Gamma-functionalization and Its Application Towards Total Synthesis

Synthetic efforts geared towards natural product synthesis highlight a clear deficiency in the synthetic technology directed at gamma-functionalization. The gamma-alkyl motif exists in numerous natural products and pharmaceutical targets. In order to address these limitations, new synthetic transformations are developed and applied towards the total synthesis of natural products. To address the challenge of accessing gamma-alkyl groups, a nickel-catalyzed gamma-alkylation reaction between α-halocarbonyls and silyl dienol ethers is discovered. Endocyclic silyl dienol ethers were previously inaccessible, so a new palladium catalyzed coupling of beta-tosyl silyl dienol ethers was developed. To demonstrate the value of gamma-functionalization, the gamma-alkylation was applied to the total synthesis of (±) mesembrine and crotontomentosin A. Gamma-amination also remains a significant synthetic challenge and a motif that exists in numerous pharmacetucial targets. The copper-catalyzed aerobic oxidation of hydroxylamines afforded the nitroso, which reacts with the silyl dienol ethers to generate acyclic or cyclic alpha,beta unsaturated gamma-hydroxylamines.