Molecular Bilateral Symmetry of Natural Products:  Prediction of Selectivity of Dimeric Molecules by Density Functional Theory and Semiempirical Calculations

A literature survey and theoretical calculations have been applied to explore bilateral symmetry in natural product systems. Molecular bilateral symmetry is defined to include C₂ (sigma plane or axis), C_s, and C_2v point groups in molecules. Natural products that possess chirality in the form of C₂-axes or sigma planes of symmetry are present in higher proportions (69%) compared to molecules bearing achiral C_s or C_2v point groups (14% and 16%, respectively). Density functional theoretical and semiempirical calculations indicate that the dimers 3,3‘-dibromo-5,5‘-[N-(2-(3-bromo-4-hydroxyphenyl)ethyl)-2-hydroxyiminoacetamide]biphenyl-2,2‘-diol (1), (S,S)-1,2-bis(2-amino-3H-imidazol-4-yl)-(R,R)-3,4-bis(1H-pyrrole-2-amido)cyclobutane (2), 2-oxo-dimethyl-1,3-bis(3,4-dibromobenzene-1,2-diol) (11), 1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (12), and bis(5-isopropyl-8-methylazulene)methane (13) evolve more energy per connecting bond than the corresponding trimers or tetramers would. This we propose is a guiding parameter that may adjust molecule growth. The corresponding trimers, tetramers, or higher oligomers of 1, 2, and 11−13 appear to represent “missing” compounds in nature. Natural products 1, 2, and 11−13, having 3-fold and higher levels of symmetry, would founder on the lack of a facile method of synthesis and on the prohibitively high-energy costs caused by steric crowding at their core.