DOCSLIB.ORG

IV. the Synthesis of (±)-Horsfiline

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
IV. the Synthesis of (±)-Horsfiline Research Collection Doctoral Thesis Novel approach to spiro-pyrrolidine-oxindoles and its application to the synthesis of (±)-horsfiline and (-)-spirotryprostatin B Author(s): Marti, Christiane Publication Date: 2003 Permanent Link: https://doi.org/10.3929/ethz-a-004489068 Rights / License: In Copyright - Non-Commercial Use Permitted This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library Diss. ETH No. 15001 Novel Approach to Spiro-Pyrrolidine-Oxindoles and its Application to the Synthesis of (±)-Horsfiline and (–)-Spirotryprostatin B A dissertation submitted to the SWISS FEDERAL INSTITUTE OF TECHNOLOGY ZÜRICH for the degree of Doctor of Natural Sciences Presented by Christiane MARTI Dipl. Ing. ECPM Strasbourg born 25. August 1972 in Stuttgart, Germany Accepted on the recommendation of Prof. Dr. Erick M. Carreira, examiner Prof. Dr. Hans-Jürg Borschberg, co-examiner Karin, Gerhard und Thomas in grosser Dankbarkeit gewidmet Und ist schon jemals ein Ziegel so vom Dach gefallen, wie es das Gesetz vorschreibt? Niemals! Nicht einmal im Laboratorium zeigen sich die Dinge so wie sie sollen. Sie weichen regellos nach allen Richtungen davon ab, und es ist einigermaβen eine Fiktion, daβ wir das als Fehler der Ausführung ansehen und in der Mitte einen wahren Wert vermuten. Robert Musil Acknowledgements My dissertation at ETH was a real learning experience that was enjoyable most of the time. Any successes during this time are also due to substantial support from others. I therefore express my deepest thanks to: Prof. Dr. Erick M. Carreira ― I benefited his guidance and support throughout the course of my thesis. He was always open for scientific discussions, has an endless supply of ideas, and allowed me the freedom to decide the direction of the project. At times when I was willing to give up; he somehow found a way of motivating me to reach the final goal. Prof. Dr. Hans-Jürg Borschberg ― He accepted the co-examination of my thesis and his interest in this work led to a thoroughly corrected manuscript. Alec Fettes ― He read and corrected my manuscript and thereby substantially improved this thesis not only in grammar and spelling, but also with clever suggestions on the presentation of the content. Christian Fischer ― His diploma work presents a noteworthy contribution to this thesis. His enthusiastic working attitude and his conscientious but efficient preparative work impressed me deeply. Brigitte Brandenberg, Philipp Zumbrunnen and Prof. Dr. Bernhard Jaun ― The spectra from the NMR-service had always a wonderful appearance, even when I only submitted the tiniest amounts. Without help interpreting some of the spectral data, I would have been lost. Rolf Häflinger, Oswald Greter, Oliver Scheidegger and Dr. Walter Amrein ― They measured my MS spectra and answered all associated questions. Volker Gramlich and Paul Seiler ― They both solved X-ray crystal structures relevant to this project and had the time to discuss their results with me in detail. The members of the ETH staff responsible for ‘Schalter’, ‘Glaswäscherei’, ‘Entsorgung’ are gratefully acknowledged for prompt service always accompanied with a smile and a friendly word. The students in the OCP1 synthesized multigram quantities of my starting material. The Carreira group is acknowledged for creating an overall pleasant working atmosphere. My special thanks go to: Claudia Dörfler and Franziska Peyer ― They solved every administrative problem and did all the paperwork. Also they always had an open ear for problems of the group and its individuals. Jeffrey Bode, Alec Fettes, Dieter Muri, Tobias Ritter ― They have all been more than just co-workers, lab-mates or ‘Settlers’ but real friends. Jeff is a wonderful person and a brilliant chemist. His suggestions on my project were always very helpful. Alec and I went a long way together (St Gallen-Zürich, Sola Duo, 8 h 15 min). His suggestions on my chemistry decided the success of this project. Didi and Tobi are real sportsman and I enjoyed playing volley and squash with them or having them chase me though the forest (jogging), up the mountains (hiking in summer) und down the hills (skiing in winter). Roger Fässler, Patrick Aschwanden, Jürg Oetiker and Stephan Schnidrig ― They where always in a good mood and made the atmosphere in the lab an enjoyable one. Aschi is the best PC-expert and was always solving my problems with ‘this stupid computer’. My friends outside of the Carreira group also contributed significantly to this thesis by encouraging me whenever it was necessary. My special thanks go to Anja Schürch, Sibylle Steimen and Ulee Speicher, but also to my friends back in Germany and France and from Volley KSOe. Many thanks go also to my family for their support and love. Last but not least: Thomas, I thank you very much for you support and love and for standing at my side all the time. Without you, I would not have made it. Publications and Presentations Alec Fettes, Christiane Marti and Erick M. Carreira “Catalytic Asymmetric Aldol Reactions” Org. Reactions, manuscript in preparation. Christiane Marti and Erick M. Carreira “Total Synthesis of (–)-Spirotryprostatin B, Synthesis and Related Studies” manuscript in preparation. Christiane Marti and Erick M. Carreira “Construction of Spiro[Pyrrolidine-3,3’-Oxindoles] ― Recent Applications to the Synthesis of Oxindole Alkaloids” Eur. J. Org. Chem. manuscript submitted. Christiane Meyers and Erick M. Carreira “Total Synthesis of (–)-Spirotryprostatin B” Angew. Chem. Int. Ed. in press. Christian Fischer, Christiane Meyers and Erick M. Carreira “Efficient Synthesis of (±)-Horsfiline through the MgI2-Catalysed Ring-Expansion Reaction of a Spiro[cyclopropane-1,3’-indol]-2’-one” Helv. Chim. Acta 2000, 83, 1175. Phil B. Alper, Christiane Meyers, Andreas Lerchner, Dionicio R. Siegel and Erick M. Carreira ”Facile, Novel Methodology for the Synthesis of Spiro[pyrrolidin-3,3’-oxindoles]: Catalyzed Ring-Expansion Reactions of Cyclopropanes by Aldimines” Angew. Chem. Int. Ed. 1999, 38, 3186. Christiane Meyers, Phil B. Alper, Christian Fischer and Erick M. Carreira “Novel Methodology for the Synthesis of Spiro-Oxindoles” Poster presentation; Bayer Informationstage, Bayer AG (Germany), July 2000. Christiane Meyers, Phil B. Alper and Erick M. Carreira “Novel Methodology for the Synthesis of Pyrrolidine-spiro-Oxindole Ring Systems” Poster presentation; Drug Discovery, Pfizer (UK), September 1999 Abstract The spiro-pyrrolidine-oxindole ring system is a recurring structural element that has been identified in a number of cytostatic alkaloids. These spiro-fused ring systems embody stereochemical and structural complexities that continue to challenge the synthetic chemist. In this thesis the development of a novel approach to spiro-pyrrolidine-oxindoles by MgI2-catalyzed ring-expansion reaction of spiro-cyclopropyl-oxindole I and a number of N-alkyl- as well as N-aryl-sulfonyl aldimines II is presented (Scheme A). MgI2 acts as a bifunctional catalyst: R' MgI2 (10-20 mol%), N THF nucleophilic R I N O R' N O activation Bn N Bn I III Mg activation by R N O I Lewis acid II major diastereomer Bn ca. 80:20 Scheme A: Ring expansion of spiro-cyclopropyl-oxindole I with aldimines II catalyzed by MgI2. MgI2 acts as a bifunctional catalyst wherein the Lewis-acidic metal and the nucleophilic counterion operate in synergy. The resulting spiro-pyrrolidine-oxindole ring systems III were obtained in good yields and with high diastereoselectivities. MeO MeO NMe MeO NMe MgI2 (5.5 mol%), THF 83 % 41 % N O N O overall N O Bn Me Bn H N IV horsfiline MeN NMe V Scheme B: Synthesis of (±)-horsfiline. Our interest in the class of spiro-pyrrolidine-oxindole natural products as well as the scope of the ring-expansion reaction led us to apply this method in the synthesis of horsfiline and spirotryprostatin B. The synthetic route to (±)-horsfiline demonstrates the use of 1,3,5-trimethyl-1,3,5-triazine (V) as an equivalent for N-methylmethanimine under the conditions of the ring-expansion reaction. The synthesis afforded (±)-horsfiline in 41% yield over 5 steps via N-benzyl-spiro-cyclopropyl-oxindole (IV) (Scheme B). In order to access the spirotryprostatin B core in a straightforward fashion, we could establish that C9-substituted (spirotryprostatin numbering) spiro-pyrrolidine-oxindole derivative VIII can be obtained in good yield from substituted cyclopropane VI and imine VII. The diastereomer distribution favors VIII possessing the required C3–C18 anti- relationship (6:1). The corresponding syn-diastereomers were found to be converted to VIII by refluxing in acetic acid. Resolution is achieved by peptide coupling with N-Boc- L-proline chloride to furnish IX. MeHC MeHC MeHC O 9 O BocN N MgI2, THF HN 18 N HN N + 3 H N O O H TIPS VI VII TIPS TIPS VIII IX AcOH, ∆ + isomers O CO2Me CO2Me O N O BocN Julia-Kociensky O BocN olefination HN 3 N HN N HN N H 18 H H O O O Me Me O Me Me spirotryprostatin B XI X Scheme C: Total synthesis of (–)-spirotryprostatin B. Introduction of the prenyl side chain was accomplished by olefination of aldehyde XII by Julia–Kocieńsky reaction to give XI, although similar transformations proved difficult in earlier syntheses. Intermediate XI was then converted to spirotryprostatin B (Scheme C). The synthetic sequence was performed in 16 steps (3.4% overall yield) and is a powerful demonstration of the utility of the ring-expansion method. Zusammenfassung Das Spiro-Pyrrolidin-Oxindol Ringsystem ist ein Strukturelement, welches in einigen zytostatisch wirkenden Alkaloiden identifiziert wurde. Die stereochemische und strukturelle Komplexität dieser Systeme machen Spiro-Pyrrolidin-Oxindole zu attraktiven Zielmolekülen für den organischen Synthetiker. Diese Abhandlung beschreibt die Entwicklung einer neuartigen Methode, die über eine MgI2-katalysierte Ring- Erweiterungs-Reaktion von Spiro-Cyclopropyl-Oxindol I mit verschiedenen N-Alkyl- bzw N-Aryl-Sulfonyl-Aldiminen II zu Spiro-Pyrrolidin-Oxindolen führt (Schema A).
Load more

Recommended publications
  • Synthesis of Indole and Oxindole Derivatives Incorporating Pyrrolidino, Pyrrolo Or Imidazolo Moieties
    From DEPARTMENT OF BIOSCIENCES AT NOVUM Karolinska Institutet, Stockholm, Sweden SYNTHESIS OF INDOLE AND OXINDOLE DERIVATIVES INCORPORATING PYRROLIDINO, PYRROLO OR IMIDAZOLO MOIETIES Stanley Rehn Stockholm 2004 All previously published papers have been reproduced with permission from the publishers. Published and printed by Karolinska University Press Box 200, SE-171 77 Stockholm, Sweden © Stanley Rehn, 2004 ISBN 91-7140-169-5 Till Amanda Abstract The focus of this thesis is on the synthesis of oxindole- and indole-derivatives incorporating pyrrolidins, pyrroles or imidazoles moieties. Pyrrolidino-2-spiro-3’-oxindole derivatives have been prepared in high yielding three-component reactions between isatin, α-amino acid derivatives, and suitable dipolarophiles. Condensation between isatin and an α-amino acid yielded a cyclic intermediate, an oxazolidinone, which decarboxylate to give a 1,3-dipolar species, an azomethine ylide, which have been reacted with several dipolarophiles such as N- benzylmaleimide and methyl acrylate. Both N-substituted and N-unsubstituted α- amino acids have been used as the amine component. 3-Methyleneoxindole acetic acid ethyl ester was reacted with p- toluenesulfonylmethyl isocyanide (TosMIC) under basic conditions which gave (in a high yield) a colourless product. Two possible structures could be deduced from the analytical data, a pyrroloquinolone and an isomeric ß-carboline. To clarify which one of the alternatives that was actually formed from the TosMIC reaction both the ß- carboline and the pyrroloquinolone were synthesised. The ß-carboline was obtained when 3-ethoxycarbonylmethyl-1H-indole-2-carboxylic acid ethyl ester was treated with a tosylimine. An alternative synthesis of the pyrroloquinolone was performed via a reduction of a 2,3,4-trisubstituted pyrrole obtained in turn by treatment of a vinyl sulfone with ethyl isocyanoacetate under basic conditions.
    [Show full text]
  • Highly Efficient Endo'- Selective Synthesis of (Dispiro 3,2
    J. Chem. Sci. Ó (2020) 132:76 Indian Academy of Sciences https://doi.org/10.1007/s12039-020-01772-7Sadhana(0123456789().,-volV)FT3](0123456789().,-volV) REGULAR ARTICLE Highly efficient endo’- selective synthesis of (dispiro 3,20- pyrrolidinyl) bisoxindoles containing three contiguous chiral stereocenters with two contiguous quaternary spirostereocenters PANNEERSELVAM YUVARAJa,* , HUIDROM BIRKUMAR SINGHa, ARUN PRASATH LINGAM KANDAPALAMb, DEVARAJAN KATHIRVELANc and SANKARANARAYANAN NAGARAJANd aCSIR-North East Institute of Science and Technology, Branch Laboratory, Imphal, Manipur 795004, India bDepartment of Chemistry, Kamaraj College, Thoothukudi, Tamil Nadu 628003, India cDepartment of Chemistry, Indian Institute of Technology-Hyderabad, Kandi, Telangana 502285, India dDepartment of Chemistry, National Institute of Technology Manipur, Imphal 795004, India E-mail: [email protected]; [email protected] MS received 15 November 2019; revised 6 January 2020; accepted 9 January 2020 Abstract. An efficient, atom economical, one-pot synthesis of endo’- selective (dispiro 3,20-pyrrolidinyl) bisoxindole containing three contiguous chiral stereocenters with two contiguous quaternary spirostereo centers have been achieved by three-component reaction of isatins, malononitrile (cyanoacetic ester) and 1,3- dicarbonyl compounds in water in the presence of L-proline. One-pot, azomethine ylide cycloaddition with a dipolarophile without using any catalyst have also been achieved in good yields. This new methodology offers many advantages of catalyst-free,
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 9.260,446 B2 Cadieux Et Al
    USOO926O446B2 (12) United States Patent (10) Patent No.: US 9.260,446 B2 Cadieux et al. (45) Date of Patent: Feb. 16, 2016 (54) SYNTHETIC METHODS FOR 5,663,431 A 9, 1997 Di Malta et al. SPIRO-OXINDOLE COMPOUNDS 5,686,624 A 11/1997 Di Malta et al. 5,696,145 A 12/1997 Foulon et al. (71) Applicant: Xenon Pharmaceuticals Inc., Burnaby 5,723,625 A 3/1998 Keplinger et al. (CA) 5,726,322 A 3, 1998 Di Malta et al. Inventors: 5,728,723 A 3, 1998 Di Malta et al. (72) Jean-Jacques Alexandre Cadieux, 5,763,471 A 6/1998 Fourtillan et al. Burnaby (CA); Mikhail Chafeev, 5,767,128 A 6/1998 Guillaumet et al. Khimki (RU); Sultan Chowdhury, 5,776,936 A 7/1998 Lee et al. Surrey (CA); Jianmin Fu, Coquitlam 5,849,780 A 12/1998 Di Malta et al. (CA); Qi Ji, Burnaby (CA); Stefanie 5,886,026 A 3, 1999 Hunter et al. 5,994,350 A 11/1999 Foulon et al. Abel, Thalwil (CH); Emad El-Sayed, 6,046,341 A 4/2000 Foulon et al. Zumikon (CH); Elke Huthmann, Buchs 6,090,818 A 7/2000 Foulon et al. (CH); Thomas Isarno, Niffer (FR) 6,099,562 A 8/2000 Ding et al. 6,110,969 A 8, 2000 Tani et al. (73) Assignee: Xenon Pharmaceuticals Inc., Burnaby 6,225,347 B1 5/2001 Buchmann et al. 6,235,780 B1 5, 2001 Ohuchida et al. (CA) 6,262.293 B1 7/2001 Tani et al.
    [Show full text]
  • Enzyme Evolution in Fungal Indole Alkaloid Biosynthesis Amy E
    REVIEW ARTICLE Enzyme evolution in fungal indole alkaloid biosynthesis Amy E. Fraley1,2 and David H. Sherman1,2,3,4 1 Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA 2 Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA 3 Department of Chemistry, University of Michigan, Ann Arbor, MI, USA 4 Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA Keywords The class of fungal indole alkaloids containing the bicyclo[2.2.2]diazaoc- biosynthesis; Diels–Alderase; natural tane ring is comprised of diverse molecules that display a range of biologi- products; nonribosomal peptides; cal activities. While much interest has been garnered due to their monooxygenase therapeutic potential, this class of molecules also displays unique chemical Correspondence functionality, making them intriguing synthetic targets. Many elegant and D. H. Sherman, Life Sciences Institute, 210 intricate total syntheses have been developed to generate these alkaloids, Washtenaw Avenue, Ann Arbor, MI 48104, but the selectivity required to produce them in high yield presents great USA barriers. Alternatively, if we can understand the molecular mechanisms Tel: +734 615 9907 behind how fungi make these complex molecules, we can leverage the E-mail: [email protected] power of nature to perform these chemical transformations. Here, we describe the various studies regarding the evolutionary development of (Received 21 August 2019, revised 24 November 2019, accepted 27 February enzymes involved in fungal indole alkaloid biosynthesis. 2020) doi:10.1111/febs.15270 Introduction to fungal indole alkaloids The fungal indole alkaloid class of natural products knowledge gaps with detailed biochemical characteri- contains molecules with unique structural properties zation.
    [Show full text]
  • Prebiotic Formation of Cyclic Dipeptides Under Potentially Early Earth
    www.nature.com/scientificreports OPEN Prebiotic formation of cyclic dipeptides under potentially early Earth conditions Received: 10 October 2017 Jianxi Ying1, Rongcan Lin1, Pengxiang Xu1, Yile Wu 1, Yan Liu1 & Yufen Zhao1,2 Accepted: 27 December 2017 Cyclic dipeptides, also known as 2,5-diketopiperazines (DKPs), represent the simplest peptides Published: xx xx xxxx that were frst completely characterized. DKPs can catalyze the chiral selection of reactions and are considered as peptide precursors. The origin of biochemical chirality and synthesis of peptides remains abstruse problem believed to be essential precondition to origin of life. Therefore, it is reasonable to believe that the DKPs could have played a key role in the origin of life. How the formation of the DKPs through the condensation of unprotected amino acids in simulated prebiotic conditions has been unclear. Herein, it was found that cyclo-Pro-Pro could be formed directly from unprotected proline in the aqueous solution of trimetaphosphate (P3m) under mild condition with the yield up to 97%. Other amino acids were found to form proline-containing DKPs under the same conditions in spite of lower yield. During the formation process of these DKPs, P3m promotes the formation of linear dipeptides in the frst step of the mechanism. The above fndings are helpful and signifcant for understanding the formation of DKPs in the process of chemical evolution of life. As one of the simplest peptide derivatives in nature1,2, Cyclic dipeptides, also known as 2, 5-diketopiperazines (DKPs), which were ubiquitously observed in microorganism, plants and animals3–10, have been found to have many biological activities (e.g., antiviral, antibiotic, anticancer)11–14 and chiral catalysis properties15.
    [Show full text]
  • Facile Synthesis of 3-Spiropyrrolizidine Oxindoles and 3-Spirotetrahydroquinoline Oxindoles Via [3+2] and [4+2] Cycloaddition Reactions
    id2143625 pdfMachine by Broadgun Software - a great PDF writer! - a great PDF creator! - http://www.pdfmachine.com http://www.broadgun.com OOrrggaanniicc ISSN: 0974 - 7516 Volume 8 Issue 3 CCHHEEMMAn IIInSSdiTTan RRJouYrYnal Trade Science Inc. Full Paper OCAIJ, 8(3), 2012 [94-102] Facile synthesis of 3-spiropyrrolizidine oxindoles and 3-spirotetrahydroquinoline oxindoles via [3+2] and [4+2] cycloaddition reactions A.Sudhakara1, H.C.Kiran Kumar2, H.Jayadevappa1, K.M.Mahadevan2* 1Department of Chemistry, Sahyadri Science College, Shimoga, Karnataka, 577 203, (INDIA) 2Department of Postgraduate Studies and Research in Chemistry, School of Chemical Sciences, Kuvempu University, Shankaraghatta, Karnataka, 577 451, (INDIA) E-mail: [email protected] Received: 22nd June, 2011 ; Accepted: 22nd July, 2011 ABSTRACT KEYWORDS A rapid and efficient synthesis of a number of functionalized 3- Isatin; spiropyrrolizidine oxindoles from [3+2] cycloaddition of azomethine ylide Imino Diels-Alder; and 3-spirotetrahydroquinoline oxindoles from [4+2] imino Diels-Alder re- Antimony(III)chloride; action; catalyzed by Antimony(III)chloride in excellent yields are reported. Spiropyrrolizidine oxindoles; 2012 Trade Science Inc. - INDIA Spirotetrahydroquinoline- oxindoles. INTRODUCTION sor for the synthesis of biologically active indole de- rivatives and natural products[2]. The Spirooxindoles core Heterocyclic compounds containing isatin (1H-in- is featured in a number of natural products and recently dole-2, 3-dione) scaffold have a wide range of biologi- has been the subject of significant synthetic interest[3]. cal activities[1] and also serves as an important precur- Oxindoles derivatized like Spirotryprostatin B, Horsfiline O Me H H O NH MeO N Me N N H MeO O H O O N N N O Me H H Spirotryprostatin B Horsfiline Alstonisine Spirooxindole alkaloid natural products Figure 1 : Spirotryprostatin B, horsfiline and alstonisine are alkaloids present in nature and are elegant targets in the organic synthesis due to their significant biological activities.
    [Show full text]
  • Non-Fullerene-Based Acce
    791 Index a – – pyridyldiimine-ligated Fe and Co complexes acceptor materials molecular design and 540–542 engineering 662 alkynylindoles 740 – fullerene-based acceptors 662–669 allenoates and electron-deficient alkenes, – non-fullerene-based acceptors 669–671 phosphine-catalyzed reaction mechanisms of acenes 760–761 574–577 Actinomycetales 157 Alstonia actinophylla 54 actinomycete bacteria 166 Alzheimer’s disease 785 actinophyllic acid 54–56 amides formation 506–508 Actinotalea fermentans 155 amination and halogenation, asymmetric acylimine and acyliminium ions 747 351–352 acyl transfer method 230 2-amino-2-deoxyglycosides 188 aerobic oxidation mechanistic study anion–π-interactions 529–530 – mechanistic characterization anomeric/gauche effect 414 – – kinetic investigations 629–634 anthradithiophene (ADT) 762 – recent progress 627–629 aplykurodinone-1 60–62 agelagalastatin 184 aqueous ascorbate procedure 253 agostic interaction 290 Arixtra (fondaparinux) 196 Agrobacterium sp. 194 aromatic hydrazide and amide oligomers aldol reaction 367–371 487–497 alkane metathesis 284 alkene polymerization, cooperative catalysis in Arthrobacter protophormiae 205 393–394 arylamide oligomers alkene polymerization, novel catalysis for – flexible 492 537–538 – modified 494–497 – early transition metal complexes 544 arylazides 111 – – chelating bis(phenoxy)-ligated group 4 metal aryl dienyl ketones Nazarov cyclization complexes 549–551 mechanism 580–583 – – phenoxyimine-ligated group 4 metal ascorbate 252 complexes 544–549 Aspergillus fumigatus 46 – – pyridylamine-ligated Hf complexes aspidophytine 43 551–553 aspirin 714 – late transition metal complexes 538 asymmetric allylic alkylation (AAA) 344–345, – – diimine-ligated Ni and Pd complexes 346 538–540 asymmetric anti-Mannich reactions 588–590 – – phenoxyimine-ligated Ni complexes asymmetric organocatalysis 378, 379 542–544 – early status of 377–378 Organic Chemistry – Breakthroughs and Perspectives, First Edition.
    [Show full text]
  • Organocatalytic Synthesis of Spiro[Pyrrolidin-3,3′-Oxindoles]
    Published on Web 09/09/2009 Organocatalytic Synthesis of Spiro[pyrrolidin-3,3′-oxindoles] with High Enantiopurity and Structural Diversity Xiao-Hua Chen,†,‡ Qiang Wei,† Shi-Wei Luo,† Han Xiao,† and Liu-Zhu Gong*,† Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, UniVersity of Science and Technology of China, Hefei, 230026, China, and Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu, 610041, China Received June 30, 2009; E-mail: [email protected] Abstract: The privileged spiro[pyrrolidin-3,3′-oxindole] derivatives exhibit important biological activities. An enantioselective organocatalytic approach to the rapid synthesis of spiro[pyrrolidin-3,3′-oxindole] derivatives with high enantiopurity and structural diversity is described. The asymmetric catalytic three-component 1,3-dipolar cycloaddition of a broad range of methyleneindolinones with aldehydes and amino esters in the presence of chiral phosphoric acid provides spirooxindole derivatives in high yield with unusual regiochemistry and excellent stereoselectivities (up to 98% ee) under mild conditions. The straightforward construction of spirooxindole skeletons with high stereo- and regioselectivity suggests a new avenue to medicinal chemistry and diversity-oriented synthesis. Theoretical calculations disclosed that both the azomethine ylide and the methyleneindolinone are hydrogen-bonded with the phosphoric acid, which accounted for the high enantio- and regioselectivity and indicated that the unusual regioselectivity results from the stabilization stemming from the favorable π-π stacking interaction between the oxo-indole ring and the conjugated esters. Introduction The significance of these heterocyclic motifs has led to a The spiro[pyrrolidin-3,3′-oxindole] ring system constitutes demand for efficient synthetic methods, particularly those ′ the core structural element found in a large family of natural producing enantiomerically pure spiro[pyrrolidin-3,3 -oxin- alkaloids and unnatural compounds exhibiting important doles].
    [Show full text]
  • Asymmetric Synthesis of Tryptophan Driviatives and Its Application to Streamlined Synthesis of Tryprosatain a and B Matthew Uih Sman University of Wisconsin-Milwaukee
    University of Wisconsin Milwaukee UWM Digital Commons Theses and Dissertations May 2015 Asymmetric Synthesis of Tryptophan Driviatives and Its Application to Streamlined Synthesis of Tryprosatain A and B Matthew uiH sman University of Wisconsin-Milwaukee Follow this and additional works at: https://dc.uwm.edu/etd Part of the Organic Chemistry Commons Recommended Citation Huisman, Matthew, "Asymmetric Synthesis of Tryptophan Driviatives and Its Application to Streamlined Synthesis of Tryprosatain A and B" (2015). Theses and Dissertations. 880. https://dc.uwm.edu/etd/880 This Dissertation is brought to you for free and open access by UWM Digital Commons. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of UWM Digital Commons. For more information, please contact [email protected]. ASYMMETRIC SYNTHESIS OF TRYPTOPHAN DRIVIATIVES AND ITS APPLICATION TO STREAMLINED SYNTHESIS OF TRYPROSATAIN A AND B. by Matthew Marcus Huisman A Dissertation Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy In Chemistry at The University of Wisconsin-Milwaukee May 2015 ii ABSRACT ASYMMETRIC SYNTHESIS OF TRYPTOPHAN DRIVIATIVES AND ITS APPLICATION TO STREAMLINED SYNTHESIS OF TRYPROSATAIN A AND B. BY Matthew Marcus Huisman The University of Wisconsin-Milwaukee, 2015 Under the Supervision of Professor Mahmun M. Hossain Tryprostatins have been shown to be potential antitumor antimitotic agents. Tryprostatins have been isolated from the fermentation broth of marine fungal strain Aspergillus fumigatus in trace amounts. Our lab has developed a phase-transfer-catalyzed asymmetric alkylation reaction to produce protected tryptophans (Trp) with high enantioselectivity (90-95% ee) as synthetic precursors to Tryprostatins.
    [Show full text]
  • Catalytic Enantioselective Synthesis of Oxindoles and Benzofuranones
    Catalytic Enantioselective Synthesis of Oxindoles and Benzofuranones bearing a Quaternary Stereocenter and Reactions of Palladium Bisphosphine Complexes Relevant to Catalytic C-C Bond Formation by Ivory Derrick Hills B.S., Chemistry University of North Carolina - Chapel Hill, 1999 Submitted to the Department of Chemistry In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY IN ORGANIC CHEMISTRY at the Massachusetts Institute of Technology August 2004 © 2004 Massachusetts Institute of Technology. All rights reserved. Signature of Author Department of Chemistry August 12, 2004 Certified by 4 J Gregory C. Fu Thesis Supervisor Accepted by Robert W. Field Chairman, Departmental Committee on Graduate Studies MASCUSTSN_!tT MASSACHUSETTS INSTITUTE OF TECHNOLOGY ,.--e- i SEP 15 2004 -Wvov tu - LIBRARIES This doctoral thesis has been examined by a committee of the Department of Chemistry as follows: ( Professor Stephen L. Buchwald Chairman Professor Gregory C. Fu t I ^ Thesis Supervisor Professor Rick L. Danheiser - 2 To Chrissy, my best friend 3 Catalytic Enantioselective Synthesis of Oxindoles and Benzofuranones bearing a Quaternary Stereocenter and Reactions of Palladium Bisphosphine Complexes Relevant to Catalytic C-C Bond Formation by Ivory D. Hills Submitted to the Department of Chemistry on August 12, 2004 In Partial Fulfillment of the Requirements For the Degree of Doctor of Philosophy in Organic Chemistry ABSTRACT In Part I the development of a new method for the construction of oxindoles and benzofuranones bearing quaternary stereocenters is discussed. A planar-chiral PPY derivative catalyzes the O-to-C acyl group migration (Black rearrangement) in a highly efficient and enantioselective manner. The utility of this method is further demonstrated by the formal total synthesis of the natural product aplysin.
    [Show full text]
  • Organic Chemistry Frontiers
    ORGANIC CHEMISTRY FRONTIERS View Article Online REVIEW View Journal | View Issue Stereoselective synthesis and applications of spirocyclic oxindoles Cite this: Org. Chem. Front., 2021, 8, 1026 Alexander J. Boddy and James A. Bull * The development of novel synthetic strategies to form new chemical entities in a stereoselective manner is an ongoing significant objective in organic and medicinal chemistry. This review analyses the develop- Received 11th September 2020, ment of new stereoselective approaches to spirocyclic oxindoles with spiro-3- to 8-membered rings. It Accepted 5th January 2021 highlights the importance of these structures for applications in medicinal chemistry, as intermediates or DOI: 10.1039/d0qo01085e final products in total synthesis and as model compounds for the development of enantioselective cata- rsc.li/frontiers-organic lytic methodologies. the substituents of the rings.2 Spirocyclic compounds can Creative Commons Attribution 3.0 Unported Licence. Introduction improve certain physicochemical properties such as lipophili- The application of spirocyclic structures in drug discovery has city, aqueous solubility and metabolic stability, in comparison seen a dramatic increase in attention in recent years, alongside to the respective monocyclic structure.3 Furthermore, they major developments in their synthetic chemistry.1 Defined as a access relatively underexplored chemical space and novel intel- bicycle connected by a single fully-substituted carbon atom, lectual property (IP) space. Saturated spirocycles provide
    [Show full text]
  • Rscpublishing ARTICLE an Asymmetric Pericyclic Cascade
    RSCPublishing ARTICLE An asymmetric pericyclic cascade approach to 3-alkyl-3-aryloxindoles; generality, applications Cite this: DOI: 10.1039/x0xx00000x and mechanistic investigations Edward Richmond,a Kenneth B. Ling,a Nicolas Duguet,a Lois B. Manton,a Nihan Received 00th January 2012, Çelebi-Ölçüm,b,c Yu-hong Lam,b Sezen Alsancak,c Alexandra M. Z. Slawin,a K. Accepted 00th January 2012 N. Houk*b and Andrew D. Smith*a DOI: 10.1039/x0xx00000x The reaction of L-serine derived N-arylnitrones with alkylarylketenes generates asymmetric 3- www.rsc.org/ alkyl-3-aryloxindoles in good to excellent yields (up to 93%) and excellent enantioselectivity (up to 98% ee) via a pericyclic cascade process. The optimization, scope and applications of this transformation are reported, alongside further synthetic and computational investigations. The preparation of the enantiomer of a Roche anti-cancer agent (RO4999200) 1 (96% ee) in three steps demonstrates the potential utility of this methodology. Introduction molecules with quaternary stereocentres,8 3,3-disubstituted oxindoles have emerged as ideal frameworks on which to Cascade reactions are highly desirable owing to the ability 9 develop new asymmetric methodologies. Typically, such to perform multiple sequential transformations without the approaches employ anilides, isatins or suitably substituted necessity for additional manipulation or introduction of further oxindole derivatives as starting materials (Fig 2), although reagents. Such approaches allow significant molecular numerous other standalone approaches have also been complexity to be rapidly assembled, provided each subsequent 9b,c,10-12 developed. Asymmetric intramolecular anilide transformation in the cascade unmasks a desirable, reactive 13 14 cyclizations or Heck reactions typically employ a palladium functionality.1 Pericyclic cascades are particularly attractive 2 catalyst in combination with chiral ligands (a), and have found given their predictable regio- and stereocontrol, coupled with 15 wide application in synthesis.
    [Show full text]