Squaramide Moiety Research Articles

Amino acid-based squaramides for anion recognition

Eight receptors 1–8 comprising an l-lysine scaffold modified at N- and C-termini with aliphatic alkyl chains and N,N′-alkyl amides, respectively, and bearing squaramide moieties on the amino acid side chain were synthesised by a combination of solid- and solution-phase chemistries and shown to complex various anions in 0.5% H2O in dimethyl sulfoxide-d6 solution. All of the receptors were found to bind Cl− , AcO− and BzO− via hydrogen-bond or acid–base interactions with the squaramide protons; however, 1 was found to bind to via hydrogen bonds formed between the anion and both the squaramide and amide NH moieties. Moreover, modification of both the N- and C-termini of the amino acids with different alkyl substituents had a negligible effect on their anion-binding properties while simultaneously conferring lipophilicities in a range that is optimal for molecules to behave as ‘drug-like’ systems as defined by Lipinski's rule of five. The results of this study demonstrate the versatility of such amino acid receptors as building blocks in the field of anion recognition.

Allosteric regulation of supramolecular oligomerization and catalytic activity via coordination-based control of competitive hydrogen-bonding events.

Herein, we demonstrate that the activity of a hydrogen-bond-donating (HBD) catalyst embedded within a coordination framework can be allosterically regulated in situ by controlling oligomerization via simple changes in coordination chemistry at distal Pt(II) nodes. Using the halide-induced ligand rearrangement reaction (HILR), a heteroligated Pt(II) triple-decker complex, which contains a catalytically active diphenylene squaramide moiety and two hydrogen-bond-accepting (HBA) ester moieties, was synthesized. The HBD and HBA moieties were functionalized with hemilabile ligands of differing chelating strengths, allowing one to assemble them around Pt(II) nodes in a heteroligated fashion. Due to the hemilabile nature of the ligands, the resulting complex can be interconverted between a flexible, semiopen state and a rigid, fully closed state in situ and reversibly. FT-IR spectroscopy, (1)H DOSY, and (1)H NMR spectroscopy titration studies were used to demonstrate that, in the semiopen state, intermolecular hydrogen-bonding between the HBD and HBA moieties drives oligomerization of the complex and prevents substrate recognition by the catalyst. In the rigid, fully closed state, these interactions are prevented by steric and geometric constraints. Thus, the diphenylene squaramide moiety is able to catalyze a Friedel-Crafts reaction in the fully closed state, while the semiopen state shows no reactivity. This work demonstrates that controlling catalytic activity by regulating aggregation through supramolecular conformational changes, a common approach in Nature, can be applied to man-made catalytic frameworks that are relevant to materials synthesis, as well as the detection and amplification of small molecules.

Anion-Induced Dimerization in p-Squaramidocalix[4]arene Derivatives

Spherical anions induce the dimerization of calix[4]arene derivatives 3 and 4 bearing squaramide moieties at the exo rim (p-squaramidocalixarenes). (1)H NMR titration experiments showed that unlike the distal isomer 3, proximal p-squaramidocalixarene 4 is also able to form dimeric complexes with trigonal-planar anions.

Bifuctional Amino-Squaramides Catalyzed Asymmetric Spiroannulation Cascades with Aliphatic β,γ-Unsaturated α-Keto Esters: Controlling an Aldehyde Enolate

A quinidine-derived squaramide Ib catalyzed cyclization reaction of β-oxo aldehydes 1 and aliphatic or aromatic β,γ-unsaturated α-keto ester 2 is described. Using cyclic aldehyde substrates, this procedure provided a promising approach to a variety of spiro-3,4-dihydropyrans bearing three continuous quaternary and tertiary stereocenters in moderate to good yield with high stereoselectivities. Substituents on the nitrogen atoms of the squaramide moiety of the catalyst proved crucial to the reaction outcome. The stereochemistry of the three newly formed chiral centers (trans-selective) of the major product indicates a Micheal addition/hemiacetalization domino sequence for the present annulations.

A Macrocyclic Ligand as Receptor and ZnII‐Complex Receptor for Anions in Water: Binding Properties and Crystal Structures

Binding properties of 24,29-dimethyl-6,7,15,16-tetraoxotetracyclo[19.5.5.0(5,8).0(14,17)]-1,4,9,13,18,21,24,29-octaazaenatriaconta-Δ(5,8),Δ(14,17)-diene ligand L towards Zn(II) and anions, such as the halide series and inorganic oxoanions (phosphate (Pi), sulfate, pyrophosphate (PPi), and others), were investigated in aqueous solution; in addition, the Zn(II)/L system was tested as a metal-ion-based receptor for the halide series. Ligand L is a cryptand receptor incorporating two squaramide functions in an over-structured chain that connects two opposite nitrogen atoms of the Me(2)[12]aneN(4) polyaza macrocyclic base. It binds Zn(II) to form mononuclear species in which the metal ion, coordinated by the Me(2)[12]aneN(4) moiety, lodges inside the three-dimensional cavity. Zn(II)-containing species are able to bind chloride and fluoride at the physiologically important pH value of 7.4; the anion is coordinated to the metal center but the squaramide units play the key role in stabilizing the anion through a hydrogen-bonding network; two crystal structures reported here clearly show this aspect. Free L is able to bind fluoride, chloride, bromide, sulfate, Pi, and PPi in aqueous solution. The halides are bound at acidic pH, whereas the oxoanions are bound in a wide range of pH values ranging from acidic to basic. The cryptand cavity, abundant in hydrogen-bonding sites at all pH values, allows excellent selectivity towards Pi to be achieved mainly at physiological pH 7.4. By joining amine and squaramide moieties and using this preorganized topology, it was possible, with preservation of the solubility of the receptor, to achieve a very wide pH range in which oxoanions can be bound. The good selectivity towards Pi allows its discrimination in a manner not easily obtainable with nonmetallic systems in aqueous environment.

A New Macrocyclic Cryptand with Squaramide Moieties: An Overstructured CuII Complex That Selectively Binds Halides: Synthesis, Acid/Base‐ and Ligational Behavior, and Crystal Structures

The synthesis and characterization of the novel 24,29-dimethyl-6,7,15,16-tetraoxotetracyclo-[19.5.5.0(5,8).0(14,17)]-1,4,9,13,18,21,24,29-octaazaenatriaconta-Delta(5,8),Delta(14,17)-diene (L) are reported. Molecule L incorporates two squaramide functions in a overstructured chain connecting two opposite nitrogen atoms of the Me(2)[12]aneN(4) polyaza macrocyclic base to obtain a cage topology. The basicity and binding properties of L towards Cu(II) were determined by means of potentiometric measurements in aqueous solution (298.1+/-0.1 K, I=0.15 mol dm(-3)). Molecule L behaves as a diprotic base under the experimental conditions employed and forms only mononuclear Cu(II) complexes in which the squaramide moieties are not involved in the stabilization of the metal ion that is stabilized by the amine functions of the polyaza base inside the three-dimensional cavity. The [CuL](2+) species was tested as a host for the series of halide anions. UV-visible spectrophotometric experiments permitted the determination of the addition constants of halides to the Cu(II)-complexed species. The [CuL](2+) species binds the anions F(-), Cl(-), and Br(-) by forming the [CuLX](+) species, but does not bind the biggest I(-) anion. A trend of selectivity as a function of the hydrogen-bonding capability as well as the dimensions of the anion were established; the maximum value of selectivity was for addition of the F(-) anion (log K=4.8). This selectivity is due to the presence of the overstructured chain containing the squaramide groups up to the Me(2)[12]aneN(4) macrocyclic base. The squaramide groups, by providing hydrogen-bond contacts, permit the [CuL](2+) species to selectively bind these anions through the formation of a hydrogen-bond network with F(-) and Cl(-). The crystal structures of the [CuLF](+) and [CuLCl](+) cations support the results obtained in aqueous solution.

Cover Picture: Synthesis and Properties of New Nucleotide Analogues Possessing Squaramide Moieties as New Phosphate Isosters (Eur. J. Org. Chem. 24/2005)

AbstractThe cover picture shows the electrostatic potential maps of methyl phosphate and N‐methylsquaramide. Various analogs of nucleotides and cyclic nucleotides were synthesized by use of the squaramide moiety as an isoelectronic mimic of the phosphate group. Details are discussed in the article by M. Sekine et al. on p. 5163 ff.

Synthesis and Properties of New Nucleotide Analogues Possessing Squaramide Moieties as New Phosphate Isosters

AbstractNew analogues of 2′‐deoxynucleotides and ribonucleotides incorporating a unique squaramide structure were synthesized. Because of the strong acidity of this moiety (pKa = 2.3), these nucleotide analogues exist in a monoanionic form, which can be regarded as an electronic isoster of 5′‐nucleotides under physiological conditions. The synthesis of the nucleotide analogues was achieved through the condensation of 5′‐ or 3′‐aminonucleosides with dimethyl squarate, whilst the selective removal of the methyl group was effectively accomplished by treatment with sodium bromide. In addition, we also synthesized 3′,5′‐cyclic nucleotide analogues from the 3′,5′‐diazidonucleoside derivatives. NMR analysis revealed that their ribose puckering was of an N‐type form, identical to that in cAMP and cGMP. Because of the unique structural, electronic, and conformational properties of squaramide‐type nucleotide analogues, these analogues should be quite interesting as potential biologically active compounds such as antiviral and anticancer agents. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)