(一)-△~(9(12))-CapneUene类的合成中间体——光学活性5-甲基-8-羟基双环[3,3,0]2一辛酮的不对称合成研究

通过手性硝基烯胺(4)与α-甲基-δ-戊内酯烯醇锌盐发生加成消除反应解决了倍半萜Capnellene类合成中构筑不对称季碳这个难题,对映体过量(e. e. )为94％。由L-脯氨酸经14步实现了(一)-△~(9(12))-Capnellene类的合成中间体——光学活性5-甲基-8-羟基双环[3 3,0]-2-辛酮(13)的对映选择合成。     

氰醇酶制备手性氰醇的研究进展

手性是自然界的普遍特征 .手性药物的研制和开发 ,是现代制药行业发展的一种必然趋势 ,也是药物研究和开发中急待解决的重大课题 .利用酶的手性合成和制备手性药物中间体是当今国外医药研究的热点 .光学活性氰醇是一类重要的手性合成子 ,它很容易转化为β-氨基醇、α-羟基酸、α-羟基酮等许多手性物质 [1～ 4 ] ,进而合成其它多种光学活性化合物 ,因而在医药、农药等精细化工领域具有广阔的应用前景 ,特别对制备手性药物中间体最具发展潜力 ,它将为手性药物的研制和开发开辟一条新的途径 .手性氰醇的巨大应用价值推动了手性氰醇制备方法的发…     

带有酰胺侧基的中空手性高分子微球的合成及其分离性能

合成了带有手性基团的多孔高分子微球, 并将其作为高效液相色谱手性固定相用于分离制备盐酸贝那普利的一个重要中间体(R)-α-羟基苯丁酸乙酯.     

(S)-1-苯基-1,2-乙二醇的合成

手性醇作为重要中间体可广泛用于药物﹑农药及食品添加剂等的合成,国内外已有许多相关的合成报道[1,2].二元手性醇具有光、热和化学稳定性,是材料科学及药物开发的重要原料,如(S)-1-苯基-1,2-乙二醇,它不仅是液晶中不可缺少的重要原料和手性添加剂,而且已成为制备具有光学活性的医药、农药和功能材料的重要中间体[3,4].     

(R)-(＋)-5-甲基-5-{4-[2-(2-(5-氯吲唑基))乙氧基]苄基}-2,4-噁唑烷二酮的合成及其绝对构型的确定

以(S)-(－)-1-苯乙胺为拆分剂对外消旋的α-羟基酸进行拆分, 得到手性α-羟基酯4, 再与尿素合环、脱甲基保护, 得到关键的手性中间体(R)-(＋)-5-甲基-5-(4-羟基苄基)-2,4-噁唑烷二酮(6). 将化合物6与甲磺酸酯(8)缩合即得具有全新化学结构的标题化合物9 (ee值100%), 其结构经1 H NMR和HRMS确证. 根据拆分盐3的单晶X射线衍射分析结果及由α-羟基酯4与尿素合环生成噁唑烷二酮的反应机理, 确定标题化合物9的绝对构型为R.     

基于醋酸铑、磺酸和手性亚磺酰胺基脲共催化的α-重氮酯与酰胺不对称N—H插入反应研究

研究了醋酸铑[Rh2(OAc)4]、手性亚磺酰胺基脲和非手性磺酸共催化的α-重氮酯与酰胺化合物的不对称N—H插入反应.研究发现α-重氮酯在醋酸铑催化下形成金属卡宾,该金属卡宾与酰胺反应生成潜手性活泼叶立德中间体.在催化剂量的手性亚磺酰胺基脲和非手性磺酸存在下,潜手性叶立德中间体发生不对称质子化,合成了手性α-氨基酸衍生物.反应过程中,手性亚磺酰胺基脲和非手性磺酸作为"手性质子梭"催化不对称质子迁移从而实现了反应的对映选择性控制.该方法发展了非手性铑、手性亚磺酰胺基脲和非手性磺酸不对称共催化体系,为合成α-氨基酸衍生物提供了一种新途径,反应收率最高可达84%,对映选择性最高可达77%.     

(R,S)-α-羟基苯丁酸乙酯的HPLC手性分离

建立了手性柱HPLC法测定盐酸贝那普利的中间体(R)-α-羟基苯丁酸乙酯中的(S)-α-羟基苯丁酸乙酯。采用Chiralcel OD-H色谱柱,流动相正己烷-异丙醇（体积比90：10),流速1．0mL／min,检测波长254nm,进样体积20μL,按外标法以峰面积计算(R)-α-羟基苯丁酸乙酯中的(S)-α-羟基苯丁酸乙酯的含量。(S)体的线性范围5．5～23．8μg／mL,检出限0．47μg／mL(S／N=3),回收率为96％～103％,精密度RSD为2．1％(n=6)。     

光学活性α-羟基膦酸(酯)合成研究进展

α-羟基膦酸及其酯具有广泛的生物活性,详细介绍了使用手性辅助基团诱导和手性催化剂催化等方法合成光学活性α-羟基膦酸(酯)的研究进展.     

3-羟基哌啶氮α-碳负离子的形成及α-羟烷化反应

合成了（S）-3-羟基哌啶苯硫醚化合物6作为3-羟基哌啶氮α-碳负离子手性合成子（B）的合成等效体.化合物6经羟基去质子现场保护、萘锂（LN）还原锂化形成手性哌啶醇双负离子中间体B.双负离子B可被质子淬灭得到还原产物2a 而与羰基化合物反应则得到α-羟烷化产物12～17和少量还原产物2a.该反应具有很高的环上2,3-位非对映立体选择性 与非对称的羰基化合物反应产生新手性中心的立体选择性从50：50到77：23.     

α-羟酸在Chiralpak AD-H手性柱上的分离研究

利用Chiralpak AD-H手性柱建立了4种重要的解热镇痛药物合成中间体苯羟乙酸(扁桃酸)、2-苯基-2-羟基丙酸(阿卓乳酸)、2-羟基-2-(4-甲氧基苯基)丙酸、2-羟基-2-(4-甲基苯基)丁酸的高效液相色谱手性拆分方法.以正己烷-乙醇-三氟乙酸(TFA)为流动相体系,通过调整正己烷与乙醇的比例、改变醇的种类以及TFA的含量着重探讨了待测组分与手性固定相(CSP)之间的作用以及分离规律,同时也实现了四种α-羟酸对映异构体的完全分离.     

Enantioselective synthesis of ethyl (S)-2-hydroxy-4-phenylbutyrate by recombinant diketoreductase

Recombinant diketoreductase showed excellent stereoselectivity in the double reduction of β,δ-diketo esters. To investigate the substrate specificity and to broaden the applications of this new biocatalyst, a number of ketone substrates were used to evaluate the substrate spectrum and enantioselectivity of this enzyme in the present study. Among the ketone substrates tested, only this enzyme displayed high efficiency and excellent enantioselectivity in the reduction of ethyl 2-oxo-4-phenylbutyrate to ethyl (S)-2-hydroxy-4-phenylbutyrate. After optimizing the reaction conditions, the bio-reduction of ethyl 2-oxo-4-phenylbutyrate at a substrate concentration of 0.8 M (164.8 g/L) was achieved by the recombinant diketoreductase in an aqueous-toluene biphasic system coupled with formate dehydrogenase for the regeneration of cofactor, resulting in an overall hydroxyl product yield of 88.7% (99.5% ee). This new enzymatic transformation may offer a practical method for the preparation of this important chiral building block.     

Highly enantioselective and efficient synthesis of flavanones including pinostrobin through the rhodium-catalyzed asymmetric 1,4-addition

An efficient synthesis of bioactive chiral flavanones (1) was achieved through the Rh-catalyzed asymmetric 1,4-addition of arylboronic acid to chromone. The reaction in toluene proceeded smoothly at room temperature in the presence of 0.5% Rh catalyst with electron-poor chiral diphosphine MeO-F(12)-BIPHEP. In this reaction, the 1,2-addition to (S)-1 frequently occurred to yield (2S,4R)-2,4-diaryl-4-chromanol as a byproduct, which could be reduced by changing the reaction solvent to CH(2)Cl(2) to deactivate the Rh catalyst (3% required).     

Efficient synthesis of a chiral precursor for angiotensin-converting enzyme (ACE) inhibitors in high space-time yield by a new reductase without external cofactors

A new reductase, CgKR2, with the ability to reduce ethyl 2-oxo-4-phenylbutyrate (OPBE) to ethyl (R)-2-hydroxy-4-phenylbutyrate ((R)-HPBE), an important chiral precursor for angiotensin-converting enzyme (ACE) inhibitors, was discovered. For the first time, (R)-HPBE with >99% ee was produced via bioreduction of OPBE at 1 M without external addition of cofactors. The space-time yield (700 g·L(-1)·d(-1)) was 27 times higher than the highest record.     

(Tetramethyltetraazaannulene)chromium chloride: a highly active catalyst for the alternating copolymerization of epoxides and carbon dioxide

A tetramethyltetraazaannulene complex incorporating a chromium(III) metal center has been shown to be highly active toward the copolymerization of cyclohexene oxide and carbon dioxide to afford poly(cyclohexene carbonate) in the presence of [PPN]N3 [PPN+=bis(triphenylphosphoranylidene)ammonium] as a cocatalyst. An asymptotical rate increase was observed, leveling at 2 equiv of cocatalyst with a maximum turnover frequency of 1300 h(-1) at 80 degrees C. A benefit of this new catalyst system over that of the previously studied less-active (salen)CrX system is that the (tmtaa)CrCl catalyst has a much lower propensity toward the formation of a cyclic carbonate byproduct throughout the copolymerization reaction.     

Catalytic asymmetric addition of carbon dioxide to propylene oxide with unprecedented enantioselectivity

New chiral catalyst systems were developed for the reaction of carbon dioxide with propylene oxide (PO) at atmospheric pressure to generate enantiomerically enriched propylene carbonate (PC). The best selectivity was achieved with a Co(III)(salen)-trifluoroacetyl complex and bis(triphenylphosphoranylidene)ammonium fluoride (PPN+F-) as catalysts, affording PC in 40% yield and 83% ee (selectivity factor = 19). In addition, PC was prepared for the first time by kinetic resolution of PO with tetrabutylammonium methyl carbonate (TBAMC, nBu4N+ (-)OOCOMe). With TBAMC as "activated CO2", up to 71% ee was obtained.     

Super acid-induced Pummerer-type cyclization reaction: improvement in the synthesis of chiral 1,3-dimethyl-1,2,3,4-tetrahydroisoquinolines

Improved synthesis of four stereoisomeric chiral 1,3-dimethyl-1,2,3,4-tetrahydroisoquinolines (1a, b, ent-1a, b) was achieved via the super acid-induced cyclization of chiral N-[1-methyl-2-(phenylsulfinyl)ethyl]-N-(1-phenylethyl)formamides (4a, b, ent-4a, b) using the Pummerer-type cyclization reaction as a key step. The cyclization leading to the isoquinoline ring proceeded in a quantitative manner when trifluoromethane sulfonic acid (TFSA) was used as the super acid, although Friedel-Crafts-type alkylation of 4-phenylsulfanyl TIQ derivatives (5) with benzene used as the solvent accompanied cyclization to yield the 4-phenyl-TIQs (7). The byproduct (7) was exclusively formed when a large excess amount of TFSA was used.     

The CGC enantiomer separation of 2-arylcarboxylic acid esters by using β-cyclodextrin derivatives as chiral stationary phases

Chiral 2-arylcarboxylic acid esters are important intermediates in preparation of enantioenriched 2-arylpropionic acids type Non-steroidal anti-inflammatory drugs (NSAIDs). Enantiomer separation of 2-arylcarboxylic acid esters is crucial for evaluation of the asymmetric synthesis efficiency and the enantiomer excess of chiral 2-arylcarboxylic acid derivatives. The capillary gas chromatography (CGC) enantiomer separation of 17 pairs of 2-arylcarboxylic acid esters enantiomers was conducted by using seven different β-cyclodextrin derivatives (CDs) as chiral stationary phases. It was found that for the 7 pairs of 2-phenylpropionates enantiomers, CDs with both alkyl and acyl substituents especially 2,6-di-O-pentyl-3-O-butyryl-β-cyclodextrin exhibited better enantiomer separation abilities than the other CDs examined. For the 7 pairs of 2-(4-substituted phenyl)propionates enantiomers, 2,3,6-tri-O-methyl-β-cyclodextrin possessed better enantiomer separation abilities than the other CDs. Among the 3 pairs of 2-phenylbutyrates enantiomers examined, only methyl 2-phenylbutyrate enantiomers could be separated by three CDs among the 7 CDs tested, while enantiomers of ethyl 2-phenylbutyrate and isopropyl 2-phenylbutyrate couldn't be separated by any of the 7 CDs tested. Besides the structures of CDs, the structures of 2-arylcarboxylic acid esters including different ester moieties, substituents of phenyl, and different carboxylic acids moieties in 2-arylcarboxylic acid esters also affected the enantiomer separation results greatly. The CGC enantiomer separation results of 2-arylcarboxylic acid esters on different CDs are useful for solving the enantiomer separation problem of 2-arylcarboxylic acid esters.     

Toward the computational design of diastereomeric resolving agents: an experimental and computational study of 1-phenylethylammonium-2-phenylacetate derivatives

The crystal structures, including two new polymorphs, of three diastereomerically related salt pairs formed by (R)-1-phenylethylammonium (1) with (S&R)-2-phenylpropanoate (2), (S&R)-2-phenylbutyrate (3), and (S&R)-mandelate (4) ions were characterized by low-temperature single crystal or powder X-ray diffraction. Thermal, solubility, and solution calorimetry measurements were used to determine the relative stabilities of the salt pairs and polymorphs. These were qualitatively predicted by lattice energy calculations combining realistic models for the dominant intermolecular electrostatic interactions and ab initio calculations for the ions' conformational energies due to the distortion of their geometries by the crystal packing forces. Crystal structure prediction studies were also performed for the highly polymorphic diastereomeric salt pair (R)-1-phenylethylammonium-(S&R)-2-phenylbutyrate (1-3) in an attempt to predict the separation efficiency without relying on experimental information. This joint experimental and computational investigation provides a stringent test for the reliability of lattice modeling approaches to explain the origins of chiral resolution via diastereomer formation (Pasteurian resolution). The further developments required for the computational screening of single-enantiomer resolving agents to achieve optimal chiral separation are discussed.     

Noncentrosymmetric organic solids with very strong harmonic generation response

The molten reaction of 2-naphthol, 4-(aminomethyl)pyridine, and 4-pyridinecarboxaldehyde at about 180 degrees C yields trans-2,3-dihydro-2,3-di(4'-pyridyl)benzo[e]indole (1) which possesses two chiral centers, rather than an expected Betti-type reaction product with only one chiral carbon center. The same reactions, using 3-pyridinecarboxaldehyde, 4-cyanobenzaldehyde, or 3- cyanobenzaldehyde instead of 4-pyridinecarboxaldehyde produce the related compounds trans-2,3-dihydro-2-(4'-pyridyl)-3-(3"-pyridyl)benzo[e]indole (2), trans-2,3-dihydro-2-(4'-pyridyl)-3-(4"-cyanophenyl)benzo[e]indole (3), and trans-2,3-dihydro-2-(4'-pyridyl)-3-(3"-cyanophenyl)benzo[e]indole (4), respectively. This reaction proceeds with a high degree of stereoselectivity with a trans/cis ratio of about 98:2 at elevated temperature. Compounds 1, 2, and 4 crystallize in a noncentrosymmetric space group (Pca2(1), Pca2(1), and Cc), while compound 3 has a chiral space group (P2(1)). These successfully acentric packing arrangements are probably due to the molecule bearing both two chiral centers and potential hydrogen-bonding groups. Furthermore, the reaction of racemic 6-hydroxy-2'-methyl-2-naphthaleneacetic acid with ethyl-2-cyano-1-(4'-pyridyl)acrylic acetate in the presence of piperidine gives 1-pyridyl-2-ethoxycarbonyl-3-amino-1H-naphtho[2,1-b]pyran-2'-methylacetic acid (5), which likewise crystallizes in a chiral space group. All of compounds are second harmonic generation (SHG) active, and have a very strong SHG response approximately about 8.0, 5.0, 12.0, 6.0, and 1.4 (for 1-5 compounds) times that of urea. Ferroelectric property measurements indicate that compounds 1, 2, 4, and 5 may display ferroelectric behavior.     

Synthesis of nonracemic polysubstituted cyclohexanes through cascade reactions of (2R,3S)-2-Acetyl-3-aryl-4-nitrobutanoates, adducts of Ni(II)-catalyzed michael addition

Stereoselective synthesis of ethyl-4,6-diaryl-2-hydroxy-2-methyl-5-nitro-3-formylcyclohexanecarboxylates was described. The formation of the asymmetric site of the required configuration is achieved by an enantioselective Michael addition of ethyl acetoacetate to nitroalkenes in the presence of a chiral Ni(II) complex with (R,R)-N,N′-dibenzylcyclohexane-1,2-diamine. Further reaction of the products obtained with cinnamic aldehyde led to the formation of polysubstituted cyclohexanes.