Methyl-oxazoles. side-chain acidity

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]. 

Meyers and Tavares also investigated radical bromination as a means to effect net oxidation of activated oxazolines. They found these reaction conditions were acceptable for preparing 2-alkyl-4-oxazolecarboxylic acid esters only if the 2-alkyl group was methyl or primary, i.e., 65 Rj = R2 = H or Rj = n-C4, R2 = H. However, these conditions failed completely if the 2-alkyl group was secondary, e.g., isopropyl or cyclohexyl. In these cases, the desired oxazole 65 was isolated in <1% yield. Instead, the sole product was 66, the result of oxidation with concomitant side chain bromination (Scheme 1.20, Table 1.1, entries 7 and 8). 

Ohba and co-workers have demonstrated that A -protected a-amino esters are compatible with the Schollkopf oxazole synthesis cf., 38->39). In the case of ammo esters derived from natural amino acids (e.g., 38), the presence of an additional acidic N-H bond in the AABoc ester substrate necessitated the use of an added excess of metalated isocyanide (2.5 equiv was found to be optimal) to obtain maximal yields. Under optimized conditions, oxazoles (39) were obtained in good yield from iV-Boc glycine, alanine, and phenylalanine. Oxazole formation from iV-Boc serine (which possesses an additional acidic site in its hydroxylic side chain) proceeded in good yield (66%) using 3.5 equiv lithiated methyl isocyanide. Notably, no epimerization was detected in the reaction of N-Boc alanine methyl ester with lithiated methyl or ethyl isocyanide under these conditions. Minor epimerization was observed (91-92% ee product) with substrates that lacked a carbamate NH hydrogen e.g., A -Boc proline methyl ester), however. ... 

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