A Facile Circular Dichroism Protocol for Rapid Determination of Enantiomeric Excess and Concentration of Chiral Primary Amines

Abstract

A protocol for the rapid determination of the absolute configuration and enantiomeric excess of α-chiral primary amines with potential applications in asymmetric reaction discovery has been developed. The protocol requires derivatization of α-chiral primary amines via condensation with pyridine carboxaldehyde to quantitatively yield the corresponding imine. The Cu(I) complex with 2,2'-bis (diphenylphosphino)-1,1'-dinaphthyl (BINAP -Cu I ) with the imine yields a metal-toligand-charge-transfer band (MLCT) in the visible region of the circular dichroism spectrum upon binding. Diastereomeric host-guest complexes give CD signals of the same signs, but different amplitudes, allowing for differentiation of enantiomers. Processing the primary optical data from the CD spectrum with linear discriminant analysis (LDA) allows for the determination of absolute configuration and identification of the amines, and processing with a supervised multi-layer perceptron artifical neural network (MLP-ANN) allows for the simultaneous determination of ee and concentration. The primary optical data necessary to determine the ee of unknown samples is obtained in 2 minutes per sample. To demonstrate the utility of the protocol in asymmetric reaction discovery, the ee's and concentrations for an asymmetric metal catalyzed reaction are determined. The potential of the protocol's application in high-throughput screening (HTS) of ee is discussed.

Determination of Enantiomeric Excess in Amine Derivatives with Molecular Self‐Assemblies

“…[8] Alas,t hese methods require high concentrations of analytes,s trict conditions,a nd-with few exceptions-are too slow for high throughput-screening (HTS). [9] Fort he above reasons we have decided to develop as ensitive and HTS-amenable assay for chiral amines and their derivatives.W et ake advantage of at ernary system comprising an a-chiral primary amine,2 -formylphenylboronic acid (FPBA), and enantiomerically pure 1,1'-bi-2-naphthol (BINOL), which assemble rapidly and lead to characteristic 1 HNMR spectroscopic shifts for each enantiomer of the amine (Scheme 1). [10] This system has also been employed for determination of ee values by using electrochemical [11] or CD methods.…”

Chiral Amine Enantiomeric Excess Determination Using Self‐Assembled Octahedral Fe(II)‐Imine Complexes

“…13 CD spectroscopy with can be used in the analysis of a wide variety of chiral analytes such as carboxylic acids, 12,14 aldehydes, 15 ketones, 16 alcohols, 17 aminoalcohols, 3 and amines, 18- 22 through assembly of optically responsive receptors.…”

In Situ Assembly of Octahedral Fe(II) Complexes for the Enantiomeric Excess Determination of Chiral Amines Using Circular Dichroism Spectroscopy

“…23–33 Measurements taken with optical instrumentation are typically fast, allowing for high-throughput. Further, the supramolecular receptors are inexpensive and can interact with a wide range of analytes.…”