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Peer-Reviewed Articles on ACD/Structure Elucidator Suite

Showing 1-18 of 18

NMR-Based Computer-Assisted Structure Elucidation (CASE) of Small Organic Molecules in Solution: Recent Advances
Sep 12, 2019
M. Elyashberg, D. Argyropoulos
CASE (computer‐assisted structure elucidation) first appeared in the late 1960s but really gained traction in the 1990s as more information‐rich 2D NMR experiments were developed. In this article, we discuss the strategies of CASE for small organic molecules in solution. Cognitive grounds and the principal CASE flow‐diagram, as well as the main obstacles impeding structure elucidation (presence of 'nonstandard' correlations and ambiguity of 2D NMR data, deficit of hydrogen, etc.) are discussed and methods to overcome these challenges are suggested. The methods are illustrated by examples of solving challenging problems. It has been shown that CASE can be used to avoid pitfalls during structure elucidation and to determine the most efficient combinations of 2D NMR experiments. Methodology of DFT‐based NMR spectrum prediction in synergistic combination with CASE is explained. The last advances in 3D structure elucidation and stereochemistry determination using RDCs and RCSAs are considered. In conclusions, perspectives of CASE development are discussed.
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Towards unbiased and more versatile NMR-based structure elucidation
Jun 01, 2018
A.V. Buevich, M.E. Elyashberg
Computer-assisted structure elucidation (CASE) is composed of two steps: (a) generation of all possible structural isomers for a given molecular formula and 2D NMR data (COSY, HSQC, and HMBC) and (b) selection of the correct isomer based on empirical chemical shift predictions. This method has been very successful in solving structural problems of small organic molecules and natural products. However, CASE applications are generally limited to structural isomer problems and can sometimes be inconclusive due to insufficient accuracy of empirical shift predictions. Here, we report a synergistic combination of a CASE algorithm and density functional theory calculations that broadens the range of amenable structural problems to encompass proton-deficient molecules, molecules with heavy elements (e.g., halogens), conformationally flexible molecules, and configurational isomers.
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Targeted Dereplication of Microbial Natural Products by High-Resolution MS and Predicted LC Retention Time
Apr 26, 2017
J. Chervin, M. Stierhof, M.H. Tong, D. Peace, K. Østnes Hansen, D.S. Urgast, J.H. Andersen, Y. Yu, R. Ebel, K. Kyeremeh, V. Paget, G. Cimpan, A. Van Wyk, H. Deng, M. Jaspars, and J.N. Tabudravu
A new strategy for the identification of known compounds in Streptomyces extracts that can be applied in the discovery of natural products is presented. The strategy incorporates screening a database of 5555 natural products including 5098 structures from Streptomyces sp., using a high-throughput LCMS data processing algorithm that utilizes HRMS data and predicted LC retention times (tR) as filters for rapid identification of known compounds in the natural product extract. The database, named StrepDB, contains for each compound the structure, molecular formula, molecular mass, and predicted LC retention time. All identified compounds are annotated and color coded for easier visualization. It is an indirect approach to quickly assess masses (which are not annotated) that may potentially lead to the discovery of new or novel structures. In addition, a spectral database named MbcDB was generated using the ACD/Spectrus DB Platform. MbcDB contains 665 natural products, each with structure, experimental HRESIMS, MS/MS, UV, and NMR spectra. StrepDB was used to screen a mutant Streptomyces albus extract, which led to the identification and isolation of two new compounds, legonmaleimides A and B, the structures of which were elucidated with the aid of MbcDB and spectroscopic techniques. The structures were confirmed by computer-assisted structure elucidation (CASE) methods using ACD/Structure Elucidator Suite. The developed methodology suggests a pipeline approach to the dereplication of extracts and discovery of novel natural products.
J. Nat. Prod., 2017, 80 (5): 1370-1377

Structure Elucidation Software Review in Magnetic Resonance in Chemistry
Aug 18, 2016
The latest edition of Magnetic Resonance in Chemistry features a special introductory tutorial to Computer-Assisted Structure Elucidation (CASE) aimed at undergraduate and graduate students, and utilizes a free CASE tutorial software package available from ACD/Labs.
Structure Elucidation Software Review in Magnetic Resonance in Chemistry

The fundamentals behind solving for unknown molecular structures using computer-assisted structure elucidation: a free software package at the undergraduate and graduate levels
May 15, 2016
A. Moser and B. Pautler
The successful elucidation of an unknown compound's molecular structure often requires an analyst with profound knowledge and experience of advanced spectroscopic techniques, such as Nuclear Magnetic Resonance (NMR) spectroscopy and mass spec-trometry. The implementation of Computer-Assisted Structure Elucidation (CASE) software in solving for unknown structures, such as isolated natural products and/or reaction impurities, can serve both as elucidation and teaching tools. As such, the intro-duction of CASE software with 112 exercises to train students in conjunction with the traditional pen and paper approach will strengthen their overall understanding of solving unknowns and explore of various structural end points to determine the validity of the results quickly.
Magn Reson Chem, 54(9): 701–704

Computer-Assisted Structure Elucidation in Routine Analysis
Jan 26, 2016
P. Wheeler, S. Hayward, M. Elyashberg
The elucidation of unknown structures, especially those with novel moieties found in natural products, often results in initially incorrect published structures, which then require either exhaustive spectroscopic analysis, full chemical synthesis or both to prove the correct structure. In many cases, the initial incorrect structure and subsequent analytical work could be avoided using computer-assisted structure elucidation (CASE).
P. Wheeler, S. Hayward, M. Elyashberg. (2016). Computer-Assisted Structure Elucidation in Routine Analysis. American Laboratory, 48(2): 12–14.

Dereplication of natural products using minimal NMR data inputs
Sep 11, 2015
R.B. Williams, M. O'Neill-Johnson, A.J. Williams, P. Wheeler, R. Pol, A. Moser
In collaboration with Sequoia Sciences Inc., we developed a strategy for the dereplication of a complete or a partial structure using 1H NMR, 1H–13C HSQC and 1H–1H COSY spectral data, a molecular formula composition range and structural fragments against a massive database of about 22 million compounds is considered. The work was based on 18 compounds and was applicable to research on natural products and synthetic compounds.
R.B. Williams, M. O'Neill-Johnson, A.J. Williams, P. Wheeler, R. Pol, A. Moser. (2015). Dereplication of natural products using minimal NMR data inputs. Org. Biomol. Chem. 13: 9957–9962.

Activity-Independent Discovery of Secondary Metabolites Using Chemical Elicitation and Cheminformatic Inference
Sep 09, 2015
S.M. Pimentel-Elardo, D. Sørensen, L. Ho, M. Ziko, S.A. Bueler, S. Lu, J. Tao, A. Moser, R. Lee, D. Agard, G. Fairn, J.L. Rubinstein, B.K. Shoichet, and J.R. Nodwell
Most existing antibiotics were discovered through screens of environmental microbes, particularly the streptomycetes, for the capacity to prevent the growth of pathogenic bacteria. This "activity-guided screening" method has been largely abandoned because it repeatedly rediscovers those compounds that are highly expressed during laboratory culture. Most of these metabolites have already been biochemically characterized. However, the sequencing of streptomycete genomes has revealed a large number of "cryptic" secondary metabolic genes that are either poorly expressed in the laboratory or that have biological activities that cannot be discovered through standard activity-guided screens. Methods that reveal these uncharacterized compounds, particularly methods that are not biased in favor of the highly expressed metabolites, would provide direct access to a large number of potentially useful biologically active small molecules. To address this need, we have devised a discovery method in which a chemical elicitor called Cl-ARC is used to elevate the expression of cryptic biosynthetic genes. We show that the resulting change in product yield permits the direct discovery of secondary metabolites without requiring knowledge of their biological activity. We used this approach to identify three rare secondary metabolites and find that two of them target eukaryotic cells and not bacterial cells. In parallel, we report the first paired use of cheminformatic inference and chemical genetic epistasis in yeast to identify the target. In this way, we demonstrate that oxohygrolidin, one of the eukaryote-active compounds we identified through activity-independent screening, targets the V1 ATPase in yeast and human cells and secondarily HSP90.
S.M. Pimentel-Elardo et al.. (2015). Activity-Independent Discovery of Secondary Metabolites Using Chemical Elicitation and Cheminformatic Inference. ACS Chem. Biol., 10 (11): 2616–2623

Turning Spiroketals Inside Out: A Rearrangement Triggered by an Enol Ether Epoxidation
Jun 17, 2015
C. Lorenc, J. Saurí, A. Moser, A.V. Buevich, A.J. Williams, R.T. Williamson, G.E. Martin, and M.W. Peczuh
Spiroketals organize small molecule structures into well-defined, three-dimensional configurations that make them good ligands of proteins. We recently discovered a tandem cycloisomerization-dimerization reaction of alkynyl hemiketals that delivered polycyclic, enol-ether-containing spiroketals. Here we describe rearrangements of those compounds, triggered by epoxidation of their enol ethers that completely remodel their structures, essentially turning them "inside out". Due to the high level of substitution on the carbon skeletons of the substrates and products, characterization resorted to X-ray crystallography and advanced computation and NMR techniques to solve the structures of representative compounds. In particular, a new proton-detected ADEQUATE NMR experiment (1,1-HD-ADEQUATE) enabled the unequivocal assignment of the carbon skeleton of one of the new compounds. Solution of the structures of the representative compounds allowed for the assignment of product structures for the other compounds in two separate series. Both the rearrangement and the methods used for structural determination of the products are valuable tools for the preparation of characterization of new small molecule compounds.
Lorenc, C. et al. (2015) Turning Spiroketals Inside Out: A Rearrangement Triggered by an Enol Ether Epoxidation. ChemstryOpen Online.

Identification and structure elucidation by NMR spectroscopy
Jun 01, 2015
M. Elyashberg
The state of the art and recent developments in application of nuclear magnetic resonance (NMR) for structure elucidation and identification of small organic molecules are discussed. The recently suggested new two-dimensional (2D)-NMR experiments combined with the advanced instrumentation allow structure elucidation of new organic compounds at a sample amount of less than 10 μg. A pure shift approach that provides 1H-decoupled proton spectra drastically simplified 1H and 2D NMR spectra interpretation. The structure elucidation of extremely hydrogen-deficient compounds was dramatically facilitated due to the methodology based on combination of new 2D-NMR experiments providing longrange heteronuclear correlations with computer-assisted structure elucidation (CASE). The capabilities of CASE systems are discussed. The role of NMR-spectrum prediction in structure verification and NMR approaches for qualitative mixture analysis are considered.
M. Elyashberg. (2015). Identification and structure elucidation by NMR spectroscopy. Trends in Analytical Chemistry, 69:88-97

Computer-Assisted Structure Elucidation of Black Chokeberry (Aronia melanocarpa) Fruit Juice Isolates with a New Fused Pentacyclic Flavonoid Skeleton
Jun 01, 2015
C. Benjamin Naman, Jie Li, Arvin Moser, Jeffery M. Hendrycks, P. Annécie Benatrehina, Heebyung Chai, Chunhua Yuan, William J. Keller, and A. Douglas Kinghorn
Melanodiol 4''-O-protocatechuate (1) and melanodiol (2) represent novel flavonoid derivatives isolated from a botanical dietary supplement ingredient, dried black chokeberry (Aronia melanocarpa) fruit juice. These noncrystalline compounds possess an unprecedented fused pentacyclic core with two contiguous hemiketals. Due to having significant hydrogen deficiency indices, their structures were determined using computer-assisted structure elucidation software. The in vitro hydroxyl radical-scavenging and quinone reductase-inducing activity of each compound are reported, and a plausible biogenetic scheme is proposed.
Naman, C.B et al. (2015) Computer-Assisted Structure Elucidation of Black Chokeberry (Aronia melanocarpa) Fruit Juice Isolates with a New Fused Pentacyclic Flavonoid Skeleton. Org. Lett. Online.

Computer-Based Structure Elucidation from Spectral Data
May 21, 2015
M.E. Elyashberg, A.J. Williams
Here, the authors introduce readers to solving molecular structure elucidation problems using the expert system ACD/Structure Elucidator. They explain in detail the concepts of the Computer-Assisted Structure Elucidation (CASE) approach and point out the crucial role of understanding the axiomatic nature of the data used to deduce the structure. Aspects covered include the main blocks of the expert system and essential features of the mathematical algorithms used. Graduate and PhD students as well as practicing chemists are provided with a detailed explanation of the various practical approaches depending on available spectral data peculiarities and the complexity of the unknown structure. This is supported by a large number of real-world completed examples, most of which are related to the structure elucidation of natural product molecules containing unusual skeletons. Dedicated software and further supplementary material are available at
Elyashberg, M.E., Williams, A.J. (2015) Computer-Based Structure Elucidation from Spectral Data. Springer-Verlag Berlin Heidelberg.

Nuclear Magnetic Resonance in the Structural Elucidation of Natural Products
Oct 21, 2014
William F. Reynolds, Eugene P. Mazzola
From its modest beginnings in the 1950s, nuclear magnetic resonance (NMR) spectroscopy has become the premier analytical tool for the determination of structure of organic natural products. Structural elucidation efforts were originally limited to proton NMR and typically required both relatively large quantities of material and considerable time. However, modern NMR spectrometers, with an array of one- and two-dimensional experiments, permit the structures of complex organic molecules to be determined, often in a day, using less than 1 mg of sample. This chapter will prepare natural product chemists to employ modern NMR techniques effectively in the determination of molecular structures. It focuses on the rapid determination of whether an isolated compound is known or new, the information content of various two-dimensional and selective one-dimensional NMR experiments, the use of these experiments in combination and avoiding or overcoming common pitfalls in determining molecular structures, the selection of optimum acquisition parameters and data processing methods and parameters, and the use of computer-assisted structure elucidation.
Reynolds, W.F., Mazzola, E.P. (2015). Nuclear Magnetic Resonance in the Structural Elucidation of Natural Products. In A.D. Kinghorn, H. Falk, J. Kobayashi (Eds.), Progress in the Chemistry of Organic Natural Products (223–309). Springer International Publishing Switzerland

Structure Revision of Asperjinone Using Computer-Assisted Structure Elucidation Methods
Jan 04, 2013
M. Elyashberg, K. Blinov, S. Molodtsov, A.J. Williams
The elucidated structure of asperjinone, a natural product isolated from thermophilic Aspergillus terreus, was revised using the expert system Structure Elucidator. The reliability of the revised structure was confirmed using 180 structures containing the (3,3-dimethyloxiran-2-yl)methyl fragment as a basis for comparison and whose chemical shifts contradict the suggested structure.
J. Nat. Prod., 76:113-116, 2013

Using a combination of atomic force microscopy and computer assisted structure elucidation to determine the structure of bjørnøyoxazole, a highly modified halogenated dipeptide from the Arctic hydrozoan Thuiaria breitfussi
Dec 03, 2012
K.Ѳ. Hanssen, B. Schuler, A..J. Williams, T. B. Demissie, E. Hansen, J. H. Andersen, J. Svenson, K. Blinov, M. Repisky, F. Mohn, G. Meyer, J.-S. Svendsen, K. Ruud, M. Elyashberg, L.Gross, M. Jaspars, and J. Isaksson
Turning a new leaf: The first structures isolated from Thuiaria breitfussi, the breitfussins, are presented. This structural class consists of indole–oxazole–pyrrole units. Limited quantities prevented crystallization; therefore, the structures were solved using a novel combination of AFM, computer-aided structure elucidation (CASE), and DFT calculations. Visualization by AFM determined all the connection points of the cyclic systems and the other substituents.
Angew. Chem. Int. Ed.. 51(49):12238-12241,2012

Heterocyclization of electrophilic alkenes with tetranitromethane revisited: regiochemistry and the mechanism of nitroisoxazole formation
Mar 21, 2012
E.B. Averina, Y.V. Samoilichenko, Y.A. Volkova, Y.K. Grishin, V.B. Rybakov, A.G. Kutateladze, M.E. Elyashberg, T.S. Kuznetsova, N. S. Zefirov
Revised regiochemistry for the heterocyclization of electrophilic alkenes with tetranitromethane (TNM) in the presence of triethylamine, providing rapid access to nitroisoxazoles, is reported. The formation of 5-nitroisoxazoles previously incorrectly assigned as 3-nitro regioisomers, has now been established unambiguously by X-ray crystallography. Empirical computations with ACD/CNMR Predictor, based both on hierarchical ordering of spherical environments (HOSE) and an algorithm of artificial neural networks (ANN), and also Density Functional Theory computations of the 13C NMR chemical shifts for the 3- versus 5-nitroisoxazoles are shown to consistently match the spectra of the experimentally observed 5-regioisomers.
Tetrahedron Letters, 53(12):1472–1475, 2012

Blind trials of Computer-Assisted Structure Elucidation software
Feb 01, 2012
A. Moser, M. Elyashberg, A.J Williams, K.A. Blinov, J. DiMartino
One of the largest challenges in chemistry today remains that of efficiently mining through vast amounts of data in order to elucidate the chemical structure for an unknown compound. The elucidated candidate compound must be fully consistent with the data and any other competing candidates efficiently eliminated without doubt by using additional data if necessary. It has become increasingly necessary to incorporate an in silico structure generation and verification tool to facilitate this elucidation process. An effective structure elucidation software technology aims to mimic the skills of a human in interpreting the complex nature of spectral data while producing a solution within a reasonable amount of time. This type of software is known as computer-assisted structure elucidation or CASE software. A systematic trial of the ACD/Structure Elucidator CASE software was conducted over an extended period of time by analysing a set of single and double-blind trials submitted by a global audience of scientists. The purpose of the blind trials was to reduce subjective bias. Double-blind trials comprised of data where the candidate compound was unknown to both the submitting scientist and the analyst. The level of expertise of the submitting scientist ranged from novice to expert structure elucidation specialists with experience in pharmaceutical, industrial, government and academic environments.
J. Cheminf. 4(5), 2012

Elucidating "Undecipherable" Chemical Structures Using Computer Assisted Structure Elucidation Approaches
Jan 01, 2012
5. M.E. Elyashberg, K.A. Blinov, S.G. Molodtsov, A.J. Williams
Structure elucidation using 2D NMR data and application of traditional methods of structure elucidation are known to fail for certain problems. In this work, it is shown that computer-assisted structure elucidation methods are capable of solving such problems. We conclude that it is now impossible to evaluate the capabilities of novel NMR experimental techniques in isolation from expert systems developed for processing fuzzy, incomplete and contradictory information obtained from 2D NMR spectra.
Magn. Reson. Chem., 50:22-27, 2012