TY - JOUR

T1 - Harnessing a p-Quinone Methide Intermediate in the Biomimetic Total Synthesis of the Highly Active Antibiotic 20-Deoxy-Elansolid B1

AU - Wang, Liangliang

AU - Candito, David

AU - Dräger, Gerald

AU - Herrmann, Jennifer

AU - Müller, Rolf

AU - Kirschning, Andreas

N1 - Funding information: The work was funded by the Deutsche Forschungsgemeinschaft (Cluster of Excellence REBIRTH; ?From Regenerative Biology to Reconstructive Therapy? EXC 62). We thank the Alexander-von-Humboldt Foundation for providing a postdoc scholarship for D. Candito. The work was funded by the Deutsche Forschungsgemeinschaft (Cluster of Excellence REBIRTH; “From Regenerative Biology to Reconstructive Therapy” EXC 62). We thank the Alexander-von-Humboldt Foundation for providing a postdoc scholarship for D. Candito.

PY - 2017/2/13

Y1 - 2017/2/13

N2 - 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.

AB - 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.

KW - antibiotics

KW - biosynthesis

KW - intramolecular Diels–Alder cycloaddition

KW - polyketides

KW - total synthesis

UR - http://www.scopus.com/inward/record.url?scp=85017275797&partnerID=8YFLogxK

U2 - 10.1002/chem.201605884

DO - 10.1002/chem.201605884

M3 - Article

C2 - 28195370

AN - SCOPUS:85017275797

VL - 23

SP - 5291

EP - 5298

JO - Chemistry - A European Journal

JF - Chemistry - A European Journal

SN - 0947-6539

IS - 22

ER -