摘要： Recent progress in asymmetric syntheses has made a significant impact on strategies for drug development in the pharmaceutical industry. Under the recent guidelines by the Food and Drug Administration (FDA), many drug firms are no longer considering the development of racemic forms of chiral drugs. This lecture presents a few examples of highly practical stereoselective syntheses of drug candidates, shown below, discovered and developed at Merck Research Laboratories.

关键词： Redox reactions   Monomers   Organic compounds   Pharmaceuticals   Dendrons  

摘要： Efficient preparation of a series of four chiral, nonracemic AB(2) monomers suitable for the construction of dendrimers is presented. Monomers 1-4 possess the common structural features of a diphenolic moiety and a benzylic or aliphatic hydroxyl which render these molecules suitable for convergent dendrimer synthesis. The same basic, high-yielding, five-step sequence is employed for 1-4. Stilbene derivatives 13 and 14 are prepared by a Horner-Wadsworth-Emmons modified Wittig reaction between 3,5- or 3,4-bis(benzyloxy)benzaldehyde (8 and 10) and an ester-substituted benzylphosphonate (11 or 12). Cinnamate derivatives 21 and 22 are prepared similarly from 8 and 10 and triethyl phosphonoacetate. Chirality is introduced in the form of a 1,2-diol unit by Sharpless asymmetric dihydroxylation (AD) (>97% ee in all cases), Protection of the 1,2-diols as their acetonide derivatives provides dioxolane intermediates 17, 18, 25, and 26. Reduction of the ester groups followed by hydrogenolysis of the benzyl ethers yields AB(2) monomers 1-4 in 57-67% overall yield from 8 and 10.

关键词： Cyclization   Stereoselectivity   Catalysts   Chemical reactions   Molecular structure  

摘要： Important advances are being made in the develop- ment ofcatalytic, asymmetric variants of the Diels-Alder reaction. A numberof systems have been reported that effect this powerfultransformation, with variable toler- ance for changes in diene anddienophile structure; however, the intermolecular version of theDiels-Alder reaction has been developed in almost exclusive prefer-ence to its intramolecular counterpart.

关键词： Mixtures   Salts   Hydrocarbons   Reaction products   Organic reactions  

摘要： A method for preparing the eight stereoisomers of the biologically active compound (1R,2S,3R)-2-acetyl-4(5)-(1,2,3,4-tetrahydroxybutyl)imidazole (THI, 1) is reported. This method employs a palladium(0)-catalyzed coupling of 1-(ethoxymethyl)-4-iodoimidazole (7) to functionalized vinylstannanes (R)- or (S)-12a,b or 13a,b or 1-alkynylstannanes (R)- or (S)-6a,b to introduce the C-4 imidazole four-carbon side chain. The 1,2-dihydroxy functionality of the butyl side chain was introduced by Sharpless catalytic asymmetric dihydroxylation reactions.

关键词： Reagents   Organic compounds   Piperidines   Ethanol   Enantioselective synthesis  

摘要： The development of methods for the asymmetric syn- thesis ofpiperidines remains an area of considerable interest due to thepresence of this heterocyclic ring in a large number of biologicallyimportant compounds. We now report a new approach to chiral,nonracemeic piper- idines, illustrated by the synthesis of thehemlock alkaloids (-)-coniine (1) and (+)-pseudoconhydrine (2).

关键词： 配合物   不对称合成   拟除虫菊酯   络合物催化剂  

摘要： 报导了新型希夫碱－铜配合物的合成，及其对菊酸不对称合成的催化诱导效应．用降解脱氢松香胺和水杨醛反应，形成希夫碱，再与醋酸铜反应，制备希夫碱－铜配合物．将该配合物作为手性催化剂，催化重氮乙酸乙酯及重氮乙酸冰片酯与２，５－二甲基－２，４己二烯合成菊酸的反应，讨论了重氮乙酸酯中醇组分及温度对催化剂的影响，该催化剂可导致菊酸乙酯及菊酸冰片酯的反式对映体超量分别为７．７９％与１５．８４％．

关键词： 微生物转化   芳基丙烯酸   氨基酸   不对称合成  

摘要： 反式-β-芳基丙烯酸(1)和氨经具有苯丙氨酸解氨酶活性的红酵母细胞催化,直接合成得到七种L-β-芳基-α-丙氨酸(2),收率为7.9～68.2%.其构型通过它们的圆二色谱在215nm处的正Cotton效应以及与文献比较比旋光值得到证实 用L-4-羟脯氨酸手性高效配体交换液相色谱柱拆分2,结果表明其对映体过量均不少于95%.

关键词： Oxides   Anions   Ketones   Condensation   Molecular structure  

摘要： The first asymmetric synthesis of oxisuran [1, (methylsulfinyl)methyl 8-pyridyl ketone], a synthetic immunosuppressive drug, is described. Both enantiomers were efficiently synthesized, in optically pure form, using DAG methodology for the key condensation step. Attempts to couple metal enolates of aryl methyl ketones with chiral sulfinyl compounds led to some epimerization at sulfur. This loss of chirality was circumvented by reacting the alpha-lithio derivatives of the N,N-dimethylhydrazones derived from these ketones with either the (R)- or the (S)-methanesulfinate of diacetone D-glucose, to yield the corresponding alpha-(methylsulfinyl)methylhydrazones, with complete inversion of chirality at sulfur. Hydrolysis of the resulting hydrazones with copper(II) chloride gave 1 in optically pure form. The generality of the method was demonstrated by the preparation of the optically active oxisuran analogs, 2-4, in which the pyridyl moiety was replaced by phenyl, furyl, and thienyl moieties, respectively. The optical purities of these products were determined by proton NMR spectroscopy, using chiral shift reagents, following conditions established by the study of racemic mixtures of the beta-keto sulfoxides.

关键词： 对映体识别   手性放大   不对称合成  

摘要： 对映体识别指的是同种构成的对映体之间的相互作用。这种现象广泛存在于固相、液相中。本文讨论了对映体识别对于溶液的物理、化学性质的影响，以及它在对映体拆分、纯度测定等方面的应用。

关键词： 不对称合成   分子内环化   氧杂双环己酮  

摘要： 采用手性铜催化剂(S)-7644,利用重氮醋酸不饱和酯的分子内不对称卡宾加成环化,合成了七个光学活性3-氧杂双环[3.1.0]-己-2-酮类化合物。产品经元素分析、红外、核磁确证了结构,并测定了比旋光度和光学收率。