Asymmetric synthesis of a protected dihydroxypiperazic acid derivative

Article abstract of DOI:10.1055/s-2007-966062

A short and flexible route for the synthesis of 1,2-diisopropyl-3-methyl- (3S,4R,5R)-4,5-dihydroxyhexahydro-1,2,3-pyridazinetricarboxylate, from readily available acrolein, is described. This approach involves an asymmetric α-hydrazination, dihydroxylatio

Full text of DOI:10.1055/s-2007-966062

PAPER
1677
Asymmetric Synthesis of a Protected Dihydroxypiperazic Acid Derivative
A
symmetric
S
.
ynthesis of
a
C
Protected
D
ihyd
h
roxypiperaz
i
a
c
A
cid
D
er
n
ivative drasekhar,*a Ganney Parimala,a Bhoopendra Tiwari,a Ch. Narsihmulu,a G. Dattatreya Sarmab
a
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500007, India
Nuclear Magnetic Resonance Division, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: srivaric@iict.res.in
b
Received 3 November 2006; revised 21 March 2007
OMe
OH
N
Abstract: A short and flexible route for the synthesis of 1,2-diiso-
propyl-3-methyl-(3S,4R,5R)-4,5-dihydroxyhexahydro-1,2,3-pyrid-
azinetricarboxylate, from readily available acrolein, is described.
This approach involves an asymmetric a-hydrazination, dihydroxy-
lation and intramolecular cyclisation as key steps.
HO
CO2Me
CO2
OH
N
OH
CO
N
CH2
CH
O2C
NH
CO
NH
HN
Key words: piperazic acid, L-proline, a-hydrazination, dihydroxy-
lation, intramolecular cyclisation
1
H
C
H
C
OC
NH
CO
C
H
Et
Me
H2C
Piperazic acids are non-proteinogenic amino acids which
contain a cyclic hydrazine skeleton. They are found in
several naturally occurring cyclodepsipeptides1 which
possess remarkable biological activities.2 They are very
useful synthetic intermediates for the preparation of me-
dicinally important compounds3 such as enzyme inhibi-
tors,4 antitumour and anti-HIV peptide antibiotics.5
Piperazic acid itself inhibits g-aminobutyric acid (GABA)
uptake. Substituted piperazic acids are key components of
several biologically active natural peptides including san-
glifehrins,6 GE37,8 and related compounds.
N
glomecidin
NH
Figure 1
The synthesis began with the preparation of the three-car-
bon synthon, aldehyde 5, from commercially available ac-
rolein via Michael addition with p-methoxybenzyl
alcohol (PMBOH; Scheme 2). Asymmetric a-hydrazina-
tion of aldehyde 5 with diisopropyl azodicarboxylate (DI-
The first member of this family was discovered as a com- AD) in the presence of a catalytic amount of L-proline (10
ponent of monamycins by Hassall and co-workers.9 Since mol%) in acetonitrile gave the a-hydrazinated compound
that time, a number of piperazic acids, their C-4 oxygen- 4, the optical purity of which was determined after reduc-
tion to the alcohol 4a,18,19 since the aldehyde 4 was con-
figurationally unstable. The a-hydrazinated compound 4
was subjected to Wittig olefination with a two-carbon
Wittig ylide, to afford 6 in 82% yield (E:Z ratio of 10:1).
The resulting a,b-unsaturated ester 6 was subjected to di-
hydroxylation using catalytic osmium tetroxide and N-
methylmorpholine N-oxide (NMO), to afford 7 and 7a in
a ratio of 4:1, respectively, in 80% yield. The two isomer-
ated variants10 and also 4-hydroxy-2,3,4,5-tetrahydropy-
ridazinecarboxylic acid (HPCA), which is a key subunit in
luzopeptin, have been found in natural peptides. The 4,5-
dihydroxypiperidazine-3-carboxylic acids (DHPC) have
been detected in a novel antifungal cyclic tetrapeptide glo-
mecidin (Figure 1), which was produced by Streptomyces
lavendulae H698SY2,11 though the stereochemistry of the
asymmetric carbons has not yet been determined.
Since a number of pseudopeptides or pseudomimetics
containing the N–N–C–C=O fragment have great poten-
tial in medicinal chemistry,12,13 several methods have
been developed that have enabled the synthesis of the pip-
erazic acid portion of biologically active depsipeptides.14
OH
O
HO
CO2Me
O
OPMB
N
CO2
N
CO2
N
N
Bearing in mind the importance of unusual amino acids
and in a continuation of our efforts towards the synthesis
of such compounds,15 we herein report in detail our syn-
thetic endeavours towards the construction of piperazic
acid derivative 1, using an organocatalysed asymmetric a-
hydrazination as a key reaction (Scheme 1).16,17
CO2
CO2
1
2
O
O
O
PMBO
H
PMBO
O2C
OH
H
N
CO2
O
N
HN CO2
HN CO2
acrolein
3
4
SYNTHESIS 2007, No. 11, pp 1677–1682
x
x.
x
x
.
2
0
0
7
Advanced online publication: 11.05.2007
DOI: 10.1055/s-2007-966062; Art ID: Z23006SS
Scheme 1
© Georg Thieme Verlag Stuttgart · New York

1678
S. Chandrasekhar et al.
PAPER
ic diols were separated through silica gel column chroma- Compound 7 was analysed using 1D and 2D NMR tech-
tography and subsequent synthesis of the required target niques such as DQF-COSY, TOCSY, NOESY and
compound was achieved using the major diastereomer 7. ROESY. The resonance signals of the H6–H12 protons
The diol 7 was treated with 2,2-dimethoxypropane to af- (Figure 2) were broad, which could be due to conforma-
ford 8 (88% yield). The reduction of ester functionality in tional flexibility of the aliphatic chain. Experiments were
compound 8 using lithium borohydride furnished the al- also carried out in order to derive the coupling constants
cohol 3 in 85% yield which, on treatment with p-toluene- at a range of temperatures from 5 °C to 30 °C; however,
sulfonyl chloride (TsCl) in the presence of triethylamine no appreciable resolution was observed. The free rotation
and a catalytic amount of 4-(N,N-dimethylamino)pyridine of C–C single bond therefore made it difficult to ascertain
(DMAP), afforded 9 in 92% yield. Sodium hydride assist- the orientation of the hydroxyl groups at this stage, though
ed intramolecular cyclisation of compound 9 afforded 2 the stereochemistry was determined through analysis of
which, on PMB deprotection with 2,3-dichloro-5,6-dicy- subsequent intermediates.
ano-1,4-benzoquinone (DDQ), gave the alcohol 10 in
6
H
9
81% yield. Compound 10 was converted into the corre-
sponding carboxylic acid methyl ester 11, in two steps, us-
ing bis(acetoxy)iodobenzene, followed by treatment with
diazomethane, in 75% overall yield. Finally, removal of
the isopropylidene group in 11 with 10-camphorsulfonic
acid (CSA) in methanol, smoothly delivered the desired
piperazic acid derivative 1 (Scheme 2).
5
H
13
H
1
2
3
13
H
8 OH O
H3C
H
H14
H14
O
11
12
OH
10
4
O 7
O
2
3
H
H
17
14
18
H
O2C
N
15
1H9 N CO2
16
17
15
Figure 2 Atom-numbering scheme for compound 7
O
R
CO2
CO2
PMBO
OEt
PMBO
O
O
d
b
a
N
N
CO2
CO2
PMBO
H
H
5
HN
acrolein
HN
6
R = CHO
4
c
R = CH2OH
4a
OH
OH
O
O
CO2Et
CO2Et
PMBO
O2C
PMBO
O2C
PMBO
O2C
OEt
e
f
OH
OH
O
+
N
N
N
HN CO2
7 (major)
HN CO2
7a (minor)
HN CO2
8
O
O
O
O
OPMB
PMBO
O2C
OH
PMBO
O2C
OTs
i
g
h
O2
C
O
O
N
N
N
N
HN CO2
HN CO2
O2C
2
3
9
OH
N
O
O
O
OH
O
CO2Me
CO2
CO2Me
CO2
j
OH
k, l
m
N
N
CO2
N
N
N
CO2
CO2
CO2
1
10
11
Scheme 2 Reagents and conditions: (a) PMBOH, AcOH, ClCH2CO2H, r.t., 6 d; (b) L-proline, DIAD, MeCN, 0 °C, 14–15 h; (c) NaBH4,
EtOH, 0 °C, 30 min; (d) Ph3P=CHCO2Et, benzene, r.t., 6 h; (e) OsO4, NMO, acetone, H2O, r.t., 24 h; (f) (i) separation of isomers; (ii) 2,2-
dimethoxypropane, CSA, acetone, r.t., 2 h; (g) LiBH4, EtOH, THF, 0 °C→r.t.; (h) TsCl, Et3N, cat. DMAP, CH2Cl2, 0 °C→r.t.; (i) NaH, THF,
0 °C→r.t., 2 h; (j) DDQ, CH2Cl2–H2O (4:1), r.t.; (k) bis(acetoxy)iodobenzene, TEMPO, MeCN–H2O (1:1), 0 °C→r.t.; (l) CH2N2, Et2O,
0 °C→r.t.; (m) CSA, MeOH, r.t., 25–30 min.
Synthesis 2007, No. 11, 1677–1682 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of a Protected Dihydroxypiperazic Acid Derivative
1679
tions were obtained on a Jasco Dip 360 digital polarimeter. Melting
points were recorded using a Fischer-Johns and are uncorrected.
NMR spectra were recorded in CDCl3 on a Varian Gemini 200,
Bruker 300 or Varian Unity 400 NMR spectrometers. Chemical
shifts (d) are quoted in parts per million (ppm) and are referenced to
tetramethylsilane (TMS) as an internal standard. Coupling con-
stants (J) are quoted in Hertz (Hz). Column chromatographic sepa-
rations were carried out on silica gel (60–120 mesh) and flash
chromatographic separations were carried out using 230–400 mesh
size silica gel. Mass spectra were obtained on Finnegan MAT
1020B or micromass VG 70-70H spectrometers operating at 70 eV,
using a direct inlet system.
The assignment of the structure and stereochemistry of
compounds 1 and 2 was achieved after detailed NMR
studies using DQF-COSY and NOESY. In compound 2
the relative configuration between the protected diol moi-
ety and the N-substituted chiral centre is in the trans-con-
formation, as evidenced by the large coupling constants
(J = 9.2 Hz and 11.5 Hz) and the presence of strong NOE
cross-peaks between H2–H6, H3–H5 and H1–H3. The six-
membered ring takes a distorted chair conformation
which is characterised by the NOE cross-peaks between
H2–H4¢ and H1–H3 as shown in Figure 3. The large cou-
plings observed between H1–H2 and between H3–H4 are
also consistent with a distorted chair conformation.
3-[(4-Methoxybenzyl)oxy]propanal (5)
Acrolein (10.2 g, 0.18 mol) was added to a solution of PMBOH (20
g, 0.14 mol), chloroacetic acid (0.82 g, 8.69 mmol) and NaOH (0.35
g, 8.69 mmol) in H2O (1.8 mL) over a period of 5 min. Subsequent-
ly, acetic acid (3.83 g, 63.7 mmol) was added and the solution was
maintained at r.t. for 6 d. The reaction mixture was diluted with
CH2Cl2 (3 × 30 mL), washed with brine (1 × 30 mL), dried over
Na2SO4, filtered and concentrated under reduced pressure. The
crude residue was purified by silica gel column chromatography
(EtOAc–hexane, 30%) to afford aldehyde 5.
10H3C
CH130
11
O
O
4H
O
13CH3
14
3H
H1
5
N
H3C
O
12
O
N
O
CH3
6
H 15
H
H15
2H 4'
H3C
O
H 16
Yield: 25 g (72%); light-brown viscous oil.
IR (KBr): 1248, 1514, 1612, 1724 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.63–2.66 (2 H, t, J = 6.1 Hz),
3.74–3.77 (2 H, t, J = 6.1 Hz), 3.78–3.79 (3 H, s), 4.43–4.45 (2 H,
s), 6.83–6.87 (2 H, d, J = 8.6 Hz), 7.21–7.24 (2 H, d, J = 8.6 Hz),
9.75–9.77 (1 H, s).
16H
7
8
7
8
9
O
CH3
13C NMR (75 MHz, CDCl3): d = 201.2, 159.2, 129.8, 129.3, 113.7,
72.8, 63.4, 55.2, 43.8.
Figure 3 NOE cross-correlations observed for compound 2
In compound 1, the relative configuration between the
diol moiety and the N-substituted chiral centre is also in
the trans-conformation as evidenced by the coupling con-
stant (J = 8.0 Hz). The six-membered ring also takes a dis-
torted chair conformation, which is suggested by the NOE
cross-peaks between H2–H4, H1–H2 and H3–H7 as shown
in Figure 4. The large coupling (J = 9.7 Hz) observed be-
tween H3–H4 is also consistent with a distorted chair con-
formation.
Diisopropyl 1-{(1R)-1-Formyl-2-[(4-methoxybenzyl)oxy]ethyl}-
1,2-hydrazinedicarboxylate (4)
To a stirred solution of 5 (5 g, 25.77 mmol) and diisopropyl azodi-
carboxylate (5.07 mL, 25.77 mmol) in MeCN (50 mL) at 0 °C, was
added L-proline (296 mg, 2.57 mmol, 10 mol%). The reaction mix-
ture was stirred at 0 °C for 15 h then the solvent was removed in
vacuo and the resulting mixture was extracted with EtOAc (3 × 30
mL), washed with sat. brine (30 mL), dried over Na2SO4, filtered
and concentrated under reduced pressure. Since, the resulting prod-
uct was unstable, the crude material was used in the next step with-
out further purification.
8
Diisopropyl 1-{(1S,2E)-4-Ethoxy-1-[(4-methoxybenzyl)oxy]-
methyl-4-oxo-2-butenyl}-1,2-hydrazinedicarboxylate (6)
The crude aldehyde 4 (4.5 g, 11.36 mmol) was taken in anhyd ben-
zene (40 mL) and (ethoxycarbonylmethylene)triphenylphospho-
rane (4.74 g, 13.6 mmol) was added. The reaction mixture was
stirred for 6 h at r.t. then the solvent was removed under reduced
pressure and the resulting crude product was purified by flash col-
umn chromatography (EtOAc–hexane, 1:3) to afford ester 6.
1 CH3
10
CH3
2H4
O
O
9
H
O
10
7
H
N
O
O
CH3
HO
CH312
6HO
N
11
5 H
3H
CH132
O
Figure 4 NOE cross-correlations observed for compound 1
20
Yield: 4.35 g (82%); colourless viscous liquid; [a]D +1.52 (c 1,
CHCl3).
IR (KBr): 821, 1035, 1249, 1386, 1714, 2982, 3301 cm–1.
In conclusion, the synthesis of a piperazic acid derivative
was achieved in reasonable yields, from readily available
starting materials. The asymmetric a-hydrazination of the
starting aldehyde with L-proline as catalyst and the utili-
sation of the chiral intermediate will be further explored in
order to extend this approach to other related isomers.
1H NMR (300 MHz, CDCl3): d = 1.21–1.33 (15 H, m), 3.47–3.65
(1 H, m), 3.77–3.81 (4 H, m), 4.10–4.24 (2 H, q, J = 7.0 Hz), 4.35–
4.51 (2 H, m), 4.84–4.99 (3 H, m), 6.29–6.61 (1 H, m), 6.76–6.88
(3 H, m), 7.15–7.25 (2 H, d, J = 7.8 Hz).
13C NMR (75 MHz, CDCl3): d = 165.8, 159.3, 156.1, 142.3, 129.2,
113.8, 77.4, 72.5, 70.4, 69.7, 60.3, 55.1, 21.9, 21.8, 14.0.
HRMS (EI): m/z [M + H]+ calcd for C23H35N2O8: 467.2393; found:
467.2404.
Commercial reagents were used without further purification. All
solvents were purified by standard techniques. Infrared (IR) spectra
were recorded on a Perkin–Elmer 683 spectrometer. Optical rota-
Synthesis 2007, No. 11, 1677–1682 © Thieme Stuttgart · New York

1680
S. Chandrasekhar et al.
PAPER
Diisopropyl 1-{(1R,2R,3S)-4-Ethoxy-2,3-dihydroxy-1-[(4-meth-
oxybenzyl)oxy]methyl-4-oxobutyl}-1,2-hydrazinedicarboxyl-
ate (7)
HRMS (EI): m/z [M + H]+ calcd for C26H41N2O10: 541.2761; found:
541.2759.
To a solution of ester 6 (2.5 g, 5.36 mmol) in a mixture of acetone–
H2O (4:1, 40 mL) was added, sequentially, OsO4 (cat.) and NMO
(817 mg, 6.9 mmol). The resulting mixture was stirred for 24 h at
r.t. then sodium metabisulfite (50 mg, 0.26 mmol) was added. After
stirring the reaction mixture for an additional 30 min, the solvent
was removed under reduced pressure. The reaction mixture was di-
luted with EtOAc (60 mL), washed with brine (20 mL), dried over
Na2SO4, filtered and concentrated under reduced pressure. Purifica-
tion of the residue by column chromatography (EtOAc–hexane,
2:3) gave 7 (1.98 g, 74%) as a colourless liquid and 7a as viscous
liquid (450 mg, 16%).
Diisopropyl 1-{(1R)-1-[(4R,5R)-5-(Hydroxymethyl)-2,2-dimeth-
yl-1,3-dioxolan-4-yl]-2-[(4-methoxybenzyl)oxy]ethyl}-1,2-
hydrazinedicarboxylate (3)
A solution of LiCl (423 mg, 9.99 mmol) and NaBH4 (369 mg, 9.99
mmol) in EtOH (20 mL) was stirred at 0 °C for 15 min under a N2
atmosphere in order to generate LiBH4. To this, a solution of com-
pound 8 (1.8 g, 3.33 mmol) in THF (30 mL) was added at 0 °C. The
reaction mixture was stirred at 0 °C for 15–20 min then allowed to
warm to r.t. with stirring overnight. The mixture was concentrated
in vacuo, quenched with sat. aq NH4Cl (20 mL) then extracted with
EtOAc (3 × 20 mL). The organic layer was washed with brine (10
mL), dried over Na2SO4, filtered and concentrated under reduced
pressure. The crude residue was purified by silica gel column chro-
matography (EtOAc–hexane, 1:1) to afford 3.
[a]D20 –0.47 (c 1, CHCl3).
IR (KBr): 1109, 1249, 1717, 2983, 3313 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.25 (6 H, d, J = 6.6 Hz), 1.26
(6 H, d, J = 6.6 Hz), 1.29 (3 H, t, J = 7.0 Hz), 3.12 (1 H, br s), 3.59
(2 H, br s), 3.81 (3 H, s), 3.84 (1 H, br s), 4.03 (1 H, br s), 4.27 (2 H,
q, J = 7.0 Hz), 4.34 (1 H, d, J = 11.7 Hz), 4.51 (1 H, d, J = 11.7 Hz),
4.64 (1 H, br s), 4.77 (1 H, br s), 4.95 (1 H, sept, J = 6.6 Hz), 4.97
(1 H, sept, J = 6.6 Hz), 6.25 (1 H, br s), 6.88 (2 H, d, J = 8.3 Hz),
7.21 (2 H, d, J = 8.3 Hz).
13C NMR (75 MHz, CDCl3): d = 172.3, 159.4, 129.3, 113.9, 77.4,
71.2, 70.7, 69.7, 66.0, 61.7, 55.2, 21.9, 21.8, 21.6, 14.1.
HRMS (EI): m/z [M + H]+ calcd for C23H37N2O10: 501.2448; found:
501.2464.
Yield: 1.42 g (85%); colourless liquid; [a]D20 –2.40 (c 1.2, CHCl3).
IR (KBr): 1052, 1109, 1683, 3019, 3459 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.19–1.30 (12 H, m), 1.31–1.39
(6 H, m), 1.61–1.69 (1 H, br s), 3.53–3.69 (3 H, m), 3.74–3.81 (4 H,
m), 3.99–4.12 (2 H, m), 4.38–4.52 (3 H, m), 4.86–4.99 (2 H, m),
6.22–6.32 (1 H, br s, NH), 6.78–6.85 (2 H, d, J = 8.3 Hz), 7.16–7.21
(2 H, d, J = 8.3 Hz).
13C NMR (75 MHz, CDCl3): d = 159.3, 156.9, 129.7, 129.3, 115.1,
108.9, 98.0, 72.9, 70.9, 65.2, 65.9, 62.1, 55.2, 51.0, 26.9, 21.7.
HRMS (EI): m/z [M + H]+ calcd for C24H39N2O9: 499.2655; found:
499.2639.
Diisopropyl 1-{(1R,2S,3R)-4-Ethoxy-2,3-dihydroxy-1-[(4-meth-
oxybenzyl)oxy]methyl-4-oxobutyl}-1,2-hydrazinedicarboxyl-
ate (7a)
Diisopropyl 1-{(1R)-1-[(4R,5S)-2,2-Dimethyl-5-[(4-methylphe-
nyl)sulfonyl]oxymethyl-1,3-dioxolan-4-yl]-2-[(4-methoxyben-
zyl)oxy]ethyl}-1,2-hydrazinedicarboxylate (9)
[a]D20 +5.58 (c 1.2, CHCl3).
To a stirred solution of alcohol 3 (1.2 g, 2.40 mmol) in anhyd
CH2Cl2 (30 mL) were added, sequentially, TsCl (549 mg, 2.88
mmol), Et3N (0.5 mL, 3.6 mmol) and DMAP (cat.) at 0 °C under N2.
After stirring for 6 h, the reaction mixture was washed with sat. aq
NaHCO3 (10 mL), diluted with CH2Cl2 (30 mL), washed with brine
(20 mL), dried over Na2SO4 and concentrated in vacuo. Purification
of the residue by column chromatography (EtOAc–hexane, 1:3)
gave the pure tosylate 9.
Yield: 1.45 g (92%); colourless oil; [a]D20 –1.22 (c 1, CHCl3).
IR (KBr): 983, 1109, 1514, 1614, 2984, 3415 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.14–1.34 (18 H, m), 2.38–2.51
(3 H, s), 3.42–3.52 (1 H, m), 3.71–3.82 (4 H, m), 3.94–4.28 (4 H,
m), 4.31–4.42 (3 H, m), 4.81–4.99 (2 H, m), 6.21–6.25 (1 H, br s,
NH), 6.78–6.85 (2 H, d, J = 6.0 Hz), 7.16–7.21 (2 H, d, J = 6.0 Hz),
7.24–7.36 (2 H, d, J = 7.5 Hz), 7.71–7.90 (2 H, d, J = 7.5 Hz).
IR (KBr): 821, 1108, 1248, 1386, 1730, 2982, 3302 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.21–1.33 (15 H, m), 3.01–3.19
(1 H, m), 3.61–3.92 (5 H, m), 3.96–4.11 (1 H, m), 4.19–4.28 (2 H,
q, J = 6.7 Hz), 4.32–4.38 (2 H, d, J = 11.3 Hz), 4.45–4.53 (2 H, d,
J = 11.3 Hz), 4.59–4.65 (1 H, m), 4.86–4.97 (2 H, m), 6.21–6.27
(1 H, br s, NH), 6.79–6.85 (2 H, d, J = 9.0 Hz), 7.15–7.22 (2 H, d,
J = 8.3 Hz).
13C NMR (75 MHz, CDCl3): d = 172.3, 159.3, 129.3, 113.9, 77.4,
71.6, 70.0, 66.7, 61.7, 57.5, 55.2, 29.6, 21.8, 21.7, 14.1.
HRMS (EI): m/z [M + H]+ calcd for C23H37N2O10: 501.2448; found:
501.2434.
Diisopropyl 1-{(1R)-1-[(4R,5S)-5-(Ethoxycarbonyl)-2,2-dimeth-
yl-1,3-dioxolan-4-yl]-2-[(4-methoxybenzyl)oxy]ethyl}-1,2-
hydrazinedicarboxylate (8)
To diol 7 (2 g, 4.0 mmol) in acetone (30 mL) was added 2,2-
dimethoxypropane (0.14 mL, 6.0 mmol) and CSA (cat.) at 0 °C.
The reaction mixture was stirred for 2 h at r.t. then neutralised with
sat. aq NaHCO3 (20 mL). The solvent was removed under reduced
pressure and the crude residue was purified by silica gel column
chromatography (EtOAc–hexane, 1:4) to give 8.
Yield: 1.9 g (88%); light-yellow liquid; [a]D20 –0.87 (c 1.6, CHCl3).
IR (KBr): 1108, 1248, 1383, 1716, 2983, 3417 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.19–1.30 (15 H, m), 1.34–1.41
(6 H, m), 3.49–3.60 (1 H, m), 3.78–3.80 (4 H, m), 4.01–4.20 (2 H,
m), 4.31–4.59 (5 H, m), 4.82–4.99 (2 H, m), 6.21–6.32(1 H, br s,
NH), 6.73–6.82 (2 H, d, J = 8.3 Hz), 7.11–7.19 (2 H, d, J = 8.3 Hz).
13C NMR (75 MHz, CDCl3): d = 159.2, 155.6, 144.6, 133.2, 129.6,
129.2, 127.8, 113.7, 109.5, 78.0, 72.7, 71.6, 69.9, 55.0, 27.5, 21.8.
HRMS (EI): m/z [M + H]+ calcd for C31H45N2O11S: 653.2744;
found: 653.2743.
Diisopropyl (3aR,4R,7aR)-4-[(4-Methoxybenzyl)oxy]methyl-
2,2-dimethylperhydro [1,3]dioxolo[4,5-d]pyridazine-5,6-di-
carboxylate (2)
To a well stirred suspension of freshly activated NaH (61.33 mg,
1.53 mmol, 60% w/v dispersion in mineral oil) in anhyd THF (20
mL), a solution of tosylated compound 9 (1 g, 1.53 mmol) in anhyd
THF (20 mL) was added dropwise at 0 °C. The reaction mixture
was stirred for 2 h at r.t. then quenched with ice and diluted with
EtOAc (20 mL), washed with brine (1 × 10 mL) and dried over
Na2SO4. The reaction mixture was concentrated under reduced
13C NMR (75 MHz, CDCl3): d = 171.1, 159.2, 129.0, 114.4, 110.1,
73.6, 70.8, 70.3, 66.1, 61.9, 57.1, 54.2, 27.1, 21.9, 14.1.
Synthesis 2007, No. 11, 1677–1682 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of a Protected Dihydroxypiperazic Acid Derivative
1681
pressure and the crude residue was purified by column chromatog-
HRMS (EI): m/z [M + H]+ calcd for C17H29N2O8: 389.1923; found:
raphy (EtOAc–hexane, 1:3) to give cyclised compound 2.
389.1915.
Yield: 600 mg (81%); yellow liquid; [a]D20 +5.61 (c 1, CHCl3).
IR (KBr): 828, 1104, 1382, 1514, 1613, 1706, 2983 cm–1.
1,2-Diisopropyl 3-Methyl (3S,4R,5R)-4,5-Dihydroxyhexahydro-
1,2,3-pyridazinetricarboxylate (1)
1H MR (600 MHz, CDCl3): d = 1.43 (3 H, s, H-5), 1.19 (3 H, d,
J = 6.2 Hz, H-13), 1.22 (3 H, d, J = 6.2 Hz, H-12), 1.25 (6 H, d,
J = 6.2 Hz, H-10), 1.38 (3 H, s, H-6), 2.90 (1 H, t, J = 11.5 Hz, H-
1), 3.47 (1 H, dd, J = 5.8, 9.2 Hz, H-3), 3.58 (1 H, dd, J = 5.8, 10.6
Hz, H-4), 3.72 (1 H, dd, J = 10.6, 9.2 Hz, H-4¢), 3.75 (1 H, t, J = 9.2
Hz, H-2), 3.81 (3 H, s, H-9), 4.46 (2 H, m, H-16), 4.72 (2 H, dd,
J = 4.7, 12.0 Hz, H-15), 4.91 (1 H, sept, J = 6.2 Hz, H-14), 4.98
(1 H, sept, J = 6.2 Hz, H-11), 6.87 (2 H, d, J = 8.4 Hz, H-8), 7.24
(2 H, d, J = 8.4 Hz, H-7).
13C NMR (75 MHz, CDCl3): d = 168.9, 154.7, 129.1, 113.6, 110.7,
72.9, 70.9, 70.2, 65.3, 58.4, 56.9, 48.4, 26.4, 21.9.
HRMS (EI): m/z [M + H]+ calcd for C24H37N2O8: 481.2549; found:
481.2550.
To a solution of compound 11 (80 mg, 0.206 mmol) in MeOH (15
mL) was added CSA (cat.) and the solution was stirred at r.t. for 30
min. The solvent was evaporated in vacuo and the reaction mixture
was neutralised with aq NaHCO3, diluted with EtOAc and purified
by column chromatography (EtOAc–hexane, 3:1) to afford 1.
Yield: 58 mg (80%); colourless liquid; [a]D20 –5.75 (c 1, CHCl3).
IR (KBr): 1106, 1618, 1713, 2984, 3414 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.23 (3 H, d, J = 6.3 Hz, H-12),
1.27 (6 H, d, J = 6.3 Hz, H-10), 2.70 (1 H, m, H-4), 3.47 (1 H, br s,
H-7, OH), 3.63 (1 H, t, J = 8.0 Hz, H-2), 3.75 (3 H, s, H-8), 4.18
(1 H, dt, J = 5.7, 9.7 Hz, H-3), 4.32 (1 H, br s, H-6, OH), 4.46 (1 H,
dd, J = 4.9, 13.6 Hz, H-5), 4.91 (1 H, sept, J = 6.3 Hz, H-11), 4.98
(1 H, sept, J = 6.3 Hz, H-9), 5.23 (1 H, d, J = 8.0 Hz, H-1).
13C NMR (75 MHz, CDCl3): d = 168.9, 154.7, 71.6, 70.1, 67.5,
Diisopropyl (3aR,4R,7aR)-4-(Hydroxymethyl)-2,2-dimethyl-
perhydro[1,3]dioxolo[4,5-d]pyridazine-5,6-dicarboxylate (10)
To a solution of cyclised compound 2 (0.6 g, 1.25 mmol) in a
CH2Cl2–H2O mixture (4:1, 20 mL) at r.t., was added DDQ (340 mg,
1.5 mmol). The resulting mixture was stirred for 30 min at r.t. and
then quenched with sat. aq NaHCO3 (10 mL) and stirred vigourous-
ly for a further 10–15 min. The reaction mixture was diluted with
CH2Cl2 (3 × 20 mL), washed with brine (10 mL), dried over Na2SO4
and concentrated in vacuo. The residue was purified by column
chromatography (EtOAc–hexane, 2:5) to give 10.
58.4, 52.5, 47.8, 21.8.
HRMS (EI): m/z [M + H]+ calcd for C14H25N2O8: 349.1610; found:
349.1606.
Acknowledgment
G.P. and B.T. thank CSIR, New Delhi for financial assistance.
Yield: 365 mg (81%); yellow liquid; [a]D20 +3.76 (c 1.4, CHCl3).
References
IR (KBr): 759, 1384, 1617, 2985, 3418 cm–1.
(1) Ciufolini, M. A.; Xi, N. Chem. Soc. Rev. 1998, 27, 437.
(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. (b) Umezawa, K.; Nakazawa, K.; Ikeda, Y.;
Naganawa, H.; Kondo, S. J. Org. Chem. 1999, 64, 3034.
(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.
1H NMR (300 MHz, CDCl3): d = 1.24–1.42 (18 H, m), 2.02–2.12
(1 H, br s), 2.84–2.98 (1 H, m), 3.41–3.78 (4 H, m), 4.40–4.54 (1 H,
dd, J = 2.9, 3.6 Hz), 4.91–5.08 (3 H, m).
13C NMR (75 MHz, CDCl3): d = 154.7, 110.9, 77.2, 70.9, 70.2,
57.2, 56.7, 50.1, 48.4, 26.4, 21.9, 21.7.
HRMS (EI): m/z [M + Na]+ calcd for C16H28N2O7Na: 383.1794;
found: 383.1776.
(3) Horton, R. W.; Collins, J. F.; Anlezark, G. M.; Meldrum, B.
S. Eur. J. Pharmacol. 1979, 59, 75.
5,6-Diisopropyl 4-Methyl (3aR,4S,7aR)-2,2-Dimethylper-
hydro[1,3]dioxolo[4,5-d]pyridazine-4,5,6-tricarboxylate (11)
Alcohol 10 (300 mg, 0.83 mmol) was dissolved in a mixture of
MeCN (4 mL) and H2O (4 mL) and bis(acetoxy)iodobenzene
(804.67 mg, 2.49 mmol) and 2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO; 55.51 mg, 0.33 mmol) were successively added at 0 °C.
The mixture was stirred for 1 h at r.t. then extracted with EtOAc
(4 × 20 mL), washed with brine (10 mL) and the combined organic
extracts were dried over Na2SO4 and evaporated under reduced
pressure. As the crude product was unstable, the following reaction
was conducted directly without further purification. The crude res-
idue (210 mg, ~0.56 mmol) was taken in anhyd Et2O (5 mL), CH2N2
(34.53 mg, 0.842 mmol) was added at 0 °C and the mixture was
stirred at r.t. for 30 min. The solvent was removed under reduced
pressure and the crude residue was purified by column chromatog-
raphy (EtOAc–hexane, 1:3) to afford 11.
Yield: 230 mg (71%); colourless liquid; [a]D20 +3.38 (c 1, CHCl3).
IR (KBr): 1106, 1180, 1385, 1714, 2927 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.18–1.36 (12 H, m), 1.38–1.42
(6 H, m), 2.82–2.94 (1 H, m), 3.39–3.48 (1 H, m), 3.71–3.79 (3 H,
s), 4.02–4.14 (1 H, m), 4.72–4.84 (1 H, dd, J = 4.5, 7.5 Hz), 4.91–
5.01 (2 H, m), 5.38–5.50 (1 H, m).
(4) Coates, R. A.; Lee, S. L.; Davis, K. A.; Patel, K. M.; Rhoads,
E. K.; Howard, M. H. J. Org. Chem. 2004, 69, 1734.
(5) (a) Konishi, M.; Ohkuma, H.; Sakai, F.; Tsuno, T.;
Koshiyama, H.; Naito, T.; Kawaguchi, H. J. Am. Chem. Soc.
1981, 103, 1241. (b) Arnold, E.; Clardy, J. J. Am. Chem.
Soc. 1981, 103, 1243.
(6) Fehr, T.; Kallen, J.; Oberer, L.; Sanglier, J.-J.; Schilling, W.
J. Antibiot. 1999, 52, 474.
(7) Agatsuma, T.; Sakai, Y.; Mizukami, T.; Saitoh, Y. J.
Antibiot. 1997, 50, 704.
(8) Sakai, Y.; Yoshida, T.; Tsujita, T.; Ochiai, K.; Agatsuma, T.;
Saitoh, Y.; Tanaka, F.; Akiyama, T.; Akinaga, S.;
Mizukami, T. J. Antibiot. 1997, 50, 659.
(9) (a) Bevan, K.; Davies, J. S.; Hassall, C. H.; Morton, R. B.;
Phillips, D. A. S. J. Chem. Soc. C 1971, 514. (b) Hassall, C.
H.; Ogihara, Y.; Thomas, W. A. J. Chem. Soc. C 1972, 522.
(10) Smitka, T. A.; Deeter, J. B.; Hunt, A. H.; Mertz, F. P.; Ellis,
R. M.; Boeck, L. D.; Yao, R. C. J. Antibiot. 1988, 41, 726.
(11) Kunihiro, S.; Kaneda, M. J. Antibiot. 2003, 56, 30.
(12) (a) Gante, J. Angew. Chem., Int. Ed. Engl. 1994, 33, 1699.
(b) Hanessian, S.; Smith, G. M. N.; Lombart, H. G.; Lubell,
W. D. Tetrahedron 1997, 53, 12789.
13C NMR (75 MHz, CDCl3): d = 168.9, 154.7, 111.2, 71.6, 70.1,
57.2, 52.5, 47.8, 26.9, 21.7.
(13) Hannachi, J.-C.; Vidal, J.; Mulatier, J.-C.; Collet, A. J. Org.
Chem. 2004, 69, 2367.
Synthesis 2007, No. 11, 1677–1682 © Thieme Stuttgart · New York

1682
S. Chandrasekhar et al.
PAPER
(14) (a) Hale, K. J.; Delisser, V.; Manaviazar, S. Tetrahedron
Lett. 1992, 33, 7613. (b) Aoyagi, Y.; Saitoh, Y.; Ueno, T.;
Horiguchi, M.; Takeya, K. J. Org. Chem. 2003, 68, 6899.
(15) (a) Chandrasekhar, S.; Ramachandar, T.; Rao, B. V.
Tetrahedron: Asymmetry 2001, 12, 2315.
(b) Chandrasekhar, S.; Raza, A.; Takhi, M. Tetrahedron:
Asymmetry 2002, 13, 423. (c) Chandrasekhar, S.;
Chandrasekhar, G. Tetrahedron: Asymmetry 2005, 16, 2209.
(16) Bogevig, A.; Juhl, K.; Kumaragurubaran, N.; Zhuang, W.;
Jorgensen, K. A. Angew. Chem. Int. Ed. 2002, 41, 1790.
(17) List, B. J. Am. Chem. Soc. 2002, 124, 5656.
(18) Henmi, Y.; Makino, K.; Yoshitomi, Y.; Hara, O.; Hamada,
Y. Tetrahedron: Asymmetry 2004, 15, 3477.
(19) Enantiomeric excess was 88%, which was determined by
HPLC (Shimadzu LC-10 AT pump) using a CHIRALCEL
OB-H Diacel column (250 × 4.6 mm; hexane–i-PrOH–
EtOH, 80:10:10; flow rate 1.0 mL/min) with UV detection at
254 nm (SPD-10A UV detector).
Synthesis 2007, No. 11, 1677–1682 © Thieme Stuttgart · New York