Accurate (rms error ∼3 ppm) predictions of 13C chemical shifts are achieved for many of the common structural types of organic molecules through empirical scaling of shieldings calculated from gauge including atomic orbitals (GIAO) theory with a small basis set and with geometries obtained from computationally inexpensive molecular mechanics methods. Earlier GIAO calculations are shown to be much better at predicting relative chemical shifts when density functional theory with the B3LYP hybrid functional is used to account for electron correlation, in comparison with Hartree−Fock calculations. The GIAO isotropic shieldings need to be empirically scaled to achieve good numerical agreement with experimental δC. GIAO calculations with different small basis sets are compared for a set of 38 model compounds containing C, H, O, and N with MMX and MM3 force fields and B3LYP/6-31G* optimizations providing the geometries. The best MM3-based results are obtained with B3LYP/3-21G(X,6-31+G*)//MM3 calculations in which the 3-21G basis set is augmented for heteroatoms with polarization and diffuse functions. The examples of the (E)- and (Z)-2-butenes, axial and equatorial methylcyclohexanes, exo- and endo-2-norbornanols, vulgarin and epivulgarin, and chair and twist-boat forms of 3α-hydroxy-2β-(4-morpholinyl)-5αH-androstan-17-one are examined to establish whether δpred values could determine the structure if only one of each pair of structures were available to provide experimental δC values. The δpred from B3LYP/3-21G(X,6-31+G*)//MM3 calculations are adequate for addressing questions of conformation and relative stereochemistry.

The (13)C chemical shifts of six tertiary amines of unambiguous conformational structure are compared to predicted (13)C NMR chemical shifts obtained via empirically scaled GIAO shieldings for geometries from MM3 molecular mechanics calculations. An average deviation, absolute value of Deltadelta(av), of 0.8 ppm and a maximum deviation, absolute value of Deltadelta(max), of 2.8 ppm between predicted and experimental (13)C shifts of the six tertiary amines of unambiguous structure are found. In several cases of tertiary amines subject to rapid exchange, where experimental (13)C shifts at room temperature are weighted averages of multiple conformers, a comparison of calculated (13)C shifts of all reasonable MM3 predicted conformers with experimental (13)C shifts via a multiple independent variable regression analysis provides an efficient method of determining the major and minor conformers. The examples presented are 2-methyl-2-azabicyclo[2.2.1]heptane and 1,6-diazabicyclo[4.3.1]decane, which each have two expected contributing structures, and 2-(diethylamino)propane and 1,8-diazabicyclo[6.3.1]dodecane, where ten and seven low-energy conformers, respectively, are predicted by MM3 calculations.

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Differences in agonist responses of the novel estrogen receptor ligands (17alpha,20Z)-(p-methoxyphenyl)vinyl estradiol (1), (17alpha, 20Z)-(o-alpha,alpha,alpha-trifluoromethylphenyl)vinyl estradiol (2), and (17alpha,20Z)-(o-hydroxymethylphenyl)vinyl estradiol (3) led us to investigate their solution conformation. In competitive binding assay studies, we observed that several phenyl-substituted (17alpha, 20E/Z)-(X-phenyl)vinyl estradiols exhibited significant estrogen receptor binding, but with variation (RBA (1) = 20; RBA (2) = 23; RBA (3) = 140 where estradiol RBA = 100) depending on the phenyl substitution pattern. Because the 17alpha-phenylvinyl substituent interacts with the key helix-12 of the ligand binding domain, we considered that differences in the preferred conformation of 1-3 could account for their varying binding affinity. 2D NMR experiments at 500 MHz allowed the complete assignment of the (13)C and (1)H spectra of 1-3. The conformations of these compounds in solution were established by 2D and 1D NOESY spectroscopy. A statistical approach of evaluating contributing conformers of 1-3 from predicted (13)C shifts correlated quite well with the NOE data. The 17alpha substituents of 1 and 2 exist in similar conformational equilibria with some differences in relative populations of conformers. In contrast, the 17alpha substituent of 3 exists in a different conformational equilibrium. The similarity in solution conformations of 1 and 2 suggests they occupy a similar receptor volume, consistent with similar RBA values of 20 and 23. Conversely, the different conformational equilibria of 3 may contribute to the significant binding affinity (RBA = 140) of this ligand.

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