Racemic oxazoline

Following the original report that the oxazoline carboxylic acid 7.5.12 can serve as an excellent side chain precursor 281), several syntheses of this compound have been reported. Thus racemic oxazoline was prepared from protected cinnamyl alcohol by addition of phenyl-selenyl triflate and azide ion to give the adduct 7.5.9, which was then converted to oxazoline 7.5.10 and ester 7.5.11 282). A similar but more efficient route used diphenyldiselenide and ammonium persulfate to give the racemic oxazoline 7.5.10 in 95% yield from cinnamyl acetate 283). 

The search for the racemic form of 15, prepared by allylic cyclopropanation of farnesyl diazoacetate 14, prompted the use of Rh2(OAc)4 for this process. But, instead of 15, addition occurred to the terminal double bond exclusively and in high yield (Eq. 6) [65]. This example initiated studies that have demonstrated the generality of the process [66-68] and its suitability for asymmetric cyclopropanation [69]. Since carbon-hydrogen insertion is in competition with addition, only the most reactive carboxamidate-ligated catalysts effect macrocyclic cyclopropanation [70] (Eq. 7), and CuPF6/bis-oxazoline 28 generally produces the highest level of enantiocontrol. 

The discovery of oxazoline hydroxamates as potential inhibitors of LpxC was the result of high-throughput screening of large libraries of compounds at the Merck Research Laboratories in collaboration with the Department of Biochemistry, Duke University Medical Center [95]. The lead compound, L-573,655, was a racemic mixture of 4-carbohydroxamido-2-phenyl-2-oxazoline, which had been previously made by Stammer et al. [96] as a precursor in the chemical synthesis of cyclosporine. Namely, (R,S)-serine methyl ester hydrochloride (149) is converted into (R,S)-4-carbomethoxy-2-phenyl-2-oxazoline (150) via treatment with ethyl benzimidate using the Elliot procedure [97]. Treatment of this ester with one equivalent each of hydroxylamine and sodium methoxide in methanol at room temperature affords the desired (R,S)-4-carbohydroxamido-2-phenyl-2-oxazoline (151), as depicted in Scheme 30. 

The results of enzymatic and antibacterial assays demonstrated that compound 165 (as a racemic mixture) exhibits activities similar to those of the parent oxazoline L-159,692 [103]. In order to identify the enantioselectiv-ity of this compound, the corresponding R and S enantiomers were separately synthesized from (R)- or (S)-3-(4-methoxyphenyl)-5-hydroxymethyl-4,5-dihydroisoxazole (166) according to the method of Ukaji et al. [107,108] and tested for LpxC inhibitory and antibacterial activities [103]. Interestingly, only the S enantiomer of 166 exhibited strong enzyme inhibitory and antibacterial activity, while the R enantiomer of L-159,692 was the active component. The enantiomeric synthesis of compound 165 is depicted in Scheme 33. 

Lim and Sulikowski (84) explored the intramolecular C-H insertion in 119 alpha to the nitrogen atom as a rapid entry to the mitomycin skeleton and the antitumor agent FR-900482. Rhodium(II) based catalysts provide nearly racemic products. Bis(oxazoline) (55b) affords highest selectivities in this system and chloroform was found to be the optimal solvent, Eq. 71. The authors note that the reaction is somewhat capricious. 

Jacobsen and co-workers (87) investigated the carbenoid-transfer reaction to inline acceptors. These workers found that bis(oxazoline)Cu(I) complexes are most effective among the catalysts screened, providing moderate yields and selec-tivities in this process. The reaction is complicated by the formation of pyrrolidines in racemic form as side products (Eq. 75). 

Bolm et al. (130) reported the asymmetric Baeyer-Villiger reaction catalyzed by Cu(II) complexes. Aerobic oxidation of racemic cyclic ketones in the presence of pivalaldehyde effects a kinetic resolution to afford lactones in moderate enan-tioselectivity. Aryloxide oxazolines are the most effective ligands among those examined. Sterically demanding substituents ortho to the phenoxide are necessary for high yields. Several neutral bis(oxazolines) provide poor selectivities and yields in this reaction. Cycloheptanones and cyclohexanones lacking an aryl group on the a carbon do not react under these conditions. 

Reaction of Ser-OMe with benzimino ethyl ester resulted in the formation of an oxazoline without racemization (Scheme 27) (85T2379). After forming an amide with 2-amino-l-phenylethanol, Af-phthalimido AAs were oxidized with CrOs and dehydrated by POCI3 to give substituted oxazoles (91JHC1241). 

Langlois and co-workers (179) found the same exo stereochemical preference through double asymmetric induction of a related ene-lactone (1 )-145 with their well-explored and efficient camphor-derived oxazoline nitrone (150-146 (Scheme 1.32). They found the cycloaddition components form a matched pair and allowed kinetic resolution of the racemic lactone in up to 70% enantiomeric excess (ee). They suggest the selectivity for exo adduct 147 arises through destabilization of the endo transition state by a steric clash between dipolarophile ring hydrogens and the bornane moiety. 

The authors applied the same synthetic strategy to racemic 4-alkyl -(iodo-methyl)-2-phenyl-5(4/ )-oxazolones 266 and obtained a diastereomeric mixture of oxazolines 267 and 268 (Scheme 7.86). The diastereoisomers were separated chromatographicaUy and then converted into dipeptides incorporating an a-alkyl-serine residue. ... 

However, racemization has been reported. For example, during the total synthesis of mycestericin, Node and co-workers reported that treatment of en-antiomerically pure fhreo-benzamide 11 with SOCI2 unexpectedly gave a 1 1 trans- and cis-mixture of oxazolines 13a and 13b. Consistent with this configurational assignment, further reaction with an electrophile would result in a racemic... 

Widenhoefer and co-workers have developed an effective Pd-catalyzed protocol for the asymmetric cyclization/ hydrosilylation of functionalized 1,6-dienes that employed chiral, non-racemic pyridine-oxazoline ligands." " " Optimization studies probed the effect of both the G(4) substituent of the pyridine-oxazoline ligand (Table 7, entries 1-6) and the nature of the silane (Table 7, entries 6-15) on the yield and enantioselectivity of the cyclization/ hydrosilylation of dimethyl diallylmalonate. These studies revealed that employment of isopropyl-substituted catalyst (N-N)Pd(Me)Gl [N-N = (i )-( )-4-isopropyl-2-(2-pyridinyl)-2-oxazoline] [(i )-43f and a stoichiometric amount of benzhydryldimethylsilane provided the best combination of asymmetric induction and chemical yield, giving the corresponding silylated cyclopentane in 98% yield as a single diastereomer with 93% ee (Table 7, entry 15). 

Simple alkylation of the chiral chelate complex leads to formation of chiral dialkylacetic acids (Scheme 109).3S5 388 Simpler chiral enamines can also be used. The formation of chiral propanoic acids results from a resolution of racemic alkyl halides by the interaction of a chiral lithiooxazoline, which recognizes and reacts with one enantiomer at the expense of the other (Scheme 110).389 The above aspects of the asymmetric carbon—carbon bond formation from chiral oxazolines have been reviewed by Meyers.390... 

The transformation of optically active epoxides with acetonitrile into optically active oxazolines (167,168) can be induced by various superacids714 [Eq. (5.264)]. The reaction proceeds with inversion of the asymmetric center with high stereospecificity with anhydrous HF and A1C13, whereas partial racemization is observed in triflic acid (Table 5.39). 

Barbera J, Cavero E, Lehmann M, Serrano J-L, Sierra T, Vazquez JT (2003) Supramolecular helical stacking of metallomesogens derived from enantiopure and racemic polycatenar oxazolines. J Am Chem Soc 125 4527-4533... 

An example is described for the UAA ( Wert-leucine (44) (Scheme 19.24).207 It uses the commercially available Lipozyme (Mucor miehei) from Novozymes to hydrolyze the racemic 2-phenyl-4-tm-butyl-oxazolin-5-(4/f)-one (45) to the (S)-./V-benzoyl-tert-leucine butyl ester (46) followed by Alcalase (subtilisin, Bacillus licheniformis from Novozymes) treatment to hydrolyze the butyl ester, which on debenzoylation yields (S)-tert-leucine (44) with an ee of 99.5% and a yield of 74%. 

Chiral bis(oxazolines) 51 with an oxalylic acid backbone were used for the Ru-catalyzed enantioselective epoxidation of tran5-stilbene yielding franx-l,2-diphenyloxirane in up to 69% ee [24]. The asymmetric addition of diethylzinc to several aldehydes has been examined with ferrocene-based oxazoline ligand 52 [25], resulting in optical yields from 78-93% ec. The imide 53 derived from Kemp s triacid containing a chiral oxazoline moiety was used for the asymmetric protonation of prochiral enolates [26]. Starting from racemic cyclopentanone- and cyclohexanone derivatives, the enantioenriched isomers were obtained in 77-98 % ee. 

A-diphenylphosphinoyl imines also react with dialkylzinc in the presence of stoichiometric or catalytic amounts of different chiral (see Chiral) ligands (Scheme 24). Acid hydrolysis of the resulting phosphinamides occms without racemization and gives enantiomerically enriched primary amines. The allylation of various cyclic imines was obtained with high enantioselectivity (see Electrophile), 77 to 99% e.e., in the presence of lithiated bis-oxazoline ligands (Scheme 25). 

Alkylalkanoic acids (6, 386-387). Full deta ils including improved procedures have been published for the synthesis of thes e acids in high optical purity from 1, The oxazoline is converted into 3 by Wittig-Hor ner olehnation via 2 only the (E)-isomer is formed. Remaining steps are addition of sm alkyllithium to 3, followed by hydrolysis to 5. One limitation is that use of stabilized carbanions (LiCH2COOC2Hs, LiCH2CN, etc.) results in essential ly racemic products. 

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