Diastereodivergent Asymmetric 1,3‐Dipolar Cycloaddition of Azomethine Ylides and β‐Fluoroalkyl Vinylsulfones: Low Copper(II) Catalyst Loading and Theoretical Studies

Abstract

A CuII‐catalyzed asymmetric 1,3‐dipolar cycloaddition using β‐fluoroalkyl alkenyl arylsulfones as dipolarophiles and glycine/alanine iminoesters as azomethine ylide precursors has been developed. Remarkably, a catalyst loading as low as 0.5 mol % is highly efficient. Accordingly, a wide range of enantioenriched 3‐fluoroalkyl pyrrolidines, as well as Δ2‐pyrroline and pyrrole derivatives, are generated in good to excellent yields with high asymmetric induction. This synthetic approach is diastereodivergent in that exo‐adducts could be converted into the corresponding exo′‐adducts by 1,8‐diazabicyclo[5.4.0]undec‐7‐ene mediated epimerization at C2 of the pyrrolidine core. The free‐energy profiles from DFT calculations suggest the Michael addition of the 1,3‐dipole to be the rate‐ and enantiodetermining step, and the origin of stereoselectivity is studied by means of the noncovalent interaction (NCI) analysis.

Diastereodivergent Asymmetric 1,3‐Dipolar Cycloaddition of Azomethine Ylides and β‐Fluoroalkyl Vinylsulfones: Low Copper(II) Catalyst Loading and Theoretical Studies

“…Thea bsolute configuration of exo-3ab (CCDC 1854582) was unambiguously determined as (2R,3S,4S,5R)b ys inglecrystal X-ray analysis, [24] and the remaining products were assigned by analogy.Anonlinear effect study suggests that the active chiral Cu II catalyst works as am onomeric species without significant aggregation to form exo-3ab with high asymmetric induction (see Figure S1 in the Supporting …”

Diastereodivergent 1,3‐Dipolar Cycloaddition of α‐Fluoro‐α,β‐Unsaturated Arylketones and Azomethine Ylides: Experimental and Theoretical DFT Studies

“…Arai and coworkers achieved endo / exo ′ diastereoselectivity switch through a metal‐controlled diastereodivergent strategy using Cu(II) and Ni(II) complexes (Scheme 1a, eq ii) [7] . In 2019, we established a base‐controlled diastereodivergent strategy to access exo and exo ′‐pyrrolidines (Scheme 1a, eq iii) [8] . Nevertheless, the diastereodivergent catalytic process to access three or four diastereomers in a simple manner is still an elusive goal.…”

The Crucial Role of S‐oxidation State on the Selectivity and Reaction Rate of the 1,3‐Dipolar Cycloaddition of Azomethine Ylides and Homochiral Thiazolines

“…[1,2] A vast number of publications have been published since several years ago dealing with the insights of this cycloaddition due to the versatile organic molecules obtained through this methodology. [3][4][5][6][7][8][9][10][11][12] More interesting is the asymmetric version of this reaction, which allows to obtain up to 4 stereogenic centers in one reaction step in a selective manner, classically achieved by the use of metal-or organocatalysis. [13][14][15][16][17][18][19][20][21] The origin of the exo/endo selectivity in the catalytic asymmetric synthesis of pyrrolidines by 1,3-dipolar cycloaddition of azomethine ylides has been brilliantly rationalized and reported recently.…”