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Organic Chemistry Highlights

Total Synthesis

Monday, February 5, 2024
Douglass F. Taber
University of Delaware

The Suzuki/Tanino Synthesis of Kamebanin

Kamebanin (3), isolated from the Japanese flowering plant Isodon kameba Okuyama (Isodon umbrosus), showed cytotoxic and antibiotic activity. Takahiro Suzuki and Keiji Tanino of Hokkaido University devised a route to 3 based on the one-electron reduction and cyclization of the epoxide 1 to the tricyclic enone 2 (Chem. Eur. J. 2023, 29, e202203511. DOI: 10.1002/chem.202203511).

The starting material for 1 was the cyclohexenone 4. Reduction followed by Eschenmoser-Claisen rearrangement with 5 led to the amide 6. Epoxidation followed by reduction with the Schwartz reagent gave the aldehyde 7, that was combined with the alkenyl lithium reagent 8, leading after hydrolysis to 1.

The cyclization of 1 presumably proceeded by initial formation of the tertiary free radical 9. Cyclization followed by dehydration then gave 2.

The secondary alcohol of 2 was protected, then addition of lithioacetonitrile followed by hydroxyl-directed epoxidation delivered the tertiary alcohol 10. This set the stage for the construction of the last cyclic quaternary center of 3 by the net 1,2-migration of the cyanomethyl group, leading to 11. Protection followed by cyclization led to the diketone 12. Selective methylenation followed by reduction gave the alkene 13, that was oxidized and deprotected to give kamebanin (3).

Several years ago, Makato Fujita of the University of Tokyo reported the use of a crystalline sponge to enable x-ray structural analysis of oily substances (C-N Ring Construction: The Makabe Synthesis of Isosolenopsin 2017, November 13). Later, Professor Fujita updated this approach (Org. Lett. 2021, 23, 9288. DOI: 10.1021/acs.orglett.1c03660). René de Gelder of Radboud University developed a water-stable crystalline sponge (Chem. Eur. J. 2019, 25, 14999. DOI: 10.1002/chem.201904174). More recently, Shanming Kuang and Jian Wang of J-STAR Research, Sivakumar Sekharan of XtalPl and Jessica F. Bruhn of Nanolmaging Services described the of microcrystal electron diffraction of cocrystal powders to assign the absolute configuration of APIs (Chem. Eur. J. 2023, 29, e202203970. DOI: 10.1002/chem.202203970).

D. F. Taber, Org. Chem. Highlights 2024, February 5.