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 HoffmannLaRoche 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.

URL: http://www.organic-chemistry.org/Highlights/2006/01May.shtm
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