Diastereodivergent and Enantioselective Access to Spiroepoxides via Organocatalytic Epoxidation of Unsaturated Pyrazolones

Abstract

Readily available chiral amine-thioureas are effective catalysts for the first diastereo- and enantioselective epoxidation of unsaturated pyrazolones. The trans- or cis-spiroepoxides are preferentially obtained in good yield and high to excellent enantioselectivity using an appropriate organocatalyst and tert-butyl hydroperoxide as the oxidant. The epoxidation appears applicable to highly challenging β,β'-substituted unsaturated pyrazolones, giving access to spiroepoxides bearing two vicinal quaternary stereocenters. The reaction represents a unique example of Weitz-Scheffer epoxidation, where the catalyst-controlled ring-closure step is usefully exploited to prepare both enantioenriched diastereomeric epoxides.

Asymmetric Addition and Cycloaddition Reactions with Ylidene‐Five‐Membered Heterocycles

“…The asymmetric Weitz−Scheffer epoxidation of 4‐arylidene‐pyrazolones using tert ‐butyl hydroperoxide as oxidant has been reported (Scheme 28). [42] Lattanzi and co‐workers developed this organocatalyzed reaction involving an oxa ‐Michael/ring closure sequence. Herein, the ratio of cis / trans epoxides is controlled by the ring closure step where the organocatalyst plays a critical role.…”

Enantioselective Construction of Multi-Nitrogen-Containing Spirocycles: Asymmetric [3+2] Annulation of 4-Isothiocyanato­pyrazolones with Azodicarboxylates

“…6 8 Although various elegant studies have been published for the synthesis of chiral spiropyrazolones containing a five- or six-membered ring, most of spiropyrazolone derivatives were limited to all-carbon spirocenters. Only a few examples for asymmetric synthesis of spiropyrazolone with 4-heteroatom attached to the spirocenter have been reported by Lattanzi, 9a Enders, 9b Jiang, 9c and Xu 9d groups. Very recently, 4-isothiocyanatopyrazolones as a powerful building block for the construction of 4-nitrogen attached spiropyrazolones have been developed by our group, and successfully applied to Mannich 10a and Michael cyclizations 10b c in an excellent stereoselective manner.…”

Catalytic Asymmetric Synthesis of Spiropyrazolones and their Application in Medicinal Chemistry

“…2 or Cat. 3 (Scheme a and Scheme b) . Alkenes 1 bearing electron‐donating or ‐withdrawing groups at the para and meta positions of the aromatic R 1 group, as well as 2‐naphthyl, heteroaromatic groups, and alkyl R 1 group (cyclohexyl), were tolerated to yield spiro‐epoxypyrazolones 5 with comparable stereocontrol, although alkenes 1 bearing ortho ‐substituted benzene ring decreases the enantioselectivity.…”

“…3 (Scheme 2a and Scheme 2b). [8] Alkenes 1 bearing electron-donating or -withdrawing groups at the para and meta positions of the aromatic R 1 group, as well as 2-naphthyl, heteroaromatic groups, and alkyl R 1 group (cyclohexyl), were tolerated to yield spiro-epoxypyrazolones 5 with comparable stereocontrol, although alkenes 1 bearing ortho-substituted benzene ring decreases the enantioselectivity. Moreover, spiroepoxides 7 bearing vicinal quaternary stereocenters were synthesized from the b,b'-substituted alkylidene pyrazolone 6 under optimized conditions as catalyzed by Cat.…”