Recent progress in our bifunctional molecular catalysts for the reductive transformation of functional groups with electronically localized C-O bond (polar functionalities) using molecular hydrogen(H2) is described. The newly developed Cp*Ru(PN) complexes have proven to be efficient catalysts for the hydrogenation of a range of polar functionalities. The structural modification of the protic amine ligand improves the catalytic performance and allows efficient access to various chiral compounds of synthetic value.
This article reviews our recent studies on cyclopolymerization of 1, 6-heptadiene derivatives catalyzed by late transition metal complexes. Pd-diimine complexes initiate cyclopolymerization of the 1, 6-heptadienes with functional groups to afford the polymers containing functionalized trans-l, 2-disubstituted cyclopentane rings along the polymer chain. Copolymerization of the dienes with ethylene and α-olefins also causes quantitative cyclization of the diene during the polymer growth. 1, 6-Octadiene and higher mono-terminal dienes undergo the cyclopolymerization accompanied by chain walking of the growing polymer, leading to the polymers with trans-l, 2-disubstituted cyclopentane groups located regularly along the linear polymer chain. The Fe and Co complexes with a bis(imino)pyridine ligand promote the polymerization of unsubstituted 1, 6-heptadiene with quantitative cyclization to yield the polymers containing five-membered rings. The Fe complex-catalyzed reaction affords the polymers composed of cis-fused five-membered rings, whereas the polymer obtained by using Co catalyst contains trans-fused rings selectively.
Asymmetric hydrogenation of α-amino-β-keto esters using ruthenium (Ru), rhodium (Rh), and iridium (Ir)-chiral phosphine catalysts proceeds anti-selectively through dynamic kinetic resolution to afford anti-β-hydroxy-α-amino acids with high enantiomeric purity, which are important intermediates for the synthesis of medicines and natural products. The mechanistic investigation has revealed that the Ru-catalyzed asymmetric hydrogenation takes place through the hydrogenation of the double bond in the enol tautomer of the substrate and the Rh- and Ir-catalyzed asymmetric hydrogenations proceed through the reduction of the keto tautomer of the substrate.
New strategies for lactams synthesis from cycloalkanes without formation of sulfates have been proposed. The synthesis of lactams from cycloalkanes through a one-pot reaction was successfully performed using N-hydroxyphthalimide (NHPI) as a key catalyst. The strategy involves nitrososation of cycloalkanes with tert-butyl nitrite under the influence of NHPI followed by isomerization to oximes and then the Beckmann rearrangement to lactams. For example, ε-caprolactam and laurolactam were prepared from cyclohexane and cyclododecane in 74% and 78% yields, respectively, in one-pot. An alternative approach for sulfate-free lactam synthesis includes the nitration of cyclohexane with NO2 to nitrocyclohexane in the presence of NHPI under mild conditions followed by the hydrogenation to cyclohexanone oxime. The Beckmann rearrangement to .ε-caprolactam was found to be achieved in quantitative yields by a very small amount of cyanuric chloride in a mixed solvent of trifluoroacetic acid and toluene.
Novel synthetic uses of oxoammonium ions enabling facile and efficient oxidation of several classes of alcohols to their related carbonyl compounds have been exploited on the basis of two strategies: (i) modifying the molecular framework of the oxoammonium ion, and (ii) enhancing its reactive nature by altering the counter ion. The reaction systems developed allow: (1) efficient oxidation of sterically crowded secondary alcohols to ketones; (2) facile, one-pot oxidation of primary alcohols to carboxylic acids; (3) oxidative rearrangement of tertiary allylic alcohols to β-substituted α, β-unsaturated carbonyl compounds under transition-metal-free conditions.
A number of environmentally benign oxidation reactions with aqueous hydrogen peroxide were carried out, including chemoselective oxidation of allylic alcohols to corresponding α, β-unsaturated carbonyl compounds by using platinum black catalyst, 1, 2-dihydroxylation of olefins in the presence of catalytic amount of resin-supported sulfonic acid, and the oxidation of cycloalkanone with tungstic acid catalyst. These reactions were carried out under organic solvent- and halide-free conditions, and they successfully gave the desired products in high yield. Platinum black and resin-supported sulfonic acid catalysts could be easily recovered and reused several times without significant loss of activity. Immobilization of quaternary ammonium and phosphonium salts, and crown etherr on the magnetic nanoparticles (MNP), and their catalytic activities in the phase-transfer reaction were also investigated. The MNP-supported catalysts showed activity comparable to those of non-supported ones. Further, they could be easily recovered by using an external magnet, and reused several times without loss of activity.
The blockade of αIIbβ3 binding to fibrinogen is known to provide a potent antiplatelet activity. We have focused on the adhesion and migration of integrin αβ3in vascular smooth muscle cells and leucocytes. An injectable αβ3 dual antagonist would be a novel drug candidate for acute ischemic diseases. For the molecular design of novel non-peptide integrin ββ3 antagonists, we focused on spatial screening and mimetics of the RGD tripeptide, which was a key recognition site. The first piperazine analogue (4) exhibited strong αIIbβ3 activity, and replacement of piperazine by 4-aminopiperidine afforded the 6alpha;β3/βIIbβ3 dual antagonist (30). Paying attention to enhancement of activity and improvement of solubility, optimization of 30 gave some preliminary candidates modified at the central aromatic or the C-terminus. Backup compounds possessing the (3S)-aminopiperidine moiety with further improvement of solubility were synthesized. These preliminary candidates exhibited preferable ADME in rats, and some of them showed acceptable water solubility, which did not provide detectable toxicity in vitro or in mice. We also generated αβ3 selective antagonists with tricyclic pharmacophore, in order to prove that in vivo efficacy of the dual antagonist was superior to that of the avf33 selective antagonist. Finally, excellent in vivo efficacy of the candidate (81) was demonstrated in both canine ACS and PTCA models by independent groups. Regarding development of 81, a partnership was established in 2006, and a clinical trial of 81 is now being prepared in the US and Canada. The selection of an integrin research program, strategies for competing with big pharmaceutical companies, and speedy medicinal chemistry are also described.
Construction of aryl and heteroaryl N-glycoside structures by way of the palladium-catalyzed Buchwald-Hartwig N-arylation of pyranosylamines with aryl and heteroaryl halide derivatives is described .This methodology was successfully applied to the total synthesis of nucleoside antibiotics, spicamycin and dapiramicin B, possessing novel heteroaryl N-glycosides. Kinetic and thermodynamic analyses of heteroaryl N-glycosides are also reported.
This article describes the enantioselective total synthesis of (+)-allocyathin B2 and (-)-erinacine B via the convergent approach using new chiral building blocks prepared by the asymmetric catalysis developed in our research, and also describes the biomimetic total synthesis of (-)-erinacine E. The convergent approach developed in these studies would enable the divergent synthesis of optically pure cyathane diterpenoids and their derivatives for SAR.
The small ligands that bind to the mismatched base pairs were found to stabilize the hairpin secondary structures of the repeat sequences found in the human genome. The trinucleotide repeats are the causatives of many neurological disorders.A whereas the telomere repeats are the sequence located in the 3' end of the human chromosome and stabilize the genome. The ligands described here induced the hairpin secondary structure upon binding to these repeat sequences.