Total synthesis and biological evaluation of (+)-neopeltolide and its analogues.
The stereocontrolled total synthesis of the originally proposed (1) and correct (2) structures of (+)-neopeltolide, a novel marine macrolide natural product with highly potent antiproliferative activity against several cancer cell lines as well as potent antifungal activity, has been achieved by exploiting a newly developed Suzuki-Miyaura coupling/ring-closing metathesis strategy. Alkylborate 44, which was generated in situ from iodide 34, was coupled with enol phosphate 8 by a Suzuki-Miyaura coupling. Ring-closing metathesis of the derived diene 45 followed by stereoselective hydrogenation afforded tetrahydropyran 47 as a single stereoisomer in high overall yield from 34. Our convergent strategy enabled us to construct the 14-membered macrolactone core structure of 2 in a rapid and efficient manner. Total synthesis and biological evaluation of synthetic intermediates and designed synthetic analogues, performed to establish the structure-activity relationships of 2, led to the discovery of a structurally simple yet potent cytotoxic analogue, 9-demethylneopeltolide (54).
Fuwa
Haruhiko
H
Graduate School of Life Sciences, Tohoku University, 1-1 Tsutsumidori-amamiya, Aoba-ku, Sendai 981-8555, Japan. hfuwa@bios.tohoku.ac.jp
Saito
Asami
A
Naito
Shinya
S
Konoki
Keiichi
K
Yotsu-Yamashita
Mari
M
Sasaki
Makoto
M
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D020128:Inhibitory Concentration 50; D007455:Iodine / Q000737:chemistry; D007700:Kinetics; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D010710:Phosphates / Q000138:chemical synthesis / Q000737:chemistry; D011714:Pyrans / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D018942:Macrolides; D010710:Phosphates; D011714:Pyrans; C519136:neopeltolide; D007455:Iodine