The title compounds, the P(3)-axially and P(3)-equatorially substituted cis-and trans-configured 8benzyl-3-fluoro-2,4-dioxa-8-aza-3-phosphadecalin 3-oxides (¼ 8-benzyl-3-fluoro-2,4-dioxa-8-aza-3-phosphabicyclo[4.4.0] [5,4-c]pyridine 2-oxides) were prepared (ee > 98%) and fully characterized (Schemes 2 and 3). The absolute configurations were established from that of their precursors, the enantiomerically pure cis-and trans-1-benzyl-4-hydroxypiperidine-3-methanols which were unambiguously assigned. Being configuratively fixed and conformationally constrained phosphorus analogues of acetyl g-homocholine (¼ 3-(acetyloxy)-N,N,N-trimethylpropan-1-aminium), they are suitable probes for the investigation of molecular interactions with acetylcholinesterase. As determined by kinetic methods, all of the compounds are weak inhibitors of the enzyme.
racemic compounds [3], the optically active (þ)-and (À)-trans-, and (þ)-and (À)-cis-1-benzyl-3-(hydroxymethyl)piperidin-4-ols ((þ)-and (À)-2, and (þ)-and (À)-3, resp.) were obtained after reduction of ethyl 1-benzyl-4-oxopiperidine-3-carboxylate (1) with NaBH 4 and LiAlH 4 (Scheme 2). The resulting mixture (ca. 2 : 1) of the diols (AE)-2/(AE)-3 was transformed in situ into the acetonides (AE)-4/(AE)-5 that could easily be separated by column chromatography (SiO 2 ) into the pure trans-and cis-diastereoisomers (AE)-4 and (AE)-5, respectively [3] [8]. Preparative HPLC (Chiralcel OD) of (AE)-4 afforded (þ)-4 ([a] D ¼ þ 29.2, ee > 99%), and (À)-4 ([a] D ¼ À 28.7, ee > 98%) 2 ), and the Helvetica Chimica Acta -Vol. 95 ( ) 18 Scheme 1 a )
2 ) Although the method had been optimized (R S > 4) [2], enantiomerically pure (À)-4 ([a] D ¼ À 29.3, ee > 99%) could be obtained only in relatively small amounts, whereas bigger fractions of (À)-4 did never exceed ee > 98%. As a consequence, the precursor (þ)-2 and the corresponding phosphadecalins (À)-10a and (À)-10b had only ee > 98% [2]. The [a] D values were determined in acetone (c ¼ 1).