An Improved and Practical Method for Synthesizing of α-Sanshools and Spilanthol

Akira Nakamura,Kazuki Mimaki,Tomohiro Maegawa,Ken-Ichi Tanigami

doi:10.3389/fchem.2020.00187

Abstract

An efficient and practical route for the synthesis of α-sanshools and spilanthol is described herein. Several modifications of an existing method enabled the preparation of the (2E,6Z,8E,10E)-tetraene precursor of hydroxy-α-sanshool in good yield. A highly selective Wittig reaction employing newly synthesized phosphonium salt with low deliquescence and long-term stability yielded the desired Z-form tetraene. This improved methodology was shown to be applicable to the efficient synthesis of α-sanshool and spilanthol.

Highlights

Sanshools are a family of polyunsaturated fatty acid amides, differing in the length and double bond geometry of the polyunsaturated (Figure 1), found in various Zanthoxylum species (Jang et al, 2008; Devkota et al, 2012; Greger, 2016)
The inherent instability of their conjugated (6Z,8E,10E)-triene structures, which are prone to isomerization, oxidation, polymerization, and/or photo-degradation, make sanshools difficult to isolate from natural products (Yang, 2008)
Our synthesis of hydroxy-α-sanshool began with the oxidation of 4-bromobutan-1-ol with PCC, which was poorly reproducible on the gram scale

Summary

Introduction

Sanshools are a family of polyunsaturated fatty acid amides, differing in the length and double bond geometry of the polyunsaturated (Figure 1), found in various Zanthoxylum species (Jang et al, 2008; Devkota et al, 2012; Greger, 2016). The inherent instability of their conjugated (6Z,8E,10E)-triene structures, which are prone to isomerization, oxidation, polymerization, and/or photo-degradation, make sanshools difficult to isolate from natural products (Yang, 2008). Toy and co-workers constructed a (6Z,8E,10E)-conjugated triene precursor moiety with moderate selectivity (6Z:6E = 2:1) using the Wittig reaction; a pure stereoisomer was isolated by recrystallization (Wu et al, 2012). Among the three existing synthesis methods, Toy’s is the simplest due to the use of more conventional reagents and procedures. Our synthesis of 1 via Toy’s method, proved difficult when following the literature, and resulted in reduced yields due to the instability or deliquescence of intermediate species. We set out to enhance the general practicality and robustness of Toy’s method of sanshool synthesis

Objectives

Results

Conclusion