Structural determination, stereochemical modeling

X-ray fiber diffraction can be used to visualize highly hydrated polymer specimens at atomic resolution. An essential part of such an analysis is the inclusion of reliable stereochemical information to supplement the diffraction data. Structure determination involves modelling and refinement of putative structures, and adjudication amongst the optimized models. This technique has been successfully applied to a number of polysaccharides. The precision of resulting structures is often sufficient to identify the critical interactions within and between molecules, that are responsible for the unique properties of these materials. 

In the early stages of the project, we reasoned that the sulfoxide unit might be expected to influence the transition state geometry of the 2-acyl side chain, perhaps by chelation to a metal counterion, and hence control the stereochemistry of a wide range of functional group transformations. Indeed, a chelation control model of the reactivity of the 2-acyl dithiane 1-oxide systems has allowed us to rationalize, and predict, the stereochemical outcome of most of the reactions studied so far. These predictions have, in many cases, been confirmed by X-ray structure determination of the relative stereochemistries within product structures.1-4... 

In evaluating a structure determination for accuracy and precision, it is usually prudent to inquire as to the quality of the electron density map according to which the final model was built, and to the properties and quality of the final model. The former question can be addressed in real space, that is, how good is the electron density map, and/or in reciprocal space, that is, how well determined were the phases, and how well measured the structure amplitudes that contributed to the map. The model, of course, can be judged by how well it predicts the diffraction intensities (the R factor), by how it explains chemical and biochemical questions, and how well it agrees with canonical stereochemical properties, such as bond lengths and angles. 

It is also possible to call upon other information which is generally available. The structures of chemically similar polymers are often known and these are often useful as a starting-point for structure determination. The stereochemical nature of the polymer chains depends upon the method of synthesis (Section 2.8) and knowledge of this is important. Spectroscopic techniques (Sections 3.19-3.20) give the detailed microstructure of the polymer molecules and information on the conformation and packing of the chains within the crystals. Also it is possible to determine the lowest-energy crystal structure by taking into account inter- and intramolecular interactions for different structural models. 

But even when the constitution of the polymer may be regarded as essentially homogeneous, considerations analogous to the previous ones may apply at the stereochemical level. For this reason the study of macromolecular stereoisomerism calls for a twofold approach. On the one hand, one must turn to ideal models that permit the identification of the type of structure existing in the polymer on the other, statistical criteria must be used to determine to what... 

It is generally recognized that in order to analyze the stereochemical features of real systems (molecules, or groups of molecules and reactions) it is useful to abstract those features which determine the properties of interest and to represent them in terms of a single model system. It is possible to perform an isomorphic mapping of the essential stereochemical features of each of the real systems onto this model, and an equivalence relation will thus exist between the real systems. We shall say that any two systems whose static stereochemistry (structure, conformation) and conformational dynamics may be represented by the same abstract model exhibit stereochemical correspondence. 

Several studies have tackled the structure of the diketopiperazine 1 in the solid state by spectroscopic and computational methods [38, 41, 42]. De Vries et al. studied the conformation of the diketopiperazine 1 by NMR in a mixture of benzene and mandelonitrile, thus mimicking reaction conditions [43]. North et al. observed that the diketopiperazine 1 catalyzes the air oxidation of benzaldehyde to benzoic acid in the presence of light [44]. In the latter study oxidation catalysis was interpreted to arise via a His-aldehyde aminol intermediate, common to both hydrocyanation and oxidation catalysis. It seems that the preferred conformation of 1 in the solid state resembles that of 1 in homogeneous solution, i.e. the phenyl substituent of Phe is folded over the diketopiperazine ring (H, Scheme 6.4). Several transition state models have been proposed. To date, it seems that the proposal by Hua et al. [45], modified by North [2a] (J, Scheme 6.4) best combines all the experimentally determined features. In this model, catalysis is effected by a diketopiperazine dimer and depends on the proton-relay properties of histidine (imidazole). R -OH represents the alcohol functionality of either a product cyanohydrin molecule or other hydroxylic components/additives. The close proximity of both R1-OH and the substrate aldehyde R2-CHO accounts for the stereochemical induction exerted by RfOH, and thus effects the asymmetric autocatalysis mentioned earlier. 

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