Synthesis of polyhydroxylated 7-aminopyrrolizidines and 8-aminoindolizidines

Article abstract of DOI:10.1016/j.tet.2009.06.043

The ammonolysis of a lactone moiety in tricyclic cycloadducts derived from non-racemic five-membered cyclic nitrone and 2(5H)-furanones furnishes an amido function, which after subsequent Hofmann rearrangement, leads to a protected amino group attached to

Full text of DOI:10.1016/j.tet.2009.06.043

Tetrahedron 65 (2009) 7056–7063
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Synthesis of polyhydroxylated 7-aminopyrrolizidines and 8-aminoindolizidines
Sebastian Stecko a, Margarita Jurczak a, Olga Staszewska-Krajewska a, Jolanta Solecka b,
,
Marek Chmielewski a
*
a Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
b National Institute of Public HealthdNational Institute of Hygiene, Chocimska 24, 01-791 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
The ammonolysis of a lactone moiety in tricyclic cycloadducts derived from non-racemic five-membered
cyclic nitrone and 2(5H)-furanones furnishes an amido function, which after subsequent Hofmann re-
arrangement, leads to a protected amino group attached to the bicyclic isoxazolidine skeleton. A suc-
cessive simple transformation, involving cleavage of N–O bond followed by intramolecular N-alkylation,
provides an access to the polyhydroxylated 7-aminopyrrolizidines and 8-aminoindolizidines, potential
glycosidases inhibitors.
Received 25 March 2009
Received in revised form 28 May 2009
Accepted 11 June 2009
Available online 18 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
Although, there are numerous strategies applicable to the
synthesis of simple amino-pyrrolizidine and amino-indolizidine
Compounds containing the amino-pyrrolizidine and amino-
indolizidine motifs are widespread in nature.1,2 Their potential
bioactivity as antidepressant, analgesic, antiviral, antibacterial, or
antitumor agents makes them a particularly attractive synthetic
alkaloids,2g,h,m,6 examples reporting preparation of their poly-
hydroxylated analogues, such as amino-iminosugars, are limited.7–12
The indolizidines 6 and 7 were synthesized by Tyler and co-
workers through modification of the castanospermine structure.7
O
O
H
H
OAc
N
N
MeHN
O
H
N
H
N
H
N
H
N
H2N
OMe
HO
1
E-isomer, absouline
3
4
5
laburnamine
loline
slaframine
2 Z -isomer, isoabsouline
H2N
R
NHAc
TolHN
MeO
H2N
OH
H
H
H
H
OSiMe2t-Bu
OH
HO
HO
OH
N
N
N
N
HO
6
7
9
10
R: OH
8 R: H
target for academic and industrial research laboratories. This trend
can be exemplified by the recent reports of syntheses of absouline 1
and its geometric isomer 2,3 laburnamine 3,4 loline 4,5 and slafr-
amine 5.2h,m
On the other hand, Pandey and co-workers8 synthesized the 1-
deoxy derivative of 6 (8) via a photoinduced electron transfer
radical cyclization of pyrrolidine with a chiral acetylene derived
from tartaric acid. It is noteworthy, that compound 8 is a weak
inhibitor of almonds’ b-glucosidase, whereas alkaloid 6 displays no
activity. Recently, Alcaide and Almendros9 presented the asym-
metric synthesis of highly functionalized indolizidine systems
based on the combination of the aza-Diels–Alder reaction of
* Corresponding author. Tel.: þ48 22 631 87 88; fax: þ48 22 632 66 81.
E-mail address: chmiel@icho.edu.pl (M. Chmielewski).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.043

S. Stecko et al. / Tetrahedron 65 (2009) 7056–7063
7057
O
H2N
H2N
H2N
HO
(OR2)x
(OR2)x
(OH)x
n( )
n( )
N
N
N
Hofmann
rearrangement
n( )
n: 1,2
O
LG
O
LG
B
reductive cleavage
A
amonolysis
O
O
O
(OR2)x
O
(OR2)x
[3+2]
+
N
R1
O
N
O
R1
R1: H, CH2OH; R2 : protecting group
C
Scheme 1.
2-azetidinone-tethered imines and subsequent rearrangement of
the 2-azetidinone ring. Following this strategy, compound 9 and its
8a-epimer were obtained.9 A similar synthetic approach has also
been applied for the synthesis of 7-amino-indolizidine de-
rivatives.10 Another example of amino-iminosugar is the amino
analogue of swansonine (10) synthesized by Hashimoto and co-
workers.11
Recognizing the potential of unexplored biological activity of
amino-iminosugars7 and our ongoing research program directed at
the search for novel glycomimetics,8 we have developed an
attractive strategy of the synthesis for 7-amino-pyrrolizidines and
8-amino-indolizidines. In contrast to the known literature pro-
tocols7,8 of amino-iminosugars synthesis, the amino function is
introduced at the early stage of the synthesis, prior to the formation
of the pyrrolizidine or indolizidine skeleton. The general approach
is depicted in Scheme 1. Both types of amino alkaloids can be
obtained from the amino-isoxazolidine A by N–O bond cleavage,
followed by intramolecular N-alkylation. The aminoisoxazolidine A
can be derived from the amide B. The attractive precursor of B is the
cycloadduct C easily accessible by the 1,3-dipolar cycloaddition
reaction between a five-membered cyclic nitrone and 2(5H)-fur-
anone. The cycloaddition step is the most important for the entire
synthesis because of the formation of three new stereogenic cen-
ters. The proper selection of cycloaddition components enables the
The synthesis of 11 was carried out following the steps shown in
Scheme 3. The cycloadduct 15a was obtained as a single product by
the 1,3-dipolar cycloaddition between nitrone 14 and lactone 13a,
following the protocol developed in our group.14a Treatment of
lactone 15a with ammonia gave amide 16 in 75% yield. Initially, the
7 N solution of ammonia in methanol was used. However, during
the scale-up optimization steps, it was found that a better result
could be obtained when the lactone, dissolved in small amount of
MeOH, is treated with liquid ammonia. After opening of the lactone
moiety, the free hydroxy group in 16 was silylated immediately to
avoid a re-cyclization process leading back to the starting lactone.
The protection of the hydroxyl group also prevents the intra-
molecular cyclization, which may occur during the next step
(Hofmann rearrangement). The treatment of the amide 17 with
PhI(OAc)2 in MeOH,15 led to the Hofmann rearrangement with the
retention of configuration at C-3 and the methoxycarbonyl pro-
tected amine 18 was obtained in 80% yield. The configuration at C-3
in 18 was proved by J2,3¼6.3 Hz and spin–spin interaction between
H-2 and H-3 protons (NOE). Unfortunately, this protocol worked
only when the reaction was carried out in MeOH leading to the N-
Moc derivative. Replacement of MeOH by t-BuOH or BnOH failed,
and the starting material was recovered. The analogous procedure
involving PhI(CF3COO)2 in acetonitrile/water mixture did not suc-
ceed either.16 On the other hand, the standard Hofmann rear-
rangement conditions (RONa or NaOH, Br2 in ROH) caused the
decomposition of the substrate. Similarly, the other protocol, in-
volving treatment of 17 with Pb(OAc)4 in DMF in presence of t-
BuOH17 was not successful.
formation of the initial cycloadduct with
a high diaster-
eoselectivity14 and provides an entry to the stereocontrolled syn-
thesis of a highly functionalized amino-azabicycloalkanes.
The desilylation of 18 with tetrabutylammonium fluoride in THF
followed by mesylation led to the mesylate 19, which was hydro-
genated under atmospheric pressure in the presence of palladium
on charcoal. The resulted pyrrolizidine was isolated as the acetate
20. Subsequently, the tert-butyl protection in 20 was removed by
treatment with trifluoroacetic acid and both hydroxy groups were
acetylated to give 21, which was easily purified by chromatography.
2. Results and discussion
To demonstrate the applicability of our methodology, we syn-
thesized the amino-iminosugars 11 and 12 that belong to the pyr-
rolizidine and indolizidine groups, respectively (Scheme 2). These
compounds may also be regarded as potential glycosidase
inhibitors.
MocHN
HO
OH
H
R: H
OH
OH
O
N
Ot-Bu
H
Ot-Bu
Ot-Bu
H
N
O
toluene
Ref. 14a
R
O
O
11
+
Ot-Bu
N
MocHN
HO
R
OH
O
H
H
O
13a
14
15a
R: H
R: H
R: CH2OH
N
13b R: CH2OH
15b R: CH2OH
HO
12
Scheme 2.

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S. Stecko et al. / Tetrahedron 65 (2009) 7056–7063
O
O
N
RO
NHMoc
H
MocHN
AcO
Ot-Bu
Ot-Bu
O
H
N
RO
NH2
H
H
e
a
c
O
H
H
Ot-Bu
O
O
N
Ot-Bu
Ot-Bu
N
Ot-Bu
18 R=SiPh2t-Bu
20
Ot-Bu
Ot-Bu
16 R=H
15a
d
b
17
19
f
R=SiPh2t-Bu
R=Ms
MocHN
HO
OH
MocHN
AcO
OAc
OAc
H
H
g
OH
N
N
11
21
Scheme 3. Reactants and conditions: (a) NH3 (liquid), MeOH, rt, 75%; (b) t-BuPh2SiCl, imidazole, CH2Cl2, ꢀ15 ꢁC then rt, 91%; (c) PhI(OAc)2, MeOH, rt, 80%; (d) i. TBAF, THF, rt, ii.
MsCl, Et3N, CH2Cl2, ꢀ15 ꢁC then rt; (e) i. H2, Pd/C, AcOEt/MeOH (4:1), rt; ii. Ac2O, Et3N, 0 ꢁC then rt, 65% (4 steps); (f) i. CF3COOH, rt; ii. Ac2O, Et3N, 0 ꢁC then rt, 79% (2 steps); (g) 1%
NH3 in MeOH, rt, 85%.
The final deacetylation using a protocol well established by our
group13 (1% NH3 in MeOH) gave the desired amino-pyrrolizidine 11
in 24% overall yield.
a revision of the original cyclization strategy leading to the indoli-
zidine skeleton. Initially, desilylation of the primary hydroxyl group
followed by its mesylation was planned. In the case of 25, however,
to avoid the unwanted migration of the acetyl group from the sec-
ondary hydroxyl to the primary one, the desilylation, and deace-
tylation sequence were performed to provide diol 26 in 80% yield.
Subsequently, diol 26 was submitted to the reaction sequence
leading to formation of the indolizidine skeleton. The mesylation
using 1 equiv of MsCl, followed by hydrogenolysis and acetylation
gave the desired indolizidine 27 in 62% yield but with a low purity.
Additionally, a small quantity of compound 28 was isolated as a by-
product. This compound, derived from the dimesylate of diol 26,
was not stable, and underwent decomposition within a few days.
Because of the unsatisfactory result of the presented trans-
formations, several alternate strategies of cyclization were
considered.
An alternative approach assumed a reductive cleavage of the
N–O bond in 26 followed by the intramolecular cyclization under
Mitsunobu conditions. Unexpectedly, this bond turned out to be
relatively strong and hydrogenolysis under standard conditions did
not proceed at all (Pd/C, H2, 1.5 bar). Another reduction method,
involving the treatment with zinc in acetic acid19 also failed. Finally,
when hydrogenolysis was carried out under elevated pressure (Pd/
C in EtOH, 60 bar) the desired aminoalcohol 29 was obtained, albeit
only in a 50% yield after 7 days. The subsequent Mitsunobu reaction
The synthesis of indolizidine 12 is shown in Scheme 4. The
starting 15b was obtained by the cycloaddition of nitrone 14 and
lactone 13b according to the reported procedure.14a After pro-
tection of the free hydroxy group in 15b with a tert-butyldiphenyl-
silyl group,13g the lactone 22 was treated with liquid ammonia.
Next, the free hydroxyl group in 23 was immediately protected to
avoid the re-cyclization process. According to the planned synthetic
sequence, the benzyl group was chosen as the most attractive
protection, which could be easily removed during hydrogenolysis
of the N–O bond step. The standard benzylation of 23, however, did
not succeed and only the re-cyclization product 15b was formed
with further N-benzylation and decomposition.13h On the other
hand, the benzylation carried out under neutral conditions by
treatment with Dudley’s reagent13h,18 did not proceed as expected
and the starting material was recovered. Finally, this problem was
resolved by acetylation of hydroxyl group in 23, which led to the
amide 24 in 91% yield.
The Hofmann rearrangement carried out with 24 and PhI(OAc)2
in MeOH led to the N-Moc protected amine 25 in 83% yield. As for
18, the configuration at C-3 in 25 was proved by J2,3¼4.4 Hz and
spin–spin interaction between H-2 and H-3 protons (NOE). The
presence of acetyl protection at the C-10 hydroxyl group forced
R1O
OR2
[Si]O
OR
O
N
MocHN
AcO
NHMoc
H
O
Ot-Bu
CONH2
H
H
N
RO
H
H
H
H
e or f or g
a
c
O
Ot-Bu
H
Ot-Bu
O
O
N
Ot-Bu
Ot-Bu
N
AcO
Ot-Bu
R1=[Si], R2=Ac
27
Ot-Bu
Ot-Bu
15b
R=H
23 R=H
25
b
d
Ref. 13g
h
24 R=Ac
22
26 R1=R2=H
R=[Si]=SiPh2t-Bu
Ot-Bu
Ot-Bu
MocHN
AcO
MocHN
HO
MocHN
AcO
MocHN
HO
H
OAc
OH
Ot-Bu
H
N
H
N
H
i
OAc
OH
HN
Ot-Bu
HO
N
OH
AcO
HO
MsO
28
29
12
30
Scheme 4. Reagents and conditons: (a) NH3 (liquid), MeOH, rt, 70%; (b) Ac2O, Et3N, 0 ꢁC then rt, 91%; (c) PhI(OAc)2, MeOH, rt, 83%; (d) i. TBAF, THF, rt, ii. 1% NH3 in MeOH, rt, 80%; (e)
i. CBr4, PPh3, CH2Cl2, 0 ꢁC then rt, ii. H2, Pd/C, EtOH, iii. Ac2O, Et3N, 0 ꢁC then rt, 70% (3 steps); (f) MsCl, Et3N, CH2Cl2, ii. H2, Pd/C, EtOH, iii. Ac2O, Et3N, 0 ꢁC then rt, 62% (3 steps); (g)
H2, Pd/C, 60 bar, EtOH, ii. DEAD, PPh3, THF, iii. Ac2O, Et3N, 0 ꢁC then rt, 10% (3 steps); (h) i. CF3COOH, rt, ii. Ac2O, Et3N, 0 ꢁC rt, 86% (2 steps); (i) 1% NH3 in MeOH, rt, 75%.

S. Stecko et al. / Tetrahedron 65 (2009) 7056–7063
7059
with 29 followed by the acetylation gave a poor yield of 27 (less
then 20%, overall after 3 steps 10%).
25 with TBAF in THF gave the primary alcohol 34 which immedi-
ately underwent intramolecular acetyl migration leading to the
secondary alcohol 35. The crude alcohol 35 was treated with mesyl
chloride to afford mesylate 36, which was hydrogenated in the
presence of Pd/C causing cleavage of the N–O bond followed by the
intramolecular alkylation of nitrogen atom. The crude 7-amino-
pyrrolizidine was acetylated and purified as acetate 37. The com-
parison of its 1H NMR spectra with that of 27 confirmed the
presence of the pyrrolizidine skeleton in acetate 37. Finally, the
pyrrolizidine 37 was transformed into target molecule 31 applying
the standard deprotection sequence described before. The overall
yield of the process from 15b, was ca. 16% (11 steps).
The best yield of 27 was achieved applying the third alternate
cyclization strategy involving the Appel reaction followed by
hydrogenolysis and acetylation. Here, the desired indolizidine 27
was obtained in a 70% yield (3 steps) and with a high purity.
Subsequently, the tert-butyl groups were removed by treatment
with CF3COOH and the product was isolated after acetylation as
compound 30. The final deacetylation was carried out as previously
described (1% NH3 in MeOH) affording the target indolizidine 12 in
a 19% overall yield starting from 15b.
Recently, we have demonstrated that compound 22 is notonlyan
attractive substrate for the synthesis of polyhydroxylated indolizi-
dines but also provides an entry to the pyrrolizidine class of imi-
nosugars.13g–i This can be achieved by changing the cyclization step
strategy.13g–i We decided to apply the new strategy to prepare the 7-
aminopyrrolizidine 31 from 25. For this purpose, the acetate 25 was
submitted to selective deprotection of the secondary hydroxyl
group by treatment with 10% ammonia solution in methanol
(Scheme 5). Subsequently, the alcohol 32 was treated with mesyl
chloride. Unexpectedly, this reaction did not proceed as expected
under standard condition and starting material was recovered. The
same result was also observed when the reaction was performed in
neat MsCl as a solvent and DMAP as a base. The elevation of reaction
temperature from ambient to 40 ꢁC caused consumption of the
starting material, but only a trace of the desired product 33 was
noticed. As a result, a complex mixture of unidentified products was
obtained. The failure of mesylation at low temperature can be
explained due to the steric hindrance, which restricts an access to
the hydroxy group. The elevated reaction temperature may initially
lead tothe formation of expected mesyl product, but simultaneously
it also promotes the participation of neighboring substituents,
which likely cause further reactions, involving nucleophilic sub-
stitution or elimination, leading finally to decomposition.
The resulting amino-iminosugars (11, 12 and 31) were tested
as potential inhibitors of several standard glycosidase enzymes:
a
D
-
L
-fucosidase (bovine kidney),
-glucuronidase (bovine liver),
dase (almond), and -mannosidase (jack bean). Unfortunately,
only compound 31 displayed weak activity toward one of tested
enzymes (inhibition of -galactosidase IC50 0.9 mM). It must be
b
-
D
D
-galactosidase (bovine liver),
b-
a-
-glucosidase (rice), -glucosi-
b-D
a-D
b-D
stressed, however, that the bicyclic amino-iminosugars are still
a relatively unexplored class of glycomimetics and the relation
between their substitution patterns, their absolute configuration
and their biological activity is hard to predict. The preliminary
unsatisfactory results do not exclude the possibility of finding
bioactivity in this class of compounds.
3. Conclusions
To conclude, we have established an attractive synthetic strat-
egy leading to the formation of amino-iminosugars. The strategy
involves the 1,3-dipolar cycloaddition between the five-membered
cyclic nitrone and 2(5H)-furanones, ammonolysis of the lactone
moiety and Hofmann rearrangement as the key steps. The general
value of this method was demonstrated by the synthesis of poly-
hydroxy-alkaloids with both indolizidine and pyrrolizidine
skeleton.
To overcome these difficulties we decided to modify the reaction
sequence and start with the removal of the silyl protection. The
altered route leading to 31 is outlined in Scheme 5. The treatment of
OR
[Si]O
NHMoc
H
H
a
25
O
Ot-Bu
N
[Si] = SiPh2t-Bu
Ot-Bu
c
b
32 R = H
33 R = Ms
OAc
OR
HO
AcO
MocHN
AcO
Ot-Bu
Ot-Bu
NHMoc
H
NHMoc
H
N
H
H
e
H
O
O
Ot-Bu
Ot-Bu
Ot-Bu
N
N
AcO
Ot-Bu
37
35
R = H
d
34
36 R = Ms
f
MocHN
HO
HO
OH
MocHN
AcO
OAc
OAc
H
N
H
N
g
OH
AcO
31
38
Scheme 5. Reagents and conditons: (a) 10% NH3 in MeOH, rt, 98%; (b) MsCl, Et3N, CH2Cl2 or MsCl, DMAP; (c) TBAF, THF, rt; 75%; (d) MsCl, Et3N, CH2Cl2, rt, 80%, 0 ꢁC then rt; (e) i. H2,
Pd/C, EtOH, rt, ii. Ac2O, Et3N, 0 ꢁC then rt, 70% (2 steps); (f) i. CF3COOH, rt, ii. Ac2O, Et3N, 0 ꢁC then rt, 85% (2 steps),(g) 1%NH3 in MeOH, 90%.

7060
S. Stecko et al. / Tetrahedron 65 (2009) 7056–7063
4. Experimental
6b), 1.22 (9H, s, t-Bu), 1.19 (9H, s, t-Bu), 1.02 (9H, s, t-Bu); 13C NMR
(125 MHz, benzen-d6) : 156.8,136.2,135.9,133.7,133.1,130.1,130.0,
d
4.1. General
127.9, 127.8, 80.9, 79.4, 77.4, 77.3, 74.2, 73.6, 62.6, 61.6, 60.9, 51.8,
28.8, 28.4, 26.9, 19.4; HRMS (ESI): m/z calcd for C33H50N2O6NaSi
[MþNaþ]: 621.3330; found: 621.3309. Anal. Calcd for C33H50N2O6Si:
C, 66.19; H, 8.42; N, 4.68. Found: C, 66.14; H, 8.40; N, 4.65.
1H and 13C NMR spectra were recorded on a Brucker DRX 500
Avance Spectrometer at 500 MHz and 125 MHz, respectively, using
deuterated solvents and TMS as an internal standard. Chemical
shifts are reported as
d
values in ppm and coupling constants are in
4.4. (1S,2S,6R,7R,7aS)-6-Acetoxy-1,2-di-tert-butoxy-7-
hertz. Proton assignment was done based on COSY experiments.
Infrared spectra were recorded on a FT-IR-1600 Perkin–Elmer
spectrophotometer. The optical rotations were measured with
JASCO J-2000 digital polarimeter. High-resolution mass spectra
were recorded on ESI-TOF Mariner Spectrometer (Perspective
Biosystem). Thin layer chromatography was performed on alu-
minium sheet Silica Gel 60 F254 (20ꢂ20ꢂ0.2) from Merck. Column
chromatography was carried out using Merck silica gel (230–400
mesh) and Florisil (100–200 mesh). All solvents were purified by
standard techniques.20
(methoxycarbonylamino)-pyrrolizidine (20)
A solution of TBAF (0.11 g, 0.36 mmol) in THF (5 mL) was added
to a solution of 18 (0.2 g, 0.33 mmol) in THF (5 mL). The progress of
reaction was monitored by TLC. Subsequently, solvent was removed
and residue was chromatographed on a silica gel (CH2Cl2/MeOH,
25:1 with 1% Et3N). Afforded alcohol was dissolved in CH2Cl2
(5 mL), Et3N was added (67 mg, 0.66 mmol) and after cooling to
ꢀ15 ꢁC, MsCl was added slowly (49 mg, 0.43 mmol). When sub-
strate was consumed, solvent was removed and residue was puri-
fied on a silica gel (CH2Cl2/MeOH, 25:1 with 1% Et3N). Obtained
mesylate 19, was immediately dissolved in mixture AcOEt/MeOH
(1:1, 10 mL), Pd/C was added (100 mg) and vigorously stirred so-
lution was saturated with hydrogen at atmospheric pressure. After
disappearance of mesylate, post-reaction mixture was filtrated
through Celite, and solvents were removed under diminished
pressure. Residue was dissolved in Et3N (5 mL), cooled and Ac2O
(2 mL) was added. After 1 h solvents were removed and residue
purified on a silica gel (CH2Cl2/MeOH, 25:1 with 1% Et3N) affording
4.2. (2S,3R,3aS,4S,5S)-4,5-Di-tert-butoxy-2-(tert-
butyldiphenylsilyloxymethyl)hexahydropyrrolo[1,2-
b]isoxazolo-3-carboxyamide (17)
A solution of compound 15a (0.31 g, 1.0 mmol) in MeOH (10 mL)
was put into ampoule (cooled to ꢀ20 ꢁC) equipped with dry-ice
condenser connected with ammonia bottle. After condensing of ca.
30 mL of liquid ammonia, the ampoule was closed and warmed up
to room temperature. After 48 h ammonia and MeOH were care-
fully removed and a residue was chromatographed on a silica gel
(CH2Cl2/MeOH, 30:1). Afforded amide 16 (0.25 g, 75%) was dis-
solved in CH2Cl2 (10 mL) and transferred to a solution of imidazole
(0.14 g, 2.0 mmol) in CH2Cl2 (10 mL). After cooling to ꢀ15 ꢁC, t-
BuPh2SiCl (0.25 g, 0.9 mmol) was added and obtained mixture was
stirred at room temperature till disappearance of starting alcohol
(TLC, CH2Cl2/MeOH, 1:1). Then solvent was removed and obtained
residue was purified on silica gel (CH2Cl2/MeOH, 30:1) affording
pyrrolizidine 20 (83 mg, 65%) as a yellowish oil. [
CH2Cl2); IR (film)
: 3325, 1730, 1723, 1239 cmꢀ1
(500 MHz, toluene-d8) : 5.30 (1H, br m, H-7), 5.19 (1H, m, H-6),
a
]
þ4.1 (c 0.35,
D
n
;
1H NMR
d
4.66 (1H, m, H-2), 4.32 (1H, br s, NH), 3.84 (1H, m, H-1), 3.51 (1H, dd,
J 8.5, 7.1 Hz, H-5a), 3.43 (3H, s, Me), 3.22 (1H, dd, J 11.4, 4.0 Hz, H-3a),
3.15 (1H, br d, J 8.5 Hz, H-5b), 3.07 (1H, m, H-7a), 2.61 (1H, dd, J 11.2,
2.4 Hz, H-3b), 1.61 (3H, s, Ac), 1.19 (9H, s, t-Bu), 1.11 (9H, s, t-Bu); 13C
NMR (125 MHz, toluene-d8) d: 170.2, 157.0, 80.2, 79.7, 76.9, 75.4,
74.0, 73.6, 60.3, 58.7, 57.3, 51.6, 28.7, 28.4, 19.9; HRMS (ESI): m/z
amide 17 (0.39 g, 91%) as a colourless oil. [
IR (film)
: 3330, 3190, 1670, 1112 cmꢀ1; 1H NMR (500 MHz, CDCl3)
: 7.70–7.25 (10H, Ar), 6.21 (1H, br s, CONHH), 5.19 (1H, br s,
a
]D þ42.1 (c 0.15, CH2Cl2);
calcd for C19H35N2O6 [MþHþ]: 387.2489; found: 387.2473.
n
d
4.5. (1S,2S,6S,7R,7aS)-1,2,6-Triacetoxy-7-
CONHH), 4.58 (1H, ddd, J 6.6, 5.8, 4.8 Hz, H-2), 3.95 (1H, dd, J 11.2,
4.8 Hz, CHHOSi), 3.90 (1H, ddd, J 6.0, 5.6, 2.3 Hz, H-5), 3.84 (1H, dd, J
11.2, 6.6 Hz, CHHOSi), 3.76–3.72 (2H, H-3a, H-4), 3.56 (1H, dd, J 12.4,
5.6 Hz, H-6a), 3.20 (1H, br d, J 5.8 Hz, H-3), 3.04 (1H, dd, J 12.4,
6.0 Hz, H-6b), 1.20 (9H, s, t-Bu), 1.18 (9H, s, t-Bu), 1.05 (9H, s, t-Bu);
(methoxycarbonylamino)-pyrrolizidine (21)
Pyrrolizidine 20 (55 mg, 0.14 mmol) was dissolved in CF3COOH
(5 mL) and stirred overnight. After removal of solvent under di-
minished pressure, residue was dissolved in Et3N (3 mL), cooled
and Ac2O (1 mL) was added slowly. After 1 h solvent was removed
and residue was chromatographed on a silica gel (hexane/AcOEt,
13C NMR (125 MHz,C6D6)
d: 172.5, 135.6, 135.5, 133.2, 133.1, 129.8,
129.7, 127.7, 127.6, 81.8, 78.4, 76.5, 74.8, 74.4, 74.3, 62.3, 61.5, 56.5,
28.8, 28.5, 26.8, 19.2; HRMS (ESI): m/z calcd for C32H48N2O5NaSi
[MþNaþ]: 591.3225; found: 591.3206. Anal. Calcd for C32H48N2O5Si:
C, 67.57; H, 8.51; N, 4.92. Found: C, 67.54; H, 8.48; N, 4.90.
1:4) affording pyrrolizidine 21 (40 mg, 79%) as a yellowish oil. [
þ9.1 (c 1.09, CH2Cl2); IR (film)
: 1731, 1723 cmꢀ1 1H NMR
(500 MHz, toluene-d8) : 5.48 (1H, m, H-7), 5.27 (1H, m, H-6), 5.20
a]
D
n
;
d
(1H, br s, NH), 5.12 (1H, q, H-2), 4.40 (1H, m, H-1), 3.44 (3H, s, Me),
3.39 (1H, dd, J 9.6, 6.7 Hz, H-5a), 3.28 (1H, dd, J 12.2, 5.0 Hz, H-3a),
3.13 (1H, dd, J 7.5, 2.0 Hz, H-7a), 2.76–2.65 (2H, H-3b, H-5b), 1.68
(3H, s, Ac), 1.65 (3H, s, Ac), 1.63 (3H, s, Ac); 13C NMR (125 MHz,
4.3. Methyl (2S,3R,3aS,4S,5S)-4,5-di-tert-butoxy-2-(tert-
butyldiphenylsilyloxymethyl)hexahydropyrrolo[1,2-
b]isoxazol-3-ylcarbamate (18)
toluene-d8) d: 170.1, 169.5, 169.2, 157.0, 80.2, 78.9, 77.3, 73.6, 59.2,
Diacetoxyiodobenzene (0.34 g, 1.06 mmol) was added to solu-
tion of amide 17 (0.3 g, 0.53 mmol) in MeOH (20 mL) and obtained
mixture was stirred at room temperature. The progress of reaction
was controlled by TLC. Then a solvent was removed and residue
was purified on a silica gel (hexane/AcOEt, 1:1) affording N-pro-
57.9, 57.5, 51.9, 30.3; HRMS (ESI): m/z calcd for C15H22N2O8Na
[MþNaþ]: 381.1274; found: 381.1269.
4.6. (1S,2S,6S,7R,7aS)-1,2,6-Trihydroxy-7-
(methoxycarbonylamino)-pyrrolizidine (11)
tected amine 18 (0.25 g, 80%) as a colourless oil. [
CH2Cl2); IR (film)
: 3325, 1725, 1113 cmꢀ1 1H NMR (500 MHz,
C6D6) : 8.00–7.20 (10H, Ar), 6.14 (1H, d, J 9.6 Hz, NH), 5.05 (1H, ddd,
J 9.6, 6.3, 4.3 Hz, H-3), 4.26 (1H, ddd, J 6.3, 3.9, 3.6 Hz, H-2), 4.18 (1H,
m, H-4), 3.98 (1H, dd, J 11.5, 3.9 Hz, CHHOSi), 3.89 (1H, ddd, J 6.1, 5.8,
3.7 Hz, H-5), 3.80 (1H, dd, J 11.5, 3.6 Hz, CHHOSi), 3.66 (1H, m, H-
3a), 3.62 (1H, dd, J 11.5, 5.8 Hz, H-6a), 2.95 (1H, dd, J 11.5, 6.1 Hz, H-
a
]
D þ43.5 (c 0.55,
n
;
Pyrrolizidine 21 (30 mg, 84 mmol) was dissolved in 5 mL of 1%
d
soln NH3 in MeOH and stirred overnight under argon atmosphere.
The progress of reaction was monitored by mass spectrometry.
After filtration through Florisil, solvent was removed affording
target pyrrolizidine 11 (16 mg, 85%) as yellowish oil. [
a]
ꢀ9.0 (c
D
0.49, MeOH); IR (film)
n
: 3330, 1720 cmꢀ1 1H NMR (500 MHz,
;

S. Stecko et al. / Tetrahedron 65 (2009) 7056–7063
7061
metanol-d4)
d
: 4.19 (1H, m, H-1), 4.11–4.06 (2H, H-2, H-6), 4.03 (1H,
in 1% soln of NH3 in MeOH (10 mL) and stirred 24 h. After removal
of solvent residue was chromatographed on a silica gel (hexane/
AcOEt, 1:1 then AcOEt 100%) affording diol 26 (91 mg, 80%) as
t, J 7.7 Hz, H-7), 3.65 (3H, s, Me), 3.24 (1H, dd, J 9.5, 5.8 Hz, H-5a),
3.18 (1H, dd, J 11.5, 4.6 Hz, H-3a), 3.03 (1H, dd, J 7.7, 3.2 Hz, H-7a),
2.90 (1H, dd, J 9.5, 8.3 Hz, H-5b), 2.85 (1H, dd, J 11.5, 4.0 Hz, H-3b);
a colourless oil. [ : 3363,
a]
þ94.3 (c 1.60, CH2Cl2); IR (film)
n
D
13C NMR (125 MHz, metanol-d4)
d
: 159.6, 81.3, 79.6, 76.3, 75.9, 62.2,
1708 cmꢀ1 1H NMR (500 MHz, metanol-d4)
;
d: 4.67 (1H, dd, J 5.1,
61.0, 60.4, 52.5; IR (film)
n
: 3330, 1720 cmꢀ1; HRMS (ESI): m/z calcd
2.5 Hz, H-3), 4.23 (1H, dd, J 7.6, 5.1 Hz, H-2), 4.02 (1H, dd, J 4.1,
3.9 Hz, H-4), 3.84 (1H, ddd, J 5.5, 5.3, 3.9 Hz, H-5), 3.74 (1H, ddd, J
7.6, 6.1, 3.5 Hz, H-10), 3.67–3.60 (4H, singlet for Me, and dd, J 11.5,
3.5 Hz, for H-20a), 3.52 (1H, dd, J 11.5, 6.1 Hz, H-20b), 3.45 (1H, dd, J
12.5, 5.5 Hz, H-6a), 3.29 (1H, dd, J 4.1, 2.5 Hz, H-3a), 2.95 (1H, dd, J
12.5, 5.3 Hz, H-6b), 1.22 (9H, s, t-Bu), 1.20 (9H, s, t-Bu); 13C NMR
for C9H17N2O5 [MþHþ]: 233.1132; found: 233.1143.
4.7. (2S,3R,3aS,4S,5S,10R)-20-(tert-Butyldiphenylsilyloxy)-10-
(4,5-di-tert-butoxy-3-carbamoylhexahydro-pyrrolo[1,2-
b]isoxazol-2-yl)ethyl acetate (24)
(125 MHz, metanol-d4) d: 159.2, 81.8, 80.4, 78.4, 77.5, 75.7, 70.5,
Ammonolysis of 22 (1.0 g, 1.72 mmol) was carried out in the
same way like for 17. After chromatographically purification on
a silica gel (CH2Cl2/MeOH, 25:1 with 1% Et3N) 0.72 g (70%) of amide
23 was obtained. This compound was immediately dissolved in
Et3N (25 mL), cooled and Ac2O (10 mL) was added slowly. After 3 h
solvents were removed and residue was chromatographed on
a silica gel (AcOEt 100%) affording amide 24 (0.7 g, 91%) as a col-
65.0, 62.5, 61.6, 52.7, 29.1, 28.8; HRMS (ESI): m/z calcd for
C18H35N2O7 [MþHþ]: 391.2444; found: 391.2440. Anal. Calcd for
C18H35N2O7$H2O: C, 52.93; H, 8.88; N, 6.82. Found: C, 52.90; H,
8.86; N, 6.81.
4.10. (1S,2S,6R,7S,8R,8aS)-6,7-Diacetoxy-1,2-di-tert-butoxy-8-
(methoxycarbonylamino)-indolizidine (27)
ourless oil. [
a
]
D
þ38.5 (c 0.65, CH2Cl2); IR (film)
n
: 3416, 1747,
1639 cmꢀ1 1H NMR (500 MHz, C6D6)
;
d
: 8.00–7.20 (10H, Ar), 5.66
A solution of CBr4 (0.12 g, 0.36 mmol) in CH2Cl2 (2 mL) was
added to cooled solution of diol 26 (90 mg, 0.28 mmol) in CH2Cl2
(5 mL) containing Ph3P (95 mg, 0.36 mmol). After consumption the
substrate solvent was removed and residue was dissolved in EtOH
and 10% Pd/C (100 mg) was added. Obtained solution was saturated
with hydrogen under atmospheric pressure. Subsequently, post-
reaction mixture was filtered through Celite and solvent was re-
moved. Residue was dissolved in Et3N (2 mL), cooled and Ac2O was
added (1 mL). After 1 h solvents were removed and residue purified
on a silica gel (hexane/AcOEt, 1:1) affording diacetate 27 (75 mg,
(1H, s, NH), 5.50 (1H, ddd, J 8.9, 4.8, 2.6 Hz, H-10), 5.37 (1H, s, NH),
4.90 (1H, dd, J 8.9, 6.2 Hz, H-2), 4.24 (1H, dd, J 11.4, 2.6 Hz, H-20a),
4.09 (1H, dd, J 11.4, 4.8 Hz, H-20b), 3.87 (1H, dd, J 4.5, 2.6 Hz, H-3a),
3.77 (1H, ddd, J 6.0, 5.1, 4.1 Hz, H-5), 3.72 (1H, dd, J 4.5, 4.1 Hz, H-4),
3.42 (1H, dd, J 12.1, 5.1 Hz, H-6a), 3.37 (1H, dd, J 6.2, 2.6 Hz, H-3),
3.07 (1H, dd, J 12.1, 6.0 Hz, H-6b), 1.96 (3H, s, Ac), 1.19 (9H, s, t-Bu),
1.05 (9H, s, t-Bu), 0.95 (9H, s, t-Bu); 13C NMR (125 MHz, C6D6, car-
bon atoms of Ph groups omitted) d: 172.5, 169.2, 82.6, 77.6, 75.6,
75.5, 74.1, 73.7, 72.3, 64.4, 61.6, 57.6, 28.8, 28.4, 27.1, 20.7, 19.6;
HRMS (ESI): m/z calcd for C35H52N2O7SiNa [MþNaþ]: 663.3436;
found: 663.3453. Anal. Calcd for C35H52N2O7Si: C, 65.59; H, 8.18; N,
4.37. Found: C, 65.54; H, 8.13; N, 4.36.
70%) as a colourless oil. [
a]
D ꢀ20.1 (c 0.94, CH2Cl2); IR (film)
n: 3363,
: 5.29 (1H, ddd, J
1746, 1708 cmꢀ1; 1H NMR (500 MHz, toluene-d8)
d
3.1, 2.7, 1.7 Hz, H-6), 4.65 (1H, dd, J 10.4, 3.1 Hz, H-7), 4.44 (1H, m, H-
8), 4.33 (1H, br s, NH), 4.07 (1H, dd, J 6.3, 2.6 Hz, H-1), 3.72 (1H, ddd,
J 6.3, 2.6, 2.0 Hz, H-2), 3.45 (3H, s, MeO), 2.87 (1H, dd, J 9.7, 2.0 Hz,
H-3b), 2.83 (1H, dd, J 13.1, 2.7 Hz, H-5a), 2.27 (1H, dd, J 9.7, 6.3 Hz,
H-3b), 2.00 (1H, dd, J 13.1, 1.7 Hz, H-5b), 1.82 (4H, H-8a, Ac), 1.71
(3H, s, Ac), 1.19 (9H, s, t-Bu), 1.03 (9H, s, t-Bu); 13C NMR (125 MHz,
4.8. (2S,3R,3aS,4S,5S,10R)-20-(tert-Butyldiphenylsilyloxy)-10-
(4,5-di-tert-butoxy-3-(methoxycarbonyl-amino)hexa-
hydropyrrolo[1,2-b]isoxazol-2-yl)ethyl acetate (25)
Diacetoxyiodobenzene (0.3 g, 0.94 mmol) was added to a solu-
tion of amide 24 (0.3 g, 0.47 mmol) in MeOH (20 mL) and stirred at
room temperature. The progress of reaction was monitored by TLC.
After disappearance of substrate MeOH was removed and residue
was chromatographed on a silica gel (hexane/AcOEt, 4:1 then 1:1)
toluene-d8) d: 170.0, 156.4, 83.5, 79.2, 74.6, 74.1, 73.5, 68.9, 60.3,
52.9, 51.6, 29.1, 29.0, 20.5, 20.4; HRMS (ESI): m/z calcd for
C22H38N2O8Na [MþNaþ]: 481.2526; found: 481.2521.
4.11. (1S,2S,6R,7S,8R,8aS)-1,2,6,7-Tetraacetoxy-8-
affording amide 25 (0.26 g, 83%) as colourless oil. [
CH2Cl2); IR (film)
3333, 1747, 1724, 1255 cmꢀ1
(500 MHz, C6D6) : 7.9–7.20 (10H, Ar), 5.95 (1H, d, J 10.3 Hz, NH),
5.47 (1H, dd, J 10.3, 4.4 Hz, H-3), 5.02 (1H, ddd, J 9.1, 4.9, 2.5 Hz, H-
10), 4.68 (1H, dd, J 9.1, 4.4 Hz, H-2), 4.16 (1H, dd, J 11.4, 2.5 Hz, H-20a),
4.01 (1H, dd, J 11.4, 4.9 Hz, H-20b), 3.87–3.77 (2H, H-4, H-5), 3.57
(1H, dd, J 11.4, 5.7 Hz, H-6a), 3.49 (4H, H-3a, MeO), 3.03 (1H, dd, J
11.4, 7.2 Hz, H-6b), 2.03 (3H, s, Ac), 1.19 (9H, s, t-Bu), 1.11 (9H, s, t-
Bu), 0.98 (9H, s, t-Bu); 13C NMR (125 MHz, C6D6, carbon atoms of Ph
a
]
þ4.4 (c 5.3,
(methoxycarbonylamino)-indolizidine (30)
D
n
:
;
1H NMR
d
Indolizidine 27 (50 mg, 0.11 mmol) was dissolved in CF3COOH
(2 mL) and stirred overnight. Subsequently, solvent was removed
under diminished pressure and residue was acetylated affording,
after chromatography on a silica gel (AcOEt/hexane, 5:1), indolizi-
dine 30 (40 mg, 86%) as a colourless oil. [
a
]
D ꢀ25.8 (c 0.73, CH2Cl2);
IR (film) d:
n
: 3363,1739,1713,1232 cmꢀ1; 1H NMR (500 MHz, C6D6)
5.58 (1H, dd, J 7.6, 2.5 Hz, H-6), 5.31 (1H, m, H-2), 5.13 (1H, dd, J 5.5,
2.5 Hz, H-7), 4.79 (1H, m, H-1), 4.32 (1H, m, H-8), 3.35 (3H, s, MeO),
2.76–2.63 (2H, H-3a, H-5a), 2.26 (1H, m, H-3b), 1.95–1.80 (2H, H-5b,
H-8a), 1.82 (3H, s, Ac), 1.77 (3H, s, Ac), 1.76 (3H, s, Ac), 1.67 (3H, s,
groups omitted) d: 169.3, 156.5, 81.1, 78.6, 76.1, 75.1, 74.1, 73.6, 70.4,
64.6, 61.1, 60.3, 28.9, 28.4, 27.0, 21.1, 19.6; HRMS (ESI): m/z calcd for
C36H54N2O8SiNa [MþNaþ]: 693.3542; found: 693.3562. Anal. Calcd
for C36H54N2O8Si: C, 64.45; H, 8.11; N, 4.18. Found: C, 64.40; H, 8.08;
N, 4.17.
Ac); 13C NMR (125 MHz, C6D6)
d: 170.5, 170.0, 169.8, 169.7, 156.3,
80.4, 77.5, 72.4, 68.5, 67.8, 57.7, 52.3, 51.5, 51.4, 20.0, 19.9, 19.8, 19.7;
HRMS (ESI): m/z calcd for C18H26N2O10Na [MþNaþ]: 453.1480;
found: 453.1486.
4.9. Methyl (2S,3R,3aS,4S,5S,10R)-4,5-Di-tert-butoxy-2-(-10,20-
dihydroxyethyl)hexahydro-pyrrolo[1,2-b]isoxazol-3-
ylcarbamate (26)
4.12. (1S,2S,6R,7S,8R,8aS)-1,2,6,7-Tetrahydroxy-8-
(methoxycarbonylamino)-indolizidine (12)
A solution of tetrabutylammonium fluoride (0.14 g, 0.43 mmol)
in THF (5 mL) was added to a solution of amide 25 (0.25 g,
0.36 mmol) in THF (15 mL). After consumption of substrate, solvent
was removed under diminished pressure and residue was dissolved
Indolizidine 30 (40 mg, 93 mmol) was dissolved in 1% soln of
NH3 in MeOH (5 mL) and stirred at room temperature under argon
atmosphere. The progress of reaction was controlled by mass

7062
S. Stecko et al. / Tetrahedron 65 (2009) 7056–7063
spectrometry. After filtration through Florisil, solvent was removed
affording indolizidine 12 (18 mg, 75%) as a colourless oil. [
D ꢀ33.0
(c 0.64, MeOH); IR (film)
: 3363, 1713 cmꢀ1 1H NMR (500 MHz,
metanol-d4) : 3.98 (1H, br d, J 6.7 Hz, H-1), 3.90–3.84 (2H, H-2, H-
6), 3.77 (1H, m, H-7), 3.37 (1H, dd, J 10.5, 2.7 Hz, H-8), 3.34 (3H, s,
MeO), 3.01 (1H, dd, J 12.1, 2.5 Hz, H-5a), 2.80 (1H, br d, J 10.1 Hz, H-
3a), 2.56 (1H, dd, J 10.1, 5.3 Hz, H-3b), 2.31 (1H, br d, J 12.1 Hz, H-5b),
1.84 (1H, dd, J 10.4, 6.7 Hz, H-8a); 13C NMR (125 MHz, metanol-d4)
argon atmosphere. The progress of reaction was controlled by
mass spectrometry. After filtration through Florisil, solvent was
removed affording pyrrolizidine 31 (21 mg, 90%) as a colourless
a
]
n
;
d
oil. [
a
]
þ0.7 (c 1.0, CH2Cl2); IR (film)
n ;
: 3334, 1748 cmꢀ1 1H
D
NMR (500 MHz, CD3OD) d: 4.10–3.98 (3H, H-1, H-2, H-6), 3.93
(1H, dd, J 11.5, 5.9 Hz, CHHOH), 3.88 (1H, dd, J 11.5, 6.6 Hz,
CHHOH), 3.35 (3H, s, MeO), 3.21 (1H, dd, J 9.3, 8.0 Hz, H-3a), 3.14
(1H, ddd, J 6.6, 5.9, 4.0 Hz, H-5), 3.08 (1H, dd, J 9.3, 5.8 Hz, H-3b),
d
: 160.1, 83.9, 79.7, 75.0, 73.7, 70.2, 60.6, 56.1, 55.3; HRMS (ESI): m/z
3.03 (1H, dd, J 5.8, 4.0 Hz, H-7a); 13C NMR (125 MHz, CD3OD)
d:
calcd for C10H19N2O6 [MþHþ]: 263.1238; found: 263.1231.
159.2, 81.9, 79.9, 77.9, 76.0, 66.5, 64.0, 58.6, 53.5, 52.6; HRMS
(ESI): m/z calcd for C10H18N2O6Na [MþNaþ]: 285.1057; found:
285.1045.
4.13. (1S,2S,5S,6S,7R,7aS)-6-Acetoxy-5-acetoxymethyl-1,2-di-
tert-butoxy-7-(methoxycarbonylamino)-pyrrolizidine (37)
References and notes
A solution of tetrabutylammonium fluoride (0.14 g, 0.43 mmol)
in THF (5 mL) was added to a solution of amide 25 (0.25 g,
0.36 mmol) in THF (15 mL). After consumption of substrate, sol-
vent was removed under diminished pressure and residue was
chromatographed on a silica gel (EtOAc/hexane 4:1). Resulting
alcohol 35 (0.27 mmol, 75% yield) was dissolved in CH2Cl2 (5 mL)
and Et3N (60 mg, 0.60 mmol) was added. After cooling to ꢀ15 ꢁC
MsCl (34 mg, 0.30 mmol) was added dropwise. After 3 h solvent
was removed and residue was chromatographed through short
silica gel pad (AcOEt/hexane 1:1) to afford mesylate 36 (110 mg,
80%) which was immediately used in next step. Its solution in
AcOEt (5 mL) containing 10 mg of 10% Pd/C was saturated with
hydrogen under atmospheric pressure. After 24 h reaction mixture
was filtered and solvent was removed. Residue was dissolved in
Et3N (1 mL), cooled and Ac2O (0.5 mL) was added. After 1 h solvent
was removed and residue was chromatographed on a silica gel
(EtOAc/hexane 9:1) to afford pyrrolizidine 37 as a yellowish oil.
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213–234.
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5. (a) Blakemore, P. R.; Schulze, V. K.; White, J. W. Chem. Commun. 2000, 1263–
1264; (b) Schardel, C.; Grossman, R. B.; Nagabhzru, P.; Faulkner, J. R.; Mallik,
U. P. Phytochemistry 2007, 68, 980–996.
6. (a) Foresti, E.; Calmieri, G.; Petrini, M.; Profeta, R. Org. Biomol. Chem. 2003, 1,
4275–4281; (b) Albano, V. G.; Gualandi, A.; Monari, M.; Savoia, D. J. Org. Chem.
2008, 73, 8376–8381; (c) Broggini, G.; La Rosa, C.; Pilati, T.; Terraneo, A.; Zecchi,
G. Tetrahedron 2001, 57, 8322–8332.
[
a
]
þ34.4 (c 0.45, CH2Cl2); IR (film)
n
: 3360, 1740, 1235 cmꢀ1
;
1H
D
NMR (500 MHz, C6D6)
d: 5.46–5.34 (3H, H-1, H-2, H-6), 4.67 (1H, s,
NH), 4.42 (1H, dd, J 11.5, 6.5 Hz, CHHOAc), 4.34 (1H, dd, J 11.5,
6.7 Hz, CHHOAc), 4.15 (1H, m, H-7), 3.60 (1H, m, H-5), 3.39 (3H, s,
MeO), 3.12 (1H, m, H-3a), 3.04 (1H, m, H-7a), 2.92 (1H, m, H-3b),
1.75 (3H, s, Ac), 1.58 (3H, s, Ac), 1.19 (9H, s, t-Bu), 1.08 (9H, s, t-Bu);
13C NMR (125 MHz, C6D6)
d: 170.4, 170.0, 168.4, 81.1, 79.6, 73.9,
73.5, 66.1, 61.5, 61.0, 53.4, 52.6, 51.9, 28.9, 28.6, 22.8, 20.5, 20.3;
HRMS (ESI): m/z calcd for C22H38N2O8Na [MþNaþ]: 481.2520;
found: 481.2534.
4.14. (1S,2S,5S,6S,7R,7aS)-1,2,6-Triacetoxy-5-(acetoxymethyl)-
7. Furneaux, R. H.; Gainsford, G. J.; Mason, J. M.; Tyler, P. Tetrahedron 1995, 51,
12611–12630.
7-(methoxycarbonylamino)-pyrrolizidine (38)
8. Pandey, G.; Dumbre, S.; Pal, S.; Khan, M.; Shabab, M. Tetrahedron 2007, 63,
4756–4761.
9. Alcaide, B.; Almendros, P.; Alonso, J. M.; Aly, M. F. Chem.dEur. J. 2003, 9,
3415–3426.
10. Alcaide, B.; Almendros, P.; Redondo, M. C.; Ruiz, M. P. J. Org. Chem. 2005, 70,
8890–8894.
Pyrrolizidine 37 (50 mg, 0.11 mmol) was dissolved in CF3COOH
(2 mL) and stirred overnight. Subsequently, solvent was removed
under diminished pressure and residue was acetylated affording,
after chromatography on a silica gel (AcOEt/hexane, 6:1), pyrro-
lizdine 38 (40 mg, 85%) as a colourless oil. [
CH2Cl2); IR (film)
: 3354, 1742, 1234 cmꢀ1 1H NMR (500 MHz,
C6D6) : 5.53 (1H, ddd, J 7.0, 5.7, 5.0 Hz, H-2), 5.48–5.40 (2H, H-1, H-
a
]
þ11.1 (c 1.45,
11. Hashimoto, S.; Setoi, H.; Takeno, S.; Ito, Y. Patent JP 61,277,685, 1986; Chem.
Abstr. 1987, 106, 138253y.
12. (a) Iminosugars as Glycosidases Inhibitors: Norjirmycin and Beyond; Stu¨ tz, A.,
Ed.; Wiley-VCH: Weinheim, 1999; (b) Compain, P.; Martin, O. R. Iminosugars:
from Synthesis to Therapeutic Applications; John Wiley and Sons: Chichester,
UK, 2007.
D
n
;
d
6), 5.28 (1H, br s, NH), 4.29 (1H, dd, J 11.7, 5.9 Hz, CHHOAc), 4.24
(1H, m, H-7), 4.13 (1H, dd, J 11.7, 6.9 Hz, CHHOAc), 3.40 (3H, s, MeO),
3.28 (1H, dd, J 9.6, 5.7 Hz, H-3a), 3.20 (1H, m, H-7a), 2.97 (1H, dd, J
9.6, 7.0 Hz, H-3b), 1.74 (3H, s, Ac), 1.66 (3H, s, Ac), 1.65 (3H, s, Ac),
13. (a) Socha, D.; Jurczak, M.; Chmielewski, M. Carbohydr. Res. 2001, 336, 315–318;
(b) Rabiczko, J.; Urban´ czyk-Lipkowska, Z.; Chmielewski, M. Tetrahedron 2002,
ꢀ
58, 1433–1441; (c) Socha, D.; Pasniczek, K.; Jurczak, M.; Solecka, J.; Chmie-
1.61 (3H, s, Ac); 13C NMR (125 MHz, C6D6)
d: 170.2, 169.9, 169.7,
ꢀ
lewski, M. Carbohydr. Res. 2006, 341, 2005–2011; (d) Pasniczek, K.; Socha, D.;
Solecka, J.; Jurczak, M.; Chmielewski, M. Can. J. Chem. 2006, 84, 534–539; (e)
Panfil, I.; Solecka, J.; Chmielewski, M. J. Carbohydr. Chem. 2006, 25, 673–684;
169.5, 156.7, 80.2, 79.8, 78.4, 72.9, 61.7, 61.2, 60.2, 51.9, 51.2, 20.34,
20.32, 20.28, 20.17; HRMS (ESI): m/z calcd for C18H26N2O10Na
[MþNaþ]: 453.1480; found: 453.1483.
ꢀ
(f) Pasniczek, K.; Solecka, J.; Chmielewski, M. J. Carbohydr. Chem. 2007, 26,
195–211; (g) Stecko, S.; Jurczak, M.; Urban´ czyk-Lipkowska, Z.; Solecka, J.;
Chmielewski, M. Carbohydr. Res. 2008, 343, 2215–2220; (h) Stecko, S.; Solecka,
J.; Chmielewski, M. Carbohydr. Res. 2009, 344, 167–176; (i) Stecko, S.;
4.15. (1S,2S,5S,6S,7R,7aS)-1,2,6-Trihydroxy-5-(hydroxymethyl)-
ꢀ
Pasniczek, K.; Jurczak, M.; Solecka, J.; Chmielewski, M. Pol. J. Chem. 2009, 83,
237–243.
7-(methoxycarbonylamino)-pyrrolizidine (31)
ꢀ
14. (a) Stecko, S.; Pasniczek, K.; Jurczak, M.; Urban´ czyk-Lipkowska, Z.; Chmie-
ꢀ
lewski, M. Tetrahedron: Asymmetry 2006, 17, 68–79; (b) Stecko, S.; Pasniczek, K.;
Pyrrolizidine 38 (40 mg, 93
mmol) was dissolved in 1% soln of
´
Jurczak, M.; Urbanczyk-Lipkowska, Z.; Chmielewski, M. Tetrahedron: Asymmetry
ꢀ
NH3 in MeOH (5 mL) and stirred at room temperature under
2007, 18, 1085–1093; (c) Stecko, S.; Pasniczek, K.; Michel, C.; Milet, A.; Perez, S.;

S. Stecko et al. / Tetrahedron 65 (2009) 7056–7063
7063
Chmielewski, M. Tetrahedron: Asymmetry 2008, 19, 1660–1669; (d) Stecko, S.;
Pasniczek, K.; Michel, C.; Milet, A.; Perez, S.; Chmielewski, M. Tetrahedron:
Asymmetry 2008, 19, 2140–2148.
18. (a) Poon, K.; House, S. E.; Dudley, G. Synlett 2005, 3142–3144; (b) Poon, K.;
Dudley, G. J. Org. Chem. 2006, 71, 3923–3929; (c) Poon, K.; Dudley, G. Org. Synth.
2007, 84, 295–299; (d) ALDRICH. ChemFiles 2007, 7, 3.
ꢀ
15. Song, H.; Chen, W.; Wang, Y.; Qin, Y. Synth. Commun. 2005, 35, 2735–2742.
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132–135.
19. Chiacchio, U.; Casuscelli, F.; Corsaro, A.; Librando, V.; Rescifina, A.; Romeo, R.;
Romeo, G. Tetrahedron 1995, 51, 5689–5700.
20. Armarego, W. L. F.; Chai, C. L. L. Purification of Laboratory Chemicals, 5th ed.;
Butterwoth-Heinemann: Burlington, MA, 2003.
˙
17. Mostowicz, D.; Be1ecki, Cz.; Chmielewski, M. Synthesis 1991, 273–275.