Session: Total Synthesis of Complex Molecules:

With prior experience in chlorofunctionalization of olefins, we had surmised that a chloroetherification route to Napyradiomycin A1, a natural product with demonstrated high anti-microbial activity against gram-positive bacteria, would not pose a major challenge. Nonetheless, the enhanced reactivity of the phenolic hydroxyl group proved detrimental in our first attempts, with substantial non-catalyzed reactivity that substantially reduced enantioselectivity. Our efforts to tame this reaction, yielding synthetically useful yields and enantioselectivities will be discussed. Furthermore, strategies towards finalizing the total synthesis of Napyradiomycin A1 will be presented. Key to these efforts is a regioselective Michael addition to an electronically differentiated quinone, with the anticipated stereocontrol resulting from the stereogenic chlorine substituted carbon. SAR studies with this family of natural products are lacking, and thus we hope to alleviate this through our modular synthetic route, enabling alterations to the A ring (resulting from a Diels-Alder reaction), and the geraniol appendage, which is installed via 1,2-migration rearrangement.

α-lapachone, a key intermediate for the divergent synthesis of Napyradiomycins.

α-lapachone, a key intermediate for the divergent synthesis of Napyradiomycins.

Babak Borhan

Appearances