4351
Synthesis of Heterocycles via Controlled Cyclization of Alpha-Enaminones
Tsvelikhovsky Dmitry, HUJI, School of Medicine - IMRIC, School of Pharmacy- Institute for Drug Research
Background
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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.
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Unfortunately, access to a large number of these target molecules, and their structural analogues, is either unknown or hindered by the multistep syntheses.
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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.
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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
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Linking simple and single enaminone core with a diverse, heterocyclic architectures.
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Unexplored, stable α-enaminone synthones, radically different from other known α- or β-counterparts by their chemical behavior.
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Unlock unusual functionalities of -enaminone synthones.
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Accurate design of the starting material allows specific and selective functionalization reactions across the unsaturated scaffold, enabling the preparation of diverse products.
Research Highlights
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α-enaminones can react as enamines (nucleophiles), as well as α,β-unsaturated ketones (electrophiles).
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Our finding uncovers unprecedented reactivity of α,β-unsaturated enaminones driven by their “dual electronic attitude”
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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.
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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.
Fig.1 : New α- enaminone synthone
Fig.2 : Dual electronic attitude of α- enaminone
Opportunity
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Collective synthesis of several important classes of heterocycles.
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A potential application for the construction of highly complex systems.
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Paves the way for novel retrosynthetic pathways in the field of chemical research.