Synergistic Catalysis for the Asymmetric [3+2] Cycloaddition of Vinyl Aziridines with α,β‐Unsaturated Aldehydes

Abstract

The first asymmetric [3+2] cycloaddition of vinyl aziridines with α,β-unsaturated aldehydes, based on synergistic catalysis, is disclosed. This methodology allows the formation of attractive pyrrolidine structures in good yields (up to 84 %), moderate diastereoselectivity, and high enantioselectivity values (up to >99 % ee). Additionally, a tricyclic pyrrolidine core structure found in biologically active molecules was synthesized in a one-pot fashion by using the presented reaction concept. Finally, a mechanistic proposal is outlined.

Highly Efficient and Diastereoselective Construction of Tricyclic Pyrrolidine‐Fused Benzo[b]thiophene 1,1‐dioxide Derivatives via 1,3‐Dipolar [3 + 2] Cycloaddition

“…The fused polycyclic pyrrolidine skeletons are privileged structural motifs that are frequently encountered in biologically active natural products, with significant applications in the pharmaceutical and biological community . Among them, the tricyclic pyrrolidine motif is the key structural moiety in alkaloids and biologically active compounds, such as Rivastigmine analogs which exhibit the significant inhibitory effects on acetylcholinesterase, as well as, the tricyclic pyrrolidine display biological activity, for example, dipeptidyl peptidase IV (DPP‐4) inhibitors, was identified . As a result, the development of efficient methods for the construction of such frameworks have triggered increasing interest in organic and medicinal chemistry .…”

Synergistic formal ring contraction for the enantioselective synthesis of spiropyrazolones

“…Michelet, 5 Jørgensen, 6 Wei Wang 7 and Rios 8 reported a formal ring expansion of vinyl cyclopropanes with enals for the formation of spiro compounds under Pd(0) and secondary amine catalysis. Later on, Jørgensen reported vinyl aziridine opening 9 and [4 + 2] decarboxylation 10 ( Scheme 1 top) using a synergistic approach with excellent results. Rios' group has been one of the pioneers in the use of synergistic catalysis merging transition metal catalysts/metal Lewis acid and amine catalysis.…”

Diastereo‐ and Enantioselective Palladium‐Catalyzed Dearomative [3+2] Cycloaddition of 3‐Nitroindoles

“…[2] Since Yamamoto and co-workersr eported the seminal study of the Pd-catalyzed [3+ +2] cycloaddition of vinyl aziridines and electron-deficient alkenes for the formation of pyrrolidines in 2002, [3] several significant achievements have appeared. [3][4][5][6][7][8][9][10] Knight adopted 5-vinyloxazolidinones as the equivalent of vinyl aziridines through decarboxylation, [4] and Ooi group provided first example of asymmetric version of the reaction. [5] In both cases highly active double-activated alkenes were needed; [3][4][5][6] however,A ggarwal revealed that the use of mono-activated alkenes as reactants were prossible, [7] ando ur group realized the enantioselective cycloaddition reactiono f vinyl aziridines with a,b-unsaturated ketones.…”

“…[9] Very recently,J ørgensen group reportedt he asymmetric [ 3 + +2] cycloaddition of vinyl aziridines with a,b-unsaturated aldehydes based on synergistic catalysis. [10] In spite of these progresses, the Michael acceptors were only those electron-deficient alkenes, and the enantioselective version of the reactions is also limited. To develop an ew type of Michael acceptor for the enantioselective [3+ +2] cycloaddition is highly valuable.…”

“…The effect of solvent was examined (entries 1-10), indicating THF was the better choicet han other variouss olvents including toluene and DME (entries 2a nd 4 versus entry 1). To test the steric and electronic effects of substituento nn itrogen of indoles, 3-nitroindoles 2 with various N-protecting groups was investigated (entries1 [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. N-Ac 3nitroindole 2b was proved to be unreactive (entry 11).…”