The development of efficient and modular synthetic methods for the preparation of complex natural product-inspired libraries with rich stereochemical and skeletal diversity remains a challenge in the field of drug design and discovery. Octahydroindolo[2,3-a]quinolizine ring system forms the basic framework comprised of more than 2000 distinct family members of natural products. Several members of this 6-5-6-6 monoterpenoid indole family have gained attention due to their broad and controversial biological activities. Despite the potential applications of this privileged substructure in drug discovery, efficient, atom-economic and modular strategies for its assembly is underdeveloped. Herein, we describe a one-step build/couple/pair strategy that uniquely allows access to diversely functionalized octahydroindolo[2,3-a]quinolizine scaffolds with more than three contiguous chiral centers and broad distribution of molecular shapes via desymmetrization of the oxidative-dearomatization products of phenols. The cascade reaction demonstrates excellent chemo-, diastereo-selectivity, and the enantioselectivity exceeded 99% when amino acids were used as chiral reagents. Additionally, the discovery of a novel OsO4 catalyzed rearrangement reaction of the octahydroindolo[2,3-a]quinolizine products is described. Furthermore, the discovery of two serendipitous diastereoselective reactions for the synthesis of oxocanes and piperazinones, is reported. Phenotypic screening of the octahydroindolo[2,3-a]quinolizine library identified small molecule probes that selectively suppressed mitochondrial membrane potential (ΔΨm), ATP contents and elevated the ROS contents in hepatoma cells (Hepa1.6) without altering the immunological activation or reprogramming of T- and B-cells, a promising approach to cancer therapy.

Multidirectional desymmetrization of pluripotent building block en route to the asymmetric/diastereoselective synthesis of complex nature-inspired scaffolds

2019 Spring National Meeting

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