THE PREPARATION OF ENANTIOMERICALLY ENRICHED OXAZOLONES AND alpha , alpha -DISUBSTITUTED AMINO ACIDS

Abstract: Allylic electrophiles are alkylated with oxazolones in the presence of a base and catalytic quantities of a transition metal complex incorporating a chiral phosphine ligand, to yield 4,4-disubstituted-5(4H)-oxazolones. These precursors may be subsequently transformed either synthetically or enzymatically to yield enantiomerically enriched alpha , alpha -disubstituted amino acids.

Description: THE PREPARATION OF ENANTIOMERICALLY ENRICHED OXAZOLONES AND α.α-DISUBSTITUTED AMINO ACIDS Field of the Invention The present invention relates to the preparation of enantiomerically enriched 4,4-disubstituted-5(4 /)-oxazolones, which can be transformed into enantiomerically enriched α,α-disubstituted amino acids. Background of the Invention α,α-Disubstituted amino acids are of great interest for a variety of reasons. They have been shown to be effective inhibitors of enzymes which normally metabolise the corresponding proteinogenic amino acids (Almond et al, Biochem., 1, 243 (1962); Pankaskieetα/,J. e-/ Chem., 23, 121 (1980)). The additional substituent of such amino acids can have a marked effect on the conformation of peptide structure; thus, they can be utilized to modify physiologically important peptides to stabilize preferred conformations (Burgess, Proc. Natl. Acad. Sci. USA, 91, 2649 (1994)). They also occur as constituent parts of interesting natural products (Koert, Nachr. Chem. Tech. Lab., 43, 347 (1995)). Effective preparation of α,α-disubstituted amino acids, in an enantiocontrolled fashion, is therefore highly desirable. 5(4 )-Oxazolones may be prepared by the direct dehydration of N-acylated α- amino acids. These 5(4 /)-oxazolones are readily substituted in the 4-position. Subsequent hydrolysis of 4,4-disubstituted-5(4 /)-oxazolone ring results in α,α- disubstituted amino acids. Chiral phosphine ligands are known. See, for example, WO-A-9609306. Summary of the Invention In one aspect of the present invention, precursors (1) of enantiomerically enriched α,α-disubstituted amino acids are prepared. Briefly, an allylic electrophile of the formula R 3 -L is alkylated with an oxazolone (2) in the presence of a base and catalytic quantities of a transition metal complex incorporating a chiral (preferably phosphine) ligand. In addition to a surprising degree of enantioselectivity, a high degree of diastereoselectivity may also be achieved with the appropriate choice of substrate, base and solvent. This reaction results in enantiomerically enriched 4,4-disubstituted-5(4H)- oxazolones (1) which may be subsequently transformed to yield enantiomerically enriched α,α-disubstituted amino acids. For these oxazolones, R 1 and R 3 are each independently hydrogen or an optionally substituted hydrocarbon group, e.g. alkyl, aryl or heteroaryl, of up to 20 C atoms, and R 2 is an optionally substituted amino acid side-chain or an optionally substituted hydrocarbon group as defined above. Most preferably, R 1 is phenyl and R 2 is an amino acid side-chain. Certain enantiomerically-enriched oxazolones (1) are novel. Description of the Invention As used herein, "enantiomerically enriched" refers to products whose enantiomeric excess (ee) is greater than zero. In general, higher enantiomeric purity (> about 50% ee) is preferred; the enantiomeric excess is more preferably at least 75% and most preferably greater than 90%. Suitable transition metal complexes for practising the invention are those based on Pd, W, Mo, Rh, Ni, and mixtures thereof (e.g. Pd and Rh). Especially preferred are complexes of Pd(0) with C2-symmetric bidentate diphosphines containing a pair of metal binding moieties of the type C(=O)-Ar-P-(Ar') 2 , wherein Ar and Ar' are aryl or heteroaryl groups, optionally comprising fused rings, as disclosed in WO-A-9609306. Such C2-symmetric ligands are available in both enantiomeric forms, thereby allowing with equal facility the preparation of a chosen enantiomer of a target compound. Preferred ligands are of formula 3 or the opposite enantiomer thereof, wherein Ar is an aromatic ring optionally substituted by one or more non-interfering groups, and the respective R groups are each any non- interfering group, or R 5 and R 6 may be joined to form a ring. The nature of R groups or any substituent on the Ar rings, e.g. of up to 10, 20 or 30 C atoms, is not critical to the invention. It will be evident to the skilled person, as to which substituents will or will not affect the reaction. Ar represents an aryl (including heteroaryl) ring. It may be monocyclic. Examples of Ar include furan, thiophene and, preferably, benzene rings. The position of the essential substituents on the ring represented by Ar is determined by the requirement that the product acts as a ligand, e.g. that it can act to complex transition metals such as palladium, rhodium, platinum or iridium. Ar is most preferably 1,2-phenylene. The most preferred ligand for use in the invention is of formula (3) where Ar is 1,2-phenylene, R 5 and R 6 together form a cyclohexane ring, and R 7 and R 8 are each phenyl. This compound is described in the Examples as "Ligand 1". Ligands 2, 3 and 4 differ in that R 5 and R 6 together are indanyl (and one NH is replaced by O); R 7 and R 8 are each 3,5-diphenylphenyl; and R 7 and R 8 are each phenyl. 5(4 /)-Oxazolones may be prepared by the direct dehydration of the corresponding N-acylated α-amino acid of the formula R'-CO-ΝH-CHR 2 -COOH. Briefly, the N-acyl α- amino acid is treated with NN'-dicyclohexylcarbodii ide (DCC) in THF for 24 hours. The only by-product, N.N'-dicyclohexylurea (DCU), may be removed by simple filtration at low temperature which results in high yields of pure 5(4//)-oxazolones (2). The allylic electrophile has the formula R 3 -L. L is any ionisable group (or leaving group). Illustrative examples of leaving groups include but are not limited to halides, esters, carbonates and carboxylates. Preferred allylic electrophiles are cyclic compounds of formula 4 and acyclic compounds of formula 5 When the allylic electrophile is of formula 4, i.e. cyclic, then n is 1-6. Particularly preferred cyclic allylic electrophiles are 2-cyclopentenyl acetate and 2-cyclohexenyl acetate (n = 1 or 2 and L is acetate). When the allylic electrophile is acyclic, then L 1 and L 2 are independently any ionizable or leaving group, e.g. as defined above for L. L 2 may also be H or a hydrocarbon group as defined above. R 4 is any group consistent with the definition of R 3 , i.e. H or R 3 when part thereof is -CH=CH-CHL 2 -. Preferred acyclic allylic electrophiles are those of formula 5 where L 1 and L 2 are acetate and R 4 is hydrogen or phenyl. In one embodiment of the present invention, a cyclic allylic electrophile (4) is alkylated with a 5(4H)-oxazolone (2) in the presence of a base and a catalytic amount of a Pd(0)-diphosphine complex to give a novel product of formula 6 The enantiomeric purity of the 4,4-disubstituted-5(4H)-oxazolones (6) is typically high and often exceeds 95% ee. The diastereomeric ratio is largely dependent upon the substrate, solvent and base; it may be between 1 : 1 and single diastereomer. Suitable solvent and base combinations include: THF and DME with NaH; CH 2 C1 2 , CH 3 CN, DMF, DMSO with Et 3 N (and other tertiary amines), or Cs 2 CO 3 . For example, in the case when the catalyst is a Pd(0) complex of the ligand (3), R 1 = phenyl, R 2 = methyl, n = 2, and L = acetate, with CH 2 C1 2 (solvent) and Et 3 N (base), the product (6) is obtained in a diastereomeric ratio of 2.75: 1, with each diastereomer having 99% ee. In contrast, when R 1 = phenyl, R 2 = CH(CH 3 ) 2 , n = 2, and L = acetate, with CH 3 CN and Et 3 N, only a single diastereomer is observed having 99% ee. In another embodiment of the invention, an acyclic allylic electrophile (5) is used, to give a novel compound of formula 7 Typically, the enantiomeric purity of the 4,4-disubstituted-5(4H)-oxazolones (7) is high and often exceeds 95% ee. The diastereomeric ratio is largely dependant upon the substrate, solvent and base, and ranges between 1 : 1 and to only a single diastereomer being observed. For example, when the catalyst is a Pd(0) complex of the ligand (3), R 1 and R 3 = phenyl, R 2 = methyl, and L 1 and L 2 = acetate, with CH 2 C1 2 (solvent) and Et 3 N (base), then the product (7) is obtained in a diastereomeric ratio of 4.4: 1, each diastereomer having 83% ee and 40% ee, respectively. In contrast, when the catalyst is a Pd(0) complex of ligand (1), R 1 and R 3 = phenyl, R 2 = CH(CH 3 ) 2 , and L 1 and L 2 = acetate, with DME and NaH, only a single diastereomer is observed having 99% ee. The enantiomerically enriched 4,4-disubstituted 5(4H)-oxazolones ( 1) may be readily transformed into enantiomerically enriched α,α-disubstituted amino acids of formula 8 (where R 1 and R 2 are as previously defined) using well known reactions (including enzymatic reactions) known in the art. For example, hydrolysis of the heterocyclic ring affords an N-acyl α-amino acid. Similarly, alcoholysis of the heterocyclic ring affords an N-acyl α-amino ester. The following Examples illustrate the invention. All reactions were carried out under Ar atmosphere using standard syringe techniques. Dried solvents were bubbled with Ar unless otherwise noted. THF, diethyl ether, dimethoxyethane, and dioxane were distilled from sodium benzophenone ketyl. Benzene and CH 2 C1 2 were distilled from CaH 2 . Acetonitrile, DMSO and DMF were dried over molecular sieves. 2-Cyclopentenol, 2-cyclopentenyl acetate, 2-cyclohexenyl acetate, and bis(η 3 -allyl)di-μ-chlorodipalladium(II) were prepared by literature methods. Melting points were taken on a Thomas-Hoover melting point apparatus in open capillaries and are uncorrected. *H ΝMR (300 MHz) and 13 C ΝMR (75 MHz) were obtained on a Varian Gemini 300 spectrometer. ΝMR spectra were recorded in CDC1 3 , and chemical shifts were reported in parts per million relative to tetramethylsilane or CDC1 3 (77.0 ppm, 13 C). Infrared spectra were recorded on a Perkin Elmer Paragon 500. Optical rotations were measured at 23-25 °C in CH 2 C1 2 on a JASCO DIP-360. Enantiomeric excess was determined by chiral HPLC (Chiracel® OD or Chiralpak® AD column, detection at 254 nm and flow rate 1 mL/min). Flash chromatography was performed on silica gel (Merck Kiegel 60, 230-400 mesh). Preparation of 2-Oxazolin-5-ones (General Procedure-) A solution of 1,3-dicyclohexylcarbodiimide (DCC, 5.21 g, 25.0 mmol) in THF (25 mL) was added dropwise to a suspension of N-acyl-amino acid (25.0 mmol) in THF (25 mL) at 0°C under Ar. After stirring overnight at room temperature, the suspension was filtered at -40 °C under Ar and the precipitate was washed twice with THF (2 x 20 mL) also at -40 °C. The combined organic layer was evaporated to dryness and the obtained 2-oxazolin-5-one was not further purified. Compounds prepared in this way are presented in Table 1. Table 1 R R' N-acyl-AA Yield (g) Methyl Phenyl 4.83 g 99% (4.34 g) Methyl 2-Methoxypheny 2.72 g 100% (2.53 g) Methyl tert-Butyl f 2.45 g 90% (1.96 g) Methyl'-" 2-Pyridyl g 0.479 g — Benzyl Phenyl 6.73 g 89% (5.61 g) Isobutyl 3 Phenyl 2.94 g 83% (2.26 g) Isopropyl" Phenyl 2.61 g 83% (2.11 g) a Scaled to 1/2; b Scaled to 3/5; c Scaled to 1/10; d Prepared from DL-alanine methyl ester hydrochloride; e Prepared from the corresponding acid and DCC-Et 3 Ν; f Prepared from pivaloyl chloride and Et 3 N; E Prepared from the corresponding acid and DCC-Et 3 N. Example 1 (formula 6 : n = 2, R 1 = phenyl, R 2 = methyl) 2-Cyclohexenyl acetate (14 mg, 100 μmol was added to a solution (0.5 mL) of amine (see Table 2; 200 μmol) and 4-methyl-2-phenyl-2-oxazolin-5-one (39.4 mg, 225 μmol). Then a preformed solution (0.5 mL) of bis(η 3 -allyl)di-μ-chlorodipalladium (II) (0.9 mg, 2.5 μmol) and chiral ligand (7.5 μmol) was added via cannula. The reaction mixture was quenched with aqueous phosphate buffer (pH 7, 20 ml) and extracted with CH 2 C1 2 (3 x 15 mL). The combined organic layer were dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether- AcOEt (95:5) or hexane- AcOEt (95:5) to give an oil as a non-separable diastereomeric mixture of 4-(2-cyclohexenyl)-4-methyl-2-phenyl-2-oxazolin-5-one. Then, enantiomeric and diastereomeric excess were determined by chiral HPLC (Chiracel® OD column, heptane/2-propanol 99.9:0.1), t R (major) = 8.5 (l'R, 4R), 14.0 (I'S, 4S), t R (minor) = 10.5 (I'S, 4R), 16.3 (17?, 4S). Further separation could be accomplished by careful flash chromatography on silica gel eluting with petroleum ether-AcOEt (97:3). ( 1 'S,4S)-4-(2'-Cyclohexenyl)-4-methyl-2-phenyl-2-oxazolin-5-one: Oil. [α] D -82.4 (c=1.03, CH 2 Cl 2 ). 1 HNMR (300 Hz, CDCl 3 ) δ: 8.01-7.98 (m, 2H), 7.56 (m, 1H), 7.50- 7.45 (m, 2H), 5.84 (m, 1H), 5.53 (m, 1H), 2.64 (m, 1H), 1.98-1.93 (m, 3H), 1.85 (m, 1H), 1.59-1.49 (m, 2H), 1.54 (s, 3H). q i S.4RV4-( ' 2'-CvclohexenylV4-methyl-2-Dhenyl-2-oxazolin-5-one: Oil. [α] D -96.2 (c=1.25, CH 2 C1 2 ). ΗNMR (300 MHz, CDC1 3 ) δ: 8.03-8.00 (m, 2H), 7.58 (m, 1H), 7.51- 7.46 (m, 2H), 5.88 (m, lH), 5.65 (m, lH), 2.64 (m, 1H), 1.98-1.96 (m, 2H), 1.84-1.78 (m, 2H), 1.58-1.49 (m, 2H), 1.56 (s, 3H). This reaction was performed under various conditions, as shown in Tables 2A and 2B. Table 2A Table 2B a Reaction scaled x 2. Example 2 (formula 6 : n = 2, R 1 = phenyl) 2-Cyclohexenyl acetate (28 g, 200 μmol) was added to a solution of triethylamine (56 μL, 400 μmol) and 4-alkyl-2-phenyl-2-oxazolin-5-one (alkyl group R 2 given in Table 3; 450 μmol) in acetonitrile (1 mL). Then a preformed solution of bis(η 3 - allyl)di-μ-chlorodipalladium (II) (1.8 mg, 4.9 μmol) and ligand 1 (10.4 mg, 15.1 μmol) in acetonitrile (1 mL) was added via cannula. The reaction mixture was quenched with aqueous phosphate buffer (pH 7, 40 ml) and extracted with CH 2 C1 2 (3 x 30 mL). The combined organic layer were dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether- AcOEt to give an oil of 4-alkyl-4-(2-cyclohexenyl)-2-phenyl-2-oxazolin-5-one. Results are shown in Table 3. Table 3 a Mixture yield; D Major isomer yield, ° Racemic ligand 1 , d In CH 2 CI 2 74% yield4.21(98):1(96). ( 1 l S,4S)-4-Benzyl-4-(2'-cvclohexenyl V2-phenyl-2-oxazolin- 5 -one: Petroleum ether - AcOEt (95:5) for chromatography. Enantiomeric excess was determined by chiral HPLC (Chiracel® OD column, heptane/2-propanol 99.9:0.1), t R = 13.0 (I'S, 4S), 15.3 (17?, 4R). [α] D = -221.8 (c=1.45, CH 2 C1 2 , for 99.1% e.e.). Oil. Η NMR (300 MHz, CDC1 3 ) δ: 7.82-7.80 (m, 2H), 7.48 (m, IH), 7.40-7.35 (m, 2H), 7.17-7.09 (m, 5H), 5.85 (m, lh), 5.60 (m, lH), 3.33 (d, J=13.2 Hz, IH), 3.18 (d, J=13.2 Hz, lH), 2.83 (m, IH), 2.08-1.99 (m, 3H), 1.88 (m, IH), 1.71-1.52 (m, 2H). ( 1 'S.4RV4-Benzyl-4-(2'-cvclohexenylV2-phenyl-2-oxazolin-5-one: Petroleum ether- AcOEt (95:5) for chromatography. Enantiomeric excess was determined by chiral HPLC (Chiracel® OD column, heptane/2-propanol 99.9:0.1), t R = 15.8 (17?, 4S), 19.6 (I'S, 4R). [α] D = +37.7 (c=0.71, CH 2 C1 2 for 98.7% e.e.). Oil. Η NMR (300 MHz, CDC1 3 ) δ: 7.85-7.82 (m, 2H), 7.51 (m, IH), 7.43-7.27 (m, 2H), 7.18-7.10 (m, 5H), 5.92 (m, IH), 5.74 (m, IH), 3.36 (d, J=13.2 Hz, IH), 3.23 (d, J=13.2 Hz, IH), 2.82 (m, IH), 2.04-1.98 (m, 2H), 1.96-1.82 (m, 2H), 1.69-1.52 (m, 2H). ( S.4S)-4-(2'-Cvclohexenvπ-4-isobutyl-2-phenyl-2-oxazolin-5-one (major isomer): Petroleum ether- AcOEt (97:3) for chromatography. Diastereomeric excess was determined by HPLC (Microsorb® Si 80-125-C5, flow 2 mL/min, 254 nm, heptane/ AcOEt 98:2, t R (major) = 4.1, t R (minor) = 4.9). Enantiomeric excess was determined by chiral HPLC (Chiracel® AD column, heptane/2-propanol 99.9:0.1), t R = 6.9 (I'S, 4S), 7.8 (17?, 4R). [α] D = -108.4 (c=l.20, CH 2 C1 2 ). Oil. Η NMR (300 MHz, CDC1 3 ) δ: 8.02-7.99 (m, 2H), 7.57 (m, IH), 7.51-7.46 (m, 2H), 5.85 (m, IH), 5.59 (m, IH), 2.63 (m, IH), 2.09-1.80 (m, 6H), 1.63-1.44 (m, 3H), 0.89 (d, J=6.6 Hz, 3H), 0.85 (d, J=6.6 Hz, 3H). ( 1 l S.4R -4-f2'-Cvclohexenvπ-4-isobutyl-2-phenyl-2-oxazolin-5-one (minor isomer): Petroleum ether- AcOEt (97:3) for chromatography. An analytical sample was purified by semipreparative HPLC (Microsorb® Si 80-199-C5, flow 2 mL/min, 254 nm, heptane/AcOEt 98:2). Oil. Η NMR (300 MHz, CDC1 3 ) δ: 8.04-8.01 (m, 2H), 7.59 (m, IH), 7.56-7.47 (m, 2H), 5.85 (m, IH), 5.56 (m, IH), 5.56 (m, IH), 2.63 (m, IH), 2.10- 1.79 (m, 6H), 1.65-1.45 (m, 3H), 0.90 (d, J=6.6 Hz, 3H), 0.85 (d, J=6.6 Hz, 3H). 4-(2'-Cyclohexenyl)-4-isopropyl-2-phenyl-2-oxazolin-5-one (single isomer): Petroleum ether-AcOEt (98:2) for chromatography. Oil. Η NMR (300 MHz, CDC1 3 ) δ: 8.02-7.99 (m, 2H), 7.57 (m, IH), 7.54-7.45 (m, 2H), 5.84 (m, IH), 5.52 (m, IH), 2.84 (m, IH), 2.44 (hp, J=6.8 Hz, IH), 2.01-1.95 (m, 2H), 1.89-1.78 (m, 2H), 1.61-138 (m, 2H), 1.01 (d, J=6.8 Hz, 3H), 0.99 (d, J=6.8 Hz, 3H). Example 3 (formula 6 : n = 1, R 1 = Ph, R 2 is benzyl) 2-Cyclopentenyl acetate (25.2 mg, 200 μmol) or /ert-butyl 2-cyclopentenyl carbonate (36.8 mg, 200 μmol) was added to a solution of triethylamine (56 μL, 400 μmol) and 4-benzyl-2-phenyl-2-oxazolin-5-one (113.1 mg, 450 μmol) in acetonitrile (1 mL). Then a preformed solution of bis(η 3 -aUyl)di-μ-chlorodipalladium (II) (1.8 mg, 4.9 μmol) and ligand 1 (10.4 mg, 15.1 μmol) in acetonitrile (1 mL) was added via cannula. After 3 hours the reaction mixture was quenched with aqueous phosphate buffer (pH 7, 40 ml) and extracted with CH 2 C1 2 (3 x 30 mL). The combined organic layer were dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether- AcOEt (97:3) to give two fractions: the first one was the major isomer, the second one was a mixture of 4-benzyl-2- phenyl-2-oxazolin-5-one and the minor isomer that could be partially separated. Results are shown in Table 4. Table 4 Isolated major isomer, b Determined by H-NMR; ° Determined by chiral H lP PIL CC., dd M Maajinorr i iςsnommeerr. 4-Benzyl-4-(2'-cvclopentenylV2-phenyl-2-oxazolin-5-one (major isomer): Oil. Enantiomeric excess was determined by chiral HPLC (Chiracel® OD column, heptane/2- propanol 99.9:0.1), t R (major) = 15.3, t R (minor) = 22.4. 'H NMR (300 MHz, CDC1 3 ) δ: 7.82-7.79 (m, 2H), 7.49 (m, IH), 7.41-7.36 (m, 2H), 7.18-7.10 (m, 5H), 5.90 (m, IH), 5.60 (m, IH), 3.55 (m, IH), 3.31 (d, J=13.4 Hz, IH), 3.19 (d, J=13.4 Hz, IH), 2.50-2.27 (m, 2H), 2.19-1.98 (m, 2H). 4-Benzyl-4-(2'-cvclopentenvD-2-phenyl-2-oxazolin-5-one (minor isomer) : Oil. 'H NMR (300 MHz, CDC1 3 ) δ: 7.86-7.83 (m, 2H), 7.52 (m, IH), 7.44-7.39 (m, 2H), 7.18- 7.11 (m, 5H), 5.97 (m, IH), 5.75 (m, IH), 3.36 (m, IH), 3.30 (d, .7=13.3 Hz, IH), 3.23 (d, J=13.3 Hz, IH), 2.50-2.28 (m, 2H), 2.15-1.90 (m, 2H). Example 4 (formula 7: R 1 = Ph, R 2 = L 2 = H) Allyl acetate (21.6 μL, 200 μmol) was added to a solution of triethylamine (56 μL, 400 μmol) or pentamethylguanidine (51.7 mg, 400 μmol) and 4-benzyl-2-phenyl-2- oxazolin-5-one (450 μmol) in acetonitrile (1 mL). Then a preformed solution of bis(η 3 - allyl)di-μ-chlorodipalladium (II) (1.8 mg, 4.9 μmol) and ligand 1 (10.4 mg, 15.1 μmol) in acetonitrile (1 mL) was added via cannula. The reaction mixture was quenched with aqueous phosphate buffer (pH 7, 40 ml) and extracted with CH 2 C1 2 (3 x 30 mL). The combined organic layer was dried over N-^SO,, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether-AcOEt (95:5) to give 4-allyl-4-benzyl-2-phenyl-2-oxazolin-5-one. Results are shown in Table 5. Table 5 Not including the catalyst; Determined by chiral HPLC. 4-Allyl-4-benzyl-2-phenyl-2-oxazolin-5-one: Enantiomeric excess was determined by chiral HPLC (Chiracel® OD column, heptane/2-propenyl 99.9:0.1), t R (major) = 14.3, t R (minor) = 17.4. Η NMR (300 MHz, CDCl 3 ) δ: 7.86-7.83 (m, 2H), 7.52 (m, 1H), 7.41 (m, 2H), 7.18-7.13 (m, 5H), 5.68 (m, IH), 5.24-5.10 (m, 2H), 3.24 (d, .7=13.4 Hz, IH), 3.16 (d, .7=13.4 Hz, IH), 2.80-2.67 (m, 2H). Example 5 (formula 7: R 1 = R 3 = Ph, L 2 = OAc) A solution (1.0 mL) of 4-(R 2 -substituted)-2-phenyl-2-oxazolin-5-one (450 μmol) was added to NaH (95% in oil, 10.1 mg, 400 μmol) at -78°C and warmed to room temperature. When hydrogen evolution ceased, a solution (0.5 mL) of bis(η 3 -allyl)di-μ- chlorodipalladium (II) (1.8 mg, 4.9 μmol) and ligand 1 (10.4 mg, 15.1 μmol) was added. Finally, another solution (1.0 mL) of 3,3-diacetoxy-l -phenylpropene (46.9 mg, 200 μmol) was added at the desired temperature. The reaction mixture was quenched with aqueous phosphate buffer (pH 7, 40 mL) and extracted with CH 2 C1 2 (3 X 30 mL). The combined organic layer was dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether-AcOEt. Results are shown in Table 6. Table 6 a Isolated yield; b Determined by chiral HPLC; c Determined by H-NMR; d 2% of the other regioisomer; c Cone, in CH 2 C1 2 . (E.l'7?.4S)-4-(l l -Acetoxy-3'-phenyl-2'-propenylV4-methyl-2-phenyl-2-oxazolin-5- one: (major isomer, first fraction). Petroleum ether-AcOΕt (9: 1) for chromatography. M.p.: 138- 139°C (isopropanol). Enantiomeric excess was determined by chiral HPLC (Chiracel® OD column, heptane/2-propanol 99 : 1 ), t R (minor) = 11.6, t R (major) = 13.7. 'H NMR (300 MHz, CDC1 3 ) δ: 8.10-8.07 (m, 2H), 7.65-7.45 (m, 5H), 7.38-7.26 (m, 3H), 6.88 (d, J=15.9 Hz, IH), 6.32 (dd, .7=15.9, 8.8 Hz, IH), 5.66 (d, .7=8.8 Hz, IH), 1.96 (s, 3H), 1.50 (s, 3H). (E.l'R.4R'>-4-(l'-Acetoxy-3'-phenyl-2'-propenvn-4-methyl-2-phenyl-2-oxazolin-5- one (minor isomer, second fraction). Petroleum ether- AcOΕt (9:1) for chromatography. M.p.: 142-144°C. Enantiomeric excess was determined by chiral HPLC (Chiracel® OD column, heptane/2-propanol 99:1), t R (major) = 12.8, t R (minor) = 15.6. X H NMR (300 MHz, CDC1 3 ) δ: 8.03-8.00 (m, 2H), 7.63-7.42 (m, 5H), 7.36-7.28 (m, 3H), 6.81 (d, J=15.9 Hz, IH), 6.36 (dd, J=l 5.9, 8.9 Hz, IH), 5.71 (d, J=8.9Hz, IH), 1.94 (s, 3H), 1.53 (s, 3H). (E.ri?.4S)-4-( -Acetoxy-3'-phenyl-2'-propenyl)-4-benzyl-2-phenyl-2-oxazolin-5- one (major isomer, first fraction). Petroleum ether-AcOΕt (9: 1) for chromatography on silica gel (2% Εt 3 N). M.p.: 138-140°C (isopropanol). Enantiomeric excess was determined by chiral HPLC (Chiracel® OD column, heptane/2-propanol 99: 1), t R (minor) = 17.2, t R (major) = 21.5. Η NMR (300 MHz, CDC1 3 ) δ: 7.91-7.88 (m, 2H), 7.57-7.27 (m, 8H), 7.14-7.11 (m, 5H), 6.95 (d, J=16.0Hz, IH), 6.42 (dd, J=l 6.0, 8.9 Hz, IH), 5.84 (d, J=8.9 Hz, IH), 3.21 (d, .7=13.3 Hz, IH), 3.12 (d, J=13.3 Hz, IH), 1.96 (s, 3H). (E.17?.4RV4-(r-Acetoxy-3'-phenyl-2'-propenvD-4-benzyl-2-phenyl-2-oxazolin-5- one (minor isomer, second fraction). Petroleum ether-AcOΕt (9:1) for chromatography on silica gel (2% Εt 3 N). Oil. Enantiomeric excess was determined by chiral HPLC (Chiracel® AD column, heptane/2-propanol 9:1), t R (major) = 7.6, t R (minor) = 13.7. 'H NMR (300 MHz, CDC1 3 ) δ: 7.87-7.84 (m, 2H), 7.57-7.30 (m, 8H), 7.18-7.13 (m, 5H), 6.84 (d, .7=15.9 Hz, IH), 6.47 (dd, J=l 5.9, 9.0 Hz, IH), 5.87 (d, J=9.0 Hz, lH), 3.25 (d, J=13.5 Hz, IH), 3.19 (d, J=13.5 Hz, IH), 1.96 (s, 3H). (E.1 ?.4S)-4-( 1 '- Acetoxy-3 '-ρhenyl-2'-propenvn-4-isobutyl-2-phenyl-2-oxazolin-5- one (major isomer, first fraction). Petroleum ether-AcOEt (95.5 to 9:1) for chromatography. M.p.: 164-165°C (racemic, heptane/2-propanol, 9:1). Enantiomeric excess was determined by chiral HPLC (Chiracel® AD column, heptane/2-propanol 99.5:0.5), t R (major) = 15.7, t R (minor) = 19.1. 1 H NMR (300 MHz, CDCl 3 ) δ: 8.11-8.01 (m, 2H), 7.63 (m, IH), 7.56-7.46 (m, 4H), 7.38-7.26 (m, 3H), 6.86 (d, J=15.9 Hz, IH), 6.30 (dd, J=15.9, 8.8 Hz, IH), 5.61 (d, J=8.8 Hz, IH), 1.95 (dd, .7=14.0, 7.1 Hz, IH), 1.95 (s, 3H), 1.79 (dd, J= 14.0, 7.1 Hz, IH), 1.57 (m, IH), 0.85 (m, .7=6.5 Hz, 3H), 0.84 (m, J=6.6 Hz, 3H). (E.17?.4RV4-( 1 '- Acetoxy-3 '-phenyl-2'-propenvD-4-isobu l-2-phenyl-2-oxazolin-5- one (minor isomer, second fraction). Petroleum ether-AcOEt (95:5 to 9: 1) for chromatography. Oil. Enantiomeric excess was determined by chiral HPLC (Chiracel® AD column, heptane/2-ρroρanol 95:5), t R (major) = 8.2, t R (minor) = 10.0. 'HNMR (300 MHz, CDC1 3 ) δ: 8.04-8.02 (m, 2H), 7.61 (m IH), 7.54-7.44 (m, 4H), 7.38-7.30 (m, 3H), 6.80 (d, J=15.9 Hz, IH), 6.39 (dd, J=15.9, 9.1 Hz, IH), 5.70 (d, J=9.1 Hz, IH), 1.94 (dd J=13.8, 4.8 Hz, IH), 1.88 (s, 3H), 1.79 (dd, J=13.8, 4.8 Hz, IH), 1.67 (m, lH), 0.89 (m, J=6.5 Hz, 3H), 0.83 (m, J=6.5 Hz, 3H). (E.17?.4S)-4-( 1 '- Acetoxy-3'-phenyl-2'-propenyl -isopropyl-2-phenyl-2-oxazolin- 5-one (major isomer, first fraction). Petroleum ether- AcOEt (95:5 to 9: 1) for chromatography. Oil. Enantiomeric excess was determined by chiral HPLC (Chiracel® OD column, heptane/2-propanol 99.8:0.2), t R (major) = 22.4, t R (minor) = 27.5. 'HNMR (300 MHz, CDC1 3 ) δ: 8.10-8.07 (m, 2H), 7.61 (m, IH), 7.55-7.49 (m, 2H), 7.46-7.43 (m, 2H), 7.36-7.26 (m, 3H), 6.9 l (d, J=l 6.1 Hz, IH), 6.33 (dd, J=16.1, 8.8 Hz, IH), 5.92 (d, J=8.8 Hz, IH), 2.29 (hp, IH), 1.96 (s, 3H), 1.18 (d, J=6.9 Hz, 3H), 0.91 (d, J=6.9 Hz, 3H). (E. R.4R)-4-( -Acetoxy-3'-phenyl-2'-propenyl -4-isopropyl-2-ρhenyl-2-oxazolin- 5 -one (minor isomer, third fraction). Petroleum ether- AcOΕt (95:5 to 9: 1) for chromatography. Oil impurified with the other regioisomer. *H NMR (300 MHz, CDC1 3 ) δ: 8.06-8.03 (m, 2H), 7.61 (m, IH), 7.55-7.44 (m, 4H), 7.38-7.28 (m, 3H), 6.88 (d, J=15.8 Hz, IH), 6.49 (dd, J=15.8, 9.3 Hz, IH), 5.87 (d, J=9.3 Hz, IH), 2.30 (hp, IH), 1.87 (s, 3H), 1.16 (d, J=6.7 Hz, 3H), 0.85 (d, J=6.7 Hz, 3H). 4- ( 3'-Acetoxy-r-phenyl-2'-propenvπ-4-iso p ropyl-2-phenyl-2-oxazolin-5-one (second fraction, only one diastereoisomer). Petroleum ether-AcOΕt (95:5 to 9:1) for chromatography. Oil impurified with the other regioisomer. 'H NMR (300 MHz, CDC1 3 ) δ: 7.87-7.85 (m, 2H), 7.61-7.44 (m, 6H), 7.17-7.10 (m, 3H), 6.07 (dd, J=12.6, 10.7 Hz, IH), 3.99 (d, J=10.7 Hz, IH), 2.38 (hp, IH), 2.13 (s, 3H), 1.27 (d, J=6.9 Hz, 3H), 0.86 (d, J=6.9 Hz, 3H). Example 6 (formula 7: R 1 = Ph, R 3 = n-propyl, L 2 = OAc) A solution of 4-(R 2 -substituted)-2-phenyl-2-oxazolin-5-one (450 μmol) was added to NaH (95% in oil, 10.1 mg, 400 μmol) at -78 °C and warmed to room temperature in DME (1.0 mL). When the bubbling stopped, a solution of bis(η 3 -allyl)di-μ- chlorodipalladium (II) (1.8 mg, 4.9 μmol) and ligand 1 (10.4 mg, 15.1 μmol) in DME (1.5 mL). Finally, l,l-diacetoxy-2-hexene (40.0 mg, 200 μmol) was added dropwise at 0°C. The reaction mixture was quenched with aqueous phosphate buffer (pH 7, 40 ml) and extracted with CH 2 C1 2 (3 x 30 mL). The combined organic layer was dried over N-^SO,, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether-AcOEt (95:5). Results are shown in Table 7. Table 7 ' Determined by H-NMR; b Isolated yield; c Determined by chiral HPLC; d The other regioisomer was obtained in 20% (12.5 mg) yield and d.r. (e.e.) 3.1 (71%):1(65%). 4-( 1 '-Acetoxy-2'-hexenylV4-benzyl-2-phenyl-2-oxazolin-5-one (major isomer, first fraction): Oil. Enantiomeric excess was determined by chiral HPLC (Chiracel® OD column, heptane/2-propanol 99.5:0.5), t R (minor) = 10.9, t R (major) = 15.5. Η NMR (300 MHz, CDC1 3 ) δ: 7.88-7.85 (m, 2H), 7.54 (m, IH), 7.46-7.41 (m, 2H), 7.14-7.10 (m, 5H), 6.07 (m, IH), 5.72-5.61 (m, 2H), 3.18 (d, J=13.4 Hz, IH), 3.09 (d, J=13.4 Hz, IH), 2.16-2.09 (m, 2H), 1.96 (s, 3H), 1.45 (m, IH), 0.91 (t, J=7.3 Hz, 3H). 4-( 1 '-Acetoxy-2'-hexenyD-4-benzyl-2-phenyl-2-oxazolin-5-one (minor isomer, second fraction): Oil. Enantiomeric excess was determined by chiral HPLC (Chiracel® OD column, heptane/2-propanol 99.5:0.5), t R (major) = 10.7, t R (minor) = 14.9. ΗNMR (300 MHz, CDC1 3 ) δ: 7.85-7.82 (m, 2H), 7.53 (m, IH), 7.44-7.39 (m, 2H), 7.17-7.11 (m, 5H), 5.96 (m, IH), 5.75-5.67 (m, 2H), 3.20 (d, J=13.4 Hz, IH), 3.15 (d, J=13.4 Hz, IH), 2.13-2.06 (m, 2H), 1.95 (s, 3H), 1.43 (m, IH), 0.89 (t, J=7.3 Hz, 3H). 4-( 1 '- Acetoxy-2'-hexenv0-4-methyl-2-phenyl-2-oxazolin-5-one (first fraction) : Oil. Enantiomeric excess (86%) was determined by chiral HPLC (Chiracel® OD column, heptane/2-propanol 99.5:0.5), t R (minor) = 8.0, t R (major) = 10.3. Η NMR (300 MHz, CDC1 3 ) δ: 8.06-8.03 (m, 2H), 7.61 (m, IH), 7.54-7.48 (m, 2H), 6.00 (m, IH), 5.58 (m, IH), 5.45 (d, J=8.8 Hz, IH), 2.13-2.05 (m, 2H), 1.95 (s, 3H), 1.46 (s, 3H), 1.49-1.37 (m, 2H), 0.89 (t, J=7.4 Hz, 3H). 4-(3'-Acetoxy-r-propenyl-2'-propenylV4-methyl-2-phenyl-2-oxazolin-5-one (second fraction): Mixture of two diastereoisomers: A (major) and B (minor). Diastereomeric and enantiomeric excess were determined by chiral HPLC (Chiracel® OD column, heptane/2-propanol 99.8:0.2), t R (A, major) = 10.6, t R (A, minor) = 12.1, t R (B, minor) = 13.71, t R (B, major) = 18.2. Spectral data of the mixture (only A is shown): *H NMR (300 MHz, CDC1 3 ) δ: 8.03-8.00 (m, 2H), 7.57 (m, IH), 7.52-7.47 (m, 2H), 7.21 (d, J=12.6 Hz, IH), 5.37 (dd, J=12.6, 10.0 Hz, IH), 2.40 (m, IH), 2.15 (s, 3H), 1.46 (s, 3H), 1.40-1.14 (m, 4H), 0.82 (t, J=7.1 Hz, 3H). 4-(l'-Acetoxy-2'-hexenylV4-methyl-2-phenyl-2-oxazolin-5-one (third fraction): Oil. Enantiomeric excess (97%) was determined by chiral HPLC (Chiracel® OD column, heptane/2-propanol 99.5:0.5), t R (major) = 9.1, t R (minor) = 13.2. 'H NMR (300 MHz, CDC1 3 ) δ: 8.01-7.99 (m, 2H), 7.60 (m, IH), 7.52-7.47 (m, 2H), 5.93 (m, IH), 5.65-5.50 (m, 2H), 2.10-2.02 (m, 2H), 1.93 (s, 3H), 1.49 (s, 3H), 1.47-1.35 (m, 2H), 0.88 (t, J=7.4 Hz, 3H).

Claims: CLAIMS 1. A method for preparing an enantiomerically enriched 4,4-disubstituted-5(4H)- oxazolone of formula (1) which comprises alkylating an allylic electrophile, R 3 -L, with a 5-(4H)-oxazolone of formula (2) in the presence of a base and a transition metal complex having one or more chiral ligands, wherein R 1 and R 3 are each independently H or an optionally substituted hydrocarbon group of up to 20 C atoms; R 2 is an optionally substituted amino acid side-chain or hydrocarbon group of up to 20 C atoms; and L is a leaving group. 2. A method according to claim 1 , wherein R 2 is an optionally substituted amino acid side-chain. 3. A method according to claim 1 or claim 2, wherein R 1 is phenyl. 4. A method according to any preceding claim, wherein the transition metal is Pd(0) and the chiral ligand is a bidentate diphosphine with a pair of metal binding moieties of the type -C(=O)-Ar-P-(Ar') 2 , wherein Ar and Ar' are aromatic substituents. 5. A method according to claim 4, wherein the chiral ligand is of formula (3) or the opposite enantiomer thereof, wherein Ar is an aromatic ring optionally substituted by one or more non-interfering groups, and the respective R groups are each any non- interfering group, or R 5 and R 6 may be joined to form a ring. 6. A method according to any preceding claim, wherein L is a halide, an ester, a carbonate, or a carboxylate. 7. A method according to any preceding claim, wherein R 3 -L is of formula (4) wherein n is 1-6. 8. A method according to claim 6, wherein R 3 -L is cyclopentenyl acetate, cyclohexenyl acetate, 3,3-diacetoxy-l-propene or 3,3-diacetoxy-l-phenyl-l-propene. 9. A method for preparing an enantiomerically enriched α,α-disubstituted amino acid of formula (8) which comprises a method according to any preceding claim and reaction of the 4,4- disubstituted-5(4H)-oxazolone with a nucleophile. 10. An enantiomerically-enriched compound of formula (6) wherein R 1 and R 2 are as defined in any of claims 1 to 3 and n is as defined in claim 7 or claim 8. 11. An enantiomerically-enriched compound of formula (7) wherein R 1 and R 2 are as defined in any of claims 1 to 3, R 4 is within the definition of R 3 , and L 2 is H, a hydrocarbon group as defined above or an ionisable group.

Inventors: PIQUER JAVIER ARIZA, TROST BARRY M, PIQUER, JAVIER, ARIZA, TROST, BARRY, M.
Applicants: CHIROTECH TECHNOLOGY LTD, UNIV LELAND STANFORD JUNIOR, CHIROTECH TECHNOLOGY LIMITED, THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIVERSITY
Application year: 1998
Main classification: C07D263
IPC codes: C07B53, C07C227, C07D263