Tetsuaki Tanaka

Rapid improvement of AA amyloidosis with humanised anti-interleukin 6 receptor antibody treatment

AA amyloidosis is a serious complication of chronic inflammatory and infectious diseases.1 Amyloid fibril deposition causes progressive deterioration in various organs. In October 2007, a 50-year-old woman was admitted to our hospital with severe diarrhoea and weight loss. She had had rheumatoid arthritis (RA) for 12 years. Despite vigorous treatment with prednisolone and disease-modifying anti-rheumatic drugs (DMARDs), including bucillamine, sulfasalazine, auranofin, leflunomide and methotrexate or tacrolimus, her disease remained active. In January 2007, treatment was started with biological drugs. Subcutaneous injection of 25 mg of etanercept twice weekly for 2 months and, subsequently, intravenous injection of 3 mg/kg infliximab for 5 months combined with 20 mg of prednisolone …

Quantification of hardness, elasticity and viscosity of the skin of patients with systemic sclerosis using a novel sensing device (Vesmeter): a proposal for a new outcome measurement procedure

OBJECTIVES No objective method to measure skin involvement in SSc has been established. We developed a novel method using a computer-linked device to simultaneously quantify physical properties of the skin such as hardness, elasticity and viscosity. METHODS Skin hardness was calculated by measuring the depth of an indenter pressed onto the skin. The Voigt model was used to calculate skin elasticity, viscosity, visco-elastic ratio and relaxation time by analysing the waveform of skin surface behaviour. The results were compared with the modified Rodnan skin score (mRSS) obtained at 17 sites on the bodies of 20 SSc patients and 20 healthy controls. A functional assessment questionnaire was administered to determine how skin hardness represents a patients disability. We also examined intra- and inter-observer variability to determine the reliability of this method. RESULTS The crude hardness obtained with this device correlated well with the standard hardness specified by the American Society for Testing and Materials (ASTM, r = 0.957). A close relationship between hardness and total mRSS was also observed (r = 0.832). Skin elasticity correlated positively, and relaxation time negatively with mRSS. Functional disability correlated more closely with skin hardness (r = 0.643) than with mRSS (r = 0.517). Intra- and inter-observer variabilities were 7.63 and 19.76%, respectively, which were lower than those reported for mRSS. CONCLUSIONS Increases in hardness and elasticity as well as shortening of relaxation time constitute objective characteristics of skin involvement in SSc. The system devised by us proved to be able to assess skin abnormalities of SSc with high reliability.

Asymmetric total synthesis of halicholactone

The asymmetric total synthesis of the marine metabolite, halicholactone 1, is described. The bisallylic triol 6 with three chiral centers at C8, C12, and C15 was constructed by [2,3]-sigmatropic rearrangement of the sulfoxide 18, which was prepared stereoselectively using the chirality of (diene)Fe(CO)3 complexes. Introduction of the trans-substituted cyclopropane subunit into 21 was successfully achieved using the modified regio- and stereoselective Simmons-Smith reaction. The use of RCM (ring-closing metathesis) methodology (4-->35) was pivotal for the formation of a nine-membered unsaturated lactone fragment of halicholactone 1. As this approach is flexible and stereoselective, other oxylipins could be synthesized by the protocol described herein.

First total synthesis of murisolinElectronic Supplementary Information (ESI) available: characterization data of synthetic murisolin (1), and 1H and 13C NMR spectra of compounds 9, 12 and 1. See http://www.rsc.org/suppdata/cc/b3/b312362f/

The first and concise total synthesis of murisolin (1) was accomplished using asymmetric alkynylation and Sonogashira coupling as the key steps. The threo/trans/threo-type THF ring moiety was constructed with excellent stereoselectivity by asymmetric alkynylation of 1,6-heptadiyne to alpha-tetrahydrofuranic aldehyde, which was also prepared via the asymmetric alkynylation.

Stereoselective Synthesis of Chiral Amino Allenes by Organocopper-Mediated anti-SN2′-Substitution Reaction of Chiral Ethynylaziridines

Abstract Chiral N-protected amino allenes have been synthesized from 3-alkyl-2-ethynylaziridines via organocopper-mediated reactions. Treatment of enantiomerically pure (2R,3S)-2,3-trans-3-alkyl-2-ethynylaziridines with RCu(CN)M (M=Li or MgX) in THF at −78°C affords exclusively the expected (S,S)-amino allenes in high yields in a regio- and stereoselective manner. On the other hand, (2S,3S)-2,3-cis-3-alkyl-2-ethynylaziridines give stereoisomeric (S,R)-amino allenes in comparable high yields.

Double CH Functionalization in Sequential Order: Direct Synthesis of Polycyclic Compounds by a Palladium-Catalyzed CH Alkenylation–Arylation Cascade

Palladium-catalyzed cascade C-H alkenylation and arylation provides convenient access to polycyclic aromatic compounds. Treatment of 3-bromoaniline derivatives bearing a bromocinnamyl group on the nitrogen atom with a catalytic amount of [Pd(OAc)(2)] and PCy(3)·HBF(4) in the presence of Cs(2)CO(3) in dioxane affords naphthalene-fused indole derivatives in good yields. This double cyclization reaction is also applicable to heterocyclic substrates, giving fused indoles containing a heteroaromatic ring such as dibenzofuran, dibenzothiophene, carbazole, indole, or benzofuran through heterocyclic C-H arylation. When using a 2,6-unsubstituted aniline derivative, the first C-H arylation preferentially proceeds at the more hindered position of the aniline ring.

Asymmetric synthesis of (diene)Fe(CO)3 complexes by a catalytic enantioselective alkylation using dialkylzincs

Abstract The reaction of meso-(2, 4-hexadien-1, 6-dial)Fe(CO)3 complex1 with several alkylzincs in the presence of 50 mol% of(S)-(+)-diphenyl(1-methylpyrrolidin-2-yl)methanol6a proceeded with high enantiotopic group- and diastereotopic face-selectivity to give(2R, 6S)-alcohol complexes2a-c as major products, except in the case with dimethylzinc (>90% de and >98% ee). On the other hand, the methylation of1 with Me2Zn proceeded with high enantioselectivity by adding 1.8 equiv. ofTi(Oi-Pr)4 in the presence of 3 mol% of(S, S)-1, 2-bis(trifluoromethylsulfonamide)cyclohexane9a (82% de, 96% ee). The enantioselective alkylation was also applied to the kinetic resolution of racemic (sorbic aldehyde)Fe(CO)3 complex10. Download : Download full-size image

First Total Synthesis of (±)-Linderol A, a Tricyclic Hexahydrodibenzofuran Constituent of Lindera umbellata Bark, with Potent Inhibitory Activity on Melanin Biosynthesis of Cultured B-16 Melanoma Cells

The first total synthesis of (+/-)-Linderol A, a hexahydrodibenzofuran constituent of Lindera umbellata bark, with potent inhibitory activity on the melanin biosynthesis of cultured B-16 melanoma cells, was achieved through 19 steps of reaction in 6.6% overall yield, in which the critical step was a tandem reaction of a 3-ethoxycarbonylcoumarin derivative with dimethylsulfoxonium methylide to yield the 2-ethoxycarbonylcyclopenta[b]benzofuran-3-ol derivative.

Novel Synthesis of Azocine, Azepine, Oxocine, and Oxepine Derivatives by Palladium-catalyzed Medium-Ring Formation from Bromoallenes (Heterocycles 30th in Anniversary Issue)

Novel and efficient synthesis of medium-sized heterocycles such as azepine, oxepine, and benzo[d]azocine derivatives is described. Treatment of bromoallenes having a nucleophilic moiety with sodium alkoxide and a palladium(0) catalyst in the presence of an alcohol leads to regioselective formation of medium-sized rings at the central position of the allenic carbon.

3-Acyl-2-(N-cyanoimino)oxazolidine derivative, a new asymmetric acylating agent for racemic secondary alkyl amines

Abstract A 3-acyl-2-(N-cyanoimino)oxazolidine derivative was found to serve as an enantioselective acylating agent for sec-alkyl amines. These reagents differentiate the enantiomers of 1-phenylethylamine derivatives up to 85% ee, and the recovered chiral auxiliary is reusable.