Efficient Method of (S)-Nicotine Synthesis

Improved methods for the synthesis of nicotine are of great importance due to the wide range of applications of synthetic nicotine, which is free from contamination with nitrosamines. Herein, we present a four-step chemical synthesis of (<i>S</i>)-nicotine, involving the reduction in myosmine, enantiomeric separation of nornicotine, and subsequent methylation of the appropriate enantiomer of nornicotine obtained. The reduction in myosmine was investigated using both electrochemical and chemical approaches, achieving up to 90% yields of pure nornicotine. To achieve the enantioseparation of nornicotine, its diastereomeric salts with chiral acids, specifically, <i>N</i>-lauroyl-(<i>R</i>)-alanine, were obtained in a mixture of methyl <i>tert</i>-butyl ether (MTBE) and chloroform, which led to the isolation of (<i>S</i>)-nornicotine with 92% <i>ee</i>. The structures of the obtained salts were determined by the X-ray diffraction (XRD) technique, which helped to explain the origin of enantiodiscrimination during the crystallization. The described methodology allows efficient regeneration of the reagents and solvents used, leading to cost-effective production of (<i>S</i>)-nicotine suitable for industrial-scale applications.