Oxazolines metallation

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 first examples of cationic exchange of bis(oxazoline)-metal complexes used clays as supports [49,50]. Cu(II) complexes of ligands ent-6a, 6b, and 6c (Fig. 15) were supported on three different clays laponite (a synthetic clay), bentonite, and montmorillonite KIO. The influence of the copper salt from which the initial complexes were prepared, as well as that of the solvent used in the cationic exchange, was analyzed. 

More recently, bis(oxazoline)-metal complexes supported in micro- and mesoporous solids have been used as catalysts of hetero-Diels-Alder and ene reactions. 

Various X-ray crystal structures of metal-ligand complexes provided evidence of the geometry of the complexes in the solid state, even though the structure of these complexes may differ in solution. The hrst crystal structure of a bis(oxazoline)-metal complex was determined in 1994 by Brown and co-workers. " This group crystallized and elucidated the structure of V,V-bis-[2-((45)-(methyl)-l,3-oxazoli-nyl)]methane-bi(ri ethene)rhodium(I), 18a, as depicted in Figure 9.3. The key features of this crystal structure include the C2-axis of symmetry, the axial positions of the methyl groups and the orientation of the ethene molecules, orthogonal to the complexation square plane. In 1995, Woodward and co-workers were able to crystallize and determine the structure of benzylbis(oxazoline) with ruthenium... 

Figure 9.3. Bis(oxazoline)-metal crystal structures (two-dimensional representation).

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%. 

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

Another example of a bis(oxazoline)-metal complex catalyzed reaction in total synthesis was illustrated by Murai and co-workers in the construction of a precursor... 

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). ... 

The J0rgensen and Desimoni groups have also carried out bis(oxazoline)-metal complex-catalyzed 1,3-dipolar cycloadditions with nitrones. Cycloaddition of a,(3-unsaturated oxazolidinones such as 69, 80a, and 130 with nitrone 127 in the presence of phe-box ligands 6 and ent-6 provided quantitative yields of cycloadducts. Selectivities of up to 100 0 endo/exo ratio and corresponding endo ee as high as 82% were achieved (Table 9.22, Fig. 9.41a). 

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). 

Another type of conjugate addition reaction in which bis(oxazoline)-metal complexes have been used is the Michael addition reaction. Early work in this... 

With Chiral Bis(oxazoline)/metal Complexes Several research groups have developed chiral Lewis acids by using chiral 1,3-bis(oxazoline) ligands for asymmetric Diels-AIder reactions. Evans designed C2-symmetric bis(oxazoline)/Cu(II) complexes derived from chiral bis(oxa-zoline)and Cu(OTf)2, and applied them to asymmetric cycloadditions of acryloyl oxazolidinones and thiazolidine-2-thione analogues. Attractive features of this catalyst system include a clearly interpretable geometry for the catalyst-dienophile complex, which rationalizes the sense of asymmetric induction for the cycloaddition process [26] (Eq. 8A.14). 

With Chiral Mono(oxazoline)/metal Complexes 2-(Tosylamino)phenyloxazoline can also be utilized as a chiral ligand for the enantioselective Diels-Alder addition of acryloyl oxazolidi-nones. The requisite chiral magnesium complex is derived from methylmagnesium iodide and this chiral ligand [38] (Eq. 8A.20). 

Fig. 6.30 Diels-Alder reaction, catalysed by a — non-dendritic - bis(oxazoline)-metal complex (according to Chow et al.)...

A.K. Ghosh et al., C2-Symmetric chiral bis(oxazoline)-metal complexes in catalytic asymmetric synthesis. Tetrahedron Asymm. 9, 1—45 (1998)... 

Chiral 2-(3-oxoalkyl)pyrroles and 3-(3-oxoalkyl)indoles can also be accessed by reaction in the presence of 10 mol% of chiral bis(oxazoline)/metal complexes in CH2C12 in very high yields and with ee values over 90% <2005JA4154>. Alkylation of pyrrole and of substituted indoles with, -unsaturated acyl phosphonates <2003JA10780> or 2-acyl N-methylimidazoles catalyzed by a chiral bis(oxazolinyl)pyridine (pybox)/scandium(III) triflate complex also exhibits good enantioselectivity over a broad range of substrates <2005JA8942>. 

Electrophilic substitution. A number of chiral nucleophilic species have been described that result in optically active a-alkyl aldehydes, ketones, acids, and acid derivatives upon alkylation and (usually) subsequent hydrolytic cleavage. Enders provides a number of examples (Figure 3) one of which results in the ant alarm pheromone, 4-methyl 3-heptanone (26 2 7). Studies by A. I. Meyers of the chemistry of anions of chiral oxazolines (Figure 4) were the first of the genre, however ( 8 ). Related reactions of chiral anions of metalloenamines and hydrazones (29, 30, 31) have in common with the alkylation of oxazolines metallated azaenolate intermediates that predispose one face of an azaenolate double bond to reaction with the electrophile. 

Initial screening reactions carried out with enone 460 and A -methyl pyrrole in the presence of 10mol% of a series of chiral bis(oxazoline)/metal complexes in CH2CI2 as solvent, revealed complexes 458 and 459 as the most effective (Equation 110) <2005JA4154>. Using these catalysts Eriedel-Crafts adduct 461 (R = BnCH2) was formed in yields of 86% and 80% and most notably, with ee 92% and 91%, respectively. Indole derivatives 462 worked as efficiently as pyrroles and provided adducts 463 in good to excellent yields and enantiomeric excess (Equation 111). 

Ghosh, A. K. Mathivanan, P Cappiello, J. C2 Symmetric Chiral Bis(Oxazoline)-Metal Complexes in Catalytic Asymmetric Synthesis, Tetrahedron.-Asymmetry 1998, 9, 1-45. 

Attempts to carry out carbene transfer reactions with chiral palladium catalysts were unsuccessful so far. Demnark et al. conducted a detailed study in which cyclopropana-tions of a,/3-unsaturated carbonyl compounds with diazomethane catalyzed by bis-(oxazoline)palladium(n) complexes were investigated. Virtual no asymmetric induction was obtained in these reactions which led to the conclusion—especially in light of the excellent asymmetric enviromnent bis(oxazolines) metal complexes offer in general—-that partial or complete ligand dissociation must have been occurred during the course of the reaction. 

Chiral bidentate bis(oxazoline)-metal complexes (metal = Cu, Ni, Mg, Zn, Sc, La) were also studied, with preference for copper (II) trifiate- and nickel (II) per-chlorate-bis(oxazolines). It was found that as little as 1 mol% of catalyst is adequate for the enantioselective electrophilic fluorination of both cyclic and acyclic (3-ketoest-ers (Scheme 44.22). NFSI was preferred to Selectfiuor or A-fluoropyridinium trifiate to produce higher enantiomeric excesses. Importantly, the use of HFIP as additive greatly improved the ee-values in all the reactions by ca. 15%. An important finding in NFSI mediated fluorination is that the (5,5)-Ph-BOX-Ni(II) complex provides the fiuorinated product with opposite configuration to that obtained with the (5,S)-Ph-BOX-Cu(ll) complex (Scheme 44.22). The origin of the reversed sense of stereoinduction could be a consequence of a change in the metal-center geometry from distorted square-planar (Cu complex) to square-pyramidal (Ni complex) in the reactive intermediates. 

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