Fluoropyridyl Sugars - Masked Imidate Glycosyl Donors that Display Reactivity, Selectivity, and Stability

Article abstract of DOI:10.1055/s-0036-1588478

Fluoropyridyl glycosides, synthesized from the corresponding glycosyl bromides, are shown to be excellent donors in glycosylation reactions. Both armed and disarmed donors were prepared and reacted smoothly with a series of glycosyl acceptors. Coupling pr

Full text of DOI:10.1055/s-0036-1588478

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–D
letter
A
en
R. Leslie et al.
Letter
Synlett
Fluoropyridyl Sugars – Masked Imidate Glycosyl Donors that Dis-
play Reactivity, Selectivity, and Stability
Ray Leslie*
OP
PO
PO
OH
Kavnen Tseke
OP
O
O
O
PO
PO
'activate'
Agneta Vitkute
Sophie L. Benjamin
L. Nitin Seetohul
O
O
O
X
N
+
PO
O
O
O
PO
O
O
O
O
O
P = Ac, Bn
X = F, CF3
Department of Chemistry, Nottingham Trent University,
Clifton Lane, Nottingham, NG11 8NS, UK
raymond.leslie@ntu.ac.uk
24 examples
35–85% yield
Received: 01.06.2017
Accepted: 01.06.2017
Our approach to developing a new glycosyl donor was
based around the use of 2-O-pyridyl sugars, which possess
an imidate structure to deliver reactivity but is masked
within an aromatic ring to provide stability. Hanessian had
already introduced such a system a few years earlier using
either an unsubstituted or 3-methoxypyridine,8b and
Schmidt has also reported on the use of heteroaromatic sys-
tems as glycosyl donors9 (Figure 1). Of particular note in
Schmidt’s research was the use of the 4-O-2,3,5,6-tetrafluo-
ropyridyl donor which was found to exhibit high reactivity.
Published online: 11.07.2017
DOI: 10.1055/s-0036-1588478; Art ID: st-2017-d0419-l
Abstract Fluoropyridyl glycosides, synthesized from the correspond-
ing glycosyl bromides, are shown to be excellent donors in glycosylation
reactions. Both armed and disarmed donors were prepared and reacted
smoothly with a series of glycosyl acceptors. Coupling proceeded in
high yields, with activation of the donor achieved using a range of pro-
moters, and also displayed unusually high selectivity. In addition these
novel systems offer the potential for introducing a series of glycosyl do-
nors with ‘tunable reactivity’.
OBn
OBn
Key words fluoropyridyl, masked imidate, donors, glycosylation, ste-
reoselectivity
BnO
BnO
BnO
BnO
O
O
F
F
BnO
BnO
O
X
N
O
F
F
Glycoconjugates have been identified as key mediators
in a variety of biological processes ranging from neuronal
development through to tumour growth and metastasis.1–5
In addition they belong to a class of natural products that
display both structural diversity and compact functionality
and, as such, the study of complex carbohydrates, and, in
particular, the development of efficient glycosylation strat-
egies continues to be an area of intense research activity.6
Despite many excellent contributions to this field,
Schmidt’s trichloroacetimidate remains the method of
choice for glycoside bond-forming reactions, combining
high yields with the more recently disclosed ability to con-
trol stereochemistry.6e The major drawback of the trichlo-
roacetimidate methodology is its hydrolytic instability, ren-
dering it incompatible with most protective-group manipu-
lations encountered in carbohydrate chemistry.7 Other
groups have tried to solve this problem by tuning the reac-
tivity of this donor8 whilst retaining the core imidate struc-
ture and its concomitant selectivity and we would now like
to communicate our results in this area.
N
X = H, OMe
(Hanessian)
(Schmidt)
Figure 1 Literature examples of pyridyl glycosides used as donors
We were interested in studying fluoropyridyl glycosides
but, like Hanessian’s work with ‘MOP’ donors, wanted to fo-
cus on monosubstituted systems. We reasoned that the re-
activity of the pyridyl donor would benefit from the pres-
ence of electron-withdrawing, rather than electron-donat-
ing, groups and also a monosubstituted system might allow
a future investigation into the effect of substitution pat-
terns on activity, thus introducing the possibility for ‘glyco-
syl tuning’.
We therefore chose to investigate fluorinated pyridines
rationalising that such systems would approach the reactiv-
ity of the trichloroacetimidate structure. Thus Scheme 1
outlines our approach to the synthesis of both the 3-fluoro-
pyridyl donor 1 and the trifluoromethyl analogue 2 by reac-
tion of commercially available acetobromogalactose with
the corresponding silver(I) 2-pyridoxide to give the glyco-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

B
R. Leslie et al.
Letter
Synlett
sides in 88% and 83% yield, respectively.10 Both systems
proved to be air stable over a prolonged period (ca. six
weeks) and the structures of both monosaccharides were
confirmed by spectroscopic and X-ray crystallographic
analysis.
mised) yields of all of the reactions varied between 35–48%
(see Scheme 2 for individual yields) which was the expect-
ed outcome as peracylated systems are known to be poor
donors. In recent years there have been reports of improved
yields with this type of system, although these results have
mainly been associated with the synthesis of aryl glyco-
sides,12 and in general most glycosylation yields remain low,
and are associated with significant byproduct formation.13
Indeed in most cases our donor matched, if not exceeded,
yields reported for other donor systems that utilised similar
protective-group motifs.14
X
OAc
OAc
AgO
N
AcO
AcO
AcO
AcO
O
O
Br
O
X
N
toluene, reflux
AcO
AcO
1 X = F
2 X = CF3
OH
OAc
O
Scheme 1 Synthesis of fluoropyridyl donors highlighting the masked
imidate structure
AcO
AcO
O
O
O
X
N
O
AcO
O
O
The next stage involved an investigation into the com-
patibility of these two donor systems with simple hydroxyl
protective groups. Cleavage of the acetate function with
catalytic sodium methoxide in methanol gave the fully
deprotected monosaccharides, which again showed their
stability to hydrolytic conditions in contrast to anomeric
trichloracetimidates. However, when we attempted either a
tetrabenzylation or silylation of the primary alcohol func-
tion both sugars appeared to undergo decomposition. In the
case of the latter reaction it might be that TBDMS-chloride
acted as an activator for the pyridyl donor, resulting in a
competing glycosylation reaction which would produce
complex mixtures of polysaccharides. The benzylation, on
the other hand, had appeared to proceed smoothly but, af-
ter an aqueous workup, we were unable to isolate the de-
sired product. Again we speculated that the strongly basic
media generated on quenching the reaction with water
could have resulted in hydrolysis of the fluoropyridyl sys-
tem. Hanessian had reported that his ‘MOP-glycosides’ were
stable to protection strategies8b and we considered a study
to optimize conditions for protection of our fluoropyridyl
systems. It was decided, however, to initially focus on an in-
vestigation into the reactivity of these systems as potential
glycosyl donors.
The fact that our system has a chelating nitrogen housed
within an aromatic ring allowed us to choose from a range
of metallic and non-metallic Lewis acids as activating sys-
tems and we decided to use Cu(OTf)2, In(OTf)3, and TMSOTf,
as standard activators for the pyridyl system, in conjunction
with diacetone galactose (3) as the acceptor. Donor 1 was
therefore mixed with acceptor 3 in dry dichloromethane
containing powdered 4Å molecular sieves and the mixture
stirred at room temperature for 30 minutes. One equivalent
of activator was then added, in a single portion, and stirring
was continued for a further 60 minutes to produce disac-
charide 4 as a single β anomer as outlined in Scheme 2.11
Similarly, donor 2 was also reacted with acceptor 3 under
identical conditions, and using the same activators, to pro-
duce disaccharide 4, again as a single anomer. The (unopti-
1 X = F
2 X = CF3
3
a, b or c
OAc
AcO
AcO
O
O
AcO
O
O
O
O
O
4
Scheme 2 Glycosylation of fluoropyridyl donors with diacetone galac-
tose using Lewis acid activation. Reagents and conditions: (a) Cu(OTf)2,
CH2Cl2, 4Å MS, r.t., for 1, 45%,2, 48%; (b) In(OTf)3,CH2Cl2, 4Å MS, r.t., for
1, 41%, 2, 42% (c) TMSOTf, CH2Cl2, 4Å MS, r.t., for 1, 35%, 2, 39%.
Having established that fluoropyridyl sugars were via-
ble donor systems for glycosylation, we turned our atten-
tion to synthesising the analogous perbenzylated glyco-
sides. We were already aware that protective-group manip-
ulation of a pyridyl galactose was not an option, so we
decided to adopt an alternative strategy based on literature
precedent.14 Starting with methyl galactopyranoside (5) a
three-stage procedure yielded crude tetrabenzyl bromoga-
lactose (6) as essentially the α anomer (we did not observe
the β anomer in the crude NMR). This was reacted, without
further purification, with the relevant sliver(I) pyridoxide
under standard conditions to give the fluoropyridyl donors
7 and 8 in excellent yields (Scheme 3).
OH
OBn
OBn
HO
HO
BnO
BnO
BnO
BnO
a, b, c
d
O
O
O
O
X
N
HO
BnO
BnO
OMe
Br
5
6
7 X = F
8 X = CF3
Scheme 3 Synthesis of benzylated fluoropyridyl donors. Reagents and
conditions: (a) NaH, BnBr, TBAI, DMF, 90%; (b) AcOH, H2SO4, reflux, 64%;
(c) (COBr)2, CH2Cl2, 89%; (d) silver(I) 2-pyridoxide, toluene, reflux, for 7,
86%, 8, 89%.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

C
R. Leslie et al.
Letter
Synlett
In both cases the β anomer was the major stereoisomer
from the reaction (ca 10:1 β/α indicating an SN2-type dis-
placement of the anomeric bromide.
played an unexpectedly high selectivity with, in all cases,
the α anomer produced as the major diastereomer in a 6:1
ratio with the β glycoside. Hanessian has, very recently, re-
ported some excellent results on a closely related system,17
achieving very high levels of stereocontrol. Although we did
not use Hanessian’s activation conditions, the same prefer-
ence for α selectivity was observed and it would appear
that pyridyl sugars can be tuned towards stereoselective
glycosylation. Similarly, acceptor 9 was also reacted with
donors 7 and 8 under our standard set of conditions to pro-
duce disaccharide 12 this time as a 4:1 mixture of diaste-
reomers favouring the α anomer. As with the synthesis of
11 these reactions also proceeded smoothly, rapidly and in
yields in excess of 80% (based on a mixture of separable
anomers). Finally we investigated the reaction of acceptor
10 with the same two donors utilizing our three methods of
activation. Surprisingly, the rate was not much slower and
reaction appeared to be complete after 15 minutes. Workup
and purification gave disaccharide 13 in yields of between
58% and 64% which we felt were more than acceptable giv-
en the unreactive nature of the acceptor. Selectivity for this
reaction was, however, poorer than the previous two exam-
ples but still favoured the α anomer in a ratio of 2:1 over
the β configuration. It is worth noting that in all cases the
trifluoromethyl analogue tended to produce higher yields
in the glycosylation reaction and (where rates could be
measured) was also slightly faster than the fluoropyridyl
sugar, suggesting it is the more reactive of the two systems
studied.
Unlike our initial donor systems 1 and 2 which are deac-
tivated due to the ‘disarming’ nature of the ester protective
groups15 and also undergo unwanted side reactions, the
perbenzylated glycosides 7 and 8 are ‘armed’ and the pro-
tective groups are non-participatory which should there-
fore result in a smooth and rapid glycosylation. We there-
fore wanted to choose a series of acceptors that displayed
an array of reactivity which would allow us to make a quick
comparison of our donor with that of other pyridyl glyco-
sides as well as Schmidt’s trichloroacetimidate. In addition
to the commercially available galactoside 3 we also chose to
investigate the use of acceptors 9 and 10 which were syn-
thesised according to literature procedure in three and four
steps, respectively.16 Acceptor 9 represents a relatively reac-
tive system and we would therefore expect a high-yielding
and rapid glycosylation reaction. However, due to the reac-
tive nature of 9 we would expect to see poor anomeric se-
lectivity and so therefore this acceptor as well as galacto-
side 3 will give an indication of the selectivity inherent in
our donor and whether it compares favourably with other
donor systems. Conversely, structure 10 is unreactive due to
both steric and electronic constraints and will therefore be
used to test the limits of reactivity for both donors.
The results of our investigation are summarised in
Scheme 4 beginning with the reaction of either donor 7 or 8
with acceptor 3 to give disaccharide 11 utilising our previ-
ous conditions mentioned above. The reactions proceeded
smoothly with yields in excess of 80% and were essentially
complete in under five minutes indicating a reactive sys-
tem. We were, however, unable to differentiate between the
reactivity of the two donors due to the high rate of reaction.
To our surprise, and delight, the glycosylation reaction dis-
In conclusion, we have introduced two new glycosyl do-
nor systems that display both high reactivity and selectivi-
ty. It is difficult to make a direct comparison between our
pyridyl donor systems and those of Hanessian as subtle dif-
ferences in the structure of the donor glycone, as well as the
acceptor, can have a profound effect on reaction outcome.
OBn
OH
O
BnO
O
O
BnO
BnO
O
O
O
O
O
O
3
O
OBn
OR
OR
O
BnO
BnO
O
OBn
O
BnO
HO
BzO
BzO
O
a, b or c
O
X
N
BnO
O
11
BnO
O
BnO
O
BzO
BzO
BzO
OMe
OMe
OBn
9
7 X = F
8 X = CF3
BzO
OR
O
OMe
BnO
BnO
OR
O
12
BnO
BzO
HO
BzO
BzO
O
O
BzO
BzO
BzO
OMe
13
10
Scheme 4 Glycosylation of ‘armed’ fluoropyridyl donors with a series of acceptors. Reagents and conditions: (a) Cu(OTf)2, CH2Cl2, 4Å MS, r.t., for donor
7; 11, 81%, 12, 85%, 13, 58%; for donor 8; 11, 86%, 12, 85%, 13, 62%; (b) In(OTf)3, CH2Cl2, 4Å MS, r.t., for donor 7; 11, 82%, 12, 80%, 13, 59%; for donor
8; 11, 85%, 12, 83%, 13, 64%; (c) TMSOTf, CH2Cl2, 4Å MS, r.t., for donor 7; 11, 80%, 12, 81%, 13, 59%; for donor 8; 11, 83%, 12, 81%, 13, 59%.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

D
R. Leslie et al.
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Synlett
In terms of yield and selectivity our fluoropyridyl systems
appear to compare favourably with the MOP donors. How-
ever, we tentatively suggest that, due to apparently shorter
reaction times, our fluorinated donors are the more reac-
tive system. This is of course offset by the fact that, current-
ly, fluoropyridyl donors are incompatible with protective-
group manipulation. More importantly, however, we are
confident that the structure of the donor could allow tuning
of the reactivity by varying the substitution pattern around
the pyridine ring which will allow us to produce further do-
nors that are compatible with standard protective-group
manipulation. Further study is needed but we are certain
that these preliminary investigations will lead to the devel-
opment of new glycosylation methodology that can easily
be applied to the stereoselective synthesis of complex oli-
gosaccharides.
evaporation of the solvent and purification of the residue by
flash chromatography (50% EtOAc/PE) gave the title compound
2 as a white solid (4.93 g, 83%). IR (neat): νmax= 2976, 1758,
1450, 1371, 1213, 1031 cm–1 1H NMR (400 MHz, CDCl3):
.
δ = 8.33 (d, 1 H, PyCH-6, JPyCH-5, 6 = 5.0 Hz), 7.91 (d, 1 H, PyCH-4,
JPyCH-4, 5 = 7.8 Hz), 7.1 (dd, 1 H, PyCH-5, JPyCH-5, 6 = 7.8 Hz and
JPyCH-4, 5 = 5.0 Hz), 6.03 (d, 1 H, H-1, J1, 2 = 8.2 Hz), 5.57 (d, 1 H,
H-2, J2 3 = 10.4 Hz), 5.47 (d, 1 H, H-4, J3, 4 = 3.3 Hz), 5.14 (dd, 1
H, H-3, J2, 3 = 10.4 Hz and J3, 4 = 3.3 Hz), 4.17 (s, 3 H, H-5, H-6a
and H-6b), 2.19 (s, 3 H, CH3) 2.02 (s, 3 H, CH3) 2.00 (s, 3 H, CH3)
1.97 (s, 3 H, CH3) ppm. 13C NMR (100 MHz, CDCl3: δ = 170.45 (2
C), 170.28 and 169.09 (C=O) 158.40 (1 C, PyC-2) 150.48 (1 C,
PyC-6) 137.05, 137.01 (1 C, q, PyC-4, J = 4.79 Hz) 123.81 and
121.10 (1 C, q, CF3, JC,F =272.2 Hz) 118.31 (1 C, PyC-5) 114.46,
114.11, 113.78 and 113.44 (1 C, q, PyC-3, JC,F3 = 33.5 Hz), 94.62
(C-1) 71.43, 71.05, 67.85 and 66.97 (C-2 to C-5) 61.12 (C-6)
20.81, 20.77, 20.71 and 20.53 (CH3) ppm. ESI-MS: m/z = 493 (1)
[M+], 331 (45) [M+ – C5H3NCF3], 169 (80), 43 (100). HRMS: m/z
calcd for C20H22NO10F3Na: 516.1094; found: 516.1172.
(11) General Procedure for Glycosylation: Synthesis of Disaccha-
ride 4
Supporting Information
Galactoside donor 1 (1.23 g, 2.79 mmol), acceptor 3 (0.83 g, 2.33
mmol), and powdered 4 Å MS (2.00 g) were added to CH2Cl2 (50
mL) and the mixture stirred for 30 min. Copper(II) triflate (1.01
g, 2.79 mmol) was added to the mixture in one portion and stir-
ring continued for a further 60 min. The reaction mixture was
filtered, the filtrate washed with CH2Cl2 (25 mL), and the com-
bined organic extracts washed with water (2 × 25 mL), sat. aq
NaHCO3 (25 mL), and dried (MgSO4). Filtration and evaporation
of the solvent and purification of the residue by flash chroma-
tography (25% EtOAc/PE) gave the title compound 4, as the β
anomer, as a white solid (0.64 g, 45%). IR (neat): νmax= 2988,
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588478.
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References and Notes
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.
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5.49 (d, 1 H, H-1′, J1,2′ = 5.03 Hz), 5.37 (d, 1 H, H-4, J3,4 = 3.2 Hz),
5.2 (dd, 1 H, H-2, J2,3 = 10.52 Hz, J1,2 = 8.23 Hz), 5.0 (dd, 1 H, H-3,
J2,3 = 10.52 Hz, J3,4 = 3.2 Hz), 4.56–4.58 (m, 2 H, H-1 and H-3′),
4.28 (dd, 1 H, H-2′, J1,2′ = 5.03 Hz, J2,3′ = 2.29 Hz), 4.01–4.18 (m, 4
H, H-6a, H-6b, H-5, and H-4′), 3.87–3.93 (m, 2 H, H-6a′ and H-
6b′), 3.66 (m, 1 H, H-5′), 2.12 (s, 3 H, CH3), 2.07 (s, 3 H, CH3), 2.03
(s, 3 H, CH3), 1.97 (s, 3 H, CH3), 1.49 (s, 3 H, CH3′), 1.43 (s, 3 H,
CH3′), 1.31 (s, 6 H, CH3′) ppm. 13C NMR (100 MHz, CDCl3): δ =
170.51, 170.37, 170.28 and 169.79 (C=O), 109.50 and 108.77
(Cquart′), 102.90 (C-1), 96.28 (C-1′), 71.37 (C-2′), 70.90 (C-4′),
70.72 (C-3′), 70.64 (C-3), 70.51 (C-2), 69.74 (C-5), 68.68 (C-5′),
67.96 (C-4), 67.14 (C-6′), 61.28 (C-6), 26.14, 26.02, 25.15 and
24.38 (CH3′), 20.90, 20.79 and 20.71 (CH3) ppm.
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(10) General Procedure for Fluoropyridyl Glycosides: Synthesis of
Donor 2
Silver(I) 3-trifluoromethyl-2-pyridoxide (3.91 g, 14.48 mmol)
was added to a vigorously stirring solution of acetobromogalac-
tose (4.95 g, 12.05 mmol) in toluene (100 mL) and the mixture
heated at reflux for 1 h. The mixture was cooled, filtered
through Celite®, and the Celite® pad washed with toluene (100
mL). The combined organic extract was washed with water (100
mL), sat. aq NaHCO3 (100 mL), and dried (MgSO4). Filtration and
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D