Experimental and Theoretical Studies on the Rearrangement of 2‐Oxoazepane α,α‐Amino Acids into 2′‐Oxopiperidine β2,3,3‐Amino Acids: An Example of Intramolecular Catalysis

Enantiopure β‐amino acids represent interesting scaffolds for peptidomimetics, foldamers and bioactive compounds. However, the synthesis of highly substituted analogues is still a major challenge. Herein, we describe the spontaneous rearrangement of 4‐carboxy‐2‐oxoazepane α,α‐amino acids to lead to 2′‐oxopiperidine‐containing β^2,3,3‐amino acids, upon basic or acid hydrolysis of the 2‐oxoazepane α,α‐amino acid ester. Under acidic conditions, a totally stereoselective synthetic route has been developed. The reordering process involved the spontaneous breakdown of an amide bond, which typically requires strong conditions, and the formation of a new bond leading to the six‐membered heterocycle. A quantum mechanical study was carried out to obtain insight into the remarkable ease of this rearrangement, which occurs at room temperature, either in solution or upon storage of the 4‐carboxylic acid substituted 2‐oxoazepane derivatives. This theoretical study suggests that the rearrangement process occurs through a concerted mechanism, in which the energy of the transition states can be lowered by the participation of a catalytic water molecule. Interestingly, it also suggested a role for the carboxylic acid at position 4 of the 2‐oxoazepane ring, which facilitates this rearrangement, participating directly in the intramolecular catalysis.     

Influence of the H/F replacement on the homoaromaticity of homotropylium ion: a GIAO/DFT theoretical study

The problem of homoaromaticity in mono-, di- and polyfluorinated- homotropylium cations is addressed by the B3LYP/6-311++G** DFT method. The energetic, structural and magnetic criteria are used for this purpose. They convincingly show that the ground state equilibrium species are aromatic, or in other words that the homoaromaticity is preserved by the (poly)fluorination. In contrast, a considerable decrease in the aromatic stabilization is observed in the transition structures (TS). According to the NICS(0) index, they vary form strongly antiaromatic, via weakly and non-aromatic to slightly aromatic transition states. However, the hierarchy of the aromaticity in fluorinated homotropylium ions predicted by NICS(0) is completely unrelated to that obtained by using the energy criterion assuming a kinetic definition of aromaticity. On the other hand the latter is closely related to geometric parameters of the equilibrium and transition structures.     

Theoretical study of peptide model dimers. Homo versus heterochiral complexes

The study of possible chiral recognition of a series of peptide models (For-Gly-NH₂, For-Ala-NH₂ and four of their fluoro substituted derivatives) has been carried out by means of DFT calculations. Homo (L,L) and heterochiral (L,D) dimers formed by hydrogen bond (HB) complexation have been considered. Initially, the conformational preferences of the monomers have been calculated and used to generate all the possible homo and heterochiral dimers. The energetic results show that in most cases, the β monomers are the most stable while in the dimers, the γ–γ complexes show the strongest interaction energies. In three of the four chiral cases studied, a heterochiral dimer is the most stable one. In addition, the electron density and nuclear shielding of the complexes have been studied.     

Study of the reaction of chalcone analogs of dehydroacetic acid and o-aminothiophenol: synthesis and structure of 1,5-benzothiazepines and 1,4-benzothiazines

Treatment of α,β-unsaturated carbonyl compounds, obtained by the reaction of DHA and aromatic (or heteroaromatic) aldehydes, with o-aminothiophenol results in the formation of 1,5-benzothiazepines and/or 1,4-benzothiazines depending upon the reaction conditions and structure of the aldehydes. The products were characterized by the combined use of multinuclear 1D and 2D NMR and GIAO/DFT calculations of ¹H, ¹³C and ¹⁵N chemical shifts. The tautomerism of these compounds in solution was determined, they have an exocyclic CC double bond.     

Ab Initio (GIAO) Calculations of Absolute Nuclear Shieldings for Representative Compounds Containing 1(2)H, 6(7)Li, 11B, 13C, 14(15)N, 17O, 19F, 29Si, 31P, 33S,and 35Cl Nuclei

Two kinds of ab initio calculations (B3LYP and HF) using the GIAO approach have been carried out for fifteen H, three Li, three B, eleven C, seven N, nine O, four F, three Si, four P, six S and five Cl containing derivatives. The calculated absolute nuclear shieldings have been compared with experimental absolute values (either measured or estimated from relative chemical shifts) when available or with relative chemical shifts (¹¹B, ³⁵Cl). The correlations range from good to excellent and only three compounds (PN, P₂H₂, SO₂) deviate significantly.     

The tautomerism of Omeprazole in solution: a 1H and 13C NMR study

The tautomerism of 5(6)-methoxy-2-([(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinyl)-1H-benzimidazole (omeprazole) was determined in solution, K(T) = 0.59 in THF at 195 K, in favor of the 6-methoxy tautomer. The assignment of the signals was made by comparison with its two N-methyl derivatives in acetone-d6 and through theoretical calculations of the absolute shieldings (GIAO/DFT/6-311++G**).     

Considerations on the recognition of the D1 receptor by agonists

Summary A model of the mechanism for recognition of the D1 receptor has been developed. Conformational analysis for 10 agonists from diverse chemical families was carried out as a first step toward the characterization of the bioactive form. First, maximum structural overlap of the features common to all ligands allowed a simple identification of the candidate bioactive form for each ligand. At a second level of characterization, steric and electronic properties were computed for all accessible structures to analyze those properties that may modulate receptor recognition.     

Comparison of methods to estimate the free energy of solvation:Importance in the modulation of the affinity of 3-benzazepines for the D1receptor

We computed the free energy of solvation for a series of ions and neutral molecules using two different continuum approaches. First, we used the AM1–SM1 technique, where the AM1 Fock matrix is modified to include a generalized Born contribution. Second, we applied the DelPhi approach, where the electrostatic component of the free energy of solvation is evaluated by resolving the Poisson–Boltzman equation by a finite difference method. Both methods appear equally reliable for ionic systems. For neutral compounds, AM1–SM1 performs better than DelPhi; however, the differences become less pronounced for compounds with larger free energies of solvation. In parallel, both methods were applied to study the influence of the solvation process in the overall drug receptor interaction for a series of closely related ligands for the D₁ dopamine receptor. An inverse linear relationship was found between the free energy of solvation and the logarithm of the affinity of the ligands; nevertheless, electrostatic properties are likely to modulate affinity as well. © 1993 John Wiley & Sons, Inc.     

A theoretical investigation of the mechanism of formation of a simplified analog of the green fluorescent protein (GFP) from a peptide model

Theoretical calculations at the B3LYP/6-311++G(d,p) level have been carried out on the reaction path connecting a dipeptide to an imidazolinone as a model for the formation of GFP. In addition, we have studied the hydration effects on the processes, adding a water molecule to assist the cyclization. The solvent effects have been taken into account by introducing the monohydrated molecules into a solvent cavity with a polarized continuum model. Significant reductions of the energy barriers for the reaction path can be observed within the water-assisted processes. The solvent effects account for a barrier lowering of 4–5 kJ mol^?1.     

Multinuclear magnetic resonance studies of five silver(I) trinuclear pyrazolate complexes

Structural Chemistry - Experimental multinuclear determination of the chemical shifts, especially 15N and 109Ag, of five silver(I) trinuclear pyrazolate complexes, (PzAg)3, coupled with ZORA...