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Toward the Total Synthesis of Onchidin, a Cytotoxic Cyclic Depsipeptide from a Mollusc
Author(s) -
Kobayashi Shū,
Kobayashi Jun,
Yazaki Ryo,
Ueno Masaharu
Publication year - 2007
Publication title -
chemistry – an asian journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.18
H-Index - 106
eISSN - 1861-471X
pISSN - 1861-4728
DOI - 10.1002/asia.200600232
Subject(s) - steric effects , chemistry , amide , catalysis , residue (chemistry) , natural product , yield (engineering) , stereocenter , diastereomer , mannich reaction , stereochemistry , depsipeptide , enantioselective synthesis , total synthesis , combinatorial chemistry , amino acid , organic chemistry , materials science , biochemistry , metallurgy
The total synthesis of onchidin ( 1 ), a cytotoxic, C 2 ‐symmetric cyclic decadepsipeptide from a marine mollusc, according to the published structure, is described. A novel β‐amino acid, (2 S ,3 S )‐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.