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One-step method determines reaction products’ yield, enantiomeric excess, and configuration

Technique accelerates evaluation of amine-containing chiral compounds

by Stu Borman
October 19, 2016 | A version of this story appeared in Volume 94, Issue 42

Reaction scheme shows how amine products form complexes that enable their ee, absolute configuration, and yield to be measured directly in a single step.
A complexation reaction forms a Schiff base with an amine, enabling measurement of yield, enantiomeric excess, and absolute configuration in a single step.

A new technique makes it much easier and cheaper to determine key characteristics of amine-containing chiral compounds synthesized individually or in parallel. The technique, which measures product yield, enantiomeric excess (ee), and absolute configuration in one step, could find widespread use in organic chemistry laboratories, including in drug discovery.

Chemists typically determine product yield by isolating synthesized compounds and weighing them. They generally measure ee by analyzing reaction products with chiral high-performance liquid chromatography and absolute configuration by using nuclear magnetic resonance spectroscopy or X-ray crystallography. These techniques are time-consuming, use large amounts of solvents and reagents, and are impractical for analyzing thousands of samples synthesized in parallel.

Christian Wolf and grad student Zeus A. De los Santos at Georgetown University have now developed a complexation reaction that makes it possible to analyze the yield, ee, and absolute configuration of amine-containing chiral products in a single step, without having to isolate the compounds (J. Am. Chem. Soc. 2016, DOI: 10.1021/jacs.6b08892). In the reaction, a carbonyl-containing ligand, in the presence of palladium acetate, forms a Schiff base with amine groups in the compounds to be analyzed.

The researchers then use circular dichroism (CD) and ultraviolet (UV) spectroscopy to directly analyze as little as 1 mg of each complexation reaction mixture. The technique works because the complexes produce much stronger and higher-wavelength CD and UV signals than the original amine groups, making it possible to use CD to measure ee and absolute configuration and UV to assess product yield without substantial interference from signals associated with other molecules in the mixtures. The method can be automated for high-throughput operation, Wolf says.

“The direct analysis of crude asymmetric reaction mixtures is a long-sought goal in the synthetic community,” comments Vadim A. Soloshonok of the University of the Basque Country, whose group developed an earlier version of the complexation reaction. The new approach “has the potential to significantly speed up reaction development at reduced cost and waste production in thousands of industrial and academic laboratories,” he says. The assay has wide substrate scope because many important chiral compounds have amine groups.

Eric Anslyn of the University of Texas, Austin, an expert on ee determination and the editor who handled the Wolf group’s JACS paper, says the technique “is far easier, far more rapid, and involves less waste and effort than current methods.” It is broadly applicable and of great utility, Anslyn adds.



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