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Total Synthesis and Biological Evaluation of (+)‐Neopeltolide and Its Analogues
Author(s) -
Fuwa Haruhiko,
Saito Asami,
Naito Shinya,
Konoki Keiichi,
YotsuYamashita Mari,
Sasaki Makoto
Publication year - 2009
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200901675
Subject(s) - total synthesis , tetrahydropyran , ring closing metathesis , metathesis , chemistry , natural product , stereochemistry , convergent synthesis , combinatorial chemistry , diene , stereoselectivity , suzuki reaction , cancer cell lines , enol , yield (engineering) , ring (chemistry) , organic chemistry , biology , palladium , cancer cell , catalysis , natural rubber , materials science , cancer , metallurgy , polymerization , genetics , polymer
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 ).