One-pot process for the preparation of a β-alkynyl β-amino acid ester

The large scale preparation of the beta-alkynyl beta-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 beta-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 degrees C) compared to the analogous two-pot reaction (-45 degrees C), Addition of 3-(trimethylsilyl)-2-propynal to LHMDS in THF at -20 degrees 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%.