Carboxylic acid derivatives synthesis synthetic utility

Six-membered nitrogen heterocycles are found in a wide variety of naturally occurring alkaloids, and are often incorporated into the design of biologically active pharmaceutical products. Of the many ways to construct these heterocycles, the aza-annulation of enamine substrates with a,(J-unsaturated carboxylic acid derivatives has been a versatile and efficient method for the formation of dihydropyridone and pyridone products. The synthetic utility of this approach has led to incorporation of aza-annulation methodology as a key step in the synthesis of a number of interesting heterocyclic molecules. 

For a complete description of the synthetic utility of the Houben-Hoesch reaction as it applies to other aromatic systems, as well as some mechanistic discussions, the reader is directed to two reviews on the subject. Due to the diminished electrophilic reactivity of nitriles compared to other carboxylic acid derivatives as well as the broad number of Friedel-Crafts substrates, most Houben-Hoesch pyrrole acylation reactions are conducted intramolecularly. However, an impressive intermolecular example was delineated by Chang and co-workers in efforts directed toward the synthesis of novel 2-[5-aroylpyrrolo]alkanoic acids, for evaluation of their potential analgesic and anti-inflammatory activities. Treatment of substituted pyrrole 4 and 3-cyanopyridine (5) with acid in dry chloroform resulted in the preparation of 6 in good yield. 

Azirine/oxazolone method, a synthetic method for the introduction of sterically highly hindered a,a-disubstituted a-amino acids into peptides. The synthesis of e.g., Aib-rich peptides requires either highly reactive coupling reagents (e.g., amino acid halides) or special derivatives (such as 3-amino-2H-azirines or a-azido carboxylic acid chlorides). The azirine/oxazolone method utilizes an amino component that... 

Carhodiimidazole-Catalyzed Chemical Synthesis of Arylazido Adenine Nucleotide Analogs. The utilization of carbodiimidazole to facilitate the formation of activated carboxylic acids was elegantly applied by Gottikh and his group to the synthesis of a wide spectrum of aminoacyl nucleosides, nucleotides, nucleoside di- and triphosphates, and tRNA derivatives. The formation of an imidazolide intermediate has been used in our work in the synthetic schemes leading to the esterification of adenosine and diphosphopyridine nucleotides. 

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