Phorbol esters are an important class of naturally occurring potent protein kinase C (PKC) agonists and as a
consequence are potent tumor promoters. However, prostratin (12-deoxy, 13-acetylphorbol) a naturally occurring
phorbol analogue, has been shown to upregulate latent HIV-1 provirus expression and inhibit viral infection. It is
our objective to develop an asymmetric synthesis of phorbol utilizing biomimetically inspired transannular
transformations. The exploitation of intramolecular and transannular bond constructions will provide important, if
not fundamental, advances in synthetic design. This design principle is illustrated in the synthesis of phorbol.
Moreover, this convergent synthesis concept will allow for the preparation of phorbol derivates and hence a
detailed study of the biological activity with regard to the possibility of further medicinal applications.
In detail we envision that the complex, polyciclic framework of phorbol will be constructed from a macrocycle via
two transannular reactions inspired by the proposed biosynthetic pathway. David. A. Evans and coworkers have
demonstrated previously that the conformation of a macrocycle can effectively relay stereochemical information to
newly forming stereocentres. The macrocycle will be formed by a Horner-Wadsworth-Emmons macrocyclization
from a linear precursor which in turn will be constructed from two equal-sized fragments.