Conia-ene Nostalgia

I’ve seen very recently a nice review on the Conia-ene reaction by Dieter Enders and co-workers and I couldn’t avoid feeling some nostalgia. A very important part of my PhD project was related to the Conia-ene reaction so today I felt like wanting to write a few lines in a post…

nostalgia

The Conia-ene reaction was, at its origins, a thermal cyclization reaction of unsaturated carbonyl compounds usually in an exo mode. An intramolecular cousin of the Ene Reaction. This reaction usually required temperatures in excess of 300 oC limiting its utility in the synthesis of complex molecules.

conia mechanism

The potential of the Conia-ene reaction attracted the interest of many groups on the development of milder variants. We can find very encouraging contributions in the literature of Conia-ene reactions catalysed at much lower temperatures by Mo, Sn, Ti, Pd, Hg or Co, however these reactions usually required hard conditions in the presence of acid, bases, photochemical activation and were limited to the exo cyclization mode.

endo vs exo

It wasn’t until the seminal works of Toste’s group using the catalytic system AuPPh3Cl/ AgOTf that we can find a general method at room temperature that can lead to both endo and exo cyclization modes.

It seems natural that the next step in the study of a reaction is an enantioselective variant. Toste and co-workers, always one step ahead, developed in 2005 the first asymmetric version of the Conia-ene reaction. The strategy: Electrophilic activation of the acetylenic moiety of b-Ketoesters with a DTBM-SEGPHOS Palladium complex as chiral promoter in the presence of the Lewis acid Yb(OTf)3.

chiral strategies

A different approach is the generation of a chiral enolate. Dixon and co-workers used this strategy in their work by combining Cu(OTf)2 with a Brønsted base.

enantioselective conia

The Conia-ene reaction has proved to be a very useful synthetic tool toward the synthesis of cyclopentanoid products. Just to name one example (of many), Toste’s group application to the synthesis of (+)-Lycopladine A.

Conia aplicacion sintesis

Do you want to know more? Take a look to these papers:

The review of the nostalgia:

Catalytic Conia-ene and related reactions. Daniel Hack, Marcus Blümel, Pankaj Chauhan, Arne R. Philipps and Dieter Enders, Chem. Soc. Rev., 2015,44, 6059-6093

Where it all begun:

The Thermal Cyclisation of Unsaturated Carbonyl Compounds. J. M. Conia, P. Le Perchec, Synthesis 1975, 1 – 19

Seminal works in gold catalysis

Gold(I)-Catalyzed 5-endo-dig Carbocyclization of Acetylenic Dicarbonyl Compounds. Steven T. Staben, Joshua J. Kennedy-Smith andF. Dean Toste, Angew. Chem. Int. Ed. 2004, 43, 5350 –5352.

Gold(I)-Catalyzed Conia-Ene Reaction of β-Ketoesters with Alkynes. Joshua J. Kennedy-Smith , Steven T. Staben , and F. Dean Toste, J. Am. Chem. Soc., 2004, 126, 4526–4527.

Enantioselective Conia-eno

Catalytic Enantioselective Conia-Ene Reaction. Britton K. Corkey and F. Dean Toste, J. Am. Chem. Soc., 2005, 127,17168–17169.

Brønsted Base/Lewis Acid Cooperative Catalysis in the Enantioselective Conia-Ene Reaction. Ting Yang, Alessandro Ferrali, Filippo Sladojevich, Leonie Campbell and Darren J. Dixon. J. Am. Chem. Soc., 2009, 131 (26), 9140–9141.

And a bonus track, one application in synthesis

Gold(I)-Catalyzed Cyclizations of Silyl Enol Ethers: Application to the Synthesis of (+)-Lycopladine A. Steven T. Staben, Joshua J. Kennedy-Smith, David Huang, Britton K. Corkey, Rebecca L. LaLonde andF. Dean Toste. Angew. Chem., Int. Ed., 2006,45, 5991.

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