Stereoselective synthesis, VCD study and conformational analysis of C-glycosyl isochromans

Isochromans and aryl-C-glycosides are important structural motifs in many natural products and drug candidates with diverse therapeutic potentials. Here we present the first application of pyranosyl aldehydes in the oxa-Pictet-Spengler cyclization to conjugate the two pharmacophore motifs. Enantiomeric pairs of aryl-2-propanols were reacted with pyranosyl dialdoses and 1-formyl sugars in a BF₃·Et₂O-mediated oxa-Pictet-Spengler reaction. The effects of the substitution pattern, configuration, and protecting groups of the reactants on the efficiency and stereochemical outcome of the reactions were studied, and the reaction conditions were optimized. A series of 1,3-cis-substituted 1-(C-glycosyl)isochromans was prepared in high yields with good to complete stereoselectivity from glucosyldialdoses and 1-formyl glucopyranosides. The reaction efficiency dropped significantly with galacto-dialdose derivatives due to steric hindrance, leading to lower yields and anomerization, which slightly limits the universality of the method. ROESY-NMR, X-ray diffraction, and VCD methods were used to determine the structure and the absolute configuration of the compounds. The method developed represents a straightforward and stereocontrolled route to a new chemotype of isochroman C-glycosides.