The Suzuki coupling of 2-and 4-chloropyridines with arylboronic acids is successfully performed under Pd(PPh 3 ) 4 catalysis. Moderate to good yields are obtained with 4-chloropyridines while 2-chloropyridines give excellent yields. The corresponding pyridine N-oxides react in the same manner. An easy and cheap access to arylpyridines, a class of compound with medicinal interest, is thus achieved.

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A new enantioselective synthesis of (+)-brefeldin A is described. The five chiral centers are created by the following methodology: asymmetric Diels-Alder reaction to prepare the cyclopentanone 13, stereocontrolled reduction of the carbonyl in the ketone 14, stereocontrolled creation of the chiral centers C-4 and (2-15 by a chiral sulfoxide group.(+)-Brefeldin A, first isolated in 1958 from Penecillium decumbensl has been shown to have both antifungal and antiviral activitye2 More recently, it has been shown that the antiviral activity of the molecule is due to inhibition of the intracellular transport of secretory proteins.3 The finding that brefeldin A specifically blocks the movement of proteins from the endoplasmic reticulum to the Golgi apparatus4 has made this molecule a powerful tool for biochemical investigati~n.~The complete structure of (+)-brefeldin A was established in 1971 by X-ray analysis.s Five years later, Corey and Wollenberg reported the first synthesis of racemic brefeldin A.' The first enantioselective synthesis was reported in 1979.8 In the years since Corey's initial report, there have been numerous partial: formal,1° and totalll syntheses described.We report in this paper an enantioselective total synthesis of (+)-brefeldin A following the retrosynthetic (1) Singleton, V. L.; Bohonos, N.; Ulletrup, A. J. Nature 1958, 181, 1072. (2) (a) Betina, V.; Drobnica,L.; Nemec, P.; Zenanova,M. J. J. Antibiot. Ser. A. 1964,17,93. (b) Betina, V.; Betinova, M.; Kutkova, M. Arch. Mikrobiol. 1966,55,1. (c) Tamura, G.; Ando, K.; Suzuki, S.; Takatauki, A.; Arina, K. J. Antibiot. 1968,21, 160. (d) Takatauki, A.; Yamaguchi, I.;Tamura,G.;Miaato,T.;Arina,K.J.Antibiot. 1969,22,442. (e)Hayashi, T.; Takatauki, A.; Tamura, G. Scheme I with a complete control of the stereochemistry of the five chiral centers. Synthesis of the Chiral Hydroxy Sulfone (+)-(55)-2. (+)-Methyl (55' 1-5-[(tert-butyldimethylsily1)oxyl hexanoate (3) was already prepared in the synthesis of zearalenone that we recently reported.12 The chiral hydroxyl group was created by asymmetric reduction of a 8-keto sulfoxide.Reduction of the ester group of 3 with LiAla, followed by bromination and reaction with sodium sulfinate, afforded the sulfone 2 in 71% overall yield (Scheme 11).Synthesis of the Cyclopentanone (-)-(3&4R)-13. The cyclopentanone 13 was prepared using an asymmetric Diels-Alder reaction. Yamamotols has previously shown that the addition of (-)-menthyl fumarate to butadiene in the presence of a Lewis acid, diisobutylaluminum chloride, at low temperature, afforded (S,S)-dimenthyl cyclohex-4-ene-1,2-dicarboxylate in 56% yield and 95% de. We repeated this experiment using (+)-dimenthy1 fumarate [obtained from unnatural (+)-menthol] and diethylaluminum chloride as Lewis acid and we got the adduct 7 in the R,R configuration in 98% yield and a de higher than 90% (about 5% of the S,S isomer was detected by lSC NMR). After reduction of the two esters (Scheme 111), the two hydroxyl groups were protected (benzaldehyde acetonide 9) and DIBAL reduct...

A novel industrial process for the antiepileptic drug oxcarbazepine 1 has been developed. Unlike the old process, the new process is free from halogenated solvents and can be performed in standard production equipment. It starts from commercially available 1,3-dihydro-1-phenyl-2H-indol-2-one 10. In the key step, an electrophilic ring closure reaction of 2-[(methoxycarbonyl)phenylamino] benzeneacetic acid 5 to 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxylic acid methyl ester 6 in poly phosphoric acid was applied. For the manufacture of 5, a highly efficient process using a dianion strategy was developed.

An efficient and economical synthesis of 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride (1) utilizing 2-aminoindan as a cheap and commercially readily available starting material is described. The newly developed synthesis involves six-steps with 49% overall yield, and it introduces two ethyl groups at the 5-and 6-positions via sequential regioselective Friedel-Crafts acetylations and hydrogenations of N-protected-2-aminoindan. The Friedel-Crafts acetylations can be carried out neat with high regioselectivity using acetyl chloride as the reagent as well as the solvent, thus avoiding the use of halogenated solvents.

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One of the characteristic features of asthma is a persistent pulmonary inflammation, with increased numbers of eosinophils and activated T-lymphocytes in the airways. T-helper cells of the Th2 phenotype play a pivotal role in the pathogenesis of asthma, and they are believed to orchestrate the asthmatic response by releasing a wide repertoire of cytokines. Herein, we describe the design, synthesis, and evaluation in models of allergic asthma of a locally active T-cell modulator, MLD987 (1). Compound 1 is a potent immunosuppressant that inhibits the activation, proliferation, and release of cytokines from T-cells with IC(50) values in the low nanomolar range. In a Brown-Norway rat model of allergic asthma, 1, when given into the airways by intratracheal administration (ED(50) = 1 mg/kg) or by inhalation (ED(50) = 0.4 mg/kg), potently reduced the influx of leukocytes into bronchoalveolar lavage fluid samples obtained from antigen-challenged animals. In contrast, 1 had an appreciably weaker activity in this model when given orally or intravenously. Pharmacokinetic evaluation in rat and rhesus monkey showed that 1 had both a low oral (2-4%) and a low pulmonary (7%, monkey) bioavailability. These findings are consistent with a local site of action of the compound and rule out that its antiinflammatory activity in the lung was caused by systemically absorbed material, which had been swallowed during inhalation or which had entered the circulation via the airways. Local administration and the metabolically soft structure of 1, which favors rapid systemic metabolism to less immunosuppressive metabolite 2, are the main reasons for the low exposure and weak systemic activity of the compound. Administration of a locally active compound such as 1, by inhalation, should reduce systemic side effects. Our results indicate that 1 has the potential to serve as an alternative to inhaled glucocorticosteroids for the long-term therapy of asthma of all grades of severity.