Application of the 2,5-Dimethylpyrrole Group as a New and Orthogonal Amine-Protecting Group in Oligosaccharide Synthesis

Full text of DOI:10.1021/jo9808728

4570
J . Org. Chem. 1998, 63, 4570-4571
Sch em e 1a
Ap p lica tion of th e 2,5-Dim eth ylp yr r ole Gr ou p
a s a New a n d Or th ogon a l Am in e-P r otectin g
Gr ou p in Oligosa cch a r id e Syn th esis
Simeon G. Bowers,† Diane M. Coe,‡ and
Geert-J an Boons*,†
School of Chemistry, The University of Birmingham,
Edgbaston Birmingham B15 2TT, U.K., and GlaxoWellcome,
Medicines Research Centre, Gunnels Wood Road,
Stevenage, SG1 2NY, U.K.
Received May 8, 1998
a
Reagents and conditions: (i) 2,5-hexanedione (1 equiv), Et3N (1
Amino sugars are widely distributed in living organisms
and occur as constituents of glycoproteins, glycolipids,
bacterial lipopolysaccharides, proteoglycans, and nodulation
factors associated with leguminous plants.1 Glucosamine
is the most common amino sugar and is generally found as
an N-acetylated and â-linked glycoside. Among the bioactive
amino sugars listed above, their N-function can also be
derivatized with fatty acids and sulfates, and several
polyamino oligosaccharides possess variously differentiated
N-acyl residues.
equiv), MeOH, then (ii) Ac2O, pyridine, 4 h, 51% (two steps); (iii)
hydrazine acetate (1.2 equiv), DMF, 50 °C, 30 min 30%; (iv) CCl3CN
(13 equiv), DBU (0.2 equiv), CH2Cl2, 1 h, 78%.
Sch em e 2a
The chemical synthesis of complex oligosaccharides con-
taining amino sugars is the focus of extensive research1,2
and requires amino protecting groups that are compatible
with common protecting group manipulations and glycosyl-
ations whereby they can be removed or exchanged readily
and chemoselectively under mild conditions.
Over the years, 2-deoxyphthalimido-protected glycosyl
donors have been the method of choice for the preparation
of 1,2-trans-glycosides of 2-amino-2-deoxyglycosides. The
N-phthalimido group can be readily installed by reaction
with phthalic anhydride1 and cleaved with hydrazine,3
butylamine,4 hydroxylamine,5 NaBH4,6 or with alkyldiamines
immobilized on polystyrene beads.7 Recently, the tetrachlo-
rophthalimido,8 dichlorophthalimido,9 N-pentenoyl,8a,10 dithio-
succinoyl,11 and N,N-diacetyl12 groups have been proposed
as alternatives to the N-phthalimido group and can be
removed under milder reaction conditions. Despite many
attractive features of these protecting-groups, they are
rather base sensitive and incompatible with many protecting
group manipulations.
a
Reagents and conditions: (i) TMSOTf (0.2 equiv), CH2Cl2, -25 °C,
15 min 78%; (ii) TMSOTf (0.2 equiv), CH2Cl2, -25 °C, 15 min, 68%;
(iii) TMSOTf (0.3 equiv), CH2Cl2, -25 °C, 30 min, 62%.
compatible with many protecting-group manipulations com-
monly employed in oligosaccharide chemistry. Interestingly,
it can be cleaved by treatment with hydroxylamine hydro-
chloride but is stable to conditions applied for cleavage of
the N-phthalimido group. Furthermore, glycosyl trichloro-
acetimidates derived from 2-deoxy-2,5-dimethylpyrrole gly-
cosides perform well in Lewis acid-mediated glycosylations
leading selectively to 1,2-trans-glycosides.
The dimethylpyrrole protecting group is readily installed
by treatment of an amine with 2,5-hexanedione in the
presence of triethylamine in methanol. When glucosamine
hydrochloride (1) (Scheme 1) was reacted under these
conditions, followed by O-acetylation with acetic anhydride
and pyridine, the fully protected sugar 2 was obtained in a
yield of 51%. Compound 2 could easily be converted into
the analogues trichloroacetimidate 4 via a two-step proce-
dure. Thus, selective anomeric O-deacetylation with hydra-
zine acetate16 gave 3 in 93% yield, which was treated with
trichloroacetonitrile in the presence of DBU17 to afford 4
exclusively as the â-anomer. As can be seen in Scheme 2,
compound 4 proved to be an efficient glycosyl donor in
TMSOTf-mediated glycosylations and gave in each case
exclusive formation of a â-glycoside. Although the pyrrole
group is highly electron rich and somewhat acid sensitive,
the yields of the glycosylations were generally high for both
primary and secondary alcohols, and the modest yield of 10
was due to the concurrent formation of trimethylsilylated
In this paper, we report that the 2,5-dimethylpyrrole13-15
functionality is a versatile amino protecting group that is
† The University of Birmingham.
‡ GlaxoWellcome.
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Chem. Soc., Perkin Trans. 1 1984, 2801.
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S0022-3263(98)00872-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/23/1998

Communications
J . Org. Chem., Vol. 63, No. 14, 1998 4571
Sch em e 3a
Sch em e 4a
a
Reagents and conditions: (i) NH2OH‚HCl (15 equiv), Et3N (10
equiv), iPrOH/H2O, (4/1, v/v), 80 °C, 3 h; (ii) Ac2O, pyridine, 2 h, 97%
(two steps); (iii) Et3N/H2O/MeOH (2/5/5, v/v), 1 h, 97%; (iv) hydrazine
monohydrate (18 equiv), EtOH, 95 °C, 2 h; (v) Ac2O, pyridine, 2 h,
78% (two steps).
amine formation, which was converted into the analogues
N-acetamido derivatives 15 in an overall yield of 97%.
Disaccharide 10 was selected as a model compound to
investigate the selective deprotection of the N-phthalimido
group in the presence of the 2,5-dimethylpyrrole. In a
previous experiment (Scheme 1), it was observed that the
dimethylpyrrole group is stable to treatment with hydrazine
acetate, and therefore, it was anticipated that the N-
phthalimido group of 10 can be cleaved with hydrazine
without affecting the dimethylpyrrole moiety. Indeed, sa-
ponification of the acetyl esters of 10 with triethylamine and
subsequent treatment with hydrazine monohydrate and
O-acetylation with acetic anhydride and pyridine gave 16
in an overall yield of 78%. A tentative explanation for such
orthogonal group stability is that the cleavage of the
dimethylpyrrole moiety requires protonation, which for
example, is delivered from the hydrochloride salt of hydroxy-
lamine. In the absence of a proton source, the pyrrole group
is unreactive, and treatment with hydrazine will only result
in cleavage of the N-phthalimido group.
In conclusion, we have demonstrated that the 2,5-di-
methylpyrrole moiety can be used as a protecting group for
the amino functionalities of saccharides. The new protecting
group can be installed and cleaved under mild conditions
but is stable to conditions required for deprotection of an
N-phthalimido group. Also, a trichloroacetamido 2-deoxy-
2,5-dimethylpyrrole glycosyl donor gives high yields and
â-anomeric selectivity in TMSOTf-promoted glycosylations.
The exploitation of the 2,5-dimethylpyrrole group for the
synthesis of complex oligosaccharides is underway and will
be reported in due course.
a
Reagents and conditions: (i) Et3N/H2O/MeOH (2/5/5, v/v), 1 h, 99%;
(ii) TBDMSCl (1.5 equiv), Et3N, pyridine, 5 h, 87%; (iii) Et3N/H2O/
MeOH (2/5/5, v/v), 1.5 h, quant; (iv) BnBr (4.5 equiv), NaH (4.5 equiv),
DMF, 1 h, 92%; (v) benzal bromide (4 equiv), Et3N, pyridine, reflux,
2.5 h, 58%.
glycosyl acceptor (13%) by its reaction with the activator.
The high â-selectivity is also remarkable since the C-2
dimethylpyrrole moiety is electronically a nonparticipating
functionality. Probably, the R-face of the glycoside is steri-
cally shielded, forcing the glycosyl acceptor to approach from
the â-face. To the best of our knowledge, this type of steric-
directed anomeric selectivity has not been reported.
A series of protecting group manipulations were per-
formed to demonstrate the versatility of the pyrrole protect-
ing group. Disaccharide 6 (Scheme 3) was deacetylated with
triethylamine in methanol/water to afford triol 11 in a
quantitative yield. The primary hydroxyl of 11 could be
regioselectively protected by reaction with TBDMSCl and
triethylamine in pyridine to give 12. Surprisingly, in the
absence of triethylamine, no product formation was ob-
served. Deacetylation of 8 followed by benzylation with
benzyl bromide and NaH in DMF afforded the fully protected
disaccharide 13 in a yield of 92%. This reaction is of special
significance since many amino-protecting groups are incom-
patible or perform unpredictably under standard benzylation
conditions. Finally, the 4,6-diol of 11 could be protected as
a benzylidene acetal by treatment with benzal bromide18 and
triethylamine in boiling pyridine to afford 14 in a yield of
58%.
The pyrrole protecting group can be easily removed by
treatment with hydroxylamine hydrochloride (Scheme 4).
Low yields of products were obtained when hydroxylamine
in refluxing methanol13 was employed. However, treatment
of 11 with an excess of hydroxylamine hydrochloride and
triethylamine in 2-propanol/water15 gave almost quantitative
Ack n ow led gm en t. This research was supported by
EPSRC and GlaxoWellcome Research and Development
(Research Studentship for S.G.B.).
Su p p or tin g In for m a tion Ava ila ble: Detailed experimental
procedures including 1H and 13C NMR spectra for all compounds
in this study (28 pages).
(18) (a) Garegg, P. J .; Maron, L.; Swahn, C. G. Acta Chem. Scand. 1972,
26, 518. (b) Garegg, P. J .; Swahn, C. G. Acta Chem. Scand. 1972, 26, 3895.
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