A Convenient Synthesis of Chiral β³-Amino Acids

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.

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

References

1a Peptides: The Wave of the Future   Lebl M. Houghton RA. American Peptide Society; San Diego: 2001. 

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For some recent works see:

2a Porter EA. Weisblum B. Gellman SH. J. Am. Chem. Soc.  2002,  124:  7324 

2b Seebach D. Rueping M. Arvidsson PI. Kimmerlin T. Micuch P. Noti C. Langenegger D. Hoyer D. Helv. Chim. Acta  2001,  84:  3503 

2c Gademann K. Seebach D. Helv. Chim. Acta  2001,  84:  2924 

2d Porter EA. Wang X. Lee H.-S. Weisblum B. Gellman SH. Nature (London)  2000,  404:  565 

2e Hamuro Y. Schneider JP. DeGrado WF. J. Am. Chem. Soc.  1999,  121:  12200 

For some representative references on the synthesis of β-amino acids see:

3a Davies HML. Venkataramani C. Angew. Chem. Int. Ed.  2002,  41:  2197 

3b Berkessel A. Glaubitz K. Lex J. Eur. J. Org. Chem.  2002,  2948 

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3d LePlae PR. Umezawa N. Lee HS. Gellman SH. J. Org. Chem.  2001,  66:  5629 

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3i Tang TP. Ellman JA. J. Org. Chem.  1999,  64:  12 

3j Myers JK. Jacobsen EN. J. Am. Chem. Soc.  1999,  121:  8959 

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4a

It is not possible to list here all the references on the synthesis of β-amino acids. However, searches in http://www.sciencedirect.com under ‘synthesis of β-amino acids’ and ‘amino acids’ in http://pubs.acs.org and http://www.wiley-vch.de/publish/en/journals/search/ will give detailed lists of most of the references.

4b For earlier references on the synthesis of β-amino acids see: Enantioselective Synthesis of β-Amino Acids   Juaristi E. Wiley-VCH; New York: 1997. 

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6d Waki M. Kitajima Y. Izumiya N. Synthesis  1981,  266 

7

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.

8

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.

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