Synthesis of the Prelog–Djerassi Lactone via an Asymmetric Hydroformylation/Crotylation Tandem Sequence

Risi, Roberto M.; Burke, Steven D.

doi:10.1021/ol3008765

Cited by 22 publications

(13 citation statements)

References 40 publications

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“…20:1) and was easily performed in one-pot in analogy to the Burke procedure. [24] Once optimized, this sequence produced 14 in 51 % yield (as above, we note that a more meaningful measure of the efficiency of this reaction is the fact that more than a gram of 14 may be produced using only 4 mg of the Landis ligand). On larger scales, however, we found it more convenient to chromatographically separate the aldehyde regioisomers prior to the crotylation reaction, both to avoid wasting large amounts of 13 and to avoid a more tedious separation of the crotylation products.…”

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confidence: 92%

“…After we began our investigations, Burke reported a similar sequence employing an orthoester-protected acrylate, in which the product aldehyde was reacted in situ with trans-crotylpinacolboronate. [24] This elegant demonstration of the power of the concept notwithstanding, significant work remained to establish whether externally controlled crotylations would work well with the products of the hydroformylation reactions and, more importantly, to establish whether and how these reactions could be easily and inexpensively scaled.…”

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confidence: 99%

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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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A Highly Step‐Economical Synthesis of Dictyostatin

Bucher

Leighton

2013

Angewandte Chemie

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“…Felkin-selective crotylation of aldehyde 12 with trans -crotylpinacolboronate 13 was highly diastereoselective (≥20:1) and was easily performed in one-pot in analogy to the Burke procedure. [24] Once optimized, this sequence produced 14 in 51% yield (as above, we note that a more meaningful measure of the efficiency of this reaction is the fact that more than a gram of 14 may be produced using only 4 mg of the Landis ligand). On larger scales, however, we found it more convenient to chromatographically separate the aldehyde regioisomers prior to the crotylation reaction, both to avoid wasting large amounts of 13 and to avoid a more tedious separation of the crotylation products.…”

mentioning

confidence: 99%

“…After we began our investigations, Burke reported a similar sequence employing an ortho ester-protected acrylate, in which the product aldehyde was reacted in situ with trans -crotylpinacolboronate. [24] This elegant demonstration of the power of the concept notwithstanding, significant work remained to establish whether externally controlled crotylations would work well with the products of the hydroformylation reactions and, more importantly, to establish whether and how these reactions could be easily and inexpensively scaled.…”

mentioning

confidence: 99%

A Highly Step‐Economical Synthesis of Dictyostatin

Bucher

Leighton

2013

Angew Chem Int Ed

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“…In designing this route, it was considered that access to 16 by hydroformylation of protected allyl alcohol derivatives would be an ideal strategy. Hydroformylation of this substrate class has been addressed by Landis et al using the bisdiazaphos ligand, [19] and similar reactions have been employed by the groups of Burke [20] and Leighton [21] for the construction of polypropionate arrays. Unfortunately, the bisdiazaphos ligands are not readily available.…”

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Synthesis of (+)‐Discodermolide by Catalytic Stereoselective Borylation Reactions

Ely

Morken

2014

Angew Chem Int Ed

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The marine natural product (+)-discodermolide was first isolated in 1990 and, to this day, remains a compelling synthesis target. Not only does the compound possess fascinating biological activity, but it also presents an opportunity to test current methods for chemical synthesis and provides a forum for the inspiration of new reaction development. In this manuscript, we present a synthesis of discodermolide that employs a previously undisclosed stereoselective catalytic diene hydroboration and also establishes a strategy for chiral enolate alkylation. In addition, this synthesis of discodermolide provides the first examples of diene 1,4-diboration and borylative diene-aldehyde couplings in complex molecule synthesis.

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Synthesis of the Prelog–Djerassi Lactone via an Asymmetric Hydroformylation/Crotylation Tandem Sequence

Cited by 22 publications

References 40 publications

A Highly Step‐Economical Synthesis of Dictyostatin

A Highly Step‐Economical Synthesis of Dictyostatin

A Highly Step‐Economical Synthesis of Dictyostatin

Synthesis of (+)‐Discodermolide by Catalytic Stereoselective Borylation Reactions

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