The commercial macrolide antibiotic fidaxomicin was synthesized in a highly convergent manner. Salient features of this synthesis include a β-selective noviosylation, a β-selective rhamnosylation, a ring-closing metathesis, a Suzuki coupling, and a vinylogous Mukaiyama aldol reaction. Careful choice of protecting groups and fine-tuning of the glycosylation reactions led to the first total synthesis of fidaxomicin. In addition, a relay synthesis of fidaxomicin was established, which gives access to a conveniently protected intermediate from the natural material for derivatization. The first total synthesis of a related congener, tiacumicin A, is presented.
Fidaxomicin, also known as tiacumicin B or lipiarmycin A3, is a novel macrocyclic antibiotic that is used in hospitals for the treatment of Clostridium difficile infections. This natural product has also been shown to have excellent bactericidal activity against multidrug-resistant Mycobacterium tuberculosis. In spite of its attractive biological activity, no total synthesis has been reported to date. The enantioselective synthesis of the central 18-membered macrolactone is reported herein. The key reactions include ring-closing metathesis between a terminal olefin and a dienoate moiety for macrocyclization, a vinylogous Mukaiyama aldol reaction, and a Stille coupling reaction of sterically demanding substrates. The retrosynthesis involves three medium-sized fragments, thus leading to a flexible yet convergent synthetic route. COMMUNICATION Total Synthesis of the Protected Aglycon of Fidaxomicin (Tiacumicin B, Lipiarmycin A3)Hideki Miyatake-Ondozabal, Elias Kaufmann and Karl Gademann* Dedication ((optional)) Abstract: Fidaxomicin, also known as tiacumicin B or lipiarmycin A3, is a novel macrocyclic antibiotic used in hospitals for the treatment of Clostridium difficile infections. This natural product has also been shown to have an excellent bactericidal activity against multi-drug resistant Mycobacterium tuberculosis. In spite of its attractive biological activity, no total synthesis has ever been reported to date. Herein, we report the enantioselective synthesis of the central 18-membered macrolactone. The noteworthy reactions include ringclosing metathesis between a terminal olefin and a dienoate moiety for macrocyclization, a vinylogous Mukaiyama aldol reaction, and a Stille coupling reaction of sterically demanding substrates. The retrosynthesis comprises of three medium sized fragments leading to a flexible yet convergent synthetic route.
The first enantioselective total synthesis of fidaxomicin, also known as tiacumicin B or lipiarmycin A3, is reported. This novel glycosylated macrolide antibiotic is used in the clinic for the treatment of Clostridium difficile infections. Key features of the synthesis involve a rapid and high-yielding access to the noviose, rhamnose, and orsellinic acid precursors; the first example of a β-selective noviosylation; an effective Suzuki coupling of highly functionalized substrates; and a ring-closing metathesis reaction of a noviosylated dienoate precursor. Careful selection of protecting groups allowed for a complete deprotection yielding totally synthetic fidaxomicin.
Synthetic studies toward highly oxygenated seco-prezizaane sesquiterpenes are reported, which culminated in a formal total synthesis of the neurotrophic agent (−)-jiadifenolide. For the construction of the tricyclic core structure, an unusual intramolecular and diastereoselective Nozaki-Hiyama-Kishi reaction involving a ketone as electrophilic coupling partner was developed. In addition, synthetic approaches toward the related natural product (2R)-hydroxy-norneomajucin, featuring a Mn-mediated radical cyclization for the tricycle assembly and a regioselective OH-directed C-H activation are presented. TOC Graphic AbstractSynthetic studies towards highly oxygenated seco-prezizaane sesquiterpenes are reported, which culminated in a formal total synthesis of the neurotrophic agent (-)-jiadifenolide.For the construction of the tricyclic core structure, an unusual intramolecular and diastereoselective Nozaki-Hiyama-Kishi reaction involving a ketone as electrophilic coupling partner was developed. In addition, synthetic approaches towards the related natural product (2R)-hydroxynorneomajucin, featuring a Mn-mediated radical cyclization for the tricycle assembly and a regioselective OH-directed C-H activation are presented.
Fidaxomicin, auch Tiacumicin B oder Lipiarmycin A3 genannt, ist ein neuartiges makrocyclisches Antibiotikum, das klinisch gegen Clostridium-difficile-Infektionen eingesetzt wird. Dieser Naturstoff zeigt zudem eine exzellente Aktivität gegen multiresistente Stämme von Mycobacterium tuberculosis. Trotz dieses attraktiven biologischen Profils gab es bisher noch keine Berichte über eine Totalsynthese. Hier berichten wir über die enantioselektive Synthese des zentralen 18-gliedrigen Makrolactons von Fidaxomicin. Die Schlüsselschritte der Synthese sind eine Ringschlussmetathese zwischen einem terminalen Olefin und einem Dienoat, eine vinyloge Mukaiyama-Aldolreaktion und eine Stille-Kupplung zweier sterisch anspruchsvoller Substrate. Der Ansatz beruht auf drei mittelgroßen Fragmenten, was eine flexible und gleichzeitig konvergente Syntheseroute ermçglicht. Tuberkulose (TB) gilt -wieweit behandelbar -immer noch als großes Problem im Gesundheitswesen. [1] Jedes Jahr gibt es ca. neun Millionen neue Erkrankungen, woraus geschätzte zwei Millionen Todesfälle resultieren. [2] Da sich resistente Formen immer stärker ausbreiten, versagen derzeit genutzte Medikamente, wie zum Beispiel die Antibiotika Rifampicin oder Isoniazid, immer çfter. [3] Daher ist die Entwicklung alternativer Wirkstoffe gegen Mycobacterium tuberculosis (MTB) eine wichtige Aufgabe in der medizinischen Forschung. In diesem Zusammenhang wurden wir auf Fidaxomicin (1; Tiacumicin B, Lipiarmycin A3) [4] aufmerksam, das einen RNS-Polymerase-Hemmer mit vielversprechender Aktivität gegen MTB darstellt. [1] Dieses komplexe 18-gliedrige Makrolid mit mehreren stereogenen Zentren ist ein attraktives Syntheseziel, wozu auch ungewçhnliche Kohlenhydrateinheiten und eine chlorierte, vollständig substituierte Resorcinoleinheit beitragen. Bedauerlicherweise eignet sich der Naturstoff wegen seiner geringen biologischen Verfügbarkeit und Instabilität im saurem Milieu nicht zur therapeutischen Behandlung von MTB. [5] Die Modifizierung der Struktur entweder über Semi-oder Totalsynthese kçnnte somit einen wichtigen Beitrag zur Verbesserung des pharmakokinetischen Profils leisten. Fidaxomicin wurde von Optimer Pharmaceuticals in 2011 zur klinischen Behandlung einer anderen Infektionskrankheit (Clostridium difficile) lanciert. [6] Dort erzielt Fidaxomicin vergleichbare Erholungsraten wie Vancomycin, jedoch mit weniger Nebenwirkungen und einer geringeren Wiedererkrankungsrate. Da das Potenzial für ein Therapeutikum gegeben ist, entschlossen wir uns, eine effiziente und konvergente Totalsynthese für Fidaxomicin (1) zu entwickeln und somit den Zugang zu strukturell diversen Derivaten mit verbesserter Pharmakokinetik für die Behandlung von TB zu ermçglichen. Es ist erstaunlich, dass seit seiner ersten Isolierung durch Fermentation von Actinoplanes deccanensis im Jahre 1975 und trotz seiner klinischen Anwendung als Pharmazeutikum bislang noch keine Totalsynthese für 1 publiziert wurde. [7] Bisher sind Synthesestudien zum zentralen Aglycon (in einer Doktorarbeit [8] ), zu den Monosaccha...
A case of pneumothorax during laparoscopic cholecystectomy is reported. Etiology, evaluation and therapy are discussed.
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