Synthesis of aza-C-disaccharides using cycloaddition reactions of a functionalized cyclic nitrone

Article abstract of DOI:10.1039/b005984f

Cycloaddition reactions of a functionalized nitrone with sugar alkenes gives stereoselective access to aza-C-disaccharide analogues of α-D-Lyx(1→6)-α-D-Man and →-D-Lyx(1→6)-D-Gal.

Full text of DOI:10.1039/b005984f

Synthesis of aza-C-disaccharides using cycloaddition reactions of a
functionalized cyclic nitrone
Fraser J. Duff, Vincent Vivien and Richard H. Wightman*
Department of Chemistry, Heriot-Watt University, Riccarton, Edinburgh, UK EH14 4AS. E-mail: cherhw@hw.ac.uk
Received (in Liverpool, UK) 18th July 2000, Accepted 14th September 2000
First published as an Advance Article on the web
Cycloaddition reactions of a functionalized nitrone with
predominantly by direct cyclisation of A,13 but also to a lesser
extent by 6-endo- ring closure of B.‡ In support of this, we have
shown that epoxide 10, on treatment with hydroxylamine, gives
(54%) a mixture of the enantiomers of 8 and 9 in a 1+1 ratio.
sugar alkenes gives stereoselective access to aza-C-disaccha-
ride analogues of a-
Lyx(1?6)- -Gal.
D-Lyx(1?6)-a-
D
-Man and a- -
D
D
Methyl a- -mannopyranoside was converted routinely (66%
D
Iminosugars have attracted much attention in recent years1 due
to their ability to act as inhibitors of glycosidases, and hence to
have potential application in the treatment of a number of
disparate disease states such as viral infections,2 diabetes3 and
tumour metastasis.4 It has been theorised that glycosidase
inhibitors which permit interaction with the aglycon binding site
should be more potent than those which lack this ability,5 and
the validity of this concept has been demonstrated.6 The
attachment of a second aglycone-mimicking sugar unit to an
iminosugar has been done in a number of ways, as for example
in the a,b-trehalose analogue 16a or by attachment via
overall) into 11 (see Scheme 2), which was oxidised and
converted to alkene 12. Reaction of 12 and nitrone 8 in toluene
at reflux led to the isolation of a crystalline cycloadduct 13 in
84% yield. The stereostructure of 13, which corresponds to
reaction on the face of 8 anti- to the isopropylidenedioxy group,
and via an exo-transition state,§ was indicated by NOESY data,
which were obtained at high temperature (120 °C) since at lower
temperatures signal-broadening was found, presumably due to
slow inversion at nitrogen. Strong interactions were observed
between 6-H and 7b-H, and between 7a-H and both 5-H and
8-H. The structure of 13 was subsequently confirmed by X-ray
crystallography.¶ The stereoselectivity of this cycloaddition is
enhanced (double stereodifferentiation) by the known facial
preference of chiral allylic ethers in cycloadditions, such that an
erythro-relationship between the stereocentres at C-5A and C-8
will be preferred.14
The cycloadduct 13 was acetylated, whereupon reductive
cleavage of the N–O bond was carried out using Mo(CO)6 in
aqueous acetonitrile,15 to give after protection of the amine the
benzyloxycarbonyl derivative 14. Deoxygenation to give 15
was carried out through the intermediacy of the imidazolyl-
thiocarbonyl derivative, but we observed that it was necessary
to carry out the reaction of 14 with thiocarbonyldiimidazole at
high concentrations and with excess of reagent in order to obtain
a high yield, an observation recently reported by others during
the synthesis of C-disaccharides.16 Routine deprotection of 15
then led to the aza-C-disaccharide 4, isolated as its hydro-
chloride (44% overall from 13).†
As a further example of this approach to aza-C-disaccharides,
reaction of nitrone 8 with the
-galactopyranosyl alkene 1617
D
gave in 88% yield the anti-, exo-cycloadduct 17† (Scheme 3),
together with 1% of the syn-, exo-isomer. The stereochemistry
of 17 again followed from NOESY spectra run at elevated
temperatures, with strong interactions being observed between
nitrogen,6c,7 but the aza-analogues of disaccharides which can
be regarded as being closest in structure to the natural sequences
are those with an all-carbon link, namely the aza-C-disaccha-
rides prepared in the laboratories of Johnson8 and of Vogel and
van Boom,9 such as 28a,9 and 3.8c,9
In this communication we describe our preliminary results on
the synthesis of aza-C-disaccharides by a different synthetic
approach to those previously employed,8,9 and in which
stereoselective cycloaddition reactions between functionalized
cyclic nitrones and sugar alkenes are employed to establish the
disaccharide analogue; our approach is illustrated by the
synthesis of 4, related to the sequence a-
D
-Man(1?6)-a- -Man
D
5, which is hydrolysed by Golgi a-mannosidase II during the
processing of N-linked glycans of glycoproteins,10 and of a
related aza-C-disaccharide 20.11
Treatment of 2,3-O-isopropylidene-
-lyxose 612 with TsCl-
D
pyridine (Scheme 1) gave in high yield the solid but somewhat
unstable tosylate 7, which was directly treated with excess
hydroxylamine to give predominantly (44–47%) the nitrone 8,†
together with smaller amounts (3–8%) of the nitrone 9 with a
five-membered ring. We consider that 9 is formed via
intermediates A and B (Scheme 1), whilst 8 is derived
Scheme 1 Reagents and conditions: i, TsCl, pyridine–CHCl3, 5 h (76%); ii,
NH2OH·HCl, NaHCO3, MeOH–H2O, rt, 20h (44–47% 8, 3–8% 9).
DOI: 10.1039/b005984f
Chem. Commun., 2000, 2127–2128
This journal is © The Royal Society of Chemistry 2000
2127

We thank EPSRC for financial support (GR/K97301) and for
access to facilities at the National Mass Spectrometry Service
Centre, and Dr Georgina Rosair for X-ray crystallography.
Notes and references
† Selected data (J values in Hz): 8: mp 162–164 °C; [a]D +235.2 (c 1.05,
CHCl3); dH (400 MHz, CDCl3) 1.39 (6H, s, CMe2), 3.90 (1H, dd, Jgem 15.2,
J 0.9, 6a-H), 4.07 (1H, dd, Jgem 15.2, J 1.1, 6b-H), 4.34 (1H, m, 4-H), 4.39
(1H, m, 5-H), 4.87 (1H, dd, J 5.1, 3.8, 3-H), 7.12 (1H, t, J 2.9, 2-H); 4·HCl:
[a]D +52.2 (c 0.67, MeOH); dH (400 MHz, CD3OD) 1.74–1.82 (1H, m, 6a-
H), 1.89–2.13 (3H, m, 6b-H and 7-H2), 3.06 (1H, dd, Jgem 12.8, J12a,11 2.4,
12a-H), 3.26 (1H, br ddd, J ~ 10, ~ 8, 2.9, 8-H), 3.31 (1H, dd, Jgem 12.8,
J12b,11 1.8, 12b-H), 3.36 (3H, s, OMe), 3.44–3.54 (2H, m, 4-H, 5-H), 3.64
(1H, dd, J3,4 9.1, J3,2 3.2, 3-H), 3.80 (1H, dd, J2,3 3.2, J 1.8, 2-H), 3.86–3.93
(2H, m, 9-H, 10-H), 4.00 (1H, m, 11-H), 4.62 (1H, d, J1,2 1.8, 1-H). 17: [a]D
253.5 (c 0.99, CHCl3); dH [400 MHz, (CDCl2)2, 120 °C] 2.10 (1H, dt, Jgem
12.6, J7a,6 ~ J7a,8 ~ 9.0, 7a-H), 2.20 (1H, br s, OH), 2.45 (1H, ddd, Jgem
12.6, J7b,6 7.0, J7b,8 3.8, 7b-H), 2.93–3.00 (1H, m, H-6), 2.96 (1H, dd, Jgem
11.0, J2b,3 3.5, 2b-H), 3.03 (1H, dd, Jgem 11.0, J2a,3 6.0, 2a-H), 3.57 (1H,
dd, J5A,8 7.4, J5A,4A 1.75, 5A-H), 3.92 (1H, br q, J ~ 4.4, 3-H), 4.00 (1H, t, J ~
5.0, 4-H), 4.15 (1H, t, J ~ 5.7, 5-H), 4.17 (1H, dd, J2A,1A 4.95, J2A,3A 2.3, 2A-H),
4.20 (1H, dd, J4A,3A 7.9, J4A,5A 1.8, 4A-H), 4.22 (1H, ddd, J8,7a 8.65, J8,5A 7.5,
J
8,7b 3.8, 8-H), 4.48 (1H, dd, J3A,4A 7.9, J3A,2A 2.3, 3A-H), 5.38 (1H, d, J1A,2A 4.95,
1A-H).
‡ It is possible that the cyclisations of A and/or B occur through the
intermediacy of geminal bis(hydroxylamine)s (see ref. 13). In a similar
cyclisation to form a stereoisomer of 8, we have also isolated and fully
characterised an N-hydroxy-2-hydroxylaminopiperidine as a byproduct (V.
Vivien, unpublished results).
§ endo-Transition states are disfavoured for cyclic nitrones on steric
grounds; see, e.g. J. J. Tufariello in 1,3-Dipolar Cycloaddition Reactions,
Vol 2, ed. A. Padwa, Academic Press, New York, 1983, p. 83.
¶ CCDC 182/1789. See http://www.rsc.org/suppdata/cc/b0/b005984f/ for
crystallographic files in .cif format.
Scheme 2 Reagents and conditions: i, PCC, DCM, then Ph3PMe·Br,
KHMDS, 278 °C to rt; ii, toluene, reflux (84%); iii, Ac2O, DMAP,
pyridine; iv, Mo(CO)6, MeCN–H2O, reflux; v, BnOCOCl, Na2CO3, acetone
(67% from 13); vi, excess (Im)2CNS, (CH2Cl)2, reflux, 2 h, then Bu3SnH,
AIBN, toluene, reflux (81% from 14); vii, NaOMe, MeOH; viii, H2,
Degussa Pd/C, MeOH; ix, HCl, MeOH (80% from 15).
1 Iminosugars as Glycosidase Inhibitors: Nojirimycin and Beyond, ed.
A. E. Stütz, Wiley–VCH, Weinheim, 1999.
2 e.g. A. Karpas, G. W. J. Fleet, R. A. Dwek, S. Petursson, S. K.
Namgoong, N. G. Ramsden, G. S. Jacob and T. W. Rademacher, Proc.
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3 G. D. Dimitriadis, P. Tessari, V. L. W. Go and J. E. Gerich, Metabolism,
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4 M. J. Humphries, K. Matsumoto, S. L. White and K. Olden, Cancer
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Scheme 3 Reagents and conditions: i, toluene, reflux (88%); ii, Ac2O,
DMAP, pyridine (82%); iii, Mo(CO)6, MeCN–H2O, reflux; iv, BnOCOCl,
Na2CO3, acetone; v, excess (Im)2CNS, (CH2Cl)2, reflux, then Bu3SnH,
AIBN, toluene, reflux; vi, NaOMe, MeOH, rt, 1.5 h; vii, H2, Pd/C, MeOH;
viii, HCl, MeOH, rt, 24h (48% overall from 18).
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Fukushima and K. Akimoto, Biosci. Biotech. Biochem., 1996, 60,
288.
6-H and 7b-H, between 7a-H and both 5-H and 8-H, and
between 5A-H and both 6-H and 7b-H; these last interactions,
and the observed value of 7.4 Hz for J5A,8 imply a preferred
rotamer about the C-8–C-5A bond as indicated in 17 (for 13, J5A,8
= 2.4 Hz). This, and the configuration of 17, was confirmed by
X-ray crystallography of the crystalline O-acetyl derivative 18.
Reduction of 18, followed by N-protection and deoxygenation
under conditions of high concentration, gave 19, deprotected as
indicated in Scheme 3 to give the aza-C-disaccharide 20, as an
anomeric mixture (a+b, 5+2), in 48% overall yield from 18.
13 For a similar cyclisation to give a nitrone related to
L-fucose, see A. Peer
and A. Vasella, Helv. Chim. Acta, 1999, 82, 1044.
14 M. Ito, M. Maeda and C. Kibayashi, Tetrahedron Lett., 1992, 33, 3765,
and references therein.
15 S. Cicchi, A. Goti, A. Brandi, A. Guarna and F. De Sarlo, Tetrahedron
Lett., 1990, 31, 3351.
16 O. Jarreton, T. Skrydstrup, J.-F. Espinosa, J. Jiménez-Barbero and J.-M.
Beau, Chem. Eur. J., 1999, 5, 430.
17 A. J. Blake, R. O. Gould, R. M. Paton and A. A. Young, J. Chem. Res.,
1993, (S) 482, (M) 3173, and refs. therein.
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Chem. Commun., 2000, 2127–2128