Total synthesis of the antitumor antibiotic (±)-streptonigrin: first- and second-generation routes for de novo pyridine formation using ring-closing metathesis.
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 di...
| Main Authors: | , , , , , , , , |
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| Format: | Journal article |
| Sprog: | English |
| Udgivet: |
2013
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| _version_ | 1826262231718821888 |
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| author | Donohoe, T Jones, C Kornahrens, A Barbosa, L Walport, L Tatton, MR O'Hagan, M Rathi, A Baker, D |
| author_facet | Donohoe, T Jones, C Kornahrens, A Barbosa, L Walport, L Tatton, MR O'Hagan, M Rathi, A Baker, D |
| author_sort | Donohoe, T |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T19:33:08Z |
| format | Journal article |
| id | oxford-uuid:1e2437ca-498e-4820-87c7-e7caf712dd4f |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T19:33:08Z |
| publishDate | 2013 |
| record_format | dspace |
| spelling | oxford-uuid:1e2437ca-498e-4820-87c7-e7caf712dd4f2022-03-26T11:14:45ZTotal synthesis of the antitumor antibiotic (±)-streptonigrin: first- and second-generation routes for de novo pyridine formation using ring-closing metathesis.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:1e2437ca-498e-4820-87c7-e7caf712dd4fEnglishSymplectic Elements at Oxford2013Donohoe, TJones, CKornahrens, ABarbosa, LWalport, LTatton, MRO'Hagan, MRathi, ABaker, DThe 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. |
| spellingShingle | Donohoe, T Jones, C Kornahrens, A Barbosa, L Walport, L Tatton, MR O'Hagan, M Rathi, A Baker, D Total synthesis of the antitumor antibiotic (±)-streptonigrin: first- and second-generation routes for de novo pyridine formation using ring-closing metathesis. |
| title | Total synthesis of the antitumor antibiotic (±)-streptonigrin: first- and second-generation routes for de novo pyridine formation using ring-closing metathesis. |
| title_full | Total synthesis of the antitumor antibiotic (±)-streptonigrin: first- and second-generation routes for de novo pyridine formation using ring-closing metathesis. |
| title_fullStr | Total synthesis of the antitumor antibiotic (±)-streptonigrin: first- and second-generation routes for de novo pyridine formation using ring-closing metathesis. |
| title_full_unstemmed | Total synthesis of the antitumor antibiotic (±)-streptonigrin: first- and second-generation routes for de novo pyridine formation using ring-closing metathesis. |
| title_short | Total synthesis of the antitumor antibiotic (±)-streptonigrin: first- and second-generation routes for de novo pyridine formation using ring-closing metathesis. |
| title_sort | 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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