β-Substituted Alkenyl Heteroarenes as Dipolarophiles in the Cu(I)-Catalyzed Asymmetric 1,3-Dipolar Cycloaddition of Azomethine Ylides Empowered by a Dual Activation Strategy: Stereoselectivity and Mechanistic Insight

Abstract

The catalytic asymmetric 1,3-dipolar cycloaddition reactions of azomethine ylides with various electron-deficient alkenes provide the most straightforward protocol for the preparation of enantioenriched pyrrolidines in organic synthesis. However, the employment of conjugated alkenyl heteroarenes as dipolarophiles in such protocols to afford a class of particularly important molecules in medicinal chemistry is still a great challenge. Herein, we report that various β-substituted alkenyl heteroarenes, challenging internal alkene substrates without a strong electron-withdrawing substituent, were successfully employed as dipolarophiles for the first time in the Cu­(I)-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides. This reaction furnishes a large array of multistereogenic heterocycles incorporating both the biologically important pyrrolidine and heteroarene skeletons in good yields with exclusive diastereoselectivity and excellent enantioselectivity. Our extensive density functional theory (DFT) calculations proposed a working model to explain the origin of the stereochemical outcome and elucidated uncommon dual activation/coordination of both the dipole and dipolarophile substrates by the metal, in which a sterically bulky, rigid, and monodentate phosphoramidite ligand with triple-homoaxial chirality plays a pivotal role in providing an effective chiral pocket around the metal center, resulting in high enantioselectivity. The additional coordination of the heteroatom in the dipolarophile substrate to Cu is also critical for the exclusive diastereoselectivity and enhanced reactivity. Our calculations also predicted the reverse and high enantioinduction for the corresponding substrates with monocyclic heteroarenes as well as regiospecific cycloaddition to the less reactive internal CC bond of one related dipolarophile diene substrate. Such unique steric effect-directed enantioswitching and coordination-directed regioselectivity were verified experimentally.

New Insights and Predictions into Complex Homogeneous Reactions Enabled by Computational Chemistry in Synergy with Experiments: Isotopes and Mechanisms

“…Recently, the Wang group overcame this hurdle by using β-substituted alkenyl heteroarenes 8 and a bulky monodentate phosphoramidite ligand (L*) to develop an efficient Cu(I)-catalyzed asymmetric 1,3-dipolar cycloaddition to form 10. 4 Professor Wang invited us to unmask the unclear origin of this high reactivity as well as their observed excellent enantioselectivity and exclusive diastereoselectivity. We then carried out an extensive computational study to decipher the mechanism and the origin of the stereochemistry, including the size effect of the ligand and substrates on the stereochemistry (Figure 3).…”

“…Our DFT study (using the M06-2X, B3LYP-D3, PBE0, and ωB97X-D functionals) showed that the reaction generally follows a two-step mechanism with the second C−C bond formation as the rate-determining step to give the cyclization product. 4 When the monodentate ligand L* was employed, uncommon dual activation/coordination of both substrates (8 and 9) by the metal was elucidated computationally. The absence of additional coordination of substrate 8 raised the computed barrier and reduced the computed stereoselectivities.…”

Synthesis of bioactive fluoropyrrolidinesviacopper(i)-catalysed asymmetric 1,3-dipolar cycloaddition of azomethine ylides

“…It is well known that the dipolarophiles of the 1,3-dipolar cycloaddition of azomethine yilde are generally limited to highly activated olefins bearing strong electron withdrawing substituents, [29][30][31][32][33][34] and only a few cases are associated with less reactive olefins, however, the utilization of inactive alkenes as dipolarophiles remains a great challenge. [70][71][72] In addition, the potential elimination of fluorine atoms in intermediates or products is another challenge for this reaction design. 73 Please do not adjust margins Please do not adjust margins…”

Catalytic asymmetric synthesis of enantioenriched α-deuterated pyrrolidine derivatives

“…In view of the importance of deuterium-labelled chiral N-heterocycles and our continuing interest in the catalytic asymmetric construction of enantioenriched pyrrolidine derivatives with azomethine ylide, 31,41,42 we envisioned that merging the H/D-exchange (H/D-Ex) protocol 15 with the 1,3-dipolar cycloaddition reaction would meet this great challenge in a catalytic asymmetric manner and exactly cater for the ever-growing demand of deuterated bioactive heterocyclic molecules in the pharmaceutical industry. 43 As shown in Scheme 1b, we proposed that base-promoted and/or transition metal-catalyzed H/D-exchange of readily available glycine-derived aldimine ester with certain deuterium reagent would deliver the corresponding deuterated intermediate 1 - d n ( n = 1 or 2); 44,45 the deuterated aldimine ester could coordinate with the transition-metal cation to form the key N -metallated azomethine ylide bearing a deuterium atom at the α-position.…”