The fluoroalkene motif as a surrogate of the amide bond: syntheses of AA-Ψ[(Z) and (E)-CFCH]-Pro pseudodipeptides and an Enalapril analogue

Synthesis of Monofluoroalkenes: A Leap Forward

“…Examples of this strategy are its utilization in the preparation of conformationally locked fluorinated bicyclic nucleosides 202 as well as fluoroalkene-based pseudopeptides. 6c, 203 With the goal of synthesizing both the E and Z isomers of rac-N-Cbz-Gly-Ψ[CF=C]-Pro-OH, Sano and co-workers optimized the olefination of 2-substituted cyclopentanones. For the Eselective olefination reaction, a cyclopentanone featuring an ortho ester in the 2-position was used in combination with triethyl 2-fluoro-2-phosphonoacetate and n-butyllithium (Scheme 200).…”

Recent progress in the racemic and enantioselective synthesis of monofluoroalkene-based dipeptide isosteres

“…Then, Pannecoucke’s group proposed a modified and more versatile approach where the monofluoroalkene 102 was synthesized by a HWE olefination of the chiral cyclopentanone 101 ( Scheme 20 ) [ 54 ]. The resulting ester was converted into the aldehyde and β-fluoroenimine 104 was obtained using Ellman’s conditions.…”

Synthesis of β-Fluoro-α,β-Unsaturated Amides from the Fragmentation of Morpholine 3,3,3-Trifluoropropanamide by Grignard Reagents

“…Fluoroalkenes have been used as surrogates for amide bonds in drug discovery, and, for example, Pannecoucke and co-workers created a fluoroalkene analogue of the antihypertensive agent, enalapril (see Figure ). Other recent examples of this strategy have been reported by Altman et al, Augustyns and co-workers, Welch and co-workers, Hollenstein and Leumann, and Fujii and co-workers . Most of these cases also demonstrated the application of innovative synthetic methods to create the requisite fluoroalkene. , …”

“…8 Most of these cases also demonstrated the application of innovative synthetic methods to create the requisite fluoroalkene. 9,10 Currently, there are general methods to synthesize α-fluoroα,β-unsaturated carbonyl compounds, 9,10 such as the Julia olefination, 11 the Peterson olefination, 12 the Horner−Wadsworth−Emmons reaction, 3 and a Reformatsky addition/ elimination process. 13 Unfortunately, fewer methods exist for the preparation of β-fluoro-α,β-unsaturated carbonyl com-pounds, and most are limited by low yields and poor stereoselectivities.…”

“…Currently, there are general methods to synthesize α-fluoro-α,β-unsaturated carbonyl compounds, , such as the Julia olefination, the Peterson olefination, the Horner–Wadsworth–Emmons reaction, and a Reformatsky addition/elimination process . Unfortunately, fewer methods exist for the preparation of β-fluoro-α,β-unsaturated carbonyl compounds, and most are limited by low yields and poor stereoselectivities. − Notable recent exceptions are the hydrofluorination of alkynes using gold catalysts that provide access to ( Z )-β-fluoro-α,β-unsaturated carbonyl compounds and the chromium-mediated reductive coupling of CBrF 2 -containing compounds with aldehydes to give ( E )-β-fluoro-α,β-unsaturated amides (Scheme ).…”