(-)-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.

2,4-Diaminopyrimidine derivatives, that were originally developed as antiviral agents, were modified to antitumor agents by: (i) introducing an amino group at C-5 on the pyrimidine ring, (ii) changing the alkyl group and the ring size of the cycloalkyl group on the beta-position of the omega-hydroxyalkylamino group, (iii) replacing the phenylalkyl group on the cycloalkyl group with the 3,4,5-trimethoxyphenylalkyl group, (iv) the esterification of the primary alcohol with diethyl phosphate and (v) introducing the thiomethyl group at C-2 on the pyrimidine ring. Among the 21 compounds prepared, 6, which has cyclobutyl at the beta-position, exhibited potent activity towards P-388 leukemia. In addition, 14, with methoxyl groups on the phenyl ring and 17, with the thiomethyl group on the pyrimidine ring, showed specific inhibition for the EGFR protein kinase. Moreover, 15 and 16, which carry the diethyl phosphoryl group on the primary alcohol, exhibited inhibitory activity towards P-glycoprotein.

An efficient new route based on intramolecular Heck cyclization of the diene 11 was developed to prepare the 4a-methyltetrahydrofluorene diterpenoids and utilized for the total synthesis of (+/-)-dichroanal B with significantly improved overall yield.

Transforming growth factor (TGF)‐β signaling facilitates tumor growth and metastasis in advanced cancer. Use of inhibitors of TGF‐β signaling may thus be a novel strategy for the treatment of patients with such cancer. In this study, we synthesized and characterized a small molecule inhibitor, A‐83‐01, which is structurally similar to previously reported ALK‐5 inhibitors developed by Sawyer et al. (2003) and blocks signaling of type I serine/threonine kinase receptors for cytokines of the TGF‐β superfamily (known as activin receptor‐like kinases; ALKs). Using a TGF‐β‐responsive reporter construct in mammalian cells, we found that A‐83‐01 inhibited the transcriptional activity induced by TGF‐β type I receptor ALK‐5 and that by activin type IB receptor ALK‐4 and nodal type I receptor ALK‐7, the kinase domains of which are structurally highly related to those of ALK‐5. A‐83‐01 was found to be more potent in the inhibition of ALK5 than a previously described ALK‐5 inhibitor, SB‐431542, and also to prevent phosphorylation of Smad2/3 and the growth inhibition induced by TGF‐β. In contrast, A‐83‐01 had little or no effect on bone morphogenetic protein type I receptors, p38 mitogen‐activated protein kinase, or extracellular regulated kinase. Consistent with these findings, A‐83‐01 inhibited the epithelial‐to‐mesenchymal transition induced by TGF‐β, suggesting that A‐83–01 and related molecules may be useful for preventing the progression of advanced cancers. (Cancer Sci 2005; 96: 791–800)

Development of odorless thiols [1-dodecanethiol (Dod-SH), 4-trimethylsilylphenylmethanethiol (TMSBM), 4-trimethylsilylbenzenethiol (TMSBT), and 6-morpholinohexanethiol (MHT)] and odorless sulfides [dodecyl methyl sulfide (Dod-S-Me), methyl 6-morpholinohexyl sulfide (MMS)] and their sulfoxides [dodecyl methyl sulfoxide (Dod-S (O) -Me), methyl 6-morpholinohexyl sulfoxide (MMSO)] as odorless substitutes for the foul-smelling ethanethiol, benzyl mercaptan, benzenethiol, and dimethyl sulfide (DMS) is described. They are conveniently applied for dealkylation, thiol exchange reaction, reductive ozonolysis, Corey-Kim oxidation, Swern oxidation, hydroboration, and reduction. The products of these reactions utilizing morpholine based thiol MHT, sulfide MMS and its sulfoxide MMSO can be easily purified by only acid-base extraction without involving chromatography, thereby eliminating unpleasant odors, saving time and protecting the environment. In view of current environmental and economic factors, the utility of these simple reagents could be enormously beneficial.

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.

The use of the bisfluorous chain-type propanoyl (Bfp) group as a fluorous protective group made it possible to rapidly synthesize the Gb2 and Gb3 oligosaccharide derivatives by a simple fluorous-organic extraction purification. Furthermore, the fluorescence-labeled Gb2 and Gb3 oligosaccharides were prepared as a potential Vero Toxins detecting reagent.

Optically active cis-β,γ-disubstituted-γ-butyrolactones, for example, cis-whisky lactone and cis-cognac lactone, were readily synthesized by using tandem Michael–Meerwein–Ponndorf–Verley reactions that employed (−)-10-mercapto-isoborneol as a chiral template in the key step.

Bis[4-(trimethylsilyl)phenyl]diselenide (3) and bis[4(trimethylsilyl)phenyl]disulfide (31) are found to be odorless equivalents of the commonly used diphenyl diselenide and diphenyl disulfide, respectively. The diselenide 3 is shown to be useful in the preparation of odorless selenium(II) chloride 26 and selenium(IV) trichloride 28 that follow similar reactivity patterns to their phenyl derivatives and can be stored refrigerated under dry conditions. The corresponding selenium(II) bromide had to be prepared fresh from 3 before use. It is also shown that the trimethylsilyl group in the sulfide products can be protodesilylated quantitatively using TFA.

Optically active 2,6-dimethylcyclohexanone-2-carboxylate was prepared by PLE-catalyzed dealkoxycarbonylation of sigma-symmetrical beta-ketodiesters, which possess quarternary carbons at alpha- and alpha'-positions. Moreover, (-)-podocarpic acid was prepared in a short sequence from 2,6-dimethyleyclohexanone-2-carboxylate.

Three crinane type of alkaloids isolated from Amaryllidaceae family were synthesized by taking advantage of the PIFA-mediated intramolecular p-p′ diphenol coupling reaction of norbelladine derivatives. Furthermore, buflavine was also prepared by using the p-p′ diphenol coupling followed by dienone–phenol rearrangement as a key step.

A new and effective asymmetric synthesis of anti-1,3-mercapto alcohols 3 from a,p-unsaturated ketones 1 utilizing tandem Michael addition-Meerwein-Ponndorf-Verley (MPV) reduction is described. Transformation of the MPV products anti-4 via the Wagner-Meerwein rearrangement was optimized under acidic or basic conditions to afford 1,3-mercapto alcohols anti-3, depending on the substituent R-2 of 4. (C) 2004 Elsevier Ltd. All rights reserved.

3β-Methoxyserrat-14-en-21β-ol (1) and 3α-methoxyserrat-14-en-21β-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 13α,14α-epoxy-3β-methoxyserratan-21β-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.

Methyl 6-morpholinohexyl sulfide (3a, MMS) and methyl 6-morpholinohexyl sulfoxide (7, MMSO) have been employed as efficient odorless substitutes for dimethyl sulfide (DMS) and dimethyl sulfoxide (DMSO) in Corey–Kim and Swern oxidations, respectively. The oxidation products and the byproduct 3a are easily separable by simple aqueous extraction. The Corey–Kim oxidation was studied in various solvents. The utility of the odorless 6-morpholinohexan-1-thiol (2a) in the dealkylation of phenyl ethers and methyl esters is also presented.

Odorless Dod-S-Me (1) and MMS (3) are developed as efficient borane carriers. The yields of hydroborations and reductions with borane complex 2 of 1 are very high and the recovery of 1 after the reaction is quantitative. The borane complexes 4 and 5 of 3 are also useful. In the latter case chromatographic separation is unnecessary when excess oxidizing agent (alkaline H2O2) is used after hydroboration.

Asymmetric reductions of methoxy substituted 2-tetralones were studied. The asymmetric transfer hydrogenation reaction developed by Noyori using chiral η6-arene–ruthenium complexes (arene = p-cymene or benzene) was found to efficiently reduce various methoxy substituted 2-tetralones with >80% ee. Their enantiomeric excesses were found to depend on the position of the methoxy group and the types of the arene complexes. The conditions were identified for the asymmetric reduction of 8-methoxy-2-tetralone to the corresponding 2-tetralol in 98% ee, which was notably higher in enantioselectivity than the other methoxy substituted 2-tetralones.

Development of the odorless dodecyl methyl sulfide (Dod-S-Me, 1) as an alternative for dimethyl sulfide (DMS) and new odorless methods for the Corey–Kim and Swern oxidations are described. These reactions have been developed with a view toward green chemistry, utilizing Dod-S-Me (1) and common solvents instead of dichloromethane.

AbstractFor Abstract see ChemInform Abstract in Full Text.

The first tandem cationic [4++2] polar cycloaddition–elimination reaction of 1-thia-1,3-butadienyl cations B with olefins to afford directly 3,4-dihydro-2H-thiopyrans D is described. The cations B were easily accessible by treatment of monothioacetals A, particularly the 2-alkenyl-4,4-dimethyl-1,3-oxathianes 1, with a hard Lewis acid. In this novel reaction, 2-alkenyl-4,4-dimethyl-1,3-oxathianes were utilized as synthetic equivalents for highly reactive α,β-unsaturated thioaldehydes. The effect of geminal dimethyl substituents on the oxathianes 1 and the mechanistic aspect of the reaction are considered. The reaction's asymmetric version was also investigated using a chiral oxathiane 4 derived from (−)-(1R,2R,5R)-2-(1-mercapto-1-methylethyl)-5-methylcyclohexanol. Although the enantioselectivities were moderate, the whole process can be done under odorless conditions.

X-Ray crystallographic analyses of fluorocyanides anti-1 and 2 revealed a novel intramolecular through-space interaction between F and CN in an acyclic system, which was applied to a stereoselective protonation of acyclic fluorocyanides 2 having flexible conformation.