Assignment of the Absolute Configuration of Monofunctional Compounds by Single Derivatization

The procedures shown in Chapter 3 allow the determination of the absolute configuration of several classes of compounds (Chapter 1, Figure 1.18), but they require the preparation of two derivatives and the comparison of their NMR spectra. Alternative methods have been developed for secondary alcohols and α-chiral primary amines. These are particularly suited for those cases where the amount of the available sample is low, and they require the preparation of only a single derivative [41–43, 55–56, 165]. There are three different approaches to using only a single derivatization to perform the assignment of those substrates [13, 165]. The first two are based on a controlled conformational change that is produced either by modification of the probe temperature [41, 165] or by selective complexation [42, 55, 56, 165]. The third one is based on the differences observed between the chemical shifts of the free alcohol and those of the 9-AMA ester derivative [43, 165]. In general, these single-derivatization procedures are limited to 1H NMR. Because the shift differences observed in 13C NMR are quite small, they produce insignificant Δδ values, and therefore the signs are not sufficiently accurate to produce a safe assignment [72]. Explanations and examples of applications are presented in the remainder of this chapter. For the assignment of secondary alcohols, a simple approach based on the use of a single MPA ester has proven to work very well [41, 165]. It is based on the controlled shift of the conformational equilibrium between the two main conformers (sp/ap) that were described in Chapter 1 for the MPA esters of secondary alcohols [36, 37]. Thus, for the assignment, it is only necessary to prepare either the (R)- or the (S)-MPA ester and then to compare the chemical shifts of L1/L2 in the spectra taken at room temperature and at a lower temperature [41]. Figure 4.2 presents a summary of the procedure and the graphical model expressing the ΔδT1T2 correlation between the sign and the stereochemistry for the assignment of secondary alcohols derivatized as (R)- or as (S)-MPA esters.