Synthesis of Hydroxy-α-sanshool

Abstract

The amide hydroxy-α-sanshool is responsible for the mild numbing sensation experienced when Sichuan (or Szechuan) peppercorns (huajiao) are eaten. It has been synthesized in six steps from simple commercially available starting materials using Wittig reactions as the key transformations for construction of the carbon skeleton. The penultimate synthetic intermediate was 2E,6Z,8E,10E-dodecatetraenoic acid, and its crystalline nature allowed it, and thus hydroxy-α-sanshool, to be purified to a very high level of stereochemical homogeneity.

Key words

natural products - isomers - alkenes - Wittig reaction - aldehydes

• References and Notes

• 1a Yasuda I, Takeya K, Itokawa H. Phytochemistry 1982; 21: 1295 ; and references cited therein
• 1b Mitzutani K, Fukunaga Y, Tanaka O, Takasugi N, Saruwatari Y.-I, Fuwa T, Yamauchi T, Wang J, Jia M.-R, Li F.-Y, Ling Y.-K. Chem. Pharm. Bull. 1988; 36: 2362
• 1c Kashiwada Y, Ito C, Katagiri H, Mase I, Komatsu K, Namba T, Ikeshiro Y. Phytochemistry 1997; 44: 1125
• 1d Xiong Q, Shi D, Yamamoto H, Mizuno M. Phytochemistry 1997; 46: 1123
• 1e Chen I.-H, Chen T.-L, Lin W.-Y, Tsai I.-L, Chen Y.-C. Phytochemistry 1999; 52: 357
• 1f Jang KH, Chang YH, Kim D.-D, Oh K.-B, Oh U, Shin J. Arch. Pharm. Res. 2008; 31: 569
• 2a Sugai E, Morimitsu Y, Iwasaki Y, Morita A, Watanabe T, Kubota K. Biosci. Biotechnol. Biochem. 2005; 69: 1951
• 2b Koo JY, Jang Y, Cho H, Lee C.-H, Jang KH, Chang YH, Shin J, Oh U. Eur. J. Neurosci. 2007; 26: 1139
• 2c Bautista DM, Sigal YM, Milstein AD, Garrison JL, Zorn JA, Tsuruda PR, Nicoll RA, Julius D. Nature Neurosci. 2008; 11: 772
• 2d Riera CE, Menozzi-Smarrito C, Affolter M, Michlig S, Munari C, Robert F, Vogel H, Simon SA, le Coutre J. Br. J. Pharmacol. 2009; 157: 1398
• 3 Menozzi-Smarrito C, Riera CE, Munari C, le Coutre J, Robert F. J. Agric. Food Chem. 2009; 57: 1982
• 4 According to Bautista et al.,^2c 50 g of dried seeds from Zanthoxylum piperitum afforded 55.2 mg of crude 1 after preparative HPLC. Repetitive chromatographic separation was required to further purify 1 to homogeneity
• 5a Baraldi PG, Preti D, Materazzi S, Geppetti P. J. Med. Chem. 2010; 53: 5085
• 5b Mathie A. J. Pharm. Pharmacol. 2010; 62: 1089
• 5c Es-Salah-Lamoureux Z, Steele DF, Fedida D. Trends Pharmacol. Sci. 2010; 31: 587
• 6a Sawyer CM, Carstens MI, Simons CT, Slack J, McCluskey TS, Furrer S, Carstens E. J. Neurophysiol. 2009; 101: 1742
• 6b Lennertz RC, Tsunozaki M, Bautista DM, Stucky CL. J. Neurosci. 2010; 30: 4353
• 6c Albin KC, Simons CT. PLoS One 2010; 5: e9520
• 6d Klein AH, Sawyer CM, Zanotto KL, Ivanov MA, Cheung S, Carstens MI, Furrer S, Simons CT, Slack JP, Carstens E. J. Neurophysiol. 2011; 105: 1701
• 7 Artaria C, Maramaldi G, Bonfigli A, Rigano L, Appendino G. Int. J. Cosmetic Sci. 2011; 33: 328
• 8 Starkenmann C, Cayeux I, Birkbeck AA. Chimia 2011; 65: 407
• 9 For what is, to our knowledge, the only previously reported synthesis of 2 (and α-sanshool) by a different route, see: Sonnet PE. J. Org. Chem. 1969; 34: 1147
• 10 See the Supporting Information for details.
• 11 This stereoselectivity is typical of such Wittig reactions involving unstabilized ylides, and we are currently exploring the purification of the E-isomer so that it can be used in the synthesis of β-sanshool derivatives.
• 12 Characterization data for synthetic 1: ¹H NMR (400 MHz, CDCl₃): δ = 1.21 (s, 6 H), 1.75–1.77 (d, J = 7.2 Hz, 3 H), 2.23–2.35 (m, 4 H), 3.13 (s, 1 H), 3.29–3.31 (d, J = 6.0 Hz, 2 H), 5.31–5.37 (dt, J = 10.4, 7.4 Hz, 1 H), 5.67–5.75 (dq, J = 14.0, 7.2 Hz, 1 H), 5.83–5.87 (d, J = 15.2 Hz, 1 H), 5.97–6.03 (dd, J = 10.8, 10.8 Hz, 1 H), 6.19–6.06 (m, 2 H), 6.27–6.33 (m, 2 H), 6.80–6.87 (dt, J = 13.2, 6.4 Hz, 1 H); ¹³C NMR (100 MHz, CDCl₃): δ = 18.4, 26.5, 27.2, 32.1, 50.6, 70.8, 124.0, 125.2, 129.4, 129.7, 130.2, 131.8, 133.6, 144.1, 167.2. This matches the data previously reported for material isolated from natural sources.^1a
• 13a Leung PS.-W, Teng Y, Toy PH. Synlett 2010; 1997
• 13b Leung PS.-W, Teng Y, Toy PH. Org. Lett. 2010; 12: 4996
• 13c Teng Y, Lu J, Toy PH. Chem. Asian J. 2012; 7: 351