Green Synthesis of (R)-Terbutaline for Recyclable Catalytic Asymmetric Transfer Hydrogenation in Ionic Liquids.

We synthesize optically active (R)-terbutaline 2, which is an anti-asthmatic drug, through recyclable catalytic asymmetric transfer hydrogenation (RCATH). Various chloroketones 4 were prepared and RCATH was performed on them. The products exhibit moderate to high enantioselectivity. In particular, the hydrogenation of acyl substituted substrates 4c yields chiral secondary alcohols 5c in good yield and enantioselectivity. Furthermore, (R)-terbutaline 2 can be synthesized in one step from the resulting secondary alcohol 5 without racemization.

A mechanistic investigation of anti-elimination in (Z)-1,2-bis(arylseleno)-1-alkenes and their sulfur analogs.

The oxidation of (Z)-1,2-bis(arylseleno)-1-alkenes is known to afford alkynyl selenoxides via a unique selenoxide anti-elimination mechanism; however, to date, there have been no mechanistic studies of this reaction. During our studies of this transformation, monoselenoxides 6 and 7 were unexpectedly isolated as stable reaction intermediates. In addition, (77)Se NMR studies of the reaction mixture revealed the presence of an intramolecular Se···O interaction and the formation of alkynyl selenoxides. Meanwhile, even at higher temperatures, the reaction of a (Z)-1,2-bis(arylsulfinyl)-1-alkene, the sulfur analog of (Z)-1,2-bis(arylseleninyl)-1-alkenes, did not proceed via sulfoxide elimination but proceeded via isomerization and disproportionation. Therefore, the intramolecular Se···O interaction can be concluded to play a pivotal role in the anti-elimination reaction.

Preparation of chiral ligands connected with quaternary ammonium group for recyclable catalytic asymmetric transfer hydrogenation in ionic liquid.

Reuse of chiral ruthenium catalyst in catalytic asymmetric transfer hydrogenation (CATH) has attracted attention from economic and environmental viewpoints, and reactions using ionic liquids (ILs) as solvent are recognized as one of the most useful methods for reuse of the catalyst. We synthesized (1S,2S)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (TsDPEN) derivatives with various ionic moieties, and investigated the effect of their structure with respect to catalytic ability and recyclability in CATH with ILs. Ligand 3a having an imidazolium group showed the best results, and significant differences were observed depending on the structure of the ionic moiety or the length of the alkyl chain connecting the ligand site and the ionic moiety. Among various prochiral ketones used as substrates at various cycles, 3a showed a relatively good result.

Preparation of benzo[b]furans having five-membered heterocycles at the 2-position and 2-(4-Alkylcarbamoylbuta-1,3-dienyl)benzo[b]furans, and their cysteinyl leukotriene receptor (cysLT1, cysLT2) inhibitory activity.

A series of benzo[b]furan derivatives having a five-membered heterocyclic substituent at the 2-position were prepared from 2-(1-chloro-2-formylvinyl)benzo[b]furans (2) and 2-(4-alkylcarbamoylbuta-1,3-dienyl)benzo[b]furans. These 2-heterocyclic benzo[b]furans were evaluated for their cysteinyl leukotriene receptor (cysLT1, cysLT2) inhibitory activity. Several compounds showed moderate inhibition of calcium mobilization in HEK 293T-cysLT2 or CHO-cysLT1 cells.

Preparation of novel (Z)-4-ylidenebenzo[b]furo[3,2-d][1,3]oxazines and their biological activity.

A reaction of 2-acetyl-3-acylaminobenzo[b]furans (9d-o) with Vilsmeier (VM) reagent afforded a mixture of (E)- and (Z)-{(E)-2-aralkenylbenzo[b]furo[3,2-d][1,3]oxazin-4-ylidene}acetaldehydes (5) with a characteristic exo-formylmethylene group on the oxazine ring. The Z-isomer was more stable than the E-isomer. The Z-isomers ((Z)-5) were reacted with phosphonate reagents under two different conditions to obtain various butadiene derivatives (12) containing benzo[b]furo[3,2-d][1,3]oxazine skeleton. Typical compounds (5 and 12) were evaluated for their anti-osteoclastic bone resorption activity, antagonistic activity for the cysLT1 receptor and growth inhibitory activity for MIA PaCa-2 and MCF-7. Compounds 12f and 12j showed potent anti-osteoclastic bone resorption activity comparable to E(2) (17beta-estradiol).

The application of phenylmethanethiol and benzenethiol derivatives as odorless organosulfur reagents in the synthesis of thiosugars and thioglycosides.

p-octyloxyphenylmethanethiol and p-dodecylbenzenethiol were prepared as new odorless organosulfur reagents. Thiosugars and thioglycosides were synthesized using these reagents without encountering any malodorous procedures.

Cancer chemopreventive activity of 3beta-methoxyserrat-14-en-21beta-ol and several serratane analogs on two-stage mouse skin carcinogenesis.

3beta-Methoxyserrat-14-en-21beta-ol (1) and 3alpha-methoxyserrat-14-en-21beta-ol (2) are the most abundant triterpenoids from two Picea plants, Picea jezoensis (Sieb. et Zucc.) Carr. var. jezoensis and P. jezoensis (Sieb. et Zucc.) Carr. hondoensis (Mayr) Rehder, and the total yield of 1 and 2 reach over 1/3 of the chloroform extract of the above two plants. This study deals with the potential of anti-tumor promoting activity of 1 and results of the assay of 22 synthetic serratane-type triterpenoids (6)-(27) derived from 1, 2, 21-episerratenediol (3), diepiserratenediol (4) and 13alpha,14alpha-epoxy-3beta-methoxyserratan-21beta-ol (5) to discuss the structure-activity relationship. As a preliminary evaluation of their potential to inhibit tumor promotion, the inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) were used. All compounds except for 12 and 19 showed potent inhibitory effects on EBV-EA induction (100% inhibition at 1000 mol ratio/TPA), their effects being stronger than that of a positive control oleanolic acid. Compounds 1, 13, 14, 18, 20 and 26 were selected to examine the effect on the in vivo two-stage mouse skin carcinogenesis test induced by 7,12-dimethylbenz[a]anthracene (DMBA) as an initiator and TPA as a promoter. The most abundant triterpenoid 1 and the synthetic compounds 13 and 14 were found to exhibit the excellent anti-tumor promoting activity in the in vivo carcinogenesis test, and compounds 18, 20 and 26 also showed strong inhibitory effects.

Preparation and application of odorless 1,3-propanedithiol reagents.

2-Dodecyl-1,3-propanedithiol (2a) was prepared without a malodorous procedure as an odorless reagent that was usable in place of 1,3-propanedithiol (1) in organic reactions, e.g., in the reduction of azides and protection of carbonyl groups. The 1,3-dithioacetals obtained in the latter reaction were effectively reduced to methylene with Raney nickel and reconverted to the original carbonyl compounds by hydrolysis with N-bromosuccinimide in aqueous 2-butanone. In addition, the anion of 1,3-dithiane prepared from 2a and formaldehyde could be utilized as a synthetic equivalent of an anionic carbonyl carbon.

Biomimetic synthesis of (+/-)-galanthamine and asymmetric synthesis of (-)-galanthamine using remote asymmetric induction.

(+/-)-Galanthamine (1) was synthesized in excellent yield by applying PIFA-mediated oxidative phenol coupling of N-(4-hydroxy)phenethyl-N-(3',4',5'-trialkoxy)benzyl formamide (15b) as a key step. Because of the symmetrical characteristics of the pyrogallol moiety in the substrate (15b), the phenol coupling resulted in a sole coupling product except for volatile components from the oxidizing agent. On the basis of the successful results of the above strategy, (-)-galanthamine (1) was synthesized by employing a novel remote asymmetric induction, where conformation of the seven-membered ring in the product of the phenol coupling was restricted by forming a fused-chiral imidazolidinone ring with D-phenylalanine on the benzylic C-N bond of the tri-O-alkylated gallyl amino moiety. The conformational restriction and successive debenzylation of the protected hydroxyl groups on the pyrogallol ring caused diastereoselective cyclization to yield a cyclic ether having the desired stereochemistry for the synthesis of (-)-1.

Synthesis of (-)-epibatidine and its derivatives from chiral allene-1,3-dicarboxylate esters.

(-)-Epibatidine, an excellent candidate of non-opioidal anesthesia, was formally synthesized in short steps from di-(l)-menthyl (R)-allene-1,3-dicarboxylate that was facilely prepared as a single isomer by means of crystallization-induced asymmetric transformation from a diastereomer mixture of (R)- and (S)-allene-1,3-dicarboxylates. Taking advantage of the chiral synthesis, derivatives of (-)-epibatidine were also prepared for targeting diagnostic agents that could bind nicotinic acetylcholine receptors (nAChRs) in the mammalian central nerve system.

Quorum sensing system lactones do not increase invasiveness of a MexAB-OprM efflux mutant but do play a partial role in Pseudomonas aeruginosa invasion.

We studied the quorum sensing (QS) system and the related homoserine lactones (HSLs) observing Pseudomonas aeruginosa invasion using the epithelial cell monolayer penetration assay model. Compared to the PAO1 wild-type, the QS mutants, DeltalasI and DeltarhlI, were compromised in their capacity to invade. The decreased invasiveness of DeltarhlI was restored by adding 100 microM exogenous C(4)-HSL. However, the decreased invasiveness of an efflux mutant, DeltamexAB-oprM, was not restored in the presence of exogenous HSLs. The QS system partially plays a role in P. aeruginosa invasion; however, C(4)-HSL and 3-O-C(12)-HSL are not the essential determinants for invasiveness for P. aeruginosa.

Recent development of asymmetric syntheses based on the Meerwein-Ponndorf-Verley reduction.

Stereoselective Meerwein-Ponndorf-Verley (MVP) reductions, including intermolecular MPV reductions, intramolecular MPV reductions (asymmetric 1,5- and 1,7-hydride shifts), catalytic MPV reduction, and reactions related to the MPV reduction are reviewed from the standpoint of asymmetric synthesis.

A new synthesis of a potent cancer chemopreventive agent, 13-oxo-15,16-dinorlabda-8(17),11E-dien-19-oic acid from trans-communic acid.

The first synthesis of a labdane diterpenoid, (-)-13-oxo-15,16-dinorlabda-8(17),11E-dien-19-oic acid [(-)-1a], isolated from the stem bark of Thuja standishii (GORD.) CARR., from the major component trans-communic acid (3a) is described.