Bicyclic Guanidinium Research Articles

Crystal structures of sulfonamide protected bicyclic guanidines: (S)-8-{[(tert-butyl-dimethyl-sil-yl)-oxy]meth-yl}-1-[(2,2,4,6,7-penta-methyl-2,3-di-hydro-benzo-furan-5-yl)sulfon-yl]-1,3,4,6,7,8-hexa-hydro-2H-pyrimido[1,2-a]pyrimidin-1-ium tri-fluoro-methane-sulfonate and (S)-8-(iodo-meth-yl)-1-tosyl-1,3,4,6,7,8-hexa-hydro-2H-pyrimido[1,2-a]pyrimidin-1-ium iodide.

Two compounds, (S)-8-{[(tert-butyl-dimethyl-sil-yl)-oxy]meth-yl}-1-[(2,2,4,6,7-penta-methyl-2,3-di-hydro-benzo-furan-5-yl)sulfon-yl]-1,3,4,6,7,8-hexa-hydro-2H-pyrimido[1,2-a]pyrimidin-1-ium tri-fluoro-methane-sulfonate, C27H46N3O4SSi+·CF3O3S-, (1) and (S)-8-(iodo-meth-yl)-1-tosyl-1,3,4,6,7,8-hexa-hydro-2H-pyrimido[1,2-a]pyrimidin-1-ium iodide, C15H21IN3O2S+·I-, (2), have been synthesized and characterized. They are bicyclic guanidinium salts and were synthesized from N-(tert-but-oxy-carbon-yl)-l-me-thio-nine (Boc-l-Met-OH). The guanidine is protected by a 2,2,4,6,7-penta-methyl-dihydro-benzo-furan-5-sulfonyl (Pbf, 1) or a tosyl (2) group. In the crystals of both compounds, the guanidinium group is almost planar and the N-H forms an intra-molecular hydrogen bond in a six-membered ring to the oxygen atom of the sulfonamide protecting group.

Structures of N-Hydroxy-Type Tetrodotoxin Analogues and Bicyclic Guanidinium Compounds Found in Toxic Newts.

The biosynthesis of tetrodotoxin (TTX, 1), a potent neurotoxin widely distributed in marine and terrestrial metazoans, remains unresolved. A significant issue has been identifying intermediates and shunt products associated with the biosynthetic pathway of TTX. We investigated TTX biosynthesis by screening and identifying new TTX-related compounds from Cynops ensicauda popei and Taricha granulosa. Mass spectrometry (MS)-guided screening identified two new N-hydroxy TTX analogues in newts: 1-hydroxy-8-epiTTX (2) and 1-hydroxy-8-epi-5,11-dideoxyTTX (3, previously reported as 1-hydroxy-5,11-dideoxyTTX). We prepared a new analogue, 8-epi-5,11-dideoxyTTX (4), from 3 via N-OH reduction and confirmed the presence of 4 in T. granulosa using hydrophilic interaction liquid chromatography (HILIC)-LCMS. The presence of 8-epi-type TTX analogues in both Cynops and Taricha supports a branched biosynthetic pathway of terrestrial TTX, which produces 6- and 8-epimers. In addition, new bicyclic guanidinium compounds Tgr-238 (5) and Tgr-240 (6) were identified as putative shunt products of our proposed TTX biosynthesis pathway. A structural analysis of Cep-228A (7), another bicyclic compound, was performed using NMR. Based on the structures of 5-7 and their analogues, we propose a model of the shunt and metabolic pathways of the terrestrial TTX biosynthesis.

Synthesis of Chiral Bicyclic Guanidinium Salts using Di(imidazole-1-yl)methanimine.

A detailed account of the synthesis of chiral bicyclic guanidinium salts is presented. This work represents the first systematic investigation of an approach toward the challenging target molecules via a key guanylation step employing di(imidazole-1-yl)methanimine (6) followed by a two-fold cyclization, which resulted in guanidinium salts 8 and 10. Factors governing the regioselectivity of the final cyclization step are discussed based on further data obtained in the course of the attempted syntheses of two additional bicyclic guanidinium salts.

ChemInform Abstract: Bicyclic Guanidinium‐Catalyzed Enantioselective Phase‐Transfer Alkylation: Direct Access to Pyrroloindolines and Furoindolines.

AbstractThe combination of a chiral bicyclic guanidinium salt and zinc iodide is an efficient catalytic system for the enantioselective alkylation of oxindoles (I) and (XI).

Asymmetric Michael Addition Using Bifunctional Bicyclic Guanidine Organocatalyst: A Theoretical Perspective

To illustrate the general principle of asymmetric organocatalysis of chiral bicyclic guanidine, a density functional theory study was carried out to examine the catalytic mechanism, activation mode, origin of stereoselectivity of a [5,5]-bicyclic guanidine-catalyzed Michael addition of dimethyl malonate to 2-cyclopenten-1-one. Two types of bifunctional activation modes were examined: Brønsted acid and Brønsted-Lewis acid. The calculated enantioselectivity (ee), based on eight C–C bond forming transition states and their pre-transition state complexes, is in excellent accord with experimental result. The ternary pre-transition state complexes are stable species, which strongly influence the stereoselectivity. Similar to enzyme catalysis, the bicyclic guanidinium catalyst plays an essential recognition role in assembling the substrates together via hydrogen bonds, multiple C–H···O interactions (as oxyanion hole), donor–acceptor, and electrostatic interactions.

Bicyclic guanidinium-catalyzed enantioselective phase-transfer alkylation: direct access to pyrroloindolines and furoindolines

Highly enantioselective phase-transfer alkylation of 3-substituted-2-oxindoles with activated bromomethanes is disclosed with a broad substrate scope by using bicyclic guanidinium as a catalyst and a Lewis acid as the co-catalyst. The alkylation adducts are versatile intermediates to accomplish the syntheses of pyrroloindolines and furoindolines.

Physicochemical properties and activity coefficients at infinite dilution for organic solutes and water in a novel bicyclic guanidinium superbase-derived protic ionic liquid

The activity coefficient at infinite dilution, γ13∞, was determined by gas–liquid chromatography at temperatures from T=308.15 to T=348.15K for 54 assorted solutes—among them, alkanes (linear, branched, or cyclic), alkenes, alkynes, aromatic hydrocarbons, alcohols, water, thiophene, tetrahydrofuran, 1,4-dioxane, ethers, acetone, ketones, acetonitrile, pyridine, and 1-nitropropane—in the novel bicyclic guanidine superbase-derived protic ionic liquid 1,3,4,6,7,8-hexahydro-1-methyl-2H-pyrimido[1,2-a]pyrimidine bis(pentafluoroethyl)sulfonylimide, [MTBDH][BETI]. The partial molar excess Gibbs free energy ΔG1E,∞, the partial molar excess enthalpy ΔH1E,∞, and entropy at reference temperature TrefΔS1E,∞ at infinite dilution were calculated from the experimental γ13∞ values obtained over this temperature range. The gas–liquid partition coefficient, KL, was calculated for each solute and discussed in light of the Abraham solvation parameter model. The density of the IL as a function of temperature was also measured. The selectivities for heptane/benzene, heptane/thiophene, heptane/pyridine, and heptane/nitropropane separation problems were calculated from γ13∞ and compared to literature values for select ILs, as these separation problems are central to the petroleum industry.

Non-peptidic cell-penetrating agents: synthesis of oligomeric chiral bicyclic guanidinium vectors

Polycationic oligo(chiral bicyclic guanidines) constitute useful non-peptidic penetrating agents for cell uptake and protein surface recognition. We report herein improved and selective procedures for the preparation of oligoguanidinium scaffolds linked through thioether bonds, with similar or different groups and functions at both ends of the chain. Two synthetic strategies were developed to obtain these compounds in relatively good yields from a common thioacetate precursor: generation of a disulfide intermediate or thiolate formation. Thus, tetraguanidinium intermediates 8 and 22 are best synthesized by the disulfide route, whereas hexamer 29, octamer 31, and trimer 37 arise from a combination of both the disulfide and the thioacetate routes. Finally, tetramer 28 can be readily obtained from either strategy.

A stereocontrolled synthesis of (+)-saxitoxin.

A concise stereoselective total synthesis of (+)-saxitoxin is described. A silver(I)-initiated hydroamination cascade constructs the bicyclic guanidinium ion core from a alkynyl bisguanidine. This sequence creates two C-N bonds, one C-O bond, and three rings and forms a single stereoisomer in a single synthetic transformation. This process enabled us to complete the synthesis of (+)-saxitoxin in 14 steps from N-Boc-l-serine methyl ester.

Nitroguanidine‐Fused Bicyclic Guanidinium Salts: A Family of High‐Density Energetic Materials

A series of nitroguanidine-fused bicyclic guanidinium energetic salts paired with inorganic energetic anions, mono- and di-tetrazolate anions were synthesized through simple metathesis reactions of 2-iminium-5-nitriminooctahydroimidazo[4,5-d]imidazole chloride and sulfate with the corresponding silver and barium salts, respectively, in aqueous solution. Key physical properties, such as melting point, thermal stability, and density were measured. The relationship between the structures of the salts and these properties was determined. The salts exhibit thermal stability and density (>1.60 g cm(-3)) that are comparable to currently used explosives The structures of the nitrate salt 1 and the dinitrocyanomethanide salt 4 were confirmed by single-crystal X-ray analysis. Densities, heats of formation, detonation pressures and velocities, and specific impulses were calculated. All of the salts possess positive calculated heats of formation and most of them exhibit promising energetic performance that is comparable with those of 1,3,5-trinitrobenzene (TNT), 1,3,5-triamino-2,4,6-trinitrobenzene (TATB), and cyclotrimethylenetrinitramine (RDX). The effect of the fused bicycle 2-iminium-5-nitriminooctahydroimidazo[4,5-d]imidazole on these physicochemical properties was examined and discussed.

Solid-Phase Synthesis of Chiral Bicyclic Guanidinium Oligomers

A simple solid-phase synthesis of thioether-linked chiral bicyclic guanidinium oligomers for cell internalization purposes has been developed. The approach is based on a Merrifield-like peptide synthesis on Rinkamide-p-methylbenzhydrylamine resin functionalized with Cys(methoxytrityl). A difunctionalized bicyclic guanidinium synthon, bearing both electrophile (O-mesyl) and protected nucleophile (S-methoxytrityl) group, is repeatedly grafted via a nucleophilic substitution. The sequence requires removal of methoxytrityl, reduction with 1,4-dithiothreitol to cleave any adventitious disulfides, coupling and capping with benzyl bromide. Moreover, Alloc protection of the alpha-amino group of the initial cysteine, provides a potential handle for cargo attachment after oligomer elongation to the desired internalizing agent and prior to cleaving it from the resin. Finally, a bicyclic guanidinium monomer containing an amino group and a carboxylic acid function has been evaluated as an alternative building block for novel amide-bridged oligomers or peptidomimetics.

Selective formation of bicyclic guanidinium chloride complexes: implication of the bifunctionality of guanidines

Two bicyclic guanidinium chloride structures in the anhydrous and the monohydrated forms were selectively synthesized and characterized, demonstrating the versatile bifunctionality of guanidine molecules.

Bicyclic Guanidinium Tetraphenylborate: A Photobase Generator and A Photocatalyst for Living Anionic Ring-Opening Polymerization and Cross-Linking of Polymeric Materials Containing Ester and Hydroxy Groups

1,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD) with pKa of 26.03 in acetonitrile can be effectively released by photolysis of TBD.HBPh4 salt, which represents a new family of short-wave UV photobase generators. This photobase generator enables the photoinduced living ring-opening polymerization of cyclic esters and the photoinduced cross-linking of various polymeric materials containing the hydroxyl-ester groups.

Addressing Association Entropy by Reconstructing Guanidinium Anchor Groups for Anion Binding: Design, Synthesis, and Host–Guest Binding Studies in Polar and Protic Solutions

The bicyclic hexahydropyrimidino[1,2a]pyrimidine cationic scaffold has a well-known capacity to bind a variety of oxoanions (phosphates, carboxylates, squarates, phosphinates). Based on this feature, the parent host was supplemented with sec-carboxamido substituents to generate compounds 1-3 in an effort to improve the anion-binding affinity and selectivity and to learn about the role and magnitude of entropic factors. Bicyclic guanidinium compounds were prepared by a convergent strategy via the corresponding tetraester 22 followed by catalytic amidation. Host-guest binding studies with isothermal titration calorimetry in acetonitrile probed the behavior of artificial hosts 1-3 in comparison with the tetraallylguanidinium compound 4 on binding p-nitrobenzoate, dihydrogenphosphate, and 2,2'-bisphenolcyclophosphate guests that showed enhanced affinities in the 10(5)-10(6) M(-1) range. Contrary to expectation, better binding emerges from more positive association entropies rather than from stronger enthalpic interactions (hydrogen bonding). In an NMR spectroscopy titration in DMSO, o-phthalate was sufficiently basic to abstract a proton from the guanidinium function, as confirmed by an X-ray crystal structure of the product. The novel carboxamide-appended anchor groups also bind carboxylates and phosphates, but not hydrogen sulfate in methanol with affinities in excess of 10(4) M(-1). The energetic signature of the complexation in methanol is inverted with respect to acetonitrile solvent and shows a pattern of general ion pairing with strong positive entropies overcompensating endothermic binding enthalpies. This study provides an example of the fact that bona fide decoration of a parent guanidinium anchor function with an additional binding functionality may provide the desired enhancement of the host-guest affinity, yet for a different reason than that implemented by design as guided by standard molecular modeling.

A strategy for the propagation of hydrogen-bonding in bicyclic guanidinium salts

Protonation of the {6,6}- and {5,5}-bicyclic guanidines 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine (hppH) and 1,4,6-triazabicyclo[3.3.0]oct-4-ene (Htbo), respectively, to afford the hydrochloride salts [hppH2][Cl] (1a) and [HtboH][Cl] (2) was achieved using [NEt3H][Cl]. Anion exchange involving 1a and NaBPh4 generated the borate salt [hppH2][BPh4] (1c). Crystal structure analysis of 1a and the analogous hydrobromide salt [hppH2][Br] (1b) showed two NH⋯X hydrogen-bonds between the cation and the anion, and association of the [hppH2][X] ion-pairs into dimeric units. In salt1c the [hppH2]+ cation was shown to be located within a cavity defined by phenyl substituents from the [BPh4]− anion, with no hydrogen bonding present. Reducing the size of the heterocyclic rings from {6,6}- to {5,5}- in the [HtboH]+ salt promotes formation of extended structures due to a wider angle between the projected hydrogen-bonds to the halide anion. Results from analysis of the bond parameters within the guanidinium cations are used to explain the distribution of π-electron density throughout the bicyclic framework.

A Novel Synthesis of Chiral Guanidinium Receptors and Their Use in Unfolding the Energetics of Enantiorecognition of Chiral Carboxylates

A novel synthetic route to the versatile chiral bicyclic guanidinium building block is described making use of l-methionine as a starting material from the natural chiral pool. Furthermore, the synthetic elaboration of this building block is shown in the construction of macrocyclic and open chain hosts, respectively. The host design employs urea functions as the connecting units and supplementary anchor groups for the complexation of anions. The binding studies of these hosts with various chiral and achiral oxoanions are performed by isothermal titration calorimetry. A trend analysis of the binding energetics in an ensemble of structurally similar guests discloses the importance of geometrical confinement of the guest. Association entropy rather than free energy (affinity) is identified as an indicator of structural uniqueness needed to distinguish configurational isomers in the recognition of enantiomeric carboxylates by the chiral guanidinium hosts.

Rapid Sequencing of Split‐and‐Mix Peptide Receptor Libraries – Identification of Binding Partners for Val‐Val‐Ile‐Ala in Aqueous Solution

AbstractSplit‐and‐mix peptide libraries have been encoded by capping cleavable, laddered sequences with p‐bromobenzoic acid, allowing rapid analysis of the cleaved ladder fragments by mass spectrometry. The encoding methodology has been applied to the synthesis of libraries of peptide receptors and a library of tripeptides functionalised with a bicyclic guanidinium unit has been successfully screened to identify binding partners for Val‐Val‐Ile‐Ala, the C‐terminal tetrapeptide sequence of the amyloid‐β protein, Aβ(1–42). (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Surprises in the Design of Anion Receptors: Calorimetry Prevents False Reasoning

Supplementing bicyclic guanidinium anion receptors with four sec-carboxamido groups leads to enhanced affinity for oxoanions, however, for a different reason than originally planned. Calorimetric analysis reveals that better binding is due to higher association entropies rather than more negative enthalpies. Thus, molecular design following geometric and functional complementarity principles may misguide supramolecular constructions aimed at a unique host-guest binding mode, as required, e.g., by self-assembly or catalysis.

Enantioselective recognition of calix[4]arene derivatives bearing chiral bicyclic guanidinium for d/ l-phenylalanine zwitterions at the air–water interface

Monolayers of the amphiphilic calixarene derivatives (BSGC, MSGC and MGC) bearing chiral bicyclic guanidinium on the surface of pure water and of aqueous subphases containing l-phenylalanine or d-phenylalanine ( l/ d-Phe) were studied by film balance measurements. LB films deposited from the monolayers on the three kinds of subphases were investigated by circular dichroism spectra (CD). All the results indicate that BSGC, MSGC and MGC can form stable monolayers on these subphases. Moreover, BSGC (with two chiral bicyclic guanidinium units) can enantioselectively recognize l-aromatic amino acid and its enantioselectivity for l-Phe is better than MSGC (with one chiral bicyclic guanidinium unit) at the air–water interface, and the enantioselectivity of MGC (without hydrophobic silylether group at the arm of the chiral bicyclic guanidinium unit) for l-Phe is higher than MSGC (with hydrophobic silylether group). Therefore their enantioselectivities for l-Phe depend on the molecular structures.

Enantioselective recognition of calix649arene derivatives bearing chiral bicyclic guanidinium for /-phenylalanine zwitterions at the air?water interface

Monolayers of the amphiphilic calixarene derivatives (BSGC, MSGC and MGC) bearing chiral bicyclic guanidinium on the surface of pure water and of aqueous subphases containing l -phenylalanine or d -phenylalanine ( l / d- Phe) were studied by film balance measurements. LB films deposited from the monolayers on the three kinds of subphases were investigated by circular dichroism spectra (CD). All the results indicate that BSGC, MSGC and MGC can form stable monolayers on these subphases. Moreover, BSGC (with two chiral bicyclic guanidinium units) can enantioselectively recognize l -aromatic amino acid and its enantioselectivity for l -Phe is better than MSGC (with one chiral bicyclic guanidinium unit) at the air–water interface, and the enantioselectivity of MGC (without hydrophobic silylether group at the arm of the chiral bicyclic guanidinium unit) for l -Phe is higher than MSGC (with hydrophobic silylether group). Therefore their enantioselectivities for l -Phe depend on the molecular structures.