At this stage, I've edited the manuscript for brevity and clarity. Queries are meant to draw your attention to edits, inconsistencies or issues that are unclear. If we just ask you to confirm edits are correct, a simple yes/ok between the brackets will do [Au:OK? Is this what you meant? Edits OK? yes]. If questions are asked, please rephrase/update the manuscript text when addressing queries, so that the message is conveyed to the reader (please do not just type your answer to our query unless it is unclear).As the reviewers noted, the manuscript is in very good shape and most comments and edits are fairly minor. However, there is an outstanding issue that must be addressed before we go forward. Figures 7 and 8 are currently referred to in the text in an alternating fashion (e.g. Figure 7A, 8A, 7B, 8B). This is against our style and might make that part of the manuscript difficult to follow for the reader owing to the need to refer to multiple figures at a time while reading the text. To clarify this issue, I recommend restructuring these figures. To do this, can you provide new chemdraw/PDFs with amended figures, including the following amendments: a. Merge Figures 7A and 8A to create a new 'Figure 7' that shows the methods of introducing CF2H at sp3-carbons. b. Merge figures 7B and 8B to make a new figure 8 that shows the main protocols of introducing CF2H at heteroaromatic carbons. 7C could be shown in it's own small figure (Figure 9) or could be added as panel B in the new figure 8. c. Amend the figure legends accordingly Apologies for another figure change but this is essential to keep the figure callouts in style and I think it will make the figures much easier for the reader to follow. I've asked the art editor to delay redrawing these particular figures until we receive these updated chemdraws/PDFs. If there are any issues with this change, please do let me know as soon as possible and we can discuss further.
Nucleoside analogs are commonly used in the treatment of cancer and viral infections. Their syntheses benefit from decades of research but are often protracted, unamenable to diversification, and reliant on a limited pool of chiral carbohydrate starting materials. We present a process for rapidly constructing nucleoside analogs from simple achiral materials. Using only proline catalysis, heteroaryl-substituted acetaldehydes are fluorinated and then directly engaged in enantioselective aldol reactions in a one-pot reaction. A subsequent intramolecular fluoride displacement reaction provides a functionalized nucleoside analog. The versatility of this process is highlighted in multigram syntheses of d- or l-nucleoside analogs, locked nucleic acids, iminonucleosides, and C2′- and C4′-modified nucleoside analogs. This de novo synthesis creates opportunities for the preparation of diversity libraries and will support efforts in both drug discovery and development.
The site-specific oxidation of strong C(sp3)–H bonds is of uncontested utility in organic synthesis. From simplifying access to metabolites and late-stage diversification of lead compounds to truncating retrosynthetic plans, there is a growing need for new reagents and methods for achieving such a transformation in both academic and industrial circles. One main drawback of current chemical reagents is the lack of diversity with regard to structure and reactivity that prevents a combinatorial approach for rapid screening to be employed. In that regard, directed evolution still holds the greatest promise for achieving complex C–H oxidations in a variety of complex settings. Herein we present a rationally designed platform that provides a step toward this 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 building blocks and trivial synthesis techniques. The ylide-based approach to C–H oxidation exhibits tunable selectivity that is often exclusive to this class of oxidants and can be applied to real-world problems in the agricultural and pharmaceutical sectors.
Mechanism-based glycoside hydrolase inhibitors are carbohydrate analogs that mimic the natural substrate’s structure. Their covalent bond formation with the glycoside hydrolase makes these compounds excellent tools for chemical biology and potential drug candidates. Here we report the synthesis of cyclohexene-based α-galactopyranoside mimics and the kinetic and structural characterization of their inhibitory activity toward an α-galactosidase from Thermotoga maritima (TmGalA). By solving the structures of several enzyme-bound species during mechanism-based covalent inhibition of TmGalA, we show that the Michaelis complexes for intact inhibitor and product have half-chair (2H3) conformations for the cyclohexene fragment, while the covalently linked intermediate adopts a flattened half-chair (2H3) conformation. Hybrid QM/MM calculations confirm the structural and electronic properties of the enzyme-bound species and provide insight into key interactions in the enzyme-active site. These insights should stimulate the design of mechanism-based glycoside hydrolase inhibitors with tailored chemical properties.
Acyl fluorides are versatile acylating agents owing to their unique stability. Their synthesis, however, can present challenges and is typically accomplished through deoxyfluorination of carboxylic acids. Here, we demonstrate that acyl fluorides can be prepared directly from aldehydes via a C(sp)-H fluorination reaction involving the inexpensive photocatalyst sodium decatungstate and electrophilic fluorinating agent N-fluorobenzenesulfonimide. This convenient fluorination strategy enables direct conversion of aliphatic and aromatic aldehydes into acylating agents.
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