Stereocontrolled Syntheses of Peptide Thioesters Containing Modified Seryl Residues as Probes of Antibiotic Biosynthesis

被引:17
作者
Gaudelli, Nicole M. [1 ]
Townsend, Craig A. [1 ]
机构
[1] Johns Hopkins Univ, Dept Chem, Baltimore, MD 21218 USA
基金
美国国家卫生研究院;
关键词
ISOPENICILLIN N-SYNTHASE; NOCARDICIN-A; ENZYMES; ACID; DOMAIN; FAMILY;
D O I
10.1021/jo4007893
中图分类号
O62 [有机化学];
学科分类号
070303 ; 081704 ;
摘要
Methods have been developed to synthesize tri- Nocardicin NRPS and pentapeptide thioesters containing one or, more p-(hydroxyphenyl)glycine (pHPG) residues and L-serine, some where the latter is O-phosphorylated, O-acetylated, or exists as a beta-lactam. Selection of orthogonal protection strategies and development of conditions to achieve seryl O-phosphorylation without beta-elimination and to maintain stereocheinical control, especially simultaneously at exceptionally base-labile pHPG alpha-carbons, are described. Intramolecular closure of a seryl peptide to a beta-lactam-containing peptide and the syntheses of corresponding thioester analogues are also reported. Modification of classical Mitsunobu conditions is described in the synthesis of the beta-lactam-containing products, and in a broadly useful observation, it was found that simple exclusion of light from the P(OEt)(3)-mediated Mitsunobu ring closure afforded yields of >95%, presumably owing to reduced photodegradation of the azodicarboxylate used These sensitive potential substrates and products will be used in mechanistic studies of the two nonribosomal peptide synthetases NocA and NocB that he at the heart of nocardicin biosynthesis a family of monocyclic beta-lactam antibiotics.
引用
收藏
页码:6412 / 6426
页数:15
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