2.5- Oxazolidine ring

Several blocked diamines or amino-alcohols are commercially available. The aldimine is an aldehyde-blocked diamine. The ketimine is a ketone-blocked diamine. The oxazolidine is a five-membered ring containing oxygen and nitrogen. The oxazolidine ring shown below is an aldehyde-blocked amino alcohol. The basic synthetic concepts of an aldimine, a ketimine, and an oxazolidine are shown below ... 

The diastereomers cannot be separated due to cleavage of the 1,3-oxazolidine ring during column chromatography. 

Herrmann has prepared several unsymmetrical salts 7 from 1-alkyl-imidazoles (Scheme 6). The chirality was introduced, after N-alkylation of the imidazole by chloro acetonitrile, by addition of enantiomerically pure aminoalcohols onto the nitrile to form an oxazolidine ring [14],... 

The clavams differ from penicillins (based on the penam structure) in two respects, namely the replacement of S in the penicillin thiazolidine ring (Fig. 5.1) with oxygen in the clavam oxazolidine ring (Fig. 5.5 A) and the absence of the side-chain at position... 

The palladium-catalyzed opening of an oxazolidine ring followed by the hydrogenolysis of a benzylic OH group was performed over 5% Pd/C in ethanol at 140 atm H2 in 45 hours (Scheme 4.17).35... 

The oxazolidine ring proved to be stable toward hydrogenation conditions using 10% Pd/C and (Boc)20 in CH2Cl2 (Scheme 4.153).592... 

Some reactions in which a preformed 1,3-oxazolidine ring is transformed into another oxazolidine derivative were described. A detailed study of the enantioselective reduction of A-tosyl-4-alkylidene-l,3-oxazolidin-2-ones under the catalysis of Rh salts and chiral ligands, was published <06T9237>. 

Table 2-5 summarizes the results of the asymmetric alkylation (Scheme 2-17) of the lithium enolates derived from 22 or 23.28 When chiral auxiliary 22 or 23 is involved in the alkylation reactions, the substituent at C-4 of the oxazolidine ring determines the stereoselectivity and therefore controls the stereogenic outcome of the alkylation reaction. 

Formation of enantio- and diastereoenriched l-aza-4-oxa-7-thiabicyclo[3.3.0]octan-8-ones 453a and 453b was accomplished by ring closure of acyl-substituted. Y-bcnzyl thiocarbamates 452 in presence of Amberlyst 15 and 1,3-propanedithiol via a rearrangement of the oxazolidine ring (Equation 213) <2000JPR828>. 

FIGURE 8.8 A peptide sequence containing an oxazolidine ring that gives rise to a serine residue on acidolysis and a thiazolidine ring that gives rise to a cysteine residue on acidolysis. Substituents at C-2 can be H2, H,Me, or Me2. A structure with a methyl group at C produces a threonine residue on acidolysis. 

One of the best examples of the utility of enzymatic synthesis in catalyzing reactions that cannot be accomplished by any other route is the synthesis of substituted oxazolidine diesters. The oxazolidine ring is extremely water sensitive, the oxazolidine rapidly reverting back to the alkanolamine and aldehyde in the presence of water. Bis-oxazolidines have been used as hardeners for polymer coatings but the diester based on the hydroxyethyl oxazolidine and adipic acid cannot be synthesized directly with chemical catalysis because of the rapid rate of reaction of the oxazolidine ring with either the water from the esterification or the alcohol from transesterification. ... 

The advent of the low temperature, enzymatic esterification process offered the opportunity to manipulate the various reaction rates so that the ester might be formed keeping the oxazolidine ring intact (Figure 5.1). 

The dimethyl ester of adipic acid, rather than adipic acid, was used as a transesterification substrate. Reaction rate studies had shown that the transesterification would be much faster than the esterification reaction. It was considered that the rate of attack on the oxazolidine ring by methanol would be slower than the rate of attack by water and that the ring opening would not be catalysed by the enzyme, whereas the rate of the transesterification would be increased significantly, particularly at the low temperature of the enzymatic esterification. 

It has been shown by thermodynamic calculations (89TH1) that, under equal structural conditions, the ratio of the tautomeric equilibrium constants for the reversible addition reaction of the SH group and that for the OH group should be 10 in favor of the sulfur addition product. A similar result (>10 ) was estimated (90T6545) from a comparison of the stability of the 1,3-thiazolidine ring with that of the 1,3-oxazolidine ring. 

The ring-chain tautomerism of tetrahydro-l,3-oxazines is very sensitive to the stability differences, the substituents and the ring-fusion effect (Section IV,A). It also reveals a considerable stability difference in favor of the cis isomers. In the reactions of the cis- and trans-2-amino-l-cyclohexanols, as compared with the hydrindane analog systems, where the heteroatoms form an oxazolidine ring cis- or tra 5-fused with cyclohexane, the corresponding stability differences were again found to be in favor of the cis isomer (93JOC1967). 

As already shown for dihydrothiazole-containing cyclic peptides (Section 6.8.5.2.2.2), basically two different synthetic routes are used for the introduction of dihydrooxazoles into cyclic peptides. In the first one, 2-(aminoalkyl)dihydrooxazole-4-carboxylic acids and related derivatives are synthesized,t554 571,572 589 590 then incorporated directly into the linear precursors, which are finally cyclized by standard protocols.1541.554.567.569.5711 Again the main disadvantage to this synthetic approach is the facile racemization of the dihydrooxazole syn-thon. Therefore, the preferred method is the production of the oxazolidine ring in the preassembled cyclic peptide. For this purpose various methods have been proposed. 

Pyrazoline 68 is converted into the V-acetyl derivative 69 by treatment with acetic anhydride and triethylamine at —5 °C (Scheme 5). Treatment of 68 with acetic acid at 40 °C caused decomposition of the dihydrotriazole ring to give the enamine 71 <1997TL5891>. Treatment with trifluoroacetic acid in dichloromethane at room temperature, however, caused decomposition of both the dihydrotriazole and the oxazolidine rings yielding the pyroglutaminol 70 <2001J(P1)2997>. 

The diastereoselectivity is reversed in the alkylation of the enolate derived from the structurally very similar bicyclic lactam, tetrahydro-3-phenyl-l//.577-pyrrolof 1,2-c]oxazol-5-one (3). Thus, the major diastereomer 4 produced has the tram relationship between the newly introduced substituent in the pyrrolidine ring and the fused oxazolidine ring residue11,12. Only active electrophiles such as iodomethane, 3-halopropenes or (halomethyl)benzenes react11,12. Base-catalyzed equilibration of the product obtained by reaction with 3-bromocyclohexene gives a 50 50 mixture of the cis- and rra s-diastereomers11. 

Die Addition von Benzonitriloxiden an 4,5-Dihydro-l,2-oxazole fiihrt zu 6,7-Dihydro-7aH-[Pg.491]

Access to the imino group of oxazolidine-4-carboxylic acid is even more sterically hindered when substitutions are performed at the C2 position. For such cases, the typical procedure is based on the conversion of the desired serine or threonine dipeptides with unprotected hydroxy groups into the oxazolidine rings by reaction with aldehydes or ketones,1139,1691 as described in Vol. E 22a, Section 2.3.2.4. 

P2i Z = 2 Dx = 1.577 R = 0.033 for 1,041 intensities. The compound is a hydrolysis product of 5-azacytidine. The conformation of the D-ribose part is 4E, with C-4 endo, similar to that observed for some a-nucleosides. The oxazolidine ring is planar. The dihedral angle between the two planes, as defined by the torsion angle 0-4-C-l-C-2-0-2 about the common C-l-C-2 bond, is +111°. The orientation of the primary alcohol group is gauche /gauche. 

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