Chiral library

A recent report (41) has highlighted the usefulness of CE to determine the enantiomeric purity of individuals coming from parallel synthesis, either during chemical assessment to help revising the experimental protocols and as a library QC tool to determine the stereochemical quality and purity of chiral libraries. The authors studied the Pictet-Spengler reaction of chiral tryptophans with carbonyl compounds on SP to provide tetrahydro-P-carbolines, and clearly highlighted the reaction conditions-dependent racemization of the reaction products. 

Another recent example by Peukert and Jacobsen (199) took advantage of the first polymer supported Jacobsen s catalyst 8.53 (Fig. 8.31) comparable with the soluble catalyst in asymmetric epoxidation and its full characterization (200, 201). The supported catalyst, prepared from the activated carbonate of hydroxymethyl PS and from a soluble phenolic catalyst (201), was used to catalyze the opening of racemic alkyl epoxides (Mi, Fig. 8.31) with substituted phenols and yielded the 50-member aryloxy alcohol library L15 with good enantiomeric purity (average >90%, never below 80% e.e.). 8.53 was also used to produce the chiral intermediate monomer set M3 (Fig. 8.31) which was used to make two 50-member chiral libraries L16 (1,4-diary-loxy 2-propanols) and L17 (3-aryloxy-2-hydroxy propanamines) with excellent enantiomeric excess following the straightforward synthetic schemes reported in Fig. 8.31. 

Single mode microwave-assisted combinatorial synthesis of biologically interesting quinoxalinones has been described by Tung and Sun [106]. It enabled chiral libraries of quinoxalinones to be assembled by use of SNAr reactions, reduction, and concomitant cyclization under the action of microwave irradiation. 

Paul Beroza and Mark J. Suto, Designing chiral libraries for drug discovery, Drug Discovery Today, 5 (2000), 364-372. 

W. H. Pirkle and B. C. Hamper, The direct preparative resolution of enantiomers by liquid chromatography on chiral stationary phases in Preparative Liquid Chromatography, B. A. Bidling-meyer (Ed.), Journal Chromatography Library Vol. 38, 3 Edition, Elsevier Science Publishers B. V, Amsterdam (1991) Chapter 7. 

Library of Cyclic Oligopeptides as Additives to Background Electrolyte for Chiral Capillary Electrophoresis... 

Enantioresolution in capillary electrophoresis (CE) is typically achieved with the help of chiral additives dissolved in the background electrolyte. A number of low as well as high molecular weight compounds such as proteins, antibiotics, crown ethers, and cyclodextrins have already been tested and optimized. Since the mechanism of retention and resolution remains ambiguous, the selection of an additive best suited for the specific separation relies on the one-at-a-time testing of each individual compound, a tedious process at best. Obviously, the use of a mixed library of chiral additives combined with an efficient deconvolution strategy has the potential to accelerate this selection. 

In addition to the development of the powerful chiral additive, this study also demonstrated that the often tedious deconvolution process can be accelerated using HPLC separation. As a result, only 15 libraries had to be synthesized instead of 64 libraries that would be required for the full-scale deconvolution. A somewhat similar approach also involving HPLC fractionations has recently been demonstrated by Griffey for the deconvolution of libraries screened for biological activity [76]. Although demonstrated only for CE, the cyclic hexapeptides might also be useful selectors for the preparation of chiral stationary phases for HPLC. However, this would require the development of non-trivial additional chemistry to appropriately link the peptide to a porous solid support. 

The screening of libraries of compounds for the desired property constitutes an essential part of the combinatorial process. The easier and the faster the screening, the higher the throughput and the more compounds can be screened in a unit of time. This paradigm has led Still s group to develop a combinatorial approach to chiral selectors that involves a visual screening step by optical microscopy that enables the manual selection of the best candidates [81]. 

Although the preparation of the quite complex selector modules prior to the synthesis of the library represented a rather significant synthetic effort, this study showed clearly the potential of combinatorial chemistry in the early development stage of a chiral separation medium and demonstrated a novel approach to rapid screening that might be amenable to full automation in the future. 

In order to perform such a correlation, our library was screened using a reciprocal CSP with an arbitrary bound chiral target (L)-(3,5-dinitrobenzoyl) leucine (Fig. 3-11). 

Our strategy consisted of the following steps A mixture of potential chiral selectors is immobilized on a solid support and packed to afford a complete-library column , which is tested in the resolution of targeted racemic compounds. If some separation is achieved, the column should be deconvoluted to identify the selector possessing the highest selectivity. The deconvolution consisted in the stepwise preparation of a series of sublibrary columns of lower diversity, each of which constitute a CSP with a reduced number of library members. 

A small library of thiazolidinones 138 has been prepared mixing directly a primary amine (as the HCl salt), an aldehyde and mercaptoacetic acid in EtOH in the presence of Hiinig s base and molecular sieves (120 °C for 30 min) [88]. Working with a chiral amine, a 1 2 mixture of diastereoisomers was obtained (Scheme 49). 

These catalysts were first tested as resin-bound derivatives via HTS, first with metals and then without. Three libraries of chiral molecules, based on three different enantiomerically pure diamines, bulky salicylidene moities and optically active ii-amino acids were used for structure optimisation (Scheme 37 TBSCN = fBuMe2SiCN) [152]. 

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