First Total Synthesis of (-)-1(10),5-Germacradien-4-ol

Abstract

This paper presents a total synthesis of (-)-1(10),5-germacradien-4-ol, a constituent of the needles of Scots pine and of the defence secretion from the larvae of the pine sawfly. The synthesis uses a strategy based on an intramolecular alkylation to form an unsaturated monocyclic 10-membered ring.

germacrane terpenoids - intramolecular alkylation - stereoselective synthesis

References

1 Wagner M. Raffa KF. Sawfly Life History Adaptations to Woody Plants   Academic Press; San Diego: 1993. 

2

PHERODIP, Pine sawfly pheromones for sustainable management of European forests; European Community contacts, no. FAIR1-CT95-0339. Final report.

3 Bergström G. Wassgren A.-B. Birgersson G. Acta Chem. Scand.  1994,  48:  187 

4a Two numbering systems of 1 occur in the literature. We have used the germacrane numbering system described in: Connolly JD. Hill RA. Dictionary of Terpenoids   Chapman & Hall; London: 1991. 

4b

Another system of numbering 1 is used e.g. in refs. 3,6,8,9,10,21,23.

5 Bohlmann F. Knoll K.-H. Zdero C. Mahanta PD. Grenz M. Suwita A. Ehlers D. Le Van N. Abraham W.-R. Natu AA. Phytochemistry  1977,  16:  965 

6 Nordin O. Hedenström E. Högberg H.-E. Acta Chem. Scand.  1999,  53:  124 

7 A review of syntheses of germacranes: Minnaard AJ. Wijnberg JBPA. de Groot A. Tetrahedron  1999,  55:  2115 

8 Ralduglin VA. Salenko VL. Gamov NS. Titova TF. Khan VA. Pentegova VA. Chem. Nat. Compd. (Engl. Transl.)  1980,  16:  154 

9 Nordin O. Stereoselective Synthesis of Semiochemicals Related to Pine Sawflies., Ph.D. Thesis   Royal Institute of Technology; Stockholm: 1999. 

10 nor-Me synthesis: Nevalainen M. Koskinen AMP. J. Org. Chem.  2002,  67:  1554 

11a Takahashi T. Nagashima T. Tsuji J. Tetrahedron Lett.  1981,  22:  1359 

11b Takahashi T. Yamashita Y. Doi T. Tsuji J. J. Org. Chem.  1989,  54:  4273 

12 KocieŇski PJ. Pritchard M. Wadman SN. Whitby RJ. Yeates CL. J. Chem. Soc., Perkin Trans. 1  1992,  3419 

13a Högberg H.-E. In Houben-Weyl   4th ed., Vol. E21a:  Helmchen G. Hoffman RW. Multzer J. Schaumann E. Thieme; Stuttgart: 1995.  p.791 

13b Herrmann R. In Houben-Weyl   4th ed., Vol. E21f:  Helmchen G. Hoffman RW. Multzer J. Schaumann E. Thieme; Stuttgart: 1996. 

14a Myers AG. Yang BH. Chen H. McKinstry L. Kopecky DJ. Gleason JL. J. Am. Chem. Soc.  1997,  119:  6496 

14b Myers AG. Yang BH. In Organic Syntheses   Vol. 77:  Hart DJ. Wiley; New York: 1999.  p.22 

14c Myers AG. Yang BH. Chen H. In Organic Syntheses   Vol. 77:  Hart DJ. Wiley; New York: 1999.  p.29 

15

Isolated yield of homogeneous substances. All new compounds showed satisfactory spectroscopic data based on data from ¹H and ¹³C NMR, IR and MS.

16 Dale JA. Dull DL. Mosher HS. J. Org. Chem.  1969,  34:  2543 

17

Attempted removal of the benzyl group with H₂/Pd-C in MeOH was inefficient, whereas migration of the silyl group was observed in THF.

18 Ley SV. Norman J. Griffith WP. Marsden SP. Synthesis  1994,  639 

19 Rychnovsky SD. Hoye RC. J. Am. Chem. Soc.  1994,  116:  1753 

20a Evans DA. Truesdale LK. Carroll GL. J. Chem. Soc., Chem. Commun.  1973,  55 

20b Lidy W. Sundermeyer W. Chem. Ber.  1973,  106:  587 

21 RCM synthesis of a nor-Me relative, a 11:1 E/Z mixture of (±)-9-tert-butyldimethylsilyloxy-8-isopropylcyclodec-4-enone: Nevalainen M. Koskinen AMP. Angew. Chem. Int. Ed.  2001,  40:  4060 

22

Data of 2: IR (neat, KBr): 2960, 2930, 2870, 1690, 1650, 1625, 1385, 1370, 1155, 1105, 990 cm^-1; ¹H NMR* (250.13 MHz, CDCl₃): δ 6.08 (dd, J = 16, 10 Hz, 1 H), 6.06 (d, J = 16 Hz, 1 H), 5.00-5.08 (m, 1 H), 2.65 (m, 1 H), 2.05-2.50 (m, 6 H), 1.91 (m, 1 H), 1.50-1.76 (m, 2 H), 1.49 (s, br, 3 H), 0.90 (d, J = 6.8 Hz, 3 H), 0.84 (d, J = 6.8 Hz, 3 H); significant shifts of minor stable conformer, or 5Z-isomer: δ 6.64 (dd,
J = 16, 10 Hz, 1 H), 5.98 (d, br, J = 16 Hz, 1 H), 5.30 (m,
1 H), 1.30 (s, br, 3 H), 0.95 (d, J = 6.7 Hz, 3 H), 0.88 (d, J = 6.6 Hz, 3 H); ¹³C NMR (62.9 MHz, CDCl₃): δ 202.4, 149.7, 136.8, 135.4, 129.0, 52.8, 40.9, 40.4, 32.3, 28.0, 25.4, 20.8, 19.5, 15.6; minor stable conformer, or 5Z-isomer: δ 201.7, 159.9, 141.1, 128.4, 126.6, 49.9, 38.9, 35.6, 34.4, 30.9, 25.4, 20.8, 20.7, 18.9; MS (EI, ion trap) m/z (rel. int.): 206 (M⁺, 40), 189(15), 163(35), 136(100), 121(35), 107(40), 93(80), 79(70), 67(45); MS (CI, ion trap, CH₃CN as ionisation gas) m/z (rel. int.): 207 (M + H⁺, 75), 189(100).
*Due to the fact that this is a mixture of two stable conformers, or 5E/5Z isomers, the ¹H NMR characterisation is still pending.

23 MS of 1 was in good agreement with: Joulain D. Laurent R. J. Essent. Oil Res. 1  1989,  299 

24 Guanti G. Banfi L. Narisano E. Riva R. Tetrahedron Lett.  1992,  33:  2221 

25 Blanchette MA. Choy W. Davis JT. Essenfeld AP. Masamune S. Roush WR. Sakai T. Tetrahedron Lett.  1984,  25:  2183