Concise Synthesis of (–)-Axenol by Using Stereocontrolled Allylic Substitution

Abstract

Synthesis of (–)-axenol was achieved stereoselectively through allylic substitution to form the quaternary carbon followed by ring-closing metathesis. The key allylic picolinate was synthesized from natural menthol.

Key words

drug discovery - allylic substitution - quaternary carbon - copper reagent - ring-closing metathesis

• References and Notes

• 1 Kurvyakov PI, Gatilov YV, Khan VA, Dubovenko ZV, Pentegova VA. Chem. Nat. Prod. 1979; 15: 138
• 2 Barrero AF, Sanchez JF, Oltra JE, Altarejos J, Ferrol N, Barragan A. Phytochemistry 1991; 30: 1551
• 3 Rosa SD, Giulio AD, Iodice C, Zavodink N. Phytochemistry 1994; 37: 1327
• 4 Weyerstahl P, Marschall H, Weirauch M, Thefeld K, Surburg H. Flavour Fragr. J. 1998; 13: 295
• 5 Barrow CJ, Blunt JW, Munro MH. G. Aust. J. Chem. 1988; 41: 1755
• 6 Bozan B, Ozek T, Kurkcuoglu M, Kirimer N, Baser KH. C. Planta Med. 1999; 65: 781
• 7a Angerhofer CK, Pezzuto JM, König GM, Wright AD, Sticher O. J. Nat. Prod. 1992; 55: 1787
• 7b Wright AD, Wang H, Gurrath M, König GM, Kocak G, Neumann G, Loria P, Foley M, Tilley L. J. Med. Chem. 2001; 44: 873
• 8 Hirota H, Tomono Y, Fusetani N. Tetrahedron 1996; 52: 2359
• 9a Caine D, Deutsch H. J. Am. Chem. Soc. 1978; 100: 8030
• 9b Oesterreich K, Spitzner D. Tetrahedron 2002; 58: 4331
• 9c Oesterreich K, Klein I, Spitzner D. Synlett 2002; 1712
• 9d Ohira S, Yoshihara N, Hasegawa T. Chem. Lett. 1998; 739
• 9e Blay G, Collado AM, García B, Pedro JR. Tetrahedron 2005; 61: 10853
• 9f Nakazaki A, Era T, Kobayashi S. Chem. Pharm. Bull. 2007; 55: 1606
• 9g Nakazaki A, Era T, Kobayashi S. Chem. Lett. 2008; 37: 770
• 9h Tamura K, Nakazaki A, Kobayashi S. Synlett 2009; 2449
• 10a Nakazaki A, Kobayashi S. Synlett 2012; 23: 1427
• 10b Fujioka H, Yoshida Y, Kita Y. J. Synth. Org. Chem. Jpn. 2003; 61: 133
• 11 Kaneko Y, Kiyotsuka Y, Acharya HP, Kobayashi Y. Chem. Commun. 2010; 46: 5482
• 12 Kawashima H, Kaneko Y, Sakai M, Kobayashi Y. Chem. Eur. J. 2014; 20: 272
• 13 Kiguchi T, Tsurusaki Y, Yamada S, Aso M, Tanaka M, Sakai K, Suemune H. Chem. Pharm. Bull. 2000; 48: 1536
• 14 Blanchette MA, Choy W, Davis JT, Essenfeld AP, Masamune S, Roush WR, Sakai T. Tetrahedron Lett. 1984; 25: 2183
• 15a Shimoji K, Taguchi H, Oshima K, Yamamoto H, Nozaki H. J. Am. Chem. Soc. 1974; 96: 1620
• 15b Taguchi H, Shimoji K, Yamamoto H, Nozaki H. Bull. Chem. Soc. Jpn. 1974; 47: 2529
• 16 Regioisomer iii was synthesized by the method shown in Scheme 5. Allylic substitution of i with CH₂=(Me)(CH₂)₂MgBr under Goering’s conditions afforded ii, regioselectively, which, upon deprotection, furnished iii in a good yield. See: Underiner TL, Paisley SD, Schmitter J, Lesheski L, Goering HL. J. Org. Chem. 1989; 54: 2369
• 17 The diagnostic absorbance in the ¹H NMR spectra: 7b: ¹H NMR: δ = 3.29 (t, J = 10.5 Hz, 1 H), 4.72 (br s, 1 H), 4.75 (br. s, 1 H), 5.22 (dd, J = 17.7, 1.7 Hz, 1 H), 5.37 (dd, J = 11.4, 1.7 Hz, 1 H), 6.12 (dd, J = 11.4, 17.7 Hz, 1 H); 18: ¹H NMR δ = 4.57 (br. s, 1 H), 4.68 (br s, 1 H), 4.71 (br s, 1 H), 5.29 (t, J = 7.5 Hz, 1 H).
• 18 Scholl M, Ding S, Lee CW, Grubbs RH. Org. Lett. 1999; 1: 953
• 19 Garber SB, Kingsbury JS, Gray BL, Hoveyda AH. J. Am. Chem. Soc. 2000; 122: 8168
• 20 A similar reactivity of the catalysts was reported: see refs. 9b and 9c.
• 21 The ¹H NMR data of 4 presented in ref. 9e was insufficient.
• 22 Karimi B, Golshani B. J. Org. Chem. 2000; 65: 7228
• 23 To an ice-cold suspension of CuBr·SMe₂ (67.3 mg, 0.327 mmol) and ZnI₂ (104 mg, 0.325 mmol) in THF (0.5 mL) was added a solution of (3-methylbut-3-en-1-yl)magnesium bromide (0.57 M in THF, 1.15 mL, 0.656 mmol) dropwise. The solution was stirred at 0 °C for 30 min, cooled to −40 °C, and a solution of TMS ether 6b (80.5 mg, 0.214 mmol) in THF (2 mL) was added. The resulting solution was warmed to −20 °C over 2 h, and diluted with sat. aq NH₄Cl and EtOAc with vigorous stirring. The layers were separated and the aqueous layer was extracted with EtOAc three times. The combined extracts were washed with brine, dried over MgSO₄, and concentrated to give 7c, which was used for the next reaction without further purification. The above product in H₂O–AcOH–THF (2.7 mL, 3:5:10) was stirred at r.t. for 1 h, and diluted with sat. aq NaHCO₃ and CH₂Cl₂ with vigorous stirring. The layers were separated and the aqueous layer was extracted with CH₂Cl₂ three times. The combined extracts were washed with brine, dried over MgSO₄, and concentrated to give a residue, which was purified by chromatography on silica gel (hexane–EtOAc) to afford alcohol 7b (45.7 mg, 85% from TMS ether 6b) as a colorless oil: ¹H NMR (300 MHz, CDCl₃): δ = 0.77 (d, J = 6.6 Hz, 3 H), 0.80 (d, J = 6.9 Hz, 3 H), 0.90 (d, J = 7.2 Hz, 3 H), 0.99–1.12 (m, 2 H), 1.18–2.21 (m, 10 H), 1.78 (s, 3 H), 3.29 (t, J = 10.5 Hz, 1 H), 4.72 (br. s, 1 H), 4.75 (br. s, 1 H), 5.22 (dd, J = 17.7, 1.7 Hz, 1 H), 5.37 (dd, J = 11.4, 1.7 Hz, 1 H), 6.12 (dd, J = 17.7, 11.4 Hz, 1 H); ¹³C NMR (75 MHz, CDCl₃): δ = 15.6 (+), 15.9 (+), 21.1 (+), 22.8 (+), 23.2 (–), 26.3 (+), 28.6 (–), 29.5 (–), 30.8 (–), 34.9 (+), 45.1 (+), 48.0 (–), 72.5 (+), 109.8 (–), 118.1 (–), 139.2 (+), 146.7 (–). [α]_D ²¹ –19.0 (c 0.61, CHCl₃). HRMS (FAB): m/z [M + H]⁺ calcd for C₁₇H₃₁O: 251.2375; found: 251.2371. To a solution of Hoveyda–Grubbs 2nd generation catalyst (2.8 mg, 0.0045 mmol) in degassed CH₂Cl₂ (0.1 mL) was added alcohol 7b (12.3 mg, 0.0491 mmol) in degassed CH₂Cl₂ (0.9 mL). The mixture was stirred and heated to reflux for 2 days, and purified directly by chromatography on silica gel (hexane–EtOAc) to afford (–)-axenol 4 (10.6 mg, 97%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃): δ = 0.79 (d, J = 6.6 Hz, 3 H), 0.80 (d, J = 6.9 Hz, 3 H), 0.90 (d, J = 7.2 Hz, 3 H), 0.98–1.13 (m, 3 H), 1.14–1.28 (m, 1 H), 1.30–1.45 (m, 1 H), 1.46–1.61 (m, 2 H), 1.72–1.83 (m, 1 H), 1.79 (s, 3 H), 2.03–2.36 (m, 4 H), 3.07 (t, J = 10.4 Hz, 1 H), 5.14 (q, J = 1.6 Hz, 1 H); ¹³C NMR (75 MHz, CDCl₃): δ = 15.8 (+), 17.0 (+), 17.3 (+), 21.2 (+), 23.2 (–), 26.2 (+), 31.9 (–), 33.2 (–), 36.9 (–), 40.8 (+), 47.1 (+), 61.3 (–), 78.4 (+), 121.8 (+), 147.3 (–). The ¹H and ¹³C NMR spectra were consistent with those reported.^{9f, 21} [α]_D ²⁰ –37.5 (c 0.82, CHCl₃); Lit.^9e [α]_D ²⁵ –35.0 (c 1.2, CHCl₃).