Total synthesis of (+)-nostocyclamide 1

Abstract

The synthesis of (+)-nostocyclamide from the oxazole 1 and thiazoles 2 and 3 is described. The oxazole amino ester 1b was prepared from N-protected alaninamide using a rhodium(II) catalysed N–H insertion reaction as a key step, and the thiazoles 2 and 3 were obtained using a modified Hantzsch reaction. The synthesis was completed in six further steps in which fragments 1 and 2 were coupled using mixed anhydride methodology to give the oxazole–thiazole 13, deprotection of which and coupling to 3 gave the linear bis-thiazole oxazole 15. Macrocyclisation using the pentafluorophenyl ester method gave (+)-nostocyclamide; the synthesis confirms that the natural product is the (+)-enantiomer and has the (2S,12R) absolute configuration.