Yoshihiro Matsushita

An efficient synthesis of a key intermediate for optically active 5,6-cis-carbapenem antibiotics

Abstract A versatile intermediate (18) for optically active 5,6- cis -carbapenem antibiotics was synthesized with a highly regioselective intramolecular aldol condensation as a key step.

Structure-based discovery of cellular-active allosteric inhibitors of FAK.

In order to develop potent and selective focal adhesion kinase (FAK) inhibitors, synthetic studies on pyrazolo[4,3-c][2,1]benzothiazines targeted for the FAK allosteric site were carried out. Based on the X-ray structural analysis of the co-crystal of the lead compound, 8-(4-ethylphenyl)-5-methyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazine 4,4-dioxide 1 with FAK, we designed and prepared 1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin derivatives which selectively inhibited kinase activity of FAK without affecting seven other kinases. The optimized compound, N-(4-tert-butylbenzyl)-1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin-8-amine 4,4-dioxide 30 possessed significant FAK kinase inhibitory activities both in cell-free (IC50=0.64μM) and in cellular assays (IC50=7.1μM). These results clearly demonstrated a potential of FAK allosteric inhibitors as antitumor agents.

Synthesis of lactivicin analogues

Abstract Aza analogues of lactivicin (1), a recently discovered novel antibiotic, were prepared by an application of our earlier convenient synthesis of 1 and its derivatives. A 1-unsubstituted pyrazolidinone derivative bearing 2-aminothiazol-4-yl-(Z)-methoxyiminoacetyl group exhibited in vitro antibacterial activity.

Optically Active Antifungal Azoles. V. Synthesis and Antifungal Activity of Stereoisomers of 3-Azolyl-2-(substituted phenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanols

The (2S,3S)-, (2R,3S)- and (2S,3R)-stereoisomers of (2R,3R)-3-azolyl-2-(substituted phenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanols [(2R,3R)-1a--d] were prepared and evaluated for antifungal activity against Candida albicans in vitro and in vivo to clarify the relationships between stereochemistry and biological activities. The results revealed that the in vitro antifungal activity in each set of the four stereoisomers [(2R,3R)-, (2S,3S)-, (2R,3S)- and (2S,3R)-1a--d] definitely paralleled the in vivo antifungal activity against candidosis in mice, and the order of potency was (2R,3R) >> (2R,3S) > or = (2S,3S) > or = (2S,3R). In addition, the four stereoisomers in each set were assessed for sterol biosynthesis-inhibitory activities in C. albicans and rat liver. The (2R,3R)-isomer was found to exert a strong and selective inhibitory effect on the sterol synthesis in C. albicans as compared with that in rat liver.

SYNTHESIS AND STRUCTURE-ACTIVITY RELATIONSHIPS OF 7β-[2-(2-AMINOTHIAZOL-4-YL)ACETAMIDO]CEPHALOSPORIN DERIVATIVES

In an effort to improve the antibacterial activity of 7 beta-[2-(2-aminothiazol-4-yl)acetamido]-cephalosporins by introducing a methoxyimino group into the 7-acyl side chain, geometrically isomeric 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acids and their derivatives were selectively synthesized. Structurally related acid derivatives were also synthesized. A facile and practical synthesis of an important starting material, 2-(2-chloroacetamidothiazol-4-yl)-(Z)-2-methoxyiminoacetic acid, for the preparation of SCE-1365 which is now under extensive clinical trial was achieved.

Synthesis of 5,6-cis-carbapenems related to C-19393 H2

The synthesis of 6,7-cis-7-(1-hydroxy-1-methylethyl)-3-oxa-1-azabicyclo[4.2.0]octan-8-ones (3a, b), key intermediates for the preparation of the 5,6-cis-carbapenem antibiotic C-19393 H2{sodium (5R, 6R)-3-[(E)-(2-acetamidoethenyl)-(R)-sulphinyl]-6-(1-hydroxy-1-methylethyl)-7-oxo-1-azabicyclo-[3.2.0]hept-2-ene-2-carboxylate}(1a) and its derivatives, was investigated. Sulphenylation of the 3-oxa-1-azabicyclo[4.2.0]octan-8-ones (2a, b), followed by the aldol reaction with acetone, gave the 7-(1-hydroxy-1-methylethyl)-7-sulphenyl derivatives (7a—e). Reductive desulphurization of compounds (7a—e) with an organotin hydride (tri-n-butyltin hydride or triphenyltin hydride) in the presence of a radical initiator gave rise to stereoselective formation of the cis-azetidinones (3a, b). A total synthesis of (±)-C-19393 H2(1a) and its derivatives having other substituents at the C (3) position, (1b—e), starting from (3a, b)via a carbene insertion reaction, is also described.

A method for the preparation of 7?-methoxycephalosporins

A method for the preparation of 7α-methoxycephalosporins has been developed. 7β-Phosphoramidodeacetoxycephalosporin (6) and 7β-phosphoramidocephalosporin (14) obtained from the 7β-amino-derivatives (5) and (13), were converted into 7α-methoxy-7β-phosphoramidodeacetoxycephalosporin (7) and 7α-methoxy-7β-phosphoramidocephalosporin (15), respectively, by reaction with LiOMe and ButOCl. Treatment of (7) with BunLi and Et3N followed by acylation with phenylacetyl chloride gave 7α-methoxy-7β-phenylketenimino-derivative (11), which were easily hydrated to 7α-methoxy-7β-(phenylacetamido)deacetoxycephalosporin (12). Treatment of (15) under similar conditions afforded, contrary to the result obtained with (7), 7α-methoxy-7β-(phenylacetamido)cephalosporin (16), without any of the corresponding ketenimine. This method was also successfully applied to the synthesis of 6α-methoxypenicillins.