Journal
JOURNAL OF ORGANIC CHEMISTRY
Volume 78, Issue 24, Pages 12338-12350Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jo402388f
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Funding
- St. John's College, Oxford
- Skaggs-Oxford Scholarship Program
- NSF GRFP
- Brazilian Research Council (CNPq)
- University of Oxford
- EPSRC
- AstraZeneca
- Exeter College & the Narotam Sekhsaria Foundation
- Lilly UK
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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.
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