Intramolecular Nucleophilic Tandem Reactions Of Tertiary Enamides

The tertiary enamides are generated when one of the N-alkyl groups of enamines is replaced by an electron-withdrawing group,such as an acyl.Owing to the N-electron-withdrawing group which alleviates the delocalization of the lone-pair electons of the nitrogen atom into the carbon-carbon double bond,tertiary enamides show diminished enaminic?nucleophilic?reactivity,therefore the nucleophilic reactions of tertiary enamides remain largely unexplored.Meanwhile nucleophilic reaction of tertiary enamides leads to iminium intermediates which can be intercepted by many nucleophilic reagents.Based on the nucleophility of tertiary enamides and the electrophility of iminium,we systematically studied the intramolecular nucleophilic tandem reactions of the tertiary enamides.We have established a novel and efficient method for rapid construction of pyrrole[2,1-a]isoquinoline and indolizino[8,7-b]indole alkaloid derivatives.A number of stable tertiary enamides containing the electrophilic groups and nucleophilic groups were designed and synthesized,their intramolecular nucleophilic tandem reactions catalyzed by Lewis acid and chiral Lewis acid were systematically studied.Sn?OTf?₂ and Sc?OTf?₃ were proved to be effective catalysts.The tandem reaction produced a series of pyrrole[2,1-a]isoquinoline and indolizino[8,7-b]indole alkaloid derivatives in good to excellent yields with high diastereoselectivity.A Cu?OTf?₂/chiral Pybox complex catalyzed the intramolecular enantioselective addition of tertiary enamides to ketonic carbonyls with subsequent diastereoselective intercepton of the resulting acyliminium by tethered electron-rich moiety.The transformations of the resulting heterocycles into various alkaloid derivatives were also demonstrated.We attempted to synthesize benzopyrrolizidine analogues using the same strategy.After investigation of steric and electronic effects,no successful synthesis of benzopyrrolizidines was achieved.Instead,however,we discovered that the tertiary enamides underwent the facile intramolecular nucleophilic tandem reaction leading to multisubstituted pyrrole derivatives.The reaction was initiated by intramolecular nucleophilic reaction of the tertiary enamides to aldehyde followed by dehydration aromatization reaction.We applied the rapid,efficient and highly selective synthetic strategy of indolizino[8,7-b]indole derivatives to the synthesis of Iboga natural products.A pre-functionalized tertiary enamide was synthesized and the precursor of Iboga natural product was obtained through the efficient intramolecular nucleophilic tandem reaction.To accomplish catalytic asymmetric synthesis of Iboga natural products,functionalgrouptransformationsoftheresulting indolizino[8,7-b]indole derivatives were studied,and interesting fused heterocyclic compounds were attained.In conclusion,as a kind of structurally stable nucleophile,tertiary enamides are very important synthons in organic chemistry and can undergo smoothly the intramolecular nucleophilic tandem reactions which provide a novel approach to N-heterocycle compounds,multisubstituted pyrroles and natural product-like compounds.