Enantioselectivity bisoxazolines

In 1997 the application of two different chiral ytterbium catalysts, 55 and 56 for the 1,3-dipolar cycloaddition reaction was reported almost simultaneously by two independent research groups [82, 83], In both works it was observed that the achiral Yb(OTf)3 and Sc(OTf)3 salts catalyze the 1,3-dipolar cycloaddition between nitrones 1 and alkenoyloxazolidinones 19 with endo selectivity. In the first study 20 mol% of the Yb(OTf)2-pyridine-bisoxazoline complex 55 was applied as the catalyst for reactions of a number of derivatives of 1 and 19. The reactions led to endo-selective 1,3-dipolar cycloadditions giving products with enantioselectivities of up to 73% ee (Scheme 6.38) [82]. In the other report Kobayashi et al. described a... 

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. 

These processes could be performed in an enantioselective manner by addition of (-)-sparteine or bisoxazoline ligands in general the yields and ees were found to... 

Asymmetric epoxidation of olefins with ruthenium catalysts based either on chiral porphyrins or on pyridine-2,6-bisoxazoline (pybox) ligands has been reported (Scheme 6.21). Berkessel et al. reported that catalysts 27 and 28 were efficient catalysts for the enantioselective epoxidation of aryl-substituted olefins (Table 6.10) [139]. Enantioselectivities of up to 83% were obtained in the epoxidation of 1,2-dihydronaphthalene with catalyst 28 and 2,6-DCPNO. Simple olefins such as oct-l-ene reacted poorly and gave epoxides with low enantioselectivity. The use of pybox ligands in ruthenium-catalyzed asymmetric epoxidations was first reported by Nishiyama et al., who used catalyst 30 in combination with iodosyl benzene, bisacetoxyiodo benzene [PhI(OAc)2], or TBHP for the oxidation of trons-stilbene [140], In their best result, with PhI(OAc)2 as oxidant, they obtained trons-stilbene oxide in 80% yield and with 63% ee. More recently, Beller and coworkers have reexamined this catalytic system, finding that asymmetric epoxidations could be perfonned with ruthenium catalysts 29 and 30 and 30% aqueous hydrogen peroxide (Table 6.11) [141]. Development of the pybox ligand provided ruthenium complex 31, which turned out to be the most efficient catalyst for asymmetric... 

Bisoxazolines (BOX) (L2a-d) give lower reaction rates and enantioselectivities than trioxazolines (TOX) (L a-m). The proposed reason is that trioxazolines provide a stronger chelation with the copper center than bisoxazolines, effectively preventing phenylethynyl copper from its polymerization (847b). 

Chiral bisoxazolines (box) ligands have been attached to a polyethylene glycol (PEG) matrix 25.24 The supported ligands were tested on a variety of reactions for their enantioselectivity. The carbonyl-ene reaction between a-methyl styrene or methylene cyclohexane (26, Equation (15)) and ethylglyoxalate 12 afforded the corresponding ene adduct 27 in 96% and 91% yield and 95% and 85% ee, respectively. 

Enantioselective radical addition to AT-acyl hydrazone using triethylborane as chain transfer reagent has been reported by Friestad. Enantiomeric excesses up to 95% were obtained in the presence of copper(II)-bisoxazolines Lewis acid (Scheme 51) [115]. 

Chiral Lewis acid promoted atom transfer reaction (Kharasch reaction) of a-halo oxazolidinone imide 90 and 1-octene 92 has been reported by Porter et al. (Scheme 23) [78]. The enantioselective atom transfer utilizing Zn(OTf)2 and phenyl bisoxazoline ligand 93 as a chiral Lewis acid. The yields of the products, however, were quite low ranging from 5-15% and only moderate enantioselectivities were achieved (up to 40%). 

Friestad and co-workers recently demonstrated that N-acyl hydrazones were excellent radical acceptors in the presence of a chiral Lewis acid [84], Valerolactam-derived hydrazone 117 proved to be the optimal substrate for enantioselective radical additions. Upon further optimization it was found that Cu(OTf )i and f-bulyl bisoxazoline ligand 96 gave the best yields and ee s (Scheme 31). Interestingly, a mixed solvent system (benzene dichloromethane in a 2 1 ratio, respectively) in the presence of molecular sieves (4 A) were necessary to achieve high yields and selectivities. 

A recent application of enantioselective conjugate radical additions was seen in the synthesis of (+)-ricciocarpins A and B [95]. The key step in the synthesis was an asymmetric addition of a functionalized radical precursor 141 to afford intermediate 142 (Scheme 37). A chiral catalyst screening revealed that Mgt and bisoxazoline ligand 19 was optimal for achieving... 

Likewise, PEG-supported bisoxazoline (40) can be used as a ligand for copper-mediated enantioselective reactions such as cyclopropanations of alkenes, [2-1-4] cycloadditions as well as ene reactions. Best results were obtained in case of the latter reactions as products were formed in yields up to 96% and ee s up to 95% (Scheme 4.25) [117]. 

Chiral, Lewis acidic bisoxazoline complexes of Mg(II) have been employed as catalysts in asymmetric Michael addition of O-benzyUiydroxylamine to unsaturated amides, (115) -> (116). The enantioselectivity (67-90% ee) was rationalized by transition state (117). This approach constimtes a promising methodology for the synthesis of jS-amino acids. °... 

Under oxidation conditions, a C—C double bond can be functionalized by either two alkoxycarbonyl groups or one alkoxycarbonyl group and one heteroatom. As shown in Scheme 4.14, two ester groups are successfully introduced to styrene in an enantioselective manner, producing a phenylsuccinic ester using a Pd/MeO-BIPHEP complex. mcw-Diols are converted into cyclic ethers in an asymmetric manner when catalyzed by Pd/chiral bisoxazoline. Intramolecular aminopallada-tion followed by carbomethoxylation gives an cyclic amino ester in moderate ee when catalyzed by a Pd/bis(isoxazoline) complex. " ... 

When terf-butyl p-nitrobenzoate was used, the desired allylic esters were obtained in high enantiomeric excesses, albeit in low yields, in the presence of copper/bisoxazoline (Scheme 5.24). The reason for high enantioselectivities was attributed to the use of terf-butyl p-nitrobenzoate and gem-dialkyl bisoxazo-... 

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. 

Chiral organomagnesium amides form an efficient method to realize enantioselective conjugate addition. Sibi and Asano have reported the Michael addition of cr-bound magnesium reagents derived from bisoxazolines to enamidomalonates (equation 41). The enantioselectivity of the addition is discussed in Section El. This method allows the preparation of chiral -amino acid derivatives. ... 

Addition of an allylic zinc reagent to cyclic aldimines has been reported129. Lithiated bisoxazoline 61 and allylzinc reagent form the reactive species, which adds to a cyclic aldimine enantioselectively with up to 97.5% (equation 29)129. 

It was also reported that diastereo- and enantioselective Mannich reactions of activated carbonyl compounds with a-imino esters were catalyzed by a chiral Lewis acid derived from Cu(OTf)2 and a bisoxazoline (BOX) ligand [31] [(Eq. (6)]. Catalytic enantioselective addition of nitro compounds to imines [32], and aza-Henry reactions of nitronates with imines [33] also proceeded under similar reaction conditions. 

Bernadi and Scolastico, and later Evans in a more effective manner, indicated that the enantioselective addition reaction using silyl enol ethers can be catalyzed by Lewis acidic copper(II) cation complexes derived from bisoxazolines [38-40]. In the presence of the copper complex (S,S)-14 (10 mol %), silyl enol ethers derived from thioesters add to alkylidenemalonates or 2-alkenoyloxazo-lidone in high ees (Scheme 12). Bernadi, Scolastico, and Seebach employed a titanium complex derived from TADDOL for the addition of silyl enol ethers to nitroalkenes or 2-cyclopentenone [41-43], although these are stoichiometric reactions. 

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