Overcoming the Challenges of Making a Single Enantiomer N‑1 Substituted Tetrazole Prodrug Using a Tin-Mediated Alkylation and Enzymatic Resolution

The synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor 3 is described. This complex structure contains a tetrazole modified by a chiral hemiaminal carbonate prodrug. A regioselective tin-mediated alkylation was utilized to access the N-1 alkylated tetrazole isomer, and a highly selective enzymatic hydrolysis efficiently provided the desired prodrug enantiomer. A Suzuki–Miyaura coupling was employed for the final fragment union, which was challenging due to base sensitivity of the prodrug. This route was enabled and used to manufacture multikilogram quantities of API 3 in an efficient manner.