Glycosylations with a septanosyl fluoride donor lacking a C2 protecting group

Article abstract of DOI:10.1016/j.tetlet.2012.08.039

Septanosyl fluorides, prepared from protected pyranoses, were used as donors in glycosylation reactions. The fluorides were synthesized by the addition of vinyl Grignard to the pyranoses followed by ozonolysis and then DAST-mediated fluorination. Activation in the presence of nucleophiles then provided the product glycosides. High α-stereoselectivity was observed for glycosylations using a donor that had a free C2 hydroxyl group; a model where the hydroxyl group participates to guide the stereochemical outcome is proposed.

Full text of DOI:10.1016/j.tetlet.2012.08.039

Tetrahedron Letters 53 (2012) 5667–5670
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Tetrahedron Letters
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Glycosylations with a septanosyl fluoride donor lacking a C2 protecting group
⇑
Jaideep Saha, Mark W. Peczuh
Department of Chemistry, University of Connecticut, 55 North Eagleville Road U3060, Storrs, CT 06269, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Septanosyl fluorides, prepared from protected pyranoses, were used as donors in glycosylation reactions.
The fluorides were synthesized by the addition of vinyl Grignard to the pyranoses followed by ozonolysis
and then DAST-mediated fluorination. Activation in the presence of nucleophiles then provided the prod-
uct glycosides. High a-stereoselectivity was observed for glycosylations using a donor that had a free C2
hydroxyl group; a model where the hydroxyl group participates to guide the stereochemical outcome is
Received 27 July 2012
Revised 8 August 2012
Accepted 9 August 2012
Available online 16 August 2012
proposed.
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Glycosylation
Septanose carbohydrate
Glycosyl fluoride
Efficient methods for the preparation of septanose glycoconju-
gates are required to properly assess their utility in glycobiology.1
Septanose carbohydrates have been incorporated into oligonucleo-
tides,2 evaluated as substrates3,4 or inhibitors5 of glycosidase en-
zymes and as ligands of lectins.6 Methods for glycosylations
involving septanoses have ranged from donor strategies co-opted
from the pyranose literature3,7–9 to ring expansion and functional-
ization sequences.10,11 Despite these successes, glycosylation reac-
tions involving septanoses are still being actively investigated.
Currently, key challenges are to suppress undesired, transannular
reactions that have been observed and to identify methods that
are sufficiently general with respect to the acceptors that can be
used. Our work has largely aimed at applying glycosylation strate-
gies from pyranose chemistry to the world of septanosides. Here
we report on a method that converts a pyranose lactol to the cor-
responding septanosyl fluoride. The fluoride, which lacks a protect-
ing group on the C2 hydroxyl group, is then utilized as a glycosyl
donor in model glycosylation reactions.
is essential for such interactions to mimic pyranoses. Accordingly,
we focused our attention on the preparation of septanose glyco-
conjugates containing this key structural element. We therefore at-
tempted glycosylation of 1,2:3,4-di-O-isopropylidene-D-galactose
2 under Lewis acidic conditions with the 1,2-anhydrosugar (not
shown) prepared from oxepine 1 but this was unsuccessful
(Scheme 1). Alternatively, we converted oxepine 18a to S-phenyl
glycoside 4. The yield of 4 was significantly lower than other in-
stances where the starting materials lacked a C6 substituent. Gly-
coside 4 was isolated in 38% yield over two steps as a mixture of a-
and b-anomers. Varying the temperature, solvent, or Lewis acid
failed to improve the yield. The C2 hydroxyl group of 4 was pro-
tected as the acetate, providing 5 in 78% yield. The donating ability
of 5 was then tested using 2 as a model acceptor under standard
In earlier work from our lab, oxepines (ring expanded glycals)
were epoxidized with dimethyldioxirane (DMDO); the product of
epoxidation, a transient 1,2-anhydroseptanose, when in the pres-
ence of an acceptor and under appropriate conditions was con-
verted to septanose-containing glycoconjugates. This method
exploited the glycal-like reactivity of the oxepines.7 Moreover,
we and others have converted 1,2-anhydroseptanoses to their cor-
responding S-phenyl septanosides which were subsequently used
as donors.8 Notably, both of those methods were used with donors
that lacked a C6 hydroxymethyl group. Our recent studies on ConA
binding to septanosides6 indicated that the hydroxymethyl group
⇑
Corresponding author. Tel.:+1 860 486 1605; fax: +1 860 486 2981.
E-mail address: mark.peczuh@uconn.edu (M.W. Peczuh).
Scheme 1. Glycosylations involving oxepine 1 as donor.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.039

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J. Saha, M. W. Peczuh / Tetrahedron Letters 53 (2012) 5667–5670
glycosylation conditions. Disaccharide 6 was obtained in 30% yield
as a mixture of anomers. Poor efficiency in both the preparation of
donor 5 and in its utilization as a glycosyl donor leads us to explore
an alternative strategy.
cosylations using septanosyl fluorides were superior to our initial
method where hydroxy aldehydes were used to make septanosides
via an acid mediated cyclization and glycosylation.12 That method
was limited by the large excess of acceptor required (acceptors
were solvents or cosolvents) and its reliance on protic acid. Instead,
we envisioned that, with some modifications, the fluoride strategy
could be extended to the preparation of septanosides that are oxy-
genated at C2.
The approach was adapted by starting the synthesis from a pro-
tected lactol rather than a glycosylamine. We expected that an
aldehydo-diol, akin to hydroxy aldehyde intermediate 8 in the 2-
amino septanoside synthesis, could be similarly parlayed into a
septanosyl fluoride. There was some risk in targeting this interme-
diate though. Unlike the addition to the glycosyl amine which
delivered an allylic amine, addition to the lactol would give an
allylic alcohol. Selectively protecting the allylic alcohol in the pres-
ence of the C6 alcohol would be problematic. Also, upon ozonoly-
We recently reported a method for the preparation of 2-amino
septanosides that utilized septanosyl fluorides as donors.9 As
shown in Scheme 2, septanosyl fluoride 9 was synthesized from
hydroxy aldehyde 8 using DAST as the fluoride source. Hydroxy
aldehyde 8 was itself prepared from glucosyl amine 7.12 Primary
and secondary alcohol acceptors as well as azide were glycosylated
by fluoride 9 in yields that ranged from 40–70%. The approach
proved to be relatively general; in addition to 9, which was pre-
pared from glucosyl amine 7, fluorides from the corresponding
galactosyl and mannosyl amines were similarly synthesized. Gly-
sis, the allylic alcohol would be transformed into an
a-hydroxy
aldehyde which would further offer challenge for the acid medi-
ated manipulation of the functionality because of its propensity
to isomerize to an a-hydroxy ketone.
Confident that these potential challenges could be surmounted
if they arose, we set about the investigation. 2,3-Di-O-benzyl-4,6-
O-benzylidine glucopyranose 11 was used as the lactol in our pre-
liminary investigations (Scheme 3). Addition of vinyl Grignard to
11 delivered an 8:1 mixture of diastereomers (92%). The major iso-
mer was tentatively assigned as 12. The stereochemical assign-
ment was based on a reported addition to glucopyranose13 which
used a Cram-chelate model.12 Addition to lactol 11 was less diaste-
reoselective than addition to glycosyl amines such as 7. We attrib-
uted this to variations in the occupancy of the open-chain
hydroxyaldehyde (versus closed hemiacetal) of the electrophile.
Specifically, under the basic conditions of the reaction, a lower
population of the open-chain form (as in the case of the glycosyl
amine) at a given instance would favor a higher selectivity of the
Scheme 2. Synthesis and glycosylations of 2-amino septanosyl fluorides.
Scheme 3. Preparation of septanosyl fluorides from protected pyranoses.

J. Saha, M. W. Peczuh / Tetrahedron Letters 53 (2012) 5667–5670
5669
addition.14 Ozonolysis of 12 provided 13 in 65% yield. Inspection of
the NMR spectra of 13 showed that the hemiacetal form (13b) was
adopted almost exclusively as mixture of anomers. Similarly, tetra-
O-benzyl glucopyranose 16 was transformed to allylic alcohol 17
and isolated in 90% yield. The major diastereomer of 17 was then
converted into 18 in 90% yield.15
arable by column chromatography. For 19
anomeric proton was characterized by a distinct downfield shift
a
, the signal for the
(dH 5.47 ppm) as a doublet of a doublets with the following cou-
pling constants: JH–F = 54.0 Hz, 3JH1,H2 = 6.2 Hz. The
a configuration
was also confirmed by the downfield 13C NMR chemical shift (dC
1
111.3 ppm) of the anomeric carbon with a JC–F coupling constant
Encouraged by the fact that 13 and 18 both favored the cyclic
lactol form (i.e., 13b and 18b), we set about the task of converting
them into their respective septanosyl fluorides. One concern how-
ever, was the possibility that fluorination at C2 followed by stereo-
specific migration of the C1 hydroxyl group16 might compete with
the desired fluorination at C1. In our case, this would lead to partial
or complete epimerization at the C2 stereocenter.17 In such a sce-
nario, four different anomeric fluorides, two from direct fluorina-
of 227 Hz. For 19b, the anomeric proton appeared as doublet (dH
5.70 ppm) with a JH–F 49.7 Hz. In the 13C NMR, the dC was
1
1
110.0 ppm and the JC–F was 215 Hz. The lower JC–F value for the
b anomer compared to the is consistent with data reported for
pyranosyl fluorides.19 19F NMR experiment performed on the b
anomer showed a resonance at À138.0 ppm, unambiguously prov-
ing the C1 fluorination of the septanose lactol.20 Proton coupled 19
a
A
F
NMR data for the mixture of anomeric fluorides 14 was collected;
chemical shifts of À134.1 and À134.5 ppm with JH–F values of 50.2
and 50.6 Hz confirmed their structures.
With an established method to prepare septanosyl fluorides, we
next evaluated their ability to act as donors in glycosylation reac-
tion at C1 (
a and b) and two by epimerization of the hydroxyl at
C2 could form. Reasoning that the C1 hydroxyl group would be
more reactive as a nucleophile,18 we anticipated that products aris-
ing from reaction at this position would dominate. Fluorination of
13 and 18 at À78 °C was sensitive to different reaction parameters
as summarized in Table 1. For example, switching the reaction sol-
vent from THF to dichloromethane (DCM) improved the yield for
converting 13 to 14 from 32% to 55% (entries 1 and 2); we had ob-
served the same solvent dependence in our previous work.9 The
reaction also showed a significant dependence on the number of
equivalents of DAST used and the reaction time (entries 2–5). Cut-
ting the reaction time to five minutes and using 1.5 equiv of DAST
proved to be most efficient, providing 14 and 19 in 75 and 66%
yields, respectively (entries 3 and 5).
tions. We began by using 1,2:4,6-di-O-isopropylidene D-galactose 2
as a model acceptor. We previously reported that both TMSOTf or a
combination of SnCl2 and AgClO4 could efficiently promote glyco-
sylation when using 2-aminoseptanosyl fluorides (i.e., 9) as donors.
Accordingly, we attempted to use these promoters in reactions
using donors 14, 15, and 19.21 Reaction of donor 14 using TMSOTf
as promoter resulted in the formation of disaccharide 21 (Fig. 1) in
18% yield as mixture of anomers (Table 2, entry 1). The C2 benzyl
protected donor 15 showed an improved yield (41% and 37% yields,
respectively) although the stereoselectivity in glycoside bond for-
mation was poor for both promoters (entries 2 and 3). Use of donor
19, with a free C2 hydroxyl group, resulted in efficient glycosyla-
tion, providing 23 in 58% and 65% yields, depending on the pro-
Formation of the septanosyl fluorides was confirmed by NMR
spectroscopy. Septanosyl fluoride 14 was obtained as an insepara-
ble mixture of anomers whereas the two anomers of 19 were sep-
moter used. Notably, when using this donor,
a
single
stereoisomer of the newly formed glycoside was isolated for sev-
eral glycosyl acceptors (entries 4–9, 11). The product glycosides
were assigned as the
Table 1
a
-anomers based on 13C chemical shifts,
DAST conversion of septanose lactols 13 and 18 to the corresponding septanosyl
fluoridesa
which were in the range of 98–103 ppm. Additional support came
1
from a 13C coupled HSQC experiment to determine the JC–H value
Entry Lactol Product Solvent DAST (equiv.) Time (min) Yield (%)
for a selected compound. The measured 1JC–H measured for 26 was
1
2
3
4
5
13
13
13
18
18
14
14
14
19
19
THF
1.0
1.2
1.5
1.2
1.5
30
30
5
30
5
32
55
75
60
66
167 Hz which is characteristic of the
a-anomeric configuration of
DCM
DCM
DCM
DCM
septanosides as has been reported.7,10 High diastereoselectivity in
glycosylation reactions involving partially protected donors is
precedented.22–24 We propose that a 1,2-anhydrosugar species
such as 32 is sufficiently populated such that it blocks the b-face
a
All reactions done at À78 °C under N2 atmosphere.
Figure 1. Products of glycosylation reactions described in Table 2.

5670
J. Saha, M. W. Peczuh / Tetrahedron Letters 53 (2012) 5667–5670
Table 2
Glycosylations of several alcohols with septanosyl donors 14, 15 and, 19
Entry
Donor
Acceptor
Promoter
Product
Yield (%)
a:b
1
2
3
4
5
6
7
8
9
14
15
15
19
19
19
19
19
19
19
19
2
2
2
2
TMSOTf
TMSOTf
SnCl2–AgClO4
TMSOTf
SnCl2–AgClO4
TMSOTf
TMSOTf
TMSOTf
TMSOTf
SnCl2–AgClO4
TMSOTf
21
22
22
23
23
24
25
26
28
28
30
18
41
37
58
65
61
52
57
60
49
54
1:1
ND
ND
a
a
a
a
a
a
ND
2
Chloroethanol
Cyclohexyl methanol
Allyloxyethanol
27
27
29
10
11
a
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/
j.tetlet.2012.08.039.
References and notes
Figure 2. Oxocarbenium ion 31 and its 1,2-anhydrosugar resonance structure 32;
32 explains the high -selectivity of the glycosylations in Table 2.
a
1. Saha, J.; Peczuh, M. W. Adv. Carbohydr. Chem. Biochem. 2011, 66, 121–186.
2. Sabatino, D.; Damha, M. J. J. Am. Chem. Soc. 2007, 129, 8259–8270.
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A.; Peczuh, M. W. Org. Biomol. Chem. 2011, 9, 154–164; (b) Castro, S.; Duff, M.;
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of the donor (Fig. 2) giving rise to the high a
-selectivity observed.22
Further, comparison of the glycosylation selectivities for 14 and 15
with those of 19 suggests that the flexibility within the ring is nec-
essary to form 32. The rigidity imposed by the benzylidine moiety
on 14 and 15 presumably does not allow the 1,2-anhydrospecies to
form and gives rise, therefore, to anomeric mixtures.
We have developed a glycosylation strategy that uses a C2 hy-
droxy (unprotected) septanosyl fluoride as donor in glycosylation
reactions. Use of anomeric fluorides as donors has allowed the syn-
thesis of septanosides that contain a substituent at the C6 position
which had previously been cumbersome and inefficient. The new
method overcomes the shortcomings associated with efficient
preparation of thioglycoside donors (Scheme 1). It also simplifies
an earlier route to prepare methyl septanosides through species
akin to 13.25 This method was limited by stepwise synthesis with
protecting group maneuvers. One of the major problems in that ap-
proach was to functionalize the anomeric group selectively in the
presence of an unprotected C2 hydroxyl group. Compounds such
15. Vinyl Grignard addition to lactol 16 was even less selective (2:1) than for 11,
consistent with the model proposed.
as 13 (Scheme 3) are complicated by a propensity for the
a-
hydroxyaldehyde to equilibrate into an -hydroxy ketone under
a
16. Nicolaou, K. D.; Ladduwahetty, T.; Randall, J. L.; Chucholowski, A. J. Am. Chem.
Soc. 1986, 108, 2466–2467.
17. See the Supplementary Data file for a rationalization of the epimerization
process.
18. (a) Morris, W. J.; Shair, M. D. Org. Lett. 2009, 11, 9–12; (b) Ryan, D. A.; Gin, D. Y.
J. Am. Chem. Soc. 2008, 130, 15228–15229; (c) Tewson, T. J.; Welch, M. J. J. Org.
Chem. 1978, 43, 1090–1092.
19. (a) Bock, K.; Pedersen, C. Acta Chem. Scand. 1975, 29B, 682–686; (b) Lin, P.-C.;
Adak, A. K.; Ueng, S.-H.; Huang, L.-D.; Huang, K.-T.; Ho, J. A.; Lin, C.-C. J. Org.
Chem. 2009, 74, 4041–4048.
the reaction conditions (via an ene-diol). Selective functionaliza-
tion of the C1 hydroxyl in the new procedure provided the sept-
anosyl fluoride donors in good yields. Furthermore, the
glycosylations that were conducted without protecting the C2 hy-
droxyl group gave efficient yields and selectivity rendering shorter
synthesis and provided more room to functionalize through C2 po-
sition for more complex septanose carbohydrates.
20. (a) Bucher, C.; Gilmour, R. Angew. Chem. Int. Ed. 2010, 49, 8724–8728; (b)
Brayer, G. D.; Sidhu, G.; Maurus, R.; Rydberg, E. H.; Braun, C.; Wang, Y.; Nguyen,
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Acknowledgements
21. Septanosyl fluorides used in glycosylation reactions were a/b mixtures.
22. Du, Y.; Gu, G.; Wei, G.; Hua, Y.; Lindhardt, R. J. Org. Lett. 2003, 5, 3627–3630.
23. Plante, O. J.; Palmacci, E. R.; Andrade, R. B.; Seeberger, P. H. J. Am. Chem. Soc.
2001, 123, 9545–9554.
24. Hanessian, S.; Lou, B. Chem. Rev. 2000, 100, 4443–4464.
25. Ramsubhag, R. R.; Peczuh, M. W. Arkivoc 2011, v, 92–101.
Bikash Surana is acknowledged for early investigations in the
synthesis of compound 6. This work was supported by a National
Science Foundation CAREER Award (CHE-0546311) to M. W. P.
NSF is also acknowledged for CRIF award to upgrade the
400 MHz NMR (CHE-1048717).