Atropisomers discovery

The search for a general synthesis of enantio-merically pure non-biaryl atropisomers has been given added impetus by the discovery [26, 27] that the absolute configuration of some atropiso-meric amides affects their biological activity. The enantiomeric atropisomers 21 and 22 (Scheme 13) differed in activity at the tachykinin NK, receptor by a factor of 6-13, with 21 being the more active. Atroposelectivity must now be an important new consideration in drug synthesis. 

During the two decades after this important discovery, a tremendous amount of research has been directed toward the polymerization of sterically demanding achiral monomers with chiral initiators to create enantiomerically pure helical polymers (also known as helix-sense selective or screw-sense-selective polymerization ). These polymers, known as atropisomers, are stable conformational isomers that arise from restricted rotation about the single bonds of their main chains. Key aspects of these reactions are enantiopure initiators that begin the polymerization with a one-handed helical twist, and monomers with bulky side-chains that can maintain the helical conformation due to steric repulsion. Notable examples of this fascinating class of polymers that are configurationally achiral but conformationally chiral include [8, 38, 39] poly(trityl methacrylate), polychloral, polyisocyanates, and polyisocyanides. Important advances in anionic and metal-based enantioselective polymerization methods have been reported in recent years. 

A paper has been devoted to the relationship between atropisomer axial chirality and drug discovery that contains many examples related to this section (11CMC505). 

The total synthesis of CP-465,022 is described. This former drug candidate exists as two separable rotational isomers (atropisomers). The discovery and separation of these rotational isomers is described, as well as the methodology used to prepare the pyridyl sidechain and the quinazolinone nucleus. Testing showed that the desired biological activity existed in just one of the atropisomers. 

LaPlante SR, Edwards PJ, Fader LD, Jakalian A, Hucke O. Revealing atropisomer axial chirality in drug discovery. Chem. Med. Chem. 2011 6(3) 505-513. 

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