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Organic Chemistry Highlights

Total Synthesis

Monday, June 4, 2012
Douglass F. Taber
University of Delaware

The Garg Synthesis of (-)-N-Methylwelwitindolinone C

Of the several welwitindolinones, (-)-N-Methylwelwitindolinone C (3) uniquely reverses P-glycoprotein mediated multiple drug resistance. The preparation of 3 reported (J. Am. Chem. Soc. 2011, 133, 15797. DOI: 10.1021/ja206538k) by Neil K. Garg of UCLA illustrates the power in complex target-directed synthesis of late stage C-H functionalization.

The starting material 7 for this enantiospecific synthesis was prepared following the Natsume strategy (Chem. Pharm. Bull. 1994, 42, 1393. DOI: 10.1248/cpb.42.1393) in the enantiomeric series. Commercial carvone 4 was reduced and protected, then oxidized and equilibrated to the dienone 6. The pivalate efficiently directed the Cu-catalyzed conjugate addition of vinyl magnesium bromide, delivering 7.

Hydrolysis of 7 gave 8, to which the bromoindole 9 was added in a conjugate sense to give the adduct as a mixture of diastereomers, of which 1 was the more stable. Exposure of 1 to NaNH2 in tBuOH presumably generated the benzyne [indolyne] 10, which cyclized to the ketone 2.

The silyl ether 2 was deprotected and the alcohol was oxidized to give the diketone, which was selectively carried on to the enol triflate and thus to the stannane 11. The alkenyl chloride of the natural product was installed by the oxidation of 11 with CuCl2. Further oxidation with N-bromosuccinimide then delivered the oxindole 12.

In the last stage of the synthesis, it was necessary to selectively aminate one of the bridgehead C-H's of 12. To this end, the ketone was reduced and carried on to the carbamate 13. Attempts to oxidatively cyclize 13 with Rh catalysts failed, but Ag was successful, delivering 14. The final conversion of 15 to (-)-N-Methylwelwitindolinone C (3) was achieved by exposure to the Kim reagent (16).

D. F. Taber, Org. Chem. Highlights 2012, June 4.