Relative configuration, specification

Table 2.14 summarizes the steps by which molecular structures can be determined using the NMR methods discussed thus far to determine the skeleton structure, relative configuration and conformation of a specific compound. 

An enzyme consists of a polypeptide chain with a particular spatial configuration specific to that sequence of amino acids. The molecule twists and turns, forming structural features that are catalytically active, these being known as active sites. There may be more than one active site per enzyme molecule. Sometimes an auxiliary catalyst, known as a coenzyme, is also needed. Apparently, only the relevant active site of the enzyme comes into contact with the substrate and is directly involved in the catalysed reaction. The active site consists of only a few amino acid residues. These are not necessarily adjacent to one another in the peptide chain but may be brought into proximity by the characteristic folding of the enzyme structure. The active site may also include the coenzyme. The remainder of the enzyme molecule fulfils the essential function of holding the components of the active site in their appropriate relative positions and orientation. 

It must not be forgotten that the concept of pure substance, referred to earlier, is very rigorous and must take into account, not just the constitution and relative configuration of a molecule, but also the absolute configuration of each chiral center that may present. For example, again in relation to quinine (i), quinidine (2) is also known and the only difference between the two molecules is the disposition in space of the groups bonded to C(8). Nevertheless 2 is a different molecule and shows no antimalarial activity. In addition, only one enantiomer of quinine (1), the laevorotatory, corresponds to the natural compound and manifests the specific physiological properties associated with this substance. 

Assessing stereoselectivity in terms of descriptors is very simple as it merely involves the CIP specification of absolute and/or relative configurations of the stereoisomeric products of a reaction. This is just the task for which the CIP system was developed. The addendum of extraction of relative configuration by the like/ unlike (// ) description1 is explained in Section 1.1.8.1. 

The last stereochemically cryptic feature of this transformation concerns the specificity of the enzyme for the diastereotopic hydrogen atoms at C-l of 1,2-propanediol. To resolve this point Zagalak et al. [18] prepared ( R,2R)- and (1 R,2S)-1,2-[ 1 -2H,]propanediols (12 and 13) by reducing (R) and (5)-lactaldehydes with (4/ )-[4-2H,]NADH and liver alcohol dehydrogenase (Fig. 9). The cyclic acetals of 12 and 13, formed from nitrobenzaldehyde, gave different H-NMR spectra, and their configurations were determined by spectral comparison [20] with racemic reference compounds of known (relative) configuration. 

To ascertain the relative configurations of the dimers, each was synthesized specifically, using protecting groups that allow directed formation of disulfide bonds. Comparison of retention behavior of the specifically synthesized dimers with those synthesized non-specifically showed that F2 corresponds to the antiparallel dimer (Fig. 1) and the slower eluting component to the parallel isomer. 

A year later, Cassady published the synthesis and study of a set of model compounds representing the full spectrum of possible stereochemical relationships in dihydroxylated mono-THF acetogenins. Six mesitoylated compounds (23a-f, Fig. 13) were synthesized and subjected to H NMR spectroscopic studies. In these bis-mesitoates, good correlation between the relative configuration and the chemical shifts of selected protons was observed (Table 6). Specifically, It was found that ... 

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