Rapid and efficient access to meso-2,5-cis-disubstituted pyrrolidines by double aza-Michael reactions of chiral primary amines

Article abstract of DOI:10.3987/COM-07-S(U)56

The double aza-Michael reaction of enantiopure primary amines on bis α,β-unsaturated diesters has been studied under various activating conditions. High pressure allowed a rapid and efficient access to meso-2,5-disubstituted pyrrolidines.

Full text of DOI:10.3987/COM-07-S(U)56

HETEROCYCLES, Vol. 73, 2007
751
HETEROCYCLES, Vol. 73, 2007, pp. 751 - 768. © The Japan Institute of Heterocyclic Chemistry
Received, 1st August, 2007, Accepted, 13th September, 2007, Published online, 14th September, 2007. COM-07-S(U)56
RAPID AND EFFICIENT ACCESS TO MESO-2,5-CIS-DISUBSTITUTED
PYRROLIDINES BY DOUBLE AZA-MICHAEL REACTIONS OF
CHIRAL PRIMARY AMINES
Leila Cabral dos Santos,a,b Zineb Bahlaouan, a,b Khadija El Kassimi,a,b Claire
Troufflard,b,c Frédéric Hendra,a,b Sandrine Delarue-Cochin,a,b Mohamed
Zahouily,d Christian Cavé,a,b and Delphine Josepha,b*
a
Univ. Paris-Sud, Department of Organic Synthesis and Medicinal Chemistry,
UMR CNRS 8076, 5, rue J.-B. Clément, F-92296 Châtenay-Malabry, France
b IFR 141, 5, rue J.-B. Clément, F-92296 Châtenay-Malabry, France
c Univ. Paris-Sud, NMR Department, UMR CNRS 8076, 5, rue J.-B. Clément,
F-92296 Châtenay-Malabry, France
d
Univ. Hassan II-Mohammedia, Faculty of Sciences and Techniques, BP 146,
20800 Mohammedia, Morocco
Abstract – The double aza-Michael reaction of enantiopure primary amines on bis
α,β-unsaturated diesters has been studied under various activating conditions.
High pressure allowed a rapid and efficient access to meso-2,5-disubstituted
pyrrolidines.
INTRODUCTION
2,5-Disubstituted pyrrolidines are naturally ubiquitous, biologically important substances and the synthesis
of this type of alkaloids is of considerable current interest.1 Access to pyrrolidine moiety can be envisaged
throughanaza-Michaeladditiononamono or bis α,β-unsaturated ester: our research group has contributed
to the synthesis of 2,5-dialkylpyrrolidines using intramolecular conjugate addition of an enamino ester
resulting from the condensation of (R)-1-phenylethylamine to ketoenedioate (Scheme 1).2
In fact, the aza-Michael addition to unsaturated esters is undoubtedly one of the most direct methods to
synthesize β-amino acids and pyrrolidines through both inter- and intra-molecular pathways respectively.
In this area, the conjugate addition of enantiomerically pure lithium amides as homochiral ammonia

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HETEROCYCLES, Vol. 73, 2007
equivalents is known to be the most efficient route to prepare β-amino acids.3 However, applied to dialkyl
(E,E)-octa-2,6-dienoates, the addition of lithium amide led to the homochiral aminocyclopentane via a
tandem conjugate addition-intramolecular cyclisation process.4
Ph
H
Me
NH
NH2
Ph
MeO2C
CO2Me
MeO2C
ZnCl2
THF, reflux
CO2Me
CO2Me
H
N
Me
N
CO2Me
NH
Ph
+
+
CO2Me
MeO2C
Ph
Me
O
Ph
Me
H
H
PhH, reflux
CO2Me
MeO2C
H
Me
40%
26%
11%
PtO2, H2
MeOH-AcOH
84%
MeO2C
CO2Me
MeO2C
N
H
N
CO2Me
+
Ph
Me
Ph
Me
H
9
:
1
Scheme 1
Furthermore, the 1,4-addition of primary amines is restricted by steric effect of the α/β-substituents
bearing by the unsaturated ester and generally require either high temperature, high pressure, microwave
irradiation or Lewis acid catalysis:3 Maddaluno has recently described hyperbaric tandem aza-Michael
addition of primary amines to the cyclic bielectrophile derived from cyclohexane-1,4-dione to prepare
azanorbornane skeleton.5 In turn, Murray has circumvented the problem related to steric disfavored
effects using hydroxylamine, small and very reactive primary amine, and has efficiently synthesized
2,5-disubstituted N-hydroxypyrrolidines by consecutive double 1,4-addition to diethyl
octa-2,6-dienedioate at room temperature.6
In this paper, we report an efficient and general method to prepare orthogonally functionalized
meso-2,5-disubstituted pyrrolidines by double conjugate addition reactions of enantiopure primary amines
to dimethyl, ditert-butyl or dibenzyl octa-2,6-dienedioates. We have demonstrated that the double
1,4-addition of primary amines requires activation and various activating conditions such as high pressure,
microwave irradiation or catalysis have been studied.
RESULTS AND DISCUSSION
The symmetrical dialkyl octa-2,6-dienedioates (4a-c) were synthesized, on multigram scale, in two steps
starting from 1,5-cyclooctadiene (2) using an ozonolysis and a subsequent Wittig reaction (Scheme 2).
The Wittig reagents (1a-c), (methoxy-, tert-butoxy- and benzyloxy-carbonylmethylene)triphenyl-

HETEROCYCLES, Vol. 73, 2007
753
phosphoranes, were prepared according to a procedure adapted from the literature with excellent yields
over two steps starting from alkyl bromoacetates.7
Then, ozonolysis of 1,5-cyclooctadiene (2) followed by the treatment with an excess of
triphenylphosphine gave, after distillation of the crude mixture, the unstable succinic aldehyde (3) in 98%
yield (Scheme 2).8 This dialdehyde was directly converted by a double Wittig reaction using a slight
excess of (alkoxycarbonylmethylene)triphenylphosphorane into the corresponding symmetrical bis
α,β-unsaturated diester (4a-c) (Scheme 2).9 These dienoates were efficiently synthesized as a mixture of
Z/Z, E/Z- and E/E-isomers separable by column chromatography. The Z/Z: E/E ratio was mostly in favor
of the E/E isomer, depending on the steric hindrance of the alkoxy substituents: the dimethyl ester 4a was
obtained in a 1: 9 Z/Z: E/E ratio and the dibenzyl ester 4c in a 2: 98 E/Z: E/E ratio. In the case of the
bulky tert-butyloxy group, the diester 4b was isolated as the single E/E isomer.
CO2R1
1. O3, CH2Cl2, EtOH, -78 °C
2. PPh3 (2.5 eq), rt, 15 h
(2.3 eq.)
Ph3P
1a-c
1/2
3. distillation under reduced
pressure
O O
R1O2C
CO2R1
CH2Cl2, rt , 15 h
2
3
98%
4a R1 = Me (90%)
b R1 = t-Bu (90%)
c R1 = Bn (80%)
Scheme 2
Then, we have studied the bis conjugate addition of both commercially available (S)- and
(R)-α-methylbenzylamine 5a, and (R)-phenylglycinol10 5b.
R1O2C
CO2R1
R2
R2
∆
6a R1 = Me, R2 = H
b R1 = Me, R2 = OH
c R1 = t-Bu, R2 = H
d R1 = t-Bu, R2 = OH
e R1 = Bn, R2 = H
f R1 = Bn, R2 = OH
g R1 = t-Bu, Me R2 = H
or µW irradation
N
H2N
+
or HP
or NP catalysis
H
H
R1O2C
6-meso
CO2R1
4a R1 = Me
b R1 = t-Bu
c R1 = Bn
5a R2 = H
b R2 = OH
Scheme 3

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HETEROCYCLES, Vol. 73, 2007
We first examined the addition of chiral α-methylbenzylamine 5a to dimethyl E,E-octa-2,6-dienedioate
4a (Scheme 3 and Table 1). To optimize the reaction conditions, solvent effect was explored using a
molar solution of diene in various solvents. The reaction is monitored by 1H NMR until the dienedioate is
entirely consumed.
Previous reports have showed that addition of amine to α,β-unsaturated esters was most efficient in protic
solvents.11 We confirmed that the reaction did not proceed using non protic solvents such as toluene, THF
or acetonitrile in the presence of DBU12 as a base (Table 1, entries 1-4). Moreover, the reaction proceeded
smoothly under solvent-free conditions. Using methanol as solvent allowed the access to the bis-adduct
6a but highly prolonged reaction time, 2 weeks, was required (Table 1, entries 5-9). In refluxing methanol,
the yield dramatically decreased due to the diene degradation. The best yields were obtained when the
reaction was performed at 40 °C (Table 1, entries 7-10). As a result, we have adopted methanol and 40 °C
respectively as the optimal solvent and reaction temperature for the following investigation. On the
opposite of the addition of hydroxylamine,6 the 1,4-addition of (R)-α-methylbenzylamine (R)-5a to
dimethyl E,E-octa-2,6-dienedioate 4a only gave the thermodynamic pseudo-meso-pyrrolidine
2,5-cis-disubstituted 6a which presented the same NMR data and the same specific rotation as those
reported in the literature2 (Scheme 4). We never observed the formation of the trans isomer.
MeO2C
(R)
H
Ph
N
(R)
CO2Me
Me
(S)
Me
H
MeOH
40 °C
MeO2C
+
H2N
Ph
meso-6a
CO2Me
E/E-4a
MeO2C
(R)-5a
(S)
H
Me
(R)
N
(R)
Ph
MeO2C
Scheme 4
Starting from the Z/Z isomer of 4a, the conjugate addition of the (R)- α-methylbenzylamine afforded the
same cis-pyrrolidine 6a in good yield (Table 1, entry 8): the diastereoselectivity of the diene had no
influence on both the rate and the stereoselectivity of the reaction. For the following exploration, the
dimethyl octa-2,6-dienedioates will, then, be used as a mixture of E/E and Z/Z isomers in a 9:1 ratio.

HETEROCYCLES, Vol. 73, 2007
755
As the addition reaction needed a prolonged time under atmospheric pressure to afford the pyrrolidine
adduct in reasonable yields, we have then investigated the effect of activation agents such as high
pressure, microwave irradiation and catalysis using natural phosphates (NP). In this area, Zahouily has
recently developed a novel catalyzed aza-Michael reaction in mild conditions: the use of natural
phosphate (NP) and potassium fluoride doped natural phosphate (KF/NP) as catalysts in methanol
accelerates at room temperature the addition reaction of aromatic amines or benzylamine on chalcones
and alkyl acrylates.13 Unfortunately, in the case of the dimethyl octa-2,6-dienedioate 4a no enhancement
of the rate of the double conjugate addition was observed (Table 1, entries 11-13). These results could be
first explained by the low reactivity of the diester 4a compared to Michael acceptors employed in the
published study and by the disfavored steric hindrance of the α-methylbenzylamine compared to
benzylamine.
Otherwise, microwave irradiation is known to activate the rate of organic reaction and efficiently
promotes Michael additions allowing shorter reaction times.14 The effects of the microwave irradiation
are not clearly established: it is assumed that the rate enhancement is partially due to dipole-dipole
interactions between the electromagnetic field and polar compounds whose orientation alternates at a very
high frequency leading to dielectric heating. Under microwave irradiation (250 W, 150 °C), the conjugate
addition of (S)-α-methylbenzylamine to the dienediester 4a, was activated and led to the cis-pyrrolidine
6a in only 10.5 hours in moderate yield due to the diene degradation at high temperature (Table 1, entry
14).
Finally, an alternative to circumvent the limitations of the high temperature sensitive diene and the
disfavored steric hindrance consists in resorting to high pressure. It is well established that the rate of the
Michael addition could be accelerated by high pressure activation without modifying its regio- and
stereoselectivity and allowing improved yield and cleaner reaction. Moreover, high pressure has already
successfully been employed to activate the 1,4-addition of bulky amines to chiral crotonates affording
β-amino esters.15 The acceleration of the reaction under hyperbaric conditions is correlated to the
activation volume associated which has to be large and negative (typically from -10 to -70 mL/mol).
Jenner has measured a highly negative activation volume associated to the aza-Michael addition
explaining the efficiency of the high pressure activation.16 Thus, applied to the dimethyl dienedioate 4a,
the hyperbaric addition (11 kbar) of the amine (S)-5a gave the pyrrolidine 6a at room temperature after 42
h in excellent yield (Table 1, entry 15).

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Table 1 Double aza-Michael reaction of α-methylbenzylamine to dimethyl octa-2,6-dienedioate 4a
Eq of
Z/Z :E/E
Product 6a
Yield (%)a
Entries
Solvent
Reaction conditions
amine 5a ratio (4a)
1
2
(R)1.5 eq
(R)1.5 eq
(R)1.5 eq
(R)1.5 eq
(R)1.5 eq
(R)1.5 eq
(R)1.5 eq
(R)1.5 eq
(R)1.5 eq
(S) 1.5 eq
(S) 1.5 eq
(S) 1.5 eq
(S) 1.5 eq
(S) 1.5 eq
(S) 1.5 eq
0 : 1
0 : 1
0 : 1
0 : 1
0 : 1
0 : 1
0 : 1
1 : 0
1 : 9
1 : 9
1 : 9
1 : 9
1 : 9
1 : 9
1 : 9
THF
rt, 15 days
reflux, 15 days
start. mat.e
THF
decomposition
start. mat.e
start. mat.e
3
toluene
MeCN
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
rt, 15 days
rt, DBU (0.5 eq),11 15 days
4
5
rt, 15 days
80
53
92
83
93
70
70
66
75
62
90
6
reflux, 15 days
7
40 °C, 7 days
8
40 °C, 7 days
9
40 °C, 7 days
10
11
12
13
14
15
40 ºC, 5 days
40 ºC, 5 days, NPb,13
40 ºC, 5 days, Na/NPc
40 ºC, 5 days, KF/NPd, 13
MeOH (6 eq), THF µW, 250W, 150 °C 10.5 h
MeOH (6 eq), THF 11 kbar, rt, 42 h
a Isolated yield;
b NP: natural phosphate;
c Na/NP: natural phosphate doped by NaNO3;
d KF/NP: natural phosphate doped by KF;
e start. mat.: starting materials
After these results, the aza-Michael addition was extended to the (R)-phenylglycinol 5b (Scheme 3 -
Table 2): the heterocycle 6b was isolated in poor yield using prolonged thermal and NP catalyzed
activations but the starting diene was recovered (Table 2, entries 1-4). The activation by the piezoprocess
was also fruitless: a small amount of pyrrolidine 6b was only isolated and we observed that the
decomposition of the diene began after 4 h of reaction (Table 2, entry 5). An explanation of the low
conversion rate could be that the amino alcohol 5b is more sterically hindered than its homologue 5a.
Again, the hyperbaric process was the appropriate method to skirt round this constraint: after 42 h at 11
kbar and room temperature, the pyrrolidine 6b was obtained in excellent yield (Table 2, entry 6).

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757
Table 2 Double aza-Michael reaction of (R)-phenylglycinol 5b to dimethyl octa-2,6-dienedioate 4a
Eq of
Z/Z :E/E
Product 6b
Yield (%)a
35
Entries
Solvent
Reaction conditions
amine 5b ratio (4a)
1
2
3
4
1.5 eq
1.5 eq
1.5 eq
2 eq
1 : 9
1 : 9
1 : 9
1 : 9
MeOH
MeOH
MeOH
MeOH
40 ºC,18 days
40 ºC, 18 days, NPb
40 ºC,18 days, Na/NPc
40 ºC,18 days, KF/NPd
35
30
33
15
decomposition
90
5
1.2 eq
1 : 9
1 : 9
MeOH (6 eq), THF
MeOH (6 eq), THF
µW, 250W, 150 °C, 10 h
11 kbar, rt, 42 h
6
1.2 eq
a Isolated yield;
b NP: natural phosphate;
c Na/NP: natural phosphate doped by NaNO3;
d KF/NP: natural phosphate doped by KF.
The following studies have successively concerned the ditert-butyl and the dibenzyl octa-2,6-dienedioates
4b and 4c and the results have been stored in the Tables 3 and 4 (Schemes 7 and 8).
When the conjugate addition took place in methanol, the prolonged reaction time until the total
consumption of the di-tert-butyl or dibenzyl diesters conduced to a mixture of mono- and
di-transesterified pyrrolidines accompanying the desired pyrrolidines 6c and 6e respectively. Using the
secondary alcohol isopropanol (iPrOH) and the tertiary alcohol tert-butanol (tBuOH) avoided the
competitive reaction. In general, the encumbrance of the ester function led to a drop in conversion rate
and an increase of the reaction time. Under thermal activation, when the conjugate addition of the
ditert-butyl E,E-octa-2,6-dienedioates 4b to the amine 5a was carried out in methanol, the paralleled
transesterification occurred giving a mixture of the 2,5-cis disubstituted pyrrolidines 6a, 6c and of the two
diastereomers of 6g (Table 3, entry 1). Unfortunately, in iPrOH, the addition did not take place at 40 °C
after 15 days and the starting bis Michael acceptor was entirely recovered (Table 3, entry 2).
Catalysis by NP and doped NP was also inefficient and the dienoate 4b remained unchanged (Table 3,
entries 3-5). Moreover, whatever the power used for the microwave irradiation activation, only the
degradation of the starting tert-butyl diester was observed and the pyrrolidine 6c has never been isolated
(Table 3, entry 6).15
Only the hyperbaric addition allowed the access to the pyrrolidines. In the presence of methanol as
external proton donating agent, the diene was converted at 11 kbar and room temperature in an
inseparable mixture of the major desired heterocycle 6c and the minor transesterified analogue 6a in good

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HETEROCYCLES, Vol. 73, 2007
yield (Table 3, entry 7). Replacing methanol by isopropanol or by tert-butanol led the expected bis adduct
6c with excellent yield avoiding the competitive reaction (Table 3, entries 8 and 9).
Finally, all attempts of 1,4-addition of the phenylglycinol 5b to the di-tertbutyl dienedioate 4b failed
under thermal or NP catalyzed activation. Similarly, the conjugate addition activated by high pressure
gave the pyrrolidines 6d in reasonable yield after 4 days at 11 kbar and at 35 ° C (Table 3, entry 10).
Table 3 Double aza-Michael reaction of chiral primary amines to di-tert-butyl dienediester 4b
Eq of
Results
Yield (%)a
Entries R2
Solvent
Reaction conditions
amine
6a 19
6g 10
1
H
(S)1.2 eq
MeOH
40 °C, 15 days
6c 28
2
3
4
5
6
H
H
H
H
H
(S)1.2 eq
(S) 2 eq
(S) 2 eq
(S) 2 eq
(S) 2 eq
iPrOH
40 °C, 15 days
40 °C,15 days, NPb
40 °C, 15 days, Na/NPc
40 °C, 15 days, KF/NPd
start. mat.e
iPrOH, H2O (6 eq)
iPrOH, H2O (6 eq)
iPrOH, H2O (6 eq)
THF, iPrOH (6 eq)
start. mat.e
start. mat.e
start. mat.e
µW, 100 W, 50 °C or 100 °C, 3.5 h degradation
6a 7
6c 64
7
H
(S)1.2 eq
THF, MeOH (6 eq)
11 kbar, rt, 42 h
8
9
H
H
(S)1.2 eq
(S)1.2 eq
THF, tBuOH (6 eq)
THF, iPrOH (6 eq)
THF, iPrOH (6 eq)
11 kbar, 35 °C, 15 h
11 kbar, 35 °C, 15 h
11 kbar, 35 °C, 4 days
6c 80
6c 90
6d 60
10
OH (R)1.2 eq
a Isolated yield;
b NP: natural phosphate;
c Na/NP: natural phosphate doped by NaNO3;
d KF/NP: natural phosphate doped by KF;
e start. mat.: starting materials.
In the case of the dibenzyl E,E-octa-2,6-dienedioates 4c, the same observations were made: (i) in the
presence of methanol, transesterification occurred (Table 4, entries 2 and 4); (ii) NP or doped catalysis
did not have significant influence on the conversion rate (Table 4, entries 5-7); (iii) using microwave
activation (250 W), the starting diene 4c decomposed at high temperature (150 °C or 200 °C) (Table 4,
entry 8); (iv) at 11 kbar and 35 °C, in the presence of tertbutanol, the pyrrolidines 6e was isolated in
acceptable yield after 5 days (Table 4, entry 10).
In the same hyperbaric reaction conditions, the conjugate addition of the amino alcohol 5b to the dibenzyl

HETEROCYCLES, Vol. 73, 2007
759
dienoate 4c led to the cis-pyrrolidine 6f in poor yield (Table 4, entry 11).
Table 4 Double aza-Michael reaction of chiral primary amines to dibenzyl octa-2,6-dienedioate 4c
Eq of
amine
Results
Entries R2
Solvent
Reaction conditions
Yield (%)a
(S) 1.5 eq
1
2
3
4
H
H
H
H
iPrOH
40 °C, 18 days
6e 15
6e 74
6c 6
iPrOH, MeOH (6 eq)
iPrOH, H2O (6 eq)
40 ºC, 20 days, Na/NPc
40 ºC, 9 days
(S) 1.5 eq
(S) 1.5 eq
(S) 1.5 eq
6e 58
6e 45
6c 11
MeOH
40 ºC, 5 days, Na/NPc
40 ºC, 5-7 days, NPb
40 ºC, 5-7 days, Na/NPc
40 ºC, 5-7 days, KF/NPd
6e 47
6e 53
6e 51
(S) 1.5 eq
(S) 1.5 eq
(S) 1.5 eq
(S) 1.5 eq
(S) 1.5 eq
(S) 1.5 eq
iPrOH, H2O (6 eq)
iPrOH, H2O (6 eq)
iPrOH, H2O (6 eq)
5
6
H
H
H
H
H
H
7
8
THF, iPrOH (6 eq) µW, 250 W, 150 °C or 200 °C, 5 h decomposition
9
THF, iPrOH (6 eq)
THF, tBuOH (6 eq)
11 kbar, 35 °C, 5 days
11 kbar, 35 °C, 5 days
11 kbar, 35 °C, 5 days
6e 30
6e 60
6f 24
10
11
OH (R) 1.5 eq THF, tBuOH (6 eq)
a Isolated yield;
b NP: natural phosphate;
c Na/NP: natural phosphate doped by NaNO3;
d KF/NP: natural phosphate doped by KF.
Carbon-carbon and carbon-hydrogen connectivities in all pyrrolidines were unambiguously determined
by two-dimensional NMR spectroscopy and the absolute structure confirmation was made by nOesy
experiments (Figure 1). In these series of pyrrolidines, only one conformer is observed due to the absence
of rotameric equilibria. Indeed,
a
symmetric 1H-NMR spectrum usually indicates the
1
cis-stereochemistry.22 Nevertheless, in our case, the H- and 13C-NMR spectra are completely
desymmetrized even at high temperature (performed in d6-DMSO) revealing the lack of free rotation of
the substituting nitrogen group around the N-C* bound (Figures 2 and 3). Noteworthy, the chemically
1
13
equivalent H and C in the cyclic compound are magnetically different owing to the fact that, in the
unique rotamer, the phenyl anisotropy effect is only affected a part of the molecule.

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HETEROCYCLES, Vol. 73, 2007
H
H
H
H
H
H
H
H
H
H
O
O
O
O
H
H
O
O
O
O
N
NX
H
H
CH3
CH3
Figure 1: nOesy data for pyrrolidine 6e
150
100
50
ppm (f1)
Figure 2: 13C-NMR spectrum for pyrrolidine 6e
CONCLUSIONS
The chemistry described above provides a convenient and efficient method to prepare a series of
orthogonally functionalized meso-2,5-disubstituted pyrrolidines by double conjugate addition reactions of
enantiopure primary amines to alkyl octa-2,6-dienedioates. Our method gave access to pyrrolidines in two
steps starting the succinaldehyde. The key step is based on a double aza-Michael addition of a primary
amine to a dialkyl octa-2,6-dienedioate which is more efficient under hyperbaric conditions. The

HETEROCYCLES, Vol. 73, 2007
761
application of these results to the synthesis of compounds of biological relevance and of C2-symmetric
pyrrolidines is in progress.
7.0
6.0
5.0
4.0
3.0
2.0
ppm (f1)
Figure 3: 1H-NMR spectra for pyrrolidine 6e
EXPERIMENTAL
General
Commercial reagents were used without purification. Prior to use, THF was freshly distilled from sodium
benzophenone, methanol and isopropanol from CaH2. Natural phosphate (NP) came from an ore extracted
in the region of Khouribga (it is available in raw form or treated form from CERPHOS Casablanca,
Morocco). NP and NP doped with KF (KF/NP) and NaNO3 (Na/NP) have been treated, prepared and
generously given by Mohamed Zahouily (Laboratoire de Catalyse, Synthese et Environnement, Faculty of
Sciences and Techniques, University Hassan II, Morocco). Treatment consisted in techniques involving
attrition, sifting, calcination, washing and recalcination.18 All anhydrous reactions were carried out under
argon atmosphere. Analytical thin layer chromatography was performed on Merck 60F-254 coated silica
(0.2 mm) on glass and was revealed by UV-light and Kägi-Misher or Dragendorf reagent. All flash
chromatography separations were performed with Merck Kieselgel (40-63 µm). Melting points were
recorded on an Electrothermal digital apparatus and were uncorrected. Infrared (IR) spectra were obtained
1
31
13
as neat films and were recorded on Bruker Vector 22 spectrophotometer. H, P and C spectra were

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recorded respectively at 200, 300 and 400 MHz, 80.96 MHz and 50, 75, 100 MHz unless otherwise
specified. CDCl3 was used as internal reference. Specific rotations [α]D were measured on a PolAAr32
polarimeter with sodium (589 nm) lamp at 20 °C in a 1 dm cell and were given in units of 10-1 deg cm2
g-1. Concentrations were quoted in g per 100 mL. The electron impact (EI) mass spectra were run on a HP
6890 series-GC system spectrometer at 70 eV ionizing voltage and equipped with HP 5973 mass selective
detector. Elemental analyses were performed by the Service de Microanalyse, Centre d’Etudes
Pharmaceutiques, Châtenay-Malabry, France, with a Perkin-Elmer 2400 analyser.
(Alkoxycarbonylmethyl)triphenylphosphonium bromide : general procedure7
A 1 L erlenmeyer fitted with a dropping funnel and a magnetic stirrer was charged with 65.5 g (0.25 mol,
1 eq.) of triphenylphosphine and 150 mL of toluene. The reaction mixture was cooled by a cold water
bath and alkyl bromoacetate (0.25 mol, 1 eq.) was slowly added dropwise. The reaction was allowed
stirring at rt overnight and the phosphonium salt was filtered. The salt was washed twice with 150 mL of
pentane and dried.
(Methoxycarbonylmethyl)triphenylphosphonium bromide19 (Colorless solid, Yield = 95%). mp
163 °C.
(tert-Butoxycarbonylmethyl)triphenylphosphonium bromide (Colorless solid, Yield = 93%). mp
176 °C. 1H NMR (CDCl3, 300 MHz): δ 1.18 (9H, s), 5.35 (2H, d, J2 = 14.1 Hz), 7.66 (6H, td, J3 = 7.8, J4
P
P
= 3.6 Hz), 7.77 (3H, td, J3 = 7.6, J4 = 1.4 Hz), 7.88 (6H, ddd, J3 = 7.1, J3 = 2.1, J4 = 1.4 Hz). 13C NMR
P
(CDCl3, 75 MHz): δ 27.5 (CH3), 34.2 (CH2, d, J1 = 54.0 Hz), 84.6 (C), 117.6 (Car, d, J1 = 88.0 Hz),
P
P
130.2 (CHar, d, J3 = 13.1 Hz); 134.5 (CHar, d, J2 = 10.0 Hz), 135.0 (CHar, d, J4 = 2.2 Hz), 163.1
P
P
P
(C=O). 31P NMR (CDCl3, 80.96 MHz): δ 22.04 . IR (neat): ν (cm-1) 746 (C-P), 1136 (C-O), 1721
(C=O), 2677 (C Har). Anal. Calcd for C24H26BrO2P: C, 63.03; H, 5.73. Found: C, 63.1; H, 5.81.
(Benzyloxycarbonylmethyl)triphenylphosphonium bromide (Colorless solid, Yield = 96%). mp
160 °C. 1H NMR (CDCl3, 300 MHz): δ 5.03 (2H, s), 5.70 (2H, d, J2 = 13.9 Hz) 7.12 (2H, dd, J3 = 7.9, J4
P
13
= 1.7 Hz), 7.23-7.30 (3H, m) 7.57-7.63 (6H, m), 7.72-7.87 (9H, m). C NMR (CDCl3, 75 MHz): δ 45.0
(CH2, d, J1 = 57.0 Hz); 72.0 (CH2), 120.0 (Car, d, J1 = 89.2 Hz), 127.3 (CHar), 127.4 (CHar), 128.0
P
P
(CHar, d, J3 = 13.2 Hz), 128.7 (CH ar), 131.5 (CHar, d, J2 = 10.9 Hz), 133.4 (CHar, d, J4 = 2.3 Hz),
P
P
P
31
140.9 (Car), 171.0 (C=O). P NMR (CDCl3, 80.96 MHz) δ 21.84. IR (neat): ν (cm-1) 748 (C-P), 1109
(C-O), 1161(C-C),1486 (C=C), 1721 (C=O). Anal. Calcd for C27H24BrO2P: C, 66.00; H, 4.92. Found: C,

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763
66.12; H, 5.01.
(Alkoxycarbonylmethylene)triphenylphosphane (1) : general procedure7
The salt of phosphonium bromide was dissolved in 2 L of water at rt. The aqueous solution was extracted
with 250 mL of Et2O, cooled in an ice bath and five drops of 2% ethanolic phenolphthalein solution were
added. 2M aqueous sodium hydroxide was added slowly until the pink endpoint was reached. The solid
phosphorane was filtered, washed with cold water and dried. The phosphorane was used for the
preparation of the corresponding diester 4 without further purification.
(Methoxycarbonylmethylene)triphenylphosphane (1a)19 (Colorless solid, Yield = 93%) mp 169 °C.
(tert-Butoxycarbonylmethylene)triphenylphosphane (1b)20 (Colorless solid, Yield = 95 %) mp 158 °C.
(Benzyloxycarbonylmethylene)triphenylphosphane (1c)20 (Colorless solid, Yield = 97%) mp 120 °C.
Succinic aldehyde (3)8
A solution of 1,5-cyclooctadiene (8.82 g, 81.5 mmol) in CH2Cl2 (370 mL) and EtOH (37 mL) was
ozonolized at -78 °C until the solution turned light blue. Triphenylphosphine (64.06 g, 244.5 mmol, ) was
added and the reaction mixture was allowed to warm to rt and stirred for 15 h. After evaporation of the
solvent, the crude product was distilled under reduced pression (bp: 63.5 °C ± 1 °C at 12 mm Hg) to yield
succinic aldehyde (13.10 g, 159.8 mmol, Yield: 98%), as a colorless liquid.23
Octa-2,6-dienedioic acid dialkyl esters (4): general procedure9
To a solution of appropriate ylide (1) (97.5 mmol, 2.5 eq.) in anhydrous CH2Cl2 (250 mL) under argon
atmosphere, was slowly added the freshly distilled succinic aldehyde (3) (3.20 g, 39 mmol, 1 eq.) and the
mixture was stirred at rt overnight. The solvent was removed under vacuum. 100 mL of Et2O was added
and the suspension was cooled to 0 °C in an ice-water bath in order to eliminate a large amount of
triphenylphosphine oxide. The resulting mixture was filtered and the solid was washed twice with cool
Et2O (2 x 50 mL). The solvent was evaporated and the residue was purified by silica gel flash
chromatography using as the eluent a mixture of cyclohexane/EtOAc in a 90:10 ratio.
(2E,6E)-Octa-2,6-dienedioic acid dimethyl ester (4a)21
Compound 4a (6.95 g, 90%) was obtained as a colorless liquid (bp 95°C / 0.15 mmHg).
(2E,6E)-Octa-2,6-dienedioic acid di-tert-butyl ester (4b)4d
Similar reaction gave 5b (9.91 g, 90%) as a colorless solid (mp 67-68°C).

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HETEROCYCLES, Vol. 73, 2007
(2E,6E)-Octa-2,6-dienedioic acid dibenzyl ester (4c)
Compound 4c (10.93 g, 80%) was obtained as a colorless syrup. 1H NMR (CDCl3, 300 MHz): δ 2.39-2.41
(4H, m), 5.20 (4H, s), 5.92 (2H, d, J = 15.4 Hz), 6.94-7.06 (2H, m), 7.31-7.43 (10H, m). 13CNMR (CDCl3,
300 MHz): δ 30.4 (CH2), 66.2 (CH2), 122.0 (CH), 128.2 (CHar), 128.4 (CHar), 128.6 (CHar), 136.0
(Car), 147.5 (CH), 166.6 (C=O). IR (neat): ν (cm-1) 1148 (C-C), 1263(C-O), 1654 (C=C), 1715 (C=O),
2942 (C-H). Anal. Calcd. for C22H22O4: C, 75.41; H, 6.33. Found: C, 75.26; H, 6.42.
General procedure for the synthesis of pyrrolidines (6a-f)
The cis-pyrrolidines were prepared from the corresponding diester (4a-c) by the following general
methods. Refer to Tables 1,2,3 and 4 for isolated yield, method type and reaction conditions.
Method A: Activation by microwave irradiation
In a 10 mL microwave glass tube were placed diester compound 4 (1 mmol), enantiopure primary amine
5 (1.5 mmol), alcohol (6 mmol), THF (1 mL) and a magnetic stir bar. The vessel was sealed with a
septum and placed into the microwave cavity. Enhanced microwave irradiation (250-300 W) was used,
the temperature being ramped from rt to 50-200 °C. Once the temperature was reached, the reaction
mixture was held for 5-10.5 h. Then, the mixture was allowed to cool to rt, the reaction vessel was opened
and the solvent was evaporated under reduced pressure. The oily residue was purified by flash
chromatography on silica gel eluting with using as the eluent a mixture of cyclohexane/EtOAc in a 95:5
to 70:30 ratio to afford the desired pyrrolidine 6.
Method B: Activation by high-pressure
A solution of diester compound 4 (1 mmol) and enantiopure primary amine 5 (1.2-1.5 mmol) in a mixture
alcohol (6 mmol) in THF was introduced by means of a syringe through the capillary inlet of a 1 mL
Pyrex glass cell. The cell was placed into the high-pressure apparatus and pressurized under 0.9 GPa at
20 °C for 7 h or 5 days. After depressurization, the solvent was evaporated and the oily residue was
purified by silica gel flash chromatography using as the eluent a mixture of cyclohexane/EtOAc in a 95:5
to 70:30 ratio to yield pure pyrrolidine 6.
Method C: Activation by thermal conditions
To a solution of diester compound 4 (1 mmol) in alcohol (MeOH, iPrOH or tBuOH) or in 5 mL of a
mixture of alcohol (MeOH, iPrOH or tBuOH) (6 mmol)/THF or 5 mL of a mixture of water (6
mmol)/alcohol (MeOH, iPrOH or tBuOH) was added enantiopure primary amine 5 (1.2-1.5 mmol). The
1
mixture was stirred at 30, 40, or 80 °C until completion of the reaction, as monitored by H NMR. The

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765
solvent was vacuum evaporated and the residue was purified by silica gel flash chromatography using as
the eluent a mixture of cyclohexane/EtOAc in a 95:5 to 70:30 leading to the pyrrolidine 6.
Method D: Activation by Natural Phosphate
To a round bottom flask containing an mixture of diester compound 4 (1 mmol) and enantiopure primary
amine 5 (1.2-1.5 mmol) in alcohol (MeOH, iPrOH or tBuOH) (1 mL) or MeOH (6 mmol) in iPrOH (1
mL) or 90% aqueous iPrOH (1 mL), NP or Na/NP or KF/NP catalyst (0.1 g) was added and the mixture
was stirred at 40°C until completion of the reaction, as monitored by 1H NMR. The reaction mixture was
filtered and the catalyst washed with the reactional solvent. After concentration of the filltrate under
reduced pressure the residue was subjected to chromatographic purification on silica using as the eluent a
mixture of cyclohexane/ EtOAc in a 95:5 to 70:30 leading to the pyrrolidine 6.
[5-Methoxycarbonylmethyl-1-(1’(R)’-phenylethyl)pyrrolidin-2-yl]acetic acid methyl ester (6a)4 [α]D
-18° (c 1.00, CH2Cl2).
[5-Methoxycarbonylmethyl-1-(2’hydroxy-1’(R)’-phenylethyl)pyrrolidin-2-yl]acetic acid methyl
ester (6b) [α]D -51° (c 1.00, CH3OH). 1H NMR (C6D6, 400 MHz): δ 1.07 (1H, m), 1.23 (1H, m), 1.33 (1H,
m), 1.48 (1H, m), 2.14 (1H, dd, J = 8.8, 15.6 Hz), 2.24 (1H, dd, J = 8.7, 15.5 Hz), 2.39 (1H, dd, J = 5.2,
10.0 Hz), 2.41 (1H, dd, J = 4.6, 11.0 Hz), 3.13 (1H, s), 3.36 (3H, s), 3.40 (3H, s), 3.42 (1H, dd, J = 8.6,
4.5 Hz), 3.57 (1H, m), 3.67 (1H, dd, J = 4.5, 11.0 Hz), 3.83 (1H, dd, J = 4.5, 11.0 Hz), 3.95 (1H, t, J = 11
13
Hz), 7.24 (5H, m). C NMR (C6D6, 100 MHz): δ 28.4 (CH2), 29.4 (CH2), 39.3 (CH2), 41.3 (CH2), 49.5
(CH3), 53.8 (CH), 59.2 (CH), 61.0 (CH2), 64.7 (CH), 136.8 (Car), 128.5 (CHar), 128.8 (CHar), 128.0
(CHar), 172.5 (C=O). IR (neat): ν (cm-1) 3449 (OH), 1729 (C=O), 1253 (C-O), 1170 (C-C), 1080 (C-N).
GC-MS (EI) m/z (%): 304 (100), 262 (12), 244 (8), 230 (11), 91 (9).
[5-tert-Butyloxycarbonylmethyl-1-(1’(R)’-phenylethyl)pyrrolidin-2-yl]acetic acid tert-butyl ester
1
(6c) [α]D -21° (c 1.00, CCl4). H NMR (CDCl3, 400 MHz): δ 1.40 (9H, s), 1.42 (3H, d, J = 6.8 Hz), 1.43
(9H, s) 1.54-1.59 (2H, m), 1.67-1.84 (2H, m), 1.95-2.05 (2H, dd, J = 8.5, 15.0 Hz), 2.20 (1H, dd, J = 8.7,
15.0 Hz), 2.42 (1H, dd, J = 4.8, 15.0 Hz), 3.30-3.37 (1H, m), 3.39-3.46 (1H, m), 3.98 (1H, q, J = 6.8 Hz),
7.21 (1H, t), 7.29 (2H, t), 7.36 (2H, d). 13C NMR (CDCl3, 100 MHz): δ 15.9 (CH3), 28.1 (CH3), 30.0
(CH2), 30.4 (CH2), 43.6 (CH2), 44.1 (CH2), 56.9 (CH), 58.0 (CH), 58.4 (CH), 79.9 (C), 80.0 (C), 126.7
(CHar), 127.9 (CHar), 128.0 (CHar), 143.6 (Car), 171.9 (C=O). IR (neat): ν (cm-1) 2974 (C-H), 1723
(C=O), 1148 (C-C), 1083 (C-N). Anal. Calcd for C24H37NO4: C, 71.46; H, 9.18; N, 3.47. Found: C, 69.16;
H, 9.07; N, 3.36.

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HETEROCYCLES, Vol. 73, 2007
[5-tert-Butyloxycarbonylmethyl-1-(2’hydroxy-1’(R)’-phenylethyl)pyrrolidin-2-yl]acetic acid tert-
1
butyl ester (6d) [α]D -60° (c 2.14, CCl4). H NMR (CDCl3, 400 MHz): δ 1.21 (1H, m), 1.37 (1H, m),
1.40 (1H, m), 1. 42 (9H, s), 1.46 (9H, s), 1.71 (1H, m), 2.14 (1H, dd, J = 8.8, 15.6 Hz), 2.27 (1H, dd, J =
8.7, 15.5 Hz), 2.36 (1H, dd, J = 5.2, 10.0 Hz), 2.50 (1H, dd, J = 4.6, 11.0 Hz), 3.29 (1H, br), 3.42 (1H, dd,
J = 4.5, 8.6 Hz), 3. 44 (1H, m), 3.62 (1H, dd, J = 4.5, 11.0 Hz), 3.88 (1H, dd, J = 4.5, 11.0 Hz), 3.89 (1H,
13
dd, J = 10.0, 12.0 Hz), 7.14-7.35 (5H, m). C NMR (CDCl3, 100 MHz): δ 28.2 (CH3), 29.8 (CH2), 30.3
(CH2), 42.1 (CH2), 44.5 (CH2), 54.5 (CH), 60,4 (CH), 62.0 (CH2), 65.1 (CH), 80.5 (C), 80.7 (C), 127.9
(CHar), 128.4 (CHar), 128.8 (CHar), 136.8 (Car), 171.4 (C=O), 171.5 (C=O). IR (neat): ν (cm-1) 3438
(OH), 2976 (C-H), 1721 (C=O), 1254 (C-O), 1149 (C-C), 1080 (C-N). GC-MS (EI) m/z (%): 388 (43.6),
304 (26.7), 276 (100.0), 230 (13.9), 91 (9.1).
[5-Benzyloxycarbonylmethyl-1-(1’-(S)-phenylethyl)pyrrolidin-2-yl]acetic acid benzyl ester (6e)
[α]D +23° (c 1.00, CH2Cl2). 1H NMR (CDCl3, 300 MHz): δ 1.39 (3H, d, J = 6.8 Hz), 1.50-1.62 (2H, m),
1.69-1.87 (2H, m), 2.14 (2H, d, J = 6.8 Hz), 2.36 (1H, dd, J = 14.9, 8.7 Hz), 2.54 (1H, dd, J = 14.9, 4.7
Hz), 3.38-3.54 (2H, m), 3.96 (1H, q, J = 6.8 Hz), 5.03 (2H, s), 5.09 (2H, s), 7.17-7.37 (m, 15H); 13C NMR
(CDCl3, 75 MHz): δ 15.67 (CH3), 30.04 (CH2), 30.46 (CH2), 42.02 (CH2), 42.43 (CH2), 56.48 (CH),
58.13 (CH), 58.34 (CH), 65.70 (CH2), 65.86 (CH2), 126.72 (CHar), 127.94 (CHar), 127.95 (CHar),
127.96 (CHar), 128.01 (CHar), 128.05 (CHar), 128.34 (CHar), 128.38 (CHar), 135.88 (Car) ,136.94 (Car),
143.24 (Car), 171.86 (C=O), 171.93 (C=O). IR (neat): ν (cm-1) 2967 (C-H), 1728 (C=O), 1164 (C-C),
1082 (C-N). Anal. Calcd for C30H33NO4: C, 76.41; H, 7.05; N, 2.97. Found: C, 76.18; H, 6.37; N, 2.92.
[5-Benzyloxycarbonylmethyl-1-(2’-hydroxy-1’(R)-phenylethyl)pyrrolidin-2-yl]acetic acid benzyl
1
ester (6f) [α]D -55° (c 1.00, CH2Cl2). H NMR (CDCl3, 300 MHz): δ 1.38-1.52 (2H, m), 1.54-1.72 (2H,
m), 2.29 (1H, dd, J = 14.5, 8.5 Hz), 2.45-2.52 (2H, m), 2.67 (1H, dd, J = 14.5, 4.9 Hz), 3.18 (1H, br),
3.50-3.61 (2H, m), 3.64-3.71 (1H, m), 3.87-3.96 (2H, m), 5.11 (2H, s), 5.15 (2H, s), 7.19-7.41 (15H, m).
13C NMR (CDCl3, 300 MHz): δ 29.8 (CH2), 30.5 (CH2), 40.8 (CH2), 42.9 (CH2), 54.6 (CH), 60.4 (CH),
62.1 (CH2), 65.5 (CH), 66.3 (CH2), 66.4 (CH2), 127.9 (CHar), 128.3 (CHar), 128.3 (CHar), 128.3 (CHar),
128.5 (CHar), 128.5 (CHar), 128.6 (CHar), 128.6 (CHar), 128.7 (CHar), 135.8 (Car), 135.8 (Car), 136.7
(Car), 171.8 (C=O). IR (neat): ν (cm-1) 3448 (OH), 2955 (C-H), 1726 (C=O), 1270 (C-O), 1165 (C-C),
1080 (C-N). GC-MS (EI) m/z (%): 379 (9), 320 (36), 230 (100), 91 (62).
ACKNOWLEDGEMENTS
This work was financially supported in part by a post-doctoral grant for L. Cabral dos Santos from the

HETEROCYCLES, Vol. 73, 2007
767
University Paris-Sud (11). We are grateful to Professor M. Zahouily, for generously providing us doped
natural phosphates. The French Ministry of Superior Education and Research and the CNRS (Centre
National de la Recherche Scientifique) are gratefully acknowledged for the financial support of this work.
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(C=O), 2839, 2734 (CH).