Asymmetric Michael/Cyclization Cascade Reaction of 3-Isothiocyanato Oxindoles and 3-Nitroindoles with Amino-Thiocarbamate Catalysts: Enantioselective Synthesis of Polycyclic Spirooxindoles

Abstract

An unprecedented organocatalytic asymmetric Michael/cyclization cascade reaction of 3-isothiocyanato oxindoles and 3-nitroindoles has been disclosed. A wide range of enantioenriched polycyclic spirooxindoles, containing three contiguous chiral centers with two of them having quaternary stereocenters, could be smoothly obtained with satisfactory results (up to 99% yield, >99:1 dr, and 96% ee). This method is very promising because the reaction is scalable, and the versatile transformations of the products into other spirocyclic oxindoles are also feasible. E xploring efficient strategies for the construction heterocyclic compounds with rich structural diversity and complexity is a continuing challenge in synthetic chemistry. The spirooxindole skeletons in particular have captured tremendous attention among synthetic and medicinal chemists, due to their prevalence in a broad range of natural and unnatural biologically active products, as well as pharmaceutically important compounds. 1 Over the past several years, we have witnessed rapid progress in the development of creative methodologies for the generation of diverse spirooxindole molecules. 2 Specifically, numerous multifunctional polycyclic spirooxindoles, featuring structural complexity and well-defined three-dimensional architecture, have been demonstrated to correlate with a wide spectrum of biological properties and pharmacological activities (Figure 1). 3 Various synthetic methods for producing functionalized spirooxindole derivatives containing a polycyclic skeleton in asymmetric catalysis have been reported. 4 Despite the substantial advances made thus far, taking into account the importance of the natural-product-like spirocyclic oxindoles in pharmaceutical science and as promising candidates for drug discovery, the development of novel approaches for the efficient synthesis of polyfunctionalized spirooxindoles is in demand.Since we initially employed 3-isothiocyanato oxindoles as nucleophiles in catalytic asymmetric synthesis, 5 many studies have documented the stereoselective construction of structurally diverse spirocyclic oxindoles using 3-isothiocyanato oxindoles as powerful and versatile precursors via cascade reaction. 6,7 Notably, 3-isothiocyanato oxindoles can easily undergo Michael/cyclization cascade reactions with some electrondeficient alkenes. 6 In addition, the indoles, bearing two electron-withdrawing substitutions at the N1-and C3-positon, have been recognized as a class of electron-deficient alkene reagents. 8 These indoles possess special reaction features; that is, they are readily attacked by nucleophiles at the C2-position and sequentially react with electrophiles at the C3-position (Scheme 1A). We noticed that 3-nitroindoles, 8 a class of potentially promising electrophilic alkenes, had barely been explored in the field of catalytic asymmetric synthesis. 9 In this context, as our continuous interest in developing new synthetic methods for the

Construction of Spirooxindole Skeleton Through Intramolecular Dieckmann Cyclization

“…Moreover, Carreira et al have developed a reliable methodology to access the pyrrolidinyl-spirooxindole structure via a MgI 2 -mediated ring-expansion reaction of a spiro[cyclopropane-1,3′′′oxindole] with an aldimine [18]. Other synthetic strategies of the spiro-pyrrolidone-3,3′-oxoindole frameworks also include Michael cyclization reaction [19–23] and C-selective SnAr reactions [24–26]. Besides, in our previous study, a completely different method has been achieved for the construction of the tetracyclic 3-spirooxindole through a transition-metal-free intramolecular cross-dehydrogenative coupling of pyridinium [27].…”

Organocatalytic asymmetric Henry reaction of 1H-pyrrole-2,3-diones with bifunctional amine-thiourea catalysts bearing multiple hydrogen-bond donors

“…Recently, our group developed a chiral bifunctional multiple hydrogen-bond amine-thiourea-catalyzed Michael reaction of acetyl phosphonates with nitroolefins, giving a series of β-substituted nitro compounds with excellent stereoselectivity [34]. Therefore, as part of our research program aimed at establishing new methods for the construction of quaternary stereocenters [35–37], we envisioned that the Henry reaction of nitroalkanes with 1 H -pyrrole-2,3-diones should take place with a chiral bifunctional amine-thiourea catalyst, leading to 3-hydroxy-3-nitromethyl-1 H -pyrrol-2(3 H )-ones bearing quaternary stereocenters (Scheme 1) [14]. Notably, this work represents the first example of 1 H -pyrrole-2,3-diones used as Henry acceptors for the asymmetric reaction.…”

Dearomatization of 3‐Nitroindoles with Highly γ‐Functionalized Allenoates in Formal (3+2) Cycloadditions

“…[4] Nitroarenes can also react in tandem (4 + 2)/(3 + 2) processes and in this case the intermediate nitronate is trappedi nasubsequent (3 + 2) cycloaddition. [5] Concerted or formal (3 + 2) reactions on nitro aromatic compounds have also been reported lately, mainlyo n3 -nitroindoles.T hose involve azomethine ylides, [6] azomethine imines, [7] trimethylenemethanes, [8] vinyl-cyclopropanes, [9] -aziridines [10] or -epoxides [11] under palladium catalysis, or isothiocyanatoo xindoles and thiol derivatives [12] (Figure 1).…”

“…Since these interactions can vary al ot during the cycloaddition process, both dipole configurations were consideredi n the calculations. Thus, combining the a/g approaches with the diastereomeric arrangements a/a' and g/g' leads to the computations of eight differentp athways ( Table 1, entries [5][6][7][8][9][10][11][12]. [26] In this case, the cis/trans diastereomers for both the a and g isomersa re possibly formed depending on the approach.…”