2.1 Aldingenins A–D

The red algal genusLaurencia has been the source of many isoprenoid natural products, including the chamigrene sesquiterpene (−)-elatol,²¹ the halogenated sesquiterpenes rhodolaureol and rhodolauradiol,²² and the brominated bisabolene derivatives aldingenin A–D (1–4).^23,24 The molecular masses of1–4 were determined using HREIMS and the structures (1a–4a) were based on analysis of 1D and 2D NMR spectra.²⁵ Comparison of NMR spectroscopic data of synthesized aldingenins B and C with natural isolates did not agree with the proposed structures2a and3a.^25,26 Studies on aldingenin C (3) and D (4) using computer-assisted chemical structure elucidator (CASE),²⁷ revealed that they were in fact the known compounds caespitol (3b) and 5S-acetoxy-caespitol (4b).²⁶ Based on this realization, Kutateladze and coworkers used a newly developed strategy to calculate spin-spin coupling constants named relativistic force field (rff), using an optimized basis set (DU8c) and scaled Fermi contacts to identify the correct structures for aldingenins A (1b) and B (2b).²⁸ Not surprisingly, the newly proposed structures bear chlorine atoms, as do caespitol (3b) and 5S-acetoxycaespitol (4b). It is unclear how the MS signatures of natural products with two bromine and one chlorine atoms could be confused with those possessing only one bromine. One possible explanation is that electron impact ionization led to weak molecular ion peaks for these non-aromatic halogenated compounds.²⁹

2.2 Decurrensides A-E

After decurrensides A–E (5–9) were isolated from the Chinese herbSolidago decurrens,³⁰ the proposed structure8a was synthesized; however, the NMR spectroscopic data did not match the natural product.³¹ This discrepancy led to the revelation that the depicted structures5a–9a did not match the compound names. More specifically, the paper proposed5–9 to be 2,6-hemiacetal-3-deoxy-d-altro-2-octulsonic acids (5a–9a) but named them 3-deoxy-d-manno-2-octulosonic acids. Further studies based on computation ofδ_C and the proton spin-spin coupling constants determined that both the original name and depiction of5–9 were incorrect and instead should be revised to 2,6-anhydro-3-deoxy-d-manno-2-octulopyranosonates (5b–9b).³² DFT-based computation ofδ_C for8a using the gauge-including atomic orbital (GIAO) method showed poor correlation with the experimental values, including a deviation of more than 10 ppm for the hemiacetal carbon. In the original proposal5a–9a, a spin system involving four consecutive 5 Hz spin-spin coupling constants was reported between H₂-3/H-4/H-5/H-6/H-7. Relativistic force field andDU8c based coupling constant calculations on the proposed structure predictedJ_H-6,H-7 to be 0.2 Hz, which was drastically smaller than the reported value of 5 Hz. When computational predictions were made forα- andβ-2,5-hemiacetals of the methyl ester of 8-O-benzoyl-3-deoxy-d-altro-2-octulosonic acid, both 2,5- and 2,6-hemiacetals of 3-deoxy-d-manno-2-octulofuranosonic acid, and the two ketal forms of 3-deoxy-d-manno-2-octulofuranosonic acid, none of the generated values for these structures matched the experimentally acquired spectral data for8. The core structure 2,6-anhydro-3-deoxy-2-octulopyranosonic acid was found to closely match experimental spectral data of8 through comparison of computationally derivedδ_C andrff-calculatedJ-coupling values. In support of the revision,5b–9b contain a common spin system with four consecutive protons all having dihedral angles of 40–50° between vicinal neighbors resulting in the expected sequential 5 Hz coupling constants. Ultimately,rff based calculations of nuclear spin-spin coupling constants and prediction ofδ_C led to the conclusion that structures5–9 consist of a 2,6-anhydro-3-deoxy-d-manno-2-octulopyranosonate core with different substitution in the C-8-O-acyl and C-1 ester.

2.3 Tristichone

Tristichone C (10) is a chamigrane-type sesquiterpene obtained from the marine red algaLaurencia tristicha.³³ Its structure (10a) was elucidated using HRMS and NMR spectroscopic analysis, but no experimental evidence was provided to support the relative positions of the bromine and chlorine atoms. Recently, Kutateladzeet al. developed a quadratic scaling correction to be used in conjunction with theirrff method to take into account the effect of spin-orbit contribution on predictedδ_C.³⁴ The correction parameters were obtained from an experimental training set of more than 400δ_C for carbon attached to S, Cl, Br or I. Among the 119 molecules chosen in this study, the structures of 16 were subsequently revised. Misassignments ranged from incorrect stereochemistry to incorrect carbon skeletons. The predicted chemical shift for the chlorine-bearing carbon atom of10a deviated by 6.6 ppm from the experimental value, but the constitutional isomer10b resulted in a much better fit. Interestingly, this computational prediction is in perfect agreement with a previous empirical study in which theδ_C for a series of polyhalogenated compounds similar to10a and10b were reported.³⁵

2.4 Glabramycins B and C

Antibiotic glabramycins B (11) and C (12) were isolated fromNeosartorya glabra, a fungus obtained from soil samples.³⁶ In the original proposal for glabramycin B (11a), ananti relationship between C-10, C-11, and C-15 was proposed based on the triplet resonance of 9.6 Hz observed for H-10 whereas the configuration at C-20 was not determined. The decalactone polyketide structure of glabramycins B (11) and C (12) are closely related to the natural product dictyosphaeric acid, where C-11 exhibits asyn configuration relative to C-10.³⁷ Prompted by this difference in the configuration at C-11, the proposed structures of glabramycins and their possible diastereomers at position C-11 and C-20 were subjected to δ_C DFT calculation. Coupling constants between H-10 and H-11 and between H-11 and H-12 were also predicted computationally for all the diastereomers.³⁸ Calculatedδ_C andJ values favored11b and12b as the correct structures of glabramycins. This result was recently confirmed through total synthesis of11b.^39,40 The original proposal lacked a key literature precedent: the structure determination of dictyosphaeric acid, which has the same decalactone moiety as glabramycins, utilized aJ based configuration analysis to explain the large coupling constant observed for the eclipsed configuration between H-10 and H-11.^37,41

2.5 Synargentolide A

Syncolostemon argenteus, a South African plant of the mint familyLamiaceae, produces the 5,6-dihydro-α-pyrone synargentolide A (13).⁴² To determine its absolute configuration, the compound was fully hydrolyzed and transformed into 5- and 6-membered acetonides. First, the 5-membered ring acetonide tethering alcohols at positions 4’ and 5’ was used to deduce the relative configurations of these positions, as well as the configuration of the free alcohol at position 6’ using derivatization of its α-methoxy-α-trifluoromethylphenylacetate ester. To relate the configuration of the alcohol at C-6’ with the two other stereocenters,δ_C of the two methyl groups on the 6-membered acetonide between alcohols 4’ and 6’ were compared with each other (Fig. 1A). Since different chemical shifts were obtained for the methyls of the acetonide, the authors concluded that the acetonide adopted a chair conformation which translates to asyn configuration of the corresponding 1,3-diol and the overall structure13a. Yet when13a was synthesized,⁴³ the NMR spectroscopic data did not match those originally reported. In a subsequent study, the 4’R,5’R,6’R isomer was synthesized and proposed as the absolute configuration of13 based on visual comparison of¹H NMR spectral features.⁴⁴ However, extraction of chemical shifts andJ coupling constants by non-linear fitting of the spectra obtained from the natural product and the synthetic diastereoisomer highlighted slight differences disproving the revision.⁴⁵ Further predictive calculation of the coupling constants by DFT computation of four possible diastereoisomers suggested the configuration to be13b. The simulation took advantage of the spin-spin option in the program Gaussian 09⁴⁶ which calculates the scalar coupling constant as a summation of Fermi contact, spin-dipolar, paramagnetic spin-orbit, and diamagnetic spin-orbit.⁴⁷ The reason for the erroneous stereochemical assessment in the original proposal is uncertain. The acetonide strategy has been extensively studied from the conformational point of view⁴⁸ and suffers no exception when the acetonide is substituted at C-5’, as in this case.⁴⁹ Also, it was shown that substituents at C-4’ or C-6’ exhibiting weak steric hindrance, like nitrile or alkyne derivatives, may produce an anti acetonide. This could mislead configurational assignment sinceanti acetonides, which normally adopt a twist-boat conformation, can flip to a chair conformation (Fig. 1B).⁵⁰ However, the methyl group of13 was not shown to be small enough for this to happen. A possible alternative hypothesis is that epimerization was triggered by the harsh hydrolysis conditions (0.5 M NaOH in MeOH/H₂O for 2.5 days, followed by acidification and heating up to 100 °C for 2 min) or during acetonide formation in acetone with amberlyst 15.⁴²

2.6 Cordycepol A

Cordycepol A (14), along with analogues B and C, were isolated fromCordyceps ophioglossoides, a fungus that colonizes other fungal species.⁵¹ NOESY cross-peaks between H₃-14/H-1, H₃-15/H-1 and H₃-14/H-9 supported the relative configuration of the spiro[4.5]decane ring system of14a (Fig. 2). However, the structures of14 and its analogues were recently revised.⁵² The calculatedJ_H-1,H-2b andJ_H-1,H-2a as well as chemical shifts of C-1, C-2, C-6, C-7, C-10, and C-12 derived using therff/DU8c parametric method for14a significantly diverged from the experimental NMR spectroscopic data. In contrast, the calculated parameters of the revised structure14b very closely match the experimental values. The original proposal contains a NOESY correlation between H₃-15 and H-1⁵¹, which should be at least 6.4 Å apart based on computational predictions. It is possible that H-1 was wrongly assigned since several¹H NMR signals were reported in the same range (δ_H 1.00–1.50), but in the absence of public access to free induction decay (FID) files as proposed by Pauli,⁵³ this cannot be confirmed.

2.7 Meridane

A complex mixture of 7β,9α-longipinene diesters extracted from the leaves and stem ofStevia lucida were subjected to hydrolysis, oxidation, acid-catalyzed dehydration, and rearrangement.⁵⁴ This yielded meridane, proposed as15a based on NMR spectroscopic evidence and a rational reaction mechanism of formation. Shortly thereafter, the structure15a was disproved based on comparison of experimental and computedδ_C using (GIAO mPW1PW91/6-311+G(d,p)).⁵⁵ Close examination of the reaction conditions and other possible rearrangement pathways led to the alternative structure15b, supported by computedδ_H,δ_C,J_H–H andJ_C–H. It is difficult to envision what could have been done to avoid this misassignment, since all HMBC correlations equally support the original and the revised structure.

2.8 Brassicicenes

The plant pathogenAlternaria brassicicola infects mostBrassica species and produces brassiciccene diterpenes16–23 that are phytotoxic.^56-58 These molecules belong to the fusicoccane terpenoid family which has been extensively studied for their interesting biological activities.^59-63 Initial computational studies predicted chemical shifts deviating 10-11 ppm from observed data for C-7 of16a and C-10, C-13 and C-18 of22a, disfavoring the proposed structures.^56,64 Also, the original proposal placed H-17 and H-18 6.8 Å apart, which did not meet expectations for an observed NOE correlation (22a,Fig. 3). Recently,22 was reisolated and revised to22b by pairing quantum-chemical predictions with extensive NMR spectroscopic analysis, resulting in stronger agreement between calculated and experimentalδ_C along with favorable NOE distances supporting correlations between H-18 and H-17 (Fig. 3).⁶⁴ The structure was further validated using X-ray crystallography and electronic circular dichroism spectroscopy (ECD) for absolute stereochemistry. Subsequently, structures of other brassicicene diterpenes17–21 and23 were also revised based onδ_C calculations.⁶⁴ In the original studies,^56,57 important HMBC correlations to support the structures were missing. For example, an isolated spin system of brassicicene G (19), composed of the methyl H₃-18 and the methine H-12, was proposed based on an HMBC correlation of H-12 with C-1, C-10, C-11 and C-13, but the more important HMBC correlations from H₃-18 were not reported.

2.9 Type C Polycyclic Polyprenylated Acylphloroglucinols

Polycyclic polyprenylated acylphloroglucinols (PPAPs) are a class of compounds featuring a highly oxygenated bicyclo[3.3.1]nonane substituted by prenyl side chains.⁶⁵ These compounds are found exclusively in plants from the Clusiaceae family, which includes St-John’s wort (Hypericum perforatum), well known for diverse medicinal properties.⁶⁶ There are three categories of PPAPs, types A, B, and C, distinguished by the position of the acyl moiety relative to the quaternary center of the prenyl side chain (Fig. 4).⁶⁵ A series of the rare type C PPAPs were isolated from the seeds ofGarcinia subelliptica with structures24a-26a elucidated by conventional MS and multidimensional NMR spectroscopy.⁶⁷ However, no experimental evidence was provided to support whether the prenyl side chain was located at C-5 (type A) or C-1 (type C). In a recent examination ofHypericum cohaerens, the structures of24–26 were revisited.⁶⁸ Three-dimensional models of both type C (24a) and type A (24b) were subjected to a molecular mechanic conformational search followed by DFT geometrical optimization, frequencies and thermochemical computation, andδ_C prediction, all at the mPW1PW91/6-31G(d,p) level of theory. The predicted spectroscopic data for24b were in closer agreement with experimental values, especially for positions 1 and 6, which were the most impacted by the acyl group. The same rationale was used to revise co-isolated PPAPs to25b–26b.⁶⁸ It is worth noting that while the 3D structures for24a and24b provided in the supplemental information of the revision were correct, the structures of24a and24b portrayed in the main manuscript were depicted incorrectly with anα-H at R³ rather than aβ-H.⁶⁸ The structures included in the current review are based on the correctly portrayed 3D structures.

3.1 Brevianamides

Diketopiperazine alkaloids are a rich class of cyclic dipeptide molecules exhibiting a range of biological properties.^71-74 Brevianamide M (27) and its oxidation product28 were isolated fromAspergillus versicolor along with a related diketopiperazine dimer and oxepin-containing alkaloids.⁷⁵ The relative configuration of the two stereocenters in27 was determined by X-ray crystallography to be (2R,13R) or (2S,13S). Hydrolysis of the natural products in aqueous solution gavel-phenylalanine suggesting anS-configuration at position 13, which led to the proposal of a (2S,13S) configuration for27a. However, in contrast to the positive optical rotation calculated for the proposed configuration27a using four different DFT quantum chemical models, the molecule showed an experimental optical rotation of −147.7°, suggesting a (2R,13R) configuration.⁷⁶ After careful analysis of this discrepancy, the hydrolysis process was questioned since it could cause epimerization at C-13 of27b to form the low energy diastereomer27c that could hydrolyze to givel-phenylalanine (Fig. 5). As expected, DFT studies predicted the epimer27c to be energetically more stable than27b with a predicted conversion rate of more than 92%. Since28 was isolated using the same procedure as27, it was proposed to share the same absolute configuration. The reassignments were confirmed by agreement between experimental data and DFT computed optical rotation, predicted VCD spectra, and the theoretical prediction of positive and negative cotton effects for ECD spectra.⁷⁶

3.2 Castalagin and vescalagin

Castalagin (29) and vescalagin (30) are epimeric ellagitannins exhibiting antioxidant, antiviral, and inhibitory activity against DNA topoisomerase II.^77,78 They were initially isolated from the wood of chestnut (Castanea sativa) and oak (Quercus sesseliflora) but their exact atropisomerism configuration could not be determined at that time.^79-81 The configuration for the nonahydroxytriphenoyl group was proposed to be (S, S) based on a comparison of the circular dichroism spectrum with the one obtained for a model compound of known configuration.⁸² In a follow-up molecular mechanics study, it was proposed that an (S,R) configuration at the nonahydroxytriphenoyl group would be more stable.⁸³ The discrepancy in proposed configurations was resolved by predicting the ECD spectra of hydrolyzed analogues castalin (31) and vescalin (32) using TDDFT calculation.⁸⁴ The hydrolysis was necessary since strong Cotton effects from the (S)-hexahydroxydiphenoyl ester overlapped with the small Cotton effects of the triphenoyl group. The experimental ECD spectra obtained for31 and32 were in agreement with the predicted spectra of the (S,R) configuration. This led the authors to conclude that castalagin and vescalagin could be revised to29b and30b, respectively. To confirm the ECD spectroscopy results, DFT prediction ofδ_H andδ_C were performed⁸⁴ and found to be in good agreement with experimental values for29 and30.⁸⁵

3.3 Nudicaulin

The flower petals ofPapaver nudicaule owe their yellow color to a group of glycosides called nudicaulins.⁸⁶ After extensive NMR spectroscopic analysis, nudicaulin I was suggested to possess an unprecedented 10H-1,10-ethenochromeno[2,3-b]indole moiety (33a). The downfield chemical shift of C-2 led the authors to propose that this position was attached to one of the oxygens of ring A, leading to the asymmetry needed to explain the two distinct¹H NMR signals of H-5 and H-7 within ring A. Similarly, the relatively upfield chemical shift of C-19 was interpreted as an indication for a bond between C-19 and the indole nitrogen. However, if33a was stable enough to be isolated, it would be expected to experience severe strain at C-2 and C-11 which would limit the aromaticity to isolated phenyl rings rendering the molecule colorless. This prompted the revision of33a to33b using NMR spectroscopic data, chemical derivatization, and comparison of experimental and predicted chiroptical properties.⁸⁷ The evidence included HMBC correlations from H-3 and H-18 to N-1 and ROESY correlations between H-2’/6’ and H-15. The ECD spectrum of33b was predicted with TDDFT using CAM-B3LYP functional and conductor-like polarizable continuum model (CPCM) for solvent effects of methanol. However, prediction at this level of theory was unsatisfactory and the size of the molecule precluded the use of a higher level of theory. Simplification of the molecule to a partially hydrolyzed derivative with one glucose unit at C-11 was evaluated but this prediction was also unsuccessful. Interestingly, modeling a hypothetical chemically unstable form of33b with a hydroxyl in place of the sugar accurately predicted the experimental spectrum. While this advanced demonstration is an example of how complex a structural elucidation with quantum-chemical computation can be, the authors missed a simpler solution: since the relative stereochemistry between the aglycon and the sugar moieties was determined by semi-quantitative ROESY, the absolute configuration of33b could have been deduced from the hydrolyzed glucose unit.

3.4 Plakinidone

Sponges belonging to the genusPlakortis are well known to produce molecules having cyclic five- or six- membered endoperoxide rings.^88-91 Plakinidone (34), isolated fromPlakortis angulospiculatus, was proposed to have ap-hydroxyphenyl and a six membered perlactone ring flanking the two ends of a ten-carbon alkyl chain (34a).⁹² Attempts to synthesize an analogue having the same perlactone moiety were unsuccessful which brought into question the validity of34a.⁹³ Careful NMR spectroscopic analysis resulted in the proposal of more plausible34b composed of a tetronic acid moiety instead of the perlactone. This compound and the 11R,17S stereoisomer34c were synthesized and their optical rotations were compared to the value for the isolated compound, leading to the conclusion that the correct configuration was 11S,17S (34b).⁹³ A subsequent study challenged this finding due to the unstable nature of34 and proceeded to conduct a thorough study of the chiroptical properties of re-isolated34.⁹⁴ TheS configuration at C-11 was unambiguously determined by comparing the optical rotation values of the degradation product35 and the corresponding synthetic compound36, obtained from a 6-step sequence starting from (S)-citronellol. The other chiral center was determined as 17R from comparison of experimental VCD and ECD spectra with those predicted from quantum chemical computation leading to the revised structure34d. The difference in molecular masses of the originally proposed34a and revised34d was attributed to air oxidation of34 which resulted in a molecular ion peak atm/z 374 for34d instead ofm/z 390 for34a.⁹³

4.1 Cycloelatanene A-B

Cycloelatanene A and B, two C₁₆ chamigrenes, were isolated from the Australian marine algaLaurencia elata.⁹⁷ A preliminary chemical profiling using HPLC-NMR spectroscopy resulted in the isolation of the two C-4 epimeric cycloelatanenes, described as A (37a) and B (37b). Their structures were proposed from NMR spectroscopic analysis with the relative configuration established by selective 1D NOE irradiations. In a recent study, the structures were revisited using the crystalline sponge method,⁹⁸ which is suitable for rigid, nonpolar molecules that are smaller than the cross-sectional area of pores of the host complex.⁹⁹ X-ray diffraction analysis of the molecules trapped inside the ordered cavities of the crystalline sponge [(ZnI₂)₃ (tpt)₂ (cyclohexane)_x] (tpt = 2,4,6 -tris-(4-pyridyl)- 1,3,5-triazine) confirmed a rigid tricyclic framework for the cycloelatanenes and ultimately structure37a was revised to37b and37b was revised to37a. A close evaluation of the reacquired 1D NOE spectroscopic data showed key correlations between H-10 and H₃-13 for37b and between H-10 and H-4 for37a, further supporting the revision (Fig. 6).

4.2 Myrtucommulone K

Myrtus communis L, a Mediterranean evergreen shrub, has been traditionally used as an antiseptic, disinfectant, and hypoglycemic agent.¹⁰⁰ A variety of bioactive compounds have been isolated fromM. communis including the cytotoxic phloroglucinol derivative myrtucommulone K (38).¹⁰¹ Structure38a was derived through MS and NMR spectroscopy, relying on two critical HMBC correlations from H-10 to C-9 and from H-9 to C-5”. When38 was later re-isolated, X-ray crysstallographic analysis led to revised structure38b.¹⁰² The MS,¹H, and¹³C NMR spectroscopic data originally published for38a were identical to those obtained for38b, prompting the structural revision of38. Recently, a biomimetic synthesis of38 was reported with agreement between NMR spectroscopic and X-ray crystallographic data of synthetic and natural38b.¹⁰³ Some originally reported HMBC correlations cannot be rationalized in light of the new structure since the hydrogens and the carbons are separated by 4–6 bonds.¹⁰¹ However, due to the wide spectral window necessary to record a full HMBC spectrum for this compound (0-220 ppm in the indirect dimension), it is likely that the resulting low resolution led to confusion in the assignment of carbons with similar chemical shifts (Fig. 7).

5.1 2β-Hydroxynagilactone F and nagilactone I

The bioactive compounds 2β-hydroxynagilactone F (39) and nagilactone I (40) were originally isolated from the root bark of the Japanese evergreenPodocarpus nagi.^104,105 The proposed structures39a and40a included anα-hydroxy at C-2, which was established from the half-height width of the H-2 NMR signal and the assumption that ring A adopted a chair conformation (Fig. 8A).¹⁰⁶ Recently,39 and40 were re-isolated from EthiopianP. falcatus and were found to be active against human colorectal adenocarcinoma.¹⁰⁷ Conformational analysis using MM2 force field suggested that a boat conformation at ring A for epimers39a and39b, with 2α- and 2β-hydroxy groups, respectively (Fig. 8B), would have lower energy than the originally proposed chair conformation.¹⁰⁷ This change in conformation required that the dddd H-2 signal (J = 12.9, 10.0, 7.2, 5.1 Hz) was axially positioned, thus supporting theβ-oriented C-2 hydroxy group in revised39b. The¹H and 2D-NOESY NMR spectra were analyzed to further support the revised orientation of the hydroxy group at C-2 and X-ray crystallographic analysis was used to confirm this new assignment. The absence of a NOESY correlation expected for structure39a due to a 1,3-diaxial interaction between H-2 and the methyl group at C-10 should have raised red a flag on the validity of the original structure.¹⁰⁵

5.2 Coniothyrione

Coniothyrione (41) is a chlorinated cyclopentadienylbenzopyrone antibiotic produced byConiothyrium cerealis, an ascomycete obtained from decaying livestock manure. A mechanistic assay involving interaction with the ribosomal protein small subunit D was used to guide the isolation of41.¹⁰⁸ Lack of HMBC correlation between olefinic H-4 and the methoxycarbonyl C-1 was used to support the proposed structure41a; however, the absence of a correlation does not affirm that they are necessarily more than three bonds apart.¹⁴ Furthermore, as the C-3/C-4 double bond is conjugated to a ketone at C-13, the assignment of C-3 atδ_C 127.2 and C-4 atδ_C 143.1 was unconvincing.¹⁰⁹ The structure was revised to41b by interchangingδ_C between C-3/C-4 along with the position of chlorine, whereas the absence of a three bond HMBC correlation from H-3 to C-1 was attributed to an unfavorable dihedral angle. Biosynthetic analysis was also used to support the revised structure41b. Although the biosynthetic claim was disputed, the revised structure41b was ultimately confirmed based on 1,1-ADEQUATE,¹J_CC-edited HSQC-1,n-ADEQUATE,J-modulated ADEQUATE experiments and computational studies.¹¹⁰ In a recent study the structure was confirmed using ACD/Structure Elucidator in combination with DFT calculations.¹⁴

5.3 Madurastatins

Madurastatins are siderophores produced by bacteria and fungi that facilitate uptake of essential metals into bacterial cells.¹¹¹ It has been well established that siderophore-dependent iron sequestration is essential for the virulence and pathogenicity of some bacteria and fungi.¹¹² Antibacterial madurastatins A1 (42) and B1 (43) are produced byActinomadura madurae,¹¹³ whereas madurastatin C1 (44)¹¹⁴ and MBJ-0035 (45)¹¹⁵ were isolated fromActinomadura sp. andStreptosporangium sp., respectively. Their structures (42a–43a), proposed based on NMR and mass spectral analysis, featured a unique aziridine ring thought to be essential for their antibacterial activity.¹¹³ The aziridine ring in the original structures42a–45a was derived from HMBC correlations between α-proton H-19 andβ-methylene protons H₂-20 to carbonyls C-18 and C-21 (Fig. 9A).¹¹³ However, these HMBC correlations are equally justified by a dihydrooxazole moiety (Fig. 9B), which was recently observed in spoxazomicin C and D.¹¹⁶ An aziridine ring carbon has an expectedδ_C of 33–44 ppm while dihydrooxazoleδ_C would be expected further downfield. The experimental values for C-19 and C-20 in42a were 67.2 and 69.4 ppm, respectively, favoring the dihydrooxazole moiety.¹¹³ In a recent study, the revised structures were further confirmed by partial synthesis of an aziridine ring, a dihydrooxazole moiety, and comparison ofδ_C at C-19 and C-20.¹¹⁷

5.4 Coagulin

There are over 900 naturally occurring withanolides originating from numerous genera of the plant family Solanaceae that exhibit biological activities including anti-inflammatory, immunomodulatory, antifeedant, and antitumor.^118,119 Withanolides are steroids that contain a characteristic highly oxygenated ergostane backbone. Comparison of¹³C NMR spectroscopic data from known with-anolides whose structures have been well established by X-ray crystallography and 2D NMR spectroscopy enabled revisions to 29 withanolide structures.¹²⁰ The observations suggested that theδ_C of C-7, C-9, C-12, and C-21 are shifted, some upfield and others downfield, by the presence of a hydroxy group at C-14 or C-17 via the γ-gauche effect and that the configuration of the hydroxy groups at C-14 and C-17 can be determined from theδ_C at C-9, C-12, and C-21. Coagulin (46), a product of the medicinal plantWithania coagulans,¹²¹ was suggested to contain an uncommon C-14/O/C-20 bridge (46a), based on the degree of unsaturation as determined by EIMS and theδ_C of three oxygenated quaternary carbons at C-14, C-17, and C-20. The proposed linkage for46a requires that the 17-hydroxy group be in aβ-orientation, but it was revised to be in aα-orientation as indicated by the upfield chemical shift of C-12.¹²⁰ Further, the¹³C NMR spectroscopic data for positions 1–22 of46 were almost identical to those of a known analogue, withanolide K. Since46 contained the same steroid nucleus as withanolide K, the structure was revised to 27-hydroxywith-anolide K (46b). It should also be noted that the authors of the original paper mistakenly concluded the observed [M – H₂O]⁺ to be the molecular ion of46, resulting in an inflated value for degrees of unsaturation.¹²⁰

5.5 Cephalosporolides and penisporolide

Cephalosporolides H (47) and I (48) and penisporolide B (49) are [5,5]-spiroacetal-cis-fused-γ-lactones originally described following their discovery from a marine-derivedPenicillium fungus.¹²² The proposed stereochemistry for cephalosporolide H (47a) was established by NOESY correlations from H-5a to H-4 and from H-5b to H-7. Penisporolide B was shown to have structure49a which, if the lateral chain is neglected, is a diastereoisomer of47a and48a. In all cases, the relative configuration of the chiral centers at C-3, C-4 and C-6 was supported by NOESY data, but the configuration at C-9, which is relatively distant from positions 3, 4, and 6, was not discussed. Recently, NMR spectroscopic data of the four possible relative stereoisomers of analogues of47–49 (R = Me) were examined.¹²³ By searching for significant patterns inδ_H andJ values, a decision tree was formulated based on three NMR spectroscopic parameters to determine the relative stereochemistry for this compound class: (i) the scalar coupling constants of H-4 with H-3 and H₂-5; (ii) the difference inδ_H between the two H-5 protons, which allows determination of the configuration at C-6 relative to the orientation of H-3/H-4; and (iii) the difference inδ_H between both protons at position 8 which determines the configuration at C-9, based on arguments of steric compression.¹²⁴ To strengthen the model, the chemical shifts of C-3 and C-7 were also considered. The decision tree was used to confirm the assignment of 21 such molecules from different sources and to revise the structures of cephalosporolide H (47a) and I (48a) and penisporolide (49a) to47b, 48b and49b, respectively.

5.6 Cryptospirolepine

The ‘Crews rule’ states that the structure of a molecule is expected to be especially difficult to solve when the ratio of the number of hydrogens to carbons is fewer than 1, since NMR spectroscopic methods are so dependent on detection through protons.¹²⁵ The polyaromatic alkaloid cryptospirolepine (50) obtained from the West African shrubCryptolepsis sanguinolenta, certainly falls into this category.¹²⁶ In addition to being proton-deficient, its yield was minimal, increasing the challenging nature of the original structure determination. The validity of structure50a was called into question when a sealed NMR tube containing degraded product52 (Fig. 10) was evaluated by members of the same research group 12 years after its report.¹²⁷ In the originally proposed50a, vinyl proton H-13 was placed near a four-spin aromatic system based on a ROESY correlation with H-12. Additionally, a strong HMBC correlation was observed between H-12 and C-13a, which is unlikely as they are four bonds apart (Fig. 10).¹²⁶ Considering these discrepancies, the structure was revised to50b, based on long-range HRSQMBC correlations between bothN-methyl groups and C-2 as well as a weak correlation from H-13 to C-2.¹²⁷ Further analysis of50 by a 1,1-HD-ADEQUATE experiment established that vinyl C-13 is bonded to carbonyl C-2 and quaternary C-13a. In addition, spiro C-1 was shown to interact with C-13 through a²J_CC correlation. The revised structure50b justifies both degradation products as well as the questionable four bond HMBC correlation observed in the original proposal. The revision was recently confirmed by the residual dipolar coupling and residual chemical shift anisotropy analysis.¹²⁸

6.1 Phyllostictine A

Phyllosticta cirsii is a pathogenic fungus that infects the perennial flowering plantCirsium arvense and produces phyllostictine A (53).¹²⁹ The molecule was reported to have an unprecedentedZ-α-(dihydrofuran-3(2H)-yli-dene)-β-lactam core (53a) which sparked interest about the possibility of a novel biosynthetic pathway. Recently, the structure was revised based on biosynthetic studies whereby feeding experiments incorporated¹³C at either C-1 or C-2 of acetate. This revealed that the distribution of carbon was complex in proposed structure53a but logical in revised structure53b, which had an alternating pattern for the distribution of¹³C atoms consistent with a hybrid polyketide synthase and nonribosomal peptide synthetase biosynthetic pathway (Fig. 11A).¹³⁰ Additionally, NMR spectra acquired for re-isolated53 showed some major discrepancies in HMBC correlations with respect to53a. For example, an HMBC correlation from the methyl protons at C-5 to C-11 would have required 7-8 bond coupling if53a was correct (Fig. 11B). The new NMR spectroscopic data led to a revision of the structure to53b, which contains similarities to other known, fungal metabolites.^131,132.

6.2 Poecillastrin C

Cytotoxic chondropsintype macrolide lactams, like poecillastrin C (54), are potent natural products that have been obtained from different genera of deep-sea sponges in very small amounts, making it difficult to fully characterize the structures.¹³³ A challenging structural aspect of these molecules is establishing which of the two carbonyls of theβ-hydroxyaspartic acid residue forms the ester linkage and which is a carboxylic acid functionality (i.e., position 1 orγ) (Fig. 12). Assignment of these carbonyl moieties was previously attempted with the related molecule chondropsin A.¹³⁴ The free carboxylic acid of chondropsin A was converted to a methyl ester and an NOE was observed between the newly formedO-methyl protons and the oxymethine protonβ, which prompted the authors to suggest that C-1 formed the ester linkage. Subsequent structure determination of other chondropsin molecules, including54, used the suggested ester linkage provided for chondropsin A, exemplified in54a.¹³³ In a recent study, this strategy was questioned based on the fact that both theα-methine andβ-methine protons are close enough to theO-methyl protons to produce observable NOEs.¹³⁵ Examination of additional NMR spectroscopic data suggested that the structure of poecillastrin C was as likely to be54b as54a. To determine whether position 1 orγ formed the ester bond, a hydride reduction of the lactam was used as a discriminatory tool due to its greater reactivity towards esters relative to carboxylic acids. If54a was the correct structure, a reduction followed by an acid hydrolysis would lead to hydroxymethyl55, keeping theγ-carboxylic acid intact while54b exposed to the same treatment would convert to hydroxymethyl56 (Fig. 12). The absolute configuration was established by subjecting the acid hydrolysate of54 to Marfey’s derivatization and comparing it to synthetic standards ofβ-hydroxyaspartic acid treated with Marfey’s reagent. Theβ-hydroxyaspartic acid residue liberated from poecillastrin C was found to be (2R,3R)-2-amino-3,4-dihydroxybutanoic acid, supporting the hypothesis that theγ-carboxyl group is esterified, consistent with revised structure54b.

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