Absolute configuration, diffraction

Among the modem procedures utilized to estabUsh the chemical stmcture of a molecule, nuclear magnetic resonance (nmr) is the most widely used technique. Mass spectrometry is distinguished by its abiUty to determine molecular formulas on minute amounts, but provides no information on stereochemistry. The third most important technique is x-ray diffraction crystallography, used to estabUsh the relative and absolute configuration of any molecule that forms suitable crystals. Other physical techniques, although useful, provide less information on stmctural problems. 

This chapter deals with single crystal x-ray diffraction as a tool to study marine natural product structures. A brief introduction to the technique is given, and the structure determination of PbTX-1 (brevetoxin A), the most potent of the neurotoxic shellfish poisons produced by Ptychodiscus brevis in the Gulf of Mexico, is presented as an example. The absolute configuration of the brevetoxins is established via the single crystal x-ray diffraction analysis of a chiral 1,2-dioxolane derivative of PbTX-2 (brevetoxin B). 

The relative stereochemistry of stephadiamine (16) was clarified by X-ray diffraction analysis, using the direct method, and the absolute configuration was solved by the heavy-atom method, using the N-p-bromobenzoyl derivative (6). Stephadiamine (16), a C-norhasubanan alkaloid, is not regarded as a hasubanan congener in the strict sense, but as a new member of oe-amino acid derivatives (6). 

X-Ray diffraction analysis was utilized for the determination of the stereochemistry of bis-boraadamantane derivatives (see Section 12.13.3.2.1) as well as for the estimation of absolute configuration of adducts of chiral... 

Further examination of the extracts of A. cannabina revealed axisonitrile-4 (7), axisothiocyanate-4 (8) and axamide-4 (9) [33], A vinylic isonitrile function was supported by H NMR signals at <51.67 and 1.89, which were assigned to the two isopropylidene methyls of 7. Difficulty in isolating the natural product 9 was circumvented, when isonitrile 7 was transformed to 9, mp 81-84 °C, by acetic acid in anhydrous ether. The absolute configurations of both axanes 1 and 7 and their analogs were later established [31] by studies including X-ray diffraction of the p-bromoaniline derivative of 2 and by CD data of ( + )-10-methyldecalone-l obtained from ozonolysis of the reduction (Na/NH3) product of 1 [1]. 

Figure 13. Absolute configuration of benzo[a]pyrene metabolites determined by anomalous dispersion (X-ray diffraction) studies of a bromoderivative.

Compounds having the same optical configuration show similar Cotton effects. If the absolute configuration is known (for example, from x-ray diffraction) for one optically active compound, a similar Cotton effect exhibited by another compound indicates that it has the same optical configuration as the known. In other words, if two compounds give electronic transitions that show Cotton effects that... 

For a molecule without a heavy atom, the absolute configuration can also be determined by attaching another chiral moiety of known configuration to the sample. The absolute configuration can then be determined by comparison with this known configuration. For example, the absolute configuration of compound 37 or 38 cannot be determined by X-ray diffraction because of the lack of heavy atoms in the molecules. But the configuration can be determined by... 

In another legume, Afzelia bella Harms (Caesalpinoidene), the same authors have isolated the new rrfree amino acids. The structure of the diacid 54 is based on mass, H, and l3C-NMR spectroscopy (95) the proposed absolute configuration of 54 was also demonstrated by X-ray diffraction (96). Compound 54 is probably identical with the diacid independently isolated from the red alga Chondria coerulescens (Crouan) Falk. (Rhodomelaceae) (97). 

Dehydrodarlingianine (69) and dehydrodarlinine (72) were synthetized by base-catalyzed reaction of hygrine with cinnamaldehyde and benzaldehyde, respectively. The relative stereochemistry of darlingianine (65) was established by X-ray diffraction (111). The structure of the other bases was established by chemical correlations as well as by spectroscopic methods. The absolute configurations of these bases remain to be determined. 

The method, also called heavy atom method, consists in introducing a heavy atom in the molecule. Then X-rays with a wave length close to the X-ray absorption of the heavy atom is introduced. As a result a phase shift is superimposed on the ordinary diffraction pattern and configuration is then deduced. The method was first employed in 1951 by Bijvoet et al. to examine sodium rubidium tartrate who concluded that it is possible to differentiate between the two optically active forms. In other words it was possible to determine the absolute configuration of the enantiomers. Since then the absolute configurations of about two hundred optically active compounds have been elucidated by their correlation with other substances of known configuration. 

The X-ray intensity diffraction data of the given crystal do not allow one to specify which of the two sets describes the actual crystal structure and thus the absolute configuration of the molecule when there is no effect of anomalous X-ray dispersion. Under such conditions Friedel s law holds, which states that the X-ray intensity diffraction pattern of a crystal is centrosymmetric whether the crystal structure is centrosymmetric or not. This does not mean that a false crystal structure containing a center of symmetry is obtained as the solution of the structural problem, but rather that the X-ray analysis cannot differentiate between the two enantiomeric structures. A simple mathematical analogy is provided by the two possible square roots of a number Vj = x. 

We illustrated in Section II why conventional X-ray diffraction cannot distinguish between enantiomorphous crystal structures. It has not been generally appreciated that, in contrast to the situation for chiral crystals, the orientations of the constituent molecules in centrosymmetric crystals may be unambiguously assigned with respect to the crystal axes. Thus, in principle, absolute configuration can be assigned to chiral molecules in centrosymmetric crystals. The problem, however, is how to use this information which is lost once the crystal is dissolved. 

In the orthorhombic point group mm2 there is an ambiguity in the sense of the polar axis c. Conventional X-ray diffraction does not allow one to differentiate, with respect to a chosen coordinate system, between the mm2 structures of Schemes 15a and b (these two structures are, in fact, related by a rotation of 180° about the a or c axis) and therefore to fix the orientation and chirality of the enantiomers with respect to the crystal faces. Nevertheless, by determining which polar end of a given crystal (e.g., face hkl or hkl) is affected by an appropriate additive, it is possible to fix the absolute sense of the polar c axis and so the absolute structure with respect to this axis. Subsequently, the absolute configuration of a chiral resolved additive may be assigned depending on which faces of the enantiotopic pair [e.g., (hkl) and (hkl) or (hkl) and (hkl)] are affected. 

This approach may also be applied to racemic bilayers built up from homo-chiral Langmuir-Blodgett monolayers. By measuring the two-dimensional diffraction pattern from such a bilayer it is possible to deduce the molecular chirality of each of the two monolayers in the order they were inserted to construct the bilayer. This approach can be extended to multilayers. Thus, in principle, we close the circle started in Section IV-G-1. It is possible to assign the absolute configuration of chiral molecules in centrosymmetric crystals provided that one can construct the crystal (in this case the multilayer) by adding homochiral layers one by one. 

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