Screening scheme

FIG. 3. (A) Screening scheme for maternal genes that can modulate apoptosis when expressed... 

Domling et al. [21] identified the first enantioselective Passerini MCR using a Lewis acid catalyst Ti(i-OPr)4 in combination with (4S,5S)-4,5-bis(diphenylhydrox-ymethyl)-2,2-dimethyldioxolane as a chiral ligand by a massive parallel catalyst screening (Scheme 9.13). 

Figure 1.22. Diversity and activity-based compound selection as part of integrated screening schemes (adapted from Stahura and Bajorath 2004)...

Bernhard and coworkers [58] have addressed the discovery of ionic iridium(III) and ruthenium(II) complexes by combinatorial luminophore synthesis and screening (Scheme 5.9). Starting from iridium trichloride, cyclometalation with (hetero)arylpyridyl ligands 45 (Fig. 5.17) gives rise to the formation of binuclear iridium complexes 46. Upon complexation with bidentate N,N- or P,P-ligands 47 (Fig. 5.17), the cationic complex 48 is formed, which upon anion metathesis with hexafluorophosphate is transformed into the target complex 49. In this sequence, the step from 46 to 48 was performed in a traditional and a parallel manner, the latter leading to a library of 100 iridium and 10 ruthenium complexes. 

The first test of the chiral /V-acylhydrazones was in tin-mediated radical addition [47,48]. Addition of isopropyl iodide to propionaldehyde hydrazone 3a was chosen for initial screening (Scheme 2). Using the tin hydride method with triethylborane initiation [51, 52] (Bu3SnH, Et3B/02), with InCl3 and ZnCU as Lewis acid additives, desired adduct 13a was obtained with high diastereoselectivity. In contrast, 13a was produced with poor selectivity (diastereomer ratio, dr 2 1) in the absence of Lewis acid. 

The feasibility of the screening scheme of fluorescent RNP sensors (Fig. 10.4) was demonstrated by utilizing libraries of fluorescent RNP receptors constructed from the 29 different ATP-binding RNP, which obtained from RRE30N RNAs (Fig. 10.2a) and Rev peptides modified with various fluorophores, 7-methoxycoumarin-3-carboxylic acid (7mC-Rev), 4-fluoro-7-nitrobenz-2-oxa-1,3-diazole (NBD-Rev), and Cy5 mono NHS ester (Cy5-Rev) at the N-terminal. Complex formation of the 29 different RNA subunits and Pyr-Rev, 7mC-Rev, NBD-Rev, or Cy5-Rev afforded four independent fluorescent RNP libraries. 

Figure 1.11. Screening scheme of combinatorial libraries by the use of multiple cleavable linkers Two-stage screening and then identification of the biologically active compound.

Heteroaromatic aldehydes are excellent electrophiles in the MBH reaction because of their increased electrophilicity. The heteroatom also facilitates the proton transfers involved in the reaction (Scheme 1.53)/ In the presence of DABCO, pyridine-2-carboxaldehyde derivatives react rapidly with acrylates, methyl vinyl ketone and acrylonitrile to give excellent yields of the MBH adducts 112, which can be further transformed into indolizines 114 by thermal cyclization of their acetate derivatives 113 (Scheme 1.54)/ Notably, a small amount of indolizine 114 was formed along with normal MBH adduct 112 in the reaction of pyridine-2-carboxaldehyde with methyl vinyl ketone. Similarly, substituted 2-chloronicotin aldehydes 115 are reactive and efficient in the MBH reaction of methyl acrylates, acrylonitrile and cyclic enones catalyzed by various tertiary amine catalysts, such as DABCO, DBU, imidazole and 1-methylimidazole, to provide novel MBH adducts 116 and 117 for biological activity screening (Scheme 1.55). ... 

At the same time, Wang and co-workers [60] reported the first examples of enantioselective transfer hydrogenation of unprotected orthohydroxyaryl alkyl N-H ketimines using chiral phosphoric acid as a catalyst and Hantzsch ester as the hydrogen source. The hindered (.S)-3,3 -bis(tilphenylsilyl)-substituted phosphoric acid turned out to be the most effective in terms of chirality transfer, and benzene was a better reaction medium amongst the solvents screened (Scheme 15.27). 

To optimise the hydrogenation of 10, a model reaction with a simpler substrate, 2-a-acetamidocinnamic acid (11), was developed and a range of phosphines was screened (Scheme 1.3). 

The reaction with Af-Boc protected allyl amine was carried out in a 10 mmol scale with a ratio of substrate/Rh = 10 000 1 for 24 h without affecting the regio-and stereochemistry found in the prehminary screening (Scheme 4.79). The iV-mono-protected P -amino aldehyde was converted into the corresponding P -amino carboxylic acid by oxidation or into the corresponding 1,3-hydroxy amine by reduction. Both are valuable chiral building blocks. 

The above rules for reservoir selection are probably not exhaustive, but they provide a reasonable basis for a preliminary screening study. They may be applied to either a large database of reservoirs, as in the USA case discussed above, or, in a more detailed way, to a smaller database as in the UK case. Again, it must be emphasised that the general philosophy is to have a screening scheme which first asks Is there a problem with sweep efficiency and why (mobility ratio or heterogeneity) , and then goes on to ask Are the... 

The most popular CSPs selected to be included in the reported chiral column screening schemes are four polysaccharide-based phases, including cellulose tris(3,5-dimethylphenylcarbamate), cellulose tris-4-methylbenzoate, amylose... 

ICgQ = 20 iM) were ako screened (Scheme 6.21) [46]. Similar azide-alkyne click coupling of azide-functionalized neuraminic acid with different nucleoside-based alkynes was extended for the creation of bacterial sialyltransferase inhibitor [47]. 

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