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Organic Chemistry Highlights

Total Synthesis

Monday, February 2, 2015
Douglass F. Taber
University of Delaware

The Paterson Synthesis of (-)-Leiodermatolide

(-)-Leiodermatolide (4), isolated from the lithistid sponge Leiodermatium sp., showed 5.0 nM activity against PANC-1 pancreatic carcinoma cells, and reduced toxicity toward normal cells. Ian Paterson of the University of Cambridge established (Angew. Chem. Int. Ed. 2014, 53, 2692. DOI: 10.1002/anie.201310164) a synthetic route to 4 based on sp2-sp2 coupling, as exemplified by the combination of 1 with 2 to give 3.

Addition of the boron enolate of the enantiomerically-pure benzoate 5 to the iodoaldehyde 6 gave 7, that was silylated, reduced and deprotected to give 1. Addition of the boron enolate of ent-5 to propanal gave 8. The α-acyloxy ketone of 8 served as a masked acylating agent. The addition of allyl magnesium bromide followed by oxidative cleavage led to the ketone 9. The preparation of 2 was completed by diastereoselective Mukaiyama aldol reaction of 9 with the ketene silyl acetal 10.

The intramolecular Heck coupling of 1 with 2 presumably proceeded by way of the organo-Pd intermediate 11. β-Hydride elimination could have given one or more of four possible dienes, but in fact the E,E product 3 dominated, as expected. The allylic H's are activated for elimination, while the H's β to the silyl ether are deactivated both electronically and sterically.

The third component of 4 was the stannane 17. Applying the same strategy, the addition of ent-5 to the aldehyde 12 gave 13, that was protected and condensed with 14 to deliver, after oxidative cleavage, the alkynyl ketone 15. Conjugate addition of iodide proceeded with good geometric control to give 16, that was protected and stannylated to complete the preparation of 17.

The diol 3 was oxidatively cleaved, and the resulting aldehyde was carried on to the iodide 18. This was coupled with the stannane 17 to give the diene 19. A sequence of deprotection, oxidation, and further deprotection yielded a tetraol, that was lactonized with high selectivity to give the 16-membered ring of (-)-Leiodermatolide (4).

D. F. Taber, Org. Chem. Highlights 2015, February 2.