1. Electrostatic Switching of Stereoselectivity in Aldol Reactions
Michelle L Coote, Li-Juan Yu J Org Chem . 2021 Jul 2;86(13):9076-9083. doi: 10.1021/acs.joc.1c01032.
Density functional theory (DFT) has been employed in predicting the enantioselectivity of the aldol reaction between acetone andp-nitrobenzaldehyde catalyzed by proline and its derivatives Me2bdc-Pro (bdc = 1,4-benzenedicarboxylate) and Me2bpdc-Pro (bpdc = 4,4'-biphenyldicarboxylate). For each catalyst, our computationally predicted values at the M062X/6-31+G(d) level of theory with the SMD solvent model are in excellent agreement with experimental results reported in the literature. Electron-donating and electron-withdrawing groups (viz., SO3-, NMe2, SO3H, and NMe3+) were installed at the C4 position of the proline-based catalysts to study the impact of electrostatic effects on stereoselectivity. The electron-donating groups decrease and even invert the enantioselectivity, while the electron-withdrawing ones increase it. Enantiomeric excesses in the range of 49-71 and 59-68% are predicted for Me2bdc-Pro and Me2bpdc-Pro catalysts with the electron-withdrawing SO3H and NMe3+installed respectively, values much higher than those of the corresponding unmodified catalysts. More interestingly, enantiomeric excesses decrease and, in the case of SO3-, are even inverted in favor of the other enantiomer when the electron-donating groups are installed. These results highlight the importance of electrostatic effects, and polar effects more generally, in optimal organocatalyst design for stereoselective C-C bond-forming reactions.
2. Synthesis and some pharmacological properties of Z-Tyr(SO3H)-Met-Gly-Trp-Met-Asp(Phe-NH2)-OH, a 32-beta-aspartyl analogue of cholecystokinin (pancreozymin) 27-33
V Mutt, M Bodanszky, J D Gardner, M D Walker, F Winternitz, J Martinez J Med Chem . 1982 May;25(5):589-93. doi: 10.1021/jm00347a019.
The heptapeptide carbobenzoxy-L-tyrosyl(O-sulfate)-L-methionylglycyl-L-tryptophyl-L-methionyl-L- aspartyl-beta-L-phenylalanine amine (Z-32-beta-Asp-CCK-27-33) was synthesized and tested for its ability to stimulate secretion from dispersed pancreatic acini in vitro, to increase protein secretion from cat pancreas in vivo, and to cause contraction of guinea pig gallbladder in situ. In increasing amylase secretion in vitro, the Z-32-beta-Asp-CCK-27-33 was equal in efficacy with but approximatively one-third as potent as the Boc-CCK-27-33, and when tested in vivo its activity is approximately 10 Ivy dog units (Idu)/microgram. In stimulation of the contraction of the gallbladder, it showed an activity lower than 1 Idu/microgram. This analogue has more pancreozyminic activity than cholecystokin-like activity. This seems to indicate different affinities for the two receptors.
3. Solid phase synthesis of a fully active analogue of cholecystokinin using the acid-stable Boc-Phe (p-CH2) SO3H as a substitute for Boc-Tyr(SO3H) in CCK8
F Bergeron, D Ficheux, B P Roques, J Pothier, R Gonzalez-Muniz, C Durieux, F Cornille Int J Pept Protein Res . 1991 Apr;37(4):331-40. doi: 10.1111/j.1399-3011.1991.tb00747.x.
Substitution of the -OSO3H group in the sulfated-tyrosine by the non-hydrolyzable-CH2SO3H group was the first described modification of the sulfate ester that does not affect CCK8 activity. In addition to its capacity to mimic the sulfated tyrosine residue, the amino acid Phe(p-CH2SO3Na) was shown to be stable in acidic media, including HF containing mixtures. The synthesis of Boc-Phe(p-CH2SO3Na)-OH in racemic and resolved forms and its introduction into the sequence of CCK8 by solid phase using standard Boc/benzyl synthesis conditions and BOP as coupling reagent is now reported. The two CCK8 analogues containing the L- or the D-Phe(p-CH2SO3Na) residue, obtained in satisfactory yields, were separated by HPLC and the stereochemistry of Phe(p-CH2SO3Na) residue in each peptide was established by NMR spectroscopy and confirmed by a separate solid phase synthesis in which the pure L isomer was used. Both CCK8 analogues displayed high affinities for peripheral and central receptors (KI approximately 1 nM) and proved to be full agonists in the stimulation of pancreatic amylase secretion. The "stabilized-CCK8 peptide", easily prepared by solid phase, could replace the native peptide in biochemical and pharmacological studies. Moreover the modified amino acid Phe (p-CH2SO3Na) could also be used in solid phase synthesis to prepare a wide variety of CCK analogues and more generally, peptides analogues containing the acid-labile O-sulfated tyrosine.
