The a-hydroxy amide is present within many natural products and medicinal agents. These motifs are commonly prepared asymmetrically through the corresponding carboxylic acids which can be accessed through enantioselective cyanohydrin or enzymatic methods. However, the following couplings to arrive at the corresponding amide products are susceptible to racemization. Alternatively, the Passerini reaction allows direct access the desired amides. However, enantioselective variants of this reaction are scarce in the literature. We sought a complementary route to these motifs based on our recently reported Umpolung Amide Synthesis (UmAS). In this approach, an asymmetric Henry reaction with bromonitromethane is added to aldehydes employing a readily available catalyst system to afford the desired a-hydroxy bromonitroalkanes with high levels of enantioselection. After MOM protection of these adducts, UmAS affords the desired a-hydroxy amides in good yields and without racemization. The reaction optimization and substrate scope for both the Henry reaction and UmAS will be discussed.

Enantioselective synthesis of α-hydroxy amides via umpolung amide synthesis

243rd National Meeting (2012)

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