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Total Synthesis and Biological Assessment of (−)‐Exiguolide and Analogues
Author(s) -
Fuwa Haruhiko,
Suzuki Takaya,
Kubo Hiroshi,
Yamori Takao,
Sasaki Makoto
Publication year - 2011
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.201003135
Subject(s) - total synthesis , tetrahydropyran , stereochemistry , chemistry , enantiomer , intramolecular force , enantioselective synthesis , natural product , metathesis , conjugate , combinatorial chemistry , ring (chemistry) , biochemistry , organic chemistry , mathematical analysis , polymer , mathematics , polymerization , catalysis
We describe herein an enantioselective total synthesis of (−)‐exiguolide, the natural enantiomer. The methylene bis(tetrahydropyran) substructure was efficiently synthesized by exploiting olefin cross‐metathesis for the assembly of readily available acyclic segments and intramolecular oxa‐conjugate cyclization and reductive etherification for the formation of the tetrahydropyran rings. The 20‐membered macrocyclic framework was constructed in an efficient manner by means of Julia–Kocienski coupling and Yamaguchi macrolactonization. Finally, the ( E , Z , E )‐triene side chain was introduced stereoselectively via Suzuki–Miyaura coupling to complete the total synthesis. Assessment of the growth inhibitory activity of synthetic (−)‐exiguolide against a panel of human cancer cell lines elucidated for the first time that this natural product is an effective antiproliferative agent against the NCI‐H460 human lung large cell carcinoma and the A549 human lung adenocarcinoma cell lines. Moreover, we have investigated structure–activity relationships of (−)‐exiguolide, which elucidated that the C5‐methoxycarbonylmethylidene group and the length of the side chain are important for the potent activity.