Total Synthesis Of Natural Cyclic Depsipeptide-Obyanamide

Total Synthesis of Natural Cyclic Depsipeptide - Obyanamide Obyanamide, which exhibits moderate cytotoxicity against KB and LoVo cells, is a kind of 19-membered cyclic depsipeptide isolated from the marine cyanobacterium Lyngbya confervoides collected in Saipan, Commonwealth of the Northern Mariana Island by Moore R.E. and his coworkers. Based on the structural features of Obyanamid, the target molecule was disconnected into four fragments by applying retrosynthetic analysis method, i.e., N-Me-Phe-N-Me-Val (Fragment A), thiazole carboxy acid derivative (Fragment B), lactic acid derivative (Fragment C) and unnatural 3-aminopentanoic acid (Fragment D). Cyclic depsipeptide, Obyanamide was synthesized successfully from synthesized Fragments A, B, C and D in overall yield of 3%. The sterically hindered N-methyl peptide (Fragment A) was synthesized from (L)-Phe and (L)-Val in an overall yield of 48.2% through ten steps, including esterification, o-NBS protection, N-Methylation, o-NBS & t-Bu deprotection, acylation, condensation and deprotection.The chiral unit containing thiazole (Fragment B) was synthesized from (S)-Serine and N-Boc-(S)-Alanine in an overall yield of 21.4% through seven steps, including esterification, condensation, TBS protection, thionation, TBS deprotection, cyclization, dehydrogenization, ester hydrolysis and esterification. The ee value of the title chiral thiazole nuit was up to 98%.Hydroxy group protection of (L)-lactic acid with acetyl chloride followed by acylated with oxalic chloride gave Fragment C in 98% yield.Fragment D, which was an unnatural β-aminopentanoic acid derivative was synthesized from (L)-2-aminobutylic acid in an overall yield of 84.8%. This synthesis was accomplished in four steps, including Boc protection, diazotisation, Wolff rearrangement and ester hydrolysis.Coupling reactions and ring closure: The resulting product of condensation of deprotected fragment A and fragment C was deprotected and coupled with fragment B to give an intermediate. And deacetylation, coupling with fragment D gave a chain depsipeptide. Finally, ring closure catalyzed by FDPP gave natural cyclic depsipeptide Obyanamide. The overall yield was up to 3% (based on (L)-Alanine).