Cochleamycin A

Recent progress of total syntheses in our laboratory has been described along with our background and methodologies. The target bioactive polyketides are classified into three categories according to their structures: (i) lactone-fused polycyclic compounds [(+)-cochleamycin A, (+)-tubelactomicin A, and (-)-tetrodecamycin], (ii) aromatic compounds [(-)-tetracycline, (-)-BE-54238B, lymphostin, and (-)-lagunamycin], and (iii) acyclic polyketides [xanthocillin X dimethylether, (+)-trichostatin D, and (+)-actinopyrone A]. Features of the total syntheses are described. Original methodologies have been developed and applied to construct the inherent structures of the target molecules. Most syntheses cited herein are the first total syntheses, and the absolute structures of the target molecules have been determined.

A tandem ring-closing metathesis of a silaketal-based dienyne substrate proceeded efficiently to provide a bicyclic siloxane, which upon removal of the silicon tether afforded an (E,Z)-1,3-dienediol. Further manipulation of this key functional motif rendered synthesis of the entire C1-C19 linear skeleton of (-)-cochleamycin A, a late-stage intermediate employed in the previous total synthesis of (+)-cochleamycin A by Roush and co-workers.

An efficient route to the fully functionalized ABC ring systems of the unnatural enantiomer of cochleamycin A was developed. L-(-)-Malic and L-(-)-ascorbic acids served well as starting materials for the two building blocks used to construct an (E,Z,E)-1,6,8-nonatriene intermediate. The AB part structure was assembled by way of a stereocontrolled intramolecular Diels-Alder cycloaddition via adoption of an endo transition state. From this vantage point, two general pathways were subsequently explored as to their suitability for elaboration of the CD rings. Initially examined was a protocol involving 10-membered carbocycle construction. When this approach was demonstrated not to be workable, attention was directed to 10-membered macrolactonization as an alternative tactic. Although assembly of the C-ring in this manner was easily achieved, ultimate closure of the six-membered ring to form ring D remains an unsolved problem.