Asymmetric Total Synthesis of (–)-Myrifabral A and B, Havellockate, and New Strategies for Acyclic Stereocontrol

Citation

Fulton, Tyler James (2022) Asymmetric Total Synthesis of (–)-Myrifabral A and B, Havellockate, and New Strategies for Acyclic Stereocontrol. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/qb9s-xj38. https://resolver.caltech.edu/CaltechTHESIS:06062022-012944875

Abstract

Research in the Stoltz group aims, generally, to develop novel technologies for the preparation of stereochemically rich molecules and, further, to apply these technologies in the context of complex natural product total synthesis. Chapter 1 of this thesis describes the strategic utilization of a Pd-catalyzed asymmetric allylic allylation and N-acyl iminium ion cyclization to accomplish short, enantioselective total syntheses of (–)-myrifabral A and (–)-myrifabral B. Chapter 2 describes the development of a Pd-catalyzed asymmetric allylic alkylation to generate acyclic α-quaternary carboxylic acid derivatives from geometrically defined fully substituted N-acyl indole-derived allyl enol carbonates. While ester-derived enol carbonates could be prepared with a high degree of enolate geometry control, they were ineffective in the asymmetric allylic alkylation reaction. Thus, N-acyl indole substrates served as excellent carboxylic ester equivalents. Chapter 3 discusses an unusual Pd-catalyzed decarboxylative α,β-dehydrogenation reaction of N-acyl indole-derived enol carbonates enabled by a novel, highly electron-deficient phosphinooxazoline ligand. Research presented in Chapter 4 delineates a globally diastereoconvergent approach to the Ireland–Claisen rearrangement for the synthesis of α-tetrasubstituted amino acids bearing vicinal tertiary stereogenic centers. Computational investigation of the diastereoconvergence in Ireland–Claisen rearrangement revealed key intramolecular interactions which enable the reaction to proceed in exceptional diastereoselectivity without the need for a selective enolization protocol. Additionally, a diastereodivergent approach for the Ireland–Claisen rearrangement in acyclic systems to generate vicinal quaternary/tertiary and quaternary/quaternary stereogenic centers in good to high diastereoselectivity is discussed. Enolate geometry control and substrate design are critical for achieving high diastereoselectivity in these transformations.

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