The regioselective synthesis of several pyrrole derivatives is described. AlCl3-catalyzed acylation reactions of l-(phenylsulfonyl)pyrrole (1) give 3-acyl derivatives, whereas the corresponding BFg-OEts-catalyzed reactions give 2-acyl derivatives predominantly. Mild alkaline hydrolysis gives the corresponding acyl-lR-pyrroles in excellent yields. AlCl3-catalyzed reactions of 1 with 1,1-dichloromethyl methyl ether and oxalyl chloride give l-(phenylsulfonyl)-2-formylpyrrole (6) and l-(phenylsulfonyl)-2-(chlorocarbonyl)pyrrole (7), respectively. 3-Pyrrolylacetic acid (10) was prepared by thallium(III) nitrate promoted rearrangement of 1 -(phenylsulfonyl)-3-acetylpyrrole (2a). Trifluoroacetic anhydride catalyzed cyclization of 4-[ 1 -(phenylsulfonyl) -3-pyrrolyl] butyric acid ( 14) gives l-(phenylsulfonyl)-7-oxo-4,5,6,7-tetrahydroindole (17). Attempts to cyclize 14 at the 4-position have been unsuccessful.

Naphthalenic lignan lactone 3a (L-702,539), a potent and selective 5-lipoxygenase (5-LO) inhibitor, is extensively metabolized at two different sites: the tetrahydropyran and the lactone rings. Early knowledge of the metabolic pathways triggered and directed a structure-activity relationship study aimed toward the improvement of metabolic stability in this series. The best modifications discovered, i.e., replacement of the lactone ring by a nitrile group, replacement of the tetrahydropyran ring by a 6,8-dioxabicyclo[3.2.1]octanyl moiety, and replacement of the pendant phenyl ring by a 3-furyl ring, were incorporated in a single molecule to produce inhibitor 9ac (L-708,780). Compound 9ac inhibits the oxidation of arachidonic acid to 5-hydroperoxy-eicosatetraenoic acid by 5-LO (IC50 = 190 nM) and the formation of leukotriene B4 in human polymorphonuclear leukocytes (IC50 = 3 nM) as well as in human whole blood (IC50 = 150 nM). The good inhibitory profile shown by naphthalenenitrile 9ac is accompanied by an improved resistance to oxidative metabolism. In addition, 9ac is orally active in the functional model of antigen-induced bronchoconstriction in allergic squirrel monkeys (95% inhibition at 0.1 mg/kg).

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Sulfenylation of indole using a sulfenyl chloride occurs initially at the 3-position of the ring, leading to a 3-indolyl sulfide. When an excess of sulfenyl chloride is used, a second sulfide group is introduced at the 2-position, and an indolyl 2,3-bis-sulfide results. We have demonstrated that this second sulfenylation occurs not by direct introduction of the second sulfide at the 2-position but via initial formation of an indolenium 3,3-bis-sulfide intermediate, followed by migration of one of the sulfide groups to the 2-position. This was achieved by the isolation of two examples of 3H-indole 3,3-bis-sulfides and by subsequent demonstration that they rearrange to the indolyl 2,3-bis-sulfides by treatment with sulfenyl halides.

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