No abstract

Hydrometalation of acetylenes illustrated in eq 1 is a superior method for preparing stereodefined alkenylmetal species, which are particularly useful for the construction of olefinic linkages with predictable stereochemistry. Hydrometalation reactions1 including hydroboration,18 -alumination,lb -magnesation,lc -silylation,ld -stannation,18 and -zirconation,lf etc., have been routinely utilized in the synthesis of complex natural products. Herein we report a new entry to this series of reactions, namely the first hydrozincation of acetylenes, and demonstrate its application to further synthetic transformations.Recently, organozinc compounds of the type RZnX (R = alkyl; X = halogen, R, etc.) have been widely recognized as versatile carbon nucleophiles in organic synthesis owing to their selective reactivities.2 Alkenylzinc compounds are usually prepared via transmetalation of appropriate organometallic reagents, typically organolithium, -magnesium, or -boron compounds, with zinc salts or diethylzinc.2a-C|3 Direct reductive metalation of alkenyl halides with zinc metal can also be effected, but the stereochemical integrity of the starting alkenyl halide is not always retained in the zinc reagent.4 If hydrozincation of acetylenes (eq 1, "M-H" = "ZnHX") could be executed in a stereoselective manner, this reaction could become a straightforward method to prepare stereochemically defined alkenylzinc reagents. While hy-

Factor Xa (FXa) is a serine protease which plays a critical role in the coagulation cascade, serving as the point of convergence of intrinsic and extrinsic pathways.3-7) It represents an attractive target for anticoagulant drug development. [8][9][10][11][12][13][14] Most nonpeptide FXa inhibitors reported in the literature are dibasic compounds. Nagahara et al. 15,16) have reported the synthesis and evaluation of a series of bis(amidino)-derivatives, and through investigation, DX-9065a (1) [17][18][19][20][21] was found to be a selective FXa inhibitor. Further, YM-60828 (2), [22][23][24][25][26][27] which is closely related to 1 in terms of structure, was found to have a more potent inhibitory effect on FXa.On the other hand, as described in the preceding paper, 1) we have synthesized M55113 (3) as a potent inhibitor of FXa (IC 50 ϭ0.06 mM) with high selectivity for FXa over trypsin and thrombin. Compared with the structure of compound 3, the features of compound 1 and compound 2 include a functional acid group in the linker part of the molecule. According to the Xray structure of the complex of compound 1 in des- GlaFXa,28) it is clear that the nitrogen atom of Gln-192 forms a weak hydrogen bond with the acid function of compound 1.In order to obtain a compound which has powerful inhibitory activity on FXa, it is necessary to introduce a functional group into the position at which compound 3 and Gln-192 of FXa protein are expected to form a hydrogen bond.In this paper, we wish to report the continuing search for potent compounds that have a substituent at the piperazine and piperidine rings of compound 3. Thus, the structure-activity relationships of compound 3 derivatives were examined. ChemistryA key intermediate 7 was prepared from glycine ethyl ester hydrochloride, as illustrated in Chart 1. The compound 5, obtained by the reaction of glycine ethyl ester hydrochloride (4) with bromoacetaldehyde diethyl acetal in the presence of cesium carbonate (Cs 2 CO 3 ) 29,30) and sodium iodide, was treated with 6-chloro-2-naphthalenesulfonyl chloride under basic conditions, and the resulting sulfonamide 6 was hydrolyzed with aqueous trifluoroacetic acid (TFA) to give the formyl compound 7.Synthetic routes of compounds 12 and 17 are shown in Chart 2. Compound 9 was prepared by protection of the primary amino group with di-tert-butyl dicarbonate (Boc 2 O) and subsequent debenzylation of a secondary amino group with H 2 over Pd/C. Condensation of 9 with 4-chloropyridine 1-oxide under basic conditions gave the 4-piperidinopyridine 1-oxide derivative 10. Hydrogenolysis of 10 over Raney Ni 31) in methanol (MeOH), followed by treatment with HClMeOH, yielded compound 11. The final compound 12 was obtained smoothly by reductive condensation of 11 with the intermediate 7. 32)Reaction conditions in the preparation of compound 17 from compound 13 33) were not much different from the conversion of 8 to 12.Synthesis of 4-substituted piperidine derivatives containing another functional group (compound 18-20) in place of the hydroxyl...

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An unprecedented Pd-catalyzed decarboxylative cyclization of 4-trifluoromethyl-4-vinyl benzoxazinanones (4) with sulfur ylides (2) is reported. While the reactions of 4-vinyl/4-CF3 benzoxazinanones (1a/1c) with 2 furnished the 3-vinyl/3-CF3 indolines (3a/3c), via an attack on the C1 carbon of the π-allyl/benzyl zwitterionic intermediates, 4 was converted into 4-trifluoromethyl-dihydroquinolines (5) in good yields via an attack on the C3 carbon of the π-allyl intermediate. The corresponding methyl-substituted analogues afford different products via an attack on the C2 carbon.

Factor Xa (FXa), a trypsin-like serine protease, holds the central position that links the intrinsic and extrinsic mechanisms in the blood coagulation cascade. FXa is known to activate prothrombin to thrombin. Thrombin has several procoagulant functions that include the activation of platelets, feedback activation of other coagulation factors, and conversion of fibrinogen to insoluble fibrin clots. [4][5][6][7][8] Comparison of hirudin 9-13) (a thrombin inhibitor) and tick anticoagulant peptide [14][15][16][17][18][19][20] (a FXa inhibitor) suggests that inhibition of FXa may result in less bleeding risk, leading to a more favorable safety/efficacy ratio. [21][22][23][24] Direct inhibition to FXa has therefore emerged as an attractive strategy for the discovery of novel antithrombotic agents. [25][26][27][28][29][30][31] In preceding papers, 1,2) we reported the synthesis and evaluation of compounds in a series of 1-arylsulfonyl-3-piperazinone derivatives, of which M55113 (1) 4--2-piperazinecarboxylic acid were found to be potent inhibitors of FXa (IC 50 ϭ60 nM, 31 nM, 6 nM, respectively) with high selectivity for FXa over trypsin and thrombin.In more recent investigations, fixation of the conformation of testing compounds is believed to affect the strength of interaction between such compounds and the target enzyme. Accordingly, in the next stage of investigation our interest was focused on the synthesis of compounds containing a rigid structure in the central part of the compound (2, 3), and on comparison of the inhibitory activities of the compounds thus synthesized for FXa with those of previously reported compounds. A molecule with a spiro structure in between the piperidine moiety and piperazine moiety was therefore designed as the next candidate for further development of FXa inhibitor. The present paper concerns the synthesis of a series of compounds 4 with a spiro[5H-oxazolo[3,2-a]pyrazine-2(3H),4Ј-piperidin]-5-one skeleton, together with the FXa inhibitory activities of these new compounds. ChemistryFirst, acyclic precursor 9 was prepared as shown in Chart 1. Sulfonylamidation of glycine ethyl ester hydrochloride (5) with 6-chloro-2-naphthalenesulfonyl chloride (6) under traditional conditions yielded the corresponding naphthalenesulfonylamide 7. When 7 was treated with 1-acetoxy-3-chloroacetone (8) in DMF in the presence of potassium carbonate, 9 was obtained in good yield as expected.When 4-(aminomethyl)-1-benzyl-4-piperidinol (10) was allowed to react with acyclic precursor 9 under acidic conditions, a product 11 containing a spiro N,O-acetal structure on the piperazinone ring was obtained, as expected.The reaction pathway of the formation of the spiro skeleton from 9 and 10 is illustrated in Chart 2. In the first step, a Schiff base was formed by dehydration between a carbonyl group in 9 and a primary amino group in 10. Subsequent nucleophilic addition of a hydroxyl group to an azomethine Discovery Research Center, Mochida Pharmaceutical Co., Ltd.; 722 Jimba-aza-uenohara, Gotemba, Shizuoka 412-852...

Treatment of unsaturated imines and hydrazones with (q2-~ropene)Ti(OPri)~ induces bicyclization in excellent yields, providing an efficient preparation of cycloalkylamines, including optically active ones.

An efficient method for the construction of 12membered heterocycles with a trifluoromethyl group (3) was achieved via a nondecarboxylative Pd-catalyzed [6 + 6] annulation of six-membered trifluoromethyl benzo [d][1,3]oxazinones (1) with four-membered vinyl oxetanes (2). A variety of relatively large heterocycles 3 featuring a stereogenic trifluoromethylated carbon center, an amino group, as well as an alkenyl and a carbonate moiety were obtained. An X-ray crystallographic analysis revealed a unique 3D architecture of the products that affords an attractive chemical space. Whereas the method can be applicable for nonfluorinated substrates, the trifluoromethyl group plays a vital role in this unexpected Pd-catalyzed nondecarboxylative ring expansion.