Synthetic Studies on Thiostrepton: Construction of Thiostrepton Analogues with the Thiazoline-Containing Macrocycle

摘要

Thiostrepton (1, Scheme 1) is a highly complex thiopeptide antibiotic endowed with an unusual molecular architecture and a mode of action that involves RNA binding. As part of our program directed towards the total synthesis of this unique natural product, we have already reported synthetic approaches to both its dehydropiperidine domain and its segment corresponding to the quinaldic acid macrocycle. Herein we disclose further advances that pave the way for an eventual total synthesis of 1 and its analogues by addressing the remaining challenges posed by the imposing and sensitive structure of the molecule. Specifically, we describe: 1) the construction of the thiazoline 7 and thiazole 8 fragments, 2) the synthesis of the dehydropyrrolidine isomer 4 of the dehydropiperidine domain and its 5S,6S diastereoisomer 4', and 3) the assembly of these fragments into thiostrepton analogues 2 and 3, which lack only the quinaldic acid macrocycle and differ from thiostrepton (1) at the imine-containing ring core (Scheme 1).