One-Pot Process for the Preparation of a β-Alkynyl β-Amino Acid Ester

• Published in: Organic process research & development 1997-05, Vol.1 (3), p.233-239
• Main Authors: Boys, Mark L, Cain-Janicki, Kimberly J, Doubleday, Wendel W, Farid, Payman N, Kar, Mangalya, Nugent, Sean T, Behling, James R, Pilipauskas, Daniel R
• Format: Article
• Language: English
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/op970102i

The large-scale preparation of the β-alkynyl β-amino acid ester (±)-1,1-dimethylethyl 3-amino-5-(trimethylsilyl)-4-pentynoate (A) is discussed. It was discovered that addition of a catalytic amount of lithium bis(trimethylsilyl)amide (LHMDS) to a mixture of tert-butyl acetate and N,3-bis(trimethylsilyl)-2-propyn-1-imine (B) initiated a self-perpetuating reaction and gave high yields of the β-amino ester A upon quench. This one-pot procedure eliminated the need to prepare the unstable lithium tert-butyl acetate in a separate reactor and enabled the reaction to be scaled up and run at a more acceptable process temperature (−20 °C) compared to the analogous two-pot reaction (−45 °C). Addition of 3-(trimethylsilyl)-2-propynal to LHMDS in THF at −20 °C followed by chlorotrimethylsilane formed the imine B in situ. tert-Butyl acetate (6 equiv) was added followed by a substoichiometric quantity (0.15−0.20 equiv) of LHMDS. After quenching with aqueous ammonium chloride the product A was obtained in a yield averaging 70%.