Fragment-based drug discovery (FBDD) has proven to be an effective means of producing high-quality chemical ligands as starting points for drug-discovery pursuits. The increasing number of clinical candidate drugs developed using FBDD approaches is a testament of the efficacy of this approach. The success of fragmentbased methods is highly dependent on the identity of the fragment library used for screening. The vast majority of FBDD has centered on the use of sp 2 -rich aromatic compounds. An expanded set of fragments that possess more 3D character would provide access to a larger chemical space of fragments than those currently used. Diversity-oriented synthesis (DOS) aims to efficiently generate a set of molecules diverse in skeletal and stereochemical properties. Molecules derived from DOS have also displayed significant success in the modulation of function of various "difficult" targets. Herein, we describe the application of DOS toward the construction of a unique set of fragments containing highly sp 3 -rich skeletons for fragment-based screening. Using cheminformatic analysis, we quantified the shapes and physical properties of the new 3D fragments and compared them with a database containing known fragment-like molecules.library development | probe discovery
The stereochemistry is one of the critical issues in the Staudinger reaction. We have proposed the origin of the stereoselectivity recently. The effects of solvents, additives, and pathways of ketene generation on the stereoselectivity were investigated by using a clean Staudinger reaction, which is a sensitive reaction system to the stereoselectivity. The results indicate that the additives, usually existed and generated in the Staudinger reaction, and the pathways of the ketene generation do not generally affect the stereoselectivity. The solvent affects the stereoselectivity. The polar solvent is favorable to the formation of trans-beta-lactams. The addition orders of the reagents affect the stereoselectivity in the Staudinger reaction between acyl chlorides and imines. The addition of a tertiary amine into a solution of the acyl chloride and the imine generally decreases the stereoselectivity, which is affected by the interval between additions of the acyl chloride and the tertiary amine, and the imine substituents. Our current results provide further understanding on the stereochemistry of the Staudinger reaction between acyl chlorides and imines and on the factors affecting the stereochemistry and also provide a method to prepare beta-lactams with the desired relative configuration via rationally tuning the stereoselectivity-controlling factors in the Staudinger reaction.
A notable and obvious ketene substituent-dependent effect of temperature on the stereoselectivity in the Staudinger reaction was observed. Most Staudinger reactions show concave Eyring plots characterized by two lines with an inversion point, following the principle of isoinversion. Their cis-selectivities decrease with increasing temperature. Reactions involving intramolecular p-pi and pi-pi interactions between the ketene substituents and imine C-substituents reveal protruding, S-shaped or straight-line Eyring plots. Their cis-selectivities increase with increasing temperature in a certain temperature region because such interactions enhance the cis-selectivity. Staudinger reactions involving cyclic imines with different ketenes clearly indicate that the temperature-dependent stereoselectivity is caused by the different rate increases of the direct ring closure, which are affected by the p-pi and pi-pi interactions between ketene substituents and imine C-substituents if they exist, and the isomerization of the zwitterionic intermediates generated from ketenes and imines during the change in the reaction temperature, not by the competition of the imine exo and endo attacks to the ketenes. Our results also indicate that nonlinear Eyring plots do not always reveal a change of the stereoselectivity-determining step. Thus, one should use them carefully to determine any changes in the stereoselectivity-determining step during the change in the reaction temperature.
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