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Organic Chemistry Highlights

Total Synthesis

Monday, December 2, 2013
Douglass F. Taber
University of Delaware

The Harran Synthesis of (+)-Roseophilin

Ansa-bridged prodiginines include (+)-Roseophilin B (3) and Streptorubin B. The observation that Sterptorubin B potentiated apoptopic signaling in cell culture led to the development of obatoclax, currently being evaluated for the treatment of leukemia. Patrick G. Harran of UCLA devised (J. Am. Chem. Soc. 2013, 135, 3788. DOI: 10.1021/ja400473v) what promises to be a general route to the prodiginines, a key step of which was the cyclization of 1 to 2.

In planning the synthesis of 1, the authors took advantage of the relative inertness of a monosubstituted alkene. Friedel-Crafts acylation of 5 proceeded smoothly without affecting the distal double bond. Reduction then completed the preparation of 7.

The preparation of 1 continued from the pyrrole 9, prepared from the pyridine 8. Addition of the derived enoate to the aldehyde 10 proceeded smoothly, to give, after oxidation and acid-mediated rearrangement, the furan 12. Selective metalation followed by carboxylation gave the acid 13, that was combined with 7 to give 15. Deprotonation of 15 gave an intermediate that reacted primarily on the pyrrole N. This intermediate was then reacted with diethylchlorophosphite to give, after oxidation, the phosphoramide 16. Advantage was then taken of the organometallic reactivity of the monosubstituted alkene of 16, as Ru-mediated cross metathesis with 17 followed by reduction completed the preparation of 1.

The diheteroaryl ketone of 1 is not enolizable. On exposure to KHMDS, the dialkyl ketone will be deprotonated reversibly. Either enolate could add to the diheteroaryl ketone, but only the adduct from deprotonation of the methylene could go on to alkene formation. This net dehydration may likely be driven by phosphoryl transfer to the intermediate alkoxide.

The enone 2 is prochiral. Hydrogenation with an enantiopure catalyst proceeded with high de and 67% ee. Re-mediated intramolecular Friedel-Crafts addition of the dialkyl ketone to the pyrrole followed by acid-mediated rearrangement then delivered (+)-Roseophilin (3).

There are several points along this synthesis at which diversity could be introduced. This should enable detailed structure-activity studies of the prodiginines.

D. F. Taber, Org. Chem. Highlights 2013, December 2.