Combinatorial heterocyclic synthesis

Combinatorial synthesis of heterocycles 96MI7, 97CRV449, 99AG(E)2494, 99CSR1. 

Combinatorial synthesis of multicomponent mixtures, among them mixtures of heterocycles, for screening of bioactive compounds 99JMC3743. 

Biologically important arylaimnes, various kinds of heterocycles, and macrocyclic potmds have been prepared by using resin-botmd nitro halo compotmds via S Such a process is very important for combinatorial synthesis of biologically important potmds Typical examples are presented in Eqs 9 13-9 31... 

Perhaps the most important issues to consider now are the application of novel methodologies, molecular diversity, and synthetic convenience. There have been several reports of novel, one-pot procedures for the preparation of 1,2,4-triazoles with diverse structures. Synthesis of 1,2,4-triazoles on polymeric supports, in both solution and solid phase, represents a step toward the combinatorial synthesis of these heterocycles. It is these novel applications of technology to organic synthesis that perhaps lead the way in 1,2,4-triazole chemistry. 

A linker originally designed for solid-phase synthesis of peptides is the backbone amide linker (11) (BAL), this anchoring approach has now been extended to the combinatorial synthesis of diverse amide [31], hydroxamate [32], oligosaccharide [33] and heterocyclic small molecule libraries [34-36]. 

Acetylenic dienophiles have also been used in conjunction with a different type of diene (150) for the combinatorial synthesis of isoindolones 151 fused with furan, pyrrole or thiophene rings (Fig. 30) [129]. In this case, the diene involved in IMDA is not the 5-membered heterocycle itself, but the one including the exocyclic double bond. The resulting dihydrobenzene is easily aromatized by oxidation with DDQ or C/O2. The synthetic protocol is accomplished in a one-pot process. 

N, N-Dimethylformamide diethyl acetal (DMFDEA) is a interesting reagent, since it can be used to form alkylaminopropenones or alkylaminopropenoates when reacted with compounds having activated methylene groups such as (3-ketoesters, acetophenone and N-acylglycine. These alkylaminopropenones or alkylaminopropenoates can subsequently be reacted with dinucleophiles to form a variety of heterocycles. Westman and co-workers32 have used DMFDEA for the synthesis of propenoates and propenones, which were used directly without intermediate purification for the formation of a number of heterocycles in a combinatorial fashion. Some examples are outlined in Scheme 5.16. The reactions were performed in a two-step one-pot procedure, which in this case were more suitable for combinatorial synthesis. 

Westman, J. and Lundin, R., Solid phase synthesis of aminopropenones and aminopropenoates. Efficient and versatile synthons for combinatorial synthesis of heterocycles, Synthesis, 2003, 7, 1025-1030. 

Groebke, K., Weber, L. and Mehlin, E, Synthesis ofimidazo[l,2-a] annulated pyridines, pyrazines and pyrimidines by a novel three-component condensation, Synlett, 1998, 661 Blackburn, C., Guan, B., Shiosaki, K. and Tsai, S., Parallel synthesis of 3-aminoimidazo[l,2-a] pyridines and pyrazines by a new three-component condensation, Tetrahedron, 1998, 3635-3638 Bienayme, H. and Bouzid, K., A new heterocyclic multicomponent reaction for the combinatorial synthesis of fused 3-aminoimidazoles, Angew. Chem., Int. Ed. Engl, 1998, 37, 2234-2237. 

Miller and co-workers, as part of their program in connection to the development of polypeptides as practical and readily modular chiral catalysts and new screening protocols for combinatorial synthesis, have been able to achieve efficient catalytic enantioselective conjugate additions of azides to acyclic enones [15]. As the example in Eq. (5) illustrates, the resulting 3-azidocarbonyls can be easily modified to afford N-containing heterocycles. 

Combinatorial synthesis and screening of heterocyclic, drug-like scaffold libraries... 

Gopalsamy A, Pallai PV, Combinatorial synthesis of heterocycles solid phase synthesis of 2-arylquinoline-4-carboxylic acid derivatives, Tetrahedron Lett., 38 907-910, 1997. 

Gordeev MF, Patel DY, Gordon EM, Approaches to combinatorial synthesis of heterocycles a solid-phase synthesis of 1,4-dihydropyridines, J. Org. Chem., 61 924-928, 1996. 

Patel DV, Gordeev MF, England BP, Gordon EM, Solid-phase and combinatorial synthesis of heterocyclic scaffolds Dihydropyridines, pyridines, and pyrido[2,3-d]pyrimidines, in Molecular Diversity and Combinatorial Chemistry (Eds Chaiken IW, Janda KD), pp. 58-69, 1996, American Chemical Society, Washington. 

A two-step method for the combinatorial synthesis of amines and amino alcohols using vinylsulfomethylpolystyrene is described. This solid-phase synthetic route requires very few reagents for the permutational synthesis of new heterocyclic amine derivatives. 

In an earlier investigation by the author [1] polystyrene-g-acrylamide, (I), was used in the combinatorial synthesis of heterocyclic amines as illustrated below. 

Using a split-and-pool combinatorial synthesis strategy, Tamanoi and coworkers developed a library of approximately 4000 heterocycles generated from resin-bound allenoates by means of phosphine catalysis [36,37]. This library was initially screened to identify GGTase I inhibitors (Table 8.1), and some potent GGTase I inhibitors with novel... 

MF Gordeev, DV Patel, J Wu, EM Gordon. Approaches to combinatorial synthesis of heterocycles solid phase synthesis of pyridines and pyrido [2,3-d] pyrimidines. Tetrahedron Lett 37 4643-4646, 1996. 

---