Molecular diversity via amino acid derived alpha-amino nitriles: synthesis of spirocyclic 2,6-dioxopiperazine derivatives.
[reaction: see text] Chiral spirocyclic 2,6-dioxopiperazines were synthesized from amino acid derived alpha-quaternary alpha-amino nitriles via H(2)SO(4)-promoted cyano hydration, followed by base-mediated cyclization and N-alkylation. This methodology, requiring the previous preparation of the amino nitrile by a modified Strecker reaction, was applied to Phe, Trp, Pro, Asp, Glu, and Ser derivatives. In the case of the Trp-derived amino nitrile the major product of the treatment with H(2)SO(4) was not the expected carboxamide, but a new tetracyclic indoline derivative containing the novel heterocyclic system hexahydropyrrolo[1',2',3':1,9a,9]imidazo[1,2-a]indole, as a result of a domino tautomerization. The treatment of this indoline derivative with refluxing 1 N HCl led to a Trp-derived 2,6-dioxopiperazine. The 2,6-dioxopiperazine ring opened under the reaction conditions of methyl ester saponification, giving N-(carboxyalkyl)amino acid derivatives. Therefore, the synthesis of 2,6-dioxopiperazines containing free carboxylic acids from the respective methyl esters required transesterification to benzyl esters, followed by hydrogenolysis.
González-Vera
Juan A
JA
Instituto de Química Médica (CSIC), Juan de la Cierva 3, E-28006 Madrid, Spain.
García-López
M Teresa
MT
Herranz
Rosario
R
D000478:Alkylation; D000596:Amino Acids / Q000737:chemistry*; D002384:Catalysis; D003500:Cyclization; D004952:Esters; D007202:Indicators and Reagents; D015394:Molecular Structure; D009570:Nitriles / Q000737:chemistry*; D010879:Piperazines / Q000138:chemical synthesis*; D013141:Spiro Compounds / Q000138:chemical synthesis*; D013237:Stereoisomerism
D000596:Amino Acids; D004952:Esters; D007202:Indicators and Reagents; D009570:Nitriles; D010879:Piperazines; D013141:Spiro Compounds