DFT-Assisted Design and Evaluation of Bifunctional Amine/Pyridine-Oxazoline Metal Catalysts for Additions of Ketones to Unactivated Alkenes and Alkynes

Bifunctional catalyst systems for the direct addition of ­ketones to unactivated alkenes/alkynes were designed and modeled by density functional theory (DFT). The designed catalysts possess bidentate ligands suitable for binding of pi-acidic group 10 metals capable of activating alkenes/alkynes, and a tethered organocatalyst amine to ­activate the ketone via formation of a nucleophilic enamine intermediate. The structures of the designed catalysts before and after C–C bond formation were optimized using DFT, and reaction steps involving group 10 metals were predicted to be significantly exergonic. A novel oxazoline precatalyst with a tethered amine separated by a meta-substituted benzene spacer was synthesized via a 10-step sequence that ­includes a key regioselective epoxide ring-opening step. It was combined with group 10 metal salts, including cationic Pd(II) and Pt(II), and screened for the direct addition of ketones to several alkenes and an ­internal alkyne. 1H NMR studies suggest that catalyst-catalyst inter­actions with this system via amine–metal coordination may preclude the desired addition reactions. The catalyst design approach disclosed here, and the promising calculations obtained with square planar group 10 metals, light a path for the discovery of novel bifunctional catalysts for C–C bond formation

Two cheers for the Monetary Control Act

This article explains how the Monetary Control Act (MCA) of 1980 paved the way for the transition away from paper to electronic check clearing and processing, ultimately leading to the successful implementation of the Check Clearing for the 21st Century Act (Check 21) in 2003.Monetary policy ; Monetary policy - United States

Design and Synthesis of Oxazoline-Based Scaffolds for Hybrid Lewis Acid/Lewis Base Catalysis of Carbon–Carbon Bond Formation

A new class of hybrid Lewis acid/Lewis base catalysts has been designed and prepared with an initial objective of promoting stereoselective direct aldol reactions. Several scaffolds were synthesized that contain amine moieties capable of enamine catalysis, connected to heterocyclic metal-chelating sections composed of an oxazole–oxazoline or thiazole–oxazoline. Early screening results have identified oxa­zole–oxazoline-based systems capable of promoting a highly diastereo- and enantioselective direct aldol reaction of propionaldehyde with 4-nitrobenzaldehyde, when combined with Lewis acids such as zinc triflate

Clustering Phase Transitions and Hysteresis: Pitfalls in Constructing Network Ensembles

Ensembles of networks are used as null models in many applications. However, simple null models often show much less clustering than their real-world counterparts. In this paper, we study a model where clustering is enhanced by means of a fugacity term as in the Strauss (or "triangle") model, but where the degree sequence is strictly preserved -- thus maintaining the quenched heterogeneity of nodes found in the original degree sequence. Similar models had been proposed previously in [R. Milo et al., Science 298, 824 (2002)]. We find that our model exhibits phase transitions as the fugacity is changed. For regular graphs (identical degrees for all nodes) with degree k > 2 we find a single first order transition. For all non-regular networks that we studied (including Erdos - Renyi and scale-free networks) we find multiple jumps resembling first order transitions, together with strong hysteresis. The latter transitions are driven by the sudden emergence of "cluster cores": groups of highly interconnected nodes with higher than average degrees. To study these cluster cores visually, we introduce q-clique adjacency plots. We find that these cluster cores constitute distinct communities which emerge spontaneously from the triangle generating process. Finally, we point out that cluster cores produce pitfalls when using the present (and similar) models as null models for strongly clustered networks, due to the very strong hysteresis which effectively leads to broken ergodicity on realistic time scales.Comment: 13 pages, 11 figure

DFT-assisted Design and Evaluation of Bifunctional Copper(I) Catalysts for the Direct Intermolecular Addition of Aldehydes and Ketones to Alkynes

Bifunctional catalysts containing discrete metal pi-acid and amine sites were designed and investigated for the direct intermolecular addition of aldehydes and ketones to unactivated alkynes. Copper(I)-based catalysts were prioritized based on intramolecular (Conia-ene type) reactions, and complexes were designed with tridentate ligands and potentially hemilabile heterocyclic spacers. The structures of the designed catalysts were computed using density functional theory (DFT), and the relative energies of putative catalytic intermediates were estimated and used to prioritize catalyst designs. Novel bifunctional precatalysts containing a thiazole spacer were synthesized via a 9-step sequence and combined with transition metals before screening for the direct addition of aldehydes and ketones to several internal and terminal alkynes. Despite the lack of desired intermolecular reactions, DFT calculations of putative catalyst intermediates appears to be a promising strategy for the design and prioritization of bifunctional catalysts for CC bond formation

Nesprin-2-dependent ERK1/2 compartmentalisation regulates the DNA damage response in vascular smooth muscle cell ageing

Prelamin A accumulation and persistent DNA damage response (DDR) are hallmarks of vascular smooth muscle cell (VSMC) ageing and dysfunction. Although prelamin A is proposed to interfere with DNA repair, our understanding of the crosstalk between prelamin A and the repair process remains limited. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) have emerged as key players in the DDR and are known to enhance ataxia telangiectasia-mutated protein (ATM)activity at DNA lesions, and in this study, we identified a novel relationship between prelamin A accumulation and ERK1/2 nuclear compartmentalisation during VSMC ageing. We show both prelamin A accumulation and increased DNA damage occur concomitantly, before VSMC replicative senescence, and induce the localisation of ERK1/2 to promyelocytic leukaemia protein nuclear bodies (PML NBs) at the sites of DNA damage via nesprin-2 and lamin A interactions. Importantly, VSMCs treated with DNA damaging agents also displayed prelamin A accumulation and ERK compartmentalisation at PML NBs, suggesting that prelamin A and nesprin-2 are novel components of the DDR. In support of this, disruption of ERK compartmentalisation at PML NBs, by either depletion of nesprin-2 or lamins A/C, resulted in the loss of ATM from DNA lesions. However, ATM signalling and DNA repair remained intact after lamins A/C depletion, whereas nesprin-2 disruptionablated downstream Chk2 activation and induced genomic instability. We conclude that lamins A/C and PML act as scaffolds to organise DNA-repair foci and compartmentalise nesprin-2/ERK signalling. However, nesprin-2/ERK signalling fidelity, but not their compartmentalisation at PML NBs, is essential for efficient DDR in VSMCs