Stereoselective synthesis of a new trihydroxyindolizidine lactone

Article abstract of DOI:10.1016/j.tetasy.2005.12.003

A general approach to 1,6,7-trihydroxyindolizidin-8-carboxylates is illustrated through the synthesis of a γ-lactone in an enantiopure form in seven steps starting from (3S)-3-t-butyloxy-1-pyrroline N-oxide and the acetonide of (2E,4S)-4,5-dihydroxy-2-pentenoic acid derived from (S)-malic acid and mannitol, respectively. The process was completely stereoselective and allowed the total control of the relative and absolute configuration of the five contiguous stereocentres of the product.

Full text of DOI:10.1016/j.tetasy.2005.12.003

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 17 (2006) 292–296
Stereoselective synthesis of a new trihydroxyindolizidine lactone
Federica Pisaneschi, Michela Piacenti, Franca M. Cordero and Alberto Brandi*
Dipartimento di Chimica Organica ‘‘Ugo Schiff ’’, Universit a` degli Studi di Firenze, via della Lastruccia 13,
I-50019 Sesto F.no (FI), Italy
Received 24 November 2005; accepted 2 December 2005
Available online 9 January 2006
Abstract—A general approach to 1,6,7-trihydroxyindolizidin-8-carboxylates is illustrated through the synthesis of a c-lactone in an
enantiopure form in seven steps starting from (3S)-3-t-butyloxy-1-pyrroline N-oxide and the acetonide of (2E,4S)-4,5-dihydroxy-2-
pentenoic acid derived from (S)-malic acid and mannitol, respectively. The process was completely stereoselective and allowed the
total control of the relative and absolute configuration of the five contiguous stereocentres of the product.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
tial in many diseases, such as viral infection, cancer and
diabetes.
Natural polyhydroxyindolizidines, such as (+)-castano-
spermine, (+)-lentiginosine and (ꢀ)-swainsonine
Our group has been involved in providing a general
access to natural and unnatural iminosugars through a
cycloaddition strategy using enantiopure mono- and
(
Fig. 1), display interesting biological activity as glycosi-
1
,2
dase inhibitors. These alkaloids, which have a nitro-
gen atom in the ring decorated with several hydroxyl
functionalities, mimic the structure of monosaccharides,
although they display a less obvious structural relation-
ship with them. For example, (+)-castanospermine can
be regarded as a bicyclic derivative of 1-deoxynojirimy-
cin (DNJ), with an ethylene bridge between the
hydroxymethyl group and the ring nitrogen. For these
reasons, they can compete with the natural substrates
of these enzymes and have enormous therapeutic poten-
3
–7
dihydroxylated pyrroline-N-oxides
as providers of
the pyrrolidine component of the molecule and of dia-
stereofacial control in the cycloaddition step, that is,
in the establishment of various stereogenic centres of
8
–15
the final compound.
The use of an intramolecular
1
5
process expands the utility of the methodology, allow-
ing the synthesis of indolizidine derivatives having a
[1,8a]-cis-relationship as in castanospermine.
Herein, we report the application of the intramolecular
1
,3-dipolar cycloaddition of an enantiopure mono-
OH
OH
OH
OH
OH
H
hydroxylated pyrroline-N-oxide to the stereoselective
synthesis of c-lactone of the (1S,6R,7S,8S,8aS)-1,6,7-tri-
hydroxyindolizidin-8-carboxylic acid.
H
H
N
HO
HO
8
1
OH
OH
6
N 3
N
(+)-castanospermine
(+)-lentiginosine
(−)-swainsonine
2. Results and discussion
OH
HO
HO
OH
The synthesis of indolizidine structures 1 containing the
highest possible number of hydroxyl groups in the six-
membered ring and a carboxylic group suitably linking
the iminosugar to aglycone moieties (or easily reducible
to hydroxymethyl group ) was planned starting from
ketone 2. The introduction of hydroxyl functionalities
could be achieved via the carbonyl group of lactone 2,
which in turn, could be prepared by a two-step intramo-
lecular 1,3-dipolar cycloaddition/thermal rearrangement
NH
1-deoxynojirimycin
DNJ
1
5
Figure 1. Naturally occurring glycosidase inhibitors.
*
Corresponding author. Tel.: +39 055 4573485; fax: +39 055
573572; e-mail: alberto.brandi@unifi.it
4
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.12.003

F. Pisaneschi et al. / Tetrahedron: Asymmetry 17 (2006) 292–296
293
O
O
O
O
O
O
O
O
H
H
H
HO
HO
O
N
N
N
N
O
O
1
2
3
4
Scheme 1.
(
1
DC–TR) sequence16,17 starting from nitrone 4 (Scheme
).
molecular variant20–22 of the process was also studied.
The cycloaddition of the nitrone 12 with ethyl cyclopro-
1
8,19
pylideneacetate 13
gave two diastereomeric cyclo-
Monohydroxylated cyclic nitrone 5, derived from L-
malic acid and protected at the OH functionality as a
tetrahydropyranyl (THP) ether, was chosen as the start-
ing material. In a previous paper, we reported that the
OH-deprotected nitrone was not configurationally sta-
ble and thus it was necessary to protect the 1,3-dipole
function before coupling a dipolarophile with the hydro-
xy moiety. The protection was achieved by means of a
adducts 14 and 15, derived, respectively, from anti-endo
and anti-exo approaches, in 5:1 ratio and good yield
(69%) (Scheme 4).
1
5
tBuO
EtO C
EtO C
OtBu
2
H
OtBu
2
H
CO Et
2
4'
N 6'
+
+
2'
N
O
69%
N
O
O
5
: 1
1
,3-dipolar cycloaddition with a dipolarophile, which
1
3
14
15
1
2
was subsequently removed by a thermally induced cyclo-
reversion. Fumaronitrile 6 proved to be the best protect-
ing dipolarophile. Nitrone 5 was added to fumaronitrile
∆ /
/
∆
EtO C
O
CO Et
2
OtBu
2
OtBu
H
N
O
6
to give isoxazolidine 7 as a mixture of three (not
separated) isomers in a very good yield (86%). The
THP group was then removed and the configurationally
stable alcohol 8 (Scheme 2) esterified with the desired
dipolarophile.
HN
1
6
17
Scheme 4.
By refluxing 14 in xylenes, a complex reaction mixture
was obtained from which only traces of enaminone 17,
a product of rearrangement with 1,5-H shift, was
recovered after purification. Indolizidinone 16 was not
even detected in the reaction mixture.
THPO
NC
OTHP
NC
OH
NC
a)
b)
1
7
+
NC
NC
N
N
N
CN
O
O
O −
5
6
7
8
Scheme 2. Reagents and conditions: (a) CH
2
Cl
2
, rt, overnight (86%);
To reach our goal, it was clear that a different strategy,
starting from the same nitrone, should be used. Another
logical option was to install the hydroxyl functionality
already in the dipolarophile. The protected enantiomeri-
cally pure E-dihydroxypentenoic acid 18 was suitable as
it could be synthesized in a straightforward way starting
15
(b) Amberlyst 15, MeOH, 55 °C (97%).
Cyclopropylideneacetic acid 9, synthesized according to
1
8,19
known procedures,
was utilized as dipolarophile and
then introduced on alcohol 8 by esterification mediated
by chlorotriazine, to give 10 in 55% yield (Scheme 3).
2
3,
from mannitol.
Esterification of alcohol 8 with 18 gave isoxazolidine 19
in 65% yield. Esters 19, when refluxed in xylenes for
10 min, lost fumaronitrile by cycloreversion and sponta-
neously underwent intramolecular cycloaddition to
exclusively give tricyclic cycloadduct 20 in 84% yield
(Scheme 5).
O
O
O
HO
2
C
O
O
a)
NC
O
H
N
3
8
+
//
NC
4
2
N 6
-
N
9
O
O
O
+
1
0
11
After hydrolysis of the acetonide, diol 21 was mesylated.
Using 1 equiv of mesylchloride and performing the
reaction at 0 °C, the primary alcohol was selectively
mesylated in the presence of the secondary. Mesylate
Scheme 3. Reagents and conditions: (a) 2-chloro-4,6-dimethoxy-1,3,5-
triazine, NMM, THF (55%).
2
2 could not be isolated as the isoxazolidine nitrogen
Unfortunately, any attempt to run the retrocycloaddi-
tion/deprotection and further the intramolecular DC–
TR process failed, probably due to the instability of
the methylenecyclopropane moiety under the reaction
conditions (refluxing toluene).
atom spontaneously underwent an intramolecular nucleo-
philic displacement. Salt 23 was directly subjected to
catalytic hydrogenation to give indolizidine lactone 24
The free acid is obtained in 83% yield from the ethyl ester by treating
the ester with NaOH 1 M in THF at rt followed by neutralization
with acid.
To verify the possibility of obtaining [1,8a]-trans-indo-
lizidinone 16 from a cyclopropylidene acetate, the inter-

294
F. Pisaneschi et al. / Tetrahedron: Asymmetry 17 (2006) 292–296
O
priately dried before use. NMR spectra were recorded in
O
CDCl and the data are reported in (ppm) from TMS.
Multiplicity of the C NMR was determined by means
of APT. In mass spectra, relative percentages are shown
3
O
O
13
O
O
NC
O
H
N
a)
b)
O
H
8
+
O
CO H
2
3
6
in brackets. R values refer to TLC on 0.25 mm silica gel
NC
f
1
8
N
O
O
O
plates.
1
9
20
4.2. (4S)-2,3-Dicyanohexahydropyrrolo[1,2-b]isoxazol-
4-yl cyclopropylideneacetate 10
Scheme 5. Reagents and conditions: (a) DMAP/DMAP.TFA cat.,
DIC, CH Cl , rt, 4 d (65%); (b) xylenes, reflux, 10 min (84%).
2
2
N-Methylmorpholine (NMM; 235 lL, 2.14 mmol) was
added dropwise to a solution of cyclopropylideneacetic
acid 9 (63 mg, 0.65 mmol) and 2-chloro-4,6-dimeth-
oxy-1,3,5-triazine (136 mg, 0.78 mmol) in dry THF
after treatment with a strongly basic ionic-exchange
resin. Finally, purification by chromatography on silica
gel afforded pure 24 in 31% overall yield from 21 and
with complete control of the five stereogenic centres
(1.5 mL). The mixture was stirred at rt for 1.5 h, then
(
Scheme 6).
a solution of isoxazolidines 8 (58 mg, 0.32 mmol) in
dry THF (2.5 mL) was added. The mixture was stirred
overnight. The solvent was removed under reduced pres-
sure and the recovered solid dissolved in CH Cl . The
O
O
2
2
O
O
H
N
H
organic layer was washed with a saturated solution of
NaHCO and with a saturated solution of NaHSO ,
H
a)
H
b)
O
HO
HO
3
4
N
O
O
O
O
then dried over Na SO , filtered and concentrated. Puri-
2 4
2
0
21
fication of the crude residue by chromatography on
silica gel (petroleum ether/AcOEt, 6:1) afforded esters
O
O
1
O
O
10 (46 mg, 55%) as a white solid. H NMR (200 MHz,
O
H
H
H
c) HO
HO
major isomer): d 6.23 (m, 1H, O CCH@), 5.34 (m, 1H,
H
2
MsO
HO
3
8
4-H), 5.10 (s, 1H, 2-H), 4.13 (m, 2H, 3-H, 3a-H), 3.73–
3.60 (m, 1H, 6-H ), 3.48–3.29 (m, 1H, 6-H ), 2.56–2.37
O
N
5
N
N
O
HO
a
b
MsO
(
m, 1H, 5-H ), 2.15–2.04 (m, 1H, 5-H ), 1.52–1.20 (m,
2
2
23
24
a
b
4
H, @CCH CH ).
2
2
Scheme 6. Reagents and conditions: (a) (i) TFA, CH
2
Cl
CN, DIPEA (99%); (b) MsCl, pyridine, 0 °C, 3 h; (c) (i)
(1 atm), MeOH, rt, overnight; (ii) Ambersep 900 OH, MeOH
2
, 0 °C then rt,
2
h; (ii) CH
3
0 0 0 0 0 0 0
.3. Ethyl (3 R,3a R,4 S)- and (3 S,3a R,4 S)-4 -tert-
butoxytetrahydro-3 H-spiro[cyclopropane-1,2 -
4
Pd/C, H
2
0
0
(31%).
0
pyrrolo[1,2-b]isoxazole]-3 -carboxylate 14 and 15
3
. Conclusion
Ethyl cyclopropylideneacetate 13 (106 mg, 0.84 mmol)
was added to a solution of nitrone 12 (100 mg,
0.64 mmol) in toluene (0.64 mL). The mixture was stir-
red at rt overnight. The solvent was removed under
reduced pressure and the crude product purified on silica
gel (petroleum ether/AcOEt, 5:1). The diastereoisomers
14 (104 mg) and 15 (20 mg) were obtained in a 5:1 ratio
The synthesis of the indolizidine lactone 24 presented
herein has many interesting aspects. The high stereose-
lectivity allowed us to run seven steps (starting from nit-
rone 5 and dipolarophile 18) without any formation of
diastereomeric by-products and, therefore, without any
need for separation. The method allowed complete con-
trol of the absolute configuration of five contiguous ste-
reogenic centres in these molecules with many
stereogenic carbons. The choice of the appropriate
configuration of the starting malic acid, and the E- or
Z-configuration of the dipolarophile, and moreover,
the intra- or intermolecular version of the cycloaddition
is able to give rise to a whole family of stereodifferenti-
ated polyhydroxyindolizidine carboxylic acid deriva-
tives. Finally, compound 24, is a suitable precursor for
the linkage of the iminosugar structure to different sub-
strates using the carboxyl tether. Research along this
line is currently in progress in our laboratories.
(overall yield: 69%). Compound 14: R = 0.22 (pentane/
f
2
D
3
1
AcOEt, 4:1); ½aꢁ ¼ þ55:2 (c 0.5, CHCl ); H NMR
3
0
(200 MHz): d 4.28–4.11 (m, 1H, 4 -H), 4.18 (q,
J = 6.9 Hz, 2H, CH CH ), 4.03 (dd, J = 9.2, 2.6 Hz,
2
3
0
0
1H, 3a -H), 3.44 (d, J = 9.5 Hz, 1H, 3 -H), 3.38–3.18
(m, 2H, 6 -H), 2.35–2.17 (m, 1H, 5 -H ), 1.78–1.65 (m,
1H, 5 -H ), 1.30 (t, J = 7.1 Hz, 3H, CH CH ), 1.15 (s,
9H, t-Bu), 1.12–0.82 (m, 4H, C-2CH CH C-2);
NMR (50 MHz): d 170.9 (s, CO), 77.4 (d, C-4 ), 73.8
(s, CMe ), 73.6 (d, C-3a ), 64.2 (s, C-2 ), 60.7 (t,
CH CH ), 55.0 (t, C-6 ), 53.8 (d, C-3 ), 34.2 (t, C-5 ),
0
0
a
0
b
2
3
1
3
C
2
2
0
0
0
3
0
0
0
2
3
28.3 (q, CMe ), 14.2 (t, CH CH ), 12.7, 7.5 (t,
3
2
3
C-2CH CH C-2); IR (CDCl ): m 2977, 1740, 1363,
2
2
3
ꢀ
1
+
1
(
174 cm ; MS (70 eV, EI): m/z (%) 283 (1) [M ], 226
18), 209 (11), 180 (14), 170 (60), 152 (13), 57 (100). Ele-
mental analysis calcd for C H NO (283.36): C, 63.58;
4
. Experimental
1
5
25
4
H, 8.89; N, 4.94. Found: C, 63.10; H, 9.00; N, 5.26.
4
.1. General
Compound 15: R = 0.18 (petroleum ether/AcOEt, 5:1);
f
2
D
3
1
All the reactions requiring anhydrous conditions were
carried out under nitrogen and the solvents were appro-
½aꢁ ¼ þ115:0 (c 0.4, CHCl ); H NMR (200 MHz): d
3
0
4.17 (dd, J = 7.0, 2.2 Hz, 1H, 4 -H), 4.23–4.02 (m, 3H,

F. Pisaneschi et al. / Tetrahedron: Asymmetry 17 (2006) 292–296
295
0
0
3
a -H, CH CH ), 3.36–3.26 (m, 2H, 6 -H), 3.16 (d,
5.7 Hz, 1H, CHHO), 3.94 (dd, J = 8.9, 4.0 Hz, 1H,
CHHO), 3.71 (dd, J = 8.8, 1.8 Hz, 1H, 2a-H), 3.47–
3.34 (m, 1H, 5-H ), 3.17–3.02 (m, 1H, 5-H ), 2.33–2.23
2
3
0
0
J = 4.4 Hz, 1H, 3 -H), 2.32–2.14 (m, 1H, 5 -H ), 1.78–
.64 (m, 1H, 5 -H ), 1.26 (t, J = 7.1 Hz, 3H, CH CH ),
a
0
1
b
2
3
a
b
1
.17 (s, 9H, t-Bu), 1.09–0.66 (m, 4H, C-2CH CH C-2);
(m, 2H, 6-H), 1.49 (s, 3H, CH ), 1.35 (s, 3H, CH );
C NMR (50 MHz): d 176.8 (s, CO), 110.1 (s, OCO),
84.1, 82.8, 74.6, 70.7 (d, C-6a, C-6b, C-3, CHO), 66.9
2
2
3 3
1
3
0
13
C NMR (50 MHz): d 170.0 (s, CO), 77.1 (d, C-4 ),
0
0
7
3.8 (s, CMe ), 73.1 (d, C-3a ), 63.9 (s, C-2 ), 61.1 (t,
3
0
0
0
CH CH ), 56.0 (d, C-3 ), 55.1 (t, C-6 ), 33.0 (t, C-5 ),
(t, CH O), 53.3 (t, C-5), 51.5 (d, C-2a), 32.1 (t, C-6),
2
3
2
2
2
1
8.4 (q, CMe ), 14.2 (q, CH CH ), 9.6–8.2 (t, C-
26.9 (q, CH ), 25.0 (q, CH ); IR (CDCl ): m 2990,
3
2
3
3
3
3
ꢀ
1
CH CH C-2); IR (CDCl ): m 2977, 1745, 1363, 1261,
2929, 1773, 1374, 1185, 1073, 1053 cm ; MS (70 eV,
2
2
3
ꢀ
1
+
+
179 cm ; MS (70 eV, EI): m/z (%) 283 (2) [M ], 238
EI): m/z (%) 255 (4) [M ], 240 (19), 226 (4), 180 (6),
(
(
3), 226 (23), 210 (7), 180 (11), 170 (20), 154 (16), 124
38), 96 (46), 57 (100). Elemental analysis calcd for
168 (9), 152 (13), 134 (46), 105 (89), 84 (100); Elemental
analysis calcd for C H NO (255.27): C, 55.68; H,
1
2
17
5
C H NO (283.36): C, 63.58; H, 8.89; N, 4.94. Found:
6.77; N, 5.41. Found: C, 56.45; H, 6.71; N, 5.73.
1
5
25
4
C, 63.39; H, 9.08; N, 5.30.
4.6. (2aS,3S,6aS,6bS)-3-[(1S)-1,2-Dihydroxyethyl]hexa-
hydro-2H-1,4-dioxa-4a-azacyclopenta[cd]pentalen-2-one
21
4
4
.4. (4S)-2,3-Dicyanohexahydropyrrolo[1,2-b]isoxazol-
-yl (2E)-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-
propenoate 19
Trifluoroacetic acid (TFA; 0.6 mL) was added dropwise
A solution of dimethylaminopyridine (DMAP; 102 mg,
to a solution of 20 (36.9 mg, 0.14 mmol) in CH Cl
2
2
0
0
.83 mmol) and trifluoroacetic acid (TFA; 31 lL,
(6.4 mL) at 0 °C. The mixture was warmed up to rt
and stirred for 2 h. The solvent was removed under
reduced pressure to give the trifluoroacetate salt of 21,
which was stirred in acetonitrile in the presence of
N,N-diisopropylethylamine (DIPEA) overnight. The
solvent was removed under reduced pressure and the
crude product purified by chromatography on silica
gel (AcOEt/MeOH, 40:5) to give 22 (29.8 mg, 99%) as
.4 mmol) in dry CH Cl (4.1 mL) was added to a solu-
2
2
tion of acid 18 (710 mg, 4.13 mmol) in dry CH Cl2
2
(
24 mL). The resulting mixture was added to isoxazoli-
dine 8 (341.5 mg, 1.91 mmol) dissolved in dry CH Cl
2
2
(
12 mL). Diisopropylcarbodiimide (DIC; 600 lL,
4
.1 mmol) was added dropwise at rt and the reaction
mixture stirred at rt for 4 days and then the solvent
was removed at reduced pressure. The residue was puri-
fied by chromatography on silica gel (petroleum ether/
AcOEt, 4:1) to afford 19 (415 mg, 65%) as a colourless
oil. R = 0.21 (petroleum ether/AcOEt, 4:1); H NMR
a deliquescent white solid. R = 0.16 (AcOEt/MeOH,
f
2
D
0
1
40:5); ½aꢁ ¼ þ28:4 (c 0.4, MeOH);
H
NMR
(200 MHz): d 5.11 (dt, J = 5.9, 4.0 Hz, 1H, 7a-H), 4.43
(dd, J = 6.2, 2.9 Hz, 1H, 7b-H), 4.35 (dd, J = 6.2,
2.9 Hz, 1H, 3-H), 3.77 (dd, J = 8.8, 2.9 Hz, 1H, 2a-H),
3.66 (td, J = 6.2, 3.3 Hz, 1H, CHOH), 3.66–3.55 (m,
1H, CHHOH), 3.46 (dd, J = 11.9, 6.0 Hz, 1H,
CHHOH), 3.10 (m, 2H, 6-H), 2.18–2.05 (m, 2H, 5-H);
1
f
(
200 MHz):
d
6.95 (dd, J = 15.2, 5.3 Hz, 1H,
O CCH@CH), 6.12 (dd, J = 15.7, 1.3 Hz, 1H,
O CCH@CH), 5.35 (m, 1H, 4-H), 5.08 (s, 1H, 2-H),
2
2
4
.69 (m, 1H, @CHCHO), 4.26–4.07 (m, 2H, 3-H,
1
3
CHHO), 4.02 (dd, J = 8.9, 2.4 Hz, 1H, 3a-H), 3.74–
C NMR (50 MHz): d 179.3 (s, CO), 83.3, 82.5 (d,
3
.60 (m, 2H, 6-H , CHHO), 3.46–3.29 (m, 1H, 6-H ),
C-7a, C-3), 70.0, 69.8 (d, C-7b, CHOH), 61.5 (t,
a
b
2
.59–2.39 (m, 1H, 5-H ), 2.15–2.05 (m, 1H, 5-H ), 1.46
CH OH), 51.4 (t, C-6), 51.0 (d, C-2a), 30.2 (t, C-7); IR
a
b
2
1
3
ꢀ1
(
s, 3H, CH ), 1.42 (s, 3H, CH ); C NMR (50 MHz):
(CDCl ): m 3633, 2928, 1771, 1361, 1186, 1053 cm
;
3
3
3
+
d 165.5 (s, CO), 146.7 (d, O CCH@CH), 120.8 (d,
MS (70 eV, EI): m/z (%) 215 (30) [M ], 198 (6), 196
(7), 184 (17), 179 (5), 153 (18), 124 (7), 86 (71),
83 (100).
2
O CCH@CH), 115.5 (s, CN), 115.3 (s, CN), 110.2
2
(
s, CMe ), 78.0, 74.6, 72.3, 68.3 (d, C-2, C-3a,
3
C-4, @CHCHO), 68.5 (t, CH O), 55.0 (t, C-6), 43.0 (d,
2
C-3), 30.5 (t, C-5), 26.3 (q, CH ), 25.5 (q, CH ); IR
4.7. (2aS,3S,4R,8aS,8bS)-3,4-Dihydroxyoctahydro-2H-
furo[4,3,2-hi]indolizin-2-one 24
3
3
(
CDCl ): m 2990, 2936, 2256, 1723, 1661, 1374, 1259,
3
1 +
ꢀ
1
3
7
064 cm ; MS (70 eV, EI): m/z (%) 333 (0.06) [M ],
18 (10), 276 (5), 240 (5), 161 (56), 97 (79), 84 (100),
7 (56).
Cold
0.17 mmol) was added dropwise to a solution of diol
1 (40.1 mg, 0.17 mmol) in dry pyridine (3 mL) at
methanesulfonylchloride
(MsCl;
14.4 lL,
2
4
4
.5. (2aS,3S,6aS,6bS)-3-[(4S)-2,2-Dimethyl-1,3-dioxolan-
-yl]hexahydro-2H-1,4-dioxa-4a-azacyclopenta-
0 °C. The mixture was stirred for 2 h at 0 °C and then
the solvent evaporated under reduced pressure. The
solid was dissolved in MeOH (3 mL) and a catalytic
amount of Pd/C added. The mixture was stirred over-
night under a hydrogen atmosphere. The catalyst was
removed by filtration and the filtrate was concentrated
under reduced pressure. The residue was dissolved in
MeOH, treated with Ambersep 900 OH, filtered and
concentrated under reduced pressure. The residue was
purified by chromatography on silica gel (CH Cl /
[
cd]pentalen-2-one 20
A solution of ester 19 (41 mg, 0.12 mmol) in xylenes
11 mL) was refluxed for 10 min. The mixture was puri-
(
fied by chromatography on silica gel (first petroleum
ether to remove the high boiling solvent, then petroleum
ether/AcOEt, 1:1). The tricyclic isoxazolidine 20
(
(
26.1 mg, 84%) was obtained as white solid. R = 0.22
f
25
2
2
petroleum ether/AcOEt, 1:1); ½aꢁ ¼ þ27:8 (c 1.28,
MeOH, 10:1) to yield 24 (10.5 mg, 31%) as a colourless
D
1
20
CHCl ); H NMR (200 MHz): d 5.47 (m, 1H, 6a-H),
oil. R = 0.12 (CH Cl /MeOH, 10:1); ½aꢁ ¼ þ5:6 (c
3
f
2
2
D
1
4
.41–4.22 (m, 3H, 3-H, 6b-H, CHO), 4.11 (dd, J = 8.9,
0.16, MeOH); H NMR (200 MHz): d 5.06 (t,

296
F. Pisaneschi et al. / Tetrahedron: Asymmetry 17 (2006) 292–296
J = 4.4 Hz, 1H, 8a-H), 4.06–3.98 (m, 2H, 3-H, 4-H),
6. Cicchi, S.; Nunes, J., Jr.; Goti, A.; Brandi, A. Eur. J. Org.
Chem. 1998, 419–421.
3
.92–3.84 (m, 1H, 8b-H), 3.53 (ddd, J = 10.4, 8.6,
7
. Cicchi, S.; Corsi, M.; Brandi, A.; Goti, A. J. Org. Chem.
002, 67, 1678–1681.
5
.5 Hz, 1H, 7-H ), 3.34 (dd, J = 14.8, 2.7 Hz, 1H, 5-
a
2
H ), 3.02 (td, J = 7.9, 1.5 Hz, 1H, 7-H ), 2.89–2.78 (m,
a
b
8
. Brandi, A.; Cicchi, S.; Cordero, F. M.; Frignoli, R.; Goti,
2
2
H, 2a-H, 5-H ), 2.22 (dd, J = 13.7, 5.3 Hz, 1H, 8-H ),
.07–1.86 (m, 1H, 8-Hb); C NMR (50 MHz): d 173.6
b a
1
3
A.; Picasso, S.; Vogel, P. J. Org. Chem. 1995, 60, 6806–
6
812.
(
8
s, C-2), 85.5, 71.0, 70.2, 61.4 (d, C-3, C-4, C-8a, C-
b), 52.7 (t, C-7), 50.6 (t, C-5); 40.6 (d, C-2a), 32.4 (t,
C-8); IR (CDCl ): m 3468, 2921, 1747, 1438, 1348,
9
. Goti, A.; Cardona, F.; Brandi, A. Tetrahedron: Asymme-
try 1996, 7, 1659–1674.
3
10. Goti, A.; Cardona, F.; Brandi, A. Synlett 1996, 8, 761–
763.
11. Goti, A.; Cicchi, S.; Fedi, V.; Nannelli, L.; Brandi, A. J.
Org. Chem. 1997, 62, 3119–3125.
ꢀ
1
1
180, 1059 cm ; MS (70 eV, EI): m/z (%): 199 (27)
+
[
M ], 197 (23), 171 (5), 107 (35), 97 (100), 84 (85). Ele-
mental analysis calcd for C H NO (199.20): C, 54.26;
9
13
4
1
1
1
1
1
1
2. Cardona, F.; Valenza, S.; Picasso, S.; Goti, A.; Brandi, A.
H, 6.58; N, 7.03. Found: C, 53.96; H, 6.18; N, 6.71.
J. Org. Chem. 1998, 63, 7311–7318.
3. Goti, A.; Cicchi, S.; Cacciarini, M.; Cardona, F.; Fedi, V.;
Brandi, A. Eur. J. Org. Chem. 2000, 3633–3645.
4. Goti, A.; Cacciarini, M.; Cardona, F.; Cordero, F. M.;
Brandi, A. Org. Lett. 2001, 3, 1367–1369.
5. Cordero, F. M.; Pisaneschi, F.; Gensini, M.; Goti, A.;
Brandi, A. Eur. J. Org. Chem. 2002, 1941–1951.
6. Brandi, A.; Cordero, F. M.; De Sarlo, F.; Goti, A.;
Guarna, A. Synlett 1993, 1–8.
Acknowledgements
Authors thank the MIUR-Rome, for financial support
(
Project PRIN 2003 and FIRB RBNE017F8N). Ente
Cassa di Risparmio di Firenze is acknowledged, for
granting a 400 MHz NMR spectrometer.
7. Cordero, F. M.; Goti, A.; Brandi, A. Top. Curr. Chem.
1
996, 178, 1–97.
18. Spitzer, D.; Swoboda, H. Tetrahedron Lett. 1986, 27,
281–1284.
References
1
1
. Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J.
Tetrahedron: Asymmetry 2000, 11, 1645–1680, and refer-
ences therein.
19. Thiemann, T.; Ohira, D.; Li, Y.; Sawada, T.; Matake, S.;
Rauch, K.; Noltameyer, M.; de Meijer, A. J. Chem. Soc.,
Perkin Trans. 1 2000, 2968–2976.
2
. Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R.
J.; Nash, R. J. Phytochemistry 2001, 56, 265–295, and
references therein.
20. Brandi, A.; Carli, S.; Goti, A. Heterocycles 1988, 27, 17–
20.
21. Brandi, A.; Cordero, F. M.; De Sarlo, F.; Gandolfi, R.;
Rastelli, A.; Bagatti, M. Tetrahedron 1992, 48, 3323–
3334.
22. Cordero, F. M.; Anichini, B.; Goti, A.; Brandi, A.
Tetrahedron 1993, 49, 9867–9876.
23. Zhao, Y.; Yang, T.; Lee, M.; Lee, D.; Newton, M. G.;
Chu, C. K. J. Org. Chem. 1995, 60, 5236–5242.
3
4
5
. Cicchi, S.; Goti, A.; Brandi, A. J. Org. Chem. 1995, 60,
4743–4748.
. Goti, A.; Cacciarini, M.; Cardona, F.; Brandi, A. Tetra-
hedron Lett. 1999, 40, 2853–2856.
. Cicchi, S.; Hold, I.; Brandi, A. J. Org. Chem. 1993, 58,
5274–5275.