Aldol reaction oxazoline

Eor the application of C2-symmetric bis-oxazoline-Lewis acids in other catalytic reactions (a) Mukaiyama-aldol reactions see, e.g., D.A. Evans, M.C. Kozlowski,... 

Cationic bis(oxazoline) and pyridil-bis(oxazoline) Cu(ll) and Zn(ll) Lewis-acid catalysts. A comparative study in catalysis of Diels-Alder and aldol reactions [101]... 

Asymmetric Lewis-Acid Catalyzed. Another important advance in aqueous Mukaiyama aldol reaction is the recent success of asymmetric catalysis.283 In aqueous ethanol, Kobayashi and co-workers achieved asymmetric inductions by using Cu(OTf)2/chiral >A(oxazoline) ligand,284 Pb(OTf)2/chiral crown ether,285 and Ln(OTf)3/chiral Mv-pyridino-18-crown-6 (Eq. 8.105).286... 

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... 

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... 

The gold(I) complex of a chiral ferrocenylphosphine complex promotes asymmetric aldol reactions of a-isocyanocarboxylates to form chiral oxazolines in high diastereo- and enantio-selectivities (Scheme 52).225,226 In these reactions, the analogous silver(I) ferrocenylphosphine complex also works well. 

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... 

Pro-chiral pyridine A-oxides have also been used as substrates in asymmetric processes. Jprgensen and co-workers explored the catalytic asymmetric Mukaiyama aldol reaction between ketene silyl acetals 61 and pyridine A-oxide carboxaldehydes 62 <06CEJ3472>. The process is catalyzed by a copper(II)-bis(oxazoline) complex 63 which gave good yields and diastereoselectivities with up to 99% enantiomeric excess. 

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... 

Treating boron reagent 45a with an oxazoline compound gives the azaeno-late 52. Subsequent aldol reaction of 52 with aldehyde yields mainly threo-product (anti-53) with good selectivities (Scheme 3-18).38... 

The C2-symmetric bis(oxazoline)-Cu(II) complexes have proved to be very effective in asymmetric aldol reactions (see Section 3.4.3), as well as Diels-Alder reactions (see Section 5.4.6). These compounds are also powerful catalysts in hetero Diels-Alder reactions. Figure 5-8 shows some of the bis(oxazoline) ligands applied in asymmetric hetero Diels-Alder reactions. 

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. 

It should be noted that the reaction of benzalde-hyde with (Z)-3-trimethylsiloxy-2-pentene in ethanol or dichloromethane in the presence of the chiral catalyst resulted in a much lower yield and selectivity. On the basis of these results, we propose the catalytic cycle shown in Scheme 2. The catalyst A formed from Cu(OTf)2 and a bis(oxazoline) ligand accelerates the aldol reaction to generate the intermediate B. In aqueous solvents, B is rapidly hydrolyzed to produce the aldol product C and regener-... 

Scheme 24. Proposed mechanism for the bis(oxazoline)-Cu(II) catalyzed aldol reaction between pyruvate esters and enolsilanes. [Adapted from (235).]...

Conversion of 2 to the highly crystalline oxazolidinone 3 with phosgene has been described by Thornton who has employed this substance as a chiral auxiliary in asymmetric aldol reactions of its N-propionyl derivative. Kelly has also used an oxazoline derived from 3 as a chiral auxiliary in asymmetric alkylation of a glycolate enolate. Oxazolidinone 3 has also been prepared from 2 with diethyl carbonate in the presence of potassium carbonate. The conversion of 2 to the oxazolidinone 3 is accomplished using triphosgene in this procedure because of the high toxicity of phosgene. 

Mukiayama aldol reactions between silyl enol ethers and various carbonyl containing compounds is yet another reaction whose stereochemical outcome can be influenced by the presence of bis(oxazoline)-metal complexes. Evans has carried out a great deal of the work in this area. In 1996, Evans and coworkers reported the copper(II)- and zinc(II)-py-box (la-c) catalyzed aldol condensation between benzyloxyacetaldehyde 146 and the trimethylsilyl enol ether [(l-ferf-butylthio)vinyl]oxy trimethylsilane I47. b82,85 Complete conversion to aldol adduct 148 was achieved with enantiomeric excesses up to 96% [using copper(II) triflate]. The use of zinc as the coordination metal led to consistently lower selectivities and longer reaction times, as shown in Table 9.25 (Eig. 9.46). 

A. Barco, S. Benetti, C. De Risi, G. P. Pollini, G. Spalluto, and V. Zanirato, 4-Isopropyl-2-oxazolin-5-one anion as a new convenient formyl anion equivalent for conjugate addition and aldol reactions. Tetrahedron Lett. 34 3907 (1993). 

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. 

It is interesting that aldol-type condensation of tosylmethyl isocyanide (16) with aldehydes is catalyzed by the silver catalyst more stereoselectively than that catalyzed by the gold catalyst under the standard reaction conditions (Scheme 8B1.9) [26], Elucidation of the mechanistic differences between the gold and silver catalysts in the asymmetric aldol reaction of 16 needs further study. Oxazoline 17 can be converted to optically active a-alkyl-p-(A-methyl-amino)ethanols. 

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. 

A new thioester aldol reaction which uses a half-thioester (PhS0C- CHMe-C02H) of methylmalonic acid and a copper-bis(oxazoline) catalyst is highly enantio- and diastereo-selective, while also being mild and tolerant of protic functional groups and enolizable aldehydes.136... 

Scheme 2. Synthesis of oxazolines by a gold-catalyzed asymmetric aldol reaction.

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. 

Two further syntheses of Lactacystin also deployed a diastereoselective aldol reaction to create a quaternary centre.250-251 Smith and co-workers,250 protected the 1,2-amino alcohol 129.1 [Scheme 3.129] by heating with trimethyl orthobenzoate to give the oxazoline 129 2 in 82% yield. The oxazoline served the dual puipose of protecting and activating group in the subsequent aldol reaction... 

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. 

Organoaluminum and Sn(IV) Lewis acid-mediated [3 + 2] cycloadditions of oxa-zoles and aldehydes or diethyl ketomalonate have been observed [116]. The reactions are highly regioselective, with stereoselectivity highly dependent upon the Lewis acid used (Eq. 76). For example, the (BINOL)AlMe-promoted reaction between benzal-dehyde and the oxazole furnishes the oxazoline with a transicis ratio of 2 98. The selectivity is reversed with SnCU which results in a transicis ratio of 85 15. trans-5-Sub-stituted 4-alkoxycarbonyl-2-oxazolines are synthesized under thermodynamic conditions in the aldol reaction of isocyanoacetates with aldehydes [117]. 

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... 

---