Complex fragment coupling by crotylation: a powerful tool for polyketide natural product synthesis

Reznik, Samuel K.; Marcus, Brian S.; Leighton, James L.

doi:10.1039/c2sc21325g

Cited by 12 publications

(11 citation statements)

References 56 publications

(32 reference statements)

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“…We have reported the development of a fragment coupling by crotylation method 13,20 that was designed to accomplish exactly that as demonstrated with simplified model dienes, and given such a large supply of 21 , we thought it prudent to evaluate its performance in the fragment coupling process. In that sequence, the diene is subjected to a Pd(PPh 3 ) 4 -catalyzed hydrosilylation reaction with HSiCl 3 according to Tsuji’s protocol, 21 and then to chiral diamine complexation.…”

Section: Resultsmentioning

confidence: 99%

“…Ozonolysis of alkene 17 provided aldehyde 18 which was, without purification, subjected to an asymmetric isoprenylation reaction according to our recently reported procedure using ( R , R )- 19 . 13 The unpurified product (analysis of which by 1 H NMR spectroscopy revealed a diastereoselectivity for the isoprenylation reaction of ≥15:1) was subjected to spiroketalization with camphorsulfonic acid (CSA), leading to the smooth production of 20 in 66% overall yield from 17 . Finally, the liberated tertiary alcohol was trifluoroacetylated to give completed AB spiroketal fragment 21 in 97% yield.…”

Section: Resultsmentioning

confidence: 99%

“…Aldehyde 23 represented the more conservative choice, and its crotylation reaction with 22 produced 24 in 59% yield and with >10:1 diastereoselectivity. We were at first concerned about the moderate efficiency of this reaction relative to the 73–79% yields that we had consistently achieved with model dienes, 13 but quickly discovered that a significant amount of the product had undergone TES ether cleavage during the work-up (with n -Bu 4 NF•(H 2 O) 3 ), a presumably fixable problem. Confirmation that diene 21 performs well was then provided by the fragment coupling crotylation reaction with aldehyde 25 , which, as we have previously reported, 13 arises very efficiently from the silylformylation of the corresponding homopropargylic alcohol ( e.g.…”

Section: Resultsmentioning

confidence: 99%

“…This reaction produced 26 in 74% yield and with >10:1 diastereoselectivity. Finally, subjection of 26 to our optimized conditions for a Tamao oxidation/diastereoselective tautomerization reaction 13 resulted in the isolation of 27 as the major product of a 5:1 mixture of diastereomers (at C(16)) in 75% yield. These model fragment coupling transformations thus serve as convincing proofs of concept for the planned coupling of the AB spiroketal 21 with a variety of CD spiroketal analogs and concurrent establishment of the C(13)–C(17) linker region in a rapid and highly efficient fashion.…”

Section: Resultsmentioning

confidence: 99%

“…For the former objective, we envisioned application of our recently reported complex fragment coupling by crotylation methodology 13 in combination with the silylformylation/crotylation/Tamao oxidation/diastereo-selective tautomerization methodology. 13,14 For the latter objective, we envisioned the use of another recently developed method, asymmetric aldehyde isoprenylation, 13 with aldehyde 4 followed by spiroketalization to produce 2 , and an aldol coupling of fragments 5 and 6 to produce 4 . Herein we describe the development of a synthesis of an AB spiroketal of type 2 that has allowed us to produce a large supply, and a demonstration of its efficient coupling with a model aldehyde derived from a homopropargyl alcohol of type 3 to directly produce the entire C(13)–C(17) linker region.…”

Section: Methodsmentioning

confidence: 99%

See 4 more Smart Citations

Toward a more step-economical and scalable synthesis of spongistatin 1 to facilitate cancer drug development efforts

Reznik

Leighton

2013

Chem. Sci.

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An efficient, step-economical, and scalable synthesis of a diene-bearing AB spiroketal fragment of spongistatin 1, and a demonstration of its efficient coupling to an aldehyde derived from silylformylation of a homopropargyl alcohol to produce the entire complex C(13)–C(17) linker region are described. The scalability of the synthesis of the AB spiroketal fragment was demonstrated by the preparation of 34.5 grams by one chemist in ~60 workdays, and more than 40 grams overall. With this material in hand and having established a method for its efficient coupling to the CD fragment, we have set the stage for the rapid synthesis and evaluation of a series of analogs of the CD spiroketal.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Toward a more step-economical and scalable synthesis of spongistatin 1 to facilitate cancer drug development efforts

Reznik

Leighton

2013

Chem. Sci.

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Enantioselective Isoprenylboration Reaction of Aldehydes Catalyzed by a Chiral Phosphoric Acid

Zhang

Xie

et al. 2019

Adv Synth Catal

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The BINOL‐derived chiral phosphoric acid (R)‐TRIP is utilized as an organocatalyst in the asymmetric isoprenylboration reaction of aldehydes, wherein hydrogen‐bond interactions play a key role in the control of enantioselectivity. A wide arrays of enantioenriched dienyl homoallyl alcohols, including two natural products (−)‐Ipsdienol and (−)‐Ipsenol, have been successfully constituted. The synthetic application to chiral isoprenylated isobenzofuranone, vinyloxirane and cyclohexene derivatives has also been disclosed.

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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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Complex fragment coupling by crotylation: a powerful tool for polyketide natural product synthesis

Cited by 12 publications

References 56 publications

Toward a more step-economical and scalable synthesis of spongistatin 1 to facilitate cancer drug development efforts

Toward a more step-economical and scalable synthesis of spongistatin 1 to facilitate cancer drug development efforts

Enantioselective Isoprenylboration Reaction of Aldehydes Catalyzed by a Chiral Phosphoric Acid

A Highly Step‐Economical Synthesis of Dictyostatin

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