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

Article abstract of DOI:10.1016/S0040-4020(02)00162-X

Aromatic ring substituted tryptophans and phenylalanines can provide valuable tools in developing highly potent and selective peptide ligands with specific structural features in addition to providing a large lipophilic surface for binding to receptors and for crossing membrane barriers. An efficient method for the synthesis of these novel amino acids has been developed. In the approach, asymmetric hydrogenations of α-enamides using Burk's DuPHOS-based Rh (I) catalysts generated high enantiomerically pure α-amino acid derivatives, which subsequently underwent Suzuki cross couplings with boronic acid derivatives to afford these aromatic substituted amino acids in high yields and high enantioselectivity. 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/S0040-4020(02)00162-X

TETRAHEDRON
Pergamon
Tetrahedron 58 22002) 3101±3110
Practical, asymmetric synthesis of aromatic-substituted bulky
and hydrophobic tryptophan and phenylalanine derivatives
Wei Wang, Chiyi Xiong, Junyi Zhang and Victor J. Hrubyp
Department of Chemistry, University of Arizona, 1306 East University Blvd., Tucson, AZ 85721, USA
Received 18 December 2001;accepted 11 February 2002
AbstractÐAromatic ring substituted tryptophans and phenylalanines can provide valuable tools in developing highly potent and selective
peptide ligands with speci®c structural features in addition to providing a large lipophilic surface for binding to receptors and for crossing
membrane barriers. An ef®cient method for the synthesis of these novel amino acids has been developed. In the approach, asymmetric
hydrogenations of a-enamides using Burk's DuPHOS-based Rh 2I) catalysts generated high enantiomerically 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 high enantioselectivity. The method can allow for the preparation of such amino acids in large scales for extensive structure±
activity studies. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
brain barriers 2BBB) and intestinal mucosa), which provide
an opportunity to address three issues simultaneously. In our
continuing a- and g-melanocyte stimulating hormone
2MSH) project, there are many aromatic amino acids in
the sequences of these peptides. For example, three such
amino acids 2His, Phe and Trp) are in the core sequence,
His-Phe-Arg-Trp, of a-MSH peptides, which plays a key
role in biological activity and selectivity.1,2 The modi®-
cation and substitution of His with Pro and l-Phe with
d-Phe or d-Nal 220) in the core sequence of the peptide
has led to potent and selective a-MSH peptide ligands.1,2
More recently,3 we identi®ed a potent g-MSH peptide with
high selectivity for hMC3R 2human melanocortin receptor
3) by replacing l-Trp8 with d-Trp.8 In our efforts to further
enhance potency and selectivity of a and g-MSH peptide
ligands, we have proposed to use more bulky and hydro-
phobic amino acids including aromatic-substituted trypto-
phans 1 and phenylalanines 2 to substitute for Trp and Phe,
respectively 2Fig. 1).
The aromatic moieties of peptide side chain groups play
important roles in the molecular recognition processes
between peptide ligands and speci®c receptors as well as
receptor subtypes. Aromatic ring substituted amino acids
can provide valuable tools in developing highly selective
peptide ligands with speci®c structural features. In addition,
they can provide a large lipophilic surface for binding to
receptors, and for crossing membrane barriers 2e.g. blood
Figure 1. Structures of 5-aryl typtophans and o, m, and p substituted-aryl
phenylalanines.
Figure 2. o-Substituted phenylalanine derivatives.
Keywords: asymmetric hydrogenation;DuPHOS;amino acids;tryptophan;phenylalanine.
Corresponding author. Tel.: 11-520-621-6332;fax: 11-520-621-8407;e-mail: hruby@u.arizona.edu
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020202)00162-X

3102
W. Wang et al. / Tetrahedron 58 ,2002) 3101±3110
Scheme 1. Synthesis of 5-aryl-substituted tryptophan derivatives.
In these novel amino acids, the 20-substituted phenylalanine
derivatives 3 and 4 are of special interest since the x2
torsional angle can be ef®ciently restricted by the interaction
between the aryl moiety and the b-hydrogens of the amino
side chain 2Fig. 2). Furthermore, some of the amino acids
themselves are important biological compounds and
synthetic intermediates.4,5 Therefore, there is a need to
develop an ef®cient method for the synthesis of such
amino acids, particularly large-scale synthesis allowing for
extensive structure±activity studies.
readily obtained through Suzuki-type cross couplings
2Schemes 1, 3, and 4).
2. Results and discussion
2.1. Synthesis of 5-aryl tryptophan derivatives
A few methods have been reported for the synthesis of
the aromatic substituted tryptophan analogues.5,9±21 The
synthetic approach used for the preparation of these unusual
amino acids started with tryptophan. However, the route
was somewhat lengthy and sometimes used harsh con-
ditions.5 Here we have developed an ef®cient method for
the synthesis of these amino acids under very mild con-
ditions, which allows for the preparation of both d and l
5-aryl tryptophan analogues from readily available starting
materials 2Scheme 1).
Our group has been long interested in the design and syn-
thesis of unnatural amino acids,6±8 and we have developed
several methods for the synthesis of b-substituted
constrained amino acids including tryptophan, phenyl-
alanine, tyrosine, and glutamic acid derivatives.9±15 Further-
more we have demonstrated that the incorporation of these
unnatural amino acids into biologically active peptides and
peptidomimetics can enhance the potency and selectivity
signi®cantly.1,7,8,16±18 In a survey of literature, we were
surprised to ®nd, however, that few methods have been
reported for the syntheses of aryl-substituted aromatic
amino acids.5,19±23 Herein we would like to report an
ef®cient method for the asymmetric synthesis of both d
and l aromatic substituted tryptophan and phenylalanine
derivatives from readily available starting materials under
very mild reaction conditions 2Schemes 1, 3, and 4). The
general strategy 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 of substituted amino acid derivatives may be
The synthesis of the 5-aryl substituted tryptophans started
from commercially available 5-bromoindole-3-carbox-
aldehyde 6. The indole amino group in the aldehyde was
protected as Boc 2t-butoxycarbonyl) using 2Boc)2O 2di-t-
butyldicarbonate) in the presence of dimethylaminopyridine
2DMAP) in 98% yield. Then the Horner±Emmons ole®na-
tion of aldehyde 7 with phosphonate 2MeO)2P2O)CH
2NHCbz)COOMe 8 gave the dehydroamino acid derivative
9 with Z-con®guration as a major product 2Z/E.95/5) in
91% yield.24 Compound 8 was synthesized in three steps
following literature procedures.25 The amino group in 8
was protected by Cbz 2benzyloxycarbonyl), which was

W. Wang et al. / Tetrahedron 58 ,2002) 3101±3110
Table 1. Suzuki cross coupling of 10 with aryl boronic acids
3103
5-phenyl-l-tryptophan methyl ester, a known compound
D
D
[a]24 ˆ142.6 2c 1.06, MeOH), lit.5 [a]25 ˆ142.4 2c
1.24, MeOH), indicated that no racemization occurred
during the cross couplings.
Boronic acids
Yields with 10a
11a, 91%
Yields with 10b
12a, 89%
2.2. Synthesis of biphenylalanine derivatives
11b, 90%
11c, 89%
12b, 92%
12c, 88%
Earlier our laboratory developed an approach to the syn-
thesis of unusual aromatic amino acids 16 using an
Evans-type auxiliaryfor the resolution of racemic amino
acids 15 2Scheme 2).23,31 The synthesis started from
Na-Boc tyrosine derivatives 13 2some of the amino acids
are commercially available), which were converted to tyro-
sine tri¯ates with tri¯uoromethanesulfonic anhydride. The
resulting tyrosine tri¯ates were then coupled with aryl-
boronic acids to give Na-Boc amino acid methyl esters 16
in high yields 2Scheme 2). However, the method involved
more synthetic steps, and in some cases, multiple-step
recrystallizations of the diastereomers were required to
obtain optically pure forms. Using a similar synthetic
strategy, Shieh and Carlson asymmetrically synthesized
40-arylphenylalanines from Na-Boc-2S)-tyrosine tri¯ate in
high optical purity 2.99% ee).22
orthogonal to the Boc protected amino group in the indole
ring of compound 7. The dehydroamino ester 9 underwent
asymmetric hydrogenations to give a-amino acid deriva-
tives. We chose 1,2-bis 222S,5S)/22R,5R)-2,5-diethylphos-
pholano)benzene2cyclooctadiene) rhodium 2I) tri¯uoro-
methane sulfonate 22S,S)/2R,R) [Et-DuPHOS-Rh] OTf) as
catalysts for the asymmetric hydrogenations since they
give almost exclusively single enantiomers 2.97% ee)
in high yields 2.95%).26,27 The catalysts showed high
ef®ciency 2at a ratio of catalyst to substrate up to 1/
2500)27 and are commercially available.28 Furthermore,
both Z and E dehydroamino acids using this type of catalysts
gave one single isomer.27 In this case, we separated the two
isomers 2Z and E) by column chromatography. The isolated
2Z)-dehydroamino acid ester 9 was used for asymmetric
hydrogenations with a higher ee than that of 2E) isomer.
The 2S,S) catalyst afforded the amino acid derivative 10a
with an absolute S con®guration based on the selectivity of
the 2S,S)-Et-DuPHOS ligand in a high yield and high ee
2.96%).27 The 2R) amino acid 10b was also obtained
using 2R,R)-Et-DuPHOS as a ligand in a high yield and
high ee as well. 5-Bromotryptophans 10 were subjected to
Suzuki cross couplings with a variety of boronic acids to
give amino acid derivatives 11 and 12 in 88±92% yields
2Table 1). We have tried several Suzuki cross coupling reac-
tion conditions and found the following reaction conditions
to give the best yields without any racemization: 5 mol%
Pd2OAc)2 and 10 mol% tri2o-tolyl)phosphine as a catalyst,
1.5 equiv. boronic acid and 2.0 equiv. Na2CO3 in a mixture
of ethylene glycol dimethyl ether 2DME) and H2O at 808C
for 3±4 h.29 The enantiomeric purity was determined by the
Mosher's agent30 and the conversion of compound 11a to
In our initial study, we applied a similar strategy for the
synthesis of m-phenylphenylalanine derivative 22 2Scheme
3). The enantiopure 2R) or 2S) m-tyrosine derivatives 20a, b
were used as starting materials instead of racemic forms.
They were prepared by asymmetric hydrogenations
2Scheme 3).
Commercially available 3-benzyloxybenzaldehyde 17 was
reacted with phosphonate 2MeO)2P2O)CHNH2Boc)COOMe
18 in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene
2DBU) as a base to give the dehydroamino acid derivative
19 with .95/5 ratio of Z/E isomers in 92% yield. The amino
group in 18 was protected as Boc, which was orthogonal to
the benzyl-protected phenol hydroxyl group in 17. 2S) and
2R) amino acid esters 20 were obtained via asymmetric
hydrogenations of the isolated 2Z) isomer 19 using 2S,S) or
2R,R) [Et-DuPHOS-Rh 2I)] OTf, respectively, in high yields
and high ee.27 The benzyl protecting group in 20a
was cleaved by Pd-catalyzed hydrogenation, and then the
resulting free hydroxyl group was acylated with tri¯uoro-
methanesulfonic anhydride to afford Na-Boc-2S)-tyrosine
Scheme 2. Synthesis of o and m biphenylalanines.

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W. Wang et al. / Tetrahedron 58 ,2002) 3101±3110
Scheme 3. Synthesis of m-biphenylalanine.
Scheme 4. Synthesis of o and p aromatic substituted phenylalanine derivatives.

W. Wang et al. / Tetrahedron 58 ,2002) 3101±3110
3105
Figure 3.
tri¯ate 21 in 87% yield, a precursor for the Suzuki coupling.
The ®nal product, m-phenylphenylalanine derivative 22 was
obtained by reacting the tri¯ate 21 with phenylboronic acid
in 83% yield under the heterogeneous conditions of 3 mol%
Pd2PPh3)4 and anhydrous K2CO3 in toluene at 908C for 2 h
following the literature procedure.22 No detectable racemi-
zation of the starting Na-Boc-2S)-tyrosine tri¯ate 13 or
product m-phenylphenylalanine 22 was observed in the
reaction under these reaction conditions.22
The side chain conformations of these o-aromatic substi-
tuted phenylalanine amino acids can be restricted due to
the interaction between the aryl moieties and the b-hydro-
gens of amino side chain. In the preliminary studies of
1
compounds 26 using H NMR 2Fig. 3), we found that the
o-phenyl group in 26a rotated freely, indicating that the
interaction between the phenyl moiety and the b-hydrogen's
of amino side chain was small. However, a larger naphthyl
group resulted in two isomers in 26c, detected by 1H NMR
with two groups of proton signals. The ratio was about 1/1
based on integrations of 1H NMR spectra. We assumed the
two isomers with 2S,S) and 2S,R) con®gurations, respec-
tively 2Fig. 3). The naphthyl groups in 26c were away
from the two b-hydrogens of amino side chain to reduce
steric hindrance. Similar interactions in m and p-substituted
naphthyl phenylalanine analogues 22 and 28 were not
observed. The detailed conformation studies of these
amino acids including the more steric 1-21-naphthyl)-2-
naphthylalanine 5 2Fig. 2) will be reported in due course
based on X-ray crystal structures, NMR, and computer
modeling. It is also realized that these conformationally
constrained amino acids carrying ¯uorophores are very
useful in structure±activity studies of peptides and
receptors.
We synthesized m-phenylphenylalanine 22 by coupling
Na-Boc-2S)-tyrosine tri¯ate 21 with phenylboronic acid.
However, by using bromo-substituted 2o and p) phenyl-
alanine derivatives rather than tyrosine tri¯ates, we can
synthesize aromatic substituted phenylalanines in two
fewer steps. Therefore, we prepared enantiometrically
pure 2S) and 2R)-Na-Cbz methyl esters of o and p-bromo-
phenylalanines 25 and 27, respectively, which subsequently
were employed in Sukuzi-type cross coupling reactions with
a variety of boronic acid derivatives 2Scheme 4). It should
be mentioned that Burk and co-workers recently reported a
similar strategy for the synthesis of such amino acids.29 In
their approach, the a-amino groups of amino acids were
protected with an acetyl group, which generally is cleaved
under rather harsh acidic hydrolysis conditions. In
certain cases, signi®cant racemization occurred during the
hydrolysis step.29 Therefore in our approach, we used Cbz as
a protecting group, which is easily removed under mild
conditions by Pd-catalyzed hydrogenations without causing
racemization.
3. Conclusion
An ef®cient method has been developed for the synthesis of
aromatic-substituted phenylalanine and tryptophan deriva-
tives. These amino acids were synthesized through asym-
metric hydrogenations using Burk's DuPHOS-based
catalysts with high ee 2.96%), 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. We have synthesized multi-grams of some of
these amino acids. The incorporation of the amino acids into
biologically active peptides and peptidomimetics, bio-
logical evaluation, and structure±biological activity rela-
tionship study of the peptides and peptidomimetics are in
progress.
The isolated 2Z) a-enamides 24a and 24b were obtained as
major products by the condensation of o-bromo and
p-bromo benzaldehydes 23a and 23b, respectively with 8
in the presence of DBU in CH2Cl2 in 68 and 79% yields,
respectively. Asymmetric hydrogenation of a-enamides 24a
and 24b in the presence of 5 mol% catalysts, Rh2I)-2S,S)-Et-
DuPHOS or Rh2I)-2R,R)-Et-DuPHOS,27 65 psi of H2, 24 h
in methanol gave Na-Cbz-2S)-o-bromophenylalanine methyl
ester 25 in 95% yield and Na-Cbz-2R)-p-bromophenyl-
alanine methyl ester 27 in 99% yield and .96% ee in
both cases, respectively. The bromophenylalanines 25 and
27 were reacted with various boronic acids through the
Suzuki cross coupling reactions. We employed the same
coupling reaction conditions as used before in high yields,
and no racemization occurred.32 A longer reaction time
26±10 h) was required for o-bromophenylalanine and
naphthylboronic acid couplings and the yields were lower
than those of p-bromophenylalanine.
4. Experimental
4.1. General
1H and 13C NMR were performed on a Varian Unity-300
and Brukers AM-250 and DRX-500 and 600 spectrometers
using TMS and CDCl3 as internal standards. High Reso-
lution Mass Spectra 2HRMS) were recorded on a JEOL
HX110A instrument in the University of Arizona Mass
As mentioned earlier, we are particularly interested in
o-aromatic substituted phenylalanine derivatives 2Fig. 2).

3106
W. Wang et al. / Tetrahedron 58 ,2002) 3101±3110
Spectrum Laboratory. Optical rotations were measured on a
JASCO-1020 polarimeter. Melting points 2mp) are uncor-
rected and were obtained on a Thomas±Hoover apparatus in
open capillaries. Commercially available starting materials
and reagents were purchased from Aldrich used as received.
THF was distilled from Na and benzophenone;methylene
chloride 2CH2Cl2) was distilled from CaH2;HPLC grade
methanol was used for hydrogenations. Column chroma-
tography was performed using silica gel 2230±400 mesh)
from EM science. Thin layer chromatography 2TLC) was
performed on 13181 silica gel-based sheet with ¯uorescent
indicator from Kodak. Unless otherwise stated, yields refer
to isolated yields of products of greater than 95% purity as
estimated by 1H and 13C NMR spectroscopy. All new
followed by adding 2S,S) 2COD) Et-DuPHOS Rh 2I) OTf
26.0 mg, 0.008 mmol). After ®ve vacuum/hydrogen cycles,
the reaction bottle was pressurized to an initial pressure of
65 psi. The reaction was allowed to proceed for 24 h. After
the evaporation of solvent, the crude produce was passed
through a short silica gel column, eluting with methylene
chloride/ethyl acetate 24/1) to remove the catalyst. The
removal of the solvent afforded a white solid 22.121 g,
25
100%). [a]D ˆ143.4 2c 1.48, CHCl3); 1H NMR
2600 MHz, CDCl3) d 7.98 21H, brs), 7.61 21H, brs), 7.30±
7.41 27H, m), 5.40 21H, d, Jˆ7.8 Hz), 5.13 22H, dd, J1ˆ
12.6 Hz, J2ˆ18.0 Hz), 4.71 21H, dd, J1ˆ5.4 Hz, J2ˆ
12.6 Hz), 3.72 23H, s), 3.25 21H, dd, J1ˆ5.4 Hz, J2ˆ
12.6 Hz), 3.19 21H, dd, J1ˆ5.4 Hz, J2ˆ12.6 Hz), 1.66
29H, s); 13C NMR 275 MHz, CDCl3) d 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,
1
compounds were characterized by H, 13C, and HRMS or
elemental analysis.
4.1.1. 1-.tert-Butoxycarbonyl)-5-bromo-indol-3-carbox-
aldehyde 7. To a solution of 5-bromo-indole-3-carbox-
aldehyde 6 23.36 g, 15 mmol) in dry CH2Cl2 230 mL) was
added di-t-butyldicarbonate 24.58 g, 21 mmol). The mixture
was stirred at RT for 4 h. Evaporation of the solvent
followed by ¯ash column chromatography, eluting with
ethyl acetate/hexanes 21/5) to give a white solid 24.74 g,
98%). Mp 162±1638C; 1H NMR 2500 MHz, CDCl3) d
10.07 21H, s), 8.46 21H, d, Jˆ1.5 Hz), 8.22 21H, s), 8.03
21H, d, Jˆ7.0 Hz), 7.52 21H, dd, J1ˆ1.5 Hz, J2ˆ7.0 Hz),
1.71 29H, s); 13C NMR 275 MHz, CDCl3) d 185.5, 148.6,
137.1, 134.8, 129.2, 127.8, 125.0, 120.8, 118.4, 116.8, 86.4,
28.3;HRMS 2FAB) calcd for C 14H15BrNO3 324.0235 2Br
79), 326.0216 2Br 81), found 324.0238 2Br 79), 326.0206
2Br 81).
52.7, 28.3;HRMS 2FAB) calcd for C 25H27BrN2O6
530.1052, 2Br 79), 532.1036 2Br 81), found 530.1052 2Br
79), 530.1057 2Br 81).
4.2. General procedures for palladium-catalyzed Suzuki
coupling reactions
A reaction ¯ask ®tted with a Te¯on valve was charged with
bromoarylalanine derivatives, boronic acid 21.5 equiv.),
Na2CO3 22.0 equiv.), Pd2OAc)2 25 mol%), P2o-tolyl)3
210 mol%), DME 26 mL/mmol), degassed water 21 mL/
mmol) was heated to 808C for 4±6 h. The reaction mixture
was passed through a short column containing a bottom 100
layer of silica gel 2230±400 mesh) and a top 100 layer of
NaHCO3 using ethyl acetate as eluent. The solvent was
removed under reduced pressure with a rotary evaporator.
The crude product was puri®ed by ¯ash column chroma-
tography using an appropriate mixture of ethyl acetate and
hexanes as eluent.
4.1.2. Methyl .Z)-2-.benzyloxycarbonyl)amino-3-[.1-tert-
butoxycarbonyl-5-bromo)indol] acrylate 9. To a solution
of 2MeO)2P2O)CH2NHCbz)COOMe 8 25.25 g, 15.85 mmol)
in 10 mL of dry CH2Cl2 under an argon atmosphere was
added DBU 22.2 mL, 14.53 mmol). After 10 min stirring,
compound 7 24.28 g, 13.21 mmol) in 10 mL of dry
CH2Cl2 was added slowly. After the reaction mixture was
stirred for 5 h, the solvent was evaporated under reduced
pressure. The residue was dissolved in 250 mL of ethyl
acetate, then the organic solution was washed with 1N
HCl 22£80 mL) and brine 280 mL), dried 2MgSO4), and
evaporated. The crude product was puri®ed by ¯ash column
chromatography 2ethyl acetate/hexanes: 1/5) to give a white
solid. The solid was recrystallized from ethyl acetate and
hexanes to give a white crystal 26.37 g, 91%). Mp 146±
4.2.1. .S) 1-tert-Butoxycarbonyl-5-phenyl-Na-benzyloxy-
carbonyl-tryptophan methyl ester 11a. 91% Yield,
[a]D ˆ122.5 2c 1.22, CHCl3); 1H NMR 2300 MHz,
22
CDCl3) d 8.15 21H, d, Jˆ8.4 Hz), 7.63±7.69 23H, m),
7.56 21H, dd, J1ˆ1.5 Hz, J2ˆ8.4 Hz), 7.40±7.45 23H, m),
7.24±7.35 26H, m), 5.43 21H, d, Jˆ8.1 Hz), 5.07 22H, dd,
J1ˆ12.3 Hz, J2ˆ31.5 Hz), 4.77 21H, dd, J1ˆ5.7 Hz, J2ˆ
13.5 Hz), 3.67 23H, s), 3.34 21H, dd, J1ˆ5.1 Hz, J2ˆ
14.7 Hz), 3.26 21H, dd, J1ˆ5.7 Hz, J2ˆ14.7 Hz), 1.67
29H, s); 13C NMR 275 MHz, CDCl3) d 172.1, 171.3,
155.8, 149.6, 141.7, 136.2, 134.9, 131.2, 128.9, 128.7,
128.3, 128.2, 127.5, 127.1, 124.9, 124.3, 17.5, 115.7,
115.3, 84.0, 67.3, 60.6, 54.4, 52.6, 28.4;HRMS 2FAB)
calcd for C31H32N2O6 528.2260, found 528.2246.
1
1488C; H NMR 2300 MHz, CDCl3) d 8.00 21H, d, Jˆ
8.7 Hz), 7.91 21H, s), 7.83 21H, d, Jˆ1.5 Hz), 7.55 21H,
s), 7.44 21H, dd, J1ˆ1.5 Hz, J2ˆ8.7 Hz), 7.32±7.36 25H,
m), 6.45 2brs, 1H), 5.14 22H, s), 3.84 23H, s), 1.64 29H, s);
13C NMR 275 MHz, CDCl3) d 165.5, 153.9, 148.9, 135.9,
133.8, 131.2, 128.7, 128.5, 128.3, 128.2, 127.8, 127.1,
123.8, 123.1, 122.1, 117.0, 113.6, 85.2, 67.8, 52.9, 28.3;
HRMS 2FAB) calcd for C25H26BrN2O6 529.0974 2Br 79),
531.0958 2Br 81), found 529.0985 2Br 79), 531.0941 2Br
81).
4.2.2. .S) 1-tert-Butoxycarbonyl-5-.p-methoxyphenyl)-
Na-benzyloxycarbonyl-tryptophan methyl ester 11b.
90% Yield, [a]D ˆ120.5 2c 1.72, CHCl3); 1H NMR
24
2300 MHz, CDCl3) d 8.12 21H, d, Jˆ8.1 Hz), 7.63 21H,
brs), 7.54±7.58 22H, m), 7.51 21H, dd, J1ˆ1.8 Hz, J2ˆ
8.7 Hz), 7.41 21H, s), 7.28±7.30 25H, m), 6.95 22H, d, Jˆ
8.4 Hz), 5.41 21H, d, Jˆ8.1 Hz), 5.08 22H, dd, J1ˆ12.3 Hz,
J2ˆ27.3 Hz), 4.76 21H, dd, J1ˆ5.4 Hz, J2ˆ13.2 Hz), 3.84
23H, s), 3.67 23H, s), 3.33 21H, dd, J1ˆ5.4 Hz, J2ˆ14.7 Hz),
3.25 21H, dd, J1ˆ5.7 Hz, J2ˆ14.7 Hz), 1.67 29H, s); 13C
NMR 275 MHz, CDCl3) d 172.2, 159.1, 155.9, 149.7,
4.1.3. .S) 5-Bromo-1-tert-butoxycarbonyl-Na-benzyloxy-
carbonyl-tryptophan methyl ester 10a. A hydrogenation
bottle charged with 9 22.116 g, 4.0 mmol) in degassed
methanol 230 mL) was purged by argon for about 30 min,

W. Wang et al. / Tetrahedron 58 ,2002) 3101±3110
3107
136.2, 135.9, 134.6, 134.3, 131.2, 128.7, 128.4, 128.3,
128.2, 124.9, 124.0, 117.0, 115.7, 115.2, 114.4, 84.0, 67.3,
60.6, 55.6, 54.4, 52.7, 28.4;HRMS 2FAB) calcd for
C32H34N2O7 558.2366, found 558.2370.
172.2, 159.1, 155.9, 149.7, 136.2, 135.9, 134.6, 134.2,
131.2, 128.7, 128.4, 128.3, 128.2, 124.9, 124.0, 117.0,
115.6, 115.2, 114.4, 84.0, 67.3, 60.4, 55.6, 54.4, 52.7,
28.4;HRMS 2FAB) calcd for C 32H34N2O7 558.2366,
found 558.2380.
4.2.3.
.S)-1-tert-Butoxycarbonyl-5-.1-naphthyl)-Na-
benzyloxycarbonyl-tryptophan methyl ester 11c. 89%
4.2.7.
.R)-1-tert-Butoxycarbonyl-5-.1-naphthyl)-Na-
benzyloxycarbonyl-tryptophan methyl ester 12c. 88%
22
Yield, [a]D ˆ136.9 2c 0.73, CHCl3); 1H NMR 2300
22
MHz, CDCl3) d 8.20 21H, d, Jˆ8.1 Hz), 7.84±7.91 23H,
m), 7.57 21H, s), 7.35±7.51 25H, m), 7.23±7.27 25H, m),
5.41 21H, d, Jˆ8.1 Hz), 5.00 22H, dd, J1ˆ12.6 Hz, J2ˆ
42.3 Hz), 4.72 21H, dd, J1ˆ5.4 Hz, J2ˆ12.9 Hz), 3.63
23H, s), 3.31 21H, dd, J1ˆ5.4 Hz, J2ˆ14.7 Hz), 3.22
21H, dd, J1ˆ5.7 Hz, J2ˆ14.7 Hz), 1.69 29H, s); 13C NMR
275 MHz, CDCl3) d 172.1, 155.9, 149.7, 140.6, 136.3,
135.5, 134.8, 133.9, 132.1, 130.8, 128.7, 128.4, 128.3,
128.1, 127.7, 127.3, 127.1, 126.3, 126.2, 125.9, 125.5,
125.0, 120.3, 115.1, 115.0, 84.1, 67.2, 60.6, 54.3, 52.6,
28.4;HRMS 2FAB) calcd for C 35H34N2O6 578.2417,
found 578.2412.
Yield, [a]D ˆ236.5 2c 1.26, CHCl3); 1H NMR 2300
MHz, CDCl3) d 8.20 21H, d, Jˆ8.1 Hz), 7.84±7.92 23H,
m), 7.57 21H, s), 7.36±7.51 26H, m), 7.25±7.28 25H, m),
5.38 21H, d, Jˆ8.1 Hz), 5.01 22H, dd, J1ˆ12.0 Hz, J2ˆ
43.2 Hz), 4.73 21H, dd, J1ˆ5.7 Hz, J2ˆ13.2 Hz), 3.64
23H, s), 3.31 21H, dd, J1ˆ5.1 Hz, J2ˆ14.7 Hz), 3.23 21H,
dd, J1ˆ5.7 Hz, J2ˆ14.7 Hz), 1.70 29H, s); 13C NMR
275 MHz, CDCl3) d 172.2, 155.9, 149.8, 140.7, 136.3,
135.6, 134.8, 134.0, 132.2, 130.8, 128.7, 128.4, 128.3,
128.2, 127.7, 127.4, 127.1, 126.4, 126.2, 125.9, 125.5,
125.0, 120.3, 115.2, 115.1, 84.1, 67.2, 60.6, 54.3, 52.7,
28.4;HRMS 2FAB) calcd for C 35H34N2O6 578.2417,
found 578.2412.
4.2.4. .R)-5-Bromo-1-tert-butoxycarbonyl-Na-benzyloxy-
carbonyl-tryptophan methyl ester 10b. In a manner
similar to the preparation of 10a, compound 9 with 2R,R)
2COD)-Et-DuPHOS Rh 2I) OTf as a catalyst provided 10b
4.2.8. Methyl .Z)-2-.tert-butoxycarbonyl)amino-3-[.3-ben-
zyloxy)phenyl]acrylate 19. To a solution of 2MeO)2CH
2NHBoc)COOMe 18 23.27 g, 11 mmol) in 20 mL of dry
methylene chloride was added DBU 21.65 mL, 11 mmol)
slowly under an argon atmosphere with stirring. After ca.
10 min, m-benzyloxybenzaldehyde 17 22.12 g, 10 mmol)
was added slowly to the above mixture. After 4 h, the
solvent was evaporated and the residue was dissolved in
180 mL of ethyl acetate. The organic solution was washed
with 1N HCl 240 mL) and brine 245 mL), dried over
2MgSO4) and evaporated. The crude product was puri®ed
by ¯ash column chromatography on silica gel, eluting with
ethyl acetate and hexanes 21/6) to give a white solid 23.52 g,
92%). Mp 10±1028C; 1H NMR 2300 MHz, CDCl3) d 7.12±
7.44 29H, m), 6.93 21H, dd, J1ˆ2.4 Hz, J2ˆ8.1 Hz), 6.19
21H, brs), 5.05 22H, s), 3.84 23H, s), 1.40 29H, s); 13C NMR
275 MHz, CDCl3) d 166.2, 158.9, 152.9, 136.9, 135.6,
129.9, 129.7, 128.8, 128.2, 127.7, 125.0, 122.7, 116.1,
115.9, 81.2, 70.2, 52.8, 28.3;HRMS 2FAB) calcd for
C22H26NO5 384.1811, found 384.1807;Anal. calcd for
C22H25NO5: C, 68.91;H, 6.57;N, 3.65. Found: C, 69.18;
H, 6.49;N, 3.76.
25
1
in a 96% yield. [a]D ˆ242.2 2c 1.17, CHCl3); H NMR
2300 MHz, CDCl3) d 7.97 21H, brs), 7.60 21H, s), 7.39 21H,
dd, J1ˆ1.8 Hz, J2ˆ9.0 Hz), 7.29±7.36 26H, m), 5.38 21H, d,
Jˆ7.8 Hz), 5.13 22H, dd, J1ˆ12.6 Hz, J2ˆ18.0 Hz), 4.71
21H, dd, J1ˆ5.4 Hz, J2ˆ12.6 Hz), 3.72 23H, s), 3.24 21H,
dd, J1ˆ5.4 Hz, J2ˆ15.0 Hz), 3.18 21H, dd, J1ˆ5.4 Hz, J2ˆ
15.0 Hz), 1.65 29H, s); 13C NMR 275 MHz, CDCl3) d 171.9,
155.8, 149.3, 136.3, 134.2, 132.4, 128.7, 128.4, 128.3,
127.6, 125.5, 121.8, 117.0, 116.2, 114.3, 84.4, 67.4, 60.6,
54.1, 52.7, 28.3;HRMS 2FAB) calcd for C 25H27BrN2O6
530.1052 2Br 79), 532.1036 2Br 81), found 530.1046 2Br
79), 532.1021 2Br 81).
4.2.5. .R)-1-tert-Butoxycarbonyl-5-phenyl-Na-benzyloxy-
carbonyl-tryptophan methyl ester 12a. 89% Yield,
23
[a]D ˆ222.2 2c 1.17, CHCl3); 1H NMR 2300 MHz,
CDCl3) d 8.15 21H, d, Jˆ8.1 Hz), 7.55±7.69 24H, m),
7.40±7.45 23H, m), 7.24±7.35 26H, m), 5.42 21H, d,
Jˆ7.8 Hz), 5.07 22H, dd, J1ˆ12.0 Hz, J2ˆ31.5 Hz), 4.77
21H, dd, J1ˆ5.4 Hz, J2ˆ12.9 Hz), 3.67 23H, s), 3.34 21H,
dd, J1ˆ5.1 Hz, J2ˆ15.0 Hz), 3.26 21H, dd, J1ˆ5.4 Hz, J2ˆ
15.0 Hz), 1.67 29H, s); 13C NMR 275 MHz, CDCl3) d 172.1,
171.3, 155.9, 149.6, 141.7, 136.2, 134.9, 131.2, 128.9,
128.7, 128.3, 128.2, 127.5, 127.1, 124.9, 124.3, 117.5,
115.7, 115.2, 84.1, 67.3, 60.5, 54.4, 52.6, 28.4;HRMS
2FAB) calcd for C31H32N2O6 528.2260, found 528.2274.
4.2.9. .S)-Na-tert-Butoxycarbonyl-m-.3-benzyloxy)phenyl-
alanine methyl ester 20a. A hydrogenation bottle charged
with 19 21.53 g, 3.13 mmol) in degassed methanol 220 mL)
was purged by argon for about 30 min, followed by adding
catalyst 2S,S) 2COD) Et-DuPHOS Rh 2I) OTf 24.5 mg,
0.0063 mmol). After ®ve vacuum/hydrogen cycles, the
reaction bottle was pressurized to an initial pressure of
65 psi. The reaction was allowed to proceed for 24 h.
After evaporation of the solvent, the crude product was
passed through a short silica gel column, eluting with
methylene chloride/ethyl acetate 24/1) to remove the cata-
lyst. The removal of the solvent afforded a white solid
4.2.6. .R)1-tert-Butoxycarbonyl-5-.p-methoxyphenyl)-
Na-benzyloxycarbonyl-tryptophan methyl ester 12b.
24
92% Yield, [a]D ˆ220.2 2c 1.46, CHCl3); 1H NMR
2300 MHz, CDCl3) d 8.12 21H, d, Jˆ8.1 Hz), 7.63 21H,
s), 7.56 22H, d, Jˆ8.7 Hz), 7.51 21H, dd, J1ˆ1.2 Hz,
J2ˆ8.7 Hz), 7.41 21H, s), 7.25±7.29 25H, m), 6.95 22H, d,
Jˆ8.7 Hz), 5.42 21H, d, Jˆ8.1 Hz), 5.07 22H, dd, J1ˆ
12.3 Hz, J2ˆ30.0 Hz), 4.76 21H, dd, J1ˆ5.4 Hz, J2ˆ
13.2 Hz), 3.84 23H, s), 3.67 23H, s), 3.33 21H, dd, J1ˆ
5.4 Hz, J2ˆ15.0 Hz), 3.25 21H, dd, J1ˆ6.0 Hz, J2ˆ
15.0 Hz), 1.67 29H, s); 13C NMR 275 MHz, CDCl3) d
25
21.538 g, 100%). Mp 80.0±82.08C;[ a]D ˆ139.1 2c 1.21,
CHCl3); 1H NMR 2300 MHz, CDCl3) d 7.30±7.44 25H, m),
7.18±7.26 21H, m), 6.84±6.88 21H, m), 6.72±6.76 22H, m),
5.04 22H, s), 4.98 21H, d, Jˆ8.1 Hz), 4.58 21H, dd, J1ˆ
6.0 Hz, J2ˆ13.8 Hz), 3.70 23H, s), 3.09 21H, dd, J1ˆ
6.0 Hz, J2ˆ13.8 Hz), 3.02 21H, dd, J1ˆ6.0 Hz, J2ˆ

3108
W. Wang et al. / Tetrahedron 58 ,2002) 3101±3110
13.8 Hz); 13C NMR 275 MHz, CDCl3) d 172.5, 159.1,
155.3, 137.8, 137.1, 129.8, 128.8, 128.2, 127.7, 122.1,
116.1, 113.5, 80.2, 70.1, 54.5, 52.4, 38.5, 28.6;HRMS
2FAB) calcd for C22H28NO5 386.1967, found 386.1974;
Anal. calcd for C22H27NO5: C, 68.55;H, 7.06;N, 3.63.
Found: C, 68.53;H, 7.01;N, 3.61.
4.2.13. .S)-Na-tert-Butoxycarbonyl-m-.phenyl)phenyl-
alanine methyl ester 22. Argon was passed through a
suspension of tri¯ate 21 2415 mg, 0.97 mmol), phenyl-
boronic acid 2177 mg, 1.46 mmol) and K2CO3 2268 mg,
1.94 mmol) in toluene 215 mL) for 15 min Pd2PPh3)4
256 mg, 0.049 mmol) was added and the reaction mixture
was heated at 908C for 2 h. The reaction mixture was passed
through a short column containing a bottom 100 layer of
silica gel 2230±400 mesh) and a top 100 layer of NaHCO3
using ethyl acetate as eluent. The solvent was removed
under reduced pressure with a rotary evaporator. The
crude product was puri®ed by ¯ash column chromatography
using ethyl acetate and hexanes 21/8) as eluent to give a
4.2.10.
.R)-Na-tert-Butoxycarbonyl-m-.3-benzyloxy)-
phenylalanine methyl ester 20b. In a manner similar to
the preparation of 20a, compound 19 with 2R,R) 2COD)-
Et-DuPHOS Rh 2I) OTf as a catalyst provided 20b in 99%
25
yield. Mp 80.5±82.08C;[ a]D ˆ238.5 2c 1.21, CHCl3); 1H
NMR 2300 MHz, CDCl3) d 7.30±7.45 25H, m), 7.18±7.27
21H, m), 6.84±6.88 21H, m), 6.72±6.76 22H, m), 5.03 22H,
s), 4.98 21H, d, Jˆ8.1 Hz), 4.58 21H, dd, J1ˆ5.7 Hz, J2ˆ
13.8 Hz), 3.70 23H, s), 3.09 21H, dd, J1ˆ5.7 Hz, J2ˆ
13.8 Hz), 3.04 21H, dd, J1ˆ5.7 Hz, J2ˆ13.8 Hz); 13C
NMR 275 MHz, CDCl3) d 172.5, 159.1, 155.3, 137.8,
137.1, 129.8, 128.8, 128.2, 127.7, 122.1, 116.1, 113.5,
80.1, 70.1, 54.5, 52.4, 38.5, 28.5;HRMS 2FAB) calcd for
C22H28NO5 386.1967, found 386.1960;Anal. calcd for
C22H27NO5: C, 68.55;H, 7.06;N, 3.63. Found: C, 68.71;
H, 7.31;N, 3.61.
26
white solid 2287 mg, 83%). Mp 85±878C;[ a]D ˆ149.7
1
2c 1.04, CHCl3); H NMR 2300 MHz, CDCl3) d 7.32±7.58
28H, m), 7.11 21H, d, Jˆ7.5 Hz), 5.02 21H, d, Jˆ7.8 Hz),
4.64 21H, dd, J1ˆ6.0 Hz, J2ˆ13.8 Hz), 3.20 21H, dd, J1ˆ
5.7 Hz, J2ˆ13.8 Hz), 3.11 21H, dd, J1ˆ6.0 Hz, J2ˆ
13.8 Hz); 13C NMR 275 MHz, CDCl3) d 172.5, 155.2,
141.6, 141.1, 136.7, 129.2, 128.9, 128.4, 128.3, 127.5,
127.3, 126.1, 80.2, 54.6, 52.5, 38.6, 28.5;HRMS 2FAB)
calcd for C21H26NO4 356.1862, found 356.1860.
4.2.14. Methyl .Z)-2-.benzyloxycarbonyl)amino-3-.o-bro-
mophenyl)acrylate 24a. To a solution of 2MeO)2CH
2NHCbz)COOMe 8 21.98 g, 6 mmol) in 15 mL of dry
methylene chloride was added DBU 20.9 mL, 6 mmol)
slowly under an argon atmosphere with stirring. After ca.
10 min, o-bromobenzaldehyde 23a 20.93 g, 5 mmol) was
added slowly into the above mixture. After 4 h, the solvent
was evaporated, and the residue was dissolved in 120 mL of
ethyl acetate. The organic solution was washed with 1N HCl
230 mL) and brine 230 mL), dried over MgSO4 and evapo-
rated. The crude product was puri®ed by ¯ash column
chromatography, eluting with ethyl acetate and hexanes
4.2.11. .S)-Na-tert-Butoxycarbonyl-m-tyrosine methyl
ester. A mixture of 20a 21.26 g, 3.27 mmol) and 10%
Pd±C 2100 mg) in 20 mL of HPLC grade methanol was
hydrogenated under a hydrogen atmosphere at 60 psi for
9 h. After the removal of the catalyst by ®ltration, the
evaporation of the solvent gave a clear oil 20.94 g, 99%).
25
[a]D ˆ134.2 2c 1.18, CHCl3); 1H NMR 2300 MHz,
CDCl3) d 7.12±7.17 21H, m), 6.64±6.75 23H, m), 5.07
21H, d, Jˆ8.1 Hz), 4.57 21H, dd, J1ˆ6.0 Hz, J2ˆ13.8 Hz),
3.71 23H, s), 3.05 21H, dd, J1ˆ6.0 Hz, J2ˆ13.8 Hz), 2.97
21H, dd, J1ˆ6.6 Hz, J2ˆ13.8 Hz); 13C NMR 275 MHz,
CDCl3) d 172.8, 156.4, 155.6, 137.7, 129.9, 121.4, 116.3,
114.4, 80.5, 54.5, 52.5, 38.4, 28.5;HRMS 2FAB) calcd for
C15H22NO5 296.1498, found 296.1492.
1
21/6) to give an oil 21.33 g, 68%). H NMR 2300 MHz,
CDCl3) d 7.13±7.61 210H, m), 6.44 21H, s), 5.04 22H,
s), 3.85 23H, s); 13C NMR d 275 MHz, CDCl3) d 165.4,
153.4, 135.9, 134.7, 133.1, 130.3, 129.6, 128.7, 128.6,
128.5, 128.4, 127.4, 126.1, 124.7, 67.7, 53.1;HRMS
2FAB) calcd for C18H17BrNO4 390.0341 2Br 79),
392.0323 2Br 81), found 390.0340 2Br 79), 392.0330
2Br 81).
4.2.12. .S)-Na-tert-Butoxycarbonyl-m-{[.tri¯uoromethyl)-
sulfonyl]oxy}phenylalanine methyl ester 21. A solution of
the above tyrosine derivative 20.93 g, 3.15 mmol) and
pyridine 21.27 mL, 15.57 mmol) in 5 mL of dry methylene
chloride was cooled to 08C. 2CF3SO2)2O 20.64 mL,
3.78 mol) was added at this temperature, and the reaction
mixture was stirred for another 30 min. The reaction
mixture was diluted with water 210 mL) and methylene
chloride 250 mL) and washed sequentially with 0.5N
NaOH solution 28 mL), water 210 mL), 5% citric acid
22£15 mL) and brine 210 mL). The organic layer was
dried over MgSO4 and evaporated to give an oil. The
crude product was puri®ed by ¯ash column chromatography
2ethyl acetate/hexanes: 1/5) to afford a slightly yellow oil
4.2.15. .S)-Na-Benzyloxycarbonyl-o-bromophenylala-
nine methyl ester 25. A hydrogenation bottle charged
with 24a 21.26 g, 2.33 mmol) in degassed methanol
220 mL) was purged with argon for about 30 min, followed
by adding 2S,S) 2COD) Et-DuPHOS Rh 2I) OTf 2.3 mg,
0.0065 mmol). After ®ve vacuum/hydrogen cycles, the
reaction bottle was pressurized to an initial pressure of
65 psi. The reaction was allowed for 24 h. After the
evaporation of solvent, the crude produce was passed
through a short silica gel column, eluting with methylene
chloride/ethyl acetate 24/1) to remove the catalyst. The
removal of the solvent afforded a white solid 21.213 g,
26
1
21.25 g, 93%). [a]D ˆ142.3 2c 1.70, CHCl3); H NMR
2300 MHz, CDCl3) d 7.36±7.41 22H, m), 7.15±7.19 22H,
m), 7.05 21H, s), 5.04 21H, d, Jˆ8.1 Hz), 4.61 21H, dd,
J1ˆ5.7 Hz, J2ˆ13.8 Hz), 3.73 23H, s), 3.20 21H, dd, J1ˆ
5.7 Hz, J2ˆ13.8 Hz), 3.09 21H, dd, J1ˆ5.7 Hz, J2ˆ
13.8 Hz), 1.43 29H, s); 13C NMR 275 MHz, CDCl3) d
171.8, 155.1, 149.7, 139.4, 130.4, 129.6, 122.5, 120.1,
118.9 2q, Jc,fˆ318.5 Hz), 80.4, 54.3, 52.7, 38.2, 28.4;
HRMS 2FAB) calcd for C16H22F3NO7S 428.0991, found
428.1006.
26
1
95%). Mp 81.5±83.58C;[ a]D ˆ13.9 2c 1.25, CHCl3); H
NMR 2300 MHz, CDCl3) d 7.54 21H, d, Jˆ7.8 Hz), 7.07±
7.34 28H, m), 5.32 21H, d, Jˆ8.1 Hz), 5.06 22H, s), 4.72
21H, dd, J1ˆ8.1 Hz, J2ˆ13.8 Hz), 3.72 23H, s), 3.33 21H,
dd, J1ˆ6.0 Hz, J2ˆ13.8 Hz), 3.15 21H, dd, J1ˆ8.1 Hz,
J2ˆ13.8 Hz); 13C NMR 275 MHz, CDCl3) d 177.2, 155.8,
136.4, 135.9, 133.2, 131.5, 129.0, 128.7, 128.3, 128.2,

W. Wang et al. / Tetrahedron 58 ,2002) 3101±3110
3109
127.7, 125.2, 67.1, 54.2, 52.7, 38.7;HRMS 2FAB) calcd for
C18H19BrNO4 392.0497 2Br 79), 394.0479 2Br 81), found
392.0486 2Br 79), 394.0485 2Br 81).
4.2.20. .R)-Na-Benzyloxycarbonyl-p-bromophenylala-
nine methyl ester 27. In a similar manner to the preparation
of 25, using 2R,R) 2COD)Et-DuPHOS Rh 2I) OTf as a
26
catalyst gave 27 in 99% yield. Mp 96±988C;[ a]D
ˆ
4.2.16. .S)-Na-Benzyloxycarbonyl-o-.phenyl)phenylala-
243.7 2c 1.28, CHCl3); H NMR 2300 MHz, CDCl3) d
7.41±7.26 27H, m), 6.94±6.98 22H, m), 5.24 21H, d,
Jˆ7.8 Hz), 5.09 22H, dd, J1ˆ12.1 Hz, J2ˆ17.8 Hz), 4.64
21H, dd, J1ˆ6.0 Hz, J2ˆ13.8 Hz), 3.73 23H, s), 3.11 21H,
dd, J1ˆ5.4 Hz, J2ˆ13.8 Hz), 3.01 21H, J1ˆ6.0 Hz, J2ˆ
13.8 Hz); 13C NMR 275 MHz, CDCl3) d 171.9, 155.7,
136.3, 134.9, 131.9, 131.2, 128.7, 128.5, 128.3, 121.3,
67.2, 54.8, 52.6, 37.9;HRMS 2FAB) calcd for
C18H19BrNO4 392.0497 2Br 79), 394.0479 2Br 81), found
392.0486 2Br 79), 394.0462 2Br 81).
1
26
nine methyl ester 26a. 71% Yield, [a]D ˆ116.0 2c
1
1.35, CHCl3); H NMR 2300 MHz, CDCl3) d 7.18±7.41
214H, m), 4.98 22H, dd, J1ˆ12.3 Hz, J2ˆ21.6 Hz), 4.79
21H, d, Jˆ11.1 Hz), 4.41 21H, dt), 3.56 23H, s), 3.22 21H,
dd, J1ˆ5.7 Hz, J2ˆ13.8 Hz), 3.00 21H, dd, J1ˆ8.4 Hz,
J2ˆ13.8 Hz); 13C NMR 275 MHz, CDCl3) d 172.4, 155.6,
142.9, 141.3, 136.4, 133.6, 130.6, 130.1, 129.5, 128.6,
128.5, 128.2, 128.1, 127.7, 127.3, 127.1, 66.9, 54.8, 52.4,
35.3;HRMS 2FAB) calcd for C 24H24NO4 390.1705, found
390.1710.
4.2.21.
.R)-Na-Benzyloxycarbonyl-p-.phenyl)phenyl-
alanine methyl ester 28a. 100% Yield, mp 83±858C;
4.2.17. .S)-Na-Benzyloxycarbonyl-o-.p-chlorophenyl)-
23
phenylalanine methyl ester 26b. 75% Yield, [a]D
ˆ
[a]D ˆ255.2 2c 1.14, CHCl3); 1H NMR 2600 MHz,
26
1
113.6 2c 1.46, CHCl3); H NMR 2300 MHz, CDCl3) d
7.14±7.37 213H, m), 4.98 22H, s), 4.43 21H, dt), 3.60 23H,
s), 3.22 21H, dd, J1ˆ5.4 Hz, J2ˆ14.1 Hz), 2.96 21H, J1ˆ
8.1 Hz, J2ˆ14.1 Hz); 13C NMR 275 MHz, CDCl3) d
172.3, 155.6, 141.7, 139.8, 136.4, 133.6, 133.4, 130.9,
130.5, 130.3, 128.7, 128.3, 128.2, 128.1, 127.3, 67.0, 54.8,
52.5, 35.5;HRMS 2FAB) calcd for C 24H23ClNO4 424.1316
2Cl 35) 426.1297 2Cl 37), found 424.1322 2Cl 35), 426.1292
2Cl 37).
CDCl3) d 7.57±7.58 22H, m), 7.52±7.50 22H, m), 7.43±
7.46 22H, m), 7.30±7.37 26H, m), 7.17±7.19 22H, m), 5.26
21H, d, Jˆ7.8 Hz), 5.12 22H, dd, J1ˆ12.0 Hz, J2ˆ20.4 Hz),
4.71 21H, dd, J1ˆ6.0 Hz, J2ˆ13.8 Hz), 3.76 23H, s), 3.20
21H, dd, J1ˆ5.4 Hz, J2ˆ13.8 Hz), 3.14 21H, dd, J1ˆ6.0 Hz,
J2ˆ13.8 Hz); 13C NMR 275 MHz, CDCl3) d 172.1, 155.8,
140.8, 140.2, 136.4, 134.9, 129.9, 129.2, 128.9, 128.7,
128.4, 128.3, 127.5, 127.2, 67.2, 54.9, 52.6, 38.0;HRMS
2FAB) C24H24NO4 390.1705, found 390.1708.
4.2.18. .S)-Na-Benzyloxycarbonyl-o-.1-naphthyl)phenyl-
alanine methyl ester 26c. 79% Yield, two diastereomers
21/1); H NMR 2300 MHz, CDCl3) d 7.84±7.89 24H, m),
4.2.22. .R)-Na-Benzyloxycarbonyl-p-.p-chlorophenyl)-
phenylalanine methyl ester 28b. 93% Yield, mp 103±
1
23
1
1068C;[ a]D ˆ254.4 2c 0.768, CHCl3); H NMR 2250
MHz, CDCl3) d 7.29±7.45 211H, m), 7.12 22H, d, Jˆ
8.1 Hz), 5.28 21H, d, Jˆ8.1 Hz), 5.06 22H, dd, J1ˆ
12.2 Hz, J2ˆ14.4 Hz), 4.66 21H, dd, J1ˆ6.0 Hz, J2ˆ
14.0 Hz), 3.70 23H, s), 3.15 21H, dd, J1ˆ5.8 Hz, J2ˆ
14.0 Hz), 3.06 21H, dd, J1ˆ6.0 Hz, J2ˆ14.0 Hz); 13C
NMR 262.5 MHz, CDCl3) d 171.9, 155.6, 139.1, 138.7,
136.2, 135.1, 133.3, 129.8, 128.9, 128.5, 128.2, 128.1,
127.1, 67.0, 54.7, 52.3, 37.8;HRMS 2FAB) for
C24H23ClNO4 424.1316 2Cl 35), 426.1297 2Cl 37), found
424.1305 2Cl 35), 426.1316 2Cl 37).
7.23±7.52 228H, m), 4.86±5.02 24H, m), 4.33±4.47 22H,
m), 3.50 23H, s), 3.47 23H, s), 3.03 21H, dd, J1ˆ5.1 Hz,
J2ˆ14.4 Hz), 2.88 21H, dd, J1ˆ5.1 Hz, J2ˆ14.4 Hz), 2.75
21H, dd, J1ˆ8.7 Hz, J2ˆ14.1 Hz), 2.59 21H, dd, J1ˆ8.7 Hz,
J2ˆ14.1 Hz); 13C NMR 275 MHz, CDCl3) d 172.4, 155.7,
155.6, 140.8, 140.7, 138.8, 138.5, 136.4, 135.2, 135.0,
133.7, 133.6, 132.3, 132.2, 131.3, 131.2, 129.7, 129.6,
128.6, 128.5, 128.2, 128.1, 128.0, 127.5, 127.3, 127.1,
127.0, 126.5, 126.4, 126.1, 126.0, 125.9, 125.5, 125.4,
66.9, 55.1, 54.7, 52.3, 35.7, 35.6, 29.9;HRMS 2FAB)
calcd for C28H26NO4 440.1862, found 440.1875.
4.2.23. .R)-Na-Benzyloxycarbonyl-p-.1-naphthyl)phenyl-
24
4.2.19. Methyl .Z)-2-.benzyloxycarbonyl)amino-3-.4-
bromophenyl)acrylate 24b. To a solution of 2MeO)2CH
2NHCbz)COOMe 8 23.97 g, 12 mmol) in 15 mL of dry
methylene chloride was added DBU 21.64 mL, 11 mmol)
slowly under an argon atmosphere with stirring. After ca.
10 min, p-bromobenzaldehyde 23b 21.85 g, 10 mmol) was
added slowly into the above mixture. After 4 h, the solvent
was evaporated, the residue was dissolved in 180 mL of
ethyl acetate. The organic solution was washed with 1N
HCl 22£40 mL) and brine 245 mL), dried over MgSO4 and
evaporated. The crude product was puri®ed by ¯ash column
chromatography, eluting with ethyl acetate and hexanes
21/5) to give a white solid 23.095 g, 79%). Mp 101±
alanine methyl ester 28c. 93% Yield, [a]D ˆ248.0;2 c
1
2.05, CHCl3); H NMR 2300 MHz, CDCl3) d 7.82±7.89
23H, m), 7.28±7.52 211H, m), 7.21 22H, d, Jˆ8.1 Hz),
5.38 21H, d, Jˆ8.1 Hz), 5.12 22H, dd, J1ˆ12.3 Hz, J2ˆ
15.3 Hz), 4.74 21H, dd, J1ˆ6.0 Hz, J2ˆ13.8 Hz), 3.23
21H, dd, J1ˆ6.0 Hz, J2ˆ13.8 Hz), 3.16 21H, J1ˆ6.0 Hz,
J2ˆ13.8 Hz); 13C NMR 275 MHz, CDCl3) d 172.2, 155.8,
139.9, 139.7, 136.4, 134.9, 133.9, 131.7, 130.4, 129.3,
128.7, 128.4, 128.3, 128.2, 127.8, 127.1, 126.2, 126.0,
125.9, 125.5, 67.2, 55.0, 52.6, 38.1;HRMS 2FAB) calcd
for C28H26NO4 440.1862, found 440.1855.
1
102.58C; H NMR 2300 MHz, CDCl3) d 7.36±7.19 210H,
m), 6.40 21H, s), 5.02 22H, s), 3.74 23H, s); 13C NMR
275 MHz, CDCl3) d 165.7, 153.6, 135.9, 132.9, 131.9,
131.2, 130.3, 128.7, 128.5, 124.5, 123.7, 98.7, 67.8, 53.0;
HRMS 2FAB) calcd for C18H17BrNO4 390.0341 2Br 79),
392.0323 2Br 81), found 390.0341 2Br 79), 392.0333 2Br
81).
Acknowledgements
This work was supported by Grants from the US Public
Health Service 2DK 17420) and the National Institute of
Drug Abuse 2DA 06284 and DA 13499). We thank
Professor Dominic V. McGrath for the use of his group's

3110
W. Wang et al. / Tetrahedron 58 ,2002) 3101±3110
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polarimeter. The views expressed are those of the authors
and not necessary those of the USPHS.
19. Sato, K.;Kozikowski, A. P. Tetrahedron Lett. 1989, 30,
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