Divergent Strategy for Diastereocontrolled Synthesis of Small- and Medium-Ring Architectures

Abstract

Nitrogen and oxygen medium rings, in particular nine-membered rings, epitomize a unique area of chemical space that occurs in many natural products and biologically appealing compounds. The scarcity of 8- to 12-membered rings among clinically approved drugs is indicative of the difficulties associated with their synthesis, principally owing to the unfavorable entropy and transannular strain. We report here a scandium triflate-catalyzed reaction that allows for a modular access to a diverse collection of nine-membered ring heterocycles in a one-pot cascade and with complete diastereocontrol. This cascade features an intramolecular addition of an acyl group-derived enol to a α,β-unsaturated carbonyl moiety, leading to N- and O-derived medium-ring systems. Computational studies using the density functional theory support the proposed mechanism. Additionally, a one-pot cascade leading to hexacyclic chromeno­[3′,4′:2,3]­indolizino­[8,7-b]­indole architectures, with six fused rings and four contiguous chiral centers, is reported. This novel cascade features many concerted events, including the formation of two azomethine ylides, [3 + 2]-cycloaddition, 1,3-sigmatropic rearrangement, Michael addition, and Pictet–Spengler reaction among others. Phenotypic screening of the resulting oxazonine collection identified chemical probes that regulate mitochondrial membrane potential, adenosine 5′-triphosphate contents, and reactive oxygen species levels in hepatoma cells (Hepa1-6), a promising approach for targeting cancer and metabolic disorders.

Discovery of novel papain-like protease inhibitors for potential treatment of COVID-19

“…Seventy compounds [ [20] , [21] , [22] , [23] , [24] , [25] , [26] , [27] ] with diverse scaffolds from our in-house pilot compounds library were initially screened to identify potential inhibitors of PLpro at a single concentration of 10 μg/mL using PLpro enzymatic inhibition assay (BPS Bioscience, San Diego, CA, USA). A PLpro inhibitor, GRL-0617, was used as a positive control.…”

“…In this study, a phenotypic screen was performed using in-house developed compound collection [ [20] , [21] , [22] , [23] , [24] , [25] , [26] , [27] ] to identify PLpro inhibitors using fluorescence resonance energy transfer (FRET)-based assay. The screening revealed that out of the 70 tested compounds, 13 exhibited over 50% inhibitory activity at a concentration of 10 μg/mL (Supp.…”

“…The tested compounds were synthesized and characterized as described before [ [20] , [21] , [22] , [23] , [24] , [25] , [26] , [27] ].…”

“…With that in mind, we took the initiative to screen an in-house collection of various classes of compounds against SARS-CoV-2 PLpro, and herein we report our findings ( Supp. Table 1 ) [ [20] , [21] , [22] , [23] , [24] , [25] , [26] , [27] ]…”

Antimalarial Dibenzannulated Medium-Ring Keto Lactams

“…Exposure of keto lactams 32 and 28 to triethylamine or aq. NaOH in ethanol , at room temperature (rt) afforded quinolones 38 and 39 in yields of 77 and 80%, respectively (Table ). Finally, the known compounds 2 , ,, 3 , , 4 , ,, 5 , and 12 were synthesized by published procedures.…”