Development of a Concise Synthesis of (+)-Ingenol

The complex diterpenoid (+)-ingenol
possesses a uniquely challenging
scaffold and constitutes the core of a recently approved anti-cancer
drug. This full account details the development of a short synthesis
of 1 that takes place in two separate phases (cyclase
and oxidase) as loosely modeled after terpene biosynthesis. Initial
model studies establishing the viability of a Pauson–Khand
approach to building up the carbon framework are recounted. Extensive
studies that led to the development of a 7-step cyclase phase to transform
(+)-3-carene into a suitable tigliane-type core are also presented.
A variety of competitive pinacol rearrangements and cyclization reactions
were overcome to develop a 7-step oxidase phase producing (+)-ingenol.
The pivotal pinacol rearrangement is further examined through DFT
calculations, and implications for the biosynthesis of (+)-ingenol
are discussed.