Oxidation of oxazolines

The oxidation of oxazoline 58 to oxazole 60 turns out to be problematical in Pattendens synthesis. Even with special oxidation techniques (tert-butyl peroxybenzoate 59/copper (I) bro-... 

A route to spirolactams involves oxidation of oxazolines derived from t)rosine. Simple amides give the corresponding spirolactones. ... 

Thus, oxidation of oxazoline derivatives of phenolic compounds 33 with IBD in trifluoroethanol leads to spirocyclic amides 34 [26]. The low yield of compound 34b is attributable to the carbamate carbonyl of 33b competing effectively with the oxazoline nitrogen to capture the electrophilic intermediate obtained by activation of the phenol (Scheme 14). 

Although new methods have been developed recently for the oxidation of oxazolines, oxidation with Ni02 is one of the oldest and still widely used methods. It was originally reported by Meyers and Evans (Scheme 1.1). ... 

Activated manganese dioxide is a closely related oxidant to Ni02 but less commonly used. Meguro, Fujita, and co-workers described oxidation of oxazolines using Mn02 in their synthesis of antidiabetic agents. For example, the serine-derived P-hydroxyamide 21 was cyclized to the oxazoline 22 with polyphosphoric acid. Oxidation of 22 with activated manganese dioxide afforded 2-styryl-4-oxazolecarboxylic acid methyl ester, 23 (Scheme 1.4). 

Oxidation of oxazolines using Mn02 was also employed in the synthesis of a beminamycin A fragment by Shin and co-workers ° and in the preparation of the naturally occiuring 2,4-disubstituted oxazole, phenoxan 28, by Yamamura s group" (Scheme 1.5). For beminamycin, the oxazoline 25 was synthesized in 61% yield by Mitsunobu dehydration of the serine-derived amide 24. 

ElectophUic iodination using I2 has also been employed to effect net oxidation of oxazolines to 2-substituted 4-oxazolecarboxylic acid esters. Koskinen and co-workers" " ° prepared an intermediate oxazole fragment of calyculin using this method (Scheme 1.18). Here, the oxazoline 57 was first treated with LiHMDS and TMSCl to protect the carbamate as a sUyl amide followed by treatment with KHMDS and iodine to generate the oxazole 58. Interestingly, the authors also isolated diastereomeric spirocyclic ortho ester aminals 59 in 25 to 30% yield under these reaction conditions. 

The successful oxidation of oxazolines to oxazoles depends greatly on the nature of the substituents. Several methods have been described that effect this conversion in good to excellent yields for activated oxazolines. However, secondary alkyl groups can suffer free radical bromination (Scheme 1.20). In addition, ring-brominated oxazoles can also be isolated (Scheme 1.19). Despite the progress to date, a general high-yield method to oxidize activated and unactivated oxazolines to oxazoles is stiU needed. 

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... 

Langlois Y. New Uses of Oxazolines, OxazoUne N-Oxides and DioxolanyUnms in Asymmetric Synthesis Curr. Org. Chem. 1998 2 1-18... 

Pfaltz and co-workers (108) reported that the allylic oxidation of cyclohexene proceeds in moderate selectivity using stoichiometric amounts of semicorrin-Cu(II) complexes. In catalytic reactions, the enantioselectivity decreased drastically. Better results were realized using bis(oxazolines) as ligands. Upon... 

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. 

Oxidation of esters of cephalosporin V (368) with 4-(ert-butyl(difluoroi-odo)benzene in CH3CN leads to the formation of oxazoline disulfides 369. This is an example where cyclization occurring by intramolecular participa-... 

In NRPS, the cyclization domain catalyzes cyclization of the side-chain nucleophile from a dipeptide moiety such as AA-Ser or AA-Cys (AA = amino acids) to form a tetrahedral intermediate, followed by dehydration to form oxazolines and thiazolines (Scheme 7.1) [20]. The synthesis of a 2-methyl oxazoline from threonine follows a similar mechanism. Once a heterocycle is formed, it can be further modified by reductase to form tetrahydro thiazolidine in the case of pyochelin biosynthesis. Conversely, oxidation of the dehydroheterocycles lead to heteroaro-mahc thiazoles or oxazoles as in the case of epothilone D (Figure 7.2) [21]. 

An alternative mechanism to form thiazoles and oxazoles is through oxidation of a dipeptide followed by cyclization from an enolate or thienolate precursor and subsequent dehydration (Scheme 7.2). This represents a higher-energy pathway and there is no accumulation of thiazoline or oxazoline intermediates [22-24]. 

Olefins also undergo the Ritter reaction with nitriles in the presence of diphenyl diselenide, ammonium persulfate, and trifluoromethanesulfonic acid to produce oxazolines.When cyanamide is used, 2-aminooxazolines are obtained. The active electrophilic agent is phenylselenyl sulfate formed by oxidation of diphenylselenide with ammonium persulfate. The reaction is trans-stereospecific. 

An oxazoline AT-oxide is a versatile dipole and can react with a variety of dipolarophiles (Scheme 8.134). Langlois group has been very active in this area and has made extensive use of the Ai-oxides of camphor-derived oxazolines for these reactions. The initial adduct can be converted to the anti aldol product after hydrolysis and hydrogenolysis. This subject has been thoroughly reviewed by Langlois, " most recently in 2000. " ... 

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