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

• in this review. C12 Dehydroxylation Chemical dehydroxylation UDCA can be obtained by a multistep chemical synthesis starting from CA. Two main steps are involved: the dehydroxylation at C12 and the epimerization of the 7-OH group. In order to achieve chemical dehydroxylation, firstly CA has to be

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

Transition-metal-free [3 + 3] annulation of indol-2-ylmethyl carbanions to nitroarenes. A novel synthesis of indolo[3,2-b]quinolines (quindolines)

• Michał Nowacki and
• Krzysztof Wojciechowski

Beilstein J. Org. Chem. 2018, 14, 194–202, doi:10.3762/bjoc.14.14

• as anticancer agents [1][6][7] (Figure 1). Synthetic strategies towards indolo[3,2-b]quinolines have been reviewed [8]. These methodologies usually employ multistep procedures. Selected starting materials applicable to the synthesis of indolo[3,2-b]quinolines are presented in Scheme 1. Bis(2

• -nitrobenzyl)malonate upon treatment with sodium hydroxide undergoes a multistep transformation resulting in 11-hydroxyindolo[3,2-b]quinoline-5-N-oxide (a) [9]. This approach is based on the first synthesis of the indolo[3,2-b]quinoline framework by Fichter and Boehringer in 1906 [10]. Indoxyl [11] and N,O

• (e) [15] and palladium(II) acetate-mediated oxidative cyclization of 3-(phenylamino)quinoline (f) afford quindoline [16]. Some of these syntheses require harsh conditions and multistep procedures. Another drawback of some of the known methodologies is the use of transition metal catalysts for the

Gram-scale preparation of negative-type liquid crystals with a CF₂CF₂-carbocycle unit via an improved short-step synthetic protocol

• Tatsuya Kumon,
• Shohei Hashishita,
• Takumi Kida,
• Shigeyuki Yamada,
• Takashi Ishihara and
• Tsutomu Konno

Beilstein J. Org. Chem. 2018, 14, 148–154, doi:10.3762/bjoc.14.10

• (VA)-type display materials. In spite of their valuable utility, synthetic procedures for generating the aforementioned CF2CF2-containing LC molecules inevitably require a multistep protocol, viz. eight steps for 1 and nine steps for 2, which is a substantial drawback for the practical application of

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

• carbon–halogen bond known [1]. Its low reactivity, in comparison to other C–X bonds, means that it is inert to all but the most harsh reaction conditions, and fluorine can generally be carried through multistep syntheses without concern over side reactions (the exception being SNAr reactions). In recent

• 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

Synthetic mRNA capping

• Fabian Muttach,
• Nils Muthmann and
• Andrea Rentmeister

Beilstein J. Org. Chem. 2017, 13, 2819–2832, doi:10.3762/bjoc.13.274

• multistep preparation of the triphosphate bridge, the Sekine group presented a synthetic route to RNA bearing a 5′-terminal TMG-capped pyrophosphate linkage on solid support. Since pyrophosphate formation is easier than triphosphate formation, this route resulted in higher coupling yields. Whether this RNA

CF₃SO₂X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation. Part 1: Use of CF₃SO₂Na

• Hélène Guyon,
• Hélène Chachignon and
• Dominique Cahard

Beilstein J. Org. Chem. 2017, 13, 2764–2799, doi:10.3762/bjoc.13.272

• . For the iodination step, the authors proposed that the β-CF3 alkyl radical was intercepted by I2, which was formed by a multistep redox process from I2O5. In continuation of this work, the same research group described the bromotrifluoromethylation of alkenes under similar reaction conditions but

•  29b) [51]. A single-electron oxidative free-radical process was ascertained for the generation of CF3•. From enynes, the iodination step was realised by I2, which was formed by a multistep redox process from I2O5. The intramolecular carbotrifluoromethylations of alkenes from acrylamides and

Preparation and isolation of isobenzofuran

• Morten K. Peters and
• Rainer Herges

Beilstein J. Org. Chem. 2017, 13, 2659–2662, doi:10.3762/bjoc.13.263

• vacuum pyrolysis and multistep syntheses of the precursors. The alternative way to synthesize IBF (1) is 1,4-elimination of 1,3-dihydro-1-methoxyisobenzofuran (7, DMIBF), which provides access to IBF (1) at ambient temperature [18]. Three methods have been published to prepare 7 (DMIBF). Reduction of

A semisynthesis of 3'-O-ethyl-5,6-dihydrospinosyn J based on the spinosyn A aglycone

• Kai Zhang,
• Shenglan Liu,
• Anjun Liu,
• Hongxin Chai,
• Jiarong Li and
• Lamusi A

Beilstein J. Org. Chem. 2017, 13, 2603–2609, doi:10.3762/bjoc.13.257

• aglycone and D-forosamine are complicated. Therefore, the aglycone and D-forosamine are obtained through a two-step hydrolysis process in our work. Preparation of 3-O-ethyl-2,4-di-O-methylrhamnose 3-O-Ethyl-2,4-di-O-methylrhamnose was synthesized from commercial rhamnose via a multistep process (Scheme 4

Consecutive hydrazino-Ugi-azide reactions: synthesis of acylhydrazines bearing 1,5-disubstituted tetrazoles

• Angélica de Fátima S. Barreto,
• Veronica Alves dos Santos and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2017, 13, 2596–2602, doi:10.3762/bjoc.13.256

• -amide bond. Furthermore, they can be used to pre-organize the amide bonds of peptides [9]. Most methods for the synthesis of tetrazoles have limitations that include multistep syntheses of starting materials and/or the use of expensive reagents. The most commonly used synthesis of 1,5-disubstituted

A concise flow synthesis of indole-3-carboxylic ester and its derivatisation to an auxin mimic

• Marcus Baumann,
• Ian R. Baxendale and
• Fabien Deplante

Beilstein J. Org. Chem. 2017, 13, 2549–2560, doi:10.3762/bjoc.13.251

• chemistry; heterocycle; hydrogenation; indole; multistep; Introduction Indoles are amongst the most important bioactive heterocyclic structures being commonly encountered in the amino acid tryptophan (1), the related neurotransmitter serotonin (2) as well as numerous complex alkaloid natural products and

• precursors in a multistep sequence prior to indole ring formation [7]. In order to address these potential shortcomings we set out to develop a benign process relying on inexpensive substrates and non-toxic reagents that would rapidly deliver the desired indole in a readily scalable and continuous fashion

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

Dialkyl dicyanofumarates and dicyanomaleates as versatile building blocks for synthetic organic chemistry and mechanistic studies

• Grzegorz Mlostoń and
• Heinz Heimgartner

Beilstein J. Org. Chem. 2017, 13, 2235–2251, doi:10.3762/bjoc.13.221

• dicyanofumarates and maleates as highly functionalized electron-deficient dipolarophiles, dienophiles and Michael acceptors is summarized. The importance for the studies on reaction mechanisms of cycloadditions is demonstrated. Multistep reactions with 1,2-diamines and β-aminoalcohols leading to diverse five- and

• exploration in mechanistic studies of their reactions. Similar to TCNE, these compounds are also attractive Michael acceptors with numerous applications for multistep reactions leading to heterocyclic products. The chemistry of E-1 and Z-1 has not been reviewed, and the goal of the present survey is to

• dimethyl 2,3-bis(hydroxyiminomethyl)fumarate with (CF3CO)2O in dioxane in the presence of pyridine at 0–10 °C [13]. The starting material was prepared in a multistep reaction from methyl β-nitropropanoate. An efficient method for the preparation of E-1b comprises the multistep reaction of dialkylselenonium

Main group mechanochemistry

• Agota A. Gečiauskaitė and
• Felipe García

Beilstein J. Org. Chem. 2017, 13, 2068–2077, doi:10.3762/bjoc.13.204

• methods (see Scheme 3).· Also noteworthy is the multistep solvent-free mechanochemical route to indium(III) complexes featuring aryl bis(imino)acenaphthene (Ar-BIAN) ligands [84]. Ar-BIAN ligands are versatile π-acceptors and have been widely employed for catalysis. These ligands are typically synthesised

• completion. A rare example of a one-pot multistep ball milling reaction is the case of an electron-rich aniline derivative that produced 4 in good yield without the need for ligand isolation. Previously reported examples typically employ “preformed” ligands and metal complexes [68][86], raising the

• orthogonality of multistep mechanochemical synthesis and widening its applicability. A significant example of the transformative potential of mechanochemistry is its ability to produce metal complexes directly from bulk metal or metal oxides [66]. Within this context, the LAG synthesis of germanes (GeR4

Intramolecular glycosylation

• Xiao G. Jia and
• Alexei V. Demchenko

Beilstein J. Org. Chem. 2017, 13, 2028–2048, doi:10.3762/bjoc.13.201

• has also made these methodologies more attractive for use in more complicated multistep syntheses. Despite the advancements made, there are still no definitive rules on why small changes may affect the stereochemical outcomes so dramatically. There is a greater need to study the underlying concepts

Solvent-free and room temperature synthesis of 3-arylquinolines from different anilines and styrene oxide in the presence of Al₂O₃/MeSO₃H

• Hashem Sharghi,
• Mahdi Aberi,
• Mohsen Khataminejad and
• Pezhman Shiri

Beilstein J. Org. Chem. 2017, 13, 1977–1981, doi:10.3762/bjoc.13.193

• ]. Transition metal-catalyzed processes [5][6][7][8] and metal-free paths [9][10][11] are two general approaches for the synthesis of this type of compounds. However, the existing methods suffer from complicated multistep processes, limited availability of substrates, toxic organic solvents, long reaction times

High-speed vibration-milling-promoted synthesis of symmetrical frameworks containing two or three pyrrole units

• Marco Leonardi,
• Mercedes Villacampa and
• J. Carlos Menéndez

Beilstein J. Org. Chem. 2017, 13, 1957–1962, doi:10.3762/bjoc.13.190

• proved to be useful include the protease of the human immunodeficiency virus HIV [1], cellular prion protein, PrPc [2], and the transient receptor potential melastatin 8 (TRPM8) channel receptor [3]. The synthesis of these symmetrical molecules normally relies on multistep sequences. Due to the special

One-pot multistep mechanochemical synthesis of fluorinated pyrazolones

• Joseph L. Howard,
• William Nicholson,
• Yerbol Sagatov and
• Duncan L. Browne

Beilstein J. Org. Chem. 2017, 13, 1950–1956, doi:10.3762/bjoc.13.189

• solvent-based processes. Herein, we describe a methodical process to run one solventless reaction directly into another through multistep mechanochemistry, effectively amplifying the solvent savings. The approach has to consider the solid form of the materials and compatibility of any auxiliary used. This

• ; mechanochemistry; multistep; solid-state synthesis; Introduction Mechanochemical methods are emerging as an alternative approach to traditional solvent-based reactions for chemical synthesis. Under mechanochemical conditions reactions are performed between neat reagents and do not require a solvent. Processing

• an up to date tool for synthesis is to gain a better insight into the ability to run multistep procedures. One-pot multistep procedures are particularly efficient, in that the same reaction vessel is used for each step, additional reagents are simply added to the reaction mixture at each stage with

Mechanochemical synthesis of small organic molecules

• Tapas Kumar Achar,
• Anima Bose and
• Prasenjit Mal

Beilstein J. Org. Chem. 2017, 13, 1907–1931, doi:10.3762/bjoc.13.186

• ]. b) Multistep and multicomponent synthesis of Re-complexes [176]. c) Mechano-synthesis of NHC-Au complex [177]. Mechanochemical activation of C–H bond of unsymmetrical azobenzene [178]. Mechanochemical synthesis of organometallic pincer complex [179]. Mechanochemical synthesis of tris(allyl)aluminum

Development of a method for the synthesis of 2,4,5-trisubstituted oxazoles composed of carboxylic acid, amino acid, and boronic acid

• Kohei Yamada,
• Naoto Kamimura and
• Munetaka Kunishima

Beilstein J. Org. Chem. 2017, 13, 1478–1485, doi:10.3762/bjoc.13.146

• materials, such as α-haloketones and primary amides [8], alkynes and nitriles [9], amines and α,β-unsaturated carbonyl compounds [10], etc. [11] have been reported. However, these reactions are often conducted under harsh reaction conditions and multistep syntheses of the starting materials are needed. ii

• ) The functionalization method: various regioselective metalations and subsequent functionalizations of the oxazole core skeleton using Cu [12], Pd [13], Mg [14], Zn [14], etc. [15] have been developed. This linear synthetic approach inevitably requires multistep processes and often needs

One-pot synthesis of block-copolyrotaxanes through controlled rotaxa-polymerization

• Jessica Hilschmann,
• Gerhard Wenz and
• Gergely Kali

Beilstein J. Org. Chem. 2017, 13, 1310–1315, doi:10.3762/bjoc.13.127

• polyrotaxanes was already investigated in the fields of biomedicine, as drug [22] or gene [23] delivery vehicles, or in materials sciences, as slide ring gels [6]. Polyrotaxanes are mostly synthesized by a threading approach [2], a multistep method starting from pre-synthesized (co)polymers. Due to the

• dethreading already takes place. This multistep reaction methodology hinders the large-scale production and broad application of these materials. Recently our group has developed a method for a simple and environmentally friendly synthesis of polyrotaxanes. This, so called rotaxa-polymerization, is an aqueous

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

• ]. On the other hand, the disadvantage is the need to synthesize NDP-sugars as substrates for the GT which is typically a multistep laborious process. Another particularly interesting application of glycosyltransferases is the chemoenzymatic synthesis of nucleosides. This is an incredibly powerful tool

• 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

An eco-compatible strategy for the diversity-oriented synthesis of macrocycles exploiting carbohydrate-derived building blocks

• Sushil K. Maurya and
• Rohit Rana

Beilstein J. Org. Chem. 2017, 13, 1106–1118, doi:10.3762/bjoc.13.110

• synthesis of sugar-embedded glycoconjugates [52][53]. Further, the linear syntheses of macrocycles based on multistep protocols are not cost-effective and the development of efficient, sustainable, greener and economical methods is highly desired. Synthetic methods to produce a diverse collection of

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

• The implementation of automation in the multistep flow synthesis is essential for transforming laboratory-scale chemistry into a reliable industrial process. In this review, we briefly introduce the role of automation based on its application in synthesis viz. auto sampling and inline monitoring

• , optimization and process control. Subsequently, we have critically reviewed a few multistep flow synthesis and suggested a possible control strategy to be implemented so that it helps to reliably transfer the laboratory-scale synthesis strategy to a pilot scale at its optimum conditions. Due to the vast

• 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