Hexacyclinol, a New Antiproliferative Metabolite of Panus rudis HKI 0254.

Schlegel, Brigitte; Haertl, Albert; Dahse, Hans‐Martin; Gollmick, Friedrich A.; Gräefe, Udo; Doerfelt, Heinrich; Kappes, Barbara

doi:10.1002/chin.200310212

Cited by 6 publications

(6 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Hexacyclinol is a widely known example of a natural product in which a constitutional structural reassignment stemmed directly from a computational evaluation of its 13 C NMR data. Structure 2a was initially assigned to this antiproliferative metabolite 36 . A total synthesis of this structure was reported 37 .…”

Section: Box 1 | Two Case Studies: Hexacyclinol (Constitution) and Vamentioning

confidence: 99%

A guide to small-molecule structure assignment through computation of (1H and 13C) NMR chemical shifts

2014

View full text Add to dashboard Cite

this protocol is intended to provide chemists who discover or make new organic compounds with a valuable tool for validating the structural assignments of those new chemical entities. experimental 1 H and/or 13 c nMr spectral data and its proper interpretation for the compound of interest is required as a starting point. the approach involves the following steps: (i) using molecular mechanics calculations (with, e.g., MacroModel) to generate a library of conformers; (ii) using density functional theory (DFt) calculations (with, e.g., Gaussian 09) to determine optimal geometry, free energies and chemical shifts for each conformer; (iii) determining Boltzmann-weighted proton and carbon chemical shifts; and (iv) comparing the computed chemical shifts for two or more candidate structures with experimental data to determine the best fit. For a typical structure assignment of a small organic molecule (e.g., fewer than ~10 non-H atoms or up to ~180 a.m.u. and ~20 conformers), this protocol can be completed in ~2 h of active effort over a 2-d period; for more complex molecules (e.g., fewer than ~30 non-H atoms or up to ~500 a.m.u. and ~50 conformers), the protocol requires ~3-6 h of active effort over a 2-week period. to demonstrate the method, we have chosen the analysis of the cis-versus the trans-diastereoisomers of 3-methylcyclohexanol (1-cis versus 1-trans). the protocol is written in a manner that makes the computation of chemical shifts tractable for chemists who may otherwise have only rudimentary computational experience. this method certainly has value, the example described next shows that when one moves to the consideration of molecules bearing more than one stereocenter, this approach is no longer adequate.Consider the case of the trans-versus the cis-diastereomers of 3-methylcyclohexanol (1-trans and 1-cis, respectively). The experimental 1 H NMR spectra for 1-trans and 1-cis are shown in Figure 1a,b (see Supplementary Data 1 for a full listing of actual chemical shift values). There are substantial differences in these two spectra, especially within the upfield 0.7-2.1 p.p.m. range. Clearly, it would be valuable if computational approaches could reproduce these sorts of differences sufficiently well to allow confident assignment of structure.Common software packages that use empirical (often increment-based) compilations of chemical shift information (e.g., tabulated shift increments or databases of known spectral data) allow users to predict the chemical shifts of a given input structure. These include 'ChemNMR' within ChemBioDraw (also known as ChemDraw) and 'C+H NMR Predictor and DB' within the ACD/Labs software suite. These methods sometimes can be sufficient for the task of resolving constitutional structural assignments. However, when issues associated with relative configuration are considered, increment-based methods are decidedly ill-equipped. Analysis of structures 1-trans and 1-cis by each of these programs quickly reveals these limitations, even for these simple structures. Namely, because Che...

show abstract

Section: Box 1 | Two Case Studies: Hexacyclinol (Constitution) and Vamentioning

confidence: 99%

A guide to small-molecule structure assignment through computation of (1H and 13C) NMR chemical shifts

2014

View full text Add to dashboard Cite

show abstract

“…A recent example is the high-profile case of the hexacyclinol structure (C 23 H 28 O 7 ). Schlegel et al [45] separated a natural product and suggested its structure based on the 2D NMR data. Le Clair [46] reported a synthesis of the structure, but Rychnovsky [47] suggested another structure based on 13 C chemical shift prediction using a GIAO-based quantum-mechanical DFT (Density Functional Theory) prediction method.…”

Section: Resultsmentioning

confidence: 99%

Computer-assisted methods for molecular structure elucidation: realizing a spectroscopist's dream

Elyashberg¹,

Blinov²,

Molodtsov

et al. 2009

J Cheminform

View full text Add to dashboard Cite

BackgroundThis article coincides with the 40 year anniversary of the first published works devoted to the creation of algorithms for computer-aided structure elucidation (CASE). The general principles on which CASE methods are based will be reviewed and the present state of the art in this field will be described using, as an example, the expert system Structure Elucidator.ResultsThe developers of CASE systems have been forced to overcome many obstacles hindering the development of a software application capable of drastically reducing the time and effort required to determine the structures of newly isolated organic compounds. Large complex molecules of up to 100 or more skeletal atoms with topological peculiarity can be quickly identified using the expert system Structure Elucidator based on spectral data. Logical analysis of 2D NMR data frequently allows for the detection of the presence of COSY and HMBC correlations of "nonstandard" length. Fuzzy structure generation provides a possibility to obtain the correct solution even in those cases when an unknown number of nonstandard correlations of unknown length are present in the spectra. The relative stereochemistry of big rigid molecules containing many stereocenters can be determined using the StrucEluc system and NOESY/ROESY 2D NMR data for this purpose.ConclusionThe StrucEluc system continues to be developed in order to expand the general applicability, provide improved workflows, usability of the system and increased reliability of the results. It is expected that expert systems similar to that described in this paper will receive increasing acceptance in the next decade and will ultimately be integrated directly to analytical instruments for the purpose of organic analysis. Work in this direction is in progress. In spite of the fact that many difficulties have already been overcome to deliver on the spectroscopist's dream of "fully automated structure elucidation" there is still work to do. Nevertheless, as the efficiency of expert systems is enhanced the solution of increasingly complex structural problems will be achievable.

show abstract

“…50 La Clair 51 claimed to have synthesized a substance with this structure in 2006. Based on spectroscopic studies, Grafe proposed 17 as its structure.…”

Section: Hexacyclinolmentioning

confidence: 99%

Computed Spectral Properties and Structure Identification

Bachrach

2014

Computational Organic Chemistry

View full text Add to dashboard Cite

Once the wavefunction is in hand, all observable properties can, at least in principle, be computed. This can include all varieties of spectral properties, which are particularly valuable in ascertaining molecular structure. The full theoretical and computational means for computing spectral properties are mathematically involved and beyond the scope of this chapter. Instead, we will focus on the use of quantum chemical computations to help identify chemical structure. The purpose of this chapter is to inspire the routine use of computed spectra to aid in structural identification.As discussed in Chapter 1, the full three-dimensional structure of a compound can be optimized with almost any of the quantum computational techniques. Since most quantum chemical computations are still performed on a single molecule in the gas phase, these computed structures can be most readily compared to gas-phase experimental structures. In the following chapters, we will present a number of case studies where computed and experimental geometries are compared. To get a sense of the quality of computed geometries, a few selected cases are discussed next. COMPUTED BOND LENGTHS AND ANGLESSchaefer and Allinger 1 examined a series of small organic compounds with a number of different computational methods. Table 2.1 compares the C-C and C-H bond lengths (r e ) in some very small compounds, and finds the coupled-cluster singles and doubles (CCSD/TZ2+P) results in excellent agreement with the limited experimental values. Importantly, the bond lengths predicted by the much more computationally efficient B3LYP/6-31G* are very similar to the CCSD results. For a group of 10 small hydrocarbons, including some alkenes and alkynes, the B3LYP/6-31G* C-C and C-H distances are on an average too small (compared with r g values) by only 0.0031 and 0.016 Å, respectively. Similar excellent performance is also seen for a group of 19 organic compounds containing oxygen or nitrogen.

show abstract

Hexacyclinol, a New Antiproliferative Metabolite of Panus rudis HKI 0254.

Cited by 6 publications

References 1 publication

A guide to small-molecule structure assignment through computation of (1H and 13C) NMR chemical shifts

A guide to small-molecule structure assignment through computation of (1H and 13C) NMR chemical shifts

Computer-assisted methods for molecular structure elucidation: realizing a spectroscopist's dream

Computed Spectral Properties and Structure Identification

Contact Info

Product

Resources

About