Synlett 2008(10): 1532-1536  
DOI: 10.1055/s-2008-1078411
© Georg Thieme Verlag Stuttgart · New York

Synthesis of the Central Tryptophan-Leucine Residue of Celogentin C

Julien Michaux*a, Pascal Retailleaub, Jean-Marc Campagne*c
a Institut de Chimie des Substances Naturelles, Avenue de la Terrasse, 91198 Gif sur Yvette, France
b Service de Cristallochimie, Institut de Chimie des Substances Naturelles, Avenue de la Terrasse, 91198 Gif sur Yvette, France
c Institut Charles Gerhardt Montpellier, ENSCM, 8 rue de l"Ecole Normale, 34296 Montpellier, France
Further Information

Publication History

Received 6 March 2008
Publication Date:
16 May 2008 (eFirst)


The synthesis of the central tryptophan residue of celogentin C is described featuring a Pd-catalyzed imine/enamine Heck-type reaction, a Pd-catalyzed Suzuki coupling, and an asymmetric Rh-catalyzed hydrogenation.

    References and Notes

  • 1a Kobayashi J. Suzuki H. Shimbo K. Takeya K. Morita H. J. Org. Chem.  2001,  66:  6626 
  • 1b Leung T.-WC. Williams DH. Barna JCJ. Foti S. Tetrahedron  1986,  42:  3333 
  • 2 Hamel E. Covell DG. Curr. Med. Chem.  2002,  2:  19 
  • 3a Srikanth GSC. Castle SL. Org. Lett.  2003,  5:  3611 
  • 3b He L. Yang L. Castle SL. Org. Lett.  2006,  8:  1165 
  • 3c Ma B. Litvinov DN. Srikanth GSC. Castle SL. Synthesis  2006,  3291 
  • 4a Harrison JR. Moody CJ. Tetrahedron Lett.  2003,  44:  5189 
  • 4b Bentley DJ. Slawin AMZ. Moody CJ. Org. Lett.  2006,  8:  1975 
  • 5 Yuen AKL. Joliffe KA. Hutton CA. Aust. J. Chem.  2006,  59:  819 
  • 6a Larock RC. Yum EK. J. Am. Chem. Soc.  1991,  113:  6689 
  • 6b Ma C. Liu X. Li X. Flippen-Anderson J. Yu S. Cook JM. J. Org. Chem.  2001,  66:  4525 
  • 8 Adamczyk M. Johnson DD. Reddy RE. Tetrahedron: Asymmetry  1999,  10:  775 
  • 9 Chen C. Lieberman DR. Larsen RD. Verhoeven TR. Reider PJ. J. Org. Chem.  1997,  62:  2676 
  • 10a Jia Y. Zhu J. Synlett  2005,  2469 
  • 10b Jia Y. Zhu J. J. Org. Chem.  2006,  71:  7826 
  • 10c Jia Y. Bois-Choussy M. Zhu J. Org. Lett.  2007,  9:  2401 
  • 11 For an alternative strategy to obtain a related boronic ester, see: Shinohara T. Deng H. Snapper ML. Hoveyda AH. J. Am. Chem. Soc.  2005,  127:  7334 
  • 12 Tour JM. Maya F. Tetrahedron  2004,  60:  81 
  • 14 Ishiyama T. Murata M. Miyaura N. J. Org. Chem.  1995,  60:  7508 
  • 16a Schmidt U. Lieberknecht A. Wild J. Synthesis  1984,  53 
  • 16b Davies SG. Rodríguez-Solla H. Tamayo JA. Cowley AR. Concellón C. Garner AC. Parkes AL. Smith AD. Org. Biomol. Chem.  2005,  3:  1435 
  • 16c Roff GJ. Lloyd RC. Turner NJ. J. Am. Chem. Soc.  2004,  126:  4098 
  • 17 Asley ER. Cruz EG. Stoltz BM. J. Am. Chem. Soc.  2003,  125:  15000 
  • 18 For a review on asymmetric hydrogenation, see: Tang WJ. Zhang XM. Chem. Rev.  2003,  103:  3029 
  • 19 Burk MJ. Gross MF. Martinez JP. J. Am. Chem. Soc.  1995,  117:  9375 
  • 20a Shultz CS. Dreher SD. Ikemoto N. Williams JM. Grabowski EJJ. Krska SW. Sun Y. Dormer PG. DiMichele L. Org. Lett.  2005,  7:  3405 
  • 20b Evans DA. Michael FE. Tedrow JS. Campos KR. J. Am. Chem. Soc.  2003,  125:  3534 
  • 20c Oohara N. Katagiri K. Imamoto T. Tetrahedron: Asymmetry  2003,  14:  2171 
  • 20d Ohashi A. Kikuchi S. Yasutake M. Imamoto T. Eur. J. Org. Chem.  2002,  2535 
  • 20e Ohashi A. Imamoto T. Org. Lett.  2001,  3:  373 
  • 20f Wada Y. Imamoto T. Tsuruta H. Yamaguchi K. Gridnev ID. Adv. Synth. Catal.  2004,  346:  777 
  • 20g Burk MJ. Bedingfield KM. Kiesman WF. Allen JG. Tetrahedron Lett.  1999,  40:  3093 
  • 20h Hoge G. Wu H. Kissel WS. Pflum DA. Greene DJ. Bao J. J. Am. Chem. Soc.  2004,  126:  5966 

For preliminary efforts to install the Leu-Trp linkage using nitro chemistry, see ref. 3c.


An alternative iodination strategy using t-BuONO and CH2I2 was also investigated and the aryl iodide was isolated in 52%.


The Heck-type reaction on 5-bromo-2-iodoaniline was attempted but was unsuccessful, mainly leading to the (6,6′)-Trp-Trp dimer (10% yield) and starting material.


Compound 14 was obtained from 10 in a manner similar to that described in Schemes [2] and [3] .


Attempts to reduce the H2 pressure were unsuccessful: at 20 bar, a 40% conversion was observed.


Eight other Josiphos-type ligands have been tested but these led to more deceptive results.


In examples described in the literature, asymmetric hydrogenations with (S,S)-MeBPE [or (S,S)-MeDuphos] have generally been described to give (S)-amino acids (ref. 19 and 20) as expected in the leucine part of celogentin C. In our synthesis, this diastereoselectivity outcome could not be yet confirmed; efforts to obtain a crystalline structure to confirm this diasteroselectivity were to date unsuccessful. Hopefully, we are expecting to get further information on this topic after the introduction of the left-handed peptidic part of celogentin C. By the way, in the presence of the (R,R)-MeBPE ligand, a 16:84 dr was obtained illustrating the role of the remote tryptophan chiral center in the asymmetric hydrogenation.