Oxazoline, chiral nucleophilic addition reactions

Chiral oxazolines developed by Albert I. Meyers and coworkers have been employed as activating groups and/or chiral auxiliaries in nucleophilic addition and substitution reactions that lead to the asymmetric construction of carbon-carbon bonds. For example, metalation of chiral oxazoline 1 followed by alkylation and hydrolysis affords enantioenriched carboxylic acid 2. Enantioenriched dihydronaphthalenes are produced via addition of alkyllithium reagents to 1-naphthyloxazoline 3 followed by alkylation of the resulting anion with an alkyl halide to give 4, which is subjected to reductive cleavage of the oxazoline moiety to yield aldehyde 5. Chiral oxazolines have also found numerous applications as ligands in asymmetric catalysis these applications have been recently reviewed, and are not discussed in this chapter. ... 

The first use of chiral oxazolines as activating groups for nucleophilic additions to arenes was described by Meyers in 1984. " Reaction of naphthyloxazoline 3 with phenyllithium followed by alkylation of the resulting anion with iodomethane afforded dihydronaphthalene 10 in 99% yield as an 83 17 mixture of separable diastereomers. Reductive cleavage of 10 by sequential treatment with methyl fluorosulfonate, NaBKi, and aqueous oxalic acid afforded the corresponding enantiopure aldehyde 11 in 88% yield. 

Chiral oxazolines employed as activating groups and/or chiral auxiliaries in nucleophilic addition and substitution reactions that lead to the asymmetric construction of carbon-carbon bonds. 

More recently, Meyers and Kolotuchin reported that nucleophilic addition to the 1-position of the 3-methoxy-(2-oxazolinyl)naphthalene 513 is preferred over methoxy group displacement." The reaction works well and as expected for RLi (R = m-Bu, iec-Bu, and Ph). However, 1,2-addition to 513 to give the oxazohdine 515 predominates for RLi (R = Me, fert-Bu, and PhMe2Si) (Scheme 8.167). When 513 contained a chiral oxazoline (Ri = fert-Bu, R2 = H), a single diastereomer of 514 was obtained in moderate yields (56 and 60% for R = n-Bu and Ph, respectively). Standard oxazoline chemistry and functional group manipulations were used to convert 514 to a variety of useful, chiral tetralones 516. 

Reviews on stoichiometric asymmetric syntheses M. M. Midland, Reductions with Chiral Boron Reagents, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 2, Academic Press, New York, 1983 E. R. Grandbois, S. I. Howard, and J. D. Morrison, Reductions with Chiral Modifications of Lithium Aluminum Hydride, in J. D. Morrison, ed.. Asymmetric Synthesis, Vol. 2, Chap. 3, Academic Press, New York, 1983 Y. Inouye, J. Oda, and N. Baba, Reductions with Chiral Dihydropyridine Reagents, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 4, Academic Press, New York, 1983 T. Oishi and T. Nakata, Acc. Chem. Res., 17, 338 (1984) G. Solladie, Addition of Chiral Nucleophiles to Aldehydes and Ketones, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 6, Academic Press, New York, 1983 D. A. Evans, Stereoselective Alkylation Reactions of Chiral Metal Enolates, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 1, Academic Press, New York, 1984. C. H. Heathcock, The Aldol Addition Reaction, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 2, Academic Press, New York, 1984 K. A. Lutomski and A. I. Meyers, Asymmetric Synthesis via Chiral Oxazolines, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 

Certain heterocycles, e.g. pyridines or quinolines, bearing of an electron-withdrawing group such as oxazoline, undergo the Michael-type nucleophilic 1,4-addition accompanied with loss of aromaticity to give the new C-C bond. Thus formed dihydropyridine or benzodihydropyridine can be oxidatively aromatized with conservation of chirality, primary induced by an influence of chiral oxazoline moiety. In this manner, Meyers and coworkers [27] described the Michael-type addition of 1-naphthyllithium (609) to the oxazoline 610 at low temperature to form 611 in 90% yield. The latter was oxidatively aromatized to the naphthylquinoline 612 in 87% yield with 88 12 ratio of two diastereomers. Diastereoselectivity in this reaction remained on the same level as obtained by the nucleophilic addition of 609 to 610 indicating the virtually complete conservation of chirahty, from sp -type in the compound 611 to the axially chiral compound 612, Scheme 11. 

A powerful application of such chiral oxazolines is found in addition reactions to substituted naphthalenes (Scheme 3.14) [71-73]. Chiral oxazoline 82 undergoes conjugate addition reactions with carbanions and other nucleophiles to furnish a stabilized carbanion intermediate 83 [71]. This could be trapped with a variety of electrophiles to provide products such as 84 with 98 2 diastereoselectivity. Following auxiliary removal, the sequence provides... 

The highest enantiomeric excess in the palladium(0)-assisted enantiosclcctive alkylation of racemic 3-cycloalkenyl acetate has so far been observed with the chiral ligands 2, 3a and 3b60-61 (Table 17). The addition of tetrahexylammonium bromide dramatically increases enantioselec-tivity in the case of ligand 2, as does changing the solvent from tetrahydrofuran to dichloro-methane. which is believed to enhance the formation of dimeric ionic salts of the nucleophile. In contrast, additives such as tetraalkylammonium salts or crown ethers diminish the enantiomeric excess in reactions catalyzed by the phosphinoaryl oxazoline ligands 3a and 3b. bearing a chiral phosphorus on the aryl moiety. 

Ma has developed a three-component allene carboamination reaction for the stereoselective synthesis of 2,5-as-disubstituted pyrrolidine derivatives [54]. A representative transformation involving allene 58, 4-iodoanisole, and imine 59 that generates 60 in 90% yield is shown below (Eq. (1.28)). The reaction is believed to proceed through the intermediate Jt-allylpalladium complex 62, which is formed by carbopalladation of the alkene to give 61 followed by addition of the malonate anion to the activated imine. Intramolecular capture of the allylpalladium moiety by the pendant nitrogen nucleophile affords the pyrrolidine product. A related asymmetric synthesis of pyrazolidines that employs azodicarboxylates as one of the electrophilic components has also been reported [55]. The pyrazolidine products are obtained with up to 84% ee when chiral bis oxazolines are employed as ligands. 

Ricci and coworkers [64] studied oxazoline moiety fused with a cyclopenta[P]thio-phene as ligands on the copper-catalyzed enantioselective addition of Et2Zn to chalcone. The structure of the active Cu species was determined by ESI-MS. Evans and coworkers [65] studied C2-symmetric copper(II) complexes as chiral Lewis acids. The catalyst-substrate species were probed using electrospray ionization mass spectrometry. Comelles and coworkers studied Cu(II)-catalyzed Michael additions of P-dicarbonyl compounds to 2-butenone in neutral media [66]. ESI-MS studies suggested that copper enolates of the a-dicarbonyl formed in situ are the active nucleophilic species. Schwarz and coworkers investigated by ESI-MS iron enolates formed in solutions of iron(III) salts and [3-ketoesters [67]. Studying the mechanism of palladium complex-catalyzed enantioselective Mannich-type reactions, Fujii and coworkers characterized a novel binuclear palladium enolate complex as intermediate by ESI-MS [68]. 

These observations can be rationalized by a model in which an addition-elimination pathway is operative, with the overall stereoselectivity determined by the two steps (Scheme 8.4). The first step presumably involves initial complexation of organomagnesium 9 with oxazoline 8. The nitrogen lone pair would lie in the plane of the oxazoline and coordinate Mg. Furthermore, Mg is also coordinated to the methoxy leaving group. Although the mechanism of the Meyers reaction has not yet been elucidated computationally [20], it is assumed that chelate B is favored sterically over chelate A. The bulky isopropyl substituent favors attack of the nucleophile from the opposite face, leading to azaenolate 12. The oxazoline moiety not only induces chirality but also favors addition of the... 

Mukaiyama variant of the Michael reaction and Michael additions of 1,3-diketones to 2-oxo-3-butenoate esters. However, these examples have always involved activation of bidentate electrophiles by Cu(II) followed by the addition of a weak nucleophile to the resultant complex. The attempts to employ bis(oxazoline)copper(II) complexes to catalyze a classical Michael reaction with p-ketoesters and monodentate enones are precedented however, racemic products were obtained in such cases. Interestingly, the Michael reaction developed in our studies is most likely to proceed via reversed activation (Scheme 11). Thus, we proposed that Cu(II) complex H chelates the enol form of p-ketoester 12a, and the resultant chiral enol complex 22 undergoes addition to electrophile (5) to provide 23. It should be noted that the precise mechanism of this reaction and particularly the step for the addition of 22 to 5 to provide 23 are yet to be investigated. 

Sibi et al reported the first example in acyclic systems where both highly diastereo-and enantioselective tandem radical reactions occurred with carbon-carbon bond formation to achieve the vicinal functionalization of cinnamates with chiral Mg(II) catalysts (Scheme 4.5) [3]. The reactions began with the addition of nucleophilic alkylradical to cinnamate (7) and trapping of the intermediate radical with allyl-stannane using a chiral bis(oxazoline)s-Mgl2 as a Lewis acid. The reaction with cinnamate (7) (1 equiv), t-Bul (10 equiv), allyltributyltin (5 equiv), and triethylborane... 

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