Article
Chemistry, Multidisciplinary
Atsushi Nakayama, Tenta Nakamura, Toshihiro Zaima, Saho Fujimoto, Sangita Karanjit, Kosuke Namba
Summary: The concise total synthesis of tronocarpine, a chippiine-type indole alkaloid, was achieved through a one-pot construction of a pentacyclic skeleton. This strategy, controlled by the stereocenter at the C14 position, can be used to synthesize other chippiine-type alkaloids with azabicyclo[3.3.1]nonane skeletons.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Chemistry, Multidisciplinary
Hai-Hua Lu, Kang-Ji Gan, Fu-Qiang Ni, Zhihan Zhang, Yao Zhu
Summary: The concise total synthesis of salimabromide was achieved using a series of novel reactions, which allowed for the construction of its unique carbon skeleton and stereocenters.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Multidisciplinary
Hong-Gang Cheng, Zhenjie Yang, Ruiming Chen, Liming Cao, Wen-Yan Tong, Qiang Wei, Qingqing Wang, Chenggui Wu, Shuanglin Qu, Qianghui Zhou
Summary: A concise total synthesis of (-)-berkelic acid is reported in eight linear steps, featuring a Catellani reaction/oxa-Michael cascade, a one-pot deprotection/spiroacetalization operation, and a late-stage Ni-catalyzed reductive coupling. Notably, four stereocenters are established from a single existing chiral center with excellent stereocontrol during the deprotection/spiroacetalization process, supported by DFT calculations.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Chemistry, Organic
Huan He, Fanglin Xue, Zhao Hu, Peng Li, Qian Xiao, Maojie Zhang, Fei Xue, Dan Zhang, Hao Song, Xiao-Yu Liu, Zhibing Zheng, Song Li, Wu Zhong, Yong Qin
Summary: Morphine and its related alkaloids are commonly used natural medicines. However, the current industrial manufacturing process of these compounds causes environmental issues. In this study, researchers developed an efficient total synthesis method for opioids such as codeine, oxycodone, naloxone, and naltrexone. The key step in this synthesis is the Pd-catalyzed dearomatization arene coupling reaction using an inexpensive and stable phosphonium ligand.
ORGANIC CHEMISTRY FRONTIERS
(2022)
Article
Chemistry, Organic
Wei Xu, Taimin Wang, Xin Zhou, Lijing Fang, Chen Zhang, Hongbin Zhai, Bin Cheng
Summary: A concise total synthesis of (+/-)-pileamartines A and B, alkaloids with an unprecedented tetracyclic skeleton, was achieved. Key steps including NHC-catalyzed tandem reaction, diastereoselective reductive allylation, and RCM were used to establish the core structure.
ORGANIC CHEMISTRY FRONTIERS
(2022)
Article
Chemistry, Multidisciplinary
Fuhao Zhang, Jingwen Zeng, Mohan Gao, Linzhou Wang, Gen-Qiang Chen, Yixin Lu, Xumu Zhang
Summary: A practical synthetic strategy for enantioselective and divergent synthesis of prostaglandins was reported, involving the construction of multiply substituted five-membered rings through key enyne cycloisomerization and installation of crucial chiral centers using asymmetric hydrogenation. Common intermediates allowed for the production of various prostaglandins and related drugs in two steps, with the preparation of fluprostenol on a 20-gram scale.
Article
Chemistry, Organic
Liu-Yang Pu, Zhiyue Li, Limin Li, Yucui Ma, Shengquan Hu, Zhengzhi Wu
Summary: In this study, we describe a concise and enantioselective total synthesis of isopavine alkaloids with a unique azabicyclo[3.2.2]nonane tetracyclic skeleton. Key steps include iridium-catalyzed asymmetric hydrogenation, Curtius rearrangement, and Eschweiler-Clarke methylation, enabling the synthesis of isopavine alkaloids in 6-7 linear steps. Additionally, we discovered that isopavine alkaloids, particularly (-)-reframidine (3), exhibit significant antiproliferative effects on various cancer cell lines for the first time.
JOURNAL OF ORGANIC CHEMISTRY
(2023)
Article
Chemistry, Organic
Liu-Yang Pu, Zhiyue Li, Limin Li, Yucui Ma, Shengquan Hu, Zhengzhi Wu
Summary: We report a concise asymmetric total synthesis of isopavine alkaloids, which possess a unique azabicyclo[3.2.2]nonane tetracyclic skeleton. The key steps involve iridium-catalyzed asymmetric hydrogenation of unsaturated carboxylic acids, Curtius rearrangement, and Eschweiler-Clarke methylation, achieving an enantioselective approach to isopavine alkaloids in 6-7 linear steps. Moreover, isopavine alkaloids, especially (-)-reframidine (3), are found to exhibit effective antiproliferative effects on various cancer cell lines for the first time.
JOURNAL OF ORGANIC CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Niklas Rauscher, Line Noesborg, Christian Jandl, Thorsten Bach
Summary: In this study, the prezizane-type sesquiterpene agarozizanol B was synthesized through a photochemical cascade reaction, successfully achieving the key step of the synthesis with a specific strategy and obtaining the (+)-enantiomer that is identical to the natural product.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Chemistry, Organic
Balasaheb R. Borade, Ravindar Kontham
Summary: A chiral-pool protecting-group-free five-step total synthesis of tetranorsesquiterpenoide (+)-lanceolactone A and its stereoisomers was achieved using linalool as building blocks. The key steps in this synthesis include regioselective ozonolysis, cycloisomerization-induced construction of furan, and dye-sensitized photo-oxidation. The absolute configuration of natural lanceolactone A was determined using electronic circular dichroism (ECD) and optical rotation data. The study also extended the application of Feringa and Gawronski's CD correlation method.
JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Emily K. Kirkeby, Zachary T. Schwartz, Myles A. Lovasz, Andrew G. Roberts
Summary: This article presents a concise strategy for preparing polycyclic heteroaromatics through a deaminative contraction cascade. The efficient deaminative ring contraction involves the methylation and rearrangement/dehydroamination of a biaryl-linked dihydroazepine. The presence of pseudosymmetry guides the retrosynthetic analysis and allows for the construction of pyridyl-containing polycyclic heteroaromatics.
Article
Chemistry, Multidisciplinary
Emily K. Kirkeby, Zachary T. Schwartz, Myles A. Lovasz, Andrew G. Roberts
Summary: This article details a concise strategy to prepare polycyclic heteroaromatics through a deaminative contraction cascade. The efficient deaminative ring contraction involves the methylation of a biaryl-linked dihydroazepine to form a cyclic ammonium cation, followed by a base-induced [1,2]-Stevens rearrangement/dehydroamination sequence. The presence of pseudosymmetry guides the retrosynthetic analysis of pyridyl-containing polycyclic heteroaromatics, enabling their construction through reductive cyclization and deaminative contraction of tertiary amine precursors.
Article
Multidisciplinary Sciences
David B. Konrad, Klaus-Peter Ruehmann, Hiroyasu Ando, Belinda E. Hetzler, Nina Strassner, Kendall N. Houk, Bryan S. Matsuura, Dirk Trauner
Summary: A stereoselective synthesis of TTX from a glucose derivative is presented, proceeding via 22 steps. This method provides ready access to biologically active derivatives.
Article
Chemistry, Multidisciplinary
Meng-Yue Cao, Bin-Jie Ma, Qing-Xiu Gu, Bei Fu, Hai-Hua Lu
Summary: This paper reports a concise protecting-group-free total synthesis of Daphenylline, a structurally unique member of the triterpenoid Daphniphyllum natural alkaloids. Key reactions include an intramolecular oxidative dearomatization reaction, a tandem reductive amination/amidation double cyclization reaction, and a highly enantioselective rhodium-catalyzed hydrogenation reaction.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Multidisciplinary
Kosuke Okada, Ken-ichi Ojima, Hirofumi Ueda, Hidetoshi Tokuyama
Summary: The synthesis of (+)-pleiocarpamine, (+)-voacalgine A and (+)-bipleiophylline was achieved in this study. The 10-step synthesis of (+)-pleiocarpamine features the construction of stereochemistry at the C16 position by radical cyclization and the synthesis of the highly strained cage-like structure via Pd-catalyzed intramolecular aromatic C-H functionalization. By modifying the biomimetic aerobic oxidative coupling of tryptophane derivatives catalyzed by FePc(CO2H)(8), the oxidative coupling of (+)-pleiocarpamine with pyrocatechuic acid produced (+)-voacalgine A. The total synthesis of (+)-bipleiophylline was completed by the second coupling of (+)-voacalgine A with (+)-pleiocarpamine or the one-pot couplings of 2 equiv of (+)-pleiocarpamine with pyrocatechuic acid.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Organic
Simon D. Schnell, Mauro Schilling, Jan Sklyaruk, Anthony Linden, Sandra Luber, Karl Gademann
Summary: The nucleophilic addition of silyl-enol ethers to nitrogen in 3-monosubstituted s-tetrazines mediated by BF3 was reported, showing preference over commonly observed inverse electron demand Diels-Alder reactions. The substrate dependency of this unusual reaction was rationalized through determination of activation barriers and employing the activation strain model using density functional theory.
Article
Chemistry, Medicinal
Inga S. Shchelik, Andrea Tomio, Karl Gademann
Summary: The study successfully investigated two light-responsive antibiotic derivatives, achieving spatiotemporal control over Gram-positive and Gram-negative bacterial strains, thereby enhancing drug activity and reducing side effects.
ACS INFECTIOUS DISEASES
(2021)
Article
Chemistry, Multidisciplinary
David Dailler, Andrea Dorst, Daniel Schafle, Peter Sander, Karl Gademann
Summary: Fidaxomicin is a marketed antibiotic for CDI treatment, with semi-synthetic modifications presenting a promising strategy to improve its pharmacokinetic properties and circumvent resistance development.
COMMUNICATIONS CHEMISTRY
(2021)
Article
Chemistry, Organic
Simon D. Schnell, Jorge A. Gonzalez, Jan Sklyaruk, Anthony Linden, Karl Gademann
Summary: This study achieved the selective preparation of 3-bromo-pyridazines and successfully synthesized functionalized pyridazines with excellent control over the substitution pattern. Utilizing Lewis acid-mediated inverse electron demand Diels-Alder reaction, the research demonstrated an effective synthetic method for downstream functionalization of 3-bromo-pyridazines.
JOURNAL OF ORGANIC CHEMISTRY
(2021)
Article
Chemistry, Organic
Lukas Hoff, Simon D. Schnell, Andrea Tomio, Anthony Linden, Karl Gademann
Summary: A silver-mediated Pd-catalyzed cross-coupling method for 3-bromo-1,2,4,5-tetrazine with boronic acids was presented in this study. It was found that electronic modification of the dppf ligand played a crucial role in achieving good turnover. Using this fast method, a variety of alkyl-, heteroatom-, and halide-substituted aryl- and heteroaryl-tetrazines were successfully prepared, with yields up to 87%.
Article
Biochemistry & Molecular Biology
Mathieu Szponarski, Karl Gademann
Summary: Stimulating the immune system against tumor cells is a promising strategy in cancer therapy. Small molecule-based approaches are gaining attention as alternatives to direct immune response, but targeting the balance between immune factors remain challenging. This study demonstrates the use of non-biological hapten to recruit antibodies to cancer cells and shows that metabolic glycoengineering and small molecule stimulators can be combined to direct antibody recognition.
Article
Chemistry, Physical
Lukas Hoff, Gleb A. Chesnokov, Anthony Linden, Karl Gademann
Summary: This study presents a thorough mechanistic investigation of the Pd-catalyzed and Ag-mediated cross-coupling reaction between monosubstituted tetrazine and boronic acids. Through kinetic analyses, isolation of intermediates, and computational methods, insights into the mechanism were obtained. The study also demonstrated the experimental confirmation of a highly electron-deficient ligand and the impact of mechanistic understanding on the generality of the reaction scope through a data-driven workflow.
Article
Chemistry, Organic
Lukas V. Hoff, Joana M. Hauser, Karl Gademann
Summary: An efficient method utilizing Pd catalysis for cross-coupling of 5-bromo-1,2,3-triazine is described. Optimization of reaction conditions enables the preparation of a diverse range of (hetero)aryl-1,2,3-triazines in high yields (up to 97%). Assessment of the reaction scope using data science techniques and subsequent diversification of products allows for the efficient synthesis of pyrimidines and pyridines.
JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Inga S. Shchelik, Karl Gademann
Summary: This study investigates the effect of newly synthesized cephalosporin derivatives with cyclic disulfide modifications on various strains of bacteria and biofilm formation. The incorporation of asparagusic acid was found to improve the activity of the drug against Gram-negative strains and reduce biofilm formation for Staphylococcus aureus and Pseudomonas aeruginosa. This suggests that incorporating cyclic disulfides may be an additional strategy to enhance antibiotic activity and combat bacterial infections.
ACS INFECTIOUS DISEASES
(2022)
Article
Chemistry, Multidisciplinary
Lukas V. Hoff, Simon D. Schnell, Elie Benchimol, Fabio Pereira Foutinho, Andrea Tomio, Michel Rickhaus, Karl Gademann
Summary: This study presents a seven-step protocol for the preparation of monosubstituted 3-bromo-1,2,4,5tetrazine. The procedure starts from commercially readily available starting materials and employs efficient transformations and purification methods. The title compound is obtained on a gram scale with 13% overall yield in reliable purity (>97%), allowing its application in various fields such as bioconjugation, protein labeling, bio-orthogonal chemistry, heterocycle syntheses, high energy materials, and drug release.
HELVETICA CHIMICA ACTA
(2023)
Article
Chemistry, Multidisciplinary
Tetiana Studer, Daria Morina, Inga S. Shchelik, Karl Gademann
Summary: This study presents the design and engineering of biohybrid microswimmers that release antibiotics through a thiol-mediated self-immolative mechanism. The microalgae Chlamydomonas reinhardtii were modified with a vancomycin conjugate using a disulfide-based linker. The addition of a thiol-based reducing agent triggered the release of the antibiotic, leading to inhibition of bacterial growth. This is the first example of a microalgae-based drug delivery system utilizing a thiol-mediated, reductive release strategy.
CHEMISTRY-A EUROPEAN JOURNAL
(2023)
Article
Chemistry, Multidisciplinary
Erik Jung, Karl Gademann
Summary: This review discusses small-molecule antibiotics approved for clinical use from 2010 to 2022, including four synthetic antibiotics (bedaquiline, pretomanid, delafloxacin, tedizolid), nine natural product derivatives (ceftaroline fosamil, cefiderocol, plazomicin, omadacycline, eravacycline, sarecycline, lefamulin, dalbavancin, oritavancin), and one natural product (fidaxomicin).
Article
Chemistry, Multidisciplinary
Gleb A. Chesnokov, Karl Gademann
Summary: Terpenoids are a class of natural compounds with diverse structures and bioactivities, which has attracted significant interest from the chemical community in the past 150 years. The presence of strained small rings in terpenoids makes their chemical synthesis challenging due to limited methods and stability issues. This feature article discusses recent examples of total syntheses of terpenoids with complex carbon frameworks featuring small rings, with a focus on the new developments in strategic and tactical approaches to constructing such systems.
CHEMICAL COMMUNICATIONS
(2022)
