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Synthesis and Characterization of Enantiomerically Pure cis ‐ and trans ‐3‐Fluoro‐2,4‐dioxa‐7‐aza‐3‐phosphadecalin 3‐Oxides as Acetylcholine Mimetics and Inhibitors of Acetylcholinesterase
Author(s) -
Wächter Michael,
Rüedi Peter
Publication year - 2012
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.201100507
Subject(s) - chemistry , conformational isomerism , acetylcholinesterase , decane , stereochemistry , acetylcholine , stereoselectivity , pyridine , enzyme , molecule , catalysis , medicinal chemistry , organic chemistry , medicine , endocrinology
The title compounds, the P(3)‐ axially and P(3)‐ equatorially substituted cis ‐ and trans ‐configured 7‐benzyl‐3‐fluoro‐2,4‐dioxa‐7‐aza‐3‐phosphadecalin 3‐oxides (=7‐benzyl‐3‐fluoro‐2,4‐dioxa‐7‐aza‐3‐phosphabicyclo[4.4.0]decane 3‐oxides=5‐benzyl‐2‐fluorohexahydro‐4 H ‐1,3,2‐dioxaphosphorino[5,4‐ b ]pyridine 2‐oxides) were prepared (ee>99%) and fully characterized ( Schemes 2 and 4 ). The absolute configurations were established from that of their precursors, the enantiomerically pure cis‐ and trans ‐1‐benzyl‐3‐hydroxypiperidine‐2‐methanols which were unambiguously assigned. Being configuratively fixed and conformationally constrained phosphorus analogues of acetylcholine, they mimic rotamers of acetylcholine and are suitable probes for the investigation of molecular interactions with acetylcholinesterase. As determined by kinetic methods, the compounds are irreversible inhibitors of the enzyme displaying significant stereoselectivity.