Despite major recent advances in C–H activation, discrimination between two similar, unactivated C–H positions is beyond the scope of current chemocatalytic methods. Here we demonstrate that integration of regioselective halogenase enzymes with Pd-catalysed cross-coupling chemistry, in one-pot reactions, successfully addresses this problem for the indole heterocycle. The resultant ‘chemobio-transformation' delivers a range of functionally diverse arylated products that are impossible to access using separate enzymatic or chemocatalytic C–H activation, under mild, aqueous conditions. This use of different biocatalysts to select different C–H positions contrasts with the prevailing substrate-control approach to the area, and presents opportunities for new pathways in C–H activation chemistry. The issues of enzyme and transition metal compatibility are overcome through membrane compartmentalization, with the optimized process requiring no intermediate work-up or purification steps.
The process development toward synthesizing a diethanolamine (DEA) boronic ester and the subsequent Suzuki− Miyaura coupling (SMC) is disclosed herein. A one-pot lithiation−borylation−transesterification was successfully developed to isolate the DEA boronic ester as a stable crystalline solid and avoided the formation of boronic acid or pinacol boronic ester analogues, which have poor physical properties and purity profiles. The crystalline DEA boronic ester was also successfully employed in the SMC, and the improved input quality allowed for a simpler and more robust process to be developed with enhanced quality of the isolated intermediate. The borylation and SMC were operated on 60 and 350 kg scales, respectively, and generated 2300 kg of the active pharmaceutical ingredient AZD5718.
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