A convenient synthesis of new enantiomerically pure trihydroxypyrrolizidines using l-erythrose glycosylhydroxylamine as a masked acyclic chiral nitrone

Article abstract of DOI:10.1016/j.tet.2008.06.093

A route has been developed for the synthesis of enantiomerically pure trihydroxylated pyrrolizidines starting from l-erythrose glycosylhydroxylamine. The latter acts as a masked acyclic nitrone and reacts diastereoselectively from its Re-face with methyl acrylate to give the corresponding isoxazolidines, which after reductive N-O cleavage are recyclized to trihydroxypyrrolizidines via a Mitsunobu condensation.

Full text of DOI:10.1016/j.tet.2008.06.093

Tetrahedron 64 (2008) 8752–8758
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A convenient synthesis of new enantiomerically pure trihydroxypyrrolizidines
using
L-erythrose glycosylhydroxylamine as a masked acyclic chiral nitrone
*
Nikolaos G. Argyropoulos , Petros Gkizis, Evdoxia Coutouli-Argyropoulou
Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 April 2008
Received in revised form 12 June 2008
Accepted 26 June 2008
Available online 28 June 2008
A route has been developed for the synthesis of enantiomerically pure trihydroxylated pyrrolizidines
starting from L-erythrose glycosylhydroxylamine. The latter acts as a masked acyclic nitrone and reacts
diastereoselectively from its Re-face with methyl acrylate to give the corresponding isoxazolidines, which
after reductive N–O cleavage are recyclized to trihydroxypyrrolizidines via a Mitsunobu condensation.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Trihydroxy pyrrolizidines
Glycosylhydroxylamine
Chiral nitrone
Aza sugars
Dipolar cycloaddition
1. Introduction
In connection with our previous studies devoted to the synthesis
of pyrrolidine and pyrrolizidine derivatives via chiral nitrone cy-
Polyhydroxylated pyrrolizidines belong to an important class of
alkaloids that display a wide range of biological activities due
mainly to their action as specific glycosidase inhibitors.1 In partic-
ular, the naturally occurring compounds alexine (1), australine (2)
and casuarine (3) have generated considerable interest as antiviral
and anticancer agents.2 Since the biological activity varies sub-
stantially with the number, the position and the stereochemistry of
the hydroxy groups on the pyrrolizidine skeleton, the synthesis of
both naturally occurring compounds as well as of their stereoiso-
mers and analogues has received much attention.3 A large part of
the synthetic work in this area involves 1,3-dipolar cycloadditions
of chiral nitrones derived from sugars. The synthetic strategy of
these reaction schemes relies on the reductive cleavage of the N–O
bond of the isoxazolidine cycloadduct and subsequent cyclization
to carbon–nitrogen heterocycles. Using cycloadditions of cyclic
cloadditions,6 we present herein a short and convenient synthesis
of two new enantiopure trihydroxypyrrolizidines 8 and 9, which to
the best of our knowledge have not yet been described. Our syn-
thetic scheme uses as a key intermediate the N-benzyl substituted
glycosylhydroxylamine 10a, which reacts as a hidden nitrone. N-
Substituted N-glycosylhydroxylamines are a relatively new class of
compounds and they have been the subject of rather few reports.7
They have been recently prepared by three independent groups of
researchers.7a,b,e They exist in equilibrium with the open chain
OH
OH
HO
HO
H
N
HO
HO
H
N
OH
OH
HO
HO
H
N
HOH2C
HOH2C
HOH
2C
1
2
3
nitrones derived from
D or L-arabinopyranose, Wightman and co-
workers have described the synthesis of the two enantiomeric
HO
HO
H
HO
HO
H
1,2,6-trihydroxypyrrolizidines 4, 5 and the racemate of structure 6.4
HO
HO
H
OH
OH
OH
ˇ
Fisera, following a different procedure and using an open chain
nitrone derived from -glucose, has synthesized another chiral
OH
N
N
N
D
4
5
stereoisomer of 1,2,6-trihydroxypyrrolizidine for which he has
6
proposed structure 7.5
HO
HO
H
HO
HO
H
HO
HO
H
OH
OH
N
N
N
* Corresponding author. Tel.: þ30 2310 997871; fax: þ30 2310 997679.
E-mail address: narg@chem.auth.gr (N.G. Argyropoulos).
7
8
9
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.06.093

N.G. Argyropoulos et al. / Tetrahedron 64 (2008) 8752–8758
8753
in dry methylene chloride in the presence of triethylamine at room
temperature following a slightly modified procedure than that
described by Goti and co-workers.7e It was identified on the basis of
its spectroscopic data, which showed a close similarity with those
given in the literature for its antipode.7e,f As shown by its 1H NMR
O
OH
OH
Ph
O
N
N
Ph
10
O
spectrum the equilibrium is predominantly shifted towards the b-
anomeric cyclic form. There is one series of main peaks corre-
sponding to the cyclic form where the anomeric proton signal at
RHC CHR
O
N
RM
11
Ph
d
4.73 shows a zero coupling constant with 3-H consistent with
their trans disposition. The existence of some low intensity addi-
tional peaks and especially a doublet at 6.80 (CH]N) are in-
OH
R
OH
*
R
RHC CHR
*
*
*
R
OH
d
O
N
N
O
dicative of the open chain nitrone in less than 10%.
O
R
*
*
Ph
N
Nitrone 10a reacted with methyl acrylate to give the two
cycloadducts 18a and 18b in a ratio 2.6:1 and 84% total yield.
Among the four possible 5-carboxymethyl stereoisomers from the
reaction of 10a with methyl acrylate (Scheme 3), structures 18a and
18b were proposed for the obtained cycloadducts assuming that
they come from transition states on the less sterically hindered Re-
face of the nitrone as predicted from molecular models. Some ev-
idence for the stereochemistry of the obtained cyclodducts comes
Ph
*
Ph
R
14
13
12
Scheme 1.
from 1H NMR spectra. The J3,4 ¼10.0 Hz of 18a is almost equal to
0
nitrones and are promising synthetic intermediates. They can be
oxidized to the nitrones 11 with the sugar moiety acting as a re-
movable chiral auxiliary or they themselves react as masked chiral
nitrones in both additions with organometallic reagents and 1,3-
dipolar cycloadditions, where the sugar framework remains em-
bodied in the final adducts (Scheme 1).
Despite their apparent versatility for synthetic purposes they
have received rather restricted attention mainly focused on their
use as precursors of nitrones 117c,e and on organometallic additions
as a synthetic path to pyrrolizidine homoazasugars.7b,d,f,g Regarding
their participation as 1,3-dipoles by themselves in 1,3-dipolar cy-
cloaddition reactions only one reaction with dimethyl maleate is
referred7c to the best of our knowledge. The involvement of com-
pounds 10 in synthetic reaction schemes leading to the synthesis of
pyrrolizidines and other azasugars offers the advantage of the
creation of a hydroxymethyl group useful for further manipulations
simultaneously with the cycloaddition step avoiding the protection
and deprotection of a preexisting hydroxymethyl group and re-
ducing the reaction steps.
0
that of 18b (J3,4 ¼10.3 Hz) indicating that 3-H has the same geom-
etry in both compounds as if they come from the same face of the
nitrone. The discrimination between the two possible endo and exo
isomers resulting from the Re-face of the nitrone was further made
on the basis of the characteristic multiplicities and coupling con-
stants of the two 4-H protons. In the major isomer 18a the one of 4-
H, which appears at
a zero coupling constant with 3-H indicating that it is trans to that.
Upon saturation of 5-H the same proton shows a large intensity
increment (10%), whereas the other 4-H at
surable increment. Thus, it follows that the proton at
5-H and trans to 3-H and consequently 3-H and 5-H are trans to
each other. This trans arrangement results from an endo transition
state assuming that nitrone 10a reacts via its Z-form as it is gen-
erally accepted for acyclic nitrones.8 In the minor isomer 18b the
two 4-H appear at
J3,4¼1.5 Hz) and
J3,4¼8.4 Hz). Thus, the 4-H at
stants with both 3-H and 5-H should be cis to both of them,
whereas the other one at 2.75 with the smaller coupling constants
d
2.97 as dd (Jgem¼13.1 Hz, J4,5¼8.7 Hz) exhibits
d
2.77 shows no mea-
2.97 is cis to
d
d
2.75 as ddd (Jgem¼13.4 Hz, J4,5¼5.8 Hz,
2.85 as ddd (Jgem¼13.4 Hz, J4,5¼10.3 Hz,
2.85 with the larger coupling con-
d
d
d
2. Results and discussion
should be trans to both 3-H and 5-H, meaning that 3-H and 5-H are
cis to each other, as it holds in the exo-cycloadducts. The over-
lapping of some crucial peaks as 3-H in both 18a and 18b along with
Compound 10a was prepared starting from
Scheme 2. Thus, the acetonide of -ribose 15 was transformed to
the acetonide of -erythrose 17 applying typical sugar manipula-
D-ribose as shown in
D
L
tions. The N-benzyl-N-glycosylhydroxylamine 10a was obtained by
reaction of the lactol 17 with benzylhydroxylamine hydrochloride
10a
CO2CH3
OH
O
O
OH
OH
OH
OH
1'
HO
HO
O
O
5'
OH
4
ii
ref.13
O
i
H
2'
3'
H
ref.13
O
O
O
O
O
O
O
CO2CH3
4'
3
CO2CH3
N
+
O
2
N
5
Ph
O
1
Ph
15
16
17
exo-Re
endo-Re
80%
iii
18b (23%)
18a (61%)
OH
Ph
OH
O
N
N
OH
O
OH
H
Ph
O
O
O
O
O
H
O
O
O
O
CO2CH3
CO2CH3
N
N
O
Ph
Ph
10a
endo-Si
exo-Si
Scheme 2. Reagents and conditions: (i) NaBH4, MeOH, 0 ꢀC to rt, 1 h; (ii) NaIO4,
t-BuOH, H2O, rt, 2 days; (iii) BnNHOH, CH2Cl2, Et3N, rt, 2 days.
Scheme 3.

8754
N.G. Argyropoulos et al. / Tetrahedron 64 (2008) 8752–8758
0
the conformational freedom of the C3–C4 bond have not permitted
more evidence from NOE measurements. However, the proposed
stereochemistry was further supported by the transformation
products of the initial cycloadducts as described below.
a reaction sequence involving isoxazolidine N–O bond cleavage, N-
debenzylation and spontaneous cyclization. The amides 19 could be
further selectively reduced to the amines 20 using BH3$Me2S. For
the condensation of the hydroxymethyl and NH moieties we have
chosen to apply the Mitsunobu reaction.11 However, typical Mit-
sunobu conditions using Ph3P and DEAD as reagents did not work
neither on the amide nor on its reduction product. After some ex-
perimentation on both 19a and 20a we found cyclodehydration of
the amide 19a to the pyrrolizidinone 21a to proceed in high yield
using 1,10-(azodicarbonyl)dipiperidine (ADDP) and tri-n-butyl-
phosphine as Mitsunobu reagents. Analogous modifications for the
Mitsunobu reaction have been adapted in cases of nucleophiles
with low basicity.12 The same reaction sequence was successfully
applied to the pyrrolidinone 19b resulting from the isoxazolidine
18b. Amides 21a and 21b were readily reduced to the corre-
sponding methylene compounds 22a and 22b using BH3$Me2S. It
should be mentioned that it was not possible to obtain amide 21b in
pure form. Even after repeated chromatographies it was contami-
nated with the hydrazide derived from ADDP during the Mitsunobu
reaction. This crude product was used for the next reduction step
and fortunately the reduction product 22b having a different Rf was
eventually separated in pure form. Acid deprotection of 21a and
21b gave the trihydroxylated pyrrolizidines 8 and 9 (Scheme 5).
The structural elucidation of the obtained pyrrolizidines was
based on their spectroscopic and elemental data. For the com-
pounds coming from the major isomer of the cycloaddition re-
action 18a the stereochemistry was supported by NOE
measurements carried out on compound 21a. The 1H NMR spec-
trum of this compound was well resolved and proton assignments
and connectivities could be established by double resonance ex-
periments. NOE data are fully in accordance with the structure 21a
as depicted in Figure 1. In particular, the significant NOE en-
hancements observed between 8-H1 and 8b-H show the close
proximity of these protons in a ladle arrangement of the three
rings as a result of the initial approach of the dipolarophile to the
Re-face of the nitrone. This is further supported by NOE en-
hancement induced on 8a-H upon saturation of one of the methyl
groups of the dioxolane ring. Also significant mutual NOE in-
crements were observed between 8-H2 and both 7-H and 8a-H
indicating that these three protons are in a cis arrangement as
a result of an endo attack of the dipolarophile for the formation of
the starting 18a cycloadduct. The proposed stereo structures for
the major cycloadduct and its transformation products were fur-
ther corroborated by the identification of the 1H NMR and 13C
NMR spectra of the final deprotected trihydroxypyrrolizidine tri-
fluoroacetate salt 23 with those given by Wightman for its race-
mate.4b Compound 23 was obtained from deprotection of 22a with
TFA for purposes of comparison with the data of Wightman. For
the compounds coming from the minor isomer 18b, that is, 19b,
21b, 22b, 9 our evidence for their stereochemistry is weaker since
none of them exhibited a fully resolved spectrum suitable for
extensive NOE measurements. Notwithstanding, in the proton
NMR spectrum of compound 22b it could be observed a remark-
able enhancement of 8a-H (8%) upon saturation of one of the
methyl groups of the dioxolane ring. This is indicative of a ladle
arrangement of the three rings corresponding to a Re-approach to
the nitrone in the initial cycloaddition step. Since the major isomer
18a of the cycloaddition reaction has assigned as the endo-Re
product, the other possible product from the Re-approach should
be the exo-Re, that is, 18b. As it has been already mentioned, this
structure is also supported by the values of proton coupling con-
stants in the initial minor cycloadduct. On the other hand, the final
Isoxazolidines 18a and 18b bearing two functional groups (a
CH2OH and a COOCH3) are suitable candidates for further trans-
formation to pyrrolizidine derivatives via reductive cleavage of the
N–O bond, which generates an NHR and an OH group.9 The con-
struction of the pyrrolizidine bicyclic system requires two ring
closures between the amino group and the preexisting functional
groups. The reaction between the NHR and the COOCH3 groups
leading to 3-hydroxypyrrolidones with retention of the stereo-
chemistry is a well documented procedure.10 For the formation of
the second ring the preexisting hydroxymethyl group can be
transformed to a good leaving group prior to the reduction step, so
the bicyclic skeleton is formed in one step as depicted in path A
(Scheme 4). Otherwise, the second cyclization via NHR, CH2OH
groups can be done after the reduction step and the formation of
the pyrrolidine ring (path B, Scheme 4).
Although path A seems to be reasonable, it did not work in our
hands. Several transformations of the hydroxyl to good leaving
groups such as mesyl, tosyl or iodo along with several reduction
conditions, that were tried on isoxazolidine 18a, were unsuccessful.
In particular the mesylation carried out by a typical procedure
(MsCl, pyridine, DMAP) afforded a polar crude product, which was
further subjected to hydrogenolysis over Pd/C or Raney Ni, but
without definite results. In small scale experiments there were
some indications for the formation of the targeted molecules but
we had not obtained any repeatable and reliable results upon
scaling up of the reaction. The attempts for transformation of hy-
droxyl group to a tosyl (TsCl, pyridine) or a iodo one (I2, Ph3P, im-
idazole) were also unsuccessful, resulted in unidentified products
in both cases.
After that, we focused our experiments on the second path.
Thus, direct hydrogenolysis of isoxazolidines 18a and 18b in
methanol in the presence of palladium on carbon catalyst afforded
pyrrolidinones 19a and 19b, respectively, in high yields via
OH
CO2CH3
N
O
Ph
A
B
OX
CO2CH3
OH
CO2CH3
N
O
OH
NH2
HN
Ph
OH
CO2CH3
OH
OX
NH2 OH
O
OH
trihydroxypyrrolizidine 9 of this reaction sequence, as an antipode
N
5
ˇ
of compound 7, described by Fisera and co-workers should
O
give the same 1H NMR and 13C NMR data. In fact these data are
different. Unfortunately, attempts to assign undoubtedly the
Scheme 4.

N.G. Argyropoulos et al. / Tetrahedron 64 (2008) 8752–8758
8755
OH
O
O
O
O
H
H
HO
HO
O
H
H
N
i
ii
OH
iii
80%
O
OH
18a
OH
OH
O
OH
HN
N
90%
80%
N
85%
v
O
19a
21a
8
22a
80%
iii
OH
94%
HO
HO
H
O
H
O
NH
CF3CO2
OH
HN
23
20a
OH
O
O
O
H
O
H
N
HO
HO
H
H
O
ii
OH
68% from 19b
i
iv
90%
iii
O
OH
18b
OH
OH
N
92%
HN
N
O
O
19b
21b
22b
9
Scheme 5. Reagents and conditions: (i) Pd/C, H2, CH3OH, rt, 2 days; (ii) PBu3, ADDP, THF, 1 day; (iii) BH3$Me2S, THF, rt, 1 day; (iv) CH3C6H4SO3H, CH3OH, rt, 1 day; (v) TFA, H2O,
rt, 1 day.
Kieselgel (particle size 0.063–0.200 mm) and solvents were dis-
tilled before use.
11%
4%
H1
7%
OH
H
6%
8a
H
6%
7
8
4%
8b
7%
5%H2
3.2. Synthesis of compound 10a
H
O
1
8% H1
6%
H3C
5
6
4%
4
N
H
Lactol 17 (844 mg, 5.2 mmol) prepared from D-ribose according
O
3a
O
9%
2
to the conditions described in the literature13 was dissolved in dry
CH2Cl2 (20 mL) and dry triethylamine (0.72 mL, 5.1 mmol) was
added. The solution was cooled to 0 ꢀC and N-benzylhydroxylamine
hydrochloride (1.25 g, 7.8 mmol) was gradually added. After that,
the reaction mixture was stirred at room temperature for 2 days.
Then a saturated solution of NH4Cl (20 mL) was added, the two
layers were separated and the aqueous layer was extracted with
CH2Cl2 (3ꢁ20 mL). The combined organic layers were concentrated
after drying with Na2SO4. The residue was purified by column
chromatography (silica gel, hexane/EtOAc, 4:1) to give compound
10a (1150 mg, 83% yield).
3%
3
2%
H2
CH3
4%
Figure 1. NOE enhancements measured on compound 21a.
proposed stereochemistry by X-ray crystal structure analysis were
unsuccessful, since despite our efforts none of the compounds of
the above reaction sequence gave crystals suitable for this pur-
pose. Thus, on the basis of the data we had in hand and following
up the two newly formed stereogenic centres in the cycloaddition
step through the whole reaction sequence, we tentatively assigned
the proposed stereochemistry despite the above mentioned dis-
3.2.1. (2S,3S,4S)-N-Benzyl-N-hydroxy-3,4-O-isopropylidene
ˇ
crepancy with Fisera’s data.
dioxytetrahydrofuran-2-amine (10a)
In conclusion, an efficient synthetic pathway to trihydroxy-
pyrrolizidines 8 and 9 has been established from L-erythrosehy-
droxylamine in five steps with yields bigger than 80% for each step.
Given the convenience of the synthesis of glycosyl hydroxylamines
from sugars this process can be extended to the synthesis of diverse
pyrrolizidines by choice of the suitable starting sugar.
This compound was obtained as a white solid, mp 83–88 ꢀC;
25
[a
]
þ63.5 (c 5.1, CHCl3); IR (KBr): nmax 3418 (OH) cmꢂ1
;
1H NMR
D
(CDCl3, 300 MHz):
d 1.35 (s, 3H, CH3), 1.50 (s, 3H, CH3), 3.88 (d,
J¼13.1 Hz, 1H, CH2C6H5), 4.07 (d, J¼8.7 Hz, 1H, 5-H), 4.09 (d,
J¼13.1 Hz, 1H, CH2C6H5), 4.27 (dd, J¼8.7, 4.3 Hz, 1H, 5-H), 4.67 (s,
1H, OH), 4.73 (s, 1H, 2-H), 4.88 (dd, J¼6.1, 4.3 Hz, 1H, 4-H), 4.92 (d,
J¼6.1 Hz, 1H, 3-H), 7.25–7.40 (m, 5H, C6H5); 13C NMR (CDCl3,
75.5 MHz): d 24.7 (CH3), 26.3 (CH3), 59.2 (C-5), 76.1 (CH2C6H5), 81.0
3. Experimental
3.1. General
(C-4), 83.5 (C-3), 99.3 (C-2), 111.9 (C(CH3)2), 127.3, 128.3, 129.6 and
136.8 (C6H5). Anal. Calcd for C14H19NO4: C, 63.38; H, 7.22; N, 5.28.
Found: C, 63.24; H, 6.95; N, 4.99.
Mps were determined on a Kofler hot-stage microscope. IR
spectra were recorded on a Perkin–Elmer 297 spectrometer. 1H
NMR spectra were recorded at 300 MHz on a Bruker 300 AM
spectrometer and 13C NMR spectra at 75.5 MHz on the same
spectrometer, and are quoted relative to tetramethylsilane as in-
ternal reference, in deuteriochloroform solutions, unless otherwise
stated. Mass spectra (EI) were performed on a VG-250 spectro-
meter with ionization energy maintained at 70 eV. High resolution
mass spectra (HRESI) were obtained with a 7T APEX II spectrome-
ter. Microanalyses were performed on a Perkin–Elmer 2400-II el-
ement analyser. Column chromatography was carried out on Merck
3.3. Cycloaddition reaction of compound 10a with methyl
acrylate
A solution of 10a (1.325 g, 5 mmol) and methyl acrylate (18 mL)
was heated under reflux and the consumption of the starting ma-
terial was monitored with TLC. After 2 days the reaction has fin-
ished and the crude product obtained after evaporating the excess
of methyl acrylate was purified by column chromatography (silica
gel, hexane/EtOAc, 4:1) to give in order of elution 985 mg of 18a,
120 mg of a mixture of 18a and 18b in a ratio 2:1 and 370 mg of 18b.

8756
N.G. Argyropoulos et al. / Tetrahedron 64 (2008) 8752–8758
3.3.1. Methyl (3R,5R)-2-benzyl-3-[(40R,50S)-50-(hydroxymethyl)-
20,20-dimethyl-10,30-dioxolan-40-yl]isoxazolidine-5-carboxylate
(18a)
CH3), 1.40 (s, 3H, CH3), 2.18 (dt, J¼14.0, 7.9, 6.8 Hz, 1H, 4-H), 2.50
(dd, J¼14.0, 7.4 Hz, 1H, 4-H), 3.60–3.78 (m, 2H, 5-H and CH2OH),
3.85 (t, J¼8.0 Hz, 1H, 3-H), 3.95 (dd, J¼7.9, 6.1 Hz, 1H, 40-H), 4.23
(dd, J¼12.5, 5.8 Hz, 1H, CH2OH), 4.42 (t, J¼7.9 Hz, 50-H), 4.60 (br s,
25
This compound was obtained as an oil in 61% total yield; [a]
þ53.2 (c 12.7, CHCl3); IR (film): nmax 3446 (OH), 1750 (CO) cmꢂ1; 1DH
2H, OH), 7.58 (br s, 1H, NH); 13C NMR (CDCl3, 75.5 MHz):
d 25.2
NMR (CDCl3, 300 MHz):
d
1.33 (s, 3H, CH3), 1.40 (s, 3H, CH3), 2.77
(CH3), 27.6 (CH3), 33.2 (C-4), 50.7 (C-5), 60.0, 68.4, 76.8 and 79.2
(C-3, C-40, C-50 and CH2OH), 108.5 (C(CH3)2), 178.5 (CO); HRESIMS
for C10H17NaNO5 (MþNa)þ: calcd 254.1004, found 254.1000.
(ddd, J¼13.1, 8.7, 7.1 Hz, 1H, 4-H), 2.97 (dd, J¼13.1, 8.7 Hz, 1H, 4-H),
3.35 (ddd, J¼12.3, 7.0, 4.3 Hz, 1H, CH2OH), 3.59–3.72 (m, 2H, CH2OH
and 3-H), 3.66–3.83 (m, 5H, CH2C6H5, OCH3, OH), 3.97 (dd, J¼10.0,
5.4 Hz, 1H, 40-H), 4.20 (d, 1H, J¼12.2 Hz, 1H, CH2C6H5), 4.32 (ddd,
J¼10.0, 5.0, 4.3 Hz, 1H, 50-H), 4.63 (t, J¼8.7 Hz, 1H, 5-H), 7.29–7.37
3.5. Mitsunobu condensation of pyrrolidinones 19 to
pyrrolizinones 21
(m, 5H, C6H5); 13C NMR (CDCl3, 75.5 MHz):
d 25.3 (CH3), 27.9 (CH3),
33.3 (C-4), 52.4 (OCH3), 59.3, 61.9, 64.6, 75.2, 77.2 and 77.4 (CH2OH,
CH2C6H5, C-3, C-5, C-40, C-50), 108.6 (C(CH3)2), 127.9, 128.5, 129.7
and 135.7 (C6H5), 172.8 (CO); MS (EI): m/z (%) 352 (Mþ, 40). Anal.
Calcd for C18H25NO6: C, 61.52; H, 7.17; N, 3.99. Found: C, 61.37; H,
7.16; N, 4.08.
A solution of pyrrolidinone 19 (1 mmol) in dry THF (5 mL) was
cooled to 0 ꢀC under an argon atmosphere and then were added tri-
n-butylphosphine (0.37 mL, 1.5 mmol) and ADDP (378 mg,
1.5 mmol). The resulting mixture was stirred at 0 ꢀC for 1 h and
then at room temperature for 1 day. After that, the solvent was
evaporated in vacuo and the crude product was purified by column
chromatography (silica gel, EtOAc).
3.3.2. Methyl (3R,5S)-2-benzyl-3-[(40R,50S)-50-(hydroxymethyl)-
20,20-dimethyl-10,30-dioxolan-40-yl]isoxazolidine-5-carboxylate
(18b)
3.5.1. (3aS,7R,8aR,8bR)-7-Hydroxy-2,2-dimethylhexahydro-6H-
This compound was obtained in 23% total yield as a white solid,
[1,3]dioxolo[4,5-a]pyrrolizin-6-one (21a)
25
mp 87–89 ꢀC; [
a
]
þ64.9 (c 7.1, CHCl3); IR (KBr): nmax 3490 (OH),
This compound was obtained from 19a in 80% yield as a white
1738 (CO) cmꢂ1; 1DH NMR (CDCl3, 300 MHz):
d
1.26 (s, 3H, CH3), 1.39
solid, mp 165–167 ꢀC; [
a]
þ58.02 (c 0.4, CHCl3); IR (KBr): nmax
25
D
(s, 3H, CH3), 2.75 (ddd, J¼13.4, 5.8, 1.5 Hz, 1H, 4-H), 2.85 (ddd,
J¼13.4, 10.3, 8.4 Hz, 1H, 4-H), 3.41 (ddd, J¼10.7, 7.8, 3.7 Hz, 1H,
CH2OH), 3.52–3.72 (m, 3H, CH2OH, 3-H, OH), 3.78 (s, 3H, OCH3),
3.83 (d, J¼12.9 Hz, 1H, CH2C6H5), 3.96 (d, J¼12.9 Hz, 1H, CH2C6H5),
4.18 (dd, J¼10.3, 5.7 Hz, 1H, 40-H), 4.35 (dt, J¼7.8, 5.7 Hz, 1H, 50-H),
4.79 (dd, J¼10.3, 5.8 Hz, 1H, 5-H), 7.29–7.37 (m, 5H, C6H5); 13C NMR
3468 (OH), 1682 (CO) cmꢂ1 1H NMR (CDCl3, 300 MHz):
; d 1.34 (s,
3H, CH3), 1.52 (s, 3H, CH3), 1.74 (ddd, J¼12.9, 10.3, 8.6 Hz, 1H, 8-H),
2.89 (ddd, J¼12.9, 7.4, 6.6 Hz, 1H, 8-H), 3.13 (dd, J¼13.1, 3.4 Hz, 1H,
4-H), 3.73 (ddd, J¼8.6, 6.6, 4.3 Hz, 1H, 8a-H), 4.13 (dd, J¼13.1, 6.4 Hz,
1H, 4-H), 4.29 (br s, 1H, OH), 4.35 (dd, J¼6.7, 4.3 Hz, 1H, 8b-H), 4.54
(dd, J¼10.3, 7.4 Hz, 1H, 7-H), 4.84 (ddd, J¼6.7, 6.4, 3.4, 1H, 3a-H); 13
C
(CDCl3, 75.5 MHz):
d
25.3 (CH3), 27.9 (CH3), 33.3 (C-4), 52.4 (OCH3),
NMR (CDCl3, 75.5 MHz): 26.4 (CH3), 28.5 (CH3), 37.2 (C-8), 48.4 (C-
4), 62.6 and 73.0 (C-8a and C-7), 81.2 and 85.8 (C-3a and C-8b),
115.2 (C(CH3)2), 175.6 (CO); HRESIMS for C10H16NO4 (MþH)þ: calcd
59.3, 61.9, 64.6, 75.2, 77.2 and 77.4 (CH2OH, CH2C6H5, C-3, C-5, C-40,
C-50), 108.6 (C(CH3)2), 127.9, 128.5, 129.7 and 135.7 (C6H5), 172.8
(CO); MS (EI): m/z (%) 352 (Mþ, 40). Anal. Calcd for C18H25NO6: C,
61.52; H, 7.17; N, 3.99. Found: C, 61.71; H, 7.08; N, 3.86.
214.1079, found 214.1075; for
236.0899, found 236.0894.
C
10H15NaNO4 (MþNa)þ: calcd
3.4. Reductive cleavage of isoxazolidines 18 to pyrro-
lidinones 19
3.5.2. (3aS,7S,8aR,8bR)-7-Hydroxy-2,2-dimethylhexahydro-6H-
[1,3]dioxolo[4,5-a]pyrrolizin-6-one (21b)
This compound was obtained from 19b after the described work
up and repeated column chromatographies as a crude oil con-
taminated with byproducts of the Mitsunobu reaction and it was
used for the next step in crude form. Its formation was certified by
its MS spectrum; HRESIMS for C10H15NaNO4 (MþNa)þ: calcd
236.0899, found 236.0896.
General procedure. A catalytic amount of Pd/C (10% w/w (about
30 mg)) was added to a previously degassed solution of iso-
xazolidine (1.2 mmol) in MeOH (10 mL) under a hydrogen atmo-
sphere (balloon). The mixture was stirred for about 2 days and then
the crude reaction mixture was passed through Celite, concen-
trated and purified by column chromatography (silica gel, EtOAc/
CH3OH 20:1).
3.6. Reduction of pyrrolidinone 19a and pyrrolizinones 21
3.4.1. (3R,5R)-3-Hydroxy-5-[(40R,50S)-50-(hydroxymethyl)-20,20-
Borane–dimethylsulfide complex (2 M in BH3, 2 mL, 4 mmol)
was added with stirring to a cool (0 ꢀC) solution of the lactam 19
or 20 (0.8 mmol) in THF (10 mL) under an argon atmosphere. The
reaction mixture was allowed to stirred at room temperature for 1
day and the reaction was quenched by addition of satd Na2SO4 and
the solvent was concentrated in vacuo. The residue was dissolved
in water and was extracted with CH2Cl2 (3ꢁ15 mL). After drying
and evaporation of the combined organic extracts the crude
product was purified by column chromatography (silica gel,
EtOAc).
dimethyl-10,30-dioxolan-40-yl]-2-pyrrolidone (19a)
This compound was obtained from 18a in 90% yield as a white
25
solid, mp 141–143 ꢀC; [
a
]
þ18.1 (c 3.4, CHCl3); IR (KBr): nmax 3435
D
(OH), 1695 (CO) cmꢂ1 1H NMR (CDCl3, 300 MHz):
; d 1.35 (s, 3H,
CH3), 1.41 (s, 3H, CH3), 1.95 (dt, J¼13.5, 7.7 Hz, 1H, 4-H), 2.71 (ddd,
J¼13.5, 8.2, 5.9 Hz, 1H, 4-H), 3.66–3.78 (m, 2H, 5-H and CH2OH),
3.82 (dd, J¼10.1, 5.2 Hz, 1H, CH2OH), 4.05 (dd, J¼9.0, 5.8 Hz, 1H, 40-
H), 4.25–4.38 (m, 4H, 50-H and 3-H), 7.36 (br s, 1H, NH); 13C NMR
(CDCl3, 75.5 MHz):
d 25.6 (CH3), 28.2(CH3), 35.1 (C-4), 50.3 (C-5),
60.7, 69.6, 77.8, 81.6 (C-3, C-40, C-50and CH2OH), 109.0 (C(CH3)2),
178.4 (CO); HRESIMS for C10H17NaNO5 (MþNa)þ: calcd 254.1004,
found 254.1001.
3.6.1. (3R,5R)-5-[(40R,50S)-5-(Hydroxymethyl)-20,20-dimethyl-10,30-
dioxolan-40-yl]pyrrolidin-3-ol (20a)
This compound was obtained from 19a in 80% yield as a white
3.4.2. (3S,5R)-3-Hydroxy-5-[(40R,50S)-50-(hydroxymethyl)-20,20-
dimethyl-10,30-dioxolan-40-yl]-2-pyrrolidone (19b)
solid, mp 129–133 ꢀC; IR: nmax 3469 (OH) cmꢂ1 1H NMR (CDCl3,
;
300 MHz): d 1.43 (s, 3H, CH3), 1.56 (s, 3H, CH3), 1.80 (br, 2H, OH or
This compound was obtained from 18b in 92% yield as a white
NH), 1.97 (ddd, J¼14.3, 4.7, 2.8 Hz, 1H, 4-H), 2.29 (ddd, J¼14.3, 9.7,
4.7 Hz, 1H, 4-H), 2.73 (td, J¼12.0, 3.0 Hz, 1H, 2-H), 3.20–3.30 (m, 2H,
2-H, 5-H), 3.68 (m as d, 2H, CH2OH), 4.30 (br, 1H, OH or NH), 4.38
25
solid, mp 102–104 ꢀC; [
a
]
ꢂ47.5 (c 4.4, CHCl3); IR (KBr): nmax 3437
D
(OH), 1695 (CO) cmꢂ1 1H NMR (CDCl3, 300 MHz):
; d 1.33 (s, 3H,

N.G. Argyropoulos et al. / Tetrahedron 64 (2008) 8752–8758
8757
(dd, J¼5.8, 2.7 Hz, 1H, 40-H), 4.42–4.50 (m, 1H, 3-H), 4.78 (m, 1H, 50-
3.8. Hydrolysis of acetonide 22a to pyrrolizidine salt 23
H); 13C NMR (CDCl3, 75.5 MHz):
d 24.3 (CH3), 26.2 (CH3), 35.8 (C-4),
60.9, 63.1, 65.4, 70.4, 73.8 and 76.9 (CH2OH, C-2, C-3, C-5, C-40 and
C-50), 109.4 (C(CH3)2); HRESIMS for C10H20NO4 (MþH)þ: calcd
254.1004, found 254.1000.
A solution of 22a (0.6 mmol) in TFA (2 mL) and water (2 mL) was
allowed to stay at room temperature for 1 day and then evaporated.
The residue was redissolved in water and reevaporated.
3.6.2. (3aS,7R,8aR,8bR)-2,2-Dimethylhexahydro-4H-
3.8.1. (1R,2S,6R,7aR)-Hexahydro-1H-pyrrolizine-1,2,6-triol
[1,3]dioxolo[4,5-a]pyrrolizin-7-ol (22a)
trifluoroacetate (23a)
This compound was obtained from 21a in 80% yield as an oil;
This compound was obtained from 22a in 94% yield as a white
þ24.8 (c 0.9, CHCl3); IR (KBr): nmax 3468 (OH) cmꢂ1; 1H NMR
solid, mp 160–162 ꢀC; [
a
]
þ22.7 (c 0.42, H2O); 1H NMR (D2O,
25
25
[
a]
D
D
(CDCl3, 300 MHz):
d
1.31 (s, 3H, CH3), 1.56 (s, 3H, CH3), 2.05 (dd,
300 MHz):
d
2.17 (br d, J¼14.6 Hz, 1H, 7-H), 2.34 (ddd, J¼14.6, 9.4,
J¼13.5, 1.2 Hz, 1H, 8-H), 2.23 (br s, 1H, OH), 2.55 (ddd, J¼13.5, 9.1,
5.5 Hz, 1H, 8-H), 2.98 (d, J¼12.8 Hz, 1H, 6-H), 3.43–3.54 (m, 2H, 4-H
and 6-H), 3.60–3.69 (m, 1H, 8a-H), 3.92 (dd, J¼11.4, 1.2 Hz, 1H, 4-H),
4.52–4.59 (m, 1H, 7-H), 4.78 (dd, J¼6.1, 3.1 Hz, 1H, 8b-H), 4.93–5.01
5.2 Hz, 1H, 7-H), 3.34 (d, J¼12.8 Hz, 1H, 5-H), 3.46 (dd, J¼12.8,
3.6 Hz, 1H, 5-H), 3.54 (dd, J¼12.9, 2.6 Hz, 1H, 3-H), 3.76 (d,
J¼12.9 Hz, 1H, 3-H), 4.09 (dt, Jz8.6, 2.6 Hz, 1H, 7a-H), 4.40 (br m
1H, 2-H), 4.47 (dd, J¼7.6, 3.4 Hz, 1H, 1-H), 4.66 (m, 1H, 6-H); 13C
(m, 1H, 3a-H); 13C NMR (CDCl3, 75.5 MHz):
d
25.4 (CH3), 27.3 (CH3),
NMR (D2O, 75.5 MHz): d 35.3 (C-7), 59.9 and 60.3 (C-3 and C-5),
38.7 (C-8), 69.2, 72.2, 72.6, 77.9, 78.8 and 86.9 (C-3a, C-4, C-6, C-7, C-
8a and C-8b), 113.8 (C(CH3)2); HRESIMS for C10H18NO3 (MþH)þ:
calcd 200.1287, found 200.1282.
68.3 (C-7a), 71.1, 71.6 and 76.6 (C-1, C-2 and C-6); HRESIMS for
C7H14NO3 (MþH)þ: calcd 160.0974, found 160.0968.
References and notes
3.6.3. (3aS,7S,8aR,8bR)-2,2-Dimethylhexahydro-4H-
[1,3]dioxolo[4,5-a]pyrrolizin-7-ol (22b)
1. (a) Elbein, A. D.; Molyneux, R. J. In Alkaloids: Chemical and Biological Perspec-
tives; Pelletier, S. W., Ed.; Wiley-VCH: New York, NY, 1987; Vol. 5, Chapter 1; (b)
Legler, G. Adv. Carbohydr. Chem. Biochem. 1990, 48, 319–384; (c) Winchester, B.;
Fleet, G. W. J. Glycobiology 1992, 2, 199–210; (d) Imino Sugars as Glycosidase
Inhibitors, Nojirimicin and Beyond; Stu¨tz, A. E., Ed.; Wiley-VCH: Weinheim, 1999;
(e) Lillelund, V. H.; Jensen, H. H.; Liang, X.; Bols, M. Chem. Rev. 2002, 102, 515–
553; (f) Martin, O. R.; Compain, P. Curr. Top. Med. Chem. 2003, 3, 471–484.
2. (a) Nash, R. J.; Fellows, L. E.; Dring, J. V.; Fleet, G. W. J.; Derome, A. E.; Hamor, T.
A.; Scofield, A. M.; Watkin, D. J. Tetrahedron Lett. 1988, 29, 2487–2490; (b)
Molyneux, R. J.; Benson, M.; Wong, R. Y.; Tropea, J. E.; Elbein, A. D. J. Nat. Prod.
1988, 51, 1198–1206; (c) Taylor, D. L.; Nash, R. J.; Fellows, L. E.; Kang, M. S.; Tyms,
A. S. Antiviral Chem. Chemother. 1992, 3, 273–277; (d) Nash, R. J.; Thomas, P. I.;
Waigh, R. D.; Fleet, G. W. J.; Wormald, M. R.; de Q. Lilley, P. M.; Watkin, D. J.
Tetrahedron Lett. 1994, 35, 7849–7852; (e) Bridges, C. G.; Ahmed, S. P.; Kang,
M. S.; Nash, R. J.; Porter, E. A.; Tyms, A. S. Glycobiology 1995, 5, 249–253; (f)
Wormald, M. R.; Nash, R. J.; Hrnciar, P.; White, J. D.; Molyneux, R. J.; Fleet, G. W.
J. Tetrahedron: Asymmetry 1998, 14, 2549–2558; (g) 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, 325–332.
This compound was obtained from crude 21b in 68% yield (for
25
two steps, calculated on 19b) as a white solid, mp 103–105 ꢀC; [
a]
D
þ11 (c 0.41, CHCl3); IR: nmax 3468 (OH) cmꢂ1
;
1H NMR (CDCl3,
300 MHz): d 1.31 (s, 3H, CH3), 1.58 (s, 3H, CH3), 2.34–2.59 (m, 2H, 8-
H), 2.23 (br s, 1H, OH), 2.98 (dd, J¼10.1, 6.1 Hz, 1H, 6-H), 3.36–
3.59 (m, 2H, 4-H and 6-H), 3.96–4.09 (m, 1H, 8a-H), 4.36–4.58 (m,
2H, 7-H and 8b-H), 4.82 (dd, J¼10.1, 6.1 Hz, 1H, 3a-H); 13C NMR
(CDCl3, 75.5 MHz):
d 25.2 (CH3), 27.0 (CH3), 39.6 (C-8), 67.9, 70.9,
71.2, 76.7, 78.3 and 86.1 (C-3a, C-4, C-6, C-7, C-8a and C-8b), 114.6
(C(CH3)2); HRESIMS for C10H18NO3 (MþH)þ: calcd 200.1287, found
200.1282.
3.7. Hydrolysis of acetonides 22 to pyrrolizidines 8 and 9
3. (a) Collin, W. F.; Fleet, G. W. J.; Haraldsson, M.; Cenci di Bello, I.; Winchester,
B. Carbohydr. Res. 1990, 202, 105–116; (b) Fairbanks, A. J.; Fleet, G. W. J.;
Jones, A. H.; Bruce, I.; Al Daher, S.; Cenci di Bello, I.; Winchester, B. Tetra-
hedron 1991, 47, 131–138; (c) Denmark, S. E.; Thorarensen, A. J. Am. Chem.
Soc. 1997, 119, 125–137; (d) Hall, A.; Meldrum, K. P.; Therond, P. R.; Wight-
man, R. H. Synlett 1997, 123–125; (e) Bell, A. A.; Pickering, L.; Watson, A. A.;
Nash, R. J.; Pan, Y. T.; Elbein, A. D.; Fleet, G. W. J. Tetrahedron Lett. 1997, 38,
5869–5872; (f) Denmark, S. E.; Hurd, A. R. J. Org. Chem. 2000, 65, 2875–
2886; (g) Goti, A.; Cicchi, S.; Cacciarini, M.; Cardona, F.; Fedi, V.; Brandi, A.
Eur. J. Org. Chem. 2000, 3633–3645; (h) Schieweck, F.; Altenbach, H.-J.
J. Chem. Soc., Perkin Trans. 1 2001, 3409–3414; (i) Rabiczko, J.; Urbanczyk-
Lipkowska, Z.; Chmielewski, M. Tetrahedron 2002, 58, 1433–1441; (j) Behr,
J. B.; Erard, A.; Guillerm, G. Eur. J. Org. Chem. 2002, 7, 1256–1262; (k) Car-
mona, A. T.; Fuentes, J.; Robina, I. Tetrahedron Lett. 2002, 43, 8543–8546; (l)
Toyao, A.; Tamura, O.; Takagi, H.; Ishibashi, H. Synlett 2003, 35–38; (m)
Cardona, F.; Faggi, E.; Liguori, F.; Cacciarini, M.; Goti, A. Tetrahedron Lett.
2003, 44, 2315–2318; (n) Carmona, A. T.; Fuentes, J.; Robina, I.; Garcia, E. R.;
Demange, R.; Vogel, P.; Winters, A. L. J. Org. Chem. 2003, 68, 3874–3883; (o)
Carmona, A. T.; Whigtman, R. H.; Robina, I.; Vogel, P. Helv. Chim. Acta 2003,
86, 3066–3073; (p) Carmona, A. T.; Fuentes, J.; Vogel, P.; Robina, I. Tetrahe-
dron: Asymmetry 2004, 15, 323–333; (q) Izquierdo, I.; Plaza, M. T.; Tamayo,
J. A. Tetrahedron 2005, 61, 6527–6533; (r) 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, 2702–2712; (s) Sletten, E. M.;
Liotta, L. J. J. Org. Chem. 2006, 71, 1335–1343; (t) Izquierdo, I.; Plaza, M.;
Tamayo, J. J. Carbohydr. Chem. 2006, 25, 281–295; (u) Cicchi, S.; Marradi,
M.; Vogel, P.; Goti, A. J. Org. Chem. 2006, 71, 1614–1619.
To a solution of 22 (57 mg, 0.28 mmol) in 6 ml of methanol, p-
toluenesulfonic acid (108 mg, 0.57 mmol) was added and the
mixture was stirred overnight. The solution was neutralized by
addition of K2CO3, the resulting solids were removed by filtration
and the filtrates were concentrated in vacuo. After that, the crude
product was purified by column chromatography (silica gel, CH2Cl2/
CH3OH 4:1).
3.7.1. (1R,2S,6R,7aR)-Hexahydro-1H-pyrrolizine-1,2,6-triol (8)
This compound was obtained from 22a in 85% yield as an oil;
25
[
a]
þ28.8 (c 0.46, CH3OH); IR (film): nmax 3460 (OH) cmꢂ1
;
1H
D
NMR (CD3OD, 300 MHz):
d
1.94 (br d, J¼13.6 Hz, 1H, 7-H), 2.17 (ddd,
J¼13.6, 9.7, 4.5 Hz, 1H, 7-H), 2.78 (br d, J¼11.2 Hz, 1H, 5-H), 3.01–
3.25 (m, 3H, 3-H and 5-H), 3.55 (br, 1H, 7a-H), 4.16 (m, 1H, 2-H),
4.24 (br m, 1H, 1-H), 4.40 (br m, 1H, 6-H); 13C NMR (CD3OD,
75.5 MHz):
d 39.4 (C-7), 62.5 and 63.7 (C-3 and C-5), 70.1 (C-7a),
74.5, 74.7 and 80.1 (C-1, C-2 and C-6); HRESIMS for C7H14NO3
(MþH)þ: calcd 160.0973, found 160.0970.
3.7.2. (1R,2S,6S,7aR)-Hexahydro-1H-pyrrolizine-1,2,6-triol (9)
4. (a) McCaig, A. E.; Wightman, R. H. Tetrahedron Lett. 1993, 34, 3939–3942; (b)
McCaig, A. E.; Meldrum, K. P.; Wightman, R. H. Tetrahedron 1998, 54, 9429–
9446.
This compound was obtained from 22b in 90% yield as an oil;
25
[
a]
þ21.2 (c 0.30, CH3OH); IR (film): nmax 3470 (OH) cmꢂ1
;
1H
D
NMR (CD3OD, 300 MHz):
d
1.78 (dt, J¼12.6, 6.5 Hz, 1H, 7-H), 2.01
´ ˇ
ˇ
ˇ
¨
´
´
5. Kuban, J.; Kolarovic, A.; Fisera, L.; Jager, V.; Humpa, O.; Pronayova, N. Synlett
2001, 1866–1868.
(ddd, J¼12.6, 7.6, 3.7 Hz, 1H, 7-H), 2.58–2.74 (m, 2H, 3-H and 5-H),
2.94 (br d, J¼10.9 Hz, 1H, 5-H), 3.07 (dd, J¼11.4, 4.5 Hz, 1H, 3-H),
3.51–3.63 (br m, 1H, 7a-H), 3.76 (dd, J¼8.7, 4.0 Hz, 1H, 2-H), 4.11–
4.19 (br m, 1H, 1-H), 4.35–4.42 (br m, 1H, 6-H); 13C NMR (CD3OD,
6. Argyropoulos, N. G.; Panagiotidis, T.; Coutouli-Argyropoulou, E.; Raptopoulou,
C. Tetrahedron 2007, 63, 321–330.
7. (a) Merino, P.; Franco, S.; Merchan, F. L.; Tejero, T. Synth. Commun. 1997, 27,
3529–3537; (b) Dondoni, A.; Perrone, D. Tetrahedron Lett. 1999, 40, 9375–9378;
(c) Cicchi, S.; Corsi, M.; Marradi, M.; Goti, A. Tetrahedron Lett. 2002, 43, 2741–
2743; (d) Dondoni, A.; Giovannini, P.; Perrone, D. J. Org. Chem. 2002, 67, 7203–
7214; (e) Cicchi, S.; Marradi, M.; Corsi, M.; Faggi, C.; Goti, A. Eur. J. Org. Chem.
2003, 4152–4160; (f) Dondoni, A.; Perrone, D. Tetrahedron 2003, 59, 4261–4273;
75.5 MHz):
d 40.2 (C-7), 60.9 and 64.9 (C-3 and C-5), 69.6 (C-7a),
74.2, 74.3 and 79.6 (C-1, C-2 and C-6); HRESIMS for C7H14NO3
(MþH)þ: calcd 160.0973, found 160.0969.

8758
N.G. Argyropoulos et al. / Tetrahedron 64 (2008) 8752–8758
ˇ
(g) Bonanni, M.; Marradi, M.; Cicchi, S.; Faggi, C.; Goti, A. Org. Lett. 2005, 7, 319–
322.
(b) Merino, P.; Anoro, S.; Franco, S.; Merchan, F. L.; Tejero, T.; Tunon, V. J. Org.
Chem. 2000, 65, 1590–1596; (c) Merino, P.; Anoro, S.; Merchan, F. L.; Tejero, T.
Heterocycles 2000, 53, 861–875; (d) Merino, P.; Mates, J. A.; Revuelta, J.; Tejero,
T.; Chiacchio, U.; Romeo, G.; Iannazzo, D.; Romeo, R. Tetrahedron: Asymmetry
2002, 13, 173–190.
8. (a) Gothelf, K. V.; Hazell, R. G.; Jorgensen, K. A. Acta Chem. Scand. 1997, 51, 1234–
1235; (b) Chiacchio, U.; Corsaro, A.; Mates, J.; Merino, P.; Piperno, A.; Rescifina,
A.; Romeo, G.; Romeo, R.; Tejero, T. Tetrahedron 2003, 59, 4733–4738.
9. (a) Torsell, K. B. G. Nitrile Oxides, Nitrones, and Nitronates; VCH: New York, NY,
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