We propose the total synthesis of a conformationally constrained organophosphorus analog of acetylcholine (5, Scheme 5). This compound will contain two crural centers, one being the phosphorus atom and the other being the pyrrolidine ring carbon beta to the phosphorus atom. The chiral beta carbon is conformationally constrained because it is part of the pyrrolidine ring. Studies with such a compound should allow us to make substantial progress towards the clarification of the stereospecificity of AChE inhibition by OP compounds and eventually help us understand more about the structure of the AChE active site. The synthesis begins with Cbz-L-proline methyl ester (1) which is commercially available. Reduction of the methyl ester with sodium borohydride in the presence of CaCl2 will yield Cbz-L-prolinol (2). Phosphorylation of the primary alcohol will yield a pair of diastereomers (3,.). After separation by flash chromatography, each diastereomer will be subjected to hydrogenolysis, to cleave the Cbz-protecting group, followed by methylation of the amine with methyl iodide. By repetition of this process with Cbz-D-proline methyl ester, we should be able to access all four stereoisomers.
Mergott '98, Justin, "The Total Synthesis of a Conformationally Constrained Organophosphorus Analog of Acetycholine" (1998). Honors Projects. Paper 10.