Determining absolute configuration

Nonempirical Methods for Determining Absolute Configurations of Chiral Compounds 

The methods for determining the absolute configurations of chiral compounds are summarized in Table 9.1 with the nonempirical methods in the top half of the table. 

It is well known that the absolute configuration of chiral compounds was first determined by the Bijvoet using X-ray crystallography [1]. In X-ray crystallography, since the anomalous dispersion effect of heavy atoms can be measured accurately under proper conditions, the absolute stereostructure obtained is unambiguous and reliable. In addition, the molecule can be projected as a three-dimensional structure, and, therefore, the method has been employed extensively. However, 

The CD exciton chirality method [2] is also useful because the absolute configuration can be determined in a nonempirical manner, and it does not require crystallization. Furthermore, chiral chemical and biological reactions are traceable by CD, and even the absolute configurations and conformations of unstable compounds can be obtained by this method. However, since some compounds are not ideal targets for this method, the results must be interpreted carefully. 

Recenfly fhe ah initio calculation mefhod of vibrational circular dichroism (VCD), optical rotatory dispersion (ORD), and electronic circular dichroism (ECD) has been developed as fhe third nonempirical method [3, 4]. The method is applicable to compounds having no chromophore, and so should be widely used in future. 

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Chemical conversion of compounds to intermediates of known absolute configuration is a method routinely used to determine absolute configuration (86). This is necessary because x-ray analysis is not always possible suitable crystals are required and deterrnination of the absolute configuration of many crystalline molecules caimot be done because of poor resolution. Such poor resolution is usually a function of either molecular instability or the complex nature of the molecule. For example, the relative configuration of the macroHde immunosuppressant FK-506 (105) (Fig. 8), which contains 14 stereocenters, was determined by x-ray crystallographic studies. However, the absolute configuration could only be elucidated by chemical degradation and isolation of L-pipecoUc acid (110) (80). 

This report presents various methods developed primarily at our laboratory for chromatographic resolution of racemates of several pharmaceuticals (e.g., -blockers, NSAIDS, anta-acids, DL-amino acids, Bupropion, Baclofen, Etodolac, Carnitine, Mexiletine). Recently, we developed methods for establishing molecular dissymmetry and determining absolute configuration of diastereomers (and thus the enantiomers) of (/< .S )-Baclofcn, (/d.SJ-Bctaxolol with complimentary application of TLC, HPLC, H NMR, LCMS this ensured the success of diastereomeric synthesis and the reliability of enantioseparation. 

Elsasser B et al.. X-ray structure determination, absolute configuration and biological activity of phomoxanthone A, Europ J Org Chem, 4563-4570, 2005. 

Ketones. The lithio derivative of ( +)-(.S )-. Y,.S -dimethyl-S-phenylsulfoxiinine (16), or its enantiomer, may be used both to resolve racemic ketones164 and to determine absolute configurations of ketones. For example, rac-19 on addition of 16 formed the diastereomeric /j-hydroxy-sulfoximines 17 and 18 which were separated. The configuration of 17 was established by an X-ray analysis. The ketones can be regenerated from the /1-hydroxysulfoximines by thermolysis. Thus, heating of 17 and 18 to 80 °C (for 12 h) furnished 19 [a precursor of (+ )-modhephen] and ent-l9165. 

Amide-linked catenanes and rotaxanes can play a major role in the study of rare forms of chirality, e.g. topological chirality and cycloenantiomerism [60]. Resolution of enantiomeric catenanes, rotaxanes, and pretzelanes has been achieved by HPLC on chiral column materials, but further work must be performed to determine absolute configurations and to realize new chiral skeletons composed of achiral building blocks. Topological asymmetric synthesis still belongs to dreams of the future yet should be kept in mind. 

In 1888 Emil Fishcer set our to discover the structure of (+) glucose. Methods for determining absolute configuration had not yet been developed so Fischer arbitrarily limited his atten-... 

In summary, even though the implicit approximations used in the application of exciton CD to determine absolute configuration ignore important complications such as the exciton splitting order, d-orbital mixing, and vibronic couplings, it has been a remarkably successful method for determination of the absolute configuration. 

The situation is more favourable for smaller chiral molecules. Computational advances in quantum chemistry have been to the interpretation of ROA what the development of laser technology and of electro-optics was to its measurement. Over a period of about two decades [31-39] the ab initio computation of ROA spectra has matured from a somewhat haphazard exercise to a reliable tool for determining absolute configurations, and solution conformations. 

Fischer Projections Stereoisomerism in Cyclic Compounds Methods of Determining Absolute Configuration Asymmetric Synthesis... 

College in London [there is an interview with Stephen Mason in this Volume], He was doing exciting things, and he needed someone to determine absolute configuration by X-ray crystallography. 

Other methods have also been used for determining absolute configuration in a variety of molecules, including optical rotatory dispersion, circular dichroism, " and asymmetric synthesis (see p. 166). Optical rotatory dispersion (ORD) is a measurement of specific rotation, [a], as a function of wavelength. The change of specific rotation [a] or molar rotation [[Pg.160]

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