Synthesis of the Aglycon of the Antibiotic Disciformycin

Wolling, Michael; Kirschning, Andreas

doi:10.1002/ejoc.201701639

Cited by 5 publications

(9 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Ein alternativer Zugang zum Aglykon des Disciformycins B ( 2 ) über den Ringschluss durch Makrolaktonisierung wurde seit der Veröffentlichung von Fürstners Arbeit zur Totalsynthese des Disciformycins B ( 2 ) von Wolling und Kirschning beschrieben . Darüberhinaus berichteten Rengarasu und Maier kürzlich über eine Synthese des C1‐C12‐Fragments des Gulmirecins B ( 4 ), und Ichikawa und Mitarbeiter beschrieben die Herstellung eines vollständig geschützten Derivats des C5‐O Dihydrogulmirecins A.…”

Section: Methodsunclassified

“…Ein alternativer Zugang zum Aglykon des Disciformycins B (2) über den Ringschluss durch Makrolaktonisierung wurde seit der Verçffentlichung von Fürstners Arbeit zur Totalsynthese des Disciformycins B (2) von Wolling und Kirschning beschrieben. [6] Darüberhinaus berichteten Rengarasu und Maier kürzlich über eine Synthese des C1-C12-Fragments des Gulmirecins B (4), [7] und Ichikawa und Mitarbeiter beschrieben die Herstellung eines vollständig geschützten Derivats des C5-O Dihydrogulmirecins A. Der Ringschluss zum 12-gliedrigen Makrolacton wurde in Ichikawas Synthese durch eine Ni 0vermitttelte, intramolekulare reduktive Kupplung eines Inals erreicht; [8] allerding ließ sich die dabei erhaltene, vollgeschüzte Vorstufe des Gulmirecins A (3) nicht erfolgreich entschützen.…”

unclassified

See 1 more Smart Citation

Die Totalsynthese des Antibiotikums Disciformycin B durch Ringschlussmetathese

Waser

Altmann

2020

Angewandte Chemie

View full text Add to dashboard Cite

Wir beschreiben die Totalsynthese des potenten neuen Antibiotikums Disciformycin B (2), das eine ausgeprägte Aktivität gegenüber Methicillin‐ und Vancomycin‐resistenten Stämmen von Staphylococcus aureus (MRSA/VRSA) aufweist. Der zentrale Syntheseschritt besteht in der Makrozyklisierung eines Tetraens zum 12‐gliedrigen Makrolactonring des Naturstoffs durch eine ringschließende Olefinmetathese. Zwar wurde neben dem Makrozyklus über einen alternativen Ringschlussmetatheseweg auch ein Cyclopentenderivat gebildet, es konnten jedoch Bedingungen gefunden werden, die das gewünschte Makrolacton als Hauptprodukt lieferten. Die Schlüsselschritte bei der Herstellung des Metathesesubstrats waren eine hocheffiziente Evans‐syn‐Aldolreaktion, die asymmetrische Brown‐Allylierung des Angelikaaldehyds, sowie die stereoselektive 1,2‐Reduktion eines Enons mittels Zn(BH4)2. Die Synthese wurde nach der Makrozyklisierung über eine dehydratative Glykosylierung zur Einführung des d‐Arabinofuranosylrests und schließlich eine chemoselektive Oxidation eines allylischen Alkohols zu Ende geführt.

show abstract

Section: Methodsunclassified

unclassified

Die Totalsynthese des Antibiotikums Disciformycin B durch Ringschlussmetathese

Waser

Altmann

2020

Angewandte Chemie

View full text Add to dashboard Cite

show abstract

“…Subsequent to Fürstners work, Wolling and Kirschning described an alternative approach towards the disciformycin B aglycone, employing a macrolactonization strategy. [6] More recently, Rengarasu and Maier have described the synthesis of a C1-C12 fragment of gulmirecin B (4), [7] and Ichikawa and co-workers have reported the synthesis of a fully protected version of C5-O dihydro gulmirecin A. Ichikawas approach entailed macrocyclization at C7-C8 by Ni 0 -mediated reductive cyclization of an ynal intermediate; [8] unfortunately, deprotection of the advanced gulmirecin A precursor could not be achieved.…”

mentioning

confidence: 99%

An RCM‐Based Total Synthesis of the Antibiotic Disciformycin B

Waser

Altmann

2020

Angew Chem Int Ed

View full text Add to dashboard Cite

The total synthesis of the potent new antibiotic disciformycin B (2) is described, which shows significant activity against methicillin‐ and vancomycin‐resistant Staphylococcus aureus (MRSA/VRSA) strains. The synthetic route is based on macrocyclization of a tetraene substrate to the 12‐membered macrolactone core by ring‐closing olefin metathesis (RCM). Although macrocyclization was accompanied by concomitant cyclopentene formation by an alternative RCM pathway, conditions were established to give the macrocycle as the major product. Key steps in the construction of the RCM substrate include a highly efficient Evans syn‐aldol reaction, the asymmetric Brown allylation of angelic aldehyde, and the stereoselective Zn(BH4)2‐mediated 1,2‐reduction of an enone. The synthesis was completed by late‐stage dehydrative glycosylation to introduce the d‐arabinofuranosyl moiety and final chemoselective allylic alcohol oxidation.

show abstract

“…Because these natural products have excellent properties for avoiding cross-resistance with methicillin and vancomycin, they have the potential to become effective antibacterial leads with activity against multidrug-resistant bacteria although their targets have not yet been clarified. The total synthesis of disciformycins has been accomplished by the groups of Müller and Fürstner, and synthesis studies of disciformycin B and gulmirecin B have also been reported by the groups of Kirschning and Maier, respectively. Despite considerable effort to synthesize gulmirecins and disciformycins, no studies of the synthesis of their analogues of gulmirecin A have been reported, and their structure–activity relationships must still be elucidated.…”

mentioning

confidence: 99%

“…Finally, the TBS group was deprotected by TBAF to afford the desired alcohol 10 . The stereochemistry of 10 was determined by comparing the specific rotation with a literature value …”

mentioning

confidence: 99%

A Synthesis Strategy for the Production of a Macrolactone of Gulmirecin A via a Ni(0)-Mediated Reductive Cyclization Reaction

2020

View full text Add to dashboard Cite

A synthesis strategy for the production of a key synthetic intermediate of gulmirecin A was described. The key reaction in the preparation of the 12-membered macrolactone is the Ni(0)-mediated reductive cyclization reaction of ynal using an N-heterocyclic carbene ligand and silane reductant. In addition, the α-selective glycosylation reaction of the macrolactone was performed to demonstrate the synthesis of gulmirecin and disciformycin precursors.S ince the discovery of antibiotics and vaccines, the number of deaths due to infectious diseases has drastically decreased. However, the frequent prescription and unregulated usage of antibiotics against infectious diseases have permitted drug-resistant bacterial pathogens to spread rapidly. 1 According to the antibiotic resistance threats reported by the U.S. Centers for Disease Control and Prevention in 2019, more than 2.8 million antibiotic-resistant infections occur in the U.S. each year, causing 35,000 deaths. 2 Hence, the development of new antibacterial drugs with novel mechanisms of action is urgently needed to avoid cross-resistance with approved drugs.In 2014, gulmirecin A (1) and B (2) were isolated from Pyxidicoccus fallax HKI 727 as potential antimicrobial agents against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) (Figure 1). 3 In the same year, disciformycin A (3) and B (4) were isolated from Pyxidicoccus fallax AndGT8 for similar use as potential antimicrobial agents. 4

show abstract

Synthesis of the Aglycon of the Antibiotic Disciformycin

Cited by 5 publications

References 42 publications

Die Totalsynthese des Antibiotikums Disciformycin B durch Ringschlussmetathese

Die Totalsynthese des Antibiotikums Disciformycin B durch Ringschlussmetathese

An RCM‐Based Total Synthesis of the Antibiotic Disciformycin B

A Synthesis Strategy for the Production of a Macrolactone of Gulmirecin A via a Ni(0)-Mediated Reductive Cyclization Reaction

Contact Info

Product

Resources

About