Simultaneous Construction of C–N Axial and Central Chirality via Silver-Catalyzed Desymmetrizative [3 + 2] Cycloaddition of Prochiral N-Aryl Maleimides with Activated Isocyanides

Abstract

Herein, we report an unprecedented strategy for the simultaneous construction of a remote C−N stereogenic axis and three contiguous stereogenic carbon centers via silver-catalyzed desymmetrizative [3 + 2] cycloaddition of prochiral N-aryl maleimides with activated isocyanides. This method features operational simplicity, wide substrate scope, high efficiency, and good to excellent stereoselectivity. Notably, it represents the first example of catalytic enantioselective synthesis of C−N atropisomers with the use of activated isocyanides.

Catalytic Asymmetric Synthesis of Atropisomers Bearing Multiple Chiral Elements: An Emerging Field

“…[29] Independently, Liao, Qian, and co-workers reported Ag-catalyzed desymmetrizative (3 + 2) cycloaddition of N-Aryl caleimides 23 with activated isocyanides 41 (Scheme 9d). [30] By these approaches, chiral products 38, 40, 42 bearing a CÀ N axis were synthesized with overall high stereoselectivities.…”

“…Using this strategy, Yuan, Han, and co‐workers developed Cu‐catalyzed desymmetrizative 1,3‐dipolar cycloaddition of N ‐arylmaleimide 23 with N ‐2,2,2‐trifluoroethylisatin ketimines 39 (Scheme 9c) [29] . Independently, Liao, Qian, and co‐workers reported Ag‐catalyzed desymmetrizative (3+2) cycloaddition of N ‐Aryl caleimides 23 with activated isocyanides 41 (Scheme 9d) [30] . By these approaches, chiral products 38 , 40 , 42 bearing a C−N axis were synthesized with overall high stereoselectivities.…”

Silver-catalyzed synthesis of nitrogen heterocycles: recent advancements

“…In 2022, an unpredicted strategy for accessing C–N atropisomers via an enantioselective catalytic pathway using activated isocyanides 50 was established. 65 The group simultaneously fabricated three nearby chiral carbon centers and a C–N axial chirality in a one-pot process, in high yields, by reacting activated isocyanides 50 with the prochiral N -aryl maleimide entity 51 in the presence of 5 mol% Ag 2 CO 3 52 and 10 mol% ligand in DCE for 12 h at 0 °C (Scheme 17). The reaction proceeded via a desymmetrizative [3 + 2] cycloaddition pathway triggered by the chiral silver catalytic system.…”

Silver‐Catalyzed and Silver‐Promoted Reactions of Isocyanides

“…[8] An unprecedented strategy for the simultaneous construction of a remote CÀ N stereogenic axis and three contiguous central chirality via silver-catalyzed desymmetrizative [3 + 2] cycloaddition of prochiral N-aryl maleimides 22 with activated isocyanides 23 was reported by Qian and Liao's group (Scheme 3). [9] A variety of highly functionalized bicyclic 1pyrrolines 25 were obtained in high yields with good to excellent stereoselectivities. Notably, the first example of catalytic enantioselective synthesis of CÀ N atropisomers with the use of activated isocyanides was represented by this work.…”