Cu(I)‐Ming‐phos Catalyzed Enantioselective [3+2] Cycloadditions of Glycine ketimines to β‐Trifluoromethyl Enones

Abstract

A catalytic asymmetric [3 + 2] cycloaddition of glycine ketimines with b-CF 3 b,b-disubstituted enones was realized in the presence of a chiral copper(I)/Ming-Phos complex. This method provides an access to construct highly functionalized pyrrolidines bearing three contiguous stereocenters, which including a trifluoromethylated allcarbon quaternary stereocenter. The features of this reaction include high chemo-, diastereo-, enantioselectivity (up to > 20:1 cr, > 20:1 dr, 98% ee), readily available starting materials, well functional-group tolerance and mild reaction conditions. Control experiments demonstrate that the fluorosubstituent is crucial for the reactivity.Pyrrolidines are an important class of five-membered nitrogen-containing heterocycles, which can be used as new catalysts and served as important motifs in many biologically active molecules. [1] Therefore, tremendous efforts for the synthesis of pyrrolidines, especially in an asymmetric manner, have been devoted, among which asymmetric [3 + 2] cycloaddition reactions [2] have been widely recognized as a powerful approach for constructing pyrrolidine derivatives, with high chemo-, regio-, and stereoselectivity. This method allows the cycloaddition to proceed under mild reaction conditions with extremely versatile and atom economical process. Among the different versions of this reaction, the most practical approach was the interaction between aldiminoesters and electron deficient alkenes. [3] While, compared to the aldiminoesters, the glycine ketimines undergo 1,4-Michael addition [4] dominantly due to the obvious steric effect and low reactivity for cyclization. Therefore, highly selec-tive [3 + 2] cycloadditions of conventional simple Schiff bases of ketiminoesters, to a,b-unsaturated carbonyl compounds have been much less explored. [5,6] Kobayashi et al. reported asymmetric [3 + 2] cycloadditions of glycine ketimines to a,b-unsaturated esters or amides in the presence of chiral Cacomplexes. [5] Wang and co-workers obtained the corresponding cycloadduct by employing dimethyl maleate.[6a] Oh's group achieved a stereodivergent synthesis of glycine ketimines to nitroalkenes, which suggested the use of glycine ketimine was a key factor in identifying the anti-selective conjugate addition product. [6b] Here, we report the first example of such asymmetric reactions using b,b-disubstituted enones.Meanwhile, the introduction of a CF 3 group at a specific site to a bioactive molecule is considered as a powerful strategy to improve its physicochemical, biological, and pharmaceutical properties. [7,8] Thus, the development of reliable synthetic approaches to CF 3bearing heterocycles, especially the construction of chiral trifluoromethylated all-carbon quaternary stereocenters, [9] became a challenging task in the past decades. Recently, we reported an enantioselective copper-catalyzed Michael addition/cycloaddition reaction of glycine ketimines with b-CF 3 b,b-disubstituted enones, [10] with the use of chiral ligand i Pr-FOXAP, but the scope of enones is quite...

β-Trifluoromethylated enones as trifluoromethylated synthons in asymmetric catalysis

“…44 After that, a similar strategy to the synthesis of optically active pyrrolidine derivatives via asymmetric intermolecular [3 + 2] cycloaddition reaction of glycine ketimines with β-trifluoromethyl β,β-disubstituted enones in the combi- nation of copper catalyst with chiral phosphine ligand-Ming-Phos L4 was developed by the Zhang group (Scheme 26b). 45 In closely related work, the group of Liu and Zhang have implemented a ligand-controlled Cu(I)-catalyzed diastereo-, regio-, and enantioselective intermolecular [3 + 2] cycloaddition reaction of α-substituted iminoesters with β-fluoromethyl β,β-disubstituted enones (Scheme 27). 46 This was the first example of the regioselectivity promoted by the selection of an appropriate chiral ligand to furnish a new avenue for the construction of pyrrolidines bearing two adjacent or discrete quaternary stereocenters and fluoromethylated group with excellent yields (up to >99%), regio-(up to >20 : 1 rr), diastereo-(up to >20 : 1 dr), and enantioselectivity (up to >99% ee).…”

“…44 After that, a similar strategy to the synthesis of optically active pyrrolidine derivatives via asymmetric intermolecular [3 + 2] cycloaddition reaction of glycine ketimines with β-trifluoromethyl β,β-disubstituted enones in the combination of copper catalyst with chiral phosphine ligand-Ming-Phos L4 was developed by the Zhang group (Scheme 26b). 45…”

Fluorine in metal-catalyzed asymmetric transformations: the lightest halogen causing a massive effect

“…92 In the presence of CuClO 4 , a chiral sulnamide monophosphine (MingPhos) ligand, bearing a pentauorophenyl substituent at the C-stereocentre, led to the [3 + 2]-cycloaddition product with lower enantioselectivity than its non-uorinated analogue (66% ee vs. 82% ee). 93 The Pd II -catalyzed allylic alkylation reaction was performed using (S)-prolinol-based uorous aminophosphine (S)-256 and (S)-257 (Scheme 29). 94 High enantioselectivities were obtained from the addition of dimethyl malonate 115, at rst deprotonated by LiOAc-N,O-bis(trimethylsilyl)acetamide (BSA), to 1,3diphenyl-2-propenyl acetate rac-114 by using both chiral catalysts ((S)-116: 86% ee using (S)-256; 92% ee using (S)-257).…”

“…In the presence of CuClO 4 , a chiral sulfinamide monophosphine (MingPhos) ligand, bearing a pentafluorophenyl substituent at the C -stereocentre, led to the [3 + 2]-cycloaddition product with lower enantioselectivity than its non-fluorinated analogue (66% ee vs. 82% ee). 93 …”

Acid-induced intermolecular [3+2] cycloaddition/oxidation to synthesize polysubstituted benzo[f]isoindole-4,9-diones

“…Examples include Hantzsch, [13][14][15][16][17][18] Trofimov, [19][20][21][22] Mannich [23][24][25][26] and Clauson-Kaas reactions, [27][28][29][30] Friedel-Crafts, [31][32][33][34] and [3+2] cycloadditions. [35][36][37][38][39] In recent years, metal-free catalysis of various organic transformations has gained more and more attention. 40,41 Benzoic acid, a high catalytically active, nontoxic, inexpensive, and readily available catalyst for the construction of five-membered heterocycles, has attracted the interest of numerous chemists.…”