The Schreiber lab has a long-standing interest in designing biologically active compounds with unique stereochemical and skeletal features. In this regard, cyclopropanes provide a three-dimensional, rigid scaffold featuring well-defined exit vectors. We describe the direct and modular synthesis of lactam-fused cyclopropanes from readily available amino olefins using unprecedented, bench-stable diazo reagents. Notably, the transformation proceeds through consecutive acylation / (3+2) cycloaddition / fragmentation reactions and does not involve reactive carbene or carbenoid intermediates, thus displaying a remarkably broad tolerance towards various functional groups. The modularity of the method furnishes a wide spectrum of complex molecular scaffolds, including fused and bridged ring systems as well as spirocycles. Moreover, the transformation generates stereogenic quaternary carbon centers, structural elements whose incorporation into small molecules is sought after but commonly proves challenging. Application of the operationally simple method is demonstrated in the efficient synthesis of milnacipran and amitifadine, therapeutic agents that are used in the clinical treatment of fibromyalgia and alcoholism, respectively. Altogether, the broad substrate scope and modularity of the reported method promise wide-spread application and studies on its use in the synthesis of structurally unprecedented DNA-encoded libraries are currently ongoing.

Modular synthesis of lactam-fused cyclopropanes enabled by underexplored diazo reagents

ACS Spring 2022

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