Keywords: Carbocations / Cycloadditions / Kinetics / Linear free-energy relationships / Reaction mechanismsThe N,N-dimethylmethyleneammonium ion 1 reacts regioand stereoselectively with the 1,3-dienes 2a−2f to yield the 1,2,5,6-tetrahydropyridinium ions 3. The kinetics of these hetero Diels−Alder reactions, which have been followed by dilatometry and 1 H-NMR spectroscopy, obey second-order rate laws. Since the observed rate constants are only 30−300 times larger than those calculated for the stepwise process by the linear free-enthalpy relationship lg k = s (E + N), it is
Stereochemical and structural aspects of the variations in the C-terminal residue of L-aspartyl-L-phenylalanine methyl ester have been investigated. Novel configurational analogues such as L-aspartyl-D-alanine benzyl ester and L-aspartyl-D-alpha-aminobutyric acid benzyl ester were found to be sweet. In addition, chiral and achiral alpha, alpha-dialkylglycine and alpha-aminocycloalkanecarboxylic acids were incorporated into the dipeptides. The L-aspartic acid based dipeptide derivatives of alpha-aminoisobutyric acid methyl ester, alpha-aminocyclopropanecarboxylic acid methyl ester, alpha-aminocyclobutanecarboxylic acid methyl ester, and alpha-aminocyclopentanecarboxylic acid methyl ester are sweet. Dipeptides with alpha-aminocyclohexanecarboxylic acid methyl ester and alpha-aminocycloheptanecarboxylic acid methyl ester are bitter, whereas the analogues with alpha-aminocyclooctanecarboxylic acid methyl ester, alpha, alpha-diethylglycine methyl ester, and alpha-aminoisobutyric acid benzyl ester are tasteless. Aspects on chirality and effective volume of the C-terminal residue are discussed and correlated with taste.
As a continuation of o u r program t o study the structure-function relationship of the peptide hormone somatostatin, we report the synthesis and biological potencies of a series of cyclic hexapeptide analogs related to somatostatin. The parent peptide of this series was designed by Veber and coworkers, c[-Pro6-Phe'-D-Trp* -Lys9 -Thr" -Phe'l-], and has been reported t o be superactive in the inhibition of the release of growth hormone. (The superscript numbers refer to the positions of residues in native somatostatin.) The series of analogs has been designed t o examine the role of the so-called bridging region, Phe" -Proh, which has been postulated to be important in maintaining the proper conformation of the biologically active tetrapeptide, Phe-D-Trp-Lys-Thr. W e have incorporated peptidomimetics and the retro-inverso modification into the bridging region of the molecule, with the aim of affecting the conformational preferences found in the parent peptide. Results from the biological assayin vitro inhibition of growth hormoneand the conformational analysis (adjoining paper) of our analogs will provide insight into the relationship between structure and biological activity of somatostatin.
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