Synthesis 2017; 49(10): 2138-2152
DOI: 10.1055/s-0036-1588791
© Georg Thieme Verlag Stuttgart · New York

Allylic Azide Rearrangement in Tandem with Intramolecular Huisgen Cycloaddition for Iminosugar and Glycomimetic Synthesis: Functionalized Piperidine, Pyrrolidine, and Pyrrolotriazoles from d-Mannose

Rekha Chadda
School of Chemistry, National University of Ireland Galway, University Road, Galway, H91 TK33, Ireland   Email:
Patrick McArdle
School of Chemistry, National University of Ireland Galway, University Road, Galway, H91 TK33, Ireland   Email:
Paul V. Murphy*
School of Chemistry, National University of Ireland Galway, University Road, Galway, H91 TK33, Ireland   Email:
› Author Affiliations
Further Information

Publication History

Received: 21 March 2017

Accepted: 23 March 2017

Publication Date:
20 April 2017 (online)


Intramolecular Huisgen azide-alkene cycloaddition reaction of 7-azido-hepta-1,5-diene-3,4-diols, prepared from methyl α-d-man­no­pyranoside, were carried out. Allylic azide rearrangement to secondary azides occurred in tandem with triazoline formation and this intermediate was then decomposed in the presence of nucleophilic reagents to give pyrrolidines, piperidines, or azepanes depending on whether cyclic constraint was incorporated or not, on diol stereochemistry and on the nucleophile. The tandem reaction worked best when aziridine formation from the triazoline was efficient, and this efficiency improved on removal of cyclic constraint. Proposals to account for the observed diastereoselectivities are provided. The allylic azide rearrangement in tandem with the intramolecular Huisgen azide-alkyne cycloaddition was also investigated from azidoheptaenyne diols and gave dihydropyrrolotriazoles. All reactions were diastereoselective, and this was high in some cases. Two X-ray crystal structural determinations, 13C NMR data, and 1D and 2D NOESY experiments were used for stereochemical assignments.

Supporting Information

Primary Data

  • References

  • 1 For a review of the applications of organic azides, see: Bräse S. Gil C. Knepper K. Zimmermann V. Angew. Chem. Int. Ed. 2005; 44: 5188

    • For reviews on intramolecular 1,3-dipolar cycloaddition in synthesis, see:
    • 2a Nair V. Suja TD. Tetrahedron 2007; 63: 12247
    • 2b Padwa A. In 1,3-Dipolar Cycloaddition Chemistry . Padwa A. Wiley-Interscience; New York: 1984: 316
  • 3 Huisgen R. Angew. Chem., Int. Ed. Engl. 1963; 2: 633 ; Angew. Chem. 1963, 75, 604
  • 4 For allylic azide rearrangement used in tandem with intramolecular Schmidt reactions, see: Liu R. Gutierrez O. Tantillo DJ. Aubé J. J. Am. Chem. Soc. 2012; 134: 6528
  • 5 Gagneux A. Winstein S. Young WG. J. Am. Chem. Soc. 1960; 82: 5956
  • 6 Zhou Y. Murphy PV. Org. Lett. 2008; 10: 3777
  • 7 Moynihan L. Chadda R. McArdle P. Murphy PV. Org. Lett. 2015; 17: 6226
  • 9 For allylic azide rearrangement followed by copper promoted intermolecular azide-alkene cycloaddition, see: Feldman AK. Colasson B. Sharpless KB. Fokin VV. J. Am. Chem. Soc. 2005; 127: 13444
  • 10 Mishra A. Hutait S. Bhowmik S. Rastogi N. Roy R. Batra S. Synthesis 2010; 2731
  • 11 Skaanderup PR. Poulsen CS. Hyldtoft L. Jørgensen MR. Madsen R. Synthesis 2002; 1721
    • 12a Bernet B. Vasella A. Helv. Chim. Acta 1979; 62: 1990
    • 12b Skaanderup PR. Hyldtoft L. Madsen R. Monatsh. Chem. 2002; 133: 467
    • 13a Brock EA. Davies SG. Lee JA. Roberts PM. Thomson JE. Org. Lett. 2011; 13: 1594
    • 13b Palmer AM. Volker J. Eur. J. Org. Chem. 2001; 1293
  • 14 Kaburagi Y. Kishi Y. Org. Lett. 2007; 9: 723
  • 15 Vekariya RH. Liu R. Aubé J. Org. Lett. 2014; 16: 1844
    • 16a Yamakado Y. Ishiguro M. Ikeda N. Yamamoto H. J. Am. Chem. Soc. 1981; 103: 5568
    • 16b Colvin EW. Hamill BJ. J. Chem. Soc., Chem. Commun. 1973; 151
  • 17 For a recent example of synthesis of sugars fused to triazoles and their biological relevance, see: Putapatri SR. Kanwal A. Sridhar B. Banerjee SK. Kantevari S. Org. Biomol. Chem. 2014; 12: 8415
  • 18 Evidence that there is a relationship between 13C NMR chemical shifts and stereochemistry has been demonstrated. For an example, see: Lee J. Kobayashi Y. Tezuka K. Kishi Y. Org. Lett. 1999; 1: 2177
  • 19 Zoidi M. Gonzalez Santana A. Torvisco A. Tysoe C. Siriwardena A. Withers SG. Wrodnigg TM. Carbohydr. Res. 2016; 429: 62
  • 20 Huisgen R. J. Org. Chem. 1968; 33: 2291
  • 21 Hoffmann RW. Chem. Rev. 1989; 89: 1841

    • For selected syntheses of bioactive hydroxylated pyrrolidines, see:
    • 22a Card PJ. Hitz WD. J. Org. Chem. 1985; 50: 891
    • 22b Trost BM. Horne DB. Woltering MJ. Chem. Eur. J. 2006; 12: 6607
    • 22c García-Moreno MI. Aguilar M. Ortiz Mellet C. García Fernández JM. Org. Lett. 2006; 8: 297
    • 22d Ayers BJ. Ngo N. Jenkinson S. Martínez RF. Shimada Y. Adachi I. Weymouth-Wilson AC. Kato A. Fleet GW. J. J. Org. Chem. 2012; 77: 7777

      For selected syntheses of iminosugars from our group, see:
    • 23a McDonnell C. Cronin L. O’Brien JL. Murphy PV. J. Org. Chem. 2004; 69: 3565
    • 23b Murphy PV. O’Brien JL. Gorey-Feret LJ. Smith III AB. Tetrahedron 2003; 59: 2259

      For recent selected applications of iminosugars, see:
    • 24a Clark N. Metcalf MC. Best D. Fleet GW. J. Garman SC. Proc. Natl. Acad. Sci. U.S.A. 2012; 109: 17400
    • 24b Ghisaidoobe AT. van den Berg RJ. B. H. N. Butt SS. Strijland A. Donker-Koopman WE. Scheij S. van den Nieuwendijk AM. C. H. Koomen G.-J. van Loevezijn A. Leemhuis M. Wennekes T. van der Stelt M. van der Marel GA. van Boeckel CA. A. Aerts JM. F. G. Overkleeft HS. J. Med. Chem. 2014; 57: 9096
    • 24c Lopez O. Qing F.-L. Pedersen CM. Bols M. Bioorg. Med. Chem. 2013; 21: 4755
    • 24d Sanchez-Fernandez EM. Risquez-Cuadro R. Mellet CO. Garcia Fernandez C. Nieto PM. Angulo J. Chem. Eur. J. 2012; 18: 8527
    • 24e Decroocq C. Stauffert F. Pamlard O. Oulaidi F. Gallienne E. Martin OR. Guillou C. Compain P. Bioorg. Med. Chem. Lett. 2015; 25: 830
    • 24f Sayce AC. Alonzi DS. Killingbeck SS. Tyrrell BE. Hill ML. Caputo AT. Iwaki R. Kinami K. Ide D. Kiappes JL. Beatty PR. Kato A. Harris E. Dwek RA. Miller JL. Zitzmann N. PLOS Neglected Tropical Diseases 2016; 10: e0004524
    • 24g Barron S. Murphy PV. Med. Chem. Commun. 2014; 5: 1150
  • 25 Compain P. Martin OR. Iminosugars: From Synthesis to Therapeutic Applications . Wiley-VCH; Weinheim: 2007: 63
  • 26 Gossan DP. A. Alabdul M. Abdulmagid K.-Y. Philomene A. Behr J.-B. Ahibo AC. Djakoure LA. Harakat D. Voutquenne-Nazabadioko L. Phytochemistry 2015; 109: 76
  • 27 Lieberman RL. D’aquino JA. Ringe D. Petsko GA. Biochemistry 2009; 48: 4816
    • 28a Murphy PV. Eur. J. Org. Chem. 2007; 4177
    • 28b Danieli E. Lalot J. Murphy PV. Tetrahedron 2007; 63: 6827
    • 28c Murphy PV. Dunne JL. Curr. Org. Synth. 2006; 3: 403
    • 28d Chagnault V. Lalot J. Murphy PV. ChemMedChem 2008; 3: 1071
  • 29 Yang M. Ye W. Schneller SW. J. Org. Chem. 2004; 69: 3993
  • 30 Zoidi M. Gonzalez Santana A. Torvisco A. Tysoe C. Siriwardena A. Withers SG. Wrodnigg TM. Carbohydr. Res. 2016; 429: 62