Synthesis of ingenol using a new method of inside-outside stereocontrol

Ingenol is a naturally occurring substance whose derivatives are potential lead compounds in the search for new anticancer treatments. Esters of ingenol mimic the natural substrate diacylglycerol in their binding to protein kinase C. Despite the structure of ingenol being known for 40 years, only in the present decade have chemists reported methods for preparing (synthesizing) this compound from scratch in the laboratory. The long timeline between the structure determination and first synthesis of ingenol is due to the structural complexity of this molecule. It contains 20 carbons (and hence is classified as a diterpene), many of which also are attached to oxygen atoms (one ketone and four alcohols), joined together in four rings of different sizes. 8 of the carbon atoms are stereogenic - they are attached to four different groups - which in practice means that many closely related structures are possible, and the synthetic chemist must prepare only one. Adding to the challenge is an additional structural feature that has thwarted many synthetic studies over the years. Two of the rings (the so called B- and C-rings) are joined together in an unusual arrangement which places atoms in closer proximity in space than an alternative form which would lead to a less strained structure overall. This arrangement is important for the overall shape of the molecule, such that alternative less strained analogues of ingenol previously synthesized were found to be essentially devoid of biological activity.The aim of this project is to devise a fundamentally new approach to the key structural element of ingenol, the inside-outside trans relationship found at the junction of the B- and C-rings. This methodology will then be applied to increasingly complex model systems, culminating in attempts to synthesize the natural product itself. The work is based on use of structurally rigid templates on which carbon-carbon bond forming reactions will occur in a predictable manner, before key bonds are broken to reveal the inside-outside stereochemistry.