Total synthesis of two potent anti-inflammatory macrolactones of the oxacyclododecindione type

Tauber, Johannes; Rohr, Markus; Walter, Thorsten; Erkel, Gerhard; Opatz, Till

doi:10.1039/c5ob01044f

Cited by 9 publications

(35 citation statements)

References 28 publications

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“…3,4,10−12 To date, two natural products and 10 synthetic derivatives of the oxacyclododecindione series have been successfully synthesized. 5,9 All of the retrosynthetic approaches followed a strategy based on the key step of an intramolecular Friedel-Crafts acylation (IFCA) at low substrate concentration and low temperature. 5,9,11 Other approaches to the ring closure of the 12-membered lactone, such as carbonylative cross-coupling, hydroacylation, or metathesis reaction, have not proved fruitful.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…5,9 All of the retrosynthetic approaches followed a strategy based on the key step of an intramolecular Friedel-Crafts acylation (IFCA) at low substrate concentration and low temperature. 5,9,11 Other approaches to the ring closure of the 12-membered lactone, such as carbonylative cross-coupling, hydroacylation, or metathesis reaction, have not proved fruitful. 7 The synthesis of 13-hydroxy-14-deoxyoxacyclododecindione (4) commenced with the preparation of the three building esterification and Wittig olefination, followed by the key IFCA.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Total Synthesis and Biological Evaluation of the Anti-Inflammatory (13R,14S,15R)-13-Hydroxy-14-deoxyoxacyclododecindione

et al. 2023

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The first total synthesis of the natural product (13R,14S,15R)-13-hydroxy-14-deoxyoxacyclododecindione, which was isolated in 2018 as a member of the oxacyclododecindione family, is reported. A synthetic strategy through intramolecular Friedel-Crafts acylation combined with the stereoselective synthesis of a new triol key fragment allowed the preparation of the macrolactone. Due to mismatching physical data of the synthetic product, a revision of the configuration of the natural product isolated in 2018 is required. Light-induced E/Z-isomerism of the macrolactone backbone is described for the first time in the class of oxacyclododecindione-type macrolactones. The hydroxylated macrolactone prepared herein was found to show highly promising IC50 values in biological assays addressing the inhibition of inflammatory responses.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Total Synthesis and Biological Evaluation of the Anti-Inflammatory (13R,14S,15R)-13-Hydroxy-14-deoxyoxacyclododecindione

et al. 2023

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“…In our previous report on the racemic total synthesis of 4-dechloro-14-deoxyoxacyclododecindione ((±)-3) and 14-deoxyoxacyclododecindione ((±)-4), we found that synthetic (±)-4 was more active on a IL-4/Stat6-dependent and a TGF-β/Smad2/3dependent transcriptional luciferase reporter in transiently transfected HepG2 cells, than the isolated natural product (+)-4. 12,13 There are two possibilities to explain this result; the isolated material had a lower degree of purity, or the unnatural enantiomer (−)-4 is more active than the naturally occurring enantiomer (+)-4. To investigate this issue and to elucidate the absolute configuration of 14-deoxyoxacyclododecindione ((+)-4), a separation of racemic (±)-4 by chiral, preparative HPLC was performed.…”

Section: Resultsmentioning

confidence: 99%

“…It should be noted that the relative configuration of the two adjacent stereocenters was assigned as (14R*,15S*) by racemic total synthesis of 4-dechloro-14-deoxyoxacyclododecindione (3) and 14-deoxyoxacyclododecindione (4). 12,13 Due to their structural analogy to the macrolactones 1 and 2 the absolute configuration was assumed to be (14R,15S). [12][13][14][15] While (−)-1 and (−)-2 show biological activities in the micromolar range, the secondary metabolites 3-5 exhibit anti-inflammatory and anti-fibrotic activities in cell culture experiments at nanomolar concentrations.…”

Section: Introductionmentioning

confidence: 99%

“…12,13 Due to their structural analogy to the macrolactones 1 and 2 the absolute configuration was assumed to be (14R,15S). [12][13][14][15] While (−)-1 and (−)-2 show biological activities in the micromolar range, the secondary metabolites 3-5 exhibit anti-inflammatory and anti-fibrotic activities in cell culture experiments at nanomolar concentrations. 2,3 Furthermore, these lactones were successfully used in an in vivo mouse model of systemic lupus erythematosus (SLE).…”

Section: Introductionmentioning

confidence: 99%

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A surprising switch in absolute configuration of anti-inflammatory macrolactones

et al. 2016

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Oxacyclododecindione-type macrolactones exhibit highly potent anti-inflammatory activities even at nanomolar concentration. After the determination of the relative configuration of the stereocenters at C14 and C15 by total synthesis of 4-dechloro-14-deoxyoxacyclododecindione and 14-deoxyoxacyclododecindione, the absolute configuration has now been assigned by X-ray crystallography. Surprisingly, the absolute configuration is (14S,15R) which differs for C15 from that of the well-known derivatives of (S)-curvularin. The biological activities of both enantiomers of 14-deoxyoxacyclododecindione, obtained by racemic synthesis and optical resolution, were investigated and the ring conformation of the natural product was compared to that of (S)-curvularin and (R)-dehydrocurvularin.

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Concise Total Syntheses of (+)‐Brefeldin A, Diastereomers and Analogs and Their Biological Activity

et al. 2023

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Brefeldin A is an important natural product and biochemical tool with cell‐modulating and other diverse biological activities. To explore its chemical space, a generally applicable strategy for total syntheses of naturally occurring (+)‐brefeldin A (BFA), 2‐epi‐BFA, their diastereomers and analogs with varying macrocyclic ring size is reported. The five‐membered ring fragment was constructed by a short three‐step sequence consisting of tandem nucleophilic epoxide opening/Brook rearrangement/radical oxygenation and subsequent thermal radical cyclization based on the persistent radical effect. Further key steps are asymmetric aldehyde vinylation, which enables control of the absolute configuration at the allylic hydroxy group of BFA, cross‐metatheses reactions for attachment of the northern and southern side chains to the cyclopentane unit and final Shiina macrolactonization. The cytotoxic activity of all compounds was determined, and several analogs proved to be similarly active as BFA, providing insight about regions of the skeleton that can be varied or have to be conserved with respect to their biological activities. Fluorescence microscopy revealed that BFA and some non‐natural analogs disassemble the Golgi apparatus in cells with large variation of the disassembly and subsequent reassembly times.

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Total synthesis of two potent anti-inflammatory macrolactones of the oxacyclododecindione type

Cited by 9 publications

References 28 publications

Total Synthesis and Biological Evaluation of the Anti-Inflammatory (13R,14S,15R)-13-Hydroxy-14-deoxyoxacyclododecindione

Total Synthesis and Biological Evaluation of the Anti-Inflammatory (13R,14S,15R)-13-Hydroxy-14-deoxyoxacyclododecindione

A surprising switch in absolute configuration of anti-inflammatory macrolactones

Concise Total Syntheses of (+)‐Brefeldin A, Diastereomers and Analogs and Their Biological Activity

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