Privileged Scaffolds for Library Design and Drug Discovery

In the search for new therapeutic agents for currently incurable diseases, attention has turned to traditionally “undruggable” targets, and collections of drug-like small molecules with high diversity and quality have become a prerequisite for new breakthroughs. To generate such collections, the diversity-oriented synthesis (DOS) strategy was developed, which aims to populate new chemical space with drug-like compounds containing a high degree of molecular diversity. The resulting DOS-derived libraries have been of great value for the discovery of various bioactive small molecules and therapeutic agents, and thus DOS has emerged as an essential tool in chemical biology and drug discovery. However, the key challenge has become how to design and synthesize drug-like small-molecule libraries with improved biological relevancy as well as maximum molecular diversity. This Perspective presents the development of privileged substructure-based DOS (pDOS), an efficient strategy for the construction of polyheterocy...

http://pubs.acs.org/doi/pdf/10.1021/ja508343a

Privileged Structures: Efficient Chemical “Navigators” toward Unexplored Biologically Relevant Chemical Spaces

In this paper we report on a novel fluorescent core skeleton, 9-aryl-1,2-dihydropyrrolo[3,4-b]indolizin-3-one, which we named Seoul-Fluor, having tunable and predictable photophysical properties. Using a concise and practical one-pot synthetic procedure, a 68-member library of new fluorescent compounds was synthesized with diverse substituents. In Seoul-Fluor, the electronic characteristics of the substituents, as well as their positional changes, have a close correlation with their photophysical properties. The systematic perturbation of electronic densities on the specific positions of Seoul-Fluor, guided with the Hammett constant, allows emission wavelength tunability covering the full color range. On the basis of these observations and a computational analysis, we extracted a simple first-order correlation of photophysical properties with the theoretical calculation and accurately predicted the emission wavelength of Seoul-Fluors through the rational design. In this study, we clearly demonstrate that Seoul-Fluor can provide a powerful gateway for the generation of desired fluorescent probes without the need for a tiresome synthesis and trial-and-error process.

Emission Wavelength Prediction of a Full-Color-Tunable Fluorescent Core Skeleton, 9-Aryl-1,2-dihydropyrrolo[3,4-b]indolizin-3-one

Current strategies for diversity-oriented synthesis.

2H-Chromenes (2H-1-benzopyran derivatives) display a broad spectrum of biological activities. The 2H-chromene substructure is an important structural motif present in a variety of medicines, natural products, and materials showing unique photophysical properties. Hence, the structural importance of the benzopyran moiety has elicited a great deal of interest in the field of organic synthesis and chemical biology to develop new and improved synthesis of these molecular skeletons. This review gives an up-to-date overview of different catalytic methodologies developed for the synthesis of 2H-chromenes and is structured around the three main approaches applied in catalytic 2H-chromene synthesis: (I) catalysis with (transition) metals, (II) metal-free Bronsted and Lewis acid/base catalysis, which includes examples of nonenantioselective organocatalysis, and (III) enantioselective organo-catalysis. The section in which the metal-catalyzed reactions are discussed describes different ring-closing strategies based ...

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Catalytic Synthesis of 2H-Chromenes

A novel strategy for the construction of benzopyranyl heterocyclic series with maximized diversity in the polar surface area on rigid scaffolds has been developed through a divergent synthetic pathway with high efficiency. s-cis-Enones embedded in a benzopyran skeleton were identified as versatile key intermediates for the synthesis of four different heterocycle libraries fused with a benzopyran substructure. These four novel core skeletons were designed by a creative recombination of the privileged skeletons: benzopyran, pyridine, pyrazole, pyrazolopyrimidine, and pyrimidine. The regioselective synthesis of each core skeleton was achieved by the introduction of three s-cis enone intermediates. This paper also explores the regioselective formation of arylpyrazole through the condensation of beta-keto aldehyde with arylhydrazine under three different conditions and presents the mechanistic information that was obtained from the regioisomeric ratio of arylpyrazole based on the substituent's electronic effect and reaction temperature. It appears that the regioselective synthesis of arylpyrazole was achieved through the intriguing interplay of the nucleophilicity on arylhydrazine and the electrophilicity on dielectrophiles.

Sung Kwang Lee

Papers

Diversity-oriented synthesis of privileged benzopyranyl heterocycles from s-cis-enones

Diversity-Oriented Synthesis of Privileged Benzopyranyl Heterocycles from s-cis-Enones.