Synthesis of enantiopure β-blocker (S)-metoprolol and derivatives by lipase catalysis

Abstract

The goal of this thesis was to synthesize the enantiomerically pure β-blocker (S)-metoprolol through the use of biocatalysis and elucidate potential factors that may influence the selectivity of enzymes.

The model substrate 1 was synthesized by an acid catalyzed epoxide opening with lithium bromide in 82% yield. A kinetic resolution (transesterification reaction) was performed on racemic 1 with Candida antarctica lipase B (CALB, Novozym 435) and an E-value greater than 200 was achieved giving the enantiomerically pure (R)-\1 in 99% ee and 91% yield. A hydrolysis was performed on the butanoate (S)-2 giving (S)-1 in 99% ee and 92% yield. The E-value decreased by increasing conversion.

The racemic building block 3a was synthesized in 29% yield by reacting 4-(2-methoxyethyl)phenol with epichlorohydrin with subsequent opening of the epoxide with dilithium tetrachlorocuprate. The alcohol 3a was resolved using CALB to produce (R)-3a in 99% ee and 51% yield and (S)-4 in 54% ee and 75% yield. (S)-4 was hydrolyzed to obtain (S)-3a in 99% ee and 86% yield. Enantiomerically pure (S)-metoprolol (S)-5) was synthesized in 99% ee and 76% yield by reacting (R)-3a with isopropylamine in water. It was shown that the ee of the chiral building block retained through the amination reaction.

A kinetic resolution of 6, a building block for β-blocker atenolol, was performed to yield (R)-6 in 99% ee and 32% yield.

A building block for the β-blocker bisoprolol was attempted synthesized, but the desired product was not obtained. All compounds were characterized by NMR, MS and IR.