This invention pertains to a process for the preparation of enantiomerically-enriched cyclopropylalanine derivatives. More specifically, this invention pertains to the synthesis of enantiomerically-enriched cyclopropylalanine derivatives by the hydrogenation of certain enamides in the presence of a catalyst comprising a transition metal and a substantially enantiomerically-pure bis-phosphine catalyst. The present invention also pertains to a novel 3-step process for the preparation of enantiomerically-enriched cyclopropylalanine derivatives comprising the steps of forming an azlactone from an N-acylglycine and cyclopropanecarboxaldehyde, converting the azlactone to the aforesaid enamide which then is hydrogenated in the presence of a catalyst comprising a transition metal and a substantially enantiomerically-pure bis-phosphine catalyst. In addition, the present invention pertains to a novel two-step process for the preparation of enantiomerically-enriched cyclopropylalanine derivatives comprising the steps of reacting cyclopropylcarboxaldehyde with a substituted phosphorylglycine to afford the aformentioned enamide which then is hydrogenated in the presence of a catalyst comprising a transition metal and a substantially enantiomerically-pure bis-phosphine catalyst. The present invention further pertains to certain novel intermediate enamide ester compounds which are intermediates in the process.
Cyclopropylalanine and its derivatives are important intermediates in the synthesis of many valuable pharmaceuticals. For example, S. Thompson and coworkers (PCT Published Patent Application 99/53039) have identified a L-cyclopropylalanine-containing peptide as an effective cysteine protease inhibitor used for the treatment of parasitic diseases. Thus, an efficient and flexible synthesis of cyclopropylalanine derivatives in high yield and high enantiomeric purity is needed.
The synthesis of racemic cyclopropylalanine has been reported previously. Amino, Y., et al., Bull. Chem. Soc. Jpn. 1991, 64,1040-1042 describe the reaction of carbon monoxide and hydrogen with cyclopropane-methanol and acetamide in the presence of a cobalt catalyst to produce racemic N-acetyl cyclopropylalanine. Meek, J. S., et al., J. Org. Chem. 1955, 6675-6678; and Black, D., et al. J. Chem. Soc. (C), 1968, 288-289 disclose the hydrolysis of diethyl cyclopropylcarbinyl(formylamido)malonate to produce cyclopropylalanine after extensive work-up. However, no method for the preparation and/or isolation of enantiomerically enriched cyclopropylalanine is mentioned.
Chemoenzymatic syntheses of enantiomerically enriched cyclopropylalanine derivatives start from racemic cyclopropylalanine. For example, Chenault, H. K., et al. J. Am. Chem. Soc. 1989, 111, 6354-6464 disclose the isolation of L-cyclopropylalanine 1 after treatment of racemic N-acetyl-cyclopropylalanine with Acylase I. Alternatively, Harmon, C.; Rawlings, C. Syn. Commun. 1996, 26, 1109-1115 disclose the treatment of racemic N-acetyl-cyclopropylalanine with porcine pancreatic acylase I to produce L-cyclopropylalanine in the completely deprotected form. These enzymatic methods generally require several steps, e.g., greater than 6 synthetic steps, and the final step is limited to 50% yield. 
Myers, A. G.; Gleason, J. L.; Yoon, T.; Kung, D. W. J. Am. Chem. Soc. 1997, 119, 656-673, describe the asymmetric synthesis of both D- and L-cyclopropylalanine derivatives using an asymmetric alkylation of the lithium enolate of pseudoephedrine glycinamide 2 with cyclopropylmethyl bromide to provide the amino acid derivative 3. However, this method requires the use of a stoichiometric amount of an expensive chiral auxiliary and further synthetic manipulation is required to remove the auxiliary after alkylation. Additionally, two distinct starting materials must be used to isolate either R- or S-cyclopropylalanine. The (S,S)-pseudoephedrine derivative provides only the D-amino acid derivative, whereas the (R,R)-pseudoephedrine derivative must be used to isolate the amino acid in the L-configuration. 
Transition-metal catalyzed asymmetric hydrogenation has been used extensively in the production of xcex1-amino acids from the corresponding enamide esters. See, for example, Burk, M. J.; et al. in Transition Metals for Organic Synthesis, Beller, M., Bolm, C. Eds.; and Wiley-VCH: Basel, 1998; vol. 2, pg 13-25. Catalytic asymmetric hydrogenation of enamide esters has the advantage of the use of catalytic amounts (substrate to catalyst ratios of  greater than 100) of expensive chiral reagents as well as access to both R- and S-enantiomers of the xcex1-amino acid from a common starting material. Additionally, in some cases, a variety of different functionalities are tolerated at both the amine and carboxyl termini of the amino acid precursor, which eliminates the need for further protecting group manipulations. However, catalytic asymmetric hydrogenation of cyclopropylalanine derivatives has not been reported in the literature. This deficiency is not surprising since hydrogenation of substrates containing cyclopropyl moieties is not trivial, as it is well known that transition metal-catalyzed hydrogenolysis of cyclopropyl groups occurs readily (Newham, J. Chem. Rev. 1963, 63,123-135).
One embodiment of the present invention is a process for the preparation of an enantiomerically-enriched cyclopropylalanine compound having the formula 
which comprises contacting an enamide having the formula 
with hydrogen in the presence of a catalyst system comprising a transition metal and a substantially enantiomerically-pure bis-phosphine under hydrogenation conditions of pressure and temperature; wherein R1 is hydrogen, substituted or unsubstituted C1 to C20 alkyl, substituted or unsubstituted C1 to C20 alkoxy, substituted or unsubstituted C3 to C8 cycloalkyl, substituted or unsubstituted C3 to C8 cycloalkoxy, substituted or unsubstituted carbocyclic C6 to C20 aryl, substituted or unsubstituted carbocyclic C6 to C20 aryloxy, substituted or unsubstituted C4 to C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen or substituted or unsubstituted C4 to C20 heteroaryloxy wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen; and R2 is hydrogen, substituted or unsubstituted C1 to C20 alkyl, substituted or unsubstituted C3 to C8 cycloalkyl, substituted or unsubstituted carbocyclic C6 to C20 aryl, or substituted or unsubstituted C4 to C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen. This embodiment of our invention is unique since it produces an enantiomerically-enriched cyclopropylalanine compound without significant hydrogenolysis of the cyclopropyl ring.
Another embodiment of the present invention is a process for the preparation of an enantiomerically-enriched cyclopropylalanine compound having formula 4 or 5 by means of a novel combination of steps comprising (1) contacting cyclopropanecarboxaldehyde (CPCA) with an N-acylglycine having the formula 
in the presence of a carboxylic acid anhydride and a base at elevated temperature to produce an azlactone having the formula 
(2) contacting azlactone 8 with an alcohol optionally in the presence of an alkali or alkaline earth metal alkoxide or hydroxide to produce an enamide having the formula 
and (3) contacting enamide 6 with hydrogen in the presence of a catalyst system comprising a transition metal and a substantially enantiomerically-pure bis-phosphine under hydrogenation conditions of pressure and temperature; wherein R1 and R2 are defined above.
A third embodiment of the present invention involves a process for the preparation of an enantiomerically-enriched cyclopropylalanine compound having formula 4 or 5 by means of another novel combination of steps comprising
(i) contacting cyclopropanecarboxaldehyde (CPCA) with an N-acylglycine having the formula 
in the presence of a carboxylic acid anhydride at elevated temperature to produce an azlactone having the formula 
(ii) contacting azlactone 10 with an alcohol optionally in the presence of an alkali or alkaline earth metal alkoxide or hydroxide to produce an enamide having the formula 
(iii) contacting enamide 11 with an acylating agent having the formula R4Oxe2x80x94C(O)xe2x80x94Oxe2x80x94C(O)xe2x80x94OR4 or R4Oxe2x80x94C(O)xe2x80x94X wherein X is fluorine, chlorine, bromine, or iodine in the presence of 4-(N,N-dimethylamino)pyridine (DMAP) and an inert (non-reactive) organic solvent to produce an amido-carbamate having formula 12 
(iv) contacting amido-carbamate 12 with a nucleophile in the presence of an inert (non-reactive) organic solvent to produce a second enamide having formula 13 
and (iv) contacting enamide 13 with hydrogen in the presence of a catalyst system comprising a transition metal and a substantially enantiomerically-pure bis-phosphine under hydrogenation conditions of pressure and temperature;
wherein
R2 is defined above; and
R3 and R4 are independently selected from substituted and unsubstituted C1 to C20 alkyl, substituted and unsubstituted C3 to C8 cycloalkyl, substituted and unsubstituted carbocyclic C6 to C20 aryl, substituted and unsubstituted C4 to C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen.
A fourth embodiment of the invention concerns a process for the preparation of an enantiomerically-enriched cyclopropylalanine compound having formula 4 or 5 by means of a novel combination of steps comprising (a) reacting cyclopropanecarboxaldehyde with a phosphonate ester having formula 19: 
in the presence of a base in an inert organic solvent to produce enamide 6 
and (b) contacting enamide 6 with hydrogen in the presence of a catalyst system comprising a transition metal and a substantially enantiomerically-pure bis-phosphine under hydrogenation conditions of pressure and temperature;
wherein
R1 and R2 are as defined above; and
R16 is selected from substituted and unsubstituted C1 to C20 alkyl, substituted and unsubstituted C3 to C8 cycloalkyl, substituted and unsubstituted carbocyclic C6 to C20 aryl, substituted and unsubstituted C4 to C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen.
Additional embodiments of our invention are represented by the enamides of formulas 6 and 13 which are novel compositions of matter.
The first embodiment of the present invention provides for the preparation of an enantiomerically-enriched cyclopropylalanine compound having formula 4 or 5 by contacting an enamide having formula 6 with hydrogen in the presence of a catalyst system comprising a transition metal and a substantially enantiomerically-pure bis-phosphine under hydrogenation conditions of pressure and temperature. This embodiment of our invention is unique since it produces an enantiomerically-enriched cyclopropylalanine compound without significant hydrogenolysis of the cyclopropyl ring. Examples of the transition metal component of the catalyst include ruthenium, rhodium and iridium with ruthenium and rhodium being preferred. Examples of the bis-phosphine component of the catalyst include, but are not limited to, either substantially pure enantiomer or diastereomer of 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane (DIOP), 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl (BINAP), 1,2-bis-(2,5-dialkylphospholano)benzene (DuPHOS), 1,2-bis-2,5-dialkylphospholano(ethane) (BPE), 2,3-bis-(diphenylphosphino)butane (CHIRAPHOS), 2-diphenylphosphinomethyl-4-diphenylphosphino-1-t-butoxycarbonylpyrrolidine (BPPM) and certain bis-phosphine compounds comprising a substantially enantiomerically pure chiral backbone linking two phosphine residues wherein one of the phosphine residues has three phosphorus-carbon bonds and the other phosphine residue has two phophorus-carbon bonds and one phosphorus-nitrogen bond wherein the nitrogen is part of the chiral backbone, e.g., N-alkyl-N-diphenylphosphino-1-[2-(diphenylphosphino)ferrocenyl]ethylamine. The bis-phosphine component preferably is N-alkyl-N-diphenylphosphino-1-[2-(diphenylphosphino)ferrocenyl]alkylamine wherein each alkyl group independently contains 1 to 6 carbon atoms, e.g., N-methyl-N-diphenylphosphino-1-[2-(diphenylphosphino)ferrocenyl]ethylamine, and 1,2-bis-(2,5-dialkylphospholano)benzene (DuPHOS) wherein each alkyl group contains 1 to 6 carbon atoms. The ratio of gram-atoms of transition metal to gram-moles of bis-phosphine may be in the range of about 0.1:1 to 2:1,preferably about 0.8:1. The active catalyst comprises a complex of the transition metal and the bis-phosphine and may be formed in situ prior to asymmetric hydrogenation or formed and isolated independently.
Except for the novel phosphinoamino-phosphines described below, the substantially enantiomerically-pure bis-phosphines described above are known compositions of matter and can be obtained commercially and/or prepared according to known procedures. The novel phosphinoamino-phosphines which may be employed in the present invention are substantially enantiomerically pure bis-phosphine compounds comprising a substantially enantiomerically pure chiral backbone linking two phosphine residues wherein one of the phosphine residues has three phosphorus-carbon bonds and the other phosphine residue has two phophorus-carbon bonds and one phosphorus-nitrogen bond wherein the nitrogen is part of the chiral backbone. These compounds are the first examples of chiral bis-phosphines combining a tri-hydrocarbylphosphine with a dihydrocarbyl-aminophosphine. Examples of the substantially enantiomerically pure, i.e., an enantiomeric excess of 90% or greater, phosphinoamino-phosphine compounds include phosphinometallocenyl-aminophosphines having the general formulas 14 and 15 (the enantiomer of 14): 
wherein
R5 is selected from substituted and unsubstituted, branched- and straight-chain C1 to C20 alkyl, substituted and unsubstituted C3 to C8 cycloalkyl, substituted and unsubstituted C6 to C20 carbocyclic aryl, and substituted and unsubstituted C4 to C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen;
R6, R7, R8, R9, and R10 are independently selected from hydrogen, substituted and unsubstituted, branched- and straight-chain C1 to C20 alkyl, substituted and unsubstituted C3 to C8 cycloalkyl, substituted and unsubstituted C6 to C20 carbocyclic aryl, and substituted and unsubstituted C4 to C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen;
n is 0 to 3;
m is 0 to 5; and
M2 is selected from the metals of Groups IVB, VB, VIB, VIIB and VIII. Examples of the groups which R5, R6, R7, R8, R9, and R10 may represent are given below in the description of the R1 and R2 radicals. The substantially enantiomerically pure, phosphinometallocenyl-aminophosphines which presently are preferred have formulas 14 and 15 wherein R5 is C1 to C6 alkyl; R6 is hydrogen or C1 to C6 alkyl; R7 and R8 are aryl, most preferably phenyl; R9 and R10 are hydrogen; and M2 is iron, ruthenium, or osmium, most preferably iron.
The bis-phosphine 14 may be prepared by the steps comprising:
(1) contacting a dialkyl amine having formula 16: 
with a carboxylic anhydride having the formula (R13CO)2O to obtain an ester compound having formula 17: 
(2) contacting the ester produced in step (1) with an amine having the formula H2Nxe2x80x94R6 to obtain an intermediate amino-phosphine compound having formula 18: 
(3) contacting intermediate compound 18 with a halophosphine having the formula Xxe2x80x94P(R7)2;
wherein R5, R6, R7, R8, R9, R10, n, m, and M2 are defined hereinabove, R11 and R12 are independently selected from substituted and unsubstituted, branched- and straight-chain C1 to C20 alkyl, substituted and unsubstituted C3 to C8 cycloalkyl, substituted and unsubstituted C6 to C20 carbocyclic aryl, and substituted and unsubstituted C4 to C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen, R13 is a C1 to C4 alkyl radical, and X is chlorine, bromine, or iodine. The compounds of formula 15 may be prepared when dialkylamine having formula 19: 
is used as the starting material affording intermediates 20 and 21 analogous to 17 and 18,respectively. 
The hydrogenation reaction is carried out in the presence of one or more inert (non-reactive) organic solvent. Examples of inert solvents include aliphatic hydrocarbons such as hexane, heptane, octane and the like, aromatic hydrocarbons such as toluene, xylenes and the like, cyclic and acyclic ethers such as tert-butyl methyl ether, diisopropyl ether, tetrahydrofuran and the like, lower alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and the like, halogenated aliphatic or aromatic hydrocarbons such as dichloromethane, tetrachloroethylene, chloroform, chlorobenzene and the like, dialkyl ketones such as acetone, 2-butanone, 3-pentanone, methyl isopropyl ketone, methyl isobutyl ketone and the like, and polar aprotic solvents such as dimethylformamide, dimethyl sulfoxide and the like. Tetrahydrofuran and acetone are preferred solvents. The hydrogenation may be carried out using enamide 6 (or 13) concentrations between about 0.01 M to 10 M, preferably about 0.1 to 3 M.
The hydrogenation conditions of pressure and temperature which may be used in the hydrogenation of enamides 6 or 13 may be in the range of about 0.5 to 69 bars gauge (barg, approximately 7 to 1000 pounds per square inch gaugexe2x80x94psig) hydrogen pressure and about xe2x88x9220 to 100xc2x0 C. The hydrogenation conditions preferably are a hydrogen pressure of about 0.69 to 20.7 barg (approximately 10 to 300 psig) and a temperature of 10 to 35xc2x0 C. The reaction may be run until the majority of the olefin of the enamide is hydrogenated to the xcex1-amino acid derivative.
The alkyl groups which may be represented by each of R1 and R2 may be straight- or branched-chain, aliphatic hydrocarbon radicals containing up to about 20 carbon atoms and may be substituted, for example, with one to three groups selected from C1 to C6 alkoxy, C1 to C6 alkylthio, cyano, nitro, C2 to C6 alkoxycarbonyl, C2 to C6 alkanoyloxy, aryl and halogen. The terms xe2x80x9cC1 to C6 alkoxyxe2x80x9d, xe2x80x9cC1 to C6 alkylthioxe2x80x9d, xe2x80x9cC2 to C6 alkoxycarbonylxe2x80x9d, and xe2x80x9cC2 to C6 alkanoyloxyxe2x80x9d are used to denote radicals corresponding to the structures xe2x80x94OR14, xe2x80x94SR14, xe2x80x94CO2R14, and xe2x80x94OCOR14, respectively, wherein R14 is C1 to C6 alkyl or substituted C1 to C6 alkyl. The term xe2x80x9cC3 to C8 cycloalkylxe2x80x9d is used to denote a saturated, carbocyclic hydrocarbon radical having three to eight carbon atoms. The aryl groups which each of R1 and R2 may represent may include phenyl and phenyl substituted with one to three substituents selected from C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, halogen, carboxy, cyano, C1 to C6 alkanoyloxy, C1 to C6 alkylthio, C1 to C6 alkylsulfonyl, trifluoromethyl, hydroxy, C2 to C6 alkoxycarbonyl, C2 to C6 alkanoylamino and xe2x80x94Oxe2x80x94R15, Sxe2x80x94R15, xe2x80x94SO2xe2x80x94R15, xe2x80x94NHSO2R15 and xe2x80x94NHCO2R15, wherein R15 is phenyl or phenyl substituted with one to three groups selected from C1 to C6 alkyl, C1 to C6 alkoxy and halogen.
The heteroaryl radicals include a 5- or 6-membered aromatic ring containing one to three hetero atom selected from oxygen, sulfur and nitrogen. Examples of such heteroaryl groups are thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidyl, benzoxazolyl, benothiazolyl, benzimidazolyl, indolyl and the like. The heteroaryl radicals may be substituted, for example, with up to three groups such as C1 to C6 alkyl, C1 to C6 alkoxy, substituted C1 to C6 alkyl, halogen, C1 to C6 alkylthio, aryl, arylthio, aryloxy, C2 to C6 alkoxycarbonyl and C2 to C6 alkanoylamino. The heteroaryl radicals also may be substituted with a fused ring system, e.g., a benzo or naphtho residue, which may be unsubstituted or substituted, for example, with up to three of the groups set forth in the preceding sentence. The term xe2x80x9chalogenxe2x80x9d is used to include fluorine, chlorine, bromine, and iodine.
The alkoxy groups which R1 may represent may be straight- or branched-chain, aliphatic hydrocarbon radicals containing up to about 20 carbon atoms and may be substituted, for example, with one to three groups selected from C1 to C6 alkoxy, C1 to C6 alkylthio, cyano, nitro, C2 to C6 alkoxycarbonyl, C2 to C6 alkanoyloxy, aryl and halogen. The term xe2x80x9cC3 to C8 cycloalkoxyxe2x80x9d is used to denote a saturated, carbocyclic hydrocarbyloxy radical having three to eight carbon atoms. The aryloxy groups which R1 may represent may include phenoxy and phenoxy substituted with one to three substituents selected from C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, halogen, carboxy, cyano, C1 to C6 alkanoyloxy, C1 to C6 alkylthio, C1 to C6 alkylsulfonyl, trifluoromethyl, hydroxy, C2 to C6 alkoxycarbonyl, C2 to C6 alkanoylamino and xe2x80x94Oxe2x80x94R15, Sxe2x80x94R15, xe2x80x94SO2xe2x80x94R15, xe2x80x94NHSO2R15 and xe2x80x94NHCO2R15, wherein R15 is defined above.
The heteroaryloxy radicals include a 5- or 6- membered aromatic ring containing one to three hetero atom selected from oxygen, sulfur and nitrogen wherein a ring carbon atom is bonded to the linking oxygen atom of the heteroaryloxy radical. Examples of such heteroaryl groups are thienyloxy, furyloxy, pyrrolyloxy, imidazolyloxy, pyrazolyloxy, thiazolyloxy, isothiazolyloxy, oxazolyloxy, isoxazolyloxy, triazolyloxy, thiadiazolyloxy, oxadiazolyloxy, tetrazolyloxy, pyridyloxy, pyrimidyloxy, benzoxazolyloxy, benothiazolyloxy, benzimidazolyloxy, indolyloxy and the like. The heteroaryloxy radicals may be substituted, for example, with up to three groups such as C1 to C6 alkyl, C1 to C6 alkoxy, substituted C1 to C6 alkyl, halogen, C1 to C6 alkylthio, aryl, arylthio, aryloxy, C2 to C6 alkoxycarbonyl and C2 to C6 alkanoylamino. The heteroaryloxy radicals also may be substituted with a fused ring system, e.g., a benzo or naphtho residue, which may be unsubstituted or substituted in the manner described above for the heteroaryl substitutents. R1 preferably represents C1 to C6 alkyl, phenyl, tolyl, C1 to C6 alkoxy, or benzyloxy; and R2 preferably represents C1 to C6 alkyl or benzyl.
A second embodiment of the invention concerns a process for the preparation of an enantiomerically-enriched cyclopropylalanine compound having formula 4 or 5 by means of a novel combination of steps comprising (1) contacting cyclopropanecarboxaldehyde (CPCA) with an N-acylglycine having the formula 
in the presence of a carboxylic acid anhydride and a base at elevated temperature to produce an azlactone having the formula 
(2) contacting azlactone 8 with an alcohol optionally in the presence of an alkali or alkaline earth metal alkoxide or hydroxide to produce an enamide having the formula 
and (3) contacting enamide 6 with hydrogen in the presence of a catalyst system comprising a transition metal and a substantially enantiomerically-pure bis-phosphine under hydrogenation conditions of pressure and temperature; wherein R1 and R2 are defined above.
In step (1) CPCA is reacted or condensed with N-acylglycine 7 to form azlactone 8 using variations of the Erylenmeyer synthesis (Greenstein, J. P.; Winitz, M. in Chemistry of the Amino Acids, Vol. 2, Wiley and Sons: New York, 1961;vol. 2,pg 823-843). N-acylglycines of formula 7 may be purchased and/or may be prepared according to published procedures, e.g., by acylating glycine with known acylating agents such as carboxylic acid anhydrides and acid halides and chloroformate esters. The mole ratio of CPCA:N-acylglycine 7 may be in the range of about 1:1 to 10:1 and preferably is in the range of about 2:1 to 3:1. Step (1) is carried out in the presence of an alkanoic (aliphatic carboxylic) acid anhydride containing 4 to 8 carbon atoms, most preferably acetic anhydride. The amount of alkanoic anhydride used may be about 2 to 10 moles equivalents, preferably about 3 moles, per mole of N-acylglycine 7. Step (1) preferably is carried out in the presence of a base such as alkanoates, carbonates and bicarbonates of the alkali metals and alkaline earth metals. Specific examples of such bases include the acetates, carbonates and bicarbonates of lithium, sodium, potassium, cesium, magnesium, calcium, lead and barium. The base preferably is sodium acetate. The amount of base may be between 0.1 and 5 equivalents, preferably 1.5-equivalents, of base per equivalent of N-acylglycine 7. Step (1) normally is carried out at a temperature of about 35 to 150xc2x0 C., preferably about 85 to 110xc2x0 C. Pressure is not an important factor in the condensation of step (1) and, thus, step (1) normally is carried out at ambient pressure although pressures moderately above or below ambient may be employed if desired. The reaction may be run until substantially all of N-acylglycine 7 is converted to azlactone 8. Azlactone 8 is isolated using standard technologies known to those in the art, e.g. extraction, concentration, precipitation.
Step (2) of the process comprises contacting azlactone 8 with an alcohol optionally in the presence of an alkali or alkaline earth metal alkoxide or hydroxide to produce an enamide having the formula 
The alkali or alkaline earth metal may be lithium, potassium, sodium, cesium and the like but preferably is sodium or potassium. The amount of alkoxide or hydroxide employed may be in the range of about 0 to 10 moles alkoxide or hydroxide per mole of azlactone 8. The reaction can be run with or without an inert (non-reactive) organic solvent. Examples of the optional solvents include aliphatic hydrocarbons such as hexane, heptane, octane and the like, and aromatic hydrocarbons such as benzene, toluene, xylene and the like. The concentration of azlactone 8 may be between 0.01 to 10M. In a preferred embodiment, step (2) is carried out in benzyl alcohol with 0.05 equivalents of sodium methoxide. If the carboxylic acid is desired (R2=H), any metal hydroxide, carbonate or bicarbonate base such as lithium, sodium, potassium, cesium, magnesium, calcium, and barium may be used, preferably in aqueous solution. The resulting carboxylate salt can be neutralized to afford the desired carboxylic acid.
Step (2) may be carried out at a temperature in the range of about xe2x88x9210 and 100xc2x0 C. with preferred embodiment at 25-50xc2x0 C. Again, pressure is not an important factor in the reaction of step (2) and, thus, step (2) normally is carried out at ambient pressure although pressures moderately above or below ambient may be employed if desired. The reaction may be run until the majority of the azlactone is converted to enamide ester.
Step (3) of the 3-step embodiment of our invention is carried out according to the procedure described above for the first embodiment.
The third embodiment of the invention is a modification of the second embodiment and provides a process for the preparation of an enantiomerically-enriched cyclopropylalanine compound having formula 4 or 5 by means of another novel combination of steps comprising (i) contacting cyclopropanecarboxaldehyde (CPCA) with an N-acylglycine having the formula 
in the presence of a carboxylic acid anhydride and a base at elevated temperature to produce an azlactone having the formula 
(ii) contacting azlactone 10 with an alcohol optionally in the presence of an alkali or alkaline earth metal alkoxide or hydroxide to produce an enamide having the formula 
(iii) contacting enamide 11 with an acylating agent having the formula R4Oxe2x80x94C(O)xe2x80x94Oxe2x80x94C(O)xe2x80x94OR4 or R4Oxe2x80x94C(O)xe2x80x94X where X is fluorine, chlorine, bromine, or iodine in the presence of 4-(N,N-dimethylamino)pyridine (DMAP) and an inert (non-reactive) organic solvent to produce an amido-carbamate having the formula 12 
(iv) contacting amido-carbamate 12 with a nucleophile in the presence of an inert (non-reactive) organic solvent to produce a second enamide having formula 13 
and (v) contacting enamide 13 with hydrogen in the presence of a catalyst system comprising a transition metal and a substantially enantiomerically-pure bis-phosphine under hydrogenation conditions of pressure and temperature;
wherein
R2 is defined above; and
R3 and R4 are independently selected from substituted and unsubstituted C1 to C20 alkyl, substituted and unsubstituted C3 to C8 cycloalkyl, substituted and unsubstituted carbocyclic C6 to C20 aryl, substituted and unsubstituted C4 to C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen.
This embodiment is particularly useful for preparing xcex1-amino acid derivatives wherein the nitrogen substituent is a carbamate. These species are particularly advantaged for standard solution and solid-phase peptide synthesis.
Steps (i), (ii) and (v) of the third embodiment process are carried out in a manner substantially identical to steps (1), (2) and (3) of the second embodiment of the invention. The primary difference is that in the third embodiment the acyl residue of the N-acylglycine reactant is a group having the formula xe2x80x94COxe2x80x94R3 wherein R3 is an alkyl, cycloalkyl, carbocyclic aryl or heterocyclic aryl radical but not an alkoxy, etc. radical. In step (iii) enamide 11 is contacted with an acylating agent having the formula R4Oxe2x80x94C(O)xe2x80x94Oxe2x80x94C(O)xe2x80x94OR4, e.g., di-tert-butyl dicarbonate, or R4Oxe2x80x94C(O)xe2x80x94X where X is fluorine, chlorine, bromine, or iodine in the presence of 4-(N,N-dimethylamino)pyridine (DMAP) and an inert (non-reactive) organic solvent to produce an amido-carbamate 12. Step (iii) can be carried out at a temperature of about xe2x88x9220 to 45xc2x0 C., preferably 15 to 35xc2x0 C. according to the general procedure described by Burk, M. J.; Allen, J. G. J. Org. Chem. 1997, 62, 7054-7057. The amount of dicarbonate or haloformate acylating agent used can be about 1.8 to 10 equivalents, preferably about 2 to 4 equivalents of dicarbonate acylating agent per mole of enamide 11. The amount of DMAP used typically is between about 0.1 and 1 equivalents, preferably 0.2 to 0.4 equivalents of DMAP per mole of enamide 11. The inert, organic solvent may be any non-reactive solvent including aliphatic hydrocarbons such as hexane, heptane, octane and the like; cyclic and acyclic ethers such as tert-butyl methyl ether, diisopropyl ether, tetrahydrofuran and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; and polar aprotic solvents such as dimethylformamide, N-methylpyrrolidone, acetonitrile and the like. The solvent preferably is a cyclic or acylic ether with tetrahydrofuran being especially preferred. Once the reaction is determined to be sufficiently complete, excess acylating agent is quenched with a C1 to C3 alkanol such as methanol, ethanol and the like, preferably methanol. The amount of alkanol added may be from about 1 to 100 equivalents based on the amount of acylating agent used, with the preferred embodiment being two equivalents of alkanol.
Step (iv) comprises contacting amido-carbamate 12 with a nucleophile to produce a second enamide 13. Step (iv) may be carried out without isolating 12 from the crude reaction mixture resulting from step (iii). The reaction is generally carried out in an alkanol solvent such as methanol, ethanol, and the like, with methanol especially preferred. Normally, the reaction mixture should be cooled before the addition of the nucleophile. Step (iv) typically is carried out at a temperature in the range of about xe2x88x9240 and 15xc2x0 C., preferably between xe2x88x925 and 50xc2x0 C. The nucleophile may be any alkali metal or alkaline earth metal hydroxide such as lithium, sodium, potassium, cesium, magnesium, calcium, and barium hydroxide or an amine such as pyridine, morpholine, hydrazine or hydrazine hydrate. Anhydrous hydrazine or hydrazine hydrate are the preferred nucleophiles. The amount of nucleophile may be between 1 and 50 equivalents with the preferred embodiment of 3-5 equivalents based on the amount of amido-carbamate 12.
Step (v) of the third embodiment of the invention is carried out by hydrogenating the second enamide 13 according to the hydrogenation procedures described herein.
A fourth embodiment of the invention concerns a process for the preparation of an enantiomerically-enriched cyclopropylalanine compound having formula 4 or 5 by means of a novel combination of steps comprising (a) reacting cyclopropanecarboxaldehyde with a phosphonate ester having the formula 19: 
in the presence of a base and an inert organic solvent to produce enamide 6 
and (b) contacting enamide 6 with hydrogen in the presence of a catalyst system comprising a transition metal and a substantially enantiomerically-pure bis-phosphine under hydrogenation conditions of pressure and temperature;
wherein
R1 and R2 are as defined above; and
R16 is selected from substituted and unsubstituted C1 to C20 alkyl, substituted and unsubstituted C3to C8 cycloalkyl, substituted and unsubstituted carbocyclic C6 to C20 aryl, and substituted and unsubstituted C4 to C20 heteroaryl wherein the heteroatoms are selected from sulfur, nitrogen, and oxygen.
In step (a), CPCA is reacted or condensed with phosphonate ester 19 in a Horner-Emmons Wittig reaction. The phosphonate ester 19 can be prepared by methods known in the art as in Schmidt, U.; Lieberknecht, A.; Wild, J., Synthesis 1984, 53-60. This type of Horner-Emmons reaction has also been reported by Schmidt, U.;Griesser, H.; Leitenberger, V.; Lieberknecht, A.; Mangold, R.; Meyer, R.; Riedl, B. Synthesis 1992, 487-490,although CPCA has not been used previously in this reaction. The amount of phosphonate ester generally is about 0.5 to 3 molar equivalents based on the amount of CPCA, and preferably is about 0.6-1.2 molar equivalents. The base employed in step (a) may be chosen from alkoxides of the alkali metals and alkaline earth metals and amines. Specific examples of alkoxide bases include the methoxide, ethoxide, isopropoxide, and t-butoxide of lithium, sodium, potassium, cesium, magnesium, calcium, lead and barium. Amine bases include 1,4-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]-octane (DABCO), and tetramethylguanidine (TMG). The base preferably is tetramethylguanidine. The reaction typically is carried out in the presence of an inert organic solvent. This solvent may be any non-reactive solvent including aliphatic hydrocarbons such as hexane, heptane, octane and the like; cyclic and acyclic ethers such as tert-butyl methyl ether, diisopropyl ether, tetrahydrofuran and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; esters such as methyl acetate, ethyl acetate, isopropyl acetate and the like; and polar aprotic solvents such as dimethylformamide, N-methylpyrrolidone, acetonitrile and the like. Tetrahydrofuran and ethyl acetate are preferred solvents. The reaction may be carried out at a temperature between xe2x88x9278xc2x0 C. and the boiling point of the solvent, preferably between xe2x88x9220xc2x0 C. and 30xc2x0 C.
Step (b) of the fourth embodiment of the invention is carried out by hydrogenating enamide 6 according to the hydrogenation procedures described herein.
As noted hereinabove, enamides 6 and 13 are believed to be novel compositions.
USPTO Backgrounds
USPTO Backgrounds