Stereoselective Synthesis of Uridine-Derived Nucleosyl Amino Acids

• Published in: Journal of organic chemistry 2011-12, Vol.76 (24), p.10083-10098
• Main Authors: Spork, Anatol P, Wiegmann, Daniel, Granitzka, Markus, Stalke, Dietmar, Ducho, Christian
• Format: Article
• Language: English
• Subjects: Amino Acids - chemistry; Anti-Bacterial Agents - analysis; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Carbohydrates. Nucleosides and nucleotides; Chemistry; Deoxyuridine - chemistry; Exact sciences and technology; General aspects; Humans; Hydrogenation; Magnetic Resonance Spectroscopy; Medical sciences; Molecular Structure; Nucleosides, nucleotides and oligonucleotides; Nucleotides - chemistry; Organic chemistry; Peptides - chemistry; Pharmacology. Drug treatments; Preparations and properties; Stereoisomerism; Structure-Activity Relationship; Urea - chemistry
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo201935w

Novel hybrid structures of 5′-deoxyuridine and glycine were conceived and synthesized. Such nucleosyl amino acids (NAAs) represent simplified analogues of the core structure of muraymycin nucleoside antibiotics, making them useful synthetic building blocks for structure–activity relationship (SAR) studies. The key step of the developed synthetic route was the efficient and highly diastereoselective asymmetric hydrogenation of didehydro amino acid precursors toward protected NAAs. It was anticipated that the synthesis of unprotected muraymycin derivatives via this route would require a suitable intermediate protecting group at the N-3 of the uracil base. After initial attempts using PMB- and BOM-N-3 protection, both of which resulted in problematic deprotection steps, an N-3 protecting group-free route was envisaged. In spite of the pronounced acidity of the uracil-3-NH, this route worked equally efficient and with identical stereoselectivities as the initial strategies involving N-3 protection. The obtained NAA building blocks were employed for the synthesis of truncated 5′-deoxymuraymycin analogues.