especially 0.75 to 2.0, on a molar basis. The molar ratio of the substrate to the catalyst system is suitably no less than 50:1 and can be up to 50000:1 , preferably between 250:1 and 5000:1 and more preferably between 500:1 and 2500:1.

If a reaction promoter is present, the reaction promoter is preferably employed in a molar excess over the substrate, especially from 1 to 5 fold or, if convenience permits, greater, for example up to 20 fold.

If a hydrogen donor and/or acceptor is present, the hydrogen donor and/or acceptor is preferably employed in a molar excess over the substrate, especially from 5 to 20 fold or, if convenience permits, greater, for example up to 500 fold.

Reaction times are typically in the range of from 1.0 min to 24h, especially up to 8h and conveniently about 3h. After reaction, the mixture is worked up by standard procedures.

A reaction solvent may be present, for example dimethylformamide, acetonitrile, tetrahydrofuran, toluene, chloroform, dichloromethane or, conveniently, the substrate alcohol or sulphide when the substrate alcohol or sulphide is liquid at the reaction temperature. Usually it is preferred to operate in substantial absence of water, but water does not appear to unduly inhibit the reaction. If the substrate amine or the reaction solvent is not miscible with water and the desired product is water soluble, it may be desirable to have water present as a second phase. The concentration of substrate may be chosen to optimise reaction time, yield and de-enrichment of enantiomeric excess. In a yet further aspect of the present invention, a composition comprising the ketones or thioketones of formula (2) resulting from reacting an enantiomerically enriched composition comprising at least a first enantiomer or diastereomer of a substrate comprising a carbon-heteroatom bond, wherein the carbon is a chiral centre and the heteroatom is a group Vl heteroatom, in the presence of a catalyst system and optionally a reaction promoter is then contacted with a transfer hydrogenation catalyst and a hydrogen donor to give a product composition comprising first and second enantiomers or diastereomers of the substrate having a carbon-heteroatom bond, the ratio of second to first enantiomer or diastereomer in the product composition being greater than the ratio of second to first enantiomer or diastereomer in the enantiomerically enriched composition.

Hydrogen donors are as defined hereinbefore above.

The reduction of compounds of Formula 2 is preferably accomplished employing a stereoselective reduction system. It is most preferred that the stereoselective reduction employs a chiral coordinated transition metal catalysed transfer hydrogenation process. Examples of such processes, and the catalysts, reagents and conditions employed therein include those disclosed in International patent application publication numbers WO97/20789, WO98/42643, and WO02/44111 each of which is incorporated herein by reference. Preferred transfer hydrogenation catalysts for use in the process of the present invention have the general formula (a):

<^E>

M

Y' V

(a) wherein:

R³ represents a neutral optionally substituted hydrocarbyl, a neutral optionally substituted perhalogenated hydrocarbyl, or an optionally substituted cyclopentadienyl ligand;

A represents an optionally substituted nitrogen;

B represents an optionally substituted nitrogen, oxygen, sulphur or phosphorous; E represents a linking group; M represents a metal capable of catalysing transfer hydrogenation; and

Y represents an anionic group, a basic ligand or a vacant site; provided that at least one of A or B comprises a substituted nitrogen and the substituent has at least one chiral centre; and provided that when Y is not a vacant site that at least one of A or B carries a hydrogen atom.

Particularly preferred transfer hydrogenation catalysts are those Ru, Rh or Ir catalysts of the type described in WO97/20789, WO98/42643, and WO02/44111 which comprise an optionally substituted diamine ligand, for example an optionally substituted ethylene diamine ligand, wherein at least one nitrogen atom of the optionally substituted diamine ligand is substituted, preferably with a group containing a chiral centre, and a neutral aromatic ligand, for example p-cymene, or an optionally substituted cyclopentadiene ligand, for example pentamethylcyclopentadiene.

Highly preferred transfer hydrogenation catalysts for use in the process of the present invention are of general Formula (A):

Formula (A)

wherein:

A represents -NR⁴-, -NR⁵-, -NHR⁴, -NR⁴R⁵ or -NR⁴R⁵ where R⁴ is H, C(O)R⁶, SO₂R⁶, C(O)NR⁶R¹⁰, C(S)NR⁶R¹⁰, C(=NR¹⁰)SR¹¹ or C(=NR¹⁰)OR¹¹, R⁵ and R⁶ each independently represents an optionally substituted hydrocarbyl, perhalogenated hydrocarbyl or an optionally substituted heterocyclyl group, and R¹⁰ and R¹¹ are each independently hydrogen or a group as defined for R⁶;

B represents -O-, -OH, OR⁷, -S-, -SH, SR⁷, -NR⁷-, -NR⁸-, -NHR⁸, -NR⁷R⁸, -NR⁷R⁹, -PR⁷- or -PR⁷R⁹ where R⁸ is H, C(O)R⁹, SO₂R⁹, C(O)NR⁹R¹², C(S)NR⁹R¹², C(=NR¹²)SR¹³ or C(=NR¹²)OR¹³, R⁷ and R⁹ each independently represents an optionally substituted hydrocarbyl, perhalogenated hydrocarbyl or an optionally substituted heterocyclyl group, and R¹² and R¹³ are each independently hydrogen or a group as defined for R⁹; E represents a linking group;

M represents a metal capable of catalysing transfer hydrogenation; and Y represents an anionic group, a basic ligand or a vacant site; and provided that when Y is not a vacant site that at least one of A or B carries a hydrogen atom.

Highly preferred are transfer hydrogenation catalysts of Formula (A) wherein at least one of A or B comprises a substituted nitrogen and the substituent has at least one chiral centre.

The catalytic species is believed to be substantially as represented in the above formula. It may be introduced on a solid support.

Optionally substituted hydrocarbyl groups represented by R^5"7 or R^9'11 include alkyl, alkenyl, alkynyl and aryl groups, and any combination thereof, such as aralkyl and alkaryl, for example benzyl groups.

Alkyl groups which may be represented by R^5"7 or R^9"11 include linear and branched alkyl groups comprising 1 to 20 carbon atoms, particularly from 1 to 7 carbon atoms and preferably from 1 to 5 carbon atoms. In certain embodiments, the alkyl group may be cyclic, commonly comprising from 3 to 10 carbon atoms in the largest ring and optionally featuring one or more bridging rings. Examples of alkyl groups which may be represented by R^5"7 or R^9"11 include methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, t-butyl and cyclohexyl groups.

Alkenyl groups which may be represented by one or more of R^5"7 or R^9'11 include C_2-20, and preferably C_2-6 alkenyl groups. One or more carbon - carbon double bonds may be present. The alkenyl group may carry one or more substituents, particularly phenyl substituents.

Alkynyl groups which may be represented by one or more of R^5"7 or R^9'11 include

C_2-20, and preferably C_2-10 alkynyl groups. One or more carbon - carbon triple bonds may be present. The alkynyl group may carry one or more substituents, particularly phenyl substituents. Examples of alkynyl groups include ethynyl, propyl and phenylethynyl groups.

Aryl groups which may be represented by one or more of R^5"7 or R^9'11 may contain

1 ring or 2 or more fused or bridged rings which may include cycloalkyl, aryl or heterocyclic rings. Examples of aryl groups which may be represented by R^5"7 or R^9"11 include phenyl, tolyl, fluorophenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, anisyl, naphthyl and ferrocenyl groups.

Perhalogenated hydrocarbyl groups which may be represented by one or more of

R⁵⁷ or R^9"11 independently include perhalogenated alkyl and aryl groups, and any combination thereof, such as aralkyl and alkaryl groups. Examples of perhalogenated alkyl groups which may be represented by R^5'7 or R^9'11 include -CF₃ and -C₂F₅.

Heterocyclic groups which may be represented by one or more of R^5'7 or R^9'11 independently include aromatic, saturated and partially unsaturated ring systems and may comprise 1 ring or 2 or more fused rings which may include cycloalkyl, aryl or heterocyclic rings. The heterocyclic group will contain at least one heterocyclic ring, the largest of which will commonly comprise from 3 to 7 ring atoms in which at least one atom is carbon and at least one atom is any of N, O, S or P. Examples of heterocyclic groups which may be represented by R^5"7 or R^9'11 include pyridyl, pyrimidyl, pyrrolyl, thiophenyl, furanyl, indolyl, quinolyl, isoquinolyl, imidazolyl and triazolyl groups. When any of R^5'7 or R^9'11 is a substituted hydrocarbyl or heterocyclic group, the substituent(s) should be such so as not to adversely affect the rate or stereoselectivity of the reaction. Optional substituents include halogen, cyano, nitro, hydroxy, amino, imino, thiol, acyl, hydrocarbyl, perhalogenated hydrocarbyl, heterocyclyl, hydrocarbyloxy, mono or di-hydrocarbylamino, hydrocarbylthio, esters, carboxy, carbonates, amides, sulphonyl and sulphonamido groups wherein the hydrocarbyl groups are as defined for R^5'7 or R^9"11 above. One or more substituents may be present. R^5"7 or R^9"11 may each contain one or more chiral centres.

The neutral optionally substituted hydrocarbyl or perhalogenated hydrocarbyl ligand which may be represented by R³ includes optionally substituted aryl and alkenyl ligands.

Optionally substituted aryl ligands which may be represented by R³ may contain 1 ring or 2 or more fused rings which include cycloalkyl, aryl or heterocyclic rings. Preferably, the ligand comprises a 6 membered aromatic ring. The ring or rings of the aryl ligand are often substituted with hydrocarbyl groups. The substitution pattern and the number of substituents will vary and may be influenced by the number of rings present, but often from 1 to 6 hydrocarbyl substituent groups are present, preferably 2, 3 or 6 hydrocarbyl groups and more preferably 6 hydrocarbyl groups. Preferred hydrocarbyl substituents include methyl, ethyl, iso-propyl, menthyl, neomenthyl and phenyl. Particularly when the aryl ligand is a single ring, the ligand is preferably benzene or a substituted benzene. When the ligand is a perhalogenated hydrocarbyl, preferably it is a polyhalogenated benzene such as hexachlorobenzene or hexafluorobenzne. When the hydrocarbyl substitutents contain enantiomeric and/or diastereomeric centres, it is preferred that the enantiomerically and/or diastereomerically purified forms of these are used. Benzene, p-cymyl, mesitylene and hexamethylbenzene are especially preferred ligands.

Optionally substituted alkenyl ligands which may be represented by R³ include C_2-30, and preferably C₆^₂, alkenes or cycloalkenes with preferably two or more carbon- carbon double bonds, preferably only two carbon-carbon double bonds. The carbon- carbon double bonds may optionally be conjugated to other unsaturated systems which may be present, but are preferably conjugated to each other. The alkenes or cycloalkenes may be substituted preferably with hydrocarbyl substituents. When the alkene has only one double bond, the optionally substituted alkenyl ligand may comprise two separate alkenes. Preferred hydrocarbyl substituents include methyl, ethyl, iso-propyl and phenyl. Examples of optionally substituted alkenyl ligands include cyclo-octa-1 ,5- diene and 2,5-norbomadiene. Cyclo-octa-1 ,5-diene is especially preferred.

Optionally substituted cyclopentadienyl groups which may be represented by R³ include cyclopentadienyl groups capable of eta-5 bonding. The cyclopentadienyl group is often substituted with from 1 to 5 hydrocarbyl groups, preferably with 3 to 5 hydrocarbyl groups and more preferably with 5 hydrocarbyl groups. Preferred hydrocarbyl substituents include methyl, ethyl and phenyl. When the hydrocarbyl substitutents contain enantiomeric and/or diastereomeric centres, it is preferred that the enantiomerically and/or diastereomerically purified forms of these are used. Examples of optionally substituted cyclopentadienyl groups include cyclopentadienyl, pentamethyl- cyclopentadienyl, pentaphenylcyclopentadienyl, tetraphenylcyclopentadienyl, ethyltetramethylpentadienyl, menthyltetraphenylcyclopentadienyl, neomenthyl- tetraphenylcyclopentadienyl, menthylcyclopentadienyl, neomenthylcyclopentadienyl, tetrahydroindenyl, menthyltetrahydroindenyl and neomenthyltetrahydroindenyl groups. Pentamethylcyclopentadienyl is especially preferred.

When either A or B is an amide group represented by -NR⁴-, -NHR⁴, NR⁴R⁵, -NR⁸- , -NHR⁸ or NR⁷R⁸ wherein R⁵ and R⁷ are as hereinbefore defined, and where R⁴ or R⁸ is an acyl group represented by -C(O)R⁶ or -C(O)R⁹, R⁶ and R⁹ independently are often linear or branched C_1-7alkyl, C_1-8-cycloalkyl or aryl, for example phenyl. Examples of acyl groups which may be represented by R⁶ or R¹⁰ include benzoyl, acetyl and halogenoacetyl, especially trifluoroacetyl groups.

When either A or B is present as a sulphonamide group represented by -NR⁴-, -NHR⁴, NR⁴R⁴, -NR⁸-, -NHR⁸ or NR⁷R⁸ wherein R⁵ and R⁷ are as hereinbefore defined, and where R⁴ or R⁸ is a sulphonyl group represented by -S(O)₂R⁶ or -S(O)₂R⁹, R⁶ and R⁹ independently are often linear or branched C_1-12alkyl, C_1-12cycloalkyl or aryl, for example phenyl. Preferred sulphonyl groups include methanesulphonyl, trifluoromethanesulphonyl, more preferably p-toluenesulphonyl groups and naphthylsulphonyl groups and especially camphorsulphonyl.

When either of A or B is present as a group represented by -NR⁴-, -NHR⁴, NR⁴R⁵, -NR⁸-, -NHR⁸ or NR⁷R⁸ wherein R⁵ and R⁷ are as hereinbefore defined, and where R⁴ or R⁸ is a group represented by C(O)NR⁶R¹⁰, C(S)NR⁶R¹⁰, C(=NR¹⁰)SR¹¹, C(=NR¹⁰)OR¹¹, C(O)NR⁹R¹², C(S)NR⁹R¹², C(=NR¹²)SR¹³ or C(=NR¹²)OR¹³, R⁶ and R⁹ independently are often linear or branched C_1-8alkyl, such as methyl, ethyl, isopropyl, C_1-8cycloalkyl or aryl, for example phenyl, groups and R^10'13 are often each independently hydrogen or linear or branched C_1-8alkyl, such as methyl, ethyl, isopropyl, C_1-8cycloalkyl or aryl, for example phenyl, groups.

When B is present as a group represented by -OR⁷, -SR⁷, -PR⁷- or -PR⁷R⁹, R⁷ and R⁹ independently are often linear or branched C_1-8alkyl, such as methyl, ethyl, isopropyl, C_1-8cycloalkyl or aryl, for example phenyl. It will be recognised that the precise nature of A and B will be determined by whether A and/or B are formally bonded to the metal or are coordinated to the metal via a lone pair of electrons.

The groups A and B are connected by a linking group E. The linking group E achieves a suitable conformation of A and B so as to allow both A and B to bond or coordinate to the metal, M. A and B are commonly linked through 2, 3 or 4 atoms. The atoms in E linking A and B may carry one or more substituents. The atoms in E, especially the atoms alpha to A or B, may be linked to A and B, in such a way as to form a heterocyclic ring, preferably a saturated ring, and particularly a 5, 6 or 7-membered ring. Such a ring may be fused to one or more other rings. Often the atoms linking A and B will be carbon atoms. Preferably, one or more of the carbon atoms linking A and B will carry substituents in' addition to A or B. Substituent groups include those which may substitute _R ⁵-⁷ _{or R} ⁹-ⁱⁱ _as defined above. Advantageously, any such substituent groups are selected to be groups which do not coordinate with the metal, M. Preferred substituents include halogen, cyano, nitro, sulphonyl, hydrocarbyl, perhalogenated hydrocarbyl and heterocyclyl groups as defined above. Most preferred substituents are C_1-6 alkyl groups, and phenyl groups. Most preferably, A and B are linked by two carbon atoms, and especially an optionally substituted ethyl moiety. When A and B are linked by two carbon atoms, the two carbon atoms linking A and B may comprise part of an aromatic or aliphatic cyclic group, particularly a 5, 6 or 7-membered ring. Such a ring may be fused to one or more other such rings. Particularly preferred are embodiments in which E represents a 2 carbon atom separation and one or both of the carbon atoms carries an optionally substituted aryl group as defined above or E represents, a 2 carbon atom separation which comprises a cyclopentane or cyclohexane ring, optionally fused to a phenyl ring.

E preferably comprises part of a compound having at least one stereospecific centre. Where any or all of the 2, 3 or 4 atoms linking A and B are substituted so as to define at least one stereospecific centre on one or more of these atoms, it is preferred that at least one of the stereospecific centres be located at the atom adjacent to either group A or B. When at least one such stereospecific centre is present, it is advantageously present in an enantiomerically purified state.

When B represents -O- or -OH, and the adjacent atom in E is carbon, it is preferred that B does not form part of a carboxylic group.

Compounds which may be represented by A-E-B, or from which A-E-B may be derived by deprotonation, are often aminoalcohols, including 4-aminoalkan-1-ols, 1-aminoalkan-4-ols, 3-aminoalkan-1-ols, 1~aminoalkan-3-ols, and especially 2-aminoalkan-1-ols, 1-aminoalkan-2-ols, 3-aminoalkan-2-ols and 2-aminoalkan-3-ols, and particularly 2-aminoethanols or 3-aminopropanols, or are diamines, including 1 ,4-diaminoalkanes, 1 ,3-diaminoalkanes, especially 1 ,2- or 2,3- diaminoalkanes and particularly ethylenediamines. Further aminoalcohols that may be represented by A-E-B are 2-aminocyclopentanols and 2-aminocyclohexanols, preferably fused to a phenyl ring. Further diamines that may be represented by A-E-B are 1 ,2-diaminocyclopentanes and 1 ,2-diaminocyclohexanes, preferably fused to a phenyl ring. The amino groups may advantageously be N-tosylated. When a diamine is represented by A-E-B, preferably at least one amino group is N-tosylated. The aminoalcohols or diamines are advantageously substituted, especially on the linking group, E, by at least one alkyl group, such as a C_1-4-alkyl, and particularly a methyl, group or at least one aryl group, particularly a phenyl group.

Specific examples of compounds which can be represented by A-E-B and the protonated equivalents from which they may be derived are:

Preferably, the enantiomerically and/or diastereomerically purified forms of these are used. Examples include (1S,2R)-(+)-norephedrine, (1R,2S)-(+)-cis-1-amino-2- indanol, (1 S,2R)-2-amino-1 ,2-diphenylethanol, (1 S,2R)-(-)-cis-1 -amino-2-indanol, (1 R,2S)-(-)-norephedrine, (S)-(+)-2-amino-1 -phenylethanol, (1 R,2S)-2-amino-1 ,2- diphenylethanol, N-tosyl-(1 R,2R)-1 ,2-diphenylethylenediamine, N-tosylr(1 S,2S)-1 ,2- diphenylethylenediamine, (1 R,2S)-cis-1 ,2-indandiamine, (1 S,2R)-cis-1 ,2-indandiamine, (R)-(-)-2-pyrrolidinemethanol and (S)-(+)-2-pyrrolidinemethanol.

Metals which may be represented by M include metals which are capable of catalysing transfer hydrogenation. Preferred metals include transition metals, more preferably the metals in Group VIII of the Periodic Table, especially ruthenium, rhodium or iridium. When the metal is ruthenium it is preferably present in valence state II. When the metal is rhodium or iridium it is preferably present in valence state I when R³ is a neutral optionally substituted hydrocarbyl or a neutral optionally substituted perhalogenated hydrocarbyl ligand, and preferably present in valence state III when R³ is an optionally substituted cyclopentadienyl ligand.

It is preferred that M, the metal, is rhodium present in valence state III and R³ is an optionally substituted cyclopentadienyl ligand.

Anionic groups which may be represented by Y include hydride, hydroxy, hydrocarbyloxy, hydrocarbylamino and halogen groups. Preferably when a halogen is represented by Y, the halogen is chloride. When a hydrocarbyloxy or hydrocarbylamino group is represented by Y, the group may be derived from the deprotonation of the hydrogen donor utilised in the reaction.

Basic ligands which may be represented by Y include water, C_1-4 alcohols, C_1-8 primary or secondary amines, or the hydrogen donor which is present in the reaction system. A preferred basic ligand represented by Y is water.

Most preferably, A-E-B, R³ and Y are chosen so that the catalyst is chiral. When such is the case, an enantiomerically and/or diastereomerically purified form is preferably employed. Such catalysts are most advantageously employed in asymmetric transfer hydrogenation processes. In many embodiments, the chirality of the catalyst is derived from the nature of A-E-B.

Especially preferred are catalysts of Formula B(i-iv):

B(iv)

The transfer hydrogenation catalysts may be prepared in advance or in-situ by combining a ligand, preferably a chiral bidentate nitrogen ligand, with a metal complex, for example a Ru, Rh or Ir metal complex containing a neutral optionally substituted hydrocarbyl complexing group, a neutral optionally substituted perhalogenated hydrocarbyl complexing group, or an optionally substituted cyclopentadienyl complexing group. Preferably a solvent is present in this operation. The solvent used may be anyone which does not adversely effect the formation of the catalyst. These solvents include acetonitrile, ethylacetate, toluene, methanol, tetrahydrofuran, ethylmethyl ketone. Preferably the solvent is methanol.

Advantageously, the process of the present invention may find use in recycling unwanted isomers obtained from chiral processes, such as chiral separations, chemical and enzymic chiral resolutions and the likes. Typically, in chiral separations or resolutions, racemic mixtures are subjected to physical, chemical or biochemical treatments which result in the separation of a desired enantiomer or enatiomeric product while often leaving behind an unreacted or unwanted enatiomers or enatiomeric bi- products. The process of the present invention provides a method for converting the unreacted enatiomers to usable feedstocks containing wanted enatiomers.

The invention is illustrated by the following Examples.

Example 1 Procedure

Rxn 1 : Std Conditions + 0.5eq 2,4-Dimethyl-3-pentanol

To a 10 ml round bottom flask was added (S)-i-phenylethanol (246.8 mg 99%, 244.3 mg, 2.0 mmol), pentamethylcyclopentadienyliridiumOII) chloride dimer (16.6 mg

96%, 15.9 mg, 0.02 mmol), tridecane (372.4 mg 99%, 368.7mg, 2.0 mmol), potassium iodide (335.4 mg 99%, 332.0 mg, 2.0 mmol), 2,4-dimethyl-3-pentanol (117.4 mg 99%,

116.2 mg, 1.0 mmol), potassium carbonate (279.2 mg 99%, 276.4 mg, 2.0 mmol) and toluene (4 ml) resulting in a pale orange solution. A water condenser was attached and the reaction vessel was placed in an oil bath at 8O⁰C and a timer started, within one minute of being in the oil bath the reaction solution became a dark orange and darkened gradually to a dark brown after 2hrs and remained this colour throughout. Samples were taken (~100μl) at regular intervals and quenched into dichloromethane (2 ml) and 0.5M sodium hydroxide solution (2 ml), the organic layer was separated, dried using sodium sulphate, filtered and analysed by achiral and chiral g.c.

Rxn 2 : Std Conditions + 1.Peg 2,4-Dimethyl-3-pentanol

To a 10 ml round bottom flask was added (S)-i-phenylethanol (246.8 mg 99%, 244.3 mg, 2.0 mmol), pentamethylcyclopentadienyliridium(lll) chloride dimer (16.6 mg 96%, 15.9 mg, 0.02 mmol), tridecane (372.4 mg 99%, 368.7mg, 2.0 mmol), potassium iodide (335.4 mg 99%, 332.0 mg, 2.0 mmol), 2,4-dimethyl-3-pentanol (234.7 mg 99%, 232.4 mg, 2.0 mmol), potassium carbonate (279.2 mg 99%, 276.4 mg, 2.0 mmol) and toluene (4 ml) resulting in a pale orange solution. A water condenser was attached and the reaction vessel was placed in an oil bath at 8O⁰C and a timer started, within one minute of being in the oil bath the reaction solution became a dark orange and darkened gradually to a dark brown after 2hrs and remained this colour throughout. Samples were taken (~100μl) at regular intervals and quenched into dichloromethane (2 ml) and 0.5M sodium hydroxide solution (2 ml), the organic layer was separated, dried using sodium sulphate, filtered and analysed by achiral and chiral g.α.

Analysis

Achiral q.c.

Chrompac 7680 CP SIL 5CB column. Length = 25.0 m, Diameter 320 μm, Film thickness = 5.0 μm. Pressure = 8.0 psi. FIoW = 1.1 ml/min.

Temperature = 25O⁰C for 22.5 mins then ramp at 20°C/min to 300⁰C.

1-Phenylethanol = 13.1 mins. Acetophenone = 13.7 mins. Tridecane = 27.5 mins

2,4-Dimethyl-3-pentanol = 5.7 mins

Chiral q.c.

CP-Chirasil-Dex-CB column. Length = 25.0 m, Diameter = 250 μm, Film thickness = 0.25 μm.

Pressure = 10.0 psi.

Flow = 0.7 ml/min.

Temperature = 11O⁰C for 40 mins then ramp at 20°C/min to 19O⁰C and hold for 5 mins.

(R)-1-Phenylethanol= 23.7 mins. (S)-1-Phenylethanol= 26.0 mins. Acetophenone = 10.0 mins. Tridecane = 21.0 mins. 2,4-Dimethyl-3-pentanol = 4.6 mins.

1-Phenylethanol racemisation using rirCp*CI212 / Kl + 1eα K2CO3 in toluene at 80deqC.

Rxn1 + 0.5eα 2,4-Dimethylpentan-3-ol

Rxn2 + 1.Peg 2,4-Dimethylpentan-3-ol

Example 2 Procedure

Rxn 2 : + potassium carbonate To a 10 ml round bottom flask was added (S)-i-phenylethanol (246.8 mg 99%, 244.3 mg, 2.0 mmol), pentamethylcyclopentadienyliridiumOII) chloride dimer (16.6 mg 96%, 15.9 mg, 0.02 mmol), tridecane (372.4 mg 99%, 368.7mg, 2.0 mmol), potassium iodide (335.4 mg 99%, 332.0 mg, 2.0 mmol), potassium carbonate (279.2 mg 99%, 276.4 mg, 2.0 mmol) and toluene (4 ml) resulting in a pale orange solution. A water condenser was attached and the reaction vessel was placed in an oil bath at 8O⁰C and a timer started, within one minute of being in the oil bath the reaction solution became a dark orange which became increasingly darker and was a dark brown after 2 hrs and remained this colour throughout. Samples were taken (~100μl) at regular intervals and quenched into dichloromethane (2 ml) and 2.5M sodium hydroxide solution (2 ml), the organic layer was separated, dried using sodium sulphate, filtered and analysed by achiral and chiral g.c.

Analysis

Achiral g.c.

Chrompac 7680 CP SIL 5CB column. Length = 25.0 m, Diameter 320 μm, Film thickness = 5.0 μm.

Pressure = 8.0 psi. Flow = 1.1 ml/min. Temperature = 25O⁰C for 22.5 mins then ramp at 20°C/min to 300⁰C.

1-Phenylethanol = 13.1 mins. Acetophenone = 13.7 mins. Tridecane = 27.5 mins

Chiral g.c.

Pressure = 10.0 psi. Flow = 0.7 ml/min. Temperature = 110⁰C for 40 mins then ramp at 20°C/min to 19O⁰C and hold for 5 mins.

(R)-1-Phenylethanol= 23.7 mins. (S)-1-Phenylethanol= 26.0 mins. Acetophenone = 10.0 mins. Tridecane = 21.0 mins.

Rxn2 Std Conditions + 1eα K2CO3

Example 3

Preparation of catalyst and reduction of acetophenone

Reactant Wt used Mol.Wt MoI ratio

[Rh(Cp*)cy₂** 0.0254g 618.08 1.0 41.2μmol

(1S.2RM+)-

Norephedrine 0.0209g 151.21 3.36 138.2μmol

2-propanol (anhydrous) 100ml 60.10 31677 1.305mol

KOH 0.1 M in

2-propanol 3.3ml 56.11 4.01 0.33mmol

Acetophenone 2.06g 120.15 209 17mmol

Notes: ** purchased from STREM Chemicals

Prior to the reaction, the solvent was degassed:

100ml of anhydrous 2-propanol was added by syringe to a sealed clean dry round bottomed flask and degassed in vacuo at under 20⁰C for 30 min.

(a) Catalyst Preparation

The (+)-norephedrine and rhodium compound were weighed out into a clean dry Schlenk flask. The flask was stoppered with a 'Suba-seal' (RTM). Its contents were evacuated, then purged at room temperature by 15 changes of nitrogen. Then 2- propanol (20ml) was added by cannula. The flask tap was closed and the flask swirled until the starting solids dissolved. The result was an orange-coloured supernatant and a dark solid. The flask tap was re-opened, a current of nitrogen fed in, and the flask contents heated at 60⁰C for 2h 5min. The catalyst was checked at 30 min intervals. At each interval it was a dark brown solution, with a black solid at the bottom.

(b) Hydrogenation

The acetophenone was dissolved in 2-propanol (80ml) then degassed for 40min. This solution was added to the catalyst-containing flask by cannula, followed via syringe by the degassed 0.1 M solution of KOH in 2-propanol. The mixture was left at room temperature, samples being taken at intervals and examined by gas chromatography. At the small scale of operation the reaction mixture was not sparged with the nitrogen, but sparging would be used in larger scale production. After 1h, (R)-i-phenylethanol was obtained conversion 92%, 84% ee.

Example 4: Reactant Wt used MoI wt mol ratio

[Rh(Cp*)CI₂]₂ 6.3mg 618.08 1.0 10.2μmol (1S,2R)-(-)-cis- 1-amino-2-indanol 3.1mg 149.19 2.0 20.8μmol acetophenone 1.29g 120.15 1039 10.6mmol 2-propanol 63857

(a) Catalyst Preparation

The rhodium compound was suspended in 50ml of 2-propanol and degassed by 3 cycles of vacuum and nitrogen flush. The mixture was heated to gentle reflux until the solid dissolved, then cooled to ambient temperature. (1S,2R)-(-)-cis-1-amino-2-indanol was added to the solution with stirring. The mixture was degassed by cycles of vacuum and nitrogen flush and warmed at 30⁰C for 30min. The resulting orange-red solution of the catalyst was passed to the next stage but could be stored under argon or nitrogen.

(b) Hydrogenation

The acetophenone was added to the catalyst solution. The mixture was stirred at ambient temperature for 1h. Sodium 2-propoxide (0.25ml of freshly prepared 0.1 M solution in 2-propanol) was added. The mixture was stirred for 2h and sampled; 57% of the acetophenone had reacted to give (R)-i-phenylethanol of 79% ee. Example 5: Reactant Wt used MoI wt mol ratio

[lr(Cp^*)Cy₂ 32.8mg 796.67 1.0 41.2μmc (1S.2RH+)- norephedrine 20mg 151.21 3.2 132μmol acetophenone 2ml 120.15 413 17mmol 2-propanol 10OmI

(a) Catalyst Preparation The iridium compound and (+)-norephedrine were suspended in degassed 2- propanol (20ml) under nitrogen, and the reaction purged with nitrogen for 30 minutes. The mixture was heated to 6O⁰C for 90min, then cooled to ambient temperature. The resulting solution of the catalyst: was passed to the next stage but could be stored under argon or nitrogen.

(b) Hvdrogenation

Acetophenone (2ml, 17mmol) was dissolved in 2-propanol (80ml) and purged with nitrogen. Then the catalyst solution was added followed by potassium hydroxide solution (3.3ml of 0.1 M solution in 2-propanol). The mixture was stirred at ambient temperature under nitrogen for 10h. This gave 1-phenylethanol. Yield 68%, ee 49%.

Claims

1. A process for the de-enrichment of enantiomerically enriched compositions which comprises reacting an enantiomerically enriched composition comprising at least a first enantiomer or diastereomer of a substrate comprising a carbon-heteroatom bond, wherein the carbon is a chiral centre and the heteroatom is a group Vl heteroatom, in the presence of a catalyst system and optionally a reaction promoter to give a product composition comprising first and second enantiomers or diastereomers of the substrate having a carbon-heteroatom bond, the ratio of second to first enantiomer or diastereomer in the product composition being greater than the ratio of second to first enantiomer or diastereomer in the enantiomerically enriched composition.

2. A process according to Claimi wherein the substrate comprising a carbon- heteroatom bond, the carbon atom being a chiral centre, is a compound of formula (1):

(D wherein:

X represents O, S;

R¹, R² each independently represents an optionally substituted hydrocarbyl, a perhalogenated hydrocarbyl, an optionally substituted heterocyclyl group; or R¹ & R² are optionally linked in such a way as to form an optionally substituted ring(s); provided that R¹ and R² are selected such that * is a chiral centre.

3. A process according to Claim 1 or Claim 2 wherein the catalyst system comprises a transition metal catalyst and optionally a ligand.

4. A process according to Claim 3 wherein the transition metal catalyst is a transition metal halide complex of the formula M_nX_pY_r wherein M is a transition metal;

X is a halide;

Y is a neutral optionally substituted hydrocarbyl complexing group, a neutral optionally substituted perhalogenated hydrocarbyl complexing group, or an optionally substituted cyclopentadienyl complexing group; and n, p and r are integers.

5. A process according to Claim 4 wherein M is Rh or Ir, and Y is an optionally substituted cyclopentadienyl group

6. A process according to Claim 5 wherein M is Ir, X is I, and Y is an optionally substituted cyclopentadienyl group, preferably a pentamethylcyclopentadienyl group.

7. A process according to Claim 6 wherein the transition metal catalyst is a transition metal halide complex of the formula M₂X₄Y₂ wherein M is Ir, X is I, and Y is an optionally substituted cyclopentadienyl group, preferably a pentamethylcyclopentadienyl group.

8. A process according to any one of Claims 1 to 7 wherein a reaction promoter is present.

9. A process according to Claim 8 wherein the reaction promoter is a halide salt.

10. A process according to Claim 9 wherein the halide salt is a metal halide.

11. A process according to Claim 10 wherein the metal halide is potassium or caesium iodide.

12. A process according to any one of Claims 1 to 10 wherein a base is present, preferably potassium carbonate or sodium carbonate.

13. A process according to any one of Claims 1 to 12 wherein a compound of formula

(2): x

A* (2) wherein:

X represents O, S;

R¹, R² each independently represents an optionally substituted hydrocarbyl, a perhalogenated hydrocarbyl, an optionally substituted heterocyclyl group; or R¹ & R² are optionally linked in such a way as to form an optionally substituted ring(s); provided that R¹ and R² are different, is obtained.

14. A process according to claim 13 wherein the ketones or thioketones of formula (2) resulting from reacting an enantiomerically enriched composition comprising at least a first enantiomer or diastereomer of a substrate comprising a carbon-heteroatom bond, wherein the carbon is a chiral centre and the heteroatom is a group Vl heteroatom, in the presence of a catalyst system and optionally a reaction promoter is then contacted with a transfer hydrogenation catalyst and a hydrogen donor to give a product composition comprising first and second enantiomers or diastereomers of the substrate having a 5 carbon-heteroatom bond, the ratio of second to first enantiomer or diastereomer in the product composition being greater than the ratio of second to first enantiomer or diastereomer in the enantiomerically enriched composition.

15. A process according to claim 14 wherein the transfer hydrogenation catalyst is a o catalyst of general formula (a):

<^E>

M

(a) wherein: 5 R³ represents a neutral optionally substituted hydrocarbyl, a neutral optionally substituted perhalogenated hydrocarbyl, or an optionally substituted cyclopentadienyl ligand;

A represents an optionally substituted nitrogen;

B represents an optionally substituted nitrogen, oxygen, sulphur or phosphorous; 0 E represents a linking group;

M represents a metal capable of catalysing transfer hydrogenation; and

Y represents an anionic group, a basic ligand or a vacant site; provided that at least one of A or B comprises a substituted nitrogen and the substituent has at least one chiral centre; and 5 provided that when Y is not a vacant site that at least one of A or B carries a hydrogen atom.

16. A process according to any one of Claims 1 to 15 wherein the enantiomerically enriched composition comprising at least a first enantiomer or diastereomer of a substrate o comprising a carbon-heteroatom bond is an unreacted enatiomer or bi-product obtained from a chiral separation, or chemical or enzymic chiral resolution.

17. A composition obtainable by contacting a transition metal halide complex of the formula M_nX_pY_r wherein M is a transition metal; X is a halide; Y is a neutral optionally 5 substituted hydrocarbyl complexing group, a neutral optionally substituted perhalogenated hydrocarbyl complexing group, or an optionally substituted cyclopentadienyl complexing group; and n, p and r are integers with an alcohol or sulphide ligand of formula (1) (D wherein:

X represents O, S;

R¹ & R² are optionally linked in such a way as to form an optionally substituted ring(s); provided that R¹ and R² are selected such that ^* is a chiral centre, and optionally a base.

18. A composition according to Claim 17 wherein a base is utilised and the base is potassium carbonate or sodium carbonate.