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Synthesis of Imidazole-Based Medicinal Molecules Utilizing the Van Leusen Imidazole Synthesis

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pharmaceuticals Review Synthesis of Imidazole-Based Medicinal Molecules Utilizing the van Leusen Imidazole Synthesis Xunan Zheng 1,2, Zhengning Ma 1,3 and Dawei Zhang 1,* 1 College of Chemistry, Jilin University, Changchun 130012, China; [email protected] (X.Z.); [email protected] (Z.M.) 2 College of Plant Science, Jilin University, Changchun 130062, China 3 Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Ministry of Education), School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China * Correspondence: [email protected]; Tel.: +86-431-8783-6471 Received: 10 February 2020; Accepted: 1 March 2020; Published: 3 March 2020 Abstract: Imidazole and its derivatives are one of the most vital and universal heterocycles in medicinal chemistry. Owing to their special structural features, these compounds exhibit a widespread spectrum of significant pharmacological or biological activities, and are widely researched and applied by pharmaceutical companies for drug discovery. The van Leusen reaction based on tosylmethylisocyanides (TosMICs) is one of the most appropriate strategies to synthetize imidazole-based medicinal molecules, which has been increasingly developed on account of its advantages. In this review, we summarize the recent developments of the chemical synthesis and bioactivity of imidazole-containing medicinal small molecules, utilizing the van Leusen imidazole synthesis from 1977. Keywords: van Leusen; TosMICs; imidazole; synthesis 1. Introduction Imidazole ring, which is widely found in natural products and medical molecules, is one of the most prominent, five-membered, nitrogen-containing, heterocyclic scaffolds. Furthermore, imidazole-based heterocyclic compounds, which possess a vital position in medicinal chemistry, have been playing a central role in the treatment of numerous types of diseases, and new derivatives for medicinal use are being energetically developed worldwide [1–5]. Due to the peculiar structural characteristic of imidazole scaffold with a worthy electron-rich feature, it is advantageous for imidazole groups to combine with various receptors and enzymes in biological systems, through diverse weak interactions, thereby showing a variety of biological activities. At present, a legion of imidazole-containing compounds with high a medical potential as a clinical drug have been widely used to treat diverse types of illnesses, such as antibacterial [6,7], antifungal [8,9], anti-inflammatory [10,11], antiviral [12,13], anti-parasitic [14,15], anticancer [16,17], antihistaminic [18,19], and enzyme inhibition [20,21]. Imidazole and its derivatives encompass a vast range of medical activities, as shown in the following Table1. Pharmaceuticals 2020, 13, 37; doi:10.3390/ph13030037 www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2020, 13, 37 2 of 19 PharmaceuticalsPharmaceuticals 2020 20, 1320, ,x 13 FOR, x FOR PEER PEER REVIEW REVIEW 2 of 219 of 19 Pharmaceuticals 2020, 13, x FOR PEER REVIEW 2 of 19 PharmaceuticalsPharmaceuticals 20202020 20,, 131320,, ,,xx 13 FORFOR,, xx FORFOR PEERPEER PEERPEER REVIEWREVIEW REVIEWREVIEW 22 ofof 2 1919 of 19 TabTable 1.le Various 1. Various pharmacological pharmacological activities activities and andchemical chemical structures structures of imidazole of imidazole-based-based molecules molecules. Table 1.TabVariousle 1. Various pharmacological pharmacological activities activities and and chemical structures structures of imidazole of imidazole-based-based molecules molecules.. TabTablele 1.1.le Various 1. Various pharmacological pharmacological activities activities and andchemical chemical structures structures of imidazoleimidazole of imidazoleimidazole--based-based molecules molecules.. .. PharmacologicalPharmacological Activities Activities ChemicalChemical Structures Structures PharmacologicalPharmacological Activities Activities Chemical Chemical Structures Structures PharmacologicalPharmacological Activities Activities A A ChemicalChemical Structurestructures Structures Cl Cl PharmacologicalPharmacological Activities Activities A ChemicalChemical Structures Structures Cl A A Clll Cll 1 1 OH OH 1 OH Cl Cl 2 2 1 1 N NOH OH 2 1 1 O2N O2N COHH3 COHH3 Cl O N N CH Clll Cll 22 2 AntibacterialAntibacterial 2 N N 3 HN HNN ClN Cl O22N O2N N CNH33 CH3 Antibacterial 2 2 N 3 3 HN N AntibacterialAntibacterialAntibacterial HN HNN N AntibacterialAntibacterial MetroMneiNdtraoznoiNdleazole HN HNN N Metronidazole MeettrrMoonneiiidttdrraoaznzooiidllleeazolle 1 1 2 2 1 2 N 11 N 1 N 22N 2 N N N N N N NN NN NN NN N N N ONH OH N ONH N N OH OH OH OH 4 4 AntifungalAntifungal 3 3 4 AntifungalAntifungal 3 44 4 AntifungalAntifungal 3 3 PhenPhetheynliemthidyalizmoildeazole BifonBiazfonleazole Phenethylimidazole Bifonazole eenneet enemt aazmzooeeazo e oonnaazzooneeazo e PhenPhetthheyyn3lililiemtthiiiddya3lilizmoiildlleazolle Biffon4Biazffoonlll4eazolle 3 4 6 6 5 5 N 33N 3 44 4 O O 6 5 Cl CNl N N O 6 6 5 5 Cl N N N O O Clll Cll N N N N N N NNON O N N N N N N NO F F N NO O AntiAnti-inflammatory-inflammatory F Anti-inflammatory F F SO2NHSO22NH2 Anti-inflammatoryAntiAnti--inflammatoryinflammatory-inflammatory H COH CO SO NH 3 3 SO2 NHSO2 NH H3CO m coxm xSO22NHSO222NH2 H3C H3C7 7 H COH COCi iCi ibico ib H C H33COH3COCimicoxib 3 7 x x H 3C H3C7 7 Ciiimiii5coCcoiimxiiibiibco5 xiib 33 3C77 6 77 6 5 6 H3C 5H5 3C 5 66 6 CH3 CH3 A A 7 7 H3C H C H CH3 A 7 H33C H3CCH CH A A 7 7 CH33 CH3 A A 7 7 N N S S N S N N O O N NN SN S N O O S S Cl Cl N N O H N H N N Cl NN SN S O O 2 2O N N NS HN HN H2N O O N N Clll Cll N 8 8 AntiviralAntiviral H N H NO O N NS HNS 8 Antiviral H22N H2ON O N N HN HN Antiviral O Cl Cl HN HN 88 8 AntiviralAntiviral Cl O O O2N O2N N N Clll Cll O N N 2 O22N O2N CNapraCvNairpirnaevirine 2 2 Capravirine CaaprrCaavaviprrirrnnaeevirrine 8 8 C p C7aiipii a7 ii ii e 8 7 88 8 77 7 N8 N8 N N N 10 10 O N O NN N 10 9 9 2 2N 10 10 9 O2N N N 10 10 O 2N O2NN N 9 9 O22N O2N H3C H3C N N AntiparasiticAntiparasitic H3C N N N Antiparasitic H C H C N N AntiparasiticAntiparasiticAntiparasitic H33CNH3C N N N N Antiparasitic N NN O O O2N O2N O O N N N NimoNiramzoolerazole O2 N O N morazo eO O O22N O2N Ni l 9 9 Nimoo1Nirr0aamzzooo1lllrere0azolle 9 10 N N 99 9 O O 1100 10 N O NH2 NH2 NO2 NO 12 12 11 N N 2 O ONH2 11 N NNO2 NH NH CH CH 12 11 NO NO NH22NH2 3 3 12 12 N NO22NO2 N N CH 12 12 11 11 N N O O N N NNNN 3N N N CH33CH3 O CH3 CH3 N N N N N 3 3 N NN NN NNCHN3 CH3 AnticancerAnticancer O CHO3 NH N NNNN N Anticancer OH OH CH CH H CH3 CH33CH3 HN N CH CH AnticancerAnticancerAnticancer OH N N CH33CH3 Anticancer OH OH H H MiOsoH nMiOidHsoaznoidleazole DacaDrbacaazirnbeazine Misonidazole Dacarbazine MisosoMin11niiiddsoaazzn11ooiidllleeazolle DacaacaD12rrbacabaazzi12irirnnbeeaziine 11 D 12Db i b i 1111a 11a 1212 12 O O 14 14 a O 14 13 13 aa a 1414 14 13 a a O O 13 13 N CNH3 CH3 13 13 N CH3 N N N CNH CH AntihistaminicAntihistaminic N N CNH33 CH3 N N O O N N N O Antihistaminic N N N N O O AntihistaminicAntihistaminicAntihistaminic NH N N O O He me N N rox arnox an HN MN thiMethipimp epip NH H Cip Cifp if H MHethimepip Ciproxifan Pharmaceuticals 2020, 13, x FOR PEER REVIEW H He mee me HN N rrooxx aaronnx an 3 of 19 Pharmaceuticals 2020, 13, x FOR PEER REVIEW Metthihi1M3meetthipp1iimi3ppepiip H H Ciiippr1oC4xiiiipffar1on4xiiffan 3 of 19 13 H H 14 1133 13 1144 14 A CH3 15 A CH3 15 16 N 16 N N N N N N N Enzyme inhibitor N O EnzymeEnzyme inhibitor inhibitor N O NO2 NO2 15 16 15 16 OwingOwing to the to thesignificant significant pharmacological pharmacological or biologicalor biological activities activities and and the theenormous enormous medicinal medicinal valuevalue of imidazole of imidazole-based-based molecul molecules, thees, thesynthes synthesis ofi sthe of theimidazole imidazole-skeleton-skeleton small small molecul molecule haes habeens been paidpaid attention attention to by to pharmaceuticalby pharmaceutical chemists chemists and and organic organic synthesis synthesis researchers researchers. However. However, there, there is is stillstill a need a need for afor simple a simple and and efficient efficient way way to construct to construct the theimidazole imidazole heterocyclic heterocyclic skeleton skeleton. In .recent In recent decades,decades, there there have have been been numerous numerous classical classical strategies strategies for forsynthesizing synthesizing this th ringis ring compound compound in the in the laboratorylaboratory, including, including van van Leusen Leusen imidazole imidazole synthesis synthesis [22], [22], Debus Debus-Radziszewski-Radziszewski imidazole imidazole synthesis synthesis [23],[23], Wallach Wallach imidazole imidazole synthesis synthesis [24] [24], etc., etc.Among Among these these synthetic synthetic strategies, strategies, it is it well is well-known-known that that the thevan van Leusen Leusen imidazole imidazole synthesis synthesis based based on TosMICson TosMICs, which, which is the is thecycloaddition cycloaddition reaction reaction, is one, is one of of the themost most convenient convenient and and attractive attractive protocols protocols for thefor thepreparation preparation of imidazole of imidazole-based-based small small molecules molecules, , duedue to its to excellentits excellent advantages advantages like like simple simple manipulation manipulation, easily, easily obta obtainedined raw raw materials materials and and a wide a wide range of substrates, which has been developed rapidly in the past decades (Scheme 1). range of substrates, which has been developed rapidly in the past decades (Scheme 1). R1 3 2 R1 R (H) 3 Base R 2 1 2 + R (H) Base NR R CH 1NR 2 + N 3 R CH NR Tos NC R (H) 3 Tos NC N R (H) N Scheme 1.
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    Literature Report 2 Total Synthesis of Caribenol A and Caribenol B Reporter : Xiao-Yong Zhai Checker : Shubo Hu Date : 2017-04-24 Hao, H.-D.; Trauner, D. J. Am. Chem. Soc. 2017, 139, 4117. CV of Dirk Trauner Education: 1986–1991 B.S., University of Vienna 1992–1995 M.S., Free University of Berlin 1996–1997 Ph.D., University of Vienna 1998–2000 Postdoc., Memorial Sloan Kettering Cancer Center 2001–2008 Associate Professor, University of California, Berkeley 2009-2017 Professor, University of Munich and New York University Dirk Trauner Research: chemical synthesis, natural product chemistry, neuroscience, cell biology and photopharmacology. 2 Contents 1 Introduction 2 Total Synthesis of Caribenol A 3 Total Synthesis of Caribenol B 4 Summary 3 Introduction Me H H B C A HO Me Me O O Caribenol A Pseudopterogorgia Isolated from the Pseudopterogorgia elisabethae in 2007; Exhibiting biological activity against Mycobacterium tuberculosis H37Rv and plasmodium; A caged structure and tricarbocyclic ring system with six stereocenters. Wei, X.; Rodríguez, I. I.; Rodríguez, A. D.; Barnes, C. L. J. Org. Chem. 2007, 72, 7386. 4 Introduction Natural products isolated from Pseudopterogorgia elisabethae Me H Me H Me H H Me H O Me O O H Me Me O H O O O OH O Aberrarone Elisabethin A Amphilectolide Me Me Me H H H H OH HO HO Me Me Me Me HO Me O OH O Me O O O Caribenol B Caribenol A Sandresolide B Wei, X.; Rodríguez, I. I.; Rodríguez, A. D.; Barnes, C. L. J. Org. Chem. 2007, 72, 7386. 5 Retrosynthetic analysis of Caribenol A O O CO Me O O O 2 Me Me Me Me Me Me TBSO Me Me A C A OH C A H C B B B H H H H H Me Me Me Caribenol A (1) 2 3 O H Me CO2Me Me CO2Me Me + + Me O I TBSO CO Me Me Me 2 4 7 6 5 Liu, L-Z.; Han, J-C.; Yue, G-Z.; Li, C-C.; Yang, Z.
  • List of Lists

    List of Lists

    United States Office of Solid Waste EPA 550-B-10-001 Environmental Protection and Emergency Response May 2010 Agency www.epa.gov/emergencies LIST OF LISTS Consolidated List of Chemicals Subject to the Emergency Planning and Community Right- To-Know Act (EPCRA), Comprehensive Environmental Response, Compensation and Liability Act (CERCLA) and Section 112(r) of the Clean Air Act • EPCRA Section 302 Extremely Hazardous Substances • CERCLA Hazardous Substances • EPCRA Section 313 Toxic Chemicals • CAA 112(r) Regulated Chemicals For Accidental Release Prevention Office of Emergency Management This page intentionally left blank. TABLE OF CONTENTS Page Introduction................................................................................................................................................ i List of Lists – Conslidated List of Chemicals (by CAS #) Subject to the Emergency Planning and Community Right-to-Know Act (EPCRA), Comprehensive Environmental Response, Compensation and Liability Act (CERCLA) and Section 112(r) of the Clean Air Act ................................................. 1 Appendix A: Alphabetical Listing of Consolidated List ..................................................................... A-1 Appendix B: Radionuclides Listed Under CERCLA .......................................................................... B-1 Appendix C: RCRA Waste Streams and Unlisted Hazardous Wastes................................................ C-1 This page intentionally left blank. LIST OF LISTS Consolidated List of Chemicals