Retrosynthetic analysis of Lenacapavir reveals four distinct building blocks 2, 3, 4 and highly functionalized central core 5a (Scheme 1). Efforts towards the synthesis of these building blocks chemically have already been reported. In view of the growing interest in the use of biocatalysis for sustainable manufacture of APIs, particularly those containing chiral amine building blocks, we envisaged preparing fragment 5a from the corresponding ketone 5 using an aminotransferase catalyzed reaction. Aminotransferases have emerged as a broadly useful class of biocatalyst for the preparation of both (S)-and (R)-configured amines but typically require extensive engineering to display good activity with sterically hindered ketones such as 5. Indeed, a survey of the literature to date revealed ketone 5 to be amongst the most sterically demanding and bulky candidate substrates for a transaminase catalyzed process. To identify an ATA with activity towards ketone 5, an in-house panel of >400 aminotransferases were initially evaluated using Lalanine as the amine donor coupled with an established pyruvate removal system. Unfortunately, from these assays we were unable to identify enzymes with detectable activity toward this sterically encumbered substrate. However, encouragingly several aminotransferases were identified with activity towards structurally related ketones (6 and 7) lacking one or both of the two bromine substituents on the pyridyl ring of the ketone substrate (Figure ). Interestingly no activity was observed with substrate 8 which contains a single 5-Br substituent ortho to the reacting ketone, highlighting this as a particularly challenging motif for aminotransferases.