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. 2010 Jan 4;16(1):227-32.
doi: 10.1002/chem.200902650.

A facile circular dichroism protocol for rapid determination of enantiomeric excess and concentration of chiral primary amines

Sonia Nieto  1 , Justin M Dragna, Eric V Anslyn
Affiliations

A facile circular dichroism protocol for rapid determination of enantiomeric excess and concentration of chiral primary amines

Sonia Nieto et al. Chemistry. .

Abstract

A protocol for the rapid determination of the absolute configuration and enantiomeric excess (ee) of alpha-chiral primary amines with potential applications in asymmetric reaction discovery has been developed. The protocol requires derivatization of alpha-chiral primary amines through 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-to-ligand charge-transfer (MLCT) band in the visible region of the circular dichroism (CD) 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 the absolute configuration and identification of the amines, and processing with a supervised multilayer perceptron artificial neural network (MLP-ANN) allows for the simultaneous determination of the ee and concentration. The primary optical data necessary to determine the ee of unknown samples is obtained in two minutes per sample. To demonstrate the utility of the protocol in asymmetric reaction discovery, the ee values and concentrations for an asymmetric metal-catalyzed reaction are determined. The potential of the application of this protocol in high-throughput screening (HTS) of ee is discussed.

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Figures

Figure 1
Figure 1
(a) (R)- and (S)-1 complexes employed as receptors; (b) Chiral primary amines employed as analytes: a-methyl-benzylamine (MBA), 1-cyclohexyl-ethylamine (CEA), 2-aminoheptane (AHP).
Figure 2
Figure 2
(a) CD spectrum for (R)-1 [0.4 mM] and the enantiomers of CPI [0.8 mM]; (b) Titration of (R)-1 [0.4 mM] with (R)- and (S)-CPI in acetonitrile at 354 nm.
Figure 3
Figure 3
LDA plot of receptor (R)-1 [0.4 mM] with all the analytes [0.8 mM].
Figure 4
Figure 4
Two-dimensional PCA plot of CPI with three ee trainings sets at three different [G]t values: 0.2 mM, 0.8 mM and 1.4 mM.
Scheme 1
Scheme 1
Derivatization of the amines to form the corresponding Schiff bases.
Scheme 2
Scheme 2
Asymmetric reaction used to synthesize a sample of MBA of unknown ee.
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