Enantiomers chiral resolution screening

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. 

Zhang T, Nguyen D, Franco P. Enantiomer resolution screening strategy using multiple immobilised polysaccharide-based chiral stationary phases. J. Chromatogr. A 2008 1191 214-222. 

In one version, classical derivatization using a chiral reagent or NMR shift agent is simply parallelized and automated by the use of flow-through cells, with about 1400 ee measurements being possible per day with a precision of +5%. In the second embodiment, illustrated here in detail, a principle related to that of the MS system described in Section III.C is applied 98). Chiral or mexo-substrates are labeled to produce /. sewiio-enantiomers or psendo-meso-compo md that are then used in the actual screen. Application is thus restricted to kinetic resolution of racemates and... 

Weingarten et al. (228) reported the synthesis of an encoded SP 60-member pool hbrary L38 that was screened to find the best chiral selector for the resolution of racemate mixtures of dye-containing amino acid Pfp esters 9.144a (L-enantiomer, blue dye) and 9.144b (D-enantiomer, red dye. Fig. 9.55). The structures of the library L38 and of the three monomer sets Mi (15 representatives, A-Fmoc a-amino acids), M2... 

Finally, the bacterial PTE mentioned above has also been exhaustively studied with regard to its enantioselectivity. Initial studies used the known crystal structure of PTE to identify the substrate-binding pocket. This was then rationally evolved for enhancement and relaxation of the stereospecificity.97 Most recently, a combinatorial library has been screened for the resolution of chiral phosphate, phosphonate, and phosphinate esters.124 This work identified two variants with markedly different preferences for 5p- and Rp-enantiomers of 4-acetylphenyl methyl phenyl phosphate. One variant preferentially catalyzed hydrolysis of the 5p-enantiomer by a factor of 3.7 x 105, while the other preferentially catalyzed hydrolysis of the A p-enantiomer by a factor of 9.7 x 102 - an enantioselective discrimination of 3.6 x 108. 

One area of chirotechnology which is undergoing rapid development is chiral HPLC, whereby the use of chiral stationary phases (CSPs) permits the direct separation of racemic compounds into constituent enantiomers. Despite the capital outlay required, for example, for columns costing upwards of 3000, the use of preparative chiral HPLC in drug discovery has a number of benefits. After development of an appropriate method based on a previously defined analytical separation has been carried out, rapid and quantitative separation of racemates can be achieved, with evaporation of solvent from column fractions affording pure enantiomers directly. Although preparative chiral HPLC is less amenable to scale-up than other resolution techniques, it may be ideal for preliminary screening of both enantiomers in circumstances where manipulation of small quantities of material, for example, by crystallization, is impractical and prone to contamination problems. 

The basis of chiral method development screening strategies is largely dictated by whether the method is to be applied to analytical or preparative applications. Preparative chromatography tends to use volatile modifiers and mobile phases for easy removal after sample collection. Sample isolation capabilities have led to the advancement of chiral SFC since CO2 is easily driven off. Chiral separations in preparative chromatography only need to be optimized to a point where pure samples can be collected. Conversely, while analytical chromatography can use a greater variety of modifiers and mobile phases, the separation needs to be optimized to a point where suitable resolution (R > 1.5) is achieved between the enantiomers of interest. 

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