Synthesis of C-Ring-Substituted Vasicinones and Luotonins via Regioselective Aza-Nazarov Cyclization of Quinazolinonyl Enones

Abstract

A facile synthesis of C-ring substituted luotonins and vasicinones has been realized via a super-acid-mediated aza-Nazarov cyclization of quinazolinonyl enones. The regioselectivity of the cyclization is highly dependent on proton availability in the reaction medium.

A Bifurcated Multicomponent Synthesis Approach to Polycyclic Quinazolinones

“…Further, aliphatic isocyanides 1-adamantyl isocyanide ( 17b , 85%), tetrahydrofuran-2-ylmethyl isocyanide ( 18b , 47%), tert -octyl isocyanide ( 19b , 91%), methyl isocyanoacetate ( 20b , 63%), and tert -butyl (2-isocyanoethyl)­carbamate ( 21b , 70%) gave good yields as well. This is meaningful since the previously reported methods either have the limited type of substitutions or are non-substituted in this position. − Meanwhile, by using our strategy, we opened the substitution possibilities at this position for all available isocyanides providing the opportunity for various further chemical modifications.…”

“…This is meaningful since the previously reported methods either have the limited type of substitutions or are non-substituted in this position. 9 − 11 Meanwhile, by using our strategy, we opened the substitution possibilities at this position for all available isocyanides providing the opportunity for various further chemical modifications.…”

“…luotonins A, B, and E ( 1 – 3 ) are naturally occurring cytotoxic alkaloids, being demonstrated as human DNA topoisomerase I (hTopI) poisons . The current synthesis of luotonin derivatives may suffered from multiple synthetic procedures and/or a limited substrate scope. − , Scheme illustrates our initial success of luotonin A derivative 35b (51%) synthesis of which the Ugi adduct 35a (43%) was assembled from the appropriate 2-bromobenzoic acid ( 6a ), 2-quinolinecarbonitrile ( 7b ), ammonia ( 9c ), and benzyl isocyanide ( 8c ). Despite this, the Passerini three-component (P-3CR) byproduct was observed in Ugi-4CR.…”

“…The application of radical cyclization as well as self-catalyzed phototandem perfluoroalkylation/cyclization of unactivated alkenes also has been reported for the synthesis of the same scaffolds . As shown in Scheme , these approaches suffer from one or many issues, such as lengthy sequential synthesis, limited scope, and generality. − Inspired by previous syntheses and based on our deep interest in MCR chemistry, we envisioned that isoindolo­[1,2- b ]­quinazolinone derivatives could be synthesized in a concise manner by an Ugi-4CR reaction of o -bromobenzoic acids, o -cyanobenzaldehydes, isocyanides, and ammonia followed by a metal-catalyzed intramolecular N-arylation to form the desired products . Alternatively, we figured, in a second strategy, that it could also be synthesized by an Ugi-4CR using o -iodobenzaldehyde, benzoic acid, isocyanides, and cyanamide followed by radical cyclization of the N-acylcyanamide moiety since the cyano group is a well-established radical acceptor that has been involved in the build of various heterocycles and carbocycles .…”

Redox Condensations of o-Nitrobenzaldehydes with Amines under Mild Conditions: Total Synthesis of the Vasicinone Family

“…These compounds possess a broad range of bioactivity, e.g., antitumor, antiendotoxic, antifungal, etc. Some state-of-the-art approaches toward quinazolinones include transformations of complex molecules using aza-Wittig or aza-Nazarov reactions, photoredox cyclizations, reductive cyclizations of different anthranilic acid derivatives, and so on . In most cases, these approaches involve a multistep synthesis from complex molecules.…”