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Organic Chemistry Highlights

Total Synthesis

Monday, July 1, 2019
Douglass F. Taber
University of Delaware

The Liang Synthesis of Trichorabdal A and Maoecrystal Z

Trichorabdal A (3), isolated from the Japanese perennial Rabdosia trichocarpa, shows nanomolar cytotoxicity against HeLa cells. The synthesis of 3 developed by Guangxin Liang of Nankai University illustrates the power of radical cyclization for constructing cyclic quaternary centers, as exemplified by the cyclization of 1 to 2 (Chem. Eur. J. 2018, 24, 9773. DOI: 10.1002/chem.201802083).

Deprotonation of β-cyclogeranic acid methyl ester (4) followed by addition to the aldehyde 5 led to the lactone 6. Deprotection followed by cyclization then delivered 2. This preparation of the crystalline 2 was readily carried out on a decagram scale.

Reductive dearomatization of 2 failed, so oxidative dearomatization was employed to convert 2 to 7. Radical cyclization of the iodo hemiacetal derived from combining 8 with 7 also failed, but selective conjugate addition of thiophenol at low temperature led to an intermediate that could be converted cleanly to 9, establishing the second cyclic quaternary center of 3.

Oxidation of 9 followed by enol ether formation led to lactone 10, that was reduced to the corresponding diol, then oxidized to the keto aldehyde. Selective reaction with the Seyferth-Gilbert reagent (11) then completed the assembly of the alkyne 12. After deprotection of the enone, radical cyclization followed by overnight exposure to silica gel delivered 13. Reductive cleavage of the ether led to a hemiketal, that was reduced to the triol, then oxidized to the axial aldehyde 14. This was equilibrated to the more stable equatorial aldehyde 15.

The last stage was reductive cleavage of the cyclopentanone. To this end, reduction gave the diol, that was selectively protected, to give 16. Oxygenation of the enolate with followed by reduction completed the conversion to the lactone and also deprotected the primary alcohol, to give 17. The last allylic oxidation was effected with SeO2, leading to 3.

It is noteworthy that the aldehyde derived from 17 was also converted, via allylic oxidation and a retroaldol/aldol transformation, to maoecrystal Z (18). These two oxidized Isodon diterpenoids are likely biosynthetically related.

D. F. Taber, Org. Chem. Highlights 2019, July 1.