Forskolin Editing via Radical Iodo- and Hydroalkylation

Abstract

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-butyl­catechol-mediated hydroalkylation procedure, highly efficient preparation of forskolin derivatives bearing an extra ester or sulfone group was achieved.

Skeletal Transformations of Terpenoid Forskolin Employing an Oxidative Rearrangement Strategy

“…Previously, a series of forskolin analogues have been reported, − including the redox rearrangement products, acid-catalyzed rearrangement products, and base-catalyzed rearrangement products (Figure S12). , The base-catalyzed rearrangement product 3 bears a unique 6/7/5 tricyclic carbon skeleton, an oxygen bridging ring, making it an ideal precursor for next oxidative rearrangements (Scheme ).…”

Radical‐Mediated Hydroperfluoroalkylation of Unactivated Alkenes

“…[34] Recently, we have developed an efficient radical mediated chain reaction for the hydroalkylation of unactivated, electron rich alkenes employing 4-tertbutylcatechol (TBC) as a source of hydrogen atoms and triethylborane as a chain transfer reagent. [35][36][37][38] This process proved to be efficient with a broad range of electrophilic radicals and its efficiency was attributed to very favorable polar effects and an unprecedented repair mechanism. [35,39] Considering the simplicity and efficiency of the method, we envisaged that it could be extended to the hydroperfluoroalkylation of unactivated alkenes (Scheme 1D).…”

“…Iodine ATRA reaction of perfluoroalkyl iodides to alkenes using triethylborane/air as an initiator has been pioneered by Utimoto, Oshima and co‐workers [34] . Recently, we have developed an efficient radical mediated chain reaction for the hydroalkylation of unactivated, electron rich alkenes employing 4‐ tert ‐butylcatechol (TBC) as a source of hydrogen atoms and triethylborane as a chain transfer reagent [35–38] . This process proved to be efficient with a broad range of electrophilic radicals and its efficiency was attributed to very favorable polar effects and an unprecedented repair mechanism [35,39] .…”

Radical Mediated Hydroperfluoroalkylation of Unactivated Alkenes

“…Hydroperfluoroalkylation of unactivated alkenes Recently, we have developed an efficient radical mediated chain reaction for the hydroalkylation of unactivated and electron rich alkenes employing 4tert-butylcatechol (TBC) as a source of hydrogen atoms and triethylborane as a chain transfer reagent. [34][35][36][37] This process proved to be efficient with a broad range of electrophilic radicals and its efficiency was attributed to very favourable polar effects and an unprecedented repair mechanism. [38,34] Considering the simplicity and efficiency of the method, we envisaged that it could be extended to the hydroperfluoroalkylation of unactivated alkenes (Scheme 1, D).…”