Data Science Meets Physical Organic Chemistry

ConspectusAt the heart of synthetic chemistry is the holy grail of predictable catalyst design. In particular, researchers involved in reaction development in asymmetric catalysis have pursued a variety of strategies toward this goal. This is driven by both the pragmatic need to achieve high selectivities and the inability to readily identify why a certain catalyst is effective for a given reaction. While empiricism and intuition have dominated the field of asymmetric catalysis since its inception, enantioselectivity offers a mechanistically rich platform to interrogate catalyst-structure response patterns that explain the performance of a particular catalyst or substrate.In the early stages of an asymmetric reaction development campaign, the overarching mechanism of the reaction, catalyst speciation, the turnover limiting step, and many other details are unknown or posited based on related reactions. Considering the unclear details leading to a successful reaction, initial enantioselectivity data are often used to intuitively guide the ultimate direction of optimization. However, if the conditions of the Curtin-Hammett principle are satisfied, then measured enantioselectivity can be directly connected to the ensemble of diastereomeric transition states (TSs) that lead to the enantiomeric products, and the associated free energy difference between competing TSs (ΔΔG⧧ = -RT ln[(S)/(R)], where (S) and (R) represent the concentrations of the enantiomeric products). We, and others, speculated that this important piece of information can be leveraged to guide reaction optimization in a quantitative way.Although traditional linear free energy relationships (LFERs), such as Hammett plots, have been used to illuminate important mechanistic features, we sought to develop data science derived tools to expand the power of LFERs in order to describe complex reactions frequently encountered in modern asymmetric catalysis. Specifically, we investigated whether enantioselectivity data from a reaction can be quantitatively connected to the attributes of reaction components, such as catalyst and substrate structural features, to harness data for asymmetric catalyst design.In this context, we developed a workflow to relate computationally derived features of reaction components to enantioselectivity using data science tools. The mathematical representation of molecules can incorporate many aspects of a transformation, such as molecular features from substrate, product, catalyst, and proposed transition states. Statistical models relating these features to reaction outputs can be used for various tasks, such as performance prediction of untested molecules. Perhaps most importantly, statistical models can guide the generation of mechanistic hypotheses that are embedded within complex patterns of reaction responses. Overall, merging traditional physical organic experiments with statistical modeling techniques creates a feedback loop that enables both evaluation of multiple mechanistic hypotheses and future catalyst design. In this Account, we highlight the evolution and application of this approach in the context of a collaborative program based on chiral phosphoric acid catalysts (CPAs) in asymmetric catalysis

Design and Synthesis of Pyrrolidinyl Ferrocene-Containing Ligands and Their Application in Highly Enantioselective Rhodium-Catalyzed Olefin Hydrogenation

Herein, we report the design and synthesis of a series of chiral pyrrolidine-substituted ferrocene-derived ligands. The proficiency of this novel structural motif was demonstrated in the Rh-catalyzed asymmetric hydrogenation of dehydroamino acid esters and α-aryl enamides. The products were obtained with full conversions and excellent levels of enantioselectivities of up to >99.9% ee and 97.7% ee, respectively, using a BINOL-substituted phosphine-phosphoaramidite ligand which possesses planar, central, and axial chirality elements

Direct Carbon Isotope Exchange Through Decarboxylative Carboxylation

A two-step degradation-reconstruction approach to the carbon-14 radiolabeling of alkyl carboxylic acids is presented. Simple activation via redox-active ester formation was followed by nickel-mediated decarboxylative carboxylation to afford a range of complex compounds with ample isotopic incorporations for drug metabolism and pharmacokinetic studies. The practicality and operational simplicity of the protocol was demonstrated by its use in an industrial carbon-14 radiolabeling setting

Stereoconvergent and -divergent Synthesis of Tetrasubstituted Alkenes by Nickel-Catalyzed Cross-Couplings

We report the development of a method to diastereoselectively access tetrasubstituted alkenes via nickel-catalyzed Suzuki-Miyaura cross-couplings of enol tosylates and boronic acid esters. Either diastereomeric product was selectively accessed from a mixture of enol tosylate starting material diastereomers in a convergent reaction by judicious choice of the ligand and reaction conditions. A similar protocol also enabled a divergent synthesis of each product isomer from diastereomerically pure enol tosylates. Notably, high-throughput optimization of the monophosphine ligands was guided by chemical space analysis of the kraken library to ensure a diverse selection of ligands was examined. Stereoelectronic analysis of the results provided insight into the requirements for reactive and selective ligands in this transformation. The synthetic utility of the optimized catalytic system was then probed in the stereoselective synthesis of various tetrasubstituted alkenes, with yields up to 94% and diastereomeric ratios up to 99:1 Z/E and 93:7 E/Z observed. Moreover, a detailed computational analysis and experimental mechanistic studies provided key insights into the nature of the underlying isomerization process impacting selectivity in the cross-coupling

N-Ammonium Ylide Mediators for Selective Electrochemical C–H Oxidation

The site-specific oxidation of strong C(sp3)-H bonds is of uncontested utility in organicsynthesis. From simplifying access to metabolites and late-stage diversification of lead compoundsto truncating retrosynthetic plans, there is a growing need for new reagents and methods forachieving such a transformation in both academic and industrial circles. One main drawback ofcurrent chemical reagents is the lack of diversity with regards to structure and reactivity thatprevent a combinatorial approach for rapid screening to be employed. In that regard, directedevolution still holds the greatest promise for achieving complex C–H oxidations in a variety ofcomplex settings. Herein we present a rationally designed platform that provides a step towardsthis challenge using N-ammonium ylides as electrochemically driven oxidants for site-specific,chemoselective C(sp3)–H oxidation. By taking a first-principles approach guided by computation,these new mediators were identified and rapidly expanded into a library using ubiquitous buildingblocks and trivial synthesis techniques. The ylide-based approach to C–H oxidation exhibitstunable selectivity that is often exclusive to this class of oxidants and can be applied to real worldproblems in the agricultural and pharmaceutical sectors.</p

Working Group on Bycatch of Protected Species (WGBYC)

WGBYC planned to address seven Terms of Reference, one of which was a special request from the European Commission on emergency bycatch mitigation measures for common dolphin in the Bay of Biscay and harbour porpoise in the Baltic Sea (ToR G). ToR G demanded a great deal of resources from WGBYC and, coupled with the COVID–19 disruption where WGBYC work had to be carried out remotely, this meant it was not possible to complete all tasks. The 2020 report is structured in the same order as the ToRs. Note that ToR E was not addressed while ToR G is reported in WKEMBYC (2020). All data submissions were requested via a formal WGBYC/ICES data call (Annex 6: below). The data call requested data on fishing effort, monitoring effort and PETS (protected, endangered, and threatened species of marine mammals, seabirds, reptiles, and fish) bycatch incidents in 2018. 19 of the 24 countries that contacted (18 ICES countries and 6 Mediterranean non-ICES countries) responded. WGBYC did not accept data brought to the meeting, but where problems were found during assessments with country submissions, updated versions were accepted. The quality and scope of Member States (MS) reports on the implementation of Regulation 812/2004 (cetacean bycatch) during 2018 remain varied (ToR A). Most countries have relied on monitoring through their DCF sampling programmes rather than implementing dedicated ob-server programmes. This means that métiers that pose the greatest risk of cetacean bycatch are generally under-sampled and bycatch is underestimated. Regulation 812/2004 was repealed and replaced in June 2019 by the Technical Conservation Measures Regulation (Regulation (EU) 2019/1241) and PETS bycatch monitoring is further implemented through the EU-MAP (Regula-tion (EU) 2017/1004). For 2018, data received through the WGBYC data call amounted to 82 cetaceans (5 species); 175 seals (4 species), 696 birds (at least 22 species); 37 644 elasmobranchs (at least 49 species); 2061 teleost fish (9 species) and 134 turtles (at least 2 species). Equivalent data from non-EU countries was also received from the USA and Iceland. Bycatch of marine mammals was observed in all ecoregions and several gears including gillnets, traps, longlines, and trawls. Seabirds were by-caught in most ecoregions, mainly in nets and longlines. In 2018, bycaught marine turtles were recorded mostly in set nets and trawls in the Mediterranean and in longlines in the Azores. High bycatch rates were observed for some elasmobranch species which are of conservation concern, particularly in trawl gears in the Celtic Sea, the Greater North Sea and Western Mediterranean, and nets in the Celtic Sea. In the US Northwest Atlantic, the gear of most concern are set nets for marine mammals and sea turtles. The gears of most concern in Iceland are set nets (birds and marine mammals) and longlines (birds). Eight countries also contributed numbers of bycaught stranded cetaceans. Bycatch was the predominant cause of death of common dolphins stranded in the Bay of Biscay and Channel. Member states compliance with the ‘pinger’ requirements of Regulation 812/2004 is difficult to gauge from the submitted reports due to reporting inconsistencies and incomplete information (ToR B). Only the United Kingdom appears to comply fully, reporting that all relevant vessels are equipped with “DDD” pingers used under a derogation and there is active enforcement in place. But in general, there has been little progress in the mitigation of cetacean bycatch and the effectiveness of pingers appears to vary among fishing métiers and geographical areas. WGBYC continues to have insufficient data to examine bycatch rates according to pinger use within their database

The book of dissertations by third year students of SAUL University of Limerick 2009-2010

The book of dissertations by third year students of SAUL University of Limerick 2009-201