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The oncolytic agents vinblastine and vincristine1-2 are "dimeric" alkaloids containing a pentacyclic indoline and a tetracyclic indole moiety. Fragmentation into these structural units is brought about readily by reduction in acidic media which in the case of vinblastine gives desacetylvindoline3 and velbanamine (14).4 These fragments are obvious intermediates in a synthesis of vinblastine, and we now describe the first total synthesis5 of velbanamine ( 14).Oxygenation6 of the isoquinuclidine V in Z-butyl alcohol-monoglyme saturated with potassium t-butoxide at -20°g ave the hydroxy ketone 2,8 mp 156-158°. The corresponding diol 3, mp 182-183°, prepared by reduction of the hydroxy ketone with sodium borohydride, was cleaved with sodium metaperiodate in aqueous methanol to give the ketone 4, mp 109-112°( ethyl acetate solvate). The latter was transformed to the ketal 5, mp 163-165°, by treatment with a mixture of methyl orthoformate and methanol in the presence of p-toluenesulfonic acid at reflux (1)

Anthelmintic efficacies of a series of 6-substituted methyl imidazo[1,2-alpha]pyridine-2-carbamates were compared to similarly substituted benzimidazole-2-carbamates. With only one exception, methyl 6-benzoylimidazo[1,2-alpha]pyridine-2-carbamate, both classes of compounds exhibited similar activity vs. Nematospiroides dubius in mice. Preliminary screening indicated methyl 6-(1,2,2-trichloroethenyl)imidazo[1,2-alpha]pyridine-2-carbamate to be the most potent derivative in the series. However, evaluation in sheep indicated that its anthelmintic spectrum was inferior to methyl 6-(phenylsulfinyl)imidazo[1,2-alpha]pyridine-2-carbamate.

A series of methyl imidazo-[11,2-a]pyridine-2-carbamates was synthesized for anthelmintic testing. The preparation of this class of compounds was simplified by utilization of a novel one-step condensation of the appropriately substituted 2-aminopyridine and methyl chloroacetylcarbamate. The most potent compound, methyl 6-(phenylsulfinyl)-imidazo[1,2-a]pyridine-2-carbamate, was orally effective against a broad range of helminths in sheep and cattle, at a dosage of 2.5 mg/kg. Limited trials in swine and dogs demonstrated anthelmintic activity at higher dosages. Limited observations in sheep and cattle indicated that, in both species, a single oral dose of 200 mg/kg was well tolerated.

A number of pyromellitic diimides were prepared and found to alter rumen fermentation in a potentially beneficial way. In vitro rumen test procedures and chemical syntheses for preparation of novel unsymmetrical N-substituted pyromellitic diimides were developed. Structure-activity investigations showed that a variety of N substituents could be tolerated while retaining high activity. The most potent compounds in the series had ID^v alues for methane suppression of approximately 1 Pg/mL and blocked methane production completely at higher levels. Volatile fatty acid composition was shifted from acetic to propionic and butyric acids. Two compounds, pyromellitic diimide and pyromellitic N-(2hydroxyethyl)diimide, have been selected for further study in sheep and cattle.The rumen, in ruminating animals, provides an ecosystem in which microorganisms, living at a pH between 5.5 and 7.0 in an anaerobic environment, can metabolize incoming materials into nutrients to be used by the host. The principal end products of carbohydrate metabolism in this system are volatile fatty acids (VFA's) such as acetic acid, propionic acid, and butyric acid, which are absorbed by the host and the gases carbon dioxide and methane.Methane is formed by the reduction of carbon dioxide by hydrogen. An outline of the principal pathways of carbohydrate metabolism is shown in Scheme I [adapted from Hungate (1966) and Leng (1970)]. Methane is expelled.A typical rumen fermentation may be approximated by the equation (Wolin, 1974) 57.5C6H1206 -65CH3COOH + 20CH3CH2COOH + 15CH3CH2CH2COOH + 60CO2 + 35CH4 + 25H20 (1) If one considers energy utilization and conservation via glycolysis, the following generalization applies (Hungate,