The intermolecular Friedel–Crafts acylation was carried out in hexafluoro-2-propanol to yield aryl and heteroaryl ketones at room temperature without any additional reagents.
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Twisted amides containing nitrogen at the bridgehead position are attractive practical prototypes for the investigation of the electronic and structural properties of nonplanar amide linkages. ...Changes that occur during rotation around the N–C(O) axis in one-carbon-bridged twisted amides have been studied using ab initio molecular orbital methods. Calculations at the MP2/6-311++G(d,p) level performed on a set of one-carbon-bridged lactams, including 20 distinct scaffolds ranging from 2.2.1 to 6.3.1 ring systems, with the CO bond on the shortest bridge indicate significant variations in structures, resonance energies, proton affinities, core ionization energies, frontier molecular orbitals, atomic charges, and infrared frequencies that reflect structural changes corresponding to the extent of resonance stabilization during rotation along the N–C(O) axis. The results are discussed in the context of resonance theory and activation of amides toward N-protonation (N-activation) by distortion. This study demonstrates that one-carbon-bridged lactamsa class of readily available, hydrolytically robust twisted amidesare ideally suited to span the whole spectrum of the amide bond distortion energy surface. Notably, this study provides a blueprint for the rational design and application of nonplanar amides in organic synthesis. The presented findings strongly support the classical amide bond resonance model in predicting the properties of nonplanar amides.
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Ring expansion provides a powerful way of introducing a heteroatom substituent into a carbocyclic framework. However, such reactions are often limited by the tendency of a given substrate to afford ...only one of the two rearrangement products or fail to achieve high selectivity at all. These limitations are particularly acute when seeking to carry out late-stage functionalization of natural products as starting points in drug discovery. In this work, we present a stereoelectronically controlled ring expansion sequence towards selective and flexible access to complementary ring systems derived from common steroidal substrates. Chemical diversification of the reaction intermediate affords over 100 isomerically pure analogs with spatial and functional diversity. This regiodivergent rearrangement, and the concept of using chiral reagents to affect regiocontrol in chiral natural products, should be broadly applicable to late-stage natural product diversification programs.
HFIP in Organic Synthesis Motiwala, Hashim F.; Armaly, Ahlam M.; Cacioppo, Jackson G. ...
Chemical reviews,
08/2022, Volume:
122, Issue:
15
Journal Article
Peer reviewed
1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) is a polar, strongly hydrogen bond-donating solvent that has found numerous uses in organic synthesis due to its ability to stabilize ionic species, transfer ...protons, and engage in a range of other intermolecular interactions. The use of this solvent has exponentially increased in the past decade and has become a solvent of choice in some areas, such as C–H functionalization chemistry. In this review, following a brief history of HFIP in organic synthesis and an overview of its physical properties, literature examples of organic reactions using HFIP as a solvent or an additive are presented, emphasizing the effect of solvent of each reaction.
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N-Protonation of amides is critical in numerous biological processes, including amide bonds proteolysis and protein folding as well as in organic synthesis as a method to activate amide bonds towards ...unconventional reactivity. A computational model enabling prediction of protonation at the amide bond nitrogen atom along the C-N rotational pathway is reported. Notably, this study provides a blueprint for the rational design and application of amides with a controlled degree of rotation in synthetic chemistry and biology.
How early-life colonization and subsequent exposure to the microbiota affect long-term tissue immunity remains poorly understood. Here, we show that the development of mucosal-associated invariant T ...(MAIT) cells relies on a specific temporal window, after which MAIT cell development is permanently impaired. This imprinting depends on early-life exposure to defined microbes that synthesize riboflavin-derived antigens. In adults, cutaneous MAIT cells are a dominant population of interleukin-17A (IL-17A)-producing lymphocytes, which display a distinct transcriptional signature and can subsequently respond to skin commensals in an IL-1-, IL-18-, and antigen-dependent manner. Consequently, local activation of cutaneous MAIT cells promotes wound healing. Together, our work uncovers a privileged interaction between defined members of the microbiota and MAIT cells, which sequentially controls both tissue-imprinting and subsequent responses to injury.
A tandem Prins/Friedel–Crafts reaction useful for the construction of the indeno-tetrahydropyridine core of the haouamine alkaloids and a formal synthesis of (−)-haouamine A are described.
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HuR, an RNA binding protein, binds to adenine- and uridine-rich elements (ARE) in the 3′-untranslated region (UTR) of target mRNAs, regulating their stability and translation. HuR is highly abundant ...in many types of cancer, and it promotes tumorigenesis by interacting with cancer-associated mRNAs, which encode proteins that are implicated in different tumor processes including cell proliferation, cell survival, angiogenesis, invasion, and metastasis. Drugs that disrupt the stabilizing effect of HuR upon mRNA targets could have dramatic effects on inhibiting cancer growth and persistence. In order to identify small molecules that directly disrupt the HuR–ARE interaction, we established a fluorescence polarization (FP) assay optimized for high throughput screening (HTS) using HuR protein and an ARE oligo from Musashi RNA-binding protein 1 (Msi1) mRNA, a HuR target. Following the performance of an HTS of ∼6000 compounds, we discovered a cluster of potential disruptors, which were then validated by AlphaLISA (Amplified Luminescent Proximity Homogeneous Assay), surface plasmon resonance (SPR), ribonucleoprotein immunoprecipitation (RNP IP) assay, and luciferase reporter functional studies. These compounds disrupted HuR–ARE interactions at the nanomolar level and blocked HuR function by competitive binding to HuR. These results support future studies toward chemical probes for a HuR function study and possibly a novel therapy for HuR-overexpressing cancers.
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Pre-equilibration of an interconverting set of isomeric allylic azides is coupled with an intramolecular Schmidt reaction to afford substituted lactams stereoselectively. The effect of substitution ...and a preliminary mechanistic study are reported. The synthetic potential of this method is demonstrated in the context of an enantioselective synthesis of an advanced intermediate leading toward pinnaic acid.
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Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes that recognize microbial vitamin B metabolites and have emerging roles in infectious disease, autoimmunity, and cancer. ...Although MAIT cells are identified by a semi-invariant TCR, their phenotypic and functional heterogeneity is not well understood. Here we present an integrated single cell transcriptomic analysis of over 76,000 human MAIT cells during early and prolonged Ag-specific activation with the MR1 ligand 5-OP-RU and nonspecific TCR stimulation. We show that MAIT cells span a broad range of homeostatic, effector, helper, tissue-infiltrating, regulatory, and exhausted phenotypes, with distinct gene expression programs associated with CD4
or CD8
coexpression. During early activation, MAIT cells rapidly adopt a cytotoxic phenotype characterized by high expression of
,
and
In contrast, prolonged stimulation induces heterogeneous states defined by proliferation, cytotoxicity, immune modulation, and exhaustion. We further demonstrate a FOXP3 expressing MAIT cell subset that phenotypically resembles conventional regulatory T cells. Moreover, scRNAseq-defined MAIT cell subpopulations were also detected in individuals recently exposed to
, confirming their presence during human infection. To our knowledge, our study provides the first comprehensive atlas of human MAIT cells in activation conditions and defines substantial functional heterogeneity, suggesting complex roles in health and disease.
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