Total Synthesis of the Bacterial RNA Polymerase Inhibitor Ripostatin B

Glaus, Florian; Altmann, Karl‐Heinz

doi:10.1002/anie.201200871

Cited by 39 publications

(38 citation statements)

References 27 publications

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“…[12] Rather surprisingly, despite their intriguing structures and biological profiles, no total synthesis of any member of the tiacumicin/lipiarmycin/clostomicin family (or the corresponding aglycones) has been reported in the literature to date. In the context of our work on new drugs against tuberculosis, [13] we have thus embarked on the total synthesis of the tiacumicin B aglycone (2; Scheme 1), in order to provide a basis for structure-activity relationship (SAR) studies. [14] Ultimately, this work aims to identify tiacumicin B analogues with improved biopharmaceutical properties.…”

Section: Florian Glaus and Karl-heinz Altmann*mentioning

confidence: 99%

Total Synthesis of the Tiacumicin B (Lipiarmycin A3/Fidaxomicin) Aglycone

Glaus

Altmann

2014

Angew Chem Int Ed

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Tiacumicin B (lipiarmycin A3, fidaxomicin) is an atypical macrolide antibiotic which is used for the treatment of Clostridium difficile infections. Tiacumicin B is also a potent inhibitor of Mycobacterium tuberculosis, but due to its limited oral bioavailability is unsuitable for systemic therapy. To provide a basis for structure-activity studies that might eventually lead to improved variants of tiacumicin B, we have developed an efficient approach to the synthesis of the tiacumicin B aglycone. The synthesis features a high-yielding intramolecular Suzuki cross-coupling reaction to effect macrocyclic ring closure. Key steps in the synthesis of the macrocyclization precursor were a highly selective, one-pot Corey-Peterson olefination and an ene-diene cross-metathesis reaction. Depending on the reaction conditions, the final deprotection delivered either the fully deprotected tiacumicin B aglycone or partially protected versions thereof.

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Section: Florian Glaus and Karl-heinz Altmann*mentioning

confidence: 99%

Total Synthesis of the Tiacumicin B (Lipiarmycin A3/Fidaxomicin) Aglycone

Glaus

Altmann

2014

Angew Chem Int Ed

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“…Consequently, we developed a convergent approach to synthesis of the ripostatin scaffold and accomplished, concurrently with two other groups, the total synthesis of ripostatin B. [4] We also reported the first total synthesis of ripostatin A. With a reliable synthetic strategy in hands, we next aimed to generate novel analogues of ripostatin A and ripostatin B for the elucidation of structure-activity relationship.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of Novel Analogues of Ripostatins

Tang

Liu

Degen

et al. 2014

Chemistry A European J

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Ripostatins are polyene macrolactones isolated from myxobacterium Sorangium cellulosum. They exhibit antibiotic activity by inhibiting bacterial RNA-polymerase through a binding site and mechanism different from those of current antibacterial drugs and thus serve as starting pointsfor the development of new anti-infective agents with a novel mode of action. In this work, several derivatives of ripostatins were produced. The 15-desoxy-ripostatin A was synthesized using one-pot carboalumination/cross-coupling. The 5,6-dihydro-ripostatin A was constructed utilizing an intramolecular Suzuki cross-coupling macrolactonization approach, and 14,14'-difluroripostatin A and both epimeric 14,14'-difluroripostatins B were synthesized using a Reformatsky-type aldol addition of haloketone, Stille cross-coupling and ring-closing metathesis. RNAP-inhibitrory and antibacterial activities are presented. Structure-activity relationships indicate that that the monocyclic keto-ol form of ripostatin A is the active form of ripostatin A, that the ripostatin 5-6 unsaturation is important for activity, and that C14 geminal difluorination can be introduced into ripostatin B without loss of activity

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“…Mainly,three independent groups have completed the total synthesis of Ripostatin B( 5)i np arallel. [23][24][25] Synthetic approaches using non-AA routes Christmann'sa pproach:C hristmann and co-workersi n2 012 describedt he total synthesiso fR ipostatin B( 5)i n1 4s teps with 4% overall yield (Scheme 2). [23] Geranyl acetate was used as the precursor for two building blocks, 35 and 40,w hich were coupled in one pot by linchpin coupling and later the ring formation was achieved by ring-closing metathesis.…”

Section: Ripostatin Bmentioning

confidence: 99%

A Comparative Synthetic Strategy Perspective on α‐Amino Acid‐ and Non‐Amino Acid‐Derived Synthons towards Total Syntheses of Selected Natural Macrolides

Manda

Tripathi

Ghoshal

et al. 2020

Chemistry A European J

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other methods derived from miscellaneous synthons towards the total synthesiso fn on-peptidic macrolides.T he synthetic routes and the key strategies involved in the total syntheses of ten natural macrolides have been discussed. Both the amino acid-derived and non-amino acid-derived synthetic routes have been illustratedt op resentacomparative study between the two approaches.Scheme3.Prusov's approach towards the total synthesis of Ripostatin B( 5).Scheme4.To tal synthesis of Ripostatin B( 5)b yA ltmann's approach. Figure 3. Biologically active analogues of Ripostatin.

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Total Synthesis of the Bacterial RNA Polymerase Inhibitor Ripostatin B

Cited by 39 publications

References 27 publications

Total Synthesis of the Tiacumicin B (Lipiarmycin A3/Fidaxomicin) Aglycone

Total Synthesis of the Tiacumicin B (Lipiarmycin A3/Fidaxomicin) Aglycone

Synthesis and Evaluation of Novel Analogues of Ripostatins

A Comparative Synthetic Strategy Perspective on α‐Amino Acid‐ and Non‐Amino Acid‐Derived Synthons towards Total Syntheses of Selected Natural Macrolides

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