Get access

Concise Total Synthesis of the Thiazolyl Peptide Antibiotic GE2270 A

Authors

  • Oscar Delgado Dr.,

    1. Lehrstuhl für Organische Chemie 1, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany, Fax: (+49) 89-289-13315
    2. Current address: Janssen-Cilag, Medicinal Chemistry Department, Jarama 75, 45007 Toledo, Spain
    Search for more papers by this author
    • Both authors contributed equally to the project.

  • H. Martin Müller Dr.,

    1. Lehrstuhl für Organische Chemie 1, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany, Fax: (+49) 89-289-13315
    2. Current address: Department of Chemistry and Biochemistry, University of Colorado at Boulder, 215 UCB, Boulder, CO 80309-0215, USA
    Search for more papers by this author
    • Both authors contributed equally to the project.

  • Thorsten Bach Prof. Dr.

    1. Lehrstuhl für Organische Chemie 1, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany, Fax: (+49) 89-289-13315
    Search for more papers by this author

Abstract

The potent antibiotic thiazolylpeptide GE2270 A was synthesized starting from N-tert-butyloxycarbonyl protected valine in a longest linear sequence of 20 steps and with an overall yield of 4.8 %. Key strategy was the assembly of the 2,3,6-trisubstituted pyridine core by consecutive cross-coupling reactions starting from 2,6-dibromo-3-iodopyridine. The complete Southern fragment was installed by Negishi cross-coupling of 3-zincated 2,6-dibromopyridine at the terminal 2-iodothiazole of a trithiazole (87 %). The substituent at C-6 representing the Northern part of the molecule was introduced in form of the truncated tert-butyl 2-bromothiazole-4-carboxylate after metalation to a zinc reagent by another Negishi cross-coupling (48 %). Decisive step of the whole sequence was the macrocyclization to a 29-membered macrolactam, which was conducted as an intramolecular Stille cross-coupling occurring at C-2 of the pyridine core and providing the desired product in 75 % yield. The required stannane was obtained by amide bond formation (87 %) between a complex dithiazole fragment representing the Eastern part of GE2270 A and a 3,6-disubstituted 2-bromopyridine. Final steps included attachment of a serine-proline amide dipeptide to the Northern part of the molecule (65 %), formation of the oxazoline ring and silyl ether deprotection (55 % overall).

Get access to the full text of this article

Ancillary