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Organic Chemistry Highlights

Total Synthesis

Monday, June 1, 2020
Douglass F. Taber
University of Delaware

The Snyder Synthesis of Conidiogenone

Conidiation of the filamentous fungus Penicillium cyclopium has been shown to be induced by an endogenously produced terpene mediator, conidiogenone (3). The route to 3 developed by Scott A. Snyder of the University of Chicago is a tour de force of transition metal-mediated carbocyclic construction, as exemplified by the cyclization of 1 to 2 (Nature 2019, 569, 703. DOI: 10.1038/s41586-019-1179-2).

The starting material for the preparation of 1 was the commercial vinylogous ester 4. Addition of 5 followed by hydrolysis delivered 6. Conjugate addition following the Hoveyda protocol then set the absolute configuration of 7, and so of 3. Regioselective enol ether formation followed by oxidation led to the enone 8, that was cyclized to 9. Alkylation of the derived hydrazone with 10 gave 11, that was carried on to 1.

The cyclization of 1 presumably proceeded via initial oxidative addition to the alkenyl triflate. Interaction of the resulting organopalladium intermediate with the vinyl group of 1 then occured across the more open face of the bicyclic system, leading, after acetate methanolysis, to the desired alcohol 2.

Oxidation of 2 to the aldehyde followed by coupling with 12 led to 13 as a 3:1 mixture of diastereomers. Reductive Heck cyclization of the major diastereomer followed by desilyation with TBAF delivered the tetracycle 14. Catalytic hydrogenation followed by oxidation then led to the enone 15. Nucleophilic epoxidation gave 16, that was selectively reduced to complete the synthesis of conidiogenone (3).

Many transformations depend on stoichiometric triphenylphosphine. Daniel J. Weix of the University of Wisconsin has shown that complexation with ZnCl2 will remove triphenylphosphine oxide, even from polar solvents (J. Org. Chem. 2017, 82, 9931. DOI: 10.1021/acs.joc.7b00459).

D. F. Taber, Org. Chem. Highlights 2020, June 1.