Biochemistry of fluoroprolines: the prospect of making fluorine a bioelement

• Vladimir Kubyshkin,
• Rebecca Davis and
• Nediljko Budisa

Beilstein J. Org. Chem. 2021, 17, 439–460, doi:10.3762/bjoc.17.40

• substitution of the proline residue with fluorinated analogues (fluoroprolines, Figure 1) creates an option for making fluorine a component of a living organism. Fluoroprolines were found to be generally compatible with the cellular machinery, in particular the one that transports them inside the cells and

• in cellular biochemistry and the potential of fluoroprolines to fulfill them. Here, by fluoroprolines, we will only refer to 4-monofluoroprolines and 4,4-difluoroproline, which are the best biochemically characterized proline analogues (Figure 1). Many other fluorinated proline analogues exist, as

• analogous structures. Most typical among proline analogues would be hydroxy-, fluoro-, alkyl-, dehydroprolines, analogues having ring size variations, and N-alkylamino acids (Figure 2C). To clearly discriminate the alanine and proline-based architectures, we recently proposed to call this set of structures

1,2,3-Triazoles as leaving groups: S_NAr reactions of 2,6-bistriazolylpurines with O- and C-nucleophiles

• Dace Cīrule,
• Irina Novosjolova,
• Ērika Bizdēna and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 410–419, doi:10.3762/bjoc.17.37

• 6-O-analogues are less common [61]. Azolylpurine derivatives are important due to their potential as drug candidates. They can be used as agonists and antagonists of adenosine receptors [58][64][65][66] and against Mycobacterium tuberculosis [60]. They also show useful fluorescent properties [11][67

• hydrogen bond. This is supported by a smaller deviation of the C(2’’) chemical shift value (61.7 ppm) in comparison to the theoretical shifts for a Csp2 centre. Similar structural analogues are known in the literature [54][83][84][85] but their structural analysis was incomplete. As the aforementioned

CF₃-substituted carbocations: underexploited intermediates with great potential in modern synthetic chemistry

• Anthony J. Fernandes,
• Armen Panossian,
• Bastien Michelet,
• Agnès Martin-Mingot,
• Frédéric R. Leroux and
• Sébastien Thibaudeau

Beilstein J. Org. Chem. 2021, 17, 343–378, doi:10.3762/bjoc.17.32

• nonfluorinated analogues (Eox (PhNMe2) = +0.71 V (SCE)), the radical cation 180 is formed under the reaction conditions, and deprotonation at the methylene unit near the CF3 group is highly favored because of the higher acidity, accounting for the observed high regioselectivity. In addition, the transient

¹⁹F NMR as a tool in chemical biology

• Diana Gimenez,
• Aoife Phelan,
• Cormac D. Murphy and
• Steven L. Cobb

Beilstein J. Org. Chem. 2021, 17, 293–318, doi:10.3762/bjoc.17.28

• introduction of unnatural amino acids into proteins have been reviewed extensively elsewhere [5][6][7] and here we will only discuss the most recent advances. The chemical structures of a selection of 19F-labelled amino acid analogues that have been utilized in 19F NMR studies in chemical biology are shown in

• , all peptides where 8 was introduced could be detected even at concentrations as low as 5 μM, demonstrating that pFtBSer is a highly sensitive tool to study binding events by way of 19F NMR chemical shift and nuclear relaxation changes. In addition to homoserine, perfluorinated analogues of both

• the aforementioned issues, Virta and co-workers have explored the application of trifluoromethyl analogues of guanosine, cytidine and uridine based in 2’-O-[(4-trifluoromethyltriazol-1-yl)methyl] reporter groups as 19F NMR probes for the detection of RNA secondary structures (Figure 14). As shown by

Exploring the possibility of using fluorine-involved non-conjugated electron-withdrawing groups for thermally activated delayed fluorescence emitters by TD-DFT calculation

• Dongyang Chen and
• Eli Zysman-Colman

Beilstein J. Org. Chem. 2021, 17, 210–223, doi:10.3762/bjoc.17.21

• mirror those observed for their Type I analogues; however, the HOMO and LUMO values in the Type II emitters are more stabilized and the energy gaps are reduced. The HOMO of 5CzBN is symmetrically distributed across the ortho- and meta-disposed carbazoles while the HOMO of 5CzTRZ is located mostly on the

Au(III) complexes with tetradentate-cyclam-based ligands

• Ann Christin Reiersølmoen,
• Thomas N. Solvi and
• Anne Fiksdahl

Beilstein J. Org. Chem. 2021, 17, 186–192, doi:10.3762/bjoc.17.18

• activity was observed for cyclam–gold complex 6a-Au(III) versus the open cyclam analogues 5a-Au(III). Complex 5a-Au(III) afforded a full conversion in the alkyne carboalkoxylation in 5.5 hours, compared to in 24 hours for complex 6a-Au(III) (Table 1, entries 1 and 2). The same trend was observed for Au(III

Benzothiazolium salts as reagents for the deoxygenative perfluoroalkylthiolation of alcohols

• Armin Ariamajd,
• Nils J. Gerwien,
• Benjamin Schwabe,
• Stefan Dix and
• Matthew N. Hopkinson

Beilstein J. Org. Chem. 2021, 17, 83–88, doi:10.3762/bjoc.17.8

• groups (SRF, RF = CnF2n+1) have received comparatively little attention despite promising applications in liquid crystal displays [13][14], as pharmaceuticals and agrochemicals [15]. For example, analogues of the drug losartan featuring SC2F5, SC3F7 and SC4F9 groups have shown promise as treatments for

Progress in the total synthesis of inthomycins

• Bidyut Kumar Senapati

Beilstein J. Org. Chem. 2021, 17, 58–82, doi:10.3762/bjoc.17.7

• application of various efforts towards the synthesis of inthomycins and their analogues systematically. Keywords: antibiotics; inthomycins; oxazololomycin; Stille coupling; total synthesis; Introduction Inthomycins, alternatively known as phthoxazolins, are a class of compounds in which a methylene

• present review provides a systematic summary of synthetic strategies for the synthesis of inthomycins and their analogues over the period of 1999 to present. Rewiew Synthesis Undoubtedly, the unique skeleton of inthomycins has acted as an inspiration for the development of new synthetic methodologies

• very low, this work certainly established the basis for the future enantioselective syntheses of inthomycins and related natural products. In 2002, Moloney et al. described an efficient synthetic route using the Stille coupling reaction as the key step to accomplish the synthesis of phenyl analogues of

An atom-economical addition of methyl azaarenes with aromatic aldehydes via benzylic C(sp³)–H bond functionalization under solvent- and catalyst-free conditions

• Divya Rohini Yennamaneni,
• Vasu Amrutham,
• Krishna Sai Gajula,
• Rammurthy Banothu,
• Murali Boosa and
• Narender Nama

Beilstein J. Org. Chem. 2020, 16, 3093–3103, doi:10.3762/bjoc.16.259

• diversity, these compounds constitute a motif in various natural alkaloid products, such as chimanine and those derived from lobelia, sedum, etc. These compounds act as anti-HIV and anti-asthma drugs [9][10][11]. Mainly, 2-substituted quinolines and their analogues exhibits magnificent bioactivity [12][13

Pentannulation of N-heterocycles by a tandem gold-catalyzed [3,3]-rearrangement/Nazarov reaction of propargyl ester derivatives: a computational study on the crucial role of the nitrogen atom

• Giovanna Zanella,
• Martina Petrović,
• Dina Scarpi,
• Ernesto G. Occhiato and
• Enrique Gómez-Bengoa

Beilstein J. Org. Chem. 2020, 16, 3059–3068, doi:10.3762/bjoc.16.255

• of the accuracy of the computational method we have used for the comparison of the isomeric complexes I and V. Our previous experience in this area taught us that seven-membered azepane-derived enynyl acetates react faster than the corresponding piperidine analogues 1, prompting us to prepare enynyl

• sluggish reactivity of the 3-substituted substrates, in comparison to the 2-substituted analogues that we have previously described. Tandem acetate rearrangement/Nazarov cyclization of different substrates. DFT-computed energy profile of the tandem Au(I)-catalyzed [3,3]-rearrangement/Nazarov reaction of 3

All-carbon [3 + 2] cycloaddition in natural product synthesis

• Zhuo Wang and
• Junyang Liu

Beilstein J. Org. Chem. 2020, 16, 3015–3031, doi:10.3762/bjoc.16.251

• take place. The use of noncyclic analogues did not give the cycloaddition product. It is suggested that the restricted rotational freedom of 151 and the related enforced conjugation of the sulfur lone pair may block certain undesired cation reactions. Cycloaddition product 154 was subjected to the

Chiral anion recognition using calix[4]arene-based ureido receptors in a 1,3-alternate conformation

• Tereza Horáčková,
• Jan Budka,
• Vaclav Eigner,
• Wen-Sheng Chung,
• Petra Cuřínová and
• Pavel Lhoták

Beilstein J. Org. Chem. 2020, 16, 2999–3007, doi:10.3762/bjoc.16.249

• reactions were carried out at room temperature in anhydrous dichloromethane, and the products 7a–d were isolated in 40–60% yields. Similarly, the propyl-substituted analogues 8a and 8b were obtained from the reaction of 6 with the corresponding isocyanates in 38% and 45% yield, respectively. The structures

• exhibited complexation constants higher than the butyl-substituted analogues 7b and 8b for all anions – compare 7a (Table 1, run 5, K = 660 M−1) vs 7b (Table 2, run 15, K = 90 M−1). On the other hand, despite the differences in the K values, the enantioselectivity remained almost the same in both receptor

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

• ; polyfluorinated carbohydrates; polyfluoroalditol analogues; Introduction The biological significance of carbohydrates includes, but are not limited to, immune regulation, infection, and cancer metastasis. Research in the field of molecular biology allowed the discovery of glycomimetics to study various

• 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

• progress to the development of innovative synthetic methodology to access polyfluorosugars [18]. For our part, we recently described the preparation of multi-vicinal trifluorinated hexopyranose analogues 6–9 using the Chiron approach from levoglucosan (1, Figure 1) [19]. Various 1,6-anhydro-2,3-dideoxy-2,3

A heterobimetallic tetrahedron from a linear platinum(II)-bis(acetylide) metalloligand

• Matthias Hardy,
• Marianne Engeser and
• Arne Lützen

Beilstein J. Org. Chem. 2020, 16, 2701–2708, doi:10.3762/bjoc.16.220

• obtain analogues cages in future work to explore the properties of these system in terms of their host–guest chemistry or their magnetic behavior. Experimental General All reagents and solvents were purchased from commercial sources and used as received without any further purification. NMR spectra were

Selective and reversible 1,3-dipolar cycloaddition of 6-aryl-1,5-diazabicyclo[3.1.0]hexanes with 1,3-diphenylprop-2-en-1-ones under microwave irradiation

• Alexander P. Molchanov,
• Mariia M. Efremova,
• Mariya A. Kryukova and
• Mikhail A. Kuznetsov

Beilstein J. Org. Chem. 2020, 16, 2679–2686, doi:10.3762/bjoc.16.218

• pyrazolidinone derivatives like LY186826 and its analogues with antibacterial activity [8][9][10][11][12]. The chemistry of azomethine imines has been actively investigated since the second half of the last century but their reactivity is still far less studied compared with nitrones or azomethine ylides – other

Chan–Evans–Lam N1-(het)arylation and N1-alkеnylation of 4-fluoroalkylpyrimidin-2(1H)-ones

• Viktor M. Tkachuk,
• Oleh O. Lukianov,
• Mykhailo V. Vovk,
• Isabelle Gillaizeau and
• Volodymyr A. Sukach

Beilstein J. Org. Chem. 2020, 16, 2304–2313, doi:10.3762/bjoc.16.191

• , heterocyclic analogues of activated ketimines (Figure 1), thus offering potential applications in the design of new heterocyclic chemotypes [21][22][23][24][25]. Compounds I are precursors of trifluoromethyl-substituted dihydropyrimidine derivatives which appear as original and potent scaffolds in medicinal

• analogues 1c,d afforded products 9b,c in high yields of 74 and 78%, respectively (see Supporting Information File 1). Unexpectedly, 4-methyl-substituted and 4-unsubstituted pyrimidin-2(1H)-ones 1e,f, when reacted under similar conditions, gave complex mixtures containing no more than 5% of target products

• an organoboron component, instead of the conventionally used boronic acids. Among the newly-synthesized compounds are the first representatives of N1-(het)aryl-4-fluoroalkylpyrimidin-2(1H)-ones as well as their synthetically promising N1-alkеnyl-substituted analogues. The success of the reaction has

Naphthalene diimide bis-guanidinio-carbonyl-pyrrole as a pH-switchable threading DNA intercalator

• Poulami Jana,
• Filip Šupljika,
• Carsten Schmuck and
• Ivo Piantanida

Beilstein J. Org. Chem. 2020, 16, 2201–2211, doi:10.3762/bjoc.16.185

• , usually also cause DNA condensation, as we have shown previously for some GCP analogues [16]. Thus, we performed AFM (Figure 6) and DLS experiments (Figure S25, Supporting Information File 1) at conditions of excess of 4 over ct-DNA. The AFM images clearly showed that the elongated structure of the free

• , as was demonstrated by AFM and DLS results. Since agents that efficiently condense DNA are often employed for cell-transfection purposes, in future prospects of the here presented results we plan to pursue this application as we have shown previously for some GCP analogues [33]. Experimental General

Lipophilicity trends upon fluorination of isopropyl, cyclopropyl and 3-oxetanyl groups

• Benjamin Jeffries,
• Zhong Wang,
• Robert I. Troup,
• Anaïs Goupille,
• Jean-Yves Le Questel,
• Charlene Fallan,
• James S. Scott,
• Elisabetta Chiarparin,
• Jérôme Graton and
• Bruno Linclau

Beilstein J. Org. Chem. 2020, 16, 2141–2150, doi:10.3762/bjoc.16.182

• give analogue 7b reduced the lipophilicity. Interestingly, while the nonfluorinated 7a and 7c diastereomers have different logD7.4 values, this is not the case for their fluorinated analogues 7b and 7d. Oxazine derivative 8 featured in the development of centrally active β-secretase (BACE1) inhibitors

• derivative C2 has a lower logD value than the nonfluorinated parent C1 [16][17]. In this contribution, we describe a systematic study on the lipophilicity modulations of the isopropyl, cyclopropyl and 3-oxetanyl groups and their various possible analogues, featuring fluorination at a single carbon atom

• decrease seen for E2 is in accord with the observations for the β-fluorinated analogues of 7a and 7c (see above, Figure 2). The cis-isomer E3 has a slightly lower lipophilicity than the trans-isomer E4. The lower lipophilicity decrease upon monofluorination in series E compared to series F could be related

Convenient access to pyrrolidin-3-ylphosphonic acids and tetrahydro-2H-pyran-3-ylphosphonates with multiple contiguous stereocenters from nonracemic adducts of a Ni(II)-catalyzed Michael reaction

• Alexander N. Reznikov,
• Dmitry S. Nikerov,
• Anastasiya E. Sibiryakova,
• Victor B. Rybakov,
• Evgeniy V. Golovin and
• Yuri N. Klimochkin

Beilstein J. Org. Chem. 2020, 16, 2073–2079, doi:10.3762/bjoc.16.174

• analogues 4 and 5 are neuraminidase inhibitors (Figure 1) [8][9]. These circumstances create an interest in discovering synthetic routes for obtaining nonracemic phosphoryl-substituted heterocycles. Thus, in recent years, effective methods for the asymmetric synthesis of chiral phosphonates containing

• octahydroindole [10], tetrahydroquinoline [11], tetrahydroisoquinoline [11][12], β-carboline [13], morpholine [14], and isoindoline [15] moieties have been developed. Obtained in an enantiomerically pure form, phosphonoproline and its analogues [16][17][18][19] were among the first compounds in this series

Naphthalene diimide–amino acid conjugates as novel fluorimetric and CD probes for differentiation between ds-DNA and ds-RNA

• Annike Weißenstein,
• Myroslav O. Vysotsky,
• Ivo Piantanida and
• Frank Würthner

Beilstein J. Org. Chem. 2020, 16, 2032–2045, doi:10.3762/bjoc.16.170

• access to large libraries of close analogues. Further, in such peptide-based chromophore systems, a multitude of different chromophores/fluorophores [10] could allow fine tuning of spectroscopic responses to various DNA/RNA sequences. With this concept in mind, Piantanida and co-workers recently

Automated high-content imaging for cellular uptake, from the Schmuck cation to the latest cyclic oligochalcogenides

• Rémi Martinent,
• Javier López-Andarias,
• Dimitri Moreau,
• Yangyang Cheng,
• Naomi Sakai and
• Stefan Matile

Beilstein J. Org. Chem. 2020, 16, 2007–2016, doi:10.3762/bjoc.16.167

• far exceeds the related tetrapeptide analogues with arginine or lysine residues. As a result, the gene transfection efficiency of 13 is better than that of polyethylenimine (PEI) with a large number of charges, which is one of the current standards in gene transfection. The uptake takes place through

A complementary approach to conjugated N-acyliminium formation through photoredox-catalyzed intermolecular radical addition to allenamides and allencarbamates

• Olusesan K. Koleoso,
• Matthew Turner,
• Felix Plasser and
• Marc C. Kimber

Beilstein J. Org. Chem. 2020, 16, 1983–1990, doi:10.3762/bjoc.16.165

• (32 to 35) in moderate to good isolated yields. 4-Bromo-2-fluoroaniline was also examined as a nucleophile, as we had previously shown this to be an effective aniline platform for developing linezolid analogues, and this delivered two N,N’-allylaminals 36 and 37, respectively. Masson had previously

Synthesis of 3(2)-phosphonylated thiazolo[3,2-a]oxopyrimidines

• Ksenia I. Kaskevich,
• Anastasia A. Babushkina,
• Vladislav V. Gurzhiy,
• Dmitrij M. Egorov,
• Nataly I. Svintsitskaya and
• Albina V. Dogadina

Beilstein J. Org. Chem. 2020, 16, 1947–1954, doi:10.3762/bjoc.16.161

• between 2-thiouracil and propargyl bromide yielded 5H-thiazolo[3,2-a]pyrimidine-5-one (Scheme 5) [20][21][22][23][24]. Despite the wide variety of thiazolopyrimidines reported to date, phosphonylated analogues of compounds of this series are unknown. Of special interest is the design of molecules

Selective preparation of tetrasubstituted fluoroalkenes by fluorine-directed oxetane ring-opening reactions

• Clément Q. Fontenelle,
• Thibault Thierry,
• Romain Laporte,
• Emmanuel Pfund and
• Thierry Lequeux

Beilstein J. Org. Chem. 2020, 16, 1936–1946, doi:10.3762/bjoc.16.160

• biological and physiological properties and can enhance the half-life of drugs in vivo [1][2][3][4]. During the last decade, fluorinated nucleoside analogues have received increasing interest, as is illustrated by the two pharmaceutical leads gemcitabine (I) and sofosbuvir (II), potent anticancer or

• antiviral agents, respectively (Figure 1) [5][6]. The field of acyclonucleotides (ACN) has been explored less, however, the introduction of fluorine atoms showed remarkable effects. The most representative examples are phosphate analogues such as the nucleoside phosphorylase inhibitor III and acyclic

• conformational changes [11][12][13]. For the latter, nucleoside analogues (Figure 2, VI) containing a trans-butenyl moiety where the endocyclic C–O bond was replaced by a C=C bond are recognized by kinases as dUMP surrogate (V) [11]. However, there is no existing data for the corresponding fluoroalkene (VII), as

Polarity effects in 4-fluoro- and 4-(trifluoromethyl)prolines

• Vladimir Kubyshkin

Beilstein J. Org. Chem. 2020, 16, 1837–1852, doi:10.3762/bjoc.16.151

• Vladimir Kubyshkin University of Manitoba, Dysart Rd. 144, Winnipeg, R3T 2N2, Canada 10.3762/bjoc.16.151 Abstract Fluorine-containing analogues of proline are valuable tools in engineering and NMR spectroscopic studies of peptides and proteins. Their use relies on the fundamental understanding of

• identify structural breaks in a sequence. This fact contributes to the reputation of proline as a polar residue [3][4][5]. There is a rich portfolio of fluorine-containing proline analogues that have been developed to date (Figure 1B): fluorinated [6][7][8][9][10][11][12], trifluoromethylated [13][14][15

• ][16][17][18][19][20][21][22][23], chimeric [16][19][24][25][26][27][28][29], conformationally restricted [30][31][32][33] having variations in the ring size [34][35][36][37][38][39], non-α [40][41][42][43][44], and other analogues [45][46][47][48]. The fluorine-containing functional groups are usually