Chemoenzymatic synthesis of the potential antihypertensive agent (2R,2′S)-β-hydroxyhomometoprolol

The kinetic resolution of 1-chloro-3-[4-(2-methoxyethyl)phenoxy]-2-propanol rac-4 with Novozym 435 and vinyl stearate, a key step in the gram-scale synthesis of (2S)-2-[[(2R)-2-hydroxy-3-[4-(2-methoxyethyl)phenoxy]propyl]amino]-1-butanol (R,S)-1 a potent antihypertensive agent currently under investigation, is reported here. Our approach differs from the previously reported synthesis, which involves a tedious and poorly effective fractional crystallization of (R,S)-1. This novel approach incorporates an enzymatic resolution for the efficient preparation of the oxirane precursor (R)-3. The two main advantages arising from this strategy are the high enantioselectivity of the enzymatic process and the facilitated recovery of the hydrophobic stearate intermediate (S)-5.

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(2S)-1-Chloro-3-[4-(2-methoxyethyl)phenoxy]-2-propanol-2-stearateC30H51ClO4[α]D20=+13.6 (c 1, CHCl3)Source of asymmetry: enzymatic resolutionAbsolute configuration: (2S)