Assignment of the absolute configuration of secondary alcohols by 13C NMR and its correlation with methyl-1-(chloromethyl)-oxopyrrolidine-2-carboxylate and quantum-mechanical GIAO calculations

Abstract

Analysis of the effect of steric compression on the chemical shifts of carbons (¹³C NMR) in diastereoisomers is an accessible strategy for assigning the absolute configuration of secondary alcohols. Here we take advantage of such chemical shift differences and establish a validation protocol to assign the absolute configuration of secondary alcohols in natural products. The two enantiomers of methyl-1-(chloromethyl)-5-oxopyrrolidine-2-carboxylate are used as derivatizing agents to treat separately a secondary alcohol producing two diastereoisomeric derivatives. These derivatives exhibit clear ¹³C NMR differences only at four carbons: first at the stereogenic oxygenated carbon and methylene of the chiral assistant with a deshielding effect up to 3 ppm, and a shielding effect for the α carbons to the stereogenic centre. With the results obtained from a 1D NMR ¹³C spectrum, we were able to establish the absolute stereochemistry of the asymmetric centre beyond the concept of anisotropy. The observed changes in chemical shifts correlate well with the results obtained by the GIAO method applying the B3LYP/6-311+(2d,p) theoretical model to calculate the NMR shielding tensors of the diastereoisomeric derivatives. Furthermore, the steric compression effect was observed as well by ¹H NMR at the methylene of the pyroglutamic moiety, since the magnitude of its geminal coupling constant is directly influenced by the stereochemistry of the secondary alcohol, thus, confirming the stereochemistry assignation of the asymmetric carbon.