Two Scaffolds from Two Flips: (αβ)/(βγ) CH2/NH Met-Im Analogues of dTTP

摘要

Novel α,β-CH2 and β,γ-NH (>1a) or α,β-NH and β,γ-CH2 (>1b) “Met-Im” dTTPs were synthesized via monodemethylation of triethyl-dimethyl phosphorimido-bisphosphonate synthons (>4a, >4b), formed via a base-induced [1,3]-rearrangement of precursors (>3a, >3b) in a reaction with dimethyl or diethyl phosphochloridate. Anomerization during final bromotrimethylsilane (BTMS) deprotection after Mitsunobu conjugation with dT was avoided by microwave conditions. >1a was 9-fold more potent in inhibiting DNA polymerase β, attributed to an NH-group interaction with R183 in the active site.