3- -4,5-dihydrooxazole amide

Cyclic peptides have been synthesized not only for the purpose of improving biological activities and selectivity, but also to explore basic features of secondary structures in peptides and to investigate with such mimetic compounds the conformational behavior of proteins. For this purpose artificial building blocks have been frequently used or amide bonds have been modified isosterically. Nature also offers a variety of modifications in cyclic peptides that are critically involved in their bioactivity. Some of the most common natural and synthetic modifications including unusual structural elements such as thiazoles (and dihy-drothiazoles) and oxazoles (and dihydrooxazoles) with broad synthetic applications will be presented in the following section. 

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 selenoxide produced by oxidation of Y-(2-phenylselenylethyl)benzamide with MCPBA undergoes cyclization to furnish 4,5-dihydrooxazoles in high yield <92TL4017>. An optically active amide bearing a 2-pyridylseleno group on the p carbon (186) is cyclized without racemization (Equation (25)). 

Optically active bis(4,5-dihydrooxazoles), which are effective ligands for asymmetric synthesis (Section 3.04.12.5), have been prepared by zinc chloride-catalyzed coupling of amino alcohols and dinitriles <91CB1173> and by sodium hydroxide induced cyclization of bis(A-(2-chloroethyl)amides) <91JA728>. 

Many chiral dihydrooxazoles and oxazolidines are derived from amino alcohols, such as valinol (Section 2.3.1.). Thus, (5>)-4-isopropyIoxazolidine (15) was obtained from (S)-valinol by reaction with formaldehyde 7 and used for the formation of chiral amides in [2,3] sigmatropic rearrangements (Section D.1.6.3.2.). A bicyclic derivative of valinol 16 was obtained by reaction with 4-oxopentanoic acid8 and used as a chiral dienophile (Section D.1.6.1.1.2.1.2.). A detailed procedure for an analogous derivative from (S,S)-2-amino-l-phenyl-1.3-propanediol has been published9. 

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 ... 

Hydroxy-substituted A -(2-arylethy)amides 51 lead to isoquinolines 48 under Bischler-Napieralski conditions. In this case, dehydrogenation is not required Pictet-Gams synthesis), because H2O elimination occurs at the dihydroisoquinoline step. The starting materials 51 are available e.g. from aryl-4,5-dihydrooxazoles (e.g. 57). 

Oxazoline Derivatives. Oxazolines are of great interest because of their ability to undergo cationic ring-opening poljunerization. In this connection, the functionalized monomers A(-[4-(4, 5 -dihydrooxazol-2-yl)phenyl]acryl amide (5a), A -[4-(4, 5 -dihydrooxazol-2-yl)phenyl]-2-methacryl amide (5b), N- 10-[4-(4, 5-dihydrooxazol-2-yl)phenylcarbamoyl]decyl -2-acryl amide (6a),... 

Propargylic amides 56 are converted to oxazoles of type 58 by Au(III)-catalyzed cycloisomerization via (spectroscopically detectable) 5-methylene-4,5-dihydrooxazoles 57 [268] ... 

The proposed mechanism hypothesized the nucleophilic attack of the oxygen to the Pd-complexed C-C triple bond, through the enol amide form, producing the oxazole skeleton by formation of the c-alkenylpalladium complex. The intervention of water provided, through its enol form, the 4,5-dihydrooxazole-5-carbaldehyde. The oxidizing system also promoted the dehydrogenation step (Scheme 54). 

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