Highly Enantioselective Copper‐Phosphoramidite‐Catalyzed Conjugate Addition of Dialkylzinc Reagents to Acyclic α,β‐Unsaturated Imides

Abstract

A new and practical way to introduce an alkyl fragment in the b-position of aliphatic carboxylic acid derivatives with high enantioselectivities by the use of a commercially available chiral ligand is reported. N-Acylpyrrolidinones, as simple derivatives of an a,b-unsaturated carboxylic acid, were found to be the substrates of choice featuring good reactivity and high enantioselectivities (up to > 99% ee).Keywords: asymmetric catalysis; C À C bond formation; conjugate addition; copper; phosphoramidite ligands; zincThe asymmetric conjugate addition (ACA) of organometallic reagents to a,b-unsaturated carbonyl compounds has been the subject of intensive research activity in the past few years.[1] However, highly enantioselective catalytic procedures which make use of acyclic unsaturated carboxylic acid derivatives are rare.[2] The high conformational mobility of these species, together with the presence of only feeble substrate-catalyst steric and electronic interactions, makes the design of effective highly enantioselective systems a real challenge. Whereas chiral imides have been widely used to perform efficient ACA in the context of a chiral auxiliary approach, [3] the addition of alkylmetals to the enantiotopic faces of a,b-unsaturated imides remained problematic until Hoveydas recent report on the asymmetric addition of dialkylzinc reagents to N-acyloxazolidinones promoted by modular triamide phosphanes.[4] However, high enantioselectivities were reached only with b-alkyl derivatives whereas, for example, simple b-aryl derivatives proved to be only poorly reactive and b-vinyl derivatives were not considered. Moreover, it has been suggested that conventional chiral ligands developed for enones were not suitable for the 1,4-addition of R 2 Zn to aliphatic bidentate substrates with chiral metal catalysts, pointing to an apparent need for specialist ligands. [5] We report here the development of a simple, practical and highly enantioselective copper-catalyzed 1,4-addition of alkylmetals to acyclic a,b-unsaturated carboxylic acid derivatives, based on the use of modular (bidentated) cyclic imides and the commercially available phosphoramidite chiral ligand 1, developed by Feringa et al. [6] We recently reported a new copper-catalyzed ACA of organometallic reagents to a,b-unsaturated lactams bearing appropriate protecting-activating groups on the nitrogen atom.[7] The use of carbonyl protecting groups on the endocyclic nitrogen of g-and d-lactams was essential to attain their reactivity and to reach high ees of the corresponding conjugate adducts. In the search for a new carbonylic protecting-activating group for the nitrogen, we considered the 2-butenoyl moiety. The copper-phosphoramidite (R,S,S)-1 catalyzed addition of Et 2 Zn to compounds 2a and b, each containing two conjugated double bonds of a different nature, afforded a reaction mixture in which the addition occurred predominantly on the acyclic framework, to give adducts 3 with a moderate to good enantioselectivity (Scheme 1).The use of imides 5a a...

Phosphoramidites: Privileged Ligands in Asymmetric Catalysis

“…A synthetic route towards b-substituted chiral carboxylic acid derivatives 80 by a catalytic conjugate addition was reported in 2006. The transformation involved the reaction of alkyl zinc reagents with acyclic a,b-unsaturated imides 79 (Scheme 23) [183] in the presence of phosphoramidite ligand ent-L2b (see Figure 4), which led to the desired products 80 with excellent ee values (up to 99 %). The addition of the less-reactive dimethylzinc to a,bunsaturated (pyridyl)sulfonylimines 81, derived from chalcone, was also investigated (Scheme 24 a).…”

Phosphoramidite: privilegierte Liganden in der asymmetrischen Katalyse

“…[178,179] Weiterhin wurden konjugierte Additionen von Dialkylzinkreagentien an cyclische stickstoffhaltige Michael-Akzeptoren wie die Lactame 72 und die Piperidone 74 beschrieben (Schema 21 a und b). [180,181] [183] Die Addition von weniger reaktivem Dimethylzink an die von Chalkon abgeleiteten, a,b-ungesättigten (Pyridyl)sulfonylimine 81 wurde ebenfalls untersucht (Schema 24 a). [184] In Gegenwart eines Katalysators mit dem PhosphoramiditLiganden ent-L2b (siehe Abbildung 4) wurden die Enamide 82 in guten Ausbeuten (bis 91 %), ee-Werten bis 80 % und Z/E-Verhältnissen > 83:17 erhalten.…”

Recent advances in enantioselective copper-catalyzed 1,4-addition

“…N-Acylpyrrolidinones, as simple derivatives of a,bunsaturated carboxylic acids, were found to be good substrates in the conjugate addition of dialkylzinc reagents since 1,4-addition products were obtained in high yield and enantioselectivity (up to 99%) in the presence of 1.5 mol% of copper source and 3 mol% of ligand L8 (Scheme 9). 33 Nitroolefins represent an important class of substrates for the 1,4-addition reaction due to the versatility of the nitro group in organic synthesis. For example, enantioselective 1,4-addition to nitroalkenes provides an attractive route to b 2 -amino acids, which are important building blocks in the synthesis of natural products, b-peptides and pharmaceuticals.…”