Total syntheses of hyacinthacine A2 and 7-deoxycasuarine by cycloaddition to a carbohydrate derived nitrone

Article abstract of DOI:10.1016/S0040-4039(03)00239-9

Practical syntheses of nitrone 8 by two different approaches from sugars are reported. Its use as a versatile intermediate in highly selective 1,3-dipolar cycloaddition reactions constitutes the key step for novel total syntheses of hyacinthacine A_2<

Full text of DOI:10.1016/S0040-4039(03)00239-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2315–2318
Total syntheses of hyacinthacine A2 and 7-deoxycasuarine by
cycloaddition to a carbohydrate derived nitrone
Francesca Cardona, Enrico Faggi, Francesca Liguori, Martina Cacciarini and Andrea Goti*
Dipartimento di Chimica Organica ‘Ugo Schiff’, Polo Scientifico, Universita` di Firenze, via della Lastruccia 13,
I-50019 Sesto Fiorentino (Firenze), Italy
Received 27 December 2002; revised 24 January 2003; accepted 24 January 2003
Abstract—Practical syntheses of nitrone 8 by two different approaches from sugars are reported. Its use as a versatile intermediate
in highly selective 1,3-dipolar cycloaddition reactions constitutes the key step for novel total syntheses of hyacinthacine A2 (3) and
7-deoxycasuarine (20) by simple transformations of a common isoxazolidine adduct. © 2003 Elsevier Science Ltd. All rights
reserved.
Necine bases are known since long time as constituents
of pyrrolizidine alkaloids.1 On the contrary, 3-(hydroxy-
methyl)pyrrolizidines have been isolated from natural
sources only recently, alexine (1)2 and australine (2)3
being the first examples of this family of alkaloids.
In this communication we report the synthesis of the
trisubstituted chiral nitrone 8, which has the correct
relative and absolute stereochemistry at C-1, C-2 and
C-3, as required for the above mentioned pyrrolizidine
alkaloids. Its huge synthetic potential in this field is
exemplified by the application to unprecedently
Polyhydroxylated pyrrolizidine alkaloids with
a
hydroxymethyl substituent at C-3 rather than at C-1
have long been thought to be of very restricted natural
occurrence.4 More recently, a relevant number of heav-
ily hydroxylated pyrrolizidines of this type have been
isolated, like hyacinthacine A2 (3),5 casuarine (4),6 and
a number of their diastereoisomers and structural
analogs,7 which belong to these new classes of the
alexines/australines and hyacinthacines.
straightforward
and
convenient
syntheses
of
hyacinthacine A2 (3) and 7-deoxycasuarine (20) by
means of 1,3-dipolar cycloaddition reactions.13
Two different approaches for the synthesis of 814,15
were pursued (Scheme 1), which gave quite comparable
results in terms of overall yield. Both of them are based
on intramolecular SN2 reactions carried out by an
oximate anion, which occur with inversion of configu-
ration at the attacked carbon atom.18 The first one,19
which employs L-xylose as chiral building block, has its
major drawback in the high cost of O-tetra-
hydropyranylhydroxylamine and of the starting sugar.20
The second procedure, based on the synthesis of a
related tribenzylated nitrone derived from
recently described by Holzapfel and co-workers,18a
starts from -arabinose and is to be preferred in terms
D-ribose
Many of these alkaloids possess potent glycosidases
inhibition activity,5,8 which makes them good candi-
dates as new drugs for the treatment of many diseases
such as viral infections, cancer and diabetes.9 Conse-
quently, these compounds became attractive synthetic
targets and their high potential for therapeutic applica-
tions has prompted many efforts for devising general
strategies for accessing them and their congeners.10–12
D
of cost of the materials employed.
In order to study the behaviour of this new nitrone in
1,3-dipolar cycloadditions, 8 was reacted with maleic
and acrylic acid derivatives 12–14 in CH2Cl2 at room
temperature (Scheme 2). With dimethyl maleate (12),
nitrone 8 reacted cleanly to afford exclusively the
adduct 15, whose relative stereochemistry as deriving
from an anti–exo approach13a was firmly established on
the basis of COSY and NOESY experiments. Albeit the
formation of a unique adduct contrasts with the
Keywords: glycosidases inhibitors; pyrrolizidine alkaloids; nitrones;
carbohydrates; enantiospecific synthesis.
* Corresponding author. Fax: +39-055-4573531; e-mail: andrea.goti@
unifi.it
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00239-9

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F. Cardona et al. / Tetrahedron Letters 44 (2003) 2315–2318
Scheme 1. Reagents and conditions: (a) i. MeOH/H2SO4, anhydr. Na2SO4, rt, 21 h; ii. BnCl/KOH, Na2SO4, reflux, 8 h; iii. 6N
HCl, CH3COOH, 60–70°C (50% over three steps); (b) NH2OTHP, no solvent, rt, 6 d, 100%; (c) MsCl, TEA, CH2Cl2, rt, 24 h,
50–70%; (d) i. DOWEX 50W X8, MeOH, rt, 24 h, 96%; ii. 0.1 M NaOH, dioxane, 0°C, 2 h, 55%; (e) i. NH2OH·HCl, py, rt, 24
h; ii. TBDPSCl, py, rt, 18 h, 100%; (f) I2, ImH, Ph3P, toluene, reflux, 1 h, 48%; (g) TBAF on silica gel, benzene, reflux, 1.5 h,
91%.
Scheme 2.
stereoisomeric mixtures produced with malic and tar-
taric acids derived nitrones,13a it parallels the high
the cycloaddition to be restored in favour of the anti–
exo adduct 17 (Scheme 2), possessing the stereochem-
istry required by casuarine at C-6.
selectivity displayed by
a trisubstituted pyrroline
nitrone possessing a similar stereochemical pattern.21 In
contrast, methyl acrylate (13) gave a mixture of the anti
The pyrroloisoxazolidine 17 was converted into the
desired pyrrolizidines 20 and 3 by simple three- and
four-step sequences, respectively (Scheme 3). Reductive
cleavage of the NꢀO bond13 with Zn in AcOH afforded
the lactam 18 in good yield, which was transformed
into 7-deoxycasuarine (20) through reduction with
LiAlH4 and removal of the benzyl protecting groups by
hydrogenation over Pd. 7-Deoxycasuarine (20) was
obtained with spectral data (1H and 13C NMR in D2O)
identical to those reported recently,12d but as a white
solid [mp 205–208°C (dec.), [h]2D0 +19.8 (c 0.40, H2O);
rep. as a yellow oil, [h]2D0 +10.9 (c 0.11, H2O)12d]. To
obtain hyacinthacine A2 (3), the alcohol 18 was con-
verted into the corresponding mesylate 21, which was
reduced with LiAlH4 to give the protected trihydroxy-
pyrrolizidine 22. Final hydrogenation over Pd
afforded hyacinthacine A2 (3) as a colourless oil, which
adducts 16 with
a scarce 2.4:1 exo selectivity.
Approaches of dipolarophiles 12 and 13 occurred exclu-
sively anti to the benzyloxy group at C-3 and to the
benzyloxymethyl group at C-5 of the nitrone, which are
located on the same side of the ring. This stereoselectiv-
ity afforded relative stereochemistry as desired at C-1/
C-7a in the final target molecules. The benzyloxy group
at C-4, which was expected to hamper formation of
endo cycloadducts,13a,21 was indeed effective with
maleate 12, that led to exclusive formation of the exo
adduct 15, but not with methyl acrylate (13), which
gave a relevant amount of the endo adduct 16b. We
reasoned that on increasing the steric demand of the
dipolarophile, the endo mode of approach should be
disfavoured. To our delight, use of the bulkier N,N-
dimethylamide 14 allowed complete stereoselectivity of
Scheme 3. Reagents and conditions: (a) Zn, CH3COOH/H2O, 50°C, 4 h, 80%; (b) LiAlH4, THF, reflux, 1.5 h, 75% for 19, 40%
for 22; (c) H2, Pd/C, MeOH, rt, 3 d, 76% for 20, 75% for 3; (d) MsCl, TEA, CH2Cl2, rt, 2 h, 100%.

F. Cardona et al. / Tetrahedron Letters 44 (2003) 2315–2318
2317
showed spectroscopic and analytical properties in
agreement with those reported for the natural
product5,11a [[h]2D4 +12.7 (c 0.13, H2O); rep. [h]D +12.5 (c
0.4, H2O),11a [h]D +20.1 (c 0.44, H2O)5].
8. (a) Tropea, J. E.; Molyneux, R. J.; Kaushal, G. P.;
Pan, Y. T.; Mitchell, M.; Elbein, A. D. Biochemistry
1989, 28, 2027–2034; (b) Wormald, M. R.; Nash, R. J.;
Hrnicar, P.; White, J. D.; Molyneux, R. J.; Fleet, G.
W. J. Tetrahedron: Asymmetry 1998, 9, 2549–2558; (c)
Nash, R. J.; Fellows, L. E.; Dring, J. V.; Fleet, G. W.
J.; Girdhar, A.; Ramsden, N. G.; Peach, J. M.;
Hegarty, M. P.; Scofield, A. M. Phytochemistry 1990,
29, 111–114.
9. (a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G.
W. J. Tetrahedron: Asymmetry 2000, 11, 1645–1680; (b)
Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux,
R. J.; Nash, R. J. Phytochemistry 2001, 56, 265–295
and references cited therein.
In conclusion, the reported syntheses of nitrone 8 allow
a straightforward and completely stereoselective entry
to polyhydroxypyrrolizidines, as demonstrated by the
total syntheses of 7-deoxycasuarine (20) and
hyacinthacine A2 (3) in only seven steps and 24%
overall yield and eight steps and 13% overall yield,
respectively, from tribenzyl derivative 5 or 9, that com-
pare very well with the only previously reported synthe-
ses of 2012d and 311a which are affected by very poor
selectivities.
10. Alexines and australines: (a) Denmark, S. E.; Herbert,
B. J. Am. Chem. Soc. 1998, 120, 7357–7358; (b) White,
J. D.; Hrnciar, P.; Yokochi, A. F. T. J. Am. Chem.
Soc. 1998, 120, 7359–7360; (c) Denmark, S. E.; Martin-
borough, E. A. J. Am. Chem. Soc. 1999, 121, 3046–
3056; (d) Denmark, S. E.; Herbert, B. J. Org. Chem.
2000, 65, 2887–2896; (e) Pearson, W. H.; Hines, J. V.
J. Org. Chem. 2000, 65, 5785–5793; (f) Yoda, H.;
Katoh, H.; Takabe, K. Tetrahedron Lett. 2000, 41,
7661–7665; (g) Romero, A.; Wong, C.-H. J. Org.
Chem. 2000, 65, 8264–8268; (h) White, J. D.; Hrnciar,
P. J. Org. Chem. 2000 65, 9129–9142; (i) Denmark, S.
E.; Cottell, J. J. J. Org. Chem. 2001, 66, 4276–4284.
11. Hyacinthacines: (a) Rambaud, L.; Compain, P.; Martin,
O. R. Tetrahedron: Asymmetry 2001, 12, 1807–1809; (b)
Izquierdo, I.; Plaza, M. T.; Robles, R.; Franco, F. Tet-
rahedron: Asymmetry 2001, 12, 2481–2487; (c)
Izquierdo, I.; Plaza, M. T.; Franco, F. Tetrahedron:
Asymmetry 2002, 13, 1581–1585; (d) Yoda, H.; Asai,
F.; Takabe, K. Synlett 2000, 1001–1003.
12. Casuarine and analogs: (a) Denmark, S. E.; Hurd, A.
R. Org. Lett. 1999, 1, 1311–1314; (b) Denmark, S. E.;
Hurd, A. R. J. Org. Chem. 2000, 65, 2875–2886; (c)
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; (d) Behr, J.-B.; Erard, A.;
Guillerm, G. Eur. J. Org. Chem. 2002, 1256–1262.
13. For our recent work on the synthesis of necine bases,
see: (a) Goti, A.; Cicchi, S.; Cacciarini, M.; Cardona,
F.; Fedi, V.; Brandi, A. Eur. J. Org. Chem. 2000, 3633–
3645; (b) Goti, A.; Cacciarini, M.; Cardona, F.;
Cordero, F. M.; Brandi, A. Org. Lett. 2001, 3, 1367–
1369; (c) Goti, A.; Fedi, V.; Nannelli, L.; De Sarlo, F.;
Brandi, A. Synlett 1997, 577–579.
Studies are currently underway in our laboratory to
extend this method to the synthesis of a broad range of
alexines, casuarines, hyacinthacines and pyrrolidine
alkaloids and analogs.
Acknowledgements
The authors thank the Ministry of Instruction, Univer-
sity and Research (MIUR, Cofin 2002), Italy.
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14. All new compounds were fully characterized and gave
satisfactory spectroscopic and analytical data.
15. (3R,4R,5R)-3,4-Dibenzyloxy-5-benzyloxymethyl-1-pyrro-
line N-oxide (8): white solid, mp 80–82°C; [h]1D9 −41.7
(c 1.00, CHCl3); 1H NMR (200 MHz, CDCl3): l 7.38–
7.26 (m, 15 H), 6.91 (d, J=1.9 Hz, 1 H), 4.69–4.67 (m,
1 H), 4.64–4.46 (m, 6 H), 4.39 (dd, J=3.2, 2.2 Hz, 1
H), 4.10–4.04 (m, 2 H), 3.78 (d, J=7.3 Hz, 1 H); 13C
NMR: l 137.7 (s), 137.2 (s), 137.1 (s), 132.9 (d), 128.6,
128.5, 128.4, 128.1, 127.9 and 127.7 (d, 15 C), 82.7 (d),
80.3 (d), 77.4 (d), 73.9 (t), 71.9 (t), 71.6 (t), 66.1 (t).
Anal. calcd for C26H27NO4: C, 74.80; H, 6.52; N, 3.35.
Found: C, 74.51; H, 6.78; N, 3.01%.
16. Fleet, J.; Smith, P. Tetrahedron 1986, 42, 5685–5692.

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L-xylose, which gave a
better yield of 8 but contaminated with a regioisomer,
will be reported in a forthcoming full paper.
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