| Abstract
| - Electrophilic fluorination of enantiomerically pure 2-pyrrolidinones (4) derived from (l)-glutamicacid has been investigated as a method for the synthesis of single stereoisomers of 4-fluorinatedglutamic acids. Reaction of the lactam enolate derived from 9 with NFSi results in a completelydiastereoselective monofluorination reaction to yield the monocyclic trans-substituted α-fluoro lactamproduct 21. Unfortunately, a decreased kinetic acidity in 21 and other structurally relatedmonofluorinated products renders them resistant to a second fluorination. In contrast, the bicycliclactam 12 is readily difluorinated under the standard conditions described to yield the α,α-difluorolactam 24. The difference in reactivity between the two types of related lactams is attributed mainlyto the presence or lack of a steric interaction between the base used for deprotonation and theprotecting group present in the pyrrolidinone substrates. This conclusion was reached based onanalysis of the X-ray crystal structure of 21, molecular modeling, and experimental evidence. Thekey intermediates 21 and 24 are converted to (2S,4R)-4-fluoroglutamic acid and (2S)-4,4-difluoroglutamic acid, respectively.
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