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Organic Chemistry Highlights

Total Synthesis

Monday, April 4, 2016
Douglass F. Taber
University of Delaware

The Nicolaou Synthesis of Shishijimicin A

The enediyne antibiotics have posed a particular challenge for organic synthesis. The recent isolation of Shishijimicin A offered the opportunity for K. C. Nicolaou of Rice University not only to apply (J. Am. Chem. Soc. 2015, 137, 8716. DOI: 10.1021/jacs.5b05575) the lessons learned from previous efforts (J. Am. Chem. Soc. 1993, 115, 7612. DOI: 10.1021/ja00070a005) toward the total synthesis of Calicheamicin γ1I, but also more recent developments, including the impressive cyclization of 1 directly to 2.

The preparation of 1 began with the ketalization of the inexpensive tetronic acid 4, followed by reduction to 5. Asymmetric addition of the anion derived from MEMO-allyl followed by selective protection delivered 6. Swern oxidation to the aldehyde and oxime formation set the stage for intramolecular dipolar cycloaddition, leading to 7 with high diastereocontrol. Deprotection and oxidation furnished 8, that was coupled with 9 to give, after acetylation, deprotection and oxidation, the ketone 10. Note that the Jones conditions did not oxidize the isoxazoline to the isoxazole, but that the Swern conditions did.

Condensation of the ketone with the phosphonate 11 led, after protecting group exchange, to the alkyne 12, with high geometric control of the newly constructed alkene. The isoxazole was then reduced, and the liberated amine protected as the corresponding phthalimide, setting the stage for the key cyclization of 1 to 2. Apparently the La(III) coordinated both the aldehyde and the acetylide in the course of the cyclization, bringing them together with high diastereocontrol.

Space does not allow a discussion of the preparation of 16, but a key step was the lateral metalation that allowed the specific functionalization of the intermediate carboline. The coupling of 15 with 16 was delicate, but finally successful, leading, via trisulfide assembly, to Shishijimicin A (3).

D. F. Taber, Org. Chem. Highlights 2016, April 4.