Dynamic resolution of α-halo chiral esters for the synthesis of 3-substituted piperazin-2-ones

Article abstract of DOI:10.1016/j.tet.2011.06.055

Dynamic resolution of α-halo esters derived from five chiral alcohols has been investigated in nucleophilic substitution with ethylenediamine nucleophiles. Stereoselective substitution of α-halo esters and following spontaneous cyclization provide a pract

Full text of DOI:10.1016/j.tet.2011.06.055

Tetrahedron 67 (2011) 6221e6226
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Dynamic resolution of
piperazin-2-ones
a
-halo chiral esters for the synthesis of 3-substituted
*
Jung In Jang, Seock Yong Kang, Kyoung Hee Kang, Yong Sun Park
Department of Chemistry, Konkuk University, Seoul 143-701, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 May 2011
Received in revised form 20 June 2011
Accepted 20 June 2011
Available online 25 June 2011
Dynamic resolution of
philic substitution with ethylenediamine nucleophiles. Stereoselective substitution of
following spontaneous cyclization provide a practical protocol for asymmetric syntheses of 3-substituted
piperazin-2-ones up to 94:6 er.
a
-halo esters derived from five chiral alcohols has been investigated in nucleo-
-halo esters and
a
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Piperazinone
Asymmetric synthesis
Chiral auxiliary
Dynamic resolution
Nucleophilic substitution
1. Introduction
NHR'
O
NHR'
Piperazin-2-one rings are of great interest since they represent
the structural core of several biologically active compounds and are
useful synthetic intermediates of various piperazines.1 While some
progress has recently been made toward the development of
asymmetric synthetic methods for these compounds, it still re-
mains a great challenge in the field of organic synthesis.2 In the
O
R'HN
Br
OR*
R'N
OR*
R
Dynamic
Resolution
R
R*OH:
chiral auxiliary
cyclization
TBAI
DIEA
_
R*OH
course of our studies on dynamic resolution of
a-halo esters in
asymmetric synthesis, we envisaged a simple method for chiral
piperazin-2-ones bearing variable substituents at C-3 position.3
The strategy to obtain the enantioenriched piperazinone scaffold
R'
N
O
O
R
Br
OR*
R
involves a chiral alcohol-controlled dynamic resolution of a-halo
N
R'
esters in nucleophilic substitution with ethylenediamine nucleo-
philes as shown in Scheme 1. The first step of this reaction would be
the stereoselective nucleophilic attack of an amino group of 1,2-
piperazin-2-one
Scheme 1. Asymmetric synthesis of 3-substituted piperazin-2-one.
diamine at the a-halo carbon center. The subsequent nucleophilic
attack of the second amino group at the ester function produces
piperazin-2-ones by ring closure and loss of chiral auxiliary. Herein
we report a novel asymmetric synthetic method for 3-substituted
piperazin-2-ones via chiral alcohol-controlled dynamic resolution
2. Results and discussion
Five different chiral alcohols, such as lactate, mandelate, diac-
etoneglucose, pantolactone, and N-methylpseudoephedrine have
been tested for their stereocontrolling ability in dynamic resolution
of
a-halo esters in nucleophilic substitution with various ethyl-
enediamine nucleophiles.
of
metric synthesis of piperazinones were carried out with ethyl (S)-
lactate.4 When the diastereomeric mixture (1:1) of
-bromo ester
RS)-1a was treated with tetrabutylammonium iodide (TBAI,
a-halo esters. Initial studies on chiral alcohol-controlled asym-
a
(a
1.0 equiv), diisopropylethylamine (DIEA, 1.0 equiv), and ethyl-
enediamine (H2NCH2CH2NH2, 1.2 equiv) in CH2Cl2 at room
* Corresponding author. Fax: þ822 3436 5382; e-mail address: parkyong@kon-
kuk.ac.kr (Y.S. Park).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.055

6222
J.I. Jang et al. / Tetrahedron 67 (2011) 6221e6226
temperature for 12 h, the substitution and spontaneous cyclization
produced piperazinone (R)-2 in 48% yield with 80:20 enantiomeric
ratio (er) as shown in Table 1, entry 1. When N-benzyl ethylenedi-
amine (BnHNCH2CH2NH2) was used as a nucleophile, the reaction
produced two regioisomeric piperazinones. Treatment of 1a with
the nucleophile, TBAI, and DIEA for 12 h gave 1-benzyl-3-phenyl-2-
piperazinone (3) as a major product with 80:20 er and 4-benzyl-3-
phenyl-2-piperazinone (4) as a minor product with 87:13 er (entry
2). The regioselectivity of 67:33 suggests different reactivities of
two amino groups. The sterically less hindered primary amino
group of the nucleophile is more reactive than the secondary N-
benzyl amino group. In addition, the reaction of 1a with N,N-
dibenzyl ethylenediamine (BnHNCH2CH2NHBn) nucleophile gave
(R)-1,4-dibenzyl-3-phenyl-2-piperazinone (5a) with a comparable
er of 83:17.
In an effort to improve the stereoselectivity, we examined a se-
ries of substitution reactions of a-bromo a-phenyl acetates with
three different chiral auxiliaries.5e7 Nucleophilic substitutions of
1bed were conducted under the same reaction condition as that
used for ethyl (S)-lactate-derived a-bromo ester 1a. No substantial
difference in stereoselectivity has been found in the reactions of 1b
derived from ethyl (S)-mandelate with three different ethylenedi-
amine nucleophiles (entries 4e6). A higher regioselectivity was
observed with N-benzyl ethylenediamine to produce 3 and 4 in
a ratio of 77:23 (entry 5). Next, we examined the reactivity and the
stereocontrolling ability of diacetone-D-glucose auxiliary in the
Table 1
Reactions of 1aed with ethylenediamine nucleophiles
H
O
N
H2N
NH2
Ph
N
H
2
Bn
N
O
H
N
O
O
BnHN
BnHN
Br
NH2
OR*
+
Ph
N
Bn
4
Ph
Ph
N
H
α
1a-d
(
RS)-
3
Bn
N
NHBn
O
N
Ph
Bn
5a
Entrya
1
Substrate
OR*
Nucleophile
Time (h)
12
Yield (%)
48
erd (R/S)
H2NCH2CH2NH2
80:20
CH3
1a
2
3
BnHNCH2CH2NH2
BnHNCH2CH2NHBn
12
12
66b (67:33)c
70
80:20
87:13e
83:17
O
CO2Et
4
H2NCH2CH2NH2
12
44
75:25
Ph
1b
1c
1d
5
6
BnHNCH2CH2NH2
BnHNCH2CH2NHBn
12
12
50b (77:23)c
87
82:18
81:19e
87:13
O
CO2Me
O
7
H2NCH2CH2NH2
12
48
19:81
O
O
8
9
BnHNCH2CH2NH2
BnHNCH2CH2NHBn
12
12
87b (89:11)c
54
15:85
20:80e
15:85
O
O
O
10
11
H2NCH2CH2NH2
3
61
8:92
O
O
BnHNCH2CH2NH2
BnHNCH2CH2NHBn
3
3
89b (58:42)c
73
10:90
13:87e
6:94
O
12
a
All reactions are carried out with DIEA and TBAI in methylene chloride at rt.
Combined isolated yields of 3 and 4.
The ratio (3/4) was determined by H NMR of the reaction mixture.
Determined by CSP-HPLC.
b
c
d
e
er of minor product 4.

J.I. Jang et al. / Tetrahedron 67 (2011) 6221e6226
6223
substitution reactions with the ethylenediamine nucleophiles.
Treatment of -bromo ester 1c with ethylenediamine, TBAI, and
DIEA gave the substitution product (S)-2 in 48% yield with 81:19 er
as shown in entry 7. Notably, the reaction of 1c with N-benzyl
ethylenediamine took place with a higher regioselectivity, affording
3 and 4 with a ratio of 89:11 (entry 8). In the substitution reactions
reaction of
a
-(4-fluoro-2-methylphenyl)
a
-chloro ester 1i took
a
place with 94:6 er, affording 5e, the key intermediate in the syn-
thesis of GW597599 known as a potent NK1 receptor antagonist2a,b
(entry 5).
Table 3
of a-bromo ester 1d derived from (R)-pantolactone, we are pleased
Asymmetric synthesis of 3-substituted piperazinones 5aeh
to observe much higher stereoselectivities (entries 10e12). The
reaction of 1d with N,N-dibenzyl ethylenediamine gave (S)-5a with
a highest stereoselectivity of 96:4 er compared to the reactions of
1aec (entry 12).
A series of reactions were examined with (R)-pantolactone-de-
rived a-bromo ester 1d to assess the effect of additive, solvent, and
temperature on yield and stereoselectivity as shown in Table 2. In
the presence of either DIEA or TBAI, almost same stereoselectivity
was observed with slightly lower yields (entries 1 and 2). However,
significant decrease in stereoselectivity was observed in the ab-
sence of both TBAI and DIEA (entry 3). We speculate that the
lowering of er in the absence of an epimerizing agent probably
Bn
N
O
BnHN
O
R
NHBn
X
O
O
TBAI
DIEA
R
N
Bn
O
5a-h
(S)-
(αRS)-1e-l
Entrya
1
S.M.
X
R
Yieldb (%)
erc (S/R)
1e
1f
Cl
72 (5a)
80 (5b)
94:6
results from the slower epimerization of a-bromo ester 1d. None of
other solvents explored gave better selectivities than CH2Cl2 and
the reaction in acetone is very slow. As shown in entries 4e11, the
substitution product 5a was obtained with 94:6 er in CHCl3, 94:6 er
in ethyl acetate, 91:9 er in CH3CN, 92:8 er in THF, 94:6 er in p-di-
oxane, 93:7 er in DMF, 93:7 er in acetone, and 91:9 er in diethyl
ether. Both reactions at 50 ꢀC and at 0 ꢀC did not show better se-
lectivity compared to the reactions at room temperature.
2
Cl
94:6
3
4
1g
1h
Br
Cl
90 (5c)
72 (5d)
93:7
93:7
Next, we examined the scope of the methodology in CH2Cl2 with
F
various
a-substituents as shown in Table 3. Initial studies were
carried out with the substitution reactions of
a
-chloro-
a-phenyl
ester 1e derived from (R)-pantolactone. When
a-chloro ester 1e
was treated with N,N-dibenzyl ethylenediamine, TBAI, and DIEA for
5 h, the substitution provided (S)-5a in 72% yield with same
CH3
enantioselectivity (94:6 er) as the reactions of a-bromo ester 1d
(entry 1). Under the same reaction condition, this methodology is
CH3
5
1i
Cl
55 (5e)
94:6
also efficient for the asymmetric preparation of 3-(1-naphtyl)
piperazinone 5b with 94:6 er (entry 2). Reactions of
a-(4-
F
fluorophenyl) -bromo ester 1g and -(4-methylphenyl) -chloro
a
a
a
6
7
8
1j
1k
1l
Br
Br
Br
CH3
CH2CH3
CH2CH2CH2CH3
56 (5f)
77 (5g)
62 (5h)
83:17
86:14
85:15
ester 1h gave the substitution products 5c and 5d, respectively,
with a stereoselectivity of 93:7 er (entries 3 and 4). In addition, the
a
All reactions are carried out for 3 h in methylene chloride at rt.
Isolated yields.
ers are determined by CSP-HPLC.
b
c
Table 2
Synthesis of 5a in various conditions
Bn
N
Encouraged by the observation of high stereoselectivities in the
O
O
BnHN
reactions with pantolactone-derived
out the nucleophilic substitutions of
dibenzyl ethylenediamine nucleophile. The reaction of
a
a
-aryl esters 1dei, we carried
-alkyl esters 1jel with N,N-
-bromo-
methyl ester 1j afforded 3-methyl piperazinone 5f with 83:17 er in
56% yield (entry 6). As with -bromo- -ethyl ester 1k and
bromo- -butyl ester 1l, the reactions with N,N-dibenzyl ethyl-
NHBn
Br
O
O
N
Bn
(S)-5a
Ph
a
a-
Ph
O
a
a
a-
(αRS)-1d
a
Entrya
Solvent
Additive
Temp
Yieldb (%)
erc (S/R)
enediamine, DIEA, and TBAI took place to afford 3-ethyl piper-
azinone 5g and 3-butyl piperazinone 5h with 86:14 er and 85:15 er,
respectively (entries 7 and 8). In all reactions of pantolactone-
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
Ethyl acetate
CH3CN
THF
Dioxane
DMF
DIEA
TBAI
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
58
66
48
66
72
58
62
50
72
18
60
43
75
93:7
93:7
65:35
94:6
94:6
91:9
92:8
94:6
93:7
93:7
91:9
93:7
94:6
No additive
DIEA, TBAI
DIEA, TBAI
DIEA, TBAI
DIEA, TBAI
DIEA, TBAI
DIEA, TBAI
DIEA, TBAI
DIEA, TBAI
DIEA, TBAI
DIEA, TBAI
derived
served compared to
a
-alkyl esters 1jel, much lower stereoselectivity was ob-
-aryl esters 1dei.
a
To understand the reaction pathway of asymmetric induction in
nucleophilic substitution with N,N-dibenzyl ethylenediamine, we
carried out a series of reactions of a-chloro ester 1e as shown in
Table 4. When a mixture of two epimers (69:31 dr) of 1e was
allowed to reach thermodynamic equilibrium in the presence of
TBAI and DIEA, the epimeric ratio of recovered 1e was determined
9
10
11
12
13
Acetone
Diethyl ether
CH2Cl2
0
ꢀC
50 ꢀC
to be 52:48 (entry 1). The result indicates that a-chloro ester 1e is
CH2Cl2
configurationally labile under the reaction condition and the ther-
modynamic stabilities of two epimers are almost same, ruling out
dynamic thermodynamic resolution as a primary pathway. When
a
All reactions are carried out for 3 h.
Isolated yields.
ers are determined by CSP-HPLC.
b
c

6224
J.I. Jang et al. / Tetrahedron 67 (2011) 6221e6226
1e with 29:71 dr was treated with N,N-dibenzyl ethylenediamine in
the presence of both TBAI and DIEA, the reaction gave 2-
piperazinone 5a with 94:6 er as shown in entry 2. In addition, al-
most same er of 5a was observed in the reaction of 1e with reversed
diastereomeric enrichment of 67:33 dr (entry 3). Thus, the er of 5a
is independent of the starting ratio of two epimers of 1e and would
depend on the difference in the epimeric transition state energies.
These results could be taken to suggest that the epimerization of 1e
promoted by TBAI and DIEA is sufficiently fast with respect to the
rate of substitution and the primary pathway of the asymmetric
induction is a dynamic kinetic resolution.
ethylenediamine compared to the reaction of ethylenediamine could
provide -bromo ester 1n more time for epimerization before the
a
substitution and the improved stereoselectivity. The stepwise epi-
merizationesubstitution protocol shown in entry 4 provided 5g in
72% yield with an increased er of 94:6. The enhancement of product
ratio compared to thermodynamic ratio (89:11 dr) of 1n suggest an
additional asymmetric induction by dynamic kinetic resolution.8b,e
The epimerizationesubstitution protocol can provide for the for-
mation of highly enantioenriched 3-alkyl piperazinones 5g and 5i
from the reaction which may seem to have a low level of stereo-
selectivity at first sight.
Table 4
3. Conclusion
Dynamic kinetic resolution of
a-bromo ester 1e
Entrya Substrate (dr)b Condition
Product
Yield (%)
We have presented a novel and practical approach for the
asymmetric syntheses of 3-substituted piperazin-2-ones via dy-
namic resolution of a-halo esters derived from various chiral al-
1
2
3
1e (69:31)b
1e (29:71)b
1e (67:33)b
TBAI, DIEA
1e (52:48 dr) 95
TBAI, DIEA, nucleophile 5a (94:6 er)c
TBAI, DIEA, nucleophile 5a (94:6 er)c
77
74
cohol auxiliaries. Pantolactone is an effective and convenient chiral
auxiliary for the asymmetric syntheses of 3-aryl substituted
piperazin-2-ones in the nucleophilic substitution with N,N-diben-
zyl ethylenediamine nucleophile. Also, preparation of highly
enantioenriched 3-alkyl substituted piperazin-2-ones was ach-
ieved using N-methyl pseudoephedrine-controlled epimer-
izationesubstitution process. The simple protocol with mild
condition and the spontaneous removal of chiral auxiliary suggests
further applications of these methodologies to asymmetric syn-
theses of various heterocyclic compounds.
a
All reactions were carried out for 3 h at rt.
The diastereomeric mixtures of 1e are prepared by column chromatography
b
with fractional collection and the drs were determined by 1H NMR.
c
S/R.
N-Methylpseudoephedrine-controlled asymmetric nucleophilic
substitution of
a-bromo esters has recently been developed in our
laboratory for stereoselective preparation of
a
-heteroatom
substituted carboxylic acids. Theprimary pathwayof theasymmetric
induction isa dynamicthermodynamicresolution(DTR)inwhich the
product ratio is determined by the ratio of two epimeric species that
is established before the addition of nucleophile.8 The successful
4. Experimental
results on a-alkyl-a-bromo esters prompt us to extend the method-
ology to asymmetric syntheses of 3-alkyl substituted piperazinones.
4.1. General procedure for the preparation of a-halo ester 1
As shown inTable 5, thereactions of (S,S)-N-methylpseudoephedrine
A chiral alcohol (1.0 equiv) was treated with racemic
a-bromo
a-bromo-a-butyl ester (aRS)-1m of 56:44 diastereomeric ratio (dr)
carboxylic acid (1.0 equiv), DCC, and DMAP (or -chloro acid chloride
a
with ethylenediamine (H2NCH2CH2NH2) produced 3-butyl piper-
azinone (R)-5i with 60:40 er (entry 1). In contrast, when 1m was
allowed to equilibrate for 20 h before the addition of the nucleophile,
the epimerization with DIEA gave the thermodynamically equili-
brated mixture (89:11 dr) of 1m and the following substitution
provided (R)-5i with 91:9 er (entry 2). The dependency of product
and Et3N) in CH2Cl2 and stirred at room temperature for 3e10 h. The
precipitate was filtered off and the organic phase was washed with
water. The organic phase was dried over MgSO4, filtered, and con-
centrated to provide the crude product that was purified by column
chromatography on silica gel. a-Halo esters 1bed, 1jem, and 1n
were prepared by previously reported procedure in Refs. 4e8.
ratios on the dr of a-bromo ester of 1m implied that the epimeriza-
tion is not fast with respect to their rate of substitution enough to get
to thermodynamic equilibrium before the substitution. When we
used N,N-dibenzyl ethylenediamine (BnHNCH2CH2NHBn) as a nu-
cleophile in the reaction of a-bromo-a-ethyl ester (aRS)-1n (52:48
dr), the substitution furnished 3-ethyl piperazinone 5g in 68% yield
with 85:15 er (R/S) (entry 3). Slower reaction of N,N-dibenzyl
4.1.1. (2-Ethoxy-(S)-1-methyl-2-oxoethyl) 2-bromo-2-phenylacetate
(1a). A pale yellow oil was obtained in 72% yield as a mixture of
two diastereomers. 1H NMR (CDCl3, 400 MHz, two diastereomers)
7.59e7.55 (m, 2H), 7.37e7.30 (m, 3H), 5.44, 5.43 (s,1H), 5.13 (m,1H),
4.20, 4.12 (m, 2H), 1.50, 1.48 (d, J¼7.2 Hz, 3H), 1.23, 1.15 (t, J¼7.1 Hz,
3H); 13C NMR (CDCl3, 100 MHz) 170.2, 168.0, 135.9, 135.8, 129.7,
129.2, 70.1, 62.0, 46.5,17.1,14.4. Anal. Calcd for C13H15BrO4: C, 49.54;
H, 4.80. Found: C, 49.47; H, 4.91.
Table 5
Asymmetric synthesis of 3-substituted piperazinones 5g and 5i
R'
N
4.1.2. 2-Chloro-2-phenylacetic acid (R)-pantolactone ester (1e). A
pale yellow oil was obtained in 83% yield as a mixture of two di-
astereomers. 1H NMR (CDCl3, 400 MHz, two diastereomers)
7.54e7.48 (m, 2H), 7.38e7.33 (m, 3H), 5.54, 5.52 (s,1H), 5.37, 5.34 (s,
1H), 3.97e3.88 (m, 2H),1.13,1.04, 0.98, 0.74 (s, 6H); 13C NMR (CDCl3,
100 MHz) 171.6, 167.7, 134.7, 129.6, 128.9, 128.0, 76.6, 76.2, 58.8,
40.5, 23.0, 19.7. Anal. Calcd for C14H15ClO4: C, 59.48; H, 5.35. Found:
C, 59.49; H, 5.13.
O
Ph
O
R
DIEA
Br
NMe2
O
N
R'
R
CH3
R'HN
NHR'
1m-n
(αRS)-
5g and 5i
Entrya
S.M.
R
Condition
R0
Yieldb (%)
erc (R/S)
1
2
3
4
1m
1m
1n
n-Bu
n-Bu
Et
No epimerization
20 h epimerization
No epimerization
20 h epimerization
H
H
Bn
Bn
67 (5i)
60 (5i)
68 (5g)
72 (5g)
60:40
91:9
85:15
94:6
4.1.3. 2-Chloro-2-(1-nathtyl)acetic acid (R)-pantolactone ester
(1f). A colorless oil was obtained in 43% yield as a mixture of two
diastereomers. 1H NMR (CDCl3, 400 MHz, two diastereomers)
8.18e7.46 (m, 7H), 6.27, 6.23 (s,1H), 5.43, 5.41 (s, 1H), 4.02e3.87 (m,
2H), 1.19, 1.02, 0.89, 0.47 (s, 6H); 13C NMR (CDCl3, 100 MHz) 171.4,
167.9,134.1,131.5, 130.6, 130.4, 129.2, 127.5, 127.1,126.4, 125.4, 123.2,
1n
Et
a
All reactions are carried out in CH3CN at rt and the substitution is performed for
12 h.
b
c
Isolated yields.
ers are determined by CSP-HPLC.

J.I. Jang et al. / Tetrahedron 67 (2011) 6221e6226
6225
76.5, 76.1, 57.6, 40.3, 22.6, 19.1; HRMS calcd for C18H18ClO4 (Mþþ1):
(d, J¼14.6 Hz, 1H), 4.13 (s, 1H), 3.74 (d, J¼13.4 Hz, 1H), 3.42 (m, 1H),
333.0894. Found: 333.0889.
3.13 (d, J¼13.4 Hz, 1H), 3.10 (m, 1H), 2.94 (m, 1H), 2.46 (m, 1H); 13
C
NMR (CDCl3, 100 MHz) 168.8, 139.9, 138.2, 137.3, 129.5, 129.2, 129.1,
128.9, 128.7, 128.6, 128.3, 127.9, 127.6, 71.7, 59.3, 50.7, 47.1, 46.3; IR
(KBr, cmꢁ1) 3029, 2923, 1650, 1453; EIMS (70eV) m/z (relative in-
tensity) 356 (1, Mþ), 327 (5), 265 (90), 251 (20), 118 (17), 91 (100).
Anal. Calcd for C24H24N2O: C, 80.87; H, 6.79; N, 7.86. Found: C,
4.1.4. 2-Bromo-2-(4-fluorophenyl)acetic acid (R)-pantolactone ester
(1g). A pale yellow oil was obtained in 51% yield as a mixture of two
diastereomers. 1H NMR (CDCl3, 400 MHz, two diastereomers)
7.61e7.56 (m, 2H), 7.09e7.04 (m, 2H), 5.53, 5.52 (s, 1H), 5.40 (s, 1H),
4.04, 4.01 (s, 2H), 1.23, 1.14, 1.12, 0.96 (s, 6H); 13C NMR (CDCl3,
100 MHz) 171.5, 167.7, 163.1 (d, J¼248.0 Hz), 131.2, 130.7, 116.0 (d,
J¼28.0 Hz), 76.7, 76.1, 45.6, 40.6, 22.9, 19.7; HRMS calcd for
C14H15BrFO4 (Mþþ1): 345.0138. Found: 345.0137.
80.77; H, 6.84; N, 7.94; ½a D20
þ51.7 (c 0.17, CHCl3); CSP-HPLC
ꢂ
(Chiralcel OD column; 10% 2-propanol in hexane; 0.5 mL/min)
94:6 er, 29.9 min (major enantiomer), 25.0 min (minor
enantiomer).
4.1.5. 2-Chloro-2-(4-methylphenyl)acetic acid (R)-pantolactone ester
(1h). A colorless oil was obtained in 60% yield as a mixture of two
diastereomers. 1H NMR (CDCl3, 400 MHz, two diastereomers)
7.43e7.38 (m, 2H), 7.26e7.19 (m, 2H), 5.50, 5.47 (s, 1H), 5.38, 5.35 (s,
1H), 4.13e3.95 (m, 2H), 2.36 (s, 3H), 1.21, 1.11, 1.06, 0.81 (s, 6H); 13C
NMR (CDCl3, 100 MHz) 171.5, 167.7, 139.7, 132.6, 129.8, 128.1, 76.5,
76.2, 58.9, 40.6, 23.1, 21.3, 19.4. Anal. Calcd for C15H17ClO4: C, 60.71;
H, 5.77. Found: C, 60.85; H, 5.69.
4.2.5. 1,4-Dibenzyl-(S)-3-(1-naphtyl)-2-piperazinone (5b). 1H NMR
(CDCl3, 400 MHz) 8.40 (d, J¼7.6 Hz, 1H), 7.87e7.05 (m, 16H), 4.88 (d,
J¼14.4 Hz, 1H), 4.59 (s, 1H), 4.42 (d, J¼14.4 Hz, 1H), 3.69 (d,
J¼13.6 Hz, 1H), 3.61 (m, 1H), 3.20 (s, 1H), 3.03 (m, 2H), 3.10 (m, 1H),
2.52 (m, 1H); 13C NMR (CDCl3, 100 MHz) 168.4, 137.9, 136.8, 134.9,
134.5, 131.8, 129.2, 129.0, 128.8, 128.7, 128.6, 128.2, 127.6, 127.1,
125.7, 125.6, 125.4, 125.1, 75.7, 59.2, 50.5, 47.6, 45.9; IR (KBr, cmꢁ1
)
3061, 2926, 1650, 1453; EIMS (70eV) m/z (relative intensity) 406 (1,
Mþ), 377 (6), 315 (100), 251 (15), 167 (7), 141 (9), 91 (70); HRMS
a 20
þ
4.1.6. 2-Chloro-2-(4-fluoro-2-methylphenyl)acetic acid (R)-pan-
tolactone ester (1i). A colorless oil was obtained in 58% yield as
a mixture of two diastereomers. 1H NMR (CDCl3, 400 MHz, two di-
astereomers) 7.61e7.50 (m,1H), 6.97e6.88 (m, 2H), 5.76, 5.72 (s,1H),
5.42, 5.38 (s,1H), 4.03, 4.00 (s, 2H), 2.40 (s, 3H),1.20,1.06, 0.81 (s, 6H);
13C NMR (CDCl3, 100 MHz) 171.4, 167.6, 162.9 (d, J¼248.0 Hz), 139.1,
130.5, 129.3, 117.8, 114.0, 76.7, 76.1, 55.3, 40.3, 22.9, 19.7, 19.4; HRMS
calcd for C15H17ClFO4 (Mþþ1): 315.0799. Found: 315.0801.
calcd for C28H27N2O (M þ1): 407.2123. Found: 407.2125; ½ ꢂD
þ58.6 (c 0.13, CHCl3); CSP-HPLC (Chiralcel OD column; 20% 2-
propanol in hexane; 0.5 mL/min) 94:6 er, 34.9 min (major enan-
tiomer), 22.4 min (minor enantiomer).
4.2.6. 1,4-Dibenzyl-(S)-3-(4-fluorophenyl)-2-piperazinone (5c). 1H
NMR (CDCl3, 400 MHz) 7.56e7.05 (m, 14H), 4.63 (d, J¼14.4 Hz, 1H),
4.52 (d, J¼14.4 Hz, 1H), 4.11 (s, 1H), 3.73 (d, J¼13.2 Hz, 1H), 3.45 (m,
1H), 3.13 (d, J¼13.2 Hz, 1H), 3.10 (m, 1H), 2.94 (m, 1H), 2.47 (m, 1H);
13C NMR (CDCl3, 100 MHz) 168.2, 162.5 (d, J¼244.0 Hz), 137.6, 136.8,
135.4, 130.7, 128.8, 128.7, 128.4, 128.3, 127.6, 127.4, 115.3 (d,
J¼21.0 Hz), 70.5, 58.9, 50.3, 46.8, 45.7; IR (KBr, cmꢁ1) 3030, 2923,
1650, 1508, 1221; EIMS (70eV) m/z (relative intensity) 374 (1, Mþ),
345 (3), 283 (100), 251 (20), 136 (12), 109 (8), 91 (75); HRMS calcd
4.2. General procedure for the asymmetric preparation of
2e4 and 5aei
To a solution of a-halo ester in CH2Cl2 or CH3CN (ca. 0.1 M) at
room temperature were added DIEA (1.0 equiv), TBAI (1.0 equiv),
and an ethylenediamine nucleophile (1.2 equiv). After the resulting
reaction mixture was stirred at room temperature for 3e24 h, the
solvent was evaporated and the crude material was purified by
column chromatography to give a 3-substituted 2-piperazinone
with 54e90% yields. The ers of 2e4 and 5aei were determined
by chiral stationary phase HPLC.
for C24H24FN2O (Mþþ1): 375.1873. Found: 375.1877; ½a 2D0
þ48.5 (c
ꢂ
0.27, CHCl3); CSP-HPLC (Chiralcel OD column; 10% 2-propanol in
hexane; 0.5 mL/min) 93:7 er, 27.2 min (major enantiomer),
22.6 min (minor enantiomer).
4.2.7. 1,4-Dibenzyl-(S)-3-(4-methylphenyl)-2-piperazinone (5d). 1H
NMR (CDCl3, 400 MHz) 7.50e7.18 (m, 14H), 4.62 (d, J¼14.6 Hz, 1H),
4.53 (d, J¼14.6 Hz, 1H), 4.10 (s, 1H), 3.76 (d, J¼13.2 Hz, 1H), 3.44
(m, 1H), 3.13 (d, J¼13.2 Hz, 1H), 3.11 (m, 1H), 2.94 (m, 1H), 2.46 (m,
1H), 2.34 (s, 3H); 13C NMR (CDCl3, 100 MHz) 168.6, 137.9, 137.5,
136.9, 136.4, 129.2, 128.9, 128.8, 128.7, 128.3, 127.5, 127.1, 71.0, 58.8,
50.2, 46.7, 45.9, 21.2; IR (KBr, cmꢁ1) 3030, 2922, 1650, 1453; EIMS
(70eV) m/z (relative intensity) 370 (1, Mþ), 341 (5), 279 (100), 251
(23), 132 (7), 105 (10), 91 (55); HRMS calcd for C25H27N2O (Mþþ1):
4.2.1. (S)-3-Phenyl-2-piperazinone (2). 1H NMR (CDCl3, 400 MHz)
7.44e7.29 (m, 5H), 6.57 (br,1H), 4.59(s,1H), 3.53(m,1H), 3.39(m,1H),
3.16 (m, 1H), 3.08 (m, 1H), 1.95 (br, 1H). The spectral data of 2 were
identical to those of the commercially available product. CSP-HPLC
(Chiralcel OJ-H column; 10% 2-propanol in hexane; 0.5 mL/min)
92:8 er, 53.3 min (major enantiomer), 51.3 min (minor enantiomer).
4.2.2. 1-Benzyl-(S)-3-phenyl-2-piperazinone (3). 1H NMR (CDCl3,
400 MHz) 7.43e7.28 (m,10H), 4.63 (m, 3H), 3.40 (m,1H), 3.21 (m,1H),
3.08 (m, 1H), 3.02 (m, 1H), 2.05 (br, 1H). The spectral data of 3 were
identical to those of the authentic material reported previously.9a CSP-
HPLC (Chiralcel OD column; 20% 2-propanol in hexane; 0.5 mL/min)
90:10 er, 26.4 min (major enantiomer), 47.1 min (minor enantiomer).
371.2123. Found: 371.2120; ½a D20
þ39.9 (c 0.09, CHCl3); CSP-HPLC
ꢂ
(Chiralcel OD column; 10% 2-propanol in hexane; 0.5 mL/min)
93:7 er, 23.8 min (major enantiomer), 21.9 min (minor
enantiomer).
4.2.8. 1,4-Dibenzyl-(S)-3-(4-fluoro-2-methylphenyl)-2-piperazinone
(5e). 1H NMR (CDCl3, 400 MHz) 7.52e6.93 (m, 15H), 4.63 (s, 2H),
4.28 (s, 1H), 3.73 (d, J¼13.2 Hz, 1H), 3.50 (m, 1H), 3.12 (m, 1H), 3.06
(d, J¼13.2 Hz, 1H), 2.99 (m, 1H), 2.05 (s, 3H), 2.46 (m, 1H); 13C NMR
(CDCl3, 100 MHz) 168.2, 162.1 (d, J¼244.0 Hz), 140.1, 140.0, 137.8,
136.7, 133.7, 133.6, 131.2, 128.7, 128.6, 128.5, 128.4, 127.6, 127.3,
117.6 (d, J¼21.5 Hz), 112.6 (d, J¼21.5 Hz), 69.0, 59.0, 50.3, 47.4, 45.9,
20.0; IR (KBr, cmꢁ1) 3039, 2970, 1676, 1366, 1217; EIMS (70eV) m/z
(relative intensity) 388 (1, Mþ), 359 (5), 297 (100), 251 (18), 150
(7), 123 (8), 91 (71); HRMS calcd for C25H26FN2O (Mþþ1):
4.2.3. 4-Benzyl-(S)-3-phenyl-2-piperazinone (4). 1H NMR (CDCl3,
400 MHz) 7.55e7.26 (m, 10H), 6.60 (br, 1H), 4.06 (s, 1H), 3.75 (d,
J¼13.4 Hz,1H), 3.45 (m,1H), 3.25 (m,1H), 3.17 (d, J¼13.4 Hz,1H), 2.98
(m,1H), 2.51 (m,1H). The spectral data of 4 were identical to those of
the authentic material reported previously.9b CSP-HPLC (Chiralpak
AD-H column; 10% 2-propanol in hexane; 0.5 mL/min) 87:13 er,
35.0 min (major enantiomer), 28.2 min (minor enantiomer).
4.2.4. 1,4-Dibenzyl-(S)-3-phenyl-2-piperazinone
(5a). 1H
NMR
389.2029. Found: 389.2028; ½a D20
þ41.7 (c 0.10, CHCl3); CSP-HPLC
ꢂ
(CDCl3, 400 MHz) 7.57e7.21 (m, 15H), 4.62 (d, J¼14.6 Hz, 1H), 4.53
(Chiralpak AD-H column; 10% 2-propanol in hexane; 0.5 mL/

6226
J.I. Jang et al. / Tetrahedron 67 (2011) 6221e6226
min) 94:6 er, 49.4 min (major enantiomer), 25.5 min (minor
enantiomer).
1.97 (m, 2H), 1.65 (m, 1H), 1.36 (m, 4H), 0.92 (t, J¼7.2 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) 173.0, 58.8, 43.1, 41.4, 31.6, 28.1, 22.6, 14.0.
The spectral data of 5i were identical to those of the commercially
available material and 5i was converted to N-benzoyl derivative for
4.2.9. 1,4-Dibenzyl-(S)-3-methyl-2-piperazinone
(5f). 1H
NMR
(CDCl3, 400 MHz) 7.35e7.24 (m, 10H), 4.59 (m, 2H), 3.93 (d,
J¼13.5 Hz, 1H), 3.39 (d, J¼13.5 Hz, 1H), 3.31 (q, J¼6.5 Hz, 1H), 3.20
(m, 1H), 3.13 (m, 1H), 2.87 (m, 1H), 2.42 (m, 1H), 1.53 (d, J¼6.6 Hz,
3H); 13C NMR (CDCl3, 100 MHz) 170.7, 137.9, 136.9, 128.9, 128.6,
128.4, 128.1, 127.5, 127.3, 60.6, 58.3, 50.0, 45.6, 45.5, 15.9; IR (KBr,
cmꢁ1) 3031, 2924, 1645, 1453; EIMS (70eV) m/z (relative intensity)
294 (5, Mþ), 279 (12), 265 (4), 251 (35), 203 (100), 91 (100). Anal.
Calcd for C19H22N2O: C, 77.52; H, 7.53; N, 9.52. Found: C, 77.57; H,
chromatographic analysis. ½a D20
ꢁ19.1 (c 0.08, CHCl3); CSP-HPLC
ꢂ
(Chiralcel OJ-H column; 20% 2-propanol in hexane; 0.5 mL/min)
91:9 er, 56.8 min (major enantiomer), 78.1 min (minor
enantiomer).
Acknowledgements
7.45; N, 9.36; ½a D20
þ38.1 (c 0.07, CHCl3); CSP-HPLC (Chiralcel OD
ꢂ
This work was supported by a grant from Korea Research Foun-
dation (2009-0089650) and Seoul R&BD Program (WR090671).
column; 5% 2-propanol in hexane; 0.5 mL/min) 83:17 er, 35.2 min
(major enantiomer), 29.3 min (minor enantiomer).
References and notes
4.2.10. 1,4-Dibenzyl-(R)-3-ethyl-2-piperazinone
(5g). 1H
NMR
(CDCl3, 400 MHz) 7.34e7.23 (m,10H), 4.69 (d, J¼14.4 Hz,1H), 4.53 (d,
J¼14.4 Hz, 1H), 3.96 (d, J¼13.6 Hz, 1H), 3.29 (d, J¼13.6 Hz, 1H), 3.20
(m, 2H), 3.07 (m,1H), 2.89 (m,1H), 2.39 (m,1H), 2.14 (m,1H),1.94 (m,
1H), 1.00 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) 170.1, 138.2,
137.0, 128.8, 128.6, 128.4, 128.2, 127.5, 127.2, 66.0, 58.4, 50.2, 46.0,
45.0, 23.4, 9.4; IR (KBr, cmꢁ1) 3029, 2969,1644,1453; EIMS (70eV)m/
z (relative intensity) 308 (3, Mþ), 279 (100), 251 (34), 217 (31), 91
(100). Anal. Calcd for C20H24N2O: C, 77.89; H, 7.84; N, 9.08. Found: C,
ꢀ
1. (a) Risi, C. D.; Pela, M.; Pollini, G. P.; Trapella, C.; Zanirato, V. Tetrahedron:
Asymmetry 2010, 21, 255; (b) Peng, H.; Carrico, D.; Thai, V.; Blaskovich, M.;
Bucher, C.; Pusateri, E. E.; Sebti, S. M.; Hamilton, A. D. Org. Biomol. Chem. 2006, 4,
1768; (c) Todorovic, A.; Haskell-Luevano, C. Peptides 2005, 26, 2026.
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Org. Process Res. Dev. 2008, 12, 1188; (b) Fabio, R. D.; Griffante, C.; Alvaro, G.;
Pentassuglia, G.; Pizzi, D. A.; Donati, D.; Rossi, T.; Guercio, G.; Mattioli, M.;
Cimarosti, Z.; Marchioro, C.; Provera, S.; Zonzini, L.; Montanari, D.; Melotto,
S.; Gerrard, P. A.; Trist, D. G.; Ratti, E.; Corsi, M. J. Med. Chem. 2009, 52,
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13, 387.
3. Park, Y. S. Tetrahedron: Asymmetry 2009, 20, 2421 and references therein.
4. Koh, K.; Ben, R. N.; Durst, T. Tetrahedron Lett. 1993, 34, 4473.
5. For reviews on mandelate auxiliary, see: (a) Lee, Y. M.; Park, Y. S. Heterocycles
2009, 73, 2233; (b) Lee, Y. M.; Kang, K. H.; Min, H.-M.; Lim, H. J.; Park, E.-H.; Park,
Y. S. Arkivoc 2010, ii, 1.
77.76; H, 7.84; N, 9.24; ½a D20
ꢁ31.0 (c 0.15, CHCl3); CSP-HPLC (Chir-
ꢂ
alcel OD column; 10% 2-propanol in hexane; 0.5 mL/min) 94:6 er,
18.7 min (major enantiomer), 26.1 min (minor enantiomer).
4.2.11. 1,4-Dibenzyl-(S)-3-butyl-2-piperazinone
(5h). 1H
NMR
(CDCl3, 400 MHz) 7.33e7.22 (m, 10H), 4.66 (d, J¼14.6 Hz, 1H), 4.54
(d, J¼14.6 Hz, 1H), 3.93 (d, J¼13.4 Hz, 1H), 3.33 (d, J¼13.4 Hz, 1H),
3.19 (m, 2H), 3.10 (m, 1H), 2.90 (m, 1H), 2.39 (m, 1H), 2.04 (m, 1H),
1.89 (m, 1H), 1.52 (m, 1H), 1.32 (m, 2H), 0.91 (t, J¼7.0 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) 170.8, 138.6, 137.4, 129.2, 129.0, 128.8, 128.6,
127.9, 127.6, 65.5, 58.8, 50.6, 46.1, 45.1, 30.7, 27.9, 23.2, 14.6; IR (KBr,
cmꢁ1) 3029, 2955, 1645, 1454; EIMS (70eV) m/z (relative intensity)
336 (2, Mþ), 279 (100), 251 (22), 91 (89). Anal. Calcd for C22H28N2O:
6. For reviews on diacetone-
D-glucose auxiliary, see: (a) Kim, H. J.; Shin, E.-K.;
Chang, J.-Y.; Kim, Y.; Park, Y. S. Tetrahedron Lett. 2005, 46, 4115; (b) Kim, H. J.;
Kim, Y.; Choi, E. T.; Lee, M. H.; No, E. S.; Park, Y. S. Tetrahedron 2006, 62, 6303; (c)
Kim, Y.; Lee, M. H.; Choi, E. T.; No, E. S.; Park, Y. S. Heterocycles 2007, 71, 5; (d)
Kang, K. H.; Lee, M. H.; Choi, E. T.; Park, Y. S. Bull. Korean Chem. Soc. 2007, 28,
1199.
7. For reviews on pantolactone auxiliary, see: (a) Koh, K.; Durst, T. J. Org. Chem.
1994, 59, 4683; (b) Koh, K.; Ben, R. N.; Durst, T. Tetrahedron Lett. 1994, 35, 375; (c)
O’Meara, J. A.; Gardee, N.; Jung, M.; Ben, R. N.; Durst, T. J. Org. Chem. 1998, 63,
3117; (d) Ben, R. N.; Durst, T. J. Org. Chem. 1999, 64, 7700.
8. (a) Nam, J.; Lee, S.-k.; Kim, K. Y.; Park, Y. S. Tetrahedron Lett. 2002, 43, 8253; (b)
Lee, S.-k.; Nam, J.; Park, Y. S. Synlett 2002, 790; (c) Nam, J.; Lee, S.-k.; Park, Y. S.
Tetrahedron 2003, 59, 2397; (d) Kang, K. H.; Heo, J. H.; Kim, Y.; Park, Y. S. Het-
erocycles 2007, 71, 1163; (e) Kim, Y.; Kang, K. H.; Choi, E. T.; Lee, M. H.; Park, Y. S.
Bull. Korean Chem. Soc. 2007, 28, 325.
C, 78.53; H, 8.39; N, 8.33. Found: C, 78.53; H, 8.34; N, 8.39; ½a D20
ꢂ
þ39.7 (c 0.12, CHCl3); CSP-HPLC (Chiralcel OD column; 10% 2-
propanol in hexane; 0.5 mL/min) 85:15 er, 18.3 min (major enan-
tiomer), 15.6 min (minor enantiomer).
9. (a) Rao, D. V. N. S.; Dandala, R.; Handa, V. K.; Sivakumaran, M.; Naidu, A. Ar-
kivoc 2006, xiv, 1; (b) Guo, B. S.; Yang, Y. S.; Ji, R. Y. Chin. Chem. Lett. 2003, 14,
365.
4.2.12. (R)-3-Butyl-2-piperazinone (5i). 1H NMR (CDCl3, 400 MHz)
7.12 (br, 1H), 3.41 (m, 2H), 3.30 (m, 1H), 3.14 (m, 1H), 2.94 (m, 1H),