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Organic Chemistry Highlights

Total Synthesis

Monday, March 3, 2014
Douglass F. Taber
University of Delaware

The Herzon Synthesis of (-)-Acutumine

The alkaloid (-)-Autumine (3), isolated from the roots of the chinese moonseed Sinomenium acutum, improves object and social recognition in the Wistar rat model. With four rings and three adjacent fully-substituted stereogenic centers, 3 presents a significant synthetic challenge. Seth B. Herzon of Yale University assembled (Angew. Chem. Int. Ed. 2013, 52, 3642. DOI: 10.1002/anie.201210076) 3 by the intramolecular Sakurai cyclization of 1 to 2.

The convergent preparation of 1 required the alkyne 10. The literature construction (Org. Lett. 2005, 7, 5075. DOI: 10.1021/ol052106a) by A. B. Smith III of the enone 7 from ribose 4 began with protection to 5. Conversion of the primary alcohol to the iodide followed by reduction delivered the aldehyde. Addition of vinyl magnesium bromide followed by exposure to the first generation Grubbs catalyst gave the cyclopentenol, that was oxidized to cyclopentenone 7. Conjugate silyation led to the triflate 8, that was carried on to 10.

In earlier work, Professor Herzon had shown (Angew. Chem. Int. Ed. 2011, 50, 8863. DOI: 10.1002/anie.201102226) that the prochiral quinone from oxidation of 11 could be added to the diene 12 under enantioselective catalysis, to give 13 in high ee. Reduction of the azide gave the imine, that was quaternized with methyl triflate. Addition of the Li salt of 10 to that sensitive intermediate proceeded with high facial selectivity. With aromatization blocked, the product from the addition of 10 could be thermolyzed to yield 14. The stannylation of the alkyne proceeded with high regio- and stereoselectivity, to give the alkene 1. Exposure of the allylic silane to tetrabutylammonium fluoride drove the desired cyclization to give 2. Chlorination followed by acetonide removal then completed the preparation of the diol 15.

The completion of the synthesis required extensive experimentation. Eventually, a protocol was established to oxidize 15 over several steps to the dienone 16. Selective reduction of the ketone (the other carbonyls are vinylogous esters) proceeded with the desired facial selectivity, to give 17. Selective hydrogenation using a Rh catalyst then delivered (-)-Acutumine (3).

This is the second total synthesis of (-)-Actumuine (3). The first, by Steven L. Castle of Brigham Young University (The Castle Synthesis of (-)-Acutumine 2009, October 5), is quite different. It is instructive to compare the two side by side.

D. F. Taber, Org. Chem. Highlights 2014, March 3.