Copper‐Catalyzed Asymmetric Conjugate Addition of Dimethylzinc to Acyl‐N‐methylimidazole Michael Acceptors: a Powerful Synthetic Platform

Abstract

An efficient copper-catalyzed enantioselective conjugate addition of dimethylzinc to α,β- and α,β,γ,δ-unsaturated 2-acyl-N-methylimidazoles has been achieved using a chiral bidentate hydroxyalkyl-NHC ligand. The reactions proceeded with both excellent regio- and enantioselectivity (14 examples, 87-95 % ee) to afford the desired 1,4-adducts, which were easily transformed to the corresponding aldehydes, esters, and ketones. Subsequently, this powerful methodology was therefore successfully applied in the synthesis of natural products. Furthermore, an iterative process was also disclosed leading to highly desirable 1,3-desoxypropionate skeletons (up to 94 % d.e.).

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

“…In our previous study, the bidentate ligand L1 , combining the bulky tert ‐leucinol chelating side arm and a flexible benzylic fragment, afforded the best results, providing product 2a in high yield (85%) and excellent ee (95%) (Scheme ). Nevertheless, and despite its high potency as a chiral ligand, this imidazolinium salt may suffer from its demanding 4‐steps synthesis.…”

“…In this context, we have recently described an unprecedented and efficient copper‐catalyzed enantioselective 1,4‐addition of dimethylzinc reagent to various unsaturated 2‐acyl‐ N ‐methylimidazoles 1 . By using a chiral hydroxyalkyl N‐heterocyclic carbene (NHC) ligand L1 , expected 1,4‐adducts were exclusively formed in good yields and excellent enantio‐inductions (typically 87–95% ee ), even in the case of extended unsaturated substrates (Figure ).…”

“…By using a chiral hydroxyalkyl N‐heterocyclic carbene (NHC) ligand L1 , expected 1,4‐adducts were exclusively formed in good yields and excellent enantio‐inductions (typically 87–95% ee ), even in the case of extended unsaturated substrates (Figure ). Thanks to the facile post‐transformation of the N ‐acylimidazole moiety into useful functional groups such as aldehydes, ketones, esters, or amines, this methodology was successfully applied in the synthesis of natural products. Iterative 1,4‐ACA was also achieved leading to a syn 1,3‐deoxypropionate fragment with excellent diastereoselectivity (94% de ).…”

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

“…Indeed, compared to other bidentate enones such as the ones showcased in Figure , acyl imidazoles have the advantage of being readily convertible to the corresponding ketones, aldehydes, amides, esters or carboxylic acids through simple synthetic transformations (Figure a) . This particularity has notably been exploited in the synthesis of various natural products and natural product analogues such as ( S )‐ar‐turmerone and an ionone derivative, as well as in the synthesis of pyrrolidines, β‐hydroxy‐β‐amino acids, 12‐( S )‐hydroxyeicosatetraenoic acid [12‐( S )‐HETE] and the alkaloid (+)‐heliotridane (Figure b) …”

Well‐Defined Chiral Copper NHC Complex in the Asymmetric Conjugated β‐Borylation and One‐Pot Metathesis‐Asymmetric β‐Borylation Reactions

“…[3] Subsequently,F ernµndez et al first successfully appliedan N-heterocyclic carbene (NHC)copperc omplex in enantioselective boration reactions. [4] Since then, catalysis mediated by NHC-based metal complexes has emerged as ap owerful tool for the synthesis of chiral organoboron compounds, [5][6][7] because these catalysts have severals ignificant advantages over their phosphine counterparts, [8] and fine tuning of the electronic and stericp roperties has ad ramatic impact [9] on the reactivity and selectivity of NHCs. Hoveyda first showeda nN HC-catalysed enantioselective, metal-free conjugateb oration reaction.…”