Design and synthesis of hydrophobic, bulky χ2-constrained phenylalanine and naphthylalanine derivatives

Article abstract of DOI:10.1016/S0040-4039(02)00249-6

A series of novel hydrophobic, bulky χ²-constrained phenylalanine and naphthylalanine derivatives were designed and synthesized. Asymmetric hydrogenations of α-enamides using Burk's DuPHOS-based Rh(I) catalysts generated high enantiomerically p

Full text of DOI:10.1016/S0040-4039(02)00249-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2137–2140
Design and synthesis of hydrophobic, bulky x2-constrained
phenylalanine and naphthylalanine derivatives
Wei Wang, Junyi Zhang, Chiyi Xiong and Victor J. Hruby*
Department of Chemistry, University of Arizona, Tucson, AZ 85721, USA
Received 12 December 2001; accepted 28 January 2002
Abstract—A series of novel hydrophobic, bulky x2-constrained phenylalanine and naphthylalanine derivatives were designed and
synthesized. Asymmetric hydrogenations of a-enamides using Burk’s DuPHOS-based Rh(I) catalysts generated high enantiomer-
ically pure a-amino acid derivatives, which subsequently underwent Suzuki cross couplings with boronic acid derivatives to afford
these aromatic substituted amino acids in high yields and with high enantioselectivity. © 2002 Elsevier Science Ltd. All rights
reserved.
The backbone conformations of peptides and proteins
such as a-helix, b-sheet, b-turn, and so forth provide
critical templates for the three-dimensional structures
when interacting with their receptors/acceptors,
whereas the overall shape and intrinsic stereoelectronic
properties of the peptides and proteins important for
molecule recognition, signal transduction, enzymatic
specificity, immunomodulation, and other biological
effects depend on arrangement of the side chain groups
of amino acid residues in three dimensional x space
(their x1, x2, etc. torsional angles). The side chain
conformation can be controlled by introducing an
alkyl/aryl group at the b-position or on the aromatic
rings of aromatic amino acid residues. These kinds of
modifications do not perturb the backbone conforma-
tion significantly, and still allow the peptide backbone
and side chain some degree of flexibility, which often is
necessary and even crucial for peptide and pepti-
domimetic activity. In the past, our group has designed
and synthesized many novel x-constrained amino acids,
mainly focusing on introducing alkyl groups at the
b-position of amino acids.1–3 We have demonstrated
Ar
O
Ar
O
OH
OH
NH2
NH2
2
1
Ar: Phenyl or Naphthyl
H
H
H
H
O
H
H
H
H
χ2
N
N
N
N
χ2
χ2
χ2
OH
OH
OH
OH
χ1
H
H
H
H
H
H
H
H
O
O
O
1a
1b
2a
2b
Figure 1. Structures of o-substituted-aryl phenylalanines and naphthylalanines.
Keywords: asymmetric hydrogenation; DuPHOS; constrained amino acids; phenylalanine; naphthylalanine.
* Corresponding author. Tel.: (520) 621-6332; fax: (520) 621-8407; e-mail: hruby@u.arizona.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00249-6

2138
W. Wang et al. / Tetrahedron Letters 43 (2002) 2137–2140
that the incorporation of these unnatural amino acids
into biologically active peptides and peptidomimetics
can enhance the potency and selectivity significantly.2–6
However, introducing an alkyl or aryl group on the
aromatic ring of an aromatic amino acid residue, par-
ticularly in the ortho position which can significantly
restrict its conformation in x2 space, has been much less
explored.2,7–9 The x2 torsional angle can be efficiently
restricted by the interaction between the aryl moiety
and the b-hydrogens of amino side chain in the o-sub-
stituted phenylalanine and naphthylalanine derivatives
1 and 2 (Fig. 1).
involves the asymmetric hydrogenation of a-enamides
to generate functional a-amino acids in high optical
purity which serve as common intermediates from
which a variety aromatic substituted amino acid deriva-
tives may be readily obtained through Suzuki-type
cross couplings (Schemes 1 and 2). Recently we used a
similar method to synthesize novel 5-aryl tryptophan
derivatives.12
The synthesis of the o-aryl substituted phenylalanines 3
and 4 started from commercially available 2-bromoben-
zylaldehyde 5 (Scheme 1). The Horner–Emmons olefi-
nation of aldehyde 5 with phosphonate (MeO)2-
P(O)CH(NHCbz)COOMe 6 gave the dehydroamino
acid derivative 7 with Z-configuration as a major
product (Z/E>95/5) in 96% yield.13 Compound 6 was
synthesized in three steps following literature proce-
dures.14 The amino group in 7 was protected by Cbz
(benzyloxycarbonyl), which can be readily removed by
Pd catalyzed hydrogenation to give a free amine, which
can be reprotected as Na-Boc (tert-butoxycarbonyl) or
Na-Fmoc (9-fluorenylmethoxycarbonyl)) for the solid-
phase peptide synthesis. The dehydroamino ester 7
underwent asymmetric hydrogenations to give a-amino
acid derivatives. We chose 1,2-bis ((2S,5S)/(2R,5R)-2,5-
diethylphospholano)benzene (cyclooctadiene) rhodi-
In our a-melanocyte stimulating hormone (MSH) pro-
ject, we have found that Phe (preferably D-Phe) plays a
critical role in activity and selectivity.4,10 For example,
the substitution of -Phe in MT-II with -Nal (naph-
D
D
thylalanine) (2%) led to a potent and selective antagonist
ligand, SHU-9119, for melanocortin receptor (MCR)
4.11 To further improve activity and selectivity and
understand the relationship of peptide ligands and their
receptors, we have proposed to use x2-constrained,
hydrophobic and bulky aromatic-substituted phenylala-
nines 1 and naphthylalanines 2 to substitute
D-Phe in
MT-II or -Nal (2%) in SHU-9119. In addition, these
D
amino acids can provide a large lipophilic surface for
binding to receptors, and for crossing membrane barri-
ers (e.g. blood brain barriers (BBB) and intestinal
mucosa), which provides an opportunity to address
three issues simultaneously. Herein we would like to
report an efficient approach to the asymmetric synthesis
of these unusual amino acids. The general strategy
um(I)
trifluoromethane
sulfonate
((S,S)/(R,R)
[Et-DuPHOS-Rh] OTf) as catalysts for the asymmetric
hydrogenations since they give almost exclusively single
enatiomer (>97% ee) in high yields (>96%).15,16 These
catalysts show high efficiency (at a ratio of catalyst to
substrate up to 1/2500)16 and are commercially avail-
Br
Br
DBU, CH2Cl2
RT, 5 h, 96%
NHCbz
OCH3
(CH3O)2P(O)CH(NHCbz)COOCH3
+
CHO
6
7
O
5
Br
Pd(OAc)2, P (o-tolyl)3
[((S, S)-Et-Du-PHOS)-Rh]OTf
NHCbz
3
OCH3
R-B(OH)2
MeOH, 65 psi H2, 24 h, 97%
DME, K2CO3, 80 oC
Br
NHCbz
OCH3
O
8a
Br
Pd(OAc)2, P (o-tolyl)3
O
[((R, R)-Et-Du-PHOS)-Rh]OTf
NHCbz
7
4
OCH3
R-B(OH)2
DME, K2CO3, 80 oC
MeOH, 65 psi H2, 24 h, 98%
O
8b
R
R
NHCbz
OCH3
NHCbz
OCH3
O
O
4
3
R
Yield (%)
Yield (%)
R
69
4a
3a
3b
71
79
98
4b
Scheme 1. Synthesis of o-substituted phenylalanine derivatives.

W. Wang et al. / Tetrahedron Letters 43 (2002) 2137–2140
2139
Scheme 2. Synthesis of o-substituted naphthylalanine derivatives.
able.17 Furthermore, both Z and E dehydroamino acids
using this type of catalysts gave one single isomer.16 In
this case, we separated the two isomers by column
chromatography. The isolated (Z)-dehydroamino acid
ester 7 was used for asymmetric hydrogenations with a
higher ee than that of (E) isomer. The (S,S) catalyst
afforded the amino acid derivative 8a with an absolute
S configuration, based on the selectivity of the (S,S)-Et-
DuPHOS ligand, in high yield and high ee (>96%).16
The (R) amino acid 8b was also obtained using (R,R)-
Et-DuPHOS as the ligand in high yield and high ee as
well. o-Bromophenylalanines 8a,b were subjected to
Suzuki cross couplings with phenyl and naphthyl
boronic acids to give amino acid derivatives 3 and 4 in
69–98% yields. We have tried several Suzuki cross
coupling reaction conditions 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 the catalyst, 1.5 equiv boronic acid
and 2.0 equiv Na2CO3 in a mixture of ethylene glycol
dimethyl ether (DME) and H2O at 80°C. A longer
reaction time (12 h) was required for the formation of
the sterically hindered products. The enantiomeric
purity was determined by chiral HPLC analysis and no
racemizations were observed during the cross
couplings.18
of DBU in CH2Cl2 in 93% yield. Asymmetric hydro-
genation of a-enamide 12 in the presence of 5 mol%
catalyst, Rh(I)-(S,S)-Et-DuPHOS or Rh(I)-(R,R)-Et-
DuPHOS, 65 psi of H2, 24 h in methanol gave (S) or
(R) Na-Cbz-o-bromonaphthylalanine methyl esters
13a,b in 95–99% yield and >98% ee, respectively.19 The
o-bromonaphthylalanines 13a,b were reacted with
phenyl and naphthyl boronic acids through Suzuki
cross coupling reactions to give final compounds 9 and
10. We employed the same coupling reaction conditions
as used before in good yields for the phenylboronic
acid-based reactions. An incomplete reaction was
observed for the coupling with naphthylboronic acid.
However, using 5 mol% Pd(PPh3)4 instead of Pd(OAc)2
and P(o-tolyl)3, 1.5 equiv. boronic acid, 2.0 equiv.
Na2CO3, in benzene–water, 80°C, for 36 h afforded a
complete reaction in high yields (>95%).
Interestingly in these o-substituted phenylalanines and
naphthylalanines, we found that two diasteromers were
1
obtained for 3b, 4b, 9b, and 10b. H NMR showed two
groups of proton signals. About 1:1 and 1:2 ratios of
diastereomers in 3b and 4b and in 9b and 10b were
observed, respectively, during the Suzuki couplings
1
based on the integrations of H NMR. Although they
are diastereomers, they could not be separated by silica
gel chromatography. Their structures are presumably
assigned as shown (4b and 10b not shown) in Fig. 2.
Because of the interaction between the large naphthyl
moiety and the b-hydrogens of amino side chain, the
naphthyl group in 3b and 9b were away from the two
b-hydrogens of amino side chain to reduce steric hin-
Using a similar strategy, we synthesized o-aromatic
substituted naphthylalanine derivatives
9 and 10
(Scheme 2). The isolated (Z) a-enamide 12 was
obtained as the major product by condensation of
1-bromo-2-naphthylaldehyde 11 with 6 in the presence

2140
W. Wang et al. / Tetrahedron Letters 43 (2002) 2137–2140
Figure 2.
drance. The detailed conformation studies of these
amino acids currently are being investigated via X-ray
crystal structures, NMR, and computer modeling and
calculations. It is also realized that these conformation-
ally constrained amino acids bearing fluorophores will
be very useful in structure–activity studies of peptides
and receptors.
Jorgensen, F. S.; Krogsgaard-Larsen, P., Eds.; Munks-
gaard Intl. Publ. Ltd: Copenhagen, 1998; pp. 51–62.
4. Hruby, V. J.; Balse, P. M. Curr. Med. Chem. 2000, 7,
945–970.
5. 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.
An efficient method has been developed for the synthe-
sis of novel aromatic-substituted x2-constrained phenyl-
alanine and naphthylalanine derivatives. These amino
acids were synthesized through asymmetric hydrogena-
tions using Burk’s DuPHOS-based catalysts with high
e.e. (>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 these amino acids.
The incorporation of the amino acids into biologically
active a-MSH peptides and peptidomimetics, biological
evaluation, and structure–biological activity relation-
ship study of the peptides and peptidomimetics are
currently under extensive investigation.
6. Liao, S.; Shenderovich, M. D.; Zhang, Z.; Maletinska, L.;
Slaninova, J.; Hruby, V. J. J. Am. Chem. Soc. 1998, 120,
7393–7394.
7. Tang, X. J.; Soloshonok, V. A.; Hruby, V. J. Tetra-
hedron: Asymmetry 2000, 11, 2917–2925.
8. Jiao, D.; Russell, K. C.; Hruby, V. J. Tetrahedron 1993,
49, 3511–3520.
9. Qian, X.; Russell, K. C.; Boteju, L. W.; Hruby, V. J.
Tetrahedron 1995, 51, 1033–1054.
10. Hruby, V. J.; Han, G. In The Melanocortin Receptors;
Cone, R. D., Ed.; Humana Press: Totowa, NJ, 2000; pp.
239–261.
11. Hruby, V. J.; Lu, D.; Sharma, S. D.; Castrucci, A.; de,
L.; Kesterson, R. A.; Al-Obeidi, F. A.; Hadley, M. E.;
Cone, R. D. J. Med. Chem. 1995, 38, 3454–3461.
12. Wang, W.; Xiong, C. Y.; Yang, J. Q.; Hruby, V. J.
Tetrahedron Lett. 2001, 42, 7717–7719.
Acknowledgements
13. Schmidt, U.; Griesser, H.; Leitenberger, V.; Lieberknecht,
A.; Mangold, R.; Meyer, R.; Riedl, B. Synthesis 1992,
487–490.
14. Schmidt, U.; Lieberknecht, A.; Wild, J. Syn. Commun.
1984, 53–60.
15. Burk, M. J. Acc. Chem. Res. 2000, 33, 363–372.
16. Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L.
J. Am. Soc. Chem. 1993, 115, 10125–10138.
17. Strem Chemicals, Inc., 7 Mulliken Way, Dexter Indus-
trial Park, Newburyport, MA 01950–9899, USA.
18. Chiralcel OD column (0.46×25 cm), hexanes/isopropanol
(90/10) at a flow rate of 1.5 mL/min. Essentially one
single peak was obtained in each case of 3a-(S) and
4a-(R). The retention time: 3a-(S): 8.1 min, 4a-(R): 11.3
min.
This work is supported by US Public Health Service
(DK 17420) and the National Institute of Drug Abuse
(DA 06284). We also thank Professor Dominic V.
McGrath for the use of his group’s polarimeter and
Professor Michael P. Doyle and Dr. Ming Yan for the
use of their chiral HPLC column and assistance. The
views expressed are those of the authors and not neces-
sary those of the USPHS.
References
1. Hruby, V. J. Life Sci. 1982, 31, 189–199.
2. Hruby, V. J.; Li, G.; Haskell-Luevano, C.; Shenderovich,
19. Use the same column and conditions as described in Ref
18. Essentially one single peak was observed in each case
of 13a-(S) and 13b-(R). The retention time: 13a-(S): 15.0
min, 13b-(R): 18.6 min.
M. Biopolym. (Pept. Sci.) 1997, 43, 219–266.
3. Hruby, V. J.; Shenderovich, M.; Liao, S.; Porreca, F.;
Yamamura, H. I. In Rational Molecular Design in Drug
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