Chemical synthesis of tripeptide thioesters for the biotechnological incorporation into the myxobacterial secondary metabolite argyrin via mutasynthesis

• David C. B. Siebert,
• Roman Sommer,
• Domen Pogorevc,
• Michael Hoffmann,
• Silke C. Wenzel,
• Rolf Müller and
• Alexander Titz

Beilstein J. Org. Chem. 2019, 15, 2922–2929, doi:10.3762/bjoc.15.286

• possibility resides in the dehydroalanine-sarcosine motif and modification seems possible as deduced from the crystal structure [11] of argyrin with elongation factor G1. Despite the successful implementation of total syntheses of argyrin derivatives, a more rapid access towards diversity in the argyrins and

• the resulting structure–activity relationship knowledge is desirable. Besides the chemical total synthesis, argyrins can be obtained from the producer organism in sufficient amounts and purity but lack the diversity desired for an extended structure–activity relationship to develop lead candidates. It

Bacterial terpene biosynthesis: challenges and opportunities for pathway engineering

• Eric J. N. Helfrich,
• Geng-Min Lin,
• Christopher A. Voigt and
• Jon Clardy

Beilstein J. Org. Chem. 2019, 15, 2889–2906, doi:10.3762/bjoc.15.283

• metabolites on the planet. To date more than 70,000 terpenoids (dictionary of natural products) have been characterized and grouped into more than 400 structural families – the vast majority of which have been isolated from plants and fungi [1]. Their structural diversity reflects the breadth of their

• restricted members possess significant biological activities, like the anticancer agent taxol (1) [4] or the antimalarial agent artemisinin (2, Figure 1) [5][6]. The structural diversity and functional utility of this class of specialized metabolites have combined to encourage efforts to apply the tools of

• synthetic biology to engineer pathways that will expand molecular diversity, especially around scaffolds associated with high-value compounds. The biosynthetic logic of terpene formation differs significantly from the logic employed by other classes of secondary metabolite biosynthetic pathways. Bacterial

Emission and biosynthesis of volatile terpenoids from the plasmodial slime mold Physarum polycephalum

• Xinlu Chen,
• Tobias G. Köllner,
• Wangdan Xiong,
• Guo Wei and
• Feng Chen

Beilstein J. Org. Chem. 2019, 15, 2872–2880, doi:10.3762/bjoc.15.281

• communication [1][2]. Rapid progress has been made in our understanding of the VOC world of microbes, especially bacteria [3][4] and fungi [5][6]. Not only the chemical diversity of microbial VOCs is continuingly to be discovered, our understanding of their biosynthesis is also growing rapidly [7][8]. Among the

• for studying a diversity of topics [19][20][21], ranging from cytoplasmic streaming to primitive intelligence [22]. In a manuscript deposited at arXiv [23], it was described that complex mixtures of volatiles including some terpenoids were detected from the headspace of P. polycephalum using two

Facile regiodivergent synthesis of spiro pyrrole-substituted pseudothiohydantoins and thiohydantoins via reaction of [e]-fused 1H-pyrrole-2,3-diones with thiourea

• Aleksandr I. Kobelev,
• Nikita A. Tretyakov,
• Ekaterina E. Stepanova,
• Maksim V. Dmitriev,
• Michael Rubin and
• Andrey N. Maslivets

Beilstein J. Org. Chem. 2019, 15, 2864–2871, doi:10.3762/bjoc.15.280

• good yields, and the products were isolated without applying preparative chromatography methods. Keywords: diversity-oriented synthesis; hydantoin; nitrogen heterocycles; rearrangement; thiourea; Introduction Hydantoin (imidazolidine-2,4-dione) derivatives are omnipresent among biologically active

• success [19]. Thus, recent development of 3D modelling methods facilitated investigations on the importance of 3D properties of small-molecular drug candidates [20][21][22] and inspired chemists to develop diversity-oriented methods for complex 3D molecules [23][24]. Considering that to the best of our

• facile preparation of libraries of heterocyclic molecules with an emphasis on skeletal diversity from a single set of reagents [25][26][27]. One of the most intriguing chemical properties of FPDs 1 is their ability to undergo a cyclocondensation with 1,3-binucleophilic reagents to form spiro[4.4

Chemical tuning of photoswitchable azobenzenes: a photopharmacological case study using nicotinic transmission

• Lorenzo Sansalone,
• Jun Zhao,
• Matthew T. Richers and
• Graham C. R. Ellis-Davies

Beilstein J. Org. Chem. 2019, 15, 2812–2821, doi:10.3762/bjoc.15.274

• )AChR. The structural difference between the native acetylcholine and nicotine are striking, and their diversity reflects the complexity of structure–activity relationships of ligands for nicotinic acetylcholine receptors. For example, the drug homocholine phenyl ether (HoChPE) is an agonist of the

Diversity-oriented synthesis of spirothiazolidinediones and their biological evaluation

• Sambasivarao Kotha,
• Gaddamedi Sreevani,
• Lilya U. Dzhemileva,
• Milyausha M. Yunusbaeva,
• Usein M. Dzhemilev and
• Vladimir A. D’yakonov

Beilstein J. Org. Chem. 2019, 15, 2774–2781, doi:10.3762/bjoc.15.269

Emission solvatochromic, solid-state and aggregation-induced emissive α-pyrones and emission-tuneable 1H-pyridines by Michael addition–cyclocondensation sequences

• Natascha Breuer,
• Irina Gruber,
• Christoph Janiak and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2019, 15, 2684–2703, doi:10.3762/bjoc.15.262

• molecular aggregation in the solid state causes fluorescence quenching [16]. In recent years, we have coined diversity-oriented syntheses of functional chromophores by multicomponent strategies [17][18], opening accesses to substance libraries for systematic studies of structure–property relationships on

Combining the Ugi-azide multicomponent reaction and rhodium(III)-catalyzed annulation for the synthesis of tetrazole-isoquinolone/pyridone hybrids

• Gerardo M. Ojeda,
• Prabhat Ranjan,
• Pavel Fedoseev,
• Lisandra Amable,
• Upendra K. Sharma,
• Daniel G. Rivera and
• Erik V. Van der Eycken

Beilstein J. Org. Chem. 2019, 15, 2447–2457, doi:10.3762/bjoc.15.237

• rhodium catalyst to promote C(sp2)–H activation in the presence of a suitable directing group. The Ugi-azide reaction provides broad molecular diversity and enables the introduction of the tetrazole moiety, which may further assist the catalytic reaction by coordinating the metal center. The scope of the

• incorporation of three different diversity-generating sites (Scheme 1A), a feature that has been exploited for the construction of libraries of tetrazole-based compounds with potential bioactivity [9][10][11][12][19]. A powerful approach for obtaining hybrid heterocyclic compounds including the tetrazole ring

• /pyridone hybrids by means of a reaction sequence comprising an Ugi-azide-4CR and a Rh(III)-catalyzed annulation as key steps (Scheme 1D). Results and Discussion In previous works, our group has described a variety of synthetic approaches that combine the diversity-generating character of multicomponent

Current understanding and biotechnological application of the bacterial diterpene synthase CotB2

• Ronja Driller,
• Daniel Garbe,
• Norbert Mehlmer,
• Monika Fuchs,
• Keren Raz,
• Dan Thomas Major,
• Thomas Brück and
• Bernhard Loll

Beilstein J. Org. Chem. 2019, 15, 2355–2368, doi:10.3762/bjoc.15.228

• , antibiotic, neuroprotective and even insecticidal activities, which makes these compounds high-value commercial targets for the chemical and pharmaceutical industry [9][10]. Structural diversity of diterpenes is created by the terpene synthase (TPS) enzyme family, which use acyclic isoprenoid precursors to

• cytochromes, CotB3 and CotB4, to cyclooctatin (5). Depending on the functionalization of the ring system, the compounds demonstrate a broad diversity of biological activities, among others fungicidal or tumor static [32][43][44][45]. Cyclooctatin (5) inhibits a lysophospholipase, which catalyzes the

Synthesis of acremines A, B and F and studies on the bisacremines

• Nils Winter and
• Dirk Trauner

Beilstein J. Org. Chem. 2019, 15, 2271–2276, doi:10.3762/bjoc.15.219

• be derived from two acremine F (5) units by a formal [4 + 2] cycloaddition followed by condensation and oxidation. Given the diversity and structural beauty of this class of natural products, it is not surprising that the acremine family has attracted the attention of the synthetic community [6][7][8

Recent advances in transition-metal-catalyzed incorporation of fluorine-containing groups

• Xiaowei Li,
• Xiaolin Shi,
• Xiangqian Li and
• Dayong Shi

Beilstein J. Org. Chem. 2019, 15, 2213–2270, doi:10.3762/bjoc.15.218

Isolation of fungi using the diffusion chamber device FIND technology

• Benjamin Libor,
• Henrik Harms,
• Stefan Kehraus,
• Ekaterina Egereva,
• Max Crüsemann and
• Gabriele M. König

Beilstein J. Org. Chem. 2019, 15, 2191–2203, doi:10.3762/bjoc.15.216

• play a prominent role as lead structures in drug discovery [1]. Apart from bacteria, fungi are an impressive group of microorganisms in this respect, due to the high structural diversity of their rich secondary metabolism. Fungi are known as producers of many therapeutically important drugs, such as

Isolation and characterisation of irinans, androstane-type withanolides from Physalis peruviana L.

• Annika Stein,
• Dave Compera,
• Bianka Karge,
• Mark Brönstrup and
• Jakob Franke

Beilstein J. Org. Chem. 2019, 15, 2003–2012, doi:10.3762/bjoc.15.196

• Withanolides are steroidal lactones widespread in Nightshade plants with often potent antiproliferative activities. Additionally, the structural diversity of this compound class holds much potential for the discovery of novel biological activity. Here, we report two newly characterised withanolides, named

Identification of optimal fluorescent probes for G-quadruplex nucleic acids through systematic exploration of mono- and distyryl dye libraries

• Xiao Xie,
• Michela Zuffo,
• Marie-Paule Teulade-Fichou and
• Anton Granzhan

Beilstein J. Org. Chem. 2019, 15, 1872–1889, doi:10.3762/bjoc.15.183

• fluorescence enhancement with any of the analytes). Can it be considered as a general rule? Considering the significant structural diversity of our library and the related works [41][49], this is highly probable, with regard to mono- and distyryl scaffolds. This implies that styryl-based fluorescent probes

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

• new compounds will be shown to underscore their biological potency. In a few cases mechanistic considerations will be presented to clarify the structural diversity of the products resulted from openings of the aziridine ring. This review was intended to cover the entire literature including patents on

Recent advances on the transition-metal-catalyzed synthesis of imidazopyridines: an updated coverage

• Gagandeep Kour Reen,
• Ashok Kumar and
• Pratibha Sharma

Beilstein J. Org. Chem. 2019, 15, 1612–1704, doi:10.3762/bjoc.15.165

• development and (ii) for the modifications needed thereof in the R&D sector. Keywords: C–H activation/functionalization; coupling reactions; imidazopyridines; multicomponent reactions; transition metal catalysis; Introduction The structural diversity and biological importance of nitrogen-containing

Molecular basis for the plasticity of aromatic prenyltransferases in hapalindole biosynthesis

• Takayoshi Awakawa and
• Ikuro Abe

Beilstein J. Org. Chem. 2019, 15, 1545–1551, doi:10.3762/bjoc.15.157

• ; prenyltransferase; Introduction Aromatic prenyltransferases (PTases) catalyze Friedel–Crafts reactions between aromatic prenyl acceptors and isoprenoid diphosphate prenyl donors to construct C–C, C–O, or C–N bonds, which enrich the structural diversity of aromatic natural products [1][2]. Their reactions are

• biosyntheses, two research groups independently sequenced the genome of a cyanobacterium, Fischerella ambigua UTEX 1903, and performed a biosynthetic study [18][19]. Among the identified biosynthetic enzymes, the major contributors of the structural diversity are two prenyltransferases (AmbP1 and AmbP3) [18

Synthesis of pyrrolo[1,2-a]quinolines by formal 1,3-dipolar cycloaddition reactions of quinolinium salts

• Anthony Choi,
• Rebecca M. Morley and
• Iain Coldham

Beilstein J. Org. Chem. 2019, 15, 1480–1484, doi:10.3762/bjoc.15.149

• explore the diversity of products that could be obtained from these adducts, we carried out a reduction of the alkene in compounds 9 and 10 by using hydrogen and palladium on charcoal (Scheme 4). This provides the tetrahydroquinoline adducts 11 and 12. Additionally, and in contrast, oxidation of the

2,3-Dibutoxynaphthalene-based tetralactam macrocycles for recognizing precious metal chloride complexes

• Li-Li Wang,
• Yi-Kuan Tu,
• Huan Yao and
• Wei Jiang

Beilstein J. Org. Chem. 2019, 15, 1460–1467, doi:10.3762/bjoc.15.146

• abovementioned precious metal chloride complexes. This is in contrast to the fact that the tetralactam macrocycle with anthracene as the sidewalls only show good binding affinities to AuCl4−. The superior binding to all three complexes may be due to the conformational diversity of the naphthalene-based

• tetralactam macrocycle with anthracene sidewalls [34]. The difference in binding affinities and selectivity may be partially due to the conformational diversity in the tetralactam macrocycles with 2,3-dibutoxynaphthalene as the sidewalls. Moreover, they are fluorescent and could in principle be used as a

Borylation and rearrangement of alkynyloxiranes: a stereospecific route to substituted α-enynes

• Ruben Pomar Fuentespina,
• José Angel Garcia de la Cruz,
• Gabriel Durin,
• Victor Mamane,
• Jean-Marc Weibel and
• Patrick Pale

Beilstein J. Org. Chem. 2019, 15, 1416–1424, doi:10.3762/bjoc.15.141

• reaction. This method is particularly appealing, providing with good to high yields a wide diversity of functionalized E or Z tri- or tetrasubstituted α-enynes. Stereospecific formation of α-enynes from alkynyloxiranes. Trapping experiments of the oxiranyllithium derived from cis or trans-alkynyloxiranes

One-pot activation–alkynylation–cyclization synthesis of 1,5-diacyl-5-hydroxypyrazolines in a consecutive three-component fashion

• Christina Görgen,
• Katharina Boden,
• Guido J. Reiss,
• Walter Frank and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2019, 15, 1360–1370, doi:10.3762/bjoc.15.136

• ] specifically have been published employing a cyclizing addition of an acylhydrazone to the carbonyl group as a ring-forming reaction [32][33][34][35][36][37][38][39][40], their diversity-oriented one-pot synthesis in a multicomponent approach has remained unexplored to date. In the course of our program

• analyses. Additionally, the structure was corroborated by an X-ray structure analysis of compound 5r showing dimers held together by inter- and intramolecular hydrogen bonding (Figure 5) [53]. The three-component synthesis allows addressing three points of diversity and especially for the hydrazide

• -diacyl-5-hydroxypyrazolines is concise, highly efficient and diversity-oriented. The deacylating aromatization of the title compounds under weakly alkaline or acidic conditions indicates acyl-transfer ability. Furthermore, the peculiar reactivity of the ynedione intermediate calls for more sophisticated

Genomics-inspired discovery of massiliachelin, an agrochelin epimer from Massilia sp. NR 4-1

• Jan Diettrich,
• Hirokazu Kage and
• Markus Nett

Beilstein J. Org. Chem. 2019, 15, 1298–1303, doi:10.3762/bjoc.15.128

• recognition of a far greater taxonomic diversity of microbes that can produce bioactive compounds [1][2][3]. The exploration of previously neglected taxa has been demonstrated to bear significant potential for finding new natural products and is thus highly promising from a drug discovery perspective [4][5

Doebner-type pyrazolopyridine carboxylic acids in an Ugi four-component reaction

• Maryna V. Murlykina,
• Oleksandr V. Kolomiets,
• Maryna M. Kornet,
• Yana I. Sakhno,
• Sergey M. Desenko,
• Victoriya V. Dyakonenko,
• Svetlana V. Shishkina,
• Oleksandr A. Brazhko,
• Vladimir I. Musatov,
• Alexander V. Tsygankov,
• Erik V. Van der Eycken and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2019, 15, 1281–1288, doi:10.3762/bjoc.15.126

• convergent and versatile manner using diversity generation strategies: combination of two multicomponent reactions and conditions-based divergence strategy. The target products contain as pharmacophores pyrazolopyridine and peptidomimetic moieties with four points of diversity introduced from readily

• available starting materials including scaffold diversity. A small focused compound library of 23 Ugi products was created and screened for antibacterial activity. Keywords: antibacterial activity; Doebner reaction; pyrazolo[3,4-b]pyridine carboxylic acids; Ugi reaction; Introduction Modern medicinal

• compounds characterized by several important features, e.g., molecular complexity and diversity at different levels, high variability and easy accessibility from relatively simple reagents. These challenges can be overcome by using multicomponent reactions (MCRs) but also other strategies can be applied in

Steroid diversification by multicomponent reactions

• Leslie Reguera,
• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Daniel G. Rivera

Beilstein J. Org. Chem. 2019, 15, 1236–1256, doi:10.3762/bjoc.15.121

• materials for relevant MCRs such as those based on imine and isocyanide. The focus is mainly posed on proving the amenability of MCRs for the diversity-oriented derivatization of naturally occurring steroids and the construction of complex steroid-based platforms for drug discovery, chemical biology and

• supramolecular chemistry applications. Keywords: conjugation; heterocycles; macrocycles; multicomponent reactions; steroids; Review 1 Introduction The utilization of multicomponent reactions (MCRs) [1] for the derivatization of biomolecules has continuously grown over the last years. These diversity-oriented

• was also employed for the ligation of amino acids to spirostanic seco-steroids at ring B and for the simultaneous incorporation of two amino acid residues [19]. Ramírez and co-workers have extended the application of the Ugi-4CR to the diversity-oriented functionalization of androstanic and preganinc

Multicomponent reactions (MCRs): a useful access to the synthesis of benzo-fused γ-lactams

• Edorta Martínez de Marigorta,
• Jesús M. de Los Santos,
• Ana M. Ochoa de Retana,
• Javier Vicario and
• Francisco Palacios

Beilstein J. Org. Chem. 2019, 15, 1065–1085, doi:10.3762/bjoc.15.104

• heterocycles. Especially interesting are the applications of these MCRs [61][62][63][64] in combinatorial chemistry [65] and diversity-oriented synthesis [66], where structurally diverse compound libraries can be rapidly synthesized. Therefore, this article reviews the procedures disclosed recently for the

• the reaction is very wide, since the three components have demonstrated the ability to be efficient sources of diversity in this reaction. Indeed, 33 isoindolinones 88 were prepared with yields ranging from moderate to very good. Even when unsymmetrical diaryliodonium salts 87 were used, the reaction

• ). Starting from several aryl and aliphatic ketones 89, more than thirty isoindolinones 90 were obtained, with three points of diversity around the lactam core. Overall, aryl ketones containing electron-donating and electron-withdrawing functions and even a heteroaryl group delivered better yields than