An expedient synthesis of 7(S)-ethyl-8(R or S)-indolizidinols based on a thiophene reductive desulfurization

Article abstract of DOI:10.1016/j.tetlet.2006.11.092

Chiral hexahydrothieno[2,3-f]indolizine-4,7-dione (S)-12 and the ancillary alcohol 13 were generated from thiophene-2-carboxaldehyde and (S)-glutamic acid in three and four steps, respectively, in good overall yields and both high enantio- and diastereome

Full text of DOI:10.1016/j.tetlet.2006.11.092

Tetrahedron Letters 48 (2007) 697–702
An expedient synthesis of 7(S)-ethyl-8(R or S)-indolizidinols
based on a thiophene reductive desulfurization
a
a
a
a
b
ˇ
ˇ
ˇ
´
´
´
´
´
´
´
Stefan Marchalın, Jozefına Zu´zˇiova, Katarına Kadlecˇıkova, Peter Safarˇ, Peter Baran,
Vincent Dallac and Adam Da¨ıchc,*
aDepartment of Organic Chemistry, Slovak University of Technology, SK-81237 Bratislava, Slovak Republic
bDepartment of Chemistry, von Liebig Science Center 2035, Juniata College, 1700 Moore Street, Huntingdon, PA 16652, USA
cLaboratoire de Chimie, URCOM, EA 3221, UFR des Sciences and Techniques de l’Universite´ du Havre,
BP 540, 25 rue Philippe Lebon, F-76058 Le Havre Cedex, France
Received 20 September 2006; revised 14 November 2006; accepted 15 November 2006
Available online 11 December 2006
Abstract—Chiral hexahydrothieno[2,3-f]indolizine-4,7-dione (S)-12 and the ancillary alcohol 13 were generated from thiophene-2-
carboxaldehyde and (S)-glutamic acid in three and four steps, respectively, in good overall yields and both high enantio- and dia-
stereomeric purities. Applying a thiophene reductive desulfurization, compound 12 was readily converted into 7(S)-ethyl-8(S)-indo-
lizidinol 9. The 8(R)-epimer of 9 was advantageously obtained using the Mitsunobu alcohol inversion or, starting from 13, by
chemical separation after O-benzylation and lactam reduction. During these studies, the reduction of regioisomers of 12 and 13,
namely 17 and 18, was investigated and the results obtained are also discussed.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
OH
OH
OH
OH
OH
H
H
H
HO
HO
OH
OH
Polyhydroxylated indolizidines alkaloids are excellent
inhibitors of biologically important pathways. These
include the binding and processing of glycoproteins,
potent glycosidase inhibitory activities,1 activity against
AIDS virus HIV and some carcinogenic cells as well as
against other important pathologies.2 In this line, cast-
anospermine3 (1), swainsonine4 (2) and lentiginosine5
(3) have shown respective glycosidase, mannosidase
and amyloglycosidase inhibitory activities, respectively
(see representative structures in Scheme 1).
N
N
N
1: (+)-Castanospermine 2: (-)-Swainsonine
3: (+)-Lentiginosine
HO
O
OH
H
H
H
HO
N
N
N
C-C or C=C
R
6: (8S
)-Indolizidinol
4: (+)-Pumiliotoxins
5: (-)-Elaeokanine-C
OH
OH
8(S or R
)
OH
8a
S
While an impressive number of total syntheses of tetra-
hydroxylated, trihydroxylated and dihydroxylated indo-
lizidines and their non-natural analogues in chiral or
racemic forms have been reported, the mono hydroxyl-
ated indolizidines have attracted far less attention. These
latter unique structures are exemplified by pumiliotoxins
of type 4 as strong neurotoxins,6 (À)-elaeokanine-C (5),7
OH
H
H
8
1
3
2
6
N
N
5
N
7
S
4
9: Our targets
7: (1
S
)-Indolizidinol
8: (1R)-Indolizidinol
Scheme 1. Representative indolizidines alkaloids 1–8 and our targets
9.
the synthetic enantiopure (8S,8aS)-perhydro-8-indol-
izidinol (6),8 the C8a hydroxyethyl-substituted indolizi-
dine (7)9 and finally the (1R,8aS)-1-indolizidinol (8).10
Whereas indolizidinols 5–7 have not revealed any signif-
icant biological activity yet, (1R,8aS)-1-indolizidinol (8)
Keywords: Chiron approach; Bioactive product; Alkaloid; Indolizid-
inol; Heterocycle; Diastereoselective; Reduction; Desulfurization;
Raney-nickel.
*
Corresponding author. Tel.: +33 02 32 74 44 03; fax: +33 02 32 74 43
91; e-mail: adam.daich@univ-lehavre.fr
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.092

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S. Marchalı´n et al. / Tetrahedron Letters 48 (2007) 697–702
698
has, interestingly, been postulated as the biosynthetic
congener of (À)-epilentiginosine (À)-3 and as a meta-
bolite of the fungus Rhizoctonia leguminicola,11 the loco-
weeds Astragalus oxyphysus12 and A. lentiginosus13
(Scheme 1).
high optical activity (>99% ee) by using the well known
Friedel–Crafts type cyclization and stereospecific
sodium borohydride reduction (Scheme 2).17,18 Ulti-
mately, the thiophene ring of compounds 12–13 could
serve advantageously the role of reservoir for the ethyl
substituent at position 7 of the indolizidine ring by
means of the well established reductive desulfurization
protocol. The potential utility of this technique is aptly
illustrated in the literature with numerous examples
given in different fields of organic chemistry, notably
including the field of stereoselective total synthesis.23,24
In this sense, considerable efforts are continuously
underway towards their synthesis and that of their ster-
eoisomers and analogues. In other respects, some struc-
tural modifications of (À)-swainsonine (2) have recently
been made and their pharmacological influence studied
by Pearson’s group and by Nagasawa and co-workers.
During these studies, the incorporation for the first time
of an hydroxymethyl, an arylalkyl-hydroxymethyl and a
carbohydrate residue at the C3 position14 resulted in an
increase of the a-manosidase activity compared to that
exhibited by swainsonine itself, whereas the introduction
of 6- or 7-ethyl and benzyloxyethyl-substituents in either
equatorial and axial orientations resulted in a loss of
activity.15 During another exploration towards greater
diversity, some new 5a-substituted swainsonine
analogues were prepared and, in contrast to Pearson’s
6- and 7-substituted analogues, were found to be more
potent a-mannosidase inhibitors than swainsonine.16
The requisite ketone skeleton 12 could be obtained in
very good yield and in a large scale (up to 10 g) in a three
step-sequence from the commercially available thio-
phene-2-carboxaldehyde (10) and (S)-glutamic acid (11)
(overall yield of 55%). With large quantities of this mate-
rial in hand, the present study started with the Raney-
nickel hydrogenolysis of its thiophene ring (Scheme 3).
The best experimental protocol turned out to be the
contact of (S)-12 with activated Ra-Ni in anhydrous
methanol under stirring and 1 atm of hydrogen at reflux
for 24 h. As might be expected, the four possible diaste-
reomers of 14 were formed in a 68:12:10:10 ratio,25
albeit in very good yield (90%). Repetition of the
reaction gave the same stereomeric distribution; unfor-
tunately, all attempts to separate this mixture failed.
However, treating the crude mixture with dry acetone
provided more satisfactory results, with the major
stereoisomer crystallizing from the mixture in a syn-
thetically useful yield of 52%. Further recrystallization
from acetone upgraded the purity of this compound,
the structure of which was unequivocally identified as
Because there are few strategies amenable to these alkyl-
ated indolizidinols, and regarding their interesting bio-
logical profiles and potential as valuable candidates for
novel therapeutic agents,15–17 the development of new
and straightforward routes for their production is
therefore quite desirable. In this preliminary report, an
expedient synthesis of prototypic alkyl substituted indol-
izidinols, namely 7-ethyl and 6-ethyl-8-indolizidinols, is
described. This original chiron approach used a key step
that creates the linkages between the C7/ethyl group and
the C8/OH function of the bicyclic targets 9 in a quite
uncommon manner, as illustrated in the disconnections
depicted in Scheme 2.
1
(7S,8S,8aS)-14 by means of H and 13C NMR spectro-
scopy and single X-ray crystallography (Fig. 1).26 In line
with other results in the furan series,27 this result high-
lights the stereo-complementarity between the NaBH4
and the hydrogenation reduction modes.
Within our interest in the synthesis of fused azacyclic
systems we have previously reported diverse indolizi-
dines annulated to thiophene,17,18 benzothiophene,18,19
both benzene and thiophene,20 and furan,21 rings using
the above strategy (Scheme 2). In connection with this
work, we now selected optically active hexahydro-
thieno[2,3-f]indolizine-4,7-dione ((S)-12)22 and the
ancillary alcohol 13 as key templates for further elabora-
tions directed towards the targeted compounds. These
key intermediates were reported recently by us with
Finally the synthesis of the targeted indolizidinol
(7S,8S,8aS)-9 was completed with LAH reduction of
the lactam (7S,8S,8aS)-14 in refluxing THF according
to Greene’s protocol.10a The reduction occurred cleanly
within 4 h to afford the title compound 7(S)-ethyl-8(S)-
indolizidinol 9 in 70% yield.28
In stark contrast to some literature reports claiming the
robustness of the ketone function to various desulfuriz-
ing agents including Ra-Ni,29 it is worth noting that the
reductive cleavage of the thiophene ring of compound
12 was accompanied by that of the ketone function.
At this stage, the question of both reduction kinetics
and the order by which the two transformations pro-
ceeded, arose. In order to learn more about that point,
and to further examine the possible influence of the
C8-substituent on the stereochemical course of the thio-
phene reductive cleavage, a set of additional experiments
were conducted.
O
H
S
N
O
S
OH
8aS
8(S or R
)
10
H
12
O
O
3 steps
+
O
Refs. 17,18
N
HO
OH
7
S
H
H
H2N
HO2C
9: Our targets
First, the enantiopure alcohol 13 was subjected to the
same protocol used for its ketone precursor 12. Interest-
ingly, a non-separable mixture of (7S,8R,8aS)-14 and
(7R,8R,8aS)-14 was obtained in a 78:22 ratio (92%
N
S
13
11
Scheme 2. Retrosynthetic scheme leading to the indolizidine targets 9.

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S. Marchalı´n et al. / Tetrahedron Letters 48 (2007) 697–702
699
O
OH
X-ray OH
OH
OH
H
H
H
H
H
H2, Ra-Ni
MeOH, reflux
8a
S
N
N
N
N
N
S
90%
O
O
O
O
O
12
nOe
(7S,8R,8aS)-14
(7
R,8R,8aS)-14
(7
S
,8
S
,8a
S
)-14
(7R,8S,8aS)-14
10%
7%
LiAlH4
THF, reflux
OH
nOe
H
70%
i
92%
8%
8% H
7%H
H
OH
OH
H
H
8a
8a
11%
H
H
7
8
8
N
N
OH
5
5
N
N
H
S
H
H
6%
O
O
)-14
(7S
,8S
,8a
S
)-9
O
(7
S
,8
S
,8aS
(7S,8R,8aS)-14
13
Scheme 3. Synthetic route to the 7(S)-ethyl-8(S)-indolizidinol target (7S,8S,8aS)-9. The four possible diastereomers (7S,8S,8aS)-14, (7R,8S,8aS)-14,
(7S,8R,8aS)-14 and (7R,8R,8aS)-14 were obtained in a 68:12:10:10 ratio determined by NMR essays as well as X-ray analysis of (7S,8S,8aS)-14.
Selected NOEs for the determination of relative configuration in the 7-ethylindolizidinols 14 were established by 1D-NOE 1H NMR experiments.
in a stereoselective manner with, quite interestingly, sim-
ilar stereomeric distributions with respect to the stereo-
genicity at carbon C7 (S/R ꢀ 80/20) regardless of the
substitution pattern at carbon C8 (@O; H,OH: Scheme
3, H,H: Scheme 4). These results strongly point out that
inherent stereocontrol exerted by the vicinity at C8 dur-
ing the thiophene reductive cleavage poorly contributes
to the observed stereoselectivities, which, therefore,
Figure 1. ORTEP drawing of indolizinone (7S,8S,8aS)-14. Thermal
ellipsoids at 30% probability level.
would be better interpreted in terms of a uniform prefer-
ential hydrogen approach from the exo (convex) face of
the thienoindolizinone tricyclic skeleton, in line with our
earlier report in the furan series.21b Moreover, the dis-
crepancy outlined in Scheme 3 in the ratios (7S,8R,
8aS)-14/(7R,8R,8aS)-14 starting from either 12 (50:50
ratio) or 13 (78:22 ratio) strongly supports a thiophene
opening-first pathway, since a ketone reduction-first
pathway of compound 12 should probably have led to
an 80:20 ratio.
H
H
H
N
H2, Ra-Ni
N
N
S
MeOH, r.t
O
O
O
95%
15
cis-16
75:25 trans-16
Scheme 4. Raney-nickel reduction of hexahydrothienoindolizinone 15.
To complete this study, we have also investigated the
reduction of the regioisomeric ketone 17 and its hydr-
oxyl derivative 18, readily available from thiophene-
3-carboxaldehyde, with the expectation of providing a
rapid entry to 6-ethylindolizidin-8-ols. Thus, treatment of
17 under the well established reductive-desulfurization
protocol led to an oily mixture of three inseparable
diastereomers in a 24:69:7 ratio favouring product
(6S,8S,8aS)-19 (see Scheme and results in Table 1).
The structures of these isomers, respectively (6R,8S,
8aS)-19, (6S,8S,8aS)-19 and (6S,8R,8aS)-19, were
yield).30 A parallel experiment was carried out starting
from the C8-deoxy analogue as 15 (Scheme 4), easily
obtained from alcohol 13 as previously reported.21b
An oily mixture of inseparable stereoisomers, surpris-
ingly favouring the cis-isomer (the cis:trans ratio of 16
was determined as 75:25 by using NOE measure-
ments),30 resulted in an excellent 95% yield.
From this first set of results, it clearly appeared that the
thiophene reductive cleavages of 12, 13 and 15 occurred
Table 1. Results of the reductive desulfurization reactiona of ketone 17 and corresponding alcohol 18b
OH
OH
OH
O
OH
OH
H
H
H
H
H
H
S
S
i
i
8aS
N
N
N
N
N
N
92%
90%
O
O
)-19
O
O
O
O
)-19
18
(6S,8R,8aS)-19
17
(6R,8S,8aS
(6R,8R,8aS
(6S,8S,8aS)-19
Starting material: ketone 17
Starting material: alcohol 18
24
b
69
b
0
77
7
23
Yield: 92%
Yield: 90%
a (i) Ra-Ni, MeOH, reflux.
b Only two possible diastereomers (6R,8R,8aS)-19 and (6S,8R,8aS)-19 were obtained in a 77:23 ratio. The diastereomers (6R,8S,8aS)-19 and
(6S,8S,8aS)-19 could not obtained from the alcohol 18.

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S. Marchalı´n et al. / Tetrahedron Letters 48 (2007) 697–702
700
unequivocally identified by NMR spectroscopy (Table
1) including notably NOE measurements. This experi-
ment revealed a dr similar as above regarding the orien-
tation of the ethyl group but, importantly, the sense of
hydride delivery was reversed (down/up ethyl–C6
24:76, Table 1 vs up/down ethyl–C7 78:22 starting from
ketone 12, Scheme 3). Otherwise reductive-desulfuriza-
tion of alcohol 18 produced the two possible diastereo-
mers (6R,8R,8aS)-19 and (6S,8R,8aS)-19 with
restoration of the usual sense ‘exo-approach’ and level
‘77:23 ratio’ of stereo-induction. Though the literature
is rather unclear regarding the stereoselectivity of hydro-
genation, it is nevertheless general that addition of
hydrogen occurs from the less hindered face of the dou-
ble bond of the thiophene ring. However, the discrepan-
cies of certain results observed herein during notably the
reduction of ketones 12 and 17 could be ascribed to the
so called haptophilic effect which causes H2 to be added
from the same side as a polar substituent such as an
hydroxyl group.31
obtained in four steps from the 78:22 mixture of 7(S
and R)-ethyl-8(R)-hydroxyindolizin-3-ones 14 prepared
from alcohol 13 (see Scheme 3). Thus, O-benzylation
of the stereomeric mixture using standard conditions
led to the expected products which, furnished by simple
deposition in hexane, the major benzylated product in
pure form as a white solid in 30% yield. Its structure
was identified as (7S,8R,8aS)-20 by spectroscopic means
and crystallographic analysis.26,34 Finally, the latter
product 20 was efficiently converted into the target indol-
izidinol (7S,8R,8aS)-9 using a debenzylation-lactam
reduction route or the inverted sequence in 41% and
52% yields via alcohol-lactam (7S,8R,8aS)-14 or ether
(7S,8R,8aS)-21, respectively.
2. Conclusion
In this letter, we have successfully introduced a new and
expedient synthetic entry to 7(S)-ethyl-8(R or S)-indol-
izidinol alkaloid cores 9 in five- and eight steps and
overall yields of 20% or 8%, respectively. Our uncom-
mon strategy uses as key step a reductive desulfurization
of the thiophene ring with a Raney-nickel reductant in
which the thiophene constitutes an original alkyl source.
The targets (7S,8S,8aS)-9 and (7S,8R,8aS)-9 were ob-
tained ultimately by lactam reduction or by a configura-
tional alcohol inversion with Mitsunobu reaction
followed by lactam reduction, respectively. In the latter
case, a chemical separation via an easy O-benzylation
reaction, lactam reduction and debenzylation were also
advantageously used.
We next directed our attention towards accessing the
C8-epimer of indolizidinol 9 referred to as (7S,8R,
8aS)-9. In a first sequence, alcohol (7S,8S,8aS)-14 iso-
lated above was efficiently converted into the expected
alcohol-lactam (7S,8R,8aS)-1432 in 64% yield by a one
pot two-step Mitsunobu inversion/saponification
sequence.33 The target (7S,8R,8aS)-9 was finally reached
in 45% yield by repeating a LAH reduction protocol
(Scheme 5). Alternatively, (7S,8R,8aS)-9 was also
Finally, thanks to the mild experimental conditions and
to the cheap and modular chiral source and thiophene
aldehydes, this method is probably the most straight-
forward for the synthesis of indolizidinols bearing an
alkyl group at C6 or C7 positions. In addition, it is shorter
and more direct than the rarely available but longer
methods starting from enantiopure lactones15a or a,b-
unsaturated d-lactams15b both derived from sugars.
Consequently, this route opens the way to the design
and synthesis of a wide variety of novel polyhydroxyl-
ated indolizidine alkaloids comprising of different
substituents and stereochemistry with promising phar-
macological profiles.
Acknowledgements
The authors thank the Grant Agency of Slovak Repub-
lic, Grant No.1/2456/2005 and the Scientific Council of
University of Le Havre, France, for their financial sup-
port for this research program. Dr. R. G. Raptis from
UPR at San Juan is gratefully acknowledged for provid-
ing access to the X-ray diffractometer. Special thinks are
also addressed to the Slovak Republic for the NMR
equipment supported by the Slovak State programme
Project No. 2003SP200280203. The authors thank
Scheme 5. Scheme leading to 7(S)-ethyl-8(R)-indolizidinol (7S,
8R,8aS)-9 and the ORTEP plot (thermal ellipsoids at 30% probability
level) of its congener 8-benzyloxyindolizidinone (7S,8R,8aS)-20.
Reagents and conditions: (i) NaH, BnBr, DMF, 40–50 ꢁC, 24 h; (ii)
hexane, separation of diastereomers; (iii) H2, 10% Pd/C, MeOH, 12 h;
(iv) LAH, THF, reflux, 4 h and (v) PhCO2H, DEAD, PPh3, toluene, rt,
1 h then K2CO3, MeOH, THF, 1 h.
ˇ
TAU-CHEM, Ltd and Dr. Pavel Cepec for HPLC and
GC–MS analyses.

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701
13. Pastuszak, I.; Molyneux, R. J.; James, L. F.; Elbein, A. D.
Biochemistry 1990, 29, 1886–1891.
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´
Kadlecˇıkova, K.; Marchalın, S.; Bobosıkova, M.; Dalla,
V.; Da¨ıch, A. Tetrahedron: Asymmetry 2004, 15, 1763–
1770.
22. For X-ray analysis of product 12, see: Lokaj, J.; Kettmann,
ˇ
V.; Marchalin, S. Acta Cryst. 1999, C55, 1103–1105.
23. For representative examples using this protocol, see: (a)
Michelliza, S.; Al-Mourabit, A.; Gateau-Olesker, A.;
Marazano, C. J. Org. Chem. 2002, 67, 6474–6478; (b)
Gol’Dfarb, Y. L.; Fabrichnyi, B. P.; Shalavina, I. F.
Tetrahedron 1961, 18, 21–36; (c) Badger, G. M.;
Rodda, H. J.; Sasse, W. H. F. J. Chem. Soc. 1954,
4162–4167.
24. For stereoselective reduction of 2,3-disubstituted and
2,3,4,5-tetrasubstituted thiophenes, see: (a) Jacobi, P. A.;
Frechette, R. F. Tetrahedron Lett. 1987, 28, 2937–2940;
(b) Jacobi, P. A.; Egberston, M.; Frechette, R. F.; Miao,
C. K.; Weiss, K. T. Tetrahedron 1988, 44, 3327–3338; (c)
Crenshaw, R. R.; Luke, G. M.; Jenks, T. A.; Partyka, R.
A.; Bialy, G.; Bierwagen, M. E. J. Med. Chem. 1973, 16,
813–823; (d) Collins, M. A.; Neville-Jones, D. Tetrahedron
Lett. 1995, 36, 4467–4470.
25. (a) Composition of 7-ethyl-8-hydroxyindolizidinones 14
was determined by HPLC analysis of the crude reaction
mixture and 1H NMR essays. (b) Spectroscopic data of
(7S,8S,8aS)-7-ethyl-8-hydroxy-1,2,3,5,6,7,8,8a-octahydro-
indolizin-3-one (14). Activated Raney-nickel (9.00 g) was
added to a solution of thienoindolizidinedione 12 (1.00 g,
4.8 mmol) in anhydrous methanol (20 mL) and the mix-
ture was stirred at reflux under hydrogen (1 atm) for 24 h.
The solution was filtered through a Celite pad to remove
the catalyst. After concentration in vacuo, the crude
product was treated with acetone (10 mL). The resulting
precipitate of 14 was filtered and recrystallized from
acetone. Yield: 52% (0.46 g), mp 123–127 ꢁC; [a]D À1.6 (c
1, EtOH); IR (m, cmÀ1, KBr): 3291, 2961, 2989, 1655, 1643
7. Hart, N. K.; Johns, S. R.; Lamberton, J. A. Aust. J. Chem.
1972, 25, 817–835.
8. Lee, H. K.; Chun, J. S.; Pak, C. S. J. Org. Chem. 2003, 68,
2471–2474.
9. Lee, Y. S.; Kim, D. W.; Lee, J. Y.; Jeong, K. S.; Pak, H.
Bull. Korean Chem. Soc. 1998, 19, 8–9.
10. (a) Rasmussen, M. O.; Delair, P.; Greene, A. E. J. Org.
Chem. 2001, 66, 5438–5443; (b) Clavestine, E. C.; Walter,
P.; Harris, T. M.; Broquist, H. P. Biochemistry 1979, 18,
3663–3667; (c) Harris, C. M.; Harris, T. M. Tetrahedron
Lett. 1987, 28, 2559–2592; (d) Shono, T.; Kise, N.;
Tanabe, T. J. Org. Chem. 1988, 53, 1364–1367; (e) Harris,
C. M.; Schneider, M. J.; Ungemach, F. S.; Hill, J. E.;
Harris, T. M. J. Am. Chem. Soc. 1988, 110, 940–949; (f)
Takahata, H.; Banba, Y.; Momose, T. Tetrahedron:
Asymmetry 1990, 1, 763–764.
11. Harris, T. M.; Harris, C. M.; Hill, J. E.; Ungemach, F. S.;
Broquist, H. P.; Wickwire, B. M. J. Org. Chem. 1987, 52,
3094–3098.
12. Harris, C. M.; Campbell, B. C.; Molyneux, R. J.; Harris,
T. M. Tetrahedron Lett. 1988, 29, 4815–4818.
1
(C@O), 1471, 1457; H NMR (600 MHz, CDCl3): d 0.95
(t, 3H, CH3, J = 7.2 Hz), 1.38 (qd, 1H, H-6, J = 2.9 and
12.8 Hz), 1.42–1.52 (m, 4H, 2 · H-9, H-6 and H-7), 2.03
(dddd, 1H, H-1peq, J = 5.7, 8.8, 10.6 and 13.7 Hz), 2.14
(tdd, 1H, H-1pax, J = 5.0, 11.0 and 12.9 Hz), 2.31 (br s,
1H, OH), 2.33 (dddd, 1 H, H-2pax, J = 1.2, 6.5, 10.6 and
16.7 Hz), 2.45 (ddd, 1H, H-2peq, J = 5.6, 10.6 and
16.7 Hz), 2.66 (t, 1H, H-5ax, J = 11.8 Hz), 3.53 (ddd,
1H, H-8a, J = 1.4, 5.3 and 8.5 Hz), 3.61 (s, 1H, H-8), 4.11

ˇ
S. Marchalı´n et al. / Tetrahedron Letters 48 (2007) 697–702
702
(dd, 1H, H-5eq, J = 4.2 and 12.4 Hz); 13C NMR
colourless oil; [a]D À59.1 (c 1, EtOH); IR (m, cmÀ1
,
(125 MHz, CDCl3): d 11.4 (C-10), 19.3 (C-1), 23.9 (C-6),
25.2 (C-9), 30.6 (C-2), 39.6 (C-5), 42.3 (C-7), 61.8 (C-8a),
68.7 (C-8), 174.7 (C-3); MS (m/z, (%)): 183 (M+, 59), 166
(18), 155 (10), 154 (20), 112 (15), 98 (100), 97 (11), 86 (75).
Anal. Calcd for C10H17NO2 (183.25) C, 65.54; H, 9.35; N,
7.64. Found C, 65.42; H, 9.15; N, 7.49.
KBr): 3379 (OH), 2962, 2874, 1666 (C@O), 1460, 1423,
1269, 1133, 1072, 882; 1H NMR (600 MHz, CDCl3): d
0.93 (t, 3H, CH3, J = 7.4 Hz), 1.09 (dq, 1H, H-6, J = 5.0
and 13.0 Hz), 1.18 (qdd, 1H, H-9, J = 7.4, 7.8 and
13.9 Hz), 1.37 (ttd, 1H, H-7, J = 3.3, 9.3 and 12.5 Hz),
1.81–1.85 (m, 1H, H-1), 1.86 (dd, 1H, H-6, J = 1.3 and
13.4 Hz), 1.88 (dqd, 1H, H-9, J = 3.2, 7.6 and 13.4 Hz),
2.33 (tdd, 1H, H-1, J = 6.8, 12.2 and 13.8 Hz), 2.39 (dd,
2H, 2 · H-2, J = 7.6 and 9.0 Hz), 2.62 (dt, 1H, H-5ax,
J = 3.3 and 13.2 Hz), 2.91 (t, 1H, H-8, J = 9.5 Hz), 3.06
(br s, 1H, OH), 3.23 (ddd, 1H, H-8a, J = 6.4, 7.6 and
8.9 Hz), 4.06 (ddd, 1H, H-5eq, J = 1.7, 5.0 and 13.2 Hz);
13C NMR (125 MHz, CDCl3): d 10.6 (C-10), 22.5, 23.6
(C-1 and C-9), 28.0 (C-6), 30.3 (C-2), 39.3 (C-5), 44.1
(C-7), 62.3 (C-8a), 76.5 (C-8), 173.8 (C-3); MS (m/z, (%)):
184 (12), 183 (43), 168 (5), 166 (17), 155 (17), 154 (18), 126
(9), 112 (16), 111 (5), 99 (73), 98 (100), 86 (32), 84 (20), 83
(12). Anal. Calcd for C10H17NO2 (183.25) C, 65.54; H,
9.35; N, 7.64. Found C, 65.42; H, 9.15; N, 7.49.
26. Full crystallographic data have been deposited with the
Cambridge Crystallographic Data Centre (CCDC refer-
ences numbers 614535 and 614534 for products
(7S,8S,8aS)-14 and (7S,8R,8aS)-20), respectively. Copies
of the data can be obtained free of charge at http://
www.ccdc.cam.ac.uk.
27. While the NaBH4 reduction of furanic keto amide
analogue to 12 furnishes the OH at C8- with a (R)
21a
stereogenicity as single isomer,
hydrogenation over an
appropriate catalyst led to the formation of the 8S epimer
in good stereoselectivity (manuscript under preparation).
28. (7S,8S,8aS)-7-Ethyl-1,2,3,5,6,7,8,8a-octahydroindolizin-8-
ol (9). Mp 38–40 ꢁC (hexane); 1H NMR (300 MHz,
CDCl3): d 0.88 (t, 3H, CH3), 1.09–1.23 (m, 1H, H-7),
1.29 (dq, 1H, H-9, J = 7.1 and 13.8 Hz), 1.38–1.53 (m, 3H,
2 · H-6 and H-9), 1.60–1.76 (m, 3H, 2 · H-2 and H-1),
1.77–1.88 (m, 1H, H-1), 1.95 (t, 1H, H-8a, J = 10.8 Hz),
1.97 (t, 1H, H-5ax, J = 10.8 Hz), 2.07 (q, 1H, H-3pax,
J = 8.9 Hz), 2.28 (br s, 1H, OH), 2.95–2.99 (m, 1H, H-
3peq), 3.00–3.04 (m, 1H, H-5eq), 3.51 (s, 1H, H-8); 13C
NMR (75 MHz, CDCl3): d 11.5 (C-10), 21.4 (C-2), 25.0
(C-1), 25.1 (C-9), 26.3 (C-6), 43.1 (C-7), 52.4 (C-5), 54.2
(C-3), 67.4 (C-8), 68.3 (C-8a). Anal. Calcd for C10H19NO
(169.27): C, 70.96; H, 11.31; N, 8.27. Found: C, 70.79; H,
11.23; N, 8.18.
33. (a) Mitsunobu, O. Synthesis 1981, 1–28; (b) Martin, S. F.;
Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017–3020; (c)
Crimmins, M. T.; Pace, J. M.; Nantermet, P. G.; Kim-
Meade, A. S.; Thomas, J. B.; Watterson, S. H.; Wagman,
A. S. J. Am. Chem. Soc. 1999, 121, 10249–10250.
34. (7S,8R,8aS)-8-Benzyloxy-7-ethyl-1,2,3,5,6,7,8,8a-octahy-
droindolizin-3-one (20). This product was isolated as a
white solid; mp 82–85 ꢁC (acetone); [a]D À68.8 (c 1,
EtOH); IR (m, cmÀ1, KBr): 3032, 2975, 2922, 2964, 1681
1
(C@O); H NMR (600 MHz, CDCl3): d 0.93 (t, 3H, CH3,
J = 7.5 Hz), 1.10 (dq, 1H, H-6, J = 4.8 and 12.9 Hz), 1.22
(qdd, 1H, H-9, J = 7.4, 7.8 and 13.8 Hz), 1.47–1.54 (m,
1H, H-7), 1.74–1.83 (m, 1H, H-1), 1.85 (dd, 1H, H-6,
J = 1.3 and 13.4 Hz), 1.94 (dqd, 1H, H-9, J = 3.2, 7.6 and
13.7 Hz), 2.29–2.40 (m, 3H, 2 · H-2 and H-1), 2.57 (dt,
1H, H-5ax, J = 2.9 and 13.0 Hz), 2.84 (t, 1H, H-8,
J = 9.6 Hz), 3.36 (td, 1H, H-8a, J = 7.2 and 8.4 Hz),
4.06 (dd, 1H, H-5eq, J = 3.7 and 13.2 Hz), 4.66 (s, 2H,
OCH2), 7.25–7.40 (m, 5H, H-arom.); 13C NMR (125 MHz,
CDCl3): d 10.8 (C-10), 24.0, 24.1 (C-1 and C-9), 28.0 (C-6),
30.6 (C-2), 39.3 (C-5), 43.8 (C-7), 61.5 (C-8a), 74.6
(OCH2), 85.3 (C-8), 127.8, 128.0, 128.5, 138.1 (C-arom),
173.7 (C-3); MS (m/z, (%)): 273 (M+, 15), 183 (15), 182
(100), 167 (25), 99 (68), 98 (48), 91 (88), 84 (23). Anal.
Calcd for C17H23NO2 (273.38) C, 74.69; H, 8.48; N, 5.12.
Found C, 74.51; H, 8.39; N, 5.01.
29. For various examples, see: Becker, S.; Fort, Y.; Vander-
`
esse, R.; Caubere, P. J. Org. Chem. 1989, 54, 4848–4853.
30. The stereochemistries of 14 were determined on the basis
of both the X-ray analysis of (7S,8S,8aS)-14 and their
NMR study obtained separately from ketone 12 and
alcohol 13, respectively. The ratio of lactams 16 cis and
trans was determined by using NOE measurements.
31. (a) Ranade, V. S.; Consiglio, G.; Prins, R. J. Org. Chem.
2000, 65, 1132–1138; (b) MaGee, D. I.; Lee, M. L.;
Decken, A. J. Org. Chem. 1999, 64, 2549–2554; (c)
Ranade, V. S.; Consiglio, G.; Prins, R. J. Org. Chem.
1999, 64, 8862–8867.
32. (7S,8R,8aS)-7-Ethyl-8-hydroxy-1,2,3,5,6,7,8,8a-octahydro-
indolizin-3-one (14). This product was isolated as a