Asymmetric nucleophilic substitution of α-bromo amides via dynamic kinetic resolution for the preparation of dipeptide analogues

Article abstract of DOI:10.1016/j.tet.2004.05.094

Asymmetric nucleophilic substitution reactions of α-bromo α-aryl acetamides derived from L-amino acids are described. The simple and practical syntheses of dipeptide analogues have been developed with dibenzylamine, TBAI and a base to provide 2a-2n and 4

Full text of DOI:10.1016/j.tet.2004.05.094

Tetrahedron 60 (2004) 6311–6318
Asymmetric nucleophilic substitution of a-bromo amides
via dynamic kinetic resolution for the preparation of
dipeptide analogues
Jiyoun Nam,a Ji-yeon Chang,a Eun-kyoung Shin,a Hyun Jung Kim,a Yangmee Kim,a
Soonmin Jangb and Yong Sun Parka
,
*
aDepartment of Chemistry, Konkuk University, Kwangjingu Hwayangdong 1, Seoul 143-701, South Korea
bDepartment of Chemistry, Seoul National University, Seoul 151-747, South Korea
Received 28 April 2004; revised 20 May 2004; accepted 24 May 2004
Available online 17 June 2004
Abstract—Asymmetric nucleophilic substitution reactions of a-bromo a-aryl acetamides derived from L-amino acids are described. The
simple and practical syntheses of dipeptide analogues have been developed with dibenzylamine, TBAI and a base to provide 2a–2n and 4 in
50–98% yields with diastereomeric ratios from 74:26 to .99:1. Mechanistic investigations suggest that a-bromo acetamides are
configurationally labile under the reaction condition and the primary pathway of the asymmetric induction is a dynamic kinetic resolution.
The semiempirical calculations of two epimeric transition states of 1b found that (aS)-epimer is the faster reacting epimer with the formation
of an intermolecular hydrogen bond that facilitates delivery of the amine nucleophile.
q 2004 Published by Elsevier Ltd.
1. Introduction
transferred to the new C–N bond formation at a-halo
carbon center, which can build an unnatural amino acid onto
the amino acid precursor with remarkable stereoselectivity.
Herein we describe our recent progress to extend the scope
of the methodology and to provide the mechanistic and
stereochemical rationale.
Chiral auxiliary mediated dynamic resolution of a-halo
carboxylic acid derivatives has been recently recognized as
an effective synthetic method for asymmetric syntheses of
a-amino acids, a-mercapto acids, and a-hydroxy acids.1
Since a-haloacyl compounds are easily obtained in racemic
form and configurational lability of them is readily induced,
dynamic resolution in nucleophilic substitutions at a-halo
carbon center can allow easy access to a wide range of
enantioenriched a-heteroatom substituted carboxylic acid
derivatives. Additionally, extension of this methodology to
stereoselective modification of peptides is of obvious
synthetic utility, in which chiral information of the adjacent
amino acids is transferred to new bond formation at a-halo
carbon center. The direct modification of peptide chain
seems to be an attractive synthetic strategy for peptidomi-
metics since numerous peptide analogues can be efficiently
prepared using easily accessible and relatively inexpensive
amino acid precursor.2 We have recently reported our
preliminary results on dynamic resolution of a-bromo
acetamides in nucleophilic substitution for asymmetric
syntheses of di- and tripeptide analogues.3 The chiral
information of an amino acid precursor is efficiently
2. Results and discussion
We previously reported that L-proline and L-leucine are
efficient precursors for asymmetric syntheses of dipeptide
analogues via dynamic resolution of the corresponding
a-bromo acetamides 1a and 1b as shown in Table 1, entries
1 and 2. When the two diastereomeric mixture (ca. 50:50)
of N-(a-bromo-a-phenylacetyl)-(L)-proline methyl ester
1a was treated with dibenzylamine (Bn2NH), tetrabutyl-
ammonium iodide (TBAI) and triethylamine (Et3N) in
CH2Cl2 at room temperature, the dipeptide analogues 2a
was obtained in 93% yield with .99:1 diastereomeric ratio
(dr, aR:aS). Also, the reactions of leucine methyl ester 1b
under the same condition gave the dipeptide analogue 2b in
83% yield with 89:11 dr (aR:aS). In this paper, the scope of
the observed dynamic resolution has been examined with 12
different L-amino acid precursors. The substitution
reactions of a-bromo-a-phenyl acetamides 1c–1n derived
from the corresponding L-amino acid methyl esters and
racemic a-bromo-a-phenyl acetic acid were investigated as
Keywords: Dynamic kinetic resolution; Peptidimimetics; Dipeptide;
Asymmetric syntheses; Nucleophilic substitution.
*
Corresponding author. Tel.: þ82-24503377; fax: þ82-23436-5382;
e-mail address: parkyong@kkucc.konkuk.ac.kr
0040–4020/$ - see front matter q 2004 Published by Elsevier Ltd.
doi:10.1016/j.tet.2004.05.094

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J. Nam et al. / Tetrahedron 60 (2004) 6311–6318
Table 1. Reactions of a-bromo acetamides 1a–1n
a-bromo acetamides 1f, 1g and 1i derived from amino acids
with aromatic side chain showed almost same drs as leucine
methyl ester 1b. Mild drops in stereoselectivity andyield
were seen with a-bromo acetamide 1h derived from
L-phenylglycine (entry 8). a-Bromo acetamides 1j–1n
derived from L-aspartic acid, L-glutamic acid, L-lysine,
L-serine, and L-cysteine were also examined with the
protection of side chain functionality as shown in Table 1,
entries 10–14. Considerable loss of stereoselectivity (74:26
dr) was observed with a-bromo acetamide 1j derived from
L-aspartic acid. Glutamic acid dimethyl ester 1k and N-Cbz
protected lysine methyl ester 1l gave the dipeptide
analogues 2k and 2l with 88:12 dr and 90:10 dr, respectively
(entries 11 and 12). Similar stereoselectivities were
observed in the reactions of O-benzyl protected serine
derivative 1m and S-benzyl protected cysteine derivative 1n
with moderate yields (entries 13 and 14). As can be seen in
Table 1, the survey of various amino acid precursors
indicates that highest stereoselectivity (.99:1) was
observed with a-bromo acetamide 1a derived from
L-proline and other a-bromo acetamides 1b–1n
provided the dipeptide analogues 2b–2n with good
stereoselectivities, ranging from 74:26 dr to 95:5 dr.
Entrya
S.M.b
L-AAb
Pro
Leu
Ala
Val
Ile
Phe
Trp
Phg
Product
%Yieldc
drd (aR:aS)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
93
83
96
81
95
91
98
52
77
86
50
91
50
57
.99:1
89:11
90:10
95:5
93:7
90:10
90:10
84:16
90:10
74:26
88:12
90:10
91:9
9
Tyr
10
11
12
13
14
Asp (O-Me)
Glu (O-Me)
Lys (N-Cbz)
Ser (O-Bn)
Cys (S-Bn)
87:13
a
All reactions were carried out in CH2Cl2 for 24 h at rt.
Initial drs of 1a–1n are approximately 50:50.
Isolated yields.
b
c
d
The drs are determined by 1H NMR of reaction mixture using the
authentic products prepared from racemic phenylglycine as a standard.
In an effort to improve the stereoselectivity of the
nucleophilic substitution of a-bromo acetamides 1b–1n
with dibenzylamine nucleophile, various reaction con-
ditions have been examined as shown in Table 2 with
leucine benzyl ester 3. Of the solvents explored, CH2Cl2
consistently gave the best results (entry 1). The dipeptide
analogue 4 was obtained from 3 with 87:13 dr in n-hexane,
85:15 dr in ether, 90:10 dr in CH3CN, 89:11 dr in NMP, 92:8
dr in DMF, and 86:14 dr in p-dioxane (entries 2–7). We also
examined the substitutions at 0 and 50 8C (entries 8 and 9).
shown in Table 1. Treatment of alanine methyl ester 1c with
Bn2NH (1.2 equiv.), TBAI (1.0 equiv.) and Et3N
(1.0 equiv.) in CH2Cl2 for 24 h at room temperature gave
2c in 96% yield with 90:10 dr (entry 3). Higher level of
selectivities were observed with L-valine ester and
L-isoleucine ester which have more sterically demanding
secondary alkyl side chain (entries 4 and 5). The reactions of
Table 2. Effects of substitution conditions on the stereoselectivities
Entrya
Solvent
Base
X2
Temperature
Yieldb
drc (aR:aS)
1
2
3
4
5
6
7
8
CH2Cl2
n-Hexane
Ether
CH3CN
NMP
DMF
p-Dioxane
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
None
Et3N
None
Et3N
Et3N
Et3N
DBN
DBU
DIEA
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
None
None
TBAI
TBAI (0.1 equiv.)
TBAB
KI
TBAI
TBAI
TBAI
rt
rt
rt
rt
rt
rt
rt
0 8C
50 8C
rt
rt
rt
rt
rt
rt
rt
95
55
73
91
48
68
68
77
85
43
51
90
88
85
73
10
46
97
93:7
87:13
85:15
90:10
89:11
92:8
86:14
92:8
93:7
66:34
71:29
89:11
88:12
88:12
92:8
90:10
86:14
94:6
9
10
11
12
13
14
15
16
17
18
rt
rt
a
All reactions were carried out for 24 h with 3 (1.0 equiv., ca. 50:50 dr), dibenzylamine (1.2 equiv.), X2 (1.0 equiv.) and a base (1.2 equiv.).
Isolated yields.
b
c
1
The drs of 4 are determined by H NMR of reaction mixture using the authentic products prepared from racemic phenylglycine as a standard.

J. Nam et al. / Tetrahedron 60 (2004) 6311–6318
6313
Temperature appeared to have little influence on the
selectivity. The results in entries 10–12 pointed to the
importance of the presence of TBAI for rate acceleration
and high stereoselectivity. The reaction in the absence of
both TBAI and Et3N for 24 h gave the product with slower
rate and much lower stereoselectivity (66:34 dr). The lack of
stereoselectivity in the absence of TBAI may be explained
by the slow epimerization of 3 with respect to the
substitution with the amine nucleophile.4 Use of catalytic
amount of TBAI eroded the selectivity, probably due to less
efficient epimerization process (entry 13). When KI was
used as an epimerizing agent, the reaction gave almost same
selectivity (92:8 dr) as the reaction with TBAI, which was
better than the reaction with bromide epimerizing agent,
TBAB (entries 14–15). Slightly diminished stereo-
selectivity with poor yield was observed by changing the
base from Et3N to DBU or DBN (entries 16 and 17).
The addition of diisopropylethylamine (DIEA) afforded the
dipeptide analogue 4 with highest stereoselctivity (94:6 dr)
in 97% yield (entry 18). We were pleased to observe that
DIEA promoted reactions of most a-bromo acetamides
gave the improved stereoselectivities, compared to the
stereoselectivities of the reactions with Et3N shown in
Table 1. The reactions of 1b, 1e, 1g, 1h, and 1i with DIEA
and TBAI provided the products with 93:7 dr, 97:3 dr, 93:7
dr, 87:13 dr and 93:7 dr, respectively.
tive, and also confirmed by comparison of chiral-HPLC
retention time with authentic epimers using racemic
material as a standard. The configurational stability of the
dipeptide analogue 4 was examined by the treatment with
Bn2NH (1.2 equiv.), TBAI (1.0 equiv.) and DIEA
(1.0 equiv.) in CH2Cl2 for 24 h. No epimerization at two
stereogenic centers of 4 was detected by 1H NMR and
Chiral-HPLC, ruling out the possibility of epimerization
after the replacement of Br with dibenzylamine. Thus, the
observed asymmetric induction is the results of dynamic
resolution in nucleophilic substitution of two epimeric
mixture of a-bromo acetamide 3.
There are two limiting pathways which could account for
the observed dynamic resolution in nucleophilic substitution
of a-bromo acetamide 3. In one limiting pathway, a-bromo
stereogenic center undergoes rapid epimerization between
(aS)-3 and (aR)-3 and one of two epimers reacts
preferentially under the reaction condition. This is a case
of dynamic kinetic resolution, in which the stereoselectivity
is determined by the difference in the epimeric transition
state energies for the reaction with dibenzylamine. In a
different limiting pathway, the stereoselectivity of the
reaction is determined by the ratio of (aS)-3 and (aR)-3
that is established before the substitution. This is termed
dynamic thermodynamic resolution because the ratio of two
epimers is thermodynamically controlled and the stereo-
selectivity of the reaction is not determined by the difference
in the rates of substitutions with dibenzylamine.
The R-configuration at a-position of major product 4 was
assigned by comparison to the 1H NMR of authentic
epimers individually prepared from the coupling of
L-leucine derivative and (S)- or (R)-phenylglycine deriva-
A series of reactions as shown in Table 3 has been carried
Table 3. Dynamic kinetic resolution of a-bromo acetamide 3
Entry
S.M.
Condition
Product (aR:aS)
Yield (%)
1
2
3
4
3 (57:43)
3 (78:22)
3 (72:28)
3 (30:70)
TBAI, DIEA, rt
TBAI, DIEA, rt
TBAI, DIEA, Bn2NH, rt
TBAI, DIEA, Bn2NH, rt
3 (52:48)
3 (52:48)
4 (94:6)
4 (95:5)
75
78
96
98
All reactions were carried out for 24 h at rt. The drs of 3 and 4 were determined by 1H NMR of reaction mixture using the authentic products prepared from
racemic a-bromo phenyl acetic acid and phenylglycine, respectively, as standards.

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J. Nam et al. / Tetrahedron 60 (2004) 6311–6318
Figure 1. Transition states for the reactions of slower reacting (aR)-1b and faster reacting (aS)-1b with dibenzylamine. Hydrogens have been removed for
clarity.
out to differentiate the two possible pathways of asymmetric
induction in nucleophilic substitution reactions of a-bromo
amides. When the mixture of two epimers was allowed to
reach thermodynamic equilibrium in the presence of TBAI
and DIEA, the epimeric ratio of recovered 3 was analyzed
by 1H NMR, determined to be 52:48 in both cases with 3 of
57:43 dr and 78:22 dr, respectively (entries 1 and 2). These
results indicate that a-bromo amide 3 is configurationally
labile under the reaction condition and the thermodynamic
stabilities of two epimers are almost same, ruling out
dynamic thermodynamic resolution as a primary pathway.
When 3 with 72:28 dr was treated with dibenzylamine in the
presence of both TBAI and DIEA, the reaction gave the
product 4 with 94:6 dr as shown in entry 3. In addition,
almost same dr of product 4 was observed in the reaction of
3 with reversed diastereomeric enrichment of 30:70 dr.
Thus, the diastereomeric ratio of product 4 is independent of
the starting ratio of two epimers of 3 and would depend
solely on the difference in the epimeric transition state
energies. These results could be taken to suggest that the
epimerization of 3 promoted by TBAI and DIEA is
sufficiently fast with respect to the rate of substitution (k1,
k21@k2[dibenzylamine], k3[dibenzylamine]) and the
primary pathway of the asymmetric induction is a dynamic
kinetic resolution.
the energy of the corresponding conformation. At this level
of theory, only one transition state was found for each
epimer, with the transition state (aS)-1b–TS having the
lower enthalpy value. The energy difference of about
3.0 kcal/mol between the transition state structures (aR)-
1b–TS and (aS)-1b–TS is fully consonant with the highly
stereoselective character of the dynamic kinetic resolution
process. Based on the results of the calculations, we
conclude that the (aS)-1b is the faster reacting diastereomer
and this is due to formation of an intermolecular hydrogen
bond that facilitates delivery of the amine nucleophile. The
model proposed here, by relying on hydrogen bonding, is
consistent with the poor stereoselectivities of the
reactions with thiol nucleophiles and metalated nucleo-
philes, relatively poor hydrogen bond donor nucleophiles.6
For further N-terminal functionalization of the dipeptide
analogues, the N,N-dibenzyl protecting group is removed
and converted to the Boc group with Pd/C, cyclohexadiene,
and (Boc)2O as shown in Scheme 1.7 N-Boc-D-phenyl-
glycyl-L-leucine methyl ester 6 was obtained in 47% overall
yield with 93:7 dr from a-phenylacetyl leucine methyl ester
1b. The diastereomerically pure N-Boc dipeptide analogues
7 was obtained in 30% overall yield after silica gel column
chromatography from a-(p-fluorophenyl)acetyl leucine
methyl ester 5. The isolated yields of 6 and 7 generally
were not high, but the procedure was performed at a
relatively small scale and no further attempts were made to
optimize the yields for the deprotection. This methodology
provides the unique possibility to synthesize a wide range of
D-arylglycine dipeptide analogues with various L-amino
acids. It is well known that D-phenylglycine dipeptides have
interesting properties and can be applied, for example, as
tumor and tissue-dissolving compounds of low toxicity and
as resolving agents.8
In order to gain further understanding of the dynamic kinetic
resolution, we proceed to calculate the transition states of
both leucine methyl esters (aR)-1b and (aS)-1b using semi-
empirical methods.5 The main results of the calculations
after full optimizations at HF/6-31G(d) level are shown in
Figure 1. The only constraint was the distance between the
two reaction centers during the transition state search.
Starting from the sufficiently long distance, this distance
constraint has been reduced systematically by monitoring
Scheme 1.

J. Nam et al. / Tetrahedron 60 (2004) 6311–6318
6315
3. Conclusion
5H), 7.15, 7.08 (d, J¼8.0, 8.2 Hz, 1H), 5.48, 5.45 (s, 1H),
4.55 (m, 1H), 3.74 (s 3H), 2.23 (m, 1H), 0.93 (m, 6H); 13C
NMR (CDCl3, 100 MHz) 172.2, 167.5, 137.6, 129.5, 129.3,
128.8, 58.3, 52.7, 51.6, 31.8, 19.3, 18.1. Anal. calcd for
C14H13BrNO3: C, 51.23; H, 5.53; N, 4.27. Found: C, 51.42;
H, 5.44; N, 3.95.
We have shown that dynamic resolution of a-bromo amides
can be successfully applied towards the preparation of
enantioenriched dipeptide analogues. The methodology has
been particularly successful for a-bromo a-aryl acetamides,
affording a generalized and practical method for the
asymmetric syntheses of D-arylglycine dipeptide
analogues.9 Mechanistic investigations along with semi-
empirical calculations suggest that a-bromo a-aryl
acetamides are configurationally labile under the reaction
condition and the primary pathway of the asymmetric
induction is a dynamic kinetic resolution. The methodology
of the present work should also be applicable to stereo-
selective syntheses and mechanistic analysis of a number of
related systems.
4.1.5. (S)-N-(a-Bromo-a-phenylacetyl) isoleucine methyl
1
ester (1e). A colorless oil was obtained in 13% yield. H
NMR (CDCl3, 400 MHz, two diastereomers) 7.49–7.29 (m,
5H), 7.19, 7.12 (d, J¼8.0, 8.0 Hz, 1H), 5.47, 5.44 (s, 1H),
4.59 (d, J¼4.6 Hz, 1H), 3.74 (s, 3H), 1.97 (m, 1H), 1.44 (m,
1H), 1.19 (m, 1H), 0.91 (m, 6H); 13C NMR (CDCl3,
100 MHz) 172.1, 167.3, 137.6, 129.5, 128.3, 128.7, 57.6,
52.6, 51.7, 38.3, 25.6, 15.9, 11.9. Anal. calcd for
C15H20BrNO3: C, 52.64; H, 5.89; N, 4.09. Found: C,
52.66; H, 5.94; N, 4.15.
4.1.6. (S)-N-(a-Bromo-a-phenylacetyl) phenylalanine
methyl ester (1f). A colorless oil was obtained in 30%
yield. 1H NMR (CDCl3, 400 MHz, two diastereomers)
7.26–7.00 (m, 11H), 5.37, 5.31 (s, 1H), 4.85 (m, 1H), 3.68,
3.66 (m, 3H), 3.10 (m, 2H); 13C NMR (CDCl3, 100 MHz)
171.8, 167.3, 137.5, 135.8, 129.7, 129.3, 129.0, 128.8,
128.3, 127.6, 54.3, 52.9, 51.1, 37.9. Anal. calcd for
C13H13BrNO3: C, 57.46; H, 4.82; N, 3.72. Found: C,
57.35; H, 4.76; N, 3.44.
4. Experimental
4.1. General procedure for the preparation of 1a–1n, 3,
and 5
L-Amino acid methyl (or benzyl) ester (1.0 equiv.), racemic
a-bromo phenylacetic acid (1.0 equiv.), DCC (1.0 equiv.),
Et3N (1.1 equiv.) and DMAP (0.2 equiv.) were dissolved in
CH2Cl2 and stirred at room temperature 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.
4.1.7. (S)-N-(a-Bromo-a-phenylacetyl) tryptophan
methyl ester (1g). A colorless oil was obtained in 40%
1
yield. H NMR (CDCl3, 400 MHz, two diastereomers) 8.3
(br, 1H), 7.54–7.06 (m, 10H), 6.82 (m, 1H), 5.32, 5.30 (s,
1H), 4.89 (m, 1H), 3.66, 3.64 (s, 3H), 3.34 (m, 2H); 13C
NMR (CDCl3, 100 MHz) 172.2, 167.5, 137.5, 136.6, 129.5,
129.3, 128.9, 127.7, 123.6, 122.6, 120.1, 118.9, 111.8,
109.7, 54.1, 53.0, 51.2, 27.8. Anal. calcd for C20H19BrN2O3:
C, 57.84; H, 4.61; N, 6.75. Found: C, 57.80 H, 4.65; N, 6.48.
4.1.1. (S)-N-(a-Bromo-a-phenylacetyl) proline methyl
1
ester (1a). A colorless oil was obtained in 36% yield. H
NMR (CDCl3, 400 MHz, two diastereomers) 7.52–7.32 (m,
5H), 5.64, 5.41 (s, 1H), 4.54, 4.45 (m, 1H), 3.72, 3.65 (s,
3H), 3.33 (m, 1H), 2.15–1.84 (m, 5H); 13C NMR (CDCl3,
100 MHz) 172.5, 166.3, 136.0, 129.3, 128.9, 128.5, 60.0,
59.8, 52.6, 47.5, 29.2, 25.3. HRMS calcd for C14H16BrNO3:
325.0314. Found: 325.0326.
4.1.8. (S)-N-(a-Bromo-a-phenylacetyl) phenylglycine
methyl ester (1h). A colorless oil was obtained in 33%
yield. 1H NMR (CDCl3, 400 MHz, two diastereomers)
7.72–7.21 (m, 11H), 5.53 (m, 1H), 5.44, 5.41 (s, 1H), 3.68,
3.67 (s, 3H); 13C NMR (CDCl3, 100 MHz) 171.2, 167.1,
137.5, 136.3, 129.5, 129.3, 129.2, 128.9, 128.4, 127.7, 57.6,
53.3, 51.0. Anal. calcd for C17H16BrNO3: C, 56.37; H, 4.45;
N, 3.87. Found: C, 56.66; H, 4.30; N, 3.62.
4.1.2. (S)-N-(a-Bromo-a-phenylacetyl) leucine methyl
1
ester (1b). A colorless oil was obtained in 34% yield. H
NMR (CDCl3, 400 MHz, two diastereomers) 7.50–7.07 (m,
6H), 5.46, 5.44 (s, 1H), 4.60 (m, 1H), 3.73, 3.72 (s, 3H), 1.63
(m, 3H), 0.92 (m, 6H); 13C NMR (CDCl3, 100 MHz) 173.1,
167.5, 137.6, 129.4, 128.9, 128.3, 52.7, 51.0, 41.5, 25.2,
23.1, 22.3. Anal. calcd for C15H20BrNO3: C, 52.64; H, 5.89;
N, 4.09. Found: C, 52.66; H, 5.92; N, 3.91.
4.1.9. (S)-N-(a-Bromo-a-phenylacetyl) tyrosine methyl
1
ester (1i). A colorless oil was obtained in 39% yield. H
NMR (CDCl3, 400 MHz, two diastereomers) 7.42–6.54 (m,
11H), 5.39, 5,38 (s, 1H), 4.83 (m, 1H), 3.76, 3.74 (s, 3H),
3.02 (m, 2H); 13C NMR (CDCl3, 100 MHz) 172.0, 167.6,
156.0, 137.3, 130.7, 129.6, 129.4, 128.7, 126.9, 116.1, 54.4,
53.0, 51.3, 37.3. Anal. calcd for C18H18BrNO4: C, 55.12; H,
4.63; N, 3.57. Found: C, 55.14; H, 4.45; N, 3.41.
4.1.3. (S)-N-(a-Bromo-a-phenylacetyl) alanine methyl
1
ester (1c). A colorless oil was obtained in 53% yield. H
NMR (CDCl3, 400 MHz, two diastereomers) 7.28–7.49 (m,
6H), 5.45, 5.38 (s, 1H), 4.55 (m, 1H), 3.71, 3.70 (s, 3H), 1.41
(m, 3H); 13C NMR (CDCl3, 100 MHz) 173.1, 167.4, 137.5,
129.5, 128.8, 128.3, 52.9, 50.8, 49.3, 18.2. Anal. calcd for
C12H14BrNO3: C, 48.02; H, 4.70; N, 4.67. Found: C, 48.02;
H, 4.82; N, 4.43.
4.1.10. (S)-N-(a-Bromo-a-phenylacetyl) aspartic acid
dimethyl ester (1j). A colorless oil was obtained in 20%
yield. 1H NMR (CDCl3, 400 MHz, two diastereomers)
7.68–7.26 (m, 6H), 5.44, 5.40 (s, 1H), 4.60 (m, 1H), 3.77,
3.69 (s, 3H), 3.07, 2.89 (m, 1H); 13C NMR (CDCl3,
100 MHz) 171.7, 170.9, 167.4, 137.5, 129.3, 128.7, 128.3,
53.4, 52.5, 51.1, 49.8, 36.0. Anal. calcd for C14H16BrNO5:
4.1.4. (S)-N-(a-Bromo-a-phenylacetyl) valine methyl
1
ester (1d). A colorless oil was obtained in 53% yield. H
NMR (CDCl3, 400 MHz, two diastereomers) 7.49–7.15 (m,

6316
J. Nam et al. / Tetrahedron 60 (2004) 6311–6318
C, 46.95; H, 4.50; N, 3.91. Found: C, 46.95; H, 4.65; N,
3.97.
4.2. General procedure for asymmetric preparation of
dipeptide analogues 2a–2n, and 4
4.1.11. (S)-N-(a-Bromo-a-phenylacetyl) glutamic acid
dimethyl ester (1k). A colorless oil was obtained in 26%
yield. 1H NMR (CDCl3, 400 MHz, two diastereomers)
7.49–7.32 (m, 6H), 5.46, 5.45 (s, 1H), 4,61 (m, 1H), 3.72 (s,
3H), 3.65 (s, 3H), 2.38 (m, 2H), 2.25 (m, 1H), 2,05 (m, 1H);
13C NMR (CDCl3, 100 MHz) 173.4, 172.0, 167.8, 137.2,
129.5, 128.8, 128.3, 61.3, 52.8, 52.3, 50.8, 30.3, 27.3. Anal.
calcd for C15H18BrNO5: C, 48.40; H, 4.87; N, 3.76. Found:
C, 48.38; H, 4.72; N, 3.61.
To a solution of (aRS)-a-bromo acetamides in dry CH2Cl2
(ca. 0.1 M) at room temperature was added dibenzylamine
(1.2 equiv.), TBAI (1.0 equiv.) and Et3N (or DIEA,
1.2 equiv.). The resulting reaction mixture was stirred at
room temperature for 24 h. The solvent in mixture was
evaporated and the crude product was purified by column
chromatography on silica gel.
4.2.1. (S)-N-[(R)-a-Phenyl-N,N-(dibenzyl)glycinyl] pro-
line methyl ester (2a). A colorless oil was obtained in 93%
1
4.1.12. (S)-N-(a-Bromo-a-phenylacetyl) lysine(N-
benzyloxycarbonyl) methyl ester (1l). A colorless oil
was obtained in 44% yield. 1H NMR (CDCl3, 400 MHz, two
diastereomers) 7.47–7.27 (m, 11H), 5.44, 5.43 (s, 1H), 5.07
(s, 2H), 5.02 (m, 1H), 4.56 (m, 1H), 3.71, 3.70 (s, 3H), 1.86
(m, 1H), 1.72 (m, 1H), 1.46 (m, 2H), 1.31 (m, 2H); 13C
NMR (CDCl3, 100 MHz) 172.6, 167.5, 157.0, 137.5, 137.0,
129.5, 129.2, 128.9, 128.5, 128.3, 128.1, 67.0, 53.1, 52.9, 51.0,
40.9, 32.0, 29.6, 22.7. Anal. calcd for C23H27BrN2O3: C,
56.22; H, 5.54; N, 5.70. Found: C, 56.19; H, 5.65; N, 5.58.
yield. H NMR (CDCl3, 400 MHz) 7.43–7.20 (m, 16H),
4.61 (m, 2H), 3.94–3.80 (m, 4H), 3.85 (s, 3H), 3.03 (m, 1H),
2.82 (m, 1H), 2.11 (m, 1H), 1.90 (m, 2H), 1.68 (m, 1H); 13C
NMR (CDCl3, 100 MHz) 173.3, 171.9, 141.1, 137.2, 129.6,
129.3, 129.0, 128.8, 128.2, 127.1, 64.1, 59.0, 54.6, 52.7,
46.8, 29.5, 25.2. Anal. calcd for C23H30N2O3: C, 75.99; H,
6.83; N, 6.33. Found: C, 75.98; H, 6.86; N, 6.20.
4.2.2. (S)-N-[(R)-a-Phenyl-N,N-(dibenzyl)glycinyl]
leucine methyl ester (2b). A colorless oil was obtained in
83% yield. 1H NMR (CDCl3, 400 MHz) 7.78 (d, J¼8.8 Hz,
1H), 7.47–7.18 (m, 15H), 4.72 (m, 1H), 4.45 (s, 1H), 3.91
(d, J¼13.6 Hz, 2H), 3.73 (s, 3H), 3.28 (d, J¼13.6 Hz, 2H),
1.63 (m, 3H), 0.94 (m, 6H); 13C NMR (CDCl3, 100 MHz)
173.8, 171.8, 139.0, 133.8, 131.0, 129.2, 129.0, 128.5,
128.3, 127.8, 67.5, 54.9, 52.6, 51.0, 42.1, 25.4, 23.3, 22.3.
Anal. calcd for C29H34N2O3: C, 75.95; H, 7.47; N, 6.11.
Found: C, 75.91; H, 7.46; N, 6.10.
4.1.13. (S)-N-(a-Bromo-a-phenylacetyl) serine(O-
benzyl) methyl ester (1m). A colorless oil was obtained
in 22% yield. 1H NMR (CDCl3, 400 MHz, two dia-
stereomers) 7.50–7.24 (m, 11H), 5.44, 5.43 (s, 1H), 4.72
(m, 1H), 4.51 (m, 2H), 3.89 (m, 1H), 3.75 (m, 3H), 3.71 (m,
1H); 13C NMR (CDCl3, 100 MHz) 170.5, 167.3, 137.8,
129.5, 129.3, 128.9, 128.4, 128.3, 128.2, 128.0, 73.6, 69.4,
53.8, 53.1, 51.3. Anal. calcd for C19H20BrNO3: C, 56.17 H,
4.96; N, 3.45. Found: C, 56.20; H, 4.97; N, 3.34.
4.2.3. (S)-N-[(R)-a-Phenyl-N,N-(dibenzyl)glycinyl]
alanine methyl ester (2c). A colorless oil was obtained in
96% yield. 1H NMR (CDCl3, 400 MHz) 7.81 (d, J¼8.8 Hz,
1H), 7.40–7.23 (m, 15H), 4.65 (m, 1H), 4.43 (s, 1H), 3.89
(d, J¼13.7 Hz, 2H), 3.76 (s, 3H), 3.28 (d, J¼13.7 Hz, 2H),
1.42 (d, J¼7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
173.8, 171.6, 139.0, 134.1, 130.9, 129.3, 129.0, 128.5,
128.3, 127.7, 67.8, 54.9, 52.9, 48.4, 18.8. Anal. calcd for
C26H28N2O3: C, 74.97; H, 6.78; N, 6.73. Found: C, 74.80;
H, 6.91; N, 6.65.
4.1.14. (S)-N-(a-Bromo-a-phenylacetyl) cysteine(S-
benzyl) methyl ester (1n). A colorless oil was obtained in
40% yield. 1H NMR (CDCl3, 400 MHz, two diastereomers)
7.51–7.25 (m, 11H), 5.44, 5.43 (s, 1H), 4.78 (m, 1H), 3.74
(s, 3H), 3.68 (m,2H), 2.95 (m, 2H); 13C NMR (CDCl3,
100 MHz) 171.0, 167.3, 137.8, 129.4, 129.6, 129.4, 129.3,
129.0, 128.3, 127.7, 53.2, 52.8, 51.2, 37.0, 33.5. Anal. calcd
for C19H20BrNO3S: C, 54.03; H, 4.77; N, 3.32. Found: C,
54.25; H, 4.77; N, 3.15.
4.2.4. (S)-N-[(R)-a-Phenyl-N,N-(dibenzyl)glycinyl]
valine methyl ester (2d). A colorless oil was obtained in
81% yield. 1H NMR (CDCl3, 400 MHz) 7.95 (d, J¼9.2 Hz,
1H), 7.45–7.23 (m 15H), 4.66 (m, 1H), 4.47 (s, 1H), 3.91 (d,
J¼13.6 Hz, 2H), 3.73 (s, 3H), 3.25 (d, J¼13.6 Hz, 2H), 2.26
(m, 1H), 0.96 (d, J¼7.2 Hz, 3H), 0.92 (d, J¼6.8 Hz, 3H);
13C NMR (CDCl3, 100 MHz) 172.8, 171.9, 138.9, 133.6,
131.1, 129.3, 129.0, 128.6, 128.3, 127.8, 67.5, 57.4, 54.8,
52.5, 31.8, 19.5, 18.1. Anal. calcd for C28H32N2O3: C,
75.65; H, 7.26; N, 6.30. Found: C, 75.73; H, 7.44; N, 6.21.
4.1.15. (S)-N-(a-Bromo-a-phenylacetyl) leucine benzyl
1
ester (3). A colorless oil was obtained in 70% yield. H
NMR (CDCl3, 400 MHz, two diastereomers) 7.45–7.29 (m,
10H), 7.01 (m, 1H), 5.45, 5.42 (s, 1H), 5.17 (m, 2H), 4.66
(m, 1H), 1.66 (m, 3H), 0.89 (m, 6H); 13C NMR (CDCl3,
100 MHz) 172.5, 167.3, 137.6, 135.6, 129.5, 129.3, 129.0,
128.8, 128.7, 128.6, 67.6, 52.2, 51.5, 41.7, 25.3, 23.2, 22.3.
Anal. calcd for C21H24BrNO3: C, 60.29; H, 5.78; N, 3.35.
Found: C, 60.54; H, 5.82; N, 3.12.
4.1.16. (S)-N-[a-Bromo-a-(p-fluorophenyl)acetyl]
leucine methyl ester (5). A colorless oil was obtained in
47% yield. 1H NMR (CDCl3, 400 MHz, two diastereomers)
7.50–7.43 (m, 2H), 7.06–7.01 (m, 3H), 5.45, 5.42 (s, 1H),
4.61 (m, 1H), 3.75, 3.74 (s, 3H), 1.64 (m, 3H), 0.94 (m, 6H);
13C NMR (CDCl3, 100 MHz) 173.2, 167.1, 164.5, 133.4,
130.8, 116.5, 52.8, 52.0, 50.0, 25.3, 23.2, 22.3. Anal. calcd
for C15H19BrFNO3: C, 50.01; H, 5.32; N, 3.89. Found: C,
50.09; H, 5.23; N, 3.74.
4.2.5. (S)-N-[(R)-a-Phenyl-N,N-(dibenzyl)glycinyl]
isoleucine methyl ester (2e). A colorless oil was obtained
in 95% yield. 1H NMR (CDCl3, 400 MHz) 7.97 (d,
J¼9.2 Hz, 1H), 7.42–7.21 (m, 15H), 4.70 (m, 1H), 4.46
(s, 1H), 3.91 (d, J¼13.6 Hz, 2H), 3.73 (s, 3H), 3.21 (d,
J¼13.6 Hz, 2H), 1.97 (m, 1H), 1.47 (m, 1H), 1.20 (m, 1H),
0.89 (m, 6H); 13C NMR (CDCl3, 100 MHz) 172.7, 171.7,
139.0, 133.6, 131.1, 129.3, 129.0, 128.5, 128.3, 127.8, 67.5,
56.8, 54.9, 52.4, 38.2, 25.7, 16.1, 12.1. Anal. calcd for

J. Nam et al. / Tetrahedron 60 (2004) 6311–6318
6317
C29H34N2O3: C, 75.95; H, 7.47; N, 6.11. Found: C, 75.99;
H, 7.60; N, 5.92.
obtained in 50% yield. 1H NMR (CDCl3, 400 MHz) 7.93 (d,
J¼8.4 Hz, 1H), 7.49–7.24 (m, 15H), 4.72 (m, 1H), 4.44 (s,
1H), 3.94 (d, J¼13.6 Hz, 2H), 3.75 (s, 3H), 3,64 (s, 3H),
3.27 (d, J¼13.6 Hz), 2.28 (m, 3H), 2.05 (m, 1H); 13C NMR
(CDCl3, 100 MHz) 173.3, 172.6, 172.0, 138.9, 133.7, 131.0,
129.3, 129.1, 128.9, 128.5, 127.8, 67.6, 54.9, 52.1, 51.8,
30.3, 27.7. Anal. calcd for C29H31N2O5: C, 70.72; H, 6.57;
N, 5.89. Found: C, 70.89; H, 6.75; N, 5.67.
4.2.6. (S)-N-[(R)-a-Phenyl-N,N-(dibenzyl)glycinyl]
phenylalanine methyl ester (2f). A colorless oil was
1
obtained in 91% yield. H NMR (CDCl3, 400 MHz) 7.80
(d, J¼8.4 Hz, 1H), 7.36–7.07 (m, 20H), 5.03 (m, 1H),
4.39 (s, 1H), 3.84 (m, 2H), 3.69 (s, 3H), 3.17 (m, 4H); 13C
NMR (CDCl3, 100 MHz) 172.4, 171.8, 138.8, 136.3, 133.1,
131.2, 129.7, 129.2, 129.1, 129.0, 128.9, 128.4, 128.2,
127.6, 67.4, 54.7, 53.2, 52.6, 38.1. Anal. calcd for
C32H32N2O3: C, 78.02; H, 6.55; N, 5.69. Found: C, 78.06;
H, 6.65; N, 5.65.
4.2.12. (S)-N-[(R)-a-Phenyl-N,N-(dibenzyl)glycinyl]
lysine(N-carbonyloxybenzyl) methyl ester (2l). A color-
less oil was obtained in 91% yield. 1H NMR (CDCl3,
400 MHz) 7.88 (d, J¼8.4 Hz, 1H), 7.40–7.22 (m, 20H),
5.04 (s, 2H), 4.68 (m, 1H), 4.44 (s, 1H), 3.88 (d, J¼13.6 Hz,
2H), 3.74 (s, 3H), 3.27 (d, J¼13.6 Hz, 2H), 3.08 (m, 2H),
1.91 (m, 1H), 1.70 (m, 1H), 1.46 (m, 2H), 1.24 (m, 2H); 13C
NMR (CDCl3, 100 MHz) 173.1, 171.8, 156.8, 139.0, 137.0,
133.9, 130.9, 129.3, 129.0, 128.9, 128.5, 128.4, 128.3,
127.8, 67.6, 66.9, 54.9, 52.8, 52.2, 41.1, 32.4, 29.7, 22.8.
Anal. calcd for C37H41N2O5: C, 73.12; H, 6.80; N, 6.91.
Found: C, 73.11; H, 6.67; N, 7.02.
4.2.7. (S)-N-[(R)-a-Phenyl-N,N-(dibenzyl)glycinyl]
tryptophan methyl ester (2g). A colorless oil was obtained
in 98% yield. 1H NMR (CDCl3, 400 MHz) 8.2 (br, 1H), 7.84
(d, J¼8.0 Hz, 1H), 7.56–7.07 (m, 20H), 6.81 (s, 1H), 5.04
(m,1H), 4.38 (s, 1H), 3.82 (d, J¼13.6 Hz, 2H), 3.64 (s, 3H),
3.39 (m, 2H), 3.13 (d, J¼13.6 Hz, 2H); 13C NMR (CDCl3,
100 MHz) 173.0, 172.0, 138.9, 136.7, 133.5, 131.2, 129.2,
128.8, 128.4, 128.2, 127.8, 127.6, 123.3, 122.7, 120.1,
119.0, 111.7, 110.2, 67.6, 54.8, 52.9, 52.7, 27.9. Anal. calcd
for C34H33N3O3: C, 76.81; H, 6.26; N, 7.90. Found: C,
76.79; H, 6.19; N, 7.69.
4.2.13. (S)-N-[(R)-a-Phenyl-N,N-(dibenzyl)glycinyl]
serine(O-benzyl) methyl ester (2m). A colorless oil was
obtained in 50% yield. 1H NMR (CDCl3, 400 MHz) 8.35 (d,
J¼8.4 Hz, 1H), 7.39–7.19 (m, 20H), 4.84 (m, 1H), 4.58 (s,
2H), 4.45 (s, 1H), 4.03 (m, 1H), 3.95 (d, J¼13.6 Hz, 2H),
3.72 (m, 4H), 3.22 (d, J¼13.6 Hz, 2H); 13C NMR (CDCl3,
100 MHz) 172.0, 171.2, 139.0, 137.9, 133.6, 131.2, 129.4,
128.9, 128.8, 128.5, 128.4, 128.3, 128.1, 127.7, 73.9, 70.2,
67.6, 54.9, 52.9. Anal. calcd for C33H34N2O3: C, 75.84; H,
6.56; N, 5.36. Found: C, 75.91; H, 6.62; N, 5.34.
4.2.8. (S)-N-[(R)-a-Phenyl-N,N-(dibenzyl)glycinyl]
phenylglycine methyl ester (2h). A colorless oil was
1
obtained in 52% yield. H NMR (CDCl3, 400 MHz) 8.33
(m, 1H), 7.45–7.22 (m, 20H), 5.62 (m, 1H), 4.44 (s, 1H),
3.94 (d, J¼13.6 Hz, 2H), 3.74 (m, 3H), 3.27 (d, J¼13.6 Hz,
2H); 13C NMR (CDCl3, 100 MHz) 171.7, 171.5, 139.0,
137.3, 133.7, 131.0, 129.3, 129.2, 129.1, 129.0, 128.9,
128.6, 128.3, 127.7, 67.6, 57.0, 55.0, 53.2. Anal. calcd for
C31H30N2O3: C, 77.80; H, 6.32; N, 5.85. Found: C, 77.71;
H, 6.39; N, 5.73.
4.2.14. (S)-N-[(R)-a-Phenyl-N,N-(dibenzyl)glycinyl]
cysteine(S-benzyl) methyl ester (2n). A colorless oil was
obtained in 57% yield. 1H NMR (CDCl3, 400 MHz) 8.32 (d,
J¼7.2 Hz, 1H), 7.68–7.22 (m, 20H), 4.92 (m, 1H), 4.46 (s,
1H), 3.90 (d, J¼13.6 Hz, 2H), 3.69 (m, 5H), 3.26 (d,
J¼13.6 Hz, 2H), 2.91 (m, 2H); 13C NMR (CDCl3,
100 MHz) 171.9, 171.7, 138.9, 137.9, 131.6, 131.1, 129.4,
129.2, 129.0, 128.9, 128.6, 128.3, 128.0, 127.7, 67.6,
55.0, 53.0, 51.6, 36.9, 33.8. Anal. calcd for C33H34N2O3S:
C, 73.58; H, 6.36; N, 5.20. Found: C, 73.35; H, 6.34; N,
5.06.
4.2.9. (S)-N-[(R)-a-Phenyl-N,N-(dibenzyl)glycinyl]
tyrosine methyl ester (2i). A colorless oil was obtained
in 77% yield. 1H NMR (CDCl3, 400 MHz) 7.84 (d,
J¼8.4 Hz, 1H), 7.38–7.20 (m, 15H), 6.95 (d, J¼8.2 Hz,
2H), 6.73 (d, J¼8.2 Hz, 2H), 5.72 (br, 1H), 4.95 (m, 1H),
3.84 (d, J¼13.6 Hz, 2H), 3.69 (s, 3H), 3.09 (m, 4H); 13C
NMR (CDCl3, 100 MHz) 172.5, 172.1, 155.6, 138.7, 133.0,
131.2, 130.8, 129.2, 128.9, 128.4, 128.3, 127.8, 127.7,
116.1, 67.5, 54.7, 53.3, 52.7, 37.3. Anal. calcd for
C32H32N2O4: C, 75.57; H, 6.34; N, 5.51. Found: C, 75.53;
H, 6.42; N, 5.40.
4.2.15. (S)-N-[(R)-a-Phenyl-N,N-(dibenzyl)glycinyl]
leucine benzyl ester (4). A colorless oil was obtained in
97% yield. 1H NMR (CDCl3, 400 MHz) 7.79 (d, J¼8.4 Hz,
1H), 7.38–7.22 (m, 20H), 5.18 (m, 2H), 4.73 (m, 1H), 4.43
(s, 1H), 3.87 (d, J¼13.6 Hz, 2H), 3.21 (d, J¼13.6 Hz, 2H),
1.74 (m, 1H), 1.61 (m, 2H), 0.92 (m, 6H); 13C NMR
(CDCl3, 100 MHz) 173.1, 171.8, 139.0, 135.8, 133.7, 131.0,
129.2, 129.0, 128.8, 128.6, 128.5, 128.2, 127.7, 67.5, 54.9,
51.2, 41.9, 25.4, 23.3, 22.2. Anal. calcd for C35H38N2O3: C,
78.62; H, 7.16; N, 5.24. Found: C, 78.83; H, 7.26; N, 4.90.
The absolute configurations of two epimers of 4 were
confirmed by comparison of Chiral-HPLC retention time
with authentic material individually prepared from the
coupling of L-leucine derivative and (S)- or (R)-phenyl-
glycine derivative using racemic material as a standard.
[Chiralcel OD column; 5% 2-propanol in hexane; 0.5 mL/
min; (aR)-epimer had a retention time of 14.8 min, (aS)-
epimer had a retention time of 14.1 min].
4.2.10. (S)-N-[(R)-a-Phenyl-N,N-(dibenzyl)glycinyl]
aspartic acid dimethyl ester (2j). A colorless oil was
1
obtained in 86% yield. H NMR (CDCl3, 400 MHz, two
diastereomers) 8.51 (d, J¼8.8 Hz, 1H), 7.44–7.24 (m, 15H),
4.99 (m, 1H), 4.42 (s, 1H), 3.92 (d, J¼13.6 Hz, 2H), 3.74 (s,
3H), 3.69 (s, 3H), 3.28 (d, J¼13.6 Hz, 2H), 3.11 (m, 1H),
2.82 (m, 1H); 13C NMR (CDCl3, 100 MHz) 173.1, 171.8,
156.8, 139.0, 137.0, 133.8, 130.9, 129.3, 129.0, 128.9,
128.5, 128.4, 128.3, 127.8, 67.6, 67.9, 54.9, 52.8, 52.2, 32.4.
Anal. calcd for C28H30N2O5: C, 70.87; H, 6.37; N, 5.90.
Found: C, 70.81; H, 6.40; N, 5.71.
4.2.11. (S)-N-[(R)-a-Phenyl-N,N-(dibenzyl)glycinyl]
glutamic acid dimethyl ester (2k). A colorless oil was

6318
J. Nam et al. / Tetrahedron 60 (2004) 6311–6318
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. (h) Kubo, A.; Kubota, H.;
Takahashi, M.; Nunami, K. J. Org. Chem. 1997, 62, 5830.
(i) Ward, R. S.; Pelter, A.; Goubet, D.; Pritchard, M. C.
Tetrahedron: Asymmetry 1995, 6, 469.
4.3. General procedure for deprotection of N,N-dibenzyl
group
To a solution of dibenzyl ester (1 equiv.) and (Boc)2O
(2 equiv.) in absolute ethanol under an N2 gas atmosphere
was added 10% Pd–C followed by 1,4-cyclohexadiene
(20 equiv.); 7 days later, the mixture was filtered through
Celite and concentrated to provide the product after column
chromatography on silica gel.
2. For reviews on stereoselective modification of peptides, see:
(a) Nandy, J. P.; Prabhakaran, E. N.; Kumar, S. K.; Kunwar,
A. C.; Iqbal, J. J. Org. Chem. 2003, 68, 1679. (b) Miyashita,
K.; Iwaki, H.; Tai, K.; Murafuji, H.; Sasaki, N.; Imanishi, T.
Tetrahedron 2001, 57, 5773. (c) Ricci, M.; Blakskjær, P.;
Skrydstrup, T. J. Am. Chem. Soc. 2000, 122, 12413.
(d) Kazmaier, U.; Maier, S. Chem. Commun. 1998, 2535.
(e) Lenman, M. M.; Ingham, S. L.; Gani, D. Chem. Commun.
1996, 85. (f) D’Angeli, F.; Marchetti, P.; Bertolasi, V. J. Org.
Chem. 1995, 60, 4013. (g) Bossler, H. G.; Waldmeier, P.;
Seebach, D. Angew. Chem. Int. Ed. 1994, 33, 439.
4.3.1. (S)-N-[(R)-a-Phenyl-N-(tert-butoxycarbonyl)-
glycinyl] leucine methyl ester (6). A colorless oil was
1
obtained in 57% yield. H NMR (CDCl3, 400 MHz) 7.38–
7.27 (m, 5H), 6.42 (d, J¼8.2 Hz, 1H), 5,80 (br, 1H), 5.20
(br, 1H), 4.58 (m, 1H), 3.72 (s, 3H), 1.20–1.65 (m, 3H),
1.40 (s, 9H), 0.76 (m, 6H); 13C NMR (CDCl3, 100 MHz)
173.6, 170.3, 155.3, 138.8, 129.3, 128.7, 127.6, 80.5, 52.7,
51.2, 41.5, 28.6, 25.1, 23.0, 21.9. The spectral data of 6 were
identical to those of the authentic material reported
previously.10
3. Nam, J.; Chang, J.-Y.; Hahm, K.-S.; Park, Y. S. Tetrahedron
Lett. 2003, 44, 7727.
4. The low selectivities in the absence of TBAI observed in
entries 10 and 11, Table 2 suggest the possibility that the
leaving group in the nucleophilic substitution in the presence
of TBAI is iodide rather than bromide. Further mechanistic
investigation for details of the process is underway.
5. Calculations are performed with a semiempirical approxi-
mation using AM1. The software used was Spartan 5.1,
wavefunction, Inc.
4.3.2. (S)-N-[(R)-a-(p-Fluorophenyl)-N-(tert-butoxy-
carbonyl)glycinyl] leucine methyl ester (7). A colorless
oil was obtained in 32% yield. 1H NMR (CDCl3, 400 MHz)
7.35 (m, 2H), 7.03 (m, 2H), 6.14 (d, J¼8.4 Hz, 1H), 5.68
(br, 1H), 5.12 (br, 1H), 4.61 (m, 1H), 3.73 (s, 3H), 1.60–
1.32 (m, 3H), 1.41 (s, 9H), 0.81 (d, J¼6.4 Hz, 6H); 13C
NMR (CDCl3, 100 MHz) 173.4, 169.9, 155.3, 135.0, 129.5,
116.5, 116.2, 78.0, 52.8, 51.2, 41.6, 28.6, 25.0, 23.0, 22.0.
[a]D¼276.4 (c¼0.021, CHCl3). HRMS calcd for
C20H29FN2O5: 396.2061. Found: 396.2045. The absolute
configuration of dipeptide analogue 7 is provisionally
assigned to aR by analogy to the formation of (aR)-6.
6. When nucleophiles such as benzylthiol, tritylthiol, sodium
malonate, sodium azide, potassium acetate, potassium thio-
acetate and potassium phthalate were used for the reaction
with 1b, the corresponding substitution products were
obtained in 17–88% yields with diastereomeric ratios from
51:49 to 55:45.
7. (a) Bajwa, J. S. Tetrahedron Lett. 1992, 33, 2955. (b) Tao, J.;
Hoffman, R. V. J. Org. Chem. 1997, 62, 6240.
8. (a) Khimiuk, A. Y.; Korennykh, A. V.; Langen, L. M.;
Acknowledgements
ˇ
Rantwijk, F.; Sheldon, R. A.; Svedas, V. K. Tetrahedron:
This paper was supported by a grant from Molecular and
Cellular BioDiscovery Research Program (M1-0311-13-
0003) from the Ministry of Science and Technology, Korea.
Asymmetry 2003, 14, 3123. (b) Langen, L. M.; Rantwijk, F.;
ˇ
Svedas, V. K.; Sheldon, R. A. Tetrahedron: Asymmetry 2000,
11, 1077. and references therein.
9. This study has also shown some limitation of the method, as it
cannot be extended to a-bromo a-alkyl acetamides success-
fully. The substitution reactions of a-bromo a-methyl
acetamides derived from various L-amino acids are generally
very slow and showed lower stereoselectivities (ca. 80:20 dr)
under the same reaction condition. All tested reactions of
a-bromo a-ethyl acetamides gave very poor yields and
selectivities.
References and notes
1. (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.;
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4669.