I present herewith enantioselective total syntheses of several bioactive natural products, such as (−)-strychnine, (+)-decursin, (−)-cryptocaryolone diacetate, (−)-fluoxetine, and aeruginosin 298-A, based on practical asymmetric catalyses (Michael reaction, epoxidation, and phase-transfer reaction) that I developed with co-workers in Prof. Shibasaki's group over the past 5 years. In the first part of this review, I discuss the great improvement of catalyst efficiency in an ALB-catalyzed asymmetric Michael reaction of malonate and application to the pre-manufacturing scale (greater than kilogram scale) and enantioselective total synthesis of (−)-strychnine with the development of novel domino cyclization. To broaden the substrate generality of the Michael reaction, we developed a highly stable, storable, and reusable La–O-linked-BINOL complex. Further extension of the reaction using β-keto ester as a Michael donor was achieved with the development of a La–NR-linked-BINOL complex, thereby improving indole alkaloid syntheses. In the second section, I discuss enantioselective total synthesis of (+)-decursin using catalytic asymmetric epoxidation. To achieve the synthesis, we developed a new La–BINOL–Ph₃As=O (1 : 1 : 1) complex catalyst system, which has much higher reactivity and broader substrate generality than the previously developed catalyst systems. This allowed us to achieve catalytic asymmetric epoxidation of α,β-unsaturated carboxylic acid derivatives with high enantioselectivity and broad substrate generality for the first time by changing the lanthanide metal and reaction conditions. Among them, catalytic asymmetric epoxidation of α,β-unsaturated morpholinyl amides is quite useful in terms of synthetic utility of the corresponding α,β-epoxy morpholinyl amides. Highly catalyst-controlled enantio- or diastereoselective epoxidation of the α,β-unsaturated morpholinyl amides, coupled with diastereoselective reduction of β-hydroxy ketones, enabled the synthesis of all possible stereoisomers of 1,3-polyol arrays with successful enantioselective total synthesis of several 1,3-polyol natural products, such as (−)-cryptocaryolone diacetate. In addition, the development of a new regioselective epoxide-opening reaction of α,β-epoxy amides to the corresponding α- and β-hydroxy amides enhanced the usefulness of the present epoxidation and was applied to the enantioselective total synthesis of (−)-fluoxetine. In the final section, I report the development of a new asymmetric two-center organocatalyst (TaDiAS) and its application to the enantioselective synthesis of aeruginosin 298-A and its analogues. Because of the remarkable structural diversity of TaDiAS, a practical asymmetric phase-transfer reaction with broad substrate generality was achieved. As a result, we succeeded in developing a highly versatile synthetic method for aeruginosin 298-A and its analogues. Inhibitory activity studies of the compounds against the serine protease trypsin provided preliminary information about their structure–activity relations.

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The mechanism of interaction of vinblastin sulphate (VBS) with bovine serum albumin (BSA) has been reported. Association constant for VBS–BSA binding was found to be 3.146±0.06×10⁴ M⁻¹. Stern–Volmer analysis of fluorescence quenching data showed that the fraction of fluorophore (protein) accessible to the quencher (drug) was close to unity indicating thereby that both tryptophan residues of BSA are involved in drug–protein interaction. The rate constant for quenching, greater than 10¹⁰ M⁻¹ S⁻¹, indicated that the drug-binding site is in close proximity to tryptophan residues of BSA. Binding studies in the presence of an hydrophobic probe, 8-anilino-1-naphthalein-sulphonic acid, sodium salt (ANS) indicated that there is hydrophobic interaction between VBS and probe and they do not share common sites in BSA. Thermodynamic parameters obtained from data at different temperatures showed that the binding of VBS to BSA involves predominant hydrophobic forces. The effects of some additives and paracetamol on binding of VBS–BSA have also been investigated. The CD spectrum of BSA in presence of VBS shows that the binding of VBS leads to change in the helicity of BSA.

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The size distribution after addition of oleate surfactant to preformed Egg yolk phosphatidylcholine (EggPC) vesicles was investigated by gel filtration chromatography combining with dynamic light scattering. Phospholipid and oleate concentration, fluorescence intensity and size of the vesicles were measured for each elution fraction. The spontaneous vesiculation of oleate at pH 8.5 was accelerated in the presence of preformed EggPC vesicles. The size distribution of newly formed vesicles was dependent on the preformed vesicular size. For example, oleate addition to large preformed vesicles (230 nm) resulted in altering of vesicles to both larger and smaller than preformed ones, while addition of oleate to small preformed vesicles (50 nm) led to the formation of only larger vesicles without exhibition of newly small vesicles. The combinations of gel filtration chromatography and dynamic light scattering could provide more detailed insight into the size change of newly formed vesicles.

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The oxidative behaviour of, a hypnotic drug, zolpidem was studied at glassy carbon electrode in Britton–Robinson buffer over the pH range 2.0—11.0 using cyclic, linear sweep and differential pulse voltammetry. Oxidation of the drug was effected in a single irreversible, diffusion-controlled step. Using differential pulse voltammetry (DPV), the drug yielded a well-defined voltammetric response in Britton–Robinson buffer, pH 8.0 at +0.889 V (vs. Ag/AgCl) on glassy carbon electrode. This process could be used to determine zolpidem concentrations in the range 5.0×10⁻⁷ M to 1.0×10⁻⁵ M with a detection limit of 2.0×10⁻⁷ M. The method was applied, without any interference from the excipients, to the determination of the drug in a tablet dosage form.

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A solid dispersion of the drug can be made using a polymer carrier to improve solubility. Generally, drugs become amorphized when solid dispersion is formed using a polymer carrier. In such high energy conditions, the solubility of the drug molecule is increased. We previously prepared solid dispersion using a spray-drying technique and reported its solubility and crystallinity. In this study, hydroxypropylmethylcellulose (HPMC) was used as the carrier, and tolubutamide was the model drug, which is water-insoluble. Solubility was evaluated by preparing a solid dispersion using a newly developed 4-fluid nozzle spray dryer. Observation of particle morphology by scanning electron microscopy (SEM) revealed that the particles from the spray drying were atomized to several microns, and they had also become spherical. Assessment of the crystallinity of the spray-dried particles by powder X-ray diffraction and differential scanning calorimetry demonstrated that the tolbutamide had been amorphized, forming a solid dispersion. The apparent release rate constant K of the drug from the spray-dried particles was 4 to 6 times faster than the original drug in pH 1.2, and it was also 1.5 to 1.9 times faster than the original drug in pH 6.8. The 70% release time (T₇₀) of the drug from the spray-dried particles was 20 to 30 times faster than the original drug in pH 1.2 solution as well as 2 to 3 times faster than the original drug in pH 6.8 solution. Pharmaceutical preparations prepared in this way using the 4-fluid nozzle system spray dryer formed composite particles, resulting in a remarkably improved dissolution rates of the drug.

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As part of a series of studies to discover new topoisomerase II inhibitors, novel pyrimidoacridones, pyrimidophenoxadines, and pyrimidocarbazoles were synthesized, and in vitro and in vivo antitumor activities and DNA-protein and/or DNA-topoisomerase II cross-linking activity as an indicator of topoisomerase II-DNA cleavable complex formation were evaluated. The pyrimidocarbazoles possessed high in vitro and in vivo potencies. Compound 26 (ER-37326), 8-acetyl-2-[2-(dimethylamino)ethyl]-1H-pyrimido[5,6,1-jk]carbazole-1,3(2H)-dione, showed in vitro growth inhibitory activity with respective IC₅₀ values of 0.049 μM and 0.35 μM against mouse leukemia P388 and human oral cancer KB. In vivo, this compound inhibited the tumor growth of mouse sarcoma M5076 implanted into mice with T/C values of 42% and 13% at 3.13 and 6.25 mg/kg/d respectively without significantly affecting the body weight. In addition, compound 26 (ER-37326) increased the formation of DNA-topoisomerase II cross-linking in P388 cells.

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Pd(0)-catalyzed intramolecular cyclic reaction via a π-allylpalladium complex provided an indolizidine skeleton in satisfactory high and reproducible yields by using allylic compound having an acetoxyl group as a leaving group. These results must be available for syntheses of various functional indolizidine alkaloids.

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From the leaves of Breynia officinalis, collected on Okinawa Island, six terpenic glucosides and six phenolic glycosides were isolated. Two of the terpenic glucosides were found to be known, and they were identified as turpinionoside B and betulalbuside A. The structures of the remaining terpenic glucosides were elucidated to be megastigmane glucosides, named breyniaionosides A—D, using spectroscopic analyses. The absolute structure of breyniaionoside D was determined using the modifed Mosher's method. The absolute structure of the known compound betulalbuside A was determined for the first time in this study. Six phenolic glycosides were found to be arbutin and its derivatives. Two known compounds were found to be robustaside A and eximine. New compounds were named isorobustaside A, and breyniosides A and B, and their structures were elucidated from spectroscopic evidence.

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Structural characterization and antiviral activities of fucoidan from sporophyll of Undaria pinnatifida (Mekabu) was examined. The fucoidan was composed of fucose and galactose with an approximately ratio of 1.0 : 1.1. Degree of substitution of sulfate was 0.72 and its apparent molecular weight was 9000. Methylation analyses showed that fucoidan had various sugar linkages, and revealed that the fucoidan might have complicated structure. This fucoidan showed potent antiviral activities against herpes simplex virus type 1 (HSV-1), HSV-2, and human cytomegalovirus.

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Six new artificial products 11—16 were obtained from the reaction of acetyllycoctonine (10) with N-bromosuccinimide (NBS). The structures of these compounds were established on the basis of spectral data. It is emphasized that the varieties and yields of the products in this reaction depended greatly upon reaction conditions and the types of substrate.

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A series of 4-anilinopyrazolopyridine derivatives were synthesized and biologically evaluated as inhibitors of phosphodiesterase (PDE4). Chemical modification of 3, a structurally new chemical lead that was found in our in-house library, was focused on 1- and 3-substituents. Full details of the discovery of a new orally active chemical lead 5 are presented. Structure–activity relationship data, pharmacological evaluation, and the subtype selectivity study are also presented.

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Direct β-glucosidation between 1,6-octanediol (5) and D-glucose (3) using the immobilized β-glucosidase (EC 3.2.1.21) from almonds with the synthetic prepolymer ENTP-4000 gave a mono-β-glucoside (6) in 61.4% yield, which was converted into the n-hexyl β-D-glucopyranoside (1) by means of a chemoenzymatic method. The coupling of the n-hexyl β-D-glucopyranoside congener (13) and 2,3,4-tri-O-acetyl-β-D-xylosyl congener (14), followed by deprotection, afforded the synthetic n-hexyl O-β-D-xylopyranosyl-(1→6)-β-D-glucopyranoside (2), which was identical to the natural 2 with respect to the spectral data and specific rotation.

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Nitrogen-functionalized cyclohexane derivatives with three contiguous chiral centers were synthesized by nitroalkene-selective conjugate addition of phenyllithium to a ω-nitro-α,β,ψ,ω-unsaturated ester and subsequent stereocontrolled intramolecular nitro-Michael cyclization with cesium fluoride and a quaternary ammonium bromide. The cyclohexanes were applicable to the total synthesis of α-, β- and γ-lycoranes.

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Oxidation of 2- and 3-hydroxycarbazoles with Frémy's salt gave the corresponding ortho-carbazolequinones. These molecules react as carbodienophiles in Diels–Alder reaction with 1-acetoxy-1,3-butadiene and 1,3-cyclopentadiene to provide the novel benzocarbazolequinone structures 15, 16, 18 and 19.

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A new group of steviolbioside amide dimers 2a—g, derivatives 2h—i and their related steviol and isosteviol amide dimers 3a and 4a were prepared by reacting aliphatic alkylamine and alkyldiamines with PyBOP and DIEA. The synthesized compounds had cytotoxic effects on cancer and human embryonic lung cells. Compounds 3a, 4a, 2b and 2h were cytotoxic to cancer cells and to a lesser extent to human embryo lung cells. Compounds 2f, 2g and 4 of this series had favorable antibacterial effects, and were superior to penicillin G at inhibiting growth of Bacillus subtilis (BCRC 10029). The cytotoxicity and antibacterial effects may depend on the dimerization and derivative moieties in relation to the respective aglycons.

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Candida antarctica lipase (CAL) catalyses the regioselective acetylation of the 10-hydroxyl group of 10-hydroxyoleoside dimethyl ester, a secoiridoid glucoside, using THF as a solvent and ethyl acetate or vinyl acetate as acetyl group suppliers. Two acetyl derivatives at 3′- and 6′-sites of the glucosidic ring of 10-acetoxyoleoside dimethylester, not previously described, were obtained by acetylation in the same conditions.

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The reactivity of two hydroxy groups in some multioxygenated cyclohexanoids was examined for basic study of the synthesis of the cytotoxic marine natural product pericosine B and related compounds. Differences in reactivity for O-methylation or O-acylation among substrates were observed.

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Synthesis of the epimer of pericosine B from (−)-quinic acid was achieved. This synthesis involves some regioselective and stereoselective processes. The desired product showed lower cytotoxic activity in comparison with natural pericosine B against the P388 leukemia cell line. The result implies that the stereocenter of C-6 in natural pericosine B plays an important role in this activity.

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Three new β-dihydroagarofuran sesquiterpene esters, 6α-acetoxy-9β-benzoyloxy-1β-cinnamoyloxy-8β-butanoyloxy-β-dihydroagarofuran (1), 6α-acetoxy-9β-benzoyloxy-1β-cinnamoyloxy-8β-(2-methylbutanoyloxy)-β-dihydroagarofuran (2), and 6α-acetoxy-1β,8β-dibenzoyloxy-9β-hydroxy-β-dihydroagarofuran (6), together with three known compounds (3—5) were isolated from the fruits of Celastrus orbiculatus THUNB. Their structures were elucidated on the basis of spectroscopic methods. Compound 4 showed moderate activity in inhibiting LPS-induced nitric oxide production in murine macrophage RAW264.7 cells with an IC₅₀ value of 43.7 μM.

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Racemic 2-amino-3-(heteroaryl)propanoic acids (1), mostly with a furan or thiophene nucleus as a heteroaryl group, were synthesized in 48—94% yield by the reduction of 3-(heteroaryl)-2-(hydroxyimino)propanoic acids (5) with zinc dust and formic acid in the presence of a catalytic amount of iron dust at 60 °C for 2 h. Under these conditions, unfavorable hydrogenolysis of bromine on the thiophene nucleus does not occur. Traditional N-formylation of the prepared 3-(heteroaryl)alanine (1) with a mixture of formic acid and acetic anhydride afforded 2-(formylamino)-3-(heteroaryl)propanoic acids (6) in 51—95% yield.

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A glycosyl inositolphosphoceramide-type ganglioside, CJP4, was obtained from the polar lipid fraction of the chloroform/methanol extract of the feather star Comanthus japonica. The structure of this ganglioside has been determined on the basis of chemical and spectroscopic evidence to be 9-O-methyl-(N-glycolyl-α-D-neuraminosyl)-(2→11)-9-O-methyl-(N-glycolyl-α-D-neuraminosyl)-(2→11)-9-O-methyl-(N-glycolyl-α-D-neuraminosyl)-(2→3)-inositolphosphoceramide, which contains C₁₆-sphingosine and C_22:0-, C_24:0-fatty acid. This is the first report on the isolation and structural elucidation of a trisialo-glycosyl inositolphosphoceramide-type ganglioside. Moreover, CJP4 exhibited neuritogenic activity toward the rat pheochromocytoma PC12 cells in the presence of nerve growth factor.

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Oxidation of 3-hydroxypiperidine with iodosylbenzene in water afforded 2-pyrrolidinone directly in good yields. The reaction probably involves oxidative Grob fragmentation yielding imino aldehyde, which upon hydrolysis produces 2-pyrrolidinone via a cyclization–oxidation sequence.

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Two new additional trijugin-type limonoids, sandrapins D (4) and E (5), which are analogues of the previously reported sandrapins A—C (1—3), were isolated as minor components from the leaves of Sandoricum koetjape (Meliaceae), and their structures were elucidated on the basis of MS and NMR spectral data.

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Two new cangorosin A type triterpene dimers, which composed of two triterpene units jointed by two ether linkages between the A and B rings, were isolated from the Brazilian medicinal plant “xuxuá” (Maytenus chuchuhuasca). Structures of new isolates, xuxuasins A (1) and B (2), were established based on several spectroscopic evidences.

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A novel phenylpropenoyl sulfonic acid, petasiformin-A (1), and a new chlorophyll, petasiphyll-A (2), were isolated from the leaves of Petasites formosanus KITAMURA (Compositae). Their structures were established by spectral and chemical transformation methods. Petasiformin-A (1) showed the significant antioxidative activity in DPPH radical scavenging assay.

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(−)-Methyl 7β-hydroxykaurenoate (3) and its 4-demethyl acetate (−)-4 were both synthesized via methods that contained radical cyclization and intramolecular Diels-Alder reactions as key steps. Both compounds displayed potent neuroprotective activity against N-methyl-D-aspartate toxicity in cultured cortical neurons.

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