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Organic Chemistry Highlights

Total Synthesis

Monday, January 3, 2011
Douglass F. Taber
University of Delaware

The Tanino Synthesis of (-)-Glycinoeclepin A

(-)-Glycinoeclepin A (3) is effective at picogram/mL concentrations as a hatch-stimulating agent for the soybean cyst nematode. Approaching the synthesis of 3, Keiji Tanino of Hokkaido University envisioned (Chem. Lett. 2010, 39, 835. DOI: 10.1246/cl.2010.835) the convergent coupling of the allylic tosylate 2 with the bridgehead anion 1. The assembly of the fragment 2 was particularly challenging, as the synthesis would require the establishment not just of the two adjacent cyclic quaternary centers, but also control of the relative configuration on the side chain.

The preparation of 1 began with the prochiral diketone 3. Enantioselective reduction of the mono enol ether 4 set the absolute configuration of 5. Iodination followed by cyclization then completed the assembly of 1.

The construction of the bicyclic tosylate 2 began with m-methyl anisole (7). Following the Rubottom procedure, Birch reduction followed by mild hydrolysis gave the ketone 8. Epoxidation followed by β-elimination delivered the racemic 9, which was exposed to lipase to give, after seven days, the residual alcohol in 40% yield and high ee.

The side chain nitrile was prepared from the diol 12. Homologation gave the nitrile 14, that was equilibrated to the more stable enol ether 15. The two cyclic quaternary centers of 3 were set in a single step, by the conjugate addition of the anion of 16 to the crystalline enone 11. Mild hydrolysis of 17 gave the keto aldehyde, that underwent aldol condensation to give the enone 18.

The hydroboration of 19 followed by Suzuki coupling of the intermediate organoborane with 20 delivered 21 with 94:6 relative diastereocontrol. Formylation of the enone 22 followed by triflation and reduction then led to 2.

Although the ketone 1 could be deprotonated with LDA, the only product observed, even at -78C, was the derived aldol dimer. The metalated dimethylhydrazone 25, in contrast, coupled smoothly with 2 to give, after hydrolyis, the desired adduct 26. Pd-mediated carboxylation of the enol triflate followed by selective oxidative cleavage and hydrolysis then completed the synthesis of (-)-Glycinoecleptin A (3).

D. F. Taber, Org. Chem. Highlights 2011, January 3.