Lin Hu

Herein we report a general catalytic asymmetric umpolung (n+1) (n = 4, 5) cyclization using bifunctional hydroxylamines as bis-electrophiles, affording five- and six-membered azaspirooxindoles in good yields with excellent enantioselectivities (up to 98% ee) under mild phase-transfer catalytic conditions. Mechanistic studies reveal cooperative halogen-bonding, together with ion-pairing interactions, between the catalyst and substrate as key to reactivity and stereocontrol. Such discovery will inspire the design of new bifunctional phase-transfer catalysts with halogen-bonding donors in the future.

We report that readily accessible N ‐haloalkyl hydroxylamines serve as bifunctional imine surrogates for novel (4 + 1) Mannich cyclizations with β ‐keto esters under mild phase‐transfer catalytic conditions. This method affords a series of cyclopentyl β ‐amino esters bearing adjacent quaternary and tertiary carbon centers in good yields. Notably, the diastereomeric products are separable by silica gel chromatography under achiral tetrabutylammonium bromide (TBAB) catalysis, enabling the streamlined synthesis of both pure trans ‐ and cis ‐derivatives in a single operation. Furthermore, by employing a chiral phase‐transfer catalyst, the reaction delivers the corresponding chiral products with high enantioselectivity and diastereoselectivity (up to 92% ee, >20:1 dr). Mechanistic studies reveal that the cyclization proceeds via a distinctive cascade involving C ‐alkylation, aza‐Kornblum–DeLaMare rearrangement, and ring‐closing Mannich reaction.

We report that readily accessible N ‐haloalkyl hydroxylamines serve as bifunctional imine surrogates for novel (4 + 1) Mannich cyclizations with β ‐keto esters under mild phase‐transfer catalytic conditions. This method affords a series of cyclopentyl β ‐amino esters bearing adjacent quaternary and tertiary carbon centers in good yields. Notably, the diastereomeric products are separable by silica gel chromatography under achiral tetrabutylammonium bromide (TBAB) catalysis, enabling the streamlined synthesis of both pure trans ‐ and cis ‐derivatives in a single operation. Furthermore, by employing a chiral phase‐transfer catalyst, the reaction delivers the corresponding chiral products with high enantioselectivity and diastereoselectivity (up to 92% ee, >20:1 dr). Mechanistic studies reveal that the cyclization proceeds via a distinctive cascade involving C ‐alkylation, aza‐Kornblum–DeLaMare rearrangement, and ring‐closing Mannich reaction.

Herein we describe a modular and umpolung (4 + 1) cyclization strategy for synthesizing functionalized 2,2-disubstituted pyrrolidines decorated with versatile alkene, alkyne, and carbonyl groups under mild basic conditions. The new approach employs readily accessible N-haloalkyl hydroxylamines as distinctive carbon-nitrogen bielectrophiles, enabling a tandem C-C alkylation and umpolung C-N ring-closing reaction with diverse carbonyl nucleophiles. Furthermore, a catalytic asymmetric variant of this reaction has been also achieved with moderate enantioselectivity (72% ee) under the chiral phase-transfer catalytic conditions.

A new annulation reaction of bifunctional peroxides allows the rapid construction of functionalized dihydrofurans with high yields and diastereoselectivities.

A complicated Michael addition–epoxidation–cyclization–Cannizzaro cascade of 2-formylallyl peroxides and β-keto esters has been developed under mild KOH basic conditions, which produces a pair of 2,2-bis(hydroxymethyl) and 2-carboxyl-2-hydroxymethyl dihydrofurans in good total yields. By switching to K₂CO₃ basic conditions, the reaction alternatively provides formyl epoxides in good yields via a Michael addition–epoxidation cascade. Detailed mechanistic investigations and the synthetic utility of the obtained products are also demonstrated.

The first iron‐catalyzed oxophosphorylation of styrene derivatives with dialkyl H‐phosphonates under open air conditions is developed, which generates a range of previously underexplored α‐substituted β‐ketophosphonates in 55~70% yields. Furthermore, a convenient one‐pot procedure by direct conversion of styrenes to α, β‐unsaturated ketones is also developed based on the new catalytic reactions, thus offering a protocol to access two classes of valuable products from simple starting materials.

A new annulation reaction between allylic/benzylic peroxides and ketones has been developed to provide the α-oxacyclic ketones in moderate yields under the KO^tBu basic conditions. Mechanistic studies reveal that these peroxides undergo the Kornblum-DeLaMare rearrangement to release the aldehyde intermediates and subsequently initiate the aldol/etherification tandem process to deliver the final products. Accordingly, these peroxides serving as "masked" enals have also been utilized to prepare the previously hard-to-achieve α-enal-tethered ketones in one step.

A general phase-transfer-catalyzed asymmetric (n+1) (n = 4 or 5) annulation reaction, featuring the direct coupling of simple oxindoles with alkyl dihalides that are allylic/benzylic and non-allylic/benzylic, has been developed to provide previously inaccessible cyclopentane- and cyclohexane-fused spirooxindole scaffolds with high yields and enantioselectivities (88–95% ee). Along with a broad scope and mild conditions, the new protocol also enables a two-step and gram-scale synthesis of the core of the drug ubrogepant.