Synthesis and reductive desulfurization of chiral non-racemic benzothienoindolizines. An efficient approach to a novel bioactive tylophorine alkaloid analogue and 6-phenylindolizidine

Article abstract of DOI:10.1016/j.tetasy.2009.08.010

Enantiopure di- and tetrahydro[1]benzothieno[3,2-f]indolizines 3,4,9 and the benzothieno analogue 5 of the bioactive alkaloid tylophorine 10 were synthesized easily from the readily available benzo[b]thiophene-3-carboxaldehyde 1 and (S)-glutamic acid 2 in

Full text of DOI:10.1016/j.tetasy.2009.08.010

Tetrahedron: Asymmetry 20 (2009) 2137–2144
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Tetrahedron: Asymmetry
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Synthesis and reductive desulfurization of chiral non-racemic
benzothienoindolizines. An efficient approach to a novel bioactive
tylophorine alkaloid analogue and 6-phenylindolizidine
a
a
a,
b
ˇ a
ˇ
ˇ
*
ˇ
Peter Šafár , Jozefína Zúziová , Mária Bobošíková , Štefan Marchalín , Nadezda Prónayová ,
Sébastien Comesse c, Adam Daïch c,
*
a Department of Organic Chemistry, Faculty of Chemical and Food Technology, Slovak University of Technology, SK-81237 Bratislava, Slovak Republic
b Central Laboratories, Faculty of Chemical and Food Technology, Slovak University of Technology, SK-81237 Bratislava, Slovak Republic
c URCOM, EA 3221, INC3M CNRS FR-3038, UFRST of the University of Le Havre, 25 rue Philippe Lebon, BP: 540F-76058 Le Havre Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantiopure di- and tetrahydro[1]benzothieno[3,2-f]indolizines 3,4,9 and the benzothieno analogue 5 of
the bioactive alkaloid tylophorine 10 were synthesized easily from the readily available benzo[b]thio-
phene-3-carboxaldehyde 1 and (S)-glutamic acid 2 in good overall yields. Applying a diastereoselective
reductive desulfurization of benzo[b]thiophene 3,4 and 5 were readily converted into the enantiopure
alcohols 11a–d, alcohols 11c,d and the target 6(R)-phenyl-8a(R)-indolizidine 6 (7 steps, 14%). During
these reduction studies, the results obtained including the stereoinduction of the reaction are also
discussed.
Received 14 July 2009
Accepted 6 August 2009
Available online 14 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
phene series allowed to successfully obtain enantiopure 7-pheny-
lindolizidinols of type III8 in better diastereoselectivities.
Synthetic work and structure–activity studies on natural poly-
hydroxylated indolizidines have now revealed that these com-
pounds are of increased pharmacological significance. This is due
to their participation in biologically important pathways as excel-
lent inhibitors of glycosidases, for example, against the AIDS virus
HIV and some carcinogenic cells as well as against other important
pathologies.1,2
Another important, scarce and emerging class of alkaloids that
have been identified as challenging targets are the nitrogen hetero-
cyclic systems V and VI containing an aryl group at the C6-position of
the indolizidine ring (Fig. 1). The alkaloid ipalbidine V9 in particular,
which was found to possess virtually no optical activity1e was ob-
tained using various strategies.10 The most frequently applied meth-
od was based on the elaboration of a-diazoimide derivatives via a
Interestingly, alkylindolizidinols of types Ia and Ib have shown
in numerous cases an increase of glycosidase activity as demon-
strated by Pearson et al. and others.3 This fact is similar to that ob-
served with the popular azasugar scaffolds and is generally due to
the enhancement of the interaction of the alkyl groups with the en-
zymes activated sites by providing favourable conformational flex-
ibility to the molecules.4
In this line, research in our laboratories has focused on the
synthesis of enantiopure benzoanalogues of lentiginosine and
swainsonine5 and enantiopure tetrahydrofuran-fused indolizidi-
nols, which could be considered as protected new indolizidinediols.6
More recently, we have described a concise and very efficient route
to enantiopure 7-ethylindolizidinols of type II7 using an uncommon
strategy based on reductive desulfurization by Raney-nickel of thio-
phene ring of chiral thienoindolizidinediones and the corresponding
thienoindolizidinols. Extension of this strategy to the benzo[b]thio-
[3+2]-cycloaddition of a phenylsulfonyl-substituted isomünchnone
intermediate with an alkene, followed by a subsequent elimination
of phenylsulfinic acid.10c–f Elsewhere, only two enantioselective to-
tal synthesis of (+)-ipalbidine were also achieved and the most
H
OH
OH
(OH)n
R2
R1
H
H
H
1
3
Ph
Ph
7
N
N
N
N
m(HO)
Ia,b
IIa,b
IIIa,b
IVa,b
H
H
H
N
6
HO
Ph
6
N
N
6
Ph
HO
Ac
V
VI
6
:
(+)-Ipalbidine
: ( )-Crepidamine Our target:
* Corresponding author. Tel.: +33 02 32 74 44 03; fax: +33 02 32 74 43 91.
E-mail address: adam.daich@univ-lehavre.fr (A. Daïch).
Figure 1. Representative natural and unnatural products I–VI containing an
indolizidine unit and one 6 of our targets.
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.08.010

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P. Šafár et al. / Tetrahedron: Asymmetry 20 (2009) 2137–2144
2138
important one of them starts with (S)-pyroglutamic acid by employ-
ing an intramolecular McMurry coupling reaction with a low-valent
titanium, as a key and pivotal step.11
2.2. Synthesis of the benzothieno analogue 5 of the bioactive
tylophorine alkaloid 10
Herein in a full account and in continuation of our interest in
the synthesis of polysubstituted indolizidines, we extend our work
to reductive desulfurization by Raney-nickel (Fig. 2) of an aromatic
ring containing-sulfur atom. In this sense, we duly report an easy
and efficient approach to novel benzo[b]thieno-analogue of the
bioactive tylophorine alkaloid 5 and the corresponding 6-pheny-
lindolizidine 6 in highly diastereoselective manner.
As highlighted in Scheme 1, our synthesis began with the ami-
no-carboxaldehyde condensation, between the well known
benzo[b]thiophene-3-carboxaldehyde 114 and the commercially
available and inexpensive L-glutamic acid 2, to provide the ex-
pected Schiff base. A subsequent in situ reduction of the imine
intermediate formed with NaBH4 taking 1.5 h at room temperature
followed by treatment with concentrated hydrochloric acid at the
same temperature gave the (S)-N-benzothienylmethyl glutamic
acid 7 in an overall yield of 80% in two steps. Ethanolic treatment
of the amino-dicarboxylic acid at reflux for 8 h formed the N-benz-
othien-3-ylmethyl-pyroglutamic acid 8 in 74% yield. The latter
pure acid 8 was subjected to thionyl chloride in dichloromethane
at reflux for 6 h followed by treatment with aluminium trichloride
of high analytical quality (99.99%) according to the Friedel–Crafts
reaction for 3 h to supply the expected tricyclic keto-lactam 3 in
72% yield. Reduction of the ketone function of the lactam 3 (e.g.,
NaBH4, MeOH, 0 °C to rt, 16 h) gave (11S)-alcohol 4 as a single
trans-diastereomer (79%). The stereochemical assignments of this
structure are based on the analysis of the NMR spectra including
HMBC, HSQC and COSY experiments. In addition, these analyses
show that there is no evidence for the formation of the epimeric
cis-alcohol-(11R) for (11S)-alcohol 4. It is believed that this result
reflects a preference for axial hydride attack from the more hin-
dered endo face of the tricyclic system 3.15
O
H
H
S
S
S
S
N
N
O
1
O
O
5
6
3
4 steps
+
Our targets
8aR
O
6R
OH
H
H
H
HO
N
H2N
HO2C
N
2
4
Figure 2. Scheme leading to benzo[b]thienoindolizidine 5 and 6-phenylindolizidine
6 from carboxaldehyde 1 and (S)-glutamic acid 2.
In a final effort to reach our first target 5, the reduction of (11S)-
alcohol 4 was conducted with the triethylsilane/trifluoroacetic acid
couple at room temperature for 4 h. Under these conditions, the
lactam 9 was isolated in 94% yield and 72% isolated yield. The
reduction of the (11aS)-lactam 9 with LAH in refluxing THF was
unsuccessful and the starting material was recovered. Ultimately,
reduction with BH3ꢀMe2S in THF provided the title compound
(11aS)-hexahydro[b]benzothieno[3,2-f]indolizine 5 in 85% yield.
2. Results and discussion
2.1. Synthetic strategy
The selection of enantiopure products 5 and 6 was influenced
by our recent proposal starting from heteroaromatic carboxaldehy-
des and enantiopure (S)-glutamic acid to provide, in few steps, a
wide range of enantiopure aromatic and heteroaromatic ana-
logues5,12 of tylophorine alkaloids.13 During these investigations,
additional manipulations based on a regioselective reduction
and/or desulfurization of an aromatic sulfur-containing ring have
led to a new class of alkyl indolizidinols6,7 including the two regioi-
somers IVa,b (Fig. 1) of the targeted product 5.8
Retrosynthetically (Fig. 2), the targeted compound 5 can be
envisioned as coming from keto-amide 3 via a double ketone and
lactam reduction. The asymmetry, as well as the nitrogen atom
source, could be effectively derived from the same chiral pool ap-
proach using (S)-glutamic acid 2 as the starting substrate. Thus,
in turn the tricyclic keto-lactam 3 may be reached by a concatena-
tion of amino-carboxaldehyde condensation, imine reduction, ami-
no-acid cyclodehydration and Friedel–Crafts reaction.
2.3. Diastereoselective synthesis of 6-phenylindolizidinols
11a–d
Based on the reductive desulfurization technique of heterocy-
clic sulfur-containing rings, which is well known,7,8 we anticipated
that by the same procedure benzo[b]thieno[3,2-f]indolizines 3–5
and 9 (Scheme 1) could serve as a phenyl reservoir more suitable
for the preparation of novel 6-phenylindolizidine and 6-phen-
ylindolizidinol derivatives.
Thus, as highlighted in Scheme 2, we began our study with our
well-established protocol using the Raney-nickel hydrogenolysis of
both carbonyl functions and the benzothiophene ring to the enan-
tiopure keto-lactam 3. As might be expected, compound 3 with
activated Ra–Ni in anhydrous methanol under stirring and under
CO2H
HO2C
H
NH2 i: 1 M NaOH
HO2C
S
EtOH, 8 h
reflux
S
54 h, rt
S
S
+
ii: NaBH4, 1.5 h, rt
N
HN
N
iii: HCl (conc.)
74%
CO2H
O
O
CO2H
1
2
7
8
80%
5
O
O
i: SOCl2, CH2Cl2
6 h, reflux
O
O
72%
ii: AlCl3, 3 h
H
O
OH
LiAlH4
THF
Et3SiH
H
H
H
N
H
N
NaBH4
S
S
TFA
S
S
4 h, rt
4 h, reflux
MeOH, 4 h
N
N
N
0 °C to rt
10-(13aS)
85%
72%
79%
O
O
O
(Tylophorine)
9
3
5
4
Scheme 1. Schematic of the synthesis of the tricyclic keto-lactam 3 and phenanthroindolizidinol 10.

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P. Šafár et al. / Tetrahedron: Asymmetry 20 (2009) 2137–2144
2139
hydroxyhexahydrothieno[3,2-f]indolizine-6-one,7 which were
readily accessible from thiophene-3-carboxaldehyde. Thus, it be-
came clear that there are no similar stereoisomeric distributions
when keto-lactams in benzothiophene 3 and the thiophene nu-
cleus were reduced. In the latter case, only three stereoisomers
were obtained (90% yield) and the distribution was of 24:69:0:7 ra-
tio for related ethyl-stereoisomers largely in favour of cis-alcohols
(93% instead of 57% in the case given herein as shown in Scheme 2).
Despite the general preference for cis-hydrogenation with respect
to the angular pyrrolidone carbon stereogenicity, these first results
made the rationalization of the reductive-cleavage cascade of the
benzothiophene ring of (11aS)-3 more difficult. In contrast, the
reductive-cleavage of the enantiopure trans-(11S)-alcohol 4 and
its thiophene analogue7 seems to be operative in the same sense
as well during the hydride deliverance (exo-approach) as the level
of the stereo-induction (trans-alcohols 11c:11d were obtained in a
65:35 ratio in the case of (11S)-alcohol 4 while trans-alcohols in
the case of the thiophene analogue were obtained in a 77:23 ra-
tio7). Finally, in light of these reductive-cleavage investigations
from both ketone 3 and alcohol 4 the benzothiophene ring was
probably opened first under the conditions used as suggested in
the thiophene series.7 This fact was corroborated by the reduc-
tive-desulfurization resulting from the (11S)-alcohol 4 showing
that if the ketone function of (11aS)-3 was reduced first, the stereo-
isomer distribution obtained for alcohols (6S,8R,8aS)-11c and
(6R,8R,8aS)-11d (19:24) in the mixture of the four stereoisomers
11a–d (17:40:19:24) would be approximately the same as the
one obtained from the reduction of (11S)-alcohol 4 (Scheme 2;
65:35 in percent or 28:15 instead of 19:24).
OH
OH
H
H
N
N
Ph
Ph
O
11a
O
O
H
(6S,8S,8aS)-
(6R,8S,8aS)-11b
S
i
11aS
OH
H
OH
H
90%
N
O
(11aS)-3
N
N
Ph
Ph
O
O
-11d
11c (6R,8R,8aS)
(6S,8R,8aS)-
(i): H2, Ra-Ni
MeOH,reflux
H
i
92%
OH
H
OH
8a
nOe
Ph
H
8 N
H
H
S
6
H
O
N
H
O
-11d
(6R,8R,8aS)
(11S,11aS)-4
Scheme 2. All four possible diastereomers (6S,8S,8aS)-11a, (6R,8S,8aS)-11b,
(6S,8R,8aS)-11c and (6R,8R,8aS)-11d were obtained in a 17:40:19:24 ratio deter-
mined by HPLC and NMR essays. Selected NOEs for the determination of relative
configuration in the 6-phenylindolizidinol 11d established by 1D-NOE 1H NMR
experiments.
203 kPa of hydrogen gas at reflux for 60 h provided the four possi-
ble diastereomers 11a–d. These inseparable products were ob-
tained in very good yield (90%) in a 17:40:19:24 ratio in which
the couple of both cis-alcohols (6S,8S,8aS)-11a, (6R,8S,8aS)-11b
represent 57% of the mixture.
For further comparison, the enantiopure trans-(11S)-alcohol 4
was obtained easily from (11aS)-keto-lactam 3 (Scheme 1) and
then submitted to the reductive cleavage of the benzothiophene
ring according to the same protocol used for (11aS)-keto-lactam
3 (Scheme 2). Under these conditions (i.e., H2, Ra–Ni, MeOH, reflux,
72 h), a solid mixture of inseparable stereoisomers (6S,8R,8aS)-11c
The structure of alcohol derivatives 11a–d was confirmed by
means of 1H and 13C NMR including HMBC, HSQC and COSY exper-
iments. Their configuration aspects were studied by using 1H NMR
data, including NOE measurements. In the case of alcohols 11a–d,
the appearance of
a doublet of doublet for H8 for 11c at
d = 3.14 ppm (J = 9.2 and 11.5 Hz) and for 11d at d = 3.40 ppm
(J = 9.4 and 9.4 Hz), respectively. This clearly indicated the trans-
diaxial relationship between H7ax, H8 and H8a. Similarly, in the case
of diastereomers (6R)-11, the appearance of a triplet of triplets for
H6 for 11b at d = 3.11 (J = 4.4 and 12.2 Hz) and 11d at d = 2.75
(J = 3.3 and 12.0 Hz), respectively, was observed. The large coupling
constants indicated the trans-diaxial orientation between H5, H6
and H7 with a phenyl group in the equatorial position at C6-carbon
(See 1H and 13C NMR details in Table 1).
and (6R,8R,8aS)-11d in
a 65:35 ratio favouring the alcohol
(6S,8R,8aS)-11c was obtained in excellent (92%) yield. Interest-
ingly, by triturating the reaction residue in dry acetone, the result-
ing precipitate was filtered off and then recrystallized from dry
THF to provide the enantiopure alcohol (6R,8R,8aS)-11d as a minor
stereoisomer (see the resulting attributions from NOE measure-
ments of this isomer in Scheme 2).
In order to measure the impact of the absence of a substituent
at the C8-position as well as the presence or the absence of the car-
These results were compared to those obtained in a thiophene
series from both enantiopure (8aS)-hexahydrothieno[3,2-f]indoli-
zine-6,9-dione and its ancillary alcohol, namely, (8aS,9R)-9-
bonyl group at the a-position of the nitrogen atom on the reductive
desulfurization process and the stereochemical course, a set of
additional experiments was carried out.
Table 1
Chemicals shifts (d in ppm) and coupling constants (J in Hz) in the 1H and 13C NMR spectra of the four diastereomers 11a–d in CD3OD solution
Proton/carbon
(6S,8S,8aS)-11a
(6R,8S,8aS)-11b
(6S,8R,8aS)-11c
(6R,8R,8aS)-11d
H-5eq/C-5
J (Hz)
H-5ax/C-5
J (Hz)
H-6/C-6
J (Hz)
3.97 dd/45.1
7.0, 13.1
3.36 dd/45.1
4.6, 12.7
3.15 q/37.3
6.7
4.10 ddd/47.4
1.4, 4.7, 12.7
2.82 t/47.4
12.4
3.11 tt/36.4
4.4, 12.2
4.43 td/42.8
1.7, 13.9
3.09 ddd/42.8
1.5, 4.5, 13.9
3.31–3.29 m/38.4
—
4.05ddd/46.9
1.6, 3.5, 12.0
2.71 tt/46.9
1.5, 12.0
2.75 tt/42.3
3.3, 12.0
H-7eq/C-7
J (Hz)
H-7ax/C-7
J (Hz)
H-8/C-8
J (Hz)
H-8a/C-8a
J (Hz)
2.38–2.31 m/39.1
—
2.20–2.05 m/39.1
—
3.95–3.88 m/68.1
—
3.95–3.88 m /60.9
—
2.20–2.05 m/39.3
—
2.01 t/39.3
13.1
3.95–3.88 m/67.7
—
3.77 dt/62.3
1.8, 7.2
2.40–2.31 m/40.5
—
2.19 dddd/41.4
1.9,2.9, 3.8, 12.5
1.77 ddt/41.4
1.9, 10.5, 12.3
3.40 dt/73.5
3.9, 9.4
1.95 ddd/40.5
4.8, 11.6, 13.2
3.14 ddd/70.3
3.9, 9.2, 11.5
3.34 tt /64.6
2.5, 7.7
3.36 ddd/64.1
5.4, 7.4, 9.2

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P. Šafár et al. / Tetrahedron: Asymmetry 20 (2009) 2137–2144
2140
Firstly, the enantiopure indolizidinone 9 was subjected to the
structure are on the same side, both heteroatoms interact favour-
ably with the reductant support but by the sulfur atom poisoned
Ra–Ni rendered the reductive desulfurization non exclusive.
Interestingly, as reported in Scheme 5 a catalytic hydrogenation
(i.e., H2, Pd/C, EtOH) of hexahydro-6-(3-methoxyphenyl)indolizine
rac-15 provided a mixture of two 6-(3-methoxyphenyl)indolizi-
dine derivatives cis-16a (axial isomer) and trans-16b (equatorial
isomer) in favour of the cis-16a one (dr = 3:2 only).16 This result
indicates that in our case a highly diastereoselective reductive
desulfurization of the tylophorine analogue 5 can proceed simulta-
neously, affording a new very effective approach to trans-6-pheny-
lindolizidine derivatives with synthetic and biological interest
notably for dopamine auto-receptor activity 3-PPP.
same protocol outlined above for the reduction of 3 and 4 (Scheme
2). Under these conditions (i.e., H2, Ra–Ni, MeOH, reflux, 72 h), lac-
tam 9 provided a mixture of two inseparable diastereomers
(6S,8aR)-12a and (6R,8aR)-12b in an excellent yield (98%, Scheme
3) and in a 70:30 ratio. This result is comparable to that observed
during the reduction of alcohol (11S,11aS)-4 in the benzothiophene
series which gives alcohols (6S,8R,8aS)-11c and (6R,8R,8aS)-11d in
similar ratio (65:35). These observations indicated that in all prob-
ability, the presence or absence of a substituent at the C8-position
had no effect on the reduction-cleavage process.
H
N
H
H
N
S
H2, Ra-Ni
H
N
H
N
H
N
N
MeOH
Ph
Ph
:
H2
Pd/C
EtOH
reflux
O
X
O
98%
(a) cis
(b) trans
9 (X=O)
12,
70
30
+
5 (X=H,H)
57%
MeOH
O
O
O
H2, Ra-Ni
H
H
68%
reflux
H
H
H
7
(R)
Ph
3:2
rac-15
cis-16a
trans-16b
8
8a
1
6
(R)
5
3
N
H
Scheme 5. Result of the catalytic hydrogenation of (S)-6-(3-methoxyphenyl)-
1,2,3,5,8,8a-hexahydroindolizine rac-15.
2
H
H
N
nOe
Ph
(6R,8aR)-6
6
(6R,8aR)-
3. Conclusion
Scheme 3. Target 6R,8aR-phenyloctahydroindolizidine
tylophorine analogue 5.
6 by reduction of the
Herein, we have improved our strategy which uses a reductive
desulfurization of the chiral heterocyclic sulfur systems with a Ra-
ney-nickel as a reducing agent to provide various alkylindolizidine,
arylindolizidines and corresponding indolizidinols related to
alkaloids.
The structure of these inseparable compounds was, in this case,
established from the mixture of diastereomeric 6-phenylindoli-
zines 12a and 12b by means of 1H and 13C NMR including HMBS,
HSQC and COSY experiments.
During the investigations shown, the diastereoselective desul-
furization of benzo[3,2-f]thienoindolizinone and the corresponding
benzo[3,2-f]thienoindolizinol was studied and its utility as a key
step in the synthesis of indolizidines fused to benzothiophenes
and phenylindolizidines related to alkaloids was confirmed. In fact,
as an application of this strategy, we have successfully synthesized
the novel enantiopure benzothieno analogue 5 of the bioactive
alkaloid tylophorine in six steps (21% yield) starting from readily
available benzo[b]thiophene-3-carboxaldehyde 1 and (S)-glutamic
acid 2. Also, by using the same strategy we have described a new
(6R)-phenyl-(8aR)-indolizidine alkaloid core 6 in seven steps in
an overall yield of 14%. The last step closing this sequence consists
of the sensitive Ra-Ni reductive-desulfurization of the tylophorine
benzothieno analogue 5 which occurred, in a diastereospecific
manner. In all these studies, Ra–Ni was used as a catalyst and
the benzothiophene ring as the phenyl group source.
Secondly, because all attempts at separation of lactams 12a and
12b as excellent precursors for the targeted cis- and trans-6-pheny-
lindolizidine derivatives failed, the reduction of the benzothieno
analogue 5 of the tylophorine alkaloid 10 was considered. In this
line, treatment of 5 under the well-established reductive-desulfur-
ization protocol (Scheme 4) led to a product which seems to be the
(6R,8aR)-6 as the sole reaction stereoisomer in 68% yield. The
structure of this isomer was identified without ambiguity by
NMR studies including NOE measurements (Scheme 3). The forma-
tion of this unique diastereomer 6 can be explained in terms of the
high basicity of the nitrogen atom of the starting indolizine 5,
which interacts favourably with the reducing support, thus render-
ing the hydrogen deliverance exclusively from the exo-face.
H
N
H
H
N
Ph
Ph
Finally, these structures deserve interest as they are analogous
to naturally occurring and/or bioactive substances with different
degrees of substitution. Further investigations using these attri-
butes aiming at preparing a small library of novel alkyl- and aryl-
indolizidinediols are currently underway in our group, and the
results will be published in the near future in a full account.
H2, Ra-Ni
MeOH, reflux
N
S
79%
Ref. 8
a
b
) trans
(
) cis
(
13
14, 90
:
10
Scheme 4. Target (7S or 7R,8aR)-phenyloctahydroindolizine 14a,b by reduction of
the tylophorine analogue 13.
4. Experimental
4.1. General
In addition, when the regioisomer of indolizine 5, namely,
(11aS)-1,2,3,5,11,11a-hexahydrobenzothieno[2,3-f]indolizine 13,
was reduced under the same conditions,8 two stereoisomers
14a,b were obtained (79%, Scheme 4) in a 90:10 ratio in favour
of the cis-phenylindolizidine isomer 14a with exactly the opposite
stereoinduction. This result suggests also that the relative position
of the sulfur atom towards the nitrogen atom plays a pivotal role in
the reductive desulfurization process. Thus, we believe that when
the sulfur and the nitrogen atoms of the benzothienoindolizine
Melting points were recorded on a Boetius hot block and are
corrected. Tetrahydrofuran was distilled under an atmosphere of
dry nitrogen from sodium benzophenone ketyl or purchased dry
from the Aldrich Chemical Company in Sure/Seal bottles; dichloro-
methane was distilled from calcium hydride. All other solvents
were used as supplied (analytical or HPLC grade) without prior
purification. The reactions performed under an atmosphere of

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P. Šafár et al. / Tetrahedron: Asymmetry 20 (2009) 2137–2144
2141
argon gas were maintained by an inflated balloon. Ascending Flash
column liquid chromatography (FLC) was performed on Silica Gel
Kieselgel 60 (40–63 ml, 230–400 mesh) and analytical thin-layer
chromatography (TLC) was performed on aluminium plates pre-
coated with either 0.2 mm (DC-Alufolien, Merck) or 0.25 mm Silica
Gel 60 F254 (ALUGRAM-SIL G/UV254, Macherey-Nagel) and by
dipping the plates in an aqueous H2SO4 solution of cerium sul-
fate/ammonium molybdate followed by charring with a heat gun.
HPLC analyses were performed on Varian system 9012 with diode
array Varian 9065 polychrom UV detector: column CC 250/3
Nucleosil 120-5 C18, 250 ꢁ 3 mm (fy Macherey Nagel). Mobile
phase: solvent A: water/acetonitrile/methane-sulfonic acid (1000/
25/1), solvent B: water/acetonitrile/ methanesulfonic acid (25/
1000/1), elution mode: gradient with 5–50% solvent B, flow rate:
0.65 mL/min, UV detection: 210 nm (DAD), 35 °C, 20 min. GC–MS
analyses were performed on GC–MS Varian Saturn 2100 T, ion trap
MS detector, 70 eV. Column: Varian, Factor Four capillary column
VF -5 ms 30m ꢁ 0.25 mm ID, DF = 0.25. Optical rotations were
measured with a POLAR L-lP polarimeter (IBZ Messtechnik) with
a water-jacketed 10 cm cell at the wavelength of sodium line D
(k = 6 589 nm). The specific rotations are given in units of
10ꢂ1 deg cm2 gꢂ1 and concentrations are given in g/100 mL.
The infrared spectra were recorded on a Nicolet 5700 FT-IR spec-
trometer as KBr disc (KBr) or as thin films on KBr plates (film). The 1H
and 13C NMR spectra were recorded on a VXR 300 and Inova 600 Var-
ian spectrometer instrument in CD3OD or CDCl3. Solvents and chem-
ical shifts (d) are quoted in ppm and are referenced to the
tetramethylsilane (TMS) as the internal standard. The COSY, NOESY
and DIFFNOE techniques were used in the assignment of 1H–1H rela-
tionships and the determination of relative configuration. The HSQC
and HMBC techniques were used throughout for the assignment of
the 1H–13C relationships. High-resolution spectrometry was per-
formed using waters UPLC system on Micromass Q-Tof Micro MS
system with ESI+ ionization (measured mass represents M+H+).
The resulting solution was filtered and concentrated in vacuo to
give a solid. Crystallization from a mixture of toluene/heptane
(9:1) afforded acid 8 (8.1 g, 74%) as colourless crystals; Rf = 0.56
(dichloromethane/acetone 3:1); mp 156–158 °C; [
1.0, MeOH); IR (
, cmꢂ1, KBr): 3060, 2871, 2598, 1721, 1693,
1633, 1452, 1441, 1417, 1393, 1353, 1325, 1298, 1261, 1228,
a]D = +42.4 (c
m
1191, 1151, 1084, 1047, 1018; UV (kmax, nm (log e)): 298 (2.68),
289 (2.65), 263 (2.83), 259 (2.85), 227 (3.45), 200 (3.40); 1H NMR
(600 MHz, CD3OD): d 7.88 (dd, 1H, HAr; J = 2.1 and 7.5 Hz), 7.81
0
(dd, 1H, HAr; J = 2.1 and 7.5 Hz), 7.48 (s, 1H, H2 ), 7.37 (dt, 1H,
HAr; J = 2.1 and 7.4 Hz), 7.36 (dt, 1H, HAr; J = 2.1 and 7.4 Hz), 5.22
(d, 1H, N–CH; J = 14.9 Hz), 4.35 (d, 1H, N–CH; J = 14.9 Hz), 3.91
(dd, 1H, H2; J = 3.3 and 9.2 Hz), 2.52 (tt, 1H, H4; J = 9.1 and
16.9 Hz), 2.41 (ddd, 1H, H4; J = 4.0, 9.4 and 16.9 Hz), 2.23 (tdd,
0
1H, H3; J = 9.0, 9.2 and 13.1 Hz), 2.05 (tdd, 1H, H3 ; J = 3.7, 9.4 and
13.1 Hz); 13C NMR (150 MHz, CD3OD): d 177.8 (s, CO2), 174.9 (s,
0
0
0
0
CO), 142.1, 139.2, 131.6 (s, C3 ,3a ,7a ), 127.6 (d, C2 ), 125.9, 125.5
0
0
0
0
(d, C5 ,6 ), 123.9, 122.8 (d, C4 ,7 ), 60.3 (d, C2), 40.2 (t, N–CH2), 30.8
(t, C4), 23.9 (t, C3); HRMS calcd for C14H13NO3S [M+1]+:275,0616,
found 276.0661.
4.4. (11aS)-1,11a-Dihydro[1]benzothieno[3,2-f]indolizine-
3,11(2H,5H)-dione 3
To a solution of a freshly crystallized carboxylic acid 8 (13.76 g,
50 mmoL) in dichloromethane (300 mL) was added thionyl chlo-
ride (4.7 mL, 6.5 mmol) at 0–5 °C. The mixture was stirred at reflux
for 6 h, and then cooled to 0 °C. Under vigorous stirring, AlCl3 (14 g,
105 mmol) was added in small portions. The mixture was stirred
for 1 h at 0 °C and then for an additional 2.5 h at room temperature.
After cooling to 0 °C, water (220 mL) and 15% HCl (5 mL) were
added carefully. The two phases were separated and the aqueous
layer was extracted twice with dichloromethane (50 mL). After
washing with brine, the dichloromethane phase was dried with
MgSO4 and concentrated. The resulting product was purified by
flash column chromatography (dichloromethane) to yield ketone
3 as a pale yellow solid. Recrystallization from toluene/n-hexane
(10:1) gave 3 (9.25 g, 72%) as light yellow crystals; mp 181–
4.2. (S)-N-(1-Benzo[b]thien-3-ylmethyl)glutamic acid 7
(S)-Glutamic acid 1 (7.36 g, 50 mmol)wasadded at roomtemper-
ature to a freshly prepared solution of NaOH (2 M, 45 mL) and EtOH
(10 mL). To the resulting mixture was added dropwise a solution of
freshly distilled benzo[b]thiophene-3-carbaldehyde14 1 (9.73 g,
60 mmol) in EtOH (18 mL) over 14 h and the reaction mixture was
then stirred for 40 h. Then, sodium borohydride (2.28 g, 60 mmol)
was added at 0 °C in small portions, and stirred for 90 min allowing
the temperature to rise to room temperature. The resulting clear
solution was extracted with ether (3 ꢁ 50 mL). The aqueous layer
was acidified to pH 3 at 0–5 °C with HCl (1:1). The crystalline precip-
itate was collected, washed with cooled water (50 mL) and dried to
give a solid. The analytically pure compound 7 was obtained by crys-
tallization from dioxane as colourless crystals (11.72 g, 80%); mp
183 °C; [a]D = +73.6 (c 1.0, MeOH); IR (m
, cmꢂ1, KBr): 3342, 3319,
3057, 1666, 1641, 1594, 1563, 1528, 1469, 1460, 1423, 1415,
1391, 1333, 1297, 1276, 1255, 1239, 1217, 1192, 1145, 1084,
1065, 1020; UV (kmax, nm (log e)): 300 (3.29), 249 (3.11), 236
(3.15), 204 (3.45); 1H NMR (600 MHz, CDCl3): d 7.92 (d, 1H, H9;
J = 8.1 Hz), 7.84 (d, 1H, H6; J = 8.1 Hz), 7.56 (dt, 1H, H8; J = 1.0 and
7.7 Hz), 7.49 (dt, 1H, H7; J = 0.7 and 7.7 Hz), 5.58 (d, 1H, H5eq
;
J = 18.0 Hz), 4.48 (tt, 1H, H11a; J = 1.5 and 6.8 Hz), 4.41 (d, 1H,
H5ax; J = 18.0 Hz), 2.63–2.55 (m, 2H, H2 and H1), 2.54–2.45 (m,
2H, H2 and H1); 13C NMR (150 MHz, CDCl3): d 189.6 (s, CO),
174.3 (s, NCO), 143.7, 143.2, 136.0 and 134.0 (s, C5a,5b,9a,10a),
128.9, 125.5, 123.8 and 123.7 (d, C6–9), 62.3 (d, C11a), 39.2 (t, C5),
30.1 (t, C2), 20.7 (t, C1); HRMS calcd for C14H11NO2S [M+1]+:
257.0510, found 258.0566.
141–146 °C; 1H NMR (300 MHz, DMSO-d6): d 7.98 (t, 2H, 2 ꢁ HAr
;
0
J = 5.9 Hz), 7.69 (s, 1H, H2 ), 7.40 (t, 2H, 2 ꢁ HAr; J = 5.9 Hz), 4.15 (d,
1H, N–CH; J = 13.9 Hz), 4.02 (d, 1H, N–CH; J = 13.9 Hz), 3.57 (br s,
2H, 2 ꢁ CO2H), 3.32 (t, 1H, H1; J = 6.5 Hz), 2.42–2.28 (m, 2H,
2 ꢁ H3), 1.97–1.81 (m, 2H, 2 ꢁ H2); 13C NMR (75 MHz, DMSO-d6): d
4.5. 4.5.(11S,11aS)-11-Hydroxy-1,5,11,11a-tetrahydro[1]
benzothieno[3,2-f]indolizin-3(2H)-one 4
0
0
0
174.0 (s, 2 ꢁ CO2), 173.0 (s, CON), 139.6, 138.0, 132.0 (s, C3 ,3a ,7a ),
0
0
0
125.5, 124.4, 124.0, 122.7, 122.2 (d, C2 ,4 –7 ), 59.9 (d, C1), 44.1 (t, N-
CH2), 30.6 (t, CH2, C3), 26.7 (t, CH2, C2). Anal. Calcd for C14H15NO4S
(293.34): C, 57.32; H, 5.15; N, 4.77; S, 10.93. Found: C, 57.06; H,
5.05; N, 4.56; S, 10.81.
To a solution of freshly crystallized ketone 3 (7.72 g, 30 mmol)
in methanol (200 mL) was added in a small portion sodium boro-
hydride (1.33 g, 35 mmol) at 0–5 °C. The mixture was then stirred
at 0 °C for 16 h until total disappearance of the starting materials
was observed. The solution was carefully neutralized with dry
10% (v/v) HCl in ethanol, and the solvent was removed under vac-
uum. The solution obtained was extracted twice with dichloro-
methane. The organic layers were dried over MgSO4 and
concentrated to afford a solid. Recrystallization from toluene/n-
hexane (15:1) gave the title compound 4 (6.16 g, 79.9%) as colourless
4.3. (S)-1-(Benzo[b]thien-3-ylmethyl)-5-oxopyrrolidine-2-
carboxylic acid 8
The suspension of crude N-substituted-(S)-glutamic acid 7
(11.72 g, 40 mmol) in EtOH (450 mL) was heated at reflux for 8 h.

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P. Šafár et al. / Tetrahedron: Asymmetry 20 (2009) 2137–2144
2142
crystals; mp 247–250 °C; [
KBr): 3188, 2860, 2475, 1645, 1612, 1494, 1455, 1466, 1421, 1376,
1349, 1334, 1292, 1267, 1231, 1176, 1151, 1138, 1096, 1063;
a
]
D = +128.6 (c 1.0, MeOH); IR (
m
, cmꢂ1
,
J = 1.0 and 8.0 Hz), 4.30 (dd, 1H, H5eq; J = 1.5 and 14.4 Hz), 3.38
(ddd, 1H, H5ax; J = 2.1, 2.9 and 14.4 Hz), 3.30 (dt, 1H, H3peq; J = 2.7
and 8.9 Hz), 3.11 (ddd, 1H, H11eq; J = 1.9, 3.8 and 16.2 Hz), 2.76
(dddd, 1H, H11ax; J = 1.9, 2.6, 10.5 and 16.2 Hz), 2.61 (ddt, 1H,
H11a; J = 3.9, 6.9 and 10.1 Hz), 2.43 (q, 1H, H3pax; J = 9.2 Hz), 2.17
UV (kmax, nm (log e)): 299 (2.63), 289 (2.64), 266 (2.95), 261
(2.95), 231 (3.49), 201 (3.42); 1H NMR (600 MHz, CD3OD): d 7.78
(d, 1H, H9; J = 7.8 Hz), 7.53 (d, 1H, H6; J = 7.8 Hz), 7.34 (dt, 1H,
H8; J = 0.9 and 7.7 Hz), 7.31 (dt, 1H, H7; J = 0.9 and 7.7 Hz), 4.95
(dd, 1H, H5eq; J = 1.6 and 16.7 Hz), 4.61 (td, 1H, H11; J = 1.9 and
0
(dddd, 1H, H1 ; J = 4.7, 6.9, 9.6 and 12.4 Hz), 2.02–1.89 (m, 2H,
2 ꢁ H2), 1.62 (dddd, 1H, H1; J = 6.7, 10.2, 11.3 and 12.5 Hz); 13C
NMR (150 MHz, CD3OD): d 140.8, 138.8, 136.7 and 129.2 (s, C5a,
8.7 Hz), 4.18 (dd, 1H, H5ax; J = 1.3 and 16.7 Hz), 3.70 (dt, 1H, H11a
;
10a), 125.3, 125.1, 123.5 and 121.3 (d, C6–9), 62.7 (d, C11a),
5b, 9a,
J = 4.6 and 8.2 Hz), 2.55–2.47 (m, 2H, 2 ꢁ H2), 2.46 (tdd, 1H, H1;
J = 8.0, 8.2 and 12.3 Hz), 2.15 (tdd, 1H, H1; J = 3.7, 9.4 and
13.1 Hz); 13C NMR (150 MHz, CD3OD): d 175.8 (s, CO), 140.6,
140.0, 137.1 and 125.9 (s, C5a,5b,9a,10a), 124.9, 124.7, 123.0, 121.1
(d, C6–9), 70.3 (d, C11), 61.6 (d, C11a), 39.8 (t, C5), 30.2 (t, C2), 22.3
(t, C1); HRMS calcd for C14H13NO2S [M+1]+: 259.0667, found
260.0719.
54.9 (t, C3), 52.1 (t, C5), 33.0 (t, C11), 31.1 (t, C1), 22.7 (t, C2); HRMS
calcd for C14H15NS [M+1]+: 229.0925, found 230.1000.
4.8. General procedure for the desulfurization of
benzothienoindolizines 3, 4, 5 and 9
Activated Raney-nickel was added to a solution of benzothieno-
indolizinone 3, 4, 5 and 9 in methanol and the mixture was stirred
at reflux under hydrogen (203 kPa) for 35–75 h. The solution was
filtered through a Celite pad to remove the catalyst. The crude
product as a mixture of diastereomeric hydroxyindolizidines was
analyzed by HPLC, GC–MS and NMR spectroscopy.
4.6. (11aS)-1,5,11,11a-Tetrahydro[1]benzothieno[3,2-f]-
indolizin-3(2H)-one 9
Triethylsilane (2.5 mL, 15 mmol) wad added dropwise to a stir-
red solution of alcohol 4 (2.59 g, 10 mmol) in trifluoroacetic acid
(20 mL) at 0 °C. The resulting yellow solution was stirred at room
temperature for 4 h. The reaction mixture was concentrated in va-
cuo, after which the crude yellow mixture was diluted with ether
(50 mL), and washed twice with 10% Na2CO3 (2 ꢁ 25 mL). The
water phase was extracted twice with ether (2 ꢁ 10 mL). The com-
bined ether extracts were washed with water (25 mL), 5% Na2CO3
(2 ꢁ 25 mL), dried over anhydrous MgSO4 and concentrated in va-
cuo. The weakly green residue (2.28 g, 94%) was purified by crys-
tallization from a mixture of toluene/n-hexane (10:1) and gave 9
4.8.1. (8R or S,8aS)-8-Hydroxy-6-phenylhexahydroindolizin-
3(5H)-ones 11a–d
This product was obtained by the hydrogenation of benzothie-
noindolizinedione 3 (1.0 g, 3.88 mmol) in methanol (150 mL) with
activated Raney-nickel (6.6 g) at reflux (203 kPa) for 60 h. After fil-
tration of the catalyst through a Celite pad and concentration in va-
cuo, the composition of four diastereomers in a colourless crude
product (0.81 g, 90%) was analyzed by NMR and HPLC measure-
ments. A mixture of four diastereomers 11a–d was obtained when
the crude product (0.90 g) was treated with acetone (2 mL) and the
solid obtained was filtered off.
as a colourless crystal (1.74 g, 71.8%); mp 125–127 °C; [
+285.1 (c 1.0, MeOH); IR (
, cmꢂ1, KBr): 3438, 3057, 2823, 1672,
1583, 1461, 1429, 1413, 1360, 1338, 1308, 1260, 1248, 1189,
a]
=
D
m
1146, 1122, 1058, 1022; UV (kmax, nm (log
e
)): 298 (2.41), 289
4.8.1.1. (6S,8S,8aS)-8-Hydroxy-6-phenylhexahydroindolizin-3-
(2.41), 265 (2.82), 261 (2.83), 230 (3.46), 201 (3.45); 1H NMR
(600 MHz, CDCl3): d 7.78 (d, 1H, H9; J = 7.9 Hz), 7.56 (d, 1H, H6;
J = 7.9 Hz), 7.37 (dt, 1H, H8; J = 1.1 and 8.0 Hz), 7.32 (dt, 1H, H7;
J = 1.1 and 8.0 Hz), 5.09 (dd, 1H, H5eq; J = 2.0 and 16.7 Hz), 4.27
(5H)-one 11a.
The characteristics of this product were ex-
tracted from spectra of four diastereomers 11a–d and are as fol-
lows: 1H NMR (600 MHz, CD3OD):
J = 7.6 Hz), 7.28 (d, 2H, 2 ꢁ HoAr; J = 7.6 Hz), 7.17 (t, 1H, HpAr
d
7.32 (t, 2H, 2 ꢁ HmAr
;
;
(ddd, 1H, H5ax; J = 1.3, 2.0 and 16.7 Hz), 3.96 (dddd, 1H, H11a
;
J = 7.2 Hz), 3.97 (dd, 1H, H5eq; J = 7.0 and 13.1 Hz), 3.95–3.88 (m,
2H, H8eq and H8a), 3.36 (dd, 1H, H5ax; J = 4.6 and 12.7 Hz), 3.15 (q,
1H, H6eq; J = 6.7 Hz), 2.52–2.40 (m, 2H, 2 ꢁ H2), 2.38–2.31 (m, 1H,
H7eq), 2.20–2.05 (m, 3H; H7ax and 2 ꢁ H1); 13C NMR (150 MHz,
CD3OD): d 177.5 (s, CO), 145.1 (s, CipsoAr), 129.5 (d, CmAr), 128.3
(d, CoAr), 127.4 (d, CpAr), 68.1 (d, C8), 60.9 (d, C8a), 45.1 (t, C5),
39.1 (t, C7), 37.3 (d, C6), 31.9 (t, C2), 20.2 (t, C1).
J = 4.5, 5.0, 7.7 and 10.2 Hz), 3.11 (ddd, 1H, H11eq; J = 1.1, 4.1 and
15.9 Hz), 2.81 (tdd, 1H, H11ax; J = 2.3, 10.6 and 15.8 Hz), 2.61–2.50
(m, 2H, 2 ꢁ H2), 2.46 (ddd, 1H, H1; J = 7.6, 12.7 and 14.8 Hz), 1.90
(dddd, 1H, H1; J = 5.4, 7.2, 9.3 and 13.8 Hz); 13C NMR (75 MHz,
CDCl3): d 174.4 (s, C@O), 138.7, 137.1, 133.3 and 125.2 (s,
C5a,5b,9a,10a), 124.5, 124.4 (d, C7,8), 122.5 and 120.3 (d, C6, 9), 54.7
(d, C11a), 39.8 (t, C5), 32.8 (t, C11), 30.3 (t, C2), 25.0 (t, C1); HRMS
calcd for C14H13NOS [M+1]+: 243.0718, found 244.0803.
4.8.1.2. (6R,8S,8aS)-8-Hydroxy-6-phenylhexahydroindolizin-3-
(5H)-one 11b.
The characteristics of this product were ex-
4.7. (11aS)-1,2,3,5,11,11a-Hexahydro[1]benzothieno[3,2-
f]indolizine 5
tracted from spectra of four diastereomers 11a–d and are as fol-
lows: 1H NMR (600 MHz, CD3OD):
d
7.32 (t, 2H, 2 ꢁ HmAr
;
;
J = 7.7 Hz), 7.28 (d, 2H, 2 ꢁ HoAr; J = 7.6 Hz), 7.22 (t, 1H, HpAr
To a solution of amide 9 (250 mg, 1.03 mmol) in THF (19 mL)
J = 7.2 Hz), 4.10 (ddd, 1H, H5eq; J = 1.4, 4.7 and 12.7 Hz), 3.95–3.88
(m, 1H, H8eq), 3.77 (dt, 1H, H8a; J = 1.8 and 7.2 Hz), 3.11 (tt, 1H,
H6ax; J = 4.4 and 12.2 Hz), 2.82 (t, 1H, H5ax; J = 12.4 Hz), 2.52–2.40
was added dropwise
a commercially available solution of
BH3ꢀMe2S 1 M in THF (8.7 mL, 8.7 mmol). The mixture was stirred
at room temperature for 72 h, then EtOH (45 mL) was added slowly
and the solution was refluxed for 5 h. After removal of the solvents,
the crude product was obtained as a solid. Recrystallization of the
solid from n-hexane gave amine 5 as colourless crystals (200 mg,
0
(m, 1H, H2), 2.39–2.32 (m, 1H, H2 ), 2.20–2.05 (m, 3H; 2 ꢁ H1 and
H7eq), 2.01 (t, 1H, H7ax; J = 13.1 Hz); 13C NMR (150 MHz, CD3OD):
d 176.9 (C3), 143.8 (s, CipsoAr), 129.7 (d, CmAr), 128.3 (d, CoAr),
127.9 (d, CpAr), 67.7 (d, C8), 62.3 (d, C8a), 47.4 (t, C5), 39.3 (t, C7),
36.4 (d, C6), 31.8 (t, C2), 20.2 (t, C1).
85%); mp 103–105 °C; [a]D = +166.0 (c 1.0, MeOH); IR (m ,
, cmꢂ1
KBr): 3381, 3053, 2967, 2938, 2920, 2872, 2792, 2740, 1460,
1431, 1392, 1355, 1330, 1294, 1261, 1254, 1219, 1159, 1144,
4.8.2. (6R,8R,8aS)-8-Hydroxy-6-phenylhexahydroindol-izin-
3(5H)-ones 11d
These products were obtained by the hydrogenation of trans-
alcohol 4 (1.0 g, 3.86 mmol) in methanol (150 mL) with activated
Raney-nickel (4.5 g) at reflux for 72 h. After filtration of the catalyst
1136, 1097, 1062, 1046; UV (kmax, nm (log e)): 299 (2.34), 289
(2.38), 266 (2.79), 262 (2.80), 232 (3.39), 200 (3.33); 1H NMR
(600 MHz, CD3OD): d 7.77 (d, 1H, H9; J = 8.0 Hz), 7.56 (d, 1H, H6;
J = 8.0 Hz), 7.34 (dt, 1H, H8; J = 1.0 and 8.0 Hz), 7.28 (dt, 1H, H7;

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P. Šafár et al. / Tetrahedron: Asymmetry 20 (2009) 2137–2144
2143
and concentration in vacuo, the crude product obtained as a mix-
ture of 11c and 11d (0.82 g, 92%) was treated with acetone
(2 mL). The resulting precipitate was filtered off. Recrystallization
from dry THF gave enantiomerically pure (6R,8R,8aS)-8-hydroxy-
6-phenylhexahydroindolizin-3(5H)-one 11d (0.18 g, 20%) as a col-
H1; J = 2.6, 7.2, 9.8 and 12.6 Hz), 2.03 (qd, 1H, H8eq; J = 3.6 and
13.1 Hz), 2.00 (dddd, 1H, H7eq; J = 2.0, 3.4, 6.5 and 13.4 Hz), 1.81
0
(dq, 1H, H7ax; J = 3.2 and 12.8 Hz), 1.72–1.66 (m, 1H, H1 ), 1.40
(ddt, 1H, H8ax; J = 3.3, 11.6 and 12.9 Hz); 13C NMR (150 MHz,
CD3OD): d 176.1 (s, C3), 144.2 (s, CipsoAr), 129.7 (d, CmAr), 128.2 (d,
ourless solid; mp 181–183 °C; [
a]
D = +14.2 (c 1.0, MeOH); IR (
m,
CoAr), 127.9 (d, CpAr), 58.6 (d, C8a), 47.6 (t, C5), 43.4 (d, C6), 34.4 (t,
C8), 32.2 (t, C7), 31.5 (t, C2), 25.7 (t, C1).
cmꢂ1, KBr): 3327, 2860, 2475, 1645, 1612, 1494, 1455, 1466,
1421, 1376, 1349, 1334, 1292, 1267, 1231, 1176, 1151, 1138,
1096, 1063, 976, 961, 893, 857, 833, 758, 699, 672, 621, 612,
4.8.4. (6R,8aR)-6-Phenyloctahydroindolizine 6
570, 550, 529, 516, 480, 458; UV (kmax, nm (log
e
)): 195 (3.31),
This product was obtained by desulfurization of the starting
benzothieno analogue of tylophorine 5 (0.20 g, 0.87 mmol) in
methanol (50 mL) with activated Raney-nickel (2.0 g) (203 kPa)
at 60 °C for 48 h. After the filtration of the catalyst, the reaction
mixture was passed through a short pad of Celite and the solvent
was removed under reduced pressure to afford the corresponding
cis-diastereomer 6. The resulting product was purified by flash col-
umn chromatography (dichloromethane) to yield a pure cis-diaste-
reomer as a slightly yellow oil (0.12 g, 68%). The characteristics of
201 (3.28); 1H NMR (600 MHz, CD3OD): d 7.33 (tt, 2H, 2 ꢁ HmAr
;
J = 1.6 and 7.7 Hz), 7.29 (td, 2H, 2 ꢁ HoAr; J = 1.7 and 7.2 Hz), 7.24
(tt, 1H, HpAr; J = 1.4 and 7.2 Hz), 4.05 (ddd, 1H, H5eq; J = 1.6, 3.5
and 12.0 Hz), 3.40 (dt, 1H, H8ax; J = 3.9 and 9.4 Hz), 3.36 (ddd, 1H,
H8a; J = 5.4, 7.4 and 9.2 Hz), 2.75 (tt, 1H, H6ax; J = 3.3 and
12.0 Hz), 2.71 (tt, 1H, H5ax; J = 1.5 and 12.0 Hz), 2.46–2.42 (m, 2H,
2 ꢁ H2), 2.35 (ddd, 1H, H1; J = 7.5, 13.1 and 15.0 Hz), 2.19 (dddd,
1H, H7eq; J = 1.9, 2.9, 3.8 and 12.5 Hz), 1.96 (dddd, 1H, H1; J = 5.3,
8.1, 9.4 and 13.4 Hz), 1.77 (ddt, 1H, H7ax; J = 1.9 and 10.5 and
12.3 Hz); 13C NMR (150 MHz, CD3OD): d 176.3 (s, CO), 143.0 (s,
product 6 are as follows: [
a]
D = ꢂ2.0 (c 1.0, MeOH); IR (
m ,
, cmꢂ1
KBr): 3060, 3028, 2962, 2929, 2783, 2475, 1603, 1495, 1452,
C
ipsoAr), 129.8 (d, CmAr), 128.2 (d, CoAr), 128.1 (d, CpAr), 73.5 (d, C8),
1383, 1349, 1228, 1165, 1132, 1111, 1068, 1030; UV (kmax, nm
64.1 (d, C8a), 46.9 (t, C5), 42.3 (d, C6), 41.4 (t, C7), 31.3 (t, C2), 23.0 (t,
(log e
)): 205 (3.03), 197 (3.06); 1H NMR (600 MHz, CD3OD): d
C1); HRMS calcd for C14H17NO2 [M+1]+: 231.1259, found 232.1319.
7.28 (tt, 1H, HmAr; J = 1.4 and 7.3 Hz), 7.24 (dd, 1H, HoAr; J = 1.4
and 7.2 Hz), 7.18 (tt, 1H, HpAr; J = 1.3 and 7.2 Hz), 3.15 (ddd, 1H,
H5eq; J = 1.3, 4.0 and 11.0 Hz), 3.05 (dt, 1H, H3peq; J = 2.3 and
4.8.2.1. (6S,8R,8aS)-8-Hydroxy-6-phenylhexahydroindolizin-
3(5H)-one 11c.
The characteristics of this product were ex-
8.8 Hz), 2.84 (tt, 1H, H6ax; J = 3.8 and 11.9 Hz), 2.20 (t, 1H, H3pax
;
tracted from a spectra of two diastereomers 11c and 11d and are
as follows: 1H NMR (600 MHz, CD3OD): d 7.28–7.26 (m, 4H,
2 ꢁ HmAr and 2 ꢁ HoAr), 7.18 (dddd, 1H, HpAr; J = 0.8, 2.5, 5.8 and
J = 9.1 Hz), 2.17 (t, 1H, H5ax; J = 11.2 Hz), 2.03–1.92 (m, 4H; H1,
H7eq, H8eq and H8a), 1.88–1.74 (m, 2H, 2 ꢁ H2), 1.60 (dq, 1H, H7ax
;
0
J = 3.9 and 12.9 Hz), 1.44 (dq, 1H, H1 ; J = 6.9 and 11.2 Hz), 1.39
(ddt, 1H, H8ax; J = 4.3, 10.8 and 13.4 Hz); 13C NMR (150 MHz,
CD3OD): d 145.3 (s, CipsoAr), 129.5 (d, CmAr), 128.3 (d, CoAr), 127.6
(d, CpAr), 65.5 (d, C8a), 60.6 (t, C5), 54.9 (t, C3), 44.0 (d, C6), 33.3 (t,
7.8 Hz), 4.43 (td, 1H, H5eq; J = 1.7 and 13.9 Hz), 3.34 (tt, 1H, H8a
;
;
J = 2.5 and 7.7 Hz), 3.31–3.29 (m, 1H, H6eq), 3.14 (ddd, 1H, H8ax
J = 3.9, 9.2 and 11.5 Hz), 3.09 (ddd, 1H, H5ax; J = 1.5, 4.5 and
13.9 Hz), 2.48–2.41 (m, 1H, H2), 2.40–2.31 (m, 3H; H1, H2 and H7),
1.95 (ddd, 1H, H7ax; J = 4.8, 11.6 and 13.2 Hz), 1.75–1.68 (m, 1H,
H1); 13C NMR (150 MHz, CD3OD): d 176.8 (s, CO), 143.7 (s, CipsoAr),
129.5 (d, CmAr), 128.1 (d, CoAr), 127.3 (d, CpAr), 70.3 (d, C8), 64.6 (d,
C8a), 42.8 (t, C5), 40.5 (d, C7), 38.4 (d, C6), 31.4 (t, C2), 24.2 (t, C1).
C7), 31.3 (t, C8), 30.2 (t, C1), 21.8 (t, C2); HRMS calcd for C14H19
N
[M+1]+: 201.1517, found 201,1586.
Acknowledgements
This work was supported by the Grant Agency of the Slovak
Republic (No. 1/0161/08), the Scientific Council of University of
Le Havre (France) and by the Slovak Research and Development
Agency under the contract No. APVV-0210-07. Special thanks are
addressed also to the Slovak Republic for the NMR equipment sup-
ported by the Slovak State programme project No. 2003SP-
200280203. The authors thank company TAU-CHEM, Ltd and Dr.
4.8.3. (8aR)-6-Phenylhexahydroindolizin-3(5H)-one 12a and
12b
These products were obtained by desulfurization of starting
indolizinone 9 (0.45 g, 1.85 mmol) in methanol (70 mL) with acti-
vated Raney-nickel (4.0 g) at reflux (203 kPa) for 72 h. After filtra-
tion of the catalyst and concentration in vacuo, the crude product
(0.39 g, 98%) was obtained as a colourless semi-solid. The charac-
teristics of these products established from the mixture of diaste-
reomeric 6-phenylindolizines 12a and 12b are as follows:
Selected data for product (6S,8aR)-12a: 1H NMR (600 MHz,
CD3OD): d 7.29–7.25 (m, 4H, 2 ꢁ HmAr and 2 ꢁ HoAr), 7.19–7.14
(m, 1H, HpAr), 4.45 (dd, 1H, H5eq; J = 0.8 and 13.7 Hz), 3.62 (tdd,
1H, H8a; J = 3.8, 7.7 and 11.3 Hz), 3.16 (dd, 1H, H6eq; J = 4.6 and
8.4 Hz), 3.13 (ddd, 1H, H5ax; J = 1.5, 4.5 and 13.5 Hz), 2.42–2.36
ˇ
Pavel Cepec for HPLC analyses.
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7.25 (m, 2H, 2 ꢁ HoAr), 7.22 (tt, 1H, HpAr; J = 1.4 and 7.3 Hz), 4.09
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