Combinatorial chemistry heterocyclic library synthesis,

At first, combinatorial chemistry focused on peptide and nucleotide libraries synthesis, but because poor pharmacokinetical properties cause poor oral availability of this kind of molecule, there is increasing interest in the development of new methods to prepare small, drug-tike molecules which obey lipinski s mle of five [303]. Heterocyclic compounds can offer a high degree of structural diversity and have proven to be useful as therapeutic agents. For these, there are recent advances in the preparation of heterocycles on solid supports [304]. The examples reported in this section are organized by their ring size. 

The first installment in this series (Volume 267, 1996) mostly covered peptide and peptidomimetic based research with just a few examples of small molecule libraries. In this volume we have compiled cutting-edge research in combinatorial chemistry, including divergent areas such as novel analytical techniques, microwave-assisted synthesis, novel linkers, and synthetic approaches in both solid-phase and polymer-assisted synthesis of peptides, small molecules, and heterocyclic systems, as well as the application of these technologies to optimize molecular properties of scientific and commercial interest. 

The Hantzsch synthesis of dihydropyridines represents a classical example of MCR, generating an array of diversely substituted heterocycles in a one-pot reaction procedure. Given that the reaction requires elevated temperatures and extended reaction times to proceed, acceleration of the process by microwave irradiation could be envisioned. Indeed, dielectric heating of aldehyde (aliphatic or aromatic) and 5 equivalents of /i-keloesler in aqueous 25% NH4OH (used both as reagent and solvent) at 140-150 °C for merely 10-15 min furnished 4-aryl-l,4-dihydropyridines in 51-92% yield after purification on a silica gel column [100]. The Hantzsch synthesis under reflux conditions ( 100 °C) featured a remarkably longer time (12 hours) and lower yields (15- 72%). To demonstrate the suitability of the procedure for the needs of combinatorial chemistry, a 24-membered library of 1,4-dihydropyridines (DHP) was prepared (Scheme 36). 

Interest in solid phase synthesis continues to increase as articles which expand the scope of non-oligomer organic synthesis are published and combinatorial chemistry is applied to an increasing variety of problems. A special thematic issue of Chemical Reviews on combinatorial chemistry [1] has been published which includes reviews of solid-phase chemistry as applied to the one bead-one compound approach [2], heterocycle synthesis [3], spatially addressable libraries [4], as well as soluble resin-based synthesis [5]. This review focuses on work published from June 1996 through September 1997. A discussion of solid-phase based reagents is not included as this topic is covered elsewhere. 

MATHEY Phosphorus-Carbon Heterocyclic Chemistry The Rise of a New Domain McKILLOP Advanced Problems in Organic Reaction Mechanisms OBRECHT Solid Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries... 

Nucleoside chemistry is traditionally labor intensive and the output of compoxmds is consequently relatively low. In order to overcome these limitations, several groups have implemented a parallel or combinatorial approach to speed up the synthesis process this chapter will only discuss the use of solid support for the synthesis of nucleoside libraries, not for the piupose of oligonucleotide synthesis. Chang <05BMC4760> attached a purine diehloride to a Merrifield 3,4-dihydropyran resin, followed by sequential displacement of the two ehloro atoms by various amines. The purine heterocyclic bases were then condensed with Dd.-ribofuranosides following a classical Vorbruggen method to yield nucleosides of general formula 171. 

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