WO2004065334A1 - Method of removing organotin residue - Google Patents

Abstract

The invention provides a method of separating soluble organotin residue from a reduced product of a reduction reaction that uses an organotin hydride as a reducing agent, the method comprising: (i) contacting a reaction medium comprising said reduced product and soluble organotin residue with a substrate which, (a) is substantially insoluble in the reaction medium, (b) binds at least a portion of said soluble organotin residue, and (c) does not substantially bind the reduced product; (ii) separating said substrate from the reaction medium, thereby removing said at least a portion of organotin residue from the reaction medium; andrecovering the reaction medium comprising the reduced product. The invention also provides a method of performing a reduction reaction using an organotin hydride as a reducing agent that incorporates the method of separating soluble organotin residue.

Description

METHOD OF REMOVING ORGANOTIN RESIDUE

FIELD OF THE INVENTION

The present invention relates to reduction reactions involving organotin hydride reducing agents, and in particular to a method for separating organotin residues from a reduced product of a reduction reaction which uses an organotin hydride as reducing agent. The invention also relates to a method of performing a reduction reaction that uses an organotin hydride as a reducing agent.

BACKGROUND

Reduction reactions play a key role in the synthesis of many organic compounds. Organotin hydrides are used extensively as reducing agents in such reactions due to their availability, stability, functional group tolerance and their particularly convenient hydrogen atom transfer rate constant. However, organotin residue that is inherently present in reaction mixtures derived from organotin hydride based reduction reactions is notoriously difficult to separate from the desired end product of the reaction. In particular, such organotin residue is often soluble in the same array of solvents to that which the desired end product is soluble in. This, coupled with the fact that many organotin compounds are neurotoxins, makes using tin reagents problematic in the synthesis of drugs, medicines and other formulations intended for human consumption.

Numerous approaches have been adopted to facilitate the separation of organotin residue from a desired end product of an organotin hydride based reduction reaction. A common approach has been to subject the reaction mixture resulting from the reduction reaction to a chromatographic purification process. However, finding suitable conditions to achieve an effective separation is often difficult due to the tendency of organotin compounds to bleed on the stationary phase. In any event, such a purification process is time consuming and laborious. Precipitation of the organotin residue as insoluble organotin fluoride derivatives has proven to be effective, but in practice this technique is often used in conjunction with a chromatographic purification process. A further approach has been to immobilise the tin hydride reagents onto an insoluble polymeric support. For example, organotin hydrides have been covalently bound to a crosslinked polystyrene support. The immobilised tin reagents are inherently easier to separate from reaction mixtures, however they can be difficult to prepare and utilise in practice and are not available commercially.

It would there be desirable to provide a simple, versatile and effective method for separating organotin residue from a desired end product of a reduction reaction that uses an organotin hydride as a reducing agent.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a method of separating soluble organotin residue from a reduced product of a reduction reaction that uses an organotin hydride as a reducing agent, said method comprising:

(i) contacting a reaction medium comprising said reduced product and soluble organotin residue with a substrate which,

(a) is substantially insoluble in the reaction medium, (b) binds at least a portion of said soluble organotin residue, and

(c) does not substantially bind the reduced product; (ii) separating said substrate from the reaction medium, thereby removing said at least a portion of organotin residue from the reaction medium; and (iii) recovering the reaction medium comprising the reduced product.

In a further aspect, the present invention also provides a method of performing a reduction reaction using an organotin hydride as a reducing agent, said method comprising forming a reduced product by reducing a precursor compound in a reaction medium using the organotin hydride as the reducing agent, contacting the reaction medium comprising said reduced product and soluble organotin residue with a substrate which,

(a) is substantially insoluble in the reaction medium, (b) binds at least a portion of said soluble organotin residue, and

(c) does not substantially bind the reduced product,

separating said substrate from the reaction medium to thereby remove said at least a portion of organotin residue from the reaction medium, and recovering the reaction medium comprising the reduced product.

Advantageously, by performing the methods of the present invention, a reduced product formed by the reduction reaction can be conveniently separated from organotin residue present in the reaction medium by separating the substrate from the reaction medium using simple means such as filtration or centrifugation and the like.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "reaction medium" is used to denote any suitable medium in which the reduction reactions may be performed. Generally, the medium will be either a polar or non-polar solvent, and can include as the solvent a compound that is to be reduced. Those skilled in the art should readily be able to select a suitable reaction medium for use in accordance with the methods of the present invention.

As used herein, the term "organotin residue" is used to denote any organotin compound present in the reaction medium. Accordingly, the term "organotin residue" embraces an organotin hydride used as the reducing agent, and also organotin reaction by-product(s) that form during the course of the reduction reaction.

As used herein, the term "reduced product" is used to denote a compound that is the recipient of a hydrogen atom from an organotin hydride during a reduction reaction between the organotin hydride and a precursor compound. It will be appreciated that in most instances, the reduced product will also be the desired end product of the reduction reaction. As used herein, the term "precursor compound" is used to denote a compound or species that is reduced to form the reduced product. The precursor compound may for example be a carbon centred radical such as a prochiral carbon centred radical.

A reduction reaction in accordance with the methods of the present invention uses an organotin hydride as reducing agent. Advantageously, it is believed that the methods are not limited by any particular reductive mechanism through which the stannane operates. Accordingly, stannane based reduction reactions such as those which operate by an ionic or radical mediated process may be used in the methods of the present invention.

A reduction reaction in accordance with the methods of the present invention may be used to prepare either an achiral or a chiral reduced product. It will be appreciated by those skilled in the art that there is an extensive range of organotin hydrides and auxiliary reagents that can be used to prepare such products. Advantageously, it is believed that the methods of the present invention are not limited to using any particular stannane or auxiliary reagent. In particular, the methods are believed to be capable of being performed with any reduction reaction that uses an organotin hydride as a reducing agent.

The substrate in accordance with the methods of the present invention has three important characteristic features. In particular, the substrate is substantially insoluble in the reaction medium, binds at least a portion of soluble organotin, and does not substantially bind the reduced product. It is these features of the substrate that enables the organotin residue to be separated from the reaction medium. In particular, organotin residue which is soluble in the reaction medium becomes bound to the substrate, and upon separation of the substrate from the reaction medium, is also separated from the reaction medium. The substrate does not substantially bind the reduced product, and the reduced product therefore remains in the reaction medium and can be isolated therefrom.

The methods of the present invention involve contacting a reaction medium comprising said reduced product and soluble organotin residue with a substrate. By the term

"contacting a reaction medium" it is meant that at some point while performing the method, the substrate is in contact with the reaction medium comprising the reduced product and soluble organotin residue. In practice, it will therefore be necessary to introduce the substrate to the reaction medium at some stage. The substrate may be introduced to the reaction medium either before, during or subsequent to the reduction reaction taking place and the reduced product being formed. Preferably, the substrate is introduced to the reaction medium prior to performing the reduction reaction and remains in the reaction medium until the reduction reaction is substantially complete. In particular, it is preferred that the reduction reaction takes place in the presence of the substrate. In this case, the reduction reaction can most conveniently be performed as a batch process.

Alternatively, by locating and retaining the substrate in a suitable flow-through reactor, the reaction medium comprising the organotin hydride and the precursor compound can be passed through the reactor to make contact with the substrate. A possible variation of this process is that the substrate is precontacted with the organotin hydride, and the reaction medium comprising the precursor compound is passed through the reactor. In either situation, the reduction reaction can proceed in the reactor with the reduced product being subsequently eluted from the reactor. Conveniently, under these operating conditions, the substrate is in effect automatically separated from the reaction medium during the reaction, and the methods may be performed as a continuous process.

There are of course many different ways in which the substrate could be introduced to the reaction medium, and those mentioned above serve only as examples and are not intended to limit the scope of the present invention.

Surprisingly, the presence of the substrate during the reduction reaction does not appear to inhibit the organotin hydride's ability to act as a reducing agent. More surprisingly, the presence of the substrate during the reduction reaction has been found to modify the stereoselective reaction pathways of stereoselective reagents used in the preparation of chiral reduced products in some circumstances. This will be discussed in more detail below. Being substantially insoluble in the reaction medium, the substrate may be in the form of large particles, finely granulated or a power. Preferably the substrate is powdered or in a fine granular form. In these forms, the substrate has a higher contact surface area with the organotin residue in the reaction medium, and may be dispersed more evenly throughout the reaction medium. This inturn facilitates the ability of the substrate to bind with the organotin residue.

In accordance with the methods of the present invention, the substrate binds at least a portion of soluble organotin residue. The organotin residue may not necessarily be irreversibly bound to the substrate, but rather exist in a state of equilibrium between being bound and un-bound in solution. However, where an equilibrium does exist, it is preferred that the rate of exchange between the bound and un-bound states is rapid enough such that separation of the substrate from the reaction medium still allows for an effective separation of organotin residue from the reaction medium.

Regardless of whether the organotin residue becomes irreversibly bound to the substrate or not, upon separation of the substrate from the reaction medium, it is preferred that at least 85 weight %, more preferably at least 90 weight %, most preferably at least 95 weight % of soluble organotin residue in the reaction medium is bound to the substrate and is also separated from the reaction medium.

The ability to separate at least 85 weight % of soluble organotin residue from the reaction medium by simply separating the substrate from the reaction medium by means such as filtration or centrifugation and the like, represents a significant improvement in both procedure and work-up time required to isolate the reduced product. In particular, by performing the methods of the present invention the need to use chromatographic purification techniques is advantageously circumvented in most instances. Where it is desirable to reduce the levels of organotin residue below that which can be obtained by simply separating the substrate from the reaction medium, other conventional separation techniques can be used in conjunction the methods of the present invention. For example, fluoride salts such as NaF or KF may be added to the reaction medium to precipitate any organotin residue not bound to the substrate, or if possible the reduced product may be recrystallised one or more times.

As indicated above, the substrate binds at least a portion of soluble organotin residue. It will be appreciated that organotin residue that is insoluble in the reaction medium could readily be separated by means such as filtration.

It is an important feature of the substrate that it does not substantially bind the reduced product. It will be appreciated that if the substrate were to bind the organotin residue as well as the reduced product, separation would be problematic. Accordingly, as the tendency for the substrate to bind with the reduced product increases, the less efficient the separation becomes. Preferably, the substrate binds not more than 15 weight %, more preferably not more than 10 weight %, most preferably not more than 5 weight % of the reduced product present in the reaction medium.

The amount of substrate used in the methods of the present invention may vary depending on the nature of the substrate and the mode in which the reduction reaction is performed. It is preferable to use the least amount of substrate required to bind the organotin residue in the reaction medium. In general, it is preferred that about 10 equivalents, more preferably about 5 equivalents, most preferably about 3 equivalents by weight of the substrate is used, relative to the amount of organotin hydride used. These preferred amounts are particularly preferred when the reduction reactions are performed in a batch mode. Higher amounts may be used if the reduction reaction is performed in a continuous mode. In this case, the amounts used will vary depending upon factors such as the flow rate of the reagents. One skilled in the art should readily be able to determine a suitable amount of substrate to use under the particular reaction conditions employed.

Preferably, the substrate used in accordance with the methods of the present invention is a zeolite.

As used herein, the term "zeolite" is intended to denote a porous oxide structure that has a well-defmed pore structure due to a high degree of crystallinity. One skilled in the art will appreciate that this reflects a more contemporary understanding of what is meant by the term "zeolite". In particular, this definition is intended to embrace synthetic zeolites which are not necessarily limited to the more classical definition of zeolites as being aluminosilicate structures. For example, a synthetic zeolite may have an aluminophosphate type structure.

Suitable zeolites include, but are not limited to, those which are commonly referred to as molecular sieves. The molecular sieves preferably have a pore size ranging from about 2 A to about 10 A, more preferably from about 2 A to about 6 A, most preferably the pore size is about 4 A.

Preferably, when used as a substrate in accordance with the methods of the present invention, the zeolites, and in particular the molecular sieves, are "activated" by means well known in the art. Typically, activation will be achieved by simply heating the zeolite at a set temperature for a set period of time.

A suitable substrate for use in accordance with the methods of the present invention may be selected by simply assessing the ability of the substrate to bind with soluble organotin residue, to not bind with the reduced product and to be separated from the reaction medium. This assessment can be conveniently achieved by simply performing the methods of the present invention using a selected substrate. The amount of organotin residue removed from the reaction medium, and the amount of reduced product remaining in the reaction medium, can be analysed using conventional analytical techniques. This data can then be compared with data from equivalent reactions where conventional techniques have been used to separate organotin residue from the reduced product.

In separating the substrate from the reaction medium, at least a portion of the organotin residue is also separated from the reaction medium. As indicated above, if the reduction is performed in a flowthrough reactor that retains the substrate, separation automatically occurs during the reaction. If however a discrete separation step is required, as would be the case for most batch type reactions, means well known in the art such as filtration and/or centrifugation and the like can be used.

Having separated the reaction medium from the substrate, the reaction medium comprising the reduced product is recovered. As indicated above, the reaction medium can be subjected to further purification techniques if desired, or the reduced product can simply be isolated directly from the reaction medium. In either case, isolation of the reduced product can be achieved by techniques well known in the art, for example the reduced product may be recrystallised or distilled from the reaction medium.

The methods of the present invention are believed to be capable of being performed with any reduction reaction that uses an organotin hydride as a reducing agent. Those skilled in the art should therefore be able to readily select suitable reagents and reaction conditions to conduct either radical or ionic mediated reduction reactions, or to prepare either achiral or chiral reduced products.

Trialkyltin hydrides, triaryltin hydrides or mixed alkyl-aryltin hydrides are commonly used as reducing agents and are also preferred reducing agent that can be used in accordance with the methods of the present invention. Exemplary trialkyltin hydrides include, but are not limited to, tributyltin hydride and trimethyltin hydride. An exemplary triaryltin hydride incudes, but is not limited to, triphenyltin hydride.

The versatility of the methods of the present invention is reflected by their ability to be performed with enantioselective reduction reactions using chiral organotin hydrides as reducing agents. In particular, the presence of the substrate during such reduction reactions does not appear to prevent the chiral organotin hydride from transferring a hydrogen atom in a stereoseletive manner. Surprisingly, it has been found that by having the substrate present during such a reduction reaction, the ee valves of the reduced product can be enhanced. More surprisingly, in some instances it has been found that by having the substrate present during such reduction reactions the enantiomeric configuration of the reduced product can be switched from that which is obtained when the reduction is performed in the absence of the substrate. For example, if in the absence of the substrate an (S)-isomer of the reduced product dominates, when the substrate is present an (R)- isomer may dominate instead. Accordingly, the dominate enantiomeric configuration afforded to a reduced product can advantageously be switched by simply conducting the reduction reaction in the presence of the substrate rather than having to prepare and utilise an appropriately configured organotin hydride.

Recently, US 2002/3133039 disclosed a method for enhancing the enantioselectivity of free radical reduction reactions using chiral non-racemic stannanes as reducing agents and Lewis acids. Advantageously, it has been found that these enantioselective reduction reactions can also be used in the methods of the present invention. In particular, the advantages afforded by these reduction reactions do not appear to be lost through being performed in accordance with the methods of the present invention.

Accordingly, a preferred reduction performed in accordance with the methods of the present invention involves 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, with a chiral non-racemic organotin hydride in the presence of a Lewis acid. In this case, the prochiral carbon centred radical is generated from a 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.

It is particularly preferred that the enantioselective reduction reaction produce optically enhanced α or β- amino acids by the reduction of a prochiral amino acid carbon centred radical with a chiral non-racemic organotin hydride in the presence of a Lewis acid, 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. 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 moieties are attached. Reduction of the prochiral carbon centred radical with a hydrogen atom donor affords the chiral compound R₁R₂R₃CH. Thus reduction reactions of this type result in the preparation of enantioselectively enhanced chiral reduced products.

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

The prochiral carbon centred radicals which can be reduced in these enantioselective reduction reactions 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 R₁R₂R₃O, 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 compound may contain more than one prochiral radical precursor site and that reduction may therefore occur at one or more of these sites.

Various combinations of the substituents R₁-R₃ attached to the prochiral carbon centred radical may be used. Preferably, at least one of R1-R₃ is an optionally substituted aryl or heteroaryl group; or at least one of R₁-R₃ is an optionally substituted alkyl, alkenyl, or alkynyl group; or 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)_n- 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 C₁-₂₀ 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 Cj.io 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 Cι-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, chrysenyl. 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, phenylbutanoyl, phenylisobutylyl, phenylpentanoyl and phenylhexanoyl) and naphthylalkanoyl (e.g. naphthylacetyl, naphthylpropanoyl and naphthylbutanoylj; 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, diarylamino, 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 Cj.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, trifluoromefhyl, 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 C].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 Cj-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, CO₂alkyl (eg Cι-₆ alkyl such as methyl ester, ethyl ester, propyl ester, butyl ester), CO₂phenyl (wherein phenyl itself may be further substituted), CONH₂, CONHphenyl (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), CONHdialkyl (eg Cι.₆ alkyl).

As used herein, the term "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 enantioselective reduction reactions are typically 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 canϊed 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); 9-BBN (Tetrahedron Lett., 1998, 39, 5437), 9-alkyl-9-BBN, (eg alkyl = ethyl, propyl, butyl etc).

Exemplary chiral non-racemic organotin hydrides have the formula LιL₂L₃SnH 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 3 -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 (lS,2R,5S)-menthyldiphenyltin hydride (a'), bis[(lR,2S,5R)-menthyl]phenyltin hydride (b) and its enantiomer bis[(lS,2R,5S)-menthyl]phenyltin hydride (b'), 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 (b') 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 chiral non-racemic organotin hydride reducing agents include, for example, (g) shown below.

Me₂N Sn(H)Phmen

(e) (f) (g)

Lewis acids for use in the enantioselective reductions 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 A1C1 , Me₃Al, MeAl(OPh)2, MAD (methyl aluminium bis(2,6-di-tert-butyl-4-methyl phenoxide)), BF₃, BBr₃, BC1₃, Ln(OTf)₃, TiCl₄, FeCl₃, ZnCl₂, zinc silicate, calcium silicate, aluminium silicate, zirconocene dichloride (herein after referred to as (i)) calcium silicate, trialkylborates (RO₃B, wherein each R is an alkyl group which can be the same or different), (S,S)- and (R,R)-(+)-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).

Preferably, the Lewis acid has a solubility, under the reaction conditions employed, of at least about 0.1 molar equivalents, preferably at least about 0.5 molar equivalents, more preferably at least about 1.0 molar equivalent, most preferably about 2.0 molar equivalents, per mole of prochiral carbon centred radicals to be reduced.

Particularly preferred Lewis acids are those which are alkaline earth metal compounds. Such compounds have been shown to afford excellent enantioselectivity.

Preferably, the alkaline earth metal compound is a Lewis acidic magnesium compound. Examples of suitable Lewis acidic magnesium compounds include MgBr₂, Mg(ClO₄)₂, Mgl₂, Mg(OAc)₂, Mg(OTf)₂ and magnesium silicate. It will be appreciated that the above list of magnesium compounds is not exhaustive and that the enantioselctive reductions may encompass the use of other Lewis acidic magnesium compounds or combinations thereof.

Where the Lewis acid used in the enantioselective reduction 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 the reduction reactions may also be provided in the form of a Lewis adduct. For example, Lewis acids such as BF₃, ZnCb, and MgBr2 may be provided and used in the form of their diethylether adducts BF₃-Et₂O, ZnCl₂-(Et₂O)₂ and MgBr₂-(Et₂O)₂, respectively.

The stamiane in the enantioselective reductions is preferably used in an amount of about 0.5-1.5 molar equivalents, more preferably about 1.1 molar equivalents, per mole of prochiral carbon centred radicals to be reduced, to effect optimum reductive conversion.

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 prochiral carbon centred radicals 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 prochiral carbon centred radicals 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 generally not result in an increase in observed ees.

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 prochiral carbon centred radicals 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 prochiral carbon centred radicals to be reduced.

The dominate stereochemistry of the reduced prochiral carbon centre in the resulting compounds formed by these reductive techniques can be (R) or (S). As previously mentioned, in some instances this can be switched by having the substrate present during the reduction reaction. Where the reduction reaction is performed in the absence of the substrate, the substrate can simply be introduced to the reaction medium after the reduction reaction is substantially complete to thereby enable the organotin residue to be separated in accordance with the methods.

These enantioselective reduction reactions 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 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 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)-(6).

1. Rι=OEt, R₂=Et, R₃=Ph X = Br 2. Rι=OEt, R₂=Me, R₃=(CH₃)₂CHCH₂Ph X = Br 3. Rι=OEt, R₂=Me, R₃=6-(OCH₃)-Napthyl X = Br 4. Rι=OEt, R₂=cyclo-pentyl, R₃=Ph X = Br 5. Rι=OBn, R₂=NHCOCF₃, R =tert-Bu X = Br 6. Rι=Ph, R₂=Me, R₃=Ph X = Br

Bn=Benzyl

Compounds (l)-(6) were prepared as follows:

Preparation of compounds 1, 4 and 6

Compounds 1, 4 and 6 (X=Br) were 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)

Racemic ibuprofen (0.5g, 2.42 mmol) and bromine (0.425g, 1.1 eq, 2.66mmol) were heated under reflux and PBr₃ (0.67g, 1.03eq, 2.49mmol) slowly added to the reaction mixture. The reaction mixture was further heated at 65-70°C until the evolution of HBr had ceased (approx. 3 hours). The reaction mixture was then distilled to remove residual HBr and low boiling impurities. A 1 : 1 mixture of ethanol/dichloromethane (5ml) was slowly added followed by a small amount of H₂SO₄ (approx 1 drop) and the reaction mixture was heated at reflux for a further 2 hours. The remaining solvent was removed in vacuo to afford (2) in sufficient purity for further use (0.265g).

Preparation of compound 3

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 (CDC1 ) (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 5

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 5 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 precursor compound to be reduced; if present, the Lewis acid of choice at about 2 molar equivalents, per mole of precursor compound to be reduced; about 1 to about 1.5 molar equivalents of the stannane per mole of prochiral carbon centred radicals to be reduced; and if present, about 1 to about 3 equivalents by weight of the substrate, relative to the stannane. Where molecular sieves were used as the substrate, the sieves were activated and ground to a powder using a mortar and pestal prior to their use. 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 substrate, if present, was filtered off and the reaction medium collected. Where a substrate was present, after filtration the reduced product was isolated with or without KF treatment of the reaction medium. In both cases, the isolated product was found to contain no organotin residue by NMR analysis. Where a substrate was not used (ie. a comparative example), the reaction medium was generally purified by conventional chromato graphic techniques and subsequently treated with KF to remove the organotin residue. To assess the enantiomeric purity of the product, 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 6 (X = H) against an internal standard (either octane or undecane). The reduced compounds 1 to 6 (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 trifluoroacteylated 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 6 (X = H), prepared by the following procedures: Procedure for the preparation of compounds 1, 4 and 6 (X = H)

Compounds 1 , 4 and 6 (X = H) were 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 commercially available (S)-ibuprofen (2g, 9.66mmol) in thionyl chloride (10ml) was heated at reflux until the evolution of gas ceased. The excess thionyl chloride was removed in vacuo and solution of ethanol (5ml) in dichloromethane (10 ml) was added and refluxing continued for further 2 hour. The mixture was cooled and the solvent removed in vacuo to give (2, X = H) as colourless oil (1.61g, 71%) and of sufficient purity for further use.

Preparation of compound 3 (X = H)

A solution of 6-methoxy-2-methyl-2-naphthaleneacetic acid (naproxen) (l.Og, 4.34mmol) in thionyl chloride (20 ml) was reflux until the evolution of HCl gas had ceased (ca.1 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%). ^]H 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 (1H, q, 7.5Hz, Ar-

CH), 1.5 (3H, d, 7.5Hz, Ar-CH- CH₃), 1.20 (3H, t, 7.5Hz, -OCH₂CH₃). ¹³C NMR

(CDC1₃): δ 173.0, 156.6, 133.0, 132.6, 129.2, 128.9, 128.4, 126.4, 126.0, 1 18.6, 105.359.8,

56.0, 42.6, 17.3, 13.6. Preparation of compound 5 (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% HCl, sat. NaHCO₃ and brine. The organic layer was dried (MgSO ) and the solvent removed in vacuo to obtain the crude product as a light yellow oil. Pure (S)-N-trifluoroacetyl-/ert-Ieucine benzyl ester was obtained as a pale oil after flash chromatography (96:4 hexane: ethyl acetate) in 65% yield.

Table 1 lists reaction data for model compounds (1) to (6) reacting with a selected stannane in the presence of a substrate and optionally a Lewis acid, at -78 °C in toluene. Table 1 also lists reaction data for comparative examples where reactions were performed in the absence of the substrate. The conversion data shown in Table 1 was measured by GC. Isolated yields for the compounds are shown in parenthesis.

TABLE 1

Reaction data for compound (1) to (6) reacting with a selected stannane, optionally in the presence of a selected Lewis acid and a selected substrate, at -78°C in toluene.

TABLE 1 - continued

TABLE 1 - continued

comparative examples achiral reduction reactions MAD = methyl aluminium bis(2,6-di-tert-butyl-4-methyl phenoxide)

A typical experimental procedure for enantioselective reduction reactions of Example 1 is described below

Reduction using mengPhSnH in the presence of MgBr? and 4 A molecular sieves - naproxen ethyl ester (entry 10).

MgBr₂.(Et₂O)₂ (0.36g, 1.4mmol) was added to a stirred suspension of powdered 4 A molecular sieves (3eq by weight) in dry toluene (1.0ml). The mixture was stiffed for 30 minutes under nitrogen, after which it was cooled to -78°C. Bromoester 3 (0.25g, 0.7mmol) 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 60 min after which a solution of men₂PhSnH (0.423g, 0.91mmol) in toluene (1.0ml) was added. Triethylborane in THF (1M, 0.15ml) was added and oxygen introduced. The reaction mixture was stirred at -78°C for a further 4 hours. An additional amount of triethylborane (0.1ml) 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 (85%) (95% ee by chiral-phase GC) (R), [α]_D ^19'5 = -13.7, chloroform). Η (NMR) CDC1₃: δ 7.8-7.1 (6H, m, Ar-H), 4.1 (2H, m, -OCH₂), 3.9 (3H, s, -OCH₃), 3.8 (1H, q, -CH-), 1.6 (3H, d, -CH₃), 1.4 (3H, t, -OCH₂CH₃). A typical experimental procedure for achiral reduction reactions of Example 1 is described below:

Reduction using Ph nH in the presence ofMgBr? and 4 A molecular sieves - naproxen ethyl ester (entry 52).

MgBr₂.(Et₂O)₂ (0.09g, 0.35mmol) was added to a stirred suspension of powdered 4A molecular sieves (3eq by weight) in dry toluene (0.3mL). The mixture was stirred for 30 minutes under nitrogen, after which it was cooled to -78°C. Bromoester 3 (0.062g, 0.175mmol) in dry toluene (0.15ml) was added slowly to the reaction mixture at -78°. The resultant mixture was allowed to stir at this temperature for a further 60 min after which a solution of Ph₃SnH (0.067g, 0.193mmol) in toluene (0.3ml) was added. Triethylborane in THF (0.05ml of 1M solution) was added and oxygen introduced. The reaction mixture was stirred at -78° for a further 4 hours. An additional amount of triethylborane (0.1ml) was added after 2 hours. The sieves were then filtered off and ether (5ml) was added. The organic layer was dried (MgSO ) and the solvent removed in vacuo to afford the racemic crude product as light yellow oil which crystallized upon standing and contained no impurities by NMR spectroscopy (82%). ^]H (NMR) CDC1₃: δ 7.8-7.1 (6H, m, Ar-H), 4.1 (2H, m, -OCH₂), 3.9 (3H, s, -OCH₃), 3.8 (1H, q, -CH-), 1.6 (3H, d, -CH₃), 1.4 (3H, t, - OCH₂CH₃).

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 of separating soluble organotin residue from a reduced product of a reduction reaction that uses an organotin hydride as a reducing agent, said method comprising:

(i) contacting a reaction medium comprising said reduced product and soluble organotin residue with a substrate which, (a) is substantially insoluble in the reaction medium, (b) binds at least a portion of said soluble organotin residue, and

(c) does not substantially bind the reduced product; (ii) separating said substrate from the reaction medium, thereby removing said at least a portion of organotin residue from the reaction medium; and (iii) recovering the reaction medium comprising the reduced product.

2. The method of claim 1 wherein the reduced product is formed from an enantioselective reduction reaction of 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, with a chiral non-racemic organotin hydride in the presence of a Lewis acid.

3. The method of claim 2, 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.

4. The method of claim 2 or 3, wherein the chiral non-racemic organotin hydride is selected from the group consisting of

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

(a¹) enan-menPh SnH (b') enan-men₂PhSnH

(d)

(e) (f)

and

Me₂N Sn(H)Phmen

(g) where,

5. The method of any one of claims 1 to 4, wherein the reduction reaction takes place in the presence of said substrate.

6. The method of claim 2, wherein the reduction reaction takes place in the presence of said substrate and the enantiomer of the reduced product in enantiomeric excess is different compared to the enantiomer of the reduced product in enantiomeric excess if the reduction reaction did not take place in the presence of said substrate.

7. The method of any one of claims 1 to 4, wherein said substrate is introduced to the reaction medium after the reduction reaction is substantially complete.

8. The method of any one of claims 1 to 7, wherein said substrate binds no more than 15 weight % of the reduced product present in the reaction medium.

9. The method of any one of claims 1 to 8, wherein upon separation of said substrate from the reaction medium at least 85 weight % of the soluble organotin residue is bound to the substrate and is also separated.

10. The method of any one of claims 1 to 9, wherein said substrate is a zeolite.

11. The method of claim 10, wherein the zeolite is a molecular sieve having a pore size ranging from 2A to lOA.

12. The method of any one of claims 1 to 11, wherein said substrate is separated from the reaction medium by filtration and/or centrifugation.

13. A method of performing a reduction reaction using an organotin hydride as a reducing agent, said method comprising forming a reduced product by reducing a precursor compound in a reaction medium using the organotin hydride as the reducing agent, contacting the reaction medium comprising said reduced product and soluble organotin residue with a substrate which,

(a) is substantially insoluble in the reaction medium, (b) binds at least a portion of said soluble organotin residue, and

(c) does not substantially bind the reduced product, separating said substrate from the reaction medium to thereby remove said at least a portion of organotin residue from the reaction medium, and recovering the reaction medium comprising the reduced product.

14. The method of claim 13, wherein the precursor compound is 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, with a chiral non-racemic organotin hydride in the presence of a Lewis acid.

15. The method of claim 14, 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.

16. The method of claim 14 or 15, wherein the chiral non-racemic organotin hydride is selected from the group consisting of

(b) menPh₂SnH (b) men₂PhSnH (c) men₃SnH (a') enan-menPh₂SnH (b') enan-me^PhSnH

(d)

(e) (f) and

Me₂N Sn(H)Phmen

(g) where,

17. The method of any one of claims 13 to 16, wherein the reduction reaction takes place in the presences of said substrate.

18. The method of claim 14, wherein the reduction reaction takes place in the presence of said substrate and the enantiomer of the reduced product in enantiomeric excess is different compared to the enantiomer of the reduced product in enantiomeric excess if the reduction reaction does not take place in the presence of said substrate.

19. The method of any one of claims 13 to 16, wherein said substrate is introduced to the reaction medium after the reduction reaction is substantially complete.

20. The method of any one of claims 13 to 19, wherein said substrate binds no more than 15 weight % of the reduced product present in the reaction medium.

21. The method of any one of claims 13 to 20, wherein upon separation of said substrate from the reaction medium at least 85 weight % of the soluble organotin residue is bound to the substrate and is also separated.

22. The method of any one of claims 13 to 21, wherein said substrate is a zeolite.

23. The method of claim 22, wherein the zeolite is a molecular sieve having a pore size ranging from 2 A to 10 A.

24. The method of any one of claims 13 to 23, wherein said substrate is separated from the reaction medium by filtration and/or centrifugation.

25. A reduced product prepared by the method of any one of claims 13 to 24.