The efficient synthesis of (3R,5R)-5-hydroxypiperazic acid and its diastereomer using Lewis acid-promoted diastereoselective Strecker synthesis

Article abstract of DOI:10.1016/j.tetasy.2006.06.004

The stereoselective synthesis of (3R,5R)-5-hydroxypiperazic acid, a component of naturally occurring antibiotic cyclodepsipeptides, and its diastereomer was achieved via the use of Lewis acid-promoted diastereoselective Strecker synthesis as a key step, i

Full text of DOI:10.1016/j.tetasy.2006.06.004

Tetrahedron: Asymmetry 17 (2006) 1644–1649
The efficient synthesis of (3R,5R)-5-hydroxypiperazic acid and
its diastereomer using Lewis acid-promoted diastereoselective
Strecker synthesis
Kazuishi Makino, Hang Jiang, Tatsuya Suzuki and Yasumasa Hamada*
Graduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Received 22 March 2006; accepted 1 June 2006
Abstract—The stereoselective synthesis of (3R,5R)-5-hydroxypiperazic acid, a component of naturally occurring antibiotic cyclodepsi-
peptides, and its diastereomer was achieved via the use of Lewis acid-promoted diastereoselective Strecker synthesis as a key step, in
which an interesting stereochemical reversal of diastereoselectivity by the choice of Lewis acid catalyst was observed.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
(2S,3R)-3-hydroxy-3-methylproline (HOMePro), and a
unique acyl side chain. HOPips are also found in antibiotic
cyclodepsipeptides, monamycins,2 and himastatin,3 as
(3S,5S)- and (3R,5R)-isomers, respectively. HOPip deriva-
tives have already been synthesized by several groups.4
However, these methods require multi-steps and give low
overall yields, meaning that there is still a need for a
concise method for large-scale production of this unique
component. Herein, we report an efficient synthesis of
(3R,5R)-5-hydroxypiperazic acid and its diastereomer from
commercially available (R)-4-chloro-3-hydroxybutanoic
Polyoxypeptins A 1 and B 2 are novel 19-membered cyclic
hexadepsipeptides isolated from the culture broth of Strep-
tomyces species as reported by Umezawa et al. in 1998
(Fig. 1).1 These cyclodepsipeptides are known to show
strong anticancer activity by induction of apoptosis against
apoptosis-resistant human pancreatic adenocarcinoma
AsPC-1 cells. In addition to their potent biological
activities, polyoxypeptins contain unusual amino acids, in
particular (3R,5R)-5-hydroxypiperazic acid (HOPip) and
Acyl side chain
OH
(R)-Pip
O
OH
O
H
Polyoxypeptin A 1: R = OH
Polyoxypeptin B 2: R = H
N-OH(S)-Ala
NH
HN
H
OH
N
H
O
H
N
R
N
H
(2S,3S)-3-OHLeu
O
O O
H
H
N
O
HO
O
H
HN
O
HN
N-OH(S)-Val
N
H
H
OH
N
O
OH
(2S,3R)-HOMePro
(3R,5R)-5-Hydroxypiperazic acid 3
OH
Figure 1. Polyoxypeptins A and B.
*
Corresponding author. E-mail: hamada@p.chiba-u.ac.jp
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.06.004

K. Makino et al. / Tetrahedron: Asymmetry 17 (2006) 1644–1649
1645
diastereoselective
H
H
N
H
Strecker synthesis
N
H
N
HN
O
BzN
BzN
CN
OH
OH
OTBS
OTBS
3
(R)-5
4
O
OMe
O
OEt
Cl
O
or
MeO
OH
OH
(R)-6
(R)-7
Scheme 1. Retrosynthetic analysis.
N
O
H
O
OMe
1) NH2NH2•H2O (10 eq)
EtOH, 0 ºC to 23 ºC, 93%
RN
TsO
O
ref. 5
MeO
2) BzCl, pyridine
OTBS
0 ºC to 23 ºC, 98%
OTBS
4 steps
OH
(S)-9: R = H
(S)-5 R = Bz
8
(S)-6
Scheme 2.
acid ester using Lewis acid-promoted diastereoselective
Strecker synthesis and an interesting stereochemical rever-
sal of the diastereoselectivity by the choice of the Lewis
acid catalyst.
by Carreira and co-workers6b showed any significant dia-
stereoselectivity. After extensive experiments, we were
Table 1. Lewis acid-promoted diastereoselective Strecker synthesis
H
N
H
N
Me3SiCN (5 eq)
N
CN
CN
2. Results and discussion
Lewis acid, additive
BzN
BzN
BzN
+
CH2Cl2
0 ºC to 23 ºC
Our synthetic plan for (3R,5R)-HOPip is shown in Scheme
1. A key reaction is the Lewis acid-promoted diastereo-
selective Strecker synthesis using chiral cyclic hydrazone
5, which could be obtained from (R)-malic acid or (R)-4-
chloro-3-hydroxybutanoic acid ester. First, we employed
the (S)-malic acid derivative as the starting material for a
model reaction (Scheme 2). The (S)-cyclic hydrazone 5
was prepared in six steps from commercially available
(S)-malic acid dimethyl ester 6. (S)-Aldehyde 8, prepared
according to the literature method,5 was treated with an
excess amount of hydrazine monohydrate in ethanol to
produce cyclic hydrazone 9, which was N-protected with
benzoyl chloride to give N-protected (S)-cyclic hydrazone
5 in excellent yield.
OTBS
(S)-5
OTBS
(3S,5S)-10
syn
OTBS
(3R,5S)-11
anti
Entry Lewis acid
Additive
Time (h) dra syn:anti Yieldb
1
2
None
—
—
24
24
—
75:25
0
52
Zn(OTf)2
(1 equiv)
Zn(OTf)2
(1 equiv)
Zn(OTf)2
(1 equiv)
c
3
4
AcOH
(1 equiv)
AcOH
(1 equiv)
NaOAc
(0.1 equiv)
NaOAc
(0.1 equiv)
—
12
24
—
—
81:19
70
5
6
Zn(OTf)2
(1 equiv)
Hf(OTf)4
(0.1 equiv)
TiCl4
Mg(OAc)2
(1 equiv)
Mg(OAc)2
(1 equiv)
Mg(OAc)2
24
86
87:13
61:39
42
72
We next investigated the diastereoselective Strecker reac-
tion of chiral cyclic hydrazone 5 (0.2 mmol) using Lewis
acids (0.1 equiv) and trimethylsilylcyanide (5 equiv) as a
cyanide source. The results are summarized in Table 1.
Since the Lewis acid-promoted diastereoselective Strecker
synthesis of the chiral cyclic pyrazolines was already re-
ported by two groups,6 our initial experiments focused on
finding an active catalyst for the diastereoselectivity. The
stereochemistry of the syn- and anti-products was deter-
mined, after their acid hydrolysis, by analyzing the N-
(2,4-dinitrophenyl) derivatives of the final HOPips using
7
8
—
—
86
24
45:55
6:94
65
75
9
AcOH
(1 equiv)
AcOH
1
17
24
7:93
3:97
—
96
99
4
10
11
(0.05 equiv) (1 equiv)
—
AcOH
(1 equiv)
1
their H NMR spectroscopy.2b,3a Surprisingly, neither the
a Determined by 1H NMR spectra.
b Isolated yield.
c Decomposition.
hafnium triflate [Hf(OTf)4] catalyst shown by Kobayashi
and co-workers6a nor titanium tetrachloride (TiCl4) used

1646
K. Makino et al. / Tetrahedron: Asymmetry 17 (2006) 1644–1649
pleased to find that zinc triflate [Zn(OTf)2] in combination
with acetic acid and sodium acetate is a syn-selective cata-
lyst providing syn amino nitrile 10 with a diastereoselectiv-
ity of ca. 4:1 (entry 4). One equivalent of Zn(OTf)2 and the
presence of acetic acid and sodium acetate were essential
for a smooth reaction and practical yield (entries 2–5).
Fortunately, the diastereomers were separable by column
chromatography on silica gel and recrystallized from
diisopropyl ether and hexane to afford enantiomericaly
pure 10 and 11. On the other hand, the reaction using mag-
nesium acetate [Mg(OAc)2] in combination with acetic acid
proceeded anti-selectively to exclusively afford the anti
product 11 in 93:7 to 97:3 diastereoselectivity (entries 8–
10). The addition of acetic acid accelerated the reaction
and reduced the amount of Mg(OAc)2 to 0.05 equiv (entry
10). To examine whether both the Strecker reactions de-
scribed above proceeded under thermodynamic control,
diastereomerically pure (3S,5S)-10 was subjected to expo-
sure to Zn(OTf)2–AcOH–NaOAc, a syn-selective catalyst,
at 23 °C for 24 h and Mg(OAc)2–AcOH, anti-selective cat-
alyst, at 23 °C for 17 h, respectively. No equilibration in
either cases was observed and pure 10 was recovered quan-
titatively. The result clearly shows that the above Strecker
reactions proceed under kinetic control. The reason for the
interesting stereochemical reversal of the diastereoselectiv-
ity by the choice of Lewis acid is unclear at present.
The (R)-chiral cyclic hydrazone 5 was also readily prepared
by a similar approach from commercially available (R)-4-
chloro-3-hydroxybutanoic acid ester 7, which could be
alternatively synthesized from ethyl 4-chloroacetoacetate
127 by asymmetric hydrogenation using a Ru-BINAP cat-
alyst (Scheme 3). Protection of 7 with t-butylchlorodimeth-
ylsilane (TBSCl)8 and the subsequent reduction of the ethyl
ester with DIBAL produced (R)-aldehyde 14 in 75% yield
(two steps). The hydrazone formation of 14 using hydr-
azine monohydrate in ethanol proceeded smoothly at room
temperature together with the intramolecular N-alkylation
followed by the protection of the amino group with benz-
oyl chloride to give the (R)-chiral cyclic hydrazone 5 in
89% yield in two steps. The diastereoselective Strecker reac-
tions using (R)-5 with syn- and anti-selection were carried
out under the same conditions described above in the same
diastereoselectivities (Scheme 4). The hydrolysis of the
resulting amino nitriles (3R,5R)-10 and (3S,5R)-11 was
accomplished with refluxing 6 M hydrochloric acid for
12 h to afford (3R,5R)- and (3S,5R)-5-hydroxypiperazic
acid hydrochlorides 3 and 15, which were unstable but
could be isolated as the N-protected esters 16 and 17 in
59% yield (three steps) and 51% yield (three steps),
respectively.
TBSCl
O
O
O
OEt
OEt
OEt
Cl
Cl
Cl
imidazole
ref. 7
DMF
0 ºC to 23 ºC
98%
3. Conclusion
O
OH
OTBS
12
(R)-13
(R)-7 (97%ee)
In conclusion, we have developed diastereoselective Strec-
ker reactions of chiral cyclic hydrazones using Lewis acids,
Zn(OTf)2–AcOH–NaOAc and Mg(OAc)2–AcOH, and suc-
ceeded in obtaining an efficient diastereoselective synthesis
of (3R,5R)- and (3S,5R)-5-hydroxypiperazic acids. In this
reaction, the interesting stereochemical reversal of the dia-
stereoselectivity due to the choice of Lewis acid was
observed. The method described is noteworthy because
the synthesis is carried out in eight steps and 22–33% over-
all yields from commercially available starting materials.
N
O
H
1) NH2NH2•H2O (10 eq)
EtOH, 0 ºC to 23 ºC, 16 h
RN
Cl
DIBAL
2) BzCl, pyridine
hexane
-78˚C
77%
OTBS
0˚C to 23 ˚C, 89% (2 steps)
OTBS
(R)-14
(R)-9: R = H
(R)-5: R = Bz
Scheme 3.
H
H
CN
CO2R2
N
N
R1N
b - d
BzN
a
OTBS
OH
N
(3R,5R)-3: R1= H•HCl, R2= H
(3R,5R)-16: R1= Boc, R2= Me
syn:anti = 81:19
e
BzN
(3R,5R)-10
OTBS
(R)-5
H
H
CN
CO2R2
N
N
R1N
b - d
BzN
syn:anti = 3:97
OTBS
OH
(3S,5R)-15: R1= H•HCl, R2= H
(3S,5R)-17: R1= Boc, R2= Me
(3S,5R)-11
Scheme 4. Reagents and conditions: (a) Me3SiCN (5 equiv), Zn(OTf)2 (1 equiv), AcOH (1 equiv), NaOAc (0.1 equiv), 0–23 °C, 24 h, 70%; (b) 6 M HCl,
reflux, 12 h under argon atmosphere; (c) TsOHÆH2O (0.05 equiv), MeOH, reflux, 19 h; (d) Boc2O (3 equiv), Et3N (3 equiv), 1,4-dioxane–H2O (1:1), 23 °C,
46 h, 59% yield in three steps for 16, 51% yield in three steps for 17; (e) Me3SiCN (4.83 equiv), Mg(OAc)2 (0.05 equiv), AcOH (1 equiv), 0–23 °C, 17 h, 99%
yield.

K. Makino et al. / Tetrahedron: Asymmetry 17 (2006) 1644–1649
1647
1
Further studies directed toward the total synthesis of poly-
oxypeptins are currently in progress.
38.5 mmol, 77%) as a colorless oil: H NMR (400 MHz,
CDCl3) d 0.09 (s, 3H), 0.13 (3H, s), 0.88 (9H, s), 2.69
(1H, ddd, J = 16.7, 6.8, 2.2 Hz), 2.79 (1H, ddd, J = 16.7,
4.8, 1.5 Hz), 3.48 (1H, dd, J = 11.0, 6.4 Hz), 3.55 (1H,
dd, J = 11.0, 4.8 Hz), 4.36–4.43 (1H, m), 9.81 (1H, dd,
J = 2.2, 1.7 Hz); 13C NMR (100 MHz, CDCl3) d ꢁ4.9,
4. Experimental
Melting points were measured with a SIBATA NEL-270
melting point apparatus. Infrared spectra were recorded
on a JASCO FT/IR-230 Fourier transform infrared spec-
trophotometer. Optical rotations were measured on a JAS-
CO P-1020 polarimeter with a sodium lamp. NMR spectra
were recorded on JEOL JNM-GSX 400A (400 MHz) and
JNM ECP400 spectrometers (400 MHz). Mass spectra
were obtained on a JEOL HX-110A (LRFAB, LREI)
spectrometer. Analytical thin layer chromatography was
performed using Merck precoated silica gel (Art. 5715)
plates. The chromatogram was visualized by UV light
and by exposure to one of the phosphomolybdic acids, cer-
ium-phosphomolybdic acid, ninhydrin, and anisaldehyde
solution, followed by heating. Column chromatography
was performed with silica gel 60 N (particle size 40–
63 lm, 230–400 mesh) and silica gel 60 N (spherical, neu-
tral 63–210 mesh). Unless otherwise noted, reagents and
solvents were purified by standard procedures or used as
received.
ꢁ4.6, 18.0, 25.6, 48.0, 48.8, 67.9, 200.4; IR (neat, cmꢁ1
)
2958, 2932, 2898, 2860, 1728, 1435, 1312. HRMS (FAB)
calcd for C10H22ClO3Si: 237.1078 (M+H). Found:
237.1076.
4.3. (R)-5-(tert-Butyldimethylsilanyloxy)-1,4,5,6-tetra-
hydropyridazine (R)-9
To a stirred solution of (R)-14 (9.11 g, 38.5 mmol) in EtOH
(190 mL) at 0 °C was added hydrazine monohydrate
(18.7 mL, 385 mmol), and the mixture was gradually
warmed to 23 °C. After 17 h, the reaction mixture was con-
centrated in vacuo. The residue was diluted with ethyl ace-
tate and saturated aqueous NaHCO3, and the resulting
mixture was extracted with ethyl acetate. The combined
organic extracts were washed with brine, dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was puri-
fied by column chromatography on silica gel (hexane–ethyl
acetate = 2:1) to give (R)-cyclic hydrazone 9 (7.53 g,
25
35.1 mmol, 91%) as a pale yellow oil: ½aꢀD ¼ ꢁ125 (c
1
4.1. Ethyl (R)-3-tert-butyldimethylsilyloxy-4-chlorobutyrate
(R)-13
1.04, CHCl3); H NMR (400 MHz, CDCl3) d 0.08 (6H, s,
CH3), 0.89 (9H, s), 2.09 (1H, ddd, J = 8.0, 2.4, 0.8 Hz),
2.14 (1H, ddd, J = 8.0, 2.0, 0.8 Hz), 2.74 (1H, dd,
J = 10.4, 9.6 Hz), 3.22 (1H, ddd, J = 10.8, 4.4, 2.0 Hz),
4.04–4.12 (1H, m), 5.43 (1H, br s), 6.69 (1H, t,
J = 2.8 Hz); 13C NMR (100 MHz, CDCl3) d ꢁ4.7, 18.0,
25.8, 35.3, 50.1, 63.1, 139.5; IR (neat, cmꢁ1) 3330, 3029,
2955, 2928, 2897, 2857, 1630, 1471, 1463, 1383, 1361,
1288, 1256, 1119. HRMS (EI) calcd for C12H22N2OSi:
214.1501 (M+). Found: 214.1515.
To a stirred solution of (R)-7 (19.1 g, 114 mmol) in DMF
(115 mL) at 0 °C under an argon atmosphere were added
imidazole (11.7 g, 172 mmol) and TBSCl (19.0 g,
126 mmol), and the mixture was gradually warmed to
23 °C. After 20 h, the reaction was quenched with water
and the resulting mixture was extracted with ethyl acetate.
The organic extracts were washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by distillation (104 °C/0.4 mmHg) to give
4.4. (R)-1-Benzoyl-5-(tert-butyldimethylsilanyloxy)-1,4,5,6-
tetrahydropyridazine (R)-5
(R)-13 (31.6 g, 112 mmol, 98%) as
a colorless oil:
26
½aꢀD ¼ þ22:2 (c 2.67, CHCl3); 1H NMR (400 MHz,
CDCl3) d 0.07 (s, 3H), 0.11 (3H, s), 0.87 (9H, s), 1.27
(3H, t, J = 7.1 Hz), 2.52 (1H, dd, J = 15.2, 7.3 Hz), 2.68
(1H, dd, J = 15.2, 4.8 Hz), 3.50 (1H, dd, J = 11.0,
6.0 Hz), 3.53 (1H, dd, J = 11.2, 5.1 Hz), 4.08–4.21 (2H,
m), 4.27–4.35 (1H, m); 13C NMR (100 MHz, CDCl3) d
ꢁ5.0, ꢁ4.6, 14.2, 17.9, 25.6, 40.4, 48.1, 60.6, 69.5, 171.0;
IR (neat, cmꢁ1) 2957, 2931, 2896, 2858, 1738, 1472, 1465,
1377, 1310, 1256, 1200, 1102. HRMS (FAB) calcd for
C12H26ClO3Si: 281.1340 (M+H). Found: 281.1338.
To a stirred solution of (R)-cyclic hydrazone 9 (1.18 g,
5.50 mmol) in pyridine (25 mL) at 0 °C was added drop-
wise benzoyl chloride (0.767 mL, 6.61 mmol), and the mix-
ture was gradually warmed to 23 °C. After 2 h, the reaction
mixture was concentrated in vacuo. The residue was di-
luted with ethyl acetate and saturated aqueous NaHCO3,
and the mixture was extracted with ethyl acetate. The
organic extracts were washed with brine, dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was puri-
fied by column chromatography on silica gel (hexane–ethyl
acetate = 4:1) to give (R)-5 (1.72 g, 5.39 mmol, 98%) as a
4.2. (R)-3-tert-Butyldimethylsilyloxy-4-chlorobutanal (R)-14
25
1
pale yellow oil: ½aꢀD ¼ ꢁ26:7 (c 1.43, CHCl3); H NMR
(400 MHz, CDCl3) d 0.12 (3H, s), 0.13 (3H, s), 0.90 (9H,
s), 2.20 (1H, ddt, J = 18.4, 5.6, 2.0 Hz), 2.49 (1H, ddt,
J = 18.4, 4.8, 2.4 Hz), 3.71 (1H, ddd, J = 13.2, 7.2,
1.6 Hz), 4.02 (1H, dt, J = 13.2, 2.4 Hz), 4.17–4.24 (1H,
m), 6.83 (1H, t, J = 2.4 Hz), 7.36–7.46 (3H, m), 7.61–7.66
(2H, m); 13C NMR (100 MHz, CDCl3) d ꢁ4.8, ꢁ4.7,
17.9, 25.6, 34.0, 46.3, 60.6, 127.6, 129.4, 130.3, 135.0,
141.5, 170.9; IR (neat, cmꢁ1) 2953, 2929, 2889, 2856,
1659, 1620, 1404, 1254, 1102. HRMS (FAB) calcd for
C17H27N2O2Si: 319.1842 (M+H). Found: 319.1841.
To a stirred solution of (R)-13 (14.1 g, 50.1 mmol) in hex-
ane (500 mL) at ꢁ78 °C under an argon atmosphere was
added dropwise DIBAL (56.5 mL, 52.6 mmol, 0.93 M in
hexane). After 2 h, a solution of potassium sodium tartrate
(200 g) in water (500 mL) was added at ꢁ78 °C, and the
resulting mixture was stirred for 1 h at 23 °C. The mixture
was extracted with ether and the combined organic extracts
were washed with brine (500 mL), dried over Na2SO4, fil-
tered, and concentrated in vacuo. The residue was purified
by distillation (90 °C/0.6 mmHg) to give (R)-14 (9.13 g,

1648
K. Makino et al. / Tetrahedron: Asymmetry 17 (2006) 1644–1649
4.5. (3R,5R)-1-Benzoyl-5-(tert-butyldimethylsilanyloxy)-
hexahydropyridazine-3-carbonitrile (3R,5R)-10 and (3S,5R)-
1-benzoyl-5-(tert-butyldimethylsilanyloxy)-hexahydropyr-
idazine-3-carbonitrile (3S,5R)-11
(5H, m); 13C NMR (100 MHz, CDCl3, 55 °C) d ꢁ5.0,
ꢁ4.9, 18.0, 25.7, 36.8, 44.3, 52.8, 63.5, 117.8, 127.9,
128.3, 130.5, 133.7, 164.5; IR (neat, cmꢁ1) 3244, 2953,
2931, 2889, 2857, 2249, 1632, 1469, 1393, 1257, 1111.
HRMS (FAB) calcd for C18H28N3O2Si: 319.1951 (M+H).
Found: 346.1924.
4.5.1. Zinc triflate method. To a stirred mixture of
Zn(OTf)2 (2.40 g, 6.60 mmol), NaOAc (54.1 mg,
0.660 mmol), cyclic hydrazone (R)-5 (2.10 g, 6.59 mmol),
and Me3SiCN (4.42 mL, 33.0 mmol) was added dropwise
at 0 °C under an argon atmosphere AcOH (0.38 mL,
6.64 mmol), and the mixture was then gradually allowed
to warm to 23 °C. After 24 h, the reaction was quenched
with saturated aqueous NaHCO3 at 0 °C. The resulting
mixture was extracted with ethyl acetate. The organic
extracts were washed with brine, dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was puri-
fied by column chromatography on silica gel (hexane–ethyl
acetate = 2:1) to give (3R,5R)-10 (1.30 g, 3.76 mmol, 57%)
and (3S,5R)-11 (296 mg, 0.857 mmol, 13%) as pale yellow
solids. Compound (3R,5R)-10 was purified by recrystalliza-
tion from diisopropyl ether to yield pure 10 with >99% ee
(judged by CHIRALPAK AD, flow rate: 0.5 mL/min,
hexane/isopropanol = 85:15, (3R,5R): 18.1 min, (3S,5S):
21.3 min).
4.6. (3R,5R)-1-tert-Butoxycarbonyl-5-hydroxypiperazic acid
methyl ester (3R,5R)-16
A stirred mixture of (3R,5R)-10 (50 mg, 0.145 mmol) in
6 M HCl (2 mL) was heated at reflux for 12 h under an
argon atmosphere. After cooling to 23 °C, the reaction
mixture was diluted with water, washed with ether, and
concentrated in vacuo to give (3R,5R)-3 as a brown solid,
which was used for the next reaction without further
purification. (3R,5R)-3: 1H NMR (400 MHz, D2O) d
1.96 (1H, dt, J = 14.3, 6.1 Hz), 2.20 (1H, dt, J = 14.1,
4.2 Hz), 2.97 (1H, dd, J = 13.2, 5.9 Hz), 3.23 (1H, dd,
J = 13.2, 2.4 Hz), 3.83 (1H, dt, J = 5.9, 0.9 Hz), 3.98–
4.05 (1H, m); 13C NMR (100 MHz, D2O) d 31.1, 49.6,
53.1, 60.8, 174.1.
A solution of the above crude hydroxypiperazic acid and
p-toluenesulfonic acid monohydrate (1.4 mg, 7.36 lmol)
in MeOH (2.0 mL) was heated at 80 °C for 19 h. The reac-
tion mixture was concentrated in vacuo to give the methyl
ester as a brown solid, which was used for the next reac-
tion without further purification. Triethylamine (62 lL,
0.447 mmol) and Boc2O (94.9 mg, 0.435 mmol) were
added to a stirred solution of the crude methyl ester in
1,4-dioxane (1 mL) and H2O (1 mL) at 0 °C and the
resulting mixture was gradually warmed to 23 °C. After
46 h, the reaction mixture was extracted with ethyl acetate.
The combined organic extracts were washed with brine,
dried over Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by silica gel column chromato-
graphy on silica gel (hexane–ethyl acetate = 1:1) to give
N-Boc piperazic acid methyl ester (3R,5R)-16 (22.4 mg,
0.0861 mmol, 59% in three steps) as a pale yellow oil:
4.5.2. Magnesium acetate method. To a stirred mixture of
Mg(OAc)2 (24.0 mg, 0.169 mmol), cyclic hydrazone (R)-5
(1.08 g, 3.39 mmol), and Me3SiCN (2.2 mL, 16.4 mmol)
at 0 °C under an argon atmosphere was added dropwise
AcOH (195 lL, 3.41 mmol), and the mixture was gradually
allowed to warm to 23 °C. After 17 h, the reaction was
quenched with saturated aqueous NaHCO3 at 0 °C. The
resulting mixture was extracted with ethyl acetate. The
organic extracts were washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by column chromatography on silica gel
(hexane–ethyl acetate = 2:1) to give (3R,5R)-10 (35.0 mg,
0.101 mmol, 3%) and (3S,5R)-11 (1.12 g, 3.24 mmol, 96%)
as pale yellow solids. Further purification of 11 was carried
out by recrystallization from hexane to afford pure 11 with
>99% ee (judged by CHIRALPAK AD, flow rate: 0.5
mL/min, hexane/isopropanol = 85:15, (3R,5S): 17.6 min,
(3S,5R): 21.2 min).
25
1
½aꢀD ¼ þ7:0 (c 1.00, CHCl3); H NMR (400 MHz, CDCl3)
d 1.49 (9H, s), 1.74 (1H, dt, J = 13.2, 4.4 Hz), 2.34 (1H,
dt, J = 13.2, 3.6 Hz), 3.11 (1H, t, J = 9.2 Hz), 3.58–3.61
(2H, m), 3.76 (3H, s), 3.96 (1H, m), 5.12 (1H, br s);
13C NMR (100 MHz, CDCl3) d 28.1, 35.5, 50.9, 52.2,
56.7, 64.4, 81.3, 154.7, 171.2; IR (KBr, cmꢁ1) 3410,
2980, 1738, 1686, 1366, 1236, 1155, 730. HRMS (FAB)
calcd for C11H20N2O5Na: 283.1270 (M+Na+). Found:
283.1265.
25
(3R,5R)-10: mp 163–164 °C (diisopropylether); ½aꢀD
¼
þ15:8 (c 0.85, CHCl3); 1H NMR (400 MHz, CDCl3,
55 °C) d ꢁ0.01 (3H, s), 0.06 (3H, s), 0.88 (9H, s), 2.01
(1H, dt, J = 13.2, 6.4 Hz), 2.22 (1H, dt, J = 13.2, 4.0 Hz),
3.52–3.81 (2H, br m), 3.82–3.88 (1H, m), 3.94–4.03 (1H,
m), 7.36–7.48 (3H, m), 7.52–7.58 (2H, m); 13C NMR
(100 MHz, CDCl3, 55 °C) d ꢁ5.0, 18.1, 25.7, 36.0, 44.3,
52.8, 64.1, 117.9, 128.0, 128.3, 130.4, 133.6, 159.4; IR (neat,
cmꢁ1) 3257, 2952, 2930, 2894, 2856, 1628, 1469, 1401, 1255,
1108. HRMS (FAB) calcd for C18H28N3O2Si: 346.1951
(M+H). Found: 346.1955.
4.7. (3S,5R)-1-tert-Butoxycarbonyl-5-hydroxypiperazic acid
methyl ester (3S,5R)-17
A stirred mixture of (3S,5R)-11 (1.00 g, 2.91 mmol) in 6 M
HCl (29 mL) was heated at reflux for 12 h under an argon
atmosphere. After cooling to 23 °C, the reaction mixture
was diluted with H2O, washed with Et2O, and concentrated
in vacuo to give the crude piperazic acid as a brown solid,
which was used for the next reaction without further puri-
fication. (3S,5R)-15: 1H NMR (400 MHz, D2O) d 1.90 (1H,
ddd, J = 13.9, 11.5, 2.4 Hz), 2.10 (1H, dt, J = 14.3, 4.2 Hz),
3.07–3.17 (2H, m), 4.12 (1H, dd, J = 11.4, 3.5 Hz), 4.15–
25
(3S,5R)-11: mp 134–135 °C (hexane); ½aꢀD ¼ ꢁ26:6 (c 1.19,
1
CHCl3); H NMR (400 MHz, CDCl3, 55 °C) d ꢁ0.05 (3H,
s), 0.02 (3H, s), 0.83 (9H, s), 1.99 (1H, ddd, J = 13.2, 6.8,
4.0 Hz), 2.18 (1H, ddd, J = 13.2, 7.6, 3.6 Hz), 3.47 (1H,
dd, J = 13.2, 6.0 Hz), 3.76 (1H, br d, J = 11.6 Hz), 3.98–
4.05 (1H, m), 4.21 (1H, dt, J = 7.2, 3.2 Hz), 7.37–7.52

K. Makino et al. / Tetrahedron: Asymmetry 17 (2006) 1644–1649
1649
4.21 (1H, m); 13C NMR (100 MHz, D2O) d 31.4, 49.5, 52.3,
References
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A solution of the above crude hydroxypiperazic acid and
p-toluenesulfonic acid monohydrate (27.7 mg, 0.146 mmol)
in MeOH (20 mL) was heated at 80 °C for 19 h. The reac-
tion mixture was concentrated in vacuo to give the methyl
ester as a brown solid, which was used for the next reaction
without further purification. Triethylamine (1.2 mL,
8.66 mmol) and Boc2O (1.91 g, 8.73 mmol) were added to
a stirred solution of the crude methyl ester in 1,4-dioxane
(7.5 mL) and H2O (7.5 mL) at 0 °C. The resulting mixture
was gradually warmed to 23 °C. After 46 h, the reaction
mixture was extracted with ethyl acetate. The combined
organic extracts were washed with brine, dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was puri-
fied by column chromatography on silica gel (hexane–ethyl
acetate = 1:1) to give N-Boc piperazic acid methyl ester
(3S,5R)-17 (386.7 mg, 1.49 mmol, 51% in three steps) as a
26
colorless solid: ½aꢀD ¼ þ2:0 (c 1.00, CHCl3); mp 91–92 °C
1
(Et2O–hexane); H NMR (400 MHz, CDCl3) d 1.49 (9H,
s), 1.89 (1H, ddd, J = 13.6, 10.8, 2.8 Hz), 2.12 (1H, ddt,
J = 13.6, 4.0, 2.0 Hz), 3.31 (1H, dd, J = 13.6, 1.2 Hz),
3.74 (3H, s), 3.91 (1H, br d, J = 13.6 Hz), 3.96 (1H, dd,
J = 10.8, 2.8 Hz), 4.06 (1H, br s, CH), 5.24 (1H, br s);
13C NMR (100 MHz, CDCl3) d 28.3, 34.0, 50.6, 52.1,
53.3, 63.6, 81.3, 156.0, 171.6; IR (KBr, cmꢁ1) 3329, 1734,
1687, 1665, 1237, 1157, 1120. HRMS (FAB) calcd for
C11H20N2O5Na: 283.1270 (M+Na+). Found: 283.1268.
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Acknowledgments
This work was financially supported in part by a Grant-in-
Aid for Scientific Research on Priority Areas (17035015)
from the Ministry of Education, Culture, Sports, Science
and Technology (MEXT) and the Sasakawa Scientific
Research Grant from Japan Science Society (to T.S.).
8. Marino, J. P.; McClure, M. S.; Holub, D. P.; Camasseto, J. V.;
Tucci, F. C. J. Am. Chem. Soc. 2002, 124, 1664–1668.