Practical, asymmetric synthesis of aromatic-substituted bulky and hydrophobic tryptophan derivatives

Article abstract of DOI:10.1016/S0040-4039(01)01626-4

An efficient method for the synthesis of novel aromatic substituted, bulky and hydrophobic tryptophan derivatives has been developed. Asymmetric hydrogenations of α-enamide 5 using Burk's DuPHOS-based catalysts generated high enantiomerically pure D- and L-α-amino acid derivatives 6, which subsequently underwent Suzuki cross couplings with boronic acid derivatives to afford aromatic substituted tryptophan derivatives 7 and 8 in high yields. The method can allow for the preparation of such amino acids in large-scales for extensive structure-activity studies.

Full text of DOI:10.1016/S0040-4039(01)01626-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7717–7719
Practical, asymmetric synthesis of aromatic-substituted bulky
and hydrophobic tryptophan derivatives
Wei Wang, Chiyi Xiong, Jianqing Yang and Victor J. Hruby*
Department of Chemistry, University of Arizona, Tucson, AZ 85721, USA
Received 27 July 2001; accepted 28 August 2001
Abstract—An efficient method for the synthesis of novel aromatic substituted, bulky and hydrophobic tryptophan derivatives has
been developed. Asymmetric hydrogenations of a-enamide 5 using Burk’s DuPHOS-based catalysts generated high enantiomeri-
cally pure
D
- and
L
-a-amino acid derivatives 6, which subsequently underwent Suzuki cross couplings with boronic acid
derivatives to afford aromatic substituted tryptophan derivatives 7 and 8 in high yields. The method can allow for the preparation
of such amino acids in large-scales for extensive structure–activity studies. © 2001 Elsevier Science Ltd. All rights reserved.
The aromatic moieties of peptide side-chain groups
play important roles in the molecular recognition pro-
cesses between peptide ligands and specific receptors as
well as receptor subtypes. Aromatic ring substituted
amino acids can provide valuable tools in developing
highly selective peptide ligands with specific structural
features. In addition, they can provide a large lipophilic
surface for binding to receptors, and for crossing mem-
brane barriers (e.g. blood–brain barriers (BBB) and
intestinal mucosa), which provide an opportunity to
address three issues simultaneously. In our continuing
a-melanocyte stimulating hormone (MSH) project,
there are three aromatic amino acids (His, Phe and
Trp) in the core sequence, His-Phe-Arg-Trp, of a-MSH
peptides, which play a key role in biological activity
and selectivity.1,2 The modification and substitution of
His and Phe in the core sequence of the peptide has led
to potent and selective a-MSH peptide ligands.1,2 In
our efforts to further enhance potency and selectivity of
a-MSH peptide ligands, we have proposed to use more
bulky and hydrophobic amino acids aromatic-substi-
tuted tryptophan analogues to replace Trp (Fig. 1).
Therefore, there is a need to develop an efficient
method for the synthesis of such amino acids, particu-
larly large-scale synthesis allowing for extensive struc-
ture–activity studies.
Our group has been long interested in the design and
synthesis of novel unnatural amino acids,3–5 and we
have developed a few methods for the synthesis of
b-substituted constrained amino acids including tryp-
tophan, tyrosine, phenylalanine, and glutamic acid
derivatives.6–10 Furthermore, we have demonstrated
that the incorporation of these novel amino acids into
biologically active peptides and peptidomimetics can
enhance the potency and selectivity significantly.1,4,5,11,12
In a survey of literature, we were surprised to find that
very few methods have been reported for the synthesis
of the aromatic substituted tryptophan analogues.13–16
For example, one of the synthetic approaches used for
the preparation of these unusual amino acids started
with tryptophan.13 However, the route was somewhat
lengthy and sometimes used harsh conditions. Herein,
we would like to report an efficient method for the
O
3
aryl
OH
asymmetric synthesis of both D- and L-aromatic substi-
5
NH2
tuted tryptophan derivatives from readily available
starting materials under very mild reaction conditions
in four steps (Scheme 1). The general strategy involves
the asymmetric hydrogenation of a-enamides 5 to gen-
erate functional a-amino acids 6 in high optical purity
which serve as common intermediates from which a
variety of substituted amino acid derivatives 7 and 8
may be readily obtained through Suzuki-type cross
couplings (Scheme 1).
1
N
H
7
1
Figure 1. Structures of 5-aryl tryptophans.
Keywords: amino acids; tryptophan; asymmetric hydrogenation;
Suzuki cross coupling.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01626-4

7718
W. Wang et al. / Tetrahedron Letters 42 (2001) 7717–7719
O
O
NHCbz
H
H
Br
(Boc)2O/DMAP
98%
Br
DBU, CH2Cl2
H3CO
OCH3
+
P
H3CO
RT, 4 h
91%
N
H
N
O
O
Boc
4
2
3
O
[((S, S)-Et-Du-PHOS)-Rh]OTf
Br
OMe
NHCbz
N
MeOH, 65 psi H2, 24 h, 94-100%
>96% ee
O
Boc
6a
Br
OMe
2
O
NHCbz
N
Br
[((R, R)-Et-Du-PHOS)-Rh]OTf
Boc
OMe
NHCbz
5
N
MeOH, 65 psi H2, 24 h, 95-100%
>96% ee
Boc
6b
O
Pd(OAc)2, P (o-tolyl)3
Ar
6a
6b
OMe
Ar-B(OH)2
DME, K2CO3, 80 oC
89-91%
NHCbz
N
Boc
7
O
Pd(OAc)2, P (o-tolyl)3
Ar
OMe
NHCbz
Ar-B(OH)2
DME, K2CO3, 80 oC
88-92%
N
Boc
8
Scheme 1. Synthesis of 5-aryl-substituted tryptophan derivatives.
matography. The isolated (Z)-dehydroamino acid ester
5 used for asymmetric hydrogenations with a higher ee
than that of (E) isomer. The (S,S) catalyst afforded the
amino acid derivative 6a with an absolute S configura-
tion based on the selectivity of the (S,S)-Et-DuPHOS
ligand in a high yield and high ee (>96%).21,23 The (R)
amino acid 6b was also obtained using (R,R)-Et-
DuPHOS as a ligand in a high yield and high ee as well.
5-Bromotryptophans 6 were subjected to Suzuki cross
couplings with a variety of boronic acids to give amino
acid derivatives 7 and 8 in 88–92% yields (Table 1). We
have tried several Suzuki cross coupling reaction condi-
tions and found the following reaction conditions to
give the best yields without any racemization: 5 mol%
Pd(OAc)2 and 10 mol% tri(o-tolyl)phosphine as a cata-
lyst, 1.5 equiv. boronic acid and 2.0 equiv. Na2CO3 in a
mixture of ethylene glycol dimethyl ether (DME) and
H2O at 80°C for 3–4 h.24 The enantiomeric purity was
determined by the Mosher’s agent25 and the conversion
The synthesis of the 5-aryl substituted tryptophans
started from commercially available 5-bromoindole-3-
carboxaldehyde 2. The indole amino group in the alde-
hyde was protected as Boc (t-butoxycarbonyl) using
(Boc)2O (di-t-butyldicarbonate) in the presence of
dimethylaminopyridine (DMAP) in 98% yield. Then the
Horner–Emmons olefination of aldehyde 3 with phos-
phonate (MeO)2P(O)CH(NHCbz)COOMe 4 gave the
dehydroamino acid 5 with Z-configuration as a major
product (Z/E>95/5) in 91% yield.17,18 Compound 4 was
synthesized in three steps following literature proce-
dures.19 The amino group in 4 was protected by Cbz
(benzyloxycarbonyl), which was orthogonal to Boc pro-
tected amino group on the indole ring of compound 5.
The dehydroamino ester 5 underwent asymmetric
hydrogenations to give a-amino acid derivatives. We
chose 1,2-bis ((2S,5S)/(2R,5R)-2,5-diethylphospho-
lano)benzene(cyclooctadiene) rhodium (I) trifluoro-
methane sulfonate ((S,S)/(R,R) [Et-DuPHOS-Rh]
OTf) as catalysts for the asymmetric hydrogenations
since they give almost exclusively single enantiomer
(>97% ee) in high yields (>95%).20,21 The catalysts
showed high efficiency (at a ratio of catalyst to sub-
strate up to 1/2500)21 and are commercially available.22
Furthermore, both Z and E dehydroamino acids using
this type of catalysts gave one single isomer.21 In this
case, we separated the two isomers by column chro-
of compound 7a to 5-phenyl-L-tryptophan methyl ester,
a known compound ([h]D24 +42.6 (c 1.06, MeOH), lit.13
([h]D25 +42.4 (c 1.24, MeOH), indicating no racemization
observed during the cross couplings.
In conclusion, we have developed an efficient method
for the synthesis of aryl-substituted tryptophan deriva-
tives. These amino acids were synthesized via asymmet-

W. Wang et al. / Tetrahedron Letters 42 (2001) 7717–7719
7719
Table 1. Suzuki cross coupling of 6 with aryl boronic
acids
7. Lin, J.; Liao, S.; Han, Y.; Qiu, W.; Hruby, V. J. Tetra-
hedron: Asymmetry 1997, 8, 3213–3221.
8. Lin, J.; Liao, S.; Hruby, V. J. Tetrahedron Lett. 1998, 39,
3117–3120.
9. Soloshonok, V. A.; Cai, C.; Hruby, V. J.; Van Meervelt,
L.; Mischenko, N. Tetrahedron 1999, 55, 12031–12044.
10. Soloshonok, V. A.; Cai, C.; Hruby, V. J. Angew. Chem.,
Int. Ed. 2000, 39, 2172–2175.
Yields with 6b
8a, 89%
Boronic aicds
B(OH)2
Yields with 6a
7a, 91%
11. Liao, S.; Lin, J.; Shenderovich, M. D.; Han, Y.; Hoso-
hata, K.; Davis, P.; Qiu, W.; Porreca, F.; Yamamura, H.
I.; Hruby, V. J. Bioorg. Med. Chem. Lett. 1997, 7,
3049–3052.
12. Liao, S.; Shenderovich, M. D.; Zhang, Z.; Maletinska, L.;
Slaninova, J.; Hruby, V. J. J. Am. Chem. Soc. 1998, 120,
7393–7394.
7b, 90%
7c, 89%
8b, 92%
8c, 88%
H3CO
B(OH)2
B(OH)2
13. Zembower, D. E.; Ames, M. M. Synthesis 1994, 1433–
1436.
14. Sato, K.; Kozikowski, A. P. Tetrahedron Lett. 1989, 30,
4073–4076.
ric hydrogenations using Burk’s DuPHOS-based cata-
lysts with high ee (>96%), followed by Suzuki crossing
couplings also in high yields. The method can be easily
scaled up for the synthesis of a large amount of the
amino acids. The incorporation of the amino acids into
biologically active a-MSH peptides and peptidomimet-
ics, biological evaluation, and structure-biological activ-
ity relationship studies of the bioactive peptides and
peptidomimetics are in progress.
15. Shima, I.; Shimazaki, N.; Imai, K.; Hemmi, K.; Hashi-
moto, M. Chem. Pharm. Bull. 1990, 38, 564–566.
16. Yokoyama, Y.; Osanai, K.; Mitsuhashi, M.; Kondo, K.;
Murakami, Y. Heterocycles 2001, 55, 653–659.
17. Schmidt, U.; Griesser, H.; Leitenberger, V.; Lieberknecht,
A.; Mangold, R.; Meyer, R.; Riedl, B. Synthesis 1992,
487–490.
18. The chemical shift of proton of C2 in 5 with (Z) configu-
ration is 7.91 ppm, whereas (E) isomer is 7.79 ppm, since
the protons of b-alkyl groups in (Z)-isomers are more
deshielded than those in (E)-isomers (see Ref. 17).
19. Schmidt, U.; Lieberknecht, A.; Wild, J. Syn. Commun.
1984, 53–60.
Acknowledgements
20. Burk, M. J. Acc. Chem. Res. 2000, 33, 363–372.
21. Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L.
J. Am. Soc. Chem. 1993, 115, 10125–10138.
22. Strem Chemicals, 7 Mulliken Way, Dexter Industrial
Park, Newburyport, MA 01950-9899, USA.
This work is supported by grants from the US Public
Health Service (DK 17420) and the National Institute
of Drug Abuse (DA 06284). We thank Professor
Dominic V. McGrath for using his group’s polarimeter.
The views expressed are those of the authors and not
necessary those of the USPHS.
1
23. Compound 6a: [h]2D5 +43.4 (c1.48, CHCl3); H NMR (600
MHz, CDCl3): l 7.98 (1H, brs), 7.61 (1H, brs), 7.30–7.41
(7H, m), 5.40 (1H, d, J=7.8 Hz), 5.13 (2H, dd, J1=12.6
Hz, J2=18.0 Hz), 4.71 (1H, dd, J1=5.4 Hz, J2=12.6 Hz),
3.72 (3H, s), 3.25 (1H, dd, J1=5.4 Hz, J2=12.6 Hz), 3.19
(1H, dd, J1=5.4 Hz, J2=12.6 Hz), 1.66 (9H, s); 13C
NMR (75 MHz, CDCl3): l 171.9, 155.8, 149.3, 136.3,
134.2, 132.3, 128.7, 128.4, 128.3, 127.6, 125.5, 121.8,
117.0, 116.2, 114.3, 84.4, 67.3, 60.6, 54.1, 52.7, 28.3;
HRMS (FAB) calcd for C25H27BrN2O6 530.1052, (Br 79),
532.1036 (Br 81), found 530.1052 (Br 79), 530.1057 (Br
81).
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shifts at −69.81 ppm for 7a derivative and −69.94 ppm
for 8a derivative (in CFCl3/CDCl3), respectively.