Biocatalytic reductive amination catalyzed by engineered imine reductase (RedAms) is a new and powerful tool for the synthesis of substituted chiral amines. Herein, we describe a streamlined synthesis of compound 3, a key intermediate to a CDK 2/4/6 inhibitor 1, relying on the enzymatic reductive amination of a hydroxyketone to introduce the chiral secondary amine with high diastereoselectivity. The improved synthesis of the hydroxyketone precursor by a titanium-catalyzed reductive cyclization and the process development for two SNAr reactions en route to 3 are also presented.

While conversion of dialkyl tartrate esters to the corresponding glyoxalic acid esters has been well-documented, large scale application of some common laboratory protocols presents a myriad of challenges. The low cost, high availability, and predictable reactivity of sodium periodate make it an attractive choice for synthetic chemistry applications; the resulting solid byproducts, however, have a high thermal potential and therefore must be handled with care during cleanup and disposal, especially on large scale. Successful demonstration of the synthesis of glyoxaldehydes by oxidative cleavage of tartrate esters with sodium periodate is discussed herein. Furthermore, this account describes the process safety/engineering investigation carried out to ensure a robust and safe process for the scale manufacture of allyl glyoxalate via sodium periodate-mediated cleavage of diallyl tartrate.