No abstract

Aryl and vinylic bromides and iodides react at 1W135O with olefins in the presence of a tertiary amine and a catalyst composed of palladium acetate and 2 equiv of triphenylphosphine. New olefins are formed in which a vinylic hydrogen in the original olefin has been replaced by the organic group of the halide. The reaction is stereospecific to the extent of about 7 0 x with cis-and trans-1-phenyl-1-propene. e have previously reported palladium metal W formed in situ from palladium acetate catalyzed the vinylic hydrogen substitution reaction of olefins with aryl iodides, benzyl chloride, and P-bromostyrene in the presence of a tertiary amine.' While this re-RX + Pd + ? [RPdX]

rinses were saturated with sodium chloride and extracted with cyclohexane (2 X 25 ml). The combined cyclohexane rinses and extracts were dried over anhydrous magnesium sulfate and the solvent was evaporated at reduced pressure. GLC analysis (10 ft X 0.25 in. FFAP column, 100°) of the residue indicated a single hydrocarbon product, which was purified by GLC (above conditions) to give 15 as a clear oil: ÓTMs(CDCla) 1.16 (s, 3 H, CHs) and 0.8-2.3 (br m, 13

Certain aspects of reactions involving the catalytic formation of -allylic palladium complexes via addition reactions to conjugated dienes and the subsequent reaction of these complexes with mild nucleophiles were investigated.

On the basis of our previous demonstration of the high inhibitory activity of a series of p-n-alkyloxybenzhydroxamic acids and n-alkyl esters of 3,4-dihydroxybenzoic acid against the trypanosome alternative oxidase in a cell-free mitochondrial preparation of Tiypanosoma brucei brucei, we synthesized a series of N-n-alkyl-3,4-dihydroxybenzamides for evaluation as inhibitors of this enzyme. This class of compounds was selected with the expectation of their having similar inhibitory activity to but greater solubility than the esters and hydroxamic acids noted above and greater resistance to serum hydrolases in vivo. We predicted that such properties would allow an inhibitor of the trypanosome alternative oxidase to be coadministered with glycerol as a means of providing treatment for infections by African trypanosomes. As expected, such benzamides were both more soluble and more stable, some being more active against the target enzyme than the corresponding ester. One, N-n-butyl-3,4-dihydroxybenzamide, was selected for evaluation in vivo against T. brucei brucei.When combined with glycerol, this benzamide was found to be curative. A regimen wherein 450 mg of N-n-butyl-3,4-dihydroxybenzamide per kg and 15 g of glycerol per kg were given hourly in three divided doses cured 17 of 19 mice with established T. brucei brucei infections. This combination is more active in vivo than any other designed to block simultaneously both the unique respiratory electron transport system and the anaerobic glycolytic pathways of these pathogenic protozoa.The Trypanosoma brucei complex, the causative agent of human and animal trypanosomiasis in Africa, has several unusual biochemical pathways, including a mitochondrial terminal oxidase known as the trypanosome alternative oxidase (TAO) (1). This enzyme is the sole terminal oxidase functioning in the life cycle stages found in the mammalian host and, by the following criteria, is similar to the alternative oxidase found in some plants. Both are ubiquinoloxygen oxidoreductases (1). With a monoclonal antibody against the plant enzyme, Western blots (immunoblots) of Trypanosoma brucei brucei show a single band of the same size (35 kDa) as the plant alternative oxidase (3). Furthermore, the two enzymes are sensitive to the same range of specific inhibitors (2).Since the TAO is an enzyme with no homolog in the mammalian host, it has been the target of a rational approach to the design of drugs for the treatment of African trypanosomiasis. Early work showed that the TAO is sensitive to substituted hydroxamic acids (6). In combination with glycerol, which blocks a glycerol-producing pathway by mass action, salicylhydroxamic acid (SHAM) is trypanocidal (4), although the concentrations required for a cure are toxic to the host (9). In a search for alternatives to SHAM, we designed, synthesized, and tested compounds against TAO activity as measured in a crude mitochondrial preparation of T. brucei brucei (5,7,8). The most active compounds were p-n-alkyloxybenzhydroxamic acids and n-alkyl 3,4-dihy...