Amino hydroxy carboxylic acid, derivative synthesis,

Microwave-assisted reactions of 5-amino-4-hydroxy-3(2//)-pyridazinone 114 with various carboxylic acid derivatives allowed a convenient and versatile approach to substituted 1,3-oxazolo[4,5-i/]pyridazinones 115. The developed methodology is suitable for rapid, parallel, automated synthesis of oxazolopyridazinone libraries <04TL4693>. 

A simplified synthesis relies on the potential to protect difunctional compounds as cyclic derivatives. For example, 1,2-diols are masked as cyclic acetals (Section 24-8), hydroxy acids as lactones (Section 19-9), amino acids as lactams (Section 19-10), and dicarboxylic acids as anhydrides (Section 19-8). The last two possibilities merit consideration as applied to Asp. However, direct lactam formation can be quickly ruled out because of the complications of ring strain (although /3-lactams have been used in the preparation of aspartame). This problem is absent with respect to dehydration to the five-membered ring anhydride. Because anhydrides are activated carboxylic acid derivatives (Section 20-3), the Asp anhydride can be coupled directly with Phe-OCHa without the help of added DCC. Nucleophilic attack of the amino end of Phe-OCHs occurs preferentially at the desired position, albeit not completely so 19% of the product derives from peptide-bond formation at the /3-carboxy group of Asp. 

Hydroxy-L-prolin is converted into a 2-methoxypyrrolidine. This can be used as a valuable chiral building block to prepare optically active 2-substituted pyrrolidines (2-allyl, 2-cyano, 2-phosphono) with different nucleophiles and employing TiQ as Lewis acid (Eq. 21) [286]. Using these latent A -acylimmonium cations (Eq. 22) [287] (Table 9, No. 31), 2-(pyrimidin-l-yl)-2-amino acids [288], and 5-fluorouracil derivatives [289] have been prepared. For the synthesis of p-lactams a 4-acetoxyazetidinone, prepared by non-Kolbe electrolysis of the corresponding 4-carboxy derivative (Eq. 23) [290], proved to be a valuable intermediate. 0-Benzoylated a-hydroxyacetic acids are decarboxylated in methanol to mixed acylals [291]. By reaction of the intermediate cation, with the carboxylic acid used as precursor, esters are obtained in acetonitrile (Eq. 24) [292] and surprisingly also in methanol as solvent (Table 9, No. 32). Hydroxy compounds are formed by decarboxylation in water or in dimethyl sulfoxide (Table 9, Nos. 34, 35). 

A number of methods for the synthesis of piperazic acid (7) and related derivatives are currently available as a result of growing interest in natural product chemistry and in their potential in medicinal chemistry. Their chemistry and conformational properties have been comprehensively reviewed. 2451 Racemic piperazic acid is obtained by condensation of penta-2,4-dienoic acid with phthalazinedione and subsequent reductive deprotection of the resulting A,A -bis(phthaloyl)-l,2,3,6-tetrahydropyridazine-3-carboxylic acid.12431 Resolution of racemic piperazic acid is achieved by fractional crystallization of the ephedrine salt of Nl-(benzyloxycarbonyl)piperazic acid from ethyl acetate. 246,2471 A typical route to enantiomerically pure (3S)-piperazic acid 56 starts from chiral 2-amino-5-hydroxyvaleric acid 55 as shown in Scheme 12.1248 Convenient stereoselective syntheses have been reported for 5-hydroxy- and 5-chloropiperazic acids as important constituents of natural cyclic peptides and depsipep-tides.1249,2521... 

In this development, both amino moieties are differentially protected and thus, incorporation of these amino acids into peptide chains either at the a- or p-position is possible. This procedure has also been applied to the synthesis of piperazine-2-carboxylic acids and derived peptides [135], Scheme 51. For example, the bicyclic a-hydroxy (S-lactam 161, upon ring expansion and subsequent coupling of the resulting NCA 162 with a-amino esters, affords 163 in good yield. 

The synthesis of the carbapenam-3-carboxylic acid 36 <03JA15746> as well as a study on carbapenem biosynthesis have been documented <03JA8486>. The cephalosporin derivative 37 has been prepared and its use as a novel fluorogenic substrate for imaging P-lactamase gene expression demonstrated <03JA11146>. The nucleus of the carbacephem antibiotic loracarbef has been synthesized in a highly efficient and enantioselective fashion from 25,3iS-2-amino-3-hydroxy-6-heptenoic acid, which was derived from enzyme-catalyzed... 

A great deal of work has been done on the in situ activation of carboxylic acids toward nucleophilic substitution by amines. This type of reaction forms the backbone of the methods for synthesis of peptides and proteins. Among the methods for carboxylate activation which have achieved importance in peptide synthesis that were mentioned in Section 3.4.1 are the carbodiimide and isoxazolium methods. Since amines are better nucleophiles than alcohols, the leaving group in a potential acylation reagent need not be as reactive as is necessary for alcohols. The p-nitrophenyl and 2,4,5-trichlorophenyl esters of amino acids are sufficiently reactive toward amines to be useful in peptide synthesis. Acyl derivatives of hydroxysuccinimide are also useful for synthesis of peptides and other types of amides.Like the p-nitrophenyl esters, the acylated A-hydroxysuccinimides can be isolated and purified, but rapidly react with free amino groups. The A-hydroxy-succinimide that is liberated is easily removed because of its solubility in dilute... 

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