In an attempt to develop novel Selective Estrogen Receptor Modulators (SERMs) containing a chirality centre, simpler 1-((2-hydroxynaphthalen-1-yl)arylmethyl)piperidin-4-ol prototypes were synthesized as racemic mixtures via the Mannich reaction protocol from 2-naphthol, 4-piperidinol, and 10 different aromatic aldehydes. These 10 chiral Mannich bases were then resolved utilizing an enzyme-assisted chemo-, regio-, and enantioselective acetylation process. The enzyme (Novozyme 435 ® ; Lipase B from Candida Antarctica) displayed exclusive chemo- and regioselectivity in acetylating the test compounds; the optical enrichment was also achieved as evidenced by measurement of the optical rotation of the mono-acetylated product and unreacted dihydroxy compound.