title: Catalysis of 3-pyrrolidinecarboxylic acid and related pyrrolidine derivatives in enantioselective anti-Mannich-type reactions: importance of the 3-acid group on pyrrolidine for stereocontrol.
abstract: The development of enantioselective anti-selective Mannich-type reactions of aldehydes and ketones with imines catalyzed by 3-pyrrolidinecarboxylic acid and related pyrrolidine derivatives is reported in detail. Both (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid and (R)-3-pyrrolidinecarboxylic acid efficiently catalyzed the reactions of aldehydes with alpha-imino esters under mild conditions and afforded anti-Mannich products with high diastereo- and enantioselectivities (anti/syn up to 99:1, up to >99% ee). For the reactions of ketones with alpha-imino esters, (R)-3-pyrrolidinecarboxylic acid was an efficient catalyst (anti/syn up to >99:1, up to 99% ee). Evaluation of a series of pyrrolidine-based catalysts indicated that the acid group at the beta-position of the pyrrolidine ring of the catalyst played an important role in forwarding the carbon-carbon bond formation and in directing anti-selectivity and enantioselectivity.
authors.affiliation: The Skaggs Institute for Chemical Biology and the Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Haile
authors.initials: H
authors.lastname: Zhang
authors.forename: Susumu
authors.initials: S
authors.lastname: Mitsumori
authors.forename: Naoto
authors.initials: N
authors.lastname: Utsumi
authors.forename: Masanori
authors.initials: M
authors.lastname: Imai
authors.forename: Noemi
authors.initials: N
authors.lastname: Garcia-Delgado
authors.forename: Maria
authors.initials: M
authors.lastname: Mifsud
authors.forename: Klaus
authors.initials: K
authors.lastname: Albertshofer
authors.forename: Paul Ha-Yeon
authors.initials: PH
authors.lastname: Cheong
authors.forename: K N
authors.initials: KN
authors.lastname: Houk
authors.forename: Fujie
authors.initials: F
authors.lastname: Tanaka
authors.forename: Carlos F
authors.initials: CF
authors.lastname: Barbas
mesh_terms: D000447:Aldehydes / Q000737:chemistry*; D002384:Catalysis; D007097:Imines / Q000737:chemistry*; D007659:Ketones / Q000737:chemistry*; D015394:Molecular Structure; D011392:Proline / Q000031:analogs & derivatives* / Q000737:chemistry; D011759:Pyrrolidines / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: C526607:5-methyl-3-pyrrolidinecarboxylic acid; D000447:Aldehydes; D007097:Imines; D007659:Ketones; D011759:Pyrrolidines; D011392:Proline; C032519:pyrrolidine; C072401:beta-proline