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

Abstract

Axially chiral 4-arylisoquinolones are endowed with pronounced bioactivity,a nd methods for their efficient synthesis have gained widespread attention. However,e nantioselective synthesis of axially chiral 4-arylisoquinolones by means of C À Ha ctivation has not been reported to date.D escribed here is ar hodium (III)-catalyzed C À Hb ond activation and annulation for the atroposelective synthesis of axially chiral 4arylisoquinolones.T he method employs chiral cyclopentadienyl ligands embodying ap iperidine ring as backbone and yields the atropisomers with good to excellent yields and enantioselectivity.B iological relevance of the 4-arylisoquinolones was demonstrated by their investigation in different cellular assays,l eading to the discovery of novel non-SMO (SMO = smoothened) binding Hedgehog pathwayi nhibitors.

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

“…In addition, the arene substrate has been extended to thiophene rings (5ja), although the enantioselectivity tends to be slightly lower. Thec onformational stability of 5aa has been examined and essentially no decay of enantiopurity was observed when as ample was heated at 80 8 8Cf or 12 hours.I nt he 1 Ha nd 13 CNMR spectra of most products,b roadened signals have been detected. This broadening is likely due to partially hindered rotation of the C-aryl bond that is proximal to the NH group.…”

“…This strategy differs from that in Scheme 1b in that the biaryl axis in the product originates from aC À Cb ond of the coupling partner instead of the arene.Alkynes are typical p-coupling partners,a nd Rh III -catalyzed CÀHa ctivation/ [n+ +2] annulation of alkynes has allowed direct construction of ad iverse array of fused (hetero)arenes. [11] Although alkynes [12,13] have been previously employed in Rh III /Ir IIIcatalyzed asymmetric C À Hactivation, they are mostly limited to (oxidative) [3+ +2] annulation or arene desymmetrization, in which reductive elimination generally constitutes the stereodetermining as well as the product-forming step.W er ationalized that migratory insertion of the Rh À 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 1c). 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 chloroalkylsubstituted alkynes by way of N À Nc leavage.…”

“…[14] In 2018, the groups of Antonchick and Waldmann reported Rh III -catalyzed intramolecular CÀHa ctivation of alkyne-tethered Nalkoxylbenzamides for enantioselective synthesis of 4-arylisoquinolones bearing as pecific alcohol tail (Scheme 1c, top). [13] Despite the great advances,t he ortho position of the benzamide substrate needs to be blocked to ensure high enantioselectivity and reactivity.T he intramolecularity of their system also circumvented and simplified the important issue of regioselectivity with respect to both CÀHa ctivation and alkyne insertion. In general, the enantioselectivity of intramolecular CÀHf unctionalization reactions seems relatively easily controlled.…”

“…In general, the enantioselectivity of intramolecular CÀHf unctionalization reactions seems relatively easily controlled. [13,15] Thed emand for structurally diverse chiral biaryls as functional molecules and ready availability of arenes and alkynes in separate entities call for asymmetric biaryl synthesis by intermolecular CÀHa ctivation. Despite the design in Scheme 1c,t he following challenges should be properly addressed:1)the alkyne and should be judiciously selected to ensure regioselectivity of alkyne insertion;2 )the enantioselectivity of the alkyne insertion needs to be well controlled; and 3) the DG should be tightly bound to the Rh in the sevenmembered rhodacycle to ensure atropomeric stability and subsequent chirality transfer.…”

Pd‐Catalyzed Atroposelective C−H Allylation through β‐O Elimination: Diverse Synthesis of Axially Chiral Biaryls

“…[8b] Zhao and co-workers recently designed an ovel N-quaternized biaryl axially chiral pyridoxal catalyst for biomimetic asymmetric Mannich reaction. [11] Seminal works by the groups of Murai, [12] Milller, [13] You, [14] Wencel-Delord and Colobert, [15] Antonchick and Waldmann, [16] and Cramer, [17] have proved the power of this strategy.D espite of these advances,t he construction of these important scaffolds with Scheme 1. Therefore,s ubstantial efforts have been devoted to the synthesis of these axially chiral biaryl backbones.…”