Advertisement

If you have an ACS member number, please enter it here so we can link this account to your membership. (optional)

ACS values your privacy. By submitting your information, you are gaining access to C&EN and subscribing to our weekly newsletter. We use the information you provide to make your reading experience better, and we will never sell your data to third party members.

ENJOY UNLIMITED ACCES TO C&EN

Synthesis

Prized Piperidines, Pronto

Organic Synthesis: Proton-guided route generates densely substituted heterocycles

by Bethany Halford
February 11, 2013 | A version of this story appeared in Volume 91, Issue 6

QUICK COMPLEXITY
This scheme shows how many piperidines can be made.
A new method uses just a few short steps to make structurally complex compounds.

From a patient’s perspective, the pain reliever morphine, the antimalarial agent quinine, and the erectile dysfunction treatment tadalafil (Cialis) don’t have much in common. But to a chemist’s eyes, they share a structural similarity: Piperidine, the nonaromatic, nitrogen-containing six-membered ring, plays a starring role in each compound.

But making a wide variety of structurally diverse piperidines, which would create a multitude of drug candidates, has been a challenge. Chemists have now developed a way to make myriad piperidines from simple starting materials and with excellent regio- and stereochemical control (Science, DOI: 10.1126/science.1230704). Yale University’s Jonathan A. Ellman and colleagues used a modular synthesis route to make two dozen different piperidines with up to seven substituents each.

Each synthesis begins with a rhodium-catalyzed cascade reaction, which couples an imine to an alkyne—both readily available starting materials. The resulting azatriene undergoes electrocyclization to produce a densely substituted dihydropyridine. From there, Ellman and coworkers protonate the compound and add a nucleophile in one pot.

This last transformation can lead to a mix of isomers, but thanks to a key insight by postdoc Simon Duttwyler, the researchers realized they could control the regio- and stereochemistry of this transformation with the type of acid they use in the protonation step. Stronger acids preferably protonate at the imine’s α position, while weaker acids protonate at the imine’s γ position. The protonation site guides the subsequent nucleophilic addition, giving chemists a high degree of control over the ultimate products.

“One reason this work has particular appeal is the simplicity by which regio- and stereochemical control is achieved,” comments Mark Lautens, an organic synthesis expert at the University of Toronto. “As is typical, the most elegant solutions to a problem are those that are easy to do from a practical perspective and also give essentially one product. I expect that industry will rapidly adopt this methodology due to the value of the products and that it will stimulate others to examine other substrates to determine the generality.”

Advertisement

Article:

This article has been sent to the following recipient:

0 /1 FREE ARTICLES LEFT THIS MONTH Remaining
Chemistry matters. Join us to get the news you need.