General Quantum-Based NMR Method for the Assignment of Absolute Configuration by Single or Double Derivatization: Scope and Limitations

Zanardi, María Marta; Biglione, Franco A.; Sortino, Maximiliano; Sarotti, Ariel M.

doi:10.1021/acs.joc.8b01749

Cited by 21 publications

(25 citation statements)

References 79 publications

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“…Nowadays, computational protocols based on DFT are widely used for the investigation of structural [29] and spectroscopic properties of organic and organometallic molecules [30]. In particular, the prediction of NMR chemical shifts has been the subject of several studies, especially concerning 1 H and 13 C chemical shifts of organic molecules [31,32,33], also for the case of natural substances including heavy atoms [34]. In the latter case, relativistic effects must be accounted for, because of the well-known HALA (heavy atom on light atom) effect [35,36].…”

Section: Introductionmentioning

confidence: 99%

The 125Te Chemical Shift of Diphenyl Ditelluride: Chasing Conformers over a Flat Energy Surface

et al. 2019

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The interest in diphenyl ditelluride (Ph2Te2) is related to its strict analogy to diphenyl diselenide (Ph2Se2), whose capacity to reduce organic peroxides is largely exploited in catalysis and green chemistry. Since the latter is also a promising candidate as an antioxidant drug and mimic of the ubiquitous enzyme glutathione peroxidase (GPx), the use of organotellurides in medicinal chemistry is gaining importance, despite the fact that tellurium has no recognized biological role and its toxicity must be cautiously pondered. Both Ph2Se2 and Ph2Te2 exhibit significant conformational freedom due to the softness of the inter-chalcogen and carbon–chalcogen bonds, preventing the existence of a unique structure in solution. Therefore, the accurate calculation of the NMR chemical shifts of these flexible molecules is not trivial. In this study, a detailed structural analysis of Ph2Te2 is carried out using a computational approach combining classical molecular dynamics and relativistic density functional theory methods. The goal is to establish how structural changes affect the electronic structure of diphenyl ditelluride, particularly the 125Te chemical shift.

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Section: Introductionmentioning

confidence: 99%

The 125Te Chemical Shift of Diphenyl Ditelluride: Chasing Conformers over a Flat Energy Surface

et al. 2019

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“…Hence, assuming a 13-S configuration in compounds 1 – 3 , the relative configuration of the 8-position remained unknown. To solve this task, we relied on GIAO 13 C-NMR calculations, a strategy that has been extensively employed in recent publications to settle structural and stereochemical issues of complex organic molecules [21,22,23,24,25]. Several strategies have been developed to determine the most likely stereostructure among several candidates, including DP4, [22] and DP4+, an updated version of DP4 including scaled and unscaled NMR shifts computed at higher levels of theory [23].…”

Section: Resultsmentioning

confidence: 99%

“…Several strategies have been developed to determine the most likely stereostructure among several candidates, including DP4, [22] and DP4+, an updated version of DP4 including scaled and unscaled NMR shifts computed at higher levels of theory [23]. The capacity of these methodologies to discriminate among candidates featuring rigid structures and contiguous or near-by stereocenters is often excellent [24], but when two or more steroclusters are separated the determination of the relative configuration becomes much more challenging [25]. In any case, we decided to explore this approach to suggest a sound stereochemical assignment of the new natural products herein reported and to validate our assignment of the planar structure of 1 discussed above.…”

Section: Resultsmentioning

confidence: 99%

An Unusual Benzoisoquinoline-9-one Derivative and Other Related Compounds with Antiproliferative Activity from Hawaiian Endophytic Fungus Peyronellaea sp. FT431

Sarotti

et al. 2019

Molecules

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A new polyketide containing the benzoisoquinoline-9-one moiety, peyronetide A (1), and three other new derivatives peyronetides B–D (2–4), as well as one known compound (5) were purified from the cultured broth of the endophytic fungus Peyronellaea sp. FT431, which was isolated from the Hawaiian indigenous plant, Verbena sp. The structures of the new compounds were determined through the analysis of HRMS and NMR spectroscopic data. Compounds 1, 2, and 5 showed cytotoxic activities against TK-10 (human kidney adenocarcinoma cells), cisplatin sensitive A2780S (human ovarian carcinoma cells), and cisplatin resistant A2780CisR cell lines, with IC50 values between 6.7 to 29.2 μM.

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“…This led to a conceptually novel strategy to determine absolute configuration of a wide substrate scope and chiral derivatizing agents following a single derivatization experiment and DP4+ analysis. 42 The classification achieved with secondary alcohols, secondary amines, and primary amines herein studied was excellent (100%), whereas more modest results (89%) were observed for primary and tertiary alcohols. To overcome this limitation, a new DP4+ integrated probability (DIP) was built to strengthen the analysis when the NMR data of the two possible diastereoisomers are available (Figure 3b).…”

Section: ■ Dp4+: Beyond Dp4mentioning

confidence: 99%

“…To overcome this limitation, a new DP4+ integrated probability (DIP) was built to strengthen the analysis when the NMR data of the two possible diastereoisomers are available (Figure 3b). 42 The results obtained for (+)-angiopterlactone B, originally misassigned as ent-3 (Figure 3c), summarize the power of DP4+ to determine both relative and absolute configuration of natural products.…”

Section: ■ Dp4+: Beyond Dp4mentioning

confidence: 99%

NMR Calculations with Quantum Methods: Development of New Tools for Structural Elucidation and Beyond

et al. 2020

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Conspectus Structural elucidation is an important and challenging stage in the discovery of new organic molecules. Single-crystal X-ray analysis provides the most unquestionable results, though in practice the availability of suitable crystals limits its broad use. On the other hand, NMR spectroscopy has become the leading and universal technique to accomplish the task. Despite continuous advances in the field, the misinterpretation of NMR data is commonplace, evidenced by the large number of erroneous structures being published in top journals. Quantum calculations of NMR chemical shifts and scalar coupling constants emerged as ideal complements to facilitate the elucidation process when experimental NMR data is inconclusive. Since seminal reports demonstrated that affordable DFT methods provide NMR predictions accurate enough to differentiate among closely related isomers, the discipline has experienced substantial growth. The impact has been felt in different areas, and nowadays the results of such calculations are routinely seen in high impact literature. This Account describes our investigations in the field of quantum NMR calculations, focusing on the development of tools for structural elucidation and practical applications. We pioneered the use of artificial intelligence methods in the development of novel strategies of structural validation. Our first generation of trained artificial neural networks (ANNs) showed excellent ability to identify mistakes at the atom connectivity level, whereas the use of multidimensional pattern recognition pushed the performance to the stereochemical limit. In a conceptually different approach, we developed DP4+, an updated version of the DP4 probability used to determine the most likely structure among two or more candidates when one set of experimental data is available. Increasing the level of theory in NMR calculations and including unscaled data in the formalism improved the performance of the method, further validated to settle the configuration of challenging motifs such as spiroepoxides or Mosher’s derivatives. One of the limitations of DP4+ is related to the relatively large computational cost involved in obtaining DFT-optimized geometries, which led to the development of a fast variant including the valuable information provided by coupling constants (J-DP4 method). These tools were explored to suggest the most probable structure of controversial natural or unnatural products originally misassigned, with some predictions further validated by synthesis (as in the case of pseudorubriflordilactone B). The possibility of predicting the structure of a natural product without requiring authentic sample was investigated in collaboration with Prof. Pilli (UNICAMP, Brazil) in the computer-guided total synthesis and stereochemical revisions of several natural products. Despite these advances, there remain considerable challenges, such as the case of configurational assessment of polar systems featuring multiple intramolecular hydrogen bonding interactions because of the po...

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General Quantum-Based NMR Method for the Assignment of Absolute Configuration by Single or Double Derivatization: Scope and Limitations

Cited by 21 publications

References 79 publications

The 125Te Chemical Shift of Diphenyl Ditelluride: Chasing Conformers over a Flat Energy Surface

The 125Te Chemical Shift of Diphenyl Ditelluride: Chasing Conformers over a Flat Energy Surface

An Unusual Benzoisoquinoline-9-one Derivative and Other Related Compounds with Antiproliferative Activity from Hawaiian Endophytic Fungus Peyronellaea sp. FT431

NMR Calculations with Quantum Methods: Development of New Tools for Structural Elucidation and Beyond

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