Synthesis based on cyclohexadienes. Part 25.¹ Total synthesis of (±)-allo-cedrol (khusiol)

Abstract

The first stereoselective total synthesis of (±)-allo-cedrol 20, an enantiomer of khusiol and a complex sesquiterpene having a novel tricyclo[5.2.2.0 ^1,5]undecane framework, is reported from 8-methoxytricyclo[6.2.2.0 ^1,6]dodec-6-en-9-one 6c. The methodology involves preparation of 9-methoxytricyclo[7.2.1.0 ^1,6]dodec-6-en-8-one 12 from 6c and its conversion through the compounds 8-benzyloxy-7,7-dimethyl-9-methoxytricyclo[7.2.1.0 ^1,6]dodec-5-ene 38, 7-benzyloxy-8-methoxy-2,6,6-trimethyltricyclo[6.2.1.0 ^1,5]undecane 48 into 8-methoxy-2,6,6-trimethyltricyclo[6.2.1.0 ^1,5]undecan-7-one 49. Wittig reaction of 49 affords the olefin 50 which has been smoothly rearranged into khusione 51. Metal–ammonia reduction of khusione under specific conditions affords (±)-allo-cedrol. Thus, bridgehead substitution of a methoxy group by a methyl group is the key reaction in this synthesis. In an alternative strategy, attempted conversion of 8-methoxy-2-methyltricyclo[6.2.1.0 ^1,5]undec-5-en-7-one 16 into khusione 37 results in an inseparable mixture of the isomers. A notable observation in this synthesis is the unusual formation of a γ-alkylated product 27 during Woodward methylation of 16.

References

1. Part 24, K. Kaliappan and G. S. R. Subba Rao, J. Chem. Soc., Perkin Trans. 1, 1997, 3393.
2. I. Alfaro, W. Ashton, K. L. Rabone and N. A. J. Rogers, Tetrahedron, 1974, 30, 559.
3. T. Uyehara, K. Osanai, M. Sugimoto, I. Suzuku and Y. Yamamoto, J. Am. Chem. Soc., 1989, 111, 7264.
4. P. S. Shanker and G. S. R. Subba Rao, J. Chem. Soc., Chem. Commun., 1994, 621; Tetrahedron Lett., 1994, 35, 5055.
5. M. A. Qasseem, N. A. J. Rogers and A. A. Othman, Tetrahedron, 1968, 24, 4535.
6. K. Pramod and G. S. R. Subba Rao, Indian J. Chem., Sect. B, 1986, 25, 783.
7. B. Tomita and Y. Hirose, Phytochemistry, 1973, 12, 1409.
8. R. N. Ganguly, G. K. Trivedi and S. C. Bhattacharyya, Indian Chem., Sect. B, 1978, 16, 23.
9. K. Naemura, T. Hasegawa, H. Miyabe and H. Chikamatsu, Bull. Chem. Soc., Jpn., 1992, 65, 203.
10. N. Chidambaram and S. Chandrasekaran, J. Org. Chem., 1987, 52, 5048.
11. N. Selvakumar and G. S. R. Subba Rao, Tetrahedron Lett., 1993, 34, 7789; J. Chem. Soc., Perkin Trans. 1, 1994, 3217.
12. H. J. Riech, J. M. Renga and I. L. Riech, J. Org. Chem., 1974, 39, 2133.
13. B. S. Huang, E. J. Parish and D. H. Milles, J. Org. Chem., 1974, 39, 2647.
14. D. H. R. Barton and R. Subrahmanian, J. Chem. Soc., Perkin Trans. 1, 1977, 1718.
15. D. H. R. Barton, D. O. Jang and J. C. Jaszberenyi, J. Org. Chem., 1993, 58, 6838.
16. (a) G. Ourisson and A. Rassat, Tetrahedron Lett., 1960, 16; (b) J. W. Huffman and J. T. Charles, J. Am. Chem. Soc., 1968, 90, 6486; (c) A. Coulombeau and A. Rassat, J. Chem. Soc., Chem. Commun., 1968, 1587.
17. P. A. Grieco, S. Burke, W. Metz and M. Nishizawa, J. Org. Chem., 1979, 44, 152.
18. Klaus P. Adam, personal communication.