No abstract

Discrepancies between chiroptical data from the literature and our determination of the structure of the title compounds (+)-5 and (+)-9a were resolved by an unambiguous assignment of their absolute configuration. Accordingly, the dextrorotatory cis-3-hydroxy esters have (3R,4R)-and the laevorotatory enantiomers 1. Introduction. -In the course of our studies on the irreversible inhibition of acetylcholinesterase and related serine hydrolases by organophosphates -in particular the investigation of the stereochemical course of the inhibition reaction [1] and the physiologically active conformation of acetylcholine [2] -we have prepared several 3-substituted, cis-and trans-2,4-dioxa-9-aza-(type I), 2,4-dioxa-8-aza-(type II), and 2,4-dioxa-7-aza-3-phosphabicyclo[4.4.0]decane 3-oxides (type III) [3] (Scheme 1). These heterocycles are configuratively fixed and structurally constrained acetylcholine (7-aza and 9-aza isomers) or g-homo-acetylcholine mimetics (8-aza isomers). Actually, we are completing the syntheses of all these organophosphates in the enantiomerically pure form (ee > 99%) and establishing their absolute configurations. Key compounds are the corresponding enantiomerically pure cis-and trans-diols 1 -3 that are accessible from suitable starting materials such as appropriately substituted pyridinone or pyridine precursors.

Dedicated to Professor Heinz Heimgartner on the occasion of his 70th birthdayThe title compounds, the P(3)-axially and P(3)-equatorially substituted cis-and trans-configured 9-benzyl-3-fluoro-2,4-dioxa-9-aza-3-phosphadecalin 3-oxides (¼ 9-benzyl-3-fluoro-2,4-dioxa-9-aza-3-phosphabicyclo[4.4.0]decane 3-oxides ¼ 7-benzyl-2-fluorohexahydro-4H-1,3,2-dioxaphosphorino[4,5-c]pyridine 2-oxides) were prepared (ee > 99%) and fully characterized (Schemes 2 and 4). The absolute configurations were deduced from that of their precursors, the enantiomerically pure ethyl 1-benzyl-3-hydroxypiperidine-4-carboxylates and 1-benzyl-3-hydroxypiperidine-4-methanols which were unambiguously assigned. Being configuratively fixed and conformationally constrained phosphorus analogues of acetylcholine, the title compounds represent acetylcholine mimetics and are suitable probes for the investigation of molecular interactions with acetylcholinesterase. As determined by kinetic methods, all of the compounds are moderate irreversible inhibitors of the enzyme.