Novel Total Synthesis of (+)-Eremantholide A

Article abstract of DOI:10.1021/jo00130a017

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 10S-isomer 38.It was found that choice of the base, solvent, and/or additive was critical to the diastereoselectivity.Furthermore, the 10R-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 means 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 10S-isomer 56 was transformed into unnatural (-)-10-epi-eremantholide A (61).