Absolute configuration of amino alcohols by 1H-NMR (original) (raw)
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Organic Letters, 2003
[reaction: see text] A new methodology for determining absolute configurations by NMR in just a few minutes is presented. The required derivatives are obtained by mixing a solid matrix-bound auxiliary reagent (MPA, MTPA, or BPG) with the chiral substrate (primary amines or secondary alcohols) directly in the NMR tube. The NMR spectra of the derivatives are obtained without any type of separation, workup, or manipulation. The use of a 1:2 (R)/(S)-MPA resin permits the configurational assignment to be carried out with just one spectrum.
Discrimination of Chiral Compounds Using NMR Spectroscopy
The absolute configuration of a 1,2-primary/secondary diol can be easily determined by preparation of its bis-(R)-and bis-(S)-9-AMA ester derivatives, followed by comparison of the NMR chemical shifts of the diastereotopic methylene protons in the two derivatives. Alternatively, the assignment can be carried out using only one derivative if the evolution with temperature of the signals corresponding to the CrH protons is analyzed. The assignment of the absolute configuration of a chiral substrate by 1 H NMR using a chiral derivatizating agent (CDA) is a well-established technique. 1 The general method, derived from the pioneering "Mosher-Trost Method", 1,2 consists of the derivatization of the chiral substrate (i.e., alcohol, amine, thiol, etc.) with the two enantiomers of a CDA (i.e., MPA: 2-methoxy-2-phenylacetic acid; 9-AMA: 2-(anthracen-9-yl)-2-methoxy-acetic acid; MTPA: 2-methoxy-2-trifluoromethyl-2-phenyl-acetic acid), followed by the comparison of the chemical shifts of the protons in the substrate moiety of the two resulting derivatives. 1 The full proton assignment in molecules with complex structure (sugars, policyclic compounds, etc.) usually requires the combination of multiple NMR techniques such as TOCSY, COSY, NOESY, etc., a fact that can make tedious the assignment of the absolute configuration by NMR. A second limitation is the need to prepare two diastereomeric derivatives from a sample that sometimes is very small. Fortunately, for some functional groups, the configuration can be determined by using only one derivative with an appropriate CDA. 3 In this communication, we will demonstrate with the help of theoretical and empirical studies that in the case of chiral 1,2-primary/secondary diols both limitations can be circum-(1) (a) Seco, J. M.; Quiñoá, E.; Riguera, R.
Assignment of the Absolute Configuration of -Chiral Primary Alcohols by NMR: Scope and Limitations
The prediction of the absolute configuration of-chiral primary alcohols from the 1 H NMR spectra of their esters with (R)-and (S)-9-anthrylmethoxyacetic acids (9-AMA, 3) is discussed. Low-temperature NMR experiments, MM, semiempirical, ab initio, and aromatic shielding effect calculations allowed the identification of the main conformers and showed that, in all alcohols for which the calculated ∆E ag (CVff) is in the range of 0.7-1.5 kcal/mol, conformer a/a is the most stable. A simple model for the assignment of the absolute configuration from NMR data is presented and its reliability corroborated with alcohols (8-20) of known configuration. Nevertheless, cyclic alcohols 21-23 have much higher ∆E ag values (2.2-3.1 kcal/ mol) due to their different conformational composition, and their absolute configuration cannot be reliably predicted by this method.
Assignment of the Absolute Configuration of β-Chiral Primary Alcohols by NMR: Scope and Limitations
Journal of the American Chemical Society, 1998
The prediction of the absolute configuration of-chiral primary alcohols from the 1 H NMR spectra of their esters with (R)-and (S)-9-anthrylmethoxyacetic acids (9-AMA, 3) is discussed. Low-temperature NMR experiments, MM, semiempirical, ab initio, and aromatic shielding effect calculations allowed the identification of the main conformers and showed that, in all alcohols for which the calculated ∆E ag (CVff) is in the range of 0.7-1.5 kcal/mol, conformer a/a is the most stable. A simple model for the assignment of the absolute configuration from NMR data is presented and its reliability corroborated with alcohols (8-20) of known configuration. Nevertheless, cyclic alcohols 21-23 have much higher ∆E ag values (2.2-3.1 kcal/ mol) due to their different conformational composition, and their absolute configuration cannot be reliably predicted by this method.
Chiral 1,2-Diols: The Assignment of Their Absolute Configuration by NMR Made Easy
Organic Letters, 2010
The absolute configuration of a 1,2-primary/secondary diol can be easily determined by preparation of its bis-(R)-and bis-(S)-9-AMA ester derivatives, followed by comparison of the NMR chemical shifts of the diastereotopic methylene protons in the two derivatives. Alternatively, the assignment can be carried out using only one derivative if the evolution with temperature of the signals corresponding to the CrH protons is analyzed.