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The application of empirical methods of 13C NMR chemical shift prediction as a filter for determining possible relative stereochemistry
The application of empirical methods of 13C NMR chemical shift prediction as a filter for determining possible relative stereochemistry
The application of empirical methods of 13C NMR chemical shift prediction as a filter for determining possible relative stereochemistry
The application of empirical methods of 13C NMR chemical shift prediction as a filter for determining possible relative stereochemistry
The application of empirical methods of 13C NMR chemical shift prediction as a filter for determining possible relative stereochemistry
The application of empirical methods of 13C NMR chemical shift prediction as a filter for determining possible relative stereochemistry
The application of empirical methods of 13C NMR chemical shift prediction as a filter for determining possible relative stereochemistry
The application of empirical methods of 13C NMR chemical shift prediction as a filter for determining possible relative stereochemistry
The application of empirical methods of 13C NMR chemical shift prediction as a filter for determining possible relative stereochemistry
The application of empirical methods of 13C NMR chemical shift prediction as a filter for determining possible relative stereochemistry
The application of empirical methods of 13C NMR chemical shift prediction as a filter for determining possible relative stereochemistry
The application of empirical methods of 13C NMR chemical shift prediction as a filter for determining possible relative stereochemistry
The application of empirical methods of 13C NMR chemical shift prediction as a filter for determining possible relative stereochemistry
The application of empirical methods of 13C NMR chemical shift prediction as a filter for determining possible relative stereochemistry
The application of empirical methods of 13C NMR chemical shift prediction as a filter for determining possible relative stereochemistry
The application of empirical methods of 13C NMR chemical shift prediction as a filter for determining possible relative stereochemistry
The application of empirical methods of 13C NMR chemical shift prediction as a filter for determining possible relative stereochemistry
The application of empirical methods of 13C NMR chemical shift prediction as a filter for determining possible relative stereochemistry
The application of empirical methods of 13C NMR chemical shift prediction as a filter for determining possible relative stereochemistry
The application of empirical methods of 13C NMR chemical shift prediction as a filter for determining possible relative stereochemistry
The application of empirical methods of 13C NMR chemical shift prediction as a filter for determining possible relative stereochemistry
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The application of empirical methods of 13C NMR chemical shift prediction as a filter for determining possible relative stereochemistry

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The reliable determination of stereocenters contained within chemical structures usually requires utilization of NMR data, chemical derivatization, molecular modeling, quantum-mechanical (QM) …

The reliable determination of stereocenters contained within chemical structures usually requires utilization of NMR data, chemical derivatization, molecular modeling, quantum-mechanical (QM) calculations and, if available, X-ray analysis. In this article, we show that the number of stereoisomers which need to be thoroughly verified, can be significantly reduced by the application of NMR chemical shift calculation to the full stereoisomer set of possibilities using a fragmental approach based on HOSE codes. The applicability of this suggested method is illustrated using experimental data published for a series of complex chemical structures.

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  • 1. The Application of Empirical Methods of 13C NMR Chemical Shift Prediction as aFilter for Determining Possible Relative Stereochemistry.A short title:The Application of Empirical NMR Prediction to Determine StereochemistryMikhail E. Elyashberg+, Kirill A. Blinov+ and Antony J.Williams*.+ Advanced Chemistry Development, Moscow Department, 6 Akademik Bakulev Street,Moscow 117513, Russian Federation, ChemZoo Inc., 904 Tamaras Circle, Wake Forest, North Carolina 27587Abstract:The reliable determination of stereocenters contained within chemical structures usuallyrequires utilization of NMR data, chemical derivatization, molecular modeling, quantum-mechanical calculations and, if available, X-ray analysis. In this article we show that thenumber of stereoisomers which need to be thoroughly verified can be significantlyreduced by the application of NMR chemical shift calculation to the full stereoisomer setof possibilities using a fragmental approach based on HOSE codes. The applicability ofthis suggested method is illustrated using experimental data published for a series ofcomplex chemical structures.Keywords:NMR, 1H, 13C, chemical shift prediction, stereochemistry.Introduction 1
  • 2. A number of different methods of NMR chemical shift prediction have been appliedto the process of molecular structure elucidation and validation. Empirical methods areattractive since they are fast enough and fully automatic. The fastest NMR spectracalculations are provided using an incremental approach and offer a computational speedof 6,000-10,000 chemical shifts per second on a normal desktop computer (circa 2007)and provides an average chemical shift deviation for carbon NMR of 1.8 ppm[1,2].Spectral prediction utilizing artificial neural networks provide similar speed and accuracyperformance[1,2]. The third most popular empirical method is slower and is based on the 13application of a database containing reference structures with assigned C or 1Hchemical shifts. The target and reference structures are described by means of HOSEcodes[3] and this allows prediction of the chemical shift of an atom from the targetstructure using the chemical shifts of the reference structures as the basis. In theACD/NMR predictor[4], the prediction algorithms use a library containing 185,000structures with NMR chemical shifts assigned to carbon and hydrogen atoms. Ifinformation regarding the relative stereochemistry of a given atom ai and its environmentis known then these data are also coded into the reference structures. To predict thechemical shift of an atom ai in the target structure its HOSE code is compared with thecodes of the corresponding atoms in reference structures. As a result of statisticalprocessing of the chemical shifts assigned to all “atom-twins” detected in the referencestructures, the chemical shift of an atom from the target structure is predicted. A strategybased on combining all mentioned methods was suggested[5,6]. It allows selection of themost probable structure from the output file of expert system developed for the molecularstructure elucidation. 2
  • 3. At the same time a series of articles have been published espousing the value of ab-initio quantum mechanical (QM) approaches for NMR chemical shift calculations (forinstance,[7-12]) and, most frequently, the GIAO option of the DFT method[13] has beenemployed for the calculation of 1H and 13C chemical shifts. It was shown that DFT basedmethods can be applied for the selection of a preferable structural hypothesis by means ofcomparing the predicted chemical shifts with those determined experimentally. Thisapproach was also an efficient tool for evaluating the different conformers of flexiblemolecules as well as the elucidation of the most probable stereoisomers[13-17]. In our previous report[18] we have shown that empirical methods of NMR chemicalshift prediction can be successfully used at the selection stage of structural hypotheseswhich are verified further with application of molecular geometry optimization and QMchemical shift prediction. In this regard we hypothesize that empirical methods can helpin preliminary selection of a set of the most probable stereoisomers for their subsequentverification by additional experimental techniques and QM chemical shift prediction.This may be possible since the stereocenters of structures included into the ACD/CNMRdatabase and stereochemistry is taken into account by the NMR chemical shift predictionalgorithms. The incremental and neural nets based algorithms of chemical shift predictionalso use the stereochemistry information related to the atoms included into 3-6-memberedcycles[2]. It was interesting to know whether this information can be useful forstereochemistry determination. We have tested our hypothesis using a series of examples. We have used examplesfrom recent literature (2007-8) for novel structures for which relative stereochemistrywas reported. These structures are deliberately absent from the ACD/CNMR database. 3
  • 4. The application of empirical methods of 13C NMR chemical shift prediction is shown toallow the selection of a set of the most probable stereoisomers and always includes thegenuine stereoconfiguration.RESULTS AND DISCUSSION. Fattorusso et al[15] utilized DFT chemical shift computation to confirm the mostprobable stereoisomer of artarborol, 1, a rare nor-caryophyllane derivative, isolated bythe authors[15] and structurally characterized by both 1D and 2D NMR spectroscopicmethods. H O 10 CH3 17 16 1 4 11 6 12 7 2 5 H 3 19 HO CH3 13 8 14 H 18 9 CH3 15 1 To select the most probable stereoisomer the authors[15] carried out a series ofinvestigations. Structure 1 contains five stereogenic carbons (numbered 1-5 on structure1) with four of them at junctions between the 9-membered ring and the small ring cycles,while both cis- and trans- junctions of rings adjacent to the nine-membered core arepossible in natural caryophyllanes. A combination of 2D ROESY experiments with Mosher’s modified method[19]was used to assess the absolute configuration of C-2 (R) and allowed the authors[15] toreduce the total number of possible stereoisomers to the following four (Figure 1): 4
  • 5. O O O O H 10 CH3 H 10 H 10 CH3 H 10 CH3 17 CH3 17 16 17 16 17 16 1 4 16 1 4 1 4 1 4 11 6 11 6 11 6 11 6 12 7 12 7 12 7 12 7 2 5 H 2 5 H 2 5 H 2 5 H 19 19 3 19 19 3 3 3 CH3 CH3 CH3 CH3 14 14 8 14 14 HO H 8 HO 8 HO H HO H 8 13 9 13 H 9 13 18 9 13 9 18 18 18 CH3 CH3 CH3 CH3 15 15 15 15 A B C DFigure 1. The four candidate stereoisomer structures of artarborol.Further selection was made by analyzing the scalar coupling constants and additionalspatial couplings across the entire molecule for which all candidate structures weresubjected to a conformational search. As a result, structures B and D were rejected at thefirst step, structure C was then excluded and finally stereoconfiguration A was assignedto artarborol. To support this stereochemical assignment each conformation of thestereoisomers A and C were fully optimized by the authors[15], and the NMR chemicalshifts were calculated using the GIAO option of the MPW1PW91/6-31G(d,p) DFTmethod[20]. A Boltzmann-weighted average of the 13C NMR chemical shifts for all carbonatoms in the low-energy conformers was calculated for each configuration, using the ab-initio standard free energies as weighting factors[21]. The total processing time for eachmolecule was approximately 60 h (PC Pentium IV). A comparison of calculated chemicalshifts with those determined experimentally for structures A and C showed thatdeviations were smaller for structure A thereby confirming the validity of the solution. Selection of the most probable stereoisomer was attained as a result of acomprehensive experimental and theoretical investigation of the compound and itsconceivable 3D models. We investigated what results would be obtained if the problem 5
  • 6. is solved using 1D and 2D NMR spectra and the empirical chemical shift predictionmethods implemented into the expert system Structure Elucidator[5,6,22]. To perform this analysis structure 1 was input into the system and all carbon andhydrogen atoms were supplied with chemical shifts in accordance with the author’sassignment. Then all 25=32 streoisomers were generated by the program and depictedusing conventional designations for stereobonds. 1H and 13 C chemical shifts werecalculated for the complete stereoisomer set using the fragment-based approach within 13the Structure Elucidator program. In addition, C NMR chemical shifts were calculatedusing both neural net (N) and incremental (I) approaches. The average deviations of the predicted chemical shifts relative to theexperimental shifts (dA = fragmental approach, dN = NN approach and dI = incrementalapproach) were calculated for each of 32 stereoisomers and all stereoisomers were rankedin ascending order of the 13C deviation values. Since the chemical shifts are insensitive tothe absolute configuration of a stereoisomer and its inverse partner the reduced rankedstereoisomer set was finally represented as a sequence of 16 stereoisomer pairs, each pairhaving equal deviations. Figure 2 shows the first 8 out of 16 “unique” stereoisomers 13ranked in ascending order of the average deviations calculated for C NMR spectrum.The remaining stereoisomers are characterized by 13C average deviations dA(13C) fallingin the range between 2.49 and 2.90 ppm. Figure 2 shows that the correct stereoisomer was distinguished both by its 13C and1 H average deviations. Our experiences in the field of computer-aided structureelucidation have shown [22] that the dA(1H) deviation is a less reliable criterion comparedwith dC and it is usually only used for additional confirmation of the most probable 6
  • 7. structural isomer[5,6,22]. The difference between the deviations dA(13C) found for thesecond and first ranked structures is not large (0.2 ppm), but this value is frequentlyobserved in the structure elucidation process when the “best structure” is selected[22] . It isworthy to note that in the stereoisomers 3, 4, 6 and 9, atoms H-17 and H-19 are situatedon opposite sides of the macrocycle and are unlikely to be close enough in space to showa ROESY coupling. Since the authors[15] made the final choice between structures A and 13C on the basis of comparison of differences between experimental and calculated Cchemical shifts of all carbon atoms we also compared these values (see Figure 3).1 (ID:29) 2 (ID:4) 3 (ID:13) 4 (ID:24) O O O O A H CH3 H CH3 H CH3 H CH3 H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H CH3 CH3 CH3 CH3 HO HO H HO H HO H H CH3 CH3 CH3 CH3dA(13C): 1.773 (v.11.01) dA(13C): 1.959 (v.11.01) dA(13C): 1.969 (v.11.01) dA(13C): 1.982 (v.11.01)dI(13C): 2.791 dI(13C): 2.893 dI(13C): 2.893 dI(13C): 2.893dN(13C): 2.738 dN(13C): 2.817 dN(13C): 2.817 dN(13C): 2.817dA(1H): 0.289 (v.11.01) dA(1H): 0.313 (v.11.01) dA(1H): 0.312 (v.11.01) dA(1H): 0.313 (v.11.01)5 (ID:8) 6 (ID:20) 7 (ID:12) 8 (ID:33) O O D O C O H CH3 H CH3 H CH3 H CH3 H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H CH H H H CH3 CH3 CH3 3 HO HO HO H HO H H H CH3 CH3 CH3 CH3dA(13C): 1.998 (v.11.01) dA(13C): 2.092 (v.11.01) dA(13C): 2.358 (v.11.01) dA(13C): 2.364 (v.11.01)dI(13C): 2.791 dI(13C): 2.791 dI(13C): 3.643 dI(13C): 2.893dN(13C): 2.738 dN(13C): 2.738 dN(13C): 3.306 dN(13C): 2.817dA(1H): 0.293 (v.11.01) dA(1H): 0.293 (v.11.01) dA(1H): 0.313 (v.11.01) dA(1H): 0.309 (v.11.01)Figure 2. The first 8 out of 16 stereoisomers ranked in ascending order of the averagedeviation dA (13C). 7
  • 8. 6 4 Chemical shift difference, ppm 2 0 1 3 5 7 9 11 13 A -2 C -4 -6 -8 -10 Atom num ber 13Figure 3. A comparison of the C chemical shift deviations calculated for the carbonatoms contained in stereoisomers A and C.Figure 3 shows that the main difference between the chemical shifts calculated forstructures A and C is observed for atoms 6 and 7. For structure A the calculated valuesare markedly closer to the experimental values. The maximum prediction errors areshown for atoms 3 and 5 at the junction between the macrocycle and the 4-memberedring. Stereoisomer ranking with dN (13C ) and dI (13C ) values in general supported thepriority of stereoisomers A-D: these fell into the first four stereoisomers for which all dN(13C ) values and all dI (13C ) values proved to be equal (see Supporting Materials, Figure1S). The approach described here looks attractive due to its simplicity and high speed: 13the C and 1H chemical shift calculations for all 32 isomers took about 2 minutes on aPentium IV, 2.8 GHz processor compared to 60 hours per prediction as reported by theauthors of the original paper. It could be useful for the preliminary assessment of a fullstereoisomer set and rejection of deliberately improbable structures when the analyzedmolecule is relatively rigid. The reliability of such conclusions can be heuristically 8
  • 9. evaluated by visual comparison of the reference structures used for chemical shiftprediction with the target structure. For instance, a series of structures containing the ringframework of artarborol were shown by the program when examining the chemical shiftprediction protocol. It should be emphasized that the artarborol molecule (a newcompound) was absent from the library of structures included with the ACD/NMRprediction program. Reference structure 2 is the most similar structure to the artarborolstructure under investigation: H O 63.65 CH3 27.60 59.80 16.90 29.45 40.10 HO 51.50 24.45 66.40 43.75 44.25 H H 39.50 34.60 CH3 21.55 CH3 29.85 2We demonstrated that removing structure 2 from the database did not influence theresults: the deviation characteristic for the best stereoisomer was only slightly increasedfrom 1.773 to 1.799 ppm. The described approach was also applied to two new ketopelenolides 3 and 4 whichwere separated and scrutinized by the same research group[23]. The stereochemistryshown in structures 3 and 4 was determined by authors[23] as a result of conformationalanalysis and QM based 13C chemical shift calculation of the most probable stereoisomers.The calculations were performed in groups of four for each structure (C1-C4 for structure3 and D1-D4 for structure 4, see Figure 4). It has been shown that C1 corresponds tostereoisomer 3 and D1 – to stereoisomer 4. 9
  • 10. HO O CH3 H H CH3 O O HH3C H H3C CH3 CH3 H H3C H H O H O H O O 3 4 HO CH3 HO CH3 HO CH3 HO CH3 H H H HO O O O H H H H H H H HH 3C H3C H3C H3C CH3 CH3 CH3 CH3 H H H H O H O H O H O H O O O O C1 C2 C3 C4 O O O O H CH3 H CH3 H CH3 H CH3O O O O H H H H H H H HH 3C H3C H CH3 H CH3 H3C H CH3 H3C H CH3 H H H H O O O O O O O O D1 D2 D3 D4Figure 4. The most probable stereoisomers of structures 3 and 4 selected for detailedtheoretical analysis in the work[23]. Structure Elucidator was used to generate all possible stereoisomers for structures 3and 4 (in both cases N=64) and to perform NMR chemical shift calculations for all 10
  • 11. 13stereoisomers using empirical methods. C chemical shift prediction using thefragmental method placed stereoisomer C2 in first position in the ranked file and thegenuine stereoisomer C1 at the second position with a difference between deviations of0.01 ppm. At the same time ranking stereoisomers using dN(13C) values broughtstereoisomers C1-C4 to the 1-4 positions with equal dN(13C) and dI(13C) values for all ofthe stereoisomers (see Supporting Materials, Figure 2S). For structure 4 the stereoisomerswere ranked by dA(13C) values in the following order: 1st – D1, 2nd – D2, 3rd – D3, 5th –D4 (see Supporting Materials, Figure 3S). The correct stereoisomer was placed in firstposition and the other most probable stereoisomers selected in[23] were distinguished bythe program as also deserving attention. For preliminary evaluation of the generality of the described approach werepeated the work using the structures of natural products belonging to a number ofdifferent classes, i.e. steroids, alkaloids, terpenes, cembranoids, etc. A set of suchstructures whose relative stereochemistry was recently described in a series ofpublications was chosen (see Table 1).Table 1. Examples of structures for which sets of preferable stereoisomers were selected 13using empirical methods of C NMR chemical shift prediction. The R and S 11
  • 12. designations shown in the structures correspond to the stereochemistry at the particularstereocenter. Nds, Sr, Ref.Example. Structure Number Position No of of Correct Stereo- Stereoisomer isomers CH3 [24] 1 HO 1024 1 R H3C R S S OH H3C CH3 H R S R R O H3C R R H HO R O H OH CH3 O [25] 2 256 1 CH3 H3C S E E R S CH3 E E H CH3 HO S R E E S H H H3C O HO O CH3 [26] 3 32 1 H N S R H S R H R N H H S O O H 12
  • 13. O [27]4 32 1 O H3C CH2 R O O CH3R H O R R H3C S S H H3C O H OH H3C [28]5 O 64 1 CH3 O H O O H R S H HO CH3 S H3C S H3C H3C S H S H O S H O CH3 CH2 OH [29]6 OH 32 3 O HO S H S S H H H S O HO H S O R O H O OH O [30]7 CH3 128 3 O HO CH3 H S S S H S R R H R N H S H H H3C 13
  • 14. H [31]8 CH3 2048 3 R CH3 O * H3C O R R OH CH3 S H H CH3 R HO R S S R H R R H OH HO H H O O [32]9 1024 3 CH3 O CH3 H H H3C R R O CH3 H R H S R H3C CH3 R O H S R O S H HO S S CH3O CH3 H3C H O O HH O CH3 O O [28]10 H3C CH3 512 3 O O HO H OH HO S R CH3 H S H3C S S O O CH3 H H3C R S E R O E O R H3C H CH 2 H H O O CH3 H [33]11 H3C CH3 64 3 H3C S N S CH3 H3C R H S R R S H H3C N H3C 14
  • 15. O [27] 12 32 4 H3C O H3C O R H CH2 S H O R H O CH3 S H S R H2C OH 13 O 256 8 [34] H3C CH3 O H OH3C CH3 O S Z O O R S S Z H HO H S H CH3 S S S O H O CH2 R H O H3C O H H3C O [35] 14 256 12 H CH3 HO CH3 S R R H H3C HO R S S R H H OH H R R HO H OAll selected structures were supplied with assigned experimental 1H and 13 C NMRchemical shifts. Three similar structures borrowed from earlier publications (of 2003 and2004) were temporarily removed from the database during our research. For eachmolecule a full set of N possible stereoisomers was generated and the 13C NMR chemicalshifts of Nds differing stereoisomers (Nds =N/2, N=2n, n – number of stereocenters) werecalculated by all three mentioned algorithms. A stereoisomer file was ranked in the sameway as in the artarborol case – in descending order of dA(13C) values, and the position of 15
  • 16. the correct stereoisomer, as determined in the corresponding article, was detected in theranked file. The result of each computational experiment was characterized by an Sr valuewhere Sr is the number of stereoisomers for which the deviations dA(13C) are less than orequal to the deviation calculated for the right stereoisomer. For instance, Sr =1 means thatthe right stereoisomer was ranked the first in the file with deviation dA1(13C), and dA1(13C)< dA2(13C), where dA2(13C) is the deviation calculated for the stereoisomer ranked insecond position. The notation Sr =4 means that the correct stereoisomer is among the firstfour stereoisomers in the ranked file. Table 1 shows that our suggested approach can indeed be used for selecting a setof the most probable stereoisomers from all possible members of the family. Even forrather complex structures the preferable stereoisomer was ranked early in the set.Stereoisomer ranking using dN(13C) is not as effective as dA(13C) but nevertheless in thiscase the right stereoisomer most frequently fell into the set of the first 8 rankedstereoisomers. Consequently, the neural net approach can be used for preliminary rankingthe stereoisomer file for subsequent spectrum prediction based on fragmental method asis common in Structure Elucidator system[6]. When NOESY/ROESY data were availablefrom the corresponding articles, application of these data to structures presented in topsets (Sr =3-12) allowed us to conclude that the right stereoisomer is the preferred onealgorithmically also. Examples of the several top ranked sets of stereoisomers arepresented in the Supporting Materials.Computational Details. 16
  • 17. All calculations were performed using ACD/NMR predictor Version 11.00. A personalcomputer equipped with a 2.8 GHz Intel processor and 2Gb of RAM and running theWindows2000 operating system was used. All computer programs are an integral part ofthe Structure Elucidator expert system. Other than supplying a set of structures,stereoisomer generation and NMR chemical shift calculation requires no interventionfrom the chemist and are performed fully automatically.Conclusions. 13The possibility of applying empirical methods of C NMR chemical shift prediction forselection of a set of the most probable stereoisomers related to a given chemical structurehas been shown for a series of examples. Application of this approach to the elucidationof the preferred stereoisomer of artarborol has been considered in more detail. Weselected the most probable stereoisomer of artarborol using a simple and fast empiricalmethod of chemical shift prediction based on HOSE codes. We suggest that it is worthemploying this approach for the preliminary evaluation of all possible stereoisomersgenerated by the expert system Structure Elucidator. We expect that this approach willshow general utility when the analyzed structure is relatively rigid and the referencestructures used for chemical shift prediction contain large common fragments with stereoassignments. This approach can markedly reduce the number of stereoisomers that shouldbe thoroughly investigated on the basis of NOE correlations, coupling constant valuesand quantum-mechanical calculations to finally establish the preferable stereoisomer. Themethod can be enhanced by utilizing the methodology suggested in our work[36] and viceversa: if a starting stereoisomer fed as input to the genetic algorithm for prediction and is 17
  • 18. close to the right one the genetic algorithm will complete the calculations in a shortertime. To continue to develop an optimal strategy and deduce further practicalrecommendations it is necessary to investigate a larger set of diverse structures. In thisway we can further refine our methods of NMR chemical shift prediction and make themmore sensitive to relative stereochemistry. For this aim a statistically relevant collectionof material must be accumulated and generalized. This work is in progress, and resultswill be presented in our next publication.References[1] Blinov KA, Smurnyy YD, Elyashberg ME, Churanova TS, Kvasha M, SteinbeckC, Lefebvre BE, Williams AJ. J. Chem. Inf. Model. 2008; 48: 550.[2] Smurnyy YD, Blinov KA, Churanova TS, Elyashberg ME, Williams AJ. J. Chem.Inf. Model. 2008; 48: 128.[3] Bremser W. Anal.Chim. Act. Comp. Techn. Optimiz. 1978; 2: 355.[4] ACD/NMR Predictor v.11. Advanced Chemistry Development, Toronto, Canada.[5] Blinov KA, Carlson D, Elyashberg ME, Martin GE, Martirosian ER, MolodtsovSG, Williams AJ. Magn. Reson. Chem. 2003; 41: 359.[6] Elyashberg ME, Blinov KA, Molodtsov SG, Williams AJ, Martin GE. J. Chem.Inf. Comput. Sci. 2004; 44: 771.[7] Bagno A, Saielli G. Theor. Chem. Acc. 2007; 117: 603.[8] Balandina A, Kalinin A, Mamedov V, Figadere B, Latypov S. Magn. Reson.Chem. 2005; 43: 816. 18
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  • 20. [23] Fattorusso E, Luciano P, Romano A, Taglialatela-Scafati O, Appendino G,Borriello M, Fattorusso E. J. Nat. Prod. 2008; 71 (web ASAP)[24] Thuong PT, Lee CH, Dao TT, Nguyen PH, Kim WG, Lee SJ, Oh WK. J. Nat.Prod.. 2008; 71: 1775.[25] Lv F, Xu M, Deng Z, de Voogd NJ, van Soest RWM, Proksch P, Lin W. J. Nat.Prod.. 2008; 71: 1738.[26] Breitmaier E, Voelter W Carbon-13 NMR spectroscopy. VCH, Weinheim, 3rdEdition, 1987.[27] Lu Y, Huang CY, Lin Y-F, Wen Z-H, Su J-H, Kuo Y-H, Chiang MY, Sheu J-H.J. Nat. Prod. 2008; 71: 1754.[28] Shi Q-W, Sauriol F, Mamer O, Zamir LO. J. Nat. Prod. 2003; 66: 1480.[29] Ge HM, Huang B, Tan SH, Shi DH, Song YC, Tan RX. J. Nat. Prod. 2006; 69:1800.[30] Zhang C-R, Yang S-P, Yue J-M. J. Nat. Prod. 2008; 71: 1663.[31] Castro A, Coll J, Tandro´n YA, Pant AK, Mathela CS. J. Nat. Prod. 2008; 71:1294.[32] Jang KH, Jeon J-E, Ryu S, Lee H-S, Oh K-B, Shin J. J. Nat. Prod. 2008; 71:1701.[33] Devkota KP, Lenta BN, Wansi JD, Choudhary MI, Kisangau DP. J. Nat. Prod.2008; 71: 1481.[34] Liaw C-C, Shen Y-C, Lin Y-S, Hwang T-L, Kuo Y-H, Khalil AT. J. Nat. Prod.2008; 71: 1551. 20
  • 21. [35] Hunyadi A, Tóth G, Simon A, Mák M, Kele Z, Máthé I, Báthori M. J. Nat. Prod.2007; 70: 412.[36] Smurnyy YD, Elyashberg ME, Blinov KA, Lefebvre B, Martin GE, Williams AJ.Tetrahedron 2005; 61 9980.CaptionsFigure 1. The four candidate stereoisomer structures of artarborol.Figure 2. The first 8 out of 16 stereoisomers ranked in ascending order of the averagedeviation dC. 13Figure 3. A comparison of the C chemical shift deviations calculated for the carbonatoms contained in stereoisomers A and C.Figure 4. The most probable stereoisomers of structures 3 and 4 selected for detailedtheoretical analysis in the work[23] 21

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