We reported asymmetric reduction of σ-symmetrical β-diketones utilizing baker's yeast. Inversion of diastereoselectivity caused by a change in substrate concentration was first observed in baker's yeast-catalyzed reduction of σ-symmetrical 2,2-dialkylated 1,3-cyclopentadiones and 1,3-cyclohexadiones which have α,β-unsaturated ester moiety in 2-position. The selectivity altered by degrees depending on the substrate concentration from 8 mM to 40 mM. Meanwhile, application of the yeast-catalyzed reduction to the hydrogenated compound of α,β-unsaturated ester afforded a single diastereomer in good yield when the reaction was conducted in high substrate concentration (40 mM).
Finally, we report the synthetic application to the asymmetric synthesis of 13-oxo-15,16-dinorlabda-8(17),11E-dien-19-oic acid which isolated from Thuja standishii (GORD.) CARR exhibited anti-tumor promoting activity.

抄録全体を表示

Recently, we have reported a straightforward chemo-enzymatic synthesis of acyl glucuronides of three NSAIDs. The methyl acetyl derivatives of these 1-β-O-acyl glucuronides, which are easily obtained, are subsequently converted to the desired products in high yields via chemo-selective deprotecting of acetyl and methyl ester groups using lipase AS Amano (LAS) and esterase from porcine liver (PLE), respectively. The chemo-selectivities in the enzymatic hydrolyses, however, depend on the nature of 1-O-acyl group of acyl glucuronide. Therefore, to improve the validity and usefulness of this method, we screened other possible enzymes alternative to LAS and PLE, and found two predominant enzymes, CSR (carboxylesterase from Streptmyces rochei) and CAL-B (Candida antarctica type B). Under appropriate conditions, we could obtain various acyl glucuronides by using not only LAS and PLE but also CSR and CAL-B.

抄録全体を表示

A few fructofuranosylation methods have been reported, however the efficient and stereospecific synthesis of non-reducing disaccharides as sucrose mimics is a still difficult problem. We examined the fructofuranosylation of 1,3,4,6-tetra-O-benzyl-D-fructofuranosyl acetate with alcohols in the presence of 5 mol% Sc(OTf)₃, and found the corresponding fructofuranosides were obtained in high yields. The a/b anomer ratios were 60/40-78/22. Next, 1,3,4,6-tetra-O-benzoyl-D-fructofuranosyl acetate was used as a glycosyl donor. This fructofuranosylation was expected to show the high a-stereoselectivities by the participating group at the 3-position of the glycosyl donor. This experiment showed the expected result that the a-fructofuranosides were stereoselectively produced. Moreover, we successfully achieved the synthesis of several non-reducing disaccharides as the sucrose mimics by the fructofuranosylation to aldopyranoses.

抄録全体を表示

We have reported our synthetic 5,8-disubstituted indolizidine alkaloid 235B' showed very nice, selective blockade on α4β2-nicotinic acetylcholine receptors. On the other hand, our synthetic 1-epi-207I showed selective blockade on α7-nicotinic receptors. We synthesized the poison-frog alkaloids 233A, 235U, and 251AA, which possess the same relative stereochemistry with 1-epi-207I, and the relative stereochemistry of these natural products was determined by these syntheses. The effects of these quinolizidines on acetylcholine-elicited currents through α7 and α4β2 nicotinic receptors expressed in Xenopus oocytes. The alkaloid 233A blocked alpha7 and α4β2 currents to a similar extent. 235U and 251AA also showed non-selective blockade of α7 and α4β2 currents.

抄録全体を表示

Evaluation of the effectiveness of organic synthesis is controversial. We had proposed three measures such as the originality rate (OR), the intellectual property factor (IPF), and the application potential factor (APF) and the formulas for calculating OR, IPF, and APF. The higher these values, the more effective synthesis.
On the basis of the above philosophy, a highly effective six-step synthetic method as a concrete example aimed at the leads for an alpha2-blocker, an inhibitor of platelet aggregation, and an anti-osteoporosis agent is established starting from tryptamine. The OR, IPF, and APF values of the method are 71, 54, and 100, respectively. The method employs only conventional reagents and reaction conditions without using any protecting groups.

抄録全体を表示

We have proposed that different tautomeric forms of certain bioorganic molecules may be preferred by sub-types of biological receptors that mediate different biological responses. To study this, we focused on the tryptamine moiety present in such important structures as melatonin and the triptan drugs. Tryptamines may have three different tautomeric forms, the indole form, the indolenine form, and the pyrrolo[2,3-b]indole form. We have synthesized 3-fluorooxindole and 3a-fluoropyrrolo[2,3-b]indole as 'pseudologs' of the indolenine and the pyrrolo[2,3-b]indole minor tautomers, respectively, by electrophilic fluorination of the corresponding indoles with selectfluor or N-fluoropyridinium salts. These fluorinated tryptamines are stable analogs of minor tautomers that have a fluorine atom at the tautomerically labile position. They are also interesting in there own pharmacological activities.

抄録全体を表示

Paclitaxel is considered to be one of the most important drugs in cancer chemotherapy. However, this agent has lack of selectivity to the tumor tissue. To overcome this problem, we designed and synthesized a photoresponsive targeting prodrug of paclitaxel, which has a coumarin derivative conjugated to an amino group of isotaxel (O-acyl isoform of paclitaxel). 7-N,N-Diethylamino-4-hydroxymethyl coumarin (DECM) was chosen as a photolabile group since DECM-caged compounds have been reported to be water-soluble, thermally stable, and rapidly photolyzed by visible light. The prodrug, phototaxel, released parent drug, paclitaxel, with a reasonable conversion time by visible light irradiation (430 nm) and subsequent spontaneous O-N intramolecular acyl migration. This result suggesting that this strategy is practically applicable for wide range of anticancer agents to develop new photoresponsive prodrugs.

抄録全体を表示

We reported potent and small-sized BACE1 inhibitors containing phenylnorstatine [(2R,3S)-3-amino-2-hydroxy-4-phenylbutyric acid; Pns] at P1 position as a transition-state mimic. We replaced the Pns by its thio-derivative. Herein, we present the synthesis of a novel phenylthionorstatine [(2R,3R)-3-amino-2-hydroxy-4-(phenylthio)butyric acid; Ptns] as a P1 moiety, and then, an application to the BACE1 inhibitors design. We have synthesized Ptns starting from readily available N-benzyloxycarbonyl-serine and after multistep reaction (including Weinreb amide formation, thiophenyl group introduction, through cyanohydrin derivative the transformation into the 2-hydroxy ester and then acid). Ptns was applied to SPPS (solid phase peptide synthesis). The peptide inhibitors of BACE1 containing Pns or Ptns at the P1 position, were adopted to enzyme assay and showed high BACE1 inhibitory activity.

抄録全体を表示

2-Arylpropionic acids 1, non-steroidal anti-inflammatory drugs, are marketed in racemic form. The exact biological activities of the individual enantiomers of 1 have never been clarified because of in vivo epimerization. To study the relationship between the stereochemistry and biological behavior of 1, we synthesized several racemic 2-aryl-2-fluoropropionic acids 2 as non-epimerizable analogs of 1 by fluorination of the corresponding acids 1 with FClO₃. Optical resolution of 2 was carried out by chromatographic separation of their diastereomeric carenediol esters. Racemic and optically active acids 2 showed lower cyclooxygenase (COX)-1 inhibitory activity and higher histamine-release inhibitory activity than did the corresponding acids 1 but showed similar COX-2 inhibitory activity as did 1. In some cases interesting differences in the activities of the (S)- and (R)-enantiomers were seen.

抄録全体を表示

Much interest has been shown in radical cyclizations for the synthesis of a variety of carbo- and heterocyclic compounds, including natural products. A combination of a radical initiator such as AIBN [azobis(isobutyronitrile)] and a hydrogen donor such as Bu3SnH has frequently been used for radical reactions. There are, however, some disadvantages in using Bu3SnH such as its toxicity and the difficulty of product purifications. Therefore, several substitutes for the use of Bu3SnH have been studied in recent years. Herein we report that radical cyclization of N-allylic trichloroacetamides can be performed by heating in 1,4-dimethylpiperazine (1,4-DMP) used as a solvent to give the corresponding lactams in good yields.

抄録全体を表示

A combination of radical and ionic processes would be a promising approach in synthetic chemistry. However, there are only limited examples which employ enolate intermediates formed by radical addition reaction so far. We have developed domino radical addition-aldol-type reaction of conjugated oxime ether via the formation of N-boryl enamine. In the presence of Me₃Al as a Lewis acid, the domino reaction of conjugated oxime ether proceeded to afford corresponding γ-butyrolactones via sequential process involving regioselective ethyl radical addition, aldol-type reaction of intermediate N-boryl enamine with aldehyde and lactonization for removal of chiral auxiliary. This reaction represents the first reported example of the electrophilic trapping reaction of an unstable N-boryl enamine generated via a radical process.

抄録全体を表示

Ketyl-radical-mediated tandem cyclization of ω-alkynyl carbonyl compound bearing activated alkene using SmI₂ was investigated. At the first α,β-unsaturated ester was treated with SmI₂ and t-BuOH in the presence of HMPA as an activator to obtain the desired spiro[4.5]decane as a single isomer in low yield. When the reaction was conducted in the presence of Sm metal instead of HMPA, spiro[4.5]decane was not formed and the bicyclic lactone was isolated quantitatively. Based on these results, we next attempted a cyclization of alkenyl phosphonate. As a result, spiro[4.5]decane was isolated in 52% yield in SmI₂-Sm-t-BuOH protocol. It was also quite interesting to find that the stereochemical course of the initial cyclization was reverse depending on the presence of either Sm or HMPA.

抄録全体を表示

Manzamine A is a potent antimaralial agents isolated in 1986 from marine sponge of genus Haliclona. This alkaloid is highly potent against malaria. In addition to its promising bioactivity, the complex and unusual structure of Manzamine A has attracted numerous synthetic studies. Despite these efforts, only 2 reports of its total synthesis have been recorded to date. We report herein construction of the A and B ring of Manzamine A. The key reaction in our synthetic route is intermolecular asymmetric Diels-Alder reaction using diene bearing chiral auxiliary developed by Rawal. The reaction proceeded smoothly to afford Diels-Alder adduct in 94% as a single isomer. We succeeded in construction of the A ring through subsequent conversions of the adduct.

抄録全体を表示

Mycalamide A was originally isolated from a New Zealand marine sponge in 1988. Mycalamide A exhibits immunosuppressive activity by suppressing T-cell more effectively than FK506. Despite the availability of many synthetic routes for mycalamide A, there still exists a need to develop strategies more efficient than currently in existence. As a result of our ongoing studies on natural product synthesis, we became interested in developing a novel convergent synthesis of mycalamide A. To prepare the left segment of mycalamide A, a unique one-pot nucleophilic substitution-lactonization process was created. For stereoselective construction of the right segment of mycalamide A, a novel catalytic system, Yb(OTf)3-TMSCl, was devised. A convergent total synthesis of mycalamide A has been achieved by coupling the left and right segments followed by functional group manipulations.

抄録全体を表示

Polygalolides A and B were isolated by Wei and co-workers in 2003 from the roots and stems of Polygala fallax. Herein, we report the first total syntheses of (–)-polygalolides A and B by a carbonyl ylide cycloaddition strategy.
The carbonyl ylide precursor was synthesized in 15 steps from the known alcohol readily obtained from D-arabinose. After considerable experimentation with regard to the key cycloaddition reaction, it was found that dropwise addition of the α-diazoketone to a solution of catalytic amounts of Rh₂(OAc)₄ in refluxing benzotrifluoride afforded the desired cycloadduct as a single isomer in 73% yield. The tricyclic cycloadduct was uneventfully transformed to the tetracyclic lactone. Installation of the aromatic moiety was achieved by exploiting a Mukaiyama aldol-type reaction, and β-elimination and deprotection completed the total syntheses of polygalolides A and B.

抄録全体を表示

We have presented "the stereochemical diversity-oriented conformational restriction strategy", which is effective in developing specific ligands for various drug target proteins. For using this strategy, we developed the versatile chiral cyclopropane units, (1S,2R)- and (1R,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane or their enantiomers. These units were employed to design and synthesize a series of conformationally restricted analogues of histamine with a chiral cis- or trans-cyclopropane structure. Thus, we successfully identified a potent histamine H₃ receptor agonist AEIC [(1S,2S)-2-(2-aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane] and also a potent H₄ receptor antagonist CAIC [(1R,2S)-2-[2-(4-chlorobenzylamino)ethyl]-1-(1H-imidazol-4-yl)- cyclopropane].

抄録全体を表示

We report here conformational analysis of atropisomeric anilide derivatives and their application to asymmetric enolate chemistry.
Atropisomeric N-(p-nitrophenyl)-o-tert-butylanilides having N-C chiral axis highly prefer to exist as the E-rotamer which has trans-disposed o-tert-butylphenyl group and carbonyl oxygen.
The E-rotamer preference is also observed in the case of the lithium enolate prepared from the anilides. The reaction of the anilide enolate with various alkyl halides gives α-alkylated products with high diastereoselectivity.
Similar highly diastereoselective α-alkylation using the lithium enolate from atropisomeric lactam is also described.

抄録全体を表示

It is well known that the amide bond can form two conformations, cis and trans. Although most aromatic N-H amides prefer trans conformation, N-methyl amides exist in cis form in crystal and solution. We investigated the conformational preference and switching of aromatic N-methyl amides bearing 2- and 2,6-substituted pyridines. One of the amides bearing three pyridine rings showed unique switching of cis-trans conformation according to solvent acceptor ability, or addition of acid. The oligomer type of N-methyl amides bearing five pyridine rings can be controlled from layered form to spiral folded form by addition of TFA or stepwise addition of perchloric acid, then flat conformation by further addition of perchloric acid. This outer stimuli responsive type conformational controlling is very hopeful as a structural unit for controlling the shape of a molecule or supramolecule.

抄録全体を表示

Replacement of peptide bonds in biologically active peptides with the non-hydrolyzable mimetics is a promising approach for peptide-lead drug discovery. In this study, we developed novel synthetic methodologies for dipeptide mimetics containing a (Z)-alkene or (E)-fluoroalkene, which could be cis-amide equivalents. For the construction of an alpha-chiral alkyl group, diastereoselectve organocopper-mediated alkylation of gamma-activated-alpha, beta-unsaturated-delta-lactams was employed. Density functional theory calculations indicated that this reaction proceeded via the formation of oxa-pi-allyl metal complex as an intermediate. Furthermore, we applied the resulting isosteres to investigation of the structural requirements of peptide transporter PEPT1 ligands.

抄録全体を表示

Herewith presented are the novel synthetic transformations that involve intramolecular activation of C-Si bonds as applied to the palladium-catalyzed organosilicon-based cross-coupling reaction and to the rhodium-catalyzed 1,4- and 1,2-carbonyl addition of organosilicon reagents and the carbocyanation reaction that involves cleavage of C-CN bonds followed by insertion of unsaturated carbon-carbon bonds. These novel synthetic methods allow us to straightforwardly construct electron-conjugated target structures that play key roles in functional materials and pharmaceutical agents.

抄録全体を表示

Ester and amide moieties constitute major backbones, as well as important functional groups, in numerous natural products and synthetic compounds. We recently reported on the simple and mild esterification of N-protected α-amino acids using approximately equimolar amounts of alcohols via tert-butoxycarbonyl esters using 1-tert-butoxy-2-tert-butoxycarbonyl-1,2-dihydroisoquinoline (BBDI) and the similar amidation of a variety of carboxylic acids with amines. This time a novel BBDI-catalyzed esterification of N-protected α-amino acids in the presence of Boc₂O has been developed. This procedure has several advantages including no requirement for additives, and no racemization occurs. In addition, the use of a new BBDI-like condensing reagent derived from 6-methoxyisoquinoline allowed the substantial reduction in reaction times. The BBDI-catalyzed amidation is also investigated.

抄録全体を表示

We have found that electrophiles such as aldehydes reacted with enamides or enecarbamates in the presence of Lewis acid catalysts. The asymmetric reactions discussed herein also proceeded smoothly in the presence of 0.1 mol% of the catalyst, providing the adducts with excellent enantioselectivity (up to 98% ee). Moreover, the nucleophilic addition reaction to aldehydes proceeded stereospecifically: E-enecarbamates gave anti adducts, whereas Z-enecarbamates produced syn adducts. The fact that enecarbamates provided products stereospecifically led us to propose a concerted aza-ene-type reaction mechanism, where proton on nitrogen of enecarbamate plays an important role not only for acceleration of the reaction but also for stereo-induction.

抄録全体を表示

Convenient synthesis of phenanthridinone derivatives by a palladium mediated domino reaction was developed. The domino process, including aryl coupling and CN bond formations concomitant with isocyanate elimination, was strongly promoted by our novel phosphine ligand. The versatility and applicability to a broad range of substrates make this reaction useful for the development of bioactive derivatives.

抄録全体を表示

(+)-Stephacidin A is an antitumor active compound isolated from the fungi Aspergillus ochraceus WC76466 in 2002. The structure of (+)-stephacidin A contains indole moiety and bicyclo[2.2.2]diazaoctane ring system including two quaternary asymmetric carbon centers on the C₄ and C₂₂. Because of its the unique structure and biological activity, we planned the total synthesis of (+)-stephacidin A. Indole moiety (BC ring) was constructed by our methodology, namely, Pd-catalyzed cyclization reaction using Pd(PPh₃)₄ and methyl propiolate. The quaternary asymmetric carbon centers on the C₄ and C₂₂ were stereoselective synthesized by Seebach's methods for self-reproduction of the center of chirality. Also D ring construction was succeeded by alkylation reaction at indole of C-3 position using Grignard reagent. Finally we have accomplished the construction of BCDEG ring and the total synthesis of (+)-stephacidin A is in progress.

抄録全体を表示

The first total synthesis of the proposed structure for methyl-kinamycin C (methyl-KC), derived from KC, isolated from Streptomyces murayamaensis, was achieved, via two key steps: Diels-Alder reaction of benz[f]indenone and Danishefsky-type diene, followed by the stereoselective construction of highly oxygenated D ring.
gamma-Hydroxyenone, which was prepared by former step, was subjected to OsO₄-TMEDA dihydroxylation to give cis,cis-triol. Silyl enol ether formation followed by Rubottom oxidation afforded tetraol, which was subjected to (CH₃)₄NBH(OAc)₃ reduction via 5-membered ring transition state to give a key tetracyclic compound with correct stereochemistry on D ring. Hydrazone formation followed by CAN oxidation gave title compound. The similarity of the spectral properties of the synthesized methyl-KC and those of natural KC allowed us to conclude that natural kinamycins possess diazoalkane structures.

抄録全体を表示

The intramolecular haloetherification reactions of chiral diene acetals from C₂-symmetric (R, R)-hydrobenzoin form the products with the multi-chiral centers in the stereo-selective manner. The chiral auxiary is internalized into the products, and it works as the chiral source for further transformations and as the protecting group (chiral auxiary multi-use methodology). Then, the reaction was applied to the asymmetric synthesis of (+)-Sch 642305, which shows the new types of anti-fungal and anti-HIV activities. Thus, the intramolecular haloetherification of the chiral cyclohexadiene acetal in the presence of MeOH gave the cyclohexene acetal with four newly formed chiral centers. The cyclohexene acetal toward the (+)-Sch 642305 was studied. During the synthesis, the internalized chiral auxiary worked for regio-selective enone formation and the stereo-selective introduction of alkyl chain. It also acted as the protecting group.

抄録全体を表示

Epsilon opioid receptor agonost, TAN-821 and antagonist, TAN1014 were designed and synthesized. These ligands have high selectivity for epsilon receptor in vivo but not in vitro. These compounds have bicyclo[2,2,2]octane skeleton. We postulated that the hydrophobicity resulted in nonselectivity for epsilon receptor in vitro. We newly designed a compound with hydrophilic group on bicyclo[2,2,2]skeleton.
Diels-Alder reaction of dienol ether (1) with ethyl acrylate and metacrylate afforded bicyclo[2,2,2]octane (2) and (3) in 91% and 67%, respectively. After hydrogenation of double bond of each compounds, the resulting compound was reduced with LAH to give primary alcohol (4) and (5). The resulting compounds 4 and 5 were esterified with trifluoromethansulfonyl or monochloromethansulfonyl chloride to give the each mesylates. We will report the reaction of the mesylates and mechanism.

抄録全体を表示

Histone deacetylases (HDACs) catalyze the deacetylation of the acetylated histone lysine residues and play important roles in the regulation of gene expression. HDAC6, which is one of HDAC family members, is unique in that it deacetylates non-histone proteins such as &alpha-tublin and HSP90, and is involved in the microtubule stabilization and the molecular chaperon activity. Furthermore, it has been reported that inhibition of HDAC6 causes growth inhibition against myeloma cells. So, HDAC6-selective inhibitors can be anticancer agents with fewer side effects. Therefore, we conducted the design and synthesis of HDAC6-selective inhibitors. Thiol-based compounds 2b-10b modeled on an HDAC6-selective substrate were designed and synthesized via a chiral intermediate 16 prepared by the optical resolution using acylase. Aliphatic compounds 7–10 showed significant HDAC6 selectivity.

抄録全体を表示

Various edaravone (3-methyl-1-phenyl-5-pyrazolone) derivatives were synthesized and evaluated for their oxidation potential and hydroxyl radical scavenging activity. The anionic form of the derivatives important for scavenging activities is assumed to be increased with the decrease in electron density of the pyrazoline moiety. On the other hand, the increase in electron density of the pyrazolone moiety is also important for one-electron oxidation reactivity. It was found 3-methyl-1-(pyridin-2-yl)-5-pyrazolone had a much higher ability to scavenge the radical than did edaravone itself. Its efficient radical scavenging activity was assumed to be due to the increase of its anion form, an active form, by a hydrogen-bonded intramolecular base without concomitant positive shift of the oxidation potential.

抄録全体を表示

Polyglycerols are oligomers of glycerol (glycerin). Their fatty acid esters (PGE) are generally dispersible in water and soluble in oil. They are widely using in food additives, cosmetic materials and toiletries as surfactants. Although polyglycerols is readily available in bulk quantities by industrial manufacture, the synthetic reaction requires drastic conditions, including high temperature and alkaline media. Therefore, commercially available polyglycerols are very complicated oligomeric mixtures and undefined molecular composition with difficult characterization. We focused our attention on the synthesis of single and fine structure of linear and cyclic polyglycerols as an authentic standard. Taking into account the synthesis of optically active polyglycerols as a next project, we adopted the synthetic approach based on convergent coupling by use of glycerol unit. Linear polyglycerols, pentamer to decamer and cyclic polyglycerols, trimer to pentamer, were prepared in good yields.

抄録全体を表示

Previtamin D₃ generates a variety of rapid nongenomic responses through a putative membrane receptor. However, biological studies of the "natural" pure previtamin D₃ are difficult, because it can inevitably isomerize back to vitamin D₃ under physiological conditions. The C-14 epimer of vitamin D₃ shows the different thermal equilibrium between vitamin D and previtamin D forms, and the pre-form is the major isomer in the equilibrium. We synthesized the new 2alpha-modified 14-epi-previtamin D₃ analogs using Roche coupling method. The 14-epi-previtamin D₃ analogs could be isolated without isomerization through [1,7] sigmatropic rearrangement at room temperature. We found that 2alpha-methyl-14-epi-previtamin D₃ showed greater effect both on the nuclear vitamin D receptor binding affinity and osteocalcin transcriptional activity on HOS-cells than 14-epi-previtamin D₃.

抄録全体を表示

Cryptosanguinolentine (isocryptolepine), isolated from a West African plant Cryptolepis sanguinolentia in 1996, is a member of indoloquinoline alkaloids, which showed antiplasmodial properties. Molina reported a useful synthesis of cryptosanguinolentine by Red-Al reduction of benzo-&gamma-carbolinone derivative, which was prepared from cyclization of azide compound, but some difficulties faced in preparation of benzo-&gamma-carbolinone derivative by using azide compound. However, Merour showed an excellent synthesis of benzo-&gamma-carbolinone derivatives by Heck cycliztion of N-(2-iodophenyl)indole-3-carboxamide prepared from indole-3-carboxylic acid and 2-iodoaniline. Here, we report a synthesis of cryptosanguinolentine by reaction of indole-2,3-dicarboxylic anhydride with N-methylaniline.

抄録全体を表示

Bleomycin-induced oxidative damage of DNA under oxygen-deficient conditions results in the formation of a C4'-oxidized abasic site (1). We found that unsaturated lactam (2) is formed in the reaction of 1 with an amine under physiological conditions. This result indicated the possibility of modifying lysine containing proteins by an oligodeoxynucleotide (ODN) containing 1. To study the reactivities of 1 in an ODN, site-specific and efficient generation of 1 in an ODN is necessary.
Herein we report the method for the generation of ODNs containing 1 from caged ODNs. We synthesized ODNs containing the 4'-o-nitrobenzyloxy thymidine (3) and the 1'-o-nitrobenzyloxy sugar. Photoirradiation of 3 at 365 nm followed by amine treatment afforded the lactam (2) efficiently. Duplexed 3 was converted to 1 faster and more efficiently than single stranded 3, whereas amine treatment of 1 formed from ss 3 resulted in slightly faster lactam formation than with duplex.

抄録全体を表示

Genome-targeting molecules would have broad application as probes in genomic study. In this study, we have attempted to establish a new binding mode in which small molecular ligands may assemble on the DNA template by multidentate coordination with the metal cation. As a starting point for such an assembling system, we designed the ligands (Bpy-H) connecting the Hoechst33258 skeleton for DNA binding and 2,2'-bipyridine for Cu²⁺ complexation. It was shown that L-Bpy-H with a long linker exhibited Cu²⁺-mediated assembly on DNA template having two A3T3 sites in a ratio of 1:2:1 DNA-ligand-Cu²⁺. Binding selectivity depends on the distance between the two A3T3 sites of DNA. In contrast, S-Bpy-H having a short linker tended to form 1:2:2 DNA-ligand-Cu²⁺ complex. The new binding mode established in this study will be useful for application of small molecular ligands to higher-ordered assembly on the long DNA template.

抄録全体を表示

When we tried to synthesize sulfur porphyrin by the reaction of OETPPLi₂ with SOCl₂, a novel oxidized octaethyltetraphenylporphyrin (OETPP) was obtained. The precise X-ray analysis of the oxidized porphyrine by Prof. Iwasaki and Dr. Hashizume revealed the absence of N-H hydrogens, and the porphyrin was much more ruffled when compared with OETPPH₂. And OETPP was stabilized partly by CH-pi interaction with CH₂Cl₂. In addition, the oxidized porphyrin showed a very clear bond altenation. These results clearly showed that it should be the first characterized 16pi non-aromatic porphyrin. Since OETPP is unstable, sterically more congested new octaisobutyltetraphenylporphyrin (OiBTPPH₂) was synthesized. As expected, OiBTPP was more stable than OETPP. Synthesis of the sterically more congested new octaisopropyltetraphenylporphyrin(OiPTPPH₂) and the oxidized OiPTPP are in progress.

抄録全体を表示

It is well known that (E)-4-hydroxy-2-nonenal is an oxidative metabolite of lipid such as polyunsaturated fatty acids and acts as an important biomarker of some diseases and aging. (E)-4-Hydroxy-2-nonenal reacts with protein containing cysteine, lysine and histidine to afford a modified protein via Michael addition and subsequent cyclization. In order to develop the quantitative analysis of modified protein by using deuterium-labeled compound, we prepared d₅-labeled (E)-4-hydroxy-2-nonenal and its reaction with a model peptide was investigated. MALDI-TOFMS of the labeled and unlabeled modified peptides showed the ion peaks reacted with three molecules of (E)-4-hydroxy-2-nonenal.

抄録全体を表示

We herein developed a novel "racemization-free segment condensation" based on the "O-acyl isopeptide method". This method allows the use of an N-segment possessing a C-terminal Ser/Thr residue for segment condensation, without any racemization, as a result of the C-terminal O-acyl isopeptide structure with a urethane-protected Ser/Thr residue. Thus, racemization-free segment condensation becomes possible at not only the C-terminal Gly/Pro but also Ser/Thr residues of the N-segment. Additionally, final deprotected peptides/proteins synthesized using the "O-acyl isopeptide method"-based segment condensation are effectively purified by HPLC, because a simple isomerization to an O-acyl isopeptide remarkably and temporarily changes the physicochemical properties of the native peptide, and an O-N intramolecular acyl migration triggers the native amide bond formation under physiological conditions.

抄録全体を表示

For the synthesis of difficult sequence-containing peptides, we have disclosed an O-acyl isopeptide method, in which a native amide bond at a hydroxyamino acid residue, e.g., Ser was isomerized to the ester bond, followed by an O-N intramolecular acyl migration. However, in some of the peptides synthesized in the method, a large amount of racemization occurred during esterification on the resin.
To avoid this problem, we have developed a novel O-acyl isodipeptide unit, Boc-Ser/Thr(Fmoc-Xaa)-OH. In the method using this unit, racemization-inducible esterification on the resin could be omitted. Crude isopeptide synthesized using the unit was of high purity with no byproduct derived from the difficult sequence or racemization. This suggests that the use of O-acyl isodipeptide units allow the application of the O-acyl isopeptide method to fully automated protocols for the synthesis of long peptides and proteins.

抄録全体を表示

Gambierol is a marine polycyclic ether isolated as a neurotoxin from the cultured cells of the ciguatera causative dinoflagellate Gambierdiscus toxicus. The structure consists of a trans-fused octacyclic polyether containing three hydroxy groups and a partially skipped triene side chain. The characteristic structure and potent biological activity make gambierol a challenging synthetic target. The synthesis of the ABCDEF ring system of gambierol is presented. The synthesis started from the preparation of the D ring using an oxiranyl anion strategy and the following construction of the C and B rings by radical cyclization and hydroxy-epoxide cyclization, respectively. The A ring was constructed by reductive etherification to give the ABCD ring fragment. Further application of the oxiranyl anion strategy followed by ring expansion reaction and vinyl radical cyclization provided the ABCDEF ring system of gambierol.

抄録全体を表示

Callipeltin A, isolated from the marine sponge Callipelta sp., collected in New Caledonia, is a first natural peptide to show the anti-HIV activity. Callipeltin A is a decapeptide containing three unusual amino acid residues: b-methoxy tyrosine (b-MeOTyr), (2R, 3R, 4S)-4-amino-7-guanidino-2,3-dihydroxyheptanoic acid (AGDHE), and (3S, 4R)-3, 4-dimethyl glutamine (diMeGln). We achieved an asymmetric synthesis of all stereoisomers of protected b-MeOTyr from cinnamyl derivatives using Sharpless asymmetric aminohydroxylation and dihydroxylation reactions. The stereochemistry of b-MeOTyr contained in callipeltin A was determined to be 2R, 3R by NMR analysis of the synthetic tripeptide, H-Gln-b-MeOTyr-N-Me-Ala-OMe. We also synthesized another diMeGln using 1, 3-asymmetric induction in enolate alkylation reaction starting from serine derivative.

抄録全体を表示

A biomimetic approach to calothrixin B via a hypothetical metabolite, 6-cyano-5-methoxyindolo[2,3-a]carbazole, is presented. The construction of a suitable indolo[2,3-a]carbazole ring system was carried out using an allene-mediated electrocyclic reaction involving two [b]-bonds of indoles as the key step.

抄録全体を表示

An enantioselective synthesis of pseudodehydrothyrsiferol (1) having 2,5-substituted tetrahydrofuran and trans-fused tetrahydropyran rings, a squalene-derived triterpene polyether isolated from red alga Laurencia, has been accomplished. Our synthetic feature involves the Suzuki-Miyaura cross coupling between two segments A and B which were synthesized from a common precursor obtained in >99% ee by baker's yeast reduction of the α-hydroxy ketone. In particular, segment B was prepared in 7 steps containing microwave-assisted Hunsdiecker reaction. The subsequent Suzuki-Miyaura coupling of both the segments underwent smoothly giving rise to the coupled product, follow by several normal reactions. Final palladium-catalyzed THF ring formation led to 1, which was indentical in all respects with natural product.

抄録全体を表示

Reveromycins are novel polyketidetype antibiotics isolated from the genus Streptomyces as inhibitors of mitogenic activity induced by the epidermal growth factor (EGF) in a mouse epidermal keratinocyte. Reveromycin A, C, and D exhibit the morphological reversion of src^ts-NRK cells, the antiproliferative activity against human tumor cell lines and antifungal activity. Furthermore, reveromycin A is a selective inhibitor of protein synthesis in eukaryotic cells.
We have already reported the total synthesis of reveromycin A. It was synthesized via succinylation of tertiary alcohols under high pressure as a kye step. However, there were a number of problems with maintenance of high pressure apparatus, skill in using it, and reaction scale. Now, we have developed novel procedure for construction of succinates of tertiary alcohols without high pressure apparatus, and applied the procedure to synthesis of reveromycins.

抄録全体を表示

ChromomycinA3 (CRA3) is an antitumour antibiotic of the aureolic acid group, and has been shown to bind the minor groove of DNA duplex. A peri-hydroxy aromatic skeleton of CRA3 is responsible for complexation with Mg ion as well as binding to DNA. In our synthetic study of peri-hydroxy aromatic derivatives as model compounds of CRA3, efficient synthesis of the peri-hydroxy aromatic is needed. In this study, we established new method to construct the peri-hydroxy aromatic skeleton. In the presence of Lewis-acid (ZnBr2) and proton sponge, [4+2] cycloaddition took place between homophthalic anhydrides and sulfinyl cyclohexenone derivatives to produce the corresponding peri-hydroxy aromatic compounds in high yields (60-85%). Mechanistic study showed that this reaction might be initiated by Lewis-acid catalyzed Michael addition. This paper also reports the synthesis of new peri-hydroxy aromatic derivatives and evaluation of their DNA-binding properties.

抄録全体を表示

Enantioselective oxidation of dl-vic-aminoaldehydes is a promising and attractive method for preparation of optically active &alpha-amino acids (or esters), which are important materials for biomedical sciences. We have recently reported that monobenzoylation of dl (or meso)-vic-diols and/or dl-vic–aminoalcohols catalyzed by chiral bisoxazoline-copper complexes efficiently proceeded with high enantioselectivity. In these reactions, a coordination of vic-diols (or -aminoalcohols) with copper ion in the complexes might form an activated five-membered intermediates, which reacted with benzoyl chloride to afford the corresponding benzoylated compounds as optically active forms. Now, the method was applied to electrochemical oxidation of dl-vic- aminoaldehydes, which was carried out in the presence of bromide salt and the complexes in methanol to give optically active &alpha-amino esters. We will report herein these details.

抄録全体を表示

Asymmetric cyclization via memory of chirality was performed under the condition of KOH / DMSO / RT. This strategy enables the direct transformation of α-amino acids into nitrogen-heterocycles with a quaternary stereocenter in up to 99% ee.

抄録全体を表示

Perfluoroalkyl groups are sterically large enough to fulfill the steric requirement of an asymmetric reaction, and their electron withdrawing effect increases the Lewis acidity of the metal coordinated and hence its activity. Based on this idea, we tried to replace the aryl groups of TADDOL with perfluoroalkyl groups, and have synthesized a new chiral ligand (1a). The reaction of benzaldehyde with dimethylzinc in the presence of only 6 mol% of 1a gave (R)-1-phenylethanol in 99% yield with 96% ee. This result shows 1a is superior to other chiral ligands for this reaction by a short reaction time, and high chemical and asymmetric yields. Other aromatic and aliphatic aldehydes gave good results similarly. Further, this ligand is recoverable using its fluorous property.

抄録全体を表示

We have developed the lipase-catalyzed enantioselective acetylation of prochiral &sigma-symmetric N-Cbz-2-alkyl-2-amino-1,3-propanediols and the enantiodivergent transformation of resulting monoacetates toward &alpha-substituted serines. Immobilized lipase from Pseudomonas sp. furnished the desired chiral monoacetates with satisfactory enantioselection of 92-98% ee in 72-94% yields in the presence of vinyl acetate in tert-butyl methyl ether (TBME) at room temperature. Enantiodivergent conversion of the monoacetate to both enantiomers of &alpha-benzylserine was achieved without isomerization. Furthermore, the absolute configurations of &alpha-substituted serines were determined by a novel method based on ¹H NMR analysis of diketopiperazines, which were obtained by the reaction of the corresponding &alpha-substituted serine with (S)- and (R)-phenylalanine, respectively.

抄録全体を表示

Aldol reaction is one of the most powerful methods for the C-C bond formation in organic synthesis. Recently, direct aldol reaction have received much attention because it does not require preformed enolate or its equivalent. We have developed direct asymmetric aldol reaction between unmodified ketones and aldehydes catalyzed by chiral phosphine oxides. The aldol reaction between 4,4-dimethylcyclohexanone and benzaldehyde in the presence of tetrachlorosilane and diisopropylethylamine catalyzed by BINAPO afforded the corresponding aldol adduct in 51% ee with high anti-selectivity. This is the first example of direct asymmetric aldol reaction involving hypervalent silicate catalyzed by Lewis bases.

抄録全体を表示

Direct detection of a reaction intermediate of chemical reaction using MICCS-NMR was described. "MICCS" (MIcro Channeled Cell for Synthesis monitoring) was developed as the micro fluidic device to observe the chemical reaction by NMR. MICCS can be used with standard NMR probe.
Herein we report the direct observation of the intermediate in the radical addition of the oxime ether mediated triethylborane(Et₃B) by ¹H and ¹¹B MICCS-NMR. We have previously reported the analysis of the intermediate by using 2D and 3D-DOSY in standard NMR sample tubes.
The results from MICCS-NMR indicate good consistency with our previous report. MICCS-NMR was much easier than ODSY meshod. Furthermore, MICCS-NMR allows observation of ¹¹B-NMR, which could not be applied to analyze the intermediates by DOSY due to the short relaxation time of ¹¹B.

抄録全体を表示