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![Approaches to Dereplication
Desirable to know:
For each compound isolated:
If new then acquire data:
Fully elucidate structure
Taxonomy of organism
Molecular Wt/formula
UV Spectrum
1H NMR Spectrum
[13C NMR Spectrum if possible]
1D and 2D NMR array, MS with
fragmentation, IR, [α]D, ORD
Identify as known or new compound. If known STOP.](https://image.slidesharecdn.com/braziliannaturalproductpresentation10262015longversion-151027212112-lva1-app6891/75/Cheminformatics-and-the-Structure-Elucidation-of-Natural-Products-9-2048.jpg)
![Approaches to Dereplication
Desirable to know:
For each compound isolated:
If new then acquire data:
Fully elucidate structure
Taxonomy of organism
Molecular wt/formula
UV Spectrum
1H NMR Spectrum
[13C NMR Spectrum]
1D and 2D NMR array, MS with
fragmentation, IR, [α]D, ORD
Identify as known or new compound. If known STOP.](https://image.slidesharecdn.com/braziliannaturalproductpresentation10262015longversion-151027212112-lva1-app6891/75/Cheminformatics-and-the-Structure-Elucidation-of-Natural-Products-53-2048.jpg)
![Revision of the [7.5.5] Core of
Cryptospirolepine to a [6.6.5] System
• Based on correlations from the 1,1- and -1,n-HD-ADEQUATE spectra,
the [7.5.5] core shown in red was revised to a [6.6.5] system.
• The γ-lactam was rearranged to a dehydropiperidinone.
• Key correlations were the 1
JCC correlation from the vinyl CH to the
flanking carbonyl and quaternary carbons.](https://image.slidesharecdn.com/braziliannaturalproductpresentation10262015longversion-151027212112-lva1-app6891/75/Cheminformatics-and-the-Structure-Elucidation-of-Natural-Products-100-2048.jpg)
Cheminformatics and the Structure Elucidation of Natural Products
The document discusses the application of cheminformatics and big data in the structure elucidation of natural products, highlighting methods for dereplication and the importance of data analysis over data generation. It outlines advancements in NMR spectroscopy and various databases available for structure verification, emphasizing the efficiency of modern techniques in identifying known and new compounds. The agenda includes calls to rethink data sharing in scientific publications and the need for improved data analysis methods.
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Cheminformatics and the Structure Elucidation of Natural Products
- 1. Cheminformatics and theStructure Elucidation of Natural Products (or can Big Data help elucidate structures!) Antony Williams 5th Brazilian Conference of Natural Products October 27th 2015 ORCID ID:0000-0002-2668-4821
- 2. A Bit AboutMe… • NMR spectroscopist by training • Chief Science Officer ACD/Labs Software • One of founders of ChemSpider database • VP for Cheminformatics at RSC
- 3. Why is thisimportant? • Structure verification and elucidation of 1000s of compounds • NMR predictors with >2,000,000 shifts & Computer-Assisted Structure Elucidation • Made >20,000,000 chemical compounds & data freely accessible to the community • Grew the dataset to over >30,000,000 chemicals & used for structure elucidation • Big data can assist structure identification
- 4. The Agenda… • Dereplicationusing prior knowledge • The increasing prevalence of online content • Data generation is not the issue. Analysis is. • Computer-assisted structure elucidation • New experiments to improve elucidation • Rethink data-sharing through publications!
- 5. The Agenda… • Dereplicationusing prior knowledge • The increasing prevalence of online content • Data generation is not the issue. Analysis is. • Computer-assisted structure elucidation • New experiments to improve elucidation • Rethink data-sharing through publications!
- 6. …for each naturalproduct dereplicated, at an average cost of $300 … a savings of $50,000 is incurred in isolation and identification time.
- 7. Dereplication • There areca. 200,000 known natural products • The chance for rediscovery is very high! • We need efficient “dereplication” processes • Most general approach – acquire analytical data and search existing databases…
- 8. Scale of DereplicationExercise 0.5 – 2 mg extract 4 mL agar slope Petri dish Bioassay & HPLC/UV/MS/NMR evaluation 100 mg sponge With gratitude to John Blunt
- 9. Approaches to Dereplication Desirableto know: For each compound isolated: If new then acquire data: Fully elucidate structure Taxonomy of organism Molecular Wt/formula UV Spectrum 1H NMR Spectrum [13C NMR Spectrum if possible] 1D and 2D NMR array, MS with fragmentation, IR, [α]D, ORD Identify as known or new compound. If known STOP.
- 10. What Databases areAvailable? Public ChemSpider CSLS PubChem NMRShift DB Naproc-13 SuperNatural SDBS Private All Pharma GVK Biosciences NPD UC UV DB DTU UV DB Marine NP DB GVK NP DB InterMed UV DB InterMed NMR DB Novartis IR DB Natl. Centre Plant Metabol. CH-NMR-NP Commercial SciFinder SpecInfo (Crossfire) Beilstein Crossfire Gmelin Reaxys ACD Spectral Libraries NaprAlert Dict. Natural Products Dict. Marine Nat. Prods AntiBase MarinLit AntiMarin With gratitude to John Blunt
- 11. PU10-F2 m/z 220 240 260280 300 320 340 360 380 400 420 440 460 480 500 520 540 560 % 0 100 SSA0006 291 (3.284) Cm (241:343) 1: TOF MS ES+ 3.92e4261.564 241.060 241.560 241.974 242.062 262.071 481.122262.517 304.098 263.024 282.074 465.101305.100 482.127 483.122 511.102 M+H Search MW = 480 in Dict. Nat. Prod. 562 hits out of 230,000 compounds!!! MW 480 MF = C28H36N2O5 Nominal Mass Searching
- 12. Molecular Formula Searching SearchMF=C28H36N2O5 in Dict. Nat. Prod. 2 hits out of 230,000 compounds!!! Compare UV spectrum and 1H NMR features
- 13. How many isomersfor a formula? C10H17Br2ClO2, 50,502,293 C15H22O2, 138,136,211,624 C15H20O1, 37,568,150,635 C12H12O3, 68,930,547,646 C13H20O3, 14,431,269,166 C11H12N2O2, 3⋅1011 <n1012
- 14. How many isomersfor a formula? C10H17Br2ClO2, 50,502,293 C15H22O2, 138,136,211,624 C15H20O1, 37,568,150,635 C12H12O3, 68,930,547,646 C13H20O3, 14,431,269,166 C11H12N2O2, 3⋅1011 <n1012
- 16. 1 x tripletmethyl 3 x methoxy 3 x olefinic H solvent ppm1234567 6.42 6.27 6.24 19.96 15.15 24.03 21.93 1 H NMR spectrum, CD3OD
- 17.
- 18. • 1 of5 hits from 230,000 compounds • The ONLY hit if MW = 480 included NMR Features Dereplication
- 20.
- 21.
- 22.
- 23. Dereplication in MarinLitOnline • Can be achieved using • 1 H NMR features e.g. number of Me groups • 13 C and 1 H chemical shifts • Molecular formula (complete or partial) • UV maxima • Exact mass • OR a combination of any or all of the above.
- 25. 1 H NMR Spectrum- new or known? 9 Me groups are obvious (from integrals) Search of MarinLit: 9 Me gave 628 answers
- 26. 4 Me singlets 4Me doublets 1 OMe singlet Aromatic protons Characterizing the spectrum further Search MarinLit for 9 total methyls: 4 singlets, 4 doublets, 1 OMe there were 39 answers,
- 27. COSY spectrum This impliesa 1,2,4- trisubstituted aromatic system A broad singlet coupled/on-coupled to 2 doublets
- 28. 4 Me singlets4 Me doublets 1 OMe singlet 4 singlets, 4 doublets, 1 OMe, 1,2,4-trisubstituted aromatic 2 answers only
- 29. Comparison of NMR data confirmedthat the unknown had this structure
- 30. Commercial Assigned Databases >320,000assigned chemical structures >2,500,000 shifts
- 31. Searching Assigned Databases •mI = 306.1 – 306.2 • 591/322,319 hits
- 32. Searching Assigned Databases •10 13 C shifts to +/- 3.0ppm • 5 1 H shifts to +/- 0.3ppm • 7 hits – very different
- 33. Including 15 N, 19 Fand 31 P data
- 34. Experimental vs. Experimental Differencesbetween C13 shifts are generally small
- 35. Experimental vs. Experimental Differencesbetween C13 shifts are generally small
- 36. Searching experimental data 30seconds from peak-picking to suggested molecules
- 37. Experimental vs. Predicted Differencesbetween exp. and pred. C13 shifts can be larger – useful to limit number of shifts searched
- 38. The Agenda… • Dereplicationusing prior knowledge • Increasing prevalence of free online content • Data generation is not the issue. Analysis is. • Computer-assisted structure elucidation • New experiments to improve elucidation • Rethink data-sharing through publications!
- 39. Online content alsoavailable! NMRShiftDB http://nmrshiftdb.nmr.uni-koeln.de/
- 40. Online content alsoavailable! NMRShiftDB http://nmrshiftdb.nmr.uni-koeln.de/
- 41. Online content alsoavailable! www.nmrdb.org
- 42. • ~35 millionchemicals and growing • Data sourced from ~500 different sources • Structure centric hub for web-searching • Already used many mass spectrometry software packages for structure ID Mining Big Data for Natural Products???
- 43. ChemSpider Interface –no NMR
- 44. 26/35,000,000 Million Hits Rankedby # of References
- 45.
- 46. What can Ifind on ChemSpider?
- 47. What can Ifind? All for free…
- 48. NMR Predictions onChemSpider Data for Dereplication
- 49. 1 2 • fC =full composition (C0-100 H0-100 O0-20 N0-10) • lC= limited composition (C10-30 H25-40 O0-15 N0-5) NMR Predictions on ChemSpider Data for Dereplication Compound 1 Compound 2
- 50. Large Fragments canbe found Top 2 hits searched by 1 H chemical shifts. Hits ranked by the 1 H NMR deviation and filtered with C10-30 H25-40 O0-15 N0- 5,Good List and Bad List. Good List was determined from 1 H shifts, integrals and 1 H-1 H COSY
- 51. • Search nominalmass 490-491 gave the following results: ChemSpider : 46,234 SciFinder: 171,904 Dictionary of Natural Products: 537 Dictionary of Marine Natural Products 90 MarinLit: 94 AntiMarin: 131 • Molecular formula obtained C30H50O5 (490.3658): ChemSpider: 208 SciFinder 2,366 Dictionary of Natural Products 238 Dictionary of Marine Natural Products 43 MarinLit 43 AntiMarin 48 Marine Natural Product Example
- 52. • Search nominalmass 490-491 gave the following results: ChemSpider : 46,234 SciFinder: 171,904 Dictionary of Natural Products: 537 Dictionary of Marine Natural Products 90 MarinLit: 94 AntiMarin: 131 • Molecular formula obtained C30H50O5 (490.3658): ChemSpider: 208 SciFinder 2,366 Dictionary of Natural Products 238 Dictionary of Marine Natural Products 43 MarinLit 43 AntiMarin 48 Marine Natural Product Example Focused Datasets Valuable
- 53. Approaches to Dereplication Desirableto know: For each compound isolated: If new then acquire data: Fully elucidate structure Taxonomy of organism Molecular wt/formula UV Spectrum 1H NMR Spectrum [13C NMR Spectrum] 1D and 2D NMR array, MS with fragmentation, IR, [α]D, ORD Identify as known or new compound. If known STOP.
- 54. The Agenda… • Dereplicationusing prior knowledge • The increasing prevalence of online content • Data generation is not the issue. Analysis is. • Computer-assisted structure elucidation • New experiments to improve elucidation • Rethink data-sharing through publications!
- 55. Modern NMR Technologies •Even a basic array of 1D/2D experiments can provide the relevant data in the majority of cases • The past few years have seen improvements in: • Hardware: Magnets, Probes and RF • Software: Data acquisition and processing • Pulse sequences to probe direct and (very) long- range homo- and heteronuclear correlations
- 56. Magnetic Field Strengthover time
- 57. NMR Developments – 30years of improvements • 1984 – First report of cryogenic NMR probe • 1986 – HMBC experiment reported • 1991 – First commercial 3 mm gradient inverse probes. • 1996 – ADEQUATE NMR experiments first reported. • 1996 – 1 H-15 N HMBC applications reported. • 1998 – Commercial 1.7 mm gradient inverse triple probes. • 1999 – First commercial cryogenic NMR probes delivered. • 2000 – First 3 mm prototype cryoprobe developed. • 2006 – First 1.7 mm MicroCryoProbes™ delivered. • 2009 – Pure shift HSQC experiments developed. • 2014 –1,1- and -1,n-HD-ADEQUATE experiments With gratitude to Gary E. Martin
- 58. COSY Correlations Vicinal H-Hcouplings Geminal H-H couplings 9 19 N N O O H H H H H H H H H H H H H H H HHH H H H H 1 2 3 4 5 6 7 8 10 11 1213 14 16 17 18 20 21 22 23
- 59. HMBC Correlations (8HzOptimized) 9 17a/b N N O O H H H H H H H H H H H H H H H HHH H H H H 1 2 3 4 5 6 7 8 10 11a 1213 1416 18a 20a 21 22 23a 23b 18b 20b 11b
- 60. Always new sequencescoming: 1,1- and -1,n-HD-ADEQUATE Examples show all three scenarios for 1,1- and 1,n-HD- ADEQUATE correlations for cryptospirolepine.
- 61. Adoption can takea long time HSQC vs. HMQC took > 20 years! • HMQC is an older technique and affords lower F1 resolution. • HSQC is a better technique but SLOWLY supplanted HMQC! Year Range #HMQC reports #HSQC reports 1990-94 52 10 1995-99 177 39 2000-04 346 111 2005-09 358 266 2010-14 345 423 Totals 1278 849 From: A. Williams, G.E. Martin, & D.J. Rovnyak, “Increasing the Adoption of Advanced Techniques for the Structure Elucidation of Natural Products,” from Modern NMR Approaches to the Structure Elucidation of Natural Products, vol. 1, A.J. Williams, G.E. Martin, and D.J. Rovnyak, Eds., RSC, London, 2015.
- 62. The Agenda… • Dereplicationusing prior knowledge • The increasing prevalence of online content • Data generation is not the issue. Analysis is. • Computer-assisted structure elucidation • New experiments to improve elucidation • Rethink data-sharing through publications!
- 63. AI Research in1965…
- 64. 50 years ofiterative development DENDRAL NMR-SAMS SENECA SpecInfo ACD/Labs CMC-SE LSD Others…
- 65. Computer Assisted Structure Elucidation:Methodology • Interpret data to extract knowledge • Molecular Formula • Integrals • Chemical shifts • Multiplicity • Connectivity • Known fragments • Known exclusions • Search structure space to derive all structures • Rank-order based on set criteria • Predicted chemical shift • Mass Spec Fragmentation
- 66. Remember how manyisomers C10H17Br2ClO2, 50,502,293 C15H22O2, 138,136,211,624 C15H20O1, 37,568,150,635 C12H12O3, 68,930,547,646 C13H20O3, 14,431,269,166 C11H12N2O2, 3⋅1011 <n1012
- 67. Computer-Aided Structure Elucidation •Eliminate “superfluous” isomers by imposing different structural constraints • Structural constraints are from: • Spectral data of various types: • NMR shifts/multiplicity constrain atom types; Correlations constrain connectivities • MS constrains formula and fragments • IR constrains functional groups • Prior information – sample origin • Chemical rules – valence, ring size, charge, etc.
- 69. CH3 17.60 CH3 18.13 CH3 20.20 CH3 31.40 18.09 19.10 19.50 19.50 28.20 29.20 41.20 34.30 42.20 63.30 33.40 61.20 67.80 68.10 80.40 174.10 OH O O O COSY 1 H -1 H coupling through 3 bonds HMBC 1 H – 13 C coupling through 2/3 bonds 2D NMR spectra: Extraction of Structural Information: COSY/HMBC
- 70. 1D & 2DNMR Synchronized Processing The Software displays correlations for assigned spectra and structures, and highlights correlations that are likely to be erroneous.
- 71. CH3 17.60(fb) CH2 18.09(fb) CH3 18.13(fb) CH2 19.10(fb) CH2 19.50(fb) CH2 19.50(fb) CH3 20.20(fb) CH2 28.20(fb) CH2 29.20(fb) CH 34.30(fb) CH2 41.20(fb) CH 42.20(fb) C 61.20 CH 63.30 C 67.80 C 68.10 C 80.40 C 174.10 O H CH3 31.40(fb) C 33.40(fb) O O O Molecular ConnectivityDiagram (MCD) Molecular Formula C20H30O4 Use spectroscopists experience to add bonds: Create C=O, COOH, Ring systems, etc.
- 72. Not that easythough… “Nonstandard Correlations” “Standard” and “Nonstandard” correlations are experimentally indistinguishable If 2D NMR data contain both “Standard” and “Nonstandard” correlations we see contradictions in interpretation H Ñ Ñ Ñ Ñ Ñ H H H H Ñ Ñ Ñ Ñ Ñ Ñ COSY HMBC Standard
- 73. CH3 1 CH3 2 CH3 3 CH3 4 5 67 8 9 CH2 10 11 12 13 14 15 16 17 18 19 20 OH 21 OH 22 Non-standardCorrelation Example 6-bond 6-bond
- 74.
- 75. Structure Generation combinedwith Structural and Spectral Filtering • Internal Badlist • User Badlist • User Goodlist • Rings: Obligatory, Forbidden • Bredt’s Rule • Maximum Match Factor • Filter Tolerance: Tight, Medium, Loose
- 76. Selection of thePreferable Structure • Remove duplicates • 1 H and 13 C shift calculation for all output structures • Rank structures in ascending order of average chemical shift deviation • Structure with minimum d is the most probable.
- 77. Low Structural Informationin 2D Spectral Data: Use Fragment DB • Number of observed 2D NMR correlations is smaller than expected • Deficit of hydrogen atoms results in a low number of correlations • Search in Fragment Library using the 13C NMR spectrum and embed in the MCD
- 79. Example of FragmentUsage. Symmetric molecule C56H78O12S1 CH 5.76 CH 6.42 CH C C C CH 2.661.38 CH 1.10 1.60 CH2 CH2 CH CH2 CH H2C CH3 0.65HC CH3 0.88 CH 4.29 CH2 2.36C C OC OH 5.35OH 3.73 CH3 1.12 CH3 1.99 CH2 4.13 OH 4.18 O O S CH 5.76 CH 6.42 CH C C C CH 2.66 1.38 CH 1.10 1.60 H2C CH2 CH CH2 CH CH2 CH CH3 0.88 CH 4.29 CH2 2.36 C C O C O CH2 4.13 OH 4.18 CH3 1.99 CH3 0.65 CH3 1.12 O OH 5.35 OH 3.73 Ashwaganhanolide Small number of correlations
- 80. 13 C NMR Fragmentsearch - 5524 found Exp. Frag. Fragment # 1 С17Н22О2
- 81. Solution • 960 MCDswere created using fragment #1 • Structure Generation from 960 MCDs gave 24 structures after filtering and 6 output structures. • Total time was tg= 29 m 30 s
- 82.
- 84. Wrong Molecular Formula OnlyCHNO in formula assumed J. Am. Chem. Soc., 2001, 123, 10870-10876. Tetrahedron Letters, 2002, 43, 5707-5710. FAB-MS: C31H54N4O8 ESI-MS: C31H54N4SO6
- 85. Wrong Molecular Formula OnlyCHNO in formula assumed J. Am. Chem. Soc., 2001, 123, 10870-10876. Tetrahedron Letters, 2002, 43, 5707-5710. FAB-MS: C31H54N4O8 ESI-MS: C31H54N4SO6
- 86. Wrong Initial Suggestion 13Cshift at 173.50 ppm is O-C=O group J. Nat. Prod., 2000, 63, 1677-1678. J. Nat. Prod., 2003, 66, 716-718. 13 C signal at 173 ppm led to COO bias Data compared to a similar compound
- 87. J. Nat. Prod.,2000, 63, 1677-1678. J. Nat. Prod., 2003, 66, 716-718. 13 C signal at 173 ppm led to COO bias Data compared to a similar compound Wrong Initial Suggestion 13C shift at 173.50 ppm is O-C=O group 13 C signal at 173 ppm led to COO bias Data compared to a similar compound
- 88. Misinterpretation of 2DNMR Data Presence of a guanidine group substituted with 2xCH3 groups was hypothesized. Absence of an expected HMBC correlation from methyls to C(159.0) ignored. J. Org. Chem., 2004, 69,9025-9029. J. Org. Chem., 2008, 73, 8719-8722. Misinterpreted HMBC signal Verified by X-ray crystallography
- 89. Misinterpretation of 2DNMR Data Presence of a guanidine group substituted with 2xCH3 groups was hypothesized. Absence of an expected HMBC correlation from methyls to C(159.0) ignored. J. Org. Chem., 2004, 69,9025-9029 J. Org. Chem., 2008, 73, 8719-8722 Misinterpreted HMBC signal Verified by X-ray crystallography
- 91.
- 92. Number of SkeletalAtoms J. Cheminf. 2012, 4:5
- 93. MW Distribution J. Cheminf.2012, 4:5
- 94. The Agenda… • Dereplicationusing prior knowledge • The increasing prevalence of online content • Data generation is not the issue. Analysis is. • Computer-assisted structure elucidation • New experiments to improve elucidation • Rethink data-sharing through publications!
- 95. New Experiments InfluenceCASE! Cervinomycin O NO O O OO OH O O 1 4 7 9 10 12 14 16 1922 26 29 30 CH3 (fb) CH2 CH2CH2 (ob) C (ob) C CH C CH CCH C CC C (ob) C (ob) C (ob) C C O O O O O H CH3 (ob) CH3 (ob) CH CH C C (ob) C (ob) C (ob) C O O O O
- 96. The Influence ofData on Elucidation Time: Cervinomycin COSY, HSQC 1 H-13 C HMBC 1 H-13 C LR-HSQMBC Structure Generation Time # of Structure s Generated 8 Hz 4 Hz 4 Hz 2 Hz + + + 49 h 314 + + + + 37 h 4 + + + + 150 s 7 + + + + + 104 s 1
- 97. New Experiments Cryptospirolepine over20 years! Inexplicably, the vinyl proton has no evident 2 JCH correlation to the carbonyl! DFT predicted ~0.3 Hz coupling! Synergistic interpretation and CASE applied to an array of 2D data elucidated this compound. Included new 1,1-ADEQUATE and 1,n-ADEQUATE data. The absence of a 2 JCH correlation from the vinyl proton to the adjacent carbonyl is perplexing. A new long-range heteronuclear correlation NMR experiment was acquired: LR-HSQMBC.
- 98. Key 1,1-HD-ADEQUATE Correlations •Experiment was optimized for 60 Hz • Typical range for 1 JCC sp2 couplings is 60-75 Hz • The 2 JCC coupling from C13 to C1/C11’ was calculated (DFT) to be 15.4 Hz, which would give a calculated intensity of 0.16 in this experiment.
- 99. • Experiment optimizedfor 7 Hz • Typical range for n JCC couplings is approximately 2-7 Hz • 2 JCC correlations across carbonyls are typically 10-16 Hz • Correlations were observed, including the 1 JCC correlations from C13 to C2 and C13a that unavoidably “leak” into all 1,n- ADEQUATE spectra. Key 1,1-HD-ADEQUATE Correlations
- 100. Revision of the[7.5.5] Core of Cryptospirolepine to a [6.6.5] System • Based on correlations from the 1,1- and -1,n-HD-ADEQUATE spectra, the [7.5.5] core shown in red was revised to a [6.6.5] system. • The γ-lactam was rearranged to a dehydropiperidinone. • Key correlations were the 1 JCC correlation from the vinyl CH to the flanking carbonyl and quaternary carbons.
- 101. Could CASE methodssort out the structure? 1,1- ADEQUATE 1,n- ADEQUATE 1 H-13 C HMBC IDR HSQC- TOCSY 1 H-13 C LR- HSQMBC 1 H-15 N LR- HSQMBC GENERATION 60 Hz 7 Hz 8 Hz 4 Hz 15 ms 2 Hz 4 Hz 2 Hz Time (s) # Structures + >420 h >10,400 + + + 140 6816 + + + + 142 3360 + + + + 40 522 + + + + + 45 258 + + + + + + + + 7 24 • Modern “1993” data set used as input failed to lead to the generation of the structure in 3 week calculation! • More complete input data reduced calculation to secs!
- 102. The Agenda… • Dereplicationusing prior knowledge • The increasing prevalence of online content • Data generation is not the issue. Analysis is. • Computer-assisted structure elucidation • New experiments to improve elucidation • Rethink data-sharing through publications!
- 103. Errors in publishedstructures…
- 104. ESI – TextSpectra
- 105. ChemSpider ID 24528095H1 NMR
- 106. ChemSpider ID 24528095C13 NMR
- 107. ChemSpider ID 24528095HHCOSY
- 108.
- 109.
- 110. What would ittake??? • PDFs containing text descriptions of spectra are problematic for reinterpretation of data • Publishers should host at least high resolution images of all spectra • Really we need the data files!!!
- 111. Conclusions • Dereplication isincreasingly feasible using online content • Analysis of data is generally a bigger issue than data generation itself • Computer-assisted structure elucidation works • Data-sharing associated with publications needs rethinking
- 112.
- 113. Acknowledgements RSC/ChemSpider/Marinlit •John Blunt •Serin Dabb •ValeryTkachenko NMR (Book) Collaborators •Gary Martin •David Rovnyak ACD/Labs •Structure Elucidator •Mikhail Elyashberg •Kirill Blinov •Arvin Moser •Patrick Wheeler
- 114. Thank you ORCID: 0000-0002-2668-4821 Twitter:@ChemConnector Personal Blog: www.chemconnector.com SLIDES: www.slideshare.net/AntonyWilliams
Editor's Notes
- #14 Number of possible isomers can be extremely large. Impossible to create all isomers to relatively simple compounds (number of stars in our galaxy 1011)
- #15 Number of possible isomers can be extremely large. Impossible to create all isomers to relatively simple compounds (number of stars in our galaxy 1011)
- #37 This is a natural product dataset and software provided a possible molecule within 30 seconds
- #57 Magnetic field strength has grown year on year with the related increase in dispersion and sensitivity
- #64 A variety of methods have been employed, using IR, NMR, and MS. Different philosophies, methodologies, interfaces.
- #65 A variety of methods have been employed, using IR, NMR, and MS. Different philosophies, methodologies, interfaces.
- #67 Number of possible isomers can be extremely large. Impossible to create all isomers to relatively simple compounds (number of stars in our galaxy 1011)
- #68 We can formulate a general CASE strategy:
- #71 Molecular Conneciivity diagram is automatically generated. This can be used for an alternative check on structures.
- #74 Атом 1 to 17: 6-bond НМВС Атом 2 to 7: а=6 COSY
- #81 Fragments are ranked in descending order of numbers of carbon atoms. Carbon atoms already possess chemical shifts.
- #83 Even when you believe that you are confident of a structure, it can still be helpful to have further confirmation of its rectitude. A CASE program can ensure that all appropriate candidates for a given set of structure space are considered.
- #85 Randazzo et al4 isolated a new compound named Halipeptin A. An elemental formula containing only CHNO was assumed: C31H54N4O9 (calculated 627.3969 for C31H55N4O9 with m=0.0104, i.e., 16.6 ppm). Structure A contains an unusual fragment (colored in red) in Fig. 1, and was suggested from 2D NMR data. In a follow-up article,5 the same group found the C31H54N4SO7 formula from HRMS, and the correct structure B was suggested. Both molecular formulae and 2D NMR data were input into ACD/Structure Elucidator. The software generated 303 structures in 36 seconds. Ranking the generated structures using 13C chemical shift prediction placed the correct structure (B) in the first position Randazzo, A.; Bifulco, G.; Giannini, C.; Bucci, M.; Debitus, C.; Cirino, G.; Gomez-Paloma, L., 4. J. Am. Chem. Soc., 123:10870-10876, 2001. Monica, C. D.; Randazzo, A.; Bifulco, G.; Cimino, P.; Aquino, M.; Izzo, I.; De Riccardisc, F.; Gomez-Paloma, L., 5. Tetrahedron Letters, 43:5707-5710, 2002. Poster: Poster: Are Pitfalls Unavoidable During the Structure Elucidation of New Organic Compounds? M. E. Elyashberg, K. A. Blinov, S.G. Molodtsov, A.J. Williams, Ryan Sasaki.
- #86 Randazzo et al4 isolated a new compound named Halipeptin A. An elemental formula containing only CHNO was assumed: C31H54N4O9 (calculated 627.3969 for C31H55N4O9 with m=0.0104, i.e., 16.6 ppm). Structure A contains an unusual fragment (colored in red) in Fig. 1, and was suggested from 2D NMR data. In a follow-up article,5 the same group found the C31H54N4SO7 formula from HRMS, and the correct structure B was suggested. Both molecular formulae and 2D NMR data were input into ACD/Structure Elucidator. The software generated 303 structures in 36 seconds. Ranking the generated structures using 13C chemical shift prediction placed the correct structure (B) in the first position Randazzo, A.; Bifulco, G.; Giannini, C.; Bucci, M.; Debitus, C.; Cirino, G.; Gomez-Paloma, L., 4. J. Am. Chem. Soc., 123:10870-10876, 2001. Monica, C. D.; Randazzo, A.; Bifulco, G.; Cimino, P.; Aquino, M.; Izzo, I.; De Riccardisc, F.; Gomez-Paloma, L., 5. Tetrahedron Letters, 43:5707-5710, 2002. Poster: Poster: Are Pitfalls Unavoidable During the Structure Elucidation of New Organic Compounds? M. E. Elyashberg, K. A. Blinov, S.G. Molodtsov, A.J. Williams, Ryan Sasaki.
- #87 Sakuno et al6 isolated a natural product with molecular formula C20H18O6. Authors9 postulated that the 13C chemical shift at 173.50 ppm was associated with the resonance of the O-C=O group, and with this assumption structure A (Fig. 2) was suggested. Wipf and Kerekes7 compared the NMR and IR spectra of this compound with a number of spectra of its structural relatives and proved that it was identical with viridol (structure B). The 2D NMR data from article6 were input into ACD/Structure Elucidator. No assumptions were used. The software generated 272 structures in 1 min 40 sec. Ranking the generated structures using 13C chemical shift prediction placed the correct structure Viridol (B) in the first position. The originally proposed structure A was placed in the second position but with a large difference in chemical shift deviation. Sakuno, E.; Yabe, K.; Hamasaki, T.; Nakajima, H., 6. J. Nat. Prod., 63:1677-1678, 2000. Wipf, P.; Kerekes, A. D., 7. J. Nat. Prod., 66:716-718, 2003.
- #88 Sakuno et al6 isolated a natural product with molecular formula C20H18O6. Authors9 postulated that the 13C chemical shift at 173.50 ppm was associated with the resonance of the O-C=O group, and with this assumption structure A (Fig. 2) was suggested. Wipf and Kerekes7 compared the NMR and IR spectra of this compound with a number of spectra of its structural relatives and proved that it was identical with viridol (structure B). The 2D NMR data from article6 were input into ACD/Structure Elucidator. No assumptions were used. The software generated 272 structures in 1 min 40 sec. Ranking the generated structures using 13C chemical shift prediction placed the correct structure Viridol (B) in the first position. The originally proposed structure A was placed in the second position but with a large difference in chemical shift deviation. Sakuno, E.; Yabe, K.; Hamasaki, T.; Nakajima, H., 6. J. Nat. Prod., 63:1677-1678, 2000. Wipf, P.; Kerekes, A. D., 7. J. Nat. Prod., 66:716-718, 2003.
- #89 Ralifo and Crews8 reported on the separation of (-)-spiroleucettadine (C20H23N3O4), structure A (Fig. 3). The presence of a guanidine group (C 159.0) substituted with two CH3 groups was hypothesized. The absence of an expected HMBC correlation from one of methyls to C(159.0) was ignored. Several attempts to synthesize this compound were undertaken but without any success. Questions regarding the original structure elucidation process therefore arose. Crews’s group9 fulfilled a successful re-isolation of spiroleucettadine, and X-ray analysis established the correct structure of spiroleucettadine, shown as B, Fig. 3. It was revealed that the postulation of the presence of a guanidine group was erroneous, and one HMBC correlation was misinterpreted in the previous work. When the old 2D NMR data were used in ACD/Structure Elucidator, it was immediately found that the original structure produced deviations that were too large for a positive identification. When the 2D NMR data from the latter study were used with the software, the correct structure was generated and present in the first position after ranking using 13C chemical shift prediction. Ralifo, P.; Crews, P., 8. J. Org. Chem., 69:9025-9029, 2004. White, K. N.; Amagata, T.; Oliver, A. G.; Tenney, K.; Wenzel, P. J.; Crews, P., 9. J. Org. Chem., 73:8719-8722, 2008.
- #90 Ralifo and Crews8 reported on the separation of (-)-spiroleucettadine (C20H23N3O4), structure A (Fig. 3). The presence of a guanidine group (C 159.0) substituted with two CH3 groups was hypothesized. The absence of an expected HMBC correlation from one of methyls to C(159.0) was ignored. Several attempts to synthesize this compound were undertaken but without any success. Questions regarding the original structure elucidation process therefore arose. Crews’s group9 fulfilled a successful re-isolation of spiroleucettadine, and X-ray analysis established the correct structure of spiroleucettadine, shown as B, Fig. 3. It was revealed that the postulation of the presence of a guanidine group was erroneous, and one HMBC correlation was misinterpreted in the previous work. When the old 2D NMR data were used in ACD/Structure Elucidator, it was immediately found that the original structure produced deviations that were too large for a positive identification. When the 2D NMR data from the latter study were used with the software, the correct structure was generated and present in the first position after ranking using 13C chemical shift prediction. Ralifo, P.; Crews, P., 8. J. Org. Chem., 69:9025-9029, 2004. White, K. N.; Amagata, T.; Oliver, A. G.; Tenney, K.; Wenzel, P. J.; Crews, P., 9. J. Org. Chem., 73:8719-8722, 2008.
- #94 Characteristics of known drug space. Natural products, their derivatives and synthetic drugs
- #97 Results obtained from various Structure Elucidator CASE program computation runs for various sets of input data for the xanthone antibiotic cervinomycin A2 (see Figure X.17B for the structure). As can be readily seen from the first two rows of the table, restricing the input data file to data that is likely to have primarily 2JCH and 3JCH correlations with perhaps only sparse 4JCH correlations (rows 1 and 2) leads to lengthy computation runs. However, when 2 Hz optimized LR-HSQMBC data, which can contain 4JCH – 6JCH correlations (rows 3 and 4), are included in the data input file computation times drop precipitously and the number of structures generated is also significantly reduced.
- #104 Errors in published structures are rampant.