Case Study of Empirical and Computational Chemical Shift Analyses: Reassignment of the Relative Configuration of Phomopsichalasin to That of Diaporthichalasin

Abstract

Phomopsichalasin was isolated and assigned structure 1 over 15 years ago. Analysis of its proton NMR data led us to hypothesize that not all aspects of the relative configuration of this structure were correct. We have used both empirical and computational methods to propose an alternative structure. Diaporthichalasin was reported several years ago, and its structure was assigned as 7, a diastereomer of structure 1, and confirmed by a single crystal X-ray study. We have shown that diaporthichalasin and phomopsichalasin are identical; i.e., both have structure 7. Additional aspects of NMR interpretation that provide guidance for avoiding some of the pitfalls that can lead to incorrect structure assignments are discussed. These recommendations/reminders include i) the use of complementary solvents for acquiring NMR data that break accidental chemical shift degeneracy, ii) the importance of assigning coupling constants as extensively as possible, and iii) exercising caution when interpreting correlations in 2D spectra where overlapping resonances are involved.

Stereochemical Studies of the Karlotoxin Class Using NMR Spectroscopy and DP4 Chemical‐Shift Analysis: Insights into their Mechanism of Action

“…The CS values for 1 were also analyzed using both mean absolute error calculations and DP4 probability statistics. [7] The computation work supports the published relative configuration of C28–C29 of 1 in the anti conformation, which has the lowest TAD value at 2.89.…”

“…Thet otal absolute deviation (TAD) was used for the comparison of the absolute value of the difference between the calculated and the experimental values.T he CS values for 1 were also analyzed using both mean absolute error calculations and DP4 probability statistics. [7] Thec omputation work supports the published relative configuration of C28-C29 of 1 in the anti conformation, which has the lowest TADv alue at 2.89.…”

“…When analyzing the larger, flexible fragments, the entire structure of 1 was analyzed using the DP4 applet. [7a] The results showed that the relative configuration assignments of the published structure of 1 for C36–C37 and C28–C29, highly flexible bonds deduced from the medium values of 3 J (H36,H37) and 3 J (H28,H29) , were correct (Figure 5). …”

A guide to small-molecule structure assignment through computation of (1H and 13C) NMR chemical shifts

“…These include (i) the use of only the global minimum from a molecular mechanics conformational search to proceed with the more computationally intensive ab initio phases of the calculations 5,27 , (ii) the use of a judiciously chosen small subset of structures from the conformer library generated in a molecular mechanics search 28,29 or (iii) the use of a judiciously chosen substructure (e.g., through truncation) as a model for the chemical shifts in question in the structurally ambiguous portion of the molecule (e.g., 3, Box 1 and 11, Fig. 3) 26,27 . A final caveat should be emphasized.…”

Isolation and stereochemical assignment of phthalides resulting from the Diels–Alder reaction between 5-isopropoxyfuran-2(5H)-one and cyclopentadiene

“…Table 4 footnote). The MAEs observed for hydrogen chemical shift are inherently smaller than carbon, and are generally considered to provide better distinction between isomer [45]. Interestingly, use of the DP4 method after assignment still indicated that carbon and proton data were in disagreement about the candidate structure corresponding to diastereomer 2b.…”