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The medicine in the 21st century will be so called "evidence based medicine" or "personalized medicine," based on the principle of "right drug to right patient." Pharmacogenomics covers the entire spectrum of genes that determines drug behavior and sensitivity, and we anticipate it will bring major impact on the healthcare system as well as the drug discovery process in the near future. Three waves of genomic impact are predicted to arise as follows: The first wave will hit on existing drugs and late-phase development candidates within the next 2-3 years, aiming to minimize the risks in clinical trials (adverse events, resistance, etc.). The wave will then affect the candidate selection process in the early pre-development stage, and finally the disease gene finding to target discovery process. The driving force will be technologies such as SNPs database, differential gene expression (DGE) analysis, proteomics, serial analysis of gene expression (SAGE) and bioinformatics. This new approach of genomic discovery (so called "integrated approach") requires knowledge on how to implement and integrate new valuable technologies from an early stage of the discovery process. The implication of SNPs, high throughput proteomics and application of structural genomics will be the key issues in the pharmacogenomics era.

The promise of pharmacogenomics includes managing patient-to-patient variability, developing better drugs faster and cheaper, and providing better medical care. However, whether there would be cost savings in clinical trials and the emergence of pharmacoeconomic modeling for diagnostic tests is still under consideration. In this talk, I would like to discuss these issues from clinical and discovery aspects of pharmacogenomics. Other ethical concerns including genomic data acquisition, data analysis, sensitivity and specificity, confidentiality and storage of patient sample, will be discussed as well. How to integrate the driven technologies with informatics will be one of the key issues to success.

We have developed a unique in vitro reconstitution system for tracheal epithelia of guinea pigs. In the system, a human amnion membrane was used as a basement membrane and the tracheal epithelial cells were cultured on the epithelial side of the membrane. Three weeks later, the tracheal fibroblasts were co-cultured on the serosal side of the amnion membrane and the culturing was continued for an additional 10 d. The morphology of the cultured epithelial cells consisted of a pseudostratified columnar ciliated epithelium from cuboidal ciliated epithelium during the last 10 d of the culture period. Epithelial cells included both goblet-like and basal cells. In addition, the frequency of each type of differentiated cells was almost identical to that of in vivo tracheas. Interestingly, the same results were obtained when the conditioned medium of the tracheal fibroblasts was used instead of the fibroblasts themselves. These results suggest that epithelial-mesenchymal interaction is likely involved in growth and differentiation of epithelial cells in vivo in a soluble factor(s)-mediated manner. As well as the epithelial cells, the fibroblasts also formed a multilayer during the last 10 d of co-culturing. This indicates that in vitro reconstitution of tracheal epithelia is achieved without addition of any exogenous growth or differentiation factors. The reconstitution system is shown to be useful for investigating the cellular and molecular interaction of epithelial and mesenchymal cells. Possible applications of the culture system and possible factors involved in growth and differentiation of epithelial cells are discussed.

The present review represents some of the recent developments in industrial syntheses of terpenoids. The main topics are [1, 3] -transpositions [allyl-, Carroll-, Claisen-, and Cope-rearrangement etc.] and applications of catalysts [oxo-reaction, methathesis, oxidative coupling reaction]. Specific industrial examples are given, and the advantages and disadvantages of these reactions are discussed. In the evaluation of a reaction the industrial point of view is emphasized.

1,2-Epoxy-3-methyl-3-butene has been synthesized from prenyl acetate by using ene-type chlo-rination.

9-(2, 6, 6-Trimethyl-1-cyclohexen-1-yl)-3, 7-dimethyl-2, 4, 7-nonatrien-1, 6-diol, an important intermediate for synthesis of vitamin A acetate, has been synthesized directly by using a polyfunctional lithium reagent prepared by the action of lithium-arenes to the corresponding chloride.

Regio- and stereoselective oxidation of ene-type chlorinated olefins has been achieved by using potassium 2-propanenitronate as an oxidant and tetrakis(triphenylphosphine)palladium as a catalyst.

Selective synthesis of pseudoionone was achieved by the acetylenic oxy-Cope rearrangement of 4-isopropenyl-3,7-dimethyl-6-octen-1-yn-3-ol ( 3 ) in N-methyl-2-pyrrolidone solvent containing a trace of hydrochloric acid, hydrobromic acid, iodine, ammonium bromide and ammonium chloride catalysts.

Preparation de cyclopentenones et de la dihydrojasmone a partir de pentenones substituees avec comme intermediaire cle une epoxycetone

Synthesis of citral from diprenyl ether is achieved by new diene forming reaction which consists of ene-type chlorination and palladium catalyzed dehydrochlorination.

A sequence of ene-type chlorination, palladium catalyzed dehydrochlorination, and the intramolecular Diels-Alder reaction afforded a new method for conversion of prenyl derivatives into bicyclic compounds.

Squalane is synthesized by the ethynylation reaction of geranylacetone with a complex of 1,3-butadiyne : N-methylpyrrolidone (=1 : 1) in the presence of a KOH catalyst and by hydrogenation with a Raney nickel catalyst, followed by hydrogenation hydrogenolysis with a mixed catalyst of nickel/diatomaceous earth and silica-alumina. An alternative synthesis of squalane from dehydronerolidol is also achieved by oxidative coupling reaction with a copper(II) catalyst under a helium atmosphere.

Unsaturated nitriles have been synthesized from trisubstituted olefins via ene-type chlorination and regioselective substitution with cyanide ion followed by double bond migration.

Various types of α-arylpropionic acid esters were effectively obtained by the coupling reaction of aryl Grignard reagents and α-bromopropionic acid esters in the presence of nickel catalysts. α-Arylpropionitriles, precursors of α-arylpropionic acids, were also synthesized by the reaction of α-methanesulfonyloxypropionitrile and arylcopper reagents prepared from equimolar amount of arylmagnesium halides and copper(I) bromide.

In order to find new aroma chemicals, various type of terpenoid compounds are prepared using prenyl chloride (1) as a raw material. The main reaction is the condensation of (1) and aldehydes with aqueous sodium hydroxide (ca. 50%) in the presence of a tetrabutylammonium iodide catalyst. The prenylated aldehydes (2) are converted to the corresponding alcohols (3), acetals (4) or nitriles (5). Alcohols (6) are also obtained from (2) and various allylic Grignard reagents. Those compounds are evaluated by their odor : 2, 5-Dimethyl-2-propyl-4-hexen-1-ol (3c), 2, 5-dimethy;-2-phenyl-4-hexenal (2 e), 2, 5-dimethyl-2- (p-methylphenyl) -4-hexenal (2 h), 2, 5-dimethyl-2-propyl-4-hexenal dimethyl acetal (4 c) each emited an odor that will qualify them for cosmetic application.

Recently much attention has been focussed on ene reactions, and their synthetic utility has been increased because of their high regio- and stereospecificity. Ene reaction is based on addition of a compound with electron-deficient multiple bond (an enophile) to an olefin possessing an allylic hydrogen (an ene).Intermolecular ene reactions are classified by functional groups in enophiles. The differences between thermal reactions and Lewis acid catalyzed ones are discussed.Intramolecular ene reactions including metallo-ene systems are reviewd according to the classification (Type I- III) reported by Oppolzer.

Selective thermal rearrangement of allylic alcohols proceeds in the presence of various O=W(OR)4. Ligand catalysts which are more stable than O=W(OR)4 catalyst and are several times more active than O=V(OR)3 catalyst.

Four new sigmatropic sequences triggered by the regiocontrolled [2,3]-Wittig rearrangement of unsymmetrical bis-allylic ethers (1) to the l,5-dien-3-ols (2) arc described, which provide unique, regiocontrolled methods for the synthesis of a wide variety of unsaturated carbonyl compounds possessing interesting molecular frameworks. The newly developed sequences include the [2,3]-Wittig-Claisen, the tandem [2,3]-Wittig-oxy-Cope, the tandem oxy-Cope-Claisen, and the tandem oxy-Cope-Cope sequences.

Synthesis of polyisoprenepolyols possessing multiple tertiary hydroxy moieties has been achieved efficiently by using hydromagnesation.

Stereocontrolled convergent synthesis of vitamin A was achieved by the double elimination method employing the C10 sulfone and the C10 aldehydes as starting materials. Thus the all-trans and 13-cis isomers were obtained with the stereochemical purity of 95% and 90%, respectively.

The ethynylation of ketone (2) in liquid ammonia at −33°C with stoichiometric sodium acetylide afforded the corresponding alcohol (3 and 4). Similar treatment of 1 resulted in only a little isomerization to 2. Favorskii ethynylation under pressure at 0°C yielded a mixture of 1, 2, 3 and 4 without any detectable 5, whichever ketone 1 or 2 being used.

Oxy-Cope rearrangement of diastereomeric l,5-hexadien-3-ols, new key intermediates for terpenoids pio-duction in industrial scale, were investigated in neat systems and solvent assisted systems. Various solvents affecting the selectivity of [3,3]-shift were classified by means of NMR studies on hydroxyl proton exchange time.

On etudie la reaction de plusieurs derives du nerol avec le reactif de Grignard, prepare a partir du bromo-4 methyl-3 butyl benzyl ether en presence de sels de cuivre

2-[4-(3-Methyl-2-butenyl)phenyl]propionic acid was synthesized in 82% yield via nickel(II) chloride or dichlorobis[η5-cyclopentadienyl]titanium-catalyzed hydromagnesation of 1-(3-methyl-2-butenyl)-4-vinylbenzene obtained in ca. 63–68% yield by the coupling reaction of 4-(3-methyl-2-butenyl)phenylmagnesium chloride with vinyl chloride.

Recently much attention has been focussed on ene reactions, and their synthetic utility has been increased because of their high regio- and stereospecificity. Ene reaction is based on addition of a compound with electron-deficient multiple bond (an enophile) to an olefin possessing an allylic hydrogen (an ene).Intermolecular ene reactions are classified by functional groups in enophiles. The differences between thermal reactions and Lewis acid catalyzed ones are discussed.Intramolecular ene reactions including metallo-ene systems are reviewd according to the classification (Type I- III) reported by Oppolzer.

Squalane is synthesized by the ethynylation reaction of geranylacetone with a complex of 1,3-butadiyne : N-methylpyrrolidone (=1 : 1) in the presence of a KOH catalyst and by hydrogenation with a Raney nickel catalyst, followed by hydrogenation hydrogenolysis with a mixed catalyst of nickel/diatomaceous earth and silica-alumina. An alternative synthesis of squalane from dehydronerolidol is also achieved by oxidative coupling reaction with a copper(II) catalyst under a helium atmosphere.

2-[4-(3-Methyl-2-butenyl)phenyl]propionic acid was synthesized in 82% yield via nickel(II) chloride or dichlorobis[η5-cyclopentadienyl]titanium-catalyzed hydromagnesation of 1-(3-methyl-2-butenyl)-4-vinylbenzene obtained in ca. 63–68% yield by the coupling reaction of 4-(3-methyl-2-butenyl)phenylmagnesium chloride with vinyl chloride.

9-(2, 6, 6-Trimethyl-1-cyclohexen-1-yl)-3, 7-dimethyl-2, 4, 7-nonatrien-1, 6-diol, an important intermediate for synthesis of vitamin A acetate, has been synthesized directly by using a polyfunctional lithium reagent prepared by the action of lithium-arenes to the corresponding chloride.

Double bond migration of 2,5-dienones 3 to 2,4-dienones 2 (e.g. pseudoionone) was effectively carried out by using nickel acetylacetonate catalyst in N-methyl-2-pyrrolidone solvent.

The Friedel–Crafts reaction of 3,6-dihydro-4-methyl-2H-pyran with 2,3,5-trimethylhydroquinone afforded 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-ethanol in good yield.

Tertiary amine N-oxides were found to be effective for converting allylic chlorides to α,β-unsaturated aldehydes.