Enantioselective Formal C(sp³)−H Bond Activation in the Synthesis of Bioactive Spiropyrazolone Derivatives

Abstract

Herein, we report the first enantioselective annulation of α‐arylidene pyrazolones through a formal C(sp3)−H activation under mild conditions enabled by highly variable RhIII‐Cpx catalysts. The method has a wide substrate scope and proceeds with good to excellent yields and enantioselectivities. Its synthetic utility was demonstrated by the late‐stage functionalization of drugs and natural products as well as the preparation of enantioenriched [3]dendralenes. Preliminary biological investigations also identified the spiropyrazolones as a novel class of Hedgehog pathway inhibitors.

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

“…Activation of C(sp 3 )−H bonds using a transition metal catalyst to form an alkylmetal intermediate is far more challenging than the activation of C(sp 2 )−H bonds due to the low acidity of C(sp 3 )−H bonds and the lack of π‐electrons that can interact with the metal center. In fact, the chiral Cp x M catalysts discussed in the previous section have not been applied to enantioselective C(sp 3 )−H functionalization reactions to date, except in the formal C(sp 3 )−H functionalization reactions reported by Antonchick and Waldmann, in which the C−H activation proceeds after C(sp 3 ) to C(sp 2 ) isomerization . In contrast, Yoshino and Matsunaga reported enantioselective C(sp 3 )−H amidation reactions of thioamides 54 using dioxazolones 38 based on a chiral carboxylate‐assisted CMD approach (Scheme ) .…”

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

“…recently disclosed the enantioselective annulation of α‐arylidene pyrazolones 51 through a formal C( sp 3 )‐H activation. [ 42 ] The reaction proceeded well under mild conditions and afforded spiropyrazolones 53 with high yields and ee values (Scheme 12). The suggested mechanism for this transformation is depicted in Scheme 12.…”

Recent Advances in Catalytic Enantioselective Synthesis of Pyrazolones with a Tetrasubstituted Stereogenic Center at the 4-Position

“…In 2019, Waldmann, Antonchick, and co-workers used alkynes as reagents in enantioselective cycloaddition reactions of 1-arylethylidenepyrazolones (Scheme 49). 80 The regio-and enantioselective vinylogous addition of 1-arylethylidenepyrazolones to internal alkynes (symmetric and asymmetric) using a chiral Rh(III) complex as a catalyst gave spirocyclopentadiene-pyrazolones as only one regioisomer (>20:1 rr) in good to high yields and high enantioselectivities. Regarding the reaction scope, electron-withdrawing and electron-donating groups are tolerated in any of the three phenyl groups of the 1-arylethylidenepyrazolones.…”