Synthesis of γ-Sanshool and Hydroxy-γ-sanshool

Abstract

Members of the family of polyunsaturated amide compounds known as the sanshools are found in various Zanthoxylum species such as Sichuan (or Szechuan) peppercorns (huajiao). γ-Sanshool and hydroxy-γ-sanshool have been synthesized from simple building blocks using an alkyne to (E,E)-1,3-diene isomerization reaction to stereoselectively install the (E,E)-2,4-diene group of the key synthetic intermediate (2E,4E,8Z,10E,12E)-tetradecapentaenoic acid, which in turn was converted into both γ-sanshool and hydroxy-γ-sanshool by reaction with the appropriate amines.

Key words

alkenes - alkynes - isomerization reactions - natural products - Wittig reactions

• References and Notes

• 1a Crombie L. J. Chem. Soc. 1955; 998
• 1b Crombie L, Tayler JL. J. Chem. Soc. 1957; 2760
• 1c Yasuda I, Takeya K, Itokawa H. Chem. Pharm. Bull. 1981; 29: 1791
• 1d Yasuda I, Takeya K, Itokawa H. Phytochemistry 1982; 21: 1295
• 1e Mizutani 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
• 1f Kashiwada Y, Ito C, Katagiri H, Mase I, Komatsu K, Namba T, Ikeshiro Y. Phytochemistry 1997; 44: 1125
• 1g Xiong Q, Shi D, Yamamoto H, Mizuno M. Phytochemistry 1997; 46: 1123
• 1h Chen I.-S, Chen T.-L, Lin W.-Y, Tsai I.-L, Chen Y.-C. Phytochemistry 1999; 52: 357
• 1i Iseli V, Potterat O, Hagmann L, Egli J, Hamburger M. Pharmazie 2007; 62: 396
• 1j Jang KH, Chang YH, Kim D.-D, Oh K.-B, Oh U, Shin J. Arch. Pharm. Res. 2008; 31: 569
• 1k Yang X. J. Agric. Food Chem. 2008; 56: 1689
• 1l Machmudah S, Izumi T, Sasaki M, Goto M. Sep. Purif. Technol. 2009; 68: 159
• 1m Huang S, Zhao L, Zhou XL, Ying M, Wang CJ, Weng J. Chin. Chem. Lett. 2012; 23: 1247
• 2a Bryant BP, Mezine I. Brain Res. 1999; 842: 452
• 2b Sugai E, Morimitsu Y, Iwasaki Y, Morita A, Watanabe T, Kubota K. Biosci. Biotechnol. Biochem. 2005; 69: 1951
• 3a Koo JY, Jang Y, Cho H, Lee C.-H, Jang KH, Chang YH, Shin J, Oh U. Eur. J. Neurosci. 2007; 26: 1139
• 3b Bautista DM, Sigal YM, Milstein AD, Garrison JL, Zorn JA, Tsuruda PR, Nicoll RA, Julius D. Nat. Neurosci. 2008; 11: 772
• 3c 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
• 3d Lennertz RC, Tsunozaki M, Bautista DM, Stucky CL. J. Neurosci. 2010; 30: 4353
• 3e Tsunozaki M, Lennertz RC, Vilceanu D, Katta S, Stucky CL, Bautista DM. J. Physiol. 2013; 591: 3325
• 3f Bader M, Stark TM, Dawid C, Lösch S, Hofmann T. J. Agric. Food Chem. 2014; 62: 2479
• 4a Baraldi PG, Preti D, Materazzi S, Geppetti P. J. Med. Chem. 2010; 53: 5085
• 4b Mathie A. J. Pharm. Pharmacol. 2010; 62: 1089
• 4c Es-Salah-Lamoureux Z, Steele DF, Fedida D. Trends Pharmacol. Sci. 2010; 31: 587
• 5 Tang X, Zhou X, Wu J, Li J, Bai L. Pestic. Biochem. Physiol. 2014; 110: 44
• 6 Starkenmann C, Cayeux I, Birkbeck AA. Chimia 2011; 65: 407
• 7 Artaria C, Maramaldi G, Bonfigli A, Rigano L, Appendino G. Int. J. Cosmetic Sci. 2011; 33: 328
• 8 According to Bautista et al.,^3b 50 g of dried seeds from Zanthoxylum piperitum afforded 55.2 mg of crude HAS after preparative HPLC. Repetitive chromatographic separation was required to further purify 1 to homogeneity.
• 9a Navarrete A, Hong E. Planta Med. 1996; 62: 250
• 9b Dossou KS. S, Devkota KP, Morton C, Egan JM, Lu G, Beutler JA, Moaddel R. J. Nat. Prod. 2013; 76: 2060
• 10 Park Y.-D, Lee WS, An S, Jeong TS. Biol. Pharm. Bull. 2007; 30: 205
• 11 Wu B, Li K, Toy PH. Synlett 2012; 23: 2564
• 12 For the synthesis of α-sanshool, see: Sonnet PE. J. Org. Chem. 1969; 34: 1147
• 13 For another synthesis of HAS and hydroxy-β-sanshool, see: Igarashi Y, Aoki K, Nishimura H, Morishita I, Usui K. Chem. Pharm. Bull. 2012; 60: 1088
• 14 For the synthesis and evaluation of simplified analogues of HAS, see: Menozzi-Smarrito C, Riera CE, Munari C, le Coutre J, Robert F. J. Agric. Food Chem. 2009; 57: 1982
• 15a Crombie L, Fisher D. Tetrahedron Lett. 1985; 26: 2477
• 15b Crombie L, Fisher D. Tetrahedron Lett. 1985; 26: 2481
• 16 Aoki K, Igarashi Y, Nishimura H, Morishita I, Usui K. Tetrahedron Lett. 2012; 53: 6000
• 17a Trost BM, Kazmaier U. J. Am. Chem. Soc. 1992; 114: 7933
• 17b Guo C, Lu X. J. Chem. Soc., Chem. Commun. 1993; 394
• 17c Rychnovsky SD, Kim J. J. Org. Chem. 1994; 59: 2659
• 17d Strunz GM, Finlay HJ. Can. J. Chem. 1996; 74: 419
• 17e Kwong CK.-W, Fu MY, Lam CS.-L, Toy PH. Synthesis 2008; 2307
• 17f Fu MY, Guo J, Toy PH. Synlett 2011; 989
• 18 For a recent example of the application of this reaciton in complex natural product synthesis, see: Wang Y, O’Doherty GA. J. Am. Chem. Soc. 2013; 135: 9334
• 19 See Supporting Information for details.
• 20 Characterization Data for 1^{1c 1}H NMR (400 MHz, CDCl₃): δ = 0.92 (d, 6 H, J = 6.5 Hz), 1.78 (d, 3 H, J = 6.5 Hz), 1.81 (q, 1 H, J = 6.5 Hz), 2.25 (t, 2 H, J = 6.7 Hz), 2.30 (t, 2 H, J = 6.7 Hz), 3.15 (t, 2 H, J = 6.5 Hz), 5.36 (dt, 1 H, J ₁ = 9.7 Hz, J ₂ = 7.4 Hz), 5.72 (dt, 1 H, J ₁ = 14.0 Hz, J ₂ = 7.0 Hz), 5.81 (d, 1 H, J = 15.2 Hz), 5.85 (s, 1 H), 5.99–6.20 (m, 5 H), 6.29–6.33 (m, 1 H), 7.17 (dd, 1 H, J ₁ = 14.6 Hz, J ₂ = 10.7 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 18.4, 20.2, 27.2, 28.7, 33.0, 47.0, 122.4, 125.4, 128.9, 129.5, 130.0, 130.1, 132.0, 133.4, 141.0, 141.8, 166.5. MS: m/z calcd for C₁₈H₂₇NO: 273.2; found: 273.2.
• 21 Characterization Data for 2^{1e 1}H NMR (400 MHz, CDCl₃): δ = 1.22 (s, 6 H), 1.78 (d, 3 H, J = 6.7 Hz), 2.25 (t, 2 H, J = 6.7 Hz), 2.30 (t, 2 H, J = 6.7 Hz), 3.33 (d, 2 H, J = 5.9 Hz), 5.35 (dt, 1 H, J ₁ = 10.1 Hz, J ₂ = 7.5 Hz), 5.72 (dt, 1 H, J ₁ = 14.0 Hz, J ₂ = 6.8 Hz), 5.84 (d, 1 H, J = 15.0 Hz), 5.99–6.02 (m, 5 H), 6.29–6.36 (m, 1 H), 7.19 (dd, 1 H, J ₁ = 15.0 Hz, J ₂ = 10.4 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 18.4, 27.1, 27.3, 33.0, 50.6, 71.0, 121.9, 125.4, 128.8, 129.6, 130.0, 130.1, 131.9, 133.5, 141.6, 142.4, 167.7. MS: m/z calcd for C₁₈H₂₇NO₂: 289.2; found: 289.2.
• 22a Leung PS.-W, Teng Y, Toy PH. Synlett 2010; 1997
• 22b Leung PS.-W, Teng Y, Toy PH. Org. Lett. 2010; 12: 4996
• 22c Teng Y, Lu J, Toy PH. Chem. Asian J. 2012; 7: 351
• 23 Kwong CK.-W, Fu MY, Law HC.-H, Toy PH. Synlett 2010; 2617