Synthesis of Cytimidine through a One-Pot Copper-Mediated Amidation Cascade

Serrano, Catherine M.; Looper, Ryan

doi:10.1021/ol2018196

Cited by 11 publications

(12 citation statements)

References 39 publications

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“…The synthesis of amicetin ( 1 ) commenced with the preparation of carboxylic acid segments 9 and 10 (Scheme 1). The known acid 7 [ 36 ] was amidated with methyl p ‐aminobenzoate in the presence of HATU [ O ‐(7‐azabenzotriazol‐1‐yl)‐ N , N , N ', N '‐tetramethyluronium hexafluorophosphate] to provide amide 8 . Hydrolysis and opening of the oxazolidine ring under acidic conditions [ 36 ] followed by selective silylation of the primary hydroxyl group afforded acids 9 and 10 in moderate yields.…”

Section: Resultsmentioning

confidence: 99%

“…The known acid 7 [ 36 ] was amidated with methyl p ‐aminobenzoate in the presence of HATU [ O ‐(7‐azabenzotriazol‐1‐yl)‐ N , N , N ', N '‐tetramethyluronium hexafluorophosphate] to provide amide 8 . Hydrolysis and opening of the oxazolidine ring under acidic conditions [ 36 ] followed by selective silylation of the primary hydroxyl group afforded acids 9 and 10 in moderate yields. Under the similar conditions for the previous synthesis of plicacetin ( 2 ) and streptcytosine A, [ 18 ] the microwave‐assisted amidation between cytosamine and acid 9 or 10 in the presence of HATU in pyridine at 80 o C failed to deliver the coupled product D .…”

Section: Resultsmentioning

confidence: 99%

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Total Synthesis of Nucleoside Antibiotics Amicetin, Plicacetin, and Cytosaminomycin A—D

2021

Chin. J. Chem.

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Main observation and conclusion Amicetin and congeners constitute a small family of complex pyrimidine nucleosides, which exhibit strong antibiotic activities against Gram‐positive bacteria and notably against strains of Mycobacterium tuberculosis. Herein, we report chemical synthesis of a series of disaccharide congeners of the amicetin family, including amicetin, plicacetin, and cytosaminomycin A—D. It is the first time for successful synthesis of amicetin, the prototypical member, and cytosaminomycins. The synthetic approach employs glycosyl N‐phenyltrifluoroacetimidate and thioglycoside donors to construct the characteristic aminodeoxydisaccharides consisting of α‐(1→4)‐glycosidic linkage, uses gold(I)‐catalyzed N‐glycosylation to furnish 2‐deoxy‐β‐nucleosides, and finally exploits amidation and global deprotection to complete the syntheses. It is noteworthy that the 3‐O‐protecting group in the 2‐deoxydisaccharide donors is found to be crucial for a successful N‐glycosylation to assemble the cytosaminomycin disaccharide nucleosides.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Total Synthesis of Nucleoside Antibiotics Amicetin, Plicacetin, and Cytosaminomycin A—D

2021

Chin. J. Chem.

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“…We were initially drawn to the problem that traditional dissection of the cytimidine potion of amicetin would require two problematic acylation reactions (Scheme A), one with the amino group of cytosine, which is a poor nucleophile, and one with the carboxyl group of a hindered α-methylserine derivative. Alternatively, a C–N amination approach would reveal the pairing of an active pyrimidylhalide and unhindered carboxamide paired with an aryl halide and an α-methylserine carboxamide that might be more reactive as the nucleophile . We prepared the α-methylserine carboxamide 3 (Scheme B). , Attempts to directly couple 3 , pyrimidylhalide 4 , and p- iodobenzamide 5 in a single operation produced only trace amounts of the coupled product 6 .…”

Section: The Peptidylcytosine Antibioticsmentioning

confidence: 99%

Dissecting the Nucleoside Antibiotics as Universal Translation Inhibitors

2021

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Metrics & MoreArticle Recommendations CONSPECTUS: Without question, natural products have provided the lion share of leads, if not drugs themselves, for the treatment of bacterial infections. The bacterial arms race, fueled by selection and survival pressures has delivered a natural arsenal of small molecules targeting the most essential of life processes. Antibiotics that target these critical intracellular processes face the formidable defense of both penetrating a bacterial cell membrane and avoiding efflux to exert their effect. These challenges are especially effective in Gramnegative (Gram-(−)) bacteria, which have a double membrane structure and efficient efflux systems from the combination of outer-membrane porins and inner membrane proton pumps. In this landscape of offense and defense, our clinically used antibiotics have only successfully targeted three intracellular processes for therapeutic intervention in Gram-(−) bacteria: dihydrofolate biosynthesis, transcription, and translation. Not surprisingly, such critical survival machinery is a popular target for bacterial warfare, and eight of our 14 classes of commonly used antibiotics target translation with the bacterial ribosome remaining one the most vetted targets for antimicrobial therapy. On the plus side, its anionic character attracts cationic inhibitors, which are generally more capable of penetrating the bacterial cell wall, and clinical resistance rates are usually manageable as mutation of such a highly evolved machine is difficult. On the down side, this highly evolved machine renders it difficult to inhibit selectively, and the inhibition of prokaryotic translation versus both eukaryotic cellular and mitochondrial translation is critical for clinical development and minimization of undesired toxicities.A class of natural products known as the "nucleoside antibiotics" have historically been recognized as universal inhibitors of the ribosome and can inhibit translation in prokaryotes, eukaryotes, and archaea. While they have served an essential role in dissecting the biochemical underpinnings of the enzymatic functions of the ribosome, they have not proven therapeutically useful as they target the highly conserved rRNA in the P-site and are toxic to mammalian cells. In this Account, we describe our studies on the natural product amicetin, a nucleoside antibiotic that we have demonstrated to break the rule of being a universal translation inhibitor. While the cytosine of amicetin mimics C75 of the 3′-CCA tail of the P-site tRNA akin to other nucleoside antibiotics, we advance a hypothesis that amicetin's unique interaction with the ribosomal protein uL16 exploits an untapped mechanism for selectively targeting the bacterial ribosome. A complex molecule comprised of a nucleoside, carbohydrates and amino acids, amicetin is also chemically unstable. Our initial attempts to stabilize and simplify this scaffold are presented with the ultimate goal of rebuilding the compound with improved penetrance to bacterial cells. If successful, this scaffold ...

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“…Nucleophilic aromatic substitution of sodium benzyloxide on pyrimidine 1 , followed by acylation with 4‐iodobenzoylchloride gave the pyrimidyliodobenzamide 2 . Subsequent copper‐catalyzed Buchwald amidation with α‐methylserine derived carboxamide 3 gave masked cytimidine 4 which could be deprotected to provide cytimidine itself that was used for biological testing …”

Section: Figurementioning

confidence: 99%

Unifying the Aminohexopyranose‐ and Peptidyl‐Nucleoside Antibiotics: Implications for Antibiotic Design

et al. 2020

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In search of new anti‐tuberculars compatible with anti‐retroviral therapy we re‐identified amicetin as a lead compound. Amicetin's binding to the 70S ribosomal subunit of Thermus thermophilus (Tth) has been unambiguously determined by crystallography and reveals it to occupy the peptidyl transferase center P‐site of the ribosome. The amicetin binding site overlaps significantly with that of the well‐known protein synthesis inhibitor balsticidin S. Amicetin, however, is the first compound structurally characterized to bind to the P‐site with demonstrated selectivity for the inhibition of prokaryotic translation. The natural product‐ribosome structure enabled the synthesis of simplified analogues that retained both potency and selectivity for the inhibition of prokaryotic translation.

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Synthesis of Cytimidine through a One-Pot Copper-Mediated Amidation Cascade

Cited by 11 publications

References 39 publications

Total Synthesis of Nucleoside Antibiotics Amicetin, Plicacetin, and Cytosaminomycin A—D

Total Synthesis of Nucleoside Antibiotics Amicetin, Plicacetin, and Cytosaminomycin A—D

Dissecting the Nucleoside Antibiotics as Universal Translation Inhibitors

Unifying the Aminohexopyranose‐ and Peptidyl‐Nucleoside Antibiotics: Implications for Antibiotic Design

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