Determining the Absolute Stereochemistry of Secondary/Secondary Diols by 1 H NMR: Basis and Applications (original) (raw)
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Journal of Organic Chemistry, 2007
Comparison of the room-and low-temperature 1 H NMR spectra of the bis-(R)-or bis-(S)-MPA ester derivative of an open chain sec,sec-1,2-diol allows the easy determination of its relative stereochemistry and in some cases absolute configuration. If the diol is anti, its absolute configuration can be directly deduced from the signs of ∆δ T1T2 for substituents R 1 /R 2 , but if the relative stereochemistry of the diol is syn, the assignment of its absolute configuration requires the preparation of two derivatives (both the bis-(R)-and bis-(S)-MPA esters), comparison of their room-temperature 1 H NMR spectra, and calculation of the ∆δ RS signs for the methines HR(R 1 ) and HR(R 2 ) and R 1 /R 2 protons. The reliability of these correlations is validated with 17 diols of known absolute configuration used as model compounds.
Chemistry-a European Journal, 2005
The absolute configuration of 1,2-diols formed by a primary and a secondary (chiral) hydroxyl group can be deduced by comparison of the 1H NMR spectra of the corresponding (R)- and bis-(S)-MPA esters (MPA=methoxyphenylacetic acid). This method involves the use of the chemical shifts of substituents L1/L2 attached to the secondary (chiral) carbon, and of the hydrogen atom linked to the chiral center (CαH) as diagnostic signals. Theoretical (AM1, HF, and B3 LYP calculations) and experimental data (dynamic and low-temperature NMR spectroscopy, studies on deuterated derivatives, constant coupling analysis, circular dichroism (CD) spectra, and NMR studies with a number of diols of known absolute configuration) prove that the signs of the ΔδRS obtained for those signals correlate with the absolute configuration of the diol. A graphical model for the reliable assignment of the absolute configuration of a 1,2-diol by comparison of the NMR spectra of its bis-(R)- and bis-(S)-MPA esters is presented.
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.
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.
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.
The Journal of organic chemistry, 2015
2,2,6,6-Tetramethylpiperidinyl-masked 1,2-diols exhibited stereochemistry-dependent hydroxyl proton chemical shifts: ca. 7 ppm for the syn diastereomer and ca. 2 ppm for the anti diastereomer. A computational search for low energy geometries revealed that the syn isomer favors a six-membered ring hydrogen bond to nitrogen and the anti isomer favors a five-membered ring hydrogen bond to oxygen. The computed low energy conformations were found to have a large difference in hydroxyl proton shielding that was reflected in the experimental chemical shift difference. This chemical shift difference was observed in a broad range of solvents, and thus may be useful as a stereochemical probe. The stereochemistry-dependent conformation and chemical shift signature appeared to be due to a syn pentane interaction between the gem-dimethyl groups on the 2,2,6,6-tetramethylpiperidinyl moiety.