Calculated and Experimental NMR Chemical Shifts of p-Menthane-3,9-diols. A Combination of Molecular Dynamics and Quantum Mechanics to Determine the Structure and the Solvent Effects

Abstract

NMR chemical shifts have been experimentally measured and theoretically estimated for all the carbon atoms of (1R,3S,4S,8S)-p-menthane-3,9-diol in chloroform solution. Theoretical estimations were performed using a combination of molecular dynamics simulations and quantum mechanical calculations. Molecular dynamics simulations were used to obtain the most populated conformations of the (1R,3S:4S,8S)-p-menthane-3,9-diol as well as the distribution of the solvent molecules around it. Quantum mechanical calculations of NMR chemical shifts were performed on the most relevant conformations employing the GIAO-DFT formalism. A special emphasis was put in evaluating the effects of the surrounding solvent molecules. For this purpose, supermolecule calculations were performed on complexes constituted by the solute and n chloroform molecules, where n ranges from 3 to 16. An excellent agreement with experimental data has been obtained following this computational strategy.

Understanding Sterol–Membrane Interactions Part I: Hartree–Fock versus DFT Calculations of 13C and 1H NMR Isotropic Chemical Shifts of Sterols in Solution and Analysis of Hydrogen‐Bonding Effects

“…These deviations are essentially identical to those obtained for different molecular systems using different theoretical approach. [32,[39][40][41] Consequently, we are confident about our calculations and we can conclude that HF calculation of isotropic chemical shifts with the 6-31G(d,p) basis set on HF/ STO3-G-optimized geometry is a good alternative for reproducing the experimental NMR spectrum of cholesterol with sufficient accuracy.…”

“…However, it has been recently shown that STO-3G basis set is able to capture the solvent effects in the determination of NMR chemical shifts. [39] A smaller molecular system was also used to demonstrate that one can reduce the computational effort for such study. Rings A and B were conserved in our molecular model of cholesterol, and C11 and C14 replaced by methyl groups.…”

Revision of the Stereochemistry of Elisabethatriene, a Putative Biosynthetic Intermediate of Pseudopterosins

“…The (1S,2S,5R,2′S)-MOM ether 5 is a known compound that can be prepared from commercially available (−)-(1R,3R,4S)-isopulegol. 12,13) The use of (−)-isopulegol would lead to the antipode of the target molecule 2b (1S,4R,9R,11S configuration). This is acceptable in the present study, because we are concerned with the relative stereochemistry of 2a.…”

“…The sample of (1R,3S,4S,2′S)-MOM ether 5 obtained by hydroboration-oxidation of the (1R,3S,4S)-neoisopulegol as described previously 12) was used in the present synthesis.…”

“…This reassignment confirmed that the identical stereochemical mechanism is operating in the enzymic formation of elisabethatriene and elisabethatrienol. A sesquiterpene analogue of elisabethatriene, nephthene (12), isolated from an Okinawan soft coral of Nephthea sp., 15) could be formed by an enzyme that cyclizes farnesyl diphosphate in the same stereochemical mode as 1 and 4. The present study indicated that the biosynthesis of pseudopterosins proceeds via compound 4, …”