Diversity-Oriented Asymmetric Synthesis

Abstract

The application of small molecules to modulate proteins by direct interactions has evolved as a powerful tool for the study of complex biological systems. Conventional genetic approaches have examined biological systems by generating random mutations which were then screened in search of a precise cellular phenotype. Analogous to the genetic approach, large random collections of small molecules can be used to elucidate the roles of specific proteins in many biological pathways. The crux of this 'chemical genetic' approach is the design and synthesis of libraries of compounds which span large tracts of biologically relevant chemical space. Diversity-oriented asymmetric synthesis (DOAS) is an exceptional methodology for preparing structurally and stereochemically diverse small molecule libraries which show a greater variety not only in their physiochemical properties but also in their biological activities. Herein, we describe some of the most effective strategies that have been used in asymmetric diversity-oriented synthesis library design and preparation.

Application of Metathesis Protocols to the Stereocontrolled Synthesis of some Functionalized β‐Amino Esters and Azaheterocycles

“…Diversity‐oriented synthesis (DOS), whose aim is the construction of valuable (structurally and chemically diverse) molecular libraries, has become an important principle during the last two decades in pharmaceutical chemistry and drug design. Three‐dimensional complex scaffolds are common DOS targets, because such compounds are more promising in drug discovery [69–81] . Ring‐rearrangement metathesis (RRM) is one of the methods which can easily and efficiently generate highly complex frameworks that would be difficult to synthesize by conventional common methods [57–58] …”

“…Three-dimensional complex scaffolds are common DOS targets, because such compounds are more promising in drug discovery. [69][70][71][72][73][74][75][76][77][78][79][80][81] Ring-rearrangement metathesis (RRM) is one of the methods which can easily and efficiently generate highly complex frameworks that would be difficult to synthesize by conventional common methods. [57][58] The present account summarizes metathesis protocols to the preparation of structurally diverse molecular entities focusing on stereocontrolled synthetic routes for accessing azaheterocyclic β-amino acid derivatives, with the strategy based on ring-rearrangement metathesis of highly strained unsaturated bicyclic compounds (Scheme 1).…”

Elucidating Hyperconjugation from Electronegativity to Predict Drug Conformational Energy in a High Throughput Manner

“…However, this diversity still covers only a small fraction of the drug structure space with privileged structures being overrepresented. As a result, the diversity of these privileged structures and libraries has been looked at computationally and experimentally. − Although increasing the diversity of the chemical databases is expected to increase the hit discovery rate, this ever-increasing diversity is a major concern in computational chemistry and more specifically molecular mechanics as large diversity correlates with a need for highly transferable methods.…”

Chemoinformatic Approach: The Case of Natural Products of Panama

“…Natural products (NPs) and their derivatives constitute a significant fraction of approved drugs [1][2][3], bioactive compounds [4][5][6][7][8], and lead compounds for drug discovery [9]. NP fragment has been used to guide the synthesis of bioactive compounds and generate BIOS combinatorial libraries [10][11][12][13][14][15]. NPs have structures with different substituent patterns, giving rise to different biological activities for compounds with very similar structures [16][17][18][19].…”