DOCSLIB.ORG

Chiral Proton Catalysis: Design and Development of Enantioselective Aza-Henry and Diels-Alder Reactions

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
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. His dedicated passion for chemistry continues to motivate me to be a better scientist and for that I will always be indebted to him. I would also like to thank all Johnston group members, both past and present. I would like to specifically acknowledge Dr. Ben Nugent, Anand Singh, Bo Shen, Travis Smith, and Abram Hess for their collaborative efforts to some of the work presented herein. Although I can not name all of them here, I would also like to specially thank Dr. Amie Williams, Dr. Rajesh Viswanathan, Dr. Ben Nugent, Dr. Jeremy Wilt, Julie Pigza, Travis Smith, Anand Singh, and Tyler Davis for their helpful discussions about chemistry as well as their for their friendships which I continue to cherish. In addition, I would like to express my gratitude to Dr. P. Andrew Evans, Dr. Daniel J. Mindiola, Dr. David R. Williams, and Dr. Jeffrey Zaleski for their participation on my graduate advisory committee. I would also like to thank Dr. John Huffman and Dr. Maren Pink for their help in obtaining the X-ray structures depicted in this work. v ABSTRACT Ryan A. Yoder CHIRAL PROTON CATALYSIS: DESIGN AND DEVELOPMENT OF ENANTIOSELECTIVE AZA-HENRY AND DIELS-ALDER REACTIONS The proton (H+) is arguably Nature's most common Lewis acid and is utilized by many enzymes to carry out asymmetric transformations. These “natural” Brønsted acid catalysts have served as an inspiration to synthetic organic chemists for the development of both regioselective and stereoselective bond forming reactions. Inspired by Nature’s elegance and motivated by the demand for inexpensive, robust and environmentally friendly catalysts, a Brønsted acid catalyst called the chiral proton was developed. This catalyst relies upon polar ionic hydrogen bonding for substrate activation and as a primary control element for enantioselection. The catalyst system was based on a coordination complex between a proton and a chiral, C2-symmetric BisAMidine ligand (BAM). This complex has demonstrated the ability to both activate and control the absolute and relative stereochemistry in the addition of silyl nitronates to Boc-protected imines. It was further demonstrated that nitroalkanes could be used in place of silyl nitronates (aza- Henry reaction), eliminating the need for preformation of the nucleophile. In the latter reaction, the amount of catalyst could be reduced to as low as 1 mol% without loss of enantioselectivity, attesting to the BAM ligand’s ability to sequester protons from bulk solvent. The products of this reaction provide access to enantioenriched 1,2-diamines. vi Furthermore, this catalyst system has been successfully applied to the enantioselective synthesis of both syn and anti α,β-diamino acids. The chiral BAM-protic acid complexes were further applied to the stereoselective intramolecular hetero-Diels-Alder reactions of azadienes. These catalysts were found to influence both the endo/exo selectivity, as well as the facial selectivity of the [4+2] cycloadditions. The azadienes used in this study were modeled after the putative Diels- Alder precursors in the biosynthesis of the brevianamide class of natural products. In addition, a novel Diels-Alder reaction was hypothesized as an alternative route to the synthesis of oseltamivir phosphate (Tamiflu). A model system was chosen to examine the effectiveness of this route. The chiral proton catalyst was shown to catalyze this model reaction to produce the desired exo Diels-Alder adduct. _____________________________________________ _____________________________________________ _____________________________________________ _____________________________________________ vii TABLE OF CONTENTS Chapter 1. Chiral Proton Catalysis and Activation Using Hydrogen Bonds: Overview 1 1.1. How Nature Serves as an Inspiration for Asymmetric Catalysis 1 1.1.1. Probing the Role of the Enzyme 1 1.1.2. Enantioselective Biomimetic Organic Syntheses 5 1.2. Asymmetric Brønsted Acid Catalysis 9 1.2.1. Brønsted Acids in Enantioselective Protonations 10 1.2.2. O-H Based Chiral Brønsted Acid Catalysts 11 1.2.3. N-H Based Chiral Brønsted Acid Catalysts 15 1.3. Polar Ionic Hydrogen Bonds 20 1.3.1. BAM Ligands 21 1.3.2. Reaction Development 26 Chapter 2. Chiral Proton Catalyzed Additions to Imines: Silyl Nitronate and Nitronic Acid Nucleophiles 29 2.1. Determination of the BAM Acidity Constant 29 2.1.1. Background on pKa Values 29 2.1.2. Determining pKa Values For Protonated BAM Complexes 32 2.2. Enantioselective Aza-Henry Reaction 34 2.2.1. Background 34 2.2.2. Silyl Nitronate Additions 39 2.2.3. Development of a Chiral Proton Catalyzed Direct Aza-Henry Reaction 46 2.3. Application of the Asymmetric Aza-Henry Reaction to the Synthesis of Enantioenriched α-Amino Acids 58 2.3.1. Enantioselective Synthesis of Anti-α,β-diamino Acids 59 2.3.2. Enantioselective Synthesis of Syn-α,β-diamino Acids 63 2.3.3. Rationale for Stereoselection of the Nitroacetates 67 Chapter 3. Chiral Proton Catalyzed Diels-Alder Reactions 71 3.1. Brevianamide 71 3.1.1. Background 71 viii 3.1.2. Previous Total Syntheses of the Brevianamides 77 3.1.3. Chiral Proton Catalyzed Hetero-Diels-Alder Reaction 82 3.2. Tamiflu 93 3.2.1. Background 93 3.2.2. Synthesis 98 3.2.3. Retro-synthetic Analysis of Tamiflu 107 3.2.4. Synthetic Studies toward Tamiflu 111 Chapter 4. Experimental Section 116 Appendices 151 Appendix 1 151 Appendix 2 154 LIST OF TABLES Table 1. Effect of Stereoelectronics of BAM Ligand on the Chiral ................................. 40 Table 2. Effect of Stereoelectronics of BAM Ligand on the Chiral ................................. 41 Table 3. Effect of Cyclohexane Diamine Substitution on the .......................................... 42 Table 4. Electronic Effect of BAM Ligand on the Chiral................................................. 43 Table 5. Effect of Additional Basic Sites on the BAM Ligand on the ............................. 44 Table 6. Effect of Cavity Shape in the BAM Ligand on the............................................. 45 Table 7. Effect of Catalyst Loading on the Chiral Proton-............................................... 48 Table 8. Effect of Nitroalkane on the Chiral Proton-........................................................ 48 Table 9. Chiral Proton-Catalyzed Direct Nitromethane ................................................... 49 Table 10. Chiral Proton- Catalyzed Direct Nitroethane.................................................... 50 Table 11. Effect of Counterion on Conversion and .......................................................... 51 Table 12. Effect of Additive on the Chiral Proton-Catalyzed .......................................... 51 Table 13. Comparison of Enantioselection in Direct and Indirect aza-Henry Reaction... 54 Table 14. Chiral Proton-Catalyzed Direct Nitromethane ................................................. 55 Table 15. Chiral Proton-Catalyzed Direct Nitromethane ................................................. 56 Table 16. Effect of Nitroacetate Ester Substitution on Stereoselection............................ 60 Table 17. Effect of Pyridine Substitution on Nitroacetate Additions ............................... 61 ix Table 18. Effect of Ligand Conformation of Enantioselection......................................... 61 Table 19. Chiral Proton Catalyzed Additions of α-Nitroesters to Azomethines: Scopea . 62 Table 20. Effect of Time and Temperature on Diastereoselection ................................... 64 Table 21. Substrate Scope of 118e Catalyzed Nitroacetate Additions to N-Boc Imines.. 66 Table 22. Substrate Scope of 118oo Catalyzed Nitroacetate Additions to N-Boc Imines 66 Table 23. Substrate Scope of 118oo Catalyzed Nitroacetate Additions to N-Boc Imines 67 Table 24. Effect of Scale and Temperature on Reverse-Prenylation................................ 86 Table 25. Optimization of Base Catalyzed Isomerization ...............................................
Load more

Recommended publications
  • Food and Drug Administration, HHS § 177.1315
    Food and Drug Administration, HHS § 177.1315 under conditions of use E through G as Food Safety and Applied Nutrition described in table 2 of § 176.170(c) of this (HFS±200), Food and Drug Administra- chapter. tion, 200 C St. SW., Washington, DC, or (d) The provisions of this section are at the Office of the Federal Register, not applicable to ethylene-acrylic acid 800 North Capitol St. NW., suite 700, copolymers used in food-packaging ad- Washington, DC. hesives complying with § 175.105 of this (3) The basic copolymer identified in chapter. paragraph (a) of this section, when ex- [42 FR 14572, Mar. 15, 1977, as amended at 51 tracted with the solvent or solvents FR 19060, May 27, 1986; 53 FR 44009, Nov. 1, characterizing the type of food and 1988] under the conditions of time and tem- perature characterizing the conditions § 177.1312 Ethylene-carbon monoxide of its intended use, as determined from copolymers. Tables 1 and 2 of § 176.170(c) of this The ethylene-carbon monoxide co- chapter, yields net chloroform-soluble polymers identified in paragraph (a) of extractives in each extracting solvent this section may be safely used as com- not to exceed 0.5 milligram per square ponents of articles intended for use in inch of food-contact surface when test- contact with food subject to the provi- ed by methods described in § 176.170(d) sions of this section. of this chapter. (a) Identity. For the purposes of this (4) The provisions of this section are section, ethylene-carbon monoxide co- not applicable to ethylene-carbon mon- polymers (CAS Reg.
    [Show full text]
  • Ethyl Acrylate
    Health Council of the Netherlands Ethyl acrylate Evaluation of the carcinogenicity and genotoxicity Gezondheidsraad Health Council of the Netherlands Aan de staatssecretaris van Sociale Zaken en Werkgelegenheid Onderwerp : aanbieding advies Ethyl acrylate Uw kenmerk : DGV/MBO/U-932342 Ons kenmerk : U-7413/BvdV/fs/246-D17 Bijlagen : 1 Datum : 13 november 2012 Geachte staatssecretaris, Graag bied ik u hierbij het advies aan over de gevolgen van beroepsmatige blootstelling aan ethylacrylaat. Dit advies maakt deel uit van een uitgebreide reeks waarin kankerverwekkende stoffen worden geclassificeerd volgens richtlijnen van de Europese Unie. Het gaat om stoffen waaraan mensen tijdens de beroepsmatige uitoefening kunnen worden blootgesteld. Dit advies is opgesteld door een vaste subcommissie van de Commissie Gezondheid en beroepsmatige blootstelling aan stoffen (GBBS), de Subcommissie Classificatie van carcinogene stoffen. Het advies is getoetst door de Beraadsgroep Gezondheid en omgeving van de Gezondheidsraad. Ik heb het advies vandaag ter kennisname toegezonden aan de staatssecretaris van Infrastructuur en Milieu en aan de minister van Volksgezondheid, Welzijn en Sport. Met vriendelijke groet, prof. dr. W.A. van Gool, voorzitter Bezoekadres Postadres Parnassusplein 5 Postbus 16052 2511 VX Den Haag 2500 BB Den Haag E-mail: [email protected] www.gr.nl Telefoon (070) 340 74 47 Ethyl acrylate Evaluation of the carcinogenicity and genotoxicity Subcommittee on the Classification of Carcinogenic Substances of the Dutch Expert Committee on Occupational Safety, a Committee of the Health Council of the Netherlands to: the State Secretary of Social Affairs and Employment No. 2012/19, The Hague, November 13, 2012 The Health Council of the Netherlands, established in 1902, is an independent scientific advisory body.
    [Show full text]
  • Catalytic, Asymmetric Synthesis of Β-Lactams
    J. Am. Chem. Soc. 2000, 122, 7831-7832 7831 Catalytic, Asymmetric Synthesis of â-Lactams Table 1. Diastereoselectivity in the Nucleophile-Catalyzed Reaction of Methylphenylketene 3b with Imine 2a Andrew E. Taggi, Ahmed M. Hafez, Harald Wack, Brandon Young, William J. Drury, III, and Thomas Lectka* Department of Chemistry Johns Hopkins UniVersity, 3400 North Charles Street Baltimore, Maryland 21218 ReceiVed May 22, 2000 The paramount importance of â-lactams (1) to pharmaceutical science and biochemistry has been well established.1 New chiral â-lactams are in demand as antibacterial agents, and their recent discovery as mechanism-based serine protease inhibitors2 has kept interest in their synthesis at a high level.3 However, most chiral methodology is auxiliary-based; only one catalytic, asymmetric synthesis of the â-lactam ring system is known, affording product a - ° in modest enantioselectivity.4 Many asymmetric auxiliary-based Reactions run with 10 mol% catalyst at 78 C and allowed to slowly warm to room temperature overnight. â-lactam syntheses rely on the reaction of imines with ketenes, a 3 process that generally proceeds without a catalyst. We recently catalyzed by 10 mol % bifunctional amine 4a gave a cis/trans dr accomplished a catalyzed reaction of imines and ketenes by of 3/97. A significant role for the H-bond contact in 4a is sug- making the imine component non-nucleophilic, as in electron- gested, as the sterically similar catalyst 4b, which does not contain deficient imino ester 2a.5 In this contribution, we report the ) 6 a hydrogen bond donor, gave low diastereoselectivity (dr 34/ catalytic, asymmetric reaction of imine 2a and ketenes 3 to 66).
    [Show full text]
  • Regiocontrolled 1,3-Dipolar Cycloadditions of Nitrile Imines With
    337 REGIOCONTROLLED 1,3-DIPOLAR CYCLOADDITIONS OF NITRILE IMINES WITH ACETYLENES AND ,-UNSATURATED SYSTEMS: SYNTHESIS OF POLYSUBSTITUTED AND RING FUSED PYRAZOLES WITH PHARMACEUTICAL ACTIVITY DOI: http://dx.medra.org/10.17374/targets.2017.20.337 Giulio Bertuzzi, Mariafrancesca Fochi and Mauro Comes Franchini Department of Industrial Chemistry “Toso Montanari”, University of Bologna, Viale Risorgimento 4, 40136 Bologna, Italy (e-mail: [email protected]) Abstract. 1,3-Dipolar cycloadditions of nitrile imines with functionalised acetylenes and ,-unsaturated systems of various sizes have been studied. After cycloaddition, mono- and ring-fused pyrazoles have been obtained. Computational studies allowed a theoretical description of the observed reactivity, in agreement with the experimentally observed regio-chemistry. Selected targeted structures for medicinal applications have been synthetized and in vitro cytotoxicity showed that these pyrazoles can be considered powerful lead compounds for further medicinally relevant targets development. Contents 1. Introduction 2. 1,3-Dipolar cycloaddition of nitrile imines with acetylenes 2.1. 1,3-Dipolar cycloaddition of nitrile imines with activated acetylenes: regiocontrolled synthesis of 4- and 5-substituted pyrazoles 2.2. 1,3-Dipolar cycloaddition with sulphur-based acetylenes: regiocontrolled synthesis of thieno[2,3- c]pyrazoles 2.3. 1,3-Dipolar cycloaddition with ynamide tert-butyl N-ethynyl-N-phenylcarbamate: experimental and theoretical investigation 3. 1,3-Dipolar cycloaddition of nitrile imines with cyclic dipolarophiles 3.1. 1,3-Dipolar cycloaddition of nitrile imines with α,β-unsaturated ketones: regiocontrolled synthesis of ring-fused pyrazoles 3.2. 1,3-Dipolar cycloaddition of nitrile imines with α,β-unsaturated lactones, thiolactones and lactams: regiocontrolled synthesis of ring-fused pyrazoles 4.
    [Show full text]
  • The Development of the First Catalyzed Reaction of Ketenes and Imines: Catalytic, Asymmetric Synthesis of Â-Lactams Andrew E
    Published on Web 00/00/0000 The Development of the First Catalyzed Reaction of Ketenes and Imines: Catalytic, Asymmetric Synthesis of â-Lactams Andrew E. Taggi, Ahmed M. Hafez, Harald Wack, Brandon Young, Dana Ferraris, and Thomas Lectka* Contribution from the Department of Chemistry, Johns Hopkins UniVersity, 3400 North Charles Street, Baltimore, Maryland 21218 Received February 5, 2002 Abstract: We report practical methodology for the catalytic, asymmetric synthesis of â-lactams resulting from the development of a catalyzed reaction of ketenes (or their derived zwitterionic enolates) and imines. The products of these asymmetric reactions can serve as precursors to a number of enzyme inhibitors and drug candidates as well as valuable synthetic intermediates. We present a detailed study of the mechanism of the â-lactam forming reaction with proton sponge as the stoichiometric base, including kinetics and isotopic labeling studies. Stereochemical models based on molecular mechanics (MM) calculations are also presented to account for the observed stereoregular sense of induction in our reactions and to provide a guidepost for the design of other catalyst systems. Introduction this structural motif a worthwhile goal for the synthetic organic 10 The clinical relevance of â-lactams continues to expand at a chemist, thus the synthesis of these nonantibiotic â-lactams surprising rate. Although their use as antibiotics is being will be the focus of this contribution. While considerable effort compromised to some extent by bacterial resistance pressures,1 has been put into synthetic methodology to construct the basic recently â-lactams (especially nonnatural ones) have achieved â-lactam skeleton, there have been few general methods many important nonantibiotic uses.
    [Show full text]
  • Robert Burns Woodward
    The Life and Achievements of Robert Burns Woodward Long Literature Seminar July 13, 2009 Erika A. Crane “The structure known, but not yet accessible by synthesis, is to the chemist what the unclimbed mountain, the uncharted sea, the untilled field, the unreached planet, are to other men. The achievement of the objective in itself cannot but thrill all chemists, who even before they know the details of the journey can apprehend from their own experience the joys and elations, the disappointments and false hopes, the obstacles overcome, the frustrations subdued, which they experienced who traversed a road to the goal. The unique challenge which chemical synthesis provides for the creative imagination and the skilled hand ensures that it will endure as long as men write books, paint pictures, and fashion things which are beautiful, or practical, or both.” “Art and Science in the Synthesis of Organic Compounds: Retrospect and Prospect,” in Pointers and Pathways in Research (Bombay:CIBA of India, 1963). Robert Burns Woodward • Graduated from MIT with his Ph.D. in chemistry at the age of 20 Woodward taught by example and captivated • A tenured professor at Harvard by the age of 29 the young... “Woodward largely taught principles and values. He showed us by • Published 196 papers before his death at age example and precept that if anything is worth 62 doing, it should be done intelligently, intensely • Received 24 honorary degrees and passionately.” • Received 26 medals & awards including the -Daniel Kemp National Medal of Science in 1964, the Nobel Prize in 1965, and he was one of the first recipients of the Arthur C.
    [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]
  • First Total Synthesis of (&Plus;)
    The Journal of Antibiotics (2015) 68, 721–724 & 2015 Japan Antibiotics Research Association All rights reserved 0021-8820/15 www.nature.com/ja ORIGINAL ARTICLE First total synthesis of (+)-epogymnolactam, a novel autophagy inducer Yuji Okado, Kengo Shigetomi, Shinya Mitsuhashi and Makoto Ubukata A novel autophagy inducer, (+)-epogymnolactam (1), was first synthesized from cis-4-benzyloxy-2-butene-1-ol (2) in eight steps. A reliable preparation of optically pure epoxy alcohol (+)-3 from monobenzyl derivative (2) was established by a tandem strategy, Sharpless epoxidation/lipase kinetic resolution. The Journal of Antibiotics (2015) 68, 721–724; doi:10.1038/ja.2015.63; published online 27 May 2015 INTRODUCTION MATERIALS AND METHODS (+)-Epogymnolactam (1) was discovered as a novel autophagy inducer Chemicals of the highest commercial purity were used without further from a mycelial culture of Gymnopus sp. in our laboratory (Figure 1).1 purification. Thin-layer and silica gel column chromatography were performed Autophagy is one of the major intracellular degradation systems in by using Merck Silica Gel 60 F254 (Merck, Frankfurt, Germany) and Kanto Chemical Co. Silica Gel 60 N (spherical, neutral; Kanto Chemical Co., eukaryotic cells, eliminating damaged organelles and protein aggre- Tokyo, Japan), respectively. A DAICEL Chiralpak AD-H column (φ 0.64 × 25 gates to maintain cytoplasmic homeostasis. This degradation pathway cm2; DAICEL, Osaka, Japan) and a Waters 600 System (Waters, Milford, MA, has important roles in such diseases as cancer, neurodegenerative and USA) were used for chiral HPLC. 1Hand13C NMR spectra were recorded infectious diseases. Thus, the application of autophagy inducer would using a JEOL JNM EX-270 FT-NMR (JEOL, Tokyo, Japan), and HSQC and help to understand the regulatory roles of autophagy in human HMBC spectra were measured with a Bruker AMX-500 (Bruker, Billerica, diseases, and provide insight into the development of therapeutic MA, USA).
    [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]
  • 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]
  • 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.
    [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]