Copper glyoxylate complex

Chiral C2-symmetric bisoxazoline-copper(II) complexes [30, 31] were introduced as catalysts for cycloaddition and ene reactions of glyoxylates with dienes [9] leading to intense activity in the use of these catalyst for different cycloaddition reactions. 

Chiral BOX-zinc(II) complexes can also catalyze the cycloaddition reaction of glyoxylates with, e.g., 2,3-dimethyl-l,3-butadiene and 1,3-cyclohexadiene [36]. The reaction gave for the former diene a higher cycloaddition product/ene product ratio compared with the corresponding chiral copper(II) complexes the ee, however, was slightly reduced. For the reaction of 1,3-cyclohexadiene slightly lower yield and ee were also found. 

Similar transformations have been performed with Danishefsky s diene and glyoxylate esters [85] catalyzed by bis (oxazoHne)-metal complexes to afford the hetero Diels-Alder product in 70% isolated yield and up to 72% ee. Jorgensen [86,87] reported a highly enantioselective, catalytic hetero Diels-Alder reaction of ketones and similar chiral copper(II) complexes leading to enantiomeric excesses up to 99% (Scheme 31, reaction 2). They also described [88] a highly diastereo- and enantioselective catalytic hetero Diels-Alder reaction of /I, y-imsaturated a-ketoesters with electron-rich alkenes... 

The considerable Lewis acidity of bis(oxazoline)-copper(II) complexes held promise for catalyzing the ene reaction, a process that usually requires strong Lewis acids. Indeed, these catalysts effect a highly selective ene reaction between a variety of alkene partners and glyoxylate esters to produce a-hydroxy esters in good yield, Eq. 210 (245). The ene reaction between cyclohexene and ethyl glyoxylate proceeds in excellent diastereoselectivity and enantioselectivity, Eq. 211. As a testament to the Lewis acidity of these complexes, it is noteworthy that... 

Evans, D.A. and Tregay, S. W. and Burgey, C.S. and Paras, N.A. and Vojkovsky, T. (2000). C2-Symmetric Copper(ll) Complexes as Chiral Lewis Acids. Enantioselective Glyoxylate-Ene Reaction with Glyoxylate and Pyruvate Esters. J. Am. Chem. Soc., 122, 7936-7943. 

Jorgensen et al. reported that C2-symmetric bis(oxazoline)-copper(II) complex 25 also acts as chiral Lewis acid catalyst for a reaction of allylic stannane with ethyl glyoxylate [37]. Meanwhile, p-Tol-BINAP-CuCl complex 26 was shown to be a promising chiral catalyst for a catalytic enantioselective allylation of ketones with allyltrimethoxysilane under the influence of the TBAT catalyst [38]. Evans and coworkers have developed (S,S)-Ph-pybox-Sc(OTf)3 complex 27 as a new chiral Lewis acid catalyst and shown that this scandium catalyst promotes enantioselective addition reactions of allenyltrimethylsilanes to ethyl glyoxylate [39]. But, when the silicon substituents become bulkier, nonracemic dihydrofurans are predominantly obtained as products of [3+2] cycloaddition. 

Enantioselective Friedel-Crafts Reactions. The copper(II) complex of the (5, 5 )-t-Bu-box ligand has been used as catalyst for the reaction of A. N-dimethylaniline with ethyl glyoxylate and it has been found that a highly regio- and enantioselective Friedel-Crafts reaction takes place. This reaction proceeds with the exclusive formation of the para-substituted isomer in up to 91% yield and 94% ee (eq 24). 

Evans, D.A., Tregey, S.W., Burgey, C.S. er a/. (2000) C2-Symmetric copper(II) complexes as chiral Lewis acids. Catalytic enantioselective carbonyl-ene reactions with glyoxylate and pyruvate esters. Journal of the American Chemical Society, 122, 7936-7943. 

The observed sense of asymmetric induction is consistent with a square planar copper(II)-glyoxylate complex with approach of the ene from the face opposite to the nearby tert-butyl substituent. Copper bis-oxazoline catalysts have also been used in the intramolecular carbonyl ene reaction. For instance, unsaturated a-ketoester (7.200) undergoes ene cyclisation to give the product (7.201) with high ee in the presence of the catalyst derived from BOX-ligand (7.34) and Cu(OTf)2. ° ... 

Jorgensenandcoworkers examined chiral bisoxazoline/copper(Il)-substrate complexes (substrate = glyoxal or methyl glyoxylate) in regard to hetero Diels-Alder reactions carried out in their labs [132] Ab initio calculations showed a 17-electron bisoxazoline/copper(II)-substrate complex to be most stable and most reactive. Furthermore, the optimized 17-electron bisoxazoline/copper(II)-substrate complexes of t-Bu-BOX (13) and Ph-BOX (15) showed that the substrate molecule was twisted 40-45° out the plane of the ligand-copper(II) plane. This observation is in good agreement with X-ray structures solved fcc the complexes of interest. Another report by Alvarez and coworkers focused on quantitative chirality analysis of molecidar subunits of spirocyclic bisoxazoline/copper(ll) complexes [133]. 

Evans has expanded the scope of the asymmetric glyoxylate-ene reaction to include less nucleophilic mono- and 1,2-disubstituted olefins by using bis(oxazoline)-copper(ll) complexes such as 334 (Scheme 2.42) [200, 201], For example, hex-l-ene (333) undergoes the ene reaction to provide hydroxy ester 335 in 96% yield and 98% ee ( /Z=96 4) [200]. In an elegant synthetic application, the copper-aqua complex 334 was used to set the C,7 stereogenic center in Evans total synthesis of the marine shellfish toxin azaspiracid-1 (339, Scheme 2.43) [202], The transformation of silyl ether 337 could be conducted on a >20-g scale in the presence of only 0.1 mol% of the robust catalyst 334 to provide hydroxy ester 338 in 86% yield and 96% ee. 

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. 

The use of chiral bis(oxazoline) copper catalysts has also been often reported as an efficient and economic way to perform asymmetric hetero-Diels-Alder reactions of carbonyl compounds and imines with conjugated dienes [81], with the main focus on the application of this methodology towards the preparation of biologically valuable synthons [82]. Only some representative examples are listed below. For example, the copper complex 54 (Scheme 26) has been successfully involved in the catalytic hetero Diels-Alder reaction of a substituted cyclohexadiene with ethyl glyoxylate [83], a key step in the total synthesis of (i )-dihydroactinidiolide (Scheme 30). 

The copper complexes of these ligands were tested in the cyclopropanation of styrene with ethyl diazoacetate (Scheme 7) and the ene reaction between a-methylstyrene and ethyl glyoxylate (Scheme 8). hi both cases moderate enantioselectivities were obtained but these were lower than those foimd with the parent hgand. 

Table 12 Results of reactions of ethyl glyoxylate with different alkenes, catalyzed by several bis(oxazoline)-copper complexes immobilized on Y zeolite...

The same, understandable bias towards the preferred use of man-made catalysts, rather than biocatalysts, continues in the area of hetero-Diels-Alder reactions1141-1. For example, in the presence of 5mol% of copper complexes of the type (47), cyclohexadiene and ethyl glyoxylate produce the oxabicyclooc-tene (58) (66% yield, 97% ee)[142]. 

It has been shown that complete selectivity for the hetero-Diels-Alder cycloadduct 109 (100% endo, 60% ee) can be achieved in the hetero-Diels-Alder reaction of 1,3-cyclohexadiene 108 and ethyl glyoxylate 99 using ent-6 and copper(II) triflate derived catalyst complex. Another interesting reaction introduced by Jprgensen and co-workers was the reaction between 1,3-cyclohexadiene 108 and diethyl ketomalonate 110 to form cycloadduct 111 in 76% yield with an ee of 84% (Fig. 9.35b, p. 558). ... 

In 1997, Evans reported on the aldol reaction using the same enol ether 147 with a variety of glyoxylates and pyruvates using tin triflate and copper triflate. As shown in Table 9.26 (Fig. 9.47a), reaction of several pyruvates using bu-box ligand 3 complexed with copper(II) triflate afforded yields of up to 99% with selectivities up to 96% (ee) for adduct 150. " ... 

In a carbonyl-ene reaction of ethyl glyoxylate with a-methylstyrene catalysed by copper triflate-bisoxazoline complexes, ees of up to 100% have been achieved, but a dramatic switchover in stereochemistry is seen for an apparently minor change in bisoxazoline structure.185 A change in the metal geometry is implicated. 

An hDA reaction between Danishefsky s diene and glyoxylate esters proceeds in the presence of bisoxazoline-lanthanide complexes with moderate levels of enantioselectivity <2000TL2203>. A similar reaction between Danishefsky s diene and a-keto esters proceeds with excellent enantioselectivity in the presence of bisoxazoline-copper <2001TL6231, 2003EJ0317, 2004TA1987> or Cr(m), Co(n and m)-salen complexes <2004TA3189>. 

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... 

Cycloaddition Reactions. Bis(oxazoline) copper complexes such as 2 (and its hydrated congener) facilitate the [2 + 2] cycloaddition between silylketenes and glyoxylate/pyruvate esters (eq 18). The reaction is tolerant to various silyl substituents and structural variation on the dicarbonyl reactant. 

Reaction of alkenes with carbonyl compounds or carbonyl derivatives in the presence of Lewis acids, the ene reaction, enables the stereoselective preparation of highly functionalized compounds. Copper Lewis acids activate both aldehydes and imines in ene reactions. Evans has reported that Cu(II) Lewis acids catalyze glyoxylates in reactions with alkenes (Sch. 56) [103]. The homoallylic alcohols 257 and 259 are produced in high yield and enantioselectivity. The bis aquo complex 260 is a readily prepared and air-stable catalyst and gave high chemical yield and excellent selectivity in the ene reactions. Another point of note is that catalysts 260 and 261 furnish enantiomeric products even though they differ from each other only by the substituent at the 4-posi-tion of the oxazoline. 

Vederas and co-workers have reported the ene reaction of an allylglycinate 262 with methyl glyoxylate using copper Lewis acids (Sch. 57) [104], Chiral binaphthol-titanium complexes did not catalyze the ene reaction and only the starting material was recovered. 

Kobayashi and coworkers pioneered the use of enamides or enecarbamates as nucleophiles in enantioselective reactions with either glyoxylates or glyoxylate derived imines catalyzed by chiral copper complexes [65]. The reaction using enamides or enecarbamates as nucleophilic components, namely, the aza ene reaction, with imines provides P amino imines that can be readily transformed into... 

Carretero and coworkers have further extended the scope of N-sulfonyl imine heterodienophiles in enantioselective copper-catalyzed aza-Diels-Alder reactions (Scheme 17.65) [94]. In contrast to previous work that had been limited to the highly reactive N-tosyl imine of ethyl glyoxylate, chiral Cu(I) complexes of phosphino sulfenyl ferrocenes catalyze cycloaddition of Danishefsky s diene (286) to N-tosyl imines (292) of both aromatic and aliphatic aldehydes. Phosphorous substitution proved to play a critical role in both reactivity and enantioselectivity of the reaction with complex [151 CuBr]2 bearing 1-naphthyl substituents on the phosphorous... 

Copper-bis oxazolidinone complex catalyzed the addition of alkyl and aromatic alkynes to the imine formed by the reaction of ethyl glyoxylate and p-anisidine, providing an easy access to chiral p,Y-alkynyl a-amino acids in good yields (61-80%) and enantioselectivities (66-74%) [38]. The presence of the two phenyl groups in the ligand was found to be crucial in the enantioselectivity enhancement and reduction of the reaction time, with aryl alkynes providing better results than alkyl acetylene derivatives [39]. Another type of Cu(II)-pybox complex led to excellent results in terms of enantioselectivities (28-93% yield, 81-98% ee) in the reaction of aliphatic alkynes with aldehydes and amines [40]. 

A glyoxylate-ene reaction has been catalysed by a chiral bis(oxazoline)-copper complex with 94% ee in an ionic liquid." ° ... 

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