title: Total synthesis of the antitumor antibiotic (±)-streptonigrin: first- and second-generation routes for de novo pyridine formation using ring-closing metathesis.
abstract: 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.
authors: Department of Chemistry, Chemistry Research Laboratory, University of Oxford , Mansfield Road, Oxford OX1 3TA, United Kingdom.
authors: Timothy J
authors: TJ
authors: Donohoe
authors: Christopher R
authors: CR
authors: Jones
authors: Anne F
authors: AF
authors: Kornahrens
authors: Luiz C A
authors: LC
authors: Barbosa
authors: Louise J
authors: LJ
authors: Walport
authors: Matthew R
authors: MR
authors: Tatton
authors: Michael
authors: M
authors: O'Hagan
authors: Akshat H
authors: AH
authors: Rathi
authors: David B
authors: DB
authors: Baker
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000737:chemistry; D003500:Cyclization; D015394:Molecular Structure; D013237:Stereoisomerism; D013308:Streptonigrin / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000903:Antibiotics, Antineoplastic; D013308:Streptonigrin