Pub Date : 2024-12-01DOI: 10.1016/j.tetlet.2024.155395
Jian Zhou , Jiaqi Liang , Qijie Gong , Guowei Zhang , Xiang Li , Xiaojin Zhang , Fulai Yang
GNE-140 is the first lactate dehydrogenase A (LDHA) inhibitor that demonstrates both sub-micromolar cellular potency and adequate pharmacokinetic properties, making it suitable for in vivo applications as a tool compound. However, the synthetic route reported by Genentech is complex, relying on transition metal catalysis and yielding low overall amounts. This study presents a practical, scalable method for constructing the core six-membered ring and quaternary carbon center of GNE-140 without transition metal catalysis, achieving a 48.5% racemic yield in a seven-step sequence, paving the way for future LDHA inhibitor development.
{"title":"A practical approach for the synthesis of lactate dehydrogenase A inhibitor GNE-140","authors":"Jian Zhou , Jiaqi Liang , Qijie Gong , Guowei Zhang , Xiang Li , Xiaojin Zhang , Fulai Yang","doi":"10.1016/j.tetlet.2024.155395","DOIUrl":"10.1016/j.tetlet.2024.155395","url":null,"abstract":"<div><div>GNE-140 is the first lactate dehydrogenase A (LDHA) inhibitor that demonstrates both sub-micromolar cellular potency and adequate pharmacokinetic properties, making it suitable for in vivo applications as a tool compound. However, the synthetic route reported by Genentech is complex, relying on transition metal catalysis and yielding low overall amounts. This study presents a practical, scalable method for constructing the core six-membered ring and quaternary carbon center of GNE-140 without transition metal catalysis, achieving a 48.5% racemic yield in a seven-step sequence, paving the way for future LDHA inhibitor development.</div></div>","PeriodicalId":438,"journal":{"name":"Tetrahedron Letters","volume":"154 ","pages":"Article 155395"},"PeriodicalIF":1.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142756991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A visible-light-induced radical cascade cyclization of 2-aryl-N-acryloyl indoles with 2‑mercaptothiazolinium salts is reported, furnishing the corresponding indolo[2,1-α]isoquinoline derivatives in good to moderate yields. A series of primary, secondary, and tertiary alkyl bromides were converted conveniently into redox-active thiazolinium salts, which are subsequently transformed into alkyl radicals through interaction with an excited-state photocatalyst. This green and environmentally protocol features broad substrate scope under mild conditions.
{"title":"Visible-light-promoted synthesis of alkylated Indolo[2,1-α]isoquinolines using 2‑Mercaptothiazolinium salts as alkyl radical source","authors":"Chi-Fan Zhu, Fei Li, Jun-Ju Mai, Xiao-Jing Li, Xiasen Dong, Mingyuan Shi, Mei-Hua Shen, Hua-Dong Xu","doi":"10.1016/j.tetlet.2024.155397","DOIUrl":"10.1016/j.tetlet.2024.155397","url":null,"abstract":"<div><div>A visible-light-induced radical cascade cyclization of 2-aryl-<em>N</em>-acryloyl indoles with 2‑mercaptothiazolinium salts is reported, furnishing the corresponding indolo[2,1-<em>α</em>]isoquinoline derivatives in good to moderate yields. A series of primary, secondary, and tertiary alkyl bromides were converted conveniently into redox-active thiazolinium salts, which are subsequently transformed into alkyl radicals through interaction with an excited-state photocatalyst. This green and environmentally protocol features broad substrate scope under mild conditions.</div></div>","PeriodicalId":438,"journal":{"name":"Tetrahedron Letters","volume":"154 ","pages":"Article 155397"},"PeriodicalIF":1.5,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142759718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
When α-alkyl substituted β-dicarbonyl compounds were reacted with allylsilanes in the presence of a rhenium catalyst, the allylation of the benzylic carbon center proceeded through the elimination of the β-dicarbonyl unit to form the corresponding alkenes in moderate to good yields. Regarding the reaction with hydrosilane, the reduction of these compounds also proceeded through the elimination of the β-dicarbonyl unit to give the corresponding alkanes.
{"title":"Rhenium-catalyzed reaction of α-alkyl substituted β-dicarbonyl compounds with organosilicon compounds","authors":"Yuya Matsuda , Shintaro Mori , Susumu Tsuda , Yutaka Nishiyama","doi":"10.1016/j.tetlet.2024.155390","DOIUrl":"10.1016/j.tetlet.2024.155390","url":null,"abstract":"<div><div>When α-alkyl substituted β-dicarbonyl compounds were reacted with allylsilanes in the presence of a rhenium catalyst, the allylation of the benzylic carbon center proceeded through the elimination of the β-dicarbonyl unit to form the corresponding alkenes in moderate to good yields. Regarding the reaction with hydrosilane, the reduction of these compounds also proceeded through the elimination of the β-dicarbonyl unit to give the corresponding alkanes.</div></div>","PeriodicalId":438,"journal":{"name":"Tetrahedron Letters","volume":"154 ","pages":"Article 155390"},"PeriodicalIF":1.5,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142744053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-27DOI: 10.1016/j.tetlet.2024.155394
Andrey V. Marchenko, Valery A. Ozeryanskii
The possibility of direct copper-catalyzed bromine-to-methoxy exchange to afford highly basic (poly)methoxy substituted 1,8-bis(dimethylamino)naphthalenes (DMANs or “proton sponges”) has been studied for the first time. The thus synthesized known or newly designed compounds are superbases with the basicities ranging within 19–23 pKa units in MeCN. Selected chemical behavior of mono-methoxylated DMANs as to methoxy group cleavage or regioselective lithiation is also reported.
{"title":"Copper-catalyzed nucleophilic methoxylation of DMAN bromides as a route to highly basic naphthalene proton sponges","authors":"Andrey V. Marchenko, Valery A. Ozeryanskii","doi":"10.1016/j.tetlet.2024.155394","DOIUrl":"10.1016/j.tetlet.2024.155394","url":null,"abstract":"<div><div>The possibility of direct copper-catalyzed bromine-to-methoxy exchange to afford highly basic (poly)methoxy substituted 1,8-bis(dimethylamino)naphthalenes (DMANs or “proton sponges”) has been studied for the first time. The thus synthesized known or newly designed compounds are superbases with the basicities ranging within 19–23 p<em>K</em><sub>a</sub> units in MeCN. Selected chemical behavior of mono-methoxylated DMANs as to methoxy group cleavage or regioselective lithiation is also reported.</div></div>","PeriodicalId":438,"journal":{"name":"Tetrahedron Letters","volume":"154 ","pages":"Article 155394"},"PeriodicalIF":1.5,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142744051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-26DOI: 10.1016/j.tetlet.2024.155372
Pan Xu , Xuenian Chen , Zhenxing Liu
Whenever a Lewis base borane is formed, the Lewis base will affect the properties of borane. The opposite is similarly true, that borane will affect the properties of Lewis base. The current development of Lewis base borane adducts mainly focuses on the borane part. Less chemistry is known about the Lewis base part. Herein, we selected examples to highlight the functionalization of the Lewis base of LB–BR3 adducts. Parts I and II focus on showing how boranes promote coupling, substitution, and reduction reactions of amine and phosphine in the corresponding borane adducts, as well as borane’s control of the regioselectivity and stereoselectivity of amine-boron and phosphine-borane analogs. Part III focuses on the effect of boranes on the chemistry of Lewis bases containing carbon, oxygen, and sulfur.
{"title":"Functionalization of Lewis base (LB) in LB–BR3 adducts","authors":"Pan Xu , Xuenian Chen , Zhenxing Liu","doi":"10.1016/j.tetlet.2024.155372","DOIUrl":"10.1016/j.tetlet.2024.155372","url":null,"abstract":"<div><div>Whenever a Lewis base borane is formed, the Lewis base will affect the properties of borane. The opposite is similarly true, that borane will affect the properties of Lewis base. The current development of Lewis base borane adducts mainly focuses on the borane part. Less chemistry is known about the Lewis base part. Herein, we selected examples to highlight the functionalization of the Lewis base of LB–BR<sub>3</sub> adducts. Parts I and II focus on showing how boranes promote coupling, substitution, and reduction reactions of amine and phosphine in the corresponding borane adducts, as well as borane’s control of the regioselectivity and stereoselectivity of amine-boron and phosphine-borane analogs. Part III focuses on the effect of boranes on the chemistry of Lewis bases containing carbon, oxygen, and sulfur.</div></div>","PeriodicalId":438,"journal":{"name":"Tetrahedron Letters","volume":"154 ","pages":"Article 155372"},"PeriodicalIF":1.5,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142744054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-24DOI: 10.1016/j.tetlet.2024.155389
Junsheng Hou , Bingxin You , Ruiqi Lv , Xinxin Zhang , Hao Zhang , Qiang Liu
An efficient methodology for the synthesis of seven-membered benzodioxepinones has been developed via electrochemical oxyselenenylation of 2-O-tethered alkenyl benzoic acid and diselenides under an external oxidant-free condition at room temperature. The experimental evidence supports this transformation through a radical mechanism.
{"title":"Synthesis of 1,4-benzodioxepinones via electrochemical oxyselenenylation of 2-O-tethered alkenyl benzoic acid and diselenides","authors":"Junsheng Hou , Bingxin You , Ruiqi Lv , Xinxin Zhang , Hao Zhang , Qiang Liu","doi":"10.1016/j.tetlet.2024.155389","DOIUrl":"10.1016/j.tetlet.2024.155389","url":null,"abstract":"<div><div>An efficient methodology for the synthesis of seven-membered benzodioxepinones has been developed via electrochemical oxyselenenylation of 2-<em>O</em>-tethered alkenyl benzoic acid and diselenides under an external oxidant-free condition at room temperature. The experimental evidence supports this transformation through a radical mechanism.</div></div>","PeriodicalId":438,"journal":{"name":"Tetrahedron Letters","volume":"154 ","pages":"Article 155389"},"PeriodicalIF":1.5,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142744052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-23DOI: 10.1016/j.tetlet.2024.155388
Sumit , Sudipta Nandi , Indrapal Singh Aidhen
Toll-like receptor 4 (TLR4) is a critical component of the innate immune system, recognizing lipopolysaccharide (LPS) from Gram-negative bacteria and triggering immune responses. The activation of TLR4 involves several key steps, including interactions with LPS-binding protein (LBP), CD14, and myeloid differentiation protein 2 (MD-2), culminating in the formation of the (LPS.MD-2 TLR4)2 complex. Structural insights show that LPS acyl chains insert into the hydrophobic pocket of MD-2, driving TLR4 activation. Inspired by this understanding, numerous natural and synthetic compounds have been developed to inhibit TLR4 by targeting the MD-2/TLR4 complex. Eritoran 1, is one such illustration. The conformational flexibility of azepane architecture inspired us to visualize O-alkylated/N-acylated polyhydroxyazepane-based compounds toward this objective. The docking studies and molecular simulation studies supported the rationale. Synthesis of O-alkylated/N-acylated polyhydroxyazepane-based compounds 2-4 (a-h) through a key building block is described herein.
{"title":"Convenient synthesis of O-alkylated/N-acylated polyhydroxyazepane based compounds for modulating MD-2-TLR4 complex formation","authors":"Sumit , Sudipta Nandi , Indrapal Singh Aidhen","doi":"10.1016/j.tetlet.2024.155388","DOIUrl":"10.1016/j.tetlet.2024.155388","url":null,"abstract":"<div><div>Toll-like receptor 4 (TLR4) is a critical component of the innate immune system, recognizing lipopolysaccharide (LPS) from Gram-negative bacteria and triggering immune responses. The activation of TLR4 involves several key steps, including interactions with LPS-binding protein (LBP), CD14, and myeloid differentiation protein 2 (MD-2), culminating in the formation of the (LPS.MD-2 TLR4)<sub>2</sub> complex. Structural insights show that LPS acyl chains insert into the hydrophobic pocket of MD-2, driving TLR4 activation. Inspired by this understanding, numerous natural and synthetic compounds have been developed to inhibit TLR4 by targeting the MD-2/TLR4 complex. Eritoran <strong>1</strong>, is one such illustration. The conformational flexibility of azepane architecture inspired us to visualize <em>O</em>-alkylated/<em>N</em>-acylated polyhydroxyazepane-based compounds toward this objective. The docking studies and molecular simulation studies supported the rationale. Synthesis of <em>O</em>-alkylated/<em>N</em>-acylated polyhydroxyazepane-based compounds <strong>2</strong>-<strong>4</strong> (<strong>a</strong>-<strong>h</strong>) through a key building block is described herein.</div></div>","PeriodicalId":438,"journal":{"name":"Tetrahedron Letters","volume":"154 ","pages":"Article 155388"},"PeriodicalIF":1.5,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142719961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-23DOI: 10.1016/j.tetlet.2024.155391
Can Jin, Yilin Wang, Xiangsheng Xu, Xiaoqing Li
(1R,2R) and (1S,2S) 2-hydroxy-cyclobutylamines are important substructures in a range of bio-active molecules and pharmaceutical candidates. In view of the potential safety issues and the low reaction efficiency associated with the earlier published synthetic process, which relies on Curtius rearrangement for the synthesis of 2-amino-cyclobutanone intermediate, a more practical and efficient process to prepare (1R,2R) and (1S,2S) 2-hydroxy-cyclobutylamines using readily available N-Cbz-2-amino-cyclobutanone was developed. Cbz protected (1R,2R) 2-hydroxy-cyclobutylamine could be synthesized in 14 % yield over 5 steps.
{"title":"A practical synthesis of Cbz protected (1R,2R) and (1S,2S) 2-hydroxy-cyclobutylamines","authors":"Can Jin, Yilin Wang, Xiangsheng Xu, Xiaoqing Li","doi":"10.1016/j.tetlet.2024.155391","DOIUrl":"10.1016/j.tetlet.2024.155391","url":null,"abstract":"<div><div><em>(1R,2R)</em> and <em>(1S,2S)</em> 2-hydroxy-cyclobutylamines are important substructures in a range of bio-active molecules and pharmaceutical candidates. In view of the potential safety issues and the low reaction efficiency associated with the earlier published synthetic process, which relies on Curtius rearrangement for the synthesis of 2-amino-cyclobutanone intermediate, a more practical and efficient process to prepare <em>(1R,2R)</em> and <em>(1S,2S)</em> 2-hydroxy-cyclobutylamines using readily available <em>N-</em>Cbz-2-amino-cyclobutanone was developed. Cbz protected <em>(1R,2R)</em> 2-hydroxy-cyclobutylamine could be synthesized in 14 % yield over 5 steps.</div></div>","PeriodicalId":438,"journal":{"name":"Tetrahedron Letters","volume":"154 ","pages":"Article 155391"},"PeriodicalIF":1.5,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142744049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-23DOI: 10.1016/j.tetlet.2024.155387
Manijeh Nematpour
In this research, the simple and efficient method for the synthesis of highly substituted benzoselenazole derivatives using the one-pot, multi-step Ullman coupling reaction of acyl isoselenocyanate-nitro compounds adducts and dihalobenzene in the vicinity of K2CO3 as a base, copper iodide, at room temperature, and in MeCN solvent has been done successfully. The use of simple and available raw materials, mild copper catalytic reaction conditions, easy purification with the help of solvent, and finally the synthesis of 16 new compounds from the benzoselenazoles family are notable features of this protocol.
{"title":"Efficient synthesis of highly substituted benzoselenazole derivatives through the one-pot, multi-step Ullmann coupling reaction","authors":"Manijeh Nematpour","doi":"10.1016/j.tetlet.2024.155387","DOIUrl":"10.1016/j.tetlet.2024.155387","url":null,"abstract":"<div><div>In this research, the simple and efficient method for the synthesis of highly substituted benzoselenazole derivatives using the one-pot, multi-step Ullman coupling reaction of acyl isoselenocyanate-nitro compounds adducts and dihalobenzene in the vicinity of K<sub>2</sub>CO<sub>3</sub> as a base, copper iodide, at room temperature, and in MeCN solvent has been done successfully. The use of simple and available raw materials, mild copper catalytic reaction conditions, easy purification with the help of solvent, and finally the synthesis of 16 new compounds from the benzoselenazoles family are notable features of this protocol.</div></div>","PeriodicalId":438,"journal":{"name":"Tetrahedron Letters","volume":"154 ","pages":"Article 155387"},"PeriodicalIF":1.5,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142744050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-22DOI: 10.1016/j.tetlet.2024.155366
He Wu, Yong Wang, Guangguang Yang, Karuppu Selvaraj, Gang Chen
Tetracycline destructases (TDases), a type of TC-inactivating enzymes, inactivate all known TC antibiotics by C11a oxidation, which is considered as a clinical threat. To provide more information on this enzymatic inactivation and oxygenated TCs, we report here a chemical oxidation of Tetracycline and its derivatives at the C11a position using m-CPBA with additives via biomimetic pathways. The structures of the oxygen-containing TCs (2h, 2i) were confirmed by X-ray analysis, and further transformations were performed with oxygen-containing TCs (2e, 2i).
四环素破坏酶（TDases）是四环素类抗生素失活酶的一种，它通过 C11a 氧化作用使所有已知的四环素类抗生素失活，这被认为是一种临床威胁。为了提供更多有关这种酶失活和含氧三环素的信息，我们在此报告利用 m-CPBA 和添加剂通过仿生途径对四环素及其衍生物的 C11a 位进行化学氧化。含氧三氯乙酸的结构（2h、2i）已通过 X 射线分析得到证实，含氧三氯乙酸的进一步转化（2e、2i）也已完成。
{"title":"Biomimetic oxidation of tetracycline and derivatives at C11a","authors":"He Wu, Yong Wang, Guangguang Yang, Karuppu Selvaraj, Gang Chen","doi":"10.1016/j.tetlet.2024.155366","DOIUrl":"10.1016/j.tetlet.2024.155366","url":null,"abstract":"<div><div>Tetracycline destructases (TDases), a type of TC-inactivating enzymes, inactivate all known TC antibiotics by C11a oxidation, which is considered as a clinical threat. To provide more information on this enzymatic inactivation and oxygenated TCs, we report here a chemical oxidation of Tetracycline and its derivatives at the C11a position using <em>m</em>-CPBA with additives via biomimetic pathways. The structures of the oxygen-containing TCs (<strong>2h, 2i</strong>) were confirmed by X-ray analysis, and further transformations were performed with oxygen-containing TCs (<strong>2e</strong>, <strong>2i</strong>).</div></div>","PeriodicalId":438,"journal":{"name":"Tetrahedron Letters","volume":"154 ","pages":"Article 155366"},"PeriodicalIF":1.5,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142702929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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