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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., Competing Interests: The authors declare the following competing financial interest(s): At the time of the work, all authors were employees of Novartis AG, which has filed patents on selective M4 agonists for the treatment of psychosis., (© 2023 American Chemical Society.)

Proteasome inhibition is a therapeutic concept of current interest in anticancer research. We report here the design, synthesis, and biological characterization of prototypes of a new class of noncovalent proteasome inhibitors showing high activity in biochemical and cellular assays.