Asymmetric synthesis of densely functionalized pyrazolidines and 1,3-diamines

Article abstract of DOI:10.1055/s-2002-33914

A versatile and straightforward access to polysubstituted 1,3-diamines with good control of relative and absolute configurations is described. The key steps involve a diastereoselective 1,3-dipolar cycloaddition of a chiral non-racemic azomethine imine ylide and a chemoselective electroreduction of densely functionalized pyrazolidines intermediates.

Full text of DOI:10.1055/s-2002-33914

PAPER
1885
Asymmetric Synthesis of Densely Functionalized Pyrazolidines and
1,3-Diamines
A
symmetric Synth
.
esis of
Dens
C
e
ly Functionaliz
e
h
d
Pyrazolidin
a
es and 1,3-
u
Diamines veau, T. Martens, M. Bonin,* L. Micouin,* H.-P. Husson
Laboratoire de Chimie Thérapeutique, UMR 8638 associée au CNRS et à l’Université René Descartes, Faculté des Sciences Pharmaceu-
tiques et Biologiques 4, av de l’Observatoire, 75270 Paris cedex 06, France
Fax +33(1)43291403; E-mail: micouin@pharmacie.univ-paris5.fr; E-mail: bonin@pharmacie.univ-paris5.fr
Received 1 June 2002; revised 14 June 2002
the asymmetric preparation of fully substituted pyrazo-
Abstract: A versatile and straightforward access to polysubstituted
lidines 3 and their transformation into densely functional-
1,3-diamines with good control of relative and absolute configura-
tions is described. The key steps involve a diastereoselective 1,3-di-
polar cycloaddition of a chiral non-racemic azomethine imine ylide
ized acyclic 1,3-diamines
4
by
a
completely
chemoselective reductive cleavage of the N–N bond
and a chemoselective electroreduction of densely functionalized (Scheme 1).
pyrazolidines intermediates.
Ph
R1
Key words: asymmetric synthesis, cycloadditions, ylides, reduc-
tions, chemoselectivity
O
Ph
O
N
N
O
O
HN
*
N
O
*
*
H
R2
Ph
R3
2
1
Recently there has been an increasing interest in the asym-
metric synthesis of polysubstituted pyrazolidines.1 These
heterocycles are not only useful building blocks but, as di-
aza-analogues of pyrrolidines, could also present some in-
teresting biological activities.2 Furthermore, they can be
considered as powerful intermediates for the preparation
of enantiopure densely functionalized 1,3-diamines after
reductive cleavage of the N–N bond. Different strategies
have been devised for the preparation of trisubstituted
pyrazolidines. A ‘two component’ approach has been re-
ported by Carreira’s and Barluenga’s groups. The former
is based on the diastereoselective cycloadditions of
Me3SiCHN2 and camphor sultam-derived dipolaro-
philes.1e The latter uses cycloadditions of chiral non-race-
O
Ph
R2
*
R1
N
H
N
H
N
N
*
*
*
PhOC
COPh
*
*
R1
4
R3
R2
R3
3
Scheme 1
Pyrazolidines 2a–f were prepared in two steps from
the carbazate 1 using a sequential cycloaddition, tandem
cycloreversion–cycloaddition process (Scheme 2 and
Table 1).
mic alkenyl Fischer carbene complexes with
Ph
R1
Ph
Ph
O
2
diazomethane derivatives.1c Both strategies afford
-
O
O
R1
N
N
HN
a
b
pyrazolines which can be transformed into polysubstitut-
ed pyrazolidines after nucleophilic additions or reduc-
tions. In a ‘three component’ approach, Stanovnik and co-
workers have shown in pioneer work that azomethine imi-
nes could react with several dipolarophiles, leading to bi-
cyclic polyfunctional pyrazolidines with good control of
the relative configurations.3 Similar results were recently
described by Sharpless and co-workers.4 Although all
these methods provide versatile access to these chiral het-
erocycles, examples of their transformation into 1,3-di-
amines by N–N bond cleavage are scarce and were only
described on substrates bearing non-reducible functional
groups.
N
O
N
O
N
O
*
*
H
*
O
R2
R3
R1
2
5
1
Scheme 2 Reagents and conditions: a) R1CHO, CHCl3, 65 °C
(R1 = Pr, dr > 98:2, 97%; R1 = CH2CH2Ph, dr = 70:20:10, 80%); b)
dipolarophile, toluene, 80–100 °C, 3 d
This procedure proved to be more efficient than the direct
cycloaddition.6 The formation of unstable ylides with ali-
phatic aldehydes is the fast step in this reaction. The use
of cycloreversion lowers the concentration of the free
ylide in the reaction mixture and avoids side reactions like
self-condensation of this reactive species. Relative con-
We have reported in previous work the regio- and dia-
stereoselective cycloadditions of chiral non-racemic
azomethine imines with various dipolarophiles, leading to
bicyclic polyfunctional pyrazolidines 2.5 We report herein
1
figurations of major isomers were assessed by H NMR
analysis and analogy with known compounds.5 When ob-
tained, mixtures of diastereomers were used in the next
step without separation.
Several experimental conditions have been reported for
the hydrogenolysis of the chiral appendage. Among them,
only the procedure described recently by Mioskowski and
Synthesis 2002, No. 13, Print: 20 09 2002.
Art Id.1437-210X,E;2002,0,13,1885,1890,ftx,en;Z08902SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1886
A. Chauveau et al.
PAPER
Ph
Table 1 Synthesis of Pyrazolidines 2a–f
Ph
O
Oxadiazolidine
Ph
Dipolar- Pyrazolidine [Yield (%),
ophile
N
O
dea (%)]
H
N
N
O
2
Pr
N
O
Ph
CO2Me
MeO2C
O
O
Ph
8a
a
c
CO2Me
O
Ph(CH2)2
N
N
MeO2C
Ph(CH2)2
methyl
maleate
6d
N
O
N
O
N
R(CH2)2
N
O
O
d
COPh
MeO2C
CO2Me
(CH2)2Ph
H
N
N
N
COPh
Ph(CH2)2
Ph(CH2)2
CO2Me
b
MeO2C
N
2a (89, >95)
5a
5a
2
CO2Me
CO2Me
Ph
MeO2C
3a
MeO2C
7a
O
Ph(CH2)2
N
methyl
fumarate
N
O
Scheme 3 Reagents and conditions: a) (R = Me) H2, Pd(OH)2, Me-
OH, 6 N aq HCl, 25%; b) (R = Ph) (i) H2, Pd(OH)2, MeOH, H2SO4 (3
equiv), (ii) silica gel, 29%; c) (R = Ph) H2, Pt black, MeOH, H2SO4 (1
equiv), 19%; d) (R = Ph) (i) H2, Pd(OH)2, MeOH, H2SO4 (2 equiv),
(ii) PhCOCl (5.5 equiv), DBU (3 equiv), CH2Cl2, 79%, dr > 98:2
MeO2C
CO2Me
2b (85, 78)
Ph
O
O
Ph(CH2)2
N
5a
methyl
Unprotected pyrazolidines, as already noted, proved to be
unstable and were readily oxidized into the corresponding
2-pyrazoline during purification on silica gel.9 These in-
termediates were therefore protected by treatment of the
crude hydrogenolysis reaction mixture with benzoyl chlo-
ride under basic conditions.1a Full protection of both nitro-
gen atoms could be obtained when performing the
benzoylation with DBU as a base, whereas the use of py-
ridine led only to partial non-selective N-protection. Pyra-
zolidines 3a–f were obtained without any racemization
following this procedure (Figure 1).
N
crotonate
MeO2C
2c (73, 67)
Me
Ph
Ph
O
O
N
Pr
N
methyl
maleate
Pr
N
O
N
O
O
Pr
5b
MeO2C
CO2Me
2d (71, >95)
5b
5b
Ph
O
COPh
N
COPh
N
COPh
N
Pr
N
methyl
fumarate
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
N
O
NCOPh
NCOPh
NCOPh
MeO2C
CO2Me
2e (54, 91)
CO2Me
Me
CO2Me
MeO2C
MeO2C
MeO2C
3c: 67%, dr = 95:5
3b: 85%, dr = 89:7:4
3a: 79%, dr > 98:2
Ph
O
COPh
COPh
N
COPh
Pr
N
methyl
crotonate
N
O
N
N
Pr
Pr
Pr
NCOPh
NCOPh
NCOPh
MeO2C
Me
Me
CO2Me
MeO2C
CO2Me
MeO2C
MeO2C
2f (40, 76)
3f: 40%, dr = 85:15
3d: 60%, dr > 98:2
3e: 62%, dr = 91:9
a Determined by 1H NMR.
Figure 1 Synthesis of pyrazolidines 3a–f
co-workers7 enabled a clean cleavage of the benzylic bond
and the carbamate function of pyrazolidine 2a in the same
pot, without any side reaction (ester hydrolysis or epimer-
ization of the sensitive asymmetric centers). The nature of
the acidic co-catalyst proved to be crucial, since the use of
6 N aqueous hydrochloric acid instead of concentrated
sulfuric acid led to compound 6d in a non-reproducible
low yield, and no reaction could be obtained with trifluo-
roacetic acid.8 Only starting material was recovered when
performing the hydrogenolysis without any acidic co-cat-
alyst or sub-stoichiometric quantities of sulfuric acid. The
change of palladium hydroxide for platinum as a catalyst
led to the reduction product 8a without hydrogenolysis or
N–N bond cleavage (Scheme 3).
Numerous methods have been developed for the cleavage
of a cyclic or an acyclic N–N bond.1a,c,9,10 However, re-
ported reductive conditions have been mostly described
on non-functional substrates. Lassaletta and co-workers11
recently described new non-reductive conditions for the
cleavage of N–N bonds but, in our hands, this procedure
failed to give the desired diamines.
Since no classical chemical methods seemed to be able to
cleave the hydrazine bond without any loss of functional-
ity, we turned our attention to electrochemical methods.
The electroreductive scission of N–N bond has been ex-
tensively studied by Horner and Jordan, who reported the
conversion of cyclic hydrazines into diamines in moderate
Synthesis 2002, No. 13, 1885–1890 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of Densely Functionalized Pyrazolidines and 1,3-Diamines
1887
to good yields.12 Furthermore, they noticed an increase of using an asymmetric three-component reaction. The cor-
reduction potential proportionally to the number of benz- responding pyrazolidines can be obtained in a simple way,
oyl groups on nitrogens. First trials were made according without any alteration of the relative configuration of the
to this work with pyrazolidine 3a at a reduction potential newly created stereogenic centers. Finally, electrochemi-
between –1.80 and –1.70 V (ref.: saturated calomel elec- cal reductive cleavage of the N–N bond afforded 1,2,3
trode) (Scheme 4).
poly-substituted, optically active 1,3 diamines. The high
versatility of this synthetic pathway provides not only
tools for the fast elaboration of bioactive compounds with
a good molecular diversity, but also useful starting mater-
ial for the preparation of more complex molecules.
PhCONH
NHCOPh
CO2Me
CO2Me
4a
Ph
a
Ph
O
Ph
NMR spectra were obtained at 300 or 400 MHz (1H field value). IR
spectra were recorded as thin film unless otherwise stated. Elemen-
tal analyses were obtained from the Service de microanalyse of the
Institut de Chimie des Substances Naturelles, Gif-sur-Yvette,
France. Compounds 1, 2d,e and 5b were prepared according to lit-
erature procedures.5a
NHCOPh
80% PhCONH
N
NH
CO2Me
b
+
3a
CO2Me
93%
Ph
MeO2C
CO2Me
9a
4a
c
PhCONH
NHCOPh
65%
1,3-Diphenethyl-7-phenyldihydro-2,5-dioxa-3a,7a-diazainden-
4-one (5a)
Compound 1 (630 mg, 3.0 mmol) and dihydrocinamaldehyde (924
mg, 9.0 mmol) were stirred for 24 h in CHCl3 at 65 °C. After solvent
evaporation, purification by flash chromatography (cyclohexane–
EtOAc, 90:10) afforded 5a.
CO2Me
CO2Me
4a
Ph
Scheme 4 Reagents and conditions : a) 2e–, n-Bu4NBr 0.5 M in Me-
OH, then aq NH4Cl; b) 2e–, AcOH 0.1 M, AcOLi 0.1 M in MeOH; c)
2e–, AcOH 0.01 M, AcOLi 0.3 M in MeOH, pH 7–8
Yield: 1.05 g (80%), white solid; dr = 70:20:10 (only major isomer
is described).
1H NMR (CDCl3): = 1.30–1.50 (m, 2 H), 2.20–2.40 (m, 2 H),
2.50–3.0 (m, 4 H), 3.68 (dd, J = 10.1, 3.5 Hz, 1 H), 4.09 (dd,
This reaction proved to be very sensitive to the pH and the
nature of the electrolyte support. When performed under J = 5.6, 2.5 Hz, 1 H), 4.12 (dd, J = 11.3, 3.5 Hz, 1 H), 4.21 (t,
J = 11.1 Hz, 1 H), 5.63 (dd, J = 5.7, 4.0 Hz, 1 H), 6.77 (d, J = 6.3
Hz, 2 H), 7.0–7.50 (m, 13 H).
13C NMR (CDCl3) = 29.1, 29.7, 33.1, 35.2, 61.5, 70.2, 87.0, 97.0,
basic conditions, the reductive cleavage led to the desired
compound, albeit with substantial racemization. The
change to more acidic medium avoided this troublesome
125.9, 128.0, 128.2, 128.3, 128.4, 129.1, 129.4, 134.5, 140.9, 141.2.
side-reaction, but partial deprotection of pyrazolidine was
MS: 429 (MH+).
observed, leading to an inseparable mixture of 4a and 9a
(55:45). Finally, the best results were obtained when using
LiOAc–HOAc as an electrolyte and with pH adjustment
(pH 7–8) by slow addition of acetic acid during the elec-
trolysis. Using this procedure, polyfunctional diamines
4a,d could be obtained with less than 3% epimerization
(Figure 2). Other compounds proved to be less prone to
partial deprotection and reductive cleavage could be per-
formed at pH 5 (LiOAc–HOAc buffer).
Compounds 2; General Procedure
The preparation of pyrazolidine 2a is representative. Compound 5a
(522 mg, 1.23 mmol) and methylmaleate (254 mg, 2.26 mmol) were
stirred for 72 h in toluene (10 mL) at 100 °C. Solvent was evaporat-
ed and the crude mixture was recrystallized from Et2O.
Yield: 480 mg (89%); de >95%.
(4R,6S,7S,8R)-1-Oxo-6-phenethyl-4-phenyltetrahydropyrazo-
lo[1,2-c][1,3,4]oxadiazine-7,8-dicarboxylic Acid Dimethyl Ester
(2a)
NHBz
NHBz
NHBz
NHBz
NHBz
NHBz
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Mp 178–180 °C (Et2O); [ ]D –125 (c 0.9, CHCl3).
IR (neat): 2361, 2340, 1746, 1695, 1469 cm–1.
CO2Me
CO2Me
Me
MeO2C
MeO2C
MeO2C
1H NMR (CDCl3): = 1.0 (m, 1 H), 1.25 (m, 1 H), 2.31 (m, 1 H),
2.39 (m, 1 H), 3.45 (dd, 1 H, J = 11.1, 8.8 Hz), 3.68 (ddd, 1 H,
J = 11.1, 6.0, 2.5 Hz), 3.69 (s, 3 H), 3.77 (s, 3 H), 4.23 (dd, 1 H,
J = 10.3, 3.2 Hz), 4.28 (dd, 1 H, J = 10.8, 3.2 Hz), (t, 1 H, J = 10.5
Hz), 4.83 (d, 1 H, J = 8.8 Hz), 6.73 (dd, 2 H, J = 6.2, 1.7 Hz), 7.15
(m, 3 H), 7.40 (m, 5 H).
4b: 73%, dr > 98:2a
4c: 71%, dr. = 97:3
4a: 65%, dr = 96:4
NHBz
Pr
NHBz
Pr
NHBz
Pr
NHBz
NHBz
NHBz
CO2Me
CO2Me
MeO2C
Me
13C NMR (CDCl3): = 29.2, 31.8, 48.5, 52.5, 52.8, 60.1, 65.3, 66.0,
72.1, 125.8, 127.8, 128.1, 128.7, 129.1, 129.6, 133.5, 140.8, 149.8,
168.7, 169.1.
MeO2C
MeO2C
4d: 90%, dr = 97:3
4f: 69%, dr = 97:3
4e: 80%, dr = 95:5
Figure 2 Synthesis of diamines 4a–f
MS: m/z = 439 (MH+).
Anal. Calcd for C24H26N2O6: C, 65.74; H, 5.98; N, 6.39. Found: C,
65.59; H, 6.13; N, 6.37.
In conclusion, we have described a versatile straightfor-
ward access to densely functionalized bicyclic hydrazines
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1888
A. Chauveau et al.
PAPER
(3R,4S,5S)-1,2-Dibenzoyl-5-phenethylpyrazolidine-3,4-dicar-
boxylic Acid Dimethyl Ester (3a)
Mp 161–163 °C (Et2O); [ ]D +82 (c 1.0, CHCl3).
(4R,6S,7S,8R)-1-Oxo-6-phenethyl-4-phenyltetrahydropyrazo-
lo[1,2-c][1,3,4]oxadiazine-7,8-dicarboxylic Acid Dimethyl Ester
(2b)
Yield: 85%; de = 78%. Only major isomer is described.
IR (neat): 3400, 2952, 2361, 1748, 1656, 1494 cm–1.
1H NMR (CDCl3): = 1.35 (m, 1 H), 1.43 (m, 1 H), 2.34 (m, 2 H),
3.33 (m, 2 H), 3.78 (s, 3 H), 3.84 (s, 3 H), 3.92 (dd, 1 H, J = 10.3,
3.2 Hz), 4.17 (dd, 1 H, J = 11.3, 3.2 Hz), 4.44 (dd, 1 H, J = 11.3,
10.3 Hz), 5.23 (d, 1 H, J = 4.1 Hz), 6.67 (dd, 2 H, J = 7.7, 2.1 Hz),
7.12 (m, 3 H), 7.39 (m, 5 H).
13C NMR (CDCl3): = 30.1, 33.5, 50.2, 52.9, 53.0, 59.8, 64.7, 69.8,
71.0, 125.8, 127.9, 128.1, 128.3, 129.0, 129.3, 134.5, 140.4, 150.2,
169.7, 171.2.
1H NMR (DMSO-d6, 50 °C): = 2.06 (ddt, 2 H, J = 15.1, 7.9, 6.1
Hz), 2.73 (t, 2 H, J = 7.9 Hz), 3.61 (s, 3 H), 3.68 (s, 3 H), 3.75 (dd,
1 H, J = 8.5, 5.1 Hz), 4.79 (dt, 1 H, J = 6.1, 5.1 Hz), 5.00 (d, 1 H,
J = 8.5 Hz), 7.1–7.3 (m, 3 H), 7.3–7.6 (m, 10 H).
13C NMR (DMSO-d6, 50 °C): = 32.5, 36.4, 52.7, 52.9, 53.1, 61.5,
63.9, 126.5, 127.4, 128.5, 128.9, 129.0, 131.0, 132.4, 168.6, 170.2,
172.0.
MS: m/z = 501 (MH+).
MS: m/z = 439 (MH+).
Anal. Calcd for C29H28N2O6: C, 69.59; H, 5.64; N, 5.60. Found: C,
69.57; H, 5.62; N, 5.64.
Anal. Calcd for C24H26N2O6: C, 65.74; H, 5.98; N, 6.39. Found: C,
65.87; H, 6.09; N, 6.30.
(3S,4S,5S)-1,2-Dibenzoyl-5-phenethylpyrazolidine-3,4-dicar-
boxylic Acid Dimethyl Ester (3b)
Yield: 85%; mp 170–172 °C (Et2O); dr = 89:7:4; major isomer
[ ]D +22 (c 1.2, CHCl3).
(4R,6S,7S,8R)-8-Methyl-1-oxo-6-phenethyl-4-phenyltetrahy-
dropyrazolo[1,2-c][1,3,4]oxadiazine-7-carboxylic Acid Methyl
Ester (2c)
Yield: 73%; de = 67%. Only major isomer is described.
IR (neat): 2360, 2340, 1741, 1695, 1654 cm–1.
1H NMR (CDCl3): = 1.30–1.50 (m, 2 H), 1.52 (d, 3 H, J = 6.5 Hz),
2.34 (t, 2 H, J = 8.7 Hz), 2.84 (dd, 1 H, J = 8.1, 5.3 Hz), 3.28 (ddd,
1 H, J = 8.1, 7.0, 3.5 Hz), 3.74 (s, 3 H), 3.87 (dd, 1 H, J = 10.1, 3.3
Hz), 4.28 (dd, 1 H, J = 11.3, 3.3 Hz), 4.54 (dd, 1 H, J = 11.3, 10.1
Hz), 4.83 (dt, 1 H, J = 6.5, 5.3 Hz), 6.65 (dd, 2 H, J = 7.7, 2.1 Hz),
7.10 (m, 3 H), 7.39 (m, 5 H).
1H NMR (C6D6, 60 °C): = 2.34 (m, 1 H), 2.68 (m, 3 H), 3.23 (s, 3
H), 3.31 (m, 1 H), 3.49 (s, 3 H), 4.53 (m, 1 H), 5.15 (d, 1 H, J = 3.2
Hz), 7.0–7.2 (m, 11 H), 7.70 (m, 2 H), 7.78 (m, 2 H).
13C NMR (C6D6, 60 °C): = 32.1, 34.5, 51.8, 51.9, 52.7, 62.7, 63.8,
126.0, 127.2, 127.6, 127.7, 127.9, 128.2, 130.6, 134.7, 140.6, 169.2,
171.0, 174.9.
13C NMR (CDCl3): = 20.4, 30.4, 33.6, 52.5, 54.6, 55.6, 64.8, 70.3,
70.5, 125.8, 127.9, 128.2, 128.5, 129.0, 135.3, 140.7, 149.8, 172.2.
MS: m/z = 501 (MH+).
MS: m/z = 395 (MH+).
Anal. Calcd for C29H28N2O6: C, 69.59; H, 5.64; N, 5.60. Found: C,
69.50; H, 5.95; N, 5.32.
Anal. Calcd for C23H26N2O4: C, 70.03; H, 6.64; N, 7.10. Found: C,
70.20; H, 6.68; N, 6.91.
(3R,4R,5S)-1,2-Dibenzoyl-3-methyl-5-phenethylpyrazolidine-4-
carboxylic Acid Methyl Ester (3c)
Yield 67%; dr = 95:5. Only major isomer is described.
1H NMR (C6D6, 50 °C): = 1.45 (d, 3 H, J = 6.5 Hz), 2.01 (m, 1 H),
2.55 (t, 1 H, J = 3.2 Hz), 2.63 (m, 1 H), 2.70 (m, 2 H), 3.21 (s, 3 H),
4.40 (m, 2 H), 6.90–7.20 (m, 11 H), 7.59 (m, 2 H), 7.67 (m, 2 H).
13C NMR (C6D6, 50 °C): = 20.1, 32.6, 35.6, 51.7, 56.5, 58.7, 62.7,
126.3, 127.2, 127.5, 127.8, 128.1, 128.3, 130.6, 140.9, 172.2.
(4R,6S,7S,8R)-8-Methyl-1-oxo-4-phenyl-6-propyltetrahydro-
pyrazolo[1,2-c][1,3,4]oxadiazine-7-carboxylic Acid Methyl
Ester (2f)
Yield: 40%; de = 67%. Only major isomer is described.
1H NMR (CDCl3): = 0.46 (m, 3 H), 0.90–1.10 (m, 4 H), 1.49 (d, 3
H, J = 6.4 Hz), 2.84 (dd, 1 H, J = 7.5, 5.8 Hz), 3.28 (dt, 1 H,
J = 7.5, 3.0 Hz), 3.72 (s, 3 H), 3.85 (dd, 1 H, J = 10.1, 3.3 Hz), 4.11
(dd, 1 H, J = 11.3, 3.3 Hz), 4.27 (dd, 1 H, J = 11.3, 10.1 Hz), 4.49
(quint, 1 H, J = 6.1 Hz), 7.37 (m, 5 H).
MS: m/z = 457 (MH+).
Anal. Calcd for C28H28N2O4: C, 73.66; H, 6.18; N, 6.14. Found: C,
73.34; H, 6.35; N, 5.86.
13C NMR (CDCl3): = 13.6, 17.3, 20.3, 33.8, 52.4, 54.7, 55.6, 64.8,
70.5, 70.7, 125.5, 128.0, 128.8, 129.0, 135.5, 149.8, 172.3.
MS: m/z = 333 (MH+).
(3R,4S,5S)-1,2-Dibenzoyl-5-propylpyrazolidine-3,4-dicarboxyl-
ic Acid Dimethyl Ester (3d)
Yield: 60%; mp 130–132 °C (Et2O); dr > 98:2; [ ]D +111 (c 0.9,
CHCl3).
HRMS: m/z calcd for C18H25N2O4: 333.1814; found: 333.1819.
Compounds 3; General Procedure
IR (neat): 2957, 2367, 2344, 1750, 1700, 1670, 1602 cm–1.
The preparation of pyrazolidine 3a is representative. Compound 2a
(153 mg, 0.35 mmol) was dissolved in anhyd MeOH (10 mL). Sul-
furic acid (18 M; 69 mg) and Pd(OH)2 (45 mg) were added and the
mixture was stirred for 36 h under a hydrogen atmosphere, filtered
under nitrogen atmosphere and the solvent was evaporated under
vacuum. CH2Cl2 (10 mL), DBU (220 L, 4 equiv) and benzoyl
chloride (225 L, 5.5 equiv) were then added and the resulting mix-
ture was stirred under a nitrogen atmosphere for 24 h, and washed
with sat. aq NaHCO3. The organic layer was separated, dried
(MgSO4), the solvent was evaporated and the crude residue was
purified by column chromatography (silica gel; cyclohexane–
EtOAc, 90:10) to give 3a.
1H NMR (C6D6, 50 °C): = 0.99 (t, 3 H, J = 7.2 Hz), 1.50–2.00 (m,
4 H), 3.00 (dd, 1 H, J = 8.1, 5.7 Hz) 3.43 (s, 3 H), 3.52 (s, 3 H), 5.21
(m, 2 H), 7.10–7.30 (m, 7 H) 7.80 (m, 3 H).
13C NMR (DMSO-d6, 50 °C): = 12.9, 18.9, 37.4, 51.0, 51.3, 53.2,
60.6, 62.8, 126.8, 127.1, 127.5, 127.6, 127.9, 129.3, 130.9, 133.2,
135.5, 167.5, 168.6, 172.3, 172.5.
MS: m/z = 439 (MH+).
Anal. Calcd for C29H28N2O6: C, 65.74; H, 5.98; N, 6.39. Found: C,
65.30; H, 6.18; N, 6.19.
Yield: 139 mg (79%); dr > 98:2.
Synthesis 2002, No. 13, 1885–1890 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of Densely Functionalized Pyrazolidines and 1,3-Diamines
1889
(3S,4S,5S)-1,2-Dibenzoyl-5-propylpyrazolidine-3,4-dicarboxyl-
ic Acid Dimethyl Ester (3e)
(1S,2S,3S)-2-Benzoylamino-3-(1-benzoylamino-3-phenylpro-
pyl)succinic Acid Dimethyl Ester (4b)
Yield: 62%; dr = 91:9. Only major isomer is described.
Yield: 73%; mp 159–161 °C (Et2O); dr > 98:2 from diastereomeri-
cally pure 3b; [ ]D +165 (c 0.9, CHCl3).
IR (neat): 3307, 2361, 2343, 1738, 1645, 1538, 1491 cm–1.
1H NMR (CDCl3): = 1.92 (m, 1 H), 2.39 (m, 1 H), 2.75 (m, 2 H),
3.24 (s, 3 H), 3.58 (dd, 1 H, J = 10.2, 2.5 Hz), 3.69 (s, 3H), 4.85 (dq,
1 H, J = 10.2, 2.8 Hz), 5.56 (dd, 1 H, J = 9.8, 2.4 Hz), 6.73 (d,1 H,
J = 10.2 Hz), 7.20 (m, 5 H), 7.40 (m, 2 H), 7.50 (m, 4 H), 7.60 (m,
2 H), 8.04 (dd, 1 H, J = 5.7, 1.5 Hz), 8.16 (d, 1 H, J = 9.8 Hz).
13C NMR (CDCl3): = 32.5, 35.6, 47.8, 51.7, 52.5, 52.7, 126.1,
127.0, 127.5, 128.3, 128.6, 131.7, 132.2, 140.9, 167.9, 171.2, 171.7.
1H NMR (C6D6, 60 °C): = 0.88 (t, 3 H, J = 7.2 Hz), 1.41 (m, 2 H),
1.95 (m, 1 H), 2.38 (m, 1 H), 3.19 (s, 3 H), 3.27 (m, 1 H), 3.48 (s, 3
H), 4.53 (m, 1 H), 5.26 (m, 1 H), 7.06 (m, 7 H) 7.92 (m, 3 H).
13C NMR (DMSO-d6, 60 °C): = 13.4, 19.2, 35.2, 51.0, 51.3, 53.2,
60.6, 62.8, 126.8, 127.0, 127.3, 127.9, 129.3, 130.9, 133.2, 135.5,
167.5, 172.3, 172.5.
MS: m/z = 439 (MH+).
HRMS: calcd for C24H27N2O6: 439.1869; found: 439.1863.
(3R,4R,5S)-1,2-Dibenzoyl-3-methyl-5-propylpyrazolidine-4-
carboxylic Acid Methyl Ester (3f)
Yield: 40%; dr = 85:15. Only major isomer is described.
1H NMR (CDCl3, 50 °C): = 1.01 (t, 3 H, J = 7.3 Hz), 1.52 (m, 2
H), 1.71 (d, 3 H, J = 6.5 Hz), 1.82 (m, 1 H), 2.34 (m, 1 H), 2.75 (m,
1 H), 3.64 (s, 3 H), 4.26 (m, 1 H), 4.45 (m, 1 H), 7.30–7.40 (m, 6 H)
7.40–7.50 (m, 4 H).
13C NMR (C6D6, 60 °C): = 13.5, 19.4, 20.6, 35.9, 51.5, 56.6, 58.6,
62.8, 127.5, 127.8, 128.0, 128.3, 130.5, 172.3.
MS: m/z = 503 (MH+).
Anal. Calcd for C29H30N2O6: C, 69.31; H, 6.02; N, 5.57. Found: C,
69.72; H, 6.08; N, 5.36.
(1R,2R,3S)-3-Benzoylamino-2-(1-benzoylaminoethyl)-5-phen-
ylpentanoic Acid Methyl Ester (4c)
Yield: 71%; mp 140–142 °C (Et2O); dr = 97:3; [ ]D –16 (c 1.0,
CHCl3).
IR (neat): 3299, 2363, 1732, 1637, 1579, 1538, 1490 cm–1.
MS: m/z = 395 (MH+).
1H NMR (CDCl3): = 1.28 (d, 3 H, J = 6.7 Hz), 1.76 (m, 1 H), 2.07
(m, 1 H), 2.69 (m, 2 H), 2.97 (t, 1 H, J = 7.0 Hz), 3.70 (s, 3 H), 4.64
(m, 2 H), 6.67 (d, 1 H, J = 8.6 Hz), 6.76 (d, 1 H, J = 9.3 Hz), 7.10
(m, 5 H), 7.50 (m, 6 H), 7.80 (m, 4 H).
13C NMR (CDCl3): = 18.9, 32.6, 34.5, 44.5, 48.6, 51.9, 55.2,
126.4, 127.6, 128.9, 129.0, 129.1, 131.6, 134.1, 141.0, 167.1, 167.6,
172.1.
HRMS: calcd for C23H27N2O4: 395.1971; found: 395.1966.
Compounds 4; General Procedure
The preparation of pyrazolidine 4a is representative. Using a cylin-
drical vessel fitted with two side arms separated from the main com-
partment with glass frits, a mercury pool electrode in the main
compartment serves as the cathode (working electrode) while a sat-
urated calomel reference electrode was placed in one side arm, and
a platinum sheet in the other side arm (anode, counter electrode).
The electrolyte solution (0.4 mol L LiOAc and 0.02 mol L HOAc)
was poured into the cell and the side arms. Compound 3a (42 mg,
0.084 mmol) was dissolved in the solution in the main compartment
(18 mL). The resulting solution was then reduced (E = – 1.85 V
SCE) under nitrogen. The pH of the electrolysis mixture was care-
fully controlled and kept around 7–8 by regular HOAc additions.
After the completion of the reduction (monitored by TLC), the ca-
thodic solution was separated and NH4Cl was added, followed by
EtOAc (60 mL) and H2O (40 mL). The organic layer was separated,
dried (MgSO4), the solvent was evaporated and the crude residue
was purified by column chromatography (silica gel; cyclohexane–
EtOAc, 50:50) to give 4a (28 mg, 65%, dr = 96:4).
MS: m/z = 459 (MH+).
Anal. Calcd for C28H30N2O4, 1/2 H2O: C, 71.93; H, 6.68; N, 5.99.
Found: C, 72.53; H, 6.71; N, 5.79.
-1
-1
(1S,2R,3S)-2-Benzoylamino-3-(1-benzoylaminobutyl)succinic
Acid Dimethyl Ester (4d)
Yield: 90%; dr = 97:3; [ ]D –47 (c 1.0, CHCl3).
IR (neat): 2368, 2344, 1718, 1684, 1651 cm–1.
1H NMR (CDCl3): = 0.97 (t, 3 H, J = 7.3 Hz), 1.46 (m, 2 H), 1.68
(m, 1 H), 1.96 (m, 1 H), 3.60 (dd, 1 H, J = 4.9, 2.4 Hz), 3.77 (s, 3
H), 4.69 (m, 1 H), 5.33 (dd, 1 H, J = 9.5, 2.4 Hz), 6.55 (d, 1 H,
J = 9.1 Hz), 7.20 (m, 2 H), 7.40 (m, 3 H), 7.50 (m, 3 H), 7.70 (m, 3
H).
13C NMR (CDCl3): = 13.7, 19.7, 35.2, 49.3, 49.8, 52.5, 53.1,
126.8, 127.2, 128.3, 128.7, 131.3, 132.1, 171.3, 173.1.
(1S,2R,3S)-2-Benzoylamino-3-(1-benzoylamino-3-phenylpro-
pyl)succinic Acid Dimethyl Ester (4a)
Yield: 65%; mp 151–153 °C (Et2O); dr = 96:4; [ ]D –20 (c 1.0,
CHCl3).
MS: m/z = 441 (MH+).
Anal. Calcd for C24H28N2O6: C, 64.13; H, 6.50; N, 6.23. Found: C,
64.66; H, 6.51; N, 6.05.
IR (neat): 3430, 1742, 1654, 1528, 1488 cm–1.
1H NMR (CDCl3): = 2.00 (m, 1 H), 2.39 (m, 1 H), 2.75 (m, 2 H),
3.33 (dd, 1 H, J = 5.5, 2.4 Hz), 3.74 (s, 3 H), 3.76 (s, 3 H), 4.64 (m,
1 H), 5.33 (dd, 1 H, J = 9.4, 2.4 Hz), 6.73 (d, 1 H, J = 9.4 Hz), 7.20
(m, 7 H), 7.40 (m, 3 H), 7.50 (m, 1 H), 7.60 (m, 3 H), 7.80 (m, 2 H).
13C NMR (CDCl3): = 32.5, 34.6, 49.6, 50.0, 52.5, 53.1, 126.0,
126.8, 127.2, 128.3, 128.4, 128.6, 131.4, 132.1, 140.9, 166.9, 167.7,
171.1, 172.7.
(1S,2R,3S)-2-Benzoylamino-3-(1-benzoylaminobutyl)succinic
Acid Dimethyl Ester (4e)
Yield: 80%; dr = 95:5. Only the major isomer is described.
IR (neat): 1738, 1641, 1547, 1492 cm–1.
1H NMR (CDCl3): = 0.94 (t, 3 H, J = 7.2 Hz), 1.50 (m, 2 H), 1.72
(m, 2 H), 3.27 (s, 3 H), 3.58 (dd, 1 H, J = 10.5, 2.3 Hz), 3.73 (s, 3
H), 4.78 (dq, 1 H, J = 10.1, 2.5 Hz), 5.56 (dd, 1 H, J = 9.8, 2.2 Hz),
6.21 (d, 1H, J = 10.1 Hz), 7.40 (m, 2H), 7.50 (m, 4H), 7.80 (d, 2H,
J = 7.5 Hz), 8.07 (m, 2 H), 8.22 (d, 1 H, J = 9.8 Hz).
13C NMR (CDCl3): = 13.6, 19.3, 36.3, 47.5, 51.8, 52.0, 52.5, 52.7,
127.1, 131.7, 132.2, 133.2, 133.5, 167.1, 168.1, 171.4, 171.9.
MS: m/z = 503 (MH+).
Anal. Calcd for C29H30N2O6: C, 69.31; H, 6.02; N, 5.57. Found: C,
69.04; H, 6.12, N; 5.19.
HRMS: m/z calcd for C24H29N2O4: 441.2026; found: 441.2025.
Synthesis 2002, No. 13, 1885–1890 ISSN 0039-7881 © Thieme Stuttgart · New York

1890
A. Chauveau et al.
PAPER
(1R,2R,3S)-3-Benzoylamino-2-(1-benzoylaminoethyl)hexanoic
Acid Methyl Ester (4f)
1 H, J = 7.2 Hz), 4.92 (m, 1 H), 7.10–7.40 (m, 8 H), 7.60 (d, 2 H,
J = 8.0 Hz).
Yield: 69%; dr = 97:3; [ ]D –11 (c 1.5, CHCl3).
IR (neat): 2361, 1736, 1640, 1536, 1492 cm–1.
13C NMR (CDCl3): = 32.2, 35.7, 52.3, 52.5, 54.4, 60.0, 62.2,
126.1, 127.7, 128.4, 128.5, 130.2, 135.4, 169.2, 170.0.
1H NMR (CDCl3): = 0.88 (d, 3 H, J = 6.7 Hz), 1.28 (d, 3 H,
J = 6.7 Hz), 1.40 (m, 2 H), 1.70–1.80 (m, 2 H), 2.95 (t, 1 H, J = 7.0
Hz), 3.76 (s, 3 H), 4.63 (m, 2 H), 6.64 (d, 1 H, J = 9.3 Hz), 6.74 (d,
1 H, J = 8.6 Hz), 7.40–7.50 (m, 6 H), 7.80–7.90 (m, 4 H).
Acknowledgement
We thank MRT (A. Chauveau) for a grant.
13C NMR (CDCl3): = 13.7, 18.9, 19.4, 35.1, 44.6, 48.5, 51.9, 55.3,
127.0, 128.6, 131.5, 134.4, 167.2, 167.7, 172.3.
References
HRMS: m/z calcd for C23H29N2O4: 397.2127; found: 397.2122.
(1) (a) Guerra, F. M.; Mish, M. R.; Carreira, E. M. Org. Lett.
2000, 2, 4265. (b) Whitlock, G. A.; Carreira, E. M. Helv.
Chim. Acta 2000, 83, 2007. (c) Barluenga, J.; Fernandez-
Mari, F.; Viado, A. L.; Aguilar, E.; Olano, B.; Garcia-
Granda, S.; Moya-Rubiera, C. Chem.–Eur. J. 1999, 5, 883.
(d) Stanovnik, B.; Jelen, B.; Turk, C.; ’Zlicar, M.; Svete, J.
J. Heterocycl. Chem. 1998, 35, 1187. (e) Mish, M. R.;
Guerra, F. M.; Carreira, E. M. J. Am. Chem. Soc. 1997, 119,
8379. (f) Rutjes, F. P. J. T.; Teerhuis, N. M.; Hiemstra, H.;
Speckhamp, W. N. Tetrahedron 1993, 49, 8605. (g) Gallos,
J. K.; Koumbis, A. E.; Apostolakis, N. E. J. Chem. Soc.,
Perkin Trans. 1 1997, 2457.
(3S,4S,5R)-3-Propylpyrazolidine-1,4,5-tricarboxylic Acid 4,5-
Dimethyl Ester 1-Phenethyl Ester (6d)
Yield: 25%; dr > 98:2.
IR (neat): 3362, 2956, 1740, 1437 cm–1.
1H NMR (C6D6): = 0.66 (t, 3 H, J = 7.3 Hz), 0.70–1.30 (m, 4 H),
2.70 (m, 2 H), 2.79 (dd, 1H, J = 8.9, 3.8 Hz), 3.19 (s, 3 H), 3.23 (m,
1 H) 3.31 (s, 3 H), 4.23 (m, 3 H), 4.86 (d, 1 H, J = 8.3 Hz), 6.90–
7.10 (m, 5H).
13C NMR (CDCl3): = 13.5, 19.4, 34.6, 35.2, 52.4, 54.1, 62.3, 66.6,
126.3, 128.3, 128.7, 137.3, 169.7, 171.4.
(2) (a) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.
Tetrahedron 1997, 53, 12789; and references therein.
(b) Kim, H.-O.; Lum, C.; Lee, M. S. Tetrahedron Lett. 1997,
38, 4935.
MS: m/z = 379 (MH+).
(4S,5S)-5-Phenethyl-4,5-dihydro-1H-pyrazole-3,4-dicarboxylic
Acid Dimethyl Ester (7a)
Yield: 29%; dr > 98:2.
1H NMR (CDCl3): = 1.97 (m, 2 H), 2.70 (m, 2 H), 3.76 (s, 3 H),
3.80 (m, 1 H), 3.83 (s, 3 H), 4.20 (dd, 1 H, J = 14.9, 7.5 Hz), 6.22
(s, 1 H), 7.20–7.40 (m, 5 H).
13C NMR (CDCl3): = 31.8, 36.2, 52.2, 52.7, 54.5, 66.9, 126.3,
128.3, 128.7, 138.4, 140.2, 162.3, 171.0.
(3) (a) Svete, J.; Preseren, B.; Stanovnik, B.; Golic, L.; Golic-
Grdadolnik, S. J. Heterocycl. Chem. 1997, 34, 1323.
(b) Zlicar, M.; Stanovnik, B.; Tisler, M. J. Heterocycl.
Chem. 1993, 30, 1209. (c) For older studies in this field, see:
Dorn, H.; Otto, A. Chem. Ber. 1968, 101, 3287. (d) Dorn,
H.; Ozegowski, R.; Gründemann, E. J. Prakt. Chem. 1979,
565. (e) Dorn, H. Tetrahedron Lett. 1985, 26, 5123.
(f) Oppolzer, W. Tetrahedron Lett. 1972, 17, 1707.
(g) Oppolzer, W. Tetrahedron Lett. 1970, 15, 2199. (h) For
solid-phase application of this methodology, see: Fuchi, N.;
Doi, T.; Cao, B.; Kahn, M.; Takahashi, T. Synlett 2002, 285.
(4) Chuang, T.-H.; Sharpless, K. B. Helv. Chim. Acta 2000, 83,
1734.
(4R,6S,7S,8R)-6-Cyclohexylmethyl-1-oxo-4-phenyltetrahydro-
pyrazolo[1,2-c][1,3,4]oxadiazine-7,8-dicarboxylic Acid Dimeth-
yl Ester (8a)
Yield:19%; dr > 98:2; [ ]D –165 (c 1.1, CHCl3).
IR (neat): 2922, 2851, 2365, 2342, 1748, 1700, 1434 cm–1.
1H NMR (CDCl3): = 0.50–1.60 (m, 15 H), 3.45 (dd, 1 H, J = 11.1,
8.9 Hz), 3.68 (ddd, 1 H, J = 11.1, 6.6, 2.3 Hz), 3.70 (s, 3 H), 3.75
(s, 3 H), 4.19 (dd, 1 H, J = 10.5, 3.2 Hz), 4.26 (dd, 1 H, J = 11.0,
3.2 Hz), 4.54 (t, 1 H, J = 10.8 Hz), 4.83 (d, 1 H, J = 8.9 Hz), 7.38
(s, 5 H).
13C NMR (CDCl3): = 26.0, 26.1, 26.4, 28.2, 30.6, 32.6, 33.1, 37.4,
48.8, 52.6, 52.8, 60.3, 65.3, 66.7, 72.3, 128.8, 129.0, 129.5, 133.7,
149.8, 168.9, 169.2.
(5) (a) Roussi, F.; Chauveau, A.; Bonin, M.; Micouin, L.;
Husson, H.-P. Synthesis 2000, 1170. (b) Roussi, F.; Bonin,
M.; Chiaroni, A.; Micouin, L.; Riche, C.; Husson, H.-P.
Tetrahedron Lett. 1999, 40, 3727.
(6) Khaus, V. V.; Martinelli, M. J. Tetrahedron Lett. 1996, 37,
4323; and ref.5a.
(7) Lucet, D.; Heyse, P.; Gissot, A.; Le Gall, T.; Mioskowski, C.
Eur. J. Org. Chem. 2000, 3575.
(8) Alker, D.; Hamblett, G.; Harwood, L. M.; Robertson, S. M.;
Watkin, D. J.; Williams, C. E. Tetrahedron 1998, 54, 6089.
(9) For similar behavior, see : Alexakis, A.; Lensen, N.;
Tranchier, J.-P.; Mangeney, P. J. Org. Chem. 1992, 57,
4563.
(10) (a) Mellor, J. M.; Smith, N. M. J. Chem. Soc., Perkin. Trans
1 1984, 2927. (b) Denmark, S. E.; Kim, J.-H. Synthesis
1992, 229. (c) Whitlock, G. A.; Carreira, E. M. J. Org.
Chem. 1997, 62, 7916. (d) Arakawa, Y.; Goto, T.; Kawase,
K.; Yoshifuji, S. Chem. Pharm. Bull. 1998, 46, 674.
(11) Fernandez, R.; Ferrete, A.; Lassaletta, J. M.; Llera, J. M.;
Monge, A. Angew. Chem. Int. Ed. 2000, 39, 2893.
(12) Horner, L.; Jordan, M. Liebigs Ann. Chem. 1978, 1505.
MS: m/z = 445 (MH+).
Anal. Calcd for C24H32N2O6: C, 64.85; H, 7.26; N, 6.30. Found: C,
64.32; H, 7.433; N, 5.98.
(3R,4S,5S)-1-Benzoyl-5-phenethylpyrazolidine-3,4-dicarboxyl-
ic Acid Dimethyl Ester (9a)
Mixture with 4a; dr > 98:2.
1H NMR (CDCl3): = 2.05 (m, 1 H), 2.23 (m, 1 H), 2.77 (m, 2 H),
3.31 (dd, 1 H, J = 7.2, 5.9 Hz), 3.62 (s, 3 H), 3.70 (s, 3 H), 4.19 (t,
Synthesis 2002, No. 13, 1885–1890 ISSN 0039-7881 © Thieme Stuttgart · New York