α-Oxoketenes are currently of major interest in synthetic and mechanistic studies. They are most conveniently generated by thermal fragmentation of 1, 3-dioxin-4-ones or acylated Meldrum's acids under a mild heating. Meldrum's acid itself also generates carboxyketene through the tautomeric 6-hydroxydioxinone under mild heating. The fragmentation of dioxinones to α-oxoketenes is of much interest from mechanistic viewpoint, because the transition structure of the ring opening is almost planner as recently revealed by ab initio calculations. α-Oxoketenes thus generated serve as powerful acylating reagents of nucleophiles to produce β-keto acid derivatives. They also serve as hetero-dienes in 4+2 cycloadditions to produce heterocyclic compounds. In addition, use of dioxinones provides ready access to hydroxylated or aminated ketenes. Intramolecular trappings of these ketenes afford lactones or lactams including macrocyclic compounds. Intramolecular dimerization of bis (oxoketene) tethered to origomethylene unit efficiently produces a series of new cyclophanes.

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During the course of our study on the Diels-Alder (DA) reaction of 2-prone, we found that base catalyst was quite effective for the reaction of 3-hydroxy-2-pyrone with electron deficient dienophile. In particular, the reactions with the reactive dienophiles such as maleimides and acrylate derivatives proceeded quite rapidly in the presence of catalytic amount of triethylamine and the yields of the adducts were almost quantitative.
Enantio- and diastereoselective DA reactions of 3-hydroxy-2-pyrone were also achieved by using chiral base and chiral dienophile, respectively. The reaction with N-methylmaleimide catalyzed by cinchonidine afforded optically active adduct in 87% ee, and the reaction with chiral N-acryloyl oxazolidinone derivative gave the adduct in 95% de.
By using these reactions, pseudo-sugars and a key intermediate of substance P antagonist were synthesized.

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There has been a resurgence of interest in thalidomide (N-α-phthalimidoglutarimide), a teratogenic hypnotic/sedative agent, in recent years due to its potential usefulness of the treatment of various diseases. The effectiveness of the drug has been attributed to its regulating activity on tumor necrosis factor alpha production. The regulating activity has been found to be bidirectional, depending on both cell-type and the cell-stimulator. The bidirectional activity was separated by structural development of the drug, resulting in novel, potent, and structurally new thalidomides. By further structural development, novel types of androgen antagonists and nonpeptide protease inhibitors have been derived. Some of the developed compounds have been found to elicit potent antiangiogenic activity and/or potent inhibitory activity on tumor cell invasion. The studies on these structural development and the expansion of biological activities is reviewed in relation to the structure-activity relationships.

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In our continuing search for bioactive substances from marine organisms, four novel alkaloids, pinnatoxins, halichlorine, pinnaic acids and norzoanthamine were isolated. The structures and functions of these marine alkaloids are described here.
Pinnatoxins, potent shellfish poison, were purified form the Okinawan bivalve Pinna muricata. Pinnatoxins activate Ca²⁺ channel. Especially, toxicity of pinnatoxins B, C is as significant as that of tetrodotoxin. Halichlorine was isolated from the marine sponge Halichondria okadai. This compound inhibits the induction of VCAM-1 at IC₅₀ 7 μg/ml. Drugs that block VCAM-1 may be useful for treating coronary artery diseases, angina and noncardiovascular inflammatory diseases. Pinnaic acids, cPLA₂ inhibitor, were also obtained from the Pinna muricata. Interestingly, the structures of pinnaic acids are closely related to that of halichlorine. Norzoanthamine hydrochloride, isolated from the colonial zoanthid Zoanthus sp. which suppresses the decrease in bone weight and strength in ovariectomized mice, could be a good candidate for an osteoporotic drug.

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Thermolysis of isonitroso Meldrum's acid (5-hydroxyimino-2, 2-dimethyl-1, 3-dioxane-4, 6-dione) generated a new reaction intermediate, nitrosoketene, which reacted with various ketones in aprotic solvent to form cyclic nitrones. These nitrones underwent 1, 3-dipolar cycloaddition reactions with electron rich olefins to give the corresponding isoxazolidine derivatives with high diastereoselectivity, which were converted to nonproteinogenic amino acids such as allylglycine and cyclopentenylglycine. Nitrosoketene was detected by FT-IR spectroscopy.

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Reduction of aryl and vinyl radicals to the corresponding organosamarium species by SmI₂ can be attained by using benzene-HMPA as a solvent system. Thus, SmI₂-mediated Barbier- and Grignardtype coupling reactions between ketones and aryl, vinyl, or alkynyl iodides proceed via organosamarium species in benzene-HMPA. Reductive dehalogenation of 1, 1-dihaloalkenes by SmI₂ in benzene-HMPA generates alkylidenecarbenes, which undergo either 1, 5-C-H insertion giving cyclopentenes or 1, 2-shift giving alkynes. On the other hand, SmI₂ was found to be useful to effect 2, 3-rearrangement under mild conditions. Metalated ethers undergoing Wittig rearrangement are regioselectively generated by either an intramolecular 1, 5-hydrogen transfer of a vinyl radical, generated by a single electron transfer from SmI₂ to γ-haloallyl ethers, or a net two-electron reduction of diallyl acetals with the liberation of an allyloxy samarium by SmI₂ in acetonitrile. 2, 3-Rearrangement of allylic sulfonium ylides can be effected by the reaction of allylic sulfides with samarium carbenoid, generated from CH₂I₂ and SmI₂ in THF.

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[in Japanese]

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