Synthesis of difluorinated β- and γ-amino acids: Investigation of a challenging deoxyfluorination reaction

Sequential Deoxyfluorination Approach for the Synthesis of Protected α,β,γ-Trifluoro-δ-amino Acids

“…This concept has been applied to optimize the properties of a variety of organofluorine molecules in which conformation influences function, such as peptides, organocatalysts, liquid crystals, and bioactive small molecules . For example, we have synthesized α,β-difluoro-γ-aminobutyric acids ( 4 , Figure ); the different stereoisomers of 4 have different preferred conformations, and this has led to applications of 4a / b as subtype-selective GABA receptor ligands and as components of shape-controlled peptides …”

“…We reasoned that the trifluoro moiety of 5 could potentially be created via a sequential nucleophilic deoxyfluorination approach (Figure ), based on methods developed by O’Hagan and co-workers for the synthesis of other multivicinal fluoroalkane systems in which the fluoroalkyl moieties are flanked by alkyl, arylalkyl, or tosylate groups. , Thus, an epoxy alcohol ( 7 ) could be subjected to deoxyfluorination, followed by epoxide opening with fluoride, followed by deoxyfluorination of the newly formed alcohol group, to deliver the required vicinal trifluoro moiety ( 6 ). Meanwhile, we reasoned that the amino group of 5 should be protected throughout, and that an aryl group could serve as a latent carboxylic acid until the end of the synthesis. ,, Finally, variation of the stereochemistry of 7 should allow different isomers of 5 to be created.…”

“…The regioisomers of 12 were inseparable, but this was inconsequential because when both compounds were subsequently treated as a mixture with neat DeoxoFluor, they converged to deliver the desired anti,syn trifluoro product 13 in good yield. The aryl nitro group played another important role during the conversion of 12 into 13 : it suppressed neighboring group participation of the aryl group, a process which has caused undesired 1,2 aryl migration in related homobenzylic deoxyfluorination reactions with systems lacking a nitro group. , …”

Homologated amino acids with three vicinal fluorines positioned along the backbone: development of a stereoselective synthesis

“…A similar problem was encountered in the synthesis of α,β-difluorinated-γ-amino acids (e.g., 5 , Fig. 1 ), which was being investigated in parallel [ 5 – 6 ].…”

Diastereoselective Synthesis and Conformational Analysis of (2R)- and (2S)-Fluorostatines: An Approach Based on Organocatalytic Fluorination of a Chiral Aldehyde

“…Another important effect of fluorine is that it can alter the molecular conformation though interaction of the polar C–F bond with neighboring functional groups . Such effects can be exploited to optimize the potency of bioactive molecules such as amino acids by preorganizing them into the correct geometry. , For example, we recently synthesized α,β-difluoro-γ-amino acids and their homologated analogues α,β,γ-trifluoro-δ-amino acids; different stereoisomers of the former possess different preferred conformations and thus lead to very different responses at GABA receptors . Further application showed that they can successfully affect the overall shape of both linear and cyclic peptides.…”