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The scope and stereoselectivity of the acid-promoted cyclization of new tryptophan-based alpha-amino nitriles derived from either ketones or aldehydes to novel hexahydropyrrolo[1',2',3':1,9a,9]imidazo-[1,2-a]indoles is described. The time and stereoselectivity of the reaction mostly depended on both the steric volume of the substituents at the amino nitrile and its stereochemistry.

Research has been conducted on the N-benzyl-N-chloroacetyl amino acid derivatives. The base-assisted intramolecular alkylation of these derivatives has been conducted and the results of the experiment are presented.

(Cyanomethylenene)amino pseudopeptides react with hydrogen peroxide to yield (carbamoylmethylene)amino pseudopeptides, in the presence of n-tetrabutylammonium hydrogen sulfate. The methyl esters of the product compound, which are associated with amino and carboxyl protecting groups and peptide bonds, cyclize to dioxopiperazine compounds.

N-protected amino aldehyde and C-protected amino acid yield unsteady aldimine intermediates which are treated with trimethylsilyl cyanide to synthesize protected Xaapsi(CH(CN)NH)Yaa pseudodipeptides. The preparation is modulated by thermodynamics and the stereoselectivity is gauged by examining the corresponding stereochemistries of Xaa and Yaa residues. The relative methyl esters exhibit a condition of saponification which is governed to derive substantial amounts of C-deprotected pseudodipeptides.

The synthesis of new indole alkaloid analogues through highly stereoselective novel domino cyclative halogenation or prenylation reactions of tryptophan-derived [alpha]-amino nitriles is described.

Research has been conducted on phenylalanine- and tryptophan-derived 5-phenyl-1,4-benzodiazepines. The authors describe the stereocontrolled synthesis of these compounds.

[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.

2-Oxopiperazine derivatives 1 have been designed as mimetics of gamma-turn conformationally constrained tripeptides. The synthetic pathway devised for the preparation of both epimers of 1 at C(5) involves a reductive amination of cyanomethyleneamino pseudopeptides with amino acid derivatives, followed by regiospecific lactamization of the resulting C-backbone branched pseudopeptides. The versatility of this methodology is illustrated in the synthesis of analogues of the tetrapeptides Boc-[Nle(31)]-CCK-4 and Boc-[Lys(o-tolylaminocarbonyl)(31)]-CCK-4. The introduction of the new conformational restriction into these Boc-CCK-4 analogues led to a loss of 2 or 3 orders of magnitude in the affinity at CCK receptors. These results suggest the absence of a gamma-turn in the bioactive conformation of the C-terminal tripeptide of CCK-4.