Copper-catalyzed conjugate additions

A remarkable number of new BINOL- and TADDOL-based diiral ligands for tlie copper-catalyzed conjugate addition of R Zn reagents have recently been introduced, witli botli monodentate and bidentate ligands having proven capable of inducing bigli enanboselectivities [6, 11, 12, 46]. 

Chiral diaminocarbene complexes of copper were used in asymmetric conjugate addition of diethylzinc to Michael acceptors. Achiral copper carbene complexes derived from imidazolium salts were synthesized and characterized for the first time by Arduengo in 1993 [43]. In 2001, Woodward reported the use of such Arduengo-type carbene in copper-catalyzed conjugate addition and showed their strong accelerating effect [44]. The same year, Alex-... 

It is important to remember that the yield and reproducibility of hydrozircona-tions and the subsequent transformations depend on the presence of ionic impurities in 1 which often hamper the desired transformations. For example, in situ preparations of 1 with liEtjBH and BuMgCl were not appropriate for hydrozircona-tion/copper-catalyzed conjugate addition sequences otherwise preformed 1 is well adapted for these protocols. 

The synthesis in Scheme 13.5 also makes use of an aromatic starting material and follows a retrosynthetic plan similar to that in Scheme 13.3. The starting material was 4-methoxybenzaldehyde. This synthesis was somewhat more convergent in that the entire side chain except for C(14) was introduced as a single unit by a mixed aldol condensation in step A. The C(14) methyl was introduced by a copper-catalyzed conjugate addition in Step B. 

A remarkable number of chiral phosphorus ligands (phosphoramidites, phosphites, and phosphines with modular structures) have been introduced into the copper-catalyzed conjugate addition of R2Zn reagents, and high enantio-selectivities (>90%) are now possible for all three different classes of substrates 2-cyclohexenones and larger ring enones, 2-cyclopentenones, and acyclic enones. 

In 1996, Feringa and co-workers (164) reported the use of binaphthol-derived phosphoramidite 232a as a ligand for the copper-catalyzed conjugate addition. Addition of 2 equiv of 232a to Cu(OTf)2 forms an effective catalyst for the selective... 

Figure 21. Selectivity of copper-catalyzed conjugate addition of Et2Zn to cyclohexenone in the presence of several ligands.

Organoaluminum reagents have been used in the copper-catalyzed conjugate addition to enones with some success. Iwata and co-workers (182) demonstrated that dimethoxyphenyl oxazoline (247) provides modest selectivities in the copper-catalyzed conjugate addition of trimethylaluminum to 3,4,4-trimethylcyclohexadi-enone to provide the adduct in 68% ee, Eq. 145. The use of TBSOTf is crucial to attain high conversion and selectivity in this process. Woodward and co-workers (183) subsequently reported that a Cu(I) complex of thiocarbamate 248 provides modest facial discrimination in the addition of trimethylaluminum to a linear enone to afford 245b in 51% ee, Eq. 146. The authors note that this catalyst system decomposes under the reaction conditions at ambient temperature. 

Copper-Catalyzed Conjugate Addition of Functionalized Organozinc Reagents to a,p-Unsaturated Ketones Preparation of Ethyl 5-(3-Oxocyclohexyljpentanoate. 

Manganese-copper-catalyzed conjugate addition of organomagnesium reagents to a,p-enones is a general synthetic method. Table I shows that the reaction can be successfully performed even with enones of low reactivity. 30% Manganese chloride is necessary to obtain good yields. In most cases, however, 0.1% cuprous chloride is sufficient.3... 

This manganese-copper-catalyzed conjugate addition reaction compares favorably with the classical copper-catalyzed reaction. The two reactions are easily and similarly carried out under mild conditions, but the first one gives higher yields. This difference, already observed in the case of p-monosubstituted o,p-ethylenic ketones, is especially noticeable with p,p-disubstituted or [Pg.70]

MANGANESE-COPPER-CATALYZED CONJUGATE ADDITION OF ORGANOMAGNESIUM CHLORIDES TO a,p-ETHYLENIC KETONES IN THF AT 0°C... 

COPPER-CATALYZED CONJUGATE ADDITION OF ORGANOMANGANESE CHLORIDES, RMnCI, TO ot.p UNSATURATED CARBONYL SUBSTRATES IN THF... 

G. Cahiez, S. Marquais, and M. Alami 135 MANGANESE-COPPER-CATALYZED CONJUGATE ADDITION OF ORGANO-MAGNESIUM REAGENTS TO a,(J-ETHYLENIC KETONES PREPARATION OF 2-(1,1 -DIMETHYL-PENTYL)-5-METHYLCYCLO-HEXANONE FROM PULEGONE... 

The first application of a copper-catalyzed conjugate addition of diethylzinc to 2-cyclohexenone, using chiral phosphorous ligand 12, was reported by AlexaHs (Fig. 7.1) [35]. An ee of 32% was obtained. 

Fig. 10.1. Proposed catalytic cycle of copper-catalyzed conjugate addition.

COPPER-CATALYZED CONJUGATE ADDITION OF A ZINC HOMOENOLATE ETHYL 3-[3-(TRIHETHYLSILYL0XY)CYCL0HEX-... 

The configurational assignment thus rests solely on the stereochemical course of the copper-catalyzed conjugate addition of vinylmagnesium bromide to 7. a reaction process known to occur with trans stereoselectivity 106. 

The copper-catalyzed conjugate addition of methyhnagnesium iodide to cyclohexenone and trapping of the resulting enolate as its trimethylsilyl enolate, followed by TrSbCle-catalyzed Mukaiyama reaction, are the first steps of an elegant synthesis of enantiomeri-caUy pure clerodanes (equation 45). 

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