Synthesis 2018; 50(03): 529-538
DOI: 10.1055/s-0036-1591836
feature
© Georg Thieme Verlag Stuttgart · New York

The Structure Elucidation of Haprolid

Jun Li
a  Leibniz Universität Hannover, Institute for Organic Chemistry (OCI), Schneiderberg 1B, 30167 Hannover, Germany   Email: markus.kalesse@oci.uni-hannover.de
b  Leibniz Universität Hannover, Center for Biomolecular Drug Research (BMWZ), Schneiderberg 38, 30167 Hannover, Germany
,
Jun Xing
c  Universitätsklinikum und Medizinische Fakultät Tübingen, Geissweg 3, 72076 Tübingen, Germany
,
Daniel Lücke
a  Leibniz Universität Hannover, Institute for Organic Chemistry (OCI), Schneiderberg 1B, 30167 Hannover, Germany   Email: markus.kalesse@oci.uni-hannover.de
b  Leibniz Universität Hannover, Center for Biomolecular Drug Research (BMWZ), Schneiderberg 38, 30167 Hannover, Germany
,
Dennis Lübken
a  Leibniz Universität Hannover, Institute for Organic Chemistry (OCI), Schneiderberg 1B, 30167 Hannover, Germany   Email: markus.kalesse@oci.uni-hannover.de
b  Leibniz Universität Hannover, Center for Biomolecular Drug Research (BMWZ), Schneiderberg 38, 30167 Hannover, Germany
d  Helmholtz-Zentrum für Infektionsforschung (HZI), Imhoffenstr. 7, 38124 Braunschweig, Germany
,
Lucas Millbrodt
a  Leibniz Universität Hannover, Institute for Organic Chemistry (OCI), Schneiderberg 1B, 30167 Hannover, Germany   Email: markus.kalesse@oci.uni-hannover.de
b  Leibniz Universität Hannover, Center for Biomolecular Drug Research (BMWZ), Schneiderberg 38, 30167 Hannover, Germany
,
Ruben R. Plentz
c  Universitätsklinikum und Medizinische Fakultät Tübingen, Geissweg 3, 72076 Tübingen, Germany
,
a  Leibniz Universität Hannover, Institute for Organic Chemistry (OCI), Schneiderberg 1B, 30167 Hannover, Germany   Email: markus.kalesse@oci.uni-hannover.de
b  Leibniz Universität Hannover, Center for Biomolecular Drug Research (BMWZ), Schneiderberg 38, 30167 Hannover, Germany
d  Helmholtz-Zentrum für Infektionsforschung (HZI), Imhoffenstr. 7, 38124 Braunschweig, Germany
› Author Affiliations
Further Information

Publication History

Received: 21 October 2017

Accepted: 26 October 2017

Publication Date:
24 November 2017 (online)


Dedicated to Professor Cesare Gennari on the occasion of his 65th birthday

Abstract

The assignment of two stereocenters of the natural product haprolid through the application of a profile hidden Markov model (HMM) and its confirmation through total synthesis of the natural product and of two of its diastereomers are reported. The structure elucidation of this polyketide-peptide hybrid natural product is a telling showcase of how difficult it can be to determine the absolute configuration of isolated stereocenters and the benefits of a gene cluster analysis for structure determination. The key steps of the synthesis are a selective epoxidation of a terminal olefin and the stereodivergent macrolactonization strategy. Furthermore, the biological evaluation of all products showed that all diastereomers are potent inhibitors of hepatocellular carcinoma cell lines.

 
  • References

  • 1 New address: Sandoz GmbH, Biochemiestraße 10, 6336 Langkampfen, Austria.
  • 2 Herrmann J. Fayad AA. Müller R. Nat. Prod. Rep. 2017; 34: 135
    • 3a Jahns C. Hoffmann T. Müller S. Gerth K. Washausen P. Höfle G. Reichenbach H. Kalesse M. Müller R. Angew. Chem. Int. Ed. 2012; 51: 5239 ; Angew. Chem. 2012, 124, 5330
    • 3b Rentsch A. Kalesse M. Angew. Chem. Int. Ed. 2012; 51: 11381 ; Angew. Chem. 2012, 124, 11543
    • 3c Hartmann O. Kalesse M. Angew. Chem. Int. Ed. 2014; 53: 7335 ; Angew. Chem. 2014, 126, 7463
    • 3d Gieseler MT. Kalesse M. Org. Lett. 2014; 16: 548
    • 3e Tautz T. Hoffmann J. Hoffmann T. Steinmetz H. Washausen P. Kunze B. Huch V. Kitsche A. Reichenbach H. Höfle G. Müller R. Kalesse M. Org. Lett. 2016; 18: 2560
    • 3f Gerstmann L. Kalesse M. Chem. Eur. J. 2016; 32: 11210
    • 3g Poock C. Kalesse M. Org. Lett. 2017; 19: 4536
  • 4 Steinmetz H. Li J. Fu C. Zaburannyi N. Kunze B. Harmrolfs K. Schmitt V. Herrmann J. Reichenbach H. Höfle G. Kalesse M. Müller R. Angew. Chem. Int. Ed. 2016; 55: 10113 ; Angew. Chem. 2016, 128, 10267
    • 5a Symkenberg G. Kalesse M. Angew. Chem. Int. Ed. 2014; 53: 1795 ; Angew. Chem. 2014, 126, 1825
    • 5b Xiao Q. Young K. Zakarian A. J. Am. Chem. Soc. 2015; 137: 5907
    • 5c Wang J. Chen S.-G. Sun B.-F. Lin G.-Q. Shang Y.-J. Chem. Eur. J. 2013; 19: 2539
    • 5d Wang Y. O’Doherty G. J. Am. Chem. Soc. 2013; 135: 9334
    • 5e Kong K. Enquist JA. Jr. McCallum ME. Smith GM. Matsumaru T. Menhaji-Klotz E. Wood JL. J. Am. Chem. Soc. 2013; 135: 10890
    • 5f Holmes MT. Britton R. Chem. Eur. J. 2013; 19: 12649
    • 5g Vadhadiya PM. Puranik VG. Ramana CV. J. Org. Chem. 2012; 77: 2169
    • 5h Florence GJ. Wlochal J. Chem. Eur. J. 2012; 18: 14250
  • 6 Janssen D. Abert D. Jansen R. Müller R. Kalesse M. Angew. Chem. Int. Ed. 2007; 46: 4898 ; Angew. Chem. 2007, 119, 4985
  • 7 Brodmann T. Janssen D. Kalesse M. J. Am. Chem. Soc. 2010; 132: 13610
  • 8 Reid R. Piagentini M. Rodriguez E. Ashley G. Viswanathan N. Carney J. Santi DV. Hutchinson CR. McDaniel R. Biochemistry 2003; 42: 72
  • 9 Caffrey P. ChemBioChem 2003; 4: 654
  • 10 Kitsche A. Kalesse M. ChemBioChem 2013; 14: 851
    • 11a Lu H.-H. Raja A. Franke R. Landsberg D. Sasse F. Kalesse M. Angew. Chem. Int. Ed. 2013; 52: 1354 ; Angew. Chem. 2013, 125, 13791
    • 11b Lu H.-H. Hinkelmann T. Tautz T. Li J. Sasse F. Franke R. Kalesse M. Org. Biomol. Chem. 2015; 13: 8029
  • 12 Appel R. Angew. Chem., Int. Ed. Engl. 1975; 14: 801 ; Angew. Chem. 1975, 87, 863
  • 13 Grignard V. C. R. Hebd. Seances Acad. Sci. 1900; 130: 1322

    • For the use of terpenes in polyketide synthesis, see:
    • 14a Swatschek J. Grothues L. Bauer JO. Strohmann C. Christmann M. J. Org. Chem. 2014; 79: 976
    • 14b Winter P. Swatschek J. Willot M. Radtke L. Olbrisch T. Schäfer A. Christmann M. Chem. Commun. 2011; 47: 12200
  • 15 Winter P. Vaxelaire C. Heinz C. Christmann M. Chem. Commun. 2011; 47: 394
  • 16 Colladon M. Scarso A. Sgarbossa P. Michelin RA. Strukul G. J. Am. Chem. Soc. 2006; 128: 14006
  • 17 Bal BS. Childers WE. Pinnick HW. Tetrahedron 1981; 37: 2091
  • 18 Shiina I. Kubota M. Oshiumi H. Hashizume M. J. Org. Chem. 2004; 69: 1822
  • 19 Mitsunobu O. Synthesis 1981; 1