Synthesis of diversely functionalized pyrrolizidines and indolizidines using olefin ring-closing metathesis

Article abstract of DOI:10.1016/j.tet.2009.04.039

Various nitrogen-fused tricyclic compounds, having benzoindolizidine and benzopyrrolizidines ring systems were synthesized via ene-ene metathesis using the first and second-generation Grubbs catalyst. The ene-ene metathesis proceeded smoothly in refluxing

Full text of DOI:10.1016/j.tet.2009.04.039

Tetrahedron 65 (2009) 4846–4854
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of diversely functionalized pyrrolizidines and indolizidines
using olefin ring-closing metathesis
,
b
b
Raja Ben-Othman a, Mohamed Othman a , Kabula Ciamala , Michael Knorr ,
*
Carsten Strohmann c, Bernard Decroix a
a
´
URCOM, EA 3221, FR CNRS 3038, Universite du Havre, BP 540, 25 rue Philippe Lebon, 76058 Le Havre Cedex, France
b Institut UTINAM UMR CNRS 6213, Universite´ de Franche-Comte´, F-25030 Besançon Cedex, France
c Anorganische Chemie, Technische Universita¨t Dortmund, D-44227 Dortmund, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Various nitrogen-fused tricyclic compounds, having benzoindolizidine and benzopyrrolizidines ring
systems were synthesized via ene–ene metathesis using the first and second-generation Grubbs cat-
alyst. The ene–ene metathesis proceeded smoothly in refluxing CH2Cl2 with 3.0 mol % of G1, giving
good yields (78–86%) of the benzoindolizidine products 12a,b. The benzopyrrolizidine 6 was prepared
after optimization in 64% yield by using 5.0þ5.0 mol % of G2. The resulting olefin moiety of the in-
dolizidine framework is a suitable precursor for polyhydroxy structures via the Sharpless process. The
structures of the polyhydroxylated adducts were determined by 1H NMR spectra and single-crystal
X-ray analysis.
Received 22 January 2009
Received in revised form 2 April 2009
Accepted 9 April 2009
Available online 17 April 2009
Keywords:
Ene–ene metathesis
Isoindole
Benzoindolizidine
Benzopyrrolizidines
Crystal structure
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
targets of many synthetic efforts due to their wide range of bio-
logical and physiological properties (Fig. 2).
During the two past decades, the transition metal-catalyzed
metathesis reaction has emerged as one of the most powerful
methods in synthetic organic chemistry.1 The ring-closing me-
tathesis (RCM) has been widely used for the construction of het-
erocyclic compounds bearing a nitrogen atom at one of the ring
fused positions. In the majority of these syntheses the first and
second-generation olefin metathesis catalysts G1 and G2 and the
Hoveyda–Grubbs catalyst, G3, have been employed (Fig. 1).
For example, indolizidines and pyrrolizidines such as castano-
spermine, crispine A, crotarecine and certain natural and synthetic
analogues attracted special interest by virtue of their varied and
pharmaceutically useful biological actions as potential antiviral,
antitumor, specific inhibitors of protein kinases (Cdk4), and glyco-
sidase inhibition agents.2–4
Unfortunately many of these compounds are also toxic to hu-
man cells. Nevertheless, there is a need to prepare new alkaloid
analogues to allow a better understanding of the structure–activity
On the other hand, nitrogen-fused polycyclic alkaloids having
indolizidine (I), and pyrrolizidine (II) ring systems, have been the
HO
MesN
Ru
PCy3
Ru
MeO
OH
NMes
Cl
MesN
NMes
Cl
H
Cl
Cl
HO
Ru
N
N
I
MeO
Crispine A
N
Ph
Ph
Cl
Cl
PCy3
HO
Castanospermine
O
PCy3
G2
Coniceine
i-Pr
G1
O
G3
OH
HO
H
N
Figure 1. Ruthenium metathesis catalysts.
HO
N
N
NH
R
B
Crotanecine
II
* Corresponding author. Tel.: þ33 02 32 74 44 01; fax: þ33 02 32 74 43 91.
E-mail address: mohamed.othman@univ-lehavre.fr (M. Othman).
Figure 2.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.04.039

R. Ben-Othman et al. / Tetrahedron 65 (2009) 4846–4854
4847
Table 1
OH
OH
Cyclization of derivative 5 produced via Scheme 2
( )n
N
( )n
N
R
R
( )n
N
OH
and/or
OH
Catalysta,b
Solvent
Time (h)
5 (%)
6 (%)
7 (%)
R
Entry
1
2
3
4
5
6
7
8
G1 (5 mol %)
CH2Cl2
CH2Cl2
C2H4Cl2
C2H4Cl2
C2H4Cl2
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
24
40
35
10
10
Traces
d
20
20
30
30
34
d
d
d
20
25
20
70
d
d
d
d
d
d
G1 (5þ5 mol %)
G1 or G2 (5 mol %)
G2 (5þ5 mol %)
G3 (5 mol %)
G1 or G2 or G3 (5 mol %)
G2 (5 mol %)
G2 (10 mol %)
G3 (5 mol %)
G2 (5þ5 mol %)
G2 (5þ5þ5 mol %)
G3 (5þ5 mol %)
8þ12
A
B
C
24
O
4þ8
24
24
8
8
R1
d
42
40
44
64
62
60
( )n
CO2Et
N
R
R
d
9
24
Traces
d
N
10
11
12
4þ8
4þ8þ8
4þ8
d
D
O
E
O
d
Scheme 1. Retrosynthetic approach.
a
All the reactions were carried out under reflux and Argon.
In this study, ethylene was not required.
b
relationship (SAR) and to develop more potent, selective, and less
toxic drugs.
8. The synthesis of diolefinic phthalimidine 5 starts from the known
bicyclic lactam 1.7b Alkylation at the
-position relative to the ni-
a
However, among these analogues, only a few structures contain
trogen of the ring junction and subsequent reduction of the ester
function under standard conditions afforded the phthalimidine 3 in
64% yield after the two steps. Oxidation of alcohol 3 by PCC in
CH2Cl2 at room temperature produced the aldehyde 4 in 93%
yield.7b The thus isolated crude aldehyde 4 was then converted into
diolefinic 5 by using PPh3]CH2 (Ph3PCH3Br/tBuOK) in 73% yield, as
previously described by our group.7b With diolefinic phthalimidine
5 in hand, we were ready to test the ring-closing metathesis to form
the pyrrolizidine derivative 6.
RCM of 5 was investigated under various conditions (Table 1).
The reaction of 5 under the catalysis of 5 mol % G1 in CH2Cl2 at
reflux for 24 h gave 6 in a low yield of 20% along with the starting
material 5 in 40% yield (Table 1, entry 1). A similar result was
obtained when 5 was treated with 5 mol % G1 in CH2Cl2 for 8 h
followed by the addition of another portion of 5 mol % G1 with
continuous stirring for 12 h (Table 1, entry 2).
When CH2Cl2 was replaced by C2H4Cl2, 6 was obtained in 30%
yield along with a migrated double bond isomer 7 in 20% yield
(Table 1, entry 3). Migration of the double bond is dependent on the
temperature at which RCM was carried out. Increasing the tem-
perature yielded an increasing amount of 7. When toluene was used
for 24 h at reflux, rearrangement product 7 was isolated in 70%
yield, devoid of any sign of the expected benzopyrrolyzidine 6
(Table 1, entry 6). This isomerization seems to be catalyzed by
a ruthenium degradation product, probably a ruthenium hydride
species.9
a quaternary carbon at the a-position to the nitrogen at the ring
junction and/or a benzene ring at the junction with the five(six)-
membered ring.5,6 Among the efforts in this area and in connection
with our current research interests in the preparation of novel
biologically relevant nitrogenated and oxygenated compounds,7,8
we have recently delineated a convenient access to various new
indolizidine and pyrrolizidine benzanalogs by using enyne ring-
closing metathesis.7b
Pursuing our investigation on the synthesis of indolizidine and
pyrrolizidines benzanalogs, we describe herein the efficient con-
struction of new benzoindolizidines, benzopyrrolizidines, and their
polyhydroxy derivatives via the ene–ene ring-closing metathesis
reaction (RCM).
Our retrosynthetic strategy is outlined in Scheme 1. Benzoin-
dolizidines (pyrrolizidines) of type A and/or B may arise from the
syn-dihydroxylation of the unsaturated indolizidine (pyrrolizidine)
precursor C, which itself can be readily prepared via a ruthenium
catalyzed ring-closing metathesis (RCM) as the key step in our
synthetic strategy from diolefinic phthalimidine D. The latter
compound D is readily accessible from the well-known phthali-
midine E.
2. Results and discussion
2.1. Synthesis of benzopyrrolizidine derivatives using RCM
In order to prevent the migration of the double bond, the use of
additives in an RCM reaction has proved to be successful in several
cases. This inspired us to investigate the role of some additives on
the RCM reaction of 5. The investigated additives were tricyclo-
hexylphosphine oxide and 1,4-benzoquinone (Table 2). Tricyclo-
hexylphosphine oxide is an additive, which has been reported by
Prunet and co-workers10 to prevent olefin migration of a specific
substrate, did not prevent the isomerization of 5 (Table 2, entries 1
As depicted in Scheme 2, we envisaged that ring-closing me-
tathesis (RCM) of diolefinic phthalimidine 5 could provide a highly
functionalized tricyclic lactam 6 that may serve as a valuable pre-
cursor for polyhydroxylated benzopyrrolizidine compounds of type
CO2Et
OH
CHO
i, ii
iii
N
N
N
1
3
O
O
4
O
iv
Table 2
Influence of additives on the product distribution
Entryc
Additiveb
Solventa
5 (%)
6 (%)
7 (%)
1
2
3
4
Tricyclohexylphosphine oxide
Tricyclohexylphosphine oxide
1,4-Benzoquinone
Toluene
C2H4Cl2
Toluene
C2H4Cl2
d
10
60
28
d
65
20
v
30
<5
36
N
and/or
N
N
1,4-Benzoquinone
d
5
7
6
O
O
O
a
All the reactions were carried out at reflux under Argon.
b
c
Scheme 2. Reagents and conditions: (i) Ethyl iodide, K2CO3, CH3CN, reflux, 8 h, 78%;
(ii) LiBH4, THF, rt, 2 h, 82%; (iii) PCC, CH2Cl2, rt, 2 h, 93%; (iv) Ph3PCH3Br/tBuOK, THF, rt,
2 h, 73%; (v) G1 or G2.
In this study, 0.1 equiv (relative to 5) are used.
The ratio of the different products was determined by integration of the 1H NMR
spectra of the crude reaction mixtures.

4848
R. Ben-Othman et al. / Tetrahedron 65 (2009) 4846–4854
and 2). On the other hand, 1,4-benzoquinones, which are described
by Grubbs and co-workers11 to prevent olefin isomerization of
a number of allylic ethers and long-chain aliphatic alkenes, work
well in suppressing olefin migration during RCM reaction of sub-
strate 5, but without real improvement of the yield of the desired
pyrrolizidine 6. When 5 was reacted together with G2 (5 mol %) and
1,4-benzoquinone (10 mol %) in toluene, only trace amounts (<5%)
of 6 were obtained (Table 2, entry 3). When toluene was replaced by
C2H4Cl2, the 1,4-benzoquinone additive is also effective to prevent
the isomerization of 5 to 7 (Table 2, entry 4). Under these condi-
tions, 6 was obtained in 36% yield along with the starting material 5
in 28% yield. Additional catalyst loading (10 mol %) did not improve
the yield.
R1
R1
CO2Et
CO2Et
R
i
ii, iii
N
N
O
N
1
O
O
9a R1 =H
9b R1 = CO2Et
iv
9a R = CO2Et
10a R = CO2H
ii
2
4
1
R
3
10a R = CO2H
11a R =H
iii
N
O
12a,b
G2 and G3 were found to be superior catalysts for the reaction of
5 in CH2Cl2 at reflux; under these conditions 6 was isolated in 42
and 44% yields, respectively (Table 1, entries 7 and 9). Encouraged
by the above results, and to improve the yield of the desired
compound, the RCM reaction of 5 was carried out under various
conditions. We reacted this compound with 10 mol % (entry 8),
2ꢀ5 mol % (entry 10) and 3ꢀ5 mol % (entry 11) of catalyst G2. We
found that the reaction of 5, catalyzed by 2ꢀ5 mol % of G2 afforded 6
in 64% yield after column chromatography. It should be noted that
the use of the Hoveyda–Grubbs catalyst, G3 gave a similar result
(entry 12). In all cases the use of ethylene gas gave no significant
improvement.
Having successfully achieved the conversion of diene 5 into
pyrrolizidine 6, the next step consisted in the syn-dihydroxylation
of the olefin moiety of the pyrrolizidine framework. Submitted to
hydroxylation conditions (osmium tetroxide (OsO4)/N-methyl-
morpholine N-oxide (NMO)),12 compound 6 gave a complex crude
mixture, in which the expected dihydroxy pyrrolizidine 8 was only
the minor product (<10%) and could not be isolated. Unfortunately,
despite a variation of reaction times, solvent ratios, and tempera-
tures, no improvement concerning the overall yield of compound 8
could be achieved (Scheme 3).
Scheme 4. Reagents and conditions: (i) Allyl bromide (ethyl 4-bromocrotonate),
K2CO3, CH3CN, reflux, 8 h, 98% (94%); (ii) NaOH, EtOH/H2O, rt, 1 h, 85%; (iii) acetone,
reflux, 8 h, 83%; (iv) G1, CH2Cl2, reflux, 1 h, 12a, 83%, 12b, 86 (78)%.
conditions applied to 9a (1 h) and 9b (1.5 h)14 afforded the fused
compound 12b in 86 and 78% yields, respectively.
The structures of indolizidines 12 were determined by the 1H
and 13C NMR spectra, including DEPT programs and elemental
analyses. For example, the 1H NMR spectrum of 12b displayed the
methylene group of the –N–CH2-function as an AB system due to
the diastereotopy with a coupling constant of J¼13.2 Hz charac-
teristic of gem protons. More interestingly, the 13C NMR spectrum
showed the disappearance of two peaks corresponding to the
methylene carbons (–CH2– in the allyl groups) in 9a at
120 ppm, and revealed the presence of two tertiary carbons (–CH–)
corresponding to C2 and C3 of the olefin moiety in the indolizidine
d
¼117 and
framework of 12b at
d¼122 ppm.
The next stage for our synthesis strategy was the diaster-
eoselective dihydroxylation of the olefin moiety of the indolizidine
framework. Introduction of cis-dihydroxylation on 12a was carried
out using osmium tetroxide (OsO4, NMO) to give a mixture of the
corresponding diol derivatives 13 and 14 in 78% yield. Since this
mixture of diastereomers could not be separated by column chro-
matography, the mixture was converted into the corresponding
acetonide derivatives 15 and 16 using 2,2-dimetoxypropane and
APTS under conventional conditions.15 Column chromatography of
the resulting mixture provided 15 and 16 (15/16w1:2) in 77% yield.
The stereochemical assignments of the relative configurations of
the bishydroxylated products 13 and 14 were deduced from the 1H
NMR coupling constants of their derivatives 15 and 16. For example,
the 1H NMR spectra of the most abundant diastereomer (less polar)
16 reveals a doublet of doublets of doublets for the axial proton H1ax
Since we were unable to obtain a chromatographically pure
sample of the dihydroxy benzopyrrolizidine 8, we turned our at-
tention to the preparation of the polyhydroxy indolizidine
benzoanalogs.
2.2. Synthesis of polyhydroxylated benzoindolizidine
derivatives
The route we employed is shown in Scheme 4, where N-allyl
phthalimidine ethyl ester 1 was a-alkylated with allyl bromide or
with ethyl 4-bromocrotonate, using K2CO3 as base to gave the first
precursors 9a,b for the synthesis of the benzoindolizidines in 98
and 94% yields, respectively. Basic saponification of the ester
function of 9a under standard conditions followed by thermal
decarboxylation7b of the resulting acid 10a, gave the second pre-
cursor 11a for the RCM reaction in 70% yield after the two steps.
RCM13 was carried out on the substrate 11a, which cyclized
smoothly (1 h) at 40 ꢁC in CH2Cl2 with 3 mol % of the first genera-
tion Grubbs catalyst G1 to afford the lactam 12a. Silica gel column
chromatography was used to remove the catalyst, yielding the pure
tricyclic 12a in isolated yield of 83%. Similarly, the same reaction
(
d
¼1.48 ppm, Jgem¼14.0 Hz, JH1ax-H10b¼11.7 Hz, JH1ax-H2¼3.1 Hz) and
a doublet of doublets of doublets for the equatorial proton H1eq
(
d
¼2.65 ppm, Jgem¼14.0 Hz, JH1eq-H10b¼3.1 Hz, JHeq-H2¼2.3 Hz). The
different coupling constants support the proposed structure in
which the dihydroxylation occurred mainly from the face of the
double bond in a cis relationship with regard to H10b (Fig. 3).
In the same manner, the 1H NMR spectrum of 15 exhibits
a doublet of doublets of doublets for the axial proton H1ax
H10bax
Me
Me
O
Heq
Heq
H1eq
H4ax
O
HO
OH
Hax
Hax
2
1
O
O
3
i
N
4
N
Hax
H2eq
10b
N
N
5
H4eq
Hax
H1ax
Heq
6
H3ax
O
8
O
O
O
16
Detected in crude
Scheme 3. Reagents and conditions: (i) OsO4 cat, NMO, acetone:H2O 1:1, rt, 6 h.
Figure 3.

R. Ben-Othman et al. / Tetrahedron 65 (2009) 4846–4854
4849
H10bax
H1eq
H2O
(OsO3)-
H
H2ax
Hax
Heq
Hax
Hax
O
H4ax
O
OsO4
N
N
20
H3eq
2
1
O
O
+
+
3
4
N
H4eq
I
Heq
10b
II
N
Hax
Heq
O
Me
Me
H1ax
O
15
O
(OsO3)
HO
OH
N
H
N
O
OsO4
Figure 4.
III
IV
OR1
OR2
OR1
OR2
H
H
H
O
O
i,ii
N
N
N
N
+
N
O
+
O
O
H+
12a
12a
V
R1, R2 = H,14
R1, R2 = H,13
iii
, 16
= C(Me)2
R1, R2
R1, R2 = C(Me)2
, 15
Figure 5. First plausible mechanism for the formation of 12a.
OH
O
H
H
O
OH
iv
Compound 20, under dihydroxylation conditions (OsO4, NMO),
did not yield the desired dihydroxyindolizidines 18 and 19. Instead,
and unexpectedly, the compound formed in the reaction was
assigned the benzoindolizidone structure 12a on the basis of ele-
mental analyses and NMR spectra.
It is interesting to note that oxidation of tertiary amines to amides
andlactams iswell-knownforreagents suchasRuO4,19 (batho)2-Cu,20
MnO2,21 KMnO4,22 Hg(OAc)2,23and recently by OsO4.24
Two different mechanistic scenarios can be proposed to explain
the formation of 12a. First, the mechanism of this oxidation (Fig. 5)
is based on the mechanistic proposals for oxidation of amines by
OsO4 recently reported by Liotta and Sletten.24
N
18
N
17
Scheme 5. Reagents and conditions: (i) OsO4 cat, NMO, acetone:H2O 1:1, rt, 6 h, 78%;
(ii) DMP, PTSA cat, CH2Cl2, rt, 2 h, 15 25%, 16 52%; (iii) LiAlH4, THF, rt, 1 h, 45%; (iv) HCl,
EtOH, rt, 12 h.
(
d
¼1.45 ppm, Jgem¼13.3 Hz, JH1ax-H10b¼9.3 Hz, JH1ax-H2¼10.1 Hz).
The proton H1eq also appears as a doublet of doublet of doublet
(d
¼2.44 ppm, Jgem¼13.3 Hz, JH1eq-H10b¼3.9 Hz, JHeq-H2¼5.4 Hz).
These observations allow us to assign an axial relationship between
H2 and H10b (H2ax and H10bax) (Fig. 4).
The following step involved the reduction of the lactam car-
bonyl. Although the reduction of amide to amine has been disclosed
several times, some of these reported procedures (BH3$Me2S)16
were not reproducible in our hands. The best reagent to obtain 17
was LiAlH4 in THF according to the protocol developed by Greene
and co-workers;17 which gave the target molecule in a moderate
yield of 45% (Scheme 5). Finally, removal of the protecting group18
failed. The desired benzoindolizidine 18 could only be detected
spectroscopically in the highly complex spectrum of the crude
mixture. These reaction products decomposed after few minutes at
room temperature. Therefore, all attempts to isolate 18 were
unsuccessful.
In an alternative scenario, the mechanism for this oxidation is
based on the proposals for the action of chiral ligands (AD-mix-
AD-mix- ) in asymmetric oxidation. For example, the action of AD-
mix- is based on a coordination of the nitrogen atom of the qui-
a or
b
a
nuclidine core on the metal center followed by an asymmetrical
oxidation of the double bond by effect of proximity.
In our case, it is probable that the tertiary amine of the substrate
20 coordinates to osmium tetroxide and that the transitory species
A resulting from this complexation uses a process of insertion of an
oxygen on the adjacent benzylic CH2 to form the OH group B, which
will be oxidized on a carbonyl function in the last step (Fig. 6).25
To complete our study, and in order to obtain polyhydroxy
We have also investigated an alternative route leading to the
polyhydroxylated indolizidines, starting from 12a. The pathways of
these transformations are summarized in Scheme 6. We thought
that the dihydroxyindolizidines 18 and 19 could be derived from
indolizidine 20 by cis-dihydroxylation and, in turn, 20 could be
prepared from 12a by LiAlH4 reduction. Thus, treatment of 12a by
the same methodology reported for the reduction of 17 gave 20 in
moderate yield of 55%.
indolizidines with a quaternary carbon at the
nitrogen at the ring junction, cis-hydroxylation of 12b was
a-position to the
O
O
Os
H
O
O
OsO4
N
+
N
Coordination
A
20
OH
+
OH
H
H
i
H
OH
Oxo
OH
ii
12a
N
Insertion
X
N
N
20
19
18
O
OH
O
O
Os
Oxidation
- OsO3H2
N
N
O
N
+
12a
B
O
12a
Scheme 6. Reagents and conditions: (i) LiAlH4, THF, rt, 1 h, 55%; (ii) OsO4 cat, NMO,
acetone:H2O 1:1, rt, 6 h, 52%.
Figure 6. Second plausible mechanism for the formation of 12a.

4850
R. Ben-Othman et al. / Tetrahedron 65 (2009) 4846–4854
OH
OH
EtO2C
i
ii
EtO2C
EtO2C
N
N
OH
OH
+
N
i
N
N
N
20
12a
O
26
12b
22
21
O
O
O
Scheme 8. Reagents and conditions: (i) LiAlH4, THF, rt, 1 h, 55%; (ii) H2, Pd/C, MeOH, rt,
6 h, 65%.
ii
OH
O
O
HO
HO
EtO2C
O
iii
O
It should be noted that in both cases a similar poor diaster-
OH
eofacial selectivity (ds¼33%) was also observed when asymmetric
N
N
N
X
oxidation was employed (AD-mix-a or AD-mix-b
),12 which dem-
25
24
23
O
onstrates control of the structure of the substrate for the dihy-
droxylation reaction. It should also be noted that the reduction of
the unprotected diol 22 gave a complex mixture of products was
from which the expected polyhydroxy indolizidine 25 could not be
isolated.
Scheme 7. Reagents and conditions: (i) OsO4 cat, NMO, acetone:H2O 1:1, rt, 6 h, 83%;
(ii) DMP, PTSA cat, CH2Cl2, rt, 2 h, 23 73%; (iii) LiAlH4, THF, rt, 1 h, 39%.
OsO4 Syn Approch when R = H
Next, and after protection of the major (less polar) diastereomer
diol 22 as acetonide 23, the lactam and the ester functions were
reduced by treatment with LiAlH4 to afford the desired compound
24 in 39% yield. As previously observed, removal of protecting
group failed to give us the desired benzoindolizidine 25.
Our final aim in this series was now the synthesis of the ben-
zoindolizidine 26 analogue of crispine A. This alkaloid has been
isolated in 2002 from , a common invasive plant occurring in Asia
and Europe. It is of interest to note that this indolizidine alkaloid
was found to exhibit superior antitumor activity against SKOV3, KB,
and HeLa human cancer lines.27 Because of its potent antitumor
activity, and in order to understand the structure–activity re-
lationship (SAR) as well as to improve the efficacy of this novel anti-
cancer agent, various analogues of crispine A were synthesized.
The route employed is outlined in Scheme 8, where the amide
12a was reduced to the amine 20 according to the method reported
previously. Next, catalytic hydrogenolysis28 of 20 efficiently affor-
ded the benzoindolizidine derivative 26 in 65% yield. The spec-
tropic data of 26 hydrochloride salt were in excellent agreement
with those already reported.29
R
Syn/Anti = 2/1
N
Anti Approch when R = CO2Et
Syn/Anti = 1/2
O
OsO4
Figure 7.
performed under the same above conditions and yielded a chro-
matographically separable mixture of two diastereoisomers 21 and
22 in 83% yield and again in modest diastereoselectivity (ds¼33%)
(Scheme 7).
Interestingly, the stereoselectivity of the syn-dihydroxylation of
the indolizidines 12 with OsO4 proved to be dependent on the
nature of the group at C10b (H in 12a and CO2Et in 12b). Thus,
whereas the dihydroxylation of 12a occurred mainly from the face
of the double bond in a syn relationship with regard to H10b (Fig. 7),
leading to a 25:50 mixture of the 15/16 diastereomeric diols, the
same reaction from the indolizidine 12b was also poorly diaster-
eoselective and in favor of the dihydroxylation anti to the bulky
ethyl ester group at the carbon C10b, providing a 25:50 mixture of
diols 21/22 (Fig. 7).
3. Conclusion
To confirm this result, a single crystal of the minor diastereomer
21 was subjected to an X-ray diffraction analysis.26 This structural
analysis depicted in Figure 8 confirms a cis disposition between the
ester function and the two hydroxyl groups on carbon atoms C(6)
and C(7), the torsion angle O(4)–C(7)–C(6)–O(3) being 60.27ꢁ.
In summary, the results reported herein demonstrate that ni-
trogen-heterocycles such as benzoindolizidines or benzopyrrolizi-
dines can easily be synthesized by using ene–ene ring-closing
metathesis. Under syn-dihydroxylation reaction conditions they
lead to a variety of interesting polyhydroxy systems. Furthermore
the synthetic strategy presented constitutes an efficient route to
new polyhydroxy benzoindolizidines bearing
a
quaternary
hydroxymethyl group. All these attributes make this strategy very
interesting and quite attractive for the design and synthesis of
a wide variety of polyhydroxylated indolizidines including alka-
loids comprising different substituents and stereochemistry with
promising pharmacological profiles.
4. Experimental part
4.1. General
All melting points were measured on a Boetius micro hotstage
and are uncorrected. 1H and 13C NMR spectra were recorded, re-
spectively, at 200 and 50 MHz on a Brucker AC-200. The infrared
spectra were recorded on a Perkin–Elmer FT-IR paragon 1000
spectrometer. Thin-layer chromatography (TLC) was performed
with aluminum plates (0.20 mm) precoated with fluorescent silica
gel, using EtOAc/hexane as eluent. Reaction components were then
visualized under UV light and dipped in a Dragendorff solution.
Silica gel (230–400 mesh) was used for flash chromatography
Figure 8. Thermal ellipsoid plot of the molecular structure of 21. Only one of two
independent molecules in the asymmetric unit is shown. Except of H4 and H3 the H
atoms are omitted for clarity. Selected bond lengths [Å] and angles [ꢁ]: C(4)–N(1)
1.463(2), C(4)–C(15) 1.520(3), C(15)–C(10) 1.387(3), C(10)–C(9) 1.475(3), C(9)–O(5)
1.235(2), C(9)–N(1) 1.354(2), N(1)–C(8) 1.448(2), C(8)–C(7) 1.527(3), C(7)–C(6)
1.5229(2), C(6)–C(5) 1.522(3), C(5)–C(4) 1.541(3), C(4)–C(5)–C(6) 111.80(15), C(5)–
C(4)–N(1) 108.84(14), C(4)–N(1)–C(8) 119.84(14), C(4)–N(1)–C(9) 113.97(15), N(1)–
C(9)–C(10) 106.53(15), N(1)–C(9)–O(5) 124.60(18), C(10)–C(15)–C(4) 109.13(16).

R. Ben-Othman et al. / Tetrahedron 65 (2009) 4846–4854
4851
separations. Gas chromatography–mass spectrometry (GC–MS)
was performed with a GC apparatus equipped with a 25 m capillary
column, at 90 ꢁC for 2 min, then 10 ꢁC/min up to 290 ꢁC. Some re-
actions were performed under an inert atmosphere. The elemental
analyses were carried out by the microanalysis laboratory of INSA,
F-76130 Mt St Aignan, France. Abbreviations: dd¼doublet of dou-
blets, ddd¼doublet of doublet of doublet, m¼multiplet, s¼singlet,
d¼doublet, q¼quartet, t¼triplet, br s¼broad singlet. Grubbs cata-
lysts G1, G2, and G3 were purchased from Sigma–Aldrich. Tetrahy-
drofuran was dried by distillation from sodium/benzophenone.
Dichloromethane and dichloroethane were dried by distillation
from calcium hydride, toluene was distilled from sodium, and
acetonitrile was dried by distillation from P2O5.
116.5 (CH2),117.7 (CH2),122.0 (CH),123.8 (CH),128.4 (CH),132.0 (CH),
132.3 (Cq), 134.0 (CH), 139.8 (CH), 147.8 (Cq), 168.8 (C]O); LRMS m/z
ꢃ
227 (Mþ , 5),199 (16),198 (Base). Anal. Calcd for C15H17NO (227.31): C,
79.26; H, 7.54; N, 6.16. Found: C, 79.68; H, 7.82; N, 6.45.
4.3. General procedure used for the ring-closing metathesis
reaction
To a solution of 5 (68 mg, 0.3 mmol) in dichloromethane (5 mL)
was added G2 (12.7 mg, 5 mol %) under argon. After the mixture
was stirred under reflux for 4 h, another portion of G2 (12.7 mg,
5 mol %) was added followed by continuous stirring (8 h); the
resulting solution was concentrated and purified by flash-column
chromatography on silica gel (cyclohexane/ACOEt 75:25) to give
the benzopyrrolizidine 6.
4.2. Preparation of benzopyrrolizidines
4.2.1. 2-Allyl-1-ethyl-3-oxo-2,3-dihydro-1H-isoindole-1-
carboxylic acid ethyl ester (2)
4.3.1. 9b-Ethyl-2,3,9b-dihydro-pyrrolo[2,1-a]isoindol-5-one (6)
Yellow liquid; yield: 64%; IR (
(200 MHz, CDCl3, 25 ꢁC)
n
, cmꢂ1, CHCl3) 1681.7; 1H NMR
This product was prepared according to our previous work.7b
d
0.77 (t, J¼7.8 Hz, 3H), 1.86 (q, J¼7.8 Hz,
Viscous liquid; yield: 78%; IR (
n
, cmꢂ1, CHCl3) 1732.4, 1688.3; 1H
0.39 (t, J¼7.0 Hz, 3H), 1.14 (t,
2H), 3.94 (dt, J¼2.3, 15.6 Hz, 1H), 4.55 (dt, J¼2.3, 15.6 Hz, 1H), 5.86
NMR (200 MHz, CDCl3, 25 ꢁC)
d
(dt, J¼2.3, 6.2 Hz, 1H), 6.03 (dt, J¼2.3, 6.2 Hz, 1H), 7.32–7.61 (m, 3H),
J¼7.0 Hz, 3H), 2.23 (dq, J¼7.8, 15.8 Hz, 1H), 2.45 (dq, J¼7.8, 15.8 Hz,
1H), 3.91–4.23 (m, 4H), 5.08–5.31 (m, 2H), 5.82–6.06 (m, 1H), 7.36–
7.59 (m, 3H), 7.81 (d, J¼6.2 Hz, 1H); 13C NMR (50 MHz, CDCl3, 25 ꢁC)
7.78 (d, J¼7.8 Hz, 1H); 13C NMR (50 MHz, CDCl3, 25 ꢁC)
d 8.7 (CH3),
31.9 (CH2), 51.7 (CH2), 80.2 (Cq), 121.9 (CH), 124.8 (CH), 128.5 (CH),
129.9 (CH), 132.6 (2CH), 132.8 (Cq), 150.9 (Cq), 176.0 (C]O); LRMS
ꢃ
d
6.9 (CH3), 14.2 (CH3), 25.9 (CH2), 44.3 (CH2), 62.2 (CH2), 72.6 (Cq),
m/z 199 (Mþ , 3), 170 (86), 115 (Base). Anal. Calcd for C13H13NO
118.1 (CH2), 121.7 (CH), 124.0 (CH), 129.2 (CH), 132.2 (CH), 133.6
(199.25): C, 78.36; H, 6.58; N, 7.03. Found: C, 78.81; H, 6.90; N, 7.35.
(CH), 143.8 (2Cq), 169.3 (C]O), 171.2 (C]O); LRMS m/z 273
ꢃ
(Mþ ꢂ29, 1), 201 (18), 200 (Base). Anal. Calcd for C16H19NO3
4.3.2. 2-(Prop-1-enyl)-3-ethyl-3-vinyl-2,3-dihydro-1H-
(273.33): C, 70.31; H, 7.01; N, 5.12. Found: C, 70.69; H, 7.32; N, 5.39.
isoindol-1-one (7)
Yellow solid; yield: 70%; mp 87–89 ꢁC; IR (
n
, cmꢂ1, CHCl3)
1
4.2.2. 2-Allyl-3-ethyl-3-hydroxymethyl-2,3-dihydro-1H-
isoindol-1-one (3)
1685.3; H NMR (200 MHz, CDCl3, 25 ꢁC)
d
0.28 (t, J¼7.0 Hz, 3H),
1.71 (dd, J¼1.5, 6.2 Hz, 3H), 1.97–2.43 (m, 2H), 5.21 (dd, J¼3.1,
10.9 Hz, 1H), 5.30 (dd, J¼3.1, 18.0 Hz, 1H), 5.53 (dq, J¼6.2, 14.8 Hz,
1H), 5.79 (dd, J¼10.9, 18.0 Hz, 1H), 6.68 (dd, J¼1.5, 14.8 Hz, 1H),
7.12–7.28 (m, 1H), 7.31–7.53 (m, 2H), 7.78 (d, J¼7.0 Hz, 1H); 13C NMR
This product was prepared according to our previous work.7b
White solid; yield: 82%; mp 88–90 ꢁC; IR (
n
, cmꢂ1, CHCl3) 3426.8,
1
1680.1; H NMR (200 MHz, CDCl3, 25 ꢁC)
d
0.36 (t, J¼7.0 Hz, 3H),
1.81–1.97 (m, 2H), 2.32–2.49 (m, 1H), 3.73–3.91 (m, 3H), 4.22–4.36
(m, 1H), 5.10–5.35 (m, 2H), 5.88–6.11 (m, 1H), 7.28–7.58 (m, 3H),
(50 MHz, CDCl3, 25 ꢁC)
d 6.7 (CH3), 16.5 (CH3), 26.6 (CH2), 70.2 (Cq),
110.4 (CH), 115.9 (CH2), 121.8 (CH), 122.1 (CH), 123.9 (CH), 128.5
7.73 (d, J¼7.83 Hz, 1H); 13C NMR (50 MHz, CDCl3, 25 ꢁC)
d
6.9 (CH3),
(CH), 132.6 (CH), 140.1 (CH), 148.0 (2Cq), 166.9 (C]O); LRMS m/z
ꢃ
25.0 (CH2), 42.4 (CH2), 66.6 (CH2), 71.2 (Cq), 117.8 (CH2), 121.3 (CH),
123.8 (CH), 128.6 (CH), 132.0 (CH), 133.0 (Cq), 134.4 (CH), 146.4 (Cq),
227 (Mþ , <1), 132 (Base). Anal. Calcd for C15H17NO (227.31): C,
79.26; H, 7.54; N, 6.16. Found: C, 79.69; H, 7.84; N, 6.44.
ꢃ
169.4 (C]O); LRMS m/z 231 (Mþ , 2.5), 202 (13), 200 (Base). Anal.
Calcd for C14H17NO2 (231.30): C, 72.70; H, 7.41; N, 6.06. Found: C,
73.12; H, 7.69; N, 6.34.
4.4. Preparation of benzoindolizidines
4.4.1. 1,2-Diallyl-3-oxo-2,3-dihydro-1H-isoindole-1-carboxylic
acid ethyl ester (9a)
4.2.3. 2-Allyl-1-ethyl-3-oxo-2,3-dihydro-1H-isoindole-1-
carbaldehyde (4)
This product was prepared according to our previous work.7b
This product was prepared according to our previous work.7b
Yellow oil; yield: 98%; IR (
(200 MHz, CDCl3, 25 ꢁC)
n
, cmꢂ1, CHCl3) 1732.5,1690.2; 1H NMR
1.09 (t, J¼7.0 Hz, 3H), 3.96 (dd, J¼6.2,
Viscous liquid; yield: 93%; IR (
n
, cmꢂ1, CHCl3) 1732.3, 1692.4; 1H
d
NMR (200 MHz, CDCl3, 25 ꢁC)
d
0.36 (t, J¼7.0 Hz, 3H), 1.91–2.48 (m,
14.8 Hz, 1H), 3.12 (dd, J¼6.2, 14.8 Hz, 1H), 3.92–4.23 (m, 4H), 4.78–
2H), 3.66 (dd, J¼7.8, 14.8 Hz, 1H), 4.46–4.65 (m, 1H), 5.08–5.32 (m,
2H), 5.67–5.94 (m,1H), 7.18 (d, J¼7.0 Hz,1H), 7.38–7.60 (m, 2H), 7.81
5.29 (m, 5H), 5.78–6.61 (m, 1H), 7.33–7.53 (m, 3H), 7.76 (d, J¼7.0 Hz,
1H); 13C NMR (50 MHz, CDCl3, 25 ꢁC)
d 13.8 (CH3), 37.2 (CH2), 44.1
(d, J¼7.0 Hz, 1H), 9.01 (s, 1H); 13C NMR (50 MHz, CDCl3, 25 ꢁC)
d
6.2
(CH2), 62.0 (CH2), 71.2 (Cq), 117.7 (CH2), 120.1 (CH2), 121.7 (CH),
123.6 (CH), 129.0 (CH), 129.9 (CH), 131.7 (Cq), 132.0 (CH), 133.4 (CH),
(CH3), 22.0 (CH2), 43.1 (CH2), 77.7 (Cq), 120.3 (CH2), 122.7 (CH),
124.3 (CH), 129.9 (CH), 132.8 (CH), 133.0 (CH), 133.1 (Cq), 139.6 (Cq),
ꢃ
143.5 (Cq), 168.7 (C]O), 170.1 (C]O); LRMS m/z 285 (Mþ , 10), 244
ꢃ
169.2 (C]O), 196.6 (C]O); LRMS m/z 229 (Mþ , <1), 200 (Base), 199
(98), 212 (Base). Anal. Calcd for C17H19NO3 (285.35): C, 71.56; H,
6.71; N, 4.91. Found: C, 71.95; H, 6.99; N, 5.20.
(85). Anal. Calcd for C14H15NO2 (229.28): C, 73.37; H, 6.59; N, 6.11.
Found: C, 73.75; H, 6.88; N, 6.38.
4.4.2. 2-Allyl-1-((E)-3-ethoxycarbonyl-allyl)-3-oxo-2,3-dihydro-
1H-isoindole-1-carboxylic acid ethyl ester (9b)
4.2.4. 2-Allyl-3-ethyl-3-vinyl-2,3-dihydro-1H-isoindol-1-one (5)
This product was prepared according to our previous work.7b
This product was prepared according to our previous work.7b
Colorless oil; yield: 73%; IR (
n
, cmꢂ1, CHCl3) 1678.4; 1H NMR
Colorless liquid; yield: 94%; IR (n
, cmꢂ1, CHCl3) 1733.4, 1698.1,
1
(200 MHz, CDCl3, 25 ꢁC)
d
0.39 (t, J¼7.0 Hz, 3H), 2.10 (q, J¼7.0 Hz, 2H),
1691.3; H NMR (200 MHz, CDCl3, 25 ꢁC)
d 1.04–1.26 (m, 6H), 3.12
3.92 (dd, J¼6.2, 14.8 Hz, 1H), 4.04 (dd, J¼6.2, 14.8 Hz, 1H), 5.05–5.41
(m, 4H), 5.68 (dd, J¼10.1, 17.2 Hz, 1H), 5.82–6.30 (m, 1H), 7.19 (d,
J¼7.0 Hz, 1H), 7.33–7.57 (m, 2H), 7.80 (d, J¼7.0 Hz, 1H); 13C NMR
(dd, J¼7.0, 15.6 Hz, 1H), 3.30 (ddd, J¼1.5, 7.0, 15.6 Hz, 1H), 3.94–4.16
(m, 6H), 5.09–5.35 (m, 2H), 5.67–5.79 (d, J¼15.6 Hz, 1H), 5.80–6.31
(m, 1H), 6.19 (dt, J¼7.0, 15.6 Hz, 1H), 7.38–7.58 (m, 3H), 7.80–7.84
13
(50 MHz, CDCl3, 25 ꢁC)
d
7.2 (CH3), 26.3 (CH2), 42.9 (CH2), 70.2 (Cq),
(m, 1H); C NMR (50 MHz, CDCl3, 25 ꢁC)
d
14.1 (CH3), 14.4 (CH3),

4852
R. Ben-Othman et al. / Tetrahedron 65 (2009) 4846–4854
36.1 (CH2), 44.5 (CH2), 60.7 (CH2), 62.7 (CH2), 71.1 (Cq), 118.4 (CH2),
121.8 (CH), 124.5 (CH), 126.4 (CH), 129.8 (CH), 131.9 (Cq), 132.6 (CH),
133.6 (CH), 140.2 (CH), 143.2 (Cq), 165.6 (C]O), 169.0 (C]O), 170.3
4.6. Dihydroxylation of indolizidine 12a,b
To a solution of the enamide 12a,b (1 mmol) in a mixture (1:1) of
acetone and water (6 mL) was added dropwise a commercially
available aqueous solution (4%) of osmium tetroxide (0.3 mL), im-
mediately followed by addition of NMO (0.14 g, 3.2 mmol). The
mixture was stirred at room temperature until total disappearance
of starting material was observed. Na2S2O4 (0.2 g, 1.1 mmol) was
then added and the mixture was stirred for 15 min. Acetone was
removed and the aqueous phase was extracted five times with
EtOAc. The organic phase was dried with MgSO4 and concentrated
under reduced pressure. The residue was purified by flash-column
chromatography on silica gel (cyclohexane/EtOAc 40:60) to give the
diols 13 and 14 or 21 and 22.
ꢃ
(C]O); LRMS m/z 357 (Mþ , 10), 284 (58), 244 (Base). Anal. Calcd for
C20H23NO5 (357.41): C, 67.21; H, 6.49; N, 3.92. Found: C, 67.49; H,
6.78; N, 4.20.
4.4.3. 1,2-Diallyl-3-oxo-2,3-dihydro-1H-isoindole-1-carboxylic
acid (10a)
This product was prepared according to our previous work.7b
White solid;yield:85%;mp138–140 ꢁC;IR(
n
, cmꢂ1, CHCl3)2979.2,
1
1727.9, 1689.4; H NMR (200 MHz, CDCl3, 25 ꢁC)
d
2.09 (dd, J¼6.2,
14.8 Hz,1H), 3.18 (dd, J¼4.7,14.8 Hz,1H), 4.10 (dd, J¼6.2,15.6 Hz), 4.20
(dd, J¼6.2, 15.6 Hz, 1H), 4.84–5.27 (m, 5H), 5.82–6.02 (m, 1H), 7.37–
7.58 (m, 3H), 7.76 (d, J¼7.0 Hz,1H),11.07 (br s,1H); 13C NMR (50 MHz,
CDCl3, 25 ꢁC)
d
37.4 (CH2), 44.9 (CH2), 72.1 (Cq), 118.5 (CH2), 120.7
4.6.1. 2,3-Dihydroxy-1,3,4,10b-tetrahydro-2H-pyrido[2,1-a]-
(CH2), 122.4 (CH), 124.4 (CH), 129.6 (CH), 130.0 (CH), 131.7 (Cq), 132.6
isoindol-6-one (13) and (14)
(CH),133.3 (CH),143.6 (Cq),169.9 (C]O),173.6 (C]O); LRMS m/z 212
Viscous liquid; yield: 78%; IR (
n
, cmꢂ1, CHCl3) 3390.0, 1675.4; 1H
1.24 (dd, J¼11.4, 13.1 Hz, 1H), 2.34
ꢃ
(Mþ ꢂ45, 2), 173 (Base), 131 (52). Anal. Calcd for C15H15NO3 (257.29):
NMR (200 MHz, CDCl3, 25 ꢁC)
d
C, 70.02; H, 5.88; N, 5.44. Found: C, 70.4; H, 6.16; N, 5.73.
(dt, J¼3.5, 4.1, 13.1 Hz, 1H), 2.94–3.06 (m, 1H), 3.38 (br s, 1H), 3.87–
3.95 (m, 2H), 4.18 (dd, J¼5.4, 11.7 Hz, 1H), 4.35–4.04 (m, 1H), 4.54
(dd, J¼3.1, 11.7 Hz, 1H), 7.21–7.34 (m, 3H), 7.61 (d, J¼7.0 Hz, 1H); 13C
4.4.4. 2,3-Diallyl-2,3-dihydro-isoindol-1-one (11a)
This product was prepared according to our previous work.7b
NMR (50 MHz, CDCl3, 25 ꢁC)
d 35.9 (CH2), 39.1 (CH2), 52.6 (CH), 67.3
Yellow oil; yield: 85%; IR (
n
, cmꢂ1, CHCl3) 1677.2; 1H NMR
(CH), 68.3 (CH), 121.8 (CH), 123.4 (CH), 127.9 (CH), 131.1 (CH), 132.2
ꢃ
(200 MHz, CDCl3, 25 ꢁC)
d
2.42–2.90 (m, 2H), 3.70 (dd, J¼7.8,
(Cq), 145.6 (Cq), 166.1 (C¼O); LRMS m/z 219 (Mþ , 45), 182 (31), 103
15.6 Hz, 1H), 4.52–4.80 (m, 2H), 4.87–5.51 (m, 5H), 5.70–5.90 (m,
(Base). Anal., Calcd for C12H13NO3 (219.24): C, 65.74; H, 5.98; N,
6.39. Found: C, 66.16; H, 6.29; N, 6.69.
1H), 7.32–7.60 (m, 3H), 7.82 (dd, J¼2.4, 9.3 Hz, 1H); 13C NMR
(50 MHz, CDCl3, 25 ꢁC)
d 29.9 (CH2), 35.4 (CH2), 43.0 (CH), 118.1
(CH2), 119.5 (CH2), 122.6 (CH), 123.8 (CH), 128.4 (CH), 131.5 (2CH),
4.6.2. 2,3-Dihydroxy-6-oxo-1,2,3,4-tetrahydro-6H-pyrido
ꢃ
132.5 (Cq), 133.5 (CH), 145.1 (Cq), 168.4 (C]O); LRMS m/z 213 (Mþ
,
[2,1-a]isoindole-10b-carboxylic acid ethyl ester (21)
4), 172 (Base), 132 (37). Anal. Calcd for C14H15NO (213.28): C, 78.84;
H, 7.09; N, 6.57. Found: C, 79.22; H, 7.38; N, 6.85.
White solid; yield 27%; mp 183–185 ꢁC; IR (
n
, cmꢂ1, CHCl3)
1.22 (t,
1
3428.7, 1738.6, 1690.1; H NMR (200 MHz, CDCl3, 25 ꢁC)
d
J¼7.0 Hz, 3H), 1.68–1.80 (m, 1H), 2.88 (dd, J¼3.9, 12.5 Hz, 1H), 3.28
(dd, J¼2.3, 14.8 Hz, 1H), 3.52 (br s, 1H), 3.81–3.86 (m, 1H), 4.06–4.27
4.5. General procedure used for the ring-closing metathesis
reaction
(m, 3H), 4.53 (dd, J¼2.3, 14.8 Hz, 1H), 7.41–7.54 (m, 3H), 7.77 (d,
13
J¼8.6 Hz, 1H); C NMR (50 MHz, CDCl3, 25 ꢁC)
d 14.4 (CH3), 36.2
(CH2), 43.2 (CH2), 62.9 (CH2), 67.2 (CH), 68.4 (CH), 68.7 (Cq), 122.1
(CH), 124.4 (CH), 129.6 (CH), 131.0 (CH), 132.5 (Cq), 144.3 (Cq), 168.5
To 1 mmol of 9a,b or 11a dissolved in5 mLofdry dichloromethane
under argon, was added 3 mol % of the Grubbs first generation cata-
lyst, G1. The mixture was refluxed until completion (z1 h). Evapo-
ration of the solvent and purification by column chromatography
(cyclohexane/EtOAc 75:25) yielded the corresponding diene.
ꢃ
(C]O), 169.8 (C]O); LRMS m/z 219 (Mþ ꢂ72, 14), 200 (Base), 103
(78). Anal. Calcd for C15H17NO5 (291.31): C, 61.85; H, 5.88; N, 4.81.
Found: C, 62.23; H, 6.19; N, 5.13.
4.6.3. 2,3-Dihydroxy-6-oxo-1,2,3,4-tetrahydro-6H-pyrido-
4.5.1. 1,10b-Dihydro-4H-pyrido[2,1-a]isoindol-6-one (12a)
[2,1-a]isoindole-10b-carboxylic acid ethyl ester (22)
Colorless solid, yield: 83%; mp 86–88 ꢁC; IR (
n
, cmꢂ1, CHCl3)
White solid; yield: 56%; mp 177–178 ꢁC; IR (
n
, cmꢂ1, CHCl3)
1.23 (t,
1
1
1673; H NMR (200 MHz, CDCl3, 25 ꢁC):
d
1.89 (m, 1H), 2.67–2.79
3448.2, 1734.0, 1689.5; H RMN (200 MHz, CDCl3, 25 ꢁC)
d
(m, 1H), 3.82 (dd, J¼3.1, 18.0 Hz, 1H), 4.42 (dd, J¼4.7, 10.9 Hz, 1H),
J¼7.0 Hz, 3H), 1.54 (d, J¼14.0 Hz, 1H), 2.28 (br s, 1H), 3.23 (br s, 1H),
3.25 (dd, J¼3.1, 14.0 Hz, 1H), 3.42 (t, J¼12.5 Hz, 1H), 3.62–3.76 (m,
1H), 4.01–4.31 (m, 3H), 4.44 (dd, J¼6.2, 12.5 Hz, 1H), 7.43–7.65 (m,
4.61 (dd, J¼3.1, 18.0 Hz, 1H), 5.81–5.93 (m, 2H), 7.40–7.56 (m, 3H),
7.85 (d, J¼7.0 Hz, 1H); 13C NMR (50 MHz, CDCl3, 25 ꢁC)
d 30.9 (CH2),
13
40.5 (CH2), 55.4 (CH), 122.7 (CH), 123.7 (CH), 124.4 (CH), 124.7 (CH),
129.0 (CH), 132.1 (CH), 133.3 (C), 146.8 (C), 167.7 (C]O). Anal. Calcd
for C12H11NO (185.23): C, 77.81; H, 5.99; N, 7.65. Found: C, 79.23; H,
6.27; N, 7.92.
3H), 7.78 (dd, J¼1.5, 6.2 Hz, 1H); C NMR (50 MHz, CDCl3, 25 ꢁC)
d
14.2 (CH3), 39.1 (CH2), 39.3 (CH2), 62.5 (CH2), 65.0 (Cq), 67.8 (CH),
68.5 (CH), 122.7 (CH), 124.3 (CH), 129.6 (CH), 131.0 (Cq), 132.5 (CH),
ꢃ
144.7 (Cq), 167.3 (C]O), 170.4 (C]O); LRMS m/z 219 (Mþ ꢂ73, 14),
200 (Base), 103 (78). Anal. Calcd for C15H17NO5 (291.31): C, 61.85; H,
5.88; N, 4.81. Found: C, 62.17; H, 6.15; N, 5.04.
4.5.2. 6-Oxo-1,4-dihydro-6H-pyrido[2,1-a]isoindole-10b-
carboxylic ethyl ester (12b)
Yellow solid; yield: 86%; mp 91–93 ꢁC; IR ( , cmꢂ1, CHCl3)
n
1732.6, 1689.9; 1H NMR (200 MHz, CDCl3, 25 ꢁC)
3H), 2.08–2.25 (m, 1H), 3.27–3.43 (m, 1H), 3.83–3.99 (m, 1H), 4.02–
d
1.16 (t, J¼7.0 Hz,
4.7. Acetonidation of diols 13, 14, and 21
4.29 (m, 2H), 4.52–4.69 (m, 1H), 5.72–5.92 (m, 2H), 7.43–7.61 (m,
To a solution of a mixture of diols (13 and 14) or 21 (1 mmol) in
dichloromethane (10 mL), was added DMP (0.5 mL, 4 mmol) and
APTS (0.04 g, 0.2 mmol). After the total disappearance of starting
material was observed, the organic solution was washed twice with
water, dried over MgSO4, and concentrated. The crude product was
purified by flash-column chromatography using cyclohexanes/
EtOAc (60:40) to give the acetonides 15, 16, and 23.
13
3H), 7.74 (d, J¼7.7 Hz, 1H); C NMR (50 MHz, CDCl3, 25 ꢁC)
d 14.3
(CH3), 33.5 (CH2), 39.5 (CH2), 62.5 (CH2), 66.1 (Cq), 122.0 (2CH),
124.1 (CH), 124.5 (CH), 129.5 (CH), 131.8 (Cq), 132.1 (CH), 144.6 (Cq),
ꢃ
167.2 (C]O), 170.3 (C]O); LRMS m/z 257 (Mþ , 9), 184 (Base), 156
(31). Anal. Calcd for C15H15NO3 (257.29): C, 70.02; H, 5.88; N, 5.44.
Found: C, 70.41; H, 6.16; N, 5.71.

R. Ben-Othman et al. / Tetrahedron 65 (2009) 4846–4854
4853
4.7.1. 2,2-Dimethyl-4,4a,10,10a-tetrahydro-3aH-1,3-dioxa-9a-aza-
CDCl3, 25 ꢁC)
d 26.2 (CH3), 28.3 (CH3), 31.6 (CH2), 54.0 (CH2), 58.3
cyclopenta[b]fluoren-9-one (16)
(CH2), 61.2 (CH), 72.5 (CH), 73.1 (CH), 108.8 (Cq), 121.3 (CH), 122.7
ꢃ
White solid, yield: 52%; mp 104–106 ꢁC; IR (
n
, cmꢂ1, CHCl3)
(CH), 127.2 (2CH), 140.2 (Cq), 143.1 (Cq); LRMS m/z 245 (Mþ , 48),
1
1682.6; H NMR (200 MHz, CDCl3, 25 ꢁC)
d
1.42 (s, 3H), 1.48 (ddd,
170 (82), 118 (Base). Anal. Calcd for C15H19NO2 (245.32): C, 73.44; H,
7.81; N, 5.71. Found: C, 73.86; H, 8.14; N, 5.99.
J¼3.1, 11.7, 14.0 Hz, 1H, H1ax), 1.57 (s, 3H, CH3), 2.65 (ddd, J¼2.3, 3.1,
14.0 Hz, 1H, H1eq), 3.42 (dd, J1¼9.4 Hz, J2¼16.4 Hz, 1H, H4ax), 4.31
(ddd, J¼6.2, 6.2, 9.4 Hz, 1H, H3ax), 4.35 (dd, J¼6.2, 16.4 Hz, 1H, H4eq),
4.42 (ddd, J¼2.3, 3.1, 6.2 Hz, 1H, H2eq), 4.64 (dd, J¼3.1, 11.7 Hz, 1H,
H10bax), 7.38–7.55 (m, 3H), 7.84 (d, J¼7.8 Hz, 1H); 13C NMR (50 MHz,
4.8.2. 2,2-Dimethyl-3a,4,10,10a-tetrahydro-9H-1,3-dioxa-9a-aza-
cyclopenta[b]fluorene-4a-carboxylic acid ethyl ester (24)
Viscous liquid; yield: 39%; IR (
(200 MHz, CDCl3, 25 ꢁC)
1.26 (s, 3H, CH3), 1.48 (s, 3H), 1.99 (dd,
n
, cmꢂ1, CHCl3) 3428.8; 1H NMR
CDCl3, 25 ꢁC)
d
25.9 (CH3), 28.2 (CH3), 33.2 (CH2), 41.1 (CH2), 52.9
d
(CH), 71.1 (CH), 72.2 (CH), 109.5 (Cq), 122.2 (CH), 124.2 (CH), 128.6
J¼8.6, 14.0 Hz, 1H), 2.15 (dd, J¼5.4, 14.0 Hz, 1H), 2.91 (br s, 1H), 2.92
(dd, J¼9.4, 14.0 Hz, 1H), 3.24 (dd, J¼5.4, 14.0 Hz, 1H), 3.50 (d,
J¼10.9 Hz, 1H), 3.60 (d, J¼10.9 Hz, 1H), 3.94–4.08 (m, 1H), 4.1 (d,
(CH), 131.7 (CH), 132.6 (Cq), 145.9 (Cq), 167.4 (C]O); LRMS m/z 259
ꢃ
(Mþ , 26), 245 (57), 244 (Base). Anal. Calcd for C15H17NO3 (259.31):
C, 69.48; H, 6.61; N, 5.40. Found: C, 69.91; H, 6.94; N, 5.73.
J¼14.8 Hz, 1H), 4.20–4.31 (m, 1H), 4.47 (d, J¼14.8 Hz, 1H), 7.15–7.26
13
(m, 4H); C NMR (50 MHz, CDCl3, 25 ꢁC)
d 25.0 (CH3), 27.5 (CH3),
4.7.2. 2,2-Dimethyl-4,4a,10,10a-tetrahydro-3aH-1,3-dioxa-9a-aza-
32.8 (CH2), 49.9 (CH2), 58.8 (CH2), 68.5 (CH2), 69.5 (CH), 70.2 (Cq),
71.3 (CH), 108.5 (Cq), 122.3 (CH), 122.6 (CH), 127.8 (CH), 128.1 (CH),
cyclopenta[b]fluoren-9-one (15)
ꢃ
ꢃ
White solid; yield: 25%; mp 182–184 ꢁC; IR (
n
, cmꢂ1, CHCl3)
139.3 (Cq), 143.6 (Cq); LRMS m/z 260 (Mþ ꢂ15), 245 (Mþ ꢂ30), 244
(Base). Anal. Calcd for C16H21NO3 (275.35): C, 69.79; H, 7.69; N, 5.09.
Found: C, 70.22; H, 8.02; N, 5.35.
1
1683.9; H NMR (200 MHz, CDCl3, 25 ꢁC)
d 1.34 (s, 6H), 1.45 (ddd,
J¼9.3, 10.1, 13.3 Hz, 1H, H1ax), 2.44 (ddd, J¼3.9, 5.4, 13.3 Hz, 1H,
H1eq), 3.38 (dd, J¼3.1, 14.8 Hz, 1H, H4ax), 4.22 (dd, J¼3.1, 5.4 Hz, 1H,
H3eq), 4.24–4.30 (m, 1H, H10bax), 4.44 (quintet, J¼5.4, 10.1 Hz, 1H,
4.8.3. 1,4,6,10b-Tetrahydro-pyrido[2,1-a]-isoindole (20)
1
H2ax), 4.76 (d, J¼14.8 Hz, 1H, H4eq), 7.36–7.56 (m, 3H), 7.85 (d,
Viscous liquid; yield: 55%; H NMR (200 MHz, CDCl3, 25 ꢁC)
13
J¼7.8 Hz, 1H); C NMR (50 MHz, CDCl3, 25 ꢁC)
d
26.4 (CH3), 28.4
d
2.10–2.32 (m, 1H), 2.52–2.65 (m, 1H), 3.11–3.22 (m, 1H), 3.42–3.59
(m, 3H), 4.19 (d, J¼11.7 Hz, 1H), 5.73–5.86 (m, 2H), 7.08–7.22 (m,
4H); 13C NMR (50 MHz, CDCl3, 25 ꢁC)
30.5 (CH2), 51.5 (CH2), 58.0
(CH3), 34.8 (CH2), 39.5 (CH2), 55.7 (CH), 71.6 (CH), 72.8 (CH), 109.4
(Cq), 122.0 (CH), 124.3 (CH), 128.7 (CH), 131.8 (CH), 132.5 (Cq), 145.3
d
ꢃ
(Cq), 167.4 (C]O); LRMS m/z 259 (Mþ , 26), 245 (57), 244 (Base).
(CH2), 63.3 (CH2), 121.1 (CH), 122.5 (CH), 125.4 (CH), 126.7 (CH),
ꢃ
Anal. Calcd for C15H17NO3 (259.31): C, 69.48; H, 6.61; N, 5.40.
Found: C, 69.91; H, 6.94; N, 5.73.
126.8 (CH), 127.0 (CH), 140.0 (Cq), 143.5 (Cq); LRMS m/z 171 (Mþ
,
58), 117 (Base), 90 (72). Anal. Calcd for C12H13N (172.24): C, 84.17; H,
7.65; N, 8.18. Found: C, 84.22; H, 7.62; N, 8.35.
4.7.3. 2,2-Dimethyl-9-oxo-3a,4,10,10a-tetrahydro-9H-1,3-dioxa-
9a-aza-cyclopenta[b]fluorene-4a-carboxylic acid ethyl ester (23)
4.9. Preparation of benzoindolizidine 26
White solid; yield: 73%; mp 172–174 ꢁC; IR ( , cmꢂ1, CHCl3)
n
1740.0, 1693.1; 1H NMR (200 MHz, CDCl3, 25 ꢁC)
d
1.18 (t, J¼7.0 Hz,
To a solution of 20 (250 mg, 1.5 mmol) in MeOH (10 mL) was
added a catalytic quantity of 10% palladium-on-carbon. The solu-
tion was stirred at room temperature under an atmosphere of hy-
drogen for a period of 6 h. The mixture was filtered over Celite and
rinsed with MeOH (3ꢀ5 mL), and the solvent was removed by
evaporation to give the amine 26. The 1H NMR and 13C NMR spectra
of the hydrochloride salt of 26 conform with the reported literature
data.29
3H), 1.29 (s, 6H), 1.58 (dd, J¼10.1, 13.3 Hz, 1H), 2.89 (dd, J¼5.4,
13.3 Hz, 1H), 3.49 (dd, J¼3.9, 15.6 Hz, 1H), 4.02–4.38 (m, 4H), 4.76
(d, J¼15.6 Hz, 1H), 7.43–7.61 (m, 3H), 7.78–7.84 (m, 1H); 13C NMR
(50 MHz, CDCl3, 25 ꢁC)
d 14.3 (CH3), 26.3 (CH3), 28.3 (CH3), 36.9
(CH2), 38.3 (CH2), 62.7 (CH2), 67.0 (Cq), 71.1 (CH), 71.4 (CH), 109.3
(Cq), 122.0 (CH), 124.5 (CH), 129.6 (CH), 131.4 (Cq), 132.3 (CH), 144.4
ꢃ
(Cq), 167.4 (C]O), 169.6 (C]O); LRMS m/z 331 (Mþ , 12), 316 (22),
258 (Base). Anal. Calcd for C18H21NO5 (331.37): C, 65.24; H, 6.39; N,
4.23. Found: C, 65.66; H, 6.71; N, 4.51.
Acknowledgements
4.8. Reduction of the amide function
The authors are grateful to Dr. Elizabeth A. Hillard (ENSCP) and
Dr. Pascal Pigeon (ENSCP) for many fruitful discussions throughout
the course of this work.
Lithium aluminum hydride (38 mg, 1 mmol) was added to a so-
lution of amides 16 or 23 (1.5 mmol) in dry THF (5 mL) at room
temperature and the mixture was stirred for 1 h. The resulting
mixture was cooled and water added cautiously until the lithium
complex was destroyed. The mixture was then diluted with water
(5 mL) and dichloromethane (10 mL). The organic layer was sepa-
rated and the aqueous layer extracted with dichloromethane
(2ꢀ10 mL). The combined extracts were washed with water, brine,
dried over MgSO4, and concentrated in vacuo to give a residue. The
crude product was purified by flash-column chromatography using
cyclohexanes/EtOAc (70:30) to give pure amines 17 and 24.
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cyclopenta[b]fluorene (17)
1
Viscous liquid; yield: 45%; H NMR (200 MHz, CDCl3, 25 ꢁC)
d
1.38 (s, 3H), 1.54 (s, 3H), 1.85 (septet, J¼3.1, 10.9, 14.0 Hz, 1H, H1ax),
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5. For some representative examples of synthesis of indolizidines with a quater-
nary carbon, see: (a) Lamberto, M.; Kilburn, J. D. Tetrahedron Lett. 2008, 49,
6364; (b) Langlois, N.; Le Nguyen, B. K.; Retailleau, P.; Tarnus, C.; Salomon, E.
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D.-C.; Yun, C.-S.; Lee, Y. J. Org. Chem. 2000, 65, 621; (g) Lee, Y. S.; Lee, J. Y.; Kim,
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26. Crystal data for 21 at 173(2) K. C15H17NO5: M¼291.30, triclinic, Pꢂ1, a¼6.
3720(5), b¼15.2030(12), c¼16.4165(14) Å, a¼116.083(10)ꢁ, b¼93.021(2)ꢁ, g¼97.
331(2)ꢁ, V¼1406.1(2) Å3, Z¼4; Dc¼1.376 Mg/m3; Bruker APEX-CCD, Mo Ka¼0.
71073 Å, m¼0.104 mmꢂ1; Theta range¼1.39 to 25.00ꢁ. Structure refined by full-
6. For some representative examples of synthesis of indolizidine and pyrrolizidine
ˇ´
´ ˇ P.; Dalla,
benzanalogs, see: (a) Marchalı´n, S.; Zu´ ziova´, J.; Kadlecıkova, K.; Safar,
´ˇ
V.; Da¨ıch, A. Tetrahedron: Asymmetry 2008, 19, 467; (b) Safar, P.; Zuziova, J.;
Bobosikova, M.; Pronayova, N.; Marchalın, S.; Kadlecıkova, K.; Dalla, V.; Daı
¨ch,
A. Tetrahedron Lett. 2007, 48, 697; (c) Zhang, F.; Simpkins, N. S.; Wilson, C.
Tetrahedron Lett. 2006, 48, 5942; (d) Kadlecıkova, K.; Baran, P.; Marchalın, S.;
Dalla, V.; Decroix, B. Tetrahedron 2005, 61, 4743; (e) Szemes, F.; Kadlecıkova, K.;
Bobosikova, M.; Marchalın, S.; Dalla, V.; Daı¨ch, A. Tetrahedron: Asymmetry 2004,
ˇ
ˇ
ˇ
ꢀ
´
ˇ
ˇ
ꢀ
´
´
´
´
´
´
ˇ´
´
matrix least-squares on observed F2 to give final indices [I>2
s
(I)] R1¼0.0427
ˇ
ˇ
and wR2 (all data)¼0.1013, GOF¼1.036. Full crystallographic data have been
deposited to the Cambridge Crystallographic Data Center (CCDC reference
number 708652 for product 21. Copies of the data can be obtained free of
charge at http://www.ccdc.cam.ac.uk
ˇ
ˇ´
´
´
ˇ´
´
ˇ
ˇ
´
´
15, 1763; (f) Alsarabi, A. E.; Canet, J.-L.; Troin, Y. Tetrahedron Lett. 2004, 45, 9003;
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