Total Synthesis of the Antimitotic Marine Macrolide (−)‐Leiodermatolide

Paterson, Ian; Ng, Kenneth K.‐H.; Williams, Simon; Millican, David C.; Dalby, Stephen M.

doi:10.1002/anie.201310164

Cited by 39 publications

(21 citation statements)

References 53 publications

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“…Our successful total synthesis of (−)‐leiodermatolide provided further verification of the assigned 3D structure 5 . While our initial studies towards the construction of the leiodermatolide macrocycle and side chain provided strong support for the relative configuration proposed in 5 , this plan proved to be unsuitable for achieving the total synthesis itself.…”

Section: Discussionsupporting

confidence: 55%

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Strategy Evolution in the Total Synthesis of (−)‐Leiodermatolide

Paterson

Williams

2016

Israel Journal of Chemistry

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This review highlights the various challenges overcome during our recent synthetic campaign towards (−)‐leiodermatolide, a potent cytotoxic and antimitotic macrolide isolated from the marine sponge Leiodermatium sp. This structurally unprecedented macrocyclic chemotype represents a promising lead for anticancer drug discovery, provided a sustainable supply can be realised by an efficient chemical synthesis. Faced with the stereochemical ambiguities arising from our structural assignment work, a flexible and modular synthetic strategy was adopted for the construction of various key fragments, as a prelude to the controlled assembly of the two diene moieties. Installation of the nine stereocentres was achieved by the strategic use of boron‐mediated aldol reactions of chiral ketone building blocks. Following the exploratory construction of the macrocyclic core, we revised our strategy to circumvent some problematic steps, enabling a highly convergent total synthesis of (−)‐leiodermatolide.

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Section: Discussionsupporting

confidence: 55%

“…Completion of the synthesis of 5 from this point, however, required modification of our initial strategy. The remainder of this review details these efforts, leading to our successful total synthesis of (−)‐leiodermatolide …”

Section: Introductionmentioning

confidence: 99%

Strategy Evolution in the Total Synthesis of (−)‐Leiodermatolide

Paterson

Williams

2016

Israel Journal of Chemistry

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“…Interestingly, they found that both diastereoisomers were almost indistinguishable from their 13 C NMR data, and only subtle differences in the 1 H NMR spectra could be observed to indisputably assign 31 as the correct leiodermatolide . In the meantime, the Paterson group reported their highly stereocontrolled total synthesis of leioermatolide employing a convergent palladium‐mediated fragment assembly and macrolactonization sequence, providing further experimental confirmation of the natural product structure …”

Section: Dp4mentioning

confidence: 99%

Computational Chemistry to the Rescue: Modern Toolboxes for the Assignment of Complex Molecules by GIAO NMR Calculations

Grimblat

Sarotti

2016

Chemistry A European J

189

147

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The calculations of NMR properties of molecules using quantum chemical methods have deeply impacted several branches of organic chemistry. They are particularly important in structural or stereochemical assignments of organic compounds, with implications in total synthesis, stereoselective reactions, and natural products chemistry. In studying the evolution of the strategies developed to support (or reject) a structural proposal, it becomes clear that the most effective and accurate ones involve sophisticated procedures to correlate experimental and computational data. Owing to their relatively high mathematical complexity, such calculations (CP3, DP4, ANN-PRA) are often carried out using additional computational resources provided by the authors (such as applets or Excel files). This Minireview will cover the state-of-the-art of these toolboxes in the assignment of organic molecules, including mathematical definitions, updates, and discussion of relevant examples.

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“…However, such discrepancies were enough to indisputably determine that the correct relative and absolute configuration of leiodermatolide was 75 (the same that Paterson et al 51 arbitrarily drawn in the original publication). The structure of leiodermatolide was further validated and re-confirmed by Paterson et al, 55 using a stereocontrolled total synthesis approach based on a convergent palladium-mediated assembly and macrolactonization sequence.…”

Section: Leiodermatolidementioning

confidence: 96%

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

Della‐Felice¹,

Pilli²,

Sarotti³

2018

J. Braz. Chem. Soc.

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Quantum chemical calculations of nuclear magnetic resonance (NMR) shifts and coupling constants have been extensively employed in recent years mainly to facilitate structural elucidation of organic molecules. When the results of such calculations are used to determine the most likely structure of a natural product in advance, guiding the subsequent synthetic work, the term "computer-guided synthesis" could be coined. This review article describes the most relevant examples from recent literature, highlighting the scope and limitations of this merged computational/experimental approach as well.

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Total Synthesis of the Antimitotic Marine Macrolide (−)‐Leiodermatolide

Cited by 39 publications

References 53 publications

Strategy Evolution in the Total Synthesis of (−)‐Leiodermatolide

Strategy Evolution in the Total Synthesis of (−)‐Leiodermatolide

Computational Chemistry to the Rescue: Modern Toolboxes for the Assignment of Complex Molecules by GIAO NMR Calculations

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

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