Total Synthesis Highlights

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).
59. The Overman Route to Gelsemine
Gelsemine 3 has no particular biological activity that recommends it, but its challenging
architecture has been a motivation to a generation of organic synthesis chemists. Larry E.
Overman of the University of California at Irvine has described (J. Am. Chem. Soc. 2005, 127,
18046, 18054,) his total synthesis of gelsemine, the key step of which was the acid-mediated
cyclization of 1 to 2.
The synthesis of 1 started with the preparation of the diene 4 from 3-methyl anisole. Diels-Alder
cycloaddition with methyl acrylate gave the endo adduct 7. The methyl group was converted to the
vinyl group of the natural product by allylic oxidation followed by methylenation. Hydrolysis
followed by inversion and trapping with p-methoxybenzyl alcohol gave the protected amine 7.
This underwent smooth aza-oxy-Cope rearrangement, to give, after protection and bromination,
the ketone 1.