Bisoxazoline Diels-Alder reaction

The cationic aqua complexes prepared from traws-chelating tridentate ligand, R,R-DBFOX/Ph, and various transition metal(II) perchlorates induce absolute enantio-selectivity in the Diels-Alder reactions of cyclopentadiene with 3-alkenoyl-2-oxazoli-dinone dienophiles. Unlike other bisoxazoline type complex catalysts [38, 43-54], the J ,J -DBFOX/Ph complex of Ni(C104)2-6H20, which has an octahedral structure with three aqua ligands, is isolable and can be stored in air for months without loss of catalytic activity. Iron(II), cobalt(II), copper(II), and zinc(II) complexes are similarly active. 

Jorgensen et al. [84] studied how solvent effects could influence the course of Diels-Alder reactions catalyzed by copper(II)-bisoxazoline. They assumed that the use of polar solvents (generally nitroalkanes) improved the activity and selectivity of the cationic copper-Lewis acid used in the hetero Diels-Alder reaction of alkylglyoxylates with dienes (Scheme 31, reaction 1). The explanation, close to that given by Evans regarding the crucial role of the counterion, is a stabilization of the dissociated ion, leading to a more defined complex conformation. They also used this reaction for the synthesis of a precursor for highly valuable sesquiterpene lactones with an enantiomeric excess superior to 99%. 

Bayardon and Sinou have reported the synthesis of chiral bisoxazolines, which also proved to be active ligands in the asymmetric allylic alkylation of l,3-diphenylprop-2-enyl acetate, as well as cyclopropanation, allylic oxidations and Diels-Alder reactions. [62] The ligands do not have a fluorine content greater than 60 wt% and so are not entirely preferentially soluble in fluorous solvents, which may lead to a significant ligand loss in the reaction system and in fact, all recycling attempts were unsuccessful. However, the catalytic results achieved were comparable with those obtained with their non-fluorous analogues. 

Diels-Alder reactions of benzo[fc]furan-43-diones and benzo[b]furan-4,7-diones have been reported <99H(50)1137>. The activation of a C-0 bond in a Mn(C0>3 complexed benzo[i>]furan was examined <99AG2343>. The enzyme-catalyzed dealkylation of (+)-marmesin to the phototoxic psoralene (and acetone) has been investigated <99AG413>. A hi yielding synthesis of bidentate bisoxazoline DBFOX/Ph [(R,R)-4,6-dibenzofutandiyl-2 2 -bis(4-phenyloxazoline)] was developed. DBFOX/Ph was subsequently tested in enantio-selective conjugate radical additions onto 3-(3-phenyl-2-propenoyl)-2-oxazolidinone <99TA2417>. 

Scheme 8C.9. Ene vr. hetero Diels-Alder reaction catalyzed by BINOL-A1 or bisoxazoline-Cu complex.

In hetero-Diels-Alder reactions, the effect of ligand structure and acidity on the catalytic activity of lanthanide catalysts has been reviewed.191 The effect of different C(2)-symmetric bisoxazolines on the zinc(II)-catalysed hetero-Diels-Alder reaction of ethyl glyoxylate with conjugated 1,3-dienes has been investigated.192 The hetero-Diels-Alder reaction 4-dimethylamino-2-phenyl-l-thiabuta-1,3 -diene with methyl acrylate and /V-cnoyloxazolidinone produces cw-3,4-disubstituted 3,4-dihydro-2//-... 

Figure 6.11 a Diels-Alder reaction of N-2-alkenoyl-l, 3-oxazolidin-2-one with cyclopentadiene. b alignment of all 23 bisoxazoline and phosphinoxazoline ligands used in the CoMFA study. Regions of space where steric bulk should enhance or decrease stereo-induction are plotted using iso-contour mapping. 

Lipkowitz, K.B. and Pradhan, M. (2003) Computational studies of chiral catalysts a comparative molecular field analysis of an asymmetric Diels—Alder reaction with catalysts containing bisoxazoline or phosphinooxazoline ligands. /. Org. Chem., 68, 4648. 

R,R)-4,6-Dibenzofiirandiyl-2,2 -bis(4-phenyloxazoline), DBFOX/Ph (5), is a novel tridentate bisoxazoline ligand developed by Kanemasa and coworkers that has been successfully used as a chiral Lewis acid in enantioselective Diels-Alder-reactions, nitrone cycloadditions and conjugate additions of radicals and thiols to 3-(2-alkenoyl)-2-oxazolidinones. Representative examples for cycloadditions using the Ni(C104)2-6H20 derived complex are shown below. 

Diels-Alder reaction is one of the premiere reactions in synthetic organic chemistry. The traditional approach to the normal Diels-Alder reaction is to activate the di-enophile by means of a Lewis acid such that the transformation can be carried out under practicable conditions. A variety of Lewis acids catalyze this reaction selectively and among these copper(II) compounds have been very successful in enantioselective transformations. The use of bisoxazolines in combination with copper triflate or copper antimony hexafluoride has afforded high selectivity. Pioneering work in this area by Evans, Jprgensen, Kanemasa, and others has shed light on the different controlling features of the copper Lewis acids. 

The use of aminoindanol-derived bisoxazolines in conjunction with copper Lewis acids led to improvements in the enantioselectivity of the Diels-Alder reaction (Sch. 44) [83]. Changes in stereoselectivity with small changes in ligand structure have also been noted (compare 198 and 200) [84], Copper also strongly coordinates phosphorus ligands. The use of PN chiral ligands in Cu(OTf)2-mediated Diels-Alder reactions has been reported [85]. 

The use of catalyst 187 or 188 (see Sch. 43) in cycloadditions requires anhydrous conditions. Recently, several practical alternatives for this requirement have been reported. Evans has shown that the easily manipulated aquo complex prepared from 187 and water can be dehydrated to the active catalyst in the reaction vessel by addition of molecular sieves, without any loss of reactivity or selectivity [87]. Copper(II) perchlorate is available commercially as a hexahydrate. Ghosh and co-workers have reported that a complex 207 prepared from an aminoindanol-derived bisoxazoline and Cu(C104)2 6H2O is an excellent Lewis acid in Diels-Alder reactions (Sch. 46). It is interesting to note that the generally sluggish reactions with oxazolidinone croto-nates proceed with very high selectivity at room temperature [88]. 

This process (hetero Diels-Alder reaction leading to a dihydropyran system) may be also conducted in an asymmetric version application of chiral transition-metal catalysts based on BINOL, BDMAP, bisoxazolines, etc. provides adducts in very high optical purity (ee up to 99%) [1,6], In a series of papers Jurczak reported recently a highly enantioselective cycloaddition of 1-methoxy-1,3-butadiene and butyl glyoxylate catalyzed with chiral salen complexes [21],... 

The group of Lipkowitz et al. also performed computational studies of chiral catalysts using COMFA of an asymmetric Diels-Alder reaction with catalysts containing bisoxazoline or phospinooxazoline ligands that are known to induce asymmetry [20]. Approximately 70% of the variance in the observed enantiomeric excess can be attributed to the sterical field and the remainder of the variance to the electrostatic field. 

A Comparative Molecular Field Analysis of an Asymmetric Diels-Alder reaction with Catalysts Containing Bisoxazoline or Phosphinooxazoline Ligands,/. Org. Chem. 2003, 68, 4648-4656. 

During recent years, the homogeneous Lewis acid-catalyzed asymmetric Diels-Alder reactions and hetero-Diels-Alder (HDA) reactions have each undergone extensive study. Various chiral Lewis acids including aluminum, titanium or boron, and chiral ligands such as chiral amino alcohols, diols, salen, bisoxazoline or N-sulfonylamino acids have been used as the catalysts [84]. Much efforts have also been made in the investigation of heterogeneous diastereoselective Diels-Alder reactions. 

Oh and Meracz were the first to report asymmetric Diels-Alder reaction in ionic liquids [43]. It has also been shown that Diels-Alder reactions in ionic liquids give unusually high stereoselectivities at room temperature as compared to those in conventional organic solvents, where a low temperature was required to achieve good stereoselectivities. For example, the Diels-Alder reaction of cyclopentadiene and dienophile 25 with Cu(ll)-bisoxazoline complex 24 as catalyst in [dbim][BF4] showed a higher endoselectivity (endo j exo = 93/7) and regioselectivity (26/27 = 96/4) than in CHjCb (endojexo = 79/21, 26/27 = 76/24) (Scheme 7.11). 

A library of chiral dihydropyrans (226) [241] was synthesized using asymmetric hetero-Diels-Alder reactions (HAD) on polymer-bound enol ethers (221) and a, 3-unsaturated oxalyl esters (222). A chiral Lewis acidic Cu -bisoxazoline complex was used because of its high efficiency, the high predictability of the reaction outcome, and its broad substrate tolerance [280]. Enol ethers were used as alkene components bearing a hydroxy function for attachment to the resin via a silyl linkage (Scheme 49). The diene components carried allyl-ester groups, which could be readily displaced by amino functions in subsequent steps of the combinatorial synthesis. 

Keywords Ene reaction, Hetero-Diels-Alder reaction, Ene cyclization, Desymmetrization, Kinetic resolution. Non-linear effect. Asymmetric activation, Metallo-ene, Carbonyl addition reaction, Aldol-type reaction. Titanium, Aluminum, Magnesium, Palladium, Copper, Lanthanides, Binaphthol, Bisoxazoline, Diphosphine, TADDOL, Schiff base. 

This explanation is described as a mnemonic rule [228], which can only be taken as a first approximation of reality. The same rule can be used to rationalize the topicity of other asymmetric Diels-Alder reactions, such as those employing titanium BINOLate catalysts (Figure 6.18i, [230]), or iron bisoxazoline catalysts (Figure 6.18j,k [206,215]). Although the explanation seems reasonable, the picture is not complete, since it does not account for a number of observations, including the fact that the dioxolane substituents exert an extraordinary effect on catalyst efficiency (c/ Table 6.6, entries 2 and 5). Additionally, both titanium TADDOLate [228] and BINOLate [230] complexes show a nonlinear relationship between enantiomeric purity of the catalyst and that of the product, which suggests that some sort of dimerization phenomenon is involved. 

The bisoxazoline catalysts, sometimes abbreviated to [Cu-(5,5)-t-Bu-box]X2, are suitable for inter- and intramolecular asymmetric Diels-Alder reactions with... 

Copper complexes of the bisoxazoline ligands have been shown to be excellent asymmetric catalysts not only for the formation of carbocyclic systems, but also for the hetero-Diels-Alder reaction. Chelation of the two carbonyl groups of a 1,2-dicarbonyl compound to the metal atom of the catalyst sets up the substrate for cycloaddition with a diene. Thus, the activated diene 20 reacts with methyl pyruvate in the presence of only 0.05 mol% of the catalyst 66 to give the adduct 138 with very high enantiomeric excess (3.99). 

Hetero-Diels-Alder reactions have been used in the construction of amino-sugars, asymmetry being induced by the use of either a chiral Lewis acid catalyst or a chiral auxiliary. Thus, the 3-amino-hexuronic acid derivatives 61 were obtained with high de and ee using a copper(II) triflate catalyst with a chiral bisoxazoline ligand. 4-Amino-4-deoxy-D-erythrose and 4-amino-4,5-dideoxy-L-lyxose (63), the latter a potent inhibitor of a-L-fucosidase, were obtained from the D-pyroglutamic add-containing diene 62 (Scheme 19). ... 

Metal-free bisoxazolines catalyzed Diels-Alder reaction of A-substituted maleim-ides 137 with anthrone 136 derivatives was achieved by Gbbel, et al. Scheme 3.45 [61]. With the photoelectron spectra and other studies, the Br0nsted-base catalysis is assumed to be involved with formation of an ion pair between the protonated catalyst 138 and the anthrone enolate, acting as diene. 

Scheme 3.45 Bisoxazoline-catalyzed Diels-Alder reaction...

This stabilization of a transition state related to tihe uncatalyzed process can also occur in reactions catalyzed by transition metal complexes, such as those catalyzed by Lewis acids. For example, Diels-Alder reactions catalyzed by transition metal complexes sometimes ocau" by mechanisms related to the concerted [4+2] mechanism of tiie imcatalyzed process. In tiiis case, the catalyst changes the electronic properties of the substrate bound to the Lewis add in a fashion that reduces the barrier for tihe [4+2] cycloaddition. Figure 14.3 shows the transition state proposed for enantioselective Etiels-Alder reactions catalyzed by copper complexes. The transition state structure is proposed on tiie basis of the calculated structure of the Lewis add complex formed between tiie copper-bisoxazoline fragment and the acrylate. 

Transition state proposed for enantioselective Diels-Alder reactions catalyzed by a copper-bisoxazoline complex. The orientation of the diene and acrylate in this transition state resembles that in the transition state for an uncatalyzed [4+2] cycloaddition. Adapted from Evans, D. A. Barnes, D. M. Johnson, J. S. Leckta, T von Matt, R Miller, S. J. Murry, J. A. Norcross, R. D. Shaughnessy, E. A. Campos, K. R. J. Am. Chem. Soc. 1999,121,7582. 

Lewis acids such as Cu(OTf)2, its chiral bisoxazoline complex Cu(oxaz)2(OTf)2, and BiCls catalyze the intramolecular Diels-Alder reaction of 1-azadienes (eq 21). The 2-cyano-l-azadienes (4), containing an electron rich enol ether dienophile component, undergo cycloaddition to give the oxazinopiperidines (5) in 59-80% yield. o... 

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