WO2004065335A1 - Enantioselective reduction method - Google Patents

Abstract

The invention provides a method for enantioselectively reducing a prochiral carbon centred radical having one or more electron donor groups attached directly to the central prochiral carbon atom of the radical, and/or attached to a carbon atom within 1 to 4 atoms of the central prochiral carbon atom of the radical, said method comprising generating said radical from a radical precursor compound and reacting said radical with a chiral non-racemic organotin hydride in the presence of a Lewis acid and a co-reducing agent, wherein said co-reducing agent is capable of regenerating chiral non-racemic organotin hydride without substantially reducing said radical or said radical precursor compound.

Description

ENANTIOSELECTIVE REDUCTION METHOD

FIELD OF THE INVENTION

The present invention relates generally to reductive methods useful in chemical synthesis. In particular, the present invention provides enantioselective reductive methods using chiral organostannanes in combination with a Lewis acid and a co-reducing agent.

BACKGROUND

The scientific literature contains numerous reports of free-radical reactions proceeding with diastereocontrol, (see for example, reviews such as Curran, D.P., et al, Stereochemistry of Radical Reactions, VCH, Weinheim, 1995; Smadja, W., et al Synlett., 1994, 1; Porter, N.A., et al, Acc.Chem., Res., 1991, 24, 296; and Sibi, M., et al, Ace. Chem., Res., 1999, 32, 163). However, there are relatively very few examples of free- radical reactions which proceed with genuine enantiocontrol. The majority of the examples that demonstrate enantioselective outcomes involve the use of chiral auxiliaries and, as a result, are actually further examples of diastereo-selectivity in free-radical chemistry.

Of the remaining few reports, the introduction of asymmetry in the substrate has been achieved through the use of chiral Lewis acid mediation (see for example, Guindon, Y., et al, Tetrahedron Lett., 1990, 31, 2845; Guindon, Y., et al, J. Am. Chem. Soc, 1991, 113, 9701 and Renaud, P., et al Angew,. Chem. Int. Ed., 1998, 37, 2563), or by a chiral reagent through the use of chiral ligands on the tin atoms in suitably constructed stannanes (Schumann, H., et al, J. Organomet. Chem. 1984, 265,145; Curran, D. P., et al, Tetrahedron; Asymmetry, 1996, 7, 2417; Blumenstein, M., et al, Angew. Chem. Int. Ed., 1997, 36, 235 and Schawrtzkopf, K., et al, Eur. J. Chem., 1998, 177).

Recently, US 2002/0133039 disclosed a method for enhancing the enantioselectivity of stannane mediated free radical reductions. In this method, a combination of a chiral non- racemic stannane and an appropriate Lewis acid are used to reduce a selected class of prochiral carbon centered radicals. Although effective at producing compounds with high enantiomeric purity, the method does however typically require a net amount of at least one molar equivalent of stannane per reductive site on a substrate to afford acceptable yields of the reduced product. This requirement presents several disadvantages. In particular, as these stannanes are generally expensive to prepare their use on at least an equimolar basis makes the process less attractive on a commercial scale. Furthermore, for every mole of reductive sites that are reduced, at least one mole of stannane residue is produced that will ultimately have to be disposed of.

It would therefore be desirable to provide an enantioselective reductive method that made use of the aforementioned stannane/Lewis acid combination, yet enabled the reduced product to be prepared using a comparatively lower net amount of stannane.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a method for enantioselectively reducing a prochiral carbon centred radical having one or more electron donor groups attached directly to the central prochiral carbon atom of the radical, and/or attached to a carbon atom within 1 to 4 atoms of the central prochiral carbon atom of the radical, said method comprising generating said radical from a radical precursor compound and reacting said radical with a chiral non-racemic organotin hydride in the presence of a Lewis acid and a co-reducing agent, wherein said co-reducing agent is capable of regenerating chiral non- racemic organotin hydride without substantially reducing said radical or said radical precursor compound.

Preferably, the electron donor group is attached directly to the central prochiral carbon atom or to a carbon atom within 1 or 2 atoms of the central prochiral carbon atom.

In a particular embodiment, the invention is directed towards a method of producing optically enhanced α or β- amino acids, by generating a prochiral amino acid carbon centred radical. from a radical precursor compound and reacting said prochiral amino acid carbon centred radical with a chiral non-racemic organotin hydride in the presence of a Lewis acid and a co-reducing agent, wherein said co-reducing agent is capable of regenerating non-racemic organotin hydride without substantially reducing said prochiral amino acid carbon centred radical or said radical precursor compound, and wherein the central prochiral carbon atom of each said radical is an α- carbon atom of an α- amino acid or a β- carbon atom of a β-amino acid.

In performing the method of the present invention, a radical precursor compound (ie. the substrate) provides a source of pro-chiral carbon centred radicals which are reduced by chiral non-racemic organotin hydride in a primary reduction reaction. The organotin residue resulting from the primary reduction reaction is then reduced by the co-reducing agent in a secondary reduction reaction to regenerate chiral non-racemic organotin hydride.

The regenerated chiral non-racemic organotin hydride can then take part in further primary reduction reactions. Accordingly, the net amount of organotin hydride used to reduce a given amount of substrate can advantageously be reduced to below a molar equivalent per mole of reductive sites provided by the substrate. Importantly, this reduction in the net amount of organotin hydride can be achieved while still maintaining acceptable yields and enantioselectivity of the reduced product.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "prochiral carbon centred radical" is a radical of formula RιR₂R₃C\ wherein each R residue is different and is not hydrogen. Accordingly, the central prochiral carbon atom is the carbon atom to which the R residues are attached. Reduction of the prochiral carbon centred radical with a hydrogen atom donor affords the chiral compound RιR₂R₃CH.

The prochiral carbon centred radical can be generated from any suitable radical precursor compound using methods known in the art. Exemplary radical precursor compounds include aryl, eg phenyl, selenides; aryl, eg phenyl, sulfides; aryl, eg phenyl, tellurides; xanthates; thionoformates and Barton esters (see for example B. Giese, Radicals in Organic Synthesis - Formation ofC-C Bonds (1986) Pergamon Press, Oxford, the contents of which are incorporated herein by reference). Particularly suitable radical precursor compounds for generating the prochiral carbon centred radicals for use in the invention are tertiary chiral halosubstrates, ie RιR₂R₃C-halogen, where R1-R₃ are different and not hydrogen and halogen is chlorine, bromine or iodine, preferably bromine.

As used herein, the term "organotin residue" is used to denote an organotin by-product that results from the overall reduction reaction between the radical precursor compound, which generates the pro-chiral carbon centred radicals, and the chiral non-racemic organotin hydride. For example, where the radical precursor compound is a tertiary chiral halo- substrate, i.e. R₁R₂R₃ C-halogen, the organotin residue would be an organotin halide.

The present invention utilises a co-reducing agent. An important characteristic of the co- reducing agent is that it should be capable of regenerating chiral non-racemic organotin hydride. By being "capable of regenerating chiral non-racemic organotin hydride", it is meant that a co-reducing should be able to react with the organotin residue formed from the primary reduction reaction between the organotin hydride and the radical precursor compound which generates the prochiral carbon centered radicals, and reduce this residue in a secondary reduction reaction to thereby regenerate chiral non-racemic organotin hydride.

Accordingly, the function of the co-reducing agent is to effectively act as a hydrogen donor toward the organotin residue. Advantageously, the regenerated organotin hydride can take part in further primary reduction reactions. In particular, by providing means to regenerate chiral non-racemic organotin hydride, the reductive method of the present invention enables the net amount of organotin hydride used to reduce a given amount of substrate to be advantageously reduced below a molar equivalent per mole of reductive sites provided by the substrate. As used herein, the term "reductive sites" is intended to denote the prochiral carbon centred radicals which are generated from the radical precursor compound. Importantly, this reduction in the net amount of organotin hydride can be achieved while still maintaining acceptable yields and enantioselectivity of the reduced product.

The method of the present invention can be applied in either batch or continuous modes of operation. In a batch mode of operation, the ability to regenerate chiral non-racemic organotin hydride in situ advantageously enables the amount of organotin hydride employed in the reaction to be reduced below about one molar equivalent per mole of reductive sites provided by the radical precursor compound to be reduced. Under these circumstances, the organotin hydride is preferably present in an amount which is less than about one molar equivalent, more preferably about 0.7 molar equivalents or less, most preferably about 0.5 molar equivalents or less, per mole of reductive sites provided by the radical precursor compound to be reduced. It is particularly preferred that when the method of the present invention is applied in batch mode that the amount of organotin hydride used is about 0.2 molar equivalents or less per mole of reductive sites provided by the radical precursor compound to be reduced.

The method of the present invention can also be applied in a continuous mode of operation, for example where the substrate, Lewis acid and co-reducing agent are passed through a flow through reactor which contains organotin hydride anchored to a solid support. In this case, the molar amount of organotin hydride present in the reactor, relative to the molar amount of reductive sites on the radical precursor compound to be reduced present in the reactor at a given point in time, may vary depending upon factors such as the rate of reaction between the organotin hydride and the substrate, the rate of the regeneration reaction and the flow rate of the reagents through the reactor. The amount of organotin hydride present may be the same as that mentioned above in relation to a batch mode. However, in certain circumstances it may be desirable have a higher molar amount of organotin hydride present in the reactor relative to the molar amount of reductive sites present on the radical precursor compound to be reduced present in the reactor at a given point in time. Having regard to the reagents employed in a given reaction, one skilled in the art should readily be able to determine the optimum operating conditions for such a continuous reaction system. Importantly, it should be appreciated that regardless of the mode in which the method of the present application is operated, the overall result of applying the method is that the net amount of organotin hydride used to reduce a given amount of substrate can advantageously be reduced to below a molar equivalent per mole of reductive sites provided by the radical precursor compound to be reduced.

In accordance with the method of the present invention, it is not only important that the co- reducing agent is capable of regenerating chiral non-racemic organotin hydride, but also that it is capable of doing so without substantially reducing the prochiral carbon centred radicals or the radical precursor compound. Accordingly, the co-reducing agent should reduce the aforementioned organotin residue to regenerate chiral non-racemic organotin hydride (i.e. the secondary reduction reaction) in preference to reducing the radicals or the precursor compound. If the co-reducing agent were to reduce the radicals or precursor compound in preference to the organotin residue, the resulting reduced product would generally be unfavoured in that it would exhibit a lower ee value than that which could be obtained in the absence of the co-reducing agent.

However, it will be appreciated that the preference of the co-reducing agent for reducing the organotin residue over the radicals or precursor compound need not necessarily be absolute, but rather the preference should be sufficient such that the ee values of the reduced product are not significantly lowered.

Accordingly, the co-reducing agent regenerates chiral non-racemic organotin hydride (ie. reduces the organotin residue) in preference to reducing the radicals or precursor compound such that the ee values of the reduced product are preferably no more than 15% lower, more preferably no more than 10% lower, most preferably no more than 5% lower, than that which can be obtained in the absence of the co-reducing agent. It is particularly preferred that the co-reducing agent reduces the organotin residue in preference to the radicals or precursor compound such that the ee values of the reduced product are no more than 2% lower than that which can be obtained in the absence of the co-reducing agent. In considering the suitability of a co-reducing agent for use in accordance with the present invention, it is important to appreciate that the aforementioned characteristics of the agent should be satisfied under the conditions of a given reaction. For example, if the reaction were to be conducted at -78°C, the co-reducing agent should be capable of regenerating non-racemic organotin hydride without substantially reducing the radicals or precursor compound at -78°C.

A suitable co-reducing agent for use in accordance with the present invention may be conveniently and readily selected by evaluating the agent's reductive properties toward the intended substrate (precursor compound), the prochiral carbon centred radical derived from the substrate, and the organotin residue resulting from the reduction reaction of the substrate with the chiral non-racemic organotin hydride, under the intended reaction conditions to be employed. The evaluation may be performed on the substrate, the prochiral carbon centred radicals and the organotin residue in separate reduction reactions and the resulting reduction efficiency measured

The amount of co-reducing agent used in the method of the present invention may vary depending upon the reagents and the reaction conditions employed. Preferably, the co- reducing agent is present in an amount ranging from about 1 to about 15 molar equivalents, more preferably in an amount ranging from about 2 to about 10 molar equivalents, per mole of reductive sites provided by the radical precursor compound to be reduced.

Exemplary co-reducing agents include, but are not limited to, BH₃, 9-BBN (9- borabicyclononane), Na BH₃CN, and PMHS (poly(methylhydrosiloxane)). PMHS may be optionally used in conjunction with a Lewis base such as TBAF (tetrabutylammonium fluoride).

As with the aforementioned Lewis acids, it will be appreciated that the co-reducing agent can also be conveniently provided, and used, in the form of a Lewis adduct. In performing the method of the present invention, the co-reducing agent may be introduced at any convenient stage. Generally, the co-reducing agent would be introduced at the beginning of the reaction, or introduced portion wise or gradually during the course of the reaction.

Advantageously, it has been found that a co-reducing agent suitable for use in accordance with the method of the present invention can also be used to first prepare the chiral non- racemic organotin hydride by reducing a precursor organotin compound. Chiral non- racemic organotin hydride prepared by such means can then be used to reduce the prochiral carbon centred radicals in accordance with the method of the present invention.

Conveniently, the same co-reducing agent used to prepare the organotin hydride can then also be used as the co-reducing agent in the method of the present invention.

Preferably, the chiral non-racemic organotin hydride to be used in accordance with the method of the present invention is prepared from a precursor organotin compound by reducing this compound with a co-reducing agent that is also used as the co-reducing agent in the method of the present invention.

The prochiral carbon centred radicals which can be reduced by the methods of the invention include radicals which bear one or more electron donor groups directly on the prochiral central carbon atom and/or attached to a carbon atom α, β, γ, or δ to the central prochiral carbon atom, ie, within 1, 2, 3 or 4 atoms, preferably within 1 or 2 atoms. Suitable electron donor groups include those containing an electron donor atom such as oxygen, nitrogen, and/or sulfur and which will not be affected by the organotin hydride. One example of an electron donor group is a carbonyl group C(=O), present, as for example, in aldehydes, ketones, carboxy acid, carboxy esters, carboxy amides, anhydrides, lactones, lactams, carbonates, carbamates and thioesters etc. Other electron donor groups include, thioalkyl groups, amines (unsubstituted or substituted once or twice by, for example, a group selected from alkyl, acyl and aryl), hydroxy groups and ethers (eg alkyl and aryl). A preferred electron donor is a carbonyl group. Preferably the carbonyl group is adjacent to, ie α- to the chiral carbon to be reduced. Expressed in another way, the prochiral carbon centred radical has at least one electron donor atom within 5 atoms (ie 1 , 2, 3, 4, or 5) of the central prochiral carbon atom. It will be recognised that some electron donor groups may contain one or more electron donating atoms, eg carboxy acid, carboxy ester, thioester, carboxy amide. A prochiral carbon centred radical may also contain more than one electron donating group attached to the central prochiral atom.

Exemplary prochiral carbon centred radicals include those of the formula RιR₂R₃C', wherein R1-R₃ are different (and not hydrogen) and are independently selected from alkyl, alkenyl, alkynyl, aryl, heterocyclyl, acyl, amino, substituted amino, carboxy, anhydride, carboxy ester, carboxy amide, lactone, lactam, thioester, formyl, optionally protected hydroxy, thioalkyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heterocyclyloxy; or alternatively, any two of R₁-R₃ can together, with the central prochiral carbon atom, form a mono- or poly- cyclic group or fused polycyclic group including as cycloalkyl, cycloalkenyl, cycloalkynyl, a lactone, a lactam, cyclic anhydride, or heterocyclyl and bi-, tri- and tetracyclic fused combinations thererof. At least one of R₁-R₃, or a cyclic group formed by any two of R₁-R₃, contains an electron donor atom within 1 to 5 atoms of the prochiral central carbon atom to be reduced. It will be understood that a radical precursor may contain more than one prochiral radical precursor sites and that reduction may therefore occur at one or more of these sites.

In one preferred embodiment, at least one of R1-R₃ is an optionally substituted aryl or heteroaryl group. In another preferred embodiment at least one of R₁-R₃ is an optionally substituted alkyl, alkenyl, or alkynyl group. In another embodiment, at least one of R₁-R₃ is a ketone, aldehyde, carboxy acid, carboxy ester, carboxy amide, anhydride, lactone, lactam or thioester, or two of R₁-R₃ together with the central prochiral carbon atom form a cyclic anhydride, lactam or lactone.

Preferred "ketones" have the formula -C(O)-R wherein R can be any residue, having a carbon atom covalently bonded to the carbonyl group, such as alkyl, alkenyl, alkynyl and aryl. An R group may have one or more carbon atoms optionally replaced with one or more heteroatoms to form, for example, heterocyclyl.

Preferred "carboxy esters" have the formula -CO₂R wherein R can be any residue, having a carbon atom covalently bonded to the non-carbonyl oxygen atom, for example, alkyl, alkenyl, alkynyl or aryl. An R group may have one or more carbon atoms optionally replaced with one or more heteroatoms, such that R is for example heterocyclyl.

Preferred "carboxy amides" have the formula CO₂NRR' wherein R and R' are independently selected from hydrogen and any residue having a carbon atom covalently bonded to the nitrogen atom such as alkyl, alkenyl, alkynyl or aryl. An R or R' group may have one or more carbon atoms optionally replaced with one or more heteroatoms to form, for example, heterocyclyl.

Preferred "thioesters" have the formula -C(O)SR wherein R can be any residue having a carbon atom covalently bonded to the sulfur atom, such as alkyl, alkenyl, alkynyl or aryl. An R group may have one or more carbon atoms optionally replaced with one or more heteroatoms to form, for example, heterocyclyl.

Preferred anhydrides contain the moiety -C(O)-OC(O)- and may be cyclic or acyclic. Preferred acyclic anhydrides contain the moiety -C(O)-O-C(O)-R wherein R can be any residue, such as alkyl, alkenyl, alkynyl or aryl. An R group may have one or more carbon atoms optionally replaced with one or more heteroatoms to form, for example, heterocyclyl. Preferred cyclic anhydrides contain the moiety -C(O)-O-C(O)-(CH₂)_n- wherein n is > 1, eg. 1, 2, 3, 4, 5 or 6.

Lactones are cyclic residues containing the moiety -C(O)O-. Preferred lactones have the formula -C(O)O-R- wherein-R-can be any residue, having a carbon atom covalently bonded to the non-carbonyl oxygen atom, eg alkylene, alkenylene, alkynylene. An R group may have one or more carbon atoms optionally replaced by one or more heteroatoms. Preferred lactones contain the moiety -C(O)-O- (CH₂)_n- wherein n is > 2, eg., 2, 3, 4, 5 or 6. Lactams are cyclic residues containing the moiety -C(O)-N(R')-R- wherein R' can be hydrogen or any hydrocarbon residue such as alkyl, acyl, aryl or alkenyl. -R- can be any hydrocarbon residue having a carbon atom covalently bonded to the nitrogen atom such as alkylene, alkenylene or alkynylene. An R' or R group may have one or more carbon atoms optionally replaced by one or more heteroatoms. Preferred lactams contain the moiety - C(O)-N(R')-(CH₂)„- wherein n is > 2, eg., 2, 3, 4, 5 or 6.

As used herein, the term "alkyl", denotes straight chain, branched or cyclic hydrocarbon residues, preferably Cι.₂o alkyl, eg C_MO or Cι.₆. Examples of straight chain and branched alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl, sec-amyl, 1 ,2-dimethylpropyl, 1,1 -dimethyl -propyl, hexyl, 4-methylpentyl, 1- methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3- dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2,-trimethylpropyl, 1,1,2- trimethylpropyl, heptyl, 5-methoxyhexyl, 1-methylhexyl, 2,2-dimethylpentyl, 3,3- dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4- dimethyl-pentyl, 1,2,3-trimethylbutyl, 1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl, octyl, 6- methylheptyl, 1-methylheptyl, 1,1,3,3-tetramethylbutyl, nonyl, 1-, 2-, 3-, 4-, 5-, 6- or 7- methyl-octyl, 1-, 2-, 3-, 4- or 5-ethylheptyl, 1-, 2- or 3-propylhexyl, decyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- and 8-methylnonyl, 1-, 2-, 3-, 4-, 5- or 6-ethyloctyl, 1-, 2-, 3- or 4-propylheptyl, undecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-methyldecyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-ethylnonyl, 1-, 2-, 3-, 4- or 5-propylocytl, 1-, 2- or 3-butylheptyl, 1-pentylhexyl, dodecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-methylundecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-ethyldecyl, 1-, 2-, 3-, 4-, 5- or 6-propylnonyl, 1-, 2-, 3- or 4-butyloctyl, 1-2-pentylheptyl and the like. Examples of cyclic alkyl include mono- or polycyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like. Where an alkyl group is referred to generally as "propyl", "butyl" etc, it will be understood that this can refer to any of straight, branched and cyclic isomers. An alkyl group may be optionally substituted by one or more optional substituents as herein defined. Accordingly, "alkyl" as used herein is taken to refer to optionally substituted alkyl. Cyclic alkyl may refer to monocyclic alkyl or, polycyclic fused or non-fused carbocyclic groups. The term "alkenyl" as used herein denotes groups formed from straight chain, branched or cyclic hydrocarbon residues containing at least one carbon to carbon double bond including ethylenically mono-, di- or poly-unsaturated alkyl or cycloalkyl groups as previously defined, preferably C1-₂₀ alkenyl (eg CM_O or Cι-₆). Examples of alkenyl include vinyl, allyl, 1-methylvinyl, butenyl, iso-butenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methyl-cyclopentenyl, 1-hexenyl, 3-hexenyl, cyclohexenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, cyclooctenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3- decenyl, 1,3-butadienyl, l-4,pentadienyl, 1,3 -cyclopentadienyl, 1,3 -hexadienyl, 1,4- hexadienyl, 1,3-cyclohexadienyl, 1 ,4-cyclohexadienyl, 1,3-cycloheptadienyl, 1,3,5- cycloheptatrienyl and 1,3,5,7-cyclooctatetraenyl. An alkenyl group may be optionally substituted by one or more optional substitutents as herein defined. Accordingly, "alkenyl" as used herein is taken to refer to optionally substituted alkenyl. Cyclic alkenyl may refer to monocyclic alkenyl or, polycyclic fused or non-fused alkenyl carbocyclic groups.

As used herein the term "alkynyl" denotes groups formed from straight chain, branched or cyclic hydrocarbon residues containing at least one carbon-carbon triple bond including ethynically mono-, di- or poly- unsaturated alkyl or cycloalkyl groups as previously defined. Unless the number of carbon atoms is specified the term preferably refers to C1.2₀ alkynyl. Examples include ethynyl, 1-propynyl, 2-propynyl, and butynyl isomers, and pentynyl isomers. An alkynyl group may be optionally substituted by one or more optional substitutents as herein defined. Accordingly, "alkynyl" as used herein is taken to refer to optionally substituted alkynyl. Cyclic alkynyl may refer to monocyclic alkynyl or, polycyclic fused or non-fused alkynyl carbocyclic groups.

The terms "alkoxy", "alkenoxy", "alkynoxy", "aryloxy" and "heterocyclyloxy" respectively denote alkyl, alkenyl, alkynyl, aril and heterocylclyl groups as hereinbefore defined when linked by oxygen.

The term "halogen" denotes chlorine, bromine or iodine. The term "aryl" denotes single, polynuclear, conjugated and fused residues of aromatic hydrocarbon ring systems. Examples of aryl include phenyl, biphenyl, terphenyl, quaterphenyl, naphthyl, tetrahydronaphthyl, anthracenyl, dihydroanthracenyl, benzanthracenyl, dibenzanthracenyl, phenanthrenyl, fluorenyl, pyrenyl, idenyl, azulenyl, clirysenyl. Aryl may be optionally substituted as herein defined and thus "aryl" as used herein is taken to refer to optionally substituted aryl.

The term "heterocyclic" denotes mono- or polycarbocyclic groups, which may be fused or conjugated, aromatic (heteroaryl) or non-aromatic, wherein at least one carbon atom is replaced by a heteroatom, preferably selected from nitrogen, sulphur and oxygen. Suitable heterocyclic groups include N-containing heterocyclic groups, such as: unsaturated 3 to 6 membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl or tetrazolyl; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as, pyrrolidinyl, imidazolidinyl, piperidyl, pyrazolidinyl or piperazinyl; condensed saturated or unsaturated heterocyclic groups containing 1 to 5 nitrogen atoms, such as, indolyl, isoindolyl, indolinyl, isoindolinyl, indolizinyl, isoindolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, purinyl, quinazolinyl, quinoxalinyl, phenanthradinyl, phenathrolinyl, phthalazinyl, naphthyridinyl, cinnolinyl, pteridinyl, perimidinyl or tetrazolopyridazinyl; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 3 oxygen atoms, such as tetrahydrofuranyl, tetrahydropyranyl, tetrahydrodioxinyl, unsaturated 3 to 6-membered hetermonocyclic group containing an oxygen atom, such as, pyranyl, dioxinyl or furyl; condensed saturated or unsaturated heterocyclic groups containing 1 to 3 oxygen atoms, such as benzofuranyl, chromenyl or xanthenyl; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms, such as, thienyl or dithiolyl; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and

1 to 3 nitrogen atoms, such as, oxazolyl, oxazolinyl, isoxazolyl, furazanyl or oxadiazolyl; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, morpholinyl; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, benzoxazolyl or benzoxadiazolyl; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as, thiazolyl, thiazolinyl or thiadiazoyl; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as, thiazolidinyl, thiomorphinyl; and unsaturated condensed heterocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as, benzothiazolyl or benzothiadiazolyl.

A heterocyclic group may be optionally substituted by an optional substituent as described herein.

The term "acyl" denotes a group containing the moiety C=O (and not being a carboxylic acid, ester or amide or thioester). Preferred acyl includes C(O)-R, wherein R is hydrogen or an alkyl, alkenyl, alkynyl, aryl or heterocyclyl, residue, preferably a C1.20 residue. Examples of acyl include formyl; straight chain or branched alkanoyl such as, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl and icosanoyl; cycloalkylcarbonyl such as cyclopropylcarbonyl cyclobutylcarbonyl, cyclopentylcarbonyl and cyclohexylcarbonyl; aroyl such as benzoyl, toluoyl and naphthoyl; aralkanoyl such as phenylalkanoyl (e.g. phenylacetyl, phenylpropanoyl, pheny Ibutanoyl, phenylisobutylyl, pheny Ipentanoyl and pheny Ihexanoyl) and naphthylalkanoyl (e.g. naphthylacetyl, naphthylpropanoyl and naphthylbutanoyl]; aralkenoyl such as phenylalkenoyl (e.g. phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl and phenylhexenoyl and naphthylalkenoyl (e.g. naphthylpropenoyl, naphthylbutenoyl and naphthylpentenoyl); aryloxyalkanoyl such as phenoxyacetyl and phenoxypropionyl; arylthiocarbamoyl such as phenylthiocarbamoyl; arylglyoxyloyl such as phenylglyoxyloyl and naphthylglyoxyloyl; arylsulfonyl such as phenylsulfonyl and napthylsulfonyl; heterocycliccarbonyl; heterocyclicalkanoyl such as thienylacetyl, thienylpropanoyl, thienylbutanoyl, thienylpentanoyl, thienylhexanoyl, thiazolylacetyl, thiadiazolylacetyl and tetrazolylacetyl; heterocyclicalkenoyl such as heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl and heterocyclichexenoyl; and heterocyclicglyoxyloyl such as thiazolyglyoxyloyl and thienylglyoxyloyl. Acyl also refers to optionally substituted acyl.

The term "acyloxy" refers to acyl, as herein before defined, when linked by oxygen.

In this specification "optionally substituted" is taken to mean that a group may or may not be further substituted or fused (so as to form a condensed polycyclic group) with one or more groups selected from alkyl, alkenyl, alkynyl, aryl, hydroxy, alkoxy, alkenyloxy, aryloxy, nitro, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroaryl, nitroheterocyclyl, amino, alkylamino, dialkylamino, alkenylamino, alkynylamino, arylamino, diarylarnino, acyl, acylamino, diacylamino, acyloxy, alkylsulphonyloxy, arylsulphenyloxy, heterocyclyl, heterocycloxy, heterocyclamino, carboalkoxy, carboaryloxy, alkylthio, arylthio, acylthio, cyano, nitro , sulfate and phosphate groups.

Preferred optional substitutents include alkyl, (eg Cι-₆ alkyl such as methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), hydroxyalkyl (eg hydroxymethyl, hydroxyethyl, hydroxypropyl), alkoxyalkyl (eg methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl etc) alkoxy (eg

Cι-₆ alkoxy such as methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy), halo, trifluoromethyl, trichloromethyl, tribromomethyl. hydroxy, phenyl (which itself may be further substituted), benzyl (wherein benzyl itself may be further substituted), phenoxy

(wherein phenyl itself may be further substituted), benzyloxy (wherein benzyl itself may be further substituted), amino, alkylamino (eg Cι.₆ alkyl, such as methylamino, ethylamino, propylamino etc), dialkylamino (eg Cι-₆ alkyl, such as dimethylamino, diethylamino, dipropylamino), acylamino (eg NHC(O)CH3), phenylamino (wherein phenyl itself may be further substituted), nitro, formyl, -C(O)-alkyl (eg Cι-₆ alkyl, such as acetyl), O-C(O)-alkyl (eg Cι.₆ alkyl, such as acetyloxy), benzoyl (wherein the phenyl group of the benzoyl may itself be further substituted), carbonyl, (ie replacement of CH₂ with C=O) CO₂H, CO₂ alkyl (eg C^ alkyl such as methyl ester, ethyl ester, propyl ester, butyl ester), CO₂ phenyl (wherein phenyl itself may be further substituted), CONH₂, CONH phenyl (wherein phenyl itself may be further substituted), CONHbenzyl (wherein benzyl itself may be further substituted),CONH alkyl (eg Cι-₆ alkyl such as methyl ester, ethyl ester, propyl ester, butyl amide), CONH dialkyl (eg Cι_₆ alkyl).

As used herein, "heteroatom" refers to any atom other than a carbon atom which may be a ring-member of a cyclic organic compound. Examples of suitable heteroatoms include nitrogen, oxygen, sulfur, phosphorous, boron, silicon, arsenic, sellenium and telluruim.

The reductive methods of the invention are carried out for a time and under conditions sufficient to effect enantioselective reduction of a suitable prochiral radical precursor by hydrogen. Suitable reaction temperatures, solvents and quantities of stannane and initiator for free radical reductions are known in the art (see for example V.T. Perchyonok et al, Tetrahedron. Lett, 1998, 39, 5437 and references cited therein). Preferred solvents include hydrocarbon solvents, eg toluene. The reduction is preferably carried out at temperature less than 0°C, preferably less than about -30°C, more preferably at about - 78°C. Preferably, the reagents used and the reaction conditions employed are substantially anhydrous. Exemplary initiators include those which are reactive at these temperatures such as AMBM (Tetrahedron Lett., 1997, 38, 6301); triethylborane; (Ishido et al, Journal of Organic Chemistry, Vol 60, 6980), 9-BBN (9-borabicyclononane) (Tetrahedron Lett., 1998, 39, 5437), 9-alkyl-9-BBN, (eg alkyl = ethyl, propyl, butyl etc). In the case of 9- BBN, this compound can function as an initiator as well as a co-reducing agent.

Exemplary chiral non-racemic organotin hydrides have the formula L₁L₂L₃S11H wherein L₁-L₃ are ligands, which may be the same or different, and wherein at least one of L₁-L₃ has a chiral centre. Suitable non-chiral ligands include optionally substituted aryl (eg optionally substituted phenyl, and napthyl) and non-chiral alkyl (eg butyl). Suitable chiral ligands include menthyl and fused polycyclics such as 3α-cholestane and those derived from cholic acid eg 3α-24-norcholanyl and 7α-24-norcholanyl (Schiesser et al, Phosphorus, Sulfur, Silicon and Related Elements, (1999) Vol 150-51, 177).

Examples of organotin hydrides include (lR,2S,5R)-menthyldiphenyltin hydride (a) and its enantiomer ( 1S,2R, 5 S)-menthyldiphenyltin hydride (a'), bis[(lR,2S,5R)-menthyl]phenyltin hydride (b) and its enantiomer bis[(lS,2R,5S)-menthyl]phenyltin hydride (b')₅ tris[(lR,2S,5R)-menthyl]tin hydride (c) and 3α-dimethylstannyl-5 α-cholestane (d), which can be prepared in accordance with the procedures described in Dakternieks et al., Organometallics, 1999, 3342-3347.

(a) menPh₂SnH (b) men₂PhSnH (c) men₃SnH

(a¹) , enan-menPh₂SnH (b¹) enan-men₂PhSnH

(d)

In the above structures,

Other suitable organotin hydrides include (e) and (f), which can be prepared by reaction of the appropriate aryl lithium with bis[(lR,2S,5R)-menthyl]phenyltin chloride followed by LiAlH reduction (Dakternieks et al., supra, and Jastrzebski et al, J. Organomet Chem., 1983, 246, C75 and van Koten et al, Tetrahedron 1989, 45, 569). Other aryl tin hydrides can be made in an analogous manner. Further examples of a suitable organotin hydride include (e) as below, where one of the menthyl groups is replaced by a phenyl group (both diasteroisomers). Other exemplary preferred compounds of the invention include, for example, (g) shown below.

(e) (f⁾ (g)

Lewis acids for use with the method of the present invention are compounds which are able to accept an electron pair, ie. co-ordinate with an electron donor. Suitable Lewis acidic compounds include transition metal complexes, alkaline earth metal compounds and other metal based compounds wherein the metal centre can accept an electron pair. Examples of suitable Lewis acids include AICI₃, Me₃Al, BF₃, BBr₃, BC1₃, Ln(OTf)₃, TiCl₄, FeCl₃, ZnCl₂, zirconocene dichloride (herein after referred to as (i)), trialkylborates (RO₃B, wherein each R is an alkyl group which can be the same or different), (S,S)- and (R,R)-(-t-)-N,N'-bis(3,5-di-tert-butylsalycidene)-l,2-diaminocyclohexamanganese (III) chloride (hereinafter referred to as, (ii) and (iii) respectively) (Jacobson's catalyst, Jacobsen et al, J. Am. Chem. Soc, 1991, 113, 7063), and (S)- and (R)-BINAD (see structures below).

(S)-BINAD (ft)-BINAD

Preferably, the Lewis acid has a solubility, under the reaction conditions employed, of at least about 0.1 molar equivalent, preferably at least about 0.5 molar equivalent, more preferably at least about 1.0 molar equivalent, most preferably about 2.0 molar equivalents, per mole of reductive sites provided by the radical precursor compound to be reduced.

Particularly preferred Lewis acids are those which are alkaline earth metal compounds. When used in accordance with the method of the present invention, such compounds surprisingly afford excellent enantioselectivity.

Preferably, the alkaline earth metal compound is a Lewis acidic magnesium compound. Examples of suitable Lewis acidic magnesium compounds include MgBr₂, Mgl₂, Mg(OAc)₂ and Mg(OTf)₂. It will be appreciated that the above list of magnesium compounds is not exhaustive and that the invention encompasses the use of other Lewis acidic magnesium compounds or combinations thereof.

Where the Lewis acid used in accordance with the method of the present invention is a Lewis acidic magnesium compound, the Lewis acidic magnesium compound is preferably MgBr₂.

Those skilled in the art will appreciate that Lewis acids can often be conveniently provided in the form of a Lewis adduct, that is an adduct formed from a Lewis acid and a Lewis base. In particular, those skilled in the art will appreciate that a Lewis adduct can be used as a convenient source for providing a Lewis acid to a reaction. Accordingly, Lewis acids used in accordance with the present invention may also be provided in the form of a Lewis adduct. For example, Lewis acids such as BF₃, ZnCl₂, and MgBr₂ may be provided and used in the form of their diethylether adducts BF₃-Et₂O, ZnCl -(Et₂O)₂ and MgBr₂-(Et₂O)₂, respectively.

In general, the Lewis acid is preferably used in an amount of about 0.9 to about 2.0 molar equivalents, more preferably in an amount of about 0.9 to about 1.1 molar equivalents, per mole of reductive sites provided by the radical precursor compound to be reduced. In particular, the Lewis acid is preferably used in an amount of about 1.5 molar equivalents, most preferably about 1.0 molar equivalents, per mole of reductive sites provided by the radical precursor compound to be reduced. Lesser amounts can be used, such as 0.1 or 0.5 molar equivalents, although lower enantiomeric excesses (ees) are usually observed. The addition of higher amounts of Lewis acid can also be used, although this does not generally result in an increase in observed ee's.

When the Lewis acid is an alkaline earth metal compound, it is preferable that the Lewis acid is used in an amount of about 1.5 molar equivalents, more preferably about 2.0 molar equivalents, per mole of reductive sites provided by the radical precursor compound to be reduced. In particular, when the Lewis acid is a magnesium compound, it is preferable that the Lewis acid is used in an amount of about 1.5 molar equivalents, more preferably about 2.0 molar equivalents, per mole of reductive sites provided by the radical precursor compound to be reduced.

The stereochemistry of the reduced prochiral carbon centre in the resulting compound can be ( ?) or (S).

The method of the invention may be particularly useful in preparing optically enhanced amino acids. Thus, α- or β-carbon centred radicals derived from α- or β-substituted amino acids may be reduced by the methods of the invention to produce optically enhanced amino acids which may be natural or unnatural, including alanine, asparagine, cysteine, glutamine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, aspartic acid, glutamic acid, arginine, histidine, lysine and their homo derivatives. Other examples include α-and β- straight and branched chain alkyl substituted amino acids, α- and β-cycloalkyl substituted amino acids, and α- and β-aryl substituted amino acids

The chiral stannanes used to reduce the prochiral carbon centred radical may also be immobilized onto a solid support, eg a polymeric support, such as pins, beads or wells, for use in the methods of the invention, eg used in combinatorial techniques known in the art.

The invention will now be described with reference to the following non-limiting examples which are included for the purpose of illustrating the invention only and are not to be construed as limiting the generality hereinbefore described.

EXAMPLES Example 1

Reduction of Compounds (l)-(3).

1. Rι=OEt, R₂=Et, R₃=Ph X = Br

2. Rι=OEt, R₂=Me, R₃=6-(OCH₃)-Napthyl X = Br

3. RjOBn, R₂=NHCOCF₃, R₃=tert-Bu X = Br Bn = Benzyl

Compounds (l)-(3) were prepared as follows:

Preparation of compound 1

Compound 1 (X=Br) was prepared according to the methods of Metzger et al Angew. Chem., Int., Ed. Engl., 1997, 36, 235 and Curran, et al, Tetrahedron: Asymmetry, 1996, 7, 2417.

Preparation of compound 2

N-bromosuccinimide (NBS) (0.37g, 2.06mmol) was added to a solution of ethyl 6- methoxy-2-methyl-2-naphthaleneacetate (0.5g, 2.06mmol) in carbon tetrachloride (5ml). The reaction mixture was then irradiated (under reflux) by a 250W tungsten lamp for 10 minutes. The solid was removed by filtration and the solvent removed in vacuo to afford the title racemic bromoester in quantitative yield and of sufficient purity for further use. 1H NMR (CDC1₃) (300): δ 7.2-7.6 (6H, m, Ar-H), 4.0-4.2 (2H, m, O-CH₂), 3.95 (3H, s, O- CH₃), 1.5 (3H, s, Ar-CBr- CH₃), 1.20 (3H, t, 7.5Hz, -OCH₂CH₃). Preparation of compound (3)

A mixture of racemic tert-leucine (0.2g), dry methanol (0.5ml), triethylamine (0.3ml) and methyl trifluoroacetate (0.16ml) was allowed to stir at room temperature for 15 hours. Removal of methanol in vacuo afforded the triethylammonium salt of N- trifluoroacetyltert-leucine as a crystalline mass which was dissolved in dry DMF (0.5ml). Triethylamine (0.14ml) and benzyl chloride (0.35g) were added and the mixture allowed to stir at room temperature for 40 hours. The resulting mixture was poured into ethyl acetate, washed with H₂O, 5% HC1, sat. NaHCO₃ and brine. The organic layer was dried (MgSO₄) and the solvent removed in vacuo to obtain the crude product as a light yellow oil. Pure N- trifluoroacetyl-tert-leucine benzyl ester was obtained as a pale oil after flash chromatography (96:4 hexane: ethyl acetate) in 65% yield.

N-bromosuccinimide (NBS) (61mg) was added to a solution of N-trifluoroacetyl-tert- leucine benzyl ester (lOOmg) in carbon tetrachloride (5ml). The mixture was irradiated (under reflux) by a 250W tungsten lamp for 45 minutes. The solid was removed by filtration and the solvent removed in vacuo to afford (3b) in quantitative yield and of sufficient purity for further use.

General reduction procedure

Reductions were carried out in toluene at -78°C. The reaction solution comprised the substrate; the Lewis acid of choice at about 2 molar equivalents, relative to the substrate; about 0.05 to about 0.2 molar equivalents of the stannane, relative to the substrate; and about 2 to about 10 molar equivalents of the co-reducing agent, relative to the substrate. The reaction was initiated Et₃B/O₂ (Ishido et al., Journal of Organic Chemistry, 1995, Vol 60, pg 6980). Reactions were carried out until TLC analysis indicated the absence of starting material (ca. l-2h) at which time the reaction mixtures were examined by chiral- phase gas chromatography (CG) and the percentage conversion and enantiomeric ratios determined by integration of the signals corresponding to the mixture of reduced compounds 1 to 3 (X = H) against an internal standard (either octane or undecane). The reduced compounds 1 to 3 (X = H) were identified by comparison of their GC retention times with those of corresponding authentic compounds. Gas Chromatographic analyses of the reaction mixtures were carried out using a chiral triffuoroacteylated γ-cyclodextrin (Chiraldex™ G-TA, 30m x 0.25mm) capillary column purchased from Alltech. The absolute configuration of the dominant isomer in each case was assigned by comparison with the GC retention times of authentic (S)-compounds 1 to 3 (X = H), prepared by the following procedures:

Preparation of compounds 1 (X = H)

Compound 1 was prepared and resolved following literature procedures (Campbell, A., et al, J. Chem. Soc, 1946, 25; Aaron, C, et al, J.Org. Chem.; and Elhafez, F.A.A., et al, J. Am. Chem. Soc, 1952, 74, 5846).

Preparation of compound 2 (X= H)

A solution of 6-methoxy-2-methyl-2-naphthaleneacetic acid (naproxen) (l.Og, 4.34mmol) in thionyl chloride (20ml) was reflux until the evolution of HC1 gas had ceased (ca.l hour). The excess of thionyl chloride was then removed in vacuo, and ethanol (30ml) and dichloromethane (20ml) were added and refluxing continued for 2 hours. The mixture was cooled and the solvent removed in vacuo to give brown oil, which was purified by flash chromatography (5% ethyl acetate/ hexane) to give ethyl 6-methoxy-2-methyl-2- naphthaleneacetate as a white solid (0.829g, 79%). 1H NMR (CDC1₃) (300): δ 7.2-7.6 (6H, m, Ar-H), 4.0-4.2 (2H, m, O-CH₂), 3.95 (3H, s, O-CH3), 3.65-3.75 (IH, q, 7.5Hz, Ar- CH), 1.5 (3H, d, 7.5Hz, Ar-CH- CH₃), 1.20 (3H, t, 7.5Hz, -OCH2CH3). ¹³C NMR (CDCI₃): δ 173.0, 156.6, 133.0, 132.6, 129.2, 128.9, 128.4, 126.4, 126.0, 118.6, 105.359.8, 56.0, 42.6, 17.3, 13.6. P reparation of compound 3 (X= H)

A mixture of (S)-tert-leucine (0.2g), dry methanol (0.5ml), triethylamine (0.3ml) and methyl trifluoroacetate (0.16ml) was allowed to stir at room temperature for 15 hours. Removal of methanol in vacuo afforded the . triethylammonium salt of N- trifluoroacetyltert-leucine as a crystalline mass which was dissolved in dry DMF (0.5ml). Triethylamine (0.14ml) and benzyl chloride (0.35g) were added and the mixture allowed to stir at room temperature for 40 hours. The resulting mixture was poured into ethyl acetate, washed with H₂O, 5% HC1, sat. NaHCO₃ and brine. The organic layer was dried (MgSO₄) and the solvent removed in vacuo to obtain the crude product as a light yellow oil. Pure (S)-N-trifluoroacetyl-tert-leucine benzyl ester was obtained as a pale oil after flash chromatography (96:4 hexane: ethyl acetate) in 65% yield.

Table 1 lists enantioselectivity data for model substrates (1) to (3) reacting with an indicated amount bis[(lS,2R,5S)-menthyl]phenyltin (b') hydride at -78 °C in toluene. The amount and type of Lewis acid and co-reducing agent used are specified in Table 1. In some cases, 4A molecular sieves were used as an additive. The results show that high enantiomeric purity and high yields can be obtained using relatively low levels of stannane.

The conversion data shown in the following Tables was measured by GC. Isolated yields for the compounds are shown in parenthesis.

TABLE 1

Enantioselectivites observed for reactions involving bis[(lS,2R,5S)-menthyl]phenyltin hydride (b¹) in toluene at -78 °C.

ND = Not determined

General procedure for preparing the organotin hydride from a precursor compound usins a co-reducing agent.

Preparation of enan-men₂PhSnH (b ') from enan-men2Ph2Sn and 9BBN. THF The procedure reported by Podesta (J.Organometal.Chem., 2002, 613, 236) for the preparation of achiral trialkyltin hydrides was adapted for a more direct preparation of eτ.-w-men₂PhSnH (b') as described below.

Protocol A: A solution of borane in THF (1.0M, 3.6ml) was added to a stirred room temperature solution of enan-mQn.₂Fh.₂ (0.2g, 0.363mmol) in dry toluene (2ml) under an atmosphere of nitrogen. The reaction mixture was heated at 60°C for 2 hours after which the resulting ercαw-me^PhSnH (b') solution was used for catalytic reactions within 24 hours.

Protocol B: A solution of 9-BBN in THF (0.5M, 1.8ml) was added to a stirred room temperature solution of e«α«-men₂Ph₂Sn (0.2g, 0.363mmol) in dry toluene (2ml) under an atmosphere of nitrogen. The reaction mixture was heated at 60°C for 2 hours after which the resulting eπα«-men PhSnH (b¹) solution was used for catalytic reactions within 24 hours.

General experimental procedure for reduction reactions of Example 1 are described below

Catalytic reduction using 20% enan-men₂PhSnH (b^f) with borane as a co-reductant in the presence of magnesium bromide -preparation ofnaproxen ethyl ester (entry 1).

MgBr₂.(Et₂O)₂ (0.308g, 1.12mmol) was added to dry toluene (0.7ml) and the solution allowed to stir for 30 min under nitrogen after which the reaction mixture was cooled down to -78°C. Bromoester 2 (0.2g, 0.59mmol) in dry toluene (0.5ml) was added slowly to the reaction mixture at -78°C. The resultant mixture was allowed to stir at this temperature for a further 45 min after which a solution of the e« «-men₂PhSnH (b') (0.056g, 0.117mmol, 1.8ml) (prepared according to protocol A above) was added, followed by the slow addition of a solution of borane in THF (1.0M, 9.0ml). Triethylborane in THF (1M, 0.15ml) was added and oxygen introduced. The mixture was stirred at -78° for a further 4 hours. An additional amount of the triethylborane solution (0.15ml) was added after 2 hours. The reaction was then quenched with H₂O (3ml) and extracted with ether (2x). The combined organic layers were dried (MgSO₄) and the solvent removed in vacuo to afford the crude product as light yellow oil which crystalyzed upon standing. Purification was achieved by flash chromatography (96:4 hexane/ethyl acetate) to yield final ester as an crystalline solid (87%) (94%ee by chiral-phase GC; (S) [α]_D ^{19 5} = +19.7, chloroform). 1H (NMR) CDC1₃: δ 7.8-7.1 (6H, m, Ar-H), 4.1 (2H, m, -OCH2), 3.9 (3H, s, -OCH₃), 3.8 (IH, q, -CH-), 1.6 (3H, d, -CH₃), 1.4 (3H, t, -OCH₂CH₃).

Catalytic reduction using 20% enan-men₂PhSnH (b') with 9-BBN as a co-reductant in the presence of magnesium bromide and 4λ molecular sieves - preparation of aproxen ethyl ester (entry 4).

MgBr₂.(Et₂O)₂ (0.072g, 0.28mmol) was added to a stirred suspension of powdered 4A molecular sieves (3eq by weight) in dry toluene (0.2mL). The mixture was stirred for 30 minutes under nitrogen, after which it was cooled to -78°C. Bromoester 2 (0.05g, 0.14mmol) in dry toluene (0.6ml) was added slowly to the reaction mixture at -78°C. The resultant mixture was allowed to stir at this temperature for a further 45 min after which a solution of et.αt7-men₂PhSnH (b') (0.014g, 0.029mmol, 157μl), (prepared according to protocol B above) was added, followed by the slow addition of a solution of 9-BBN in THF (0.5M, 628μl). Triethylborane in THF (IM, 0.05ml) was added and oxygen introduced. The reaction mixture was stirred at -78°C for a further 4 hours. An additional amount of triethylborane (0.05ml) was added after 2 hours. The sieves were then filtered off and ether (5mL) was added. Satd. aqueous potassium fluoride was then added (5mL) and the resulting mixture stirred for a further 12 hours. The organic layer was dried (MgSO ) and the solvent removed in vacuo to afford the crude product as light yellow oil which crystallized upon standing and contained no impurities by NMR spectroscopy (65%) (99% ee by chiral-phase GC) (S)).

Catalytic reduction using 20% enan-men₂PhSnH (b¹) with borane as a co-reductant in the presence of magnesium bromide -preparation ofN-TFA-tert-leucine benzyl ester (entry 5). MgBr₂.(Et2θ)2 (0.308g, 1.12mmol) was added to dry toluene (0.7ml) and the solution allowed to stir for 30 min under nitrogen after which the reaction mixture was cooled down to -78°C. Bromoester 3 (0.2g, 0.59mmol) in dry toluene (0.5ml) was added slowly to the reaction mixture at -78°C. The resultant mixture was allowed to stir at this temperature for a further 45 min after which a solution of the et7α«-men₂PhSnH (0.039g, 0.117mmol, 1.8ml) (prepared according to protocol A above) was added, followed by the slow addition of a solution of borane in THF (1.0M, 9.0ml). Triethylborane in THF (IM, 0.15ml) was added and oxygen introduced. The mixture was stirred at -78° for a further 4 hours. An additional amount of the triethylborane solution (0.15ml) was added after 2 hours. The reaction was then quenched with H₂O (3mL) and extracted with ether (2x). The combined organic layers were dried (MgSO₄) and the solvent removed in vacuo to afford the crude product as light yellow oil which crystalyzed upon standing (80%) (99%ee by chiral-phase GC; (S).

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications which fall within the spirit and scope. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.

Claims

CLAIMS:

1. A method for enantioselectively reducing a prochiral carbon centred radical having one or more electron donor groups attached directly to the central prochiral carbon atom of the radical, and/or attached to a carbon atom within 1 to 4 atoms of the central prochiral carbon atom of the radical, said method comprising generating said radical from a radical precursor compound and reacting said radical with a chiral non-racemic organotin hydride in the presence of a Lewis acid and a co-reducing agent, wherein said co-reducing agent is capable of regenerating chiral non-racemic organotin hydride without substantially reducing said radical or said radical precursor compound.

2. The method of claim 1, wherein the organotin hydride is present in an amount which is less than one molar equivalent per mole of prochiral carbon centred radicals provided by the radical precursor compound.

3. The method of claim 1 or 2, wherein the co-reducing agent is selected such that reduction of the carbon centred radical provides a reduced product having an ee value which is no more than 15% lower than that obtained in the absence of the co-reducing agent.

4. The method of any one of claims 1 to 3, wherein the co-reducing agent is present in an amount ranging from 1 to 15 molar equivalents per mole of prochiral carbon centred radicals provided by the radical precursor compound.

5. The method of any one of claims 1 to 4, wherein the co-reducing agent is selected from the group consisting of BH₃, 9-borabicyclononane, NaBHsCN and poly(methylhydrosiloxane).

6. The method of claim 5, wherein the poly(methylhydrosiloxane) is used in conjunction with a Lewis base.

7. The method of any one of claims 1 to 6, wherein the electron donor group is attached directly to the central prochiral carbon atom or to a carbon atom within 1 or 2 atoms of the central prochiral carbon atom.

8. The method of any one of claims 1 to 7, wherein the prochiral carbon centred radical is a prochiral amino acid carbon centred radical wherein the central prochiral carbon atom is an α-carbon atom of an α- amino acid or a β-carbon atom of an β-amino acid.

9. The method of any one of claims 1 to 8, wherein the prochiral carbon centred radical is generated from a radical precursor compound selected from the group consisting of aryl selenides, aryl sulphides, aryl tellurides, xanthates, thionoformates, Barton esters and tertiary chiral halosubstrates.

10. The method of any one of claims 1 to 9, wherein the electron donor group is a carbonyl group.

11. The method of any one of claims 1 to 10, wherein the organotin hydride is selected from the group consisting of

(a) menPh₂SnH (b) men₂PhSnH (c) men₃SnH

(a') enan-menPh₂SnH (b¹) enan-men₂PhSnH

(d)

(e) (f) and

Me,N Sn(H)Phmen

(g) where,

12. The method of any one of claims 1 to 11 , wherein the Lewis acid is provided in the form of a Lewis adduct.

13. The method of any one of claims 1 to 12, wherein the Lewis acid is used in an amount of about 0.9 to about 2.0 molar equivalents per mole of prochiral carbon centred radicals to be reduced.

14. The method of any one of claims 1 to 13, wherein the organotin hydride is immobilized onto a solid support.