Transaminases Provide Key Chiral Building Blocks for the Synthesis of Selective M1/M4 Agonists.

We have developed a chiral route toward the synthesis of muscarinic M4 agonists that was enabled by the biocatalytic synthesis of the key spirocyclic diamine building blocks 10 and 12. Using these bifunctional compounds we were able to optimize a synthetic sequence toward a collection of advanced intermediates for further elaboration. These advanced intermediates were then used as starting points for early medicinal chemistry and the identification of selective M1/M4 agonists.

A concise synthesis of pawhuskin A.

Pawhuskin A is an isoprenylated stilbene that was isolated from Dalea purpurea and reported to have affinity for the opioid receptor in vitro. It has been synthesized through a convergent sequence that joins a prenylated aldehyde with a geranylated phosphonate in a stereoselective Horner-Wadsworth-Emmons condensation to afford the target E olefin isomer. This synthesis confirms the structure assigned to the natural product and establishes a route that may be used to explore its biological activity and to prepare more active analogues.