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Organic Chemistry Highlights

Total Synthesis

Monday, January 7, 2013
Douglass F. Taber
University of Delaware

The Thomson Synthesis of (-)-GB17

(-)-GB17 (3) is one of the Galbulimima alkaloids, a family that shows a wide range of interesting physiological activity. Regan J. Thomson of Northwestern University devised (Angew. Chem. Int. Ed. 2012, 51, 2481. DOI: 10.1002/anie.201108227) a convergent assembly of 3, a key step of which was the intramolecular Michael cyclization of 1 to 2.

The hydroxy aldehyde 6 was prepared by alkylation of the dithiane 4 with 5, followed by hydrolysis. The preparation of 9, by condensation of 8 with 7 followed by hydrogenation and protection, had been reported by Lhommet. Condensation of 9 with the linchpin reagent 10 gave an intermediate keto phosphonate, that was combined with 6 to give, after oxidation, the aldehyde 1.

Two new stereogenic centers are created in the course of the cyclization of 1. The authors found that the TFA salt 11 of the Hayashi catalyst delivered 2 with high diastereocontrol. Control experiments showed that the buttressing effect of the dithiane was required for the cyclization.

The authors then explored the next intramolecular Michael cyclization, of 13 to 14. In this cyclization, the stereogenic center at 6 is in jeopardy, by elimination and readdition. Cyclization of the trans unsaturated ester led to the wrong diastereomer of 14, but cyclization of the cis ester 13, prepared by the Still-Gennari protocol, cleanly gave the desired diastereomer. The reaction worked best with the free amine. Under the conditions of the reaction the Michael addition product spontaneously cyclized to the lactam 14.

The ketone of 14 was selectively enolized, then converted to its enol triflate, that under Pd-mediated reduction gave the alkene 15. Alkylation of 15 with 16 gave predominantly the diene 18. Hydrolysis of the dithiane to the ketone followed by reduction gave mainly the desired equatorial alcohol, which was cleaved oxidatively to (-)-GB17 (3).

Although there have been many isolated reports of the utility of intramolecular Michael addition as a synthetic method, there has been little systematic investigation. The optimization studies that are the heart of this work are a welcome addition.

D. F. Taber, Org. Chem. Highlights 2013, January 7.