Efficient Synthesis of Piperidine Derivatives. Development of Metal Triflate-Catalyzed Diastereoselective Nucleophilic Substitution Reactions of 2-Methoxy- and 2-Acyloxypiperidines

Nucleophilic substitution reactions of 2-methoxy- and 2-acyloxypiperidines were investigated. First, new and efficient methods for the preparation of the starting piperidine derivatives were developed. N-Benzyloxycarbonyl-2-methoxypiperidine (3) and 3-substituted-2-acyloxy-N-benzyloxycarbonylpiperidines (4a-d), which are recognized as the simplest imino-sugars, were prepared and were examined as substrates for nucleophilic substitution reactions with silyl enolates under the influence of catalytic amounts of metal triflates (Sc(OTf)3, Sn(OTf)2, Cu(OTf)2, Hf(OTf)4, etc). Among the triflates tested, Sc(OTf)3 gave the best results. It was found that 2-acetoxy-3-benzyloxy-N-benzyloxycarbonylpiperidine (4a) reacted with silyl enolates to afford the 2-alkylated adducts in high cis-selectivity, while 2,3-diacyloxy-N-benzyloxycarbonylpiperidines (4b-d) showed transselectivity. The stereochemical assignments were carefully performed using NMR analysis, X-ray crystallography, and synthetic transformations. Febrifugine (1), a potent antimalarial alkaloid, was successfully synthesized from 2,3-diacetoxy-N-benzyloxycarbonylpiperidine (4b) on the basis of these diastereoselective nucleophilic substitution reactions.