摘要： N-tert-Butanesulfinyl imines are exceedingly versatile intermediates for the asymmetric synthesis of a wide variety of amines because of a number of ideal features associated with this structure. One of the effective methods to prepare enantiomerically enriched amines is nucleophilic additions to N-tert-butanesulfinyl imines. In Chapter 1, an overview of the progress made in the asymmetric synthesis of amines by nucleophilic additions to N-tert-butanesulfinyl imines is described. This method is applicable to the preparation of diverse classes of α-chiral amines, and the generality of this chemistry has rapidly led to the extensive use of N-tert-butanesulfinyl imines in both academics and industry. Another general way to form stereocenters using imines is metalloenamine addition to electrophiles. However, use of metalloenamines derived from N-sulfinyl imines has not previously been reported. In Chapter 2, a general method for the asymmetric synthesis of both syn- and anti-1,3-amino alcohols is presented. The highly diastereoselective addition to aldehydes is developed as the first application of metalloenamines derived from N-sulfinyl imines. The reduction of the product β-hydroxy N-sulfinyl imines with catecholborane and LiBHEt3 provides syn- and anti-1,3-amino alcohols in high yields with very high diastereomeric ratios. The application of this method to the convergent and efficient asymmetric syntheses of the two natural products, (−)-8-epihalosaline and (−)-halosaline, is also presented. In Chapter 3, highly diastereoselective α-alkylation of N ′-tert-butanesulfinyl amidines is described along with methods for converting the alkylation products to N-sulfinyl aldimines and ketimines, which are versatile precursors for enantiomerically enriched amines. This method should provide for the efficient synthesis of a wide variety of chiral amines incorporating both (α- and β-stereocenters. In Chapter 4, application of this method to the first enantioselective total synth

关键词： Aromatic compounds  

摘要： The 2,2'-methylenebis[furan] (1) was converted to 1-{(4R,6S))-6-[(2R)-2,4-dihydroxybutyl]-2,2-dimethyl-1,3-dioxan-4-yl}-3-[(2R,4R)-tetrahydro-4,6-dihydroxy-2H-pyran-2-yl)propan-2-one ((+)-18) and its (4S)-epimer (-)-19 with high stereo- and enantioselectivity (Schemes 1-3). Under acidic methanolysis, (+)-18 yielded a single spiroketal, (3R)-4-1(1R,3S,4'R,5R,6'S,7R)-3',4',5',6'-tetrahydro-4'-hydroxy-7-methoxyspiro[2,6-dioxabicyclo[3.3.1]nonane-3,2'-[2H]pyran]-6'-yl]butane-1,3-diol ((-)-20), in which both O-atoms at the spiro center reside in equatorial positions, this being due to the tricyclic nature of (-)-20 (methyl pyranoside formation). Compound (-)-19 was converted similarly into the (4'S)-epimeric tricyclic spiroketal (-)-21 that also adopts a similar (3S)-configuration and conformation. Spiroketals (-)-20, (-)-21 and analog (-)-23, i.e., (1R,3S,4'R,5R,6'R)-3',4',5',6'-tetrahydro-6'-[(2S)-2-hydroxybut-3-enyl]-7-methoxyspiro[2,6-dioxabicyclo[3.3.1]nonane-3,2'-[2H]pyran]-4'-ol, derived from (-)-20, were assayed for their cytotoxicity toward marine P388 lymphocytic leukemia and six human cancer cell lines. Only racemic ()-21 showed evidence of cancer-cell-growth inhibition (P388, ED50: 6.9 mug/ml).

关键词： Haliclorensin   isohaliclorensin   aza-Claisen反应   Zip反应   indolzidine   不对称合成  

摘要： 生物碱在从天然界提取的活性成分中具有重要比例。直接利用它们或通过这些有效成分作为母体化合物进行结构改造始终是开发和研究新药的有效途径。针对这类化合物的合成和应用研究一直备受人们的关注。近年来，从海洋各种动植物和微生物提取出许多新结构生物碱，对其不对称合成的研究十分活跃。 本论文的目的在于发展海洋大环生物碱haliclorensin和halitulin手性片断isohaliclorensin的新不对称合成方法。并在合成过程中，探索扩环反应在不对称合成中的新应用。此外，在本实验室过去研究工作的基础上，拓展苹果酰亚胺还原烷基化方法在不对称合成中的应用。取得的主要结果如下： 一、从(R)-苯基甘氨醇1出发，通过已知的哌啶手性合成砌块2的加成反应，建立了经aza-Claisen重排反应进行海洋生物碱halitulin手性分子片断的对映体(+)-(R)-isohaliclorensin 3不对称合成的路线。从(R)-苯基甘氨醇1出发，整个合成路线经十步反应，总产率5.3％。 利用合成(R)-isohaliclorensin 3的中间体腈化物(R)-4，建立了通过Zip重排反应进行具有细胞毒性的海洋天然产物(R)-haliclorensin 5不对称合成的路线。以(R)-苯基甘氨醇1为原料，整个合成路线共经十二步反应，总产率2.7％。 二、从(R)-苯基甘氨醇1出发，通过已知的哌啶手性合成砌块6的加成反应，建立了经aza-Claisen重排反应进行海洋生物碱halitulin的手性分子片断 摘要 ---一---------- C)一沟一isohalidorensin3不对称合成的路线。从(R)一苯基甘氨醇1出发，整个合 成路线经十步反应，总产率5.9%。 利用合成沟一isohaliclorensin3的中间体睛化物沟一4，建立了通过Zip重排 反应进行具有细胞毒性的海洋天然产物阎一haliclorensins不对称合成的路线。 以(R)一苯基甘氨醇1为原料，整个合成路线共经十二步反应，总产率3.0%。 Ph 厂一入 HZN OH pn..二C〕户’’叹戈 ‘仓“:.u2·刁一夕- 6 X== Btl andB产 (S)一3 (S)4 郑 (S)一5 上述从(R)一苯基甘氨醇l出发，进行halielorensin和halitulin手性片断 isohaliclorensin两对对映体不对称合成工作的主要结果已发表在Organic Letters。 三、在以上不对称合成中，详细研究了: (l)以(R)一苯基甘氨醇1为手性源，经两步反应合成了呱睫手性合成砌块2 的方法，总产率51%。该合成路线与文献方法相比，反应条件较温和，也缩短 了反应时间;(2)呱陡衍生物2与乙烯基格氏试剂进行加成反应的条件和立体选择性， 取得了较好的结果(差向异构体比为80:20，产率95%左右);(3)不饱和呱睫衍生物7在不影响碳碳双键的情况下去除苯基甘氨醇手性 辅助基的条件;(4)具有拨基。位手性的氨基酞胺8在不同条件下经zip重排反应转变为 9的反应，控制反应条件，可使反应中消旋化减小到最小的程度。 摘委 -一--一一.一一.--一-一一-一 0 工..ee产 下人|、!N //目曰9 式戈 。ZN广冲夕 四、以沟一苹果酸10为手性源，从沟一苹果酞亚胺11出发，建立了通过还 原烷基化反应不对称合成(IS，saR)1一轻基叫噪里西吮12的方法。研究了4一(2- 四氢毗喃基)氧丁基澳化镁与苹果酞亚胺的血游还原脱育劣还原涝寡必反应。 最终高区域和立体选择性地合成了天然产物的差向异构体(IS，saR卜l一经基叫垛 里西淀12。从沟一苹果酞亚胺n出发，整条合成路线经五步反应，总产率46%。 H仇e丈veoZH Bn 11 H沙 五.从尚一苹果酞亚胺n出发，合成了stellettamide系列海洋生物碱的手 性杂环核心(IS，saR)一1一氨甲基叫噪里西淀13的前体化合物(IR，saR卜1一氰基叫噪 里西吮14。为进一步合成天然产物stellett田爪lde C15奠定了基础。 Nc..‘ H’N姚q臼Nc’.rtM气‘门”’ 妙一公尸‘.C厂汁入了协 弓1 名夕\z产、.乡

关键词： alkynes   arenes   chirality   copper   cross-coupling   helical structures   palladium   synthesis design  

摘要： )We have developed the synthesis of model nonracemic aromatic triynes (-)-( S)- 1 - 4 containing the 1-{[2-(but-3-yn-1-yl)- 1- naphthyl] ethynyl}- 2-{[(( S)- 1- methylprop-2-yn-1-yl) oxy]methyl} naphthalene unit. The common 1,2- di(2- substituted-1-naphthyl) acetylene part was constructed via Sonogashira coupling of appropriate 1- iodonaphthalenes with 1- ethynylnaphthalenes both bearing tethered acetylene units in positions 2. The chirality of triynes ( -)-( S)- 1 - 4 was introduced by incorporating commercially available ( -)-( S)- but-3-yn-2-ol ( 10) into tethered acetylene units. The nonracemic triynes are intended to be used as substrates in stereoselective [2+2+2] triyne cycloisomerization catalyzed by transition metal complexes.

关键词： VICINAL AMINO-ALCOHOLS   ENANTIOSELECTIVE SYNTHESIS   NICKEL BORIDE   REDUCTION   NITROALKENES   NITROOLEFINS   SYSTEM   ANIONS  

摘要： The "naked" anion of (S)-6-methyl delta lactol undergoes efficient oxy-Michael addition to alpha,beta-disubstituted nitro olefins to give the THP* protected Henry products with excellent (95-->98% de) stereocontrol at the beta-position and moderate (up to 3:1) stereocontrol at the alpha-position in favour of the syn-diastereoisomer. Nitro group reduction with in situ N-Boc protection and THP* removal provides alpha,beta-disubstituted ethanolamine derivatives, while treatment with tetrapropylammonium perruthenate gives THP* protected alpha-hydroxy ketone derivatives in high diasteromeric excess.

摘要： Calyculin C and Amphotericin B are biologically active natural products. Amphotericin B is an antifungal agent, which has been a widely used drug in antifungal chemotherapy. Calyculin C is a potent protein phosphatase inhibitor and plays an important role in cancer research. Calyculin C and Amphotericin B contain a stereotetrad fragment. The synthesis of the syn, anti, anti stereotetrad of Amphotericin B was based on the thiopyranone ring and a chiral auxiliary strategies. The synthesis began with the introduction of the asymmetry into the thiopyranone ring via a tartrate derived chiral ortho ester, followed by a highly diastereoselective Mukaiyama aldol reaction and 1,3-syn diol reduction. The synthesis was complete in only six steps with reasonable yield and diastereoselectivity. The all-anti stereotetrad of Calyculin C was first approached through a convergent strategy but it yielded a wrong diastereomer as the major product. The linear synthesis began with a chiral boron crotylation followed by ozonolysis. The second crotylation with (Z)-crotyl trifluorosilane produced the desired anti, anti, anti stereochemistry with high diastereoselectivity.

关键词： .dehydro   tri-peptides   Moroidin   stephanotic acid  

摘要： The C-6 substituted tryptophan di- and tri-peptides 5 and 6, representing the tryptophan core of stephanotic acid, have been synthesized, the key steps being the formation of the phosphono-di- and tri-peptides 8 and 10 by a highly chemo-selective rhodium(II) catalyzed carbene N-H insertion reaction, their subsequent Horner-Wadsworth-Emmons reactions with N-Boc-6-bromoindole-3-carboxaldehyde, and the rhodium(I) catalyzed asymmetric hydrogenation of the resulting dehydro di- and tri-peptides.

关键词： 不对称硅氰化反应   手性磷配体   不对称合成   不对称Baylis-Hillman 反应  

摘要： 在醛的不对称硅氰化反应中,从D-樟脑出发,设计并合成了一类新的具有游离酚羟基的手性环状膦酰二胺(+)-c 和(+)-d。通过重结晶的方法培养了三个手性环状膦(磷)酰二胺的单晶,对它们进行了X 光衍射晶体结构分析,并确定 了它们的绝对构型。考察了此类手性磷试剂作为配体催化剂在醛的不对称硅氰化反应中的催化效果。对反应条件如催化剂用量、反应温度、反应底物及催化剂结构等进行了优化选择。结果表明,此类手性磷化合物有较好的催化活性。以(+)-d 为配体催化剂,邻甲氧基苯甲醛为反应底物,得到98.3%的对映选择性。 在合成(+)-c 和(+)-d 的过程中,研究了正丁基锂作用下磷酰基从氧到碳的重排反应,确定该重排反应的动态立体化学对磷原子来说是构型保留,并深入讨论了该重排反应的机理。 在不对称Baylis-Hillman 反应中,从多种便宜易得的手性源出发合成了5 类手性活化烯。在Me3N·H2O/溶剂体系中,研究了它们的不对称Baylis-Hillman 反应,取得了较好的不对称诱导效果。其中,丙烯酸薄荷醇酯与醛的反应,de 值最高可达98.4%;N-α-苯乙基丙烯酸酰胺与醛的反应,非对映选择性高达97.4%。将Salen 钴(Ⅱ)配体与叔胺作为催化剂共同催化Baylis-Hillman 反应,得到具有一定旋光值的产物。

摘要： Irofulven (1) is a potent antitumor compound derived from the sesquiterpene illudin S (2). The latter is produced in cultures of the basidiomycete Omphalotus illudens. Irofulven is currently being tested in phase II clinical trials against several solid tumor types. In order to better understand the biological mechanism of irofulven's antitumor activity and what role the tertiary hydroxyl stereocenter plays, the asymmetric synthesis of both enantiomers of irofulven was conducted. Enantiopure (−)-irofulven was obtained in a new 11-step synthesis in 3.6% overall yield starting with a 1,3-dipolar cycloaddition reaction of 1-acetyl-1-diazoacetylcyclopropane with (S)-5-chloro-5-methyl-2-cyclopentenone. (+)-Irofulven was similarly obtained beginning with (R)-5-chloro-5-methyl-2-cyclopentenone. The unnatural (+)-enantiomer of irofulven was about 5 to 6 times less toxic in vitro than “natural” (−)-irofulven to MV522 lung adenocarcinoma cells. Early in vivo studies determined that (+)-irofulven had less antitumor activity than its “natural” (−)-enantiomer, though both had nearly identical toxicity. Antitumor compounds have previously been linked to peptides that are cleaved by prostate-specific antigen (PSA) to create highly tumor-selective conjugates termed “prodrugs.” Two new potential peptide conjugate “prodrugs” have been synthesized from the hydroxypropyl analog of irofulven. The compound Ac-Hyp-Ser-Ser-Chg-Gln-Ser-Ser-Pro-O-(CH2 )3-acylfulvene has been synthesized and was found to be far more toxic to PSA-secreting prostate tumor cells than PSA-nonsecreting cells. Another peptide conjugate, Mu-His-Ser-Ser-Lys-Leu-Gln-Leu-NH-(CH2) 3-acylfulvene, was synthesized. In vitro studies for the latter conjugate are forthcoming. In vivo studies of both conjugates may be performed in the future. Other new analogs of irofulven were made, most of which possessed good in vitro antitumor activity. The hydroxyurea derivatives were found to be the most potent. In vivo studies revealed

关键词： asymmetric synthesis   conformation analysis   metathesis   natural products   total synthesis  

摘要： Pochonin C was isolated from a high-throughput screening program aimed atdiscovering novel antiviral agents against Herpes Simplex Virus (HSV).Pochonin C (Scheme 1)belongsto a family of six related macrolides (pochonins A-F) but attracted our attention by having thehighest selectivity index (Tox_50/IC_50) against HSV amongst the pochonins and by being closelyrelated to radicicol (also known as mono-rden),a potent HSP90 inhibitor.