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Organic Chemistry Highlights

Total Synthesis

Monday, December 4, 2017
Douglass F. Taber
University of Delaware

The Ding Synthesis of Pharicin A

The densely-functionalized ent-kaurenoid pharicin A (3) perturbs mitotic progression and intiates mitotic catastrophe. Hanfeng Ding of Zhejiang University envisioned (J. Am. Chem. Soc. 2017, 139, 6098. DOI: 10.1021/jacs.7b02746) assembling 3 by the oxidative cylization of 1 to the tetracyclic 2.

The ready availability of the enantiomerically-pure bicyclic enone 4 incorporating many of the elements of 1 suggested a ring-cleaving approach. To this end, the diketone 4, prepared by the literature method and brought to 95% ee by recrystallization, was ketalized, then submitted to reductive alkylation to give 5. Reduction to the axial alcohol by L-selectride followed by deketalization and acetylation gave 6. Oxidation to the cyclohexenone followed by nucleophilic epoxidation gave 7, that was fragmented by the Tanabe modification of the Eschenmoser protocol, leading, after selective hydrogenation, to the aldehyde 9. The aryl lithium generated by the addition of two equivalents of n-Buli to 10 added to 9 to give 1 and its readily-separated diastereomer, that was converted to 1 by oxidation followed by reduction.

On exposure to PhI(OTFA)2 in hexafluoroisopropanol, following the conditions developed by the authors, the alcohol 1 was smoothly converted into the diketone 2. This conversion was thought to proceed by way of 5+2 cycloaddition to the carbocation 11, followed by 1,2-acyl shift.

To complete the synthesis of 3, it was necessary to adjust the relative configuration of the secondary alcohol of 2, and differentiate the two ketones. To this end, oxidation to the triketone followed by global reduction gave the triol 12. Selective acetylation of the most accesible alcohol followed by oxidation of the next most accesible alcohol led to the ketone 13. On brief exposure to acid, the last of the secondary alcohols was inverted by a retro-aldol/aldol process. The ketone was then reduced to the alcohol 14. Photochemically-driven allylic oxidation led to an intermediate hydroperoxide, that on exposure to trichloroisocyanuric acid was carried on to pharicin A (3).

D. F. Taber, Org. Chem. Highlights 2017, December 4.