“Asymmetric desymmetrization” is an efficient and powerful methodology for optically active substances with complex structures. Enantiotopic group differentiation reactions starting from meso compound with chiral centers can afford chiral/non-racemic compounds bearing controlled multi-chiral centers. We introduce many useful examples of asymmetric desymmetrization, which have ever been reported, and our results on asymmetric desymmetrization using asymmetric ene reactions catalyzed by chiral BINOL-Ti complex.
In recent years there has been a broadly expanding interest in the synthesis of α-fluorophos-phonates. This interest has resulted from their potential utilities as mimics for biological phos-phates in the biological processes. This review is focussed on the recent development for the effi-cient synthesis of α-fluorophosphonates. The examples cited in this review are divided in four dis-tinct types of methods : (a) fluorination of phosphonates, (b) C-C bond formation of activated fluo-romethylphosphonate, (c) phosphonylation of fluoroolefins, (d) transformations of α-fluorophos-phonates.
Planar chiral cyclopentadienyl complexes of late transition metals were synthesized by using trisubstituted cyclopentadienes. Each enantiomer has been isolated as an optically pure form by fractional recrystallization of (l) -menthyl ester derivatives followed by the removal of the (l) -men-thyl group. Cyclopentadienyl ruthenium complexes possessing an anchor phosphine ligand, which prevents the rotation of the cyclopentadienyl ring, were also prepared. The planar-chiral ruthenium complexes showed high diastereoselectivity in some reactions such as complexation of dienes and substitution with phosphines. The planar-chiral ruthenium complexes with anchor phosphine ligands were successfully applied to asymmetric allylic amination and alkylation. In these reac-tions, the anchor phosphine ligand acts as an important role to control the stereochemistry of the products.
Recent theoretical and experimental studies on conformational dependence of the oligosilane chromophore are described. CIS/3-21 G* calculations suggested that a tetrasilane has four transitions into valence excited states. Two of them are of B symmetry, one at lower and one at higher energy. It is not so much the excitation energies as the oscillator strengths of these transitions that are functions of the SiSiSiSi dihedral angle ω (avoided crossing model). This model has been confirmed by experimental efforts such as spectral separation of n-Si4Me10 conformers in low temperature matrices and measurements on conformationally constrained tetrasilane compounds, e.g.., tetrasilanes incorporated into five-to-eight-membered carbosilane ring systems and ones composed of configurationally constrained bicyclic disilane unit (s). In addition to tetrasilanes, three hexasilane conformers were investigated as well. The examination revealed that incorporation of a syn-segment into an anti chain raises the excitation energy of the first transition.
The potential of synthetic thiasugars, the ring sulfur analogs of carbohydrate, as glycosidase inhibitor was discussed in terms of activity and specificity, based on our own studies. The syntheses of these analogs including di- and tri-saccharide derivatives were also outlined. 5-Thiofucose was the first thiapyran to show a Ki value of micromolar range against a glycosidase. The structure-activity relationship studies indicated that its fucosidase inhibition was due in part to a hydrophobic interaction between the ring sulfur and the enzyme. A sulfylimine compound having a thiafuran structure was created as a transition-state analog inhibitor of glucosidases and found to have a weak activity. The same thiafuran structure was later found by another group in a natural product, salacinol, which is a sulfonium derivative and is a strong glucosidase inhibitor. The structure-activity relationship study with synthetic analogs of salacinol indicated importance of the sulfonium ion and its internal counter anion, sulfate, for the inhibition activity.
Farnesyl diphosphate (FPP) synthase (FPS) catalyzes the condensation of isopentenyl diphos-phate (IPP) with allylic primer to give FPP as final product. The FPS from pig liver has been successfully applied to syntheses of bioactive compounds. Molecular cloning and expression of the gene for thermostable FPS from Bacillus stearothermophilus made it possible to produce sufficient amounts of the enzyme. However, it can hardly accept the substrate analogs having oxygen atom in their alkyl chain, which are easily accepted by pig liver enzyme. We constructed many mutated FPP synthases (FPSs) from B. stearothermophilus, in which Tyr-81 was substituted with Ser (S), Arg (R), Asp (D), or Gly (G). Interestingly, the substrate specificities of the mutated enzymes have been dramatically altered. They can easily accept the substrate analogs having oxygen atom. These results indicate further possibilities in application of the mutated enzymes to organic syn-thesis.
The key issue of the present drug development is to find the lead compound in the minimum time and cost by using all kinds of new and traditional technology such as genomic drug discovery, random High Throughput Screening (HTS), virtual screening, combinatorial chemistry, X-ray crystal analysis, molecular modeling and so on. It is crucial to build up efficiently Chemical Compound Library with wide diversity to be applied to HTS for any kind of biological activity. University Compound Project at Foundation for Education of Science and Technology was started on February 2002, to use more efficiently not commercially-available domestic and abroad University Compounds (UC) for the drug development by building up the University Compound Data Base (UCDB). So far, 60 chemists at 35 universities and institutes, and 12 companies have joined to the project. The project has collected about 29, 000 UCDB available to the participating companies for the selection of UC and would add about 10, 000 UCDB every year.