Toward the Total Synthesis of Onchidin, a Cytotoxic Cyclic Depsipeptide from a Mollusc

Abstract

The total synthesis of onchidin (1), a cytotoxic, C2‐symmetric cyclic decadepsipeptide from a marine mollusc, according to the published structure, is described. A novel β‐amino acid, (2S,3S)‐3‐amino‐2‐methyl‐7‐octynoic acid (AMO), was efficiently prepared in high yield with high diastereo‐ and enantioselectivity based on a catalytic asymmetric three‐component Mannich‐type reaction with a chiral zirconium catalyst. The formation of sterically unfavorable N‐methyl amide and hindered ester bonds were successfully demonstrated, and final macrocyclization was achieved at a secondary‐amide site. Completion of the synthesis of 1 suggested that a revision of the structure of the natural product is required. Two diastereomers were also synthesized as candidates for the actual structure of onchidin. Furthermore, efficient solid‐phase methods were employed for the combinatorial synthesis of other derivatives to clarify the real structure of onchidin. The solid‐phase assembly of a pentadepsipeptide containing all the building blocks was established followed by dimeric cyclization in solution.

Survey of marine natural product structure revisions: A synergy of spectroscopy and chemical synthesis

“…150 In several of these cases, the lack of readily available authentic natural product sample precludes definitive structural revision, and therefore awaits re-isolation of the natural product or a close analogue. Total synthesis also revealed misassignment of the relative configurations for amphidinolide B2, 157 lituarines B and C from a sea pen, 158 marine fungal metabolite LL15G256γ, 159 and the molluscandepsipeptideonchidin 160 (Figure 4). Thus, total synthesis has been instrumental in the detection of marine natural product structural misassignments.…”

Depsipeptide Companeramides from a Panamanian Marine Cyanobacterium Associated with the Coibamide Producer

“…The (2 S ,3 S )-configuration was also assigned to the Amoya unit in onchidin based on NOE studies and 1 H NMR coupling constant analysis; however, the total synthesis of onchidin suggested that a revision of the structure was necessary. 19 Therefore, it was planned to use Marfey’s analysis for assignment of the Amoya unit in companeramides A and B, facilitated by the availability of the synthetic 3( R )-amino-2( R,S )-methyloctanoate (Amo) standards. 20 …”

Recent Developments in Enantioselective Metal‐Catalyzed Domino Reactions

“…In addition, Kobayashi et al have developed enantioselective Mannich-type reaction of 5hexynal, 2-amino-m-cresol and a ketene silyl acetal derived from phenyl propionate by using an in situ generated chiral zirconium catalyst of (S)-6,6'-(C 2 F 5 ) 2 -BINOL. [147] As shown in Scheme 62, the process led to the formation of the corresponding Mannich adduct 246 in 85% yield, good synstereoselectivity (syn:anti = 91:9) in combination with excellent enantioselectivity of 96% ee for the major syn-product. Product 246 was further converted into onchidin, which is a natural cytotoxic, C 2symmetric cyclic decadepsipeptide.…”