title: Electrophilic fluorination of pyroglutamic acid derivatives: application of substrate-dependent reactivity and diastereoselectivity to the synthesis of optically active 4-fluoroglutamic acids.
abstract: Electrophilic fluorination of enantiomerically pure 2-pyrrolidinones (4) derived from (L)-glutamic acid has been investigated as a method for the synthesis of single stereoisomers of 4-fluorinated glutamic acids. Reaction of the lactam enolate derived from 9 with NFSi results in a completely diastereoselective monofluorination reaction to yield the monocyclic trans-substituted alpha-fluoro lactam product 21. Unfortunately, a decreased kinetic acidity in 21 and other structurally related monofluorinated products renders them resistant to a second fluorination. In contrast, the bicyclic lactam 12 is readily difluorinated under the standard conditions described to yield the alpha,alpha-difluoro lactam 24. The difference in reactivity between the two types of related lactams is attributed mainly to the presence or lack of a steric interaction between the base used for deprotonation and the protecting group present in the pyrrolidinone substrates. This conclusion was reached based on analysis of the X-ray crystal structure of 21, molecular modeling, and experimental evidence. The key intermediates 21 and 24 are converted to (2S,4R)-4-fluoroglutamic acid and (2S)-4,4-difluoroglutamic acid, respectively.
authors.affiliation: Department of Chemistry, The University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: D W
authors.initials: DW
authors.lastname: Konas
authors.forename: J K
authors.initials: JK
authors.lastname: Coward
mesh_terms: D002855:Chromatography, Thin Layer; D005461:Fluorine; D005971:Glutamates / Q000138:chemical synthesis*; D007202:Indicators and Reagents; D007769:Lactams / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D011761:Pyrrolidonecarboxylic Acid / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D005971:Glutamates; D007202:Indicators and Reagents; D007769:Lactams; C038473:4-fluoroglutamic acid; D005461:Fluorine; D011761:Pyrrolidonecarboxylic Acid