An enantioselective synthesis of cyclic and acyclic β-aryl ketones and esters via palladium (II) - or rhodium (I) -catalyzed 1, 4-addition of Ar- [m] (m=B(OH)2, BF3K, Si(OMe)3, SiF3, BiAr2) to α, β-unsaturated ketones or esters is described. The catalytic cycle involves transmetalation between Ar- [M] and palladium (II) or rhodium (I) complexes as the key process, the mechanism of which is discussed on the basis of characterization of the transmetalation intermediate and electronic effect of the substituents. The enantioselection mechanism and efficiency of a chiraphos ligand for structurally planar α, β-unsaturated ketones are discussed on the basis of the X-ray structure of the catalyst and results of DFT computational studies on the modes of coordination of the substrates to the phenylrhodium (I) / (S, S) -chiraphos intermediate.
A library of designed DNA compaction agents based on multicationic polyamines, which can fold a DNA polymer chain into condensates with high density due to negative charge neutralization of DNA, are synthesized, and the structure-activity relationship in DNA compaction is investigated. It becomes obvious that the activity is strongly affected by non-electrostatic interactions with DNA, such as hydrophobic (hydrophilic), intercalation, and chirality effects, as well as by efficiency of charge interactions and geometry matching between charged groups of DNA and compaction agents.
Highly enantioselective asymmetric Baylis-Hillman reactions employing (3R, 8R, 9S) -10, 11-dihydro-3, 9-epoxy-6'-hydroxy-cinchonane, β-isocupreidine (β-ICD), as a chiral amine catalyst and 1, 1, 1, 3, 3, 3-hexafluoroisopropyl acrylate (HFIPA) as an activated alkene are described for aldehydes including chiral N-Boc-α-amino aldehydes and aromatic N-diphenylphosphinoyl imines. The key features of this β-ICD-HFIPA method and a plausible reaction mechanism governed by hydrogen bonding are presented.
Bifunctional thiourea-catalyzed asymmetric addition of several nucleophiles with nitrones, imines, and electron-deficient unsaturated compounds is described. These urea and thiourea catalysts were designed and synthesized based on the mechanism of hydrolytic enzymes. By taking advantage of the strong hydrogen-bonding ability of diaryl thioureas, several electrophiles such as nitrones and aldehydes were revealed to be activated in the reactions with TMSCN and ketene silyl acetals. In addition, we discovered that use of bifunctional thioureas bearing a tertiary amino group significantly expanded the applicability of the thiourea-catalyzed enantioselective nucleophilic addition by the simultaneous activation of both nucleophiles and electrophiles. These organocatalyzed asymmetric reactions were successfully applied to the concise asymmetric synthesis of natural products and medical supplies such as epibatidine, baclofen, and CP-99, 994.
Mechanistic studies on and synthetic application of epoxysilane rearrangement, a novel synthetic use of α, β-epoxysilanes, in which an anion-induced ring-opening of epoxide and Brook rearrangement in the resulting α-silyl alkoxide occur in a tandem fashion to provide a β-siloxy allyl anion, are described.
This article describes the investigation of the molecular mechanism of the catalytic antibodies elicited against a phosphonate transition state analog. We have investigated the biochemical properties within a panel of six hydrolytic catalytic antibodies. The transition-state analysis (kcatkuncat versus Km/ Ki) displayed a linear relationship with five antibodies, 6D9, 8D11, 4D5, 3G6, and 9C10, which have homologous primary amino acid sequences, while 7C8 deviates from the linear relationship. These results suggest that the five antibodies catalyze the hydrolysis by the same mechanism of transition-state stabilization and that factors other than transition state-stabilization are involved for antibody 7C8. The structures of complexes of 6D9 Fab and 7C8 Fab with the transition-state analog (TSA) have been solved. Antibodies 6D9 and 7C8 bind the phosphonate of TSA by forming one hydrogen bond with His L27d and TyrH95, respectively. The kinetic, structural, and thermodynamic analyses of 6D9 indicate that this antibody provides an efficient catalyst by the transition state stabilization through the hydrogen bond with HisL27d and the destabilization of the substrate. The most probable catalytic mechanism of the 7C8-catalyzed hydrolysis of an ester is the nucleophilic catalysis by the deprotonated TyrH95. Our results demonstrate that substantial diversity may be present among the antibodies raised against a single TSA and which catalyze the same reaction.
Sulfonamide-focused compound libraries have been synthesized in our laboratories for biological evaluation using antitumor phenotypic screens such as cancer cell proliferation assay, flow cytometric cell cycle analysis, and rat aorta tube formation assay. Among thousands of sulfonamide compounds evaluated, E7010 (a microtubule depolymerizing agent), E7070 (a G1 phase cell cycle inhibitor), and E7820 (an antiangiogenesis agent) have progressed to clinical trials, thereby demonstrating some objective responses in cancer patients so far. The sequential discovery of these drug candidates allowed us to carry out a research approach of forward chemical genetics, in which phenotypically bioactive compounds are selected from a large collection of small molecules and then utilized for understanding the functions of their protein partners and relevant biological pathways via target identification. This paper describes our attempt using oligonucleotide microarray and quantitative proteomic analyses not only for identifying drug targets and downstream pathways applicable to biomarkers but also for exploring druggable chemical space in medicinal chemistry research.
Tools for chemo-, regio- and stereo-selective introduction of various functional groups onto organic molecules are still quite limited in their applicability. Our new approaches to functionalizing organic compounds by means of development of the chemistry of dianion-type zinc ate complexes are described. Reactivity and selectivity of tetra-coordinated dianion-type zincates have been ignored for a long time. Halogen-zinc exchange reaction on aromatic rings and silylzincation of terminal alkynes (and alkenes) using dianion-type zincates followed by electrophilic trapping proved a powerful tool for C-C bond formations. The functionalized aromatic or aliphatic zincate intermediate was also found to undergo copper- and palladium-catalyzed C-C bond-forming reactions with good yields and high chemoselectivity. On the other hand, a sharp difference in regioselectivity in the epoxide-opening reaction between monoanion-type and dianion-type zincates was disclosed. These results clearly suggest that these dianion-type zincates should be distinguished from ordinary tri-coordinated monoanion-type zincates in terms of structure, reactivity, and selectivity, and hence they would open a new window in synthetic organic chemistry.
A new class of artificial catechin polymers has been developed by an acid-catalyzed regioselective polymerization of catechin and aldehydes. The polymers showed much higher antioxidant activities than intact catechin. In addition, they efficiently inhibited disease-related enzymes such as xanthine oxidase, tyrosinase, collagenase, and elastase.
We have developed a number of direct, regioselective arylation reactions of appropriately functionalized aromatic compounds via C-H bond cleavage. Thus, treatment of the substrates including phenols, aromatic ketones and amides, and benzylic alcohols with aryl halides under palladium catalysis gives the corresponding ortho-arylated products. In combination with α-arylation, which is also catalyzed by palladium multiple arylation of the substrates can proceed by a single treatment with excess aryl halides to produce oligoaryl compounds. On the other hand, we have also found that tert-benzyl alcohols undergo arylation via not only C-H but also C-C bond cleavage accompanied by liberation of ketones to afford biaryls. In this account are summarized these new coupling reactions.