Merger of Visible Light‐Driven Chiral Organocatalysis and Continuous Flow Chemistry: An Accelerated and Scalable Access into Enantioselective α‐Alkylation of Aldehydes

Article

Author: Kappe, C. Oliver ; Ötvös, Sándor B. ; Molnár, Márk

AbstractThe electron donor‐acceptor complex‐enabled asymmetric photochemical alkylation strategy holds potential to attain elusive chiral α‐alkylated aldehydes without an external photoredox catalyst. The photosensitizer‐free conditions are beneficial concerning process costs and sustainability. However, lengthy organocatalyst preparation steps as well as limited productivity and difficult scalability render the current approaches unsuitable for synthesis on enlarged scales. Inspired by these limitations, a protocol was developed for the enantioselective α‐alkylation of aldehydes based on the synergistic combination of visible light‐driven asymmetric organocatalysis and a controlled continuous flow reaction environment. With the aim to reduce process costs, a commercially available chiral catalyst has been exploited to achieve photosensitizer‐free enantioselective α‐alkylations using phenacyl bromide derivates as alkylating agents. As a result of elaborate optimization and process development, the present flow strategy furnishes an accelerated and inherently scalable entry into enantioenriched α‐alkylated aldehydes including a chiral key intermediate of the antirheumatic esonarimod.

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15 Mar 2023·Journal of the American Chemical Society

Direct Synthesis of Thioesters from Feedstock Chemicals and Elemental Sulfur

Article

Author: Wu, Jie ; Luo, Penghao ; Ravelli, Davide ; Zhang, Muliang ; Tang, Haidi ; Zhang, Yuchao

The development of a mild, atom- and step-economical catalytic strategy that effectively generates value-added molecules directly from readily available commodity chemicals is a central goal of organic synthesis. In this context, the thiol-ene click chemistry for carbon-sulfur (C-S) bond construction has found widespread applications in the synthesis of pharmaceuticals and functional materials. In contrast, the selective carbonyl thiyl radical addition to carbon-carbon multiple bonds remains underdeveloped. Herein, we report a carbonyl thiyl radical-based thioester synthesis through three-component coupling from feedstock aldehydes, alkenes, or alkynes and elemental sulfur by direct photocatalyzed hydrogen atom transfer. This method represents an orthogonal strategy to the conventional thiol-based nucleophilic substitution and exhibits a remarkably broad substrate scope ranging from simple commodity chemicals such as ethylene and acetylene to complex pharmaceutical molecules. This protocol can be easily extended to the synthesis of thiolactones, oligomer/polymers, and thioacids. Its synthetic utility has been demonstrated by a two-step synthesis of the drug esonarimod. Mechanistic studies indicate that the use of elemental sulfur to trap acyl radicals is both thermodynamically and kinetically favored, illustrating its great potential for the synthesis of sulfur-containing molecules.

07 Jul 2008·Clinical and Experimental ImmunologyQ3 · MEDICINE

Expression of membrane-type 1 matrix metalloproteinase in rheumatoid synovial cells

Q3 · MEDICINE

Article

Author: Kamachi, M ; Honda, S ; Kawakami, A ; Hirai, Y ; Shibatomi, K ; Aoyagi, T ; Kita, M ; Kawabe, Y ; Eguchi, K ; Migita, K ; Hida, A ; Yamasaki, S ; Origuchi, T ; Ida, H ; Oizumi, K ; Fukuda, T

SummaryMembrane-type 1 matrix metalloproteinase (MT1-MMP) is thought to be a putative regulator of pro-gelatinase A (MMP-2) in the rheumatoid synovium. In this study, we examined the effects of IL-1β, one of the inflammatory cytokines, on the expression of MT1-MMP and the activation of pro-MMP-2 using rheumatoid synovial cells. We also studied the effects of KE-298 (2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid), a new disease-modifying anti-rheumatic drug (DMARD), on MT1-MMP expression of rheumatoid synovial cells. Type B synovial cells (fibroblast-like synovial cells) were cultured with KE-298 (25–100 µg/ml) in the presence of IL-1β for 48 h. Activation of pro-MMP-2 secreted from synovial cells was analysed by gelatin zymography. Reverse transcription–polymerase chain reaction (RT–PCR) methods were used to detect MT1-MMP mRNA. MT1-MMP protein expression on synovial cells was examined by anti-MT1-MMP immunoblot. An active form of MMP-2 was demonstrated in the culture media conditioned by IL-1β-stimulated synovial cells. In addition, MT1-MMP mRNA and protein expression of rheumatoid synovial cells were increased by IL-1β treatment. KE-298 blocked this IL-1β-induced pro-MMP-2 activation and MT1-MMP expression, but did not affect IL-1β-induced tissue inhibitor of metalloproteinase-2 (TIMP-2) secretion from rheumatoid synovial cells. These findings indicate that activation of rheumatoid synovial cells by IL-1β results in the induction of MT1-MMP expression. Given that MT1-MMP promotes matrix degradation by activating pro-MMP-2, these results suggest a novel mechanism whereby cytokine may contribute to articular destruction in rheumatoid arthritis (RA). KE-298 may prevent this process by down-regulating MT1-MMP expression.

100 Deals associated with Esonarimod

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KEGG	Wiki	ATC	Drug Bank
D01102	-	-	-

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Indication	Highest Phase	Country/Location	Organization	Date
Rheumatoid Arthritis	Phase 3	-	Taisho Pharmaceutical Holdings Co., Ltd.	-
Rheumatoid Arthritis	Phase 3	JP	Taisho Pharmaceutical Co., Ltd.	-

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