- Total synthesis of the antitumor antibiotic (±)-streptonigrin: First- and second-generation routes for de novo pyridine formation using ring-closing metathesis
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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.
- Donohoe, Timothy J.,Jones, Christopher R.,Kornahrens, Anne F.,Barbosa, Luiz C. A.,Walport, Louise J.,Tatton, Matthew R.,O'Hagan, Michael,Rathi, Akshat H.,Baker, David B.
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p. 12338 - 12350
(2014/01/17)
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- Total synthesis of (±)-streptonigrin: De novo construction of a pentasubstituted pyridine using ring-closing metathesis
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The synthesis of the potent antitumor agent (±)-streptonigrin has been achieved in 14 linear steps and 11% overall yield from ethyl glyoxalate. The synthesis features a challenging ring-closing metathesis reaction, followed by elimination and aromatization, to furnish a key pentasubstituted pyridine fragment.
- Donohoe, Timothy J.,Jones, Christopher R.,Barbosa, Luiz C. A.
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supporting information; experimental part
p. 16418 - 16421
(2011/11/29)
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