Asymmetric synthesis of 3,4,6-trisubstituted 2,5-diketopiperazines by using dynamic kinetic resolution of α-bromo tertiary acetamides

Article abstract of DOI:10.1002/ejoc.201301936

A new and efficient method for the asymmetric synthesis of 3,4,6-trisubstituted 2,5-diketopiperazines has been developed. The dynamic kinetic resolution of L-amino-acid-derived α-bromo tertiary amides in the nucleophilic substitution reaction with p-anisi

Full text of DOI:10.1002/ejoc.201301936

FULL PAPER
DOI: 10.1002/ejoc.201301936
Asymmetric Synthesis of 3,4,6-Trisubstituted 2,5-Diketopiperazines by Using
Dynamic Kinetic Resolution of α-Bromo Tertiary Acetamides
Jinho Baek,[a] Seock Yong Kang,[a] Chan Im,[a] and Yong Sun Park*[a]
Keywords: Synthetic methods / Asymmetric synthesis / Amino acids / Peptidomimetics / Chirality
A new and efficient method for the asymmetric synthesis of
3,4,6-trisubstituted 2,5-diketopiperazines has been devel-
clization process provides rapid access to diverse cis-2,5-di-
ketopiperazines 5a–5o and proline-containing trans-2,5-di-
oped. The dynamic kinetic resolution of
L-amino-acid-de- ketopiperazines 5p–5t in enantiomerically pure form in 45–
rived α-bromo tertiary amides in the nucleophilic substitution
reaction with p-anisidine and a subsequent deprotection-cy-
67% overall yields.
H), cyclization of the dipeptide is not a trivial task, and
careful selection of reaction conditions is required to pre-
vent undesirable epimerization and degradation reactions.[3]
This is attributed to a high preference for the thermo-
dynamically stable trans-amide rotamer that cannot un-
dergo an intramolecular reaction. However, cyclization of a
dipeptide containing a tertiary amide linkage was relatively
easy, presumably because of the presence of a substantial
amount of the required cis-amide rotamer.[4] The introduc-
tion of a R1 substituent prior to cyclization may facilitate
the intramolecular cyclization of the dipeptide under mild
reaction conditions. In the next step of the strategy (Fig-
ure 1, Step B), the N-alkyl-substituted (R1) dipeptide can be
obtained by asymmetric nucleophilic substitution reaction
of l-amino-acid-derived α-bromo tertiary acetamide with
an amine nucleophile.
Introduction
2,5-Diketopiperazines are the smallest cyclic peptides
prepared by the cyclization of two α-amino acids. Their
characteristic backbone is common in many natural prod-
ucts and in pharmacologically active compounds with a
wide range of biological activities.[1] They are small, confor-
mationally constrained heterocyclic scaffolds in which di-
versity can be introduced at up to four positions. The vari-
ety of substituents arranged in a well-defined spatial man-
ner makes them interesting scaffolds for drug design and
peptide chemistry.[2] Thus, the development of synthetic
methods for highly enantioenriched unnatural α-amino ac-
ids and regioselective alkylation on the lactam nitrogens is
highly desirable for extending the diversity of the substitu-
ents of 2,5-diketopiperazines.
Herein, we have developed a new and mild procedure
for the asymmetric preparation of 3,4,6-trisubstituted 2,5-
diketopiperazines from unnatural dipeptide derivatives. The
dipeptide derivatives were easily prepared by dynamic ki-
netic resolution in the nucleophilic substitution reactions
of N-alkyl-N-(α-bromoacetyl)-l-amino acids with an amine
nucleophile. Because various α-bromo carboxylic acid de-
rivatives can be easily obtained in racemic form and their
configurational lability can be readily induced, the dynamic
kinetic resolution process is quite general for the asymmet-
ric preparation of unnatural dipeptides.
Figure 1. Retrosynthesis of 3,4,6-trisubstituted 2,5-diketopiperaz-
ines.
Our strategy to construct the 3,4,6-trisubstituted 2,5-di-
ketopiperazines involves the intramolecular amide forma-
tion of an N-alkyl-substituted (R1) dipeptide as illustrated
retrosynthetically in Figure 1, Step A. In the case of second-
ary amides with no substituent at the amide nitrogen (R1 =
Results and Discussion
We previously reported that l-amino acids are efficient
precursors for the asymmetric synthesis of dipeptide ana-
logues through dynamic kinetic resolution in nucleophilic
substitution reactions.[5] As shown in Scheme 1, the reac-
tion of a diastereomeric mixture (1:1) of N-(α-bromo-α-
phenylacetyl)-l-alanine methyl ester (1) with dibenzylamine
(Bn2NH), tetrabutylammonium iodide (TBAI) and diiso-
propylethylamine (DIEA) afforded d-Phg-l-Ala dipeptide
[a] Department of Chemistry and KFnSC, Konkuk University,
120 Neungdong-ro, Gwangjin-gu, Seoul, 143-701, Korea
E-mail: parkyong@konkuk.ac.kr
http://konkuk.ac.kr/~parkyong/lab.htm
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301936.
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Asymmetric Synthesis of 3,4,6-Trisubstituted 2,5-Diketopiperazines
analogue 2 in a 89:11 diastereomeric ratio (dr).[5a] Thus, the
chiral information was transferred from l-alanine to the α-
bromo carbon center through dynamic kinetic resolution in
the nucleophilic substitution reaction of 1 with Bn2NH.
Figure 2. Proposed transition-state structures for the substitution
reactions.
eclipses the plane of the amide group as shown in Figure 2.
With the shown conformational alignment, nucleophilic at-
tack of the amine could be promoted through hydrogen
bonding to the basic oxygen atom of the ester, thus ex-
plaining the αR-product formation from secondary amide
1 and the αS-product formation from tertiary amide 3.
Next, the one-pot hydrogenolytic removal of the N-benzyl
group of 4 followed by cyclization under basic conditions
(EtOAc/NaHCO3 biphasic system) afforded 3,4,6-trisubsti-
tuted 2,5-diketopiperazine (5a), a cis-diketopiperazine with
Scheme 1. Asymmetric nucleophilic substitution with dibenzyl-
amine.
To evaluate the effect of the N-alkyl group (R1) on the 90:10 dr in 85% yield with no evidence of epimerization.[9]
substitution reaction, we first carried out the reaction of N- The absolute configuration of the C-6 position of 5a was
1
benzyl-N-(α-bromo-α-phenylacetyl)-l-alanine methyl ester determined by analysis of the H NMR spectrum of the
(3).[6] An interesting result was obtained when 3 (≈ 50:50 authentic epimer prepared from commercially available l-
dr) was subjected to the same reaction conditions as for 1. alanine and (S)-phenylglycine.
The N-benzyl group led to the reversal of product configu-
We then screened several amine nucleophiles and found
ration to afford (αS)-4 as the major product, with a stereo- that p-anisidine gave the best stereoselectivity in the nucleo-
selectivity of 90:10 dr in 75% yield (Scheme 1). Inspection philic substitution reactions of 3. p-Anisidine produced di-
1
of the H NMR (CDCl3) spectrum of N-benzyl-substituted peptide analogue 12a with a much higher dr of 97:3 relative
3 revealed a 1:1 mixture of amide rotamers in solution. It to the substitution of 3 with dibenzylamine nucleophile
is speculated that a substantial amount of the cis-amide rot- (Table 1, Entry 1). Encouraged by the high stereoselectivity
amer can change the major transition-state structure and in the reaction of 3 with p-anisidine, we examined seven
induce reversal of configuration.[7] Based on previous mech- different
N-alkyl-N-(α-bromo-α-phenylacetyl)-l-alanine
anistic studies of analogous reaction systems,[8] we propose methyl esters 6–11 to study the effect of the N-substituent
two transition-state structures in which the phenyl group on the stereochemical outcome. The reaction of 6 and 7
adopts a cis conformation relative to the carbonyl group with p-anisidine (1.2 equiv.), TBAI (1.0 equiv.) and DIEA
and the hydrogen atom at the α-position of alanine nearly (1.0 equiv.) in CH3CN for 20 h at room temperature af-
Table 1. Nucleophilic substitutions reactions of N-alkyl-substituted (R1) α-bromo tertiary acetamides.
Entry[a]
Substrate
R1
Product
Yield [%][b]
dr (αS/αR)[c]
1
2
3
4
5
6
7
8
9
3
PhCH2
12a
12b
12c
12d
12e
12f
12g
12a
12a
12a
73
75
70
64
82
85
80
77
74
93
97:3
96:4
92:8
84:16
82:18
78:22
51:49
97:3
6
p-Br–PhCH2
PhCH=CHCH2
CH3CH2CH2CH2
EtO2CCH2CH2CH2
HCϵCCH2
tBuO2CCH2
PhCH2
7
8
9
10
11
3 (72:28)
3 (32:68)
12a (92:8)
PhCH2
PhCH2
97:3
92:8
10
[a] All the reactions were carried out in CH3CN at room temp. for 20 h. [b] Isolated yields. [c] The dr values were determined from the
1H NMR spectroscopic data of the reaction mixtures.
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J. Baek, S. Y. Kang, C. Im, Y. S. Park
FULL PAPER
forded N-(p-bromobenzyl) substituted 12b and N-(trans- starting dr of 3. As shown in Table 1, Entry 10, the configu-
cinnamyl)-substituted 12c in good yields, with 96:4 dr and rational stability of 12a under the reaction conditions was
92:8 dr, respectively (Table 1, Entries 2 and 3). Moderate examined by the reaction of 12a (92:8 dr) with p-anisidine,
stereoselectivities were obtained in the reactions of 8, 9 and TBAI and DIEA in CH3CN for 20 h. No epimerization was
10 (Table 1, Entries 4–6). The reactions of N-butyl-substi- detected by 1H NMR spectroscopy, thus eliminating the
tuted 8, N-(3-ethoxycarbonyl)propyl-substituted 9 and N- possibility of epimerization after replacement of Br with p-
propargyl-substituted 10 afforded the corresponding di- anisidine in the nucleophilic substitution reaction. These
peptide analogues 12d–12f with stereoselectivities of 84:16, preliminary results indicate that the epimerization pro-
82:18 and 78:22 dr, respectively. Interestingly, no stereose- moted by TBAI and DIEA is sufficiently fast with respect
lectivity was observed for the reaction of N-(tert-butoxycar- to the rate of substitution. The primary pathway of the
bonyl)methyl-substituted 11. (Table 1, Entry 7) The brief asymmetric induction is a dynamic kinetic resolution in
survey of the N-substituents (R1) indicates that subtle N- which the product dr is determined by the difference in the
alkyl group modifications can lead to substantial variations diastereomeric transition-state energies for the substitution
in stereoselectivity. The results shown in Table 1, Entries 1– reaction.[5]
6 suggest that the steric bulk of the N-alkyl group is an
The initial studies on the cyclization of N-p-meth-
important factor in determining the stereoselectivity. α- oxyphenyl (PMP)-substituted dipeptide were carried out
Bromo tertiary acetamide 11 contains two ester groups that with tertiary amide 12a as shown in Table 2. The cleavage
are capable of hydrogen bonding to facilitate the delivery of the N-PMP group of 12a (97:3 dr) was easily achieved
of the amine nucleophile. The two competing hydrogen- through oxidative removal with trichloroisocyanuric acid
bonding interactions with p-anisidine in the substitution re- (TCCA) in CH3CN/H2O to afford the deprotected dipept-
action produce nearly equal amounts of epimers to give ide.[10] As shown in Scheme 1, the deprotected amino group
51:49 dr as shown in Table 1, Entry 7.[8]
spontaneously attacked the ester functionality under the
To better understand the source of asymmetric induction basic reaction conditions (EtOAc/NaHCO3 biphasic sys-
in the nucleophilic substitution reactions of α-bromo terti- tem) to form diketopiperazine 5a with 97:3 dr.[9] After puri-
ary acetamides, we carried out a series of reactions as fication by silica gel column chromatography, dia-
shown in Table 1, Entries 8–10. The reaction of 3 (72:28 dr) stereomerically pure cis-diketopiperazine 5a was easily iso-
with p-anisidine in the presence of TBAI and DIEA af- lated in 76% yield. (55% overall yield from 3; Table 2, En-
forded 12a with 97:3 dr (Table 1, Entry 8). In addition, 12a try 1) The cis-configuration indicates that nucleophilic sub-
with the same dr was obtained in the reaction of 3 with stitution with p-anisidine afforded (S)-phenylglycine as for
reversed diastereomeric enrichment 32:68 dr. (Table 1, En- the reaction of 3 with Bn2NH. Furthermore, oxidative de-
try 9) Thus, the dr of product 12a is independent of the protection and cyclization of N-p-bromobenzyl-substituted
Table 2. Asymmetric synthesis of 3,4,6-trisubstituted 2,5-diketopiperazines.
Entry[a]
Substrate R1
R2
R3
dr of substitution[b] (αS/αR)
Product
Overall
yield [%][c]
1
3
PhCH2
p-Br–PhCH2
PhCH=CHCH2 CH3
CH3
CH3
Ph
Ph
Ph
Ph
Ph
Ph
97:3
96:4
92:8
99:1
94:6
96:4
99:1
94:6
95:5
91:9
91:9
85:15
87:13
77:23
72:28
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
55
55
52
66
51
56
55
64
60
49
63
54
45
52
47
2
6
3d
4
7
13
14
15
16
17
18
19
20
21
22
23
24
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
CH2Ph
CH2CH(CH3)2
CH2CO2CH3
5
6
7
8
CH2CH2CO2CH3 Ph
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
p-F–Ph
p-Cl–Ph
p-Br–Ph
p-MeO–Ph
CH3
CH3CH2
CH3(CH2)2CH2
CH3(CH2)4CH2
9
10
11
12
13
14
15
[a] All the substitution reactions were carried out in CH3CN at room temp. [b] The dr values were determined from the 1H NMR
spectroscopic data of the reaction mixtures. [c] Isolated yields after two steps. [d] Ceric ammonium nitrate was used for N-PMP group
deprotection.
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Asymmetric Synthesis of 3,4,6-Trisubstituted 2,5-Diketopiperazines
tertiary amide 12b and N-cinnamyl-substituted tertiary tions of α-bromo acetamides 21–24 bearing α-methyl, α-
amide 12c afforded diastereomerically pure 3,4,6-trisubsti- ethyl, α-butyl and α-hexyl substituents afforded the corre-
tuted 2,5-diketopiperazines 5b and 5c in 73% and 74% sponding products with lower dr values ranging from 87:13
yields, respectively. (55% and 52% overall yields; Table 2, to 72:28. However, after the deprotection-cyclization pro-
Entries 2 and 3) The results indicate that the cyclization effi- cess, useful yields of diastereomerically pure cis-diketopip-
ciency is independent of the nature of the N-substituents erazines 5l–5o were obtained from 21–24, respectively.[11]
(R1) and the two diastereomers of diketopiperazines can be
easily separated and isolated in a diastereomerically pure the preparation of l-proline-derived 2,5-diketopiperazines
form by using column chromatography. with high selectivities and good yields as shown in Table 3.
Finally, this methodology is also shown to be efficient for
In an effort to establish the generality of the synthetic l-Proline-derived 2,5-diketopiperazines may be used as ver-
methodology, the substrate scope of the dynamic kinetic satile intermediates not only for the sequential asymmetric
resolution in nucleophilic substitution was examined with preparation of unnatural peptides but also for the asymmet-
four different l-amino acid precursors. The substitution re- ric preparation of a variety of chiral ligands and auxilia-
actions of N-benzyl-substituted α-bromo acetamides 13–16 ries.[12,13] The reaction of N-(α-bromo-α-phenylacetyl)-l-
derived from l-phenylalanine, l-leucine, l-aspartic acid and proline methyl ester (25) with p-anisidine as the nucleophile
l-glutamic acid were investigated as shown in Table 2, En- afforded the corresponding dipeptide analogue with 99:1 dr.
tries 4–7. The reaction of l-Phe-derived α-bromo acetamide In contrast to the formation of cis-diketopiperazines from
13 with p-anisidine, TBAI and DIEA gave the correspond- N-benzyl-substituted α-bromo acetamides, trans-diketopip-
ing dipeptide analogue with a 99:1 dr. Following N-PMP erazine 5p was obtained in 60% overall yield from 25.[14]
group deprotection with TCCA and cyclization dia- Furthermore, the reactions of α-bromo acetamides 26–29
stereomerically pure diketopiperazine 5d was afforded in bearing p-methoxyphenyl, p-chlorophenyl, methyl and ethyl
66% overall yield for two steps (Table 2, Entry 4) Although groups, respectively, also afforded the corresponding prod-
the substitution of l-Glu-derived α-bromo acetamide 17 ucts with high stereoselectivities, and the subsequent depro-
showed a high dr of 99:1, lower selectivities were observed tection-cyclization afforded trans-diketopiperazines 5q–5t in
with l-Leu and l-Asp-derived α-bromo acetamides 14 and 49–67% overall yields, respectively. (Table 3, Entries 2–5)
15 (Table 2, Entries 5–7) In all cases, diastereomerically The trans-configuration of diketopiperazines 5p and 5s was
pure diketopiperazines 5d–5g were obtained after the de- assigned by analysis of the 1H NMR spectra with authentic
protection-cyclization process in 51–66% overall yields epimers.[4a,15]
from 13–16, respectively. Next, we studied the effect of the
R3 substituents on the stereoselectivity of the substitution
reaction (Table 2, Entries 8–15). The initial studies were
carried out with various aromatic substituents such as p-
Conclusions
fluorophenyl, p-chlorophenyl, p-bromophenyl, and p-meth-
We have developed a general and efficient method for the
oxyphenyl groups. The reactions of α-bromo acetamides asymmetric synthesis of 3,4,6-trisubstituted 2,5-diketopip-
17–20 with p-anisidine, TBAI and DIEA gave the corre- erazines. The dynamic kinetic resolution of l-amino-acid-
sponding products with dr values ranging from 95:5 to 91:9. derived α-bromo tertiary acetamides in the nucleophilic
No clear trend was observed that relates electronic effect of substitution with p-anisidine afforded the corresponding
the substituents to dr and yield of the reaction. The sub- highly diastereoenriched dipeptide analogues, and subse-
strate scope of the dynamic kinetic resolution was also ex- quent deprotection and cyclization produced 2,5-diketopip-
amined with aliphatic alkyl groups under identical reaction erazines. Starting from N-benzyl-substituted α-bromo terti-
conditions. As shown in Table 2, Entries 12–15, the reac- ary amides, cis-configured 2,5-diketopiperazines were selec-
Table 3. Synthesis of l-proline-derived 3,4,6-trisubstituted 2,5-diketopiperazines.
Entry[a]
Substrate
R3
dr of substitution[d] (αR/αS)
Product
Overall yield [%][c]
1
2
3
4
5
25
26
27
28
29
Ph
99:1
99:1
99:1
85:15
86:14
5p
5q
5r
5s
5t
60
67
57
49
55
p-MeO-Ph
p-Cl-Ph
CH3
CH3CH2
[a] All the substitution reactions were carried out in CH3CN at room temp. [b] The dr values were determined from the 1H NMR
spectroscopic data of the reaction mixtures. [c] Isolated yields after two steps.
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J. Baek, S. Y. Kang, C. Im, Y. S. Park
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N-(α-Bromo-α-phenylacetyl)-N-butyl-(S)-alanine Methyl Ester (8):
1H NMR (CDCl3, 400 MHz, two rotamers of a diastereomer): δ =
7.54–7.28 (m, 5 H), 5.71, 5.67 (s, 1 H), 4.40, 4.22 (q, J = 7.2 Hz, 1
H), 3.69, 3.67 (s, 3 H), 3.40–3.22 (m, 2 H), 1.46, 1.42 (d, 3 H), 1.30
(m, 4 H), 0.90 (m, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ =
171.6, 166.9, 136.4, 129.0, 128.8, 128.5, 55.8, 52.2, 48.5, 47.4, 31.9,
20.4, 14.6, 13.7 ppm. C16H22BrNO3 (356.26): calcd. C 53.94, H
6.22, N 3.93; found C 53.78, H 6.49, N 3.79.
tively synthesized, whereas trans-configured 2,5-diketopip-
erazines were selectively formed from l-proline-derived α-
bromo acetamides. This synthetic methodology takes ad-
vantage of the existing structure and provides rapid access
to highly functionalized 2,5-diketopiperazines in enantio-
merically pure form. This simple and convenient synthetic
method may be amenable to combinatorial synthesis of 2,5-
diketopiperazines to produce sizeable libraries.
N-(α-Bromo-α-phenylacetyl)-N-(3-ethoxycarbonylpropyl)-(S)-
alanine Methyl Ester (9): 1H NMR (CDCl3, 400 MHz, two rota-
mers of a diastereomer): δ = 7.61–7.28 (m, 5 H), 5.96, 5.89 (s, 1
H), 4.46, 4.34 (q, J = 7.2 Hz, 1 H), 4.18 (q, J = 6.8 Hz, 2 H), 3.68
(s, 3 H), 3.52–3.21 (m, 2 H), 2.35 (m, 2 H), 2.04–1.72 (m, 2 H),
1.50, 1.47 (d, J = 6.8 Hz, 3 H), 1.30 (t, J = 6.4 Hz, 3 H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 172.7, 171.5, 167.5, 136.4, 129.1,
128.9, 128.8, 60.9, 55.8, 52.4, 46.9, 45.9, 30.5, 25.1, 14.6, 14.3 ppm.
C18H24BrNO5 (414.30): calcd. C 52.18, H 5.84, N 3.38; found C
52.32, H 6.01, N 3.66.
Experimental Section
General Methods: All reactions were performed in oven-dried glass-
ware under a nitrogen atmosphere. All chemicals were obtained
from commercial sources and were used as received. Analytical thin
layer chromatography was performed on silica gel plates with QF-
254 indicator and visualization was carried out with UV-light.
Flash column chromatography was performed with 230–400 mesh
1
silica gel. H and 13C NMR spectra were acquired with a Bruker
N-(α-Bromo-α-phenylacetyl)-N-propargyl-(S)-alanine Methyl Ester
(10): 1H NMR (CDCl3, 400 MHz, two rotamers of a diastereomer):
δ = 7.61–7.27 (m, 5 H), 6.00, 5.83 (s, 1 H), 5.11, 5.00 (q, J = 7.2 Hz,
1 H), 4.36–3.92 (m, 2 H), 3.76, 3.67 (s, 3 H), 2.42 (m, 1 H), 1.51
(d, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 171.7, 167.6,
135.7, 129.4, 129.1, 128.6, 128.3, 79.1, 73.8, 57.1, 54.0, 52.4, 45.1,
35.6, 14.7 ppm. C15H16BrNO3 (338.20): calcd. C 53.27, H 4.77, N
4.14; found C 53.44, H 5.03, N 4.40.
(400 MHz 1H, 100.6 MHz 13C) spectrometer. Chemical shifts (δ)
are reported in ppm relative to CDCl3 (δ = 7.26 ppm 1H, 77.07 ppm
13C) as internal standard. Multiplicities are indicated by: s (singlet),
d (doublet), t (triplet), q (quartet) and br. (broad). HRMS spectra
were measured with a JEOL JMS-700 instrument by using FAB
techniques.
General Procedure for the Preparation of Two Diastereomeric Mix-
ture of α-Bromo Tertiary Amides 3, 6–11 and 13–29: N-Alkyl-l-
amino acid methyl ester (1.0 equiv.), racemic α-substituted α-bromo
acetyl chloride (1.0 equiv.) and Et3N (1.1 equiv.) were dissolved in
CH2Cl2 and stirred at room temperature. The resulting reaction
mixture was stirred at room temperature for 3 h, before the mixture
was treated with extractive work up and the organic phase was
dried with MgSO4. Filtration and concentration provided the crude
product that was purified by column chromatography on silica gel.
A 1:1 mixture of two diastereomers was obtained in 53–41% yields.
No further attempts were made to optimize the yields.
N-(α-Bromo-α-phenylacetyl)-N-(tert-butoxycarbonylmethyl)-(S)-
alanine Methyl Ester (11): H NMR (CDCl3, 400 MHz, two rota-
1
mers of a diastereomer): δ = 7.58–7.30 (m, 5 H), 5.63, 5.46 (s, 1
H), 5.10 (m, 1 H), 4.34–4.24 (m, 1 H), 3.97–3.92 (m, 1 H), 3.71,
3.64 (s, 3 H), 1.51, 1.50 (s, 9 H), 1.41, 1.38 (d, J = 7.6 Hz, 3 H) ppm.
13C NMR (CDCl3, 100 MHz): δ = 171.8, 168.5, 167.8, 135.6, 129.3,
129.0, 128.8, 83.0, 55.5, 52.3, 48.4, 45.2, 27.9, 14.6 ppm.
C18H24BrNO5 (414.30): calcd. C 52.18, H 5.84, N 3.38; found C
52.34, H 5.72, N 3.60.
N-Benzyl-N-(α-bromo-α-phenylacetyl)-(S)-phenylalanine Methyl Es-
ter (13): 1H NMR (CDCl3, 400 MHz, two rotamers of a dia-
stereomer): δ = 7.48–6.92 (m, 15 H), 5.50, 5.48 (s, 1 H), 4.51, 4.46
(d, J = 18.4 Hz, 1 H), 4.38, 4.31 (m, 1 H), 3.92, 3.86 (d, J = 17.2 Hz,
1 H), 3.66, 3.59 (s, 3 H), 3.35, 3.31 (m, 1 H), 3.19, 3.00 (m, 1
N-Benzyl-N-(α-bromo-α-phenylacetyl)-(S)-alanine Methyl Ester (3):
1H NMR (CDCl3, 400 MHz, two rotamers of a diastereomer): δ =
7.42–7.24 (m, 10 H), 5.56, 5.43 (s, 1 H), 4.84–4.47 (m, 3 H), 3.71,
3.66 (s, 3 H), 1.42, 1.38 (d, J = 7.2 Hz, 3 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 171.9, 168.6, 136.2, 129.6, 129.5, 129.4, H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 169.4, 167.4, 136.5,
129.0, 128.9, 128.4, 126.6, 55.2, 52.3, 50.4, 45.4, 15.0 ppm.
C19H20BrNO3 (390.28): calcd. C 58.47, H 5.17, N 3.59; found C
58.28, H 5.33, N 3.41.
134.7, 128.9, 128.5, 128.4, 128.2, 128.0, 127.9, 127.6, 127.1, 126.6,
125.9, 61.5, 51.4, 45.6, 38.5, 34.2 ppm. C25H24BrNO3 (466.37):
calcd. C 64.38, H 5.19, N 3.00; found C 64.09, H 5.32, N 3.11.
N-(p-Bromobenzyl)-N-(α-bromo-α-phenylacetyl)-(S)-alanine Methyl
Ester (6): 1H NMR (CDCl3, 400 MHz, two rotamers of a dia-
N-Benzyl-N-(α-bromo-α-phenylacetyl)-(S)-leucine Methyl Ester
(14): 1H NMR (CDCl3, 400 MHz, two rotamers of a diastereomer):
stereomer): δ = 7.44–7.08 (m, 9 H), 5.55, 5.44 (s, 1 H), 4.80–4.47 δ = 7.39–7.22 (m, 10 H), 5.52, 5.48 (s, 1 H), 5.07, 4.88 (t, J =
(m, 3 H), 3.69, 3.66 (s, 3 H), 1.40, 1.37 (d, J = 7.2 Hz, 3 H) ppm. 7.6 Hz, 1 H), 4.81–4.51 (m, 2 H), 3.63, 3.57 (s, 3 H), 1.82 (m, 1 H),
13C NMR (CDCl3, 100 MHz): δ = 171.4, 168.6, 135.7, 132.1, 129.8, 1.63–1.49 (m, 2 H), 0.92, 0.86 (d, J = 6.4 Hz, 3 H), 0.81, 0.77 (d,
129.0, 128.9, 128.2, 127.5, 121.8, 55.5, 52.5, 50.3, 45.7, 14.6 ppm.
J = 7.2 Hz, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 171.5,
C19H19Br2NO3 (469.17): calcd. C 48.64, H 4.08, N 2.99; found C 168.8, 135.7, 135.8, 129.2, 128.8, 128.6, 128.4, 127.9, 126.3, 56.6,
48.55, H 4.31, N 3.12.
52.0, 49.7, 46.6, 38.3, 25.2, 22.7, 22.4 ppm. C22H26BrNO3 (432.36):
calcd. C 61.12, H 6.06, N 3.24; found C 61.19, H 5.96, N 3.17.
N-(α-Bromo-α-phenylacetyl)-N-cinnamyl-(S)-alanine Methyl Ester
1
(7): H NMR (CDCl3, 400 MHz, two rotamers of a diastereomer):
Methyl N-Benzyl-N-(α-bromo-α-phenylacetyl)-(S)-aspartate (15):
1H NMR (CDCl3, 400 MHz, two rotamers of a diastereomer): δ =
7.41–7.23 (m, 10 H), 5.59, 5.58 (s, 1 H), 4.79–4.52 (m, 3 H), 3.71,
δ = 7.48–7.23 (m, 10 H), 6.55 (m, 1 H), 6.12 (m, 1 H), 5.79, 5.68
(s, 1 H), 4.86, 4.75 (q, J = 7.2 Hz, 1 H), 4.09–4.02 (m, 2 H), 3.71,
3.67 (s, 3 H), 1.48, 1.46 (d, 3 H) ppm. 13C NMR (CDCl3, 3.63, 3.62, 3.56 (s, 6 H), 3.36–3.24 (m, 1 H), 2.85–2.71 (m, 1
100 MHz): δ = 171.7, 168.0, 136.1, 132.4, 129.3, 129.1, 128.6, 128.0,
126.5, 124.5, 54.9, 52.3, 49.0, 42.9, 14.6 ppm. C21H22BrNO3 135.8, 135.6, 129.2, 129.1, 128.9, 128.3, 128.0, 127.0, 58.2, 53.6,
H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 171.4, 169.6, 168.0,
(416.31): calcd. C 60.59, H 5.33, N 3.36; found C 60.51, H 5.32, N
3.55.
52.6, 52.0, 46.5, 34.2 ppm. C21H22BrNO5 (448.31): calcd. C 56.26,
H 4.95, N 3.12; found C 56.11, H 4.88, N 3.39.
2784
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Eur. J. Org. Chem. 2014, 2780–2789

Asymmetric Synthesis of 3,4,6-Trisubstituted 2,5-Diketopiperazines
Methyl N-Benzyl-N-(α-bromo-α-phenylacetyl)-(S)-glutamate (16):
1H NMR (CDCl3, 400 MHz, two rotamers of a diastereomer): δ =
(m, 2 H), 1.40 (d, J = 6.4 Hz, 3 H), 1.37–1.13 (m, 4 H), 0.83 (m, 3
H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 171.6, 169.7, 137.1,
7.40–7.23 (m, 10 H), 5.55, 5.54 (s, 1 H), 4.81–4.39 (m, 3 H), 3.61 128.9, 127.8, 126.5, 55.4, 52.2, 50.2, 43.7, 34.5, 29.4, 22.1, 14.7,
(s, 3 H), 3.60 (s, 3 H), 2.43–2.36 (m, 3 H), 2.12–2.03 (m, 1 H) ppm.
13.8 ppm. C17H24BrNO3 (370.29): calcd. C 55.14, H 6.53, N 3.78;
13C NMR (CDCl3, 100 MHz): δ = 173.2, 170.5, 168.6, 136.0, 135.7, found C 55.33, H 6.81, N 4.01.
128.5, 128.2, 127.4, 127.0, 126.9, 59.2, 52.3, 51.9, 50.9, 46.4, 30.5,
24.5 ppm. C22H24BrNO5 (462.34): calcd. C 57.15, H 5.23, N 3.03;
found C 56.92, H 5.17, N 3.31.
1
N-Benzyl-N-(α-bromooctanoyl)-(S)-alanine Methyl Ester (24): H
NMR (CDCl3, 400 MHz, two rotamers of a diastereomer): δ =
7.40–7.28 (m, 5 H), 4.87, 4.77 (d, J = 18.0 Hz, 1 H), 4.69–4.45 (m,
2 H), 4.29, 4.16 (t, J = 7.2 Hz, 1 H), 3.73, 3.64 (s, 3 H), 2.17–1.92
(m, 2 H), 1.45 (d, J = 6.4 Hz, 3 H), 1.41–1.11 (m, 8 H), 0.84 (m, 3
H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 171.6, 169.8, 137.1,
129.0, 127.9, 126.5, 54.9, 52.2, 50.2, 43.8, 34.8, 31.5, 28.6, 27.3,
22.5, 14.7, 14.0 ppm. C19H28BrNO3 (398.34): calcd. C 57.29, H
7.09, N 3.52; found C 57.39, H 6.91, N 3.71.
N-Benzyl-N-[α-bromo-α-(p-fluorophenyl)acetyl]-(S)-alanine Methyl
Ester (17): 1H NMR (CDCl3, 400 MHz, two rotamers of a dia-
stereomer): δ = 7.43–7.23 (m, 9 H), 5.52, 5.37 (s, 1 H), 4.88–4.49
(m, 3 H), 3.72, 3.67 (s, 3 H), 1.42, 1.39 (d, 3 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 171.6, 168.4, 163.8 (d), 135.4, 132.9 (d),
129.0, 128.2 (d), 127.8, 127.4, 115.7 (d), 55.2, 52.4, 50.5, 43.9,
14.6 ppm. C19H19BrFNO3 (408.27): calcd. C 55.90, H 4.69, N 3.43;
found C 55.81, H 4.52, N 3.33.
N-(α-Bromo-α-phenylacetyl)-(S)-proline Methyl Ester (25): 1H
NMR (CDCl3, 400 MHz, two diastereomers): δ = 7.52–7.32 (m, 5
H), 5.64, 5.41 (s, 1 H), 4.54, 4.45 (m, 1 H), 3.72, 3.65 (s, 3 H), 3.33
(m, 1 H), 2.18–1.87 (m, 5 H) ppm. 13C NMR (CDCl3, 100 MHz):
δ = 172.5, 166.3, 136.0, 129.3, 128.9, 128.5, 60.0, 59.8, 52.6, 47.5,
29.2, 25.3 ppm. The spectroscopic data of 25 were identical to those
of the authentic material reported previously.[5]
N-Benzyl-N-[α-bromo-α-(p-chlorophenyl)acetyl]-(S)-alanine Methyl
Ester (18): 1H NMR (CDCl3, 400 MHz, two rotamers of a dia-
stereomer): δ = 7.40–7.23 (m, 9 H), 5.50, 5.36 (s, 1 H), 4.86–4.55
(m, 3 H), 3.71, 3.66 (s, 3 H), 1.42, 1.39 (d, J = 7.2 Hz, 3 H) ppm.
13C NMR (CDCl3, 100 MHz): δ = 171.6, 168.4, 136.9, 134.5, 130.7,
129.7, 129.2, 128.7, 128.5, 126.1, 55.0, 52.4, 50.4, 43.9, 14.6 ppm.
C19H19BrClNO3 (424.72): calcd. C 53.73, H 4.51, N 3.30; found C
53.90, H 4.44, N 3.52.
N-[α-Bromo-α-(p-methoxyphenyl)acetyl]-(S)-proline Methyl Ester
(26): 1H NMR (CDCl3, 400 MHz, two diastereomers): δ = 7.43 (m,
2 H), 6.90 (m, 2 H), 5.59, 5.57 (s, 1 H), 4.58, 4.45 (m, 1 H), 3.81,
3.70 (s, 3 H), 3.34 (m, 1 H), 2.23–1.80 (m, 5 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 172.2, 166.2, 160.1, 130.0, 129.4, 114.2,
59.6, 59.0, 53.3, 52.3, 47.2, 28.8, 24.8 ppm. C15H18BrNO4 (356.22):
calcd. C 50.58, H 5.09, N 3.93; found C 50.38, H 4.91, N 3.99.
N-Benzyl-N-[α-bromo-α-(p-bromophenyl)acetyl]-(S)-alanine Methyl
Ester (19): 1H NMR (CDCl3, 400 MHz, two rotamers of a dia-
stereomer): δ = 7.41–7.18 (m, 9 H), 5.48, 5.35 (s, 1 H), 4.85–4.50
(m, 3 H), 3.71, 3.66 (s, 3 H), 1.42, 1.39 (d, J = 7.2 Hz, 3 H) ppm.
13C NMR (CDCl3, 100 MHz): δ = 171.5, 168.3, 136.9, 134.7, 131.8,
129.9, 129.2, 128.7, 128.4, 126.3, 55.2, 52.3, 50.6, 43.9, 14.8 ppm.
C19H19Br2NO3 (469.17): calcd. C 48.64, H 4.08, N 2.99; found C
48.89, H 4.31, N 3.18.
N-[α-Bromo-α-(p-chlorophenyl)acetyl]-(S)-proline Methyl Ester (27):
1H NMR (CDCl3, 400 MHz, two diastereomers): δ = 7.48–7.35 (m,
4 H), 5.55, 5.53 (s, 1 H), 4.58, 4.48 (m, 1 H), 3.76, 3.70 (s, 3 H), 3.42
(m, 1 H), 2.28–1.83 (m, 5 H) ppm. 13C NMR (CDCl3, 100 MHz): δ
= 172.1, 165.7, 135.1, 130.0, 129.6, 128.6, 59.7, 58.2, 52.4, 47.1,
28.9, 24.8 ppm. C14H15BrClNO3 (360.63): calcd. C 46.63, H 4.19,
N 3.88; found C 46.88, H 4.34, N 3.94.
N-Benzyl-N-[α-bromo-α-(p-methoxyphenyl)acetyl]-(S)-alanine
1
Methyl Ester (20): H NMR (CDCl3, 400 MHz, two rotamers of a
diastereomer): δ = 7.41–6.83 (m, 9 H), 5.51, 5.48 (s, 1 H), 4.84–
4.44 (m, 3 H), 3.80, 3.78 (s, 3 H), 3.68, 3.67 (s, 3 H), 1.42, 1.37 (d,
J = 7.2 Hz, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 171.7,
168.5, 160.3, 136.5, 129.7, 128.3, 127.8, 126.7, 126.1, 114.4, 58.8,
57.1, 55.4, 52.3, 50.7, 14.6 ppm. C20H22BrNO4 (420.30): calcd. C
57.15, H 5.28, N 3.33; found C 57.36, H 5.44, N 3.61.
N-(α-Bromopropanoyl)-(S)-proline Methyl Ester (28): 1H NMR
(CDCl3, 400 MHz, two diastereomers): δ = 3.86–3.61 (m, 1 H),
3.71, 3.69 (s, 3 H), 3.14 (m, 1 H), 2.85, 2.75 (q, J = 8.0 Hz, 1 H),
2.21–1.78 (m, 5 H), 1.39, 1.33 (d, J = 7.2 Hz, 3 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 174.8, 173.8, 62.7, 57.5, 51.7, 47.7, 29.8,
23.7, 16.7 ppm. The spectroscopic data of 28 were identical to those
of the authentic material reported previously.[5]
N-Benzyl-N-(α-bromopropanoyl)-(S)-alanine Methyl Ester (21): 1H
NMR (CDCl3, 400 MHz, two rotamers of a diastereomer): δ =
7.40–7.20 (m, 5 H), 4.93–4.35 (m, 4 H), 3.73, 3.61 (s, 3 H), 1.80,
1.75 (d, J = 6.4 Hz, 3 H), 1.41 (m, 3 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 171.6, 170.1, 137.0, 129.1, 127.9, 125.9, 54.7, 52.3,
50.1, 38.7, 21.4, 14.2 ppm. C14H18BrNO3 (328.21): calcd. C 51.23,
H 5.53, N 4.27; found C 51.45, H 5.81, N 4.47.
N-(α-Bromobutanoyl)-(S)-proline Methyl Ester (29): 1H NMR
(CDCl3, 400 MHz, two diastereomers): δ = 4.51 (m, 1 H), 4.25 (m,
1 H), 3.89–3.51 (m, 1 H), 3.74, 3.73 (s, 3 H), 2.32–1.90 (m, 7 H),
1.04 (m, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 174.8, 173.8,
59.3, 57.0, 52.2, 47.0, 29.0, 28.9, 24.7, 12.2 ppm. C10H16BrNO3
(278.15): calcd. C 43.18, H 5.80, N 5.04; found C 43.41, H 5.56, N
5.30.
1
N-Benzyl-N-(α-bromobutanoyl)-(S)-alanine Methyl Ester (22): H
NMR (CDCl3, 400 MHz, two rotamers of a diastereomer): δ =
7.40–7.22 (m, 5 H), 4.91–4.06 (m, 4 H), 3.75, 3.64 (s, 3 H), 2.20,
1.96 (m, 2 H), 1.40 (d, J = 6.4 Hz, 3 H), 0.92, 0.87 (t, 3 H) ppm.
13C NMR (CDCl3, 100 MHz): δ = 172.5, 170.5, 137.9, 129.8, 128.7,
127.2, 56.1, 53.1, 51.8, 46.6, 29.4, 15.5, 13.0 ppm. C15H20BrNO3
(342.23): calcd. C 52.64, H 5.89, N 4.09; found C 52.88, H 5.80, N
4.31.
General Procedure for the Preparation of Dipeptides 4 and 12a–12g:
To a solution of (αRS)-α-bromo tertiary acetamide in dry CH3CN
(≈ 0.1 m) at room temperature was added dibenzylamine (or p-
anisidine) (1.2 equiv.), TBAI (1.0 equiv.) and DIEA (1.0 equiv.).
The resulting reaction mixture was stirred at room temperature for
20 h, before the solvent was evaporated and the crude product puri-
fied by column chromatography on silica gel. The purity (Ͼ 95%)
of products was estimated by NMR spectroscopy.
1
N-Benzyl-N-(α-bromohexanoyl)-(S)-alanine Methyl Ester (23): H
NMR (CDCl3, 400 MHz, two rotamers of a diastereomer) 7.39– N-Benzyl-N-[N,N-dibenzyl-(S)-phenylglycinyl]-(S)-alanine Methyl
7.20 (m, 5 H): δ = 4.88, 4.78 (d, J = 18.0 Hz, 1 H), 4.69–4.45 (m,
2 H), 4.29, 4.16 (t, J = 6.8 Hz, 1 H), 3.74, 3.62 (s, 3 H), 2.19–1.92
Ester (4): A colorless oil was obtained in 50% yield. 1H NMR
(CDCl3, 400 MHz, major diastereomer, major rotamer): δ = 7.39–
Eur. J. Org. Chem. 2014, 2780–2789
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2785

J. Baek, S. Y. Kang, C. Im, Y. S. Park
FULL PAPER
6.80 (m, 20 H), 4.84 (s, 1 H), 4.21–4.04 (m, 4 H), 3.89–3.80 (m, 3 N-Propargyl-N-[N-(p-methoxyphenyl)-(S)-phenylglycinyl]-(S)-
H), 3.76 (s, 3 H), 1.40 (d, J = 7.2 Hz, 3 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 173.6, 172.4, 141.1, 137.0, 129.7, 129.5, 129.3, 128.8,
128.7, 128.6, 128.3, 128.1, 127.8, 127.6, 127.5, 127.2, 126.8, 126.7,
alanine Methyl Ester (12f): A yellow oil was obtained in 85% yield.
1H NMR (CDCl3, 400 MHz, major diastereomer, major rotamer):
δ = 7.46–7.26 (m, 5 H), 6.74 (m, 4 H), 5.47 (s, 1 H), 5.15 (q, J =
63.4, 54.6, 54.4, 52.1, 50.8, 14.2 ppm. HRMS: calcd. for 7.2 Hz, 1 H), 4.10 (m, 1 H), 3.77 (m, 1 H), 3.67 (s, 3 H), 3.61 (s, 3
C33H35N2O3 [M+ + 1] 507.2648; found 507.2647.
H), 2.43 (s, 1 H), 1.51 (d, J = 7.2 Hz, 3 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 172.0, 171.8, 152.7, 140.9, 137.1, 129.4, 128.7, 127.9,
115.6, 114.8, 79.1, 73.6, 60.2, 55.7, 53.1, 52.2, 36.0, 34.5, 14.8 ppm.
HRMS: calcd. for C22H25N2O4 [M+ + 1] 381.1814; found 381.1814.
N-Benzyl-N-[N-(p-methoxyphenyl)-(S)-phenylglycinyl]-(S)-alanine
Methyl Ester (12a): A yellow oil was obtained in 73% yield. 1H
NMR (CDCl3, 400 MHz, major diastereomer, major rotamer): δ =
7.42–7.12 (m, 10 H), 6.67 (d, J = 8.8 Hz, 2 H), 6.47 (d, J = 8.8 Hz,
2 H), 5.07 (s, 1 H), 4.66 (q, J = 6.8 Hz, 1 H), 4.59 (d, J = 17.6 Hz,
1 H), 4.31 (d, J = 17.6 Hz, 1 H), 3.71 (s, 3 H), 3.61 (s, 3 H), 1.33
(d, J = 7.2 Hz, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 172.5,
171.9, 152.8, 140.8, 137.7, 136.7, 129.1, 128.4, 128.0, 127.9, 127.4,
126.5, 116.4, 114.8, 60.8, 55.7, 54.6, 52.1, 49.5, 14.3 ppm. HRMS:
calcd. for C26H29N2O4 [M+ + 1] 433.2127; found 433.2127.
N-(tert-Butoxycarbonylmethyl)-N-[N-(p-methoxyphenyl)-(S)-phenyl-
glycinyl]-(S)-alanine Methyl Ester (12g): A yellow oil was obtained
in 80% yield. 1H NMR (CDCl3, 400 MHz, major diastereomer,
major rotamer): δ = 7.40–7.24 (m, 5 H), 6.75–6.65 (m, 4 H), 5.17
(s, 1 H), 4.66 (m, 1 H), 4.24 (d, J = 17.2 Hz, 1 H), 4.04 (d, J =
17.2 Hz, 1 H), 3.70 (s, 3 H), 3.58 (s, 3 H), 1.55–1.31 (m, 12 H) ppm.
13C NMR (CDCl3, 100 MHz): δ = 172.2, 171.3, 168.7, 152.6, 141.0,
137.3, 129.1, 128.7, 127.9, 115.2, 114.8, 81.5, 60.4, 55.4, 53.2, 47.4,
46.0, 28.0, 14.8 ppm. HRMS: calcd. for C25H33N2O6 [M+ + 1]
457.2339; found 457.2339.
N-(p-Bromobenzyl)-N-[N-(p-methoxyphenyl)-(S)-phenylglycinyl]-
(S)-alanine Methyl Ester (12b): A yellow oil was obtained in 75%
yield. 1H NMR (CDCl3, 400 MHz, major diastereomer, major rot-
amer): δ = 7.43–7.30 (m, 7 H), 6.92 (m, 2 H), 6.68 (d, J = 8.8 Hz,
2 H), 6.49 (d, J = 8.8 Hz, 2 H), 5.02 (s, 1 H), 4.64–4.51 (m, 2 H),
4.28 (d, J = 18.0 Hz, 1 H), 3.70 (s, 3 H), 3.59 (s, 3 H), 1.30 (d, J =
7.2 Hz, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 172.4, 171.7,
153.0, 140.8, 137.7, 135.8, 132.0, 131.3, 129.1, 128.7, 128.2, 121.7,
115.5, 114.4, 61.1, 55.7, 54.8, 53.5, 52.2, 49.2, 46.2, 14.3 ppm.
HRMS: calcd. for C26H28BrN2O4 [M+ + 1] 511.1232; found
511.1232.
General Procedure for the Preparation of 2,5-Diketopiperazines 5a–
5t: To a solution of l-amino acid-derived (αRS)-α-bromo tertiary
acetamide (1.0 mmol) in dry CH3CN (≈ 0.1 m) at room temperature
was added p-anisidine (1.2 equiv.), TBAI (1.0 equiv.) and DIEA
(1.0 equiv.). The resulting reaction mixture was stirred at room tem-
perature for 20 h before the solvent was evaporated in vacuo. The
resulting residue was purified by passing through a short silica gel
column (EtOAc/hexanes) to afford N-(p-methoxyphenyl)-substi-
tuted dipeptide as a mixture of two diastereomers. To a solution of
the products in a 1:1 mixture of CH3CN/H2O (≈ 1.0 m), TCCA
(0.5 equiv.) and a drop of HCl (2.0 m⁾ were added. The mixture was
stirred at room temperature for 4 h, CH3CN was removed in vacuo
and then EtOAc (2 mL) and satd. aqueous NaHCO3 (2 mL) were
added. The resulting reaction mixture was stirred at room tempera-
ture for 1 h before extractive work up and the organic phase was
dried with MgSO4. Filtration and concentration provided the crude
product that was purified by column chromatography on silica gel.
The purity (Ͼ 95 %) of products was estimated by NMR spec-
troscopy.
N-Cinnamyl-N-[N-(p-methoxyphenyl)-(S)-phenylglycinyl]-(S)-
alanine Methyl Ester (12c): A yellow oil was obtained in 70% yield.
1H NMR (CDCl3, 400 MHz, major diastereomer, major rotamer):
δ = 7.46–7.21 (m, 10 H), 6.72–6.49 (m, 4 H), 6.51 (d, J = 16.0 Hz,
1 H), 5.91 (m, 1 H), 5.29 (s, 1 H), 4.67 (q, J = 7.2 Hz, 1 H), 4.11
(dd, J = 6.8 and 14.0 Hz, 1 H), 4.11 (dd, J = 3.2 and 18.0 Hz, 1
H), 3.69 (s, 3 H), 3.59 (s, 3 H), 1.41 (d, J = 7.6 Hz, 3 H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 171.9, 171.7, 153.0, 140.5, 137.6,
135.9, 132.7, 129.2, 128.9, 127.9, 126.5, 124.6, 116.6, 114.7, 60.9,
55.7, 54.3, 52.2, 48.1, 14.1 ppm. HRMS: calcd. for C28H31N2O4
[M+ + 1] 459.2284; found 459.2284.
(3S,6S)-4-Benzyl-3-methyl-6-phenylpiperazine-2,5-dione (5a): A col-
orless oil was obtained in 55% overall yield. 1H NMR (CDCl3,
400 MHz): δ = 8.27 (br., 1 H), 7.47–7.19 (m, 10 H), 5.18–5.13 (m,
2 H), 3.89 (d, J = 15.2 Hz, 1 H), 3.83 (q, J = 7.2 Hz, 1 H), 1.25 (d,
J = 6.8 Hz, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 170.2,
164.9, 137.4, 135.6, 128.9, 128.8, 128.4, 128.2, 128.1, 126.1, 58.7,
54.8, 47.5, 18.5 ppm. HRMS: calcd. for C18H19N2O2 [M+ + 1]
295.1447; found 295.1447.
N-Butyl-N-[N-(p-methoxyphenyl)-(S)-phenylglycinyl]-(S)-alanine
Methyl Ester (12d): A yellow oil was obtained in 64% yield. 1H
NMR (CDCl3, 400 MHz, major diastereomer, major rotamer): δ =
7.43–7.26 (m, 5 H), 6.72 (d, J = 8.8 Hz, 2 H), 6.61 (d, J = 8.8 Hz,
2 H), 5.15 (s, 1 H), 4.23 (q, J = 7.2 Hz, 1 H), 3.71 (s, 3 H), 3.60 (s,
3 H), 3.37 (m, 1 H), 3.07 (m, 1 H), 1.41 (d, J = 7.2 Hz, 3 H), 1.29–
1.23 (m, 4 H), 0.88 (m, 3 H) ppm. 13C NMR (CDCl3, 100 MHz):
δ = 171.8, 170.8, 152.6, 140.9, 138.3, 128.9, 128.0, 127.8, 115.8,
114.7, 60.1, 55.7, 55.4, 52.1, 47.2, 31.6, 20.1, 14.3, 13.8 ppm.
HRMS: calcd. for C23H31N2O4 [M+ + 1] 399.2284; found 399.2284.
(3S,6S)-4-(p-Bromobenzyl)-3-methyl-6-phenylpiperazine-2,5-dione
(5b): A white solid was obtained in 55% overall yield. 1H NMR
(CDCl3, 400 MHz): δ = 8.05 (br., 1 H), 7.47–7.08 (m, 9 H), 5.20
(d, J = 3.6 Hz, 1 H), 5.00 (d, J = 15.2 Hz, 1 H), 3.94 (d, J =
15.2 Hz, 1 H), 3.83 (q, J = 7.2 Hz, 1 H), 1.26 (d, J = 7.2 Hz, 3
H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 170.0, 164.9, 137.2,
134.8, 132.0, 129.9, 128.9, 128.5, 126.0, 122.0, 58.7, 55.2, 47.2,
18.6 ppm. HRMS: calcd. for C18H18BrN2O2 [M+ + 1] 373.0552;
found 373.0552.
N-(3-Ethoxycarbonylpropyl)-N-[N-(p-methoxyphenyl)-(S)-phenyl-
glycinyl]-(S)-alanine Methyl Ester (12e): A yellow oil was obtained
in 82% yield. 1H NMR (CDCl3, 400 MHz, major diastereomer,
major rotamer): δ = 7.46–7.26 (m, 5 H), 6.72 (m, 4 H), 5.34 (s, 1
H), 4.24–4.10 (m, 3 H), 3.71 (s, 3 H), 3.58 (s, 3 H), 3.51 (m, 1 H),
3.00 (m, 1 H), 2.38–2.19 (m, 2 H), 1.95 (m, 1 H), 1.68 (m, 1 H), (3S,6S)-4-Cinnamyl-3-methyl-6-phenylpiperazine-2,5-dione (5c): A
1
1.40 (d, J = 7.2 Hz, 3 H), 1.27 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 172.8, 171.7, 171.2, 152.6, 140.9, 138.2, 400 MHz): δ = 7.43–7.18 (m, 11 H), 6.44 (d, J = 15.6 Hz, 1 H),
128.9, 128.1, 127.7, 115.7, 114.7, 60.8, 59.7, 55.7, 55.4, 52.1, 46.3, 6.03 (m, 1 H), 5.14 (s, 1 H), 4.56 (m, 1 H), 3.98 (m, 1 H), 3.57 (m,
30.5, 24.5, 14.2 ppm. HRMS: calcd. for C25H33N2O6 [M+ + 1] 1 H), 1.31 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR (CDCl3, 100 MHz):
457.2339; found 457.2339. δ = 170.0, 164.3, 137.1, 136.0, 134.5, 128.9, 128.7, 128.5, 128.1,
colorless oil was obtained in 52% overall yield. H NMR (CDCl3,
2786
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2780–2789

Asymmetric Synthesis of 3,4,6-Trisubstituted 2,5-Diketopiperazines
126.5, 126.0, 122.7, 58.9, 55.1, 46.7, 18.9 ppm. HRMS: calcd. for
C20H21N2O2 [M+ + 1] 321.1603; found 321.1603.
122.6, 58.2, 54.8, 47.6, 18.7 ppm. HRMS: calcd. for C18H18BrN2O2
[M+ + 1] 373.0552; found 373.0552.
(3S,6S)-3,4-Dibenzyl-6-phenylpiperazine-2,5-dione (5d): A white so-
lid was obtained in 66 % overall yield. 1H NMR (CDCl3,
400 MHz): δ = 7.89 (br., 1 H), 7.32–6.96 (m, 15 H), 5.36 (d, J =
(3S,6S)-4-Benzyl-6-(4-methoxyphenyl)-3-methylpiperazine-2,5-dione
(5k): A colorless oil was obtained in 63% overall yield. H NMR
(CDCl3, 400 MHz): δ = 7.62 (br., 1 H), 7.41–7.22 (m, 7 H), 6.89
1
14.8 Hz, 1 H), 5.16 (d, J = 3.2 Hz, 1 H), 4.08 (m, 1 H), 3.30 (d, J (d, J = 8.8 Hz, 2 H), 5.23–5.18 (m, 2 H), 3.94–3.87 (m, 2 H), 3.79
= 14.8 Hz, 1 H), 3.11 (dd, J = 14.0 and 4.4 Hz, 1 H), 2.81 (dd, J
(s, 3 H), 1.33 (d, J = 7.2 Hz, 3 H) ppm. 13C NMR (CDCl3,
= 14.0 and 7.2 Hz, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 100 MHz): δ = 170.1, 165.0, 159.7, 135.5, 129.2, 129.0, 128.3, 128.1,
168.4, 165.1, 137.0, 135.8, 135.3, 129.7, 129.0, 128.9, 128.8, 128.4,
128.3, 128.1, 127.5, 126.2, 60.2, 58.8, 47.9, 38.3 ppm. HRMS:
calcd. for C24H23N2O2 [M+ + 1] 371.1760; found 371.1761.
127.2, 114.3, 58.3, 55.4, 54.7, 47.4, 18.6 ppm. HRMS: calcd. for
C19H21N2O3 [M+ + 1] 325.1552; found 325.1552.
(3S,6S)-4-Benzyl-3,6-dimethylpiperazine-2,5-dione (5l): A colorless
oil was obtained in 54 % overall yield. 1H NMR (CDCl3,
400 MHz): δ = 7.78 (br., 1 H), 7.35–7.23 (m, 5 H), 5.28 (d, J =
14.8 Hz, 1 H), 4.14 (m, 1 H), 3.99 (d, J = 14.8 Hz, 1 H), 3.83 (q, J
= 6.8 Hz, 1 H), 1.55 (d, J = 7.2 Hz, 3 H), 1.51 (d, J = 6.8 Hz, 3
(3S,6S)-4-Benzyl-3-Isobutyl-6-phenylpiperazine-2,5-dione (5e): A
1
colorless oil was obtained in 51% overall yield. H NMR (CDCl3,
400 MHz): δ = 7.52 (br., 1 H), 7.39–7.21 (m, 10 H), 5.33–5.27 (m,
2 H), 3.83 (d, J = 14.8 Hz, 1 H), 3.77 (m, 1 H), 1.78 (m, 1 H),
1.44–1.27 (m, 2 H), 0.81 (d, J = 6.4 Hz, 1 H), 0.75 (d, J = 6.8 Hz, H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 169.5, 167.0, 135.6,
1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 169.7, 165.4, 137.1,
128.9, 128.2, 128.0, 54.5, 51.5, 47.0, 22.2, 19.0 ppm. The spectro-
135.6, 129.0, 128.8, 128.3, 128.2, 128.1, 125.7, 58.6, 57.3, 48.0, 42.3,
scopic data of 5l were identical to those of the authentic material
24.7, 23.1, 21.6 ppm. HRMS: calcd. for C21H25N2O2 [M+ + 1] reported previously.[11]
337.1916; found 337.1916.
(3S,6S)-4-Benzyl-6-ethyl-3-methylpiperazine-2,5-dione (5m): A col-
(3S,6S)-4-Benzyl-3-methoxycarbonylmethyl-6-phenylpiperazine-
2,5-dione (5f): A colorless oil was obtained in 56% overall yield.
orless oil was obtained in 45% overall yield. 1H NMR (CDCl3,
400 MHz): δ = 7.35–7.22 (m, 5 H), 7.11 (br., 1 H), 5.29 (d, J =
1H NMR (CDCl3, 400 MHz): δ = 7.79 (br., 1 H), 7.53–7.22 (m, 10 14.8 Hz, 1 H), 4.04–3.91 (m, 2 H), 3.83 (m, 1 H), 1.98 (m, 1 H),
H), 5.23 (d, J = 3.2 Hz, 1 H), 5.08 (d, J = 15.2 Hz, 1 H), 4.37 (m,
1.81 (m, 1 H), 1.51 (d, J = 7.2 Hz, 3 H), 1.05 (t, J = 6.8 Hz, 3
1 H), 4.10 (d, J = 15.2 Hz, 1 H), 3.53 (s, 3 H), 2.67 (dd, J = 5.6 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 169.3, 166.1, 135.6,
and 16.0 Hz, 1 H), 2.54 (dd, J = 6.0 and 16.0 Hz, 1 H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 170.1, 168.2, 165.1, 137.0, 135.5,
129.0, 128.9, 128.6, 128.2, 128.0, 126.3, 58.8, 56.0, 52.2, 48.1,
37.9 ppm. HRMS: calcd. for C20H21N2O4 [M+ + 1] 353.1501;
found 353.1501.
128.9, 128.3, 128.0, 57.1, 54.4, 47.1, 29.1, 19.1, 10.0 ppm. The spec-
troscopic data of 5l were identical to those of the authentic material
reported previously.[11]
(3S,6S)-4-Benzyl-6-butyl-3-methylpiperazine-2,5-dione (5n): A col-
orless oil was obtained in 52% overall yield. 1H NMR (CDCl3,
(3S,6S)-4-Benzyl-3-(2-methoxycarbonylethyl)-6-phenylpiperazine- 400 MHz): δ = 7.69 (br., 1 H), 7.35–7.24 (m, 5 H), 5.29 (d, J =
2,5-dione (5g): A colorless oil was obtained in 56% overall yield. 14.8 Hz, 1 H), 4.02–3.98 (m, 2 H), 3.85 (q, J = 7.2 Hz, 1 H), 1.98
1H NMR (CDCl3, 400 MHz): δ = 7.56–7.26 (m, 10 H), 7.07 (br., 1 (m, 1 H), 1.75 (m, 1 H), 1.50 (d, J = 6.8 Hz, 3 H), 1.38 (m, 4 H),
H), 5.33–5.27 (m, 2 H), 3.96 (d, J = 14.8 Hz, 1 H), 3.88 (m, 1 H),
3.67 (s, 3 H), 2.54 (m, 1 H), 2.37 (m, 1 H), 2.11 (m, 1 H), 1.75 (m,
1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 172.8, 168.3, 164.7,
136.9, 135.6, 129.0, 128.9, 128.5, 128.4, 128.1, 125.8, 58.7, 57.7,
0.91 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ =
169.6, 166.4, 135.7, 128.9, 128.2, 128.0, 55.9, 54.4, 47.0, 35.8, 27.6,
22.3, 19.0, 13.9 ppm. HRMS: calcd. for C16H23N2O2 [M+ + 1]
275.1760; found 275.1758.
51.8, 47.6, 29.5, 27.3 ppm. HRMS: calcd. for C21H23N2O4 [M+
1] 367.1658; found 367.1658.
+
(3S,6S)-4-Benzyl-6-hexyl-3-methylpiperazine-2,5-dione (5o): A
1
white solid was obtained in 47% overall yield. H NMR (CDCl3,
(3S,6S)-4-Benzyl-6-(4-fluorophenyl)-3-methylpiperazine-2,5-dione
(5h): A pale yellow oil was obtained in 64% overall yield. 1H NMR
400 MHz): δ = 7.87 (br., 1 H), 7.34–7.23 (m, 5 H), 5.28 (d, J =
15.2 Hz, 1 H), 4.02–3.98 (m, 2 H), 3.84 (q, J = 7.2 Hz, 1 H), 1.95
(CDCl3, 400 MHz): δ = 7.56 (br., 1 H), 7.51–7.06 (m, 9 H), 5.24– (m, 1 H), 1.73 (m, 1 H), 1.50 (d, J = 7.2 Hz, 3 H), 1.47–1.29 (m, 8
5.20 (m, 2 H), 3.93 (d, J = 14.8 Hz, 1 H), 3.89 (q, J = 7.2 Hz, 1
H), 0.88 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR (CDCl3, 100 MHz):
H), 1.34 (d, J = 7.2 Hz, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 169.6, 166.4, 135.7, 128.9, 128.2, 128.0, 55.9, 54.4, 47.1, 36.1,
δ = 169.9, 164.5, 162.8 (d), 135.4, 132.9 (d), 129.0, 128.2 (d), 127.8,
127.4, 115.8 (d), 58.2, 54.7, 47.5, 18.7 ppm. HRMS: calcd. for
C18H18FN2O2 [M+ + 1] 313.1352; found 313.1352.
31.6, 28.8, 25.5, 22.5, 19.0, 14.0 ppm. HRMS: calcd. for
C18H27N2O2 [M+ + 1] 303.2073; found 303.2073.
(3R,8aS)-3-Phenylhexahydropyrrolo[1,2-a]pyrazine-1,4-dione (5p):
A white solid was obtained in 60% overall yield. 1H NMR (CDCl3,
400 MHz): δ = 7.56 (br., 1 H), 7.46–7.27 (m, 5 H), 5.15 (d, J =
(3S,6S)-4-Benzyl-6-(4-chlorophenyl)-3-methylpiperazine-2,5-dione
(5i): A white solid was obtained in 60% overall yield. 1H NMR
(CDCl3, 400 MHz): δ = 8.06 (br., 1 H), 7.45–7.20 (m, 9 H), 5.21– 4.4 Hz, 1 H), 3.98 (m, 1 H), 3.63 (m, 1 H), 3.43 (m, 1 H), 2.31 (m,
5.16 (m, 2 H), 3.93 (d, J = 14.8 Hz, 1 H), 3.85 (q, J = 7.2 Hz, 1
1 H), 2.03 (m, 2 H), 1.78 (m, 1 H) ppm. 13C NMR (CDCl3,
H), 1.29 (d, J = 7.2 Hz, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): 100 MHz): δ = 170.6, 164.5, 135.9, 129.1, 128.4, 125.5, 60.8, 57.9,
δ = 170.2, 164.4, 135.8, 135.3, 134.5, 129.0, 128.9, 128.2, 128.1,
127.4, 58.2, 54.7, 47.5, 18.7 ppm. HRMS: calcd. for C18H18ClN2O2
[M+ + 1] 329.1057; found 329.1057.
45.8, 28.7, 22.3 ppm. The spectroscopic data of 5p were identical
to those of the authentic material reported previously.[4a]
(3R,8aS)-3-(p-Methoxy)phenylhexahydropyrrolo[1,2-a]pyrazine-
1,4-dione (5q): A colorless oil was obtained in 67% overall yield.
1H NMR (CDCl3, 400 MHz): δ = 8.03 (br., 1 H), 7.33 (d, J =
(3S,6S)-4-Benzyl-6-(4-bromophenyl)-3-methylpiperazine-2,5-dione
(5j): A colorless oil was obtained in 49% overall yield. 1H NMR
(CDCl3, 400 MHz): δ = 8.30 (br., 1 H), 7.67–7.12 (m, 9 H), 5.17– 12.4 Hz, 2 H), 6.87 (d, J = 12.4 Hz, 2 H), 5.08 (d, J = 4.4 Hz, 1
5.12 (m, 2 H), 3.92 (d, J = 15.2 Hz, 1 H), 3.81 (q, J = 7.2 Hz, 1 H), 3.98 (m, 1 H), 3.78 (s, 3 H), 3.59 (m, 1 H), 3.43 (m, 1 H), 2.28
H), 1.24 (d, J = 7.2 Hz, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): (m, 1 H), 1.99 (m, 2 H), 1.78 (m, 1 H) ppm. 13C NMR (CDCl3,
δ = 170.2, 164.4, 136.4, 135.3, 132.0, 129.0, 128.2, 128.1, 127.7, 100 MHz): δ = 170.6, 164.9, 159.6, 128.1, 126.7, 114.3, 60.1, 57.9,
Eur. J. Org. Chem. 2014, 2780–2789
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2787

J. Baek, S. Y. Kang, C. Im, Y. S. Park
FULL PAPER
55.3, 45.7, 28.7, 22.2 ppm. HRMS: calcd. for C14H17N2O3 [M+
1] 261.1239; found 261.1239.
+
[4]
a) S. Selvakumar, D. Sivasankaran, V. K. Singh, Org. Biomol.
Chem. 2009, 7, 3156–3162; b) C. Malavasˇic, U. Grosˇelj, A. Go-
lobic, J. Bezensˇek, B. Stanovnik, K. Stare, J. Wagger, J. Svete,
Tetrahedron: Asymmetry 2011, 22, 629–640; c) C. J. Creighton,
A. B. Reitz, Org. Lett. 2001, 3, 893–895; d) T. Kawakami, A.
Kamauchi, E. Harada, S. Aimoto, Tetrahedron Lett. 2014, 55,
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a) J. Nam, J.-y. Chang, K.-S. Hahm, Y. S. Park, Tetrahedron
Lett. 2003, 44, 7727–7730; b) J. Nam, J.-y. Chang, E.-k. Shin,
H. J. Kim, Y. Kim, S. Jang, Y. S. Park, Tetrahedron 2004, 60,
6311–6318; c) J.-y. Chang, E.-k. Shin, H. J. Kim, Y. Kim, Y. S.
Park, Tetrahedron 2005, 61, 2743–2750.
In both solution- and solid-phase synthesis of 2,5-diketopiper-
azines, N-benzylation of the central amide of the dipeptide has
been frequently used for temporary exploitation of the tertiary
amide bond, yet ultimately produces an N-unsubstituted 2,5-
diketopiperazine; a) P. Besada, L. Mamedova, C. J. Thomas, S.
Costanzi, K. A. Jacobson, Org. Biomol. Chem. 2005, 3, 2016–
2025; b) M. del Fresno, D. B. Fernandez-Forner, M. Miralpeix,
V. Segarra, H. Ryder, M. Royo, F. Albericio, Bioorg. Med.
Chem. Lett. 2005, 15, 1659–1664; c) M. del Fresno, J. Alsina,
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5452; e) Y. Du, C. J. Creighton, B. A. Tounge, A. B. Reitz, Org.
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(3R,8aS)-3-(4-Chlorophenyl)hexahydropyrrolo[1,2-a]pyrazine-1,4-di-
one (5r): A colorless oil was obtained in 57 % overall yield. 1H
NMR (CDCl3, 400 MHz): δ = 7.98 (br., 1 H), 7.40–7.33 (m, 4 H),
5.13 (d, J = 4.4 Hz, 1 H), 3.95 (m, 1 H), 3.63 (m, 1 H), 3.45 (m, 1
H), 2.33 (m, 1 H), 2.03 (m, 2 H), 1.82 (m, 1 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 170.3, 163.9, 134.2, 128.9, 126.6, 59.9, 57.6,
45.6, 28.4, 21.9 ppm. HRMS: calcd. for C13H14ClN2O2 [M+ + 1]
265.0744; found 265.0744.
[5]
[6]
(3R,8aS)-3-Methylhexahydropyrrolo[1,2-a]pyrazine-1,4-dione (5s):
A white solid was obtained in 49% overall yield. 1H NMR (CDCl3,
400 MHz): δ = 7.40 (br., 1 H), 4.13–4.02 (m, 2 H), 3.66 (m, 1 H),
3.54 (m, 1 H), 2.41 (m, 1 H), 2.08–1.86 (m, 3 H), 1.48 (d, J =
7.2 Hz, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 169.5, 166.7,
58.0, 53.6, 45.5, 29.0, 22.1, 20.1 ppm. The spectroscopic data of 5s
were identical to those of the authentic material reported pre-
viously.[15]
(3R,8aS)-3-Ethylhexahydropyrrolo[1,2-a]pyrazine-1,4-dione (5t): A
1
colorless oil was obtained in 55% overall yield. H NMR (CDCl3,
400 MHz): δ = 7.29 (br., 1 H), 4.09 (m, 1 H), 3.86 (m, 1 H), 3.67
(m, 1 H), 3.54 (m, 1 H), 2.40 (m, 1 H), 2.06–1.76 (m, 5 H), 1.04
(d, J = 7.2 Hz, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 169.6,
166.1, 59.2, 58.2, 45.5, 29.1, 27.6, 22.1, 9.8 ppm. HRMS: calcd. for
C9H15N2O2 [M+ + 1] 183.1134; found 183.1133.
[7]
[8]
a) H. A. Baldoni, G. N. Zamarbide, R. D. Enriz, E. A. Jaure-
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Supporting Information (see footnote on the first page of this arti-
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It has been proposed that the formation of a hydrogen bond
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Acknowledgments
This work was supported by the Basic Science Research Program
through the National Research Foundation (NRF), Ministry of
Education, Science and Technology, Korea (grant number
2012R1A1A2004794) and the Konkuk–Fraunhofer Next Genera-
tion Solar Cell Research Center (grant number WR090671, Seoul
R&BD Program).
[9]
[10]
Oxidative deprotection of the N-PMP group in the preparation
of 2,5-diketopiperazines 5 with TCCA gave much better yields
than with ceric ammonium nitrate except in the preparation of
5c. For reviews on the successful use of TCCA, see: a) J. M. M.
Verkade, L. J. C. Hemert, P. J. L. M. Quaedflieg, P. L. Alsters,
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47, 7075–7078; Angew. Chem. 2008, 120, 7183–7186.
The cis-configuration of diketopiperazines 5l and 5m was con-
firmed through analysis with 1H NMR spectroscopic data of
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Nukui, M. Teng, E. Tompkins, C. Yin, Novel 3-amido-pyr-
rolo[3,4-c]pyrazole-5(1H,4H,6H)carbaldehyde derivatives, WO
2008/125945 A2, October 23, 2008; b) F. X. Chen, T. D. Cutar-
elli, X. Fu, X. Liang, T. L. Mcallister, R. K. Orr, J. Yin, K. H.
Yong, M. Zhu, Process and intermediates for the synthesis of
heterocyclic substituted piperazines with CXCR3 antagonist
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with dibenzylamine nucleophile favored the formation of (αR)-
Received: December 31, 2013
Published Online: March 6, 2014
Eur. J. Org. Chem. 2014, 2780–2789
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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