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Harnessing a p ‐Quinone Methide Intermediate in the Biomimetic Total Synthesis of the Highly Active Antibiotic 20‐Deoxy‐Elansolid B1
Author(s) -
Wang Liang Liang,
Candito David,
Dräger Gerald,
Herrmann Jennifer,
Müller Rolf,
Kirschning Andreas
Publication year - 2017
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201605884
Subject(s) - quinone methide , chemistry , total synthesis , quinone , stereochemistry , intramolecular force , polyketide , stille reaction , isomerization , cycloaddition , bacillus subtilis , pyridazine , biomimetic synthesis , combinatorial chemistry , organic chemistry , catalysis , bacteria , biosynthesis , biology , genetics , enzyme
The polyketide, 20‐deoxy elansolid B1, was prepared by a convergent strategy that relied on a putative biomimetic intramolecular Diels–Alder cycloaddition (IMDA) via a vinylic p ‐quinone methide intermediate to furnish the key tetrahydroindane unit. The ( Z , E , Z )‐configured triene unit was constructed by Pd‐catalyzed Suzuki–Miyaura and Stille cross‐coupling reactions without isomerization of any of the olefinic double bonds. Formation of a p ‐methide quinone intermediate under basic conditions and subsequent Michael addition by water to this intermediate proceeded with high facial selectivity which terminated this total synthesis. Remarkably, the new elansolid derivative 2 c shows very good inhibitory effect against Bacillus subtilis and Staphylococcus aureus (including MRSA) similarly to the best elansolid derivatives reported so far. Consequently, the hydroxyl group at C20 is not essential for antibacterial activity.