No abstract

The complex ABC-tricyclic structure of crotophorbolone, a derivative of the tigliane diterpenoids, was assembled by coupling of simple fragments. The six-membered C-ring fragment, having five contiguous stereocenters, was stereoselectively constructed from (R)-carvone. After attachment of the five-membered A-ring through the π-allyl Stille coupling reaction, the α-alkoxy bridgehead radical reaction effected the endo-cyclization of the seven-membered B-ring by forming the sterically congested bond at C9 and C10 stereospecifically and stereoselectively, respectively. Finally, the functional groups on the 5/7/6-membered ring system were manipulated by rhodium-catalyzed C2 olefin isomerization, C13 decarboxylative oxidation, and C4 hydroxylation, thus completing the first total synthesis of crotophorbolone.

The complex ABC-tricyclic structure of crotophorbolone,aderivative of the tigliane diterpenoids,was assembled by coupling of simple fragments.T he six-membered C-ring fragment, having five contiguous stereocenters,w as stereoselectively constructed from (R)-carvone.After attachment of the five-membered A-ring through the p-allyl Stille coupling reaction, the a-alkoxy bridgehead radical reaction effected the endo-cyclization of the seven-membered B-ring by forming the sterically congested bond at C9 and C10 stereospecifically and stereoselectively,r espectively.F inally,t he functional groups on the 5/7/6-membered ring system were manipulated by rhodium-catalyzed C2 olefin isomerization, C13 decarboxylative oxidation, and C4 hydroxylation, thus completing the first total synthesis of crotophorbolone.

This account describes the development of a synthetic route to crotophorbolone (1). Compound 1 is classified as a derivative of the tigliane diterpenoids, and possesses a highly oxygenated 5/7/6-fused ABC-ring system. First, the six-membered C-ring fragment with five contiguous stereocenters was stereoselectively constructed from (R)-carvone. Nucleophilic addition of the three-carbon unit to the C-ring and stereoselective attachment of the five-membered A-ring through a π-allyl Stille coupling reaction provided the substrate for the key radical cyclization. Next, treatment of the O,Se-acetal with V-40 and (TMS) 3 SiH in refluxing toluene generated the α-alkoxy bridge- head radical, which participated in the endo-cyclization of the seven-membered B-ring with formation of the sterically congested bond in C9-stereospecific and C10-stereoselective manners. The C11-methyl group controlled the C10-stereochemical outcome via a long-range steric interaction, which was supported by the calculated transition state of the abbreviated α-alkoxy bridgehead radical structure. Finally, the functional groups on the 5/7/6-membered ring system were manipulated by Rh-catalyzed C2-olefin isomerization, C13-decarboxylative oxidation and C4-hydroxylation, completing the first total synthesis of 1 in 33 steps from (R)-carvone.

Convergent Strategies in Total Syntheses of Complex Terpenoids -[301 refs.]. -(URABE, D.; ASABA, T.; INOUE, M.; Chem. Rev. (Washington, DC, U. S.) 115 (2015) 17, 9207-9231, http://dx.doi.org/10.1021/cr500716f ; Grad. Sch. Pharm. Sci., Univ. Tokyo, Bunkyo, Tokyo 113, Japan; Eng.) -Koehler 45-252