Synthesis of homologated halovinyl derivatives from aristeromycin and their inhibition of human placental S-adenosyl-L-homocysteine hydrolase.

Moffatt oxidation of 2',3'-O-isopropylidenearisteromycin (1a) and treatment of the 5'-carboxaldehyde with [(p-tolylsulfonyl)methylene]triphenylphosphorane gave the homologated vinylsulfone 2. Treatment of 2 with tributylstannane/AIBN gave the (E/Z)-vinylstannanes which were converted into the E and Z fluoro- and iodovinyl analogs. Chain extension via the 5'-cyano-5'-deoxy derivative 10a gave the 6'-carboxaldehyde of homoaristeromycin. S-Adenosyl-L-homocysteine hydrolase was strongly inhibited by the fluorovinyl, 5b, and iodovinyl, 4b and 7b, compounds, and time-dependent kinetics were observed [1-2 microM (Ki) and 0.1-0.2 min-1 (kinact)]. The mechanism of inactivation was shown to involve addition of water at the vinyl 5' or 6' carbons with elimination of halide.