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Organic Chemistry Highlights

Total Synthesis

Monday, November 1, 2010
Douglass F. Taber
University of Delaware

The Shair Synthesis of Cephalostatin 1

The cephalostatins and ritterazines, represented by Cephalostatin 1 (3), have the remarkable property of inducing apoptosis in apoptosis-resistant malignant cell lines. The total synthesis (J. Am. Chem. Soc. 2010, 132, 275. DOI: 10.1021/ja906996c) of 3 by Matthew D. Shair of Harvard University required the practical preparation of the complex hexacyclic ketones 1 and 2.

The preparation of 1 started with irradiation of commercial hecogenin acetate 4 to give the known aldehyde 5. Reaction of 5 with N-phenyltriazolenedione (6) led to the ketal 7. Oxidative cleavage generated an aldehyde, that on reduction and allylation was converted to 8. Acid-mediated cyclization led to 9.

The sidechain of 9 was removed, giving 10, that was selectively reduced, leading to 11. Intramolecular aldol condensation gave 12. The relative configuration of the spiroketal 1 was established by kinetic bromoetherification of the alcohol 13, followed by free radical reduction of the resulting tertiary bromide, and acid-catalyzed equilibration.

The synthesis of 2 began with the inexpensive steroid 14. Following the Schönecker protocol, C-H functionalization led to the ketone 15. Pd-mediated coupling of the derived enol triflate with the alkyne gave 16, that was oxidized and cyclized to 17. Simmons-Smith conditions converted the dihydrofuran of 17 into the cyclopropane, that was again opened kinetically with bromine (NBS) to set the relative configuration of the spiroketal. Free radical reduction followed by protection and oxidation then completed the preparation of 2.

The coupling of 1 and 2 (not illustrated) to form the central pyrazine of 3 followed the precedent of Fuchs, combining the 2-azido ketone derived from 1 with the 2-amino methoxime derived from 2. Remarkably, tens of milligrams of 1 and of 2 were prepared, assuring a reasonable supply of 3 for further studies.

D. F. Taber, Org. Chem. Highlights 2010, November 1.