Controlled oligomerization of [1.1.1]propellane through radical polarity matching: selective synthesis of SF₅- and CF₃SF₄-containing [2]staffanes

• Jón Atiba Buldt,
• Wang-Yeuk Kong,
• Yannick Kraemer,
• Masiel M. Belsuzarri,
• Ansh Hiten Patel,
• James C. Fettinger,
• Dean J. Tantillo and
• Cody Ross Pitts

Beilstein J. Org. Chem. 2024, 20, 3134–3143, doi:10.3762/bjoc.20.259

• nanotechnology [5], liquid crystal design [6][7][8][9][10], and the study of energy-transfer [11][12] or electron-transfer [13][14][15][16][17] processes. We also posit that lower-order [n]staffanes (i.e., n = 2 or 3) are potentially valuable C(sp3)-rich bioisosteres [18][19] that have been seemingly overlooked

2-Heteroarylethylamines in medicinal chemistry: a review of 2-phenethylamine satellite chemical space

• Carlos Nieto,
• Alejandro Manchado,
• Ángel García-González,
• David Díez and
• Narciso M. Garrido

Beilstein J. Org. Chem. 2024, 20, 1880–1893, doi:10.3762/bjoc.20.163

• examples, which will be a valuable repository of phenyl, heteroaryl, and other replacement units of high value to the drug discovery community. Keywords: bioisosteres; 2-heteroarylethylamines; medicinal chemistry; 2-phenethylamine; scaffold hopping; Introduction One of the major hit-2-lead exploration

• -ring bioisostere, but as carboxylic acid one, Schwarz et al. [79] developed tetrazole-based pregabalin bioisosteres 113–118 (Scheme 18). The target protein α2-δ is involved in neurotransmitters release reduction, as a model of anxiety and neuropathic pain. In general, submicromolar affinities were

Synthesis and optical properties of bis- and tris-alkynyl-2-trifluoromethylquinolines

• Stefan Jopp,
• Franziska Spruner von Mertz,
• Peter Ehlers,
• Alexander Villinger and
• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 1246–1255, doi:10.3762/bjoc.20.107

• ). Fluorine-containing quinolines and quinolinones are of particular interest, since fluorine atoms are known to enhance the pharmacological properties of organic molecules [7][8][9][10][11][12][13][14][15]. Fluorine atoms act as bioisosteres of hydrogen atoms, while CF3 groups are bioisosteres of hydroxy and

Innovative synthesis of drug-like molecules using tetrazole as core building blocks

• Jingyao Li,
• Ajay L. Chandgude,
• Qiang Zheng and
• Alexander Dömling

Beilstein J. Org. Chem. 2024, 20, 950–958, doi:10.3762/bjoc.20.85

• developed building block approach, we decided to incorporate an oxo-tetrazole into an Ugi four-component reaction, the most studied and versatile MCR in organic synthesis and drug discovery [31][32]. Despite tremendous exploration, finding novel substrates or bioisosteres as a starting material in the Ugi

(Bio)isosteres of ortho- and meta-substituted benzenes

• H. Erik Diepers and
• Johannes C. L. Walker

Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78

• H. Erik Diepers Johannes C. L. Walker Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstraße 2, 37077 Göttingen, Germany 10.3762/bjoc.20.78 Abstract Saturated bioisosteres of substituted benzenes offer opportunities to fine-tune the properties of drug

• candidates in development. Bioisosteres of para-benzenes, such as those based on bicyclo[1.1.1]pentane, are now very common and can be used to increase aqueous solubility and improve metabolic stability, among other benefits. Bioisosteres of ortho- and meta-benzenes were for a long time severely

• underdeveloped by comparison. This has begun to change in recent years, with a number of potential systems being reported that can act as bioisosteres for these important fragments. In this review, we will discuss these recent developments, summarizing the synthetic approaches to the different bioisosteres as

On drug discovery against infectious diseases and academic medicinal chemistry contributions

• Yves L. Janin

Beilstein J. Org. Chem. 2022, 18, 1355–1378, doi:10.3762/bjoc.18.141

• approach to identify bioisosteres [70][71] or to undertake scaffold hoping [72] from an actual hit. On the other hand, concerning the virtual docking [73][74] of molecules on structurally characterized targets, past a rather sobering 2010 domesday report [75], a more recent review [76] is noteworthy at the

An isoxazole strategy for the synthesis of 4-oxo-1,4-dihydropyridine-3-carboxylates

• Timur O. Zanakhov,
• Ekaterina E. Galenko,
• Mikhail S. Novikov and
• Alexander F. Khlebnikov

Beilstein J. Org. Chem. 2022, 18, 738–745, doi:10.3762/bjoc.18.74

• due to their specific characteristics such as basicity, hydrogen bond forming ability, water solubility, and especially because of pyridine rings are bioisosteres of amines, amides, N-heterocyclic rings and benzene rings [1][2][3][4][5]. A special type of pyridine, the 4-pyridones, is also fairly well

Synthesis of sulfur karrikin bioisosteres as potential neuroprotectives

• Martin Pošta,
• Václav Zima,
• Lenka Poštová Slavětínská,
• Marika Matoušová and
• Petr Beier

Beilstein J. Org. Chem. 2022, 18, 549–554, doi:10.3762/bjoc.18.57

• oxygen with sulfur. In particular, we present synthetic procedures toward bioisosteres of karrikins with one or two sulfur heteroatoms incorporated into the core backbone together with evaluation of their biological activity in inhibition of acetylcholinesterase. Keywords: acetylcholinesterase

• ) (Scheme 2) and provided the target compounds in good to high yields. Synthesis of KAR analogues with sulfur in position 6 Two different synthetic approaches were used for the preparation of C6 sulfur bioisosteres bearing a thiopyran moiety. For the synthesis of KAR1, KAR3 and KAR4 analogues, we proposed a

Unexpected chiral vicinal tetrasubstituted diamines via borylcopper-mediated homocoupling of isatin imines

• Marco Manenti,
• Leonardo Lo Presti,
• Giorgio Molteni and
• Alessandra Silvani

Beilstein J. Org. Chem. 2022, 18, 303–308, doi:10.3762/bjoc.18.34

• -butanesulfinyl ketimine; homocoupling; Introduction As bioisosteres of carboxylic acid derivatives, boronic acids have recently emerged as a novel chemotype in drug design, with a number of boron-containing compounds recently being approved by the FDA [1][2][3][4]. In particular, α- and β-aminoboronic acids are

Chemical synthesis of C6-tetrazole ᴅ-mannose building blocks and access to a bioisostere of mannuronic acid 1-phosphate

• Eleni Dimitriou and
• Gavin J. Miller

Beilstein J. Org. Chem. 2021, 17, 1527–1532, doi:10.3762/bjoc.17.110

• approach to provide structurally defined building blocks containing bioisosteres of ᴅ-mannuronic acid. Building on our recently reported synthesis and glycosylation capability of hydroxamate-modified ᴅ-mannuronate building blocks [11], we now demonstrate the synthesis of a second carboxylate C6-bioisostere

Fluorine effect in nucleophilic fluorination at C4 of 1,6-anhydro-2,3-dideoxy-2,3-difluoro-β-D-hexopyranose

• Danny Lainé,
• Vincent Denavit,
• Olivier Lessard,
• Laurie Carrier,
• Charles-Émile Fecteau,
• Paul A. Johnson and
• Denis Giguère

Beilstein J. Org. Chem. 2020, 16, 2880–2887, doi:10.3762/bjoc.16.237

• biochemical processes [1]. Therefore, the use of bioisosteres of carbohydrates functional groups is a popular approach in glycobiology [2]. As such, the synthesis of fluorosugars, including polyfluorinated analogues, is an interesting strategy to study biological systems [3][4][5][6][7]. The replacement of OH

Recent advances in Cu-catalyzed C(sp³)–Si and C(sp³)–B bond formation

• Balaram S. Takale,
• Ruchita R. Thakore,
• Elham Etemadi-Davan and
• Bruce H. Lipshutz

Beilstein J. Org. Chem. 2020, 16, 691–737, doi:10.3762/bjoc.16.67

• functional groups into existing or new drugs. Examples include the incorporation of silicon bioisosteres that help increase lipophilicity, subsequently altering the existing metabolic pathway of a drug due to differences in its physicochemical properties [8]. On the other hand, the trigonal planar nature of

Insertion of [1.1.1]propellane into aromatic disulfides

• Robin M. Bär,
• Gregor Heinrich,
• Martin Nieger,
• Olaf Fuhr and
• Stefan Bräse

Beilstein J. Org. Chem. 2019, 15, 1172–1180, doi:10.3762/bjoc.15.114

• in most cases. Single crystal X-ray diffraction analysis confirms the rod-like structure of the [2]staffanes that is often required in material applications. Keywords: bicyclo[1.1.1]pentane; bioisosteres; disulfides; linkers; [1.1.1]propellane; Introduction Rigid structures are emerging in both

• materials science and medicinal chemistry [1]. Often referred to as bioisosteres, small strained hydrocarbons are used to replace phenyl [2][3][4] or alkyne groups [5] in well-known compounds, e.g., imatinib [3] and tazarotene [5]. The increase of the three-dimensionality and the disruption of the π-system

Applications of organocatalysed visible-light photoredox reactions for medicinal chemistry

• Michael K. Bogdos,
• Emmanuel Pinard and
• John A. Murphy

Beilstein J. Org. Chem. 2018, 14, 2035–2064, doi:10.3762/bjoc.14.179

• -trifluoromethylamines, which are attractive due to their low basicity, ability to act as amide bioisosteres [42] and higher metabolic stability. The number of medicinal chemists who specialise in peptides has been increasing in recent years. This is largely due to the increasing interest in macrocyclic peptides. A key

Synthesis and stability of strongly acidic benzamide derivatives

• Frederik Diness,
• Niels J. Bjerrum and
• Mikael Begtrup

Beilstein J. Org. Chem. 2018, 14, 523–530, doi:10.3762/bjoc.14.38

• trifluoromethanesulfonamide (1) group [9][10][11]. Interestingly, these types of compounds have attracted little attention and have not thoroughly been explored with regards to their applications. Few publications report the application of N-triflylbenzamides as benzoic acid bioisosteres in receptor antagonists and enzyme

Solvent-free copper-catalyzed click chemistry for the synthesis of N-heterocyclic hybrids based on quinoline and 1,2,3-triazole

• Martina Tireli,
• Silvija Maračić,
• Stipe Lukin,
• Marina Juribašić Kulcsár,
• Dijana Žilić,
• Mario Cetina,
• Ivan Halasz,
• Silvana Raić-Malić and
• Krunoslav Užarević

Beilstein J. Org. Chem. 2017, 13, 2352–2363, doi:10.3762/bjoc.13.232

• bond bioisosteres made the click reaction a valuable synthetic methodology for conjugation of bioactive molecules [7][8][9] aiming to improve their biological activities [4][10][11]. Discovery of copper(I) ion catalysis in azide–alkyne cycloadditions was decisive for applications of this reaction, as

Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules

• Thilo Focken and
• Stephen Hanessian

Beilstein J. Org. Chem. 2014, 10, 1848–1877, doi:10.3762/bjoc.10.195

• ) [57]. Pellicciari and co-workers also reported on the synthesis of other constrained bioisosteres of L-glutamic acid, such as PCCG-4 (163) (Figure 9) [124]. To this end, phosphonocyclopropylamino acid 21 was designed as an analogue to 163 by replacing a carboxylic acid with a phosphonic acid moiety

Deoxygenative gem-difluoroolefination of carbonyl compounds with (chlorodifluoromethyl)trimethylsilane and triphenylphosphine

• Fei Wang,
• Lingchun Li,
• Chuanfa Ni and
• Jinbo Hu

Beilstein J. Org. Chem. 2014, 10, 344–351, doi:10.3762/bjoc.10.32

• precursors for organic synthesis, but also act as bioisosteres for enzyme inhibitors. Among various methods for their preparation, the carbonyl olefination with difluoromethylene phosphonium ylide represents one of the most straightforward methods. Results: The combination of (chlorodifluoromethyl

Synthesis and characterization of novel bioactive 1,2,4-oxadiazole natural product analogs bearing the N-phenylmaleimide and N-phenylsuccinimide moieties

• Catalin V. Maftei,
• Elena Fodor,
• Peter G. Jones,
• M. Heiko Franz,
• Gerhard Kelter,
• Heiner Fiebig and
• Ion Neda

Beilstein J. Org. Chem. 2013, 9, 2202–2215, doi:10.3762/bjoc.9.259

• starting from tert-butylamidoxime and 4-aminobenzoic acid or 4-nitrobenzonitrile. The structures of compounds 1, 2, 4, 5 and 6 were confirmed by X-ray crystallography. Keywords: antitumor activity; bioisosteres; maleimide; natural product analogs; 1,2,4-oxadiazoles; Introduction The five-membered

• heterocyclic 1,2,4-oxadiazole motif is of synthetic and pharmacological interest. It also forms an important constituent of biologically active compounds including natural products [1]. Sawyer et al. have described such compounds as bioisosteres for amides and esters [2], with the 1,2,4-oxadiazoles showing