Synlett 2015; 26(14): 1930-1939
DOI: 10.1055/s-0034-1380781
account
© Georg Thieme Verlag Stuttgart · New York

Multifunctionality of the N-Trichloroacetyl Group Developed in the Synthesis of Tetrodotoxin, a Puffer Fish Toxin

Toshio Nishikawa*
a   Graduate School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan   Email: nisikawa@agr.nagoya-u.ac.jp
,
Daisuke Urabe
b   Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
,
Masaatsu Adachi
a   Graduate School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan   Email: nisikawa@agr.nagoya-u.ac.jp
,
Minoru Isobe*
c   Department of Chemistry, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan   Email: minoru@mail.nsysu.edu.tw
› Author Affiliations
Further Information

Publication History

Received: 09 March 2015

Accepted after revision: 15 April 2015

Publication Date:
24 July 2015 (online)


Abstract

This account describes a serendipitous discovery and the development of unique reactions associated with trichloroacetamide during synthetic studies of tetrodotoxin in our laboratory. The reactions include site-selective hydroxylation using the neighboring-group participation of trichloroacetamide, guanidinylation from a trichloroacetamide, protecting-group transformation, and removal of the N-trichloroacetyl group. These studies indicate the importance of the total synthesis of densely functionalized natural products as a field for the development of new reactions.

1 Introduction

2 Improvement of the Conditions for the Overman Rearrangement to Introduce Trichloroacetamide

3 Site-Selective Hydroxylation Using the Neighboring-Group Participation of Trichloroacetamide

4 Guanidine Synthesis

5 Protecting-Group Transformation of the N-Trichloroacetyl Group

6 New Deprotection Conditions for the Removal of the N-Trichloroacetyl Group

7 Conclusion

 
  • References

  • 2 Schelhaas M, Waldmann H. Angew. Chem. Int. Ed. Engl. 1996; 35: 2056
  • 4 Nishikawa T, Isobe M. Chem. Rec. 2013; 13: 286

    • Recent reviews of the chemistry and biology of tetrodotoxin:
    • 5a Moczydlowski EG. Toxicon 2013; 63: 165
    • 5b Narahashi T. Proc. Jpn. Acad., Ser. B 2008; 84: 147

      Syntheses of the common intermediates:
    • 6a Nishikawa T, Asai M, Ohyabu N, Yamamoto N, Fukuda Y, Isobe M. Tetrahedron 2001; 57: 3875
    • 6b Satake Y, Nishikawa T, Hiramatsu T, Araki H, Isobe M. Synthesis 2010; 1992
    • 7a Overman LE. J. Am. Chem. Soc. 1974; 96: 597

    • For a review, see:
    • 7b Overman LE, Carpenter NE In Organic Reactions . Vol. 66. Overman LE. John Wiley & Sons; New York: 2005: 1-107
  • 8 Nishikawa T, Asai M, Ohyabu N, Isobe M. J. Org. Chem. 1998; 63: 188
    • 9a Takeda K, Kaji E, Konda Y, Sato N, Nakamura H, Miya N, Morizane A, Yanagisawa Y, Akiyama A, Zen S, Harigaya Y. Tetrahedron Lett. 1992; 33: 7145
    • 9b Eguchi T, Kakinuma K. J. Synth. Org. Chem., Jpn. 1997; 55: 814
    • 10a Tsujimoto T, Nishikawa T, Urabe D, Isobe M. Synlett 2005; 433
    • 10b Matsumoto N, Tsujimoto T, Nakazaki A, Isobe M, Nishikawa T. RSC Adv. 2012; 2: 9448

      For examples, see:
    • 11a Donohoe TJ, Blades K, Helliwell M, Moore PR, Winter JJ. G, Stemp G. J. Org. Chem. 1999; 64: 2980
    • 11b Takahashi K, Yamaguchi D, Ishihara J, Hatakeyama S. Org. Lett. 2012; 14: 1644
    • 11c Xu C, Wang L, Hao X, Wang DZ. J. Org. Chem. 2012; 77: 6307
    • 12a Nishikawa T, Asai M, Ohyabu N, Yamamoto N, Isobe M. Angew. Chem. Int. Ed. 1999; 38: 3081
    • 12b Asai M, Nishikawa T, Ohyabu N, Yamamoto N, Isobe M. Tetrahedron 2001; 57: 4543
  • 13 Because the thin-layer chromatography (TLC) behavior (Rf values and colors) of 24 and 28 was nearly identical, we did not notice this unusual reaction until NMR spectroscopic measurements of the crude product were obtained. It was later revealed that the repeated development of a TLC plate with dichloromethane as the sole solvent showed slightly different Rf values. If our student had not worked up the crude product and measured the NMR spectra we would not have found this unusual reaction!
    • 14a Nishikawa T, Urabe D, Yoshida K, Iwabuchi T, Asai M, Isobe M. Org. Lett. 2002; 4: 2679
    • 14b Nishikawa T, Urabe D, Yoshida K, Iwabuchi T, Asai M, Isobe M. Chem. Eur. J. 2004; 10: 452
  • 15 Nishikawa T, Koide Y, Adachi M, Isobe M. Bull. Chem. Soc. Jpn. 2010; 83: 66
  • 16 Atanassova IA, Petrov JS, Mollov NM. Synthesis 1987; 734
  • 17 Weygand F, Frauendorfer E. Chem. Ber. 1970; 103: 2437

    • Guanidine synthesis:
    • 18a Nishikawa T, Ohyabu N, Yamamoto N, Isobe M. Tetrahedron 1999; 55: 4325
    • 18b Yamamoto N, Isobe M. Chem. Lett. 1994; 23: 2299
  • 19 Acetylation of the dibenzylguanidine was required for the next deprotection involving the removal of the benzyl groups by hydrogenolysis with palladium(II) hydroxide on carbon.
  • 20 Nishikawa T, Urabe D, Tomita M, Tsujimoto T, Iwabuchi T, Isobe M. Org. Lett. 2006; 8: 3263
  • 21 Adachi M, Imazu T, Sakakibara R, Satake Y, Isobe M, Nishikawa T. Chem. Eur. J. 2014; 20: 1247
  • 22 Oishi T, Ando K, Inomiya K, Sato H, Iida M, Chida N. Org. Lett. 2002; 4: 151
  • 23 Urabe D, Nishikawa T, Isobe M. Chem. Asian J. 2006; 1: 125
  • 24 In general we used Na2CO3 to generate the isocyanate. Potassium carbonate was used in this case because of a misunderstanding by our student, who soon observed the removal of the N-trichloroacetyl group.
  • 25 Urabe D, Sugino K, Nishikawa T, Isobe M. Tetrahedron Lett. 2004; 45: 9405
  • 26 Adachi M, Imazu T, Isobe M, Nishikawa T. J. Org. Chem. 2013; 78: 1699
  • 27 Satake Y, Adachi M, Tokoro S, Yotsu-Yamashita M, Isobe M, Nishikawa T. Chem. Asian J. 2014; 9: 1922
  • 28 Adachi M, Sakakibara R, Satake Y, Isobe M, Nishikawa T. Chem. Lett. 2014; 43: 1719
  • 29 This deprotection condition was used in other laboratories; for examples, see: Nie L.-D, Wang F.-F, Ding W, Shi X.-X, Lu X. Tetrahedron: Asymmetry 2013; 24: 638

    • For other uses of trichloroacetamide, see:
    • 30a Nagashima H, Wakamatsu H, Itoh K. J. Chem. Soc., Chem. Commun. 1984; 652
    • 30b Seigal BA, Fajardo C, Snapper ML. J. Am. Chem. Soc. 2005; 127: 16329
    • 30c Diaba F, Martínez-Laporta A, Bonjoch J, Pereira A, Muñoz-Molina JM, Pérez PJ, Belderrain TR. Chem. Commun. 2012; 48: 8799
    • 30d Li Q, Li G, Ma S, Feng P, Shi Y. Org. Lett. 2013; 15: 2601
  • 31 Trichloroacetimidate, which is related to the N-trichloroacetyl group, is also useful for several transformations owing to neighboring-group participation, although it is not a protecting group; for examples, see: Kang SH, Kang SY, Lee H.-S, Buglass AJ. Chem. Rev. 2005; 105: 4537
  • 32 Ueda M. Chem. Lett. 2012; 41: 658