NMR Methods for Stereochemical Assignments

Abstract

Various NMR techniques have been developed that allow assignment of the relative and absolute configuration of many of the stereogenic carbons that occur in marine natural products. The application of chiral anisotropic reagents in conjunction with NMR analyses has been particularly useful for determining the absolute configuration of secondary alcohols, α-substituted primary amines, and α-substituted carboxylic acids. Derivatization of these functional groups with appropriate chiral reagents (e.g., MTPA) provides diastereomeric products that have diagnostic differences in their ¹H chemical shifts. A recently developed technique known as J-based configurational analysis uses proton–proton couplings and 2- and 3-bond carbon–proton couplings (^2,3 J _CH) to assign the relative configuration of adjacent (1, 2) stereogenic carbons in conformationally flexible molecules. The J-based method involves comparing experimentally measured scalar couplings and NOE interactions with those predicted from this model to assign the relative configuration of the chiral methines. This technique is also applicable to oxygenated systems since there is a dihedral angle dependence for ² J _CH couplings between a proton and an adjacent carbon that bears an electronegative oxygen substituent. Strategies have also been developed to utilize J-based configurational analysis when there is a methylene separating the two stereogenic methine carbons, and even when conformational interconversion results in the coexistence of two major conformers.