Aryl boronic acids and their esters are amongst the most valuable and widely used intermediates in modern organic synthesis due to their high applicability to formation of C-C, C-N and C-O bonds, etc. These compounds are generally accessed via a functional group interconversion strategy from corresponding aryl halides and triflates. However, the development of alternative synthetic methods has been required for the preparation of a wider range of boronic acid derivatives having various functional groups. In this symposium we are going to present a novel method for the synthesis of multisubstituted aryl boronic acid derivatives based on the unprecedented generation of borylbenzynes and their regioselective Diels-Alder reactions with furans.

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We have developed the domino elimination-rearrangement-addition reaction of N-alkoxy(arylmethyl)amines using organo-lithium and magnesium reagents for the first time. This newly found domino reaction consists of three types of reactions: elimination of alcohol, rearrangement of the aryl group, and addition of either an organo-lithium or a magnesium reagent. The -branched arylamines readily prepared by this domino reaction are widely found as a core structure in pharmaceuticals. This domino reaction was successfully applied to the synthesis of galipinine and martinellic acid. Furthermore, very efficient synthesis of N-(diallylmethyl)arylamines was achieved via domino reactions involving addition-elimination-rearrangement-addition reactions of oxime ethers with allylmagnesium bromide.

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We have established that trialkylborane-air, a readily available source of free radicals, enables hydrogen abstraction directly from sp³C-H bonds adjacent to the nitrogen atom of organic molecules, and successfully mediates subsequent coupling of the resultant alpha-aminoalkyl radicals with aldehydes or aryl isocyanates, providing unique access to nitrogen-containing molecular scaffolds. This presentation will disclose new insights into hydroxyalkylation and carbamoylation of alpha-nitrogen-substituted sp³C-H bonds of tertiary amines and lactams, as well as their application to the synthesis of bioactive compounds, with a view to highlighting a new design concept for organic synthesis.

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(+)-Stachyflin, isolated from the Stachybotrys sp. RF-7260, was found to be a novel anti-influenza A virus activity by the Shionogi research group in 2002. Structurally, stachyflin consists of a novel pentacyclic benzo[d]xanthene skeleton (ABCDE ring system), in which cis-fused AB and BC rings, and an ether bond at the bridgehead of the decalin ring junction are characteristic features. We have achieved the total synthesis of (+)-stachyflin starting from the known (+)-Wieland-Mischer keton derivative. The key steps of this synthesis are (i) coupling reaction of the (+)-Wieland-Mischer ketone derivative with the isoindolinone segment, (ii) sequential BF₃·OEt₂-induced epoxy rearrangement/cyclization reaction, and (iii) deprotection of the N-3,4-dimethoxybenzyl (DMB) group using hypervalent iodine reagent PIFA.

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The recent emergence of world-shaking avian flu virus H5N1 has prompted many nations to stock Tamiflu^TM, the potent anti-influenza drug developed by Gilead Science. The present commercial production, however, relies heavily on the semisynthesis starting from shikimic acid of limited availability, which would hamper to stock a sufficient amount of Tamiflu. Given the current supply issue, we have started our program directed toward the synthesis of oseltamivir, the free base of Tamiflu. Recently we have succeeded in developing a synthetic route starting from L-methionine. The key features of the present method are: (1) ready availability of the starting material, (2) azide-free synthetic route, and (3) highly stereoselective construction of the three contiguous chiral centers by means of Staudinger reaction.

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Morphine (1) is a fascinating compound that has been used as an efficient analgesic and is indispensable in treating pains associated with cancer. However, morphine is strictly controlled by authorities due to its addictive nature. On the other hand, the structure of morphine is quite attractive from a synthetic point of view. Its complicated pentacyclic skeleton, including a quaternary carbon center, has stimulated extensive synthetic efforts. Hence, a number of synthetic studies and the total syntheses of morphine have been reported to date. In an effort to develop a novel morphine-type drug that is not addictive, we initiated our own studies of an efficient total synthesis of morphine.
Herein, we disclose a total synthesis of (−)-morphine which involves a construction of the morphinan skeleton using intramolecular aldol reaction and Michael reaction.

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Organosilanols are now attracting more and more attentions due to its usefulness for metal-catalyzed cross-coupling reactions. Among the most powerful methods are Stille, Suzuki, and Negishi couplings, but they have some problems such as toxicity (Sn) or handling (B, Zn). On the other hand, organosilanols are more environmentally friendly, less hazardous and easier to handle, which can provide a viable alternative to those problems. Therefore effectively preparing silanol compounds has profound meanings.
During our study, we found a new method for preparing silanols: oxidation of silylmethanols to silanols. After we optimized its reaction conditions, TEMPO oxidation turned out to be the most successful method. This reaction was extended to several kinds of silylmethanols and most of them gave corresponding silanols in good to excellent yields. Furthermore, we also found that bromomethylsilanes were converted into silanols when reacted with TMANO.

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The 1,2-differentiated diamination of unactivated alkenes was achieved using dichloramine-T (TsNCl₂ and CH₃CN as nitrogen sources in the presence of a catalytic amount of copper(II) complex. Various alkenes and nitriles could be applicable for the diamination, in which the cis-selectivities were observed in all cases. However, a few substrates gave poor yields mainly due to the formation of haloamine side product which would arised from ring-opening of the aziridinium intermediates by Cl^- in an S_N2 manner instead of CH₃CN. In these cases, the enhanced formation of diamine was observed when the reaction was performed at -20 C. The methodology described herein allows rapid access to cis-vicinal diamines.

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The acid-catalyzed Friedel-Crafts alkylation of arenes with aromatic aldehydes has been known since 1886. However, the reaction using Lewis acid such as AlCl3 had not received much attention until recently because of the formation of many products such as triarylmethanes, triarylmethanols, diarylmethanes, and anthracene derivatives. We found that alkylation of electron-rich arenes with aldehyde and acetyl bromide (AcBr) using silica gel-supported zinc bromide (ZnBr2/SiO2) gave the corresponding triarylmethanes and 1,1-diarylalkanes in high yields under mild conditions

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A simple copper- and base-free palladium-catalyzed cross-coupling reaction, the reaction of triarylantimony diacetates as electrophile with terminal alkynes in the presence of 1 mol% of PdCl2(PPh3)2 led to the formation of cross-coupling products in good to excellent yields without any copper salt and base under an aerobic condition. In the present reaction two aryl groups on antimony can be utilized. And triarylantimony diacetates bearing an electron-donating group on the aromatic ring as electrophile show high reactivity in the Sonogashira-type reaction.

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6H-Dibenzo[b,d]pyran-6-one is one of the basic structure included in the compounds such as a natural product, drug medicine. It is reported that analogues having 6H-dibenzo[b,d]pyran-6-ones show various kinds of bioactivity. We reported a palladium-mediated intramolecular aryl-aryl coupling reaction for the effective construction of 6H-dibenzo[b,d]pyran-6-ones. Two kinds of regioisomers having the aryl-aryl linkage to ortho or para position of substituent (R) are isolated in the case of substrate with substituent (R) on the phenoxy part. In this time, we investigate this coupling reaction, and we consider that reaction system and the substituent of the substrate influence to regioselectivity.

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The scientific value of biaryls is easily recognized from the broad utilization of these compounds as versatile building blocks for functional materials such as liquid crystals, or ligands for metal catalysts and pharmaceuticals since the structures are frequently seen in natural products. Of the synthetic methods of biaryls, oxidative coupling reaction of arenes is the most ideal one reducing the number of synthetic steps and production of wastes. However, the usual methods still have limited applications owing to the difficulty in obtaining cross-coupling products, because undesired homocoupling dimers are formed. In this symposium, we report a novel oxidative cross-coupling between two unfunctionalized arenes using hypervalent iodine(III) reagents as the oxidants. The key aspect of the reaction is the selective single-electron oxidation ability of hypervalent iodine(III) reagents toward arenes to produce the corresponding cation radical intermediates.

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cis-2-Fluorocyclopropanecarboxylic acid (cis-FCpCA) is a key intermediate for the synthesis of an antibacterial agent Sitafloxacin, therefore many synthetic efforts for the synthesis of dl-cis-FCpCA have been reported so far. We herein report an efficient stereoselective synthesis of dl-cis-FCpCA. The strategy for the synthesis of dl-cis-FCpCA derives from employment of stereoselective rhodium-catalyzed cyclopropanation reaction of (1-fluorovinylsulfonyl)benzene (1) with diazo esters 2. The cyclopropanation reaction of 1 with tert-butyl diazoacetate catalyzed by [Rh(O2CCPh3)2]2 proceeded stereoselectively to the desired tert-butyl trans-2-fluoro-2-phenylsulfonylcyclopropane carboxylate (trans-3, R = tert-Bu) in an 80% yield (trans:cis = 93:7). The synthesis of dl-cis-FCpCA was completed by reductive cleavage of a phenylsulfonyl group of trans-3 and subsequent hydrolysis of an ester group.

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4-[3,5-Bis(trimethylsilyl)benzamido]benzoic acid (TAC-101) is being developed as a novel anticancer drug which is a synthetic retinobenzoic acid with selective affinity for RAR-a receptor.
During pre-clinical and clinical studies, three metabolites, oxidized at the trimethylsilyl group of TAC-101, were found, and we developed and reported synthetically efficient routes of these metabolites.
In these snthetic studies, we found that the C-Si bond of hydroxymethyldimethyl arylsilane was easily cleaved by weak base such as K₂CO₃. After detailed optimization of the reaction condition, we selected NaOMe as base and MeOD as reaction medium for introducing the deuterium atom into the ipso-position of hydroxymethyldimethyl arylsilane. Herein, we wish to report the details of scope and limitaion of applicable substrates for the desilylation reaction.

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Addition reaction of 1-chlorovinyl p-tolyl sulfoxides, which were derived from various aldehydes,
with lithium enolate of tert-butyl acetate gave adducts in high yields. Magnesium carbenoids were generated by treatment of these adducts with Grignard reagents via the sulfoxide-magnesium exchange reaction. When the adducts were derived from alkyl aldehydes or electron-deficient aromatic aldehydes, b,g-unsaturated esters were obtained by 1,2-CH insertion reaction. On the contrary, when the adducts were derived from electron-rich aromatic aldehydes, b,g-unsaturated butyric esters were obtained by stereospecific 1,2-CC insertion reaction. When the addition reactions were quenched with iodoalkanes, tri-substituted b,g-unsaturated esters were obtained by the treatment of these adducts with EtMgCl. These procedure provide a good way for a new synthesis of b,g-unsaturated esters from aldehydes with two or three carbon-carbon bond-formations.

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We have developed a new convenient tandem reaction, that is Sonogashira reaction, dehydration reaction, and cyclization reaction by nucleophilic attack of imine nitrogen to alkyne carbon under microwave irradiation. This method would be more useful and more applicable than the standard conventional methods. Furthermore, since the concept presented here would be applicable to a wide range of substituted aromatic 2-bromoaldehydes, substituted alkynes, and substituted 1,2-diaminocompounds to afford more functionalized condensed ring heteroaromatic compounds. We also developed new convenient synthetic methods of 1,4-bezoxazepines and 1,4-bezothiazepines under microwave irradiation.

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An efficient route has been developed for the synthesis of tetrahydoropyrido[4,3-d]pyrimidines which are useful in treating allergic, inflammatory and hyperproliferative skin diseases. The route features a quite unique conversion of an enaminonitrile to a tetrahydropyridopyrimidine using carbon dioxide in the presence of DBU (1,8-diazobicyclo[5.4.0]undec-7-ene). The intermediate is transformed to the desired drug substance in a few additional steps. This process is not only general but also expected to apply for the large scale synthesis.

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In construction of 3-iodobenzo[b]furans by iodocyclization of 2-alkynylphenol derivatives, there are some problems that 2-alkynylphenol itself is unstable or hazardous halomethanes are generated in the reaction. Herein, we report an iodocyclization of ethoxyethylethers to alkynes for the synthesis of 3-iodobenzo[b]furans. The advantages of our method are: 1) ethoxyethylether serves not only as the protecting group but also as a directing group for the preparation of precursors for iodocyclization; 2) the synthesis requires a reasonable number of steps from starting material to 3-iodobenzo[b]furans; 3) the title compounds are afforded not only in short reaction but also in high yields without the generation of hazardous halomethanes; and 4) various 3-iodobenzo[b]furans can be obtained in good to excellent yields.

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A simple and efficient method has been developed for the synthesis of furans from a -haloketone and b -diketones using a base and an acid supported reagents system "Na₂CO₃/Al₂O₃-PPA/SiO₂" in one-pot. C-alkylation reaction using a-haloketone and b-diketones was promoted to afford 1,4-diketones in the presence of Na₂CO₃/ Al₂O₃. Then PPA/SiO₂ catalyzed the cyclo-condensation reaction of the product to afford furans. The yield of furans using one-pot process was as good as using stepwise process. Furthermore, total reaction time from a-haloketone to furan was shorter than using stepwise process.

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A new method for the direct perfluoroalkylation of an aromatic sp2 carbon in phenol derivatives has been developed. The novel perfluoroalkylation protocol described herein involves the use of a radical initiator V-70L, which allows the reaction to be carried out at room temperature, and cesium carbonate as the mild base. Treatment of a variety of phenols with perfluoroalkyliodide in the presence of cesium carbonate and V-70L provided the corresponding perfluoroalkylated products in moderate to good yields. The reaction generally proceeds smoothly at room temperature to yield regioselective perfluoroalkylated products.

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The C-H insertion reaction of rhodium carbenoids derived from diazo compounds offers new strategies for the synthesis of complex organic targets. Herein, we developed the rhodium dimers with a hydrophobic binding site based on oligoarene structure.
We synthesized the oligoarene-type catalyst by two-step repetitive method that developed in our group.
Thus, the Suzuki-Miyaura coupling of aryl triflates with hydroxyphenylboronic acids proceeded well at room temperature, giving an oligoarene-type compound in high yield. The subsequent alkylation with ethylene glycol mono 2-chloroethylether and hydrolysis with LiOH produced the oligoarene-type carboxylic acids. The oligoarene-type rhodium dimer was easily synthesized by stirring with rhodium acetate in chlorobenzene.
This catalyst was applied for the C-H insertion reactions of dimethylanilines with diazo compounds, giving better results than commercial available rhodium catalysts.

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The most common synthetic method for the preparation of secondary or tertiary alkyl amines is base-promoted N<I/>-alkylation of the primary amines. The method, however, suffers serious drawbacks: the use of toxic and corrosive alkylating reagents such as alkyl halides; the frequent generation of a large quantity of wasteful salts as by-products; the limited selectivity between secondary and tertiary amine formation. We have recently developed a Pd/C-catalyzed reductive alkylation of primary amines using nitriles as alkylating reagents. During the course of the study, it was found that the absence of primary amines led to an efficient and selective formation of tertiary amines via the one-pot reduction and N<I/>-alkylation of nitriles. Furthermore, use of Rh/C instead of Pd/C as a catalyst achieved a selective synthesis of secondary amines.

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Copper-promoted unsaturated carbon-nitrogen oxidative-coupling reactions of NH-containing substrates with aryl, alkenyl, alkynyl halides , boronic acids, and borates have emerged as a powerful synthetic methodology for pharmaceuticals. Although organobismuth(III) and (V) compounds also used as carbon reagents, no report exists of the utility as alkenyl and alkynyl reagents. Now I report a new copper-catalyzed coupling of imides with alkynyltriarylbismuthonium salts in the presence of amine to give N-alkynyl imides. Diyne and N-aryl imide were also obtained as byproducts. However, electron-donating substituents on the aromatic ring of alkynyltriarylbismuthonium salt and low reaction temperature lead to high selectivity of N-alkynyl imides.

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Replacement of naturally occurring peptide bonds with (Z)-fluoroalkenes affords potential dipeptide mimetics named (Z)-fluoroalkene dipeptide isosteres (FADIs). We have reported the synthesis of FADIs utilizing the intermolecular redox reaction of gamma, gamma-difluoro-alpha, beta-enoates with an organocopper or SmI₂. In this study, we aimed at intramolecular redox reaction using N-heterocyclic carbenes (NHCs) or cyanide anion for the preparation of FADIs. We assumed that nucleophilic attack of NHCs or cyanide anion to gamma, gamma-difluoro-alpha, beta-enoylsilanes should cause an S_N2'-type reductive elimination of fluoride anion followed by oxidation of the acylsilane unit to esters or amides in the presence of nucleophiles (alcohols or amines). Optimization of the reaction conditions resulted in the successful preparation of ester-type FADIs and amide-type FADIs.

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Efficient synthesis of p-quinols using catalytic hypervalent iodine oxidation of p-substituted phenols was achieved. Reaction of p-arylphenols with a catalytic amount of 4-iodophenoxyacetic acid in the presence of Oxone (2KHSO₅•KHSO₄•K₂SO₄) as a co-oxidant in tetrahydrofuran or 1,4-dioxane-water gave the corresponding p-quinols in excellent yields without purification. Oxidation of p-methylphenols gave also the corresponding p-quinols.

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Treatment of 1-allenyl-1-diethynyl acetates 1 in the presence of a Au or Pt catalyst (5 mol %) in toluene at room temperature, followed by methanolysis, gave 4-methylene-2-cyclopentenones 2. The new cationic bisoxazoline(box)-Au(III) complex, [(S,S)-phbox-AuCl2]SbF6 or [(R,R)-bnbox-AuCl2]SbF6 accelerated the reaction, providing 2 in moderate yield (60-69%).

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alpha-Aminophosphinic acid derivatives have been utilized as useful phosphinyl dipeptide isosteres (PDIs) for developing inhibitors against aspartic acid and Zn metallo proteases. We have established a new and efficient method for the synthesis of optically active aminomethylphosphinate bearing asymmetric center at phosphorus atom, which was an important starting compound for the preparation of PDIs. The method was based upon lipase-mediated kinetic resolution of a hydroxymethylphosphinate and its conversion into the corresponding amine derivative. This lipase-mediated acylation using vinyl acetate could be applicable to 10-gram scale giving 1.5-gram of hydroxymethylphosphinate with high optical purity (>99% ee).

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We herein developed a 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, segment condensation becomes possible at not only the C-terminal Gly/Pro but also Ser/Thr residues without epimerization. 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.

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We developed the S-acyl isopeptide method for the synthesis of difficult sequence-containing peptides and applied it to the synthesis of a model pentapeptide, Ac-Val-Val-Cys-Val-Val-NH₂ (1). In the conventional manner, purification of 1 was tedious due to an extreme low solubility. On the other hand, the synthesis of S-acyl isopeptide, H-Cys(Ac-Val-Val)-Val-Val-NH₂ (2) was efficiently achieved using S-acyl isodipeptide unit, Boc-Cys(Fmoc-Val)-OH. S-Acyl isopeptide 2 was readily purified by RP-HPLC owing to its highly hydrophilic nature, and quantitatively converted to 1 via an S-N intramolecular acyl migration reaction in phosphate buffer (pH 7.4) at r.t. Thus, we obtained 1 in a two fold higher yield compared to the conventional SPPS. These results indicate that not only Ser or Thr but also Cys could be used for effective synthesis of difficult sequence-containing peptides by the method.

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Because of the usefulness of organoboronic acids such as low toxicity and easy manipulation and the importance of the addition products as intermediates, transition metal-catalyzed 1,2-addition reactions of organoboronic acids to aldehydes have been attracting much attention. Recently, potassium organotrifluoroborates have been focused as alternatives to organoboronic acids because of their superior features. In spite of the advantages, only two types of rhodium(I)-phosphine complexes as catalysts for the transition metal-catalyzed 1,2-addition of potassium organotrifluoroborates to aldehydes were reported. We achieved the palladium-catalyzed 1,2-additon reactions of potassium aryl- and alkenyltrifluoroborates to aldehydes using the thioether-imidazolinium carbene ligand in good to excellent yields. They were carried out rapidly using 0.5 mol % of catalyst loading with good substrate tolerance, giving a variety of carbinol derivatives.

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Consistent with our continued studies on the Ti-Claisen condensation and relevant reactions, we have developed a TiCl₄ – N-methylimidazole-promoted Morita-Baylis-Hillman-type acylation reaction of a,b-unsaturated esters with acyl chlorides through a reactive acyl ammonium intermediate to give a-methylene-b-ketoesters. The present reaction proceeded in a significantly short reaction period, compared with conventional base-mediated methods.
Michael addition of the obtained a-methylene-b-ketoesters, a kind of powerful Michael acceptor, with ketene silyl acetals gave the desired adducts in high yields without any use of catalyst. a-Methylene-b-keto esters and their derivatives were expected to serve achiral and chiral synthons utilizing recent asymmetry reductions.

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The H-D exchange reaction is a powerful tool to prepare the deuterium labeled compounds. However, conventional deuteration methods especially on non-activated aliphatic carbons require harsh conditions such as high temperature and pressure and expensive reagents.
We have recently developed a Pd/C catalyzed mild and efficient deuteration method of diverse aromatic compounds. During the course of the investigation, we discovered that the Rh/C can catalyze multiple H-D exchange of non-activated alkanes at 160 ^oC under nonpressurized H₂ conditions.
On the other hand, we have also developed regioselective deuterium labeling method at the a-position of aliphatic alcohols. The use of Ru/C as a catalyst was effective for the preferential deuteration at the a-position of hydroxy groups. The highly regioselective deuteration of primary and secondary alcohols were achieved in excellent deuterium efficiency at rt-80 ^oC under H₂ atmosphere.

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We present the highly stereoselective synthesis of indanone compounds by the Sb(V)-catalyzed reaction of phenylalkyne derivatives with aldehydes in the presence of alcohol. Thus, SbF₅ catalyst (10 mol%) and a stoichiometric EtOH additive efficiently brought about the corresponding 2,3-disubstituted indanones in moderate to high yields (45-89%) with the high trans selectivity (> 95:5). The formation of indanone compounds consists of: i) the formal alkyne-carbonyl metathesis of phenylalkyne derivatives with aldehydes, and ii) the Nazarov cyclization of phenyl alkenyl ketone intermediates.

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We already reported that CF₃-I (1) and silyl enol ethers of ketone (2) were dealt with Et₂Zn in the presence of RhCl(PPh₃)₃ to give α-trifluoromethylated (α-CF₃) ketones (3) in good yields. This is a useful reaction because the α-CF₃ ketones were described as difficult to synthesize for a long time (Scheme 1). In this reaction, we found an interesting result as it not gave the corresponding α-CF₃ ketone (3a) but a dimer product (4a), when TMS enol ether of acetophenone (2a) was used as the substrate (Scheme 2). So we tried to use a benzyl halide (5), the corresponding dimer product (6) was obtained as expected (Scheme 3). In this time, we would like to report a new homo-coupling reaction of benzyl halides which gave the dimer product in an excellent yield.

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Asymmetric Michael addition of amines to a,b-unsaturated esters are very promising because they afford units of b-amino acids that are a part of a number of naturally occurring bioactive compounds. So we investigated the asymmetric Michael addition of a chiral amino ether 2 to a variety of a,b-unsaturated esters and tandem Michael-aldol reaction, in which the enolate intermediate allowed to react with aldehyde for aimed to construction of three contiguous stereogenic centers. In addition, the chiral auxiliary linked to the amino group in the products was facilely removed and the products were converted to b-aminoesters and aldehydes 4 by reaction using N-iodosucinimide. Moreover, this aldehyde can be reclaimed to the chiral amine 2 by reductive amination with benzylamine.

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We have developed a highly efficient acid-catalyzed Nazarov reaction of β-alkoxy divinylketones providing 5-oxycyclopent-2-enones, as a single regioisomer. This Nazarov cyclization, involving 1,3-shift of the β-alkoxy group, was accomplished within a few minutes catalyzed by TfOH, Tf₂O (0.1-0.001 mol%) or Sc(OTf)₃ (10 mol%), in which the β-alkoxy group accelerates the catalytic reaction and controls the regioselectivity by the stabilization of the intermediates and the spontaneous elimination followed by trapping.
In order to advance this reaction, we have developed the asymmetric transformation, and found that Sc(OTf)₃-pybox/Ph complex is an efficient catalyst. In the presence of iPrOH as a solvent, stereoselectivity was improved up to 91% ee. It is noteworthy that this reaction constructs a quaternary asymmetric center by nucleophilic addition to the α-position of the resulting ketone.

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We have reported the synthesis of seven-membered rings by the nickel-catalyzed [3+2+2] cycloaddition of electron-deficient alkylidenecyclopropanes with alkynes. Herein, we examined the [3+2+2] cycloaddition of ethyl cyclopropylideneacetate with conjugated enynes in the presence of a nickel catalyst and vinylcycloheptadiene derivatives were isolated in good yields. The products were useful substrates for the Diels-Alder reaction with various dienophiles, and the reaction proceeded smoothly to give the corresponding polycyclic compounds. Furthermore, the one-pot [3+2+2]/[4+2] cycloaddition was carried out successfully.

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Synthesis of various heterocycles containing 7- and 8-membered rings was investigated. Starting ene-ynamides were easily synthesized by the known method. When a toluene solution of ene-ynamide was stirred in the presence of a catalytic amount of the second-generation ruthenium carbene complex under ethylene atmosphere, RCM proceeded smoothly to provide heterocyclic compound having a diene moiety in good to high yield. Various substrates could be used for this reaction to afford the cyclic dienamide derivatives. When the construction of 8-membered rings was examined, the lower temperature and the longer reaction time gave good results. Substituent on the alkyne of ynamide affected the yield of the cyclized product. The cyclic dienamide derivatives obtained in this reaction were subjected to the Diels-Alder reaction to provide fused cyclic compounds in good yields.

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Molecular chemical chaperone is a small molecule that interacts with proteins to induce some changes in their forms and functions. Isofagomine is known to function as a molecular chemical chaperone of glycosidase and is expected as a new molecular therapy for glycosphingolipid storage disorders such as Gaucher disease. We focused our attentions on design of new isofagomine derivatives in order to develop more promising molecules. It is reported that introduction of an aliphatic chain into isofagomine changed reactivity and selectivity against glycosidase. Based on these results we designed 2-alkylisofagomines. In this study, we have developed a concise synthetic root to 2-alkylisofagomines using allylic hydroxy group accelerated ring-closing enyne metathesis as a key step. This root accomplished construction of 2-propylisofagomine. Details of the root are reported.

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Indole-fused 1,4-diazepines are found in various biologycally active compounds and can be considered as an attractive drug template. We recently reported a novel copper(I)-catalyzed synthesis of 2-(aminomethyl)indoles by a three-component coupling–cyclization reaction. This reaction prompted us to develop a new method for the preparation of indole-fused 1,4-diazepines by three-component indole formation and simultaneous copper-catalyzed N-arylation. Starting from simple 2-ethynylanilines and o-bromobenzylamines, complex indole-fused tetracyclic compounds including 1,4-benzodiazepines were easily and directly constructed in a single reaction vessel. This is the first example of copper-catalyzed one-pot reaction including three catalytic cycles and formation of four bonds.

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Ergot alkaloids have been reported to exhibit broad biological activity. Several synthetic derivatives are used as important drugs (e.g., for Parkinson's disease). We investigated direct construction of the C/D ring system of ergot alkaloids based on palladium-catalyzed domino cyclization of amino allenes. Treatment of amino allene derivatives bearing a bromoindolyl group with Pd(PPh₃)₄ (5 mol%) and K₂CO₃ in DMF at 120 ^oC gave the desired tetracyclic indoles having the common core structure of ergot alkaloids in good yields. With this biscyclization as the key step, total synthesis of (+/-)-lysergic acid, (+/-)-lysergol and (+/-)-isolysergol was achieved. The proposed mechanism for biscyclization based on the stereochemical course of the reaction is also presented.

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The 3,5-disubstituted pyrrolizidine 251O, detected in the poison-frog from Mantella of Madagascar, is one of the major poison-frog alkaloid, which has also been found in Malagasy ant Anochetus grandidieri. So far several syntheses of trans, trans-type of 3,5-disubstituted pyrrolizidine such as xenovenine have been reported to date, whereas no synthesis of trans, cis-type of pyrrolizidine alkaloid has been reported. This interesting alkaloid 251O possesses trans, cis-type of pyrrolizidine ring system, however both relative and absolute stereochemistry are still unknown. Here we report the efficient enantio- and diastereo-divergent synthesis of 251O starting from common lactam.

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Maitotoxin (MTX), a polyether marine natural product, is currently one of the most toxic and complex natural products (MW 3422) known. It possesses 32 fused ether rings, 28 hydroxyl groups, 21 methyl groups, 2 sulfates, and 98 chiral centers. We have accomplished the stereoselective synthesis of the GHIJK- ring of MTX through a linear strategy for the construction of polycyclic ether based on SmI₂-induced reductive cyclization of beta-alkoxyacrylate or (E)-beta-alkoxyvinyl (S)-sulfoxides with aldehyde. Recently, Gallimore and Spencer questioned the originally proposed JK-ring structure of MTX and proposed the isomeric structure. In order to answer to this question, we synthesized the originally proposed HIJK-ring and the newly proposed isomeric HIJK-ring. Comparison of the ¹³C-NMR chemical shifts of two synthetic segments with those of MTX confirmed the original structure determined by Yasumoto et al.

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A total synthesis of (+)-trachyspic acid, a tumor cell heparanase, was accomplished. Aldol reaction of di-tert-butyl 4-(4-methoxybenzyloxy)-2-oxobutanoate with pent-4-enal using (S)-1-(3,5-bis(trifluoromethyl)phenyl)-3-(pyrrolidin-2-ylmethyl)thiourea hydrochloride as an organocatalyst, followed by Pinnick oxidation and tert-butyl esterification, gave (2S,3S)-di-tert-butyl 2-(2-(4-methoxybenzyloxy)ethyl)-3-allyl-2-hydroxysuccinate in high optical purity (85% ee). Following the procedure we established in the synthesis of racemic tracyspic acid, the (2S,3S)-diester was transformed to (+)-trachyspic acid via Cr(II)/Ni(II)-mediated Nozaki-Hiyama-Kishi coupling of the alkyl citrate moiety and the long chain triflate.

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(-)-Colchicine is the main alkaloid which was extracted from meadow saffron. A structural feature of (-)-Colchicine is the 6-7-7 tricyclic skeleton which contains one aromatic ring and tropolone ring. Recently, we have reported a new Ni-catalyzed [3 + 2 + 2] cycloaddition of 1,5-diynes or 1,6-diynes with ethyl cyclopropylideneacetate. We anticipated that the two 7 membered rings of (-)-Colchicine could be synthesized by the [3 + 2 + 2] cycloaddition of a 1,7-diyne with ethyl cyclopropylideneacetate in the presence of Ni(0) catalyst. Based on this retrosynthetic analysis, we prepared a 1,7-diyne with a benzene ring as a tether from commercially available 3,4,5-trimethoxycinnamic acid in 9 steps. The [3 + 2 + 2] cycloaddition of 1,7-diyne with ethyl cyclopropylideneacetate was carried out in the presence of Ni(0) catalyst and the desired 6-7-7 tricyclic compound was obtained in 54% yield. The reaction was applied to the synthesis of (-)-Colchicine.

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