The 1 H NMR Method for the Determination of the Absolute Configuration of 1,2,3- p rim , s ec , s ec- Triols (original) (raw)
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The Stereochemistry of 1,2,3-Triols Revealed by 1 H NMR Spectroscopy: Principles and Applications
Chemistry-a European Journal, 2009
The conformational compositions of the tris(α-methoxy-α-phenylacetic acid) ester derivatives of 1,2,3-prim,sec,sec-triols are presented. These conformations have been determined by theoretical and experimental data (i.e., energy- and chemical-shift calculations, circular dichroism (CD) experiments, coupling-constant analysis, enantioselective deuteration experiments, and low-temperature NMR spectroscopic studies). A detailed analysis of the anisotropic effects due to the most significant conformers in the 1H NMR spectra supported the correlation between the 1H NMR spectra (ΔδRS value of H(3′) and |Δ(ΔδRS)| parameters) and the absolute configuration of the substrate. The study also allows the identification of the pro-R and pro-S methylene protons from their vicinal coupling constants and relative chemical shifts.
The absolute configuration of a secondary alcohol can be deduced from the 1 H NMR spectra of a single methoxyphenylacetic ester derivative [MPA, either the (R) or the (S)] recorded at two different temperatures. This new approach simplifies the current NMR-based methodologies, requiring just one derivatizing reaction, instead of two, and, correspondingly, half of the usual amount of sample. At low temperature, the relative population of the most stable sp conformer is increased and the resonances of the substituents of the alcohol (L 1 /L 2), located under the shielding cone of the phenyl ring, are shifted upfield. At the same time, those protons under the shielding cone in the less populated ap conformer are shifted downfield. In this way, the spatial location of L 1 /L 2 around the asymmetric center of the alcohol can be established comparing the 1 H NMR spectra both at room and low temperatures. Application of this finding to alcohols of known absolute configuration, including complex structures such as cis-androsterone, is presented.
Tetrahedron letters, 1999
A new method has been developed for determining the absolute configurations of acyclic [5-or ~-methyl substituted secondary alcohols using their 2NMA esters. The 1H-NMR spectra of (R)-and (S)-2NMA esters of model compounds were measured, and A6 values (6R.este r-6S_este r) for the corresponding protons were compared between syn and anti compounds. Threshold values important for judging the relative stereoehemistry of the two chiral centers bearing methyl and hydroxy groups were obtained. The absolute configuration of the chiral omter bearing a secondary hydroxy group is easily determined based on the sign of A6 values as in the MTPA method and thus in the present study it was also possible to clearly determine the absolute configuration of the chiral center bearing a methyl group.
The absolute configuration of a 1,n-diol can be assigned from the 1 H NMR spectra of its (R)-and (S)-AMAA diesters if the chemical shifts are interpreted as the result of the joint action of the two chiral auxiliaries. The reliability of NMR spectroscopy for the determination of the absolute configuration of chiral secondary alcohols and other monofunctional compounds using arylmethoxy-acetic acids [AMAAs, e.g., methoxyphenylacetic acid, MPA (1); 9-anthrylmethoxyacetic acid, 9-AMA (2)] as auxiliaries has been amply demonstrated theoretically and experimentally with a wide variety of compounds of known configuration. 1 Attempts to assign the absolute stereochemistry of some polyalcohols of natural origin by comparison of the NMR data of their MTPA (methoxytrifluormethylphenyl-acetic acid) peresters have been described. 2a However, this procedure is far from being well established basically because no systematic studies with compounds of known absolute configuration have been carried out to confirm the reliability of the assignments. Indeed, identical signs of ∆δ SR for the two substituents (L 1 /L 2) directly bonded to the asymmetric carbon have been obtained in certain cases, a situation that does not allow a safe assignment. 2b Apart from that, the main problem with those reports 2a resides in the assumption made by the authors that in a polyalcohol the configuration of a given hydroxylic carbon can be deduced by considering that only the MTPA directly bonded to that-OH contributes to the ∆δ SR values 3 used for its assignment and therefore that the model developed for monoalcohols can be directly applied to every hydroxylated carbon of the polyol. and references therein. (b) The conformational composition of MTPA esters is more complex than that of AMAAs (MPA, 9-AMA), which makes that reagent less recommended. See refs 2a and 4b.
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.
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.