The synthesis of Aplysiapyranoid A and related novel epoxide rearrangements

Chapter 1. The synthesis of the cytotoxic marine natural product Aplysiapyranoid A via an intramolecular bromoetherification is described. The key reaction, namely cyclization of a {dollar}gamma{dollar}-hydroxyl group onto a bromonium ion, proceeds in a stereoselective manner. Molecular mechanics calculations (MM2) predict the main factor governing the cyclization are the opposing 1.3-diaxial interactions in the transition state which could be approximated by the energies of the product tetrahydropyrans. Diastereoselectivity was achieved by lowering the energy of one of these two 1,3-diaxial interactions. In doing so, Aplysiapyranoid A was synthesized in five steps where the final cyclization gave the product with 1.3:1 selectivity.; Chapter 2. A total of three new reactions of epoxides were discovered and characterized. Specifically, treatment of 2-vinyl-2-methyl-3-alkyloxiranes with BF{dollar}sb3{dollar}-Et{dollar}sb2{dollar}O led to 1,2-alkyl migration producing {dollar}alpha{dollar}-methyl-{dollar}alpha{dollar}-vinylaldehydes of high enantiomeric purity. The rearrangement proceeds with less that 2% loss of optical purity, and is complete in under 2 minutes at {dollar}-{dollar}78{dollar}spcirc{dollar}C. This has direct application to quaternary carbon assemblage, and was pivotal in the synthesis of {dollar}alpha{dollar}-methyl phenylalanine in optically active form.; A second stereoselective rearrangement is described and gives non-racemic 3-trialkylsilyloxy-2-methylalkanals from 2-methyl-2,3-epoxy-1-ols. The mechanism involves 1,2-hydride migration with concomitant opening of the oxirane by trialkylsiyl trifluoromethanesulfonates giving all possible stereoisomers of aldol products. Extension of this methodology to include polypropionates has led to the development of a iterative approach to complex molecules. Namely, the product of rearrangement (the aldol) undergoes Wittig extension, reduction to afford an allylic alcohol, and epoxidation to give the requisite epoxy alcohol starting material to begin the process again. Initial studies show that sixteen of the possible 32 diastereomeric epoxy alcohols are accessible by this route without additional chiral reagents.; These homologated epoxy alcohols, with one noted exception, are not prone to hydride migration. Rather these substrates are precursors to highly functionalized tetrahydrofurans by a third novel epoxide rearrangement. The mechanism involves activation of the tertiary epoxide carbon with Lewis acid followed by cyclization of a {dollar}gamma{dollar}-triethylsilyl ether in a 5-endo-epoxy fashion. Three of the four diastereomeric homologated epoxy alcohols were successfully cyclized to give tetrahydrofurans where all of the ring carbons are asymmetric centers. The fourth diastereomeric substrate did not yield tetrahydrofuran, but rather afforded a tetrahydropyran. The formation of this product could only be explained by hydride migration of the epoxy alcohol to afford the first example of a homologated aldol.