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Synlett 2002(12): 2039-2040
DOI: 10.1055/s-2002-35608
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Convenient Synthesis of Chiral β3-Amino Acids

Tushar K. Chakraborty*, Animesh Ghosh
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax: +91(40)7160387; e-Mail: chakraborty@iict.ap.nic.in; e-Mail: chakraborty@iict.res.in;
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Publication History

Received 7 September 2002
Publication Date:
20 November 2002 (online)

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Abstract

A novel method for the synthesis of chiral β3-amino acids is developed where the acid functionality was built by oxidative cleavage of an α-allylic group that was introduced by Evans’ asymmetric alkylation of an appropriate acid substrate and the amino part came from the amide of the original carboxyl group following a modified Hofmann rearrangement reaction.

Key words

β-amino acids - Hofmann rearrangement - oxazolidi­none - Evans’ reaction

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All new compounds were characterized by IR, NMR and mass spectroscopic studies. Representative experimental procedures for the key steps: Synthesis of 2a: To a stirred solution of 1a (2.5 g, 8.47 mmol) in anhyd THF (20 mL) at -78 °C, NaHMDS (6.35 mL, 2 M solution in THF, 12.7 mmol) was added and stirring was continued at the same temperature for 1 h. Next, allyl bromide (2.93 mL, 33.88 mmol) was added to the reaction mixture and the temperature was slowly raised to -45 °C over a period of 45 minutes. After stirring for 4 h at -45 °C, the reaction mixture was quenched with saturated NH4Cl solution and allowed to warm up to room temperature. It was extracted with EtOAc (2 × 50 mL), the extracts were combined, washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography (SiO2, 12.5% EtOAc in petroleum ether as eluant) furnished the major isomer 2a (1.84 g, 65%) as a syrup.
Synthesis of 6a: To a stirred solution of 5a (0.10 g, 0.48 mmol) in CH3CN-H2O (2 mL, 1:1 v/v), PhI(CF3CO2)2 (0.25 g, 0.58 mmol) was added at room temperature. After stirring for 1 h, it was cooled to 0 °C and Et3N (0.27 mL, 1.93 mmol), followed by Boc2O (0.20 mL, 0.96 mmol) were added and stirring was continued for 1 h at the same temperature. The reaction mixture was then diluted with CH2Cl2 (10 mL), washed with saturated NH4Cl (5 mL), brine (5 mL), dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography (SiO2, 20% EtOAc in petroleum ether as eluant) furnished 6a (92 mg, 68%) as a colorless syrupy liquid.

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The ratios for the isomers: 92:8 for 2a; 98:2 for 2b (at -78 °C); 93:7 for 2c; 95:5 for 2d; 95:5 for 2e. The minor isomer in each case could be separated easily by standard silica gel column chromatography.