Diastereoselective access to hexahydro- and octahydrofuro[f]indolizines analogues of phenanthro[f]indolizidines alkaloids

Article abstract of DOI:10.1016/j.tetasy.2004.04.015

Enantiospecific syntheses of furo[f]indolizines with different degrees of unstauration (4a,b, 8a, 9a, and 10a) as analogues of phenanthro[f]indolizidine alkaloids have been completed from (S)-glutamic acid in a few-step sequence. This was achieved from the known optically active alcohol-lactams 2a and 2b by utilizing chemical and catalytic reduction processes. During these transformations, we have shown that partial furan ring reduction can be achieved conveniently. The resulting products 5a and 8a readily constituted platforms to access stereoselectively the partially 6a and 7a or totally 9a and 9b reduced furo[f]indolizines. The key step of the stereocontrolled reduction seems to be the catalytic hydrogenation of the furan nucleus in the (4aS,9aS)-(+)-5a product. Assignments of the absolute stereochemistry are made and some mechanistic aspects of these transformations also discussed.

Full text of DOI:10.1016/j.tetasy.2004.04.015

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 1763–1770
Diastereoselective access to hexahydro- and
octahydrofuro[f]indolizines analogues of
phenanthro[f]indolizidines alkaloids
a
Fridrich Szemes, Katarına Kadlecıkova, Stefan Marchalın, Maria Bobosıkova,
a
ꢁꢀ ꢀ a
ꢀ
ꢁꢀ ꢀ a
ꢁ
ꢀ
Vincent Dalla and Adam Daıch
b
b,
*
€
aDepartment of Organic Chemistry, Slovak University of Technology, SK-81237 Bratislava, Slovak Republic
bLaboratoire de Chimie, URCOM, EA 3221, UFR des Sciences & Techniques de l’Universitꢀe du Havre, B.P: 540,
25 rue Philippe Lebon, F-76058 Le Havre Cedex, France
Received 25 March 2004; accepted 6 April 2004
Available online
Abstract—Enantiospecific syntheses of furo[f]indolizines with different degrees of unstauration (4a,b, 8a, 9a, and 10a) as analogues
of phenanthro[f]indolizidine alkaloids have been completed from (S)-glutamic acid in a few-step sequence. This was achieved from
the known optically active alcohol-lactams 2a and 2b by utilizing chemical and catalytic reduction processes. During these trans-
formations, we have shown that partial furan ring reduction can be achieved conveniently. The resulting products 5a and 8a readily
constituted platforms to access stereoselectively the partially 6a and 7a or totally 9a and 9b reduced furo[f]indolizines. The key step
of the stereocontrolled reduction seems to be the catalytic hydrogenation of the furan nucleus in the (4aS,9aS)-(þ)-5a product.
Assignments of the absolute stereochemistry are made and some mechanistic aspects of these transformations also discussed.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
H
N
H
The octahydroindolizidine framework A and its oxi-
dized and reduced forms are found in a wide array of
alkaloids (up to 20% of all alkaloids) and other phar-
maceutically important compounds (Chart 1). These
latter are exemplified by phenanthroindolizidines1;2
typified by tylocrebrine C, tylophorine D,3 and antofine
E,4 which are known for their profound cytotoxic
activity through the inhibition of protein and nucleic
acid syntheses.1;5 Polyhydroxylated indolizidines (often
referred to as ‘amino-sugars’ or ‘aza-sugars’)6 and ana-
logues of pumiliotoxins,7 as naturally occurring mem-
bers of this class of alkaloids, show glycosidase
inhibitory activities6 and constitute metabolites, which
serve as chemical defense compounds (numerous com-
pounds of this family are found in skin secretions of
amphibians; frogs notably),7 respectively. As a conse-
quence, in recent years there has been a great deal of
Ar
N
B: Ar = Aryl
A: Indolizine core
R1
C: R1=OMe
R2=H
R3=OMe
D: R1=R2=OMe
R3=H
E: R1=OMe
R2=R3=H
R1
H
N
R3
R1
R2
Phenanthroindolizidine alkaloids core
Chart 1. Representatives indolizidines and their aromatic homologues.
interest not only in the synthesis of these natural prod-
ucts themselves but also in that of chemically modified
analogues (B: Chart 1) with promising pharmaceutical
properties and lower toxicity.8
* Corresponding author. Tel.: +33-02-32-74-44-03; fax: +33-02-32-74-
43-91; e-mail: adam.daich@univ-lehavre.fr
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.04.015

1764
F. Szemes et al. / Tetrahedron: Asymmetry 15 (2004) 1763–1770
2. Results and discussion
OH
H
H
N
i
During our studies on the synthesis of diversely substi-
tuted polycyclic systems, we have previously reported
indolizidines annulated to thiophene,9;10 benzothio-
phene,10;11 both benzene and thiophene,12 and furan13
rings.
N
30%
O
O
O
O
(4R,4aS)-(+)-2a
(S)-(+)-3a
H
ii
72%
82%
i
Because of the lower stability of the furan ring in acidic
medium allied to the fact that its diene character is more
pronounced, such furo[f]indolizindiones skeletons 2a
and 2b warrant additional investigations. In fact, these
alcohol-lactams 2a and 2b could be valuable synthons
for the synthesis of novel saturated tricyclic furo[f]indo-
lizines, which could be considered analogous to dihy-
droxy indolizidines (polyhydroxylated indolizidines).
We focused our attention on the reduction of the chiral
alcohol and/or the lactam carbonyl to the corresponding
alkanes 4a and 4b. These tertiary amine bases are able to
activate electrophiles through hydrogen bonding, which
should have an influence during the phase differentia-
tion14 and consequently make them promising candi-
dates as catalysts in catalytic asymmetric synthesis.
Herein, we report our findings in this area starting from
enantiopure alcohols 2a and 2b.
N
O
H
O
(4aS,9aS)-(+)-5a
Scheme 2. Reagents and conditions: (i) Et3SiH (1.5 equiv), TFA, rt,
1 h; (ii) Et3SiH (5.0 equiv.), TFA, rt, 8 h.
the reaction sequence, the lactam function of indolizines
(S)-3a and 3b was reduced classically with LiAlH4 in
THF at reflux to produce enantiopure (S)-hexahydro-
furo[2,3-f]- and [3,2-f]indolizines (S)-4a and 4b in 66%
and 72% yields, respectively.
Intrigued by the above results and with the capability of
the furo[2,3-f]indolizidinone 5a to furnish saturated tri-
cyclic systems bearing a strong tertiary amine base and
two additional stereogenic centers, we directed our
attention to examining the selectivity of the reduction
process. Screening of reaction conditions (Scheme 2)
revealed triethylsilane, in large excess (5.0 equiv) and
prolonged reaction time (8 h), to be the most effective
reducing protocol for total regioselective reduction in
favor of the expected (4aS,9aS)-(þ)-5a. Under these
conditions the reaction proceeded cleanly with a good
yield of 72%. Interestingly, this product was also
obtained as the single isomer from the parent (4aS)-(þ)-
3a by partial reduction (82% yield). In this case, the
reaction occurred under similar conditions. However,
only a slight excess of Et3SiH was necessary.
The requisite alcohols 2a and 2b were obtained in a
three-step sequence from (S)-glutamic acid as previously
reported by us (Scheme 1).13 In the next synthetic step
we subjected the hydroxyhexahydroindolizines 2a and
2b to a 1 h reduction with 1.5 equiv of triethylsilane in
trifluoroacetic acid at room temperature. The reduction
of hydroxyindolizine 2a afforded the desired (S)-hexa-
hydrofuro[2,3-f]indolizinone 3a albeit only in low yield
(30%). In addition to (S)-(þ)-hexahydrofuroindolizine-
7-one 3a, octahydrofuro[2,3-f]indolizine-7-one 5a was
also formed as a separable 1:1 mixture. Similarly, regio-
isomer (S)-hexahydrofuro[3,2-f]indolizinone 3b was
prepared in a comparable yield of 45%. In this particular
case, the reduction did not affect the furan ring even
after a longer reaction time (4 h) or using a large excess
of triethylsilane as the hydride source. In the last step of
Semi-reduction of a furan nucleus into its 2,5-dihydro
analogue is a well known useful transformation.15 All
contributions so far investigated in this field involve a
single electron transfer (SET) process.16 An impressive
utilization of the so-called Birch reduction has been
reported by Donohoe and co-workers.17 Although an
asymmetric variant could be implemented, thus allowing
multiple accesses to structurally diverse natural prod-
ucts, this reaction suffers from some drawbacks such as
low yields and use of both metallic lithium and liquid
ammonia, naphthalene, or di-tert-butylbiphenyl (DBB).
We believe that, under certain appropriate circum-
stances, this reaction may be a simpler alternative to the
usual laborious Birch process.
OH
HO2C
H
O
i, ii
N
O
N
O
(47-79%)
and
(65-67%)
O
(S)-(+)-1a,b
(+)-2a,b
O
=
O
iii
O
a
b
H
H
iv
O
O
The following mechanism has been proposed to account
for both the structure and stereochemistry of 5a. The
furanic double bond is protonized at position 5 to give
oxonium ion I, in resonance with tertiary carbcation J,
which in turn undergoes a nucleophilic attack by a hy-
dride anion. Due to the bulk of the anionic pentavalent
silyl hydride species, attack is exclusively from the ste-
rically less demanding exo side. This process, leading to
N
N
O
(S)-(+)-3a,b
(30-45%)
(S)-(+)-4a,b
(66-72%)
Scheme 1. Reagents and conditions to access furo[f]indolizinones 4a
and b: (i) (a) (COCl)2, CH2Cl2; (b) AlCl3, CH2Cl2; (ii) NaBH4, MeOH;
(iii) Et3SiH, TFA; (iv) LiAlH4, THF.

F. Szemes et al. / Tetrahedron: Asymmetry 15 (2004) 1763–1770
1765
a trans-diaxial arrangement of hydrogens at positions 4a
H
N
H
O
H
O
and 9a in a thermodynamically controlled fashion, gives
rise to the more stable 1,4-trans-diaxial product 5a. The
structural determination of this product was based on
an array of NMR considerations. Furthermore, our
predictions were confirmed in the final stage by X-ray
crystallography, which provided unequivocal proof of
its absolute configuration (Scheme 3).18;19 Finally, it is
worth mentioning that reduction of such conjugated
oxonium cations, either in the acyclic or the cyclic form,
seems to have never been investigated.
H
H
N
H
H
O
(S)-(+)-3b
K
O
Et3 Si OCOCF3
H
H
H
H
N
H
O
H
O
X
N
H
H
O
O
L
5b
Scheme 4. Mechanism of the nonreduction of lactam 3b.
H
H
H
H
H
H
i
+
N
N
N
O
O
O
H
H
O
O
O
6a
7a
5a
5%
3
H
H
H
3aH
2H
H
9
4a
4
H
H
3
H
O9a
N
H
H
H
H
3a
H
H
9
4a
4
14%
O
O9a
N
10%
H
H
H
O
NOE 10%
NOE 3%
6a
7a
Scheme 5. Reduction of 5a under various conditions: (i) H2, cat.,
MeOH.
Catalytic hydrogenation of 5a resulted in the creation of
a third stereogenic center to afford the diastereomeric
mixture in 93% yield. The product obtained was found
to be a mixture of two diastereomers in a 1:1 ratio
resulting from the cis addition of the dihydrogen mole-
cule (Table 1, entry 1). As we can see when the reduction
conditions were changed (entries 4–5), moderate to
complete diastereoselectivities were achieved with best
results being obtained (dr >95%) using 5% ruthenium on
alumina and 50% Raney nickel as the catalysts. In both
cases, the diastereoselectivity was in favor of lactam 6a
at the cost of its regioisomer 7a.
Scheme 3. Mechanism of the reduction of lactam 3a with the tandem
Et3SiH/TFA and ORTEP plot of the obtained product 5a.
From these results, we investigated the behavior of the
regioisomer of 3a toward this reduction protocol. Under
identical conditions as above with starting material (S)-
3b, the reaction surprisingly failed to give the corre-
sponding dihydrofuro[3,2-f]indolizinone 5b. This finding
could be best explained by the bulk of the reducing
agent (Scheme 4); the access of which is hindered by
axial hydrogens at positions 4 and 8a. Another reason
for the failed reduction of the furan ring may be the
higher aromaticity of 3b [(S)-3a has a more pronounced
diene character] and hence better stabilization of the
potentially formed carbocation L.
The configuration of furolactams 6a and 7a was as-
signed by NOE difference measurements in CDCl3
solution. In fact, for 6a the experiments showed strong
enhancement of the intensity of the H-3a signal
(d ¼ 2:46–2:58 ppm) by 14% when signal of H-9a signal
(d ¼ 3:98–4:08 ppm) was irradiated. Conversely, the
signal of H-9a was enhanced by 12% when H-3a reso-
nance was irradiated (Scheme 5). NOE experiments did
not show any interaction between H-3a (or H-9a) and
H-4a protons. Similarly for 7a, no interactions were
observed between H-3a, H-4a, and/or H-9a showing a
cis relationship between the H-3a and H-9a protons in
the major product 6a. The observed high stereoselec-
tivity during the reduction process and the configuration
found at both C-3a and C-9a of 6a (7a as minor
Taking into account that small modifications of the
structure of indolizidines and its analogues, notably at
the relative 6 and 7 positions of the indolizine ring, in-
duces changes in their biological activity or their speci-
ficity,20 it is interesting to consider the chemical and
catalytic hydrogenation of the unsaturated furo[3,2-
f]indolizidinone 5a (Scheme 5).

1766
F. Szemes et al. / Tetrahedron: Asymmetry 15 (2004) 1763–1770
Table 1. Saturated furoindolizines 6a and 7a obtained by reduction of 5a
Entry
Catalyst
Time (h)
Substrate/catalysta
De (cis:6a, %)b
Yield (%)
1
2
3
4
5
10% Pd/C
5% Rh/Al2O3
5% Ru/C
20
12
15
2
1.0/0.2
1.0/0.2
1.0/0.2
1.0/0.2
1.0/1.0
50
74
93
89
91
97
96
83
5% Ru/Al2O3
50% Ra-Ni
>95
>95
12
a The ratio between substrate 5a and the catalyst used.
b Determined by 1H, 13CNMR, and GC–MS spectroscopy.
reduction product) suggests that the origin for the ste-
reoselection is likely to be the same as mentioned above
for the synthesis of 5b. This may result from a prefer-
ential hydrogen approach from the exo (convex) face to
avoid 1,3-steric diaxial interactions. This is in agreement
with both the model of 5a rationalized by ChemDraw
3D (Chart 2) and the corresponding X-ray structure (see
Scheme 4).
H
N
O
ii
H
i
(4aS,9aS)-8a
H
N
H
H
N
O
O
H
O
H
(4aS,9aS)-5a
(3aR,4aS,9aS)-9a
ii
i
H
H
H
N
O
O
(3aR,4aS,9aS)-6a
H
H
N
O
H
(3aS,4aS,9aS)-10a
Scheme 6. Reagents and conditions: (i) LiAlH4, THF; (ii) Ra-Ni,
MeOH.
Chart 2. ChemDraw 3D plot of dihydrofuro[2,3-f]indolizinone 5a.
In continuation of our experiments on the reduction of
dihydrofuro[2,3-f]indolizinone 5a, chemical reduction
with LAH in THF at reflux furnished the optically ac-
tive tricyclic amine (4aS,9aS)-8a as the sole reaction
product in 82% yield. No trace of the totally reduced
tricyclic amines 9a and/or 10a was detected (Scheme 6)
thus showing that the dihydrofuranic double bond is
inert in chemical reducing conditions. The compound
(3aR,4aS,9aS)-2,3,3a,4,4a,5,6,7,9,9a-decahydrofuro[2,3-
f]indolizine 9a was obtained in enantiopure form by
catalytic hydrogenation using the well established pro-
tocol (i.e., 50% Ra-Ni, MeOH, 2 h, 96%). Interestingly,
when reduction of 8a was performed with 5% Pd–C in
dry methanol, an inseparable mixture of two diastereo-
mers 9a and 10a in a 7:1 ratio was obtained in 95% yield.
Alternatively, compound 9a can also be obtained as the
sole product (in 75% yield) or in a mixture with 10a (in
78% yield) in a two-step sequence, via 6a or a mixture of
6a and 7a obtained by catalytic reduction of their con-
gener octahydrofuro[2,3-f]indolizine 5a. The reduction
of the lactam function was performed in the final stage
under standard conditions (LiAlH4, THF, reflux).
bond of octahydroindolizines 5a and 8a in the presence
of Raney nickel. Furthermore, it is worth noting that 9a
could be synthesized with similar yield and stereoselec-
tivity by inverting the order of reaction. This result
minimized the role of nitrogen in the sense of stereo
induction.
3. Conclusion
By means of new synthetic approaches involving regio-
selective and diasteroselective reduction processes, we
have disclosed a concise and efficient synthesis of the
enantiopure unsaturated dihydrofuro[2,3-f]indolizinone
5a. This latter, which led by additional chemical and
catalytic reductions to totally reduced chiral phenan-
throindolizidines furo-analogues in good yields, could
be considered as the virtually rare enantiopure 6(7)-hy-
droxy-7(6)-hydroxyethylindolizidines alkaloids homo-
logues. Finally, owing to the efficiency and simplicity of
these new transformations, the dihydrofuro[2,3-f]indo-
lizidinone 5a in particular shows a promising potential
for further development, notably for the use indepen-
dently of the dihydrofuran double bond and tetrahy-
drofuran ring as a diol surrogates. Investigations in this
From these results, it has been clearly established that in
both sequences, the keystep of the process was the ste-
reo-controlled hydrogenation of the C-3@C-3a double

F. Szemes et al. / Tetrahedron: Asymmetry 15 (2004) 1763–1770
1767
sense are currently underway in our laboratory and the
results to be published soon.
3), 115.1 (C-3a), 142.1 (C-2), 145.5 (C-9a), 174.5 (C-7);
MS (m=z (%)): 177 (Mþ, 30), 95 (5), 94 (100), 66 (10), 65
(8), 39 (15). Anal. Calcd for C10H11NO2 (177.08): C,
67.78; H, 6.26; N, 7.90. Found C, 67.61; H, 6.14; N,
7.79.
4. Experimental part
4.1. General
4.2.2. (8aS)-(+)-4,6,7,8,8a,9-Hexahydrofuro[3,2-f]indoli-
zin-6-one 3b. This product was isolated in 45% yield; mp
All melting points were measured on a Boetius micro
hot-stage and are uncorrected. The infrared spectra of
solids (potassium bromide) and liquids (neat) were re-
corded on a Philips Analytical PV 9800 FT IR spec-
25
D
99–101 °C; ½aꢁ ¼ þ116:7 (c 1, EtOH); IR (m cmꢂ1
,
1
KBr): 3110, 2914, 1680 (C@O), 1437, 1417; H NMR
(300 MHz, CDCl3): d 1.83–1.92 (m, 1H, H-8), 2.37–2.63
(m, 4H, H-8, H-9ax, 2 ꢀ H-7), 2.93 (ddd, 1H, H-9eq,
J ¼ 1:8, 4.7, and 15.6 Hz), 3.87–3.96 (m, 2H, H-8a, H-
4ax), 4.77 (dd, 1H, H-4eq, J ¼ 2:1 and 16.1 Hz), 6.26 (d,
1H, H-3, J ¼ 1:8 Hz), 7.30 (d, 1H, H-2, J ¼ 1:8 Hz); 13C
NMR (75 MHz, CDCl3): d 24.8 (C-8), 30.1 (C-7), 30.9
(C-9), 37.7 (C-4), 54.7 (C-8a), 108.3 (C-3), 113.8 (C-3a),
142.0 (C-2), 147.0 (C-9a), 174.1 (C-6); MS (m=z (%)): 177
(Mþ, 26), 95 (6), 94 (100), 66 (7), 65 (5), 51 (4), 41 (4), 40
(4), 39 (11), 32 (10), 31 (11), 28 (43). Anal. Calcd for
C10H11NO2 (177.08): C, 67.78; H, 6.26; N, 7.90. Found
C, 67.69; H, 6.08; N, 7.68.
1
trometer. The H and 13C NMR spectra were recorded
on a Bruker AC-200 (200 MHz) and Varian VXR-300
(300 MHz) instrument in deuteriochloroform unless
otherwise indicated. Solvents and chemical shifts (d) are
expressed in ppm relative to TMS as internal standard.
The assignment of 1H and 13C signals was supported by
1
1
one- and two-dimensional H–1H COSY, DEPT, H–
13C HMBC, and HSQC experiments. All the experi-
ments were recorded using CDCl3 as the solvent.
Approximately 20 mg of the sample were dissolved with
0.5 mL of solvent. Ascending thin layer chromatography
was performed on precoated plates of silica gel 60 F 254
(Merck) and the spots visualized using an ultraviolet
lamp or iodine vapor. Mass spectra measurements were
recorded on a AEI MS 902 S spectrophotometer.
Optical rotations were determined with a Perkin–Elmer
241 MC instrument at 25 °C in the indicated solvent.
Elemental analyses were carried out by the microanal-
ysis laboratory of INSA, F-76130 at Mt. St. Aignan in
France.
4.3. General procedure for the synthesis of the hexa-
hydrofuro[f]indolizines 4a and 4b
Lithium aluminum hydride (0.46 g, 12 mmol) was added
to a solution of amides 3a and 3b (0.53 g, 3 mmol) in dry
THF (20 mL) at room temperature and the mixture then
heated under reflux 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 (20 mL) and chloroform (40 mL). The chlo-
roform layer was separated and the aqueous layer ex-
tracted with chloroform (2 ꢀ 40 mL). The combined
extracts were washed with water, brine, dried over
MgSO4, and concentrated in vacuo to give a residue.
Recrystallization of the solid from hexane gave pure
amines 4a and 4b.
4.2. General procedure for the synthesis of the hexa-
hydrofuro[f]indolizinones 3a and 3b
Triethylsilane (0.25 mL, 1.5 mmol) was added to a stir-
red solution of alcohols 2a and 2b (0.2 g, 1.0 mmol) in
trifluoroacetic acid (2 mL) at 0 °C. The resulting yellow
solution was stirred at room temperature for 2 h. The
reaction mixture was concentrated in vacuo, diluted
with water (7 mL), made alkaline with 10% Na2CO3,
and extracted with chloroform (3 ꢀ 10 mL). The com-
bined extracts were washed with water, dried over
anhydrous MgSO4, and concentrated in vacuo. The
residue was purified by flash chromatography on a silica
gel column eluting with chloroform. Recrystallization of
the solid from cyclohexane gave amides 3a and 3b as
colorless crystals.
4.3.1. (4aS)-())-4,4a,5,6,7,9-Hexahydrofuro[2,3-f]indoli-
zine 4a. This product was isolated in 66% yield; mp
25
40–41 °C; ½aꢁ ¼ ꢂ20:5 (c 0.1, EtOH); IR (m cmꢂ1, KBr):
D
2970, 2933, 2793, 2774, 1504, 1376; 1H NMR (300 MHz,
CDCl3): d 1.54–1.65 (m, 1H, H-5), 1.80–2.11 (m, 3H,
2 ꢀ H-6, H-5), 2.30–2.39 (m, 3H, H-7, H-4a, H-4ax),
2.66 (ddd, 1H, H-4eq, J ¼ 2:0, 3.4, and 14.5 Hz), 3.25–
3.31 (m, 2H, H-7, H-9ax), 4.04 (dd, 1H, H-9eq, J ¼ 4
and 14.1 Hz), 6.21 (d, 1H, H-3, J ¼ 1:9 Hz), 7.26 (d, 1H,
H-2, J ¼ 1:9 Hz); 13C NMR (75 MHz, CDCl3): d 22.3
(C-6), 28.6 (C-4), 29.8 (C-5), 50.1 (C-9), 54.1 (C-7), 61.2
(C-4a), 110.0 (C-3), 115.9 (C-3a), 141.1 (C-2), 148.5 (C-
9a); MS (m=z (%)): 163 (Mþ, 18), 95 (7), 94 (100), 66
(12), 65 (10), 51 (8), 42 (4), 41 (14), 39 (18). Anal. Calcd
for C10H13NO (163.10): C, 73.59; H, 8.03; N, 8.58.
Found C, 73.48; H, 7.88; N, 8.39.
4.2.1. (4aS)-(+)-4,4a,5,6,7,9-Hexahydrofuro[2,3-f]indoli-
zin-7-one 3a. This product was isolated in 30% yield; mp
25
71–73 °C; ½aꢁ ¼ þ1:4 (c 0.1, EtOH); IR (m cmꢂ1, KBr):
D
3092, 2910, 1677 (C@O), 1432; 1H NMR (300 MHz,
CDCl3): d 1.78–1.90 (m, 1H, H-5), 2.35–2.53 (m, 4H, H-
5, H-4ax, 2 ꢀ H-6), 2.71 (ddd, 1H, H-4eq, J ¼ 1:7, 4.5
and 15.2 Hz), 3.79–3.87 (m, 1H, H-4a), 4.03 (d, 1H, H-
9ax, J ¼ 16:5 Hz), 4.85 (d, 1H, H-9eq, J ¼ 16:5 Hz),
6.24 (d, 1H, H-3, J ¼ 1:8 Hz), 7.32 (d, 1H, H-2,
J ¼ 1:8 Hz); 13C NMR (75 MHz, CDCl3): d 24.8 (C-5),
29.5 (C-4), 30.4 (C-6), 38.9 (C-9), 54.9 (C-4a), 110.1 (C-
4.3.2. (8aS)-(+)-4,6,7,8,8a,9-Hexahydrofuro[3,2-f]indoli-
zine 4b. This product was isolated in 72% yield; mp

1768
F. Szemes et al. / Tetrahedron: Asymmetry 15 (2004) 1763–1770
25
51–54 °C; ½aꢁ ¼ þ110 (c 0.1, EtOH); IR (m cmꢂ1, KBr):
chloroform/acetone (20/1) to give a mixture of indolizi-
nones 6a and 7a (93%) in a 3:1 ratio as pale yellow oil.
Method B: Activated Raney nickel (50% in water) (0.9 g)
was added to a solution of amide 5a (0.9 g, 5 mmol) in
anhydrous methanol (10 mL) and stirred at room tem-
perature under hydrogen atmosphere for 12 h. The
solution was filtered through a Celite pad to remove the
catalyst. After concentration in vacuo, the residue was
purified by flash chromatography on a silica gel column
eluting with chloroform/acetone (20/1) to give enantio-
merically pure indolizinone (6a) (96%) as an colorless
oil.
D
1
2962, 2925, 2773, 1501; H NMR (300 MHz, CDCl3): d
1.55–1.67 (m, 1H, H-8), 1.81–2.10 (m, 3H, 2 ꢀ H-7, H-
8), 2.31 (q, 1H, H-6, J ¼ 9 Hz), 2.48–2.53 (m, 2H, H-8a,
H-9ax), 2.80–2.90 (m, 1H, H-9eq), 3.13 (dt, 1H, H-4ax,
J ¼ 2:6 and 13.4 Hz), 3.23 (ddd, 1H, H-6, J ¼ 2:3 and
8.6 Hz), 3.88 (dd, 1H, H-4eq, J ¼ 1:2 and 13.6 Hz), 6.18
(d, 1H, H-3, J ¼ 1:85 Hz), 7.25 (d, 1H, H-2,
J ¼ 1:85 Hz); 13C NMR (75 MHz, CDCl3): d 22.4 (C-7),
30.3 (C-8), 30.6 (C-9), 48.9 (C-4), 53.6 (C-6), 61.0 (C-8a),
108.4 (C-3), 116.1 (C-3a), 141.2 (C-2), 149.4 (C-9a); MS
(m=z (%)): 163 (Mþ, 20), 162 (4), 95 (7), 94 (67), 66 (6),
39 (4), 32 (20), 28 (100). Anal. Calcd for C10H13NO
(163.10): C, 73.59; H, 8.03; N, 8.58. Found C, 73.50; H,
7.75; N, 8.40.
4.5.1. (4aS,3aS,9aS)-2,3,3a,4,4a,5,6,7,9,9a-Decahydro-
25
D
furo[2,3-f]indolizin-7-one 6a. ½aꢁ ¼ þ32:6 (c 1, CHCl3);
1
IR (m cmꢂ1, KBr): 2929, 2880, 1686 (C@O), 1301; H
4.4. (4aS,9aS)-())-2,4,4a,5,6,7,9,9a-Octahydrofuro[2,3-
f]indolizin-7-one 5a
NMR (300 MHz, CDCl3): d 1.56–1.72 (m, 2H, H-5, H-
4ax), 1.94–2.08 (m, 3H, H-4eq, 2 ꢀ H-3), 2.19–2.29 (m,
1H, H-5), 2.36–2.42 (m, 2H, 2 ꢀ H-6), 2.46–2.58 (m, 1H,
H-3a), 2.83 (dd, 1H, H-9ax, J ¼ 8:1 and 13.5 Hz), 3.65–
3.73 (m, 1H, H-4a), 3.79 (dd, 1H, H-2, J ¼ 8:8 and 16.4
Hz), 3.90 (dd, 1H, H-9eq, J ¼ 6:3 and 13.2 Hz), 3.98–
4.08 (m, 2H, H-9a, H-2); 13C NMR (75 MHz, CDCl3): d
24.4 (C-5), 28.1 (C-3), 30.0 (C-6), 32.6 (C-4), 35.6 (C-3a),
39.7 (C-9), 50.6 (C-4a), 66.5 (C-2), 72.7 (C-9a), 173.2 (C-
7);); MS (m=z (%)): 181 (Mþ, 11), 180 (76), 166 (19), 153
(18), 150 (16), 138 (54), 137 (19), 136 (74), 98 (100), 84
(30), 70 (30), 55 (35), 41 (23). Anal. Calcd for
C10H15NO2 (181.11) C, 66.27; H, 8.34; N, 7.73. Found
C, 66.09; H, 8.15; N, 7.40.
Triethylsilane (3 g, 25.9 mmol) was added to a stirred
solution of alcohol 2a (1 g, 5.2 mmol) in trifluoroacetic
acid (10 mL) at 0 °C. The resulting yellow solution was
stirred under an argon atmosphere at rt for 8 h. The
reaction mixture was concentrated in vacuo, diluted
with water (10 mL), made alkaline with saturated solu-
tion of Na2CO3 (pH ꢃ 9) and extracted with chloroform
(3 ꢀ 25 mL). The combined extracts were washed with
water, dried over anhydrous MgSO4, and concentrated
in vacuo. The residue was purified by flash chromato-
graphy on a silica gel column eluting with chloroform/
acetone (10/1). Recrystallization of the solid from n-
hexane/THF (20/1) gave amide 5a as colorless crystals.
25
D
Yield: 72%; mp 132–135 °C; ½aꢁ ¼ ꢂ61:4 (c 1, EtOH);
4.5.2. (4aS,3aR,9aS)-2,3,3a,4,4a,5,6,7,9,9a-Decahydro-
furo[2,3-f]indolizin-7-one 7a. From the NMR spectra of
the mixture; 1H NMR (300 MHz, CDCl3): d 1.20 (q, 1H,
H-4ax, J ¼ 12:9 Hz), 1.54–1.80 (m, 3H, H-4eq, H-5, H-
6), 2.10–2.30 (m, 3H, H-6, H-5, H-3a), 2.34–2.43 (m, 2H,
2 ꢀ H-3), 2.95 (dd, 1H, H-9ax, J ¼ 3:3 and 14.7 Hz),
3.42–3.52 (m, 1H, H-4a), 3.77–3.81 (m, 1H, H-2), 3.85
(td, 1H, H-9a, J ¼ 3 and 10 Hz), 3.93 (q, 1H, H-2,
J ¼ 8:5 Hz), 4.33 (d, 1H, H-9eq, J ¼ 14:8 Hz); 13C NMR
(75 MHz, CDCl3): d 24.5 (C-5), 29.4 (C-3), 31.8 (C-6),
33.9 (C-4), 35.8 (C-3a), 40.6 (C-9), 55.0 (C-4a), 65.6 (C-
2), 74.2 (C-9a), 174.2 (C-7).
IR (m cmꢂ1, KBr): 2974, 2910, 2872, 2844, 1670 (C@O),
1442; 1H NMR (300 MHz, CDCl3): d 1.66–1.78 (m, 1H,
H-5), 2.00 (t, 1H, H-4ax, J ¼ 13:3 Hz), 2.23–2.35 (m,
1H, H-5), 2.43–2.53 (m, 3H, 2 ꢀ H-6, H-9ax), 2.77 (dd,
1H, H-4eq, J ¼ 4 and 13.3 Hz), 3.39–3.49 (m, 1H, H-
4a), 4.47–4.53 (m, 2H, H-9eq, H-9a), 4.70 (m, 2H,
2 ꢀ H-2), 5.63 (t, 1H, H-3, J ¼ 1:8 Hz); 13C NMR
(75 MHz, CDCl3): d 24.0 (C-5), 30.3 (C-6), 34.2 (C-4),
46.4 (C-9), 57.3 (C-4a), 75.9 (C-2), 80.2 (C-9a), 118.9 (C-
3), 137.3 (C-3a), 173.8 (C-7); MS (m=z (%)): 180 (17),
179 (Mþ, 100), 151 (52), 150 (21), 136 (13), 98 (27), 97
(67), 96 (24), 95 (16), 94 (15), 84 (46), 69 (61), 68 (25), 67
(22), 55 (30), 54 (13), 53 (25), 41 (65). Anal. Calcd for
C10H13NO2 (179.09): C, 67.02; H, 7.31; N, 7.82. Found
C, 66.89; H, 7.18; N, 7.69.
4.6. (4aS,9aS)-())-2,4,4a,5,6,7,9,9a-Octahydro-
furo[2,3-f]indolizine 8a
Lithium aluminum hydride (0.74 g, 19.6 mmol) was
added to a solution of amide 5a (0.88 g, 4.9 mmol) in dry
THF (60 mL) at room temperature and the mixture
heated under reflux for 1 h. The resulting mixture was
cooled and water added cautiously until the lithium
complex was destroyed. The mixture was diluted with
water (20 mL) and extracted with chloroform
(3 ꢀ 15 mL). The combined extracts were washed with
water, dried over MgSO4 and concentrated in vacuo.
The obtained residue was purified by flash chromato-
graphy on a silica gel column eluting with chloroform/
acetone (10/1) to give pure 8a as yellow oil. Yield: 82%;
4.5. (4aS,3aS,9aS)-2,3,3a,4,4a,5,6,7,9,9a-Decahydro-
furo[2,3-f]indolizin-7-one 6a and (4aS,3aR,9aS)-
2,3,3a,4,4a,5,6,7,9,9a-decahydrofuro[2,3-f]indolizin-
7-one 7a
Method A: A catalytic amount of 10% Pd/C was added
to a solution of amide 5a (0.46 g, 2.56 mmol) in anhy-
drous methanol (10 mL) and stirred at rt under a
hydrogen atmosphere for 20 h. The solution was filtered
through a Celite pad to remove the catalyst. After
concentration in vacuo the residue was purified by flash
chromatography on a silica gel column eluting with
25
1
½aꢁ ¼ ꢂ1 (c 1, EtOH); H NMR (300 MHz, CDCl3): d
D

F. Szemes et al. / Tetrahedron: Asymmetry 15 (2004) 1763–1770
1769
1.40–1.53 (m, 1H, H-5), 1.71–1.82 (m, 1H, H-6), 1.85–
Acknowledgements
1.94 (m, 5H, H-4ax, H-4a, H-5, H-6, H-9ax), 2.19 (q,
1H, H-7, J ¼ 8:9 Hz), 2.68 (d, 1H, H-4eq, J ¼ 10:7 Hz),
3.03 (td, 1H, H-7, J ¼ 2 and 8.7 Hz), 3.42 (dd, 1H, H-
9eq, J ¼ 5:8 and 9.5 Hz), 4.63–4.67 (m, 2H, 2 ꢀ H-2),
4.68–4.76 (m, 1H, H-9a), 5.48 (s, 1H, H-3); 13C NMR
(75 MHz, CDCl3): d 21.9 (C-6), 29.7 (C-5), 32.2 (C-4),
53.0 (C-7), 58.6 (C-9), 64.2 (C-4a), 75.6 (C-2), 82.2 (C-
9a), 117.0 (C-3), 139.9 (C-3a). Anal. Calcd for
C10H15NO (165.12) C, 72.69; H, 9.15; N, 8.48. Found:
C, 72.34; H, 9.00; N, 8.22.
The authors thank the Grant Agency of the Slovak
Republic, Grant No1/9249/2002, and the Scientific
Council of the University of Le Havre, France, for their
financial support for this research program.
References and notes
1. Suffness, M.; Cordell, G. A. In The Alkaloids, Chemistry
and Pharmacology; Bossi, A., Ed.; Academic: New York,
1985; Vol. 25, pp 3–355.
2. (a) Gellert, E. In Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; Academic: New York,
1987; pp 55–132; See also the following review: (b) Li, Z.;
Zhong, J.; Huang, R. Synthesis 2001, 2365–2378.
3. (a) Donaldson, G. R.; Atkinson, M. R.; Murray, A. W.
Biochem. Biophys. Res. Commun. 1986, 31, 104–112; (b)
Huang, M. T.; Grollman, A. P. Mol. Pharmacol. 1972, 8,
538–549; (c) Buckley, T. F., III; Rapoport, H. J. Org.
Chem. 1983, 48, 4222–4232; (d) Iida, H.; Watanabe, Y.;
Tanaka, M.; Kibayashi, C. J. Org. Chem. 1984, 49, 2412–
2418.
4. (a) Kim, S.; Lee, J.; Lee, T.; Park, H.-G.; Kim, D. Org.
Lett. 2003, 5, 2703–2706; (b) Among these alkaloids, (ꢂ)-
antofine E (Chart 1) has recently attracted attention
because of its extremely potent inhibition of cancer cell
growth and is comparable to that of clinically employed
cytotoxic drugs.
4.7. (4aS,3aS,9aS)-2,3,3a,4,4a,5,6,7,9,9a-Decahydro-
furo[2,3-f]indolizine 9a and (4aS,3aR,9aS)-2,3,3a,4,4a,-
5,6,7,9,9a-decahydrofuro[2,3-f]indolizine 10a
Method A: Decahydrofuro[2,3-f]indolizines 9a and 10a
was prepared by the same procedure as octahydro-
furo[2,3-f]indolizine 8a from the mixture (3:1) of indo-
lizinones 6a and 7a, in 78% yield as a pale yellow oil.
Pure 9a was prepared from 6a, which was prepared by
Method B, in 75% yield as pale yellow oil. Method C: A
catalytic amount of 10% Pd/C was added to a solution
of amine 8a (0.5 g, 3 mmol) in anhydrous methanol
(10 mL) and stirred at room temperature under hydro-
gen atmosphere for 10 h. The solution was filtered
through Celite, concentrated in vacuo and the residue
purified by flash chromatography on a silica gel column
eluting with chloroform/acetone (20/1) to give an
inseparable mixture of indolizinones 9a and 10a (95%)
in a 7:1 ratio as pale yellow oil.
5. Staerk, D.; Lykkeberg, A. K.; Christensen, J.; Budnik, B.
A.; Abe, F.; Jaroszewski, J. W. J. Nat. Prod. 2002, 65,
1299–1302, and references cited therein.
6. (a) Elbein, A. D. Ann. Rev. Biochem. 1987, 56, 497–534;
(b) El Nemr, A. Tetrahedron 2000, 56, 8579–8629.
7. (a) Franklin, A.; Overman, L. E. Chem. Rev. 1996, 96,
505–522; (b) Tang, X.-Q.; Montgomery, T. J. Am. Chem.
Soc. 2000, 122, 6654–6950, and references cited therein.
8. Elbein, A. D.; Molyneux, R. J. In Alkaloids: Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; John Wiley
and Sons: New York, 1987; Vol. 5, pp 1–54, Chapter 1.
9. (a) Le Bosquain, D.; Decroix, B. Heterocycles 1993, 36,
4.7.1. (4aS,3aS,9aS)-2,3,3a,4,4a,5,6,7,9,9a-Decahydro-
25
D
1
furo[2,3-f]indolizine 9a. ½aꢁ ¼ þ42:4 (c 1, CHCl3); H
NMR (300 MHz, CDCl3): d 1.33–1.43 (m, 1H, H-5),
1.60–2.06 (m, 10H, 2 ꢀ H-3, 2 ꢀ H-4, H-4a, H-5, 2 ꢀ H-
6, H-7, H-9ax), 2.40–2.51 (m, 1H, H-3a, J ¼ 6 Hz),
2.95–3.08 (m, 2H, H-7, H-9eq), 3.80 (q, 1H, H-2,
J ¼ 8:4 Hz), 3.99 (td, 1H, H-2, J ¼ 2:7 and 8.5 Hz),
4.18–4.26 (m, 1H, H-9a); 13C NMR (75 MHz, CDCl3): d
21.6 (C-6), 28.0 (C-3), 30.3 (C-5), 30.8 (C-4), 36.9 (C-3a),
54.2 (C-9, C-7), 58.4 (C-4a), 67.0 (C-2), 75.2 (C-9a); MS
(m=z (%)): 168 (Mþ, 31), 166 (19), 140 (19), 124 (21), 122
(19), 112 (23), 98 (10), 97 (19), 96 (26), 84 (38), 70 (64),
55 (33), 42 (19), 28 (100). Anal. Calcd for C10H17NO
(167.13) C, 71.81; H, 10.25; N, 8.37. Found: C, 71.50; H,
10.08; N, 8.21.
ꢁ
ꢀ
2303–2314; (b) Marchalın, S.; Szemes, F.; Bar, N.;
Decroix, B. Heterocycles 1999, 50, 445–452.
ꢁ
ꢀ
10. Marchalın, S.; Decroix, B.; Morel, J. Acta Chem. Scand.
1993, 47, 287–291.
€
11. Daıch, A.; Decroix, B. J. Heterocycl. Chem. 1996, 33, 873–
878.
12. (a) Pigeon, P.; Decroix, B. Tetrahedron Lett. 1996, 37,
7707–7710; (b) Othman, M.; Pigeon, P.; Decroix, B.
Tetrahedron 1997, 53, 2495–2504.
ꢁ
ꢀ
13. Szemes, F.; Marchalın, S.; Bar, N.; Decroix, B. J.
Heterocycl. Chem. 1998, 35, 1371–1375.
14. Ostendorf, M.; Van der Neut, S.; Rutjes, F. P. J.;
Hiemstra, H. Eur. J. Org. Chem. 2000, 105–113.
15. For reviews for the Birch reduction, see: (a) Birch, A. J.;
Rao, S. Adv. Org. Chem. 1972, 8, 1–65; (b) Mander, L. N.
In Comprehensive Organic Synthesis; Trost, B. M., Flem-
ing, I., Eds.; Pergamon: New York, 1991; Vol. 8; See also
in furan series: (c) Semple, J. E.; Wang, P. C.; Lysenko, Z.;
4.7.2. (4aS,3aR,9aS)-2,3,3a,4,4a,5,6,7,9,9a-Decahydro-
furo[2,3-f]indolizine 10a. From the NMR spectra of the
mixture; H NMR (300 MHz, CDCl3): d 1.22–1.35 (m,
1
1H, H-4ax), 1.48–1.58 (m, 1H, H-3), 1.60–1.82 (m, 6H,
H-3, H-4eq, H-4a, H-5), 1.93–2.02 (m, 3H, H-3a, H-5,
H-7), 2.18 (dd, 1H, H-9ax, J ¼ 2:5 and 12.5 Hz), 2.95
(td, 1H, H-7, J ¼ 2:4 and 8.5 Hz), 3.27 (dd, 1H, H-9eq,
J ¼ 1:8 and 12.5 Hz), 3.68–3.75 (m, 2H, H-2, H-9a), 3.89
(q, 1H, H-2, J ¼ 8:0 Hz); 13C NMR (75 MHz, CDCl3)1:
d 21.1 (C-6), 30.3 (C-3), 32.2 (C-5), 33.0 (C-4), 36.6 (C-
3a), 53.9 (C-9), 54.2 (C-7), 62.5 (C-4a), 66.2 (C-2), 76.8
(C-9a).
ꢀ
Joullie, M. M. J. Am. Chem. Soc. 1980, 102, 7505–7510;
(d) Hultin, P. G.; Mueseler, F.-J.; Jones, J. B. J. Org.
Chem. 1991, 56, 5375–5380.
16. See for example the following reference: Zimmerman, H.
E.; Wang, P. A. J. Am. Chem. Soc. 1990, 112, 1280–1281.
17. For representative reports in the furan reduction area, see
the following: (a) Beddoes, R. L.; Lewis, M. L.; Gilbert,
P.; Quayle, P.; Thompson, S. P.; Wang, S.; Mills, K.
Tetrahedron Lett. 1996, 37, 9119–9122; (b) Donohoe, T. J.;

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19. Vrabel, V.; Kozisek, J.; Marchalın, S. Acta Cryst. E (in
ꢀ
press).
ꢁ ꢁ
ꢀ
Guillermin, J. B.; Calabrese, A. A.; Walter, D. S.
Tetrahedron Lett. 2001, 42, 5841–5844; (c) Donohoe, T.
J.; House, D. J. Org. Chem. 2002, 67, 5015–5018, and
references cited therein; (d) Donohoe, T. J.; Fisher, J. W.;
Edwards, P. J.; Walter, D. S. Org. Lett. 2004, 6, 465–467.
20. (a) Saul, R.; Ghidoni, J. J.; Molyneux, R. J.; Elbein, A. D.
Proc. Natl. Acad. Sci. U.S.A 1985, 82, 93–97; (b)
Winchester, B. G.; Al Daher, S.; Carpenter, N. C.; Cenci
di Bello, I.; Choi, S. S.; Fairbanks, A. J.; Fleet, G. W. J.
Biochem. J. 1993, 290, 743–749.
18. Szemes, F. Ph.D. Dissertation, Bratislava University,
2001.