In contrast to observations with carbohydrates, experiments with 4‐alkoxy‐substituted acetals indicate that an alkoxy group can accelerate acetal hydrolysis by up to 20‐fold compared to substrates ...without an alkoxy group. The acceleration of ionization in more flexible acetals can be up to 200‐fold when compensated for inductive effects.
Making an approach: In contrast to observations with carbohydrates, alkoxy groups can accelerate acetal hydrolysis even though they are inductively electron withdrawing. The alkoxy group must be able to approach the acetal carbon atom without developing too much strain. The data are most consistent with the alkoxy group stabilizing the developing positive charge by electrostatic stabilization, not formation of a new covalent bond.
Addition of allylmagnesium reagents to an aliphatic aldehyde bearing a radical clock gave only addition products and no evidence of ring-opened products that would suggest single-electron-transfer ...reactions. The analogous Barbier reaction also did not provide evidence for a single-electron-transfer mechanism in the addition step. Other Grignard reagents (methyl-, vinyl-, t-Bu-, and triphenylmethylmagnesium halides) also do not appear to add to an alkyl aldehyde by a single-electron-transfer mechanism.
The hydrolysis of 4-alkoxy-substituted acetals was accelerated by about 20-fold compared to that of sterically comparable substrates that do not have an alkoxy group. Rate accelerations are largest ...when the two functional groups are linked by a flexible cyclic tether. When controlled for the inductive destabilization, an alkoxy group can accelerate acetal hydrolysis by up to 200-fold. The difference in rates of acetal hydrolysis between a substrate where the alkoxy group was tethered to the acetal group by a five-membered ring compared to one where it was tethered by an eight-membered ring was less than 100-fold, suggesting that fused-ring intermediates were not formed. By comparison, the difference in rates of solvolysis of structurally related tosylates were nearly 106-fold between the five- and eight-membered ring series. This observation implicates neighboring-group participation in the solvolysis of tosylates but not in the hydrolysis of acetals. The acceleration of acetal hydrolysis by an alkoxy group is better explained by electrostatic stabilization of intermediates that accumulate positive charge at the acetal carbon atom.
Gefapixant citrate (MK-7264) is a P2X3 antagonist for the treatment of chronic cough. The second generation manufacturing route developed for the Step 3A/3B formylation–cyclization reaction to ...generate the key intermediate diaminopyrimidine (1) (AF-072) required a significant excess of ethyl formate (EF), potassium tert-butoxide (KOt-Bu), and guanidine•HCl (G•HCl) when both steps were run as batch processes. It was imperative to develop an alternative process that required less of each reagent and generated less carbon monoxide byproducts, as the annual production of the final active pharmaceutical ingredient (API) is expected to be over 50 MT. In addition, the second generation process was misaligned with our company’s strategy of having the best science in place at the first regulatory filing. The final flow–batch process described herein, which features a flow-based formylation combined with a batch cyclization, has been performed on a 500 kg scale and now requires 35% less EF (leading to a 70% reduction in waste carbon monoxide), 38% less KOt-Bu, and 50% less G•HCl. These improvements, along with a twofold increase in concentration, have resulted in a 54% reduction in the step process mass intensity (step-PMI) from the second generation two-step batch–batch process (PMI of 17.16) to the flow–batch process (PMI of 7.86), without sacrificing reaction performance.
Polycomb group proteins are essential for early development in metazoans, but their contributions to human development are not well understood. We have mapped the Polycomb Repressive Complex 2 (PRC2) ...subunit SUZ12 across the entire nonrepeat portion of the genome in human embryonic stem (ES) cells. We found that SUZ12 is distributed across large portions of over two hundred genes encoding key developmental regulators. These genes are occupied by nucleosomes trimethylated at histone H3K27, are transcriptionally repressed, and contain some of the most highly conserved noncoding elements in the genome. We found that PRC2 target genes are preferentially activated during ES cell differentiation and that the ES cell regulators OCT4, SOX2, and NANOG cooccupy a significant subset of these genes. These results indicate that PRC2 occupies a special set of developmental genes in ES cells that must be repressed to maintain pluripotency and that are poised for activation during ES cell differentiation.
Single-molecule fluorescence microscopy provided information about the real-time distribution of chemical reactivity on silicon oxide supports at the solution−surface interface, at a level of detail ...which would be unavailable from a traditional ensemble technique or from a technique that imaged the static physical properties of the surface. Chemical reactions on the surface were found to be uncorrelated; that is, the chemical reaction of one metal complex did not influence the location of a future chemical reaction of another metal complex.
A robust, green, and sustainable manufacturing process has been developed for the synthesis of gefapixant citrate, a P2X3 receptor antagonist that is under investigation for the treatment of ...refractory and unexplained chronic cough. The newly developed commercial process features low process mass intensity (PMI), short synthetic sequence, high overall yield, minimal environmental impact, and significantly reduced API costs. The key innovations are the implementation of a highly efficient two-step methoxyphenol synthesis, an innovative pyrimidine synthesis in flow, a simplified sulfonamide synthesis, and a novel salt metathesis approach to consistently deliver the correct active pharmaceutical ingredient (API) salt form in high purity.
13C NMR spectroscopic integration employing short relaxation delays was evaluated as a quantitative tool to obtain ratios of diastereomers, regioisomers, constitutional isomers, mixtures of unrelated ...compounds, peptoids, and sugars. The results were compared to established quantitative methods such as 1H NMR spectroscopic integration, gas chromatography, and high-performance liquid chromatography and were found to be within <3.4% of 1H NMR spectroscopic values (most examples give results within <2%). Acquisition of the spectra took 2–30 min on as little as 10 mg of sample, proving the general utility of the technique. The simple protocol was extended to include end group analysis of low molecular weight polymers, which afforded results in accordance with 1H NMR spectroscopy and matrix-assisted laser desorption-ionization time-of-flight spectrometry.
On the occasion of Professor Donna G. Blackmond’s winning of the 2023 James Flack Norris Award in Physical Organic Chemistry from the American Chemical Society, we honor her numerous and exceptional ...contributions to the field of physical organic chemistry. Blackmond’s groundbreaking work has paved the way for significant advancements in various areas. Specifically, we focus on her pioneering work in the development of revolutionary RPKA methodologies, the discovery of a groundbreaking paradigm for stereocontrol in organocatalysis, and the development of mathematical models to understand nonlinear effects in asymmetric synthesis. Through these invaluable contributions, Blackmond ushered in a modern and cutting-edge paradigm within the vast realm of catalysis. Her interdisciplinary research not only has deepened our understanding of catalytic reaction mechanisms but also has laid a foundation for the development of innovative approaches in this field. We celebrate her accomplishments and look forward to witnessing the lasting impact of her research in the field of catalysis and beyond.
In contrast to observations with carbohydrates, experiments with 4‐alkoxy‐substituted acetals indicate that an alkoxy group can accelerate acetal hydrolysis by up to 20‐fold compared to substrates ...without an alkoxy group. The acceleration of ionization in more flexible acetals can be up to 200‐fold when compensated for inductive effects.
Annäherungsversuche: Anders als für Kohlenhydrate beobachtet, kann eine Alkoxygruppe – trotz ihres negativen induktiven Effekts – die Acetalhydrolyse beschleunigen. Dafür muss die Alkoxygruppe in der Lage sein, das Acetal‐Kohlenstoffatom ohne große Spannungsentwicklung anzugreifen. Vermutlich begünstigt die Alkoxygruppe nicht die Bildung einer neuen kovalenten Bindung, sondern sie stabilisiert die entstehende positive Ladung durch elektrostatische Wirkung.
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