Stereostructure Assignment of Medium-Sized Rings through an NMR−Computational Combined Approach. Application to the New Germacranes Ketopelenolides C and D

Abstract

The new germacrane derivatives ketopelenolides C and D have been isolated from great mugwort (Artemisia arborescens). Their stereostructure elucidation exemplifies some of the most common pitfalls facing the configurational assignment of medium-sized polyfunctionalized compounds. It was established through a combined strategy including chemical derivatization, NMR data analysis, molecular modeling, and quantum-mechanical calculations including a comparison between experimental 13C NMR data and a Boltzmann-weighted average of DFT-calculated 13C NMR chemical shifts.

Quantum Mechanical Calculation of NMR Parameters in the Stereostructural Determination of Natural Products

“…[33] Even though germacrane derivative ketopelenolide C (8) presents five stereogenic carbon atoms, thanks to determination of the absolute configuration of C-1 by a modified Mosher's method [34] and analysis of the NMR spectroscopic data, only four stereoisomers 8a-d were considered as possible candidates for the configurational assignment (Scheme 6). In this case, the general 13 C-based protocol ( Figure 1) reported above was applied.…”

Use of Integrated Computational Approaches in the Search for New Therapeutic Agents

“…In the course of our experience in the field of redoxactive antimalarials, [19][20][21][22][23][24][25][26][27][28][29] we developed ac omputational protocol (summarized in Figure 6) which combines the exhaustive samplingo ft he conformational space of the ligands -b yu sing ac ombination of empirical (MD/MM) and semi-empirical (i.e.,P M6 and PM7; [96] Eigenvector Following routine [97] )m ethods -w ith density functional theory (DFT) calculations on the resulting conformers (Gaussian 09). [98][99][100] Depending on the caseu nder study, the ligands can be consideredi nt he neutral, ionized, and/or radical state.…”

“…At the same time, computational tools are evolving in the direction of combining molecular-mechanics (MM), molecular dynamics (MD), and quantum-mechanical (QM) methods in order to achieve an overall better simulation of the actual molecular behaviour. [13,14] In this context, in the course of our ongoing research on molecular recognition processes in biological systems, we experienceds everal multi-disciplinary research projects where ac ombination of experimental and computational techniques was applied to thes earch of new therapeutic agents.I nt he present paper,w er eview some examples of such research projects, in which we faced two common problems of current CADD: i) modeling of the dynamics of ligand-protein interactions (to identify new therapeutics againstc hemo-resistant solid tumors [15][16][17][18] )a nd ii)d esigning of redox-active chemotherapeutics (to develop new antimalarials from natural leads [19][20][21][22][23][24][25][26][27][28][29] ).…”

The application of empirical methods of 13C NMR chemical shift prediction as a filter for determining possible relative stereochemistry

“…[23] The stereochemistry shown in structures 3 and 4 was determined by authors [23] as a result of conformational analysis and QM based 13 C chemical shift calculation of the most probable stereoisomers. The calculations were performed in groups of four for each structure (C1-C4 for structure 3 and D1-D4 for structure 4, Fig.…”

“…The most probable stereoisomers of structures 3 and 4 selected for detailed theoretical analysis in the work. [23] www.interscience.wiley.com/journal/mrc selected in [23] were distinguished by the program as also deserving attention. For preliminary evaluation of the generality of the described approach we repeated the work using the structures of natural products belonging to a number of different classes, i.e.…”