Stereoisomeric sugar-derived indolizines as versatile building blocks: Synthesis of enantiopure Di- and tetrahydroxyindolizidines

Article abstract of DOI:10.1021/jo0016428

The synthesis of the sugar-derived (1S,2R,8aR)-1,2-di-O-isopropylidene-1,2,3,5,6,8a-hexahydro-5oxoindolizine (8) and by analogy of the corresponding stereoisomers ent-8 and ent-7, an epimer at C₂ of ent-8, has been accomplished in a straightforward manner. The carbon-carbon double bond and the carbonyl functionalities on the six-membered ring make these nitrogen-containing heterocycles useful building blocks for the efficient preparation of a variety of enantiopure polyhydroxylated indolizidines of interest for their glycosidase inhibitory activity. We report here the synthesis of 2,8a-diepilentiginosine 12 from 8 and the preparation of stereoisomeric 1,2,7,8tetrahydroxyindolizidines 9-11 performed by OsO₄-catalyzed double bond syn dihydroxylation of 7 and 8, followed by deoxygenation of the amide group.

Full text of DOI:10.1021/jo0016428

J . Org. Chem. 2001, 66, 4787-4794
4787
Ster eoisom er ic Su ga r -Der ived In d olizin es a s Ver sa tile Bu ild in g
Block s: Syn th esis of En a n tiop u r e Di- a n d
Tetr a h yd r oxyin d olizid in es†
Claudio Paolucci* and Lucia Mattioli
Department of Organic Chemistry “A. Mangini”, University of Bologna,
Viale Risorgimento 4, I-40136 Bologna, Italy
paolucci@ms.fci.unibo.it.
Received November 20, 2000
The synthesis of the sugar-derived (1S,2R,8aR)-1,2-di-O-isopropylidene-1,2,3,5,6,8a-hexahydro-5-
oxoindolizine (8) and by analogy of the corresponding stereoisomers ent-8 and ent-7, an epimer at
C2 of ent-8, has been accomplished in a straightforward manner. The carbon-carbon double bond
and the carbonyl functionalities on the six-membered ring make these nitrogen-containing
heterocycles useful building blocks for the efficient preparation of a variety of enantiopure
polyhydroxylated indolizidines of interest for their glycosidase inhibitory activity. We report here
the synthesis of 2,8a-diepilentiginosine 12 from 8 and the preparation of stereoisomeric 1,2,7,8-
tetrahydroxyindolizidines 9-11 performed by OsO4-catalyzed double bond syn dihydroxylation of
7 and 8, followed by deoxygenation of the amide group.
Ch a r t 1
In tr od u ction
Polyhydroxylated indolizidines such as castanosper-
mine1 (1, Chart 1, isolated from the Australian legume
Castanospermun australe),1a swainsonine2 (2, found in
the seeds of Swainsona canence), and lentiginosine3 (3,
recently extracted from Austragalus lentiginosus) are
interesting and challenging targets for the synthetic
organic chemist. Because of their biological activity,
mainly as glycosidase inhibitors,4-6 these compounds are
regarded as potential antiviral, antitumor, and immuno-
modulating agents.7 The specificity toward their molec-
ular target remains, however, to be optimized,8 and new
methodologies to generate structural analogues are
needed. This is further reinforced by the observation that
even small structural modifications may induce very
(4) Castanospermine (1) as glucosidases inhibitor: (a) Saul, R.;
Chambers, J . P.; Molyneux, R. J .; Elbein, A. D. Arch. Biochem. Biophys.
1983, 221, 593. (b) Durham, P. L.; Poulton, J . E. Plant Physiol. 1989,
90, 48. (c) Scofield, A. M.; Rossiter, J . T.; Witham, P.; Kite, G. C.; Nash,
R. J .; Fellow, L. E. Phytochemistry 1990, 29, 107. (d) Saul, R.;
Molyneux, R. J .; Elbein, A. D. Arch. Biochem. Biophys. 1984, 230, 668.
(e) Scofield, A. M.; Witham, P.; Nash, R. J .; Kite, G. C.; Fellows, L. E.
Comp. Biochem. Physiol., A 1995, II2, 187. (f).Winchester, B. G.; Cenci
di Bello, I.; Richardson, A. C.; Nash, R. J .; Fellows, L. E.; Ramsden,
N. G.; Fleet, G. W. J . Biochem. J . 1990, 269, 227. (g) Saul, R.; Ghidoni,
J . J .; Molyneux, R. J .; Elbein, A. D. Proc. Natl. Acad. Sci. U.S.A. 1985,
82, 93. (h) Review: Asano, N.; Nash, R. J .; Molyneux, R. J .; Fleet, G.
W. Tetrahedron: Asymmetry 2000, 11, 1645-1680.
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D.; Molyneux, R. J . In Alkaloids: Chemical and Biological Perspectives;
Pelletiers, S. W., Ed.; Wiley: New York, 1997; p 1. (b) Kotai, K.;
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21, 107. (c) See ref 2c. (d) Fleet, G. W. J .; Smith, P. W.; Evans, S. V.;
Fellows, L. E. J . Chem. Soc., Chem. Commun. 1984, 1240. (e) Tulsiani,
D. R. P.; Broquist, H. P.; Touster, O. Arch. Biochem. Biophys. 1985,
236, 427. (f) Tadano, K. I.; Morita, M.; Hotta, Y.; Ogawa, S.; Winchester,
B. G.; Cenci di Bello, I. J . Org. Chem. 1988, 53, 5209. (g) Elbein, A.
D.; Tropez, J . E.; Mitchell, M.; Kansal, G. P. J . Biol. Chem. 1990, 265,
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131. (i) Picasso, S.; Chen, Y.; Vogel, P. Carbohydr. Lett. 1993, 1, 1. (j)
Winchester, B. G.; Al Daher, S.; Carpenter, N. C.; Cenci di Bello, I.;
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743. (k) Pearson, W. H.; Hembre, E. J . J . Org. Chem. 1996, 61, 5537.
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A. D. Arch. Biochem. Biophys. 1997, 251, 450. (m) Tulsiani, D. R. P.;
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4h.
* To whom correspondence should be addressed. Fax (+39) 051
2093634.
† Dedicated to the memory of Professor Antonino Fava.
(1) (a) Hohenschutz, L. D.; Bell, E. A.; J ewess, P. J .; Leworthy, D.
P.; Price, R. J .; Arnold, E.; Clardy, J . Phytochemistry 1981, 20, 811.
Castanospermine (1) from dried pods of Alexa leiopetala: (b) Nash, R.
J .; Fellows, L. E.; Dring, J . V.; Stirton, C. H.; Carter, D.; Hegarty, M.
P.; Bell, E. A. Phytochemistry 1988, 27, 1403. More recent synthesis
of 1: (c) Denmark, S. E.; Martinborough, E. A. J . Am. Chem. Soc. 1999,
121, 3046. (d) Kang, S. H.; Kim, J . S. J . Chem. Soc., Chem. Commun.
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1979, 32, 2257. Swainsonine (2) is also present in (b) locoweeds
(Astragalis and Oxytropis species): Molyneux, R. J .; J ames, L. F.
Science 1982, 216, 190 and (c) fungus Metarhiriun anisopliae:
Scheider, M. J .; Ungemach, F. S.; Broquist, H. P.; Harris, T. M.
Tetrahedron 1983, 39, 29. (d) Hini, M.; Nakayama, O.; Tsurumi, Y.;
Adaki, K.; Terano, H.; Kohsaka, M.; Aoki, H. J . Antibiot. 1985, 38,
926. More recent synthesis of 2: (e) Vincente, J .; Arra´yas, R. G.;
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E. J . J . Org. Chem. 1996, 61, 7217 and references therein for
carbohydrates as starting materials.
(3) (a) Pastuszak, I.; Molyneux, R. J .; J ames, L. F.; Elbein, A. D.
Biochemistry 1990, 29, 886. Synthesis of 3: (b) Brandi, A.; Cicchi, S.;
Cordero, F. M.; Frignoli, R.; Goti, A.; Picasso, S.; Vogel, P. J . Org. Chem.
1995, 60, 6806. (c) Yoda, H.; Kitayama, H.; Katagiri, T.; Takabe, K.
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(6) Lentiginosine (3) as an amyloglucosidase inhibitor (a) See ref
3a. (b) Molyneux, R. J .; Pan, Y. T.; Tropea, J . E.; Benson, M.; Kaushal,
G. P.; Elbein, A. D. Biochemistry 1991, 30, 9981. (c) See ref 3b,c.
10.1021/jo0016428 CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/14/2001

4788 J . Org. Chem., Vol. 66, No. 14, 2001
Paolucci and Mattioli
Ch a r t 2
Ch a r t 3
significant changes in terms of inhibiting potency and
selectivity on the glycosidase enzymes.9 On the basis of
these considerations, ready access to the unnatural
epimers of polyhydroxylated indolizidines 1-3 has re-
ceived much attention.10-12
We have previously reported the preparation of chiral
building blocks 4-6 (Chart 2) from D-mannitol or D-
sorbitol and their use for the syntheses of several enantio-
pure insect pheromones13a,b as well as the Geissman-
Waiss lactone,14 developing the “chiral pool approach”.26
More recently, we have shown how chiral synthons such
as 4-6 can be used to prepare a dihydroxyindolizidine
such as (-)-8a-epilentiginosine in high enantiomeric
purity.12c
In this paper, we report the application of our meth-
odology to the novel optically pure polyhydroxylated
indolizidines 9-12 (Chart 3) via 5-oxohexahydroindol-
izines 7 and 8. To the best of our knowledge, 1,2,7,8-
tetrahydroxyindolizines do not occur naturally, and tet-
raol 13 has been prepared by diethylaminosulfur tri-
fluoride (DAST)-induced rearrangement of 1,6,7-tri-O-
benzoylcastanospermine,15 while 14 and 15 have been
obtained from D-glucoheptonic γ-lactone.11k
(7) (a) Elbein, A. D. FASEB J . 1991, 5, 3055. (b) Cenci di Bello, I.;
Fleet, G. W. J .; Namgoong, S. K.; Tadano, K. I.; Winchester, B. G.
Biochem. J . 1989, 259, 855. (c) Kino, I.; Inamura, N.; Klakahara, K.;
Kiyoto, S.; Goto, T.; Terano, H.; Kohsaka, M. J . Antibiot. 1985, 38,
936. (d) Goss, P. E.; Baker, M. A.; Carver, J . P.; Dennis, J . W. Clin.
Cancer Res. 1995, 1, 935. (e) Das, P. C.; Robert, J . D.; White, S. L.;
Olden, K. Oncol. Res. 1995, 7, 425. (f) Elbein, A. D.; Molyneux, R. J .
In Iminosugars as Glycosidase Inhibitors; Stu¨tz, A. E., Ed.; Wiley-
VCH: Weinheim, 1999, pp 216-251 and references therein.
(8) (a) Tulisani, D. R. P.; Harris, T. R.; Touster, O. J . J . Biol. Chem.
1982, 257, 7936. (b) Kausal, G. P.; Elbein, A. D. Methods Enzymol.
1994, 230, 316.
(9) (a) Burgess, K.; Henderson, I. Tetrahedron 1992, 48, 4045. (b)
See refs 4g, 5j, and 7b.
(10) Synthesis and biological activity of castanospermine close
analogues: Tayle, P. C.; Winchester, B. G. In Iminosugars as Glycosi-
dase Inhibitors; Stu¨tz, A. E., Ed.; Wiley-VCH: Weinheim, 1999; pp
125-156 and references therein.
(11) Synthesis and biological activity of swainsonine close ana-
logues: (a) Tarentino, A. L.; Maley, F. J . Biol. Chem. 1974, 249, 811.
(b) Tadano, K. I.; Hotta, Y.; Morita, M.; Suami, T.; Winchester, B. G.;
Cenci di Bello, I. Chem. Lett. 1986, 2105. (c) Tadano, K. I.; Imura, Y.;
Hotta, Y.; Fukabori, C.; Suami, T. Bull. Chem. Soc. J pn. 1986, 59, 3885.
(d) Elbein, A. D.; Szumilo, T.; Sandord, B. A.; Sharpless, K. B.; Adams,
C. Biochemisty 1987, 26, 2502. (e) Tadano, K. I.; Hotta, Y.; Morita,
M.; Suami, T.; Winchester, B. G.; Cenci di Bello, I. Bull. Chem. Soc.
J pn. 1987, 60, 1403. (f) See ref 5g. (g) Herczegh, P.; Kovaks, I.; Szilagyi,
L.; Zsely, M.; Sztaricskai, F. Tetrahedron Lett. 1992, 33, 3133. (h) See
ref 7c. (i) Herczegh, P.; Kovaks, I.; Szilagyi, L.; Staricskai, F. Tetra-
hedron 1994, 50, 13671. (j) Oishi, T.; Iwakuma, T.; Hirama, M.; Ito, S.
Synlett 1995, 404. (k) Davis, B.; Bell, A. A.; Nash, R. J .; Watson, A.
A.; Griffith, R. C.; J ones, M. G.; Smith, C.; Fleet, G. W. J . Tetrahedron
Lett. 1996, 37, 8565. (l) Goti, A.; Cardona, F.; Brandi, A.; Picasso, S.;
Vogel, P. Tetrahedron: Asymmetry 1996, 7, 1659. (m) Winkler, D. A.;
Hollan, G. J . Med. Chem. 1989, 32, 2084.
Resu lt a n d Discu ssion
P r ep a r a tion of Oxoin d olizin e 8 a n d F or m a l Syn -
th esis of Its Ster eoisom er s en t-8 a n d en t-7. To extend
the methodology initiated with our synthesis of (-)-8a-
epilentiginosine12c via derivative 7, we first prepared
amide 8 as depicted in Scheme 1. Pyrrolidine 17, obtained
from the epoxide 612c via dihydrofuran derivative 16, was
deprotected with Me3SiI16 and converted to 3-butenoyl
derivative 20. The diene moiety of 20 was then submitted
to a ruthenium-catalyzed ring-closing metathesis17 to give
the desired bicyclic product 8 with a 78% overall yield
from 17.
The same synthetic sequence may be used to prepare
ent-8 starting from building block ent-6, readily available
from L-sorbitol18 though L-isosorbide27a,b (Chart 4). The
fourth and last stereoisomer in this series,19 ent-7, could
be prepared likewise from L-mannitol, although this is
(12) Synthesis and biological activity of lentiginosine close ana-
logues: (a) Colegate, S. M.; Dorling, R. R.; Huxtable, C. R. Aust. J .
Chem. 1984, 37, 1503. (b) See ref 3b,c. (c) Paolucci, C.; Musiani, L.;
Venturelli, F.; Fava, A. Synthesis 1997, 1415. (d) Heitz, M. P.;
Overman, L. E. J . Org. Chem. 1989, 54, 2951.
(13) (a) Cere`, V.; Mazzini, C.; Paolucci, C.; Pollicino, S.; Fava, A. J .
Org. Chem. 1993, 58, 4567. (b) Paolucci, C.; Mazzini, C.; Fava, A. J .
Org. Chem. 1995, 60, 169.
(14) Paolucci, C.; Venturelli, F.; Fava, A. Tetrahedron Lett. 1995,
36, 8127.
(15) Forneaux, R. H.; Gainsford, G. J .; Mason, J . M.; Teyler, P. C.;
Hartley, O.; Winchester, B. G. Tetrahedron 1995, 51, 12611.
(16) Lott, R. S.; Chanhan, V. S.; Stammer, C. H. J . Chem. Soc.,
Chem. Commun. 1979, 495.
(20) ent-Lentiginosine: (a) Gurjar, M. K.; Ghosh, L.; Syamala, M.;
J ayasree, V. Tetrahedron Lett. 1994, 8871. (b) See ref 3b,g. 2,8a-
Diepilentiginosine: (c) Harris, T. M.; Harris, C. M.; Hill, J . E.;
Ungemach, F. S. J . Org. Chem. 1987, 52, 3094. (d) Pearson, W. H.;
Lin, K. C. Tetrahedron Lett. 1990, 31, 7571. 2-Epilentiginosine: (e)
See ref 20b. (f) Takahata, H.; Banba, Y.; Momose, T. Tetrahedron:
Asymmetry 1992, 3, 999. (g) Heitz, M.-P.; Overman, L. E. J . Org. Chem.
1989, 54, 2591. 1,8a-Diepilentiginosine: (h) See ref 20e. 8a-Epilen-
tiginosine: (i) See ref 12c. 1-Epilentiginosine: (l) See ref 3e.
(21) Performed as implemented in Chem3D Pro, Ser. 495965;
CambridgeSoft: Cambridge, MA.
(22) (a) Wilson, C. W. Org. React. 1957, 9, 332. (b) Woodward, R.
B.; Brutche, F. V. J . Am. Chem. Soc. 1958, 80, 209.
(17) Schwab, P.; Grubbs, R. H.; Ziller, J . W. J . Am. Chem. Soc. 1996,
118, 100. Our catalyst was a commercial sample purchased from Strem
Chemicals.
(23) (a) Cambie, R. C.; Hayward, R. C.; Robert, J . L.; Ritledge, P. S.
J . Chem. Soc., Perkin Trans 1 1974, 1858. (b) Seebach, D.; Liesmer,
M.; Wilka, E. M. Org. Synth. 1980, 59, 169.
(18) Synthesis of L-sobitol from commercially available D-gulonic acid
γ-lactone: Wolfrom, M. L.; Thompson, A. In Methods in Carbohydrate
Chemistry; Whistler, R. L., Wolfrom, M. L., Eds.; Academic Press,
Inc.: New York, 1962; Vol. II, pp 66-67 and references therein.
(19) Only four of the eight possible stereoisomers can be synthesized
by this way because the bridgehead carbon configuration, C8a, is fixed
by the stereochemistry at C1, as a consequence of the synthetic protocol
used.12c
(24) Because of the slow rotation of the N-C(O) bond in the NMR
time scale, the amide 32 gives rise to broad or split signals at the
spectrometer temperature (22 °C). When this is the case, the signals
of both conformers (3:1* ratio) are reported as separated by a dash.
(25) Benzyl alcohol (39 mg, 40% yield) was isolated as a byproduct.
(26) Hanessian, S. In Total Synthesis of Natural Products: The
“Chiron” Approach; Baldwing, J . E., FRS, Ed.; Organic Chemistry
Series; Pergamon Press Ltd.: Elmsford, New York, 1983; Vol. 3.

Enantiopure Di- and Tetrahydroxyindolizidines
J . Org. Chem., Vol. 66, No. 14, 2001 4789
Sch em e 1a
Sch em e 2a
a
Reagents: (i) H2-Pd/C. (ii) (a) BH3‚Me2S/THF, rt to reflux.
(b) EtOH, reflux. (iii) HCl (2 M), 60 °C.
Sch em e 3a
a
Reagents: (i) (a) TMSI, acetone; (b) CH2dCHCH2COCl, Et3N,
CH2Cl2. (ii) (Cl)2(Cy3P)2RuCHPh (1 mol %), C6H6, rt to reflux. (iii)
(a) PPh3, PhCO2H, DEAD, THF, rt (75%). (b) K2CO3, MeOH-H2O
(90%).
Ch a r t 4
a
Reagents: (i) OsO4 catalyst, NMO, acetone-water. (ii) H2-
Pd/C. (iii) (a) BH3‚Me2S/THF, rt to reflux. (b) EtOH, reflux. (iv)
H2Pd (black), EtOH/HCl concentration (10:1).
5.12c An interesting stereoisomer of 3 is 2,8-diepilentigi-
nosine 12, which was previously obtained as a di-O-
acetate derivative by a regioselective dehydroxylation of
1,2-di-O-isopropylidene swainsonine.20c Interestingly, 12
can be efficiently converted into swainsonine (2) by
Rhizoctonia leguminicola.20c Another efficient preparation
of 12 starting from 2,3-di-O-isopropylidene-D-erythrose
has been reported by Pearson.20d Scheme 2 illustrates our
approach to indolizidine 12, which consists of catalytic
hydrogenation of indolizine 8 to saturated amide 21, a
borane reduction of the carbonyl to amine 22, and finally
a deprotection of the diol to the desired target 12.
Syn th esis of Tetr a h yd r oxyin d olizid in es 9-11. The
presence of a carbonyl and a nonconjugated double bond
in the six-member ring adds versatility to chiral building
blocks 7 and 8. Reactions at the double bond were
examined first, and when the â,γ-unsaturated amide
derivative 7 was submitted to syn-dihydroxylation cata-
lyzed with osmium tetroxide, two isomeric diols (23 and
24) were obtained in a 5:1 ratio Scheme 3.28
not a convenient starting material because of its elevated
cost. The feasibility of diastereodivergent synthesis start-
ing from L-sorbitol was therefore evaluated via an inver-
sion of configuration at the hydroxylated carbon adjacent
to the dihydrofuranic ring on ent-16 (Chart 4).
When submitted to Mitsunobu’s conditions in the
presence of benzoic acid, urethane 16 gave benzoic ester
18, which after alkaline hydrolysis afforded urethane 19
in 67% overall yield (Scheme 1). Consequently, both
stereoisomers, ent-7 and ent-8, could be obtained from
L-sorbitol, which demonstrate the high flexibility of our
methodology. Moreover, ent-7 opens a way to the 1,2-
diepilentiginosine, the only unknown lentiginosine stereo-
isomer,20 by applying the same synthetic protocol used
to obtain the 8a-epilentiginosine from 7.12c
After chromatographic separation, the main isomer
(exo-23) could be converted to the desired tetrahydrox-
ylated indolizidine 9 by a Pd(0)/C-catalyzed debenzylation
followed by borane reduction of the carbonyl. The low
yield (45%) of last step is probably due to low solubility
of intermediate 25. By reversing the two steps, tetraol 9
was obtained in 70% overall yield from 23 (Scheme 3).
Syn th esis of Dih yd r oxyin d olizid in e 12. Naturally
occurring lentiginosine (3) was found to be a potent and
selective inhibitor of amyloglucosidase,6a-c and its syn-
thesis,3b-f as well as those of its stereoisomers, has been
the subject of several reports,20 including our own prepa-
ration of 8a-epilentiginosine from D-mannitol via epoxide
(28) The exo-configuration of the newly formed diol was unambigu-
ously assigned to the major isomer 23, by means of 1H NMR analysis
on the corresponding reduction products 26 and 9. The coupling
constants between H8a (hydrogen on the bridgehead carbon, see 1 in
Chart 1) and H8 were 9.7 Hz for 26 and 9.4 Hz for 9, typical values for
the 1,2-di-axial relationship between H8a and H8; otherwise, the
reduction products 27 and 10, derived from the minor isomer 24,
showed J 8a-8 of 5.7 and 4.9 Hz, respectively, typical values for the
equatorial-axial relationship between H8 and H8a (see Abraham, R.
J .; Fisher, J .; Loftus, R. Introduction to NMR Spectroscopy; J ohn Wiley
& Sons: Chichester, 1988; Chapter 3.).
(27) (a) Montgomery, R.; Wiggins, L. F. J . Chem. Soc. 1946, 390.
(b) Hockett, R. C.; Fletcher, H. G., J r.; Sheffield, E. L.; Goepp, R. M.,
J r. J . Am. Chem. Soc. 1946, 68, 1946.

4790 J . Org. Chem., Vol. 66, No. 14, 2001
Paolucci and Mattioli
Sch em e 4a
of the 7,8-diepitetrahydroxyindolizidine isomer of 11 (the
counterpart of 10 in Scheme 3). This remains a rather
puzzling result since both Dreiding models and MM2
calculations21 show that the endo face of 8 is not
particularly more sterically hindered when compared to
epimeric dibenzyl derivative 7. In an attempt to elucidate
this point (Scheme 5), our general methodology was
applied to bicyclic derivative 3012c to afford amide 33, the
corresponding di-O-benzyl derivative of 8. Again, when
33 was submitted to OsO4-catalyzed dihydroxylation, diol
34 was obtained as a single diastereomer. Alternatively,
amine 35, obtained by LAH carbonyl reduction of 33,
resisted OsO4-catalyzed oxidation and was recovered
unreacted after 5 days. The addition of small amounts
of acetic acid to the same reaction mixture allowed the
dihydroxylation to proceed, generating the diastereo-
isomer 36 as a single product. This product was revealed
to be identical to the that obtained by borane reduction
of 34 (Scheme 5). Acetic acid probably reactivates the
catalytic cycle by displacing the osmium from amine
complexation. When 36 was submitted to diol, deprotec-
tion furnished the tetraol 11,29 and this fact confirmed
the exo-selectivity of double bond dihydroxylation of 33
and 35 (Scheme 5).
a
Reagents: (i) OsO4 catalyst, NMO, acetone-water. (ii) (a)
BH3‚Me2S/THF, rt to reflux. (b) EtOH, reflux. (iii) 2 M HCl, 60
°C.
Sch em e 5a
A final attempt at an endo-selective dihydroxylation
33 was performed under Pre´vost conditions using AgOAc/
I222 in acetic acid as well as its Cambie modification with
TlOAc,23 but only an amide decomposition was observed.
Con clu sion s
In conclusion, this work, completing a previous one,12c
provides a straightforward approach to prepare enan-
tiopure stereoisomeric 5-oxohexahydroindolizines 7 and
8, starting from the sugar-derived epoxides 5 and 6,
already shown to be important and useful precursors in
synthesis.13a,b Moreover, a route is depicted to prepare
the corresponding enantiomers ent-7 and ent-8 by a
stereodivergent synthesis from ent-6, achievable from
D-gulono-1,4-lactone. From these hydroxylated nitrogen-
containing bicycles, sets of stereoisomeric indolizidines
can be obtained in enantiopure form and in an efficient
manner. The preparation of two sets of these interesting
compounds (12 and 9-11) is reported here as an example
of the method. Our efforts are aimed to give a contribu-
tion in gaining more insights about the mechanism by
which these substances act on glycosidase enzymes.
a
Reagents: (i) (a) n-C12H25SH, MeOH (deg). (b) NaH, BnBr,
THF-DMF. (ii) (a) TFA, CH2Cl2. (b) CH2dCHCH2COCl, Et3N,
CH2Cl2. (iii) (Cl)2(Cy3P)2RuCHPh, C6H6, rt to reflux. (iv) OsO4
catalyst, NMO, acetone-water. (v) LAH, THF. (vi) (a) BH3‚Me2S/
THF, rt to reflux. (b) EtOH, reflux. (vii) OsO4 catalyst, NMO, AcOH
(3 equiv), acetone-water. (viii) H2-Pd (black), EtOH/HCl concen-
tration (10:1).
Exp er im en ta l Section
Gen er a l. Bulb to bulb distillations were done on a Bu¨chi
GRK-50 Kugelrohr apparatus; boiling points refer to air-bath
temperatures and are uncorrected. Melting points were ob-
tained with a Bu¨chi apparatus and are uncorrected. Yields are
for isolated compounds. Unless otherwise specified, 1H and 13C
spectra were recorded at 300 and 75 MHz, respectively, in
CDCl3 as solvent. Chemical shifts are in ppm downfield of TMS
as an internal standard. Electron impact mass spectra were
obtained with a VG 7070 instrument at 70 eV. For optical
rotation measurements, a Perkin-Elmer 341 was used. Pre-
parative flash chromatographic separations were performed
using Merck silica gel 60 (70-230 mesh ASTM). For TLC,
Merck precoated glass plates (silica gel 60 GF254, 0.25 mm)
were used. Dry solvents and reagents were obtained prior to
use as follows: THF was distilled from benzophenone ketyl;
MeCN, CH2Cl2, benzene, Et3N, and DMF were distilled from
CaH2; acetone was from K2CO3; and Me3SiCl was on magne-
sium turnings. NaI was dried at 100 °C under reduced
pressure (0.1 mm) for 4 h.
Isomeric tetraol 10 was prepared with a similar reaction
sequence with a 42% overall yield from the minor
dihydroxyl amide endo-24.
The OsO4-catalyzed syn-dihydroxylation of amide 8, on
the other hand, showed an exclusive exo-selectivity
providing diol 28 as the sole product29 (Scheme 4).
Borane-mediated carbonyl reduction to amine 29, fol-
lowed by diol deprotection, furnished the desired tetraol
11, enantiomeric to 1511k (Chart 3).
The high exo-diastereofacial selectivity in the OsO4-
catalyzed dihydroxylation of 8 precluded the preparation
(29) The exo-configuration of the diol moiety was confirmed from
the enantiomeric relationship between the tetraol 11, derived from 28
(Scheme 4), and the tetraol 15 in Chart 4 (see Experimental Section).
Moreover, 11 showed a coupling constant between H8a and H8 of 10.2
Hz (see ref 28).

Enantiopure Di- and Tetrahydroxyindolizidines
J . Org. Chem., Vol. 66, No. 14, 2001 4791
(2R,3S,4R)-(-)-N-Vin yla cetyl-3,4-d i-O-isop r op ylid en e-
2-vin ylp yr r olid in e (20). To a dried NaI (1.5 g, 10 mmol)
solution in anhyd MeCN (10 mL), Me3SiCl (0.734 mL, 10
mmol) was added dropwise under nitrogen at 0-5 °C. After 5
min, the orange suspension was allowed to warm to ambient
temperature and maintained for 30 min. The stirring was
stopped, and the decanted Me3SiI solution (7 mL, ∼7 mmol)
was transferred, by syringe, into an oven-dried flask under
nitrogen, and then a solution of N-Boc derivative 1712c (1 g,
3.7 mmol) in acetone (15 mL) was added. The resulting mixture
was stirred at rt for 45 min and then warmed to 45 °C. The
progress of the reaction was monitored by TLC (20% Et2O/
petroleum ether). After 30 min at 45 °C, the starting material
disappeared. The reaction mixture was cooled to 0 °C and
quenched with 1 mL of NaOMe (3 M solution in methanol, 3
mmol) followed by CH2Cl2 (30 mL) addition. The insoluble solid
was filtered off, solvents were removed under reduced pres-
sure, and the residue was treated with CH2Cl2 (30 mL) and
refiltered to completely remove the insoluble salt. Solvent
evaporation furnished 1 g of amine (Rf ) 0.15, 20% MeOH/
EtOAc), which then dissolved in 4 mL of CHCl3 (filtered
through neutral alumina) cooled at -10 °C, and Et3N (0.733
mL, 5.5 mmol) was added. To the resulting mixture, vinyl-
acetyl chloride (0.338 mL, 4 mmol) was slowly added by
syringe. The reaction was followed by TLC (20% MeOH/
EtOAc), and after 1 h at -10 °C, Et2O (40 mL) was added.
The reaction mixture was then washed twice with water (3
mL) and dried on MgSO4. After the solvent evaporated, the
crude product was flash chromatographed on silica gel to
furnish 0.811 g (92% yield) of diene 20 as a colorless oil. Bulb
to bulb distillation at 0.05 mm (bp 145 °C) furnished 0.75 g
(85%) of colorless oil: [R]28D ) -23.6° (c 0.64, CHCl3). 1H NMR
(T ) 55 °C): δ 6.04-5.80 (m, 2H), 5.33-5.08 (m, 4H), 4.86-
4.76 (m, 2H), 4.57 (bs, 1H), 4.05 (bs, 1H), 3.57-3.48 (m, 1H),
3.12-3.06 (m, 2H), 1.52 (s, 3H), 1.37 (s, 3H). 13C NMR (T )
55 °C): δ 170.11, 134.12 (br), 131.25, 117.58, 116.16, 113.29,
80.79, 77.68, 62.22, 49.92 (br), 39.26, 26.07, 25.08. Anal. Calcd
for C13H19NO3: C, 65.80; H, 8.07; N, 5.90. Found: C, 66.01;
H, 8.09, N, 5.89.
7.47-7.39 (m, 2H), 5.98-5.91 (m, 1H), 5.84-5.77 (m, 1H),
5.31-5.24 (m, 1H), 5.18-5.00 (m, 2H), 4.77-4.54 (m, 2H),
3.66-3.40 (m, 2H), 1.39 (s, 9H). 13C NMR: δ 165.91, 155.81,
132.92, 129.82, 129.58, 128.76, 128.20, 125.56, 85.65, 79.22,
75.70, 73.87, 41.30, 28.16. Anal. Calcd for C18H23NO5: C, 64.85;
H, 6.95; N, 4.20. Found: C, 64.87; H, 6.95; N, 4.20.
(2S,1′S)-(-)-N-ter t-Bu t oxyca r b on yl-2-(2′-a m in o-1′-h y-
d r oxyeth yl)-2,5-d ih yd r ofu r a n (19). A solution of benzoate
18 (0.87 g, 2.61 mmol) in MeOH/water 95:5 (6 mL) was treated
with solid K2CO3 (0.481 g, 3.48 mmol). After 12 h, the reaction
mixture was diluted with CH2Cl2 (10 mL), and the inorganic
salt was filtered. After the solvent evaporated, the crude
product was purified by flash chromatography (Et2O) to give
0.538 (90% yield) of alcohol 19 as a colorless oil: [R]22D ) -93.6
(c 1.06, CHCl3) [lit12c -94.5° (c 1.31, CHCl3)]. 1H and 13C NMR
spectra coincided with those of the literature.12c
(1S,2R,8a R)-(+)-1,2-Di-O-isop r op ylid en e-5-oxoin d olizi-
d in e (21). A mixture of lactam 8 (0.67 g, 3.2 mmol), 10% Pd
on carbon (67 mg), and MeOH (30 mL) was treated with
hydrogen (3.3 bar). TLC monitoring (EtOAc) indicated that the
reaction was complete in 1 h. After filtration through Celite
and flash chromatography (5% MeOH/EtOAc), the title com-
pound 21 was isolated and distilled (bulb to bulb at 150 °C/01
mm) to give 0.608 g (90% yield) of white solid: mp 63-65 °C;
1
[R]22 ) +61.1° (c 1.16, CHCl3). H NMR (200 MHz): δ 4.78-
D
4.70 (m, 1H), 4.62 (dd, J ) 6.0, 4.1 Hz, 1H), 4.22 (d, J ) 13.5
Hz, 1H), 3.42 (m, 1H), 3.10 (dd, J ) 13.5, 5.1 Hz, 1H), 2.50-
2.19 (m, 2H), 2.08-1.62 (m, 4H), 1.41 (s, 3H), 1.32 (s, 3H). 13
C
NMR (50 MHz): δ 169.31, 111.75, 81.08, 77.60, 61.18, 50.24,
31.22, 26.45, 24.75, 22.50, 20.92. Anal. Calcd for C11H17NO3:
C, 62.54; H, 8.11; N, 6.63. Found: C, 62.53; H, 8.12; N, 6.63.
(1S,2R,8aR)-(-)-1,2-Di-O-isopr opyliden in dolizidin e (22).
To a solution of lactam 21 (0.23 g, 1.09 mmol) in dry THF (10
mL), a solution of Me2S‚BH3 (2 M in THF, 2.5 mL, 5 mmol)
was added under Ar, and the reaction mixture was kept at rt
for 2 h and refluxed for 1 h. The excess of reducing agent was
quenched by careful addition of EtOH (2 mL) at -5 °C. After
the solvent evaporated, the residue was dissolved in EtOH (2
mL) and heated to reflux for 2 h and then cooled to rt and
concentrated under reduced pressure. The residue was purified
by flash chromatography (2% MeOH/EtOAc) to give 0.172 g
(1S,2R,8a R)-(+)-1,2-Di-O-isop r op ylid en e-1,2,3,5,6,8a -
h exa h yd r o-5-oxoin d olizin e (8). An oven-dried, 250-mL,
three-necked, round-bottomed flask, equipped with a reflux
condenser and an argon inlet, was charged with (Cl)2(Cy3P)2-
RudCHPh (56 mg, 1 mol %) and degassed dry benzene (100
mL). The distilled diene 20 (1.6 g, 6.8 mmol) was added under
Ar into the purple solution, and the mixture was slowly
brought to reflux at which time the color changed to orange-
brown and after 50 min changed to green. The residue, after
the solvent evaporated, was supported on silica gel and
purified by flash chromatography (75% EtOAc/petroleum
ether, 1% MeOH/CH2Cl2) to give 1.32 g (92%) of 13 as a light
brown waxy solid: mp 64-65 °C (crystallized from n-hexane);
[R]23D ) +84.8° (c 1.05, CHCl3). 1H NMR: δ 5.96-5.89 (m, 1H),
5.88-5.81 (m, 1H), 4.80-4.75 (m, 1H), 4.71 (dd, J ) 5.8, 4.0
Hz, 1H), 4.43 (d, J ) 13.5 Hz, 1H), 4.08-4.01 (m, 1H), 3.04
(dd, J ) 13.5, 4.7 Hz, 1H), 2.99-2.94 (m, 2H), 1.35 (s, 3H),
1.31 (s, 3H). 13C NMR: δ 166.15, 124.14, 119.49, 111.66, 80.21,
(80%) of amine 22 as a white solid: mp 89-91 °C; [R]23
)
D
-38.0° (c 0.95, CH3OH). 1H and 13C NMR spectra were
identical to those previously reported.20c
(1S,2R,8a R)-(-)-1,2-Dih yd r oxyin d olizid in e (12). Ace-
tonide 22 (0.18 g, 0.91 mmol) was treated with 2 M HCl (5
mL) for 18 h at 60 °C. The solvent was evaporated, and the
residue was basified with saturated aqueous KOH (1 mL) and
extracted with THF (10 mL). The organic phase was dried
(K2CO3) and concentrated under reduced pressure. The puri-
fication of the residue by flash chromatography (10% MeOH/
CH2Cl2) gave 0.109 g (76% yield) of amine 12 as a white solid:
mp 109-111 °C (crystallized from n-hexane); [R]24 ) -37.1°
D
(c 0.55, CH3OH). 1H NMR: δ 4.27-4.17 (m, 1H), 3.98 (dd, J )
6.1, 4.2 Hz, 1H), 3.65 (bs, 2H, (2OH)), 3.10-3.00 (m, 1H), 2.96
(d, J ) 10.7 Hz, 1H), 2.31 (dd, J ) 10.7, 7.1 Hz, 1H), 1.98-
1.47 (m, 7H), 1.33-1.13 (m, 1H). 13C NMR: δ 72.37, 69.48,
68.19, 62.57, 53.28, 24.95, 24.84, 23.80. HRMS (m/z): (M+)
calcd for C8H15NO2, 157.1104; found, 157.1103. MS m/z: 157
(16), 140 (11), 97 (100), 84 (24), 69 (23).
77.79, 62.05, 49.51, 31.67, 26.22, 24.54. Anal. Calcd for C11H15
-
NO3: C, 63.14; H, 7.23; N, 6.69. Found: C, 63.19; H, 7.22; N,
6.70.
(2S,1′S)-(-)-N-ter t-Bu t oxyca r b on yl-2-(2′-a m in o-1′-O-
ben zoyl)-2,5-d ih yd r ofu r a n (18). Diethylazodicarboxylate
(1.73 mL, 10.63 mmol) was added to an ice-cooled solution of
PPh3 (2.88 g, 11 mmol), PhCO2H (1.34 g, 11 mmol), and the
alcohol derivative 1612c (1.14 g, 5 mmol) in dry THF (60 mL)
under nitrogen. The reaction mixture was stirred at rt and
monitored on TLC (50% EtOAc/petroleum ether). After 18 h,
the reaction was quenched with MeOH (0.3 mL), stirred for 1
h, and diluted with Et2O (60 mL), and the solid was filtered.
The solvents were evaporated under reduced pressure, and the
residue was purified by flash chromatography (50% Et2O/
petroleum ether) to give 1.35 g of benzoate derivative 18. Bulb
to bulb distillation at 0.1 mm (bp 150 °C) afforded 1.25 g (75%
(1S,2S,7R,8S,8a R)-(-)- (23) a n d (1S,2S,7S,8R,8a R)-(-)-
1,2-Diben zyloxy-7,8-d ih yd r oxy-5-oxoin d olizid in e (24). To
a solution of N-methylmorpholine N-oxide (0.78 g, 1.5 equiv)
in water (0.5 mL) was added, in succession, a solution of 0.19
M OsO4 (0.9 mL, 0.04 equiv) and the unsaturated amide 7 (1.5
g, 4.29 mmol) dissolved in acetone (3 mL). The solution was
stirred at rt and monitored by TLC (1% MeOH/EtOAc). After
36 h, saturated aqueous sodium hydrosulfite (0.5 mL) was
added, and after 30 min, the resulting reaction mixture was
filtered through Celite and rinsed with acetone. The solvents
were evaporated, and the dark oil was purified by flash
chromatography (2-5% MeOH/CH2Cl2) to give the isomeric
amides 23 (1.07 g, 65% yield) and 24 (0.214 g, 13% yield) as
1
yield) of product as a colorless oil: [R]21 ) -124.9° (c 2.06,
colorless oils. Amide 23: [R]22 ) -49.1° (c 1.01, CHCl3). H
D
D
CHCl3). 1H NMR: δ 8.10-7.99 (m, 2H), 7.61-7.51 (m, 1H),
NMR: δ 7.40-7.22 (m, 10H), 4.58 (AB q, δν ) 14.1 Hz, J )

4792 J . Org. Chem., Vol. 66, No. 14, 2001
Paolucci and Mattioli
11.8 Hz, 2H), 4.45 (AB q, δν ) 15.1 Hz, J ) 12.0 Hz, 2H), 4.18-
4.08 (m, 2H), 4.02-3.94 (m, 3H), 3.78 (dd, J ) 13.5, 5.1 Hz,
1H), 3.56 (bs, 1Η (ÃΗ)), 3.52 (d, J ) 13.5 Hz, 1H), 3.23 (bs,
1H (OH)), 2.62 (m, 2H). 13C NMR: δ 167.96 137.65, 137.29,
128.46, 127.96, 127.87, 127.74, 127.66, 127.61, 80.02, 77.12,
72.25, 71.12, 68.14, 66.64, 59.66, 50.48, 38.35. Anal. Calcd for
5.9 Hz, 1H), 2.00-1.91 (m, 1H), 1.90-1.77 (m, 1H). 13C NMR
(D2O, MeOH as an internal standard): δ 78.24, 77.62, 68.88,
68.64, 65.48, 61.32, 46.62, 31.14. HRMS (m/z): (M+) calcd for
C8H15NO4, 189.10018; found, 189.10011. MS m/z: 189 (20), 172
(14), 154 (6), 129 (100), 116 (26).
9 fr om 25. The lactam 25 (50 mg, 0.25 mmol) was submitted
to Me2S‚BH3 reduction according to the procedure described
for 26 synthesis. After concentration, ∼3 mL of the mixture
C22H25NO5: C, 68.91; H, 6.57; N, 3.65. Found: C, 68.71; H,
1
6.59; N, 3.66. Amide 24: [R]22 ) -42.6° (c 0.97, CHCl3). H
D
was purified on
a
Dowex 50WX8-100 (H+) ion-exchange
NMR: δ 7.41-7.22 (m, 10H), 4.57 (AB q, δν ) 47.4 Hz, J )
11.7 Hz, 2H), 4.51 (AB q, δν ) 35.3 Hz, J ) 11.9 Hz, 2H), 4.39-
4.36 (m, 1H), 4.27-4.23 (m, 2H, (1OH)), 4.06-4.02 (m, 1H),
4.00-3.87 (m, 1H), 3.83-3.72 (m, 2H), 3.63 (d, J ) 13.4 Hz,
1H), 2.75 (dd, J ) 17.4, 7.0 Hz, 1H), 2.73 (bs, 1H, (OH)), 2.54
(dd, J ) 17.4, 10.1 Hz, 1H). 13C NMR: δ 168.29, 137.00, 136.01,
128.93, 128.70, 128.66, 128.21, 127.96, 127.74, 83.73, 76.53,
72.24, 71.47, 68.92, 68.29, 58.91, 48.83, 36.69. Anal. Calcd for
C22H25NO5: C, 68.91; H, 6.57; N, 3.65. Found: C, 69.19; H,
6.55; N, 6.88.
column; after being washed with 20% MeOH/water (50 mL),
the unreacted lactam 25 was recovered (20 mg, 40% yield, after
flash chromatography purification), and then with 2 M NH4OH
(3×, 30 mL), the amine 9 was isolated, and purification as
described above led to the recovery of 21 mg (45% yield) of 9
as a white solid.
(1S,2S,7S,8R,8a R)-(-)-1,2-Diben zyloxy-7,8-d ih yd r oxy-
in d olizid in e (27). The lactam 24 (0.154 g, 0.4 mmol) was
reduced with Me2S‚BH3 (2 M in THF, 1.2 mL, 2.4 mmol) as
described for the reduction of 21. After solvent evaporation
and flash chromatography purification (5% MeOH/CH2Cl2),
0.111 g (75% yield) of amine 27 was obtained as a white waxy
(1S,2S,7R,8S,8aR)-(-)-1,2,7,8-Tetr ah ydr oxy-5-oxoin doli-
zid in e (25). A mixture of lactam 23 (0.386 g, 1.01 mmol), 10%
Pd on carbon (50 mg), MeOH (20 mL), and 6 M HCl (1 mL)
was treated with hydrogen at 2 bar. TLC monitoring (5%
MeOH/CH2Cl2) indicated that the reaction was complete in 3
h. After filtration through Celite, an aqueous solution of NaOH
(3 M, 2.2 mL) was added, and the solvents were evaporated
under reduced pressure. The crude material was adsorbed on
silica gel and column chromatographed (30% MeOH/CH2Cl2).
The title compound 25 was obtained (0.165 g, 81% yield) as a
material: mp 72-73 °C (crystallized from n-hexane); [R]21
)
D
1
-29.7° (c 1.11, CHCl3). H NMR: δ 7.40-7.25 (m, 10H), 4.56
(AB q, δν ) 50.7 Hz, J ) 11.7 Hz, 2H), 4.48 (AB q, δν ) 22.9
Hz, J ) 11.6 Hz, 2H), 4.19-4.11 (m, 3H), 4.08 (bs, 1H (OH)),
3.61-3.37 (m, 2H), 3.10-3.00 (m, 1H), 2.63 (bs, 1H (OH)), 2.19
(dd, J ) 5.7, 1.1 Hz, 1H), 2.07 (dd, J ) 9.3, 2.5 Hz, 1H), 2.05-
1.89 (m, 2H), 1.85-1.70 (m, 1H). 13C NMR: δ 137.47, 136.84,
128.60, 128.49, 128.15, 128.05, 127.99, 127.84, 86.32, 82.75,
71.75, 71.45, 70.90, 68.40, 67.20, 58.79, 50.43, 28.70. Anal.
Calcd for C22H27NO4: C, 71.52; H, 7.37; N, 3.79. Found: C,
71.34; H, 7.39; N, 3.78.
white solid, highly hygroscopic: [R]20 ) -64.5° (c 0.97,
D
1
CH3OH). H NMR (D2O): δ 4.33-4.22 (m, 3H), 3.98 (dd, J )
9.9, 2.1 Hz, 1H) 3.92 (dd, J ) 10.1, 2.3 Hz, 1H), 3.81 (dd, J )
13.7, 4.7 Hz, 1H), 3.36 (d, J ) 13.7 Hz, 1H), 2.72 (dd, J ) 18.7,
3.8 Hz, 1H), 2.53 (dd, J ) 18.7, 1.9 Hz, 1H). 13C NMR (MeOH
as initial standard): δ 170.52, 74.70, 72.54, 68.00, 65.92, 59.26,
52.49, 38.06. Anal. Calcd for C8H13NO5: C, 47.29; H, 6.45; N,
6.89. Found: C, 47.35; H, 6.43; N, 6.88.
(1S,2S,7S,8R,8a R)-(-)-1,2,7,8-Tet r a h yd r oxyin d olizi-
d in e (10). Benzyl ether hydrogenolysis of amine derivative
27 (0.103 g, 0.28 mmol) was performed using the condition
described above for 26. The crude product, a light brown oil,
was purified through a Dowex 50WX8-100 (H+) ion-exchange
column (4 g), washed with water (50 mL), and eluted with 2
M NH4OH (3×, 50 mL) to give the amine 10. After water
evaporation under reduced pressure with a water bath tem-
perature below 35 °C, the amine was stored in a desiccator
under vacuum in the presence of CaCl2 overnight to give 30
mg (57% yield) of amine 10 as a white solid: mp 174-175 °C
(1S,2S,7R,8S,8a R)-(-)-1,2-Diben zyloxy-7,8-d ih yd r oxy-
in d olizid in e (26). A solution of lactam 23 (0.48 g, 1.25 mmol)
in dry THF (30 mL) was treated with Me2S‚BH3 (2 M in THF,
3.5 mL, 7 mmol) using conditions described for 21. After the
solvent evaporated, the crude product was flash chromato-
graphed (6% MeOH/CH2Cl2) to give 0.453 g (98% yield) of
amine 26 as a white semisolid material: [R]22 ) -62.7° (c
D
1
1.30, CHCl3). H NMR: δ 7.43-7.25 (m, 10H), 4.59 (AB q, δν
(crystallized from EtOH); [R]24 ) -18.5° (c 0.53, H2O). 1H
D
) 60 Hz, J ) 12.1 Hz, 2H), 4.45 (AB q, δν ) 15.2 Hz, J ) 11.6
Hz, 2H), 4.10-4.03 (m, 2H), 3.98 (dd, J ) 5.2, 1.1 Hz, 1H),
3.89 (dd, J ) 9.7, 3.2 Hz, 1H), 3.53 (dd, J ) 9.4, 6.9 Hz, 1H),
2.78-2.69 (m, 1H), 2.55 (dd, J ) 9.7, 5.2 Hz, 1H), 2.40-2.30
(m, 1H), 2.24 (dd, J ) 9.4, 6.2 Hz, 1H), 2.20 (bs, 2H, (2 OH)),
1.90-1.73 (m, 2H). 13C NMR: δ 138.15, 137.78, 128.53, 128.45,
128.00, 127.89, 127.82, 127.71, 82.29, 82.24, 71.63, 71.22,
NMR (D2O, MeOH as an internal standard): δ 4.48-4.43 (m,
1H), 4.37 (dd, J ) 4.9, 1.5 HZ, 1H), 4.35-4.29 (m, 1H), 3.88
(ddd, J ) 11.7, 4.9, 2.9 Hz, 1H), 3.63 (dd, J ) 10.4, 7.0 Hz,
1H), 3.28-3.19 (m, 1H), 2.63 (d, J ) 4.9 Hz, 1H), 2.48-2.36
(m, 1H), 2.24 (dd, J ) 10.4, 6.0 Hz, 1H), 2.14-1.98 (m, 1H),
1.94-1.83 (m, 1H). 13C NMR (D2O, MeOH initial standard):
δ 79.78, 77.20, 70.13, 68.76, 66.12, 58.97, 49.93, 26.49. HRMS
(m/z): (M+) calcd for C8H15NO4, 189.10047; found, 189.10011.
MS m/z: 189 (17), 172 (15), 154 (7), 129 (100), 116 (28).
68.72, 67.67, 64.82, 59.56, 46.08, 30.61. Anal. Calcd for C22H27
-
NO4: C, 71.52; H, 7.37; N, 3.79. Found: C,71.31; H, 7.39; N,
3.80.
(1S,2R,7R,8S,8a R)-(-)-1,2-Di-O-isop r op ylid en e-7,8-d i-
h yd r oxy-5-oxoin d olizid in e (28). To a solution of N-methyl-
morpholine N-oxide (0.63 g, 4.65 mmol) in water (0.3 mL) was
added, in succession, a solution of OsO4 (0.19 M, 0.63 mL, 0.12
mmol) and the unsaturated amide 8 (0.65 g, 3.1 mmol)
dissolved in acetone (1.5 mL). The solution was stirred for 43
h at rt and monitored by TLC (5% MeOH/EtOAc). After
addition of saturated aqueous sodium hydrosulfite (0.4 mL),
the reaction mixture was filtered through Celite and rinsed
with acetone. The solvents were evaporated, and the dark oil
was purified by flash chromatography (1-10% MeOH/CH2Cl2)
to give 0.679 g (90% yield) of lactam 28 as a white solid: mp
(1S,2S,7R,8S,8a R)-(-)-1,2,7,8-Tet r a h yd r oxyin d olizi-
d in e (9) fr om 26. A suspension of palladium black (75 mg)
in 95% EtOH (3 mL) and HCl (concentrated, 1 mL) was
prehydrogenated in a Parr hydrogenator under 3 bar of
hydrogen for 15 min, a solution of amine 26 (0.15 g, 0.406
mmol) in 95% EtOH (8 mL) was added, and the suspension
was shaken under 3 bar of hydrogen for 8 h. The reaction
mixture was basified by aqueous solution of NaOH addition
(3 M, 4.5 mL) and filtered on Celite. The crude product
dissolved in 5 mL of water was purified through a Dowex
50WX8-100 (H+) ion-exchange column (5 g) washed with water
(2×, 50 mL) and eluted with 2 M NH4OH (4×, 50 mL) to give
the amine 9. After the solvent evaporated, under reduced
pressure, the crude material was adsorbed on silica gel and
column chromatographed (0-5% NH4OH concentrated/MeOH)
to give the amine 9 as a white solid: 56 mg (72% yield); mp
184-185 °C (crystallized from i-PrOH); [R]23D ) -68.3° (c 0.95,
H2O). 1H NMR (D2O, MeOH as an internal standard): δ 4.25-
4.16 (m, 3H), 3.84 (dd, J ) 10.3, 3.2 Hz, 1H), 3.57 (dd, J )
10.3, 7.1 Hz, 1H), 2.85 (ddd, J ) 11.3, 4.8, 2.2 Hz, 1H), 2.61
(dd, J ) 10.3, 4.4 Hz, 1H), 2.42 (m, 1H), 2.20 (dd, J ) 10.3,
145-146 °C (crystallized from n-hexane/i-PrOH 5:1); [R]26
)
D
1
-29.2° (c 1.09, CHCl3). H NMR: δ 4.83 (dd, J ) 5.9, 4.3 Hz,
1H), 4.78-4.73 (m, 1H), 4.25-4.20 (m, 1H), 4.15-4.05 (m, 2H),
4.10 (bs, 1H (OH)), 3.90 (bs, 1H (OH)), 3.63 (dd, J ) 8.8, 4.3
Hz, 1H), 3.15 (dd, J ) 13.6, 4.9 Hz, 1H), 2.60-2.55 (m, 2H),
1.41 (s, 3H), 1.34 (s, 3H). 13C NMR: δ 167.69, 111.74, 79.57,
72.28, 68.32, 66.91, 60.83, 50.76, 37.79, 26.33, 24.49. Anal.
Calcd for C11H17NO5: C, 54.31; H, 7.04; N, 5.76. Found: C,
54.40; H, 7.03; N, 5.77.

Enantiopure Di- and Tetrahydroxyindolizidines
J . Org. Chem., Vol. 66, No. 14, 2001 4793
(1S,2R,7R,8S,8a R)-(-)-1,2-Di-O-isop r op ylid en e-7,8-d i-
h yd r oxyin d olizid in e (29). Lactam 28 (0.5 g, 2.05 mmol)
reduction with Me2S‚BH3 was performed according to the
procedure described for 21. Purification by flash chromatog-
raphy (10% MeOH/CH2Cl2) afforded 0.423 g (90% yield) of
dissolved in CH2Cl2 (10 mL) containing Et3N (1.34 mL, 9.48
mmol) and cooled at -10 °C, vinylacetyl chloride (0.806 g, 7.7
mmol) was added dropwise. The mixture was stirred at 0 °C,
and the reaction was followed on TLC (8% MeOH/CH2Cl2).
After 4 h, Et2O (70 mL) was added, and the solid material was
filtered off on paper. Solvent evaporation gave a crude product
that was flash chromatographed (35% EtOAc/petroleum ether)
to give 2.2 g (92% yield) of diene 32 as a colorless oil: bp 220
amine 29 as white solid material: mp 114-116 °C (crystallized
1
from n-hexane); [R]24 ) -68.0° (c 1.03, CHCl3). H NMR: δ
D
4.68 (dd, J ) 6.3, 4.4 Hz, 1H), 4.63 (dd, J ) 6.3, 4.1 Hz, 1H),
4.09 (m, 1H), 3.89 (dd, J ) 9.7, 3.2 Hz, 1H), 3.16 (d, J ) 10.7
Hz, 1H), 2.83-2.70 (m, 3H (2 OH)), 2.33-2.23 (m, 1H), 2.22-
°C/0.05 mm; [R]23 ) +32.7° (c 1.11, CHCl3). 1H NMR:24
δ
D
7.38-7.24 (m, 10H), 6.24-6.04 (m, 1H), 6.02-5.86 (m, 1H),
5.41-5.20 (m, 2H), 5.17-5.04 (m, 2H), [4.81-4.53 (m)/4.41-
4.34 (m), 5H], 4.13-4.04 (m, 1H), 4.00-3.91 (m, 1H), [3.77 (d,
J ) 13.5 Hz)/3.63* (dd, J ) 11.3, 2.2 Hz), 1H], [3.56-3.51 (m)/
3.51-3.46* (m), 1H], [3.17-3.02 (m)/3.01-2.94* (m), 2H]. 13C
NMR:24 δ 170.85/169.94*, 138.08*/137.94, 137.65*/137.49,
135.52/134.05*, 131.55/131.01*, 128.46, 128.42, 128.37, 127.92,
127.69, 127.62, 118.78*/118.37, 117.96*/117.80, 79.90/78.78*,
77.03*/74.49, 72.51*/71.89, 72.04*/71.76, 61.87/60.42*, 50.50*/
49.32, 39.66*/39.48. Anal. Calcd for C24H27NO3: C, 76.36; H,
7.21; N, 3.71. Found: C, 76.61; H, 7.19; N, 3.70.
2.14 (m, 2H), 1.92-1.81 (m, 2H), 1.51 (s, 3H), 1.34 (s, 3H). 13
C
NMR: δ 111.18, 79.28, 78.25, 68.99, 67.92, 66.20, 59.69, 45.71,
30.83, 25.84, 24.69. HRMS (m/z): (M+) calcd for C11H15NO4,
229.13119; found, 229.13141. MS m/z: 229 (43), 214 (15), 171
(13), 154 (56), 129 (100).
(1S,2R,7R,8S,8a R)-(-)-1,2,7,8-Tet r a h yd r oxyin d olizi-
d in e (11) fr om 29. A solution of 29 (0.22 g, 0.96 mmol) in
MeOH (7.5 mmol) was treated with HCl (concentrated, 2.5
mL), and the resulting mixture was stirred at 60 °C for 24 h.
The crude product, obtained after solvent evaporation under
reduced pressure, was purified on Dowex 50WX8-100 (H+)
column (5 g) washing with water (2×, 50 mL) and eluting with
2 M NH4OH (3×, 50 mL). From solvent evaporation, 0.173 g
(95% yield) of tetraol 11 was obtained: mp 179-181 °C
(1S,2R,8aR)-(+)-1,2-Diben zyloxy-1,2,3,5,6,8a-h exah ydr o-
5-oxoin d olizin e (33). The diene 32 (2 g, 5.3 mmol) was
submitted to ring-closing metathesis in the presence of
(Cl)2(Cy3P)2RudCHPh (44 mg, 1 mol %) as described previ-
ously for the corresponding acetonide derivative 20. The crude
product was chromatographed (EtOAc) to give the unsaturated
(crystallized from i-PrOH); [R]25 ) -103.9° (c 0.40, H2O) [its
D
enantiomer 15:11k [R]25 ) +22.0° (c 0.05, H2O)]. 1H and 13C
D
NMR spectra were identical to those previously reported.11k
HRMS (m/z): (M+) calcd for C8H15NO4, 189.099 74; found,
189.100 11. MS m/z: 189 (21), 172 (14), 154 (8), 129 (100), 116
(17).
lactam 33 (1.57 g, 83% yield) as a light brown oil: bp 220 °C/
1
0.05 mm; [R]23 ) +24.7° (c 1.17, CHCl3). H NMR: δ 7.40-
D
7.22 (m, 10 H), 5.91-5.83 (m, 1H), 5.80-5.73 (m, 1H), 4.78
(AB q, δν ) 42.0 Hz, J ) 12.2 Hz, 2H), 4.59 (AB q, δν ) 14.6
Hz, J ) 12.2 Hz, 2H), 4.19-4.09 (m, 2H), 4.06-4.03 (m, 1H),
3.76-3.69 (m, 2H), 3.02-2.82 (m, 2H). 13C NMR: δ 166.90,
138.28, 137.56, 128.49, 128.28, 127.89, 127.78, 127.64, 127.52,
124.73, 121.66, 77.85, 76.69, 73.08, 72.15, 61.42, 46.75, 32.47.
Anal. Calcd for C22H23NO3: C, 75.62; H, 6.63; N 4.01. Found:
C, 75.83; H, 6.64; N, 4.04.
11 fr om 36. The dibenzyl derivative 36 (75 mg, 0.0203
mmol) was hydrogenated in the presence of palladium black
(40 mg) following the procedure described previously for its
C-2 epimer, 26. After purification, 23 mg (60% yield) of tetraol
11 was obtained as a white solid.
(2R,3S,4R)-(+)-N-ter t-Bu toxycar bon yl-2-vin yl-3,4-diben -
zyloxyp yr r olid in e (31). To a solution of chloromercury
derivative 3012c (4.04 g, 8.7 mmol) in degassed MeOH (300 mL),
dodecane-1-thiol (2.15 g, 10.44 mmol) was added at rt under
Ar. The mixture was protected from light, and the reaction
course was followed on TLC (60% EtOAc/petroleum ether).
After 6 h, the mixture was filtered on paper, and the solid was
washed with MeOH. The solvent was removed under reduced
pressure, and the residue was dried under high vacuum. The
crude diol so obtained was dissolved in dry DMF (20.2 mL)
and added dropwise under Ar to a suspension of NaH (0.905
g, 22.62 mmol, washed with n-hexane) in dry THF (20.2 mL)
and cooled at -10 °C. The temperature was allowed to rise to
rt under stirring, and benzyl bromide (2.83 mL, 23.46 mmol)
was added dropwise. The mixture was stirred at rt until the
diol was not detectable on TLC (5% MeOH/CH2Cl2). After 5 h,
the reaction was quenched by careful addition of water (0.5
mL) at -10 °C, and the resulting mixture was poured onto
EtOAc:benzene 1:1 (40 mL) and then dried (MgSO4). The
residue, after solvent evaporation, was flash chromatographed
(15% EtOAc/petroleum ether) to give 31 as a colorless oil: 2.92
(1S,2R,7R,8S,8a R)-(-)-1,2-Diben zyloxy-7,8-d ih yd r oxy-
5-oxoin d olizid in e (34). The unsaturated lactam 33 (0.15 g,
0.39 mmol) was submitted to OsO4-catalyzed dihydroxylation
according to the procedure described previously for 7. The
crude product was supported on silica gel and flash chromato-
graphed (5% MeOH/CH2Cl2, Rf ) 0.18) to give 0.12 g (80%
yield) of titled diol 34 as a white solid (insoluble in CHCl3 and
low solubility in CH3OH): mp 188-189 °C (crystallized from
i-PrOH); [R]26D ) -29.5° (c 0.83, 1,4-dioxane:H2O 9:1). 1H NMR
(CD3OD): δ 7.34-7.18 (m, 10H), 4.75 (AB q, δν ) 35.2 Hz, J
) 11.3 Hz, 2H), 4.51 (AB q, δν ) 17.2 Hz, J ) 11.8 Hz, 2H),
4.26-4.17 (m, 2H), 4.07-4.02 (m, 1H), 3.93 (dd, J ) 9.5, 2.2
Hz, 1H), 3.75 (bd, J ) 9.5 Hz, 1H), 3.68-3.59 (m, 1H), 3.38-
3.28 (m, 1H), 2.52 (dd, J ) 18.3, 3.9 Hz, 1H), 2.35 (dd, J )
18.3, 1.9 Hz, 1H). 13C NMR (CD3OD): δ 169.67, 139.89, 139.33,
129.43, 129.27, 129.08, 128.83, 128.80, 128.66, 79.31, 77.71,
74.96, 73.47, 69.14, 67.52, 61.48, 48.72, 39.30. Anal. Calcd for
C
22H25NO5: C, 68.91; H, 6.57; N, 3.65. Found: C, 68.98; H,
6.58; N, 3.66.
(1S,2R,8a R)-(+)-1,2-Dib en zyloxy-1,2,3,5,6,8a -h exa h y-
d r oin d olizin e (35). The unsaturated lactam 33 (0.16 g, 0.458
mmol), dissolved in dry THF (2.5 mL), was added to a
suspension of LiAlH4 (23 mg, 0.6 mmol) in dry THF (5 mL)
under nitrogen. The reaction was maintained for 1 h at rt and
then refluxed. After 4 h, the reaction mixture was cooled at
-10 °C and quenched with a THF solution of triethanolamine
(90 mg, 0.6 mmol) followed by 5% aqueous NH4Cl (0.2 mL).
The solid was removed by filtration and rinsed with EtOAc
(10 mL), and the organic solution was dried (MgSO4). The
crude material was purified by flash chromatography (1-5%
MeOH/CH2Cl2) to give the title product 35 (69 mg, 45%)25 as
g (82% yield); bp 210 °C/0.01 mm; [R]22 ) -29.3° (c 1.67,
D
CHCl3). 1H NMR (T ) 55 °C): δ 7.36-7.22 (m, 10H), 6.13 (ddd,
J ) 17.2, 10.1, 8.4 Hz, 1H), 5.38-5.08 (m, 2H), 4.73-4.53 (m,
4H), 4.34 (bs, 1H), 4.06-3.99 (m, 1H), 3.95 (dd, J ) 7.1, 4.1
Hz, 1H), 3.63-3.48 (m, 1H), 3.45 (dd, J ) 12.1, 4.9 Hz, 1H),
1.42 (s, 9H). 13C NMR (T ) 55 °C; *broad signals): δ 154.50*,
138.36, 137.98, 135.63*, 128.27, 128.23, 127.59, 127.52 (2 C's),
127.44, 117.26*, 79.89*, 79.51, 76.13*, 72.09, 71.98, 61.23*,
49.35*, 28.41. Anal. Calcd for C25H31NO4: C, 73.32; H, 7.63;
N, 3.42. Found: C, 73.12; H, 7.65; N, 3.43.
(2R,3S,4R)-(+)-N-(Vin yla cetyl)-2-vin yl-3,4-d iben zyloxy-
p yr r olid in e (32). The dibenzyloxypyrrolidine 31 (2.6 g, 6.34
mmol), dissolved in CH2Cl2 (7 mL), was treated with TFA (7
mL) at rt and stirred for 30 min. The residue, after solvent
and TFA evaporation at reduced pressure, was dissolved in
THF:MeOH 5:1 (6 mL), and NaHCO3 (0.5 g) was added. The
suspension was stirred for 15 min, diluted with CH2Cl2 (30
mL), and filtered. Evaporation of the solvent left a light brown
oil (Rf ) 0.5, 10% MeOH/CH2Cl2). To this crude material
a colorless oil: [R]26 ) +71.9° (c 0,86 CHCl3). 1H NMR: δ
D
7.42-7.21 (m, 10H), 5.98-5.89 (m, 1H), 5.84-5.76 (m, 1H),
4.70 (AB q, δν ) 23.9 Hz, J ) 12.3 Hz, 2H), 4.56 (AB q, δν )
16.9 Hz, J ) 12.1 Hz, 2H), 4.14-4.06 (m, 1H), 4.00-3.95 (m,
1H), 3.58-3.50 (m, 1H), 3.22 (dd, J ) 10 Hz, 7.2 Hz, 1H), 3.05-
2.85 (m, 3H), 2.33-2.29 (m, 1H), 2.13-1.98 (m, H). 13C NMR:
δ 138.54, 138.21, 128.30, 128.22, 127.68, 127.61, 127.58,
127.47, 126.69, 124.28, 78.54, 78.04, 72.87, 72.16, 60.53, 55.40,

4794 J . Org. Chem., Vol. 66, No. 14, 2001
Paolucci and Mattioli
47.35, 22.42. Anal. Calcd for C22H25NO2: C, 78.77; H, 7.51; N,
4.18. Found: C, 79.07; H, 7.53; N, 4.18.
mL, 3 mmol). After 2 h at rt, the reaction mixture was refluxed
for an additional 2 h and then cooled at -5 °C, and MeOH
was added until effervescence ceased (=300 µL). The solvent
was removed under reduced pressure, the crude product was
dissolved in MeOH (5 mL), and the resulting solution was
refluxed for 36 h. After solvent evaporation, the crude product
was dissolved in MeOH (3×, 5 mL) and supported on silica
gel. From flash chromatography purification, 95.8 mg (68%
yield) of diol 36 was obtained as a colorless oil.
(1S,2R,7R,8S,8a R)-(-)-1,2-Diben zyloxy-7,8-d ih yd r oxy-
in d olizid in e (36) fr om 35. To a solution of N-methylmor-
pholine N-oxide (28 mg, 0.23 mmol) in water (0.24 mL) was
added, in succession, a 0.19 M solution of OsO4 (32 µL, 5 mol
%) and unsaturated amine 35 (40 mg, 0.12 mmol) dissolved
in a 0.3 M solution of AcOH in acetone (1.2 mL, 3 equiv of
AcOH) at rt and stirred for 56 h. The oxidant was quenched
with a saturated aqueous sodium hydrosulfite (50 µL) and
stirred for 30 min. The reaction mixture was supported on
silica gel and purified by flash chromatography (6% MeOH/
CH2Cl2, Rf ) 0.8) to give the diol 36 (18 mg, 40%) as a colorless
oil: [R]24D ) -99.3° (c 1.75, CDCl3). 1H NMR: δ 7.54-7.20 (m,
10H), 4.72 (AB q, δν ) 106.1 Hz, J ) 11.9 Hz, 2H), 4.56 (AB
q, δν ) 32.8 Hz, J ) 12.1 Hz, 2H), 4.13-4.01 (m, 3H), 3.96
(dd, J ) 9.6, 3.1 Hz, 1H), 3.20 (dd, J ) 10.2, 4.5 Hz, 1H), 2.69
(ddd, J ) 11.4, 4.7, 2.3 Hz, 1H), 2.50 (dd, J ) 10.2, 7.0 Hz,
1H), 2.39 (dd, J ) 9.6, 4.5 Hz, 1H), 2.34 (dd, J ) 11.4, 3.7 Hz,
1H), 2.10 (bs, 2H (2 OH)), 1.93-1.73 (m, 2H). 13C NMR: δ
138.64, 138.20, 128.50, 128.31, 128.27, 127.85, 127.71, 127.60,
77.20, 77.10, 73.56, 72.03, 68.43, 67.73, 64.64, 57.74, 45.43,
29.74. Anal. Calcd for C22H27NO4: C, 71.52; H, 7.37; N, 3.79.
Found: C, 71.79; H, 7.39; N, 3.78.
Ack n ow led gm en t. This work was supported in part
by a research grant from the Ministero dell’Universita`
e della Ricerca Scientifica e Tecnologica (MURST), Italy;
by the Consiglio Nazionale delle Ricerche (CNR), Italy;
and by the University of Bologna, Italy (Progetto
d’Ateneo: Biomodulatori Organici). Financial support
from the MURST (Rome, Italy) and the University of
Bologna (Italy) is appreciated (National Project “Stereo-
selezione in Sintesi Organica. Metodologie ed Appli-
cazioni”).
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C (includ-
ing DEPT) spectra of 8-12. This material is available free of
charge via the Internet at http://pubs.acs.org.
36 fr om 34. The lactam 34 (0.132 g, 0.377 mmol) was
dissolved in warm THF (10 mL) under Ar and then cooled at
ca. 15 °C before the addition of 2 M Me2S‚BH3 in THF (1.5
J O0016428