Dipolarophile-Controlled Regioselective 1,3-Dipolar Cycloaddition: A Switchable Divergent Access to Functionalized N-Fused Pyrrolidinyl Spirooxindoles

Abstract

N-fused pyrrolidinyl spirooxindole belongs to a class of privileged heterocyclic scaffolds and is prevalent in natural alkaloids and synthetic pharmaceutical molecules. To realize the switchable synthesis of divergent N-fused pyrrolidinyl spirooxindoles for further biological activity evaluation via a substrate-controlled strategy, a chemically sustainable, catalysis-free, and dipolarophile-controlled three-component 1,3-dipolar cycloaddition of isatin-derived azomethine ylides with diverse dipolarophiles is described in this work. A total of 40 functionalized N-fused pyrrolidinyl spirooxindoles were synthesized in 76–95% yields with excellent diastereoselectivities (up to >99:1 dr). The scaffolds of these products can be well-controlled by employing different 1,4-enedione derivatives as dipolarophiles in EtOH at room temperature. This study provides an efficient strategy to afford a spectrum of natural-like and potentially bioactive N-fused pyrrolidinyl spirooxindoles.

Diastereoselective Three-Component 1,3-Dipolar Cycloaddition to Access Functionalized β-Tetrahydrocarboline- and Tetrahydroisoquinoline-Fused Spirooxindoles

“…Additionally, abundant of methodologies also have been developed to access functionalized spirooxindoles [32][33][34][35][36][37]. Herein, the multicomponent 1,3-dipolar cycloaddition has been proved to be one of the most efficient strategie [38,39], while limited on the use of α-amino acids [40][41][42] and benzylamines [43][44][45] as dipolarophiles. Accordingly, the development of efficient synthesis strategies for preparing polycyclic indoles with potential biological activity is still highly desirable.…”

Chemo-/Regio-Selective Synthesis of Novel Functionalized Spiro[pyrrolidine-2,3′-oxindoles] under Microwave Irradiation and Their Anticancer Activity

“…Therefore, considering all the facts, we designed a hybrid prototype ( Figure 2 ). Although there are only a few reports available in the literature on nitrostyrene-based spirooxindoles [ 68 , 69 , 70 , 71 , 72 ], and several types of spirooxindoles have also been highlighted, only a few of them emphasized their anticancer activity [ 73 , 74 , 75 , 76 , 77 , 78 , 79 ]. Herein, in pursuit of a new anticancer agent using our designed prototype, for the first time we report the synthesis and in vitro anticancer activities of twenty-three various nitrostyrene-based spirooxindole derivatives 4a – w against human lung (A549) and liver (HepG2) cancer cell lines along with immortalized normal lung (BEAS-2B) and liver (LO2) cell lines.…”

[3+2]-Cycloaddition of Nitrile Imines to Parabanic Acid Derivatives—An Approach to Novel Spiroimidazolidinediones

“…Nitrile imines are widely recognized for their high reactivity in 1,3-dipolar cycloaddition reactions, both in carbon-carbon multiple bonds and carbon-heteroatom bonds [ 1 ]. The reactions of nitrile imines with asymmetric dipolarophiles usually proceed regio- and chemoselectively [ 2 ]. The addition of nitrile imine to the C=C double bond results in the formation of a pyrazoline fragment, which is found in compounds possessing a broad spectrum of biological activities, such as anti-inflammatory [ 3 ], antiviral, antimicrobial [ 4 ], analgesic, immunosuppressive, antibacterial [ 5 ], anticancer [ 6 ], antidepressant, and neuroprotective [ 7 ] properties ( Figure 1 ).…”