FIELD OF THE INVENTION The present invention relates to novel chiral hydride complexes useful as reducing agents for chemical entities bearing carbonyl groups or their equivalents, compositions comprising the chiral hydride complexes, and methods for their synthesis and use.

0 BACKGROUND OF THE INVENTION

In recent years there has been intensive investigations to further the cause of asymmetric reduction specifically as it relates to the development of new pharmaceutical intermediates and bulk drugs. This effort has been spurred by the benefits of single isomer or enantiopure compounds used as pharmaceutical drug agents. Factors such - as availability and the overall economics and safety related to the use of new reagents has promoted the idea that an ideal chiral reducing agent could be fabricated from cost effective precursors with the chiral moiety being derived from readily available members of the chiral pool.

Among the techniques for introducing chirality that are available to the industrial chemist, the one that has proven especially useful is asymmetric reduction. Reduction of unsymmetrical ketones to alcohols is among the most useful. This reaction is achieved by the overall addition of hydride ("H-") to one face of the carbonyl group leading preferentially to the formation of one enantiomer.

It is known in the art that several lithium-based chiral reagents have been synthesized via selective substitution of 1-3 hydrogen atoms of lithium aluminum hydride ("LAH") by protic chiral ligands. Early attempts (A. . Bothner-By, J. Am. Chem. Soc. 73, 846 (1951)) focused on the reaction of LAH with camphor to produce a reagent consisting of LAH complexed with one equivalent of (+) - isoborneol. This reagent was used to reduce prochiral ketones like methyl ethyl ketone or methyl-t-butyl ketone to

produce optically active carbinols. These results were later challenged (P.S. Portoghese, J. Org. Che . 27, 3359 (1962)) by suggesting that the alcohols obtained by Bothner-By were actually achiral and contaminated with small amounts of (+)- borneol. The failure to induce chirality in simple ketones upon reduction with a reagent utilizing LAH and chiral auxiliaries (-)menthol and (+) borneol was later reported (O. Cervinka, Collect. Czech. Chem. Commun. 30, 1684 (1965) ; O. Cervinka, Collect. Czech. Chem. Commun. 30, 2403 (1965)) . Cervinka was able to demonstrate in later papers that the reduction of pyrrolinium salts and ketamines using LAH modified with chiral terpenoids, such as (+) -borneol, (+)- camphor, (-) -menthol and (+) -homopherehyl alcohol, resulted in the corresponding amines having low optical purity, indicating that only partial enantioselectivity had been achieved.

In 1967, onohydroxy sugar derivatives as well as chiral phenylmethyl- and t-butylcarbinols were used as LAH modifiers in the reductions of simple prochiral ketones with only modest success (O.Cervinka et al., Tetrahedron Lett., 1179 (1967)) . While (+) -camphor-modified LAH induced chirality in reduction of methyl ethyl ketone, the resulting enantio eric excess was only 2% (Y. Minoura et al., J. Polym. Sci. Part A-l 6, 2013 (1968)) . Other investigators have reported that successful asymmetric reduction of alpha and beta-dialkyla ino ketones could be obtained using LAH modified with three equivalents of (-) -menthol in up to 95% enantiomeric excess (R. Andrisano et al., Tetrahedron, 913 (1973); A.S. Angeloni et al., Gazz. Chim. Ital. 107, 421 (1977)) . Some of these results have been unable to be reproduced (S. Yamaguchi et al., Bull. Chem. Soc. Jpn. 50, 3033 (1977).

The use of glucose derivatives as LAH modifiers in the reduction of various substrates has also been reported, although with generally low optical yields (S.R. Landor et al., J. Chem. Soc. Chem. Commun., 585 (1966); S.R. Landor et al., J. Chem. Soc. Chem. Commun., 1822 (1966) ; S.R. Landor

et al., J. Chem. Soc. C, 2339 (1971); S.R. Landor et al., J. Chem. Soc. Perkin Trans. 1, 1902 (1974) . S.R. Landor et al., J. Chem. Soc. Perkin Trans. 1, p. 605 (1974) . Mannitol derivatives which had a C2 axis of symmetry have been used as LAH modifiers, but the values of enantiomeric excess obtained in the resulting products were less than 15% (N. Baggett et al., J. Chem. Soc. Perkin Trans. I, 1123 (1977) .

The most efficient chiral auxiliary reported to modify LAH was binaphthol ("BINOL") . Use of BINOL and an achiral auxiliary like ethanol as a ligand for LAH has been reported to result in a reagent that reduces several ketones with high enantiomeric excess (e.e.) (>99%) (R. Noyori et al., J. Am. Chem. Soc. 101, 3129 (1979) ; R. Noyori et al., J. Am. Chem. Soc. 101, 5843 (1979)) . However, commercial interest in binaphthol as a stoichiometric reducing agent has been limited due to its extremely high initial cost, complicated synthesis and difficult recovery from a reduction reaction.

Another report has stated that 1,2-amino alcohols and several dia ines have been able to impart some asymmetry to hydride reducing agents (M. Asa i, and T. I^ukaiyama, Heterocycles 12, 499 (1979)) .

To the knowledge of the inventors, prior studies have not demonstrated the utility of inexpensive, readily available chiral auxiliaries in boron or aluminum hydride reducing agents, with or without the use of achiral auxiliaries, to impart significant enantioselectivities when reacted with prochiral ketones.

Thus, there is a need for new chiral hydride reducing agents which can be readily derived from inexpensive sources or easily synthesized, and which are capable of enantioselectively delivering a source of hydride to carbonyl or carbonyl-equivalent bearing chemical entities to afford reduction products in good yield and with high enantioselectivity.

SUMMARY OF THE INVENTION

The present invention provides novel chiral boron or aluminum hydride complexes having the structures of the general formulas: MBH ₄ . _n . _a (R ^' ) _n (R') _a ;

MBH ₂ . _b (R ^" ) (R') _b ;

MBH(R ^* ") ;

MBH(R') (R* ') ;

MAlH _4.n . _a (R ^* ) _n (R')„; MAlH ₂ . _b (R ^" ) (R') _b ;

MA1H(R ^*** ) ; and AIH(R') (R' *) , wherein

M is Na ⁺ , Li ⁺ or K ⁺ ; each R ^* is independently a monodentate chiral ligand derived from optionally protected carbohydrates, amino acids, amino alcohols, alkaloids, chiral aromatic or alkyl alcohols, chiral aromatic or alkyl amines or combinations thereof;

R" is a bidentate chiral ligand derived from optionally protected carbohydrates, amino acids, amino alcohols, alkaloids, chiral aromatic or alkyl -alcohols, chiral aromatic or alkyl amines, chiral diamines, chiral diols, chiral biaryl alcohols, chiral biaryl amines, D- or L- tartaric acid or combinations thereof; R ^*** is a tridentate chiral ligand derived from optionally protected carbohydrates, amino acids, amino alcohols, alkaloids, chiral aromatic or alkyl alcohols, chiral aromatic or alkyl amines or combinations thereof;

R' is a monodentate achiral ligand selected from the group consisting of alkylalcohols, arylalcohols, arylalkyl alcohols, alkyla ines, arylamines, arylalkyl amines, alkylthiols, arylthiols, arylalkyl thiols and, in the case of MBH ₄ . _n.a (R ^* ) _n (R' ) _a , and MBH ₂ . _b (R ^** ) (R' ) _b , R ¹ may also be cyanide; R' ' is a bidentate achiral ligand selected from the group consisting of alkyldiols, aryldiols, arylalkyl diols,

alkyldiamines, aryldiamines, arylalkyl dia ines, alkyldithiols, arylthiols, arylalkyl thiols, mercaptoalcohols, ercaptoamines, and aminoalcohols; n is 1-3; a is 0-2; and b is 0-1, with the proviso that n + a < 3, and with the further proviso that when R" is S-BINOL, M is not Li ⁺ . These complexes are useful as enantioselective hydride reducing agents for carbonyl groups and carbonyl equivalents.

The invention also encompasses certain novel chiral ligands which are used for synthesizing these complexes.

In these methods, the novel chiral hydride complexes are synthesized by admixing in the presence of an organic solvent 1 equivalent of MA1H ₄ or MBH ₄ with 1 to 3 equivalents of R ^* , and optionally with 1-2 equivalents of R' , such that the total equivalents of R ^* and R ¹ relative to MA1H ₄ or MBH ₄ does not exceed three; with 1 equivalent of R ^* and optionally with 1 equivalent of R' ¹ ; with 1 equivalent of R ^** , and optionally with 1 equivalent of R'; or with 1 equivalent R .

The invention further provides methods for synthesizing the novel chiral complexes comprising admixing in the presence of an organic solvent 1 equivalent of MBH ₃ (CN) with 1-2 equivalents of R ^* and optionally with 1 equivalent of R' , such that the total equivalents of R ^* and R' relative to MBH _j (CN) does not exceed two; or with 1 equivalent of R".

The invention still further provides compositions useful for enantioselectively reducing a chemical entity having a carbonyl group or a carbonyl equivalent, the compositions being obtained by the previous methods. Such compositions optionally contain other agents useful for imparting enantioselectivity to carbonyl group and carbonyl equivalent-containing substrates. Still further, the invention provides methods for obtaining an enantiomeric excess of a reduction product

comprising enantioselectively reducing a carbonyl group or carbonyl equivalent of a chemical entity by admixing the chemical entity with the chiral hydride complex of the present invention, or with a composition that includes such complexes.

Further still, the invention provides chiral hydride reducing agents comprising a solid phase support.

The present invention may be understood more fully by reference to the following detailed description and illustrative examples which are intended to exemplify non- limiting embodiments of the invention.

DETAILED DESCRIPTION OF THE INVENTION SYNTHESIS OF THE CHIRAL HYDRIDE COMPLEXES The chiral boron or aluminum hydride complexes of the present invention are represented by the general formulas:

MBH ₄ . _n . _a (R ^* ) _n (R') _a ; MBH ₂ .„(R ^** ) (R'h; MBH(R ^*** ) ;

MBH(R ^* ) (R' ') ;

MAlH ₄ . _n . _a (R ^* ) _n (R')a; MAlH ₂ . _b (R") (R') _b ; MA1H(R ^* ") ; and MA1H(R ^* ) (R' ') , wherein:

M is Na ⁺ , Li ⁺ or κ ⁺ ; each R ^* is independently a monodentate chiral ligand derived from optionally protected carbohydrates, amino acids, amino alcohols, alkaloids, chiral aromatic or alkyl alcohols, chiral aromatic or alkyl amines or combinations thereof;

R" is a bidentate chiral ligand derived from optionally protected carbohydrates, amino acids, amino alcohols, alkaloids, chiral aromatic or alkyl alcohols, chiral aromatic or alkyl amines, chiral diamines, chiral

diols, chiral biaryl alcohols, chiral biaryl amines, D- or L- tartaric acid or combinations thereof;

R ^* " ^* is a tridentate chiral ligand derived from optionally protected carbohydrates, amino acids, amino alcohols, alkaloids, chiral aromatic or alkyl alcohols, chiral aromatic or alkyl amines or combinations thereof;

R' is a monodentate achiral ligand selected from the group consisting of alkylalcohols, arylalcohols, arylalkyl alcohols, alkylamines, arylamines, arylalkyl amines, alkylthiols, arylthiols, arylalkyl thiols and, in the case of MBH ₄ . _D . _a (R ^* ) _n (R')_ and MBH ₂ . _b (R") (R' ) _b , cyanide;

R' ' is a bidentate achiral ligand selected from the group consisting of alkyldiols, aryldiols, arylalkyl diols, alkyldiamines, aryldiamines, arylalkyl diamines, alkyldithiols, arylthiols, arylalkyl thiols, mercaptoalcohols, mercaptoamines, and aminoalcohols; n is 1-3; a is 0-2 ; and b is 0-1, with the proviso that n + a < 3, and with the further proviso that when R" is S-BINOL, M is not Li ⁺ .

These complexes are generally obtained by admixing 1 equivalent of MBH ₄ , MBH ₃ (CN) or MA1H with R ^* , R ^** or R""; optionally with 1-2 equivalents of an achiral ligand (R ¹ ); or optionally 1 equivalent of R' ' . The chiral boron or aluminum hydride complexes of the present invention can be obtained from 1 equivalent of MBH ₄ or MA1H ₄ and 1 to 3 equivalents of a monodentate chiral ligand (R ^* ) or a mixture of different R ^* s, 1 equivalent of monodentate chiral ligand (R ^* ) and 1 equivalent of bidentate achiral ligand (R' ¹ ) , 1 eq. of a bidentate chiral ligand (R") or 1 eq. of a tridentate chiral ligand (R ^*** ) . The chiral boron hydride complexes of the present invention can also be obtained from 1 equivalent of MBHj(CN) and 2 equivalents of R ^* or 1 equivalent of R ^* '. By "monodentate," "bidentate," and "tridentate" is meant a

ligand having 1, 2 or 3 active hydrogen moieties, respectively.

It will be understood that when the chiral hydride complexes are obtained from MBH ₄ or MA1H ₄ , 1 equivalent of MBH or MA1H ₄ can be admixed in the presence of an organic solvent with 1-3 equivalents of R" and optionally with 1-2 equivalents of R', such that the total equivalents of R" and R' relative to MA1H ₄ or MBH ₄ does not exceed three; with 1 equivalent of R ^* and 1 equivalent of R' ¹ ; with 1 equivalent of R ^** , and optionally with 1 equivalent of R'; or with 1 equivalent of R"\

When the chiral hydride complexes are obtained from MBH ₃ (CN), 1 equivalent of MBH ₃ (CN) can be admixed in the presence of an organic solvent with 1-2 equivalents of R ^* and optionally with 1 equivalent of R', such that the total equivalents of R ^* and R* does not exceed 2; or with 1 equivalent of R".

The chiral hydride complexes can also comprise a chiral or an achiral solid phase support, as discussed below. Such a chiral or achiral solid phase support is admixed with a metal hydride selected from the group consisting of MBH ₄ , MBH ₃ (CN) and MA1H ₄ , in the presence of an organic solvent. Where the solid phase support is achiral, the solid phase support is admixed with a metal hydride selected from the group consisting of MBH ₄ , MBH ₃ (CN) and MA1H ₄ , in the presence of a chiral ligand (R ^* or R ^** ) and an organic solvent. It is to be understood that the solid phase support can have a plurality of moieties capable of forming a stable complex with MBH ₄ , MBH ₃ (CN) or MA1H ₄ , such as hydroxyl, amino or sulfide groups. Accordingly, 1 equivalent of MBH ₄ , MBH ₃ (CN) or MA1H ₄ can react with up to about 1 equivalent, preferably from about 0.01 to about 0.5 equivalents, and most preferably from about 0.05 to about 0.3 equivalents of solid phase support.

MBH ₄ and MA1H ₄ can be obtained commercially; e.g.,

NaBH ₄ , Na(CN)BH ₃ , LiBH ₄ , KBH and LiAlH ₄ are available from

Aldrich Chemical Co., Milwaukee, Wisconsin, and NaAlH ₄ is available from Albemarle Corporation, Baton Rouge, Louisiana. Alternatively, MBH ₄ and MA1H ₄ can be prepared by synthetic methods known to those skilled in the art. The invention also encompasses chiral boron or aluminum hydride complexes having oligomeric structures. The skilled artisan will recognize that such complexes may exist in oligomeric form.

Useful monodentate, bidentate, and tridentate chiral ligands are those that are derived from optionally protected carbohydrates, amino acids, amino alcohols, alkaloids, chiral aromatic or alkyl alcohols, chiral aromatic or alkyl amines, chiral diamines, chiral diols, chiral biaryl alcohols, chiral biaryl amines, D- or L-tartaric acid or combinations thereof, and are capable of forming chiral hydride complexes with MBH ₄ , MBH ₃ (CN) or MA1H such that the resulting chiral hydride complex is capable of enantioselectively reducing a carbonyl group or a carbonyl equivalent of a chemical entity. By "protected" is meant that the carbohydrates, amino acids, amino alcohols, alkaloids, chiral aromatic or alkyl alcohols, chiral aromatic or alkyl amines, chiral diamines, chiral diols, chiral biaryl alcohols, chiral biaryl amines, D- or L-tartaric acid or combinations thereof, comprise protecting groups including, but not limited to, ketals, trimethylsilyl ethers, tetrahydropyranyl ethers, triphenyl ethyl ethers, benzyl ethers, etc. Examples of such protecting groups, as well as methods for their use and removal, are found in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1981. Such chiral ligands have one or more chiral centers and are optically active. The chiral ligands have 1- 3 active hydrogen atoms per ligand that can react with one or more hydride groups of MBH ₄ , MBH ₃ (CN) or MA1H ₄ , so as to form a sodium, lithium or potassium boron or aluminum hydride:chiral ligand complex, with the release of H ₂ .

Useful chiral ligands include naturally occurring carbohydrates, amino acids, amino alcohols, alkaloids, chiral

aromatic or alkyl alcohols, chiral aromatic or alkyl amines, chiral diamines, chiral diols, chiral biaryl alcohols, chiral biaryl amines, D- or L-tartaric acid or combinations thereof; or synthetic analogs obtained using organic synthesis methods which are known to those skilled in the art.

Preferable chiral ligands include 1, 2 : 5, 6-Di-O- isopropylidene-D-mannitol ("DIPM") ; 3 , 5: 4 , 6-Di-O-ethylidene- D-glucitol ("DES") ; S-BINOL; (S) -l-tert-Butylamino-2 , 3- propanediol (" (S) -PROP") ; 1, 2: 5, 6-Di-O-cyclohexylidene-α-D- glucofuranose ("DCG") ; 3-O-Benzyl-l,2 : 5, 6-di-O- cyclohexylidene- -D-glucofuranose ("BDCG") ; 3-O-Benzyl-l, 2-0- cyclohexylidene-α-D-glucofuranose ("BCG") ; 2-0-Benzyl- 3,5:4,6-diethylidene-D-glucidol ("BDG"); 1, 3 : 4 , 6-Di-O- benzyliden-D-mannitol ("DBM") ; (S,S) -1, 3-Bis- (1- phenylethylamino)-2-propanol (" (S,S) -BPAP") ; 1-Anilino- 3, 5:4,6-di-0-ethylidene-D-glucitol ("Ligand 5b") ; (S)-N- isobutyl-α-phenylethylamine (" (S) -IBPA") ; (R) -N-isobutyl- - phenylethylamine (" (R) -IBPA") ; (S,S)-N,N- Bis(methylbenzyl) ethylenediamine (" (S,S) -BMBE") ; 1,2-0- isopropylidene-α-D-xylofuranose ("IXF") ; (R)-l-tert-

Butylamino-2 , 3-propanediol ("BAP") ; 1,2-O-Cyclohexylidene-α- D-xylofuranose ("CXF") ; (S) -Phenylalaninol ("(S)-PA ^M ) ; (S)- N,N-(Dimethyl)phenylalaninol (" (S) -DMPA") ; (3S, 4S) -1-Benzyl- 3 ,4-dihydroxypyrrolidine ("BDHP") ; 1-0-Triphenylmethyl- 3,5:4,6-di-0-ethylidene-D-glucitol ("TDG") ; 1, 3 : 4, 6-Di-O- (p- anisylidene) -D-mannitol ("DAM"); 1, 3 :4, 6-Di-O- (p- toluylidene) -D-mannitol ("DTM1") ; 2, 3-O-Cyclohexylidene- 1,1,4,4-tetraphenyl-L-threitol ("CYTOL") ; Di-O- cyclohexylidene-D-allofuranose ("DCAF") ; Di-O-isopropylidene- D-allofuranose ("DIPAF") ; 2, 3 : 4 , 6-Di-O-isopropylidene-L- sorbofuranose ("DIPS"); (+) -trans-α,α'- (2 , 2-Dimethyl-l, 3- dioxolane-4 , 5-diyl)bis(diphenyl ethanol) ("(+)-DDM") ; (-)- trans- ,α'-(2, 2-Dimethyl-l, 3-dioxolane-4 ,5- diyl) bis (diphenylmethanol) ( ^M (-)-DDM ^M ) ; (-) -8-methoxy-trans- p-menth-3-ol ("MTM") ; 1,2:3,5-Di-O-benzylidene-D- glucofuranose ( "DBGLU" ) ; L- ( - ) -2 , 4 : 3 , 5-Di-O-methylidene-D- xylitol ( "L-DMX" ) ; D- ( + ) -2 , 4 : 3 , 5-Di-O-methylidene-D-xylitol

("D-DMX") ; (S)-(-)-α,α-diphenyl-(1, 2,3,4- tetrahydroisoquinolin-3-yl) - ethanol ("DTM2") ; (lR,2S)-(-)- ephedrine ("Eph"); 1, 6-anhydro-β-D-glucose ("AG") ; (S)-α- phenethylamine ("(S)-PEA); (S)-(-)- , α-diphenyl-2- pyrrolidine ethanol ("DPP"); (IS, 2S, 3R, 5R) - (+) -pinanediol (" (+)-PDOL") ; (S)-2-(anilinomethyl)pyrrolidine ("AMP") ; and (4R, 5R) -2 , 2-di ethyl-α,c.,α ^, ,a'-tetra-(2-naphthyl) -dioxolane- 4 , 5-dimethanol ("0-DND") . The abbreviations of these ligands will be used to facilitate reading of this specification. Especially preferred are those R ^** chiral ligands having a C ₂ axis of symmetry. By "C ₂ axis of symmetry" is meant a molecule having a C ₂ axis as the sole element of symmetry, and therefore not possessing reflection symmetry (no sigma plane) . The R" chiral ligands can also be described as "axially disymmetric. "

Where the chiral boron or aluminum complexes of the present invention comprise R ^* but not R ^** or R ^* ", such complexes can comprise a mixture of up to three different R ^* ligands, as long as there is at least one hydride per equivalent of chiral complex available for imparting enantioselectivity to carbonyl group and carbonyl equivalent- containing substrates; or can comprise one R ^* ligand and one R' ' ligand. Where the chiral boron or aluminum complexes of the present invention comprise R", such complexes can additionally comprise R ^* , as long as there is at least one hydride per equivalent of chiral complex available for imparting enantioselectivity to carbonyl group and carbonyl equivalent-containing substrates.

In addition to comprising 1-3 chiral ligands, the chiral hydride complexes of the present invention can optionally further comprise 1-2 achiral ligand(s) (R ¹ ) , selected from the group consisting of alkylalcohols, arylalcohols, arylalkyl alcohols, alkylamines, arylamines, arylalkyl amines, alkylthiols, arylthiols, arylalkyl thiols and, in the case of chiral borohydride complexes, cyanide.

The R' achiral ligands have 1 active hydrogen atom per ligand

and can react with one or more hydride groups of MBH ₄ or MA1H ₄ , preferably with one or more hydride groups of a sodium, lithium or potassium boron or aluminum hydride:chiral ligand complex, so as to form a sodium, lithium or potassium boron or aluminum hydride:chiral ligand:achiral ligand complex with the release of H ₂ . It is important that if the present chiral hydride complexes comprise R' , there must be at least one hydride per equivalent of chiral complex available for imparting enantioselectivity to carbonyl group and carbonyl equivalent-containing substrates. In other words, if the present chiral hydride complexes comprise R', the total equivalents of R ^* or R", and R', relative to MBH ₄ or MA1H ₄ , cannot exceed three. In addition, if the present chiral hydride complexes comprise R', the total equivalents of R ^* and R ¹ , relative to MBH ₃ (CN), cannot exceed two.

Furthermore, the chiral hydride complexes of the present invention can comprise 1 bidentate achiral ligand R ¹ ', selected from the group consisting of alkyldiols, aryldiols, arylalkyl diols, alkyldiamines, aryldia ines, arylalkyl diamines, alkyldithiols, arylthiols, arylalkyl thiols, mercaptoalcohols, mercaptoamines, and -a inoalcohols selected from the group consist. Because R' ' comprises two active hydrogen moieties, it is preferable that when R' ^» is used as an achiral ligand, it is used in conjunction with R ^* . The R' and R ¹ ' achiral ligands can be used to optimize the yield of the product of reduction of the carbonyl group- or carbonyl equivalent-bearing chemical entity with the chiral hydride complexes of the present invention, or to optimize the enantiomeric excess of a desired enantiomeric product.

Alkylalcohol, alkylamine and alkylthiol ligands useful as R' include C,-C ₁₈ , preferably C,-C ₁₀ and most preferably C _[ -C ₆ alkylalcohols, alkylamines and alkylthiols. Preferable alkylalcohols include methanol, ethanol, 2- ethoxyethanol, n-propanol, iso-propanol, n-butanol, iso- butanol, sec-butanol, tert-butanol l-methylcyclobutanol and

the like. Preferable alkylamines include methylamine, ethylamine, dimethylamine, diethyla ine, diisopropylamine dicyclohexylamine and the like. Preferable alkylthiols include methanethiol, ethanethiol, propanethiol, butanethiol and the like.

Arylalcohols, arylamines and arylthiols useful as R' include phenyl- and naphthylalcohols, -amines and -thiols optionally substituted with one or more C,-C ₆ alkyl or alkoxy groups. Preferable arylalcohols include phenol, o-tert- butylphenol, p-tert-butylphenol, 1-naphthol and 2-naphthol. Preferable arylamines include aniline, p-methoxyaniline, diphenyla ine and the like. Preferable arylthiols include thiophenol, o-methoxythiophenol, p-methoxythiophenol and the like. Arylalkyl alcohols, arylalkyl amines and arylalkyl thiols useful as R' include phenyl- and naphthyl-substituted alkanols, including benzylalcohol, alkylamines including benzylamine, alkylthiols including benzylthiol.

Alkyldiol, alkyldia ine and alkyldithiol ligands useful as R' ' include C^C^, preferably C,-C _1(l and most preferably C,-C ₆ alkyldiols, alkyldiamines and alkyldithiols. Preferable alkyldiols include ethylene glycol, propylene glycol, 1,4-butanediol, 1, 5-pentanediol, 1, 6-hexanediol and the like. Preferable alkyldiamines include ethylene diamine, 1, 3-propanediamine, 1,4-butanediamine and the like. Preferable alkyldithiols include ethanedithiol, 1,3- propanedithiol, 1,4-butanedithiol, 2, 3-butanedithiol and the like.

Aryldiols, aryldia ines and aryldithiols useful as R" include phenyl- and naphthyldiols, -diamines and - dithiols optionally substituted with one or more C,-C ₆ alkyl or alkoxy groups. Preferable aryldiols include catechol, resorcinol, 3-methoxycatechol, 5-methoxyresorcinol, and the like. Preferable aryldiamines include 1, 2-phenylenediamine, l, 3-phenylenediamine, 4-methoxy-l, 2-phenylenediamine, and the like. Preferable aryldithiols include 1, 2-benzenedithiol, 1, 3-benzenedithiol, and the like.

Arylalkyl diols, arylalkyl diamines and arylalkyl dithiols useful as R' ' include phenyl- and naphthyl- substituted diols, including 2-hydroxybenzyl alcohol and 3- hydroxylbenzyl alcohol; aralkyl diamines including 2- aminobenzyla ine; and aralkyl dithiols including 2-thiobenzyl mercaptan.

Useful R ¹ ' ligands also comprise mercaptoalcohols, such as mercaptoethanol, 3-mercaptobutanol and the like; mercaptoamines, such as 2-aminoethanethiol and the like; and aminoalcoholε, such as aminoethanol , 3-aminobutanol, and the like.

The present chiral boron or aluminum hydride complexes are synthesized such that the MBH , MBH,(CN) or MA1H ₄ ; chiral ligand (R ^* , R" or R ^* ") and optionally the achiral ligands (R ¹ or R' ') are admixed in the presence of an organic solvent lacking active hydrogens or other groups capable of reacting with hydride groups. Suitable organic solvents include, but are not limited to alkyl hydrocarbons, such as pentane, hexane and heptane; cyclic or acylic ethers, such as THF and diethyl ether; optionally substituted aromatics, such as benzene, toluene, xylene and chlorobenzene; . polyethers such as diglyme and trigly e; other solvents that are inert to hydride reducing agents; and mixtures thereof. Preferably, the organic solvent is THF, diglyme or mixtures thereof. The solution of the organic solvent and the chiral hydride complex thus obtained can be used directly as a composition for enantioselectively reducing a chemical entity having a carbonyl group or a carbonyl equivalent, or can be concentrated, optionally in vacuo, to afford a chiral hydride complex free from solvent. In the latter case, the chiral hydride complex can be stored, preferably under an inert atmosphere, for future use.

In one embodiment of the invention, the chiral hydride complexes are prepared by admixing in the presence of organic solvent 1 equivalent of MBH ₄ or MA1H ₄ with 3 equivalents of R ^* .

In another embodiment of the invention, the chiral hydride complexes are prepared by admixing in the presence of organic solvent 1 equivalent of MBH ₄ or MA1H, with 2 equivalents of R ^* ; and 1 equivalent of R' . In another embodiment of the invention, the chiral hydride complexes are prepared by admixing in the presence of organic solvent 1 equivalent of MBH ₄ or MA1H ₄ with 1 equivalent of R ^* ; and 2 equivalents of R'.

In another embodiment of the invention, the chiral hydride complexes are prepared by admixing in the presence of organic solvent 1 equivalent of MBH ₄ or MA1H ₄ with 1 equivalent of R ^* ; and 1 equivalent of R ¹ ' .

In another embodiment of the invention, the chiral hydride complexes are prepared by admixing in the presence of organic solvent 1 equivalent of MBH ₄ or MA1H ₄ with 1 equivalent of R ^** ; and 1 equivalent of R'.

In another embodiment of the invention, the chiral hydride complexes are prepared by admixing in the presence of organic solvent 1 equivalent of MBH ₄ or MA1H ₄ with 1 equivalent of R ^*** .

In another embodiment of the invention, the chiral hydride complexes are prepared by admixing in the presence of organic solvent 1 equivalent of MBH or MA1H ₄ with 2 equivalents of R ^* . In another embodiment of the invention, the chiral hydride complexes are prepared by admixing in the presence of organic solvent 1 equivalent of MBH ₄ or MA1H ₄ with 1 equivalent of R".

In another embodiment of the invention, the chiral hydride complexes are prepared by admixing in the presence of organic solvent 1 equivalent of MBH ₄ or MA1H ₄ with 1 equivalent of R ^* .

In a further embodiment of the invention, the chiral hydride complexes are prepared by admixing in the presence of organic solvent 1 equivalent of MBH ₃ (CN) with 1 equivalent of R ^* .

In a further embodiment of the invention, the chiral hydride complexes are prepared by admixing in the presence of organic solvent 1 equivalent of MBH ₃ (CN) with 1 equivalent of R ^* and 1 equivalent of R' . In a further embodiment of the invention, the chiral hydride complexes are prepared by admixing in the presence of organic solvent 1 equivalent of MBH ₃ (CN) with 2 equivalents of R ^* .

In a further embodiment of the invention, the chiral hydride complexes are prepared by admixing in the presence of organic solvent 1 equivalent of MBH^CN) with 1 equivalent of R ^** .

The chiral hydride complexes can be prepared by adding the MBH ₄ or MA1H ₄ , preferably as a solution in organic solvent, to the chiral ligand(s), preferably as a solution in organic solvent, or to a mixture of chiral and achiral ligands, preferably as a solution in organic solvent. Alternatively, the chiral ligand(s) , preferably as a solution in organic solvent, can be added to the MBH ₄ or MA1H ₄ , preferably as a solution in organic solvent, optionally followed by addition of an achiral ligand, pre-ferably as a solution in organic solvent. Preferably, an organic solution of the chiral ligand(s) is added to an organic solution of MBH ₄ or MA1H ₄ , optionally followed by the addition of an organic solution of an achiral ligand (R ¹ or R ¹ ') . Most preferably, the organic solvent is THF, diglyme or mixtures thereof. Because the chiral boron or aluminum hydride complexes of the present invention are moisture sensitive, the chiral hydride complexes are preferably prepared under an inert atmosphere such as nitrogen or argon.

When cyanide is used as an achiral ligand in the case of the present chiral borohydride complexes, MBH ₃ (CN) can be prepared from the reaction of BH ₃ with MCN, or preferably, MBH ₃ (CN) is obtained commercially (e.g., in the case of NaBH ₃ (CN) , Aldrich Chemical Co., Milwaukee, Wisconsin) . In

this case, an organic solution of MBH ₃ (CN) can be added to an organic solution of chiral ligand(s) , or vice versa.

The admixture of the MBH ₄ , MBH ₃ (CN) or MA1H ₄ ; the chiral ligand(s); and optionally the achiral ligand can occur from about -78° C to reflux temperatures, preferably from about -78° C to about 40° C and most preferably from about -78° C to about room temperature. The reaction mixture comprising the organic solution of the MBH ₄ , MBH,(CN) or MA1H ₄ ; the chiral ligand(s); and optionally achiral ligands R' or R ^» ', can stir for 1 min. to 10 days, preferably from 2 min. to 7 days and most preferably from 5 min. to 3 days. Those skilled in the art will recognize that enantioselectivity tends to increase at lower temperatures.

COMPOSITIONS COMPRISING CHIRAL HYDRIDE COMPLEXES

The present invention provides compositions useful for enantioselectively reducing a chemical entity having a carbonyl group or a carbonyl equivalent. Such compositions comprise 1 equivalent of sodium cation (Na ⁺ ) , lithium cation (Li ⁺ ) or potassium cation (K ⁺ ) ; 1 equivalent of boron cation (B ³⁺ ) or aluminum cation (Al ³⁺ ) ; 1-3 equivalents of hydride; 1-3 equivalents of a monodentate ligand (R ^* ) , 1 equivalent of a bidentate ligand (R ^** ) or tridentate ligand (R ^*** ) ; optionally 1-2 equivalents of a monodentate achiral ligand (R') or 1 equivalent of a bidentate achiral ligand (R ^{1 1} ) , wherein R ^* , R", R ^** ' and R' are defined above; and preferably an inert organic solvent. It is to be understood that the compositions that comprise 1 equivalent of R ^* can comprise 1-2 equivalents of R', or 1 equivalent of R' ¹ . The compositions that comprise R ^* " can comprise 1 equivalent of R' .

In one embodiment of the invention, the chiral hydride complexes comprise 1 equivalent of sodium cation (Na ⁺ ) , lithium cation (Li ⁺ ) or potassium cation (K ⁺ ) ; 1 equivalent of boron cation (B ¹⁺ ) or aluminum cation (Al ³⁺ ) ; 1 equivalent of hydride; and 3 equivalents of R ^* .

In another embodiment of the invention, the chiral hydride complexes comprise 1 equivalent of sodium cation (Na ⁺ ) , lithium cation (Li ⁺ ) or potassium cation (K ⁺ ) ; 1 equivalent of boron cation (B ³⁺ ) or aluminum cation (Al ³⁺ ) ; 1 equivalent of hydride; 2 equivalents of R ^* ; and 1 equivalent of R* .

In another embodiment of the invention, the chiral hydride complexes comprise 1 equivalent of sodium cation (Na ⁺ ) , lithium cation (Li ⁺ ) or potassium cation (K ⁺ ) ; 1 equivalent of boron cation (B ³⁺ ) or aluminum cation (Al ³⁺ ) ; 1 equivalent of hydride; 1 equivalent of R ^* ; and 2 equivalents of R' .

In another embodiment of the invention, the chiral hydride complexes comprise 1 equivalent of sodium cation (Na ⁺ ) , lithium cation (Li ⁺ ) or potassium cation (K ⁺ ) ; 1 equivalent of boron cation (B ³⁺ ) or aluminum cation (Al ¹⁺ ) ; 1 equivalent of hydride; 1 equivalent of R ^* ; and 1 equivalent of R' • .

In another embodiment of the invention, the chiral hydride complexes comprise 1 equivalent of sodium cation (Na ⁺ ) , lithium cation (Li ⁺ ) or potassium cation (K ⁺ ) ; 1 equivalent of boron cation (B ³⁺ ) or aluminum cation (Al ⁺ ) ; 1 equivalent of hydride; 1 equivalent of R ^** ; and 1 equivalent of R' . In another embodiment of the invention, the chiral hydride complexes comprise 1 equivalent of sodium cation (Na ⁺ ) , lithium cation (Li ⁺ ) or potassium cation (K ⁺ ) ; 1 equivalent of boron cation (B ³⁺ ) or aluminum cation (Al ³⁺ ) ; 1 equivalent of hydride; and 1 equivalent of R ^* ".

In another embodiment of the invention, the chiral hydride complexes comprise 1 equivalent of sodium cation (Na ⁺ ) , lithium cation (Li ⁺ ) or potassium cation (K ⁺ ) ; 1 equivalent of boron cation (B ³⁺ ) or aluminum cation (Al ³⁺ ) ; 2 equivalents of hydride; and 2 equivalents of R ^* .

In another embodiment of the invention, the chiral hydride complexes comprise 1 equivalent of sodium cation

(Na ⁺ ) , lithium cation (Li ⁺ ) or potassium cation (K ⁺ ) ; 1 equivalent of boron cation (B ³⁺ ) or aluminum cation (Al ³⁺ ) ; 2 equivalents of hydride; and 1 equivalent of R ^** .

In another embodiment of the invention, the chiral hydride complexes comprise 1 equivalent of sodium cation (Na ⁺ ) , lithium cation (Li ⁺ ) or potassium cation (K ⁺ ) ; 1 equivalent of boron cation (B ³⁺ ) or aluminum cation (Al ³⁺ ) ; 3 equivalents of hydride; and 1 equivalent of R ^* .

The present invention also encompasses compositions which comprise Na ⁺ , Li ⁺ or K ⁺ ; B ³⁺ or Al ³⁺ ; hydride; R ^* , R" or R ^*** ; and optionally R' in stoichio etries outside of the ranges described above. Such compositions comprise chiral hydride complexes having oligomeric structure. The present compositions useful for enantiomerically reducing a chemical entity having a carbonyl group or carbonyl equivalent are obtained by the methods described above.

By "inert organic solvent" is meant that the organic solvent lacks active hydrogens or other groups capable of reacting with the hydride species. Suitable organic solvents include, but are not limited -to alkyl hydrocarbons, such as pentane, hexane and heptane; cyclic or acylic ethers, such as THF and diethyl ether; optionally substituted aromatics, such as benzene, toluene, xylene and chlorobenzene; polyethers such as diglyme and triglyme; other solvents that are inert to hydride reducing agents; and mixtures thereof. Preferably, the organic solvent is THF, diglyme or mixtures thereof.

The present compositions encompass those which lack organic solvent. After admixing in the presence of organic solvent the MBH ₄ , MBH ₃ (CN) or MA1H ₄ ; chiral ligand(s); and optionally the achiral ligand, the compositions can be concentrated, preferably in vacuo, so as to obtain a solid, solvent-free chiral hydride complex. Such solvent-free chiral hydride complexes are preferably stored under an inert atmosphere, e.g., nitrogen or argon, in a dark, air tight

vessel. When stored in this manner, the solvent-free chiral hydride complexes should be stable at room temperature for several months, and at low (<0° C) temperatures for several years. The chiral boron or aluminum hydride complex compositions of the present invention optionally comprise other agents useful for imparting and/or fine-tuning enantioselectivity to carbonyl group and carbonyl equivalent- containing substrates. Such agents include chiral alkoxide bases; trialkylamines, such as triethylamine; and Lewis acids such as aluminum chloride, titanium tetrachloride, boron trifluoride and the like, and can be added to the present compositions at any stage of the synthesis of the present chiral hydride complexes. The present compositions are useful for enantioselectively reducing a chemical entity having a carbonyl group or a carbonyl equivalent. By "enantioselectively reducing" is meant delivering an equivalent of hydride from a present chiral boron or aluminum hydride complex preferentially to one face of a prochiral chemical entity, so as to obtain an enantiomeric excess of a particular reduction product thereof, or in the case where the prochiral chemical entity contains at least one chiral center, a diastereomeric excess of a particular reaction product thereof. By "carbonyl equivalent" is meant an organic moiety derived from a carbonyl group and capable of undergoing asymmetric reduction to yield an asymmetric reduction product. Such carbonyl equivalents include ketones, thioketones, imines (Schiff bases) , unsymmetrical diaryl or dialkyloximes, unsymmetrical diaryl or dialkyloxime ethers, epoxides, thioepoxides, ena ineε, and the like. Such carbonyl equivalents are available commercially from, for example, Aldrich Chemical Co., Milwaukee, Wisconsin, or obtainable from conventional organic synthesis via means known to those skilled in the art.

In addition, the present compositions are useful for reducing a carbon-carbon double bond of an , β-

unsaturated carbonyl, or ,j8-unsaturated carbonyl equivalent system, via 1,4-addition of hydride to the 0-carbon atom the α,β-unsaturated carbonyl or ,j8-unsaturated carbonyl equivalent system. Such reductions are advantageously conducted at temperatures ranging from about -78° C to room temperature, preferably from about -78° c to about 0° C, and in inert organic solvents described above.

SOLID PHASE CHIRAL HYDRIDE COMPLEXES The chiral hydride complexes of the present invention can comprise a solid phase support, allowing the chiral hydride complexes to be more easily synthesized, weighed and transferred, and recovered from a reaction mixture. Such solid phase supports can be chiral or achiral. Suitable chiral solid phase supports include, but are not limited to, optionally protected chiral polysaccharides, such as α-, β- or 7-cyclodextrin or chitosan, which have pendant moieties that are capable of forming a stable complex with MBH ₄ , MBH ₃ (CN) and MA1H ₄ . Preferably, the solid phase support is a chiral polysaccharide. As used in this context,

"protected" means that at least one, but less .than all, of the polysaccharide hydroxyl groups is protected with a protecting group, such as one found in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1981.

Suitable achiral solid phase supports include, but are not limited to, polyacrylic acid, polystyrene, polyvinyl alcohol, poly(dimethylacrylamide) -grafted styrene co- divinylbenzene, polyamide resin, polystyrene grafted with polyethylene glycol, polydimethylacrylamide resin, and polyacrylamide.

Where the solid phase support is chiral, the solid phase support is admixed in the presence of an organic solvent with MBH ₄ , MBH ₃ (CN) or MA1H ₄ , optionally in the presence of an achiral ligand, according to the methods described above, to provide a chiral hydride complex comprising a solid phase support. Where the chiral solid

phase support comprises a plurality of moieties capable of forming a stable complex with MBH ₄ , MBH ₃ (CN) or MA1H ₄ , e.g., hydroxyl, amino or sulfide groups, some of these moieties can be optionally protected with one or more protecting group prior to reaction with MBH ₄ , MBH ₃ (CN) or MA1H ₄ . In this regard, the use of one or more protecting group will prevent all of the hydrides of MBH ₄ , MBH ₃ (CN) and MA1H ₄ from reacting with the moieties and ensure that the resulting chiral hydride complex has at least one hydride available for reaction with a carbonyl group or carbonyl-equivalent containing substrate. Following reaction with MBH ₄ , MBH ₃ (CN) or MA1H ₄ , a protecting-group bearing solid phase support can optionally be deprotected. Suitable protecting groups and methods for use and deprotection can be found in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1981.

Where the solid phase support is achiral, the achiral solid phase support can be covalently bonded to a chiral ligand (R ^* , R" or R ^* " ^* ) , or to an achiral ligand (R' or R' ') used in conjunction with R ^* or R ^" , prior to reaction with MBH ₄ , MBH ₃ (CN) or MA1H ₄ via the above-described, methods. In this case, the chiral or achiral ligand bears a reactive group, such as a carboxyl (or its equivalent) or an epoxy group, capable of forming a covalent bond with a reactive moiety, e.g., a hydroxyl, amino or sulfide group, on an achiral solid phase support. Such a covalent bond is formed by admixing the reactive group-bearing chiral or achiral ligand with the solid phase support in the presence of a suitable reaction solvent, such as an alkyl hydrocarbon, e.g. , pentane, hexane or heptane; a cyclic or acylic ether, e.g.. THF or diethyl ether; an optionally substituted aromatic, e.g., benzene, toluene, xylene or chlorobenzene; a polyether e.g. , diglyme or triglyme; any other solvent that is inert to hydride reducing agents; and mixtures thereof, optionally with heating. Preferably, the reactive moiety of the achiral solid phase support is an amino or hydroxyl

group, and the reactive group of the chiral or achiral ligand is a carboxyl group.

Alternatively, the achiral solid phase support can serve as an achiral ligand that reacts with MBH ₄ , MBH ₃ (CN) or MA1H ₄ , preferably in the presence of a monodentate or bidentate chiral ligand (R ^* or R ^** ) and an organic solvent, to form a chiral hydride complex.

METHODS FOR USING THE CHIRAL HYDRIDE COMPLEXES The present chiral boron or aluminum hydride complexes, or compositions comprising the chiral hydride complexes, are useful for obtaining an enantiomeric excess of a reduction product. It will be understood that the reduction product of a chiral hydride complex and a carbonyl group will be an alcohol. Where the carbonyl equivalent is a thioketone, the reduction product will be mercaptan. Where the carbonyl equivalent is an imine, the reduction product will be an amine. Where the carbonyl equivalent is an oxime or an oxime ether, the reduction product will be a species having an -NH-O- group. Where the carbonyl equivalent is an epoxide, the reduction product will be an alcohol. Where the carbonyl equivalent is a thioepoxide, the reduction product will be a mercaptan. Where the carbonyl equivalent is an enamine, the reduction product will be an amine. Reduction of the carbonyl group or carbonyl equivalent is achieved by admixing the desired chiral hydride complex or composition comprising the chiral hydride complex with the substrate to be reduced. By "substrate to be reduced" is meant a chemical entity having a carbonyl group or carbonyl equivalent. Such admixture can be accomplished by adding the chiral hydride complex, preferably as a composition comprising the chiral hydride complex and organic solvent, to a substrate to be reduced, preferably as a solution in organic solvent. Alternatively, the substrate to be reduced, preferably as a solution in organic solvent, can be added to the chiral hydride complex, preferably as a composition comprising the chiral hydride complex and organic

solvent. Preferably, an organic solution of the substrate to be reduced is added dropwise to a composition comprising the chiral hydride complex and organic solution. Most preferably, the reduction is achieved by freshly preparing a composition comprising the chiral hydride complex and organic solvent, via methods described above, and thereafter adding to the complex an organic solution of the substrate to be reduced, such that the synthesis of the chiral hydride complex and reduction of the desired substrate are achieved in a one-pot method.

Organic solvents useful for reduction using the present chiral hydride complexes are those that are unreactive to hydride and include, but are not limited to alkyl hydrocarbons, such as pentane, hexane and heptane; cyclic or acylic ethers, such as THF and diethyl ether; optionally substituted aromatics, such as benzene, toluene, xylene and chlorobenzene; polyethers such as diglyme and triglyme; and mixtures thereof.

Reduction of the desired substrate with the present chiral hydride complexes can occur at a temperature from -78° C to the reflux temperature of the solvent used in the reaction mixture, preferably from -70° C to room temperature. Reaction times may vary from several minutes to up to 7 days, depending upon the reaction temperature and nature of chiral hydride complex and substrate.

The ratio of chiral hydride complex to substrate to be reduced can range from about 15:1 to about 1:1, preferably from about 12:1 to about 3:1. Because the chiral hydride complexes of the present invention are moisture sensitive, the reductions are preferentially conducted under an inert atmosphere such as nitrogen or argon.

Once the chiral hydride complex is admixed with the substrate to be reduced, and reacted therewith such that the substrate to be reduced is reduced by the chiral hydride complex, the reaction is quenched, typically with water, aqueous acid, aqueous ammonium chloride, aqueous tartrate solution, or the like.

In addition, the present chiral hydride complexes can be used in conjunction with other hydride reducing agents known to those skilled in the art, such that the present complexes are auxiliary reducing agents. In this instance, the present complexes are present in less than stoichiometric amounts, whereas the other hydride reducing agents are present in stoichiometric or excess quantities. In this instance, the present chiral hydride complexes are continuously regenerated via reaction with the other hydride reducing agent(s) .

EXAMPLES The following series of Examples are presented by way of illustration and not by way of limitation on the scope of the invention.

EXAMPLE: SYNTHESIS OF CHIRAL HYDRIDE COMPLEXES CHIRAL LIGANDS SYNTHESIZED

Example 1 1,2:5,6-Di-O-isopropylidene-D-mannitol (Ligand 2) (DIPM) . Ligand 2 was prepared according to the method described in J. Am. Chem. Soc, 1945, 67, 338. 20 g of D- mannitol, 100 g of acetone and 120 g of zinc chloride were heated at 20° C for 72h to afford 15.6 g (54%) crude product of the above-titled compound (80% purity by ¹³ C NMR) and 8.5 g (29%) following recrystallization: p. = 122-23° C; ¹³ C NMR (CDC1 ₃ ) δ 25.17, 26.70, 66.71, 71.08, 76.10, 109.34.

Example 2 l,2:5,6-Di-0-isopropylidene-D-mannitol (Ligand 2) (DIPM) . DIPM was prepared according to the method described in J. Org. Chem., 1991, 56, 4056. A mixture of 37.5 g of D- mannitol, 60 mL of 2,2-dimethoxypropane and 37 mg of SnCl ₂ were heated at reflux in glyme (74° C) until a clear solution was obtained (approximately lh) , and then for an additional

30 min, to provide 42 g (39%) of the above-titled compound: mp. = 122-23° C; ¹³ C NMR (CDC1,) <S 25.17, 26.70, 66.71, 71.08, 76.10, 109.34.

Example 3

3,5:4,6-Di-0-ethylidene-D-glucitol (Ligand 5a) (DES) . A mixture of D-glucitol and excess paraacetaldehyde were stirred in the presence of concentrated HCl at 20° C for lOh to provide 1, 2 : 3 , 5:4, 6-tri-O-ethylidene, which was deprotected at the 1,2-hydroxyl groups using acetic acid at 23° C to afford 37% of the title compound as a white solid: mp. = 210-12° C (from ethanol) ; [α ^2l ] +13.5 (c 4.1; H ₂ 0) ; Η NMR (CD ₃ 0H) cS 3.67 and 3.53 (m, H-l) , 3.78 (d, H-2) , 3.57 (d, H-3) , 3.79 (t, H-4), 3.52 (q, H-5) , 3.87-3.96 (m, H-6) , 4.75 (q, H-7 and H-9) , 1.28 and 1.26 (CH ; C NMR (CD ₃ OH) 6 64.0 (C-l) , 69.8 (C-2), 78.8 (C-3), 69.3 (C-4) , 71.6 (C-5) , 70.6 (C-6) , 99.78 and 99.94 (C-7 and C-9) , 20.99 and 20.92 (C-8 and C-10) .

Example 4

Diisopropyl (R,R) -tartrate. Diisopropyl (R,R)- tartrate was prepared according to the procedure described in J. Am. Chem. Soc, 1981, 6237. 400 g of (R,R) -tartaric acid, 400 mL of isopropanol and 5 g of p-TsOH were heated in refluxing benzene to afford, following distillation, 201 g (55%) of the above-titled compound: bp. = 103-105° C (2 torr) (lit. 152° C (12 torr) ) .

Example 5 N,N,N' ,N'-Tetramethyl- (R,R) -tartaramide.

N,N,N' ,N'-Tetramethyl-(R,R)-tartara ide was obtained according to the procedure described in Org. Syn. 61, 24. A mixture of 23.4 g of the product of Example 4 and 13.5 g of dimethylamine was stirred in methanol at 25° C for 24h to afford 18.2 g (90%) of the above-titled compound following crystallization from EtOH: mp. = 186° C (lit. 185-88° C) .

Example 6 R,R-(+)-2,3-Dimethoxy-N,N,N' ,N'- tetramethylsuccinamide. R,R-(+) -2, 3-Dimethoxy-N,N,N' ,N'- tetramethylsuccina ide was obtained according to the procedure described in Org. Syn. 61, 24. A mixture of 10 g of the product of Example 5 and 15.75 g of dimethylsulfate in 50% K0H/CH ₂ C1 ₂ was stirred at 25° C for 6h to afford 7.9 g (70%) of the above-titled compound following crystallization: mp. = 63-64° C.

Example 7 R,S-Binol. R,S-Binol was obtained according to the procedure described in Ber. , 1926, 2160. A mixture of 60 g of -naphthol and 132 g of FeCl ₃ ^« 6H ₂ 0 was heated in boiling water to afford 39 g (65%) of the above-titled compound following crystallization: mp. = 219° C.

Example 8 S-Binol. S-Binol was obtained according to the method described in Chem. Lett. 1988, 1371 and in J. Org. Chem. 1988, 53, 3607. To 50 g of the product of Example 7 and 40.6 g of the product of Example 6 was added a mixture of 200 L of benzene and 60 mL of hexane. To the resulting (S)- binol/R,R-(+) -2, 3-dimethoxy-N,N,N' ,N'-tetramethylsuccinamide complex was added 1 eq. hydrazine to afford 33.7 g of the title compound following recrystallization.

Example 9 (S) -l-tert-Butylamino-2 3-propanediol (Ligand 3) ((S)-PROP). (S)-Glycidol was added dropwise, with stirring, to a mixture of 54.7 g of tert-butylamine and 25 mL of water, heated at reflux. The resulting mixture was heated at reflux for 12h, and was thereafter allowed to cool to room temperature. The mixture was concentrated in vacuo and was treated with ether to effect crystallization. 28.6 g (78%) of crystalline product was thus obtained: Η NMR (CDC1 ₃ ) δ 1.0 (s, C(CH ₃ ) ₃ ) , 2.4-2.6 (m) , 3.3-4.2 (m) ; ^l C NMR (CDC1 ₃ ) δ 28.6

(3 CH ₃ ) , 45.2 (CH ₂ NH) , 50.2 (C(CH ₃ ) ₃ ), 65.5 (CH ₂ OH) , 70.6 (CHOH) .

Example 10 1,2:5,6-Di-O-cyclohexylidene-α-D-glucofuranose

(Ligand 12) (DCG) . DCG was prepared according to the procedure described in J. Am. Chem. Soc, 1949, 71, 3072. A mixture of 90 g of α-D-glucose, 200 L of cyclohexanone and 13 L of sulfuric acid was allowed to stir at 20° C for 12h to afford 43.9 g (29%) of the above-titled compound, after two crystallizations: mp. = 130.5-131.5° C (lit. 131.1-132.4 C).

Example 11 3-O-Benzyl-l,2:5, 6-di-O-cyclohexylidene-α-D- glucofuranose (BDCG) . A mixture of 40 g of DCG obtained from Example 10, 138 mL of benzyl chloride and 92.5 g of KOH was heated at 150° C for 4h to afford 45.5 g of the above-titled compound.

Example 12 3-0-Benzyl-l,2-o-cyclohexylidene-α-D-glucofuranose (Ligand 9b) (BCG) . A mixture of 20 g of BDCG obtained from Example 11 and 75 mL of Ac0H/H ₂ 0 (3:1) were heated at 73° C for 4h to afford 8.38 g (52%) of the above-titled compound: bp. = 200-205° C (0.005 torr) (lit. 200° C (0.005 torr)) .

Example 13 2-0-Benzyl-3,5:4, 6-diethylidene-D-glucidol (Ligand 5c) (BDG) . 2-0-Benzyl-3,5:4,6-diethylidene-D-glucidol (BDG) was obtained according to the procedure of Izv. Akad. Nauk. SSSR, Ser. Khim. 1993 (4), 776 (Russ. Chem. Bull. 1993 (4) , 744 (Engl. Trans.)) . A mixture of 7 g of DES obtained from Example 3, 4.5 g of benzyl chloride and 2 g of KOH in dimethylsulfoxide was allowed to stir at 20° C for 3h. The reaction product was chromatographed on Alu iniumoxid 60 λ ₂₅₄ Type E (Merck) using 5:1 Et ₂ 0:CHCl ₃ to afford 6 g (64.7%) of

the title compound: mp. = 78° C; [α] _D ²⁰ -13.55° (c=l, in CHCl _j ) ; Η NMR (CDCI ₃ , 250 MHz) S 1.32 and 1.40 (d, 6H, CH ₃ ) , 3.60-3.89 (m, 6H, H. , 4.13 (d, 2H, CH ₂ Ph) , 4.49-4.58 (m, 4H, H _f . _g ) , 7.28 (m, 5H, C ₆ H ₅ ) ; ¹³ C NMR (CDC1 ₃ , 75.5 MHz) δ 61.3 (C , 77.2 (C _b ) , 76.5 (C _c ) , 68.0 (C _d ) , 69.6 (C _e ) , 69.2 (C _f ) 98.2 and 98.3 (C _g ) and 20.5 and 20.7 (C _h ) .

Example 14 l,3:4,6-Di-0-benzyliden-D-mannitol (Ligand 7) (DBM) . DBM was obtained according to the method described in J. Chem. Soc, I, 1977, 1123 or by the following procedure. A mixture of 12.5 g of D-mannitol, 12.5 g of benzaldehyde in 40 mL of dimethylformamide was treated with 5 mL of sulfuric acid added in one portion. The resulting mixture was allowed to stand at room temperature for 72h and then poured into a mixture of 5 g of potassium carbonate, 0.5 L of ice water covered with a layer of hexane. The hexane layer containing unreacted benzaldehyde was removed and the aqueous layer was allowed to stand at 5-10° C whereupon a white, cheese-like solid deposited thereon. The aqueous layer was filtered, and the solid air-dried and recrystallized from CHC1 ₃ to afford 13.3 g (53%) of the above-titled compound as white crystals. The resulting white crystals were washed with dry hexane (2 x 10 L) and benzene (10 mL) , and then dissolved in hot benzene. The benzene solution was evaporated and the resulting solid residue dried over P ₂ 0 ₅ in an Abderhalden apparatus for 18h at 40° C/0.3 torr to provide an analytical specimen melting at 152-53° C (189-91° C (MeOH) ) : Η NMR (90 MHz, CDCI ₃ ) S 3.54-3.65 (m, 2H, H-2 and H-5) , 4.0 (d, 4H, H-l and H-6) , 4.22 (d, 2H, H-3 and H-4) , 4.38 (br. s. , 2H, OH), 5.52 (c, 2H, H-7 and H-8) , 7.24-7.48 (m, Ph, Ph) ; ¹³ C δ 58.8 (C-3 and C-4) , 70.55 (C-2, C-5) , 78.1 (C-l, C-6) , 100.34 (C- 7, C-8), 125.49, 127.05, 127.17, 137.77 (Ph groups) .

Example 15 (S,S) -1, 3-Bis- (l-phenylethylamino) -2-propanol ( (S,S) -BPAP) . A mixture of 2.57 mL of (S) -phenethylamine and 0.39 L of epichlorohydrin in 20 mL of methanol was allowed to reflux for 30 min. The reaction mixture was concentrated in vacuo then diluted with 5 mL of HCl-saturated isopropanol. Crystallization afforded the dihydrochloride salt (66%) of the above-titled compound. The resulting dihydrochloride salt was neutralized with NaOH and extracted into toluene to afford the above-titled compound in its free-base form:

(dihydrochloride salt) decomp. point = 255° C; [ a ] _D ⁿ = -36 (c = 2.0, MeOH) ; ^l H NMR (200 MHz, 1:1 CDC1,: CC1 ₄ ) 8 1.5 (d, 2 CH ₃ ) , 2.3-2.8 (m, 2 CH ₂ N,), 3.2 (br. s, 2 NH, OH) , 3.7-4.0 (2 CHN + CHO) , 7.1-7.6 (m, 10H, arom.) ; ^π C NMR (200 MHz, 1:1 CDC1 ₃ : CC1 ₄ ) δ 24.20 (2 CH ₃ ) , 51.3, 51.75 (2 CH ₂ N) , 68.55

(CHO), 126.50, 127.0, 128.45 (3 CH arom.) , 144.7 (1C arom.) .

Example 16 l-Chloro-3,5: , 6-di-O-ethylidene-D-gluci ol. A mixture of 2.34 g of DES obtained from Example 3, 5.24 g of triphenylphosphine, 80 L of pyridine and 15.4.g of carbon tetrachloride were heated at 55° C for 2h. The resulting reaction mixture was chromatographed on Aluminiumoxid 60 λ _2M Type E (Merck) using CHC1 ₃ , then CHC1,:CH ₃ 0H (10:1 - 3:1, v/v) to give 0.75 g (30%) of the above-titled compound as white crystals (R _f = 0.41) : mp. = 142° C (from benzene-hexane) ; ^l H NMR (90 MHZ, CDC1 ₃ ) <S 1.32 and 1.43 (d, 6H, CH,) , 3.50 (s, 1H, OH) , 3.60-3.90 (m, H _a . _e ) , 4.08-4.28 (m, 2H, H _f ) , 4.71-4.80 (m. 2H, H.) ; ¹³ C NMR (75.5 MHz, CDC1 ₃ ) <5 47.7 (C.) , 67.7 (C _b ) , 77.5 (C _c ) , 68.2 (C _d ) , 69.9 (C , 69.5 (C _f ) , 98.80 and 98.85 (C _g ) and 20.8 and 20.9 (C _h ) .

Example 17 l-Anilino-3,5:4, 6-di-O-ethylidene-D-glucitol (Ligand 5b). A mixture of 0.38 g of l-chloro-3 , 5: 4 , 6-di-0- ethylidene-D-glucitol obtained from Example 16, 0.465 g of

aniline and 0.53 g of sodium carbonate in 50 mL of acetonitrile was allowed to heat at 80° C for 5 days. The reaction mixture was purified via silica gel chromatography (Aluminiumoxid 60 λ ₂₅₄ Type E (Merck) ) using chloroform as an eluent (R _f = 0.30) to obtain 0.138 g of the above-titled compound as a viscous oil.

Example 18 l-Tosyl-3,5:4,6-di-0-ethylidene-D-glucitol. A mixture of 7.8 g of DES obtained from Example 3, 6 g of p- toluenesulfonyl chloride, 30 mL of chloroform and 30 mL of pyridine was allowed to stir at 20° C for 2 days. The reaction mixture was purified via silica gel chromatography (Aluminiumoxid 60 λ _2<i4 Type E (Merck) ) using chloroform as an eluent (R _f = 0.30) to obtain 0.75 g (30%) of the above-titled compound as white crystals: mp. = 101-102° C (from Et ₂ 0) ; [α] _D ²⁰ +4.3 (c 1, CDC1 ₃ ) ; Η NMR (CDC1,, 90 MHz) <S 1.28 and 1.33 (d, 6H, CH,) _; 3.50 (s, 1H, OH) , 3.60 and 3.90 (m, 4H (H _b - _e ) ) , 4.08 and 4.30 (m, 4H (H ₀ and H _f ) , 4.60-4.80 (m, 2H, H _g ) , 7.35 and 7.80 (d, 4H, Ph group); ^π C NMR (CDC1 ₃ , 90 MHz) δ 66.54 (C , 67.99 (C _b ), 77.73 (C _c ) , 69.49 (C _d ) , 69.75 (C _e ) , 71.14 (C _f ) , 98.57 and 98.74 (C _g ) , 20.66 and 20.85 (C _h ) . Ts group: 21.85 (CH ₃ ) , 128.01, 129.94, 132.46 and 145.13 (Ph) .

Example 19 l-Anilino-3,5:4,6-di-O-ethylidene-D-glucitol. A mixture of 1 eq. of l-tosyl-3, 5:4 , 6-di-O-ethylidene-D- glucitol obtained from Example 16, 2.4 g of aniline and 2.7 g of sodium carbonate in 130 mL of acetonitrile was allowed to heat at 30° C for 7 days. The reaction mixture was purified via silica gel chromatography (Aluminiumoxid 60 λ _2M Type E (Merck)) using chloroform as an eluent (R _f = 0.30) to obtain 1.2 g (65.2%) of the above-titled compound which crystallized upon standing: mp. = 167-168° C; [α] _D ² +5.1 (c 1, CDC1 ₃ ) ; Η NMR (CDC1 _3/ 90 MHz) δ 1.39 and 1.48 (d, 6H, CH ₃ ) , 2.45 (br. s, 2H, OH, NH), 3.40-3.68 ( , 4H (H _g - _f ) ) , 3.70-4.30 (m, 4H (H„- _e ) ,

4.65-4.90 (m, 2H, H _g ) , 6.72 and 7.28 (m, 5H, Ph group) ; ¹³ C NMR (CDC1 ₃ , 90 MHZ) δ 46.62 (C _a ) , 66.68 (C _b ) , 77.74 (C , 68.10 (C _d ) , 69.90 (C _e ) , 69.66 (C _f ) , 98.77 and 98.90 (C„) , 20.98 and 21.04 (C _h ) ; 128.08, 129.35, 130.01 and 148.29 (Ph) . 5

Example 20 (S)-N-isobutyl-α-phenylethylamine ((S)-IBPA). A mixture of 12.1 g (S) -phenethylamine, 15.9 g isobutyryl chloride and 14 g of KOH in 75 L of water and 150 mL of

10 diethyl ether was heated at 40-45° C for several hours to afford 15.5 g (81%) of intermediate A.

A mixture of 15 g of intermediate A, 7.5 g of LAH and 60 L of THF were heated at reflux. The reaction product was treated with 10 mL of HCl-saturated isopropanol to afford

15 15.4 g (92%) of the above-titled compound as white needles: p. >200° C (dec); [α] _D ²⁰ -26.9 (c = 4.02, MeOH) ; Η NMR (CDC1 ₃ ) δ 0.9-1.1 (dd, CHMe ₂ ) , 1.95 (d, CH,CHPh) , 2.2-2.4 (m, CHMe ₂ ) , 2.4-2.7 ( , CH ₂ ) , 4.2-4.4 (m, CHPh) , 7.3-7.5 ( , Ph, 3H) 7.6-7.8 (Ph, 2H (ortho) ) , 9.4-9.8 (br. s, NH ₂ ⁺ , 1H) , 9.8-

²⁰ 10.1 (br. Ξ, NH ₂ ⁺ , 1H) , ; ¹³ C NMR (CDC1 ₃ ) δ 20.20, 20.70, 20.85, 25.55 (3 CH ₃ , CHMe ₂ ) , 53.00, 59.50 (CH ₂ N, CHN) , -127.65, 129.05, 129.20 (Ph, 4 CH) , 136.15 (Ph, C-CH) .

Example 21 ²⁵ (R)-N-isobutyl-α-phenylethylamine ((R)-IBPA). (R)-

IPBA was obtained according to the synthesis of (S)-IBPA in Example 20, except that (R) -phenethylamine was used in place of (S) -phenethylamine.

³⁰ Example 22

(S,S) -N,N-Bis(methylbenzyl) ethylenediamine ( (S,S) -

BMBE) . A mixture of 36.7 g of (S) -phenethylamine and 22 mL of diethyloxalate was allowed to warm to 40° C over 30 min.

The reaction mixture was diluted with 600 mL of THF, treated ³⁵ with 34 g of LAH, and allowed to heat at reflux for lOh to afford, following distillation, 15.3 g (38%) of the above-

titled compound: bp. = 170° C/l torr; [αj ¹⁸ -70.7 (neat) (lit. [α] _D ²⁵ -65.6 (Tetrahedron Lett., 1980, 3467)) ; Η NMR (CDC1 ₃ ) <S 1.4 (d, CH ₃ ) , 1.65 (br. ε, NH) , 2.6 (s, CH ₂ CH ₂ ) , 3.7 (q, CH) , 1 . 2-1 . ( , arom.).

Example 23 l,2:3,5-Di-0-isopropylidene-α-D-xylofuranose (DIXF) . A mixture of 33 g of D-xylose, 667 mL of acetone, 3.3 mL of cone sulfuric acid and 66.7 g of CuS0 ₄ were allowed to stir at room temperature for 25h. Distillation (110-113° C/l torr) of the reaction mixture afforded 42 g (89%) of the above-titled compound (lit. (J. Am. Chem. Soc , 1955, 77, 5900) 90-92° C/0.2 torr) .

Example 24

1,2-O-isopropylidene-α-D-xylofuranose (IXF, Ligand 10) . Ligand 10 was prepared according to the procedure described in J. Am. Chem. Soc, 1955, 77, 5900. 13.5 g of DIXF obtained from Example 23 and 60 L of 0.2% HCl were heated for lh with intensive stirring to afford 9.6 g (86%) of the above-titled compound: [ a ] _D ² ' ¹ = -17° (c 2.1, MeOH) (lit. (Ber., 1923, 56, 863) [α] _D ²⁵ = -19° (c 0.7, MeOH)) ; Η NMR (CDC1 ₃ ) δ 1.21 and 1.36 (2s, Me ₂ C) , 3.6 (s, 2 OH) , 3.86 (d, CH ₂ ) , 3.82-4.42 ( , 1 CH ₂ 0, 3 CHO) , 5.86 (d, OCHO) ; _π C NMR (CDC1 ₃ ) δ 111.42, 104.48, 85.18, 79.26, 77.0, 75.62, 66.72, 60.22.

Example 25 (R) -l-tert-Butylamino-2, 3-propanediol (BAP) . BAP was obtained according to the procedure of Example 9, above.

Example 26 1,2-θ-Cyclohexylidene-α-D-xylofuranose (CXF) . CXF was obtained according to the method described in J. Org. Chem. 1965, 30(4), 1288. A mixture of 9.5 g of D-xylose, 100 mL of cyclohexanone and catalytic sulfuric acid was allowed

to stir at room temperature for approximately 25h to afford, following recrystallization, 10.05 g (50%) of 1 , 2 : 3 , 5-di-α-D- xylofuranose (DCXF) : mp. = 101-102° C (lit. 103-104° C) .

5 g of DCXF obtained above were allowed to stir in 150 mL of 60% aqueous acetic acid at 20° C for 20h to obtain, following recrystallization, the above-titled compound: mp. = 84-85 (lit. 83-84) .

Example 27 (S)-Phenylalaninol ((S)-PA). (S)-PA was prepared according to the method described in Tetrahedron Lett., 1992, 33 , 5517. 5 g of (S) -phenylalanine were treated with 2 g of sodium borohydride and 2 mL of H ₂ S0 ₄ in 30 mL of THF, maintaining the reaction temperature below 10° C. The reaction mixture was allowed to stir at this temperature for 3h, then at 30° C for 12h. The resulting mixture was treated was 30 mL of NaOH and was heated at just below 100° C for 3h to afford 4 g of the above-titled compound: mp. = 94-95° C; ["] _D ² ° = -21 (c = 2, MeOH) (lit. 95° C; [or],, ²⁰ = -23.3 (c = 2, MeOH) (Indian J. Chem., 1966, 4 _. , 177)) .

Example 28 (S)-N,N- (Dimethyl)phenylalaninol [(S)-DMPA]. (S)- DMPA was synthesized according to the method described in J. Chem. Soc, 1950, 1342; and J. Am. Chem. Soc, 1970, 92, 2476. The structure of the above-titled compound is consistent with Η and ^I3 C NMR data.

Example 29 (3S,4S) -l-Benzyl-3, -dihydroxypyrrolidine (BDHP) .

BDHP was obtained according to the method described in Ber. , 1986, 199, 3326 and in Chem. Phar. Bull., 1991, 3_9, 2219. A mixture of 15 g of L-tartaric acid and 1.9 mL of benzylamine in xylene was heated at reflux for 7h to afford, after crystallization, 11 g (52%) of an N-benzylimide intermediate: mp. = 199-201° C (lit. 196-98° C, Can. J. Chem. 1968, 46,

3091) ; [α] _D ²³ = +138 (c = 1, MeOH) (lit. [a] _u ²³ = +138 (c = 1, MeOH) , Chem. Phar. Bull., 1991, 19, 2219) .

The N-benzylimide intermediate obtained above was added to a suspension of LAH in THF with stirring, under argon, at 0° C. The resulting mixture was heated at reflux for 12h to provide 5.1 g (53%) of the above-titled compound: mp. = 99-100° C (lit. 109-110° C) ; [α] _D ²⁰ = +8.1 (c = 1, CHC1 ₃ ) (lit. [α] _D ²⁰ = +8.3 (c = 1, CHClj)) .

Example 30 l-O-Triphenylmethyl-3,5:4, 6-di-O-ethylidene-D- glucitol (TDG). A mixture of 11.7 g of DES obtained from Example 3, 16.3 g of triphenylmethyl chloride and 80 L of pyridine were allowed to stir at room temperature for 3 days, to afford, following crystallization from 10:1 hexane:benzene, 15.3 g (64%) of the above-titled compound: mp. = 92° C (MeOH) ; ¹³ C NMR data consistent with that reported in M.I. Struchkova et al., Izv. Akad. Nauk. Ser. Khim. , 1989, 2492.

Example 31 1,3:4, 6-Di-O- (p-anisylidene) -D-mannitol (DAM) . A mixture of 20 g of D-mannitol, 26 mL of p-anisaldehyde in 60 mL of dimethylformamide was treated with 4 L of sulfuric acid added in one portion. The resulting mixture was allowed to stand at room temperature for 72h and then poured into a mixture of 12 g of potassium carbonate and 0.6 L of ice water. The unreacted p-anisaldehyde was extracted in hexane and 1:1 hexane:benzene. The resulting aqueous layer was allowed to stand at 5-10° C whereupon a white, cheese-like solid deposited thereon. The aqueous layer was filtered, and the solid air-dried and recrystallized from 6:1 benzene:ethanol to afford 4.3 g (11%) of the above-titled compound. The above-titled compound was dried over P ₂ 0 ₅ in an Abderhalden apparatus for 18h at 40° C (CH ₂ C1 ₂ ) under reduced pressure to provide an analytical specimen melting at 186-88°

C: [α] _D ¹⁶ 24° (c = 1 , acetone) ; ^l H NMR (200 MHz, DMSO-d ₆ ) δ 3.5 (dd, 2H, H-2 and H-5) , 3.73 (s, 6H, OMe) , 3.8 ( , 4H, H-l and H-6) , 4.15 (dd, 2H, H-3 and H-4) , 5.32 (d) and 5.48 (s, OH, and PhCH) , 6.9 (d) and 7.35 (d, 8H, Ph) ; ¹³ C (50 MHz, DMSO-d ₆ ) δ 55.11 (OMe) , 58.66 (C-2, C-5) , 70.97 (C-l, C-6) , 78.05 (C-3 and C-4) , 100.1 (C-7, C-8) , 113.30, 127.44, 130.68 and 159.37 (Ph) .

Example 32 ι,3:4,6-Di-0-(p-toluylidene) -D-mannitol (DTM1) . A mixture of 20 g of D-mannitol, 26 mL of p-toluylaldehyde in 60 mL of dimethylformamide was treated with 4 mL of sulfuric acid added in one portion. The resulting mixture was allowed to stand at room temperature for 72h and then poured into a mixture of 12 g of potassium carbonate and 0.6 L of ice water. The unreacted p-toluylaldehyde was extracted in hexane. The resulting aqueous layer was allowed to stand at 5-10° C whereupon a white, cheese-like solid deposited thereon. The aqueous layer was filtered, and the solid air- dried and recrystallized from 6:1 benzene:ethanol to afford 13.8 g (32.5%) of the above-titled compound. ^' The above- titled compound was dried over P ₂ 0 ₃ in an Abderhalden apparatus for 18h at 40° C (CH ₂ C1 ₂ ) under reduced pressure to provide an analytical specimen melting at 156-58° C: [α] _D ¹⁶ ιι° ( _C _ o.5, acetone) ; ^l H NMR (200 MHz, DMS0-d ₆ ) δ 2.3 (s, 6H, CH ₃ Ph) , 3.5 (dd, 2H, H-2 and H-5) , 3.8 (m, 4H, H-l and H- 6) , 4.15 (dd, 2H, H-3 and H-4) , 5.32 (d) and 5.48 (s, OH, and PhCH), 7.16 (d) and 7.32 (d, 8H, Ph) ; ¹³ C (50 MHz, DMS0-d ₆ ) δ 20.81 (MePh) , 58.66 (C-2, C-5) , 71.10 (C-l, C-6) , 78.10 (C-3 and C-4), 100.25 (C-7, C-8) , 126.04, 128.46, 135.50 and 137.76 (Ph) .

Example 33 2,3-O-Cyclohexylidene-l, l,4,4-tetraphenyl-L- threitol (CYTOL) . A solution of 25 g of dimethyl-L-tartrate and 0.9 g of p-TsOH in 225 L of abs. benzene was heated at

reflux, and to it was added 15 mL of freshly distilled cyclohexanone over a period of 30 minutes. The resulting solution was heated for 8h and the water thus produced was continuously removed via a Dean-Stark apparatus. After cooling to room temperature, the reaction mixture was diluted with 200 L of diethyl ether and the resulting mixture was washed three times with 200 L water and 200 mL of brine, and dried over MgS0 ₄ . Concentration afforded 28 mL of an oil, which was subsequently diluted with 15 mL of 1:1 ether:hexane and chromatographed on silica gel using a 20 x 2 cm column and 1:1 etherrhexane eluent to provide 28.6 g (79%) dimethyl- 2,3-O-cyclohexylidene-L-tartrate as a light, yellow oil, which was approximately 90% pure, and was used in the next step without further purification. A diethyl ether solution (300 mL) of phenylmagnesium bromide obtained from the reaction of 50 mL of bromobenzene and 11.6 g of magnesium was added dropwise with stirring to a diethyl ether solution (130 mL) of the 28.6 g of dimethyl-2 , 3-O-cyclohexylidene-L- tartrate obtained above at 3-5° C over 4.5h. The resulting mixture was heated at reflux for 2h, allowed to cool to room temperature, and poured onto ice-water (approx. -5° C) containing NH ₄ C1. The resulting organic layer was washed with 10% HCl (10 mL) and water, and then dried over MgS0 ₄ . Evaporation of the solvent provided allowed the product to crystallize to afford 17 g (34%) of the above-titled compound: mp. = 200-202° C (lit. 195-196° C; Helv. Chim. Acta, 1987, 7_0, 954) ; Η NMR (CDC1 ₃ ) δ 1.2-1.6 ( , 5H) , 4.65 (c, 2CH) , 4.77 (c, 20H) , 7.3-7.6 ( , 20 CH aromatic) .

Example 34 Di-O-cyclohexylidene-D-allofuranose (DCAF) . 45 g of D-glucose were added to a mixture of 10 mL of cyclohexanone and 0.7 L of sulfuric acid. The resulting mixture was allowed to stir at 20-22° C for 12h, forming a suspension. 25 mL of heptane were added, and the resulting mixture was allowed to stir at 55-60° c until two separate

liquid layer formed and dissolved the suspension. The upper heptane layer was decanted, and the dark, lower layer was cooled and stored in a refrigerator at 4° C The crude, solid product that formed after approximately lOh was 5 filtered and recrystallized from toluene and then from hexane to give 3.7 g (43%) of 1,2 :5, 6-di-O-cyclohexylidene-D- glucofuranose: mp. = 130-131.5° C (lit. 131-132.5, R.C Hockett et al., J. Am. Chem. Soc, 1949, iχ , 3072) . 1.0 g of 1, 2:5, 6-di-O-cyclohexylidene-D- 0 glucofuranose obtained above was added to a reaction vessel containing a mixture of 2.0 mL of acetic anhydride and 8.0 mL of dimethylsulfoxide preheated at 70° C. The reaction vessel was quickly stoppered and heated at 70° c in a water bath for 75 min. After cooling to room temperature, the reaction 5 mixture was concentrated in vacuo at 70° C/2 torr to give crude ketone as a syrup, which was used in the next step without further purification.

0.85 g of the crude ketone obtained above was dissolved in 6 mL of 96% aqueous ethanol. The resulting 0 solution was cooled to 0° C and treated with 0.07 g of NaBH ₄ in one portion with vigorous magnetic stirring The resulting mixture was allowed to stir at 0° C for 10 min, and at room temperature for lh. The reaction mixture was concentrated in vacuo, diluted with water (3 L) , and

25 extracted with CHC1 ₃ (3 x 15 mL) . The extract was washed with water, dried (Na ₂ S0 ₄ ) and concentrated in vacuo. The resulting solidified syrup was recrystallized from diethyl ether-hexane to afford 0.35 g (35%) of the above-titled compound: mp. = 127-28° C; Η NMR (CDC1 ₃ ) δ 1.40-1.80 (m,

30 10H) , 2.65 (d, IH J = 2.5 Hz, OH), 3.95-4.45 (m, 5H, 6-H ₂ , 5- H, 4-H, 3-H) , 4.55 (d, IH, J = 3Hz, 2-H) , 5.95 (d, IH, J = 3Hz, 1-H) .

Example 35 35 Di-O-isopropylidene-D-allofuranose (DIPAF) . 25 g of D-glucose were added to a mixture of 600 mL of acetone and 24 L of sulfuric acid pre-cooled to 0-5° C. The resulting

suspension was allowed to stir at room temperature for lOh. A stream of gaseous NH ₃ was added at 0-10° C forming (NH ) ₂ S0 ₄ , which was removed by filtration. The filtrate was diluted with 30 mL of 0.1N ammonium hydroxide, and the resulting mixture was concentrated in vacuo. The resulting residue was diluted with water (100 mL) and extracted with CHC1 ₃ (3 x 15 L) . Combined CHC1 ₃ extracts were washed with water, dried (Na ₂ S0 ₄ ) and evaporated, and the resulting residue was dissolved in benzene. The benzene solution was warmed to 65- 70° C and diluted with 45 mL of hot hexane. Crystals deposited upon standing at room temperature. Recrystallization from 1:4 benzene:hexane afforded 1,2:5,6- di-O-isopropylidene-D-glucofuranose: mp. = 109-110° C; [α] _D ²⁰ -18°. 5.0 g of l,2:5,6-di-0-isopropylidene-D- glucofuranose obtained above was added in one portion to a reaction vessel containing a mixture of 10 mL of acetic anhydride and 40 mL of di ethylsulfoxide preheated at 70° C. The reaction vessel was quickly stoppered and heated at 70° C in a water bath for 75 min. After cooling to room temperature, the reaction mixture was concentrated in vacuo at 70° C/2 torr to give crude ketone as an oil, which was used in the next step without further purification. 2 g of the crude ketone obtained above was dissolved in 30 mL of 96% aqueous ethanol. The resulting solution was cooled to 0° C and treated with 0.120 g of NaBH ₄ in one portion. The resulting mixture was allowed to stir at 0° C for 10 min, and then at room temperature for lh. The reaction mixture was concentrated in vacuo. and shaken with a mixture of water (15 mL) and CHC1 ₃ (5 L) . The aqueous layer was separated and extracted with CHC1 ₃ (2 x 5 mL) . Combined organic extracts were washed with water, dried (Na ₂ S0 ₄ ) and concentrated in vacuo to afford a syrup. The syrup was dissolved in 3 mL of benzene, heated to 65-70° C, diluted with 12 mL of hot hexane and left to stand at room temperature overnight. The resulting crystalline precipitate

was recrystallized from 1:4 benzene:hexane to afford 0.9 g (45%) of the above-titled compound: mp. = 77-78° C (lit. 77- 78° C, 0. Theander, Acta Chem, Scand., 1964, 18 _. , 2209) ; Η NMR (CDC1 ₃ ) δ 1.36 (s, 3H) , 1.41 (s, 3H) , 1.47 (ε, 3H) , 1.50 (s, 5 3H) , 2.50 (br. s, IH, OH), 3.60-4.45 (m, 5H, 6-H ₂ , 5-H, 4-H, 3-H) , 4.65 (d, IH, J = 3Hz, 2-H) , 5.83 (d, IH, J = 3Hz, 1-H) .

Example 36 2,3:4,6-Di-0-isopropylidene-L-sorbofuranose (DIPS) .

10 24 L of sulfuric acid were added dropwise, with vigorous stirring, to 100 mL of acetone cooled to 0-5° C, at a rate such that the reaction temperature remained below 20° C. 5 g of L-sorbose were added to the reaction mixture, and stirring was allowed to continue for 4h at room temperature. The

15 reaction mixture was allowed to stand at room temperature overnight, and was cooled to -8° C (ice-NaCl bath) . The cooled reaction mixture was neutralized to pH 8 with saturated NaHC0 ₃ at a rate such that the reaction temperature remained below 0° C. The resulting mixture containing 0 precipitated Na ₂ S0 ₄ was allowed to warm to room temperature and the Na ₂ S0 ₄ was filtered and washed twice with dry acetone. Combined organic filtrate and washings were concentrated in vacuo at 20° C, and the resulting oily residue was extracted with chloroform (5 x 10 L) . The chloroform extract was

²⁵ dried (MgS0 ₄ ) and evaporated to afford a viscous gum which crystallized (mp. = 59-61° C) upon standing. Recrystallization (benzene) of the above crystallized gum afforded 4.8 g (67%) of the above-titled compound as fine crystals: mp. = 76-77° C (lit. 77-78° C (T. Reichstein et

30 al., Helv. Chim. Acta, 1934, 17, 331) ; Η NMR (CDC1 ₃ ) <5 1.35 (ε, 6H) , 1.45 (s, 3H) , 1.52 (s, 3H) , 2.50 (br. s, IH, OH) , 3.75-3.90 (m, 2H, 6-H ₂ ) , 4.05-4.15 (m, 3H) , 4.33 (d, IH, 3H) , 4.5 (d, IH, J - IH, 1-H) .

35

Example 37 (-)-8-Methoxy-trans-p-menth-3-ol (MTM) . A mixture of 1.54 g of (-) -isopulegol (Fluka Chemical Corporation, Ronkonkoma, New York) , 1.13 g of acetic anhydride and 3 mL of pyridine were allowed to stir at room temperature for 12h. The resulting mixture was concentrated at 60° C/20 torr, and the resulting residue was dissolved in diethyl ether. The ether solution was washed with dilute HCl, aqueous NaHC0 ₃ , and water, and then dried (MgS0 ₄ ) and concentrated to provide (-)- isopulegol acetate as a colorless oil: IR (y/cπT ¹ , CC1 ₄ ) 3040, 1740, 1665, 9052.

A solution of 1.78 g of (-) -isopulegol acetate obtained above in 30 mL of MeOH was cooled to 0° C, and to it was added 3.2 g of Hg(0Ac) ₂ . After 3h, 15 L of 3M NaOH were added, followed by 15 mL of 0.5M NaBH ₄ in 3M NaOH. The resulting mixture was concentrated at 40° C/20 torr. The resulting residue was dissolved in diethyl ether, washed with water, dried (MgS0 ₄ ) and concentrated to provide a crude product, which was chromatographed on silica gel using hexane and 4:1 hexane:diethyl ether to provide 1.34 g (72%) of the above-titled compound: R _f 1:9 EtOAc:heptane = 0:18; IR (y/cirϊ ¹ , CC1 ₄ ) 3600-3200, 3040-2760, 1450, 1385, 1370, 1150, 1052; Η NMR (300 MHz, CDCl ₃ ) δ 0.9 (d, 3H, 5-Me) , 0.93 (m, 3H) , 1.16 and 1.20 (s, 6H, CMe ₂ ) , 1.43 (m, 2H) , 1.63 (m, 2H) , 1.96 (dm, IH, 2-H) , 3.24 (s, 3H, OMe), 3.62 (ddd, IH, 1-H) , 5.15 (br. s, IH, OH); ¹³ C NMR (75.5 MHz, CDC1 ₃ ) δ 19.65, 21.83 and 23.36 (CH ₃ ) , 26.46 (CH ₂ ) , 30.77 (CH) , 34.49 (CH ₂ ) , 43.72 (CH ₂ ) , 48.27 (OCH ₃ ) , 50.05 (CH) , 71.77 (CH) , 80.40 (C) .

Example 38 l,2:3,5-Di-0-benzylidene-D-glucofuranose (DBGLU) .

A mixture of powdered 10 g of D-glucose, 20 g of anhydrous, freshly fused ZnCl ₂ , 60 mL of benzaldehyde and 7.7 mL of glacial acetic acid was shaken at room temperature for 17h. The resulting light straw-colored solution was poured into 200 mL of ice water, extracted with ether (3 x 100 mL) ,

washed with aqueous NaHC0 ₃ , dried (Na ₂ S0 ₄ ) , treated with 1 g of decolorizing carbon, and filtered. The filtrate was concentrated (70° C/l mm) and purified using silica gel chromatography (benzene, then 4:1 benzene:ether) to afford a pure product (R _f = 0.3 (4:1 benzene:ether) ) which was recrystallized from 2:1 benzene:ethyl acetate to afford 1.38 g (7%) of the above-titled compound: mp. = 160-61° C; [α] _D ^2ϋ 40° (c 1.0, CHC1 ₃ ; identical with literature values, J. Am. Chem. Soc. 1957, 79., 3862); Η NMR spectrum identical with that described in Carbohydrate Research, 1968, 8 , 125.

Example 39 L-(-)-2,4:3,5-Di-0-methylidene-D-xylitol (L-DMX) .

Xylitol (Fluka Chemical Corporation, Ronkonkoma, New York) was converted to DL-2,4 :3 , 5-di-0-methylidenexylitol according to the procedure of R.M. Hann et al., J. Am. Chem. Soc, 1944, 66 _/ 670 in 65% yield: mp. = 201-202° C (5:1 Et0H:H ₂ O; lit. 201-202° C (R.M. Hann et al., J. Am. Chem. Soc, 1944, 66. 670)) ; Η NMR (CDCl ₃ ) δ 1.36 (br. s, IH, OH), 3.55-3.95 (7H, 1-H ₂ , 5-H ₂ , 2-H, 3-H, 4-H) , 4.75 (ddd, 2H, AB-syste , OCH ₂ 0) , 5.20 (ddd, 2H, AB-system, 0CH,0) .

A mixture of 4.4 g of the DL-2 , 4 : 3 , 5-di-O- methylidenexylitol obtained above, 3.06 g of acetic anhydride and 5 mL of pyridine were allowed to mechanically stir at 20- 22° C for 3h, whereupon crystalline acetate product began to precipitate. Stirring continued for an additional 3h, whereupon the resulting crystals were filtered, washed with water, and recrystallized from methanol. Aqueous washings were combined with the original mother liquor, concentrated in vacuo and recrystallized from methanol to provide DL-l-O- acetyl-2,4 : 3 ,5-di-O-methylidenexylitol in a combined yield of 81.5%: mp. = 154-55° C (lit. 156-57° C (R.M. Hann et al., J. Am. Chem. Soc, 1944, 66, 670)); Η NMR (CDC1 ₃ ) <5 2.10 (s, 3H) , 3.6 (d) and 3.85 (dd, 2H, AB-system, J _AB = 15 Hz, J = 2Hz, 5-H ₂ ) overlapped with 3.90 (m, IH, J = 2Hz, 4-H) , 4.15- 4.45 ( , 4H, 2-H, 3-H, 1-H ₂ ) , 4.75 (d, 2H, AB-pattern,

-0CH ₂ 0-) , 5.15 and 5.25 (d, 2H, AB-pattern, -OCH ₂ 0-) .

To a magnetically stirred suspension of porcine pancreatic lipase (specific activity = 47.8 U/mg; Olainfarm, Latvia) in 6 mL of 0.1M phosphate buffer, was added 0.327 g of DL-l-O-acetyl-2,4 : 3, 5-di-O-methylidenexylitol obtained above. The resulting mixture was allowed to stir at 20-22° C for 24h in a stoppered flask and under an atmosphere of argon. The reaction mixture was diluted with water (4 mL) , and extracted with chloroform (10 mL) . The aqueous layer containing the above-titled compound was set aside, and the chloroform layer containing D-(+) -O-acetyl-2 , 4 :3 , 5-di-O- ethylidenexylitol was concentrated. The residue from the concentration of the chloroform layer was recrystallized from MeOH to provide D-(+) -0-acetyl-2 ,4 : 3 , 5-di-O- methylidenexylitol in 95% yield: mp. = 154-55° C; [c.] _D ²⁰ +2.5° (c = 0.5, CHC1 ₃ ) .

The above-mentioned aqueous layer was filtered through a pad of Celite, concentrated in vacuo (45° C) , diluted with MeOH (10 mL) and filtered. The resulting filtrate was diluted with 2 mL of diethyl ether to afford 123 mg (93%) of the above-titled compound as white; silky crystals: mp. = 214-17° C; [α] _D ²⁰ -25.7° (c = 0.54, water) (lit. 217-19° C; [α] _D ²⁰ -25.3° (water) (R.M. Hann et al., J. Am. Chem. Soc, 1944, 6€>, 670)); Η NMR indistinguishable from that obtained for DL-2,4: 3,5-di-O-methylidenexylitol, above.

Example 40 D-(+)-2,4:3,5-Di-0-methylidene-D-xylitol (D-DMX) .

To a stirred solution of 0.084 g of KOH in 10 mL of 1:1 Me0H:H ₂ 0 were added, in one portion, 0.218 g of D-(+)-0- acetyl-2,4:3 ,5-di-0-methylidenexylitol obtained according to the procedure of Example 39, above. The resulting mixture was allowed to stir at 22-23° C for 2.5h, whereupon the mixture was concentrated in vacuo to approximately half its volume, and extracted with CHC1 ₃ (3 mL) . The resulting aqueous phase was evaporated, and the resulted solid residue

was treated with 10 mL of dry methanol, filtered and concentrated. This step was repeated several times to provide a clear solution from which crystals of the above- titled compound were obtained upon the gradual addition of Et ₂ 0. Recrystallization from EtOH afforded 0.114 g (65%) of the above-titled compound: mp. = 213-16° c; ["I _D ²⁰ +23.0° (c = 0.25, water) . Additional recrystallization from EtOH provided a substantially pure specimen: [ ] ²⁰ +25.2° (c = 0.30, water; lit. (L-enantiomer) [α] _D ²⁰ -25.3° (water)) .

Example 41 (S)-(-)-α,α-Diphenyl-(l,2,3,4- tetrahydroisoquinolin-3-yl) -methanol (DTM2). A mixture of 1 eq. of (S) -1, 2, 3,4-tetrahydro-3-isoquinolinecarboxylic acid (Aldrich Chemical Co., Milwaukee, Wisconsin) , 5 eq. of trimethylorthoformate, methanol and catalytic HCl were allowed to heat at reflux for 5h. Concentration in vacuo provided methyl (S) -1, 2 , 3 , 4-tetrahydro-3- isoquinolinecarboxylate. (S) -1, 2 , 3,4-tetrahydro-3-isoquinolinecarboxylate obtained by the procedure above was treated with 2 eq. of phenylmagnesium bromide according to the procedure of Example 33, to obtain the above-titled compound.

CHIRAL HYDRIDE COMPLEXES SYNTHESIZED

Materials and Methods Tetrahydrofuran (THF) was dried over NaOH, passed twice through columns of freshly preheated (300° C) neutral alumina, dried over metallic sodium (2 days) and distilled over calcium hydride. Sodium aluminum hydride (Cambrex Co.) was dissolved in THF at reflux under an argon atmosphere for lOh until no H ₂ evolved and decanted into a well stoppered vessel .

Example 42 NaAlH(DIPM) (OMe) . A mixture of a 30 mL solution (THF) of 2.46 g of DIPM obtained above in Example 2, and a solution of 8.48 mmol of sodium aluminum hydride in 30 mL of THF was cooled to 0° C for lh, whereupon 0.34 L of MeOH were added, providing a homogeneous reaction mixture of the above- titled complex after lh.

Example 43 NaAlH(Ligand 3). A mixture of 0.259 g of Ligand 3 obtained above from Example 9 and 0.054 g of sodium aluminum hydride in 5 mL of toluene was heated gradually to 100° C and stirred at that temperature until hydrogen evolution ceased (approx. 2h) . The resulting pale yellow solution of the above-titled complex was filtered off and titrated with MeOH, providing 21.5 cm ³ of hydrogen.

Example 44 NaAlH( (S) -PROP) . A mixture of 0.259 g of ((S)- PROP) obtained above from Example 9 and 0.108 g of sodium aluminum hydride in 5 mL of toluene was heated- gradually to 100° C and stirred at that temperature until hydrogen evolution ceased (approx. 2h) . The resulting pale yellow solution of the above-titled complex was filtered off and titrated with MeOH, providing 20 cm ³ of hydrogen.

Example 45 NaAlH[ (S) -BINOL] (OMe) . A mixture of 0.239 g of sodium aluminum hydride and 0.17 mL of MeOH in 10 mL of THF was allowed to stir at room temperature for 20 min. A 12 L solution (THF) of 1.21 g of (S)-Binol obtained from Example 8 was added, and the resulting mixture was allowed to stir at room temperature for over 40 min affording a THF solution of the above-titled complex.

Example 46 NaAlH ₂ (DES). A mixture of 0.9 g of DES obtained from Example 3 in 150 mL of THF and 3.9 mmol of sodium aluminum hydride in 15 L of THF were allowed to stir at 0° C for 20 minutes to afford a THF solution of the above-titled complex.

Example 47 NaAlH(DES) (OMe) . A solution of 0.083 g of MeOH in 20 mL of THF was added to 2.6 mmol of sodium aluminum hydride in 10 mL of THF at 0° C for lh. A solution of 0.6 g of DES obtained from Example 3 in 100 mL of THF was added to the above solution over lh, and the resulting solution was allowed to stir at 0° C for 20 min. , affording a THF solution of the above-titled complex.

Example 48 NaAlH ₂ (BCG). A mixture of 0.23 g of sodium aluminum hydride in 15 mL of THF and 1.49 g of BCG obtained from Example 12 in 20 mL of THF were allowed to stir at 0° C for 30 min. to afford a THF solution of the above-titled complex.

Example 49 NaAlH(BCG) (OMe) . A mixture of 0.088 g of MeOH in 7 mL of THF and 0.148 g of sodium aluminum hydride in 9.7 mL of THF was allowed to stir at 0° C for 5 min. To the resulting solution was added 0.96 g of BCG obtained from Example 12 in 27 L of THF. The resulting solution was allowed to stir at 0° C for 20 min. to afford a THF solution of the above-titled complex.

Example 50 NaAlH ₂ (DCG) ₂ . To 0.153 g of sodium aluminum hydride in 10 L of THF was added 1.93 g of DCG obtained from Example 10 in 20 L of THF. The resulting solution was allowed to stir at 0° C for 25 min. to afford a THF solution of the above-titled complex.

Example 51 NaAlH(DCG) ₂ (OMe) . To 0.229 g of sodium aluminum hydride in 15 mL of THF was added 0.108 g of MeOH in 17 L of THF. The resulting solution was allowed to stir at 0° C for 5 min. To the resulting solution was added 2.89 g of DCG obtained from Example 10 in 30 mL of THF. The resulting solution was allowed to stir at 0° C for 15 min. to afford a THF solution of the above-titled complex.

Example 52

NaAlH(DCG) ₃ . To 0.153 g of sodium aluminum hydride in 10 L of THF was added 2.89 g of DCG obtained according to the procedure of Example 10 in 40 mL of THF. The resulting solution was allowed to stir at 0° C for 40 min. to afford a THF solution of the above-titled complex.

Example 53 NaAlH(Eph) (OMe) . To 0.420 g of sodium aluminum hydride in 27.5 L of THF was added 0.256 g of MeOH in 5 mL of THF. The resulting solution was allowed to stir at 0° C for 5 min. To the resulting solution was added 1.32 g of (lR,2S)-(-)-ephedrine ("Eph") (Aldrich Chemical Co., Milwaukee, Wisconsin) in 25 mL of THF. The resulting solution was allowed to stir at 0° C for 10 min. to afford a THF solution of the above-titled complex.

Example 54 NaAlH ₂ (DBM) ₂ . To 0.32 mmol of sodium aluminum hydride in 1 mL of THF was added 0.115 g of DBM obtained from the procedure of Example 14 in 1.8 mL of THF. The resulting solution was allowed to stir at 25° C for 20 min. to afford a THF solution of the above-titled complex.

Example 55 NaAlH ₂ [ (S)-BINOL] . A mixture of 1.57 g of sodium aluminum hydride and a 5 L solution (THF) of 0.582 g of (S)- binol obtained from Example 8 was added, and the resulting

mixture was allowed to stir at 21° C for 15 min affording a THF solution of the above-titled complex.

Example 56 NaAlH[ (S) -BINOL] (OEt) . A mixture of 1.57 g of sodium aluminum hydride and 1.42 g of EtOH in 10 mL of THF was allowed to stir at room temperature for 20 min. A 5 L solution (THF) of 0.582 g of (S)-Binol obtained from Example 8 was added, and the resulting mixture was allowed to stir at 21° C for 15 min affording a THF solution of the above-titled complex.

Example 57 NaAlH(DIPM) (2-NfOH) . A mixture of 0.153 g of sodium aluminum hydride in 10 mL of THF and 0.74 g of DIPM obtained above in Example 2 in 20 mL of THF was allowed to stir at 0° C for 15 min. A 20 mL solution (THF) of 0.41 g of 2-naphthol (2-NfOH) was added, and the resulting mixture was allowed to stir at 0° C for 15 min affording a THF solution of the above-titled complex.

Example 58 NaAlH(DCG) (2-NfOH) ₂ . A mixture of 0.136 g of sodium aluminum hydride in 9 L of THF and 0.86 g of DCG obtained according to the procedure of Example 10 in 20 mL of THF was allowed to stir at 0° C for 15 min. A 20 L solution (THF) of 0.73 g of 2-naphthol (2-NfOH) was added, and the resulting mixture was allowed to stir at 0° C for 15 min affording a THF solution of the above-titled complex.

Example 59 NaAlH(AG). A mixture of 0.153 g of sodium aluminum hydride in 10 mL of THF and 0.458 g of 1, 6-anhydro-/3-D- glucose ("AG") (Aldrich Chemical Co., Milwaukee, Wisconsin) in 30 mL of THF was allowed to stir at 0° C for 15 min. affording a THF solution of the above-titled complex.

Example 60 NaAlH[ (S,S)-BPAP] . A mixture of 0.142 g of sodium aluminum hydride and 0.86 g of (S,S)-BPAP obtained according to the procedure of Example 15 in 5 mL of THF was allowed to stir at room temperature for 15 min. affording a THF solution of the above-titled complex.

Example 61 NaAlH(DBM) (iso-Bu) . To 0.140 g of sodium aluminum hydride in 10 mL of THF was added 0.93 g of DBM obtained from the procedure of Example 14 in 50 mL of THF. To the resulting solution was added 0.19 g of isobutyl alcohol (iso- Bu) in 20 mL of THF. The resulting solution was allowed to stir at 24° C for 20 minutes to afford a THF solution of the above-titled complex.

Example 62 NaAlH(DIPM) [ (S) -IBPA] . A mixture of 0.066 g of sodium aluminum hydride in 5 L of THF and 0.32 g of DIPM obtained above in Example 2 in 10 mL of THF was allowed to stir at 0° C for 15 min. A 10 mL solution (THF) of 0.216 g of (S)-IBPA obtained according to the procedure of Example 20 was added, and the resulting mixture was allowed to stir at 0° C for 15 min affording a THF solution of the above-titled complex.

Example 63 NaAlH(DIPM) [ (R)-IBPA] . A mixture of 0.066 g of sodium aluminum hydride in 5 mL of THF and 0.32 g of DIPM obtained above in Example 2 in 10 mL of THF was allowed to stir at 0° C for 15 min. A 10 mL solution (THF) of 0.216 g of (S)-IBPA obtained according to the procedure of Example 21 was added, and the resulting mixture was allowed to stir at 0° C for 15 min affording a THF solution of the above-titled complex.

Example 64 NaAlH ₂ (BDG) ₂ . A mixture of 0.140 g of sodium aluminum hydride in 10 L of THF and 1.68 g of BDG obtained above in Example 13 in 100 mL of THF was allowed to stir at 20° C for 20 minutes affording a THF solution of the above- titled complex.

Example 65 NaAlH[ (S,S) -BMBE] (OMe) . A mixture of 0.0716 g of sodium aluminum hydride in 5 mL of THF and 0.356 g of (S,S)- BMBE obtained according to the procedure of Example 22 in 10 L of THF was allowed to stir at 20° C for lh. A 5 mL solution (THF) of 0.0424 g of MeOH was added, and the resulting mixture was allowed to stir at room temperature for 20 min. affording a THF solution of the above-titled complex.

Example 66 NaAlH ₂ (DIPM) . A mixture of 0.0716 g of sodium aluminum hydride in 5 mL of THF and 0.35 g of DIPM obtained according to the procedure of Example 2 in 15 mL of THF was allowed to stir at 0° C for 10 min. affording a THF solution of the above-titled complex.

Example 67 NaAlH ₂ [ (S)-IBPA] ₂ . A mixture of 0.0716 g of sodium aluminum hydride in 5 mL of THF and 0.705 g of (S)-IBPA obtained according to the procedure of Example 20 in 15 mL of THF was allowed to stir at 30° C for 85 min. affording a THF solution of the above-titled complex.

Example 68 [NaAlH(OEt) ( (S) -PEA) ] _n . 6.53 mL of a 0.306 M solution of NaAlH ₃ (0Et) in THF was added dropwise to 2 mL of a 1 M solution (THF) of (S)-α-phenylethylamine ("(S)-PEA") (Zeeland Chemicals, Zeeland, Michigan) at 20° C and was allowed to stir for lh affording a THF solution of the above- titled complex.

Example 69 Na ₂ {[AlH ₂ (OEt) ] ₂ [(S)-PEA]}. 6.53 mL of a 0.306 M solution of NaAlH ₃ (0Et) in THF was added dropwise to 1 mL of a 1 M solution (THF) of (S) -α-phenylethylamine (" (S)-PEA") (Zeeland Chemicals, Zeeland, Michigan) at 20° C and was allowed to stir for lh affording a THF solution of the above- titled complex.

Example 70 Na ₂ {[AlH ₃ ] ₂ [ (S)-PEA]}. 1 mL of a 1 M solution of

(S) -α-phenylethylamine (" (S)-PEA") (Zeeland Chemicals, Zeeland, Michigan) in THF was added dropwise to 0.112 g of sodium aluminum hydride at 20° C and was allowed to stir for lh affording a THF solution of the above-titled complex.

Example 71 [NaAlH ₂ ( (S)-PEA)] _n . 2 mL of a 1 M solution of (S)- α-phenylethylamine ("(S)-PEA") (Zeeland Chemicals, Zeeland, Michigan) in THF were added dropwise to 0.112 g of sodium aluminum hydride at 20° C and was allowed to stir for lh affording a THF solution of the above-titled complex.

Example 72 (S)-PEA{Na[AlH((S)-PEA)] _n } ₂ . 3 mL of a 1 M solution of (S)-α-phenylethylamine (" (S)-PEA") (Zeeland Chemicals, Zeeland, Michigan) in THF were added dropwise to 0.112 g of sodium aluminum hydride at 20° C. The resulting solution was allowed to stir for lh affording a THF solution of the above- titled complex.

Example 73 NaAlH ₂ [ (S)-PROP]. 4.1 mL of an 0.54 M solution of (S)-PROP obtained from the procedure of Example 9 in THF were added dropwise to 0.112 g of sodium aluminum hydride at 20° c. The resulting solution was allowed to stir for lh affording a THF solution of the above-titled complex.

Example 74 NaAlH(OEt) [ <S) -PROP] . 6.53 mL of a 0.306 M solution of NaAlH ₃ (0Et) in THF was added dropwise to 4 mL of an 0.5 M solution (THF) of (S)-PROP obtained from the procedure of Example 9 at 20° C. The resulting solution was allowed to stir for lh affording a THF solution of the above- titled complex.

Example 75 NaAlH ₂ (IXF). A 5 L solution (THF) of 0.252 g of

IXF obtained from the procedure of Example 24 was added dropwise to 0.0716 g of sodium aluminum hydride in 5 mL of THF at 0° C. The resulting solution was allowed to stir at that temperature for 15 min. affording a THF solution of the above-titled complex.

Example 76 NaAlH(IXF) (OMe) . A 5 L solution (THF) of 0.0424 g of MeOH was added dropwise to 0.0716 g of sodium aluminum hydride in 5 mL of THF at 0° C. The resulting solution was allowed to stir at that temperature for 15 min.. To the resulting solution was added 0.252 g of IXF obtained from the procedure of Example 24 in 12 mL of THF. The resulting solution was allowed to stir at that temperature for 15 min. affording a THF solution of the above-titled complex.

Example 77 NaAlH ₂ ((+)-DDM) . A 15 L solution (THF) of 0.618 g of (+)-DDM (Aldrich Chemical Co., Milwaukee, Wisconsin) was added dropwise to 0.0716 g of sodium aluminum hydride in 5 mL of THF at 20° C. The resulting solution was allowed to stir at that temperature for 20 min. affording a THF solution of the above-titled complex.

Example 78 NaAlH(BAP). 0.25 mmol of sodium aluminum hydride and 0.25 mmol of BAP obtained from the procedure of Example 25 were mixed in the presence of 5 mL of THF and were allowed to stir at least 10 min. affording a THF solution of the above-titled complex.

Example 79 NaAlH ₂ (DPP). To a 4.85 mL solution (THF) of 1.25 mmol of sodium aluminum hydride was added a 4 L solution

(THF) of 1.02 g of (S)-(-)-α,α-diphenyl-2-pyrrolidinemethanol ("DPP") (Aldrich Chemical Co., Milwaukee, Wisconsin) . The resulting solution was allowed to stir at room temperature for 5 min. affording a THF solution of the above-titled complex.

Example 80 NaAlH(DPP) (OMe) . 0.25 mmol of sodium aluminum hydride and 0.25 mmol of (S) -(-) -α,α-diphenyl-2- pyrrolidinemethanol ("DPP") (Aldrich Chemical Co., Milwaukee, Wisconsin) were mixed in the presence of THF and were allowed to stir at least 10 min. To the resulting solution was added 0.25 mmol of MeOH in THF affording a THF solution of the above-titled complex.

Example 81 NaAlH(DPP) (OEt) . 0.25 mmol of sodium aluminum hydride and 0.25 mmol of (S)-(-)-α,α-diphenyl-2- pyrrolidine ethanol ("DPP") (Aldrich Chemical Co., Milwaukee, Wisconsin) were mixed in the presence of THF and were allowed to stir at least 10 min. To the resulting solution was added 0.25 mmol of EtOH in THF affording a THF solution of the above-titled complex.

Example 82 NaAlH(DPP) (OPh) . A 1 mL solution of 1M phenol in THF was added dropwise to an 0.258M solution of sodium aluminum hydride in 3.88 mL of THF. The reaction mixture was diluted with 11 mL of THF and was allowed to stir at room temperature. To the resulting solution was added an 0.25M solution of (S)-(-)-α,α-diphenyl-2-pyrrolidinemethanol ("DPP") (Aldrich Chemical Co., Milwaukee, Wisconsin) in 4 mL of THF. The resulting solution was diluted with 11 mL of THF and was agitated for lh affording a THF solution of the above-titled complex.

Example 83 NaAlH(IXF) (OPh) . A 5 mL solution (THF) of 0.125 g of phenol was added dropwise to 0.0716 g of sodium aluminum hydride in 5 mL of THF at 20° C. The resulting solution was allowed to stir at that temperature for 5 min. To the resulting solution was added 0.252 g of IXF obtained from the procedure of Example 24 in 10 L of THF. The resulting solution was allowed to stir at that temperature for 10 min. affording a THF solution of the above-titled complex.

Example 84 NaAlH(IXF) (OPh-p-tert-Bu) . A 5 mL solution (THF) of 0.199 g of p-tertbutylphenol (p-tert-BuPhOH) was added dropwise to 0.0716 g of sodium aluminum hydride in 5 L of THF at 20° C. The resulting solution was allowed to stir at that temperature for 5 min. To the resulting solution was added 0.252 g of IXF obtained from the procedure of Example 24 in 10 L of THF. The resulting solution was allowed to stir at that temperature for 10 min. affording a THF solution of the above-titled complex.

Example 85 NaAlH(OPh) [ (S) -PROP] . To 5.85 mL of a 0.258 M solution (THF) of sodium aluminum hydride was added, dropwise, 1.5 L of a 1M solution (THF) of phenol, followed

by 3 mL of an 0.5M solution (THF) of (S)-PROP obtained from the procedure of Example 9 at 20° C. The resulting solution was diluted with 1.5 mL of THF and allowed to stir at room temperature for 10 min. affording a THF solution of the above-titled complex.

Example 86 NaAlH ₂ (CXF). To a 5 L solution (THF) of 0.0716 g of sodium aluminum hydride was added a 15 mL solution (THF) of 0.305 g of 1,2-O-cyclohexylidene-α-D-xylofuranose (CXF) obtained according to the procedure of Example 26. The resulting solution was allowed to stir at room temperature for 15 min. affording a THF solution of the above-titled complex.

Example 87 NaAlH(CXF) (OMe) . A 5 mL solution (THF) of 1.325 mmol of MeOH was added dropwise to 0.0716 g of sodium aluminum hydride in 5 L of THF at 20° C. The resulting solution was allowed to stir at that temperature for 5 min. To the resulting solution was added 0.305 g of CXF obtained from the procedure of Example 26 in 10 mL of THF. The resulting solution was allowed to stir at that temperature for 10 min. affording a THF solution of the above-titled complex.

Example 88 NaAlH(CXF) (O-1-Me-CyBu) . A 5 mL solution (THF) of 1.325 mmol of 1-methylcyclobutan-l-ol, obtained from the addition of 1 eq. of methyl magnesium bromide to 1 eq. of cyclobutanone, was added dropwise to 0.0716 g of sodium aluminum hydride in 5 mL of THF at 20° C. The resulting solution was allowed to stir at that temperature for 5 min. To the resulting solution was added 0.305 g of CXF obtained from the procedure of Example 26 in 10 L of THF. The resulting solution was allowed to stir at that temperature

for 10 min. affording a THF solution of the above-titled complex.

Example 89 NaAlH(CXF) (OPh) . A 5 mL solution (THF) of

1.325mmol of phenol was added dropwise to 0.0716 g of sodium aluminum hydride in 5 L of THF at 20° c. The resulting solution was allowed to stir at that temperature for 5 min. To the resulting solution was added 0.305 g of CXF obtained from the procedure of Example 26 in 10 mL of THF. The resulting solution was allowed to stir at that temperature for 10 min. affording a THF solution of the above-titled complex.

Example 90

NaAlH(CXF) (OPh-p-tert-Bu) . A 5 mL solution (THF) of 1.325mmol of p-tertbutylphenol (p-tert-BuPhOH) was added dropwise to 0.0716 g of sodium aluminum hydride in 5 mL of THF at 20° C. The resulting solution was allowed to stir at that temperature for 5 min. To the resulting solution was added 0.305 g of CXF obtained from the procedure of Example 26 in 10 L of THF. The resulting solution was allowed to stir at that temperature for 10 min. affording a THF solution of the above-titled complex.

Example 91 NaAlH(CXF) (2-NfOH) . A 5 mL solution (THF) of 1.325mmol of 2-naphthol (2-NfOH) was added dropwise to 0.0716 g of sodium aluminum hydride in 5 mL of THF at 20° C. The resulting solution was allowed to stir at that temperature for 5 min. To the resulting solution was added 0.305 g of CXF obtained from the procedure of Example 26 in 10 mL of THF. The resulting solution was allowed to stir at that temperature for 10 min. affording a THF solution of the above-titled complex.

Example 92 NaAlH(S-PA). A 15 mL solution (THF) of 0.20 g of S-phenylalininol (S-PA) obtained according to the procedure of Example 27 was added dropwise to 0.0716 g of sodium aluminum hydride in 5 mL of THF at 20° C. The resulting solution was allowed to stir at that temperature for 15 min. affording a THF solution of the above-titled complex.

Example 93 NaAlH ₃ (S-DMPA) . A 1 mL solution (THF) of 1M

(S)-DMPA obtained according to the procedure of Example 28 was added dropwise to 3.88 L of an 0.258M solution (THF) of sodium aluminum hydride at room temperature. The resulting solution was allowed to stir at that temperature for 10 min. affording a THF solution of the above-titled complex.

Example 94 NaAlH ₂ (S-DMPA) ₂ . An 0.5 mL solution (THF) of 1M (S)-DMPA obtained according to the procedure of Example 28 was added dropwise to 2.44 mL of a THF solution of NaAlH ₃ (S- DMPA) obtained according to the procedure of Example 84 at room temperature. The resulting solution was allowed to stir at that temperature for 10 min. affording a THF solution of the above-titled complex.

Example 95 NaAlH ₂ [(+)-PDOL]. To a 7 L solution (THF) of 0.2 g of (lS,2S,3R,5R)-(+)-pinanediol ("(+)-PD0L") (Aldrich Chemical Co., Milwaukee, Wisconsin) was added dropwise a 5 L solution (THF) of 0.0716 g of sodium aluminum hydride at 20° C. The resulting solution was allowed to stir at that temperature for 20 min. affording a THF solution of the above-titled complex.

Example 96 NaAlH[ (+)-PDOL] (OMe) . A solution of 0.64 mmol of MeOH and a solution of 0.64 mmol of (+)-PDOL (total 5 mL of THF) were consecutively added dropwise to a solution (THF) of 0.64 mmol of sodium aluminum hydride at 20° c. The resulting solution was allowed to stir at that temperature for 10 min. affording a THF solution of the above-titled complex.

Example 97 NaAlH[(+)-PDOL][N-Me-(S)-PEA]. A solution (THF) of

0.32 mmol of sodium aluminum hydride was added dropwise to 0.32 mmol of N-methyl-(S)-α-phenylethylamine (N-Me-(S)-PEA) (Zeeland Chemicals, Zeeland, Michigan) . The resulting solution was allowed to stir for 10 min. To the resulting solution was added a 2 mL solution (THF) of 0.32 mmol of (+)- PDOL. The resulting solution was allowed to stir for 20 min. affording a THF solution of the above-titled complex.

Example 98 NaAlH[(+)-PDOL][(S)-l-OBu-2-Me]. An 0.5 mL solution (THF) of 0.32 mmol of (S)-(-)-2-methyl-l-butanol (Fluka Chemical Co., Ronkonkoma, New York) [ (S)-l-OBu-2-Me] was added dropwise to a 1 mL solution (THF) of 0.32 mmol of sodium aluminum hydride over 10 min. To the resulting solution was added a 1 mL solution (THF) of 0.32 mmol of (+)- PDOL. The resulting solution was allowed to stir for 30 min. affording a THF solution of the above-titled complex.

Example 99 NaAlH[ (+)-PDOL] (OPh) . An 0.5 mL solution (THF) of

0.32 mmol of phenol was added dropwise to a 1 L solution (THF) of 0.32 mmol of sodium aluminum hydride over 10 min. To the resulting solution was added a 1 mL solution (THF) of 0.32 mmol of (+)-PDOL. The resulting solution was allowed to stir for 30 min. affording a THF solution of the above-titled complex.

Example 100 NaAlH ₂ (BDG) ₂ . A 1 mL solution (THF) of 0.64 mmol of BDG obtained from the procedure of Example 13 was added dropwise to a 1 L solution (THF) of 0.32 mmol of sodium aluminum hydride at 20° C. The resulting solution was allowed to stir for 30 min. affording a THF solution of the above-titled complex.

Example 101 NaAlH(BDG) ₃ . A 1.8 mL solution (THF) of 0.96 mmol of BDG obtained from the procedure of Example 13 was added dropwise to a 1 mL solution (THF) of 0.32 mmol of sodium aluminum hydride at 20° C. The resulting solution was allowed to stir for 30 min. affording a THF solution of the above-titled complex.

Example 102 NaAlH(CXF) (l-NfOH) . A 5 mL solution (THF) of 1.325mmol of 1-naphthol (l-NfOH) was added dropwise to 0.0716 g of sodium aluminum hydride in 5 mL of THF at 20° C. The resulting solution was allowed to stir at that- temperature for 5 min. To the resulting solution was added 0.305 g of CXF obtained from the procedure of Example 26 in 10 L of THF. The resulting solution was allowed to stir at that temperature for 10 min. affording a THF solution of the above-titled complex.

Example 103 NaAlH((+)-DDM) (OMe) . An 8 L solution (THF) of 0.0185 g of methanol and 0.27 g of (+)-DDM was added dropwise to 0.0312 g of sodium aluminum hydride in 2.2 mL of THF at room temperature under argon. The resulting solution was allowed to stir at room temperature for 5 min. affording a THF solution of the above-titled complex.

Example 104 NaAlH( (+)-DDM) (OEt) . A 3 L solution (THF) of 0.663 mmol of ethanol was added dropwise to 0.0358 g of sodium aluminum hydride in 2.5 L of THF at room temperature. To the resulting solution was added a 5 mL solution (THF) of 0.310 g of (+)-DDM. The resulting solution was allowed to stir at room temperature for 5 min. affording a THF solution of the above-titled complex.

Example 105

NaAlH( (+)-DDM) (O-tertBu) . A 3 mL solution (THF) of

0.663 mmol of tert-butanol was added dropwise to 0.0358 g of sodium aluminum hydride in 2.5 L of THF at room temperature.

To the resulting solution was added a 5 mL solution (THF) of 0.310 g of (+)-DDM. The resulting solution was allowed to stir at room temperature for 5 min. affording a THF solution of the above-titled complex.

Example 106 NaAlH( (+)-DDM) (OPh) . A 3 mL solution (THF) of

0.663 mmol of phenol was added dropwise to 0.0358 g of sodium aluminum hydride in 2.5 mL of THF at room temperature. To the resulting solution was added a 5 L solution (THF) of 0.310 g of (+)-DDM. The resulting solution was allowed to stir at room temperature for 5 min. affording a THF solution of the above-titled complex.

Example 107 NaAlH( (+)-DDM) (l-NfOH) . A 3 mL εolution (THF) of 0.663 mmol of 1-naphthol (l-NfOH) was added dropwise to

0.0358 g of sodium aluminum hydride in 2.5 L of THF at room temperature. To the resulting solution was added a 5 mL solution (THF) of 0.310 g of (+)-DDM. The resulting solution was allowed to stir at room temperature for 5 min. affording a THF solution of the above-titled complex.

Example 108 NaAlH[ (S)-DMPA] ₃ . A 1 mL solution (THF) of 0.75 mmol of (S)-DMPA obtained according to the procedure of Example 28 was added dropwise to a 1.4-2 mL solution (THF) of 0.25 mmol of sodium aluminum hydride at room temperature. The resulting solution was allowed to stir at room temperature for 5 min. affording a THF solution of the above- titled complex.

Example 109

NaAlH ₂ [ (S)-DMPA] (OMe) . A 1 L solution (THF) of 0.25 mmol of (S)-DMPA obtained according to the procedure of Example 28 was added dropwise to a 1.4-2 L εolution (THF) of 0.25 mmol of sodium aluminum hydride at room temperature. To the resulting solution was added 0.25 mL of a 1M solution (THF) of methanol. The resulting solution was allowed to stir at room temperature for 5 min. affording a THF solution of the above-titled complex.

Example 110

NaAlH[ (S)-DMPA] (OMe) ₂ . A 1 L solution (THF) of 0.25 mmol of (S)-DMPA obtained according to the procedure of Example 28 was added dropwise to a 1.4-2 L solution (THF) of 0.25 mmol of sodium aluminum hydride at room temperature. To the resulting solution was added 0.5 mL of a 1M solution (THF) of methanol. The resulting solution was allowed to stir at room temperature for 5 min. affording a THF solution of the above-titled complex.

Example 111

NaAlH[ (S)-DMPA] ₂ (OMe) . A 1 mL solution (THF) of 0.5 mmol of (S)-DMPA obtained according to the procedure of Example 28 was added dropwise to a 1.4-2 L solution (THF) of 0.25 mmol of sodium aluminum hydride at room temperature. To the resulting solution was added 0.25 mL of a 1M solution (THF) of methanol. The resulting solution was allowed to

stir at room temperature for 5 min. affording a THF solution of the above-titled complex.

Example 112 NaAlH ₂ [ (S)-DMPA] (O-tertBu) . A 1 mL solution (THF) of 0.25 mmol of (S)-DMPA obtained according to the procedure of Example 28 was added dropwise to a 1.4-2 mL solution (THF) of 0.25 mmol of sodium aluminum hydride at room temperature. To the resulting solution was added 0.25 L of a 1M solution (THF) of tert-butanol. The resulting solution was allowed to stir at room temperature for 5 min. affording a THF solution of the above-titled complex.

Example 113 NaAlH[ (S)-DMPA] (0-tertBu) ₂ . A 1 mL solution (THF) of 0.25 mmol of (S) -DMPA obtained according to the procedure of Example 28 was added dropwise to a 1.4-2 mL solution (THF) of 0.25 mmol of sodium aluminum hydride at room temperature. To the resulting solution was added 0.5 mL of a 1M solution (THF) of tert-butanol. The resulting solution was allowed to stir at room temperature for 5 min. affording a THF solution of the above-titled complex.

Example 114 NaAlH[ (S) -DMPA] ₂ (0-tertBu) . A 1 mL solution (THF) of 0.5 mmol of (S)-DMPA obtained according to the procedure of Example 28 was added dropwise to a 1.4-2 mL solution (THF) of 0.25 mmol of sodium aluminum hydride at room temperature. To the resulting solution was added 0.25 mL of a 1M solution (THF) of tert-butanol. The resulting solution was allowed to stir at room temperature for 5 min. affording a THF εolution of the above-titled complex.

Example 115 NaAlH[ (S) -DMPA] ₂ (0Ar) . A 1 mL solution (THF) of

0.25 mmol of (S)-DMPA obtained according to the procedure of Example 28 was added dropwise to a 1.4-2 L solution (THF) of

0.25 mmol of sodium aluminum hydride at room temperature. To the resulting εolution was added 0.5 mL of a 1M solution (THF) of 8-hydroxyquinoline (HOAr) . The resulting solution was allowed to stir at room temperature for 5 min. affording a THF solution of the above-titled complex.

Example 116 NaAlH ₂ [ (S,S)-BDHP] . A 15 L solution (THF) of 0.293 g of (3S,4S) -l-benzyl-3,4-dihydroxypyrrolidine ((S,S)-BDHP) obtained according to the procedure of Example 29 was added dropwise to a 5 mL solution (THF) of 0.0716 g of sodium aluminum hydride at 20° C. The resulting εolution was allowed to stir at room temperature for 30 min. affording a THF εolution of the above-titled complex.

Example 117 NaAlH[ (S,S) -BDHP] (OMe) . A 15 mL solution (THF) of 0.043 g of methanol was added to a 5 mL solution (THF) of 0.0716 g of sodium aluminum hydride at room temperature. The resulting solution was allowed to stir at room temperature for 15 min. To the resulting solution was added dropwise 0.256 g of (3S,4S) -l-benzyl-3 ,4-dihydroxypyrrolidine ((S,S)- BDHP) obtained according to the procedure of Example 29. The resulting solution was allowed to stir at room temperature affording a THF solution of the above-titled complex.

Example 118 NaAlH(BDG) ₂ (OMe) . 0.01 mL of methanol followed by a 1.8 mL solution (THF) of 0.21 g of BDG obtained from the procedure of Example 13 were added dropwise to a 1 mL solution (THF) of 0.32 mmol of sodium aluminum hydride at 20° C. The resulting solution was allowed to stir for 10 min. and was then heated at 40° C for 10 min. affording a THF solution of the above-titled complex.

Example 119 NaAlH ₂ (TDG) ₂ . A 1.8 mL solution (THF) of 0.3 g of 1-O-triphenylmethyl-3,5:4, 6-di-O-ethylidene-D-glucitol (TDG) obtained according to the procedure of Example 30 was added dropwise to a 1 mL solution (THF) of 0.032 mmol of sodium aluminum hydride at 20° C. The resulting solution was allowed to stir for 20 min. affording a THF solution of the above-titled complex.

Example 120

NaAlH(TDG) ₃ . A 1.8 mL solution (THF) of 0.45 g of l-0-triphenylmethyl-3 ,5:4, 6-di-O-ethylidene-D-glucitol (TDG) obtained according to the procedure of Example 30 was added dropwise to a 1 mL solution (THF) of 0.032 mmol of sodium aluminum hydride at 20° C. The resulting solution was allowed to stir for 10 min. and was then heated at 40° C for .10 min. affording a THF solution of the above-titled complex.

Example 121 Na ₂ Al ₂ H ₂ [ (S) -BINOL] ₃ . A mixture of 1.57 g of sodium aluminum hydride and a 5 mL solution (THF) of '0.873 g of (S)- binol obtained from Example 8 was added, and the resulting mixture was allowed to stir at 21° C for 15 min affording a THF solution of the above-titled complex.

Example 122 NaAlH(TDG) ₃ . A 1.8 mL solution (THF) of 0.45 g of l-O-triphenylmethyl-3 ,5:4, 6-di-O-ethylidene-D-glucitol (TDG) obtained according to the procedure of Example 30 was added dropwise to a 1 mL solution (THF) of 0.032 mmol of sodium aluminum hydride at 20° C. The resulting solution was allowed to stir for 10 min. and was then heated at 40° C for 10 min. affording a THF solution of the above-titled complex.

Example 123 NaAlH ₂ (AMP). A solution (THF) of 1 eq. of (S)-2- (anilinomethyl)pyrrolidine ("AMP") (Aldrich Chemical Co., Milwaukee, Wisconεin) waε added dropwiεe to a εolution (THF) of 1 eq. of sodium aluminum hydride. The resulting solution was allowed to stir at room temperature for 60 min. affording an 0.25M solution (THF) of the above-titled complex.

Example 124 NaAlH(AMP) (OMe) . A solution (THF) of 1 eq. of AMP followed by a solution (THF) of 1 eq. of methanol was added dropwise to a solution (THF) of 1 eq. of sodium aluminum hydride. The resulting solution was allowed to stir at room temperature for 60 min. affording an 0.25M solution (THF) of the above-titled complex.

Example 125 NaAlH(AMP) (OPh) . A solution (THF) of 1 eq. of AMP followed by a solution (THF) of 1 eq. of phenol was added dropwise at -70° C to a solution (THF) of 1 eq. of εodium aluminum hydride. The reεulting εolution waε allowed to εtir at room temperature for 60 min. affording a IM solution (THF) of the above-titled complex.

Example 126

NaAlH(AMP) (NPh ₂ ) . A solution (THF) of 1 eq. of AMP followed by a solution (THF) of 1 eq. of diphenylamine was added dropwise at -70° C to a solution (THF) of 1 eq. of sodium aluminum hydride. The resulting solution was allowed to stir at room temperature for 60 min. affording a IM solution (THF) of the above-titled complex.

Example 127 NaAlH ₂ ( (+)-DDM) . A solution (diglyme) of 0.6 mmol of ((+)-DDM) was added dropwise to a solution (diglyme) of 0.6 mmol of sodium aluminum hydride at 20° C. The resulting solution was allowed to stir at room temperature for 5 min.

affording an 0.07M (diglyme) solution of the above-titled complex.

Example 128 NaAlH((+)-DDM) (OEt-2-OMe) . A solution (diglyme) of

0.6 mmol of (+)-DDM followed by a solution (diglyme) of 0.6 mmol of 2-methoxyethanol was added dropwise to a solution (diglyme) of 0.6 mmol of sodium aluminum hydride at 20° C. The resulting solution was allowed to stir at room temperature for 5 min. affording an 0.07M (diglyme) solution of the above-titled complex.

Example 129 NaAlH((+)-DDM) (OEt-2-OMe) . A solution (3:1 diglyme:THF) of 0.6 mmol of (+)-DDM followed by a solution (3:1 diglyme:THF) of 0.6 mmol of 2-methoxyethanol was added dropwise to a solution (3:1 diglyme:THF) of 0.6 mmol of sodium aluminum hydride at 20° C. The resulting solution was allowed to stir at room temperature for 5 min. affording an 0.07M solution (3:1 diglyme:THF) of the above-titled complex.

Example 130 NaAlH ₂ (DTM2) . A solution (THF) of 1 eq. of (S) -(-) -α,α-diphenyl-(l,2,3,4-tetrahydroisoquinolin-3-yl) - methanol ("DTM2") obtained according to the procedure of

Example 41 was added dropwise to a solution (THF) of 1 eq. of sodium aluminum hydride at 25° C. The resulting solution was allowed to stir at room temperature for 45 min. affording a THF solution of the above-titled complex.

Example 131 Na ₂ Al ₂ H ₂ (DTM2) ₃ . A solution (THF) of 1.5 eq. of (S)- ,α-diphenyl-(1, 2 , 3 ,4-tetrahydroisoquinolin-3-yl) -methanol ("DTM2") obtained according to the procedure of Example 41 was added dropwise to a solution (THF) of 1 eq. of sodium aluminum hydride at 20° C. The resulting solution was

allowed to stir at room temperature for 20 min. affording a THF solution of the above-titled complex.

Example 132 NaAlH (/?-DND) . A solution (THF) of 0.3 mmol of

(4R,5R) -2,2-dimethyl-α,α,α' ,α' ,-tetra-(2-naphthyl) -dioxolane- 4,5-dimethanol ("j8-DND") (Aldrich Chemical Co., Milwaukee, Wisconsin) was added dropwise to a solution (THF) of 0.3 mmol of sodium aluminum hydride at 25° C. The resulting solution was allowed to εtir at room temperature for 60 min. affording a THF solution of the above-titled complex.

Example 133 NaAlH ₂ (j3-DND) . A solution (diglyme) of 0.2 mmol of β-DND waε added dropwise to a solution (diglyme) of 0.2 mmol of sodium aluminum hydride at 17° C. The resulting solution waε allowed to stir at room temperature for 60 min. affording a diglyme solution of the above-titled complex.

Example 134

Na ₂ Al ₂ H ₂ (/3-DND) ₃ . A solution (THF) of'0-DND was added dropwise to a solution (THF) of 0.6 mmol of sodium aluminum hydride at 17° C. The resulting solution was allowed to stir at room temperature for 7 min. affording a THF solution of the above-titled complex.

Example 135 NaAlH ₂ (CXF). A solution (diglyme) of 0.6 mmol of CXF obtained according to the procedure of Example 26 was added dropwise to a solution (THF) of 0.6 mmol of sodium aluminum hydride at 17° C. The reεulting solution was allowed to stir at room temperature for 10 min. affording a THF solution of the above-titled complex.

Example 136 NaAlH ₂ (CYTOL) . A solution (diglyme) of 2.6 mmol of CYTOL obtained according to the procedure of Example 33 was added dropwise to an 0.3-0.4M solution (diglyme) of 2.6 mmol of sodium aluminum hydride at 17° C. The resulting solution was allowed to stir at room temperature for 25 min. affording a THF solution of the above-titled complex.

CHIRAL HYDRIDE COMPLEXES COMPRISING A SOLID PHASE SUPPORT Example 137

2,3-o- (Cyclohexylidene-4-carboxylic acid) -1,1,4,4- tetra-phenyl-L-threitol. Ethyl 4-oxocyclohexanecarboxylate (Aldrich Chemical Co., Milwaukee, Wisconsin) is reduced with excess lithium aluminum hydride in tetrahydrofuran to provide 4-(hydroxymethyl)cylohexan-l-ol.

The 4-(hydroxymethyl)cylohexan-l-ol obtained above iε treated with 1 eq. of acetic anhydride and 2 eq. of pyridine to provide 4-acetoxymethylcylohexan-l-ol.

The 4-(acetoxymethyl)cylohexan-l-ol obtained above is oxidized with 3.0 equivalents of pyridinium dichromate in refluxing methylene chloride to afford 4- (acetoxymethyl)cyclohexan-l-one.

A mixture of 4-(acetoxymethyl) cyclohexan-1-one obtained above, dimethyl L-tartrate and p-TsOH are heated together according to the method described in Example 33 to afford dimethyl-2, 3-0-(4-acetoxy)methylcyclohexylidene-L- tartrate.

The dimethyl-2,3-0-(4- acetoxy)methylcyclohexylidene-L-tartrate obtained above is diluted in methanol and treated with excess potassium carbonate to afford, following filtration of the excess potassium carbonate and concentration of the filtrate, dimethyl-2, 3-0-(4-hydroxy)methylcyclohexylidene-L-tartrate. The dimethyl-2,3-0-(4- hydroxy)methylcyclohexylidene-L-tartrate obtained above is treated with 5.5 eq. of phenyl magnesium bromide according to the procedure of Example 33 to obtain 2, 3-0- (4-

hydroxy)methylcyclohexylidene-1,1,4 , 4-tetra-phenyl-L- threitol.

The 2,3-θ-(4-hydroxy)methylcyclohexylidene-l, 1,4,4- tetra-phenyl-L-threitol obtained above is oxidized with 3.0 equivalents of pyridinium dichromate in refluxing methylene chloride to afford the above-titled compound.

Example 138 2,3-0-(Cyclohexylidene-4-carboxylic acid) -1, 1,4,4- tetra-phenyl-L-threitol-Grafted Polyacrylamide. A mixture of polyacrylamide and 2 , 3-0-(cyclohexylidene-4-carboxylic acid) - 1,1,4,4-tetra-phenyl-L-threitol (0.02 eq. per acrylamide unit) obtained by the procedure of Example 137 in toluene is allowed to heat at reflux for 24h, affording the above-titled polymer.

Example 139 NaAlH ₂ (2,3-0-(Cyclohexylidene-4-carboxylic acid) - 1, 1,4,4-tetra-phenyl-L-threitol-Grafted Polyacrylamide). A solution (diglyme) of 2.6 mmol of cyclohexylidene-4- carboxylic acid) -1,1,4, 4-tetra-phenyl-L-threitol-grafted polyacrylamide obtained according to the procedure of Example 138 is added dropwise to an 0.3-0.4M solution (diglyme) of 2.6 mmol of sodium aluminum hydride at 17° C. The resulting solution is allowed to stir at room temperature for 25 min. affording a THF solution of the above-titled complex.

The above-titled complex is useful for enantioselectively reducing a chemical entity having a carbonyl group or carbonyl equivalent.

Example 140 A mixture of 0.3 eq. of 0-cyclodextrin and 1 eq. of NaAlH ₄ is allowed to stir in THF at room temperature for 24h to afford a chiral hydride complex capable of enantioselectively reducing a chemical entity having a carbonyl group or carbonyl equivalent.

Example 141 1 Equivalent of polyvinyl alcohol (per vinyl alcohol repeat unit) , 1 equivalent of NaAlH ₄ and 1 eq. of (+)- DDM are combined in THF at room temperature and allowed to stir at room temperature for 24h to afford a chiral hydride complex capable of enantioselectively reducing a chemical entity having a carbonyl group or carbonyl equivalent.

Example 142 1 Equivalent of polyacrylic acid (per acrylic acid repeat unit) , 5 equivalents of thionyl chloride and catalytic dimethyl formamide are heated at reflux for 5h. Concentration of the unreacted thionyl chloride affords polyacryloyl chloride.

Example 143 A mixture of 1 equivalent of polyacryloyl chloride (per acryloyl chloride repeat unit) obtained according to the procedure of Example 142 and 0.1 equivalent of S-(+) -2-amino- l-butanol (Aldrich Chemical Co., Milwaukee, Wisconsin) is allowed to εtir in methylene chloride for 5h to afford a methylene chloride solution of S-(+) -2-amino-l-butanol- functionalized polyacryloyl chloride.

The methylene chloride solution of S- (+) -2-amino-l- butanol-functionalized polyacryloyl chloride is concentrated, and diluted with THF. To the THF solution is added, at 0° C, excess water and catalytic HCl. The resulting mixture is allowed to warm to room temperature and stir at that temperature for 24h to afford an aqueouε THF εolution of S- (+) -2-amino-l-butanol-functionalized polyacrylic acid. The aqueous THF solution of S-(+) -2-amino-l- butanol-functionalized polyacrylic acid is treated with 0.9 equivalents of sodium bicarbonate, to afford an aqueous solution of sodium S-(+) -2-amino-l-butanol-functionalized polyacrylate.

The aqueous solution of sodium S-(+) -2-amino-l- butanol-functionalized polyacrylate is concentrated in vacuo

to remove the THF, then lyophilized to afford solid sodium S- (+) -2-amino-l-butanol-functionalized polyacrylate.

To THF is added, at room temperature, 0.1 equivalent of 0.1 solid sodium S- (+) -2-amino-l-butanol- functionalized polyacrylate, 0.1 equivalent of NaAlH ₄ and 0.1 equivalent of MeOH. The resulting mixture is allowed to stir at room temperature for 24h to afford a chiral hydride complex capable of enantioselectively reducing a chemical entity having a carbonyl group or carbonyl equivalent.

INFRARED SPECTRAL DATA FOR ILLUSTRATIVE CHIRAL HYDRIDE COMPLEXES SYNTHESIZED

Materials and Methods

Solutions of illustrative chiral hydride complexes were obtained according to the procedures of the above

Examples. The hydride complexes were stored at room temperature in hermetically capped flaεkε an aliquotε

(approx. 1 mL) were removed via syringe for infrared (IR) spectral data. IR spectra were recorded on a Perkin Elmer

577 Spectrometer using a KBr cell (0.218 mm) in THF solvent.

Prior to recording the IR spectra, the KBr cel.1 was evacuated and filled with Ar three times. The KBr cell was then washed with THF and the IR spectrum run immediately thereafter. IR data for illustrative hydride complexes of the preεent invention are εhown below in Table 1

Table 1

Complex NaAlH

NaAlH ₃ (0Et) NaAlH ₂ (0Et) ₂

NaAlH ₂ (DPP) NaAlH ₂ (DBM)

1900 weak (broad)

NMR DATA FOR ILLUSTRATIVE HYDRIDE COMPLEXES

Materials and Methods NMR experiments were recorded using a Bruker AC-200 NMR spectrometer in THF-d ₈ solvent. THF-d _H was refluxed with sodium aluminum hydride prior to use. An 0.532M solution of sodium aluminum hydride in THF-d ₈ was used for the preparation of all hydride complexes used in this study. _. NMR data for illustrative hydride complexes, including NaAlH[(S)- BINOL] (OMe) , are shown below in Table 2.

Table 2

Sodium Aluminum Complex

NaAlH ₄

NaAlH,(OMe)

NaAlH ₂ (OMe) ₂ NaAlH(OMe) ₃ NaAl(OMe) ₄ /MeOH

Sodium Aluminum ^l H NMR ¹³ C NMR

Complex ( δ . ppm) ( δ . ppm)

NaAlH[ (S)-BINOL] (OMe) 3.55 (s, OMe)

3.0-4.2 broad

EXAMPLE: ENANTIOSELECTIVE

REDUCTIONS USING ILLUSTRATIVE CHIRAL HYDRIDE COMPLEXES

Example 144 ° The CXF ligand was prepared in two stages from D- xylose according to the procedure described in Example 26 and in J.Org. Chem, 1965, 30 _. (4), 1288.

A solution of 1,2-O-cyclohexylidene-α-D- xylofuranoεe (CXF, 0.305g, 1.325mmol) in THF (15mL) was added 5 with stirring under Ar to solution of sodium aluminum hydride (0.0716g, 1.325mmol) in THF (5mL) for 15min (r.t.) . The mixture was cooled to -70°C followed by acetophenone injection by a syringe (0.05mL, O.44mmol) . The colorless, clear solution was allowed to stand at -70°C for 20h and the ⁰ reaction mixture was hydrolyzed using 90% MeOH until evolution of H ₂ discontinued (6mL) . The solvent was evaporated in vacuo and resulting residue was extracted by hexane (3x30mL) . The extract was washed with water (3xl0mL) up to pH~7, the solvent evaporated and residue analyzed by ⁵ GC. Conversion of AP into PET 75%, e.e. 52% (S) .

Example 145 A solution of (S)-(-)-α, -α-diphenyl-2- pyrrolidinemethanol (DPP) (Aldrich) (l.02g, 4.03 mmol) in ⁰ carefully dried THF (4mL) was added to a solution of sodium aluminum hydride in THF (4.85mL of 0.252M solution, 1.25mmol) with stirring under argon at r.t. for 5min, 45.5 cm ³ H ₂ being evolved (calcld. 56mL for A1H ₂ complex formation) . 1.2mL of the solution thus obtained was placed by syringe in another ⁵ flask, and was allowed to stand at r.t. for lh. The solution was cooled to -70°C and acetophenone (0.6mL of 0.133M

solution in THF, 0.083mmol) was added. Within 24h (-70°C) the first probe of reaction mixture was taken and analyzed by GC (30m capillary column, stationary phaεe was pentylated and trifluoroacetylated 7-cyclodextrine) . GC analysis gave 86% conversion of AP into 1-phenylethanol, e.e. 69% (R) . After an additional 24h, the reaction mixture was warmed to -20° c and was allowed to stand at this temperature for 4 days. GC analysis of the reaction mixture gave conversion of AP 88% and e.e. value 70% (R) . After an additional 3 days, the reaction mixture was hydrolyzed using MeOH-ether (1:10) until evolution of H ₂ ceased. The mixture was diluted by 4-fold volume of ether and extracted by 10% HCl to remove the aluminum compounds and the ligand. The ether layer was separated and analyzed by GC: conversion of AP 91%., e.e. 67% (R).

Example 146 A solution of (+)-DDM (0.27g, 0.578mmol) (Aldrich Chemical Co., Milwaukee, Wisconsin) and MeOH (0.0185g, 0.578mmol) in THF (8mL) was added with stirring at r.t. over 5 min. to solution of sodium aluminum hydride (0.03l2g, 0.578mmol) in THF (2.2mL) under Ar. The resulting solution was allowed to stir at room temperature for lh. The flask was cooled to 0°C, acetophenone (0.022mL, 0.193mmol) was added by syringe and the reaction mixture (clear, colorless εolution) was allowed to stand in a refrigerator at 0°C for 24h. The mixture was then analyzed by GC. Conversion of AP 8%, e.e. 67 (R) . Another probe of the reaction mixture was analyzed by HPLC using chiral stationary phase of Pyrcle type. The second probe gave the same results within +5% range.

Example 147 The ligand DBM was prepared as discloεed in Example 14 and in J.Chem Soc, Perkin Tran . I . , 1997 (10), p. 1123, except that the second recrystallization of the product from methanol was omitted.

D-Mannitol (12.5g, 70 mmol; Fluka Chemical Corporation, Ronkonkoma, New York, CH-9470) and benzaldehyde (Russia, TU-6-09-1672-77; 12.5g, 140 mmol) were dissolved in pure N,N-dimethylformamide (40mL, Fluka Chemical Corporation, Ronkonkoma, New York) and treated with cone. H ₂ S0 ₄ (Russia, GOST 4204-77; 5mL) added in one portion. The resulting mixture was allowed to stand for 72h at r.t. and was then poured into a solution of K ₂ C0 ₃ (5g) in ice-cold water (0.5L) covered with a layer of hexane. The unreacted aldehyde was extracted into hexane with vigorous stirring, and the aqueous layer was allowed to stand at 5-10°C, depositing a white cheese-like solid thereon. The solid was collected by filtration, air-dried, and recrystallized from CHC1 ₃ . The resulting white crystals were washed with dry hexane (2xl0mL) and benzene (lOmL), then dissolved in hot benzene. The benzene solution was evaporated and the resulting solid reεidue was dried over P ₂ 0 ₅ in an Abderhalden apparatus for 18h at 40°C/0.3torr. to afford 13.3g (53%) DBM: mp. = 152- 153°C (189-191°C from MeOH) . A solution of DBM (0.115g, 0.32mmol) in THF (1.8mL) was added dropwise under Ar over 10 min at r.t; to a stirred solution of sodium aluminum hydride (0.32mmol in lmL of THF) , and the resulting mixture was warmed to 25°C for 20min to attain the full substitution of the two H atoms in sodium aluminum hydride. There evolved 18 cm ³ of H ₂ (theory: 14.3mL) .

The mixture was then cooled to 0°C and treated with AP (0.019mL, 0.16mmol) in THF (0.4mL) , injected in one portion. The mixture was stirred for 3h at 0°C, quenched with water (5mL) , and extracted with Et ₂ 0 (5mL) . The ether solution was evaporated and the resulting residue was extracted into hexane (2.5mL) for analysis by GC.

The conversion of AP (GC) : 9.5%, e.e. (GC) : 95% (S) .

Example 148 Abs. methanol (O.OlmL, 0.32mmol) and carefully washed (hexane) and dried BDG (0.21g, 0.64mmol, weight after 12h at 40°C/10 torr) , obtained according to the procedure of Example 13, were dissolved in abs. THF (1.8mL) . The resulting solution was added dropwise over 10 min. at 20°C (under Ar) to a stirred solution of sodium aluminum hydride (0.32mmol in lmL of THF). The reaction mixture waε heated for 10 min. at 40° C to attain the full substitution of the three H atoms in SAH; the evolution of H ₂ was 26.6 cm3 (theory: 21.5mL) . The mixture was then cooled to 20°C and treated with AP (0.019mL, 0.16mmol) in THF (0.4mL) , injected in one portion. Stirring at 20°C waε continued for 3h, then the reaction was quenched with water (0.5mL) . The reaction mass was filtered prior to analysis through a thin pad of Florisil.

The conversion of AP (GC) : 3.5%, e.e. (GC) : 93% (R) .

ENANTIOMERICALLY ENRICHED ALCOHOLS SYNTHESIZED FROM KETONES AND ILLUSTRATIVE CHIRAL HYDRIDE COMPLEXES

Materials and Methods

Acetophenone ("AP") was used, unless otherwise noted, as an illustrative ketone substrate for reductions using representative chiral hydride complexes of the present invention. Reduction afforded 1-phenylethan-l-ol ("PET") with an excess of either the (R)- or (S) -enantio er, as indicated. Amounts of individual PET enantiomerε were quantified using either the high-performance liquid chromatography (HPLC) or the gas chromatography (GC) method.

Hydride reductions were performed in THF, unlesε otherwiεe noted

HPLC Method Enantiomerically enriched mixtures of PET obtained from the reduction of AP with the chiral hydride complexes of the present invention were converted to their carbamate derivatives using (S)-α-(1-naphthyl)ethylisocyanate and Et ₃ N

so as to provide a more easily separable mixture of (S,R)- and (S,S) -diastereomerε.

The above diastereomeric mixtures were separated on a Laboratornj Pristoje Praha HPLC with a HPP 5001 high pressure pump, LCO-2563 UV-VIS detector (λ = 254 nm) , CI-1002 computing integrator and TZ 4620 line recorder. A 150 x 3.3 mm column was used with Separon-NH ₂ (a inopropylated silica, 5μ) sorbent. The eluent was 0.5:99.5 iPrOH:n-hexane, passed at a rate of 0.6 mL/min. Capacity factors (K') for each component were calculated using the equation K' = (τ-τ ₀ )/τ ₀ , where T is a retention time, τ ₀ is that for toluene (1.64 min. under the conditions employed) . The retention times (r) and capacity factor (K') values for diastereomeric adducts were aε follows: (S,R) : T = 14.4 min., K' = 7.78; (S,S) : r = 17.5 min. , K' = 9.65.

GC Method GC analysiε waε performed using a Biochrome-J instrument (Russia) with a quartz capillary column (30 m x o.2 mm) containing dipentylated and trifluoroacetylated 7- cyclodextrin (Carbohydrate Res., 131, 209-217 (1984)), film thickness = 0.2 mm. V _He = 1 mL/min.; initial column temperature = 50° C, raising temperature (8° C/min.2 within 10 min. after probe injection. GC analyεiε of trifluoroacetylated derivatives of (R)- and (S)-PET (Zh.

Analyt. Khim. , 1973, 18(7), 41427) gave completely resolved peaks, with the retention time of the (R) -derivative being longer than that of the (S)-derivative.

Data for illustrative hydride complexes of the present invention, showing ratio of hydride complex:acetophenone (AP) , reduction conditions, % yield of 1-phenylethanol (PET) product and enantiomeric excess (e.e.) of either the (R)- or (S)-PET enantiomer are εhown below in Table 3:

Table 3

Ratio

Complex [NaAlH ₂ ((S)-PEA)) ₀ 1:0.33

(S)-PEA{Na[AlH(S)- 1:0.33 PEA].} ₂

Ratio Reduction Enantiomeric

Complex (Complex: AP) Conditions % PET Excess (e.e.)

NaAlH(CFX)(2-Nf0H) 1:0.33 20°C, 18h 77% 26.5% (S), GC

NaAlH[(S)-PA] 1:0.33 -75°C, 48h 82% 4.5% (S), GC

NaAlH ₃ ((S)-DMPA) 1:0.33 0°C, 24h 99% 4% (S) GC

NaAlH ₂ ((S)-DMPA) ₂ 1:0.33 -20°C, 24h 36% 19% (R), GC

NaAlH ₂ [( + )-PDOL] 1:0.7 -10°C, 20h 97.5% 14% (S), GC

NaAJH[(+)-PDOL](OMe) 1:0.5 20°C, 20h 42.5% 6% (S), GC

NaAIH[( + )-PDOL][N-Me- 1:0.6 20°C, 18h 67% 9.5% (S), GC (S)-PEA]

NaAlHK + )-PDOL][(S)-l- 1:0.5 20°C, 3h 1% 11% (S), GC OBu-2-Me]

NaAlH[( + )-PDOL](OPh) 1:0.5 20°C, 3h 67% 8.5% (S), GC

NaAlH ₂ (BDG) ₂ 1:1 0°C, 1.5h; 52% 21.5% (R), GC then 20°C,

22.5h'

NaAlH(BDG) ₃ 1:1 -10°C, 70h 10% 89.5% (R), GC

NaAlH(CXF)(l-NfOH 1:0.33 -75°C, 48h 97% 46.5% (S), GC

NaAlH(( + )-DDM)(OMe) 1:0.33 0°C, 24h 87% 67% (R), GC NaAlH((+)-DDM)(OEt) 1:0.33 -20°C, 20h 93% 58% (S), GC

NaAlH(( + )-DDM)(OPh) 1:0.33 -20°C, 24h 100% ^' 74% (S), GC

NaAlH(( + )-DDM)(l- 1:0.33 -20°C, 24h 99.5% 56% (S), GC NfOH)

NaAlH((S)-DMPA) ₃ 1:0.33 0°C, 68h 0.6% 28% (S), GC NaAlH ₂ ((S)-DMPA)(OMe) 1:0.33 -70°C, 24h 90% 3% (S), GC

NaAlH((S)-DMPA)(OMe) ₂ 1:0.33 -70°C, 24h 77% 2% (S), GC

NaAlH((S)-DMPA) ₂ (OMe) 1:0.33 0°C, 44h 0.4% 37% (R), GC

NaAlH ₂ ((S)-DMPA)(0- 1:0.33 -20°C, 24h 98% 2.5% (S), GC tertBu) NaAlH((S)-DMPA)(0- 1:0.33 -70°C, 24h 83% 6.5% (S), GC tertBu) ₂

NaAlH((S)-DMPA) ₂ (0- 1:0.33 -20°C, 68h 11% 5% (S), GC tertBu)

NaAlH((S)-DMPA) ₂ (OAr) 1:0.33 -70°C, 22h 0.5% 26% (S), GC NaAlH ₂ (BDHP) 1:0.33 0°C, 72h 97% 10.5% (S), GC

NaAlH(BDHP)(OMe) 1:0.33 0°C, 48h 98% 8.5% (S), GC

Ratio Reduction Enantiomeric

Complex (Complex: AP) Conditions % PET Excess (e.e.)

NaAlH((+)-DDM) (OEt-2- 1 :0.33 0°C, 18h ² 84% 87% (R), GC OMe)

¹ reaction performed in toluene

² reaction performed in diglyme

³ reaction performed in 3: 1 diglyme:THF ketone substrate was propiophenone; reaction product was 1 -phenylpropanol

⁵ ketone substrate was 2-acetylfluoreπe; reaction product was 2-( l -hydroxyethyl)fluorene

As can be seen from Table 3, the complexes that are most efficient in terms of yield and e.e. , possess a C ₂ axis of symmetry. Axially disymmetric molecules such as these are thought to be lesε susceptible to disproportionation reactions and hence provide complexes with a higher degree of enantioselectivity.

It is to be understood that for a particular chiral hydride complex, the chiral ligand thereof will produce an enantiomeric excess of a reduction product such that for that particular hydride complex, the use of the same chiral ligand but of the opposite enantiomer will give riεe to the reduction product of the opposite stereochemistry. For example, whereas NaAlH ₂ ( (+) -DDM) reduces acetophenone to (R)- 1-phenylethan-l-ol in 91% enantiomeric excesε (0° C; 48h; diglyme), reduction of acetophenone with NaAlH ₂ ( (-) -DDM) under identical conditionε will give an enantiomeric excess of (S)- 1-phenylethan-l-ol.

It is to be understood that while most of the illustrative chiral hydride complexes of Table 3 are sodium aluminum hydride complexes, chiral hydride complexes comprising a chiral ligand (R ^* , R ^** or R ^*** ) and optionally an achiral ligand (R ¹ or R' ') will function effectively to reduce a carbonyl group or a carbonyl equivalent, regardlesε of whether M is Na ⁺ , Li ⁺ or K ⁺ , or whether Al is replaced with B.

COMPARISON OF NaAlH[ (S)-BINOL] (OMe) AND

LiAlH[ (S)-BINOL] (OMe) WITH REGARD TO

CONVERSION AND ENANTIOSELECTIVITY

NaAlH[ (S) -BINOL] (OMe) gave surprisingly and unexpectedly high conversion (chemical yield) and enantioselectivity values relative to LiAlH[ (S) -BINOL] (OMe) , when admixed with acetophenone (AP) . In a comparative experiment, NaAlH[ (S) -BINOL] (OMe) was admixed with AP in THF at -70° C to afford 79% 1-phenylethanol (PET) with the (S)- enantiomer in 97% enantiomeric excess, whereas under similar conditions, LiAlH[ (S) -BINOL] (OMe) afforded only 60% PET with the (S) -enantiomer in only 87% enantiomeric excesε (J. Am.

Chem. Soc, 1984, 106# 6709) . Thus, NaAlH[ (S) -BINOL] (OMe) is surprisingly and unexpectedly a more efficient and enantioselective reducing agent than itε lithium analog.

COMPARISON OF NaAlH ₂ (DDM) AND

LiAlH ₂ (DDM) WITH REGARD TO CONVERSION

AND ENANTIOSELECTIVITY

NaAlH ₂ (DDM) and NaAlH ₂ (CYTOL) gave surprisingly and unexpectedly high conversion and enantioselectivity values relative to their lithium analogs, when admixed with AP. The results are shown below in Table 4 :

Complex

NaAlH ₂ (DDM)

NaAlH ₂ (DDM)

LiAlH ₂ H(DDM) LiAlH ₂ H(DDM)

LiAlH ₂ H(DDM)

LiAlH ₂ H(DDM)

NaAlH ₂ (CYTOL)

LiAlHjH (CYTOL)

LiAlH ₂ H(DDM)

Thus, NaAlH ₂ (DDM) and NaAlH ₂ (CYTOL) are surprisingly and unexpectedly more efficient and enantioselective reducing agents than their lithium analogs.

The present invention is not to be limited in scope by the specific embodiments disclosed in the examples which are intended as illustrations of a few aspectε of the invention and any embodiments which are functionally equivalent are within the εcope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the appended claims.

A number of references have been cited and the entire disclosures of which are incorporated herein by reference.