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A simple route to polyenes.

Organic chemists attempt to mimic desaturase enzymes with a copper catalyst.

Go to the profile of Giovanni Bottari
Feb 01, 2018
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Polyene molecules are widely distributed in Nature, for example in long-chain fatty acids, vitamins, pigments, moreover highly conjugated structures are also found in antibiotics, such as Amphotericin B. The biosynthetic pathways to long carbon chains with multiple unsaturations feature high atom economy and efficiency, two aspects that synthetic chemists pursue diligently in their labs. However, dehydrogenation reactions perfomed in the lab rarely proceed further after the first unsaturation is formed, for example at the acidic and reactive α position of a carbonyl compound. Palladium and iridium catalysts have shown great potential in the dehydrogenation of simple linear and cyclic alkanes to aromatic compounds (benzenes, phenols, N-heterocycles). Despite the progress in this area of catalysis, additional challenges involve the use of less expensive metals and new mechanisms that not only would allow to access aromatic compounds, but also linear highly conjugated polyolefins. Weiping Su and coworkers took up both challenges and in their recent Nature Communications paper describe an operationally simple copper-catalyzed strategy for the sequential dehydrogenation of carbonyl compounds, alcohols and amines to highly unsaturated compounds.

How does the sequential dehydrogenation process work?

The process starts with α,β-desaturation of a reactive site of the molecule. Remarkably, the dehydrogenation reactivity of the α-carbon can be transferred through carbon–carbon double bond or a longer π-system to the carbons at the positions γ, ε, and η to carbonyls.. T Consecutive dehydrogenations take place via polarization/activation of C-H bonds next to the newly formed unsaturation, impressively mimicking the job of desaturase enzymes. The intermediates are more readily oxidized than the starting materials due to the greater stabilization provided by the increased conjugation of the intermediate radical. While the α,β-desaturation of carbonyl compounds, reported by the same authors in a precedent work, was somewhat expected, the current study goes far beyond the formation of enones and shows the full potential of the “dehydrogenative desaturation-relay” strategy, as the authors define it.

Key features of this process are the suitable choice of a Cu/N-N ligand pair able to generate radicals via polarization of Csp3-H bonds and an oxidant (TEMPO) responsible for the net “dehydrogenation”. The substrates are cooked with the above components under inert atmosphere and the products are isolated in moderate to good yields. The methodology is applicable to ketones, aldehydes, alcohols which are converted to dienes, trienes and, more in general, polyenes; additionally tetrahydroquinolines and indolines are converted into the corresponding aromatic counterparts. It is noteworthy to observe the full aromatization of purely aliphatic cyclohexyl groups to benzene rings. As polyenes are common motifs in natural compounds, Su and coworkers targeted two complex molecules: lignarenone B and navenone B, two alarm feromones. The two compounds were isolated in modest overall yields via a simple two-step (instead of seven or more) synthesis comprising the new copper-catalyzed successive dehydrogenation and a Wittig olefination. Remarkably, the methodology shows a high degree of stereocontrol in the polyene formation with exclusive formation of E-isomers which, as an additional bonus, are naturally predominant.

The authors have attempted a mechanistic rationalization of this useful process and trapped some hypothesized radical intermediates of the consecutive dehydrogenations confirming the key role of remote π-stabilized radical species.

This work is expected to greatly stimulate future research on remote functionalization via cascade processes involving the π-stabilization of radical intermediates and the organic chemistry community will certainly benefit from the application of this methodology to the synthesis of natural products.

The full paper can be found here: https://www.nature.com/articles/s41467-017-02381-8

 

Go to the profile of Giovanni Bottari

Giovanni Bottari

Associate Editor, Springer Nature

Giovanni joined Nature Communications in January 2017. During his past research experience, he focused on the development of homogeneous catalysts, in particular for stereoselective hydrogenation and C-C/C-heteroatom bond formation, and heterogeneous catalysts for biomass conversion. Giovanni is based in the London office, where he handles organic chemistry and homogeneous catalysis.

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