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 <i>C</i><sub>2</sub> (sigma plane or axis), <i>C</i><i><sub>s</sub></i>, and <i>C</i><sub>2</sub><i><sub>v</sub></i> point groups in molecules. Natural products that possess chirality in the form of <i>C</i><sub>2</sub>-axes or sigma planes of symmetry are present in higher proportions (69%) compared to molecules bearing achiral <i>C</i><i><sub>s</sub></i> or <i>C</i><sub>2</sub><i><sub>v</sub></i> point groups (14% and 16%, respectively). Density functional theoretical and semiempirical calculations indicate that the dimers 3,3‘-dibromo-5,5‘-[<i>N</i>-(2-(3-bromo-4-hydroxyphenyl)ethyl)-2-hydroxyiminoacetamide]biphenyl-2,2‘-diol (<b>1</b>), (<i>S</i>,<i>S</i>)-1,2-bis(2-amino-3<i>H</i>-imidazol-4-yl)-(<i>R</i>,<i>R</i>)-3,4-bis(1<i>H</i>-pyrrole-2-amido)cyclobutane (<b>2</b>), 2-oxo-dimethyl-1,3-bis(3,4-dibromobenzene-1,2-diol) (<b>11</b>), 1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (<b>12</b>), and bis(5-isopropyl-8-methylazulene)methane (<b>13</b>) 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 <b>1</b>,<b> 2</b>, and <b>11</b>−<b>13 </b>appear to represent “missing” compounds in nature. Natural products <b>1</b>,<b> 2</b>, and <b>11</b>−<b>13</b>, 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.