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Enantioselective Total Synthesis of (−)-Acutumine

2009; American Chemical Society; Volume: 74; Issue: 23 Linguagem: Inglês

10.1021/jo902006q

1520-6904

Fang Li, Samuel S. Tartakoff, Steven L. Castle,

Alkaloids: synthesis and pharmacology

An account of the total synthesis of the tetracyclic alkaloid (−)-acutumine is presented. A first-generation approach to the spirocyclic subunit was unsuccessful as a result of incorrect regioselectivity in a radical cyclization. However, this work spawned a second-generation strategy in which the spirocycle was fashioned via a radical−polar crossover reaction. This process merged an intramolecular radical conjugate addition with an enolate hydroxylation and created two stereocenters with excellent diastereoselectivity. The reaction was promoted by irradiation with a sunlamp, and a ditin reagent was required for aryl radical formation. These facts suggest that the substrate may function as a sensitizer, thereby facilitating homolytic cleavage of the ditin reagent. The propellane motif of the target was then installed via annulation of a pyrrolidine ring onto the spirocycle. The sequence of reactions used included a phenolic oxidation, an asymmetric ketone allylation mediated by Nakamura's chiral allylzinc reagent, an anionic oxy-Cope rearrangement, a one-pot ozonolysis−reductive amination, and a Lewis acid promoted cyclization of an amine onto an α,β-unsaturated dimethyl ketal. Further studies of the asymmetric ketone allylation demonstrated the ability of the Nakamura reagent to function well in a mismatched situation. A TiCl4-catalyzed regioselective methyl enol etherification of a 1,3-diketone completed the synthesis.