Stereoselective Ligand Research Articles

Stereocontrolled Self-Assembly of a Helicate-Bridged CuI12L4 Cage That Emits Circularly Polarized Light.

Control over the stereochemistry of metal-organic cages can give rise to useful functions that are entwined with chirality, such as stereoselective guest binding and chiroptical applications. Here, we report a chiral CuI12L4 pseudo-octahedral cage that self-assembled from condensation of triaminotriptycene, aminoquinaldine, and diformylpyridine subcomponents around CuI templates. The corners of this cage consist of six head-to-tail dicopper(I) helicates whose helical chirality can be controlled by the addition of enantiopure 1,1'-bi-2-naphthol (BINOL) during the assembly process. Chiroptical and nuclear magnetic resonance (NMR) studies elucidated the process and mechanism of stereochemical information transfer from BINOL to the cage during the assembly process. Initially formed CuI(BINOL)2 thus underwent stereoselective ligand exchange during the formation of the chiral helicate corners of the cage, which determined the overall cage stereochemistry. The resulting dicopper(I) helicate corners of the cage were also shown to generate circularly polarized luminescence.

A proteome-wide map of 20(S)-hydroxycholesterol interactors in cell membranes.

Oxysterols (OHCs) are hydroxylated cholesterol metabolites that play ubiquitous roles in health and disease. Due to the non-covalent nature of their interactions and their unique partitioning in membranes, the analysis of live-cell, proteome-wide interactions of OHCs remains an unmet challenge. In this manuscript, we present a structurally precise chemoproteomics probe for the biologically active molecule 20(S)-hydroxycholesterol (20(S)-OHC) and provide a map of its proteome-wide targets in the membranes of living cells. Our target catalogue consolidates diverse OHC ontologies and demonstrates that OHC-interacting proteins cluster with specific processes in immune response and cancer. Competition experiments reveal that 20(S)-OHC is a chemo-, regio-, and stereoselective ligand for the protein Tmem97 (the σ2 receptor), enabling us to reconstruct the 20(S)-OHC:Tmem97 binding site. Our results demonstrate that multiplexed, quantitative analysis of cellular target engagement can expose new dimensions of metabolite activity and identify actionable targets for molecular therapy.

Robert S. Paton

Angewandte Chemie International EditionVolume 56, Issue 45 p. 13936-13936 Author ProfileFree Access Robert S. Paton First published: 05 July 2017 https://doi.org/10.1002/anie.201706565AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Graphical Abstract “If I were not a scientist, I would be working in a record store. My favorite piece of music is Steve Reich's New York Counterpoint ...” This and more about Robert S. Paton can be found on page 13936. Robert S. Paton The author presented on this page has recently published his 10th article in Angewandte Chemie in the last 10 years: “Enantioselective Silver and Amine Co-catalyzed Desymmetrizing Cycloisomerization of Alkyne-Linked Cyclohexanones”: R. Manzano, S. Datta, R. S. Paton, D. J. Dixon, Angew. Chem. Int. Ed. 2017, 56, 5834; Angew. Chem. 2017, 129, 5928. Date of birth: December 1981 Position: Associate Professor, Department of Chemistry, University of Oxford E-mail: robert.paton@chem.ox.ac.uk Homepage: paton.chem.ox.ac.uk ORCID: 0000-0002-0104-4166 Education: 2004 MSci, University of Cambridge 2008 PhD with Jonathan Goodman, University of Cambridge 2009 Postdoctoral research with K. N. Houk, University of California, Los Angeles Awards: 2015 RSC Harrison–Meldola Memorial Medal; 2015 ACS COMP Division Outstanding Junior Faculty Award; 2014 Silver Jubilee Award, Molecular Graphics and Modelling Society; 2014 ACS Organic Division Academic Young Investigator; 2015 Thieme Chemistry Journal Award Research: Catalysts and ligand design; contact ion pairs; epigenetic mechanisms Hobbies: Music collection; DJing; trivia If I were not a scientist, I would be working in a record store. My favorite piece of music is Steve Reich's New York Counterpoint. My favorite foods are (kal-guksu), (gimbap), and (sujebi). My favorite quote is “It doesn't matter how beautiful your theory is, it doesn't matter how smart you are. If it doesn't agree with experiment, it's wrong” (Feynmann). The most significant scientific advance of the last 100 years has been the discovery of penicillin. The biggest problem that scientists face is that “people have had enough of experts” (Brexiteer politician Michael Gove). My favorite piece of research is John Snow's use of statistics in 1854 to pinpoint the source of a London cholera epidemic to a communal water pump. Guaranteed to make me laugh are Stewart Lee; Aziz Ansari; a dog on a skateboard. If I could go back in time and do any experiment, it would be to discover molecular chirality with Pasteur. My greatest achievement has been meeting my wife. My favorite place on earth is Trinity Hall, Cambridge. My 5 top papers: 1“Computational ligand design in enantio- and diastereoselective ynamide [5+ 2] cycloisomerization”: R. Straker, Q. Peng, A. Mekareeya, R. S. Paton, E. A. Anderson, Nature Communications 2016, 7, 10109. (Theory-led optimization of stereoselective ligands, validated for higher-order cycloisomerizations.) 2“Catalytic enantioselective synthesis of indanes via cation-directed 5-endo-trig cyclization”: C. P. Johnston, A. Kothari, T. Sergeieva, S. L. Okovytyy, K. E. Jackson, R. S. Paton, M. D. Smith, Nature Chem. 2015, 7, 171. (Geometric restriction is not always decisive in competitive kinetically controlled ring-closing reactions.) 3“Enantioselective Desymmetrization of Prochiral Cyclohexanones via Organocatalytic Intramolecular Michael Additions to α,β-Unsaturated Esters”: A. D. Gammack-Yamaguta, S. Datta, K. E. Jackson, L. Stegbauer, R. S. Paton, D. J. Dixon, Angew. Chem. Int. Ed. 2015, 54, 4899; Angew. Chem. 2015, 127, 4981. (Calculations enabled the development of a highly enantioselective primary amine catalyst.) 4“A Counterion-Directed Approach to the Diels–Alder Paradigm: Cascade Synthesis of Tricyclic Fused Cyclopropanes”: E. Kiss, C. D. Campbell, R. W. Driver, J. D. Jolliffe, R. Lang, T. Sergieiva, S. Okovytyy, R. S. Paton, M. D. Smith, Angew. Chem. Int. Ed. 2016, 55, 13813; Angew. Chem. 2016, 128, 14017. (Synthesis and computation show how counterion coordination controls diastereoselectivity.) 5“Correlating Reactivity and Selectivity to Cyclopentadienyl Ligand Properties in Rh(III)-Catalyzed C−H Activation Reactions: An Experimental and Computational Study”: T. Piou et al., J. Am. Chem. Soc. 2017, 139, 1296 (A predictive tool for C−H functionalization.) Volume56, Issue45November 6, 2017Pages 13936-13936 ReferencesRelatedInformation

Explaining the Disparate Stereoselectivities of N-Oxide Catalyzed Allylations and Propargylations of Aldehydes

A simple electrostatic model explains the enhanced stereoselectivity of N-oxide catalyzed allylations compared to propargylations, which in turn explicates the dearth of stereoselective N-oxide propargylation catalysts. These results suggest that N-oxide catalysts that are effective for both allylations and propargylations can be designed by targeting inherently stereoselective ligand configurations and through the manipulation of distortion effects in the operative transition states.

Nona-Coordinated Chiral Eu(III) Complexes with Stereoselective Ligand–Ligand Noncovalent Interactions for Enhanced Circularly Polarized Luminescence

Circularly polarized luminescence (CPL) of chiral Eu(III) complexes with nona- and octa-coordinated structures, [Eu(R/S-iPr-Pybox)(D-facam)(3)] (1-R/1-S; R/S-iPr-Pybox, 2,6-bis(4R/4S-isopropyl-2-oxazolin-2-yl)pyridine; D-facam, 3-trifluoroacetyl-d-camphor), [Eu(S,S-Me-Ph-Pybox)(D-facam)(3)] (2-SS; S,S-Me-Ph-Pybox, 2,6-bis(4S-methyl-5S-phenyl-2-oxazolin-2-yl)pyridine), and [Eu(Phen)(D-facam)(3)] (3; Phen, 1,10-phenanthroline) are reported, and their structural features are discussed on the basis of X-ray crystallographic analyses. These chiral Eu(III) complexes showed relatively intense photoluminescence due to their (5)D(0) → (7)F(1) (magnetic-dipole) and (5)D(0) → (7)F(2) (electric-dipole) transition. The dissymmetry factors of CPL (g(CPL)) at the former band of 1-R and 1-S were as large as -1.0 and -0.8, respectively, while the g(CPL) of 3 at the (5)D(0) → (7)F(1) transition was relatively small (g(CPL) = -0.46). X-ray crystallographic data indicated specific ligand-ligand hydrogen bonding in these compounds which was expected to stabilize their chiral structures even in solution phase. CPL properties of 1-R and 1-S were discussed in terms of transition nature of lanthanide luminescence.

Frontal affinity chromatography with MS detection of the ligand binding domain of PPARγ receptor: Ligand affinity screening and stereoselective ligand–macromolecule interaction

In this study we report the development of new chromatographic tools for binding studies based on the gamma isoform ligand binding domain (LBD) of peroxisome proliferator-activated receptor (PPARγ) belonging to the nuclear receptor superfamily of ligand-activated transcription factors. PPARγ subtype plays important roles in the functions of adipocytes, muscles, and macrophages with a direct impact on type 2 diabetes, dyslipidemia, atherosclerosis, and cardiovascular disease. In order to set up a suitable immobilization chemistry, the LBD of PPARγ receptor was first covalently immobilized onto the surface of aminopropyl silica particles to create a PPARγ-Silica column for zonal elution experiments and then onto the surface of open tubular (OT) capillaries to create PPARγ-OT capillaries following different immobilization conditions. The capillaries were used in frontal affinity chromatography coupled to mass spectrometry (FAC–MS) experiments to determine the relative binding affinities of a series of chiral fibrates. The relative affinity orders obtained for these derivatives were consistent with the EC50 values reported in literature. The optimized PPARγ-OT capillary was validated by determining the Kd values of two selected compounds. Known the role of stereoselectivity in the binding of chiral fibrates, for the first time a detailed study was carried out by analysing two enantioselective couples on the LBD-PPARγ capillary by FAC and a characteristic two-stairs frontal profile was derived as the result of the two saturation events. All the obtained data indicate that the immobilized form of PPARγ-LBD retained the ability to specifically bind ligands.

Exploration of regeneration and reusability of human serum albumin as a stereoselective ligand for chiral separation in affinity ultrafiltration

The reusability of human serum albumin (HSA) as a stereoselective ligand for d,l-tryptophan separation in the affinity ultrafiltration (UF) system has been demonstrated by readjusting the medium pH from an acidic condition to a basic condition in this work. The native and recovered HSA molecules exhibit a similar d,l-tryptophan separation factor of 5–7 under the same experimental conditions. In addition, a high recovery percentage of HSA of above 80% has also been obtained by controlling both the membrane pore size and the membrane hydrophilicity. The combination of these two features (i.e. HSA reusability and high recovery) is very helpful for the large-scale industrial application of the affinity UF system in chiral separation. On the other hand, it has been found that the HSA binding capability to l-tryptophan could be affected by the solution ionic strength. A higher solution ionic strength may result in a decrease in amounts of l-tryptophan bound to HSA due to the changes in solution environment and HSA structure.

Polymeric Membranes for Chiral Separation of Pharmaceuticals and Chemicals

The optical resolution or chiral separation of one specific enantiomer from others is in demand for the production of pharmaceuticals because many pharmaceuticals exist as stereoisomers, with each enantiomer having different biological activity. There is considerable demand for separation techniques appropriate for the large-scale resolution of chiral molecules. Chiral separation of racemic mixtures of pharmaceuticals through chiral or achiral polymeric membranes with or without a chiral selector represents a promising system for future commercial application. This article reviews several polymeric materials for the chiral separation of pharmaceuticals. Several chiral separation membranes were prepared from chiral polymers where enantioselectivity was generated from chiral carbons in the main chain. However, it is rather difficult to generate excellent chiral separation membranes from chiral polymers alone, because racemic penetrants mainly encounter the flexible side chains of the membrane polymers. Therefore, chiral separation membranes were also prepared using polymers with a chiral branch. Furthermore, several molecules have been used for specific interactions between the molecules and specific pharmaceuticals or drugs in chiral separation membranes. Cyclodextrins, crown ether derivatives, albumin, and DNA are commonly used as stereoselective ligands in chiral separation membranes. Finally, this article discusses future trends in polymeric materials for chiral separation membranes.

A fine match between the stereoselective ligands and membrane pore size for enhanced chiral separation

AbstractA D,L‐tryptophan separation factor of 12–15 and D‐tryptophan yield of >95% have been successfully achieved through using human serum albumin (HSA) as the stereoselective ligand in an affinity ultrafiltration (UF) system. The obtained separation factor in this work is even higher than the intrinsic value of 8.5 of HSA. This synergism may arise from the fact that a fine match between the regular crystalline structure of HSA molecules and suitable pore size of membranes makes some HSA molecules be retained within the membrane cross‐section, thus offering a second‐stage binding opportunity for L‐tryptophan molecules. Therefore, a simultaneous enhancement in separation factor and D‐tryptophan yield has been fulfilled in this work. The feasibility of HSA regeneration after D,L‐tryptophan separation has also been demonstrated through a series of pH adjustment experiments. This study reveals the applicability of HSA in affinity UF systems for chiral separation due to economization of material costs. © 2009 American Institute of Chemical Engineers AIChE J, 2009

ChemInform Abstract: New Synthesis and Evaluation of Enantiomers of 7‐Methyl‐2‐exo‐(3′‐iodo‐5′‐pyridinyl)‐7‐azabicyclo[2.2.1]heptane as Stereoselective Ligands for PET Imaging of Nicotinic Acetylcholine Receptors.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

New synthesis and evaluation of enantiomers of 7-methyl-2-exo-(3′-iodo-5′-pyridinyl)-7-azabicyclo[2.2.1]heptane as stereoselective ligands for PET imaging of nicotinic acetylcholine receptors

A simple and efficient synthesis of nAChR antagonist (±)-7-methyl-2-exo-(3′-iodo-5′-pyridinyl)-7-azabicyclo[2.2.1]-heptane ((±)-NMI-EPB) has been developed. Both enantiomers of (±)-NMI-EPB were separated by semi-preparative chiral HPLC. The enantiomers manifested a substantial difference in their inhibition binding affinities ((+)-NMI-EPB, Ki=2310, 1680pM; (−)-NMI-EPB, Ki=55, 68pM). The enantiomers were stereoselectively radiolabeled with 11C. In the distribution studies in the rodent brain [11C](−)-NMI-EPB specifically labeled nAChR whereas [11C](+)-NMI-EPB exhibited little specific binding. In the baboon PET study [11C](−)-NMI-EPB did not reach steady-state within 90min post-injection suggesting that the radioligand may have some limitations for quantitative imaging.

Stereoselective Binding of Indomethacin Ethanolamide Derivatives to Cyclooxygenase-1

We have used molecular modeling studies and molecular dynamics simulations to generate three-dimensional models for cyclooxygenase-1 complexes with a series of indomethacin ethanolamide derivatives. These studies provide a plausible explanation for the stereoselective ligand binding preferences observed experimentally for these inhibitors and predict the general binding mode as well as specific structural details for the ligand-enzyme complexes. These studies provide insight into the nature of cyclooxygenase-1 interactions with a series of novel inhibitors and should help increase our understanding of key structural determinants for cyclooxygenase isozyme-selective inhibitor binding.

A Review of Pharmacology of NCS‐382, a Putative Antagonist of γ‐Hydroxybutyric Acid (GHB) Receptor

Gamma-hydroxybutyric acid (GHB), a naturally occurring metabolite of gamma-aminobutyric acid (GABA), has been postulated to act as a specific agonist of GHB receptors and as well as a weak GABA(B) receptor agonist. To date, 6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylideneacetic acid (NCS-382), a semirigid compound structurally related to GHB, is the only compound reported to be an antagonist of the GHB receptor sites. In this article we review the in vivo and in vitro pharmacological properties of NCS-382 and its interaction with GHB and GABA(B) receptors. Binding studies have demonstrated that NCS-382 is a stereoselective ligand for GHB-binding sites, with both, the high and the low component of population, showing the same distribution of GHB receptors. Indeed, this compound did not display affinity for GABA(A), GABA(B), or any other known receptors, while conflicting data have been reported as to its selective antagonist action at GHB receptor. Only a few studies have shown that NCS-382 antagonizes GHB-induced effect, but a re-evaluation of all data reported in the literature suggests that the antagonistic effect of this compound could be due to an indirect action at GABA(B) receptors. As revealed by several behavioral studies, NCS-382 fails to antagonize GHB discriminative stimuli, GHB-induced inhibition of locomotor activity and ataxia or suppression of operant responses. Moreover, it is capable of either eliciting qualitatively similar effects to those of GHB or enhancing some actions of GHB. In addition, the NCS-382-sensitive electrophysiological effects of endogenous and exogenous GHB observed in vivo have not been completely replicated in vitro. The only electrophysiological action of GHB antagonized in vitro by NCS-382 required a previous blockade of GABA(B) receptors. We concluded that NCS-382 is a good ligand but not a selective antagonist for GHB receptor.

Chiral ferrocene-based phosphine-imine and sulfur-imine ligands for palladium-catalyzed asymmetric allylic alkylation of cycloalkenyl esters

Chiral ferrocene-based phosphine-imine ligands 1-3 and sulfur-imine ligand 4 were applied in the palladium-catalyzed asymmetric allylic alkylation of cycloalkenyl esters. The results revealed that the substitutents in aryl ring, ferrocenylmethyl and benzyliene position strongly affected the enantioselective induction of phosphine-imine ligands, and the most stereoselective ligand was ferrocenylphosphine-imine 1b with a nitro group in the meta-position of phenyl ring. Under the optimized condition, up to 91% (enantiomeric excesses) e.e. of cyclic alkylation product was obtained by the use of 1b. (C) 2004 Elsevier B.V. All rights reserved.

Chiral ferrocene-based phosphine-imine and sulfur-imine ligands for palladium-catalyzed asymmetric allylic alkylation of cycloalkenyl esters

Chiral ferrocene-based phosphine-imine ligands 1–3 and sulfur-imine ligand 4 were applied in the palladium-catalyzed asymmetric allylic alkylation of cycloalkenyl esters. The results revealed that the substitutents in aryl ring, ferrocenylmethyl and benzyliene position strongly affected the enantioselective induction of phosphine-imine ligands, and the most stereoselective ligand was ferrocenylphosphine-imine 1b with a nitro group in the meta-position of phenyl ring. Under the optimized condition, up to 91% (enantiomeric excesses) e.e. of cyclic alkylation product was obtained by the use of 1b.

High-performance liquid chromatographic assay of lactic, pyruvic and acetic acids and lactic acid stereoisomers in calf feces, rumen fluid and urine

To facilitate clinical investigation of metabolic acidosis, a high-performance liquid chromatographic method was adapted and validated for the chiral separation of d-(−) and l-(+)-lactic acid in calf feces, rumen fluid and urine. A non-chiral method was also adapted and validated for the separation of pyruvic, acetic and dl-(±)-lactic acids in calf feces and dl-(±)-lactic and pyruvic acids in rumen fluid. Separation and quantification were achieved using a reversed phase sulphonated polystyrenedivinylbenzene analytical column for pyruvic, acetic and racemic lactic acids and by a 3 μm octadecylsilane (ODS) packed analytical column coated with N, N-dioctyl- l-alanine as the chiral selector for the separation of lactic acid enantiomers with Cu(II)-containing eluents by stereoselective ligand exchange chromatography. Endogenous analytes were present in validation samples over a range of concentrations (0.2–14.8 mmol/l). For the stereoselective assay, mean intra-day accuracy ranged from 90.6 to 108.4% and intra-day precision from 0.3 to 13.8%. For the non-stereoselective assay, mean intra-day accuracy ranged from 90.4 to 108.8% and intra-day precision from 1.5 to 11.1%. The limit of quantitation was 1.0 mmol/l for d- and l-lactic acid, 0.06125 mmol/l for pyruvic acid, 1.0 mmol/l for dl-lactic acid and 1 mmol/l for acetic acid. These assays can be used to study the role of the gastrointestinal tract and kidney in metabolic acidosis.

Differential recognition of resveratrol isomers by the human estrogen receptor-alpha: molecular dynamics evidence for stereoselective ligand binding.

Resveratrol (RSVL) is a phytoestrogen that occurs naturally in two forms (trans- (E) and cis- (Z)). We have conducted molecular dynamics (MD) studies to differentially characterize the estrogen receptor-alpha (ER-alpha) binding profiles of RSVL stereoisomers. Favorable orientations for RSVL isomers at the ER-alpha pocket were first inferred from (1) alignment with pharmacophoric elements of the pure ER-alpha agonists estradiol (E2) and (2) assessment of ligand recognition by the ER-alpha binding domain. Subsequently, these orientations for RSVL isomers were subjected to MD analyses versus E2. A 100-picosecond MD simulation revealed that E2 contributed four stable hydrogen bonds with the key ER-alpha pocket residue: Arg394, Glu353, His524, and Leu525. Further, E2 displayed favorable binding energy, conformational energy change (DeltaE), and movement of the binding pocket residues (RMSd). Compared to E2, (E)-RSVL lacked a hydrogen bond (HB) with His524 but formed three additional bonds with Gly521, Phe404, and Met343 of the ER-alpha pocket. Further, (E)-RSVL conferred more favorable energy of interaction, less favorable DeltaE, but comparable RMSd values. In contrast, (Z)-RSVL orientations missed hydrogen bonding (HB) with His524 and Leu525, two essential ligand binding residues, and/or produced considerably less favorable-binding energy, -DeltaE, and -RMSd values than did (E)-RSVL. In conclusion, the present study demonstrates the utility of this MD model in distinguishing between RSVL stereoisomers. The weak binding of (Z)-RSVL by the human ER-alpha binding is congruent with its inferior ligand profiles in ER-endowed biological systems. Further, evidence is provided for a considerable variation in the mode of recognition of the mixed agonist/antagonist (E)-RSVL, and the pure agonist E2.

Molecular Determinants of the Stereoselectivity of Agonist Activity of Estrogen Receptors (ER) α and ॆ

The two known estrogen receptors, ERalpha and ERbeta, are hormone-inducible transcription factors that have distinct roles in regulating cell proliferation and differentiation. Previously, our laboratory demonstrated that ERalpha exhibits stereoselective ligand binding and transactivation for several structural derivatives and metabolites of the synthetic estrogen diethylstilbestrol. We have previously described the properties of indenestrol A (IA) enantiomers on ERalpha. In the study presented here, the estrogenic properties of the S and R enantiomers of IA, IA-S and IA-R, respectively, were expanded to examine the activity in different cell and promoter contexts using ERalpha and ERbeta. Using human cell lines stably expressing either ERalpha or ERbeta, we found that IA-S was a more potent activator of transcription than IA-R through ERalpha in human endometrial Ishikawa and breast MDA-MB 231 (MDA) cells. Interestingly, IA-R was more potent on ERbeta when compared with ERalpha in MDA, but not in Ishikawa cells, and IA-R exhibited equally low binding affinities to ERalpha and ERbeta in vitro in contrast to its cell line-dependent preferential activation of ERbeta. Alignment of the protein structures of the ligand-binding domains of ERalpha and ERbeta revealed one mismatched residue, Leu-384 in ERalpha and Met-283 in ERbeta, which may be responsible for making contact with the methyl substituent at the chiral carbon of IA-S and IA-R. Mutagenesis and exchange of this one residue showed that the binding of IA-R and IA-S was not affected by this mutation in ERalpha and ERbeta. However, in transactivation studies, IA-R showed higher potency in activating L384M-mutated ERalpha and wild-type ERbeta compared with wild-type ERalpha and M283L-mutated ERbeta in all cell and promoter contexts examined. Furthermore, IA-R-bound ERalpha L384M and wild-type ERbeta displayed enhanced interactions with the nuclear receptor interaction domains of the coactivators SRC-1 and GRIP1. These data demonstrate that a single residue in the ligand-binding domain determines the stereoselectivity of ERalpha and ERbeta for indenestrol ligands and that IA-R shows cell type selectivity through ERbeta.

Silver(I)-mediated isomerisation of trans-[RuCl2(P–P)2] (P–P = four-membered ring chelate diphosphine ligand) to cis-[{Ru(P–P)2(μ-Cl)2}nAg]+ species, and applications in stereoselective syntheses of cis- and trans-[RuCl(L)(P–P)2]+ (L = neutral ligand) †

When complexes trans-[RuCl2(diphos)2] (diphos = (Ph2P)2CCH2, Ph2PCH2PPh2 or Ph2PNHPPh2) were treated with silver salts of poorly coordinating anions (e.g. AgBF4, AgO3SCF3) in 1,2-dichloroethane halide abstraction was slow, even at reflux, and the reaction proceeded by an interesting mechanism involving a trans to cis isomerisation. At room temperature, a complex, characterized as [RuCl(diphos)2(μ-Cl)Ag]+, forms. When heated to reflux for 5–10 min this reacts to give a mixture, which includes cis-[RuCl2(diphos)2], and species of the type [{Ru(diphos)2(μ-Cl)2}nAg]+ (n = 1 or 2) in which the exact coordination geometry at AgI is unknown. The reactions have been followed by 31P-{1H} NMR spectroscopy, and electronic spectroscopy results also support the isomerisation. The ruthenium and silver K-edge EXAFS spectra of the solid isolated from the reaction of trans-[RuCl2(dppm)2] and AgO3SCF3 lend support to this formulation; in particular, the best fit for the silver(I) environment includes coordination to one oxygen (from the −O3SCF3; Ru–O 2.43 Å), two Cl (2.79 Å) and between one and two Ru (3.94 Å). Over 30–40 min at reflux, AgCl precipitates, the signals due to cis-[RuCl2(diphos)2] disappear from the 31P-{1H} NMR spectra, those due to the [{Ru(diphos)2(μ-Cl)2}nAg]+ mixture diminish, and new resonances, attributed to five-coordinate [RuCl(diphos)2]+, appear. This reaction has been investigated for stereoselective ligand substitution. Treatment of trans-[RuCl2(diphos)2] with AgBF4 or AgO3SCF3 in DCE in the presence of CH3CN or CO yields exclusively trans-[RuCl(L)(diphos)2]+ (L = CH3CN or CO), but treatment of trans-[RuCl2(diphos)2] with AgBF4 or AgO3SCF3 in DCE, followed by treatment with L, usually gave exclusively cis-[RuCl(L)(diphos)2]+ (L = CH3CN or CO).

Carbohydrate‐Modified Metal Carbenes: Synthesis And First Applications

AbstractCarbohydrate‐modified carbene complexes can be synthesised by combining a sugar electrophile with a metalate nucleophile or vice versa. Acyclic sugar skeletons adopt conformations that are controlled by the minimisation of 1,3‐interactions and are not significantly affected by the incorporation of a metal fragment. Thus, the latter can be used exclusively for reactivity tuning. Sugar carbene complexes undergo regio‐ and stereoselective ligand‐ and metal‐centred reactions such as C2‐homologisation and benzannulation.