The complex three-dimensional structures of Csp3- and stereocenter-rich small molecules offer tremendous potential to serve transformative roles in society. For instance, there is a strong positive correlation between Csp3 content and successful drug development. Natural products rich in sp3 carbons and stereocenters also perform a plethora of remarkable, albeit frequently underutilized, functions. Understanding and harnessing the functional potential of these and many other natural products often requires synthetic access to the parent molecule and many structural derivatives, but due to their inherent complexity, the requisite time and labor to create customized total syntheses still remains a major bottleneck. To accelerate synthetic access to complex small molecules, we need to begin the transition away from the traditional approach of using highly customized routes featuring many different kinds of reactions towards a more generalized, rapid, and automatable synthesis platform.
Stereochemically-complex, Csp3-rich small molecules can perform extraordinary functions, but accessing this potential often requires the time-consuming optimization of highly customized synthetic routes. The development of a more generalized building block-based synthesis strategy has the potential to substantially improve the efficiency and flexibility of small molecule synthesis. However, applying this approach to structurally complex small molecules requires highly precise Csp3 coupling methods that form discrete products free of stereo- and regioisomers.
Lego-like assembly of pre-fabricated organoboronate building blocks has emerged as a promising strategy for generalizing and automating the synthesis of complex molecules (Burke and coworkers, Science 2015, 347 (6227), 1221-6). Already, this approach has accelerated synthetic access to many different types of compounds rich in Csp2 carbons, including natural products, pharmaceuticals, biological probes, and materials components.
The problem is that the synthesis of stereochemically complex Csp3-rich small molecules remains a highly customized, slow, and specialist-dependent process, and thus represents a major bottleneck in efforts to access the substantial untapped functional potential that this class of chemical matter possesses. Accordingly, there is a need for catalysts with specialized ligands that can efficiently, and cost effectively, catalyze the stereospecific formation of carbon-carbon bonds.