Glyoxylate enantioselective

The interest in chiral titanium(IV) complexes as catalysts for reactions of carbonyl compounds has, e.g., been the application of BINOL-titanium(IV) complexes for ene reactions [8, 19]. In the field of catalytic enantioselective cycloaddition reactions, methyl glyoxylate 4b reacts with isoprene 5b catalyzed by BINOL-TiX2 20 to give the cycloaddition product 6c and the ene product 7b in 1 4 ratio enantio-selectivity is excellent - 97% ee for the cycloaddition product (Scheme 4.19) [28]. 

The enantioselective inverse electron-demand 1,3-dipolar cycloaddition reactions of nitrones with alkenes described so far were catalyzed by metal complexes that favor a monodentate coordination of the nitrone, such as boron and aluminum complexes. However, the glyoxylate-derived nitrone 36 favors a bidentate coordination to the catalyst. This nitrone is a very interesting substrate, since the products that are obtained from the reaction with alkenes are masked a-amino acids. One of the characteristics of nitrones such as 36, having an ester moiety in the a position, is the swift E/Z equilibrium at room temperature (Scheme 6.28). In the crystalline form nitrone 36 exists as the pure Z isomer, however, in solution nitrone 36 have been shown to exists as a mixture of the E and Z isomers. This equilibrium could however be shifted to the Z isomer in the presence of a Lewis acid [74]. 

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. 

A combination of diethylzinc with sulfonamides 18 or 19 offers another possibility for the enantioselective acetate aldol reaction39,41. The addition of silyl enol ethers to glyoxylates can be directed in a highly enantioselective manner when mediated by the binaphthol derived titanium complex 2040. 

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 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. 

Finally, Mikami and Motoyama have used a p-hydroxy sulfonamide ligand to catalyse the enantioselective B-catalysed Diels-Alder reaction of glyoxylate with Danishefsky s dienes." " A favourable transition-state assembly for a one-directional diene-approach from the site proximal to the sulfonylamino moiety was proposed to explain the observed high enantio- and c (e fi o)-diastereos-electivity (Scheme 5.28). 

The idea of enantioselective activation was first reported by Mikami and Matsukawa111 for carbonyl-ene reactions. Using an additional catalytic amount of (R)-BINOL or (/ )-5.5 -dichloro-4,4, 6,fi -tctramcthyl biphenyl as the chiral activator, (R)-ene products were obtained in high ee when a catalyst system consisting of rac-BINOL and Ti(OPri)4 was employed for the enantioselective carbonyl ene reaction of glyoxylate (Scheme 8-54). Amazingly, racemic BINOL can also be used in this system as an activator for the (R)-BINOL-Ti catalyst, affording an enhanced level of enantioselectivity (96% ee). 

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... 

The diastereoselective addition to imines proceeds well with aromatic enolsi-lanes (249). Propiophenone- and tetralone-derived enolsilanes provide good levels of diastereoselectivity (>95 5) and excellent enantioselectivity (>98% ee) with selective formation of the anti diastereomer. Nonaromatic enolsilanes are somewhat less selective although cyclohexanone enolsilane still provides useful levels of diastereoselectivity and enantioselectivity (92 8 anti/syn and 88% ee at -78°C). A one-pot procedure using glyoxylate, sulfonamide, and enolsilane as coupling partners was developed subsequently, leading to the product in comparable yields and selectivities (250, 251). 

Asymmetric C=0 hydrogenations in water were also reported by Lemaire et al. This catalytic system is based on Ir(cod)L complexes, where L is a hydrophilic chiral C2-symmetric diamine ligand such as p-substituted (IR 2R)-(-i-)-l,2-diphenylethylenediamine derivatives (29a-e Scheme 4.12). The use of such ligands allowed catalyst recovery without loss of activity and enantioselectivity in at least four acetophenone hydrogenation cycles [29]. The ee-values observed in the reduction of phenyl glyoxylate in the water phase were, however, lower than were found when running the tests in THF (Table 4.3), when the substituents were H and Me, and about the same with OH, OMe and 0-(C2H40)3Me. 

Mandoli, A. and Orlandi, S. and Pini, D. and Salvador , P. (2004). Insoluble polystyrene-bound bis(oxazoline) batch and continuous-flow heterogeneous enantioselective glyoxylate-ene reaction. Tetrahedron Asymmetry, 15, 3233-3244. 

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. 

The role of multicomponent ligand assembly into a highly enantioselective catalyst is shown in the enantioselective catalysis for the carbonyl-ene reaction (Table 8.9). The catalyst is prepared from an achiral precatalyst, Ti(0 Pr)4 and a combination of BINOL with various chiral diols such as TADDOL and 5-Cl-BIPOL in a molar ratio of 1 1 1 (10mol% with respect to the olefin and glyoxylate) in... 

The metal complexes even with tropos ligands can thus be used as asymmetric catalysts for carbon-carbon bond-forming reactions in the same manner as atropos catalysts. The single diastereomer (7 )-32/(/ )-DABN can be employed as an activated asymmetric catalyst for the Diels-Alder reaction at room temperature (Table 8.11). The high chemical yield and enantioselectivity (62%, 94% ee) in the Diels-Alder reaction of ethyl glyoxylate with 1,3-cyclohexadiene are obtained... 

An asymmetric intermolecular carbonyl-ene reaction catalyzed by 1 mol% of chiral A-triflyl phosphoramide (/ )-4t (1 mol%, R = 4-MeO-CgH ) was developed by Rueping and coworkers (Scheme 69) [88], Various a-methyl styrene derivatives 163 underwent the desired reaction with ethyl a,a,a-trifluoropyruvate 164 to afford the corresponding a-hydroxy-a-trifluoromethyl esters 165 in good yields along with high enantioselectivities (55-96%, 92-97% ee). The presence of the trifluoromethyl group was crucial and the use of methyl pyruvate or glyoxylate instead of 164 resulted in lower reactivities or selectivities. 

The enantioselective inverse electron-demand 1,3-dipolar cycloadditions of nitrones with alkenes described so far are catalyzed by metal complexes that favor a monodentate coordination of the nitrone, such as boron and aluminium complexes. However, the glyoxylate-derived nitrone 256 favors abidentate coordination to the catalyst, and this nitrone is an interesting substrate, since the products that are obtained from the reaction with alkenes are masked ot-amino acids (Scheme 12.81). 

The addition of olefins to aldehydes can take place via an ene reaction. As shown in Figure 9.34, reaction of methylenecyclohexene 98 with ethyl glyoxylate 99 forms the ene product 100. Evans and co-workers showed that such an ene reaction can be carried out enantioselectively by utilizing bis(oxazoline)-metal complexes. Examples of ene products with yields up to 99% and ee up to 97% are summarized in Table 9.16 (Fig. 9.34). ... 

TABLE 9.14 DIELS-ALDER REACTIONS OE A-ACYL OXAZOLIDINONES, 553 TABLE 9.15 DIELS-ALDER REACTIONS WITH VARIOUS DIENOPHILES, 553 TABLE 9.16 ENANTIOSELECTIVE ENE REACTIONS OF ETHYL GLYOXYLATE, 556... 

While lanthanide triflates have been demonstrated to promote the reaction of indoles with imines <99SL498>, Johannsen has developed a new synthesis of optically active p-indolyl N-tosyl a-amino acids 110 via the enantioselective addition of A-tosylimnio esters of ethyl glyoxylate 109 to indoles 108 bearing both electron-donor and electron-acceptor substituents at C-5 using 1-5 mol% of a chiral copper(I)-Tol-BINAP catalyst <99CC2233>. 

A similar nonlinearity is seen in the ene reaction of methyl glyoxylate and a-methylstyrene (Scheme 43) (69). Thus, the reaction catalyzed by a complex in situ formed from dibromo(diisopropoxy)titanium(IV) and (/ )-binaphthol in 33% ee affords the chiral adduct in 91% ee with the same enantioselectivity as would have been obtained had enantiomerically pure binaphthol been used. Molecular weight measurements suggest the catalyst is a dinuclear titanium compound, although the structure has not been elucidated. This nonlinear effect is interpreted by the difference in the dissociation constant of the diastereomeric dimers as... 

A full account5 describes the enantioselective carbonyl-ene reaction of glyoxylate esters catalyzed by a binaphthol-derived chiral titanium complex that is potentially useful for the asymmetric synthesis of a-hydroxy esters of biological and synthetic importance.6 The present procedure is applicable to a variety of 1,1-disubstituted olefins to provide ene products in extremely high enantiomeric purity by the judicious choice of the dichloro or dibromo chiral catalyst (see Table). In certain glyoxylate-ene reactions involving removal of a methyl hydrogen, the dichloro catalyst... 

It was reported that proline catalyzed the direct catalytic asymmetric Mannich reactions of hydroxyacetone, aldehydes, and aniline derivatives [(Eq. (10)] [40-44]. Not only aromatic aldehydes but also aliphatic aldehydes worked well in this reaction, and good to excellent enantioselectivity and moderate to excellent yields were observed. Mannich reactions of glyoxylate imines with aldehydes or ketones were also successfully performed [45,46]. 

Mikami and Nakai et al. have developed a chiral titanium catalyst for the glyoxylate-ene reaction, which provides the corresponding a-hydroxy esters of biological and synthetic importance [7] in an enantioselective fashion (Scheme 8C.3) [8,9]. Various chiral titanium catalysts were screened [ 10]. The best result was obtained with the titanium catalyst (1) prepared in situ in the presence of MS 4A from diisopropoxytitanium dihalides (X2Ti(OPr,)2 X=Br [11] or Cl [12]) and enantiopure BINOL or 6-Br-BINOL [13], The remarkable levels of enantiose-lectivity and rate acceleration observed with these BINOL-Ti catalysts (1) [14] stem from the... 

Catalysis of racemic BINOL-Ti(OPr )2 ( 2) in the glyoxylate-ene reaction with 2-phenyl-propene achieves extremely high enantioselectivity by adding another diol for enantiomer-selective activation (Scheme 8C.15, Table 8C.3) [42], For example, excellent enantioselectivity (90% ee, R) was achieved by adding just a half-molar equiv. (5 mol %) of (/ )-BINOL activator to racemic ( )-BINOL-Ti(OPr )2 complex ( 2) (10 mol %) in this reaction (Table 8C.3, entry 4). 

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