Enantioselective total synthesis of (-)-acutumine.
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 alpha,beta-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 TiCl(4)-catalyzed regioselective methyl enol etherification of a 1,3-diketone completed the synthesis.
Li
Fang
F
Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602, USA.
Tartakoff
Samuel S
SS
Castle
Steven L
SL
D000470:Alkaloids / Q000138:chemical synthesis*; D003500:Cyclization; D011759:Pyrrolidines; D013141:Spiro Compounds / Q000138:chemical synthesis*; D013237:Stereoisomerism
D000470:Alkaloids; D011759:Pyrrolidines; D013141:Spiro Compounds; C442344:acutumine; C032519:pyrrolidine