Oxazoline oxidation, oxazole synthesis

In NRPS, the cyclization domain catalyzes cyclization of the side-chain nucleophile from a dipeptide moiety such as AA-Ser or AA-Cys (AA = amino acids) to form a tetrahedral intermediate, followed by dehydration to form oxazolines and thiazolines (Scheme 7.1) [20]. The synthesis of a 2-methyl oxazoline from threonine follows a similar mechanism. Once a heterocycle is formed, it can be further modified by reductase to form tetrahydro thiazolidine in the case of pyochelin biosynthesis. Conversely, oxidation of the dehydroheterocycles lead to heteroaro-mahc thiazoles or oxazoles as in the case of epothilone D (Figure 7.2) [21]. 

The oxidation of oxazoline 58 to oxazole 60 turns out to be problematical in Pattendens synthesis. Even with special oxidation techniques (tert-butyl peroxybenzoate 59/copper (I) bro-... 

In the laboratory of A.I. Meyers, the first enantioselective total synthesis of the streptogramin antibiotic (-)-madumycin II was achieved. The natural product contains an oxazole moiety, which may be considered a masked dehydropeptide. The oxazole moiety was introduced in two steps by the Burgess cyciodehydration reaction followed by oxidation of the resulting oxazoline to the corresponding oxazole. 

Heterocydes are common motifs in natural products, which may occur as single, tandem, and multiple moieties within a given molecule (Scheme 8.5) [35-37]. These motifs often provide molecular interaction with nudeotide and protein targets. In the biosynthesis of NRPs, an oxazoline was usually formed from a dipeptide containing serine in the second position upon dehydration (Scheme 8.5) [38]. The syntheses of a thiazoline from cysteine and a 2-methyloxazoline from threonine follow a similar mechanism. These heterocycles can be further custom-made to provide thiazolidines/oxazolidines upon reduction or thiazoles/oxazoles upon oxidation. Enzymatic heterocyclization can be portable, as demonstrated in the synthesis of novel chiral heterocyclic carboxylic adds by hybrid enzymes [39]. 

Oxidation of oxazolines using Mn02 was also employed in the synthesis of a beminamycin A fragment by Shin and co-workers ° and in the preparation of the naturally occiuring 2,4-disubstituted oxazole, phenoxan 28, by Yamamura s group" (Scheme 1.5). For beminamycin, the oxazoline 25 was synthesized in 61% yield by Mitsunobu dehydration of the serine-derived amide 24. 

Balaban and co-workers " prepared 2,5-disubstituted oxazoles via side-chain bromination with NBS, followed by dehydrobromination with pyridine. Kashima and Arao described a synthesis of oxazoles using NBS/AIBN to effect oxidation of an oxazoline. In this case, the product was a 5-bromooxazole, e.g., 63 (Scheme 1.19). This study was limited to only three examples of 2-aryloxazoles. 

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