Synlett 2015; 26(08): 1085-1088
DOI: 10.1055/s-0034-1380273
letter
© Georg Thieme Verlag Stuttgart · New York

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

Takuri Ozaki
Department of Bioengineering, Tokyo Institute of Technology, Box B-52, Nagatsuta-cho 4259, Midori-ku, Yokohama 226-8501, Japan   Email: ykobayas@bio.titech.ac.jp
,
Yuichi Kobayashi*
Department of Bioengineering, Tokyo Institute of Technology, Box B-52, Nagatsuta-cho 4259, Midori-ku, Yokohama 226-8501, Japan   Email: ykobayas@bio.titech.ac.jp
› Author Affiliations
Further Information

Publication History

Received: 24 December 2014

Accepted after revision: 05 February 2015

Publication Date:
05 March 2015 (online)


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.

Supporting Information

 
  • 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).