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Organic Chemistry Highlights

Total Synthesis

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

The Tanino/Miyashita Synthesis of Solanoeclepin A

Building on the Tanino synthesis of Glycinoeclepin (The Tanino Synthesis of (-)-Glycinoeclepin A 2011, January 3), the hatch-stimulating substance for the soybean cyst nematode, Keiji Tanino of Hokkaido University and Masaaki Miyashita, now at Kogakuin University, described (Nature Chem. 2011, 3, 484. DOI: 10.1038/nchem.1044) a convergent synthesis of Solanoeclepin A (3), the hatch-stimulating substance for the potato cyst nematode. A key step in the synthesis was the diastereoselective Diels-Alder cyclization of 1 to 2.

The starting point for the synthesis was the conjugate addition of 5 to 3-methyl cyclohexenone (4), followed by aldol condensation. The secondary acetate corresponding to 6 was readily resolved by lipase hydrolysis. The next challenge was the installation of the angular vinyl group. Enone transposition gave 7, to which vinyl Grignard added with high diastereocontrol, leading to the diol 8. TMSOTf-mediated epoxide rearrangement with concomitant 1,2 vinyl shift then delivered 9. Epoxidation followed by Stork cyclization completed the construction of the cyclobutane 10.

The allylic alcohol 12 was enantiomerically pure, so the relative configuration of the sidechain cyclopropane could be set by the Charette protocol. Grieco dehydration of 14 then gave 16, a latent form of the cyclobutanone of 3. Condensation of the ketone 17 with 18 delivered the expected keto enamine, that rearranged nicely on exposure to Tf2O to the aldehyde 19. Diastereoselective addition of the furyl lithium 20 followed by Pd-catalyzed coupling with 21 then completed the assembly of the Diels-Alder substrate 1.

The Me2AlCl-mediated intramolecular Diels-Alder cyclization of 1 led to 2 with remarkable diastereocontrol. Oxidation gave 22, that was further oxidized to the protected enol 23. Reduction, alkene cleavage and protecting group manipulation then set the stage for the final oxidation of 24 to Solanoeclepin A (3).

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