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Organic Chemistry Highlights

Total Synthesis

Monday, May 1, 2006
Douglass Taber
University of Delaware

The Stork Synthesis of (-)-Reserpine

The history of reserpine (3), isolated from the Indian shrub Rauwolfia serpentina, is storied. The anxiolytic activity of reserpine, the first tranquilizer, pointed the way to the development by Hoffmann-LaRoche of the blockbuster drugs Librium and Valium.

The spectacular first total synthesis of reserpine was achieved by R.B. Woodward in 1956. Several alternative approaches have been been published since that time. The most recent (J. Am. Chem. Soc. 2005, 127, 16255. DOI: 10.1021/ja055744x), by Gilbert Stork of Columbia University, centering on the aldehyde tosylate 2, illustrates the power of chiral induction for the kinetic establishment of distal stereocenters. Condensation of 2 with 6-methoxytryptamine (1) led to reserpine (3).

The preparation of 2 started with the previously-reported enantioselective addition of acrylate to butadiene, to give the acid 6. Iodolactone formation followed by reduction gave the diol 7. Under the conditions of benzyl ether formation, the iodohydrin cyclized to the epoxide, giving 8. Phenyl selenide added to 8 to give the expected diaxial product 9, which on oxidation gave 10 in high enantiomeric excess.

The key reaction in the assembly of 2 was the addition of the kinetic lithium enolate of 10 to the silyl acrylate 11 to give 12. This reaction is seen as involving two sequential Michael additions, but the stereochemical outcome is the same as would be expected from a concerted Diels-Alder cycloaddition. Exposure to TBAF converted the furyl silane to the fluorosilane, which was debenzylated and carried on to the tosylate 13. On exposure to two equivalents of hydrogen peroxide, the ketone underwent Baeyer-Villiger oxidation with high regioselectivity. The silane was also oxidized, delivering 14. Methylation followed by Dibal reduction then gave 2.

An additional stereogenic center is created when 1 and 2 are combined. Initial attempts to carry out the condensation gave the wrong stereochemical outcome, as Pictet-Spengler condensation preceded tosylate displacement. To work around this problem, 1 and 2 were combined in the presence of cyanide ion, to give 15. Heating of 15 gave cyclization, but again to the wrong diastereomer, perhaps because in the intermediate ion pair from cyanide ionization, the cyanide ion was blocking one face of the intermediate cation. Fortunately, on stirring at room temperature in aqueous HCl, 15 did cyclize to the correct diastereomer, providing, after acylation, reserpine (3).

D. F. Taber, Org. Chem. Highlights 2006, May 1.