Coordination chemistry of N-tetraalkylated cyclam ligands—A status report

N-alkylation of macrocyclic amines has a significant impact on their properties as ligands for metal ions. This article examines the development of the coordination chemistry of N-alkylated cyclam ligands from its inception in 1973 with the first report of tetramethylcyclam. Emphasis is on: (1) the stereochemistry of metal complexation, including the effects of inclusion of functional groups in one or two of the N-alkyl groups; (2) the effect of N-alkylation on the metal–donor interaction; (3) the ability of tertiary amine ligands to stabilize complexes of metal ions in unusual oxidation states.     

Fluorescent chemosensor for chloroalkanes

Two structurally related macrocyclic amines with naphthalene groups are shown to act as fluorescent dosimeters for reactive chloroalkanes, including the common industrial solvent dichloromethane. The macrocyclic structures contain two NH residues which greatly accelerate N-alkylation by activating the chloride leaving group. The chemical reaction increases fluorescence intensity by promoting excimer emission and attenuating the quenching induced by photoinduced electron transfer (PET).     

Dramatic acceleration of the Menschutkin reaction and distortion of halide leaving-group order

Compared to structurally related linear trialkylamines, a simple macrocyclic amine with an anion-binding cavity exhibits very large rate enhancements (>10(5)) for stoichiometric N-alkylation with primary alkyl, allyl, and benzyl halides in the weakly polar solvent CDCl3. There is also a major distortion of the halide leaving-group order. For example, with benzyl halides the relative leaving-group order with a control amine is Cl (1) < Br (71) < I (160), whereas the leaving-group order with the macrocyclic amine is I (0.4) < Cl (1) < Br (8.5). Reaction with the macrocyclic amine is inhibited by the addition of DMSO, which is unusual because the Menschutkin reaction is normally enhanced by the presence of a polar aprotic solvent. Competitive inhibition studies indicate that the reaction proceeds through a prereaction complex. Effective molarities for the subsequent unimolecular N-alkylation step with 4-t-butylbenzyl halides are 4-t-BuBnCl (62,000 M) > 4-t-BuBnBr (2200 M) > 4-t-BuBnI (35 M); thus, the free energy of activation is selectively decreased for organohalides having smaller and more charge dense leaving groups. Likely reasons for this selective enhancement effect are: (a) increased transition-state stabilization due to hydrogen bonding in the macrocyclic pocket and (b) reduced entropic penalty in the transition state due to an increased fraction of prereaction complexes that are oriented in a near attack conformation. The study suggests that it should be possible to develop highly reactive macrocyclic amines that selectively sense or scavenge carcinogenic haloalkanes from the atmosphere.     

Synthetic studies on lycopodine: construction of hexahydrojulolidine core by intramolecular Mannich reaction

The tricyclic core skeleton of lycopodine was constructed by the intramolecular Mannich reaction of a 12-membered cyclic amine. The concise assembly of the macrocyclic intermediate was executed by the sequential inter- and intramolecular N-alkylation of a linear diol using Ns-amide. The fully functionalized diol was prepared via Michael reaction of enone and malonate. The key Mannich reaction proceeded smoothly in the presence of silica gel to provide the tricyclic core skeleton of lycopodine.     

新型手性环状胺膦配体的设计合成及在酮的不对称还原中的应用

新型手性配体的设计合成是不对称催化研究的重要内容,其中手性胺膦配体因同时含有"软"的磷原子和"硬"的氮原子而具有丰富的配位化学性能和优秀的不对称诱导能力.本文总结了本研究组最近设计合成的手性环状胺膦配体的制备、表征及其在铁催化酮的不对称还原中的应用.手性1,2-环己二胺与双(2-甲酰基苯基)苯基膦通过[2+2]环缩合反应能够顺利获得手性22元环的亚胺膦配体21,该配体经Na BH4还原后生成大环胺膦配体22.利用手性大环胺膦配体22与Fe3(CO)12原位生成的催化体系,能够高活性、高对映选择性地实现包括杂环芳香酮在内50多种酮的不对称转移氢化和不对称氢化反应,其S/C(底物与催化剂的摩尔比)最高可达5000:1,产物手性芳香醇的光学纯度高达99%ee.     

Highly nonplanar, electron deficient, N-substituted tetra-oxocyclohexadienylidene porphyrinogens: structural, computational, and electrochemical investigations

The structures and electrochemistry of N-benzylated meso-tetrakis (3,5-di-tert-butyl-4-oxo-cyclohexa-2,5-dienylidene) porphyrinogens have been investigated. Structural determinations reveal the isomeric identity of the products obtained from the N-alkylation of the parent meso-tetra (oxo-cyclohexadienylidene) porphyrinogen. The compounds are subject to increased macrocyclic deformations upon increasing N-substitution culminating in the tetra-N-benzyl derivative, which has a buckling superimposed on the already highly puckered macrocycle. The electrochemical analyses emphasize the electron deficiency of the N-benzylated meso-tetra(oxo-cyclohexadienylidene) porphyrinogens and indicate that they can be considered as quinones conjugated via the unsaturated tetrapyrrolic macrocycle. The N-benzylated compounds studied form stable and well-defined pi-cation radical and pi-anion radical species because of their highly conjugated nature. Ab initio molecular orbital calculations at the B3LYP/3-21G() level confirmed the high degree of conjugation between tetrapyrrole and meso substituents and also gave good agreement between calculated and experimentally determined HOMO-LUMO band gap energies.     

手性双二茂铁基配体的合成、表征及固体CD光谱

以甲酰基二茂铁(1)和手性1,2-二苯基乙二胺[(1R, 2R)-1,2-二苯基乙二胺(2R), (1S,2S)-1,2-二苯基乙二胺(2S)]为原料, 经缩合、还原和N-烷基化反应, 制备了一对新型手性四齿双二茂铁基配体[N,N’-二(二茂铁基甲基)-N,N’-二(2-羟基丙基)-(1R,2R)-1,2-二苯基乙二胺(5R)和N,N’-二(二茂铁基甲基)-N,N’-二(2-羟基丙基)-(1S,2S)-1,2-二苯基乙二胺(5S)]. 用元素分析、红外(IR)、质子核磁共振(1H NMR)、紫外-可见(UV-Vis)、固体圆二色(CD)光谱等对手性产物(3R-5S)进行了表征. 固体CD光谱研究表明, 配体5R(或5S)的手性特征和4R(或4S)相似而与3R(或3S)却有一定差别.     

Pyridine N-alkylation by lithium, magnesium, and zinc alkyl reagents: synthetic, structural, and mechanistic studies on the bis(imino)pyridine system

The 2,6-bis(alpha-iminoalkyl)pyridines 2,6-[ArNC(CR(3))](2)C(5)H(3)N [R = H, D; Ar = 2,6-i-Pr(2)C(6)H(3) (DIPP), 2,6-Me(2)C(6)H(3) (DMP)] react with MeLi in Et(2)O to give a binary mixture of products: the pyridine N-methylated species 2,6-[ArNC(CR(3))](2)C(5)H(3)N(Me)Li(OEt(2)) and the deprotonated/dedeuterated species 2-[ArNC(CR(3))],6-[ArNC(=CR(2))]C(5)H(3)NLi(OEt(2)). For R = D, the product ratio is 2:1 in favor of the N-methylated product, while, for R = H, the deprotonated product is favored by 5:1, increasing to 8:1 in toluene solvent. Warming solutions of the N-methylated species leads to clean conversion to the thermodynamically preferred deprotonated species. Crossover experiments show that MeLi is re-formed and dissociates from the terdentate ligand before deprotonating the ketimine methyl unit. For MgR(2) (R = Et, i-Pr) and ZnR(2) (R = Et) reagents, N-alkylation products are formed exclusively, but derivatives containing bulky aryl substituents are found to undergo further rearrangement to 2-alkylated species, arising by migration of the alkyl group of the N-alkyl moiety to the adjacent ring carbon atom. The reversibility of the N-alkylation process has been probed using deuterio-labeled Mg alkyl reagents and mixed alkyl zinc species. A cationic zinc derivative is shown to undergo "reverse" alkyl migration, from the heterocycle nitrogen atom to the zinc center. EPR spectroscopy reveals a paramagnetic intermediate in which the unpaired electron is delocalized over the heterocycle and di-imine moieties of the ligand, indicating that the N-alkylation reactions proceed via single electron-transfer processes.     

原位合成苯并咪唑衍生物调控一维PbI_3~-盐的晶体结构和光学性质

以原位N-烷基化合成的苯并咪唑衍生物R2-bzim(R=H-,CH3-,C6H5CH2-;bzim=苯并咪唑)为模板,合成了3个含一维PbI3-盐的无机-有机杂化材料.X射线单晶衍射结果表明,随着模板剂尺寸的增大一维无机链由双链结构转变为单链结构.相对于体相PbI2,这些化合物有0.38～0.46eV的带隙蓝移,体现出比较强的量子限域效应.光致发光研究表明,通过模板剂的调控,3个化合物分别表现出绿、橙、黄光发射.     

Design, synthesis, and biological evaluation of novel C14-C3'BzN-linked macrocyclic taxoids

Novel macrocyclic paclitaxel congeners were designed to mimic the bioactive conformation of paclitaxel. Computational analysis of the "REDOR-Taxol" structure revealed that this structure could be rigidified by connecting the C14 position of the baccatin moiety and the ortho position of C3'N-benzoyl group (C3'BzN), which are ca. 7.5 A apart, with a short linker (4-6 atoms). 7-TES-14beta-allyloxybaccatin III and (3R,4S)-1-(2-alkenylbenzoyl)-beta-lactams were selected as key components, and the Ojima-Holton coupling afforded the corresponding paclitaxel-dienes. The Ru-catalyzed ring-closing metathesis (RCM) of paclitaxel-dienes gave the designed 15- and 16-membered macrocyclic taxoids. However, the RCM reaction to form the designed 14-membered macrocyclic taxoid did not proceed as planned. Instead, the attempted RCM reaction led to the occurrence of an unprecedented novel Ru-catalyzed diene-coupling process, giving the corresponding 15-membered macrocyclic taxoid (SB-T-2054). The biological activities of the novel macrocyclic taxoids were evaluated by tumor cell growth inhibition (i.e., cytotoxicity) and tubulin-polymerization assays. Those assays revealed high sensitivity of cytotoxicity to subtle conformational changes. Among the novel macrocyclic taxoids evaluated, SB-T-2054 is the most active compound, which possesses virtually the same potency as that of paclitaxel. The result may also indicate that SB-T-2054 structure is an excellent mimic of the bioactive conformation of paclitaxel. Computational analysis for the observed structure-activity relationships is also performed and discussed.     

若干多氮双核银(Ⅰ)大环化合物的合成和电化学

本文在硝酸银存在下,用二乙撑三胺、三（2－氨基乙基）胺分别和以间苯二醛为母体的二醛缩合,得到了系列双核银（Ⅰ）和多氮环合物和穴合物。对所得产物进行了表征,并利用循环伏安法对配合物的电化学进行了研究。探讨了环空腔大小及取代基不同对配合物中银（Ⅰ）电化学行为的影响。     

Synthesis and characterisation of bis-cyclen based dinuclear lanthanide complexes

The design and synthesis of several bis-macrocyclic cyclen (1,4,7,10-tetraazacyclododecane) ligands and their corresponding lanthanum or europium complexes is described; these dinuclear lanthanide systems were made by connecting two macrocyclic cyclen moieties through a rigid, covalent, p-xylylenediamide bridge or a flexible aliphatic hexane bridge. These ligands were subsequently functionalised with six acetamide pendant arms (CONR1R2: R1 = R2 = H or CH3, or R1 = H, R2 = CH3). The corresponding lanthanide bis-complexes were then formed by reaction with La(III) and Eu(III) triflates, yielding overall cationic (+VI charged) complexes.     

2种吲哚衍生物的N-烷基化产物的制备

吲哚-3-乙醛酸甲酯和3-吲哚乙腈在碱存在下,以烷基卤或硫酸烷基酯为亲电试剂进行N-烷基化反应,合成了6种新的N-烷基化吲哚化合物。 研究了吲哚化合物及烷基化试剂的结构、溶剂和碱对N-烷基化反应的影响。 具有强吸电子取代基的吲哚-3-乙醛酸甲酯使用弱碱Cs2CO3在室温就可顺利进行烷基化反应,产率达到93%;而具有较弱吸电子取代基的3-吲哚乙腈,需要使用强碱NaH才能进行烷基化反应。     

Macrocyclic diorganotin complexes of gamma-amino acid dithiocarbamates as hosts for ion-pair recognition

The dimethyl-, di-n-butyl-, and diphenyltin(IV) dithiocarbamate (dtc) complexes [{R2Sn(L-dtc)}x] 1-7 (1, L = L1, R = Me; 2, L = L1, R = n-Bu; 3, L = L2, R = Me, x = infinity; 4, L = L2, R = n-Bu; 5, L = L3, R = Me, x = 2; 6, L = L3, R = n-Bu, x = 2; 7, L = L3, R = Ph, x = 2) have been prepared from a series of secondary amino acid (AA) homologues as starting materials: N-benzylglycine (alpha-AA derivative = L1), N-benzyl-3-aminopropionic acid (beta-AA derivative = L2), and N-benzyl-4-aminobutyric acid (gamma-AA derivative = L3). The resulting compounds have been characterized by elemental analysis, mass spectrometry, IR and NMR ((1)H, (13)C, and (119)Sn) spectroscopy, thermogravimetric analysis, and X-ray crystallography, showing that in all complexes both functional groups of the heteroleptic ligands are coordinated to the tin atoms. By X-ray diffraction analysis, it could be shown that [{Me2Sn(L2-dtc)}x] (3) is polymeric in the solid state, while the complexes derived from L3 (5-7) have dinuclear 18-membered macrocyclic structures of the composition [{R2Sn(L3-dtc)}2]. For the remaining compounds, it could not be established with certainty whether the structures are macrocyclic or polymeric. A theoretical investigation at the B3LYP/SBKJC(d,p) level of theory indicated that the alpha-AA-dtc complexes might have trinuclear macrocyclic structures. The macrocyclic complexes 5-7 have a double-calix-shaped conformation with two cavities large enough for the inclusion of aliphatic and aromatic guest molecules. They are self-complementary for the formation of supramolecuar synthons that give rise to 1D molecular arrangements in the solid state. Preliminary recognition experiments with tetrabutylammonium acetate have shown that the [{R2Sn(L3-dtc)}2] macrocycles 6 and 7 might interact simultaneously with anions (AcO(-)), which coordinate to the tin atoms, and organic cations (TBA(+)), which accommodate within the hydrophobic cavity (ion-pair recognition).     

原位液相催化氮烷基化法反应

以胺和醇为原料,在Ni-Sn/Al2O3催化下液相合成氮烷基胺类化合物。反应工艺为连续式反应,醇既是烷基化试剂,又是供氢体和溶剂。考察了180 ℃下不同的胺与各类醇在Ni-Sn/Al2O3催化作用下的氮烷基化反应。研究表明该烷基化反应具有普遍的适用性,多数胺与甲醇、乙醇、正丁醇反应,具有较高的氮烷基化总产率。一些胺与醇反应产率甚至在99%以上。本文作了催化剂稳定性测试,并通过XRD和TEM对催化剂进行了表征,分析了催化剂失活的原因。研究表明,该催化剂具有很高的稳定性可保持高活性超过480 h,Lewis酸中心是氮烷基化反应的活性中心,随着反应进行,Lewis酸中心转化为Brφnested酸中心,致使催化剂活性降低。     

New ferrocenyl chiral auxiliary substituents for amines: applications to syntheses of mossambine and vinblastine

(+)-(R)-1,2-(alpha-(R)-Mesyloxy-beta-dimethyltetramethylene)-ferrocene was synthesized and used as a chiral auxiliary for N-alkylation of methyl 1,2,3,4,5,6-hexahydroazepino[4,5-b] indole-5-xi-carboxylates. Condensation with aldehydes then provided tetracyclic products in a diastereomeric ratio of at least 97:3. Gentle cleavage in acetic acid removed the chiral auxiliary to give the corresponding secondary amines in >99% ee. Thus, key intermediates leading to mossambine and vinblastine could be synthesized with high enantioselectivity. The enantioselectivity greatly exceeds that found with other chiral N-auxiliaries developed in our studies.     

Versatile approach to enantiopure 2,6-disubstituted piperidin-3-ol framework: application to the total synthesis of (+)-deoxoprosopinine

An efficient synthesis of enantiopure 2,6-disubstituted piperidin-3-ol 19 is developed featuring two key steps: (a). Julia olefination of (2R)-3-phenylsulfonyl-2-tert-butyloxycarbamoylpropanol benzyl ether 9B and (2R,3S)-2-tert-butyldiphenyl-3,4-O-isopropylidine-2,3,4-trihydroxybutyraldehyde 8 and (b). intramolecular N-alkylation. A straightforward asymmetric synthesis of (+)-deoxoprosopinine(2) from 19 is described demonstrating the versatility of this novel approach.     

Self-assembly of achiral and chiral macrocyclic ligands: synthesis,protonation constants,conformation and asymmetric catalysis

New 30-membered achiral and chiral polyaza macrocyclic ligands, L1 and L2 were synthesized directly from [3 + 3] condensation of phthalic dicarboxaldehyde with cis- and (1R,2R)-diaminocyclohexane, respectively. The trimeric macrocyclic structures were confirmed by electrospray ionization mass spectrometry (ESI-MS), 1H NMR, 13C NMR spectroscopy and elemental analysis. Potentiometry was used to determine the protonation constants of the ligands. UV-vis spectrophotometric titration was employed to investigate the coordination and conformational properties of the chiral ligand (L2). Direct enantioselective aldol reaction has been successfully performed using 4-nitrobenzaldehyde and acetone in the presence of the chiral macrocycle and its zinc(II) complexes as catalysts.     

Comparison of column performances in direct high-performance liquid chromatographic enantioseparation of 1- or 3-methyl-substituted tetrahydroisoquinoline analogs. Application of direct and indirect methods

The enantioseparability of 1- or 3-methyl-substituted tetrahydroisoquinolines was investigated by direct and indirect high-performance liquid chromatography. Alpha- and beta-cyclodextrin-, macrocyclic glycopeptide- and cellulose-based chiral columns and isothiocyanate- and Sanger-type chiral derivatizing agents (CDAs) were applied to attain satisfactory enantioseparation. Of the chiral columns, beta-cyclodextrin-, vancomycin- and teicoplanin-containing macrocyclic glycopeptide-based columns appeared to be most suitable; of the CDAs, (1S,2R)-1-acetoxy-1-phenyl-2-propyl isothiocyanate was most favorable. The differences between the selectivities of the columns and CDAs were compared and optimized to yield the best resolution.     

Gold-catalyzed reactions of 2-alkynyl-phenylamines with alpha,beta-enones

[reaction: see text] The gold-catalyzed reaction of 2-alkynyl-phenylamines with alpha,beta-enones represents a new general one-pot entry into C-3-alkyl-indoles by sequential reactions. Gold-catalyzed sequential cyclization/alkylation, N-alkylation/cyclization, or N-alkylation/cyclization/alkylation reactions leading to different indoles can be directed by changing the 2-alkynyl-phenylamine 1/alpha,beta-enone 3 ratio and the reaction temperature. Unusual gold-catalyzed rearrangement reaction of indoles are observed at 140 degrees C. New gold-catalyzed formation of propargyl-alkyl ether under mild conditions and the hydration reaction of N-acetyl-2-ethynyl-phenylamine are reported.