Exploiting the regioselectivity of pyroglutamate alkylations for the synthesis of 6-azabicyclo[3.2.1]octanes and 4-azabicyclo[3.3.0]octanes

Article abstract of DOI:10.1016/j.tet.2007.03.084

Depending on the N-protecting group of pyroglutamates, the reactivity can be directed to the formation of 6-azabicyclo[3.2.1]octanes or 4-azabicyclo[3.3.0]octanes, which are conformationally restricted glutamate analogues.

Full text of DOI:10.1016/j.tet.2007.03.084

Tetrahedron 63 (2007) 4712–4724
Exploiting the regioselectivity of pyroglutamate alkylations
for the synthesis of 6-azabicyclo[3.2.1]octanes and
4-azabicyclo[3.3.0]octanes
y
*
Kurt G. R. Masschelein, Christian V. Stevens, Nicolai Dieltiens and Diederica D. Claeys
Research Group SynBioC, Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University,
Coupure Links 653, B-9000 Ghent, Belgium
Received 25 January 2007; revised 14 March 2007; accepted 15 March 2007
Available online 18 March 2007
Abstract—Depending on the N-protecting group of pyroglutamates, the reactivity can be directed to the formation of 6-azabicyclo[3.2.1]-
octanes or 4-azabicyclo[3.3.0]octanes, which are conformationally restricted glutamate analogues.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
reviewed, such as radical and ionic cyclisations.6 Other
procedures such as Claisen-like intramolecular acylation
involving a-pyrrolidinyl sulfones,7 ring-closing metathesis
of disubstituted ethenyl pyrrolidines,8 or intramolecular tita-
nium-mediated coupling reactions of a-substituted succin-
imides9 have been described. Other processes include the
cis allylation of a chiral lactam skeleton derived from
D-malic acid,10 cyclisations of N-propargylaminyl radicals11
and cycloaddition processes including tandem inter[4+2]/
inter[3+2]-additions,12 hetero Diels–Alder reactions,13
[2+2]-cycloadditions14 and 1,3-dipolar cycloadditions.15
Recently, some other processes for the synthesis of the pyr-
rolizidine skeleton were described in the literature.16
Azabicyclic systems have been extensively used in recent
years as key structural components of various pharmaceuti-
cal agents. Consequently, flexible methods for the construc-
tion of different azabicycles are of considerable interest.
Among the wide variety of alkaloids, both the 6-azabicy-
clo[3.2.1]octanes 1 and 4-azabicyclo[3.3.0]octanes 2 have
received a lot of attention synthetically (Fig. 1).
Prominent among the early synthetic methods for the prep-
aration of 6-azabicyclo[3.2.1]octane derivatives 1 are the
€
Hofmann–Loffler–Freytag reaction of monocyclic N-chloro
amines1 and the reductive cyclisation of aminobenzoic acids
or benzamides.2 More recently, several highly efficient strat-
egies based on rearrangements,3 cycloadditions4 and multi-
component couplings have been reported.5
During our research on azabicyclic compounds, pyrogluta-
mates were selected for the construction of conformationally
restricted molecules. Over the years, pyroglutamates have
received a lot of attention because of their importance in sev-
eral domains and as a versatile starting material for the syn-
thesis of both natural and unnatural products.17 Intensive
study on glutamate analogues resulted in specific inhibitors
of different receptor types of the mammalian central nervous
system.18 It has also been used for the synthesis of pyrrol-
idine alkaloids,19 kainoids,20 (ꢀ)-bulgecinine, 21 (ꢀ)-domoic
acid,22 enantiomerically pure glycine and proline deriva-
tives,23 a wide variety of non-proteinogenic amino acids,24
etc. The attractiveness of pyroglutamate as a building block
is connected to the fact that the site of alkylation can be
directed by changing the protecting group on nitrogen.
Alkylation of N-Boc protected pyroglutamates results in
C-4 functionalised derivatives, whereas alkylation of N-
benzyl or N-unprotected pyroglutamates occurs at the
2-position.25
The formation of the pyrrolizidine framework 2 generally
takes place by cyclisation of a conveniently substituted
pyrrolidine moiety. Several types of processes have been
HN
N
1
2
Figure 1.
* Corresponding author. Tel.: +32 (0)9 2645957; fax: +32 (0)9 2646243;
e-mail: chris.stevens@ugent.be
Diederica D. Claeys is aspirant of the FWO-Vlaanderen.
y
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.084

K. G. R. Masschelein et al. / Tetrahedron 63 (2007) 4712–4724
4713
2. Results
reaction was stirred overnight, about 25% of the compound
had already cyclised.
2.1. Synthesis of the 6-azabicyclo[3.2.1]octane skeleton
by ring closure from C-4 to C-2
In order to activate the C-4 position, compounds 5 were pro-
tected with a Boc group under standard conditions using
Boc-anhydride and DMAP as a catalyst in acetonitrile at
0 ꢁC. Unfortunately, treating derivatives 6 with 1.1 equiv
of LiHMDS at ꢀ78 ꢁC did not result in the desired cyclisa-
tion to 7. Only unreacted starting material could be recov-
ered. This lack of reactivity could result from the ability of
the Li cation to form a six-membered ring counter-ion com-
plex 8 (Li complex) giving additional stability to the C-4 an-
ion, effectively preventing it from reacting further (Scheme
2).28 If this extra stabilisation indeed prevents the formation
of bicyclic compound 7, changing to KHMDS as a base
should circumvent this problem since the bigger potassium
cation does not fit as well in the six-membered ring confor-
mation as the Li cation. Indeed we observed that treating 6
with 1.1 equiv of KHMDS at ꢀ78 ꢁC for 2 h resulted in
complete conversion to the desired compounds 7.
Recently we observed that N-Boc protected pyroglutamates,
substituted at the C-4 position with no or poor electrophilic
moieties, undergo a Boc migration.26 This reaction pre-
vented the synthesis of bicyclic skeletons by alkylation at
C-4 followed by ring closure to C-2. Since the Boc migration
is competitive with ring closure from C-4 to C-2, a better
electrophilic moiety, 3-chloro-2-chloromethyl-1-propene,
was introduced at C-4. In this case only ring closure was ob-
served leading to compound 4 in good yield and comprising
a new skeleton (Scheme 1).
COOBn
Cl
COOBn
tBuOOC
1.5 eq. LiHMDS
-78 °C
Boc
N
O
N
Boc
3
COOtBu
4; 81%
to RT on.
O
Further functionalisation of compound 7b was performed by
treating it with ozone in CH2Cl2/MeOH (95/5) at ꢀ78 ꢁC
and subsequent work-up with Me2S leading to compound
9 in 60% yield after purification, a new type of constrained
glutamic acid analogue (Scheme 3).
Scheme 1.
2.2. Synthesis of the 6-azabicyclo[3.2.1]octane skeleton
by ring closure from C-2 to C-4
The competing Boc migration prompted us to change the site
of ring closure. If an unprotected pyroglutamate is properly
functionalised at the C-2 position, subsequent protection
with a Boc group (activation of C-4) and treatment with
base could also lead to the 6-azabicyclo[3.2.1]octane
skeleton.
COOEt
COOEt
Boc
O
Boc
O
1) O3 / -78° C
N
N
CH2Cl2/MeOH 95/5
2) Me2S
O
7b
9; 60%
Scheme 3.
As we have recently shown, treating a mixture of a pyroglu-
tamate and an electrophile with 2.1 equiv of LiHMDS at
ꢀ40 ꢁC in THF results in C-2 functionalisation without
any reaction on the N-atom.27 Again, we chose 3-chloro-2-
chloromethyl-1-propene as electrophile since the allylic po-
sitions increase its electrophilic properties and would thus
facilitate both alkylation and ring closure. In order to prevent
reaction at the N-atom and accompanying cyclisation to
a pyrrolizidinone structure, it is crucial to limit the reaction
time to 1 h at ꢀ40 ꢁC and 2 h at room temperature. If the
2.3. A one-pot synthesis of the 6-azabicyclo[3.2.1]octane
skeleton
Because the abovementioned synthetic strategies involve
several steps to get to the 6-azabicyclo[3.2.1]octane skele-
ton, a one-pot strategy for its synthesis was studied. There-
fore, N-benzyl protected pyroglutamates 10 were treated
with 2.1 equiv of LiHMDS and 1.1 equiv of 3-chloro-2-
chloromethyl-1-propene. The first equivalent of LiHMDS
COOR1
COOR1
COOR1
Boc
O
1.1 eq. KHMDS
-78 °C / 2h
N
O
O
0.1 eq. DMAP
N
H
N
Boc
1.3 eq. (Boc)2O
Cl
Cl
6a R = Bn; 80%
6b R = Et; 90%
5a R = Bn
5b R = Et
7a R = Bn; 44%
7b R = Et; 75%
1.1 eq. LiHMDS
-78 °C
COOR1
O
Li
N
O
O
Cl
8
Scheme 2.

4714
K. G. R. Masschelein et al. / Tetrahedron 63 (2007) 4712–4724
deprotonates the C-2 position, which reacts with the electro-
phile. The second equivalent of LiHMDS then deprotonates
at C-4 leading to ring closure. After purification, the 6-aza-
bicyclo[3.2.1]octane 11 was indeed isolated, although in
rather poor yields (Scheme 4).
Using the pyroglutamides 15 in the same one-pot strategy as
mentioned above for the corresponding pyroglutamates,
a different regioselectivity was observed. Instead of the for-
mation of the 6-azabicyclo[3.2.1]octane skeleton, double
alkylation at C-4 was observed (Scheme 7).
Cl
Cl
Cl
1.1 eq. electrophile
2.1 eq. LiHMDS
COOR1
Cl
O
COOR1
O
N
Bn
R
R
N
Bn
1.1 eq. electrophile
2.1 eq. LiHMDS
-40 °C
-40 °C
N
N
O
O
N
Bn
1 = M
N
Bn
10a
e
n
O
O
1 = B
10b
Bn
O
15a
16; 52% (electrophile
as limiting reagent)
Cl
COOR1
N
work-up
Scheme 7.
COOR1
O
N
Bn
Apparently, the most acidic (and the least sterically hin-
dered) protons of N-benzyl pyroglutamides are located at
the 4-position. With this in mind, treatment of 15b with
3 equiv of base and 2 equiv of electrophile could lead to
the 1-substituted 6-azabicyclo[3.2.1]octane skeleton 18
(Scheme 8). This reaction was indeed successful; although
a conversion of 56% was observed, only a 25% yield was
obtained after chromatography.
11a R1 = Me; 22%
11b R1 = Bn; 29%
Scheme 4.
In the same way, the 7-azabicyclo[4.2.1]nonane skeleton
could be synthesised with 2,3-bis(iodomethyl)-1,3-butadi-
ene 1229 as electrophile (Scheme 5). Although the yields
of this one-pot strategy were quite poor, a seven-membered
ring, which is normally not easily formed, could be obtained.
The substitution pattern at the 1-position of the 6-azabi-
cyclo[3.2.1]octane skeleton could be varied by a preceding
alkylation at the 4-position of the N-benzyl pyroglutamides
with subsequent ring closure. To mention one example,
15a was substituted at the 4-position with a benzyl group
after alkylation with benzylbromide. When treating the
purified product 19 with 3-chloro-2-chloromethyl-1-propene
as electrophile and LiHMDS as base, compound 21 was iso-
lated, besides 19 and 20 (Scheme 9). Apparently, the alkyl-
ation and ring closure appears to be slow. The disappointing
yield after purification discouraged further efforts in this
direction.
I
1.1 eq.
I
O
O
COOMe
N
N
12
COOMe
Bn
Bn
2.1 eq. LiHMDS
-40 °C
10a
13; 10%
Scheme 5.
Till now, the 7-azabicyclo[4.2.1]nonane skeleton was
mainly used in the synthesis of some Gelsemium alkaloids,
such as gelsemine, gelsedine and gelsemicine. Several syn-
thetic strategies have been published to construct these phar-
maceutically interesting products.30
2.5. Synthesis of the 4-azabicyclo[3.3.0]octane skeleton
by ring closure from C-2 to N
The synthesis of the 4-azabicyclo[3.3.0]octane skeletons
22a and 22b was performed by treating 5a and 5b (no Boc
protection) with 1.5 equiv of NaH in refluxing THF for
16 h and subsequent bulb-to-bulb distillation (Scheme 10).
2.4. Pyroglutamides: another regioselectivity
Although the one-pot strategy for the 6-azabicyclo[3.2.1]-
octane and 7-azabicyclo[4.2.1]nonane skeleton was success-
ful, the yields after purification were rather low. During
earlier research at our laboratory, we observed that forma-
tion of an anion at C-2 resulted in fragmentation of the pyro-
glutamate.26 This was confirmed by the detection of benzyl
alcohol when using benzyl pyroglutamate as starting mate-
rial. Therefore, the corresponding pyroglutamides 15 were
synthesised since it was expected that these compounds
would fragment less easily (Scheme 6).
The pyrrolizidinone 22b was easily converted to the amino
alcohol 23, a member of an interesting class of com-
pounds,31 in 70% yield by treatment with LiAlH4 in re-
fluxing THF and subsequent bulb-to-bulb distillation.
Compound 22b was also converted to pyrrolizidinedione
24 by ozonisation followed by work-up with Me2S
(Scheme 11).
Besides pyrrolizidinones, we were also able to construct an
indolizidine skeleton applying the same methodology. Treat-
ing a mixture of pyroglutamate 25 and cis-1,4-dichloro-
2-butene with 2.1 equiv of LiHMDS in THF at ꢀ40 ꢁC
resulted in a mixture, which consists of compounds 26 and
27 in a 1/3 ratio (Scheme 12). Treatment of this mixture
with 1 equiv of NaH in refluxing THF resulted in complete
cyclisation of 26. Indolizidine 27 was obtained in 24% yield
1. NaOH
2. SOCl2
3. R2NH, NEt3
NR2
COOEt
O
O
N
Bn
N
Bn
14
O
15a R = isopropyl; 74%
15b R = allyl; 76%
Scheme 6.

K. G. R. Masschelein et al. / Tetrahedron 63 (2007) 4712–4724
4715
Cl
Cl
O
Cl
2 eq. electrophile
3 eq. LiHMDS
N
O
N
N
Bn
N
O
O
N
Bn
N
Bn
-40 °C
O
O
15b
17
18; 25% (56%
conversion)
Scheme 8.
COOEt
2.1 eq. LiHMDS
-40 °C / THF
COOEt
N
O
COOEt
O
O
N
N
+
N
H
N
Bn
15a
Cl
Cl
Cl
H
26
O
4eq.
O
27
25
1:3
1.05 eq. benzylbromide -78 °C
1.1 eq. LiHMDS
NaH
Δ/THF
Bn
COOEt
N
N
O
N
Bn
O
O
19; 37% (*)
27; 24%
33% (**)
Scheme 12.
1.1 eq. electrophile -40 °C
2.1 eq. LiHMDS
2.6. Evaluation of chiral induction during alkylation
Cl
R = isopropyl
Having this new entry to interesting azabicyclic molecules in
hand, the possibility of chiral induction during alkylation
was evaluated. Moeller and Rutledge have described an elec-
trochemical method for the enantioselective alkylation of the
(+)-menthyl ester of pyroglutamic acid.32 The ester of (S)-
pyroglutamic acid and (ꢀ)-menthol or (+)-fenchol was pre-
pared using DCC as a coupling agent and DMAP as a catalyst
(Scheme 13).
Bn
O
Bn
O
Bn
+
NR2
+
NR2
N
O
O
N
Bn
N
Bn
Bn
NR2
O
O
19; 33% (*)
21; 17% (*)
20; 50% (*)
7% (**)
Scheme 9. (*) Observed in 1H NMR of crude mixture; (**) after purifica-
tion.
Unfortunately, treatment of 29a with 2.1 equiv of LiHMDS
at ꢀ40 ꢁC resulted in complete fragmentation of the ester.
Only menthol could be identified in the organic fraction.
Treatment of a mixture of 29b and 3-chloro-2-chloro-
methyl-1-propene with 2.1 equiv of LiHMDS resulted in
a mixture of 30 and 31 in a 3/2 ratio. This mixture was quan-
titatively converted to pyrrolizidinone 31 upon treatment
with NaH in refluxing THF. To our disappointment, 31
was obtained as a mixture of both diastereoisomers with
a diastereomeric excess of only 12% (after chromatography
and crystallisation). In the crude reaction mixture no dia-
stereomeric excess was observed, showing that the chiral
fenchol group has no effect on the diastereoselectivity of
the alkylation (Scheme 14).
COOR1
COOR1
O
1.5 eq. NaH
N
H
N
Δ THF
16h
O
Cl
5a R1 = Bn
5b R1 = Et
22a R1 = Bn; 68%
22b R1 = Et; 75%
Scheme 10.
OH
N
COOEt
COOEt
N
2 eq. LiAlH4
Δ THF / 3h
1) O3 / -78 °C
CH2Cl2/MeOH 95/5
O
N
In conclusion, we have shown that both the 6-azabicy-
clo[3.2.1]octane and 4-azabicyclo[3.3.0]octane skeletons
are accessible from the same precursor depending on the
protecting group on the N-atom. Although this approach is
straightforward and interesting, the difficulty in purification
of the products, reducing the yields considerably, stays prob-
lematic. The advantage, however, is the limited number of
steps needed to construct these interesting skeletons starting
from a readily available precursor.
2) Me2S
O
O
23; 70%
24; 58%
22b
Scheme 11.
after purification by column chromatography. The low yield
of this procedure can be explained by a severe loss of mate-
rial during purification.

4716
K. G. R. Masschelein et al. / Tetrahedron 63 (2007) 4712–4724
1 eq. DCC
OH
OR*
0.8 eq. R*OH
O
O
N
H
N
H
HO
0.25 eq. DMAP
O
O
OH
28
29a R* = menthyl; 93%
29b R* = fenchyl; 54%
(+)-fenchol (-)-menthol
Scheme 13.
COOR*
COOR*
OR* 4 eq. electrophile
2.1 eq. LiHMDS
O
O
+
N
H
N
H
N
O
-40 °C / THF
O
Cl
29b R* = fenchyl
30 R* = fenchyl
3:2
31 R* = fenchyl
NaH
Δ THF
COOR*
N
O
31 R* = fenchyl
84% (de = 12%)
Scheme 14.
3. Experimental
3.2. Typical experimental procedure for the alkylation of
pyroglutamates at the C-4 position with di-tert-butyldi-
carbonate and an alkyl halide
3.1. General
High-resolution H NMR (270 MHz or 300 MHz) and 13C
NMR (68 MHz or 75 MHz) spectra were run with a Jeol
JNM-EX 270 NMR spectrometer or on a Jeol JNM-EX
300 NMR spectrometer. Peak assignments were obtained
with the aid of DEPT, 2D-HETCOR, 2D-HSQC and 2D-
COSY spectra. The compounds were diluted in deuterated
solvents and the used solvent is indicated for each com-
pound. Mass spectra were recorded on a Varian MAT 112
spectrometer (70 eV), using either GC–MS coupling or a di-
rect inlet system. Some volatile samples were recorded on
an HP 6890 GC coupled with a HP 5973 MSD (Mass selec-
tive detector; quadrupole). Mass spectra of molecules with
a high molecular weight were recorded on an Agilent
1100 Series VS (ES, 4000 V) mass spectrometer. The ele-
mental analysis was performed with a Perkin–Elmer 2400
Elemental Analyser. High-resolution mass spectra were re-
corded on a Finnigan MAT 95 XP-API-GC-Trap tandem
Mass spectrometer system (ES, 5000 V). IR-spectra were
obtained from a Perkin–Elmer Spectrum One infrared spec-
trometer. For liquid samples the spectra were collected by
preparing a thin film of compound between two sodium
chloride plates. The crystalline compounds were mixed
with potassium bromide and pressed until a transparent
potassium bromide plate was obtained. Melting points of
A Boc-protected pyroglutamate ester (7.8 mmol)is dissolved
in THF (30 mL, freshly distilled from Na metal) and cooled
in an acetone bath to ꢀ78 ꢁC. At this temperature and under
a nitrogen atmosphere, 15.6 mL (15.6 mmol, 2 equiv) of
a 1 M LiHMDS solution is added while stirring is continued
at this temperature. After 2 h, 11.7 mmol of di-tert-butyldi-
carbonate (1.5 equiv) is added (dissolved in 10 mL of THF)
and the reaction mixture is allowed to warm to room temper-
ature. The reaction is quenched with 5 mL of saturated
NH4Cl/NH4OH solution and 40 mL of water is added. The
mixture is extracted with diethyl ether and dried with
MgSO4. After filtration and evaporation of the solvent the
crude product is purified by means of chromatography.
1
The purified 4-substituted N-Boc pyroglutamate (2.3 mmol)
is dissolved in 10 mL of dry THF and kept under a positive
N2-pressure. KOtBu (2.5 mmol, 1.1 equiv) is added and
the mixture is stirred for 30 min when 4.6 mmol of electro-
phile (2 equiv) is added. The reaction mixture is subse-
quently refluxed overnight. After cooling, the solution is
poured in water and extracted with diethyl ether. The organic
layers are combined and dried with MgSO4. Filtering off the
drying agent and evaporating the solvent lead to a mixture,
which is purified by chromatography to remove the excess
of electrophile.
€
crystalline compounds were measured with a Buchi 540
apparatus and are uncorrected. The purification of reaction
mixtures was performed by chromatography using a glass
column with silica gel (Across, particle size: 0.035–
0.070 mm, pore diameter: ca. 6 nm).
3.2.1. Synthesis of 2-benzyl 1,4-di-tert-butyl-4-[2-(chloro-
methyl)-2-propenyl]-5-oxo-1,2,4-pyrrolidinetricarboxy-
late (3). The product was obtained as an oil (yield: 60%).

K. G. R. Masschelein et al. / Tetrahedron 63 (2007) 4712–4724
4717
1H NMR (270 MHz, CDCl3) d: Major: 1.41 (9H, s, t-Bu),
1.43 (9H, s, t-Bu), 2.32 (1H, dd, J¼13.6, 10.2 Hz, CHAHB
ring), 2.52 (1H, d, J¼15.5 Hz, CHAHBC]CH2), 2.93 (1H,
dd, J¼13.6, 2.0 Hz, CHAHB ring), 3.09 (1H, d, J¼15.5 Hz,
CHAHBC]CH2), 3.92 (2H, s, CH2Cl), 4.61 (1H, dd,
J¼10.2, 2.0 Hz, CH ring), 5.01 (1H, br s, C]CHAHB),
5.13 (1H, d, J¼12.2 Hz, CHAHBPh), 5.19 (1H, br s,
C]CHAHB), 5.24 (1H, d, J¼12.5 Hz, CHAHBPh), 7.36
(5H, s, Ph). Minor: 1.41 (9H, s, t-Bu), 1.44 (9H, s, t-Bu),
1.96 (1H, dd, J¼13.8, 6.9 Hz, CHAHB ring), 2.60 (1H,
d, J¼16.0 Hz, CHAHBC]CH2), 2.88 (1H, dd, J¼
13.8, 8.9 Hz, CHAHB ring), 3.01 (1H, d, J¼16 Hz,
CHAHBC]CH2), 3.99 (2H, s, CH2Cl), 4.64 (1H, dd,
J¼8.9, 6.9 Hz, CH ring), 4.86 (1H, br s, C]CHAHB), 5.20
(1H, d, J¼13.2 Hz, CHAHBPh), 5.24 (1H, d, J¼13.2 Hz,
CHAHBPh), 5.28 (1H, br s, C]CHAHB), 7.36 (5H, s, Ph).
13C NMR (68 MHz, CDCl3) d: Major 28.21 (t-Bu), 28.32
(t-Bu), 31.61 (CH2 ring), 39.43 (CH2), 48.88 (CH2Cl),
56.91 (CH, C-2), 57.22 (Cquat, C-4), 67.98 (CH2Ph), 83.88
(Cquat, t-Bu), 84.37 (Cquat, t-Bu), 119.35 (C]CH2), 129.04
(CH), 129.15 (CH), 135.72 (Cquat, Ph), 140.93 (C]CH2),
149.60 (C]O, Boc), 168.09 (C]O), 170.49 (C]O),
170.73 (C]O), 171.54 (C]O). Minor: 28.25 (t-Bu),
28.47 (t-Bu), 30.39 (CH2 ring), 37.38 (CH2), 48.99
(CH2Cl), 57.22 (CH), 57.45 (Cquat, C-4), 67.98 (CH2Ph),
83.99 (Cquat, t-Bu), 84.71 (Cquat, t-Bu), 119.01 (C]CH2),
129.18 (CH), 129.25 (CH), 135.47 (Cquat, Ph), 140.93
(C]CH2), 149.60 (C]O, Boc), 168.89 (C]O), 170.73
J¼12.2 Hz, CHAHBPh), 7.35 (5H, br s, Ph). 13C NMR
(68 MHz, CDCl3) d: 27.78 (t-Bu), 27.89 (t-Bu), 37.48
(CH2), 38.10 (CH2), 41.10 (CH2), 56.24 (Cquat, C-4), 64.71
(Cquat, C-2), 67.40 (CH2Ph), 82.68 (Cquat, t-Bu), 83.95
(Cquat, t-Bu), 117.30 (C]CH2), 128.28 (CH), 128.50
(CH), 128.61 (CH), 135.00 (Cquat, Ph), 138.36 (C]CH2),
148.80 (C]O, Boc), 167.54 (C]O), 169.86 (C]O),
170.10 (C]O), 177.59 (C]O). IR (cmꢀ1) nmax: 1795,
1728. MS m/z (%): (ES, Pos) no M+, 316 (M+ꢀCOOtBu,
100), 91 (15). Chromatography: Hex/EtOAc (90/10)
Rf ¼0.31. C26H33NO7: calcd C 66.22, H 7.05, N 2.97; found
C 66.17, H 6.87, N 3.11.
3.4. Typical experimental procedure for the alkylation of
pyroglutamates at the 2-position
A Boc-protected pyroglutamate ester (12 mmol) is dissolved
in THF (15 mL, freshly distilled from Na metal) and the
alkyl halide (48 mmol, 4 equiv) is added. The mixture is
cooled to ꢀ40 ꢁC under a N2 atmosphere. Over a period of
30–40 min, 25.2 mL of a LiHMDS solution (25.2 mmol,
1 M solution in hexanes, 2.1 equiv) is added at this temper-
ature. The reaction mixture is allowed to stir at room temper-
ature for an additional 2 h. The reaction is quenched by
addition of saturated aqueous NH4Cl until the pH is neutral.
The mixture is extracted with EtOAc, and the organic frac-
tions are dried (MgSO4) and filtered. The solvent is removed
under reduced pressure.
(C]O), 170.93 (C]O), 171.54 (C]O). IR (cmꢀ1) nmax
:
1795, 1725. MS m/z (%): (ES, Pos) no M+, 354 (30), 352
(85), 91 (100). Chromatography: Hex/EtOAc (64/36).
C26H34ClNO7: calcd C 61.47, H 6.75, N 2.76; found C
61.59, H 6.89, N 2.59.
3.4.1. Synthesis of benzyl 2-(2-chloromethyl-2-propenyl)-
5-oxopyrrolidine-2-carboxylate (5a). Recrystallised from
hexanes. White crystals (yield: 40%).
1H NMR (270 MHz, CDCl3) d: 2.17–2.24 (1H, m, CHAHB
ring, C-3), 2.37–2.50 (3H, m, CHAHB ring, C-3+CH2 ring,
C-4), 2.57 (1H, d, J¼14.5 Hz, CHAHBC]CH2), 2.96 (1H,
d, J¼14.5 Hz, CHAHBC]CH2), 3.96 (2H, s, CH2Cl), 5.02
(1H, s, C]CHAHB), 5.20 (1H, d, J¼12.0 Hz, CHAHBPh),
5.23 (1H, d, J¼12.0 Hz, CHAHBPh), 5.30 (1H, s,
C]CHAHB), 7.40 (5H, s, Ph). 13C NMR (68 MHz,
CDCl3) d: 29.61 (CH2 ring, C-3), 31.25 (CH2 ring, C-4),
41.71 (CH2C]CH2), 48.37 (CH2Cl), 65.14 (Cquat, C-2),
67.65 (COOCH2Ph), 120.09 (C]CH2), 128.52 (CH, Ph),
128.68 (CH, Ph), 134.89 (Cquat, Ph), 139.67 (C]CH2),
172.97 (C]O), 177.18 (C]O). IR (cmꢀ1) nmax: 1701
(C]O), 1735 (C]O). MS m/z (%): 308 (M+H+, 100),
257 (7), 91 (Bn+, 7). Chromatography: Hex/EtOAc (25/75)
Rf ¼0.45. Mp: 47.3–50.3 ꢁC. HRMS calcd for
C16H1835ClNO3 (M+H+) 308.1048, found 308.1036.
3.3. Synthesis of 5-benzyl 1,6-di-tert-butyl-3-methylene-
7-oxo-6-azabicyclo[3.2.1]octane-1,5,6-tricarboxylate (4)
2-Benzyl-1,4-di-tert-butyl-4-[2-(chloromethyl)-2-propenyl]-
5-oxo-1,2,4-pyrrolidinetricarboxylate 3 of 0.28 g (0.55
mmol) was dissolved in 4 mL of dry THF and kept under
a positive N2-pressure during the reaction. The mixture
was cooled to ꢀ78 ꢁC and 0.66 mL of a LiHMDS solution
(0.66 mmol, 1 M solution in hexanes, 1.2 equiv) was added
and the solution was slowly allowed to warm up to room
temperature overnight keeping the flask in the acetone
bath. After quenching the reaction with NH4Cl/NH4OH
solution, an extra amount of 10 mL of water was added
and the reaction mixture was extracted with diethyl ether
(3ꢂ40 mL). The organic phases were combined and dried
with MgSO4. Filtering off the MgSO4 and evaporating the
solvent gave the crude product as an oil and was further
purified by column chromatography. 5-Benzyl-1,6-di-tert-
butyl-3-methylene-7-oxo-6-azabicyclo[3.2.1]-octane-1,5,6-
tricarboxylate 4 of 0.21 g was obtained as an oil
(yield: 81%).
3.4.2. Synthesis of ethyl 2-(2-chloromethyl-2-propenyl)-
5-oxopyrrolidine-2-carboxylate (5b). White crystals
(yield: 62%).
1H NMR (270 MHz, CDCl3) d: 1.31 (3H, t, J¼7.1 Hz,
CH2CH3), 2.12–2.22 (1H, m, CHAHB ring, C-4), 2.37–
2.54 (3H, m, CHAHB ring, C-4+CH2 ring, C-3), 2.54 (1H,
d, J¼14.5 Hz, CHAHBC]CH2), 2.94 (1H, d, J¼14.5 Hz,
CHAHBC]CH2), 4.00 (2H, s, CH2Cl), 4.22 (2H, q,
J¼7.1 Hz, CH2CH3), 5.06 (1H, s, C]CHAHB), 5.33 (1H,
s, CHAHB), 6.41 (1H, br s, NH). 13C NMR (68 MHz,
CDCl3) d: 14.11 (CH2CH3), 29.69 (CH2 ring, C-3), 31.23
(CH2 ring, C-4), 41.74 (CH2C]CH2), 48.41 (CH2Cl),
1H NMR (270 MHz, CDCl3) d: 1.42 (9H, s, t-Bu), 1.48 (9H,
s, t-Bu), 1.96 (1H, d, J¼11.2 Hz, CHAHB), 2.45 (1H, d,
J¼13.9 Hz, CHCHD), 2.65 (1H, dd, J¼14.4, 1.0 Hz,
CHEHF), 2.79 (1H, d, J¼11.2 Hz, CHAHB), 2.87 (1H, d,
J¼13.9 Hz, CHCHD), 3.04 (1H, d, J¼14.4 Hz, CHEHF),
4.94 (1H, br s, C]CHAHB), 5.00 (1H, br s, C]CHAHB),
5.19 (1H, d, J¼12.2 Hz, CHAHBPh), 5.24 (1H, d,

4718
K. G. R. Masschelein et al. / Tetrahedron 63 (2007) 4712–4724
61.99 (CH2CH3), 65.07 (Cquat, C-2), 120.03 (C]CH2),
139.91 (C]CH2), 173.19 (C]O, ring), 177.21 (C]O,
COOEt). IR (cmꢀ1) nmax: 1707 (C]O), 1741 (C]O).
MS m/z (%): 246 (M+H+, 100). Mp: 55.4–56.6 ꢁC.
HRMS calcd for C11H1635ClNO3 (M+H+) 246.0891, found
246.0894.
62.04 (CH2CH3), 67.65 (Cquat, C-2), 121.63 (C]CH2),
140.22 (C]CH2), 149.41 (C]O, Boc), 172.54 (C]O,
ring), 174.08 (C]O, COOEt). IR (cmꢀ1) nmax: 1721
(C]O), 1742 (C]O), 1791 (C]O). MS m/z (%): no M+,
246 (MꢀBoc+H+, 100), 210 (15), 172 (15), 136 (10).
C16H24ClNO5: calcd C 55.57, H 7.00, N 4.05; found C
55.76, H 7.19, N 4.10.
3.5. Typical experimental procedure for the Boc
protection of 5a and 5b
3.6. Typical experimental procedure for the synthesis of
7a and 7b
The pyroglutamate ester 5 (12 mmol) is dissolved in aceto-
nitrile (20 mL). The flask is cooled in an ice bath. To this
solution are added DMAP (1.2 mmol, 0.1 equiv) and di-
tert-butyldicarbonate (15.6 mmol, 1.3 equiv) dissolved in
acetonitrile (15 mL). The mixture is allowed to stir overnight
after which H2O (5 mL) and brine (5 mL) are added. The
mixture is extracted twice with diethyl ether, and the organic
fractions are dried (MgSO4) and filtered. The solvent is
removed under reduced pressure.
The pyroglutamate ester 6 (12 mmol) is dissolved in THF
(15 mL, freshly distilled from Na metal). The mixture is
cooled to ꢀ78 ꢁC under a N2 atmosphere. Over a period of
5 min, 25.2 mL of a KHMDS solution (25.2 mmol, 1 M so-
lution in toluene, 1.1 equiv) is added at this temperature. The
reaction mixture is allowed to stir for an additional 2 h at
ꢀ78 ꢁC. The reaction is quenched by addition of saturated
aqueous NH4Cl until the pH is neutral. The mixture is ex-
tracted twice with diethyl ether (25 mL), and the organic
fractions are dried (MgSO4) and filtered. The solvent is re-
moved under reduced pressure. The products are purified
by chromatography.
3.5.1. Synthesis of benzyl 2-(2-chloromethyl-2-propenyl)-
1-(tert-butoxycarbonyl)-5-oxopyrrolidine-2-carboxylate
(6a). Brown oil (yield: 80%).
1H NMR (270 MHz, CDCl3) d: 1.46 (9H, s, t-Bu), 2.01–2.10
(1H, m, CHAHB ring, C-3), 2.15–2.24 (1H, m, CHAHB ring,
C-3), 2.45–2.56 (2H, m, CH2 ring, C-4), 2.82 (1H, d,
J¼15.0 Hz, CHAHBC]CH2), 3.33 (1H, d, J¼15.0 Hz,
CHAHBC]CH2), 3.97 (1H, d, J¼12.0 Hz, CHAHBCl),
4.04 (1H, d, J¼12.0 Hz, CHAHBCl), 5.11 (1H, s,
C]CHAHB), 5.15 (1H, d, J¼12.2 Hz, CHAHBPh), 5.23
(1H, d, J¼12.2 Hz, CHAHBPh), 5.40 (1H, s, C]CHAHB),
7.35 (5H, s, Ph). 13C NMR (68 MHz, CDCl3) d: 26.61
(CH2 ring, C-3), 27.80 (t-Bu), 30.75 (CH2 ring, C-4),
3.6.1. Synthesis of 5-benzyl 6-(tert-butyl)-3-methylene-7-
oxo-6-azabicyclo[3.2.1]octane-5,6-dicarboxylate (7a).
Brown oil (yield: 44%).
1H NMR (270 MHz, CDCl3) d: 1.42 (9H, s, t-Bu), 1.87 (1H,
d, J¼11.2 Hz, CHAHB, C-4), 2.37 (1H, d, J¼11.2 Hz,
CHAHB, C-4), 2.34–2.41 (1H, m, CHAHB, C-8), 2.58 (1H,
d, J¼14.2 Hz, CHAHB, C-8), 2.72 (1H, d, J¼14.9 Hz,
CHAHB, C-2), 2.75–2.79 (1H, m, CH, C1), 3.04 (1H, d,
J¼14.9 Hz, CHAHB, C-2), 4.91–5.20 (2H, m, C]CH2),
5.18 (1H, d, J¼12.4 Hz, CHAHBPh), 5.20 (1H, d,
J¼12.4 Hz, CHAHBPh), 7.35 (5H, br s, Ph). 13C NMR
(68 MHz, CDCl3) d: 27.83 (t-Bu), 35.76 (CH2, C-8), 38.15
36.69 (CH2C]CH2), 48.71 (CH2Cl), 67.60 (CH2Ph+Cquat
,
C-2), 84.29 (Cquat, t-Bu), 121.60 (C]CH2), 128.37 (CH,
Ph), 128.61 (CH, Ph), 128.70 (CH, Ph), 134.95 (Cquat, Ph),
140.05 (C]CH2), 149.32 (C]O), 172.25 (C]O), 173.83
(C]O). 13C NMR (68 MHz, C6D6) d: 27.03 (CH2 ring,
C-3), 28.27 (t-Bu), 31.02 (CH2 ring, C-4), 37.07
(CH2C]CH2), 49.16 (CH2Cl), 67.74 (Cquat, C-2), 67.87
(CH2Ph), 83.79 (Cquat, t-Bu), 121.44 (C]CH2), 136.24
(Cquat, Ph), 141.11 (C]CH2), 150.96 (C]O), 172.76
(C]O), 172.85 (C]O). IR (cmꢀ1) nmax: 1720 (C]O),
1746 (C]O), 1791 (C]O). MS m/z (%): no M+, 308
(MꢀBoc+H+), 201 (21), 199 (7), 91 (12). Chromatography:
Hex/EtOAc (60/40) Rf ¼0.33. C21H26ClNO5: calcd C 61.84,
H 6.42, N 3.43; found C 61.80, H 6.68, N 3.46.
(CH2, C-2), 38.45 (CH2, C-4), 42.55 (CH, C1), 66.18 (Cquat
,
C-3), 67.31 (CH2Ph), 83.57 (t-Bu, Cquat), 116.69 (C]CH2),
128.30 (CH, Ph), 128.52 (CH, Ph), 128.66 (CH, Ph), 135.04
(Cquat, Ph), 139.12 (C]CH2), 148.89 (C]O, Boc), 170.55
(C]O), 174.12 (C]O). IR (cmꢀ1) nmax: 1716 (C]O),
1747 (C]O), 1790 (C]O). MS m/z (%): 272 (MꢀBoc+H+,
100), 91 (7). Chromatography: Hex/EtOAc (70/30) Rf¼0.27.
C21H25NO5: calcd C 67.91, H 6.78, N 3.77; found C 67.88,
H 6.82, N 3.59.
3.6.2. Synthesis of 5-ethyl 6-(tert-butyl)-3-methylene-7-
oxo-6-azabicyclo[3.2.1]octane-5,6-dicarboxylate (7b).
Brown oil (yield: 75%).
3.5.2. Synthesis of ethyl 2-(2-chloromethyl-2-propenyl)-
1-(tert-butoxycarbonyl)-5-oxopyrrolidine-2-carboxylate
(6b). Brown oil (yield: 90%).
1H NMR (300 MHz, CDCl3) d: 1.28 (3H, t, J¼7.2 Hz,
CH2CH3), 1.47 (9H, s, t-Bu), 1.86 (1H, d, J¼11.3 Hz,
CHAHB, C-4), 2.34–2.41 (2H, m, CHAHB, C-4+CHAHB,
C-8), 2.59 (1H, br d, J¼14.3 Hz, CHAHB, C-8), 2.69 (1H,
dd, J¼15.0, 1.9 Hz, CHAHB, C-2), 2.76–2.82 (1H, m, CH,
C1), 3.00 (1H, d, J¼15.0 Hz, CHAHB, C-2), 4.21 (2H,
m, CH2CH3), 4.90–5.95 (2H, m, C]CH2). 13C NMR
(75 MHz, CDCl3) d: 13.99 (CH2CH3), 27.78 (t-Bu), 35.66
(CH2, C-8), 38.06 (CH2, C-2), 38.40 (CH2, C-4), 42.49
1H NMR (300 MHz, CDCl3) d: 1.28 (3H, t, J¼7.1 Hz,
CH2CH3), 1.51 (9H, s, t-Bu), 2.03–2.26 (2H, m, CH2 ring,
C-3), 2.37–2.64 (2H, m, CH2 ring, C-4), 2.79 (1H, d,
J¼15.0 Hz, CHAHBC]CH2), 3.29 (1H, d, J¼15.0 Hz,
CHAHBC]CH2), 3.97 (1H, d, J¼12.1 Hz, CHAHBCl),
4.03 (1H, d, J¼12.1 Hz, CHAHBCl), 4.18–4.25 (2H,
m, CH2CH3), 5.11 (1H, s, C]CHAHB), 5.40 (1H, s,
C]CHAHB). 13C NMR (75 MHz, CDCl3) d: 14.14
(CH2CH3), 26.81 (CH2 ring, C-3), 27.93 (t-Bu), 30.87
(CH2 ring, C-4), 36.76 (CH2C]CH2), 48.83 (CH2Cl),
(CH, C1), 61.52 (CH2CH3), 66.07 (Cquat, C-3), 83.24 (Cquat
t-Bu), 116.34 (C]CH2), 139.35 (C]CH2), 148.74 (C]O,
Boc), 170.60 (C]O), 174.22 (C]O). IR (cmꢀ1
,
)

K. G. R. Masschelein et al. / Tetrahedron 63 (2007) 4712–4724
4719
nmax: 1716 (C]O), 1742 (C]O), 1790 (C]O). MS m/z
(%): no M+, 210 (MꢀBoc+H+, 100), 136 (7). Chromato-
graphy: Hex/EtOAc (70/30) Rf¼0.21. C16H23NO5: calcd C
62.12, H 7.49, N 4.53; found C 62.07, H 7.42, N 4.55.
(1H, dd, J¼17.7, 2.0 Hz, CHAHB, C-4), 2.51–2.61 (3H, m,
CHAHB, C-8+CHAHB, C-2+CHAHB, C-4), 2.74–2.77 (1H,
m, CH, C1), 3.43 (3H, s, CH3), 4.22 (1H, d, J¼15.0 Hz,
CHAHBPh), 4.55 (1H, d, J¼15.0 Hz, CHAHBPh), 4.63
(1H, d, J¼2.0 Hz, C]CHAHB), 4.90 (1H, d, J¼2.0 Hz,
C]CHAHB), 7.19–7.30 (5H, m, Ph). 13C NMR (75 MHz,
CDCl3) d: 35.14 (CH2, C-2), 37.29 (CH2, C-4), 40.00 (CH,
C1), 40.18 (CH2, C-8), 44.18 (CH2Ph), 52.23 (CH3), 66.39
(Cquat, C-5), 116.93 (C]CH2), 127.33 (CH, Ph), 128.11
(CH, Ph), 128.73 (CH, Ph), 136.90 (Cquat, Ph), 138.95
3.7. Synthesis of 5-ethyl 6-(tert-butyl)-3,7-dioxo-6-aza-
bicyclo[3.2.1]octane-5,6-dicarboxylate (9)
Compound 7b (1.6 mmol) is dissolved in a mixture of
CH2Cl2 (10 mL, freshly distilled from CaH2) and methanol
(0.5 mL). The mixture is cooled to ꢀ78 ꢁC. Ozone is bub-
bled through until the mixture remains blue. Air is bubbled
through the mixture to remove the excess of ozone after
which dimethylsulfide (3.24 mmol, 2 equiv) is added. The
flask is put in the freezer (ꢀ20 ꢁC) for an overnight period.
The mixture is washed twice with brine (10 mL). The aque-
ous layer is extracted once with CH2Cl2 (10 mL). The com-
bined organic fractions are dried (MgSO4) and filtered. The
solvent is removed under reduced pressure. The product is
purified by chromatography and a brown oil is obtained
(yield: 60%).
(C]CH2), 171.03 (C]O), 176.77 (C]O). IR (cmꢀ1
)
nmax: 1702 (C]O), 1740 (C]O). MS m/z (%): (ES, pos)
286 (M+H+, 100). Chromatography: Hex/EtOAc (70/30)
Rf ¼0.19. HRMS calcd for C17H19NO3 (M+H+) 286.1438,
found 286.1441.
3.8.2. Synthesis of benzyl 6-benzyl-3-methylene-7-oxo-6-
azabicyclo[3.2.1]octane-5-carboxylate (11b). Brown oil
(yield: 29%).
1H NMR (300 MHz, CDCl3) d: 1.83 (1H, d, J¼11.0 Hz,
CHAHB, C-8), 2.31 (1H, br d, J¼14.3 Hz, CHAHB, C-2),
2.46 (2H, br s, CH2, C-4), 2.51–2.60 (2H, m, CHAHB, C-
8+CHAHB, C-2), 2.71–2.75 (1H, m, CH, C1), 4.33 (1H,
d, J¼15.1 Hz, NCHAHBPh), 4.43 (1H, d, J¼15.1 Hz,
NCHAHBPh), 4.55 (1H, br s, C]CHAHB), 4.75 (1H, d,
J¼12.4 Hz, OCHAHBPh), 4.87 (1H, br s, C]CHAHB),
5.01 (1H, d, J¼12.4 Hz, OCHAHBPh), 7.14–7.36 (10H, m,
Ph). 13C NMR (75 MHz, CDCl3) d: 35.11 (CH2, C-2),
37.45 (CH2, C-4), 40.12 (CH, C1), 40.25 (CH2, C-8),
44.17 (NCH2Ph), 66.60 (Cquat, C-5), 67.19 (OCH2Ph),
116.97 (C]CH2), 127.37 (CH, Ph), 128.11 (CH, Ph), 128.37
(CH, Ph), 128.54 (CH, Ph), 128.60 (CH, Ph), 128.91 (CH,
Ph), 134.91 (Cquat, Ph), 136.86 (Cquat, Ph), 138.85 (C]CH2),
170.45 (C]O), 176.67 (C]O). IR (cmꢀ1) nmax: 1649
(C]C), 1704 (C]O), 1735 (C]O). MS m/z (%): (ES,
pos) 362 (M+H+, 100). Chromatography: Hex/EtOAc
(70/30) Rf¼0.33. HRMS calcd for C23H23NO3 (M+H+)
362.1751, found 362.1749.
1H NMR (300 MHz, CDCl3) d: 1.30 (3H, t, J¼7.2 Hz,
CH2CH3), 1.47 (9H, s, t-Bu), 2.10 (1H, d, J¼11.8 Hz,
CHAHB, C-4), 2.52–2.61 (2H, m, CHAHB, C-4+CHAHB,
C-8), 2.75 (1H, br d, J¼18.4 Hz, CHAHB, C-8), 2.97–3.02
(1H, m, CH, C1), 3.00 (1H, d, J¼18.6 Hz, CHAHB, C-2),
3.18 (1H, br d, J¼18.6 Hz, CHAHB, C-2), 4.22 (1H, dq,
J¼13.8, 7.0 Hz, CHAHBCH3), 4.23 (1H, dq, J¼13.8,
7.0 Hz, CHAHBCH3). 13C NMR (75 MHz, CDCl3) d:
13.99 (CH2CH3), 27.81 (t-Bu), 37.03 (CH2, C-4), 40.39
(CH, C1), 42.68 (CH2, C-8), 45.93 (CH2, C-2), 62.26
(CH2CH3), 65.52 (Cquat, C-3), 84.56 (Cquat, t-Bu), 148.38
(C]O, Boc), 169.42 (C]O), 173.20 (C]O), 204.53
(C]O, C-3). IR (cmꢀ1) nmax: 1721 (C]O), 1745 (C]O),
1790 (C]O). MS m/z (%): no M+, 212 (MꢀBoc+H+,
100), 166 (7). Chromatography: Hex/EtOAc (50/50)
Rf ¼0.24. C15H21NO6: calcd C 57.87, H 6.80, N 4.50; found
C 58.03, H 6.95, N 4.44.
3.8. Typical experimental procedure for the synthesis of
11a, 11b and 13
3.8.3. Synthesis of methyl 7-benzyl-3,4-dimethylene-
8-oxo-7-azabicyclo[4.2.1]-nonane-6-carboxylate (13).
White crystals (yield: 10%).
The pyroglutamate ester 10 (4.29 mmol) is dissolved in THF
(15 mL, freshly distilled from Na metal) and the alkyl halide
(4.72 mmol, 1.1 equiv) is added. The mixture is cooled to
ꢀ40 ꢁC under a N2 atmosphere. Over a period of 30–
40 min, 9 mL of a LiHMDS solution (9.01 mmol, 1 M solu-
tion in hexanes, 2.1 equiv) is added at this temperature. The
reaction mixture is allowed to stir at room temperature for
an additional 2 h. The reaction is quenched by addition of
saturated aqueous NH4Cl. An extra amount of 15 mL of
water is added and the mixture is extracted with EtOAc
(3ꢂ15 mL). The organic fractions are dried (MgSO4) and
filtered. The solvent is removed under reduced pressure
and the crude product is purified by chromatography.
1H NMR (300 MHz, CDCl3) d: 2.05 (1H, d, J¼12.7 Hz,
CHAHB, C-9), 2.54–2.62 (3H, m, CHAHB, C-9+CHAHB,
C-2+CHAHB, C-5), 2.79–2.84 (2H, m, CH, C1+CHAHB,
C-2), 2.96 (1H, br d, J¼14.9 Hz, CHAHB, C-5), 3.29 (3H,
s, CH3), 4.01 (1H, d, J¼15.1 Hz, CHAHBPh), 4.70 (1H, d,
J¼15.1 Hz, CHAHBPh), 4.79 (1H, br s, C4]CHAHB), 4.82
(1H, t, J¼1.9 Hz, C3]CHAHB), 4.85 (1H, d, J¼1.4 Hz,
C4]CHAHB), 4.90 (1H, br s, C3]CHAHB), 7.19–7.31
(5H, m, Ph). 13C NMR (75 MHz, CDCl3) d: 33.87 (CH2,
C-9), 38.37 (CH, C1), 39.42 (CH, C-2), 42.89 (CH2, C-5),
44.29 (CH2, CH2Ph), 52.25 (CH3), 67.61 (Cquat, C-6),
115.43 (C3]CH2), 117.76 (C4]CH2), 127.20 (CH, Ph),
128.18 (CH, Ph), 128.54 (CH, Ph), 136.97 (Cquat, Ph),
145.45 (C3]CH2), 148.13 (C4]CH2), 172.07 (C]O),
178.13 (C]O). IR (cmꢀ1) nmax: 1625 (C]C), 1698
(C]O), 1737 (C]O). MS m/z (%): (ES, pos) 312 (M+H+,
100). Chromatography: Hex/EtOAc (70/30) Rf ¼0.25. Mp:
114–117 ꢁC. HRMS calcd for C19H21NO3 (M+H+)
312.1594, found 312.1591.
3.8.1. Synthesis of methyl 6-benzyl-3-methylene-7-oxo-6-
azabicyclo[3.2.1]octane-5-carboxylate (11a). Brown oil
(yield: 22%).
1H NMR (300 MHz, CDCl3) d: 1.83 (1H, d, J¼11.0 Hz,
CHAHB, C-8), 2.32 (1H, d, J¼14.3 Hz, CHAHB, C-2), 2.44

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K. G. R. Masschelein et al. / Tetrahedron 63 (2007) 4712–4724
3.9. Typical experimental procedure for the synthesis of
15a and 15b
5.41–5.53 (1H, m, CH2CH]CH2), 5.68–5.81 (1H, m,
CH2CH]CH2), 7.17–7.35 (5H, m, Ph). 13C NMR
(75 MHz, CDCl3) d: 23.33 (CH2 ring, C-3), 29.70 (CH2
ring, C-4), 45.31 (CH2Ph), 48.41 (CH2CH]CH2), 48.49
(CH2CH]CH2), 56.19 (CH ring, C-2), 117.14
(CH2CH]CH2), 118.05 (CH2CH]CH2), 127.70 (CH,
Ph), 128.51 (CH, Ph), 128.71 (CH, Ph), 132.16
To 28.83 mmol of pyroglutamate 14 is added 14.4 mL of
a 2 N NaOH solution (28.83 mmol, 1.0 equiv). After stir-
ring overnight at room temperature the solvent is removed
under reduced pressure. The sodium salt of 1-benzyl-5-
oxopyrrolidine-2-carboxylic acid is obtained in 99%
yield.
(CH2CH]CH2), 132.59 (CH2CH]CH2), 136.16 (Cquat
,
Ph), 170.76 (C]O), 175.44 (C]O). IR (cmꢀ1) nmax: 1656
(C]O), 1690 (C]O). MS m/z (%): (ES, pos) 299 (M+H+,
100). HRMS calcd for C18H22N2O2 (M+H+) 299.1754, found
299.1761.
To a suspension of 20.75 mmol 1-benzyl-5-oxopyrrolidine-
2-carboxylic acid in 30 mL CH2Cl2 is added 62.25 mmol
(3 equiv) SOCl2. The reaction mixture is allowed to stir
at room temperature for 30 min. After removal of the sol-
vent under reduced pressure, 19.9 mmol of 1-benzyl-5-
oxopyrrolidine-2-carbonyl chloride is obtained (yield:
96%).
3.10. Synthesis of 1-benzyl-4,4-bis-(2-chloromethyl-
allyl)-N,N-diisopropyl-5-oxopyrrolidine-2-carboxamide
(16)
1-Benzyl-N,N-diisopropyl-5-oxopyrrolidine-2-carboxamide
15a (0.75 g, 2.48 mmol) is dissolved in THF (10 mL,
freshly distilled from Na metal) and 0.34 g of 3-chloro-2-
chloromethyl-1-propene (2.73 mmol, 1.1 equiv) is added.
The mixture is cooled to ꢀ40 ꢁC under a N2 atmosphere.
Over a period of 30–40 min, 5.2 mL of a LiHMDS solution
(5.2 mmol, 1 M solution in hexanes, 2.1 equiv) is added at
this temperature. The reaction mixture is allowed to stir at
room temperature for an additional 2 h. The reaction is
quenched by addition of saturated aqueous NH4Cl. An extra
amount of 15 mL of water is added and the mixture is extracted
with EtOAc (3ꢂ15 mL), and the organic fractions are dried
(MgSO4). After filtration, the solvent is removed under
reduced pressure. Purification by chromatography gives
0.34 g of 1-benzyl-4,4-bis-(2-chloromethyl-allyl)-N,N-di-
isopropyl-5-oxopyrrolidine-2-carboxamide (yield: 29%).
When considering the electrophile as limiting reagent, the
yield is 52%.
To a solution of 6.33 mmol of 1-benzyl-5-oxopyrrolidine-2-
carbonyl chloride in 15 mL CH2Cl2 is added 12.7 mmol
of triethylamine (2.0 equiv) and 12.7 mmol of amine
(2.0 equiv). After stirring for 1 h at room temperature,
25 mL of water is added. The reaction mixture is extracted
with CH2Cl2 (3ꢂ20 mL). The organic fractions are
combined and dried with MgSO4. After filtration and evap-
oration under reduced pressure, 1-benzyl-N,N-dialkyl-5-
oxopyrrolidine-2-carboxamides are obtained.
3.9.1. Synthesis of 1-benzyl-N,N-diisopropyl-5-oxopyrro-
lidine-2-carboxamide (15a). Brown powder (yield: 74%).
1H NMR (300 MHz, CDCl3) d: 0.90 (3H, d, J¼6.6 Hz, CH3),
1.12 (3H, d, J¼6.6 Hz, CH3), 1.39 (3H, d, J¼6.6 Hz, CH3),
1.44 (3H, d, J¼6.6 Hz, CH3), 1.79–1.89 (1H, m, CHAHB
ring, C-3), 2.11–2.24 (1H, m, CHAHB ring, C-3), 2.37–
2.47 (1H, m, CHAHB ring, C-4), 2.54–2.65 (1H, m, CHAHB
ring, C-4), 3.32–3.50 (1H, m, NCH), 3.59 (1H, sept,
J¼6.6 Hz, NCH), 3.87 (1H, d, J¼14.6 Hz, CHAHBPh),
4.04 (1H, d, J¼8.8, 3.9 Hz, CH ring, C-2), 5.19 (1H, d,
J¼14.6 Hz, CHAHBPh), 7.19–7.33 (5H, m, Ph). 13C NMR
(75 MHz, CDCl3) d: 19.21 (CH3), 20.45 (CH3), 20.56
(CH3), 20.77 (CH3), 22.89 (CH2 ring, C-3), 29.88 (CH2
ring, C-4), 45.53 (CH2Ph), 46.19 (NCH), 47.82 (NCH),
57.12 (CH ring, C-2), 127.72 (CH, Ph), 128.68 (CH, Ph),
129.02 (CH, Ph), 136.21 (Cquat, Ph), 169.07 (C]O),
175.25 (C]O). IR (cmꢀ1) nmax: 1634 (C]O), 1682
(C]O). MS m/z (%): (ES, pos) 303 (M+H+, 100). Mp:
100.5–102.5 ꢁC. HRMS calcd for C18H26N2O2 (M+H+)
303.2067, found 303.2079.
1H NMR (300 MHz, CDCl3) d: 0.88 (3H, d, J¼6.6 Hz, CH3),
1.12 (3H, d, J¼6.6 Hz, CH3), 1.38 (3H, d, J¼6.6 Hz,
CH3), 1.45 (3H, d, J¼6.6 Hz, CH3), 1.92 (1H, dd,
J¼13.2, 5.2 Hz, CHAHB ring, C-3), 2.21 (1H, dd, J¼
13.2, 9.6 Hz, CHAHB ring, C-3), 2.30 (1H, d, J¼14.2
Hz, CHAHB(C]CH2)CH2Cl), 2.32 (1H, d, J¼14.2 Hz,
CHAHB(C]CH2)CH2Cl), 2.62 (1H, d, J¼14.2 Hz, CHAHB
(C]CH2)CH2Cl), 2.76 (1H, d, J¼14.2 Hz, CHAHB(C]
CH2)CH2Cl), 3.36 (1H, sp, J¼6.6 Hz, NCH), 3.52 (1H,
sept, J¼6.6 Hz, NCH), 3.84 (1H, dd, J¼9.6, 5.2 Hz, CH
ring, C-2), 4.01 (1H, d, J¼14.3 Hz, CHAHBPh), 4.02 (2H,
s, 2ꢂCHAHBCl), 4.07 (2H, s, 2ꢂCHAHBCl), 5.04 (2H, s,
2ꢂC]CHAHB), 5.16 (1H, d, J¼14.3 Hz, CHAHBPh),
5.30 (2H, s, 2ꢂC]CHAHB), 7.14–7.34 (5H, m, Ph).
13C NMR (75 MHz, CDCl3) d: 20.26 (CH3), 20.44 (CH3),
20.52 (CH3), 20.66 (CH3), 30.92 (CH2 ring, C-3), 40.72
(CH2(C]CH2)CH2Cl), 41.00 (CH2(C]CH2)CH2Cl), 46.02
(NCH2Ph), 46.11 (NCH), 47.29 (Cquat ring, C-4), 47.96
(NCH), 48.78 (CH2Cl), 48.87 (CH2Cl), 54.55 (CH ring, C-
2), 119.03 (C]CH2), 119.79 (C]CH2), 127.87 (CH, Ph),
3.9.2. Synthesis of 1-benzyl-N,N-diallyl-5-oxopyrrol-
idine-2-carboxamide (15b). Brown oil (yield: 76%).
1H NMR (300 MHz, CDCl3) d: 1.87–1.97 (1H, m, CHAHB
ring, C-3), 2.14–2.27 (1H, m, CHAHB ring, C-3), 2.39–2.49
(1H, m, CHAHB ring, C-4), 2.57–2.72 (1H, m, CHAHB
ring, C-4), 3.52 (1H, dd, J¼17.6, 5.0 Hz, CHAHBCH]CH2),
3.66 (1H, dd, J¼17.6, 3.9 Hz, CHAHBCH]CH2), 3.76 (1H,
d, J¼14.9 Hz, CHAHBPh), 3.89 (1H, dd, J¼15.1, 6.2 Hz,
CHAHBCH]CH2), 4.07 (1H, dd, J¼15.1, 5.8 Hz,
CHAHBCH]CH2), 4.15 (1H, dd, J¼9.0, 3.7 Hz, CH ring,
C-2), 4.93–5.07 (2H, m, CH2CH]CH2), 5.11–5.23 (2H,
m, CH2CH]CH2), 5.20 (1H, d, J¼14.9 Hz, CHAHBPh),
128.71 (2ꢂCH, Ph), 129.40 (2ꢂCH, Ph), 135.41 (Cquat
,
Ph), 141.38 (C]CH2), 141.57 (C]CH2), 168.64 (C]O),
176.70 (C]O). IR (cmꢀ1) nmax: 1649 (C]O), 1683
(C]O). MS m/z (%): (ES, pos) 480/482/484 (M+H+, 100).
Chromatography: Hex/EtOAc (85/15) Rf ¼0.17. HRMS
calcd for C26H3635Cl2N2O2 (M+H+) 479.2227, found
479.2212.

K. G. R. Masschelein et al. / Tetrahedron 63 (2007) 4712–4724
4721
3.11. Synthesis of 6-benzyl-1-(2-chloromethyl-allyl)-
N,N-diallyl-3-methylene-7-oxo-6-azabicyclo[3.2.1]-
octane-5-carboxamide (18)
is added and the mixture is extracted with diethyl ether
(3ꢂ20 mL). The combined organic fractions are dried
(MgSO4) and filtered. The solvent is removed under reduced
pressure. The compound is purified by bulb-to-bulb
distillation.
1-Benzyl-N,N-diisopropyl-5-oxopyrrolidine-2-carboxamide
15a of 0.25 g (0.84 mmol) is dissolved in THF (5 mL,
freshly distilled from Na metal) and 0.21 g of 3-chloro-2-
chloromethyl-1-propene (1.68 mmol, 2.0 equiv) is added.
The mixture is cooled to ꢀ40 ꢁC under a N2 atmosphere.
Over a period of 30–40 min, 2.5 mL of LiHMDS
(2.5 mmol, 1 M solution in hexanes, 3.0 equiv) is added at
this temperature. The reaction mixture is allowed to stir at
room temperature for an additional 2 h. The reaction is
quenched by addition of saturated aqueous NH4Cl. An extra
amount of 10 mL water is added and the mixture is extracted
with EtOAc (3ꢂ10 mL). The organic fractions are dried
(MgSO4) and filtered. The solvent is removed under reduced
pressure. A crude reaction mixture of 0.34 g is obtained
(conversion: 56%). After purification by chromatography,
0.09 g of 6-benzyl-1-(2-chloromethyl-allyl)-N,N-diallyl-3-
methylene-7-oxo-6-azabicyclo[3.2.1]octane-5-carboxamide
18 is obtained as white crystals (yield: 25%).
3.12.1. Synthesis of benzyl 2-methylene-5-oxotetrahydro-
1H-pyrrolizine-7a(5H)-carboxylate (22a). Colourless oil
(yield: 68%).
1H NMR (270 MHz, CDCl3) d: 2.05–2.17 (1H, m, CHAHB,
C-7), 2.33–2.79 (4H, m, CH2, C-6+CHAHB, C-7+CHAHB,
C1), 3.05 (1H, d, J¼15.5 Hz, CHAHB, C1), 3.71 (1H, d,
J¼15.7 Hz, CHAHB, C-3), 4.28 (1H, d, J¼15.7 Hz, CHAHB,
C-3), 5.01–5.07 (2H, m, C]CH2), 5.17 (2H, s, CH2Ph),
7.28–7.37 (5H, m, Ph). 13C NMR (68 MHz, CDCl3) d:
31.37 (CH2, C-7), 33.30 (CH2, C-6), 43.85 (CH2, C1),
46.54 (CH2, C-3), 67.84 (CH2Ph), 72.87 (Cquat, C-7a),
109.22 (C]CH2), 127.96 (CH, Ph), 128.48 (CH, Ph),
128.66 (CH, Ph), 135.27 (Cquat, Ph), 145.17 (C]CH2),
172.94 (C]O), 174.23 (C]O). IR (cmꢀ1) nmax: 1703
(C]O), 1736 (C]O). MS m/z (%): 272 (M+H+, 100). Bp:
145–160 ꢁC/0.13 mbar. HRMS calcd for C16H17NO3
(M+H+) 272.1281, found 272.1285.
1H NMR (300 MHz, CDCl3) d: 1.74 (1H, d, J¼11.6 Hz,
CHAHB, C-8), 2.16 (1H, d, J¼13.6 Hz, CHAHB, C-4),
2.28 (1H, d, J¼14.3 Hz, CHAHB(C]CH2)CH2Cl), 2.30
(1H, d, J¼13.6 Hz, CHAHB, C-4), 2.44–2.50 (2H, m,
CHAHB, C-2+CHAHB, C-8), 2.78 (1H, d, J¼14.3 Hz,
CHAHB(C]CH2)CH2Cl), 2.80 (1H, d, J¼14.9 Hz, CHAHB,
C-2), 2.94 (1H, dd, J¼17.6, 4.7 Hz, CHAHBCH]CH2), 3.39
(1H, dd, J¼13.8, 7.7 Hz, CHAHBCH]CH2), 3.96 (1H, d,
J¼12.1 Hz, CHAHBCl), 4.03 (1H, d, J¼12.1 Hz, CHAHBCl),
4.17 (1H, d, J¼14.6 Hz, CHAHBPh), 4.18–4.24 (2H, m,
2ꢂCHAHBCH]CH2), 4.30 (1H, d, J¼14.6 Hz, CHAHBPh),
4.41 (1H, br s, C3]CHAHB), 4.74 (1H, br s, C3]CHAHB),
4.98–5.20 (4H, m, 2ꢂCH2CH]CH2), 5.07 (1H, br s,
CH2(C]CHAHB)CH2Cl), 5.29 (1H, br s, CH2(C]CHAHB)
CH2Cl), 5.44–5.60 (1H, m, CH2CH]CH2), 5.60–5.79 (1H,
m, CH2CH]CH2), 7.24–7.35 (5H, m, Ph). 13C NMR
(75 MHz, CDCl3) d: 36.34 (CH2(C]CH2)CH2Cl), 39.27
(CH2, C-2), 42.02 (CH2, C-8), 42.80 (CH2, C-4), 45.52
(NCH2Ph), 48.04 (Cquat, C1), 48.80 (CH2CH]CH2), 49.06
(CH2Cl), 49.99 (CH2CH]CH2), 66.63 (Cquat, C-5), 116.65
(C3]CH2), 117.57 (CH2CH]CH2), 118.74 (CH2CH]
CH2), 118.86 (CH2(C]CH2)CH2Cl), 127.80 (CH, Ph),
128.33 (2ꢂCH, Ph), 130.06 (2ꢂCH, Ph), 132.51
3.12.2. Synthesis of ethyl 2-methylene-5-oxotetrahydro-
1H-pyrrolizine-7a(5H)-carboxylate (22b). Colourless oil
(yield: 75%).
1H NMR (270 MHz, CDCl3) d: 1.27 (3H, t, J¼7.1 Hz,
CH2CH3), 2.07–2.19 (1H, m, CHAHB, C-7), 2.40–2.82
(4H, m, CH2, C-6+CHAHB, C1+CHAHB, C-7), 3.05 (1H,
d, J¼15.5 Hz, CHAHB, C1), 3.73 (1H, d, J¼15.8 Hz,
CHAHB, C-3), 4.21 (2H, q, J¼7.1 Hz, CH2CH3), 4.29 (1H,
d, J¼15.8 Hz, CHAHB, C-3), 5.03–5.08 (2H, m, C]CH2).
13C NMR (68 MHz, CDCl3) d: 14.12 (CH2CH3), 31.48
(CH2, C-7), 33.33 (CH2, C-6), 43.86 (CH2, C1), 46.49
(CH2, C-3), 61.80 (CH2CH3), 72.79 (Cquat, C-7a), 109.06
(C]CH2), 145.32 (C]CH2), 173.15 (C]O), 174.23
(C]O). IR (cmꢀ1) nmax: 1708 (C]O), 1732 (C]O). MS
m/z (%): 210 (M+H+, 100). Bp: 80–90 ꢁC/0.01 mbar.
HRMS calcd for C11H15NO3 (M+H+) 210.1125, found
210.1134.
3.13. Synthesis of (2-methylenetetrahydro-1H-pyrro-
lizin-7a(5H)-yl)methanol (23)
(CH2CH]CH2), 132.86 (CH2CH]CH2), 136.41 (Cquat
,
Ph), 139.35 (Cquat, C-3), 141.05 (CH2(C]CH2)CH2Cl),
169.14 (C]O), 177.13 (C]O). IR (cmꢀ1) nmax: 1625
(C]O), 1691 (C]O). MS m/z (%): (ES, pos) 440/442
(M+H+, 100). Chromatography: Hex/EtOAc (70/30) Rf ¼
0.56. Mp: 109–111 ꢁC. HRMS calcd for C26H3135ClN2O2
(M+H+) 439.2147, found 439.2142.
In an oven dry flask, 0.23 g of LiAlH4 (5.8 mmol, 2 equiv)
is dispersed in THF (10 mL, freshly distilled from Na
metal). The flask is put in an ice bath under a N2 atmo-
sphere. To this dispersion derivative 22b (2.9 mmol,
1 equiv), dissolved in THF (10 mL), is added. The ice
bath is removed and the mixture is refluxed for 3 h under
a N2 atmosphere. Very carefully water is added until all
remaining LiAlH4 is decomposed. The mixture is filtered
over a combination MgSO4/Celite (50/50) and the solvent
is removed under reduced pressure. The compound is puri-
fied by bulb-to-bulb distillation and a colourless oil is ob-
tained (yield: 70%).
3.12. Typical experimental procedure for the synthesis
of 22a and 22b
In an oven dry flask, NaH (0.11 g of a 60% suspension in
mineral oil washed with hexanes, 3.32 mmol, 1.2 equiv) is
dispersed in THF (5 mL, freshly distilled from Na metal).
To this dispersion derivative 5 (2.77 mmol, 1 equiv), dis-
solved in THF (10 mL), is added. The mixture is refluxed
under a N2 atmosphere for 16 h. Very carefully water (5 mL)
1H NMR (300 MHz, CDCl3) d: 1.62–1.94 (4H, m, CH2,
C-6+CH2, C-7), 2.32 (1H, dd, J¼15.8, 2.0 Hz, CHAHB,
C1), 2.43 (1H, ddd, J¼15.8, 2.1, 1.5 Hz, CHAHB, C1),

4722
K. G. R. Masschelein et al. / Tetrahedron 63 (2007) 4712–4724
2.60–2.69 (1H, m, CHAHB, C-5), 3.02–3.10 (1H, m,
CHAHB, C-5), 3.24 (1H, d, J¼13.5 Hz, CHAHB, C-3), 3.25
(1H, d, J¼10.9 Hz, CHAHBOH), 3.27 (1H, d, J¼10.9 Hz,
CHAHBOH), 3.61 (1H, d, J¼13.5 Hz, CHAHB, C-3), 4.87–
4.92 (2H, m, C]CH2). 13C NMR (75 MHz, CDCl3) d:
25.18 (CH2, C-6), 34.45 (CH2, C-7), 41.26 (CH2, C1),
55.54 (CH2, C-5), 59.12 (CH2, C-3), 66.56 (CH2OH),
74.32 (Cquat, C-7a), 106.13 (C]CH2), 149.07 (C]CH2).
IR (cmꢀ1) nmax: 3368 (br OH). MS m/z (%): 154 (M+H+,
100). Bp: 80–100 ꢁC/0.27 mbar. HRMS calcd for
C9H15NO (M+H+) 154.1226, found 154.1229.
5.65–5.77 (2H, m, CH, C-6+CH, C-7). 13C NMR
(75 MHz, CDCl3) d: 14.19 (CH2CH3), 29.17 (CH2, C1),
31.19 (CH2, C-2), 34.52 (CH2, C-8), 40.02 (CH2, C-5),
61.81 (CH2CH3), 64.33 (Cquat, C-8a), 122.92 (CH, C-7),
123.53 (CH, C-6), 173.14 (C]O), 174.66 (C]O). IR
(cmꢀ1) nmax: 1701 (C]O), 1732 (C]O). MS m/z (%):
210 (M+H+, 100). Chromatography: Hex/EtOAc (10/90)
Rf ¼0.30. HRMS calcd for C11H15NO3 (M+H+) 210.1125,
found 210.1128.
3.15.2. Synthesis of ethyl 2-[(2Z)-4-chloro-2-butenyl]-5-
oxopyrrolidine-2-carboxylate (26). H NMR (300 MHz,
1
3.14. Synthesis of ethyl 2,5-dioxotetrahydro-1H-pyrro-
lizine-7a(5H)-carboxylate (24)
CDCl3) d: 1.30 (3H, t, J¼7.1 Hz, CH2CH3), 2.08–
2.13 (1H, m, CHAHB ring, C-3), 2.29–2.48 (3H, m, CH2
ring, C-4+CHAHB), 2.57 (1H, dd, J¼14.4, 7.3 Hz,
CHAHBHC]CH), 2.67 (1H, dd, J¼14.4, 8.5 Hz,
CHAHBHC]CH), 4.05 (1H, d, J¼8.0 Hz, CHAHBCl),
4.03–4.25 (3H, m, CHAHBCl+CH2CH3), 5.48–5.57 (1H,
m, CHCH2Cl), 5.81–5.89 (1H, m, HC]CHCH2Cl), 6.39
(1H, br s, NH). 13C NMR (75 MHz, CDCl3) d: 14.16
(CH2CH3), 29.79 (CH2 ring, C-3), 30.30 (CH2 ring, C-4),
36.32 (CH2HC]CH2), 38.76 (CH2Cl), 61.99 (CH2CH3),
65.14 (Cquat ring, C-2), 126.90 (CH2HC]CH), 130.06
(HC]CHCH2Cl), 172.94 (C]O), 177.18 (C]O). IR
(cmꢀ1) nmax: 1703 (C]O), 1732 (C]O). MS m/z (%):
246 (M+H+, 100). Chromatography: Hex/EtOAc (10/90)
Rf ¼0.30. HRMS calcd for C11H1635ClNO3 (M+H+)
246.0891, found 246.0898.
Compound 22b (1.2 mmol) is dissolved in a mixture of
CH2Cl2 (10 mL, freshly distilled from CaH2) and methanol
(0.5 mL). The mixture is cooled to ꢀ78 ꢁC. Ozone is bub-
bled through until the mixture remains blue. Air is bubbled
through the mixture to remove the excess of ozone after
which dimethylsulfide (2.3 mmol, 2 equiv) is added. The
flask is put in the freezer (ꢀ20 ꢁC) for an overnight period.
The mixture is washed twice with brine (10 mL). The aque-
ous layer is extracted once with CH2Cl2 (10 mL). The com-
bined organic fractions are dried (MgSO4) and filtered. The
solvent is removed under reduced pressure. After purifica-
tion by chromatography, a brown oil is obtained (yield:
58%).
1H NMR (300 MHz, CDCl3) d: 1.26 (3H, t, J¼7.1 Hz,
CH2CH3), 2.16 (1H, ddd, J¼12.9, 11.1, 9.5 Hz, CHAHB,
C-6), 2.40–2.49 (1H, m, CHAHB, C-7), 2.52 (1H, d,
J¼18.0 Hz, CHAHB, C1), 2.74–2.88 (1H, m, CHAHB,
C-7), 2.97–2.99 (1H, m, CHAHB, C-6), 2.97 (1H, d,
J¼18.0 Hz, CHAHB, C1), 3.54 (1H, d, J¼18.5 Hz, CHAHB,
C-3), 4.10 (1H, d, J¼18.5 Hz, CHAHB, C-3), 4.23 (2H, q,
J¼7.1 Hz, CH2CH3). 13C NMR (75 MHz, CDCl3) d: 14.05
(CH2CH3), 31.57 (CH2, C-7), 31.66 (CH2, C-6), 48.52
3.16. Synthesis of (2S)-[L-(L)-menthyl]-5-oxopyrrol-
idine-2-carboxylate (29a)
To a solution of (2S)-pyroglutamic acid (6.46 g, 50 mmol)
in dry CH2Cl2 (100 mL, freshly distilled from CaH2) is
added L-(ꢀ)-menthol (6.26 g, 40 mmol, 0.8 equiv). After-
wards DMAP (1.52 g, 12.5 mmol, 0.25 g equiv) and
DCC (10.34 g, 50 mmol, 1 equiv) are added. The mix-
ture is allowed to stir for 16 h, the volatiles are removed
under reduced pressure and the product is purified
by chromatography. A yellow oil is obtained (yield:
93%).
(CH2, C1), 49.74 (CH2, C-3), 62.48 (CH2CH3), 68.95 (Cquat
,
C-7a), 171.53 (C]O), 174.44 (C]O), 208.87 (C]O). IR
(cmꢀ1) nmax: 1709 (C]O), 1738 (C]O), 1765 (C]O).
MS m/z (%): 212 (M+H+, 100). Chromatography: Hex/
EtOAc (35/65) Rf ¼0.16. HRMS calcd for C10H13NO4
(M+H+) 212.0917, found 212.0918.
1H NMR (300 MHz, CDCl3) d: 0.76 (3H, d, J¼6.9 Hz, CH3,
C-90), 0.90 (3H, d, J¼7.2 Hz, CH3, C-100), 0.92 (3H, d,
J¼6.3 Hz, CH3, C-70), 0.8–1.13 (3H, m, CHAHB, C-
20+CHAHB, C-50+CHAHB, C-60), 1.36–1.56 (2H, m, CH,
C10+CH, C-40), 1.64–1.74 (2H, m, CHAHB, C-50+CHAHB,
C-60), 1.84 (1H, septd, J¼7.1, 2.8 Hz, CH, C-80), 1.93–
2.01 (1H, m, CHAHB, C-20), 2.13–2.45 (1H, m, CHAHB,
C-3), 2.33–2.41 (2H, m, CH2, C-4), 2.43–2.55 (1H, m,
CHAHB, C-3), 4.61 (1H, dd, J¼8.7, 5.4 Hz, CH, C-2), 4.78
(1H, dt, J¼10.7, 4.4 Hz, CH, C-30), 5.98 (1H, br s, NH).
13C NMR (75 MHz, CDCl3) d: 16.33 (CH3, C-90), 20.82
(CH3, C-100), 22.04 (CH3, C-70), 23.40 (CH2, C-50), 25.13
(CH2, C-3), 26.41 (CH, C-80), 29.29 (CH2, C-4), 31.45
(CH, C10), 34.16 (CH2, C-60), 40.78 (CH2, C-20), 46.96
(CH, C-40), 55.48 (CH, C-2), 75.85 (CH, C-30), 171.64
(C]O), 177.68 (C]O). IR (cmꢀ1) nmax: 1711 (C]O, br),
2871, 2951, 3110, 3230. MS m/z (%): (ES, pos) 268
(M+H+, 53), 225 (7). Chromatography: Hex/EtOAc (30/
70) Rf ¼0.30. Polarimetry: [a]546 ꢀ77.3 (1.022 g/100 mL,
CH2Cl2, 27 ꢁC). HRMS calcd for C15H25NO3 (M+H+)
268.1907, found 268.1910.
3.15. Synthesis of 26 and 27
The procedure is the same as for the synthesis of derivatives
5. After work-up, a mixture of compounds 26 and 27 is ob-
tained. This mixture is treated with NaH in THF and stirred
at room temperature for 16 h. The work-up is the same as
described for the synthesis of 22. After chromatography
a brown oil is obtained (yield: 24%).
3.15.1. Synthesis of ethyl 3-oxo-2,3,5,8-tetrahydro-
8a(1H)-indolizine-carboxylate (27). H NMR (300 MHz,
1
CDCl3) d: 1.22 (3H, t, J¼7.0 Hz, CH2CH3), 1.95–2.06
(1H, m, CHAHB, C1), 2.18 (1H, br d, J¼15.9 Hz, CHAHB,
C-8), 2.28–2.51 (3H, m, CHAHB, C1+CH2, C-2), 2.96 (1H,
ddd, J¼15.9, 5.4 Hz, J¼1.9 Hz, CHAHB, C-8), 3.66 (1H,
dd, J¼19.0, 1.4 Hz, CHAHB, C-5), 4.14 (1H, dq, J¼10.9,
7.0 Hz, CHAHBCH3), 4.17 (1H, dq, J¼10.9, 7.0 Hz,
CHAHBCH3), 4.21 (1H, dd, J¼19.0, 2.5 Hz, CHAHB, C-5),

K. G. R. Masschelein et al. / Tetrahedron 63 (2007) 4712–4724
4723
3.17. Synthesis of (2S)-[(1R,2R,4S)-fenchyl]-5-oxopyr-
rolidine-2-carboxylate (29b)
calcd for C19H2835ClNO3 (M+H+) 354.1830, found
354.1823.
The procedure is identical as for the synthesis of 29a. White
crystals are obtained (yield: 54%).
3.19. Synthesis of [(1R,2R,4S)-fenchyl]-2-methylene-5-
oxotetrahydropyrrolizine-7a-carboxylate (31)
1H NMR (300 MHz, CDCl3) d: 0.78 (3H, s, CH3), 1.05 (3H,
s, CH3), 1.11 (3H, s, CH3), 1.22 (1H, d, J¼10.4 Hz, CHAHB,
C-60); 1.44–1.51 (1H, m, CHAHB, C-50), 1.60 (1H, d,
J¼10.4 Hz, CHAHB, C-60), 1.07–1.16 and 1.53–1.74 (4H,
m, CHAHB, C-50+CH2, C-70+CH, C-40), 2.17–2.32 (1H, m,
CHAHB, C-3), 2.35–2.42 (2H, m, CH2, C-4), 2.44–2.58
(1H, m, CHAHB, C-3), 4.29 (1H, dd, J¼8.2, 5.2 Hz, CH,
C-2), 4.42 (1H, d, J¼1.7 Hz, CH, C-20), 6.31 (1H, br s,
NH). 13C NMR (75 MHz, CDCl3) d: 19.38 (CH3), 20.19
(CH3), 25.23 (CH2, C-50), 25.81 (CH2, C-3), 26.68 (CH2,
C-60), 29.29 (CH2, C-4), 29.69 (CH3), 39.58 (Cquat, C-30),
41.34 (CH2, C-70), 48.35 (Cquat, C10), 48.44 (CH, C-40),
55.68 (CH, C-2), 87.60 (CH, C-20), 172.34 (C]O, lactam),
177.65 (C]O, ester). IR (cmꢀ1) nmax: 1709 (C]O), 1736
(C]O), 3432 (NH). MS m/z (%): (ES, Pos) 266 (M+H+,
100). Chromatography: Hex/EtOAc (20/80) Rf ¼0.31. Mp:
78.0–81.5 ꢁC. Polarimetry: [a]546 +39.60 (1.01 g/100 mL,
CH2Cl2, 27 ꢁC). HRMS calcd for C15H23NO3 (M+H+)
266.1751, found 266.1757.
The procedure is identical as for the synthesis of 22. In
the crude reaction mixture no diastereomeric excess was
observed. After purification (chromatography and crystalli-
sation) white crystals are obtained (yield: 84%, diastereo-
meric excess 12%).
1H NMR (300 MHz, CDCl3) d: Major (in italic), minor,
overlap (underlined): 0.74 (3H, s, CH3), 0.75 (3H, s, CH3),
1.01 (3H, s, CH3), 1.03 (3H, s, CH3), 1.11 (6H, s, CH3),
1.14–1.75 (14H, m, CH, C-40+CH2, C-50+CH2, C-60+CH2,
C-70), 2.08–2.20 (2H, m, CHAHB, C-7), 2.43–2.54 (4H, m,
CHAHB, C-6 and CHAHB, C1), 2.62–2.71 (2H, m, CHAHB,
C-7), 2.71–2.86 (2H, m, CHAHB, C-6), 3.06 (2H, pseudo t,
J¼14.2 Hz, CHAHB, C1), 3.73 (1H, d, J¼15.7 Hz, CHAHB,
C-3), 3.74 (1H, d, J¼15.7 Hz, CHAHB, C-3), 4.31 (2H, d,
J¼15.7 Hz, CHAHB, C-3), 4.36 (1H, s, CH, C-20), 4.37
(1H, s, CH, C-20), 5.06–5.10 (4H, m, C]CH2). 13C NMR
(75 MHz, CDCl3) d: Major (in italic), minor, overlap (under-
lined): 19.37 (CH3), 19.48 (CH3), 20.09 (CH3), 25.84 (CH2,
C-70), 26.84 (CH2, C-50), 29.63 (CH3), 31.86 (CH2, C-7),
33.55 (CH2, C-6), 33.63 (CH2, C-6), 39.52 (Cquat, C-30),
41.26 (CH2, C-60), 43.98 (CH2, C1), 44.26 (CH2, C1),
46.61 (CH2, C-3), 48.32 (CH, C-40), 48.38 (CH, C-40 of
Cquat, C10), 48.43 (CH, C-40 of Cquat, C10), 73.16 (Cquat, C-
7a), 88.02 (CH, C-20), 88.08 (CH, C-20), 109.28 (C]CH2),
145.55 (C]CH2), 173.56 (C]O), 173.70 (C]O), 174.10
(C]O), 174.20 (C]O). IR (cmꢀ1) nmax: 1709 (C]O),
1732 (C]O). MS m/z (%): (ES, Pos) 318 (M+H+, 100).
Chromatography: Hex/EtOAc (40/60) Rf ¼0.43. Mp: 214–
217 ꢁC. Polarimetry: [a]546 +21.93 (0.23 g/100 mL,
CH2Cl2, 27 ꢁC). HRMS calcd for C19H27NO3 (M+H+)
318.2064, found 318.2051.
3.18. Synthesis of [(1R,2R,4S)-fenchyl]-2-(2-chloro-
methyl-allyl)-5-oxopyrrolidine-2-carboxylate (30)
The procedure is identical as for the synthesis of 5a and 5b.
Upon work-up a mixture of 30 and 31 is obtained. In the
crude reaction mixture no diastereomeric excess was ob-
served. After purification (chromatography and crystallisa-
tion in hexanes) compound 30 is obtained as white crystals
(yield: 20%, diastereomeric excess 12%).
1H NMR (300 MHz, CDCl3) d: Major (in italic), minor,
overlap (underlined): 0.78 (6H, s, CH3), 1.03 (3H, s, CH3),
1.05 (3H, s, CH3), 1.08–1.19 (2H, m, CHAHB, C-70), 1.11
(6H, s, CH3), 1.22 (2H, d, J¼10.3 Hz, CHAHB, C-60),
1.40–1.54 (2H, m, CHAHB, C-70), 1.60 (2H, d, J¼10.3 Hz,
CHAHB, C-60), 1.66–1.72 (2H, m, CHAHB, C-50), 1.71
(2H, s, CH, C-40), 1.72–1.75 (2H, m, CHAHB, C-50), 2.16–
2.25 (2H, m, CHAHB, C-3), 2.38–2.43 (4H, m, CH2,
C-4), 2.46–2.55 (2H, m, CHAHB, C-3), 2.55 (2H, d,
J¼15.0 Hz, CHAHBC]CH2), 2.95 (2H, d, J¼15.0 Hz,
CHAHBC]CH2), 4.02 (4H, d, J¼0.6 Hz, CH2Cl), 4.38
(2H, t, J¼2.1 Hz, CH, C-20), 5.06 (1H, s, C]CHAHB),
5.07 (1H, s, C]CHAHB), 5.35 (2H, s, C]CHAHB), 6.38
(2H, s, NH). 13C NMR (75 MHz, CDCl3) d: Major (in italic),
minor, overlap (underlined): 19.81 (CH3), 19.91 (CH3),
20.64 (CH3), 20.72 (CH3), 26.12 (CH2, C-70), 26.96 (CH2,
C-50), 29.89 (CH3), 29.95 (CH2, C-4), 31.86 (CH2, C-3),
32.01 (CH2, C-3), 39.94 (Cquat, C-30), 41.60 (CH2, C-60),
41.77 (CH2, C-60), 42.01 (CH2HC]CH2), 48.35 (CH, C-
40), 48.53 (CH, C-40), 48.82 (Cquat, C10), 48.93 (Cquat, C10),
49.04 (CH2Cl), 65.41 (Cquat, C-2), 65.56 (Cquat, C-2),
88.58 (CH, C-20), 119.99 (C]CH2), 120.16 (C]CH2),
140.26 (C]CH2), 173.98 (C]O), 177.11 (C]O). IR
(cmꢀ1) nmax: 1699 (C]O), 1745 (C]O), 3193 (br NH).
MS m/z (%): (ES, pos) 354/356 (M+H+, 100). Chromato-
graphy: Hex/EtOAc (40/60) Rf ¼0.42. Mp: 95 ꢁC. Polari-
metry: [a]546 +30.41 (0.88 g/100 mL, CH2Cl2, 27 ꢁC). HRMS
Acknowledgements
We thank the BOF (Bijzonder Onderzoeksfonds Universiteit
Gent, Research Fund Ghent University), the IWT (Instituut
voor de Aanmoediging van Innovatie door Wetenschap en
Technologie in Vlaanderen, Institute for the Promotion of
Innovation by Science and Technology in Flanders) and
the FWO (Fonds voor Wetenschappelijk Onderzoek Vlaan-
deren, Fund for Scientific research Flanders) for financial
support of this research.
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