The First Enantioselective Organocatalytic Synthesis of 3‐Spiro‐α‐Alkylidene‐γ‐Butyrolactone Oxindoles

Abstract

A new and flexible methodology catalyzed by bifunctional chiral thioureas has been developed to react β-nitro oxindoles 1 with aldehydes. This approach allowed us to achieve the first enantioselective organocatalytic synthesis of 3-spiro-α-alkylidene-γ-butyrolactone oxindoles 3. We examined the scope of the two starting materials and, varying the structure of the β-nitro oxindole 1, intriguing new products, derived from unexpected transformations, have been stereoselectively obtained. The aim of this study was to merge two potentially bioactive structural motifs: the spirooxindole substructure and the α-alkylidene-γ-butyrolactone moiety. A preliminary NMR study on the ability to reversibly trap 2-aminoethanethiol gave us promising results.

Asymmetric Aldol Reaction with Formaldehyde: a Challenging Process

“…Very recently, Quintavalla et al . reported an aldol/lactonization/elimination domino sequence catalysed by bifunctional thioureas paving the way for the first enantioselective synthesis of 3‐spiro‐α‐alkylidene‐γ‐butyrolactones oxindoles 59 , products which have two potentially bioactive structural motifs: the spirofused oxindole and the α‐alkylidene‐γ‐butyrolactone moieties (Scheme ) 66…”

Rhodium‐Catalyzed [5+1]‐Cycloaddition Reactions to Spiro‐Benzo[e][1,3]Oxazineindoline Imines

“…The synthesis of spirocyclicindolines from readily available indolin‐2‐one derivatives features a most straightforward avenue toward the spiroindoline substructures which bearing a quaternary carbon center at the C3 position. To date, various 1,3‐dipolar [3+2]‐cycloaddition reactions of 3‐alkyloxindoles, 3‐alkenyloxindoles, 3‐hydroxyloxindoles, 3‐aminooxindoles, or 3‐spiroepoxyoxindoles were utilized as starting materials to give access to spiro[pyrrolidine‐2,3′‐oxindole]s. In 2016, Enders group developed N ‐heterocyclic carbene (NHC) catalyzed [3+4]‐cycloaddition reactions of isatin‐derived enals to synthesize spirobenzazepinones, spiro‐1,2‐diazepinones and spiro‐1,2‐oxazepinones in good yield . Soon after, Tanaka et al reported organocatalytic enantioselective Michael‐Henry cascade reactions to construct spirooxindole polyheterocycles …”

Enantioselective Synthesis of 2‐Oxindole Spirofused Lactones and Lactams by Heck/Carbonylative Cylization Sequences: Method Development and Applications

“…In 2014, Liang and Xu developed a novel approach to chiral spirooxindole δ‐lactones through bifunctional thiourea catalyzed [5+1] annulation of oxindoles with ester‐linked bisenones (Scheme a) . An enantioselective synthesis of spirooxindole alkylidene‐γ‐lactones was successfully developed by Quintavalla and co‐workers through organocatalytic aldol reaction of C3‐alkylated oxindoles with aldehydes (Scheme b) . The first asymmetric synthesis of spirooxindole γ‐lactams was accessed by an oxoindolin‐3‐ylidene involving a four‐component reaction promoted by a recyclable fluorous bifunctional cinchona alkaloid/thiourea organocatalyst (Scheme c) .…”