Boron-mediated thermodynamic resolution of axially chiral pyridines and its application in the asymmetric total synthesis of streptonigrin

Atropisomers represent an important class of chiral molecules and there are many prominent natural products and pharmaceuticals that exhibit atropisomerism, however general stereoselective synthetic routes to these compounds are relatively rare. In this work, we developed a novel thermodynamic resolution process that allows access to these compounds in enantioenriched form. This approach takes advantage of several features of organoboron chemistry:

• a mild boron-directed regioselective cycloaddition for the construction of highly functionalised pyridines;
• boron ligand substitution for the synthesis of chiral organoboronic esters;
• control of atroposelectivity through a dynamic resolution process that exploits the Lewis acidity of trivalent boron chemistry
• stereoretentive synthesis of atropisomeric products by virtue of the versatile organoboronic ester functional group;
• recycle of the minor diastereomer is possible thanks to the thermodynamic nature of the resolution.

Furthermore, the strategy is the first reported thermodynamic strategy for the resolution of atropisomers. The applicability of this method is further highlighted by the first highly enantioselective synthesis of streptonigrin. Even though this molecule has been deeply studied since its discovery in 1959 and is a very well-known example of atropoisomeric natural products, a synthetic method that allows access to this compound with high levels of enantiocontrol has been lacking until now.