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.

Advances in Exploring Cyclopentadienyl (Cp) Rhodium Catalysts Featuring Diastereotopic or Enantiotopic Cp Faces for Asymmetric C–H Activation

“…In 2019 Antonchick, Waldmann, and co-workers reported a JasCpRh-catalyzed [3+2] spiroannulation via formal C(sp 3 )–H activation (Scheme 6 ). 23 The reaction of α-arylidene pyrazolones 19 with alkynes 20 proceeded well under mild reaction conditions and provided spiropyrazolones 22 in moderate to excellent yields and enantioselectivities (32–90% yield and 34–97% ee).…”

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 ) .…”

Absolute Configurations of Synthetic Molecular Scaffolds from Vibrational CD Spectroscopy

“…66 The all-carbon quaternary βstereocenter of γ-butyrolactones of the type of 32 were enantioselectively prepared by a tandem aldol/lactonization sequence in presence of a cinchona alkaloid-derived organocatalyst. 67 Further examples are propellane 34 (which may be considered axially chiral as well), 68 the building block for α v β 6 integrin inhibitors 35, 69 the products of the anodic oxidation of 2,4-dimethylphenol such as 36, 70 the bioactive spiropyrazolone derivatives 37, 71 and the lactone 38. 72 Stoltz and co-workers investigated the enantioselective Pd-catalyzed allylic alkylation yielding dialkylated N-heterocycles such as 74 are interesting examples from a field of asymmetric synthesis, which takes advantage of the concept of memory of chirality (MOC).…”