Absolute Configuration of Secondary Alcohols by ¹H NMR:  In Situ Complexation of α-Methoxyphenylacetic Acid Esters with Barium(II)

Abstract

A novel methodology that allows the assignment of the absolute configuration of chiral secondary alcohols by NMR using only one derivative is presented. All that is needed is (a) the derivatization of the alcohol of unknown configuration with one enantiomer--either the (R)- or the (S)--of alpha-methoxyphenylacetic acid (MPA), (b) the recording of the 1H NMR spectrum of the resulting ester in MeCN-d3, and (c) addition of a barium(II) salt [i.e. Ba(ClO4)2] to the NMR tube till saturation and recording of a second spectrum. The assignment of the R/S configuration to the alcohol takes a few minutes and consists on the comparison of the signs of the shifts (Deltadelta(Ba)) produced by addition of the barium(II) with those predicted for the (R) and the (S) enantiomers in accordance to a simplified model that reflects the conformational changes produced by the complexation with barium and their consequences in the chemical shifts. These conformational changes are based on experimental NMR and CD results showing that the formation of a barium(II) complex with the MPA ester moves the conformational equilibrium between syn- (sp) and anti-periplanar (ap) forms toward the most stable ones (sp), and that this leads to the increase of the shielding caused by the MPA phenyl group on a certain substituent of the alcohol. In addition, ab initio Hartree-Fock (HF) and density functional theory (DFT) calculations provide further evidence on the formation, structure, and stability of the complexes with Ba2+, Mg2+, and the influence of the solvent. The general applicability of this methodology and the reliability of the configurational assignment were assured by the study of about twenty alcohols of known configuration and diverse structural features. Its scope and limitations have also being established and other representative cations (i.e. Li+, Rb+, Cs+, Mg2+, Ca2+, Sc3+, V3+, Zn2+) were also evaluated. The procedure proposed is simple, fast, and cheap because it requires a very small amount of sample, only one derivatization, and the recording of only two 1H NMR spectra at rt. A graphical guide to facilitate the application of this new method is included at the end of the paper.

Chiral reagents for the determination of enantiomeric excess and absolute configuration using NMR spectroscopy

“…23 The resulting esters or amides exist in two conformers, the sp and ap form. [24][25][26] The Ba(II) associates with the ester and stabilizes the sp conformer, as illustrated in Figure 3. For the two enantiomers, caution is needed when interpreting the data and a similar anthryl derivative [1-(10-bromo-1-anthryl)-2naphthoic acid] provided more reliable results.…”

“…For these derivatives, the sp form is dominant; however, the NMR spectrum of the ap form shows a greater distinction. 26 Optically pure, primary amines are often used as CDAs for carboxylic acids. 23 A similar conformational preference is observed with the MPA esters of alcohols and amines.…”

Assignment of absolute configuration using chiral reagents and NMR spectroscopy

“…143 MTPA has also been used to assign the configuration of compounds with a chiral center b to the amine. In this case, specific trends in the 19 F signals of the CF 3 group were used to make the assignment. 146 In contrast to MTPA, MPA derivatives of primary amines show a preference for the ap conformation.…”

“…In the absence of other donor atoms, the lanthanide ion binds in a chelate manner through the carbonyl and methoxy oxygen atoms. In many cases, the relative magnitudes of the lanthanideinduced shifts of either the 19 F signal of the CF 3 group of 1 H resonance of the methoxy group correlate with the absolute configuration. 20,21 Paramagnetic chelates cause line broaden- ing that is exacerbated at higher field strengths, which may preclude the use of this method in assigning absolute configuration on some NMR spectrometers.…”

Mycophenolic Derivatives from Eupenicillium parvum

“…The absolute stereochemistry was assigned for 5 , using Riguera’s method for the determination of the absolute stereochemistry of secondary alcohols. (11) Thus, compound 5 was converted to a methyl ester ( 6 ) with TMSCHN 2 , which also methylated the phenol group. Then, the methyl ester was treated with DMAP, DCC, and ( S )-MPA reagent in dry CH 2 Cl 2 .…”