Dynamic catalytic highly enantioselective 1,3‐dipolar cycloadditions

In dynamic covalent chemistry, reactions follow a thermodynamically controlled pathway through equilibria. Reversible covalent-bond formation and breaking in a dynamic process enables the interconversion of products formed under kinetic control to thermodynamically more stable isomers. Notably, enantioselective catalysis of dynamic transformations has not been reported and applied in complex molecule synthesis. We describe the discovery of dynamic covalent enantioselective metal-complex-catalyzed 1,3-dipolar cycloaddition reactions. We have developed a stereodivergent tandem synthesis of structurally and stereochemically complex molecules that generates eight stereocenters with high diastereo- and enantioselectivity through asymmetric reversible bond formation in a dynamic process in two consecutive Ag-catalyzed 1,3-dipolar cycloadditions of azomethine ylides with electron-poor olefins. Time-dependent reversible dynamic covalent-bond formation gives enantiodivergent and diastereodivergent access to structurally complex double cycloadducts with high selectivity from a common set of reagents

The pseudo‐natural product rhonin targets RHOGDI

For the discovery of novel chemical matter generally endowed with bioactivity, strategies may be particularly efficient that combine previous insight about biological relevance, e.g., natural product (NP) structure, with methods that enable efficient coverage of chemical space, such as fragment-based design. We describe the de novo combination of different 5-membered NP-derived N-heteroatom fragments to structurally unprecedented “pseudo-natural products” in an efficient complexity-generating and enantioselective one-pot synthesis sequence. The pseudo-NPs inherit characteristic elements of NP structure but occupy areas of chemical space not covered by NP-derived chemotypes, and may have novel biological targets. Investigation of the pseudo-NPs in unbiased phenotypic assays and target identification led to the discovery of the first small-molecule ligand of the RHO GDP-dissociation inhibitor 1 (RHOGDI1), termed Rhonin. Rhonin inhibits the binding of the RHOGDI1 chaperone to GDP-bound RHO GTPases and alters the subcellular localization of RHO GTPases

The pseudo‐natural product rhonin targets RHOGDI

For the discovery of novel chemical matter generally endowed with bioactivity, strategies may be particularly efficient that combine previous insight about biological relevance, e.g., natural product (NP) structure, with methods that enable efficient coverage of chemical space, such as fragment-based design. We describe the de novo combination of different 5-membered NP-derived N-heteroatom fragments to structurally unprecedented “pseudo-natural products” in an efficient complexity-generating and enantioselective one-pot synthesis sequence. The pseudo-NPs inherit characteristic elements of NP structure but occupy areas of chemical space not covered by NP-derived chemotypes, and may have novel biological targets. Investigation of the pseudo-NPs in unbiased phenotypic assays and target identification led to the discovery of the first small-molecule ligand of the RHO GDP-dissociation inhibitor 1 (RHOGDI1), termed Rhonin. Rhonin inhibits the binding of the RHOGDI1 chaperone to GDP-bound RHO GTPases and alters the subcellular localization of RHO GTPases

A spatial-economic multimodal transportation simulation model for US coastal container ports

Assessing the potential demand for container ports and related multimodal transportation is critical for several purposes, including financial feasibility analysis and the evaluation of net economic benefits and their distribution. When developed in conjunction with a geographical information system, port-related demand analysis also provides needed input for assessment of selected environmental issues, such as truck traffic on local roads and related potential external costs, such as air pollution and noise. However, container port demand analysis is very difficult due to the complexities of international trade in containerised goods, inter-port competition, and potential strategic behaviour by several parties. Difficulties also arise from the many factors to be considered, major data requirements, and the computationally intensive nature of the problem. This paper summarises the development and application of a spatial-economic, multimodal container transportation demand simulation model for major US container ports. The underlying economic framework assumes shippers minimise the total general cost of moving containers from sources to markets. The model is validated and then used to estimate (1) annual container transportation service demand for major container ports, (2) the market areas served by selected ports, and (3) the impact on port demand and interport competition due to hypothetical changes in port use fees at selected ports. This paper first describes the model and the underlying economic reasoning, followed by the assumptions, computational algorithms, and the software architecture. Then, the trade data, transportation networks, and economic variables are described. After that, model simulation results are presented with qualifications, needed refinements, and future directions. © 2003 Palgrave Macmillan Ltd. All rights reserved

Chemical Evolution of Natural Product Structure

[Image: see text] Natural products are the result of Nature’s exploration of biologically relevant chemical space through evolution and an invaluable source of bioactive small molecules for chemical biology and medicinal chemistry. Novel concepts for the discovery of new bioactive compound classes based on natural product structure may enable exploration of wider biologically relevant chemical space. The pseudo-natural product concept merges the relevance of natural product structure with efficient exploration of chemical space by means of fragment-based compound development to inspire the discovery of new bioactive chemical matter through de novo combination of natural product fragments in unprecedented arrangements. The novel scaffolds retain the biological relevance of natural products but are not obtainable through known biosynthetic pathways which can lead to new chemotypes that may have unexpected or unprecedented bioactivities. Herein, we cover the workflow of pseudo-natural product design and development, highlight recent examples, and discuss a cheminformatic analysis in which a significant portion of biologically active synthetic compounds were found to be pseudo-natural products. We compare the concept to natural evolution and discuss pseudo-natural products as the human-made equivalent, i.e. the chemical evolution of natural product structure

The economic costs to fisheries from marine sediment disposal: Case study of Providence, RI, USA

Ports worldwide are under pressure to dredge channels and berths to accommodate deep-draft vessels. Marine disposal of the dredged sediments, however, often is a controversial issue due, in part, to potential impacts on commercial and recreational fisheries. We use an integrated framework employing engineering, economic, and biological data and concepts to estimate the economic costs to fisheries from disposal of clean dredged sediments from in and around Providence Harbor, RI, USA. The fishery impacts considered include short-term, direct effects that occur during disposal, long-term effects that arise during the recovery period following disposal, and indirect effects that occur through the food web. Economic damages to commercial and recreational fisheries are assessed for seven potential disposal sites, using conservative assumptions that tend to overstate costs. Damages across sites range from about $256 thousand to$1.9 million. A series of sensitivity analyses is done in recognition of the many uncertainties involved. The sensitivity analyses increase the estimated disposal costs, but do not affect to relative sizes of costs across sites. Considering all sensitivity analyses simultaneously, estimated damages range from about $460 thousand to$3.4 million between the lowest- and highest-cost sites. © 2001 Elsevier Science B.V