Copper Lewis acids

Jorgensen et al. [84] studied how solvent effects could influence the course of Diels-Alder reactions catalyzed by copper(II)-bisoxazoline. They assumed that the use of polar solvents (generally nitroalkanes) improved the activity and selectivity of the cationic copper-Lewis acid used in the hetero Diels-Alder reaction of alkylglyoxylates with dienes (Scheme 31, reaction 1). The explanation, close to that given by Evans regarding the crucial role of the counterion, is a stabilization of the dissociated ion, leading to a more defined complex conformation. They also used this reaction for the synthesis of a precursor for highly valuable sesquiterpene lactones with an enantiomeric excess superior to 99%. 

Copper-based Lewis acids have some advantages for hydrolysis reactions they are mild, nonacidic, and can control reactions due to chelation by the substrate to achieve high selectivity. CuS04 is effective for acetal deprotection (Scheme 47).197 Thioacetals198,199 and selenoacetals200-202 are also hydrolyzed by copper Lewis acids, and dehydration is accelerated by Cu11 Lewis acids under mild conditions.203... 

Asymmetric reactions using chiral copper Lewis acids are also performed in aqueous media. It has been reported that an asymmetric Diels-Alder reaction proceeds smoothly in water using Cu(OTf)2 and abrine as a chiral ligand (Scheme 49).214 The Cu -bis(oxazoline) system is effective in asymmetric aldol reactions in an aqueous solvent such as water/ethanol and even in pure water.215... 

Sibi and Chen demonstrated for the first time that relative and absolute stereocenters of both a and fJ> carbons can be controlled in the intermolecular addition trapping experiments (Scheme 55) [149]. Magnesium and copper Lewis acids performed better than zinc. The use of 30 mol % of chiral Lewis acid gave higher selectivities than the stoichiometric amounts for both magnesium and copper. Interestingly, copper triflate gave better selectivities with... 

Aluminium and copper Lewis acids effect a regioselective [l,3]-rearrangement of allyl vinyl ethers in moderate to good yields (Scheme 30). The use of trisubstituted alkenes leads to depressed levels of Claisen products.53... 

The choice of solvent has had little, if any, influence on the majority of Diels-Alder reactions.210,211 Although the addition of a Lewis acid might be expected to show more solvent dependence, generally there appears to be little effect on asymmetric induction.118129 However, a dramatic effect of solvent polarity has been observed for chiral metallocene triflate complexes.212 The use of polar solvents, such as nitromethane and nitropropane, leads to a significant improvement in the catalytic properties of a copper Lewis acid complex in the hetero Diels-Alder reaction of glyoxylate esters with dienes.213... 

Table 1. The most widely used copper Lewis acids [1]...

Copper Lewis acids have found many applications in the last decade in a variety of organic transformations and more notably in enantioselective reactions. In particular, Cu(OTf)2 and Cu(SbFg)2 in conjunction with chiral bisoxazolines are the chiral Lewis acids of choice for cycloadditions, aldol reactions, ene reactions, and other selective transformations. Moderately Lewis acidic copper salts are also reagents for transesterifications, dehydrations, and hydrolysis. The thiophilic nature of copper makes them ideal for selective deprotection of thio acetals and thioesters and offer practical advantages over mercury salts. 

There are several reasons for the extensive use of copper Lewis acids in stereoselective transformations (i) predictable coordination geometry about the metal, (ii) ready availability, (iii) two oxidation states, and (iv) moderate Lewis acidity. Copper(II) complexes usually adopt a square planar, square pyramidal, or trigonal bipyramidal geometry, whereas Cu(I) complexes have a preference for tetrahedral geometry (Figure 1). 

The mild deprotection of acetal 15 with CUSO4 in acetone was accomplished in high yield [12]. The mildness of copper Lewis acids for the hydrolysis of hydra-zones [13] is advantageous for acid-sensitive substrates (Sch. 5). The /3,a-unsaturated hydrazone 17 was effectively hydrolyzed without conjugation of the double bond to afford 18 in good yield (Sch. 5) [14]. SAMP-Hydrazones can be hydrolyzed without racemization [15]. The two-step alkylation and hydrolysis of 19 provided 20 in 84 % overall yield and 94 % ee. 

The chelating capacity of copper Lewis acids has been exploited in a variety of selective alcoholysis reactions. Kobayashi used Cu(OTf)2 to affect remote activation of the anomeric carbon for formation of a glycosyl bond (Sch. 13) [34]. The 2-pyridinecarboxylate group was crucial for success of the alcoholysis of 50 to afford disaccharides 51. The 4-pyridyl derivative and simple dialkylamino derivatives were unreactive. A chelating Lewis acid was required, because BF3 -OEt2 or TMSOTf were ineffective, whereas Sn(OTf)2 afforded a level of reactivity similar to that of Cu(OTf)2. 

The decarboxylation of amino acids is facilitated by copper Lewis acids. Treatment of tryptophan with copper(II) acetate in HMPA afforded tryptamine 117 in 45 % yield (Sch. 26) [58]. Chelation is thought to activate the carboxylate for elimination. The stable chelate can be isolated and undergoes decarboxylation when heated. An asymmetric version of a similar decarboxylation of malonate derivatives has been reported poor selectivity resulted from addition of chiral alkaloids [59]. 

Copper(I) triflate was used as a co-catalyst in a palladium-catalyzed carbonylation reaction (Sch. 27). The copper Lewis acid was required for the transformation of homoallylic alcohol 118 to lactone 119. It was suggested that the CuOTf removes chloride from the organopalladium intermediate to effect olefin complexation and subsequent migratory insertion [60]. Copper(I) and copper(II) chlorides activate ruthenium alkylidene complexes for olefin metathesis by facilitating decomplexation of phosphines from the transition metal [61]. 

Although copper reagents, hahdes and triflates, are widely used in atom-transfer polymerization reactions (ATRP) [63], these processes do not fall under the category of Lewis acid-mediated reactions. Sherrington and co-workers have shown that a vinyl monomer coordinated to a chiral copper Lewis acid (122) undergoes stereoselective polymerization (Sch. 29) [64]. A chiral block-copolymer 124 was prepared under radical conditions. 

An example of conjugate free-radical addition to methyl acrylate mediated by a copper Lewis acid has been reported (Sch. 30) [65]. In this example the Lewis acid 127 activates the substrate for conjugate addition by the aryl radical which is followed by an enantioselective chlorine atom-transfer step. Chemical and optical yield for the transformation are both low. 

Nucleophilic addition to C=0 or C=X multiple bonds is faeilitated by Lewis acid activation. The extent of activation required is dependent on the electrophilicity of the carbon atom and on the nucleophilicity of the reagent. Copper Lewis acids have found utility in a variety of reactions involving nucleophilic addition. 

Nucleophilic addition to less reactive ketone carbonyls by Lewis acid activation is also possible. Evans and co-workers have reported enol silane addition to pyruvate esters mediated by chiral copper Lewis acids (Sch. 36) [72]. The aldol reactions proceed with high facial selectivity to provide the tertiary alcohol products 153. The chemical efficiency is, however, reduced when a bulky alkyl group is present at the ketone carbonyl. Addition of more functionalized enol silanes (155) to keto esters enables the establishment of two contiguous chiral centers, a substitution pattern present in a variety of natural products. The stereochemistry of the major product is syn, irrespective of the enol silane geometry. Once again, bidentate coordination of the substrate to the Lewis acid was essential for obtaining high selectivity. 

Activation of C=N double bonds by copper Lewis acids for nucleophilic addition has also been reported (Sch. 37) [73]. The a-imino ester 157 undergoes alkylation at the imine carbon with a variety of nucleophiles when catalyzed by copper Lewis acids. The presence of the electron-withdrawing ester group increases the reactivity of the imine and also assists in the formation of a stable five-membered chelate with the Lewis acid. Evidence for Cu(I) Lewis-acid catalysis and a tetrahedral chelate was obtained by FTIR spectroscopy, from the crystal structure of the catalyst, and from several control experiments. The authors rule out the intermediacy of a copper enol-ate in these transformations. The asymmetric alkylation of A,0-acetals with enol silanes mediated by a copper Lewis acid proceeding with high selectivity has been reported [74],... 

Cycloadditions are one of the most important bond-forming strategies in synthetic organic chemistry. Most of these reactions require some sort of activation if reasonable chemical yields are to be obtained. The traditional methods are heat, light, pressure, and use of a Lewis acid. Copper Lewis acids have found utility in a variety of cycloaddition reactions. They can activate carbon-carbon double bonds through a jr-complex and carbon-hetero atom multiple bonds by means of a sigma complex. 

An example of intramolecular [2 + 2] cycloaddition of a 1,6-diene 172 catalyzed by Cu(I) in the synthesis of grandisol is shown in Sch. 40 [78]. The bicycloheptanes can be prepared selectively by starting with chiral starting material, chiral catalysts or chiral auxiliaries. The reactions with chiral copper Lewis acids gave very poor selectivity (< 5 %ee). 

Dienes are also amenable for activation by copper Lewis acids (Sch. 41) [79]. The intramolecular Diels-Alder reaction of 176 under thermal conditions gave all the possible isomers. In contrast, the Cu(I) promoted reaction gave the isomer 177 as a major product, with minor amounts of 180. Copper(II) Lewis acids were less efficient in the cycloaddition. It is also worth noting that the Lewis acid-catalyzed reaction proceeds at a much lower temperature. 

Diels-Alder reaction is one of the premiere reactions in synthetic organic chemistry. The traditional approach to the normal Diels-Alder reaction is to activate the di-enophile by means of a Lewis acid such that the transformation can be carried out under practicable conditions. A variety of Lewis acids catalyze this reaction selectively and among these copper(II) compounds have been very successful in enantioselective transformations. The use of bisoxazolines in combination with copper triflate or copper antimony hexafluoride has afforded high selectivity. Pioneering work in this area by Evans, Jprgensen, Kanemasa, and others has shed light on the different controlling features of the copper Lewis acids. 

Corey reported one of the earliest examples of dienophile activation by a copper Lewis acid (Sch. 42) [80]. The copper tetrafluoroborate coordinates to the cyano group and facilitates the Diels-Alder reaction without marked isomerization of the diene. 

The use of aminoindanol-derived bisoxazolines in conjunction with copper Lewis acids led to improvements in the enantioselectivity of the Diels-Alder reaction (Sch. 44) [83]. Changes in stereoselectivity with small changes in ligand structure have also been noted (compare 198 and 200) [84], Copper also strongly coordinates phosphorus ligands. The use of PN chiral ligands in Cu(OTf)2-mediated Diels-Alder reactions has been reported [85]. 

Copper Lewis acids also find utility in Diels-Alder reactions in aqueous media. Engberts et al. have reported large rate acceleration of Diels-Alder reactions by Cu(N03)2 in water [89]. The higher Lewis acidity of Cu(II) compared with Co(II), Ni(II), and Zn(II) in aqueous media was also established in their study. An enantio-selective variant of the Diels-Alder reaction using a catalyst derived from L-arbine and Cu(OTf)2 (210) in water was reported recently (Sch. 47) [90]. 

The copper catalyzed Diels-Alder reactions of a variety of dienes have been elegantly exploited by Evans as a key step in the synthesis of natural products (Sch. 49). The synthesis of tetrahydrocannabinol (219) [92] employs the acyclic diene 217 furan is used as a diene in the synthesis of shikimic acid (222) [93]. Although the methodology uses the very reactive catalyst 188, the reactions are still slow, suggesting that less reactive dienes require longer reaction times and higher temperatures for completion. A copper Lewis acid-mediated intramolecular Diels-Alder reaction has served as a key step in the total synthesis of isopulo upone [94]. 

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