All four corners: NMR and chiral carbons

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  • Published: Apr 15, 2016
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: All four corners: NMR and chiral carbons

It's going to be mild

Prof. Paolo Melchiorre (left), Dr. John J. Murphy, Dr. David Bastida and Dr. Suva Pavia at the Institute of Chemical Research of Catalonia. CREDIT Credit: Institute of Chemical Research of Catalonia

A new approach to chiral synthesis that works under mild conditions has been validated with nuclear magnetic resonance (NMR) spectroscopy and other tools by scientists in Europe. Paolo Melchiorre of ICIQ, Institute of Chemical Research oOf Catalonia, and colleagues developed the technique using enantioselective iminium ion chemistry and photoredox catalysis to form quaternary carbon stereocentres with high enantioselectivity.

Chiral compounds with quaternary stereocentres on a carbon atom (i.e. chiral carbons attached to four other carbons) are a critical part of chemistry, in particular the chemistry of more selective and safer pharmaceuticals, and of novel agrochemicals. Finding ways to construct chiral centres efficiently, under mild conditions and with minimal waste and great enantioselective yields has been a major focus of organic chemists for many years. As such, the work of Melchiorre's group represents a breakthrough in the synthesis of chiral molecules as it manages to perform the selective synthesis of the desired molecule via a new radical route that combines the action of a photocatalyst activated by visible light with a chiral organic catalyst.

"Key to success was the design of a chiral organic catalyst which drives the stereoselective interception of photochemically generated carbon-centred radicals," Melchiorre explains. "This catalyst may provide further opportunities to stereoselectively generate quaternary stereocentres that cannot be forged by using traditional polar reactivity. We are currently exploring these possibilities."

Sidestepping the common

A common approach to the synthesis of chiral molecules involves the use of chiral organometallic compounds, but these can be costly and require carefully controlled reaction conditions. The ICIQ team - Melchiorre, John Murphy, David Bastida and Suva Paria working with Maurizio Fagnoni from the University of Pavia, however, has found a way to perform the reaction under mild conditions using visible light photocatalysis and a metal-free organocatalytic process. Melchiorre's work potentially provides a new framework for enantioselective organocatalytic synthesis.

"Combining the potential of metal-free enantioselective organocatalysis and visible light photocatalysis can significantly advance the development of a more responsible and sustainable stereoselective chemistry while strengthening the chemistry toolbox to better face the challenges of modern organic chemistry," adds Melchiorre.

Crucially chiral

The team explains that crucial to their success was that they could design a chiral organic catalyst, containing a redox-active carbazole moiety. It was this that drives the formation of iminium ions and the stereoselective trapping of photochemically generated carbon-centred radicals through an electron-relay mechanism. "We have developed the first (to our knowledge) catalytic strategy that allows quaternary carbon stereocentres to be obtained with high fidelity using an enantioselective radical conjugate addition manifold. The approach requires mild conditions and unfunctionalized substrates, effectively complementing established polar conjugate addition technologies based on preformed organometallic reagents," the team says.

"By translating the tools governing the success of enantioselective iminium ion catalysis into the realm of photo-triggered radical reactivity, we can provide novel catalytic frameworks for making quaternary carbon stereocentres using light, "Melchiorre told SpectroscopyNOW. "This may expand the way organic chemists think about making chiral molecules using environmentally respectful chemical processes."

Related Links

Nature 2016, 532, 218–222: "Asymmetric catalytic formation of quaternary carbons by iminium ion trapping of radicals"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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