Synthesis of the central tryptophan-leucine residue of celogentin C

Article abstract of DOI:10.1055/s-2008-1078411

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.

Full text of DOI:10.1055/s-2008-1078411

1532
LETTER
Synthesis of the Central Tryptophan-Leucine Residue of Celogentin C
A
pproache
u
s
to
C
elogen
l
tin
C
ien Michaux,*a Pascal Retailleau,b Jean-Marc Campagne*c
a
b
c
Institut de Chimie des Substances Naturelles, Avenue de la Terrasse, 91198 Gif sur Yvette, France
Service de Cristallochimie, Institut de Chimie des Substances Naturelles, Avenue de la Terrasse, 91198 Gif sur Yvette, France
Institut Charles Gerhardt Montpellier, ENSCM, 8 rue de l'Ecole Normale, 34296 Montpellier, France
E-mail: jean-marc.campagne@enscm.fr
Received 6 March 2008
Due to their original structures and potent biological ac-
tivity, this family, and more particularly celogentin C, has
attracted the attention of synthetic chemists but to date no
total synthesis has yet been reported.3–5 The synthesis of
the right-hand part of moroidin/celogentin have been de-
scribed by Moody and Castle.3,4 Castle has described an
elegant synthesis of the right-hand ring of celogentin C
using an oxidative coupling to construct the indole–imida-
zole linkage.3b The right-hand cycle Trp-His-Gly-Arg of
moroidin was also obtained by Moody using the possibil-
ity of a chlorine displacement on 3-formyl tryptophan de-
rivatives.4a Installation of the left-hand part (the b-
leucine–tryptophan connection) is far from trivial, espe-
cially with respect to the stereochemical outcome. Asym-
metric syntheses of C-6-substituted tryptophan
derivatives have been described by Castle3a and Hutton5
based on Cook–Larock methodologies,6 but a stereoselec-
tive access to the leucine–tryptophan link has not yet been
disclosed.7 Moody has also described a total synthesis of
Abstract: The synthesis of the central tryptophan residue of celo-
gentin 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
The moroidin/celogentin family of natural products
(Figure 1) is characterized by the presence of unusual ar-
chitecture joining, within a macrocyclic peptide array,
three pseudo amino acids: leucine, tryptophan, and histi-
dine residues.1 The leucine b-carbon is linked with the in-
dole C-6 of tryptophan, and the tryptophan indole C-2 is
connected to the imidazole N-1 of histidine (Figure 1).
Moreover, these compounds, isolated from the seeds of
Celosia argentea, inhibit the polymerization of tubulin at
micromolar levels: celogentin C (IC50 0.8 mM) is more po-
tent than vinblastin (IC50 3.6 mM).2
H
N
NH
H
O
N
O
O
N
O
H
O
NH
H2N
NH
H
N
N
N
H
O
O
HN
H2N
N
N
H
O
H
O
HN
O
HN
O
HN
O
O
O
NH
N
H
N
H
HN
N
HN
N
N
N
H
O
N
CO2H
CO2H
H
O
N
celogentin C (1)
moroidin (2)
O
O
O
H
N
N
OH
N
H
O
H
O
HN
O
O
N
N
HN
N
N
N
H
H
HN
CO2H
H
N
H
O
leucine
tryptophan
histidine
stephanotic acid (3)
Figure 1
SYNLETT 2008, No. 10, pp 1532–1536
x
x
.x
x
.2
0
0
8
Advanced online publication: 16.05.2008
DOI: 10.1055/s-2008-1078411; Art ID: G07408ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Approaches to Celogentin C
1533
stephanotic acid (3): The leucine–tryptophan linkage was the presence of ICl to give 5 in 42% yield (Scheme 1).
obtained by the achiral and nonstereoselective reduction Starting from this aryl iodide 5 and glutamic acid deriva-
of the corresponding dehydroamino acid (the diastereo- tive 6,8 the palladium-catalyzed Heck-type cyclization,9,10
isomers were next separated after introduction of the gave the 6-nitrotryptophan derivative 7 in 81% yield. The
chiral nonracemic isoleucine and valine amino acids).
NH-indole was next protected as a Boc and the 6-NO2 re-
duced to the corresponding aniline 8. Boronate ester 9 was
next obtained from aniline 8 in a two-step sequence.11 The
iodination of aniline 8 under classical acidic conditions
(NaNO2, HCl then KI) was disappointing in our hands
leading to substantial amounts of the reduced compound.
Moving to the procedure developed by Tour, in the pres-
ence of NOBF4,12,13 was the key to obtain the aryl iodide
in 55% yield. This iodination reaction was then followed
by a Pd-catalyzed Miyaura borylation to give compound
9 in 96% yield.14,15
In our retrosynthetic analysis (Figure 2), we anticipated
that the leucine–tryptophan connection could be obtained
stereoselectively by the asymmetric hydrogenation of the
corresponding dehydroamino acid.
Pd-catalyzed intramolecular
Heck-type reaction
NBoc2
CO2Me
CO2t-Bu
AcHN
N
The (Z)-iododehydroamino acid 12 was obtained in three
steps starting from commercially available phosphonate
10 (Scheme 2).16 The Z-stereochemistry of compound 12
was confirmed by an X-ray crystallographic analysis
(Figure 3).
Boc
Pd-catalyzed
Suzuki coupling
Rh-catalyzed
asymmetric hydrogenation
Figure 2
The sensitive Pd-catalyzed Suzuki–Miyaura coupling on
the hindered dehydroamino acid 12 proved to be challeng-
ing and after some experimentation, we found that the
conditions developed by Stoltz in the total synthesis of
(–)-lemonomycin17 were suitable leading to the dehydro-
leucine–tryptophan derivative 13 in a gratifying 76%
yield (Scheme 3).
Such an amino acid could be obtained by a Suzuki cou-
pling on a C-6-modified tryptophan residue, which itself
could be obtained ultimately using a Pd-catalyzed Heck-
type cyclization. Accordingly, commercialy available 3-
nitroaniline (4) was subjected to an iodination reaction in
O
CO2Me
1) H2, Ac2O,
MeOH, r.t.
I
ICl
(MeO)2P
CO2Me
NHAc
AcOH, 80 °C
42%
2) i-PrCHO, DBU,
CH2Cl2, –10 °C
O2N
NH2
O2N
NH2
NHCbz
10
11
4
5
77%
O
1) NIS, CH2Cl2, r.t.
2) DABCO
Pd(OAc)2
DABCO
DMF, 80 °C
81%
66%
CO2t-Bu
NBoc2
H
6
CO2t-Bu
NBoc2
CO2Me
NHAc
1) Boc2O, DMAP, 96%
2) Zn, AcOH, 90%
12
I
Scheme 2
N
H
O2N
CO2t-Bu
7
NBoc2
8
N
H2N
Boc
1) NOBF4, MeCN –40 °C
then NaI, I2, 55%
2) [B(pin)]2, PdCl2(dppf)
KOAc, DMSO, 80 °C
96%
CO2t-Bu
NBoc2
O
9
N
B
Boc
O
Figure 3 X-ray crystal structure of 12
Scheme 1
Synlett 2008, No. 10, 1532–1536 © Thieme Stuttgart · New York

1534
J. Michaux et al.
LETTER
CO2t-Bu
NBoc2
Table 1 Asymmetric Hydrogenation of 13 – Ligand Survey
Ligand
H2
Conversion dra
Pd(PPh3)4,
K2CO3
NHAc
(bar)
(%)
100
98
12
+
9
N
MeO2C
1
2
3
4
5
6
7
8
9
(S,S)-MeDuphos
(S)-Phanephos
(R)-Solphos
50
50
50
50
50
50
50
50
50
78:22
65:35
–
PhH–MeOH–H2O
75 °C
Boc
13
76%
3
Scheme 3
all(S)-Rophos
0
–
The next goal was the asymmetric hydrogenation of the
dehydroamino acid 13.18 Asymmetric hydrogenations on
tetrasubstituted alkenes have been scarcely described in
the literature, mainly on dehydrovaline and dehydroisole-
ucine residues and b,b¢-cyclic derivatives.19,20 But to the
best of our knowledge asymmetric hydrogenations have
not been described on such hindered tetrasubstituted alk-
enes like 13. Indeed, Moody, during the total synthesis of
stephanotic acid (3), faced poor selectivities (up to 28%
ee) in the asymmetric hydrogenation on a Cbz-protected
tetrasubstituted dehydroamino acid.4b
(R)-(S)-Josiphos
(R)-(R)-Walphos
(R)-(S)-Mandyphos
(R)-(S)-Taniaphos
(S,S)-Me-BPE
100
100
21
92:8
31:69
nd
36
52:48
100
94:6
a Mesured by chiral HPLC: OD column (Chiralcel) (25 cm × 4.6 mm),
hexane–i-PrOH (95:5), 1 mL/min.
(Table 1, entries 5–8) were next tried but only Josiphos
lead to an interesting 92:8 diastereomeric ratio.23 Howev-
er, the highest diastereoselectivity (dr = 94:6) was ob-
served for the (S,S)-Me-BPE ligand (Table 1, entry 9)
demonstrating that some flexibility is required in such
hindered systems.24 Following this initial screening (on a
10 mg scale), the hydrogenation protocol could be scaled
up to a 200 mg scale, leading to 15 in 92–96% yield and
94:6 diastereoselectivity.
During preliminary investigations, we found that replac-
ing the Cbz protecting group by an acetamide was the key
to increase the enantioselectivity. Indeed, a complete con-
version of the Cbz-protected derivative 1421 requires a
100 bar H2 atmosphere {in the presence of [(S,S)-MeDu-
phos-Rh]OTf to give a modest 68:32 diastereomeric ratio,
whereas, under the same catalytic system, the Ac-protect-
ed derivative 13 gives a 78:22 ratio} under a 50 bar H2
atmosphere22 (Scheme 4). Encouraged by these prelimi-
nary results, we sought an improved catalyst by screening
various ligands in the asymmetric hydrogenation of 13.
Table 1 contains the results of a ligand survey for this re-
action.
We next focused our attention on the removal of the acet-
amido protecting group in compound 15 (Scheme 5). The
acetamido protecting group was essential in our hands to
obtain high selectivities in the asymmetric hydrogenation,
but it is also known that the deprotection of such protect-
ing group might require harsh conditions, incompatible
with sensitive structures.
CO2t-Bu
P
NBoc2
NH
13 P = Ac
14 P = Cbz
CO2t-Bu
N
MeO2C
Boc
NBoc2
P
1) Boc2O, DMAP
THF, r.t., 68%
NH
N
17 P = Boc
MeO2C
H2
Boc
2) NH2NH2
DCE–MeOH, r.t., 92%
[(S,S)-MeDuphos-Rh]OTf
MeOH, r.t.
15 P = Ac
CO2t-Bu
Scheme 5
P
NBoc2
NH
Although it was envisaged in our strategy to deprotect the
acetamido group at a later stage of the synthesis (after the
introduction of the peptidic chain on the tryptophan resi-
due), we were keen to explore the possibilities of remov-
ing it earlier. In our hands, the acetamido group could
efficiently be exchanged for a Boc protecting group in a
two-step sequence by protection of the acetamide with a
Boc group (in 68% yield) and then removing the acet-
amide in the presence of hydrazine (in 92% yield).
N
MeO2C
Boc
15 P = Ac 100% conv, 78:22 dr (50 bar)
16 P = Cbz 97% conv, 68:32 dr (100 bar)
Scheme 4
Several C2-symmetric ligands (Phanephos, Solphos,
Rophos, Figure 4) were first examined (Table 1, entries
2–4) but disappointing selectivities or very low conver-
sions were obtained. Non-C2-symmetric ferrocenes
In conclusion, we have developed an efficient asymmetric
access to the central tryptophan core of celogentin C in ten
Synlett 2008, No. 10, 1532–1536 © Thieme Stuttgart · New York

LETTER
Approaches to Celogentin C
1535
PCy2
PPh2
P
Ph2P
Me
H
Fe
PPh2
P
Josiphos
Phanephos
Me-Duphos
N
PPh2
N
PPh2
Me
Ph2P
Ph
H
PPh2
PPh2
O
O
Fe
Fe
H
Ph
H
N
PPh2
Mandyphos
N
Walphos
Solphos
Ph2P
H
P+
P+
H
P
P
Ph2P
OH
N
Fe
HO
H
OH
OH
Taniaphos
Rophos
Me-BPE
Figure 4
(4) (a) Harrison, J. R.; Moody, C. J. Tetrahedron Lett. 2003, 44,
5189. (b) Bentley, D. J.; Slawin, A. M. Z.; Moody, C. J. Org.
Lett. 2006, 8, 1975.
(5) Yuen, A. K. L.; Joliffe, K. A.; Hutton, C. A. Aust. J. Chem.
2006, 59, 819.
(6) (a) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113,
6689. (b) Ma, C.; Liu, X.; Li, X.; Flippen-Anderson, J.; Yu,
S.; Cook, J. M. J. Org. Chem. 2001, 66, 4525.
(7) For preliminary efforts to install the Leu–Trp linkage using
nitro chemistry, see ref. 3c.
(8) Adamczyk, M.; Johnson, D. D.; Reddy, R. E. Tetrahedron:
Asymmetry 1999, 10, 775.
(9) Chen, C.; Lieberman, D. R.; Larsen, R. D.; Verhoeven, T.
R.; Reider, P. J. J. Org. Chem. 1997, 62, 2676.
(10) (a) Jia, Y.; Zhu, J. Synlett 2005, 2469. (b) Jia, Y.; Zhu, J. J.
Org. Chem. 2006, 71, 7826. (c) Jia, Y.; Bois-Choussy, M.;
Zhu, J. Org. Lett. 2007, 9, 2401.
steps from commercialy available 3-nitroaniline (4). Our
strategy is based on a Pd-catalyzed Heck-type cyclization,
a Pd-catalyzed Miyaura borylation, a Pd-catalyzed Suzu-
ki–Miyaura cross-coupling reaction. The tryptophan–leu-
cine
connection
of
celogentin
has
been
diastereoselectively (dr = 94:6) achieved using an asym-
metric Rh(Me-BPE)-catalyzed hydrogenation on a highly
hindered tetrasubstituted substrate. To the best of our
knowledge, this type of reactions has only been scarcely
described in the literature.18–20 The construction of the
tryptophan–histidine connection of celogentin C is cur-
rently under investigation.
Acknowledgment
(11) For an alternative strategy to obtain a related boronic ester,
see: Shinohara, T.; Deng, H.; Snapper, M. L.; Hoveyda, A.
H. J. Am. Chem. Soc. 2005, 127, 7334.
(12) Tour, J. M.; Maya, F. Tetrahedron 2004, 60, 81.
(13) An alternative iodination strategy using t-BuONO and CH2I2
was also investigated and the aryl iodide was isolated in
52%.
This work was supported by the CNRS and the Institut de Chimie
des Substances Naturelles. Dr. M. Thommen (Solvias) is gratefully
acknowledged for a generous gift of chiral ligands; we warmly
thank Dr. J. Zhu and Dr. Y. Jia for sharing information on the Pd-
catalyzed Heck/indole synthesis (ref. 10).
(14) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995,
60, 7508.
References and Notes
(1) (a) Kobayashi, J.; Suzuki, H.; Shimbo, K.; Takeya, K.;
Morita, H. J. Org. Chem. 2001, 66, 6626. (b) Leung, T.-W.
C.; Williams, D. H.; Barna, J. C. J.; Foti, S. Tetrahedron
1986, 42, 3333.
(2) Hamel, E.; Covell, D. G. Curr. Med. Chem. 2002, 2, 19.
(3) (a) Srikanth, G. S. C.; Castle, S. L. Org. Lett. 2003, 5, 3611.
(b) He, L.; Yang, L.; Castle, S. L. Org. Lett. 2006, 8, 1165.
(c) Ma, B.; Litvinov, D. N.; Srikanth, G. S. C.; Castle, S. L.
Synthesis 2006, 3291.
(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.
(16) (a) Schmidt, U.; Lieberknecht, A.; Wild, J. Synthesis 1984,
53. (b) Davies, S. G.; Rodríguez-Solla, H.; Tamayo, J. A.;
Cowley, A. R.; Concellón, C.; Garner, A. C.; Parkes, A. L.;
Smith, A. D. Org. Biomol. Chem. 2005, 3, 1435. (c) Roff,
G. J.; Lloyd, R. C.; Turner, N. J. J. Am. Chem. Soc. 2004,
126, 4098.
Synlett 2008, No. 10, 1532–1536 © Thieme Stuttgart · New York

1536
J. Michaux et al.
LETTER
(17) Asley, E. R.; Cruz, E. G.; Stoltz, B. M. J. Am. Chem. Soc.
2003, 125, 15000.
(18) For a review on asymmetric hydrogenation, see: Tang, W. J.;
Zhang, X. M. Chem. Rev. 2003, 103, 3029.
(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.
(19) Burk, M. J.; Gross, M. F.; Martinez, J. P. J. Am. Chem. Soc.
1995, 117, 9375.
(23) Eight other Josiphos-type ligands have been tested but these
led to more deceptive results.
(20) (a) Shultz, C. S.; Dreher, S. D.; Ikemoto, N.; Williams, J. M.;
Grabowski, E. J. J.; Krska, S. W.; Sun, Y.; Dormer, P. G.;
DiMichele, L. Org. Lett. 2005, 7, 3405. (b) Evans, D. A.;
Michael, F. E.; Tedrow, J. S.; Campos, K. R. J. Am. Chem.
Soc. 2003, 125, 3534. (c) Oohara, N.; Katagiri, K.;
Imamoto, T. Tetrahedron: Asymmetry 2003, 14, 2171.
(d) Ohashi, A.; Kikuchi, S.; Yasutake, M.; Imamoto, T. Eur.
J. Org. Chem. 2002, 2535. (e) Ohashi, A.; Imamoto, T. Org.
Lett. 2001, 3, 373. (f) Wada, Y.; Imamoto, T.; Tsuruta, H.;
Yamaguchi, K.; Gridnev, I. D. Adv. Synth. Catal. 2004, 346,
777. (g) Burk, M. J.; Bedingfield, K. M.; Kiesman, W. F.;
Allen, J. G. Tetrahedron Lett. 1999, 40, 3093. (h) Hoge, G.;
Wu, H.; Kissel, W. S.; Pflum, D. A.; Greene, D. J.; Bao, J.
J. Am. Chem. Soc. 2004, 126, 5966.
(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.
Synlett 2008, No. 10, 1532–1536 © Thieme Stuttgart · New York

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