甘油骨架上含芳硒基的替加氟硫代磷脂缀合物的合成及生物活性

以O-(2-邻苯二甲酰亚氨基)乙基-1,3,2-二氧磷杂环戊烷硫代磷酸酯1及2-邻苯二甲酰亚氨基乙醇环甘油硫代磷脂缀合物2为模型,研究开环反应的条件.结果表明,在室温下,甲醇对化合物1中1,3,2-二氧磷杂环戊烷中的磷原子的亲核进攻,生成O-甲基-O-羟乙基-O-(2-邻苯二甲酰亚氨基)乙基硫代磷酸酯3,但是在此条件下,甲醇与化合物2不反应.在室温下,以异丙醇作溶剂,苯硒酚与化合物2不反应.在氢氧化钾存在下,以异丙醇/水作溶剂(体积比20:1),在室温下,硒酚可以有效地进攻中化合物2中1,3,2-二氧磷杂环戊烷中的碳原子生成相应的开环产物.按照这一反应条件,顺利实现了硒酚对N1-(2-呋喃基)-N3-羟烷基-5-氟脲嘧啶硫代环甘油磷脂缀合物的亲核开环,生成甘油骨架的端碳原子上带有芳硒基新颖的磷脂核苷缀合物.对开环反应的机理进行了探讨.体外细胞毒性试验结果表明:产物对膀胱癌细胞T-24、胃癌细胞BGC-823的恶性增殖抑制效果优于替加氟;但对正常肝上皮细胞毒性也大于替加氟.     

O-(1,3-二芳硒基)异丙基-O-2-(N3-替加氟)乙基硫代磷酯的合成及其抗癌活性

六乙基亚磷酰三胺依次与羟乙基替加氟、1-芳硒基甘油及硫反应,得到环甘油硫代磷脂替加氟缀合物(2a～2e);通过苯硒化钾对2进行亲核开环,得到O-(1,3-二芳硒基)异丙基-O-2-(N-替加氟)乙基硫代磷酯(3a～3e),其结构经1H NMR,31P NMR,MS及元素分析确证.3对膀胱癌细胞PGA1有一定的抑制作用.     

内盐式O-2-(N~3-替加氟)乙基-O-(1-芳硫基-3-铵基)异丙基-硒代磷酯缀合物的合成

六乙基亚磷酰三胺依次与羟乙基替加氟、1-芳硫基甘油及硒反应,制备环甘油硒代磷替加氟缀合物(2);2再与三乙胺或三甲胺反应,完成亲核开环合成了内盐式O-2-(N3-替加氟)乙基-O-(1-芳硫基-3-铵基)异丙基-硒代磷酯缀合物.其结构经1H NMR, 31P NMR及元素分析确证.     

O-(1-芳硫基-3-铵基)异丙基-O-2-(N3-替加氟)乙基硫代磷酯的合成及其抗癌活性

六乙基亚磷酰三胺与羟乙基替加氟、1-芳硫基甘油及硫一锅反应得到环甘油硫代磷脂替加氟缀合物(2),三乙胺对2进行亲核开环合成了O-(1-芳硫基-3-铵基)异丙基-O-2-(N3-替加氟)乙基硫代磷酯(3)。2和3的结构经1HNMR,31PNMR和元素分析表征。生物活性测试结果表明,3对膀胱癌细胞PGA1有一定的抑制作用。     

O-(1-芳硒基-3-叠氮基)异丙基- O-2-(N3-替加氟)烷基硫代磷酯的合成与活性

以碘作催化剂, 无水苯为溶剂, 六乙基亚磷酰三胺依次与羟乙基替加氟、1-芳硒基甘油及硫反应, 得中间体硒代环甘油磷脂替加氟缀合物2a～2f. 以无水N,N-二甲基甲酰胺(DMF)作溶剂, 室温下, 叠氮化钠中对2a～2f进行亲核开环, 得到O-(1-芳硒基-3-叠氮基)异丙基-O-2-(N3-替加氟)乙基硫代磷酯. 体外活性测试结果表明, 目标化合物3a～3f 对膀胱癌细胞PGA1抑制作用比替加氟高, 对胃癌细胞BGC-823的抑制作用与替加氟相当.     

N3-羟烷基替加氟制备方法改良及其环甘油磷脂缀合物的合成与抗肿瘤活性

在药物-载体复合型前药的研究中,磷脂-药物缀合物(如脂核苷酸)特别引人注目,它以磷脂作为载体,与核苷等药物分子以共价连接形成的一类新型脂核苷酸前药[1～3].     

非对称氮杂环丙烷的亲核开环反应及其区域选择性

本文系统地总结了各类亲核试剂对非对称氮杂环丙烷(吖丙啶)的亲核开环反应及开环的区域选择性.氮杂环丙烷亲核开环的区域选择性是一种空间效应和电子效应平衡的结果,非芳基和非烯基取代的氮杂环丙烷的亲核开环通常发生在氮杂环丙烷取代少的碳原子上,空间效应起主导作用;而芳基和烯基取代的氮杂环丙烷的亲核开环通常发生在氮杂环丙烷芳甲位和烯丙位的碳原子上,电子效应起主导作用,烯基取代的氮杂环丙烷的亲核开环还可以发生在烯基的β-碳原子上;分子内的亲核开环反应主要受成环时环大小的控制,成环时的倾向是五元环>六元环>七元环.对于亲核试剂,一般的亲核试剂也同时受电子效应和空间效应的影响; 而亲核性强的亲核试剂通常只受空间效应的影响.容易生成稳定自由基的亲核试剂容易发生单电子转移机理的开环反应,生成相当于亲核试剂进攻氮杂环丙烷中取代多的碳原子得到的开环产物.     

用(R)-(+)-缩水甘油的亲核开环反应制备手性连二醇

以D-甘露醇为原料合成(R)-(+)-缩水甘油1。该环氧化合物的亲核开环反应为高立体选择性地(93%-96%e.e.)制备各种手性连二醇提供了一条简便途径。     

非对称环硫乙烷的区域选择性亲核开环反应

环硫乙烷与它的氧类似物环氧乙烷和氮类似物氮杂环丙烷一样,是一类重要的有机合成中间体,在医药和农用化学品工业领域也得到广泛应用。通过开环和异构化反应,还广泛用于制备硫醇和硫醚等含硫化合物。本文总结了常用亲核试剂对非对称环硫乙烷的亲核开环反应及其区域选择性。环硫乙烷的亲核开环反应通常只受空间效应影响,亲核试剂进攻非对称环硫乙烷位阻小的碳原子,对于烯基取代的环硫乙烷有时可以进攻烯基的β碳原子发生SN2’开环反应。强亲核性的亲核试剂容易致使环硫乙烷脱硫生成烯烃,而亲核性相对较弱的亲核试剂容易发生多聚反应生成多硫醚。在Lewis酸存在下,电子效应会对开环反应的区域选择性产生影响,甚至起主导作用。虽然烷基取代环硫乙烷在Lewis酸存在下的开环仍然主要发生在其取代基少的碳原子上(位阻控制),但受电子效应影响,芳基和烯基取代环硫乙烷的亲核开环,其亲核试剂一般倾向于进攻环硫乙烷的芳甲位和烯丙位碳原子(电子效应控制)。     

微波促进的6-位磷功能化的非环嘌呤核苷类似物的合成

以2,6-二氯嘌呤核苷和亚磷酸酯为原料,通过微波促进的Arbuzov反应,一步合成6位磷酸酯取代的嘌呤核苷类化合物,然后再进一步衍生,得到6-位磷酸单酯和6-位磷酸取代的嘌呤核苷类新化合物.得到的非环嘌呤核苷类化合物通过核磁共振图谱、高分辨质谱和红外光谱进行了结构确认.     

Computational evaluation of radical ring‐opening polymerization

The tendencies of ring‐opening processes in radical ring‐opening polymerizations were evaluated by AM1 and PM3 semi‐empirical calculations and 6‐31G*‐level calculations based on the density functional theory (DFT) B3LYP models. Sixteen cyclic monomers bearing vinyl or exomethylene groups were categorized into ring‐opening and no‐ring‐opening monomers by the evaluation of the differences of the internal energies and the lengths of the cleaving bonds between the ground states of the initial radicals and the activated states in the ring‐opening processes. Although the semi‐empirical calculations not parameterized to radical reactions resulted in the moderate categorization of the ring‐opening monomers, the DFT calculation clearly distinguished the ring‐opening and no‐ring‐opening monomers. The ring‐opening tendencies were also evaluated with the changes in the internal energies throughout the ring‐opening processes, but this method could not group the ring‐opening and no‐ring‐opening monomers clearly. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 2827–2834, 2007     

Polyesters by a Radical Pathway: Rationalization of the Cyclic Ketene Acetal Efficiency

Radical ring‐opening polymerization (rROP) of cyclic ketene acetals (CKAs) combines the advantages of both ring‐opening polymerization and radical polymerization thereby allowing the robust production of polyesters coupled with the mild polymerization conditions of a radical process. rROP was recently rejuvenated by the possibility to copolymerize CKAs with classic vinyl monomers leading to the insertion of cleavable functionality into a vinyl‐based copolymer backbone and thus imparting (bio)degradability. Such materials are suitable for a large scope of applications, particularly within the biomedical field. The competition between the ring‐opening and ring‐retaining propagation routes is a major complication in the development of efficient CKA monomers, ultimately leading to the use of only four monomers that are known to completely ring‐open under all experimental conditions. In this article we investigate the radical ring‐opening polymerization of model CKA monomers and demonstrate by the combination of DFT calculations and kinetic modeling using PREDICI software that we are now able to predict in silico the ring‐opening ability of CKA monomers.     

Synthesis of S-functionalized thioesters using thioaroylate ions derived from carboxylic acids and tetrathiomolybdate via acyloxyphosphonium intermediates

Thioaroylate ions generated in situ from acyloxyphosphonium salts and tetrathiomolybdate upon Michael addition or ring opening of three membered systems led to a facile synthesis of S-functionalized thioesters. While the ring opening of aziridines gave very good yield of the products, Michael addition and epoxide ring opening gave moderate yields.     

Highly Enantioselective Ring‐Opening Reactions of Aziridines with Indole and Its Application in the Building of C3‐Halogenated Pyrroloindolines

A magnesium‐catalyzed asymmetric ring‐opening reaction of aziridine with indole has been realized by employing commercially available chiral ligands. Both of the enantiomers of the ring‐opening product could be obtained with good yields and a high level of enantioselectivity. The corresponding ring‐opening product could be further transformed to various types of enantioenriched C₃‐halogenated‐pyrroloindolines.     

Effects of geminal methyl groups on the tunnelling rates in the ring opening of cyclopropylcarbinyl radical at cryogenic temperature

CVT + SCT calculations on the rate of tunnelling at 20 K in the ring opening of cyclopropylcarbinyl radical, substituted with geminal methyl groups at a ring carbon (1b), have been performed. The calculations predict that, contrary to expectations based on the effect of mass on the rate of tunnelling, the geminal methyl substituents in 1b should make the rate of ring opening to 1,1-dimethyl-3-butenyl radical (2b) 10(4) times faster than the rate of ring opening of unsubstituted cyclopropylcarbinyl radical (1a) to 3-butenyl radical (2a) and almost 10(6) times faster than the rate of ring opening of 1b to 2,2-dimethyl-3-butenyl radical (2c). The reasons for these unexpected findings are discussed.     

A novel synthesis of 1,3,5-trisubstituted pyrazoles through a spiro-pyrazoline intermediate via a tandem 1,3-dipolar cycloaddition/elimination

The syntheses of an important class of hitherto unreported 1,3,5-pyrazoles, inspired by an unanticipated eliminatory ring opening are described. The reported pyrazole compounds were constructed through the Huisgen cyclization of 2-methylene-1,3,3-trimethylindoline and an in situ generated nitrile imine. The newly formed spiro-pyrazoline intermediate presumably then undergoes a ring opening/elimination process to afford a pyrazole, as evidenced by single X-ray crystal data. The current report constitutes the first formal observation of this kind of ring opening involving a spiro-pyrazoline intermediate.     

Polymerization of cyclobutene rings. VII. Polymerization of bicyclo[4,2,0]octa-7-ene and bicyclo[3,2,0]hepta-2,6-diene with Ziegler-Natta catalysts and with group VIII metal halides

The polymerization of bicyclic olefins containing a cyclobutene and a higher-membered ring was studied by using Ziegler-Natta systems as well as group VIII metal halides as catalysts. Only the cyclobutene moiety of the monomers proved reactive in polymerization, whereas the higher-membered ring moieties enter unchanged in the polymer chains as side groups. In spite of the considerable bulkiness of the monomers, homopolymerization by opening of the double bond as well as by ring opening take place readily. Steric isomerism of the monomer units and the problem of the site of opening of the cyclobutene ring are discussed.     

Comparative study of the ring opening of 1-CF3-epoxy ethers mediated by Brönsted acids and hexafluoro-2-propanol

In order to evaluate more deeply the nature of the activation of oxirane ring opening reactions by HFIP, ring opening of both CF₃-epoxy ethers 1a (R = Ph) and 1b (R = CH₂CH₂Ph) with HFIP alone, and with hard (MeOH) or soft (PhSH) nucleophiles in HFIP, were investigated and compared to reactions performed with Brönsted acids. Nucleophilic ring opening reactions in HFIP were facilitated with PhSH and only α-substituted trifluoromethyl ketone 5 was isolated (nucleophilic ring opening), while with MeOH, both processes, nucleophile and electrophile-assisted ring opening were in competition. In the Brönsted acid-catalysed ring opening of 1-CF₃-epoxy ethers 1 in HFIP, only the acid-catalysed ring opening process occurred with an inversed regioselectivity.     

Stereoselective synthesis of piperidinone and quinolinone systems via ring opening reactions using TiCl4/silyl reagents

Titanium(IV) chloride and silyl reagents mediated regio- and chemoselective ring opening reactions of oxa-bridged piperidinone ring systems were demonstrated. This methodology interestingly undergoes the stereoselective ring opening at the C-O bond of oxa-bridged piperidinone ring systems. Study of TiCl₄ with hydride or non-hydride silyl reagents furnished the product with selectivity. This protocol is highly valuable to synthesize a range of stereoselective piperidinones, quinolinones ring systems.