DOCSLIB.ORG

Asymmetric Total Synthesis of Congeners of Hydramycin, an Anthraquinone-Type Antitumor Agent

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Asymmetric Total Synthesis of Congeners of Hydramycin, an Anthraquinone-Type Antitumor Agent University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Doctoral Dissertations Graduate School 12-2011 Asymmetric Total Synthesis of Congeners of Hydramycin, an Anthraquinone-Type Antitumor Agent Costyl Ngnouomeuchi Njiojob [email protected] Follow this and additional works at: https://trace.tennessee.edu/utk_graddiss Part of the Heterocyclic Compounds Commons, Organic Chemicals Commons, and the Polycyclic Compounds Commons Recommended Citation Njiojob, Costyl Ngnouomeuchi, "Asymmetric Total Synthesis of Congeners of Hydramycin, an Anthraquinone-Type Antitumor Agent. " PhD diss., University of Tennessee, 2011. https://trace.tennessee.edu/utk_graddiss/1210 This Dissertation is brought to you for free and open access by the Graduate School at TRACE: Tennessee Research and Creative Exchange. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of TRACE: Tennessee Research and Creative Exchange. For more information, please contact [email protected]. To the Graduate Council: I am submitting herewith a dissertation written by Costyl Ngnouomeuchi Njiojob entitled "Asymmetric Total Synthesis of Congeners of Hydramycin, an Anthraquinone-Type Antitumor Agent." I have examined the final electronic copy of this dissertation for form and content and recommend that it be accepted in partial fulfillment of the equirr ements for the degree of Doctor of Philosophy, with a major in Chemistry. David C. Baker, Major Professor We have read this dissertation and recommend its acceptance: Shawn Campagna, Ben Xue, Elizabeth Howell Accepted for the Council: Carolyn R. Hodges Vice Provost and Dean of the Graduate School (Original signatures are on file with official studentecor r ds.) Asymmetric Total Synthesis of Congeners of Hydramycin, an Anthraquinone-Type Antitumor Agent A Dissertation Presented for the Doctor of Philosophy Degree The University of Tennessee, Knoxville Costyl Ngnouomeuchi Njiojob December 2011 DEDICATION This dissertation is dedicated to my Parents Francois Ngnouomeuchi and Lydie T. Nguepnang Ngnouomeuchi who initiated my education process and gave me the zeal to always work hard in order to achieve success. I also give special thanks to my wife Tatiana K. Njiojob and my son Iann Davis N. Njiojob for their fabulous support during my years of graduate school. ii AKNOWLEDGEMENTS First, I would like to express my sincere gratitude to my research advisor Prof. David C. Baker for the opportunity he provided me with to do research in his group, and the encouragement and support throughout my years of graduate school. I also express my appreciation to Drs. Howell, Xue and Campagna, for accepting to serve in my dissertation committee and for their contribution to my research. I would also like to thank the past and present members of the Baker group: Dr. Medhanit Bahta, Dr. Julio Gutierrez and Dr. Riyam Kafri for teaching me various laboratory techniques; Dr. Samson Francis for his assistance with chemistry and computer related issues. Chad LeCroix for his assistance with NMR related problems. Steven Glass, Irene Abia, Yundi Gan, Bo Meng, Veronica Gantert, Andy Hahn, Andy Rowe, Andrew Moss, Robert Simion and Adnan Dervishi for their support and friendship throughout these years. I would also like to thank Dr. Carlos Steren for his assistance with 2D NMR techniques used for the elucidation of my final compounds and Dr. Joel Putnam for providing me with the chiral columns and knowledge required to analyze my final compounds. I will also use this opportunity to thank everybody in the Department of chemistry of the University of Tennessee-Knoxville who contributed to the accomplishment of this project. Finally, I am sincerely grateful to my Family: My parents Francois Ngnouomeuchi and Lydie Nguepnang T. Ngnouomeuchi for their incredible moral support and prayers throughout my years of graduate school. I am also thankful to my brothers and sisters Romeo N. Kepomi, Bernice N. Ngnouomeuchi, Yannick T. Ngnouomeuchi and Patricia N. Moffo for their encouragement and support. I am infinitely grateful to my wife Tatiana K. Njiojob for always iii being very supportive and patient throughout my years of graduate school and my son Iann Davis N. Njiojob for entertaining me during tough times. Above all, I give thanks to God who provided me with the necessary strength throughout these years. iv ABSTRACT Hydramycin is an antitumor antibiotic isolated from Streptomyces violaceus. It is a pyranoanthraquinone-type antitumor agent that has shown broad-spectrum activity against a variety of human-derived cancer cell lines. Among tumors evaluated at the National Cancer −10 Institute (lung, colon, melanoma, breast and prostate), GI50s were <10 M in the NCI's 60-cell- line panel. We embarked on the synthesis and evaluation of a simplified congener 2-(1-hydroxy- 1-(oxiran-2-yl)ethyl)-4H-naphtho[2,3-h]chromene-4,7,12-trione(17), which would facilitate synthesis while retaining the potent activity. Hydramycin has two chiral centers, and our goal is to design and synthesize all the possible enantiomers (four in total) for the congener of hydramycin 17 in order to ascertain which of the enantiomers is responsible for the observed antitumor activity. The use of enantiospecific techniques such as the Sharpless epoxidation was initially tried to introduce the chiral centers at a later stage during the multi-step synthesis and obtain the required pure enantiomers. Due to some limitations observed with this technique and many other asymmetric epoxidation techniques which utilize very substrate-specific ligands, we then modified the synthetic scheme to use another procedure, the Sharpless asymmetric dihydroxylation in order to obtain two of the pure enantiomers of this congener of hydramycin. The other two enantiomers are selectively obtained using the Sharpless asymmetric dihydroxylation procedure via cyclic sulfate intermediates, followed by a modified irreversible Payne rearrangement procedure. These routes then allowed us to obtain separately all four stereoisomers, each having more than 90% ee as determined on chiral columns with HPLC. The four stereoisomers have been fully characterized and will then be tested separately to ascertain which of the isomers is responsible for the observed antitumor activity. v TABLE OF CONTENTS I. INTRODUCTION………………………………………………………………...1 A. Anthraquinone…………………………………………………………………..1 B. Anthraquinone derivatives and their applications………………………………3 C. Pyranoanthraquinone and related biological activity………………………… 5 D. Hydramycin……………………………………………………………………..7 E. Mode of action of antitumor agents having hydramycin-like structures………..8 F. Hydramycin and antitumor activity……………………………………………..11 II. STATEMENT OF THE PROBLEM…………………………………………….16 A. Synthetic challenges…………………………………………………………….16 B. Research plan and general retrosynthetic strategy……………………………...18 C. Dissertation summary…………………………………………………………...20 III. DISCUSSION……………………………………………………………………...21 A. First attempt for the synthesis of asymmetric hydramycin congener 17………..21 B. Synthesis of a model compound to test the Sharpless asymmetric epoxidation reaction…………………………………………………………………………..27 C. Synthesis of second model compound to test the SAE reaction………………...28 D. Synthesis of asymmetric tertiary epoxy alcohols using the Cram-chelate rule….31 E. Second attempt to synthesize asymmetric hydramycin congener 17……………33 F. Attempts of enantioselective coupling reaction between the alkyne containing the tertiary allylic alcohol and the aldehyde intermediate……………………….36 vi G. Attempts to synthesize the asymmetric version of hydramycin congener 17 using the Sharpless asymmetric dihydroxylation technique…..............................39 1. First attempt for the synthesis of asymmetric hydrymacin congener 17A and 17A’ via the SAD route…………………………………………….……42 2. Final attempt for the synthesis of asymmetric hydramycin congeners 17A and 17A’ via the SAD reaction………………………………………………45 H. First attempt of the synthesis of two other hydramycin congeners 17B and 17B’……………………………………………………………………………...54 1. Mitsunobu trial on intermediate 16 or 18……………………………………54 2. Second attempt to synthesize the hydramycin congeners 17B and 17B’ by applying the Mitsunobu reaction to intermediate 20 and 21……………...55 I. Formation of a trans-diol using the modified irreversible Payne rearrangement reaction……………………………………………………………………….…..56 J. Analysis of final compounds and some asymmetric intermediates with 1D and 2D NMR spectroscopy, and chiral column HPLC…………………………….…65 IV. CONCLUSIONS AND FUTURE WORK…………………………………….…..77 V. EXPERIMENTALS………………………………………………………………...81 A. General methods………………………………………………………...........81 B. Preparation of tert-Butyldimethyl(pent-1-en-4-yn-3-yloxy)silane (34)...........82 C. Synthesis of 2-(4-((tert-Butyldimethylsilyl)oxy)-1-hydroxyhex-5-en-2-yn- 1-yl)-1-hydroxyanthracene-9,10-dione (35)……………………………….….85 D. Synthesis of 2-(prop-1-en-2-yl)-4H-naphtho[2,3-h]chromene-4,7,12-trione (40)……………………………………………………………………………86 vii E. Preparation of 2-(2-hydroxybut-3-en-2-yl)-4H-naphtho[2,3-h]chromene- 4,7,12-trione (55)…………………………………………………………….90 F. Preparation of 2-phenylbut-3-en-2-ol (63)…………………………………..92 G. Synthesis of (S)-1-((S)-oxiran-2-yl)-1-phenylethanol (61)…………………..93 H. Preparation of (E)-3-Methyl-5-(trimethylsilyl)pent-2-en-4-yn-1-ol (4)……..97 I. Synthesis of tert-Butyl(dimethyl){[(2E)-3-methylpent-2-en-4-yn-1- yl]oxy}silane (6)……………………………………………………………..100 J. Preparation of 1-Hydroxy-9,10-dioxo-9,10-dihydroanthracene-2- carbaldehyde
Load more

Recommended publications
  • Chiral Proton Catalysis: Design and Development of Enantioselective Aza-Henry and Diels-Alder Reactions
    CHIRAL PROTON CATALYSIS: DESIGN AND DEVELOPMENT OF ENANTIOSELECTIVE AZA-HENRY AND DIELS-ALDER REACTIONS Ryan A. Yoder 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 Chemistry, Indiana University June 2008 Accepted by the Graduate Faculty, Indiana University, in partial fulfillment of the requirements for the degree of Doctor of Philosophy. Doctoral Committee _____________________________ Jeffrey N. Johnston, Ph.D. _____________________________ Daniel J. Mindiola, Ph.D. _____________________________ David R. Williams, Ph.D. _____________________________ Jeffrey Zaleski, Ph.D. April 24, 2008 ii © 2008 Ryan A. Yoder ALL RIGHTS RESERVED iii DEDICATION This work is dedicated to my parents, David and Doreen Yoder, and my sister, LeeAnna Loudermilk. Their unwavering love and support provided the inspiration for me to pursue my dreams. The sacrifices they have made and the strength they have shown continue to motivate me to be a better person each and every day. Thank you mom, dad, and little sis for being the rocks that I can lean on and the foundation that allowed me to find the happiness I have today. Without you, none of this would have been possible. iv ACKNOWLEDGEMENTS First and foremost I want to thank my research advisor, Professor Jeffrey N. Johnston. I am incredibly grateful for his mentoring and guidance throughout my time in the Johnston group. He has instilled in me a solid foundation in the fundamentals of organic chemistry and at the same time has taught me how to apply innovative and creative solutions to complex problems.
    [Show full text]
  • Oxidation of Secondary Alcohols to Ketones
    Oxidation of secondary alcohols to ketones The oxidation of secondary alcohols to ketones is an important oxidation reaction in organic chemistry. Where a secondary alcohol is oxidised, it is converted to a ketone. The hydrogen from the hydroxyl group is lost along with the hydrogen bonded to the second carbon. The remaining oxygen then forms double bonds with the carbon. This leaves a ketone, as R1–COR2. Ketones cannot normally be oxidised any further because this would involve breaking a C–C bond, which requires too much energy.[1] The reaction can occur using a variety of oxidants. Contents Potassium dichromate PCC (Pyridinium chlorochromate) Dess–Martin oxidation Swern oxidation Oppenauer oxidation Fétizon oxidation See also References Potassium dichromate A secondary alcohol can be oxidised into a ketone using acidified potassium dichromate and heating under 2− 3+ reflux. The orange-red dichromate ion, Cr2O7 , is reduced to the green Cr ion. This reaction was once used in an alcohol breath test. PCC (Pyridinium chlorochromate) PCC, when used in an organic solvent, can be used to oxidise a secondary alcohol into a ketone. It has the advantage of doing so selectively without the tendency to over-oxidise. Dess–Martin oxidation The Dess–Martin periodinane is a mild oxidant for the conversion of alcohols to aldehydes or ketones.[2] The reaction is performed under standard conditions, at room temperature, most often in dichloromethane. The reaction takes between half an hour and two hours to complete. The product is then separated from the spent periodinane.[3] Swern oxidation Swern oxidation oxidises secondary alcohols into ketones using oxalyl chloride and dimethylsulfoxide.
    [Show full text]
  • Alcohol Oxidation
    Alcohol oxidation Alcohol oxidation is an important organic reaction. Primary alcohols (R-CH2-OH) can be oxidized either Mechanism of oxidation of primary alcohols to carboxylic acids via aldehydes and The indirect oxidation of aldehyde hydrates primary alcohols to carboxylic acids normally proceeds via the corresponding aldehyde, which is transformed via an aldehyde hydrate (R- CH(OH)2) by reaction with water. The oxidation of a primary alcohol at the aldehyde level is possible by performing the reaction in absence of water, so that no aldehyde hydrate can be formed. Contents Oxidation to aldehydes Oxidation to ketones Oxidation to carboxylic acids Diol oxidation References Oxidation to aldehydes Oxidation of alcohols to aldehydes is partial oxidation; aldehydes are further oxidized to carboxylic acids. Conditions required for making aldehydes are heat and distillation. In aldehyde formation, the temperature of the reaction should be kept above the boiling point of the aldehyde and below the boiling point of the alcohol. Reagents useful for the transformation of primary alcohols to aldehydes are normally also suitable for the oxidation of secondary alcohols to ketones. These include: Oxidation of alcohols to aldehydes and ketones Chromium-based reagents, such as Collins reagent (CrO3·Py2), PDC or PCC. Sulfonium species known as "activated DMSO" which can result from reaction of DMSO with electrophiles, such as oxalyl chloride (Swern oxidation), a carbodiimide (Pfitzner-Moffatt oxidation) or the complex SO3·Py (Parikh-Doering oxidation). Hypervalent iodine compounds, such as Dess-Martin periodinane or 2-Iodoxybenzoic acid. Catalytic TPAP in presence of excess of NMO (Ley oxidation). Catalytic TEMPO in presence of excess bleach (NaOCl) (Oxoammonium-catalyzed oxidation).
    [Show full text]
  • Chiral Phosphorus Containing Calix[4]Arenes for Asymmetric Catalysis Andrii Karpus
    Chiral phosphorus containing calix[4]arenes for asymmetric catalysis Andrii Karpus To cite this version: Andrii Karpus. Chiral phosphorus containing calix[4]arenes for asymmetric catalysis. Catalysis. Uni- versité Paul Sabatier - Toulouse III, 2017. English. NNT : 2017TOU30045. tel-01811136 HAL Id: tel-01811136 https://tel.archives-ouvertes.fr/tel-01811136 Submitted on 8 Jun 2018 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. 5)µ4& &OWVFEFMPCUFOUJPOEV %0$503"5%&-6/*7&34*5²%&506-064& %ÏMJWSÏQBS Université Toulouse 3 Paul Sabatier (UT3 Paul Sabatier) Cotutelle internationale avec Université nationale Taras-Chevtchenko de Kiev 1SÏTFOUÏFFUTPVUFOVFQBS KARPUS Andrii le mardi 24 janvier 2017 5JUSF Calix[4]arènes chiraux contenant des groupes phosphine comme ligands pour la catalyse ²DPMF EPDUPSBMF et discipline ou spécialité ED SDM : Chimie organométallique de coordination - CO 043 6OJUÏEFSFDIFSDIF CNRS - UPR 8241 - Laboratoire de Chimie de Coordination (LCC) %JSFDUFVSUSJDF T EFʾÒTF Dr. MANOURY Eric Pr. VOITENKO Zoia Jury : Dr. MANOURY Eric, Directeur de thèse Pr. VOITENKO Zoia, Co-directrice de thèse Dr. SEMERIL David, Rapporteur Pr. KOROTKIKH Nikolay, Rapporteur Pr. GENISSON YVES, Examinateur Dr. SMOLII Oleg, Examinateur Université Toulouse III Paul Sabatier (UT3 Paul Sabatier) Andrii O.
    [Show full text]
  • Regioselective and Stereodivergent Synthesis of Enantiomerically Pure Vic-Diamines from Chiral Β-Amino Alcohols with 2-Pyridyl and 0 † 6-(2,2 -Bipyridyl) Moieties
    molecules Article Regioselective and Stereodivergent Synthesis of Enantiomerically Pure Vic-Diamines from Chiral β-Amino Alcohols with 2-Pyridyl and 0 y 6-(2,2 -Bipyridyl) Moieties Marzena Wosi ´nska-Hrydczuk,Przemysław J. Boraty ´nski and Jacek Skar˙zewski* Chair of Organic and Medicinal Chemistry, Faculty of Chemistry, Wrocław University of Science and Technology, Wyb. Wyspia´nskiego27, 50-370 Wrocław, Poland; [email protected] (M.W.-H.); [email protected] (P.J.B.) * Correspondence: [email protected]; Tel.: +48-71-320-2464 This paper is dedicated to Professor Grzegorz Mlosto´non the occasion of his 70-th birthday. y Academic Editors: Zbigniew Czarnocki and Joanna Szawkało Received: 11 January 2020; Accepted: 6 February 2020; Published: 7 February 2020 Abstract: In this report, we describe the synthetic elaboration of the easily available enantiomerically pure β-amino alcohols. Attempted direct substitution of the hydroxyl group by azido-functionality in the Mitsunobu reaction with hydrazoic acid was inefficient or led to a diastereomeric mixture. These outcomes resulted from the participation of aziridines. Intentionally performed internal Mitsunobu reaction of β-amino alcohols gave eight chiral aziridines in 45–82% yield. The structural and configuration identity of products was confirmed by NMR data compared to the DFT calculated GIAO values. For 1,2,3-trisubstituted aziridines slow configurational inversion at the endocyclic nitrogen atom was observed by NMR at room temperature. Moreover, when aziridine was titrated with Zn(OAc)2 under NMR control, only one of two N-epimers directly participated in complexation. The aziridines underwent ring opening with HN3 to form the corresponding azido amines as single regio- and diastereomers in 90–97% yield.
    [Show full text]
  • 20 More About Oxidation–Reduction Reactions
    More About 20 Oxidation–Reduction Reactions OOC n important group of organic reactions consists of those that O A involve the transfer of electrons C from one molecule to another. Organic chemists H OH use these reactions—called oxidation–reduction reactions or redox reactions—to synthesize a large O variety of compounds. Redox reactions are also important C in biological systems because many of these reactions produce HH energy. You have seen a number of oxidation and reduction reactions in other chapters, but discussing them as a group will give you the opportunity to CH3OH compare them. In an oxidation–reduction reaction, one compound loses electrons and one com- pound gains electrons. The compound that loses electrons is oxidized, and the one that gains electrons is reduced. One way to remember the difference between oxidation and reduction is with the phrase “LEO the lion says GER”: Loss of Electrons is Oxi- dation; Gain of Electrons is Reduction. The following is an example of an oxidation–reduction reaction involving inorganic reagents: Cu+ + Fe3+ ¡ Cu2+ + Fe2+ In this reaction,Cu+ loses an electron, so Cu+ is oxidized. Fe3+ gains an electron, so Fe3+ is reduced. The reaction demonstrates two important points about oxidation– reduction reactions. First, oxidation is always coupled with reduction. In other words, a compound cannot gain electrons (be reduced) unless another compound in the reaction simultaneously loses electrons (is oxidized). Second, the compound that is oxidized (Cu+) is called the reducing agent because it loses the electrons that are used to reduce the other compound (Fe3+). Similarly, the compound that is reduced (Fe3+) is called the oxidizing agent because it gains the electrons given up by the other compound (Cu+) when it is oxidized.
    [Show full text]
  • Synthesis of Peptide and Protein Thioesters Through an N→S Acyl Shift
    Native Chemical Thioesterification: Synthesis of Peptide and Protein Thioesters through an N→S Acyl Shift Jaskiranjit Kang A thesis submitted in partial fulfilment of the requirements for the degree award of: Doctor of Philosophy University College London Department of Chemistry 2010 Native Chemical Thioesterification: Synthesis of Peptide and Protein Thioesters through an N→S Acyl Shift Declaration I, Jaskiranjit Kang, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. 2 Native Chemical Thioesterification: Synthesis of Peptide and Protein Thioesters through an N→S Acyl Shift Abstract The total chemical synthesis of a protein provides atomic-level control over its covalent structure, however polypeptides prepared by solid phase peptide synthesis are limited to approximately fifty amino acid residues. This limitation has been overcome by 'Native Chemical Ligation‘, which involves amide bond formation between two unprotected polypeptides: a peptide with a C-terminal thioester and an N-terminal cysteinyl peptide. Synthesis of the required peptide thioester is difficult, particularly by Fmoc-chemistry. During our studies towards the semisynthesis of erythropoietin, we discovered reaction conditions that reversed Native Chemical Ligation and generated peptide and protein thioesters through an N→S acyl transfer. O HS H3N O O O + H3O RSH N S SR H O A peptide with both a Gly-Cys and an Ala-Cys-Pro-glycolate ester sequence was selectively thioesterified between the Gly-Cys sequence upon microwave-heating at 80 °C with 30 % v/v 3-mercaptopropionic acid (MPA), to afford the peptide-Gly-MPA thioester (84 % yield).
    [Show full text]
  • Oxidation States of Carbon Oxidation and Reduction in Biology
    Oxidation States of Carbon • Addition of H (or “H-”) Reduction 2 • Loss of O2 or O H R H H carboxylic aldehyde alcohol alkane acid (or ketone) • Loss of H 2 Oxidation • Addition of O2 or O + Neither oxidation nor reduction: Addition or loss of H , H2O, or HX Oxidation and Reduction in Biology • Addition of H (or “H-”) Reduction 2 • Loss of O2 or O + h, in plants H OH carbon dioxide e.gg,g., glucose H O 4 C-O bonds per C HO 1 C-O bond per C 0 C-H bond per C HO OH 1 C-H bond per C H OH H H +O+ O2, in animals • Loss of H 2 Oxidation • Addition of O2 or O + Neither oxidation nor reduction: Addition or loss of H , H2O, or HX Biological Oxidation Gone Wrong component of glue alcohol 2 NAD+ dehydrogenase 2 NADH gamma-hydroxybutyrate (GHB, an intoxicant/ date rape drug) Dr. Kevin Carpenter, biochemical geneticist (specialist in pediatric metabolic disorders), Children’s Hospital at Westmead (Sydney), Australia. Behind him: The Agilent GC/MS New York Times, Nov. 8, 2007 used to analyze the Aqua Dots. “Sleuthing for Danger in Toy Beads” Hydrides as Reducing Agents Lithium aluminum hydride (LiAlH4) is a strong reducing agent. It will reduce any C=O containing functional group to an alcohol. + 2. H3O 1. LiAlH4 (or just H2O) carboxylic acid primary alcohol andthd then ano ther equivalent adds, unavoidably. One Reduced by LiAlH : equivalent of 4 H- adds, aldehyde ketone carboxylic ester acyl halide amide acid Hydrides as Reducing Agents Sodium borohydride (NaBH4) is a mild reducing agent.
    [Show full text]
  • Practical and Scalable Synthesis of Syn-Β-Hydroxyamino Acids
    Total Synthesis of Caprazamycin A: Practical and Scalable Title Synthesis of syn-β-Hydroxyamino Acids and Introduction of a Fatty Acid Side Chain to 1,4-Diazepanone Nakamura, Hugh; Tsukano, Chihiro; Yoshida, Takuma; Yasui, Author(s) Motohiro; Yokouchi, Shinsuke; Kobayashi, Yusuke; Igarashi, Masayuki; Takemoto, Yoshiji Journal of the American Chemical Society (2019), 141(21): Citation 8527-8540 Issue Date 2019-05-29 URL http://hdl.handle.net/2433/243177 This is the accepted manuscript of the article, which has been published in final form at https://doi.org/10.1021/jacs.9b02220.; The full-text file will be made open to the public on 8 May 2020 in accordance with Right publisher's 'Terms and Conditions for Self-Archiving'.; This is not the published version. Please cite only the published version. この論文は出版社版でありません。引用の際には 出版社版をご確認ご利用ください。 Type Journal Article Textversion author Kyoto University Total Synthesis of Caprazamycin A: Practical and Scalable Synthesis of syn--Hydroxyamino Acids and Introduction of a Fatty Acid Side Chain to 1,4-Diazepanone Hugh Nakamura,† Chihiro Tsukano,*,† Takuma Yoshida,† Motohiro Yasui,† Shinsuke Yokou- chi,† Yusuke Kobayashi,† Masayuki Igarashi,‡ and Yoshiji Takemoto*,† †Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan ‡Institute of Microbial Chemistry (BIKAKEN), Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan Supporting Information Placeholder ABSTRACT: The first total synthesis of caprazamycin A (1), a representative liponucleoside antibiotic, is described. Diastereoselective aldol reactions of aldehydes 12 and 25– 27, derived from uridine, with diethyl isocyanomalonate 13 and phenylcarbamate 21 were investigated using thiourea catalysts 14 or bases to synthesize syn--hydroxyamino acid derivatives.
    [Show full text]
  • Activation of Alcohols Toward Nucleophilic Substitution: Conversion of Alcohols to Alkyl Halides Amani Atiyalla Abdugadar
    University of Northern Colorado Scholarship & Creative Works @ Digital UNC Theses Student Research 12-1-2012 Activation of Alcohols Toward Nucleophilic Substitution: Conversion of Alcohols to Alkyl Halides Amani Atiyalla Abdugadar Follow this and additional works at: http://digscholarship.unco.edu/theses Recommended Citation Abdugadar, Amani Atiyalla, "Activation of Alcohols Toward Nucleophilic Substitution: Conversion of Alcohols to Alkyl Halides" (2012). Theses. Paper 22. This Text is brought to you for free and open access by the Student Research at Scholarship & Creative Works @ Digital UNC. It has been accepted for inclusion in Theses by an authorized administrator of Scholarship & Creative Works @ Digital UNC. For more information, please contact [email protected]. © 2012 Amani Abdugadar ALL RIGHTS RESERVED UNIVERSITY OF NORTHERN COLORADO Greeley, Colorado The Graduate School ACTIVATION OF ALCOHOLS TOWARD NEOCLEOPHILIC SUBSTITUTION: CONVERSION OF ALCOHOLS TO ALKYL HALIDES A Thesis Submitted in Partial Fulfillment of the Requirements for the Degree of Master of Science Amani Abdugadar College of Natural and Health Sciences Department of Chemistry and Biochemistry December, 2012 This Thesis by: Amani Abdugadar Entitled: Activation of Alcohols Toward Neocleophilic Substitution: Conversion of Alcohols to Alkyl Halides has been approved as meeting the requirement for the Master of Science in College of Natural and Health Sciences in Department of Chemistry and Biochemistry Accepted by the Thesis Committee ______________________________________________________ Michael D. Mosher, Ph.D., Research Co-Advisor ______________________________________________________ Richard W. Schwenz, Ph.D., Research Co-Advisor ______________________________________________________ David L. Pringle, Ph.D., Committee Member Accepted by the Graduate School _________________________________________________________ Linda L. Black, Ed.D., LPC Acting Dean of the Graduate School and International Admissions ABSTRACT Abdugadar, Amani.
    [Show full text]
  • A Tractable and Efficient One-Pot Synthesis of 5'-Azido-5'-Deoxyribonucleosides
    Molecules 2014, 19, 2434-2444; doi:10.3390/molecules19022434 OPEN ACCESS molecules ISSN 1420-3049 www.mdpi.com/journal/molecules Article A Tractable and Efficient One-Pot Synthesis of 5'-Azido-5'-deoxyribonucleosides Theodore V. Peterson, Tobin U. B. Streamland and Ahmed M. Awad * Chemistry Program, California State University Channel Islands, One University Drive, Camarillo, CA 93012, USA; E-Mails: [email protected] (T.V.P.); [email protected] (T.U.B.S.) * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1-805-437-2794; Fax: +1-805-437-8895. Received: 11 September 2013; in revised form: 11 February 2014 / Accepted: 12 February 2014 / Published: 21 February 2014 Abstract: Synthetic routes to 5'-azidoribonucleosides are reported for adenosine, cytidine, guanosine, and uridine, resulting in a widely applicable one-pot methodology for the synthesis of these and related compounds. The target compounds are appropriate as precursors in a variety of purposive syntheses, as the synthetic and therapeutic relevance of azido- and amino-modified nucleosides is expansive. Furthermore, in the conversion of alcohols to azides, these methods offer a tractable alternative to the Mitsunobu and other more difficult reactions. Keywords: modified nucleosides; 5'-azido nucleosides; Appel reaction; Mitsunobu reaction; antisense oligonucleotides; ribonucleic guanidine (RNG) 1. Introduction The synthesis and chemical modification of nucleosides is a major research topic in medicinal and bioorganic chemistry. The vast utilization of nucleosides in most aspects of cellular function makes them a tantalizing target for a variety of therapies with potentially wide ranging physiological and pharmacological effects [1–4].
    [Show full text]
  • 215 F12-Notes-Ch 13
    Chem 215 F12-Notes – Dr. Masato Koreeda - Page 1 of 13 Date: September 10, 2012 Chapter 13. Alcohols, Diols, and Ethers Overview: Chemistry and reactions of sp3 oxygen groups, particularly oxidation of an alcohol, ether formation, and reactions of oxirane (epoxide) groups. I. What are alcohols, phenols, and ethers? IUPAC names Common names Alcohols (R-OH) Primary alcohols CH3OH methanol methyl alcohol (1°-alcohols) CH3CH2OH ethanol ethyl alcohol pKa ~16-17 CH3CH2CH2OH 1-propanol n-propyl alcohol H3C C CH2OH 2-methyl-1-propanol isobutyl alcohol H3C H H3C C CH2OH 2,2-dimethyl-1-propanol neopentyl alcohol H3C CH3 H C Secondary alcohols 3 C OH 2-propanol isopropyl alcohol (2°-alcohols) H3C H pKa ~17-18 H C-CH 3 2 C OH 2-butanol sec-butyl alcohol H3C H Tertiary alcohols H3C C OH 2-methyl-2-propanol tert-butyl alcohol (3°-alcohols) H3C CH pKa ~19 3 Phenols (Ph-OH) pKa ~10-12 diethyl ether Ethers (R-O-R') CH3CH2-O-CH2CH3 Ph-O-CH=CH2 phenyl vinyl ether RO-: alkoxy CH3O methoxy CH3CH2O ethoxy ArO-: aryloxy PhO phenoxy II. Oxidation Oxidation – historical use of the term: (1) oxide (oxyd/oxyde) – the ‘acid’ form of an element; e.g., S + air → oxide of S (acid of sulfur) (2) oxidation or oxidize – to make such an acid, to make the oxide (3) oxygen – Lavoisier: substance in the air that makes acids; “the bringer of acids” = “oxygen” (4) oxidation or oxidize – to increase the % oxygen in a substance (reduction: to reduce the % oxygen) More modern definition: oxidation or oxidize – loss of electrons (coupled with reduction as gain of electrons) Note: The loss of electrons (oxidation) by one atom or compound must be matched by the gain of electrons (reduction) by another.
    [Show full text]