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

Article

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

18 Feb 2010·Journal of Pharmacy and PharmacologyQ3 · MEDICINE

Formation of a disulfide protein conjugate of the SH-group-containing metabolite (M-I) of esonarimod (kE-298) and its elimination in rats

Q3 · MEDICINE

Article

Author: Higuchi, Shohei ; Hasegawa, Masatoshi ; Omi, Naoko ; Yoshida, Hideo ; Endo, Hiromi

AbstractThe reactivity of the thiol moiety of the active main metabolite (M-I) of esonarimod (kE-298), a novel anti-rheumatic agent, was investigated in rats. After repeated oral administration of 14C-kE-298, the radioactivity decreased rapidly and no tendency towards accumulation was found, in marked contrast to other common SH-group-containing drugs. At 30 min after intravenous administration of 14C-M-I to rats, the concentration of the 14C-M-I plasma protein conjugate in plasma was extremely low at 0.143 nmol mL−1 (0.66% of total plasma radioactivity). The 14C-M-I plasma protein conjugate that formed in rat plasma was mixed disulfide with plasma protein. After intravenous administration of synthetic 14C-M-I plasma protein conjugate to rats, the radioactivity in plasma decreased rapidly, with the terminal half-life at 6.90 h. In-vitro, the 14C-M-I plasma protein conjugate was readily dissociated by the endogenous thiol compounds, cysteine and glutathione. These results suggest that the reactivity of the thiol moiety of M-I is extremely low. Furthermore, the 14C-M-I plasma protein conjugate decreased rapidly in-vivo, which would be related to interaction with endogenous thiol compounds. These properties of M-I are principally responsible for the zero accumulation in rat tissues. kE-298 could therefore be expected to have reduced adverse effects compared with other SH-group-containing anti-rheumatic drugs.

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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