Synthesis of novel pipecolic acid derivatives. Part 2. Addition of trimethylsilyl cyanide to 3,4,5,6-tetrahydropyridines

Abstract

The synthesis of alkyl- and aryl-substituted derivatives of pipecolic acid (piperidine-2-carboxylic acid) by a modified Strecker protocol is described. Addition of trimethylsilyl cyanide (TMSCN) to various tetrahydropyridines 1 and subsequent hydrolysis of the obtained α-amino nitriles 2 yielded pipecolic acid derivatives 3. Addition of TMSCN to cyclic imines 1 proceeded rapidly and led to α-amino nitriles in excellent yields without any necessary further purification. Almost quantitative diastereoselectivity for the formation of 2,6-trans-substituted amino nitrile 2g was observed at low temperature, when chiral imine 1g was used as reactant. Acidic hydrolysis of α-amino nitriles 2 yielded the corresponding amino acids 3 in good to excellent yields. Furthermore, an efficient protocol for the optical resolution of N-formylated derivatives of pipecolic acid by separation of diastereomeric norephedrinium salts is described.