3-Fluoro-2,4-dioxa-7-aza-3-phosphadecalin 3-Oxides as Rigid Acetylcholine Mimetics: Conformational Analysis and Direct Evidence of the Anomeric Effect

Abstract

Conformational analyses of the P(3)-axially and P(3)-equatorially F-substituted (� )-cis- and (� )trans-2,4-dioxa-7-aza-3-phosphadecalin 3-oxides (3-fluoro-2,4-dioxa-7-aza-3-phosphabicyclo[4.4.0]decane 3-oxides) were performed. The results are based on independent studies in both solution and the solid state by 1 H- and 31 P-NMR experiments and computational and X-ray crystallographic data. As expected, the axial epimers adopt neat double-chair conformations in solution and in the crystal. Due to the anomeric effect of the electron withdrawing F-substituent, the 2,4-dioxa-3-phospha moiety in the equatorial epimers adopts a mixture of conformations in solution, mainly chair and twist-boat; whereas a neat twist-boat (trans-isomer) and the unusual envelope conformation (cis-isomer) were detected in the solid state. This is the first report of a straight visualization of these conformations and the impact of the anomeric effect in such systems. 1. Introduction. – In a recent paper [1], we have reported on the synthesis and characterization of 3-substituted, cis- and trans-2,4-dioxa-9-aza- (I), 2,4-dioxa-8-aza- (II), and 2,4-dioxa-7-aza-3-phosphabicyclo[4.4.0]decane 3-oxides (III )( Fig. 1). The novel heterocycles are configuratively fixed and conformationally constrained P-analogues of acetylcholine (7-aza- and 9-aza isomers) or g-homo-acetylcholine mimetics (8-aza isomers). Being inhibitors of acetylcholinesterase (AChE) [2], the compounds are considered to be suitable probes for the investigation of molecular interactions with the enzyme, such as the recognition conformation of acetylcholine (ACh) and the stereochemistry of the inhibition reaction.