Bisoxazolines copper catalysts

Chiral C2-symmetric bisoxazoline-copper(II) complexes [30, 31] were introduced as catalysts for cycloaddition and ene reactions of glyoxylates with dienes [9] leading to intense activity in the use of these catalyst for different cycloaddition reactions. 

Jorgensen has recently reported similar enantioselective reactions between N-tosylimines 107 and trimethylsilyldiazomethane (TMSD) catalyzed by chiral Lewis acid complexes (Scheme 1.32) [57, 53]. The cis-aziridine could be obtained in 72% ee with use of a BINAP-copper(i) catalyst, but when a bisoxazoline-copper(i) complex was used the corresponding trans isomer was fonned in 69% ee but with very poor diastereoselectivity. 

Arylation of activated double bonds with diazonium salts in the presence of copper catalysts is known as the Meerwin reaction. The reaction is postulated to either proceed through an organocopper intermediate or through a chlorine atom transfer from chiral CuCl complex to the a-acyl radical intermediate. Brunner and Doyle carried out the addition of mesityldiazonium tetrafluoroborate with methyl acrylate using catalytic amounts of a Cu(I)-bisoxazoline ligand complex and were able to obtain 19.5% ee for the product (data not shown) [79]. Since the mechanism of the Meerwin reaction is unclear, it is difficult to rationalize the low ee s obtained and to plan for further modifications. 

Chiral dirhodium(II) carboxamidates are preferred for intramolecular cyclopropanation of allylic and homoallylic diazoacetates (Eq. 2). The catalyst of choice is Rh2(MEPY)4 when R " and R are H, but Rh2(MPPIM)4 gives the highest selectivities when these substituents are alkyl or aryl. Representative examples of the applications of these catalysts are listed in Scheme 15.1 according to the cyclopropane synthesized. Use of the catalyst with mirror image chirality produces the enantiomeric cyclopropane with the same enantiomeric excess [33]. Enantioselectivities fall off to a level of 40-70% ee when n is increased beyond 2 and up to 8 (Eq. 2) [32], and in these cases the use of the chiral bisoxazoline-copper complexes is advantageous. 

Enantioselective catalysis has also been used for the synthesis of optically active sulfimines [51]. By application of 5 mol % of the bisoxazoline-copper(I) catalyst 80, the sulfide 77 is oxidized catalytically to 78 which undergoes a [2,3]-sigmatropic rearrangement to give allyl amine 79 in 80% yield and with 58% ee (Eq. (20)). Other alkenes were found to give lower ee. 

Independently, the groups of Evans [375,376,377] and J0rgensen [378] have shown that /3,y-unsaturated a-keto esters react with ethyl vinyl ether in the presence of enantiomerically pure bisoxazoline copper(II) complexes as catalysts leading to enantiomerically enriched dihydropyrans. For instance 212 and 213 in ether at 20 °C and in the presence of complex 214 add to give the endo adduct 215 in 60% yield and with 96.5% ee. The latter is then converted into ethyl -D-ma no-p)Tanoside tetraacetate 216 (O Scheme 77) [379]. 

Many other chiral copper catalysts have been reported, most of them being derived from C2-symmetrical bidentate nitrogen ligands [13, 27]. Some ligands such as the bipyridine derivatives 14 [60, 61, 62], the diamine 15 [63] and the bis(azaferrocene) 16 [64] are capable to induce high ees, but none of them can compete so far with chiral bisoxazolines in terms of high selectivity combined with effectiveness, general applicability and ease of preparation. 

However, at this stage relatively little progress has been made in research on asymmetric catalytic carbene transfer to imines. In 1995, Jacobsen and Jorgensen reported independently that reaction of ethyl diazoacetate with selected imines can be catalyzed by copper salts [27,28]. In the former case [27], moderate levels of enantioselection were found to be imparted by bisoxazoline ligands associated with the copper catalyst (Scheme 11). The observation of racemic pyrrolidine byproducts in the reaction was taken to support a mechanism of catalysis involving initial formation of a copper-bound azomethine yhde intermediate (Scheme 12 ). Collapse of this intermediate to the optically active aziridine apparently competes with dissociation of the copper to a free azomethine ylide. The latter can react with fumarate formed by diazoester decomposition in a dipolar cycloaddition to afford racemic pyrrolidine. 

Analogous alkylations with unsaturated ketones can also be effected with silica-supported benzenesul-fonic acid sodium salt or, with some stereoselectivity, using a chiral imidazolidinone organo-catalyst. Optical induction can also be achieved in the addition of indole to alkyhdene malonates using bisoxazoline copper(II) complexes. ... 

The enantioselective a-chlorination of -keto esters was achieved with up to 88% ee using NCS with a commercially available TADDOL ligand. The chiral bisoxazoline copper(II) complexes have also been reported to induce the asymmetric a-chlorination of -keto esters when reacted with NCS. The asymmetric a-chlorination of aldehydes has been achieved using NCS and (2/ ,5/ )-diphenylpyrrolidine as a chiral catalyst. For example, the enantioselective chlorination of 3-methylbutanal with NCS proceeds in 95% yield and 94% ee (eq 17). ... 

Given the utility of chiral Cu(II)/bisoxazoline complexes in enantioselective Mukaiyama aldol reactions, a number of reports detailing the development of polymer-bound or dendritic bisoxazoline copper (I I) complexes have been developed. Development of such catalyst systems provides the potential for easy recovery and reuse of the relatively expensive catalyst. To this end, Salvadori and CO workers reported Mukaiyama aldol addition of ketene thioacetal (57) to methyl pyruvate catalyzed by a Cu(OTf)2 complex of polystyrene-supported bisoxazoline (89) (Scheme 17.18) [23]. The enantioselectivity of the addition remained high over eight cycles of the catalyst, however, reactivity was gradually reduced over time. 

In addition to the experimental applications of chiral copper Lewis acids in organic synthesis discussed previously, a number of theoretical investigations on the nature of chiral copper Lewis acids have been reported. Much of this work has been focused on the investigation of chiral bisoxazoline copper(ll) complexes and/or reactions catalyzed by these chiral Lewis acids. Deeth and Fey reported a molecidar mechanics study of Cu(II)/bisoxazoline-catalyzed Diels-Alder reactions [131). The work details conformational preferences of various catalyst/substrate complexes and likely transition states. The study also found good success in predicting... 

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. 

Lowenthal and Masamune also reported that the copper complex bearing a bisoxazoline ligand 30 was an effective catalyst for aziridination of styrene (88% ee) (Scheme 6B.31) [76], However, Evans et al. later claimed that this result was not reproducible [75],... 

An enantioselective nitro-Mannich reaction of alkyl- and aryl-benzylimines gives /3-nitroamines in high ee, using a chiral copper(II)-bisoxazoline catalyst, with the products affording 1,2-diamines by reduction.30... 

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