Formal Synthesis of (+)-Discodermolide

Francavilla, Charles; Chen, and Weichun; Kinder, Frederick R.

doi:10.1021/ol034186t

Cited by 39 publications

(24 citation statements)

References 26 publications

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“…Thus, the Nozaki-Hiyama/Peterson protocol was used to prepare (Z)-diene 100 from 101, which was converted to ethyl ketone 102 (Scheme 25). [30] On trying to convert 102 into the (Z)-enolborinate, (À)-diisopinocampheylborontriflate failed to react, [31a] whereas dibutylboron triflate smoothly gave an aldol adduct (103), [31b] which, based on literature precedence, could either be 103 a or 103 b.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of (Z)‐Trisubstituted Olefins by Decarboxylative Grob‐Type Fragmentations: Epothilone D, Discodermolide, and Peloruside A

Prantz

Mulzer

2009

Chemistry A European J

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Methyl-branched (Z)-trisubstituted olefins are found in many polyketides with interesting biological activity, such as epothilone D (1), discodermolide (3), and peloruside A (2). Despite the employment of numerous different strategies, this motif has often been the weak point in total synthesis. Thus, we present a novel hydroxide- induced Grob-type fragmentation as an easy access to trisubstituted olefins. In our case, beta-mesyloxy delta-lactones with three stereogenic centers were chosen whose fragmentation underlies a high stereoelectronic control. Major challenges in the syntheses were the installation of quaternary stereocenters, achieved by enzymatic desymmetrization of meso-diesters and by aluminium-promoted stereoselective rearrangement of chiral epoxides, respectively. Different aldol strategies were developed for the formation of the fragmentation precursors. Additionally a short survey about nucleophilic additions to aldehydes with quaternary alpha-centers is presented.

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Section: Resultsmentioning

confidence: 99%

Synthesis of (Z)‐Trisubstituted Olefins by Decarboxylative Grob‐Type Fragmentations: Epothilone D, Discodermolide, and Peloruside A

Prantz

Mulzer

2009

Chemistry A European J

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“…Total or semisynthesis has been the traditional choice of supply, but the molecular complexity of many candidate molecules require multi-step processes having inefficient yields that prove too costly for commercial-scale production. Chemical synthesis has been useful to confirm structural elucidation and to prepare small quantities for clinical investigations, notable examples being (+)-discodermolide (1) [82] with a plan towards commercial synthesis (83), the mitotic inhibitor dolastatin 10 (19) derived from the Indian Ocean sea-hare Dolabella auricularia [84] and ecteinascidin 743 (20) from the tunicate (sea-squirt) Ecteinascidia turbinata [85] including a semi-synthetic preparation starting from the bacterial cyanosafracin B antibiotic available in kilogram quantities from industrial-scale fermentation of Pseudomonas fluorescens [86].…”

Section: Achieving a Sustainable Supplymentioning

confidence: 99%

New Methods for Medicinal Chemistry - Universal Gene Cloning and Expression Systems for Production of Marine Bioactive Metabolites

Dunlap

Jaspars²,

Hranueli³

et al. 2006

CMC

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Natural products from symbiotic or commensal associations between marine invertebrate and microbial organisms show exceptional promise as pharmaceuticals in many therapeutic areas. An economic and sustainable global market supply due to difficulty of synthesis is cited as the main obstacle for exploitation of these otherwise exciting marine bioactive compounds. Different strategies have been evoked to overcome this impediment as long-term harvesting of wild stocks from the environment is considered unsound, and other modes of production based on biosynthesis, such as aquaculture, have not yet been proven as reliable. One option is to clone the genes encoding the biosynthetic expression of a lead metabolite into a surrogate host suitable for industrial-scale fermentation. To facilitate this goal we are developing a universal system to clone and express genes responsible for biosynthesis of natural products from both eukaryotic and prokaryotic partners of marine symbioses. The ability to harness the complete meta-transcriptome of entire biosynthetic pathways is particularly valuable where the biogenesis of a target natural product occurring within a complex symbiotic association is unclear.

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“…Different accesses to this stereotriad have been developed using efficient asymmetric aldol, 5,8,9 crotylation, 4,10 or allenylmetal 7 methodologies. We have recently reported 12 a stereoselective access to lactone 2, which possesses the correct syn/anti stereotriad and interestingly, a well-positioned Z-double bond (Scheme 1).…”

Section: Methodsmentioning

confidence: 99%

Stereoselective Syntheses of the C1-C5, C7-C15 and C17-C24 Fragments of (+)-Discodermolide Using a Catalytic and Asymmetric Vinylogous Mukaiyama Reaction

Bazan‐Tejeda¹,

Georgy²,

Campagne³

2004

Synlett

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Formal Synthesis of (+)-Discodermolide

Abstract: [structure: see text] Herein we report the formal total synthesis of (+)-discodermolide in 21 steps (longest linear sequence) from commercially available Roche ester. This synthesis features the assembly of C(9-18) and C(19-24) fragments via a metal-chelated aldol coupling reaction.

Cited by 39 publications

References 26 publications

Synthesis of (Z)‐Trisubstituted Olefins by Decarboxylative Grob‐Type Fragmentations: Epothilone D, Discodermolide, and Peloruside A

Synthesis of (Z)‐Trisubstituted Olefins by Decarboxylative Grob‐Type Fragmentations: Epothilone D, Discodermolide, and Peloruside A

New Methods for Medicinal Chemistry - Universal Gene Cloning and Expression Systems for Production of Marine Bioactive Metabolites

Stereoselective Syntheses of the C1-C5, C7-C15 and C17-C24 Fragments of (+)-Discodermolide Using a Catalytic and Asymmetric Vinylogous Mukaiyama Reaction

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