Mechanism of Asymmetric Hydrogenation of Aromatic Ketones Catalyzed by a Combined System of Ru(π-CH2C(CH3)CH2)2(cod) and the Chiral sp(2)N/sp(3)NH Hybrid Linear N4 Ligand Ph-BINAN-H-Py.

The combination of a Goodwin-Lions-type chiral N4 ligand, (R)-Ph-BINAN-H-Py ((R)-3,3'-diphenyl-N(2),N(2')-bis((pyridin-2-yl)methyl)-1,1'-binaphthyl-2,2'-diamine; L), with Ru(π-CH2C(CH3)CH2)2(cod) (A) (cod = 1,5-cyclooctadiene) catalyzes the hydrogenation of acetophenone (AP) to (R)-1-phenylethanol (PE) with a high enantiomer ratio (er). Almost no Ru complex forms, with A and L remaining intact throughout the reaction while generating PE quantitatively according to [PE] = k(obs)t(2). An infinitesimal amount of reactive and unstable RuH2L (B) with C2-Λ-cis-α stereochemistry is very slowly and irreversibly generated from A by the action of H2 and L, which rapidly catalyzes the hydrogenation of AP via Noyori's donor-acceptor bifunctional mechanism. A CH-π-stabilized Si-face selective transition state, CSi, gives (R)-PE together with an intermediary Ru amide, D, which is inhibited predominantly by formation of the Ru enolate of AP. The rate-determining hydrogenolysis of D completes the cycle. The time-squared term relates both to the preliminary step before the cycle and to the cycle itself, with a highly unusual eight-order difference in the generation and turnover frequency of B. This mechanism is fully supported by a series of experiments including a detailed kinetic study, rate law analysis, simulation of t/[PE] curves with fitting to the experimental observations at the initial reaction stage, X-ray crystallographic analyses of B-related octahedral metal complexes, and Hammett plot analyses of electronically different substrates and ligands in their enantioselectivities.

Reaction of frustrated Lewis pairs with ketones and esters.

The frustrated Lewis pair (FLP) Mes(2)PCH(2)CH(2)B(C(6)F(5))(2) (1) reacts with an enolizable conjugated ynone by 1,4-addition involving enolate tautomerization to give an eight-membered zwitterionic heterocycle. The conjugated endione PhCO-CH=CH-COPh reacts with the intermolecular FLP tBu(3)P/B(C(6)F(5))(3) by a simple 1,4-addition to an enone subunit. The same substrate undergoes a more complex reaction with the FLP 1 that involves internal acetal formation to give a heterobicyclic zwitterionic product. FLP 1 reacts with dimethyl maleate by selective overall addition to the C=C double bond to give a six-membered heterocycle. It adds analogously to the triple bond of an acetylenic ester to give a similarly structured six-membered heterocycle. The intermolecular FLP P(o-tolyl)(3)/B(C(6)F(5))(3) reacts analogously with acetylenic ester by trans-addition to the carbon-carbon triple bond. An excess of the intermolecular FLP tBu(3)P/B(C(6)F(5))(3), which contains a more nucleophilic phosphane, reacts differently with acetylenic ester examples, namely by O-C(alkyl) bond cleavage to give the {R-CO(2)[B(C(6)F(5))(3)](2)(-)}[alkyl-PtBu(3)(+)] salts. Simple aryl or alkyl esters react analogously by using the borane-stabilized carboxylates as good leaving groups. All essential products were characterized by X-ray diffraction.

Mechanistic insight into NOYORI asymmetric hydrogenations.

The BINAP-Ru-catalyzed asymmetric hydrogenations have contributed fundamentally to "molecular catalyst chemistry", as well as the "chemical industry", in terms of the production of important chiral compounds such as pharmaceuticals, agrochemicals, flavors, fragrances, and health supplements since 1986 when the great breakthrough was made through an efficient asymmetric synthesis of tetrahydroisoquinolines. This highlight overviews mechanistic models proposed in the Noyori hydrogenation of olefins and ketones.

Synthesis of 3,3'-diaryl-substituted 2,2'-diamino-1,1'-binaphthyl and its derivatives.

Substitution at the 3 and/or 3' position of a binaphthyl skeleton sometimes enhances stereoselectivity during asymmetric reactions. High-yield and stepwise introduction of aryl groups into the 2,2'-diamino derivative has been established for the first time via an ortho-lithiation/iodization/Suzuki-Miyaura coupling protocol. The results described herein will facilitate the synthesis of a variety of 3,3'-substituted 2,2'-diamino-1,1'-binaphthyl compounds, which are key intermediates for obtaining valuable related ligands and organocatalysts.

Primary hepatic carcinoid tumor (a case report).

A primary hepatic carcinoid tumor arising in a 77-year-old woman is reported. The patient was admitted with a huge tumor in the right lobe of the liver and treated by an extended right lobectomy of the liver. Light microscopic findings showed that the tumor cells had small oval-shaped nuclei and eosinophilic cytoplasm with small granules forming trabecular, glandular, and rosette patterns. Immunohistochemically, tumor cells were stained positive with neuron-specific enolase and synaptophysin and were stained slightly positive with chromogranin and carcinoembryonic antigen. Careful examination before and after the operation revealed no other origin of the tumor. Based on the findings, the liver tumor was diagnosed as a primary carcinoid. The clinical features and diagnosis of this rare tumor are discussed in this report.

Job strain and risk of cardiovascular events in treated hypertensive Japanese workers: hypertension follow-up group study.

In Japan, Karoshi, which means "death from overwork", has become a focus of social concern. However, no previous study has examined long working hours and job strain simultaneously in relation to incidence of cardiovascular events (CVE) in Japanese workers. We prospectively evaluated the relation between job strain or long working hours and risk of CVE in treated hypertensives during the years 1994-2000. In this study, we followed a sample of 1,615 participants (908 men and 707 women) aged 40-65 yr who were working more than 5 working hours per day. Participants completed questions about work-related conditions and lifestyle variables at baseline, and were free of diagnosed cardiovascular disease, stroke or cancer. Job strain (the combination of job demands and job control) was assessed using a simple questionnaire developed with reference to Karasek's model. The main outcome measure was incidence of CVE. During the mean follow-up period of 5.6 yr, we documented 38 cases of initial CVE. Analyses were conducted using the Cox proportional hazard model. We found a significant association between incidence of CVE and job strain categories, but not long working hours. Multivariate relative risks for CVE in active jobs and high strain jobs overall were 2.89 (95% CI: 1.33-6.28) and 2.45 (95% CI: 0.87-6.93); for men 2.94 (95% CI: 1.29-6.73) and 1.86 (95% CI: 0.51-6.75), and for women 3.97 (95% CI: 0.34-46.88) and 9.05 (95% CI: 1.17-69.86), respectively. In conclusion, active jobs and high strain jobs were associated with increased risk of CVE for treated hypertensive workers.