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. 2020 Apr 6;59(15):6115-6121.
doi: 10.1002/anie.202000252. Epub 2020 Feb 25.

Cobalt-Catalyzed Hydrogen-Atom Transfer Induces Bicyclizations that Tolerate Electron-Rich and Electron-Deficient Intermediate Alkenes

Darius Vrubliauskas  1 , Christopher D Vanderwal  1
Affiliations

Cobalt-Catalyzed Hydrogen-Atom Transfer Induces Bicyclizations that Tolerate Electron-Rich and Electron-Deficient Intermediate Alkenes

Darius Vrubliauskas et al. Angew Chem Int Ed Engl. .

Abstract

A novel CoII -catalyzed polyene cyclization was developed that is uniquely effective when performed in hexafluoroisopropanol as the solvent. The process is presumably initiated by metal-catalyzed hydrogen-atom transfer (MHAT) to 1,1-disubstituted or monosubstituted alkenes, and the reaction is remarkable for its tolerance of internal alkenes bearing either electron-rich methyl or electron-deficient nitrile substituents. Electron-rich aromatic terminators are required in both cases. Terpenoid scaffolds with different substitution patterns are obtained with excellent diastereoselectivities, and the bioactive C20-oxidized abietane diterpenoid carnosaldehyde was made to showcase the utility of the nitrile-bearing products. Also provided are the results of several mechanistic experiments that suggest the process features an MHAT-induced radical bicyclization with late-stage oxidation to regenerate the aromatic terminator.

Keywords: cobalt; cyclizations; polycycles; reaction mechanisms; terpenoids.

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Figures

Figure 1.
Figure 1.
A. Atisane alkaloids and neotripterifordin inspired our efforts to develop bicyclization reactions with electron-withdrawing groups at C20.
Figure 2.
Figure 2.
Scope of the bicyclization of nitrile-substituted substrates (yields shown are for isolated and purified compounds). Boc: tert-butoxycarbonyl; Ts: para-toluenesulfonyl.
Figure 3.
Figure 3.
The reactivity of methyl-substituted substrates mirrors that of the corresponding nitrile-bearing compounds (yields shown are for isolated and purified compounds)
Figure 4.
Figure 4.
Stereochemical outcomes of bicyclizations initiated by HAT to monosubstituted alkenes (product ratios and yields determined using 1H NMR with an internal standard)
Scheme 1.
Scheme 1.
Plausible mechanistic options for bicyclization reactions
Scheme 2.
Scheme 2.
Attempted bicyclizations with acrylate esters as the internal alkene
Scheme 3.
Scheme 3.
An attempt to probe the intermediacy of cationic intermediates instead supports radical-based reactivity (yields shown are isolated yields of purified compounds)
Scheme 4.
Scheme 4.
Deuteration experiments suggest oxidation followed by proton transfer, rather than back MHAT, as the final stages of the reactions.
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