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Computed NMR spectra predicts the structure of Nobilisitine A
Nobilisitine A was isolated by Evidente and coworkers, who proposed the structure1.1Banwell and co-workers then synthesized the enantiomer of1, but its NMR did not correspond to that of reported for Nobilisitine A.; the largest differences are 4.7 ppm for the13C NMR and 0.79 ppm for the1H NMR.2
Lodewyk and Tantillo3examined seven diastereomers of1, all of which have acisfusion 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 thispost). The computed NMR shifts for1were compared with the experimental values, and the mean deviations for the13C and1H svalues is 1.2 and 0.13 ppm, respectively. (The largest outlier is 3.4 ppm for13C and 0.31 for1H 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 for13C and 0.21 ppm for1H) is for structure2. However, the agreement is not substantially better than for a couple of the other diasteomers.
They next employed the DP4 analysis developed by Smith and Goodman5for just such a situation – where you have an experimental spectrum and a number of potential diastereomeric structures. (Seethis post for a discussion of the DP4 method.)The DP4 analysis suggests that2is the correct structure with a probability of 99.8%.
Banwell has now synthesized the compound with structure2and its NMR matches that of the original natural product.6Thus Nobilisitine A has the structure2.
(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