Progress toward the assembly of the bicyclic theonellamide skeleton

Abstract

An orthogonally protected τ-histidinoalanine residue was synthesized via regioselective alkylation of optically pure Boc-l-His-OTCE (TCE = trichloroethyl) with a sulfamidate electrophile derived from Fmoc-d-Ser-OBn. The goal was the synthesis of a non-natural theonellamide, invoking readily accessible variants of the other 10 amino acids. Peptide fragments corresponding to the east and west rings of “theonellamide X″ were synthesized in solution. Each ring was formed independently, providing insights into protecting group limitations, side reactions, and the optimal order of events to approach the formation of the bicyclic system. Ultimately, an undecapeptide was prepared, with the eastern ring formed. The twelfth amino acid, an l-α-aminoadipic acid building block, was prepared and preliminary investigations into its attachment to the undecapeptide are reported.