Total Synthesis of Gelsemium Alkaloids and Synthesis of Ketohydroperoxides

The Gelsemium alkaloids were first isolated from Gelsemium elegans and sempervirens in the 1870s. Despite their acute toxicity, they were documented for their potent analgesic properties and were first used in traditional Asian medicine. Our group achieved the first total synthesis of gelsenicine in 2016 using an Au(I)-catalyzed cycloisomerization/Cope rearrangement to forge the oxabicyclo[3.2.2]nonane skeletal core, representative of the gelsedine, humantenine, and other structural-type families.¹ After this key transformation, we converted the alkyne into an ethyl ketone for pyrroline formation, paving the way to gelsenicine and gelsedine. Recently, we have demonstrated an enantioselective version of this total synthesis to access (+)-gelsenicine enabled by asymmetric catalysis.² The modularity of a “Common Core” strategy allows us to convert an alkyne into a different functional group handle, allowing divergency to different structural types, including gelsemine and gelsevirine. This seminar will present the current progress of this “Common Core” strategy, establishing a platform to maximize availability to different structural family of gelsemium alkaloids, specifically gelsemine and gelsevirine. 

Ketohydroperoxides (KHPs) was a class of organic compound structurally features a presence of both hydroperoxide and carbonyl. KHPs was hypothesized as a key precursor in the chain-branching stage of the low temperature oxidation process of the hydrocarbon fuel reported by Korcek and coworker in 1979.³ Chain-branching stage is still an unknown process with a lack of direct study. Collaborated with the combustion study from Rotavera lab (UGA), we envisioned a chemically synthesized ketohydroperoxide as a singular components would provide an opportunity for the chemical kinetics or the mechanistic study of this elusive process. This seminar would present a multigram-scale synthesis of such metastable KHP species as a singular conponent⁴ with an improved Caglioti procedure5 of alkyl hydroperoxide species from alkyl hydrazine and a potential general access to ketohydroperoxide. 

Reference 

1. Newcomb, E. T.; Knutson, P. C.; Pedersen, B. A.; Ferreira, E. M. J. Am. Chem. Soc. 2016, 138, 108-111.
2. Knutson, P. C.; Ji, H.; Harrington, C. M.; Ke, Y.-T.; Ferreira, E. M. Org. Lett. 2022, 24, 4971-4976.
3. Jensen, R. K.; Korcek, S.; Mahoney, L. R.; Zinbo, M. J. Am. Chem. Soc. 1979, 101, 7574-7584.
4. Ke, Y.-T., Gall, B. K.; Dewey, N. S.; Rotavera, B.; Ferreira, E. M. Chem. Eur. J. 2022, 28, e202202266.
5. a) Caglioti, L. F.; Gasparrini F. G.; Palmieri, G. D.; Misiti, D. Tetrahedron Lett. 1976, 17, 3987-3988. b) Caglioti, L. F.; Gasparrini F. G.; Misiti, D.; Palmieri, G. D. Tetrahedron 1978, 34, 135-139.