DOCSLIB.ORG

Aspects of Chemical Transglycosylations in Modern Glycoside Synthesis† Anupama Das and N

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Aspects of Chemical Transglycosylations in Modern Glycoside Synthesis† Anupama Das and N Special Issue on "Synthetic Carbohydrate Chemistry" J. Indian Chem. Soc., Vol. 97, February 2020, pp. 135-156 Aspects of chemical transglycosylations in modern glycoside synthesis† Anupama Das and N. Jayaraman* Department of Organic Chemistry, Indian Institute of Science, Bangalore- 560 012, India E-mail: [email protected] Manuscript received online 08 November 2019, revised and accepted 23 December 2019 Application of chemical methods forms as a powerful approach to achieve synthesis of custom-designed oligosaccharides. Chemical glycosylation methods continue to evolve till date even when the first such method dates back more than a century ago. The recent past has witnessed the emergence of the transglycosylations, wherein a preponderant O-glycoside acts as a glycosyl donor to afford yet another O-glycoside product bearing the newly introduced glycan/aglycan at the reducing end. Critical requirements of the aglycan portion of a glycoside donor are discussed, as also the mechanistic formulations based on a set of experimental observations. A critical review of the expanding facets of transglycosylations in the garb of modern glycosylation methods is presented herein. Keywords: Carbohydrates, conformations, glycosylations, oligosaccharides, oxocarbenium ion. 1. Introduction of the anomeric substituent as the leaving moiety. The re- Chemical glycosylations constitute to be one of the ma- sulting oxocarbenium ion acts as the reactive intermediate jor concurrent advancements in the general area in carbohy- to react with a glycosyl acceptor nucleophile and yield the drate chemistry1. Multiple hydroxyl groups containing sug- glycoside product. Chemical glycosylations to date practi- ars present a plethora of challenges at the outset, yet a judi- cally relied on the generation of the oxocarbenium ion as the cious underpinning of the reactivities of each hydroxyl groups intermediate. Although commendable efforts pertain to the also provides a facile route to implement chosen reactions recent reports of endocylic oxygen cleavage and on such sugar scaffolds. One of the earliest reactions of sug- anomerization as fruitful approaches to alter anomeric ste- 7 ars is the so-called glycosylation, particularly involving the reochemistry of glycosides . Significant advancements in chemical methods. Fischer glycosylation in 18952 and glycosylation started to emerge from late 1980’s, advancing Koenigs-Knorr glycosylation in 19013 continue to be hall-mark chemical methods to conduct glycosylations using a number reactions benefitting their applications in glycoside synthe- of reagents and reaction conditions. These advancements sis. Improvements on these very early methods add further helped not only to increase the arsenal of methods for values and these reactions are practiced rather routinely glycosylations under varying substrate conditions, but also through the improved chemical methods, examples of such to uncover the finer details of the glycosylation reactions. improvements are the Helferich condition in 1930’s4 and Further, elegant developments relating to glycosylation re- Hanessian-Banoub method5 of glycosylations, reported in actions to be conducted under solid-phase methods have 1977. A major change in the outlook of chemical emerged, leading to secure oligomeric glycosides in a facile 8 glycosylations can be attributed to the early establishing of manner and in a short duration . Excellent reviews on gen- thioglycosides as a versatile glycosyl donor by Lönn, and eral glycosylation reactions can be referred to many articles 9–11 Garegg and Fügedi in mid-1980’s6. An imminent understand- that appear in the recent years . ing is the control of chemical glycosylations under the Glycosylations in natural systems eminently adopt en- oxocarbenium or the glycosyl cation manifold, upon removal zymes as a source to catalyze the reaction, bringing together †Review. 135 J. Indian Chem. Soc., Vol. 97, February 2020 reactivities between the glycosyl donor and acceptor to af- being identified continuously. A major focus in glycosylation ford the glycoside. Glycosyl transferases and glycosyl hy- reactions is the generation of the oxocarbenium ion or glyco- drolases are two classes of enzymes that catalyze the syl cation intermediate from the glycosyl donor under the glycosylation reactions. Within these enzymes, requirements reaction conditions and the reactivity of this intermediate with of nucleotide factors in the case of glycosyl transferases, incoming alcohols as nucleophiles, leading to the glycoside and favorable thermodynamic equilibrium in the case of gly- bond formation. Generation of this intermediate with the es- cosyl hydrolases are stringent. Excellent reviews are referred timated lifetime of >2.5×10–12 s in aq. solution bears greater to read through the enzyme-mediated glycosylations12–14. relevance and importance in glycosylation reaction in gen- 15 A defining feature of chemical glycosylations is the ability eral . to generate the oxocarbenium ion as the reactive partner to Although the generation of the oxocarbenium ion forms react with acceptor nucleophile. Stringent requirements fur- the key step of a glycosylation, conformational preferences ther are the activator of the glycosyl donor, promoter of the of this species possess a crucial role in the stereochemical reaction, temperature, solvent, presence of molecular sieves outcome of the glycosylation, along with factors as that aris- and above all, the nature of protecting groups in the reactive ing from reactivities of individual hydroxyl moieties, protect- partners. Paulsen’s statement1 in 1982 that there is no single ing groups, reagents, promoters, temperature and solvent reagent or reaction condition that allow glycosylations on the polarity. Few salient aspects of these controls on glycosylation varieties of glycosyl donors and acceptors to secure assort- are discussed below briefly. ment of glycosides still stands largely true. Concerning the oxocarbenium ion generation in the pres- Within the preamble of the present article, chemical ence of triflate promoter, the work of Hosoya and co-workers transglycosylations are considered as a viable and fruitful demonstrates further that intermediate species in the form approach to conduct glycosylations, having the merits that of / contact ion pairs (CIP) (I, II and V) or solvent sepa- are otherwise un-available through other types of chemical rated ion pairs (SSIP) (III and IV) form and these species glycosylations. Herein, a transglycosylation refers to the re- equilibrate with one another in the solution phase between 16,17 actions wherein a glycosyl donor is an O-glycoside, which anomeric triflates 1a and 1b (Fig. 1) . reacts with the hydroxyl moiety in a glycosyl/aglycosyl ac- Inducing conformational constraints in the oxocarbenium ceptor and affords the newly formed O-glycoside. ion species through bicyclic formation: Inducing conforma- tional constraints onto the oxocarbenium ion species through 2.1. Relevance of oxocarbenium ion protecting groups, particularly benzylidene acetal, leads the Chemical glycosylations are warranted immensely, in or- species to be bicyclic in nature. This approach of conforma- der to secure homogeneous oligosaccharides and their con- tional constraints was systematically studied by Crich and jugates of biological importance. Chemical glycosylation co-workers, in order to ascertain the conformational equilib- methodologies are improved upon and newer methods are rium associated with the oxocarbenium ion. Among gluco- Fig. 1. Oxocarbenium ion equilibration in the CIP, SSIP and covalent forms in the presence of triflate promoter16,17. 136 Das et al.: Aspects of chemical transglycosylations in modern glycoside synthesis and mannopyranose derived oxocarbenium ions, having the oxocarbenium ion, the antiperiplanarity of the C2-O bond benzylidene acetal, the axial-orientation of the hydroxyl moi- would block the equatorial (-) face at C-1 anomeric carbon, ety in mannopyranose-derived intermediate species shifted thereby the axial (-) attack at C-1 carbon by the nucleo- the covalent triflate-CIP-SSIP equilibria towards the cova- phile become feasible, in the course of the formation of the lent intermediate, resulting in a high -selectivity of the gly- glycoside product with the chair conformation. Whereas cosidic bond. As a corollary, glucopyranose-derived mannosyl oxocarbenium ion species adopts B2,5 conforma- oxocarbenium ion species, having the equatorial hydroxyl tion and projects the C2-O bond in the -face, lying moiety at C-2 carbon, shifted the equilibrium far away from antiperiplanar to the bond. As a result, the nucleophilic at- the covalent triflate18. tack occurs through the -face, resulting in the glycoside 1 The stereoselectivity observed in the O- and C- with an initial S5 conformation (7). glycosylation of gluco- and mannopyranosides having 4,6- Blériot and co-workers used superacid HF/SbF5 on O-benzylidene moiety was evaluated by invoking the bent peracetate-protected 2-deoxy sugars 8 and 10, in an attempt bond model, advanced by Deslongchamps and co-workers19. to monitor the oxocarbenium formation (Scheme 1), during 4 The model predicts that H3 (Gluco-2) (Fig. 2) conformation the formation of the corresponding methyl glycosides 9 and evolves on the oxocarbenium ion having the gluco-configu- 1120,21. Under the conditions, the oxocarbenium ion was 1 13 ration, whereas that in manno-configured species is the B2,5 stable at room temperature, the corresponding H and C conformation
Load more

Recommended publications
  • Trimethylsilyl Trifluoromethanesulfonate-Mediated Additions to Acetals, Nitrones, and Aminals Chelsea Safran
    University of Richmond UR Scholarship Repository Honors Theses Student Research 4-1-2013 Trimethylsilyl trifluoromethanesulfonate-mediated additions to acetals, nitrones, and aminals Chelsea Safran Follow this and additional works at: http://scholarship.richmond.edu/honors-theses Recommended Citation Safran, Chelsea, "Trimethylsilyl trifluoromethanesulfonate-mediated additions to acetals, nitrones, and aminals" (2013). Honors Theses. Paper 71. This Thesis is brought to you for free and open access by the Student Research at UR Scholarship Repository. It has been accepted for inclusion in Honors Theses by an authorized administrator of UR Scholarship Repository. For more information, please contact [email protected]. Trimethylsilyl trifluoromethanesulfonate-mediated additions to acetals, nitrones, and aminals By Chelsea Safran Honors Thesis In Program In Biochemistry and Molecular Biology University of Richmond Richmond, VA Spring 2012 Advisor: Dr. C. Wade Downey This thesis has been accepted as part of the honors requirements in the Program in Biochemistry and Molecular Biology ______________________________ _________________ (advisor signature) (date) ______________________________ _________________ (reader signature) (date) Table of Contents i. Acknowledgements ii ii. Abstract iii iii. Chapter I: Introduction 1-4 iv. Chapter II: Amides 4-15 v. Chapter III: I. Bisthione Synthesis 16-18 II. Reactions with other N,O-acetals 18-22 vi. Chapter IV: I. Additions to Nitrones 22-25 II. Future Work 25 vii. Chapter V: Experimental I. N,O-acetal Formation 25-28 II. Addition to Nitrones 28-29 viii. Chapter VI: References 30 i Acknowledgments I would like to acknowledge my research Dr. Wade Downey for all of his time and dedication to my research for the past two years.
    [Show full text]
  • Furanosyl Oxocarbenium Ion Conformational Energy Landscape
    DOI: 10.1002/chem.201900651 Full Paper & Stereoselectivity |Hot Paper| Furanosyl Oxocarbenium Ion Conformational Energy Landscape Maps as a Tool to Study the Glycosylation Stereoselectivity of 2-Azidofuranoses, 2-Fluorofuranoses and Methyl Furanosyl Uronates Stefan van der Vorm, Thomas Hansen, Erwin R. van Rijssel, Rolf Dekkers, Jerre M. Madern, Herman S. Overkleeft, Dmitri V. Filippov, Gijsbert A. van der Marel, and Jeroen D. C. Code*[a] Abstract: The 3D shape of glycosyl oxocarbenium ions de- ic furanoses by using a combined computational and experi- termines their stability and reactivity and the stereochemical mental approach. Surprisingly, all furanosyl donors studied course of SN1 reactions taking place on these reactive inter- react in a highly stereoselective manner to provide the 1,2- mediates is dictated by the conformation of these species. cis products, except for the reactions in the xylose series. The nature and configuration of functional groups on the The 1,2-cis selectivity for the ribo-, arabino- and lyxo-config- carbohydrate ring affect the stability of glycosyl oxocarbeni- ured furanosides can be traced back to the lowest-energy 3E um ions and control the overall shape of the cations. We or E3 conformers of the intermediate oxocarbenium ions. herein map the stereoelectronic substituent effects of the The lack of selectivity for the xylosyl donors is related to the C2-azide, C2-fluoride and C4-carboxylic acid ester on the sta- occurrence of oxocarbenium ions adopting other conforma- bility and reactivity of the complete suite of diastereoisomer- tions. Introduction and they may in fact outweigh steric effects. For example, pro- tonated iminosugars, that is, carbohydrates having the endocy- Stereoelectonic effects dictate the shape and behaviour of clic oxygen replaced by a nitrogen, may change their confor- molecules.
    [Show full text]
  • A Thesis Entitled Thio-Arylglycosides with Various Aglycon Para-Substituents, a Useful Tool for Mechanistic Investigation Of
    A Thesis entitled Thio-arylglycosides with Various Aglycon Para-Substituents, a Useful Tool for Mechanistic Investigation of Chemical Glycosylations by Xiaoning Li Submitted as partial fulfillment of the requirements for the Master of Science Degree in Chemistry ___________________________ Advisor: Dr. Xuefei Huang ___________________________ College of Graduate Studies The University of Toledo August 2007 An Abstract of Thio-arylglycosides with Various Aglycon Para-Substituents, a Useful Tool for Mechanistic Investigation of Chemical Glycosylations by Xiaoning Li Submitted as partial fulfillment of the requirements for the Master of Science Degree in Chemistry The University of Toledo August 2007 Oligosaccharides are usually found as protein or lipid conjugates in cellular systems. They play crucial roles in many biological processes. Among many approaches, organic synthesis is a very important way to obtain the desired oligosaccharides for biological studies. To date, no general synthetic procedures are available for oligosaccharide synthesis. Laborious synthetic transformations are generally required in order to obtain the desired regio- and/or stereo-selective control in oligosaccharide synthesis, due to their diverse and complex structures and many chemical equivalent ii hydroxyl functional groups. To achieve a rapid synthetic routine with high yields, a key step - glycosylation in oligosaccharide synthesis needs to be well understood. Thus an insight into the mechanism of glycosylation will provide valuable information potentially leading to the development of generalized glycosylation method. In this work, kinetic properties of glycosylation were evaluated by model reactions between three different series of glycosyl donors and three different glycosyl acceptors. The glycosylation mechanism was analyzed in the context of a linear-free energy relationship.
    [Show full text]
  • Discovery, Characterization, and Development of Small
    DISCOVERY, CHARACTERIZATION, AND DEVELOPMENT OF SMALL MOLECULE INHIBITORS OF GLYCOGEN SYNTHASE Buyun Tang Submitted to the faculty of the University Graduate School in partial fulfillment of the requirements for the degree Doctor of Philosophy in the Department of Biochemistry and Molecular Biology, Indiana University June 2020 Accepted by the Graduate Faculty of Indiana University, in partial fulfillment of the requirements for the degree of Doctor of Philosophy. Doctoral Committee ______________________________________ Thomas D. Hurley, Ph.D., Chair ______________________________________ Peter J. Roach, Ph.D. April 30, 2020 ______________________________________ Millie M. Georgiadis, Ph.D. ______________________________________ Steven M. Johnson, Ph.D. ______________________________________ Jeffrey S. Elmendorf, Ph.D. ii © 2020 Buyun Tang iii Dedication I dedicate this work to my beloved family, my grandparents, my parents, and my brother. iv Acknowledgement First and foremost, I would like to express my deepest gratitude to my thesis advisor, Dr. Thomas D. Hurley. I am grateful to have him as my research mentor over the past four years. He has continuously guided, supported, and inspired me during my study at IUSM. His passion for science and devotion of mentorship offered me the best training experience I could ever receive in graduate school. His easygoing personality reminded me of all the wonderful times inside and outside of the lab. I remember him instructing me handling crystal instrument hand by hand, flying with me to San Diego for a conference, and driving me to a farm restaurant at Illinois. Dr. Hurley is not only an outstanding research mentor, but also a trustful friend. I deeply thank him for all his time, patience, and encouragement along my graduate training.
    [Show full text]
  • Increased Glycosidic Bond Stabilities in 4-C-Hydroxymethyl Linked Disaccharides ⇑ Gour Chand Daskhan, Narayanaswamy Jayaraman
    Carbohydrate Research 346 (2011) 2394–2400 Contents lists available at SciVerse ScienceDirect Carbohydrate Research journal homepage: www.elsevier.com/locate/carres Increased glycosidic bond stabilities in 4-C-hydroxymethyl linked disaccharides ⇑ Gour Chand Daskhan, Narayanaswamy Jayaraman Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India article info abstract Article history: Three new hydroxymethyl-linked non-natural disaccharide analogues, containing an additional methy- Received 25 May 2011 lene group in between the glycosidic linkage, were synthesized by utilizing 4-C-hydroxymethyl-a-D- Received in revised form 24 August 2011 glucopyranoside as the glycosyl donor. A kinetic study was undertaken to assess the hydrolytic stabilities Accepted 25 August 2011 of these new disaccharide analogues toward acid-catalyzed hydrolysis, at 60 °C and 70 °C. The studies Available online 2 September 2011 showed that the disaccharide analogues were stable, by an order of magnitude, than naturally-occurring disaccharides, such as, cellobiose, lactose, and maltose. The first order rate constants were lower than Keywords: that of methyl glycosides and the trend of hydrolysis rate constants followed that of naturally-occurring Acid hydrolysis disaccharides. -Anomer showed faster hydrolysis than the b-anomer and the presence of axial hydroxyl Carbohydrates a Disaccharide analogues group also led to faster hydrolysis among the disaccharide analogues. Energy minimized structures, Glycosidic bond derived through molecular modeling, showed that dihedral angles around the glycosidic bond in disac- Kinetics charide analogues were nearly similar to that of naturally-occurring disaccharides. Oxocarbenium ion Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction determined to be important, prior to heterolysis of C1–O1 bond.
    [Show full text]
  • Characterization of Glycosyl Dioxolenium Ions and Their Role in Glycosylation Reactions
    ARTICLE https://doi.org/10.1038/s41467-020-16362-x OPEN Characterization of glycosyl dioxolenium ions and their role in glycosylation reactions Thomas Hansen 1,4, Hidde Elferink2,4, Jacob M. A. van Hengst1, Kas J. Houthuijs 2, Wouter A. Remmerswaal 1, Alexandra Kromm2, Giel Berden 3, Stefan van der Vorm 1, Anouk M. Rijs 3, Hermen S. Overkleeft1, Dmitri V. Filippov1, Floris P. J. T. Rutjes2, Gijsbert A. van der Marel1, Jonathan Martens3, ✉ ✉ ✉ Jos Oomens 3 , Jeroen D. C. Codée 1 & Thomas J. Boltje 2 1234567890():,; Controlling the chemical glycosylation reaction remains the major challenge in the synthesis of oligosaccharides. Though 1,2-trans glycosidic linkages can be installed using neighboring group participation, the construction of 1,2-cis linkages is difficult and has no general solution. Long-range participation (LRP) by distal acyl groups may steer the stereoselectivity, but contradictory results have been reported on the role and strength of this stereoelectronic effect. It has been exceedingly difficult to study the bridging dioxolenium ion intermediates because of their high reactivity and fleeting nature. Here we report an integrated approach, using infrared ion spectroscopy, DFT computations, and a systematic series of glycosylation reactions to probe these ions in detail. Our study reveals how distal acyl groups can play a decisive role in shaping the stereochemical outcome of a glycosylation reaction, and opens new avenues to exploit these species in the assembly of oligosaccharides and glycoconju- gates to fuel biological research. 1 Leiden University, Leiden Institute of Chemistry, Einsteinweg 55, 2333 CC Leiden, The Netherlands. 2 Radboud University Institute for Molecules and Materials, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands.
    [Show full text]
  • Controlling the Stereoselectivity of Glycosylation Via Solvent Effects
    Canadian Journal of Chemistry Controlling the Stereoselectivity of Glycosylation via Solvent Effects Journal: Canadian Journal of Chemistry Manuscript ID cjc-2016-0417.R1 Manuscript Type: Invited Review Date Submitted by the Author: 16-Sep-2016 Complete List of Authors: Kafle, Arjun; University of New Mexico Liu, Jun; University of New Mexico Cui, Lina; University of New Mexico, Chemistry and Chemical Biology; University Draftof New Mexico, UNM Comprehensive Cancer Center Glycosylation, Stereoselectivity, Synthesis, Solvent effect, Carbohydrate Keyword: chemistry https://mc06.manuscriptcentral.com/cjc-pubs Page 1 of 29 Canadian Journal of Chemistry Controlling the Stereoselectivity of Glycosylation via Solvent Effects Arjun Kafle, Jun Liu, and Lina Cui* Address: Department of Chemistry and Chemical Biology, UNM Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM 87131, U.S.A. Corresponding author: e-mail: [email protected]; Tel: 505-277-6519; Fax: 505-277-2609 Invited Review Dedicated to Prof. David R. Bundle onDraft the occasion of his retirement (Special Issue for Prof. Bundle) 1 https://mc06.manuscriptcentral.com/cjc-pubs Canadian Journal of Chemistry Page 2 of 29 Abstract: This review covers a special topic in carbohydrate chemistry – solvent effects on the stereoselectivity of glycosylation reactions. Obtaining highly stereoselective glycosidic linkages is one of the most challenging tasks in organic synthesis, as it is affected by various controlling factors. One of the least understood factors is the effect of solvents. We have described the known solvent effects while providing both general rules and specific examples. We hope this review will not only help fellow researchers understand the known aspects of solvent effects and use that in their experiments, moreover we expect more studies on this topic will be started and continued to expand our understanding of the mechanistic aspects of solvent effects in glycosylation reactions.
    [Show full text]
  • 1 General Aspects of the Glycosidic Bond Formation Alexei V
    j1 1 General Aspects of the Glycosidic Bond Formation Alexei V. Demchenko 1.1 Introduction Since the first attempts at the turn of the twentieth century, enormous progress has been made in the area of the chemical synthesis of O-glycosides. However, it was only in the past two decades that the scientificworldhadwitnessedadramatic improvement the methods used for chemical glycosylation. The development of new classes of glycosyl donors has not only allowed accessing novel types of glycosidic linkages but also led to the discovery of rapid and convergent strategies for expeditious oligosaccharide synthesis. This chapter summarizes major prin- ciples of the glycosidic bond formation and strategies to obtain certain classes of compounds, ranging from glycosides of uncommon sugars to complex oligosac- charide sequences. 1.2 Major Types of O-Glycosidic Linkages There are two major types of O-glycosides, which are, depending on nomen- clature, most commonly defined as a-andb-, or 1,2-cis and 1,2-trans glycosides. The 1,2-cis glycosyl residues, a-glycosides for D-glucose, D-galactose, L-fucose, D-xylose or b-glycosides for D-mannose, L-arabinose, as well as their 1,2-trans counter- parts (b-glycosides for D-glucose, D-galactose, a-glycosides for D-mannose,etc.),are equally important components in a variety of natural compounds. Representative examples of common glycosides are shown in Figure 1.1. Some other types of glycosides, in particular 2-deoxyglycosides and sialosides, can be defined neither as 1,2-cis nor as 1,2-trans derivatives, yet are important targets because of their com- mon occurrence as components of many classes of natural glycostructures.
    [Show full text]
  • Glycogen, Branched Polymer of Glucose Serves As a Major Repository of Carbon and Energy in Many Organisms Form Bacteria to Highe
    STRUCTURE AND REGULATION OF YEAST GLYCOGEN SYNTHASE Sulochanadevi Baskaran Submitted to the faculty of the University Graduate School in partial fulfillment of the requirements for the degree Doctor of Philosophy in the Department of Biochemistry and Molecular Biology Indiana University August 2010 Accepted by the Faculty of Indiana University, in partial fulfillment of the requirements for the degree of Doctor of Philosophy. Thomas D. Hurley, Ph.D., Chair Anna A. DePaoli-Roach, Ph.D. Doctoral Committee Millie M. Georgiadis, Ph.D. Peter J. Roach, Ph.D. May 19, 2010 William J. Sullivan Jr., Ph.D. ii Dedication I dedicate this work to my family, friends and mentors, for their support, encouragement, inspiration and guidance. iii Acknowledgements The work presented here is a result of the collaborative effort of many people and it is my pleasure to thank everyone who made this possible. First and foremost, I am indebted to my advisor, Dr. Thomas Hurley, for his invaluable scientific guidance, enthusiastic supervision and encouragement throughout my thesis research work. I am very grateful for his support, patience and his efforts in explaining and teaching me the concepts of macromolecular crystallography. I will always be thankful to him for teaching me the most important factor that is required for scientific research - perseverance. I would like to express my sincere gratitude to my committee members Drs. Peter Roach, Anna DePaoli-Roach, Millie Georgiadis and William Sullivan for their time, support, guidance and helpful suggestions. I am thankful to lab colleagues Dr. Samantha Perez-Miller, Dr. Heather Larson, Dr. Jianzhong Zhou, Dr. Lillian González-Segura, Ram Vanam, Jason Braid, Lili Zang, Bibek Parajuli, Dr.
    [Show full text]
  • The Influence of Acceptor Nucleophilicity on the Glycosylation Reaction Mechanism
    Chemical Science View Article Online EDGE ARTICLE View Journal | View Issue The influence of acceptor nucleophilicity on the glycosylation reaction mechanism† Cite this: Chem. Sci.,2017,8, 1867 S. van der Vorm, T. Hansen, H. S. Overkleeft, G. A. van der Marel and J. D. C. Codee´ * A set of model nucleophiles of gradually changing nucleophilicity is used to probe the glycosylation reaction mechanism. Glycosylations of ethanol-based acceptors, bearing varying amounts of fluorine atoms, report on the dependency of the stereochemistry in condensation reactions on the nucleophilicity of the acceptor. Three different glycosylation systems were scrutinized, that differ in the reaction mechanism, that – putatively – prevails during the coupling reaction. It is revealed that the stereoselectivity in glycosylations of benzylidene protected glucose donors are very susceptible to acceptor nucleophilicity whereas condensations of benzylidene mannose and mannuronic acid donors represent more robust glycosylation systems in terms of diastereoselectivity. The change in stereoselectivity with decreasing acceptor nucleophilicity is related to a change in reaction mechanism Received 17th October 2016 shifting from the SN2 side to the SN1 side of the reactivity spectrum. Carbohydrate acceptors are Creative Commons Attribution 3.0 Unported Licence. Accepted 8th November 2016 examined and the reactivity–selectivity profile of these nucleophiles mirrored those of the model DOI: 10.1039/c6sc04638j acceptors studied. The set of model ethanol acceptors thus provides a simple and effective “toolbox” to www.rsc.org/chemicalscience investigate glycosylation reaction mechanisms and report on the robustness of glycosylation protocols. Introduction are displaced in a reaction mechanism having an associative SN2- character, while the oxocarbenium ion-like intermediates are The connection of two carbohydrate building blocks to construct engaged in an SN1-like reaction.
    [Show full text]
  • Predictive Model for Oxidative C−H Bond Functionalization Reactivity with 2,3-Dichloro-5,6-Dicyano-1,4-Benzoquinone (DDQ)
    Predictive Model for Oxidative C!H Bond Functionalization Reactivity with 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) Cristian A. Morales-Rivera, Paul E. Floreancig*, and Peng Liu* Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States ABSTRACT: 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) is a highly effective reagent for promoting C!H bond functionalization. The oxidative cleavage of benzylic and allylic C−H bonds using DDQ can be coupled with an intra- or intermolecular nucleophilic addition to generate new carbon–carbon or carbon–heteroatom bonds in a wide range of substrates. The factors that control the reactivity of these reactions are well defined experimentally but the mechanistic details and the role of substituents in promoting the transformations have not been firmly established. Herein, we report a detailed computational study on the mechanism and substituent effects for DDQ-mediated oxidative C−H cleavage reactions in a variety of substrates. DFT calculations show that these reactions proceed through a hydride transfer within a charge transfer complex. Reactivity is dictated by the stability of the carbocation intermediate, the degree of charge transfer in the transition states, and, in certain cases, secondary orbital interactions between the π orbital of the forming cation and the LUMO of DDQ. A linear free energy relationship was established to offer a predictive model for reactivity of different types of C−H bonds based on the electronic properties of the substrate. 1. Introduction DDQ-mediated C–H functionalization has been performed on Carbon–hydrogen bond functionalization reactions can greatly a wide variety of substrates, with specific examples being illustrated facilitate chemical synthesis due to their capability to increase in Scheme 2.
    [Show full text]
  • Template for Electronic Submission to ACS Journals
    Max-Planck-Institut für Kohlenforschung This is the peer-reviewed version of the following article: Nature Chemistry 2018, 10, 888-894, which has been published in final form at: https://www.nature.com/articles/s41557-018-0065-0. This article may be used for non-commercial purposes. DOI: 10.1038/s41557-018-0065-0 Approaching Sub-ppm Level Asymmetric Organocatalysis of a Highly Challenging and Scalable Carbon–Carbon Bond Forming Reaction Han Yong Bae,a Denis Höfler,a Philip S. J. Kaib,a Pinar Kasaplar,a Chandra Kanta De,a Arno Döhring,a Sunggi Lee,a Karl Kaupmees,b Ivo Leitob and Benjamin Lista* aMax-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470 Mülheim an der Ruhr, Germany. bUniversity of Tartu, Institute of Chemistry, Ravila 14a, Tartu 50411, Estonia. *email: [email protected] Abstract: The chemical synthesis of organic molecules involves, at its very essence, the creation of carbon–carbon bonds. In this context, the aldol reaction is among the most important synthetic methods, and a wide variety of catalytic and stereoselective versions have been reported. However, aldolizations yielding tertiary aldols, which result from the reaction of an enolate with a ketone, are challenging and only a few catalytic asymmetric Mukaiyama aldol reactions with ketones as electrophiles have been described. These methods typically require relatively high catalyst loadings, deliver substandard enantioselectivity or need special reagents or additives. We now report extremely potent catalysts that readily enable the reaction of silyl ketene acetals with a diverse set of ketones to furnish the corresponding tertiary aldol products in excellent yields and enantioselectivities.
    [Show full text]