A Facile Two‐Step Synthesis of Novel Ring‐A Double Substituted Tryptophan Building Blocks (IV) for Combinatorial Chemistry.

Abstract

A fast synthesis of ring-A disubstituted Fmoc and Boc protected L-tryptophan analogs was achieved starting from the appropriate 2,4-or 2,3-disubstituted phenylhydrazines and optically active N,N-diprotected L-glutamic acid g-aldehydes, utilizing a Fischer-indole synthesis as a key step. Unlike most of the previously reported methods, that required the multistep stereoselective generation of a chiral carbon, this fast methodology is useful for generating optically active ring-A disubstituted protected tryptophans starting from a simple and common chiral precursor. These building blocks have a wide application scope in peptide and combinatorial chemistry fields.

An Optimized Synthesis of Fmoc-l-Homopropargylglycine-OH

“…We were attracted by the route reported by Davis and co-workers, which began with the two-step conversion of Boc- l -Glu-O t Bu ( 1 ) to Weinreb amide 3 (Scheme ) according to a procedure by Gellerman. According to this procedure, installation of a second N-Boc protecting group was initially carried out with Boc 2 O, triethylamine, and DMAP under the conditions shown in entry 1 of Table . After the mixture had been stirred overnight, only 22% of starting amino acid 2 was consumed and the reaction stopped.…”

“…According to this procedure, installation of a second N-Boc protecting group was initially carried out with Boc 2 O, triethylamine, and DMAP under the conditions shown in entry 1 of Table 1. 28 After the mixture had been stirred overnight, only 22% of starting amino acid 2 was consumed and the reaction stopped. As expected, addition of multiple additional equivalents of Boc 2 O and base could push the reaction further, but full conversion was not reproducibly achieved (entry 2), even after multiple days, heating, and additions of Boc 2 O.…”