Scaffold-decoration

Abstract An overview on the microwave-enhanced synthesis and decoration of the 2(lH)-pyrazinone system is presented. Scaffold decoration using microwave-enhanced transition-metal-catalyzed reactions for generating structural diversity, as well as the conversion of the 2(lH)-pyrazinone skeleton applying Diels-Alder reactions to generate novel heterocyclic moieties are discussed. The transfer of the solution phase to polymer-supported chemistry (SPOS) is also described in detail. 

Scheme 36 Scaffold decoration via Stille and Suzuki-Miyaura reactions on solid support...

Scheme 38 Scaffold decoration via UUmann-type reaction...

Scheme 6.19 Scaffold decoration of heterocycles using Suzuki cross-coupling chemistry.

Scheme 6.38 Scaffold decoration and modification of heterocycles using Stille cross-coupling chemistry.

Scheme 7.24 Scaffold decoration of polymer-bound pyrazinone scaffolds.

One of the key steps in combinatorial solid-phase synthesis is clearly the cleavage of the desired product from the solid support. A variety of cleavage protocols have been investigated, depending on the nature of the linker employed. A complete micro-wave-assisted protocol, involving attachment of the starting material to the solid support, scaffold preparation, scaffold decoration, and cleavage of the resin-bound product, would seem desirable. 

Reaction scale must deliver multi-100 mg quantities of material for further scaffold decoration work. 

Resulting fragments are clustered and reclassified into sets of monomers for subsequent library design. The RECAP procedure derives not only suitable chemotypes but also appropriate building blocks for scaffold decoration. Since the monomers are extracted from biologically active compounds, there is a high likelihood that new molecules derived from them will contain biologically important motifs. 

Figure 5 Examples of scaffold decoration for the solution-phase synthesis of pooled combinatorial libraries from Rebek and Isis. In both cases, biologically active compounds were identified...

A classic illustration of scaffold decoration is the trisubstituted 1,3,5-triazine. The starting material trichloro-l,3,5-triazine is inexpensive, and the halogens can be displaced by nucleophilic aromatic substitutions one by one. Such chemistry was well precedented in pre-combinatorial days, and used on a large scale for the synthesis of colour-fast reactive dyes. The overall reaction sequence has an appeal in its simplicity, and both academic and industrial practitioners have reported a steady trickle of such triazine-based libraries over the last 20 years. Novelty will come either from the particular set of nucleophiles employed or the assay targets. 

A number of high-yielding variants of the traditional three-component Biginelli condensation employing a variety of catalysts, reagents, and reaction conditions/techniques have been developed (09M115) these are beyond the scope of this review. Reference is made to some excellent reviews (Tables 1-4). However, scaffold decoration of Biginelli DHPMs is presented by us. 

BUS 14] EUSTACHE E., TILMANT P., MORGENROTH L., Silicon-microtube scaffold decorated with anatase Ti02 as a negative electrode for a 3d litium-ion microbattery . Advanced Energy Materials, vol. 4, pp. 1301612-130162, 2014. 

FIGURE 2.9 Three examples of combinatorial chemistry involving scaffold decoration of readily available natural products — yohimbine, scopolamine, and sorangicin (readily available to those who isolated it ). 

FIGURE 5.7 The synthetic strategies of scaffold decoration, core extension, and pharmacophore introduction. 

A functional library based on betulinic acid (17, Figure 5.8), a scaffold isolated from plants, is an example of using a synthetic strategy that involves semisynthetic modifications and DOS by scaffold decoration. Kashiwada et al. described the library design and evaluation of betulinic acid derivatives as anti-HIV (human immunodeficiency virus) compounds. ... 

Here we describe an in-house functional library based on fredericamycin A (18, Figure 5.9), a scaffold isolated from the fermentation broth of an actinomycete. The focused semisynthetic library used the DOS and scaffold decoration approaches. 

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