Synthesis of α-D-idoseptanosyl glycosides using an S-phenyl septanoside donor

Article abstract of DOI:10.1021/ol051912e

(Chemical Equation Presented) An S-phenyl α-D-idoseptanoside donor was used in the selective preparation of a series of α-D-idoseptanosyl glycosides. Glycosylation of a methyl β-D-glycero-D-guloseptanoside acceptor with the new donor constituted the first

Full text of DOI:10.1021/ol051912e

ORGANIC
LETTERS
2005
Vol. 7, No. 21
4709-4712
Synthesis of
Glycosides Using an S-Phenyl
Septanoside Donor
r- -Idoseptanosyl
D
Steve Castro,† W. Sean Fyvie,† Susan A. Hatcher,‡ and Mark W. Peczuh†,*
Department of Chemistry, The UniVersity of Connecticut, 55 North EagleVille Road
U-3060, Storrs, Connecticut 06269, and Department of Chemistry, The Ohio State
UniVersity, 100 West 18th AVenue, Columbus, Ohio 43210
mark.peczuh@uconn.edu
Received August 8, 2005
ABSTRACT
An S-phenyl
r
-D-idoseptanoside donor was used in the selective preparation of a series of
r
-D-idoseptanosyl glycosides. Glycosylation of a
methyl -glycero-D-guloseptanoside acceptor with the new donor constituted the first synthesis of a septanose disaccharide.
â
-D
A growing appreciation for the role of carbohydrates in
biological processes has spurred the development of ana-
logues that can serve as tools for glycobiology.1 We have
been interested in utilizing seven-membered ring (septanose)
carbohydrates as analogues of natural pyranose sugars for
the investigation of protein-carbohydrate interactions.2 Sep-
tanoses may be able to effectively adopt distorted conforma-
tions in glyco-enzyme binding sites3 or be used to define
new types of protein-carbohydrate interactions.4 The syn-
thesis and characterization of septanose carbohydrates,
however, has received only limited attention relative to the
naturally occurring furanose and pyranose ring forms.5 A
challenge central to the synthesis of any class of oligo- or
polysaccharide is the formation of the glycosidic linkages
between saccharide units.6 Herein we report the efficient and
selective synthesis of a variety of R-D-idoseptanosyl glyco-
sides from an S-phenyl septanoside donor. The new donor
was activated under mild conditions and formed R-septano-
sides in good yields. Glycosylation of a methyl septanoside
acceptor using the new donor provided an R-1,7-linked
diseptanoside; this is the first reported synthesis of a
disaccharide containing a septanose residue at both the
reducing and nonreducing end of the structure.
Previously, glycosylations using anomeric chlorides7 or
acyclic chloro-thioethyl acetals8 as septanosyl donors were
reported. Additionally, we have investigated the glycal-like
reactivity of the D-xylose based oxepine 1.9 Epoxidation of
1, using DMDO, formed the â-1,2-anhydroseptanose 2,
† The University of Connecticut.
‡ The Ohio State University.
(1) (a) Gruner, S. A. W.; Locardi, E.; Lohof, W.; Kessler, H. Chem.
ReV. 2002, 102, 491. (b) Bertozzi, C. R.; Kiessling, L. L. Science 2001,
291, 2357. (c) Koeller, K. M.; Wong, C. H. Nat. Biotech. 2000, 18, 835.
(2) Castro. S.; Duff, M.; Snyder, N.; Morton, M. Kumar, C. V.; Peczuh,
M. W. Org. Biomol. Chem. 2005, DOI 10.1039/b509243d.
(3) (a) Mart´ınez-Mayora, K.; Medina-Franco, J. L.; Mari, S.; Can˜ada,
F. J.; Rodr´ıguez-Garcia, E.; Vogel, P.; Li, H.; Ble´riot, Y.; Sinay¨, P.; Jime´nez-
Barbero, J. Eur. J. Org. Chem. 2004, 4119. (b) Li, H.; Ble´riot, Y.;
Chantereau, C.; Mallet, J.-M.; Sollogoub, M.; Zhang, Y.; Rodr´ıguez-Garcia,
E.; Vogel, P.; Jime´nez-Barbero, J.; Sinay¨, P. Org. Biomol. Chem. 2004, 2,
1492. (c) Mor´ıs-Varas, F.; Qian, X.-H.; Wong, C. H. J. Am. Chem. Soc.
1996, 118, 7647.
(5) Pakulski, Z. Pol. J. Chem. 1996, 70, 667.
(6) (a) Davis, B. G. J. Chem. Soc., Perkin Trans. 1 2000, 2137. (b)
Toshima, K.; Tatsuda, K. Chem. ReV. 1993, 93, 1503.
(7) Micheel, F.; Suckfu¨ll, F. Ann. Chim. 1933, 507, 138.
(8) McAuliffe, J. C.; Hindsgaul, O. Synlett 1998, 307.
(9) (a) Peczuh, M. W.; Snyder, N. L.; Fyvie, W. S. Carbohydr. Res.
3
(4) (a) Benner, S. A.; Sismour, A. M. Nat. ReV. Genet. 2005, 6, 533. (b)
Benner, S. A. Nature 2003, 421, 118.
2004, 339, 1163. (b) JH1,H2 values of these 1,2-trans glycoside products
were between 6.6 and 8.4 Hz.
10.1021/ol051912e CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/23/2005

which was reacted with nucleophiles to give septanosides
such as 3 (Figure 1). Although this method was relatively
Having established a synthetic route to S-phenyl septano-
sides 4a and 4b, we next explored their ability to serve as
donors for glycosylation reactions. Activation using N-
iodosuccinimide (NIS) and silver triflate in the presence of
a series of alcohol acceptors 7-12 (Table 1) afforded the
corresponding septanosides (13-18) in moderate to very
good yields with a high degree of stereocontrol in the
formation of the R-glycosides.10 Table 1 collects information
on the specific glycosylation reactions. The stereochemistry
of the anomeric center was assigned on the basis of the
3
similarity of the product C1 chemical shifts and JH1,H2
coupling constants to our previously reported R-D-idosep-
tanosides.9 In general, the donors 4a and 4b provided the
product glycosides with similar efficiency, although the
yields using 4b were consistently lower than those with 4a.
Also, the activation11 of 4a occurred rapidly at -40 °C,
whereas reactions using 4b often were allowed to warm to
-25 °C before activation was noted. These observations are
consistent with a slight deactivation of donor 4b due to the
acetate group at C2.12
Figure 1. Glycosylation strategies for the preparation of septanosyl
glycosides.
Simple alcohol acceptors such as 7 and 8 gave exclusively
the corresponding R-glycosides in very good yields (entries
1-4). Peculiar among this group of reactions was the
glycosylation of 7 using the acetate-protected donor 4b (entry
2). The main product of this reaction (13b) was accompanied
by a side product corresponding to the deacetylated glycoside
in 14% yield.13 This material most likely arises from a
transesterification reaction between 13b and the excess
acceptor 7 that is present in the reaction mixture. Factors
that likely contributed to the transesterification are (i) excess
acceptor present in the glycosylations (2-3 equiv) and (ii)
the higher reaction temperature relative to glycosylations
involving 4a. Donor 4b was also used to glycosylate 4-tert-
butylphenol (9) as acceptor to provide the aryl glycoside 15
(entry 5). Glycosylation of 2,6-dimethylphenol (not shown)
with 4b was unsuccessful, presumably as a result of steric
hindrance of the phenolic hydroxyl group.
Readily available carbohydrate alcohols 10-12 were next
investigated (entries 6-11). Di-O-isopropylidene galactose
(10), a primary alcohol, gave a high yield of the R-septano-
side product 16. The preparation of this pyranosyl septano-
side is a significant improvement on our previous oxidative
glycosylation reaction9 in terms of both yield (79% versus
45%) and selectivity (R only versus 3:2 R:â). Reactions with
more hindered secondary alcohol groups on di-O-isopropyl-
idene glucose (11) and methyl 2,3,6-tri-O-benzyl-D-glucoside
(12) gave moderate yields of the corresponding glycosides
17 and 18. The lower yields in these examples are attributed
to steric congestion around the nucleophilic hydroxyl groups
of the acceptors. Results for the glycosylation of 11 with
either donor were unique in giving mixtures (R/â) of
glycoside products. In fact, glycosylation of 11 with a donor
efficient for the preparation of simple (-OCH3, -OiPr)
septanosides, with di-O-isopropylidene-R-D-galactose (10) as
the acceptor only a modest yield (45%) of the pyranosyl
septanoside resulted along with poor anomeric selectivity (3:2
R:â). At the outset of this investigation, we endeavored to
improve the yield and selectivity of such glycosylations using
more elaborate acceptors.
Several factors made S-phenyl R-D-idoseptanoside 4
(Figure 1) an attractive donor for the preparation of sep-
tanosyl glycosides. S-Phenyl septanosides would be analo-
gous to the broadly utilitized S-phenyl pyranosides in
“normal” glycosylation reactions. We reasoned that activation
of the S-phenyl group under standard conditions would
produce an oxonium such as 5 that could be attacked by a
nucleophile to give septanosides such as 3. Participatory
protecting groups (R ) Ac) on the C2 oxygen could also be
utilized to enhance the selectivity for the formation of the
R-septanoside. The preparation of 4 (Scheme 1) utilized
Scheme 1. Synthesis of 4
oxepine 1 as a starting material. Epoxidation of 1 with
DMDO and exposure to the lithium salt of thiophenol in
THF gave S-phenyl septanoside 6 (73%) as reported.9 The
C2 alcohol of 6 was thereafter protected as either the benzyl
ether (4a) or the acetate (4b) in 87% and 89% yields,
respectively. Attempts at improving the yield of donors 4a
and 4b from 1 by forming the thiophenyl septanoside and
protecting C2 in a two-step, one-pot procedure were not
successful.
(10) (a) Gadikota, R. R.; Callam, C. S.; Wagner, T.; Del Fraino, B.;
Lowary, T. L. J. Am. Chem. Soc. 2003, 125, 4155. (b) Gadikota, R. R.;
Callam, C. S.; Lowary, T. L. Org. Lett. 2001, 3, 607.
(11) Activation here was estimated by the disappearance of donor by
TLC and color change (to magenta) of the reaction mixture.
(12) Veeneman, G. H.; van Boom, J. H. Tetrahedron Lett. 1990, 31,
275.
(13) NMR spectra of the material isolated are in Supporting Information.
4710
Org. Lett., Vol. 7, No. 21, 2005

Table 1. Glycosylations with S-Phenyl Septanosides 4a and 4ba
a Reaction conditions: S-phenyl glycoside 4a or 4b (0.1 mmol), alcohol (0.15-0.3 mmol), 4 Å molecular sieves, N-iodosuccinimide (0.13 mmol), and
silver triflate (0.03 mmol) in 3 mL of CH2Cl2 for 30 min at -40 to -25 °C. b Characterization data is in Supporting Information. c Stereochemistry based
3
on δ C1 and JH1,H2
.
d 14% yield of 13b lacking the C2 acetate was also recovered in this reaction.
lacking a participatory group at C2 (4a) was more selective
(10:1 R:â) than with the acetate-protected donor 4b (1:1).
This result leaves open the question of the participatory
nature of the C2 acetate group in this system and is further
complicated by the low nucleophilicity of acceptor 11. In
total, the new donors are useful reagents for the selective
preparation of a variety of novel R-septanosides.
Encouraged by these results, we undertook the synthesis
of a disaccharide composed solely of septanose residues as
an extended demonstration of the donating capability of
S-phenyl septanosides. To the best of our knowledge,
diseptanosides with a septanose at the reducing and nonre-
ducing end have not been previously described in the
literature.
Epoxidation of 19 with DMDO was followed by attack with
NaOCH3/CH3OH to give the methyl â-septanoside 20 in 68%
yield over two steps; the assignment of â-stereochemistry
was based on the high selectivity observed in the epoxidation
reaction,14 SN2-like opening of the R-1,2-anhydroseptanose,
and comparison of the NMR data of the hydrogenolysis
product of 20, which was found to be that of the known
methyl â-D-glycero-D-guloseptanoside.15 Protection of the C2
hydroxyl group gave benzyl ether 21 (95%). Regioselective
functionalization of 4,6-O-benzylidenes is precedented for
pyranoses, and similar reaction conditions were utilized to
open the 5,7-O-benzylidene ring of methyl septanoside 21.
Reduction of 21 with lithium aluminum hydride (LAH) in
the presence of aluminum chloride in DCM/Et2O gave a
mixture of 22 (13%) and 23 (42%).16 A slightly better yield
was obtained using BH3‚NH(CH3)2 as reductant with BF3‚
Et2O in DCM/Et2O, giving 22 and 23 in 13% and 55%,
respectively.17,18 Changing the solvent to acetonitrile under
these reaction conditions gave the C5 hydroxy material (22)
in 61% yield.
Oxepine 19 served as a starting material for the preparation
of methyl septanoside acceptors 22 and 23 (Scheme 2).
Scheme 2. Preparation of Septanoside Acceptors 22/23
(14) The parameters that govern the selectivity in epoxidation of
carbohydrate-based oxepines is currently under investigation.
(15) DeMatteo, M.; Snyder, N. L.; Morton, M.; Baldisseri, D. M.; Hadad,
C. M.; Peczuh, M. W. J. Org. Chem. 2005, 70, 24.
(16) Liptak, A.; Jodal, I.; Nanasi, P. Carbohydr. Res. 1975, 44, 1.
(17) (a) Fukase, K.; Fukase, Y.; Oikawa, M.; Liu, W.; Suda, Y.;
Kusamoto, S. Tetrahedron 1998, 54, 4033. (b) Toone, E. J.; Debenham, S.
S. Tetrahedron: Asymmetry 2000, 11, 384.
(18) Reduction of the glycosidic linkage under the BH3‚NH(CH3)2/BF3‚
OEt2 reaction conditions to form an acyclic methyl ether was also observed.
NMR spectra of the product of this overeduction are provided in Supporting
Information.
Org. Lett., Vol. 7, No. 21, 2005
4711

Methyl septanosides 22 and 23 were then tested as
acceptors in glycosylations under the established reaction
conditions. The inspiration for preparing diseptanosides was
based on two major factors. First, we were interested in
evaluating diseptanosides as ligands for carbohydrate binding
proteins. Second, the synthesis of diseptanosides is a step
toward the preparation of larger linear and branched oligo-
septanosides. Attempts at glycosylation of 22 with either 4a
or 4b to form the 1,5-linked diseptanoside were unsuccess-
ful.19 The inability to effect this glycosylation is a limitation
and may be ascribed to poor nucleophilicity of the C5
hydroxyl group of 22, similar to that of acceptor 12. On the
other hand, glycosylation of 23 with 4b under the conditions
established for the other acceptors gave the R-1,7-linked
diseptanoside 24 (76%) (Scheme 3). The yield of this reaction
In conclusion, we have introduced S-phenyl R-D-idosep-
tanoside (4) as a donor for septanose glycosylations. A
number of alcohols were glycosylated, with 4 affording the
corresponding idoseptanosides in good yields and high
selectivity in forming the R-anomer. An R-1,7-linked di-
septanoside (24) was synthesized from 4b and methyl
septanoside acceptor 23. This is the first reported preparation
of a disaccharide where both the reducing and nonreducing
unit are composed of septanose carbohydrates and highlights
the utility of the donor. On the basis of the general ability
to transform oxepines into S-phenyl septanosides, we an-
ticipate that a wide variety of septanosyl glycosides should
be accessible by this strategy. Progress on these fronts will
be reported in due course.
Acknowledgment. Financial support was provided by the
Petroleum Research Fund administered by the American
Chemical Society and the University of Connecticut.
Scheme 3. Preparation of R-1,7-Linked Diseptanoside 24
Supporting Information Available: Complete crystal-
lographic data for the structural analysis of oxepine 19 have
been deposited in the Cambridge Crystallographic Data
Centre (CCDC), no. 280201. Copies of this information may
be obtained free of charge from CCDC, 12 Union Road,
Cambridge CB2 1EZ, U.K. (Fax: +44-1223-336033. Web:
www.ccdc.cam.ac.uk/conts/retrieving/html. Email: deposit@
ccdc.cam.ac.uk). General experimental procedures and char-
acterization data for all compounds not previously reported.
This material is available free of charge via the Internet at
http://pubs.acs.org.
is comparable to the glycosylations using di-O-isopropyli-
dene-R-D-galactose (10), the primary alcohol acceptor in the
pyranose series (Table 1).
(19) No disaccharide product was observed in an attempted glycosylation
of 22 using donor 4b under NBS activation in dry DCM at room
temperature.
OL051912E
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Org. Lett., Vol. 7, No. 21, 2005