Keita Matsumoto

Stereocontrolled synthesis of hydroxymethylene phosphonate analogues of phosphorylated tyrosine and their conversion to monofluoromethylene phosphonate analogues

Abstract A stereocontrolled synthesis of protected variants 13 and 15 of HPmp 2 , a mimic of phosphorylated tyrosine, was achieved through either chiral-auxiliary assisted or chiral heterobimetal catalyzed stereoselective hydrophosphonylation of 4-formyl- l -phenylalanine derivative 7 . Fluorination of HPmp derivatives 13 and 15 thus obtained was carried out to give FPmp derivatives 16 and 17 .

Synthesis of (2′S,3′S)-9-(4′-phosphono-4′,4′-difluoro-2′,3′-methanobutyl)guanine and its enantiomer. Evaluation of the inhibitory activity for purine nucleoside phosphorylase

Abstract Conformationally constrained analogues 2a and ent - 2a of 9-(difluorophosphonopentyl)guanines 1 , a multi-substrate analogue inhibitor of PNP, were prepared from optically active trans -1-(diethoxyphosphinyl)difluromethy-2-hydroxymethylcyclopropanes (+)− 6 and (−)− 6 . Enzymatic double resolution was applied to obtain (+)- 6 and (−)- 6 with high enantiomeric purity. Inhibitory activity of 2a and ent - 2a were found to be 2400-fold less potent than 1 .

Aragusterol C : a novel halogenated marine steroid from an Okinawan sponge, Xestospongia sp., possessing potent antitumor activity

A novel chlorinated steroid, aragusterol C, was isolated from an Okinawan marine sponge of the genusXestospongia. The compound strongly inhibited the proliferation of KB cells in vitro, and also showed potent in vivo antitumor activity against L1210 cells in mice. The complete structure of aragusterol C was determined by spectroscopic analysis and X-ray crystallographic analysis.

Lipase-catalyzed kinetic resolution of cis-1-diethylphosphonomethyl-2-hydroxymethylcyclohexane. Application to enantioselective synthesis of 1-diethylphosphonomethyl-2-(5′-hydantoinyl)cyclohexane

Abstract A kinetic resolution of cis-1-diethylphosphonomethyl-2-hydroxymethylcyclohexane1 by lipase has been developed. The transesterification of (±)− 1 with vinyl acetate in the presence of Lipase AK without solvent proceeded to give (+)−1 and the corresponding acetate (+)−5 in good yield and high enantiomeric ratio. The alcohol (+)−1 was transformed to the optically active hydantoins 12 and 13, possible intermediates for the synthesis of conformational constrained analogues of AP-5.

A highly asymmetric Pummerer-type cyclization of chiral, non-racemic β-amidosulfoxides induced by O-silylated ketene acetals

The first highly asymmetric Pummerer-type cyclization of chiral, non-racemic β-amidosulfoxides leading to enantiomerically enriched β-lactams (80–85 % ee) is described. S-and R-sulfoxides (S-2a-d and R-2a-c) were treated with O-methyl-O-tert-butyldimethylsilyl ketene acetal (1) in the presence of a catalytic amount of ZnCl2 in CH2Cl2 to predominantly give the corresponding 4R- and 4S-β-lactams (R-4a-d and S-4a-c) in more than 80 % ee. These results show that the stereoinduction is completely influenced by the absolute configuration of the sulfoxides.

Preparation of bis(arylthio)iodobenzene and reaction with 1-alkynes. A novel route to 1,2-bis(arylthio)alkenes

The in situ reaction of a novel hypervalent iodine reagent 2b having an arylthio ligand, prepared from phenyliodine diacetate and 2,3,5,6-tetrafluorothiophenol 1b in pyridine, with 1-alkynes 3 gave 1,2-bis(arylthio)alkenes 4 in good yields.

Clarification of substrate specificity of papain by crystal analyses of complexes with covalent-type inhibitors

In order to investigate the stereo specificity of papain Sn subsites (n = 1-4) at the atomic level, two kinds of covalent-type inhibitors were designed based on the previous results on papain-E-64 and papain-E-64-c interactions, and their complex crystals with papain were analyzed by X-ray diffraction. The results show that the hydrophobic regions consisting of Val-133, Val-157 and Asp-158 and of Tyr-61, Gly-66 and Tyr-67 residues interact with the hydrophobic P2 and P3 side chains of inhibitors, thus indicating the function of the former and latter binding pockets as S2 and S3 subsites, respectively. Furthermore, the X-ray analysis suggests that the papain has no definite Sn subsite of n > or = 4, and the S3-P3 hydrophobic interaction is significantly affected by the Pn side chain (n > or = 4) of both the substrate and the inhibitor.

Stereochemistry of the 2-hydroxy-1,2,3,4-tetrahydropyridine intermediate of hantzsch cyclization

Abstract Hantzsch cyclization of cyanoethyl 3-aminocrotonate and (E,Z)-4-dialkoxymethyl-2-benzylidene-acetoacetates (5a,b) afforded 3,4-trans-2-hydr

Highly asymmetric Pummerer-type cyclization of chiral, non-racemic β-amido sulfoxides

The first highly asymmetric Pummerer-type cyclization of chiral, non-racemic β-amido sulfoxides to enantiomerically enriched β-lactams (80–85% ee) is described. S- and R-Sulfoxides (S-2a–d and R-2a–c) were treated with O-methyl-O-tert-butyldimethylsilyl ketene acetal 1 in the presence of a catalytic amount of zinc chloride in methylene dichloride to give predominantly the corresponding 4R- and 4S-β-lactams (R-3a–d and S-3a–c) in more than 80% ee. These results show that the stereoinduction is governed by the absolute configuration of the sulfoxides. Optically pure R- and S-3c were readily obtained by simple recrystallization in about 60% yield. The usefulness of the chiral, non-racemic 4-tolylsulfanyl-β-lactams 3a–d has been shown by their conversion into the key intermediate 11 for the optically pure carbapenem antibiotic, (+)-PS-5.

Diastereotopic group selective intramolecular conjugate addition of 4-(2-hydroxyethyl)-p-quinol derivatives: Synthesis of the optically pure cis-7-oxabicyclo[4.3.0]non-2-en-4-one skeleton

Abstract Diastereotopic group selective cyclizadon of 4-(2-hydroxyethyl)-p-quinol derivatives was achieved and the reaction applied to the synthesis of the optically pure cis-7-oxabicyclo[4.3.0]non-2-en-4-one skeleton.