Synthesis of a branched chain aza-C-disaccharide via the cycloaddition of a chiral nitrone to an alkene, both sugar derivatives

Article abstract of DOI:10.1016/j.tetlet.2004.04.031

A multistep synthesis of a protected aza-C-disaccharide derivative with a pyrrolidine ring as the azasugar component is described. The key step is a stereoselective cycloaddition reaction of a chiral nitrone derived from D-ribose and a sugar alkene derived from D-galactose. An intramolecular N-alkylation followed by a reductive cleavage of the isoxazolidine N-O bond, in one pot, gave the final product.

Full text of DOI:10.1016/j.tetlet.2004.04.031

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4237–4240
Synthesis of a branched chain aza-C-disaccharide via the
cycloaddition of a chiral nitrone to an alkene, both sugar derivatives
Nikolaos G. Argyropoulos* and Vassiliki C. Sarli
Department of Chemistry, Laboratory of Organic Chemistry, University of Thessaloniki, Thessaloniki 54124, Greece
Received 24 February 2004; revised 29March 2004; accepted 7 April 2004
Abstract—A multistep synthesis of a protected aza-C-disaccharide derivative with a pyrrolidine ring as the azasugar component is
described. The key step is a stereoselective cycloaddition reaction of a chiral nitrone derived from D-ribose and a sugar alkene
derived from D-galactose. An intramolecular N-alkylation followed by a reductive cleavage of the isoxazolidine N–O bond, in one
pot, gave the final product.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Aza-C-disaccharides are a relatively new class of sugar
mimics in which an azasugar unit (polyhydroxylated
pyrrolidines or piperidines) is linked to a second
monosaccharide unit by a methylene group. It is
expected that these sugar mimics may improve the
effectiveness and selectivity of the well known inhibition
properties of aza sugars.1;2 This assumption is based
mainly on the fact that incorporation of a nonhydro-
lyzable monosaccharide unit into the azasugar may
provide all the steric information of the glycosidic
moiety including that of the aglycon, thus combining the
features of both azasugars and C-glycosides.
several imino-C-disaccharides and other analogues,
starting from an iminosugar substrate and an enantio-
merically pure 7-oxabicyclo[2.2.1]heptyl derivative via a
cross aldolization reaction.9–14 According to another
approach, also introduced by Vogel’s group, various
(1 fi 2) and (1 fi 4) C-linked iminodisaccharides were
obtained from leavoglucosenone or isoleavoglucosene
and iminosugars using either a Nozaki–Kishi cou-
pling15;16 or an aldol condensation reaction.17 In another
approach, which appeared during the course of our
study on the subject, linear (1 fi 6) aza-C-disaccharides
were obtained by cycloaddition of six-membered chiral
nitrones and sugar derived alkenes.18 The synthesis of
(1 fi 2) pseudo-aza-C-disaccharides by cycloaddition
reactions of cyclic nitrones to glycals is also relevant.19
Several synthetic approaches towards this class of
compounds have been reported. Johnson and co-work-
ers obtained various (1 fi 6), (1 fi 4) and (1 fi 1) linked
compounds, using alkyl boron compounds generated
from hydroboration of olefinated sugar precursors and a
vinyl compound via a Suzuki coupling as the key step.3;4
Another methodology utilized a Barbier coupling of an
aldehydo sugar and an aza sugar,5 while others built up
the C-linked bridge by a Wittig olefination.6 Other
approaches utilized double reductive aminations either
of a carbohydrate-derived acetylenic diketone,7 or an
appropriate 1,5-diketone obtained from a C1-substi-
tuted galactal.8 Vogel and co-workers introduced the
‘naked sugar’ methodology for the total synthesis of
Our approach is based on a cycloaddition reaction of an
open chain nitrone and an alkene both obtained from
sugar precursors. The nitrone has a protected hydroxyl
group that could be transformed to a good leaving
group (e.g. a mesylate), to give the desired pyrrolidine
nucleus by an intramolecular N-alkylation followed
by the reductive cleavage of the isoxazolidine cyclo-
adduct.
The synthesis of the nitrone is outlined in Scheme 1.
Starting from L-erythrose monoacetonide, alkene 2 was
obtained by a Wittig olefination20 and a subsequent
protection of the resulting hydroxy group as a t-butyl
dimethylsilyl ether (TBDMS). Compound 2 was then
transformed into the desired nitrone 3 without isolation
of intermediates, by the illustrated three step sequence,
* Corresponding author. Tel.: +30-2310-997871; fax: +30-2310-9976-
77; e-mail: narg@chem.auth.gr
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.031

4238
N. G. Argyropoulos, V. C. Sarli / Tetrahedron Letters 45 (2004) 4237–4240
Bn
O
At this point crucial removal of the TBDMS group was
left for a later stage and the reduction of the ester group
was carried out instead. This was done using LiBH4 and
the resulting primary hydroxy group was protected as an
acetate by reaction with Ac2O/pyridine. Compound 6,
thus obtained was subjected to selective removal of the
TBDMS group, carried out by short treatment with dilute
acetic acid to give compound 7,23 fortunately without
affecting the acetonide. This compound after treatment
with MsCl in pyridine gave compound 8 as a mesylate
salt; analogous intermediates have been previously re-
ported.24;25 Without isolation, catalytic hydrogenolysis
using Pd/C gave the desired final product 9,26 in an 65%
overall yield (from compound 7) (Scheme 3).
O
HO
OTBDMS
iii
N
OTBDMS
i, ii
O
O
O
O
O
O
3
2
1
Scheme 1. Reagents and conditions: (i) Ph3PþCH2BrÀ, n-BuLi, THF,
)78 ꢁC, 90%, (ii) TBDMSCl, imidazole, DMF, overnight, rt, 92%, (iii)
OsO4 (4% H2O), NMO, CH3COCH3, H2O, 5 h, rt, then NaIO4, THF,
H2O, overnight, rt, then BnNHOHÆHCl, Et3N, CH2Cl2, overnight, rt,
3%.
in 93% overall yield. All steps of this synthetic scheme
were optimized so that a reasonably good overall yield
was attained.21
The regioselectivity of the cycloadduct 5 as well as the
stereochemical course of the cycloaddition step was
deduced from the 1H and 13C NMR data of compounds
7 and 9. These compounds show well-defined signals so
that it was possible to unambiguously assign them. As
expected, the regiochemistry of cycloadduct 5 is as
The cycloaddition step was performed using a slight
excess (1:1.2) of nitrone 3 and the known alkene 4.22
Preliminary experiments showed that after prolonged
heating (five days) in refluxing toluene, besides cycload-
duct 5, two other stereoisomers of unknown stereo-
chemistry were also formed. Meanwhile, considerable
amounts of the nitrone 3 were decomposed so additional
quantities needed to be added in order to get the reaction
to go to completion. Interestingly the reaction was en-
hanced by the addition of a catalytic amount of trieth-
ylamine and was complete after two days heating in
refluxing benzene. A remarkable stereo-selectivity was
observed and only stereoisomer 5 was formed in very
good yield. We cannot yet evaluate the exact catalytic
effect of the added triethylamine. One possibility is that it
may prevent Z- to E-isomerization of the reacting nit-
rone. This hypothesis is supported by blank experiments,
carried out by heating nitrone 3 in refluxing benzene and
by adding a catalytic amount of triethylamine. In the first
experiment, after heating for 4 h, a new peak at d 6.8
O
O
OR
OTBDMS
CO2Me
O
O
H
H
H
H
H
H
CH2OAc
i
Bn
N
Bn
N
H
O
H
O
O
O
O
O
O
O
O
O
O
O
5
6 R=TBDMS
7 R=H
ii
iii
1
appeared in the H NMR spectrum, which was attrib-
O
N
O
N
O
O
uted to the methine proton of the E-isomer of nitrone 3,
when the experiment was repeated, and adding a cata-
lytic amount of triethylamine, no appreciable change in
H
H
H
H
CH2OAc
CH2OAc
H
O
H
O
1
Bn
MsO
Bn
HO
O
O
O
O
the H NMR spectrum was observed.
O
iv
H
H
O
Attempts to selectively deprotect the primary hydroxyl
group of cycloadduct 5, using standard procedures, with
tetrabutylammonium fluoride did not proceed well and
resulted in complex mixtures. Also, attempts to carry
out the deprotection using acetic acid resulted in partial
removal of the acetonide group prior to the completion
of the deprotection.
O
O
O
9
8
Scheme 3. Reagents and conditions: (i) (a) LiBH4, THF, overnight, rt,
98% (b) Ac2O/Py, overnight, rt, 90%; (ii) AcOH; 3 h, rt, 95%, (iii)
MsCl/Py, 0 ꢁC, 1 h, 90%; (iv) H2, Pd/C, EtOH, 12 h, rt, 65%.
O
OTBDMS
OTBDMS
CO2Me
O
O
H
H
O
O
CO2Me
+
H
Bn
N
O
H
O
O
O
O
O
O
N+
H
-
O
Bn
O
O
3
4
O
5
Scheme 2. Reagents and conditions: benzene, NEt3 (cat.), reflux, two days, 75%.

N. G. Argyropoulos, V. C. Sarli / Tetrahedron Letters 45 (2004) 4237–4240
4239
2. Carbohydrate Mimics; Chapleur, Y., Ed.; Wiley VCH:
Weinheim, 1998.
3. Johnson, C. R.; Miller, M. W.; Golebiowski, A.; Sun-
dram, H.; Ksebati, M. B. Tetrahedron Lett. 1994, 35,
8991–8994.
4. Johns, B. A.; Pan, Y. T.; Elbein, A. D.; Johnson, C. R.
J. Am. Chem. Soc. 1997, 119, 4856–4865.
5. Martin, O. R.; Liu, L.; Yang, F. Tetrahedron Lett. 1996,
37, 1991–1994.
H1a
H2
O
OH
H1b
O
H3
H4
O
O
H2
1.5%
H3
H4
H5
H5
CH2OAc
CH2OAc
H1b
1.5%
H11
H6
O
H11
O
H6
O
CH2
N
N
H1a
Bn
HO
H7
O
Ph
O
H7
0.7%
O
O
H10
H10
O
O
H8
H8
6. Dondoni, A.; Giovannini, P. P.; Marra, A. Tetrahedron
Lett. 2000, 41, 6195–6199.
H9
H9
O
O
7. Leeuwenburgh, M. A.; Picasso, S.; Overkleeft, H. S.; van
der Marel, G. A.; Vogel, P.; van Boom, J. H. Eur. J. Org.
Chem. 1999, 1185–1189.
8. Cheng, X.; Kumaran, G.; Mootoo, D. R. Chem. Commun.
2001, 81–812.
9
7
Figure 1. Representative NOE and ROESY interactions observed for
cycloadduct 7 and aza-C-disaccharide derivative 9.
9. Baudat, A.; Vogel, P. Tetrahedron Lett. 1996, 37, 483–484.
10. Baudat, A.; Vogel, P. J. Org. Chem. 1997, 62, 6252–6260.
11. Frenot, E.; Marquis, C.; Vogel, P. Tetrahedron Lett. 1996,
37, 2023–2026.
12. Kraehenbuehl, K.; Picasso, S.; Vogel, P. Helv. Chim. Acta
1988, 81, 1439–1479.
illustrated in Scheme 2 and is in accordance with that
observed from other analogous reactions of nitrones
with a,b-unsaturated esters.27
The stereochemistry of the final product is obviously
determined by the stereochemical course of the cyclo-
addition step, in particular by the reacting form of nit-
rone 3 (Z or E) in combination with a possible exo/endo
and p facial selectivity. In principle four diastereomers
are possible, by altering either the nitrone stereochem-
istry or the approaching mode.
13. Marquis, C.; Picasso, S.; Vogel, P. Synthesis 1999, 1441.
14. Vogel, P. Curr. Org. Chem. 2000, 4, 455–480, and
references cited therein.
15. Zhu, Y. H.; Vogel, P. Chem. Commun. 1999, 1873–1874.
16. Navarro, I.; Vogel, P. Helv. Chim. Acta 2002, 85, 152–160.
17. Zhu, Y. H.; Vogel, P. J. Org. Chem. 1999, 64, 666–669.
18. Duff, F. J.; Vivien, V.; Wightman, R. H. Chem. Commun.
2000, 2127–2128.
19. Cardona, F.; Valenza, S.; Picasso, S.; Goti, A.; Brandi, A.
J. Org. Chem. 1998, 63, 7311–7318.
20. Gypser, A.; Flasche, M.; Scharf, H. D. Liebigs Ann. Chem.
1994, 775–780.
The stereochemistry of the starting nitrone 3 was
determined by NOE experiments. Irradiation of the
azomethine proton resulted in a significant enhancement
(ꢀ12%) of the benzylic proton signals, indicative of a Z-
form of nitrone 3.
21. Selected spectroscopic data for compound 3: 1H NMR
(300 MHz, CDCl3) d 0.02 (3H, s, SiCH3), 0.03 (3H, s,
SiCH3), 0.95 (9H, s, C(CH3)3), 1.36 (3H, s, CH3), 1.47
(3H, s, CH3), 3.51 (1H, dd, J ¼ 3:9, 11.5 Hz, CH2OT-
BDMS), 3.67 (1H, dd, J ¼ 3:4, 11.5 Hz, CH2OTBDMS),
4.51 (1H, ddd, J ¼ 3:4, 3.9, 6.4 Hz, CH–O), 4.86 (1H, s,
NCHPh), 4.87 (1H, s, NCHPh), 5.36 (1H, dd, J ¼ 5:4,
6.4 Hz, CH–O), 6.93 (1H, d, J ¼ 5:4 Hz, CH@N), 7.39–
7.47 (5H, m, C6H5). 13C NMR (75 MHz, CDCl3) d )5.4,
)5.3, 18.2, 24.5, 25.9, 26.7, 62.3, 69.0, 72.5, 78.9, 109.2,
128.3, 128.9, 129.3, 132.4, 138.1. HRMS (MALDI-FTMS)
m=z obsd. 402.2087 calcd for C20H33NO4SiNa (MNaþ)
The absolute configuration of the new stereogenic centre
at the C-3 of the isoxazolidine ring was assigned using
proton decoupling, NOE and ROESY experiments,
carried out on compounds 7 and 9 (Fig. 1). ROESY
correlation peaks were observed between H-4 and H-6
of compound 7, which indicated their cis arrangement.
On the other hand, the absence of coupling between H-3
and H-4 in compound 9 suggests a dihedral angle of
ꢀ90ꢁ consistent with a trans arrangement. This is also
supported by the observed NOE interactions between
H-3 and H-5.
402.2071 ½aꢁ )106.8 (c 1.96, CHCl3).
D
22. Valverde, S.; Martin-Lomas, M.; Herradon, B.; Garcia-
Ochoa, S. Tetrahedron 1987, 43, 1895–1901.
23. Selected spectroscopic data for compound 7: 1H NMR
(600 MHz, CDCl3) d 1.34 (9H, s, CH3), 1.45 (3H, s, CH3),
1.49(3H, s, CH 3), 1.53 (3H, s, CH3), 2.08 (3H, s, COCH3),
3.24 (1H, m, H-5), 3.54 (1H, m, H-1), 3.65 (1H, m, H-1),
3.95 (1H, t, J ¼ 5:3 Hz, H-4), 4.04 (1H, d, J ¼ 8:8 Hz, H-
6), 4.11 (1H, d, J ¼ 13:2 Hz, NCHPh), 4.17 (1H, d,
J ¼ 9:2 Hz, H-8), 4.19(1H, dd, J ¼ 6:1, 11.6 Hz, H-2),
4.24 (1H, dd, J ¼ 6:4, 10.9Hz, CHOAc), 4.28 (1H, d,
J ¼ 13:2 Hz, NCHPh), 4.36 (1H, dd, J ¼ 1:7, 5.3 Hz, H-
10), 4.38–4.45 (3H, m, CHOAc, H-7, H-3), 4.47 (1H, br s,
OH), 4.62 (1H, dd, J ¼ 2:2, 7.9Hz, H-9), 5.59 (1H, d,
J ¼ 5:3 Hz, H-11), 7.27 (1H, t, J ¼ 7:9Hz, Ph–H), 7.32
(2H, t, J ¼ 7:4, 7.9Hz, Ph–H), 7.37 (2H, d, J ¼ 7:4 Hz,
Ph–H). 13C NMR (75 MHz, CDCl3) d 20.9, 24.5, 24.7,
25.5, 26.0, 27.4, 46.0, 60.7, 62.9, 63.7, 65.1, 65.5, 70.1, 71.1,
72.2, 77.2, 77.5, 96.7, 108.1, 108.7, 109.6, 127.6, 128.4,
129.6, 136.6, 170.5. Anal. Calcd for C30H43NO11 MW
593.284: C ¼ 60.70%, H ¼ 7.30%, N ¼ 2.36%; found
C ¼ 60.31%, H ¼ 7.23%, N ¼ 2.26%. HRMS (MALDI-
All these data are in accordance with the assumption
that the cycloaddition step follows an exo-attack of the
sugar alkene to the Re face of sugar Z-nitrone 3, al-
though the alternative endo mode to the Re face of sugar
E-nitrone can not be excluded.
Further work is in progress using other sugar alkenes in
order to clarify the stereochemical consequences in this
synthetic scheme and to obtain other branched chain
aza-C-disaccharide derivatives.
References and notes
€
1. Iminosugars as Glycosidase Inhibitors; Stutz, A. F., Ed.;
Wiley VCH: Weinheim, 1999.

4240
N. G. Argyropoulos, V. C. Sarli / Tetrahedron Letters 45 (2004) 4237–4240
FTMS) m=z obsd 594.2908 calcd for C30H44NO11 (MHþ)
13C NMR (75 MHz, CDCl3) 24.1, 24.4, 24.7, 25.8, 26.0,
27.2, 42.1, 56.6, 61.5, 65.3, 67.4, 70.3, 70.7, 70.9, 71.0, 72.1,
80.8, 86.5, 96.7, 108.4, 109.0, 127.2, 128.5, 129.0, 138.9,
171.0. HRMS (MALDI-FTMS) m=z obsd 578.2980 calcd
594.2909. ½aꢁ )4.0 (c 2.70, CHCl3).
D
24. McCaig, A. E.; Wightman, R. H. Tetrahedron Lett. 1993,
34, 3939–3942.
25. Goti, A.; Cardona, F.; Brandi, A. Synlett 1996, 761–763.
26. Selected spectroscopic data for compound 9: 1H NMR
(300 MHz, CDCl3) d 1.28 (3H, s, CH3), 1.31 (3H, s, CH3),
1.35 (3H, s, CH3), 1.37 (3H, s, CH3), 1.46 (3H, s, CH3),
for C30H44NO10 (MHþ) 578.2960. ½aꢁ )41,3 (c 0.35,
D
CHCl3).
27. (a) Tufariello, J. J. In 1,3-Dipolar Cycloaddition Chemistry;
Padwa, A., Ed.; John Wiley & Sons: New York, 1984; Vol.
2, p 83; (b) Torssell, K. B. G. Nitrile Oxides, Nitrones, and
Nitronates; VCH: Weinheim, 1988; (c) Breuer, E.; Aurich,
H. G.; Nielsen, A. In Nitrones, Nitronates and Nitroxides;
Patai, S., Rappoport, Z., Eds.; John Wiley & Sons:
Chichester, 1989; p 245; (d) Confalone, P. N.; Huie, E. M.
In The [3 + 2] Nitrone–Olefin Cycloaddition Reaction in
‘Organic Reactions’; John Wiley & Sons: New York, 1988;
Vol. 36.
1.59(3H, s, CH ), 2.10 (3H, s, COCH3), 2.26 (1H, m, H-
3
5), 2.86 (1H, dd, J ¼ 2:4, 13.4 Hz, H-1a), 3.03 (1H, dd,
J ¼ 5:5, 13.4 Hz, H-1b), 3.79(1H, d, J ¼ 5:5 Hz, H-4),
3.99–4.13 (3H, m, H-6, CH2OAc), 4.15 (1H, d,
J ¼ 11:0 Hz, NCHPh), 4.25–4.32 (4H, m, H-8, H-10, H-
7, NCHPh), 4.59(1H, dd, J ¼ 2:4, 8.3 Hz, H-9), 4.69 (1H,
ddd, J ¼ 2:4, 5.5, 5.5 Hz, H-2), 4.91 (1H, d, J ¼ 5:5 Hz, H-
3), 5.60 (1H, d, J ¼ 5:5 Hz, H-11), 7.28 (5H, m, Ph–H).