Oxazole-Claisen rearrangement

The first syntheses of a-allenic a-amino acids [131,133] took advantage of Steg-lich s [134] protocol for the oxazole-Claisen rearrangement of unsaturated N-ben-zoylamino acid esters (Scheme 18.46). Thus, treatment of the propargylic ester 143 with triphenylphosphine and tetrachlormethane furnished the allenic oxazolone 144, which was converted into the amino acid derivative 145 by methanolysis. Stepwise deprotection finally led to the allenic DOPA analog 146, which shows a much higher decarboxylase-inhibiting activity than a-vinyl- and a-ethynyl-DOPA [133],... 

In a similar way, propargyl esters of A -benzoyl-a-amino acids have been converted into a-allenyl-a-amino acid esters 113 by cyclization to oxazoles 111 followed by Claisen rearrangement to the 4-allenyl-2-phenyl-5(4//)-oxazolones 112. Oxazolone ring opening with methanol then afforded 113 (Scheme 7.32). ... 

The sequence with oxazole 73 also proves to be applicable to systems in which the double bond of the allylic alcohol fragment is incorporated into a heteroaromatic ring, such as in furfuryl alcohol (77a) and thiophene-2-methanol (77b).28 After hydrolysis of the oxazolone ring with water, V-benzoyl-3,3,3-trifluoro-2-(2-methyl-3-furyl)alanine (79a) and /V-benzoyl-3,3,3-trifluoro-2-(2-melhyl-3-thienyl)alanine (79b) are obtained. The 2-methylene helerocyclcs 78 originally formed in the Claisen rearrangement undergo rearomatizalion under the reaction conditions. 

Diastereoselective aza-Claisen rearrangement,1 The oxazole 1 prepared by reaction of L-valinol with propionic acid is readily convertible into an N-allylketene acetal (2), which rearranges at 150° to 3 in 94% de and 80% overall chemical yield. Acid catalyzed hydrolysis of 3 gives (R)-( - )-2-methyl-4-pentenoic acid (4) (85% yield) with recovery of L-valinol. 

A wide variety of a-trifluoromethyl-substituted amino acids are now available from the reaction of 5-fluoro-4-trifluoromethyl-l,3-oxazoles with allylic alcohols and benzyl alcohols. The reaction sequence involves a low-temperature Claisen rearrangement or a radical 1,3-benzyl shift from oxygen to carbon, respectively [88AG(E)848 89S850] (Scheme 86). 

Ireland demonstrated the usefulness of this reaction in the total s)uithesis of the complex polyether antibiotic, lasalocid A (X537A) [89]. Two Claisen rearrangements were used as key steps for the introduction of the carbon chain to the tetrahydrofuran and tetrahydropyrane rings (arrows indicate the bonds generated by the Claisen rearrangement in Scheme 61). Claisen rearrangement of an oxazole derived from ester of alanine has also been reported (O Scheme 62) [90]. The product was further transformed into C-mannosyl-alanine. 

Padwa, A., Cohen, L. A. Aza-Claisen rearrangements in the 2-allyloxy substituted oxazole system. Tetrahedron Lett. 1982, 23, 915-918. 

Allyloxy-substituted 4,5-diphenyloxazoles undergo [3,3]-sigmatropic aza-Claisen rearrangements to 3-allyl-2(3//)oxazolones <84JOC399>. The 2-propynyloxy-oxazole (61) affords an allene... 

For a closely related method for the synthesis of a-substituted a-amino acids via rearrangement of allyloxy-substituted oxazoles (derived from At-benzoyl-protected a-amino acids) see p 3448. For the synthesis of substituted 2-aminopent-4-enals by Claisen rearrangement of substituted (l-methyl-3-oxahexa-l,5-dienyl)amines see ref 85. 

Oxazoles readily participate in cycloaddition reactions as dienophiles and as dienes in Diels-Alder reactions, and suitably substituted oxazoles participate in sigmatropic rearrangements (e.g., aza-Claisen rearrangements). In particular, the Diels-Alder reaction of oxazoles is one of the most widely explored and synthetically useful reactions, and as such, it has been used extensively both in natural product syntheses and to convert oxazoles to other heterocyclic ring systems. For example, a partial list of heterocyclic systems readily accessible from oxazoles via Diels-Alder reactions or other cycloadditions include pyridines hydroxy-pyridines isoindoles pyridazines tetrahydronaphthyridines benzo[h]-l,6-naphthyridines benzopyrano[3,4-b]pyridines 2-substituted, 2,4-disubstituted,... 

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