Organic Chemistry Portal
Organic Chemistry Highlights

Search Org. Chem. Highlights:

Match: or and


Total Synthesis

Monday, October 5, 2009
Douglass F. Taber
University of Delaware

The Castle Synthesis of (-)-Acutumine

The complex tetracyclic alkaloid (-)-acutumine 3, isolated from the Asian vine Menispermum dauricum, shows selective T-cell toxicity. The two adjacent cyclic all-carbon quaternary centers of 3 offered a particular challenge. Steven L. Castle of Brigham Young University solved (J. Am. Chem. Soc. 2009, 131, 6674. ) this problem by effecting net enantioselective conjugate allylation of the enantiomerically pure substrate 1 to give 2 with high diastereocontrol.

The starting coupling partners (Org. Lett. 2006, 8, 3757, ; Org. Lett. 2007, 9, 4033, ) for the synthesis were the Weinreb amide 4, prepared over several steps from 2,3-dimethoxyphenol, and the diastereomerically- and enantiomerically-pure cyclopentenyl iodide 5, prepared by singlet oxygenation of cyclopentadiene followed by enzymatic hydrolysis. Transmetalation of 5 by the Knochel protocol, addition of the resulting organometallic to 4 and enantioselective (and therefore diastereoselective) reduction of the resulting ketone delivered the alcohol 6. Methods for installing cyclic halogenated stereogenic centers are not well developed. Exposure of the allylic alcohol to mesyl chloride gave the chloride 7 with inversion of absolute configuration. Remarkably, this chlorinated center was carried through the rest of the synthesis without being disturbed.

A central step in the synthesis of 3 was the spirocyclization of 7 to 8. Initially, iodine atom abstraction generated the aryl radical. The diastereoselectivity of the radical addition to the cyclopentene was set by the adjacent silyloxy group. The α-keto radical so generated reacted with the Et3Al to give a species that was oxidized by the oxaziridine to the α-keto alcohol, again with remarkable diastereocontrol.

Conjugate addition to the cyclohexenone 1 failed, so an alternative strategy was developed, diastereoselective 1,2-allylation of the ketone followed by oxy-Cope rearrangement. The stereogenic centers of 1 are remote from the cyclohexenone carbonyl, so could not be used to control the facial selectivity of the addition. Fortunately, the stoichiometric enantiomerically-pure Nakamura reagent delivered the allyl group preferentially to one face of the ketone 1, to give 9. The subsequent sigmatropic rearrangement to establish the very congested second quaternary center of 2 then proceeded with remarkable facility, at 0C for one hour.

Oxidative cleavage to the aldehyde followed by reductive amination gave 10, that looks as though it could be poised for intramolecular displacement of the secondary chloride. Nonetheless, Lewis acid mediated ionization followed by cyclization proceeded smoothly, to establish the fourth ring of the natural product. Oxidation state adjustment then completed the synthesis of (-)-Acutumine (3).

The face selective enone allylation followed by oxy-Cope rearrangement (12), a highlight of the approach presented here, will have many applications in target-directed synthesis.

D. F. Taber, Org. Chem. Highlights 2009, October 5.