Copper -mediated conjugate addition

Conjugate addition [2] to Michael acceptors is the most important and useful reaction in organocopper chemistry, and the reaction is often used as the key step in the synthesis of numerous natural and unnatural products. Perhaps one of the most efficient methods for the synthesis of quaternary carbon centers is organo-copper-mediated conjugate addition to /I, yS-disubstituted enones. 

Copper-mediated conjugate addition of an alkylzinc iodide to a nitro olefin preparation of 1-chloro-5-(nitromethyl)octaneZ0... 

The prototype of copper-mediated conjugate addition reactions is the transformation of acceptor-substituted alkenes and alkynes into the corresponding adducts (Scheme 1). Whereas full control of the regio- and chemoselectivity in these Michael additions has been possible for a long time,3 the emphasis of the last decade has been put on the use of new copper reagents, the broadening of the substrate scope, and the control of the stereoselectivity of the conjugate addition. 

Due to their high conformational flexibility, chiral acyclic Michael acceptors often display low diastereofacial selectivities in copper-mediated conjugate addition reactions.80 Nevertheless, acceptable levels of diastereoselection can be obtained, in particular with heteroatom-substituted Michael acceptors. For example, treatment of the y-benzyloxymethyl-substituted enoate 100 with lithium dimethylcuprate in the presence of chlorotrimethylsilane gives the anti-adduct 101 with excellent diastereoselectivity (Scheme 26). a Products of this type can be easily... 

Table 3.6 Copper-mediated conjugate additions of organozinc halides with a,p-unsaturated ketones.

A detailed experimental procedure for the copper-mediated conjugate addition of organozinc reagents to a,p-unsaturated ketones is given later in the text. 

Typical Copper-Mediated Conjugate Addition Reaction of Organozinc Halides to a,p-Unsaturated Ketones... 

Copper has long played a dominant role in stoichiometric organometallic reactions in synthesis. Organocuprate mediated conjugate addition reactions are a cornerstone of carbon-carbon bond-forming reactions. Its preeminence has not been overlooked in the search for asymmetric versions of the reaction (134-136). However, the requirement for stoichiometric amounts of the metal has dampened efforts to introduce chirality into this process. 

The introduction of asymmetry in conjugate additions can be promoted by chiral acceptors. The preparation of regio-defined magnesium enolates from copper(I)-mediated conjugate addition of Grignard reagents has been extensively used in many important... 

The synthesis of enantioenriched acyl chloride 54 was originally conducted using a modification of procedures described by Villieras and coworkers for the preparation of racemic alcohol 55 (Scheme 12). Thus, the synthesis commenced with the preparation of racemic allylic alcohol 55 from 2,5-dimethoxytetrahydrofuran. The alcohol was resolved enzymatically, following procedures reported by Ogasawara, to provide enantioenriched alcohol (S)-55 in 50% yield and 99% ee. Protection of the alcohol with the sterically encumbered ferf-butyl dimethylsilyl group allowed a diastereoselective copper(I)-mediated conjugate addition of methyl magnesium bromide to... 

A derivatization of zinc enolates like 418, formed in a copper-catalyzed conjugate addition, by trapping as silyl enol ethers 419 was reported by Alexakis group [209]. The addition occurred in very high enantioselectivity when mediated by phosphoramidite 417 or related ligands. Remarkably, the selectivity was distinctly lower when chlorotrimethylsilane was present from the beginning. Therefore,... 

Copper-mediated Diastereoselective Conjugate Addition and Allylic Substitution Reactions... 

Phosphite compounds, which have been discussed in the context of their application in asymmetric hydrogenation reactions (see Section 6.1.2.6), can also be used to effect the copper salt-mediated asymmetric conjugate addition of diethylzinc to enones.74 As shown in Scheme 8-33, in the presence of diphosphite 92 and copper salt [Cu(OTf)2], the asymmetric conjugate addition proceeds smoothly, giving the corresponding addition product with high conversion and ee. In contrast, the monophosphite 93 gave substantially lower ee. 

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