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  • Contiguous Quaternary Carbons: A Selection of Total Syntheses.

    Eggert, Alina; Etling, Christoph; Lübken, Dennis; Saxarra, Marius; Kalesse, Markus (2020-08-24)
    Contiguous quaternary carbons in terpene natural products remain a major challenge in total synthesis. Synthetic strategies to overcome this challenge will be a pivotal prerequisite to the medicinal application of natural products and their analogs or derivatives. In this review, we cover syntheses of natural products that exhibit a dense assembly of quaternary carbons and whose syntheses were uncompleted until recently. While discussing their syntheses, we not only cover the most recent total syntheses but also provide an update on the status quo of modern syntheses of complex natural products. Herein, we review (±)-canataxpropellane, (+)-waihoensene, (-)-illisimonin A and (±)-11-O-debenzoyltashironin as prominent examples of natural products bearing contiguous quaternary carbons.
  • Towards the total synthesis of chondrochloren A: synthesis of the (Z)-enamide fragment.

    Geldsetzer, Jan; Kalesse, Markus (2020-04-14)
    The stereoselective synthesis of the (Z)-enamide fragment of chondrochloren (1) is described. A Buchwald-type coupling between amide 3 and (Z)-bromide 4 was used to generate the required fragment. The employed amide 3 comprising three chiral centers was obtained through a seven-step sequence starting from ᴅ-ribonic acid-1,4-lactone. The (Z)-vinyl bromide 4 is accessible in four steps from 4-hydroxybenzaldehyde. The pivotal cross coupling between both fragments was achieved after extensive experimentation with copper(I) iodide, K2CO3 and N,N'-dimethylethane-1,2-diamine.
  • Recent Applications of the Diels-Alder Reaction in the Synthesis of Natural Products (2017-2020)

    Sara, Alexandru A.; Um-E-Farwa, Um E.Farwa; Saeed, Aamer; Kalesse, Markus; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Thieme, 2021-06-21)
    The Diels-Alder reaction has long been established as an extremely useful procedure in the toolbox of natural product chemists. It tolerates a wide spectrum of building blocks of different complexity and degrees of derivatization, and enables the formation of six-membered rings with well-defined stereochemistry. In recent years, many total syntheses of natural products have been reported that rely, at some point, on the use of a [4+2]-cycloaddition step. Among classic approaches, several modifications of the Diels-Alder reaction, such as hetero-Diels-Alder reactions, dehydro-Diels-Alder reactions and domino-Diels-Alder reactions, have been employed to extend the scope of this process in the synthesis of natural products. Our short review covers applications of the Diels-Alder reaction in natural product syntheses between 2017 and 2020, as well as selected methodologies which are inspired by, or that can be used to access natural products. 1 Introduction 2 Syntheses from 2017 3 Syntheses from 2018 4 Syntheses from 2019 5 Syntheses from 2020 6 Conclusion. © 2021 Georg Thieme Verlag. All rights reserved
  • Synthesis of Desepoxy-Tedanolide C.

    Lücke, Daniel; Kalesse, Markus; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Wiley, 2021-04-09)
    The synthesis of desepoxy-tedanolide C was accomplished and provided experimental evidence on the configuration of tedanolide C. The reported chemical shifts and coupling constants point to a configuration different from the published structure and analogous to the structures of the other members of this family of natural products. The key step is a Kiyooka aldol protocol for the stereoselective synthesis of the tertiary alcohol flanked by three additional oxygenated carbon atoms. Furthermore, two additional aldol reactions and a Julia-Kocienski olefination were used to assemble the carbon framework.
  • The Total Synthesis of Chondrochloren A.

    Linne, Yannick; Bonandi, Elisa; Tabet, Christopher; Geldsetzer, Jan; Kalesse, Markus; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Wiley-VCH, 2021-02-25)
    The first total synthesis of chondrochloren A is accomplished using a 1,2-metallate rearrangement addition as an alternative for the Nozaki-Hiyama-Kishi reaction. This transformation also avoids the inherent challenges of this polyketide segment and provides a new, unprecedented strategy to assemble polyketidal frameworks. The formation of the Z-enamide is accomplished using a Z-selective cross coupling of the corresponding amide to a Z-vinyl bromide.
  • Ribosome-Targeting Antibiotics Impair T Cell Effector Function and Ameliorate Autoimmunity by Blocking Mitochondrial Protein Synthesis.

    Almeida, Luís; Dhillon-LaBrooy, Ayesha; Castro, Carla N; Adossa, Nigatu; Carriche, Guilhermina M; Guderian, Melanie; Lippens, Saskia; Dennerlein, Sven; Hesse, Christina; Lambrecht, Bart N; et al. (Elsevier (Cell Press), 2020-11-24)
    While antibiotics are intended to specifically target bacteria, most are known to affect host cell physiology. In addition, some antibiotic classes are reported as immunosuppressive for reasons that remain unclear. Here, we show that Linezolid, a ribosomal-targeting antibiotic (RAbo), effectively blocked the course of a T cell-mediated autoimmune disease. Linezolid and other RAbos were strong inhibitors of T helper-17 cell effector function in vitro, showing that this effect was independent of their antibiotic activity. Perturbing mitochondrial translation in differentiating T cells, either with RAbos or through the inhibition of mitochondrial elongation factor G1 (mEF-G1) progressively compromised the integrity of the electron transport chain. Ultimately, this led to deficient oxidative phosphorylation, diminishing nicotinamide adenine dinucleotide concentrations and impairing cytokine production in differentiating T cells. In accordance, mice lacking mEF-G1 in T cells were protected from experimental autoimmune encephalomyelitis, demonstrating that this pathway is crucial in maintaining T cell function and pathogenicity.
  • Total Synthesis and Structure Revision of Halioxepine.

    Poock, Caroline; Kalesse, Markus; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Wiley, 2020-11-20)
    The first total synthesis of halioxepine is accomplished using a 1,4-addition for constructing the quaternary center at C10 and a halo etherification for the generation of the tertiary ether at C7. The correct structure of halioxepine was determined by assembling different enantiomeric building blocks and by changing the relative configuration between C10 and C15.
  • Desymmetrization of C -Symmetric Bis(Boronic Esters) by Zweifel Olefinations.

    Linne, Yannick; Schönwald, Axel; Weißbach, Sebastian; Kalesse, Markus; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Wiley, 2020-06-03)
    anti-Configured 1,3-dimethyl deoxypropionate motifs are important sub structures in natural products. Herein, we describe a bidirectional approach for the rapid construction of natural products featuring such motifs by using C2 -symmetrical 1,3-bis(boronic esters). As for its application in convergent syntheses it was important to establish a selective mono-Zweifel olefination we describe the scope and limitations by using different 1,3-bis(boronic esters) and nucleophiles. This protocol takes advantage of the combination of the Hoppe-Matteson-Zweifel chemistry, which was elegantly put into practice by Aggarwal et al. In order to show its applicability the total syntheses of two natural products, serricornin and (+)-invictolide, were performed.
  • Resolving Inflammation: Synthesis, Configurational Assignment, and Biological Evaluations of RvD1.

    Tungen, Jørn Eivind; Gerstmann, Lisa; Vik, Anders; De Matteis, Roberta; Colas, Romain Alexandre; Dalli, Jesmond; Chiang, Nan; Serhan, Charles Nicholas; Kalesse, Markus; Hansen, Trond Vidar; et al. (Wiley, 2018-12-20)
    New drugs that can resolve inflammation without immunosuppressive effects are at the medicinal chemistry frontier. Pro-resolving endogenously formed small molecules, that is, the resolvins, are excellent candidates displaying such bioactions. The first total synthesis of the specialized pro-resolving mediator RvD1n-3 DPA has been achieved using the underutilized sp3 -sp3 Negishi cross coupling reaction and an alkyne hydrosilylation-protodesilylation protocol. Biological evaluations revealed that this novel mediator displays low nanomolar pro-resolving properties and potently activates the human DRV1/GPR32 receptor. As such, this endogenous natural product is a lead compound for the development of novel immunoresolvents.
  • A functional interplay between intein and extein sequences in protein splicing compensates for the essential block B histidine

    Friedel, Kristina; Popp, Monika A.; Matern, Julian C. J.; Gazdag, Emerich M.; Thiel, Ilka V.; Volkmann, Gerrit; Blankenfeldt, Wulf; Mootz, Henning D.; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Royal Society of Chemistry, 2018-10-03)
    Inteins remove themselves from a precursor protein by protein splicing. Due to the concomitant structural changes of the host protein, this self-processing reaction has enabled many applications in protein biotechnology and chemical biology. We show that the evolved M86 mutant of the Ssp DnaB intein displays a significantly improved tolerance towards non-native amino acids at the N-terminally flanking (−1) extein position compared to the parent intein, in the form of both an artificially trans-splicing split intein and the cis-splicing mini-intein. Surprisingly, side chains with increased steric bulk compared to the native Gly(−1) residue, including D-amino acids, were found to compensate for the essential block B histidine in His73Ala mutants in the initial N–S acyl shift of the protein splicing pathway. In the case of the M86 intein, large (−1) side chains can even rescue protein splicing activity as a whole. With the comparison of three crystal structures, namely of the M86 intein as well as of its Gly(−1)Phe and Gly(−1)Phe/His73Ala mutants, our data supports a model in which the intein's active site can exert a strain by varying mechanisms on the different angles of the scissile bond at the extein–intein junction to effect a ground-state destabilization. The compensatory mechanism of the block B histidine is the first example for the direct functional role of an extein residue in protein splicing. It sheds new light on the extein–intein interplay and on possible consequences of their co-evolution as well as on the laboratory engineering of improved inteins.
  • Tris(acetylacetonato) Iron(III): Recent Developments and Synthetic Applications

    Lübken, Dennis; Saxarra, Marius; Kalesse, Markus; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Thieme, 2018-11-27)
    Tris(acetylacetonato) iron(III) [Fe(acac)3] is an indispensable reagent in synthetic chemistry. Its applications range from hydrogen atom transfer to cross-coupling reactions and to use as a Lewis acid. Consequently, the exceptional utility of Fe(acac)3 has been demonstrated in several total syntheses. This short review summarizes the applications of Fe(acac)3 in methodology and catalysis and highlights its use for the synthesis of medicinally relevant structures and in natural product syntheses.
  • Photocontrol of Antibacterial Activity: Shifting from UV to Red Light Activation.

    Wegener, Michael; Hansen, Mickel J; Driessen, Arnold J M; Szymanski, Wiktor; Feringa, Ben L; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (2017-12-13)
    The field of photopharmacology aims to introduce smart drugs that, through the incorporation of molecular photoswitches, allow for the remote spatial and temporal control of bioactivity by light. This concept could be particularly beneficial in the treatment of bacterial infections, by reducing the systemic and environmental side effects of antibiotics. A major concern in the realization of such light-responsive drugs is the wavelength of the light that is applied. Studies on the photocontrol of biologically active agents mostly rely on UV light, which is cytotoxic and poorly suited for tissue penetration. In our efforts to develop photoswitchable antibiotics, we introduce here antibacterial agents whose activity can be controlled by visible light, while getting into the therapeutic window. For that purpose, a UV-light-responsive core structure based on diaminopyrimidines with suitable antibacterial properties was identified. Subsequent modification of an azobenzene photoswitch moiety led to structures that allowed us to control their activity against Escherichia coli in both directions with light in the visible region. For the first time, full in situ photocontrol of antibacterial activity in the presence of bacteria was attained with green and violet light. Most remarkably, one of the diaminopyrimidines revealed an at least 8-fold difference in activity before and after irradiation with red light at 652 nm, showcasing the effective "activation" of a biological agent otherwise inactive within the investigated concentration range, and doing so with red light in the therapeutic window.
  • Total Synthesis of Nannocystin Ax.

    Poock, Caroline; Kalesse, Markus; Hemholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2017-09-01)
    The total synthesis of nannocystin Ax in an overall yield of 11% with 14 steps as the longest linear sequence is reported. Nannocystin Ax is a cytotoxic 21-membered depsipeptide and was isolated from the myxobacterial genus Nannocystis sp. The synthesis uses a vinylogous Horner-Wadsworth-Emmons reaction (HWE) and a vinylogous Mukaiyama aldol reaction (VMAR) as the key steps for the construction of the polyketide fragment. The macrocycle was closed via a macrolactamization reaction using COMU.
  • RNA polymerase motions during promoter melting.

    Feklistov, Andrey; Bae, Brian; Hauver, Jesse; Lass-Napiorkowska, Agnieszka; Kalesse, Markus; Glaus, Florian; Altmann, Karl-Heinz; Heyduk, Tomasz; Landick, Robert; Darst, Seth A; et al. (2017-05-26)
    All cellular RNA polymerases (RNAPs), from those of bacteria to those of man, possess a clamp that can open and close, and it has been assumed that the open RNAP separates promoter DNA strands and then closes to establish a tight grip on the DNA template. Here, we resolve successive motions of the initiating bacterial RNAP by studying real-time signatures of fluorescent reporters placed on RNAP and DNA in the presence of ligands locking the clamp in distinct conformations. We report evidence for an unexpected and obligatory step early in the initiation involving a transient clamp closure as a prerequisite for DNA melting. We also present a 2.6-angstrom crystal structure of a late-initiation intermediate harboring a rotationally unconstrained downstream DNA duplex within the open RNAP active site cleft. Our findings explain how RNAP thermal motions control the promoter search and drive DNA melting in the absence of external energy sources.
  • A simple and efficient method for the preparation of 5-hydroxy-3-acyltetramic acids.

    Trenner, Johanna; Prusov, Evgeny V; Helmholtz Centre for infection research, Inhoffenstr. 7, D-38124 Braunschweig, Germany. (2015)
    Oxidation of the bisenolates of 3-acyltetramic acid to the corresponding 5-hydroxylated compounds using molecular oxygen is reported. The deprotection of the resulting compounds was also achieved.
  • Synthesis of the spiroketal core of integramycin.

    Prusov, Evgeny V; Department of Medicinal Chemistry, Helmholtz Centre for Infection Research, Inhoffenstr. 7, 38124 Braunschweig, Germany (2013)
    A concise synthetic strategy towards the spiroketal core of the HIV-integrase inhibitor integramycin (1) was developed. The required ketone precursor was efficiently constructed from two simple and easily accessible subunits by means of a hydrozirconation/copper catalyzed acylation reaction. The effects of different protecting groups on the spiroketalization step were also investigated.
  • Total synthesis of antibiotics: recent achievements, limitations, and perspectives.

    Prusov, Evgeny V; Helmholtz Zentrum für Infektionsforschung, Braunschweig, Germany. (2013-04)
    Several recently accomplished total syntheses of antibiotic natural products were summarized in this review in order to present current trends in this area of research. Compounds from different substance classes, including polyketide, depsipeptide, polyketide-polypeptide hybrid, and saccharide, were chosen to demonstrate the advancement in both chemical methodology and corresponding synthetic strategy.
  • Mode of action of epoxyphomalins A and B and characterization of related metabolites from the marine-derived fungus Paraconiothyrium sp.

    Mohamed, Ietidal E; Kehraus, Stefan; Krick, Anja; König, Gabriele M; Kelter, Gerhard; Maier, Armin; Fiebig, Heinz-Herbert; Kalesse, Markus; Malek, Nisar P; Gross, Harald; et al. (2010-12-27)
    Epoxyphomalins A (1) and B (2) are highly potent cytotoxic fungal metabolites. During the course of purifying larger quantities of 1 and 2 from Paraconiothyrium sp. fermentation extracts, three new epoxyphomalins (3-5) were isolated and characterized, showing modifications to the oxidation pattern of the cyclohexene moiety or of C-9 of the decalin system. IC(50) values for cytotoxicity against a panel of 36 human tumor cell lines were determined for all new compounds. Compound 4 was found to be cytotoxic particularly toward prostate PC3M (IC(50) = 0.72 μM) and bladder BXF 1218 L (IC(50) = 1.43 μM) cancer cell lines. In addition, inhibition of chymotrypsin-, caspase-, and trypsin-like activity of purified 20S proteasomes was determined for epoxyphomalins A (1) and B (2). The results indicate that compounds 1 and 2 exert their cytotoxic effect through potent inhibition of the 20S proteasome.
  • Stereoselective total synthesis of etnangien and etnangien methyl ester.

    Li, Pengfei; Li, Jun; Arikan, Fatih; Ahlbrecht, Wiebke; Dieckmann, Michael; Menche, Dirk; Institut für Organische Chemie, Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 270, D-69120 Heidelberg, Germany. (2010-04-16)
    A highly stereoselective joint total synthesis of the potent polyketide macrolide antibiotics etnangien and etnangien methyl ester was accomplished by a convergent strategy and proceeds in 23 steps (longest linear sequence). Notable synthetic features include a sequence of highly stereoselective substrate-controlled aldol reactions to set the characteristic assembly of methyl- and hydroxyl-bearing stereogenic centers of the propionate portions, an efficient diastereoselective Heck macrocyclization of a deliberately conformationally biased precursor, and a late-stage introduction of the labile side chain by means of a high-yielding Stille coupling of protective-group-free precursors. Along the way, an improved, reliable protocol for a Z-selective Stork-Zhao-Wittig olefination of aldehydes was developed, and an effective protocol for a 1,3-syn reduction of sterically particularly hindered beta-hydroxy ketones was devised. Within the synthetic campaign, a more detailed understanding of the intrinsic isomerization pathways of these labile natural products was elaborated. The expedient and flexible strategy of the etnangiens should be amenable to designed analogues of these RNA-polymerase inhibitors, thus enabling further exploration of the promising biological potential of these macrolide antibiotics.
  • Thiourea-catalyzed direct reductive amination of aldehydes

    Menche, Dirk; Arikan, Fatih (Thieme, 2007-09-25)

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