Development and mechanistic investigations of a catalytic asymmetric conjugate addition of aromatic thiols to unsaturated imides, and, Progress toward the total synthesis of bipinnatin I

1. Aluminum salen complex 1a catalyzes the asymmetric addition of thiophenols to alpha,beta-unsaturated imide 2 with high yields and enantioselectivities. A study of the effect of water on this reaction led to the discovery, isolation, and characterization of bimetallic complex 1c, a more selective catalyst than 1a. Complex 1c catalyzes the asymmetric addition of thiophenol to alpha,beta-unsaturated imides 9 bearing aliphatic or aryl beta-substituents in high yields and enantioselectivies. Detailed mechanistic studies support a dual-activation mechanism involving activation of both imide and thiol. The mechanistic insights led to a study of the asymmetric 1,6 conjugate addition of thiols to alpha,beta,gamma,delta-unsaturated imides 14.*; 2. Bipinnatin I (19), a highly oxygenated member of the furanocembrane family of diterpenes, inhibits leukemia cell growth at nanomolar concentrations. Our analysis of bipinnatin I (19 ) divided the target into three fragments, the C7-C12 gamma-butenolide, the C13-C2 masked dihydropyran, and the C3-C6 furan. The modular nature of three fragments allowed the facile preparation of macrocyclization precursors 30 and 103. The C7-C12 butenolide 32 was accessed from epoxide 35 utilizing the ynamine opening of terminal epoxides. Epoxide 35 was derived from (S)-epichlorohydrin. The Cr(III)-catalyzed asymmetric inverse electron demand hetero-Diels-Alder cycloaddition was applied to the efficient syntheses of dihydropyrans 33 and 104. The fragment coupling of butenolide 32 with either stannane 33 or 104 was facilitated by the novel application of the S-PHOS ligand to a regioselective Stille coupling. Macrocyclizations of 30 or 103 by the Kishi-Nozaki-Hiyama coupling or the Hiyama cross-coupling, respectively, were unsuccessful. In addition to the exploration of macrocyclization strategies, a possible solution to the construction of the sensitive C7-C8 epoxide was discovered.*; *Please refer to dissertation for diagrams.