Hydroxyl group orientation affects hydrolysis rates of methyl α-septanosides

Article abstract of DOI:10.1016/j.tetlet.2009.12.109

Hydrolysis rates for three related methyl α-septanosides were obtained. The septanosides were synthesized via mCPBA epoxidation and methanolysis of d-mannose, d-galactose, and d-glucose-based oxepines. The rate of hydrolysis correlates with the orientation of hydroxyl groups on the septanose ring in a manner analogous to pyranosides.

Full text of DOI:10.1016/j.tetlet.2009.12.109

Tetrahedron Letters 51 (2010) 1209–1212
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Hydroxyl group orientation affects hydrolysis rates of methyl a-septanosides
*
Shankar D. Markad, Shawn M. Miller, Martha Morton, Mark W. Peczuh
Department of Chemistry, University of Connecticut, 55 North Eagleville Road U-3060, Storrs, CT 06269, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Hydrolysis rates for three related methyl
sized via mCPBA epoxidation and methanolysis of
The rate of hydrolysis correlates with the orientation of hydroxyl groups on the septanose ring in a man-
ner analogous to pyranosides.
a
-septanosides were obtained. The septanosides were synthe-
-mannose, -galactose, and -glucose-based oxepines.
Received 7 December 2009
Accepted 17 December 2009
Available online 28 December 2009
D
D
D
Ó 2009 Elsevier Ltd. All rights reserved.
We first endeavored to prepare a group of related methyl sept-
We recently reported on the unexpected formation of methyl
septanoside 2 via DMDO-mediated epoxidation of 1 followed by
basic methanolysis (Scheme 1, conditions a).1 A trans relationship
between the aglycon and C2 hydroxyl group (a trans-1,2 glycoside)
arising from backside attack on the 1,2-anhydrosugar was antici-
pated; instead, a cis-1,2 glycoside 2 was obtained. Further, a bicy-
clic product, 3, accompanied 2. It was proposed that 2 and 3 arose
from the corresponding oxacarbenium ion 4a even under the basic
reaction conditions. Attack on the oxacarbenium by methoxide
anosides that would serve as substrates of the hydrolysis reactions.
Formation of cis-1,2 methyl septanosides from oxepines via tan-
dem mCPBA epoxidation and methanolysis seemed appropriate
because these conditions were presumed to be more conducive
to oxacarbenium ion formation. Products and yields for the reac-
tion of oxepines 1, 7, and 10 are shown in Schemes 1–3. For man-
nose-based oxepine 1, the reaction gave essentially the same result
as the DMDO epoxidation followed by methanolysis. The cis-1,2
methyl septanoside 2 was the major product (57%) accompanied
by the cyclization product 3 (24%). Epoxidation and methanolysis
of galactose-based oxepine 7 under the mCPBA reaction conditions
gave, after C2 acetylation, methyl septanosides 8 (40%) and 9 (45%).
Likewise, oxepine 10 delivered 11–13 in 29%, 35%, and 18% yields,
respectively. In these latter two cases, cis-1,2 methyl septanoside
products 8 and 12 most likely arose via oxacarbenium ions 5a
and 6a, respectively. Oxacarbenium ion intermediates are invoked
in the formation of 2, 8, and 12 because syn attack on the 1,2-any-
droseptanoses is unlikely.1,7 Hydrogenolysis of 2 provided 14. Both
8 and 12 were deprotected by hydrolysis of the C2 acetate under
Zemplén conditions followed by hydrogenolysis of the benzyl
groups to afford 15 and 16.
from the a-face provided 2 while intramolecular attack by the C5
benzyloxy moiety and subsequent loss of a benzylic group pro-
vided 3. Under the same reaction conditions, oxepines2,3 derived
from
D-galactose 7 and D-glucose 10 delivered only trans-1,2
methyl septanoside products.4
We had previously invoked an oxacarbenium ion in the forma-
tion of a cis-1,2 methyl septanoside from a xylose-based oxepine.5
Also, S-phenyl septanosides, which presumably form reactive
oxacarbenium ions upon activation, have been used to prepare a
number of septanose glycosides.3a,6 A formal investigation of oxa-
carbenium ions related to septanose carbohydrates has not been
reported, however. On the other hand, considerable advances have
been made recently on the role that substituent effects, stereo-
chemistry, and conformation play in the formation of pyranosyl
oxacarbenium ions. The present work aimed to measure the hydro-
OBn
OBn
lysis rates of some related methyl
a-septanosides in an effort to
BnO
BnO
O
O
a or b
correlate specific structural features of the molecules with the for-
mation of septanose oxacarbenium ions.
BnO
BnO
BnO
BnO
OCH3
OH
OR
OR
OR
OR
1
2
RO
O
O
O
RO
RO
RO
RO
a - DMDO, DCM 0 °C;
NaOMe, MeOH
a 2:3 59%:25%
b 2:3 57%:24%
RO
RO
RO
O
OBn
OH
OH
OH
b - mCPBA, MeOH
OBn
4a R = Bn
4b R = H
5a R = Bn
5b R = H
6a R = Bn
6b R = H
OBn
O
OH
3
* Corresponding author. Tel.: +1 860 486 1605; fax: +1 860 486 2981.
E-mail address: mark.peczuh@uconn.edu (M.W. Peczuh).
Scheme 1. Epoxidation and methanolysis of oxepine 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.109

1210
S. D. Markad et al. / Tetrahedron Letters 51 (2010) 1209–1212
OBn
on the septanoside ring. These structural similarities would allow
OBn
the direct comparison of the hydrolysis rates to specific stereo-
chemical features. Preliminary experiments explored the details
of the hydrolysis reactions. The fact that a hydrolysis reaction
had indeed occurred was confirmed by MS analysis of the product
materials after the NMR kinetics experiments.10 Potential mecha-
nistic pathways for the hydrolysis of the methyl glycosides (e.g.,
17) were next considered (Scheme 4). Pathway a depicts an A2
mechanism where protonation of the exocyclic O-methyl oxygen
would be followed by SN2 attack by water to give 18b. Based on
the literature estimates of the relative stabilities of septanoses ver-
sus pyranoses, 18b could be expected to equilibrate to the substi-
tuted pyranose 19.11 Pathways b and c represent alternative A1
mechanisms that differ in which anomeric C–O bond is broken
en route to the respective oxacarbenium ions; in b, the endocyclic
oxygen would be protonated followed by C–O bond breakage to
form 20.12 Alternatively, in c the exocyclic oxygen would be pro-
tonated and C–O bond breakage would form 22. Addition of water
to either of the oxacarbenium species would give rise to interme-
diate 21 or 18 that would then equilibrate to 19. Pathway c was
considered the most likely route of hydrolysis based on the follow-
ing observations. First, oxacarbeniums were invoked in the forma-
tion of cis-1,2 methyl septanosides 2, 8, and 12 from their
corresponding 1,2-anhydroseptanoses as previously discussed.
Second, oxacarbenium 6b was directly observed by MS. Although
this was a gas-phase experiment, the result indicated that the exo-
cyclic C–O bond breakage was preferred under the reaction condi-
tions. Further, qualitative correspondence between the gas-phase
observation of oxacarbenium ions and rate of hydrolysis has been
demonstrated.13,14
O
BnO
OCH3
OAc
BnO
OBn
OBn
mCPBA
MeOH
1)
2)
8
O
BnO
Ac2O, DMAP
Pyr.
OBn
OBn
BnO
OCH3
O
7
8:9 40%:45%
(2 steps)
BnO
BnO
OAc
9
Scheme 2. mCPBA epoxidation and methanolysis of oxepine 7.
OAc
OBn
O
BnO
BnO
OCH3
BnO
11
OBn
OBn
mCPBA
MeOH
1)
2)
O
O
BnO
BnO
BnO
BnO
Ac2O, DMAP
Pyr.
OCH3
OAc
12
BnO
BnO
10
OBn
OCH3
O
BnO
BnO
11:12:13 29%:35%:18%
(2 steps)
BnO
OAc
13
Scheme 3. mCPBA epoxidation and methanolysis of oxepine 10.
A 1H NMR integration assay was used to measure the hydrolysis
kinetics of 14–16. Preliminary experiments using 16 as a test sub-
strate (1–2 mM) varied the reaction temperature and DCl concen-
tration. Conditions of 50 °C and 0.5 M DCl seemed well suited to
observe hydrolysis based on these experiments. Integration values
for the protons associated with the methyl group of the aglycon
were collected at regular intervals for each compound 14–16
(Fig. 1) and were used to calculate the concentration of the starting
OH
OH
OH
OH
HO
O
O
O
HO
HO
HO
HO
HO
OCH3
OH
OCH3
OH
OCH3
OH
HO
HO
16
methyl a-septanoside that remained in the solution. Curve fitting
gave kobs values of 5.97 Â 10À4 sÀ1, 8.91 Â 10À4 sÀ1, and 1.14 Â
10À4 sÀ1, respectively. The apparent concentration for the methyl
glycoside peak of 14 does not approach zero in the same way that
15 and 16 do; this is due to coincidental overlap of the methyl
glycoside peak with a signal arising from the product pyranose.
15
14
The next objective was to characterize the hydrolysis rates of
cis-1,2 methyl septanosides 14–16.8,9 The cis-1,2 methyl septano-
sides were chosen because they share the same stereochemistry
at C1 and C2, and because they vary by just one other stereocenter
OH
HO
OH
OH
O
O
HO
HO
OH
a
OH
OH
18β
19
HO
HO
HO
OH
b
O
OH
OH
19
OCH3
HO
HO
HO
OCH3
OCH3
OH
OH
OH
20
21
17
c
HO
HO
O
OH
O
HO
19
HO
OH
OH
18
22
Scheme 4. Mechanistic pathways for methyl septanoside hydrolysis.

S. D. Markad et al. / Tetrahedron Letters 51 (2010) 1209–1212
1211
is related to the 4C1 conformation of pyranosides. Further, this
conformation is highly populated (>90% of the ground state Boltz-
mann) with the aglycon group in an axial configuration. In the
3,4TC5,6 conformation, all the hydroxyl groups in 16 except C2
are equatorial and related structures 14 (C3) and 15 (C5) each
have one additional axial hydroxyl group. Our data then suggest
that equatorial hydroxyl groups are similarly electron-withdraw-
ing in septanosides. Importantly, we interpret the parallel trends
in rates of hydrolysis as further evidence for a common oxacarbe-
nium pathway.
OH
OH
OH
HO
OH
O
O
O
HO
HO
HO
HO
HO
OH
OH
OCH3
OCH3
OCH3
23
24
25
The structure of the hydrolysis products remained to be con-
firmed. As depicted in Scheme 4, addition of water to the oxacarbe-
nium ion should provide a septanose hemi-acetal such as 18.
Septanose hemi-acetals have been observed in aqueous solutions,
but only in low concentrations in systems that otherwise block
(by deoxygenation or protection of hydroxyls) the formation of
the furanose or pyranose hemi-acetals.11,23,24 We anticipated that
a pyranose such as 19 would be the preferred configuration of
the hydrolysis product because of the inherent stability of the
six-membered ring and the availability of the appropriate hydroxyl
groups for it to form. NMR analysis (1H, COSY, and HSQC) of the
reaction solution after hydrolysis kinetics that had been obtained
Figure 1. Methyl a-septanoside hydrolysis curves. The plot shows concentration of
methyl septanoside versus time over the course of the reaction.
Table 1
Rate constants for glycoside hydrolysis by 1H NMR integration assay at 50 °C in 0.5 M
DCl
Glycoside CH3
CH3OH
104 kobs (sÀ1
Avg.
Lit. valuea
)
14
15
16
23
24
25
5.97 0.60
8.91 0.14
1.14 0.17
7.54 0.56
7.95 0.28
0.97 0.24
6.76
8.43
1.01
for 14 showed that 26 was present as a mixture of
a- and b-ano-
mers. The most diagnostic data were the H1 chemical shifts
0.209
0.355
0.071
3
(5.00 ppm for
a-26, 4.34 ppm for b-26) and the associated JH1,H2
coupling constants (3.4 and 7.9 Hz, respectively).25
a
OH
Hydrolysis of 23–25 was at 60 °C in 2 M HCl. See Ref. 8b.
OH
OH
O
OH
HO
Methanol, the other product in the hydrolysis reaction, was moni-
tored in the same way, however. Analysis of this signal gave similar
values of kobs for each of the methyl septanosides (Table 1). The
agreement between the rate constants between the different sig-
nals provides a measure of their accuracy.15
OH
26
In summary, we have provided the first data on the rates of
methyl
rates of related methyl
a
-septanoside hydrolysis and have compared them to the
a
-pyranosides. Importantly, the results
Consideration of the kinetics data suggested parallels between
demonstrated that hydroxyl group orientation affects the rate of
hydrolysis in this group of septanosides. Correlation between hy-
droxyl group orientation and relative rate reported here mirrors
the methyl
a
a-septanosides 14–16 reported here and their methyl
-pyranoside counterparts 23–25.16 The rates of hydrolysis for
14–16 are faster compared to those of 23–25 (Table 1) despite
the milder reaction conditions used on the septanosides. This
likely reflects an inherent instability of the seven-membered ring
septanosides versus six-membered ring pyranosides.17 Addition-
that of methyl
a-pyranosides and suggests that, as with pyrano-
sides, equatorial hydroxyl groups are more electron-withdrawing
than the axial hydroxyl groups. Investigation of the hydrolysis
products showed that the septanose hemi-acetal products equili-
brated to the more stable pyranose ring forms. The results have
provided insight into the fundamental reactivity of these unnatural
carbohydrates.
ally, the rank ordering of methyl
that of methyl -pyranosides 23–25. Methyl
hydrolyzed fastest followed by methyl -mannoside 23 and then
methyl -glucoside 25. For the methyl -septanosides, galactoside
a
-septanosides 14–16 mirrors
a
a
-galactoside 24 is
a
a
a
analog 15 was the fastest followed by mannoside and glucoside
analogs 14 and 16, respectively. One implication from the parallel
between 24 and 15 is that the C5 hydroxyl stabilizes 5b via
through-space electron donation in a fashion akin to the way
the C4 hydroxyl stabilizes the galactopyranosyl oxacarbenium
ion.18 Overall, the data for the septanosides here compare well
with the results from other groups that have correlated substitu-
ent electronics,19 stereochemistry of hydroxyl groups,20 and con-
formation21 with the rate of oxacarbenium ion formation for
pyranosides. Of particular importance to this investigation is the
fact that equatorial hydroxyl groups in a pyranoside are known
to be more electron withdrawing than are axial hydroxyl groups.
Acknowledgments
Chad Engle and Bikash Surana (U. of Connecticut) conducted
experiments reported here. We thank Srikanth Rapole (U. of Con-
necticut) for technical assistance with HRMS. M.W.P. thanks NSF
for a CAREER award (CHE-0546311). S.M.M. was the recipient of
a UConn Summer Undergraduate Research Fellowship (SURF).
Supplementary data
Supplementary data (kinetics, characterization and other exper-
imental data) associated with this article can be found, in the on-
line version, at doi:10.1016/j.tetlet.2009.12.109.
Our conformational analyses on
a
-septanosides4,22 showed that
the preferred conformation for 16 is a 3,4TC5,6 conformation which

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S. D. Markad et al. / Tetrahedron Letters 51 (2010) 1209–1212
13. Buckley, N.; Handlon, A. L.; Maltby, D.; Burlingame, A. L.; Oppenheimer, N. J. J.
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15. The Supplementary data contains kinetics traces.
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(septanose numbering) with 23 and they are therefore considered counterparts
here. Similarly, 15 is linked to 24 and 16 to 25.
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to the reaction conditions did not anomerize to the methyl
the Supplementary data for details.
a-septanoside. See
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