Stereoselective Synthesis of Polyhydroxylated Indolizidines from γ-Hydroxy α,β-Unsaturated Sulfones

Article abstract of DOI:10.1021/jo972167p

The polyhydroxylated indolizidines castanospermine and swainsonine as well as some of their stereoisomers are powerful glycosidase inhibitors. An efficient and stereochemically flexible synthesis of racemic 1,7,8-trihydroxylated and 1,6,7,8-tetrahydroxylated indolizidines (castanospermine stereoisomers) from readily available N-substituted γ-oxygenated α,β-unsaturated sulfones 3 and 4 has been developed. The construction of the bicyclic skeleton of 1-hydroxyindolizidine has been accomplished by intramolecular conjugate addition of the nitrogen moiety of 3 and 4 to the α,β-unsaturated sulfone unit to give the pyrrolidine intermediates 5 and 6, followed by formation of the C(7)-C(8) bond by intramolecular acylation (or alkylation) of the α-sulfonyl carbanion. The stereoselectivity of the pyrrolidine synthesis was highly dependent on the bulkiness of the γ-oxygenated function; thus, the free alcohols gave predominantly cis-pyrrolidines while the OTIPS derivatives led to the trans isomers. After straightforward functional group transformations, the removal of the sulfonyl group at C(8) either by Julia reaction or by basic elimination (depending on the substrate used) afforded the key C(7)C(8) unsaturated indolizidines 10, 22, 30, and 31, whose stereoselective dihydroxylations with OsO₄ gave a variety of cis C(1)C(8a) and trans C(1)C(8a) trihydroxylated and tetrahydroxylated indolizidines, among which (±) 1,7-di-epi-castanospermine and (±)-1,8-di-epi-castanospermine have been reported for the first time.

Full text of DOI:10.1021/jo972167p

J . Org. Chem. 1998, 63, 2993-3005
2993
Ster eoselective Syn th esis of P olyh yd r oxyla ted In d olizid in es fr om
γ-Hyd r oxy r,â-Un sa tu r a ted Su lfon es
J uan C. Carretero* and Ramo´n Go´mez Arraya´s
Departamento de Quı´mica Orga´nica, Facultad de Ciencias, Universidad Auto´noma de Madrid,
Cantoblanco, 28049 Madrid, Spain
Received December 1, 1997
The polyhydroxylated indolizidines castanospermine and swainsonine as well as some of their
stereoisomers are powerful glycosidase inhibitors. An efficient and stereochemically flexible
synthesis of racemic 1,7,8-trihydroxylated and 1,6,7,8-tetrahydroxylated indolizidines (castano-
spermine stereoisomers) from readily available N-substituted γ-oxygenated R,â-unsaturated sulfones
3 and 4 has been developed. The construction of the bicyclic skeleton of 1-hydroxyindolizidine has
been accomplished by intramolecular conjugate addition of the nitrogen moiety of 3 and 4 to the
R,â-unsaturated sulfone unit to give the pyrrolidine intermediates 5 and 6, followed by formation
of the C(7)-C(8) bond by intramolecular acylation (or alkylation) of the R-sulfonyl carbanion. The
stereoselectivity of the pyrrolidine synthesis was highly dependent on the bulkiness of the
γ-oxygenated function; thus, the free alcohols gave predominantly cis-pyrrolidines while the OTIPS
derivatives led to the trans isomers. After straightforward functional group transformations, the
removal of the sulfonyl group at C(8) either by J ulia reaction or by basic elimination (depending
on the substrate used) afforded the key C(7)C(8) unsaturated indolizidines 10, 22, 30, and 31, whose
stereoselective dihydroxylations with OsO4 gave a variety of cis C(1)C(8a) and trans C(1)C(8a)
trihydroxylated and tetrahydroxylated indolizidines, among which (()-1,7-di-epi-castanospermine
and (()-1,8-di-epi-castanospermine have been reported for the first time.
In tr od u ction
hibitor) have attracted the greatest attention from both
synthetic and biological points of view and represent good
examples of tetrahydroxylated, trihydroxylated, and di-
hydroxylated indolizidines, respectively (Figure 1).
A variety of alkaloids having the structure of polyhy-
droxylated indolizidine have been isolated from natural
sources,1 mainly plants and microorganisms, and some
of them are excellent inhibitors of biologically important
pathways, including the binding and processing of gly-
coproteins.1,2 Among naturally occurring polyhydroxy-
lated indolizidines, castanospermine3 (a potent R-glu-
cosidase inhibitor), swainsonine4 (a potent R-mannosidase
inhibitor), and lentiginosine5 (an amyloglucosidase in-
To find structure-activity relationships,6 this interest
has been extended to the synthesis of stereoisomers and
analogues.3-5 Although in some cases there is a close
structural resemblance between the biologically active
indolizidine and the natural sugar substrate, in many
other cases this resemblance does not exist. For instance,
swainsonine, which is one of the strongest R-mannosidase
inhibitors, lacks any significant resemblance with man-
(1) For some recent reviews and books, see: (a) Michael, J . P. Nat.
Prod. Rep. 1997, 14, 619. (b) Elbein, A. D.; Molyneux, R. J . In
Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.;
Wiley-Interscience: New York, 1987; Vol. 5, Chapter 1. (c) Howard,
A. S.; Michael, J . P. in The Alkaloids; Brossi, A., Ed.; Academic Press:
New York, 1986; Vol. 28, Chapter 3.
(4) For some recent references on the synthesis of swainsonine and
analogues, see: (a) Hunt, J . A.; Roush, W. R. J . Org. Chem. 1997, 62,
1112. (b) Pearson, W. H.; Hembre, E. J . J . Org. Chem. 1996, 61, 7217.
(c) Zhou, W. S.; Xie, W.-G.; Lu, Z.-H.; Pan, X.-F. J . Chem. Soc., Perkin
Trans. 1 1995, 2599. (d) Angermann, J .; Homann, K.; Reissig, H.-U.;
Zimmer, R. Synlett 1995, 1014. (e) Oishi, T.; Iwakura, T.; Hirama,
M.; Ito, S. Synlett 1995, 404. (f) Kang, S. H.; Kim, G. T. Tetrahedron
Lett. 1995, 36, 5049. (g) Zhou, W.-S.; Xie, W. G.; Lu, Z.-H.; Pan, X.-F.
Tetrahedron Lett. 1995, 36, 1291. (h) Hunt, J . A.; Roush, W. R.
Tetrahedron Lett. 1995, 36, 501. (i) Honda, T.; Hoshi, M.; Kanai, K.;
Tsubuki, M. J . Chem. Soc., Perkin Trans. 1 1994, 2091. (j) Naruse,
M.; Aoyagi, S.; Kibayashi, C. J . Org. Chem. 1994, 59, 1358.
(5) For recent references on the synthesis of lentiginosine and
analogues, see: (a) Goti, A.; Cardona, F.; Brandi, A. Synlett 1996, 761.
(b) Goti, A.; Cardona, F.; Brandi, A.; Picasso, S.; Vogel, P. Tetrahe-
dron: Asymmetry 1996, 7, 1659. (c) Nukui, S.; Sodeoka, M.; Sasai,
H.; Shibasaki, M. J . Org. Chem. 1995, 60, 398. (d) Brandi, A.; Cicchi,
S.; Cordero, F. M.; Frignoli, R.; Goti, A.; Picasso, S.; Vogel, P. J . Org.
Chem. 1995, 60, 6806. (e) Nukui, S.; Sodeoka, M.; Sasai, H.; Shibasaki,
M. J . Org. Chem. 1995, 60, 398. (f) Cordero, F. M.; Cicchi, S.; Goti,
A.; Brandi, A. Tetrahedron Lett. 1994, 35, 949. (g) Gurjar, M. K.;
Ghost, L.; Syamala, M.; J ayasree, V. Tetrahedron Lett. 1994, 35, 8871.
(6) (a) Winchester, B. G.; Al Daher, S.; Carpenter, N. C.; Cenci di
Bello, I.; Choi, S. S.; Fairbanks, A. J ., Fleet, G. W. J . Biochem. J . 1993,
290, 743. (b) Winchester, B. G.; Cenci di Bello, I.; Richardson, A. C.;
Nash, R. J .; Fellows, L. E.; Ramsden, N. G.; Feet, G. Biochem. J . 1990,
269, 227. (c) Cenci di Bello, I.; Fleet, G.; Namgoong, S. K.; Tadano,
K.-I.; Winchester, B. Biochem. J . 1989, 259, 855. (d) Winkler, D. A.;
Holan, G. J . Med. Chem. 1989, 32, 2084.
(2) a) Winchester, B.; Fleet, G. W. J . Glycobiology 1992, 2, 199. (b)
Legler, G. Adv. Carbohydr. Chem. Biochem. 1990, 48, 319. (c) Sinnott,
M. L. Chem. Rev. 1990, 90, 1171. (d) Elbein, A. D. Annu. Rev. Biochem.
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232, 759. (e) Elbein, A. D. Crit. Rev. Biochem. 1984, 16, 21.
(3) For a review on the synthesis of castanospermine and stereoi-
somers, see: Burgess, K.; Henderson, I. Tetrahedron 1992, 48, 4045
and references therein. For recent references, see: (a) Bell, A. A.;
Pickering, L.; Watson, A. A.; Nash, R. J .; Griffiths, R. C.; J ones, M.
G.; Fleet, G. W. J . Tetrahedron Lett. 1996, 37, 8561. (b) Overkleeft,
H. S.; Pandit, U. K. Tetrahedron Lett. 1996, 37, 547. (c) Zhao, H.;
Mootoo, A. R. J . Org. Chem. 1996, 61, 6762. (d) Martin, S. F.; Chen,
H.-J .; Lynch, V. M. J . Org. Chem. 1995, 60, 276. (e) Furneaux, R. H.;
Mason, J . M.; Tyler, P. C. Tetrahedron Lett. 1995, 36, 3055. (f) Leeper,
F. J .; Howard, S. Tetrahedron Lett. 1995, 36, 2335. (g) Furneaux, R.
H.; Mason, J . M.; Tyler, P. C. Tetrahedron Lett. 1994, 35, 3143. (h)
Chen, Y.; Vogel, P. J . Org. Chem. 1994, 59, 2487. (i) Kim, N.-S.; Kang,
C. H.; Cha, J . K. Tetrahedron Lett. 1994, 35, 3489. (j) Furneaux, R.
H.; Gainsford, G. J .; Mason, J . M.; Tyler, P. C. Tetrahedron 1994, 50,
2131. (k) Casiraghi, G.; Ulgheri, F.; Spanu, P.; Rassu, G.; Pinna, L.;
Fava, G. G.; Ferrari, M. B.; Pelosi, G. J . Chem. Soc., Perkin Trans. 1
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Kim, N.-S.; Choi, J .-R.; Cha, J . K. J . Org. Chem. 1993, 58, 7096. (n)
Siriwardena, A. H.; Chiaroni, A.; Riche, C.; Grierson, D. S. J . Org.
Chem. 1992, 57, 5661.
S0022-3263(97)02167-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/17/1998

2994 J . Org. Chem., Vol. 63, No. 9, 1998
Carretero and Arraya´s
Sch em e 2a
F igu r e 1. Representative examples of glycosidase inhibitors
with the structure of polyhydroxylated indolizidine.
Sch em e 1
nose. Since the structure-activity relationships in in-
dolizidines are not straightforward, as many stereoiso-
mers and analogues as possible should be synthesized
and tested for their biological activity. Due to their
vicinal polyhydroxylated structure, most of the reported
syntheses of castanospermine, swainsonine, and ana-
logues employ natural sugars as starting materials.3-5
However, this approach often has the drawback of lacking
enough flexibility for the ready preparation of a wide
range of stereoisomers from a common intermediate.
As part of our current interest in the use of γ-hydroxy
R,â-unsaturated sulfones as versatile intermediates in
stereoselective synthesis,7 here we describe in detail a
concise and stereochemically flexible approach to the
synthesis of a wide range of polyhydroxylated indol-
izidines based on these readily available vinyl sulfones.8
In our retrosynthetic analysis, we envisaged that using
the vinyl sulfone moiety as a Michael acceptor the bicyclic
skeleton of these alkaloids could be readily prepared by
two successive ring closures: intramolecular conjugate
addition of the amine moiety to the sulfones A followed
by intramolecular acylation of the R-sulfonyl carbanion
with the ester function (Scheme 1). Further functional
group manipulations would allow the preparation of
olefins B, which would be suitable substrates for the
introduction of hydroxyl groups at C(6) (by allylic oxida-
tion) and at C(7)-C(8) (by dihydroxylation). Interest-
ingly, as the stereogenic centers would be incorporated
gradually, a stereochemical control could be achieved in
each step, allowing the preparation of different stereoi-
somers from a common intermediate.
a
Reagents: (a) CHdCH2CO2Me, EtOH, 0 °C’; (b) BOC2O,
CH2Cl2, rt; (c) AcOH/H2 2:1, rt; (d) PhSO2CH2SO-p-Tol, piperidine,
CH2Cl2, 0 °C; (e) ClCH2OCH2CH3, i-Pr2EtN, CH2Cl2, rt; (f)
TBDMSCl, imidazole, CH2Cl2, rt; (g) TIPSOTf, 2,6-lutidine, CH2Cl2,
rt; (h) n-BuLi, BOC2O, THF, 0 °C.
aldehydes on a multigram scale.9 The required protected
4-aminobutyraldehyde 1 was readily prepared in three
steps from commercially available 4-aminobutyraldehyde
diethyl acetal as follows: conjugate addition to methyl
acrylate (EtOH, 0 °C, 90%), subsequent protection of the
amine as BOC derivative (BOC2O, CH2Cl2, 0 °C, 98%),
and acid hydrolysis of the acetal moiety (AcOH/H2O 2:1,
rt, 88%). As expected, the condensation of 1 with (()-
(phenylsulfonyl)(p-tolylsulfinyl)methane (piperidine, CH2-
Cl2, 0 °C) afforded the racemic vinyl sulfone 3a in
excellent yield (96%). Similarly, the N,N-diprotected
aminobutyraldehyde 2 was prepared from the same
starting material by two successive BOC protections
(BOC2O, CH2Cl2, 0 °C, then n-BuLi, BOC2O, THF, 0 °C;
92%) and further hydrolysis of the acetal (Scheme 2). The
reaction of 2 with (phenylsulfonyl)(p-tolylsulfinyl)methane
gave cleanly the corresponding γ-hydroxyvinyl sulfone 4a
(94% yield).
To determine if the size of the oxygenated substitution
at the γ-position had a significant effect on the stereo-
selectivity of the intramolecular conjugate addition, the
hydroxyl group of 3a and 4a was protected as
ethoxymethoxy acetals 3b and 4b (chloromethyl ethyl
ether, i-Pr2EtN, CH2Cl2, rt) and as the silyl ethers
OTBDMS 3c and 4c (TBSCl, imidazole, CH2Cl2, rt) and
OTIPS 3d and 4d (TIPSOTf, 2,6-lutidine, CH2Cl2, rt).
Deprotection of carbamates 3 and 4 with TFA at room
temperature afforded quantitatively the corresponding
ammonium salts, which after isolation were redissolved
in THF, cooled at -78 °C, and treated with Et3N (10
equiv) to liberate in situ the free amines. In all cases, a
clean and fast cyclization was observed, being complete
Resu lts a n d Discu ssion
Syn th esis of th e γ-Hyd r oxy r,â-Un sa tu r a ted Su l-
fon es a n d Con str u ction of th e P yr r olid in e Rin g. We
reported that γ-hydroxy R,â-unsaturated sulfones can be
prepared from sulfonylsulfinylmethanes and enolizable
(7) (a) Adrio, J .; Carretero, J . C.; Go´mez Arraya´s, R. Synlett. 1996,
640. (b) De Blas, J .; Carretero, J . C.; Dom´ınguez, E. Tetrahedron:
Asymmetry 1995, 5, 1035. (c) Dom´ınguez, E.; Carretero, J . C.
Tetrahedron 1994, 50, 7557. (d) De Blas, J .; Carretero, J . C.;
Dom´ınguez, E. Tetrahedron Lett. 1994, 35, 4603. (e) Carretero, J . C.;
Dom´ınguez, E. J . Org. Chem. 1993, 58, 1596.
(8) For previous communications, see: (a) Carretero, J . C.; Go´mez
Arraya´s, R.; Storch de Gracia, I. Tetrahedron Lett. 1996, 37, 3379. (b)
Carretero, J . C.; Go´mez Arraya´s, R. J . Org. Chem. 1995, 60, 6000.
(9) For the preparation of (()-γ-hydroxy-R,â-unsaturated sulfones,
see: (a) Dom´ınguez, E.; Carretero, J . C. Tetrahedron 1990, 46, 7197.
(b) Trost, B. M.; Grese, T. A. J . Org. Chem. 1991, 56, 3189. For the
synthesis of enantiomerically pure γ-hydroxy R,â-unsaturated sulfones,
see: Carretero, J . C.; Dom´ınguez, E. J . Org. Chem. 1992, 57, 3867.

Synthesis of Polyhydroxylated Indolizidines
J . Org. Chem., Vol. 63, No. 9, 1998 2995
Ta ble 1. In tr a m olecu la r Con ju ga te Ad d ition of th e
γ-Oxygen a ted r,â-Un sa tu r a ted Su lfon es 3 a n d 4
Sch em e 3
entry substrate product
R1
OR2
cis/transa
1
2
3
4
5
6
7
8
3a
3b
3c
3d
4a
4b
4c
4d
5a
5b
5c
5d
6a
6b
6c
6d
CH2CH2CO2Me OH
81/19b
36/64
19/81
10/90
80/20
44/56
40/60
22/78
for preparing pyrrolidines 5 and 6 with a trans or cis
configuration, their independent use would lead to the
stereoselective synthesis of indolizidines with a trans or
cis configuration at C(1)-C(8a),12 respectively. The
overall transformation of trans-5d into the pair of 1,7,8-
trihydroxylated indolizidines with cis-stereochemistry at
C(7)-C(8) is depicted in Scheme 4.
CH2CH2CO2Me OCH2OEt
CH2CH2CO2Me OTBDMS
CH2CH2CO2Me OTIPS
H
H
H
H
OH
OCH2OEt
OTBDMS
OTIPS
a
b
Determined by 1H NMR on the crude mixture. Reaction run
The formation of the indolizidine skeleton was ac-
complished cleanly by intramolecular acylation of the
R-sulfonyl anion obtained by deprotonation of trans-5d
with LHDMS (2 equiv, THF, 0 °C).13 The resulting crude
R-sulfonyl ketones 7 were obtained as a 60:40 mixture
of epimers at C(8), being the isomer having the sulfone
group in axial position the major one (7a x).14 Reduction
of 7 with NaBH4 resulted in a 42:58 mixture of alcohols
8 and 9, which could be separated by flash chromatog-
raphy (31% and 48% yields from trans-5d , respectively).
This result showed that the reduction of 7eq and 7a x
with NaBH4 was in both cases fully stereoselective.
Whereas 7eq furnished the axial alcohol 8, in the case
of 7a x the presence of the phenylsulfonyl group in the
axial position precludes the equatorial approach of the
hydride to the carbonyl group, leading exclusively to the
formation of the equatorial alcohol 9. Similar stereo-
chemical results have been reported for the reduction of
equatorially and axially conformationally restricted 2-sul-
fonylcyclohexanones.15
in toluene.
in less than 30 min at -78 °C, to afford cis/ trans
mixtures of pyrrolidines 5-6 in nearly quantitative yields
(Table 1).8a
Interestingly, the hydroxyvinyl sulfones (substrates a ,
entries 1 and 5) and their TIPS derivatives (substrates
d , entries 4 and 8) showed remarkable and opposite
stereoselectivities. Thus, whereas the cyclizations of 3a
and 4a were cis-stereoselective (cis/trans ) 81/19 from
3a and cis/trans ) 80/20 from 4a ), those of 3d and 4d
were trans-stereoselective (cis/trans ) 10/90 from 3d and
cis/trans ) 22/78 from 4d ).10
The dependence between stereoselectivity and substi-
tution at the γ-position might be roughly explained
taking into account the likely most stable chairlike
transition states leading to cis- and trans-pyrrolidines8a
(C and D in Scheme 3, respectively). From a steric point
of view, due to the presence of the substituent OR2 in
the axial position, the participation of the transition state
C should decrease as the bulkiness of OR2 rises, decreas-
ing consequently the amount of the cis-pyrrolidine.11 In
good agreement with this model, the trans-stereoselec-
tivity of the cyclization increases in the following order
from both substrates 3 and 4: OTIPS > OTBDMS >
OCH2OEt > OH.
A different reaction outcome was observed in the
reaction of 8 and 9 with Na-Hg (MeOH, rt). The axial
alcohol 8 gave the desired J ulia olefination product 10
(11) Taking into account the conformational analysis around the Câ-
Cγ bond of compounds 3-4, the conformation E (OR/HR in 1,3-parallel
arrangement) would be more stable than conformation F (HR/Hγ in
1,3-parallel arrangement) as it is deduced from the low value of J â,γ
(see below), especially significant in the case of the hydroxy derivatives
that show the lowest J â,γ values (3a and 4a : J â,γ ) 3.0 Hz). We assume
that this conformational preference would act in an opposite sense to
the steric effects discussed in Scheme 3, because it would favor the
transition state C (conformationally similar to E) to a larger extent
than D (conformationally similar to F ). This conformational effect
could explain why in the case of the hydroxy derivatives 3a and 4a sthe
substrates besides with the sterically least demanding OR groupstheir
cyclizations gave predominantly the pyrrolidines of cis configuration.
For conformational analysis in allylic alcohols and derivatives, see:
Gung, B. W.; Melnick, J . P.; Wolf, M. A.; King, A. J . Org. Chem. 1995,
60, 1947.
Ster eoselective Syn th esis of Tr ih yd r oxyla ted In -
d olizid in es. Having developed a stereoselective method
(10) The mixtures of cis and trans isomers 5b-d could be easily
separated by flash chromatography but not those of 5a and 6a -d ,
which were used in the next step as cis + trans isomers and then
separated. The stereochemical assignment of cis- and trans-5a -d and
-6a -d has been firmly established by a combination of chemical
correlations and NMR studies. 5a was transformed into the ketal or
silyl derivatives (compounds 5b-d ), or vice versa, by straightforward
protection or deprotection reactions, whereas compounds 6a -d were
transformed into the corresponding N-alkylated compounds 5a -d by
reaction with methyl acrylate (as solvent) at room temperature. From
a spectroscopic point of view, as it has been reported for related 2,3-
disubstituted pyrrolidines (Gallina, C.; Paci, M.; Viglino, P. Org. Magn.
Reson. 1972, 4, 31), the vicinal coupling constant J 2,3 is significantly
higher in the cis isomers (J 2,3-cis ≈ 6.5 H) than in the trans ones (J 2,3
-
trans ≈ 2.5 Hz). Furthermore, the NOESY spectra of cis-5d and trans-
5d are in fully agreement with this assignment (see below).
(12) The use of the stereochemical terms cis and trans refers to the
H(1)/H(8a) relationship.
(13) Unexpectedly, the use of other bases such as LDA led to the
formation of mixtures of products.

2996 J . Org. Chem., Vol. 63, No. 9, 1998
Carretero and Arraya´s
Sch em e 4
leaving group determined that both isomers evolved by
J ulia reaction, affording olefin 10 in 82% yield after
purification.
The syn-dihydroxylation of 10 with OsO4 under stan-
dard catalytic conditions (OsO4 3 mol %, Me3NO, acetone/
water 5:1, rt) was moderately stereoselective, leading to
a 2:1 mixture of diols 13 and 14, which were separated
by chromatography (52% and 27%, respectively).16 As the
last step, quantitative desilylation of 13 and 14 (HCl) and
neutralization gave the trihydroxylated indolizidines 15
and 16.16
Following a similar reaction sequence, in Scheme 5 is
shown the stereoselective transformation of a cis-pyrrol-
idine into hydroxylated indolizidines of cis-stereochem-
istry at C(1)C(8a). Pyrrolidine cis-5c was prepared in
71% yield by silylation of the 80:20 mixture of cis-5a +
trans-5a (TBDMSCl, imidazole, DMAP, CH2Cl2, rt) and
chromatographic separation. Unlike cyclization of trans-
5d , intramolecular acylation of cis-5c with LHMDS
(THF, 0 °C) occurred in a complete stereoselective man-
ner to give the indolizidine bearing the sulfonyl group
at the equatorial position (compound 17).14 In this case,
the absence of the epimer at C(8), which would have the
sulfone in axial position, might be due to its higher
thermodynamic instability derived from the presence of
a 1,3-parallel interaction between the bulky substituents
at C(1) and C(8) (silyl ether and sulfone, respectively).
According to this hypothesis, 17 was recovered un-
changed after treatment with 1 M LiOH in THF/H2O,
proving that it is the thermodynamically most stable
epimer at C(8).
As expected, the stereoselectivity of the carbonyl
reduction of 17 was highly dependent on the hydride
used. The reaction with DIBALH (CH2Cl2, -78 °C)
afforded exclusively the equatorial alcohol 18 (75% yield
from cis-5c), while the reduction with a typical hydride
of equatorial attack such as LiEt3BH (THF, -78 °C) was
(73% yield), while the equatorial alcohol 9 under other-
wise identical conditions yielded predominantly the
alcohol 11 (82%) as a result of the reductive elimination
of the sulfone. Further hydrolysis of the silyl ether (5 M
HCl) and neutralization (Dowex 1-X8 ion-exchange chro-
matography) provided the 1,7-dihydroxylated indolizidine
12 (99% yield). To improve the overall yield in the
preparation of the key unsaturated indolizidine 10, the
crude mixture of alcohols 8 + 9 obtained after reduction
of 7 was mesylated (MsCl, Et3N, CH2Cl2, rt), and the
resulting mixture was treated with Na-Hg (MeOH, rt).
In that case, the excellent ability of the mesylate as
(16) Con figu r a tion a l a ssign m en t of tr ih yd r oxyla ted a n d tet-
r a h yd r oxyla ted in d olizid in es: as is usual in this kind of compounds,
the stereochemistry of the substitution at the chair conformation of
the six-membered ring has been established by 1H NMR, mainly from
the typical gauche or anti values of J 8,8a, J 8,7, J 7,6, J 6,5eq, and J 6,5ax. To
assign unequivocally the signals corresponding to H(1), H(8a), H(8),
H(7), and H(6) and obtain accurate values of the coupling constants,
compounds lacking overlap between these hydrogens were particularly
useful (see below). Similarly, with regard to the substitution at the
five-membered ring, as expected, it was observed that J 1,8a in the cis
isomers is always significantly lower (4.8-5.0 Hz, H1 and H8a in gauche
relationship) than in the trans ones (6.5-8.3 Hz, H1 and H8a in anti
relationship).
(14) Interestingly, the treatment of the mixture of sulfonyl ketones
7eq + 7a x with Et3N in CHCl3 at room temperature (or LiOH in THF/
H2O) afforded the isomer 17 as the major product, proving its higher
thermodynamic stability and the easiness of the reverse conjugate
addition in these compounds. The configuration at C-8 of the R-sulfonyl
ketones 7eq, 7a x, and 17 was tentatively established from their 1H
3
NMR data, mainly from the values of δ1 and J 8,8a
. 7eq: δ1 ) 4.49
3
3
ppm, J 8,8a ) 6.3 Hz; 7a x: δ1 ) 5.41 ppm, J 8,8a ) 3.2 Hz; 17: δ1
)
4.69 ppm, 3J 8,8a ) 7.9 Hz. This stereochemical assignment was further
confirmed by analysis of the 1H NMR and NOESY spectra of their
hydroxy derivatives 8, acetate of 9 (9-OAc), and 19 (see below).
(15) For a general study on the stereoselectivity of the reduction of
conformationally restrained 2-sulfonylcyclohexanones, see: Carren˜o,
J . C.; Dom´ınguez, E.; Garc´ıa Ruano, J . L.; Rubio, A. J . Org. Chem.
1987, 52, 3619.

Synthesis of Polyhydroxylated Indolizidines
J . Org. Chem., Vol. 63, No. 9, 1998 2997
Sch em e 5
F igu r e 2. Proposed models for the dihydroxylation of 10 and
22.
Sch em e 6
also fully stereoselective but in favor of the axial alcohol
19. It is interesting to note that in the subsequent
sulfonyl elimination step with Na-Hg the reaction
pathways of epimers 18 and 19 were identical to those
previously observed for the pair of isomers 8 and 9. Thus,
reductive elimination occurred from the equatorial alco-
hol 18 to give the hydroxylated indolizidine 20 (78%
yield), which was transformed into the dihydroxylated
indolizidine 21 after acid hydrolysis, while the axial
alcohol 19 evolved by J ulia olefination to yield predomi-
nantly the unsaturated indolizidine 22. Due to its
moderate stability, crude 22 was immediately dihydroxyl-
ated (OsO4 cat., Me3NO, acetone/water 5:1, rt) to provide
diol 23 as a single isomer (49% yield from 19). The very
high stereoselectivity in the dihydroxylation of 22 con-
trasts with the poor stereocontrol observed from its
epimer 10, suggesting that in 22 the bulky silyl ether at
C(1), presumably in a pseudoaxial position (J 1,8a ) 2.2
Hz), provokes a significant steric differentiation of both
olefin faces, reinforcing the approach of the oxidant syn
to H8a (Figure 2). Finally, deprotection of 23 (5 M HCl)
and neutralization (Dowex-OH) furnished quantitatively
the trihydroxylated indolizidine 24.16
Ster eoselective Syn th esis of 1,6,7,8-Tetr a h yd r ox-
yla ted In d olizid in es. Next, we focused our attention
on the synthesis of 1,6,7,8-tetrahydroxylated indolizidines
(castanospermine stereoisomers). Since all trials to
achieve the allylic oxidation at C(6) of olefins 10 and 22
were unsuccessful,17 we slightly modified our initial
retrosynthetic approach in order to introduce the func-
tionalization at C(6) in an earlier stage of the reaction
sequence. To this end, the enones 30 and 31 were
particularly appealing substrates because via stereose-
lective carbonyl reduction at C(6) and dihydroxylation at
C(7)-C(8) (or vice versa) a wide range of tetrahydroxyl-
ated isomers could be prepared.
We found that suitable precursors of such enones were
the 6-methyleneindolizidines 27 + 28 and 29 shown in
Scheme 6. N-Alkylation of the mixtures of cis-6d +
trans-6d (22:78) and cis-6a + trans-6a (80:20), obtained
directly from the cyclization of 4d and 4a , respectively,
with 3-chloro-2-chloromethylpropene (K2CO3, cat. LiI,
CH3CN, rt), followed by silica gel chromatography, af-
forded separately trans-25, and cis-25 in good overall
yields (72% and 61%, respectively). Further intramo-
lecular C-alkylation of trans-25 and cis-25 took place
almost quantitatively using LHMDS as base (THF, 0 °C).
In the case of trans-25, a mixture of both epimers 27 +
28 was obtained, while from cis-25 only the epimer 29,
that avoiding the 1,3-parallel diaxial interaction between
substituents at C(1) and C(8), was detected.18 After
extensive experimentation, it was observed that the
ozonolysis of 27 + 28 and 29 only occurred cleanly when
pure TFA was used as solvent, likely due to the competi-
tive amine oxidation and formation of side products in
(18) The attempts to perform directly the synthesis of 27-29 in one
step by double alkylation of 6d with 3-chloro-2-(chloromethyl)propene
in the presence of 2 equiv of n-BuLi were unfruitful. For direct
dialkylation of â-nitrogenated sulfones, see: (a) Alonso, D. A.; Costa,
A.; Manchen˜o, B.; Na´jera, C. Tetrahedron 1997, 53, 4791. (b) Caturla,
F.; Na´jera, C. Tetrahedron Lett. 1997, 38, 3789.
(17) In all attempts of allylic oxidation of 10 or 22 with PCC/
tBuOOH (cat.), PDC/t-BuOOH (cat.), SeO2, or SeO2/t-BuOOH (cat.),
complex mixtures of products were obtained.

2998 J . Org. Chem., Vol. 63, No. 9, 1998
Carretero and Arraya´s
Sch em e 7
Sch em e 8
nonacidic solvents.19 Subsequent reductive workup (PPh3)
and in situ addition of Et3N to promote the basic
elimination of the sulfonyl group led to the enones 30
20
and 31 in 70% and 67% overall yields, respectively.
Because compounds 30 and 31 proved to be rather
unstable at room temperature, they must be immediately
used after chromatographic purification. Due at least in
part to this instability, all attempts to dihydroxylate
them with OsO4 (a reaction that usually requires long
periods of time) were unfruitful, giving complex mixtures
of products. In contrast, a quantitative and fast reaction
occurred in the reduction of these enones with L-Selec-
tride or DIBALH in THF at -78 °C (Scheme 7). Both
hydrides afforded similar stereochemical results, the
reductions with L-Selectride being somewhat more ster-
eoselective. However, while the reductions of 30 (trans-
stereochemistry at C(1)C(8a)) to give the alcohols 32 +
33 was hardly stereoselective in favor of 32 (de ) 20-
26%), the reaction of its diastereomer 31 (cis-stereochem-
istry at C(1)C(8a)) occurred with much higher stereocon-
trol, leading predominantly to the alcohol 34 (de ) 70-
80%) as a result of the approach of the hydride from the
face opposite to the OTIPS group at C(1). These results
parallel those obtained in the dihydroxylation of the
diastereomeric olefins 10 and 22, where it was also noted
that the compound having cis-sterochemistry at C(1)C-
(8a) (22) evolved in a much more stereoselective manner
than the isomer of trans configuration (10). This behav-
ior was ascribed to the presence of the bulky OTIPS unit
in a pseudoaxial position in the compounds of trans
configuration at C(1)C(8a), which would induce an im-
portant steric differentiation between both sides of the
indolizidine (Figure 2). Interestingly, this effect seems
to be effective even at a relatively far position such as
C(6).
36 and 37 was mainly controlled by the benzoate sub-
stituent at C(6). Indeed, the reaction of 36 occurred with
very high stereocontrol from the face opposite to the
benzoate group to give diol 38 as a single isomer (80%
yield). Similarly, the reaction of the epimer 37 also took
place preferentially in the anti position with regard to
the benzoate group, furnishing a 85:15 mixture of diols
39 + 40 that could be separated by flash chromatography
(67% and 10% yields, respectively).16
Basic hydrolysis (NaOH, MeOH, rt) of the benzoate
groups of 38 and 39, followed by cleavage of the OTIPS
(HCl and then neutralization), gave quantitatively (()-
8,8a-di-epi-castanospermine(41)and(()-1,8-di-epi-castano-
spermine (42), respectively. To the best of our knowl-
edge, these castanospermine stereoisomers had not been
previously reported.
Unexpectedly, all attempts to dihydroxylate the allylic
alcohols 34 and 35, both with cis stereochemistry at
C(1)C(8a), as well as their TIPS, benzoyl, or MOM
derivatives under the usual catalytic conditions (OsO4 3
mol %, Me3NO, acetone, rt) were completely unsuccessful,
recovering the starting olefins after 2 days of reaction.
In an attempt to improve the reactivity of this process,
we turned to the conditions recently reported by Donohoe
et al.21 for the dihydroxylation of allylic alcohols, which
employ stoichiometric amounts of OsO4 and TMEDA in
CH2Cl2 at -78 °C. We were pleased to find that under
these conditions a 9:1 mixture of alcohols 34 + 35 reacted
cleanly and with complete stereocontrol, leading in 15
min to an inseparable 9:1 mixture of the corresponding
triols. To separate these compounds, the crude mixture
was desilylated (HCl), fully acetylated (CH3COCl, Et3N,
DMPA, CH2Cl2), and then separated by flash chroma-
tography. The tetraacetates 43 and 44 were obtained in
The preparation of tetrahydroxylated indolizidines by
syn dihydroxylation of substrates 32-35 is depicted in
Schemes 8 and 9. As we were unable to separate the
mixture of allylic alcohols 32 + 33, this crude mixture
was benzoylated (PhCOCl, Et3N, DMAP, CH2Cl2, rt) and
then separated by flash chromatography. Pure benzoates
36 and 37 were obtained in 57% and 36% yields,
respectively. Taking into account that the dihydroxyla-
tion of the C(6)-unsubstituted indolizidine 10 (Scheme
4) was hardly stereoselective, it could be anticipated that
the stereoselectivity in the dihydroxylation of the epimers
(19) Pearson, W. H.; Bergmeier, S. C.; Williams, J . P. J . Org. Chem.
1992, 57, 3977.

Synthesis of Polyhydroxylated Indolizidines
J . Org. Chem., Vol. 63, No. 9, 1998 2999
Sch em e 9
tion sequence, the minor tetraacetate 44 was converted
into (()-7-epi-castanospermine (46). The preparation of
enantiopure 44 and 46 from castanospermine has been
recently reported.23
Con clu sion s
In conclusion, the approach described in this paper for
the preparation of polyhydroxylated indolizidines com-
bines efficiency and stereochemical flexibility, allowing
the preparation of a wide variety of both 1,7,8-trihy-
droxylated and 1,6,7,8-tetrahydroxylated stereoisomers.
The γ-oxygenated R,â-unsaturated sulfones 3 and 4 used
as starting products were readily prepared in multigram
quantities from 4-aminobutyraldehyde diethyl acetal. The
two-step construction of the indolizidine skeleton from 3
and 4 takes place in excellent yield, and a remarkable
stereochemical control is achieved at the C(1)C(8a) ring
junction depending on the bulkiness of the γ-oxygenated
substitution. Further stereochemical control at C(6) and
at C(7)/C(8) have been attained by carbonyl reduction and
dihydroxylation reactions, respectively. The extension
of this methodology to the preparation of optically pure
indolizidines from enantiopure sulfones is underway.
79% and 10% yields, respectively, from 34 + 35 (Scheme
9). The fact that in both cases, and regardless the
stereochemistry at C(6), the acetates at C(7)/C(8) are
located in an anti relationship with respect to the OTIPS
group at C(1) indicates that the stereoselectivity of the
dihydroxylation in compounds having the cis configura-
tion at C(1)C(8a) is controlled by the steric effects
associated with the axially oriented OTIPS group at C(1)
and not by the substitution at C(6). As previously
discussed, similar steric arguments have been invoked
to explain the high stereoselectivity observed in the
reaction of other C(1)C(8a) cis-indolizidines, such as 22
and 31.
Quantitative deacetylation of 43 (NaOH, MeOH, rt,)
and desilylation (HCl) gave (()-6,7-di-epi-castanosper-
mine (45) in 98% yield, whose 1H and 13C NMR data were
identical with those reported for enantiomerically pure
(+)-6,7-di-epi-castanospermine.22 This natural product
has been isolated from the seeds of Castanospermum
australe and shows a remarkable biological activity as
an amyloglucosidase inhibitor. Following the same reac-
Exp er im en ta l Section
Melting points are uncorrected. 1H NMR and 13C NMR
spectra were acquired at 200 and 50 MHz, respectively.
Chemical shifts (δ) are reported in ppm, relative to the solvent
used: CDCl3 (7.26 and 77 ppm), C6D6 (7.15 and 128 ppm), CD3-
OD (3.4 and 49.9 ppm), and DHO (4.6 ppm). Mass spectra
(MS) and high-resolution mass spectra (HRMS) were deter-
mined at an ionizing voltage of 70 eV. Reaction were usually
carried out under a dry Ar atmosphere in anhydrous solvents.
THF was distilled from sodium benzophenone under argon.
CH2Cl2 was distilled from P2O5. MeOH was distilled from
CaH2. Flash column chromatographies were performed using
silica gel Merck-60 (230-400 mesh) or with aluminum oxide
Merck-90 active (neutral, activity I) where indicated. In the
last case, alumina was previously deactivated with H2O (8 wt
%). “Standard workup” refers to separation of the organic
layer, extraction of the aqueous layer with an organic solvent,
CH2Cl2, or EtOAc, drying over Na2SO4 of the combined organic
layers, and removal of the solvents under reduced pressure on
a rotary evaporator.
(±)-(P h en ylsu lfon yl)(p -Tolylsu lfin yl)m et h a n e. To
a
solution of phenyl methyl sulfone (20 g, 128 mmol) in THF
(110 mL), cooled at -78 °C, was slowly added 2.5 M n-BuLi in
hexane (51 mL, 128 mmol). The solution was stirred at -78
°C for 1 h. Then, a solution of p-tolyl disulfide (15.7 g, 64.0
mmol) in THF (40 mL) was slowly added by cannula. After
being stirred at -78 °C for 1 h, saturated aqueous NH4Cl (60
mL) was added. After standard workup, the residue was
dissolved in MeOH (80 mL), and the solution was stored
overnight at -20 °C to induce the precipitation of (()-
(phenylsulfonyl)(p-tolylsulfenyl)methane. After filtration, (()-
(phenylsulfonyl)(p-tolylsulfenyl)methane (11.5 g, 70%) was
obtained as a white solid: mp 56-58 °C; 1H NMR (CDCl3)
7.95-7.90 (m, 2H), 7.68-7.49 (m, 3H), 7.28 and 7.06 (AA′BB′
system, 4H), 4.31 (s, 2H), 2.30 (s, 3H). The filtrate can be
evaporated and the residue purified by flash chromatography
(n-hexane/EtOAc 4:1) to afford a second crop of (()-(phenyl-
sulfonyl)(p-tolylsulfenyl)methane (5.0 g, 23%), followed by the
excess phenyl methyl sulfone (10.5 g).
(20) Alternatively, enones 30 and 31 have been prepared as fol-
lows: alkylation of cis+trans-6d with glycidyc mesylate, intramolecular
opening of the epoxide using MeMgBr as base, Swern oxidation of the
resulting alcohols (DMSO, Cl2CO), and basic elimination of the sulfone
(Et3N). However, mainly due to an incomplete regioselectivity in the
opening of the epoxide, and the rather different reactivity exhibited
by each stereoisomer of the resulting mixture of hydroxy sulfones, the
overall yields in the preparation of 30 and 31 were much lower than
those obtained by applying the reactions of Scheme 6.
To a solution of (()-(phenylsulfonyl)(p-tolylsulfenyl)methane
(24.6 g, 88.6 mmol) in CH2Cl2 (100 mL), cooled at -78 °C, was
added dropwise a solution of m-CPBA (15.3 g, 88.6 mmol) in
CH2Cl2 (40 mL). After the mixture was stirred for 15 min at
(21) Donohoe, T. J .; Moore, P. R.; Waring, M. J .; Newcombe, N. J .
Tetrahedron Lett. 1997, 38, 5027.
(22) Molyneux, R. J .; Pan, Y. T.; Tropea, J . E.; Benson, M.; Kaushal,
G. P.; Elbein, A. D. Biochemistry 1991, 30, 9981.
(23) Furneaux, R. H.; Gainsford, G. J .; Mason, J . M.; Tyler, P. C.;
Hartley, O.; Winchester, B. G. Tetrahedron 1997, 53, 245.

3000 J . Org. Chem., Vol. 63, No. 9, 1998
Carretero and Arraya´s
-78 °C, saturated aqueous Na2SO3 (30 mL) was added, the
mixture was allowed to reach rt, and saturated aqueous
NaHCO3 (150 mL) was added. After standard workup, (()-
(phenylsulfonyl)(p-tolylsulfinyl)methane (25.8 g, 99%) was
obtained as a white solid.13a
1.82 (m, 2H), 1.44 (s, 9H), 1.13 (t, 3H, J ) 7.1 Hz, 3H); 13C
NMR (CDCl3) 171.9, 154.9, 145.4, 140.0, 133.3, 130.7, 129.1
(2C), 127.4 (2C), 93.7, 79.7, 72.8, 63.7, 51.4, 43.9, 43.4, 33.2,
33.1, 28.2 (3C), 14.7. Anal. Calcd for C23H34NO8S: C, 57.01;
H, 7.07; N, 2.89. Found: C, 57.02; H, 7.28; N, 2.86.
Meth yl 4-Aza -4-(ter t-bu toxyca r bon yl)-8-oxoocta n oa te
(1). To a solution of 4-aminobutyraldehyde diethyl acetal (3.0
g, 18.60 mmol) in EtOH (38 mL), cooled at 0 °C, was added
methyl acrylate (1.84 mL, 20.46 mmol). After the mixture was
stirred at 0 °C for 2 h, the solvent and the excess of methyl
acrylate were removed at reduced pressure. The residue was
dissolved in CH2Cl2, cooled at 0 °C, and treated with BOC2O
(4.70 mL, 20.46 mmol). The solution was allowed to reach rt
and stirred for 30 min. Then solvent was evaporated, and the
residue was dissolved in a 2:1 mixture of AcOH/H2O (50 mL).
The solution was stirred at room temperature for 5 h and then
neutralized with saturated aqueous NaHCO3. After standard
workup, the residue was purified by flash chromatography (n-
hexanes-EtOAc 3:1) to afford aldehyde 1 (3.7 g, 78%) as a
colorless oil: 1H NMR (CDCl3) 9.73 (bs, 1H), 3.63 (s, 3H), 3.42
(t, J ) 7.1 Hz, 2H), 3.20 (t, J ) 7.1 Hz, 2H), 2.53 (t, J ) 7.1
Hz, 2H), 2.41 (t, J ) 7.1 Hz, 2H), 1.80 (quint, J ) 7.1 Hz, 2H),
1.45 (s, 9H); 13C NMR (CDCl3) 201.4, 172.2, 155.2, 79.8, 51.6,
46.8, 43.3, 40.9, 33.4, 28.3 (3C), 20.9.
4-[N,N-Bis(ter t-bu toxycar bon yl)]bu tyr aldeh yde (2). To
a solution of 4-aminobutyraldehyde diethyl acetal (10.0 g, 62.0
mmol) in CH2Cl2 (100 mL), cooled at 0 °C, was added BOC2O
(15 mL, 65 mmol). The solution was allowed to reach rt and
stirred for 30 min. The solvent was evaporated, and the
residue was dissolved in THF (130 mL), cooled at 0 °C, and
treated with 2.5 M n-BuLi in hexane (26 mL, 65 mmol). After
the mixture was stirred at 0 °C for 30 min, saturated aqueous
NH4Cl (30 mL) was added. After standard workup, the residue
was dissolved in a 2:1 mixture of AcOH/H2O (150 mL) and
stirred at room temperature for 6 h. Then, the mixture was
neutralized with saturated aqueous NaHCO3. After standard
workup, the residue was purified by flash chromatography (n-
hexane/EtOAc 6:1) to afford aldehyde 2 (16 g, 90%) as a
colorless oil: 1H NMR (CDCl3) 9.72 (m, 1H), 3.56 (t, J ) 7.0
Hz, 2H), 2.41 (t, J ) 7.0 Hz, 2H), 1.84 (quint, J ) 7.0 Hz, 2H),
1.45 (s, 18H); 13C NMR (CDCl3) 201.0, 152.3, 82.1, 45.1, 40.7,
27.8 (6C), 21.3.
(E)-Met h yl 4-Aza -4-(ter t-b u t oxyca r b on yl)-9-(p h en yl-
su lfon yl)-7-[(ter t-bu tyldim eth ylsilyl)oxy]n on -8-en oate (3c).
To a solution of 3a (200 mg, 0.47 mmol) in CH2Cl2 (2.5 mL)
were added imidazole (64 mg, 0.94 mmol) and tert-butyldi-
methylsilyl chloride (142 mg, 0.94 mmol). After the mixture
was stirred overnight at room temperature, water (3 mL) was
added. After standard workup, the residue was purified by
flash chromatography (n-hexanes-EtOAc 4:1) to give 3c (253
mg, 98%) as a colorless oil: 1H NMR (CDCl3) 7.90-7.83 (m,
2H), 7.64-7.47 (m, 3H), 6.94 (dd, 1H, J ) 14.7, 4.0 Hz, 1H),
6.50 (dd, 1H, J ) 14.7, 1.6 Hz, 1H), 4.37 (m, 1H), 3.65 (s, 3H),
3.39 (m, 2H), 3.32-3.07 (m, 2H), 2.51 (m, 2H), 1.76 (m, 2H),
1.43 (s, 9H), 0.83 (s, 9H), 0.00 (s, 3H), -0.09 (s, 3H); 13C NMR
(CDCl3) 171.9, 155.0, 147.8, 140.3, 133.3, 130.1, 129.2 (2C),
127.5 (2C), 79.9, 69.1, 51.6, 44.1, 43.6, 35.4, 33.6, 28.3 (3C),
25.6 (3C), 18.0, -4.0, -3.7; MS 468 (M+ - ButO, 9) 454 (12),
428 (85), 396 (82), 384 (51), 368 (38), 142 (100).
(E)-Met h yl 4-Aza -4-(ter t-b u t oxyca r b on yl)-9-(p h en yl-
su lfon yl)-7-[(tr iisop r op ylsilyl)oxy]n on -8-en oa te (3d ). To
a solution of 3a (2.23 g, 5.2 mmol) and 2,6-lutidine (0.82 mL,
6.76 mmol) in CH2Cl2 (30 mL), cooled at 0 °C, was slowly added
triisopropylsilyl trifluoromethanesulfonate (1.36 mL, 6.24
mmol). After the mixture was stirred at 0 °C for 5 min and at
room temperature for 2 h, 0.3 M HCl (50 mL) was added. After
standard workup, the residue was purified by flash chroma-
tography (n-hexanes-EtOAc 4:1) to give 3d (2.92 g, 97%) as a
colorless oil: IR (CHCl3) 2950, 2870, 1730, 1680, 1470, 1450,
1420, 1370, 1330, 1150 cm-1; 1H NMR (CDCl3) 7.92-7.86 (m,
2H), 7.66-7.49 (m, 3H), 6.99 (dd, J ) 14.9, 4.4 Hz, 1H), 6.57
(dd, J ) 14.9, 1.5 Hz, 1H), 4.56 (m, 1H), 3.67 (s, 3H), 3.39 (m,
2H), 3.21 (m, 2H), 2.53 (m, 2H), 1.85 (m, 2H), 1.45 (s, 9H),
0.97 (m, 21H); 13C NMR (CDCl3) 172.0, 155.0, 147.8, 140.4,
133.3, 130.3, 129.2 (2C), 127.6 (2C), 79.9, 69.3, 51.5, 43.5, 43.3,
35.9, 33.3, 28.3 (3C), 17.8(6C), 12.1(3C). Anal. Calcd for
C
29H49NO7SSi: C, 59.66; H, 8.47; N, 2.40. Found: C, 59.46;
H, 8.72; N, 2.62.
(E)-5-[N,N-Bis(ter t-bu toxyca r bon yl)a m in o]-1-(p h en yl-
su lfon yl)p en t-1-en -3-ol (4a ). Following a procedure identical
to that described for the preparation of 3a , the reaction of
(phenylsulfonyl)(p-tolylsulfinyl)methane (5.0 g, 17.0 mmol) and
piperidine (3.5 mL, 34.0 mmol) in CH2Cl2 (40 mL) with
aldehyde 2 (6.8 g, 23.8 mmol) in CH2Cl2 (30 mL) at 0 °C
afforded 4a (7.0 g, 94%) as a white solid after flash chroma-
tography (n-hexanes-EtOAc 3:1): mp 72-73 °C; 1H NMR
(CDCl3) 7.88-7.85 (m, 2H), 7.62-7.48 (m, 3H), 6.94 (dd, J )
14.8, 3.0 Hz, 1H), 6.67 (dd, J ) 14.8, 2.0 Hz, 1H), 4.32 (m,1H),
4.07 (bs, 1H), 3.78-3.72 (m, 2H), 2.03-1.86 (m, 2H), 1.49 (s,
18H); 13C NMR (CDCl3) 153.5, 147.2, 140.4, 133.3, 129.6, 129.2
(2C), 127.6 (2C), 83.4, 66.6, 42.3, 35.3, 28.0 (6C). Anal. Calcd
for C21H31NO7S: C, 57.13; H, 7.08; N, 3.17. Found: C, 57.21;
H, 6.95; N, 3.15.
(E)-N,N-Bis(ter t-bu toxyca r bon yl)-3-(eth oxym eth oxy)-
5-(p h en ylsu lfon yl)p en t-4-en -1-a m in e (4b). By a procedure
identical to that described for 3b, the reaction of 4a (350 mg,
0.80 mmol), diisopropylethylamine (210 mL, 1.2 mmol), and
chloromethyl ethyl ether (370 mL, 4.0 mmol) in CH2Cl2 (2.5
mL) afforded 4b (351 mg, 88%, colorless oil) after flash
chromatography (n-hexanes-EtOAc 10:1): 1H NMR (CDCl3)
7.90-7.84 (m, 2H), 7.64-7.46 (m, 3H), 6.89 (dd, J ) 15.0, 5.0
Hz, 1H), 6.54 (dd, J ) 15.0, 1.3 Hz, 1H), 4.62 and 4.58 (AB
system, J ) 7.1 Hz, 2H), 4.30 (q, J ) 5.7 Hz, 1H), 3.64-3.43
(m, 4H), 1.85 (m, 2H), 1.47 (s, 18H), 1.10 (t, J ) 7.0 Hz, 3H);
13C NMR (CDCl3) 152.2, 145.3, 140.1, 133.2, 130.9, 129.1 (2C),
127.4 (2C), 93.6, 82.2, 72.6, 63.6, 42.4, 33.2, 27.8 (6C), 14.7.
(E)-N,N-Bis(ter t-bu toxyca r bon yl)-3-[(ter t-bu tyld im eth -
ylsilyl)oxy]-5-(p h en ylsu lfon yl)-p en t-4-en -1-a m in e (4c). By
a procedure identical to that described for 3c, the reaction of
4a (400 mg, 0.91 mmol), imidazole (75 mg, 1.10 mmol), and
tert-butyldimethylsilyl chloride (206 mg, 1.3 mmol) in CH2Cl2
(3 mL) afforded 4c (484 mg, 96%, colorless oil) after flash
(E)-Met h yl 4-Aza -4-(ter t-b u t oxyca r b on yl)-7-h yd r oxy-
9-(p h en ylsu lfon yl)n on -8-en oa te (3a ). To a solution of (()-
(phenylsulfonyl)(p-tolylsulfinyl)methane (5.7 g, 19.4 mmol) and
piperidine (3.9 mL, 39.5 mmol) in CH2Cl2 (45 mL), cooled at 0
°C, was added a solution of aldehyde 1 (7.0 g, 26 mmol) in
CH2Cl2 (35 mL). After the mixture was stirred at 0 °C for 10
h, saturated aqueous NH4Cl was added. After standard
workup, the residue was purified by flash chromatography (n-
hexanes-EtOAc 2:1) to give 3a (8.0 g, 96%). Recrystallization
from n-hexanes-Et2O gave 3a as colorless crystals: mp 64-
65 °C; IR (CHCl3) 3370, 2960, 1730, 1660, 1480, 1370, 1310,
1150 cm-1; 1H NMR (CDCl3) 7.91-7.86 (m, 2H), 7.61-7.48 (m,
3H), 6.95 (m, 1H), 6.70 (dd, J ) 14.8, 2.0 Hz, 1H), 4.88 (bs,
1H), 4.23 (m, 1H), 3.75 (m, 1H), 3.70 (s, 3H), 3.52 (m, 1H),
3.33 (m, 1H), 3.06 (m, 1H), 2.58 (t, J ) 7.1 Hz, 2H), 1.84 (m,
1H), 1.49 (m, 1H), 1.45 (s, 9H); 13C NMR (CDCl3) 171.9, 157.1,
147.4, 140.4, 133.2, 129.4, 129.2 (2C), 127.6 (2C), 81.1, 66.2,
51.8, 43.4, 34.7, 33.4, 28.2 (3C). Anal. Calcd for C20H29NO7S:
C, 56.18; H, 6.84; N, 3.28. Found: C, 55.89; H, 6.90; N, 3.21.
(E)-Met h yl 4-Aza -4-(ter t-b u t oxyca r b on yl)-7-(et h oxy-
m eth oxy)-9-(p h en ylsu lfon yl)n on -8-en oa te (3b). To a solu-
tion of 3a (400 mg, 0.94 mmol) in CH2Cl2 (3 mL) were added
diisopropylethylamine (348 mL, 2.0 mmol) and chloromethyl
ethyl ether (350 mL, 3.8 mmol) at 0 °C. After the solution
was stirred at room temperature for 7.5 h, aqueous NaHCO3
(5 mL) was added. After standard workup, the residue was
purified by flash chromatography (n-hexanes-EtOAc 3:1) to
give 3b (405 mg, 89%) as a colorless oil: IR (CHCl3) 2980, 1730,
1680, 1470, 1440, 1410, 1370, 1310, 1150 cm-1 1H NMR
;
(CDCl3) 7.91-7.86 (m, 2H), 7.62-7.49 (m, 3H), 6.89 (dd, 1H,
J ) 15.1, 5.1 Hz, 1H), 6.55 (dd, 1H, J ) 15.1, 1.2 Hz, 1H),
4.63 and 4.60 (AB system, J ) 7.1 Hz, 2H), 4.26 (m, 1H), 3.66
(s, 3H), 3.63-3.39 (m, 4H), 3.38-3.25 (m, 2H), 2.53 (m, 2H),

Synthesis of Polyhydroxylated Indolizidines
J . Org. Chem., Vol. 63, No. 9, 1998 3001
chromatography (n-hexanes-EtOAc 10:1): 1H NMR (CDCl3)
7.89-7.84 (m, 2H), 7.63-7.46 (m, 3H), 6.98 (dd, J ) 14.9, 3.9
Hz, 1H), 6.50 (dd, J ) 14.9, 1.6 Hz, 1H), 4.39 (m, 1H), 3.55
(m, 2H), 1.81 (m, 2H), 1.47 (s, 18H), 0.83 (s, 9H), 0.00 (s, 3H),
-0.10 (s, 3H); 13C NMR (CDCl3) 152.2 (2C), 147.8, 140.2, 133.2,
130.0, 129.1 (2C), 127.4 (2C), 82.2, 69.2, 42.7, 35.7, 27.9 (6C),
25.5, 17.9, -5.0, -5.2. Anal. Calcd for C27H45NO7SSi: C,
58.35; H, 8.17; N, 2.52; S, 5.76. Found: C, 58.82; H, 8.61; N,
2.55; S, 5.40.
(E)-N,N-Bis(ter t-bu toxyca r bon yl)-5-(p h en ylsu lfon yl)-
3-[(tr iisop r op ylsilyl)oxy]p en t-4-en -1-a m in e (4d ). By a
procedure identical to that described for the preparation of 3d ,
the reaction of 4a (2 g, 4.5 mmol), 2,6-lutidine (630 mL, 5.4
mmol), and triisopropylsilyl trifluoromethane sulfonate (1.1
mL, 0.5 mmol) in CH2Cl2 (20 mL) afforded 4d (2.54 g, 95%,
colorless oil) after flash chromatography (n-hexanes-EtOAc
10:1): 1H NMR (CDCl3) 7.91-7.87 (m, 2H), 7.64-7.48 (m, 3H),
7.03 (dd, J ) 14.9, 4.5 Hz, 1H), 6.59 (dd, J ) 14.9, 1.6 Hz,
1H), 4.55 (m, 1H), 3.68-3.45 (m, 2H), 1.98-1.81 (m, 2H), 1.50
(s, 18H), 0.96 (bs, 21H); 13C NMR (CDCl3) 152.4 (2C), 148.0,
140.5, 133.2, 130.4, 129.2 (2C), 127.6 (2C), 82.4, 69.4, 42.2, 36.6,
28.0 (6C), 17.9 (6C), 12.1 (3C). Anal. Calcd for C30H51NO7-
SSi: C, 60.27; H, 8.60; N, 2.34; S, 5.36. Found: C, 60.77; H,
8.63; N, 2.73; S, 5.48.
Gen er a l P r oced u r e for th e Cycliza tion of γ-Oxygen -
a ted r,â-Un sa tu r a ted Su lfon es 3a -d a n d 4a -d . To a
solution of the corresponding γ-oxygenated R,â-unsaturated
sulfone (6.8 mmol) in CH2Cl2 (50 mL) was added TFA (9.0 mL).
After the mixture was stirred at room temperature for 5 h,
the solvent was removed in vacuo. The resulting ammonium
salt was dissolved in THF (90 mL), cooled at -78 °C, and
treated with Et3N (2 mL). After being stirred at -78 °C for
20 min, the solvent was removed, and then CH2Cl2 (50 mL)
and 10% aqueous NaOH (10 mL) were added. After standard
workup, mixtures of cis- and trans-pyrrolidines were obtained.
(2R*,3S*)- a n d (2R*,3R*)-3-Hyd r oxy-1-[2-(m eth oxyca r -
bon yl)eth yl]-2-[(p h en ylsu lfon yl)m eth yl]p yr r olid in e (cis-
5a ) a n d (tr a n s-5a ). Following the general procedure but
using toluene as solvent instead of THF, 3a (3.0 g, 7.03 mmol)
was transformed into a 81:19 mixture of cis-5a and trans-5a
(2.18 g, 96%), which could not be separated by flash chroma-
tography. Alternatively, pure cis-5a and trans-5a were ob-
tained by quantitative desilylation (TBAF, THF, 0 °C) of pure
cis-5d and trans-5d , respectively. cis-5a : 1H NMR (CDCl3)
7.97-7.92 (m, 2H), 7.73-7.54 (m, 3H), 4.49 (m, 1H), 3.65 (dd,
J ) 14.0, 10.1 Hz, 1H), 3.63 (s, 3H), 3.23 (dd, J ) 14.0, 2.3 Hz,
1H), 3.16 (m, 1H), 3.04-2.81 (m, 3H), 2.45-2.06 (m, 4H), 1.85-
1.72 (m, 1H); 13C NMR (CDCl3) 172.6, 139.5, 133.9, 129.4 (2C),
127.8 (2C), 71.3, 62.9, 54.4, 51.6, 50.9, 49.2, 33.1, 32.1. tr a n s-
5a : 1H NMR (CDCl3) 7.98-7.93 (m, 2H), 7.73-7.55 (m, 3H),
4.32 (dt, J ) 6.8, 3.1 Hz, 1H), 3.63 (s, 3H), 3.44 (dd, J ) 14.3,
2.0 Hz, 1H), 3.08 (dd, J ) 14.3, 10.3 Hz, 1H), 3.05-2.71 (m,
4H), 2.50-2.13 (m, 3H), 2.06 (m, 1H), 1.81 (m, 1H), 1.69 (bs,
1H);13C NMR (CDCl3) 172.6, 139.3, 134.0, 129.4 (2C), 127.9
(2C), 77.1, 67.7, 58.9, 51.6, 50.8, 49.1, 33.1, 32.0.
2H), 2.05 (m, 1H), 1.65 (m, 1H), 0.87 (s, 9H), 0.09 (s, 3H), 0.06
(s, 3H); 13C NMR (CDCl3) 172.6, 140.1, 133.4, 129.1 (2C), 127.7
(2C), 71.9, 62.3, 54.3, 51.4, 50.0, 49.3, 33.7, 33.1, 25.7 (3C),
17.9, -3.5, -3.8; HRMS calcd for C21H35NO5SSi 441.2005,
found 441.2003. tr a n s-5c: 1H NMR (CDCl3) 7.97-7.90 (m,
2H), 7.70-7.51 (m, 3H), 4.39 (m, 1H), 3.63 (s, 3H), 3.18 (dd, J
) 13.3, 2.0 Hz, 1H), 3.04-2.85 (m, 4H), 2.74-2.48 (m, 2H),
2.30 (m, 2H), 1.89-1.63 (m, 2H), 0.87 (s, 9H), 0.14 (s, 3H), 0.08
(s, 3H); 13C NMR (CDCl3) 172.7, 140.0, 133.5, 129.1 (2C), 127.8
(2C), 75.8, 67.7, 59.5, 51.4, 50.7, 50.4, 33.5, 33.4, 25.6 (3C),
17.7, -4.8 (2C); HRMS calcd for C21H35NO5SSi 441.2005, found
441.2003.
(2R*,3S*)- a n d (2R*,3R*)-1-[2-(Meth oxyca r bon yl)eth yl]-
2-[(ph en ylsu lfon yl)m eth yl]-3-[(tr iisopr opylsilyl)oxy)]pyr -
r olid in e (cis-5d ) a n d (tr a n s-5d ). Following the general
procedure, 3d (2.9 g, 5.0 mmol) was transformed into a 10:90
mixture of cis-5d and trans-5d , which was separated by flash
chromatography (n-hexanes-EtOAc 4:1) to give pyrrolidine
cis-5d (220 mg, 9%) followed by the major isomer trans-5d (2.0
g, 84%), both as colorless oils. cis-5d : IR (CHCl3) 3050, 2940,
2870, 2720, 1440, 1310, 1210, 1150 cm-1; 1H NMR (C6D6) 7.97-
7.92 (m, 2H), 6.96-6.91 (m, 3H), 4.39 (q, J ) 6.4 Hz, 1H), 3.95
(dd, J ) 14.5, 4.9 Hz, 1H), 3.40 (m, 1H), 3.31 (s, 3H), 3.27-
3.16 (m, 2H), 2.75 (m, 1H), 2.52 (m, 1H), 2.29 (m, 2H), 1.97
(dt, J ) 9.3, 7.9 Hz, 1H), 1.77-1.68 (m, 1H), 1.46 (m, 1H), 1.08
(m, 21H); 13C NMR (CDCl3) 172.7, 140.3, 133.3, 129.1 (2C),
127.7 (2C), 72.1, 61.8, 54.8, 51.4, 49.5, 49.4, 33.4, 33.2, 17.9
(6C), 12.2 (3C); HRMS calcd for C24H41O5NSSi 483.2475, found
483.2470. tr a n s-5d : 1H NMR (CDCl3) 7.97-7.91 (m, 2H),
7.69-7.51 (m, 3H), 4.52 (m, 1H), 3.65 (s, 3H), 3.23-2.93 (m,
5H), 2.82-2.56 (m, 2H), 2.31 (m, 2H), 1.87-1.78 (m, 2H), 1.08
(m, 21H); 13C NMR (CDCl3) 172.5, 140.1, 133.3, 129.0 (2C),
127.6 (2C), 76.2, 67.8, 59.7, 51.3, 51.0, 50.5, 33.6, 33.5, 17.9
(6C), 12.2 (3C). Anal. Calcd for C24H41O5NSSi: C, 59.60; H,
8.55; N, 2.90. Found: C, 59.68; H, 8.76; N, 2.92.
(2R*,3S*)- a n d (2R*,3R*)-3-Hyd r oxy-2-[(p h en ylsu lfon yl)-
m eth yl]p yr r olid in e (cis-6a ) a n d (tr a n s-6a ). Following the
general procedure, 4a (3.0 g, 6.80 mmol) was transformed into
an 80:20 mixture of hydroxypyrrolidines cis-6a and trans-6a
(1.62 g, 99%). Compound cis-6a was isolated diastereomeri-
cally pure by recrystallization from EtOAc/EtOH/ether. cis-
6a : mp 133-134 °C; 1H NMR (CDCl3): 7.95-7.89 (m, 2H),
7.71-7.52 (m, 3H), 4.32 (m, 1H), 3.48 (dd, J ) 15.8, 8.6 Hz,
1H), 3.37-3.24 (m, 2H), 3.12 (ddd, J ) 10.5, 8.5, 5.6 Hz, 1H),
2.81 (m, 1H), 2.59 (bs, 2H), 2.10 (m, 1H), 1.85-1.69 (m, 1H);
13C NMR (CDCl3) 139.4, 133.9, 129.4 (2C), 127.8 (2C), 72.4,
57.6, 56.6, 44.0, 34.6. Anal. Calcd for C11H15NO3S: C, 54.75;
H, 6.27; N, 5.81; S, 13.26. Found: C, 54.59; H, 5.91; N, 5.73;
S, 13.51. tr a n s-6a : 1H NMR (CDCl3) 7.95-7.89 (m, 2H),
7.71-7.52 (m, 3H), 4.05 (dt, J ) 9.0, 4.6 Hz, 1H), 3.40-2.88
(m, 5H), 2.02 (m, 1H), 1.72 (m, 1H); 13C NMR (CDCl3) 139.3,
133.8, 129.3 (2C), 127.8 (2C), 76.0, 60.4, 59.9, 43.9, 33.2.
(2R*,3S*)- a n d (2R*,3R*)-2-[(P h en ylsu lfon yl)m eth yl]-3-
[(tr iisop r op ylsilyl)oxy]p yr r olid in e (cis-6d ) a n d (tr a n s-
6d ). Following the general procedure, 4d (2.3 g, 3.85 mmol)
was transformed into an 80:20 mixture of cis-6d and trans-
6d (1.5 g, 98%), which could be only partially separated by
flash cromatography (EtOAc). cis-6d : 1H NMR (CDCl3) 7.95-
7.89 (m, 2H), 7.64-7.50 (m, 3H), 4.41 (q, J ) 5.5 Hz, 1H), 3.48-
3.30 (m, 3H), 3.16 (dd, J ) 14.7, 9.9 Hz, 1H), 3.11 (m, 1H),
2.87 (ddd, J ) 10.4, 8.4, 6.5 Hz, 1H), 2.04 (m, 1H), 1.67 (m,
1H); 13C NMR (CDCl3) 139.6, 133.6, 129.2 (2C), 127.9 (2C),
73.6, 56.8, 56.1, 43.0, 33.9, 17.9 (6C), 12.1 (3C). tr a n s-6d : 1H
NMR (CDCl3) 7.96-7.90 (m, 2H), 7.70-7.22 (m, 3H), 4.08 (dt,
J ) 6.7, 4.3 Hz, 1H), 3.34 (dd, J ) 13.6, 2.2 Hz, 1H), 3.33-
2.93 (m, 4H), 2.21 (bs, 1H), 1.99 (m, 1H), 1.71 (m, 1H), 0.98
(m, 21H); 13C NMR (CDCl3) 139.2, 133.6, 129.1 (2C), 127.7 (2C),
76.4, 60.8, 59.8, 43.7, 33.3, 17.7 (6C), 11.8 (3C); MS 397 (M+,
(2R*,3S*)- an d (2R*,3R*)-3-[(ter t-Bu tyldim eth ylsilyl)oxy]-
1-[2-(m eth oxyca r bon yl)eth yl]-2-[(p h en ylsu lfon yl)m eth -
yl]p yr r olid in e (cis-5c) a n d (tr a n s-5c). Meth od A. Fol-
lowing the general procedure, 3c (2.0 g, 3.70 mmol) was
transformed into a 19:81 mixture of cis-5c and trans-5c that
was separated by flash chromatography (n-hexanes-EtOAc
4:1) to afford successively cis-5c (285 mg, 17%) and trans-5c
(1.22 g, 75%).
Meth od B. To a solution of a 81:19 mixture of cis-5a and
trans-5a (2.18 g, 6.67 mmol) in CH2Cl2 (80 mL) were suc-
cessively added imidazole (590 mg, 8.67 mmol), DMAP (817
mg, 6.7 mmol), and tert-butyldimethylsilyl chloride (2.0 g, 13.3
mmol). After the solution was stirred at room temperature
for 24 h, saturated aqueous NH4Cl was added. After standard
workup, the residue was purified by flash chromatography (n-
hexanes-EtOAc 4:1) to afford successively cis-5c (2.20 g, 71%)
and trans-5c (540 mg, 17%). cis-5c: IR (CHCl3) 2940, 2860,
3), 354 (M+ - i-Pr, 73), 255 (42); HRMS (FAB) calcd for C20H30
NO3SSi (M + H+) 398.2182, found 398.2185.
-
(1R*,7S*,8R*,8a R*)- a n d (1R*,7R*,8S*,8a R*)-7-Hyd r oxy-
8-(p h e n ylsu lfon yl)-1-[(t r iisop r op ylsilyl)oxy]in d olizi-
d in e (8) a n d (9). To a solution of trans-5d (2.0 g, 4.14 mmol)
in THF (55 mL), cooled at 0 °C, was added 1 M LHMDS in
THF (9.5 mL). After the solution was stirred at 0 °C for 2.5
1730, 1440, 1310, 1260, 1150, 1120 cm-1 1H NMR (CDCl3)
;
7.97-7.91 (m, 2H), 7.68-7.51 (m, 3H), 4.36 (m, 1H), 3.78 (m,
1H), 3.64 (s, 3H), 3.11-2.89 (m, 4H), 2.41 (m, 2H), 2.18 (m,

3002 J . Org. Chem., Vol. 63, No. 9, 1998
Carretero and Arraya´s
h, saturated aqueous NH4Cl (100 mL) was added. After
standard workup, a 60:40 mixture of keto sulfones 7eq and
7a x (1.85 g, 100%) was obtained as a yellow solid. This crude
mixture was dissolved in a mixture of CH2Cl2 (16 mL) and
EtOH (28 mL), cooled at 0 °C, and treated with solid NaBH4
(280 mg, 7.4 mmol). After the mixture was stirred at 0 °C for
30 min, saturated aqueous NH4Cl (50 mL) and CH2Cl2 (50 mL)
were added. After standard workup, the residue was purified
by flash chromatography (n-hexanes-EtOAc 2:1) to give
hydroxy sulfone 9 (882 mg, 48%) as a white solid, followed by
8 (570 mg, 31%) as a colorless oil. 8: 1H NMR (CDCl3) 7.96-
7.91 (m, 2H), 7.72-7.54 (m, 3H), 5.03 (m, 1H), 3.72 (m, 2H),
3.17-2.59 (m, 5H), 2.39 (m, 1H), 1.84-1.69 (m, 2H), 1.51 (m,
1H), 1.13 (m, 21H); 13C NMR (CDCl3) 138.2, 134.0, 129.4 (2C),
128.4 (2C), 74.4, 66.3 66.1, 64.2, 51.2, 45.5, 34.5, 31.0, 18.3
(6C), 12.9 (3C); HRMS (FAB) calcd for C23H40NO4SSi (M + H+)
454.2444, found 454.2447. 9: mp 143-144 °C; IR (CHCl3)
1.43-1.09 (m, 2H), 0.95 (q, J ) 11.1 Hz, 1H); 13C NMR (D2O)
74.2, 68.4, 68.2, 50.5, 49.1, 36.0, 32.5, 31.0; HRMS (FAB) calcd
for C8H16NO2 (M + H+) 158.1177, found 158.1181.
(1R*,7S*,8R*,8aS*)- an d (1R*,7R*,8S*,8aS*)-7,8-Dih ydr oxy-
1-[(tr iisop r op ylsilyl)oxy]in d olizid in es (13) a n d (14). To
a solution of olefin 10 (83 mg, 0.29 mmol) in acetone/water
5:1 (3.6 mL) were added trimethylamine N-oxide (35.6 mg, 0.32
mmol) and catalytic OsO4 (4 wt % in water, 55 mL, 9 × 10-3
mmol). After the solution was stirred at room temperature
for 4 h, solid Na2SO3 (40 mg) was added, and the mixture was
stirred for a further 30 min. The reaction mixture was
concentrated to dryness, and the residue was stirred vigorously
in CH2Cl2. The suspension was filtered through a short
column of Celite and the column washed several times with
CH2Cl2. The combined filtrates were evaporated, and the
residue was purified by flash chromatography on alumina
(CH2Cl2-0.4% MeOH) to give 13 (37 mg, 52%) as a colorless
oil, followed by 14 (19 mg, 27%) as a white solid. 13: 1H NMR
(CDCl3) 4.28 (q, J ) 8.3 Hz, 1H), 3.99 (q, J ) 3.0 Hz, 1H), 3.64
(dd, J ) 9.2, 3.0 Hz, 1H), 3.03 (td, J ) 8.9, 3.3 Hz, 1H), 2.64
(ddd, J ) 7.1, 5.0, 2.0 Hz, 1H), 5.49-2.10 (m, 5H), 1.94 (dq, J
) 14.3, 2.7 Hz, 1H), 1.78-1.53 (m, 2H), 1.07 (m, 21H); 13C
NMR (CDCl3) 77.8, 74.8, 66.6, 51.7, 46.3, 31.3, 30.0, 29.7, 18.0
3500, 3020, 2950, 1510, 1420, 1210, 1140 cm-1 1H NMR
;
(CDCl3) 7.97-7.92 (m, 2H), 7.64-7.47 (m, 3H), 4.85 (m, 1H),
3.99 (m, 1H), 3.83 (m, 1H), 3.63 (m, 1H), 3.19 (ddd, J ) 10.6,
4.7, 1.9 Hz, 1H), 3.02 (m, 1H), 2.48-2.06 (m, 5H), 1.93 (m,
1H), 1.64 (m, 1H), 0.87 (m, 21H); 13C NMR (CDCl3) 143.4,
133.1, 128.9 (2C), 127.5 (2C), 76.4, 73.2, 72.6, 67.8, 52.0, 50.4,
35.3, 31.2, 17.8 (6C), 11.9 (3C). Anal. Calcd for C23H39NO4-
SSi: C, 60.90; H, 8.67; N, 3.09. Found: C, 61.22; H, 8.30; N,
3.20.
(3C), 17.9 (3C), 12.4 (3C); HRMS calcd for
C17H35NO3Si
329.2386, found 329.2384. 14: mp 115-116 °C; IR (CHCl3)
2920, 2860, 1460, 1380, 1260, 1120, 1090 cm-1; 1H NMR (C6D6)
4.46 (ddd, J ) 8.6, 6.5, 3.9 Hz, 1H), 4.07 (m, 1H), 3.34 (ddd, J
) 11.1, 5.4, 2.9 Hz, 1H), 2.59 (td, J ) 8.3, 2.4 Hz, 1H), 2.42
(ddd, J ) 10.7, 4.5, 2.4, 1H), 2.10 (q, J ) 8.8 Hz, 1H), 1.91 (m,
2H), 1.66-1.10 (m, 4H), 1.12 (m, 21H); 13C NMR (CDCl3) 74.4,
71.5, 71.0, 68.1, 51.9, 49.7, 34.1, 28.9, 17.9 (6C), 12.1 (3C). Anal.
Calcd for C17H35NO3Si: C, 61.96; H, 10.70; N, 4.25. Found:
C, 61.95; H, 11.00; N, 4.21.
(1R *,8a S *)-1,2,3,5,6,8a -H e xa h yd r o-1-[(t r iisop r op yl-
silyl)oxy]in d olizin e (10). Meth od A. To a solution of
hydroxy sulfone 8 (184 mg, 0.41 mmol) in MeOH (7 mL) were
added solid Na2HPO4 (810 mg, 5.70 mmol) and freshly
prepared powdered 6% Na(Hg) (651 mg). The solution was
vigorously stirred at room temperature for 4 h. Then, the
resulting Hg was decanted, and the reaction mixture was
diluted with CH2Cl2 (50 mL) and washed with 1% aqueous
NaOH (25 mL). After standard workup, the residue was
purified by flash chromatography (EtOAc) to give 10 (88 mg,
73%) as a colorless oil. Meth od B. To a solution of a 58:42
mixture of alcohols 8 and 9 (250 mg, 0.55 mmol) in CH2Cl2 (4
mL), cooled at 0 °C, were added Et3N (382 mL, 2.75 mmol)
and MsCl (49 mL, 0.63 mmol). After the solution was stirred
at room temperature for 4 h, aqueous saturated NH4Cl (1 mL)
was added. After standard workup, the residue was dissolved
in MeOH (8 mL) and treated with Na2HPO4 (1.09 g, 7.51 mmol)
and powdered 6% Na(Hg) (873 mg). Following an isolation
procedure identical to that described in method A, 10 (133 mg,
82%, colorless oil) was obtained after flash chromatography
(EtOAc): 1H NMR (CDCl3) 5.87 (m, 1H), 5.78 (m, 1H), 4.10
(ddd, J ) 8.1, 6.4, 4.8 Hz, 1H), 3.00-2.71 (m, 3H), 2.64 (ddd,
J ) 11.5, 9.3, 4.9, Hz, 1H), 2.39-2.18 (m, 3H), 2.11-1.92 (m,
1H), 1.73 (ddd, J ) 13.4, 9.3, 4.8 Hz, 1H), 1.07 (m, 21H); 13C
NMR (CDCl3) 127.0, 125.6, 76.0, 67.7, 50.6, 47.3, 33.5, 24.0,
17.8 (6C), 12.0 (3C).
(1R*,7S*,8R*,8a R*)-1,7,8-Tr ih yd r oxyin d olizid in e (15).
Following a procedure identical to that described for the
preparation of 12, TIPS derivative 13 (113 mg, 0.34 mmol) was
deprotected to give 15 (59.3 mg, 100%) as a crystalline solid:
mp 145-146 °C; 1H NMR (D2O) 4.04 (ddd, J ) 9.2, 7.0, 3.8
Hz, 1H), 3.91 (q, J ) 3.0 Hz, 1H), 3.40 (dd, J ) 10.0, 3.0 Hz,
1H), 2.78 (td, J ) 8.9, 1.8 Hz, 1H), 2.60 (ddd, J ) 11.5, 4.9,
2.3 Hz, 1H), 2.36 (q, J ) 9.2 Hz, 1H), 2.26 (qd, J ) 11.5, 3.9
Hz, 1H), 2.12 (dd, J ) 10.0, 7.0 Hz, 1H), 2.06 (dq, J ) 13.7,
9.2 Hz, 1H), 1.77-1.57 (m, 2H), 1.55-1.39 (m, 1H); 13C NMR
(D2O) 74.0, 72.6, 67.8, 67.5, 50.9, 45.3, 31.2, 30.0; MS 173 (M+,
34), 156 (26), 129 (100); HRMS (FAB) calcd for C8H16NO3 (M
+ H+) 174.1132, found 174.1130. Anal. Calcd for C8H15NO3:
C, 55.47; H, 8.73; N, 8.09. Found: C, 55.47; H, 9.11; N, 7.94.
(1R*,7R*,8S*,8aR*)-1,7,8-Tr ih ydr oxyin dolizidin e (16). By
a procedure identical to that described for the preparation of
12, TIPS derivate 14 (50.2 mg, 0.15 mmol) was desilylated to
give 16 (26.2 mg, 100%) as a crystalline solid: mp 155-156
°C dec; 1H NMR (D2O) 4.04 (m, 1H), 3.77 (m, 1H), 3.47 (m,
1H), 2.68 (m, 2H), 2.11 (q, J ) 9.2 Hz), 2.04-1.76 (m, 4H),
1.62-1.30 (m, 3H); 13C NMR (D2O) 72.3, 70.3, 69.4, 66.3, 51.2,
49.2, 31.3, 26.4; HRMS calcd for C8H15NO3 173.1048, found
173.1053. Anal. Calcd for C8H15NO3: C, 55.47; H, 8.73; N,
8.09. Found: C. 55.68; H, 8.56; N, 7.89.
(1R*,7R*,8a S*)-7-Hyd r oxy-1-[(tr iisop r op ylsilyl)oxy]in -
d olizid in e (11). By a procedure identical to that described
for the preparation of olefin 10 (method A), the reaction of 9
(215 mg, 0.47 mmol) with Na2HPO4 (930 mg, 6.5 mmol) and
6% Na(Hg) (750 mg) in MeOH (8 mL) at room temperature,
for 4 h, followed by purification by flash chromatography
(EtOAc) afforded alcohol 11 (121 mg, 82%) as a white solid:
mp 79-80 °C; 1H NMR (CDCl3) 4.06 (m, 1H), 3.67 (m, 1H),
3.04-2.90 (m, 2H), 2.43-1.46 (m, 7H), 1.62 (m, 2H), 1.24 (q,
J ) 11.2 Hz, 1H); 13C NMR (CDCl3) 76.2, 69.5, 69.3, 51.7, 50.6,
38.5, 34.2, 33.5, 17.9 (6C), 12.1 (3C); MS 313 (M+, 15), 270.2
(M+ - i-Pr, 19); HRMS (FAB) calcd for C17H36NO2Si (M + H+)
314.2518, found 314.2515.
(1S*,8R*,8a R*)-1-[(ter t-Bu tyld im eth ylsilyl)oxy]-7-oxo-8-
(p h en ylsu lfon yl)in d olizid in e (17). To a solution of cis-5c
(2.0 g, 4.54 mmol) in THF (400 mL), cooled at 0 °C, was added
1 M LHMDS in THF (10 mL, 10 mmol). After the solution
was stirred at 0 °C for 1 h, saturated aqueous NH4Cl (80 mL)
was added. After standard workup, keto sulfone 17 (1.85 g,
100%) was obtained: 1H NMR (CDCl3) 7.85-7.80 (m, 2H),
7.66-7.49 (m, 3H), 4.56 (m, 1H), 4.41 (dd, J ) 7.9, 1.4 Hz,
1H), 3.28 (dd, J ) 7.9, 5.0 Hz, 1H), 3.31 (m, 1H), 2.85-2.52
(m, 4H), 2.39-2.20 (m, 2H), 1.86 (m, 1H), 0.89 (s, 9H), 0.15 (s,
3H), 0.11 (s, 3H); 13C NMR (CDCl3) 199.7, 137.9, 133.9, 128.7
(4C), 72.3, 70.2, 65.9, 52.1, 47.4, 37.6, 34.9, 25.7 (3C), 17.7,
-4.6, -5.1.
(1R*,7R*,8a S*)-1,7-Dih yd r oxyin d olizid in e (12). A solu-
tion of 11 (65 mg, 0.21 mmol) in 5 M HCl (5 mL) was stirred
at room temperature for 10 h. The reaction mixture was
extracted with CH2Cl2 (2 × 5 mL), and the aqueous layer was
concentrated to dryness. The resulting chlorohydrate was
dissolved in MeOH and chromatographed on a Dowex 1 × 8
200 (OH- form) ion-exchange column. The ninhydrin-positive
fractions were combined and concentrated to dryness to afford
diol 12 (32.4 mg, 99%) as a colorless oil: 1H NMR (D2O) 3.67
(m, 1H), 3.50 (m, 1H), 2.79-2.61 (m, 2H), 2.19-1.62 (m, 6H),
(1S*,7R*,8R*,8a R*)-1-[(ter t-Bu t yld im et h ylsilyl)oxy]-7-
h yd r oxy-8-(p h en ylsu lfon yl)in d olizid in e (18). To a solu-
tion of keto sulfone 17 (500 mg, 1.22 mmol) in CH2Cl2 (10 mL),
cooled at -78 °C, was added 1 M DIBALH in hexane (2.44
mL, 2.44 mmol). After the mixture was stirred at -78 °C for

Synthesis of Polyhydroxylated Indolizidines
J . Org. Chem., Vol. 63, No. 9, 1998 3003
3 h, a few drops of MeOH followed by EtOAc (20 mL) and
saturated aqueous sodium potassium tartrate (60 mL) were
added. The mixture was stirred at room temperature for
further 30 min. After standard workup, the residue was
purified by flash chromatography (n-hexanes-EtOAc 2:1) to
give the hydroxy sulfone 18 as a white solid (376 mg, 75%):
mp 98-99 °C; 1H NMR (CDCl3) 7.91-7.85 (m, 2H), 7.71-7.50
(m, 3H), 4.54 (m,1H), 4.52 (bs, 1H), 3.71 (m, 2H), 3.09-2.93
(m, 2H) 2.15-1.43 (m, 7H), 0.90 (s, 9H), 0.14 (s, 3H), 0.08 (s,
3H); 13C NMR (CDCl3) 137.7, 133.9, 129.1 (4C), 71.9, 67.4, 65.9,
65.7, 51.6, 47.8, 33.8, 31.5, 26.1 (3C), 18.1, -3.7, -4.7.
(1S*,7S*,8R*,8a R*)-1-[(ter t-Bu t yld im et h ylsilyl)oxy]-7-
h yd r oxy-8-(p h en ylsu lfon yl)in d olizid in e (19). To a solu-
tion of keto sulfone 17 (1.8 g, 4.54 mmol) in THF (20 mL),
cooled at -78 °C, was added 1 M lithium triethylborohydride
in THF (9.1 mL, 9.1 mmol). After the solution was stirred at
-78 °C for 1 h, a few drops of MeOH was added, and the
mixture was allowed to reach rt. Then 20% NaOH (50 mL)
and CH2Cl2 (80 mL) were added. After standard workup, the
residue was purified by flash chromatography on alumina (n-
hexanes-EtOAc 3:1) to give hydroxy sulfone 19 (1.24 g, 68%)
as a white solid: mp 121-122 °C; 1H NMR (CDCl3) 7.97-7.92
(m, 2H), 7.74-7.55 (m, 3H), 4.76 (dd, J ) 5.4, 3.3 Hz, 1H),
4.19 (d, J ) 1.7 Hz, 1H), 3.83 (m, 1H), 3.41 (dd, J ) 10.7, 2.1
Hz, 1H), 3.15 (td, J ) 9.0, 3.3 Hz, 1H), 2.85-2.68 (m, 2H),
2.55 (td, J ) 11.9, 2.7 Hz, 1H), 2.25 (m, 1H), 2.06 (m, 1H),
1.90-1.72 (m, 2H), 1.55 (m, 1H), 0.96 (s, 9H), 0.23 (s, 3H), 0.14
(s, 3H); 13C NMR (CDCl3) 138.1, 134.0, 129.3 (2C), 128.3 (2C),
72.6, 63.6, 63.2, 60.7, 51.2, 44.9, 32.7, 31.9, 26.4 (3C), 18.2,
-3.5, -4.2. Anal. Calcd for C20H33NO4SSi: C, 58.36; H, 8.08;
N, 3.40; S, 7.79. Found: C, 58.41; H, 8.25; N, 3.47; S, 8.26.
(1S*,7R*,8a S*)-1-[(ter t-Bu t yld im et h ylsilyl)oxy]-7-h y-
d r oxyin d olizid in e (20). By a procedure identical to that
described for the preparation of olefin 10, the reaction of
hydroxy sulfone 18 (100 mg, 0.24 mmol), Na2HPO4 (465 mg,
3.2 mmol), and Na(Hg) (375 mg) in MeOH (4 mL) at room
temperature for 4 h afforded 20 (51 mg, 78%, colorless oil) after
flash cromatography (EtOAc): 1H NMR (CDCl3) 4.14 (ddd, J
) 7.2, 4.8, 2.3 Hz, 1H), 3.62 (m, 1H), 3.12 (m, 2H), 2.45 (bs,
1H), 2.15 (m, 1H), 1.96-1.40 (m, 8H), 0.85 (s, 9H), 0.19 (s, 6H);
13C NMR (CDCl3) 72.9, 69.9, 67.9, 52.4, 50.4, 35.1, 34.9, 34.4,
25.9 (3C), 18.3, -4.8 (2C); HRMS (FAB) calcd for C14H30NO2-
Si (M + H+) 272.2046, found 272.2046.
2.04 (m, 4H), 1.91-1.63 (m, 3H), 0.90 (s, 9H), 0.10 (s, 3H), 0.09
(s, 3H); 13C NMR (CDCl3) 72.3, 69.0, 68.0, 67.9, 53.0, 46.5, 34.4,
31.1, 26.1 (3C), 18.4, -4.5, -4.9.
(1S*,7S*,8R*,8aR*)-1,7,8-Tr ih ydr oxyin dolizidin e (24). By
a procedure identical to that described for the preparation of
12, TBDMS derivative 23 (70 mg, 0.24 mmol) was deprotected
to afford 24 (42.2 mg, 100%) as a crystalline solid: mp 148-
1
149 °C dec; H NMR (D2O) 4.15 (m, 1H), 3.85 (q, J ) 3.0 Hz,
1H), 3.53 (dd, J ) 10.2, 3.0 Hz, 1H), 2.83 (td, J ) 9.1, 2.0 Hz,
1H), 2.55 (ddd, J ) 11.5, 4.4, 2.3 Hz, 1H), 2.11-1.85 (m, 4H),
1.66-1.33 (m, 3H); 13C NMR (D2O) 70.0, 68.2, 67.6, 66.2, 51.9,
45.5, 31.6, 30.0. Anal. Calcd for C8H15NO3: C, 55.47; H, 8.73;
N, 8.09. Found: C, 55.44; H, 8.50; N, 8.52.
(2R*,3R*)-1-[2-(Ch lor om eth yl)-2-p r op en yl]-2-[(p h en yl-
su lfon yl)m et h yl]-3-[(t r iisop r op ylsilyl)oxy]p yr r olid in e
(tr a n s-25). To a solution of a 78:22 mixture of pyrrolidines
trans-6d and cis-6d (750 mg, 1.89 mmol) in acetonitrile (6 mL)
were added K2CO3 (260 mg, 1.89 mmol), 3-chloro-2-(chloro-
methyl)prop-1-ene (245 µL, 2.1 mmol), and LiI (26 mg, 0.189
mmol). After the solution was stirred at room temperature
for 16 h, water (10 mL) and CH2Cl2 (35 mL) were added. After
standard workup, the residue was purified by flash chroma-
tography (n-hexanes-EtOAc 20:1) to give trans-25 (660 mg,
72%) followed by cis-25 (177 mg, 19%), both as colorless oils.
tr a n s-25: 1H NMR (CDCl3) 7.93-7.88 (m, 2H), 7.67-7.49 (m,
3H), 5.07 (s, 1H), 5.00 (s, 1H), 4.53 (m, 1H), 4.07 and 3.98 (AB
system, J ) 11.5 Hz, 2H), 3.48 (d, J ) 14.3 Hz, 1H), 3.21-
2.95 (m, 3H), 2.85 (m, 1H), 2.58 (m, 1H), 1.82 (m, 1H), 1.08
(m, 21H); 13C NMR (CDCl3) 143.4, 140.1, 133.5, 129.2 (2C),
127.8 (2C), 116.2, 76.6, 68.1, 60.1, 58.3, 50.9, 45.9, 33.8, 18.1
(6C), 12.2 (3C); HRMS (FAB) calcd for C24H41NO3ClSSi (M +
H+) 486.2262, found 486.2265. Anal. Calcd for C24H39NO3-
SSiCl: C, 59.29; H, 8.29; N, 2.88; S, 6.59. Found: C, 59.59;
H, 8.37; N, 2.82; S, 6.66.
(2R*,3S*)- a n d (2R*,3R*)-1-[2-(Ch lor om eth yl)-2-p r op e-
n yl]-3-h ydr oxy-2-[(ph en ylsu lfon yl)m eth yl]pyr r olidin e (cis-
26) a n d (tr a n s-26). By a procedure identical to that described
for the preparation of trans-25, a 80:20 mixture of pyrrolidines
cis-6a and trans-6a (1.0 g, 4.15 mmol) in acetonitrile (12 mL)
was treated with K2CO3 (572 mg, 4.15 mmol), 3-chloro-2-
(chloromethyl)prop-1-ene (532 µL, 4.6 mmol), and LiI (57 mg,
0.42 mmol) at 70 °C for 16 h. After flash chromatography (n-
hexanes-EtOAc 2:1), cis-26 (895 mg, 66%, colorless oil)
followed by the trans-26 (218 mg, 16%, white solid) were
obtained. cis-26: 1H NMR (CDCl3) 7.96-7.91 (m, 2H), 7.72-
7.54 (m, 3H), 5.14 (s, 1H), 5.07 (s, 1H), 4.53 (m, 1H), 4.11 and
3.95 (AB system, J ) 11.3 Hz, 2H), 3.73 (dd, J ) 14.0, 10.0
Hz, 1H), 3.37 and 2.69 (AB system, J ) 13.5 Hz, 2H), 3.22
(dd, J ) 14.0, 2.3 Hz, 1H) 3.05-2.82 (m, 2H), 2.27-2.01 (m,
2H), 1.75 (m, 1H); 13C NMR (CDCl3) 142.5, 139.1, 133.7, 129.2
(2C), 127.5 (2C), 116.4, 71.2, 62.9, 56.1, 54.3, 51.1, 45.8, 32.0.
Anal. Calcd for C15H20NO3ClS: C, 54.52; H, 6.11; N, 4.25; S,
9.72. Found: C, 54.14; H, 5.91; N, 4.19; S, 9.46. tr a n s-26:
mp 82-83 °C; 1H NMR (CDCl3) 7.97-7.92 (m, 2H), 7.73-7.55
(m, 3H), 5.12 (s, 1H), 5.03 (s, 1H), 4.36 (dq, J ) 7.2, 3.0 Hz,
1H), 4.07 and 3.94 (AB system, J ) 11.2 Hz, 2H), 3.42 (dd, J
) 14.4, 2.1 Hz, 1H), 3.30 (d, J ) 13.4 Hz, 1H), 3.15 (dd, J )
14.4, 10.3 Hz, 1H), 3.03 (m, 1H), 2.89-2.70 (m, 2H), 2.39 (td,
J ) 9.7, 7.2 Hz, 1H), 2.16-1.95 (m, 1H), 1.85-1.73 (m, 1H);
13C NMR (CDCl3) 142.8, 139.3, 134.0, 129.5 (2C), 127.9 (2C),
116.8, 77.4, 68.0, 59.2, 56.2, 51.3, 45.9, 32.1. Anal. Calcd for
(1S*,7R*,8a S*)-1,7-Dih yd r oxyin d olizid in e (21). By a
procedure identical to that described for the preparation of 12,
TIPS derivative 20 (55 mg, 0.20 mmol) was desilylated to give
21 (31.3 mg, 99%): 1H NMR (CD3OD) 4.21 (ddd, J ) 6.9, 4.4,
2.1 Hz, 1H), 3.72 (m, 1H), 3.20-3.08 (m, 2H), 2.42-2.25 (m,
1H), 2.16-1.53 (m, 8H); 13C NMR (D2O) 71.5, 69.0, 66.8, 51.2,
49.3, 32.8, 32.6 (2C); HRMS (FAB) calcd for C8H16NO2 (M +
H+) 158.1175, found 158.1181.
(1S*,7S*,8R*,8a S*)-1-[(ter t-Bu tyld im eth ylsilyl)oxy]-7,8-
d ih yd r oxyin d olizid in e (23). To a solution of hydroxy sul-
fone 19 (475 mg, 1.16 mmol) in MeOH (10 mL) were added
solid Na2HPO4 (696 mg, 4.9 mmol) and freshly prepared 6%
Na(Hg) (1.89 g). After the mixture was stirred at room
temperature for 4 h, the resulting Hg was decanted, and the
reaction mixture was diluted with CH2Cl2 (50 mL) and washed
with 1% NaOH. After standard workup, the residue was
purified by flash chromatography on alumina (n-hexanes-
EtOAc 1:4), and 22 was obtained as a colorless oil: 1H NMR
(CDCl3) 5.86 (dtd, J ) 10.0, 3.5, 2.0 Hz, 1H), 5.71 (dq, J )
10.0, 2.0 Hz, 1H), 4.32 (ddd, J ) 6.6, 4.8, 3.3 Hz, 1H), 3.21 (m,
1H), 3.07-2.71 (m, 4H), 2.38-1.98 (m, 3H), 1.81 (m, 1H), 0.88
(s, 9H), 0.07 (s, 3H), 0.05 (s, 3H).
Due to its relative instability, olefin 22 was immediately
dihydroxylated. To a solution of 22 (245 mg, 0.97 mmol) in
acetone/water 5:1 (3 mL) were added OsO4 (4 wt % in water,
150 µL, 0.024 mmol) and Me3NO (129 mg, 1.16 mmol). The
solution was stirred at room temperature for 4 days. Following
the isolation procedure described for the preparation of 13 and
14, diol 23 (161 mg, 49%) was obtained after flash chroma-
tography on alumina (EtOAc). 23 (colorless oil): 1H NMR
(CDCl3) 4.44 (m, 1H), 4.09 (q, J ) 3.0 Hz, 1H), 3.88 (dd, J )
9.5, 3.2 Hz, 1H), 3.13 (m, 1H), 2.81 (m, 1H), 2.75 (bs, 2H), 2.41-
C
15H20NO3ClS: C, 54.52; H, 6.11; N, 4.25; S, 9.72. Found: C,
54.72; H, 5.94; N, 4.16; S, 9.42.
(2R*,3S*)-1-[2-(Ch lor om eth yl)-2-p r op en yl]-2-[(p h en yl-
su lfon yl)m et h yl]-3-[(t r iisop r op ylsilyl)oxy]p yr r olid in e
(cis-25). To a solution of cis-26 (800 mg, 2.4 mmol) in CH2-
Cl2 (20 mL), cooled at -78 °C, were added 2,6-lutidine (340
µL, 2.9 mmol) and triisopropylsilyl trifluoromethanesulfonate
(680 µL, 3.1 mmol). After the solution was stirred at room
temperature for 6 h, water (10 mL) was added. After standard
workup and purification by flash chromatography (n-hexanes-
EtOAc 20:1), cis-25 (1.08 g, 93%) was obtained as a colorless
oil: 1H NMR (CDCl3) 7.93-7.89 (m, 2H), 7.66-7.49 (m, 3H),
5.16 (s, 1H), 5.08 (s, 1H), 4.48 (q, J ) 6.2 Hz, 1H), 4.12 and
4.02 (AB system, J ) 11.7 Hz, 2H), 3.87 (dd, J ) 14.6, 4.5 Hz,

3004 J . Org. Chem., Vol. 63, No. 9, 1998
Carretero and Arraya´s
1H), 3.52 and 2.87 (AB system, J ) 13.5 Hz, 2H), 3.22 (m,
1H), 3.10 (dd, J ) 14.6, 4.7 Hz, 1H), 2.95-2-83 (m, 1H) 2.22
(m, 1H), 2.07 (m, 1H), 1,66 (m, 1H), 1.04 (m, 21H); 13C NMR
(CDCl3) 143.2, 140.4, 133.3, 129.1 (2C), 127.7 (2C), 115.9, 72.4,
62.2, 56.7, 55.3, 49.7, 46.0, 33.5, 18.0 (6C), 12.3 (3C); HRMS
(FAB) calcd for C24H41NO3ClSi (M + H+) 486.2263, found
486.2265. Anal. Calcd for C24H40NO3ClSSi: C, 59.29; H, 8.29;
N, 2.88. Found: C, 59.50; H, 8.61; N, 2.44.
1H), 1.14-1.03 (m, 21H); 13C NMR (CDCl3) 197.8, 146.8, 129.0,
73.7, 63.1, 58.3, 49.4, 34.0, 18.0 (6C), 12.0 (3C).
(1R*,6S*,8a S*)- a n d (1R*,6R*,8a S*)-1,2,3,5,6,8a -Hexa h y-
d r o-6-h yd r oxy-1-[(tr iisop r op ylsilyl)oxy]in d olizin es (32)
a n d (33) a n d (1R*,6S*,8a S*)- a n d (1R*,6R*,8a S*)-6-(Ben -
zoyloxy)-1,2,3,5,6,8a-h exah ydr o-1-[(tr iisopr opylsilyl)oxy]-
in d olizin es (36) a n d (37). To a solution of 30 (350 mg, 1.13
mmol) in THF (6 mL), cooled at -78 °C, was added 1 M
DIBALH in hexane (1.36 mL, 1.36 mmol). The solution was
stirred at -78 °C for 30 min. Then, a few drops of MeOH
followed by EtOAc (30 mL) and saturated aqueous sodium
potassium tartrate (60 mL) were added, and the mixture was
stirred at room temperature for further 1 h. After standard
workup, a 60:40 mixture of 32 and 33 was obtained as a yellow
oil. This mixture could not be separated by flash chroma-
tography: 1H NMR (CDCl3) 32 + 33 6.13 (dd, J ) 9.8, 1.7 Hz,
1H, compound 32), 6.02 (m, 1H, 33), 5.90 (m, 1H, 33), 5.84
(dt, J ) 9.8, 2.6 Hz, 1H, 32), 4.32-4.01 (m, 32 and 33), 3.13
(dd, J ) 10.8, 5.1 Hz 1H, 32), 3.20-2.80 (m, 32 and 33), 2.68-
2.12 (m, 32 and 33), 1.74-1.57 (m, 32 and 33), 1.08 (m, 32
and 33).
(1R*,8S*,8aR*)- a n d (1R*,8R*,8aR*)-6-Meth ylen e-8-(p h en -
ylsu lfon yl)-1-[(tr iisopr opylsilyl)oxy]in dolizidin es (27 an d
28). To a solution of trans-25 (310 mg, 0.64 mmol) in THF (7
mL), cooled at 0 °C, was added a 0.5 M solution of LHMDS in
THF (1.6 mL, 0.80 mmol). After the solution was stirred at 0
°C for 15 min, saturated aqueous NH4Cl (5 mL) was added.
After standard workup and purification by flash chromatog-
raphy (n-hexanes-EtOAc 6:1), 28 (81 mg, 28%) followed by
27 (198 mg, 69%) were obtained, both as colorless oils. 27:
1H NMR (CDCl3) 7.93-7.88 (m, 2H), 7.70-7.52 (m, 3H), 5.08
(dt, J ) 7.3, 1.7 Hz, 1H), 4.77 (m, 1H), 4.67 (s, 1H), 3.30 and
3.15 (AB system, J ) 14.0 Hz, 2H), 3.09-2.91 (m, 2H), 2.75
(dd, J ) 8.1, 6.1 Hz, 2H), 2.35-2.04 (m, 3H), 1.87 (m, 1H),
1.09 (m, 21H); 13C NMR (CDCl3) 139.3, 137.9, 133.7, 129.1 (2C),
129.0 (2C), 112.1, 75.1, 69.2, 61.9, 55.5, 49.4, 34.7, 34.5, 18.3
(6C), 12.7 (3C); HRMS (FAB) calcd for C24H40NO3SSi (M + H+)
450.2495, found 450.2498. 28: 1H NMR (CDCl3) 7.92-7.86
(m, 2H), 7.61-7.42 (m, 3H), 5.36 (m, 1H), 4.68 (m, 1H), 4.60
(m, 1H), 3.61 (m, 1H), 3.44 (d, J ) 12.1 Hz, 1H), 2.97 (m, 1H),
2.68 (m, 2H), 2.44 (dd, J ) 5.0, 2.8 Hz, 1H), 2.37-2.09 (m,
3H), 1.78-1.61 (m, 1H), 1.09 (m, 21H); 13C NMR (CDCl3) 140.5,
137.9, 133.2, 129.5 (2C), 128.4 (2C), 112.0, 75.6, 72.2, 61.4, 59.6,
52.7, 34.4, 34.2, 18.1 (6C), 12.2 (3C); HRMS (FAB) calcd for
A 60:40 mixture of 32 + 33 was dissolved in CH2Cl2 (5 mL)
and treated with Et3N (780 µL, 5.6 mmol) and benzoyl chloride
(232 µL, 2.0 mmol). After the solution was stirred at room
temperature overnight, saturated aqueous NaHCO3 (5 mL)
was added. After standard workup and purification by flash
chromatography (CH2Cl2-EtOAc 33:1), 37 (187 mg, 36%)
followed by 36 (280 mg, 57%) were obtained, both as colorless
oils. 36: 1H NMR (C6D6) 8.27-8.21 (m, 2H), 7.16-6.99 (m,
3H), 6.31 (m, 1H), 5.99 (m, 1H), 5.56 (m, 1H), 4.18 (ddd, J )
8.3, 6.8, 5.0 Hz, 1H), 3.12 (m, 1H), 2.94-2.84 (m, 2H), 2.66
(dd, J ) 13.0, 3.9 Hz, 1H), 2.54 (td, J ) 9.0, 7.0 Hz, 1H), 2.11
(m, 1H), 1.64 (m, 1H), 1.10 (m, 21H); 13C NMR (CDCl3) 166.4,
133.0, 132.9, 130.3, 129.7 (2C), 128.2 (2C), 123.9, 75.7, 67.7,
67.3, 52.5, 51.1, 34.3, 18.0 (6C), 12.1 (3C); HRMS (FAB) calcd
for C24H38NO3Si (M + H+) 416.2630, found 416.2621. 37: 1H
NMR (CDCl3) 8.08-8.02 (m, 2H), 7.59-7.37 (m, 3H), 6.11 (m,
1H), 5.86 (m, 1H), 5.65 (m, 1H), 4.14 (dt, J ) 7.7, 5.5 Hz, 1H),
3.45 (dd, J ) 11.8, 6.1 Hz, 1H), 3.16 (m, 1H), 3.02-2.86 (m,
2H), 2.95 (m, 2H), 2.77 (dd, J ) 11.8, 8.6 Hz, 1H), 2.25 (m,
1H), 1.73 (m, 1H), 1.08 (m, 21H); 13C NMR (CDCl3) 166.2,
132.9, 131.2, 130.2, 129.6 (2C), 128.3 (2C), 125.7, 76.4, 67.2,
66.1, 51.4, 50.4, 33.5, 17.9 (6C), 12.1 (3C); HRMS (FAB) calcd
for C24H38NO3Si (M + H+) 416.2630, found 416.2621.
C
24H40NO3SSi (M + H+) 450.2501, found 450.2498.
(1S*,8S*,8a R*)-6-Met h ylen e-8-(p h en ylsu lfon yl)-1-[(t r i-
isop r op ylsilyl)oxy]in d olizid in e (29). To a solution of cis-
25 (500 mg, 1.03 mmol) in THF (10 mL), cooled at 0 °C, was
added a 0.5 M solution of LHMDS in THF (2.6 mL, 1.3 mmol).
After the solution was stirred at 0 °C for 15 min, saturated
aqueous NH4Cl (7 mL) was added. After standard workup and
purification by flash chromatography (n-hexanes-EtOAc 10:
1), 29 (439 mg, 96%) was obtained as a yellow solid: mp 88-
89 °C; 1H NMR (CDCl3) 7.90-7.85 (m, 2H), 7.70-7.52 (m, 3H),
4.84 (m, 1H), 4.78 (s, 1H), 4.67 (s, 1H), 3.70 (m, 2H), 3.47 (d,
J ) 12.4 Hz, 1H), 3.16 (m, 1H), 2.61 (d, J ) 12.4 Hz, 1H), 2.40
(dd, J ) 9.3, 3.6 Hz, 1H), 2.31 (d, J ) 7.7 Hz, 2H), 2.23-2.04
(m, 2H), 1.97-1.81 (m, 1H), 1.13 (m, 21H); 13C NMR (CDCl3)
140.2, 137.9, 133.6, 129.1 (2C), 128.9 (2C), 110.7, 72.4, 65.3,
59.3, 57.1, 51.5, 33.4, 32.4, 18.4 (3C), 18.3 (3C), 13.0 (3C). Anal.
Calcd for C24H39NO3SSi: C, 64.10; H, 8.74; N, 3.11; S, 7.13.
Found: C, 63.8; H, 8.74; N, 3.37; S, 7.15.
(1S*,6S*,8a S*)- a n d (1S*,6R*,8a S*)-1,2,3,5,6,8a -Hexa h y-
dr o-6-h ydr oxy-1-[(tr iisopr opylsilyl)oxy]in dolizidin es (34)
a n d (35) a n d (1S*,6S*,8a S*)- a n d (1S*,6R*,8a S*)-6-(Ben zo-
yloxy)-1,2,3,5,6,8a -h exa h yd r o-1-[(tr iisop r op ylsilyl)oxy]-
in d olizid in es (34-OBz) a n d (35-OBz). Following the ex-
perimental procedure mentioned above, the reaction of 31 (250
mg, 0.81 mmol) with 1 M DIBALH in hexane (0.90 mL, 0.90
mmol) afforded a 85:15 mixture of 34 and 35 that could not
be separated by flash chromatography. 34: 1H NMR (CDCl3)
5.96 (ddd, J ) 10.2, 3.8, 2.1 Hz, 1H), 5.87 (dd, J ) 10.2, 1.6
Hz, 1H), 4.29 (ddd, J ) 6.5, 4.3, 2.1 Hz, 1H), 4.08 (m, 1H),
3.12 (m, 2H), 2.95 (bs, 1H), 2.68 (m, 1H), 2.59 (dd, J ) 11.8,
3.2 Hz, 1H), 2.43 (q, J ) 8.6 Hz, 1H), 2.12 (m, 1H), 1.82 (m,
1H). The benzoylation of this mixture with benzoyl chloride
(188 µL, 1.43 mmol) and Et3N (560 µL, 4.0 mmol) in CH2Cl2
(3.5 mL), according to the previous procedure, and purification
by flash chromatography (n-hexanes-ether 9:1), afforded 34-
OBz (255 mg, 76%), followed by 35-OBz (45 mg, 13%). 34-
OBz: 1H NMR (C6D6) 8.24-8.19 (m, 2H), 7.22-7.05 (m, 3H),
6.17 (dt, J ) 10.4, 1.4 Hz, 1H), 6.07 (m, 1H), 5.59 (m, 1H),
4.46 (q, J ) 5.6 Hz, 1H), 3.45 (m, 1H), 3.27 (dd, J ) 13.7, 2.4
Hz, 1H), 3.24 (m, 1H), 3.14 (dd, J ) 13.7, 4.7 Hz, 1H), 2.89
(ddd, J ) 9.7, 9.3, 6.5 Hz, 1H), 2.02 (m, 2H), 1.09 (m, 21H);
13C NMR (CDCl3) 166.1, 132.8, 130.7, 129.6 (2C), 128.3 (2C),
126.2, 124.8, 73.7, 66.5, 62.2, 50.9, 49.0, 34.1, 18.0 (6C), 12.1
(3C); HRMS (FAB) calcd for C24H38NO3Si (M + H+) 416.2630,
found 416.2621. 35-OBz: 1H NMR (C6D6) 8.27-8.22 (m, 2H),
7.16-7.04 (m, 3H), 6.18-6.05 (m, 2H), 5.88 (m, 1H), 4.28 (q,
J ) 5.5 Hz, 1H), 3.52 (dd, J ) 12.4, 5.5 Hz, 1H), 3.39 (m, 1H),
3.00 (dd, J ) 12.4, 7.7 Hz, 1H), 2.92-2.66 (m, 2H), 1.86-1.67
(m, 2H), 1.09 (m, 21H); 13C NMR (C6D6) 166.1, 132.8, 131.2,
(1R*,8a S*)-1,2,3,5,6,8a -H exa h yd r o-6-oxo-1-[(t r iisop r o-
p ylsilyl)oxy]in d olizin e (30). A solution of a 70:30 mixture
of 27 and 28 (550 mg, 1.22 mmol) in TFA (5 mL) and CH2Cl2
(2 mL) was ozonolyzed at -20 °C for 20 min. Then, Ph3P (352
mg, 1.34 mmol) was added, and the solution was stirred at
room temperature for 1 h. The solvent and TFA were
evaporated. The residue was dissolved in CH2Cl2 (8 mL), and
cooled at 0 °C, and Et3N (1 mL) was added. The solution was
stirred at room temperature for 40 min. The solvents were
evaporated, and the residue was purified by flash chromatog-
raphy (n-hexanes-EtOAc 10:1) to give enone 30 (263 mg, 70%)
as a colorless oil: 1H NMR (CDCl3) 7.10 (dd, J ) 10.1, 1.6 Hz,
1H), 6.10 (dd, J ) 10.1, 2.5 Hz, 1H), 4.27 (ddd, J ) 5.0, 6.3,
8.3 Hz, 1H), 3.51 (d, J ) 16.7 Hz, 1H), 3.26-3.16 (m, 2H), 2.98
(td, J ) 8.9, 4.8, 1H), 2.79 (td, J ) 8.9, 6.4 Hz, 1H), 2.29 (m,
1H), 1.77 (ddd, J ) 13.8, 9.1, 5.0 Hz, 1H), 1.08 (m, 21H); 13C
NMR (CDCl3) 202.5, 148.4, 128.5, 75.3, 68.0, 59.6, 50.9, 33.5,
18.0 (6C), 12.2 (3C); MS (FAB) 296 (M + H+, 100).
(1S*,8a S*)-1,2,3,5,6,8a -H exa h yd r o-6-oxo-1-[(t r iisop r o-
p ylsilyl)oxy]in d olizin e (31). Following a procedure identical
to that described for the preparation of enone 30, the ozonolysis
of 29 (450 mg, 1 mmol) afforded enone 31 (222 mg, 72%) as a
pale yellow oil after flash chromatography (n-hexanes-EtOAc
4:1): 1H NMR (CDCl3) 7.14 (dd, 1H, J ) 10.5, 1.9 Hz, 1H),
6.16 (dd, 1H, J ) 10.5, 2.5 Hz, 1H), 4.65 (m, 1H), 3.66 (m,
1H), 3.46 (s, 2H), 3.00-2.76 (m, 2H), 2.22 (m, 1H), 1.76 (m,

Synthesis of Polyhydroxylated Indolizidines
J . Org. Chem., Vol. 63, No. 9, 1998 3005
130.4, 130.0 (2C), 128.3 (2C), 126.7, 74.1, 66.0, 63.5, 51.5, 49.7,
34.7, 18.2 (6C), 12.4 (3C); HRMS (FAB) calcd for C24H38NO3Si
(M + H+) 416.2630, found 416.2621.
Hz, 1H), 1.41 (dddd, J ) 10.4, 8.9, 4.2, 2.0 Hz, 1H); 13C NMR
(D2O) 75.3, 72.4, 69.2, 67.2, 66.4, 55.6, 51.1, 31.7; HRMS calcd
for C8H15NO4 189.1001, found 189.0998.
(1R*,6R*,7R*,8R*,8a S*)-6-(Ben zoyloxy)-7,8-d ih yd r oxy-1-
[(tr iisop r op ylsilyl)oxy]in d olizid in e (38). To a solution of
36 (50 mg, 0.12 mmol) and Me3NO dihydrate (16 mg, 0.14
mmol) in acetone (0.5 mL) was added a catalytic amount of
OsO4 (4 wt % in water, 50 µL, 0.009 mmol). The solution was
stirred at room temperature for 16 h. By an isolation
procedure identical to that described for the preparation of 13
and 14, and further purification by flash chromatography (n-
hexanes-EtOAc 4:1), 38 (43 mg, 80%) was obtained as a white
solid: mp 172-173 °C; 1H NMR (C6D6) 8.17-8.11 (m, 2H),
7.05-6.92 (m, 2H), 5.42 (q, J ) 2.2 Hz, 1H), 4.33 (ddd, J )
8.4, 7.2, 5.5 Hz, 1H), 4.11-4.03 (m, 2H), 2.95 (dd, J ) 12.5,
2.2 Hz, 1H), 2.72-2.62 (m, 2H), 2.39 (dd, J ) 7.2, 8.9 Hz, 1H),
2.16 (m, 1H), 1.89 (m, 1H), 1.47-1.32 (m, 1H), 1.05 (m, 21H);
13C NMR (CDCl3) 165.7, 133.1, 130.2, 129.9 (2C), 128.3 (2C),
76.4, 72.6, 72.0, 68.5, 66.4, 51.6, 50.8, 31.6, 18.0 (6C), 12.4 (3C);
HRMS (FAB) calcd for C24H40NO5Si (M + H+) 450.2676, found
450.2676.
(1S*,6R*,7S*,8R*,8a R*)- a n d (1S*,6S*,7S*,8R*,8a R*)-1,6,7,8-
Tetr a a cetoxyin d olizid in es (43) a n d (44). To a solution of
a 9:1 mixture of 34 + 35 in CH2Cl2 (2 mL), cooled at -78 °C,
were added TMEDA (147 µL, 0.97 mmol) and a solution of
OsO4 (250 mg, 0.98 mmol) in CH2Cl2 (2 mL). After the solution
was stirred at -78 °C for 15 min, THF (10 mL) and saturated
aqueous sodium sulfite (10 mL) were added. The mixture was
heated at reflux for 3 h and then extracted with EtOAc (3 ×
20 mL). The combined organic extracts were dried (Na2SO4)
and filtered through Celite. Evaporation under reduced
pressure gave a 90:10 mixture of the corresponding dihydroxyl-
ated compounds as a brown oil. This mixture was dissolved
in pyridine (3 mL) and treated with DMAP (20 mg, 0.16 mmol)
and acetic anhydride (610 µL, 6.48 mmol). After the solution
was stirred at room temperature overnight, saturated aqueous
NaHCO3 (5 mL) and CH2Cl2 (10 mL) were added. After
standard workup and purification of the residue by flash
chromatography (n-hexanes-EtOAc 2:1), 44 (29 mg, 10%,
colorless oil) followed by 43 (227 mg, 79%, colorless oil) were
obtained. 43: 1H NMR (C6D6) 5.78-5.71 (m, 2H) 5.54 (m, 1H),
5.04 (q, J ) 2.8 Hz, 1H), 3.09 (dd, J ) 12.8, 2.0 Hz, 1H), 2.86-
2.73 (m, 1H), 2.42 (dd, J ) 9.6, 5.0 Hz, 1H), 2.26 (dd, J ) 12.8,
2.3 Hz, 1H), 1.87 (s, 3H), 1.80 (s, 3H), 1.73 (s, 3H), 1.82-1.56
(m, 3H), 1.55 (s, 3H); 13C NMR (C6D6) 169.8, 169.4 (2C), 168.7,
71.9, 70.0, 68.3, 67.38, 63.9, 52.7, 51.3, 31.0, 20.6, 20.4, 20.3
(2C); HRMS (FAB) calcd for C16H24NO38 (M + H+) 358.1510,
found 358.1502. 44: 1H NMR (C6D6) 5.97 (t, J ) 3.0 Hz, 1H),
5.48 (m, 1H), 5.41 (dd, J ) 10.2, 3.0 Hz, 1H), 5.12 (ddd, J )
10.7, 5.1, 3.0 Hz, 1H), 2.97 (dd, J ) 5.1, 10.0 Hz, 1H), 2.75 (m,
1H), 2.51 (dd, J ) 10.1, 4.8 Hz, 1H), 2.31 (t, J ) 10.0 Hz, 1H),
1.86 (s, 3H), 1.85 (s, 3H), 1.83 (s, 3H), 1.64 (s, 3H), 1.90-1.55
(m, 3H); 13C NMR (C6D6) 169.8, 169.4, 169,2, 168.8, 71.2, 69.0,
68.8, 67.4, 63.8, 51.7, 49.5, 31.3, 20.6, 20.3 (3C).
(1R*,6S*,7S*,8S*,8aS*)- an d (1R*,6S*,7R*,8R*,8aS*)-6-(Ben z-
oyloxy)-7,8-d ih yd r oxy-1-[(tr iisop r op ylsilyl)oxy]in d olizi-
d in es (39 a n d 40). To a solution of 37 (60 mg, 0.14 mmol)
and Me3NO dihydrate (18 mg, 0.16 mmol) in acetone (0.5 mL)
was added a catalytic amount of OsO4 (4 wt % in water, 55
µL, 0.009 mmol). The solution was stirred at room tempera-
ture for 48 h. By a procedure identical to that described for
the isolation of 13 + 14, and further purification by flash
chromatography (n-hexanes-EtOAc 5:1), 39 (42 mg, 67%)
followed by 40 (6.5 mg, 10%) was obtained. 39: mp 171-172
1
°C; H NMR (CDCl3) 8.06-8.02 (m, 3H), 7.61-7.39 (m, 3H),
5.19 (td, J ) 9.9, 5.5 Hz, 1H), 4.52 (ddd, J ) 8.7, 6.5, 3.9 Hz,
1H), 4.12 (m, 1H), 3.70 (dd, J ) 9.6, 3.2 Hz, 1H), 3.33 (dd, J )
10.2, 5.5 Hz, 1H), 3.02 (td, J ) 8.8, 2.1 Hz, 1H), 2.53 (q, J )
8.8 Hz, 1H), 2.30-2.17 (m, 2H), 1.72 (m, 1H), 1.07 (m, 21H);
13C NMR (CDCl3) 166.8, 133.2, 129.8 (3C), 128.4 (2C), 74.6,
74.0, 72.6, 71.0, 68.0, 53.5, 51.6, 34.4, 17.9 (6C), 12.2 (3C);
HRMS calcd for C24H39NO5Si 449.2598, found 449.2600. 40:
1H NMR (CDCl3) 8.09-8.05 (m, 2H), 7.61-7.40 (m, 3H), 5.14
(ddd, J ) 10.4, 5.2, 2.7 Hz, 1H), 4.37-4.26 (m, 1H), 4.29 (t, J
) 2.7 Hz, 1H), 3.73 (dd, J ) 9.3, 2.7 Hz, 1H), 3.08-3.75 (m,
1H), 2.99 (dd, J ) 10.3, 5.2 Hz, 1H), 2.70 (t, J ) 10.3 Hz, 1H),
2.61 (m, 1H), 2.40 (dd, J ) 9.3, 7.3 Hz, 1H), 2.34-2.15 (m,
1H), 1.70 (m, 1H), 1.10 (s, 21H); 13C NMR (CDCl3) 165.7, 133.2,
129.7 (3C), 128.4 (2C), 72.9, 71.2, 69.1, 66.7, 50.9, 48.6, 32.4,
17.9 (6C), 12.3 (3C); HRMS (FAB) calcd for C24H40NO5Si (M
+ H+) 450.2677, found 2676.
(1S *,6R *,7S *,8R *,8a R *)-1,6,7,8-Te t r a h yd r oxyin d olizi-
d in e [(±)-6,7-Di-epi-ca sta n osp er m in e] (45).22 By a proce-
dure identical to that described for the preparation of 41,
deprotection of 43 (200 mg, 0.56 mmol) afforded 45 (104 mg,
98%) as a colorless oil: 1H NMR (D2O) 4.37 (m, 1H), 4.02 (dd,
J ) 10.0, 3.0 Hz 1H), 3.94 (m, 1H), 3.07 (m, 1H), 2.94 (dd, J )
12.7, 2.3 Hz, 1H), 2.41 (dd, J ) 12.7, 2.0 Hz, 1H), 2.35-2.08
(m, 4H), 1.74-1.59 (m, 1H); 13C NMR (D2O) 71.8, 71.5, 70.9,
67.3, 66.7, 53.3, 53.2, 32.8.
(1R*,6R*,7S*,8R*,8a R*)-1,6,7,8-Te t r a h yd r oxyin d olizi-
d in e [(±)-1,7-Di-epi-ca sta n osp er m in e] (41). To a solution
of 38 (40 mg, 0.089 mmol) in MeOH (1.5 mL) was added 10%
aqueous NaOH (400 µL). The solution was stirred for 1 h at
room temperature. Then, the reaction mixture was concen-
trated, 5 M HCl (3 mL) was added, and the mixture was stirred
at room temperature for 2 h. The reaction mixture was
extracted with CH2Cl2 (2 × 5 mL), and the aqueous layer was
concentrated to dryness. The residue was dissolved in MeOH
and chromatographed on a Dowex 1-X8 200 (OH- form) ion-
exchanged column. The combined ninhidrin-positive fractions
were concentrated to afford 41 (16.5 mg, 98%, colorless oil):
1H NMR (D2O) 4.31 (ddd, J ) 8.6, 6.6, 3.9 Hz, 1H), 3.96 (q, J
) 2.6 Hz, 1H), 3.90-3.83 (m, 2H), 3.27 (m, 1H), 3.12-2.94 (m,
3H), 2.87 (dd, J ) 6.6, 9.6 Hz, 1H), 2.30 (dq, J ) 14.2, 9.0 Hz,
1H), 1.71 (m, 1H); 13C NMR (D2O) 72.0, 69.6, 68.0, 67.1 (2C),
51.7, 51.2, 30.3; HRMS (FAB) calcd for C8H16NO4 (M + H+)
190.1080, found 190.1079.
(1S *,6S *,7S *,8R *,8a R *)-1,6,7,8-Te t r a h yd r oxyin d olizi-
d in e [(±)-7-epi-Ca sta n osp er m in e] (46).23 By a procedure
identical to that described for the preparation of 41, depro-
tection of 44 (8 mg, 0.022 mmol) afforded 46 (4.1 mg, 97%) as
a colorless oil: 1H NMR (D2O) 4.37 (m 1H), 4.07 (t, J ) 2.9
Hz, 1H), 3.85-3.75 (m, 2H), 3.06 (m, 1H), 2.90 (dd, J ) 10.4,
4.9 Hz, 1H), 2.39-2.14 (m, 4H), 1.69 (m, 1H); 13C NMR (D2O)
72.5, 70.4, 68.8, 67.8, 66.8, 52.4, 52.0, 33.2; HRMS calcd for
C8H15NO4 189.1001, found 189.0998.
Ack n ow led gm en t. We are grateful to DGICYT
(projects PB93-0244 and PB96-0021) for financial sup-
port of this work.
(1R *,6S *,7R *,8S *,8a R *)-1,6,7,8-Te t r a h yd r oxyin d olizi-
d in e [(±)-1,8-Di-epi-ca sta n osp er m in e] (42). By a procedure
identical to that described for the preparation of 41, depro-
tection of 39 (40 mg, 0.089 mmol) afforded 42 (16.4 mg, 97%,
colorless oil): 1H NMR (D2O) 4.05 (ddd, J ) 9.2, 7.5, 4.2 Hz,
1H), 3.85 (dd, J ) 3.3, 1.6 Hz, 1H), 3.55 (td, J ) 9.7, 5.2 Hz,
1H), 3.21 (dd, J ) 9.7, 3.3 Hz, 1H), 2.87 (dd, J ) 10.5, 5.2 Hz,
1H), 2.68 (td, J ) 8.9, 2.0 Hz, 1H), 2.20 (q, J ) 8.9 Hz, 1H),
2.00 (m, 1H), 1.88 (dd, J ) 7.5, 1.6 Hz, 1H), 1.81 (t, J ) 10.5
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