Synthesis of trihydroxylated pyrrolizidine using 1,3-Dipolar cycloaddition of D-erythrose derived nitrone

Article abstract of DOI:10.1055/s-2001-18783

A route has been developed for the synthesis of enantiomerically and diastereomerically pure trihydroxylated pyrrolizidines. A chiral sugar derived nitrone undergoes diastereoselective dipolar cycloaddition with methyl acrylate to afford erythro-cis isoxazolidine; a suitable cycloadduct undergoes N-O cleavage and recyclization to (1S,2R,6R,7aS)-trihydroxylated pyrrolizidine.

Full text of DOI:10.1055/s-2001-18783

1866
LETTER
Synthesis of Trihydroxylated Pyrrolizidine using 1,3-Dipolar Cycloaddition of
D-Erythrose Derived Nitrone
Synthesis
u
of Trihydrox
r
ylated P
a
yrrolizidine
j
by Cycloadd
K
ition of
D
-Erythro
u
se Derived
N
b
itrone á ,a Andrej Kolarovi ,a Lubor Fišera,*a Volker Jäger,*b Otakar Humpa,c Nada Prónayovád
a
Department of Organic Chemistry, Slovak University of Technology, SK-812 37 Bratislava, Slovak Republic
E-mail: fisera@cvt.stuba.sk
b
c
d
Institute of Organic Chemistry, University of Stuttgart, 70569 Stuttgart, Germany
Department of Organic Chemistry, Masaryk University, CZ-611 37 Brno, Czech Republic
Central Laboratory of Chemical Techniques, Slovak University of Technology, SK-812 37 Bratislava, Slovak Republic
Received 4 September 2001
Pyrrolizidine syntheses involving 1,3-dipolar cycloaddi-
tions have been recently reviewed.3 Most of these ap-
proaches make use of carbohydrates as chiral auxiliaries
or chiral building blocks. In connection with our interest
Abstract: A route has been developed for the synthesis of enantio-
merically and diastereomerically pure trihydroxylated pyrroliz-
idines. A chiral sugar derived nitrone undergoes diastereoselective
dipolar cycloaddition with methyl acrylate to afford erythro-cis
isoxazolidine; a suitable cycloadduct undergoes N-O cleavage and concerning the utilization of chiral nitrones in asymmetric
cycloadditions,4 we have designed sugar-derived
recyclization to (1S,2R,6R,7aS)-trihydroxylated pyrrolizidine.
nitrones5 as templates for synthesis of polyhydroxylated
Key words: cycloadditions, nitrones, isoxazolidines, stereoselec-
tivity, pyrrolizidine alkaloid
derivatives of pyrrolizidines. Nitrones are 1,3-dipoles
known to undergo cycloadditions to form isoxazolidines
and cleavage of the N-O bond to enable recyclization to
carbon-nitrogen heterocycles is a recognized synthetic
strategy.6
Many naturally occurring polyhydroxylated pyrrolizidine
alkaloids are endowed with a wide spectrum of biological
activities and therapeutic applications in diabetes, obesity
and AIDS due to their action of glycosidase inhibitors be-
cause of a structural resemblance to the sugar moiety of
the natural substrate.1 The high potential of pyrrolizidine
alkaloids in a range of biological applications makes them
inviting targets for synthesis. In particular the preparation
of other structural analogs of alexine (1) and australine
(2), that are specific inhibitors of amylglycosidase, has
created much interest since the biological activity of these
molecules varies substantially with the number, position,
and stereochemistry of the hydroxy groups in the pyrroliz-
idine skeleton (Figure 1).2
As part of our program devoted to developing of a simple
route to polyhydroxylated derivatives of pyrrolizidines,
we describe herein a stereoselective synthesis of enan-
tiopure (1S,2R,6R,7aS)-trihydroxylated pyrrolizidine 3.
The synthesis of diastereoisomers ( )-4, (+)-5 and ( )-5
using the cycloadditions of 3,4-disubstituted pyrroline-N-
oxides with O-silyl-protected allyl alcohol has been de-
scribed by Wightman7 but, to the best of our knowledge,
3 has not been described previously.
In the foregoing paper we have shown that sugar derived
nitrones react with methyl acrylate with useful stereose-
lectivity, particularly if hydroxy group in the nitrone is
protected with the bulky tert-butyldimethylsilyl group.8
We decided to exploit this knowledge of the stereochem-
ical course of these cycloadditions in the development of
a synthetic method to (1S,2R,6R,7aS)-pyrrolizidine-1,2,6-
triol (3) from carbohydrate precursors. Our retrosynthetic
strategy is outlined in Figure 2 in which we proposed to
build the pyrrolizidine skeleton of general formula 3 via
nitrone cycloaddition. Reaction of nitrone 6 with methyl
acrylate opens a way for the novel functionalization of
isoxazolidine cycloadduct 7 in which the methyl ester
may be converted into a hydroxymethyl group for ring
closure to the pyrrolizidine skeleton. Stereoselective cy-
cloaddition, followed by reduction of the N-O bond, to
produce both an amino and a hydroxy function, allows the
synthesis of tailor-made products of possible biological
interest.
HO
OH
HO
OH
HO
H
N
H
N
H
N
HO
HO
HO
OH
HOH2C
HOH2C
1
2
3
HO
HO
HO
HO
HO
H
N
H
N
H
OH
OH
HO
OH
N
5
4
ent-5
Figure 1
Synlett 2001, No. 12, 30 11 2001. Article Identifier:
1437-2096,E;2001,0,12,1866,1868,ftx,en;D20501ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Synthesis of Trihydroxylated Pyrrolizidine by Cycloaddition of D-Erythrose Derived Nitrone
1867
As shown in Scheme, 1,3-dipolar cycloaddition of sugar
derived O-silylated nitrone 6 prepared from D-glucose
with methyl acrylate gave the diastereoisomerically pure
isoxazolidine 7 in 88% yield.8–10 NO-heterocycles are
prone to hydrogenolysis since the relatively weak N-O
bond is easily cleaved.6
OH
OPG
LGO
OLG
HO
N
OH
OPG NH2 OPG
O
OPG OPG
RO
Therefore, the C-COOMe functionalized isoxazolidine 7
represents a sub-unit with potential for cleavage and recy-
clization to form the pyrrolizidine 3. This opens a new
route to the stereocontrolled formation of polyhydrox-
ysubtituted pyrrolizidines. To demonstrate this, the dias-
tereoisomerically pure isoxazolidine 7 was reduced with
DIBALH to yield the primary alcohol 8.11 Treatment of
the crude 8 with excess mesyl chloride in the presence of
triethylamine furnished the spectroscopically pure mesy-
late 9 in 83% yield (Scheme).
LGO
O
O
N
OPG OPG
OH
OH
PG
N
PG
OH OH
HO
HO
OPG OPG
OH
O
O
OH
Figure 2
Direct hydrogenolysis of 9 in the presence of catalyst pal-
ladium hydroxide on carbon in methanol resulted in a cas-
cade reaction sequence involving isoxazolidine N O
bond cleavage, N-debenzylation and spontaneous cycliza-
tion affording pyrrolidine 10, pure enough for the next
step, although pyrrolidine 10 was converted to its mesy-
late for characterization purposes. The hydroxy group of
10 was protected as its tert-butyldimethylsilyl ether in
82% yield (purified by flash chromatography) before lib-
eration of the 1,3-diol functionality. Hydrolysis of eth-
ylidene acetal in 11 was achieved using 80% acetic acid at
80 °C yielded crude diol 12. Cyclization of this product 12
with mesyl chloride/triethylamine afforded the expected
pyrrolizidine derivative 13 (77% overall yield from 11, af-
ter column chromatography). Finally, removal of the pro-
tecting groups in 13 with NH4F with TBAF in aqueous
THF gave an oily triol 3 in 61% yield (Scheme).
O
O
O
HO
HO
HO
6 steps
OTDMBS
O
a
OH
88 %
42 %
N
OH
overall yield
Bn
D-Glucose
6
O
O
O
O
OTBDMS
OTBDMS
NBn
d
b
NBn
O
~100 %
98 %
Product identification was carried out by NMR spectros-
copy.12 A detailed NMR study using 2D COSY and NOE
experiments was undertaken in order to decide the stere-
ochemistry of 13. NOE experiments revealed the cis loca-
tion of 1-H and 6-H in the 13 and confirmed the 3,4’-
erythro stereochemistry in adduct 7.8
O
RO
MeOOC
8, R = H
7
c
9, R = Ms
83 %
O
O
HO
HO
OTBDMS
NH
OTBDMS
g
f
NH
In summary an efficient synthetic pathway to pyrrolizi-
dine 3 has been established from D-glucose via enantio-
merically pure isoxazolidine intermediate in 14 steps with
an overall yield of 12%. This process will be widely appli-
cable to the synthesis of other pyrrolizidine alkaloids.
~96 %
77 %
RO
TBSO
10, R = H
12
e
11, R = TBS
98 %
HO
HO
Acknowledgement
H
N
H
h
The authors are grateful to the Slovak Grant Agency (No. 1/7314/
20) and Volkswagen-Stiftung for financial support.
TBDMSO
OTBDMS
HO
OH
61 %
N
13
3
References
Scheme (a) Methyl acrylate in toluene, 4 h at 110 °C (b) DIBALH
in THF, 1.5 h at –10 °C (c) MsCl, Et3N in CH2Cl2, 12 h at 0 °C–r.t.
(d) H2, Pd(OH)2/C in MeOH, 72 h at r.t. (e) TBDMSCl, Et3N in
CH2Cl2, 23 h at r.t. (f) 80% AcOH, 6 h at 80 °C (g) MsCl, Et3N in
CH2Cl2, 3 h at –10 °C, then 16 h at r.t. (h) NH4F, TBAF, in THF–wa-
ter, 50 h at r.t.
(1) (a) Taylor, D. L.; Nash, R.; Fellows, L. E.; Kang, M. S.;
Syms, A. S. Antiviral Chem. Chemother. 1992, 3, 273.
(b) Liddell, J. R. Nat. Prod. Rep. 1996, 13, 187. (c) Asano,
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Asymmetry 2000, 11, 1645.
Synlett 2001, No. 12, 1866–1868 ISSN 0936-5214 © Thieme Stuttgart · New York

1868
J. Kubá et al.
LETTER
solid, mp 71-74 °C; yield 83%; [ ]D = –29.6 (CH2Cl2, c
(2) (a) Müller, R.; Leibold, T.; Pätzel, M.; Jäger, V. Angew.
Chem., Int. Ed. Engl. 1994, 1295. (b) Pearson, W. H.;
Hembre, J. E. J. Org. Chem. 1996, 61, 5546. (c) Denmark,
S. E.; Hurd, R. A.; Sacha, H. J. J. Org. Chem. 1997, 62,
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Wightman, R. H. Synlett 1997, 123. (e) Denmark, S. E.;
Hurd, R. A. J. Org. Chem. 2000, 65, 2875. (f) Yoda, H.;
Asai, F.; Takabe, K. Synlett 2000, 1001.
(3) Broggini, G.; Zecchi, G. Synthesis 1999, 905.
(4) (a) Fišera, L.; Al-Timari, U. A. R.; Ertl, P. In Cycloadditions
in Carbohydrate Chemistry; ACS Monograph., Am. Chem.
Soc.: Washington, 1992, 158. (b) Al-Timari, U. A. R.;
Fišera, L.; Ertl, P.; Goljer, I.; Prónayová, N. Monatsh. Chem.
1992, 123, 999. (c) Kubá , J.; Blanáriková, I.; Fišera, L.;
Prónayová, N. Chem. Pap. 1997, 51, 378.
(5) (a) Kubá , J.; Blanáriková, I.; Fengler-Veith, M.; Jäger, V.;
Fišera, L. Chem. Pap. 1998, 52, 780. (b) Kubá , J.;
Blanáriková, I.; Fišera, L.; Jarošková, L.; Fengler-Veith, M.;
Jäger, V.; Kozíšek, J.; Humpa, O.; Langer, V. Tetrahedron
1999, 55, 9501. (c) Blanáriková, I.; Dugovi , B.; Fišera, L.;
Hametner, C. ARKIVOC 2001, 2, 1091.
(6) (a) Torssell, K. B. G. Nitrile Oxides, Nitrones, and
Nitronates; VCH Publishers Inc.: New York, 1988.
(b) Grünanger, P.; Vita-Finzi, P. Isoxazoles. Part One. In
The Chemistry of Heterocyclic Compounds; Taylor, E. C.;
Weissberger, E., Eds.; Wiley: New York, 1991.
(7) (a) McGaig, A. E.; Wightman, R. H. Tetrahedron Lett. 1993,
34, 3939. (b) McGaig, A. E.; Meldrum, K. P.; Wightman, R.
H. Tetrahedron 1998, 54, 9429.
(8) Kubá , J.; Kolarovi , A.; Fišera, L.; Jäger, V.; Humpa, O.;
Prónayová, N.; Ertl, P. Synlett 2001, 1862.
(9) The alternative access to the cycloadduct 7 via the
cycloaddition of the unprotected nitrone 6 with methyl
acrylate with the subsequent silylation (90% yield) has also
been performed. The cycloaddition was less selective and
gave a 48:29:18:5 diastereomeric mixture of cycloadducts.8
(10) In addition, allyl alcohol and its mesyl derivative were used
for the cycloaddition, but the cycloaddition with nitrone 6
gave a 62:17:11:10 and 73:18:7:2 diastereomeric mixture of
cycloadducts in low yield (43% and 37%), respectively.
(11) The use of LiAlH4 instead of DIBALH lowers the yield from
98% to 75%.
0.21); 1H NMR (500 MHz, CDCl3): = 7.34-7.19 (m, 5 H),
4.60 (q, 1 H, J = 5.1 Hz), 4.37-4.32 (m, 1 H), 4.26-4.25 (m,
2 H), 3.99 (s, 2 H), 3.94 (dd, 1 H, J = 10.8 and 4.6 Hz), 3.41
(ddd, 1 H, J = 9.5, 9.0 and 4.6 Hz), 3.40-3.38 (m, 1 H), 3.35
(dd, 1 H, J = 9.0 and 4.7 Hz), 3.25 (dd, 1 H, J = 10.8 and 9.5
Hz), 2.92 (s, 3 H), 2.52 (ddd, 1 H, J = 12.1, 7.4 and 4.7 Hz),
1.99 (ddd, 1 H, J = 12.1, 8.7 and 8.7 Hz), 1.28 (d, 3 H, J =
5.1 Hz), 0.78 (s, 9 H), 0.02 and –0.01 (2 s, 2 3 H); 13
C
NMR (125 MHz, CDCl3): = 136.7, 129.2, 128.3, 127.5
(NCH2Ph), 98.8 (C-2’), 81.3 (C-4’), 75.9(C-5), 71.1 (C-6’),
70.1 (CH2OMs), 64.1 (C-3), 63.9 (C-5’), 62.5 (NCH2Ph),
37.7 (OSO2CH3), 30.4 (C-4), 25.6 (OSiC(CH3)3), 20.5 (2’-
CH3), 17.7 (OSiC(CH3)3), -4.3 and -4.8 (OSi(CH3)2);
C23H39NO7SSi (501.71) calcd C 55.06, H 7.83, N 2.79, S
6.39; found: C 54.88, H 7.76, N 2.93, S 6.04.
(2R,4S,5R,1’S,4’R)-5-O-tert-butyldimethylsilyloxy-4-(4-
hydroxypyrrolidine-2-yl)-2-methyl-1,3-dioxane
methanesulfonate (10): Colourless oil, yield 99%; 1H NMR
(250 MHz, CDCl3): = 9.52 and 8.54 (2 s, 2 1 H), 4.81
(q, 1 H, J = 5.0 Hz), 4.48-4.42 (m, 1 H), 4.06 (s, 1 H), 3.97
(dd, 1 H, J = 10.2 and 4.5 Hz), 3.89 (dd, 1 H, J = 9.0 and 2.3
Hz), 3.48-3.20 (m, 4 H), 2.66 (s, 3 H), 2.25 (ddd, 1 H, J =
13.9, 9.7 and 6.2 Hz), 2.11-2.02 (m, 2 H), 1.31 (d, 3 H, J =
5.0 Hz), 0.81 (s, 9 H), 0.02 and 0.03 (2 s, 2 3 H).
(2R,4S,5R,2’S,4’R)-5-tert-butyldimethylsilyloxy-4-(4’-
tert-butyldimethylsilyloxy-pyrrolidine-2-yl)-2-methyl-
1,3-dioxolane (11): Colorless oil; yield 82%; [ ]D = –48.2
(CH2Cl2, c 0.25); 1H NMR (250 MHz, CDCl3): = 4.70 (q,
1 H, J = 5.1 Hz), 4.34-4.26 (m, 1 H), 3.95 (dd, 1 H, J = 11.1
and 4.8 Hz), 3.84-3.68 (m, 1 H), 3.64-3.25 (m, 5 H), 1.98
(dddd, 1 H, J = 13.7, 6.2, 1.5 and 1.5 Hz), 1.76 (ddd, 1 H,
J = 13.7, 11.7 and 4.4 Hz), 1.27 (d, 3 H, J = 5.1 Hz), 0.85 and
0.81 (2 s, 2 9 H), 0.03, 0.02, 0.00 and 0.01 (4 s, 4
3
H); 13C NMR (75 MHz, CDCl3): = 98.5 (CHCH3), 79.7 (C-
5), 71.4 (C-2), 70.9 (C-7), 64.2 (C-6), 56.5 (C-4), 55.6 (C-1),
34.2 (C-3), 25.6 and 25.4 (OSiC(CH3)3), 20.2 (CHCH3),
17.9 and 17.6 (OSiC(CH3)3), -4.3, -4.5, -4.9 and -5.0
(OSi(CH3)2).
(1S,2R,6R,7aS)-2,6-O-di-tert-butyldimethylsilyl-
pyrrolizidine-1,2,6-triol (13) Slightly yellow viscous
syrup; yield 77%; 1H NMR (500 MHz, CDCl3): = 4.83 (dd,
1 H, J = 9.8 and 6.9 Hz), 4.54 (ddd, 2 H, J = 9.8, 8.4 and 1.5
Hz), 4.48-4.44 (m, 1 H), 4.21 (ddd, 1 H, J = 10.0, 6.9 and 6.2
Hz), 3.45 (dd, 1 H, J = 12.8 and 4.1 Hz), 3.28 (dd, 1 H, J =
9.8 and 1.5 Hz), 3.21 (dd, 1 H, J = 12.8 and 1.7 Hz), 2.88 (dd,
1 H, J = 9.8 and 8.4 Hz), 2.21 (ddd, 1 H, J = 13.8, 6.2 and 2.1
Hz), 1.82 (ddd, 1 H, J = 13.8, 10.0 and 4.7 Hz), 0.79 and 0.77
(2 s, 2 9 H), 0.02, 0.01, 0.01 and 0.02 (4 s, 4 3 H);
13C NMR (125 MHz, CDCl3): = 83.4 (C-1), 82.7 (C-2),
72.0 (C-6), 67.3 (C-7a), 57.4 (C-3), 55.7 (C-5), 34.5 (C-7),
25.5 and 25.4 (OSiC(CH3)3), 17.8 and 17.7 (OSiC(CH3)3),
4.6, 4.7, 5.0 and -5.1 (OSi(CH3)2).
(1S,2R,6R,7aS)-pyrrolizidine-1,2,6-triol (3): Colourless
oil; yield 61%; [ ]D = +49.1 (MeOH, c 0.30); 1H NMR (300
MHz, CD3OD): = 4.83-4.73 (m, 3 H), 4.18 (ddd, 1 H, J =
10.1, 6.8 and 6.2 Hz), 3.57-3.28 (m, 3 H), 3.01 (dd, 1 H, J =
10.0 and 7.8 Hz), 2.34 (ddd, 1 H, J = 13.5, 6.2 and 2.6 Hz),
2.05-1.97 (m, 1 H); 13C NMR (125 MHz, CD3OD): = 84.9
(C-1), 84.6 (C-2), 74.1 (C-6), 69.9 (C-7a), 58.4 (C-3), 56.9
(C-5), 35.1 (C-7).
(12) Selected data:
(3S,5R,2’R,4’S,5’R)-2-N-benzyl-3-(5-tert-butyldimethyl-
silyloxy-2-methyl-1,3-dioxan-4-yl)-5-hydroxy-
methylisoxazolidine (8): Colourless oil, yield 98%; 1H
NMR (500 MHz, CDCl3): = 7.42-7.28 (m, 5 H), 4.65 (q, 1
H, J = 5.1 Hz), 4.30-4.21 (m, 1 H), 4.01 (s, 2 H), 4.00 (dd, 1
H, J = 10.8 and 4.9 Hz), 3.81 (dd, 1 H, J = 12.0 and 2.9 Hz),
3.58 (dd, 1 H, J = 12.0 and 4.4 Hz), 3.50 (ddd, 1 H, J = 9.6,
9.4 and 4.9 Hz), 3.44-3.42 (m, 1 H), 3.39-3.35 (m, 1 H), 3.31
(dd, 1 H, J = 10.8 and 9.6 Hz), 2.50 (ddd, 1 H, J = 12.0, 7.4
and 5.7 Hz), 2.12 (ddd, 1 H, J = 12.0, 8.6 and 8.2 Hz), 1.79
(s, 1 H), 1.35 (d, 3 H, J = 5.1 Hz), 0.85 (s, 9 H), 0.05 and 0.03
(2 s, 2 3 H); 13C NMR (125 MHz, CDCl3): = 136.7,
129.2, 128.3, 126.9 (NCH2Ph), 98.8 (C-2’), 81.1 (C-4’), 78.6
(C-5), 71.2 (C-6’), 64.3 (C-3), 64.1 (C-5’), 63.4 (CH2OH),
62.4 (NCH2Ph), 29.8 (C-4), 25.6 (OSiC(CH3)3), 20.5 (2’-
CH3), 17.7 (OSiC(CH3)3), 4.3 and 4.9 (OSi(CH3)2).
(3S,5R,2’R,4’S,5’R)-2-N-benzyl-3-(5-tert-butyldimethyl-
silyloxy-2-methyl-1,3-dioxan-4-yl)-5-(-O-methane-
sulfonyl)hydroxymethylisoxazolidine (9): Colourless
Synlett 2001, No. 12, 1866–1868 ISSN 0936-5214 © Thieme Stuttgart · New York