The Assignment of the Absolute Configuration of 1,2-Diols by Low-Temperature NMR of a Single MPA Derivative (original) (raw)
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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.
Journal of Organic Chemistry, 2005
The absolute configuration of 1,2-, 1,3-, 1,4-, and 1,5-diols formed by two secondary (chiral) hydroxy groups can be deduced by comparison of the NMR spectra of the corresponding bis-(R)-and bis-(S)-MPA esters. The correlation between the NMR spectra of the bis-ester derivatives and the absolute stereochemistry of the diol involves the comparison of the chemical shifts of the signals for substituents R 1 /R 2 and for the hydrogens attached to the two chiral centers [H R (R 1 ) and H R (R 2 )] in the bis-(R)-and the bis-(S)-ester and is expressed as ∆δ. RS Theoretical calculations [energy minimization by semiempirical (AM1), ab initio (HF), DFT (B3LYP), and Onsager methods, and aromatic shielding effect calculations] and experimental data (NMR and CD spectroscopy) indicate that in these bis-MPA esters, the experimental ∆δ RS values are the result of the contribution of the shielding/deshielding effects produced by the two MPA units that combine according to the actual stereochemistry of the diol. The reliability of these correlations is demonstrated with a wide range of diols of known absolute configuration derivatized with MPA and 9-AMA as auxiliary reagents. A simple graphical model that allows the simultaneous assignment of the two asymmetric carbons of a 1,n-diol by comparison of the NMR spectra (∆δ RS signs) of its bis-(R)-and bis-(S)-AMAA ester derivatives is presented.
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.
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.
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.
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.