Kilogram-Scale Preparation of the Amino Alcohol Fragment of Selgantolimod by Enzymatic Resolution of an α,α-Disubstituted Amino Ester

The chiral amino alcohol (R)-2-amino-2-methylhexan-1-ol (1) is a key fragment in the synthesis of selgantolimod, a TLR8 agonist that is being evaluated for the treatment of hepatitis B infection. This report describes the development of a robust and scalable synthesis of the targeted amino alcohol featuring a hydrolase-catalyzed kinetic resolution of an α,α-disubstituted amino ester. The results highlight considerations for substrate design for the enzymatic resolution, the impact of pH on the resolution of an unprotected α,α-disubstituted amino ester derivative, and implementation of this substrate within a route to the desired amino alcohol fragment.