Highly efficient synthesis of (R)- and (S)-piperazic acids using proline-catalyzed asymmetric α-hydrazination

Article abstract of DOI:10.1016/j.tetasy.2004.09.025

The highly efficient synthesis of (R)- and (S)-piperazic acids, components of naturally occurring antibiotic cyclodepsipeptides, was achieved in 80% overall yield by the use of a proline-catalyzed asymmetric α-hydrazination as the key step.

Full text of DOI:10.1016/j.tetasy.2004.09.025

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3477–3481
Highly efficient synthesis of (R)- and (S)-piperazic acids using
proline-catalyzed asymmetric a-hydrazination
Yoshiaki Henmi,a Kazuishi Makino,a Yayoi Yoshitomi,a Osamu Harab and
Yasumasa Hamadaa,*
aGraduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
bFaculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 460-8503, Japan
Received 16 September 2004; accepted 30 September 2004
Abstract—The highly efficient synthesis of (R)- and (S)-piperazic acids, components of naturally occurring antibiotic cyclodepsipep-
tides, was achieved in 80% overall yield by the use of a proline-catalyzed asymmetric a-hydrazination as the key step.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
HN
HN
N
H
CO2H
N
H
CO2H
Piperazic acids (R)- and (S)-1, cyclic a-hydrazino acids,
are not only components of several naturally occurring
cyclodepsipeptides1,2 with remarkable biological activi-
ties, but also useful synthetic intermediates in the prep-
aration of medicinally important compounds, such as
enzyme inhibitors.3 To construct polyoxypeptins and
GE3,4 cyclodepsipeptides containing piperazic acids, in
the quantities required for biological evaluation, we
needed to produce multigram amounts of (R)- and
(S)-piperazic acids. Several approaches have been
reported so far,5 although these methods require multi
steps and/or expensive chiral auxiliaries, none of which
are practical for large-scale production. Recent reports
on proline-catalyzed asymmetric synthesis have
disclosed that the selectivities of >90% ee are obtained
in numerous aldol reactions, Mannich reactions, and
a-oxidations.6,7 In particular, we were quite interested
in ListÕs method,8 which can be used for enantioselective
a-hydrazination of aldehydes in high enantiomeric
excess and yield. Herein we report a highly efficient
synthesis of (R)- and (S)-piperazic acids using the
proline-catalyzed asymmetric a-hydrazination as a key
step (Fig. 1).
(R)-Piperazic acid (R)-1
(S)-Piperazic acid (S)-1
Figure 1.
2. Results and discussion
The synthesis was commenced with optimization of the
proline-catalyzed asymmetric a-hydrazination as shown
in Table 1. The required bromoaldehyde 2 was
prepared from commercially available pentane-1,5-diol
in two steps according to the literature.9 First, the
reaction was carried out by the use of 2 and dibenzyl
azodicarboxylate 3 in the presence of a catalytic
amount of (S)-proline in acetonitrile at 0–23°C for
8h (entries 1 and 2). Since the resulting product was
configurationally unstable, the enantiomeric excess
was determined after reduction of the aldehyde with
sodium borohydride in ethanol by the chiral HPLC
analysis of the resulting alcohol. The enantiomeric
excess was 85–87% but was still unsatisfactory. This
problem was solved by maintaining the temperature
at 0°C. Finally, the reaction using a slight excess of
aldehyde at 0°C for 15h was found to proceed in
92% yield and >99% enantiomeric excess. The absolute
stereochemistry of the resulting 4a was established to
be of an (R)-configuration by its conversion to the final
*
Corresponding author. Tel./fax: +81 43 290 2987; e-mail: hamada@
p.chiba-u.ac.jp
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.09.025

3478
Y. Henmi et al. / Tetrahedron: Asymmetry 15 (2004) 3477–3481
Table 1. Asymmetric a-hydrazination using (S)-proline
(S)-proline (10 mol %)
R
N
R
N
R
R
NH
O
3
N
R'O
Br
H
Br
CH3CN
2
4a: R = BnOCO
4b: R = t-BuOCO
then,
NaBH4, EtOH
0°C, 40 min
Entry
Aldehyde (equiv)
Azocarboxylate (R)
Conditions
Yield (%)a
% Eeb
1
1
BnOCO
BnOCO
BnOCO
BnOCO
t-BuOCO
0–23°C, 8h
0–23°C, 8h
0°C, 15h
0°C, 15h
0°C, 28h
43
83
92
91
53
87
85
2
1.48
1.51
1.50
1.50
3
4c
>99
>99
80d
5
a Isolated yields.
b Determined by HPLC analysis using CHIRALCEL OD-H.
c Large scale experiment (55.6mmol scale).
d Determined as the O-benzoyl derivative.
piperazic acid trifluoroacetate and comparisons of the
spectral and physical values with the literature values.
For a demonstration of the reaction in large-scale
synthesis, the reaction in a 55.6mmol (16.1g) of
dibenzyl azodicarboxylate was performed with almost
the same result as in the case of entry 3 being obtained
(entry 4). In the case of di-tert-butyl azodicarboxylate,
the efficiency of the reaction was found to decrease to
53% yield and 80% ee. With a generous amount of the
key hydrazino alcohol 4a in hand, we carried out the
synthesis of (R)- and (S)-piperazic acids as summarized
in Scheme 1. Alcohol (R)-4a was first protected with
tert-butylchlorodimethylsilane (TBSCl) and imidazole
because of failing the direct cyclization of (R)-4a with
sodium hydride. Treatment of silyl protected (R)-5 with
sodium hydride in dimethylformamide at 0°C for
40min, however, produced tetrahydropyridazine (R)-6
in 97% yield (two steps). Deprotection of (R)-6 with
tetra-n-butylammonium fluoride (TBAF) and oxidation
of the resulting alcohol with sodium hypochlorite–
sodium chlorite in the presence of 2,2,6,6-tetramethyl-
1-piperidinyloxy (TEMPO)10 in acetonitrile–phosphate
buffer (pH6.8) afforded di-Cbz-piperazic acid (R)-8 in
90% yield (two steps). Careful examination about a
loss of the stereointegrity during the oxidation revealed
that the reaction proceeded with little to no racemiza-
tion.11 Final deprotection of (R)-8 in the presence of
trifluoroacetic acid in methylene chloride furnished pip-
erazic acid trifluoroacetate (R)-1 in quantitative yield.
Interestingly, the use of methanol, a common solvent
in hydrogenolysis, instead of methylene chloride in
the hydrogenolysis unexpectedly yielded the aromatized
product. The stereointegrity of (R)-1 was unambigu-
ously confirmed after its conversion to the DNP deriv-
ative by chiral HPLC analysis.12 (S)-Piperazic acid (S)-
1 was also obtained by use of (R)- instead of (S)-pro-
line in similar efficiency through the same reaction
sequence.
Cbz
O
Cbz
NH
a
N
c
H
Br
RO
Br
2
4a: R = H
5: R = TBS
b
e
f
TFA•HN
N
OR
N
N
H
CO2H
Cbz
N
Cbz
Cbz
N
CO2H
Cbz
(R)-1
6: R = TBS
7: R = H
8
d
Scheme 1. Synthesis of (R)-piperazic acid. Reagents and conditions: (a) dibenzyl azodicarboxylate 3 (1.51equiv), 5-bromopentanal 2, (S)-proline
(10mol%), acetonitrile, 0°C, 15h, then sodium borohydride, ethanol, 0°C, 40min, 91% yield (two steps in one-pot reaction), >99% ee; (b) TBSCl,
imidazole, DMF, 23°C, 3.5h, 100% yield; (c) sodium hydride, DMF, 0°C, 40min, 97% yield; (d) TBAF, THF, 0°C, 40min, 100% yield; (e) TEMPO,
NaClO–NaClO2, acetonitrile, phosphate buffer (pH6.8), 23°C, 4h, 90% yield; (f) hydrogen, 5% Pd–C, trifluoroacetic acid, methylene chloride, 23°C,
12h, 100% yield.

Y. Henmi et al. / Tetrahedron: Asymmetry 15 (2004) 3477–3481
3479
3. Conclusion
465.0979. Anal. Calcd for C21H25BrN2O5: C, 54.20; H,
5.42; N, 6.02. Found: C, 54.27; H, 5.45; N, 5.95.
We have succeeded in the development of a highly
efficient method for the synthesis of (R)- and (S)-piper-
azic acids from readily available bromoaldehyde 2 in
80% overall yield and six steps using the proline-cata-
lyzed asymmetric a-hydrazination as a key step.
The described method is noteworthy because most
of the synthetic steps proceed in greater than 90% yield
and will promote the use of piperazic acids to medici-
nal chemistry due to its simplicity and cost-
effectiveness.
4.3. (S)-5-Bromo-2-N,N0-dibenzyloxycarbonyhydrazino-
1-pentanol (S)-4a
Prepared according to the procedure described above
for (R)-4a in 100% yield: mp 95.0–96.0°C (ethyl ace-
22
tate/hexane); ½aꢀ ¼ þ12:4 (c 1.03, CHCl3); IR (neat)
D
3265, 3032, 2952, 1712, 1408, 1332, 1266, 1216, 1057,
743cmꢁ1 1H NMR (400MHz, d6-DMSO, 373 K) d
;
1.40–1.49 (m, 1H), 1.56 (br s, 1H), 1.78–1.87 (m, 1H),
1.98 (br s, 1H), 3.31–3.51 (br s, 4H), 4.11 (br s, 1H),
4.72 (br s, 1H), 5.11 (br s, 4H), 7,33 (br s, 10H). HRMS
(FAB, NBA) calcd for C21H26BrN2O5: 465.1025
(M+H+). Found: 465.1015.
4. Experimental
4.1. General
4.4. (R)-5-Bromo-2-N,N0-di-tert-butylcarbonyhydrazino-
1-pentanol (R)-4b
Melting points were measured with a SHIBATA NEL-
270 melting point apparatus. IR spectra were recorded
on a JASCO FT/IR-230 spectrometer. NMR spectra
were recorded on JEOL JNM GSX400A and JNM
ECP400 spectrometers. FAB mass spectra were
obtained with a JEOL JMS-HX-110A spectrometer.
Optical resolutions were determined on a JASCO DIP-
140 and JASCO P-1020 polarimeter. Column chroma-
tography was carried out with silica gel BW-820MH
(Fuji silysia). Analytical thin layer chromatography
was performed on Merck Kieselgel 60F254 0.25mm
thickness plates.
A solution of 5-bromopentanal (840mg, 5.09mmol),
di-tert-butyl azodicarboxylate (781mg, 3.39mmol),
and (S)-proline (39.0mg, 0.339mmol) in CH3CN
(35mL) was stirred at 0°C for 28h. Ethanol (35mL)
and NaBH4 (135mg, 3.55mmol) were added at 0°C
and the mixture stirred at the same temperature. After
2h, the reaction was quenched by the addition of sat-
urated aqueous NH4Cl. The resulting mixture was
extracted with ethyl acetate, washed with saturated
brine, dried over sodium sulfate, filtered, and concen-
trated in vacuo. The residue was purified by silica gel
4.2. (R)-5-Bromo-2-N,N0-dibenzyloxycarbonyhydrazino-
1-pentanol (R)-4a
column chromatography (hexane–ethyl acetate = 2:l)
23
D
to give 4b, (715mg, 53%, 80% ee, ½aꢀ ¼ ꢁ8:0 (c
1.00, CHCl3)) as white solids. The enantiomeric excess
was determined by chiral HPLC analysis of the benzoyl
derivative of 4b (Daicel Chiralcel OD-H, flow rate
1.0mL/min, hexane/i-PrOH = 99:1, retention time:
major 12.9min, minor 9.9min). The analytic sample of
4b was obtained by recrystallization from ethyl acetate/
To a stirred solution of 5-bromopentanal (13.8g,
83.3mmol) and dibenzyl azodicarboxylate (16.1g,
55.6mmol) in CH3CN (400mL) at 0°C was added (S)-
proline (638mg, 5.54mmol, 10mol%). After stirring
the mixture at 0°C for 15h, ethanol (160mL) and
NaBH4 (1.70g, 45.0mmol) was added, and the mixture
was stirred at 0°C for 40min. The reaction was
quenched by slow addition of 10% aqueous citric acid
and the whole solution concentrated in vacuo. This res-
idue was diluted with ethyl acetate, washed with satu-
rated brine, dried over sodium sulfate, filtered, and
concentrated in vacuo to give the title compound as col-
orless solids (>99% ee judged by the chiral HPLC anal-
ysis). The crude material was purified by
recrystallization from ethyl acetate/hexane to give pure
hexane as colorless needles: mp 106–108°C;
24
½aꢀ ¼ ꢁ8:1 (c 1.00, CHCl3); IR (KBr) 3320, 3161,
D
2979, 1685, 1542, 1458, 1397, 1366cmꢁ1
;
1H NMR
(400MHz, CDCl3, 328 K) d 1.30–1.90 (m, 4H), 1.40–
1.60 (m, 18H), 3.35–3.57 (m, 3H), 4.25 (m, 1H), 6.17
(m, 1H); 13C NMR (100MHz, CDCl3, 328 K) d 26.7,
28.1, 28.2, 29.4, 62.4, 81.4, 155.7. HRMS (FAB,
NBA) calcd for C15H30BrN2O5: 397.1338 (M+H+).
Found: 397.1313.
4a (23.5g, 50.4mmol, 91%) as colorless solids: mp
4.5. (R)-2-(N,N0-Dibenzyloxycarbonylhydrazino)-5-
bromo-1-(tert-butyldimethylsiloxy)pentane (R)-5
22
D
94.0–95.5°C; ½aꢀ ¼ ꢁ10:7 (c 1.04, CHCl3); IR 3244,
3037, 1720, 1682, 1543, 1431cmꢁ1
;
1H NMR
(400MHz, d6-DMSO, 373 K) d 1.41–1.45 (m, 1H),
1.54 (br s, 1H), 1.82 (br s, 1H), 1.97 (br s, 1H), 3.29–
3.34 (m, 2H), 3.41–3.46 (m, 2H), 4.09 (br s, 1H), 5.10
(br s, 4H), 7.32 (br s, 10H). HRMS (FAB, NBA) calcd
for C21H26BrN2O5: 465.1025 (M+H+). Found:
To a stirred solution of alcohol (R)-4a (121mg,
0.260mmol) and imidazole (91.1mg, 1.34mmol) in
DMF (3mL) at 23°C was added TBSCl (45.2mg,
0.300mmol) and the mixture stirred for 3.5h. The reac-
tion mixture was diluted with hexane/ethyl acetate,
washed with saturated brine, dried over sodium sulfate,
filtered, and concentrated in vacuo. The residue was
purified by silica gel column chromatography (hexane–
ethyl acetate = 10:1) to give protected alcohol (R)-5
Enantiomeric excess was determined by HPLC using CHIRALCEL
OD-H (hexane/i-PrOH = 90/10 contained 0.1% TFA, flow rate 0.6
mL/min), retention time: 39.9 min for (R) and 34.8 min for (S).
(150mg, 0.259mmol, 100%) as colorless solids: mp
22
D
87°C; ½aꢀ ¼ þ12:3 (c 0.95, MeOH); IR (neat) 3291,

3480
Y. Henmi et al. / Tetrahedron: Asymmetry 15 (2004) 3477–3481
3033, 2953, 2927, 2856, 1758, 1716, 1455, 1408, 1256,
1217, 1109, 836, 776cmꢁ1 1H NMR (400MHz, d6-
(FAB, NBA) calcd for C27H39N2O5Si: 499.2628
(M+H+). Found: 499.2658.
;
DMSO, 373 K) d 0.00 (s, 6H), 0.84 (s, 9H), 1.47–1.52
(m, 1H), l.71 (br s, 2H), 1.89 (br s, 1H), 3.41–3.53 (m,
3H), 3.68 (dd, 1H, J = 5.6, 10.0Hz), 4.03 (br s, 1H),
5.07 (s, 2H), 5.08 (s, 2H), 7.26–7.34 (m, 10H). HRMS
(FAB, NBA) calcd for C27H40BrN2O5Si: 579.1890
(M+H+). Found: 579.1873. Anal. Calcd for
C27H38N2O5Si: C, 65.03; H, 7.68; N, 5.62. Found: C,
64.73; H, 7.63; N, 5.59.
4.9. (R)-1,2-Dibenzyloxycarbonyl-3-hydroxymethyl-
tetrahydropyridazine (R)-7
To a stirred solution of (R)-6 (1.65g, 3.30mmol) in
THF (20.0mL) at 0°C was added 0.5M TBAF
(8.0mL, 4.00mmol). After stirring the mixture at 0°C
for 40min, the reaction was quenched with saturated
brine, and extracted with ethyl acetate. The combined
extracts were washed with brine, dried over sodium
sulfate, filtered, and concentrated in vacuo. The residue
was purified by silica gel column chromatography
4.6. (S)-2-(N,N0-Dibenzyloxycarbonylhydrazino)-5-
bromo-1-(tert-butyldimethylsiloxy)pentane (S)-5
Prepared according to the procedure described above
for (R)-5 in 82% yield: mp 86°C (ethyl acetate/hexane);
(hexane–ethyl acetate = 2:1 to 1:1) to give alcohol (R)-
7 (1.27g, 100%) as a colorless oil: ½aꢀ ¼ ꢁ11:0 (c
;
1414, 1261, 1070, 753cmꢁ1 1H NMR (400MHz, d6-
DMSO, 373 K) d 1.41–1.46 (m, 1H), 1.66–1.76 (br s,
2 + 1H), 3.04 (br s, 1H), 3.37–3.43 (m, 1H), 3.51–3.56
(m, 1H), 3.95 (br s, 1H), 4.20 (br s, 1H), 5.12 (br s,
4H), 7.30 (br s, 10H). HRMS (FAB, NBA) calcd for
C21H25N2O5: 385.1763. Found: 385.1748.
23
D
1.48, CHCl3); IR (neat) 3481, 2948, 2874, 1708, 1455,
23
½aꢀ ¼ ꢁ12:2 (c 1.13, MeOH); IR (neat) 3288, 2953,
D
2927, 2883, 2856, 1720, 1497, 1454, 1255, 1218, 1110,
1
837, 777cmꢁ1; H NMR (400MHz, d6-DMSO, 373 K)
d 0.02 (s, 6H), 0.86 (s, 9H), 1.50–1.57 (m, 1H), 1.73–
2.49 (br s, 3H), 3.41–3.55 (br s, 3H), 3.69–3.73 (dd,
1H, J = 5.6, 10.0Hz), 4.07 (br s, 1H), 5.09 (br s, 4H),
7.30–7.35 (m, 10H). HRMS (FAB, NBA) calcd for
C27H40BrN2O5Si: 579.1890 (M+H+). Found: 579.1873.
Anal. Calcd for C27H38N2O5Si: C, 65.03; H, 7.68; N,
5.62. Found: C, 64.77; H, 7.58; N, 5.58.
4.10. (S)-1,2-Dibenzyloxycarbonyl-3-hydroxymethyl-
tetrahydropyridazine (S)-7
4.7. (R)-1,2-Dibenzyloxycarbonyl-3-(tert-butyldimethyl-
siloxymethyl)tetrahydropyridazine (R)-6
Prepared according to the procedure described above
for (R)-7 in 97% yield: ½aꢀ ¼ þ12:6 (c 1.03
22
D
CHCl3); IR (neat) 3471, 2948, 2975, 1708, 1453, 1413,
1
To a stirred solution of (R)-5 (12.0g, 20.7mmol) in
DMF (100mL) at 0°C was added a suspension of
sodium hydride (60%, 1.78g, 37.0mmol) in DMF
(30mL). After stirring the mixture at 0°C for 40min,
the reaction mixture was quenched with 10% citric acid,
and extracted with hexane/ethyl acetate. The combined
extracts were washed with saturated brine, dried over
sodium sulfate, filtered, and concentrated in vacuo.
The residue was purified by silica gel column chroma-
tography (hexane–ethyl acetate = 10:1) to give (R)-6
1359, 1321, 1262, 1217, 1145, 1071, 1029, 753cmꢁ1; H
NMR (400MHz, d6-DMSO, 373 K) d 1.42–1.47 (m,
1H), 1.65–1.78 (br s, 3H), 3.02 (br s, 1H), 3.41–3.45
(m, 1H), 3.53–3.59 (m, 1H), 3.96–4.00 (m, 1H), 4.22
(br s, 1H), 5.14 (br s, 4H), 7.32 (br s, 10H). HRMS
(FAB, NBA) calcd for C21H25N2O5: 385.1763
(M+H+). Found: 385.1737.
4.11. (R)-1,2-Dibenzyloxycarbonylpiperazic acid (R)-8
(10.0g, 20.1mmol, 97%) as
½aꢀ ¼ þ17:5 (c 1.10, CHCl3); IR (neat) 2952, 2928,
;
837cmꢁ1 1H NMR (400MHz, d6-DMSO, 373 K) d
ꢁ0.02 (s, 6H), 0.83 (s, 9H), 1.44–1.48 (m, 1H), 1.62–
1,77 (m, 3H), 3.04 (br s, 1H), 3.54 (dd, 1H, J = 8.4,
10.0Hz), 3.67–3.71 (m, 1H), 3.93–3.98 (m, 1H), 4.18–
4.21 (m, 1H), 5.04–5.15 (m, 4H), 7.30 (br s, 10H).
HRMS (FAB, NBA) calcd for C27H39N2O5Si:
499.2628 (M+H+). Found: 499.2617.
a
colorless oil:
To a stirred solution of alcohol (R)-7 (1.53g,
23
D
2883, 2856, 1709, 1456, 1413, 1299, 1256, 1085,
3.99mmol), TEMPO (97.7mg, 0.63mmol), and Na-
ClO2 (726mg, 8.02mmol) in CH3CN (20mL) and
phosphate buffer (pH6.8, 20mL) at 23°C was added
1.6M NaClO (500lL). After stirring the mixture at
room temperature for 4h, 1M NaOH (10mL) was
added, and the mixture added to 1M aqueous sodium
sulfite (30mL). The mixture was acidified with 1M
aqueous potassium hydrogen sulfate and extracted with
ethyl acetate. The combined organic extracts were
washed with saturated brine, dried over sodium sulfate,
filtered, and concentrated in vacuo. The residue was
purified by silica gel column chromatography (hexane–
4.8. (S)-1,2-Dibenzyloxycarbonyl-3-(tert-butyldimethyl-
siloxymethyl)tetrahydropyridazine (S)-6
ethyl acetate = 1:1) to give (R)-8 (1.43g, 3.59mmol,
23
D
Prepared according to the procedure described above
90%) as a colorless oil: ½aꢀ ¼ þ20:0 (c 0.975, CHCl3);
23
D
for (R)-6 in 90% yield: ½aꢀ ¼ ꢁ16:7 (c 1.16
IR (neat) 3178, 3033, 2955, 1716, 1456, 1418, 1360,
1254, 1192, 1130, 1088, 1052, 959, 913, 752,
CHCl3); IR (neat) 2953, 2928, 2883, 2856, 1709, 1455,
1414, 1360, 1299, 1255, 1196, 1085, 837, 777, 752,
698cmꢁ1; H NMR (400MHz, CDCl3, 328 K) d 1.59
1
696cmꢁ1
;
1H NMR (400MHz, d6-DMSO, 373 K) d
(br s, 1H), 1.59–1.90 (br s, 2H), 2.17 (br s, 1H), 2.98–
3.16 (br s, 1H), 4.02–4.16 (br s, 1H), 5.00 (br s, 1H),
5.21 (br s, 4H), 7.32 (br s, 10H). HRMS (FAB,
NBA) calcd for C21H23N2O6: 399.1556 (M+H+).
Found: 399.1523.
ꢁ0.01 (s, 6H), 0.84 (s, 9H), 1.45–1.49 (m, 1H), 1.63–
1.77 (m, 3H), 3.06 (br s, 1H), 3.56 (dd, 1H, J = 8.4,
10.0Hz), 3.68–3.72 (m, 1H), 3.95–3.99 (m, 1H), 4.21
(br s, 1H), 5.05–5.17 (m, 4H), 7.31 (br s, 10H). HRMS

Y. Henmi et al. / Tetrahedron: Asymmetry 15 (2004) 3477–3481
3481
4.12. (S)-1,2-Dibenzyloxycarbonylpiperazic acid (S)-8
the Ministry of Education, Culture, Sports, Science,
and Technology, Japan.
Prepared according to the procedure described above
23
D
CHCl3); IR (neat) 3160, 3033, 2954, 1711, 1421, 1358,
for (R)-8 in 91% yield: ½aꢀ ¼ ꢁ19:6 (c 1.04
References
1
1305, 1253, 1191, 1129, 1088, 1051, 752, 697cmꢁ1; H
1. For a review on synthesis of piperazic acids, see Ciufolini,
M. A.; Xi, N. Chem. Soc. Rev. 1998, 27, 437–
445.
NMR (400MHz, CDCl3, 328 K) d 1.59 (br s, 1H),
1.71–2.02 (br s, 3H), 2.20 (br s, 1H), 2.98–3.16 (br s,
1H), 3.99–4.14 (br s, 1H), 4.99 (br s, 1H), 5.11–
5.28 (br s, 4H), 7.33 (br s, 10H). HRMS (FAB, NBA)
calcd for C21H23N2O6: 399.1556 (M+H+). Found:
399.1531.
2. (a) Umezawa, K.; Nakazawa, K.; Uemura, T.; Ikeda, Y.;
Kondo, S.; Naganawa, H.; Kinoshita, N.; Hashizume, H.;
Hamada, M.; Takeuchi, T.; Ohba, S. Tetrahedron Lett.
1998, 39, 1389–1392; (b) Umezawa, K.; Nakazawa, K.;
Ikeda, Y.; Naganawa, H.; Kondo, S. J. Org. Chem. 1999,
64, 3034–3038; (c) Sanglier, J.-J.; Quesniaux, V.; Fehr, T.;
Hofmann, H.; Mahnke, M.; Memmert, K.; Schuler, W.;
Zenke, G.; Gschwind, L.; Maurer, C.; Schilling, W. J.
Antibiot. 1999, 52, 466–473; (d) Fehr, T.; Kallen, J.;
Oberer, L.; Sanglier, J.-J.; Schilling, W. J. Antibiot. 1999,
52, 474–479.
3. Coates, R. A.; Lee, S.-L.; Davis, K. A.; Patel, K. M.;
Rhoads, E. K.; Howard, M. H. J. Org. Chem. 2004, 69,
1734–1737.
4. (a) Makino, K.; Suzuki, T.; Awane, S.; Hara, O.; Hamada,
Y. Tetrahedron Lett. 2002, 43, 9391–9395; (b) Makino, K.;
Suzuki, T.; Hamada, Y. Bull. Chem. Soc. Jpn. 2004, 77,
1649–1653; (c) Makino, K.; Goto, T.; Hiroki, Y.;
Hamada, Y. Angew. Chem., Int. Ed. 2004, 43, 882–884,
and references therein.
4.13. (R)-Piperazic acid trifluoroacetic acid salt (R)-1
A suspension of (R)-8 (3.70g, 9.29mmol), trifluoroacetic
acid (7.0mL, 90.9mmol), and 5% Pd–C (346.5mg) in
methylene chloride (50mL) was stirred under hydrogen
atmosphere at 23°C for 12h. Methanol (50mL) was
added and the mixture filtered through a pad of Celite.
The filtrate was concentrated in vacuo and the residue
purified by recrystallization from ethyl acetate/ethanol
to give trifluoroacetic acid salt (R)-1 (2.26g, 100%) as
colorless solids: mp 149–151°C (lit.11 mp 147–149°C);
22
½aꢀ ¼ ꢁ10:5 (c 0.96, MeOH); IR (KBr) 3292, 3080,
D
2967, 2922, 2835, 2760, 1720, 1664, 1589, 1518, 1421,
1232, 1198, 1130, 1104, 1083, 916, 842, 801, 725cmꢁ1
;
1H NMR (400MHz, D2O) d 1.78–1.97 (m, 3H), 2.15–
2.20 (m, 1H), 3.17–3.23 (m, 1H), 3.29–3.34 (m, 1H),
3.91–3.94 (m, IH); 13C NMR (100MHz, d6-DMSO) d
20.24, 24.92, 43.99, 55.88, 117.12 (q, J = 297.8Hz),
158.49 (q, J = 31.3Hz), 171.52. Anal. Calcd for
C7H11F3N2O4: C, 34.43; H, 4.54; N, 11.47. Found: C,
34.38; H, 4.57; N, 11.42.
5. (a) Hale, K. J.; Cai, J.; Delisser, V.; Manariazar, S.
Tetrahedron Lett. 1992, 33, 7613–7616; (b) Aoyagi, Y.;
Saitoh, Y.; Ueno, T.; Horiguchi, M.; Takeya, K. J. Org.
Chem. 2003, 68, 6899–6904.
6. (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem.
Soc. 2000, 122, 2395–2396; (b) Bogevig, A.; Kumaragu-
rubaran, N.; Jorgensen, K. A. Chem. Commun. 2002, 620–
621; (c) Pidathala, C.; Hoang, L.; Vignola, N.; List, B.
Angew. Chem., Int. Ed. 2003, 42, 2785–2788; (d) List, B. J.
Am. Chem. Soc. 2000, 122, 9336–9337; (e) List, B.;
Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem.
Soc. 2002, 124, 827–833; (f) Cordova, A.; Notz, W.;
Zhong, G.; Betancort, J. M.; Barbas, C. F., III. J. Am.
Chem. Soc. 2002, 124, 1842–1843; (g) Cordova, A.;
Barbas, C. F., III. Tetrahedron Lett. 2003, 44, 1923–
1926; (h) Brown, S. P.; Brochu, M. P.; Sinz, C. J.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 10808–
10809.
7. List, B. Acc. Chem. Res. 2004, 37, 548–557.
8. List, B. J. Am. Chem. Soc. 2002, 124, 5656–5657.
9. Chong, M.; Heuft, M. A.; Rabbat, P. J. Org. Chem. 2002,
65, 5837–5838.
10. Zhao, M. L.; Mano, E.; Song, Z.; Tschaen, D. M.;
Grabowski, E. J.; Reider, P. J. J. Org. Chem. 1999, 64,
2564–2566.
4.14. (S)-Piperazic acid trifluoroacetic acid salt (S)-1
Prepared according to the procedure described above
for (R)-1 in 99% yield: mp 149–151° (ethyl acetate/etha-
22
nol); ½aꢀ ¼ þ11:1 (c 0.98 MeOH); IR (KBr) 3292, 3080,
D
2967, 2922, 2836, 2760, 1720, 1664, 1589, 1509, 1421,
1232, 1198, 1183, 1130, 1082, 916, 842, 801, 725cmꢁ1
;
1H NMR (400MHz, D2O) d 1.85–1.95 (m, 3H), 2.13–
2.18 (m, 1H), 3.14–3.21 (m, 1H), 3.27 (m, 1H), 3.89
(m, 1H); 13C NMR (100MHz, d6-DMSO) d 20.22,
24.91, 43.99, 55.86, 117.12 (q, J = 297.8Hz), 158.47 (q,
J = 31.3Hz), 171.52. Anal. Calcd for C7H11F3N2O4: C,
34.43; H, 4.54; N, 11.47. Found : C, 34.32; H, 4.46; N,
11.38.
11. After conversion of the carboxylic acid 8 to the methyl
ester using iodomethane and potassium hydrogen carbon-
ate in dimethylformamide, the HPLC analysis (Chiralcel
OD-H, hexane–i-PrOH = 80:20) showed 98% ee.
12. Hale, K. J.; Cai, J.; Delisser, V.; Manariazar, S.; Peak, S.
A.; Bhatia, G. S.; Collins, T. C.; Jogiya, N. Tetrahedron
1996, 52, 1047–1068.
Acknowledgements
This work was financially supported in part by a Grant-
in-Aid for Scientific Research on Priority Areas (A)
ÔExploitation of Multi-Element Cyclic MoleculesÕ from