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Peer-Reviewed Articles on ACD/Structure Elucidator Suite

Showing 1-25 of 25

CASE Study for an Undergraduate Organic Chemistry Class
Feb 07, 2020
R. Soong, et al.
This article examines the use of ACD/Structure Elucidator to facilitate the teaching of NMR spectroscopic principles and its application in de novo structure elucidation of large complex organic molecules in an upper level organic chemistry class.
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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. A spectral database named MbcDB was generated using the ACD/Spectrus DB Platform. 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

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.

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.

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

Enhanced automated structure elucidation by inclusion of two-bond specific data
Aug 01, 2010
S.F. Cheatham, M. Kline, R. R. Sasaki, K. A. Blinov, M. E. Elyashberg. S. G. Molodtsov
The availability of cryogenically cooled probes permits routine acquisition of data from low sensitivity pulse sequences such as inadequate and 1,1-adequate. We demonstrate that the use of cryo-probe generated 1,1-adequate data in conjunction with HMBC dramatically improves computer-assisted structure elucidation (CASE) both in terms of speed and accuracy of structure generation. In this study data were obtained on two dissimilar natural products and subjected to CASE analysis with and without the incorporation of two-bond specific data. Dramatic improvements in both structure calculation times and structure candidates were observed by the inclusion of the two-bond specific data.
Magn. Reson. Chem., 48:571-574, 2010

Computer-assisted Structure Verification and Elucidation Tools In NMR-Based Structure Elucidation. (REVIEW)
Jul 08, 2008
M. E. Elyashberg, A.J. Williams, G. E. Martin
The involvement of several scientists in the development of Computer-Aided Structure Elucidation (CASE) methods has resulted into the development of a series of expert systems based on 2D NMR data utilization. R. Dunkel has also developed a series of software algorithms and applications that claim to elucidate chemical structures on the spectrometer. Dunkel, in collaboration with the NMR hardware vendor Varian has developed a series of applications for the spectrometer computer platform.
Progress in NMR spectroscopy, 53 (1/2):1-104, 2008

Applying computer assisted structure elucidation algorithms for the purpose of structure validation—revisiting the NMR assignments of hexacyclinol
Feb 08, 2008
A.J. Williams, M. Elyashberg, K.A. Blinov, D.C. Lankin, G.E. Martin, W.F. Reynolds, J.A. Jr. Porco, C.A. Singleton S. Su
Computer-assisted structure elucidation (CASE) using a combination of 1D and 2D NMR data has been available for a number of years. These algorithms can be considered as "logic machines" capable of deriving all plausible structures from a set of structural constraints or "axioms", defined by the spectroscopic data and associated chemical information or prior knowledge. CASE programs allow the spectroscopist not only to determine structures from spectroscopic data but also to study the dependence of the proposed structure on changes to the set of axioms. In this article, we describe the application of the ACD/Structure Elucidator expert system to help resolve the conflict between two different hypothetical hexacyclinol structures derived by different researchers from the NMR spectra of this complex natural product. It has been shown that the combination of algorithms for both structure elucidation and structure validation delivered by the expert system enables the identification of the most probable structure as well as the associated chemical shift assignments.
J. Nat. Prod., 71:581–588, 2008

Fuzzy Structure Generation: A New Efficient Tool for Computer-Aided Structure Elucidation (CASE)
Mar 27, 2007
M. Elyashberg, K.A. Blinov, A.J. Williams, S.G. Molodtsov, G.E. Martin
In this work we suggest a new approach that we term Fuzzy Structure Generation. This allows the solution of structural problems whose 2D NMR data contain an unknown number of nonstandard correlations having different and unknown lengths. We conclude that Fuzzy Structure Generation is efficient, and there is no real alternative at present in terms of a universal practical method for the structure elucidation of organic molecules from 2D NMR data.
J. Chem. Inform. Model., 47:1053-1066, 2007

Are deterministic expert systems for computer assisted structure elucidation obsolete?
May 11, 2006
M. Elyashberg, K.A. Blinov, A.J. Williams, S.G. Molodtsov, G.E. Martin
Expert systems for spectroscopic molecular structure elucidation have been developed since the mid-1960s. Algorithms associated with the structure generation process within these systems are deterministic; that is, they are based on graph theory and combinatorial analysis. A series of expert systems utilizing 2D NMR spectra have been described in the literature and are capable of determining the molecular structures of large organic molecules including complex natural products. Recently, an opinion was expressed in the literature that these systems would fail when elucidating structures containing more than 30 heavy atoms. A suggestion was put forward that stochastic algorithms for structure generation would be necessary to overcome this shortcoming. In this article, we describe a comprehensive investigation of the capabilities of the deterministic expert system Structure Elucidator. The results of performing the structure elucidation of 250 complex natural products with this program were studied and generalized. The conclusion is that 2D NMR deterministic expert systems are certainly capable of elucidating large structures (up to about 100 heavy atoms) and can deal with the complexities associated with both poor and contradictory spectral data.
J. Chem. Inform. Model, 46:1643-1656, 2006

Computer-Aided Determination of Relative Stereochemistry and 3D Models of Complex Organic Molecules from 2D NMR Spectra
Sep 07, 2005
Y.D. Smurnyy, M.E. Elyashberg, K.A. Blinov, B. Lefebvre, G.E. Martin, A.J. Williams
A method for elucidation of the relative stereoconfiguration of natural product molecular structures and their 3D models based on NOE data and the application of a genetic algorithm is described. The method is applicable mainly for rigid polycyclic structures commonly encountered in natural products. It is demonstrated that the technique of simulated annealing cannot be easily used when dealing with low-weight fused ring molecules but the application of a genetic algorithm is proven successful. Examples of a typical genetic algorithm workflow and the optimization of the algorithmic parameters are discussed. The efficiency of the approach developed here is demonstrated on the complex natural products of both TaxolŽ (C47H51NO14) and brevetoxin B (C50H70O14).
Tetrahedron, 61(42); 9980-9989, 2005

Structure Elucidation from 2D NMR Spectra Using the StrucEluc Expert System: Detection and Removal of Contradictions in the Data
Aug 04, 2004
S.G Molodtsov, M.E. Elyashberg, K.A. Blinov, A.J. Williams, G.E. Martin, B. Lefebvre
The elucidation of chemical structures from 2D NMR data commonly utilizes a combination of COSY, HMQC/HSQC, and HMBC data. Generally COSY connectivities are assumed to mostly describe the separation of protons that are separated by 1 skeletal bond (3JHH), while HMBC connectivities represent protons separated from carbon atoms by 1 to 2 skeletal bonds (2JCH and 3JCH). Obviously COSY and HMBC connectivities of lengths greater than those described have been detected. Though experimental techniques have recently been described to aid in the identification of the nature of the couplings the detection of whether a coupling is 2-bond or greater still remains a challenge in most laboratories. In the StrucEluc software system the common lengths of the connectivities, 1-bond for COSY and 1- or 2-bond for HMBC, derived from 2D NMR data are set as the default. Therefore, in the presence of any extended connectivities contradictions can appear in the 2D NMR data. In this article, algorithmic methods for the detection and removal of contradictions in 2D NMR data that have been developed in support of StrucEluc are described. The methods are based on the analysis of molecular connectivity diagrams, MCDs. These methods have been implemented in the StrucEluc system and tested by solving 50 structural problems with 2D NMR spectral data containing contradictions. The presence of contradictions was detected by the algorithm in 90% of the cases, and the contradictions were automatically removed in 50% of the problems. A method of "fuzzy" structure generation in the presence of contradictions has been suggested and successfully tested in this work. This work will demonstrate examples of the application of developed methods to a number of structural problems.
J. Chem. Inf. Comput. Sci., 44:1737-1751, 2004

Automated Structure Elucidation of Two Unexpected Reaction Products in a Reaction of an α, β-Unsaturated Pyruvate
Jul 01, 2004
G.J. Sharman, I.C. Jones, M.J. Parnell, M. Willis, D.V. Carlson, A.J. Williams, M.E. Elyashberg, K.A. Blinov, S.G. Molodtsov
The reaction between an α,β-unsaturated pyruvate and ethyl diazoacetate (EDA) yielded two unexpected products. The structures of these products were determined by automated elucidation of the chemical structures using spectroscopic inputs of a series of 1D and 2D NMR data using the computer program ACD/Structure Elucidator, StrucEluc. The formation of these products is rationalised. Their structures were also confirmed by x-ray crystallography.
Magn. Reson. Chem., 42(7):567-572, 2004

Structure Elucidator: A Versatile Expert System for Molecular Structure Elucidation from 1D and 2D NMR Data and Molecular Fragments
Mar 23, 2004
M.E. Elyashberg, K.A. Blinov, S.G. Molodtsov, A.J. Williams, G.E. Martin
A strategy to utilize molecular fragments has been developed and optimized based on specific challenging examples. Experience gained by solving more than 150 structure elucidation problems from a variety of literature sources is also reviewed in this work.
J. Chem. Inf. Comput. Sci., 44:771-79, 2004

Automated structure elucidation—the benefits of a symbiotic relationship between the spectroscopist and the expert system
Dec 01, 2003
M.E. Elyashberg, K.A. Blinov, E.R. Martirosian, S.G. Molodtsov, A.J. Williams, G.E. Martin
Characteristic features of a new expert system StrucEluc are described. The system is intended for the structure elucidation of complex organic molecules using a variety of spectroscopic data including 2D NMR. We review here the results of challenging this system with over 100 structure elucidation problems where the 2D NMR peak tables presented in original journal publications provided the input data. This contribution is focused on methods to overcome difficult situations that can arise when contradictions are present in the input data and/or when the structure is underdetermined as a result of insufficient 2D NMR correlations. Methods by which to address these situations are examined. It has been shown that synergy between the spectroscopist and the expert system allows the solution of problems that seemed to be hopeless at the outset of the structure elucidation process.
Journal of Heterocyclic Chemistry, 40(6):1017-1029, 2003

Quindolinocryptotackieine: The Elucidation of a Novel Indoloquinoline Alkaloid Structure through the use of Computer-Assisted Structure Elucidation and 2D NMR
Jun 01, 2003
K.A. Blinov, M.E. Elyashberg, E.R. Martirosian, S.G. Molodtsov, A.J. Williams, M.M.H. Sharaf, P.L. Jr Schiff, R.C. Crouch, G.E. Martin, C.E. Hadden, J.E. Guido K.A. Mills
Numerous indoloquinoline alkaloid structures have been identified from extracts of the West African plant Cryptolepis sanguinolenta. Recently, through the use of 2D NMR methods and cryogenic NMR probe technology in conjunction with computer-assisted structure elucidation (CASE) methods, the structures of some chemical degradation products of this family of alkaloids have also been reported. We now report the characterization of a novel indoloquinoline dimeric alkaloid, quindolinocryptotackieine, through the extensive utilization of CASE methods. The NMR data presented here were collected over a decade earlier before the elucidation of the structure was possible, since manual analysis did not present a conclusive structure, whereas CASE produced a series of structures from which the structure could be verified. The original mass spectrometric (MS) data collected for the sample were problematic. Contemporary MS data were instead recollected from remaining small quantities of this alkaloid using modern instrumentation. The re-collected data gave a usable molecular ion and several key fragment ions that were diagnostically useful.
Magn. Reson. Chem., 41:577-584, 2003

Computer Assisted Structure Elucidation of Natural Products with Limited Data: Application of the StrucEluc System
Mar 31, 2003
K.A. Blinov, D. Carlson, M.E. Elyashberg, G.E. Martin, E.R. Martirosian, S.G. Molodtsov, A.J. Williams
This paper considers the strategy of the StrucEluc expert system application for structure elucidation of new natural products when there is a lack of connectivity information that is characteristic of proton-deficient molecules. It is shown that in this case, a database search for fragments using a 13C NMR spectrum as input allows an investigator to fill gaps in the recorded data.
J. Magn. Reson. Chem., 41:359-372, 2003

Applications and Advances in Cryogenic NMR Probes and Computer-Assisted Structure Elucidation
Jan 01, 2003
G. E. Martin, D.J. Russell, K.A. Blinov, M.E. Elyashberg, A.J. Williams
The Assignment of 1H and 13C NMR Spectra and X-ray Crystallographic Analysis of Furanoflavan Isolated from Diplotropis ferruginea Benth.
Ann. Magn. Reson., 1(1/2), 1-31, 2003

Identification of Degradants of a Complex Alkaloid Using NMR Cryoprobe Technology and ACD/Structure Elucidator
Nov 20, 2002
G.E. Martin, B.D. Hadden, C.E. Russell, D.J. Kaluzny, J.E. Guido, W.K. Duholke, B.A. Stiemsma, T.J. Thamann, R.C. Crouch, K.A. Blinov, M.E. Elyashberg, E.R. Martirosian, S.G. Molodtsov, A.J. Williams, P.L. Jr Schiff
Identification of degradants of pharmaceuticals is a necessary challenge of the drug development process following the subjection of candidate molecules to a variety of physico-chemical stresses. It would be desirable to be able to conduct such studies on a minimal amount of material. As a prototypical study, the isolation and identification of degradants of a sample of the complex indoloquinoline alkaloid, cryptospirolepine, was undertaken after prolonged storage in DMSO solution using a combination of cryogenic NMR probe technology and CASE (Computer-Assisted Structure Elucidation) programs. None of the starting alkaloid remained after storage; a chromatogram of the DMSO solution demonstrated the presence of >25 components in the mixture. The two most abundant degradation products were identified as the known alkaloid cryptolepinone (∼35%) and an unprecedented rearrangement product, DP-2, (∼16%).
J. Het. Chem., 39:1241-1250, 2002