Lewis Base Catalysis in Organic Synthesis Denmark, Scott E; Beutner, Gregory L
Angewandte Chemie (International ed.),
February 15, 2008, Volume:
47, Issue:
9
Journal Article
Peer reviewed
The legacy of Gilbert Newton Lewis (1875-1946) pervades the lexicon of chemical bonding and reactivity. The power of his concept of donor-acceptor bonding is evident in the eponymous foundations of ...electron-pair acceptors (Lewis acids) and donors (Lewis bases). Lewis recognized that acids are not restricted to those substances that contain hydrogen (Brønsted acids), and helped overthrow the "modern cult of the proton". His discovery ushered in the use of Lewis acids as reagents and catalysts for organic reactions. However, in recent years, the recognition that Lewis bases can also serve in this capacity has grown enormously. Most importantly, it has become increasingly apparent that the behavior of Lewis bases as agents for promoting chemical reactions is not merely as an electronic complement of the cognate Lewis acids: in fact Lewis bases are capable of enhancing both the electrophilic and nucleophilic character of molecules to which they are bound. This diversity of behavior leads to a remarkable versatility for the catalysis of reactions by Lewis bases.
Challenging couplings of hindered carboxylic acids with non-nucleophilic amines to form amide bonds can be accomplished in high yields, and in many cases, with complete retention of the adjacent ...stereogenic centers using the combination of N,N,N′,N′-tetramethylchloroformamidinium hexafluorophosphate (TCFH) and N-methylimidazole (NMI). This method allows for in situ generation of highly reactive acyl imidazolium ions, which have been demonstrated to be intermediates in the reaction. The reagent delivers high reactivity similar to acid chlorides with the ease of use of modern uronium reagents.
Since the landmark publications of the first directed aldol addition reaction in 1973, the site, diastereo-, and enantioselective aldol reaction has been elevated to the rarefied status of being both ...a named and a strategy-level reaction (the Mukaiyama directed aldol reaction). The importance of this reaction in the stereoselective synthesis of untold numbers of organic compounds, both natural and unnatural, cannot be overstated. However, its impact on the field extends beyond the impressive applications in synthesis. The directed aldol reaction has served as a fertile proving ground for new concepts and new methods for stereocontrol and catalysis. This Minireview provides a case history of how the challenges of merging site selectivity, diastereoselectivity, enantioselectivity, and catalysis into a unified reaction manifold stimulated the development of Lewis base catalyzed aldol addition reactions. The evolution of this process is chronicled from the authors' laboratories as well as in those of Professor Teruaki Mukaiyama.
In 1935, R. C. Fuson formulated the principle of vinylogy to explain how the influence of a functional group may be felt at a distant point in the molecule when this position is connected by ...conjugated double‐bond linkages to the group. In polar reactions, this concept allows the extension of the electrophilic or nucleophilic character of a functional group through the π system of a carbon–carbon double bond. This vinylogous extension has been applied to the aldol reaction by employing “extended” dienol ethers derived from γ‐enolizable α,β‐unsaturated carbonyl compounds. Since 1994, several methods for the catalytic, enantioselective, vinylogous aldol reaction have appeared, with which varying degrees of regio‐ (site), enantio‐, and diastereoselectivity can be attained. In this Review, the current scope and limitations of this transformation, as well as its application in natural product synthesis, are discussed.
The power of the aldol reaction is extended through the use of γ‐enolizable α,β‐unsaturated carbonyl substrates as “extended dienolates” in the addition to aldehydes. This process gives δ‐hydroxy carbonyl compounds 1 or 2 with up to two new stereocenters (see scheme). New methods for the catalytic, enantioselective, vinylogous aldol reaction are summarized, and the scope and limitations of these systems are discussed.
Peptide couplers (also known as amide bond-forming reagents or coupling reagents) are broadly used in organic chemical syntheses, especially in the pharmaceutical industry. Yet, occupational health ...hazards associated with this chemical class are largely unexplored, which is disconcerting given the intrinsic reactivity of these compounds. Several case studies involving occupational exposures reported adverse respiratory and dermal health effects, providing initial evidence of chemical sensitization. To address the paucity of toxicological data, a pharmaceutical cross-industry task force was formed to evaluate and assess the potential of these compounds to cause eye and dermal irritation as well as corrosivity and dermal sensitization. The goal of our work was to inform health and safety professionals as well as pharmaceutical and organic chemists of the occupational health hazards associated with this chemical class. To that end, 25 of the most commonly used peptide couplers and five hydrolysis products were selected for in vivo, in vitro, and in silico testing. Our findings confirmed that dermal sensitization is a concern for this chemical class with 21/25 peptide couplers testing positive for dermal sensitization and 15 of these being strong/extreme sensitizers. We also found that dermal corrosion and irritation (8/25) as well as eye irritation (9/25) were health hazards associated with peptide couplers and their hydrolysis products (4/5 were dermal irritants or corrosive and 4/5 were eye irritants). Resulting outcomes were synthesized to inform decision making in peptide coupler selection and enable data-driven hazard communication to workers. The latter includes harmonized hazard classifications, appropriate handling recommendations, and accurate safety data sheets, which support the industrial hygiene hierarchy of control strategies and risk assessment. Our study demonstrates the merits of an integrated, in vivo -in silico analysis, applied here to the skin sensitization endpoint using the Computer-Aided Discovery and REdesign (CADRE) and Derek Nexus programs. We show that experimental data can improve predictive models by filling existing data gaps while, concurrently, providing computational insights into key initiating events and elucidating the chemical structural features contributing to adverse health effects. This interactive, interdisciplinary approach is consistent with Green Chemistry principles that seek to improve the selection and design of less hazardous reagents in industrial processes and applications.
A nickel(0)-catalyzed method for the synthesis of quinazolinediones from isatoic anhydrides and isocyanates is described. High-throughput ligand screening revealed that XANTPHOS was the optimal ...ligand for this transformation. Subsequent optimization studies, supported by kinetic analysis, significantly expanded the reaction scope. The reaction exhibits a case of substrate inhibition kinetics with respect to the isocyanate. Preliminary results on an asymmetric synthesis of atropisomeric quinazolinediones are reported.
Having robust and reliable methods for monitoring catalyst activation processes is an important part of ensuring the reproducibility of a catalytic reaction. For asymmetric Diels–Alder reactions, ...chiral oxazaborolidine or oxazaborolidinium catalysts are powerful reagents that promote these reactions in high yield and selectivity. Supported by mechanistic findings, several modern analytical methods are compared for quantitating the oxazaborolidine catalyst formation from amino alcohol and boroxine to arrive at useful monitoring methods for this important transformation.
In response to an increased awareness of sensitization issues with amide bond forming agents, a detailed toxicological analysis of this broad family of reagents was undertaken which led to a ...quantitative ranking of the sensitization potential of these commonly used compounds. This data enables occupational toxicologists to guide the safer use of these reagents in the laboratory, but it also provides an opportunity for chemists working on reaction development, optimization and scale‐up. To illustrate this, one of the strongest sensitizers, EDAC, is compared with the performance of one of the weakest, TCFH, showing the potential of this data for minimizing risks for researchers when using this family of reagents.
In this Communication, an investigation of the combination of N,N,N′,N′-tetramethylchloroformamidinium hexafluorophosphate (TCFH) and N-methylimidazole (NMI) for the synthesis of esters and ...thioesters is described. This work revealed the unique challenges of the reactions of less nucleophilic alcohols and more reactive thiols with the N-acyl imidazolium intermediate and led to the identification of general enabling conditions that provide high yields and selectivity for a range of alcohols and thiols.
The palladium-catalyzed coupling of aryl and heteroaryl chlorides with primary amides under mild homogeneous reaction conditions is reported. Successful C–N coupling is enabled by the use of a unique ...“dual-base” system consisting of DBU and NaTFA, which serve as proton acceptor and halide scavenger, respectively, using low catalyst loadings (0.5 mol %) with readily available, air-stable palladium precatalysts. The DBU/NaTFA system also enables the room-temperature coupling of primary aryl amines with aryl chlorides and is tolerant of a variety of base-sensitive functional groups.
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