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WO2004011473A1 - Composes d'organogermanium et procedes d'utilisation de ces composes - Google Patents

Composes d'organogermanium et procedes d'utilisation de ces composes Download PDF

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WO2004011473A1
WO2004011473A1 PCT/AU2003/000902 AU0300902W WO2004011473A1 WO 2004011473 A1 WO2004011473 A1 WO 2004011473A1 AU 0300902 W AU0300902 W AU 0300902W WO 2004011473 A1 WO2004011473 A1 WO 2004011473A1
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chiral
organogermanium
compound
racemic
hydride
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Dainis Dakternieks
Carl Schiesser
Tamara Perchyonok
Andrew Michael Duthie
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Chirogen Pty Ltd
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Chirogen Pty Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/30—Germanium compounds

Definitions

  • the present invention relates generally to reductive methods useful in chemical synthesis.
  • the invention relates to enantioselective reductive methods using chiral organogermanium hydrides, to a novel class of chiral organogermanium hydrides, and to a method of preparing chiral organogermanium compounds.
  • 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 withm 1 to 4 atoms of the central prochiral carbon atom, comprising treating said radical with a chiral non-racemic organogermanium hydride in the presence of a Lewis acid.
  • 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.
  • the present invention provides a chiral non-racemic organogermanium hydride of general formula (I):
  • Li, L and L 3 are organic substituents which may be the same or different, and where at least one of Li, L 2 and L 3 is chiral, with the proviso that formula (I) is not 4-tert- butyl-3,5-dithia-4-germacyclohepa[2,l- ⁇ ; 3,4- ⁇ ']dinaphthalene or 4-tert-butyl-2,6- bis(tiimethylsilyl)-3,5-dithia-4-germacyclohepa[2,l-a; 3,4- ⁇ ']dinaphthalene.
  • the first aspect of the invention relates to the use of any suitable chiral non-racemic organogermanium hydride reagents, even those which may have been described in the prior art.
  • the invention is directed towards a method of preparing optically enhanced ⁇ or ⁇ - amino acids by treatment of a prochiral amino acid carbon centred radical with a chiral non-racemic organogermanium hydride in the presence of a Lewis acid, wherein the central prochiral carbon atom is an ⁇ - carbon atom of an ⁇ - amino acid or a ⁇ - carbon atom of an ⁇ -amino acid.
  • chiral non-racemic organogermanium hydride reagents can be used in conjunction with a Lewis acid to enantioselectively prepare chiral compounds.
  • the germanium reagents demonstrate reduced hydrogen transfer rate constants compared with their stannane counterparts, the effect of which provides for superior kinetic control over the reduction chemistry.
  • the superior kinetic control can enable the range of suitable prochiral substrates to be extended beyond that available to stannane analogues.
  • the germanium reagents are able to sustain chirality at the germanium atom and therefore demonstrate the potential to provide enhanced chiral recognition.
  • the structural integrity germanium reagents should be sufficiently stable so as not to racemise during the reduction reaction. DETAILED DESCRIPTION OF THE INVENTION
  • prochiral carbon centred radical is a radical of formula R ⁇ R 2 R 3 C ⁇ 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[R R 3 CH.
  • 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 inco ⁇ orated herein by reference).
  • Particularly suitable radical precursors for generating the prochiral carbon centred radicals for use in the invention are tertiary chiral halosubstrates, ie R ⁇ R R 3 C- halogen, where R 1 -R 3 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 ⁇ , ⁇ , ⁇ , or ⁇ 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 organogermanium hydride.
  • 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.
  • the carbonyl group is adjacent to, ie ⁇ - to the chiral carbon to be reduced.
  • 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.
  • prochiral carbon centred radicals include those of the formula R ⁇ R 2 R 3 ⁇ , wherein R 1 -R 3 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 R 1 -R 3 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 and bi
  • R 3 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.
  • At least one of R1-R 3 is an optionally substituted aryl or heteroaryl group. In another preferred embodiment at least one of R 1 -R 3 is an optionally substituted alkyl, alkenyl, or alkynyl group. In another embodiment, at least one of R 1 -R 3 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.
  • 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 -C0 2 R 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.
  • 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 CO 2 NRR' 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.
  • 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.
  • 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(0)-O-C(O)-(CH 2 ) 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- (CH 2 ) 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')-(CH 2 ) n - wherein n is > 2, eg., 2, 3, 4, 5 or 6.
  • alkyl denotes straight chain, branched or cyclic hydrocarbon residues, preferably C ⁇ -20 alkyl, eg C ⁇ -10 or C ⁇ -6.
  • 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, hepty
  • cyclic alkyl examples 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.
  • alkenyl 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 C 1-2 o alkenyl (eg C MO or C ⁇ _ 6 ).
  • alkenyl examples 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, l-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-cyclohexadie ⁇ yl, 1,4-cyclohexadienyl, 1,3-cycloheptadienyl, 1,3,5-
  • 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.
  • alkynyl denotes groups formed from straight chain, branched or cyclic hydrocarbon residues containing at least one carbon-carbon triple bond including ethynicallv 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 C 1- Q 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.
  • 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.
  • alkoxy alkenoxy
  • alkynoxy alkynoxy
  • aryloxy alkyloxy
  • heterocyclyloxy respectively denote alkyl, alkenyl, alkynyl, aril and heterocylclyl groups as hereinbefore defined when linked by oxygen.
  • halogen denotes chlorine, bromine or iodine.
  • aryl denotes single, polynuclear, conjugated and fused residues of aromatic hydrocarbon ring systems.
  • 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.
  • 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, benz
  • a heterocyclic group may be optionally substituted by an optional substituent as described herein.
  • Preferred acyl includes C(O)-R, wherein R is hydrogen or an alkyl, alkenyl, alkynyl, aryl or heterocyclyl, residue, preferably a C ⁇ - o residue.
  • acyl examples include formyl; straight chain or branched alkanoyl such as, acetyl, propanoyi, 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, tolu
  • phenylacetyl phenylpropanoyl, phenylbutanoyl, phenylisobutylyl, phenylpentanoyl and phenylhexanoyl
  • naphthylalkanoyl e.g. naphthylacetyl, naphthylpropanoyl and naphthylbutanoyl]
  • aralkenoyl such as phenylalkenoyl (e.g.
  • phenylpropenoyl e.g., phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl and phenylhexenoyl and naphthylalkenoyl (e.g.
  • 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
  • acyloxy refers to acyl, as herein before defined, when linked by oxygen.
  • 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
  • Preferred optional substitutents include alkyl, (eg C 1-6 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 Ci- 6 alkoxy such as methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy), halo, trifluoromethyl, trichloromethyl, tribromomethyl.
  • alkyl eg C 1-6 alkyl such as methyl, ethyl, propyl, butyl, cyclopropyl, cyclo
  • 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 C ⁇ -6 alkyl, such as dimethylamino, diethylamino, dipropylamino), acylamino (eg NHC(O)CH 3 ), 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 C ⁇ -6 alkyl, such as acetyloxy), benzoy
  • heteroatom refers to any atom other than a carbon atom which may be a ring-member of a cyclic organic compound.
  • 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 stannane and initiator for free radical reductions are known in the art (see for example V.T. Perchyonok et al, Tetrahedron. Lett, 1998, 39, 5437 and references cited therein).
  • Preferred solvents include hydrocarbon solvents, eg toluene.
  • the reduction is preferably carried out at temperature less than 0°C, preferably less than about -30°C, more preferably at about -78°C.
  • the reagents used and the reaction conditions employed are substantially anhydrous.
  • Exemplary chiral non-racemic organogermanium hydrides for use in accordance with the method of the invention have the formula L ⁇ L 2 L 3 GeH, wherein Li, L 2 and L 3 are different (ie. L[ ⁇ (L 2 or L 3) and L 2 ⁇ L 3 ).
  • L 1 -L 3 may be the same or different wherein at least on of L1-L 3 has a chiral centre.
  • chiral non-racemic organogermanium hydrides suitable for use in the method of the invention can derive their chirality from a chiral germanium atom, or from at least one chiral ligand attached to a non-chiral L J -
  • Suitable achiral ligands include, but are not limited to, optionally substituted aryl (eg. optionally substituted phenyl, and naphthyl) and optionally substituted achiral alkyl (eg. methyl, and butyl) as defined previously.
  • Suitable chiral ligands include, but are not limited to, menthyl and fused polycyclics such as 3 ⁇ -cholestane and those derived from cholic acid, eg. 3 ⁇ -24-norcholanyl and 7 ⁇ -24-norcholanyl (Schiesser et al, Aust. J. Chem., 2001).
  • chiral germanium 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.
  • non-chiral germanium atom denotes a germanium atom that has at least two substituents attached to it which are the same. Accordingly, a non-chiral germanium atom may form part of a molecule that can be superimposed on its mirror image.
  • chiral ligand or “chiral organic substituent” denotes an organic molecule that is not superimposable on its mirror image.
  • Examples of chiral non-racemic organogermanium hydrides that may be used in accordance with the method of the invention include, but are not limited to, (R)- and (S)- methyl(2-naphthyl)phenylgermanium hydride (a) and (b) (and related compounds), which can be prepared by the method of Carre (J Organomet.
  • suitable chiral non-racemic organogermanium hydrides include (f) and (g), which can be prepared by reaction of the appropriate aryl lithium with bis [ ⁇ 1R,2S, 5R)- menthyljphenylgermanium chloride followed by LiAlH reduction, where bis[(iR,2S JR)- menthyl]phenylgermanium chloride is prepared in a similar manner to (1R, 2S, 5R)- menthyldiphenylgermanium bromide as described below.
  • Other suitable aryl germanium hydrides can be made in an analogous manner.
  • Further examples of a suitable organogermanium hydride include (f) and (g), where one of the menthyl groups is replaced by an aryl or alkyl substituent as defined previously (both diastereoisomers).
  • chiral non-racemic germanium hydrides include (h) and related compounds which can be prepared from 1,1'thiobinaphthol as described by Gualtieri (PhD Thesis, The University of Pittsburgh, 2000), in which the ligand (R) is alkyl, or optionally substituted aryl as defined previously, and X is alkyl or trialkylsilyl.
  • 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.
  • Lewis acids examples include A1C1 , Me 3 Al, MeAl(OPh) 2 , MAD (methyl aluminum bis(2-6-di-tert-butyl-4-mthyl phenoxide)), BF 3 , BBr 3 , BCI 3 , Ln(OTf) 3 , Yb(OTf) 3 , TiCl , FeC , ZnCl 2 , zinc silicate, calcium silicate, aluminium silicate, zirconocene dichloride (herein after referred to as (i)), trialkylborates (RO 3 B, 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 j referred to as, (ii) and (iii
  • 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.
  • the alkaline earth metal compound is a Lewis acidic magnesium compound.
  • suitable Lewis acidic magnesium compounds include MgBr 2 , Mgl 2 , Mg(OAc) 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.
  • MgBr 2 as a Lewis acid in accordance with the present invention has a particular advantage in that it is cheap and readily available.
  • 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 MgBr 2 .
  • 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.
  • a Lewis adduct can be used as a convenient source for providing a Lewis acid to a reaction.
  • Lewis acids used in accordance with the present invention may also be provided in the form of a Lewis adduct.
  • Lewis acids such as BF 3 , ZnCl 2 , and MgBr 2 may be provided and used in the form of their diethylether adducts BF 3 ⁇ t 2 O, ZnCl 2 -(Et O) 2 and MgBr 2 -(Et 2 O) 2 , respectively.
  • the germane 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • ⁇ - or ⁇ -carbon centred radicals derived from ⁇ - 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 ⁇ -and ⁇ - straight and branched chain alkyl substituted amino acids, ⁇ - and ⁇ -cycloalkyl substituted amino acids, and ⁇ - and ⁇ -aryl substituted amino acids
  • the chiral germanes 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.
  • a solid support eg a polymeric support, such as pins, beads or wells
  • the present invention provides for a novel class of chiral non-racemic organogermanium organo germanium hydride of general formula (I) : L ⁇ L 2 L 3 GeH (I)
  • Li, L 2 and L 3 are organic substituents which may be the same or different, and where at least one of L l3 L 2 and L 3 is chiral, with the proviso that formula (I) is not 4-tert- butyl-3,5-dithia-4-germacyclohepa[2,l- ⁇ ; 3,4- ']dinaphthalene or 4-tert-butyl-2,6- bis(trimethylsilyl)-3 ,5 -dithia-4-germacyclohepa[2, 1 -a; 3 ,4- ⁇ '] dinaphthalene.
  • the organic substituents L[, L 2 and L 3 of general formula (I) are not derived from l,l'-binaptho-2,2'-dithiol or 3,3'-bis(trimethylsilyl)-l,r-binaptho-2,2'-dithiol.
  • the chiral non-racemic organogermanium hydrides of general formula (I) have a non-chiral germanium atom and therefore derive their chirality from at least one chiral organic substituent.
  • 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.
  • Lj, L 2 and L 3 are not chiral, they may be selected from any achiral organic substituents.
  • Suitable achiral ligands include, but are not limited to, optionally substituted aryl (eg. optionally substituted phenyl, and naphthyl) and optionally substituent achiral alkyl (eg. methyl, and butyl) as defined previously.
  • Li, L 2 and L 3 each form a single covalent bond with the germanium atom of general formula (I).
  • L ls L 2 and L 3 may form part of a bidentate or tridentate ligand in which case general formula (I) may be represented as L ⁇ -2 L 3 GeH or L 1- -3 GeH, respectively.
  • At least one of Li, L 2 and L 3 of general formula (I) is an organic substituent selected from the group of naturally occurring chiral organic compounds, or the so called chiral pool.
  • naturally occurring chiral organic compounds are 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 at least one of Li, L and L3 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.
  • 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
  • Exemplary chiral organic compounds include, but are not limited to, menthyl, 3 ⁇ - cholestanyl, 3 ⁇ -24-norcholanyl, 7 ⁇ -24-norcholanyl, tetra-O-acetylglucosyl, tetra-O- benzylgalactosyl, gamma-cyclodextrinyl, phenylglycinyl, leucinyl and morphinyl. Some of these compounds may also form part of the chiral pool.
  • a preferred chiral organic compound is menthyl
  • preferred organogermanium hydride reagents of general formula (I) are (lR,2S,5R)-menthyl diphenylgermanium hydride (c) and its enantiomer (lS,2R,5S)-menthyl diphenylgermanium hydride (c').
  • analogous tin compounds are prepared by reacting a chiral organometallic reagent with a triorganotin halide compound.
  • the resulting chiral tetraorganotin compound is then converted into the tin hydride reagent by means well known in the art.
  • the use of a triorganotin halide in such a procedure is particularly preferred given the well known difficulties associated with using higher halide substituted tin compounds. In particular, a controlled reaction of organometallic reagents with a tin tetrahalide is difficult.
  • a method of preparing a chiral non-racemic organogermanium compound comprising reacting a chiral non-racemic organometallic reagent with a germanium tetrahalide.
  • the reaction of the organometallic reagent with the germanium tetrahalide is performed under an inert atmosphere such as nitrogen or argon.
  • the reaction is generally conducted in an inert solvent, typically an ether solvent such as tetrahydrofuran or diethylether.
  • an inert solvent typically an ether solvent such as tetrahydrofuran or diethylether.
  • the reaction is performed at temperatures of about 0°C or less, more preferably of about -20°C or less.
  • the germanium tetrahalide can be substituted with a single chiral organic group in a controlled manner without any signification formation of higher organo-substituted germanium byproducts.
  • the steric bulk of the organometallic reagent used in the reaction plays a role in facilitating the unique selective and controlled substitution of the germanium tetrahalide.
  • chiral organometallic reagent is reacted with about 1 mole of the germanium tetrahalide to afford a chiral non-racemic mono-organogerrnanium trihalide compound as the major germanium reaction product.
  • major germanium reaction product means that the product is present in the reaction mixture as the most abundant germanium reaction product.
  • the mono-organogermanium trihalide, di-organogermanium dihalide and triorganogermanium halide compounds prepared in accordance with the method are formed in at leajrt a 40% yield, more preferably in at least a 50% yield, and most preferably in at least a 65% yield.
  • the organometallic reagents used in accordance with the method are nucleophilic in nature and can readily react with halide substituted compounds such as a germanium tetrahalide.
  • halide substituted compounds such as a germanium tetrahalide.
  • the reagents can include, but are not limited to, lithium, sodium, potassium and magnesium (Grignard) organometallic reagents.
  • the organometallic reagent is a Grignard reagent.
  • the organometallic reagents may be prepared by means well known in the art. Typically, the reagents will be derived from a suitable organohalide compound.
  • the organo group of the organometallic reagent is selected from menthyl, 3 ⁇ - cholestanyl, 3 ⁇ -24-norcholanyl, 7 ⁇ -24-norcholanyl, tetra-O-acetylglucosyl, tetra-O- benzylgalactosyl, gamma-cyclodextrinyl, phenylglycinyl, leucinyl and morphinyl groups.
  • the organometallic reagent is also preferably a Grignard reagent.
  • the method of this aspect of the invention utilises a germaniumtetrahalide compound.
  • the halide component of the compound may be either I, Br, CI or F.
  • Preferably the halide component of the compound is CI.
  • the method of this aspect of the invention provides a chiral non-racemic organogermanium compound. Accordingly, the compound must contain at least one chiral substituent. It will therefore be appreciated that the method can also be used to attach non- chiral substituents to the germanium compound. In this case, a non-chiral organometallic reagent is used in place of the chiral organometallic reagent.
  • the compound can be conveniently converted to a chiral non-racemic organogermanium hydride reagent by methods known in the art.
  • the method of this aspect of the invention may be used to .prepare a triorganogermanium halide compound, wherein at least one of the three i organo groups is a chiral organo group.
  • This triorganogermanium halide may then be reacted with a reducing agent such as lithium aluminium hydride (LiAlH ) to afford a chiral non-racemic organogermanium hydride reagent.
  • a reducing agent such as lithium aluminium hydride (LiAlH )
  • the method may be used to prepare a tetraorganogermanium compound, wherein at least one of the organo groups is a chiral organo group.
  • the tetraorganogermanium compound can then be halogenated to afford a triorganogermanium halide compound which can be converted to a chiral non-racemic organogermanium hydride reagent in a manner described above.
  • at least one of the organo groups is preferably a phenyl group. Phenyl groups that are attached to a germanium atom can generally be readily replaced by a halide atom such as Br or CI.
  • Figure 1 (a) shows a representation of the crystal structure of (-)-menGePh3.
  • Figure 1 (b) shows a representation of the crystal structure of (+)-menGePh 3 .
  • carbon tetrachloride (5ml) 1 equiv
  • N-bromosuccinimide (NBS) 1 equiv
  • the mixture was irradiated (under reflux) by a 250W tungsten lamp for 45 minutes.
  • N-bromosuccinimide (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.
  • Reductions were carried out in toluene at -78°C.
  • the reaction solution comprised the substrate at a concentration of approximately 0.1M, about 1.1 molar equivalents, relative to the substrate, of the required germane and the 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).
  • Reactions were initiated with Et3B/O .
  • Reactions were carried out until TLC analysis indicated no change in the reaction (ca.
  • Table 1 lists enantioselectivity data for substrates 1 - 5 used in this study reacting with (1R, 2S, 5R)-menthyldiphenylgermanium hydride (c), and its enantiomer (c') at -78° in toluene and in the presence of about 1 - 2 molar equivalents of a Lewis acid, relative to the substrate.

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Abstract

Cette invention se rapporte à un procédé servant à réduire par voie énantiosélective un radical centré sur un carbone prochiral ayant un ou plusieurs groupes donneurs d'électrons liés directement à l'atome de carbone prochiral central du radical, et/ou liés à un atome de carbone contenu dans un à quatre atomes de l'atome de carbone prochiral central, ce procédé consistant à traiter ce radical avec un hydrure d'organogermanium non racémique chiral en présence d'un acide de Lewis. Cette invention concerne également une nouvelle classe d'hydrures d'organogermanium non racémiques chiraux et un procédé pour préparer des composés d'organogermanium non racémiques chiraux.
PCT/AU2003/000902 2002-07-26 2003-07-11 Composes d'organogermanium et procedes d'utilisation de ces composes Ceased WO2004011473A1 (fr)

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US7045451B2 (en) 2003-04-05 2006-05-16 Rohm And Haas Electronic Materials Llc Preparation of group IVA and group VIA compounds
US7141488B2 (en) 2003-04-05 2006-11-28 Rohm And Haas Electronic Materials Llc Method of depositing germanium-containing films
US7413776B2 (en) 2003-04-05 2008-08-19 Rohm And Haas Electronic Materials Llc Method of depositing a metal-containing film
EP2098530A1 (fr) * 2008-03-05 2009-09-09 Hanwha Chemical Corporation Procédé de préparation de complexes hydrure de métal de transition organique et leur utilisation comme matériaux de stockage d'hydrogène
CN116574127A (zh) * 2023-04-13 2023-08-11 广东先导微电子科技有限公司 一种二乙基二卤化锗的合成方法

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7045451B2 (en) 2003-04-05 2006-05-16 Rohm And Haas Electronic Materials Llc Preparation of group IVA and group VIA compounds
US7141488B2 (en) 2003-04-05 2006-11-28 Rohm And Haas Electronic Materials Llc Method of depositing germanium-containing films
US7413776B2 (en) 2003-04-05 2008-08-19 Rohm And Haas Electronic Materials Llc Method of depositing a metal-containing film
US7767840B2 (en) 2003-04-05 2010-08-03 Rohm And Haas Electronic Materials Llc Organometallic compounds
EP2098530A1 (fr) * 2008-03-05 2009-09-09 Hanwha Chemical Corporation Procédé de préparation de complexes hydrure de métal de transition organique et leur utilisation comme matériaux de stockage d'hydrogène
JP2009215291A (ja) * 2008-03-05 2009-09-24 Hanwha Chem Corp 水素貯蔵物質としての有機−遷移金属ハイドライドの改善された製造方法
KR100960355B1 (ko) 2008-03-05 2010-05-28 한화케미칼 주식회사 수소 저장 물질로서 유기-전이 금속 하이드라이드의 개선된제조 방법
CN116574127A (zh) * 2023-04-13 2023-08-11 广东先导微电子科技有限公司 一种二乙基二卤化锗的合成方法

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