We
first developed a novel and efficient chemoenzymatic process
to prepare (S)-1-(pyridin-4-yl)-1,3-propanediol,
a vital HepDirect prodrug intermediate, from inexpensive and commercially
available isonicotinic acid. Through this process, we provide a creative
way to obtain the key chiral intermediate, β-hydroxyester, with
ketoreductase (KRED) EA. After optimization of the process, we performed
the reaction on a 100 g scale with a substrate concentration of up
to 150 g/L, a yield of 93%, and an ee value of up to 99.9%. Additionally,
we used a simple and effective NaBH4/MgCl2 reduction
system to obtain (S)-1-(pyridin-4-yl)-1,3-propanediol
with >99.9% ee and an 80% yield. This novel chemoenzymatic process
has the potential to be a cost-effective and environmentally friendly
process suitable for industrial use.