title: Trienamines in asymmetric organocatalysis: Diels-Alder and tandem reactions.
abstract: The discovery of a novel activation mode provided by organocatalysis is presented. It is demonstrated that the merger of optically active secondary amines and polyenals generates reactive trienamine intermediates, which readily participate in Diels-Alder reactions with different classes of dienophiles, hence, providing a facile entry to highly complex molecular frameworks with excellent stereocontrol. For the Diels-Alder reactions with 3-olefinic oxindoles, spirocyclic oxidoles are formed in high yields, and with enantioselectivities in the range of 94-98% ee. It is demonstrated, that some of these products can be transformed into the hexahydrofuro[2,3-b]indole fragment. The organocatalytic trienamine concept has been extended to also include Diels-Alder reactions of olefins substituted with cyanoacetates providing multifunctional cyclohexenes with three contiguous stereocenters in high yield and good stereocontrol. The novelty of this activation strategy lies within the perfect chirality relay over a distance of up to eight bonds. Moreover, we also present the first trienamine tandem reaction by combining trienamine catalysis with enamine activation. In addition to the experimental results, a detailed mechanistic survey is also provided including NMR spectroscopic studies and calculations of the reactive trienamine intermediates, rationalizing the origin of stereochemistry.
authors.affiliation: Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
authors.forename: Zhi-Jun
authors.initials: ZJ
authors.lastname: Jia
authors.forename: Hao
authors.initials: H
authors.lastname: Jiang
authors.forename: Jun-Long
authors.initials: JL
authors.lastname: Li
authors.forename: Björn
authors.initials: B
authors.lastname: Gschwend
authors.forename: Qing-Zhu
authors.initials: QZ
authors.lastname: Li
authors.forename: Xiang
authors.initials: X
authors.lastname: Yin
authors.forename: Julie
authors.initials: J
authors.lastname: Grouleff
authors.forename: Ying-Chun
authors.initials: YC
authors.lastname: Chen
authors.forename: Karl Anker
authors.initials: KA
authors.lastname: Jørgensen
mesh_terms: D000588:Amines / Q000737:chemistry*; D002384:Catalysis; D003500:Cyclization; D053138:Cyclohexenes / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D013237:Stereoisomerism
chemical_list: D000588:Amines; D053138:Cyclohexenes