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To improve the in vivo potency of the potent GPIIb/IIIa antagonist 2-[(3S)-4-[(2S)-2-(4-amidinobenzoylamino)-3-(4-methoxyphenyl)propanoyl]-3-(2-methoxy-2-oxoethyl)-2-oxopiperazinyl]acetic acid (4), the amidino group was converted to an oxadiazole ring, thiadiazole ring or substituted amidoxime group. These groups were expected to be metabolized to an amidino group in vivo. The compounds synthesized were evaluated for their potency to inhibit the ex vivo adenosine 5'-diphosphate (ADP)-induced aggregation of guinea pig platelets. Among the compounds examined, the methoxycarbonyloxyamidine 8a exhibited the most potent ex vivo inhibitory activity with a fast onset and prolonged duration of action after oral administration.

Reaction of gem-dibromocyclopropanes (1) with a higher-order organocuprate prepared from cuprous thiocyanate and methyllithium, followed by the addition of methyl iodide in situ, readily afforded dimethylcyclopropanes (2) in good to excellent yields regardless of the functional group in 1.

Treatment of 8, 8-dibromobicyclo [5.1.0] octanes (A) with a higher order organocuprate prepared from cuprous thiocyanate (method A) or cuprous cyanide (method B) and methyllithium, followed by the addition of methyl iodide in situ, readily afforded 8, 8-dimethylbicyclo [5.1.0] octanes (B) in good yields. The results are summarized in Table I. Interestingly, reaction of the cisdibromides (4 and 19) under the present conditions gave tricyclic compounds (15 and 16, and 20, respectively)

Total synthesis of dl-aspterric acid (1) has been accomplished. Robinson annulation of the keto ester (2) with methyl vinyl ketone, followed by reduction with LiAlH4 and oxidation with MnO2, afforded the enone alcohol (4), which was converted to the hydroxy-ether (6) via three steps (I2-Ag2O, AgOAc, and alkaline hydrolysis). Successive treatment of 6 with tert-butyldimethylsilyl chloride, tert-BuOK-MeI, NaBH4, Ac2O-pyridine and 5% HCl afforded the hydroxy acetate (18). The hydroxy acetate (18) was converted to the hydroxy ketone (20) via catalytic hydrogenation under medium pressure, Jones oxidation, and alkaline hydrolysis. Treatment of 20 with PCl5 gave the norketone (21), which is the degradation product of 1. The dimethylacetal (25) of 20 was treated with Me3SiCN-SnCl2 to give the methoxy cyanides A (26) and B (27). The major methoxy cyanide B (27) was successively treated with KOH, Me3SiCl-NaI, Ac2O, and 5% HCl to give the monoacetate (31), which was finally converted to 1 via ring contraction with PCl5 and alkaline hydrolysis.