Cu /BOX catalyst

The Cu-BOX catalysts function as Lewis acids at the carbonyl oxygen. The chiral ligands promote facial selectivity, as shown in Figure 2.3. 

Among other types of electrophilic compounds that give alkylation of indoles are alkylidene malonate esters. Jorgensen and coworkers observed 50-70% ee using a Cu(BOX) catalyst [262]. 

It should be noted that in most cases it is Cu-eatalyzed asymmetric oxidative biaryl homo-coupling reactions that are deseribed. On the contrary, successful examples of asymmetric oxidative biaryl eross-coupling reactions are rare. Habaue and co-workers discussed a highly eross-selective oxidative biaryl coupling between 3-hydroxy-2-naphthoates and 2-naphthols without ester functionality by a chiral Cu-BOX catalyst.The reactions proceed in a highly cross-eoupling selective manner with moderate enantioselectivity (up to 70% ee) (Scheme 3.7). Later, it was found that Lewis acids such as... 

The enantioselectivity of [Cu(S,S)-tBu-box](OTf)2 (13b)Claisen rearrangement is explained as follows (Fig. 2.4). The alkoxycarbonyl and ether oxygens coordinate in a bidentate fashion to the Cu (box) complexes. The square planer geometry around the copper(II) cation has been proposed and a chair-hke transition-state model is suggested. The aUyUc ether moiety should approach the vinyl ether moiety from the opposite direction of the t-Bu substituents on the box-hgand. The Cu"(box) catalyst differentiates between two enantiomeric chair-hke transition state by selective coordination of enantiotopic lone pairs on oxygen to form (S,S,pro-S)-14a. 

Scheme 5.36 1,4-Phenylation of cyclohexen-2-one with Cu-BOX catalyst, as described by Reiser and coworkers [98].

The catalyzed version of this rearrangement is useful for the synthesis of medium and large-sized carbocycles [84]. For example, the enantioselective synthesis of carbocyclic natural product, (-)-9,10-dihydroecklonialactone B 121 was done successfully by catalytic asymmetric Claisen rearrangement of a GosteU-type aUyl vinyl ether 122 in the presence of (S,S)-Cu (box)-catalyst A to produce a chiral a-ketoester 123, as a building block unit [85]. 

Asymmetric C—C bond-forming reactions have also been accomplished in flow. Chiral bisoxazolines (Box) are utilized in many asymmetric catalytic reactions as nitrogen-containing bidantate ligands for Lewis acidic metals as well as transition metals. Chiral Cu-Box can be utilized as a Lewis acid catalyst. Salvador et cd. investigated the enantioselective ene reaction using a polystyrene-bound Cu-Box catalyst (33) under flow conditions (Scheme 7.29) [125]. 

Intramolecular cyclopropanations catalyzed by Cu-BOX catalysts have been frequently used for the synthesis of multicyclic compounds. For example, Nakada and coworkers examined intramolecular cyclopropanation to prepare... 

The reactions of nitrones constitute the absolute majority of metal-catalyzed asymmetric 1,3-dipolar cycloaddition reactions. Boron, aluminum, titanium, copper and palladium catalysts have been tested for the inverse electron-demand 1,3-dipolar cycloaddition reaction of nitrones with electron-rich alkenes. Fair enantioselectivities of up to 79% ee were obtained with oxazaborolidinone catalysts. However, the AlMe-3,3 -Ar-BINOL complexes proved to be superior for reactions of both acyclic and cyclic nitrones and more than >99% ee was obtained in some reactions. The Cu(OTf)2-BOX catalyst was efficient for reactions of the glyoxylate-derived nitrones with vinyl ethers and enantioselectivities of up to 93% ee were obtained. 

Table2.9 Scope of radical addition to 66a 66c promoted by Cu (tBu Box)(H2O)2(OTf)2 and effects of Cu(ll) catalyst loading. ...

One group of chiral catalysts consists of metal ion complexes, usually Cu +, of M-oxazolines (referred to as box catalysts). ... 

In section B, many examples reported by Jorgensen in 2001 of successful asymmetric 1,2-attack of electron-rich arenes onto the carbonyl moiety of an a-ketoester catalyzed by 5-10 mol % (. -Cu(OTf)2- Bu-BOX catalysts (92i-iv) were shown. During the same time period. Jorgensen also reported many examples of asymmetric thermodynamic conjugate addition of... 

To test this concept, we applied [Cu" (trisox)] complexes in the asymmetric Mannich reaction [24] of a P-ketoester with an activated JV-tosyl-a-imino ester, a reaction that had been previously reported by Jorgensen et al. [25] using chiral copper(II)-BOX catalysts (10mol%). After optimization of the reaction conditions, the reaction product was obtained with an excellent enantiomeric excess of 90% using 10 mol% of the catalyst (Table 15.2) [24a]. 

Chiral copper Lewis acids have also found broad utility in a variety of hetero Diels-Alder reactions. Examples in which the copper Lewis acid activates either the diene or dienophile component have been reported. Evans and coworkers utilized Cu(II)/BOX catalysts in hetero Diels-Alder reactions using unsaturated acyl phosphonates (272) or acyl esters as dienes (Scheme 17.62, Equation 17.8)... 

The cycloaddition reaction between ethyl glyoxylate 4a and Danishefsky s diene 2a has been investigated by Ghosh et al. applying catalyst systems derived from Cu(OTf)2 and ligands (S)-Ph-BOX (S)-21a, (S)-t-Bu-BOX (S)-21b, and the confer-... 

The chiral BOX-metal(II) complexes can also catalyze cycloaddition reactions of other ketonic substrates [45]. The reaction of ethyl ketomalonate 37 with 1,3-conju-gated dienes, e.g. 1,3-cyclohexadiene 5c can occur with chiral BOX-copper(II) and zinc(II) complexes, Ph-BOX-Cu(OTf)2 (l )-21a, and Ph-BOX-Zn(OTf)2 (l )-39, as the catalysts (Scheme 4.29). The reaction proceeds with good yield and ee using the latter complex as the catalyst. Compared to the copper(II)-derived catalyst, which affects a much faster reaction, the use of the zinc(II)-derived catalyst is more convenient because the reaction gives 94% yield and 94% ee of the cycloaddition product 38. The cycloaddition product 38 can be transformed into the optically active CO2-... 

The absolute configuration of products obtained in the highly stereoselective cycloaddition reactions with inverse electron-demand catalyzed by the t-Bu-BOX-Cu(II) complex can also be accounted for by a square-planar geometry at the cop-per(II) center. A square-planar intermediate is supported by the X-ray structure of the hydrolyzed enone bound to the chiral BOX-copper(II) catalyst, shown as 29b in Scheme 4.24. 

We therefore prepared a new chiral ligand, (l ,J )-isopropylidene-2,2 -bis[4-(o-hy-droxybenzyl)oxazoline)], hereafter designated J ,J -BOX/o-HOBn. To our delight, the copper(II) complex catalyst prepared from J ,J -BOX/o-HOBn ligand and Cu(OTf)2 was quite effective (Scheme 7.45). Especially, the reaction of O-benzylhydroxylamine with l-crotonoyl-3-isopropyl-2-imidazolidinone in dichloromethane (0.15 m) at -40°C in the presence of J ,J -BOX/o-HOBn-Cu(OTf)2 (10 mol%) provided the maximum enantioselectivity of 94% ee. 

The importance of the o-hydroxyl moiety of the 4-benzyl-shielding group of R,R-BOX/o-HOBn-Cu(OTf)2 complex was indicated when enantioselectivities were compared between the following two reactions. Thus, the enantioselectivity observed in the reaction of O-benzylhydroxylamine with l-crotonoyl-3-phenyl-2-imi-dazolidinone catalyzed by this catalyst was 85% ee, while that observed in a similar reaction catalyzed by J ,J -BOX/Bn.Cu(OTf)2 having no hydroxyl moiety was much lower (71% ee). In these reactions, the same mode of chirality was induced (Scheme 7.46). We believe the free hydroxyl groups can weakly coordinate to the copper(II) ion to hinder the free rotation of the benzyl-shielding substituent across the C(4)-CH2 bond. This conformational lock would either make the coordination of acceptor molecules to the metallic center of catalyst easy or increase the efficiency of chiral shielding of the coordinated acceptor molecules. 

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