W. Anthony Thomas

The design and synthesis of new triazolo, pyrazolo-, and pyridazo-pyridazine derivatives as inhibitors of angiotensin converting enzyme

Bicyclic mimetics of the antihypertensive, angiotensin converting enzyme (A.C.E.) inhibitor, captopril, have been designed with the aid of computer graphics. The synthesis and structure activity relationships of the three bicyclic systems tetrahydro[1,2,4]triazolo[1,2-a]-, hexahydropyrazoio[1,2-a]- and octahydropyridazo[1,2-a]-pyridazinediones are described. The compounds with the terminal carboxy group, the thiol, and the amide carbonyl function orientated most closely to correspond to the three-dimensional array of these groups in bound captopril are the most active inhibitors of angiotensin converting enzyme, in vitro.

Conformational analysis. Part 28. OH⋯F hydrogen bonding and the conformation of trans-2-fluorocyclohexanol

The 1H and 13C NMR spectra of trans-2-fluorocyclohexanol 1 and the methyl ether 2 have been obtained in a variety of solvents and temperatures. From the low-temperature spectra the proportions of the ax–ax and eq–eq conformers were obtained by direct integration together with the vicinal HH couplings of the 2-proton in the dominant eq–eq conformer. From these results the conformer populations and energies in a variety of solvents are given.In 1 ΔG(aa–ee) varies from 1.5 kcal mol–1(1 cal = 4.184 J) in non polar solvents (e.g. CCl4) to ca. 1.2 kcal mol–1 in very polar solvents (acetone), whereas in 2 the corresponding values are 0.4 and 1.0 kcal mol–1. The proton donor solvents CDCl3 and CD2Cl2 are exceptions due to preferential CH⋯O hydrogen bonding in the eq–eq form.These figures are explained by solvation theory, which also provides the vapour state free energy differences of 1.6 kcal mol–1 1 and 0.1 kcal mol–1 2. In 1 ΔS is zero and ΔH equals ΔG but in 2 values of ΔS of 2.0 cal mol–1 K–1 and of ΔH of 1.1 kcal mol–1 in non polar media and 0.7 kcal mol–1 for the vapour are obtained. These values may be compared with those calculated by ab initio theory at the 6-31G*(MP2) level of 1.1 kcal mol–1 1 and –0.75 kcal mol–1 2. In both cases the eq–eq conformer is more stable than predicted, by 0.5 and 1.5 kcal mol–1.Comparison of the conformer energies with those obtained from the ΔG values for the monosubstituted cyclohexanes gives the OH⋯F hydrogen bonding attraction in the eq–eq conformer as 1.6 kcal mol–1 whilst the gauche OMe⋯F interaction is neutral, neither repulsive nor attractive. These figures support previous theoretical interpretations that the gauche form of 2-fluoroethanol is predominant due to OH⋯F hydrogen bonding and show also that the previous discrepancy between experimental measurements in the condensed phase and theory is due to solvation.

The design of a new group of angiotensin-converting enzyme inhibitors.

Using X‐ray and NMR data relating to the conformation of the antihypertensive, angiotensin‐converting enzyme inhibitor, captopril, and structure—activity relationships of analogues, it has been possible to postulate with the aid of computer graphics, the orientation of the three functions, the thiol, the terminal carboxyl and the carbonyl group which are involved in binding to the enzyme. Bicyclic mimetics of captopril, with related arrays of these functions, have been designed and synthesized. Compounds with the closest approximation to the array in captopril are the most active inhibitors of angiotensin converting enzyme, in vitro.

Conformational Analysis Part 26—An Objective Method for Determining Conformer Populations and Coupling Constants in NMR Spectroscopy

An objective method of obtaining conformer populations and coupling constants from molecules rapidly interconverting between a number of conformers is given. The method relies on the acquisition of a sufficient data set by varying the solvent and/or temperature until the system is over‐determined with more equations than unknowns. No assumptions concerning either the conformer populations or couplings are necessary. The general conditions for an over‐determined data set are derived for systems interconverting between two and three conformers, and illustrative examples are given of 1,2‐dichloro‐1‐fluoroethane (1) 1,1,2‐trifluoroethane (2) and trans‐2‐fluoro‐3‐hydroxy‐tetrahydronaphthalene (3). The analysis of the vicinal H–H and H–F couplings of 1 in seven solvents of different polarities gave the couplings and relative energies of the three interconverting conformers. Extrapolation to the vapour using solvation theory gives ΔE (g→t) = 0.8 kcal mol−1 and ΔE (g′→t) = 1.1 kcal mol−1 (1 kcal = 4.184 kJ). A similar analysis of the solvation dependence of the vicinal couplings of 2 shows that the vicinal F–F couplings cannot be used to derive the conformer energies. An alternative treatment based on solvation theory gives the vicinal H–H and H–F couplings in the two interconverting conformers. The direct analysis of the solvent dependence of the couplings of 3 in seven solvents gives the conformer couplings in the two equilibrating half‐chair conformers and the energy differences ΔE (ax, ax→eq, eq) which vary from 1.2 kcal mol−1 in CCl4 solution to 0.21 kcal mol−1 in DMSO.

Nuclear magnetic resonance studies and conformational analysis of bicyclic inhibitors of angiotensin-converting enzyme. Part 2. The octahydro-6H-pyridazo[1,2-a][1,2]diazepines

The conformations are determined of a number of bicyclic heterocycles synthesised as part of a programme related to the design of inhibitors of angiotensin-converting enzyme (ACE). In these compounds, a six-membered ring is fused to a seven-membered ring via a diaza bridge. By detailed 1H n.m.r. spectroscopy, the 6-oxo series is shown to be rigid with the axial 1-carboxy anchoring the system. In the 6-deoxy series some flexibility in the seven-membered ring is apparent, though nitrogen inversion is prevented. X-Ray diffraction, molecular graphics, and MNDO calculations are employed to assist in the conformational analyses. The three-dimensional arrangement of the three enzyme-binding groups in these compounds provides very potent inhibitors (l50 1.6–3nM).

Conformational analysis. Part 21. Conformational isomerism in cis-cyclohexane-1,3-diol

cis-Cyclohexane-1,3-diol (CHD) has been isolated from a cis/trans isomeric mixture by first synthesizing the cyclic acetal 2,4-dioxabicyclo[3.3.1]nonane (D). The 1H NMR spectra of CHD, D, cis-and trans-4-tert-butylcyclohexanol and tert-butylcyclohexane are reported. 1H NMR parameters obtained have enabled calculation of the Gibbs free energy change (ΔG°) for the diequatorial ⇔ diaxial equilibrium of CHD in 14 solvents. Values for ΔG° range from 0.1 kcal mol–1 in CCl4 to 2.7 kcal mol–1 in aqueous solution in favour of the conformation in which both hydroxy groups are equatorial. Similar measurements on cyclohexanol show that the ΔG° value of the hydroxy group in inert solvents CCl4 and CDCl3 has a significant concentration dependence. The value of 0.9 kcal mol–1 for ΔG° characteristic for protic solvents in 1 mol dm–3 solutions decreases to the lower value of 0.7 kcal mol–1 characteristic of a free OH group in <10–2 mol dm–3 solutions. There was no concentration dependence of the ΔG° value (0.80 kcal mol–1) in acetone solution.These results when considered with the results for CHD show: (i) there is no intramolecular hydrogen bonding in CHD in water, alcohols or strong hydrogen bond acceptor solvents e.g. acetone or DMSO. The differences in the observed ΔG° values in these solvents can be attributed to (a) the varying polarity of the solvent and (b) to increased preferential solvation of the diequatorial isomer in HBD solvents. (ii) An intramolecular hydrogen bond of ca. 1.6 kcal mol–1 energy is formed in CHD in CCl4 solution. This hydrogen bond may be present in the more polar solvents, but its effect is much less noticeable.

A nuclear magnetic resonance and theoretical investigation of the effect of charge and solvation on the conformations of 1,2-disubstituted ethanes

The conformational energies of a number of 1,2-disubstituted ethanes (CH2X·CH2Y) have been obtained by ab initio and MNDO calculations (i.e. for the vapour phase) and by 1H n.m.r. spectroscopy (for aqueous solutions). There is generally good agreement between theory and experiment for the neutral molecules. The 2-halogenoethylamines (X = F or Cl, Y = NH2), 3-chloropropionic acid (X = Cl, Y = CO2H), and succinic acid (X = Y = CO2H) all favour the gauche conformer, whereas ethylenediamine (X = Y = NH2) has no conformational preference.For the charged molecules, although theory correctly predicts the direction of the conformer energy changes on ionisation of the amino and carboxy groups, it vastly overrates the extent of these changes. The most extreme case is β-alanine zwitterion (X =+NH3, Y = CO2–), which is predicted to be wholly in the gauche form (by 10–30 kcal mol–1), yet which shows no conformational preference in aqueous solution (ΔEg–t– 0.1 kcal mol–1).These results suggest that in carrying out molecular mechanics calculations on molecules containing charged groups exposed to aqueous solution, the dominant effect of the solvent in ‘neutralising’ the electrostatic interactions of the charged species must always be considered.

The synthesis and rotational isomerism of 1-amino-2-imidazol-4-ylethylphosphonic acid [phosphonohistidine, His(P)] and 1-amino-2-imidazol-2-ylethylphosphonic acid [phosphonoisohistidine, Isohis(P)]

The synthesis of phosphonohistidine [His(P)] and phosphonoisohistidine [Isohis(P)] is described, in each case by a strategy in which the α-aminophosphonic acid grouping is assembled first and the imidazole ring is built last. The key α-aminophosphonic acid building block is phosphonoaspartic acid, protected as the N-acetyl phosphonate diethyl ester derivative. The n.m.r. spectra of histidine, isohistidine, phosphonohistidine, and phosphonoisohistidine are analysed at three pH values, using an iterative spin simulation program to confirm results where necessary. The preferred conformations of the four compounds are determined from vicinal H,H and H,P coupling constants. This allows prediction of the conformational differences to be expected in replacing carboxylate by phosphonate groups. In free energy terms, phosphonate appears to exert a larger steric effect than carboxylate by ca. 1 kcal mol–1.

An experimental and theoretical investigation of orientational dependence of H–F couplings in fluoro-olefins

The 1H and 19F n.m.r. spectra of several monofluoro-olefins are reported. Coupling of vinylic fluorine to hydrogen bound to sp3-hybridised carbon has been observed over three, four, and five bonds. The four-bond ‘allylic’ F–H coupling has been examined in detail, with FPT-INDO calculations for several cases. The trans-CH·C:CF coupling changes sign as the HC·C:C torsion angle varies, as predicted, but the cis-CH·C:CF coupling is positive for all H·C·C:C angles, contrary to predictions. Alkyl substituents have an appreciable effect on the allylic couplings; this effect is primarily due to changes in geometry on substitution. The 5JHF couplings are also sensitive to orientation; in particular, the observation of a cis-5JHF coupling depends on the proximity of the fluorine and the coupled hydrogen.

1H NMR studies on cyclo[-Arg(Mtr)-Gly-Asp(But)-Ser(But)-Lys(Boc)-] and cyclo(-Arg-Gly-Asp-Ser-Lys-), cyclic analogues of the ‘adhesion’ domain of fibronectin

High-field 1H NMR techniques in DMSO solution, augmented by a comparison with calculated conformations based on cyclo(-Ala-Gly-Ala-Ala-Ala-), and restrained molecular dynamics calculations have revealed preferred conformations for both of the conformationally constrained-Arg-Gly-Asp-Ser-analogues studied. A type II′β-turn spanning Gly-Asp and a slightly less stable γ-turn at the Lys residue were revealed for both peptides.