Late-Stage C(sp2)-C(sp3) Diversification via Nickel Oxidative Addition Complexes.

Herein, we describe nickel oxidative addition complexes (Ni-OACs) of drug-like molecules as a platform to rapidly generate lead candidates with enhanced C(sp3) fraction. The potential of Ni-OACs to access new chemical space has been assessed not only in C(sp2)-C(sp3) couplings but also in additional bond formations without recourse to specialized ligands and with improved generality when compared to Ni-catalyzed reactions. The development of an automated diversification process further illustrates the robustness of Ni-OACs, thus offering a new gateway to expedite the design-make-test-analyze (DMTA) cycle in drug discovery.

Accelerated Synthesis of Bicyclo[1.1.1]pentylamines: A High-Throughput Approach.

Strained bicyclic substructures such as bicyclo[1.1.1]pentylamines (BCPAs) are increasingly targeted in medicinal chemistry as arylamine bioisosteres. Here, we leverage high-throughput automated synthesis to rapidly develop library-amenable reaction conditions and maximize design space to expand access to BCPAs. This new protocol relies on a copper-mediated C-N coupling approach and uses accessible and bench-stable iodo-BCP building blocks. Its applicability has been exemplified by incorporating BCPs in drug-like compounds, providing straightforward access to a library of valuable aniline-like isosteres.

Catalytic undirected borylation of tertiary C-H bonds in bicyclo[1.1.1]pentanes and bicyclo[2.1.1]hexanes.

Catalytic borylations of sp3 C-H bonds occur with high selectivities for primary C-H bonds or secondary C-H bonds that are activated by nearby electron-withdrawing substituents. Catalytic borylation at tertiary C-H bonds has not been observed. Here we describe a broadly applicable method for the synthesis of boron-substituted bicyclo[1.1.1]pentanes and (hetero)bicyclo[2.1.1]hexanes by an iridium-catalysed borylation of the bridgehead tertiary C-H bond. This reaction is highly selective for the formation of bridgehead boronic esters and is compatible with a broad range of functional groups (>35 examples). The method is applicable to the late-stage modification of pharmaceuticals containing this substructure and the synthesis of novel bicyclic building blocks. Kinetic and computational studies suggest that C-H bond cleavage occurs with a modest barrier and that the turnover-limiting step of this reaction is an isomerization that occurs prior to reductive elimination that forms the C-B bond.

Azeotropic reflux chromatography: an efficient solution to a difficult separation in the scale-up synthesis of spongistatin 1.

Azeotropic reflux chromatography (in which the eluent is continuously recycled by means of refluxing) was used to separate a mixture of spiroketal intermediates in the scale-up synthesis of spongistatin 1, leading to an improved separation and an approximately 35-fold reduction in the amount of solvent used.