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Conformational rigidity has been conferred upon the OCCN portion of acetylcholine by incorporation of the C atoms into a cyclopropane ring. trans-2-Acetoxycyclopropyltrimethylammonium iodide has been prepared from an olefinic starting material, 2-vinyloxytetrahydropyran; assignment of the trans configuration to the 1,2-disubstituted cyclopropane systems was based upon literature precedent and upon nmr data, and was confirmed by X-ray crystallographic analysis. Resolution of one of the racemic intermediates in the reaction sequence was achieved, which permitted preparation of both enantiomers of the final product. X-Ray crystallographic analysis has demonstrated that the muscarinically active (+)-trans-2-acetoxycyclopropyltrimethylammonium iodide possesses the same absolute configuration as the muscarinically active enantiomers of Acetyl-β-methylcholine and muscarine.


Reprinted with permission from Armstrong, P. D., & Cannon, J. G. (1970). Small ring analogs of aceylcholine. Synthesis and absolute configurations of cyclopropane derivatives. Journal of Medicinal Chemistry, 13(6): 1037-1039. Copyright 1970 American Chemical Society.

Excerpt from 2008 text indicating the significance of this research:

“The most significant study in this regard is that of Armstrong, et al … They synthesized and evaluated the muscarinic and nicotinic activity of cis- and trans-isomers of a conformationally rigid model of acetylcholine, cis- and trans-2-acetoxycycloproplytrimethylammonium iodide.…” (Foye, W. O., Lemke, T. L., & Williams, D. A. (2008). Foye’s principles of medicinal chemistry (6th ed.). Philadelphia : Lippincott Williams & Wilkins, 370-371.)