Computational Methods in Natural Products Chemistry
1. Key Words:
Use of force field, semiempirical, density functional, and ab-initio methods for the computational calculation of structures, dynamics, and chemical reactivities of molecules; computational correlation of biological activities with molecular structures (SAR) (see 'Naphthylisoquinoline Alkaloids', see also www.sfb630.de), prediction of NMR shifts; simulation of IR, Raman, and UV spectra; quantum chemical calculations of circular dichroism (CD) spectra for the assignment of the absolute configuration of novel-type compounds with stereogenic centers, or with elements of axial, planar, or helical chirality, or combinations thereof (see also 'Naphthylisoquinoline Alkaloids', 'Anthraquinones and Knipholones', 'Marine Natural Products', 'The TaClo Concept', 'The Lactone Concept', and 'Natural Product Synthesis'); combination of LC-CD coupling with quantum chemical CD calculations for the online elucidation of the absolute stereostructures of chiral compounds, directly from the peak in the chromatogram (see also 'Natural Product Analysis'); intense collaboration between experimentally and theoretically working researchers within the group, and numerous collaborations with external scientists from organic, inorganic, and physical chemistry, natural product chemistry, pharmacy, pharmaceutical biology, plant biochemistry, marine research, and microbiology.
For the calculations of ground-state properties, the following methods are in use:
- force fields (TRIPOS, MM3),
- semiempirical Hamiltonians (AM1, PM3),
- ab initio approaches (HF, MPn), and
- density functional theory (DFT).
The excited-states computations are performed with:
- semiempirical Hamiltonians (CNDO/S, INDO/S, OM2) combined with CI calculations,
- time-dependent density functional theory (TDDFT), and
- multi-reference methods (DFT/MRCI, MR-MP2).
2. Graphical Abstract:
Subtopic A: Circular Dichroism (CD) Calculations – Theoretical Background
Subtopic B: Absolute Stereostructures of Chiral Compounds by Quantum Chemical Calculation of CD Spectra
Subtopic C: Combination of LC-CD Coupling with Quantum Chemical CD Calculations
Subtopic D: Natural Products with Unusual CD Effects – Two Examples
3. Brief Description:
One of the most efficient if not ideal methods for the attribution of the absolute configuration of chiral compounds is the investigation of their circular dichroism (CD), which is often done by an empirical comparison with the spectral data of related compounds of known absolute configurations. More specific approaches to the interpretation of CD spectra are the application of the octant rule or of the exciton chirality method; the use of the former however is restricted to centrochiral ketones, the second one to systems containing two (near-)identical chromophores. By contrast, these restrictions are avoided by the quantum chemical calculation of the CD spectra for both enantiomers of a chiral molecule and comparison of these predicted spectra with the experimental ones [1-4]. This procedure has become a most valuable tool for assigning absolute configurations to a broad variety of chiral compounds of synthetic or natural origin, involving all kinds of chirality, not only stereogenic centers, but also axial and / or planar chirality [5-30]. The consistently extended approach to calculate the circular dichroism of organic molecules often facilitated the experimental work of natural product chemists of our research group [i.a., 5,7,8,17,20-25] and that of our scientific partners [i.a., 6,10,12,14,18,19,28,30]. The chiral structures shown in the Figures 2-10 represent a selection of compounds whose absolute configurations had previously been unkown, but were clearly assigned by theoretical CD investigations in our group.
Since the CD spectrum strongly depends on the molecular flexibility of the chromophors, more than for any other spectroscopic method, a detailed investigation of the conformational space is indispensable for the simulation of a CD curve. Starting with an arbitrarily chosen enantiomer of the chiral compound, a set of reasonable starting structures of the molecular framework is generated manually by taking into account the most relevant conformational freedom degrees of flexible substituents. These are then subjected to a refinement by investigating the corresponding rotations, usually at a semiempirical level (AM1, PM3), in order to find all minimum geometries that are significantly populated at ambient temperature. For all conformers thus obtained within an energetic cut-off of 3 kcal/mol above the global minimum, the single CD spectra are calculated and added up following the Boltzmann statistics, i.e., according to their energetic contents (see examples in Figure 2, Figure 3, Figure 4, and Figure 7).
For more flexible molecules, the absolute configuration can be assigned by replacing the AM1-/Boltzmann-based calculation by a molecular dynamics (MD) simulation, using different force fields like TRIPOS or MM3. Within this approach the different geometries for the calculation of the single CD spectra are extracted from the trajectory of the MD simulation. Averaging these single spectra over the trajectory results in the MD-based theoretical overall CD spectrum (see examples in Figure 5, Figure 9, and Figure 10).
In order to receive trustable wave functions for the ground state and the excited states, together with the corresponding energies, several methodologies are applicable. The most common one is the configuration interaction (CI) approach. Based on this method, our group has frequently applied the semiempirical CNDO/S and OM2 Hamiltonians with a CI expansion that covers single excitations (e.g., see Figure 2, Figure 3, Figure 4, and Figure 5). However, to account for the dynamic electron correlation, at least the double excitations have to be included in the CI progression, since the mere single ones do not interact with the ground state wave function. This is accounted for by likewise performing OM2-CISD calculations (see, e.g., Figure 3 and Figure 7) [1,2,4].
Another technique to compute electronic transitions uses the propagator method, which applies a time-dependent (TD) perturbation to the system, generated by a fluctuating linear electric field. This approach has been applied to both, the Hartree Fock (HF) and the density functional theory (DFT) method, while the latter one, TDDFT (TD = time dependent), is undoubtedly superior and nowadays frequently used. Besides the aforementioned semiempirical techniques, we also use TDDFT by default, adopting the B3LYP hybrid functional or BLYP, the latter one together with the resolution-of-the-identity (RI) approximation, each with a triple-zeta valence polarized basis set (TZVP) (see, e.g., Figure 4 and Figure 7) [3,4].
Before simulated and experimental CD curves are compared in order to attribute the respective absolute configuration, a correction step is performed that is able to compensate systematic computational errors. For that purpose the overall UV spectrum calculated by the same conformational analysis is compared with the measured UV curve and the shift necessary to match the peaks of the two graphs is determined. This wavelength scaling by UV matching (‘UV correction’) is easier and more unequivocal than for the CD spectra because of the usually larger number of – positive and negative – peaks of the latter. Our general strategy for quantum chemical calculation of CD spectra is schematically displayed in Figure 1 [1,4].
Besides the more detailed presentations in the Figures 2-5 [5-8], in Figure 7 , Figure 9 [28,29], and Figure 10 , a further selection of structurally most diverse natural and synthetic products with stereogenic centers or elements of axial or planar chirality stereochemically attributed by our CD calculations is given in Figure 6 [9-18] and Figure 8 [20-27], the latter one shows intriguing compounds whose absolute configurations have been established by LC-CD in combination with quantum chemical CD calculations . The application of hyphenated techniques like high-performance liquid chromatography (HPLC) coupled to nuclear magnetic resonance spectroscopy (NMR), to electrospray ionization tandem mass spectrometry (ESI-MS/MS), and to circular dichroism spectroscopy (CD) is a sensitive and powerful tool in natural product chemistry permitting a fast screening of the metabolic profiles of plant extracts, with a minimum amount of material. In particular, by the combined application of HPLC-NMR, HPLC-ESI-MS/MS, and HPLC-CD as established in our group, it is not only possible to rapidly identify known structures, but also to investigate new metabolites and to establish their full absolute stereostructures online, directly from crude extracts, without the necessity of isolation and purification (see also 'Natural Product Analysis').
Summarizing, in many of the cases presented here, an assignment of the absolute stereostructure would not have been possible by any of the existing conventional methods for the interpretation of CD spectra. Without having to rely on empirical data or reference material, the CD calculations can be done directly, without the necessity of chemically introducing additional chromophores – which, for several of the cases investigated, would not have been possible, anyhow. The quantum chemical attribution of the absolute stereostructures of further classes of compounds is underway.
4. Selected Publications:
5. Cooperations and Research Grants
a) Within a special research project entitled "A New Class of Active Agents against Infectious Diseases" incorporated into the Collaborative Research Centre „Recognition, Preparation, and Functional Analysis of Agents against Infectious Diseases“ (Sonderforschungsbereich 630), sponsored by the Deutsche Forschungsgemeinschaft (DFG).
b) Within a special research project entitled "Enantioselective Synthesis of Bisbibenzyl Natural Products of the Isoplagiochin-Type with Combined Axially and Helical Chirality", in collaboration with PD Dr. Andreas Speicher (Universität des Saarlandes, Fachrichtung 8.1. Chemie – Organische Chemie), sponsored by the DFG (Individual Grant Br 699/12);
c) Within a special research project entitled "Natural Products from African Plants ", in collaboration with Prof. Dr. M.G. Peter (Institut für Chemie der Univerisität Potsdam) and Dr. A. Yenesew (Department of Chemistry, University of Nairobi, Kenya), sponsored by the DFG (Individual Grant Br 699/13-5);
d) Within a special research project entitled "Convergence in the Biosynthesis of Acetate- or Prenyl-Derived Natural Products", incorporated into the DFG priority programme 1152 "Evolution of Metabolic Diversity", Individual Grant Br 699/9-3);
e) Within a special research project entitled "Molecular Phylogeny and Chemotaxonomy of the Ancistrocladaceae Plant Family", in collaboration with Prof. Dr. G. Heubl (Institut für Systematische Botanik der LMU München), sponsored by the DFG (Individual Grants Br 699/7 and Br 699/14-2);
f) Within the special research project entitled „BIOTECmarin – Center of Competence: Molecular Biotechnology and New Agents from Marine Sponges and Associated Microorganisms“, sponsored by the Bundesminsterium für Bildung, Forschung, Wissenschaft und Technologie (BMBF), in collaboration with
g) Within the Research Training Group "Modification of the Electron Density in Chemical and Biological Systems – a Symbiosis between Theory and Experiment for Postgraduate Education" (Graduiertenkolleg 690, coordinator: Prof. Dr. B. Engels, Institut für Organische Chemie der Universität Würzburg), sponsored by the DFG (completed).
h) Within a special research project entitled "Metal-Induced Synthesis and Utilization of Axially Chiral Biaryls" incorporated into the collaborative research centre „Selective Reactions of Metal-Activated Molecules“ (Sonderforschungsbereich 347), sponsored by the DFG (completed).