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

• be coupled to form a diphosphate (plus some dimerized UMP–UMP) that is fully isolatable. Adding to the power of this method is the ability for the in situ formed diphosphate to react enzymatically with for example the known GlcNAc analog shown in Scheme 29 using either an inverting (shown) or

G-Protein coupled receptors: answers from simulations

• Timothy Clark

Beilstein J. Org. Chem. 2017, 13, 1071–1078, doi:10.3762/bjoc.13.106

• the G-protein. On activation, bound guanosine diphosphate (GDP) in the G-protein is replaced by the triphosphate (GTP) and the α-subunit separates from β/γ. The separated G-protein subunits migrate to effectors in the nearby membrane, where GTP is hydrolyzed to GDP and the signaling cascade initiated

Opportunities and challenges for the sustainable production of structurally complex diterpenoids in recombinant microbial systems

• Katarina Kemper,
• Max Hirte,
• Markus Reinbold,
• Monika Fuchs and
• Thomas Brück

Beilstein J. Org. Chem. 2017, 13, 845–854, doi:10.3762/bjoc.13.85

• , fragrances, fuels and fuel additives. Central building blocks of all terpenes are the isoprenoid compounds isopentenyl diphosphate and dimethylallyl diphosphate. Bacteria like Escherichia coli harbor a native metabolic pathway for these isoprenoids that is quite amenable for genetic engineering. Together

• describing the metabolic engineering of a bacterial host. Precursor formation All terpenes derive from the ubiquitous central metabolites isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) [24] (see Scheme 1). Interestingly, only two metabolic pathways (MEP and MEV) have been identified for

• prevent accumulation of the desired lead structures [33]. Isoprenyl diphosphate formation Downstream of precursor formation condensation of IPP and DMAPP to longer-chain polyprenyls precedes subsequent metabolization to linear or mono- and polycyclic products, respectively, by the terpene synthases [24

Posttranslational isoprenylation of tryptophan in bacteria

• Masahiro Okada,
• Tomotoshi Sugita and
• Ikuro Abe

Beilstein J. Org. Chem. 2017, 13, 338–346, doi:10.3762/bjoc.13.37

• . ComQ lacks homology to cysteine isoprenyltransferases, tryptophan dimethylallyltransferases for cyanobactins [2][37][38] or prenyltransferases for indole alkaloids [39][40][41][42]. However, ComQ shares some homology with farnesyl diphosphate (FPP) synthases and geranylgeranyl diphosphate (GGPP

• ) synthases, which catalyze the condensation of isopentenyl diphosphate (IPP) with geranyl diphosphate (GPP) or FPP to form C5-extended isoprenyl diphosphates FPP or GGPP (Figure 4B) [43][44]. In the both typical diphosphate synthases, two aspartate-rich motifs containing “DDxxD” residues, in which x refers

• -rich motif and the pseudo aspartate-rich motif in ComQ from seven Bacillus strains. Essential amino acid residues for function are shown in bold and colored blue. EcGGPPS is a geranylgeranyl diphosphate synthase derived from Escherichia coli ISC56. It’s essential amino acid residues for function are

Electron-transfer-initiated benzoin- and Stetter-like reactions in packed-bed reactors for process intensification

• Anna Zaghi,
• Daniele Ragno,
• Graziano Di Carmine,
• Carmela De Risi,
• Olga Bortolini,
• Pier Paolo Giovannini,
• Giancarlo Fantin and
• Alessandro Massi

Beilstein J. Org. Chem. 2016, 12, 2719–2730, doi:10.3762/bjoc.12.268

• asymmetric version of acyloin-type reactions was also investigated in our laboratory operating packed-bed bioreactors functionalized with a suitable thiamine diphosphate (ThDP)-dependent enzyme supported on mesoporous silica [17]. Overall, the so far reported umpolung flow processes [12][13][14][15][16][17

A detailed view on 1,8-cineol biosynthesis by Streptomyces clavuligerus

• Jan Rinkel,
• Patrick Rabe,
• Laura zur Horst and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2016, 12, 2317–2324, doi:10.3762/bjoc.12.225

• -cineol synthase from Streptomyces clavuligerus was investigated using stereospecifically deuterated substrates. In contrast to the well investigated plant enzyme from Salvia officinalis, the reaction proceeds via (S)-linalyl diphosphate and the (S)-terpinyl cation, while the final cyclisation reaction is

• in both cases a syn addition, as could be shown by incubation of (2-13C)geranyl diphosphate in deuterium oxide. Keywords: biosynthesis; enzyme mechanisms; isotopic labelling; stereochemistry; terpenes; Introduction Among all classes of natural products the climax of structural diversity and

• and achiral precursors such as geranyl diphosphate (GPP, monoterpenes), farnesyl diphosphate (FPP, sesquiterpenes) and geranylgeranyl diphosphate (GGPP, diterpenes). Terpene cyclases (type I) contain a trinuclear (Mg2+)3 cluster in their active site that is stabilised by binding to several highly

Mechanistic investigations on six bacterial terpene cyclases

• Patrick Rabe,
• Thomas Schmitz and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2016, 12, 1839–1850, doi:10.3762/bjoc.12.173

• Patrick Rabe Thomas Schmitz Jeroen S. Dickschat Kekulé-Institute of Organic Chemistry and Biochemistry, University of Bonn, Gerhard-Domagk-Straße 1, 53121 Bonn, Germany 10.3762/bjoc.12.173 Abstract The products obtained by incubation of farnesyl diphosphate (FPP) with six purified bacterial

• bacterial [28][35] and fungal [36][37] terpene cyclases. Results and Discussion Incubation of a recombinant terpene cyclase from Streptomyces viridochromogenes DSM 40736 (NCBI accession number WP_039931950) with farnesyl diphosphate (FPP) yielded a single product that was identified as α-amorphene (1

• , Figure 1) by GC–MS analysis (Figure S1, Supporting Information File 1) [32], while the enzyme incubations with geranyl diphosphate (GPP) and geranylgeranyl diphosphate (GGPP) gave no products. Although 1 was isolated from vetiver oil (Vetiveria zizanioides, Gramineae) nearly five decades ago [38], the

The EIMS fragmentation mechanisms of the sesquiterpenes corvol ethers A and B, epi-cubebol and isodauc-8-en-11-ol

• Patrick Rabe and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2016, 12, 1380–1394, doi:10.3762/bjoc.12.132

• Patrick Rabe Jeroen S. Dickschat Kekulé-Institute of Organic Chemistry and Biochemistry, University of Bonn, Gerhard-Domagk-Straße 1, 53121 Bonn, Germany 10.3762/bjoc.12.132 Abstract Farnesyl diphosphate (FPP) and all fifteen positional isomers of (13C1)FPP were enzymatically converted by the

• incorporation rates and usually delivers a mixture of various isotopomers. We have recently synthesised all fifteen isotopomers of (13C1)farnesyl diphosphate (FPP) that can be enzymatically converted with a sesquiterpene cyclase into the corresponding labelled sesquiterpene products [16]. These enzyme products

• isotopomers of farnesyl diphosphate. Incubation experiments were carried out using 1 mL of the enzyme fraction and 1 mL of a solution of the isotopomer of (13C1)FPP (0.2 mg/mL in H2O) for 3 h at 28 °C. The reaction mixtures were extracted with n-hexane (300 μL) and analyzed by GC–MS and GC–QTOF MS. Mass

Muraymycin nucleoside-peptide antibiotics: uridine-derived natural products as lead structures for the development of novel antibacterial agents

• Daniel Wiegmann,
• Stefan Koppermann,
• Marius Wirth,
• Giuliana Niro,
• Kristin Leyerer and
• Christian Ducho

Beilstein J. Org. Chem. 2016, 12, 769–795, doi:10.3762/bjoc.12.77

• , transformation to a disaccharide and transport to the extracellular side of the membrane (Figure 4, steps B, C); finally, polymerisation to long oligosaccharide chains and cross-linking occur (Figure 4, steps D, F). In the cytosol, uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc), that is formed from

• -isoprenoid lipid carrier that is located in the cellular membrane. With concomitant release of uridine monophosphate (UMP), this furnishes a diphosphate linkage between the two substrates. The reaction is reversible and MraY accelerates the adjustment of the equilibrium state. Whereas this reaction was known

• -catalysed displacement of the uracil with a phosphate moiety to afford 5-amino-5-deoxyribose-1-phosphate (116). The LipM-mediated reaction of ribosyl phosphate 116 with a nucleoside triphosphate (NTP) then yields nucleoside diphosphate (NDP)-aminoribose 117. Finally, aminoribosylation of 101 with glycosyl

Dynamic behavior of rearranging carbocations – implications for terpene biosynthesis

• Stephanie R. Hare and
• Dean J. Tantillo

Beilstein J. Org. Chem. 2016, 12, 377–390, doi:10.3762/bjoc.12.41

• rings that are transformed in only one or two enzyme-promoted reactions. These reactions involve generation of a carbocation by protonation or loss of a diphosphate group followed by cyclization, alkyl shift, hydride shift and/or proton transfer reactions to generate new, more complex, carbocations

• . Ultimately these carbocations are either trapped by a nucleophile (e.g., water, diphosphate) or deprotonated to form alkenes. The details of terpene-forming carbocation cyclization/rearrangement processes have been of interest for decades [1][2][3][4][5][6]. Although much has been learned, new observations

• the absence of specifically oriented noncovalent interactions with groups in terpene synthase active sites. Molecular dynamics calculations using the full bornyl diphosphate synthase enzyme were also carried out (here using a combination of DFT and molecular mechanics) [21][22]. These simulations

Mycothiol synthesis by an anomerization reaction through endocyclic cleavage

• Shino Manabe and
• Yukishige Ito

Beilstein J. Org. Chem. 2016, 12, 328–333, doi:10.3762/bjoc.12.35

• Gram-negative bacteria. MSH undergoes metal-catalyzed autoxidation more rapidly than glutathione [16]. The biosynthetic pathway of MSH has been well investigated; MSH is synthesized from 1-inositol phosphate and uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) in five steps [15]. It is used by

Synthesis of cyclic N¹-pentylinosine phosphate, a new structurally reduced cADPR analogue with calcium-mobilizing activity on PC12 cells

• Ahmed Mahal,
• Stefano D’Errico,
• Nicola Borbone,
• Brunella Pinto,
• Agnese Secondo,
• Valeria Costantino,
• Valentina Tedeschi,
• Giorgia Oliviero,
• Vincenzo Piccialli and
• Gennaro Piccialli

Beilstein J. Org. Chem. 2015, 11, 2689–2695, doi:10.3762/bjoc.11.289

• neuronal cells in comparison with the pyrophosphate bridge present in the cyclic N1-pentylinosine diphosphate analogue (cpIDP) previously synthesized in our laboratories. The preliminary biological tests indicated that cpIMP and cpIDP induce a rapid increase of intracellular Ca2+ concentration in PC12

• analogues of the cADPR in which the adenine base was replaced by a hypoxanthine ring [24]. This kind of modification produced the cyclic inosine diphosphate ribose (cIDPR) 2 which proved to be stable in hydrolytic physiological conditions and showed significant Ca2+ mobilizing activity, thus fostering the

Synthesis of Xenia diterpenoids and related metabolites isolated from marine organisms

• Tatjana Huber,
• Lara Weisheit and
• Thomas Magauer

Beilstein J. Org. Chem. 2015, 11, 2521–2539, doi:10.3762/bjoc.11.273

• ]. Initial loss of a diphosphate anion from GGPP generates an allylic cation in 29 which is intramolecularly trapped by nucleophilic attack of the C3,C10-double bond, forming the secondary cation 30. Attack of the newly generated C1,C2-double bond with simultaneous loss of a proton then affords the bicyclo

Recent highlights in biosynthesis research using stable isotopes

• Jan Rinkel and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2015, 11, 2493–2508, doi:10.3762/bjoc.11.271

• skeletons (Figure 6). The fascination of terpene biosynthesis arises from the complexity and variety of carbon scaffolds, terpene cyclases are able to build up using few linear oligoprenyl diphosphate precursors. This promotes investigations using isotopically labeled compounds both on acetate- and

• -labeled isotopomers of farnesyl diphosphate (FPP) [60]. These precursors were used to unambiguously assign both 13C NMR and (via HSQC) 1H NMR data of (1(10)E,4E)-germacradien-6-ol (34) from Streptomyces pratensis. The NMR spectra of this compound are complicated because of a mixture of conformers (Figure

• (42) and B (43) provides an interesting example (Scheme 7) [61]. The proposed mechanism starts with isomerization of farnesyl diphoshate (FPP, 35) to nerolidyl diphosphate (36) followed by 1,10-ring closure to the helminthogermacradienyl cation (37). A 1,3-hydride shift to the allylic cation 38 and

Two strategies for the synthesis of the biologically important ATP analogue ApppI, at a multi-milligram scale

• Janne Weisell,
• Jouko Vepsäläinen and
• Petri A. Turhanen

Beilstein J. Org. Chem. 2015, 11, 2189–2193, doi:10.3762/bjoc.11.237

• isopentenyl diphosphate (IPP) [4]. ApppI has interesting properties and their clarification might explain many of the biological functions of N-BPs. Unfortunately, these studies are hampered by the very limited availability of ApppI. There are only few methods described in the literature which can be used in

• any NMR characterization data, only HPLC and MS data were presented, and these are rather unsatisfactory methods with which to prove the purity of a product. They also stated that there was 5–10% ADP (adenosine diphosphate) as an impurity in some preparations and that it is possible that there may

Towards inhibitors of glycosyltransferases: A novel approach to the synthesis of 3-acetamido-3-deoxy-D-psicofuranose derivatives

• Maroš Bella,
• Miroslav Koóš and
• Chun-Hung Lin

Beilstein J. Org. Chem. 2015, 11, 1547–1552, doi:10.3762/bjoc.11.170

• diphosphate)] acts as the donor of the GlcNAc residue while a hydroxy group situated at a specific site of the growing oligosaccharide chain serves as the acceptor [9]. The target-directed search for effective GnTs inhibitors based on the rational design of model compounds remains a difficult task due to the

A procedure for the preparation and isolation of nucleoside-5’-diphosphates

• Heidi J. Korhonen,
• Hannah L. Bolt and
• David R. W. Hodgson

Beilstein J. Org. Chem. 2015, 11, 469–472, doi:10.3762/bjoc.11.52

• synthesis; nucleic acids; nucleoside-5’-diphosphate; phosphorylation; Introduction Nucleoside-5'-phosphates are key to many mechanistic studies and chemical biology applications [1][2][3]. Synthetic approaches towards nucleoside-5'-phosphates are well-established [4], however, the methods tend to be

• problems [4][19]. In addition, excess pyrophosphate is usually employed in order to drive the kinetics of the displacement process, however, this excess material tends to co-elute with nucleoside-5’-diphosphate products during anion exchange chromatographic purifications. We have recently reported the

•  3, Table 1). Protected substrate 3 showed conversion to diphosphate 4 after 91 h of reaction, however, we were unable to precipitate this material after removal of excess pyrophosphate ions (Scheme 4). We believe the isopropylidene protecting group decreases the polarity of diphosphate 4 to such an

Aspergiloid I, an unprecedented spirolactone norditerpenoid from the plant-derived endophytic fungus Aspergillus sp. YXf3

• Zhi Kai Guo,
• Rong Wang,
• Wei Huang,
• Xiao Nian Li,
• Rong Jiang,
• Ren Xiang Tan and
• Hui Ming Ge

Beilstein J. Org. Chem. 2014, 10, 2677–2682, doi:10.3762/bjoc.10.282

• . Here the hypothetical pimarane compound 2, the hemiketal lactone ring-opening product of aspergiloid E, was proposed as the most probable biosynthetic intermediate. As shown in Scheme 1, we suggest the biosynthesis of 1 starts from the classical diterpene precursor geranylgeranyl diphosphate [14], and

Gold(I)-catalysed synthesis of a furan analogue of thiamine pyrophosphate

• Amjid Iqbal,
• El-Habib Sahraoui and
• Finian J. Leeper

Beilstein J. Org. Chem. 2014, 10, 2580–2585, doi:10.3762/bjoc.10.270

• , involving gold(I)-catalysed cyclisation of an alkynyl alcohol to form the furan ring. The furan analogue of thiamine diphosphate (ThDP) was also made and tested for binding to and inhibition of pyruvate decarboxylase (PDC) from Zymomonas mobilis (overexpressed in E. coli with a N-terminal His-tag). It is a

• ; pyruvate decarboxylase; thiamine diphosphate; Introduction The biologically active form of vitamin B1 is thiamine diphosphate (ThDP, 1, Figure 1), which is an essential cofactor and involved in a number of metabolic pathways, including oxidative and non-oxidative decarboxylation of α-keto acids (e.g

• synthesis of a furan-based analogue of thiamine. This analogue was converted to its diphosphate, which is another extremely potent inhibitor of ZmPDC, and could also be functionalised at the 2-position using a Friedel–Crafts acylation. Results and Discussion Synthesis of ThDP analogue 17 The key step in our

Organophosphorus chemistry

• Paul R. Hanson

Beilstein J. Org. Chem. 2014, 10, 2087–2088, doi:10.3762/bjoc.10.217

• phosphanylidenecarbenes and phosphoryl azides, and bisphosphonate ethers as promising inhibitors of geranylgeranyl diphosphate synthase (GGDPS). The articles and reviews capture the emerging potential of organophosphorus compounds and exciting opportunities in the field, and hopefully, will inspire and motivate

Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules

• Thilo Focken and
• Stephen Hanessian

Beilstein J. Org. Chem. 2014, 10, 1848–1877, doi:10.3762/bjoc.10.195

• inhibitor (1996) Inhibitors of squalene synthase have sparked interest as selective cholesterol lowering agents [76][77]. The enzyme is involved in the first committed step in the cholesterol synthesis and catalyses the conversion of two molecules of farnesyl diphosphate into squalene, which is later

Synthesis of isoprenoid bisphosphonate ethers through C–P bond formations: Potential inhibitors of geranylgeranyl diphosphate synthase

• Xiang Zhou,
• Jacqueline E. Reilly,
• Kathleen A. Loerch,
• Raymond J. Hohl and
• David F. Wiemer

Beilstein J. Org. Chem. 2014, 10, 1645–1650, doi:10.3762/bjoc.10.171

• enzyme geranylgeranyl diphosphate synthase (GGDPS). Five of the new compounds show IC50 values of less than 1 μM against GGDPS with little to no activity against the related enzyme farnesyl diphosphate synthase (FDPS). The most active compound displayed an IC50 value of 82 nM when assayed with GGDPS, and

• CoA reductase (HMGCoA) is viewed as the first committed step of isoprenoid and steroid biosynthesis, and is the target of the statin class of cholesterol-lowering agents including lovastatin (1, Figure 1) and pravastatin (2) [1]. The downstream enzyme farnesyl diphosphate synthase (FDPS) is the target

• other enzymes in these pathways also may have value as drug targets. One of our interests in isoprenoid biosynthesis has been the enzyme geranylgeranyl diphosphate synthase (GGDPS), which mediates the reaction of the C15 compound farnesyl diphosphate (FPP) with the C5 isopentenyl diphosphate to form the

[²H₂₆]-1-epi-Cubenol, a completely deuterated natural product from Streptomyces griseus

• Christian A. Citron and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2013, 9, 2841–2845, doi:10.3762/bjoc.9.319

• observed on DMM (Figure 2). This demonstrated that all relevant terpene biosynthetic pathways including the deoxyxylulose phosphate pathway for the biosynthesis of the terpene monomers dimethylallyl diphosphate (DMAPP) and isopentenyl diphosphate (IPP) as well as polyisoprenoid biosynthesis for the linear

• precursors geranyl diphosphate (GPP) and farnesyl diphosphate (FPP) were active. However, the volatile 2 was found only in traces, while the production of 1 was completely abolished. Reasons for these findings may be that the production of 2 is under positive control of the bacterial hormone A-factor [1

Biosynthesis of rare hexoses using microorganisms and related enzymes

• Zijie Li,
• Yahui Gao,
• Hideki Nakanishi,
• Xiaodong Gao and
• Li Cai

Beilstein J. Org. Chem. 2013, 9, 2434–2445, doi:10.3762/bjoc.9.281

• engineered Corynebacterium glutamicum was used to produce guanosine-5’-diphosphate (GDP)-L-fucose, the precursor of fucosyl-oligosaccharides, from glucose and mannose [95]. L-Fucose (or its analogs) can also be prepared in vitro enzymatically in a three-step procedure (Scheme 16) [96]. Firstly, L-fuculose-1

The chemistry of isoindole natural products

• Klaus Speck and
• Thomas Magauer

Beilstein J. Org. Chem. 2013, 9, 2048–2078, doi:10.3762/bjoc.9.243

• putative biosynthetic pathway for the formation of the hetisine alkaloids is derived from phytochemical data and basic biochemical transformations (Scheme 30) [167]. Cyclization of geranylgeranyl pyrophosphate (229), involving the ent-copalyl diphosphate synthase, could give ent-copalyl diphosphate (230