The utility of Lewis base catalyzed acylation has made it one of the most active areas in the broad family of Lewis base catalyzed transformations. This is in no small part due to the success of chiral Lewis bases in promoting kinetic resolution of alcohols. Remarkably high levels of selectivity can be obtained with a wide variety of structurally diverse Lewis bases. But advances in this area extend beyond the development of novel catalysts into identification of novel transformations, which can enable the more efficient preparation of enantioenriched compounds. During efforts to synthesize nucleoside reverse transcriptase inhibitor 1 for the treatment of HIV, we required access to large amounts of the enantioenriched ester (S)-3. Although a scalable route for the preparation of ester (S)-3 was developed which relied on enzymatic resolution, the loss of ~50% of the material as the undesired enantiomer was not desirable in the long term. Investigations into the acylation of the corresponding lactol precursor 2 with common chiral Lewis bases revealed that a dynamic resolution of 2 was possible, leading to &gt;50% yield of (S)-3 using Levamisole (4) as catalyst. This talk will detail the development of this asymmetric transformation and its application to the synthesis of 1.

Lewis-base catalyzed, dynamic kinetic resolution in the synthesis of a complex nucleoside

251st National Meeting (2016)

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