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Significant progress has been made in asymmetric synthesis through the use of transition metal catalysts combined with Lewis bases. However, the use of a dual catalytic system involving 4-aminopyridine and transition metal has received little attention. Here we show a metal/Lewis base relay catalytic system featuring silver acetate and a modified chiral pyrrolidinopyridine (PPY). It was successfully applied in the cycloisomerization/(2 + 3) cycloaddition reaction of enynamides. Bispirocyclopentene pyrazolone products could be efficiently synthesized in a stereoselective and economical manner (up to >19:1 dr, 99.5:0.5 er). Transformations of the product could access stereodivergent diastereoisomers and densely functionalized polycyclic derivatives. Mechanistic studies illustrated the relay catalytic model and the origin of the uncommon chemoselectivity. In subsequent bioassays, the products containing a privileged drug-like scaffold exhibited isoform-selective phosphodiesterase 1 (PDE1) inhibitory activity in vitro. The optimal lead compound displayed a good therapeutic effect for ameliorating pulmonary fibrosis via inhibiting PDE1 in vivo. Cycloisomerization/cyclization cascade reactions for yne-enones and enyamides can be used to construct diverse fused furans, however, the corresponding (2 + n) reaction remains challenging. Here, the authors report cycloisomerization/(2 + 3) cycloadditions catalyzed by silver acetate and a modified chiral pyrrolidinopyridine relay system, to generate bispirocyclopentene pyrazolone products with isoform-selective phosphodiesterase 1 (PDE1) inhibitory activity. [ABSTRACT FROM AUTHOR]

Carbon bisnucleophiles are important building blocks in organic synthesis and have widespread applications in the construction of carbocyclic compounds. Among them, 1,2‐carbon bisnucleophile has been much less explored. Herein, we developed a [2+3] annulation of 2‐(2‐oxoindolin‐3‐yl)malononitrile with 2‐nitroallylic acetates, where 2‐(2‐oxoindolin‐3‐yl)malononitrile served as a new type of 1,2‐carbon bisnucleophile. Remarkably, the annulation reaction exhibits exclusive chemo‐ and regioselectivity. A Michael addition/SN2 mechanism was proposed to avoid the "anti‐Baldwin" cyclization. This stereoselective strategy provides a facile synthetic route for a new series of spirocyclopentane oxindole derivatives containing three stereogenic centers. [ABSTRACT FROM AUTHOR]

A highly regio-, diastereo- and enantioselective formal (3+2) cycloaddition reaction of nitrone ylides from isatins and α,β-unsaturated aldehydes was developed via iminium catalysis in the presence of an additional base, furnishing a spectrum of 1′-hydroxy-3,2′-pyrrolidinylspirooxindole frameworks. Interestingly, the regioselectivity could be finely switched in the reactions between nitrone ylides and crotonaldehyde by adding catalytic amounts of lithium perchlorate and copper(II) bromide. [ABSTRACT FROM AUTHOR]

Regulating both the chemo- and diastereoselectivity, divergently, of a reaction is highly attractive but extremely challenging. Presented herein is a catalyst-controlled switch in the chemo- and diastereodivergent annulation reactions of Morita-Baylis-Hillman carbonates, derived from isatins and 2-alkylidene-1 H-indene-1,3(2 H)-diones, in exclusive α-regioselectivity. α-Isocupreine efficiently catalyzed [2+1] reactions to access cyclopropane derivatives, and the diastereodivergent [3+2] annulations were accomplished by employing either a chiral phosphine or a DMAP-type molecule. All reactions exhibited excellent chemoselectivities, and good to remarkable stereoselectivities were furnished, thus leading to a collection of compounds with skeletal and stereogenic diversity. Moreover, DFT computational calculations elucidated the catalyst-based switch in mechanism. [ABSTRACT FROM AUTHOR]

• Access to halogenated contiguous quaternary carbon stereocenters (CQCS). • Halogenated CQCS and CF 3 group were introduced into spiro[pyrrolidin-3,2′-oxindoles]. • High stereoselectivity and high efficiency. • The transformation of the products discloses potential use as covalent inhibitors. The highly stereoselective synthesis of pyrrolidine-fused spirooxindole derivatives bearing a carbon-halogen bond and contiguous quaternary carbon stereocenters was achieved via a [3 + 2] cycloaddition reaction. This method provided facile access to a collection of enantiomerically pure spiro[pyrrolidin-3,2′-oxindoles] containing halogenated contiguous quaternary carbon stereocenters in good to high yields (48–84%) and excellent stereoselectivity (up to >20:1 dr and >99% ee). The halogen-containing products can be stereoselectively transformed into sulfurated derivatives via nucleophilic substitution (S N 2) reactions, indicating that they may serve as candidates in the development of covalent inhibitors with potential biological activity. [ABSTRACT FROM AUTHOR]