Chiral N,O-Ligand/[Cu(OAc)2]-Catalyzed Asymmetric Construction of 4-Aminopyrrolidine Derivatives by 1,3-Dipolar Cycloaddition of Azomethine Ylides with α-Phthalimidoacrylates

• Published in: Chemistry : a European journal Vol. 21; no. 29; pp. 10457 - 10465
• Main Authors: Wang, Zheng, Yu, Xingxin, Tian, Bo-Xue, Payne, Daniel T., Yang, Wu-Lin, Liu, Yang-Zi, Fossey, John S., Deng, Wei-Ping
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 13.07.2015; WILEY‐VCH Verlag
• Subjects: asymmetric synthesis; copper; cycloaddition; density functional calculations; ligands; density functional calculations; ligands; copper; asymmetric synthesis; cycloaddition
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201500966

A protocol to access useful 4‐aminopyrrolidine‐2,4‐dicarboxylate derivatives has been developed. A variety of chiral N,O‐ligands derived from 2,3‐dihydroimidazo[1,2‐a]pyridine motifs have been evaluated in the asymmetric 1,3‐dipolar cycloaddition of azomethine ylides to α‐phthalimidoacrylates. Reactions catalyzed by copper in combination with ligand 7‐Cl‐DHIPOH provided the highest level of stereoselectivity for the 1,3‐dipolar cycloaddition reaction. The reaction tolerates both β‐substituted and β‐unsubstituted α‐phthalimidoacrylate as dipolarophiles, affording the corresponding quaternary 4‐aminopyrrolidine cycloadducts with excellent diastereo‐ (>98:2 d.r.) and enantioselectivities (up to 97 % ee). Removal of the phthalimido protecting group can be accomplished by a simple NaBH4 reduction. Theoretical calculations employing DFT methods show this cycloaddition reaction is likely to proceed through a stepwise mechanism and the stereochemistry was also theoretically rationalized. N,O means yes: Catalytic asymmetric 1,3‐dipolar cycloaddition of azomethine ylides to α‐phthalimidoacrylates catalyzed by a new chiral N,O‐ligand/[Cu(OAc)2] system has been developed. The reaction tolerates both β‐substituted and β‐unsubstituted α‐phthalimidoacrylate as dipolarophiles. Theoretical calculations show this cycloaddition reaction is likely to proceed through a stepwise mechanism.