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Synlett 2008(10): 1532-1536  
DOI: 10.1055/s-2008-1078411
LETTER
© 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
e-Mail: jean-marc.campagne@enscm.fr;
Further Information

Publication History

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

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Abstract

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.

Key words

asymmetric catalysis - palladium - rhodium - natural products - total synthesis

7

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

13

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

15

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.

21

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

22

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

23

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

24

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.