Computed NMR spectra predicts the structure of Nobilisitine A

Nobilisitine A was isolated by Evidente and coworkers, who proposed the structure 1.¹ Banwell and co-workers then synthesized the enantiomer of 1, but its NMR did not correspond to that of reported for Nobilisitine A.; the largest differences are 4.7 ppm for the ¹³C NMR and 0.79 ppm for the ¹H NMR.²

1

Lodewyk and Tantillo³ examined seven diastereomers of 1, all of which have a cis fusion between the saturated 5 and six-member rings (rings C and D). Low energy conformations were computed for each of these diasteromers at B3LYP/6-31+G(d,p). NMR shielding constants were then computed in solvent (using a continuum approach) at mPW1PW91/6-311+G(2d,p). A Boltzmann weighting of the shielding contants was then computed, and these shifts were then scaled as described by Jain, Bally and Rablen⁴ (discussed in this post). The computed NMR shifts for 1 were compared with the experimental values, and the mean deviations for the ¹³C and ¹H svalues is 1.2 and 0.13 ppm, respectively. (The largest outlier is 3.4 ppm for ¹³C and 0.31 for ¹H shifts.) Comparison was then made between the computed shifts of the seven diasteomers and the reported spectrum of Nobilisitine A, and the lowest mean deviations (1.4 ppm for ¹³C and 0.21 ppm for ¹H) is for structure 2. However, the agreement is not substantially better than for a couple of the other diasteomers.

2

They next employed the DP4 analysis developed by Smith and Goodman⁵ for just such a situation – where you have an experimental spectrum and a number of potential diastereomeric structures. (See this post for a discussion of the DP4 method.)The DP4 analysis suggests that 2 is the correct structure with a probability of 99.8%.

Banwell has now synthesized the compound with structure 2 and its NMR matches that of the original natural product.⁶ Thus Nobilisitine A has the structure 2.

References

(1) Evidente, A.; Abou-Donia, A. H.; Darwish, F. A.; Amer, M. E.; Kassem, F. F.; Hammoda, H. A. m.; Motta, A., "Nobilisitine A and B, two masanane-type alkaloids from Clivia nobilis,"Phytochemistry, 1999, 51, 1151-1155, DOI: 10.1016/S0031-9422(98)00714-6.

(2) Schwartz, B. D.; Jones, M. T.; Banwell, M. G.; Cade, I. A., "Synthesis of the Enantiomer of the Structure Assigned to the Natural Product Nobilisitine A," Org. Lett., 2010, 12, 5210-5213, DOI:10.1021/ol102249q

(3) Lodewyk, M. W.; Tantillo, D. J., "Prediction of the Structure of Nobilisitine A Using Computed NMR Chemical Shifts," J. Nat. Prod., 2011, 74, 1339-1343, DOI: 10.1021/np2000446

(4) Jain, R.; Bally, T.; Rablen, P. R., "Calculating Accurate Proton Chemical Shifts of Organic Molecules with Density Functional Methods and Modest Basis Sets," J. Org. Chem., 2009, DOI:10.1021/jo900482q.

(5) Smith, S. G.; Goodman, J. M., "Assigning Stereochemistry to Single Diastereoisomers by GIAO NMR Calculation: The DP4 Probability," J. Am. Chem. Soc., 2010, 132, 12946-12959, DOI:10.1021/ja105035r

(6) Schwartz, B. D.; White, L. V.; Banwell, M. G.; Willis, A. C., "Structure of the Lycorinine Alkaloid Nobilisitine A," J. Org. Chem., 2011, ASAP, DOI: 10.1021/jo2016899




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Computed NMR spectra predicts the structure of Nobilisitine A

Nobilisitine A was isolated by Evidente and coworkers, who proposed the structure 1.¹ Banwell and co-workers then synthesized the enantiomer of 1, but its NMR did not correspond to that of reported for Nobilisitine A.; the largest differences are 4.7 ppm for the ¹³C NMR and 0.79 ppm for the ¹H NMR.²

1

Lodewyk and Tantillo³ examined seven diastereomers of 1, all of which have a cis fusion between the saturated 5 and six-member rings (rings C and D). Low energy conformations were computed for each of these diasteromers at B3LYP/6-31+G(d,p). NMR shielding constants were then computed in solvent (using a continuum approach) at mPW1PW91/6-311+G(2d,p). A Boltzmann weighting of the shielding contants was then computed, and these shifts were then scaled as described by Jain, Bally and Rablen⁴ (discussed in this post). The computed NMR shifts for 1 were compared with the experimental values, and the mean deviations for the ¹³C and ¹H svalues is 1.2 and 0.13 ppm, respectively. (The largest outlier is 3.4 ppm for ¹³C and 0.31 for ¹H shifts.) Comparison was then made between the computed shifts of the seven diasteomers and the reported spectrum of Nobilisitine A, and the lowest mean deviations (1.4 ppm for ¹³C and 0.21 ppm for ¹H) is for structure 2. However, the agreement is not substantially better than for a couple of the other diasteomers.

2

They next employed the DP4 analysis developed by Smith and Goodman⁵ for just such a situation – where you have an experimental spectrum and a number of potential diastereomeric structures. (See this post for a discussion of the DP4 method.)The DP4 analysis suggests that 2 is the correct structure with a probability of 99.8%.

Banwell has now synthesized the compound with structure 2 and its NMR matches that of the original natural product.⁶ Thus Nobilisitine A has the structure 2.

References

(1) Evidente, A.; Abou-Donia, A. H.; Darwish, F. A.; Amer, M. E.; Kassem, F. F.; Hammoda, H. A. m.; Motta, A., "Nobilisitine A and B, two masanane-type alkaloids from Clivia nobilis,"Phytochemistry, 1999, 51, 1151-1155, DOI: 10.1016/S0031-9422(98)00714-6.

(2) Schwartz, B. D.; Jones, M. T.; Banwell, M. G.; Cade, I. A., "Synthesis of the Enantiomer of the Structure Assigned to the Natural Product Nobilisitine A," Org. Lett., 2010, 12, 5210-5213, DOI:10.1021/ol102249q

(3) Lodewyk, M. W.; Tantillo, D. J., "Prediction of the Structure of Nobilisitine A Using Computed NMR Chemical Shifts," J. Nat. Prod., 2011, 74, 1339-1343, DOI: 10.1021/np2000446

(4) Jain, R.; Bally, T.; Rablen, P. R., "Calculating Accurate Proton Chemical Shifts of Organic Molecules with Density Functional Methods and Modest Basis Sets," J. Org. Chem., 2009, DOI:10.1021/jo900482q.

(5) Smith, S. G.; Goodman, J. M., "Assigning Stereochemistry to Single Diastereoisomers by GIAO NMR Calculation: The DP4 Probability," J. Am. Chem. Soc., 2010, 132, 12946-12959, DOI:10.1021/ja105035r

(6) Schwartz, B. D.; White, L. V.; Banwell, M. G.; Willis, A. C., "Structure of the Lycorinine Alkaloid Nobilisitine A," J. Org. Chem., 2011, ASAP, DOI: 10.1021/jo2016899