Nuclear magnetic resonance (NMR) spectroscopy is one of the most important tools for determining the structures of organic molecules. Despite the advances made in this technique, revisions of erroneously established structures for natural products are still commonly published in the literature. In this context, the prediction of chemical shifts through ab initio and density functional theory (DFT) calculations has become a very powerful tool for assisting with the structural determination of complex organic molecules. In this work, we present the development of a protocol for (13)C chemical shift calculations of terpenes, a class of natural products that are widely distributed among plant species and are very important due to their biological and pharmacological activities. This protocol consists of GIAO-DFT calculations of chemical shifts and the application of a parameterized scaling factor in order to ensure accurate structural determination of this class of natural products. The application of this protocol to a set of five terpenes yielded accurate calculated chemical shifts, showing that this is a very attractive tool for the calculation of complex organic structures such as terpenes.
IntroductionIn the last decades, Nuclear Magnetic Resonance (NMR) spectroscopy has established itself as one of the most important techniques for structural determination of natural products. 1 Despite the current advances in multidimensional techniques and in probe technology, 1,2 instances of revision of structures erroneously established for natural products are still common in the literature. 3 With the recent development of quantum mechanical methods and the availability of modern computers, the prediction of chemical shifts through ab initio and Density Functional Theory (DFT) calculations has become a very powerful tool for assistance in the assignment of chemical shifts and in the structural determination of complex organic molecules, such as natural products. [4][5][6] With the aim to achieve a good ratio between accuracy and computational cost, calculated chemical shifts can be corrected through the use of scaling factor procedures. It has been established in the literature that the application of this approach can reduce systematic errors inherent in theoretical calculations. 6 Even though in recent years there has been the development of several scaling factors, 7-11 there are no studies in the literature reporting the use of scaling factors parameterized for a specific class of natural products.In this work, we present the development of a calculation protocol for terpenes, a class of natural products with a board distribution among plant species and with great importance due to its biological and pharmacological activities. 12 This protocol consists of GIAO-DFT calculations of chemical shifts and application of a scaling factor parameterized with terpenes, in order to ensure accurate structural determination of this class of natural products. MethodsIn order to reduce the computational costs in our calculations, we parameterized the scaling factor using sesquiterpene molecules, a sub-class of terpenes with structural frameworks containing only 15 carbon atoms. 13 A set of 10 sesquiterpene molecules (figure 1), whose structures have been reliably elucidated in literature, [14][15][16][17][18][19][20][21][22][23] were selected and submitted to randomized conformational searches using Monte Carlo method and MMFF force field. The most significant conformations of each compound, considering an initial energy cutoff of 10 kcal.mol -1 , were selected to single-point energy calculations at the B3LYP/6-31G(d) level of theory. All conformations within 5 kcal. mol -1 of energy were selected to geometry optimization calculations carried out at the mPW1PW91/6-31G(d) level of theory. Population-averaged ¹³C nuclear magnetic shielding constants (δ) were calculated using GIAO method at the same level of theory and assuming Boltzmann statistics. Chemical shifts (δ) were obtained as δ calc = δ TMS -δ, where δTMS is the shielding constant of the reference compound, tetramethylsilane (TMS), calculated at the same level of theory. All quantum mechanical calculations were performed in gas phase, using Gaussian 09 softwar...
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