Organokatalytische Synthese von enantiomerenreinen 2H‐ und 3H‐Pyrrolen: Inhibitoren des Hedgehog‐Signalwegs

Abstract

Es wird über die organokatalytische divergente Synthese von enantiomerenreinen 2H-und 3H-Pyrrolen, unter Verwendung einer Fischer-Indolisierung und einer [1,5]-Alkyl-Verschiebung, berichtet. Katalysiert durch die chirale Phosphorsäure STRIP konnten die entsprechenden Produkte in guten bis exzellenten Ausbeuten sowieE nantioselektivitäten erhalten werden. Bemerkenswerterweise zeigten biologische Untersuchungen, dass eines der neuartigen 2H-Pyrrole ein potenter aber nicht toxischer Inhibitor des Hedgehog-Signalwegs ist und an das Smoothened-Protein bindet.

Recent Advances in Synthetic Methods for 2H‐Pyrroles

“…In 2016, an organocatalytic synthetic approach for enantiopure 2 H ‐pyrroles 93 was reported by List group, involving asymmetric Fisher indolization and the sequential [1,5]‐alkyl shift of generated 3 H ‐pyrroles (Scheme 25). [50] The reaction proceeded through two steps. The first Fisher indolization reaction using hydrazine 90 , cyclohexanone 91 , and chiral phosphoric acid L14 occurred to afford chiral 3 H ‐pyrroles 92 (up to 90% yield with a 95:5 er ).…”

Brønsted Acid Catalyzed Dearomatization by Intramolecular Hydroalkoxylation/Claisen Rearrangement: Diastereo‐ and Enantioselective Synthesis of Spirolactams

“…[6a] This strategy was also extended to the synthesis of chiral 2H-a nd 3H-pyrroles via ad earomatizing Fischer indolization and an in situ [1,5]-alkyl shift by the same group. [6b] Despite these significant advances, [5,6] the substrate scopes of these reactions were still limited to heterocyclic aromatic compounds and activated arenes.Thus,the development of adearomatization of nonactivated arenes via a[3,3]sigmatropic rearrangement, especially in an enantioselective, atom-economic,a nd environmentally friendly way,i sh ighly desirable.…”