A series of carbamoylpyridone analogs have served as the basis for the discovery of dolutegravir, an HIV integrase inhibitor in late stage clinical development.  During the course of lead optimization studies, the need to control a variety of aminal or hemiaminal stereocenters became a primary issue for the medicinal chemistry team.  A strategy was devised to use a set of amino alcohols and diamines available from the chiral pool in a diastereoselective substrate control approach.  This minor increase in complexity of the series was enormously powerful as a method to control the relative and absolute stereochemistry.  This presentation will elaborate on the strategy and findings along with structure-activity relationship data for the work supporting the discovery of dolutegravir.

Substrate-controlled approach to the synthesis of HIV-1 integrase inhibitors

244th National Meeting (2012)

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