We intend to continue our development of new synthetic reagents and procedures needed for the total synthesis of quassinoids such as brusatol and similikalactone D. These qquassinoids display a variety of interesting biological activities including antiviral, antiparasitic, insecticidal, antifeedant, anti-amoebicidal and anti-inflammatory activity, and through collaborative arrangements, various synthetic intermediates will be evaluated. The synthetic focus of this proposal involves the preparation of a chiral AB ring precursor which we will elaborate to a tetracyclic picrasane intermediate according to a route that we have already successfully devised. The further elaboration of this picrasane intermediate to various quassinoids will involve several different stages requiring the following operations: (1) introduction of either a C-13 carbomethoxy or methyl group; (2) oxidation of the C ring functionality to facilitate a cyclization leading to the tetrahydrofuran E ring; and (3) manipulation of A, C, and D ring functionality to complete the projected synthesis. In addition, we will develop a variety of selective reactions necessary to manipulate functional groups in polyfunctional substrates. We anticipate, as in the past, that our discoveries will find application in the synthesis of natural products other than just quassinoids, and we intend to demonstrate the suitability of our new reagents and procedures where appropriate.
