C−H Bond Activation for the Synthesis of Heterocyclic Atropisomers Yields Hedgehog Pathway Inhibitors

Abstract

Axially chiral 4-arylisoquinolones are endowed with pronounced bioactivity, and methods for their efficient synthesis have gained widespread attention. However, enantioselective synthesis of axially chiral 4-arylisoquinolones by means of C-H activation has not been reported to date. Described here is a rhodium (III)-catalyzed C-H bond activation and annulation for the atroposelective synthesis of axially chiral 4-arylisoquinolones. The method employs chiral cyclopentadienyl ligands embodying a piperidine ring as backbone and yields the atropisomers with good to excellent yields and enantioselectivity. Biological relevance of the 4-arylisoquinolones was demonstrated by their investigation in different cellular assays, leading to the discovery of novel non-SMO (SMO= smoothened) binding Hedgehog pathway inhibitors.

Diverse Approaches for Enantioselective C−H Functionalization Reactions Using Group 9 CpxMIII Catalysts

“…The corresponding Rh catalysts (Rh-4)w ere prepared and tested in the enantioselective cyclization of 1 and 2 as well as the enantioselective CÀHalkylation of 4 using allenes 5,a nd were found to provide good to excellent enantioselectivities when appropriate ligand structures were chosen. [22] In the context of the accessibility of chiral ligands, Cramer reported simple C2-symmetric chiral Cp x ligands that bear two pendanta ryl groups (18;S cheme 6). [23] An organo-catalyzed enantioselective ene-type reactiona nd one-pot intramolecular condensation reaction originallyr eportedb yH ayashi, [24] enabled the efficient synthesis of almost enantiomerically pure 17.Asubsequentd iastereoselective addition of an aryllithium reagent provided 18,w hichw as installed into Rh and Ir complexes (Rh-5 and Ir-5).…”

Applications of Chiral Cyclopentadienyl (Cpx) Metal Complexes in Asymmetric Catalysis

“…Later, an intramolecular C-H activation with alkynes was described, furnishing axially chiral 4-arylisoquinolones 65 (Scheme 15b). [46] Scheme 15. RhJasCp-catalysed atroposelective construction of biaryls 62 and 65.…”

Rhodium(III)‐Catalyzed Atroposelective Synthesis of Biaryls by C−H Activation and Intermolecular Coupling with Sterically Hindered Alkynes

“…Alkynes are typical π‐coupling partners, and Rh III ‐catalyzed C−H activation/[ n +2] annulation of alkynes has allowed direct construction of a diverse array of fused (hetero)arenes . Although alkynes have been previously employed in Rh III /Ir III ‐catalyzed asymmetric C−H activation, they are mostly limited to (oxidative) [3+2] annulation or arene desymmetrization, in which reductive elimination generally constitutes the stereo‐determining as well as the product‐forming step. We rationalized that migratory insertion of the Rh−C(aryl) bond into the alkyne is stereodetermining in our design, affording an atropomerically stable biaryl‐like rhodacyclic intermediate that eventually leads to biaryl products following the annulation with retention of axial chirality (Scheme c).…”

“…This stereodetermining insertion has been elegantly exemplified by Tan, Liu, and co‐workers in Ni 0 /oxazoline‐catalyzed asymmetric [4+2] coupling of triazinones and chloroalkyl‐substituted alkynes by way of N−N cleavage . In 2018, the groups of Antonchick and Waldmann reported Rh III ‐catalyzed intramolecular C−H activation of alkyne‐tethered N‐alkoxylbenzamides for enantioselective synthesis of 4‐arylisoquinolones bearing a specific alcohol tail (Scheme c, top) . Despite the great advances, the ortho position of the benzamide substrate needs to be blocked to ensure high enantioselectivity and reactivity.…”

“…The intramolecularity of their system also circumvented and simplified the important issue of regioselectivity with respect to both C−H activation and alkyne insertion. In general, the enantioselectivity of intramolecular C−H functionalization reactions seems relatively easily controlled …”