SELECπVΕ ASYMMETRIC HYDROGENAΗON OF DEHYDROAMINO

ACID DERIVATIVES USING RHODIUM AND IRIDIUM

DIPHOSPHINITE CARBOHYDRATE CATALYST COMPOSITIONS FTF.T D OF THE INVENTION

This invention relates to a process and catalyst composition for the asymmetric hydrogenation of dehydroamino acid derivatives to selectively produce either D or L amino acid compounds. The process utilizes a catalyst composition comprising rhodium or iridium and a diphosphinite carbohydrate ligand, wherein the ordered absolute configuration of the two phosphinite groups on the carbohydrate determines whether the α amino acids produced will be D or L. Further, the ligands of the invention comprising phosphinite groups which have aromatic groups substituted with electron-donating substituents, result in catalysts which display very efficient enantioselectivity during the hydrogenation reaction. BACKGROUND OF THE INVENTION

The subject of asymmetric hydrogenation, especially using dehydroamino acid derivatives as substrates, is a commercially important area, particularly in the pharmaceutical field.

Cullen reported the use of the 2,3-glucopyranose system for asymmetric hydrogenation of dehydroamino acid derivatives in 1978 (Tetrahedron Lett. 1978, 1635). Similar disclosures were made by Thompson (J. Organometal. Chem. 1978, 159, C29; U.K. 41,806,177 7/10^77).

Jackson and Thompson (/. Organomet. Chem. 1978, 159 , C29) describe the use of 2,3-diphenylphosphinites of a "D-glucopyranose" for S-phenylalanine and 4,6-diphenylphosphinite of a "D-xylofuranose" for the corresponding R amino acid. Thus, unlike the present invention, in order to make R and S amino acid derivatives altogether different sugar back bones were previously employed. Habus, Raza and Sunjic (/. Mol. Cata. 1987, 42, 173) also report similar results using "D-glucopyranose" and "D-xylopyranose"-derived bis-diphenylphosphinites for the synthesis of R and S-phenylalanine derivatives. The enantioselectivity in each case is low and in contrast to the present invention, reaction conditions are not practical for large scale preparation of these compounds, where high selectivity is needed.

Selke et al. began work in this area in 1978 and has published a series of papers and also patented some of this work. (J. Mol. Catal. 1986, 37, 213,227;

/. Prakt. Chem. 1987, 329(4), 717; /. Mol. Catal. 1989, 56, 315; DD 140 036; DD 240372; and DD 248 028). Similar to Cullen and Thompson, Selke discloses using a phenyl group on the phosphorus. Unlike Applicants' process, however, the phosphorus phenyl group was unsubstituted and no recognition was disclosed of enhanced enantioselectivity as a function of electron-rich substituents on the phenyl. Further, the Selke, Cullen and Thompson disclosures are limited to ligands using "2,3-dideoxyglucopyranose", "mannopyranose" and "galactopyranose" in systems yielding only S amino acid derivatives.

Other sugar diphosphinites have been examined in both rhodium (J. Org. Chem. 1980, 45, 62) and ruthenium (J. Mol. Catal. 1980, 9, 307) catalyzed hydrogenation reactions. However, low ee's were obtained. Some simple derivatives have also been reported by Sunjic (Sunjic: J. Mol. Catal. 1987, 42, 173); again, in processes yielding low ee values.

Other references disclose carbohydrates as the chiral auxiliary for monophosphinites (Yamashita: Carbohydrate Res. 1981, 95 C9; Bull. Chem. Soc. Jpn. 1982, 55, 2917; Bull. Chem. Soc. Jpn. 1986, 59, 175) and phosphines (Sunjic: J. Organometal. Chem. 1989, 370, 295; Nakamura: Chem. Lett. 1980, 7).

-Aminophoshine-phosphinites from readily available amino acids have also been used as ligands for asymmetric hydrogenations. (U.S. Patent 5,099,077, 3/24/1992; Petit, M.; Mortreaux, A.; Petit, F.; Buono, G.; Peiffer, G. Nou. J. Chem. 1983, 593.)

SUMMARY OF THE INVENTION The present invention provides a process for asymmetric hydrogenation, comprising: reacting a dehydroamino acid derivative of formula I

ZZC=C(CO2Z)(NHZ) I

wherein each Z is independently H or a Ci to C40 carboalkoxy, Ci to C40 aromatic or nonaromatic hydrocarbyl or Ci to C40 aromatic or nonaromatic heterocyclic radical; optionally substituted with one or more halo, alkoxy, carboalkoxy, nitro, haloalkyl, hydroxy, amido, keto, or sulfur containing groups; with a source of hydrogen;

in the presence of a catalyst composition comprising iridium or rhodium and a chiral, nonracemic diphosphinite ligand of formula II

(R ^l )2-P-X-R ² -X-P-(R ¹ )2 π

wherein R ² is a C4 to C4 ₀ dideoxycarbohydrate; each X is independently O or NR ³ , wherein R ³ is H, a Ci to C2 ₀ alkyl or aryl; and each R ¹ is independently an aromatic hydrocarbyl substituted with one or more amino, dialkylamino, hydroxy, alkoxy, alkyl, triarylsilyl, or trialkylsilyl groups, or an aromatic heterocycle substituted with one or more amino, dialkylamino, hydroxy, alkoxy, alkyl, trialkylsilyl, or triarylsilyl groups; to yield a chiral, nonracemic mixture of compounds of formula IQ

ZZCH-CH(Cθ2Z)(NHZ) m

wherein Z is defined as above. This invention further provides a method for predicting whether the above hydrogenation process will yield an R or S amino acid derivative, based upon whether the absolute configuration of the phosphinite groups "X" attached to the carbohydrate R ² are configured in Right-Left configuration to yield the S amino acid derivation of Formula m, or are configured in a Left-Right configuration to yield the R amino acid derivative of Formula UL

This invention further provides a catalyst composition comprising iridium or rhodium and a chiral, nonracemic diphosphinite ligand of formula π

(Rl) ₂ .p-X.R2.χ.p.( _R l) ₂ π

wherein R ² is a C4 to C ₄₀ dideoxycarbohydrate; each X is independently O or NR ³ , wherein R ³ is H, a Ci to C2 ₀ alkyl or aryl; and each R ¹ is independently an aromatic hydrocarbyl substituted with amino, dialkylamino, hydroxy, alkoxy, alkyl, trialkylsilyl, or triarylsilyl groups or

an aromatic heterocycle substituted with amino, dialkylamino, hydroxy, alkoxy, alkyl, trialkylsilyl, or triarylsilyl groups.

This invention further provides a process for asymmetric hydrogenation, comprising reacting a dehydroamino acid derivative of formula I

ZZC=C(CO2Z)(NHZ) I

wherein each Z is independenfly H or a Ci to C ₄ 0 carboalkoxy, Ci to C40 aromatic or nonaromatic hydrocarbyl or Ci to C40 aromatic or nonaromatic heterocycUc radical, optionaUy substituted with one or more halo, alkoxy, carboalkoxy, nitro, haloalkyl, hydroxy, amido, keto or sulfur containing groups; with a source of hydrogen; in the presence of a catalyst composition comprising iridium or rhodium and a chiral nonracemic diphosphinite Ugand of formula -Q

(R ^l )2-P-X-R ² -X-P-(R ^! )2 π

wherein R ² is a C4 to C ₄₀ dideoxycarbohydrate; each X is independently O or NR ³ , wherein R ³ is H, a Ci to C20 alkyl or aryl; and each R ¹ is an unsubstituted aromatic hydrocarbyl, to yield a chiral, nonracemic mixture of compounds of formula UI

ZZCH-CH(C02Z)(NHZ) m

wherein Z is defined as above; and wherein in formula II the X groups are attached to R ² in the

Left-Right diphosphinite configuration whereby the asymmetric hydrogenation process selectively yields compounds of formula UI in R-configuration.

DF AΠ Π DESCRIPTION OF THE INVENTION

The process and catalyst composition of the instant invention whereby enantioselective hydrogenation is accomplished by reacting a dehydroamino acid

derivative of the formula ZZC=C(CO2Z)(NHZ) with hydrogen in the presence of a chiral, nonracemic, metal (Rh, Ir) hydrogenation catalyst, are useful, for example to produce opticaUy active amino acid derivatives. These amino acid derivatives are useful precursors for pharmaceutical products. The enantioselective hydrogenation reaction is performed by reacting a dehydroamino acid derivative of the formula ZZC=C(CC»2Z)(NHZ) with hydrogen in the presence of a chiral, nonracemic, metal (Rh, Ir) hydrogenation catalyst.

These reactions selectively provide opticaUy active D or L -α- amino acid derivatives of the formula ZZCHCH(Cθ ₂ Z)(NHZ), where the absolute configuration of the amino acid derivative is determined by the nature of the chiral metal hydrogenation catalyst

By the term "carbohydrate", Applicants mean the class of organic compounds comprising the general formula (CH2θ) _n , wherein n is equal to or greater than four. The carbohydrate-derived Ugands of the invention are derived from to Gjo carbohydrates including monosaccharides, disaccharides and oligosaccharides.

By the term "hydrocarbyl", AppUcants include aU alkyl, aryl, aralkyl or alkylaryl carbon substituents, either straight-chained, cycUc, or branched, accordingly substituted with hydrogen. By the term "heterocycle", AppUcants mean a cycUc carbon compound containing at least one oxygen, nitrogen or sulfur atom in the ring.

By the term electron-donating group, AppUcants include those groups that have σ-values (any σ-values such as Op, σ _m or their modifications) less than zero

(as defined by the Hammett equation, see, for example, March, J. Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4th ed.; 1992, Wiley:

New York, 278-286). Such groups include but are not limited to O', NMe2, NH2,

OH, OMe, CMe3, Me, Mβ3Si, SMe, and F.

In describing a carbohydrate group of the formula X-R ² -X, the "X" can be the same or different and can be O or NR ³ , where R ³ is H, alkyl or aryl; and as it appears within the Ugand of the present disclosure, the group R ² is named by using the prefix "dideoxy" with the name of the parent diol of the formula HO-R ² -OH.

The suffix "pyranose" or "furanose" in combination with the carbohydrate root names shall include those compounds wherein the sugar exists as an internal 6-

(pyranose) or 5- (furanose) membered acetal. The OH groups may or may not be

protected as esters or ethers. For example, the name "2,3-dideoxy-glucopyranose" refers to the group:

and "3,4-dideoxy-glucopyranose" refers to the group:

Accordingly, the corresponding carbohydrate groups O-R ² -O are:

Nitrogen may be substituted for one or both of the oxygens in the above formula O-R ² -O to provide an aminosugar. An example of the carbohydrate group O-R ² -NR ³ is the "2,3-dideoxyglucose":

The suffix -ose- when used in combination with carbohydrate root names, shall include those compounds wherein the OH groups are protected as ethers or esters. By this definition, for example, the pyranoside structure shown below is termed a "glucopyranose" since the configuration of the sugar back-bone (C ₁ -C5) is that of the sugar glucose,

wherein Ac is an acetyl.

By the term "chiral", AppUcants mean "existing as a pair of enantiomers." These enantiomers, where the chiral centers are designated the R and S isomers, are nonsuperimposable mirror images of one another. A chiral material may either contain an equal amount of the R and S isomers in which case it is caUed "racemic" or it may contain inequivalent amounts of R and S isomer in which case it is caUed "opticaUy active", or "nonracemic". In referring to the amino acid products of the invention, Applicants also use the more famiUar "D" and "L" designations to indicate the isomers. By the term "enantiomeric excess" ("ee"), AppUcants mean the absolute difference between the percent of R enantiomer and the percent of S enantiomer of an opticaUy active compound. For example, a compound which contains 75% S isomer and 25% R isomer wiU have an enantiomeric excess of 50%.

By the terms "enantioselective" or "asymmetric" AppUcants mean the abiUty to produce a product in an opticaUy active form.

The substrates of the invention are the class of dehydroamino acid derivatives. They are described by the formula ZZC=C(CO2Z)(NHZ), where each Z is independently H, or a to C20 carboalkoxy, Ci to C40 aromatic or nonaromatic hydrocarbyl or Ci to C40 aromatic or nonaromatic heterocycUc radical; each of which may be substituted with one or more halo, alkoxy, carboalkoxy, nitro, haloalkyl, hydroxy, amido, keto, or sulfur containing groups. Preferably one of the Zs in the group "ZZC=" is H. Examples of Z include, but are not limited to, phenyl, substituted phenyl, polyaromatic (e.g., napthyl, anthryl), substituted polyaromatic, heteroaromatic, acetoxy, alkyl and substituted alkyl. Representative examples of substrates used in the invention include, but are not limited to, α-acetamidocinnamic acid and its methyl ester, 2-acetamido-3-(4~fluoro- phenyl)-prop-2-enoic acid and its methyl ester, 2-acetamido-3-(3-methoxyphenyl)- prop-2-enoic acid and its methyl ester, methyl 2-acetamido-3-(4-trifluoromethyl- phenyl)-prop-2-enoate, methyl 2-acetamido-3-(4-methoxyphenyl)-prop-2-enoic acid and its methyl ester, methyl 2-acetamido-3-(4-bromophenyl)-prop-2-enoic

acid, methyl 2-N-benzyloxycarbonyl-3-(4-fluorophenyl)-prop-2-enoate, 2-acetamidoacryUc acid, 2-acetamido-3-isopropylacryUc acid, 2-acetamido-3-(2- naphthyl)prop-2-enoic acid and its methyl ester, and methyl 2-acetamido-3-(3- thienyl)prop-2-enoate. The dehydroamino acid derivatives of the invention may be made by methods which are weU-known in the art, e.g., (a) Herbst, R. M.; Shemin, D. in Organic Synthesis, Blatt, A. H. Ed.; John Wiley & Sons Inc., New York; 1943, CoU. Vol π, p 1, (b) U. Schmidt, et al. Synthesis 1992, 487, which are hereby incorporated by reference. Several substrates are also available commerciaUy. For aU embodiments of the AppUcants' invention, the chiral, nonracemic, metal hydrogenation catalyst composition comprises a chiral, nonracemic, carbohydrate diphosphinite Ugand and a source of one or more of the metals Rh and Ir. Suitable sources of the rhodium and iridium include, but are not limited to, the metal haUdes, olefin complexes, acetoacetates, and carbonyls. Metal compounds that contain Ugands which can be displaced by the chiral carbohydrate phosphorus Ugand are a preferred source of the metal. In the case, for example, of rhodium (I) intermediates, (COD)2RhY species (COD is 1,5-cyclooctadiene) are the precursors of choice, with the counterion Y being tetrafluoroborate (BF4), hexafluσro- antimonate (SbFό), or trifluoromethanesulfonate (OTf); although other counterions such as tetraphenylborate (BPh-4), PFβ and perchlorate (CIO4) would also be suitable. Chiral iridium compounds can be prepared simUarly from (COD)2lrY or (COD)fr(CH3CN)2Y. Rhodium is the preferred metal.

The catalyst composition also employs a Ugand comprising a chiral, nonracemic diphosphinite of the formula (R ¹ )2-P-X-R ² -X-P-(R ¹ )2, wherein the R ² is a C4 to C40 dideoxycarbohydrate, optionally substituted with one or more hydrocarbyl, halo, alkoxy, carboalkoxy, hydroxy, amido or keto groups; and such that the fragment of the Ugand defined by the structure PX-R ² -XP is chiral. i this embodiment X can be the same or different and can be O or NR ³ where R ³ is H, alkyl or aryl. By this definition AppUcants intend that the chirality of the diphosphinite Ugand arises from the chiraUty of the parent carbohydrate diol HO-R ² -OH.

Specifically, the process is carried out by employing chiral, nonracemic, O-substituted carbohydrate phosphorus Ugands; including particularly pyranose, furanose, disaccharide and oUgosaccharide organophosphorus Ugands. Examples are represented by the formulas 1-4:

wherein: n = 0-2; m = 0-3;

R ⁴ groups are independently H, Ci to C20 hydrocarbyl, alkoxy, aryloxy, O-substituted pyranose or O-substituted furanose;

R5 groups are independently H, hydroxymethyl (CH2OH), alkoxymethyl, aryloxymethyl, or CH2OP(R ¹ )2 where R ¹ is aryl, alkoxy, or aryloxy; R ⁶ groups are independently H, Ci to C20 hydrocarbyl, acyl, or P(R )2 where R ¹ is aryl, alkoxy, or aryloxy;

R ⁷ is H, aryloxy, alkyl, alkoxy, aryloxyalkyl or alkoxyalkyl and the sum total of P(R ^! )2 groups present in the X-substituted pyranose, furanose, dissacharide or oUgosaccharide organophosphorus Ugand is preferably equal to 2. Examples of R ² include, but are not limited to 2,3-dideoxyglucose,

3,4-dideoxyglucose, 3,4-dideoxyfiructose, 3,4-dideoxymannose. By analogy pyranose and furanose forms (whenever appUcable) of the foUowing sugars are also possible: 2,3-dideoxyxylose, 2,3-dideoxyarabinose, 3,4-dideoxyxylose, 3,4-dideoxyarabinose, 3,4-dideoxysorbose, 2,3-dideoxymaltose, 2',3'-dideoxy- maltose, 3',4'-dideoxymaltose, 2,3-dideoxymannose, 2,3-dideoxyaUose, 2,3-dideoxylactose, 2',3'-dideoxylactose, 3',4'-dideoxylactose. The

corresponding aminosugar derivatives wherein the oxygen is replaced with acyl or alkyl amino groups are also possible. An example of these derivatives described in this application is:

AppUcants also specifically include within the carbohydrate Ugand compositions of the invention those carbohydrates containing protective groups. By the term "protective group", AppUcants include groups such as ethers and esters which function to provide chiral recognition of the sugar molecule, and further are commonly employed to protect the sugar molecule from nonselective reactions. AppUcants further intend to particularly include disaccharides formed by joining two of the structures shown in formulas 1-4 through an oxygen atom at the anomeric position of the furanose or pyranose ring. Two examples of such dissacharides are shown below, wherein Ph is phenyl and Ac is acetyl.

Most preferably, the chiral, nonracemic, organophosphorus Ugand is a chiral, nonracemic, O-substituted glucopyranose organophosphorus Ugand of the formula 5,

wherein:

R ⁸ is H, Ci to C20 hydrocarbyl, alkoxy, or aryloxy;

R ⁹ is independently selected from H, Ci to C20 hydrocarbyl, acyl or

P(R ¹ )2, where R ¹ is aryl, alkoxy, aryloxy; and the sum total of P(R*)2 groups present in the O-substituted glucopyranose organophosphorus Ugand is equal to 2. Examples of the Ugands used in the present invention include the following:

A. R^Ph D. R FC6-H4 G. R ¹ -4-< F_0C-6H4

Using the above representation of the Ugands, the catalysts are described as foUows: [IA] Rh(COD)SbF6 refers to a catalyst prepared from Ugand IA and Rh(COD)2SbF6; [IIB] Rh(COD)BF4 refers to a catalyst prepared from Ugand IIB and Rh(COD)2BF4, etc. 5 For Ulustrative purpose, Ugands IA, IB, IE and IF may be defined as foUows in the context of the general definition (i.e., (R ¹ )2-P-X-R ² -X-P-(R ¹ )2) of the:

IA: R ² : "2,3-dideoxyglucopyranose" X = O, X = O; R ¹ = Phenyl IB; R ² : "2,3-dideo ^χ yglucopyranose" X = O, X = O; Rl ₌ 3,5-dimethylphenyl 0 IE: R ² : "2,3-dideoxyglucopyranose" X = O, X = O; R ¹ = 3,5-difluorophenyl IF: R ² : "2,3-dideoxyglucopyranose" X = O, X = O; R ¹ = 3,5-bis(CF3) phenyl

The Ugands of the invention are defined to contain R ¹ groups which are substituted with electron-donating groups. The beneficial electronic effect of these Ugands can be Ulustrated by comparing Ugands IA, IB, IE and IF in the 5 Rh(+)-catalyzed hydrogenation of methyl 2-acetamido-3-(4-fluorophenyl)propen-2- oate. An 85% ee was obtained when diphenylphosphinite IA was used, whereas a 96% ee was obtained with the more electron rich 3,5-dimethylphenyl phosphinite IB. Very low ee's of 13% ad 9% were obtained using electron-deficient systems, 3,5-difluorophenylphosphinite IE and 3,5-bis-trifluoromethylphenyl-phosphinite 0 IF, respectively. AppUcants beUeve that utilization of this electronic effect wiU prove to be highly significant and beneficial in appUcations necessitating practical means of synthesis of amino acids in very high enantioselectivity.

Examples where high ee's were obtained for the Rh(+)-catalyzed hydrogenation of methyl 2-acetamidocinnamate include IB (5-99.0%), IIB R-

93.0%), πiB (R-97.0%), and IVB (R-98.3%). The hydrogenation of other substrates are illustrated in the tables.

Another highly significant aspect of the present invention relates to AppUcants' recognition that the relative regiochemistry of the vicinal-phosphinites with respect to their location on a given sugar back-bone ("glucose", for example) dictates which amino acid (R or S; or D or L) is generated in the hydrogenation. For example, 5-amino acids are obtained when Ugands I and VIII are used, whereas R-amino acids are obtained when Ugands π, m or IV are used in the reduction of dehydroamino acid derivatives. For purposes of clarity and uniformity, AppUcants have characterized and described this element of the invention in terms of the ordered absolute configurations of the phosphinites on sugar back-bone Fisher Projections. In this context, the ordered absolute configuration of the phosphinites on the sugar will be designated unambiguously as either Right-Left, or Left-Right. AppUcants are the first to recognize that a Right- Left (occupying the 2,3-position of the sugar) Ugand configuration results in formation of the S enantiomer or L amino acid, whereas the Left-Right Ugand configuration (occupying the 3,4-position of the sugar) results in formation of the R enantiomer or D amino acid. More specificaUy, using Fisher Projections (see, for example, Stryer, L. Biochemistry, 3rd ed.; 1988, Freeman: New York, 332-336) of furanose and pyranose derived vicinal diphosphinites, the sense of chiraUty of products formed in the Rh-catalyzed hydrogenation of dehydroamino acid derivatives can be predicted. In doing so the configuration of the carbon with the lower number is indicated first. Thus, Right-Left diphosphinite indicates that the carbon carrying the right phosphinite is lower in number in the context of the Fisher Projection.

Pyranose and furanose sugars that have a Right-Left diphosphinite configuration (see text for convention) give L-amino acid derivatives (corresponding to S configurations) and those sugars with a Left-Right diphosphinite configuration give D-amino acid derivatives (corresponding to R configurations) when used in the Rh or Ir catalyzed hydrogenation of dehydro¬ amino acid derivatives.

When the diphosphinites are on the 2,3-positions of D-glucose as shown, the product of the hydrogenation is a L-amino acid (S-confϊguration). Using Fisher Projections of the sugar derivatives, one can pictoriaUy define the relative location of the diphosphinites on either the left or right side. In this way, by using the

standard numbering for carbohydrate nomenclature, the first phosphinite (on the 2-position) is on the right side and the second phosphinite (on the 3-position) is on the left side of the glucose systems. We are defining this as a Right-Left diphosphinite.

Left side Right side

Right-Left diphosphinite from D-Glucose

Accordingly, when diphosphinites are on the 3,4-positions of D-glucose as shown, the product of the hydrogenation is a D-amino acid (R-confϊguration). Once again using the standard numbering for carbohydrate nomenclature, the first phosphinite (on the 3-position) is on the left side and the second phosphinite (on the 4-position) is on the right side of the glucose systems. We are defining this as a Left-Right diphosphinite.

Left-Right diphosphinite from D-Glucose

Correspondingly, other sugar derivatives where a Right-Left diphosphinite is present wiU provide L-amino acids, whereas a Left-Right diphosphinite wiU provide D-amino acids when these Ugands are used in the hydrogenation of dehydroamino acid derivatives.

Other examples enable us to -further iUustrate the understanding of this relationship of the sugar diphosphinites to the configuration of the product amino acid derivatives. The 3,4-diphosphinite derived from D-mannose and the 3,4-diphosphinite derived from D-fructose, both Left-Right diphosphinites provide D-amino acid derivatives under the hydrogenation conditions.

Left-Right diphosphinite from D-Mannose Left-Right diphosphinite from D-Fructos<

Also, the 2-deoxy-2-acetamido glucose derivative shown below is a Left- Right diphosphinite and provides D-amino acids under the hydrogenation conditions

Left side ; Right side Left-Right diphosphinite from D-Glucose

Within the context of the Ugand formula II (R ¹ )2-P-X-R ² -X-P-(R ¹ )2 and the Ugand nomenclature developed above, the Ugands IB, iii-B and IVB may be compared in the process of the invention to further illustrate this configurational effect:

IB: R ² : "2,3-dideoxyglucopyranose" X = O, X = O; R ¹ = 3,5-dimethylphenyl πiB: R ² : "3,4-dideoxyglucopyranose" X = O, X = O; R ¹ = 3,5-dimethylphenyl IVB: R ² : "3,4-dideoxyglucopyranose" X = O, X = O; R ¹ = 3,5-dimethylphenyl When R ¹ = bis-(2,3-dimethylphenyl)phosphino, Ugand IB serves as an efficient Ugand for Rh(+) in the catalytic hydrogenation of methyl acetamido- cinnamate which is reduced to the corresponding S(+) methyl phenylalaninate in 99.0% ee. Under identical conditions, 93.0 and 98.3% ee of the R(-) isomer are obtained using Ugand IIIB and IVB, respectively.

The configurationaUy specific chiral, nonracemic carbohydrate-derived diphosphorus Ugands can be prepared according to techniques well-known in the art. (Selke, R.; Facklam, C; Foken, H.; HeUer, D. Tetrahedron Asymmetry 1993, 4, 369; Baker, M. J.; Pringle, P. G.; /. Chem. Soc. Commun. 1991, 1292; Habus, I.; Raza, Z; Sunjic, V. /. Mol. Catal. 1987, 42, 173.; Jackson, W. R.; Lovel, C. G. Aust. J. Chem. 1982, 35, 2069; Jackson, R.; Thompson, D. J.

/. Organomet. Chem. 1978, 159, C29; CuUen, W. R.; Sugi, Y.; Tetrahedron Lett. 1978, 1635). In general, diol derivatives containing unprotected hydroxyl groups are treated with a P(R)2C1 (wherein R may generally be an alkyl, aryl, alkoxy, or aryloxy) reagent, in the presence of a base, such as pyridine or triethylamine, to produce the desired phosphinite or phosphite. Some P(R)2θ reagents are commerciaUy available, such as PPh2Cl (Ph = phenyl). Other P(R)2C1 reagents, where R = aryl or alkyl, can be prepared by two methods. Method A involves the reaction of (amino)dichlorophosphines such as Et2NPCl2 with RMgBr foUowed by reaction with HC1 [Methoden Der Organischen Chemie (Houben-Weyl): Vol 12, Part 1; MuUer, E., ed.; Georg Theme Verlag: Stuggart, 1963, 213-215; de Koe, P.; Bickelhaupt, F. Angew. Chem. Int. Ed., Eng. 1967, 6, 567; Quin, L. D.; Anderson, H. G. /. Org. Chem. 1966, 31, 1206.; Montgomery, R. E.; Quin, L. D. J. Org. Chem. 1965, 30, 2393; Frank, A. /. Org. Chem. 1961, 26, 850]. -Alternatively, treatment of readily avaUable dialkyl phosphites, such as dibutyl phosphite, HP(O)(OBu)2, with RMgBr foUowed by reaction with PCI3 provides P(R)2C1 derivatives (U.S. Patent 5,175,335). P(R)2C1 reagents, where R = alkoxy or aryloxy, can be prepared in two steps by treatment of P(NEt2) ₃ with ROH to generate P(OR) ₂ (NEt ₂ ), foUowed by treatment with CH ₃ COCI to generate P(OR) ₂ d -Ulustrative preparations are provided below. For all embodiments of the invention the chiral, nonracemic metal hydrogenation catalyst may be prepared by mixing the metal source and the chiral, nonracemic, organophosphorus Ugand, preferably in a suitable organic solvent under an inert atmosphere such as N2 or Ar in a temperature range from 0°C to 120°C, preferably in a temperature range from 0°C to 80°C. The metal compound may be used in this solution or the metal compound can be obtained in the pure form upon removal of the solvent Rh is the preferred metal. Counter ions BF4 and SBF6 are preferred.

The preferred molar ratio of chiral, nonracemic, organophosphorus Ugand to the metal may vary between 1:1 to 2:1, most preferably between 1:1 to 1.2:1. The preferred molar ratio of metal complex to vinyl compound may vary between 0.00005:1 to 1:1, most preferably between 0.0001:1 to 0.01:1.

The dehydroamino acid derivative, represented by the formula ZZC=C(CO2Z)(NHZ) may be dissolved in any organic solvent such as, but not limited to, tetrahydrofuran, methanol, ethanol, dimethoxyethane, toluene or hexane.

Tetrahydrofuran (THF), methanol, ethanol and dimethoxyethane and mixtures thereof are preferred solvents. THF is the most preferred.

The hydrogen can be provided by contacting the reaction mixture with hydrogen gas. The hydrogenation reaction is preferably conducted over a temperature range from -25°C to 100°C, most preferably 25 to 30°C. AppUcants note that higher ee's are observed at lower temperatures. Suitable pressure range is 10-100 psi (1 psi = 6.9 kPa).

The enantioselective hydrogenation reactions are typicaUy complete within 3-24 hours.

To demonstrate a preferred mode of the invention which produces a particularly useful product, preparation of opticaUy active (R)-(+)-phenylalanine can be achieved. The catalyst composition comprises a cationic riiodium (I) compound and the Ugand formula (R ¹ )2P-X-R ² -XP(R ¹ )2 wherein each R ¹ is the aryl group 3,5-dimethylphenyl and R ² is the O-substituted β-D-glucopyranose of the formula πiB, the starting acrylate derivative is α-acetamidocinnamic acid, and the source of rhodium metal is (COD)2RhSbF6.

For the preparation of (R)-(+)-phenylalanine, the enantioselective hydrogenation is preferably carried out at 25°C under 40 psi pressure of hydrogen. A mixture of α-aceta-midocinnamic acid and the chiral riiodium catalyst is stirred in a suitable solvent such as THF, DME, or CH3OH for 3 h. In this preferred embodiment, a molar ratio between 0.0025: 1 to 0.05: 1 of rhodium catalyst to acrylate derivative is used.

Using these preferred conditions, ee's greater than 95% are typicaUy obtained. Isolation of the product amino acid in 90-100% yield can be achieved by crystallization from the reaction mixture.

SUBSTITUTE SH€ET (RULE 26)

General Procedures for the Preparation of Chiral Carbohydrate Diols, Phosphinite Ligands (R ¹ )2P-X-R2-X-P(R ¹ )2 and Rh and Ir Catalysts Derived Therefrom

A. Synthesis of Diols

The requisite diols for the Ugand synthesis (see Table 1) were prepared by procedures outlined below.

Phenvl4.6-0-benzvlidene-β-D-γlucoτ)vranoside. The title compound was prepared by treatment of commerciaUy available phenyl-β-D-glucσpyranoside with di ethoxytoluene in the presence of p-toluenesulfonic acid in acetonitrile (for leading references see Carbohydrates, Ed. Collins, P. M., Chapman and HaU, New York, 1987, 414).

Methvl2.6-di-0-pivalo\l-a-D-glucopvranoside and MetM2.6-di-Q- benzoyl-a-D-glucopyranoside. The requisite carbohydrate diols were synthesized according to Uterature procedures: (Ogawa, T.; Matsui, M. Tetrahedron 1981, 37, 2369; Tomic-Kulenovic, S.; Keglevic, D. Carbohydrate Res. 1980, 85, 302.). Methvl2-acetamido-2-deoxv-6-0-t-hutvldimethvlxil\l-β-D-γlu co- pyranoside. This compound was prepared from the corresponding methyl glucoside, Methyl 2-acetamido-2-deoxy-β-D-glucopyranoside (Carbohydrates, Ed. Collins, P. M., Chapman and HaU, New York, 1987, p.414) by treatment with f-butyldimethylchlorosilane in DMF and imidazole. lH NMR δ 0.00 (2Xs, 6 H), 0.80 (2Xs, 9 H), 1.98 (s, br, 3H), 3.20-3.32 (m, 1 H), 3.32-3.50

(s superimposed on m 5 H), 3.59 (dd, J = 12, 8, 1 H), 3.76, 3.84 (ABX, JAB = 18, 2 H), 4.28 (d, J = 8, 1 H), 6.42 (d br J = 4, 3 H).

Methvl2-denxv-6-0-t-hutvldimethvl- -D- lucopvranoside. This compound was prepared from the corresponding methyl glucoside, Methyl 2- deoxy-a-D-glucopyranoside . (Carbohydrates, Ed. Collins, P. M, Chapman and HaU, New York, 1987, p. 352) by treatment with t-butyldimethylchlorosilane in DMF and imidazole. ^l H NMR δ 4.73 (d, 1, J = 3 Hz), 3.85-3.78 (m, 4), 3.55-3.46 (m, 2), 3.35 (m, 1), 3.29 (s, 3), 2.05 (m, 1), 1.61 (m, 1), 0.88 (m, 9), 0.07 (m, 6). Methvl 2.6-di-O-henzvl-a-D-mannopvranoside. A ca.2: 1 mixture of exo- and endo-isomers of bis-[(2,3-O-), (4,6-0-)] benzyUdene-α-D-mannopyranoside (Carbohydrates, Ed. Collins, P. M, Chapman and Hall, New York, 1987, p. 350) was prepared by reaction of methyl α-D-mannopyranoside with 2.2 eq of ocα-dimethoxytoluene and catalytic p-toluenesulfonic acid in acetonitrile. This compound was treated with NaBH4 and HC1 (Garegg, P. J.; Hultberg, H.

Carbohydrate Res. 1981, 93, CIO) to provide a mixture of products from which the methyl 2,6-O-benzyl-α-D-mannopyranoside was isolated by flash chromatography. The assignment of this isomer was confirmed by *H decoupling experiments on the corresponding bis-(3,4-O-diphenylphosphino) derivative (Ugand VA). tø NMR δ 7.42-7.24 (m, 10), 4.81 (d, 1, J = 1 Hz), 4.75-4.54 (m,

4), 3.78-3.71 (m, 6), 3.36 (s, 3), 2.83 (bs, 1), 2.43 (bs, 1).

Methvl 1.6-O-tritvl-a-D-fructoΛιranoside. The starting diol was prepared by tritylation of Methyl -α-D-fructofuranoside. (Carbohydrates, Ed. Collins, P. M., Chapman and HaU, New York, 1987, 356) with trityl chloride in pyridine.

B. Example of Modified Procedure for the Synthesis of A^PCl

Di-[(3J-bis-trifluoromethyl)-phenyl]chlorophosphine. A 1.0 M solution of (3,5-bis-trifluoromethyl)phenylmagnesium bromide was prepared by slow addition of 18.5 g (60 mmol) of (3,5-bis-trifluoromethyl)bromobenzene in 40 mL of THF to a slurry of Mg turnings in 20 mL of THF. After 1 h, this solution was added slowly to a solution of 5.0 g (29 mmol) of Et2NPCl2 in 30 mL of THF at 0°C. After 2 h, the mixture was concentrated in vacuo. Cyclohexane (100 mL) was added and the mixture was filtered through ceUte to provide a solution of [di-3,5-bis(t-rifluoromethyl)phenyl](diethyl-amino)phosphine . Dry HC1 was passed through this solution for 1 h. After filtration under a nitrogen atmosphere (in some instances, it was necessary to degas the solution to precipitate the a ine hydro- chloride) and concentration, 12.4 g (88%) of la was coUected as a white soUd. ³¹ P NMR δ 69.8; ^l NMR δ 7.66 (m, 4) 7.52 (s, 2).

Bis-(4-methoxyphenyl)chlorophosphine. ³¹ P NMR δ 85.4; *H NMR δ 7.54 (m, 4), 6.65 (m, 4), 3.17 (s, 6); ¹ C δ 134.0 (d, 1, Jpc = 26 Hz), 128.4 (d, 1, JPC = 24 Hz), 128.2 (d, 1, JPC = 24 Hz), 114.6 (d, 1, JPC = 8 Hz), 54.8.

Bis-(3J-dimethylphenyl)chlorophosphine. ³¹ P NMR d 85.3; *H NMR d 7.25 (m, 4), 6.62 (s, 2), 1.85 (m, 12).

Bis-(3j-difluorophenyl)chlorophosphine. ³¹ P NMR δ 75.3; ^l H NMR δ 6.93 (m, 4), 6.43 (m, 2).

Bis-(3J-dimethyl-4-methoxyphenyl)chlorophosphine. ³¹ P NMR δ 89.2; »H NMR δ 7.42 (d, 4, J = 12 Hz), 3.18 (s, 6), 1.98 (s, 12).

Bis-(4-fluorophenyl)chlorophosphine. ³¹ P NMR δ 80.6; ^l H NMR δ 7.12 (m, 4), 6.58 (m, 4).

Bis-(4-trifluoromethylphenyl)chlorophosphine. ³¹ P NMR δ 76.3; H NMR δ 7.33 (m, 8).

C. Synthesis of Phosphinites The Ugands were synthesized according to methods previously reported in

U.S. Patent 5,175,335 (Casalnuovo, A. L.; RajanBabu, T. V.) and the reference, Selke, R.; Pracejus, H. /. Mol. Catal. 1986, 37, 213.

D. Synthesis of Metal Catalysts In a dry box under nitrogen, a solution of 0.49 mmols of Rh(COD)2 ⁺ X"

(X = SbF6, BF4, OSO2CF3) in 5 mL of CH2CI2 was added to 0.50 mmol of phosphinite in 5 mL of CH2CI2 at room temperature. The mixture was stirred for 30 min to 3 h and the solvent was carefuUy removed under vacuum. A fine powder of the Rh-complex may be obtained by redissolving the complex in 8 mL of benzene and freeze-drying the sample under high vacuum.

The following Ugands and the corresponding catalysts were prepared according to general procedures (A-D) outlined eariier and the structures were confirmed by *H NMR and ³¹ P NMR.

I. Ligands and catalysts from phenyl 4.6-O-benzvUdene-β-D-glucopyranoside

IA. (2,3-diphenylphosphinite), R ¹ = Ph (see U.S. Patent 5,175,335, and Selke, R.; Pracejus, H. /. Mol. Catal. 1986, 37, 213 for Ugand synthesis): tIA]Rh(COD)SbF ₆ ³¹ P NMR(CDC1 ₃ ): ABX (= P ₁ P2RI1), n _a = 137.5, n _b = 138.6, JAB = 27 Hz, JAX = JBX (= JRhP) = 176 Hz; [IA]Rh(COD)BF ₄ ¹ P NMR: ABX (= P1P2RI1), η _A = 136.5, η _B = 138.0, JAB = 27 Hz, JAX = JBX (= JRhP) = 178 Hz.

Iridium Catalyst [IA]Ir(COD)BF ₄ ³¹ P NMR: 118.6 (d, 1, J _pp = 28 Hz), 120.0 (d, 1, Jp _P = 28 Hz).

IB. (Di-(bis-3,5-dimethylphenyl)phosphinite), R ¹ = 3,5-(CH3)2C6H3 (for Ugand see: U.S. Patent 5,175,335): [ffi]Rh(COD)SbF ₆ ¹ P NMR(CDC1 ): ABX (= P1P2RI1), n _a = 136.6, n _b = 136.8, JAB = 27 Hz, JAX = JBX (= JRhP) = 177 Hz; in CβD ₆ ABX (= PιP ₂ Rh), η _A = 134.0, η _B = 136.0, JAB = 29 Hz, J _A χ = J _B X (= JRhP) = 178 Hz.

IC. (Di-(4-methoxyphenyl)phosphinite), R ¹ = 4-MeO-C6H4: IC. H NMR 3.12 (s, 3 H), 3.17 (s, 3 H), 3.18 (s, 3 H), 3.20 (s, 3 H), 3.29 (t J = 10,

1 H), 3.54 (t, 10, 1 H), 3.92 (dd, J = 10, 4, 1 H), (4.51 - 4.55 (2 X dd, 2 H), 4.58 (s, 1 H), 4.59 (d, J = 8 Hz), 6.50-7.60 (m, aromatic); ³¹ P 116.59 (d, J = 3, 1 P), 121.06 (d, J = 3, 1 P). [IC]Rh(COD)SbF ₆ ¹ P NMR (CeDe) ABX (= PιP ₂ Rh), n _a = 139.5, n _b = 140.1, J _A B = 24 Hz, J _A χ = JβX (= JRhP) = 182 Hz.; [IC]Rh(COD)OTf ³ *P NMR (CβD ₆ ) ABX (= P1P2RI1), η _A = 136.8, η _B = 138.5, JAB = 28 Hz, J _A χ = JBX (= JRhP) = 181 Hz.

ID. (Di-(4-fluorophenyl)phosphinite), R ¹ = 4-F-C6H4: *H NMR δ 7.35-6.40

(m, 26), 4.82 (d, 1, J = 8 Hz), 4.80 (s, 1), 4.42 (m, 2), 3.91 (dd,l J = 5, 10 Hz), 3.28 (m, 2), 3.11 (m, 1); ³ *P NMR δ 118.0, 114.8. [ID]Rh(COD)SbF6 ³¹ P NMR(CDα3): multiplet superimposed on an ABX 8-line pattern with further smaU coupling presumably due to long range interaction with fluorines. dl26.5, 126.8, 128.0, 128.3, 129.2, 129.5, 130.8, 131.1.

IE. (Di-(3,5-difluorophenyl)ρhosphinite), R ¹ = 3,5-F2C6H3 (for Ugand, see U.S. Patent 5,175,335). [ΪE]Rh(COD)SbF ₆ ³¹ P NMR(CDCl3): ABX (= PιP2Rh), η _A = 134.7, η _B = 137.9, JAB = 28 Hz, JAX = JβX (= JRhP) = 182 Hz.

IF. (Di-(bis-3,5-trifluoromethylphenyl)phosphinite), R ¹ = 3,5-(CF3)2C6H3 (for Ugand, see U.S. Patent 5,175,335). [IF]Rh(COD)SbF6 ³¹ P NMR(C6D ₆ ): ABX (= PιP ₂ Rh), η _A = 126.8, η _B = 130.5, JAB = 36 Hz, JAX = JBX (= JRhp) = 182 Hz.

IG. (Di-(4-trifluoromethylphenyl)phosphinite), R ¹ = 4-CF3C6-H4: ^! H NMR (C6D ₆ ) 3.05(m, 1 H), 3.10-3.20 (m, 2 H), 3.90 (dd, J = 10, 6, 1 H), 4.36 (m,

2 H), 4.71 (s, 1 H), 4.78 (d, J = 7 Hz, 1 H), 6.28 (d, J = 7 Hz, 1 H), 6.60-7.40

(m, aromatic); ³ *P 113.0, 115.7; [IG]Rh(COD)BF ₄ ³¹ P NMR(C6D ₆ ): 125.0 (JPP = 36, 1 P), 117.3 (J _PP = 36 Hz, 1 P), JR _h P = 173 Hz.

IJ. (([R]-2,2'-O-Binapthyl)phosphite), R ¹ , (for ligand, see U.S. Patent 5,175,335). [U]Rh(COD)BF ₄ ³¹ P NMR(C6D ₆ ): ABX (= PιP ₂ Rh), η _A = 132.7, η _B = 138.7, JAB = HPP) = 55 Hz, JAX = JBX (=

II. Ligands and catalysts from Methyl-2.6-O-bis-(trimethvacetvlVα-D- glucopvranoside

HA. (3,4-diphenylphosphinite), R ¹ = Ph: *H NMR δ 7.50-6.78 (m, 20), 5.25 (dd, 1, J = 4, 10 Hz), 5.05 (m, 1), 5.00 (d, 1, J = 3 Hz), 4.44 (m, 1), 4.17 (dd, 1, J = 2, 12 Hz), 3.94 (ddd, 1, J = 2, 5, 10 Hz), 3.75 (dd, 1, J = 5, 12 Hz), 2.97 (s, 3), 1.14 (s, 9) 0.93 (s, 9); ³ *P NMR δ 118.0 (d, 1, J _pp = 5 Hz), 114.8 (d, 1, Jpp = 5 Hz); [IIA]Rh(COD)BF4 ³¹ P NMR(C6D ₆ ): ABX (= P1P2RI1), ηA = 134.0, η _B = 136.5, JAB = 30 Hz, JAX = JBX (= JRhP) = 178 Hz.

IIB. (3,4-Di-(bis-3,5-dimethylphenyl)phosρhinite), R ¹ = 3,5-(CH3)2C6H3: *H NMR δ 7.35-7.18 (m, 6), 6.95-6.85 (m, 2), 6.64 (s, 1), 6.53 (s, 1), 6.47 (s, 1), 6.33 (s, 1), 5.30 (m, 1), 5.08 (m, 1), 4.89 (m, 1), 4.50 (m, 1), 4.12 (dm, 1, J = 12 Hz), 3.95 (m, 1), 3.72 (m, 1), 2.88 (s, 3), 1.99 (s, 6), 1.98 (s, 6), 1.93 (s, 6), 1.90 (s, 6); ¹ P NMR δ 122.1, 117.9; [HB]Rh(COD)BF ₄ 1P NMR(C6D ₆ ): ABX (= PιP ₂ Rh), η _A = 129.0, η _B = 135.2, JAB = 30 Hz, J _A χ = JBX (= JRhP) = 176.

IIF. (3,4-Di-(bis-3,5-trifluoromethylphenyl)phosphinite), R ¹ - 3,5-(CF ₃ )2C6H3: *H NMR δ 8.01-6.63 (m, 12), 5.02 (dd, 1, J = 4, 10 Hz), 4.86 (m, 1), 4.83 (d, 1, J = 4 Hz), 4.06 (m, 1), 3.86 (m, 2), 3.65 (dd, 1, J = 6, 12 Hz), 2.90 (s, 3), 1.01 (s, 9), 0.85 (s, 9); ¹ P NMR δ 111.9, 105.7.; [πF]Rh(COD)BF ₄ In addition to the eight line pattern at 125.3, 125.7, 126.1, 126.4, 127.2, 127.6, 127.9 there is another set of broad doublets which appear around δ 130, 132, 141 and 143.

Iffl. (3,4-Di-{(bis-3,5-dimethyl)-4-O-methyl-phenyl}phosphinite), R ¹ = 3,5-

(CH ₃ ) ₂ -4-(CH ₃ O)-C6H ₂ : *H NMR δ 7.39 (m, 4), 7.30 (m, 2), 7.09 (m, 2), 5.39 (dd, 1, J = 4, 10 Hz), 5.19 (m, 1), 4.97 (d, 1, J = 4 Hz), 4.57 (m, 1), 4.12 (dd, 1, J = 1, 12 Hz), 4.04 (ddd, 1, J = 1, 4, 10 Hz), 3.77 (dd, 1, J = 5, 12 Hz), 3.38 (m, 3), 3.28 (m, 3), 3.22 (s, 3), 3.14 (s, 3), 2.95 (s, 3), 2.17 (s, 3), 2.12 (s, 6), 2.11 (s, 3), 1.16 (s, 9), 0.96 (s, 9); ³¹ P NMR δ 123.2 (d, 1, J _pp = 3 Hz), 117.8 (d, 1, Jpp = 3 Hz). [IIH]Rh(COD)BF4 ³¹ P NMR(CβD ₆ ): ABX (= PiP∑Rh), ηA = 129.3, η _B = 135.6, JAB = 30 Hz, JAX = JBX (= JRhP) = 176 Hz.

III. Ligands and catalysts from methyl 2.6-O-dibenzoyl-α-D-glucopyranoside

mA. (3,4-diphenylphosphinite), R ^! = Ph: Η NMR δ 8.12 (m, 2), 7.85 (m, 2), 7.50-6.49 (m, 16), 5.40 (dd, 1, J = 4, 12 Hz), 5.22 (m, 1), 5.08 (d, 1, J = 3 Hz), 4.70 (m, 1), 4.39 (d, 1, J = 12 Hz), 4.04 (dd, 1, J = 4, 10 Hz), 3.91 (dd, 1, J = 4, 12 Hz), 2.78 (s, 3); ³¹ P NMR δ 120.0 (d, 1, J _pp = 4 Hz), 116.0 (d, 1, Jpp = 4 Hz). [πiA]Rh(COD)BF NMR(C6D ₆ ): ABX (= PιP Rh), η _A = 130.8, η _B = 133.7, JAB = 32 Hz, J _A χ = JBX (= JRhP) = 176 Hz.

πiB. (3,4-Di-(bis-3,5-dimethylphenyl)phosphinite), R ¹ = 3,5-(CH3)2C6H3: H NMR δ 8.13 (m, 2), 7.80 (m, 2), 7.30-6.70 (m, 14), 6.63 (s, 1), 6.46 (s, 1), 6.32 (s, 1), 6.03 (s, 1), 5.51 (dd, 1, J = 4, 10 Hz), 5.23 (m, 1), 5.00 (d, 1, J = 3 Hz), 4.89 (m, 1), 4.42 (d, 1, J = 12 Hz), 4.04 (dd, 1, J = 4, 10 Hz), 3.90 (dd, 1, J = 4, 12 Hz), 2.75 (s, 3), 2.02 (s, 6), 1.91 (s, 6),1.88 (s, 6), 1.73 (s, 6); ³¹ P NMR δ 124.7, 118.8. [mB]Rh(COD)BF NMR(QsD6): ABX (= PιP ₂ Rh), η _A = 129.0, η _B = 130.4, JAB = 10 Hz, JAX = JBX (= JRhP) = 175 Hz; [mA]Rh(COD)SbF6 NMR(C6D ₆ ): ABX (= P^Rh), ηA = 132.8, η _B = 134.2, JAB = 30 Hz, JAX = JBX (= JRhP) = 151 Hz.

mC. (3,4-Di-(4-methoxyphenyl)phosphinite), R ¹ = 4-(CH ₃ O)C6H4: *H NMR δ

8.40-6.46 (m, 26), 5.69 (dd, 1, J = 4, 10 Hz), 5.45 (m, 1), 5.27 (d, 1, J = 4 Hz), 4.93 (m, 1), 4.65 (dd, 1, J = 2, 12 Hz), 4.29 (m, 1), 4.19 (m, 1), 3.41 (s, 3), 3.34 (s, 3), 3.32 (s, 3), 3.19 (s, 3), 3.02 (s, 3); ³¹ P NMR δ 120.5 (d, 1, J _pp = 5 Hz), 117.8 (d, 1, Jpp = 5 Hz). [mC]Rh(COD)BF4 NMR(C6D ₆ ): ABX

(= PιP ₂ Rh), η _A = 134.4, η _B = 136.1, JAB = 28 Hz, JAX = JBX (= JRhP) = 181 Hz.

[mE]Rh(COD)BF4 NMR(C6D ₆ ): ABX (= PiP _∑ Rh), η _A = 126.7, η _B = 127.6, JAB = 39 Hz, JAX = JBX (= JRhp) = 179 Hz.

πiF. (3,4-Di-(bis-3,5-trifluoromethylphenyl)phosphinite), R ¹ = 3,5-(CF3)2C6H3: *H NMR δ 8.22-6.89 (m, 32), 5.45 (dd, 1, J = 4, 10 Hz), 5.19 (m, 1), 5.11 (d, 1, J = 4 HZ), 4.52 (m, 1), 4.28 (d, 1, J = 12 Hz), 4.11 (dd, 1, J = 5, 10 Hz), 3.98 (dd, 1, J = 5 12 Hz), 2.93 (s, 3); ³¹ P NMR δ 113.0, 107.5.

G. (3,4-Di-(4-trifluoromethylphenyl)phosphinite), R ¹ = 4-CF3C6H3 *H NMR(C6D ₆ ) 2.80 (s, 3 H), 3.85 (dd, J = 13, 4, 1 H), 4.06 (ddm, J = 8, 4, 1 H), 4.28 (dd, J = 13, 2, 1 H), 4.60 (dt, J = 12, 12 1 H), 5.00 (m, 1 H), 5.03 (d, J = 4, 1 H), 5.28 (dd, 12, 4, 1 H), 6.70-7.60 (m, aromatic);

[iπG]Rh(COD)BF NMR(CόD6): ABX (= P^Rh), η _A = 125.2, η _B = 127.4, JAB = 37 Hz, J _A χ = JBX (= Rhp) = 177 Hz.

IV. Ligands and catalysts from methyl-2-acetamido-6-O-(t-butyldimethylsilyl)- 2-deoxv-β-D-glucopvranoside

IVA. (3,4-diphenylphosphinite), Rl = Ph Ligand: ³¹ P NMR (C6D6) 112.70 (d, Jpp = 5 Hz), 117.17 (d, Jpp = 5 Hz); [IVA]RhSbF6 (Cφβ) ABX (= PPRh), η _A = 122.5, η _B = 129.2, JAB (JPP) = 35, J _RhP = 173.

IVB. (3,4-Di-(bis-3,5-dimethylphenyl)phosphinite), R ¹ = 3,5-(CH3)2C6H : 1H NMR δ 7.55-7.22 (m, 8), 6.86 (s, 1), 6.72 (s, 1), 6.64 (s, 1), 6.59 (s, 1), 5.26 (m, 1), 5.13 (d, 1, J = 8 Hz), 4.73 (m, 2), 4.42 (m, 1), 3.80 (m, 3), 3.49 (s, 3), 2.20 (s, 15), 2.17 (s, 6), 2.11 (s, 6), 1.12 (s, 9), 0.16 (s, 3), 0.15 (s, 3); ¹ P NMR δ 120.4 (d, 1, J _pp = 4 Hz), 115.7 (d, 1, J _pp = 4 Hz); [IVB]RhBF (C6D ₆ ) ABX (= PPRh), η _A = 118.9, η _B = 126.6, JAB (JPP) = 34, JRUP = 170.

V. Ligands and catalysts from methyl-2.6-O-dibenzvl-α-D-mannopvranoside

VA. (3,4-diphenylphosphinite), R ^l = Ph: *H NMR δ 7.78-6.80 (m, 20), 5.09 (m, 1), 4.95 (m, 1), 4.72 (d, 1, J = 2, Hz), 4.22 (m, 4), 4.11 (m, 1), 4.02 (m, 1), 3.55 (m, 2), 3.13 (s, 3); *P NMR δ 117.3, 110.4; [VA]Rh(COD)BF ₄ (C6D ₆ ) ^3l P: η _A = 129.2, η _B = 137.2, J _PP = 27, J _RhP = 177; [VB]Rh(COD)BF4(C6D ₆ ) ^3l P: η _A = 124.8, η _B = 133.9, J _pp = 30; JRI,^ = 176.

SUBSTTT

VI. Ligands and catalysts from methyl-6-O-fr-butyldimethvlsilvlV2-deoxv-α-D- glucopyranoside

VIB. (3,4-Di-(bis-3,5-dimethylphenyl)phosphinite), R ¹ =3,5-(CH3)2C6H3: 1H NMR δ 7.61-7.26 (m, 8), 6.88 (s, 1), 6.81 (s, 1), 6.65 (s, 1), 6.60 (s, 1), 5.20 (m, 1), 4.64 (m, 1), 4.45 (d, 1, J = 3 Hz), 3.14 (s, 3), 2.21 (s, 6), 2.16 (s, 6), 2.14 (s, 6), 2.12 (s, 6), 1.11 (s, 9), 0.11 (s, 3), 0.11 (s, 3); ¹ P NMR δ 121.1 (d, 1 Jpp = 2 Hz), 113.1 (d, 1, Jpp = 2 Hz); [VIB]Rh OTf (C ₆ D ₆ ) ABX (= PPRh), η _A = 123.6, η _B = 128.2, JAB (JPP) = 34, J _RhP = 173. [VIB]Ph(COD)BF4 ³¹ P(C6D ₆ ) ABX (=PPRh) η _A = 124.9, η _B = 127.4, JAB =

VII. Ligands and catalysts from methvl-5.6-O-triphenvlmethvl-α-D- fructofuranoside

Tr = triphenylmethyl

VIIA. (3,4-diphenylphosphinite), R ¹ = Ph: *H NMR (C6D ₆ ) 3.10 (s, 3H), 3.35, 3.45 (ABX, J _A B = 10, JAX = 7, J _B χ = 6, 2 H), 3.60, 3.78 (AB, JAB = 10, 2 H), 4.50 (ddm, br, 1H), 4.88 (m, 1H), 5.00 (d, J = 10, 1 H), 6.80-7.80 (m, aromatic); ³¹ P NMR (C6D ₆ ) 114 , 115.1 (AB, J _PP = 9). [VIIA]RhSbF6 (C6D ₆ ) ABX (= PPRh), η _A = 119.7, η _B = 122.8 JAB (Jpp) = 29, J _RhP = 166.

VIIB. (3,4-Di-(bis-3,5-dimethylphenyl)phosphinite), Rl =3,5-(CH ₃ )2C6H3: 1H NMR δ 1.85, 1.91, 1.94, 2.05 (4Xs, 3H each), 3.10 (s, 3H), 3.45-3.60

(ABX, JAB = 9, JAX = JBX = 5, 2H), 3.67, 3.80 (ABq, JAB = 10, 2H), 4.47 (qm, br, 1H), 5.63 (d, J = 11 Hz, 1 H), 5.20 (m, 1 H), 6.50-7.80 (m, aromatic); ³ *P NMR (QjDo) δ 116.41(d, J _PP = 8, 1 P), 118.53(d, J _PP = 8, 1 P).

[VHB]Rh(COD)BF ₄ : ³¹ P NMR(C ₆ D ₆ ): 114.2 (dd, J _Rh p = 169, J _PP = 28, 1 P), 131.5 (dd, JR _h P = 169, J _PP = 28, 1 P).

VπC. (3,4-Di-(4-methoxyphenyl)phosphinite), R! = 4-(CH3θ)C6H4: ^! H NMR (C6D ₆ ) 3.05-3.30 (4Xs total 15 H), 3.40, 3.50 (ABX, JAB = 10, JAX = 7, JBX = 6, 2 H), 3.61, 3.79 (AB, J _A B = 10, 2 H), 4.58 (ddm, br, 1H), 4.90 (m, 1H), 5.05 (d, J = 10, 1 H), 6.42-7.61 (m, aromatic); ³ *P NMR (C6D ₆ ) 115.0, 115.2 (AB, Jpp = 7). [VπC]Rh(COD)SbF ₆ (QjDβ) ABX (= PPRh), n _A = 121.8, n _B =

122.1, JAB (= JPP) = 27, J _Rh p = 167; [VπC]Rh(COD)OTf (CβD ₆ ) ABX (= PPRh), η _A = 121.3, η _B = 121.9, JAB (= JPP) = 28, J _RhP = 166.

Vm. Ligands and catalysts from 2-naphthyl 4.6-O-benzylidene-β-D- glucopyranoside

VmA. (2,3-diphenylphosphinite), R ¹ = Ph: *H NMR 3.25 (dt, J = 8, 4, 1 H), 3.35 (t, J = 9, 1 H), 3.51 (t, J = 9, 1 H), 4.00 (dd, J = 8, 4, 1 H), 4.40-4.60 (m, 2 H), 4.85 (s, 1 H), 5.02 (d, J = 8, 1 H), 6. 50-7.52 (m, aromatic). [VmA]Rh(COD)SbF ₆ ³¹ P NMR(CDC1 ₃ ): ABX (= PιP2Rh), η _A = 137.9, η _B =

139.2, JAB = 21 Hz, JAX = JBX (= JRhP) = 192 Hz

Asymmetric Hydrogenation Reactions:

General Procedure for Scouting Reactions. In the dry box, a 150 mL Fisher-Porter tube was charged with 50 mg of acetamidoacrylate derivative, 1 mg of L*Rh(COD)A, and 1 mL of solvent (THF, MeOH, DME, etc.). The tube was sealed and charged with H2 (10-100 psi). After 3 h, the tube was vented. When Z ³ = CH3, the crude product was analyzed directly by GC (25 m x 0.25 mm ChiralsU L- VAL capillary column) for enantiomeric excess determination. In the case of Z ³ = H, the crude product was treated with diazomethane prior to analysis by GC. Pure samples of the amino acid derivatives were obtained by recrystalUzation or by flash chromatography and characterized by *H NMR.

Synthesis of D-amino acid derivatives flR-configurationl

Examples 1-56 provide D-amino acids under the hydrogenation conditions desribed above.

Table 1

Hydrogenation of Dehydroamin- D Acid Derivatives

[Z ¹ Z ² C=C(Cθ2Z ³ )(NHZ ⁴ ), Z ¹ = H, Z ⁴ = = Ac] Using L*Rh(COD)A*

Ex. Cat Z2 Z ³ % ee (R-) Conditions ⁸

1 [πA]Rh(COD)BF C6H5 CH3 80.2

2 [IIA]Rh(COD)BF4 C6H5 CH3 84 run at-10°C

3 [IIB]Rh(COD)BF4 C6H5 CH3 92.4

4 [IIB]Rh(COD)BF4 C6H5 CH3 94.5 run at-10°C

5 [IIF]Rh(COD)BF4 C6H5 CH3 11

6 [πH]Rh(COD)BF4 C6H5 CH3 93.1

7 [πA]Rh(COD)BF4 C6H5 CH3 39.8 run in MeOH

8 [IIB]Rh(COD)BF4 C6H5 CH3 91.4 run inDME

9 [HB]Rh(COD)BF4 C6H5 CH3 88.1 run in Toluene

10 [-HB]Rh(COD)BF ₄ C6H5 CH3 87.6 run in Bu2θ

11 [IIB]Rh(COD)BF4 Q5H5 CH3 76.4 run in EtOH

12 [-HB]Rh(COD)BF ₄ C6H5 CH3 74.5 run in MeOH

13 [πH]Rh(COD)BF ₄ C6H5 CH3 88.4 run in BU2O

14 [πH]Rh(COD)BF ₄ C6H5 CH3 88.2 run in Toulene

15 [πH]Rh(COD)BF C6H5 CH3 92.4 ru inDME

16 [πH]Rh(COD)BF C6H5 CH3 80.0 runin EtOH

17 [im]Rh(COD)BF4 C6H ₅ CH3 79.0 run in MeOH

18 [IIB]Rh(COD)BF4 C6H5 H 94.5

19 [IIB]Rh(COD)BF4 4-FC6-H4 CH3 92.0

20 [IIB]Rh(COD)BF4 3-(MeO)C6H4 CH3 93.1

21 [IIB]Rh(COD)BF4 2-Napth CH ₃ 92.0

22 [IIB]Rh(COD)BF4 2-Napth H 93.0

23 [mA]Rh(COD)BF ₄ C6H5 CH3 58.7

24 [mB]Rh(COD)BF4 C6H5 CH ₃ 93.0

25 [mC]Rh(COD)BF C6H5 CH3 84.7

26 [mE]Rh(COD)BF4 C6H5 CH3 1.0

27 [mF]Rh(COD)BF4 C6H5 CH3 2.3

28 [mG]Rh(COD)BF ₄ C6H5 CH3 2.0

29 [mB]Rh(COD)SbF ₆ C6H5 CH3 96.0

30 [mB]Rh(COD)BF4 C6H5 CH3 94.0 run inDME

31 [DIB]Rh(COD)BF4 C6H5 CH3 77.9 run in MeOH

32 [mB]Rh(COD)BF ₄ C6H5 CH3 87.6 run in Toluene

33 [mB]Rh(COD)BF4 C6H5 H 95.8

34 [mB]Rh(COD)SbF6 C6H5 H 97.0

35 [IIIB]Rh(COD)SbF6 4-FC6H4 CH3 96.2

36 [mB]Rh(COD)BF4 4-FC6-H4 CH3 80.2 run in MeOH 37b [mB]Rh(COD)SbF ₆ 4-FC6H4 CH3 90«

38 [mB]Rh(COD)BF4 4-FC6H4 H 95.4

39 [mB]Rh(COD)SbF6 4-FC6H4 H 96.4

40 [mB]Rh(COD)SbF6 (CH ₃ )2CH H 89.2 41 [mB]Rh(COD)SbF6 3-thienyl CH ₃ 97.0

42 [IVA]Rh(COD)BF ₄ C6H5 CH3 94.9

43 [IVB]Rh(COD)BF4 C6H5 CH3 98.3

44 [IVA]Rh(COD)BF4 C6H5 H 94.5

45 [IVB]Rh(COD)BF4 C6H5 H 94.5

46 [IVB]Rh(COD)BF4 4-FC6H4 CH3 97.8

47 [VA]Rh(COD)BF ₄ C6H5 CH3 55.4

48 [VA]Rh(COD)BF C6H5 CH3 18.1 run in MeOH

49 [VB]-Rh(COD)BF ₄ C6H5 CH3 72.2

50 [VIB]Rh(COD)OTf C6H5 CH3 76.0

51 [VIB]Rh(COD)BF4 C6H5 CH3 65.1 52 [VIIA]Rh(COD)SbF6 C6H5 CH3 48.0

53 [VπC]Rh(COD)SbF ₆ C6H5 CH3 51

54 rVΗA]Rh(COD)SbF ₆ C6H5 H 51.0

55 [VπA]Rh(COD)SbF ₆ 4-FC6H4 CH3 53.0

56 [VIIB]Rh(COD)BF4 4-FC6H4 CH ₃ 56.8

57 rvπC]Rh(COD)SbF ₆ 4-FC6H4 CH3 57.0 ^a Reaction performed at ambient temperature in THF under 40 psi of H pressure unless noted. ^b In this case, Z ⁴ = C(0)OCH ₂ Ph (Cbz).

^C EE determined on alcohol after reduction of crude product with UBH ₄ .

Synthesis of L-amino acid derivatives (S-configuration ^' )

Examples 57-98 provide L-amino acids under the hydrogenation conditions desribed above.

Table 2

Hydrogenation 1 of Dehydroamino Acid Derivatives Z ¹ = H, Z ⁴ = Ac] Using L*Rh(COD)A ⁸

Ex. Cat Z2 Z ³ % ee (S-) Remarks ⁸

57 [ffi]Rh(COD)SbF ₆ C6H5 CH3 96

58 [IE]Rh(COD)SbF6 C6H5 CH ₃ 2.0

59 [IG]Rh(COD)BF4 C6H5 CH3 9.8

60 [IA]Rh(COD)SbF ₆ C6H5 H 94.0

61 [-ffi]Rh(COD)SbF ₆ C6H5 H 99

62 [IC]Rh(COD)SbF ₆ C6H5 H 93.0

63 [IC]Rh(COD)OTf C6H5 H 96.0

64 [ID]Rh(COD)SbF6 C6H5 H 91

65 [IE]Rh(COD)SbF6 C6H5 H 60

66 [IF]Rh(COD)SbF6 C6H5 H 71

67 [U]Rh(COD)SbF ₆ C6H5 H 47.0

68 [IA]Rh(COD)SbF ₆ 4-FC6H4 CH3 84.0

69 [IA]Rh(COD)BF ₄ 4-FC6H4 CH3 85.0

70 [-ffi]Rh(COD)SbF ₆ 4-FC6H4 CH ₃ 97.2

71 [IC]Rh(COD)SbF ₆ 4-FC6H4 CH3 89

72 [ID]Rh(COD)SbF6 4-FC6H4 CH3 81.0

73 [IE]Rh(COD)SbF6 4-FC6H4 CH3 13

74 [IF]Rh(COD)SbF6 4-FC6H4 CH3 9

75 [IB]Rh(COD)SbF6 4-FC6H4 CH3 96.7 run in EtOH

76 [IB]Rh(COD)SbF6 4-FC6H4 H 98.0

77b [IA]Rh(COD)SbF ₆ 4-FC6H4 CH ₃ 62c

78 ^b [IB]Rh(COD)SbF6 4-FC6H4 CH3 97.0 ^C

79b [IC]Rh(COD)SbF ₆ 4-FC6H4 CH ₃ 85.0c

80 ^b [IF]Rh(COD)SbF6 4-FC6H4 CH3 54 ^C

81 [IB]-Rh(COD)SbF ₆ 3-(MeO)C6H4 CH3 98.1

82 [IE]Rh(COD)SbF6 3-(MeO)C6H4 CH3 21.0

83 [IA]Rh(COD)SbF6 3-(MeO)C6H4 H 91

84 [IB]Rh(COD)SbF6 3-(MeO)C6H4 H 97.0

85 [ffi]Rh(COD)SbF ₆ 3-(MeO)C6H4 H 53.0

86 [IF]Rh(COD)SbF6 3-(MeO)C6H4 H 5

87 [IA]Rh(COD)BF ₄ 2-Napth H 94.2

88 [-ffi]Rh(COD)SbF ₆ 2-Napth H 97.9

89 [IB]Rh(COD)SbF6 4-BrC6H4 H 98

90 [ffi]Rh(COD)SbF ₆ 4-BrC6H4 H 47

91 [IA]Rh(COD)SbF ₆ (CH ₃ ) ₂ CH H 90.0

92 [IB]Rh(COD)SbF6 (CH ₃ ) ₂ CH H 91.0

93 [IC]Rh(COD)SbF ₆ (CH ₃ )2CH H 83.3

94 [IF]Rh(COD)SbF6 (CH ₃ ) CH H 26.0

95 [IA]Rh(COD)SbF ₆ 3-thienyl CH3 86.6

96 [IB]Rh(COD)SbF6 3-thienyl CH3 96.7

97 [VmA]Rh(COD)SbF ₆ Q3H5 H 89

98 [VmA]Rh(COD)SbF ₆ 3-(MeO)CβH4 H 89.0 ^a Reaction performed at ambient temperature in THF under 40 psi of H ₂ pressure unless noted. ^b In this case, Z ⁴ = C(0)OCH2Ph (Cbz).

^C EE determined on alcohol after reduction of crude product with UBH ₄ .

Hydrogenation using Ir catalyst

A solution of 50 mg (0.23 mmol) of methyl acetamidocinnamte and 1 mg of [IA]Ir(COD)BF4 in 1 mL of THF was placed in a Fisher-Porter tube in the drybox. This material was charged with 30 psi of H2 pressure and heated to 100°C. The pressure rose to 50 psi. After 3 h, the tube was vented and analyzed as usual. A 7.7% ee (enriched with S-isomer) was obtained.