Copper‐Catalyzed Asymmetric Conjugate Addition of Dimethylzinc to Acyl‐N‐methylimidazole Michael Acceptors: Scope, Limitations and Iterative Reactions

Abstract

An efficient copper-catalyzede nantioselective conjugate addition of dimethylzinc to unsaturated 2-acyl-N-methylimidazoles has been achieved using ac hiral bidentateh ydroxyalkyl-NHC ligand. Ther eactions proceed with excellent regioselectivity (1,4 vs. 1,6 and 1,8) in extended conjugateds ystems to affordt he 1,4-adducts in high enantioselectivities. This regioselectivity could be ascertained by DFT studies highlightingt he crucial role of the imidazole ring. Thanks to the development of efficient protocols to regenerate the unsaturated 2-acyl-N-methylimidazole moiety,a ni terative process has been developed ultimately leading to 3,5,7 all-syn or anti-anti polydeoxypropionate stereodiads.Scheme 5. Applicationo ft he ACA/post-functionalizations equence involving a,b-unsaturated 2-acyl-N-methylimidazole 1h to the synthesis of (+ +)-(S)-Florhydral .Scheme 6. Synthesis of unsaturated di-andt rienic2 -acyl-Nmethylimidazole subtrates 1i-n. Scheme 7. Substrate scope for the 1,4-regioselective ACAo f dimethylzinc to poly-unsaturated 2-acyl-N-methylimidazoles 1i-n catalyzed by L1/Cu(OTf) 2 .Scheme 12. Synthesis of anti,anti 3-(S),5-(R),7-(S)a cyl-N-methylimidazole 2p.

Catalytically Active Species in Copper/DiPPAM‐Catalyzed 1,6‐Asymmetric Conjugate Addition of Dialkylzinc to Dienones: A Computational Overview

“…In 1 b , in the case of 1,6‐addition, the C−C bond formation fully breaks the conjugation of the phenyl group with the π system whereas, in the 1,4‐addition, conjugation of the terminal C=C bond with Ph is kept. Conjugation is thus proposed to be the factor tuning regioselectivity between 1 a and 1 b , in parallel to the already observed ligand effects (reported for BINAP) or to the additional substrate‐catalyst interaction (reported for Acyl‐N‐methylimidazole) . This is confirmed by computations on a simple model including only electronic effects in 1 a and 1 b (see Tables S2–S4 in SI).…”

“…The relevance of this catalytic active species was supported by the good agreement with selectivity between experimental observations and calculations. Indeed, it was used to rationalize the effect of the nature of the substituent at C=O position in substrate on the regioselectivity towards 1,4‐ or 1,6‐conjugate addition, evidencing the possibility for an electron‐rich substituent (methyl‐imidazole for instance) to establish an interaction with the electro‐deficient copper. The same model also allowed to reproduce and analyze the enantioselectivity of the ACA, which was proposed to originate from a stabilizing π‐stacking network in the p‐complex .…”

Acyl‐Imidazoles: A Privileged Ester Surrogate for Enantioselective Synthesis

“…As depicted in Scheme , the reaction proceeds with a remarkable 1,4 regioselectivity ( vs 1,6 and 1,8) with high enantio discriminations. Interestingly, DFT calculations highlighted the crucial role of the N ‐imidazole heterocycle towards the 1,4‐regioselectivity …”

α,β‐Unsaturated 2‐Acyl‐Imidazoles in Asymmetric Biohybrid Catalysis

“…Ultimately, a tandem aldol/crotonization between aldehyde 19 and N ‐methyl‐2‐acylimidazole 20 or a Wittig reaction with the appropriate phosphorous ylide 21 also leads to the title compound. Finally, the phosphorous ylide can be replaced by a phosphonate derivative such as 22 , which can readily undergo a Horner‐Wadsworth‐Emmons type olefination …”

“…Finally, the phosphorous ylide can be replaced by a phosphonate derivative such as 22, which can readily undergo a Horner-Wadsworth-Emmons type olefination. [23,24] In addition to improving catalytic performances, the imidazole moiety presents the advantage of being very versatile.…”