A Survival Guide for the “Electro-curious” Kingston, Cian; Palkowitz, Maximilian D; Takahira, Yusuke ...
Accounts of chemical research,
01/2020, Letnik:
53, Številka:
1
Journal Article
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Conspectus The appeal and promise of synthetic organic electrochemistry have been appreciated over the past century. In terms of redox chemistry, which is frequently encountered when forging new ...bonds, it is difficult to conceive of a more economical way to add or remove electrons than electrochemistry. Indeed, many of the largest industrial synthetic chemical processes are achieved in a practical way using electrons as a reagent. Why then, after so many years of the documented benefits of electrochemistry, is it not more widely embraced by mainstream practitioners? Erroneous perceptions that electrochemistry is a “black box” combined with a lack of intuitive and inexpensive standardized equipment likely contributed to this stagnation in interest within the synthetic organic community. This barrier to entry is magnified by the fact that many redox processes can already be accomplished using simple chemical reagents even if they are less atom-economic. Time has proven that sustainability and economics are not strong enough driving forces for the adoption of electrochemical techniques within the broader community. Indeed, like many synthetic organic chemists that have dabbled in this age-old technique, our first foray into this area was not by choice but rather through sheer necessity. The unique reactivity benefits of this old redox-modulating technique must therefore be highlighted and leveraged in order to draw organic chemists into the field. Enabling new bonds to be forged with higher levels of chemo- and regioselectivity will likely accomplish this goal. In doing so, it is envisioned that widespread adoption of electrochemistry will go beyond supplanting unsustainable reagents in mundane redox reactions to the development of exciting reactivity paradigms that enable heretofore unimagined retrosynthetic pathways. Whereas the rigorous physical organic chemical principles of electroorganic synthesis have been reviewed elsewhere, it is often the case that such summaries leave out the pragmatic aspects of designing, optimizing, and scaling up preparative electrochemical reactions. Taken together, the task of setting up an electrochemical reaction, much less inventing a new one, can be vexing for even seasoned organic chemists. This Account therefore features a unique format that focuses on addressing this exact issue within the context of our own studies. The graphically rich presentation style pinpoints basic concepts, typical challenges, and key insights for those “electro-curious” chemists who seek to rapidly explore the power of electrochemistry in their research.
A practical electrochemical oxidation of unactivated C–H bonds is presented. This reaction utilizes a simple redox mediator, quinuclidine, with inexpensive carbon and nickel electrodes to selectively ...functionalize “deep-seated” methylene and methine moieties. The process exhibits a broad scope and good functional group compatibility. The scalability, as illustrated by a 50 g scale oxidation of sclareolide, bodes well for immediate and widespread adoption.
A new approach to the enantiocontrolled synthesis of α‐amino ketone derivatives is disclosed by employing a decarboxylative acylation strategy. Thus, when an acyl chloride and an α‐amido‐containing ...redox‐active ester are exposed to a nickel catalyst, chiral ligand, and metal reductant, α‐amido ketones are produced in good yield and high ee. The reaction exhibits broad substrate scope, can be easily scaled up, and is applied to dramatically simplify the synthesis of several known structures.
A new approach to the enantiocontrolled synthesis of α‐amino ketone derivatives is disclosed by employing a nickel‐catalyzed decarboxylative acylation strategy. Starting from readily available acyl chlorides and α‐amino acids‐derived redox‐active esters, the reaction exhibits broad substrate scope, easy scalability, and is applied to dramatically simplify the synthesis of several known structures.
This Article details the development of the iron-catalyzed conversion of olefins to radicals and their subsequent use in the construction of C–C bonds. Optimization of a reductive diene cyclization ...led to the development of an intermolecular cross-coupling of electronically-differentiated donor and acceptor olefins. Although the substitution on the donor olefins was initially limited to alkyl and aryl groups, additional efforts culminated in the expansion of the scope of the substitution to various heteroatom-based functionalities, providing a unified olefin reactivity. A vinyl sulfone acceptor olefin was developed, which allowed for the efficient synthesis of sulfone adducts that could be used as branch points for further diversification. Moreover, this reactivity was extended into an olefin-based Minisci reaction to functionalize heterocyclic scaffolds. Finally, mechanistic studies resulted in a more thorough understanding of the reaction, giving rise to the development of a more efficient second-generation set of olefin cross-coupling conditions.
The detection of chemical or biological analytes upon molecular reactions relies increasingly on fluorescence methods, and there is a demand for more sensitive, more specific, and more versatile ...fluorescent molecules. We have designed long wavelength fluorogenic probes with a turn-ON mechanism based on a donor–two-acceptor π-electron system that can undergo an internal charge transfer to form new fluorochromes with longer π-electron systems. Several latent donors and multiple acceptor molecules were incorporated into the probe modular structure to generate versatile dye compounds. This new library of dyes had fluorescence emission in the near-infrared (NIR) region. Computational studies reproduced the observed experimental trends well and suggest factors responsible for high fluorescence of the donor–two-acceptor active form and the low fluorescence observed from the latent form. Confocal images of HeLa cells indicate a lysosomal penetration pathway of a selected dye. The ability of these dyes to emit NIR fluorescence through a turn-ON activation mechanism makes them promising candidate probes for in vivo imaging applications.
Challenges in the selective manipulation of functional groups (chemoselectivity) in organic synthesis have historically been overcome either by using reagents/catalysts that tunably interact with a ...substrate or through modification to shield undesired sites of reactivity (protecting groups). Although electrochemistry offers precise redox control to achieve unique chemoselectivity, this approach often becomes challenging in the presence of multiple redox-active functionalities. Historically, electrosynthesis has been performed almost solely by using direct current (DC). In contrast, applying alternating current (AC) has been known to change reaction outcomes considerably on an analytical scale but has rarely been strategically exploited for use in complex preparative organic synthesis. Here we show how a square waveform employed to deliver electric currentrapid alternating polarity (rAP)enables control over reaction outcomes in the chemoselective reduction of carbonyl compounds, one of the most widely used reaction manifolds. The reactivity observed cannot be recapitulated using DC electrolysis or chemical reagents. The synthetic value brought by this new method for controlling chemoselectivity is vividly demonstrated in the context of classical reactivity problems such as chiral auxiliary removal and cutting-edge medicinal chemistry topics such as the synthesis of PROTACs.
The economies of synthesis Newhouse, Timothy; Baran, Phil S; Hoffmann, Reinhard W
Chemical Society reviews
38, Številka:
11
Journal Article
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In this tutorial review the economies of synthesis are analysed from both detailed and macroscopic perspectives, using case-studies from complex molecule synthesis. Atom, step, and redox economy are ...more than philosophical constructs, but rather guidelines, which enable the synthetic chemist to design and execute an efficient synthesis. Students entering the field of synthesis might find this tutorial helpful for understanding the subtle differences between these economic principles and also see real-world situations where such principles are put into practice.
The first examples of enantioselective doubly decarboxylative cross coupling are disclosed. Malonate half amides are smoothly coupled to a variety of primary carboxylic acids after formation of the ...corresponding redox-active esters under Ni-electrocatalytic conditions using a new chiral ligand based on PyBox, resulting in amides with α-alkylated stereocenters. The scope of the reaction is broad, tolerating numerous functional groups, and uniformly proceeds with high ee. Finally, the potential utility of this enantioselective radical–radical reductive cross coupling to simplify synthesis is demonstrated with numerous case studies.
Cyclophane natural products comprise an intriguing class of structurally diverse compounds. As inherent for all cyclic compounds regardless of their origin, macrocyclization is naturally the most ...decisive step, which defines the overall efficiency of the synthetic pathway. Especially in small cyclophane molecules, this key step constitutes an even greater challenge. Due to the strain imparted by the macrocyclic system, free rotation of the benzene ring(s) is often restricted depending on both the constitution of the tether and the aromatic portions. Not surprisingly, the synthesis of natural cyclophanes with their often outstanding pharmaceutical activities and the inherent issues associated with their preparation has attracted much attention among the synthetic community. In particular, it stimulated the development of new strategies for the ring-closing step, as often otherwise well established and robust reactions fail to perform effectively. In this review, we describe the challenges synthetic chemists are facing during the synthesis of this small, but structurally and biologically fascinating class of natural products, concentrating on the representatives exhibiting configurational stability. The main focus will be on the different concepts for the installation of the macrocyclic system, in most cases the central problem in assembling these extremely rigid molecules.
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