Novel synthesis of convulsants with a unique ring system: dihydro-1,4-ethano-1H,3H-thieno[3,4-c]thiophene-3,6(4H)-dione.
Dihydro-1,4-ethano-1H,3H-thieno[3,4-c]thiophene-3,6(4H)-dione (1) was obtained in 28% yield by an unusual rearrangement reaction on addition of 4 equiv of BBr3 to O,O-diethyl endo,exo-7-oxabicyclo[2.2.1]heptane-2,3-dicarbothioate. The 5-methyl, 1,4-dimethyl, 5-n-butyl, and 5,6-benzo analogues of 1 were synthesized by similar procedures. Dihydro-1,4-ethano-1H,3H-furo[3,4c]furan-3,6(4H)-dione (6) and its 1,4-dimethyl analogue were obtained by acid-catalyzed cyclization of the appropriate endo,exo-7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acids. Lawesson's reagent was used to convert 1 and 6 to their monothiono and dithiono derivatives. The exo,exo isomers of several of the starting oxabicycloheptanedicarboxylic acids and their anhydrides are potent vesicants and hepatotoxins interacting with the cantharidin binding site of liver cytosol whereas some of the new bis-thiololactones and their thiono analogues are convulsants that probably act in the brain as GABAA receptor antagonists.
Kawamura
N
N
Department of Entomological Sciences, University of California, Berkeley 94720.
Casida
J E
JE
D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003292:Convulsants / Q000138:chemical synthesis* / Q000378:metabolism; D018756:GABA Antagonists; D051379:Mice; D011963:Receptors, GABA-A / Q000187:drug effects; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis*
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003292:Convulsants; D018756:GABA Antagonists; D011963:Receptors, GABA-A; D013876:Thiophenes; C072540:dihydro-1,4-ethano-1H,3H-thieno(3,4-c)thiophene-3,6(4H)-dione; C037476:tert-butylbicyclophosphorothionate