The Organocatalytic Approach to Enantiopure 2H- and 3H-Pyrroles: Inhibitors of the Hedgehog Signaling Pathway
Lisa Kötzner
Max-Planck-Institut für Kohlenforschung, Kaiser Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
Search for more papers by this authorDr. Markus Leutzsch
Max-Planck-Institut für Kohlenforschung, Kaiser Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
Search for more papers by this authorDr. Sonja Sievers
Max-Planck-Institut für Molekulare Physiologie, Compound Management and Screening Center (COMAS), Otto-Hahn-Strasse 11, 44227 Dortmund, Germany
Search for more papers by this authorSumersing Patil
Max-Planck-Institut für Molekulare Physiologie, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany
Search for more papers by this authorProf. Dr. Herbert Waldmann
Max-Planck-Institut für Molekulare Physiologie, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany
Search for more papers by this authorDr. Yiying Zheng
Max-Planck-Institut für Kohlenforschung, Kaiser Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
Search for more papers by this authorProf. Dr. Walter Thiel
Max-Planck-Institut für Kohlenforschung, Kaiser Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
Search for more papers by this authorCorresponding Author
Prof. Dr. Benjamin List
Max-Planck-Institut für Kohlenforschung, Kaiser Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
Search for more papers by this authorLisa Kötzner
Max-Planck-Institut für Kohlenforschung, Kaiser Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
Search for more papers by this authorDr. Markus Leutzsch
Max-Planck-Institut für Kohlenforschung, Kaiser Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
Search for more papers by this authorDr. Sonja Sievers
Max-Planck-Institut für Molekulare Physiologie, Compound Management and Screening Center (COMAS), Otto-Hahn-Strasse 11, 44227 Dortmund, Germany
Search for more papers by this authorSumersing Patil
Max-Planck-Institut für Molekulare Physiologie, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany
Search for more papers by this authorProf. Dr. Herbert Waldmann
Max-Planck-Institut für Molekulare Physiologie, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany
Search for more papers by this authorDr. Yiying Zheng
Max-Planck-Institut für Kohlenforschung, Kaiser Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
Search for more papers by this authorProf. Dr. Walter Thiel
Max-Planck-Institut für Kohlenforschung, Kaiser Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
Search for more papers by this authorCorresponding Author
Prof. Dr. Benjamin List
Max-Planck-Institut für Kohlenforschung, Kaiser Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
Search for more papers by this authorGraphical Abstract
The versatility of pyrroles: A Fischer indolization and a [1,5]-alkyl shift were used in the title reaction to obtain enantioenriched 2H- or 3H-pyrroles. The products could be generated in good to excellent yields and enantiomeric ratios by using a chiral SPINOL-derived phosphoric acid derivative as catalyst. Biological evaluations revealed the novel 2H-pyrroles to be potent inhibitors of the Hedgehog signaling pathway.
Abstract
A divergent approach to enantioenriched 2H- and 3H-pyrroles catalyzed by a spirocyclic phosphoric acid is reported that makes use of a Fischer-type indolization and a [1,5]-alkyl shift. Catalyzed by the chiral phosphoric acid STRIP, good to excellent yields and enantioselectivities could be obtained. Remarkably, biological evaluation reveals one of these novel 2H-pyrroles to be a potent but nontoxic inhibitor of the Hedgehog signaling pathway by binding to the Smoothened protein.
Supporting Information
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