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Addressing the Challenges of Structure Elucidation in Natural Products Possessing the Oxirane Moiety Andrei G. Kutateladze, Dmitry M. Kuznetsov, Anastasiya A Beloglazkina, and Tina A Holt J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01027 • Publication Date (Web): 18 Jun 2018 Downloaded from http://pubs.acs.org on June 19, 2018
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The Journal of Organic Chemistry
Addressing the Challenges of Structure Elucidation in Natural Products Possessing the Oxirane Moiety Andrei G. Kutateladze,* Dmitry M. Kuznetsov, Anastasiya A. Beloglazkina, and Tina Holt Department of Chemistry and Biochemistry, University of Denver, Denver, CO 80208
ABSTRACT: NMR data for natural products containing the epoxy moiety has been revisited and reanalyzed with the help of a recently developed parametric/DFT hybrid computational method, DU8+. More than twenty structures needed revision, which points to challenges in NMR solution structure assignment for molecules possessing this structural feature. Among the revised structures: achicretin 2, acremine P, aromaticane I, artanomalide B, botryosphaerihydrofuran, chloroklotzchin, crithmifolide, crotodichogamoin A, emervaridone C, 9α,15-epoxyafricanane, fischambiguine B, grandilobalide B, guaianolide A, guatterfriesols A and B, juncenolide G, roscotane D, secoafricane 7, taccalonolides AJ and AF, and related compounds
INTRODUCTION Large numbers of oxygenated natural products possess epoxy moiety which, judging by a number of misassigned structures, presents an additional challenge for structure elucidation. As pyramidalization of carbons in epoxides is not as pronounced, their protons exhibit overlapping ranges for the syn- and antispin-spin coupling constants (SSCCs) with neighboring protons. This weak pyramidalization often presents challenges not only for spin-spin coupling constants, but also for the interpretation of NOE enhancements in di-, tri-, and tetrasubstituted oxiranes. Spiro-oxiranes derived from epoxidation of exocyclic double-bonds are also difficult, whether their methylene moiety is substituted or not. Structure revision of caespitenone is a representative example of these challenges. Initially it was isolated from the liverwort Porella caespitans and assigned structure A, 1 Figure 1. 14
2 1 5 4
O
O
O
11 10 9 7 12
O 13
15
A initially assigned structure of caespitenone
B revised structure of caespitenone
Figure 1. Original and revised caespitenone
Additional 2D NMR experiments revealed discrepancies and the structure of caespitenone was revised to an africane type sesquiterpene B. 2 Instructively, in order to relate the mutual orientation of the two small rings in B, the authors subjected caespitenone to the Miyashita reaction 3 conditions, with oxirane ring-opening and subsequent NOESY experiment revealing the cross-peak between the newly formed 5-OH and H11 protons and thus confirming the syn orientation of the small rings in B. We note that modern developments in computational methods for prediction of NMR spectra 4 make the task of structure elucidation less strenuous. For example, our own hybrid DFTparametric DU8+ computations 5 on the revised structure B took only 11 minutes of total computational time ("wall-clock time") on a single node of a Linux cluster and gave excellent agreement with both 1H and 13C NMR experimental data for caespitenone: rmsd(δC) = 1.18 ppm, rmsd(JHH) = 0.38 Hz, and rmsd(δH) = 0.19 ppm. Such computations for structure A took similar amount of time, 10 min, and revealed irreconcilable problems, including large deviations for 13C chemical shifts, rmsd(δC) > 5 ppm. Examples of "difficult" epoxides are plentiful and include the iconic saga of hexacyclinol, for which a computationally-driven revision of the originally misassigned 6 structure was proposed by Rychnovsky, 7 and later confirmed by Porco's elegant synthesis. 8 In complex oxygenated steroid systems such as the withanolides, a statistically significant sample of reliable structures and 13C NMR data sets have been compiled by Timmermann
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and others. As a result, empirical rules to predict chemical shift perturbations introduced by oxygen atoms, for example γgauche effect, have been developed and successfully utilized for structure correction. 9 It is instructive that a considerable number of structures in need of such correction contained the epoxy moiety. Faster computational approaches to aid NMR analysis of complex organic molecules include such parametric methods as Goodman's DP4. 10 Subsequent improvements of these approaches often address challenges related to structural features poorly described by fast (i.e. low level of theory) methods. For example, Sarotti's improved DP4+ method 11 was developed to include more sophisticated calculations of chemical shifts for unusually hybridized carbons, especially in epoxides. This was recently successfully tested on a set of 24 selected spiro or terminal epoxides. 12 A further expansion of DP4 probability theory, DiCE (Diastereomeric in silico Chiral Elucidation), was recently developed for higher accuracy and relatively low computational costs. 13 Another example of a fast parametric approach is computeraided structure elucidation (CASE) which utilizes parameterized chemical shifts, offering practical tools for structure discovery. 14 Again, these methods are often only as good as the quality of calculated chemical shifts. For this reason, a better hybrid CASE approaches are suggested, with the DFTcomputed shifts augmenting empirical corrections. 15 Nuclear spin-spin coupling constants (SSCCs) contain more structural information, but are challenging to compute. However, practical parametric methods are now emerging for fast and accurate evaluation of SSCCs: Bally and Rablen’s work on linear scaling of the easily computed Fermi contacts, 16 and our own related method which we termed relativistic force field (rff). 17,18 To streamline solution structure elucidation and validation process, we combined the rff computations of SSCCs with empirical corrections of the DFT-computed chemical shifts in an integrated DU8+ method,5 which allows for a high-throughput analysis of reported structures based on ubiquitous 1D NMR data. DU8+ combines computations of structure and NMR properties of organic molecules at a light level of DFT theory and is implemented with the following components: (a) structure optimization: B3LYP/6-31G(d); (b) magnetic shielding: ωB97xD/6-31G(d); (c) Fermi contacts: B3LYP/DU8; (d) scaling of the computed Fermi contacts according to ref.17 b,c “rff” to obtain spin-spin coupling constants; (e) scaling of isotropic magnetic shielding values according to ref.5 to obtain chemical shifts. DU8+ has expedited not only identification of misassigned structures, but also accelerated the process of structure revision. The computed spin-spin coupling constants offer more intuitive guidance for generating hypothetical structure candidates than the calculated chemical shifts alone. In the past, as a result of this high-throughput screening, we encountered a number of incorrectly assigned epoxides in the series of halogenated marine natural products (NP); for example, 1β-bromo-4α,5α-epoxyselinane 19 or, in the triquinane series, hirsutenol E. 20 This prompted us to revisit NMR data for a number of NPs possessing the oxirane moiety. More than twenty of these structures needed revision.
RESULTS AND DISCUSSION
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The structures of the epoxy-containing natural products were pre-optimized with the force field MMFF94 as implemented in OpenBabel. 21 For structures with freely rotatable groups, conformers were generated using OpenBabel’s confab, whereas the conformers resulting from conformational changes in cyclic cores were generated manually, using Chem3D. As the empirical corrections for DU8+ were developed on a training set of 1 H and 13C NMR spectra recorded in CDCl3, we use fast gas phase computations for such cases. For experimental data obtained in DMSO-d6 or methanol-d4 a PCM model with additional linear scaling of chemical shifts was utilized. 22 DU8+ performs adequately in predicting spectra of complex epoxidized natural products as exemplified in Figure 2. For entisoineleganolide A (its structure was unambiguously established by Stoltz via xray crystallography as a part of a synthetic campaign toward furanobutenolide-derived norcembranoid diterpenes 23 making it a suitable test case for DU8+) the rootmean-square deviations for calculated 13C and 1H chemical shifts and proton spin-spin coupling constants were rmsd(δH) = 0.20 ppm and rmsd(δC) = 1.03 ppm, rmsd(JHH) = 0.26 Hz. 22
O 1
O OH
6
3 17
O HN
18
8
H
12 11
14
9
15 19
16
21
20 15
6 16
2 8
18
19
H COOMe
7
12
O Me
14
3
13
H
O
O
Me N 5
O
H
9
11 10
ent-isoineleganolide A
scholarisine K
(xray)
(xray)
rmsd(δ C) = 1.03 ppm rmsd(δ H) = 0.20 ppm rmsd(J HH) = 0.26 Hz
rmsd(δ C) = 1.20 ppm rmsd(δ H) = 0.15 ppm rmsd(J HH) = 0.55 Hz 14
O O
14
2 1 4 5
O
O
8
O
7 11
H
15
2 1 10 4 5 6 7
10 12
O
15
H
O 12
-epoxy-8α-acetoxyachillin
1β,10β
(xray) rmsd(δ C) = 1.05 ppm rmsd(δ H) = 0.22 ppm rmsd(J HH) = 0.51 Hz
rmsd(δ C) = 1.33 ppm rmsd(δ H) = 0.19 ppm rmsd(J HH) = 0.54 Hz
O
12
13
7 2 3
14
O
H 11
6
O
O
5 4
15 9
H
12
11
1
8 10
O
O
corianlactone (xray) PCM - pyridine rmsd(δ C) = 1.05 ppm rmsd(δ H) = 0.22 ppm rmsd(J HH) = 0.63 Hz
13
11
O
13
diepoxyguaianolide from Stevia tomentosa (compound 1, xray)
14
OAc H
9
1 8
14
15 3
H
2 4 7
H
12
H 11 9
1 8
15 3
H
2 4 7
O
O 13
13
ledene epoxide 2
ledene epoxide 3
rmsd(δ C) = 1.00 ppm rmsd(δ H) = 0.24 ppm rmsd(J HH) = 0.88 Hz
rmsd(δ C) = 0.98 ppm rmsd(δ H) = 0.21 ppm rmsd(J HH) = 0.72 Hz
Figure 2. Selected test cases demonstrating the accuracy of DU8+ calculations for the correctly assigned complex epoxides. Monoterpenoid indole alkaloid scholarisine K, 24 diepoxyguaianolide from Stevia tomentosa (compound 1 in the original paper), 25 and sesquiterpene lactones 1β,10β-epoxy-8α-acetoxyachillin 26 and corianlactone, 27 for which xray structures are
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available, all gave good matches, Figure 2. Additional test cases of ledene epoxides 2 and 3, 28 which were obtained by epoxidation of ledene from both faces, gave an opportunity to compare the performance of the method on both diastereomers (rmsd(δC) = 1.0 ppm and 0.98 ppm respectively). In contrast, comparison of the 13C chemical shifts computed for ledene epoxide 2 with the experimental chemical shifts for ledene epoxide 3 gave inferior rmsd(δC) of 2.5 ppm. A similar poor match, rmsd(δC) = 2.1 ppm, was obtained for the experimental data of ledene epoxide 2, fitted with the computed data for ledene epoxide 3. Overall, the current training set of 13C chemical shifts for DU8+ exceeds 6080 reliable experimental measurements calculated with the rmsd(δC) of 1.28 ppm. This accuracy is currently better than any method we know, especially given the fact that the set contains carbons bearing chlorine, bromine and other heavy atoms. As a result, the majority of validated (i.e. correct) structures fall into the rmsd range of 1.0-1.8 ppm or even better. Proton spin-spin coupling constants (SSCCs) are computed with the accuracy of 0.3 Hz as determined on the training set of more than 4K reliable experimental values. In any given case, the calculated values may deviate from the experimental for extraneous reasons. For example, there are very few practitioners in the field reporting J-coupling constants with sufficiently high accuracy, 29 which potentially could be achieved with approaches such as HiFSA (1H iterative Full Spin Analysis). 30 However, as described below, most of the time the validated original (or revised) structure gives superior match across the primary two criteria; i.e. rmsd(δC) and rmsd(JHH), augmented by the secondary criterion – rmsd(δH) – which is less reliable, but still useful in the final analysis. Before we proceed any further with the examination of misassigned structures of complex natural products containing the oxirane moiety, we reiterate that stereochemistry assignment is challenging even for very small epoxidized molecules. For example, DU8+ analysis reveals that the syn stereochemistry of the reported toluene dioxide, Figure 3 (compound 11e in ref. 31) is erroneous and needs revision to anti, which may further necessitate revisions in the mechanism of its formation proposed by the authors.
rmsd(δH) = 0.37 ppm, rmsd(δC) = 2.66 ppm, rmsd(JHH) = 0.32 Hz; whereas the anti-isomer gave much better rmsd(δH) = 0.16 ppm and fit: rmsd(δC) = 1.03 ppm, rmsd(JHH) = 0.30 Hz. Therefore, we revise its structure to the anti-diastereomer, i.e. epi-4,5 shown in Figure 4 (relative stereochemistry is implied in this and subsequent revisions). The structure of grandilobalide B, Figure 4, was possibly misassigned because of similar challenges, i.e. the lack of oxirane protons and too subtle a structural perturbation introduced by the oxirane oxygen, when placed on either face of the molecule. Nonetheless, DU8+ is capable of differentiating the two stereoisomers: rmsd(δC) is 0.99 ppm for the revised, i.e. epi-5,6 structure, while the original structure gave rmsd(δC) of 1.98 ppm. The most offending chemical shifts in the original structure belonged to oxirane's C5 (∆δ = 4.96 ppm discrepancy between the calculated and experimental value) and C15 (∆δ = 4.24 ppm). The chemical shift belonging to the lactone's carbonyl carbon (C15) is clearly perturbed via a through-space interaction with oxirane's lone pair, as the distance between the oxirane oxygen and the carbonyl's carbon in the revised structure is less than 2.7Å. 14
O
2
O
14
11
revised
10 9 1
4
5
O
2
O
7
4
12
O
10 9 1
5
7 12
O
13
15
11
13
15
secoafricane (compound 7)
epi-4,5
rmsd(δ C) = 2.66 ppm rmsd(δ H) = 0.37 ppm rmsd(J HH) = 0.32 Hz
rmsd(δ C) = 1.03 ppm rmsd(δ H) = 0.16 ppm rmsd(J HH) = 0.3 Hz
O
15
O
11
5 6
O O
4
O
11
7
O O
4
5 6
O
3 9 8 1
7 13
12
13
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14
10
revised
3 9 8 1
O
O
15
14
10
grandilobalide B
epi-5,6
rmsd(δ C) = 1.98 ppm rmsd(δ H) = 0.27 ppm rmsd(J HH) = 0.57 Hz
rmsd(δ C) = 0.99 ppm rmsd(δ H) = 0.33 ppm rmsd(J HH) = 0.30 Hz
O
O revised O
HO syn-diepoxy (11e) rmsd(δ C) = 3.66 ppm rmsd(δ H) = 0.33 ppm rmsd(J HH) = 1.20 Hz
14
14
O
O O
2 3
anti-diepoxy
4
1 5
H
O rmsd(δ C) = 0.59 ppm rmsd(δ H) = 0.20 ppm rmsd(J HH) = 0.98 Hz
15
HO
10
revised
O
11
2 3
6 7 13
12
O O 1 5
4
H
O 15
10 6 7
O
11
O
O
Figure 3. Revision of the toluene-based syn-diepoxide 11e to anti Africane-type sesquiterpenoid (compound 7 in ref. 32) represents the most common challenge in the assignment of oxirane stereochemistry because it lacks protons at positions 4 and 5. Additionally, the two small cycles – oxirane and cyclopropane – which could be either syn- or anti- to each other, are too distant to cause sufficient perturbation of chemical shifts of the intervening atoms or spin-spin coupling constants to make the stereochemical assignment with confidence. DU8+ calculations on the original (syn) structure produced a relatively poor match
3
13
12
crithmifolide
epi-3,4
rmsd(δ C) = 2.09 ppm rmsd(δ H) = 0.19 ppm rmsd(J HH) = 0.16 Hz
rmsd(δ C) = 1.33 ppm rmsd(δ H) = 0.11 ppm rmsd(J HH) = 0.14 Hz
Figure 4. Revision of secoafricane compound 7, grandilobalide B, and crithmifolide Crithmifolide, a sesquiterpene lactone from Achillea Crithmifolia required a similar revision, despite the fact that one of the oxirane carbons, C3, conveniently carries a hydrogen atom vicinal to H-C2. The vicinal H-C2-C3-H constant is too small
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to be helpful. Nonetheless, based on DU8+ analysis of chemical shifts the structure of crithmifolide is now revised to the shown epi-3,4 diastereomer. Another candidate structure, the epi-2,3,4 isomer, gave less accurate fit: rmsd(δC) = 1.61 ppm, rmsd(δH) = 0.16 ppm and rmsd(JHH) = 0.23 Hz (see Supporting Information) and was rejected. Achicretin 2 (also referred to as sesquitunin 2) was recently isolated from Achillea cretica growing in Tunisia. 33 It had the same molecular formula as another epichlorohydrin, guaianolide A, isolated by the authors earlier from the same plant, 34 resulting in the structure assignment shown in Figure 5. DU8+ computations on both originally proposed structures of achicretin 2 and guaianolide A showed irreconcilable differences with the experimental NMR data. After careful analysis of all the discrepancies in the achicretin 2 data, another epichlorohydrin (with the chlorine atom transposed from C-1 to C-3) was proposed as a revision, which exhibited an excellent match with experimental data.
misassigned. Because its NMR data is reported in DMSO-d6, they are somewhat different from that of achicretin 2. Yet, we found enough similarity to suggest that chloroklotzchin is most likely the same 3α-chloro-4β,10α-dihydroxy-1β,2β-epoxy5α,7αH-guai-11(13)-en-12,6α-olide shown in Figure 5 (see Table S1 for comparison of the experimental data). Guaianolide A was then revised to the 2-chloro-3,4-epoxy structure shown in Figure 5. The revised structure of guaianolide A is depicted keeping the absolute configuration at the C6C7 ring fusion the same as in 3α-chloro-4β,10α-dihydroxy1β,2β-epoxy-5α,7αH-guai-11(13)-en-12,6α-olide (i.e. revised achicretin 2). The fact that achicretin 2 and guaianolide A were isolated from the same plant may point to their common precursor (Figure 6), diepoxide artecanin, which itself had an interesting history of reassignment and renaming (also known as chrysartemin B). 37 14
14
14 14
Cl O HO 15
4
5 6
H
5
7
HO
11
O
15
13
12
H
7 12
originally proposed structure of achicretin 2 rmsd(δ C) > 4.2 ppm
2 1 4
Cl 15
5
H
6
7
O
12
O originally proposed structure of guaianolide A rmsd(δ C) > 5.5 ppm
4
15
6
7
O
12
O
13
15
H
7 11
O
4
13
12
5
O 15
H
6
7
O
12
11 13
O
O
artecanin (or chrysartemin B)
revised guaianolide A
Figure 6. Diepoxide sesquiterpene lactone artecanin as a plausible common precursor to revised achicretin 2 and guaianolide A As far as we can tell, the revised guaianolide A is the only example of the formal HCl opening of 1,2-epoxide (i.e. not the 3,4-epoxide) in artecanin or canin (the incorrect structure of chloroklotzchin notwithstanding). However, a related 9-acetate, algerianolide, was isolated from A. ligustica and its structure was established by xray analysis. 38 Comparison of the experimental 13C NMR chemical shifts for guaianolide A and algerianolide reveals strong similarity. In fact, when the carbons proximal to the C9-OAc substitution, i.e. C7-C10 and C14, were omitted from this comparison the remaining ten carbons gave rmsd of 0.37 ppm, Figure 7.
OH
5
11 12
6
10
2 1
[HCl]
5
O
O
10
H
H
4
7
revised achicretin 2
originally proposed structure of chloroklotzchin
2 1
O 13
12
O
Cl HO
11
15
6
10
2 1
[HCl]
5
OH
Cl HO
13
rmsd(δ C) > 7.7 ppm
revised
10
O
15
14
OH
HO
HO
7 11
13
rmsd(δ C) = 1.22 ppm rmsd(δ H) = 0.18 ppm rmsd(J HH) = 0.22 Hz 14
6
O
11
O
5
4
4
14
OH
O
10
2 1
Cl
10
2 1
O revised structure of achicretin and chloroklotzchin same as 3α-chloro-4β,10α-epoxy-5α,7α Hdihydroxy-1β,2β -olide guai-11(13)-en-12,6α
O
O
6
revised
OH
O
OH
HO Cl
10
2 1
Cl
revised
10
2 1 4
O
OH
14
OH
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11 13
O revised structure of guaianolide A rmsd(δ C) = 1.60 ppm rmsd(δ H) = 0.15 ppm rmsd(J HH) = 0.32 Hz
14 14 Cl HO OH Cl HO OH OAc 2 1 10 2 1 10 4 56 7 4 56 7 O O 11 11 H 13 H 13 15 O 12 15 O 12
Figure 5. Revision of achicretin 2 (sesquitunin 2), chloroklotzchin, and guaianolide A The only remaining inconsistency was that the original experimental data reported the H2→C1 HMBC cross-peak and no such cross-peak was reported for H3→C1, whereas we expected the opposite based on the computed C-H spin-spin coupling constants, J(H2-C1) < 0.4Hz, J(H3-C1) = 8.5Hz. Luckily, a literature search revealed that the revised structure of achicretin 2 belongs to a known sesquiterpene isolated from Achillea clavennae, i.e. 3α-chloro-4β,10α-dihydroxy-1β,2βepoxy-5α,7αH-guai-11(13)-en-12,6α-olide. 35 Besides the fact that its experimental 1H and 13C chemical shifts and proton spinspin coupling constants matched achicretin 2 perfectly, the authors reported only the H3→C1 HMBC cross-peak, which is in agreement with our J(CH) computations. We also found a report on another similar epoxide-chlorohydrin, chloroklotzchin, isolated from Artemisia klotzchiana in 1985. 36 According to our calculations, chloroklotzchin was also
4
O
O
revised guaianolide A C1 C2 C3 C4 C5 C6 *** C11 C12 C13 *** C15
algerianolide
84.5 61.6 63.7 67.4 46.4 81.3
84.4 ( 0.1) 62.3 (-0.7) 63.5 ( 0.2) 67.1 ( 0.3) 46.5 (-0.1) 81.4 (-0.1)
138.5 169.9 119.4
139.1 (-0.6) 170.1 (-0.2) 118.8 ( 0.6)
18.0
17.9 ( 0.1) rmsd = 0.37 ppm
Figure 7. Comparison of experimental 13C NMR chemical shifts for guaianolide A and algerianolide (∆δ is shown in parentheses).
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The Journal of Organic Chemistry
Another chlorohydrin-containing sesquiterpene lactone, artanomalide B, 39 was isolated from Artemisia anomala, one of the species of the genus Artemisia, broadly used in Chinese folk medicines. As shown in Figure 8, we found irreconcilable differences between the calculated and experimental NMR data for artanomalide B, prompting revision. The revised structure (the shown epi-1,2,3 diastereomer) gave an excellent agreement with the experimental NMR, except this structure was in conflict with the NOE cross-peak between H3 and H5, reported in the paper39 and originally used to assign the C3(Cl) stereochemistry. However, our additional examination of the NOESY spectrum in the supplementary data did not reveal any H3-H5 cross-peaks, indicating an error in interpretation of the experimental data. Thus, artanomalide B is revised to the shown 1,2,3-epimer. By analogy with the common diepoxide precursor in Figure 6, it is plausible that the revised artanomalide B is a result of the 3,4-epoxide ring opening in the 10-epimer of artecanin, as shown in Figure 8. This diepoxide precursor is known; it was isolated from Tanacetum parthenium (incorrectly named epi10-canin) 40 and independently – from Ajania fastigiata and named isochrysartemin B. 41 According to the current consensus on the structures of canin and artecanin, isochrysartemin B should be referred to as epi-10-artecanin. 14
4
HO 15
revised
10
2 1
Cl
5 6
H
12
13
O originally proposed structure of artanomalide B rmsd(δ C) = 4.10 ppm rmsd(δ H) = 0.39 ppm rmsd(J HH) = 0.56 Hz
10
2 1
Cl
7 11
O
HO 14 O
HO 14 O
OH
O
4
15
5
6
H OH O
[HCl] 7 11 12
13
O epi-1,2,3 rmsd(δ C) = 1.18 ppm rmsd(δ H) = 0.14 ppm rmsd(J HH) = 0.41 Hz
?O
10
2 1 4
5
H 15
6
O
7 11 12
13
O epi-10-artecanin
(isochrysartemin "epi-10-canin")B,
Figure 8. Revision of artanomalide B. If epichlorohydrin sesquiterpene lactones of this type are products of an HCl-induced ring opening of one of the epoxide units in diepoxides canin/artecanin or their diastereomers, then 3β-chloro-4α,10α-dihydroxy-1β,2β-epoxy-5α,7αH-guai11(13)-en-12,6α-olide isolated from Achillea ligustica in 2003 (reported as compound 6 in the original paper 42) should have resulted from an anti-diepoxide precursor. As such a precursor is not described in the literature, we were curious if this sesquiterpene lactone itself is misassigned. DU8+ computations showed that this was indeed the case. The revised structure for compound 6 has the 1,2-epoxy moiety on the opposite face of the molecule, thus making 6 the product of HCl-induced ring opening in canin, Figure 9. Further search of the literature has revealed that 3β-chloro-4α,10α-dihydroxy-1α,2α-epoxy5α,7αH-guai-11(13)-en-12,6α-olide is a known NP, and its structure was unambiguously determined by xray analysis 43 (see Table S2 for comparison of experimental chemical shifts).
5
14
14
OH
O 2 1
Cl
4
HO 15
revised
10 5 6
H
11
O
12
13
O originally proposed structure of compound 6
4
HO
5
H 15
6
O
OH
O
10
2 1
Cl
7
14
OH
O
[HCl] 7 11 12
13
?O
O epi-1,2
3β-chloro-4α,10α-dihydroxy-epoxy-5α,7α H-guaia1β,2β -olide 11(13)-en-12,6α
3β-chloro-4α,10α-dihydroxy-epoxy-5α,7α H-guaia1α,2α -olide 11(13)-en-12,6α
rmsd(δ C) = 2.40 ppm rmsd(δ H) = 0.18 ppm rmsd(J HH) = 0.35 Hz
rmsd(δ C) = 1.26 ppm rmsd(δ H) = 0.17 ppm rmsd(J HH) = 0.31 Hz
10
2 1 4
5
H 15
6
O
7 11 12
13
O canin
Figure 9. Revision of 3β-chloro-4α,10α-dihydroxy-1β,2βepoxy-5α,7αH-guai-11(13)-en-12,6α-olide (compound 6) to 3β-chloro-4α,10α-dihydroxy-1α,2α-epoxy-5α,7αH-guai11(13)-en-12,6α-olide, i.e. epi-1,2 (a known guaianolide) Another common challenge is that diols (or chlorohydrins) are often confused for epoxides. For example, 9α,15-epoxyafricanane 2 was isolated together with the corresponding diol, 9α,15-dihydroxyafricanane 3 from soft coral Sinularia dissecta, Figure 10. 44 While the experimental NMR data for diol 3 showed satisfactory agreement with our calculated data, epoxide 2 clearly needed revision. The epoxide carbons normally exhibit higher field chemical shifts compared with alcohols. However, comparison of experimental 13C chemical shifts for the putative epoxide 2 and diol 3 revealed close similarity, rmsd(exp-exp) = 1.52 ppm, indicating that "epoxide 2" could be an isomer of diol 3. DU8+ computations did confirm this hypothesis, as the calculated data for the 9-epimer of diol 3 matched the experimental data for "epoxide" 2 with rmsd(δC) = 1.41 ppm. Literature search revealed that the same two diol epimers were isolated from a similar soft coral, Sinularia intacta, and correctly characterized. 45 Moreover, in 2011 Nakata and coworkers have synthesized both pairs of 9-epimers for the diols and the epoxides, 46 noting that the epoxide is definitely misassigned. Our computations of 13C NMR chemical shifts produced excellent matches on all four synthetic compounds, i.e. two synthetic epoxides and two diols, Figure 10(B). Possibly, because of one discrepancy with the 13C NMR data in the original isolation paper (in which C10 was assigned 29.6ppm, ref.44), Nakata and co-workers stopped short of revising the misassigned epoxide to 9β,15-dihydroxyafricanane, writing in the conclusions, "Although we are uncertain about the structure of the compound isolated from the soft coral Sinularia dissecta, our results indicate that the structure of the natural product named epoxyafricanane was incorrectly assigned." With DU8+ we double-checked computationally that the purported 9α,15-epoxyafricanane (compound 2 in ref.44) is not a chlorohydrin, i.e. a product of HCl-induced epoxide opening. This could be a plausible epoxide degradation channel, as some batches of CDCl3 contain considerable amounts of HCl capable of epoxide ring-opening. The computational results clearly indicate that this is not the case, as the match with the experimental data among the potential chlorohydrins had poor rmsd(δC) > 2.1ppm. On the other hand, removal of the offending C10/29.6ppm peak from the experimental dataset improved the fit for 9β,15-dihydroxyafricanane from rmsd(δC) of 1.41 to 1.02ppm. Similarly the diol 3, i.e. the correctly assigned 9β,15-
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dihydroxyafricanane, showed commensurate improvement from rmsd(δC) 1.50ppm to 1.26ppm, when we ignored the same 29.6ppm peak ascribed to its C10 carbon in ref.44 After all the considerations, we revised 9α,15-epoxyafricanane to 9β,15-dihydroxyafricanane, Figure 10(A). The misreported C10 observed at 29.6ppm peak most likely belongs to acetone or other impurity in the sample. and
(A) Originally isolated compounds 2 15
9 11
11
HO HO
13 6
8 1
15
revised
9
8 1
11
H
13
8a
8
O O
O 12
2 6
1
5
4a
OH 3
4
3a 8a
2
O 7 8 OH 1 revised botryosphaerihydrofuran 7a
rmsd(δ C) = 1.14 ppm rmsd(δ H) = 0.14 ppm rmsd(J HH) = 0.45 Hz
rmsd(δ C) > 10 ppm
9β,15-dihydroxyafricanane rmsd(δ C) = 1.41 ppm
9
10
botryosphaerihydrofuran (compound 5)
3
12
4
revised
3
3a
7a
6 2 4
H
3
9α,15-epoxyafricanane (compound 2) rmsd(δ C) = 6.91 ppm
4a
7
11
9
10 5
6
14
H
2 4
12
fungus in the same campaign and correctly assigned, possessed an extra carbonyl group (C7) and helped resolve this reassignment impasse. We hypothesized that botryosphaerihydrofuran belongs to the eremophilane structural type. While we do not have an explanation for the reported HRMS data, there is very little doubt that the NMR spectra for botryosphaerihydrofuran belong to the revised structure shown in Figure 11.
3
14
H
O
Page 6 of 13
12 11
HO HO
15
H 9
11
8 1
4
O
14
7
13
OH
5
3 2
6
8 9
2 4
10
O
1
eremophilane structural type
botryosphaeridione (compound 4) correctly assigned
H 3
12
6
9α,15-dihydroxyafricanane - correctly assigned) (compound 3 rmsd(δ C) = 1.50 ppm
rmsd(δ C) = 1.38 ppm rmsd(δ H) = 0.14 ppm rmsd(J HH) = 0.28 Hz
(B) Synthetic samples (Nakata ref. 46) 15
9 11
15
14
H
O
13
9
6
8 1
2 4
12
HO HO
15
14
H 9
11
8 1
13 6 2 4
H 12
6
3
9α,15-dihydroxyafricanane (sesquiterpene unit 2) rmsd(δ C) = 1.31 ppm
3
2 4 3
15
10
6
9
7 8
11
12
O OMe
rmsd(δ C) = 1.22 ppm rmsd(δ H) = 0.12 ppm rmsd(J HH) = 0.35 Hz
C1-d 143.9 C2-d 126.3 C3-s 204.2 C4-d 53.5 C5-s 39.7 C6-t 42.1 C7-s 78.2 C8-s 101.3 C9-d 126.9 C10-s 140.9 C11-d 42.9 C12-t 72.8 C13-q 14.4 C14-q 27.4 14.6 C15-q C-OMe-q 48.3
143.6 (0.3) 126.4 (-0.1) not reported 53.6 (-0.1) 38.8 (0.9) 33.1 (9.0) 77.0 (1.2) 99.4 (1.9) -4.8 131.7 ( ) 139.3 (1.6) 43.4 (-0.5) 71.3 (1.5) 8.9 (5.5) 27.8 (-0.4) 14.4 (0.2) -
14
H 9
11
5
OH
microsphaeropsisin correctly assigned
9β,15-epoxyafricanane (epi-9-africane-9,15-diol 7) rmsd(δ C) = 0.84 ppm
HO HO
4
2 1
12
3
9α,15-epoxyafricanane (africane-9,15-diol 6) rmsd(δ C) = 0.94 ppm
O
H
H
13
14
13
8 1
11
15
14
H
O
botryosphaeri- microsphahydrofuran eropsisin
8 1
13 6
Figure 11. Revision of botryosphaerihydrofuran. A related known fungal metabolite, microsphaeropsisin is shown; the inset table compares experimental 13C chemical shifts of botryosphaerihydrofuran and microsphaeropsisin (microsphaeropsisin's numbering is used for this comparison).
2 4
H 12
3
9β,15-dihydroxyafricanane (9-epimer of sesquiterpene unit, 19) rmsd(δ C) = 1.06 ppm
Figure 10. (A) Revision of 9α,15-epoxyafricanane to 9β,15dihydroxyafricanane. (B) Experimental NMR data for Nakata's synthetic samples show excellent match with computed values (the original names, ref.44 are matched with the names and product numbers in Nakata's paper, ref.46). A second example of a hydroxylated compound confused for an epoxide is botryosphaerihydrofuran 5, isolated from the endophytic fungi Botryosphaeria rhodina, Figure 11. 47 In addition to problems with underestimated 13C chemical shifts for the epoxide carbons C3a and C8a, calculations of the NMR spectra for the originally proposed structure revealed many other irreconcilable differences, including the challenge that 13C chemical shifts for carbons C6, C7, C7a, and C8 were deviating significantly from the experimental data. Eventually we concluded that this NP possesses an extra carbonyl group, with its 13C peak being overlooked in the experimental spectrum. Another metabolite, botryosphaeridione 4, Figure 11, isolated from this
6
This exact revised structure was not reported in the literature. However, our literature search yielded a very similar metabolite, microsphaeropsisin, isolated by König, 48 who investigated marine sponges Ectyplasia perox and Myxilla incrustans for associated fungal strains. There are only two differences: microsphaeropsisin is a methyl acetal, not hemiacetal, and it is an 11-epimer of the revised botryosphaerihydrofuran (we do not address the issues of absolute configuration in this work). DU8+ confirms the correct assignment of microsphaeropsisin with high accuracy. As shown in Figure 11, the experimental 13 C data for both compounds match very closely, except for the carbons proximal to C11 and C8 in microsphaeropsisin, i.e. the ones most affected by the two differences in these structures. This additional experimental evidence imparts confidence that our computationally driven revision of botryosphaerihydrofuran is indeed correct. A new diterpenoid, aromaticane I recently isolated from a herb Curcuma aromatica Salisb. possessed a peculiar epoxidized bicyclo[2.2.2]octene moiety, 49 Figure 12. However, a
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The Journal of Organic Chemistry
cursory analysis of its 13C chemical shifts, especially C-15 and C-16, indicated that the compound is unlikely to have the purported oxirane. Further computational analysis confirmed that aromaticane I is misassigned, and that the experimental data belong to the structural type of a kauroic acid. Additional searching of the literature gave a good match with the known ent11α,16α-epoxy-15α-hydroxy-16S-kaur-19-oic acid, 50 (see Table S4 for comparison of experimental chemical shifts). Furthermore, based on DU8+ analysis, aromaticane D, a 5,10-epoxy sesquiterpene (an oxetane, not oxirane) also isolated from the same herb needed a relative stereochemistry correction as shown in Figure 12.
HO
11
20
1
O
13
10
H
H
12 11 20 14 1
17
12
revised
15
8
10
H
5 14
19
10 8
H 9
1
15
H
6
O
16 2
O
4
5
17
13 7
O
14
16 15
H
6
17
crotodichogamoin A
O 20 H epi-2,4,9
rmsd(δ C) = 2.64 ppm rmsd(δ H) = 0.25 ppm rmsd(J HH) = 0.93 Hz
rmsd(δ C) = 1.66 ppm rmsd(δ H) = 0.17 ppm rmsd(J HH) = 0.49 Hz
O
H
20
11
12
18
AcO 1 19
2
H 9 4
10 8
O 5
13 7
O
14
6
H
16 15 17
(x-ray)
17
rmsd(δ C) = 1.04 ppm
OH
Figure 13. Revision of crotodichogamoin A
ent-11α,16α-epoxy-15αhydroxy-16S-kaur-19-oic acid (known NP)
A new terpene-polyketide hybrid meroterpenoid, emervaridone C, containing an oxirane moiety derived from an exocyclic terminal alkene, Figure 14, was isolated from cultures of fungus Emericella sp. TJ29. 54 Its putative alkenic precursor, emervaridone B, was characterized by xray. However, epoxidation of exo-methylenecycloalkanes could occur from either face, and the resulting spiro-oxiranes constitute a particular challenge to structural assignment. Therefore, it is not surprising that DU8+ analysis necessitated the revision of stereochemistry of emervaridone C at carbon C-3'.
15
15
4
5
14
7
12
18
revised
O
15
18 19
aromaticane I rmsd(δ C) > 9 ppm
10
O
O
4
13
13
COOH
COOH
18 19
1
2
11
12
5
5
H
9
1 19
10 8
H
O 20 H crotohaumanoxide
O 8
H
11 18
O
8 7
revised
H O
10
1
O
4 5
12 11
H
8 7
O
H O 12 11
O
13
13
aromaticane D
epi-8
rmsd(δ C) = 1.73 ppm rmsd(δ H) = 0.20 ppm rmsd(J HH) = 0.56 Hz
rmsd(δ C) = 1.18 ppm rmsd(δ H) = 0.16 ppm rmsd(J HH) = 0.76 Hz
10'
10'
O
Figure 12. Revision of aromaticanes I and D 1
DU8+ computations on the structure of crotofolane diterpenoid crotodichogamoin A, 51 recently isolated from the root of Croton dichogamus, gave poor match with the experimental data. Its 2,4,9-epimer matched these data the best, and we revised the structure of crotodichogamoin A to its 2,4,9-epimer shown in Figure 13. We do not have a good rationale that crotodichogamoin A is isolated together with a very similar diterpene crotohaumanoxide, which was previously characterized by xray as syn- not anti- diepoxide, 52 Figure 13. Incidentally, a control DU8+ run gave a perfect match for crotohaumanoxide, rmsd(δC) = 1.04 ppm. The stereochemistry of crotodichogamoin A51 was assigned by analogy with that of crotohaumanoxide. Nonetheless, we assert that the structure of crotodichogamoin A needs revision, and that its 2,4,9-epimer is, at this point, the best structure. 53
13 11 10
H
3
O
5'
3' 8
revised
6'
O
9'
H
O
4'
7' 2' 1'
O
H
O
1
4'
13 11
5'
3'
8' 10
O
6
H 14 15
H
3
O
6'
9'
8
7' 2' 1'
O
8'
O
6
H 14 15
emervaridone C
epi-3'
rmsd(δ C) = 2.13 ppm rmsd(δ H) = 0.20 ppm rmsd(J HH) = 0.33 Hz
rmsd(δ C) = 0.81 ppm rmsd(δ H) = 0.13 ppm rmsd(J HH) = 0.23 Hz
Figure 14. Revision of emervaridone C The largest deviation in calculated 13C chemical shifts for the originally proposed structure, ∆δC = 7.6 ppm, is observed for the oxirane’s methylene C-9’. It is surprising that the next largest deviation, i.e. ∆δC = 4.0 ppm, belongs to C-5, accented with the second yellow circle in Figure 14. In the flat drawing C-5 appears distal from the problematic spiro-oxirane: C-5 and the oxirane’s oxygen are five bonds apart from each other. The structure of emervaridone C is conformationally rigid; it can be described by a single low energy conformer shown in Figure 14
7
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for the revised structure. In it, the oxirane oxygen is “intruding” into the σ* orbital of the H–C-5 bond, with the O----H distance of only 2.22Å, which qualifies for a non-classical hydrogen bond, O-----H-C. This produces a ~3 ppm effect on the calculated chemical shift of C-5 thus providing a secondary criterion for this structure revision. A similar rationale based on the oxirane-methylene chemical shift, augmented with a secondary criterion is applicable to the case of the correctly assigned fungal metabolite isotrichodermin, Figure 15. 55 Overall rmsd(δC) favors the correct isomer, but the differences are marginal for confident assignment. However, analysis of individual deviations reveals that the chemical shift of the oxirane's methylene deviates from the experimental value by 2.9 ppm in the alternative incorrect structure. The additional criterion is that the calculated chemical shift for a proximal methyl group, Me14, in the incorrect candidate structure deviates by 4.3 ppm, which imparts confidence that the originally assigned structure is indeed correct. 10
16 8
7
H 11 6
O 13 5
O
3
OAc
8
12
7
H
O O
11 6
2.9 ppm
OAc 12 4
15
14
∆δC
2
5
4
15
10
16
2
14
epi-12
∆δC
= 4.3 ppm
originally assigned correct structure of isotrichodermin
(incorrect candidate structure)
rmsd(δ C) = 1.42 ppm
rmsd(δ C) = 1.83 ppm
Figure 16. Correctly assigned plagiochiline J presents challenges for structure validation, with only one carbon difference lending itself as the sole criterion for differentiation (ΔδC is the difference between the computed and experimental 13C chemical shift for C-11) A complex hapalindole-related alkaloid fischambiguine B 57 also possesses a spiro-oxirane moiety. Its DU8+ analysis seems to confirm that the discrepancy in computed and experimental 13C chemical shift for oxirane’s methylene carbon (C26) is indeed a reliable criterion for validating spiro-oxiranes. As shown in Figure 17, the stereochemistry at the spiro carbon C-25 of fischambiguine B needs revision, as the 13C chemical shift value for C-26 in the originally assigned configuration deviates by 7.9 ppm. The spectra were acquired in DMSO-d6 known to complicate proton chemical shift computations of alcohols. This complication is due to the difficulty in predicting coordination of solvent through H-bonding with OH or NH moieties and the relative strength of the intramolecular hydrogen bonds. The proton chemical shifts are therefore omitted from the analysis, as we normally do not consider their calculated values in DMSO reliable, especially for the substrates capable of forming hydrogen bonds with the solvent. Cl 18 17 5
1.8 ppm
∆δC 11
O O
2
3
O
H 1 5
10
O
O
O H
2
1 5
3
7
3.3 ppm
∆δC
11
10 7
H
H 13
12
15
14
13
12
15
14
originally assigned correct structure of plagiochiline J
(incorrect)
rmsd(δ C) = 1.19 ppm rmsd(δ H) = 0.21 ppm rmsd(J HH) = 0.54 Hz
rmsd(δ C) = 1.32 ppm rmsd(δ H) = 0.24 ppm rmsd(J HH) = 0.96 Hz
epi-10
8
20 NC 23
15 OH 11 10 25 16 H 3 24 4 2 9 1
Such helpful secondary criterion is not always available. This constitutes a recurring challenge for stereochemical assignment of epoxidized exocyclic methylenes. For example, calculations for the correctly assigned structure of plagiochiline J, Figure 16, isolated from the liverwort Plagiochila Fruticosa, 56 revealed that with the omission of the oxirane’s methylene carbon, the correctly assigned original structure and its spiro epimer both gave a very good match, rmsd(δC) = 1.14 and 1.09 ppm, respectively. Inclusion of C-11 offers only marginal preference of 1.19 ppm over 1.32 ppm – not a comfortable margin at all comparable to the DU8+ accuracy of 1.28 ppm. What saves the day and validates the original correct assignment for plagiochiline J is that the calculated chemical shift for C-11 in the incorrect candidate structure deviates by 3.3 ppm from the experimental value; whereas, it is predicted within 1.8 ppm for the correct isomer, Figure 16. This difference of only 1.5 ppm in calculated values underscores the importance of accurate methods for computing NMR chemical shifts (or SSCCs) with a narrow distribution of errors.
21
19
13
Figure 15. Correctly assigned structure of isotrichodermin
Page 8 of 13
8
NH
∆δC
26
O 28
Cl
= 7.9 ppm
19
revised
18 17 5
21 20
13
NC 23 ∆δC 15 OH O 11 10 25 16 H 3 24 26 4 2
9
1
27 8
NH
= 2.6 ppm
28 27
fischambiguine B
epi-25
rmsd(δ C) = 2.66 ppm rmsd(J HH) = 0.44 Hz
rmsd(δ C) = 1.69 ppm rmsd(J HH) = 0.57 Hz
Figure 17. Revision of fischambiguine B. A potential problem with the revised structure is that the oxirane's methylene exhibits a NOESY cross-peak with the C(10)-OH group, implying that the CH2 and OH groups are syn, i.e. on the same face of the molecule. However, analysis of the calculated structures shows that due to insignificant pyramidalization of the oxirane's methylene, the distance between C(10) and the proximal H26 atom of the methylene group is nearly identical in both structures, ~ 4.2 Å. If one assumes free rotation of the OH group, these two structures should be indistinguishable based on this NOESY cross-peak. As further shown in Figure 17, the difference is that the revised structure has a strong hydrogen bond between the OH group and the oxirane oxygen. This rotates the OH group favorably and reduces the
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The Journal of Organic Chemistry
distance between H26 and OH to 3.8 Å. In the original structure, such an H-bond is impossible and, in the lowest energy conformer, OH points in the direction of indole's π density, with the OH-H26 distance increasing to 4.85 Å. Same conformation is expected with an H-bonded solvent molecule. Guatterfriesols A and B 58 were recently isolated from the stem bark of G. friesiana and assigned the sesquiterpene lactone structures shown in Figure 18. Our computations revealed that the experimental data for guatterfriesol A fit the structure originally proposed for guatterfriesol B. Guatterfriesol B, in turn, is revised to its 4,5,6-epimer. This revision could accommodate a hypothesis of a common alkenone precursor, epoxidated from both faces, with the hemiacetal’s OH group assuming the syn configuration to the respective epoxides, presumably due to intramolecular hydrogen bonding. 14
14
H
H
10
revised
1 HO 7 5 11 4 6 12 O
13
O
O
15
10
1 HO 7 5 11 4 6 12 O 15
O epi-4,5,10 (guatterfriesol B)
O
guatterfriesol A rmsd(δ C) = 1.12 ppm rmsd(δ H) = 0.14 ppm rmsd(J HH) = 0.68 Hz
rmsd(δ C) > 4.1 ppm
H
10
4
An unusual endo-peroxide containing the oxirane moiety, acremine P, was recently isolated from fungus Acremonium persicinum. 60 Its calculated spectra do not match the experiment, rmsd(δC) > 9 ppm. As shown in Figure 20, the largest two deviations from the calculated values were for C2 and C7 (∆δexp-calc = 102.4 – 121.8 = -19.4 ppm) (∆δexp-calc = 95.0 – 72.3 = 22.7 ppm). Given the experimental chemical shift of C2 we hypothesized that acremine P could be a 3-alkoxy-2-cyclohexenone. Comparison with the experimental spectrum of epoxyserinone A 61 shows that the chemical shifts for alpha carbon in similar alkoxy enones is expected in the vicinity of 100 ppm. The chemical shift value for C7 (a simple allylic alcohol) in the original structure of acremine P was too high, 95.0 ppm. A simple "insertion" of an oxygen atom at C3 and swapping C7 and C9 of the isoprene module resolved most of the issues. The final revised structure of acremine P, shown in Figure 20, emerged after comparison between the four possible diastereomers. 62 Another experimental observation, which is consistent with the C3-C7 "disconnect" was that NOEDIF excitation of H7 produced no effect on H2; yet, the distance between these protons in the original structure, 3.06 Å, would necessitate a NOE enhancement. In the revised structure the distance between these two protons is 5.78 Å.
14
14
H
Figure 19. Revision of roscotane D
1 HO 7 5 11 6 12 O
10
1 HO 7 5 11 6 12 O
4
15
O
O O O
guatterfriesol B
rmsd(δ C) = 1.28 ppm rmsd(δ H) = 0.14 ppm rmsd(J HH) = 1.15 Hz
11 10 9
Diepoxyabietane diterpenoid roscotane D was recently isolated from the whole plants of Kaempferia roscoeana. 59 Again, there is very little information in the proton spectrum to suspect misassignment. However, accurate calculations of all three NMR parameter sets for the original structure and alternative candidates, i.e. proton and carbon chemical shifts, and proton SSCCs, reveal that the correct structure for roscotane D is its 13,14-epimer, Figure 19. The other candidates, i.e. epi-7,8 or epi-7,8,13,14, produced inferior matches for the experimental data. 16
16
15 20
13 14
9
H
8 7
O
15 17
O
H 18 19
20
revised
13 14
9 1
H
8 7
O
17
O
H 18 19
roscotane D
epi-13,14
rmsd(δ C) = 2.76 ppm rmsd(δ H) = 0.24 ppm rmsd(J HH) = 1.04 Hz
rmsd(δ C) = 1.06 ppm rmsd(δ H) = 0.21 ppm rmsd(J HH) = 0.62 Hz
9
O O O
H
OH revised 3
4 5 6 1
HO
O
9
8
O O3
7
O
2
O
Figure 18. Revision of guatterfriesols A and B
1
8
O epi-4,5,6
rmsd(δ C) > 2.3 ppm
11 10
H 7
9
13
O
O
15
11
10
revised
4 5
2 6
1
O
O
acremine P
revised acremine P
rmsd(δ C) = 9.4 ppm rmsd(δ H) = 0.56 ppm
rmsd(δ C) = 1.14 ppm rmsd(δ H) = 0.20 ppm 11
95.0 72.3
H
95.0 93.2
OH 7
8 3
4 5 6 1
O
162.5 159.52 102.4 121.8 2
O
acremine P
HO
H
10
7
8 9
O
OO 3
4 5 6 1
O
162.5 162.0 102.4 104.1 2
O
revised acremine P
HO OMe 168.4 168.1 O 99.8 99.8
O
O
epoxyserinone A
Figure 20. Revision of acremine P. Green values are experimental 13C chemical shifts for select carbons; calculated values are shown in maroon. A 3-alkoxy-substituted enone, epoxyserinone A, is shown for comparison – see text. Monoepoxidized complex steroids taccalonolides were originally isolated from the Chinese medicinal plant Tacca plantaginea in 1997. 63 As potent microtubule-stabilizing agents, they were further investigated and modified; for example, two new diepoxides, taccalonolides AJ and AF, were obtained by semisynthesis. 64 Computed spectra for these diepoxides revealed that the assignment of the 22,23-epoxide needs revision, i.e. the correct structures for taccalonolides AJ and AF are the shown epi-22,23 epoxides, Figure 21. In such “congested” steroids, positioning of the oxirane oxygen on the opposite face of the polycyclic framework often causes a ripple effect on computed chemical shifts of the sur-
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rounding atoms for various reasons, including profound conformational changes. In this particular case, the largest deviation in the 13C chemical shifts computed for the original structures – ca. 10 ppm – was found for Me28, leaving no doubt that the structures are misassigned. 21 22 O AcO 18 20 AcO 23 O H AcO 19 111213 17 26 24 H 14 25 9 15 O revised 1 H 10 2 28 OH O 5 H 7 H OH 27 6 OH H O
O
AcO AcO AcO H
H
O
H H OH OH
H
O
O
H
OH
O
taccalonolide AJ
epi-22,23
rmsd(δ C) = 2.83 ppm rmsd(δ H) = 0.17 ppm rmsd(J HH) = 0.96 Hz
rmsd(δ C) = 1.79 ppm rmsd(δ H) = 0.1 ppm rmsd(J HH) = 1.04 Hz
O
AcO AcO AcO H
H H OAc OH
H
O H
O
revised
OH
O
AcO AcO AcO H
O
H
H H H OAc OH
H
O H
O
O O OH
O
taccalonolide AF
epi-22,23
rmsd(δ C) = 2.91 ppm
rmsd(δ C) = 1.80 ppm
CONCLUSIONS As a fast and accurate method for NMR computations, DU8+ offers expeditious structure validation or revision for large collections of natural products. With this computational tool we analyzed a number of NPs containing the oxirane moiety and revised 21 structures. Judging by this relatively high rate of misassignment, the presence of oxirane moiety in natural products constitutes an additional challenge for structure elucidation. We cannot offer a statistically rigorous estimate of the rate of misassignment in naturally occurring epoxides, as our initial selection of natural epoxides from the literature is arbitrary. However, as we examined approximately a hundred compounds, the rate of misassignment in the examined subset of natural epoxides exceeded 20%, which is slightly higher than our earlier observations of 13-15% for the rate of misassignment of other natural products. However statistically imperfect, these misassignment rates are of concern. DFT computations of the ubiquitous 1D NMR spectra, presently available to the practitioners in the field, could help alleviate the majority of these misassignments. As we noted before, another additional difficulty of structure validation/revision is a high rate of typos in the reported NMR data. This underscores the importance of dissemination of the original NMR data (i.e., FID data deposited in a digital format suitable for subsequent analysis). There have been several calls for action, the latest being coordinated by Guido Pauli under the community project on structural correctness.29
ASSOCIATED CONTENT
Figure 21. Revision of taccalonolides AJ and AF Finally, diterpenoid γ-lactone of briarane structural type, juncenolide G, was isolated from the gorgonian coral Junceella juncea, 65 Figure 22 (authors' original structure drawing style is preserved for consistency, although the configuration at some carbon atoms, especially C8, is difficult to discern).
Supporting Information. Computational details. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION Corresponding Author *E-mail:
[email protected]
ORCID: 0000-0003-3066-517X OAc O
AcO 14
4
1
11
3 9
7
H
O 20
AcO
O6
17
OH Cl
O 18
19
O
OAc O
AcO
16
revised
14 11
3
O6
9
H O 20 AcO
Notes
16 4
1
7
OH
The authors declare no competing financial interest.
Cl
O
17
ACKNOWLEDGMENT
18 19
Page 10 of 13
O
This research is supported by the NSF, CHE-1665342 juncenolide G
epi-3,4
rmsd(δ C) = 3.70 ppm rmsd(δ H) = 0.34 ppm rmsd(J HH) = 0.80 Hz
rmsd(δ C) = 1.71 ppm rmsd(δ H) = 0.18 ppm rmsd(J HH) = 0.15 Hz
Figure 22. Revision of juncenolide G. DU8+ computations revealed that the structure of juncenolide G is misassigned, rmsd(δC) = 3.7 ppm. Large deviations in computed 13C chemical shifts were observed for the C26 fragment, indicating potential misassignment of the 3,4-epoxy moiety. A number of candidate structures were analyzed to confirm this hypothesis. Based on this analysis, the structure of juncenolide G is revised to its epi-3,4 (still trans) stereoisomer.
10
REFERENCES
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(47) Rukachaisirikul, V.; Arunpanichlert, J.; Sukpondma, Y.; Phongpaichit, S.; Sakayaroj, J. Metabolites from the endophytic fungi Botryosphaeria rhodina PSU-M35 and PSU-M114. Tetrahedron, 2009, 65, 10590-10595. (48) Höller, U.; König, G. M.; Wright, A. D. Three New Metabolites from Marine-Derived Fungi of the Genera Coniothyrium and Microsphaeropsis. J. Nat. Prod. 1999, 62, 114-118. (49) Dong, S.; Li, B.; Dai, W.; Wang, D.; Qin, Y.; Zhang, M. Sesqui- and Diterpenoids from the Radix of Curcuma aromatica. J. Nat. Prod. 2017, 80, 3093-3102. (50) (a) for 13C NMR data see the original paper: Murakami, T.; Iida, H.; Tanaka, N.; Saiki,Y,; Chen, C. -M.; Iitaka, Y. Chemische und chemotaxonomische Untersuchungen von Filices. XXXIII. Chemische Untersuchungen der Inhaltsstoffe von Pteris longipes DON. Chem. Pharm. Bull. 1981, 29, 657-662. (b) The structure of this kauroic acid was later confirmed by xray: Hu, X. -Y.; Luo, Y. -G.; Chen, X. -Z.; Zhou, L.; Zhang, G. -L. Chemical constituents of Nouelia insignis Franch. J. Asian Nat. Prod. Res. 2008, 10, 125131. The nomenclature/numbering is adopted from this article. (51) Aldhaher, A.; Langat, M.; Ndunda, B.; Chirchir, D.; Midiwo, J. O.; Njue, A.; Schwikkard, S.; Carew, M.; Mulholland, D. Diterpenoids from the roots of Croton dichogamus Pax. Phytochem. 2017, 144, 1-8. (52) Tchissambou, L.; Chiaroni, A.; Riche, C.; Khuong-Huu, F. Crotocorylifuran and crotohaumanoxide, new diterpenes from Croton Haumanianus J. Leonard. Tetrahedron 1990, 46, 5199-5202. (53) Additional challenge in this case has to do with the fact that the potential energy surface for fused methylcyclopentanones is often very shallow, and is difficult to accurately describe at the light B3LYP/6-31G(d) level of DFT theory. A useful practical procedure in such cases is to augment the ensemble of conformers with a flat conformation of cyclopentanone and mix it in according to its “Boltzman population” derived from the relative energy, even though it is not an energy minimum, see Supporting Information. (54) He, Y.; Hu, Z.; Li, Q.; Huang, J.; Li, X. -N.; Zhu, H.; Liu, J.; Wang, J.; Xue, Y.; Zhang, Y. Bioassay-Guided Isolation of Antibacterial Metabolites from Emericella sp. TJ29. J. Nat. Prod. 2017, 80, 2399-2405. (55) (a) Greenhalgh, R.; Meier, R. -M.; Blackwell, B. A.; Miller, J. D.; Taylor, A.; ApSimon, J. W. Minor metabolites of Fusarium roseum (ATCC 28114). J. Agric. Food Chem. 1984, 32, 12611264. (b) Greenhalgh, R.; Meier, R. -M.; Blackwell, B. A.; Miller, J. D.; Taylor, A.; ApSimon, J. W. Minor metabolites of Fusarium roseum (ATCC 28114). J. Agric. Food Chem. 1986, 34, 115-
(56) Fukuyama, Y.; Asakawa, Y. Neurotrophic secoaromadendrane-type sesquiterpenes from the liverwort Plagiochila fruticosa. Phytochem. 1991, 30, 4061-4065. (57) Mo, S.; Krunic, A.; Santarsiero, B. D.; Franzblau, S. G.; Orjala, J. Hapalindole-related alkaloids from the cultured cyanobacterium Fischerella ambigua. Phytochem. 2010, 71, 2116-2123. (58) Costa, E. V.; Soares, L. N.; Pinheiro, M. L. B.; Maia, B. H. L. N. S.; Marques, F. A.; Barison, A.; Almeida, J. R. G. S.; Sousa, I. L.; Galaverna, R. S.; Heerdt, G.; Morgon, N. H.; Acho, L. D. R.; Lima, E. S.; da Silva, F. M. A.; Koolen, H. H. F. Guaianolide sesquiterpene lactones and aporphine alkaloids from the stem bark of Guatteria friesiana. Phytochem. 2018, 145, 18-25. (59) Boonsombat, J.; Mahidol, C.; Chawengrum, P.; ReukNgam, N.; Chimnoi, N.; Techasakul, S.; Ruchirawat, S.; Thongnest, S. Roscotanes and roscoranes: Oxygenated abietane and pimarane diterpenoids from Kaempferia roscoeana. Phytochem. 2017, 143, 36-44. (60) Suciati; Fraser, J. A.; Lambert, L. K.; Pierens, G. K.; Bernhardt, P. V.; Garson, M. J. Secondary Metabolites of the SpongeDerived Fungus Acremonium persicinum. J. Nat. Prod. 2013, 76, 1432-1440. (61) Gautschi, J. T.; Amagata, T.; Amagata, A.; Valeriote, F. A.; Mooberry, S. L.; Crews, P. Expanding the Strategies in Natural Product Studies of Marine-Derived Fungi: A Chemical Investigation of Penicillium Obtained from Deep Water Sediment. J. Nat. Prod. 2004, 67, 362-367. (62) The only remaining mystery for acremine P is that the
authors catalytically hydrogenated it with H2 over Pd/C producing acremine A, a known NP which has a C3-C7 bond. As the catalytic hydrogenation required two attempts on an initial amount of 0.7 mg of acremine P with subsequent HPLC purification, one wonders if the identity of the hydrogenation product was misinterpreted. (63) Chen, Z. L.; Shen, J. -H.; Gao, Y. -S.; Wichtl, M. Five Taccalonolides from Tacca plantaginea. Planta Medica 1997, 63, 4043. (64) Li, J.; Risinger, A. L.; Peng, J.; Chen. Z.; Hu, L.; Mooberry, S. L. Potent Taccalonolides, AF and AJ, Inform Significant Structure–Activity Relationships and Tubulin as the Binding Site of These Microtubule Stabilizers. J. Am. Chem. Soc. 2011, 133, 19064-19067. (65) Lin, Y.-C.; Huang, Y.-L.; Khalil, A. T.; Chen, M.-H.; Shen, Y.-C. Juncenolides F and G, Two New Briarane Diterpenoids from Taiwanese Gorgonian Junceella juncea. Chem. Pharm. Bull. 2005, 53, 128-130.
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