Oxazoline complex Diels-Alder reaction

The bis-oxazoline-catalysed Diels-Alder reaction is not restricted to the use of oxazolidinone-based dienophiles. For instance the a-sulfenylacrylate (8.74) and oi-hydroxyenones such as (8.75) undergo enantioselective Diels-Alder reaction with cyclopentadiene in the presence of the copper complex of (8.67) and (8.68) respectively. 

The magnesium and copper bis-oxazoline catalysts used in the asymmetric Diels-Alder reaction (see Section 8.1) display high levels of selectivity in the nitrone cyclo addition with bidentate, electron-deficient dipolarophiles. The magnesium bis-oxazoline catalysts effect moderate to good ee in the cycloaddition with oxazolidines such as (8.51), while copper bis-oxazoline complexes show good selectivity in the addition to bidentate pyrazolidinones rather than oxazo-lidinones and also a-hydroxyenones such as (8.75) used as substrates in the copper bis-oxazoline-catalysed Diels-Alder reaction. ... 

Since Evans s initial report, several chiral Lewis acids with copper as the central metal have been reported. Davies et al. and Ghosh et al. independently developed a bis(oxazoline) ligand prepared from aminoindanol, and applied the copper complex of this ligand to the asymmetric Diels-Alder reaction. Davies varied the link between the two oxazolines and found that cyclopropyl is the best connector (see catalyst 26), giving the cycloadduct of acryloyloxazolidinone and cyclopentadiene in high optical purity (98.4% ee) [35] (Scheme 1.45). Ghosh et al., on the other hand, obtained the same cycloadduct in 99% ee by the use of unsubstituted ligand (see catalyst 27) [36] (Scheme 1.46, Table 1.19). 

Keywords hefero-Diels-Alder reaction, chiral bis(oxazoline) copper(ll) complexes... 

Ghosh et al. [70] reviewed a few years ago the utihty of C2-symmetric chiral bis(oxazoline)-metal complexes for catalytic asymmetric synthesis, and they reserved an important place for Diels-Alder and related transformations. Bis(oxazoline) copper(II)triflate derivatives have been indeed described by Evans et al. as effective catalysts for the asymmetric Diels-Alder reaction [71]. The bis(oxazoline) Ugand 54 allowed the Diels-Alder transformation of two-point binding N-acylimide dienophiles with good yields, good diastereos-electivities (in favor of the endo diastereoisomer) and excellent ee values (up to 99%) [72]. These substrates represent the standard test for new catalysts development. To widen the use of Lewis acidic chiral Cu(ll) complexes, Evans et al. prepared and tested bis(oxazoHnyl)pyridine (PyBOx, structure 55, Scheme 26) as ligand [73]. 

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). 

Fujisawa et al. [Ill] have reported that the magnesiiun complex prepared from chiral 2-[2-[(tolylsulfonyl)amino]phenyl]-4-phenyl-l,3-oxazoline 81 and methyl-magnesium iodide was efficient, in a stoechiometric amount, for promoting the enantioselective Diels-Alder reaction of 3-alkenoyl-l,3-oxazohdin-2-one with cyclopentadiene (Scheme 45) leading exclusively to the endo adducts in up to 92% ee. The use of 10 mol% of the complex led to an important decrease in enantioselectivity of the product (51% ee). 

Apart from the cyclopropanation reaction, only one example has been published of the application of ionic liquids as reaction media for enantio-selective catalysis with bis(oxazoline) ligands. In this case, the complex 6b-ZnCl2 was used as a catalyst for the Diels-Alder reaction between cyclopen-tadiene and N-crotonyloxazolidin-2-one in dibutyUmidazoUiun tetrafluorob-orate (Scheme 9) [48]. Compared with the same process in CH2CI2, the reaction was faster and both the endofexo selectivity and the enantioselectivity in the endo product were excellent. However, experiments aimed at recovering the catalysts were not carried out. 

In the case of the Diels-Alder reaction [68] (Scheme 12), several soUds (AlSBA-15, MCM-41, MSU-2 and zeolite HY) were tested as supports for the bis(oxazoline)-copper complexes. The best enantioselectivity results were obtained with the zeolite HY, although the yield was the poorest (16% yield, 41% ee). As happened with the aziridination reaction, the enantioselectivity changed with time. Short reaction times led to the same major enantiomer as observed in homogeneous reactions. However, at higher conversions, i.e., longer reaction times, the opposite major enantiomer was obtained. 

The only example of immobilization of a bis(oxazoline) complex by adsorption onto silica was published very recently [70]. The complexes 6a-Cu(OTf)2 and 6b-Cu(OTf)2 were adsorbed onto a chromatographic grade of silica gel and the resulting solids used as catalysts in two Diels-Alder reactions. 

In stereoselective reactions, Zn11 Lewis acids work well to achieve high selectivities (Scheme 54). Chiral complexes of Zn11 with chiral bis(oxazoline) ligands act as effective catalysts in Diels-Alder reactions of reactive dienes with dienophiles having bidentate chelating moieties such as... 

Corey and Ishihara29 report the synthesis of a new bis(oxazoline). This catalyst effects Diels-Alder reaction via a tetracoordinated metal complex. Ligand (.S )-8I is synthesized from (iS )-phenylglycine, as depicted in Scheme 5-25. Treatment of 81 with Mgl2 L gives a dark solution of complex 82, which can be utilized as a Diels-Alder reaction catalyst. Thus, reaction of cyclopentadiene with 71 in the presence of 82 yields product 72a with an enantiomeric ratio of over 20 1 (Scheme 5-26). 

Ghosh et al.32 have demonstrated another bis(oxazoline) derivative chiral ligand 86 for asymmetric Diels-Alder reaction and obtained excellent results. Reaction of an equimolar mixture of chiral ligand 86 and Cu(C104)2 6H20 produces the aqua complex 87 (w being water molecule), which shows excellent catalytic power in asymmetric Diels-Alder reactions. As depicted in Scheme 5 27, the reaction of 88 with cyclopentadiene gives product 89 with more than 80% yield, over 99 1 diastereoselectivity and up to 99% ee. 

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. 

Jorgensen s group44a carried out the reaction using the anhydrous form of chiral bis(oxazoline) coordinated copper complex. Complex 106 containing 83 as the chiral ligand was found to be the most effective. As shown in Scheme 5-32, the asymmetric hetero Diels-Alder reaction of //.y-unsaturated a-keto esters with acyclic enol ethers results in products with excellent yield and enantioselectivity. 

The copper complex of these bis(oxazoline) compounds can also be used for hetero Diels-Alder reactions of acyl phosphonates with enol ethers.43 5 A favorable acyl phosphonate-catalyst association is achieved via complexation between the vicinal C=0 and P=0 functional groups. The acyl phosphonates are activated, leading to facile cycloaddition with electron-rich alkenes such as enol ethers. The product cyclic enol phosphonates can be used as building blocks in the asymmetric synthesis of complicated molecules. Scheme 5-36 shows the results of such reactions. 

Another successful aza Diels-Alder reaction involves 2-azadienes of type 125 with dienophile 126 in the presence of bis(oxazoline) catalyst 106a.53 Product 127 is obtained in a high exo endo ratio, as well as high enantiomeric excess for the exo-isomer of 127. The high enantioselectivity and high yield rely on the chiral catalyst 106a, which activates the dienophile by complexation with an appropriate functional group and does not irreversibly coordinate with the... 

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. 

Copper(II)-bis(oxazoline) complexes (48) are robust, valuable catalysts for a wide variety of stereoselective Diels-Alder reactions. In a key step en route to... 

In 1993, Evans et al. (198) demonstrated that bis(oxazoline)-Cu(II) complexes are effective Lewis acids for Diels-Alder reaction of acryloylimide and cyclopen-tadiene. These Lewis acids are capable of inducing reaction at -78°C with only 5 mol% catalyst loadings, providing the cycloadduct in 86% isolated yield and 98 2... 

The utility of bis(oxazoline)-Cu(II) complexes as catalysts for the Diels-Alder reaction has been examined in a number of other systems. Aggarwal et al. (205) demonstrated that a-thioacrylates behave as effective two-point binding substrates for these catalysts. With cyclopentadiene, catalyst 271d induces the reaction at -78°C to provide the cycloadduct in 94 6 diastereoselectivity and >95% ee. Aggarwal proposes that the metal binds to the carbonyl oxygen and to the sulfur atom. The sulfur substituent is placed opposite the ligand substituent thereby shielding the bottom face of the alkene. Considerably lower selectivities are observed with 5-Me substrates. 

Helmchen and co-worker investigated the use of phosphinooxazolines as ligands for copper(II) catalyzed Diels-Alder reactions (Scheme 19) (214). Optimal selectivities are found for a-naphthyl-substituted phosphinooxazoline (299). These catalysts require 2.5 h to induce complete conversion to cycloadduct, compared to 18 h using the triflate complex 269c under identical conditions. Helmchen invokes a square-planar metal geometry to explain the stereochemistry of the adducts, similar to the model proposed by Evans. He suggests that the bulky phosphine substituents are required to orient binding of the dienophile in such a way as to place the olefin directly below the terf-butyl substituent on the oxazoline. 

Metal complexes of bis(oxazoline) ligands are excellent catalysts for the enantioselective Diels-Alder reaction of cyclopentadiene and 3-acryloyl-l,3-oxa-zolidin-2-one. This reaction was most commonly utilized for initial investigation of the catalytic system. The selectivity in this reaction can be twofold. Approach of the dienophile (in this case, 3-acryloyl-l,3-oxazolidin-2-one) can be from the endo or exo face and the orientation of the oxazolidinone ring can lead to formation of either enantiomer R or S) on each face. The ideal catalyst would offer control over both of these factors leading to reaction at exclusively one face (endo or exo) and yielding exclusively one enantiomer. Corey and co-workers first experimented with the use of bis(oxazoline)-metal complexes as catalysts in the Diels-Alder reaction between cyclopentadiene 68 and 3-acryloyl-l,3-oxazolidin-2-one 69 the results are summarized in Table 9.7 (Fig. 9.20). For this reaction, 10 mol% of various iron(III)-phe-box 6 complexes were utilized at a reaction temperature of —50 °C for 2-15 h. The yields of cycloadducts were 85%. The best selectivities were observed when iron(III) chloride was used as the metal source and the reaction was stirred at —50 °C for 15 h. Under these conditions the facial selectivity was determined to be 99 1 (endo/exo) with an endo ee of 84%. 

Ghosh and co-workers have also demonstrated that the Cu(II)-bis(oxazoline) complexes of conformationally constrained inda-box ligands 9a and ent-9a are excellent catalysts for the enantioselective Diels-Alder reaction. Using copper(II) trrflate as the metal source, the reaction resulted in selectivities up to >99 1 endo/ exo ratio with endo ee up to 99% (2R isomer), as shown in Table 9.10 (Fig. 9.24). Of particular interest, Cu(II)-phe-box ligand 6-derived catalyst complex exhibited considerably lower enantioselectivity (30%)." Furthermore, they have shown that the use of Mg(II) as the chelating metal resulted in a reversal of stereochemistry [up to 98 2 endo/exo and 61% endo ee for the (25) isomer]. Davies also showed that the use of copper(II) triflate with his stmcturally related inda-box ligands 9b and 34a led to similar selectivities. 

There are also several other examples of bis(oxazoline)-metal complex catalyzed Diels-Alder reactions of cyclopentadiene and other unsaturated esters. 

Evans has reported that the cationic C2-symmetric chiral Lewis acid Cu(ll)bis(oxazoline) complex promotes the hetero-Diels-Alder reaction of 0 ,/3-unsaturated acyl phosphonates with enol ethers to give the cycloadducts with excellent ee (Scheme 52). As well as simple dihydropyrans, various fused bis-dihydropyrans are also reported <1998JA4895, 2000JA1635>. 

Cationic chiral Rh and Ru complexes were prepared by reaction of [(T -C5H5)RhCl2]2 and [RuCl2(T 6-mes)]2 with chiral bidentate or monodentate oxazoline ligands, respectively. Treatment of these monocationic metal complexes, with AgSbF produced dicationic complexes, which were also found to be highly effective for the enantioselective Diels-Alder reaction of methacrolein [12,13] (Eq. 8A.6). On the basis of spectroscopic and structural studies, a full catalytic cycle of a chiral Ru complex was proposed for the Diels-Alder reaction of cyclopen-tadiene with methacrolein [14]. 

With Chiral Bis(oxazoline)/Mg Complexes A chiral bis(oxazoline)/MgI2 complex has been utilized for the enantioselective Diels-Alder reaction of cyclopentadiene and ethyl 2-benzoylacrylate that acts as a two-point binding dienophile [49] (Eq. 8A.27). This reaction proceeds with virtually complete endo/exo selectivity (>99 1). 

Chiral bis(oxazoline)/Copper(II) complexes are evaluated for asymmetric Diels-Alder reaction of naphthoquinone derivatives, and moderate levels of enantiomeric excess are observed in certain cases [56] (Eq. 8A.33). 

A similar chiral bis(oxazoline)/Cu(II) catalyst is useful for the asymmetric hetero Diels-Alder reaction of Danishefsky s diene and glyoxylates [63] (Eq. 8A.39). Other bis(oxa-zoline)/M(OTf)2 (M = Sn, Mg) complexes are not effective. This method provides new routes to asymmetric aldol synthesis upon hydrolysis of the resulting adducts. 

The chiral bis(oxazoline)/Cu(II) complex with OTf or SbFg as a counter anion effectively promotes the enantioselective hetero Diels-Alder reaction of enol ethers with acyl phosphonates to give chiral enol phosphonates as synthetically useful chiral building blocks [64] (Eq. 8A.40). 

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