Efficient synthesis of enantiomerically pure (S)-δ-azaproline starting from (R)-α-hydroxy-γ-butyrolactone via the Mitsunobu reaction

Article abstract of DOI:10.1016/j.tetasy.2009.07.003

The synthesis of enantiomerically pure orthogonally protected δ-azaproline has been performed in five steps including two successive Mitsunobu reactions starting from benzyloxycarbonylaminophthalimide and the (R)-α-hydroxy-γ-butyrolactone.

Full text of DOI:10.1016/j.tetasy.2009.07.003

Tetrahedron: Asymmetry 20 (2009) 1809–1812
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Efficient synthesis of enantiomerically pure (S)-d-azaproline starting
from (R)-
a-hydroxy-
c-butyrolactone via the Mitsunobu reaction
*
Emelyne Voss, Axelle Arrault, Jacques Bodiguel, Brigitte Jamart-Grégoire
Laboratoire de Chimie-Physique Macromoléculaire, UMR CNRS-INPL 7568, Nancy-Université, ENSIC, 1 rue Grandville, BP 20451, 54001 Nancy Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of enantiomerically pure orthogonally protected d-azaproline has been performed in five
steps including two successive Mitsunobu reactions starting from benzyloxycarbonylaminophthalimide
and the (R)-a-hydroxy-c-butyrolactone.
Received 4 June 2009
Accepted 2 July 2009
Available online 7 August 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
of the Mitsunobu reaction. a-Hydroxy-c-butyrolactone seemed
to be the most suitable one as it was commercially available in
an enantiomerically pure form and is not too hindered to allow
the Mitsunobu substitution. As a result, we decided to perform
the reaction between substituted N-benzyloxycarbonylamino-
Among pseudopeptides and peptidomimetics, a-hydrazinopep-
tides have been used extensively for the elucidation of biological
mechanisms.1 From a structural point of view, the presence of an
extra nitrogen in the backbone of a peptide chain generally induces
specific conformations such as hydrazinoturn.2 The family of
azaprolines is of great interest in biology as several studies de-
scribed dramatic conformational change and a concomitant alter-
phthalimide 1 with (R)-a-hydroxy-c-butyrolactone via the Mits-
unobu reaction. As this reaction proceeds with total inversion of
configuration, we obtained the corresponding compound 2 in pure
(S)-form with a very good yield of 80% (Scheme 1).
ation of biological response of
a
-azaproline-containing peptides.3
Some syntheses of racemic d-azaproline, a cyclic hydrazine analo-
gous to proline, have been described in the literature.4 However,
O
O
a
-hydrazinoacids as starting materials.1,5 Carre-
Z
Z
none of them use
ira and co-workers reported that substituted
a
2-pyrazoline, ob-
N
N
N
N
D
tained via a dipolar cycloaddition of Me3SiCHN2 and camphor
sultam-derived dipolarophiles, could give enantiomerically pure
d-azaprolines, after enantiomeric resolution.6 Kim et al. have also
synthesized enantiomerically pure d-azaproline, as intermediate
for the synthesis of a peptidic secondary structure mimetic, start-
ing from malic acid.7
H
O
O
O
O
Z
1
2
Boc
Boc
Z
Boc
H
b
c
N
N
N
N
2. Results and discussion
O
O
O
O
A few years ago, we developed an easy and convenient method
to replace a hydroxyl group by a hydrazino group by using a Mits-
unobu8 protocol using N-alkoxy-carbonylaminophthalimide deriv-
atives as acidic partners. This pathway was used successfully in the
synthesis of enantiomerically pure bis-nitrogen containing ana-
4
3
Scheme 1. Reagents and conditions: (a) (R)-
a
-hydroxy-c-butyrolactone, DBAD,
PPh3, THF, rt, 80%; (b) (i) MeNH2/MeOH, THF, rt; (ii) Boc2O, cat. DMAP, THF, rt, 94%;
(c) Mg(ClO4)2, CH3CN, rt, 90%.
logues such as
a-hydrazinoacid and N-aminodipeptide deriva-
tives.9 We thought that the same kind of protocol could be
adapted to obtain enantiomerically pure d-azaproline. The main
difficulty of this work was to find the appropriate alcohol partner
By using a two-step one-pot protocol reaction developed in the
laboratory,10 we were able to transform the phthalimide protecting
group into a bis-tert-butyloxycarbonyl group to obtain compound
3. One of the two tert-butyloxycarbonyl groups can also be re-
moved by using Mg(ClO4)2.11 This trans-protection allowed the
introduction of a Boc protecting group on the nitrogen which is
one of the most used protecting groups in amino acid and peptide
* Corresponding author. Tel.: +33 (0)383175279; fax: +33 (0)383379977.
E-mail address: Brigitte.Jamart@ensic.inpl-nancy.fr (B. Jamart-Grégoire).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.07.003

1810
E. Voss et al. / Tetrahedron: Asymmetry 20 (2009) 1809–1812
NaOH
R'Br, Bu4NBr
THF/H2O
RT, 24 h
Boc
R
Z
Boc
R
Z
acetone
55 ºC, 24 h
N
O
N
N
O
N
3 or 4
quantitative
80%
OH
OH
O-Na+
OR'
6a R=Boc, R'=Bn
7a R=Boc, R'= iPr
5a R=Boc
5b R=H
Scheme 2. Formation of carboxylates 5a/5b and hydroxyesters 6a/7a.
chemistry. As we chose a Z group to protect the N-aminophthali-
mide starting material, we obtained orthogonally protected com-
pounds (Scheme 1).
Boc
H
Z
Boc
H
Z
iPrX, Bu4NY a
acetone or THF
30º C, 76 h
N
O
N
N
O
N
The next step consisted of finding the best conditions to open
the lactone. Two possibilities were offered. The opening of the lac-
tone can be performed either from bis-protected compound 3 or
from mono-protected compound 4. By using basic conditions, we
were able to obtain the carboxylates 5a and 5b from lactones 3
or 4, respectively, in quantitative yield. The greatest difficulty in
this work was to find good conditions to transform the carboxylate
groups of 5a and 5b in an ester group, stable enough to avoid retro
reaction.12 Starting from sodium salt 5a, the esterification with
benzyl bromide, in the dipolar aprotic solvent DMF, did not lead
to the formation of benzyl ester 6a. This was probably due to the
low solubility of the carboxylate 5a in DMF.13 At the same time,
the use of benzyl bromide in the presence of a catalytic amount
of tetrabutylammonium bromide in acetone enabled us to obtain
the corresponding stable benzyl ester 6a (Scheme 2).14
Unfortunately, the Boc-monodeprotection of compound 6a
failed under whatever the conditions we used, catalytic or stoichi-
ometric amounts of Mg(ClO4)2. Furthermore, using the same condi-
tions of esterification on sodium salt 5b gave the unwanted lactone
4, quantitatively. An identical result was obtained when the Boc-
monodeprotection of ester 6a was carried out in basic conditions,
using potassium carbonate in refluxing methanol.15 In fact, we
thought that the simultaneous presence of the free NH and the la-
bile benzyl ester group was responsible for the retro lactonization
(Scheme 3).
a
OH
OH
49−100%
O-Na+
O
5b
7b
a X = Br, Y = Br, acetone, 49%
X = I, Y = F, THF, 100%
Scheme 4. Formation of isopropyl ester 7b.
The last step of the synthesis of orthogonally protected d-azapr-
oline 8 consisted of a cyclization, which was performed via an
intramolecular Mitsunobu reaction between the hydroxyl and the
NH groups of compound 7b. As we demonstrated before, the intro-
duction of a hydrazine function on a molecule via an intermolecu-
lar Mitsunobu protocol necessitated the use of a hydrazine bearing
three electron-withdrawing groups, which contributed to a de-
crease in the pKa of the sole NH group around 11.9b For this reason,
very good yields were obtained when N-alkoxy or benzyloxy car-
bonylaminophthalimides were used as acidic partner. On the con-
trary, no reaction occurred when only two electron-withdrawing
groups were present on the hydrazino acidic partner. As intramo-
lecular processes are generally easier to perform when compared
to intermolecular ones, Mitsunobu reaction can give good results
even if these rules are not respected. This behaviour was effectively
described once in the literature for the synthesis of (S)-3-carbo-
benzoxyamino-1-amino-2-azetidinones.17 Taking into account this
result, we thought that the presence of only two electron-with-
drawing groups, the Z and the Boc protecting groups, on compound
7b could be sufficient to allow the substitution. Hence, by using
classical Mitsunobu conditions we were able to obtain the
desired enantiomerically pure protected d-azaproline in 61% yield
(Scheme 5).
Boc
H
Z
Boc
H
Z
N
O
N
OH
N
N
PhCH2OH
O
OCH2Ph
O
4
6b
DEAD, PPh3
THF
O
Scheme 3. Retro-lactonization of benzylester 6b.
RT, 24 h
O
7b
N
N
61%
Boc
Z
This problem could be prevented by replacing the benzyl ester
group by the more stable isopropyl one. The corresponding isopro-
pyl ester 7a was obtained in 97% yield by adding 6 equiv of isopro-
pyl bromide and a catalytic amount of tetrabutylammonium
bromide in acetone at 55 °C (Scheme 2) to the carboxylate 5a.
Unfortunately, when the same reaction was applied to carboxylate
5b, it led to the formation of a mixture of the desired ester 7b (23%)
and lactone 4. A better yield (49%) was obtained when the esterifi-
cation was performed at 30 °C. A quantitative amount of 7b was fi-
nally produced when isopropyl iodide and tetrabutylammonium
fluoride were used in THF at 30 °C (Scheme 4).16
8 : protected δ-azaproline
Scheme 5. Formation of d-azaproline.
3. Conclusion
In conclusion, we have developed a new and very convenient
synthesis leading, in only five steps to orthogonally protected
(S)-d-azaproline with 41% overall yield. The presence of orthogonal
protecting groups of both nitrogens allows the possibility of intro-

E. Voss et al. / Tetrahedron: Asymmetry 20 (2009) 1809–1812
1811
ducing this proline analogue into peptide chains either by the d or
by the nitrogen leading to different types of pseudopeptides. This
oil. ½a 2D2
ꢁ
¼ ꢀ2:5 (c 1.180, EtOH). Rf = 0.44 (EP/EtOAc 7/3). IR (NaCl)
e
m .
1792, 1767, 1726 cmꢀ1 1H NMR (CDCl3) d 7.41–7.22 (m, 5H,
work is currently under active investigation.
Harom), 5.31–5.14 (m, 2H, OCH2), 4.54–4.32 (m, 2H, OCH2), 4.32–
4.07 (m, 1H, CHCH2), 2.79–2.45 (m, 2H, CHCH2), 1.61–1.26 (m,
18H, 2 C(CH3)3). 13C NMR (CDCl3) d 171.6 (CO), 154.3 (CO), 151.0
(CO), 150.8 (CO), 136.1 (C), 129.2 (2CH), 129.0 (CH), 128.7 (2CH),
85.4 (C), 85.3 (C), 69.1 (OCH2), 66.1 (OCH2), 59.9 (CH), 28.5
(6CH3), 27.2 (CH2). ESI calcd for C22H30N2O8 [M+Na]+ m/z =
473.1894, found 473.1891.
4. Experimental
4.1. General experimental
All reactions were carried out with dry solvents. Dry THF was
obtained by distillation over sodium and benzophenone; MeCN
and acetone were purchased in an anhydrous form. Reagents were
obtained commercially and used without further purification.
Reactions were monitored by Thin Layer Chromatography (TLC)
using Kieselgel 60 with fluorescent indicator UV254 (purchased
from Merck or Macherey-Nagel). Detection was performed by
UV, phosphomolybdic acid or ninhydrine. Columns chromatogra-
a
4.4. (S)-
hydrazino]-
a
-[N -(Benzyloxycarbonyl)-Nb-(tert-butyl-oxycarbonyl)-
c-butyrolactone 4
To a solution of compound 3 (1.55 g, 3.4 mmol) in CH3CN
(40 mL) was added magnesium perchlorate (150.00 mg,
0.68 mmol). The solution was stirred at room temperature over-
night and then partitioned between water (100 mL) and diethyl-
ether (50 mL). The aqueous layer was extracted with diethylether
(2 ꢂ 50 mL) and the combined organic layers were dried over
MgSO4, filtered and concentrated in vacuo. The residue was chro-
matographed on silica gel with a mixture of petroleum ether and
ethyl acetate (7/3) as eluant to give butyrolactone 4 (1.07 g, 90%)
phy was carried out on Silica Gel 60 (70–200 lm). All yields have
been calculated from pure isolated products. 1H and 13C NMR spec-
tra were recorded on a spectrometer operating at 300 MHz, in deu-
terated chloroform (CDCl3) or deuterated dimethylsulfoxide
(DMSO-d6). Chemical shifts (d) are reported in parts per million
(ppm) and are referenced to the residual solvent signal for deuter-
ated DMSO or to the signal of tetramethylsilane (TMS) as internal
standard. Coupling constants (J values) are given in hertz. Peaks
are described using the following abbreviations: br, broad; s, sin-
glet; t, triplet; m, multiplet. HRMS spectra were obtained in ESI
as
a
white solid, mp = 103 °C.
Rf = 0.40 (EP/EtOAc 7/3). IR (KBr)
½
a 2D2
ꢁ
¼ ꢀ2:9 (c 1.050, EtOH).
m
3263, 1781, 1742, 1701 cmꢀ1
.
1H NMR (CDCl3) d 7.53–7.00 (m, 5H, Harom), 6.52 (br s, 1H, NH),
5.43–4.75 (m, 3H, CHCH2 and OCH2), 4.40–4.08 (m, 2H, OCH2),
2.61–2.29 (m, 2H, CHCH2), 1.52–1.15 (m, 9H, C(CH3)3). 13C NMR
(CDCl3) d 172.9 (CO), 155.0 (CO), 154.8 (CO), 134.8 (C), 128.0
(2CH), 127.9 (CH), 127.5 (2CH), 81.6 (C), 68.3 (OCH2), 65.3
(OCH2), 57.4 (CH), 27.3 (3CH3), 25.3 (CH2). ESI calcd for
C17H22N2O6 [M+Na]+ m/z = 373.1370, found 373.1370.
method. All melting points are uncorrected. [
a] is given in units
D
of deg dmꢀ1 cm2 gꢀ1; concentrations are quoted in g/100 mL.
4.2. (S)-
a-(N-Benzyloxycarbonylaminophthamilido)-c-
butyrolactone 2
a
4.5. Benzyl 2-[N -(benzyloxycarbonyl)-Nb,Nb-bis-(tert-butyloxy-
To a solution of compound 1 (5.15 g, 17.40 mmol), triphenyl-
phosphine (5.48 g, 20.90 mmol) and (R)- -hydroxy- -butyrolac-
carbonyl)hydrazino]-4-hydroxybutanoate 6a
a
c
tone (1.36 mL, 17.40 mmol) in dry THF (80 mL), under nitrogen,
were added, in one portion, di-tert-butyl azodicarboxylate
(4.80 g, 20.90 mmol) with stirring at 0 °C. The resulting solution
was stirred at room temperature for 4 h and concentrated in vacuo.
The residue was chromatographed on silica gel with a mixture of
petroleum ether and ethyl acetate as eluant to give butyrolactone
To a solution of compound 3 (180 mg, 0.40 mmol, racemic mix-
ture) in THF/H2O (6 mL, 1:1) was added at room temperature a 1 M
aqueous solution of sodium hydroxide (0.40 mL, 0.40 mmol). The
mixture was stirred at room temperature for 24 h and concentrated
in vacuo. The resultant white solid was suspended in toluene and
concentrated to remove traces of water to give sodium carboxylate
salt 5a. Acetone (10 mL), tetrabutylammonium bromide (7.00 mg,
0.02 mmol) and a solution of benzyl bromide (0.05 mL, 0.44 mmol)
in acetone (1 mL) were added. After stirring at reflux for 24 h, the
reaction mixture was cooled and concentrated. The residue was
partitioned between ethyl acetate (25 mL) and 0.5 M aqueous so-
dium bisulfate (10 mL). The organic phase was washed with por-
tions of saturated aqueous sodium bicarbonate (1 ꢂ 10 mL) and
brine (1 ꢂ 10 mL), dried over MgSO4, filtered and concentrated in
vacuo. The residue was chromatographed on silica gel with a mix-
ture of petroleum ether and ethyl acetate as eluant to give ester
2 (5.29 g, 80%) as a white solid, mp = 136 °C. ½a D22
¼ ꢀ2:6 (c 0.760,
ꢁ
EtOH). Rf = 0.27 (EP/EtOAc 6/4). IR (KBr)
m .
1800, 1780, 1740 cmꢀ1
1H NMR (CDCl3) d 7.85–7.70 (m, 4H, HPht), 7.35–6.90 (m, 5H, Harom),
5.25–4.91 (m, 2H, OCH2), 4.82–4.68 (t, J 10.5 Hz, 1H, CHCH2), 4.42–
4.27 (m, 1H, OCH2), 4.27–4.05 (m, 1H, OCH2), 2.79–2.40 (m, 2H,
CHCH2). 13C NMR (CDCl3) d 171.8 (CO), 165.8 (CO), 155.3 (CO),
154.0 (CO), 135.7 (CH), 135.6 (CH), 130.5 (C), 130.2 (2C), 129.2
(2CH), 129.1 (2CH), 127.9 (CH), 124.8 (CH), 124.7 (CH), 69.5
(OCH2), 66.1 (OCH2), 59.1 (CH), 28.1 (CH2). ESI calcd for
C20H16N2O6 [M+Na]+ m/z = 403.0901, found 403.0886.
6a (178 mg, 80%) as an oil. Rf = 0.61 (EP/EtOAc 8/2). IR (NaCl)
m
a
3322, 1741 cmꢀ1 1H NMR (CDCl3) d 7.45–7.25 (m, 10H, Harom),
.
4.3. (S)-
a
-[N -(Benzyloxycarbonyl)-Nb,Nb-bis(tert-butyl-
oxycarbonyl)hydrazino]-c-butyrolactone 3
6.49 (br s, 1H, OH), 5.32–4.88 (m, 5H, CHCH2 and 2OCH2), 4.43–
4.10 (m, 2H, OCH2), 2.40–2.22 (m, 1H, CHCH2), 2.20–2.05 (m, 1H,
CHCH2), 1.50–1.27 (m, 18H, C(CH3)3). 13C NMR (CDCl3) d 171.5
(CO), 157.0 (CO), 155.7 (CO), 154.0 (CO), 136.3 (C), 135.8 (C),
129.4–127.6 (10CH), 82.6 (2C), 69.2 (CH2), 68.1 (CH2), 64.1
(OCH2), 58.6 (CH), 28.7 (2CH3), 28.4 (4CH3), 28.4 (CH2). ESI calcd.
for C29H38N2O9 [M+Na]+ m/z = 581.2470, found 581.2470.
To a solution of compound 2 (1.90 g, 5.00 mmol) in THF
(100 mL) was added at room temperature a solution of methyl-
amine (2 M) in MeOH (3.75 mL, 7.50 mmol). The mixture was stir-
red at room temperature for 1 h. The solvent and the excess of
methylamine were removed in vacuo. The white solid obtained
was dissolved in THF (100 mL) and di-tert-butyl dicarbonate
(3.27 g, 15.00 mmol) and a catalytic amount of 4-dimethylamino-
pyridine were added. The mixture was stirred at room temperature
overnight and concentrated in vacuo. The residue was chromato-
graphed on silica gel with a mixture of petroleum ether and ethyl
acetate as eluant to give butyrolactone 3 (2.12 g, 94%) as a yellow
a
4.6. Isopropyl 2-[N -(benzyloxycarbonyl)-Nb,Nb-bis-(tert-butyloxy-
carbonyl)hydrazino]-4-hydroxybutanoate 7a
To a solution of compound 3 (180 mg, 0.40 mmol, racemic mix-
ture) in THF/H2O (6 mL, 1:1) was added at room temperature, a

1812
E. Voss et al. / Tetrahedron: Asymmetry 20 (2009) 1809–1812
1 M aqueous solution of sodium hydroxide (0.40 mL, 0.40 mmol).
The mixture was stirred at room temperature for 24 h and concen-
trated in vacuo. The resultant white solid was suspended in tolu-
ene and concentrated to remove trace of water to give sodium
carboxylate salt 5a. Acetone (10 mL), tetrabutylammonium bro-
mide (7.00 mg, 0.02 mmol) and isopropyl bromide (0.22 mL,
2.4 mmol) were added. After stirring at reflux for 24 h, the reaction
mixture was cooled and concentrated. The residue was partitioned
between ethyl acetate (25 mL) and 0.5 M aqueous sodium bisulfate
(10 mL). The organic phase was washed with portions of saturated
aqueous sodium bicarbonate (1 ꢂ 10 mL) and brine (1 ꢂ 10 mL),
dried over MgSO4, filtered and concentrated in vacuo to give ester
7a (198 mg, 97%) as a yellow oil. Rf = 0.37 (EP/EtOAc 8/2). IR (NaCl)
ate (170.00 mg, 0.99 mmol) with stirring at 0 °C. The resulting
solution was stirred at room temperature overnight and concen-
trated in vacuo. The residue was chromatographed on silica gel
with a mixture of petroleum ether and ethyl acetate as eluant to
give (S)-d-azaproline 8 (156 mg, 61%) as an oil. ½a D22
ꢁ
¼ ꢀ12:94 (c
0.850, EtOH). Rf = 0.62 (EP/EtOAc 70/30). IR (NaCl)
m
1708 cmꢀ1
.
1H NMR (CDCl3) d 7.39–7.27 (m, 5H, Harom), 5.27–5.13 (m, 2H,
OCH2), 5.13–4.90 (m, 1H, CH(CH3)2), 4.72–4.58 (br s, 1H, CHCH2),
4.07 (br s, 1H, NCH2), 3.22–3.20 (br s, 1H, NCH2), 2.43–2.14 (m,
2H, CHCH2), 1.52–1.30 (m, 9H, C(CH3)3), 1.30–1.10 (m, 6H,
CH(CH3)2). 13C NMR (CDCl3) d 170.6 (CO), 156.9 (2CO), 136.6 (C),
129.1 (2CH), 128.7 (CH), 128.5 (2CH), 82.2 (C), 69.7 (CH), 68.6
(OCH2), 60.4 (CH), 46.9 (NCH2), 31.0 (CH2), 28.6 (3CH3), 22.3
(2CH3). ESI calcd for C20H28N2O6 [M+Na]+ m/z = 415.1840, found
415.1840.
m
3334, 1740 cmꢀ1 1H NMR (CDCl3) d 7.33–7.27 (m, 5H, Harom),
.
6.54 (br s, 1H, OH), 5.35–4.75 (m, 4H, CHCH2, OCH2 and CH(CH3)2),
4.43–4.10 (m, 2H, OCH2), 2.39–2.20 (m, 1H, CHCH2), 2.20–1.95 (m,
1H, CHCH2), 1.67–1.30 (m, 18H, C(CH3)3), 1.30–1.08 (m, 6H,
CH(CH3)2). 13C NMR (CDCl3) d 171.1 (CO), 157.2 (CO), 154.0
(2CO), 136.3 (C), 129.1 (2CH), 128.9 (CH), 128.5 (2CH), 82.6 (2C),
70.3 (CH), 69.1 (CH2), 64.2 (OCH2), 58.5 (CH), 28.7 (CH2), 28.7
(2CH3), 28.4 (4CH3), 22.4 (2CH3). ESI calcd for C25H38N2O9 [M+H]+
m/z = 511.2650, found 511.2624.
Acknowledgement
The authors thank the National Research Agency (ANR) for
financial support (No. NT05_4_42848).
References
a
4.7. Isopropyl (2S)-2-[N -(benzyloxycarbonyl)-Nb-(tert-butyloxy-
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3949.
carbonyl)hydrazino]-4-hydroxybutanoate 7b
To a solution of compound 4 (140 mg, 0.40 mmol) in a mixture
of THF/H2O (6 mL, 1:1) was added at room temperature a 1 M
aqueous solution of NaOH (0.40 mL, 0.40 mmol). The mixture
was stirred at room temperature for 24 h and concentrated in va-
cuo. The resultant white solid was suspended in toluene and con-
centrated to remove trace of water to give sodium carboxylate salt
5b. THF (1.50 mL), tetrabutylammonium fluoride (0.48 mL,
0.48 mmol) and isopropyl iodide (0.05 mL, 0.48 mmol) were added.
The solution was heated at 30 °C for 76 h. The reaction mixture was
cooled and concentrated. The residue was partitioned between
ethyl acetate (25 mL) and 0.5 M aqueous sodium bisulfate
(10 mL). The organic phase was washed with portions of 0.5 M
aqueous sodium bisulfate (2 ꢂ 10 mL), saturated aqueous sodium
bicarbonate (3 ꢂ 10 mL) and brine (3x10 mL), dried over MgSO4,
filtered and concentrated in vacuo to give ester 7b (164 mg,
5. For recent preparations of
a-hydrazino acid derivatives, see: (a) Bouillon, I.;
Brosse, N.; Vanderesse, R.; Jamart-Grégoire, B. Tetrahedron 2007, 63, 2223–
2234; (b) Oguz, U.; Guilbeau, G. G.; McLaughlin, M. L. Tetrahedron Lett. 2002, 43,
2873–2875; (c) Portlock, D. E.; Naskar, D.; West, L.; Li, M. Tetrahedron Lett.
2002, 43, 6845–6847.
100%) as a yellow oil. ½a D22
ꢁ
¼ ꢀ0:7 (c 1.360, EtOH). Rf = 0.37 (EP/
6. Mish, M. R.; Guerra, F. M.; Carreira, E. M. J. Am. Chem. Soc. 1997, 119, 8379–
8380.
7. Kim, H.-O.; Lum, C.; Lee, M. S. Tetrahedron Lett. 1997, 38, 4935–4938.
8. Mitsunobu, O. Synthesis 1981, 1–28.
9. (a) Brosse, N.; Pinto, M.-F.; Jamart-Grégoire, B. J. Org. Chem. 2000, 65, 4370–
4374; (b) Brosse, N.; Pinto, M.-F.; Bodiguel, J.; Jamart-Grégoire, B. J. Org. Chem.
2001, 66, 2869–2873.
10. Brosse, N.; Jamart-Grégoire, B. Tetrahedron Lett. 2001, 43, 249–251.
11. Stafford, J. A.; Brackeen, M. F.; Valvano, N. L. Tetrahedron Lett. 1993, 34, 7873–
7876.
EtOAc 8/2). IR (NaCl)
m .
3337, 3322, 1731 cmꢀ1 1H NMR (DMSO-
d6) d 9.00 (br s, 1H, NH), 7.35–7.32 (m, 5H, Harom), 5.33–5.06 (m,
2H, OCH2), 5.06–4.76 (m, 2H, CHCH2 and CH(CH3)2), 4.51 (br s,
1H, OH), 3.69–3.47 (m, 2H, OCH2), 1.98–1.68 (m, 2H, CHCH2),
1,52.1.24 (m, 9H, C(CH3)3), 1.24–1.05 (m, 6H, CH(CH3)2). 13C NMR
(DMSO-d6) d 170.1 (CO), 155.4 (3CO), 136.2 (C), 128.2 (2CH),
127.8 (CH), 127.2 (2CH), 79.6 (C), 68.3 (CH), 67.0 (OCH2), 57.9
(CH), 57.2 (OCH2), 31.4 (CH2), 27.9 (3CH3), 21.4 (CH3), 21.3 (CH3).
ESI calcd for C20H30N2O7 [M+H]+ m/z = 411.2126, found 411.2098.
12. Hayashi, Y.; Yamaguchi, J.; Shoji, M. Tetrahedron 2002, 58, 9839–
9846.
13. Civitello, E. R.; Rapoport, H. J. Org. Chem. 1994, 59, 3775–3782.
14. Weber, A. E.; Halgren, T. A.; Doyle, J. J.; Lynch, R. J.; Siegl, P. K. S.; Parsons, W. H.;
Grennlee, W. J.; Patchett, A. A. J. Med. Chem. 1991, 34, 2692–2701.
15. Schlosser, M.; Heiss, C.; Marzi, E.; Scopelliti, R. Eur. J. Org. Chem. 2006, 4398–
4404.
4.8. Isopropyl (3S)-3-[2-(benzyloxycarbonyl)-(tert-butyl-
oxycarbonyl)pyrazolidine]-carboxylate 8
16. Wu, C. Y.; Brik, A.; Wang, S. K.; Chen, Y. H.; Wong, C. H. ChemBioChem 2005, 6,
2176–2180.
17. Iwagami, H.; Yasuda, N. Heterocycles 1990, 31, 529–536.
To
a solution of compound 7b (266 mg, 0.66 mmol) and
triphenylphosphine (259.00 mg, 0.99 mmol) in dry THF (10 mL),
under nitrogen, was added, in one portion, diethyl azodicarboxyl-