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

Abstract

Monofluoroalkenes are fluorinated motifs that can be used to replace amide bonds. In order to be incorporated into peptides, it is normally necessary to first synthesize a dipeptide where the amide bond has been replaced with a monofluoroalkene. In that context, this review will present the racemic and enantioselective synthesis of monofluoroalkene-based dipeptide isosteres described since 2007. Some applications of those compounds will also be presented.

Keywords: dipeptide isosteres; monofluoroalkene-based amide bonds; monofluoroalkenes; peptides; synthesis.

Figure 1

Selected amide bond isosteres.

Figure 2

Monofluoroalkene as an amide bond isostere.

Scheme 1

Synthesis of Cbz-Gly-ψ[(Z)-CF=CH]-Gly using a HWE olefination by Sano and co-workers.

Scheme 2

Synthesis of Phth-Gly-ψ[CF=CH]-Gly using the Julia–Kocienski olefination by Lequeux and co-workers.

Scheme 3

Synthesis of Boc-Nva-ψ[(Z)-CF=CH]-Gly by Taguchi and co-workers.

Figure 3

Mutant tripeptide containing two different peptide bond isosteres.

Scheme 4

Chromium-mediated synthesis of Boc-Ser(PMB)-ψ[(Z)-CF=CH]-Gly-OMe by Konno and co-workers.

Scheme 5

Synthesis of Cbz-Gly-ψ[(E)-CF=C]-Pro by Sano and co-workers.

Scheme 6

Synthesis of Cbz-Gly-ψ[(Z)-CF=C]-Pro by Sano and co-workers.

Scheme 7

Stereoselective synthesis of Fmoc-Gly-ψ[(Z)-CF=CH]-Phe by Pannecoucke and co-workers.

Scheme 8

Ring-closure metathesis to prepare Gly-ψ[(E)-CF=CH]-Phg by Couve-Bonnaire and co-workers.

Scheme 9

Stereoselective synthesis of Fmoc-Gly-ψ[(Z)-CF=CH]-Phe by Dory and co-workers.

Scheme 10

Diastereoselective addition of Grignard reagents to sulfinylamines derived from α-fluoroenals by Pannecoucke and co-workers.

Scheme 11

NHC-mediated synthesis of monofluoroalkenes by Otaka and co-workers.

Scheme 12

Stereoselective synthesis of Boc-Tyr-ψ[(Z)-CF=CH]-Gly by Altman and co-workers.

Scheme 13

Synthesis of the tripeptide Boc-Asp(OBn)-Pro-ψ[(Z)-CF=CH)-Val-CH₂OH by Miller and co-workers.

Scheme 14

Copper-catalyzed synthesis of monofluoralkenes by Taguchi and co-workers.

Scheme 15

One-pot intramolecular redox reaction to access amide-type isosteres by Otaka and co-workers.

Scheme 16

Copper-mediated reduction, transmetalation and asymmetric alkylation by Fujii and co-workers.

Scheme 17

Synthesis of (E)-monofluoroalkene-based dipeptide isostere by Fujii and co-workers.

Scheme 18

Diastereoselective synthesis of MeOCO-Val-ψ[(Z)-CF=C]-Pro isostere by Chang and co-workers.

Scheme 19

Asymmetric synthesis of Fmoc-Ala-ψ[(Z)-CF=C]-Pro by Pannecoucke and co-workers.

Scheme 20

Synthesis of Fmoc-Val-ψ[(E)-CF=C]-Pro by Pannecoucke and co-workers.

Figure 4

BMS-790052 and its fluorinated analogue.

Figure 5

Bioactivities of pentapeptide analogues based on the relative maximum agonistic activity at 10 nM of the compound to 1 μM kisspeptin-10 (%). 100% = maximum agonistic activity at 1 μm kisspeptin-10.

Figure 6

Structures and affinities of the Leu-enkephalin and its fluorinated analogue. The affinity towards DOPr was measured by competitive binding assays.

Figure 7

Activation of the opioid receptor DOPr by Leu-enkephaline and a fluorinated analogue.