WO2004018487A1 - Chiral organosilicon hydrides - 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, comprising treating said radical with an activated chiral non-racemic organosilicon hydride in the presence of a Lewis acid. The invention also provides a novel class of activated chiral non-racemic organosilicon hydrides.

Description

Chiral organosilicon hydrides

FIELD OF THE INVENTION

The present invention relates generally to reductive methods useful in chemical synthesis. In particular, the present invention relates to enantioselective reductive methods using chiral organosilicon hydrides, and to the novel class of chiral organosilicon hydrides.

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; Blumstein, M, et al, Angew. Chem. Int. Ed., 1997, 36, 235 and Schartzkopf, K., et al, Eur. J. Chem., 1998, 177). Recently, chiral non-racemic stannanes, in conjunction with appropriate chiral or achiral Lewis acids, have been shown to reduce a variety of prochiral radicals with enhanced enantioselectivity when compared to results obtained in the absence of Lewis acid mediation (Chem Commun. 1999, 1665-1666).

While providing effective means to enantioselectively prepare chiral compounds, the enantioselective reducing capacity of chiral non-racemic stannanes is limited. In particular, inherently high hydrogen transfer rate constants preclude such stannanes from reducing several classes of prochiral radicals with acceptable chiral discrimination. Furthermore, the chiral recognition of the stannane reducing agents is limited due to the inability for such reagents to sustain chirality at the tin atom.

Accordingly, there is a need to develop a more versatile reducing agent for use in the enantioselective preparation of chiral compounds.

SUMMARY OF THE INVENTION

In a first aspect, 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, comprising treating said radical with an activated chiral non-racemic organosilicon hydride in the presence of a Lewis acid.

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 second aspect, the present invention provides an activated chiral non-racemic organosilicon hydride of general formula (I):

L,L₂L₃SiH (I) where Li, L₂ and L are organic substituents which may be the same or different, and where at least two of Li , L₂ and L₃ each contain an activating group which is attached directly to the silicon atom.

Preferably, Li, L₂, and L each contain an activating group which is attached directly to the silicon atom.

It is to be understood that while the second aspect of the invention is not intended to encompass known chiral non-racemic organosilicon hydride reagents, the first aspect of the invention relates to the use of any suitable chiral non-racemic organosilicon hydride reagents, even those which may have been described in the prior art.

In a particular embodiment, the invention is directed towards a method of preparing optically enhanced a or β- amino acids by treatment of a prochiral amino acid carbon centred radical with an activated chiral non-racemic organosilicon hydride in the presence of a Lewis acid, wherein the central prochiral carbon atom is an a- carbon atom of an α- amino acid or a β- carbon atom of an α-amino acid.

Chiral silicon hydride reagents (silanes) have been prepared in the past, however, such reagents have not been used to make chiral compounds through free-radical reduction chemistry. In general, such silanes are renowned for their limited ability to act as effective reducing agents due to inherently unfavourable hydrogen transfer rate constants.

It has now been found that chiral non-racemic organosilicon hydride reagents, bearing activating groups on the silicon atom, can be used to enantioselectively prepare chiral compounds. Such activated silicon reagents demonstrate accelerated hydrogen transfer rate constants relative to ordinary non-activated silanes and reduced hydrogen transfer rate constants relative to their organostannane counterparts. This, coupled with the ability to vary the hydrogen transfer rate constants by altering the nature of the activating groups provides the silicon reagents with superior kinetic control over the reduction chemistry. Advantageously, the superior kinetic control can enable the range of suitable prochiral substrates to be extended beyond that available to stannane analogues. Furthermore, the silane reagents are able to sustain chirality at the silicon atom bearing the transferable hydrogen and therefore demonstrate the potential to provide enhanced chiral recognition. In this case, the structural integrity of the silane reagents should be sufficiently stable so as not to racemise during the reduction reaction.

Surprisingly, it has also been found that the activated silanes are capable of enantioselectively reducing prochiral carbon centred radicals at significantly higher temperatures relative to their organostannane counterparts. In particular, the silanes have been found to be capable of enantioselectively reducing prochiral carbon centred radicals at temperatures as high as 0°C.

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 R)R₂R₃CH. The present invention thus relates to the enantioselective preparation of chiral compounds.

The prochiral carbon centred radical can be generated from any suitable radical precursor using methods known in the art. Exemplary radical precursors 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 of C-C Bonds (1986) Pergamon Press, Oxford, the contents of which are incorporated herein by reference). Particularly suitable radical precursors 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.

The prochiral carbon centred radicals which can be reduced by the methods of the invention include radicals which bear one or more electron donator 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 donator groups include those containing an electron donator atom such as oxygen, nitrogen, and/or sulfur and which will not be affected by the organosilicon hydride. One example of an electron donator 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 donator 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 donator 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 donator atom within 5 atoms (ie 1, 2, 3, 4, or 5) of the central prochiral carbon atom. It will be recognised that some electron donator 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 Rι-R 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 donator 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 a 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)_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 C|.₂₀ alkyl, eg C_MQ 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-, 1-, 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 Cι-₂₀ alkenyl (eg Cι-ι₀ 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, 1 -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 "heterocychc" 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 heterocychc groups include N-containing heterocychc groups, such as: unsaturated 3 to 6 membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolmyl, 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 heterocychc 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 heterocychc 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 heterocychc 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 heterocychc group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as, benzothiazolyl or benzothiadiazolyl.

A heterocychc 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 Cι-₂o 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 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, 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 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-₍₎ alkyl, such as methylamino, ethyl amino, 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 C_.-₆ alkyl, such as acetyl), O-C(O)-alkyl (eg -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),CONHalkyl (eg Cι-₆ alkyl such as methyl ester, ethyl ester, propyl ester, butyl amide), CONHdialkyl (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 tellurium.

The reductive method of the invention is 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 reducing agent 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 of 0°C or less, preferably at about -30°C or less. 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); and Et₃B/O₂.

As previously mentioned, the activated silanes in accordance with the present invention can enantioselectively reduce prochiral carbon centred radicals at temperatures as high as 0°C. Surprisingly, it has also been found that the enantioselectivity of the reduction reactions can be enhanced through the addition of a Lewis base. Accordingly, the method of the present invention is preferably conducted in the presence of a Lewis base. Without wishing to be limited by theory, the Lewis base is believed to form a complex with the organosilane, the resulting structure of which affords a more highly activated organosilane compound. In practice, it is often preferable to conduct the method of the invention by pre-complexing the Lewis base with the organosilane before the prochiral carbon centred radical is treated with the organosilane. The Lewis base is preferably used in an amount of about 1 to about 3 molar equivalents per mole of organosilane compound used.

Lewis bases for use with the method are compounds which are able to donate an electron pair, i.e. co-ordinate with an electron acceptor, in this case the silicon atom bearing the transferable hydrogen. Those skilled in the art will appreciate that there are a large array of Lewis bases that could be used in accordance with the method of the present invention. Examples of suitable Lewis bases include, but are not limited to, tetraalkylammonium fluoride, such as tetrabutylammonium fluoride, and trialkyl or triaryl phosphine, such as triphenyl phosphine.

As used herein, the term "activated" chiral non-racemic organosilane hydride (silane) is intended to denote a silane which has a hydrogen transfer rate constant that is sufficiently fast to enable the silane to function as a free radical reducing agent. In this context, the term "activating group" is used herein to denote a group or atom which is directly attached to the silicon atom bearing the transferable hydrogen which promotes the transfer rate constant of the transferable hydrogen such that the silane can function as a free radical reducing agent.

Exemplary activated chiral non-racemic organosilicon hydrides for use in accordance with the method of the invention have the general formula LιL₂L₃SiH, wherein Li, L₂ and L₃ are substituents, preferably organic, that are different (ie. Li ≠ (L₂ or L₃) and L₂ ≠ L₃). Alternatively, L|-L₃ can be substituents, preferably organic, which are the same or different wherein at least one of L|-L₃ has a chiral centre. Accordingly, chiral non-racemic organosilicon hydrides suitable for use in the method of the invention may derive their chirality from a chiral silicon atom bearing the transferable hydrogen, and/or from at least one chiral organic substituent attached to the silicon atom bearing the transferable hydrogen. In addition, at least two of L1-L₃ should contain an activating group (eg. silicon-, phosphorus-, sulfur-containing substituent) in which an activating element (ie. the silicon, sulfur, phosphorus or other atom known to those skilled in the art) is attached directly to the silicon atom bearing the transferable hydrogen. Preferably, each L₁-L₃ contains an activating group in which the activating element is attached directly to the silicon atom bearing the transferable hydrogen.

Where one of L₁-L₃ does not contain an activating group, suitable L₁-L₃ substituents include, but are not limited to, chiral and achiral optionally substituted aryl (eg. phenyl, and naphthyl), and chiral and achiral optionally substituted alkyl (eg. methyl, butyl), where "alkyl" and "aryl" are as previously defined. Suitable chiral groups also include, but are not limited to, those derived from a- and β-pinene (through hydrosilation chemistry), fused polycyclics such as 3α-cholestane and those derived from cholic acid, eg. 3α-24- norcholanyl and 7α-24-norcholanyl (Schiesser et al, Aust. J. Chem., 2001).

Where Lι-L₃ do contain an activating group, any one of L₁-L₃ can conveniently be represented as Ri-X-, where Ri is preferably an organic group and X is an activating group or element which is directly attached to the silicon atom bearing the transferable hydrogen. Suitable organic groups Ri include, but are not limited to, chiral and achiral optionally substituted aryl (e.g. phenyl, and naphthyl), chiral and achiral optionally substituted silyl (e.g. trialkylsilyl, and triarylsilyl) and chiral and achiral optionally substituted alkyl (e.g. methyl, and butyl), where "alkyl" and "aryl" are as previously defined. Suitable chiral organic groups Ri also include, but are not limited to, those derived from - and β-pinene (through hydrosilation chemistry), fused polycyclics such as 3ocholestane and those derived from cholic acid, eg. 3α-24-norcholanyl and 7c--24-norcholanyl (Schiesser et al, Aust. J. Chem., 2001) as well as 1,1 'thiobinaphthol and binap. Suitable activating groups or elements, X, include, but are not limited to, -Si(R₄R₅)-, -S- and -P(R₆)-, where R -R₆ are as defined for R| . Other activating groups or elements, X, known to those skilled in the art can also be used.

Prefen ed organic substituents L₁-L₃ which contain an activating group, that is preferred Ri-X- groups include, but are not limited to, trialkylsilyl, alkylthiyl and dialkylphosphonyl.

As used herein the term "chiral silicon atom" or "chiral atom" denotes an atom which has different substituents attached to it, and which can form part of a molecule to render the molecule non-superimposable on its mirror image.

As used herein the term "non-chiral silicon atom" denotes a silicon atom that has at least two substituents attached to it which are the same. Accordingly, a non-chiral silicon atom may form part of a molecule that can be superimposed on its mirror image.

As used herein the term "chiral substituents" or "chiral organic substituent" denotes an organic molecule that is not superimposable on its mirror image.

Examples of activated chiral non-racemic organosilanes include but are not limited to, those derived from 1,1 'thiobinaphthol (a) and those derived from binap (and their enantiomers) (b), in which the groups R' and R" are independently selected from optionally substituted alkyl, and optionally substituted aryl as defined previously, and Y is independently selected from optionally substituted alkyl and trialkylsilyl.

(a) (b)

Further examples include (R)- and (S)-(tπmethylsilylphenyltriphenylsilyl) silanes (c) and (d) (and related compounds), 3α-bis(trimethylsilyl)silyl-5α-24-norcl.olane (e) (and the 3β analogue), tris[(lS,2S,5S)-myrtanyldimethyl] silane (f) and its enantiomer tris[(lR,2R,5R)- myrtanyldimethyl] silane (f), tris[(l S,2R,5S)-myrtanyldimethyl] silane (h) and its enantiomer tris[(lR,2S,5R)-myrtanyldimethyl] silane (h'), as well as the two enantiomeric tris(triorgano)silylsilanes of general structure (g) in which each R^a, R^b and R^c [within each (SiR^a ₃), (SiR^b ₃) and (SiR^C ₃)] is chiral or achiral, and independently selected from optionally substituted alkyl and optionally substituted aryl, as previously defined. In other words, each of the three R^a groups attached to its silicon atom may be the same or different, and each (SiR^a ₃) group can be the same or different to each other (SiR^a ₃) group. The same applies to R^b and R^c, provided the result is a chiral non-racemic organosilane.

(c) (d)

(e) (f)

(f ) (g)

(h) (h')

Other activated chiral non-racemic organosilanes may be evident to those skilled in the art.

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 A1C1₃, Me₃Al, MeAl(OPh)₂, MAD (methyl aluminum bis(2-6-di-tert-butyl-4-mthyl phenoxide)), BF₃, BBr₃, BCI₃, Ln(OTf)₃, Yb(OTf)₃, TiCl₄, FeCh, ZnC^, zinc silicate, calcium silicate, aluminium silicate, 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)-(+)-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, more preferably at least about 0.5 molar equivalents, still 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.

Preferred Lewis acids are those which are alkaline earth metal compounds.

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.

The use of MgBr₂ as a Lewis acid in accordance with the present invention has a particular advantage in that it is cheap and readily available.

Accordingly, 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, ZnCl₂-(Et₂O)2 and MgBr₂ (Et₂O)₂, respectively.

The activated silane is preferably used in an amount of about 0.5-1.5 molar equivalents, more preferably about 1.1 molar equivalents per mole of reductive sites on the substrate, ie central prochiral carbon atoms, 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 reductive sites on the substrate, ie central prochiral carbon atoms. 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 on the substrate, ie central prochiral carbon atoms. 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 molecule of prochiral carbon centred radicals to be reduced.

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

The methods of the invention may be particularly useful in preparing optically enhanced amino acids. Thus, a- or -carbon centred radicals derived from a- or /^-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, a- and β-cycloalkyl substituted amino acids, and - and β-aryl substituted amino acids As would be appreciated by a person skilled in the art the method of the present invention can also be used to introduce isotopes of hydrogen, such as deuterium and tritium in an enantioselective manner.

The activated chiral silanes contemplated by the present invention 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 present invention provides for a novel class of activated chiral non-racemic organosilicon hydrides of general formula (I):

L,L₂L₃SiH (I)

where Li, L₂ and L₃ are organic substituents which may be the same or different, and where at least two of Li, L₂ and L₃ contain and activating group which is directly attached to the silicon atom.

Preferably, each Li, L₂ and L₃ of general formula (I) contains an activating group which is directly attached to the silicon atom.

Preferably, the activating group which is directly attached to the silicon atom includes another silicon atom, a phosphorous atom or a sulfur atom. Other activating groups known to those skilled in the art may also be used.

Preferably, the activated chiral non-racemic organosilicon hydrides of general formula (I) have a non-chiral silicon atom bearing the transferable hydrogen and therefore derive their chirality from at least one chiral organic substituent. There is no particular limitation as to how the organic substituent(s) derives its chirality, although it is preferred that the chirality is derived from a chiral atom, such as a chiral carbon atom, which forms part of the molecular structure of the substituent. Where one of Li, L₂ and L₃ does not contain an activating group, suitable L1-L₃ substituents include, but are not limited to, chiral and achiral optionally substituted aryl (eg. phenyl, and naphthyl) and chiral and achiral optionally substituted alkyl (eg. methyl, and butyl), as defined previously.

Where L1-L₃ do contain an activating group, any one of L₁-L₃ can conveniently be represented as R_.-X-, where R₁ is an organic group and X is an activating group which is directly attached to the silicon atom bearing the transferable hydrogen. Suitable organic groups Ri include, but are not limited to, chiral and achiral optionally substituted aryl (e.g. phenyl, and naphthyl), chiral and achiral optionally substituted silyl (e.g. trialkylsilyl, and triarylsilyl) and chiral and achiral optionally substituted alkyl (e.g. methyl, and butyl), as previously defined. Suitable activating groups X, include, but are not limited to, Si(R₄R₅), -S- and -P(R₆)-, where -R -R₆ are as defined for R_\ . Other activating groups or elements, X, known to those skilled in the art can also be used.

Generally, each Li, L₂ and L₃ forms a single covalent bond with the silicon atom of general formula (I). However, Li, L₂ and L₃ may form part of a bidentate or tridentate ligand in which case general formula (I) may be represented as Lι-₂L₃SiH or Lι- - SiH, respectively.

Where one of Li, L₂, and L₃ (or Ri) of general formula (I) is a chiral organic substituent (group), the chiral substituent (group) is preferably selected from the group of naturally occurring chiral organic compounds, or the so called chiral pool. Those skilled in the art will appreciate the diverse array natural chiral organic compounds that exist, and those which could be selected for use in accordance with the present invention. By "naturally occurring chiral organic compounds" is meant those chiral compounds which have been identified as occurring in nature. Reference to naturally occurring chiral organic compounds is however not intended to limit such compounds to those which are obtained from a natural source. For example, the natural chiral compounds may be prepared by a synthetic process.

Suitable classes of chiral organic compounds from which Li, L₂ and L₃ (or Ri) may be selected, include, but are not limited to, terpenes and their derivatives (eg. menthol, fenchenol, pinene etc.), steroids and their derivatives (eg. cholestanol, cholane, cortisone etc.), carbohydrates and their derivatives, including mono, di, tri and polysaccharides, as well as cyclodextrins, amino acids, peptides, proteins and their derivatives, as well as alkaloids and their derivatives as well as numerous biological metabolites and their derivatives. Some of these compounds may form part of the chiral pool.

Exemplary chiral organic compounds include, but are not limited to, myrtanyl, menthyl, 3α-cholestanyl, 3α-24-norcholanyl, 7α-24-norcholanyl, tetra-O-acetylglucosyl, tetra-O- benzylgalactosyl, gamma-cyclodextrinyl, phenylglycinyl, leucinyl and moφhinyl. Some of these compounds may also form part of the chiral pool.

A preferred chiral organic compound is myrtanyl, and preferred organosilicon hydride reagents of general formula (I) are tris[(lS,2S,5S)-myrtanyl dimethyl] si lane (f) and its enantiomer tris[(lR,2R,5R)-myrtanyl dimethyl] silane (f '), and tris[(lS,2R,5S)-myrtanyl dimethyljsilane (h) and its enantiomer tris[(lR,2S,5R)-myrtanyl dimethyl]silane (h').

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

EXAMPLES Example 1

Reduction of compounds 1, (2a)-(2b). 3. 4 and 5.

1. R = Et, X = Br 2a. R=tert-Bu,

R'=Benzyl, X = Br 2b. R=Ph,

R'=Me, X=Br

3. X=Br

4. X=Br 5. X=Br Compounds 1. (2a), (2b), and (3-5) (X=Br) were prepared as follows:

Preparation of compounds 1 and (5) (X-Br)

Compounds 1 and (5) (X=Br) were are 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 (2a, X=Br)

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 (MgSO ) 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 (2a, X=Br) in quantitative yield and of sufficient purity for further use.

Preparation of compound (2b, X = Br).

The N-trifluoroacetyl amino acid methyl esters (2b, X = H) (100 mg), prepared as described above, were dissolved in carbon tetrachloride (5ml) and N-bromosuccinimide (NBS) (1 equiv) was added. 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 (2b, X = Br) in quantitative yield and of sufficient purity for further use.

Preparation of compound (3. X=Br)

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° 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 H₂SO (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 (3, X=Br) in sufficient purity for further use (0.265g).

Preparation of racemic 2-bromonaproxen ethyl ester (4, X = Br)

A solution of commercially available racemic naproxen (0.92g, 4.0 mmol) in thionyl chloride (5mL) was refluxed until the evolution of the HCl gas had ceased (ca. 4 h). The excess thionyl chloride was removed in vacuo and a 1 :1 mixture of ethanol (3mL):dichloromethane (3mL) was added with refluxing for further 2h. The solution was cooled and the solvent removed in vacuo to give naproxen ethyl ester as a colourless oil (1.03g, 80%) after purification via flash chromatography (96:4)) (hexane: ethyl acetate).

N-bromosuccinimide (NBS) (0.33g, 1.85mmol) was added to a solution of the previously- prepared racemic naproxen ethyl ester (0.470g, 1.85mmol) in carbon tetrachloride (5.0mL) and the reaction mixture irradiated (under reflux) by a 250W tungsten lamp for 15 minutes. After cooling in ice, 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. General reduction procedure

Reductions were carried out in toluene at a variety of temperatures. The reaction solution typically comprised the substrate at a concentration of approximately 0.1M, about 1.1 molar equivalents, relative to the substrate, of the required silane, and if present, a Lewis acid of choice in either about 1.0 or 2.0 molar equivalents, relative to the substrate, depending on the Lewis acid chosen (see Table 1). In some reduction reactions a Lewis base, such as Bu NF, was used. Where the Lewis base was used, the silane was typically precomplexed with about 1 to 3 molar equivalents of the Lewis base. Reactions were initiated with Et₃B/O₂. Reactions were carried out until TLC analysis indicated no change in the reaction (ca. 6h), sometimes the reactions required reinitiatation through the addition of further E.₃B. The reaction mixtures were examined by chiral-phase gas chromatography (CG) or high performance liquid chromatography (HPLC) and the percentage conversion and enantiomeric ratios determined by integration of the signals corresponding to the mixture of reduced compounds 1-5 (X = H) against an internal standard (either octane or undecane). Reduced compounds 1-5 (X = H) were identified by comparison of their GC and/or HPLC retention times with those of the 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 the (S)-products 1 (X=H), prepared and resolved following a literature procedure (Campbell, A., et al, J. Chem. Soc, 1946, 25; Aaron, C, et al, J.Org. Chem.), the (S)-product (5, X=H) was prepared and resolved following a literature procedure (Perchyonok, V.T., Schiesser, C.H., Phosphorous Sulfur Silicon Relat. Elem., 1999, 150151 , 193), and the (S)-products (2a), (2b), and 3 (X=H), prepared by the following procedures:

Preparation of ^'(S)-N-triβuoroacetyl-tert-leucine benzyl ester (2a, X = H)

A mixture of (S)-ter/-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 (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.

Preparation of (2b. X = H).

Commercially available racemic phenyl glycine (lg) was stirred overnight at room temperature in dry methanol (3ml) containing trimethylsilyl chloride (Me₃SiCl) (3-5 equivalents). The solvent was removed in vacuo to obtain the corresponding amino acid methyl ester hydrochloride as a white solid with no need for further purification.

Triethyl amine (1.1 eq) was added to a stirred solution of the amino acid methyl ester hydrochloride and methyl trifluoroacetate (1.5 equivalents) in dry methanol (10 ml). The reaction was heated under reflux for 12 hours, after which the solvent was removed and resulting residue redissolved in ether (20ml). The solution was washed with sat. ammonium chloride, dried (MgSO ) and the ether removed in vacuo to obtain the corresponding required N-trifluoroacetyl amino acid methyl ester of sufficient purity for further use.

Preparation of (S)-Ibuprofen methyl ester (3. 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 (3, X = H) as colourless oil ( 1.61g, 71%) and of sufficient purity for further use. Table 1 lists enantioselectivity data for substrates 1 - 5 used in this study reacting with tris[(lS, 2S, 5S)-mertynyldimethyl]silane (f).

TABLE 1

Enantioselectivities observed for reactions involving tris[(lS, 2S, 5S)- mertynyldimethyl]silane (f) at various temperatures in toluene. MgBr₂-(Et₂O)₂ was used in about 2 molar equivalents and all other Lewis acids were used in about 1 molar equivalents, relative to the substrate. When present, the Lewis base (Bu₄NF) was used in about 3 molar equivalents, relative to the silane.

*MAD = methyl aluminium bis(2,6-di-tert-butyl-4-methyl phenoxide) Typical procedure for small-scale low-temperature silane reductions.

Reduction of benzyl N-trifluoroacetyl-2-bromo-tert-leucinate.

Magnesium bromide etherate (MgBr₂.Et₂O) (0.075g, 0.291mmol) was added to dry toluene (0.2mL) and the mixture allowed to stir for 20 min under N₂ after which reaction mixture was cooled to -30°C. The bromoester (0.05g, 0.146 mmol) in dry toluene (0.1 mL) was added slowly to a reaction mixture. After stirring at -30° for a further 45 min, a precomplexed solution of tris[(lS, 2S, 5S)-myrtanyl dimethyl] silane (f) (0.25g, 0.171 mmol) and tetrabutyl ammonium fluoride (0.126g, 0.482mmol ) in toluene (0.25 L) were added slowly, followed by triethylborane (O.lmL of 1M solution in THF) and oxygen was introduced. The reaction mixture was stirred at this temperature for 4 hours. A further aliquot of triethylborane (O.lmL of 1M solution in THF) was added after 2 hours. The mixture was quenched with water (1 mL) and extracted with ether (2x). The organic layer was dried (MgSO₄) and excess solvent removed in vacuo to afford the crude product as light yellow oil. Crude product was analysed directly by GC (99%ee (S), 62%) and shown to be identical with an authentic sample.

Procedure for the preparation of trisf(lS,2S,5S)-myrtanyl dimethyllsilane (f)

Preparation of(-)-(lS.2S.5S)-myrtanyl dimethyl silicon chloride

(-)-(lS2S5S)-MyrMe₂SiCl was prepared by a H₂PtCl₆ catalyzed hydrosilylation of commercially available (-)-(lS,5S)-/?-pinene with HSiMe₂Cl according to a literature procedure (Wang, D.; Chan, T. H. Tetrahedron Lett. 1983, 24, 1573).

Preparation of tris I (IS, 2S,5S)-myrtanyl dimethyl/ silane (f)

A suspension of lithium powder (6.81 g, 0.981 mol) in THF (70 L) and (-)-(] S,2S,5S)- yrMe₂SiCl (69.3 g, 0.300 mol) was cooled at 0°C and a solution of HSiCl₃ (13.6 g, 0.100 mol) in THF (30 mL) was slowly added within 2 h. The reaction mixture stirred for 4 h at r. t. and was heated under reflux for 10 h. The resulting black suspension was filtered to remove insoluble by-products and the excess of lithium powder. The solvent was removed under reduced pressure and the residue passed down a silica gel column (silica gel 60; 63 - 200 μm; Merck) using hexane as eluent. Volatile by-products were removed at 250°C / 0.005 mmHg. The remainder was subjected to reverse phase silica gel column chromatography (silica gel 60 RP; 40 - 63 μm; Merck) using THF / MeOH (15:85) as eluent. Yield 8.21 g (13.3 %), [α]: + 5.18). ²⁹Si NMR (C₆D₆) δ: -8.6, -1 17.1. ^,3C NMR (C₆D₆) δ: 49.6, 40.8, 39.6, 32.3, 26.9, 26.8, 25.8, 24.9, 23.2, 20.1, 1.7, 1.4. Η NMR (C₆D₆) δ: 2.64 (IH), 2.31 (3H), 2.09 (3H), 1.87 (3H), 1.77 (15H), 1.45 (3H), 1.23 (9H), 0.86 (12H), 0.83 (3H), 0.36 (18H). Anal. Calcd. for C₃₆H₇₀Si₄ (615.30): C 70.29, H 11.47; Found: C 70.31, H 11.32 %.

Procedure for the preparation of tris[(lR,2R,5R)-myrtanyl dimethyl] silane (f)

A mixture of (+)-(lR,5R)- ?-pinene and (+)-(lR,5R)-o:-pinene (5:1) was prepared by a borane-assisted isomerization from commercially available (+)-(lR,5R)-c.-pinene (optical purity 91 % ee) according to a literature procedure (Brown, H. C, Joshi, N. N. J. Org. Chem. 1988, 53, 4059).

Preparation of (+)-(! R, 2R,5R)-myrtanyl dimethyl silicon chloride.

(+)-(lR,2R,5R)-MyrMe₂SiCl: A suspension of H₂PtCl₆ (50 mg) in HSiMe₂Cl (19.9 g, 0.210 mol) was cooled at 0°C and a 5:1 mixture of (+)-(lR,5R)- ?-pinene and (+)-(lR,5R)- α-pinene (27.2 g, 0.200 mol; weight based on (+)-(lR,5R)- ?-pinene) was slowly added within 1 h. The reaction mixture was stirred at r. t. for 2 h and was heated to 35°C for 10 h. The excess of HSiMe₂Cl was removed by condensation in vacuum. The product was purified by fractional distillation at 90°C / 0.005 mmHg. Yield 40.6 g (88 %). [α]: 4.49. ²⁹Si NMR (C₆D₆) δ: 30.8. ¹³C NMR (C₆D₆) δ: 49.0, 40.6, 39.5, 30.7, 27.1 , 26.9, 25.0, 24.7, 23.0, 19.9, 2.8. Η NMR (C₆D₆) δ: 2.21 (IH), 2.00 (IH), 1.81 (IH), 1.66 (2H), 1.62 (I H), 1.61 (I H), 1.31 ( I H), 1.18 (IH), 1.17 (3H), 0.78 (3H), 0.74 (IH), 0.67 (I H), 0.25 (6H). Anal. Calcd. for C,₂H₂₃ClSi (230.85): C 62.43, H 10.04; Found: C 62.31, H 9.95 %. Preparation of tris f(lR,2R,5R)-myrtanyl dimethyl/ silane (f)

A suspension of lithium powder (2.61 g, 0.376 mol) in THF (40 mL) and (+)-(lR,2R,5R)- MyrMe₂SiCl (26.34 g, 0.114 mol) was cooled at 0°C and a solution of HSiCl₃ (5.15 g, 0.0380 mol) in THF (20 mL) was slowly added within 2 h. The reaction mixture stirred for 4 h at r. t. and was heated under reflux for 10 h. The resulting black suspension was filtered to remove insoluble by-products and the excess of lithium powder. The solvent was removed under reduced pressure and the residue passed down a silica gel column (silica gel 60; 63 - 200 μm; Merck) using hexane as eluent. Volatile by-products were removed at 250°C / 0.005 mmHg. The remainder was subjected to reverse phase silica gel column chromatography (silica gel 60 RP; 40 - 63 μm; Merck) using THF / MeOH (15:85) as eluent. Yield 0.950 g (4.1 %), [α]: -3.35. ²⁹Si NMR (C₆D₆) δ: -8.6, -117.1. ¹³C NMR (C₆D₆) δ: 49.6, 40.8, 39.6, 32.3, 26.9, 26.8, 25.8, 24.9, 23.2, 20.1, 1.7, 1.4. Η NMR (C₆D₆) δ: 2.64 (IH), 2.31 (3H), 2.09 (3H), 1.87 (3H), 1.77 (15H), 1.45 (3H), 1.23 (9H), 0.86 (12H), 0.83 (3H), 0.36 (18H).

Procedure for the preparation of tris[(lS,2R,5S)-myrtanyl dimethyllsilane (h)

Preparation of ^' (-)-(l S.2R,5S)-myrtanyl chloride.

(-)-(lS2R,5S)-myrtanyl chloride was prepared by hydroboration / oxidation of (-)- (lS,5S)- ?-pinene and subsequent chlorination of the resulting (-)-(lS,2R,5S)-c/-s-myrtanol with CC1₄ / PPI1₃ according to a literature procedure (Marinetti, A.; Buzin, F.-X.; Ricard, L. J. Org. Chem. 1997, 62, 297.

Preparation oftrisf(lS,2R,5S)-myrtanyl dimethyl] silane (h)

To a suspension of activated magnesium turnings (1 .4 g, 0.800 mol) in ether (100 mL), a solution of (-)-(lS,2R,5S)-myrtanyl chloride (103.6 g, 0.600 mol) in ether (700 mL) was slowly added within 45 min. The reaction mixture was heated under reflux for 2 h to give the corresponding Grignard reagent. Then, a solution of HSiMe₂Cl (42.6 g 0.450 mol) in ether (50mL) was slowly added within 15 min. The reaction mixture was heated under for 10 h, before it was hydrolyzed with water (200 mL). The aqueous layer was extracted hexane (2 x 200 mL). The combined organic extracts were dried over Na₂SO₄ and the solvents were removed in vacuum. The product was purified by distillation at 50°C / 0.005 mmHg. Yield 81.5 g (92.2 %). [α]: -28.1. ²⁹Si NMR (C₆D₆) δ: -14.8. ¹³C NMR (C₆D₆) δ: 49.2, 41.4, 38.8, 37.9, 34.0, 28.3, 26.8, 25.3, 24.4, 23.2, -3.9, -4.0. 1H NMR (C₆D₆) δ: 4.16 (IH) 2.32 (IH), 2.18 (IH), 1.95 (2H), 1.91 (IH), 1.86 (2H), 1.46 (IH), 1.20 (3H), 1.04 (3H), 0.86 (IH), 0.78 (2H), 0.05 (3H), 0.04 (3H). Anal. Calcd. for C,₂H₂₄Si (196.41): C 73.38, H 12.32; Found: C 73.47, H 12.42 %.

Procedure for the preparation of tris[(lR,2S,5R)-myrtanyl dimethyll silane (h')

(-)-(lR.2S.5R)-MyrMe₂SiCl: Neat (-)-(l 2S,5R)-MyrtMe₂SiH (74.6 g, 0.380 mol) was cooled to 0 °C and SO₂Cl₂ (52.6 g, 0.390 mol) was slowly added within 1 h. After a short induction period (approx. 5 min) a vigorous reaction occurred and HCl and SO evolved. When the evolution of gas ceased, the reaction mixture was stirred for 10 min at r. t. and for 20 min at 35°C. The excess of SO₂Cl was removed by condensation in vacuum and the product was purified by distillation at 85°C / 0.005 mmHg. Yield 81.5 g (92.9 %). [α]: - 22.0. ²⁹Si NMR (C₆D₆) δ: 31.0 ¹³C NMR (C₆D₆) δ: 49.1, 41.2, 38.8, 36.7, 33.8, 29.1, 28.3, 26.7, 25.1, 23.4, 2.8. 1H NMR (C₆D₆) δ: 2.29 (2H), 2.08 (IH), 2.02 (IH), 1.83 (IH), 1.81 (2H), 1.49 (IH), 1.18 (3H), 1.04 (3H), 0.90 (2H), 0.47 (IH), 0.41 (6H). Anal. Calcd. for C,₂H₂₃ClSi (230.85): C 62.43, H 10.04; Found: C 62.51 , H 10.14 %.

Preparation of trisf(lR,2S,5R)-myrtanyl dimethyll silane (h')

A suspension of lithium powder (6.50 g, 0.941 mol) in THF (100 mL) and (-)-(l 2S- 5R)- MyrtMe₂SiCl (72.0 g, 0.31 mol) was cooled at 0°C and a solution of HSiCl₃ (14.0 g, 0.103 mol) in THF (30 mL) was slowly added within 2 h. The reaction mixture stirred for 4 h at r. t. and was heated under reflux for 10 h. The resulting black suspension was filtered to remove insoluble by-products and the excess of lithium powder. The solvent was removed under reduced pressure and the residue passed down a silica gel column (silica gel 60; 63 - 200 μm; Merck) using hexane as eluent. Volatile by-products were removed at 250°C / 0.005 mmHg. The remainder was subjected to reverse phase silica gel column chromatography (silica gel 60 RP; 40 - 63 μm; Merck) using THF / MeOH (15:85) as eluent. Yield 0.800 g (1.3 %). [α]: -32.6. ²⁹Si NMR (C₆D₆) δ: -8.8, -118.1. ¹³C NMR (C₆D₆) δ: 49.8, 41.4, 38.8, 38.4, 33.9, 28.7, 28.3, 26.8, 25.8, 23.4, 1.4, 1.1. Η NMR (C₆D₆) δ: 2.62 (IH), 2.35 (3H), 2.34 (3H), 2.07 (3H), 1.96 (3H), 1.90 (6H), 1.83 (3H), 1.49 (3H), 1.24 (9H), 1.11 (9H), 1.07 (6H), 0.94 (3H), 0.36 (18H). Anal. Calcd. for C₃₆H₇₀Si₄ (615.30): C 70.29, H 11.47; Found: C 70.18, H 11.59 %.

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.

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

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

What is claimed

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, comprising treating said radical with an activated chiral non-racemic organosilicon hydride in the presence of a Lewis acid.

2. A method of Claim 1, 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.

3. A method of Claim 1 or Claim 2, wherein the prochiral carbon centred radical is a prochiral amino acid carbon centred radical wherein the central prochiral carbon atom is an - carbon atom of an α- amino acid or a β- carbon atom of an β-amino acid.

4. A method of any one of Claims 1 to 3, wherein the prochiral carbon centred radical is generated from a radical precursor selected from the group consisting of: aryl selenides, aryl sulphides, aryl tellurides, xanthates, thionoformates, Barton esters and tertiary chiral halosubstrates.

5. A method of any one of Claims 1 to 4, wherein the electron donor group is a carbonyl group.

6. A method of any one of Claims 1 to 5, wherein the activated chiral non-racemic organosilicon hydride is of general formula (I):

L,L₂L₃SiH (I)

where Li, L₂ and L₃ are substituents which may be the same or different, and where at least two of Li, L₂ and L₃ each contain an activating group which is attached directly to the silicon atom.

7. A method according to Claim 6, wherein Li, L₂ and L₃ each contain an activating group which is directly attached to the silicon atom.

8. A method according to Claim 6 or 7, wherein the activating group directly attached to the silicon atom includes an atom selected from a silicon atom, a phosphorous atom and a sulfur atom.

9. A method of any one of Claims 1 to 8, wherein the organosilicon hydride is selected from the group consisting of:

(a) (b)

(c) (d)

(f ) (g)

(h) (IV)

where R' and R" are independently selected from optionally substituted alkyl and optionally substituted aryl, Y is independently selected from optionally substituted alkyl and trialkylsilyl, and where each R^a, R^b and R^c is independently selected from optionally substituted aryl and optionally substituted alkyl.

10. A method of any one of Claims 1 to 9, wherein the Lewis acid is selected from the group consisting of: A1C1₃, Me₃Al, MeAl(OPh) , MAD (methyl aluminum bis(26-di-tert- butyl-4-methyl phenoxide)), BF₃, BBr₃, BC1₃, Ln(OTf)₃, Yb(OTf)₃, TiCl₄, FeCl₃, ZnCl₂, zinc silicate, calcium silicate, aluminium silicate, zirconocene dichloride, an alkaline earth metal compound, trialkylborates and (S,S)- and (R,R)-(+)-N,N'-bis (3,5-di-tert- butylsalycidene)-l,2-diaminocyclohexamanganese (III) chloride.

1 1. A method of Claim 10, wherein the alkaline earth metal compound is a Lewis acidic magnesium compound.

12. A method of Claim 11, wherein the Lewis acidic magnesium compound is selected from the group consisting of MgBr₂, Mgl₂, Mg(OAc)₂, Mg(OTf)₂.

13. A method of Claim 12, wherein the Lewis acidic magnesium compound is MgBr₂.

14. A method of any one of Claims 1 to 13, wherein the Lewis acid is provided in the form of a Lewis adduct.

15. A method of Claim 14, wherein the Lewis adduct is selected from the group consisting of BF₃ Et₂O, ZnCl₂-(Et₂O)₂ and MgBr₂ (Et₂O)₂.

16. A method of Claim 15, wherein the Lewis adduct is MgBr₂-(Et₂O)₂.

17. A method of any one of Claims 1 to 16, wherein the Lewis acid has a solubility, under the reaction conditions employed, of at least about 0.1 molar equivalents per mole of prochiral carbon centred radicals to be reduced.

18. A method of Claim 1 1, wherein the Lewis acidic magnesium compound has a solubility, under the reaction conditions employed, of about 2 molar equivalents per mole of prochiral carbon centred radicals to be reduced.

19. A method of any one of Claims 1 to 18, wherein the Lewis acid is used in an amount of about 0.9 to about 2 molar equivalents per mole of prochiral carbon centred radicals to be reduced.

20. A method of Claim 19, wherein the Lewis acid is used in an amount of about 0.9 to about 1.1 molar equivalents per mole of prochiral carbon centred radicals to be reduced.

21. A method of Claim 10, wherein the alkaline earth metal compound is used in an amount of about 2 molar equivalents per mole of prochiral carbon centred radicals to be reduced.

22. A method of Claim 11, wherein the Lewis acidic magnesium compound is used in an amount of about 2 molar equivalents per mole of prochiral carbon centred radicals to be reduced.

23. A method of any one of Claims 1 to 22, wherein the organosilicon hydride is used in an amount of about 0.5 to about 1.5 molar equivalents per mole of prochiral carbon centred radicals to be reduced.

24. A method according to any one of Claims 1 to 23, wherein the radical is treated with the organosilicon hydride in the presence of a Lewis base.

25. A method according to Claim 24, wherein the Lewis base is selected from tetrabutylammonium fluoride and triphenylphosphine.

26. A method according to Claim 24 or 25, wherein the Lewis base is used in an amount of about 1 to about 3 molar equivalents per mole of organosilicon hydride.

27. A method of any one of Claims 1 to 26, wherein the organosilicon hydride is immobilized onto a solid support.

28. An activated chiral non-racemic organosilicon hydride of formula (I):

L,L₂L₃SiH (I)

where Li, L₂ and L₃ are organic substituents which may be the same or different, and where at least two of Li, L₂ and L₃ contain an activating group which is directly attached to the silicon atom.

29. An organosilicon hydride of Claim 28, wherein each Li, L₂ and L₃ contains an activating group which is directly attached to the silicon atom.

30. An organosilicon hydride of Claim 28 or 29 where at least two of Li, L₂ and L₃ are selected from organic substituents of the formula Ri-X-, where R_\ is an organic group selected from chiral and achiral optionally substituted aryl, chiral and achiral optionally substituted silyl, and chiral and achiral optionally substituted alkyl, and where each X is an activating group that includes an atom selected from a silicon atom, a phosphorous atom and a sulfur atom.

31. An organosilicon hydride of claim 30 wherein the activating groups are independently selected from -S(RjR₅)-, -S- and -P(R₆)- where each R» and R₅ is independently an organic group.

32. An organosilicon hydride of any one of Claims 28 to 30 which is complexed with a Lewis base.

33. An organosilicon hydride of any one of Claims 28 to 31 wherein at least one of L], L and L₃ contains at least one chiral carbon atom.