Scaffold-Inspired Enantioselective Synthesis of Biologically Important Spiro[pyrrolidin-3,2′-oxindoles] with Structural Diversity through Catalytic Isatin-Derived 1,3-Dipolar Cycloadditions

• Published in: Chemistry : a European journal Vol. 18; no. 22; pp. 6885 - 6894
• Main Authors: Shi, Feng, Tao, Zhong-Lin, Luo, Shi-Wei, Tu, Shu-Jiang, Gong, Liu-Zhu
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 29-05-2012; WILEY‐VCH Verlag; Wiley Subscription Services, Inc
• Subjects: asymmetric synthesis; Asymmetry; Catalysis; Catalysts; Chemistry; Construction; Crystallography, X-Ray; Cyclization; Cycloaddition; Indoles - chemical synthesis; Indoles - chemistry; Isatin - chemistry; Ketones; Molecular Structure; multicomponent reactions; organocatalysis; Scaffolds; spiro compounds; Spiro Compounds - chemical synthesis; Spiro Compounds - chemistry; Stereoisomerism; Stereoselectivity
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201200358

Catalytic asymmetric construction of the biologically important spiro[pyrrolidin‐3,2′‐oxindole] scaffold with contiguous quaternary stereogenic centers in excellent stereoselectivities (up to >99:1 d.r., 98 % ee) has been established by using an organocatalytic 1,3‐dipolar cycloaddition of isatin‐based azomethine ylides. This protocol represents the first example of catalytic asymmetric 1,3‐dipolar cycloadditions involving azomethine ylides generated in situ from unsymmetrical cyclic ketones. In addition, theoretical calculations were performed on the transition state of the reaction to understand the stereochemistry. Preliminary bioassays with these spiro[pyrrolidin‐3,2′‐oxindole] revealed that several compounds showed moderate cytotoxicity to SW116 cells.
The organocatalytic approach: The first catalytic asymmetric construction of a spiro[pyrrolidin‐3,2′‐oxindole] scaffold with contiguous quaternary stereogenic centers in excellent stereoselectivities has been established (see scheme). This protocol represents the first example of catalytic asymmetric 1,3‐dipolar cycloadditions involving azomethine ylides generated in situ from unsymmetrical cyclic ketones.