Forskolin Editing via Radical Iodo- and Hydroalkylation

The modification of highly oxygenated forskolin as well as manoyl and epi-manoyl oxide, two less functionalized model substrates sharing the same polycyclic skeleton, via intermolecular carbon-centered radical addition to the vinyl moiety has been investigated. Highly regio- and reasonably stereoselective iodine atom transfer radical addition (ATRA) reactions were developed. Unprotected forskolin afforded an unexpected cyclic ether derivative. Protection of the 1,3-diol as an acetonide led the formation of the iodine ATRA product. Interestingly, by changing the mode of initiation of the radical process, in situ protection of the forskolin 1,3-diol moiety as a cyclic boronic ester took place during the iodine ATRA process without disruption of the radical chain process. This very mild radical-mediated in situ protection of 1,3-diol is expected to be of interest for a broad range of radical and non-radical transformations. Finally, by using our recently developed tert-butyl-catechol-mediated hydroalkylation procedure, highly efficient preparation of forskolin derivatives bearing an extra ester or sulfone group was achieved.

Automated summary

The modification of highly oxygenated forskolin and two less functionalized model substrates was investigated via intermolecular carbon-centered radical addition, leading to highly regio- and reasonably stereoselective iodine atom transfer radical addition reactions. Unexpected cyclic ether derivative was obtained from unprotected forskolin, while in situ protection of the 1,3-diol moiety as a cyclic boronic ester occurred during the iodine ATRA process by changing the mode of radical process initiation. This mild radical-mediated in situ protection of 1,3-diol may have broad applications in radical and non-radical transformations.