Asymmetric Organocatalysis in Complex Target Synthesis: Progress Towards the Total Synthesis of Diazonamide A

Citation

Knowles, Robert Randolph (2009) Asymmetric Organocatalysis in Complex Target Synthesis: Progress Towards the Total Synthesis of Diazonamide A. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/40HC-7C37. https://resolver.caltech.edu/CaltechETD:etd-10282008-080437

Abstract

Progress towards the total synthesis of the marine natural product diazonamide A is described. The synthesis was conceived around an iminium-catalyzed alkylation/cyclization cascade that stereoselectively installs the central C(10) quaternary carbon stereocenter and the complete furanoindoline core of the natural product in an asymmetric, organocatalytic manner. The manner in which this idea was brought to bear is illustrated, with the remainder of the work focused on devising and executing strategies toward the synthesis of the two twelve-membered macrocycles of the target structure. Considerable efforts were made in this regard, and highlights include execution of a Witkop photo-annulation, development of a novel and highly selective magnesium-mediated macroaldolization reaction to close a thirteen-membered ring, a Suzuki biaryl macrocyclization, an unusual oxidative ring contraction, and the development of a new DAST-mediated method for the synthesis of 4-acyl oxazoles. Five distinct approaches towards the endgame of the synthesis are described. In all cases these approaches came only a single synthetic operation from the assured completion of the natural product, but none proved ultimately viable.

Also described is work focused on replacing a late-stage auxiliary-based aldol reaction in a previously completed MacMillan group synthesis of the macrolide antibiotic erythronolide B, with a substrate-controlled, diastereoselective variant. The overarching synthetic strategy and forward synthesis will be described along with a detailed discussion of the aforementioned, late stage aldol reaction to install the C(1)-C(2) portion of the seco acid.

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