We have been working on finding new bioactive microbial metabolites at the Kitasato Institute. Their microbial natural products have a variety of unique and complex skeletones with many chiral centers and functional groups, and biological activities. We also have been working on total synthesis of them, which is effective and concise convergent approach, designed to afford easy access to both the natural products and a variety of analogs to clarify the structure-activity relationships. We have succeeded the efficient total syntheses of bioactive microbial metabolites; pyripyropene A (1) and E, arisugacin (2), paspalicine (3) and paspalinine (4), lactacystin (5), macrosphelide (6), and madindoline (7). We also have succeeded to create better analogs of pyripyropene A (1) and lactacystin (5).
Enantioselective reactions involving hypervalent silicate generated from trichlorosilane derivatives in the presence of chiral Lewis bases as catalysts are reviewed. Highly diastereo- and enantioselective allylations of aromatic and conjugate aldehydes with allyltrichlorosilanes have been developed by using chiral hexamethylphosphoramide (HMPA) derivatives or chiral bipyridine N, N' -dioxide derivatives as catalysts. Enantioselective allylations of aliphatic aldehydes have been accomplished by using chiral dimethylformamide (DMF) derivatives. It is strongly suggested that the present allylations proceed via cyclic chair-like transition structures involving hypervalent silicates. Enantioselective aldol reactions of aldehyde with trichlorosilyl enol ethers have been achieved by using chiral HMPA derivatives, which have been also effective in enantioselective ring opening of epoxides with tetrachlorosilane.
Development of a new methodology for an asymmetric reaction of organolithium reagents constitutes fundamental progress in recent synthetic organic chemistry. The methodology we developed relies on an external chiral coordinating reagent which forms a chelated complex with organolithium reagents. Under the positive control of a chiral dimethyl ether of stilbenediol 8, an asymmetric conjugate addition reaction of organolithium reagents with unsaturated imines and esters proceeded successfully to afford the corresponding addition products in reasonably high stereoselectivity. The sense of stereochemistry is predictable based on a coordination model. The methodology has been extended to a catalytic asymmetric 1, 2-addition reaction of organolithium reagents with imines. Asymmetric Horner-Wadsworth-Emmons reaction of phosphonate with 4-substituted cyclohexanone and enantiotopic selective opening of cyclohexene oxide were also another successful application of the methodology. The methodology has been successfully applied to an asymmetric synthesis of biologically potent compounds. Dihydrexidine, promising anti-Parkinsonism candidate, and salsolidine, a representative isoquinoline alkaloid, have been synthesized using asymmetric addition reactions of organolithium reagents as the key steps.
2-Substituted 2-lithio-1, 3-dithiane derivatives have been used as an excellent acyl anion equivalent for carbon-carbon bond formation. One of the representative examples is their coupling with monosubstituted oxiranes. We found that 2-substituted 1, 3-dithiane derivatives were lithiated with n-BuLi at room temperature and the resulting anions reacted with 2, 3-disubstituted oxiranes at room temperarure, giving the coupling products in satisfactory yield. This type of coupling reaction has not been used in natural product syntheses, because the temperature-dependent instability of dithianide anions and the poor electrophilicity of 2, 3-disubstituted oxiranes should be discouraging factors. This article describes effective metallation conditions of 2-substituted 1, 3-dithiane derivatives and the practical synthesis of four stereoisomers of bis-propionates via the dithiane coupling with oxiranes.
The Horner-Wadsworth-Emmons modification of the Wittig reaction is a widely used method for the preparation of α, β-unsaturated esters. The phosphonate anions are strongly nucleophilic and react readily with carbonyl compounds under mild conditions to form olefins and water-soluble phosphate esters in good yields. Since this reaction preferentially gives more stable E-olefins in general, extensive efforts have been devoted to the stereoselective construction of Z -α, β-unsaturated esters. Several attempts have been made by the choice of cation, temperature, and solvent, but they are with a limited success. On the other hand, the special phosphonate reagents including (CF3CH2O) 2P (O) CH2CO2Me and (ArO) 2P (O) CH2CO2R gave highly selective routes to a wide range of Z-α, β-unsaturated esters. This review describes these efforts. The mechanism of the HWE reaction is also described briefly.
The first total synthesis of pinnatoxin A (1), a Ca2+-channel activator isolated in 1995 by Uemura and co-workers from the shellfish Pinna muricata, is reported. The synthetic plan was based on Uemura's biosynthetic proposal, and consists of an intramolecular Diels-Alder reaction for construction of the G-ring as well as the macrocycle, followed by imine formation to establish the 6, 7-spiro-ring system. During this investigation, factors controlling the stereochemistry of the BCD bis-spiroketal ring system were investigated, and the chemoselectivity and efficiency of the Ni (II) /Cr (II) -mediated coupling protocol were demonstrated. This synthesis has also established the absolute stereochemistry of natural pinnatoxin A as the antipode of structure 1.
Recently, a new class of organic materials, i.e., self-organizing molecular semiconductors has been created. This materials exhibit self-organizing molecular alignment and excellent carrier transport properties compared with the conventional amorphous organic semiconductors. In this article, a concept of the new materials, their design, synthesis, and general features of opto-electronic properties are described comparing with the conventional ones. In addition, some potential applications to a high speed photo-sensor with a microsecond response and a polarized light emitting diode are mentioned in order to demonstrate how the new materials are promising as a class of the opt-electronic materials.