Total Synthesis and Configurational Assignment of (−)‐Dictyostatin, a Microtubule‐Stabilizing Macrolide of Marine Sponge Origin

Paterson, Ian; Britton, Robert; Delgado, Oscar; Meyer, Arnd; Poullennec, Karine G.

doi:10.1002/anie.200460589

Cited by 115 publications

(62 citation statements)

References 29 publications

(28 reference statements)

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“…The similarity of its bioactive and X-ray conformations had been anticipated on the basis of SAR data and of its structural homology to dictyostatin [125] . Dictyostatin ( Fig.…”

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confidence: 99%

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The Tubulin Binding Mode of MT Stabilizing and Destabilizing Agents Studied by NMR

Sánchez-Pedregal

Griesinger

2008

Topics in Current Chemistry

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Tubulin is a fascinating molecule that forms the cytoskeleton of the cells and plays an important role in cell division and trafficking of molecules. It polymerizes and depolymerizes in order to fulfill this biological function. This function can be modulated by small molecules that interfere with the polymerization or the depolymerization. In this article, the structural basis of this behavior is reviewed with special attention to the contribution of NMR spectroscopy. Complex structures of small molecules that bind to tubulin and microtubules will be discussed. Many of them have been determined using NMR spectroscopy, which proves to be an important method in tubulin research.

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“…The similarity of its bioactive and X-ray conformations had been anticipated on the basis of SAR data and of its structural homology to dictyostatin [125] . Dictyostatin ( Fig.…”

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confidence: 99%

“…Dictyostatin ( Fig. 16 ) is another MT-stabilizing agent that competes with PTX and has a similar effect on MT dynamics [125] . The preferred solution structure of the conformationally constrained dictyostatin overlays quite closely the tubulin-bound conformation of DDM, suggesting that they interact in a similar way with MT ( Fig.…”

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confidence: 99%

The Tubulin Binding Mode of MT Stabilizing and Destabilizing Agents Studied by NMR

Sánchez-Pedregal

Griesinger

2008

Topics in Current Chemistry

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“…[1] Wright subsequently isolated a sample that allowed initial biological characterization of dictyostatin as a potent inducer of tubulin polymerization, [2] and that was used by Wright and Paterson to make a full structural assignment in 2004. [3] This assignment was confirmed soon thereafter by total syntheses by Paterson [4] and Curran, [5] and the material thus obtained facilitated more detailed characterization of dictyostatin's mechanism of action. [6,7] Total syntheses by Phillips [8] and Ramachandran, [9] formal syntheses by Micalizio [10] and Cossy, [11] a synthesis of C(9)-epi-dictyostatin by Gennari, [12] second generation syntheses by Paterson [13] and Curran, [14] and several fragment syntheses [15] followed these initial reports.…”

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confidence: 83%

A Highly Step‐Economical Synthesis of Dictyostatin

Bucher

Leighton

2013

Angewandte Chemie

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In 1994 Petit reported the isolation and anti-cancer activity of the marine sponge-derived macrolide dictyostatin. [1] Wright subsequently isolated a sample that allowed initial biological characterization of dictyostatin as a potent inducer of tubulin polymerization, [2] and that was used by Wright and Paterson to make a full structural assignment in 2004. [3] This assignment was confirmed soon thereafter by total syntheses by Paterson [4] and Curran, [5] and the material thus obtained facilitated more detailed characterization of dictyostatin's mechanism of action. [6,7] Total syntheses by Phillips [8] and Ramachandran, [9] formal syntheses by Micalizio [10] and Cossy, [11] a synthesis of C(9)-epi-dictyostatin by Gennari, [12] second generation syntheses by Paterson [13] and Curran, [14] and several fragment syntheses [15] followed these initial reports. In addition, the Paterson/Wright [16] and Curran/Day [17] teams have reported extensive SAR studies, while the Paterson/Díaz/ Jiménez-Barbero [18] and Curran/Snyder [19] teams have advanced models for the interaction of dictyostatin with the taxane binding site on -tubulin. Because dictyostatin and some of the prepared analogs are among the most potent microtubule-stabilizing agents characterized to date, there has been and continues to be intense interest in the possibility of advancing dictyostatin or an analog thereof into the clinic, a goal which might be facilitated by the development of a significantly more efficient and step-economical synthesis. As part of a larger program devoted to the development of new strategies and methods for the synthesis of complex and precious marine macrolides with high levels of step-economy, efficiency, and scalability, [20] we have developed and report herein a synthesis of dictyostatin that comprises just 14 steps in the longest linear sequence.Similarly to the previous syntheses of dictyostatin, our retrosynthesis disconnected the target into three roughly equally complex fragments, 1, 2, and 3 (Fig. 1A). It was in the synthesis of the fragments, and especially the C(12)-C(14) and C(20)-C(22) stereotriad-containing fragments 1 and 2 that we saw an opportunity for a streamlining of the synthesis. Ever since its introduction by Roush more than 20 years ago, what might be called the "Roche ester strategy" has reigned supreme for the synthesis of such stereotriads, [21] and indeed was employed in the Paterson, Curran, and Ramachandran syntheses, in most of the approaches reported by others, and in most of the syntheses of the related natural product discodermolide. [22] In this approach, the requisite enantiomer of the Roche ester is protected, reduced, and oxidized to the corresponding aldehyde, which is then subjected to diastereoselective crotylation, followed by several additional functional group manipulations (Fig. 1B). Thus, these stereotriad syntheses typically comprise at least 6-7 steps of which all Correspondence to: James L. Leighton, leighton@chem.columbia.edu. Supporting information for this article is ava...

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“…3,4 The structure of dictyostatin was deduced by Pettit and co-workers, 1 and the stereochemical assignments were made on the basis of the total syntheses described by the research groups of Paterson and Curran. 5,6 Due to its potent antitumor activity, a number of research groups have described the total synthesis of dictyostatin. 5,6 Our research group also initiated a project toward the total synthesis of dictyostatin, which resulted in the synthesis of the C11-C23 fragment.…”

Section: Introductionmentioning

confidence: 99%

“…5,6 Due to its potent antitumor activity, a number of research groups have described the total synthesis of dictyostatin. 5,6 Our research group also initiated a project toward the total synthesis of dictyostatin, which resulted in the synthesis of the C11-C23 fragment. 7 In this work we wish to describe a practical synthesis of the C1-C9 fragment of this potent antitumor agent.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of the C1-C9 fragment of the potent antitumor agent dictyostatin

Dias¹,

Sant’Ana²,

Vieira³

et al. 2012

J. Braz. Chem. Soc.

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Descrevemos neste trabalho uma síntese curta e eficiente para o fragmento C1-C9 do potente agente antitumoral dictiostatina. Esta abordagem sintética inclui uma reação de epoxidação assimétrica de Sharpless seguida da abertura de epóxido nas condições de Myashita para introduzir os centros estereogênicos em C6 e C7 e uma reação de olefinação tipo Horner-Wadsworth-Emmons nas condições de Ando para construir a ligação com geometria /Z/do dieno 1,3-/Z/,/E/.We describe herein a short and efficient synthesis of the C1-C9 fragment of the potent antitumor agent dictyostatin. Notable features of this approach include a Sharpless asymmetric epoxidation followed by epoxide opening under Myashita's conditions to introduce the stereogenic centers at C6 and C7, and a Horner-Wadsworth-Emmons type reaction under Ando's conditions to construct the Z-double bond of the 1,3-(Z,E)-diene system.

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Total Synthesis and Configurational Assignment of (−)‐Dictyostatin, a Microtubule‐Stabilizing Macrolide of Marine Sponge Origin

Cited by 115 publications

References 29 publications

The Tubulin Binding Mode of MT Stabilizing and Destabilizing Agents Studied by NMR

The Tubulin Binding Mode of MT Stabilizing and Destabilizing Agents Studied by NMR

A Highly Step‐Economical Synthesis of Dictyostatin

Synthesis of the C1-C9 fragment of the potent antitumor agent dictyostatin

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