Synthesis of a TNF inhibitor, flurbiprofen and an i-Pr analogue in enantioenriched forms by copper-catalyzed propargylic substitution with Grignard reagents.

The copper-catalyzed substitution reaction of diethyl phosphate derived from TMSCCCH(OH)CH2CH2OTBDPS with 3-c-C5H9-4-MeOC6H3MgBr, followed by several transformations, afforded a tumor necrosis factor inhibitor possessing a Ph-acetylene moiety. The inhibitor was also synthesized from phenylacetylene phosphate PhCCCH(OP(O)(OEt)2)CH2CH2OTBDPS. Furthermore, the substitution of phosphates derived from TMSCCCH(OH)CH3 and TMSCCCH(OH)-i-Pr with 3-F-4-PhC6H3MgBr gave the corresponding substitution products, which were transformed to flurbiprofen and its i-Pr analogue, respectively. The copper-catalyzed substitutions in these syntheses proceeded in a regio- and stereoselective manner.

Transcatheter aortic valve implantation in rheumatic aortic stenosis with a functioning mitral prosthesis.

Transcatheter aortic valve implantation (TAVI) for patients with rheumatic aortic stenosis (AS) is not well-known. We herein report a case of TAVI in rheumatic AS without significant calcification and prior mitral valve replacement. An 80-year-old woman underwent TAVI for severe AS. Preoperative computed tomography revealed tricuspid aortic valve leaflets with commissural fusion, minimal calcification, and a minimal distance between the aortic annulus and mechanical mitral valve. TAVI was performed through a transfemoral approach under general anesthesia. After predilatation of the aortic valve with a 20-mm balloon, a 23-mm SAPIEN 3 valve was successfully deployed via slow inflation. Valve embolization did not occur, and the valve did not interfere with the prosthetic mitral leaflets. This report shows that TAVI can be safe, feasible, and effective in patients with rheumatic AS without significant calcification and prior mitral valve replacement. .

α- and γ-Regiocontrol and Enantiospecificity in the Copper-Catalyzed Substitution Reaction of Propargylic Phosphates with Grignard Reagents.

The regioselectivity (r.s.) and enantiospecificity (e.s.) of the substitution reactions of secondary propargylic alcohol derivatives using reagents derived from ArMgBr and Cu salts were studied. First, the picolinate, 3-methylpicolinate, and diethylphosphonate derivatives of Ph(CH2 )2 CH(OH)C≡CTMS were reacted with PhMgBr/CuCN in ratios of 2.5:2.7-2.5:0.25. The use of 2.5:0.25 ratio in THF/DME (6:1) at 0 °C for 1 h afforded the α-substitution product from the phosphate with ≥98 % r.s. and 99 % e.s. CuBr⋅Me2 S gave similar selectivity. The reaction system was then applied to phosphates derived from R1 CH(OH)C≡CR2 and ArMgBr to obtain synthetically sufficient r.s. and e.s. values with R2 =TMS, Ph, whereas iPr was borderline in terms of size as an R1 substituent. The presence of a substituent at the o-position of Ar marginally affected the selectivity. We also found that the use of PhMgBr/Cu(acac)2 in a 2:1 ratio in THF produced the γ-substitution products (allenes) with high r.s. and e.s.

Naphthoquinone Derivatives from Diospyros maritima.

From the chloroform extract of the fresh fruits of Diospyros maritima BLUME (Ebenaceae), five new naphthoquinone derivatives, 2,7'-dimethyl-2',3-bijuglone (27), 2,7'-dimethyl-3,3'-bijuglone (28), 2,7'-dimethyl-6,8'-bijuglone (29), 7,7'-dimethyl-3,3'-ethylidenebijuglone (30), and 2',7-dimethyl-3,6'-ethylidenebijuglone (31), were isolated, in addition to twenty-one known naphthoquinone derivatives: plumbagin (4), droserone (5), 2,3-epoxyplumbagin (8), 3,3'-biplumbagin (9), chitranone (10), 3,8'-biplumbagin (11), elliptinone (12), maritinone (13), isozeylanone (14), methylene-3,3'-biplumbagin (15), ethylidene-3,3'-biplumbagin (16), ethylidene-3,6'-biplumbagin (17), ethylidene-6,6'-biplumbagin (18), 7-methyl-ß-dihydrojuglone (19), 7-methyljuglone (20), 2,3-epoxy-7-methyljuglone (21), neodiospyrin (22), mamegakinone (23), ehretione (24), isoxylospyrin (25) and ß-dihydroplumbagin (26). The structures of the new compounds were established by spectral analysis. The quinones obtained from the chloroform extract of the fruits were compared with previously reported quinones obtained from ethanol extracts. The quinones in the fruits were categorized in three groups: quinones from ethanol extract only, quinones from chloroform extract only, and quinones from both extracts. The six naphthoquinones, 19-21, 25, 26, and 29, were examined for their ichthyotoxic activity and germination inhibitory activity. Quinones 19-21, 26, and 29 showed ichthyotoxic activity against Japanese killifish (Oryzias latipes var.) at 10 ppm; quinones 19 to 21 and 26 showed germination inhibitory activity toward lettuce seeds (Lactuca sativa L. var. Great Lakes) at 100 ppm.

Synthesis of (S)-imperanene by using allylic substitution.

Synthesis of (S)-imperanene (1) was studied by using copper-assisted allylic substitution of ArCH=CHCH(L)CH(2)Ar (L: leaving group) and (i-PrO)Me(2)SiCH(2)MgCl. Preliminary substitution between PhCH=CHCH(L)Me (L = AcO, PivO, MeOCO(2), (2-Py)CO(2)) and Bu copper reagents derived from BuMgX (X = Br, Cl) and CuBr.Me(2)S or CuCl in 1:1-40:1 ratios suggested acetate 28 as the best substrate. To prepare 28, kinetic resolution of racemic (E)-TMSCH=CHCH(OH)CH(2)Ar(2) (Ar(2) = (p-TBSO)(m-MeO)C(6)H(3)) carried out by using the asymmetric epoxidation with (-)-DIPT afforded the corresponding epoxy alcohol and (S)-allylic alcohol. After separation by chromatography, these products were converted to (S,E)-Bu(3)SnCH=CHCH(OH)CH(2)Ar(2), which upon palladium-catalyzed coupling with Ar(2)-I followed by acetylation gave 28 (95-98% ee). Substitution of 28 with (i-PrO)Me(2)SiCH(2)MgCl and CuBr.Me(2)S in a 4:1 ratio at 0 degrees C proceeded cleanly to produce 29 with 100% inversion in 92% yield. Finally, Tamao oxidation furnished 1.

Chemiluminescence in molecular recognition: base-induced decomposition of optically active dioxetanes bearing a bisnaphthol moiety with a complex of optically active crown ether-potassium tert-butoxide.

Four optically pure isomers of dioxetane (1) were decomposed by the action of the complex of an optically active crown ether with potassium tert-butoxide to afford light with lambda(max)CL and gave four different spectrum shapes.

FGFR3 isoforms have distinct functions in the regulation of growth and cell morphology.

We have previously cloned the alternatively spliced isoform of fibroblast growth factor receptor 3 (FGFR3DeltaAB) that lacks the acid box in the extracellular region. To understand the biological functions and signal transduction of these FGFR3 isoforms, we analyzed the effect of FGF1 in ATDC5 cells, chondroprogenitor cell lines overexpressing these isoforms. In response to FGF1, FGFR3 induced a marked cell-morphology change to a round shape, while FGFR3DeltaAB did not. Furthermore, FGFR3 induced complete growth arrest, whereas FGFR3DeltaAB induced only moderate growth inhibition. Both receptors induced the expression of the CDK inhibitor p21(CIP1). However, only FGFR3 induced STAT1 phosphorylation that mediates the transcriptional induction of p21(CIP1), although both FGFR3 isoforms could induce a strong activation of mitogen-activated protein (MAP) kinases. Taken together, the different biological responses mediated by FGFR3 and FGFR3DeltaAB appear to be due to a difference in their ability to utilize STAT1 pathway and signals involved in cell rounding.