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The Structure Elucidation Challenge
Between 2003 and 2011, 112 different datasets were
submitted from various industries as challenges to the
ACD/Structure Elucidator Suite system. [3] The structures
determined ranged from 100 to more than 1000 Da (Figure 5)
and the software had excellent success determining the
correct structures (Figure 6).
In one recent example, Structure Elucidator Suite was able to
determine the structure of a large, symmetrical dimer known
as Bacillusin A [4] (containing 86 skeletal units) even with the
presence of ambiguous
connectivities. [5]
Conclusions
Modern CASE systems such as Structure Elucidator Suite
provide the necessary capability accurately elucidate a novel
chemical structure for complex molecules based on readily
available NMR data sets. This allows organizations to avoid
expensive, labor-intensive, and time-consuming synthetic
efforts. The routine use of CASE tools should also prevent the
introduction of many improper structures into the literature, or
into compound registries.
IntroductionComputer-Assisted Structure Elucidation (CASE) has
come to be a broadly accepted method for the derivation
of novel or difficult chemical structures, especially those of
natural products or drug metabolites and impurities. For
completely error-free structure determination, one must
first evaluate all isomers that truly match connectivity
criteria defined by experiment – but it is impossible to do
this manually without bias.
Modern NMR techniques give ever-increasing amounts of
valuable data to substantiate structural evaluations,
including lower limits of detection, and more information
on connectivities. However, errors in published structures
are rampant [1] giving weight to the argument for
computer-assisted evaluation of structures. [2]
CASE Methodology
CASE follows a simple set of steps to comprehensively
evaluate structures against available data:
1. Interpret experimental data to extract knowledge:
• Molecular Formula
• Integrals
• Chemical shifts
• Multiplicities
• Connectivities
• Known fragments
• Known exclusions
2. Search structure space to derive all possible structures
3. Rank-order based on set criteria
• Predicted chemical shift
Data Interpretation
The Case for CASE:
Computer-Assisted Structure Elucidation
References1. Nicolaou, KC; Snyder, SA. Angew. Chem. Int. Ed. Engl., 2005, Feb 4:44(7); 1012-44.
2. Elyashberg, ME; Williams, AJ; Blinov, KA. Nat. Prod. Rep., 2010, 27(9): 1296-1328.
3. Moser, A; Elyashberg, ME; Williams, AJ; Blinov, KA; DiMartino, JC. J. Cheminf., 2012 4:5.
4. Ravu, RR, et al. J. Nat Prod., 2015, 78(4): 924-8.
5. http://www.acdlabs.com/comm/elucidation/2015_05.php
Advanced Chemistry Development, Inc.
Tel: (416) 368-3435
Fax: (416) 368-5596
Toll Free: 1-800-304-3988
Email: [email protected]
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Reprints:
Structure Generation
Ranking the Best CandidatesUsing the advanced algorithms of ACD/Structure Elucidator
Suite, the entirety of the chemical space can be queried for
possible structures which agree with the experimental data.
The software efficiently evaluates all structural possibilities,
and then ranks the best candidates for review based on the
differences between the experimental and predicted chemical
shifts.
Rapid Identification of StructuresWith the right databases, known structures can also be
quickly identified from previous work. The following DBs are
available using ACD/Labs software:
• ACD/HNMR and CNMR DB
• 320,000 assigned chemical structures
• ACD/Structure Elucidator DB
• 425,000 structures
• 2,300,000 structural fragments
• ChemSpider DB
• 22,000,000 predicted compounds with 13C, 1H, 19F,
31P, and 15N NMR
• Dictionary of Natural Products
• Over 220,000 compounds
• Marinlit
• > 21,000 compounds (marine sources)
• AntiBase
• > 35,000 compounds (microorganisms and higher
fungi)
Cl
Br
OH
Br
OH OH
O
C10H17Br2ClO2, 50,502,293 C15H22O2, 138,136,211,624
O
O
O
O
C15H20O1, 37,568,150,635 C12H12O3, 68,930,547,646
O
OH
OH
NH
NH2
OHO
C13H20O3, 14,431,269,166 C11H12N2O2, 31011<n1012
Figure 1: The large number of possible isomers for some
relatively small organic molecules.
Figure 2: In ACD/Labs NMR software, peak assignments
are synchronized throughout a set of related NMR
experiments with NMRSync. During interpretation, the
software displays correlations for assigned spectra and
structures, highlighting those which are likely to be
erroneous.
Figure 3: A Molecular Connectivity Diagram (MCD) is
created automatically during data interpretation. This can
be used both for de novo elucidation, or to perform an
alternative check on proposed structures.
Figure 4: A list of potential structures, ranked by their
associated chemical shift deviations. Structural
assignments are color-coded based on their agreement
with the experimental data.
Figure 6: The outcomes of structural evaluations performed
by ACD/Structure Elucidator Suite from 2003-2011.
Figure 5: The distribution of molecular weight in structural
challenges submitted to ACD/Labs.
CH333
CH333
CH3 32
CH332
CH3 34
CH334
26
26
28
28
20
20
30
30
22
22
18
18
31
31
27
27
21
21
19
19
23
23
29
29
4
4
6
6
25
25
16
16
8
8
14
14
15
15
12
12
9
9
11
11
13
13
24
24
10
10
2
2
7
7
17
17
3
3
5
5
11
O
O
O
O
OO
OH
OH
OH
OH
OH
OH
OH
OH
OH
OHOH
OH
Figure 5: The elucidated structure of Bacillusin A
