Chiral combinatorial library

First the primary combinatorial library of chiral ligands LI —L5 and chiral activators Al —A5 (Scheme 12) were studied in order to optimize the lead structure of the next generation of chiral ligands and activators.87,89... 

Liu, J. West, K. R. Bondy, C. R. Sanders, J. K. M. Dynamic combinatorial libraries of hydrazone-linked pseudo-peptides Dependence of diversity on building block structure and chirality. Org. Biomol. Chem. 2007,5, 778-786. 

Sharpless et al. coined the word ligand-accelerated catalysis (LAC), which means the construction of an active chiral catalyst from an achiral precatalyst via ligand exchange with a chiral ligand. By contrast, a combinatorial library approach in which an achiral pre-catalyst combined with several chiral ligand components (L, L, —) may selectively assemble in the presence of several chiral activators (A, A, —) into the most catalytically active and enantioselective activated catalyst (ML A" ) (Scheme 8.16). ... 

The availability of ctetq) advanced synthons that carry the required chirality is an advantage, particularly in projects aimed at industrial total synthesis. Natural products are often used as synthons, ideally fi om a renewable source, such as microbial fermentations. In a few cases, biotechnology has become an ahemative source. The total theses of the antitumor agent esperamicin A and the immunosuppressant FK-506 are exanq>les. In both cases, the synthon was quinic acid (Barco 1997), cheaply obtained by biotechnology (Chapter 14.1.e) rather than fi om the environmentally noxious extraction fi om the bark of Cinchona spp. Used to build up combinatorial libraries, quinic acid has gained further inq)ortance in organic thesis (Phoon 1999). 

Gennari, C. and Piarulli, U. (2003) Combinatorial libraries of chiral ligands... 

Selectivity in enantiotopos-differentiating acylation and phosphorylation of meso-diols can rival that of enzymes. The organocatalysts employed include chiral phosphines, chiral diamines, chiral DMAP derivatives and peptides identified from combinatorial libraries. The highest selectivity in meso diol desymmetrization has been achieved with a planar-chiral Fu catalyst. It seems the substrate scope of this process is not yet broadly explored. Because of their sequential variability it is to be... 

After the advent of combinatorial chemistry and its lack of success, it was recognised that the combinatorial libraries lacked diversity. Hence, new approaches were applied to design compounds that allowed the introduction of many points of diversity, such as chiral centres to mimic natural products.6 These libraries are also called natural product-like libraries.7... 

Finally, libraries aimed to chiral resolution of racemates will be covered here in particular, the use of chiral stationary phases (CSPs) has recently been reported for the identification of materials to be used for chiral separation of racemates by HPLC. The group of Frechet reported the selection of two macroporous poly methacrylate-supported 4-aryl-1,4-dihydropyrimidines (DHPs) as CSPs for the separation of amino acid, anti-inflammatory drugs, and DHP racemates from an 140-member discrete DHP library (214,215) as well as a deconvolutive approach for the identification of the best selector phase from a 36-member pool library of macroporous polymethacrylate-grafted amino acid anilides (216,217). Welch and co-workers (218,219) reported the selection of the best CSP for the separation of a racemic amino acid amide from a 50-member discrete dipeptide iV-3,5-dinitrobenzoyl amide hbrary and the follow-up, focused 71-member library (220). Wang and Li (221) reported the synthesis and the Circular Dichroism- (CD) based screening of a 16-member library of CSPs for the HPLC resolution of a leucine ester. Welch et al. recentiy reviewed the field of combinatorial libraries for the discovery of novel CSPs (222). Dyer et al. (223) reported an automated synthetic and screening procedure based on Differential Scanning Calorimetry (DSC) for the selection of chiral diastereomeric salts to resolve racemic mixtures by crystallization. Clark Still rejxrrted another example which is discussed in detail in Section 9.5.4. 

To overcome the problem of their limited range of applicability and to extend the spectrum of application other than to the imprint molecule, molecularly imprinted polymer combinatorial libraries for multiple simultaneous chiral separations have been prepared [ 191 ], demonstrating that the ligand cross-reactivities of molecularly imprinted polymers can be beneficially employed for the simultaneous separation of different stereoisomeric structures. 

The assymetric Strecker reaction of diverse imines, including aldimines as well as ketoimines, with HCN or TMSCN provides a direct access to various unnatural and natural amino acids in high enantiomeric excesses, using soluble or resin-linked non-metal Schiff bases the corresponding chiral catalysts are obtained and optimized by parallel combinatorial library synthesis [93]. A rather general asymmetric Strecker-type synthesis of various imines and a, 9-unsaturated derivatives is catalyzed by chiral bifunctional Lewis acid-Lewis base aluminum-containing complexes [94]. When chiral (salen)Al(III) complexes are employed for the hydrocyanation of aromatic substituted imines, excellent yields and enatio-selectivities are obtained [94]. 

Figure 7-19. Primary combinatorial library of cbiral ligands (L L ) and chiral activators...

Bluhm, L. H., Wang, Y., Li, T. An alternative procedure to screen mixture combinatorial libraries for selectors for chiral chromatography, Anal Chem., 2000, 72, 5201-5205. 

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. 

Combinatorial libraries of chiral heterocyclic ligands for enantioselective catalysis 03CRV3071. 

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