Enantioselective Synthesis of (R)-α-Alkylhomoserines and (R)-α-Alkylhomocysteines via Phase-Transfer Catalytic Alkylation

Abstract

Efficient enantioselective synthetic methods for (R)-α-alkylhomoserines and (R)-α-alkylhomocysteines have been developed. The phase-transfer catalytic alkylation of 2-phenyl-5,6-di­hydro-4H-1,3-oxazine-4-carboxylic acid tert-butyl ester and 2-phenyl-5,6-dihydro-4H-1,3-thiazine-4-carboxylic acid tert-butyl ester, in the presence of N-2′,3′,4′-trifluorobenzylcinchonidinium bromide, gave the corresponding alkylated products, which could be hydrolyzed to provide (R)-α-alkylhomoserines (up to 97% ee) and (R)-α-alkylhomocysteines (up to 91% ee), respectively.

Key words

phase-transfer catalytic alkylation - enantioselective synthesis - (R)-α-alkylhomoserines - (R)-α-alkylhomocysteines

References and Notes

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10

Representative Procedure for the Enantioselective Alkylation (Benzylation) of tert -Butyl 2-Phenyl-5,6-dihydro-4 H -1,3-oxazine-4-carboxylate (7)
To a solution of tert-butyl 2-phenyl-5,6-dihydro-4H-1,3-oxazine-4-carboxylate (7, 50 mg, 0.2 mmol) in toluene (1.0 mL) were successively added the chiral PTC 16 (11 mg, 0.02 mmol), solid KOH (54.1 mg, 1.0 mmol), and benzyl bromide (0.1 mL, 1.0 mmol) at 0 ˚C. The reaction mixture was stirred for 1 h at 0 ˚C. After completion of the reaction, the reaction mixture was diluted with EtOAc (20 mL), and the EtOAc solution was washed with brine (2 × 5 mL). The organic solution was then dried over anhyd MgSO₄, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO₂; hexanes-EtOAc, 50:1) to afford the benzylated product 9d (47 mg, 70% yield) as a pale yellow oil. Because the two enantiomers of 9d were not fully separated by chiral HPLC, the enantioselectivity was determined by the chiral HPLC analysis of the corresponding methyl ester which was prepared from the hydrolysis of 9d followed by methylation using the excess of diazomethane. The enantioselectivity was determined as 97% ee [Chiralcel AD-H column, hexanes-2-PrOH (95:5), flow rate = 1.0 mL/min, 23 ˚C, 254 nm, t _R (R, major) = 5.2 min; t _R (S, minor) = 6.8 min, 97% ee]. Absolute configu-ration was tentatively determined as R based on the absolute configuration of 9a.