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

• 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

Regioselectively α- and β-alkynylated BODIPY dyes via gold(I)-catalyzed direct C–H functionalization and their photophysical properties

• Takahide Shimada,
• Shigeki Mori,
• Masatoshi Ishida and
• Hiroyuki Furuta

Beilstein J. Org. Chem. 2020, 16, 587–595, doi:10.3762/bjoc.16.53

• ], and borylation [32]), has been in great demand recently rather than the conventional multistep synthesis with nucleophilic substitution/cross-coupling via halogenation of BODIPYs [33] or from the activated precursors [34] via unstable pyrrolic intermediates. In particular, halogenation (e.g

Understanding the role of active site residues in CotB2 catalysis using a cluster model

• Keren Raz,
• Ronja Driller,
• Thomas Brück,
• Bernhard Loll and
• Dan T. Major

Beilstein J. Org. Chem. 2020, 16, 50–59, doi:10.3762/bjoc.16.7

• , Dept. of Chemistry, Technical University of Munich (TUM), Lichtenbergstr. 4, 85748 Garching, Germany 10.3762/bjoc.16.7 Abstract Terpene cyclases are responsible for the initial cyclization cascade in the multistep synthesis of a large number of terpenes. CotB2 is a diterpene cyclase from Streptomyces

N-(1-Phenylethyl)aziridine-2-carboxylate esters in the synthesis of biologically relevant compounds

• Iwona E. Głowacka,
• Aleksandra Trocha,
• Andrzej E. Wróblewski and
• Dorota G. Piotrowska

Beilstein J. Org. Chem. 2019, 15, 1722–1757, doi:10.3762/bjoc.15.168

• N-(1-phenylethyl)aziridine-2-methanols 7 Aziridine alcohols 7 are usually prepared by LiAlH4 reduction of the corresponding esters 5 [22][35][36] although a milder method with a NaBH4 and LiCl mixture was also elaborated [37]. A multistep synthesis of (2S,1'R)-7 employing the aziridine ring closure

Selenophene-containing heterotriacenes by a C–Se coupling/cyclization reaction

• Pierre-Olivier Schwartz,
• Sebastian Förtsch,
• Astrid Vogt,
• Elena Mena-Osteritz and
• Peter Bäuerle

Beilstein J. Org. Chem. 2019, 15, 1379–1393, doi:10.3762/bjoc.15.138

• preparation, efficient multistep synthesis routes with good overall yields based on recently published transition metal-catalyzed C–S and C–Se coupling/cyclization reactions in the crucial cyclization steps of iodinated bithiophene and biselenophene precursors. Heterotriacenes 1–4 turned out to be stable and

Mechanochemistry of supramolecules

• Anima Bose and
• Prasenjit Mal

Beilstein J. Org. Chem. 2019, 15, 881–900, doi:10.3762/bjoc.15.86

• liberation of undesired byproducts [34][35]. In literature, classical small organic molecules’ synthesis has been well explored which includes multistep synthesis [36][37][38][39]. However, the concept of supramolecular chemistry under mechano-milling conditions only has limited number of examples [40][41

Synthesis of a novel category of pseudo-peptides using an Ugi three-component reaction of levulinic acid as bifunctional substrate, amines, and amino acid-based isocyanides

• Maryam Khalesi,
• Azim Ziyaei Halimehjani and
• Jürgen Martens

Beilstein J. Org. Chem. 2019, 15, 852–857, doi:10.3762/bjoc.15.82

• ; multicomponent; pseudo-peptides; Ugi reaction; Introduction The multistep synthesis of complex molecules normally requires a large number of repetitive synthetic operations, such as extraction, separation, chromatography and other purification steps. These disadvantages encouraged chemists to synthesize complex

Synthesis of nonracemic hydroxyglutamic acids

• Dorota G. Piotrowska,
• Iwona E. Głowacka,
• Andrzej E. Wróblewski and
• Liwia Lubowiecka

Beilstein J. Org. Chem. 2019, 15, 236–255, doi:10.3762/bjoc.15.22

• of the alkaloid hemerocallisamine skeleton [37], its tert-butyl counterpart was used as a starting material in a multistep synthesis of a functionalized exo-methylenecyclopentane skeleton as an entecavir intermediate [116]. On the other hand, the stereospecific alkylation of methyl (2R,4R)-4

Ruthenium-based olefin metathesis catalysts with monodentate unsymmetrical NHC ligands

• Veronica Paradiso,
• Chiara Costabile and
• Fabia Grisi

Beilstein J. Org. Chem. 2018, 14, 3122–3149, doi:10.3762/bjoc.14.292

• metathesis of 96 (Table 4, entries 8 and 9, respectively). Indeed, the one-step multicomponent synthesis of unsaturated unsymmetrical NHCs could provide a cost-effective alternative to the multistep synthesis of their saturated counterparts [36]. The catalyst 85 was identified as the catalyst of choice for

Enhanced single-isomer separation and pseudoenantiomer resolution of new primary rim heterobifunctionalized α-cyclodextrin derivatives

• Iveta Tichá,
• Gábor Benkovics,
• Milo Malanga and
• Jindřich Jindřich

Beilstein J. Org. Chem. 2018, 14, 2829–2837, doi:10.3762/bjoc.14.261

• indirect method generally led to selectively homobifunctionalized CDs. In contrast, heterobifunctionalized CDs have been prepared via multistep synthesis (depending on the steric hindrance of the moiety on the CD scaffold and on the bulkiness of reagents [22]) or by modification of homobifunctionalized CDs

Molecular iodine-catalyzed one-pot multicomponent synthesis of 5-amino-4-(arylselanyl)-1H-pyrazoles

• Camila S. Pires,
• Daniela H. de Oliveira,
• Maria R. B. Pontel,
• Jean C. Kazmierczak,
• Roberta Cargnelutti,
• Diego Alves,
• Raquel G. Jacob and
• Ricardo F. Schumacher

Beilstein J. Org. Chem. 2018, 14, 2789–2798, doi:10.3762/bjoc.14.256

• /direct selanylation is a practical and economical way to incorporate organylselanyl moieties in aryl and heteroaryl compounds avoiding the necessity of pre-functionalization, multistep synthesis and tedious work-up [4][5]. In this context, the preparation of diverse selanylated indoles and

Microwave-assisted synthesis of biologically relevant steroidal 17-exo-pyrazol-5'-ones from a norpregnene precursor by a side-chain elongation/heterocyclization sequence

• Gergő Mótyán,
• László Mérai,
• Márton Attila Kiss,
• Zsuzsanna Schelz,
• Izabella Sinka,
• István Zupkó and
• Éva Frank

Beilstein J. Org. Chem. 2018, 14, 2589–2596, doi:10.3762/bjoc.14.236

• . This indicates that the pyrazolone heterocyclic ring at the 17β position is a promising scaffold for the design of anticancer agents of the Δ5 androstene series. 1H NMR spectra of compound 7f in CDCl3 (top; # solvent signal) and in DMSO-d6 (bottom; # solvent signal). Multistep synthesis of steroidal β

Assessing the possibilities of designing a unified multistep continuous flow synthesis platform

• Mrityunjay K. Sharma,
• Roopashri B. Acharya,
• Chinmay A. Shukla and
• Amol A. Kulkarni

Beilstein J. Org. Chem. 2018, 14, 1917–1936, doi:10.3762/bjoc.14.166

• unified flow synthesis platform that can facilitate multistep synthesis involving a wider range of reactions over a varied range of conditions. Such a platform would help to reduce the time in planning of experimental set-ups for individual reaction(s) or sequences and will also help to do a seamless

• of the challenges are as follows: A varied range of conditions: A multistep synthesis platform developed for one target molecule cannot always be utilized for different products since each product either requires different chemistry or a different set of unit operations or unit operation sequences

• /solvents/byproducts. Even the change in the sequence should be adaptable such a system can be very expensive as well. Skills: With the advent of many flow synthesis tools available in the market much of the above issues may be taken care of. However, the automation in multistep synthesis needs careful

One hundred years of benzotropone chemistry

• Arif Dastan,
• Haydar Kilic and
• Nurullah Saracoglu

Beilstein J. Org. Chem. 2018, 14, 1120–1180, doi:10.3762/bjoc.14.98

• the dibromides 24 and 25 are the result of the addition of HBr, which is formed under the reaction conditions. 2.1.2. Multistep synthesis of 4,5-benzotropone (11): The first multistep synthesis for 4,5-benzotropone (11) is the original procedure described by Thiele, Schneider, and Weitz, which

• rather than the 1,2-double bond to 1-methoxynaphthalene (310). The position of the halogen substituent in 311 and 312 was also determined by the cycloadducts 320 and 321 between 5-halo-2,3-benzotropones and maleic anhydride (Figure 14) [185][187]. 6.1.2. Multistep synthesis via dihalocarbene addition: As

Heterogeneous Pd catalysts as emulsifiers in Pickering emulsions for integrated multistep synthesis in flow chemistry

• Katharina Hiebler,
• Georg J. Lichtenegger,
• Manuel C. Maier,
• Eun Sung Park,
• Renie Gonzales-Groom,
• Bernard P. Binks and
• Heidrun Gruber-Woelfler

Beilstein J. Org. Chem. 2018, 14, 648–658, doi:10.3762/bjoc.14.52

• is also suitable for the multistep synthesis of 1 and 2. Therefore, the so-called plug & play reactor, a versatile device featuring both exchangeable reaction segments and modules for heating/cooling and mixing [38], was employed to test the activity and stability of the catalysts in continuous flow

• potential for realising other reactions of interest to produce pharmaceutical and fine chemical intermediates in continuous flow, including the multistep synthesis of valsartan (1) and sacubitril (2). In addition to the approach with the compartmentalised catalysts in Pickering emulsions and thus the usage

• for oral pharmaceuticals. Furthermore, the palladium catalysts proved to be stable for more than 30 h in continuous flow using the so-called plug & play reactor. Since this device can feature multiple HPLC columns, it can also be used for multistep synthesis as planned for the APIs valsartan and

Continuous multistep synthesis of 2-(azidomethyl)oxazoles

• Thaís A. Rossa,
• Nícolas S. Suveges,
• Marcus M. Sá,
• David Cantillo and
• C. Oliver Kappe

Beilstein J. Org. Chem. 2018, 14, 506–514, doi:10.3762/bjoc.14.36

Latest development in the synthesis of ursodeoxycholic acid (UDCA): a critical review

• Fabio Tonin and
• Isabel W. C. E. Arends

Beilstein J. Org. Chem. 2018, 14, 470–483, doi:10.3762/bjoc.14.33

• for this multistep synthesis will be discussed. Review Precursor availability Bile acids The most important active ingredients of bile are the bile acids. Together with their salts, they allow the emulsification of lipids, a fundamental step for their absorption and digestion. Bile acids are 24-carbon

One-pot sequential synthesis of tetrasubstituted thiophenes via sulfur ylide-like intermediates

• Jun Ki Kim,
• Hwan Jung Lim,
• Kyung Chae Jeong and
• Seong Jun Park

Beilstein J. Org. Chem. 2018, 14, 243–252, doi:10.3762/bjoc.14.16

• tetrasubstituted thiophenes via the intramolecular cyclization of S-alkylated heterocyclic–aryl dithioesters [56]. However, these approaches are limited by the multistep synthesis (Figure 2A) [54][55] and the complicated dithioester preparation (Figure 2B) [56]. In general, tetrasubstituted thiophenes have

Stereochemical outcomes of C–F activation reactions of benzyl fluoride

• Neil S. Keddie,
• Pier Alexandre Champagne,
• Justine Desroches,
• Jean-François Paquin and
• David O'Hagan

Beilstein J. Org. Chem. 2018, 14, 106–113, doi:10.3762/bjoc.14.6

• years, there has been an increasing interest in C–F bond activation [2], with a view to using organic bound fluoride as a leaving group in substitution reactions that typically require more activated leaving groups. Such an approach could circumvent the requirement for protecting groups in multistep

• synthesis by capitalizing on the low reactivity of the C–F bond. Paquin et al. have published extensively on non-metal based methods for benzylic C–F bond activation [3][4][5][6][7]. The reactivity relies on protic activation driven by the capacity of organic fluoride to form hydrogen bonds [8][9

Exploring mechanochemistry to turn organic bio-relevant molecules into metal-organic frameworks: a short review

• Vânia André,
• Sílvia Quaresma,
• João Luís Ferreira da Silva and
• M. Teresa Duarte

Beilstein J. Org. Chem. 2017, 13, 2416–2427, doi:10.3762/bjoc.13.239

• bioactive molecules is achieved by degradation of the framework, ii) no multistep synthesis is required as the molecules are part of the matrix itself, iii) synergetic effects between the active molecule and the metal may be explored, and iv) co-delivery of drugs is possible if a porous network is built

Synthesis, effect of substituents on the regiochemistry and equilibrium studies of tetrazolo[1,5-a]pyrimidine/2-azidopyrimidines

• Elisandra Scapin,
• Paulo R. S. Salbego,
• Caroline R. Bender,
• Alexandre R. Meyer,
• Anderson B. Pagliari,
• Tainára Orlando,
• Geórgia C. Zimmer,
• Clarissa P. Frizzo,
• Helio G. Bonacorso,
• Nilo Zanatta and
• Marcos A. P. Martins

Beilstein J. Org. Chem. 2017, 13, 2396–2407, doi:10.3762/bjoc.13.237

• formed from 5-aminotetrazole, such as 1,3-binucleophile synthons, have not been sufficiently discussed [17]. Today, several existing methods are known to have several disadvantages, including long reaction time, the use of harmful solvents, and multistep synthesis [18][19]. Moreover, researchers in the

Strategies toward protecting group-free glycosylation through selective activation of the anomeric center

• A. Michael Downey and
• Michal Hocek

Beilstein J. Org. Chem. 2017, 13, 1239–1279, doi:10.3762/bjoc.13.123

• SN2-like reaction (Scheme 9). The most unfortunate drawbacks of the procedure include the need for a large excess of the alcohol acceptor and the multistep synthesis of the galactosyl donor. The synthesis of the monoprotected activated galactosyl donor requires the use of protecting groups, however

• furanosides. These may find application as enzyme substrates and possibly as inhibitors in several bacterial diseases, as well as in solid-phase-oligosaccharide synthesis, as shown. However, the main drawback is still the multistep synthesis of these anomeric activating donors. 3.2 Self-activation of the

Automating multistep flow synthesis: approach and challenges in integrating chemistry, machines and logic

• Chinmay A. Shukla and
• Amol A. Kulkarni

Beilstein J. Org. Chem. 2017, 13, 960–987, doi:10.3762/bjoc.13.97

• literature in multistep synthesis, we have classified the literature and have identified the case studies based on few criteria viz. type of reaction, heating methods, processes involving in-line separation units, telescopic synthesis, processes involving in-line quenching and process with the smallest time

• scale of operation. This classification will cover the broader range in the multistep synthesis literature. Keywords: automation; control strategy; flow chemistry; in-line monitoring; multistep synthesis optimization; Introduction Multistep flow synthesis In the recent time the concept of flow

• complexity of synthesis depends upon the method and/or a number of steps and/or specific functional activity, etc. Most of the useful synthetic organic compounds involve a series of chemical transformations of very different nature, which can be termed simply as ‘multistep synthesis’. The final products can

Contribution of microreactor technology and flow chemistry to the development of green and sustainable synthesis

• Flavio Fanelli,
• Giovanna Parisi,
• Leonardo Degennaro and
• Renzo Luisi

Beilstein J. Org. Chem. 2017, 13, 520–542, doi:10.3762/bjoc.13.51

• produce enantioenriched materials were employed. It is worth mentioning that this work represents a very nice example on the use of chiral catalysis in a multistep flow synthesis of a drug target on gram scale. The multistep synthesis of (S)-rolipram reported in Scheme 23 begins from a benzaldehyde

• very compact in size [1.0 m × 0.7 m × 1.8 m, (W × L × H)], and low-weighing (about 100 kg) and was able to perform complex multistep synthesis, work-up procedures as well as purification operations such as crystallization. This platform was also equipped with devices for real-time monitoring and final

• artemisinic acid. Flow reactor system for multistep synthesis of (S)-rolipram. Pumps are labelled a, b, c, d and e; Labels A, B, C, D, E and F are flow lines. X are molecular sieves; Y is Amberlyst 15Dry; Z is Celite. (Reproduced with permission from [84], copyright 2015 Nature Publishing Group).

Continuous-flow synthesis of highly functionalized imidazo-oxadiazoles facilitated by microfluidic extraction

• Ananda Herath and
• Nicholas D. P. Cosford

Beilstein J. Org. Chem. 2017, 13, 239–246, doi:10.3762/bjoc.13.26

• -oxadiazoles starting from carboxylic acids is reported. This process was applied to the multistep synthesis of imidazo[1,2-a]pyridin-2-yl-1,2,4-oxadiazoles, using a three reactor, multistep continuous-flow system without isolation of intermediates. This continuous-flow method was successfully combined with a