SYNTHESIS OF 1,4,7,10-TETRA-N-ALKYL-1,4,7,10-TETRAAZA-CYCLODODECANES

ABSTRACT

We report a concise method for the preparation of 1,4,7,10-tetra-N-alkyl-1,4,7,10-tetraaza-cyclododecanes via deprotonation to the fourfold lithium amide followed by alkylation with alkyl bromides. The procedure circumvents the problem of ammonium salt formation and provides direct access to hydrophobic 1,4,7,10-tetraaza-cyclododecanes in moderate yield. The so obtained hydrophobic macrocycles were converted into the corresponding zinc(II), copper(II), nickel(II) and cobalt(II) complexes, that may be used as water stable Lewis-acids in catalysis and anion extraction.     

Synthesis and Crystal Structure of 1,4,7,10-Tetrakis （2-（（4-hydroxy）phenoxy）ethyl）-1,4,7,10- tetraazacyclododecane

A novel molecule tetra-N-alkylation of cyclen （1,4,7,10-tetraazacyclododecane）, 1,4,7,10-tetrakis（2-（（4-hydroxy）phenoxy）ethyl）-1,4,7,10-tetraazacyclododecane 2, was synthesized and structurally characterized by single-crystal X-ray diffraction. The molecule turned into chiral helical compound crystals grown from EtOH by slow diffusion at room temperature and three of the four hydroquinone groups of the benzene ring formed a g-electron-rich cavity by C-H…π stacking interaction. The crystal belongs to the monoclinic system, space group P21/C with a = 13.9192（9）, b = 13.2871（6）, c = 22.1894（15）A^°, β = 91.4600（10）°, V = 4102.5（4）A^°3, Z = 4, Dc = 1.219 g/cm^3, C40H52N4O8, Mr = 752.89, F（000） = 1616,μ = 0.088 mm^-1, MoKa radiation （λ = 0.71073）, R = 0.0578 and wR = 0.1389 for 5588 observed reflections with I 〉 2σ（I）. Moreover, compound 2 was characterized with ^1H NMR, ^13C NMR, IR spectra and MS.     

Synthesis and acid-base and complex-forming properties of 1,4,7,10-tetrakis(dihydroxyphosphorylmethyl)-1,4,7,10-tetraazacyclododecane

Conclusions A new complexone, 1,4,7,10-tetrakis(dihydroxyphosphorylmethyl)-1,4,7,10-tetraazacyclododecane, has been synthesized and its acid-base and complex-forming properties have been studied. It shows a very high complexing capability and marked selectivity for cations of large ionic radius (Cd²⁺, Hg²⁺, Pb²⁺, La³⁺).Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 4, pp. 844–849, April, 1984.     

Synthesis of novel 1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid (DOTA) derivatives for chemoselective attachment to unprotected polyfunctionalized compounds

A convenient synthesis of novel bifunctional poly(amino carboxylate) chelating agents allowing chemoselective attachment to highly functionalized biomolecules is described. Based on the well known chelator 1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid (DOTA), we synthesized novel bifunctional chelating agents bearing additional functional groups by alkylating 1,4,7,10-tetraazacyclododecane (cyclen) with one equivalent of para-functionalized alkyl 2-bromophenyl-acetate and three equivalents of tert-butyl 2-bromoacetate. The resulting compounds, which contain an additional carbonyl or alkyne functionality, allow site specific labeling of appropriately functionalized unprotected biomolecules in a rapid manner via click reactions. This was demonstrated by the attachment of our new DOTA derivatives to the somatostatin analogue Tyr3-octreotate by chemoselective oxime ligation and CuI-catalyzed azide-alkyne cycloaddition. Initial biodistribution studies in mice with the radiometalated compound demonstrated the applicability of the described DOTA conjugation.     

Synthesis and Crystal Structure of 1,4,7,10-Tetrakis-（2-（2,3-difluorophenyl）-ethyl）-1,4,7,10-tetraazacyclododecane

The new compound 1,4,7,10-tetrakis-(2-(2,3-difluorophenyl) ethyl) -1,4,7,10-tetra-zacyclododecane 2 has been synthesized and structurally characterized by single-crystal X-ray diffraction. The molecule turned into diamond crystals grown from CH3CN by slow diffusion at room temperature. It crystallizes in the triclinic system,space group P1 with a = 9.543(2) ,b = 10.507(3) ,c = 10.734(3) ,α = 60.979(3) ,β = 81.870(4) ,γ = 84.279(4) o,V = 931.1(4) 3,Z = 1,Dc = 1.307 g/cm3,C40H44F8N4,Mr = 732.79,F(000) = 384,μ = 0.105 mm-1,T = 296(2) K,MoKa radiation(λ = 0.71073) ,R = 0.0494 and wR = 0.0989 for 1589 observed reflections with I > 2σ(I) . Hydrogen bonds and C-H···π stacking interactions in 2 contribute to a supramolecular structure. Moreover,compound 2 has been determined by 1H NMR,13C NMR,MS,IR spectra and elemental analysis.     

Chelators for radioimmunotherapy: I. NMR and ab initio calculation studies on 1,4,7,10-tetra(carboxyethyl)-1,4,7,10-tetraazacyclododecane (DO4Pr) and 1,4,7-tris(carboxymethyl)-10-(carboxyethyl)-1,4,7,10-tetraazacyclododecane (DO3A1Pr)

This work describes the modification of the chelating agent 1,4,7,10-tetraazacyclododecane-N,N',N' ',N' "-tetraacetic acid (DOTA) to improve the rate of metal loading for radioimmunotherapy applications. Previous ab initio calculations predicted that the compounds 1,4,7,10-tetra(carboxyethyl)-1,4,7,10-tetraazacyclododecane (DO4Pr) and 1,4,7-tris(carboxymethyl)-10-(carboxyethyl)-1,4,7,10-tetraazacyclododecane (DO3A1Pr) have a ca. 2000-fold improvement in yttrium metal loading rates compared to those of DOTA (Jang, Y. H.; Blanco, M.; Dasgupta, S.; Keire, D. A.; Shively, J. E.; Goddard, W. A., III. J. Am. Chem. Soc. 1999, 121, 6142-6151). In this study, we report the synthesis, purification, (1)H-NMR chemical shift assignments, pK(a) values, metal loading rate measurements, and additional ab initio calculations of these two compounds. The yttrium loading rates of DO3A1Pr are approximately twice those of DOTA, at pH 4.6 and 37 degrees C. The NMR data indicates that the DO4Pr analogue forms a stable type I complex but does not form a type II complex. The new ab initio calculations performed on DO4Pr and DO3A1Pr indicate that the rate-determining step is the deprotonation of the first macrocycle amine proton, not the second proton as assumed in the previous calculations. The new calculations predict an improvement in the rate of metal loading that more closely matches the experimentally observed change in the rate.     

Über Reaktionen Oxygenierter Kobalt (II)-Komplexe. X. 1,4,7,10-Tetraazadecan-kobalt (II) und 4, 7-dimethyl-1,4,7,10-tetraazadecan-kobalt (II) als sauerstoffträger

Reactions of oxygenated cobalt (II) complexes. X. 1,4,7,10-tetraazadecanecobalt (II) and 4,7-dimethyl-1,4,7,10-tetraazadecanecobalt (II) as dioxygen carriers

1 IX: siehe [1].

Oxygenation of cobalt (II) chelates with fourdentate amines such as 1,4,7,10-tetraazadecane (= tad) in aqueous solution yields μ-peroxo-μ-hydroxo-dicobalt (III) complexes. Due to facultative ligand disposition of the amine, 8 different diastereoisomers are possible. Introducing methyl groups in positions 4 and 7 of tad destabilizes the isomers with β-configuration. A crystallized perchlorate, obtained by oxygenation of 4, 7-dimethyl-1,4,7,10-tetraazadecanecobalt (II) (= dmtad) in alcaline solution, proved to be of the expected μ-peroxo-μ-hydroxo type. The ligand configuration is and lattice constants a (ΔΔ/ΛΛ). The X-ray structure was solved by Patterson's method and refined to R = 0.093. The crystals are orthorhombic with space group Pna2₁ and lattice constants a = 14.632 (4), b = 17.525 (5), c = 12.888 (5) Å. In its UV./VIS. absorption spectrum and its solution reactivity the binuclear cation is closely related to oxygenation products obtained with the chelate of unsubstituted tad. The kinetic parameters of the decomposition reaction of the μ-peroxo complexes in acidic solution are compared. The binuclear cations with 4, 7-dimethyl-1,4,7,10-tetraazadecane as ligand are generally more reactive. In slightly alcaline solution isomerization of the μ-peroxo-μ-hydroxo complexes has been observed.     

A new tetraazamacrocycle functionalized with pendant pyridyl groups: synthesis and crystal structure of a copper(II) complex of 1,4,7,10-tetrakis(2-pyridylmethyl)-1,4,7,10-tetraazacyclododecane (L), [CuL]·(ClO4)2

The [CuL](ClO4)2 complex, L=1,4,7,10-tetrakis- (2-pyridylmethyl)-1,4,7,10-tetraazacyclododecane, was prepared in EtOH and characterized. The crystal structure of the complex was determined by single-crystal X-ray analysis. The coordination geometry about the copper ion can be described as a strongly distorted octahedron, with CuN distances ranging from 2.01(1)–2.82(1)AÅ.     

On the Synthesis of 1,4,7-Tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane

1,4,7-Tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane is widely used as an intermediate in the preparation of medically important DO3A and DOTA metal chelators. Despite its commercial availability and importance, the literature describing the preparation and properties of the free base is limited and sometimes unclear. We present herein an efficient synthesis of the hydrobromide salt of 1,4,7-tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane, characterize this compound spectroscopically and by X-ray crystallographic analysis, describe its simple conversion to the corresponding free base, characterize this compound spectroscopically and by X-ray crystallographic analysis, and make observations on the reactivity of this interesting and useful compound.     

Rapid synthesis of 1,7-bis(t-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (DO2A-t-Bu ester)

A three-step route was used to synthesize 1,7-bis(t-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (DO2A-t-Bu ester) from 1,4,7,10-tetraazacyclododecane (cyclen). The overall time of reaction was reduced from a combined ∼56 h to 2.3 h with an overall yield comparable to previously reported methods.     

(1,4,7,10-Tetraazacyclododecane) (diamine or alanine)-Cobalt(III) complexes

(1,4,7,10-Tetraazacyclododecane) [diamine or (S)-alanine]-cobalt(III) complexes [diamine = ethylenediamine, 2-(aminomethyl)pyridine, (R)-1,2-propanediamine, (R,R)-1,2-diaminocyclohexane, trimethylenediamine and 2-methyl-1,3-diaminopropane] are prepared and characterized spectroscopically. The ligand field transitions occur at lower energies than those of the corresponding tetraamine analogues. Severe distortions caused by the too small size of the cyclic ligand are one of the origins. The distortions also exert influence upon circular dichroism spectra.     

SYNTHESIS OF NEW CRYPTANDS STARTING FROM TRANS (DIPROTECTED AND DISUBSTITUTED) 1,4,7,10-TETRAAZACYCLODODECANE

ABSTRACT

New cryptands are synthesised by aminolysis between 1,7-di(ethylacetate)-4,10-di(tosyl)-1,4,7,10-tetraazacyclododecane and various diamines.     

Improved Synthesis of 10-(2-Alkylamino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic Acid Derivatives Bearing Acid-Sensitive Linkers

Alkylation of the hydrobromide salts of 1,4,7-tris(methoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane and 1,4,7-tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane with appropriate α-bromoacetamides, followed by hydrolysis, provides convenient access to 10-(2-alkylamino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid derivatives that contain acid-sensitive functional groups. The utility of the method is demonstrated by improved syntheses of two known 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid monoamides bearing acid-sensitive ω-tritylthio alkyl chains in much greater yields based on cyclen as the starting material.

[Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.]     

Cyclododecatetraene tetraepoxide: highly diastereofacial epoxidation of all-(Z)-1,4,7,10-cyclododecatetraene and selective synthesis of bridged bis-oxocanes

Epoxidation of all-(Z)-1,4,7,10-cyclododecatetraene has been investigated with use of m-CPBA and dimethyldioxirane in anhydrous solvent. The diastereoselectivity of multiple epoxidation steps is complete affording only exo,exo,exo,endo-1,4,7,10-tetraepoxide. To understand this result, the step-by-step epoxidation reaction was investigated and each step was found to be highly regio- and stereoselective. Finally, a Lewis acid-catalyzed ethanolysis or treatment with HBr/KBr of the tetraepoxide gave rearranged diepoxy-oxabicyclo[5.5.1]tridecane (bridged bis-oxocanes) in which eight stereocenters were controlled.     

A new zinc(II) fluorophore 2-(9-anthrylmethylamino)ethyl-appended 1,4,7,10-tetraazacyclododecane

A new 2-(9-anthrylmethylamino)ethyl-appended cyclen, L(3) (1-(2-(9-anthrylmethylamino)ethyl)-1,4,7,10-tetraazacyclododecane) (cyclen = 1,4,7,10-tetraazacyclododecane), was synthesized and characterized for a new Zn(2+) chelation-enhanced fluorophore, in comparison with previously reported 9-anthrylmethylcyclen L(1) (1-(9-anthrylmethyl)-1,4,7,10-tetraazacyclododecane) and dansylamide cyclen L(2). L(3) showed protonation constants log K(a)(i)() of 10.57 +/- 0.02, 9.10 +/- 0.02, 7.15 +/- 0.02, <2, and <2. The log K(a3) value of 7.15 was assigned to the pendant 2-(9-anthrylmethylamino)ethyl on the basis of the pH-dependent (1)H NMR and fluorescence spectroscopic measurements. The potentiometric pH titration study indicated extremely stable 1:1 Zn(2+)-L(3) complexation with a stability constant log K(s)(ZnL(3)) (where K(s)(ZnL(3)) = [ZnL(3)]/[Zn(2+)][L(3)] (M(-)(1))) of 17.6 at 25 degrees C with I = 0.1 (NaNO(3)), which is translated into the much smaller apparent dissociation constant K(d) (=[Zn(2+)](free)[L(3)](free)/[ZnL(3)]) of 2 x 10(-)(11) M with respect to 5 x 10(-)(8) M for L(1) at pH 7.4. The quantum yield (Phi = 0.14) in the fluorescent emission of L(3) increased to Phi = 0.44 upon complexation with zinc(II) ion at pH 7.4 (excitation at 368 nm). The fluorescence of 5 microM L(3) at pH 7.4 linearly increased with a 0.1-5 microM concentration of zinc(II). By comparison, the fluorescent emission of the free ligand L(1) decreased upon binding to Zn(2+) (from Phi = 0.27 to Phi = 0.19) at pH 7.4 (excitation at 368 nm). The Zn(2+) complexation with L(3) occurred more rapidly (the second-order rate constant k(2) is 4.6 x 10(2) M(-)(1) s(-)(1)) at pH 7.4 than that with L(1) (k(2) = 5.6 x 10 M(-)(1) s(-)(1)) and L(2) (k(2) = 1.4 x 10(2) M(-)(1) s(-)(1)). With an additionally inserted ethylamine in the pendant group, the macrocyclic ligand L(3) is a more effective and practical zinc(II) fluorophore than L(1).     

1，4，7，10－四氮杂环十三烷的改良合成

报道了用１，３－丙二醇二对甲苯磺酸酯和Ｎ，Ｎ′，Ｎ″，Ｎ－四（对甲苯磺酰基）三乙撑四胺经环化、硫酸水解等步骤合成１，４，７，１０－四氮杂环十三烷的新途径     

Metal ion-dependent molecular inclusion chemistry: inclusion of aromatic anions by coordinated 1,4,7,10-tetrakis((S)-2-hydroxy-3-phenoxypropyl)-1,4,7,10-tetraazacyclododecane

The ability of the pendant donor macrocyclic ligand 1,4,7,10-tetrakis((S)-2-hydroxy-3-phenoxypropyl)-1,4,7,10-tetraaza- cyclododecane((S)-thphpc12) (or [Cd((S)-thphpc12)](2+)) to act as a metal ion-dependent receptor for aromatic anions has been investigated in solution and in the solid state. [Cd((S)-thphpc12)](2+) adopts a stable conical conformation with a large hydrophobic cavity, which has been shown to contain, via complementary multiple hydrogen bonding, p-nitrophenolate, aromatic carboxylates, p-toluenesulfonate, certain aromatic amino acid anions, phenoxyacetate, and acetate. In the case of p-nitrophenolate only, one or two anions can be contained within the receptor cavity. The crystal structure of [Cd((S)-thphpc12)(p-nitrophenolate)(2)] shows a coplanar arrangement of the p-nitrophenolates, where each is retained in the cavity by a pair of hydrogen bonds to cis hydroxyl groups. The crystal structure of the p-aminobenzoate inclusion complex indicates retention of the guest via a pair of hydrogen bonds to each oxygen atom of the carboxylate moiety. The crystal structure of the (L)-phenylalaninate inclusion complex indicates that the amino acid is retained by five hydrogen bonds, two involving the nitrogen atom and three to the oxygen atoms of the carboxylate moiety. Binding constants (10(3)-10(5) M(-1)) for the inclusion of some of the aforementioned anions in [Cd((S)-thphpc12)](2+) and related receptors were measured by (1)H NMR titration in DMSO-d(6) at 298 K.     

微波辐射技术在1,4,7,10-四氮杂环十二烷四乙酸合成中的应用

应用微波技术合成了1,4,7,10-四氮杂环十二烷四乙酸的关键中间体———1,4,7,10-四氮杂环十二烷盐酸盐。与传统的实验方法相比,该方法反应时间缩短了4 000倍且收率从70%增至88%。     

Density-functional theory structures of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid complexes for ions across the lanthanide series

The use of organically chelated lanthanides in diagnosis and treatment is a rapidly growing field in medicine. In order to gain a deeper understanding into the properties of these chelates, particularly spectroscopic, density-functional calculations have been performed on a series of lanthanide ions chelated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid. Based on the results of these calculations, it has been concluded that the local symmetry experienced by the chelated lanthanide ion may be treated as being axial, which will make the interpretation of their spectroscopic properties greatly simplified. It has also been suggested that the so-called "capping" water molecule at the ninth coordination position of the lanthanide is hydrogen bonded to the acetate oxygens of the sidearms, rather than coordinated as the ninth ligand of the lanthanide.     

Synthesis,structure and antitumor activities of a new macrocyclic ligand with four neutral pendent groups: 1,4,7,10-tetrakisbenzyl-1,4,7,10-tetraazacyclododecane (L) and its Co,Ni and Cu complexes

A new macrocyclic ligand, 1,4,7,10-tetrakisbenzyl-1,4,7,10-tetraazacyclododecane (L) and its three new divalent metal complexes of general formula: M(NO₃)₂(L)nH2O [M = Co(1), Ni(2), n = 0; M = Cu(3), n = 1.5] have been synthesized and characterized by elemental analysis, i.r., EI mass spectra and molecular conductance. Complex (2) has been characterized by X-ray diffraction. In complex (2), the central Ni^II atom coordinatively bonds to four nitrogen atoms of the macrocyclic ligand and two oxygen atoms of nitrate anion, to form a distorted octahedron. X-ray diffraction indicated that the bonds Ni–N(1), Ni–N(2), Ni–N(3) and Ni–N(4) are of almost equal length, i.e. 2.11(1), 2.12(1), 2.10(1) and 2.17(1)Å, respectively. Bond lengths of Ni–O(1) and Ni– O(2) are 2.11(1) and 2.10(1)Å. Preliminary pharmacological tests show that these complexes have high antitumor activity towards HL-60 tumor cell lines.