Practical Stereoselective Synthesis of C3‐Spirooxindole‐ and C2‐Spiropseudoindoxyl‐Pyrrolidines via Organocatalyzed Pictet‐Spengler Reaction/Oxidative Rearrangement Sequence

Abstract

A stereoselective synthetic route to chiral C3-spirooxindole-and C2-spiropseudoindoxyl-pyrrolidines was accomplished by an enantioselective organocatalyzed Pictet-Spengler reaction of tryptamines and isotryptamines followed by a diastereoselective oxidative rearrangement using eco-friendly oxidants (i. e., NaOCl • 5H 2 O and Oxone ® ). This sequential reaction enables rapid access to chiral C3-spirooxindole-and C2-spiropseudoindoxyl-pyrrolidines in a one-pot process. A Wnt signaling inhibitory assay of the prepared enantioenriched spiro compounds demonstrated that they exhibited moderate activities.

Screening for Generality in Asymmetric Catalysis

“…3A) is a venerable reaction with crucially important applications in laboratory and biological synthesis (27,28). The reaction has inspired intensive research efforts in search of asymmetric catalytic variants, and so far over a dozen distinct catalytic systems have been described (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43). Each study relied on optimization of catalyst and conditions around very limited numbers of model substrates, and resulted in the identification of highly enantioselective reactions.…”

“…Pictet-Spengler reactions can proceed via N-acyl-, N-protio-, and N-alkyl-iminium ion intermediates, and enantioselective catalytic variants have been identified for each of these manifolds (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43). We selected reactions between N-benzyl tryptamines and aldehydes as a particularly convenient platform to survey the substrate/catalyst landscape.…”

Organocatalyzed Asymmetric Pictet‐Spengler Reactions

“…Further extension of this methodology was achieved by a diastereoselective oxidative rearrangement of carbolines by sodium hypochlorite pentahydrate or oxone as the sole oxidant to produce structurally more complex C-3spirooxindole-pyrrolidines 257 (from tetrahydro-β-carbolines) and C-2-spiropseudoindoxyl-pyrrolidines 258 (from tetrahydroγ-carbolines) (Scheme 68). [69] In the same year, Zhou and co-workers also documented another C-3 functiolization of indole derivatives promoted by chiral phosphoric acid catalyst. In this methodology, 2-(1Hindolyl)anilines 264 were merged with isatins producing a complex molecular architecture 265 comprising of spirocyclic and tetraheterocyclic motifs featuring a spiroaza quaternary sterocenter.…”

“…Further extension of this methodology was achieved by a diastereoselective oxidative rearrangement of carbolines by sodium hypochlorite pentahydrate or oxone as the sole oxidant to produce structurally more complex C‐3‐spirooxindole‐pyrrolidines 257 (from tetrahydro‐ β ‐carbolines) and C‐2‐spiropseudoindoxyl‐pyrrolidines 258 (from tetrahydro‐ γ ‐carbolines) (Scheme 68). [69] …”

Enantioselective Pictet–Spengler Reaction of Acyclic α-Ketoesters Using Chiral Imidazoline-Phosphoric Acid Catalysts

“…One of the most efficient methods for the synthesis of chiral tetrahydro-β-carbolines is the asymmetric Pictet–Spengler reaction, which involves an acid-catalyzed imine formation of tryptamines with carbonyl compounds and asymmetric intramolecular aza-Friedel–Crafts reactions. Therefore, many enantioselective Pictet–Spengler reactions of tryptamines with aldehydes as carbonyl compounds using chiral organocatalysts and metal catalysts have been reported. However, enantioselective Pictet–Spengler reactions with ketones are rare.…”