A ring expansion-glycosylation strategy toward the synthesis of septano-oligosaccharides

Article abstract of DOI:10.1021/ol302677z

A one-pot ring-expansion-glycosylation reaction was performed using 1,2-cyclopropanated sugars as glycosyl donors and carbohydrate O-nucleophiles as acceptors to provide septanohexose mimics of pyranose and furanose derivatives. The methodology was succes

Full text of DOI:10.1021/ol302677z

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
A Ring ExpansionꢀGlycosylation
Strategy toward the Synthesis of
Septano-oligosaccharides
Perali Ramu Sridhar* and Patteti Venukumar
School of Chemistry, University of Hyderabad, Hyderabad 500046, India
prssc@uohyd.ernet.in
Received September 28, 2012
ABSTRACT
A one-pot ring-expansionꢀglycosylation reaction was performed using 1,2-cyclopropanated sugars as glycosyl donors and carbohydrate
O-nucleophiles as acceptors to provide septanohexose mimics of pyranose and furanose derivatives. The methodology was successfully
extended to the synthesis of septano-oligosaccharides by adopting a divergent strategy as well as an iterative protocol.
Mimicking natural glycans1 is one of the intellectual
ways of misleading microorganisms and enzymes that are
responsible for a variety of diseases. An important method
of mimicking natural carbohydrates is by expanding or
contracting the ring size. The ring-expanded versions of
hexoses are the so-called septanoses/carbohydrate-based
oxepanes,2 which have been shown to be very important
mimics of carbohydrates. Structureꢀactivity studies on
oral antithrombotic beciparcil derivatives revealed that
ring-expansion to a seven-membered thio sugar exhibited
a 10-fold increase in activity relative to the reference
compound, beciparcil.3 Proteinꢀcarbohydrate interaction
studies by Peczuh et al., involving concanavalin A and
methyl septanosides, provided preliminary evidence that
septanosides can resemble pyranosides.4 Septanose mimics
of nucleosides5 and nucleic acids6 have also been synthe-
sized and evaluated for their antiviral and RNA-cleavage7
properties. Even though several methods are available for
the synthesis of septanose monosaccharides,8 not many
reports have been published on the preparation of septa-
nose containing oligo- and polysaccharides.9,8b In this con-
text, stereoselective construction of glycosidic linkage is a
central challenge in the formation of di- and oligosaccharides.
(5) Richard, S.; Gilles, G.; David, D.; Frederic, L.; Jean-Christophe,
M.; Thierry, C. WO 2007/025043 A2 and references cited therein.
(6) (a) Sabatino, D.; Damha, M. J. J. Am. Chem. Soc. 2007, 129,
8259–8270. (b) Sabatino, D.; Damha, M. J. Nucleosides Nucleotides
Nucleic acids 2007, 26, 1185–1188.
(7) Mangos, M. M.; Min, K. L.; Viazovkina, E.; Galarneau, A.;
Elzagheid, M. I.; Parniak, M. A.; Damha, M. J. J. Am. Chem. Soc. 2003,
125, 654–661.
(8) (a) Castro, S.; Peczuh, M. W. J. Org. Chem. 2005, 70, 3312–3315.
(b) Peczuh, M. W.; Snyder, N. L.; Fyvie, W. S. Carbohydr. Res. 2004,
339, 1163–1171. (c) Ovaa, H.; Leeuwenburgh, M. A.; Overkleeft, H. S.;
Van der Marel, G. A.; Van Boom, J. A. TetrahedronLett. 1998, 39, 3025–
3028. (d) Chida, N.; Tobe, T.; Ogawa, S. Tetrahedron Lett. 1994, 35,
7249–7252.
(1) (a) Chapleur, Y. Carbohydrate Mimics: Concepts and Methods;
Wiley-VCH: Weinheim, 1998. (b) Koester, D. C.; Holkenbrink, A.; Werz,
D. B. Synthesis 2010, 3217–3242.
(2) For reviews on oxepanes, see: (a) Pakulski, Z. Pol. J. Chem. 1996,
70, 667. (b) Hoberg, J. O. Tetrahedron 1998, 54, 12631–12670. (c)
Pakulski, Z. Pol. J. Chem. 2006, 80, 1293–1326. For a review on
septanoses, see: Jaideep, S.; Peczuh, M. W. Advances in Carbohydrate
Chemistry and Biochemistry; Academic Press: New York, 2011; Vol 66,
pp 121 ꢀ 186.
(3) (a) Bozo, E.; Medgyes, A.; Boros, S.; Kuszmann, J. Carbohydr.
Res. 2000, 329, 25–40. (b) Bozo, E.; Boros, S.; Parkanyi, L.; Kuszmann,
J. Carbohydr. Res. 2000, 329, 269–286.
€
(9) Using anomeric chlorides: (a) Micheel, F.; Suckfull, F. Ann. Chim.
1933, 507, 138. Using acyclic chlorothioethyl acetals: (b) McAuliffe, J. C.;
Hindsgaul, O. Synlett 1998, 307–309. Using S-phenyl septanosides (c)
Castro, S.; Fyvie, W. S.; Hatcher, S. A.; Peczuh, M. W. Org. Lett. 2005, 7,
4709–4712. (d) Boone, M. A.; McDonald, F. E.; Lichter, J.; Lutz, S.; Cao,
R.; Hardcastle, K. I. Org. Lett. 2009, 11, 851–854.
(4) (a) Castro, S.; Duff, M.; Snyder, N. L.; Morton, M.; Kumar,
C. V.; Peczuh, M. W. Org. Biomol. Chem. 2005, 3, 3869–3872. (b) Duff,
M. R.; Fyvie, W. S.; Markad, S. D.; Frankel, A. E.; Kumar, C. V.;
Gascon, J. A.; Peczuh, M. W. Org. Biomol. Chem. 2011, 9, 154–164.
r
10.1021/ol302677z
XXXX American Chemical Society

In our efforts to explore the application of 1,2-cyclo-
propanated sugars in the synthesis of unnatural glyco-
analogues,10 herein we report the stereoselective synthesis
of 2,3-dideoxyseptanohexoses by TMSOTf-mediated one-
step ring-expansionꢀglycosylation of sugar-derived 1,2-
cyclopropanated donors with a series of carbohydrate
acceptors.
Scheme 1. Synthesis of Glucose-Derived 1,2-Cyclopropanated
Donor
The use of 1,2-cyclopropanated sugars for the synthesis
of carbohydrate-based oxepanes has been reported via
either the standard Ferrier rearrangement conditions11 or
by nucleophilic ring-opening of geminal dihalocyclopro-
panated sugar derivatives.12 However, to the best of
our knowledge, no reports are available for the synthesis
of di- and oligoseptanosides from this type of glycosyl
donor.
We envisaged that incorporating an electron-withdrawing
functionality at the C-3 position of 1,2-cyclopropanated
sugar derivatives would provide access to cyclic donorꢀ
acceptor cyclopropanes, which might undergo a regiose-
lective electrophilic ring-opening reactions, assisted by the
endocyclic oxygen, to give oxepane derivatives. Based on
this protocol, we herein present stereoselective ring-open-
ing of 3-oxo-1,2-cyclopropanated sugar derivatives, with
carbohydrate O-nucleophilic glycosyl acceptors. Even
though this kind of donorꢀacceptor cyclopropanes have
been shown to undergo Lewis acid promoted ring-expansion
with silyl enolates,13 to the best of our knowledge, this is the
first report of using these sugar derivatives as glycosyl
donors in oligosaccharide synthesis. Further, an iterative
glycosylation technology has been developed and utilized for
the synthesis of a diseptanohexose oligosaccharide.
The 1,2-cyclopropanated glycosyl donors were prepared
from known sugar-derived enones.14 Luche reduction15 of
114 produced the allal derivative 216 as a single diastereo-
mer. Hydroxyl-directed cyclopropanation11d of 2 using
CH2I2 and Et2Zn under SimmonsꢀSmith reaction
conditions17 produced 1,2-cyclopropanated allose deriva-
tive 3, which upon Swern oxidation18 provided the 1,2-
cyclopropa-3-pyranone 4 in excellent yield (Scheme 1).13
Our preliminary investigations focused on optimiza-
tion of the glycosylation reaction conditions using 4
as the glycosyl donor and sugar-derived O-nucleophiles
as glycosyl acceptors. Toward this end, 4 (1 mmol) was
glycosylated with 2,3;4,5-di-O-isopropylidene-R-D-fructo-
pyranose 5 (1.1 mmol) as an acceptor in CH2Cl2 at ꢀ78 °C
using catalytic BF3 Et2O (0.2 equiv) as Lewis acid. The
3
glycosylation reaction proceeded smoothly and provided
the septanohexose disaccharide 6 in 65% yeild, respec-
tively (Table 1, entry 1). A slight improvement that
favored the R-glycoside formation was observed by using
(CF3SO2)2O or InCl3 as Lewis acids under similar reaction
conditions (Table 1, entries 2ꢀ4). Interestingly, when
TMSOTf was used as a catalyst, the ring-expansion gly-
cosylation proceeded fruitfully, with excellent R-selectiv-
ity, providing the disaccharide 6 with 1:0.11 R:β selectivity
in excellent yield (Table 1, entry 5). Carrying out the
reaction either at ꢀ78 °C or from ꢀ10 to 0 °C did not
improve the stereoselectivity of the glycosylation reaction
(Table 1, entries 6 and 7).
Table 1. Optimization of Reaction Conditions for One-Step
Ring-Expansion-Glycosylation Reaction Using 1,2-Cyclopro-
panated Sugar Donor 4
(10) (a) Sridhar, P. R.; Ashalu, K. C.; Chandrasekaran, S. Org. Lett.
2004, 6, 1777–1779. (b) Sridhar, P. R.; Kumar, P. V.; Seshadri, K.;
Satyavathi, R. Chem. ;Eur. J. 2009, 15, 7526–7529. (c) Sridhar, P. R.;
Seshadri, K.; Reddy, G. M. Chem. Commun. 2012, 48, 756–758.
(11) (a) Hoberg, J. O.; Bozell, J. J. Tetrahedron Lett. 1995, 36, 6831–
6834. (b) Batchelor, R.; Harvey, J. E.; Northcote, P. T.; Teesdale-Spittle,
P.; Hoberg, J. O. J. Org. Chem. 2009, 74, 7627–7632. (c) Cousins, G. S.;
Hoberg, J. O. Chem. Soc. Rev. 2000, 29, 165–174. (d) Hoberg, J. O.
J. Org. Chem. 1997, 62, 6615–6618.
(12) (a) Ramana, C. V.; Murali, R.; Nagarajan, M. J. Org. Chem.
1997, 62, 7694–7703. (b) Ganesh, N. V.; Raghothama, S.; Sonti, R.;
Jayaraman, N. J. Org. Chem. 2010, 75, 215–218. (c) Hewitt, R. J.;
Harvey, J. E. Chem. Commun. 2011, 47, 421–423. (d) Hewitt, R. J.;
Harvey, J. E. J. Org. Chem. 2010, 75, 955–958.
(13) Sugita, Y.; Kimura, C.; Hosoya, H.; Yamadoi, S.; Yokoe, I.
Tetrahedron Lett. 2001, 42, 1095–1098.
(14) Kirschning, A. J. Org. Chem. 1995, 60, 1228–1232.
(15) Luche, J. ꢀL.; Gemal, A. L. J. Am. Chem. Soc. 1979, 101, 5848–
5849.
(16) Kirschning, A.; Hary, J.; Plumeier, C.; Ries, M.; Rose, L.
J. Chem. Soc., Perkin Trans 1 1999, 519–528.
entry catalyst (0.2 equiv) temp conditions (°C) yielda (%) R:βc
1
2
3
4
5
6
7
BF3 OEt2
(CF3SO2)2O
lnCI3
ꢀ78 to þ25
ꢀ78 to þ25
ꢀ78 to þ25
ꢀ78 to þ25
ꢀ78 to þ25
ꢀ78
65
60
<5
50
89
72
82
1:0.71
1:0.57
b
lnCI3
1:0.45
1:.0.11
1:0.71
1:0.42
TMSOTf
TMSOTf
TMSOTf
ꢀ10 to 0
(17) Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1959, 81, 4256–
4264.
(18) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43,
2480–2482.
a Yield represents pure and isolated products. b 1 equiv of catalyst
was used. c Based on septanosyl anomeric proton ratio.
B
Org. Lett., Vol. XX, No. XX, XXXX

The major R-glycosylated product can be envisaged
arising by a preferential approach of the nucleophile
along an axial trajectory toward the oxocarbonium ion
intermediate.19 As shown in Scheme 2, activation of the
glycosyl donor 4 with TMSOTf would generate the oxo-
carbenium ion intermediate 7 via the cleavage of C1ꢀC2
bond. The trimethylsilyl vinyl ether 7 would react with
acceptor 5, preferentially in the axial direction, due to the
anomeric effect,20 provide the R-selective septanohexose 6
as the major product.
Table 2. Stereoselective Synthesis of Septanohexoses
Scheme 2. Proposed Mechanism for the Stereoselective
Formation of R-Glycoside
After optimizing these conditions, the aforementioned
ring expansionꢀglycosylation of sugar derived 1,2-cyclo-
propa-3-pyranone donors was extended to other carbo-
hydrate-derived O-nucleophilic glycosyl bond acceptors.
Thus, the reaction of acceptor 8 with 1,2-cyclopropanated
donors 4 and 10 gave rise to septanohexose derivatives 9
and 11, respectively, with modest diastereoselectivity at the
newly formed C100 anomeric center (R:β (7:3)) in excellent
yield (Table 2, entries 1 and 2). The methodology was also
applied to sugar acceptors possessing less reactive second-
ary alcohols. Thus, different 1,2-cyclopropa-3-pyranone
donors, 4, 10, and 15 were glycosylated with the sugar
acceptor 12, possessing a free hydroxyl group at the C2
position (Table 2, entries 3ꢀ5). Interestingly, donors 4 and
15, upon glycosylation with 12, provided selectively the
R-glycosylated septanohexoses 13 and 16, whereas donor
10 with acceptor 12 provided a diastereomeric mixture of
14r and 14β in7:3 ratio, respectively(Table 2, entry 4). The
structure of the minor diastereomer 14β was confirmed by
X-ray crystallography.21
a Isolated yield after column chromatography.
based on the chemical shift value of the anomeric carbon22
00
(δC1 for R-septanosides ranges from 99 to 104 ppm while
for β-septanosides it ranges from δ 104ꢀ111 ppm) as well
as two-dimensional NMR experiments. For the septano-
hexoses possessing a β-glycosidic bond, a strong NOE was
observed between the 1,3-diaxial hydrogens at C100 and
C600 which was absent in the case of septanosides with
R-glycosidic linkage. The sugar-derived enone acceptor 22
was also very reactive toward the one-step ring-expansionꢀ
glycosylation reaction with donor 20 and produced the
disaccharide derivative 23 as a single diastereomer in
excellent yield (Table 2, entry 9). It is well-known that
Glycosylation of donors 4, 15, and 20 with acceptor 17,
in which the free hydroxyl is at C3, provided the corre-
sponding septanohexoses 18, 19, and 21 as single diaste-
reomers with the R-configuration at the newly formed
glycosidic center (Table 2, entries 6ꢀ8). The stereochem-
istry atC100 for all the disaccharide derivativeswasassigned
(19) (a) Stevens, R. V.; Lee, A. W. M. J. Am. Chem. Soc. 1979, 101,
7032–7035. (b) Deslongchamps, P. Stereoelectronic Effects in Organic
Chemistry; Pergamon: New York, 1983.
(20) Desilets, S., St.; Jacques, M. J. Am. Chem. Soc. 1987, 109, 1641–
1648.
(21) CCDC deposition no. 903373.
(22) Demateo, M. P.; Snyder, N. L.; Morton, M.; Baldisseri, D. M.;
Hadad, C. M.; Peczuh, M. W. J. Org. Chem. 2005, 70, 24–38.
Org. Lett., Vol. XX, No. XX, XXXX
C

the stereoselectivity in the glycosylation of hexose derived
oxocarbenium ions is dictated by stereoelectronic effects in
the glycosyl donor and nonbonding steric interactions
from the glycosyl acceptors.19,23 The above experimental
results provide ample evidence that similar effects play a
role in the glycosylation of septanosides as well.
corresponding diol, followed by SimmonsꢀSmith cyclo-
propanation and subsequent Swern oxidation of the diol
provided the donor 30 as a mixture of R- and β-cyclopro-
panated products in 2:1 ratio, respectively, in 75% yield
after three steps. Glycosidation of 30 with acceptor 28,
using TMSOTf in CH2Cl2 at ꢀ78 °C, provided the trisac-
charide derivative 31 as a single diastereomer in which the
second glycosylation was also R selective (Scheme 4).
After successful synthesis of a series of septanohexose
disaccharide derivatives, we focused our attention on the
synthesis of diseptanohexose trisaccharides. Thus, stereo-
selective reduction of disaccharide 18 with lithium tri-tert-
butoxyaluminum hydride in ethanol at ꢀ78 °C provided
theacceptor alcohol24. However, glycosidation ofdonor 4
with acceptor 24 did not proceed under the optimized
reaction conditions. We reasoned that the very low reac-
tivity of the acceptor 24 might be due to the axial orienta-
tion of hydroxyl group. Therefore, inversion of the axial
hydroxyl in 24 via the Mitsunobu reaction provided the
acceptor 25. Gratifyingly, glycosylation of 4 with acceptor
disaccharide 25 proceeded smoothly, generating the dis-
eptanohexose trisaccharide derivative 26 as a single
diastereomer (Scheme 3). Stereoselective reduction of
ketone provided the trisaccharide acceptor 27-r,r which
can be used further for the synthesis of septano-
oligosaccharides.
Scheme 4. Iterative Protocol for the Synthesis of Septano-
oligosaccharide
In conclusion, a novel ring expansionꢀglycosylation
reaction has been developed for the synthesis of septanose
derivatives which uses sugar-derived 1,2-cyclopropa-3-
pyranones as glycosyl donors and carbohydrate-derived
O-nucleophiles as acceptors. The generality of the reaction
was evaluated by performing a number of glycosylation
reactions and synthesizing several septanohexose deriva-
tives. Two different methods (a divergent synthesis and an
iterative technique) for the synthesis of septanose-derived
oligosaccharides were successfully performed. Ligation of
these ring-expanded sugar mimics to natural products and
evaluation of their biological properties are presently
under investigation.
Scheme 3. Synthesis of Diseptanohexose Trisaccharide
Acknowledgment. This work was supported by the
Department of Science and Technology (DST). P.V.K.
thanks CSIR for a Senior Research Fellowship.
Finally, an iterative protocol for the synthesis of septano-
oligosaccharides was investigated. Many biologically
active natural products possess deoxysugar subunits in
their structures.24 Therefore, we planned to use 6-deoxy
glucal derived 1,2-cyclopropanated sugar 20 as a glycosyl
donor and alcohol 28 as an acceptor. Thus, glycosylation
of 20 with 28 provided disaccharide 29 as a single diaste-
reomer in good yield. Reduction of diketone 29 to the
Supporting Information Available. Experimental pro-
cedures, full spectroscopic data, and 1H and 13C spectra
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(24) (a) Kirschning, A.; Bechthold, A.; Rohr, J. Top. Curr. Chem.
1997, 188, 1–84. (b) Thorson, J. S.; Hosted, T. J.; Jiang, J.; Biggins, J. B.;
Ahlert, J. Curr. Org. Chem. 2001, 5, 139–167. (c) Salas, J.; Mendez, C.
Trends Microobiol. 2007, 15, 219–232.
(23) (a) Lemieux, R.; Hendriks, K. B.; Srick, R. V.; James, K. J. Am.
Chem. Soc. 1975, 97, 4056–4062. (b) Lewis, M. D.; Cha, J. K.; Kishi, Y.
J. Am. Chem. Soc. 1982, 104, 4976–4978. (c) Toshima, K.; Tatsuta, K.
Chem. Rev. 1993, 93, 1503–1531 and references cited therein. (d) Juaristi,
E.; Cuevas, G. Tetrahedron 1992, 48, 5019–5087and references cited
therein.
The authors declare no competing financial interest.
D
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