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Organic Chemistry Highlights

Total Synthesis

Monday, February 4, 2013
Douglass F. Taber
University of Delaware

The Li Synthesis of (-)-Fusarisetin A

Fusarisetin A (3) is an intriguing inhibitor of cell migration and invasion that is not itself cytotoxic. Ang Li of the Shanghai Institute of Organic Chemistry developed (J. Am. Chem. Soc. 2012, 134, 920. DOI: 10.1021/ja211444m) a total synthesis of (-)-Fusarisetin A, demonstrating that the natural material had the opposite absolute configuration to that originally assigned. A key step in the synthesis was the highly diastereoselective cyclization of 1 to 2.

The absolute configuration of 1 and so of synthetic 3 was derived from commercial citronellol, which is prepared on an industrial scale by asymmetric synthesis. To this end, the reagents 6 and 8 were required. The β-keto thio ester 6 was prepared from the Meldrum’s acid 4, and the phosphonate 8 was derived from methyl sorbate 7.

The acetal of citronellal 9 was ozonized with reductive work-up to give the alcohol 10. Protection followed by hydrolysis gave the aldehyde 11, that was condensed with 8 to give the triene 12. Deprotection followed by oxidation delivered an aldehyde, that was condensed with 6 to give the Diels-Alder precursor 1.

With BF3•OEt2 catalysis, the Diels-Alder cycloaddition proceeded under mild conditions, -40C for forty minutes, leading to 2 as a single diastereomer. Comparable intramolecular Diels-Alder cyclizations with single carbonyl activation gave mixtures of diastereomers.

The alcohol 13 was prepared by transesterification of 2 with trifluoroethanol. Activation with MsCl led directly to the kinetic O-alkylation product 14. Following the precedent of Trost (J. Am. Chem. Soc. 1980, 102, 2840. DOI: 10.1021/ja00528a055), exposure to a Pd catalyst smoothly converted 14 into 15, as the desired diastereomer.

Condensation of the ester 15 with the amine 16 gave the diene 17. Selective oxidation of the monosubstituted alkene under Wacker conditions gave the ketone, that was reduced selectively by the Luche protocol to the alcohol 18. Exposure of 18 to NaOCH3 initiated Dieckmann cyclization, leading to (-)-Fusarisetin A (3).

D. F. Taber, Org. Chem. Highlights 2013, February 4.