Structure-activity relationships of the phosphonate antibiotic dehydrophos

Abstract

Synthetic derivatives of the phosphonate antibiotic dehydrophos were tested for antimicrobial activity. Both the phosphonate monomethyl ester and the vinyl phosphonate moiety proved to be important for bacteriocidal activity of the natural product.

Fig. 1

Structures of synthetic compounds 1–6. Note that in aqueous solutions, the anions of 4 and 6 are not chiral at phosphorus.

Fig. 2

Bioassay against E. coli: (−) negative control (water), (+) positive control (ampicillin), left: compounds 1, ent-1, 2, 3; right: compound 4, 4b, 5 and 5b. See also ESI.

Scheme 1

Synthesis of desmethyl dehydrophos 2: (a) Pb(OAc)₄, DMF, 0 °C to 25 °C; (b) TiCl₄, P(OMe)₃, CH₂Cl₂, −78 °C to 25 °C; (c) Pd/C, H₂(g), MeOH, 25 °C; (d) Cbz-Leu-OH, EDC, CH₂Cl₂, 25 °C; (e) Pd/C, H₂(g), MeOH, 25 °C; (f) Cbz-Gly-OH, EDC, CH₂Cl₂, 25 °C; (g) TBAF, THF, 25 °C; (h) MsCl, NEt₃, CH₂Cl₂, 0 °C to 25 °C; (i) DBU, CH₂ClCH₂Cl, 84 °C; (k) BBr₃, hexanes, toluene 0 °C to 70 °C.

Scheme 2

Synthesis of the derivative 4. (a) Toluene, 110 °C; (b) HPO(OMe)₂, 100 °C, (c) HCl in MeOH, 25 °C; (d) Boc-Leu-OH, EDC, NMM, CH₂Cl₂, 25 °C; (e) HCl in MeOH, 65 °C; (f) Boc-Gly-OH, EDC, NMM, CH₂Cl₂, 25 °C; (g) HCl in MeOH, 65 °C; (h) NaOH, H₂O, 25 °C.