Total syntheses and re-assignment of configurations of the cyclopeptides lissoclinamide 4 and lissoclinamide 5 from Lissoclinum patella

Abstract

The total synthesis of lissoclinamide 4 and lissoclinamide 5, which are novel oxazoline/thiazole/thiazoline-based cyclopeptides isolated from the ascidian (“sea squirt”) Lissoclinum patella, are described. The synthesis of the bis-thiazole based lissoclinamide 5 necessitated the development of practical solutions to the elaboration of enantiomerically pure valine and phenylalanine substituted thiazoles. To overcome the problems associated with the configurational lability of enantiopure amino acid substituted thiazolines, the thiazoline-based cyclopeptide lissoclinamide 4 was synthesised using a novel strategy whereby both the oxazoline and the thiazoline rings in the natural product were formed simultaneously in a “one-pot” double cyclodehydration sequence from an appropriate thioamide/amide cyclopeptide precursor. Based on our synthetic work the stereochemistries 2 and 1 published for natural lissoclinamide 4 and lissoclinamide 5 were re-assigned to 16 and 15 respectively.