Biomedical subjects
Publications and source records attributed to Richard Goddard.
A versatile synthetic method has been developed to incorporate photochromic azobenzene moieties into tetraphenylporphyrin frameworks in an orthogonal fashion, positioning the phenylazo substituents above and below the plane of the macrocycle. Surprisingly, photoisomerization is completely suppressed in the resulting azobenzene-confined porphyrins.
Facile rearrangement of azobenzenes is shown to occur in cases where the azo group is placed in the ortho position to carbonyl electrophiles to furnish the indazole skeleton. While this study demonstrates the illusive nature of o-formylazobenzenes, it offers potential for the synthesis of indazoles and related heterocycles.
The solution conformations of tetrameric and hexameric cyclopeptides containing alternating L-proline and 6-aminopicolinic acid subunits strongly depend on solvent polarity. Whereas in polar solvents, such as d6-DMSO, both peptides prefer on average symmetric conformations with converging NH groups, in less polar chloroform intramolecular hydrogen bonds to the peptide NH groups stabilize other, and in the case of the hexapeptide, non-symmetrical conformations. Independent of the solvent, both peptides interact with anions via their NH groups but whereas anion binding requires a cleavage of the intramolecular hydrogen bonds accompanied by a conformational reorganization in chloroform, in polar solvents the peptides are already well preorganized for anion complexation. Complex formation between anions and the cyclic hexapeptide was even detected in highly competitive D2O/CD3OD or H2O/CH3CN mixtures, which was attributed to the special sandwich-type structure of the complexes formed. Stabilizing these 2:1 aggregates by covalently linking two cyclopeptide rings together affords ditopic receptors with a high anion affinity in protic solvents. Complex stability depends on the structure of the linker with which the two receptor moieties are connected and even more potent anion receptors were obtained by a dynamic combinatorial optimization of this linking unit.
We report two crystal structures of a synthetic porphyrin molecule which was programmed for self-assembly. The same groups which ensure that bacteriochlorophylls c, d, and e can self-assemble into the chlorosomal nanorods, the photosynthetic antenna system of some green bacteria, have been engineered into desired positions of the tetrapyrrolic macrocycle. In the case of the 5,15-meso-substituted anchoring groups, depending upon the concentration, by using the same crystallization solvents, either a tetragonal or a layered structure of porphyrin stacks were encountered. Surprisingly, pi-pi interactions combined with extensive dispersive interactions, which also encompass cyclohexane, one of the crystallization solvents, win over putative hydrogen bonding. We are aware that our compounds differ considerably from the natural bacteriochlorophylls, but based upon our findings, we now question the hydrogen-bonding network, previously proposed to organize stacks of bacteriochlorophylls. Transmission electron microscopy (TEM), atomic force microscopy (AFM), and small-angle X-ray scattering (SAXS) on various isomeric compounds support our challenge of current models for the chlorosomal antenna as these show structures, astonishingly similar to those of chlorosomes.
The structure and vibrational spectra of hexamethylpyrromethene (HMPM) have been investigated by X-ray crystallography, IR and Raman spectroscopies, and density functional theory calculations. HMPM crystallizes in the form of dimers, which are held together by bifurcated N-H(...N)(2) hydrogen bonds, involving one intramolecular and one intermolecular N-H...N interaction. The monomers are essentially planar, and the mean planes of the monomers lie approximately perpendicular to one another, so that the four N atoms in the dimer form a distorted tetrahedron. The structure of the HMPM dimer is well-reproduced by B3LYP/6-31G calculations. A comparison of the calculated geometry of the dimer with that of the monomer reveals only small changes in the N-H...N entity and the methine bridge angles upon dimerization. These are a result of weakening of the intramolecular N-H...N hydrogen bond and the formation of a more linear N-H...N intermolecular hydrogen bond. Using an empirical relation between the shift of the N-H stretching frequency of pyrrole and the enthalpy of adduct formation with bases [Nozari, M. S.; Drago, R. S. J. Am. Chem. Soc. 1970, 92, 7086-7090], estimates of the strength of the intra- and intermolecular hydrogen bonds are obtained. IR and Raman spectroscopies of HMPM and its isotopomers deuterated at the pyrrolic nitrogen atom and at the methine bridge reveal that the molecule is monomeric in nonpolar organic solvents but dimeric in a solid Ar matrix and in KBr pellets. The matrix IR spectra show a splitting of vibrational modes for the dimer, particularly those involving the N-H coordinates. Due to intrinsic deficiencies of the B3LYP/6-31G approximation, a satisfactory reproduction of these modes of the monomeric and dimeric HMPM requires specific adjustments of the NH scaling factors for the calculated force constants and, in the case of the NH out-of-plane modes of HMPM dimers, also of intra- and intermolecular coupling constants. This parametrization does not significantly affect the other calculated modes, which in general reveal a very good agreement with the experimental data.
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A unique family of N-heterocyclic carbenes derived from bioxazolines (IBiox) suitable for application in transition-metal catalysis is described. The ligands are electron rich, sterically demanding, and have restricted flexibility. Their usefulness has been demonstrated in the Suzuki-Miyaura cross-coupling of sterically hindered aryl chlorides and boronic acids. For the first time, tetraortho-substituted biaryls with methyl and larger ortho-substituents have been synthesized from aryl chlorides using the Suzuki-Miyaura method.
The preparation and resolution of a series of axially chiral quinazoline-containing ligands is described in which the key steps are the metal-catalyzed naphthyl-phosphorus bond formation, the naphthalene-quinazoline Suzuki coupling, and the preparation of the Suzuki electrophilic components from the corresponding imidate and anthranilic acid. Diastereomeric palladacycles derived from the racemic phosphinamines and (+)-di-mu-chlorobis[(R)-dimethyl(1-(1-naphthyl)ethyl)aminato-C2,N]dipalladium(II) were separated by fractional crystallization. The configuration of the resulting diastereomers was determined by X-ray crystallographic analysis. Displacement of the resolving agent by reaction with 1,2-bis(diphenylphosphino)ethane afforded enantiopure ligand in each case. Their rhodium complexes were prepared and applied in the enantioselective hydroboration of a range of vinylarenes. The quinazolinap catalysts were found to be extremely active, giving excellent conversions, good to complete regioselectivities, and the highest enantioselectivities obtained to date for several members of the vinylarene class, including cis-beta-methylstyrene (97%), cis-stilbene (99%), and indene (99.5%).
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There are nearly 43,000 hip replacements and 33,000 knee replacements performed each year in the United Kingdom. Many of these require a blood transfusion. However, there has been increased public concern about the safety of blood transfusion and various techniques are used to decrease the need for allogenic transfusion. Postoperative blood salvage and reinfusion is one of them. We studied 186 consecutive patients who underwent unilateral uncemented hip or knee arthroplasty. Ninety-four had re-infusion drains and 92 had suction drains. We have compared the allogenic transfusion requirements for the two groups. We have analyzed patient and operative factors to determine whether they are predictive for risk of allogenic blood transfusion. Cost analysis was performed to determine whether the use of a re-infusion drain is a cost effective technique. Re-infusion drains significantly decreased the requirements for allogenic blood transfusion (p = 0.001). Twenty-one percent of the re-infusion drain group and 45.7 % of the suction drain group required allogenic blood transfusion. The only preoperative factor that determined whether the patient required allogenic blood transfusion was pre-operative haemoglobin. We found that age, gender, type of surgery (hip replacement or knee replacement) and whether the patient had tourniquet or not (in knee replacement) did not alter the requirements for allogenic blood transfusion. The mean transfusion costs were slightly less for re-infusion drain group (ł 182.70 per patient for re-infusion drain group and ł 196.75 per patient for suction drain group, p = 0.009). The hospital stay was also significantly reduced (11.0 days for re-infusion drain group as opposed to 12.6 days for suction drain group (p = 0.0248). Based on these findings, re-infusion drains appear as a cost effective means of reducing the requirement for allogenic blood transfusion following primary hip and knee arthroplasty.
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The 2-aminopyrimidin-5-yl ligand is revealed to be a promising candidate for the construction of supramolecular porphyrin arrays with broad absorption bands for efficient light-harvesting. 10-Mono- and 10,20-di(2-aminopyrimidin-5-yl) derivatives of 5,15-bis(3,5-di-tert-butylphenyl)porphyrin have been synthesized in high yield. Their Zn(II) salts show variable concentration and temperature-dependent UV/vis spectra in solution, consistent with supramolecular aggregation. Whereas the FAB mass spectra of the monosubsituted derivative in toluene suggest the formation of a tetramer at high concentrations and low temperatures (estimated association free enthalpy Delta H = 220 +/- 10 kJ/mol), the larger splitting of the Sorret band (ca. 40 nm) in the variable temperature UV/vis spectra of the disubstituted bis(3,5-di-tert-butylphenyl)porphyrin is indicative of yet higher aggregates involving both 2-aminopyrimidin-5-yl groups. The tetrameric nature of the monosubsituted derivative is confirmed by X-ray analysis, which reveals that two of the 2-aminopyrimidin-5-yl groups are encapsulated by the aggregate and consequently are prevented from undergoing hydrogen bonding. NMR studies show there is no exchange of the 2-aminopyrimidin-5-yl groups, so the tetramer is rigid, which is confirmed by molecular modeling calculations. The tetramer formation is governed by pi-pi interactions, metal coordination, and hydrogen bonding. The di(2-aminopyrimidin-5-yl) derivative forms strongly scattering solutions, which upon standing form green flocculate precipitates, reminiscent of shaken suspensions of bacteriochlorophyll c.
Enantiomerically pure imidazolium triflates can be readily prepared from bioxazolines and oxazolineimines; deprotonation of imidazolium triflate 2 gives a chiral N-heterocyclic carbene that can act as a ligand in a catalytically active palladium complex.
A concise approach to a family of potent herbicidal 10-membered lactones is described on the basis of ring-closing metathesis (RCM) as the key step for the formation of the medium-sized ring. This includes the first total syntheses of herbarumin I (1) and II (2) as well as the synthesis of several possible macrolides of the pinolidoxin series. A comparison of their spectral and analytical data with those of the natural product allowed us to establish the stereostructure of pinolidoxin, a potent inhibitor of induced phenylalanine ammonia lyase (PAL) activity, as shown in 46. This finding, however, makes clear that a previous study dealing with the relative and absolute stereochemistry of this phytotoxic agent cannot be correct. An important aspect from the preparative point of view is the fact that the stereochemical outcome of the RCM reaction can be controlled by the choice of the catalyst. Thus, use of the ruthenium indenylidene complex 16 always leads to the corresponding (E)-alkenes, whereas the second generation catalyst 17 bearing an N-heterocyclic carbene ligand affords the isomeric (Z)-olefin with good selectivity. This course is deemed to reflect kinetic versus thermodynamic control of the cyclization reaction and therefore has potentially broader ramifications for the synthesis of medium-sized rings in general. A further noteworthy design feature is the fact that D-ribose is used as a convenient starting material for the preparation of both enantiomers of the key building block 14 by means of a "head-to-tail" interconversion strategy.
The preparation of [2-(S(p))-[(trans-(2R,5R)-2,5-dialkylpyrrolidinyl)methyl]]ferrocenyldiphenyl phosphines, new ferrocenylphosphinamine ligands possessing one site of planar and two stereogenic centers, is described. trans-(2R,5R)-2,5-Dialkyl-1-(ferrocenylmethyl)pyrrolidines were diastereoselectively lithiated and quenched with chlorodiphenylphosphine. For the dimethyl ligand, chemical yields of up to 65% and des of up to 90% were obtained whereas the diethyl ligand afforded lower chemical yields (10%) and des of 78%. Diastereomerically pure material was obtained in both cases after a single recrystallization from ethanol. (S)-Planar chirality was confirmed by X-ray crystallographic analysis of the dimethyl ligand. The palladium complexes of the new ligands were applied in the allylic alkylation of 1,3-diphenylprop-2-enyl acetate with reasonable chemical yields and moderate ees of up to 36% and 38% when dimethyl malonate and dimethyl methyl malonate were employed as nucleophiles, respectively. Importantly, it was found that the new ligands possessing the combination of planar and central chirality gave the opposite enantiomeric alkylation products compared to ligands which possess only the central chirality of the trans-2,5-dimethylpyrrolidinyl moiety. Solution NMR studies of the 1,3-diphenylallyl palladium complex of the dimethyl ligand revealed the presence of only the exo-configured allyl diastereomer.
Two cyclic hexapeptides containing alternating all R and all S configured Ll-(4R/S)-hydroxyproline and 6-aminopicolinic acid subunits are presented, and the influence of the hydroxyl groups on the solubility, conformation, and receptor properties is investigated. Cyclopeptide 2, containing the natural 4R configured hydroxyproline, adopts a conformation similar to that of the unsubstituted peptide 1, which is able to bind anions such as halides and sulfate in aqueous solution. 2 also interacts with these anions, but whereas 1 forms sandwich type 2:1 complexes, in which the anion is bound by two cyclopeptide moieties, 2 forms 1:1 complexes. The stabilities of the halide and sulfate complexes of 2 range between 10(0) and 10(2) M(-1) in 80% D(2)O/CD(3)OD. Complex formation is detectable even in water, but with slightly smaller stability constants. Using this information a quantitative evaluation of the stability of the 2:1 complexes of 1, for which overall stability constants in the order 10(4) to 10(5) M(-2) in 80% D(2)O/CD(3)OD were observed, was made. In contrast to 2, the conformation of 3, containing the non-natural 4S configured hydroxyproline, is strongly affected by the presence of the hydroxyl groups. In d(6)-DMSO and methanol/water mixtures a slow conformational equilibrium between two C(3)-symmetrical conformers is observed, and 3 is thus much less preorganized for anion binding than either 1 or 2.
Despite the comprehensive treatment of test validity in most technical manuals, test authors appear to routinely assume that clients and professionals will score their instruments without error. Recently Allard and Faust challenged this assumption by suggesting that error rates "may not be rare or benign" and demonstrated that tests with more complex scoring procedures were associated with a greater number of scoring errors. This study investigated error rates that resulted from hand scoring seven psychometric tests commonly employed in psychological practice. Significant and serious error rates were identified for both psychologist and client scorers across all tests investigated. Scoring complexity was found to predict the base rate of scorer errors. The findings suggest that greater development in and attention to test-scoring procedures is required to restrict the likelihood of scorer error.