2-Oxazolines protecting groups

An organolithium initiator with an oxazoline protecting group has been examined for the preparation of a-carboxyl-... 

These oxazolines have cationic surface-active properties and are emulsifying agents of the water-in-oil type. They ate acid acceptors and, in some cases, corrosion inhibitors (see Corrosion). Reaction to oxazoline also is useful as a tool for determination of double-bond location in fatty acids (2), or for use as a protective group in synthesis (3). The oxazolines from AEPD and TRIS AMINO contain hydroxyl groups that can be esterified easily, giving waxes (qv) with saturated acids and drying oils (qv) with unsaturated acids. 

In a recent modification of the second synthesis (50S) effected for fluvibactin (45) an o-xylene protection group was proposed (reaction of 2,3-dihydroxy-benzoic acid methyl ester with 1,2-di(bromomethyl)benzene) which could be removed later by hydrogenolysis. The formation of the oxazoline ring from protected DHB-L-threonine methyl ester was achieved with Mo(VI) catalysts (e.g. (NH4)2Mo04) without affecting the chiral centers. Derivatization of the primary amino groups of norspermidine with the protected DHB methyl ester was catalyzed by Sb(OC2115)3. 

The major problems with industrial-scale applications of this procedure are the use of expensive reagents, the required chromatographic separation of the side products and the competitive formation of oxazolines. The use of carbamate protecting groups avoided the oxazoline problem and is usually preferred, since the resulting protected 3-amino-substituted /3-lactams 150 can later be deprotected and reacylated. 

Ring closure of (3-hydroxy-a-amino acids with sulfuryl chloride/triethylamine 68 is accompanied by formation of (3-chloroalanine,16 1 whereas cyclization of urethane-protected serine and threonine by the Mitsunobu reaction 54 69 70 leads to oxazoline and dehydroalanine formation as side products. 47,71 Formation of dehydroalanine can be prevented by bulky carboxy protecting groups such as tert-butyl esters. 69 ... 

Oxazoles and oxazolines in organic synthesis 86CH(45)963. Oxazolidin-3-yl as a protecting group in asymmetric synthesis 92 PAC1889. 

Do you need a chiral starting material which can be converted into a number of enantiopure products Or a chiral auxiliary to perform an asymmetric transformation at a certain point of a complex molecule Would you like to have a protecting group for an acid, which activates the ortho-position of an aromatic ring Or do you need an easy-to-synthesize chiral catalyst For all these problems oxazolines can be the solution. 

In aromatic systems, oxazolines can have three different functions (Fig. 4). Firstly, they can be used as protecting groups for carboxylic acids. Secondly, they activate even electron-rich aromatic systems for nucleophilic substitution. Fluorine or alkoxy groups in the ortho position can be substituted by strong nucleophiles such as Grignard reagents. Thirdly, when biaryl compounds with axial chirality are synthesized in these reactions, oxazolines can induce the formation of only one atropisomer with excellent selectivity. These three qualities were all used in the synthesis of 20, a precursor of the natural product isochizandrine [10]. 

Meyers Al, Temple DL et al (1974) Oxazolines. XL Synthesis of functionalized aromatic and aliphatic acids. Useful protecting group for carboxylic acids against Grignard and hydride reagents. J Org Chem 39 2787-2793... 

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. 

The reaction of oxazolines (331) derived from L-serine with diethylphosphite leads to a mixture of racemic a- and p-phosphono alanines (332) and (333). This new reaction proceeds without the use of any halogenated intermediate, and offers a simple route for various phosphonoamino acids bearing suitable protecting groups (Scheme 89). " ... 

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