Optical purity determination methods

Optical Purity, Modern Methods for the Determination of (Raban and Mislow) 2 199... 

Optical Purity, Modem Methods for the Determination of Raban and... 

Chiral lanthanide shift reagents represent the most important NMR method for optical purity determination. The potential importance of configuration for chiral drugs has... 

Once again, the ratio of diastereomers is the same as that of the original enantiomers. High-pressure liquid chromatography has been used in a similar manner and has wider applicability. The direct separation of enantiomers by gas or liquid chromatography on a chiral column has also been used to determine optical purity. " Other methods... 

Lammerhoffer, M. and Lindner, W., Optical purity determination of (R)- and (S)-econazole nitrate by enantioselective HPLC Method development and application, Poster presented at the 17th International Symposium on Column Liquid Chromatography, Hamburg 9th - 14th May, 1993. 

Advances in ILs have made synthesis of chiral ILs a subject of intense study in recent years.The popularity stems from the fact that it is possible to use chiral ILs as chiral solvents for optical resolutions, for asymmetric induction in synthesis and as chiral stationary phase in chromatography. It may also be possible to use chiral IL to replace the solvent as well as the added carbohydrate compound for tire enantiomeric purity determination method. Specifically, the chiral IL with its high solubility... 

Allenmark, S.G. Chromatographic methods for optical purity determination of drugs. Acta Pharm. Nord. 1990, 2, 161-170. 

As already mentioned, chiral cations are involved in many areas of chemistry and, unfortunately, only few simple methods are available to determine their optical purity with precision. In the last decades, NMR has evolved as one of the methods of choice for the measurement of the enantiomeric purity of chiral species [ 110,111 ]. Anionic substances have an advantage over neutral reagents to behave as NMR chiral shift agents for chiral cations. They can form dia-stereomeric contact pairs directly and the short-range interactions that result can lead to clear differences in the NMR spectra of the diastereomeric salts. 

Our approach for chiral resolution is quite systematic. Instead of randomly screening different chiral acids with racemic 7, optically pure N-pMB 19 was prepared from 2, provided to us from Medicinal Chemistry. With 19, several salts with both enantiomers of chiral acids were prepared for evaluation of their crystallinity and solubility in various solvent systems. This is a more systematic way to discover an efficient classical resolution. First, a (+)-camphorsulfonic acid salt of 19 crystallized from EtOAc. One month later, a diastereomeric (-)-camphorsulfonic acid salt of 19 also crystallized. After several investigations on the two diastereomeric crystalline salts, it was determined that racemic 7 could be resolved nicely with (+)-camphorsulfonic acid from n-BuOAc kinetically. In practice, by heating racemic 7 with 1.3equiv (+)-camphorsulfonic acid in n-BuOAc under reflux for 30 min then slowly cooling to room temperature, a cmde diastereomeric mixture of the salt (59% ee) was obtained as a first crop. The first crop was recrystallized from n-BuOAc providing 95% ee salt 20 in 43% isolated yield. (The optical purity was further improved to -100% ee by additional recrystallization from n-BuOAc and the overall crystallization yield was 41%). This chiral resolution method was more efficient and economical than the original bis-camphanyl amide method. 

The optical purity of almost all the organotin compounds described in this chapter is not yet known. In order to determine the stereoselectivity of substitution reactions at the tin atom of these organotin compounds, it is almost always necessary to know the optical purity of the starting compound and of the final product. The method described in this section can be used not only for the resolution of racemic organotin compounds but also for the determination of their optical purity 50). It will be a valuable tool for the determination of the stereoselectivity of the reactions described in Chapter 5, and of other reactions which will be studied. 

The 3,4-dihydrodiol is a major component of the free dihydrodiols formed in mouse skin maintained in short-term culture (28). The optical purities of these dihydrodiols were determined by a CSP-HPLC method (43). The metabolic fates of the enantiomeric DMBA 3,4-dihydrodiols are not yet known. Studies in our laboratory indicate that the products formed in liver microsomal metabolism of DMBA 3,4-dihydrodiol bind extensively to the components of liver microsomes and the expected 1,2,3,4-tetrols of DMBA were not detected in the acetone/ethyl acetate extract of the incubation mixture (unpublished results). It is known that these products bind extensively to DNA... 

J Gerhardt, GJ Nichlson. Validation of a GC-MS method for determination of the optical purity of peptides, in J Martinez, J-A Ferentz, eds. Peptides 2000. Proceedings of the 26th European Peptide Symposium, EDK, Paris, 2001, pp 563-565. 

For a nonracemic mixture of enantiomers prepared by resolution or asymmetric synthesis, the composition of the mixture was given earlier as percent optical purity (equation 1), an operational term, which is determined by dividing the observed specific rotation (Mobs) of a particular sample of enantiomer with that of the pure enantiomer ( max), both of which were measured under identical conditions. Since at the present, the amount of enantiomers in a mixture is often measured by nonpolarimetric methods, use of the term percent optical purity is obsolete, and in general has been replaced by the term percent enantiomeric excess (ee) (equation 2) introduced in 197163, usually equal to the percent optical purity, [/ ] and [5] representing the relative amounts of the respective enantiomers in the sample. 

Although many previous reviews (5-12) and literature compilations (13-16) have dealt with sulfur stereochemistry, we decided to write a new report on chiral sulfur compounds to provide a survey of the topic with emphasis on the most recent findings. This chapter consists of four major parts treating syntheses of chiral sulfur compounds, methods for determination of their absolute configuration and optical purity, the dynamic stereochemistry of organosulfur compounds, and the use of chiral sulfur compounds in asymmetric synthesis. 

NMR spectroscopy was found to be a valuable technique for differentiation between the enantiomers of optically active compounds. The principles of the methods used to distinguish between enantiomers by means of NMR have been developed and reviewed by Mis-low and Raban (217). The best results from the point of view of the determination of optical purity and absolute configuration of chiral sulfur compounds, especially of sulfinyl compounds, have been obtained with the help of chiral solvents (218). Pirkle (86) was the first to demonstrate that enantiomeric sulfoxides have nonidentical NMR spectra when dissolved in chiral alcohols having the following general formula ... 

As in the case of other chiral compounds, the optical and enantiomeric purity of chiral organosulfur compounds can be determined by various methods (241). The simplest and most common method for the determination of optical purity of a mixture of enantiomers is based on polarimetric measurements. However, this method requires a knowledge of the specific rotation of the pure enantiomer. In the... 

The polarimetric method, in combination with the results of chemical correlation, made it possible to determine the optical purity of a range of chiral sulftnates (105-107), thiosulfinates (35,105), and sulfinamides (83) with the sulfur atom as a sole center of chirality. These compounds were converted by means of Grignard or alkyl-lithium reagents into sulfoxides of known specific rotations. This approach to the determination of optical purity of chiral sulfinyl compounds has at least two limitations. The first is that it cannot be applied to sterically hindered compounds [e.g., t-butyl /-butanethio-sulfinate 72 does not react with Grignard reagents]. Second, this... 

An interesting method for the estimation of optical purity of sulfoxides, which consists of the combination of chemical methods with NMR spectroscopy, was elaborated by Mislow and Raban (241). The optical purity is usually determined by the conversion of a mixture of enantiomers into a mixture of diastereomers, the ratio of which may be easily determined by NMR spectroscopy. In contrast to this, Mislow and Raban used as starting material for the synthesis of enantiomeric sulfoxides a diastereomeric mixture of pinacolyl p-toluenesulfinates 210. The ratio of the starting sulfinates 210 was 60.5 39.5, as evidenced by the H NMR spectrum. Since the Grignard reaction occurs with full stereospecificity, the ratio of enantiomers of the sulfoxide formed is expected to be almost identical to that of 210. This corresponds to a calculated optical purity of the sulfoxide of 20%. In this way the specific rotations of other alkyl or aryl p-tolyl sulfoxides can conveniently be determined. 

As was already mentioned, the phenomenon of nonequivalence of NMR spectra of enantiomers in chiral solvents is a basis for the determination of enantiomeric purity of a variety of chiral sulfur compounds. This method, developed by Pirkle, has the advantage over other methods of being absolute that is, the chemical shift difference between enantiotopic nuclei induced by the chiral solvent increases with increasing optical purity of the solvent, whereas the relative intensities of the signals that are used to measure the enantiomeric composition of the solute are not affected. 

A new and detailed tetralin study deals with the resolution and the determination of the optical purity of the enantiomers of 5-OH-DPAT (21). Of particular interest is that an analytical HPLC method that measures very small amounts of optical impurity was used [72]. It could be shown that the i -enantiomer really possesses antagonistic properties, as measured biochemically, in non-pretreated animals [73]. These findings support the modelling results of Froimowitz and co-workers [74,75]. Other studies have not revealed such properties of (/ -21) [64,76]. These new and interesting findings have implications for the atypical D2 antagonsits with preferential action on D2 autoreceptors, developed from D2 agonists, as discussed below. 

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