Stereochemistry of furofuran lignans from optical rotatory dispersion: potential and pitfalls
Abstract
The absolute configuration assignment of chiral secondary metabolites is one of the main bottlenecks in natural product chemistry. Many methods are available to solve this structural puzzle, such as X-ray crystallography, nuclear magnetic resonance, and chiroptical spectroscopy. Among chiroptical spectroscopic methods, optical rotation (OR) and electronic circular dichroism have been by far the most frequently used by natural product chemists. Such a use, however, has been predominantly based on empirical comparisons of data obtained for structurally related molecules. This is a risky approach especially considering optical rotation, which is commonly obtained at a single wavelength (sodium D line). Besides the wavelength range, another important aspect in chiroptical spectroscopy is the effect of solvents on the properties of interest. Recently, we have demonstrated the impact of solvents of different polarities and H-bond capabilities on the vibrational circular dichroism of furofuran lignans. In order to further investigate the solvation effects on the chiroptical properties of this class of secondary metabolites, as well as to explore more reliable protocols to assign absolute configuration based on OR, herein, we present a systematic experimental and theoretical investigation of the optical rotatory dispersion (ORD) of a series of furofuran lignans in CH 3 CN, CHCl 3 , and CH 3 OH. Specific rotations were measured at 589, 578, 546, 436, 405, and 365 nm and compared to DFT simulations at the B3LYP/PCM/6–311G++(d,p) level. Comparisons between experimental and calculated data revealed that the absolute configurations of the target lignans could be unambiguously assigned in all cases, but that of sesamin (2) in CH 3 OH solution. The latter case was then investigated using molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) calculations. Our results indicate that CHCl 3 is the preferable solvent for ORD, while CH 3 OH should be used with caution as it unpredictably affects the simulations of electronic properties of this class of natural products.