Total Synthesis Highlights
Total Synthesis Highlights
Total Synthesis Highlights
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An additional stereogenic center is created when 1 and 2 are combined. Initial attempts to carry<br />
out the condensation gave the wrong stereochemical outcome, as Pictet-Spengler condensation<br />
preceded tosylate displacement. To work around this problem, 1 and 2 were combined in the<br />
presence of cyanide ion, to give 15. Heating of 15 gave cyclization, but again to the wrong<br />
diastereomer, perhaps because in the intermediate ion pair from cyanide ionization, the cyanide<br />
ion was blocking one face of the intermediate cation. Fortunately, on stirring at room temperature<br />
in aqueous HCl, 15 did cyclize to the correct diastereomer, providing, after acylation, reserpine<br />
(3).<br />
59. The Overman Route to Gelsemine<br />
Gelsemine 3 has no particular biological activity that recommends it, but its challenging<br />
architecture has been a motivation to a generation of organic synthesis chemists. Larry E.<br />
Overman of the University of California at Irvine has described (J. Am. Chem. Soc. 2005, 127,<br />
18046, 18054,) his total synthesis of gelsemine, the key step of which was the acid-mediated<br />
cyclization of 1 to 2.<br />
The synthesis of 1 started with the preparation of the diene 4 from 3-methyl anisole. Diels-Alder<br />
cycloaddition with methyl acrylate gave the endo adduct 7. The methyl group was converted to the<br />
vinyl group of the natural product by allylic oxidation followed by methylenation. Hydrolysis<br />
followed by inversion and trapping with p-methoxybenzyl alcohol gave the protected amine 7.<br />
This underwent smooth aza-oxy-Cope rearrangement, to give, after protection and bromination,<br />
the ketone 1.