Ligand libraries for high throughput screening of homogeneous catalysts.

To accelerate the discovery of new or improved homogeneous catalysts, research groups in industry and academia have embraced high throughput experimentation (HTE). Such methodologies consist of preparing and testing large numbers of catalysts in parallel. Homogeneous metal catalysts are very well-suited for HTE, since in many cases, they can be prepared by simply mixing a metal precursor and a ligand. However, an HTE program requires a large set of chemically diverse ligands, i.e. a ligand library. In this review, we describe five different approaches for assembling ligand libraries based on an extensive survey of the literature. These approaches are based on commercial ligands, modular ligands, mixtures of ligands, supramolecular ligands or ligands prepared via the tools of biochemistry.

Selective Hydrogenation of α,ß-Unsaturated Aldehydes and Ketones by Air-Stable Ruthenium NNS Complexes.

The selective hydrogenation of the carbonyl functionality of α,ß-unsaturated aldehydes and ketones is catalysed by ruthenium dichloride complexes bearing a tridentate NNS ligand as well as triphenylphosphine. The tridentate ligand backbone is flexible, as evidenced by the equilibrium observed in solution between the cis- and trans-isomers of the dichloride precatalysts, as well as crystal structures of several of these complexes. The complexes are activated by base in the presence of hydrogen and readily hydrogenate carbonyl functionalities under mild conditions. Despite the activation by base, side reactions are negligible, even for aldehyde substrates, because of the low amount of base. Thus, the corresponding allylic alcohols can be isolated in very good yields on a 10-25 mmol scale. Turnover numbers up to 200 000 were achieved.

A Formal Synthesis of (-)-Perhydrohistrionicotoxin Using a Cross Metathesis-Hydrogenation Approach.

The development of an efficient, high yielding six-step convergent synthesis of the semisynthetic alkaloid (-)-perhydrohistrionicotoxin is described. The key transformations include the cross metathesis of a Brønsted-acid masked primary homoallylic amine with a vinyl cyclohexenone and a regioselective palladium catalyzed hydrogenation. This sequence generated the advanced Winterfeldt spirocyclic precursor in 47% overall yield, with a longest linear sequence of five steps.

Non-Pincer-Type Manganese Complexes as Efficient Catalysts for the Hydrogenation of Esters.

Catalytic hydrogenation of carboxylic acid esters is essential for the green production of pharmaceuticals, fragrances, and fine chemicals. Herein, we report the efficient hydrogenation of esters with manganese catalysts based on simple bidentate aminophosphine ligands. Monoligated Mn PN complexes are particularly active for the conversion of esters into the corresponding alcohols at Mn concentrations as low as 0.2 mol % in the presence of sub-stoichiometric amounts of KOt Bu base.

Asymmetric Hydrogenation of 3-Substituted Pyridinium Salts.

The use of an equivalent amount of an organic base leads to high enantiomeric excess in the asymmetric hydrogenation of N-benzylated 3-substituted pyridinium salts into the corresponding piperidines. Indeed, in the presence of Et3 N, a Rh-JosiPhos catalyst reduced a range of pyridinium salts with ee values up to 90 %. The role of the base was elucidated with a mechanistic study involving the isolation of the various reaction intermediates and isotopic labeling experiments. Additionally, this study provided some evidence for an enantiodetermining step involving a dihydropyridine intermediate.

Bis-N-heterocyclic Carbene Aminopincer Ligands Enable High Activity in Ru-Catalyzed Ester Hydrogenation.

Bis-N-heterocyclic carbene (NHC) aminopincer ligands were successfully applied for the first time in the catalytic hydrogenation of esters. We have isolated and characterized a well-defined catalyst precursor as a dimeric [Ru2(L)2Cl3]PF6 complex and studied its reactivity and catalytic performance. Remarkable initial activities up to 283,000 h(-1) were achieved in the hydrogenation of ethyl hexanoate at only 12.5 ppm Ru loading. A wide range of aliphatic and aromatic esters can be converted with this catalyst to corresponding alcohols in near quantitative yields. The described synthetic protocol makes use of air-stable reagents available in multigram quantities, rendering the bis-NHC ligands an attractive alternative to the conventional phosphine-based systems.

Probing machine learning models based on high throughput experimentation data for the discovery of asymmetric hydrogenation catalysts.

Enantioselective hydrogenation of olefins by Rh-based chiral catalysts has been extensively studied for more than 50 years. Naively, one would expect that everything about this transformation is known and that selecting a catalyst that induces the desired reactivity or selectivity is a trivial task. Nonetheless, ligand engineering or selection for any new prochiral olefin remains an empirical trial-error exercise. In this study, we investigated whether machine learning techniques could be used to accelerate the identification of the most efficient chiral ligand. For this purpose, we used high throughput experimentation to build a large dataset consisting of results for Rh-catalyzed asymmetric olefin hydrogenation, specially designed for applications in machine learning. We showcased its alignment with existing literature while addressing observed discrepancies. Additionally, a computational framework for the automated and reproducible quantum-chemistry based featurization of catalyst structures was created. Together with less computationally demanding representations, these descriptors were fed into our machine learning pipeline for both out-of-domain and in-domain prediction tasks of selectivity and reactivity. For out-of-domain purposes, our models provided limited efficacy. It was found that even the most expensive descriptors do not impart significant meaning to the model predictions. The in-domain application, while partly successful for predictions of conversion, emphasizes the need for evaluating the cost-benefit ratio of computationally intensive descriptors and for tailored descriptor design. Challenges persist in predicting enantioselectivity, calling for caution in interpreting results from small datasets. Our insights underscore the importance of dataset diversity with broad substrate inclusion and suggest that mechanistic considerations could improve the accuracy of statistical models.

A method for the semantic enrichment of clinical trial data.

Clinical trial data have historically been implemented using relational databases. While this has expedited the dissemination of data among partners, it has hindered on the ability to swiftly query the data by relying on monolithic tables. This paper outlines a project that investigates the semantic enrichment of a large-scale longitudinal clinical trial, the AIBL study, by reusing entities from existing ontologies. The implication of the semantic enrichment of the AIBL study is that it is possible to query the data more effectively and efficiently. We are now able to implement our model and focus on an end-to-end data capture and analysis pipeline to query and visualise clinical trial data. The main contribution of this paper is a discussion of the methodology to semantically enrich clinical trial data using entities from existing ontologies.

Unravelling the reaction path of rhodium-MonoPhos-catalysed olefin hydrogenation.

The mechanism of the asymmetric hydrogenation of methyl (Z)-2-acetamidocinnamate (mac) catalysed by [Rh(MonoPhos)(2)(nbd)]SbF(6) (MonoPhos: 3,5-dioxa-4-phosphacyclohepta[2,1-a:3,4-a']dinaphthalen-4-yl)dimethylamine) was elucidated by using (1)H, (31)P and (103)Rh NMR spectroscopy and ESI-MS. The use of nbd allows one to obtain in pure form the rhodium complex that contains two units of the ligand. In contrast to the analogous complexes that contain cis,cis-1,5-cyclooctadiene (cod), this complex shows well-resolved NMR spectroscopic signals. Hydrogenation of these catalyst precursors at 1 bar total pressure gave rise to the formation of a bimetallic complex of general formula [Rh(MonoPhos)(2)](2)(SbF(6))(2); no solvate complexes were detected. In the dimeric complex both rhodium atoms are ligated to two MonoPhos ligands but, in addition, each rhodium atom also binds to one of the binaphthyl rings of a ligand that is bound to the other rhodium metal. Upon addition of mac, a mixture of diastereomeric complexes [Rh(MonoPhos)(2)(mac)]SbF(6) is formed in which the substrate is bound in a chelate fashion to the metal. Upon hydrogenation, these adducts are converted into a new complex [Rh(MonoPhos)(2){mac(H)(2)}]SbF(6) in which the methyl phenylalaninate mac(H)(2) is bound through its aromatic ring to rhodium. Addition of mac to this complex leads to displacement of the product by the substrate. No hydride intermediates could be detected and no evidence was found for the involvement at any stage of the process of complexes with only one coordinated MonoPhos. The collected data suggest that the asymmetric hydrogenation follows a Halpern-like mechanism in which the less abundant substrate-catalyst adduct is preferentially hydrogenated to phenylalanine methyl ester.

Catalytic asymmetric Baeyer-Villiger oxidation in water by using Pt(II) catalysts and hydrogen peroxide: supramolecular control of enantioselectivity.

The enantioselective Baeyer-Villiger oxidation of cyclic ketones is a challenging reaction, especially when using environmentally friendly oxidants. The reaction was carried out in water by using soft Lewis acid Pt(II) complexes that have chiral diphosphines as well as monophosphines. Addition of a surfactant is crucial, which leads to the formation of micelles that act as nanoreactors in which the substrate and catalyst encounter each other in an ordered medium that in several cases positively influences both the conversion and the selectivity of the reactions. This is due to the combination of the hydrophobic effect (which confines the components of the reaction in the micelles), together with supramolecular interactions between the partners within the ordered palisade provided by the alkyl chains of the surfactant. For the oxidation of meso-cyclobutanones, addition of surfactant allowed the reaction to proceed in high yields and the enantiometic excess (ee; 56%) was higher than in organic solvents. Subsequent extension to meso-cyclohexanones resulted in a general decrease in yields but an enhancement of enantioselectivity (ee up to 92%) moving from organic to water-surfactant media, regardless of the substrate or the catalyst employed. Different behaviour was observed with chiral cyclobutanones 7 and 10: with 7 the best catalyst was 1 g, whereas with the larger substrate, 10, complexes 1 a-b performed better in terms of enantioselectivity. Each combination of substrate, catalyst and surfactant is a new system and supramolecular reciprocal interactions together with the hydrophobic character of the counterparts play crucial roles. The asymmetric Baeyer-Villiger oxidation in water catalyzed by 1 a-h in the presence of micelles is a viable reaction that often benefits from the hydrophobic effect, leading to substantial increases in enantioselectivity.

Soluble iron nanoparticles as cheap and environmentally benign alkene and alkyne hydrogenation catalysts.

Iron nanoparticles prepared by reducing FeCl(3) with three equivalents of EtMgCl in THF are effective catalysts for the hydrogenation of alkenes and alkynes under moderate conditions.

Mechanistic Complexity of Asymmetric Transfer Hydrogenation with Simple Mn-Diamine Catalysts.

The catalytic asymmetric transfer hydrogenation (ATH) of ketones is a powerful methodology for the practical and efficient installation of chiral centers. Herein, we describe the synthesis, characterization, and catalytic application of a series of manganese complexes bearing simple chiral diamine ligands. We performed an extensive experimental and computational mechanistic study and present the first detailed experimental kinetic study of Mn-catalyzed ATH. We demonstrate that conventional mechanistic approaches toward catalyst optimization fail and how apparently different precatalysts lead to identical intermediates and thus catalytic performance. Ultimately, the Mn-N,N complexes under study enable quantitative ATH of acetophenones to the corresponding chiral alcohols with 75-87% ee.

Supported nickel-rhenium catalysts for selective hydrogenation of methyl esters to alcohols.

The addition of Re to Ni on TiO2 yields efficient catalysts for the hydrogenation of acids and esters to alcohols under mild conditions. Rhenium promotes the formation of atomically dispersed and sub-nanometre-sized bimetallic species interacting strongly with the oxide support.

Semantic enrichment of longitudinal clinical study data using the CDISC standards and the semantic statistics vocabularies.

BACKGROUND: There is an increasing recognition of the need for the data capture phase of clinical studies to be improved and for more effective sharing of clinical data. The Health Care and Life Sciences community has embraced semantic technologies to facilitate the integration of health data from electronic health records, clinical studies and pharmaceutical research. This paper explores the integration of clinical study data exchange standards and semantic statistic vocabularies to deliver clinical data as linked data in a format that is easier to enrich with links to complementary data sources and consume by a broad user base. METHODS: We propose a Linked Clinical Data Cube (LCDC), which combines the strength of the RDF Data Cube and DDI-RDF vocabulary to enrich clinical data based on the CDISC standards. The CDISC standards provide the mechanisms for the data to be standardised, made more accessible and accountable whereas the RDF Data Cube and DDI-RDF vocabularies provide novel approaches to managing large volumes of heterogeneous linked data resources. RESULTS: We validate our approach using a large-scale longitudinal clinical study into neurodegenerative diseases. This dataset, comprising more than 1600 variables clustered in 25 different sub-domains, has been fully converted into RDF forming one main data cube and one specialised cube for each sub-domain. One sub-domain, the Medications specialised cube, has been linked to relevant external vocabularies, such as the Australian Medicines Terminology and the ATC DDD taxonomy and DrugBank terminology. This provides new dimensions on which to query the data that promote the exploration of drug-drug and drug-disease interactions. CONCLUSIONS: This implementation highlights the effectiveness of the association of the semantic statistics vocabularies for the publication of large heterogeneous data sets as linked data and the integration of the semantic statistics vocabularies with the CDISC standards. In particular, it demonstrates the potential of the two vocabularies in overcoming the monolithic nature of the underlying model and improving the navigation and querying of the data from multiple angles to support richer data analysis of clinical study data. The forecasted benefits are more efficient use of clinicians' time and the potential to facilitate cross-study analysis.

Enantio- and diastereoselective synthesis of γ-amino alcohols.

The γ-amino alcohol structural motif is often encountered in drugs and natural products. We developed two complementary catalytic diastereoselective methods for the synthesis of N-PMP-protected γ-amino alcohols from the corresponding ketones. The anti-products were obtained through Ir-catalyzed asymmetric transfer hydrogenation, the syn-products via Rh-catalyzed asymmetric hydrogenation.

Efficient coherent combining of widely tunable fiber lasers.

We have experimentally demonstrated coherent combining of 2 and then 4 fiber lasers, with respectively 99% and 95% combining efficiency. The combining method investigated here is based on a multi-arm resonator of interferometric configuration. In spite of its interferometric nature, the multi-arm laser operates without significant power fluctuations, even in an unprotected environment. This occurs when the arm length difference is large enough to introduce spectral modulations of period smaller than the laser bandwidth. We have also experimentally shown that the combining method is compatible with wavelength tuning. A Mach- Zehnder Fiber Laser was tuned over a wide spectral range of 60nm. Theoretically then, we confirm that the combining method can be scaled to a large number of lasers without decreasing the combining efficiency.

Instant ligand libraries. Parallel synthesis of monodentate phosphoramidites and in situ screening in asymmetric hydrogenation.

Chiral phosphoramidites have been identified as excellent ligands for various metal-catalyzed enantioselective transformations. Taking advantage of their easy preparation and modular nature, we designed a fully automated protocol for the parallel preparation of a library of 32 phosphoramidites and its screening in asymmetric hydrogenation of amino acid precursors. This initial study led to the discovery of a new ligand for the preparation of an enantiopure beta(3)-homoalanine precursor. [structure--see text]

Metathesis of Alkanes: Evidence for Degenerate Metathesis of Ethane over a Silica-Supported Tantalum Hydride Prepared by Surface Organometallic Chemistry.

The mutual exchange of methyl groups of ethane molecules is catalyzed by a silica-supported tantalum hydride surface complex (see the schematic representation of the transition states). This process, which resembles degenerate olefin metathesis, is five times faster than the productive alkane metathesis.