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In total and formal syntheses of dictyodendrins A, B, C, D, E and F, the key step involved the direct construction of the pyrrolo[2,3-c]carbazole core by the gold-catalyzed annulation of a conjugated diyne with a pyrrole to form three bonds and two aromatic rings. The subsequent introduction of substituents at the C1 (Suzuki-Miyaura coupling), C2 (acylation), N3 (alkylation) and C5 positions (Ullmann coupling) provided divergent access to dictyodendrins. Some dictyodendrin analogues exhibited inhibitory activities toward CDK2/CycA2 and GSK3.

This review describes two novel synthetic routes from (S)-pyroglutaminol to (+)-lactacystin, a potent inhibitor of the 20S proteasome and from d-gluconolactone derivative to zaragozic acid C, a potent squalene synthase inhibitor. In lactacystin synthesis, the photoinduced intermolecular C(sp 3 )-H alkynylation and intramolecular C(sp 3 )-H acylation chemoselectively and stereoselectively constructed the tetrasubstituted and trisubstituted carbon centers, respectively. In the synthesis of zaragozic acid C, the stereoselective installation of the two contiguous tetrasubstituted carbons was achieved by the photochemical intramolecular C(sp 3 )-H acylation of a densely oxygenated intermediate.

We have developed regio- and chemoselective heteroelement-introducing reactions based on ate complex formation. This review is focused on novelly designed reactive species for efficient access to perfluoroalkylated aliphatic and aromatic compounds as well as Csp 2 -borylated compounds.

Multi-substituted β-lactam compounds have not only attracted considerable interest as core structures of pharmaceutical compounds such as antibiotics but also have been used as building blocks for the construction of β-amino acids. Electrophilic β-lactams can be used to enhance essential biological activities. Furthermore, the ring-opening reactions of electrophilic β-lactams can be used to provide facile access to β-amino acids. The introduction of an electronegative fluorine atom to a β-lactam ring to give the corresponding fluoro-β-lactam can be used as an effective strategy for the preparation of electrophilic β-lactams. In this review, we provide a summary of our recent research towards the direct functionalization of fluoro-β-lactams. This review has been divided into four topics, including: 1) the alkylation and hydroxyalkylation of α-bromo-α-fluoro-β-lactams (1); 2) the nickel-catalyzed cross coupling reaction of 1; 3) the asymmetric synthesis of fluoro-β-lactams using chiral ligands; and 4) the utilization of fluoro-β-lactams as highly electrophilic building blocks.

We are studying the medicinal synthetic chemistry of biomolecular component mimics such as carbohydrates, nucleosides, amino acids, and peptides. In this review, the synthesis and biological activities of iminosugars as carbohydrate mimics are discussed. Glycosidases and glycosyltransferases are involved in a wide range of anabolic and catabolic process, including digestion, the lysosomal catabolism of glycoconjugates, glycoprotein biosynthesis. Hence, modifying or blocking these processes in vivo using inhibitors is a topic of great interest from the therapeutic point of view. Iminosugars are sugars in which the endocyclic oxygen is replaced by a basic nitrogen atom. They are regarded as transition state mimics in certain types of enzyme reactions. This makes the field of iminosugars as carbohydrate mimics an exciting area of research. We synthesized all of the stereoisomers of polyhydroxypiperidines such as fagomine, 1-deoxynojirimycine, and isofagomine. In addition, their both enantiomers, as substrates for a variety of glycosidases were evaluated. Secondly, the asymmetric synthesis of α-1-C-alkyl-arabinoiminofuranoses was achieved by asymmetric allylic alkylation, RCM, and Negishi cross coupling as key reactions. Surprisingly, the L-forms showed a quite potent inhibitory activity toward rat intestinal maltase, while the activities of the D-forms were much weaker. Some of the prepared L-forms showed potent inhibitory activities towards intestinal maltase, with IC₅₀ values comparable to those of commercial drugs such as acarbose, voglibose, and miglitol, which are used in the treatment of type 2 diabetes. Among them, the inhibitory activity towards intestinal sucrase of α-1-C-L-butylarabinoiminofuranose was quite strong towards intestinal sucrase compared to the above commercial drugs.

O-Silyl cyanohydrins of beta-silyl-alpha,beta-epoxyaldehyde can function as a highly functionalized homoenolate equivalent via a tandem sequence involving base-promoted ring opening, Brook rearrangement, and alkylation at the allylic position. We named this rearrangement epoxysilane rearrangement. Based on results of mechanistic studies involving competitive experiments using diastereomeric cyanohydrins, we propose a reaction pathway involving a silicate intermediate formed by a concerted process via an anti-opening of the epoxide followed by the formation of an O-Si bond. Moreover, results of mechanistic studies on the rearrangement led to a conceptually novel approach to the chirality transfer in which epoxide chirality can be transferred into carbanion. We demonstrate the usefulness of the rearrangement through application to the following reactions: (1) reaction of gamma-p-toluenesulfonyl-alpha,beta-epoxysilane with alkyl halides and aldehydes followed by treatment with n-Bu4NF, which affords alpha,beta-unsaturated aldehydes (2) reaction of gamma-phosphonio-alpha,beta-epoxysilane with aldehydes, which affords dienol silyl ether derivatives (3) reaction of an enoate bearing an eposysilane moiety at the alpha-position with lithium enolate of 2-chloroacetamide, which affords highly functionalized cyclopropane derivatives.

Novel fluoroalkylated products where a CF(2)COOEt group was introduced at the alpha-position of alpha,beta-unsaturated ketones or the Reformatsky-type products have been obtained selectively by the reaction of BrCF(2)COOEt and alpha,beta-unsaturated ketones with Et(2)Zn in the presence of RhCl(PPh(3))(3) depending on the solvents. Furthermore, the novel alpha-fluoroalkylated products could synthesize by using various halofluoroalkyl compounds (R(f)-X) instead of BrCF(2)COOEt. On the other hand, this Reformatsky-type reaction by imines gave difluoro-beta-lactams or 3-amino-2,2-difluorocalboxylic esters without or with MgSO(4) . 7H(2)O, selectively.

Infants, whose growth and development are highly dependent upon the endocrine system, are particularly vulnerable to endocrine disruptor exposure. In our study, we examined whether or not alkylphenols, bisphenol A, benzophenone, di(2-ethylhexyl)adipate and 10 phthalates are present in containers of baby food. Furthermore, the migration into food-simulating solvents was also examined. Sixteen types of containers of baby food, obtained on the Japanese market in 2001, were examined: 8 glass bottle types, 1 plastic type, 1 metallic package (laminated with plastic) and 6 multilayered laminated film packages. Alkylphenols, benzophenone, bisphenol A and di(2-ethylhexyl)adipate were not detected in any of the samples. On the other hand, dibutylphthalate (DBP) was detected in 7 samples (1.2-9.1 micrograms/sample), and di(2-ethylhexyl)phthalate (DEHP) was detected in 15 samples (1.3-18 micrograms/sample). Migration tests were carried out for 5 samples, and the levels of DBP and DEHP that migrated into n-heptane were 0.68-1.7 micrograms/sample and 0.33-3.5 micrograms/sample, respectively. From these results, a baby's intake levels of DBP and DEHP were estimated to be about 1/2,500 and 1/90-300 of the tolerable daily intake (TDI), respectively.

This article reviews for our two kinds of projects that lipase-catalyzed asymmetric resolution of bicyclic lactams, 3-oxo-2-azabicyclo[2.2.0]hex-5-enes and 2-azabicyclo[2.2.1]hept-5-en-3-ones, possessing synthetic versatility and the development of a new type of a bicyclic amine-based chiral ligand for a catalytic asymmetric synthesis. Thus, optically active 3-oxo-2-azabicyclo[2.2.0]hex- and 3-oxo-2-azabicyclo[2.2.1]hept-5-enes were obtained conveniently by lipase-catalyzed enantioselective acylation or hydrolysis of racemates, and absolute configurations were determined by chemical correlation, X-ray crystallographic and CD spectral analyses. Furthermore, optically active 2-azanorbornylmethanols, isoquinuclidinylmethanols, 2-azanorbornylmethanethiol, and isoquinuclidinylmethanethiol were prepared from ethyl (1S,3S,4R)-2-[(R)-1-phenylethyl]-2-azabicyclo[2.2.1]hept-5-ene-3- carboxylate easily and their abilities as ligands were examined in the addition of diethylzinc to aldehydes to furnish secondary alcohols up to > 99% ee. Particularly, 2-azanorbornylmethanethiol was the most effective as ligand in the alkylation.

Nitrosamines are environmental carcinogens, and their relevance to human cancer is highly suspected. Dialkylnitrosamines require activation through metabolizing enzymes before they become ultimate electrophilic active species. This review summarizes two model systems for metabolic oxidation of dialkylnitrosamines. One system utilizes porphyrin and oxidant as a model for shunt pathway in the metabolizing pathway of cytochrome P450, and the other one utilizes Fenton reagent. Porphyrin and oxidant activated nitrosodialkylamines into direct acting mutagen by releasing aldehydes. During the process the alkylating activity was observed and alcohols are formed from the alkylation of water. Fenton reagent, consisting of iron salt and hydrogen peroxide supplemented with copper salt, activated dialkylnitrosamines into mutagens of a novel type containing an oxadiazine ring as their proposed structures. These works with model systems open a new aspect into the elucidation of the mechanism of xenobiotic metabolism.

This article reviews the efficient methods for diastereoselective and enantioselective syntheses of alpha-substituted serines. A newly designed bislactim ether, ethyl (5S)- or (5R)-3,6-diethoxy-2,5-dihydro-5-isopropyl-2-pyrazinecarboxylate, was treated with base or Lewis acid-tertiary amine to generate an enolate or enaminate (imine anion, metalloenamine). Alkylation or aldol-type reaction with the resultant enolate or enaminate proceeded in a highly diastereoselective manner to give the corresponding alkylated or aldol products, respectively. Reduction of these products with diisobutylaluminum hydride (DIBAL) followed by hydrolysis with hydrochloric acid afforded the desirable alpha-substituted serines. The enantioselective aldol-type reaction of an achiral bislactim ether, ethyl 3,6-diethoxy-2,5-dihydro-2-pyrazinecarboxylate, was also investigated by employing Sn(OSO2CF3)2-triethylamine in the presence of an external chiral ligand, (--)-sparteine. Not only a stoichiometric amount, but also a catalytic amount of (--)-sparteine promoted the highly enantioselective aldol-type reactions. Interestingly, the stereoselective outcome of the Sn(II)-mediated reaction differed from that of the Mg(II)-mediated one in the aldol-type reaction of the bislactim ethers with aliphatic aldehydes. On the other hand, chemoenzymatic synthesis of enantiomerically pure alpha-substituted serines must also be a convenient and useful procedure. Porcine liver esterase (PLE) or rabbit liver esterase (RLE) catalyzed hydrolysis of the pro-S ester group of diethyl alpha-alkyl-alpha-(benzyloxycarbonylamino)malonates to afford (R)-ethyl alpha-alkyl-alpha-(benzyloxycarbonylamino)malonates each in excellent enantiomeric excess. Enantiodivergent reductions of these acid esters readily proceeded to furnish both the corresponding enantiomeric alpha-substituted serines. Finally, the application of these methodologies mentioned above to a total synthesis of ISP-I (a potent immunosuppressive principle in the Isaria sinclairii metabolite) is described. Asymmetric total synthesis of ISP-I has been achieved in a highly stereoselective manner by utilizing the Mg(II)-promoted aldol-type reaction with ethyl (5R)-3,6-diethoxy-2,5-dihydro-5-isopropyl-2-pyrazinecarboxylate and Schlosser modification of the Wittig reaction.

New methods for asymmetric reactions developed by the author's group are outlined. They include asymmetric nitroolefination through an addition-elimination process, asymmetric synthesis utilizing 2,2'-disubstituted and 8,8'-disubstituted binaphthyl derivatives, and enantioselective alpha-alkylation of carbonyl compounds under conditions with absolutely no external chiral environmental factors.

A number of benzimidazole derivatives were synthesized and tested for cholecystokinin A (CCK-A) receptor inhibitory activity in order to study structure-activity relationships. Significant CCK-A receptor inhibitory activities were found in the compounds having carboxyl or tetrazolyl group. As the most preferred compound, 4-(5,6-dichlorobenzimidazol-2-yl)-N-(3-methoxypropyl)-N-pentylg lutaramic acid (4g) was selected.

A historical development of the chemistry of cyclic tautomer of tryptophan is reviewed. The cyclic tautomer of tryptophan, pyrrolo [2,3-b]indole-2-carboxylic acid, was prepared by dissolving N-methoxycarbonyltryptophan ester derivatives in 85% phosphoric acid or trifluoroacetic acid. The cyclic tautomer can be reverted to the indolic form with a dilute acid. The cyclic tautomer is an aniline derivative and the enamine reactivity of the indole ring in tryptophan is protected. The electrophilic substitution and oxidation of these cyclic tautomers opened a new method to prepare 5-substituted and/or 6-substituted tryptophan derivatives such as 5-bromo-, 5-hydroxy, and 6-methoxy-tryptophans. The formation and reactions of cyclic tautomers of diketopiperazines containing tryptophan and 3-indoleacetamide are also discussed. Some indole alkaloids having substituents at the benzene ring such as fumitremorgins, flustramine B, and eudistomines were synthesized by the use of these reactions. Furthermore, enantioselective alkylations of the carbanion at the 2-position of the cyclic tautomer established a new route to optically pure alpha-substituted tryptophans. The 2,3-dehydro derivative of the cyclic tautomer is an alpha, beta-unsaturated ester and was found to be a good precursor of optically pure beta-substituted tryptophans. The 3a-position of the cyclic tautomer is a benzylic position and subjected to radical reactions to give 3a-substituted-pyrroloindoles.

Immunoglobulin G (IgG) is an important protein in humoral immunity. After IgG binds to the specific foreign antigen, IgG-antigen complexes are eliminated either by making it easier for a phagocytic cell to ingest them or by activating a complement system. We found that the carboxyamidemethylated subfragments obtained from human serum IgG by reduction and alkylation of its interchain disulfide bonds, have anti-ulcerogenic, anti-inflammatory and anti-allergic activities, while no activity was recognized in the original IgG. On the other hand, some saturated and unsaturated fatty acids generally existing in microorganisms were found to have anti-inflammatory and anti-ulcerogenic activities. As the application of these researches, we synthesized hybrid compounds from sulfur-containing amines and fatty acids to make a lead compound for developing a new medicine. In this review, the experimental process will be discussed.

The reaction of gem-dibromocyclopropanes (1) with a higher-order organ-ocuprate prepared from CuCN and commercially available MeLi, followed by the addition of MeI in situ, afforded dimethylcyclopropanes (2) in good yields. The differential substitution reaction of dibromide (1a) in one pot with the higher-order organocuprate and allyl bromide gave a compound (8) in the moderate selectivity as shown in Table 3. Its stereochemistry was deduced by the reaction mechanism.