4351

Synthesis of Heterocycles via Controlled Cyclization of Alpha-Enaminones

Tsvelikhovsky Dmitry, HUJI, School of Medicine - IMRIC, School of Pharmacy- Institute for Drug Research

Category

Chemistry&Materials   

Keywords

α-enaminone, heterocycles, cyclization

Current development stage

General list: TRL2  Technology Concept Formulated       

Application

  • Oxazine, azaspirone, quinolines, quinolinone, and quinolinol structures are frequently observed as scaffold segments in various biochemical compounds. These architectures have been identified as building blocks of a numerous alkaloids and often remotely related metabolites.
  • Unfortunately, access to a large number of these target molecules, and their structural analogues, is either unknown or hindered by the multistep syntheses.
  • An in-depth analysis of the introduced cores suggests that α-enaminone scaffold of Type-1 has the potential to serve as an operational, collective key unit for their construction via controlled intramolecular cyclizations.
  • However, little is known about α-enaminones, apparently because they are often not directly accessible from the corresponding diketones.  Furthermore, methods for the preparation of heterocycles using α-ketoenamines are limited.

Our Innovation

A novel methodology for the synthesis of heterocycles via controlled cyclization of an easily accessible α -Enaminones common key precursors

  • Linking simple and single enaminone core with a diverse, heterocyclic architectures.
  • Unexplored, stable α-enaminone synthones, radically different from other known α- or β-counterparts by their chemical behavior.
  • Unlock unusual functionalities of -enaminone synthones.
  • Accurate design of the starting material allows specific and selective functionalization reactions across the unsaturated scaffold, enabling the preparation of diverse products.

Research Highlights

  • α-enaminones can react as enamines (nucleophiles), as well as α,β-unsaturated ketones (electrophiles).
  • Our finding uncovers unprecedented reactivity of α,β-unsaturated enaminones driven by their “dual electronic attitude”
  • The feasibility of this new concept is demonstrated in the direct functionalization of enaminone precursors, such as alkylation; 1,2- 1,3-, or 1,4-addition; and C−O bond formation.
  • It was successfully demonstrated that readily available α-enaminone precursors undergo facile cyclizations under basic conditions to afford a broad spectrum of heterocycles, such as azaspirones, quinolinones, quinolines, quinolinols, and oxazines.  

4351-1.jpg

Fig.1 : New α- enaminone synthone

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Fig.2 : Dual electronic attitude of α- enaminone

Opportunity

  • Collective synthesis of several important classes of heterocycles.
  • A potential application for the construction of highly complex systems.
  • Paves the way for novel retrosynthetic pathways in the field of chemical research.

 

 

 

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