Exploring New Chemical Space by Stereocontrolled Diversity-Oriented Synthesis

Abstract

Natural products that act as highly specific, small-molecule protein-binding agents and as modulators of protein-protein interactions are highly complex and exhibit functional groups with three-dimensional and stereochemical diversity. The complex three-dimensional display of chiral functional groups appears to be crucial for exhibiting specificity in protein binding and in differentiating between closely related proteins. The development of methods that allow a high-throughput access to three-dimensional, skelatally complex, polycyclic compounds having few asymmetric diversity sites is essential and a highly challenging task. In the postgenomic chemical biology age, in which there is a great desire to understand protein-protein interactions and to dissect protein networking-based signaling pathways by small molecules, the need for developing "stereocontrolled, diversity-oriented synthesis" methods to generate natural product-like libraries is of utmost importance.

Scaffold Diversity Synthesis and Its Application in Probe and Drug Discovery

“…In some of the presented examples,anoverlap with other divergent synthesis approaches may be unavoidable;however, we did not include examples from already extensively reviewed topics,s uch as DOS.R eaders interested in the various other divergent synthesis approaches and their applications are referred to the cited references. [8,20,21] Miguel …”

Principles, implementation, and application of biology-oriented synthesis (BIOS)

“…This demands a continuous improvement of synthetic methods that allow the synthesis of collections of small molecules in a parallel and rapid manner. Consequently, the development of synthetic methods that allow, for example, the stereoselective synthesis of compound libraries or of 'unbiased' compound libraries (e.g., by application of traceless-linker methodologies) is still required (Arya et al, 2005;Leßmann and Waldmann, 2006;Nandy et al, 2009;Yoshida et al, 2009).…”

Part 3. A Novel Stereocontrolled, In Situ, Solution- and Solid-Phase, Aza Michael Approach for High-Throughput Generation of Tetrahydroaminoquinoline-Derived Natural-Product-like Architectures

“…1 H NMR (400 MHz) spectra were recorded at room temperature in CDCl 3 or C 6 D 6 solutions and referenced to residual CHCl 3 (7.27 ppm) or C 6 H 6 (7.16 ppm). Fully decoupled 13 C NMR (100 MHz) spectra were recorded in CDCl 3 or C 6 D 6 solutions. The center peaks of CDCl 3 (77.0 ppm) and C 6 D 6 (128.7 ppm) were used as the internal reference.…”

“…Another objective was to validate our hypothesis that the compounds generated from this project were highly likely to yield interesting biological properties because these derivatives were anticipated to occupy the chemical space currently being championed by quinoline and tetrahydroquinoline alkaloids. 13 …”