Total synthesis of the antitumor antibiotic (土)-streptonigrin: first- and second-generation routes for de novo pyridine formation using ring-closing metathesis
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Timothy J Donohoe Christopher R Jones Anne F Kornahrens Luiz CA Barbosa Louise Walport Matthew R Tatton Michael O'Hagan Akshat H Rathi David B BakerAbstract
The total synthesis of (±)-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 (±)-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-Miyaura cross-coupling reaction has enabled enantioenriched (up to 42% ee) synthetic streptonigrin intermediates to be prepared for the first time.
Journal details
Journal Journal of Organic Chemistry
Volume 78
Issue number 24
Pages 12338-12350
Publication date
Full text links
Publisher website (DOI) 10.1021/jo402388f
Europe PubMed Central 24328139
Pubmed 24328139
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