A family of the novel chiral helical C-3-symmetric monophosphite ligands has been synthesized from axially chiral (R)- or (S)-H-8-BINOL and PCl3. The performance of these ligands in asymmetric catalysis was evaluated by the Rh-catalyzed asymmetric hydroformylation of styrene, and the Cu-catalyzed asymmetric 1,4-conjugate addition of diethylzinc to acyclic enones. The catalytic hydroformylation of styrene gave rather high conversion (93%), high regioselectivity (b/n=95/5) and low enantioselectivity [28% ee (R)] using ligand (R)-2 in tetrahydrofuran at room temperature. Under the optimal 1,4-conjugate addition of ZnEt2 to chalcone 3a conditions, eleven acyclic enones 4a similar to 4k were all converted smoothly to the 1,4-adducts with high enantiomeric excess. Using Cu(OTf)(2) as catalyst precursor and Et2O as solvent at -20 degrees C, the structure of ligand (R)-3 comprising a partially hydrogenated 2,2'-(1,1'-binaphthyl)-phosphite scaffold and an adamantyl moiety was key factor in improving catalytic activity and the enantioselectivity with up to 98% yield and 72% ee (R). The sense of enantiodiscrimination of the reaction was controlled by the configuration of the diaryl phosphite moieties.

Five novel tropos (3R,4R)- and/or (3S,4S)-N-benzyltartarimide-derived biphenylphosphite ligands were synthesized and applied in the Cu-catalyzed asymmetric conjugate addition of diethylzinc to cyclic enones with up to 75% e.e. Compared with the reported ligand 1-N-benzylpyrrolidine-3,4-bis[(R)-1,1’-binaphthyl-2,2’-diyl]phosphite-L-tartaric acid, the issue that L-(+)-tartaric acid backbone and (R)-binaphthyl showed strong matched/mismatched character was solved with these tropos ligands. It was found that the enantioselectivity was mainly controlled by the absolute configuration of N-benzyltartarimide backbone, and both enantiomers of the addition products can be obtained by simply changing the configuration of N-benzyltartarimide substituent.

A novel Pd/1,2-diphosphite catalyzed asymmetric allylic alkylation of 1,3-diarylpropenyl acetate with malonates was developed. Catalyst optimization via a variation in the protecting groups at the 1,2- and/or 5,6-positions of d-mannitol skeleton and in biaryl moieties of the ligands led to a ‘lead’ catalyst, which efficiently mediated the allylic alkylations. The activities and enantioselectivities of the reaction clearly showed that the stereogenic centers of the skeleton and the axially chiral diaryl moieties of the ligands had a synergic effect. The ligand 1,2:5,6-di-O-isopropylidene-3,4-bis[(S)-1,1′-binaphthyl-2,2′-diyl]phosphite-d-mannitol afforded excellent yields (up to 99%) and high levels of enantioselectivies (ee up to 98%) in 1,4-dioxane/CH2Cl2 mixture (v/v, 1:1) using [Pd(π-allyl)Cl]2 as catalytic precursor and LiOAc as base. Dramatic changes in the sense and in the degree of the enantioselectivity depending on the configuration of the diaryl moieties of the ligands and reaction conditions were observed.

Objective To investigate the expression variation of peroxisome proliferator-activated receptor γ (PPAR-γ) in pulmonary vasculature in rats exposed to cigarette smoke and its role in pulmonary vascular remodeling.Methods 30 male SD rats were randomly divided into a control group,a smoke exposure for 6 weeks group,a smoke exposure for 12 weeks group,with 10 rats in each group.The ratio of pulmonary vascular wall thickness/vascular external diameter (WT％)and the ratio of pulmonary vascular wall area/total pulmonary vascular area (WA％)were measured by the image analysis system.The expression of PPAR-γ protein in pulmonary vascular of each group was detected by Immunohistochemistry.Results ①WT％ and WA％ increased significantly in the smoke exposure for 6 weeks group [(45.61 ± 2.43)％,(59.69±12.59)％] and smoke exposure for 12 weeks group [(54.23 ±6.22) ％,(76.26±8.36)％] compared to those of control group [(32.89±7.65)％,(33.05±14.84)％] (all P＜0.05). The WT％ and WA％ in the smoke exposure for 12 weeks group increased significantly compared to those of smoke exposure for 6 weeks group (all P ＜0.05).②The expression of PPAR-γ protein in pulmonary vascular decreased significantly in the smoke exposure for 6 weeks group (0.48±0.08)and the smoke exposure for 12 weeks group (0.37±0.07) compared to control group (0.51±0.07)(all P＜0.05).The expression of PPAR-γ protein decreased in the smoke exposure for 12 weeks group compared to the smoke exposure for 6 weeks group (P＜0.05).③The expression of PPAR-γ protein in pulmonary vascular was respectively negatively correlated with WT％ and WA％ ( r =-0.715 and -0.683)(all P＜ 0.05).Conclusions By down-regulating the expression of PPAR-γ protein in pulmonary vascular,cigarette smoke exposure induces the remodeling of pulmonary vascular.

Objective To explore the effects of cigarette smoke exposure on pulmonary artery pressure and levels of endothelium nitric oxide synthase (eNOS) and nitric oxide (NO) of pulmonary vascular in rats.Methods Twenty-one male SD rats were divided randomly into control group (C group),smoke exposure one month group (S1m group) and smoke exposure three months group (S3m group),seven rats in each group.Mean right ventricular systolic pressure (mRVSP) and right ventricular hypertrophy index (RVHI) were observed.Nitrate reductase enzymatic was employed to detect the expression of NO in lung tissue.The expression of eNOS protein in pulmonary vascular was measured by immunohistochemistry.Results ① The mRVSP and RVHI in S3m group [(65.63 ± 0.93) mmHg,( 54.79 ± 7.13) ％]were significantly higher than those in S1 m group [ ( 23.57 ± 14.51 ) mm Hg,(36.62 ±1.32)％]and C group [(16.85±1.26) mmHg,(32.41±0.26)％](all P＜0.01).There were no statistical difference in mRVSP and RVHI between C group and S1m group ( P ＞0.05).②The eNOS protein expression of pulmonary vascular in SIm group and S3m group (0.32 ±0.04,0.24 ±0.03) were lower than that in group C (0.43 ± 0.06) (all P ＜0.01),and that in S3m group was lower than that in S1m group ( P ＜0.01).③The NO expression of lung tissue in S1m group and S3m group[ (1.98±0.20) μmol/gprot,(0.95± 0.09) μmol/gprot]was lower than that in group C [(2.98±0.19) μmol/gprot](all P ＜ 0.01 ),and that in S3m group was less than that in S1m group ( P ＜ 0.01 ).④ mRVSP was positively correlated with RVHI (r =0.713,P ＜0.01).NO in lung tissue was negatively correlated with mRVSP ( r=-0.615,P＜0.05).eNOS in pulmonary vascular was positively associated with NO in lung tissue ( r =0.944,P ＜ 0.01).Conclusions By down-regulating the expression of eNOS protein in endothelial cell of pulmonary vascular,cigarette smoke exposure induces the biosynthesis of NO,which induces the increase of pulmonary artery pressure,and the effect is time dependence in certain scope.

Pulmonary artery hypertension (PAH) is a severe disease characterized with progressive increase of pulmonary vascular resistance that finally causes right ventricular failure and premature death. Cigarette smoke (CS) is a major factor of Chronic Obstructive Pulmonary Disease (COPD) that can lead to PAH. However, the mechanism of CS-induced PAH is poorly understood. Mounting evidence supports that pulmonary vascular remodeling play an important role in the development of PAH. PDGF signaling has been demonstrated to be a major mediator of vascular remodeling implicated in PAH. However, the association of PDGF signaling with CS-induced PAH has not been documented. In this study, we investigated CS-induced PAH in rats and the expression of platelet derived growth factor (PDGF) and PDGF receptor (PDGFR) in pulmonary artery. Forty male rats were randomly divided into control group and three experimental groups that were exposed to CS for 1, 2, and 3 months, respectively. CS significantly increased right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index (RVHI). Histology staining demonstrated that CS significantly increased the thickness of pulmonary artery wall and collagen deposition. The expression of PDGF isoform B (PDGF-B) and PDGF receptor beta (PDGFRβ) were significantly increased at both protein and mRNA levels in pulmonary artery of rats with CS exposure. Furthermore, Cigarette smoke extract (CSE) significantly increased rat pulmonary artery smooth muscle cell (PASMC) proliferation, which was inhibited by PDGFR inhibitor Imatinib. Thus, our data suggest PDGF signaling is implicated in CS-induced PAH.

Accumulating evidence suggests a direct role for cigarette smoke in pulmonary vascular remodeling, which contributes to the development of pulmonary hypertension. However, the molecular mechanisms underlying this process remain poorly understood. Platelet-derived growth factor (PDGF) is a potential mitogen and chemoattractant implicated in several biological processes, including cell survival, proliferation, and migration. In this study, we investigated the effect of cigarette smoke extract (CSE) on cell proliferation of rat pulmonary artery smooth muscle cells (rPASMCs). We found that stimulation of rPASMCs with CSE significantly increased cell proliferation and promoted cell cycle progression from G1 phase to the S and G2 phases. CSE treatment also significantly upregulated the mRNA and protein levels of PDGFB and PDGFR β . Our study also revealed that Rottlerin, an inhibitor of PKC δ signaling, prevented CSE-induced cell proliferation, attenuated the increase of S and G2 phase populations induced by CSE treatment, and downregulated PDGFB and PDGFR β mRNA and protein levels in rPASMCs exposed to CSE. Collectively, our data demonstrated that CSE-induced cell proliferation of rPASMCs involved upregulation of the PKC δ -PDGFB pathway.

Pulmonary hypertension (PH)is a common complication of chronic obstructive pulmonary disease(COPD).In COPD,PH tends to be of moderate severity and progresses slowly. Its presence is associated with shorter survival and worse clinical evolution.The combined effects appear to contribute to the development of PH associated with COPD.Toxic effects of cigarette smoke components or inflammation products may damage endothelial cells and produce endothelial dysfunction.Hypoxia may induce vasoconstriction.Pulmonary vascular remodeling leads to reduction of arterial lumen and distensibility of the pulmonary vessels,which increase pulmonary vascular resistance.Severe emphysema leads to reduction in the total number of pulmonary vessels.All these contribute to the development of PH in COPD.

A new series of chiral phosphite ligands derived from readily available l-(+)-tartaric acid and binaphthol derivatives were designed and prepared in convenient synthetic routes. These ligands were successfully employed in the Cu-catalyzed asymmetric conjugate addition of organozincs to cyclic enones. The ligands bearing (R)- and (S)-binaphthol and/or 3,3′-bis(trimethylsilyl)-2,2′-dihydroxy-1,1′-binaphthol afforded both enantiomers of the product in high yields and good enantioselectivities (up to 95% ee). The chiral organocopper reagent did exhibit high enantioselectivities for cyclic enones bearing different ring sizes. The stereochemically matched combination of l-(+)-tartaric acid backbone and (R)-binaphthyl in ligand 1-N-benzylpyrrolidine-3,4-bis[(R)-1,1′-binaphthyl-2,2′-diyl]phosphite-l-tartaric acid was essential to afford 95% (R) ee for 3-ethylcyclopentanone, 95% ee (S) for 3-ethyl-cyclohexanone, and 63% ee (R) for 3-ethylcycloheptanone in ether as solvent, using (CuOTf)2·C6H6 as a catalytic precursor. Moreover, the sense of the enantio discrimination of the products was mainly determined by the configuration of the binaphthyl phosphite moieties.

A series of new bulky monophosphite ligands were synthesized from axially chiral BINOL/H-8-BINOL (BINOL: 1-(2-hydroxynaphthalen-1-yl)naphthalen-2-ol) and highly sterically hindered adamantylcarbonyl chloride. The effectiveness of these ligands was evaluated by the Cu-catalyzed asymmetric 1,4-conjugate addition of diethylzinc to cyclic enones with enantioselectivities of up to 79% ee. The results showed that a ligand structure comprising a partially hydrogenated 2,2'-(1,1'-binaphthyl)phosphite scaffold and an adamantyl moiety was effective in improving the enantioselectivity.

The in situ prepared chiral catalyst of Pd/unchelating bidentate phosphine ligand L1(DPPFF),bipyridine bidentate phosphine ligand L2(P-PHOS),and bidentate phosphine ligand L3((S,Rp)-BPPF),and Rh/phosphite ligands L4-L6,have been applied in amidocarbonylation of cyclohexanecarboxaldehyde or phenylacetaldehyde.Pd/bipyridine bidentate phosphine ligand L2 gave the enantioselectivity 25%(S) and the yield 11% in amidocarbonylation of phenylacetaldehyde,When Pd/unchelating bidentate phosphine ligand L1 was employed in asymmetric amidocarbonylation of cyclohexanecarboxaldehyde,the enantioselectivity 4.3%(S) and the yield 15% were received.

Novel chiral diphosphite ligands derived from glucopyranoside and H8-binaphthol were synthesized, and successfully employed in the Cu-catalyzed asymmetric 1,4-addition of organozinc reagents dimethylzinc, diethylzinc, and diphenylzinc to cyclic and acyclic enones with up to 96% ee. The stereochemically matched combination of d-glucopyranoside backbone and (R)-H8-binaphthyl in the ligand 2,4-bis{[(R)-1,1′-H8-binaphthyl-2,2′-diyl] phosphite}-phenyl 3,6-anhydro-β-d-glucopyranoside was essential for inducing high enantioselectivity. A significant dependence of stereoselectivity on the type of enones and the ring size of cyclic enones was observed. Moreover, the sense of the enantiodiscrimination of the products was mainly determined by the configuration of the H8-binaphthyl moieties.

<正>获得对映异构体纯的手性化合物在药物、农用化学品、香料等领域愈来愈引起了科学界和工业界的广泛关注.不对称催化反应作为获得光学纯化合物的一种有效手段,由于其手性增殖的突出优势而特别引人注目.不对称催化一般通过含有手性配体

A series of novel chiral diphosphite ligands have been synthesized from d-mannitol derivatives and chlorophosphoric acid diary ester, and were successfully employed in the copper catalyzed enantioselective conjugate addition of organozinc reagents diethylzinc and dimethylzinc to cyclic and acyclic enones. The stereochemically matched combination of d-mannitol and (R)-H8-binaphthyl in ligand 1,2:5,6-di-O-isopropylidene-3,4-bis[(R)-1,1′-H8-binaphthyl-2,2′-diyl] phosphite-d-mannitol was essential to afford 93% ee for 3-ethylcyclohexanone, 92% ee for 3-ethylcyclopentanone, and 90% ee for 3-ethylcycloheptanone in toluene, using Cu(OTf)2 as a catalytic precursor. The results clearly indicated that the chiral organocopper reagent exhibited high enantioselectivies for cyclic enones bearing different ring sizes. As for the backbone of this type of ligand, it has been demonstrated that 1,2:5,6-di-O-isopropylidene-d-mannitol was more efficient than 1,2:5,6-di-O-cyclohexylidene-d-mannitol. The sense of the enantiodiscrimination was mainly determined by the configuration of the diaryl phosphite moieties in the 1,4-addition of cyclic enones.