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Organic Chemistry Highlights

Total Synthesis

Monday, August 6, 2012
Douglass F. Taber
University of Delaware

The Fukuyama Synthesis of Gelsemoxonine

The compact and highly functionalized Gelsemium alkaloids, exemplified by Gelsemine (The Overman Route to Gelsemine 2008, March 24) and Gelsemoxonine 3, offer a substantial challenge. The cytotoxicity of closely related alkaloids adds to the interest in this class. Tohru Fukuyama of the University of Tokyo envisioned (J. Am. Chem. Soc. 2011, 133, 17634. DOI: 10.1021/ja208617c) that cyclopropane-accelerated Cope rearrangement of 1 could deliver 2, ready for further functionalization to 3.

The starting material for the synthesis was the enantiomerically-pure acetate 4, for which a practical synthetic route was developed. Conjugate addition of 5 then proceeded away from the acetoxy group, to give, after intramolecular alkylation, the cyclopropane 6. Selective protection of the derived triol 7 led to a monopivalate that was oxidized to the keto aldehyde 8. Condensation with the oxindole 9 followed by silyation then completed the assembly of 1.

The trisubstituted alkene of 1 was established as a single geometric isomer. It followed that in the product 2, the oxindole and the bridging ether had the appropriate relative stereochemical arrangement. The product silyl enol ether was deprotected with fluoride to liberate the ketone 2.

With 2 in hand, the next challenge was the kinetic installation of the less stable secondary aminated stereogenic center. To this end, the aldehyde 10 was exposed to TMS-CN and DBU. Under the reaction conditions, the alkene of the intermediate β,γ-unsaturated silylated cyanohydrin was brought into conjugation. Kinetic quench with allyl alcohol gave 11 with a 4:1 preference for the desired endo diastereomer 11. Inversion of the carboxyl then led to the protected amine 12.

The ketone 12 was formylated under modified Vilsmeier-Haack conditions, first with Bredereck's reagent 13, then with oxalyl chloride, leading to the chloro aldehyde 14. The chlorine was removed by selective Pd-catalyzed reduction, and the product aldehyde was exposed to ethyl magnesium bromide followed by IBX to give the ethyl ketone 15. Epoxidation of the α,β-unsaturated ketone proceeded across the expected exo face, leading to 16. The deprotected amine then opened the epoxide to establish the aminated quaternary center and complete the synthesis of Gelsemoxonine 3.

This synthesis of 3 is an elegant illustration of designed stereochemical control. It is noteworthy that the secondary acetate of 4, that sets the absolute configuration of the final product, is not in that product, and in fact was removed as soon as it had served its purpose.

D. F. Taber, Org. Chem. Highlights 2012, August 6.