Oxazolines enantioselective aldol reaction

Enantioselective aldol reactions with high threo- or erythro-scleciivity are obtained with boron azaenolates derived from chiral and achiral oxazolines, respectively. Moving the chirality from the boron in (50), to the heterocyclic in (51), causes the reaction to switch from threo- to eryt/iro-products with high... 

Chiral //A(oxazolinc) ligands disubstituted at the carbon atom linking the two oxazolines by Frechet-type polyether dendrimers coordinated with copper(II) triflate were found to provide good yields and moderate enantioselectivities for Mukaiyama aldol reactions in water that are comparable with those resulting from the corresponding smaller catalysts.291 AgPF6-BINAP is very active in this reaction and the addition of a small amount of water enhanced the reactivity.292... 

Catalytic asymmetric aldol reactions of a-heterosubstituted substrates such as glyoxaldehyde, and methyl pyruvate have been reported (Scheme 81). High diastereo- and enantioselectivity have been obtained by using combined use of Sn(OTf)2 and bis(oxazoline) or pyridinebis(oxazoline) ligands.341... 

Aldol reactions of isocyanides with aldehydes are catalyzed by cationic platinum complexes having P-C-P or N-C-N ligands in the presence of a catalytic amount of an amine base to give 2-oxazolines (Equation (126)) 48S>485a>485b Platinum-coordinated a-isocyano carbanions presumably serve as nucleophiles toward aldehydes. Low to moderate enantioselectivities were obtained by using chiral platinum complexes.485 4853... 

Bis(oxazoline)-type complexes, which have been found useful for asymmetric aldol reactions, Diels-Alder, and hetero Diels-Alder reactions can also be used for inducing 1,3-dipolar reactions. Chiral nickel complex 180, which can be prepared by reacting equimolar amounts of Ni(C10)4 6H20 and the corresponding (J ,J )-4,6-dibenzofurandiyl-2,2 -bis(4-phenyloxazoline) (DBFOX/Ph) in dichloromethane, can be used for highly endo-selective and enantioselective asymmetric nitrone cycloaddition. The presence of 4 A molecular sieves is essential to attain high selectivities.88 In the absence of molecular sieves, both the diastereoselectivity and enantioselectivity will be lower. Representative results are shown in Scheme 5-55. 

It is well recognized that chiral tridentate ligands generally form a deeper chiral cavity around the metal center than a bidentate ligand. For example, as mentioned in previous chapters, the chiral tridentate ligand Pybox 120 has been used in asymmetric aldol reactions (see Section 3.4.3) and asymmetric Diels-Alder reactions (see Section 5.7). The two substituents on the oxazoline rings of 120 form a highly enantioselective chiral environment that can effectively differentiate the prochiral faces of many substrates. 

As pointed out by Togni and Pastor, enantioselectivities in the gold-catalyzed aldol reaction of aldehydes containing an a-heteroatom are significantly different from those of simple aldehydes (Table 8B1.3) [15,16]. Low enantioselectivities for rrani-oxazolines are observed in the aldol reactions of 2-thiophene-, 2-furan-, and 2-pyridinecarboxaldehyde (entries 2, 4,7). In the reactions of the 2-furan- and 2-pyridinecarboxaldehyde, cA-oxazolines with fairly high enantiomeric purities are formed as the minor product but in a rather low trans/cis ratio. A similar a-heteroatom effect is also observed in the aldol reaction of 2,3-Oisopropylidene-D-glyceraldehyde. 

Scandium(III) and lutetium(ni)133 and zinc134 complexes of C2-symmetric pyri-dine-bis(oxazoline) (PYBOX) ligands are highly effective enantioselective catalysts of Mukaiyama aldol reactions. 

The Mukaiyama aldol reaction could be catalyzed by chiral bis(oxazoline) copper(II) complexes resulting in excellent enantioselectivities (Fig. 7) [23]. A wide range of silylketene acetals 46 and 49 were added to (benzyloxy[acetaldehyde 45 and pyruvate ester 48 in a highly stereoselective manner. The authors were also able to propose a model to predict the stereochemical outcome of these reactions. 

Catalytic asymmetric aldol reactions in water have been attained by a combination of Cu(DS)2 and chiral bis(oxazoline) ligand 4. In this case, addition of a Br0sted acid, especially a carboxylic acid such as lauric acid, is essential for good yield and enantioselectivity (Equation (5)) [29]. This is the first example of Lewis acid-catalysed asymmetric aldol reactions in water without using organic solvents. Although the yield and the selectivities have not yet been optimized, it is noted that this enantioselectivity has been achieved at ambient temperature in water. 

Evans et al. recently reported the use of structurally well-defined Sn(II) Lewis acids for the enantioselective aldol addition reactions of a-heterosubstituted substrates [47]. These complexes are readily assembled from Sn(OTf)2 and C2-symmetric bis(oxazoline) ligands. The facile synthesis of these ligands commences with optically active 1,2-diamino alcohols, which are themselves readily available from the corresponding a-amino acids. The Sn(II)-bis(oxazoline) complexes were shown to function optimally as catalysts for enantioselective aldol addition reactions with aldehydes and ketone substrates that are suited to putatively chelate the Lewis acid. For example, use of 10 mol % Sn(II) catalyst, thioacetate, and thiopropionate derived silyl ketene acetals added at -78 °C in dichloromethane to glyoxaldehyde to give hydroxy diesters in superb yields, enantioselectivity, and diastereoselectivity (Eq. 27). The process represents an unusual example wherein 2,3-ant/-aldol adducts are obtained stereoselec-tively. 

The chiral ferrocenylphosphine.gold(I)-catalyzed aldol reaction of a-alkyl a-isocya-nocarboxylates 92 with paraformaldehyde gives optically active 4-alkyl-2-oxazoline-4-carboxylates 93 with moderate to good enantioselectivity [46], The absolute configuration (S) of the product indicates that the reaction occurs selectively at the si face of the enolate as illustrated in Fig. 2. These oxazolines 93 can be converted into a-alkyl-serine derivatives 94 (Sch. 24). 

The same group further developed the asymmetric aldol reaction of A -methoxy-A -methyl-a-isocyanoacetamide (a-isocyano Weinreb amide) with aldehydes (Sch. 25). The reaction of the Weinreb amide 96 with acetaldehyde in the presence of 86c Au(I) catalyst gives the optically active tram-oxazoline 98 (E = CON(Me)OMe R = Me) with high diastereo- and enantioselectivities similar to those of 95 [49], The oxazoline can be transformed into A,0-protected /3-hydroxy-a-amino aldehydes or ketones. 

Both /ranj-selectivity and enantioselectivity depend on the structure of the terminal amino group, six-membered ring amines represented by piperidino 8g and morpholino 8h generally being most selective [71]. Substituted aromatic aldehydes, a,i -unsaturated aldehydes, and secondary and tertiary alkyl aldehydes can be converted into the corresponding /ranj-oxazolines with high enantioselectivity. Enantiomeric purities and transjcis ratios obtained for the aldol reaction of several aldehydes in the presence of Au/(R)-(S)-8h are shown in Scheme 2-51. The gold-catalyzed aldol reaction of isocyanoacetate has been applied to the synthesis... 

For the aldol reaction of small alkyl aldehydes such as acetaldehyde, the enantioselectivity is improved by the use of Ar,A -dialkyl-oe-isocyanoacetamides instead of isocyanoacetate esters (Scheme 2-54) [76]. For example, the reaction of acetaldehyde with AT,iV-dialkyl-a-isocyanoacetamides 64 in the presence of R)- S)-8g/gold catalyst gives the corresponding /ranj-oxazoline 65 of 99% ee, which is much higher than the enantioselectivity (85% ee) observed in the reaction with methyl isocyanoacetate under the same reaction conditions. 

Silver(i) complex coordinated with the ferrocenylbisphosphine ligand 8g is also effective as a catalyst for the asymmetric aldol reaction of isocyanoacetate when the isocyanoacetate is kept in low concentration in the reaction system (Scheme 2-58) [82], Thus, by the slow addition of isocyanoacetate over a period of 1 h to a solution of aldehyde and the silver catalyst, iranj-oxazolines are formed in 80—90% ee, the enantioselectivity being only a little lower than that observed in the gold(i)-catalyzed... 

The Cu(n)-catalyzed reaction of silyl enol ethers with oxomalonic esters in the presence of a bis(oxazoline) ligand constitutes the first step of an access to chiral p-hydroxy acids. Enantioselective Mukaiyama aldol reaction performed in the presence of 52, and that in aqueous ethanol has been accomplished to a certain degree of success (32-85% ee). ... 

Chiral Catalysts Containing Group 11 Metals (Cu, Ag, and Au). The most recent publications on the chiral copper catalysts are mainly dealing with those containing bis(oxazoline)-type ligands (Fig. 22). Cationic [Cu( Bu-BOX)] + complexes with OTf , [SbFe] , counterions catalyze Michael reactions, and various types of cycloadditions (292). Copper(II)-PYBOX complexes have been shown to catalyze enantioselective Mukaiyama aldol reactions (293). Similarly, bisoxa-zoline derivatives serve as ligands in the catalytic system prepared in situ from Cud) salts and are used for asymmetric peroxidation and enantioselective Meer-wein arylation of activated olefins (294). The copper-BOX-triflate complexes have found wide applications in cyclopropanation of alkenes (60), furans (295), and aziridination of alkenes (296). 

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