An Approach to the Total Synthesis of Phragmalin-Type Limonoids

It has been argued that certain limonoid natural products constitute some of the most structurally complex and synthetically challenging targets for modern chemical synthesis. Relatively few organic chemists attempt to synthesize the tetranortriterpenoids (limonoids). Indeed, since 2010, only two groups have disclosed results in this field and, of those two reports, only one constituted a completed total synthesis of a targeted limonoid structure. For this reason, it was very exciting to see that one of the outstanding academic synthetic investigators, Richmond Sarpong, who has already provided brilliant solutions to the total synthesis of a selection of lycopodium alkaloids, is now working in the limonoid area. The Sarpong laboratory has recently identified phragmalin-type limonoids (e.g. xyloccensin O, shown above), putatively derived (biosynthetically) from the well-known mexicanolide terpenoids, as targets of interest. In Organic Letters (2012, Articles ASAP), Sarpong and co-workers recently disclosed the successful preparation of the tricyclic core of the phragmalin-type limonoids from a hydrindanone Diels-Alder cycloadduct. The key bond formation was accomplished by means of an irreversible intramolecular alkylative cyclization (see above, conversion of 1 to 2) or, with a more functionalized substrate (3), via a highly efficient Michael addition. To quote from a recent review of limonoid chemistry, "...certain oxidatively modified limonoids signify a frontier for chemical synthesis and present an educational platform to advance the development of organic chemistry." It is encouraging that a small number of today's synthetic chemists are willing to face the daunting scientific challenges that limonoid natural products present. There is little doubt that this type of work will lead to important advancements in organic methodology as well as pharmacology and drug development.