Oxazolines, chiral

In readily available (see p. 22f.) cyclic imidoesters (e.g. 2-oxazolines) the ot-carbon atom, is metallated by LDA or butyllithium. The heterocycle may be regarded as a masked formyl or carboxyl group (see p. 22f.), and the alkyl substituent represents the carbon chain. The lithium ion is mainly localized on the nitrogen. Suitable chiral oxazolines form chiral chelates with the lithium ion, which are stable at —78°C (A.I. Meyers, 1976 see p. 22f.). 

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 synthesis and use of a chiral oxazoline was reported by Meyers in 1974. The chiral oxazoline 1 was prepared in two steps by condensation of (-i-)-l-phenyl-2-amino-1,3-propanediol (6) with the ethyl imidate of propionitrile followed by 0-methylation of the resulting alcohol 7 with NaH/Mel. Meyers demonstrated chiral oxazoline 1 could be... 

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. 

The mechanism of the asymmetric alkylation of chiral oxazolines is believed to occur through initial metalation of the oxazoline to afford a rapidly interconverting mixture of 12 and 13 with the methoxy group forming a chelate with the lithium cation." Alkylation of the lithiooxazoline occurs on the less hindered face of the oxazoline 13 (opposite the bulky phenyl substituent) to provide 14 the alkylation may proceed via complexation of the halide to the lithium cation. The fact that decreased enantioselectivity is observed with chiral oxazoline derivatives bearing substituents smaller than the phenyl group of 3 is consistent with this hypothesis. Intermediate 13 is believed to react faster than 12 because the approach of the electrophile is impeded by the alkyl group in 12. 

Variations and Improvements on Alkylations of Chiral OxazoUnes Metalated chiral oxazolines can be trapped with a variety of different electrophiles including alkyl halides, aldehydes,and epoxides to afford useful products. For example, treatment of oxazoline 20 with -BuLi followed by addition of ethylene oxide and chlorotrimethylsilane yields silyl ether 21. A second metalation/alkylation followed by acidic hydrolysis provides chiral lactone 22 in 54% yield and 86% ee. A similar... 

Unsaturated chiral oxazolines have been employed in conjugate addition reactions... 

Chiral oxazolines have also been utilized for the synthesis of ehiral ketones bearing quaternary earbon stereoeenters. As shown below, reaetion of substituted oxazoline 30 with 2 equiv PhLi followed by treatment with benzyl bromide gives ketone 33 upon aeidie hydrolysis. This reaetion is believed to proeeed via addition of PhLi to keteneimine 31 to afford metalated enamine 32, whieh undergoes alkylation at the nueleophilie earbon to provide 33 after aqueous workup. ... 

Chiral oxazolines were the first ehiral auxiliaries used for asymmetrie enolate alkylations. Subsequent studies led to the development of a number of other ehiral auxiliaries (34-38) ineluding those reported by Evans, Myers, Enders, Sehollkopf, and others, whieh are now widely used in asymmetrie synthesis. Although these new auxiliaries frequently provide higher yields and enantioseleetivities than the oxazolines originally developed by Meyers, the pioneering work of Meyers laid the groundwork for these later studies. 

Meyers has demonstrated that chiral oxazolines derived from valine or rert-leucine are also effective auxiliaries for asymmetric additions to naphthalene. These chiral oxazolines (39 and 40) are more readily available than the methoxymethyl substituted compounds (3) described above but provide comparable yields and stereoselectivities in the tandem alkylation reactions. For example, addition of -butyllithium to naphthyl oxazoline 39 followed by treatment of the resulting anion with iodomethane afforded 41 in 99% yield as a 99 1 mixture of diastereomers. The identical transformation of valine derived substrate 40 led to a 97% yield of 42 with 94% de. As described above, sequential treatment of the oxazoline products 41 and 42 with MeOTf, NaBKi and aqueous oxalic acid afforded aldehydes 43 in > 98% ee and 90% ee, respectively. These experiments demonstrate that a chelating (methoxymethyl) group is not necessary for reactions to proceed with high asymmetric induction. 

Meyers has also reported the use of chiral oxazolines in asymmetric copper-catalyzed Ullmann coupling reactions. For example, treatment of bromooxazoline 50 with activated copper powder in refluxing DMF afforded binaphthyl oxazoline 51 as a 93 7 mixture of atropisomers diastereomerically pure material was obtained in 57% yield after a single recrystallization. Reductive cleavage of the oxazoline groups as described above afforded diol 52 in 88% yield. This methodology has also been applied to the synthesis of biaryl derivatives. 

Chiral oxazoline-based synthetic methods have been employed in the asymmetric synthesis of a large number of natural products. A few representative examples of these applications are shown below. 

A similar influence of the lithium-magnesium exchange is documented for tetrahydroisoquino-lines, derived from chiral oxazolines (see Section 1.3.2.3.3.2 ). The tuning by magnesium bromide also serves well in the carbonyl addition of lithiated tetrahydro-2-isoquinolinecarboxy-late24, prepared by the Katritzky protection/activation method27,28. 

Burgess followed a similar strategy for the preparation of the salts 8 (Scheme 7). On that occasion several routes to mono-N-substituted imidazoles were explored yielding the desired compoimds in variable yields depending on the nature of the amines. The chirality was introduced via alkylating reagents 9 bearing chiral oxazolines [15]. 

Gade and Bellemin-Laponnaz have reported the synthesis, in good yields, of chiral oxazoline-imidazoliums salts 10a (Scheme 8) obtained by reaction of 2-bromo-4(S)-t-butyl oxazoline with several mono-N-substituted imidazoles [16]. Similaly an imidazolium salt 10b bearing a paracyclophane substituent was prepared by Bolm [17]. 

Wallbaum, S. Martens. J. Tetrahedron Asymmetry, 1993, 4, 637 With a chiral oxazoline additive, 60% ee... 

In 1999, Ikeda et al. reported a new type of sulfur-oxazoline ligands with an axis-fixed or -unfixed biphenyl backbone prepared in good yields by coupling reactions of methoxybenzene derivatives substituted with a chiral oxazoline and a sulfur-containing Grignard reagent. These ligands were subsequently evaluated for the test palladium-catalysed asymmetric allylic alkylation... 

In addition, Bryce and Chesney have developed chiral oxazolines linked to tetrathiafulvalene in order to use these ligands as redox-active ligands. When applied to the test reaction, these ligands gave only low enantioselec-tivities (<21% ee), as shown in Scheme 1.32. 

Whereas the mono- and the S/S-dithioether moieties have been used to date, the 1,3-dithianyl motif was used for the first time in 2005 by Ricci et al. as a new hybrid ligand in asymmetric catalysis. Hence, a series of new chiral oxazoline-1,3-dithianes have been successfully applied to the copper-catalysed conjugate addition of ZnEt2 to enones (Scheme 2.16). The expected products were obtained in almost quantitative yields and enantioselectivities of up to 69% ee. 

Scheme 2.16 Cu-catalysed 1,4-additions of ZnEt2 to enones with chiral oxazoline-1,3-dithiane ligands.

Diethylaluminum cyanide mediates conjugate addition of cyanide to a, (3-unsaturated oxazolines. With a chiral oxazoline, 30-50% diastereomeric excess can be achieved. Hydrolysis gives partially resolved a-substituted succinic acids. The rather low enantioselectivity presumably reflects the small size of the cyanide ion. 

Aromatic and vinylic sulfides take part in cross-coupling reactions with Grignard reagents in the presence of Ni catalysts.336,337 This reaction has been applied to the enantioselective synthesis of binaphthyls using a standard chiral oxazoline ligand (Equation (25)) 338... 

The gold(I) complex of a chiral ferrocenylphosphine complex promotes asymmetric aldol reactions of a-isocyanocarboxylates to form chiral oxazolines in high diastereo- and enantio-selectivities (Scheme 52).225,226 In these reactions, the analogous silver(I) ferrocenylphosphine complex also works well. 

In addition to the simple substitutions shown in Scheme 1, this reaction has been used in a variety of complex systems as a route to optically active substances. For example, use of chiral oxazolines in this coupling process has led to an asymmetric synthesis of (-)-steganone,3 podophyllotoxin,4 (-)-schizandrin,5 and (+)-phylictralin.6 The synthesis of (-)-schizandrin is sketched in Scheme 2. 

An alternative protocol for treating alkylzinc bromides with primary and secondary alkyl bromides and iodides was described by Zhou and Fu.409 In the study, a combination of Ni(cod)2 and a chiral oxazoline ligand 306 was used as a catalytic system providing 62-88% yield of product 307 A,A-dimethylacetamide (DMA) was the reaction solvent (Scheme 156). 

When trimethylaluminum reacted with 3-methyl-cyclohexa-2,5-dienone in the presence of chiral oxazoline ligands 86, the conjugate addition proceeded efficiently at the less-substituted double bond with up to 68% ee (Scheme 43).129,129a tw0 0 0-substituents on the phenyl ring of ligands 86 were considered to be important for selectivity. 

Recently, asymmetric NHK reactions have been investigated. Among them, catalytic versions of this reaction have been successful a Cr-chiral salen complex 127,226-228 a Cr-chiral sulfonylamide complex 128,229 a Cr-tridentate ligand 129 complex,230,231 and a Cr-chiral oxazoline ligand 130 complex232 were found to be effective to achieve good to high enantioselectivity (Scheme 57). 

Lithiated chiral oxazolines have been shown to react with various electrophiles, generating a new asymmetric center with considerable bias. This process has led to the synthesis of optically active a-alkylalkanoic acids,47 n-hydroxy(methoxy)alkanoic acids,48 / -hydroxy(methoxy)alkanoic acids,49 n-substituted y-butyrolactones,50 and 2-substituted-l,4-butanediols (Fig. 2-4).50... 

Scheme 2-25. Alkylation of chiral oxazolines to carbonyl acids 44.

TABLE 2-7. Alkylation of Chiral Oxazolines to Carbonyl Acids 4446... 

Sammakia and Stangeland112 reported another type of chiral ligand 119 bearing a chiral oxazoline moiety and tested its asymmetric induction capability in transfer hydrogenation. As shown in Scheme 6-51, 90% or higher ee values were observed in all cases, along with high conversion of the substrates. 

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