Enantioselective Synthesis of Indolines, Benzodihydrothiophenes, and Indanes by C−H Insertion of Donor/Donor Carbenes

We employ a single catalyst/oxidant system to enable the asymmetric syntheses of indolines, benzodihydrothiophenes, and indanes by C−H insertion of donor/donor carbenes. This methodology enables the rapid construction of densely substituted five‐membered rings that form the core of many drug targets...

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Bibliographic Details
Published in:Angewandte Chemie 2018-11, Vol.130 (46), p.15433-15436
Main Authors: Souza, Lucas W., Squitieri, Richard A., Dimirjian, Christine A., Hodur, Blanka M., Nickerson, Leslie A., Penrod, Corinne N., Cordova, Jesus, Fettinger, James C., Shaw, Jared T.
Format: Article
Language:English
Subjects:
Alkanes
Asymmetrische Synthesen
C-H-Insertionen
Cancer
Carbenes
Chemistry
Diastereoselektivität
Enantiomers
Enantioselektivität
Estrogens
Heterocyclic compounds
Hydrazones
Insertion
Natural products
Oxidation
Regioselectivity
Rhodiumcarbene
Substrates
Synthesis
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Summary:We employ a single catalyst/oxidant system to enable the asymmetric syntheses of indolines, benzodihydrothiophenes, and indanes by C−H insertion of donor/donor carbenes. This methodology enables the rapid construction of densely substituted five‐membered rings that form the core of many drug targets and natural products. Furthermore, oxidation of hydrazones to the corresponding diazo compounds proceeds in situ, enabling a relatively facile one‐ or two‐pot protocol in which isolation of potentially explosive diazo alkanes is avoided. Regioselectivity studies were performed to determine the impact of sterics and electronics in donor/donor metal carbene C−H insertions to form indolines. This methodology was applied to a variety of substrates in high yield, diastereomeric, and enantiomeric ratios and to the synthesis of a patented indane estrogen receptor agonist with anti‐cancer activity. Rhodiumcarbene, die aus Substraten ohne elektronenziehende Gruppen erzeugt werden, ermöglichen selektive Indolin‐ und Benzodihydrothiophensynthesen. Die Reaktionen weisen von allen bekannten enantioselektiven C‐H‐Insertionen den höchsten Grad an Toleranz gegenüber funktionellen Gruppen auf. Ein einziges Katalysator‐Oxidationsmittel‐System wurde für alle Substrate verwendet, und in den meisten Fällen gelingt die C‐H‐Insertion als Eintopfprozess ausgehend vom Hydrazon.
ISSN:0044-8249
1521-3757
DOI:10.1002/ange.201809344