Syntheses of enantiopure Si-centrochiral silicon-based muscarinic antagonists using an enantioselective enzymatic esterification as the key step

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The muscarinic antagonists (R)-cyclopentyl(hydroxymethyl)phenyl[2-(piperidin-1-yl)ethyl]silane[(R)-1] and(R)-1-{2-[cyclopentyl(hydroxymethyl)phenylsilyl]ethyl}-1-methylpiperidinium iodide [(R)-2] were synthesized using anenantioselective enzymatic transformation as the key step. Apapain-catalyzed (E.C. 3.4.22.2) esterification ofrac-cyclopentyl(hydroxymethyl)phenyl(vinyl)silane(rac-3) with 5-phenylpentanoic acid afforded(R)-cyclopentyl(phenyl)[(5-phenylpentanoyloxy)methyl]vinylsilane[(R)-4] which upon chemical hydrolysis gave enantiomericallyenriched (R)-3 (68% ee). Repetition of thisesterification/hydrolysis sequence, starting from enantiomericallyenriched (R)-3, finally gave the enantiopure silane (R)-3(≥98% ee) which served as the starting material for thesubsequent chemical synthesis of (R)-1 and (R)-2{(R)-3 →(R)-cyclopentyl(phenyl)[(trimethylsilyloxy)methyl]vinylsilane[(R)-5] → (R)-1 → (R)-2}.