Ferrocenoyl peptides with sulfur-containing side chains: synthesis, solid state and solution structures

The synthesis and full characterization of a number of amino acid and dipeptide derivatives with sulfur-containing side chains derived from ferrocene carboxylic acid and ferrocene-1,1′-dicarboxylic acid is presented. In particular, compounds Fc-CO-(Aaa)_n-OMe (4) and Fe[C₅H₄-CO-(Aaa)_n-OMe]₂ (3) with (Aaa)_n = Cys(Bzl) (a), Cys(Bzl)-Cys(Bzl) (b), Cys(p-OMe-Bzl) (c), Cys(p-OMe-Bzl)-Cys(p-OMe-Bzl) (d), Met (e), and Met-Met (f) were prepared. Also, the free acid derivatives Fe[C₅H₄-CO-Met-OH]₂ (6e) and Fc-CO-Met-OH (7e) were prepared and characterized. The solid state structures of 3a, 4b, and 4e were determined by single crystal X-ray diffraction. Compound 3a shows a 1,3′ substitution pattern on the Cp rings in the solid state. Structures in solution were determined by NMR, IR and CD spectroscopy, with particular emphasis on the question of hydrogen bonding and helical chirality of the metallocene. As an example, the full assignment for the Cp signals in the disubstituted derivative 3a was achieved by simulation of the ¹H NMR signals from the cyclopentadienyl ring in combination with 2D-NOESY spectra. In solution, 3a has the known 1,2′ substitution pattern, which is stabilized by intramolecular hydrogen bonds.     

Structural properties of new spiro-1,3-propanediaminocyclotriphosphazene derivatives

New 1,3-propanediaminocyclotriphosphazene derivatives (7-17) were synthesized from the reactions of spiro-1,3-propanediaminocyclotriphosphazene, N₃P₃Cl₄[NH(CH₂)₃NH] (1) with the cyclopropanemethylamine (2), cyclohexylamine (3), pyrrolidine (4) cyclohexanol (5), cyclopropylmethanol (6). The structures of the novel compounds (7-17) were characterized by elemental analysis, mass spectrometry, ¹H and ³¹P NMR spectroscopy. The molecular structures of 8, 12 and 13 were determined by X-ray crystallography. The structures of all these three compounds are in the monoclinic crystal system; compounds 8 and 12 have the P21/c space group while compound 13 has the P21/n space group. The ring conformation of the cyclotriphosphazene and other external rings were investigated based on the X-ray crystal structures.     

Design of a stabilized short helical peptide and its application to catalytic enantioselective epoxidation of (E)-chalcone

Stabilized short helical heptapeptides containing a combination of an α-aminoisobutyric acid as a helical promoter and l/d-serine derivatives to produce cross-linked units were synthesized. The cyclic peptide R₃,₇R-2, which had d-serine derivatives at its 3rd and 7th positions, formed a stable right-handed (P) α-helix in solution and the crystalline state. Furthermore, its N-terminal free helical peptide catalyzed the enantioselective epoxidation of (E)-chalcone to afford the epoxide in a high yield and moderate enantioselectivity.     

Stryphnosides A-F, six new triterpene glycosides from the pericarps of Stryphnodendron fissuratum

Six new triterpene glycosides stryphnosides A-F (1-6) were isolated from the pericarps of Stryphnodendron fissuratum (Leguminosae). The structures of 1-6 were determined on the basis of extensive spectroscopic analysis, including two-dimensional (2D) NMR data, and the results of hydrolytic cleavage. The sugar moieties of 3-6 are very unique in structure having not only novel sugar sequences but also the terminal α-l-arabinopyranosyl unit with a ¹C₄ conformation. Stryphnosides C (3)-F (6) are the first representative of naturally occurring glycosides with the ¹C₄ terminal α-l-arabinopyranosyl group.     

Synthesis of 3,4-di-O-acylated glucose-derived furanoid sugar amino acids (Gaa): conformational analysis of a Leu-enkephalin analog containing di-O-myristoylated Gaa

3,4-Di-O-acylated derivatives 1-3 of a glucose-derived furanoid sugar amino acid (Gaa) were synthesized as novel peptide building blocks to study their effects on peptide conformation. Structural analysis of the di-O-myristoylated Gaa 3-containing Leu-enkephalin analog 4 by various NMR techniques and constrained molecular dynamics (MD) simulation studies established a well-defined β-turn structure in DMSO-d₆ with an intramolecular hydrogen bond between PheNH → TyrCO.     

Hydrogen bonding-mediated self-assembly of rigid and planar metallocyclophanes and their recognition for mono- and disaccharides

A hydrogen bonding approach has been developed to facilitate the self-assembly of a new series of rigid and planar metallocyclophanes. Two new anthranilamide derivatives 1 and 2, which are incorporated with two acetylene units, respectively, have been synthesized and characterized. X-ray analysis (for 1), 1D and 2D ¹H NMR and IR experiments reveal that, due to the formation of intramolecular three-centered hydrogen bonding, both compounds adopt rigid and planar conformations with the two acetylene units located at the same side of the anthranilamide skeleton. Two new metallocyclophanes 17 and 18 have been constructed in moderate yields from the reaction of 1 and 2 with trans-Pt(PEt₃)₂Cl₂, respectively, in dichloromethane in the presence of diethylamine and cupric chloride. Fluorescent and ¹H NMR investigations reveal that both 17 and 18 can efficiently complex mono- and disaccharide derivatives in chloroform, with a binding selectivity for disaccharides, which is driven by intermolecular hydrogen bonding.     

Nickel(II) chloride hexahydrate catalyzed reaction of aromatic aldehydes with 2-mercaptoethanol: formation of supramolecular helical assemblage of the product

Various aromatic aldehydes on reaction with 2-mercaptoethanol provided an unanticipated product, bis(2-hydroxyethyl)dithioacetals (3) as the major product along with the expected product 1,3-oxathiolanes (4) in the presence of 0.05 equiv amount of nickel(II) chloride hexahydrate (NiCl₂·6H₂O) under solvent-free conditions. Products 3c and 3e exhibit an interesting hydrogen-bonded infinite supra-molecular helical structure.     

Phosphite ligands derived from distally and proximally substituted dipropyloxy calix[4]arenes and their palladium complexes: Solution dynamics, solid-state structures and catalysis

Two bisphosphite ligands, 25,27-bis-(2,2′-biphenyldioxyphosphinoxy)-26,28-dipropyloxy-p-tert-butyl calix[4]arene (3) and 25,26-bis-(2,2′-biphenyldioxyphosphinoxy)-27,28-dipropyloxy-p-tert-butyl calix[4]arene (4) and two monophosphite ligands, 25-hydroxy-27-(2,2′-biphenyldioxyphosphinoxy)-26,28-dipropyloxy-p-tert-butyl calix[4]arene (5) and 25-hydroxy-26-(2,2′-biphenyldioxyphosphinoxy)-27,28-dipropyloxy- p-tert-butyl calix[4]arene (6) have been synthesized. Treatment of (allyl) palladium precursors [(η³-1,3-R,R′-C₃H₄)Pd(Cl)]₂ with ligand 3 in the presence of NH₄PF₆ gives a series of cationic allyl palladium complexes (3a-3d). Neutral allyl complexes (3e-3g) are obtained by the treatment of the allyl palladium precursors with ligand 3 in the absence of NH₄PF₆. The cationic allyl complexes [(η³-C₃H₅)Pd(4)]PF₆ (4a) and [(η³-Ph₂C₃H₃)Pd(4)]PF₆ (4b) have been synthesized from the proximally (1,2-) substituted bisphosphite ligand 4. Treatment of ligand 4 with [Pd(COD)Cl₂] gives the palladium dichloride complex, [PdCl₂(4)] (4c). The solid-state structures of [{(η³-1-CH₃-C₃H₄)Pd(Cl)}₂(3)] (3f) and [PdCl₂(4)] (4c) have been determined by X-ray crystallography; the calixarene framework in 3f adopts the pinched cone conformation whereas in 4c, the conformation is in between that of cone and pinched cone. Solution dynamics of 3f has been studied in detail with the help of two-dimensional NMR spectroscopy.The solid-state structures of the monophosphite ligands 5 and 6 have also been determined; the calix[4]arene framework in both molecules adopts the cone conformation. Reaction of the monophosphite ligands (5, 6) with (allyl) palladium precursors, in the absence of NH₄PF₆, yield a series of neutral allyl palladium complexes (5a-5c; 6a-6d). Allyl palladium complexes of proximally substituted ligand 6 showed two diastereomers in solution owing to the inherently chiral calix[4]arene framework. Ligands 3, 6 and the allyl palladium complex 3f have been tested for catalytic activity in allylic alkylation reactions.     

Enantioselective epoxidation of α,β-unsaturated ketones catalyzed by stapled helical l-Leu-based peptides

Stapled helical l-leucine-based heptapeptides were synthesized and used as catalysts for the enantioselective epoxidation of α,β-unsaturated ketones. All N-terminal free stapled peptides were successfully used as chiral catalysts. Among them, the use of H-hS₃,₇hS-10 gave epoxide products with high enantioselectivities of up to 99% ee. Furthermore, the dominant conformations of the N-terminal protected stapled peptides R₃,₇R-10 and hS₃,₇hS-10 were investigated by ¹H NMR, IR, CD spectra, and X-ray crystallographic analysis. The peptide R₃,₇R-10 formed a right-handed (P) α-helix in solution and in the crystalline state, while hS₃,₇hS-10 formed a right-handed (P) 3₁₀-helix in solution.     

Hexabromide salt of a tiny octaazacryptand as a receptor for encapsulation of lower homolog halides: structural evidence on halide selectivity inside the tiny cage

Tiny azacryptand 1,4,7,10,13,16,21,24-octaazabicyclo[8.8.8]hexacosane (L) upon reaction with 48% hydrobromic acid (containing <0.05% chloride contamination) forms hexabromide salt (1). Single crystal X-ray crystallographic investigation of the hexaprotonated bromide (1) shows no guest encapsulation inside the tiny cage. This bromide salt 1 with an empty proton cage has been utilized as the receptor for encapsulation of chloride (2) and fluoride (3). Crystallographic results of mixed chloride/bromide (2) and fluoride/bromide (3) complexes of L are examined, which show monotopic recognition of chloride in the case of 2 and fluoride in the case of 3 inside the proton cage with five bromide and three water molecules outside the cavity. Single crystals obtained from an experiment on mixed anionic system (chloride and fluoride), 1 shows selective encapsulation of fluoride, which supports the formation of complex 3 and crystals obtained upon treatment of 2 with tetrabutyl ammonium fluoride also yields complex 3. In a separate reaction between L and 49% hydrobromic acid containing higher chloride contamination (<0.2%) forms chloride/bromide salt (2). ¹H NMR studies of 1 with sodium chloride and fluoride support the encapsulation of the respective anions inside the proton cage.     

Application of tri- and tetrasubstituted alkene dipeptide mimetics to conformational studies of cyclic RGD peptides

The first application of a combination of novel ψ[(E)-CXCX]-type alkene dipeptide isosteres to conformation studies of cyclic bioactive peptides was carried out (X=H or Me). For exploration of bioactive conformations of Kessler's cyclic RGD peptides, cyclo(-Arg-Gly-Asp-d-Phe-Val-) 1 and cyclo(-Arg-Gly-Asp-d-Phe-N-MeVal-) 2, d-Phe-ψ[(E)-CXCX]-l-Val-type dipeptide isosteres were utilized having di-, tri- and tetrasubstituted alkenes containing the γ-methylated isosteres that have been reported to be potential type II′ β-turn promoters. All of the (E)-alkene pseudopeptides 3-6 exhibited higher antagonistic potency against α_vβ₃ integrin than 1, although potencies were slightly lower than 2. Detailed structural analysis using ¹H NMR spectroscopy revealed that representative type II′ β/γ backbone arrangements proposed for 1, were not observed in peptides 3-6. Rather on the basis of ¹H NMR data, the conformations of peptides 3-6 were estimated to be more analogous to those of the N-methylated peptide 2.     

Binding studies of tetrathiafulvalene-calix[4]pyrroles with electron-deficient guests

The neutral meso-octamethylporphyrinogen derivative, tetraTTF-calix[4]pyrrole 1 (TTF=tetrathiafulvalene), acts as a multi-faceted receptor in that it interacts with an assortment of different guests in different ways. The conformation of receptor 1 can be reversibly switched between the 1,3-alternate conformation (i.e., 1, Fig. 1) and the cone conformation (i.e., 1·Cl⁻, Fig. 2) by the repetitive addition of chloride and sodium ions. In this paper, the results of detailed and systematic complexation studies involving both 1 and its chloride-bound complex, 1·Cl⁻, with a variety of guests are described. Receptor 1 binds quasi-planar nitroaromatic guests in its 1,3-alternate conformation, while release of these guests takes place upon addition of chloride anions. On the other hand, spherical fullerene guests are strongly bound by 1·Cl⁻. Finally, it was found that a bidentate guest, consisting of a quasi-planar 2,5,7-trinitro-9-dicyanomethylenefluorene moiety tethered to a spherical C₆₀ fullerene, could be recognized by receptor 1 in either its 1,3-alternate or its chloride-bound cone conformation, albeit through very different binding modes.     

Cyclopentadienyl chromium and tungsten complexes with halide, methyl and σ-phenylethynyl ligands: Structures of (η-C5H5)Cr(NO)2(-CC-C6H5), (η-C5H5)Cr(NO)2I and [(η-C5H4)-COOCH3]W(CO)3Cl

With copper(I) iodide as catalyst, σ-alkynyls, compounds (η⁵-C₅H₅)Cr(NO)₂(CC-C₆H₅) (5), [(η⁵-C₅H₄)-COOCH₃]Cr(NO)₂(CC-C₆H₅) (10), and [(η⁵-C₅H₄)-COOCH₃]W(CO)₃(CC-C₆H₅) (13), were prepared from their corresponding metal chloride 1, 6 and 12. Structures of compound 3, 5 and 12 have been solved by X-ray diffraction studies. In the case of 5, there is an internal mirror plane passing through the phenylethynyl ligand and bisecting the Cp ring. The phenyl group is oriented perpendicularly to the Cp with an eclipsed conformation. The twist angle is 0° and 118.4° for -CC-Ph and two NO ligands, respectively. The orientation is rationalized in terms of orbital overlap between ψ₃ of Cp, dπ of Cr atom, and π^∗ of alkynyl ligand, and complemented by molecular orbital calculation. The opposite correlation was observed on the chemical shift assignments of C(2)-C(5) on Cp ring in compounds 6 and 12, using HetCOR NMR spectroscopy. The electron density distribution in the cyclopentadienyl ring is discussed on the basis of ¹³C NMR data and compared with the calculations via density functional B3LYP correlation-exchange method.     

Nucleation of β-hairpin structure in a pyrrole amino acid containing peptide

Synthesis and conformational studies of two short peptides containing pyrrole amino acids (1, Paa), Boc-Paa-Paa-d-Pro-Gly-Xaa-Paa-Paa-OMe (2: Xaa=Ala; 3: Xaa=Val), were carried out in which it was established that replacement of Ala in 2 with a Val residue helps peptide 3 to adopt a well-defined β-hairpin conformation in a nonpolar solvent, like CDCl₃.     

Translation of helical chirality from polymer into monomer: supramolecular polymerization of a chirality-memory molecule with an asymmetric Pd(II) complex

A chirality-memorizing saddle-shaped porphyrin (1_2H) with 3,5-dipyridylphenyl side arms at the opposite meso positions underwent supramolecular polymerization in CH₂Cl₂ with a chiral Pd(II) complex of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (Pd^II(BINAP)), forming a ladder-shaped polymer (3_2H) with a prevailing one-handed helical chirality. When this polymer was poured into AcOH containing 1,3-bis(diphenylphosphino)propane (DPPP) as a decomplexing agent, 3_2H was depolymerized in a stereochemically retentive way to give optically active 1_2H, hydrogen-bonded with AcOH. Although a cyclodimeric reference of 3_2H, formed from 2_2H having two 3-pyridylphenyl meso substituents in conjunction with Pd^II(BINAP), behaved similar to 3_2H, the translation efficiency of helical chirality was lower than that in the case with 3_2H.     

Cationic olefin Pd(II) complexes bearing α-iminoketone N,O-ligands: synthesis, intramolecular and interionic characterization and reactivity with olefins and alkynes

Complexes [Pd(η¹, η²-5-OMe-C₈H₁₂)(N,O)]BF₄ (N,O=2,6-(i-Pr)₂(C₆H₃)NC(Ph)-C(Ph)O, 1; 2,6-(i-Pr)₂(C₆H₃)NC(Me)-C(Ph)O, 2; 2-benzoylpyridine, 3) were synthesized by the reactions of [Pd(η¹,η²-5-OMe-C₈H₁₂)Cl]₂ with the suitable N,O-ligand. They were tested as catalysts for olefin or alkyne polymerizations. During such reactions 1-3 quantitatively transformed into their η¹,η²-1-OMe-C₈H₁₂ isomers (1a-3a). The same isomerization occurred in methylene chloride, even in the absence of olefins or alkynes, with a much slower rate. All complexes were fully characterized in solution by multinuclear and multidimensional low temperature NMR spectroscopy. The solid state structures of complexes 1 and 1a were investigated by X-ray single crystal studies. ¹⁹F, ¹H-HOESY NMR experiments carried out in methylene chloride-d₂ at 217 K indicated that the anion prefers to locate on the side of N,O-ligand shifted toward the O-arm in 1-1a and 2-2a while it approaches the N-arm in 3 and 3a compounds.     

Ionic liquid phase organic synthesis (IoLiPOS) methodology applied to the three component preparation of 2-thioxo tetrahydropyrimidin-4-(1H)-ones under microwave dielectric heating

An ionic liquid phase organic synthesis (IoLiPOS) has been developed for the preparation of 2-thioxo tetrahydropyrimidin-4(1H)-ones. Treatment of the starting poly(ethyleneglycol)ionic liquid phases (PEG_n-ILPs) 1 with acryloyl chloride 2 afforded a serie of (PEG_n)-ILPs bound acrylate 3 in quantitative yields. Michael addition of aliphatic primary amines 5 to the PEG₁-ILPs 3(a,d) allowed the preparation of β-aminoesters 6 in high yields. Addition of alkyl isothiocyanates 7 to 6 gave the corresponding thioureido esters 8 in the third step. The final cyclization-cleavage under microwave/solventless strategy provides, under basic conditions, the expected 2-thioxo tetrahydropyrimidin-4(1H)-ones 9 in high purity after flash chromatography. According to the IoLiPOS methodology, the NMR method was used to establish loading of all the PEG-ionic liquid phases intermediates.     

Homohelicity-enriched zinc bilinone dimers with chiral aliphatic spacers. Synthesis and application to chiral induction of a nematic liquid crystal

The zinc bilinone (ZnBL) dimers 4 and 5 bearing chiral aliphatic spacers ((2S,4S)-2,4-pentanedioxy and (3S,5S)-2,6-dimethyl-3,5-heptanedioxy for 4 and 5, respectively) were newly prepared, and their conformational distribution was investigated. The ¹H NMR and circular dichroism spectra revealed that the present dimers predominantly adopted the homohelicity conformation (MM and PP for 4 and 5, respectively), although the reference monomers with the corresponding subunit structures exhibited poor helicity enrichment. The helical twisting powers of these ZnBL dimers for a nematic liquid crystal (N-(4-methoxybenzylidene)-4-butylaniline, MBBA) were also investigated. With the dimers doped into MBBA, highly efficient chiral nematic induction was achieved. Especially, the dimer 5 exhibited the β_M value of +1800 μm⁻¹.     

Synthesis of selenium bridged metallacycles via oxidative addition of diaryl diselenide across Re-Re bond: Novel one-pot reaction approach

One-pot synthesis of novel M₂E₂L₂ type metallacycles [L(CO)₃Re(μ-SeR)₂Re(CO)₃L] (1-5) was accomplished by oxidative addition of diaryl diselenide to low-valent transition metal carbonyl with monodentate pyridine ligands. In metallacycles 1-5, where L = pyridine ligand, R = C₆H₅, CH₂C₆H₅, the pyridyl groups bonded to metal centres invariably adopted cis conformation due to π-π interaction whereas, in compounds 1a and 2a, the pyridyl ligands were oriented in trans conformation. When bulky phenyl groups are introduced at para position of pyridyl rings, as in case of metallacycle 3, the steric hindrance disrupts the soft interaction and resulted into the expansion of space in between two phenylpyridyl groups and created a void. The Metallacycles 1-5 have been characterised by elemental analysis, NMR, IR, absorption and emission spectroscopic techniques. Molecular structures of 1, 1a, 2, 2a, 3 and 4 were determined by single crystal X-ray diffraction analysis and the structural studies of 1, 2, 3 and 4 revealed that the pyridyl groups attached to the metal centres exhibited cis conformation, while 1a, 2a displayed trans conformation.     

Chiral organotin (IV) carboxylates complexes: Syntheses, characterization, and crystal structures with chiral (S)-(+)-6-methoxy-α-methyl-2-naphthaleneaceto acid ligand

Eight new organotin (IV) carboxylates, (R₃Sn)₄(nap)₄ (R = Me 1, n-Bu 2), [(R₃Sn) (nap)]_n (R = Ph 3, PhCH₂4), (R₂Sn) (nap)₂ (R = n-Bu 5, Ph 6, PhCH₂7) and {[R₂Sn(nap)]₂O}₂ (R = Me 8) (nap = (S)-(+)-6-methoxy-α-methyl-2-naphthaleneaceto anion) have been synthesized. All of the complexes have been characterized by elemental analysis, FT-IR, NMR (¹H, ¹³C and ¹¹⁹Sn) spectra. Among these complexes, complexes 1, 3, 5 and 8 were also characterized by X-ray crystallography diffraction analysis, and the data of X-ray crystallography diffraction indicated that complexes 1, 3 and 5 are new chiral organotin (IV) carboxylates complexes. The structural analyses show that complex 1 has a tetranuclear Sn₄O₈ macrocycle structure, complex 3 has a 1D spring-like chiral helical chain with a columnar channel, complex 5 possesses a dimer structure, and complex 8 has a supramolecular chainlike ladder structure through weak intermolecular non-covalent O^…O interactions.