Computer-Guided Total Synthesis of Natural Products. Recent Examples and Future Perspectives

Della‐Felice, Franco; Pilli, Ronaldo Aloise; Sarotti, Ariel M.

doi:10.21577/0103-5053.20180027

Cited by 5 publications

(4 citation statements)

References 77 publications

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“…30 In 2019, Krische, Pilli and co-workers validated the structural assignment proposed for phosdiecin A ( 5 ) through computer-guided total synthesis. 31,32…”

Section: Isolation Structural Diversity and Pharmacological And Biolo...mentioning

confidence: 99%

The phosphate ester group in secondary metabolites

2022

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“…30 In 2019, Krische, Pilli and co-workers validated the structural assignment proposed for phosdiecin A ( 5 ) through computer-guided total synthesis. 31,32…”

Section: Isolation Structural Diversity and Pharmacological And Biolo...mentioning

confidence: 99%

The phosphate ester group in secondary metabolites

2022

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“…Over the past decades, the application of computer-aided methods has undergone a remarkable transformation, emerging as an incredibly convenient tool for streamlining the process of structural elucidation. − One of the great advantages of such calculations is that they can be used to determine in advance the most likely structure of a molecule prior to the synthesis work. This so-called “computer-guided total synthesis” not only allows the synthesis teams to direct the experimental effort toward the right structure but also prevents the frustration of synthesizing the putative structure in the first place. − Among the numerous precedents in this field, the aquatolide case stands out as an excellent example that demonstrates the impact of NMR calculations on the structural reassignment of natural products …”

Section: Introductionmentioning

confidence: 99%

Road Map Toward Computer-Guided Total Synthesis of Natural Products. The Dysiherbol A Case Study: What if Serendipity Hadn’t Intervened?

Cortés,

Sarotti

2023

J. Org. Chem.

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We present a computational study inspired by the story of dysiherbol A, a natural product whose putative structure was found incorrect through synthesis by a completely fortuitous event. While the carbon connectivity and chemical environment between both structures remain similar, the real dysiherbol A has a different molecular weight than that reported for the natural product. Had the synthesis groups not been favored by fortune, it could be speculated that a substantial amount of time and effort would have been required to solve the structural puzzle. Within the realm of computer-guided total synthesis of natural products, the question arose whether a synthesis group could have in silico reassigned the structure before embarking on the experimental adventure. To address this query, we evaluated some state-of-the-art computational procedures based on their computational demand and ease of implementation for nonexpert users with basic skills in computational chemistry (including HOSE, CASCADE, ANN-PRA, ML-J-DP4, DP4, and DP4+). While discussing the strengths and limitations of these methods, this case study provides a roadmap of what could be done before venturing into complex and time-demanding total synthesis projects.

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“…Knowing the most likely structure of a natural product in advance is of utmost importance for synthetic groups, allowing them to save time, money, and man-power by directing the experimental efforts toward the right candidate (in contrast to the still popular approach of preparing different isomers). In collaboration with the group of Ronaldo Pilli (UNICAMP, Brazil), we have explored this “computer-guided total synthesis of natural products” idea, which to date has led to the synthesis and stereochemical revision or validation of three natural products (Figure ). In the case of cryptomoscatone E3, the DP4 calculations were carried out to determine the most likely configuration of the C8–C12 stereotriad (which was not irrefutably determined in the isolation report) .…”

Section: In Silico Revision Of Natural Productsmentioning

confidence: 96%

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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Computer-Guided Total Synthesis of Natural Products. Recent Examples and Future Perspectives

Cited by 5 publications

References 77 publications

The phosphate ester group in secondary metabolites

The phosphate ester group in secondary metabolites

Road Map Toward Computer-Guided Total Synthesis of Natural Products. The Dysiherbol A Case Study: What if Serendipity Hadn’t Intervened?

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

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