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) 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, which on reduction and allylation was converted to 8. Acid-mediated cyclization led to 9. The sidechain of 9 was removed, giving 10, which 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, which was oxidized and cyclized to 17. Simmons-Smith conditions converted the dihydrofuran of 17 into the cyclopropane, which was again opened kinetically with Br (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.

Selective transformations of cephalostatin analogues

The highly tumor inhibitory cephalostatins (e.g., cephalostatin 1), a marine natural product isolated from Cephalodiscus gilcristi, have attracted us to synthesize biologically active analogues. The goal of this study is to shed more light on selective desymmetrization of a symmetrical starting analogue through the F-ring opening route applied to certain analogues using different borane complexes. Previously, we have reported a selective opening of the spiroketal in the northern part of an analogue using catechol-borane and D-(N-tosyl) valine-borane complexes. We demonstrate here the possibility of opening the southern part of the same analogue using salicylic acid-borane complex by which extra flexibility is harvested. In contrast, a different reaction type took place when another analogue was treated with 3,4-diaminobenzonitrile-borane complex, which give after H2O2 oxidation, products arising from ∆14 bond hydration. This led us to conclude that the geometry of both borane complex and substrate govern the regioselectivity of the products. However, the electronic nature of both substrate and borane-complex govern the chemoselectivity.