Total Synthesis Highlights

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. ) 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 Me 3 Al,
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 SmI 2 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.