Rhodathiaboranes with `anomalous' electron counts: synthesis, structure and reactivity

Analysis of the structures of 8,8-(PPh₃)₂-8,7-nido-RhSB₉H₁₀ and 9,9-(PPh₃)₂-9,7,8-nido-RhC₂B₈H₁₁ by RMS misfit calculations has confirmed that these rhodaheteroboranes possess nido 11-vertex cluster geometries in apparent contravention of Wade's rules. However, examination of the molecular structures of both species shows that the {RhP₂} planes are inclined by ca. 66° with respect to the metal-bonded SB₃ or CB₃ faces, and that two weak ortho-CHRh agostic interactions occupy the vacant co-ordination position thereby created. As a consequence of these agostic bonds the Rh atom, and hence the overall cluster, is provided with an additional electron pair, meaning that their nido structures are now fully consistent with Wade's rules. The chelated diphosphine compound 8,8-(dppe)-8,7-nido-RhSB₉H₁₀ is similar to the PPh₃ compound in showing the same agostic bonding. Attempts to prepare a bis-P(OMe)₃ analogue result in ligand scavenging and the formation of 8,8,8-{P(OMe)₃}₃-8,7-nido-RhSB₉H₁₀. Similarly, reaction between Cs[6-arachno-SB₉H₁₂] and RhCl(dmpe)CO does not result in CO loss but in formation of 8,8-(dmpe)-8-(CO)-8,7-nido-RhSB₉H₁₀, shown to exist as a mixture of two of three possible rotamers. Deprotonation of 8,8-(PPh₃)₂-8,7-nido-RhSB₉H₁₀ and 8,8-(dppe)-8,7-nido-RhSB₉H₁₀ with MeLi yields the anions [1,1-(PPh₃)₂-1,2-closo-RhSB₉H₉]⁻ and [1,1-dppe-1,2-closo-RhSB₉H₉]⁻, respectively, with octadecahedral cage structures. It is argued that anion formation causes the agostic bonding to be `switched-off' and results in the cluster adopting the closo architecture predicted by Wade's rules. This structural change is fully reversible on reprotonation, and if reprotonation of [1,1-(dppe)-1,2-closo-RhSB₉H₉]⁻ is carried out in MeCN, the product 8,8-(dppe)-8-(MeCN)-8,7-nido-RhSB₉H₁₀ forms. Interestingly, 8,8-(dppe)-8-(MeCN)-8,7-nido-RhSB₉H₁₀ reconverts to 8,8-(dppe)-8,7-nido-RhSB₉H₁₀ on standing in CDCl₃, suggesting that the agostic bonding is sufficiently strong to displace co-ordinated MeCN. All new compounds are fully characterised by multinuclear NMR spectroscopy and, in many cases, by single crystal X-ray diffraction.     

Local elevation: A method for improving the searching properties of molecular dynamics simulation

Summary The concept of memory has been introduced into a molecular dynamics algorithm. This was done so as to persuade a molecular system to visit new areas of conformational space rather than be confined to a small number of low-energy regions. The method is demonstrated on a simple model system and the 11-residue cyclic peptide cyclosporin A. For comparison, calculations were also performed using simulated temperature annealing and a potential energy annealing scheme. Although the method can only be applied to systems with a small number of degrees of freedom, it offers the chance to generate a multitude of different low-energy structures, where other methods only give a single one or few. This is clearly important in problems such as drug design, where one is interested in the conformational spread of a system.     

Construction of multiporphyrin arrays using ruthenium and rhodium coordination to phosphines

The synthesis of linear multiporphyrin arrays with mono- and bisphosphine-substituted porphyrins as ligand donors and ruthenium(II) or rhodium(III) porphyrins as ligand acceptors is described. With appropriate amounts of the building blocks mixed, linear dimeric and trimeric arrays have been synthesized and analyzed by (1)H NMR and (31)P NMR spectroscopy. The Ru/Rh acceptor porphyrins can be located either at the periphery or in the center of the array. Likewise, the monophosphine porphyrins can be positioned at the periphery, thus allowing a high degree of freedom in the overall composition of the arrays. This way, both donor and acceptor porphyrins can act as chain extenders or terminators. One of the trimeric complexes with two nickel and one ruthenium porphyrin has also been analyzed by X-ray crystallography. Attempts have also been made to synthesize higher order arrays by mixing appropriate amounts of the porphyrins; however, from the NMR data it cannot be concluded if monodisperse five, seven, or nine porphyrin arrays are present or if the solutions are composed of a statistical mixture of smaller and larger arrays.     

Efficient solid-phase-based total synthesis of the bisintercalator TANDEM

[reaction: see text] In this article, the first solid-phase-based total synthesis of TANDEM, a synthetic analogue of triostin A, is described. In initial studies, the synthesis incorporated depsipeptide formation, introduction of chromophores, and disulfide bond formation on the solid phase, prior to a final solution-phase macrolactamization, to give the target molecule. Although pure TANDEM was obtained in an overall yield comparable to those for all syntheses to date, the yield of the final cyclization was low (11%). A more efficient approach involved removal from the solid phase prior to disulfide bond formation. The resulting linear peptide underwent macrolactamization under mild conditions and high dilution. Final disulfide bond formation was essentially quantitative and gave the target molecule, TANDEM, in an overall yield of 18%. The final compound was assessed for its ability to bind to 5'-TpA sequences on DNA by DNase I footprinting. This efficient synthesis sets the stage for a study of the structure-activity relationship of TANDEM and the natural product triostin A, with analogues containing "point mutations" at every site within the cyclic compounds.     

The mechanism of photoinduced acylation of amines by N-acyl-5,7-dinitroindoline as determined by time-resolved infrared spectroscopy

[reaction: see text] The photochemistry of N-acyl-5,7-dinitroindoline (1) was studied in acetonitrile using nanosecond time-resolved infrared (TRIR) spectroscopy. Upon photolysis, two nearly but not completely overlapping sets of transient IR bands are observed that are assigned to two non-interconvertible conformers of mixed acetic nitronic anhydride 7. While syn-7 reverts rapidly to 1, anti-7 is long-lived and is able to acylate amines. Results of density functional theory calculations support conclusions based on experimental TRIR data.     

Inorganic-organic hybrids of the p,p′-diphenylmethylenediphosphinate ligand with bivalent metals: a new 2D-layered phenylphosphinate zinc(II) complex

By reaction of Zn(CH₃COO)₂ with p,p′-diphenylmethylenediphosphinic acid in water a new inorganic-organic polymeric hybrid of formula [Zn(CH₂(P(Ph)O₂)₂)] has been synthesized and completely characterized. The X-ray analysis established that the structure consists of 2D-layered polymeric array, the 2D-sheets being built up through strong covalent linkages between the zinc metal and the oxygen donors of the phenylphosphinate ligand. The 2D-layers, which are featuring a mesh-net fashion, present voids of various dimensionality, up to 24-membered rings. The organic parts of the hybrid ligand, namely the phenyl rings, are shielding the inorganic skeleton of the layers, preventing the propagation of the polymer in the third dimension. No water molecules are present in the lattice, both of coordination and crystallization. Crystal data are: monoclinic, P2₁/c, a=11.840(2), b=9.646(9), c=12.516(5) Å, β=95.03(2), V=1423.9(15) Å³, Z=4. The solid material has been characterized by ³¹P MAS NMR spectroscopy and thermogravimetric analysis.     

High resolution protein separations using affinity ultrafiltration with small charged ligands

Although the feasibility of affinity ultrafiltration was demonstrated more than 20 years ago, commercial applications have not developed due to the high cost and practical limitations of the large macroligands needed for highly selective separations. The objective of this study was to examine the use of small charged affinity ligands for protein purification by exploiting electrostatic interactions between the charged complex and an electrically-charged membrane. Experiments were performed using bovine serum albumin and ovalbumin with Cibacron Blue as the affinity ligand. Negatively charged versions of a composite regenerated cellulose membrane were generated by covalent attachment of a sulfonic acid functionality. Binding experiments were used to identify appropriate conditions for protein separations. The selectivity for the separation of BSA and ovalbumin was a function of the solution conditions, Cibacron Blue concentration, and membrane charge, with the addition of Cibacron Blue causing a 30-fold increase in selectivity. A diafiltration process was performed at the optimal conditions, giving a BSA product with a purification factor of more than 90-fold and a yield greater than 90%. These results clearly demonstrate the potential of using a small charged affinity ligand for high resolution protein separations.     

High-throughput purification of combinatorial libraries I: a high-throughput purification system using an accelerated retention window approach

We have developed a high-throughput purification system to purify combinatorial libraries at a 50-100-mg scale with a throughput of 250 samples/instrument/day. We applied an accelerated retention window method to shorten the purification time and targeted one fraction per injection to simplify data tracking, lower QC workload, and simplify the postpurification processing. First, we determined the accurate retention time and peak height for all compounds using an eight-channel parallel LC/UV/MS system, and calculated the specific preparative HPLC conditions for individual compounds. The preparative HPLC conditions include the compound-specific gradient segment for individual compounds with a fixed gradient slope and the compound-specific UV or ELSD threshold for triggering a fraction collection device. A unique solvent composition or solvent strength was programmed for each compound in the preparative HPLC in order to elute all compounds at the same target time. Considering the possible deviation of the predicted retention time, a 1-min window around the target time was set to collect peaks above a threshold based on UV or ELSD detection. Dual column preparative instruments were used to maximize throughput. We have purified more than 500 000 druglike compounds using this system in the past 3 years. We report various components of this high-throughput purification system and some of our purification results.     

An ESR study of some group IVB free radical adducts of diethylketomalonate

The formation of the compound RSnX(acac)₂ (acac = 2,4-pentanedionato) by reaction of bis(2,4-pentanedionato)tin(II) on a halide RX with R = CH₃, C₂H₅, C₄H₉, C₆H₅, CH₂I, (C₆H₅)₃SnCH₂, (C₂H₅)₃SnCH₂ and X = I, Br has been studied by polarography. At 25°C, it is in fact an equilibrium whose constant has been measured. The intermediate formation of the ion-pair [RSn(acac)₂⁺X^?] has allowed us to explain the experimental results.