A sort synthesis of polyhydroxylated pyrrolizidines via sequential 1,3-dipolar cycloaddition and reductive amination

Article abstract of DOI:10.1016/j.tet.2013.07.098

Polyhydroxylated pyrrolizidines bearing a methyl group at C-5 have been synthesized by 1,3-dipolar cycloaddition of five membered cyclic nitrones with methyl vinyl ketone followed by a N-O reductive cleavage and in situ intramolecular reductive amination. The stereochemistry of the obtained compounds is examined in relation to the reactions mechanism.

Full text of DOI:10.1016/j.tet.2013.07.098

Tetrahedron 69 (2013) 8921e8928
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journal homepage: www.elsevier.com/locate/tet
A sort synthesis of polyhydroxylated pyrrolizidines via sequential
1,3-dipolar cycloaddition and reductive amination
*
Petros Gkizis, Nikolaos G. Argyropoulos, Evdoxia Coutouli-Argyropoulou
Department of Chemistry, Laboratory of Organic Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 May 2013
Received in revised form 15 July 2013
Accepted 30 July 2013
Available online 4 August 2013
Polyhydroxylated pyrrolizidines bearing a methyl group at C-5 have been synthesized by 1,3-dipolar
cycloaddition of five membered cyclic nitrones with methyl vinyl ketone followed by a NeO reductive
cleavage and in situ intramolecular reductive amination. The stereochemistry of the obtained com-
pounds is examined in relation to the reactions mechanism.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Pyrrolizidines
Reductive amination
1,3-Dipolar cycloaddition
Nitrones
Azasugars
1. Introduction
groups on the pyrrolizine skeleton, the synthesis of both naturally
occurring compounds and their stereoisomers and analogues has
Polyhydroxylated pyrrolizidines belong to an important class of
alkaloids that display a wide range of biological activities mainly
due to their action as specific glycosidase inhibitors.1 Most of the
naturally occurring polyhydroxylated pyrrolizidines possess a fur-
ther hydroxymethyl group and representative alkaloids of this type,
such as alexine, australine, casuarine and hyacinthacine (Fig. 1),
have gained considerable interest as antiviral and anticancer
agents.2 Since the biological activity varies substantially with the
number, the position and the stereochemistry of the hydroxy
received much attention.3
A methyl group occurs also in many polyhydroxylated alkaloids
as iminoaldilols, pyrrolizidines of hyacinthacine and necine families
and indolizines.1a,2b,4 In particular, the introduction of a methyl
group at C-6 in L
-swansonine increases its naringinase inhibition.4
In connection with our previous studies5 on the synthesis of
azasugars, we present in this paper a short and stereoselective
synthesis of new polyhydroxylated pyrrolizidines bearing a methyl
group at C-5. For this purpose we have planned a short reaction
scheme comprised of 1,3-dipolar cycloaddition of five membered
cyclic nitrones with methyl vinyl ketone followed by a NeO re-
ductive cleavage and in situ intramolecular reductive amination to
give pyrrolizidines (Scheme 1).
Fig. 1. Representative members of pyrrolizidine and indolizidine alkaloids.
* Corresponding author. Tel.: þ30 2310 997733; fax: þ30 2310 997679; e-mail
Scheme 1. General reaction scheme.
address: evd@chem.auth.gr (E. Coutouli-Argyropoulou).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.07.098

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P. Gkizis et al. / Tetrahedron 69 (2013) 8921e8928
The 1,3-dipolar cycloaddition of nitrones to alkenes and sub-
sequent reductive cleavage is a well documented pathway for the
formation of the pyrrolidine ring in many reaction schemes.6 In
most cases acrylates or allyl alcohol derivatives are chosen as
alkenes and after the reductive cleavage of the NeO bond the
cyclization to the pyrrolidine ring takes place through a nucleo-
philic attack by the amino group on the ester carbonyl or the
activated hydroxymethyl group. Although the use of
a,b-un-
saturated ketones or aldehydes as dipolarophiles may offer
a convenient alternative way for the formation of the pyrrolidine
following an analogous methodology, to the best of our knowl-
edge, has not received considerable attention with exception of
a few cases.7
2. Results and discussion
For our study we chose the racemic protected cis-dihydroxy
nitrone 1 and the enantiomerically pure nitrones 2e4 (Fig. 2). All
these compounds were prepared from inexpensive starting ma-
terials applying previously described procedures with small
modifications. In particular nitrone 18a,b and nitrone 48e,f were
prepared from
D
-ribose, nitrone 28c from
-arabinose. The choice of these nitrones would
L-tartaric acid, and
nitrone 38d from
D
permit to study the influence of the substituents geometry on
both cycloaddition and reductive amination steps. Furthermore,
the use of nitrones
3 and 4 bearing a 3,4-dihydroxy-5-
hydroxymethyl substitution pattern will lead to hyacinthacine
analogues.
Scheme 2. Reagents and conditions: i) CH2Cl2, reflux, 48 h.
The stereochemical assignment of the obtained cycloadducts
was based mainly on NOE measurements performed either on the
initial cycloadducts or on the sequential reductive amination
products. In all cases the proton assignment was made by H,H,
Cosy spectra. In Fig. 3 are given the observed crucial NOE en-
hancements, which strongly support the proposed stereochem-
istry for structures 7e11. The stereochemistry of compound 6 the
main product of the reaction with nitrone 1 was not possible to
rely on NOE measurements due to the overlapping of the crucial
for the structure determination protons. However, it was proved
in its reduction products 13 and 14 as described below. Con-
cerning the compound 12, the minor product of the reaction with
nitrone 4, although NOE measurements are not so obvious due to
the overlaps, offer considerable evidence. Thus the 3-H1 is over-
Fig. 2. Applied nitrones.
The cycloaddition reaction of the nitrones 1e4 with methyl
vinyl ketone 5 took place under mild conditions (reflux in
dichloromethane solution for 2 days) affording the expected
cycloadducts in high yields. The reactions showed absolute
regioselectivity and high stereoselectivity and among the eight
possible isomers gave only isomers bearing the acetyl moiety at
the 5-position of the isoxazolidine ring, two diastereoisomers in
the case of nitrones 1, 3 and 4 and one diastereoisomer in the
case of nitrone 2 (Scheme 2). In particular, nitrone 1 gave the two
cycloadducts 6 and 7 in a ratio 1.6:1 and 92% total yield. Cyclo-
adducts 6 and 7 come from exo-anti and endo-anti transition
states, respectively as a result of the tendency of the nitrone 1 to
react from its less hindered face. The reaction of nitrone 2 was
highly selective and afforded as sole product in 85% yield the
isoxazolidine 8, which comes from an exo-anti (relative the C-3
nitrone substituent) transition state. Nitrone 3 reacted also from
its less hindered Re-face to give in a ratio 1.9:1 and 90% total yield
cycloadducts 9 and 10 coming from exo-anti and endo-anti
transition states, respectively. Nitrone 4 showed a lower face
selectivity and gave in a ratio 2:1and 96% total yield cycloadducts
11 and 12 resulting from exo-anti and exo-syn transition states,
respectively. The spectra data of the obtained cycloadducts are in
accordance with the proposed structures.
lapped with methyl protons (
methylene benzyl protons (
2.12e2.28), whereas 3a-H and 3-H2
appear as separate peaks at 3.83 and 2.69, respectively. Satu-
d 2.12e2.28), the 2-H with the
d
d
ration of 3a-H increases the intensity of the multiplet including
3-H1 and not 3-H2. Also saturation of 3-H2 increases the intensity
of the multiplet including 2-H and not 3a-H. These measure-
ments show that 2-H is cis to the one of the two 3-H and 3a-H is
cis to other one. So 2-H and 3a-H are in trans-disposition. This
disposition is possible to the diastereoisomers that come from an
exo-transition state. Since the structure from an exo-anti transi-
tion state was ascribed to the major cycloadduct 11, the minor
cycloadduct should have structure 12 from an exo-syn transition
state.
The reductive cleavage of the NeO bond and the subsequent
reductive amination of the obtained cycloadducts was carried out
in one stage by hydrogenolysis over Pd/C catalyst at room tem-
perature. Under these conditions the protective benzyl groups
were not removed. For the cycloadducts 6e8 this procedure was
not stereoselective and they gave both the expected isomers. Thus
compound 6 gave the two pyrrolizidines 13 and 14 in a ratio 1.15:1
and 92% total yield, compound 7 the pyrrolizidines 15 and 16 in

P. Gkizis et al. / Tetrahedron 69 (2013) 8921e8928
8923
7%
10%
6%
5%
10%
7%
H2
H1
8%
8%
H
H
H1
H
O
H
H
1
2
H2
OBn
OBn
8
3
8b 3a
8a
O
H
4
6
3
7
3a
5
H3COC
6
2
5
N
4
H
7
O
1
N
H
H3COC
5%
O
H
3%
7%
H
H
H
11%
8
7
8%
11%
5%
4%
4%
H
H2
OBn
7%
12%
11%
7%
H2
H1
5%
H1
H
H2
H
5
OBn
14%
H
10%
H3COC
5%
H
H
4
6
3
H
3a
12%
8%
H1
OBn
H
2
5
H
7
1
N
OBn
OBn
4
6
3
H
H
4
6
3a
H
3
3a
7%
7
O
2
2
5
7
1
N
OBn
OBn
6%
1
N
OBn
OBn
H
H3COC
H3COC
O
O
H
H
9%
11
9
10
Fig. 3. NOE enhancements measured in compounds 7e11.
a ratio 1.3:1 and 85% total yield and compound 8 the pyrrolizi-
dines 17 and 18 in a ratio 1:2.7 and 95% total yield. On the con-
trary, the reductive amination of compounds 9e12 bearing
a benzyloxymethyl group at the 6-position showed high stereo-
selectivity and gave only one of the possible two stereoisomers in
80e85% yields (Scheme 3). The spectra data of the obtained pyr-
rolizidines are in accordance with the proposed structures The
stereochemical assignment was based on NOE measurements as
depicted in Fig. 4. Due to the overlapping of the peaks informative
NOE measurements were not possible in compounds 15, 18 and
22. The proposed stereochemistry of compounds 15 and 18 relies
on the stereochemical assignment of their isomers 16 and 17,
respectively, whereas stereo structure of compound 22 is tenta-
tively proposed in analogy with the other benzyloxymethyl
derivatives.
The obtained results offer considerable evidence for the mech-
anism of the reaction. Reductive NeO cleavage of compounds A
leads to the formation of the intermediate amino alcohols B, which
are transformed to the bicyclic intermediates C via a nucleophilic
attack of the NH group to the carbonyl bond. Intermediate C can be
further transformed to the pyrrolizidines F via an iminium in-
termediate D or enamine E. Involvement of an enamine in-
termediate E should result in the lost of the stereogenic centre at
the carbon bearing the hydroxyl group. The configuration of this
Scheme 3. Reagents and conditions: i) Pd/C, H2, atm pressure, CH3OH, rt, 48 h.

8924
P. Gkizis et al. / Tetrahedron 69 (2013) 8921e8928
Fig. 4. NOE enhancements measured in compounds 13, 14, 16, 17, 19e21.
stereocentre is determined by the arrangement of the acetyl group
in the initial cycloadducts (marked with asterisk carbon in Scheme
4). Thus diastereomeric cycloadducts 6 and 7 as well as 9 and 10
differentiating at the stereochemistry of the carbon bearing the
acetyl group should be expected to give the same reduction prod-
ucts bearing the 2-H and 3-H in cis disposition. The formation of
different products and especially in the case of 6 and 7 the for-
mation of four different products gives evidence for iminium ion D
as intermediate, in which the configuration of the carbon bearing
the hydroxyl group is retained. The formation of only one dia-
steoisomer in the case of compounds 9e12 bearing in addition to
the C-4 and C-5 substituents a benzyloxymethyl substituent at C-6
can be attributed to a particular shape of the bicycle intermediate,
which permits the hydrogen attack only from the exo-face directing
the methyl group to the opposite face trans to the bridgehead hy-
drogen. Absolute stereoselectivity has been also mentioned in the
hydrogenation reaction of analogous intermediates by Izquierdo
and Franco in a series of papers.9
The removal of the protective groups can be done by standard
procedures. Thus compounds 13 and 14 were transformed to the
trihydroxypyrrolizidines 23 and 24, respectively by acid hydrolysis,
whereas compounds 19 and 21 were transformed to the tetrahy-
droxypyrrolizidines 25 and 26, respectively by reductive debenzy-
lation under pressure at 70 ꢀC (Scheme 5).
Scheme 4. Mechanistic scheme for the reductive amination.

P. Gkizis et al. / Tetrahedron 69 (2013) 8921e8928
8925
(CO) cmꢁ1. 1H NMR (CDCl3)
d: 1.27 (s, 3H, CH3),1.46 (s, 3H, CH3), 2.21
(s, 3H, COCH3), 2.36 (dddd, J¼13.2, 9.3, 4.2, 0.7 Hz, 1H, 8-H), 2.7
(dddd, J¼13.2, 8.2, 4.3, 1.1 Hz, 1H, 8-H), 3.23 (dd, J¼14.0, 4.0 Hz, 1H,
4-H), 3.51 (dd, J¼14.0, 5.9 Hz, 1H, 4-H), 3.63 (ddd, J¼8.2, 4.2, 2.4 Hz,
1H, 8a-H), 4.31 (dd, J¼9.3, 4.3 Hz, 1H, 7-H), 4.52 (dd, J¼7.2, 2.4 Hz,
1H, 8b-H), 4.89e4.98 (m, 1H, 3a-H). 13C NMR (CDCl3)
d: 24.8, 25.4
and 26.9 (CH3), 35.9 (C-8), 60.9, 70.8, 81.0, 81.2 and 85.8 (C-3a, C-4,
C-7, C-8a and C-8b), 113.4 (C-2), 210.0 (CO). MS (m/z, %): 250 [100,
(MþNa)þ]. Anal. Calcd for C11H17NO4: C, 58.14; H, 7.54; N, 6.16%.
Found: C, 58.40; H, 7.75; N, 5.99%.
4.2.1.2. 1-[(3aSR, 7SR, 8aRS, 8bRS)-2,2-Dimethylhexahydro [1,3]
dioxolo[40,50:3,4]pyrrolo[1,2-b]isoxazol-7-yl]-1-ethanone
(7). This
Scheme 5. Reagents and conditions: i) p-CH3C6H4SO3H, CH3OH acid, rt, 5 h ii) Pd/C, H2,
sealed tube, CH3OH, 70 ꢀC, rt, 48 h.
compound was obtained from nitrone 1 in 35% yield (79 mg) as
a white solid, mp 120e121 ꢀC; Rf (hexane/EtOAc 3:1) 0.4; IR (KBr):
nmax 1715 (CO) cmꢁ1. 1H NMR (CDCl3)
d: 1.33 (s, 3H, CH3), 1.52 (s, 3H,
3. Conclusions
CH3), 2.22e2.33 (overlapped s and m, 4H, CH3 and 8-H), 2.69 (dt,
J¼13.1, 8.4 Hz, 1H, 8-H), 3.47 (d, J¼4.3 Hz, 2H, 4-H), 3.83 (ddd, J¼8.4,
5.8, 2.3 Hz, 1H, 8a-H), 4.47 (t, J¼8.4 Hz, 1H, 7-H), 4.58 (dd, J¼6.5,
2.3 Hz, 1H, 8b-H), 4.98 (dt, 1H, J¼6.5, 4.3 Hz, 3a-H). 13C NMR (CDCl3)
In conclusion, we have developed a convenient and short syn-
thesis of polyhydroxylated pyrrolizidines starting from easily
available cyclic nitrones. The stereochemical outcome of the re-
actions is determined by the stereochemistry of the starting
nitrone. By choice of suitable nitrones hyacinthacine analogues as
19e22 can be obtained. The existence of a benzyloxymethoxy
group at the C-5 position of the starting nitrone induces high
stereoselectivity in the reductive amination step resulting one
stereoisomer of the two possible ones in all cases.
d: 24.9, 26.8 and 27.1 (CH3), 35.3 (C-8), 61.01, 71.7, 80.4, 83.3 and
84.5 (C-3a, C-4, C-7, C-8a and C-8b),113.1 (C-2), 206.2 (CO). MS (m/z,
%): 250 [100, (MþNa)þ]. Anal. Calcd for C11H17NO4: C, 58.14; H, 7.54;
N, 6.16%. Found: C, 58.38; H, 7.57; N, 5.94%.
4.2.1.3. 1-[(2S, 3aS, 4S, 5S)-4,5-Bis(benzyloxy)hexahydropyrro lo
[1,2-b]isoxazol-2-yl]ethanone (8). This compound was obtained
from nitrone 2 in 85% yield (312 mg) as a pale yellow oil; [
(c 3.8, CHCl3); Rf (hexane/EtOAc 3:1) 0.5; IR (liquid film): nmax 1715
(CO) cmꢁ1 1H NMR (CDCl3)
: 2.28 (s, 3H, COCH3), 2.42 (ddd,
a]
25 13.7
D
4. Experimental
4.1. General
.
d
J¼12.8, 8.2, 3.9 Hz, 1H, 3-H), 2.68 (ddd, J¼12.8, 8.5, 5.5 Hz, 1H, 3-H),
3.44e3.58 (m, 2H, 6-H), 3.68 (ddd, J¼8.5, 4.2, 3.9 Hz, 1H, 3a-H),
3.99 (dd, J¼4.2, 2.7 Hz, 1H, 4-H), 4.11e4.17 (m, 1H, 5-H), 4.48 (dd,
J¼8.2, 5.5 Hz, 1H, 2-H), 4.52e4.63 (m, 4H, CH2Ph), 7.25e7.42 (m,
Melting points are uncorrected and were determined on a Kofler
hot-stage microscope. IR spectra were recorded on a PerkineElmer
297 spectrometer. 1H NMR spectra were recorded at 300 MHz on
a Bruker AVANCEIII 300 spectrometer and 13C NMR spectra at
75.5 MHz on the same spectrometer and are quoted relative to
tetramethylsilane as internal reference, in deuteriochloroform so-
lutions, unless otherwise stated. Mass spectra were performed on
a Shimadzu LCMS-2010 EV instrument under Electrospray Ioniza-
tion conditions. High resolution mass spectra (HRESI) were ob-
tained with a 7 T APEX II spectrometer. Microanalyses were
performed on a PerkineElmer 2400-II element analyser. Column
chromatography was carried out on Merck Kieselgel (particle size
0.063e0.200 mm) and solvents were distilled before use. Optical
10H, Ph-H). 13C NMR (CDCl3)
d: 25.5 (CH3), 36.8 (C-3), 59.5, 69.9,
71.7, 71.8, 81.3, 84.3 and 89.1 (C-2, C-3a, C-4, C-5, C-6 and CH2Ph),
127.4, 127.5, 127.6, 127.7, 127.8, 128.2, 128.3, 137.5 and 137.6 (CePh),
209.8 (CO). MS (m/z, %): 390 [100, (MþNa)þ]. Anal. Calcd for
C22H25NO4: C, 71.91; H, 6.86; N, 3.81%. Found: C, 71.80; H, 6.90; N,
3.67%.
4.2.1.4. 1-[((2R, 3aR, 4R, 5R, 6R)-4,5-Bis(benzyloxy)-6-benzyl
oxymethyl)hexahydropyrrolo[1,2-b]isoxazol-2-yl] ethanone (9). This
compound was obtained from nitrone 3 in 59% yield (287 mg) as
25
a pale yellow oil; Rf (hexane/EtOAc 3:1) 0.6; [
a
]
D
ꢁ16.1 (c 3.46,
€
CHCl3); IR (liquid film): nmax 1715(CO) cmꢁ1. 1H NMR (CDCl3)
d: 2.28
rotations were measured with a A. KRUSS Optronic P3002, oper-
ating at 589 nm (l¼1 dm, 25 ꢀC).
(s, 3H, COCH3), 2.42 (ddd, J¼12.7, 8.3, 5.2 Hz, 1H, 3-H), 2.58 (ddd,
J¼12.7, 8.5, 6.2 Hz, 1H, 3-H), 3.52 (q, J¼5.4, 1H, 6-H), 3.58e3.76 (m,
3H, 3a-H and CH2O), 4.01 (t, J¼5.4 Hz, 1H, 4-H), 4.12 (t, J¼5.4 Hz, 1H,
5-H), 4.48 (dd, J¼8.3, 6.2 Hz, 1H, 2-H), 4.52e4.68 (m, 6H, CH2Ph),
4.2. Reactions of nitrones 1e4 with methyl vinyl ketone 5
4.2.1. General procedure. A solution of the nitrone 1, 2, 3 or 4
(1 mmol) and methyl vinyl ketone (1.5 mmol) in dry dichloro-
methane (5 mL) was heated to reflux and the reaction was moni-
tored by TLC for the consumption of the nitrone. After two days
only traces of the nitrone were detected in the TLC. The heating was
stopped and, after evaporation of the solvent, the residue was
chromatographed on a silica gel column with hexaneeethyl acetate
(3:1) as the eluent. From the reaction with nitrone 2 only one
product 8 was isolated, whereas from the reactions with nitrones 1,
3 and 4 the two diastereoisomeric products 6/7, 9/10 and 11/12,
respectively were obtained separately.
7.21e7.45 (m,15H, PheH). 13C NMR (CDCl3)
d: 25.9 (CH3), 36.9 (C-3),
68.0, 69.9, 70.5, 72.0, 72.3, 73.4, 81.4, 84.8 and 87.8 (C-2, C-3a, C-4,
C-5, C-6, CH2O and CH2Ph), 127.5, 127.6, 127.7, 127.8, 127.9, 128.2,
128.3, 128.4, 137.6, 137.9 and 138.2 (CePh), 208.9 (CO). MS (m/z, %):
510 [100, (MþNa)þ]. Anal. Calcd for C30H33NO5: C, 73.90; H, 6.82; N,
2.87%. Found: C, 73.80; H, 6.90; N, 2.67%.
4.2.1.5. 1-[((2S, 3aR, 4R, 5R, 6R)-4,5-Bis(benzyloxy)-6-benzyl oxy-
methyl)hexahydropyrrolo[1,2-b]isoxazol-2-yl] ethanone (10). This
compound was obtained from nitrone 3 in 31% yield (149 mg) as
25
a pale yellow oil; Rf (hexane/EtOAc 3:1) 0.5; [
a
]
ꢁ32.3 (c 3.46,
D
CHCl3); IR (liquid film): nmax 1715 cmꢁ1. 1H NMR (CDCl3)
d: 2.23 (s,
4.2.1.1. 1-[(3aSR, 7RS, 8aRS, 8bRS)-2,2-Dimethylhexahydro [1,3]
3H, COCH3), 2.37 (ddd, J¼12.7, 8.3, 7.5 Hz, 1H, 3-H), 2.62 (ddd, J¼12.7,
8.3, 7.5 Hz, 1H, 3-H), 3.51 (q, J¼5.4, 1H, 6-H), 3.60e3.73 (m, 2H,
CH2O), 3.78 (dt, J¼7.5, 4.1 Hz, 1H, 3a-H), 4.01 (t, J¼4.1 Hz, 1H, 4-H),
4.12 (dd, J¼5.4, 4.1 Hz,1H, 5-H), 4.45 (t, J¼8.3 Hz,1H, 2-H), 4.52e4.63
dioxolo[40,50:3,4]pyrrolo[1,2-b]isoxazol-7-yl]-1-ethanone
(6). This
compound was obtained from nitrone 1 in 57% yield (129 mg) as
a colourless oil; Rf (hexane/EtOAc 3:1) 0.6; IR (liquid film): nmax 1715

8926
P. Gkizis et al. / Tetrahedron 69 (2013) 8921e8928
(m, 6H, CH2Ph), 7.21e7.45 (m, 15H, PheH). 13C NMR (CDCl3)
d: 26.4
SJ¼10.9 Hz, 1H, 3a-H). 13C NMR (CDCl3)
d: 11.1, 24.5 and 26.5 (CH3),
(CH3), 36.6 (C-3), 68.8, 69.6, 70.4, 72.0, 72.2, 73.3, 83.8, 85.3 and 87.1
(C-2, C-3a, C-4, C-5, C-6, CH2O and CH2Ph), 127.5, 127.6, 127.7, 127.8,
128.2,128.3,128.4, 137.5,137.9 and 138.1 (CePh), 207.1 (CO). MS (m/z,
%): 510 [100, (MþNa)þ]. Anal. Calcd for C30H33NO5: C, 73.90; H, 6.82;
N, 2.87%. Found: C, 73, 81; H, 6.75; N, 2.77%.
38.5 (C-8), 52.3, 61.9, 69.9, 75.3, 80.6 and 84.6 (C-3a, C-4, C-6, C-7, C-
8a and C-8b), 111.5 (C-2). HRESIMS for C11H20NO3 (MþH)þ: calcd
214.1443, found 214.1438.
4.3.1.2. (3aSR, 6SR, 7RS, 8aRS, 8bRS)-2,2-6-Trimethylhexa hydro-
4H-[1,3]dioxolo[4,5-a]pyrrolizin-7-ol (14). This compound was ob-
tained from cycloadduct 6 in 43% yield (37 mg) as a white solid, mp
4.2.1.6. 1-[((2S, 3aS, 4S, 5R, 6R)-4,5-Bis(benzyloxy)-6-benzyl oxy-
methyl)hexahydropyrrolo[1,2-b]isoxazol-2-yl] ethanone (11). This
compound was obtained from nitrone 4 in 64% (312 mg) yield as
118e121 ꢀC; Rf (EtOAc/CH3OH 4:1) 0.3; IR (KBr): nmax 3300 (OH) cmꢁ1
.
1H NMR (CDCl3)
d
: 1.13 (d, J¼6.4 Hz, 3H, CH3),1.35 (s, 3H, CH3),1.52 (s,
25
a pale yellow oil; Rf (hexane/EtOAc 3:1) 0.6; [
a
]
þ77.2 (c 6.7,
3H, CH3), 1.68 (dt, J¼13.2, 6.7 Hz, 1H, 8-H), 2.47 (ddd, J¼13.2, 8.3,
6.7 Hz, 1H, 8-H), 2.53 (br s, 1H, OH), 2.63 (qn, J¼6.4 Hz, 1H, 6-H), 3.16
(dd, J¼10.9, 4.6 Hz, 1H, 4-H), 3.26 (dd, J¼10.9, 5.6 Hz, 1H, 4-H), 3.59
(ddd, J¼8.3, 6.7, 3.2 Hz,1H, 8a-H), 3.93(psq, SJ¼19.8 Hz,1H, 7-H), 4.58
(dd, J¼6.2, 3.2 Hz,1H, 8b-H), 4.90 (ddd as q, SJ¼16.4 Hz,1H, 3a-H).13C
D
CHCl3); IR (liquid film): nmax 1710 (CO) cmꢁ1. 1H NMR (CDCl3/C6D6
4:1)
d
: 1.93 (ddd, J¼12.8, 8.8, 2.9 Hz, 1H, 3-H), 2.15 (s, 3H, COCH3),
2.69 (ddd, J¼12.8, 8.7, 3.7 Hz, 1H, 3-H), 3.51 (dd, J¼5.6, 3.7 Hz, 1H, 4-
H), 3.55e3.62 (m,1H, 3a-H), 3.66e3.77 (m, 2H, CH2O), 3.82e3.92 (m,
2H, 5-H and 6-H), 3.95 (dd, J¼8.8, 3.7 Hz,1H, 2-H), 4.32e4.53 (m, 6H,
NMR (CDCl3) d: 18.6, 25.4 and 27.5 (CH3), 38.0 (C-8), 58.2, 68.0, 68.6,
CH2Ph), 7.10e7.30 (m, 15H, PheH). 13C NMR (CDCl3)
d: 25.2 (CH3),
78.6, 80.9 and 87.2 (C-3a, C-4, C-6, C-7, C-8a and C-8b), 112.8 (C-2).
36.3 (C-3), 67.6, 69.4, 69.7, 71.8, 72.5, 73.1, 78.6, 80.8 and 81.7 (C-2, C-
3a, C-4, C-5, C-6, CH2O and CH2Ph), 127.5, 127.7, 127.8, 127.9, 128.2,
128.3, 128.4, 137.5, 137.7 and 138.1 (CePh), 211.8 (CO). MS (m/z, %):
510 [100, (MþNa)þ]. Anal. Calcd for C30H33NO5: C, 73.90; H, 6.82; N,
2.87%. Found: C, 73, 77; H, 6.90; N, 2.71%.
HRESIMS for C11H20NO3 (MþH)þ: calcd 214.1443, found 214.1437.
4.3.1.3. (3aSR, 6RS, 7SR, 8aRS, 8bRS)-2,2-6-Trimethyl hexa hydro-
4H-[1,3]dioxolo[4,5-a]pyrrolizin-7-ol (15). This compound was ob-
tained from cycloadduct 7 in 48% yield (31 mg as a mixture with 16
determined from 1H NMR and 10 mg separately as a white solid, mp
142e144 ꢀC); Rf (EtOAc/CH3OH 4:1) 0.2; IR (KBr): nmax 3450 (OH)
4.2.1.7. 1-[((2R, 3aR, 4S, 5R, 6R)-4,5-Bis(benzyloxy)-6-benzyl oxy-
methyl)hexahydropyrrolo[1,2-b]isoxazol-2-yl] ethanone (12). This
cmꢁ1
.
1H NMR (CDCl3)
d
: 1.33 (s, 3H, CH3), 1.42 (d, J¼6.6 Hz, 3H,
compound was obtained from nitrone 4 in 32% yield (156 mg) as
CH3), 1.59 (s, 3H, CH3), 2.01 (ddd, J¼13.9, 8.6, 4.7 Hz, 1H, 8-H), 2.53
(dd, J¼13.9, 8.3 Hz, 1H, 8-H), 2.88e2.98 (m, 1H, 6-H), 3.23 (dd,
J¼13.0, 6.2 Hz, 1H, 4-H), 3.40 (br s, 1H, OH), 3.55 (dd, J¼13.00,
4.7 Hz, 1H, 4-H), 4.23 (t, J¼4.7 Hz, 1H, 7-H), 4.38 (ddd, J¼8.6, 8.3,
4.7 Hz, 1H, 8a-H), 4.56 (dd, J¼5.5, 3.0 Hz, 1H, 8b-H), 4.80 (ddd as q,
25
a pale yellow oil; Rf (hexane/EtOAc 3:1) 0.4; [
a
]
ꢁ7.6 (c 2.8,
D
CHCl3); IR (liquid film): nmax 1710 (CO) cmꢁ1
.
1H NMR (CDCl3)
d:
2.12e2.28 (overlapped s and m, 4H, 3-H and COCH3), 2.69 (ddd,
J¼12.1, 7.5, 4.4 Hz, 1H, 3-H), 3.53 (q, J¼4.5 Hz, 1H, 6-H), 3.68 (d,
J¼4.5 Hz, 2H, CH2O), 3.83 (dt, J¼9.0, 4.4 Hz, 1H, 3a-H), 3.92e3.03
(m, 2H, 4-H and 5-H), 4.50e4.68 (m, 6H, CH2Ph and 2-H), 4.77 (d,
J¼11.8 Hz, 1H, CH2Ph) 7.22e7.44 (m, 15H, PheH). 13C NMR (CDCl3)
SJ¼16.4 Hz, 1H, 3a-H). 13C NMR (CDCl3)
d: 11.9, 25.4 and 27.4 (CH3),
38.7 (C-8), 55.7, 69.0, 69.2, 74.6, 80.1 and 85.4 (C-3a, C-4, C-6, C-7, C-
8a and C-8b), 114.1 (C-2). HRESIMS for C11H20NO3 (MþH)þ: calcd
214.1443, found 214.1448.
d
: 26.0 (CH3), 32.9 (C-3), 65.7, 69.6, 70.1, 72.5, 73.1, 73.4, 77.1, 79.0
and 82.5 (C-2, C-3a, C-4, C-5, C-6, CH2O and CH2Ph), 127.5, 127.6,
127.7, 127.8, 128.2, 128.3, 128.4, 137.9, 138.0 and 138.2 (CePh),
207.9 (CO). MS (m/z, %): 510 [100, (MþNa)þ]. Anal. Calcd for
C30H33NO5: C, 73.90; H, 6.82; N, 2.87%. Found: C, 73.88; H, 6.97;
N, 2.63%.
4.3.1.4. (3aSR, 6RS, 7SR, 8aRS, 8bRS)-2,2-6-Trimethylhexa hydro-
4H-[1,3]dioxolo[4,5-a]pyrrolizin-7-ol (16). This compound was ob-
tained from cycloadduct 7 in 37% yield (22 mg as a mixture with 15
determined from 1H NMR and 10 mg separately as a white solid, mp
145e147 ꢀC); Rf (EtOAc/CH3OH 4:1) 0.1; IR (KBr): nmax 3450 (OH)
4.3. Reductive amination of compounds 6e12
cmꢁ1. 1H NMR (CDCl3)
d
: 1.13 (d, J¼6.4 Hz, 3H, CH3),1.33 (s, 3H, CH3),
1.56 (s, 3H, CH3), 1.89 (ddd, J¼14.0, 7.7, 5.0 Hz, 1H, 8-H), 2.04 (br s,
1H, OH), 2.28 (dd, J¼14.0, 8.0 Hz, 1H, 8-H), 2.63e2.73 (m, 1H, 6-H),
3.08 (dd, J¼13.0, 6.1 Hz, 1H, 4-H), 3.18 (dd, J¼13.00, 4.7 Hz, 1H, 4-H),
3.8 (ddd as td, SJ¼19.2 Hz, 1H, 8a-H), 4.13 (dd as t, SJ¼8.1 Hz, 1H, 7-
H), 4.42 (dd, J¼6.2, 3.5 Hz, 1H, 8b-H), 4.87 (ddd as q, SJ¼17.0 Hz, 1H,
4.3.1. General procedure. The cycloaddition product 6, 7, 8, 9, 10, 11,
or 12 (0.4 mmol) was dissolved in methanol (5 mL), a catalytic
amount of Pd/C (a spatula tip) was added and the reaction mixture
was stirred for two days under a hydrogen atmosphere at room
temperature. After, the crude reaction mixture was passed over
Celite and concentrated. The residue was chromatographed on
a silica gel column with ethyl acetateemethanol (4:1) (for the re-
actions of 6e8), ethyl acetate (for the reactions of 9, 10) or ethyl
acetateehexane (1:1) (for the reactions of 11, 12) as the eluent.
From the reactions of 6e8 there were isolated two diastereomeric
products 13/14, 15/16 and 17/18, respectively partially separately
and partially as a mixture. From the reactions of 9e12 only one
product was isolated, 19e22, respectively.
3a-H). 13C NMR (CDCl3)
d: 14.3, 25.4 and 27.6 (CH3), 39.1 (C-8), 56.7,
55.4, 69.1, 75.7, 81.3 and 87.3 (C-3a, C-4, C-6, C-7, C-8a and C-8b),
112.9 (C-2). HRESIMS for C11H20NO3 (MþH)þ: calcd 214.1443, found
214.1435.
4.3.1.5. (2S, 3R, 6S, 7S, 7aS)-6,7-Bis(benzyloxy)-3-methylhexa
hydro-1H-pyrrolizin-2-ol (17). This compound was obtained from
cycloadduct 8 in 69% yield (77 mg as a mixture with 18 determined
from 1H NMR and 20 mg separately as a pale yellow oil); Rf (EtOAc/
CH3OH 4:1) 0.2; IR (liquid film): nmax 3300 (OH) cmꢁ1 1H NMR
.
4.3.1.1. 1-(3aSR, 6RS, 7RS, 8aRS, 8bRS)-2,2-6-Trimethyl hexa hy-
dro-4H-[1,3]dioxolo[4,5-a]pyrrolizin-7-ol (13). This compound was
obtained from cycloadduct 6 in 49% yield (42 mg) as a white solid,
mp 108e111 ꢀC; Rf (EtOAc/CH3OH 4:1) 0.2; IR (KBr): nmax 3300 (OH)
(CDCl3)
d
: 1.41 (d, J¼6.6 Hz, 3H, CH3), 2.03 (br s, 1H, OH), 2.28e2.38
(m, 2H, 1-H), 3.32 (dd, J¼11.0, 3.1 Hz, 1H, 5-H), 3.50 (d, J¼11.0, 1H, 5-
H), 3.62e3.72 (m, 1H, 3-H), 4.02 (d, J¼5.0 Hz, 1H, 7-H), 4.10e4.20
(m, 2H, 2-H and 6-H), 4.43 (d, J¼12.0 Hz, 1H, CH2Ph), 4.49e4.71 (m,
3H, 7a-H and CH2Ph), 4.77 (d, J¼12.0 Hz, 1H, CH2Ph), 7.17e7.49 (m,
cmꢁ1
.
1H NMR (CDCl3)
d: 1.26 (d, J¼7.0 Hz, 3H, CH3), 1.30 (s, 3H,
CH3), 1.53 (s, 3H, CH3), 1.57 (ddd, J¼14.4, 8.4, 2.8 Hz, 1H, 8-H), 2.41
(ddd, J¼14.4, 9.2, 7.1 Hz, 1H, 8-H), 3.09 (d, J¼11.6, 1H, 4-H), 3.18 (qd,
J¼7.1, 4.7 Hz, 1H, 6-H), 3.33 (dd, J¼11.6, 4.9 Hz, 1H, 4-H), 3.47 (br s,
1H, OH), 3.53 (ddd as t, SJ¼17.6 Hz, 1H, 8a-H), 4.26 (ddd, J¼7.1, 4.7,
2.8 Hz, 1H, 7-H), 4.56 (d, J¼6.0 Hz, 1H, 8b-H), 4.80 (ddd as t,
10H, PheH). 13C NMR (CDCl3)
d: 9.9 (CH3), 32.4 (C-1), 49.7 (C-5),
62.4, 67.1, 71.4, 73.6, 74.2, 80.4 and 81.3 (C-2, C-3, C-6, C-7, C-7a and
CH2Ph), 127.9, 128.0, 128.2, 128.6, 128.9, 129.0, 135.8 and 137.1
(CePh). HRESIMS for C22H28NO3 (MþH)þ: calcd 354.2069, found
354.2061.

P. Gkizis et al. / Tetrahedron 69 (2013) 8921e8928
8927
4.3.1.6. (2S, 3S, 6S, 7S, 7aS)-6,7-Bis(benzyloxy)-3-methylhexa
hydro-1H-pyrrolizin-2-ol (18). This compound was obtained from
cycloadduct 8 in 26% yield (27 mg as a mixture with 17 determined
from 1H NMR and 10 mg separately as a pale yellow oil); Rf (EtOAc/
compound was obtained from cycloadduct 12 in 83% yield (157 mg)
25
as a pale yellow oil; Rf (hexane/EtOAc 1:1) 0.3; [
a
]
ꢁ8.1 (c 2.28,
D
CHCl3); IR (liquid film): nmax 3380 (OH) cmꢁ1 1H NMR (CDCl3)
.
d:
1.21 (d, J¼6.9 Hz, 3H, CH3), 2.20 (br s, 1H, OH), 2.38 (dd, J¼18.8,
8.9 Hz, 1H, 1-H), 2.72 (ddd, J¼18.8, 3.4, 1.5 Hz, 1H, 1-H), 3.19e3.28
(m, 2H, 3-H and 5-H), 3.60 (t, J¼4.5 Hz, 2H, CH2OPh), 3.71 (dt, J¼8.9,
3.4 Hz, 1H, 7a-H), 3.96 (t, J¼3.4 Hz, 1H, 7-H), 4.11 (dd, J¼8.1, 3.4 Hz,
1H, 6-H), 4.49e4.68 (m, 6H, CH2Ph and 2-H), 4.74 (d, J¼11.8 Hz, 1H,
CH3OH 4:1) 0.1; IR (liquid film): nmax 3280 (OH) cmꢁ1 1H NMR
.
(CDCl3)
d
: 1.51 (d, J¼6.8 Hz, 3H, CH3), 1.93 (dd, J¼14.0, 3.2 Hz, 1H,
1-H), 2.03 (br s, 1H, OH), 2.35 (ddd, J¼14.0, 10.7, 5.9 Hz, 1H, 1-H),
3.32e3.58 (m, 3H, 3-H and 5-H), 3.96e4.07 (m, 1H, 7a-H), 4.13 (t,
J¼4.9 Hz, 1H, 7-H), 4.21e4.36 (m, 2H, 2-H and 6-H), 4.53e4.70 (m,
CH2Ph), 7.20e7.40 (m, 15H, PheH). 13C NMR (CDCl3)
d: 17.8 (CH3),
4H, CH2Ph), 7.21e7.49 (m, 10H, PheH). 13C NMR (CDCl3)
d: 10.2
35.6 (C-1), 60.2, 68.1, 69.8, 71.9, 73.1, 73.2, 73.3, 73.4, 78.5 and 84.0
(C-2, C-3, C-5, C-6, C-7, C-7a and CH2Ph), 127.3, 127.4, 127.5, 127.6,
127.7, 127.9, 128.1, 128.2, 128.3, 137.8, 138.2 and 138.3 (CePh).
HRESIMS for C30H35NNaO4 (MþNa)þ: calcd 496.2464, found
496.2469.
(CH3), 38.4 (C-1), 49.8 (C-5), 63.2, 67.0, 72.3, 73.2, 74.5, 82.6 and
86.7 (C-2, C-3, C-6, C-7, C-7a and CH2Ph), 127.8, 128.0, 128.1, 128.3,
128.5, 128.7, 136.8 and 137.5 (CePh). HRESIMS for C22H28NO3
(MþH)þ: calcd 354.2069, found 354.2073.
4.3.1.7. (2R, 3R, 5R, 6R, 7R, 7aR)-6,7-Bis(benzyloxy)-5-(benzyl
oxymethyl)-3-methylhexahydro-1H-pyrrolizin-2-ol (19). This com-
pound was obtained from cycloadduct 9 in 85% yield (160 mg) as pale
4.4. Deprotection of isopropylidene group
4.4.1. General procedure. The pyrrolizidine 13 or 14 (0.1 mmol) was
dissolved in methanol (2 mL), p-toluenesulfonic acid (0.2 mmol)
was added and the reaction mixture was stirred at room temper-
ature for 5 h. After the acid was neutralized by addition of potas-
sium carbonate and the formed solids were removed by filtration.
The solvent was evaporated from the filtrate and the residue was
chromatographed on a silica gel column with methanol as eluent.
yellow oil; Rf (EtOAc) 0.4; [
a
]
25 ꢁ20.9 (c 2.78, CHCl3); IR (liquid film):
D
nmax 3300 (OH) cmꢁ1. 1H NMR (CDCl3)
d: 1.32 (d, J¼6.4 Hz, 3H, CH3),
1.78 (dd, J¼14.6, 3.7 Hz,1H,1-H), 2.01 (br s,1H, OH), 2.29 (ddd, J¼14.6,
10.4, 6.2 Hz, 1H, 1-H), 3.08e3.20 (m, 1H, 3-H), 3.41 (d, J¼7.7 Hz, 2H,
CH2OPh), 3.67 (dd, J¼10.4, 3.7 Hz, 1H, 7a-H), 3.85 (t, J¼7.7, 1H, 5-H),
3.90e3.98(brm,1H,2-H), 4.08(s,1H, 7-H), 4.12(s,1H,6-H), 4.41e4.62
(m, 6H, CH2Ph), 7.15e7.37 (m, 15H, PheH). 13C NMR (CDCl3)
d: 11.8
(CH3), 39.8(C-1), 62.8, 62.85, 68.6, 71.3, 71.8, 73.0, 73.1, 75.3, 85.9 and
88.2(C-2, C-3, C-5, C-6, C-7, C-7aand CH2Ph),127.4, 127.6, 128.0,128.0,
128.1, 128.2, 128.3, 137.0, 138.0 and 138.5 (CePh). HRESIMS for
C30H36NO4 (MþH)þ: calcd 474.2644, found 474.2651.
4.4.1.1. (1RS, 2SR, 5RS, 6RS, 7aRS)-5-Methylohexahydro-1H-pyr-
rolizine-1,2,6-triol (23). This compound was obtained from pyrro-
lizidine 13 in 93% yield (16 mg) as a colourless oil; Rf (CH3OH) 0.2; IR
(liquid film): nmax 3420 (OH) cmꢁ1 1H NMR (CD3OD)
. d: 1.17 (d,
J¼6.2 Hz, 3H, CH3), 1.65 (dt, J¼12.5, 8.6 Hz, 1H, 7-H), 2.43 (dt, J¼125,
6.6 Hz, 1H, 7-H), 2.49e2.59 (br m, 1H, 5-H), 2.89 (dd, J¼11.5, 4.1 Hz,
1H, 3-H), 3.06 (dd, J¼11.5, 3.9 Hz, 1H, 3-H), 3.38e3.46 (br m, 1H, 7a-
H), 3.75 (ddd as q, SJ¼23.0 Hz, 1H, 6-H), 3.91 (t, J¼5.2 Hz 1H, 1-H),
4.3.1.8. (2S, 3R, 5R, 6R, 7R, 7aR)-6,7-Bis(benzyloxy)-5-(benzyl
oxymethyl)-3-methylhexahydro-1H-pyrrolizin-2-ol (20). This com-
pound was obtained from cycloadduct 10 in 80% yield (151 mg) as
25
a pale yellow oil; Rf (EtOAc) 0.3; [
a
.
]
ꢁ31.1 (c 1.28, CHCl3); IR
4.26 (ddd as q, SJ¼13.2 Hz, 1H, 2-H). 13C NMR (CD3OD)
d: 17.4 (CH3),
D
(liquid film): nmax 3350 (OH) cmꢁ1
1H NMR (CDCl3)
d
: 1.19 (d,
38.3 (C-7), 58.5 (C-3), 66.6, 69.7, 73.3, 78.6 and 79.4 (C-1, C-2, C-5, C-
6 and C-7a). HRESIMS for C8H16NO3 (MþH)þ: calcd 174.1130, found
174.1138.
J¼6.4 Hz, 3H, CH3), 1.97 (ddd, J¼13.4, 8.5, 4.5 Hz, 1H, 1-H), 2.19 (dt,
J¼13.4, 7.6 Hz, 1H, 1-H), 2.48 (br s, 1H, OH), 3.14 (qd, J¼6.4, 3.5 Hz,
1H, 3-H), 3.25 (dt, J¼7.5, 3.3 Hz, 1H, 5-H), 3.49e3.61 (m, 2H,
CH2OPh), 3.84e3.98 (m, 2H, 7-H and 7a-H), 4.08e4.17 (m, 2H, 2-H
4.4.1.2. (1RS, 2SR, 5SR, 6RS, 7aRS)-5-Methylohexahydro-1H-pyr-
rolizine-1,2,6-triol (24). This compound was obtained from pyrro-
lizidine 14 in 90% yield (16 mg as white solid, mp 112e114 ꢀC); Rf
kai 6-H), 4.41e4.62 (m, 6H, CH2Ph), 7.15e7.45 (m, 15H, PheH). 13
C
NMR (CDCl3) d: 14.4 (CH3), 39.9 (C-1), 66.8, 67.3, 68.3, 71.4, 71.8,
72.1, 73.3, 75.9, 87.0 and 88.8 (C-2, C-3, C-5, C-6, C-7, C-7a and
CH2Ph), 127.3, 127.4, 127.5, 127.6, 127.7, 127.9, 128.0, 128.1, 128.2,
138.0, 138.3 and 138.5 (CePh). HRESIMS for C30H36NO4 (MþH)þ:
calcd 474.2644, found 474.2641.
(CH3OH) 0.1; IR (KBr): nmax 3425 (OH) cmꢁ1 1H NMR (CD3OD)
. d:
1.30 (d, J¼7.0 Hz, 3H, CH3), 1.86 (ddd, J¼14.8, 3.2, 1.8 Hz, 1H, 7-H),
2.17 (ddd, J¼14.8, 8.4, 5.1 Hz,1H, 7-H), 2.86 (dd, J¼10.7, 2.4,1H, 3-H),
2.96e3.05 (m, 1H, 5-H), 3.38e3.49 (m, 2H, 3-H, 7a-H), 4.11 (dd,
J¼6.3, 4.1, 1H, 1-H), 4.14e4.25 (m, 2H, 2-H, 6-H). 13C NMR (CD3OD)
4.3.1.9. (2S, 3S, 5R, 6R, 7S, 7aS)-6,7-Bis(benzyloxy)-5-(benzyl
oxymethyl)-3-methylhexahydro-1H-pyrrolizin-2-ol (21). This com-
d: 11.0 (CH3), 39.3 (C-7), 53.8 (C-3), 62.3, 68.9, 73.7, 76.5 and 80.2 (C-
1, C-2, C-5, C-6 and C-7a). HRESIMS for C8H16NO3 (MþH)þ: calcd
pound was obtained from cycloadduct 11 in 83% yield (157 mg) as
174.1130, found 174.1128.
25
a pale yellow oil; Rf (hexane/EtOAc 1:1) 0.4; [
a
]
D
þ2.1 (c 4.85,
CHCl3); IR (liquid film): nmax 3380 (OH) cmꢁ1.1H NMR (CDCl3)
d
: 1.12
4.5. Deprotection of benzyl group
(d, J¼6.3 Hz, 3H, CH3),1.35 (ddd, J¼13.1,10.2, 6.0 Hz,1H,1-H),1.89 (br
s, 1H, OH), 2.41 (ddd, J¼13.1, 7.0, 6.0 Hz, 1H, 1-H), 2.49 (qn, J¼6.3 Hz,
1H, 3-H), 2.82 (ddd as q, SJ¼14.0 Hz, 1H, 5-H), 2.88 (ddd, J¼8.7, 7.0,
6.0 Hz 1H, 7a-H), 3.44 (dd, J¼10.1, 5.8 Hz, 1H, CH2OPh), 3.56 (dd,
J¼10.1, 4.2 Hz,1H, CH2OPh), 3.65 (dd, J¼8.7, 6.3 Hz,1H, 7-H), 4.08 (dd,
J¼6.3, 4.0 Hz, 1H, 6-H), 4.24 (ddd as q, SJ¼22.5 Hz, 1H, 2-H),
4.49e4.65 (m, 5H, CH2Ph), 4.74 (d, J¼12.0 Hz, 1H, CH2Ph), 7.22e7.42
4.5.1. General procedure. To a vial equipped with a screw cap there
were added a solution of pyrrolizidine 19 or 21 (0.1 mmol) in
methanol (2 mL) and a catalytic amount Pd/C (a spatula tip) was
added. A balloon, filled with hydrogen was adapted to the reaction
flask by means of a septum. After repeated evacuations and flash-
ings with hydrogen gas the vial was closed and it was heated at
70 ꢀC for two days. After the reaction mixture was passed over
Celite and concentrated to give compounds 25 or 26 in satisfactory
pure form.
(m, 15H, PheH). 13C NMR (CDCl3)
d: 14.1 (CH3), 37.4 (C-1), 60.6, 66.1,
69.0, 70.9, 71.7, 72.1, 73.2, 77.5, 79.4 and 83.3 (C-2, C-3, C-5, C-6, C-7,
C-7a and CH2Ph), 127.3, 127.4, 127.5, 127.6, 127.7, 127.9, 128.0, 128.1,
128.2, 138.0, 138.3 and 138.5 (CePh). HRESIMS for HRESIMS for
C30H35NNaO4 (MþNa)þ: calcd 496.2464, found 496.2465.
4.5.1.1. (1R, 2R, 3R, 5R, 6R, 7aR)-3-(Hydroxymethyl)-5-methyl
hexahydro-1H-pyrrolizine-1,2,6-triol (25). This compound was ob-
tained from pyrrolizidine 19 in 90% yield (18 mg as a pale yellow oil);
4.3.1.10. (2R, 3R, 5R, 6R, 7S, 7aR)-6,7-Bis(benzyloxy)-5-(benzyl
oxymethyl)-3-methylhexahydro-1H-pyrrolizin-2-ol
(22). This
[a]
25 ꢁ9.3 (c 6.2, CH3OH); IR (liquid film): nmax 3420 (OH) cmꢁ1. 1H
D

8928
P. Gkizis et al. / Tetrahedron 69 (2013) 8921e8928
Chem. 2005, 70, 7297e7304; (h) Chikkanna, D.; Singh, O. V.; Kong, S. B.; Han, H.
Tetrahedron Lett. 2005, 46, 8865e8868; (i) Dewi-Wulfing, P.; Blechert, S. Eur. J.
NMR (CD3OD)
d
: 1.51 (d, J¼6.9 Hz, 3H, CH3), 2.24 (br d, J¼13.8 Hz, 1H,
€
7H), 2.35 (ddd, J¼13.8, 9.3,4.6 Hz,1H,7-H), 3.29e3.39(m, 3H, 5-Hand
Org. Chem. 2006, 1852e1856; (j) Van Ameijde, J.; Horne, G.; Wormald, M. R.;
Dwek, R. A.; Nash, R. J.; Jones, P. W.; Evinson, E. L.; Fleet, G. W. J. Tetrahedron:
Asymmetry 2006, 17, 2702e2712; (k) Sletten, E. M.; Liotta, L. J. J. Org. Chem.
2006, 71, 1335e1343; (l) Cicchi, S.; Marradi, M.; Vogel, P.; Goti, A. J. Org. Chem.
2006, 71, 1614e1619; (m) Koch, D.; Maechling, S.; Blechert, S. Tetrahedron 2007,
63, 7112e7119; (n) Chandrasekhar, S.; Parida, B. B.; Rambabu, C. J. Org. Chem.
2008, 73, 7826e7828; (o) Sengoku, T.; Satoh, Y.; Oshima, M.; Takahashi, M.;
Yoda, H. Tetrahedron 2008, 64, 8052e8058; (p) Takahasi, M.; Maehara, T.;
Sengoku, T.; Fujita, N.; Takabe, K.; Hoda, H. Tetrahedron 2008, 64, 5254e5261;
(q) Brandi, A.; Cardona, F.; Cicchi, S.; Cordero, F. M.; Goti, A. Chem.dEur. J. 2009,
15, 7808e7821; (r) Bonaccini, C.; Chioccioli, M.; Parmeggiani, C.; Cardona, F.; Lo
Re, D.; Soldaini, G.; Vogel, P.; Bello, C.; Goti, A.; Gratteri, P. Eur. J. Org. Chem.
CH2OH), 3.63e4.04(m, 3H,1-H, 3-Hand7a-H), 4.20e4.36(m, 2H, 2-H
and 6-H). 13C NMR (CD3OD)
d: 10.5 (CH3), 37.5 (C-7), 58.4 (C-3), 66.6,
66.9 (C-5, CH2OH), 71.1, 74.7, 76.3 and 80.7 (C-1, C-2, C-6 and C-7a).
HRESIMS for C9H18NO4 (MþH)þ: calcd 204.1236, found 204.1235.
4.5.1.2. (1S, 2R, 3R, 5S, 6S, 7aS)-3-(Hydroxymethyl)-5-methyl
hexahydro-1H-pyrrolizine-1,2,6-triol (26). This compound was ob-
tained from pyrrolizidine 21 in 90% yield (18 mg as a pale yellow oil);
[a]
25 ꢁ7.2 (c 4.0, CH3OH); IR (liquid film): nmax 3560, 3300 (OH) cmꢁ1
.
D
ꢀꢀ
ꢁ
ꢀ
ꢀ ꢀ
2010, 5574e5585; (s) Podolan, G.; Klescíkova, L.; Fisera, L.; Kozísek, J.; Fronc, M.
Synlett 2011, 1668e1672; (t) Ritthiwigrom, T.; Au, C. W. G.; Pyne, S. G. Curr. Org.
Synth. 2012, 9, 583e612.
1H NMR (CD3OD)
d: 1.35 (d, J¼6.5 Hz, 3H, CH3),1.98 (ddd, J¼13.2, 9.4,
1.4 Hz,1H, 7-H), 2.60 (ddd, J¼13.2, 7.6, 5.1 Hz,1H, 7-H), 3.00 (dt, J¼5.4,
3.3 Hz, 1H, 3-H), 3.17 (dq, J¼4.0, 6.5 Hz, 1H, 5-H), 3.52e3.57 (m, 1H,
7a-H), 3.85 (dd, J¼11.1, 3.3 Hz,1H, CH2OH), 3.92 (dd, J¼11.1, 3.3 Hz, 1H,
CH2OH), 4.05 (br, 1H, 1-H), 4.31e4.42 (m, 2H, 2-H and 6-H). 13C NMR
4. (a) Pandey, G.; Chakrabarti, D. Tetrahedron Lett. 1996, 37, 2285e2288; (b)
ꢂ
Hakansson, A. E.; Ameijde, J.; Horne, G.; Nash, R. J.; Wormald, M. R.; Kato,
A.; Besra, G. S.; Gurcha, S.; Fleet, G. W. J. Tetrahedron Lett. 2008, 49,
179e184; (c) Stecko, S.; Solecka, J.; Chmielewski, M. Carbohydr. Res. 2009,
344, 167e176; (d) Despiony, X. L. M.; McNab, H. Org. Biomol. Chem. 2009, 7,
4502e4511.
5. (a) Argyropoulos, N. G.; Panagiotidis, T.; Coutouli-Argyropoulou, E.; Raptopou-
lou, C. Tetrahedron 2007, 63, 321e330; (b) Argyropoulos, N. G.; Gkizis, P.; Cou-
touli-Argyropoulou, E. Tetrahedron 2008, 64, 8752e8758; (c) Argyropoulos, N.
G.; Gkizis, P.; Coutouli-Argyropoulou, E. ARKIVOC 2008, xvi, 223e234.
6. Coutouli-Argyropoulou, E.; Trakossas, S. Tetrahedron 2011, 67, 1915e1923 and
references cited therein.
(CD3OD) d: 15.6 (CH3), 33.1 (C-7), 63.1 (C-4), 66.0, 68.0 (C-5, CH2OH),
70.7, 73.7, 77.2 and 77.6 (C-1, C-2, C-6 and C-7a). HRESIMS for
C9H18NO4 (MþH)þ: calcd 204.1236, found 204.1235.
References and notes
€
7. (a) Hara, J.; Inouye, Y.; Kakisawa, H. B. Soc. Chem. Jpn. 1981, 54, 3871e3872; (b)
Lathbury, D.; Gallagher, T. J. Chem. Soc., Chem. Commun. 1986, 1017e1018; (c)
Cordero, F. M.; Brandi, A.; Cristilli, S.; De Sarlo, F.; Viti, G. Tetrahedron 1994, 50,
12713e12726.
1. (a) Imino Sugars as Glycosidase Inhibitors, Nojirimicin and Beyond; Stutz, A. E., Ed.;
Wiley-VCH: Weinheim, Germany, 1999; (b) Lillelund, V. H.; Jensen, H. H.; Liang,
X.; Bols, M. Chem. Rev. 2002, 102, 515e553; (c) Martin, O. R.; Compain, P. Curr.
Top. Med. Chem. 2003, 3, ieiv; (d) Lopez, M. D.; Cobo, J.; Nogueras, M. Curr. Org.
Chem. 2008, 12, 718e750; (e) Gloster, T. M.; Davies, G. J. Org. Biomol. Chem. 2010,
8, 305e320; (f) Gloster, T. M. Biochem. Soc. T. 2012, 40, 913e918.
2. (a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry
2000, 11, 1645e1680; (b) Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.;
Nash, R. J. Phytochemistry 2001, 56, 265e295; (c) Kato, A.; Kano, E.; Adachi, I.;
Molyneux, R. J.; Watson, A. A.; Nash, R. J.; Fleet, G. W. J.; Wormald, M. R.; Kizu, H.;
Ikeda, K.; Asano, N. Tetrahedron: Asymmetry 2003, 14, 325e331; (d) Kato, A.;
Kato, N.; Adachi, I.; Hollinshead, J.; Fleet, G. W. J.; Kuriyama, C.; Ikeda, K.; Asano,
N.; Nash, R. J. J. Nat. Prod. 2007, 70, 993e997.
3. (a) Denmark, S. E.; Hurd, A. R. J. Org. Chem. 2000, 65, 2875e2886; (b) Schie-
weck, F.; Altenbach, H.-J. J. Chem. Soc., Perkin Trans. 1 2001, 3409e3414; (c)
Rabiczko, J.; Urbanczyk-Lipkowska, Z.; Chmielewski, M. Tetrahedron 2002, 58,
1433e1441; (d) Behr, J.-B.; Erard, A.; Guillerm, G. Eur. J. Org. Chem. 2002,
1256e1262; (e) Toyao, A.; Tamura, O.; Takagi, H.; Ishibashi, H. Synlett 2003,
35e38; (f) Carmona, A. T.; Fuentes, J.; Vogel, P.; Robina, I. Tetrahedron: Asym-
metry 2004, 15, 323e333; (g) Donohoe, T. J.; Sintim, H. O.; Hollinshead, J. J. Org.
8. (a) Kotsuki, H.; Miyazaki, A.; Ochi, M. Tetrahedron Lett. 1991, 32, 4503e4504; (b)
Goti, A.; Cicchi, S.; Cacciarini, M.; Cardona, F.; Fedi, V.; Brandi, A. Eur. J. Org. Chem.
€
2000, 3633e3645; (c) Cicchi, S.; Hold, I.; Brandi, A. J. Org. Chem. 1993, 58,
5274e5275; (d) Carmona, A. T.; Wightman, R. H.; Robina, I.; Vogel, P. Helv. Chim.
Acta 2003, 86, 3066e3073; (e) Holzapfel, C. W.; Crous, R. Heterocycles 1998, 48,
1337e1342; (f) Tsou, E.-L.; Yeh, Y.-T.; Liang, P.-H.; Cheng, W.-C. Tetrahedron 2009,
65, 93e100.
9. (a) Izquierdo, I.; Plaza, M. T.; Franco, F. Tetrahedron: Asymmetry 2002, 13,
1581e1585; (b) Izquierdo, I.; Plaza, M. T.; Franco, F. Tetrahedron: Asymmetry
2003, 14, 3933e3935; (c) Izquierdo, I.; Plaza, M. T.; Franco, F. Tetrahedron:
Asymmetry 2004, 15, 1465e1469; (d) Izquierdo, I.; Plaza, M. T.; Tamayo, J. A.
Tetrahedron: Asymmetry 2004, 15, 3635e3642; (e) Izquierdo, I.; Plaza, M. T.;
Tamayo, J. A.; Rodríguez, M.; Martos, A. Tetrahedron 2006, 62, 6006e6011; (f)
ꢁ
Izquierdo, I.; Plaza, M. T.; Tamayo, J. A.; Franco, F.; Sanchez-Cantalejo, F. Tetra-
ꢁ
hedron 2010, 66, 3788e3794; (g) Tamayo, J. A.; Franco, F.; Sanchez-Cantalejo, F.
Eur. J. Org. Chem. 2011, 7182e7188.