Fluorinated phenylalanines: synthesis and pharmaceutical applications

Abstract

Recent advances in the chemistry of peptides containing fluorinated phenylalanines (Phe) represents a hot topic in drug research over the last few decades. ᴅ- or ʟ-fluorinated phenylalanines have had considerable industrial and pharmaceutical applications and they have been expanded also to play an important role as potential enzyme inhibitors as well as therapeutic agents and topography imaging of tumor ecosystems using PET. Incorporation of fluorinated aromatic amino acids into proteins increases their catabolic stability especially in therapeutic proteins and peptide-based vaccines. This review seeks to summarize the different synthetic approaches in the literature to prepare ᴅ- or ʟ-fluorinated phenylalanines and their pharmaceutical applications with a focus on published synthetic methods that introduce fluorine into the phenyl, the β-carbon or the α-carbon of ᴅ-or ʟ-phenylalanines.

Keywords: PET; fluorinated phenylalanines; pharmaceuticals application; α-fluorophenylalanine; β- and β,β-difluorophenylalanine.

Figure 1

Categories I–V of fluorinated phenylalanines.

Scheme 1

Synthesis of fluorinated phenylalanines via Jackson’s method.

Scheme 2

Synthesis of all-cis-tetrafluorocyclohexylphenylalanines.

Scheme 3

Synthesis of ʟ-4-[sulfono(difluoromethyl)]phenylalanine (nPt: neopentyl, TCE: trichloroethyl).

Scheme 4

Synthesis of ʟ-4-[sulfono(difluoromethyl)]phenylalanine derivatives 17.

Scheme 5

Synthesis of fluorinated Phe analogues from Cbz-protected aminomalonates.

Scheme 6

Synthesis of tetrafluorophenylalanine analogues via the 3-methyl-4-imidazolidinone auxiliary 25.

Scheme 7

Synthesis of tetrafluoro-Phe derivatives via chiral auxiliary 31.

Scheme 8

Synthesis of 2,5-difluoro-Phe and 2,4,5-trifluoro-Phe via Schöllkopf reagent 34.

Scheme 9

Synthesis of 2-fluoro- and 2,6-difluoro Fmoc-Phe derivatives starting from chiral auxiliary 39.

Scheme 10

Synthesis of 2-[¹⁸F]FPhe via chiral auxiliary 43.

Scheme 11

Synthesis of FPhe 49a via photooxidative cyanation.

Scheme 12

Synthesis of FPhe derivatives via Erlenmeyer azalactone synthesis.

Scheme 13

Synthesis of (R)- and (S)-2,5-difluoro Phe via the azalactone method.

Scheme 14

Synthesis of 3-bromo-4-fluoro-(S)-Phe (65).

Scheme 15

Synthesis of [¹⁸F]FPhe via radiofluorination of phenylalanine with [¹⁸F]F₂ or [¹⁸F]AcOF.

Scheme 16

Synthesis of 4-borono-2-[¹⁸F]FPhe.

Scheme 17

Synthesis of protected 4-[¹⁸F]FPhe via arylstannane derivatives.

Scheme 18

Synthesis of FPhe derivatives via intermediate imine formation.

Scheme 19

Synthesis of FPhe derivatives via Knoevenagel condensation.

Scheme 20

Synthesis of FPhe derivatives 88a,b from aspartic acid derivatives.

Scheme 21

Synthesis of 2-(2-fluoroethyl)phenylalanine derivatives 93 and 95.

Scheme 22

Synthesis of FPhe derivatives via Zn²⁺ complexes.

Scheme 23

Synthesis of FPhe derivatives via Ni²⁺ complexes.

Scheme 24

Synthesis of 3,4,5-trifluorophenylalanine hydrochloride (109).

Scheme 25

Synthesis of FPhe derivatives via phenylalanine aminomutase (PAM).

Scheme 26

Synthesis of (R)-2,5-difluorophenylalanine 115.

Scheme 27

Synthesis of β-fluorophenylalanine via 2-amino-1,3-diol derivatives.

Scheme 28

Synthesis of β-fluorophenylalanine derivatives via the oxazolidinone chiral auxiliary 122.

Scheme 29

Synthesis of β-fluorophenylalanine from pyruvate hemiketal 130.

Scheme 30

Synthesis of β-fluorophenylalanine (136) via fluorination of β-hydroxyphenylalanine (137).

Scheme 31

Synthesis of β-fluorophenylalanine from aziridine derivatives.

Scheme 32

Synthesis of β-fluorophenylalanine 136 via direct fluorination of pyruvate esters.

Scheme 33

Synthesis of β-fluorophenylalanine via fluorination of ethyl 3-phenylpyruvate enol using DAST.

Scheme 34

Synthesis of β-fluorophenylalanine derivatives using photosensitizer TCB.

Scheme 35

Synthesis of β-fluorophenylalanine derivatives using Selectflour and dibenzosuberenone.

Scheme 36

Synthesis of protected β-fluorophenylalanine via aziridinium intermediate 150.

Scheme 37

Synthesis of β-fluorophenylalanine derivatives via fluorination of α-hydroxy-β-aminophenylalanine derivatives 152.

Scheme 38

Synthesis of β-fluorophenylalanine derivatives from α- or β-hydroxy esters 152a and 155.

Scheme 39

Synthesis of a series of β-fluoro-Phe derivatives via Pd-catalyzed direct fluorination of β-methylene C(sp³)–H bonds in Phe substrates functionalized with the PIP auxiliary group.

Scheme 40

Synthesis of series of β-fluorinated Phe derivatives using quinoline-based ligand 162 in the Pd-catalyzed direct fluorination of β-methylene C(sp³)–H bonds.

Scheme 41

Synthesis of β,β-difluorophenylalanine derivatives from 2,2-difluoroacetaldehyde derivatives 164a,b.

Scheme 42

Synthesis of β,β-difluorophenylalanine derivatives via an imine chiral auxiliary.

Scheme 43

Synthesis of α-fluorophenylalanine derivatives via direct fluorination of protected Phe 174.

Figure 2

Structures of PET radiotracers of ¹⁸FPhe derivatives.

Figure 3

Structures of melfufen (179) and melphalan (180) anticancer drugs.

Figure 4

Structure of gastrazole (JB95008, 181), a CCK2 receptor antagonist.

Figure 5

Dual CCK1/CCK2 antagonist 182.

Figure 6

Structure of sitagliptin (183), an antidiabetic drug.

Figure 7

Structure of retaglpitin (184) and antidiabetic drug.

Figure 8

Structure of evogliptin (185), an antidiabetic drug.

Figure 9

Structure of LY2497282 (186) a DPP-4 inhibitor for the treatment of type II diabetes.

Figure 10

Structure of ulimorelin (187).

Figure 11

Structure of GLP1R (188).

Figure 12

Structures of Nav1.7 blockers 189 and 190.