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Organic Chemistry Highlights

Total Synthesis

Monday, September 4, 2006
Douglass Taber
University of Delaware

The Corey Route to the Dolabellanes: Isoedunol and β-Araneosene

A variety of dolabellanes, some of which show substantial physiological activity, have been isolated from natural sources. E. J. Corey of Harvard University has introduced (J. Am. Chem. Soc. 2005, 127, 13813. DOI: 10.1021/ja055137+) a unfied approach to the dolabellanes, represented by isoedunol (3), based on the designed rearrangement of the mesylate 1 to 2.

The key to this approach was the stereocontrolled construction of the cyclobutane 1. The starting material was the racemic iodo acetonide 4 derived from farnesol. Alkylation of 5 using the Seebach protocol followed by hydrolysis led the methylthiomethyl ether 7. The ester was converted to the hydroxy cyclopropane 8 by the Kulinkovic procedure. On activation with Me3Al, 8 was smoothly carried on to the enantiomerically-pure cyclobutanone 9. The ring expansion must not be proceeding by full ionization, as carbocation formation would have led to the racemic product. The aldehyde derived from 9 was cyclized with SmI2 to the trans diol 10.

In medium ring derivatives such as 10, one substituent on a ring carbon will be inside, and the other will be outside. The conformation of 10 is such that formation of the mesylate from the secondary alcohol led to migration of the more substituted cyclobutane bond, delivering 11. It follows that the conformation of the diol 12 will be flipped, to keep the OH outside the ring. Formation of the mesylate from the secondary alcohol of 12 led cleanly to migration of the less substituted cyclobutane bond, to give the desired cyclopentanone 2.

Addition of 2-propenyl lithium to the cyclopentanone 2 gave the dolebellane isoedunol (3). Deoxygenation converted 3 to the dolabellane β-araneosene (13). This strategy for the construction of the dolabellanes may open a route for the preparation of the cytotoxic dolabellanes clavulactone (14) and clavirolide (15).

D. F. Taber, Org. Chem. Highlights 2006, September 4.