A convenient stereoselective route to novel tetrahydroxyindolizidines

Article abstract of DOI:10.1016/S0040-4039(02)02084-1

A convenient stereoselective route, for the preparation of novel tetrahydroxyindolizidines, based on syn-hydroxylation reactions of alkenyl pyrrolidines followed by cyclization, is reported. Derivatives of (+)-swainsonine are prepared.

Full text of DOI:10.1016/S0040-4039(02)02084-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8543–8546
A convenient stereoselective route to novel
tetrahydroxyindolizidines
Ana T. Carmona, Jose´ Fuentes and Inmaculada Robina*
Departamento de Qu´ımica Orga´nica, Facultad de Qu´ımica, Universidad de Sevilla, Apartado 553, E-41071 Sevilla, Spain
Received 29 July 2002; accepted 19 September 2002
Abstract—A convenient stereoselective route, for the preparation of novel tetrahydroxyindolizidines, based on syn-hydroxylation
reactions of alkenyl pyrrolidines followed by cyclization, is reported. Derivatives of (+)-swainsonine are prepared. © 2002 Elsevier
Science Ltd. All rights reserved.
Polyhydroxylated indolizidines belong to an important
class of alkaloids that possess a wide range of biological
applications, mainly as glycosidase inhibitors,1 and can
be used as antiviral, antitumor, and immunomodulating
agents.2 This fact, together with their attractive chemi-
cal structures have led to many synthetic approaches.3
Since small modifications in their structure may induce
significant changes in their biological activity, potency
and/or specificity on glycosidase enzymes or receptors,4
the preparation of unnatural epimers and other struc-
tural analogues of the natural indolizidines has received
much attention,5 and new methodologies to generate
structural analogues are still needed. To the best of our
knowledge, of the synthetic analogues of polyhydroxy-
indolizidines, indolizidinones 8 and 9 and indolizidines
17, 19 have not been described. Of these, 8 is a precur-
sor of a hydroxy analogue of (+)-swainsonine described
by Fleet and co-workers6 to be a good inhibitor of
naringinase.
regioisomers 2 and 3 in 50 and 40% yield, respectively
(Scheme 1).
In the case of compound 2, dihydroxylation reaction
with a catalytic amount of osmium tetraoxide9 gave a
mixture of diols 4 and 5 in 91% yield and a low
stereoselectivity of 1.7:110 (Scheme 2), which indicates
that the sugar moiety exerts a weak control into the
stereoselectivity. Reaction of the mixture 4 and 5 with
trifluoroacetic acid followed by heating with NaOMe in
MeOH under reflux afforded a mixture of indolizidi-
nones that were separated by chromatography, after
acetylation, giving compounds 6 and 7 in 47 and 35%
yield, respectively. Compound 6 is the major one indi-
In this communication we report the preparation of
novel optically pure tetrahydroxyindolizidines via the
cyclization of chiral imino-C-polyols, the latter being
formed by elongation of pyrrolidines-carbaldehydes
through Knoevenagel reaction followed by Sharpless
asymmetric dihydroxylations, an approach that, as far
as we are aware, has not been applied to that field.
Starting from 3,6-(tert-butoxycarbonyl)imino-2,3,6-
trideoxy-4,5-O-isopropylidene-
L
-arabino-hexose7
(1)
Knoevenagel–Doebner reaction8 with hydrogen methyl
malonate gave, after 3 h, a mixture of the two trans-
* Corresponding authors. Fax: +34-95-462-4960; e-mail: robina@
us.es
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02084-1

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A. T. Carmona et al. / Tetrahedron Letters 43 (2002) 8543–8546
produce an excellent control in the diastereoselectivity
when using the pseudoenantiomeric Cinchona alkaloid
ligands for Sharpless reagents. Thus, hydroxyl-
ation of compound 10 with AD-mixb14 gave 11 as
major compound (60% yield, d.e.=91%). On the other
hand, reaction of 10 with AD-mixa gave 12 as major
compound (72% yield, d.e.=97%).
Treatment of 11 and 12 separately with NaOMe/MeOH
followed by regioselective tosylation of the primary
alcohol afforded compounds 13 and 14 in moderate-to-
good yield. Boc-deprotection of 13 (TFA aq.) followed
by
NH4OH
neutralization
afforded
tetra-
hydroxyindolizidine 15 (69%) and pyrrolizidine 16
(28%), via ring opening of the terminal epoxide formed
from 13. When the same conditions were applied to 14,
Scheme 2. Reaction conditions: (a) OsO4 (cat.), NMO, ace-
tone–H2O 4:1, rt, 4 days; (b) 1. TFA aq., 2 h, 2. NaOMe,
MeOH reflux, 16 h; 3. Ac2O, Py, DMAP, rt, 16 h; (c)
NaOMe, MeOH, rt, 2 h.
cating that the OsO4 attack has taken place with prefer-
ence for the top face. In order to improve the selectivity
of the reaction, double asymmetric reactions11 with the
commercial reagents AD-mixa and AD-mixb were car-
ried out, although the reaction failed probably due to
the high steric hindrance between the catalyst and the
bulky protecting group. Treatment of 6 and 7 sepa-
rately with NaOMe in MeOH rendered compounds 8
and 9 in quantitative yield. The spectral data of 6 and
712 were consistent with the configuration assigned.
Compound 6 shows large coupling constants J7,8
8,8a=8.9 Hz and NOEs between pairs of protons H7/
H8a. On the other hand, compound 7, presents a
gauche relationship between H7, H8 and H8a (J7,8
8,8a=4.6 Hz) and NOEs between pairs of protons
H8/H8a.
=
J
=
J
Similar results were obtained for compound 3. Dihy-
droxylation reaction with a catalytic amount of OsO4
and N-methylmorpholine at rt for 24 h, gave a mixture
of the two diastereoisomeric diols in quantitative yield
and a 1.4:1 ratio. With the idea of having a better
diastereoselectivity in the hydroxylation reaction, we
envisaged carrying out asymmetric Sharpless dihydroxy-
lation in the p-methoxybenzoyl ester 10 (Scheme 3)
obtained from 3 after reduction of the ester group with
DIBALH (60%) and reaction with p-methoxybenzoyl
chloride in the presence of triethylamine and dimethyl-
aminopyridine (94%). Compound 10 is a good substrate
for asymmetric dihydroxylation, because it is known13
that aromatic moieties attached to allylic alcohols
Scheme 3. Reaction conditions: (a) DIBALH, DCM, −15°C;
(b) 4-MeOBzCl, TEA, DMAP; (c) AD-mixb, 0°C, 48 h; (d)
AD-mixa, 0°C, 24 h; (e) NaOMe/MeOH, rt, 3 h; (f) TsCl, Py,
−15°C, 2 h; (g) 1. TFA aq., 2. NH4OH; (h) Ac2O, Py.

A. T. Carmona et al. / Tetrahedron Letters 43 (2002) 8543–8546
8545
Table 1.
2. See e.g.: (a) Goss, P. E.; Baker, M. A.; Carver, J. P.;
Dennis, J. W. Clin. Cancer Res. 1995, 1, 935; (b) Das, P.
C.; Robert, J. D.; White, S. L.; Olden, K. Oncol. Res.
1995, 7, 425.
3. For reviews, see e.g.: (a) Cossy, J.; Vogel, P. Studies in
Natural Products Chemistry; Atta-ur-Rahman, Ed.;
Elsevier: Amsterdam, 1993; Vol. 12, pp. 275–363; (b) El
Nemr, A. Tetrahedron 2000, 56, 8579–8629; (c) El Ashry,
E. S. H.; Rahed, N.; Shobier, A. H. S. Pharmazie 2000,
55, 331–348.
4. See e.g.: lentiginosine and derivatives: (a) Brandi, A.;
Cicchi, S.; Cordero, F. M.; Frignoli, R.; Goti, A.;
Picasso, S.; Vogel, P. J. Org. Chem. 1995, 60, 6806–6812;
(b) Cardona, F.; Goti, A.; Picasso, S.; Vogel, P.; Brandi,
A. J. Carbohydr. Chem. 2000, 19, 585–601; (c) pentahy-
droxyindolizidines: Chen, Y.; Vogel, P. J. Org. Chem.
1994, 59, 2487–2496; Picasso, S.; Chen, Y.; Vogel, P.
Carbohydr. Lett. 1993, 1, 1–8; (d) Izquierdo, I.; Plaza, M.
J.; Robles, R.; Mota, A. J. Tetrahedron: Asymmetry 1998,
9, 1015–1027; 5-azacastanospermine: (e) Søndergard, K.;
Liang, X.; Bols, M. Chem. Eur. J. 2001, 7, 2324–2331.
5. (a) Patil, N. T.; Tilekar, J. N.; Dhavale, D. D. J. Org.
Chem. 2001, 6, 1065–1074; (b) Back, T. G.; Nakajima, K.
Org. Lett. 1999, 1, 261–263; (c) Kawakami, T.; Ohtake,
H.; Arakawa, H.; Okachi, T.; Imada, Y.; Murahashi,
S.-I. Org. Lett. 1999, 1, 107–110; (d) Clark, R. B.; Pear-
son, W. H. Org. Lett. 1999, 1, 349–351.
Comp.
H-1
H-2
H-6
H-7
15
18
17
19
4.06
5.42
3.99
5.33
4.42
5.33
4.31
5.29
3.76
4.89
3.50
5.08
3.94
5.05
3.40
4.28
only indolizidine 17 was obtained in 94% yield. The
spectroscopic data of 15, 16 and 17 confirmed the
proposed structures.15 The absolute configuration of
compounds 15 and 17 were based upon NOEs between
pair of protons H7/H8-b for compound 15 and NOEs
between H7/H8a, H7/H8-a and H6/H8-b for com-
pound 17. The indolizidine character of compounds 15
1
and 17 was demonstrated with the H NMR spectra of
their corresponding peracetates derivatives 18 and 19
(Table 1). A deshielding of the resonances for H1, H2,
H6 and H7, was observed confirming the proposed
structures. In the case of compound 16, the
pyrrolizidine structure and absolute configuration was
based on its MSCI spectrum, where a loss of a hydroxy-
methyl group were observed and on its 1H NMR
spectrum where NOEs between pair of protons H7a/
H7-a, H5/H7-a, H6/H7-b and H3-b/H-8 were
observed.
6. Davis, B.; Bell, A. A.; Nash, R. J.; Watson, A. A.;
Griffiths, R. C.; Jones, M. G.; Smith, C.; Fleet, G. W. J.
Tetrahedron Lett. 1996, 37, 8565–8568.
This work presents a new synthetic approach for the
construction of polyhydroxyindolizidines based on syn-
hydroxylation of alkenyl pyrrolidines followed by
cyclization. High stereoselectivity is obtained when
using double asymmetric reactions. The present paper
discloses for the first time the preparation of tetra-
hydroxyderivatives 8, 9, 15, 17.
7. Cardona, F.; Robina, I.; Vogel, P. J. Carbohydr. Chem.
2000, 19, 555–571.
8. Lo´pez-Herrera, F. J.; Pino Gonza´lez, M. S. Carbohydr.
Res. 1986, 152, 283–291 and references cited therein.
9. Donohoe, T. J.; Moore, P. R.; Beddoes, R. L. J. Chem.
Soc., Perkin Trans. 1 1997, 43–51.
10. Typical procedure for osmylation: Alkene 2 or 3 (1
mmol) was dissolved in acetone:H2O 4:1 (3 mL), N-
methylmorpholine (4 equiv.) and OsO4/ButOH (0.1
equiv.) was added and the reaction mixture stirred for 24
h at rt. An excess of Na2SO3 was added and the mixture
stirred for 30 min at rt and then extracted with AcOEt.
The combined extracts were washed with brine and
water, dried and evaporated. Purification was achieved by
column chromatography with DCM:acetone 25:1 as
eluant.
Biological evaluation of the new molecules will be
carried out and be reported in a forthcoming paper.
Acknowledgements
We thank Professor Pierre Vogel of the ‘Institut des
Sciences Mole´culaires de l’Ecole Polytechnique Fe´d-
e´rale de Lausanne, Suisse’ for discussions. This work
was supported by the Ministerio de Educacio´n y Cul-
tura, (PB97/0730), the Junta de Andaluc´ıa, Spain
(FQM 134). This work is part of the Action COST-
D13-0001/99.
11. Kolb, K. C.; van Nieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 2483–2547.
1
12. Selected data for 6: H NMR (500 MHz, CDCl3, l ppm,
J Hz) l 5.27 (t, 1H, J8,8a=J8,7=9.4, H-8), 5.21 (ddd, 1H,
J
7,6=6.9, J7,6%=8.8, H-7), 3.80 (dd, 1H, J1,8a=2.8, H-8a),
2
3.04 (dd, 1H, J6,6%=17.8, H-6), 2.49 (dd, 1 H, H-6%).
Selected data for 7: H NMR (300 MHz, CDCl3, l ppm,
1
J Hz) l 5.61 (t, 1H, J8,8a=J8,7=4.6, H-8), 5.36 (td, 1H,
References
J7,6=7.2, H-7), 4.21 (dd, 1H, J1,8a=3.2, H-8a), 3.77 (d,
2H, H-6).
1. See e.g.: (a) Casiraghi, G.; Zanardi, F. Chem. Rev. 1995,
95, 1677–1716; (b) Iminosugars as Glycosidase Inhibitors;
Stu¨tz, A. E., Ed.; Wiley-VCH: Weinheim, 1999; (c) Zeng,
Y.; Pan, Y. T.; Asano, N.; Nash, R. J.; Elbein, A. D.
Glycobiology 1997, 7, 297; (d) Asano, N.; Nash, R. J.;
Molyneux, R. J. Fleet, G. W. Tetrahedron: Asymmetry
2000, 11, 1645–1680; (e) Lillelund, V. H.; Jensen, H. H.;
Liang, X.; Bols. M. Chem. Rev. 2002, 102, 515–553.
13. Guzma´n Pe´rez, A.; Corey, E. J. Tetrahedron Lett. 1997,
38, 5941–5944.
14. Typical procedure for asymmetric dihydroxylation: To a
solution of alkene 10 (0.1 mmol) in ButOH:H2O 1:1 (1.2
mL) at 0°C, AD-mixa or AD-mixb (0.14 g) and
MeSO2NH2 (0.1 equiv.) was added. The reaction mixture
was stirred at 0°C for x days (AD-mixa, x=1; AD-mixb,
x=2). Work-up procedure is as described for osmylation.

8546
A. T. Carmona et al. / Tetrahedron Letters 43 (2002) 8543–8546
15. Selected data for 15: 1H NMR (300 MHz, MeOD, l
ppm, J Hz) l 3.94 (c, 1H, J7,6=J7,8b=J7,8a=3.0, H-7),
3.76 (m, 1H, H-6), 3.23–3.06 (m, 5H, H-3a, H-3b, H-5a,
H-5b, H-8a), 2.30 (ddd, 1H, J8b,8a=12.5, 2J8b,8a=14.5,
H-8b), 1.79 (dt, 1H, J8a,8a=2.7, H-8a). Selected data for
16: 1H NMR (500 MHz, MeOD, l ppm, J Hz) l 4.43
(dt, 1H, J7a,7a=9.9, J7a,7b=J7a,1=4.1, H-7a), 4.33 (ddd,
1H, J2,1=4.0, J2,3b=6.3, J2,3a=10.4, H-2), 4.26 (ddd,
1H, H-6), 4.07 (t, 1H, H-1), 3.92 (dd, 1H, J8,5=3.6,
2J8,8%=13.0, H-8), 3.81 (dd, 1H, J8%,5=9.1, H-8%), 3.52
(td, 1H, J5,6=8.6, H-5), 3.46 (dd, 1H, 2J3b,3a=10.8, H-
3b), 3.27 (t, 1H, H-3a), 2.48 (ddd, 1H, J7b,6=6.2,
2J7b,7a=12.6, H-7b), 1.92 (dd, 1H, J7a,6=8.0, H-7a).
Selected data for 17: 1H NMR (300 MHz, MeOD, l
ppm, J Hz) l 3.50 (ddd, 1H, J6,5a=10.0, J6,7=8.9,
J
6,5b=4.8, H-6), 3.40 (ddd, 1H, J7,8a=4.9, J7,8b=11.0,
H-7), 3.17 (dd, 1H, 2J5b,5a=10.8, H-5b), 2.28 (ddd, 1H,
J8a,1=3.9, J8a,8b=11.7, H-8a), 2.04 (t, 1H, J5a,6=10.5,
H-5a), 1.97 (ddd, 1H, J8a,8a=2.6, 2J8a,8b=13.1, H-8a),
1.68 (ddd, 1H, J8b,8a=1.2, H-8b).