Short and Efficient Chemoenzymatic Syntheses of non-Natural (−)-Muscarine and (+)-allo-Muscarine from Cyano-Sugar Precursors Catalyzed by Immobilized Burkholderia cepacia Lipase

Abstract

Enantiopure (2R)-configured non-natural (−)-muscarine and (+)-allo-muscarine were efficiently synthesized by a chemoenzymatic approach from an easily accessible cyano-sugar available on large-scale. The key enzymatic hydrolysis step was accomplished by immobilized Burkholderia cepacia lipase (also known as Pseudomonas cepacia lipase, PSL-IM). The PSL-IM mediated regioselective hydrolysis of the 5-O-toluoyl ester group in cyano-sugars α− and β−, furnished 3-O-toluoyl-α-cyano-sugar and 3-O-toluoyl-β-cyano-sugar, respectively, with total selectivity and in excellent yields. To demonstrate the industrial utility of this method, 3-O-toluoyl-β-cyano-sugar was synthesized on 10 g scale using PSL-IM and catalyst reused. A key feature of the synthesis route described herein is the simultaneous hydrogenolysis of a tosyl group, reduction of a nitrile and deprotection of a toluoyl group using LiAlH4 in one-pot procedure. This study offers green protocol for synthesis of two muscarine derivatives in high yields employing a concise four-step strategy.