The Stereochemistry of 1,2,3-Triols Revealed by 1 H NMR Spectroscopy: Principles and Applications (original) (raw)
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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.
Both theoretical and experimental evidences prove that the absolute configuration of an et-chiral carboxylic acid can be safely assigned by comparison of the 1H NMR spectra of its esters with (R)-and (S)-ethyl 2-(9-anthryl)-2-hydroxyacetate (5, AHA). A simplified conformational model, based on the dominance of the ap over the sp conformer and the selective effect of the anthryl group, allows the (R/S) assignment directly from the NMR chemical shifts. (~) 1997 Elsevier Science Ltd The determination of the absolute stereochemistry of organic compounds by NMR of selected derivatives constitutes one of the most useful stereochemical techniques. In spite of its wide use, this methodology has been applied to very few organic functional groups and, in fact, only secondary alcohols and et-substituted primary amines have been fully investigated. In a recent publication I we showed preliminary results on the application of this method to primary alcohols and we now focus our attention on carboxylic acids because there are a large number of optically active organic compounds that present this functionality. o % = CO2Et Rt A~T ~R2 o (R)-I RI= NH 2 R 2=NMe 2 PGDA (R)-2 RI=NH2 R2-OMe PGME (R)-3 RI= OH R 2-OMe MA (aR)-4 BNDO (R)-$ AHA A few reports that correlate the absolute configuration of carboxylic acids with the NMR spectra of certain esters and amides have been recently published} In those papers, auxiliary reagents (R)-and (S)-(1-4) are used and the configuration is derived in the usual way by comparison of the NMR spectra of the corresponding derivatives. Although the results of those studies are apparently good, the absence of reliable information about the conformational composition (structure, populations), the real influence of the aryl group on the substituents at the carboxylic acid part in each conformer and the sensitivity of the chemical shifts to the structure of the acids, limit the consideration of 1-4 as reagents for general application. Moreover, the models proposed are surprisingly identical for esters and amides, without conformational support and in conflict with former studies. 3 In this communication we present theoretical'* (Molecular Mechanics, semiempirical A/VII and aromatic shielding effect calculations) and experimental data (DNMR and testing with acids of known configuration) to support the conformational composition of the esters of carboxylic acids with (R)-and (S)-arylhydroxyacetates (i.e. 3) and demonstrate that the absolute configuration of an et-chiral
Organic Letters, 2006
The absolute configuration of 1,2,3-prim,sec,sec-triols can be assigned by comparison of the 1 H NMR spectra of the tris-(R)-and the tris-(S)-MPA ester derivatives. An experimental demonstration of this correlation with 24 triols of known absolute configuration and a protocol using two parameterss∆δ RS (H3) and the difference between ∆δ RS (H2) and ∆δ RS (H3) ) |∆(∆δ RS )|sfor its application to the determination of the absolute configuration of other triols are presented.
Assignment of the Absolute Configuration of α-Chiral Carboxylic Acids by 1H NMR Spectroscopy
The Journal of Organic Chemistry, 2000
The prediction of the absolute configuration of R-chiral carboxylic acids from the 1 H NMR spectra of their esters with (R)-and (S)-ethyl 2-hydroxy-2-(9-anthryl) acetate [(R)-and (S)-9-AHA, 5] is discussed. Low-temperature NMR experiments, MM, semiempirical, and aromatic shielding effect calculations allowed the identification of the main conformers and showed that, in all esters studied, conformer ap is the most stable. A simple model for the assignment of the absolute configuration from NMR data is presented, and its reliability is corroborated with acids 6-31 of known absolute configuration. In addition to 5, other auxiliary reagents with open (32-38) and cyclic (39-42) structures have also been studied. trans-(+)-and (-)-2-phenyl-1-cyclohexanol (41) was found to be particularly efficient and produced ∆δ RS values similar to those of 5.