Molecular Study on the Enantiomeric Relationships of Carvedilol Fragment A, 4-(2-Hydroxypropoxy)carbazol, along with Selected Analogues

Abstract

Chirality and activity relationships are paramount to pharmaceutical design and synthesis. Generally, point chirality (enantiomeric R and S configurations) is emphasized most in molecules and drugs; however, axis chirality (present when structures adopt conformations with asymmetrical distributions of electron density) must also be considered as a stereogenic unit of interest. Together, stereogenic units and optical isomerism describe the chiral disposition of electron density about nuclei. In this essence, different components of chirality are always present in molecular systems. In assessing the different chiral parameters of pharmaceuticals, the cardiovascular drug carvedilol serves as an ideal example because both enantiomers produce different physiological effects. In the current study, R- and S-4-(2-hydroxypropoxy)carbazol (carvedilol fragment A), along with prochiral and chiral analogues, are studied to investigate the chiral components of carvedilol. Further, the effects of substituent variation about a stereocenter are investigated and discussed using conformational energy as a surrogate of structure (based on the fact that energy is a function of molecular spatial orientation) to determine the energetic equivalency of prochiral and chiral structures. Multidimensional conformational analysis (MDCA) was performed on selected structures using restricted Hartree−Fock (RHF) and density functional theory (DFT with the Becke 3LYP hybrid exchange-correlation functional) molecular orbital computations to elucidate the structural and energetic basis of chirality. The analogues had the following prochiral and chiral structures: R−CH2−OH, [R] and [S] R−CHMe−OH, and R−CMe2−OH, with substituent R being either MeCH2- or ArCH2-, where Ar is the carbazole moiety. Potential energy curves (PECs) of torsional angles χ1, χ2, χ3, and χ10 for R- and S-4-(2-hydroxypropoxy)carbazol verified that all torsional angles are indeed enantiomeric. Correspondingly, the potential energy hypersurfaces (PEHSs) of R- and S-4-(2-hydroxypropoxy)carbazol were also enantiomeric, as illustrated with optimizations of conformational minima; converged minima occurred in equivalent point chiral and axis chiral pairs. Similarly to R- and S-4-(2-hydroxypropoxy)carbazol, achiral and chiral analogues analyzed by MDCA displayed axis chirality while chiral structures displayed both axis and point chirality. As such, the presence of point and axis chirality in molecular systems allows predictions to be made concerning the orientations of viable conformations of a respective PEHS. Further, the data indicate that chirality induced by an asymmetric distribution of electron density (axis chirality) is always present whenever a structure adopts asymmetric conformations. Like enantiomers of point chirality, axis chiral conformers also occur in pairs. Potential energy surfaces (PESs) were generated about the prochiral and chiral centers for all structures at the RHF/3-21G level of theory and used to test the equivalency of conformational energy between sufficiently constructed achiral and chiral structures. It is hypothesized that, with regard to conformational energy, the addition of two chiral enantiomers minus the addition of two achiral structures will give a zero result (assuming the only structural differences occur at the stereocenters). The combination of prochiral and chiral potential energy surfaces, according to an equation describing two consecutive and concerted methyl substitutions, gave a practically flat, virtually zero surface, indicating that sufficiently constructed achiral structures are energetically equivalent to chiral enantiomers. Thus, solely on the basis of molecular structure, chiral properties such as energy, number of converged conformers in a PEHS, conformations of corresponding point chiral and axis chiral pairs, and intramolecular interactions can be predicted from achiral structures. It remains to be seen how this can be utilized in drug research and development.