Stereoselective syntheses of tri- and tetrapeptide analogues by dynamic resolution of α-halo amides in nucleophilic substitution

Article abstract of DOI:10.1016/j.tet.2005.01.091

Dynamic resolution of α-bromo and α-chloro acetamides in nucleophilic substitution with amine nucleophiles in the presence of TBAI has been investigated for stereoselective syntheses of tri- and tetrapeptide analogues. Mechanistic investigations suggest t

Full text of DOI:10.1016/j.tet.2005.01.091

Tetrahedron 61 (2005) 2743–2750
Stereoselective syntheses of tri- and tetrapeptide analogues by
dynamic resolution of a-halo amides in nucleophilic substitution
*
Ji-yeon Chang, Eun-kyoung Shin, Hyun Jung Kim, Yangmee Kim and Yong Sun Park
Department of Chemistry, Konkuk University, Kwangjingu Hwayangdong 1, Seoul 143-701, South Korea
Received 30 December 2004; revised 25 January 2005; accepted 25 January 2005
Abstract—Dynamic resolution of a-bromo and a-chloro acetamides in nucleophilic substitution with amine nucleophiles in the presence of
TBAI has been investigated for stereoselective syntheses of tri- and tetrapeptide analogues. Mechanistic investigations suggest that primary
pathway of the asymmetric induction is a dynamic kinetic resolution and real intermediate for the substitution is a-iodo acetamides. Also,
application of this mild and simple methodology to stereoselective preparations of N-carboxyalkyl, N-aminoalkyl and N-hydroxyalkyl
peptide analogues is demonstrated.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Stereospecific nucleophilic substitution (SN2) reaction of
optically pure a-halo or a-sulfonyloxy acetamides with an
amine nucleophile is widely used for stereoselective
preparation of peptidomimetics.1 However, most of opti-
cally pure a-halo or a-sulfonyloxy acetamides are made
from natural amino acids and, consequently, this synthetic
method seems to lack generality. Since various a-halo
amides can be easily obtained in racemic form and
configurational lability of them is readily induced, dynamic
resolution of N-(a-haloacetyl) peptides in the substitution
reaction would be more attractive strategy for asymmetric
syntheses of peptide analogues. Recently, it has been shown
from our group that the chiral information of adjacent amino
acid residue is efficiently transferred to the new C–N bond
formation at a-bromo carbon center for asymmetric
syntheses of dipeptide analogues.2 Herein we describe our
recent progress to extend the scope of the methodology to
tri- and tetrapeptide analogues via dynamic resolution of
a-chloro or a-bromo acetamides with various amine
nucleophiles. Application of this methodology to highly
stereoselective N-terminal functionalization of peptides is
also presented.
We have previously reported that the treatment of N-(a-
bromo-a-phenylacetyl)-L-leucine methyl ester 1 with
dibenzylamine (1.2 equiv, Bn2NH), tetrabutylammonium
iodide (1.0 equiv, TBAI) and diisopropylethylamine
(1.0 equiv, DIEA) in CH2Cl2 at rt provided the dipeptide
analogues 14 in 83% yield with 93:7 diastereomeric ratio
(dr, aR:aS) as shown in Table 1, entry 1.2a The chiral
information of L-leucine is transferred to the substitution at
a-bromo carbon center via dynamic kinetic resolution in the
nucleophilic substitution with dibenzylamine. In order to
assess the effect of the additional C-terminal amino acid
residues on stereoselectivity, a series of N-(a-bromo-a-
phenylacetyl)-L-leucine derivatives was initially examined
as shown in Table 1. No stereoselectivity was observed in
the reaction of glycine-L-leucine derivative 2, where the
C-terminal L-leucine was positioned apart from the reaction
center (entry 2). In all cases of N-(a-bromoacetyl) L-leucine
derivatives 3–5 having an additional C-terminal amino acid
residue in 1, tripeptide analogues 16, 17 and 18 were
obtained with lower selectivities (87:13–80:20 drs) com-
pared to the reaction of 1 as shown in Table 1, entries 3–5. It
is also noteworthy that chirality of the additional amino acid
residue affects the stereoselectivity as replacing L-Ala in 4
with D-Ala gives rise to loss of asymmetric induction
(entries 4 and 5).
In the reaction of N-(a-bromo-a-phenylacetyl)-L-proline
derivative 7 having an additional C-terminal glycine in 6,
the stereoselectivity was lower compared to the reaction of 6
as shown in entries 6 and 7. Under the same reaction
Keywords: Dynamic kinetic resolution; Peptidimimetics; Asymmetric
syntheses; Nucleophilic substitution.
* Corresponding author. Tel.: C82 2 450 3377; fax: C82 2 3436 5382;
e-mail: parkyong@konkuk.ac.kr
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.091

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J. Chang et al. / Tetrahedron 61 (2005) 2743–2750
Table 1. Effect of additional C-terminal amino acid residues
Entry
X
AA (S.M.)a
% Yieldb,c (product)
drd (aR:aS)
1
2
3
4
5
6
7
8
Br
Br
Br
Br
Br
Br
Br
Cl
Br
Cl
Cl
Cl
Cl
L-Leu (1)
Gly-L-Leu (2)
L-Leu-Gly (3)
L-Leu-L-Ala (4)
L-Leu-D-Ala (5)
L-Pro (6)
83 (14)
69 (15)
69 (16)
64 (17)
75 (18)
93 (19)
91 (20)
84 (20)
85 (21)
82 (21)
77 (22)
71 (23)
68 (24)
93:7
50:50
81:19
87:13
80:20
O99:1
95:5
L-Pro-Gly (7)
L-Pro-Gly (8)
95:5
9
L-Pro-L-Leu (9)
L-Pro-L-Leu (10)
L-Pro-D-Leu (11)
L-Pro-L-Leu-L-Ala (12)
L-Pro-L-Leu-D-Ala (13)
O99:1
O99:1
96:4
81:19
76:24
10
11
12
13
a Initial drs of 1–13 are approximately 50:50.
b All reactions were carried out in CH2Cl2 for 24 h at rt.
c Isolated yields.
d The drs are determined by 1H NMR of reaction mixture using the authentic products prepared from racemic phenylglycine as a standard.
condition a-chloro acetamide 8 produced 20 in 84% yield
with same selectivity as in the reaction of a-bromo
acetamide 7 (entry 8). This is somewhat surprising
considering the low reactivity of a-chloro acetamide and
hence inefficient epimerization for dynamic resolution. This
interesting fact was further supported by the reactions of
a-bromo acetamide 9 and a-chloro acetamide 10, where
both reactions gave tripeptide analogue 21 with O99:1 dr in
high yields (entries 9 and 10). While the additional
C-terminal L-leucine in 6 did not affect the stereoselectivity,
the selectivity was reduced with the additional C-terminal
D-leucine (entry 11). Moreover, nucleophilic substitutions
of both N-(a-chloroacetyl) tripeptides 12 and 13 were found
to be less stereoselective compared to those of 10 and 11
(entries 12 and 13). It is also interesting to note here that
chirality of third amino acid residue affects the stereo-
selectivity as replacing L-Ala in 12 with D-Ala gives rise to
loss of asymmetric induction. The absolute configurations
of major isomers of 14–24 were assigned as aR
by comparison to the 1H NMR of authentic epimers
individually prepared from the coupling of L-leucine and
L-proline derivatives and N,N-dibenzyl (S)- or (R)-
phenylglycine.
difference in activation energies between substitution
reactions of each epimer.4 In the reaction of 3 (49:51 dr)
with 0.2 equiv of dibenzylamine in the absence of TBAI, the
product 16 with 81:19 dr was obtained in 13% yield (entry
2). At rt, this dr of 81:19 corresponds to a difference in free
energies of activation of about 0.9 kcal/mol. When 3 of
15:85 dr was treated with 1.2 equiv of dibenzylamine in the
presence of both TBAI and DIEA, the reaction gave the
product 16 with 81:19 dr as shown in entry 3. The dr is
identical to the dr of both reactions of 3 in entry 3 (Table 1)
and entry 2 (Table 2). This could be taken to suggest that the
stereoselectivity depend mainly on the difference in the
epimeric transition states energies and the primary pathway
of the asymmetric induction is a dynamic kinetic resolution.
However, with reversed diastereomeric enrichment of 3
(85:15 dr) slightly diminished dr of product 16 (73:27) was
observed in the reaction of 3 (entry 4). The results indicate
that the epimerization of 3 is not fast enough to get to
complete thermodynamic equilibrium with respect to the
substitution. As shown in entries 5–8, a series of reactions of
L-leucine-D-alanine derivative 5 showed same tendency of
stereochemical outcome as the reactions of L-leucine-
glycine derivative 3.
To understand the reaction pathway and the origin of
stereoselectivity, we carried out a series of reactions as
shown in Table 2, focusing on epimerization process and
transition state energy difference which may have a
profound role in dictating the stereoselectivity of the
substitution.3 Two N-(a-bromoacetyl) dipeptides 3 and 5
were initially chosen for detailed study of their moderate
stereoselectivities. When the mixture of two epimers of 3
(78:22 dr) was allowed to reach thermodynamic equilibrium
in the presence of TBAI and DIEA, the epimeric ratio of
recovered 3 was determined to be 52:48 (entry 1). The result
indicates that a-bromo amide 3 is configurationally labile
under the reaction condition and the thermodynamic
stabilities of two epimers are almost same. Reaction of
same population of two epimers with a deficient amount of
nucleophile will give rise to a dr that reflects the intrinsic
As expected, the reaction of a-chloro acetamide 8 does not
produce the substitution product in the absence of TBAI
(entry 9). In the presence of TBAB, the reactions of
a-chloro acetamide 8 and a-bromo acetamide 10 gave the
products 20 and 21, respectively, with same stereo-
selectivities observed in the reaction with TBAI (Table 1,
entries 8 and 10). However, the rate of the substitution is
substantially decreased compared to the reactions with
TBAI and require longer reaction time (60 h) to obtain
moderate yields shown in entries 10 and 11. In addition, as
shown in Table 2, entries 12 and 13, the reactions of
a-bromo acetamides 3 and 4 in the presence of TBAB gave
16 and 18 with much lower stereoselectivities (55:45 and
64:36 dr) compared to the reactions with TBAI (Table 1,
entries 3 and 4). The lower selectivity of the reaction of 3
than the selectivity estimated by the reaction with 0.2 equiv

J. Chang et al. / Tetrahedron 61 (2005) 2743–2750
Table 2. Dynamic kinetic resolution of a-bromo and a-chloro acetamides
2745
Entry
X
AA
S.M. (dr)a
Conditionb
% Yieldc (product)
drd (aR:aS)
1
2
3
4
5
6
7
8
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Br
Br
Br
L-Leu-Gly
L-Leu-Gly
L-Leu-Gly
L-Leu-Gly
L-Leu-D-Ala
L-Leu-D-Ala
L-Leu-D-Ala
L-Leu-D-Ala
L-Pro-Gly
3 (78:22)
3 (49:51)
3 (15:85)
3 (85:15)
5 (94:4)
5 (47:53)
5 (19:81)
5 (83:17)
8 (50:50)
8 (50:50)
10 (48:52)
3 (49:51)
4 (44:56)
TBAI, DIEA
67 (3)
52:48
81:19
81:19
73:27
53:47
84:16
84:16
80:20
—
Bn2NH (0.2 equiv)
TBAI, DIEA, Bn2NH
TBAI, DIEA, Bn2NH
TBAI, DIEA
Bn2NH (0.2 equiv)
TBAI, DIEA, Bn2NH
TBAI, DIEA, Bn2NH
DIEA, Bn2NH
TBAB, DIEA, Bn2NH
TBAB, DIEA, Bn2NH
TBAB, DIEA, Bn2NH
TBAB, DIEA, Bn2NH
13 (16)
74 (16)
83 (16)
85 (18)
11 (18)
59 (18)
85 (18)
N.R.
77 (20)
70 (21)
48 (16)
51 (18)
9
10
11
12
13
L-Pro-Gly
95:5
L-Pro-L-Leu
L-Leu-Gly
L-Leu-L-Ala
O99:1
55:45
64:36
a dr of S.M. before the reaction.
b All reactions were carried out in CH2Cl2 at rt.
c Isolated yields.
1
d The drs are determined by H NMR of reaction mixture using the authentic products prepared from racemic phenylglycine as a standard.
of nucleophile (Table 2, entry 2) may be explained by less
efficient epimerization process in the presence of TBAB.
Although it is not exactly clear how iodide exerts its rate-
accelerating effects on the substitution, these results in
entries 9–13 can be taken to suggest that real intermediate
for the substitution in the presence of TBAI is a-iodo
acetamide rather than a-bromo and a-chloro acetamides.
analogues, the scope of the methodology was examined
with a-amino ester nucleophiles for the preparation of
N-carboxyalkyl peptide analogues as shown in Table 3.
Several N-carboxyalkyl peptides are known inhibitors of
various metalloproteinases and angiotensin converting
enzymes (ACE).5 Treatment of N-(a-bromo-a-phenyl-
acetyl)-L-leucine benzyl ester with glycine methyl ester
hydrochloride (1.0 equiv), TBAI (1.0 equiv) and DIEA
(2.2 equiv) in CH2Cl2 at rt provided the tripeptide analogue
25 in 99% yield with 86:14 dr (aR:aS) as shown in Table 3,
Within the frame of a broad project aimed at asymmetric
syntheses of various N-terminal functionalized peptide
Table 3. Stereoselective syntheses of N-carboxyalkyl peptide derivatives
Entrya,b
AA-OBn
Product
Yieldc (%)
drd (aR:aS)
AA0-OMe
1
2
3
4
5
6
7
8
Gly-OMe
L-Leu-OBn
L-Leu-OBn
L-Leu-OBn
L-Leu-OBn
L-Leu-OBn
L-Leu-OBn
L-Leu-OBn
L-Pro-OBn
25
26
27
28
29
30
31
32
99
84
83
80
63
36
49
44
86:14
88:12
91:9
89:11
93:7
87:13
92:8
93:7
L-Ala-OMe
D-Ala-OMe
L-Leu-OMe
D-Leu-OMe
L-Phe-OMe
D-Phe-OMe
L-Leu-OMe
a Initial drs of S.M. are approximately 50:50.
b All reactions were carried out in CH2Cl2 for 24–48 h at rt.
c Isolated yields.
1
d The drs are determined by H NMR of reaction mixture and HPLC analysis.

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J. Chang et al. / Tetrahedron 61 (2005) 2743–2750
entry 1.6 When two enantiomers of alanine methyl esters
were used as nucleophiles, moderate double stereo-
differentiation is observed as shown in entries 2 and 3.
N-(a-Bromo-a-phenylacetyl)-L-leucine benzyl ester
experienced matching with D-alanine methyl esters to
afford tripeptide analogue 27 in a ratio of 91:9 (aR:aS) and
mismatching with L-leucine amino ester to provide 26 in a
88:12 (aR:aS) ratio.6,7 Furthermore, we found that this
tendency of stereodifferentiation was also observed in both
reactions of leucine and phenylalanine methyl ester
nucleophiles (entries 4–7). As shown in Table 3, even
mismatched cases (entries 2, 4 and 6) gave still high
stereoselectivities, which allows us to have easy access to
diverse N-carboxyalkyl peptide analogues. The substitution
of N-(a-bromo-a-phenylacetyl)-L-proline benzyl ester with
L-leucine methyl ester gave the tripeptide analogue 32 in
44% yield with 93:7 dr as shown in entry 8.
methodology has potential advantages over N-alkylation
of optically active arylglycine analogues in simplicity and
cost. The products 33–35 should serve as versatile
intermediates not only for the sequential asymmetric
construction of non-natural oligopeptides but also for the
asymmetric preparation of a variety of chiral ligands.
3. Conclusion
We have shown that dynamic kinetic resolution of a-bromo
and a-chloro amides in nucleophilic substitution reaction
with dibenzylamine can be successfully applied towards the
preparation of tri- and tetrapeptide analogues. Mechanistic
investigations suggest that a-iodo acetamides is real
intermediate for the nucleophilic substitutions of both
a-bromo and a-chloro amides in the presence of TBAI.
The methodology has also been successful for the
N-terminal functionalization of peptides, affording a
generalized and practical method for the asymmetric
syntheses of N-carboxyalkyl, N-aminoalkyl and N-hydroxy-
alkyl peptide analogues. This mild and practical chemistry
requires no special precautions and can be run on a multi-
gram scale. The methodology of the present work should
also be applicable to stereoselective syntheses of a number
of related peptide analogues, now being used for the
asymmetric syntheses of chiral ligands and macrocycles.
Finally, we were very pleased to demonstrate that this
methodology is also efficient for the substitution with
N-aminoxyalkyl and N-hydroxyalkyl amines, affording
N-(aminoalkyl) peptides 33–34 and N-(hydroxyalkyl)
peptide 35 with high selectivities and good yields as
shown in Scheme 1. For example, when N-Boc N,N0-
dibenzyl 1,3-propanediamine was used as a nucleophile for
the reaction with N-(a-bromo-a-phenylacetyl)-L-leucine
benzyl ester, the product 33 was formed in 63% yield
with 96:4 dr. Also, treatment of N-(a-bromo-a-phenyl-
acetyl)-L-proline benzyl ester with N,N0-dibenzyl 2,20-
(ethylenedioxy)diethyleneamine produced the mono sub-
stituted product 34 in 70% yield with 90:10 dr. Furthermore,
we attempted the substitution reaction of L-proline methyl
ester derivative with 2-(benzylamino)ethanol and found that
the amino substituted product 35 was produced in 69% yield
with 93:7 dr. For stereoselective preparation of various N,N-
dialkyl substituted arylglycine peptide analogues, this
4. Experimental
4.1. General procedure for the preparation of 1–13
For a-bromo acetamides. Dipeptide or tripeptide alkyl ester
(1.0 equiv), racemic a-bromo phenylacetic acid (1.0 equiv),
DCC (1.0 equiv), Et3N (2.2 equiv) and DMAP (0.2 equiv)
were dissolved in CH2Cl2 and stirred at rt for 3 h. The
precipitate was filtered off and the organic phase was
washed with water. The organic phase was dried over
MgSO4, filtered and concentrated to provide the crude
product that was purified by column chromatography on
silica gel.
For a-chloro acetamides. Dipeptide or tripeptide alkyl ester
(1.0 equiv), racemic a-chloro a-phenylacetyl chloride
(1.0 equiv) and Et3N (2.2 equiv) were dissolved in CH2Cl2
and stirred at rt for 2 h. The mixture was treated with
extractive work up and the organic phase was dried over
MgSO4. Filtration and concentration provided the crude
product that was purified by column chromatography on
silica gel.
4.1.1. N-(a-Bromo-a-phenylacetyl)-glycine-(S)-leucine,
methyl ester (2). A colorless oil was obtained in 55%
yield. 1H NMR (CDCl3, 400 MHz, two diastereomers)
7.61–7.27 (m, 6H), 6.91–6.89 (m, 1H), 5.45, 5.39 (s, 1H),
4.60–4.55 (m, 1H), 4.05–4.00 (m, 2H), 3.71 (s, 3H), 1.62–
1.47 (m, 3H), 0.90–0.89 (s, 6H); 13C NMR (CDCl3,
100 MHz) 173.5, 168.7, 168.5, 168.4, 137.3, 129.4, 128.9,
128.8, 128.4, 128.3, 52.8, 51.3, 50.6, 44.1, 41.5, 25.2, 23.2,
22.2. HRMS calcd for C17H24BrN2O4 (MCC1): 399.0919.
Found: 399.0954.
Scheme 1.

J. Chang et al. / Tetrahedron 61 (2005) 2743–2750
2747
4.1.2. N-(a-Bromo-a-phenylacetyl)-(S)-leucine-glycine,
methyl ester (3). A colorless oil was obtained in 49%
yield. 1H NMR (CDCl3, 400 MHz, two diastereomers)
7.50–7.27 (m, 7H), 5.53, 5.50 (s, 1H), 4.75–4.73 (m, 1H),
3.98–3.94 (m, 1H), 3.77–3.71 (m, 1H), 3.67, 3.65 (m, 3H),
1.71–1.57 (m, 3H) 0.94–0.82 (m, 6H); 13C NMR (CDCl3,
100 MHz) 172.9, 170.3, 168.4, 137.3, 129.4, 129.2, 129.1,
128.9, 128.3, 52.6, 50.6, 49.8, 41.7, 41.5, 25.1, 23.2, 22.6.
HRMS calcd for C17H24BrN2O4 (MCC1): 399.0919.
Found: 399.0883.
4.1.8. N-(a-Chloro-a-phenylacetyl)-(S)-proline-(S)-leu-
cine, methyl ester (10). A colorless oil was obtained in
68% yield. 1H NMR (CDCl3, 400 MHz, two diastereomers)
7.52–7.29 (m, 6H), 5.60, 5.57 (s, 1H), 4.71–4.61 (m, 1H),
4.55–4.40 (m, 1H), 3.72–3.37 (m, 5H), 2.35–2.32 (m, 1H),
2.03–1.48 (m, 6H), 0.97–0.80 (m, 6H); 13C NMR (CDCl3,
100 MHz) 173.5, 170.7, 167.7, 136.0, 135.7, 129.6, 129.4,
129.3, 128.7, 128.5, 60.9, 58.9, 52.6, 51.4, 47.8, 41.4, 27.4,
25.5, 25.2, 23.3, 22.2. HRMS calcd for C20H28BrN2O4
(MCC1): 395.1738. Found: 395.1737.
4.1.3. N-(a-Bromo-a-phenylacetyl)-(S)-leucine-(S)-ala-
nine, methyl ester (4). A pale yellow oil was obtained in
66% yield. 1H NMR (CDCl3, 400 MHz, two diastereomers)
7.48–7.27 (m, 6H), 7.02–6.81 (m, 1H), 5.44, 5.43 (s, 1H),
4.54–4.46 (m, 2H), 3.73, 3.72 (s, 3H), 1.68–1.62 (m, 3H),
1.34–1.24 (m, 3H), 0.92–0.86 (m, 6H); 13C NMR (CDCl3,
100 MHz) 173.4, 171.5, 168.2, 137.3, 129.5, 129.3, 128.8,
128.2, 128.1, 52.8, 52.5, 50.9, 48.5, 41.3, 25.3, 23.2, 22.5,
18.3. HRMS calcd for C18H26BrN2O4 (MCC1): 413.1076.
Found: 413.1084.
4.1.9. N-(a-Chloro-a-phenylacetyl)-(S)-proline-(R)-leu-
cine, methyl ester (11). A colorless oil was obtained in
25% yield. 1H NMR (CDCl3, 400 MHz, two diastereomers)
7.55–7.08 (m, 6H), 5.63, 5.59 (s, 1H), 4.75–4.64 (m, 2H),
3.76–3.61 (m, 3H), 3.58–3.41 (m, 2H), 2.36, 2.35 (m, 1H),
2.17–1.96 (m, 3H), 1.67–1.58 (m, 3H), 0.96–0.90 (m, 6H);
13C NMR (CDCl3, 100 MHz) 173.2, 170.6, 167.9, 135.5,
129.6, 129.5, 129.1, 128.8, 128.6, 61.0, 59.0, 52.6, 51.3,
47.8, 41.6, 27.5, 25.4, 25.2, 23.2, 22.2. HRMS calcd for
C20H28ClN2O4 (MCC1): 395.1738. Found: 395.1766.
4.1.4. N-(a-Bromo-a-phenylacetyl)-(S)-leucine-(R)-ala-
nine, methyl ester (5). A colorless oil was obtained in
45% yield. 1H NMR (CDCl3, 400 MHz, two diastereomers)
7.48–7.27 (m, 6H), 7.02–6.81 (m, 1H), 5.44, 5.43 (s, 1H),
4.54–4.46 (m, 2H), 3.73, 3.72 (s, 3H), 1.68–1.62 (m, 3H),
1.34–1.24 (m, 3H), 0.92–0.86 (m, 6H); 13C NMR (CDCl3,
100 MHz) 173.4, 171.5, 168.2, 137.3, 129.5, 129.3, 128.8,
128.2, 128.1, 52.8, 52.5, 50.9, 48.5, 41.3, 25.3, 23.2, 22.5,
18.3. HRMS calcd for C18H26BrN2O4 (MCC1): 413.1076.
Found: 413.1071.
4.1.10. N-(a-Chloro-a-phenylacetyl)-(S)-proline-(S)-leu-
cine-(S)-alanine, methyl ester (12). A colorless oil was
obtained in 49% yield. H NMR (CDCl3, 400 MHz, two
1
diastereomers) 7.49–7.04 (m, 7H), 5.60, 5.59 (s, 1H), 4.55–
4.32 (m, 3H), 3.72–3.58 (m, 4H), 3.57–3.26 (m, 1H), 2.18–
1.71 (m, 4H), 1.69–1.34 (m, 6H), 0.94–0.78 (m, 6H); 13C
NMR (CDCl3, 100 MHz) 173.5, 172.4, 171.6, 167.6, 135.7,
129.7, 129.4, 129.3, 129.1, 128.6, 61.3, 59.3, 52.7, 52.4,
48.5, 47.9, 40.8, 28.4, 25.5, 25.4, 23.3, 22.1, 18.2. HRMS
calcd for C23H33ClN3O5 (MCC1): 466.2109. Found:
466.2101.
4.1.5. N-(a-Bromo-a-phenylacetyl)-(S)-proline-glycine,
methyl ester (7). A colorless oil was obtained in 27%
yield. 1H NMR (CDCl3, 400 MHz, two diastereomers)
7.52–7.25 (m, 6H), 5.62, 5.61 (s, 1H), 4.69–4.59 (m, 1H),
4.10–3.94 (m, 2H), 3.76–3.68 (m, 4H), 3.57–3.33 (m, 1H),
2.30–1.86 (m, 4H); 13C NMR (CDCl3, 100 MHz) 171.4,
170.4, 167.6, 135.9, 129.7, 129.6, 129.4, 128.7, 128.6, 61.0,
59.5, 52.7, 47.8, 41.7, 28.1, 25.4. HRMS calcd for
C16H20BrN2O4 (MCC1): 383.0606. Found: 383.0587.
4.1.11. N-(a-Chloro-a-phenylacetyl)-(S)-proline-(S)-leu-
cine-(R)-alanine, methyl ester (13). A colorless oil was
obtained in 17% yield. H NMR (CDCl3, 400 MHz, two
diastereomers) 7.55–6.99 (m, 7H), 5.61 (s, 1H), 4.54–4.47
(m, 3H), 3.73–3.67 (m, 4H), 3.66–3.31 (m, 1H), 2.28–1.38
(m, 10H), 0.94–0.78 (m, 6H); 13C NMR (CDCl3, 100 MHz)
173.6, 171.9, 171.5, 168.0, 135.5, 129.8, 129.7, 129.6,
129.2, 128.7, 61.7, 59.3, 52.7, 52.1, 48.6, 48.0, 40.4, 28.7,
25.5, 25.3, 23.5, 21.9, 17.9. HRMS calcd for C23H33ClN3O5
(MCC1): 466.2109. Found: 466.2080.
1
4.1.6. N-(a-Chloro-a-phenylacetyl)-(S)-proline-glycine,
methyl ester (8). A colorless oil was obtained in 55%
yield. 1H NMR (CDCl3, 400 MHz, two diastereomers)
7.50–7.25 (m, 6H), 5.63, 5.62 (s, 1H), 4.68–4.59 (m, 1H),
4.04–3.93 (m, 2H), 3.75–3.32 (m, 5H), 2.28–2.26 (m, 1H),
2.03–1.85 (m, 3H); 13C NMR (CDCl3, 100 MHz) 171.5,
170.4, 167.6, 135.8, 129.6, 129.4, 129.3, 128.7, 128.6, 61.0,
59.5, 52.6, 47.8, 41.5, 28.2, 25.4. HRMS calcd for
C16H20ClN2O4 (MCC1): 339.1122. Found: 339.1120
4.2. General procedure for asymmetric preparation of
peptide analogues 14–35
To a solution of (aRS)-a-bromo or a-chloro acetamides in
dry CH2Cl2 (ca. 0.1 M) at rt was added amine nucleophile
(1.2 equiv), TBAI or TBAB (1.0 equiv) and DIEA (1.0 or
2.2 equiv). The resulting reaction mixture was stirred at rt
for 24 h. The solvent in mixture was evaporated and the
crude product was purified by column chromatography on
silica gel.
4.1.7. N-(a-Bromo-a-phenylacetyl)-(S)-proline-(S)-
leucine, methyl ester (9). A colorless oil was obtained in
43% yield. 1H NMR (CDCl3, 400 MHz, two diastereomers)
7.52–7.23 (m, 6H), 5.58, 5.56 (s, 1H), 4.70–4.62 (m, 1H),
4.52–4.43 (m, 1H), 3.72–3.40 (m, 5H), 2.37–2.34 (m, 1H),
2.04–1.46 (m, 6H), 0.97–0.79 (m, 6H); 13C NMR (CDCl3,
100 MHz) 173.5, 170.7, 167.7, 135.7, 129.7, 129.6, 129.3,
128.7, 128.6, 61.9, 59.2, 52.6, 51.4, 47.8, 41.5, 27.4, 25.5,
25.2, 23.3, 22.2. HRMS calcd for C20H28BrN2O4 (MCC1):
439.1232. Found: 439.1248
4.2.1. N-[(R)-a-Phenyl-N,N-(dibenzyl)glycinyl]-glycine-
(S)-leucine, methyl ester (15). A colorless oil was obtained
in 69% yield (two diastereomers). 1H NMR (CDCl3,
400 MHz) 8.07–8.06 (m, 1H), 7.40–7.21 (m, 15H), 7.03–
7.01 (d, JZ8.2 Hz, 1H) 4.64–4.52 (m, 1H), 4.44 (s, 1H),
4.13–4.08 (m, 2H), 3.84 (m, 2H), 3.67 (m, 3H), 3.27 (d,
JZ13.7 Hz, 2H), 1.53–1.49 (m, 2H), 1.26–1.22 (m, 1H),

2748
J. Chang et al. / Tetrahedron 61 (2005) 2743–2750
0.87–0.80 (m, 6H); 13C NMR (CDCl3, 100 MHz) 173.5,
172.8, 169.1, 138.8, 134.3, 130.7, 129.4, 129.3, 129.0,
128.7, 128.6, 128.4, 127.8, 68.4, 55.1, 52.6, 51.2, 43.7, 41.4,
25.4, 23.2, 22.2. HRMS calcd for C31H38N3O4 (MCC1):
516.2862. Found: 516.2841.
171.7, 140.7, 136.7, 130.0, 129.6, 129.4, 129.2, 129.0,
128.9, 128.8, 128.7, 128.6, 128.4, 127.6, 127.4, 64.4, 60.3,
54.9, 52.7, 51.6, 47.4, 42.0, 27.7, 25.3, 25.2, 23.4, 22.4.
HRMS calcd for C34H42N3O4 (MCC1): 556.3175. Found:
556.3178.
4.2.2. N-[(R)-a-Phenyl-N,N-(dibenzyl)glycinyl]-(S)-leu-
cine-glycine, methyl ester (16). A colorless oil was
obtained in 69% yield (two diastereomers). 1H NMR
(CDCl3, 400 MHz) 7.80 (d, JZ6.4 Hz, 1H), 7.41–7.24 (m,
15H), 6.86 (m, 1H), 4.56 (m, 1H), 4.44 (s, 1H), 3.94–3.84
(m, 4H), 3.69 (s, 3H), 3.23 (d, JZ14.0 Hz, 2H), 1.78–1.59
(m, 3H), 0.95–0.88 (m, 6H); 13C NMR (CDCl3, 100 MHz)
172.6, 172.5, 170.4, 138.8, 133.8, 131.0, 129.4, 129.1,
129.0, 128.7, 128.6, 128.4, 127.8, 67.7, 54.9, 52.6, 51.8,
41.6, 41.4, 25.2, 23.5, 22.4. HRMS calcd for C31H38N3O4
(MCC1): 516.2862. Found: 516.2887.
4.2.7. N-[(R)-a-Phenyl-N,N-(dibenzyl)glycinyl]-(S)-pro-
line-(R)-leucine, methyl ester (22). A colorless oil was
obtained in 77% yield (two diastereomers). 1H NMR
(CDCl3, 400 MHz) 7.94 (d, JZ7.8 Hz, 1H), 7.41–7.22 (m,
15H), 4.80 (d, JZ6.6 Hz, 1H), 4.66 (m, 2H), 3.93–3.91 (m,
4H), 3.72 (s, 3H), 2.96 (m, 1H), 2.74 (m, 1H), 2.44 (m, 1H),
1.89–1.64 (m, 6H), 1.03–1.00 (m, 6H); 13C NMR (CDCl3,
100 MHz) 174.2, 173.5, 171.4, 140.8, 136.7, 129.4, 129.2,
129.0, 128.7, 128.5, 127.3, 64.5, 60.1, 54.9, 52.6, 51.5, 47.3,
42.0, 27.1, 25.3, 25.1, 23.4, 22.4. HRMS calcd for
C34H42N3O4 (MCC1): 556.3175. Found: 556.3162.
4.2.3. N-[(R)-a-Phenyl-N,N-(dibenzyl)glycinyl]-(S)-leu-
cine-(S)-alanine, methyl ester (17). A colorless oil was
obtained in 64% yield (two diastereomers). 1H NMR
(CDCl3, 400 MHz) 7.87 (d, JZ7.5 Hz, 1H), 7.37–7.25 (m,
15H), 6.78 (d, JZ7.3 Hz, 1H), 4.57–4.51 (m, 2H), 4.42 (s,
1H), 4.11 (d, JZ13.7 Hz, 2H), 3.71 (s, 3H), 3.27 (d, JZ
13.7 Hz, 2H), 1.73–1.56 (m, 3H), 1.28–1.23 (m, 3H), 0.93–
0.87 (m, 6H); 13C NMR (CDCl3, 100 MHz) 173.5, 172.3,
171.9, 138.7, 134.1, 130.8, 129.3, 129.0, 128.6, 68.0, 54.9,
52.8, 51.9, 48.4, 41.6, 25.2, 23.4, 22.3, 18.4. HRMS calcd
for C32H40N3O4 (MCC1): 530.3019. Found: 530.3043.
4.2.8. N-[(R)-a-Phenyl-N,N-(dibenzyl)glycinyl]-(S)-pro-
line-(S)-leucine-(S)-alanine, methyl ester (23). A colorless
oil was obtained in 71% yield (two diastereomers). 1H NMR
(CDCl3, 400 MHz) 7.41–7.22 (m, 16H), 6.96 (d, JZ7.1 Hz,
1H), 4.68–4.58 (m, 4H), 3.90–3.82 (m, 4H), 3.74 (s, 3H),
2.98–2.70 (m, 2H), 2.25 (m, 1H), 1.91–1.75 (m, 6H), 1.47–
1.42 (m, 3H), 1.03–0.91 (m, 6H); 13C NMR (CDCl3,
100 MHz) 173.6, 173.5, 172.0, 171.9, 140.6, 136.6, 129.7,
129.5, 129.3, 129.2, 129.1, 128.9, 128.7, 128.5, 127.4, 64.2,
60.4, 55.0, 54.9, 52.8, 52.5, 48.6, 47.4, 41.6, 28.3, 25.2,
23.6, 23.3, 18.6. HRMS calcd for C37H47N4O5 (MCC1):
627.3546. Found: 627.3546.
4.2.4. N-[(R)-a-Phenyl-N,N-(dibenzyl)glycinyl]-(S)-leu-
cine-(R)-alanine, methyl ester (18). A colorless oil was
obtained in 72% yield (two diastereomers). 1H NMR
(CDCl3, 400 MHz) 7.77 (d, JZ8.2 Hz, 1H), 7.41–7.26 (m,
15H), 6.78 (d, JZ7.4 Hz, 1H), 4.56–4.48 (m, 2H), 4.44 (s,
1H), 3.89–3.84 (m, 2H), 3.63 (s, 3H), 3.22 (d, JZ13.6 Hz,
2H), 1.76–1.53 (m, 3H), 1.37–1.35 (m, 3H), 0.95–0.87 (m,
6H); 13C NMR (CDCl3, 100 MHz) 173.5, 172.6, 171.9,
138.7, 133.9, 131.0, 130.6, 129.4, 129.1, 129.0, 128.9,
128.7, 128.4, 127.8, 67.8, 54.8, 52.7, 51.7, 48.5, 25.2, 23.5,
22.3, 18.5. HRMS calcd for C32H40N3O4 (MCC1):
530.3019. Found: 530.3011.
4.2.9. N-[(R)-a-Phenyl-N,N-(dibenzyl)glycinyl]-(S)-pro-
line-(S)-leucine-(R)-alanine, methyl ester (24). A color-
less oil was obtained in 68% yield (two diastereomers). H
1
NMR (CDCl3, 400 MHz) 7.45–7.18 (m, 17H), 4.67–4.58
(m, 4H), 3.94–3.78 (m, 4H), 3.72–3.64 (m, 3H), 2.98–2.73
(m, 2H), 2.22 (m, 1H), 1.91–1.48 (m, 9H), 1.02–0.86 (m,
6H); 13C NMR (CDCl3, 100 MHz) 173.6, 173.4, 172.1,
172.0, 140.6, 136.5, 129.9, 129.8, 129.5, 129.3, 129.1,
128.9, 128.8, 128.7, 128.5, 127.7, 127.4, 64.6, 60.8, 54.9,
52.7, 52.3, 48.6, 47.5, 41.1, 28.7, 25.4, 23.6, 23.4, 22.2,
18.6. HRMS calcd for C37H47N4O5 (MCC1): 627.3546.
Found: 627.3536.
4.2.5. N-[(R)-a-Phenyl-N,N-(dibenzyl)glycinyl]-(S)-pro-
line-glycine, methyl ester (20). A colorless oil was
obtained in 91% yield (two diastereomers). 1H NMR
(CDCl3, 400 MHz) 7.77–7.71 (m, 1H), 7.39–7.19 (m,
16H), 4.77–4.74 (m, 1H), 4.64 (s, 1H), 4.18–4.09 (m, 2H),
3.95–3.86 (m, 4H), 3.76 (s, 3H), 2.96 (m, 1H), 2.75 (m, 1H),
2.35 (m, 1H), 2.03–1.66 (m, 3H); 13C NMR (CDCl3,
100 MHz) 173.7, 172.2, 170.5, 140.8, 136.8, 130.4, 129.7,
129.5, 129.2, 129.1, 129.0, 128.8, 128.7, 128.4, 128.3,
127.6, 127.3, 64.5, 60.1, 55.1, 52.7, 47.3, 41.8, 27.8, 25.2.
HRMS calcd for C30H34N3O4 (MCC1): 500.2549. Found:
500.2538.
4.2.10. N-[1-(Methoxycarbonyl)methyl]-(R)-phenyl-
glycine-(S)-leucine, benzyl ester (25). A colorless oil was
obtained in 99% yield (two diastereomers). 1H NMR
(CDCl3, 400 MHz) 7.49 (d, JZ8.6 Hz, 1H), 7.39–7.28 (m,
10H), 5.16–5.08 (m, 2H), 4.69 (m, 1H), 4.26 (s, 1H), 3.71 (s,
3H), 3.46 (m, 2H), 2.30 (br, 1H), 1.70–1.57 (m, 3H), 0.92–
0.82 (m, 6H); 13C NMR (CDCl3, 100 MHz) 173.1, 172.8,
171.8, 138.8, 135.8, 129.3, 129.2, 128.9, 128.6, 128.5,
128.3, 128.1, 128.0, 127.9, 127.7, 67.6, 52.4, 51.0, 50.8,
41.8, 25.4, 25.3, 22.2. HRMS calcd for C24H31N2O5 (MCC
1): 427.2233. Found: 427.2207.
4.2.6. N-[(R)-a-Phenyl-N,N-(dibenzyl)glycinyl]-(S)-pro-
line-(S)-leucine, methyl ester (21). A colorless oil was
obtained in 85% yield. 1H NMR (CDCl3, 400 MHz) 7.54 (d,
JZ7.6 Hz, 1H), 7.36–7.20 (m, 16H), 4.71–4.63 (m, 3H),
3.86 (s, 4H), 3.76 (s, 3H), 2.96, 2.95 (m, 1H), 2.76 (m, 1H),
2.34 (m, 1H), 1.97–1.90 (m, 2H), 1.79–1.67 (m, 4H), 1.02–
0.99 (m, 6H); 13C NMR (CDCl3, 100 MHz) 173.7, 173.5,
4.2.11. N-[1-(S)-(Methoxycarbonyl)ethyl]-(R)-phenyl-
glycine-(S)-leucine, benzyl ester (26). A colorless oil was
obtained in 84% yield (two diastereomers). 1H NMR
(CDCl3, 400 MHz) 7.36–7.23 (m, 10H), 5.18–5.08 (m,
2H), 4.67 (m, 1H), 4.31 (s, 1H), 3.69 (s, 3H), 3.26 (m, 1H),
2.25 (br, 1H), 1.66–1.53 (m, 3H), 1.30 (d, JZ6.8 Hz, 3H),
0.90–0.85 (m, 6H); 13C NMR (CDCl3, 100 MHz) 175.3,

J. Chang et al. / Tetrahedron 61 (2005) 2743–2750
2749
173.1, 172.2, 138.9, 135.8, 129.3, 129.2, 129.1, 129.0,
128.9, 128.8, 128.7, 128.6, 128.3, 127.5, 77.5, 67.5, 54.6,
52.4, 51.1, 42.0, 25.3, 23.2, 22.2 19.1. HRMS calcd for
C5H33N2O5 (MCC1): 441.2389. Found: 441.2379.
130.0, 129.8, 129.3, 129.2, 129.0, 128.9, 128.8, 128.7,
128.1, 127.9, 127.4, 67.3, 66.5, 63.0, 52.6, 50.5, 41.3, 40.6,
25.3, 23.3, 22.0. HRMS calcd for C31H37N2O5 (MCC1):
517.2702. Found: 517.2683.
4.2.12. N-[1-(R)-(Methoxycarbonyl)ethyl]-(R)-phenyl-
glycine-(S)-leucine, benzyl ester (27). A colorless oil was
obtained in 83% yield (two diastereomers). 1H NMR
(CDCl3, 400 MHz) 7.79 (d, JZ8.6 Hz, 1H), 7.41–7.27 (m,
10H), 5.18 (m, 2H), 4.69 (m, 1H), 4.16 (s, 1H) 3.71 (s, 3H),
3.34 (m, 1H) 2.25 (br, 1H), 1.74–1.61 (m, 3H), 1.33 (d,, JZ
7.3 Hz, 3H), 0.96 (d, JZ6.4 Hz, 6H); 13C NMR (CDCl3,
100 MHz) 175.8, 172.9, 172.1, 139.2, 135.8, 129.3, 129.2,
128.9, 128.8, 128.7, 128.6, 128.5, 128.4, 129.3, 128.0, 67.5,
66.7, 56.4, 52.4, 51.0, 41.8, 25.6, 23.3, 22.2, 19.9. HRMS
calcd for C25H33N2O5 (MCC1): 441.2389. Found:
441.2420.
4.2.17. N-[1-(S)-(Methoxycarbonyl)-3-methylbutyl]-(R)-
phenylglycine-(S)-proline, benzyl ester (32). A colorless
oil was obtained in 44% yield (two diastereomers). 1H NMR
(CDCl3, 400 MHz) 7.37–7.24 (m, 10H), 7.15 (m, 1H), 5.19
(m, 2H), 4.50 (m, 2H), 3.69 (s, 3H), 3.55 (m, 1H), 3.08 (m,
2H), 2.85 (br, 1H), 1.99–1.43 (m, 7H), 0.83 (d, JZ6.6 Hz,
3H), 0.65 (d, JZ6.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
175.9, 172.3, 171.6, 138.2, 136.2, 129.5, 129.0, 128.9,
128.8, 128.7, 128.6, 128.5, 128.4, 128.3, 67.1, 63.5, 59.9,
56.6, 52.1, 47.2, 427, 32.0, 29.4, 29.3, 25.2, 22.1, 22.0.
HRMS calcd for C27H35N2O5 (MCC1): 467.2546. Found:
467.2523.
4.2.13. N-[1-(S)-(Methoxycarbonyl)-3-methylbutyl]-(R)-
phenylglycine-(S)-leucine, benzyl ester (28). A colorless
oil was obtained in 80% yield (two diastereomers). 1H NMR
(CDCl3, 400 MHz) 7.36–6.99 (m, 10H), 6.99 (d, JZ8.4 Hz,
1H), 5.17 (m, 2H), 4.69 (m, 1H), 4.26 (m, 1H), 3.69 (S, 3H),
3.13 (br, 1H), 2.25 (br, 1H), 1.73–1.47 (m, 6H), 0.93–0.74
(m, 12H); 13C NMR (CDCl3, 100 MHz) 175.7, 172.9, 171.8,
138.7, 135.8, 129.3, 129.2, 129.0, 128.8, 128.7, 128.6,
128.5, 128.4, 128.3, 127., 67.4, 66.7, 57.6, 52.2, 51.1, 42.8,
41.9, 25.4, 25.3, 25.1, 25.0, 23.2, 22.2. HRMS calcd for
C28H39N2O5 (MCC1): 483.2859. Found: 483.2842.
4.2.18. N-Benzyl-N-(N-Boc-N-benzyl-3-aminopropyl)-
(R)-phenylglycine-(S)-leucine, benzyl ester (33). A color-
less oil was obtained in 63% yield (two diastereomers). H
1
NMR (CDCl3, 400 MHz) 7.46–7.19 (m, 20H), 5.17 (m, 2H),
4.70 (m, 1H), 4.34 (m, 3H), 3.81 (m, 1H), 3.30–3.08 (m,
3H), 2.57 (m, 1H), 2.16 (m, 1H), 1.7–1.26 (m, 14H), 0.97–
0.88 (m, 6H); 13C NMR (CDCl3, 100 MHz) 173.2, 171.9,
139.1, 135.9, 134.3, 131.6, 130.7, 129.2, 129.0, 128.9,
128.8, 128.7, 128.6, 128.5, 128.3, 128.1, 128.0, 127.9,
127.8, 127.7, 127.6, 127.5, 127.4, 127.3, 80.1, 69.0, 67.4,
59.4, 51.0, 48.5, 45.1, 41.9, 28.9, 26.2, 25.4, 23.3, 22.2.
HRMS calcd for C43H54N3O5 (MCC1): 692.4063. Found:
692.4047.
4.2.14. N-[1-(R)-(Methoxycarbonyl)-3-methylbutyl]-(R)-
phenylglycine-(S)-leucine, benzyl ester (29). A colorless
oil was obtained in 63% yield (two diastereomers). 1H NMR
(CDCl3, 400 MHz) 7.81 (d, JZ8.8 Hz, 1H), 7.38–7.25 (m,
10H), 5.13 (m, 2H), 4.72 (m, 1H), 4.11 (s, 1H), 3.71 (s, 3H),
3.34 (m, 1H), 2.09 (br, 1H), 1.89–1.47 (m, 6H), 0.97–0.86
(m, 12H); 13C NMR (CDCl3, 100 MHz) 176.0, 172.9, 172.1,
129.5, 135.8, 129.2, 129.0, 128.9, 128.8, 128.6, 128.4,
128.3, 128.2, 128.1, 127.9, 67.5, 66.7, 59.8, 52.3, 50.9, 43.8,
42.2, 25.4, 25.3, 23.2, 23.1, 22.9, 22.2. HRMS calcd for
C28H39N2O5 (MCC1): 483.2859. Found: 483.2867.
4.2.19. N-Benzyl-N-[2-[2-(N-benzyl-2-aminoethoxy)-
ethoxy]ethyl]-(R)-phenylglycine-(S)-leucine, benzyl
ester (34). A colorless oil was obtained in 70% yield (two
diastereomers). 1H NMR (CDCl3, 400 MHz) 7.38–7.23 (m,
20H), 5.29 (m, 2H), 4.72 (m, 1H), 4.65 (m, 1H), 3.89–3.68
(m, 3H), 3.44–3.30 (m, 9H), 3.10–2.68 (m, 5H), 1.94–1.69
(m, 4H); 13C NMR (CDCl3, 100 MHz) 172.6, 172.0, 141.1,
140.0, 137.4, 136.3, 130.0, 129.8, 129.7, 129.6, 129.5,
129.4, 129.3, 129.2, 129.1, 129.0, 128.9, 128.8, 128.7,
128.6, 128.5, 128.2, 128.1, 127.3, 127.2, 127.0, 71.8, 70.7,
70.2, 67.9, 66.0, 59.3, 56.7, 53.0, 52.2, 51.3, 50.0, 46.9,
29.5, 25.3. HRMS calcd for C40H48N3O5 (MCC1):
650.3594. Found: 650.3582.
4.2.15. N-[1-(S)-(Methoxycarbonyl)-2-phenylethyl]-(R)-
phenylglycine-(S)-leucine, benzyl ester (30). A colorless
oil was obtained in 36% yield (two diastereomers). 1H NMR
(CDCl3, 400 MHz) 7.35–7.09 (m, 16H), 5.16–5.07 (m, 2H),
4.60 (m, 1H), 4.24 (s, 1H), 3.65 (s, 3H), 3.40–3.39 (m, 1H),
3.05–3.00 (m, 1H), 2.90–2.79 (m, 1H), 2.27 (br, 1H), 1.66–
1.46 (m, 3H), 0.90–0.74 (m, 6H); 13C NMR (CDCl3,
100 MHz) 174.4, 172.8, 171.8, 138.1, 137.2, 135.8, 130.2,
129.6, 129.2, 129.0, 128.9, 128.8, 128.7, 128.6, 128.4,
127.6, 127.3, 67.4, 65.9, 60.5, 52.3, 51.1, 41.7, 39.8, 25.3,
23.3, 22.2. HRMS calcd for C31H37N2O5 (MCC1):
517.2702. Found: 517.2688.
4.2.20. N-Benzyl-N-(2-hydroxyethyl)-(R)-phenylglycine-
(S)-proline, methyl ester (35). A colorless oil was obtained
in 69% yield (two diastereomers). 1H NMR (CDCl3,
400 MHz) 7.43–7.24 (m, 10H), 4.68 (s, 1H), 4.55 (m, 1H),
3.88 (m, 2H), 3.81 (s, 3H), 3.60 (m, 1H), 3.37 (m, 1H), 2.96
(m, 3H), 2.15–1.67 (m, 5H); 13C NMR (CDCl3, 100 MHz)
173.4, 171.8, 140.2, 13.6, 130.4, 130.0, 129.7, 129.5, 129.1,
129.0, 128.9, 128.8, 128.7, 128.6, 65., 59.8, 59.3, 55.7, 52.8,
52.6, 46.8, 29.4, 25.2. HRMS calcd for C23H29N2O4 (MCC
1): 397.2127. Found: 397.2125.
4.2.16. N-[1-(R)-(Methoxycarbonyl)-2-phenylethyl]-(R)-
phenylglycine-(S)-leucine, benzyl ester (31). A colorless
oil was obtained in 49% yield (two diastereomers). 1H NMR
(CDCl3, 400 MHz) 7.37–7.25 (m, 16H), 5.10 (q, JZ
12.3 Hz, 2H), 4.47–4.44 (m, 1H), 4.09 (s, 1H), 3.73 (s,
3H), 3.41–3.39 (m, 1H), 3.03–2.68 (m, 2H), 2.17 (d, JZ
12.6, 1H), 1.39–1.36 (m, 2H), 1.01–0.84 (m, 7H); 13C NMR
(CDCl3, 100 MHz) 175.0, 172.5, 171.7, 139.4, 138.0, 136.0,
Acknowledgements
This paper was supported by a grant from Molecular &
Cellular BioDiscovery Research Program (M1-0311-13-
0003) from the Ministry of Science and Technology, Korea.

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J. Chang et al. / Tetrahedron 61 (2005) 2743–2750
4. Seeman, J. I. Chem. Rev. 1983, 83, 83.
References and notes
5. (a) Huffman, M. A.; Reider, P. J. Tetrahedron Lett. 1999, 40,
831. (b) Chapman, K. T.; Kopka, I. E.; Durette, P. L.; Esser,
C. K.; Lanza, T. J.; Izquierdo-Martin, M.; Niedzwiecki, L.;
Chang, B.; Harrison, R. K.; Kuo, D. W.; Lin, T.-Y.; Stein, R. L.;
Hagmann, W. K. J. Med. Chem. 1993, 36, 4293–4301.
6. The absolute configurations of 25, 26 and 27 were assigned as
aR by comparison to the 1H NMR of authentic epimers
individually prepared from the coupling of L-leucine derivative
and (S)- or (R)-phenylglycine derivative followed by N-
alkylation with methyl a-bromo acetate or methyl (S)-a-
bromo-a-methyl acetate. The absolute configurations of 28–32
are provisionally assigned by analogy to the formation of 25, 26
and 27.
1. (a) Yuan, Z.; Blomberg, D.; Sethson, I.; Brickmann, K.;
Ekholm, K.; Johansson, B.; Nilsson, A.; Kihlberg, J. J. Med.
Chem. 2002, 45, 2512. (b) Fujisawa, T.; Igeta, K.; Odake, S.;
Morita, Y.; Yasuda, J.; Morikawa, T. Bioorg. Med. Chem. 2002,
10, 2569. (c) Souers, A. J.; Ellman, J. A. Tetrahedron 2001, 57,
7431. (d) Haskell-Luevano, C.; Rosenquist, A.; Souers, A.;
Khong, K. C.; Ellman, J. A.; Cone, R. D. J. Med. Chem. 1999,
42, 4380.
2. (a) Nam, J.; Chang, J.-Y.; Shin, E.-k.; Kim, H. J.; Kim, Y.; Jang,
S.; Park, Y. S. Tetrahedron 2004, 60, 6311. (b) Nam, J.; Chang,
J.-Y.; Hahm, K.-S.; Park, Y. S. Tetrahedron Lett. 2003, 44,
7727.
7. In the substitution reactions of L-alanine methyl ester and L-
leucine methyl ester with methyl a-bromo-a-phenyl acetate
under the same condition, the (aS)-products were produced as
major isomer with 65:35 and 70:30 dr, respectively. The
absolute configurations of major (aS)-isomers were assigned by
3. (a) Valenrod, Y.; Myung, J.; Ben, R. N. Tetrahedron Lett. 2004,
45, 2545. (b) Nam, J.; Lee, S.-k.; Park, Y. S. Tetrahedron 2003,
59, 2397. (c) Nam, J.; Lee, S.-k.; Kim, K. Y.; Park, Y. S.
Tetrahedron Lett. 2002, 43, 8253. (d) Lee, S.-k.; Nam, J.; Park,
Y. S. Synlett 2002, 790. (e) Caddick, S.; Afonso, C. A. M.;
Candeias, S. X.; Hitchcock, P. B.; Jenkins, K.; Murtagh, L.;
Pardoe, D.; Santos, A. G.; Treweeke, N. R.; Weaving, R.
Tetrahedron 2001, 57, 6589. (f) Lee, S.-k.; Lee, S. Y.; Park,
Y. S. Synlett 2001, 1941. (g) Ben, R. N.; Durst, T. J. Org. Chem.
1999, 64, 7700.
1
comparison to the H NMR of authentic epimers individually
prepared from the substitution of methyl (R)-a-bromo a-methyl
or a-isobutyl acetate with (S)-phenylglycine methyl ester on the
basis of inversion mechanism.