Synthetic Methods of Phosphonopeptides

Abstract

Phosphonopeptides are phosphorus analogues of peptides and have been widely applied as enzyme inhibitors and antigens to induce catalytic antibodies. Phosphonopeptides generally contain one aminoalkylphosphonic acid residue and include phosphonopeptides with C-terminal aminoalkylphosphonic acids and phosphonopeptides with a phosphonamidate bond. The phosphonamidate bond in the phosphonopeptides is generally formed via phosphonylation with phosphonochloridates, condensation with coupling reagents and enzymes, and phosphinylation followed by oxidation. Pseudo four-component condensation reaction of amides, aldehydes, alkyl dichlorophosphites, and amino/peptide esters is an alternative, convergent, and efficient strategy for synthesis of phosphonopeptides through simultaneous construction of aminoalkylphosphonic acids and formation of the phosphonamidate bond. This review focuses on the synthetic methods of phosphonopeptides containing a phosphonamidate bond.

Keywords: peptide; phosphonamidate; phosphonopeptide; β-phosphonopeptide; γ-phosphonopeptide.

Figure 1

Different classes of phosphonopeptides.

Scheme 1

First synthesis of phosphonopeptide.

Scheme 2

Synthesis of phosphonopeptides as inhibitors of enkephalinase and angiotensin-converting enzyme.

Scheme 3

Synthesis of phosphonopeptide from phosphonochloridate generated by chlorination of diethyl phosphonate with phosphorus oxychloride.

Scheme 4

Synthesis of phosphonopeptide as the inhibitor of d-alanine:d-alanine ligase.

Scheme 5

Synthesis of phosphonopeptides from aminoalkylphosphintes.

Scheme 6

Synthesis of phosphonopeptides composing of one or two 1-aminoalkylphosphonic acid residue(s).

Scheme 7

Synthesis of phosphonopeptide inhibitors of VanX.

Scheme 8

Synthesis of phosphonopeptide and its transesterification.

Scheme 9

Synthesis of N-Fmoc protected phosphonopeptides.

Scheme 10

Synthesis of phosphonopeptides from diallyl N-Cbz aminomethylphosphonate.

Scheme 11

Synthesis of β-phosphonopeptide containing aromatic N-terminal amino group.

Scheme 12

Synthesis of phosphonopeptides under mild conditions.

Scheme 13

Synthesis of phosphonopeptides as potential immunomodulators.

Scheme 14

Synthesis of γ-phosphonopeptides.

Scheme 15

Synthesis of phosphonopeptides via chlorination of aminoalkylphosphonites.

Scheme 16

Synthesis of phosphonopeptides from aminoalkylphosphinates.

Scheme 17

Synthesis of phosphonopeptides via phosphonobromidates.

Scheme 18

Synthesis of phosphonopeptides and triazole-containing phosphonopeptides via 1-azidoalkylphosphonochloridates.

Scheme 19

Synthesis of phosphonopeptides with N,N’-dicyclohexylcarbodiimide (DCC) as a coupling reagent.

Scheme 20

Synthesis of phosphonopeptides with N,N’-diisopropylcarbodiimide (DIC) as a coupling reagent.

Scheme 21

Synthesis of phosphonopeptides with diphenylphosphoryl azide (DPPA) as coupling reagent.

Scheme 22

Synthesis of phosphonopeptides with benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBop) as a coupling reagent.

Scheme 23

Synthesis of α- and δ-phosphonopeptides.

Scheme 24

Synthesis of phosphonopeptides composing of γ- and δ-aminoalkylphosphonic acid residues.

Scheme 25

Synthesis of phosphonopeptides containing a cyclodipeptide core.

Scheme 26

Synthesis of thiophosphonopeptides.

Scheme 27

Synthesis of phosphonopeptides via phosphonochliridites.

Scheme 28

Synthesis of phosphonopeptides via pseudo four-component condensation.

Scheme 29

Mechanism for the synthesis of phosphonopeptides via pseudo four-component condensation.

Scheme 30

Synthesis of cyclophosphonopeptides via nucleophilic addition.