Toward the total synthesis of onchidin, a cytotoxic cyclic depsipeptide from a mollusc.
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 beta-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.
Kobayashi
Shū
S
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. skobayas@mol.f.u-tokyo.ac.jp
Kobayashi
Jun
J
Yazaki
Ryo
R
Ueno
Masaharu
M
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000302:isolation & purification / Q000494:pharmacology; D002384:Catalysis; D018360:Crystallography, X-Ray; D003500:Cyclization; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000302:isolation & purification / Q000494:pharmacology; D008352:Mannich Bases / Q000737:chemistry; D008974:Mollusca / Q000737:chemistry*; D011487:Protein Conformation; D015040:Zirconium / Q000737:chemistry
D000970:Antineoplastic Agents; D047630:Depsipeptides; D008352:Mannich Bases; C519815:onichidin; D015040:Zirconium