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Organic Chemistry Highlights

Total Synthesis

Monday, June 3, 2013
Douglass F. Taber
University of Delaware

The Williams Synthesis of (-)-Khayasin

The tetranortriterpenoid (-)-Khayasin (3) recently emerged as a potent and selective insecticide against the Coconut leaf beetle Brontispa longissima. In considering a synthetic route to 3, Craig M. Williams of the University of Queensland envisioned (J. Org. Chem. 2012, 77, 8913. DOI: 10.1021/jo301182f) the convergent preparation of the allyl vinyl ether 1 and subsequent Claisen rearrangement to the enone 2.

To pursue this strategy, the ketone 8 and the allylic alcohol 15 had to be prepared in enantiomerically pure form. To this end, the DIP-Cl-derived enolate of the ketone 7 was added to the aldehyde 6 to give a secondary alcohol, exposure of which to KH led to the enone 8 in high ee. Methyl triflate converted the enone into the enol ether 9. The α-pinene used in the preparation of the diisopineocampheyl chloroborane (DIP-Cl) was 83% ee.

The authors have optimized (Adv. Synth. Catal. 2009, 351, 1148. DOI: 10.1002/adsc.200800739) the Morita-Baylis-Hillman addition of cyclohexenone 10 to formaldehyde to give, after silylation, the enone 11. Methylation followed by DIP-mediated aldol reaction with 13 led to the alcohol 14. Exposure of the derived acetate to lithium diisopropylamide induced cyclization and dehydration. Deprotection completed the preparation (Tetrahedron 2006, 62, 7355. DOI: 10.1016/j.tet.2006.05.030) of 15. Fortunately, the enantiomers of 15 could be separated chromatographically. Material having >99% ee was taken on to the next step.

Warming of 9 and 15 in the presence of acid delivered the coupled ketone 2, accompanied by the ether 1. Further heating of 1 converted it (Chem. Commun. 2011, 47, 258. DOI: 10.1039/C0CC04698A) to 2. To form the last ring, the enone 2 was epoxidized, to give 16. The reduction of 16 with aluminum amalgam gave preparatively useful amounts of 17. Esterification completed the synthesis of 3. Most total syntheses only yield the target natural product. In this biomimetic project, intermediates 15, 2, and 17 were themselves natural products, and oxidation of 17 delivered an additional natural product, 18.

The preparation of 14 and of 8 underscore the importance of the asymmetric transformation of prochiral starting materials, cyclic and acyclic. While DIP-Cl is used in stoichiometric amounts in both cases, it is not expensive. The preparation of 8 in particular offers a potentially general approach to high ee substituted cyclohexenones.

D. F. Taber, Org. Chem. Highlights 2013, June 3.