Heterocyclic libraries

Iterative deconvolution is the original deconvolution method and remains quite reliable. The method relies on the synthesis of the library by the divide, couple, and recombine method to prepare a series of mixtures each with one residue of a selected diversity position being unique to each mixture. An active mixture(s) is selected and a resynthesis is performed whereby a second diversity position is defined. This is repeated until the resynthesis produces individual compounds. The highly active individual compounds this yields are the actives observed in the original active pool(s) ofthe library. The iterative method has been modeled by computer simulations. The results reported indicate that, even when accounting for experimental variability, an iterative deconvolution will converge to a molecule(s) that is the most active or very close to the most active (within 1 kcal) even for very large pools ( 65 000 compounds/pool) [18,19], 

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The Ugi reaction is the four-component condensation of an amine, aldehyde or ketone, carboxylic acid and isocyanide to give an o -acylamino amide [22-24], Although this process has the potential to introduce considerable diversity, the products themselves are not heterocycles but through appropriate choice of substrates, latent functionality in one of the precursors can intercept either an intermediate or further derivatize the acylamino amide Ugi product through post-modification. Thus variants of the Ugi reaction have been investigated under microwave-assisted conditions for the synthesis of diverse heterocyclic libraries [16,19-24],... 

For the preparation of the anticipated heterocyclic library compounds (Scheme 6.257), solutions of the prepared enamine synthons were split and diluted with an appropriate solvent, and 1.2 equivalents of a dinucleophile (hydrazine, hydroxylamine, amidines see Scheme 6.257 for more complex building blocks) was added. Subsequent exposure to microwave conditions in acetic acid/DMF mixtures... 

Commensurately with the development of various catalyst systems, the Pd-catalyzed G-O cross-coupling has found a number of synthetic applications. Examples include the syntheses of the protein kinase G (PKC) activator (+)-decursin,104 the natural product heliannuol E,105 a chiral 2-methyl chroman,106 and a series of aryloxy and alkoxy porphyrins.107 The Buchwald-Hartwig coupling has also been utilized in the preparation of a heterocycle library.108 Intramolecular O-arylation has also been achieved in the reactions of enolates with aryl halides leading to benzofur-ans.109,110 Finally, a double cross-coupling between an 0-dibromobenzene and a glycol has also been applied for the preparation of benzodioxanes (Equation (16)).1... 

Wu, X., Ding, Q., Schultz, P. G. (2002) A combinatorial scaffold approach toward kinase-directed heterocycle libraries. J Am Chem Soc 124, 1594-1596. 

Fig. 3. Perruthenate resin, an oxidizing resin based on ion exchange of heavy metal oxides, has been successfully employed in the preparation of heterocycle libraries. In this example, benzaldehydes were generated and reacted in aldol reactions with Nafion-TMS as Lewis acid.

A large number of drugs feature a heterocyclic component. Thus, the design, synthesis, and evaluation of heterocyclic libraries have rapidly become a major field of organic chemistry. Over the past decade, we have developed synthetic routes to a wide range of different heterocycles starting from resin-bound amino acids, short peptides, and polyamines. 

Cleavage of Resin-Bound Heterocyclic Libraries from the MBHA Resin... 

A U.S. patent has been issued covering nonnatural antisense structures in a combinatorial library format that claims the combinatorial library itself in an independent claim [89], The consequences of this type of claim and/or the likelihood this type of claim will be granted for heterocyclic libraries are unknown at this time. 

Figure 9.10 Solution-phase discrete five-membered heterocyclic libraries L2-L3 obtained from the solution-phase discrete chalcone library LI.

Small-Molecule Inhibitors of GGTase-I from the Heterocycle Library Derived from Phosphine Catalysis... 

Knepper K, Gil C, Brase S. Natnral prodnct-like and other biologically active heterocyclic libraries nsing solid-phase techniques in the post-genomic era. Comb. Chem. High Throughpnt Screen. 2003 6 673-691. 

The virtue of multifunctional triazene linkers in the efficient solid-phase synthesis of heterocyclic libraries 04ACR805. 

A particularly effective strategy for the design of new heterocyclic libraries employs a tandem N-acyliminium ion cyclization/nucleophilic addition for ring-forming processes [108] (Scheme 19). The described methodology provides access to bi-, tri-, and tetracyclic derivatives of l-acyl-3-oxopiperazines. The bicyclic variants in particular represent an interesting probe for a constrained type I p-turn motif with potential for combinatorial diversification. 

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