Endocyclic Enamides Derived from Aza‐Diketopiperazines as Olefin Partners in Povarov Reaction: An Access to Tetracyclic N‐Heterocycles

• Published in: European journal of organic chemistry Vol. 2020; no. 47; pp. 7385 - 7395
• Main Authors: Maujean, Timothé, Chataigner, Isabelle, Girard, Nicolas, Gulea, Mihaela, Bonnet, Dominique
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 20.12.2020; Wiley Subscription Services, Inc; Wiley-VCH Verlag
• Subjects: Aldehydes; Aza‐diketopiperazines; Chemical Sciences; Chemistry; Chemistry, Organic; Cycloaddition; DFT study; Enamides; Lewis acid; Nitrogen atoms; N‐heterocycles; Organic chemistry; Physical Sciences; Povarov reaction; Science & Technology; diketopiperazines; DIVERSIFICATION; MECHANISM; N‐ Povarov reaction; DFT study; Enamides; Aza‐ ORIGIN; STEREOSELECTIVITY; heterocycles; CHEMISTRY; SCAFFOLDS
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.202001339

Original endocyclic enamides based on a bicyclic aza‐diketopiperazine (aza‐DKP) structure have been used as dienophile partners in the Povarov reaction. The reported method represents a successful strategy for the structural diversification of the aza‐DKP scaffold, giving access to a new family of fused tetracyclic N‐heterocycles, which contain at least four nitrogen atoms in the heterocyclic structure. Depending on the nature of the aldehyde partner, the cycloadditions have been performed either as a two‐component or a three‐component Povarov reaction (2CPR or 3CPR), in the presence of BF3 as a Lewis acid catalyst. With aliphatic aldehydes the reaction proceeds with high diastereoselectivities in favor of the cis compounds. Some mechanistic aspects of this cycloaddition have been examined computationally. An endocyclic enamide having a unique bicyclic structure including a 1,2,4‐triazine‐3,6‐dione subunit was used as an olefin partner in the Povarov reaction. This represents an efficient strategy to access a new family of fused tetracyclic N‐heterocycles which combine in their structure two scaffolds of interest in medicinal chemistry, a tetrahydroquinoline (THQ and an aza‐diketopiperazine (aza‐DKP).