SUMMARY Metabolites in the kynurenine pathway of tryptophan degradation are thought to play an important role in neurodegenerative disorders such as Alzheimer’s disease and Huntington’s disease. Metabolites that cause glutamate receptor-mediated excitotoxicity and free radical formation are elevated in the blood and vulnerable brain regions in these diseases, while levels of the neuroprotective metabolite kynurenic acid are often decreased. Here we describe the synthesis and characterization of JM6, a novel small-molecule pro-drug inhibitor of kynurenine 3-monooxygenase (KMO). JM6 raises kynurenic acid and reduces extracellular glutamate in the brain after chronic oral administration by inhibiting KMO in blood. In a transgenic mouse model of Alzheimer’s disease, JM6 prevented spatial memory deficits, anxiety-related behavior, and synaptic loss. JM6 also extended life span, prevented synaptic loss, and decreased microglial activation in a mouse model of Huntington’s disease. These findings support a critical link between blood cells and neurodegeneration that is mediated by KMO and the kynurenine pathway.

A very effective strategy has been devised for the synthesis of 3-substituted pyrroles based on the use of the triisopropylsilyl (TIPS) moiety as a sterically demanding nitrogen substituent to obstruct the attack of electrophilic reagents at the a positions. 1 -(Triisopropylsilyl) pyrrole (1) undergoes highly preferential kinetic electrophilic substitution at the ß position with a variety of electrophiles (Br+, I+, N02+, RCO+, etc.) and fluoride ion induced desilylation of the products provides the corresponding 3-substituted pyrroles in good overall yields. Competitive trifluoroacetylation experiments demonstrate that substitution of TIPS-pyrrole at the a positions is decelerated by a factor of >104, vs pyrrole at the same sites, without affecting reactivity at the ß positions. l-(Triisopropylsilyl)-3-bromopyrrole ( 2) is readily converted into the 3-lithio compound 44 by bromine-lithium interchange with alkyllithium reagents. This previously unavailable, formal equivalent of 3-lithiopyrrole is itself an excellent source of a wide range of /3-substituted pyrroles, many of which would not be directly preparable from 1.TIPS-pyrrole can be 3,4-dihalogenated and these compounds undergo sequential halogen-metal interchange trapping reactions. This process is exemplified by an efficient, three-step synthesis of the antibiotic verrucarin E (63) from the dibromo compound 5. * Contribution no. 792.

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Addition of excess hydrogen peroxide (10 equiv) to a sonicated solution of FeS04:7Hz0 ( 1 equiv) in DMSO containing the N-(o4odoalkyl)indoles 4,5, 11, and 13 effected oxidative radical cyclization to 6,7,14, and 15, respectively. The (o4odoalkyl)pyrroles 21,22,27,38, and 49 underwent analogous cyclization reactions to 23, 24, 28, 39, and 50, respectively. The regiochemistry of these radical cyclization reactions was correctly predicted by FMO calculations in all cases but one. For compound 38, FMO calculations indicated that radical attack should take place at both C-3 and C-5. Only the product of cyclization at C-5, i.e., 39, was observed. The enantiomerically pure bicyclic ketone 42, prepared by the above technique from the iodide 53, was converted into 56 which, on catalytic reductio; (HdRh-Al203), gave a mixture of (-)-monomorine (40) and three of ita diastereomers 56-58 (see, however, Note Added in Proof).The intramolecular addition of a radical to an aromatic nucleus followed by oxidation of the new resonancestabilized radical thus produced back to the aromatic system (oxidative radical cyclization) is a process which has considerable synthetic utility, and several methods have recently been devised to effect such cyclizations. For example, oxidative intramolecular additions to aromatic systems mediated by Mn(III),1*2 Fe(II1),2 Cu(II),3 Ce(IV),2p3 and tri-n-butyltin hydride4ts which proceed with varying degrees of efficiency have been reported. As a long-term goal, we have been interested in devising efficient and inexpensive methods of effecting oxidative radical cyclization to aromatic systems. In addition, we have been investigating the use of simple computational methods as a possible means of predicting the regioselectivity of such reactions (Artis et al., ref 1). This publication describes some of our recent results in the indole and pyrrole areas.Dixon et al.6 showed by EPR spectroscopy that methyl radicals were produced in the reaction of hydroxyl radicals (generated from Ti(II1) and hydrogen peroxide) with DMSO. This reaction (eq 1) proceeds in >90 % yield based on hydroxyl radicals produced and also can be applied to sulfoxides other than DMSO.' Torsell and co-workers* + Contribution no. 881 from the

The electrophilic substitution of N-alkylated isocarbostyrils was examined in considerable detail. Bromination, acylation, nitration, and acid-catalyzed condensation with formaldehyde occurred exclusively at C-4 under relatively mild conditions. The acylation of isocarbostyrils has heretofore not been reported.The bromination of 2-methyl-5-nitroisocarbostyril in aqueous acetic acid gave 2-methyl-3,4-dihydro-3-hydroxy-4-bromo-5-nitroisocarbostyril (7) of unknown stereochemistry, as the sole product. When heated above its melting point, 7 lost the elements of water to give the "normal" product of bromination 8.In aqueous acetic acid, excess bromine was shown to convert isocarbostyrils to the corresponding 3,4-dihydro-3-hydroxy-4,4-dibromo derivatives whose structures were supported by spectral and degradative evidence.

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