Use of N,O-dimethylhydroxylamine as an anomeric protecting group in carbohydrate synthesis

Article abstract of DOI:10.1021/jo102372m

The N,O-dimethyloxyamine-N-glycosides are introducedas anomerically protected building blocks for carbohydrate synthesis. These N-glycosides are stable to a variety of protecting group manipulations including acylation, alkylation, silylation, and acetal formation. The alkoxyamine-N-glycosides can be cleaved selectively with N-chlorosuccinimide to give the desired hemiacetals in excellent yield. Furthermore, these Nglycosides are stable to the activation conditions required for glycosylation using thioglycoside and trichloroacetimidate glycosyl donors suggesting N,O-dialkoxyamine-N-glycosides will be useful for complex oligosaccharide synthesis.

Full text of DOI:10.1021/jo102372m

NOTE
pubs.acs.org/joc
Use of N,O-Dimethylhydroxylamine As an Anomeric Protecting
Group in Carbohydrate Synthesis
Somnath Dasgupta and Mark Nitz*
Department of Chemistry, University of Toronto, 80 St. George St., Toronto, ON, Canada M5S 3H6
S Supporting Information
b
ABSTRACT: The N,O-dimethyloxyamine-N-glycosides are in-
troduced as anomerically protected building blocks for carbohy-
drate synthesis. These N-glycosides are stable to a variety of
protecting group manipulations including acylation, alkylation,
silylation, and acetal formation. The alkoxyamine-N-glycosides
can be cleaved selectively with N-chlorosuccinimide to give the desired hemiacetals in excellent yield. Furthermore, these N-
glycosides are stable to the activation conditions required for glycosylation using thioglycoside and trichloroacetimidate glycosyl
donors suggesting N,O-dialkoxyamine-N-glycosides will be useful for complex oligosaccharide synthesis.
nomeric protecting groups are often used in convergent
oligosaccharide syntheses which require that complex glycosyl
glycosides are compatible with numerous protecting groups, that the
glycosides can be selectively hydrolyzed with N-chlorosuccinimide
(NCS), and that N,O-dialkyloxyamine-N-glycosides are stable to
thioglycoside and trichloroacetimidate glycosylation conditions.
Similar to the synthesis previously reported, the N,O-dialkylox-
yamine-N-glycoside 1 was formed in high yield under mildly acidic
conditions.8 An equal molar solution of sodium acetate, N,O-
dimethylhydroxylamine hydrochloride, and glucose (0.7 M) gave
the desired glycoside 1 in 92% yield. The protection of 1 with a range
of common protecting groups was explored. Peracetylation under
standard conditions (Ac2O/Pyr) and perbenzylation (NaH, BnBr/
DMF) proceeded smoothly to give 2 and 3 in greater than 90% yield.
Similarly the regioselective addition of a TBDPS ether, using TBDPS-
Cl in pyridine, gave high yields of the desired selectively protected
glycoside 4. Wewerepleasedtofind that the N,O-dimethyloxyamine-
N-glycoside was also stable to acetal formation giving 71% yield of the
protected 4,6-O-benzylidene glycoside 5 (Scheme 1).
The chemoselective deprotection of the hydroxylamine was
explored under various conditions using the acetylated glycoside 1.
As was expected, treatment under standard acetal cleavage conditions
(AcOH/H2O, 4:1) cleaved the glycoside giving the free hemiacetal 7
in 80% yield. Unfortunately these conditions also led to partial
removal of the protecting groups on compounds 4 and 5 leading
to poor yields. A variety of Lewis acids were explored in water/organic
solutions for hydrolysis of the N-glycosides but overall this process led
to low yields of the desired hemiacetals. Given our previous success
activating anomeric hydrazides under oxidative conditions we ex-
plored the use of halosuccinimides for cleavage of the N-glycosides.20
The glycosides proved stable to NIS and NBS but were cleanly
hydrolyzed with NCS in THF/water solutions (9:1) at 50-60 °C.
These conditions proved to be compatible with the acetyl, benzyli-
dene, benzyl, and TBDPS protecting groups on compounds 1-5,
giving high yields of the desired hemiacetals (Table 1).
A
donors be generated late in a synthesis.1 An ideal anomeric
protecting group would be one that is easily installed, is stable
under conditions necessary for protecting group manipulations, and
is readily hydrolyzed to yield the desired hemiacetal. Further
versatility in an anomeric protecting group would be provided if
the protecting group could be activated to serve as a leaving group
for glycosidation. Many anomeric protecting groups have been
developed with these criteria in mind. Some of the most commonly
used groups include allyl, pentenyl,2,3 thioglycosides,4 TMSEt,5 p-
methoxyphenyl,6 and most recently the propargyl glycosides.7
These groups are robust to many protecting group manipulations
and they can be cleaved under an orthogonal set of conditions. But
the formation of these glycosides is not ideal, as they are introduced
either via a Fischer glycosidation, requiring separation of anomers,
or through a multistep route decreasing the overall efficiency of
oligosaccharide synthesis. Here we introduce the use of N,O-
dimethylhydroxylamine as an anomeric protecting group for use
in oligosaccharide synthesis. The advantage of N,O-dimethyloxya-
mine-N-glycosides is that they can be directly introduced on an
unprotected mono- or oligosaccharide, reducing the number of
chemical steps required in an oligosaccharide synthesis.
In a very important contribution, the synthesis of N,O-dialkylox-
yamine-N-glycosides was demonstrated by Dumy et al.8 These
glycosidations were shown to give primarily the equatorial glyco-
sides in high yield when glycoside formation was carried out under
concentrated mildly acidic (pH 4-5) aqueous conditions.8,9 The
simplicity of the glycosylation and the stability of the resulting
glycosides has made this glycosidation exceptionally useful for the
generation of glycoconjugates,10-14 the formation of glycoside
mimics,8,15,16 glycopeptide mimics,17,18 and to “sweeten” natural
products.19 However, despite the ease of installation, the compat-
ibility of N,O-dialkyloxyamine-N-glycosides with protecting group
chemistry and glycosylation conditions associated with oligosac-
charide synthesis has not been explored. Here we show that these
Received: December 4, 2010
Published: February 18, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo102372m J. Org. Chem. 2011, 76, 1918–1921
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The Journal of Organic Chemistry
NOTE
Scheme 1. Protection of N,O-Dimethyloxyamine Glucosides
Table 1. N,O-Dimethyloxyamine-N-glycoside Hydrolysis
glycoside
reaction conditionsa
product
yield (%)
2
3
4
5
2
3
5
2
3
4
5
A
A
A
A
B
B
B
C
C
C
C
6
7
8
9
6
7
9
6
7
8
9
80
77
61
30
64
65
20
91
90
91
81
We explored the possibility of forming O-glycosides under
solvolysis conditions using NCS. Unfortunately, the acetylated
derivative 2 did not give clean conversion into the methyl
glycoside upon activation with NCS in methanol. After extended
reaction times (24-48 h) glycosidation was evident but many
deacetylation products were also produced. The more reactive
benzylated N-glycoside 4 was converted to the methyl glycoside
under similar conditions in moderate yield (60% 1:10 (R:β)).
Given that the more armed benzylated glycoside could be
activated for glycosidation we explored the tribenzylated
N-acetylglucosamine donor 11. This donor provides an acetyl
group at the 2-position to control the stereochemistry of the
glycosidation and donating benzyl groups to activate the donor
toward glycosidation. The N,O-dimethylalkoxyamine-N-glyco-
side (11) was synthesized without difficulty using a similar
approach as that detailed above, in a two-step, one-pot, 64%
overall yield (Scheme 2). The N-glycoside 11 could be activated
with NCS and gave glycosides of simple alcohols in good to
moderate yield (54-60%). These results indicate that only in the
case of strongly armed donors can these N,O-dimethyloxyamine-
N-glycosides be glycosidated in synthetically useful yields.
Further work is required before they can serve as donors in
oligosaccharide synthesis.
a Conditions: (A) AcOH/H2O (4:1), 60 °C, 1 h; (B) FeCl3 (2 equiv),
THF/H2O (9:1), 60 °C, 2 h; (C) NCS (2 equiv), THF/H2O (9:1),
60 °C, 1 h.
Scheme 2. Glycosidation with N-Glycosides
Finally given the stability of these glycosides to protection and
deprotection conditions, we sought to explore the stability of the N,
O-dimethyloxyamine-N-glycosides as glycosyl acceptors. We fo-
cused our attention on the synthesis of two disaccharides containing
(1f6) linked and (1f4) rhamnose linkages. We examined typical
glycosylation conditions commonly used for thioglycoside activa-
tion (NIS/TMSOTf)21 and trichloracetimidate22 activation.
The glycosyl acceptors were prepared starting from compound 4;
after acetylation the TBDPS group was removed by using TBAF.
Under the deprotection conditions the expected partial acetyl migration
was observed giving the expected 6-OH (15, 55%) glucoside as well
as the 4-OH (16, 30%).23 Glycosylation of the N-glycoside acceptor
15 with 2,3,4-tri-O-acetyl-R-L-rhamnosyltrichloroacetimidate24 using
TMSOTf activation gave disaccharide 17 in 91% yield. Reaction be-
tween known ethyl-2,3,4-tri-O-acetyl-1-thio-R-L-rhamnoside donor25
and N,O-dimethyloxyamine acceptor 16 under NIS/TMSOTf
activation conditions led to disaccharide 19 in 85% yield. These
reactions demonstrate that the N,O-dimethyloxyamine-N-glyco-
sides are stable to standard glycosylation conditions.
It was possible to hydrolyze both N-glycoside disaccharides
(17 and 19) with NCS to give hemiacetals in high yield. These
hemiacetals could be used as precursors for the formation of
disaccharide glycosyl donors in oligosaccharide synthesis (Scheme 3).
In conclusion, we have demonstrated that the N,O-dimethylhy-
droxyamine can be used as an anomeric protecting group under a
range of conditions. These glycosides are tolerant of a range of
protecting group manipulation conditions and are stable under
glycosylation conditions. N,O-Dialkoxyamine-N-glycosides can be
activated for glycosidation but in their current form these glycosides
lack the reactivity required of effective glycosyl donors. Future work to
increase the activity of these glycosides or find alternate conditions for
activation is ongoing.
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NOTE
Scheme 3. Glycosylation of N,O-Dimethyloxyamine-N-gly-
coside Acceptors
(m, 1H), 2.16, 2.14, 2.08, 2.04, 2.01, 1.98 (6s, 18H), 1.21 (d, 3H, J = 6.2 Hz);
13C NMR (75 MHz, CDCl3) δ 170.6, 170.4, 170.3, 170.1, 170.0, 169.9,
169.7, 169.6, 98.4, 98.2, 95.2, 89.7, 73.7, 72.8, 72.4, 71.0, 70.8, 70.7, 69.8, 69.7,
69.3, 69.2, 69.1, 69.0, 68.8, 67.5, 66.7, 29.6, 20.9 (2), 20.7 (3), 20.6, 20.5, 17.3;
ESI-HRMS calcd for C24H34O16Na [M þ Na]þ 601.1745, found 601.1741.
Glycosidation Procedure
Butyl 2-Acetamido-3,4,6-tri-O-benzyl-2-deoxy-β-D-gluco-
pyranoside (13). Compound 11 (100 mg, 0.18 mmol) was dissolved
in butanol (5 mL) and to it was added NCS (63 mg, 0.47 mmol). The
solution was warmed to 60 °C for 2.5 h after which time TLC analysis
showed conversion of the starting material to a new product (EtOAc:n-
pentane, 1:1, Rf 0.6). The solvent was evaporated and the crude oil was
purified by flash chromatography eluting with n-pentane:EtOAc (2:1) to
furnish butyl 2-acetamido-3,4,6-tri-O-benzyl-2-deoxy-β-D-glucopyrano-
side (13) (53 mg, 54%) as a white solid: 1H NMR (400 MHz, CDCl3) δ
7.33-7.18 (m, 15H, ArH), 5.57 (d, 1H, J = 7.8 Hz), 4.82-4.76 (m, 3H),
4.67-4.52 (m, 4H), 4.11 (dd, 1H, J = 7.8, 7.9 Hz), 3.86 (ddd, 1H, J = 7.8,
7.9, 7.4 Hz), 3.77-3.71 (m, 2H), 3.64-3.58 (m, 2H), 3.47-3.36 (m,
2H), 1.84 (s, 3H), 1.57-1.48 (m, 2H), 1.36-1.30 (m, 2H), 0.89 (t, 1H,
J = 7.3 Hz); 13C NMR (75 MHz, CDCl3) δ 170.2, 138.5, 138.2, 138.0,
128.4 (4), 128.3 (2), 127.9 (2), 127.8 (2), 127.7 (4), 127.5, 99.7, 80.3,
78.7, 74.7, 74.5 (2), 73.4, 69.2, 69.0, 57.1, 31.5, 23.5, 19.1, 13.8; ESI-
HRMS calcd for C33H41NO6Na [M þ Na]þ 570.2832, found 570.2828.
’ ASSOCIATED CONTENT
S
Supporting Information. General experimental meth-
b
ods, full experimental procedures, and 1H and 13C NMR spectra.
This material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
mnitz@chem.utoronto.ca
’ EXPERIMENTAL SECTION
Representative Procedures
Formation of N,O-Dimethylamine-N-glycosides
’ ACKNOWLEDGMENT
N,O-Dimethyl-N-(β-D-glucopyranosyl)hydroxylamine (1). Glu-
cose (2.00 g, 11.1 mmol) was dissolved in water (15 mL) in a round-
bottomed flask. N,O-Dimethylhydroxylamine hydrochloride (1.19 g,
12.2 mmol) and sodium acetate (1.00 g, 12.2 mmol) were dissolved in
approximately 1 mL of water and the solution was added slowly to the
glucose solution at 0 °C. The reaction was allowed to proceed for 20 h at
rt at which time TLC analysis showed conversion of the starting material
to a faster moving product (CH2Cl2:MeOH 5:1, Rf 0.4). The water was
evaporated from the reaction in vacuo and the product was purified by
flash column chromatography eluting with CH2Cl2:MeOH (6:1) to give
compound 1 (2.27 g, 92%) as a white solid. Analytical data agree with
previous reports.8
The authors are grateful for financial support from the Natural
Science and Engineering Research Council of Canada (NSERC).
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