Novel Total Synthesis of (+)-Eremantholide A

Ken Ichi Takao, Hiroshi Ochiai, Ken Ichi Yoshida, Takahiko Hashizuka, Hirokazu Koshimura, Kin Ichi Tadano, Senchiro Ogawa

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Abstract

Stereoselective total synthesis of (+)-eremantholide A (1), a cytotoxic furanoheliangolide sesquiterpene, was accomplished in an enantiospecific fashion. The total synthesis featured the following three key synthetic strategies. (1) Intramolecular cyclization of carbon-radicals derived from xanthates 19a or 19b proceeded regio- and stereoselectively in an exclusive 5-exo-dig mode to provide bicyclic lactones 20a or 20b. Further functional group manipulations of 20a and 20b efficiently afforded a highly substituted 3, 7-dioxabicyclo[3.3.0]octan-2-one derivative 34, which served as a synthetic equivalent to the A/B ring system in 1. (2) Alkylation of the enolate of 3 (2H)-furanone 36 with triflate 35 was thoroughly investigated to maximize formation of the C-alkylated diastereomers, either 10R-isomer 37 or 1OS-isomer 38. It was found that choice of the base, solvent, and/or additive was critical to the diastereoselectivity. Furthermore, the 1OR-isomer 50 was also prepared in increased yield and improved diastereoselectivity by coupling 36 with A/B ring equivalent 49. (3) In a later stage of the total synthesis, construction of the strained 11-oxabicyclo-[6.2.1]undeca-2, 10-dien-9-one system (the C/D ring) was accomplished by meass of an intramolecular vinylogous aldol reaction of aldehyde 52, prepared from 10R-isomer 40, followed by base-catalyzed β-elimination of the corresponding mesylates 54. On the other hand, by employing analogous reaction conditions, the 1OS-isomer 56 was transformed into unnatural (-)-10-epi-eremantholide A (61).

Original languageEnglish
Pages (from-to)8179-8193
Number of pages15
JournalJournal of Organic Chemistry
Volume60
Issue number25
DOIs
Publication statusPublished - 1995 Dec 1

ASJC Scopus subject areas

  • Organic Chemistry

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    Takao, K. I., Ochiai, H., Yoshida, K. I., Hashizuka, T., Koshimura, H., Tadano, K. I., & Ogawa, S. (1995). Novel Total Synthesis of (+)-Eremantholide A. Journal of Organic Chemistry, 60(25), 8179-8193. https://doi.org/10.1021/jo00130a017