Prof. Dr. Thomas C. Nugent, Professor of Chemistry - Jacobs University Bremen
Title of the talk:
Beyond Chemoselectivity: Catalytic Site-Selective Aldolization of Diketones and Exploitation for Enantioselective Alzheimer Drug Candidate Synthesis
Site-selectivity, differentiating members of the same functional group type on one substrate, represents a forward-looking theme within chemistry: reduced dependence on protection/deprotection protocols for increased overall yield and step-efficiency. Despite these potential benefits and the expanded tactical advantages afforded to synthetic design, site-selectivity remains elusive and especially so for ketone-based substrates. Here we report on the site-selective intermolecular mono-aldolization of an array of prochiral 4-ketosubstituted cyclohexanones with concomitant regio-, diastereo-, and enantiocontrol using enamine directed reactions. Importantly, the aldol products allow rapid access to molecularly complex keto-lactones or keto-1,3-diols respectively containing three and four stereogenic centers. The reaction conditions are of immediate practical value and general enough to be applicable to other reaction types. The relevance of these achievements in relation to the reaction capabilities normally associated with a cellular environment will be briefly discussed. Finally, these findings are encapsulated by the first enantioselective formal synthesis of a leading Alzheimer research drug, a -secretase modulator (GSM), in the highest known yield.