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Organic Chemistry Highlights

Total Synthesis

Monday, February 5, 2018
Douglass F. Taber
University of Delaware

The Sato/Chida Synthesis of Madangamine A

Madangamine A (3) was isolated from the marine sponge Xestospongia ingens. Takaaki Sato and Noritaka Chida of Keio University envisioned (J. Am. Chem. Soc. 2017, 139, 2952. DOI: 10.1021/jacs.7b00807) the silyl-Mannich cyclization of 1 to 2 to assemble the tricyclic core of 3.

The requisite 12-carbon bridge of 3 was prepared from the alkyne 4. Coupling with 5 led to 6, that was reduced to the (Z, Z)-diene 7. Skipped-conjugation dienes such as 7 are often degraded by Pd catalysts, so the hydrogenation was effected with catalytic Ni. The derived phosphonium salt 8 was readily purified by silica gel chromatography.

The Pd-catalyzed combination of the alkyne 9 with the ketone 10 led to a 10:1 mixture of regioisomers, with the desired enone 11 predominating. Itsuno-Corey reduction set the absolute configuration, leading, after desilylation and Steglich esterification, to 12. The quaternary center of 1 was then established by Cu-mediated coupling of 13, leading to 14. This was combined with 15 to give 16, that was cyclized to 17. Reduction to 18 followed by conversion to the alkyne 19 and alkylation with 20 gave 1.

Exposure of 1 to acid converted it to 2. Hydroboration of the allene from the more open face led to 21, that was coupled with the stannane 22 to give 23. After the first macrocyclic ring was closed by intramolecular acylation, desilylation followed by oxidation led to 24. Wittig reaction with the phosphonium salt 8 led to the intermediate amino alcohol, that was induced to cyclize by warming the derived tosylate with Hunig's base in CH3CN. Reduction then completed the synthesis of madangamine A (3).

Through the course of this synthesis, the geometry of the skipped conjugation dienes was monitored by 1H nOe measurements. The 13C chemical shift of the linking CH2 is also a reliable reporter of skipped conjugation diene geometry (J. Org. Chem. 1995, 60, 139). DOI: 10.1021/jo00106a026)

We recognize the many creative contributions to organic synthesis by Theodore Cohen of the University of Pittsburgh (May 11, 1929 - December 13, 2017). His work was most recently highlighted in these pages May 16, 2016 ().

D. F. Taber, Org. Chem. Highlights 2018, February 5.