REVBLOCKS is a generalizable, modular strategy for synthesizing complex small molecules based on the Suzuki-Miyaura (SM) reaction for covalent carbon-carbon (C-C) bond formation. In a prototypical reaction cycle shown here, a selected chemical subunit containing a reactive haloboronic acid is first protected using the trivalent ligand N-methyliminodiacetic acid, or MIDA. After an SM coupling reaction in which a selective C-C bond is formed between the MIDA-protected subunit and a second unprotected subunit, deprotection under mild conditions exposes a new reactive boronic acid that can participate in a subsequent cycle of coupling with another protected subunit.

In REVBLOCKS, cycles of coupling and deprotection are performed iteratively to allow successive incorporation of selected chemical subunits. After the coupling reaction, a standardized “catch-and-release” purification step takes advantage of the MIDA boronate motif, which confers on the growing compound binary affinity for silica gel with select pairs of eluents. This general approach is applicable to a range of C-C couplings (including Csp2 and Csp3), as well as C-X (heteroatom) couplings. Furthermore, cyclic and polycyclic structures can be assembled by a strategy of iterative synthesis to generate linear compounds that are subsequently cyclized. 

REVBLOCKS drives directed introduction of chemical diversity into complex chemical scaffolds. In this process, the parental scaffold is envisioned as a covalent aggregate of simpler building blocks. By making focused atomic changes to individual building blocks as needed and incorporating these revised building blocks into a complex scaffold via iterative cross-coupling, novel compounds are created that can be tested for pharmacologic and pharmaceutical properties. The coupling, purification and deprotection cycle is being industrialized. This process generates optimized lead compounds and drug candidates that otherwise may have not been possible by conventional synthetic means.