Cyclodehydration oxazole rings

One of the most reliable methods for constructing the oxazole ring is the cyclodehydration of a-acylamino ketones, the Robinson-Gabriel synthesis (1909/1910) (equation 93). The reaction is usually conducted in the presence of sulfuric add or phosphorus pentachloride and more recently polyphosphoric add, phosgene or anhydrous hydrogen fluoride have... 

Titanium(rv)-mediated tandem deprotection-cyclodehydration of a protected cysteine A -amide was used in the synthesis of thiazolone- and thiazole-containing heterocycles as building blocks for macrocycle synthesis <20000L3289>. Similarly, the directly connected thiazole-oxazole ring system present in microcin B17 was synthesized from aminoacetonitrile hydrochloride <1996JOC778>. 

The key to this approach was the formation of the oxazole ring in the presence of the thiazoline rings. Cyclization of 1298 with Burgess reagent" gave the expected intermediate oxazoline (not shown), but this could not be oxidized to 1299 using Ni02, NBS/benzoyl peroxide, or CuBr/tert-butyl perbenzoate. Thionyl chloride, phosphorus oxychloride, titanium tetrachloride, or triphenylphosphine/iodine did not effect cyclodehydration of the p-ketoamide produced from the Dess-Martin periodinane oxidation. 

Nicolaou and co-workers established the severely strained A-ring oxazole (21) in their total synthesis of antitumor agent diazonamide A through initial oxidation of the hindered alcohol of intermediate 20 with TPAP and subsequent Robinson-Gabriel cyclodehydration of the resultant ketoamide with a mixture of POCI3 and pyridine (1 2) at 70°C. ... 

Similarly, the (—)-p-lactone 1316 was ring opened with thiolacetic acid to yield (5)-At-t-Boc-(5-acetyl)-a-methylcysteine (not shown). In this case, Jones oxidation followed by cyclodehydration generated the key oxazole 1318. 

The biosynthesis of thiazole/oxazole-modified microcines was investigated with regard to the role of the enzymes in cyclodehydration/dehydrogenation function and to the order of ring formation starting from Ser, Cys, and Thr residues of the native peptides (14B413). 

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