3- -4,5-dihydrooxazole carboxylic acid

Results of nucleophilic addition reactions to various a-oxo 4,5-dihydrooxazoles are summarized in Table 24. In general, the diastereoselectivity of these reactions is low to moderate, although an increased selectivity is found in the presence of triethylamine or N,N,N, N -te-tramethylethylenediamine, which slow down the rate of reaction. Nevertheless, enantiomerical-ly pure 2-hydroxy carboxylic acids can be prepared by this method, since the diastereomeric addition products are separable either by recrystallization or HPLC21. 

The addition of various alkyllithium reagents to ( )-2-(l-alkenyl)-4,5-dihydrooxazoles in THF at —78 °C followed by acid hydrolysis gave nonracemic chiral / ,/>-disubstituted carboxylic acids in high enantiomeric purity (>91% ee). 

The biosynthesis 237,5381 involves enzymatic dehydration of serine and threonine residues in a manner similar to the formation of thiazoles and dihydrothiazoles vide supra) with or without subsequent oxidation to yield the 2-(l-aminoalkyl)oxazole-4-carboxylic acid and 2-(l-aminoalkyl)dihydrooxazole-4-carboxylic acid shown in Scheme 38. These cyclic peptides display interesting physiological properties such as cytotoxicity/541, 569,5831 antitumor activities, or antineoplastic effects/523,5291 but as for the sulfur-containing compounds the mechanism of action is not yet understood despite extensive SAR studies. 515,521,540,5431... 

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. 

The alkylation of metalated imines, hydrazones, 4,5-dihydrooxazoles, 4,5-dihydroisoxazoles, 5,6-dihydro-4/7-1,2-oxazines and 2,5-dialkoxy-3,6-dihydropyrazines (i.e., azaenolates) is a commonly used method in asymmetric synthesis of enantiomerically enriched aldehydes, ketones, spiroacetals, amines, /J-oxo esters, carboxylic acids, lactones, 1,3-amino alcohols, /(-hydroxy ketones and amino acids. 

Alkylated 4,5-dihydrooxazoles are hydrolyzed by aqueous sulfuric acid (4N, 3.5 h, reflux) to give / -aminoaIkylalkanoale hydrochlorides which precipitate from the aqueous solution. Further heating provides the chiral carboxylic acids in 62-67% optical purity. Partial racemization of the ester (5-10%) has been observed during hydrolysis14. 

Dihydrooxazoles are readily prepared from (V-acyl derivatives of /3-hydroxylamines by heating or by the action of thionyl chloride, sulfuric acid or phosphorus pentoxide (equation 167) (79JCS(P1)539>. The direct condensation of carboxylic acids with 13-hydroxylamines succeeds best with substituted compounds, such as norephedrine (equation 168). There are many variations of this general method, such as the use of imino ether hydrochlorides (equation 169) (78ACR375) and of cyanides (equation 170) (74LA996). 

Dihydrooxazoles such as 263 have also been prepared <2004T7591> via an oxidative decarboxylation and elimination of the corresponding oxazolidine -carboxylic acid 262 (Scheme 77). The oxazolidine-4-carboxylic acids were in turn derived from L-serine. The thermal oxidative decarboxylation using lead tetraacetate was reported to be higher yielding and more practical than the analogous electrochemical version. Dihydrooxazoles 263 have been extensively used as chiral olefmic components in cycloaddition reactions and these reactions are discussed in Section 4.04.6.2.1. 

Dihydrooxazoles continue to occupy an important place in organic synthesis and medicinal chemistry as they have found use as versatile synthetic intermediates, protecting groups/pro-drugs for carboxylic acids, and chiral auxiliaries in asymmetric synthesis. There are several protocols in the literature for the transformations of functional groups such as acids, esters, nitriles, hydroxyl amides, aldehydes, and alkenes to 2-oxazolines. Newer additions to these methods feature greater ease of synthesis and milder conditions. 

There are many methods for the cleavage of 4,5-dihydrooxazoles once they have served their purpose. An effective method for hydrolyzing them back to carboxylic acids employs trifluoro-methanesulfonic anhydride <92SC13>. Intermediate ring-opened esters (100) are A(-methylated, then saponified to the acids (Scheme 34). The oxazoles may also be converted into aldehydes or nitriles. In a one-pot, two-step procedure, 4,5-dihydrooxazoles are transformed into alcohols (101) <93TIj4893>. Chloromethyl methyl ether converts the dihydrooxazoles into ring-opened amides in the first step, and these are reduced with diisobutylaluminum hydride (Scheme 35). 

The starting dihydrooxazoles 1 are readily prepared by condensing an amino alcohol with an appropriate imidate hydrochloride or the free carboxylic acid. A-Allylation of 1 with ally] tosylate has proved to be superior to other procedures. Neutralization of the dihydrooxazolium salt 2 and rearrangement of 3 are conveniently performed as a one-pot operation. The potential of this method has been demonstrated by the enamioselective synthesis of (- )-(/ )-2-methylpent-4-enoic acid on the basis of L-valine. 

An equimolar mixture of the appropriate amino alcohol and carboxylic acid is refluxed in xylene (0.5 M) under N, with a/.eolropie removal of 11,0 for 12 36 h. After cooling, the reaction mixture is extracted with cold 10% aq HC1 and the resulting aqueous layer neutralized with cold 40% aq NaOH. The mixture is extracted with Et,0. dried over Na2S04, and evaporated. Distillation gives the desired dihydrooxazole (44-86%) as a colorless oil. 

On the basis of this reaction, 4,5-dihydrooxazoles can be regarded as carboxylic acid dervatives, i.e. as cyclic imido esters [74]. 

Dihydrooxazoles are prepared from y0-amino alcohols (from oxiranes and ammonia, see p 18) and carboxylic acids or carboxylic esters [75]. A -(2-Hydroxyalkyl)carboxylic acid amides can be isolated as intermediates and subsequently subjected to thermal cyclodehydration or to the action of H2SO4, SOCI2 or to other dehydrating agents ... 

Methyl-4,5-dihydrooxazole 4 can be metalated by -butyllithium and subsequently alkylated with haloalkanes. The hydrolysis of 5 yields carboxylic acid 6 in which the chain of the haloalkane has been lengthened by two C-atoms ... 

Dihydrooxazoles are weak bases and form salts with strong acids. They undergo a stepwise hydrolysis in aqueous acid medium to give salts of fS-amino alcohols and carboxylic acids. The nucleophile attacks at the 2-position, as in oxazohum salts ... 

Dihydrooxazoles 275 can be made by the condensation of aryl nitriles with amino alcohols catalyzed by Bi(iii) salts <2005SL2747> or acidic clay <1998TL459> in good yields (Bi salts - 70-92% kaolinitic clay -56-96%) (Equation 16). The use of Bi salts is only applicable to the formation of 2-aryloxazolines while the latter method works well for both aromatic as well as aliphatic substrates. The conversion of carboxylic esters to 2-oxazolines 276 in good (44-82%) yields with lanthanide chloride as catalyst <1997TL7019> has also been described (Equation 17). 

The (S)-serine derived methyl ( R)-2- erJ-butyl-2,3-dihydrooxazole-3-carboxylate reacts with ethyl diazoacetate under bis(2,4-pentanedionato)copper catalysis to afford the expected bi-cyclic product in good yield54, but in this case the inducing power exhibited by the bulky 2-tm-butyl group is rather weak (diastereofacial selectivity 70 30). However, the major diastereomer can be easily separated by chromatography and selective saponification to give the enantiomerically pure cyclopropanecarboxylic acid. 

Oxazoles and 4,5-dihydrooxazoles can be transformed into quinolines. For instance, 5-(o-acylamino-aryl)oxazole-4-carboxylic esters 104, made from benzoxazinones 103 and isocyanoacetic ester, are converted into 3-aminO 4-hydroxy-2-quinolones 105 in an acid medium [109]. 

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