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

Vunnam Srinivasulu, Paul Schilf, Saleh Ibrahim, Ihsan A. Shehadi, Omar G. Malik, Scott Sieburth, Monther A. Khanfar, Mohamad Hamad, Imad A. Abu-Yousef, Amin F. Majdalawieh, Taleb H. Al-Tel*

*Corresponding author for this work
1 Citation (Scopus)


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.

Original languageEnglish
JournalJournal of Organic Chemistry
Issue number16
Pages (from-to)10695-10708
Number of pages14
Publication statusPublished - 21.08.2020


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