Development of Fmoc-O-N(CH₃)-Bz as a novel Fmoc protecting reagent for the preparation of various Fmoc-protected amino acids.

Abstract

A novel series of Fmoc-O-N(CH₃)-sulfonyl/acyl protecting reagents was developed to overcome challenges associated with the formation of Fmoc-β-Ala-OH via the Lossen rearrangement, a limitation of commonly used Fmoc-OSu reagents. These reagents were efficiently synthesized from the cost-effective and commercially available starting material, N-methylhydroxylamine hydrochloride. Fmoc-O-N(CH₃)-Bz was identified as the optimal Fmoc reagent, providing the highest reaction yields under optimized mild conditions. Additionally, Fmoc-O-N(CH₃)-Bz demonstrated versatility in synthesizing a wide range of Fmoc-protected amino acids with moderate to excellent yields, with yields ranging from 70 % to 93 % for cyclic amino acids.