Enantioselective Synthesis of 3-Methylisochromans and Determination of Their Absolute Configurations by Circular Dichroism†

Seven (S)-3-methylisochromans with different substitution patterns on their aromatic rings, and hence with different directions of their sum electric transition moments, were synthesized by ring-closure of optically active (S)-1-arylpropan-2-ol derivatives. The (S)-1-arylpropan-2-ols were obtained by kinetic resolution and their absolute configurations were determined with the aid of a zinc porphyrin tweezer and by Mosher’s method. A systematic CD study of substituted isochroman derivatives revealed that, unlike in the cases of chiral tetralin and 2,3-dihydrobenzo[b]furan chromophores, the presence of achiral substituents of large spectroscopic moment (e.g., OMe) on the aromatic ring does not change the helicity rule of the “unsubstituted” isochroman chromophore: (P)/(M) helicity of the isochroman heteroring resulted in positive/negative1Lb band Cotton effects (CE) regardless of the nature(s) and position(s) of the substituent(s). (S)-3-Methylisochromans were oxidized at C-1, allowing access to the corresponding dihydroisocoumarins, in which positive CE of the nπ* transitions were correlated with (P) helicity and (S) absolute configuration. On DDQ-assisted oxidation, two trans-1-methoxy-3-methylisochroman derivatives were prepared and used to study the effect of the axial benzylic C-1 methoxy group on the conformation of the heteroring and the 1Lb band CE. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)