Synthesis of ring-A-substituted tryptophan by a palladium-catalyzed heteroannulation reaction

Article abstract of DOI:10.1055/s-2005-917079

Coupling of substituted o-iodoanilines with methyl (S)-2-N,N-di-tert- butoxycarbonyl-5-oxo-pentanoate, derived from glutamic acid, in DMF in the presence of palladium acetate and DABCO provides substituted tryptophans in good to excellent yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-917079

LETTER
2469
Synthesis of Ring-A-Substituted Tryptophan by a Palladium-Catalyzed
Heteroannulation Reaction
S
Y
ynthesis of Ring-
a
A Substitut
n
ed Tryptopha
x
n
ing Jia, Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France
Fax +33(1)69077247; E-mail: zhu@icsn.cnrs-gif.fr
Received 15 July 2005
powerful reaction has not been used for the synthesis of
enantiomerically pure tryptophan derivatives. Indeed
aldehyde was notably absent as a reaction partner in this
Abstract: Coupling of substituted o-iodoanilines with methyl (S)-
-N,N-di-tert-butoxycarbonyl-5-oxo-pentanoate, derived from
glutamic acid, in DMF in the presence of palladium acetate and
2
DABCO provides substituted tryptophans in good to excellent preliminary report. We describe herein an alternative and
yields.
highly efficient synthesis of substituted tryptophan deriv-
atives based on a palladium-catalyzed heteroannulation
reaction of o-iodoanilines 3 and enantiomerically en-
riched methyl (S)-2-N,N-di-tert-butoxycarbonyl-5-oxo-
pentanoate (6, equation 2 in Scheme 1). Parallel to our
work, Baran et al. have reported a synthesis of racemic 6-
hydroxy-tryptophan using a similar strategy in connection
with their total synthesis of stephacidin A.23
Key words: palladium-catalyzed heteroannulation, indole synthe-
sis, substituted tryptophan
L-Tryptophan is an essential amino acid which provides
the biosynthetic precursor for many naturally occurring
indole alkaloids. Interestingly, simple ring-A-substituted
1
tryptophan derivatives, such as plakohypaphorines
2
3
COO–
(
1a–c) and 6-bromo L-hypaphorine (1d), have also been
isolated from marine sponge. On the other hand, synthetic
NMe3+ 1a R = R1 = H, R = I
2
R
4
6
-chloro D-tryptophan has been claimed to be an inhibi-
b R = H, R1 = R2 = I
1
5
1c R = R = I, R1 = H
2
tor of indoleamin 2,3-dioxygenase (IDO) that is implicat-
ed in HIV- and AIDS-associated dementia and other
acute/chronic immunological and inflammatory diseases.6
They have also been found in a number of biologically im-
portant complex cyclopeptides such as chloropeptin (2,
R1
N
H
1d R = R2 = H, R1 = Br
R2
OH
H
N
O
7
8
Figure 1) and moroidin class of bicyclic octapeptide.
H
N
O
O
O
HOOC
H
N
H
H
Not surprisingly, synthesis of enantiomerically pure ring-
A-substituted tryptophan has attracted attention of syn-
thetic chemists and various methodologies have been
N
O
N
N
N
Me
H
H
O
O
O
9
developed including: a) enzymatic resolution of racemic
Cl
Cl Cl
Cl Cl
Cl
1
0
compounds; b) tryptophan-synthetase catalyzed alkyla-
OH
OH
OH
OH
1
1
tion of indole by L-serine; c) functionalization of cyclic
1
2
chloropeptin I (2)
tautomer of tryptophan; d) enantioselective hydrogena-
1
3
14
tion of dehydrotryptophan; e) diastereoseletive and Figure 1 Structure of plakohypaphorines (1) and chloropeptin (2)
1
5
enantioselective alkylation of indole derivatives; f)
enantioselective ene reaction; g) palladium-catalyzed
Larock heteroannulation reaction, elegantly exploited
1
6
1
7
EtO
EtO
N
N
N
by Cook for the synthesis of a range of substituted
"Pd(0)"
I
1
8
OEt
N
tryptophan derivatives (equation 1 in Scheme 1).
+
OEt
(1)
NH
2
TES
The intramolecular Heck reaction involving 5-exo cy-
clization followed by double-bond isomerization19 has
been widely used for the synthesis of substituted indole
N
R
H
TES
R
3
3
4
5
2
0
derivatives since the initial disclosure of Mori and He-
MeO
+
2
C
NBoc
2
CO
2
Me
2
1
I
NH
gedus. Recently, a variation involving in situ generation
of enamine from an o-iodoaniline and a cyclic ketone
followed by a 5-endo cyclization has been developed by
"Pd(0)"
N(Boc)
2
2
N
H
CHO
R
R
2
2
Chen and co-workers at Merck. Interestingly, this
(2)
6
7
Scheme 1 Synthesis of trypthophan derivatives by palladium-
catalyzed heteroannulation processes
SYNLETT 2005, No. 16, pp 2469–2472
Advanced online publication: 21.09.2005
0
4
.1
0
.2
0
0
5
DOI: 10.1055/s-2005-917079; Art ID: G22605ST
©
Georg Thieme Verlag Stuttgart · New York

2
470
Y. Jia, J. Zhu
LETTER
Our initial studies focused on the coupling of o-iodo- Table 1 Palladium-Catalyzed Heteroannulation of o-Iodoaniline
a
(
3a, R = H) and w-Amino Aldehyde 6
aniline 3a (R = H) and (2S)-2-N-Boc-5-oxopentanoic acid
methyl ester (9a). The aldehyde 9a was synthesized from
N-Boc-L-glutamic acid a-methyl ester 8 via a reduction–
oxidation sequence and was found to exist mainly as the
cyclic hemiaminal form 9b (Scheme 2). Submitting 9a,b
Entry
Base
Additive Temp (°C) Time (h) Yield (%)b
1
2
3
4
5
6
K CO
–
–
–
85
85
8
10
8
0
0
2
3
PMP
and 3a to Chen’s conditions [Pd(OAc) , DMF, DABCO,
2
8
5 °C] afforded the desired L-tryptophan in 15% isolated
DABCO
85
81
0
2
4
yield. Although yield remained low, the result is encour-
aging since it proved the feasibility of this approach which
constituted probably one of the shortest route to 10.
DABCO TBAClc
85
8
TBAIc
DABCO
85
20
7
48
40
0
DABCO TBAIc
DABCO
105
85
a) EtOCOCl, Et3N, THF
then NaBH4, THF–H2O
MeO2C
NHBoc
7d
MeO2C
NHBoc
–
8
a
b) (COCl)2, DMSO, CH2Cl2,
General reaction conditions: concentration 0.2 M in DMF,
–
4
78 °C, then Et3N
0% for two steps
Pd(OAc) (0.05 equiv) as palladium source except for entry 7, molar
CHO
2
COOH
ratio: 3a:6 = 1.1:1 in the presence of 3 equiv of base.
9a
b
8
Yield referred to isolated yield.
c
3 Equiv.
Pd(PPh ) was used as catalyst; abbreviations: PMP = 1,2,2,6,6-
3 4
d
3
a, Pd(OAc)2, DABCO
HO
CO2Me
N
pentamethylpiperidine; DABCO = 1,4-diazabicyclo[2,2,2]octane;
TBACl = tetrabutylammonium chloride;
TBAI = tetrabutylammonium iodide.
Boc
DMF, 85 °C, 12 h
5%
1
9b
CO2Me
NHBoc
shown in Scheme 3. 3-Methoxy-2-iodoaniline (3b) and 6-
methoxy-2-iodoaniline (3c) were prepared from commer-
cially available 3-methoxyaniline (11) and 2-methoxy-
N
H
10
Scheme 2
aniline (12), respectively, following
a
literature
28
procedure. The 2-iodo-4-nitroaniline (3d) was prepared
2
9
Reasoning that clean formation of enamine may be dis- by direct iodination of 4-nitroaniline (13), while 5-meth-
turbed by the presence of nucleophilic amide nitrogen, we oxy-2-iodoaniline (3e) was synthesized from 2-nitro-4-
turned our attention to the enantiomerically pure 2-N,N- methoxyaniline (14) by a sequence of a) iodination of di-
di-tert-butoxycarbonyl-5-oxopentanoate (6), readily syn- azonium salt and b) reduction of nitro function.1 Submit-
thesized in four conventional steps from glutamic acid.25 ting of 3b–e to the palladium-catalyzed heteroannulation
The enantiomeric excess of aldehyde 6 was determined to protocol with 6 provided the corrsponding ring-A-substi-
be 99% by its conversion to N,N-di-tert-butoxycarbonyl- tuted tryptophan derivatives. The results are summarized
8a
5
-hydroxy-pentanoate. Condensation of 3a and 6 was in Table 2. As is seen, the reaction worked well for o-io-
performed under a variety of conditions and the results are doaniline with both electron-donating (MeO, entry 1, 2, 4)
summarized in Table 1. As is seen, the choice of base is of and electron-withdrawing group (NO , entry 3). Thus
2
utmost importance, no product was formed with even with 3d, the corresponding tryptophan 7d was ob-
potassium carbonate (entry 1) and 1,2,2,6,6-penta- tained in 74% yield although the basicity of the amino
methylpiperidine (entry 2). Gratefully, when 1,4-diazabi- function in 3d should be significantly reduced (entry 3).
cyclo[2,2,2]octane (DABCO) was used as a base, the Steric hinderance was also tolerated since both N,N-di-
desired L-N,N-diBoc tryptophan methyl ester (7a, R = H) tert-butoxycarbonyl-4-methoxy tryptophan (7b, entry 1)
2
6
was isolated in 81% yield. We have also briefly exam- and N,N-di-tert-butoxycarbonyl-7-methoxy tryptophan
ined the effect of additives and found that yield of 7a (7c, entry 2) can be synthesized by this methodology,
decreased in the presence of tetrabutylammonium iodide although two equivalents of aniline 3b were required for
(
TBAI) or tetrabutylammonium chloride (TBACl) the synthesis of 7b.
(
entries 4–6). The palladium source was also important
While no detailed mechanistic studies have been carried
out, we assumed that the present domino heteroannulation
reaction would be initiated by the condensation of amine
and aldehyde leading to imine, then to enamine 15 after
tautomerization (Scheme 4). From 15 onwards, two
reaction pathways could be envisaged to account for the
since no desired product was produced when Pd(PPh3)4
was used under otherwise identical conditions (entry 7).
The enantiomeric purity of 7a was determined to be 93%
by its conversion to 10 (CeCl ·7H O, NaI, MeCN) and
subsequent chiral HPLC analysis.
27
3
2
30
Having established the optimal reaction conditions, we formation of indole ring. One would involve the carbo-
next investigated the generality of this reaction for the palladation via an 5-endo process to afford 16, b-elimina-
synthesis of other benzenoid-substituted tryptophans. The tion would produce the 3H-indole derivative 17 that
requisited o-iodoaniline derivatives were synthesized as underwent tautomerization to furnish the substituted
Synlett 2005, No. 16, 2469–2472 © Thieme Stuttgart · New York

LETTER
Synthesis of Ring-A-Substituted Tryptophan
2471
a) Boc2O, THF, 99%
b) t-BuLi (2.5 equiv),
Et2O, –20 °C, then
I
OMe
OMe
R
PdILn
CO2Me
N(Boc)2
Pd(OAc) , DABCO
2
I
NH2
R
ICH2CH2I, –78 °C to
room temperature, 84%
c) TFA, CH2Cl2, 95%
3
6
DMF, 85 °C
N
+
NH2
NH2
NH2
H
15
CO Me
2
O
11
3b
N(Boc)2
I
idem
Ln
CO Me
2
75% overall yield
NH2
Pd
2
CO Me
OMe
R
OMe
N(Boc)2
PdILn
R
N
H
N(Boc)2
N
H
12
3c
1
6
Pd(0)Ln
18
O2N
I2, Ag2SO4
EtOH, 95%
O2N
I
CO2Me
N(Boc)2
NH2
NH2
2
CO Me
R
R
13
3d
N(Boc)2
N
N
a) NaNO2/HCl, 0 °C
then KI, 90%
H
I
NH2
NO2
1
7
7
b) NH2NH2, FeCl3
MeOH, reflux
MeO
NH2
MeO
Scheme 4 Palladium-catalyzed annulation of 3 and 6: mechanistic
hypothesis
14
3e
Scheme 3 Synthesis of substituted ortho-iodoaniline
In conclusion, we have developed a novel synthesis of
ring-A-substituted tryptophan based on a palladium-
catalyzed heteroannulation reaction between two readily
accessible starting materials: the substituted o-iodo
aniline 3 and 2-N,N-di-tert-butoxycarbonylamino-5-oxo-
pentanoate (6). The chemistry developed herein is robust
and has been applied to the synthesis of 4-, 5-, 6-, and 7-
substituted tryptophan. It represented one of the shortest
and efficient routes for the access of this important class
of non-proteinogenic amino acids. Further investigation
on the scope and limitation of this methodology and its
application to the synthesis of more elaborate molecules
are in progress.
Table 2 Palladium-Catalyzed Heteroannulation Reaction to
Ring-A-Substituted Tryptophansa
Entry o-Iodoaniline
Product
Yield
b
(
%)
1
2
OMe
OMe
55
CO2Me
N(Boc)2
I
N
H
NH2
3
3
bc
7
7
b
I
2
CO Me
71
N(Boc)2
NH2
N
H
Acknowledgment
OMe
OMe
c
c
We thank this institute and CNRS for financial support.
3
4
O N
I
CO Me
74
58
2
O N
2
2
N(Boc)2
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(
Synlett 2005, No. 16, 2469–2472 © Thieme Stuttgart · New York

2
472
Y. Jia, J. Zhu
LETTER
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(
(
(
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Synlett 2005, No. 16, 2469–2472 © Thieme Stuttgart · New York