Targeting active site residues and structural anchoring positions in terpene synthases

• Anwei Hou and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2021, 17, 2441–2449, doi:10.3762/bjoc.17.161

• attack of an olefinic double bond to the cationic centre Wagner–Meerwein rearrangements, and proton or hydride migrations [2]. These multistep cascade reactions ultimately result in terpene hydrocarbons that are often (poly)cyclic and contain several stereogenic centres [3][4]. In some cases, water is

A visible-light-induced, metal-free bis-arylation of 2,5-dichlorobenzoquinone

• Pieterjan Winant and
• Wim Dehaen

Beilstein J. Org. Chem. 2021, 17, 2315–2320, doi:10.3762/bjoc.17.149

• multistep procedures requiring large amounts of toxic metal complexes [12][33][34]. Later improvements still demand prefunctionalization of the quinone substrate [35][36][37]. While effectively eliminating this requirement, CH bis-arylation using palladium complexes still suffers from regioselectivity

Post-functionalization of drug-loaded nanoparticles prepared by polymerization-induced self-assembly (PISA) with mitochondria targeting ligands

• Janina-Miriam Noy,
• Fan Chen and
• Martina Stenzel

Beilstein J. Org. Chem. 2021, 17, 2302–2314, doi:10.3762/bjoc.17.148

• suitability as a potential vehicle to deliver these drugs. Disadvantage is however the multistep procedure to generate micelles ranging from the synthesis of block copolymers to the self-assembly into micelles, often in low dilution, making the process inefficient. Micelles obtained by the PISA process can in

Recent advances in the syntheses of anthracene derivatives

• Giovanni S. Baviera and
• Paulo M. Donate

Beilstein J. Org. Chem. 2021, 17, 2028–2050, doi:10.3762/bjoc.17.131

• activity for iodoethynyl groups [63]. Intramolecular cyclization In 2009, Swager’s research group published the synthesis of fluorescent macrocycles based on 1,3-butadiyne-bridged dibenzo[a,j]anthracene subunits via a multistep route (Scheme 30) [64]. They synthesized substituted dibenzo[a,j]anthracenes

• published in 2018, de Koning and co-workers reported a new methodology to synthesize the benzo[a]anthracene skeleton of angucycline derivatives 146 by using a multistep strategy based on Suzuki–Miyaura, isomerization, and ring-closing metathesis reactions (Scheme 33) [67]. The commercially available 2

Progress and challenges in the synthesis of sequence controlled polysaccharides

• Giulio Fittolani,
• Theodore Tyrikos-Ergas,
• Denisa Vargová,
• Manishkumar A. Chaube and
• Martina Delbianco

Beilstein J. Org. Chem. 2021, 17, 1981–2025, doi:10.3762/bjoc.17.129

• glycosylation or complicating the deprotection steps. Orthogonality and stability become particularly crucial when the goal is the multistep synthesis of long COS. Other glucosamine-based polysaccharides Other polymers of glucosamine based on the β(1–3) or β(1–6) linkages exist, but have gained less synthetic

A recent overview on the synthesis of 1,4,5-trisubstituted 1,2,3-triazoles

• Pezhman Shiri,
• Ali Mohammad Amani and
• Thomas Mayer-Gall

Beilstein J. Org. Chem. 2021, 17, 1600–1628, doi:10.3762/bjoc.17.114

• exploitation of triazole rings as beneficial directing groups to produce complex triazoles has been screened. Although the postfunctionalization of disubstituted 1,2,3-triazoles may include multistep reactions for the synthesis of this kind of products, it is an easy and efficient strategy (Scheme 1). The

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

• ][23][24][25][26][27]. As such our aim is not to include a comprehensive review here but to simply highlight the principle characteristics and direct the reader to the listed references for further consultation. In overview a basic depiction of a sequential batch vs flow approach for a multistep

• reduction; there are many potential applications of this field in the small scale chemistry as well. For example, areas like combinatorial chemistry [33][34][35], complex multistep syntheses [14][36][37], synthesis of pharmaceutical substances have witnessed tremendous growth using flow chemistry approach

• reagents has also greatly aided in the development of impressive sequential multistep sequences in flow by acting as direct in-line quenching, work-up and purification steps [28][80][81][82][83][84][85]. Indeed, the scavenger approach to removing excess solution phase reagents or byproducts has had a

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

• Joseane A. Mendes,
• Paulo R. R. Costa,
• Miguel Yus,
• Francisco Foubelo and
• Camilla D. Buarque

Beilstein J. Org. Chem. 2021, 17, 1096–1140, doi:10.3762/bjoc.17.86

DNA with zwitterionic and negatively charged phosphate modifications: Formation of DNA triplexes, duplexes and cell uptake studies

• Yongdong Su,
• Maitsetseg Bayarjargal,
• Tracy K. Hale and
• Vyacheslav V. Filichev

Beilstein J. Org. Chem. 2021, 17, 749–761, doi:10.3762/bjoc.17.65

• ) have an enhanced thermal stability in DNA triplexes and duplexes, a high binding affinity to RNA, and are nuclease resistant [22][26][27][28]. These properties have led to LNA (BNA) being used in various therapeutic ONs that have reached clinical trials [29]. However, the multistep synthesis of LNA and

Designed whole-cell-catalysis-assisted synthesis of 9,11-secosterols

• Marek Kõllo,
• Marje Kasari,
• Villu Kasari,
• Tõnis Pehk,
• Ivar Järving,
• Margus Lopp,
• Arvi Jõers and
• Tõnis Kanger

Beilstein J. Org. Chem. 2021, 17, 581–588, doi:10.3762/bjoc.17.52

• synthetic methods for secosteroids is wide. However, usually these are multistep sequences exploiting toxic oxidants. Marine invertebrates are a rich source of oxidated and highly functionalized steroidal metabolites, including secosteroids. Since the first isolation of 9,11-secosterol from

• synthetic schemes starts with natural steroids, taking advantage of the appropriate stereochemistry of existing stereogenic centres [16][17][18][19][20]. However, the synthesis of target compounds is a multistep procedure, often including several protections and deprotections of functional groups. Our

A new and efficient methodology for olefin epoxidation catalyzed by supported cobalt nanoparticles

• Lucía Rossi-Fernández,
• Viviana Dorn and
• Gabriel Radivoy

Beilstein J. Org. Chem. 2021, 17, 519–526, doi:10.3762/bjoc.17.46

• a variety of alkenes as an interesting heterogeneous system. This cobalt oxide mesoporous nanomaterial showed good activity and selectivity to the epoxide product and could be recovered and reused, but the multistep (not straightforward) synthesis of the catalyst and the use of DMF as the solvent

Regioselective chemoenzymatic syntheses of ferulate conjugates as chromogenic substrates for feruloyl esterases

• Olga Gherbovet,
• Fernando Ferreira,
• Apolline Clément,
• Mélanie Ragon,
• Julien Durand,
• Sophie Bozonnet,
• Michael J. O'Donohue and
• Régis Fauré

Beilstein J. Org. Chem. 2021, 17, 325–333, doi:10.3762/bjoc.17.30

• biologically relevant substrates contain a feruloylated ʟ-arabinofuranosyl moiety [12][15][16][17]. These structurally more complex compounds are obtained using multistep syntheses, considerably limiting the availability. Moreover, they might be specific to certain subcategories of feruloyl esterases [18][19

• chromogenic 5-O-feruloylated α-ʟ-arabinofuranosides 1a and 1b is usually achieved using a multistep pathway that involves trapping the furanose conformation, anomeric activation, glycosidation, regioselective deprotection of the primary hydroxy group, feruloylation, and final deprotection to yield the target

• evaluation of 12 as a chromogenic substrate for Fae assays To synthesize chromogenic (±)-4-O-(2-hydroxy-4-nitrophenyl)-1-O-trans-feruloyl-1,2,4-butanetriol (4NTC–linker–Fe, 12), which contains 4NTC bound via a cleavable linker to a ferulate motif, a multistep route was devised (Scheme 1). First, a shorter

Direct synthesis of anomeric tetrazolyl iminosugars from sugar-derived lactams

• Michał M. Więcław and
• Bartłomiej Furman

Beilstein J. Org. Chem. 2021, 17, 115–123, doi:10.3762/bjoc.17.12

• first example of using Schwartz’s reagent-mediated partial reduction of lactams and the Ugi–azide multicomponent reaction in a tandem process. Yields of the described products are moderate to good, a satisfying result for such a multistep process. We have shown that such a reaction does not necessarily

Synthesis of tetrafluorinated piperidines from nitrones via a visible-light-promoted annelation reaction

• Vyacheslav I. Supranovich,
• Igor A. Dmitriev and
• Alexander D. Dilman

Beilstein J. Org. Chem. 2020, 16, 3104–3108, doi:10.3762/bjoc.16.260

• implies multistep protocols, since two distinct bond-forming reactions are necessary for the cycle formation. While mono- and difluorinated piperidines are well known, tetrafluorinated piperidines are rare [19]. At the same time, the chemistry of compounds containing the tetrafluoroethylene fragment

On the mass spectrometric fragmentations of the bacterial sesterterpenes sestermobaraenes A–C

• Anwei Hou and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2020, 16, 2807–2819, doi:10.3762/bjoc.16.231

• a multistep process (Scheme 6A). Starting from 3•+, a hydride shift to n3•+ and skeletal rearrangement lead to o3•+. A subsequent hydrogen rearrangement of this primary radical yields the tertiary radical p3•+ that can undergo an α-fragmentation to q3•+, followed by hydrogen rearrangement to r3

Synthesis and characterization of S,N-heterotetracenes

• Astrid Vogt,
• Florian Henne,
• Christoph Wetzel,
• Elena Mena-Osteritz and
• Peter Bäuerle

Beilstein J. Org. Chem. 2020, 16, 2636–2644, doi:10.3762/bjoc.16.214

• nitrogen heteroatoms were synthesized in multistep synthetic routes. A Buchwald–Hartwig amination of brominated precursors, thermolysis of azide precursors, and a Cadogan reaction of nitro-substituted precursors were successfully applied to eventually build-up pyrrole rings to stable and soluble fused

• application in organic electronics. Results and Discussion Synthesis of N-alkylated S,N-heterotetracene 9 by Pd-catalyzed amination. Asymmetric S,N-heterotetracene Hex-SN4 9 comprises the sequence of heteroatoms ‘SSNS’ in the tetracyclic conjugated π-system [37]. In a multistep synthesis, 2,6

• -heterotetracene system SN4'' comprising the heteroatom sequence ‘SNNS’ is built-up by annulation of two ‘outer’ thiophene and two ‘inner’ pyrrole rings resulting in the symmetric sequence of heteroatoms in the tetracyclic conjugated π-system. The multistep synthesis of Pr-SN4'' 33 started from 2

Tools for generating and analyzing glycan microarray data

• Akul Y. Mehta,
• Jamie Heimburg-Molinaro and
• Richard D. Cummings

Beilstein J. Org. Chem. 2020, 16, 2260–2271, doi:10.3762/bjoc.16.187

• comparison of glycan microarray data. We identify a variety of glycan microarray repositories where interested readers can find microarray data to build new software. We also highlight manual and automated data analysis tools. One must always be aware that the intrinsic complexity of the multistep process of

One-pot and metal-free synthesis of 3-arylated-4-nitrophenols via polyfunctionalized cyclohexanones from β-nitrostyrenes

• Haruyasu Asahara,
• Minami Hiraishi and
• Nagatoshi Nishiwaki

Beilstein J. Org. Chem. 2020, 16, 1830–1836, doi:10.3762/bjoc.16.150

• [8][9]. However, these nitration methods are less effective because the yield of the desired product is reduced by the formation of regioisomers. Although the hydroxylation of 3-arylated-1-fluoro-4-nitrobenzene has also been reported as a related strategy, multistep reactions are necessary for

Et₃N/DMSO-supported one-pot synthesis of highly fluorescent β-carboline-linked benzothiophenones via sulfur insertion and estimation of the photophysical properties

• Dharmender Singh,
• Vipin Kumar and
• Virender Singh

Beilstein J. Org. Chem. 2020, 16, 1740–1753, doi:10.3762/bjoc.16.146

• multistep syntheses. To overcome these drawbacks, elemental sulfur has emerged as a surrogate approach, where it can be inserted in situ. In this context, several research groups are actively involved in the development of novel and efficient approaches for the synthesis of sulfur-containing heterocycles

Microwave-assisted efficient one-pot synthesis of N²-(tetrazol-5-yl)-6-aryl/heteroaryl-5,6-dihydro-1,3,5-triazine-2,4-diamines

• Moustafa Sherief Moustafa,
• Ramadan Ahmed Mekheimer,
• Saleh Mohammed Al-Mousawi,
• Mohamed Abd-Elmonem,
• Hesham El-Zorba,
• Afaf Mohamed Abdel Hameed,
• Tahany Mahmoud Mohamed and
• Kamal Usef Sadek

Beilstein J. Org. Chem. 2020, 16, 1706–1712, doi:10.3762/bjoc.16.142

• a multistep synthesis route. A first approach relied on the nucleophilic substitution of chlorine in cyanuric chloride with Grignard reagents, ammonia or amines [25][26], which suffered from the high reactivity of the Grignard reagents that prevents further functionalization. Moreover, this protocol

Azidophosphonium salt-directed chemoselective synthesis of (E)/(Z)-cinnamyl-1H-triazoles and regiospecific access to bromomethylcoumarins from Morita–Baylis–Hillman adducts

• Soundararajan Karthikeyan,
• Radha Krishnan Shobana,
• Kamarajapurathu Raju Subimol,
• J. Helen Ratna Monica and
• Ayyanoth Karthik Krishna Kumar

Beilstein J. Org. Chem. 2020, 16, 1579–1587, doi:10.3762/bjoc.16.130

• ) acetylation, (ii) azidation, and (iii) cycloaddition to produce IV–VIII. In spite of the broad scope and synthetic utility, it is evident that the multistep synthetic methodology is the only existing module for cycloaddition reactions. Our research group is focused on developing one-pot synthetic

• transformations for complex molecules [29][30][31]. Two individual research groups have reported the multistep pathway to access the cinnamyl-1H-1,2,3-triazole derivatives IX from acetates of MBH adducts (Scheme 2) [32][33]. The other preferable moiety for triazole transformations is the allyl halide of MBH

One-step route to tricyclic fused 1,2,3,4-tetrahydroisoquinoline systems via the Castagnoli–Cushman protocol

• Aleksandar Pashev,
• Nikola Burdzhiev and
• Elena Stanoeva

Beilstein J. Org. Chem. 2020, 16, 1456–1464, doi:10.3762/bjoc.16.121

• enhances the treatment by sensitizing cancer cells to anticancer drugs [5]. The presence of such structural pattern has driven the development of various approaches for its obtaining – based either on isolation from naturally occurring sources or through multistep synthetic routes [6]. The pyrrolo[2,1-a

Fluorinated phenylalanines: synthesis and pharmaceutical applications

• Laila F. Awad and
• Mohammed Salah Ayoup

Beilstein J. Org. Chem. 2020, 16, 1022–1050, doi:10.3762/bjoc.16.91

• nitrile 48a with 30% HCl aq/acetic acid, gave the 4-fluorophenylalanine·HCl 49a in a good overall yield (67%) [47] (Scheme 11). 1.4. Hydrolysis of Erlenmeyer’s azalactone A multistep Erlenmeyer azalactone synthesis was reported as an important method for the synthesis of fluorinated α-amino acids 53a–h

• (126). Then, reaction of 127 (1.0 mmol) with 1.5/1.0 equiv of diethylaluminum cyanide (Et2AlCN)/iPrOH at −78 °C in THF gave nitrile 128. Deprotection of the latter, followed by hydrolysis of the nitrile group afforded syn-(2S,3S)-(+)-3-fluorophenylalanine (129) [65] (Scheme 28) . 2.3. Multistep

Combining enyne metathesis with long-established organic transformations: a powerful strategy for the sustainable synthesis of bioactive molecules

• Valerian Dragutan,
• Ileana Dragutan,
• Albert Demonceau and
• Lionel Delaude

Beilstein J. Org. Chem. 2020, 16, 738–755, doi:10.3762/bjoc.16.68

• and technologies [21][22][23][24][25][26][27][28][29][30]. Thus, numerous multistep total syntheses of organic compounds, including bioactive molecules [31][32][33][34][35] and natural products [36][37], have been performed in a highly chemo- and stereoselective manner through metathesis routes [38

Design and synthesis of diazine-based panobinostat analogues for HDAC8 inhibition

• Sivaraman Balasubramaniam,
• Sajith Vijayan,
• Liam V. Goldman,
• Xavier A. May,
• Kyra Dodson,
• Sweta Adhikari,
• Fatima Rivas,
• Davita L. Watkins and
• Shana V. Stoddard

Beilstein J. Org. Chem. 2020, 16, 628–637, doi:10.3762/bjoc.16.59

• inhibition activities comparable to that of panobinostat. Multistep syntheses afforded the visualized targets TOI1, TOI2, TOI3-rev and TOI4 whose biological evaluation confirmed the strength of HDAC8 inhibition with TOI4 displaying the greatest efficacy at varying concentrations. The results of this study

• developing single agent therapeutic hydroxamate derivatives, we began the synthesis of four leading HDAC8 diazine-based HDACis: TOI1, TOI2, TOI3-rev and TOI4 (Figure 1). Herein, we provide a summary of the design process followed by an outline of the multistep synthesis and preliminary biological evaluation