Formal synthesis of optically active ingenol via ring-closing olefin metathesis.
The construction of strained carbon skeletons by ring-closing olefin metathesis (RCM) was investigated. With well-designed diene 4, RCM was found to be applicable to the formation of a highly strained inside-outside bicyclo[4.4.1]undecane skeleton of ingenol, a bioactive diterpenoid, and formal total synthesis of optically active ingenol (1) was achieved. The key features of this synthesis are construction of an A-ring by spirocyclization of the ketone with an allylic chloride unit, 26, and ring closure of a B-ring by olefin metathesis. Starting from Funk's keto ester 6, the key intermediate aldehyde 9 in Winkler's total synthesis was synthesized in eight steps in 12.5% overall yield. This strategy of direct cyclization of a strained inside-outside skeleton provided the first easy access to optically active ingenol.
Watanabe
Kazushi
K
Department of Chemistry, University of Tsukuba, Tennoudai, Tsukuba, Ibaraki 305-8571, Japan.
Suzuki
Yuto
Y
Aoki
Kenta
K
Sakakura
Akira
A
Suenaga
Kiyotake
K
Kigoshi
Hideo
H
D000475:Alkenes / Q000737:chemistry*; D003500:Cyclization; D004224:Diterpenes / Q000138:chemical synthesis*; D008968:Molecular Conformation; D015394:Molecular Structure; D013237:Stereoisomerism
D000475:Alkenes; D004224:Diterpenes; C008125:ingenol