Total Synthesis of (−)-Muraymycin D2 and Its Epimer

• Published in: Journal of organic chemistry Vol. 75; no. 5; pp. 1366 - 1377
• Main Authors: Tanino, Tetsuya, Ichikawa, Satoshi, Shiro, Motoo, Matsuda, Akira
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 05.03.2010; Amer Chemical Soc
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Carbohydrates. Nucleosides and nucleotides; Catalysis; Catalysts: preparations and properties; Chemistry; Chemistry, Organic; Chromatography, High Pressure Liquid; Crystallography, X-Ray; Dipeptides - chemical synthesis; Dipeptides - chemistry; Exact sciences and technology; General and physical chemistry; Imines - chemistry; Nucleosides - chemical synthesis; Nucleosides - chemistry; Nucleosides, nucleotides and oligonucleotides; Organic chemistry; Peptides - chemical synthesis; Peptides - chemistry; Physical Sciences; Preparations and properties; Science & Technology; Stereoisomerism; Theory of reactions, general kinetics. Catalysis. Nomenclature, chemical documentation, computer chemistry; MULTICOMPONENT REACTIONS; ASYMMETRIC-SYNTHESIS; BAD BUGS; ONE-POT SYNTHESIS; NATURAL-PRODUCTS; DRUGS; ANTIBACTERIAL; CORE STRUCTURE; C-H AMINATION; PEPTIDOGLYCAN BIOSYNTHESIS INHIBITORS; Separation; Peptides; Ugi reaction; Epimer; Deprotection; Acetolysis; HPLC chromatography; Alcohol; Nitrene; Selectivity; Desulfonylation; Amine; Rhodium Complexes; Carboxylic acid; Nucleoside; Ureas; Oxidation; Chemical synthesis; Protection; Guanidines; Natural compound; Total synthesis; Organic amidosulfate; Cyclization; Cyclic compound; Analog; Dipeptides; Antibacterial agent; Isocyanide; Catalyst; Diastereomer; Mercury Bromides
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo9027193

Full details of the first total synthesis of (−)-muraymycin (MRY) D2 and its epimer, the antibacterial nucleoside natural product, are described. Key strategic elements of the approach include the preparation of the urea dipeptide moiety found in the muraymycins containing an l-epi-capreomycidine via a nitrene C−H insertion of the sulfamate 10 and the fully protected muraymycin skeleton at a late stage by an Ugi four-component reaction. Thus, the nitrene C−H insertion of the sulfamate 10 with 10 mol % of Rh2(esp)2 catalyst gave the cyclic sulfamates 11a and 11b in 47% yield (11a:11b = 1:2.0). Construction of the cyclic guanidine skeleton was effected through the HgBr2-promoted cyclization of 42 followed by desulfonylation upon acetolysis of the oxathiazinane ring to give 43 in good yield. The amine obtained by selective removal of the Cbz group of the alcohol 44 was reacted with MeSC(O)-l-Val-O-t-Bu (38) to provide 45, which was oxidized to the carboxylic acid 46. Reaction of 46, isonitrile 51, isovaleraldehyde, and 2,4-dimethoxybenzylamine furnished the desired Ugi products, the final deprotection of which successfully afforded (−)-MRY D2 and epi-MRY D2 (53) after HPLC separation of the diastereomers. This approach would afford ready access to a range of analogues simply by altering each component.