2-Oxazolidinone ring substitution

Substituted oxazolidin-5-one derivatives, which are prepared from N -protected a-annino dicarboxyhc acids and paraformaldehyde, are employed for dual protection of the a-annino and a-carboxy groups in the synthesis of P-aspartyl and y-glutamyl esters (Scheme 4).Py For this purpose the oxazolidinone derivatives are synthesized by treatment of the Z amino acids with paraformaldehyde in a nnixture of acetic anhydride, acetic acid, and traces of thionyl chloride or by azeotropic distillation of the Z amino acids with paraformaldehyde and 4-toluenesulfonic acid in benzene. The resulting heterocychc compounds are readily converted into the tert-butyl esters with isobutene under acid catalysis. Esterification is achieved with tert-butyl bromidet or with Boc-F.P l Finally, the oxazolidinone ring is opened by alkaline hydrolysis or catalytic hydrogenolysis to yield the tert-butyl esters. 

For the isoxazolines 284 substituted at position 3, ring-chain tautomerism is depicted by the equilibrium 284 and 285-287 (Scheme 103). In general the cyclic tautomers 284 are strongly preferred. The ring-opened forms exist in equilibrium with 284 in rare cases [95ZOB705 96AHC(66)1, p. 21]. The equilibrium of the oxazolidinones 288 [78MI1, p. 107] is affected by the nature of the solvent. 

Next, Evans et al. [15] reported that Cu-based catalysts were superior in the Diels-Alder reaction of the oxazolidinone 9 with cyclopentadiene 8. ITie (5,5)-bis(oxazo-line)-Cu(II) and -Zn(II) complexes were very effective catalysts of the reaction. The optimum tert-butyl ligand 13-Cu(II) complex afforded (2S)-endo-ll with > 98 % ee. In contrast, the optimum catalyst system for the phenyl-substituted ligand 12-Zn complex afforded the enantiomeric (R) product, (2R)-endo-ll, with 92 % ee. The different direction of asymmetric induction was explained in terms of the geometry of cata-lyst-dienophile complexes at the corresponding metal centers. The bis(oxazoline)-Zn(II) complex-catalyzed reaction proceeded via the tetrahedral chiral Zn-dienophile complex VIII, in a manner similar to the bis(oxazoline)-Mg catalyst reported by Corey [13], whereas the reaction catalyzed by the cationic bis(oxazoline)-Cu complex proceeded via the square-planar Cu(II)-dienophile intermediate VII, so the diene preferred to approach from the opposite si face of the bound dienophile with s-cis configuration, avoiding steric repulsion by one of the tert-butyl substituents on the oxazoline rings. 

Oxazoles 1, benzoxazoles 2, oxazolium salts 3, and oxazole A -oxides 4 are fully conjugated compounds (Figure 1). In addition, the two mesoionic structures l,3-oxazolium-5-olates 5 and (l,3-oxazolium-4-olates) 6, commonly known as miinchnones and isomiinchnones, respectively, are also considered to be conjugated rings. There are five systems of hydroxyl-substituted oxazoles and they exist in their oxo forms the 2(3H)-, 2(5H)-, 4(5//)-, 5(2//)-, 5(4//)-oxazolones 7-11. Three forms of dihydrooxazoles are known 2,3-, 2,5-, and 4,5-dihydrooxazoles respectively 12-14. The fully saturated ring is called oxazoline 15. The monooxo derivatives are 2-oxazolidinone 16,4-oxazolidinone 17, and 5-oxazolidinone 18. The three variants of oxazolidinediones are 19-21 and the fully oxidized oxazolidi-netrione is 22. 

Vigroux, A. Bergon, M. Zedde, C. Cyclization-activated prodmgs n-(substituted 2-hydroxyphenyl and 2-hydroxy-propyl)carbamates based on ring-opened derivatives of active benzoxazolones and oxazolidinones as mutual prodrugs of acetaminophen. J. Med. Chem. 1995, 38, 3983-3994. 

Cleavage of oxazolidines. A route to a-substituted allyl amines starts from A-acetyl (X-amino acids via the oxazolidinones. The latter compounds are converted to dichloromethylene derivatives by reaction with PhjP-CCl and the final step involves dechlorination and ring opening (and removal of an HCO unit) with Na in refluxing THF. 

Experimental data show that the rings of oxazole and 4,5-dihydrooxazole are planar. Oxazo-lidines, on the other hand, are not flat, and their conformation depends on the nature and position of substituents. The conformations of 4- and 5-oxazolidinones were studied using circular dichroism <83X3139,85T603>. 4-Oxazolidinones exist predominantly in the envelope conformer (29). As the size of the C-2 substituents increase, this conformer is destabilized. 4-Substituted-3-alkylsulfonyl-5-oxazolidinones exist mostly in conformer (30), in which the C-4 substituent is in the axial position, but conformer (31) also contributes. The equilibrium shifts towards the diaxial conformer as the size of the C-4 substituent or the alkylsulfonyl group increases. In contrast to these results, an x-ray analysis of crystalline (32) revealed an almost planar structure <92HCA913). 

Another strategy is based on the creation of the pyrrolidine ring in the last step. Thus, deben-zylation (Hj, PdCl2) of 2-oxazolidinone (253) followed by subsequent 0-sulfonylation and cyclization (NaH, THF) furnished 3-oxo-7-substituted perhydropyrrolo[l,2-c]oxazole (254) <89CL1449>. All these reactions are shown in Scheme 44. 

Methyl-2-oxazolidinone (NMO) is isostructural with EC with an N-CH3 group substituted for one of the EC ring oxygen atoms. It is a highly polar solvent (er=78 at 25 °C) and was once used in primary lithium cells [54]. However, its oxidation potential on a glassy carbon is much lower than that of PC [55]. To increase its... 

The reaction system is versatile, achieving both aryl, and alkyl substituted 2-oxazolidinones in 84-98% yield depending on the substrate type. The mechanism of the reaction is thought to occur by a CO insertion to the alkyne followed by an amidation reaction with secondary amine to afford an amidoyne species. The amidoyne species undergoes a second CO insertion on the secondary amine followed by Pd-assisted oxidative ring closure to the oxazolidinones (140). 

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