RESUMO
The commercial macrolide antibiotic fidaxomicin was synthesized in a highly convergent manner. Salient features of this synthesis include a ß-selective noviosylation, a ß-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.
RESUMO
The macrocyclic antibiotic mangrolideâ A has been described to exhibit potent activity against a number of clinically important Gram-negative pathogens. Reported is the first enantioselective total synthesis of mangrolideâ A and derivatives. Salient features of this synthesis include a highly convergent macrocycle preparation, stereoselective synthesis of the disaccharide moiety, and two ß-selective glycosylations. The synthesis of mangrolide A and its analogues enabled the re-examination of its activity against bacterial pathogens, and only minimal activity was observed.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacologia , Antibacterianos/química , Sequência de Carboidratos , Farmacorresistência Bacteriana , Glicosilação , Compostos Macrocíclicos/química , Testes de Sensibilidade Microbiana , EstereoisomerismoRESUMO
Fidaxomicin, also known as tiacumicinâ B or lipiarmycinâ 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.
Assuntos
Aminoglicosídeos/síntese química , Aminoglicosídeos/química , FidaxomicinaRESUMO
Transient receptor potential ankyrin 1 (TRPA1) is a voltage-dependent, ligand-gated ion channel, and activation thereof is linked to a variety of painful conditions. Preclinical studies have demonstrated the role of TRPA1 receptors in a broad range of animal models of acute, inflammatory, and neuropathic pain. In addition, a clinical study using the TRPA1 antagonist GRC-17536 (Glenmark Pharmaceuticals) demonstrated efficacy in a subgroup of patients with painful diabetic neuropathy. Consequently, there is an increasing interest in TRPA1 inhibitors as potential analgesics. Herein, we report the identification of a fragment-like hit from a high-throughput screening (HTS) campaign and subsequent optimization to provide a novel and brain-penetrant TRPA1 inhibitor (compound 18, BAY-390), which is now being made available to the research community as an open-source in vivo probe.
Assuntos
Neuralgia , Canais de Potencial de Receptor Transitório , Animais , Analgésicos/farmacologia , Anquirinas , Canal de Cátion TRPA1RESUMO
The synthesis of the Securinega alkaloid secu'amamine E (ent-virosine A) has been accomplished for the first time in 12 steps and 8.5% overall yield. In addition, bubbialine has been prepared and characterized. These two alkaloids and bubbialidine, all featuring an azabicyclo[2.2.2]octane core, were rearranged to their azabicyclo[3.2.1]octane congeners, a framework found in many Securinega alkaloids. These experiments suggest that azabicyclo[2.2.2]octane derivatives could serve as intermediates in the biosynthesis of the rearranged azabicyclo[3.2.1]octane products.
Assuntos
Euphorbiaceae/química , Alcaloides , Compostos Heterocíclicos de 4 ou mais Anéis , Estrutura Molecular , EstereoisomerismoRESUMO
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 ß-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.
Assuntos
Aminoglicosídeos/síntese química , Antibacterianos/síntese química , Infecções por Clostridium/tratamento farmacológico , Macrolídeos/síntese química , Vancomicina/química , Aminoglicosídeos/química , Antibacterianos/química , Antibacterianos/farmacologia , Clostridioides difficile/efeitos dos fármacos , Fidaxomicina , Glicosilação , Macrolídeos/química , Estrutura MolecularRESUMO
The first enantioselective total syntheses of virosaine A and bubbialidine are described. Key transformations include the formation of a tetracyclic intermediate via an intramolecular aza-Michael addition, generation of a N-hydroxy-pyrrolidine through a Cope elimination and an intramolecular [1,3]-dipolar cycloaddition to generate a complex 7-oxa-1-azabicyclo[3.2.1]octane ring system.
Assuntos
Antineoplásicos/química , Antineoplásicos/síntese química , Tropanos/química , Tropanos/síntese química , Técnicas de Química Sintética , Estereoisomerismo , Especificidade por SubstratoRESUMO
The biomimetic total synthesis of LL-Z1640-2 (3) is reported without the use of phenol protection. The aromatic unit was constructed via the transannular aromatization of macrocyclic triketo-ester 2, which in turn was synthesized by macrolactonization using an intramolecular trapping of a triketo-ketene derived from dioxinone 1.
Assuntos
Lactonas/síntese química , MAP Quinase Quinase Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Ciclização , Dioxolanos/síntese química , Estrutura MolecularRESUMO
The first enantioselective synthesis of the antihistamine agent clemastine, as its (S,S)-stereoisomer, has been achieved by ether formation between a proline-derived chloroethylpyrrolidine and an enantiomerically enriched tertiary alcohol. The tertiary alcohol was formed from the carbamate derivative of alpha-methyl-p-chlorobenzyl alcohol by invertive aryl migration on lithiation. The (S,S)-stereochemistry of the product confirms the invertive nature of the rearrangement.