Here is another nice example of the partnership between experiment and computation in ascertaining molecular structure. The Sarpong, Tantillo, Andersen, Berlinck, and Miller groups collaborated on the synthesis, characterization and biosynthesis of some metabolites from Penniculium strains.1 I will focus here on just the structural identification component of this paper; the synthesis and the biosynthesis are very interesting too!
Cyclopiamine A 1 and cyclopiamine B 2 interconvert through an intermediate that allows for the epimerization at carbon bearing the nitro group.2
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Citrinalin A 3 might also seem to undergo the same type of ring opening-ring closing reaction to produce citrinalin B. However, the original proposed structure3 of citrinalin B 4 implies an epimerization at a different carbon (at the ring fusion to the terminal 5 member ring). These authors suggested that perhaps the proper structure of citrinalin B is 5, which differs from citrinalin A only at the carbon bearing the nitro group, analogous to the relationship between 1 and 2.
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The low energy conformations of both 4 and 5 (actually the trifluoroacetic acid salts) were optimized at B3LYP/6-31+G(d,p) and the chemical shifts for both 1H and 13C were computed, Boltzmann-weighted and scaled, and then compared with the NMR spectra of authentic citrinalin B. (The lowest energy conformations of 4 and 5 are shown in Figure 1.) The corrected mean absolute deviations for the 1H and 13C chemical shift for the original structure 4 are 0.45 ppm and 2.0 ppm, respectively (with the largest outliers of 2.3 ppm for H and 9.6 ppm for C). These errors are about twice what is observed in comparing the experimental and computed 1H and 13C chemical shifts of 3. The agreement between the computed and experimental values using 5 are much improved, with mean deviations of 0.12 and 1.6ppm, and largest deviations of 0.38 ppm for 1H and 4.4 ppm for 13C. Use of Goodman’s DP4 method indicates a 100% probability that the structure of citrinalin B is 5. This prediction is confirmed by the x-ray structure.
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Figure 1. B3LYP/6-31+G(d,p) optimized lowest energy conformers of 4 and 5.
References
(1) Mercado-Marin, E. V.; Garcia-Reynaga, P.; Romminger, S.; Pimenta, E. F.; Romney, D. K.; Lodewyk, M. W.; Williams, D. E.; Andersen, R. J.; Miller, S. J.; Tantillo, D. J.; Berlinck, R. G. S.; Sarpong, R. "Total synthesis and isolation of citrinalin and cyclopiamine congeners," Nature 2014, 509, 318-324, DOI: 10.1038/nature13273.
(2) Bond, R. F.; Boeyens, J. C. A.; Holzapfel, C. W.; Steyn, P. S. "Cyclopiamines A and B, novel oxindole metabolites of Penicillium cyclopium westling," J. Chem. Soc., Perkin Trans I 1979, 1751-1761, DOI: 10.1039/P19790001751.
(3) Pimenta, E. F.; Vita-Marques, A. M.; Tininis, A.; Seleghim, M. H. R.; Sette, L. D.; Veloso, K.; Ferreira, A. G.; Williams, D. E.; Patrick, B. O.; Dalisay, D. S.; Andersen, R. J.; Berlinck, R. G. S. "Use of Experimental Design for the Optimization of the Production of New Secondary Metabolites by Two Penicillium Species," J. Nat. Prod. 2010, 73, 1821-1832, DOI: 10.1021/np100470h.
InChIs
1: InChI=1S/C26H33N3O5/c1-23(2)12-17(30)20-18(34-5)9-8-16-21(20)28(23)22(31)26(16)13-25(29(32)33)14-27-10-6-7-15(27)11-19(25)24(26,3)4/h8-9,15,19H,6-7,10-14H2,1-5H3/t15-,19+,25+,26-/m1/s1
InChIKey=LUESCPPTDJZZQN-VBPSCBQFSA-N
2: InChI=1S/C26H33N3O5/c1-23(2)12-17(30)20-18(34-5)9-8-16-21(20)28(23)22(31)26(16)13-25(29(32)33)14-27-10-6-7-15(27)11-19(25)24(26,3)4/h8-9,15,19H,6-7,10-14H2,1-5H3/t15-,19+,25-,26-/m1/s1
InChIKey=LUESCPPTDJZZQN-DCWDXPITSA-N
3: InChI=1S/C25H31N3O5/c1-22(2)11-16(29)19-17(33-22)8-7-15-20(19)26-21(30)25(15)12-24(28(31)32)13-27-9-5-6-14(27)10-18(24)23(25,3)4/h7-8,14,18H,5-6,9-13H2,1-4H3,(H,26,30)/t14-,18+,24+,25-/m0/s1
InChIKey=QVBARITWSQCBBV-DTKOROOESA-N
4: InChI=1S/C25H31N3O5/c1-22(2)11-16(29)19-17(33-22)8-7-15-20(19)26-21(30)25(15)12-24(28(31)32)13-27-9-5-6-14(27)10-18(24)23(25,3)4/h7-8,14,18H,5-6,9-13H2,1-4H3,(H,26,30)/t14-,18-,24-,25+/m1/s1
InChIKey=QVBARITWSQCBBV-KUCRYEJDSA-N
5: InChI=1S/C25H31N3O5/c1-22(2)11-16(29)19-17(33-22)8-7-15-20(19)26-21(30)25(15)12-24(28(31)32)13-27-9-5-6-14(27)10-18(24)23(25,3)4/h7-8,14,18H,5-6,9-13H2,1-4H3,(H,26,30)/t14-,18+,24-,25-/m0/s1
InChIKey=QVBARITWSQCBBV-QBDGMKJCSA-N
Roberto G. S. Berlinck responded on 27 Jun 2014 at 11:11 pm #
Dear Dr. Bachrach,
Congratulations for your very interesting and very well organized blog.
Thank you for disseminating our recently published research in Nature. Just a note: the complete set of biosynthetic experiments was designed and performed by my group at the University of Sao Paulo, in Brazil, together with the group of Professor Raymond J. Andersen at the University of British Columbia at Vancouver, Canada.
Best regards,
Roberto G. S. Berlinck
Steven Bachrach responded on 30 Jun 2014 at 3:24 pm #
Thanks for this note, and I apologize for the oversight! I have added the names of the two other groups to the post.
Steven
Henry Rzepa responded on 05 Jul 2014 at 3:19 am #
I am interested in absolute configurations, an analysis that comes after the connectivities and relative stereochemistry have been established, and not discussed in Steve’s post. You can find more on this particular topic here.
The 5σ-confidence level: how much chemistry achieves this? « Henry Rzepa's blog responded on 08 Jul 2015 at 10:49 am #
[…] chemistry is asserted at that level of confidence? Today, I read Steve Bachrach’s post on the structure of Citrinalin B and how “use of Goodman’s DP4 method indicates a 100% probability that the structure of […]