Stereoselective Synthesis of Axially Chiral 5,5′-Linked bis-1-Arylisochromans with Antibacterial Activity

Inspired by naturally occurring <i>bis</i>-isochromans such as penicisteckins, we envisaged the first synthesis of biaryl-type <i>bis</i>-1-arylisochromans containing a stereogenic <i>ortho</i>-trisubstituted biaryl axis. We achieved the stereoselective synthesis of 5,5'-linked heterodimeric <i>bis</i>-isochromans containing both central and axial chirality elements by performing diastereoselective Suzuki-Miyaura biaryl coupling reactions on two optically active 1-arylpropan-2-ol derivatives, followed by two oxa-Pictet-Spengler cyclizations with aryl aldehydes or methoxymethyl chloride. We studied the diastereoselectivity of the cyclization step, separated the stereoisomeric products with chiral preparative HPLC and determined the absolute configuration through a combination of vibrational circular dichroism (VCD), NMR and single-crystal X-ray diffraction analysis. We demonstrated that different aryl groups could be introduced into the two isochroman subunits, since the dimethoxyaryl subunit reacted faster, enabling the two oxa-Pictet-Spengler cyclizations to be performed separately with different aryl aldehydes. We also explored the acid-catalyzed isomerization and oxidation to axially chiral <i>ortho</i>-quinones in order to produce stereoisomeric and oxidized analogs, respectively. We identified the antibacterial activity of our target <i>bis</i>-isochromans against <i>Bacillus subtilis</i> and <i>Enterococcus faecalis</i> with minimum inhibitory concentrations down to 4.0 and 0.5 μg/mL, respectively, which depend on the stereochemistry and substitution pattern of the <i>bis</i>-isochroman skeleton.