Solid Phase versus Solution Phase Synthesis of Heterocyclic Macrocycles

Abstract

Comparing a solution phase route to a solid phase route in the synthesis of the cytotoxic natural product urukthapelstatin A (Ustat A) confirmed that a solid phase method is superior. The solution phase approach was tedious and involved cyclization of a ridged heterocyclic precursor, while solid phase allowed the rapid generation of a flexible linear peptide. Cyclization of the linear peptide was facile and subsequent generation of three oxazoles located within the structure of Ustat A proved relatively straightforward. Given the ease with which the oxazole Ustat A precursor is formed via our solid phase approach, this route is amenable to rapid analog synthesis.

Keywords

• urukthapelstatin A
• cytotoxic
• macrocycle
• peptides
• heterocycle
• thiazole
• oxazole
• telomestatin
• solid phase peptide synthesis