Synthesis of Thelepamide via Catalyst-Controlled 1,4-Addition of Cysteine Derivatives and Structure Revision of Thelepamide

Seitz, Tobias; Millán, Ramón E; Lentz, Dieter; Jiménez, Carlos; Rodrı́guez, Jaime; Christmann, Mathias

doi:10.1021/acs.orglett.7b03706

Cited by 10 publications

(9 citation statements)

References 34 publications

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“…In 2013, the Rodríguez group proposed the chemical structure of thelepamide for the first time after its isolation from the tidal zone-derived marine worm Thelepus crispus [ 108 ]. However, in 2018, it was revealed that there was an error in their stereochemical assignment of its structure, as indicated by total syntheses performed by the Rodríguez and Christmann groups [ 33 ]. The structure of thelepamide possesses unusual N , O -acetal and hemiacetal moieties, and it has been speculated that valine and cysteine may be involved in their biosyntheses due to the presence of a thioether and an isopropyl group.…”

Section: Examples Of Total Synthesis Of Marine Natural Products Resul...mentioning

confidence: 99%

Recent Achievements in Total Synthesis for Integral Structural Revisions of Marine Natural Products

Kim

Paek

2022

Marine Drugs

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A great effort to discover new therapeutic ingredients is often initiated through the discovery of the existence of novel marine natural products. Since substances produced by the marine environment might be structurally more complex and unique than terrestrial natural products, there have been cases of misassignments of their structures despite the availability of modern spectroscopic and computational chemistry techniques. When it comes to refutation to erroneously or tentatively proposed structures empirical preparations through organic chemical synthesis has the greatest contribution along with close and sophiscated inspection of spectroscopic data. Herein, we analyzed the total synthetic studies that have decisively achieved in revelation of errors, ambiguities, or incompleteness of the isolated structures of marine natural products covering the period from 2018 to 2021.

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Section: Examples Of Total Synthesis Of Marine Natural Products Resul...mentioning

confidence: 99%

Recent Achievements in Total Synthesis for Integral Structural Revisions of Marine Natural Products

Kim

Paek

2022

Marine Drugs

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“…The diversity of structures evaluated is noteworthy, covering different complexity levels, functional groups, and conformational freedom. Some representative examples are shown in Figure c. − …”

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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“…The sulfur derivative thelepamide was previously isolated from the marine annelid Thelepus crispus. 5,16 Similarly to the nebulosins, this natural product was thought to originate from a thia−Michael condensation between a tetraketide subunit and a cysteine residue, even though a radical cyclization described for penicillins could also be postulated. 17 We anticipate the condensation to be stereoselective as only one stereoisomer was identified for thelepamide (Scheme 2).…”

Section: Ms/msmentioning

confidence: 99%

“…Nebulosin C (3) was isolated as an optically active white solid, and its molecular formula C 15 H 28 NO 16) and δ H 2.41 (2H, q, J = 7.5 Hz, H 2 -15) when compared to 1 and 2. The 13 C NMR spectrum exhibited an additional signal at δ C 177.0 (C-14).…”

Section: ■ Introductionmentioning

confidence: 99%

“…NOEs between H 2 -8, H-5, and H-3 suggested a cis configuration between H-3, H-5, and the n-propyl. In addition, the presence of rotamers was again evident due to the splitting of signals in the 1 16). Further analysis of the COSY NMR spectrum revealed the connection of the methine to an ABX system of a methylene group at δ H 2.61 (1H, dd, J = 15.5, 7.0 Hz, H-15a) and δ H 2.50 (1H, dd, J = 15.5, 6.0 Hz, H-15b).…”

Section: ■ Introductionmentioning

confidence: 99%

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Nebulosins: Trisubstituted Thiolane Natural Products from the Northeastern Atlantic Annelid Eupolymnia nebulosa

et al. 2020

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Using both multi-informative molecular network and score-based approaches as prioritization strategies, the Northeastern Atlantic marine terebellid Eupolymnia nebulosa was selected for in-depth chemical investigation. A family of 16 new metabolites named nebulosins was isolated and structurally characterized from extensive analyses of HRMS/MS and NMR spectroscopic data. Nebulosins feature an unprecedented highly substituted thiolane ring leading to up to four contiguous chiral centers. The relative configurations were assigned through a combination of NOESY analysis, spin−spin coupling constant analysis, and NMR chemical shifts measurements, while the absolute configurations were determined by comparison between experimental and theoretical ECD spectra. This family of natural product exhibits promising antioxidant activities in both ORAC and ROS assays.

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Synthesis of Thelepamide via Catalyst-Controlled 1,4-Addition of Cysteine Derivatives and Structure Revision of Thelepamide

Cited by 10 publications

References 34 publications

Recent Achievements in Total Synthesis for Integral Structural Revisions of Marine Natural Products

Recent Achievements in Total Synthesis for Integral Structural Revisions of Marine Natural Products

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

Nebulosins: Trisubstituted Thiolane Natural Products from the Northeastern Atlantic Annelid Eupolymnia nebulosa

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