Enantioselective Synthesis of 2,3,4,5‐Tetra(hydroxyalkyl)pyrrolidines through 1,3‐Dipolar Cycloadditions

• Published in: European journal of organic chemistry 2022-08, Vol.2022 (31), p.n/a
• Main Authors: Vardé, Mariana, Marino, Carla, Repetto, Evangelina, Varela, Oscar
• Format: Article
• Language: English
• Subjects: 1,3-Dipolar cycloaddition; Alanine; Aldehydes; Azomethine ylide; Configurations; Cycloaddition; Enantiomers; Enzyme inhibiton; Esters; Fungi; Glycine; Hydroxypyrrolidine; Imines; Rings (mathematics); Stereoselectivity; Sugar enone
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.202200589

1,3‐Dipolar cycloadditions were conducted starting from azomethine ylides and enantiomerically pure sugar‐derived dihydropyranones. The ylide intermediates were generated from imines obtained by condensation of glycine or L‐alanine esters and 2,2‐dimethoxyacetaldehyde. This aldehyde was employed as precursor of a dimethoxymethyl group attached to the pyrrolidine ring, instead of the usual aryl group derived from aromatic aldehydes. Under silver catalysis the cycloaddition was highly regio‐ and diastereoselective, affording good yields of the 2,5‐cis cycloadducts, with the endo configuration strongly prevailing. The enantioselectivity was controlled by the acetal stereocenter of the pyranone: the (S)‐isomer gave a pyrrolidine with a defined configuration for the four asymmetric ring carbons, while the (R)‐dihydropyranone gave the enantiomeric ring. A sequence of reactions applied to the cycloadducts derived from (S)‐enone afforded the target 2,3,4,5‐tetra(hydroxyalkyl)pyrrolidines. The enantiomers were obtained from cycloadducts synthesized from the (R)‐enone. The pyrrolidines were evaluated as inhibitors of the β‐galactofuranosidase from Penicillium fellutanum. 1,3‐Dipolar cycloadditions of azomethine ylides, prepared from 2,2‐dimethoxyacetaldehyde, and enantiomerically pure sugar‐derived dihydropyranones led to tetrasubstituted pyrrolidines. The cycloadditions were highly regio‐, diastereo‐ and enantioselective, with the endo approach strongly prevailing. The adducts were subjected to hydrolysis and reductions to afford the target 2,3,4,5‐tetrahydroxyalkylpyrrolidines. According to the (R) or (S) stereocenter of the enone, enantiomeric pyrrolidines were obtained.