Formation of contiguous stereogenic quaternary carbon centers in natural products synthesis: The enantioselective total synthesis of (-)-idiospermuline and approaches toward the total synthesis of communesins A and B

Chapter 1 of this thesis reviews a variety of methods for the formation of stereogenic vicinal quaternary centers in the context of natural products synthesis. The review is limited to syntheses in which the contiguous quaternary centers are formed stereoselectively in a single transformation.; Chapter 2 describes the enantioselective total synthesis of the trispyrrolidinoindoline (-)-idiospermuline, which was accomplished in 22 steps (longest linear sequence) and 6% overall yield. This synthesis also established the absolute configuration of (-)-calycanthidine, a natural product that is an intermediate in the (-)-idiospermuline synthesis. The vicinal quaternary carbon centers of (-)-idiospermuline and (-)-calycanthidine were constructed in a single step by dialkylation of an unsymmetrical prostereogenic dienolate with a chiral tartrate-derived biselectrophile. The second key transformation was a diastereoselective Heck cyclization to form the third quaternary carbon center contained within the (-)-idiospermuline framework. Chiral catalyst control using (S)-Tol-BINAP was achieved for this Heck cyclization, which formed the diaryl-substituted quaternary center in 97% yield and 6:1 diastereoselectivity. Use of (R)-Tol BINAP gave the corresponding epimer in 99% yield and 1:18 selectivity. The development of catalyst control in this cyclization allowed both (-)-idiospermuline and its unnatural diastereomer 3a ″,8a″-bisepiidiospermuline to be selectively targeted from the same synthetic intermediate.; Chapter 3 of this dissertation describes four separate approaches toward the total synthesis of communesins A and B. The key step planned in three of the attempted strategies was dialkylation of a prostereogenic dienolate with a chiral tartrate-derived electrophile to install the contiguous quaternary centers. The first dialkylation approach utilized an unsymmetrical 4-iododihydroisoindigo. The steric constraints introduced by the additional substitution of the dihydroisoindigo prevented successful dialkylation. The second approach employed a quinolone substrate, which proved to be unstable to strongly basic conditions. The third dialkylation strategy employed a dihydroquinolone substrate that provided only monoalkylation products. The fourth approach toward the communesin alkaloids was a reductive intramolecular Heck cyclization of a 2-aminoquinoline-tethered arene to form one of the quaternary centers. In this case, premature reduction of the arene electrophile was observed to be more facile than the desired Heck cyclization.