2,4(5)-Disubstituted imidazoles containing a variety of substituents have been prepared via a modified literature procedure. An extensive study regarding the site of N-alkylation is reported which demonstrates that a strong preference exists for 1,2,4-trisubstituted products with little or no formation of the corresponding 1,2,5-trisubstituted isomers. The relationship of imidazoles with this substitution pattern to the phencyclopeptines is disclosed in

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A number of 1,2,4-trioxanes were prepared and tested for antimalarial activity in search of a simplified analogue of the naturally occurring antimalarial qinghaosu. The compounds were assayed in an in vitro system for antimalarial activity against chloroquine-susceptible and chloroquine-resistant strains of Plasmodium falciparum. The most active compounds were methyl 2-(2,4a-epidioxy-4a,5,6,7,8,8a-hexahydro-5,5,8a-trimethyl-2H-1-benzop yra n-2-yl) acetate (3b), which showed IC20's of 96 and 39 ng/mL, respectively, and 2,4a-epidioxy-3,4,4a,5,6,7,8,8a-octahydro-2-[2-(benzoyloxy)propyl]-5,5,8 a- trimethyl-2H-1-benzopyran (12), which showed IC50's of 24 and 99 ng/mL, respectively. For comparison, qinghaosu exhibits an IC50 of 1 ng/mL for both strains.

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2419General Procedure. Diisobutylaluminum hydride (1.0 M, hexanes) was added portionwise to a 0.3 M toluene solution of the unsaturated lactone (7.0 mmol) cooled to -78 O C (dry ice-CH30H bath) until TLC analysis judged the reaction complete.It was then poured into a rapidly stirred mixture of ice (25 g) and acetic acid (7 mL). Chloroform (50 mL) was added and the twephase system stirred vigorously for 10 min. Another 100-mL portion of chloroform was added and vigorous stirring continued until two distinct layers formed when the stirring was halted (typically 3 0 4 min). The layers were separated, and the organic layer was washed with bicarbonate (2 X 100 mL) and brine (75 mL). Drying and removal of the solvents afforded a colorless oil which was used without purification.The crude lactol and triethylsilane (1.22 g, 10.5 mmol) in dichloromethane (25 mL) were cooled under nitrogen. Dropwise addition of boron trifluoride etherate (0.95 mL, 7.7 mmol) gave a solution which was stirred until TLC indicated that no lactol was present and then quenched by addition of ca. 10 mL of aqueous bicarbonate. The cooling bath was removed and the solution allowed to warm to room temperature with vigorous stirring. After the mixture was transferred to a separatory funnel, ether (100 mL) was added and the whole washed with bicarbonate (20 mL) and brine (20 mL). Drying and removal of the solvents afforded an oil which was chromatographed (silica gel, hexanes-EtOAc). 695 cm-'; NMR (CDClJ 6 1.74 (m, 3 H), 2.20 (m, 4 H), 4.34 (m, 2 H), 4.55 (dd, J = 5, 9 Hz), 5.52 (m, 1 H), 7.40 (s, 5 H).2: IR (film) 2980,2895, 1065; NMR (CDClJ 6 1.52-2.42 (m, 4 H), 3.704.18 (m, 2 H), 4.68-4.94 (m, 1 H), 7.03-7.30 (m, 5 H); ' % NMR 143.315,128.146,126.954, 125.492,80.527,68.446,34.534, 25.919. The boiling point [105-107 "C (15 mmHg)] was identical with the literature13 boiling point.