Syn Configuration Research Articles

Conformation and Structure of Dichlorophosphoryl Isocyanate in the Gaseous and Solid Phases

The conformational properties and the molecular structure of dichlorophosphoryl isocyanate, Cl2P(O)NCO, were studied by combining vibrational spectroscopy (IR and Raman), gas‐phase electron diffraction (GED), X‐ray crystallography (XRD), and quantum‐chemical calculations. Computationally, two conformers of Cs symmetry with the P=O bond being in syn or anti configuration relative to the NCO group are predicted to be close in energy (ca. 2 kJ mol–1). Experimentally, both gas‐phase and matrix‐isolation IR spectra of Cl2P(O)NCO suggest the presence of a single conformer, which was determined to be the energetically more favorable syn‐conformer. This was also found to exist in the solid state by low‐temperature XRD. However, the molecule in the solid state is significantly distorted from ideal Cs symmetry with an O–P–N–C dihedral angle of 38.1(1)° due to intermolecular C···O contacts [2.881(4) Å]. In the gas phase, the GED analysis suggests that the molecule exists predominantly as syn‐conformer but with dynamic behavior about the two minimum structures (syn and anti).

Electronic structure and structural diversity in indenyl in heterobinuclear transition-metal half-sandwich complexes

DFT calculations have been performed on a series of heterobimetallic compounds of the type [MCp][M′Cp](Ind), [M(CO)3][M′(CO)3](Ind) and [M(CO)2][M′(CO)3](Ind) (Ind = Indenyl). The flexibility of the indenyl ligand favors the possibility of the existence of several isomers. The structure and electronic structure of this large family of compounds were analyzed with respect to their total number of electrons (TNE) and the nature of the ancillary ligands. The structures with electron counts lower than 34-TNE adopt the syn configuration to compensate the electronic deficiency.

Structural diversity of homobinuclear transition metal complexes of the phenazine ligand: theoretical investigation

DFT/BP86 calculations have been carried out on a series of hypothetical binuclear compounds of general formula (L3M)2(C12N2H8) (M = Sc–Ni, L3 = (CO)3, (PH3)3 and Cp−, and C12N2H8 = phenazine ligand-denoted Phn). The various structures with syn and anti configurations have been investigated, in order to determine the phenazine’s coordination to first-row transition metals of various spin states with syn and anti conformations. The lowest energy structures depend on the nature of the metal, the spin state, and the molecular symmetry. This study has shown that the electronic communication between the metal centers depends on their oxidation state and the attached ligands. The tricarbonyl and the triphosphine ligands gave rise to comparable results in terms of stability order of isomers, metal-metal bond distances, and the coordination modes. Metal-metal multiple bonding has been evidenced for Sc, Ti, and V complexes to compensate the electronic deficiency. The Cr, Mn, Fe, Co, and Ni-rich metals prefer the anti conformation due to the enhancement of the metal valence electron count. The spin density values calculated for the triplet and quintet spin structures point out that the unpaired electrons are localized generally on the metal centers. The Wiberg bond indices are used to evaluate the metal-metal bonding. Furthermore, calculations using the BP86-D functional which take into account the attractive part of the van der Waals type interaction potential between atoms and molecules that are not directly connected to each other gave comparable results to those obtained by BP86 functional in terms of coordination modes, HOMO-LUMO gaps, metal-metal bond orders, and the stability order between isomers, but with slight deviation of M–C, M–N, and M–M bond distances not exceeding 3%.

Influence of Sodium Cationization versus Protonation on the Gas-Phase Conformations and Glycosidic Bond Stabilities of 2'-Deoxyadenosine and Adenosine.

The influence of noncovalent interactions with a sodium cation on the gas-phase structures and N-glycosidic bond stabilities of 2'-deoxyadenosine (dAdo) and adenosine (Ado), [dAdo+Na](+) and [Ado+Na](+), are probed via infrared multiple photon dissociation (IRMPD) action spectroscopy and energy-resolved collision-induced dissociation (ER-CID) experiments. ER-CID experiments are also performed on the protonated forms of these nucleosides, [dAdo+H](+) and [Ado+H](+), for comparison purposes. Complementary electronic structure calculations are performed to determine the structures and relative stabilities of the stable low-energy conformations of the sodium cationized nucleoside complexes and to predict their IR spectra. Comparison between the measured IRMPD action spectra and calculated IR spectra enables the conformations of the sodium cationized nucleosides present in the experiments to be elucidated. The influence of sodium cationization versus protonation on the structures and IR spectra is elucidated by comparison to IRMPD and theoretical results previously reported for the protonated forms of these nucleosides. The influence of sodium cationization versus protonation on the glycosidic bond stability of the adenine nucleosides is determined by comparison of the ER-CID behavior of these systems. All structures present in the experiments are found to involve tridentate binding of Na(+) to the N3, O4', and O5' atoms forming favorable 5- and 6-membered chelation rings, which requires that adenine rotate to a syn configuration. This mode of sodium cation binding results in moderate flexibility of the sugar moiety such that the sugar puckering of the conformations present varies between C2'-endo and O4'-endo. Sodium cationization is found to be less effective toward activating the N-glycosidic bond than protonation for both dAdo and Ado. Both the IRMPD yields and ER-CID behavior indicate that the 2'-hydroxyl substituent of Ado stabilizes the N-glycosidic bond relative to that of dAdo.

Development of a syn-Selective Mannich Reaction of Aldehydes with Propargylic Imines by Dual Catalysis: Asymmetric Synthesis of Functionalized Propargylic Amines.

Direct coupling of enolizable aldehydes with C-alkynyl imines is realized affording the corresponding propargylic Mannich adducts of syn configuration, thus complementing previous methods that gave access to the anti-isomers. The combination of proline and a urea Brønsted base cocatalyst is key for the reactions to proceed under very mild conditions (3-10 mol % catalyst loading, dichloromethane as solvent, -20 °C, 1.2 molar equivalents of aldehyde) and with virtually total stereocontrol (syn/anti ratio up to 99:1; ee up to 99 %). Some possibilities of further chemical elaboration of adducts are also briefly illustrated.

Stereochemistry and spectroscopic analysis of bis-Betti base derivatives of 2,3-dihydroxynaphthalene.

Density functional theory (DFT) was used to study the stereochemistry, thermodynamic stability, and spectra of recently synthesized bis-Betti base derivatives of 2,3-dihydroxynaphthalene obtained through multicomponent reactions of 2,3-dihydroxynaphthalene with aminoisoxazole and benzaldehyde derivatives. The stereochemistry of the products was investigated by theoretically calculating the infrared (IR) and proton nuclear magnetic resonance ((1)H NMR) spectra of the diastereomers and comparing them to the corresponding experimental data. The thermochemical properties of the reactions, including the enthalpy, internal energy, entropy, and Gibbs free energy, were also calculated. The diastereoselectivity of the reactions was estimated from the equilibrium distribution of diastereomers. According to the results, the synthesis of bis-Betti bases is exothermic and accompanied by a decrease in entropy. The energy difference between the diastereomers is quite small, but the Gibbs free energy change for the equilibrium syn <−> anti favors the anti over syn configuration. These results are in good agreement with experimental observations.

Synthetic Studies Towards (-) Mesembrine

Mesembrine is a naturally occurring alkaloid which has been isolated from Sceletium tortosum, family Aizoaceae. It has a therapeutic value in the treatment of depression as selective serotonin reuptake inhibitor. Because of its challenging chemical features such as a cis-3a-aryloctahydroindole moiety with syn configuration at two bridge-head stereogenic centers. [1] Several synthetic studies have been published to control the construction of the sterically hindered, benzylic quaternary stereogenic center at C-3a. [2] By utilizing Michael addition on chiral enolate derived from benzyl oxazoline, the desired stereogenic center at carbon 3a was created early in the synthesis followed by carbene insertion and intramolecular aldol reactions to complete the aryloctahydroindole scaffold. The complete details of synthetic transformations will be discussed. Acknowledgements: This research is supported in part by The United States Department of Agriculture, Agricultural Research Service, Specific Cooperative Agreement No. 58 – 6408 – 1-603 – 07

Discovery of the oxazabicyclo[3.3.1]nonane derivatives as potent and orally active GPR119 agonists

The design and synthesis of two conformationally restricted oxazabicyclo octane derivatives as GRP119 agonists is described. Derivatives of scaffold C, with syn configuration, have the best overall profiles with respect to solubility and in vivo efficacy. Compound 25a was found to have extremely potent agonistic activity and was orally active in lowering blood glucose levels in a mouse oral glucose tolerance test at a dose of 0.1 mg/kg.

Restricting the ψ Torsion Angle Has Stereoelectronic Consequences on a Scissile Bond: An Electronic Structure Analysis.

Protein motion is intimately linked to enzymatic catalysis, yet the stereoelectronic changes that accompany different conformational states of a substrate are poorly defined. Here we investigate the relationship between conformation and stereoelectronic effects of a scissile amide bond. Structural studies have revealed that the C-terminal glycine of ubiquitin and ubiquitin-like proteins adopts a syn (ψ ∼ 0°) or gauche (ψ ∼ ±60°) conformation upon interacting with deubiquitinases/ubiquitin-like proteases. We used hybrid density functional theory and natural bond orbital analysis to understand how the stereoelectronic effects of the scissile bond change as a function of φ and ψ torsion angles. This led to the discovery that when ψ is between 30° and -30° the scissile bond becomes geometrically and electronically deformed. Geometric distortion occurs through pyramidalization of the carbonyl carbon and amide nitrogen. Electronic distortion is manifested by a decrease in the strength of the donor-acceptor interaction between the amide nitrogen and antibonding orbital (π*) of the carbonyl. Concomitant with the reduction in nN → π* delocalization energy, the sp(2) hybrid orbital of the carbonyl carbon becomes richer in p-character, suggesting the syn configuration causes the carbonyl carbon hybrid orbitals to adopt a geometry reminiscent of a tetrahedral-like intermediate. Our work reveals important insights into the role of substrate conformation in activating the reactive carbonyl of a scissile bond. These findings have implications for designing potent active site inhibitors based on the concept of transition state analogues.

Accurate placement of substrate RNA by Gar1 in H/ACA RNA-guided pseudouridylation.

H/ACA RNA-guided ribonucleoprotein particle (RNP), the most complicated RNA pseudouridylase so far known, uses H/ACA guide RNA for substrate capture and four proteins (Cbf5, Nop10, L7Ae and Gar1) for pseudouridylation. Although it was shown that Gar1 not only facilitates the product release, but also enhances the catalytic activity, the chemical role that Gar1 plays in this complicated machinery is largely unknown. Kinetics measurement on Pyrococcus furiosus RNPs at different temperatures making use of fluorescence anisotropy showed that Gar1 reduces the catalytic barrier through affecting the activation entropy instead of enthalpy. Site-directed mutagenesis combined with molecular dynamics simulations demonstrated that V149 in the thumb loop of Cbf5 is critical in placing the target uridine to the right position toward catalytic D85 of Cbf5. The enzyme elegantly aligns the position of uridine in the catalytic site with the help of Gar1. In addition, conversion of uridine to pseudouridine results in a rigid syn configuration of the target nucleotide in the active site and causes Gar1 to pull out the thumb. Both factors guarantee the efficient release of the product.

Synthesis of Molybdenum and Tungsten Alkylidene Complexes That Contain the 2,6-Bis(2,4,6-triisopropylphenyl)phenylimido (NHIPT) Ligand

Molybdenum and tungsten alkylidene complexes that contain the sterically demanding hexaisopropylterphenylimido ligand, N-2,6-(2,4,6-i-Pr3C6H2)2C6H3 (NHIPT), have been prepared from Mo(N-t-Bu)2Cl2(1,2-dimethoxyethane) or W(N-t-Bu)2Cl2(pyridine)2, employing tert-butylimido ligands as sacrificial proton acceptors. These complexes include M(NHIPT)(CH-t-Bu)Cl2 (M = Mo, W), Mo(NHIPT)(CH-t-Bu)(pyrrolide)2, and Mo(NHIPT)(CH-t-Bu)(pyrrolide)(OC6F5)(CH3CN). In all cases only anti alkylidene isomers are observed in solution, as a consequence of the steric demands of the NHIPT ligand. An X-ray structure of W(NHIPT)(CH-t-Bu)Cl2 showed it to be a monomer with a disordered alkylidene that is 86% in the anti configuration and 14% in the syn configuration.

Coordination chemistry of highly hemilabile bidentate sulfoxide N-heterocyclic carbenes with palladium(II).

Imidazolium salts, [RS(O)-CH2 (C3 H3 N2 )Mes]Cl (R=Me (L1a), Ph (L1b)); Mes=mesityl), make convenient carbene precursors. Palladation of L1a affords the monodentate dinuclear complex, [(PdCl2 {MeS(O)CH2 (C3 H2 N2 )Mes})2 ] (2a), which is converted into trans-[PdCl2 (NHC)2] (trans-4a; N-heterocyclic carbene) with two rotamers in anti and syn configurations. Complex trans-4a can isomerize into cis-4a(anti) at reflux in acetonitrile. Abstraction of chlorides from 4a or 4b leads to the formation of a new dication: trans-[Pd{RS(O)CH2(C3H2N2)Mes}2](PF6)2 (R=Me (5a), Ph (5b)). The X-ray structure of 5a provides evidence that the two bidentate SO-NHC ligands at palladium(II) are in square-planar geometry. Two sulfoxides are sulfur- and oxygen-bound, and constitute five- and six-membered chelate rings with the metal center, respectively. In acetonitrile, complexes 5a or 5b spontaneously transform into cis-[Pd(NHC)2(NCMe)2](PF6)2. Similar studies of thioether-NHCs have also been examined for comparison. The results indicate that sulfoxides are more labile than thioethers.

CH 3 N=SF 2 =NCH 3 : Structural, Conformational, and Configurational Properties in the Gaseous and in the Condensed Phases

The structural and configurational properties of CH3–N=SF2=N–CH3 were studied by vibrational spectroscopy, quantum chemical calculations, and X-ray crystallography. Only vibrational spectroscopy shows evidence of a conformational equilibrium of the anti–anti form and a slightly less favored anti–syn configuration. The crystalline solid at 120 K is consistent with an anti–anti form.

Manganese(II) Alkyl/π-Allyl Complexes Resistant to Ligand Redistribution

The reaction of [Li(THF)4][(Mn{C(SiMe3)3})3(μ-Cl)4(THF)] (1) with K(allylTMS2) (allylTMS2 = 1,3-C3H3(SiMe3)2) afforded [(η3-allylTMS2)Mn{C(SiMe3)3}{ClLi(THF)3}] (2). Attempted sublimation of 2 yielded [(η3-allylTMS2)Mn{C(SiMe3)3}(THF)] (3), indicating that 2 extrudes LiCl at elevated temperatures. Additionally, LiCl in 2 was displaced by reaction with PMe3, quinuclidine, and dmap (dmap = 4-(dimethylamino)pyridine), providing [(η3-allylTMS2)Mn{C(SiMe3)3}(L)] (L = PMe3 (4), quinuclidine (5), dmap (6)). Treatment of PMe3 complex 4 with BPh3 yielded bright red [(allylTMS2)Mn{C(SiMe3)3}] (7) accompanied by a precipitate of Ph3B(PMe3). Mixed alkyl/π-allyl manganese(II) complexes 2–7 are pyrophoric red solids with a high-spin d5 configuration, and all were crystallographically characterized. In the solid-state structures, the allyl ligands in 2–6 adopt a syn,syn configuration, whereas in base-free 7, the allyl ligand has a syn,anti configuration. Complexes 4, 5, and 7 sublimed cleanly (5 mTorr) at 70, 90, and 50...

N,N′‐Bis(2,6‐diisopropylphenyl)benzamidinates and ‐pivalamidinates of the s‐Block Metals Lithium, Potassium, and Calcium

AbstractMetalation of N,N′‐bis(2,6‐diisopropylphenyl)benzamidine (1a) and ‐pivalamidine (1b) in tetrahydrofuran (THF) with n‐butyllithium and potassium bis(trimethylsilyl)amide gives the corresponding N,N′‐bis(2,6‐diisopropylphenyl)benzamidinates and ‐pivalamidinates of lithium, [(thf)2Li{(Dipp‐N)2C‐Ph}] (2a) and [(thf)Li{(Dipp‐N)2C‐tBu}] (2b), as well as of potassium, [(thf)3K{(Dipp‐N)2C‐Ph}] (3a) and [(thf)3K{(Dipp‐N)2C‐tBu}] (3b) (Dipp = 2,6‐diisopropylphenyl). Because metalation of these amidines is not possible with [(thf)2Ca{N(SiMe3)2}2], a metathetical approach has been chosen. Hence, the reaction of 3a with calcium iodide in THF yields (tetrahydrofuran)calcium bis[N,N′‐bis(2,6‐diisopropylphenyl)benzamidinate] (4a). For the bulkier N,N′‐bis(2,6‐diisopropylphenyl)pivalamidinate, heteroleptic [(thf)Ca{(Dipp‐N)2C‐tBu}{N(SiMe3)2}] (4b) forms. Depending on the softness and charge‐to‐radius ratio, syn configuration of the amidinate ligands is observed for 2a, 4a, and 4b, whereas the anti configuration is realized in complexes 2b, 3a, and 3b, the latter being stabilized by intramolecular metal–π interactions.

Support Effect on Stereoselectivities of Vinylogous Mukaiyama–Michael Reactions Catalyzed by Immobilized Chiral Copper Complexes

Chiral bis(oxazoline)- and azabis(oxazoline)-copper complexes, used as homogeneous catalysts or immobilized onto laponite, are able to catalyze vinylogous Mukaiyama–Michael reactions between 2-(trimethylsilyloxy)furan and several electron-deficient alkenes. A study of the support effect has been conducted and different changes on the diastereoselectivities and enantioselectivities has been observed. The behavior of the catalyst is different, depending on the structure of the substrate (Michael acceptor). When diethyl benzylidenemalonate was used, the major diastereomer was that with syn configuration, but the homogeneous and the heterogeneous catalysts lead to opposite enantiomers (−80% ee in solution and 38% ee in the heterogeneous phase). This change represents a support effect of ∼1.8 kcal/mol. With N-(E)-but-2-enoyloxazolidinone, the most relevant change is in the diastereomer preference. In solution, the anti isomer is the major one (anti/syn = 98/2); however, in contrast, syn isomer is preferred wit...

Highly stereoselective anti-aldol reactions catalyzed by simple chiral diamines and their unique application in configuration switch of aldol products

Chiral derivatives of trans-1,2-diaminocyclohexane with different N,N-dialkyl groups in well-defined orientations have been synthesized, and applied as catalysts for the asymmetric aldol reaction between a variety of aldehydes and ketones. Enantiomeric catalyst 1j catalyzed the reaction in ethanol and provided excellent diastereoselectivity and enantioselectivity. Significantly, simple replacement of organic solvents with water switched the products of the aldol reactions from anti to syn configuration. Such catalytic reactions led to the products with anti to syn diastereoselectivity up to 99:1 in ethanol, while in water gave the products with syn to anti diastereoselectivity up to 99:1.

ChemInform Abstract: Pd‐Catalyzed Diastereoselective Allylation of Aldehydes with 3‐Bromomethyl‐5H‐furan‐2‐one: Stereoselective Synthesis of β‐(Hydroxymethylaryl/Alkyl) ‐α‐methylene‐γ‐butyrolactones with a syn Configuration.

An efficient and diastereoselective Pd-catalyzed method of allylation of aldehydes with 3-bromomethyl-5H-furan-2-one is described. The proposed method allows the synthesis of β-(hydroxymethylaryl/alkyl)-α-methylene-γ-butyrolactones with a syn relative configuration for the first time.

Shape‐Persistent (Pt‐salphen)2 Phosphorescent Coordination Frameworks: Structural Insights and Selective Perturbations

The development of molecular frameworks derived from binuclear platinum(II) aromatic Schiff base (salphen) complexes and their supramolecular chemistry have been undertaken. A series of axially rotating (Pt-salphen)2 luminophores, tethered in a cofacial manner by a rigid linker (xanthene, 1; dibenzofuran, 2; biphenylene, 3), was synthesized in which the O(salphen) groups are potentially amenable for guest-binding. The molecular structures of 1 and 3 have been determined by X-ray crystallography, revealing intra- and intermolecular π-stacking interactions, as well as contrasting syn (1) and anti (3) configurations, for the (Pt-salphen)2 moiety. All complexes are luminescent in solution at room temperature. Their photophysical and solvatochromic properties have been examined, and the emissions are assigned to mixed triplet O(p)/Pt(d)→π*(diimine) excited states. The red-shifted fluid emissions and lower quantum yields of 1 and 3, relative to 2, are ascribed to enhanced intramolecular π-stacking interactions. Photophysical changes and selective responses to metal ions (particularly Pb(2+)) have been investigated by using various spectroscopic methods and DFT calculations, and through comparative studies with control complexes. A plausible binding mechanism is proposed based on occupation of the O(salphen)-binding cavity, which induces perturbation of intramolecular π-π interactions, and hence the self-quenching and emission properties, of the (Pt-salphen)2 unit.

Synthesis and Coordination Behavior of a Bipyridine Platinum(II) Complex with Thioglucose

A mononuclear platinum(II) complex with two monodentate-S H4tg(-) ligands, [Pt(H4tg-κS)2(bpy)] (1), was newly synthesized by the reaction of [PtCl2(bpy)] (bpy = 2,2'-bipyridyl) with NaH4tg (NaH4tg =1-thio-β-d-glucose sodium salt) in water. Complex 1 reacted with additional [PtCl2(bpy)] in water to give an S-bridged dinuclear complex, [Pt2(μ2-H4tg-κ(1)S:κ(1)S)2(bpy)2](2+) ([2](2+)), in which a square-planar [Pt(H4tg)2(bpy)] unit binds to a [Pt(bpy)](2+) moiety through two thiolato groups. Treatments of 1 with Cu(2+) and Ni(2+) in water in the presence of bpy produced S-bridged dinuclear complexes [PtCu(μ2-H4tg-κ(1)S:κ(2)O,S)2(bpy)2](2+) ([3](2+)) and [PtNi(μ2-H4tg-κ(1)S:κ(2)O,S)2(bpy)2](2+) ([4](2+)), respectively, in which a square-planar [Pt(H4tg)2(bpy)] unit binds to a [M(bpy)](2+) (M = Cu(II), Ni(II)) moiety through two thiolato and two hydroxyl groups to form a chiral [M(N)2(O)2(S)2] octahedron with the Δ configuration. On the other hand, similar treatment with Cd(2+) in the presence of bpy resulted in the formation of an S-bridged trinuclear complex, [Cd{Pt(μ2-H4tg-κ(1)S:κ(2)O,S)(μ2-H4tg-κ(1)S:κ(1)S)(bpy)}2](2+) ([5](2+)), in which each of two square-planar [Pt(H4tg)2(bpy)] units binds to a Cd(II) ion through two thiolato groups and one hydroxyl group to form a chiral [Cd(O)2(S)4] octahedron with the Λ configuration. Of two geometrical configurations, syn and anti, which arise from the relative arrangement of two β-D-pyranose moieties, [2](2+) adopts the syn configuration with symmetric bridging sulfur atoms, while [3](2+), [4](2+), and [5](2+) all have the anti configuration with R configurational bridging sulfur atoms. All of the complexes were fully characterized by electronic absorption, CD, and NMR spectroscopies, along with single-crystal X-ray crystallography.