Total Synthesis of the Antitumor Antibiotic (卤)-Streptonigrin: First- and Second-Generation Routes for de Novo Pyridine Formation Using Ring-Closing Metathesis

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• 作者：Timothy J. Donohoe ; Christopher R. Jones ; Anne F. Kornahrens ; Luiz C. A. Barbosa ; Louise J. Walport ; Matthew R. Tatton ; Michael O鈥橦agan ; Akshat H. Rathi ; David B. Baker
• 刊名：Journal of Organic Chemistry
• 出版年：2013
• 出版时间：December 20, 2013
• 年：2013
• 卷：78
• 期：24
• 页码：12338-12350
• 全文大小：669K
• 年卷期：v.78,no.24(December 20, 2013)
• ISSN：1520-6904

文摘

The total synthesis of (卤)-streptonigrin, a potent tetracyclic aminoquinoline-5,8-dione antitumor antibiotic that reached phase II clinical trials in the 1970s, is described. Two routes to construct a key pentasubstituted pyridine fragment are depicted, both relying on ring-closing metathesis but differing in the substitution and complexity of the precursor to cyclization. Both routes are short and high yielding, with the second-generation approach ultimately furnishing (卤)-streptonigrin in 14 linear steps and 11% overall yield from inexpensive ethyl glyoxalate. This synthesis will allow for the design and creation of druglike late-stage natural product analogues to address pharmacological limitations. Furthermore, assessment of a number of chiral ligands in a challenging asymmetric Suzuki鈥揗iyaura cross-coupling reaction has enabled enantioenriched (up to 42% ee) synthetic streptonigrin intermediates to be prepared for the first time.