Total Synthesis of Crotophorbolone

Abstract

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.

Generation of Alkyl Radicals: From the Tyranny of Tin to the Photon Democracy

“… 305 A decarboxylative hydroxylation may be carried out with the intermediacy of Barton esters that upon irradiation in oxygen-saturated toluene followed by treatment with P(OEt) 3 afforded an alcohol intermediate for the total synthesis of Crotophorbolone. 306 The more challenging oxidation of unactivated alkanes to alcohols or ketones can be achieved through a photoelectrochemical approach, as testified by the C–H bond activation of cyclohexane to prepare a mixture of cyclohexanone and cyclohexanol (the so-called KA oil) with high partial oxidation selectivity (99%) and high current utilization ratio (76%). The highest current ratio was obtained illuminating the solution with 365 nm wavelength.…”

Navigating the Chiral Pool in the Total Synthesis of Complex Terpene Natural Products

“…298,299 A structural analysis of 241 identifies a monocyclic monoterpene substructure embedded within its carbon skeleton and in 2015, Inoue and coworkers disclosed the inaugural total synthesis of crotophorbolone starting from (+)-carvone. 300 …”

Total Synthesis of (±)-Prostratin

“…In 2015, the first total synthesis of crotophorbolone (4) was disclosed by the Inoue group (33 steps). 55 An alkoxy bridgehead radical reaction was used to forge the key C9-C10 bond. Furthermore, the first total synthesis of resiniferatoxin (5) was achieved by the Wender group in 1997 (44 steps).…”