Cascade Reactions to Access Bioactive Scaffolds

In the recent decade there has been a shift in drug development to favor planar, aromatic small molecules with easy synthetic access, despite centuries of research in bioactive natural products, which are often highly rigid, three-dimensional structures like spirocycles. These scaffolds remain underexplored in drug development efforts, predominantly due to the challenges associated with their synthesis, and lack of a general, convergent methodology. To address these challenges, we have designed an O–H Insertion/Conia-ene reaction cascade between homopropargylic alcohols and acceptor/acceptor diazo compounds, which uses dual Rh/Au+ catalytic system. This cascade occurs instantly at room temperature, and has been applied towards the synthesis of substituted tetrahydrofurans when linear diazo compounds are used. Thus far, the cascade accommodates a variety of substituted diazo compounds with carboxylic acids/alcohols to provide functionalized tetrahydrofurans, and g-butyrolactones, with a high degree of regio- and stereo-selectivity. Next, we were able to extend the utility of our O–H Insertion/Conia-ene reaction cascade towards the synthesis of spiroheterocycles by employing cyclic diazo substrates with propargylic alcohols. This convergent approach furnishes an array of spiroheterocycles by employing the same dual Rh/Au+ catalytic system in refluxing dichloromethane. This approach has proven general, and was used to synthesize a substrate scope of twenty-four substrates based on natural product scaffolds, including spirobarbituates, spiromeldrum’s acids, spirooxindoles, and the spirocyclic core of the pseurotin natural products. Lastly, we have extended our X–H Insertion/Conia-ene strategy towards uncommon nucleophiles, for the synthesis of sulfur- and all-carbon spirocycles. When propargylic thiols are employed as substrates with linear diazos, we have found that the S-H insertion reaction proceeds in high yield, and Conia-ene cyclization can be promoted when the reaction is conducted in a stepwise fashion. However, when the reaction is conducted in a single pot, we isolated a new, thiofuranofuran compound, which we expect forms via undesired 5-endo-dig cyclization of the propargylic thiol, followed by cyclopropanation and subsequent ring opening. Additionally, by changing our retrosynthetic approach to an intramolecular disconnection, we were able to synthesize an all-carbon spirocycle through a benzylic C-H Insertion/Conia-ene cascade, by using a catalytic mixture consisting of Rh2(HFB)4, ClAuPPh3, and CuOTf in refluxing dichloromethane. In an orthogonal research effort, we have also developed a metal-free cascade for the synthesis of aromatic heterocycles. This cascade uses precursors synthesized from readily accessible 2’-hydroxy/aminochalcones, and commences with a DBU-mediated intramolecular aldol condensation, which occurs within 90 minutes at room temperature, to generate a 1,3,5-triene. This triene is heated overnight (80 – 120 °C) to promote a 6p-electrocyclization, and oxidative aromatization to generate a new aromatic ring. This cascade has proven general, and has been applied towards the synthesis of benzo[c]coumarins, phenanthradinones, dibenzofurans, and carbazoles, up to a 1-gram scale. The cascade reactions developed throughout the course of this dissertation research provide new retrosynthetic strategies for the formation of natural product cores, which could be used to expand the chemical space in drug discovery

A multi-decade record of high quality fCO2 data in version 3 of the Surface Ocean CO2 Atlas (SOCAT)

The Surface Ocean CO2 Atlas (SOCAT) is a synthesis of quality-controlled fCO2 (fugacity of carbon dioxide) values for the global surface oceans and coastal seas with regular updates. Version 3 of SOCAT has 14.7 million fCO2 values from 3646 data sets covering the years 1957 to 2014. This latest version has an additional 4.6 million fCO2 values relative to version 2 and extends the record from 2011 to 2014. Version 3 also significantly increases the data availability for 2005 to 2013. SOCAT has an average of approximately 1.2 million surface water fCO2 values per year for the years 2006 to 2012. Quality and documentation of the data has improved. A new feature is the data set quality control (QC) flag of E for data from alternative sensors and platforms. The accuracy of surface water fCO2 has been defined for all data set QC flags. Automated range checking has been carried out for all data sets during their upload into SOCAT. The upgrade of the interactive Data Set Viewer (previously known as the Cruise Data Viewer) allows better interrogation of the SOCAT data collection and rapid creation of high-quality figures for scientific presentations. Automated data upload has been launched for version 4 and will enable more frequent SOCAT releases in the future. High-profile scientific applications of SOCAT include quantification of the ocean sink for atmospheric carbon dioxide and its long-term variation, detection of ocean acidification, as well as evaluation of coupled-climate and ocean-only biogeochemical models. Users of SOCAT data products are urged to acknowledge the contribution of data providers, as stated in the SOCAT Fair Data Use Statement. This ESSD (Earth System Science Data) “living data” publication documents the methods and data sets used for the assembly of this new version of the SOCAT data collection and compares these with those used for earlier versions of the data collection (Pfeil et al., 2013; Sabine et al., 2013; Bakker et al., 2014). Individual data set files, included in the synthesis product, can be downloaded here: doi:10.1594/PANGAEA.849770. The gridded products are available here: doi:10.3334/CDIAC/OTG.SOCAT_V3_GRID

The GEOTRACES Intermediate Data Product 2014

The GEOTRACES Intermediate Data Product 2014 (IDP2014) is the first publicly available data product of the international GEOTRACES programme, and contains data measured and quality controlled before the end of 2013. It consists of two parts: (1) a compilation of digital data for more than 200 trace elements and isotopes (TEIs) as well as classical hydrographic parameters, and (2) the eGEOTRACES Electronic Atlas providing a strongly inter-linked on-line atlas including more than 300 section plots and 90 animated 3D scenes. The IDP2014 covers the Atlantic, Arctic, and Indian oceans, exhibiting highest data density in the Atlantic. The TEI data in the IDP2014 are quality controlled by careful assessment of intercalibration results and multi-laboratory data comparisons at cross-over stations. The digital data are provided in several formats, including ASCII spreadsheet, Excel spreadsheet, netCDF, and Ocean Data View collection. In addition to the actual data values the IDP2014 also contains data quality flags and 1-? data error values where available. Quality flags and error values are useful for data filtering. Metadata about data originators, analytical methods and original publications related to the data are linked to the data in an easily accessible way. The eGEOTRACES Electronic Atlas is the visual representation of the IDP2014 data providing section plots and a new kind of animated 3D scenes. The basin-wide 3D scenes allow for viewing of data from many cruises at the same time, thereby providing quick overviews of large-scale tracer distributions. In addition, the 3D scenes provide geographical and bathymetric context that is crucial for the interpretation and assessment of observed tracer plumes, as well as for making inferences about controlling processes

A Convergent Approach to Diverse Spiroethers through Stereoselective Trapping of Rhodium Carbenoids with Gold-Activated Alkynols

A convergent approach for the stereoselective synthesis of diverse spiroethers is described. The reaction involves stereoselective trapping of diazo-derived rhodium carbenoids with gold-activated alkynols for the installation of spiro cores. The reaction has proven general with a range of readily accessible homopropargylic alcohols and diazo carbonyls to provide functionalized spiroether cores of bioactive scaffolds such as spirobarbiturates, spirooxindoles, and pseurotin natural products

A Convergent Approach to Diverse Spiroethers through Stereoselective Trapping of Rhodium Carbenoids with Gold-Activated Alkynols

A convergent approach for the stereoselective synthesis of diverse spiroethers is described. The reaction involves stereoselective trapping of diazo-derived rhodium carbenoids with gold-activated alkynols for the installation of spiro cores. The reaction has proven general with a range of readily accessible homopropargylic alcohols and diazo carbonyls to provide functionalized spiroether cores of bioactive scaffolds such as spirobarbiturates, spirooxindoles, and pseurotin natural products

A Convergent Approach to Diverse Spiroethers through Stereoselective Trapping of Rhodium Carbenoids with Gold-Activated Alkynols

A convergent approach for the stereoselective synthesis of diverse spiroethers is described. The reaction involves stereoselective trapping of diazo-derived rhodium carbenoids with gold-activated alkynols for the installation of spiro cores. The reaction has proven general with a range of readily accessible homopropargylic alcohols and diazo carbonyls to provide functionalized spiroether cores of bioactive scaffolds such as spirobarbiturates, spirooxindoles, and pseurotin natural products

Starlikeness of Libera transformation (II) (Applications of Complex Function Theory to Differential Equations)

The GEOTRACES Intermediate Data Product 2017 (IDP2017) is the second publicly available data product of the international GEOTRACES programme, and contains data measured and quality controlled before the end of 2016. The IDP2017 includes data from the Atlantic, Pacific, Arctic, Southern and Indian oceans, with about twice the data volume of the previous IDP2014. For the first time, the IDP2017 contains data for a large suite of biogeochemical parameters as well as aerosol and rain data characterising atmospheric trace element and isotope (TEI) sources. The TEI data in the IDP2017 are quality controlled by careful assessment of intercalibration results and multi-laboratory data comparisons at crossover stations. The IDP2017 consists of two parts: (1) a compilation of digital data for more than 450 TEIs as well as standard hydrographic parameters, and (2) the eGEOTRACES Electronic Atlas providing an on-line atlas that includes more than 590 section plots and 130 animated 3D scenes. The digital data are provided in several formats, including ASCII, Excel spreadsheet, netCDF, and Ocean Data View collection. Users can download the full data packages or make their own custom selections with a new on-line data extraction service. In addition to the actual data values, the IDP2017 also contains data quality flags and 1-σ data error values where available. Quality flags and error values are useful for data filtering and for statistical analysis. Metadata about data originators, analytical methods and original publications related to the data are linked in an easily accessible way. The eGEOTRACES Electronic Atlas is the visual representation of the IDP2017 as section plots and rotating 3D scenes. The basin-wide 3D scenes combine data from many cruises and provide quick overviews of large-scale tracer distributions. These 3D scenes provide geographical and bathymetric context that is crucial for the interpretation and assessment of tracer plumes near ocean margins or along ridges. The IDP2017 is the result of a truly international effort involving 326 researchers from 25 countries. This publication provides the critical reference for unpublished data, as well as for studies that make use of a large cross-section of data from the IDP2017. This article is part of a special issue entitled: Conway GEOTRACES - edited by Tim M. Conway, Tristan Horner, Yves Plancherel, and Aridane G. González