Lipase‐Catalyzed Kinetic Resolution of 2‐Phenylethanol Derivatives and Chiral Oxa‐Pictet–Spengler Reaction as the Key Steps in the Synthesis of Enantiomerically Pure Tricyclic Amines

Abstract A series of 5,6,7,8,9,10‐hexahydro‐5,9‐epoxybenzocycloocten‐6‐amines have been synthesized and pharmacologically evaluated in receptor binding studies (σ 1 , σ 2 , NMDA, κ, and μ receptors). The first key step of the synthesis was a chiral oxa‐Pictet–Spengler reaction with enantiomerically pure 2‐phenylethanol derivatives ( S )‐ and ( R )‐ 14 . After transformation of the dimethylamide 18 into the ester 19 , the tricyclic system 20 was established by Dieckmann cyclization reaction. Finally, amino moieties were introduced diastereoselectively into the 6‐position by reductive amination and S N 2 reaction. The enantiomerically pure building blocks ( S )‐ 14 (>99.0 % ee ) and ( R )‐ 14 (98.4 % ee ) were synthesized by enantioselective acetylation of racemic alcohol 14 catalyzed by Pseudomonas fluorescens lipase and enantioselective hydrolysis of racemic acetate 16 catalyzed by Candida rugosa lipase. The absolute configurations were determined by theoretical calculations of the specific optical rotation and CD spectra, as well as by X‐ray crystal structure analysis of ( S , S , S )‐ 25 by the three‐beam interference method. Although enantiomerically pure dimethylamines ( S , R , S )‐ and ( R , S , R )‐ 29 with an axial amino moiety showed low‐to‐moderate affinity towards σ 1 and σ 2 receptors, a promising σ 2 affinity ( K i = 2.9 μ M ) was found for ( S , S , S )‐ 24 with an equatorially oriented dimethylamino group.