Enantioselective metallo-organocatalyzed preparation of cyclopentanes bearing an all-carbon quaternary stereocenter

Enantioselective metallo-organocatalyzed carbocyclizations of formyl-alkynes have been developed. The cooperation between aminocatalysis and a chiral copper(I) complex granted access to enantio-enriched cyclopentanes through the challenging formation of all-carbon quaternary stereocenters.     

New Organophosphorus Proligands and Amide Precursors: Crystal and Molecular Structures of Ph2P(X)NH(C6H3Pri 2-2,6) (X = O,S) and (OPPh2)(O2SMe)N(C6H3Pri 2-2,6)

The new organophosphorus proligand (OPPh₂)(O₂SMe)NR (R = C₆H₃Prⁱ ₂–2,6) (3) was prepared as a white crystalline solid by reacting the lithiated compound Li[Ph₂P(O)NR] with MeSO₂Cl in a 1:1 molar ratio. The precursor Ph₂P(O)NHR (1), as well as its thio analogue Ph₂P(S)NHR (2), were obtained in the reaction between the lithiated amine RNHLi and the corresponding organophosphorus chloride. All compounds were characterized by multinuclear (¹H, ¹³C, and ³¹P) NMR spectroscopy. The molecular structures of 1–3 were established by single-crystal X-ray diffraction. A zigzag polymeric chain is formed in the crystals of 1 and 2 by hydrogen N–H···X (X = O, S) bonding, while the crystal of 3 contains discrete monomeric units with a syn–syn conformation of the O?P(C)₂–N–S(C)(?O)₂ skeleton.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.     

Influence of protonation on substrate and inhibitor interactions at the active site of human monoamine oxidase-A

Although substrate conversion mediated by human monoaminooxidase (hMAO) has been associated with the deprotonated state of their amine moiety, data regarding the influence of protonation on substrate binding at the active site are scarce. Thus, in order to assess protonation influence, steered molecular dynamics (SMD) runs were carried out. These simulations revealed that the protonated form of the substrate serotonin (5-HT) exhibited stronger interactions at the protein surface compared to the neutral form. The latter displayed stronger interactions in the active site cavity. These observations support the possible role of the deprotonated form in substrate conversion. Multigrid docking studies carried out to rationalize the role of 5-HT protonation in other sites besides the active site indicated two energetically favored docking sites for the protonated form of 5-HT on the enzyme surface. These sites seem to be interconnected with the substrate/inhibitor cavity, as revealed by the tunnels observed by means of CAVER program. pK(a) calculations in the surface loci pointed to Glu32?, Asp32?, His???, and Asp132 as candidates for a possible in situ deprotonation step. Docking analysis of a group of inhibitors (structurally related to substrates) showed further interactions with the same two docking access sites. Interestingly, the protonated/deprotonated amine moiety of almost all compounds attained different docking poses in the active site, none of them oriented to the flavin moiety, thus producing a more variable and less productive orientations to act as substrates. Our results highlight the role of deprotonation in facilitating substrate conversion and also might reflect the necessity of inhibitor molecules to adopt specific orientations to achieve enzyme inhibition.     

Accurate intermolecular ground state potential of the Ne-N2 van der Waals complex

Ab initio ground state potential energy surfaces are obtained from interaction energies calculated with the coupled cluster singles and doubles model including connected triples corrections [CCSD(T)] and the aug-cc-pVXZ (X=5,Q,T,D) basis sets augmented with two different sets of midbond functions (denoted 33221 and 33211). The aug-cc-pV5Z-33221 surface is characterized by a T-shaped 49.5 cm(-1) minimum at Re=3.38 Angstroms and a linear saddle point at 3.95 Angstroms with De=36.6 cm(-1). These results agree well with the values provided by the accurate semiempirical potentials available. The rovibronic spectroscopic properties are determined and compared to the available experimental data and previous theoretical results. We study the basis set convergence of the intermolecular potentials and the rotational frequencies. The aug-cc-pVTZ basis sets provide reasonable binding parameters, but seem not to be converged enough for the evaluation of the microwave spectra. The aug-cc-pVQZ basis sets considerably improve the triple zeta results. The differences between the results obtained with the aug-cc-pVTZ-33221 basis set surface and those with the aug-cc-pVQZ-33221 are smaller than those of the corresponding bases with the set of 33211 midbond functions. The aug-cc-pVQZ surfaces are close to the aug-cc-pV5Z, that are expected to be close to convergence. With our best surfaces the errors in the frequencies with respect to the accurate experimental results go down to 0.6%.     

Two-phase channel structures based on alpha-cyclodextrin-polyethylene glycol inclusion complexes

Wide-angle X-ray scattering observations of alpha-cyclodextrin (CD)-poly(ethylene glycol) (PEG) inclusion complexes (ICs) have shown for the first time that two crystalline columnar modifications (forms I and II) are produced in the process of their formation. This was made possible by precise azimuthal X-ray diffraction scanning of oriented IC samples. Form I is characterized by CDs threaded onto PEG chains and arranged along channels in the order head-to-head/tail-to-tail, while form II is formed by unbound CDs also arranged into columns in a head-to-tail and also possibly a head-to-head/tail-to-tail manner, probably as a result of template crystallization on the form I IC crystals. It was shown that similar structural peculiarities are inherent for channel structures based on ICs obtained with PEG with a wide range of molecular weights (MWs). The characteristic feature of ICs based on PEG, especially with MW > 8000, is the presence of unbound polymer in the composition of the complex. The amount of unbound PEG was shown to rise with increasing MW of PEG, resulting in greater imperfections in the IC crystalline structure. The polyblock structure of ICs based on alpha-CD and PEG was therefore proposed.     

Accurate intermolecular ground state potential of the Ar-N2 van der Waals complex

After carrying out a systematic basis set convergence study, we evaluate several ground state potential energy surfaces of the Ar-N(2) van der Waals complex at the coupled cluster singles and doubles model including connected triples corrections. We use the aug-cc-pVXZ (X=5,Q,D) and the daug-cc-pVQZ basis sets augmented with a set of 3s3p2d1f1g (denoted 33211) and 3s3p2d2f1g (denoted 33221) midbond functions, respectively. aug-cc-pVTZ-33211 results were available in the literature. The aug-cc-pV5Z-33211 (daug-cc-pVQZ-33221) surface is characterized by a T-shaped minimum at R(e)=3.709 (3.701) A and of 99.01 (102.50) cm(-1), and a linear saddle point at 4.260 (4.257) A and D(e)=75.28 (79.73) cm(-1). These results are compared with the values provided by the semiempirical potentials available, and those of previous theoretical studies. The basis set convergence of the intermolecular potentials is also analyzed. From the potentials the rovibronic spectroscopic properties are determined. We study the basis set convergence of the rotational frequencies. The binding parameters that characterized the aug-cc-pVTZ-33211 surface are reasonable, but the surface is not good enough to evaluate the microwave spectra. The aug-cc-pVQZ-33211 basis set results considerably improve the triple zeta and are close to the aug-cc-pV5Z-33211. Considering the small differences between the quadruple and the quintuple zeta surfaces, the latter results can be expected to be close to convergence. At this level the differences with respect to the accurate experimental frequencies are in the order of 0.7%. In the case of the daug-cc-pVXZ-33211,33221 (X=5,Q,T,D) series, the convergence of the interaction energies with respect to basis set improvement is not so smooth. The errors in the frequencies obtained with the daug-cc-pVQZ-33221 basis set with respect to experiment are in the order of 0.4%.     

Open-shell localized Hartree-Fock method based on the generalized adiabatic connection Kohn-Sham formalism for a self-consistent treatment of excited states

An effective exact-exchange Kohn-Sham approach for the treatment of excited electronic states, the generalized adiabatic connection open-shell localized Hartree-Fock (GAC-OSLHF) method is presented. The GAC-OSLHF method is based on the generalized adiabatic connection Kohn-Sham formalism and therefore capable of treating excited electronic states, which are not the energetically lowest of their symmetry. The method is self-interaction free and allows for a fully self-consistent computation of excited valence as well as Rydberg states. Results for atoms and small- and medium-size molecules are presented and compared to restricted open-shell Hartree-Fock (ROHF) and time-dependent density-functional results as well as to experimental data. While GAC-OSLHF and ROHF results are quite close to each other, the GAC-OSLHF method shows a much better convergence behavior. Moreover, the GAC-OSLHF method as a Kohn-Sham method, in contrast to the ROHF approach, represents a framework which allows also for a treatment of correlation besides an exchange by appropriate functionals. In contrast to the common time-dependent density-functional methods, the GAC-OSLHF approach is capable of treating doubly or multiply excited states and can be easily applied to molecules with an open-shell ground state. On the nodal planes of the energetically highest occupied orbital, the local multiplicative GAC-OSLHF exchange potential asymptotically approaches a different, i.e., nonzero, value than in other regions, an asymptotic behavior which is known from exact Kohn-Sham exchange potentials of ground states of molecules.     

Protein–Inorganic Array Construction: Design and Synthesis of the Building Blocks

Herein we describe the design and synthesis of the first series of di‐functional ligands for the directed construction of inorganic‐protein frameworks. The synthesized ligands are composed of a metal‐ion binding moiety (terpyridine‐based) conjugated to an epoxysuccinyl peptide, known to covalently bind active cysteine proteases through the active‐site cysteine. We explore and optimize two different conjugation chemistries between the di‐functionalized metal‐ion ligand and the epoxysuccinyl‐containing peptide moiety: peptide‐bond formation (with limited success) and Cu^I‐catalysed click chemistry (with good results). Further, the complexation of the synthesized ligands with Fe^II and Ni^II ions is investigated: the di‐functional ligands are confirmed to behave similarly to the parent terpyridine. As designed, the peptidic moiety does not interfere with the complexation reaction, in spite of the presence of two triazole rings that result from the click reaction. ES‐MS together with NMR and UV/Vis studies establish the structure, the stoichiometry of the complexation reactions, as well as the conditions under which chemically sensitive peptide‐containing polypyridine ligands can undergo the self‐assembly process. These results establish the versatility of our approach and open the way to the synthesis of di‐functional ligands containing more elaborated polypyridine ligands as well as affinity labels for different enzyme families. As such, this paper is the first step towards the construction of robust supramolecular species that cover a size‐regime and organization level previously unexplored.     

Sampling diffusive transition paths

The authors address the problem of sampling double-ended diffusive paths. The ensemble of paths is expressed using a symmetric version of the Onsager-Machlup formula, which only requires evaluation of the force field and which, upon direct time discretization, gives rise to a symmetric integrator that is accurate to second order. Efficiently sampling this ensemble requires avoiding the well-known stiffness problem associated with the sampling of infinitesimal Brownian increments of the path, as well as a different type of stiffness associated with the sampling of the coarse features of long paths. The fine-feature sampling stiffness is eliminated with the use of the fast sampling algorithm, and the coarse-feature sampling stiffness is avoided by introducing the sliding and sampling (S&S) algorithm. A key feature of the S&S algorithm is that it enables massively parallel computers to sample diffusive trajectories that are long in time. The authors use the algorithm to sample the transition path ensemble for the structural interconversion of the 38-atom Lennard-Jones cluster at low temperature.     

New Perspectives for Old Clusters: Anderson–Evans Anions as Building Blocks of Large Polyoxometalate Frameworks in a Series of Heterometallic 3 d–4 f Species

A series of nine [Sb₇W₃₆O₁₃₃Ln₃M₂(OAc)(H₂O)₈]^17? heterometallic anions ( Ln₃M₂ ; Ln=La–Gd, M=Co; Ln=Ce, M=Ni and Zn) have been obtained by reacting 3 d metal disubstituted Krebs‐type tungstoantimonates(III) with early lanthanides. Their unique tetrameric structure contains a novel {MW₉O₃₃} capping unit formed by a planar {MW₆O₂₄} fragment to which three {WO₂} groups are condensed to form a tungstate skeleton identical to that of a hypothetical trilacunary derivative of the ?‐Keggin cluster. It is shown, for the first time, that classical Anderson–Evans {MW₆O₂₄} anions can act as building blocks to construct purely inorganic large frameworks. Unprecedented reactivity in the outer ring of these disk‐shaped species is also revealed. The Ln₃M₂ anions possess chirality owing to a {Sb₄O₄} cluster being encapsulated in left‐ or right‐handed orientations. Their ability to self‐associate in blackberry‐type vesicles in solution has been assessed for the Ce₃Co₂ derivative.