Solid-phase access to polyhydroxypyrrolizidines by 1,3-dipolar cycloaddition of (S)-3-alkoxypyrroline N-oxide to maleate and crotonate derivatives

Article abstract of DOI:10.1016/S0040-4039(02)01208-X

2,7-Dihydroxyhexahydropyrrolizine-1-carboxylic acid derivatives have been prepared in solid-phase by intermolecular 1,3-dipolar cycloaddition between an immobilised maleate or 4-hydroxycrotonate and an enantiopure 3-alkoxypyrroline N-oxide.

Full text of DOI:10.1016/S0040-4039(02)01208-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5711–5714
Solid-phase access to polyhydroxypyrrolizidines by 1,3-dipolar
cycloaddition of (S)-3-alkoxypyrroline N-oxide to maleate and
crotonate derivatives
Federica Pisaneschi, Carmela Della Monica, Franca M. Cordero* and Alberto Brandi*
Dipartimento di Chimica Organica ‘Ugo Schiff’, Universita` degli Studi di Firenze, Polo Scientifico, via della Lastruccia 13,
I-50019 Sesto Fiorentino (FI), Italy
Received 29 May 2002; revised 14 June 2002; accepted 25 June 2002
Abstract—2,7-Dihydroxyhexahydropyrrolizine-1-carboxylic acid derivatives have been prepared in solid-phase by intermolecular
1,3-dipolar cycloaddition between an immobilised maleate or 4-hydroxycrotonate and an enantiopure 3-alkoxypyrroline N-oxide.
© 2002 Elsevier Science Ltd. All rights reserved.
Polyhydroxypyrrolizidines,1 as well as indolizidines and
1,3-Dipolar cycloaddition of (S)-3-tert-butoxy-1-pyrro-
imminosugars are potential inhibitors of glycosidases, a
class of enzymes which hydrolyse glycosidic bonds in
oligo- and polysaccharide chains. Glycosidases are
involved in the biosynthesis of glycoproteins, which are
responsible for cell to cell and cell to exogen molecular
recognition processes. Inhibitors of these enzymes can
therefore be active as antibacterial, antitumoral and
antiviral agents. The great interest mounted in recent
years in the synthesis of these compounds prompted the
search for new general and stereoselective synthetic
methods. Solid-phase synthesis2 has recently imposed as
a modern mean of synthesis particularly to produce
combinatorial libraries of compounds of biological
interest. We have investigated two different syntheses of
line-N-oxide 5 and methylmaleate 6 in toluene at rt for
3 days,5 gave three diastereomeric adducts in a 5:1:1
ratio in favour of the exo–anti isoxazolidine 7 (89%
total yield). Treatment of 7 with Mo(CO)6 in refluxing
CH3CN6 afforded directly the pyrrolizidinone 8 in 82%
yield, through a two-step domino process consisting of
reduction of NꢀO bond followed by intramolecular
amidation (Scheme 2).
The solid-phase version of this process was studied with
the aim of obtaining a pyrrolizidine scaffold linked to a
resin. Monoethyl maleate was linked to Wang resin in
standard coupling conditions (DIC, DMAP, CH2Cl2).7
3-Tetrahydropyranyloxy-1-pyrroline N-oxide 103d,e
reacted with the supported dipolarophile 9 in CH2Cl2 at
2,7-dihydroxyhexahydropyrrolizine-1-carboxylic
acid
derivatives either in solution and on solid-phase, based
on 1,3-dipolar cycloaddition of pyrroline N-oxide 1.3
Actually the hydroxy pyrrolizidine skeleton 4 could be
easily obtained by 1,3-dipolar cycloaddition4 of an
enantiopure cyclic hydroxylated nitrone 1 and a
maleate 2a or a crotonate 2b derivative, followed by a
suitable elaboration of the adducts. In particular the
primary adducts 3 were transformed in the polyhydroxy-
pyrrolizidines 4 (Scheme 1) by reductive cleavage of
NꢀO bond followed by cyclisation.
OR
CO2R1
R2
*
CO2R1
2a
R1O2C
+
N
O
-
2b
1
CO2R1
CO2R1
RO
RO
*
*
*
CO2R1
*
*
*
*
*
*
N
N
3b
R2
O
3a
O
CO2R1
CO2R1
RO
RO
*
*
*
*
*
OH
OH
*
*
N
N
4b
Keywords: solid-phase synthesis; 1,3-dipolar cycloaddition; nitrone;
pyrrolizidines.
4a
O
* Corresponding authors. Tel.: +39-055-4573498; fax: +39-055-
4573531; e-mail: franca.cordero@unifi.it
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01208-X

5712
F. Pisaneschi et al. / Tetrahedron Letters 43 (2002) 5711–5714
pyrrolizidine 13 was obtained in 40% total yield. Only
OtBu
CO2Me
traces of minor diastereomeric pyrrolizidinones were
present in the crude mixtures, suggesting that the
cycloaddition occurs with higher diastereoselectivity on
solid-phase than in solution. On the contrary, no
regioselectivity was observed in the reaction of 10 with
the asymmetric diester 9.
+
+
N
O
5
CO2Me
-
6
CO2Me
OH
tBuO
CO2Me
tBuO
H
H
CO2Me
N
N
O
To bypass this problem, we decided to link a crotonic
acid derivative to the solid support. Actually in solu-
tion, cycloadditions of cyclic nitrones with these dipo-
larophiles run in a regio- and stereoselective manner to
give usually only one adduct.3d,e,9 The synthesis of
crotonates 14 and 15 were performed starting from
commercially available cis-1,4-butendiol (16) which was
protected as p-methoxybenzyl (PMB) ether by
acetalysation10 with p-anisaldehyde followed by reduc-
tion with DIBAL. Oxidation with Jones reagent fur-
nished the trans-4-p-methoxybenzyloxy crotonic acid
(14), that was coupled with hydroxypolystyrenic Mer-
rifield and Wang resins in the solid-phase path. Esterifi-
cation and mesylation of 14 gave 15 (Scheme 4) which
was used as dipolarophiles in the solution path.
O
7
8
Scheme 2.
rt in 14 days. The reaction progress was monitored by
cleaving small amount of products from resin and
analysing the mixture by 1H NMR. The spectra showed
the presence of two regioisomeric isoxazolidines deriv-
ing from the adducts 11a and 11b in ca 1:1 ratio.
Treatment of the resin with Mo(CO)6 in toluene/
CH3CN/water mixture at reflux induced the reduction/
cyclisation process that in the case of 11b resulted in the
concurrent cleavage of the product from the resin
(Scheme 3). THP deprotection of 12b followed by
purification on silica-gel afforded the pyrrolizidinone
138 in 22% yield with respect to the resin loading (1.10
mmol/g). The resin 12a, containing the second part of
the product, was left dark brown after treatment with
Mo(CO)6. Several attempts were made to clean the
resin from traces of the metal. Only the treatment with
ethylenediamine appeared to be able to clean resin, but
caused also the cleavage of a significant amount of
pyrrolizidinone by a transamidation reaction. The
cleavage of the dark resin 12a with TFA followed by
esterification allowed the recovery of the second batch
The solution-procedure used by Tufariello9 to obtain
racemic pyrrolizidines, was repeated using the optically
active nitrone 5 and then adapted to the solid-phase
synthesis of enantiomerically pure products. Nitrone 5
was allowed to react with ethyl 4-mesyloxy crotonate
(15) in toluene at rt for 7 days. The regio- and
diastereoselective 1,3-dipolar cycloaddition furnished 18
as a single adduct. The regioselectivity was driven by
orbital interactions, while both orbital and steric factors
favoured stereoselectively the endo(COOEt)–anti transi-
tion state. Hydrogenation of the adduct 18 followed by
final base-treatment gave pyrrolizidine 1911 in three
steps and 52% overall yield (Scheme 5).
of product 13 in
a 18% yield. In conclusion
a
b
HO
OH
HO
c
OPMB
17
16
EtO2C
OMs
HO2C
OPMB
15
14
Scheme 4. Reagents and conditions: (a) (1) p-anisaldehyde,
pTsOH, benzene, reflux, (2) DIBAL, toluene, 0°C (87%); (b)
CrO3, H2SO4, acetone, rt (52%); (c) (1) pTsOH, EtOH, ben-
zene, reflux (62%), (2) MsCl, TEA, CH2Cl2, 0°C“rt (68%).
OtBu
a
+
EtO2C
OMs
N
+
-
15
O
5
CO2Et
CO2Et
tBuO
tBuO
H
N
H
b
OH
N
O
OMs
Scheme 3. Reagents and conditions: (a) DIC, DMAP, CH2Cl2,
12 h; (b) CH2Cl2, rt, 14 days; (c) Mo(CO)6, toluene, CH3CN,
H2O, reflux, 4 h; (d) (1) TFA, CH2Cl2, (2) TMSCl, EtOH; (e)
EtOH, Amberlyst 15.
18
19
Scheme 5. Reagents and conditions: (a) toluene, rt, 7 days; (b)
(1) Pd(OH)2/C, EtOH, H2, rt, (2) Ambersep 900 OH (52%).

F. Pisaneschi et al. / Tetrahedron Letters 43 (2002) 5711–5714
5713
For the solid-phase synthesis of the same pyrrolizidine
Acknowledgements
19 both hydroxypolystyrenic Merrifield and Wang
resins were employed and the first coupling step
between the resins and the protected alcohol 14 was
performed by using the standard coupling procedure
(Scheme 6). Resin 20 was deprotected with DDQ and
mesylated. Treatment of resin 21 with 4 equiv. of
nitrone 10 for 11 days furnished resin 22 (Scheme 6),
whose formation was monitored by cleaving and
The authors thank Italfarmaco SpA and MIUR (Minis-
tero dell’Istruzione, dell’Universita` e della Ricerca,
Italy, COFIN 2000) for financial support and Professor
M. Taddei for helpful discussions.
1
recording an H NMR spectrum of the residue. As in
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filtration of the solid residue. Crude 23 was esterified in
dry EtOH in the presence of trimethylsilylchloride
(TMSCl) and treated with basic ion-exchange resin
Ambersep 900 OH to furnish 2415 in 11% overall yield
(Scheme 7) with respect to the loading of resins (Wang
resin: 1.10 mmol/g, Merrifield resin: 0.68 mmol/g).
In conclusion, the solid-phase synthesis of highly func-
tionalised enantiopure pyrrolizidines has been achieved.
A selective method to reduce the NꢀO bond of isoxazo-
lidine without removal from the resin is still necessary
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Scheme 6. Reagents and conditions: (a) DIC, DMAP, CH2Cl2,
rt; (b) (1) DDQ, H2O, CH2Cl2, rt, (2) MsCl, CH2Cl2, rt; (c)
10, toluene, rt, 11 days.
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rolizine-1-carboxylate (13): H NMR (200 MHz, CDCl3):
l 4.78 (d, J=9.9 Hz, 1H; H-2), 4.24 (q, J=7.0 Hz, 2H;
CH2CH3), 4.15 (q, J=6.6 Hz, 1H; H-7), 3.65 (m, 2H;
Ha-5, H-7a), 3.23 (m, 1H; Hb-5), 2.92 (dd, J=9.8, 8.5 Hz,
1H; H-1), 2.35–2.19 (m, 1H; Ha-6), 2.08–1.90 (m, 1H;
Hb-6), 1.29 (t, J=7.0 Hz, 3H; CH2CH3); 13C NMR (50
MHz, CDCl3): l 172.2 (s), 171.0 (s), 75.2 (d), 74.6 (d),
64.7 (d), 61.8 (t), 54.4 (d), 40.5 (t), 33.8 (t), 14.1 (q).
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Scheme 7. Reagents and conditions: (a) Pd(OAc)2, DMF, H2,
35 atm, rt; (b) (1) TMSCl, EtOH, rt, (2) Ambersep 900 OH.
10. Rollins, S. B.; Williams, R. M. Tetrahedron Lett. 1997,
23, 4033–4036.

5714
F. Pisaneschi et al. / Tetrahedron Letters 43 (2002) 5711–5714
11. Ethyl
(1R,2R,7S,7aR)-7-tert-butoxy-2-hydroxyhexahy-
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dropyrrolizine-1-carboxylate (19): 1H NMR (200 MHz,
CDCl3): l 4.56 (dt, J=6.1, 7.7 Hz, 1H; H-2), 4.19 (q,
J=7.1 Hz, 1H; CHHCH3), 4.18 (q, J=7.1 Hz, 1H;
CHHCH3), 4.14–4.04 (m, 1H; H-7), 3.42 (dd, J=8.5, 3.2
Hz, 1H; H-7a), 3.35 (dd, J=10.0, 6.1 Hz, 1H; Ha-3),
3.24–3.11 (m, 1H; Ha-5), 2.73 (ddd, J=11.7, 6.1, 4.8 Hz,
1H; Hb-5), 2.57 (dd, J=7.9, 2.2 Hz, 1H; H-1), 2.52 (dd,
J=7.8, 4.1 Hz, 1H; Hb-3), 2.16–1.93 (m, 1H; Ha-6),
1.79–1.59 (m, 1H; Hb-6), 1.28 (t, J=7.1 Hz, 3H;
CH2CH3); 1.17 (s, 9H; tBu); 13C NMR (50 MHz,
CDCl3): l 172.8 (s), 76.8 (d), 75.1 (d), 73.6 (s), 73.3 (d),
60.9 (t), 60.8 (t), 56.2 (d), 53.2 (t), 33.1 (t), 28.4 (q, 3C),
14.2 (q).
15. Ethyl
(1R,2R,7S,7aR)-2,7-dihydroxyhexahydropyrroli-
1
zine-1-carboxylate (24): H NMR (500 MHz, CDCl3): l
4.63 (dt, J=6.1, 7.9 Hz, 1H, H-2), 4.33 (dt, J=3.3, 5.0
Hz, 1H; H-7), 4.23 (q, J=7.2 Hz, 2H, OCH2CH3), 3.56
(dd, J=9.3, 3.2 Hz, 1H, H-7a), 3.48 (dd, J=10.1, 6.1 Hz,
1H; Ha-3), 3.36 (dt, J=12.7, 6.7 Hz, 1H; Ha-5), 2.82 (dt,
J=12.7, 6.3 Hz, Hb-5), 2.63 (dd, J=10.1, 7.9 Hz, 1H;
Hb-3), 2.59 (t, J=8.4 Hz, 1H; H-1), 2.28–2.19 (m, 1H;
Ha-6), 1.98–1.70 (m, 3H; Hb-6, OH, OH), 1.31 (t, J=7.2
Hz, 3H; OCH2CH3); 13C NMR (50 MHz, CDCl3): l
173.3 (s), 77.4 (d), 74.3 (d), 73.1 (d), 61.3 (t), 60.4 (t), 55.7
(d), 53.1 (t), 33.6 (t), 14.2 (q).
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