Chemoenzymatic route to β-blockers via 3-hydroxy esters

Enantiomerically pure precursors of β-blockers (propranolol, alprenolol and 1-(isopropylamino)-3-p-methoxy-phenoxy-2-propanol) were synthesized. Key step is the lipase-catalyzed kinetic resolution of rac-3-hydroxy esters either by O-acylation using vinyl acetate or by hydrolysis of the ester group. Both approaches were highly enantioselective (> 95 %ee) with E-values > 150 using lipase from Pseudomonas cepacia. The formal synthesis of (−)-(S)-propranolol was developed in subsequent steps.

Three precursors of β-blockers were synthesized enantiomerically pure through the lipase-catalyzed kinetic resolution of rac-3-hydroxy ester intermediates by acylation or hydrolysis using lipase from Pseudomonas cepacia. The formal synthesis of (−)-(S)-propranolol was developed in following steps.Figure optionsDownload as PowerPoint slide

3-Hydroxy-4-(4-methoxyphenoxy)-butanoic acidC11H14O5E.e.: 99% [GC on chiral column, & 1H-NMR with Eu(hfc)3][α]D20=−9.48(c=0.795, CHCI3)Source of chirality: enzymatic hydrolysisAbsolute configuration: S, mp. 81–82°C

3-Acetoxy-4-(4-methoxyphenoxy)-butanoic acid methylesterC14H18O6E.e.: 97% [GC on chiral column, & 1H-NMR with Eu(hfc)3][α]D20=+25.00(c=1.255, CHCI3)Source of chirality: enzymatic irreversible acylationAbsolute configuration: R, oil

3-Hydroxy-4-(4-methoxyphenoxy)-butanoic acid methylesterC12H16O5E.e.: 97% [GC on chiral column, & 1H-NMR with Eu(hfc)3][α]D20=−3.30(c=0.93, MeOH)Source of chirality: enzymatic irreversible acylationAbsolute configuration: S, mp. 81°C

3-Hydroxy-4-(2-prop-2-enylphenoxy)-butanoic acidC13H16O4E.e.: 98% [GC on chiral column, & 1H-NMR with Eu(hfc)3][α]D20=−8.72(c=1.56, MeOH)Source of chirality: enzymatic hydrolysisAbsolute configuration: S, oil

3-Acetoxy-4-(2-prop-2-enylphenoxy)-butanoic acid methylesterC16H20O5E.e.: 99% [GC on chiral column, & 1H-NMR with Eu(hfc)3][α]D20=+30.58(c=1.615, CHCI3)Source of chirality: enzymatic irreversible acylationAbsolute configuration: R, oil

3-Hydroxy-4-(2-prop-2-enylphenoxy)-butanoic acid methylesterC14H18O4E.e.: 98% [GC on chiral column, & 1H-NMR with Eu(hfc)3][α]D20=−10.63(c=1.355, MeOH)Source of chirality: enzymatic irreversible acylationAbsolute configuration: S, oil

3-Hydroxy-4-(naphthalen-1-yl-oxy)-butanoic acidC14H14O4E.e.: 98% [GC on chiral column, & 1H-NMR with Eu(hfc)3][α]D20=−15.76(c=1.225, CHCI3)Source of chirality: enzymatic hydrolysisAbsolute configuration: S, mp. 69°C

3-Acetoxy-4-(naphthalen-1-yl-oxy)-butanoic acid methylesterC17H18O5E.e.: 99% [GC on chiral column, & 1H-NMR with Eu(hfc)3][α]D20=+27.96(c=1.08, CHCI3)Source of chirality: enzymatic irreversible acylationAbsolute configuration: R, oil

3-Hydroxy-4-(naphthalen-1-yl-oxy)-butanoic acid methyl esterC15H16O4E.e.: 99% [GC on chiral column, & 1H-NMR with Eu(hfc)3][α]D20=−4.91(c=1.16, MeOH)Source of chirality: enzymatic irreversible acylationAbsolute configuration: S, oil