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

Abstract

Octahydroindolo[2,3-a]quinolizine ring system forms the basic framework comprised of more than 2000 distinct family members of natural products. Despite the potential applications of this privileged substructure in drug discovery, efficient, atom-economic and modular strategies for its assembly, is underdeveloped. Here we show a one-step build/couple/pair strategy that uniquely allows access to diverse 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 demonstrates excellent diastereoselectivity, and the enantioselectivity exceeded 99% when amino acids are used as chiral reagents. Furthermore, two diastereoselective reactions for the synthesis of oxocanes and piperazinones, is reported. Phenotypic screening of the octahydroindolo[2,3-a]quinolizine library identifies small molecule probes that selectively suppress mitochondrial membrane potential, ATP contents and elevate 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.

A Novel Benzopyrane Derivative Targeting Cancer Cell Metabolic and Survival Pathways

“…The recent decade has witnessed an upsurge in the employment of diversity-oriented synthesis strategies for the de novo construction of first-in-class small molecules needed for phenotypic screening campaigns [ 22 , 23 , 24 ]. Among the structural options, the benzopyrane scaffold is a privileged architecture representing the core structure of a wide range of biologically appealing molecules [ 25 ].…”

Recent Advances in Divergent Synthetic Strategies for Indole-Based Natural Product Libraries

“…More recently, the Al-Tel group reported a new Ctd strategy for the nature-inspired indole monoterpenoid compounds 36 and 37 [ 45 ], prepared from compounds 34 and 35 [ 46 ] ( Scheme 3 ). The compounds 36 and 37 have inherent complexity and transformable moieties such as cyclohexanone, piperidine, and indole rings, which makes them efficient starting points for the Ctd strategy.…”

“…In contrast, natural product biosynthesis in living organisms allows facile access to structurally complex and distinct skeletons from relatively simple common intermediates through enzyme-catalyzed processes. This tremendous efficiency and diversity-generating power of the biosynthetic pathways allows for the rapid generation of diverse natural products and related compounds, including indole-based compounds [ 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ].…”

Identification of Spiro-Fused Pyrrolo[3,4-a]pyrrolizines and Tryptanthrines as Potential Antitumor Agents: Synthesis and In Vitro Evaluation

“…In most cases, these are compounds of complex structure that can be obtained only as a result of complex multistage synthesis. Recent advances in the synthesis of such complex heterocyclic systems have led to a significant increase in interest in the development of efficient methods for the synthesis of various derivatives and structural analogues of these compounds as potential drugs or biological probes [ 3 , 4 ]. Therefore, oxindole, azabicyclohexane, pyrrolizine, pyrroloisoquinoline and indoloquinazoline units are heterocyclic motifs that form the core of a large family of alkaloid natural products with strong bioactivity profiles and interesting structural properties [ 5 ].…”