Approaches to Synthesis and Isolation of Enantiomerically Pure Biologically Active Atropisomers

CONSPECTUS: Atropisomerism is a stereochemical phenomenon exhibited by molecules containing a rotationally restricted sigma bond. Contrary to classical point chirality, the two atropisomeric stereoisomers exist as a dynamic mixture and can be interconverted without the requirement of breaking and reforming a bond . Although this feature increases structural comple x i t y , atropisomer s have become frequent targets in medicinal chemistry projects. Their axial chirality, e.g., from axially chiral biaryl motifs, gives access to unique 3D structures. It is often desirable to have access to both enantiomers of the atropisomers via a nonselective reaction during the early discovery phase as it allows the medicinal chemistry team to probe the structure activity relationship in both directions. Howe v e r , once a single atropisomer is selected, it presents several problems. First, the pure single atropisomer may interconvert to the undesired stereoisomer under certain conditions. Second, separation of atropisomers is nontrivial and often requires expensive chiral stationary phases using chromatography or additives if a salt resolution approach is chosen. Other options can be kinetic resolution using enzymes or chiral catalysts. Howe v e r , apart from the high cost often associated with the two latter methods, a maximum yield of only 50% of the desired atropisomer can be obtained. The ideal approach is to instal l the chiral atropisomeric axis enantioselectively or employing a dynamic kinetic resolution approach. In theory, both approaches have the potential to provide a single atropisomer in quantitative yield. This Account wi l l discuss the successes/failures and challenges we have experienced in developing methods for resolution/separation and asymmetric synthesis of atropisomeric drug candidates in one of our early phase drug development projects. Suitability for the different methods at various stages of the drug development phase is discussed. Depending on the scale and time available, a separation of a mixture of atropisomers by chromatography was sometimes preferred, whereas asymmetric-or resolution approaches were desired for long-term supply. With the use of chromatography, the impact on separation efficiency and solvent consumption, depending on the nature of the substrate, is discussed . We hope that with this Account the readers will get a better view on the challenges medicinal and process chemists meet when designing new atropisomeric drug candidates and developing processes for manufacture of a single atropisomer.

Automated summary

Atropisomerism is a stereochemical phenomenon exhibited by molecules with a rotationally restricted sigma bond. Atropisomers exist as a dynamic mixture and can be interconverted without breaking and reforming bonds. They are frequent targets in medicinal chemistry projects due to their axial chirality and unique 3D structures. However, selecting a single atropisomer presents problems such as interconversion and separation challenges. Chromatography, enzymatic or chiral catalysts can be used for separation, but each method has limitations. This Account discusses the successes, failures, and challenges of developing methods for resolution and synthesis of atropisomeric drug candidates.