PANIC, March 3-7, 2019 | ACD/Labs
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PANIC

March 3-7, 2019
Sonesta Resort, Hilton Head, SC, USA

Related Materials

Related presentations, posters, and scientific talks from this event have been posted here for your reference. Please click the associated link to download.

A New Method for the Reliable Detection of 13C Multiplets of Fluorine Containing Compounds, D. Argyropoulos, R. Pol, V. Mikhailenko, and S. Golotvin
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NMR Software Symposium

Please join us in Hilton Head for our NMR Software Symposium.

Sunday, March 3rd, 8:30–11:00 AM EST

Agenda

Presentation Details
8:30-8:40 AM
Introductions and Welcome
8:40-9:05 AM 20 Years of ACD/Structure Elucidator: What CASE has Accomplished and What Lies Ahead
Jessica Litman, ACD/Labs
9:05-9:30 AM Structure Elucidation of Fluorinated Compounds
Charlotte Corbett, DEA Special Testing and Research Laboratory
9:30-9:55 AM The Latest Developments in Analysis Workflows and Chemical Knowledge Extraction
Arvin Moser, ACD/Labs
9:55-10:20 AM Implementation of Software Automation and Data Management Tools to Improve Throughput and Quality of Chemical Inventory
Chris Snyder, Cayman Chemical
10:20-10:45 AM Using Open Resources and Predicted 13C NMR Spectra for Structure Dereplication
Dimitris Argyropoulos, ACD/Labs
10:45-11:00 AM Questions and Follow-up Discussion

Poster Schedule

Using Predicted 13C NMR Spectra with Open Resources for Structure Dereplication of Natural Products
Arvin Moser, Dimitris Argyropoulos, Sergey Golotvin, Rostislav Pol, Nico Ortlieb, Steffen Breinlinger, Tomasz Chilczuk and Timo H. J. Niedermeyer
View Abstract

Using Predicted 13C NMR Spectra with Open Resources for Structure Dereplication of Natural Products

Arvin Moser1, Dimitris Argyropoulos1, Sergey Golotvin1, Rostislav Pol1, Nico Ortlieb2, Steffen Breinlinger2, Tomasz Chilczuk2 and Timo H. J. Niedermeyer2

1. Advanced Chemistry Development, Toronto, ON, Canada
2. Institute of Pharmacy, RG Pharmacognosy, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany

For successful natural product-based drug discovery, it is critical to reliably separate and identify active components in natural product mixtures. Dereplication is the practice of screening active compounds early in the development process, to recognize and eliminate compounds that have been previously studied. This enables scientists to focus on testing truly 'unknown' compounds. For efficient dereplication, the workflow follows as:

  1. determine a characteristic "fingerprint" region(s) within a spectrum
  2. identify the corresponding structure from a database containing known structures.

The 13C NMR spectrum of a compound can be considered a fingerprint due to its uniquesness and consistency. As a result, the spectrum is very easy and accurate to predict. To identify the structure based on an experimental 13C NMR chemical shifts, one can consider predicting the 13C NMR spectra of known chemical structures found in "open" chemistry databases (e.g., PubChem[1]) and seeing if there is a chemical shift match. Predicted spectra benefit from being magnetic field independent, can be adjusted for solvents, and can be very accurate if the correct algorithms are utilized [2].

Isolated compounds in natural product research are typically low in quantity, thus it may not be experimentally possible to acquire a 1D-13C NMR spectrum. As a result, 13C chemical shift information is often obtained from indirect detection experiments like HSQC and HMBC. The proposed dereplication method can be adopted to work with this data, providing a very valuable resource to natural products chemists. This presentation explores the possibilities and limitations of this novel technique and applies it to natural products from the fungus Ganoderma pfeifferi, cyanobacteria strains from the genera Nostoc and Cylindrospermum, and actimomycetes of the genus Streptomyces.

  1. Kim S, Thiessen PA, Bolton EE, Chen J, Fu G, Gindulyte A, Han L, He J, He S, Shoemaker BA, Wang J, Yu B, Zhang J, Bryant SH. (2016). Nucleic Acids Res., 44:, 1202–1213.
  2. Data presented by Burkhard Kirste, FU Berlin, 38th FGNMR Meeting, Sept. 2016, Dusseldorf

A New Method for the Reliable Detection of 13C Multiplets of Fluorine Containing Compounds
Dimitris Argyropoulos, Rostislav Pol, Vladimir Mikhailenko and Sergey Golotvin
View Abstract

A New Method for the Reliable Detection of 13C Multiplets of Fluorine Containing Compounds

Dimitris Argyropoulos, Rostislav Pol, Vladimir Mikhailenko and Sergey Golotvin

In modern organic and medicinal chemistry, fluorine is commonly used to enhance the chemical properties of molecules in many desirable ways: it may delay the metabolism of the molecule due to the increased stability of the C-F bond, reduce the toxicity of aromatic groups by forbidding the formation of poisonous peroxides during metabolism, or increase the bioavailability due to the higher lipophilicity of the C-F bond vs the C-H bond. As a result, it is estimated that more than 20% of commercial pharmaceutical APIs and 30% of agrochemicals contain at least one fluorine atom [1,2].

In contrast to these benefits, the 13C NMR spectra of fluorinated organic compounds are highly susceptible to interpretation errors. This is because 13C spectra are commonly recorded using only 1H broadband decoupling and the 13C-19F couplings are still present. These coupling constants can be very large (up to 250 Hz or more), which may result in multiplets severely overlapping with other peaks in the spectrum. Additionaly, since 13C spectra inherently have low S/N, it is not uncommon that the lower (outer) parts of a multiplet are below the noise level and not visible. To mitigate this, it is possible to record 13C spectra broadband decoupled from both 1H and 19F but this requires specialized NMR probes and decoupling techniques. Moreover the very broad range of 19F chemical shifts could pose a danger of damage to the probe due to the excessive power that would be required. Consequently, this approach is not considered practical for routine use.

Expansion of the 1H decoupled 13C spectrum of 1,2,3-Trichloro-5-(trifluoromethyl)benzene, indicating the overlapping multiplets due to the 19F-13C couplings

Figure 1: Expansion of the 1H decoupled 13C spectrum of 1,2,3-Trichloro-5-(trifluoromethyl)benzene, indicating the overlapping multiplets due to the 19F–13C couplings.

Here we present an analysis method that reliably peak-picks and identifies multiplets in the 13C spectra of organic compounds. This technique is based on accurately predicting the 19F coupled 13C spectrum of the proposed compound. Following prediction, we examine the regions of the experimental spectrum where the 19F coupled carbons are expected in order to identify multiplets by peak position and the agreement in the predicted and observed coupling constants. Provisions are taken if only part of a multiplet is observed. We show that regardless of whether the final results contain multiple, overlapping multiplets, the expected carbon resonances are reliably identified and assigned for each spectrum. Typical examples from common fluorine containing compounds are shown.

  1. Emsley, John. (2011). Nature's Building Blocks: An A–Z Guide to the Elements (2nd ed.). Oxford, England, UK: Oxford University Press. pp. 178.
  2. Swinson, Joel. (2005). Fluorine—A vital element in the medicine chest. Pharmaceutical Chemistry, 26–27.