Steric Effects Are Not the Cause of the Rate Difference in Hydrolysis of Stereoisomeric Glycosides

Article abstract of DOI:10.1021/ol030081e

(Equation presented) A long-lived and plausible explanation as to why glycosides with axial substituents are more reactive than those with equatorial substituents was given in 1955 by Edward based on sterical hindrance being relieved in the transition state. Using model compounds 5, 6, 8, and 10, we here show conclusively that sterical hindrance not is the controlling factor in glycoside hydrolysis.

Full text of DOI:10.1021/ol030081e

ORGANIC
LETTERS
2003
Vol. 5, No. 19
3419-3421
Steric Effects Are Not the Cause of the
Rate Difference in Hydrolysis of
Stereoisomeric Glycosides
Henrik Helligsø Jensen and Mikael Bols*
Department of Chemistry, UniVersity of Aarhus, Langelandsgade 140,
DK-8000 Aarhus C, Denmark
mb@chem.au.dk
Received June 19, 2003
ABSTRACT
A long-lived and plausible explanation as to why glycosides with axial substituents are more reactive than those with equatorial substituents
was given in 1955 by Edward based on sterical hindrance being relieved in the transition state. Using model compounds 5, 6, 8, and 10, we
here show conclusively that sterical hindrance not is the controlling factor in glycoside hydrolysis.
Nonenzymatic hydrolysis of alkyl glycopyranosides is a
much-studied reaction with a well-established mechanism.1,2
The process is specific-acid-catalyzed where the rate-
determining step is the formation of a cyclic oxacarbenium
ion intermediate (1a) (Scheme 1). Rate constants (kobs) of
this reaction are an expression of the energy difference
between the neutral reactant state and the transition state
leading to this oxacarbenium ion.
It has been known for many years3 that stereoisomeric
glycosides hydrolyze with increasing rate depending on the
number of axial hydroxyl groups. On the basis of available
data and some assumptions on pyranoside reactant-state
conformations and the mechanism of hydrolysis, J. T.
Edward gave in 1955 a very plausible explanation to this
phenomenon.4,5 His rationale as to why guloside 3 reacts
faster than galactoside 2, which again reacts faster than
glucoside 1 (Figure 1), was based on relief of steric strain.
He envisioned that axial substituents would ease the rotation
around the C2-C3 and C4-C5 bonds and thereby facilitate
the transformation from reactant into intermediate, which was
assumed to possess a more flattened half-chair conformation.
Previous experimental results published by Withers and
co-workers show that field effects dictate the rate of
hydrolysis. Replacement of a hydroxyl group with fluorine
decreases the reactivity, whereas deoxygenation enhances the
reactivity.6,7 This is evidently due to destabilization of the
incipient oxacarbenium ion in the transition state by electron-
withdrawing groups. Withers and co-workers’ study, how-
ever, was limited as to only study field effects within groups
of glycosides with conserved stereochemistry. Recent results
from our group go one step further.8,9 They show a sizable
(5) This celebrated article is perhaps mostly known for the observation
that pyranosides having axial anomeric substituents appear to be more stable
than their equatorial counterparts. This effect was given the name the
anomeric effect but has later been found to operate in many systems other
than carbohydrates.5a Another name suggested for this general effect has
in fact been the Edward-Lemieux effect.5b (a) The Anomeric Effect and
Associated Stereoelectronic Effects; Thatcher, G. R. J., Ed.; ACS Symposium
Series 539; American Chemical Society: Washington, DC, 1993. (b) Wolfe,
S.; Shi, Z. Isr. J. Chem. 2000, 40, 343-355. Wolfe, S.; Rauk, A. Tel, L.
M.; Csizmadia, I. G. J. Chem. Soc. B. 1971, 136-145.
(1) Bennet, A. J.; Kitos, T. E. J. Chem. Soc., Perkin Trans. 2 2002, 1207-
1222. Bochkov, A. F.; Zaikov, G. E. Chemistry of the O-Glycosidic Bond;
Pergamon: Oxford, 1979. Capon, B. Chem. ReV. 1969, 69, 407-498.
Feather, M. S.; Harris, J. F. J. Org. Chem. 1965, 30, 153-157.
(2) Overend, W. G.; Rees, C. W.; Sequeira, J. S. J. Chem. Soc. 1962,
3429-3440.
(3) Armstrong, H. E.; Glover, W. H. Proc. R. Soc. London B 1908, 80,
312-331.
(4) Edward, J. T. Chem. Ind. (London) 1955, 1102-1104.
(6) Withers, S. G.; Percival, M. D.; Street, I. P. Carbohydr. Res. 1989,
187, 43-66.
(7) Namchuk, M. N.; McCarter, J. D.; Becalski, A.; Andrews, T.; Withers,
S. G. J. Am. Chem. Soc. 2000, 122, 1270-1277.
(8) Jensen, H. H.; Lyngbye, L.; Bols, M. Angew. Chem., Int. Ed. 2001,
40, 3447-3449.
10.1021/ol030081e CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/27/2003

Scheme 1
difference in the de facto electron-withdrawing properties
Introduction of a sterically demanding methyl group in
the 4-position of methyl gluco- and galactopyranoside (5/6)
would expectedly reverse the order of reactivity if sterical
hindrance were to be the major factor controlling rate of
hydrolysis. Glycosides with hydroxyl groups replaced for
methyl groups (8/10) were also of interest in this context,
as it was anticipated from Edward’s hypothesis4 that the
galactoside 8 would hydrolyze considerably faster than the
glucoside 10, which was known from unmodified sugars.2
of axially and equatorially placed hydroxyl groups. This
could be an alternative explanation to the higher reactivity
of a galactoside (2) (axial 4-OH) compared to a glucoside
(1) (equatorial 4-OH).
Scheme 2
Figure 1.
This result was obtained from Hammett-like plots where
σ-values were derived from studies of base strengths of
hydroxylated piperidines (azasugars).10 These could be
correlated to oxacarbenium ion stability relative to reactant-
state stability, i.e., glycoside hydrolysis rates. Because of this
connection between base strengths of azasugars and reaction
rates of glycosides it seemed questionable that steric effects
would be the controlling factor of the latter. This was,
however, what was proposed by Edward.4
On the basis of molecular mechanics calculations in the
gas phase, an electronic argument has also been given by
Woods et al. to account for the variation in reactivity of
glycosides undergoing hydrolysis.11 Miljkovic and co-work-
ers have published a related result based on ab initio
calculations where they addressed the reactivity difference
of galactosides and glucosides in acetolysis.12
Despite the above suggestions that electronic factors do
play an important role, no rigorous experimental study had
been conducted to clarify to which extent glycopyranoside
reactivity was controlled by sterics or electronics.13 As a
consequence, we decided to prepare modified glycosides and
test our hypothesis independently of earlier results. Our study
was to focus on the noteworthy difference in reactivity of
galactosides and glucosides. Substitution at C4 was therefore
to be investigated.
These four modified glycosides were prepared in a few steps
from known intermediates. Tertiary alcohols 5/6 were
prepared via methyl addition (CH3MgI or CH3Li) to the
known ketone 4.14 The selectivity, however, was not as high
as when trityl was used instead of benzyl protection of O6
(Scheme 2).15
4-Deoxy-4-methylgalactoside 8 was obtained as the major
product of hydrogenation of the known olefin 7,14 whereas
the epimeric glycoside (10) (minor product) could not be
obtained in satisfactory purity even after protecting group
removal or exchange for acetyl groups. 4-Deoxy-4-methyl-
glucoside 10 was obtained through reduction of primary
iodide 9 (Scheme 2).14 All compounds were characterized
by NMR that in every case suggested the pyranoside
4
(9) Bols, M.; Liang, X.; Jensen, H. H. J. Org. Chem. 2002, 67, 8970-
8974.
conformation to be C1.
Acidic hydrolysis in 2.0 M HCl of the 4 synthesized
glycosides and unmodified methyl glucoside and galactoside
were assumed to proceed by identical mechanisms. The
(10) Jensen, H. H.; Lyngbye, L.; Jensen, A.; Bols, M. Chem. Eur. J.
2002, 8, 1218-1226.
(11) Woods, R. J.; Andrews, C. W.; Bowen, J. P. J. Am. Chem. Soc.
1992, 114, 859-864.
(12) Miljkovic, M.; Yeagly, D.; Deslongchamps, P.; Dory, Y. L. J. Org.
Chem. 1997, 62, 7597-7604.
(14) Preuss, R.; Jung, K.-H.; Schmidt, R. R. Liebigs Ann. Chem. 1992,
377-382.
(15) Sato, K.; Kubo, K.; Hong, N.; Kodama, H.; Yoshimura, J. Bull.
Chem. Soc. Jpn. 1982, 55, 938-942.
(13) For a study of torsional effects on the reactivity of glycosyl transfer,
see: Dean, K. E. S.; Kirby, A. J.; Komarov, I. V. J. Chem. Soc., Perkin
Trans. 2, 2002, 337-341.
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Org. Lett., Vol. 5, No. 19, 2003

hydrolyses of glycosides were followed by optical rotation
carried out at 74°C in a polarimeter cell. To ensure that the
expected products had formed, a mass spectrum was recorded
after each run and only masses corresponding to the expected
hemiacetal were detected. The observed R-values could be
Altogether, these results disprove the previous hypothesis
given by Edward.4 It is clear that in this case the reactivity
is governed by the configuration of hydroxyl groups and not
sterical effects. If the latter were to be the controlling factor,
the order of reactivity of 5/6 and 8/10 would have been the
opposite of that observed. In addition, the difference in
reactivity between galactoside 8 and glucoside 10 should
have been greater than 5.2 in favor of 8, which is not the
case.
fitted to an exponential decay curve, and rate constants (kobs
)
were thereby obtained. Averaged values are listed in Table
1. In the case of 1 and 2, good agreement was found with
A few explanations of the nature of the electronic effect
controlling glycoside reactivity have been offered. We have
suggested that the field effect imposed by an electron-
withdrawing group is less when placed axially than equa-
torially (vide supra). This, together with the fact that methyl
groups either placed axially or equatorially impose a
negligible electronic effect, could be an explanation.8-10
It may appear inconsistent that while a rather small
difference in reactivity is seen between galactosides 2 and 6
(1.18), the differences between sets 1/5 and 10/8 are
somewhat larger (1.5-1.6). However, this phenomena can
be explained by the likely influence of an axial methyl group
on the rotamer population around the C5-C6 bond. A methyl
substituent placed axially in the 4-position (5 and 8) would
be expected to lower the population of the gg conformer,
thereby increasing the population gt and tg conformers. Due
to the anti relationship between O5 and O6 in the tg
conformer, the oxacarbenium ion-like transition state will
be destabilized compared to when O5 is close in space to
O6 (as in gg and gt). The somewhat lower reactivity of 5
and 8 compared to 1 and 10, respectively, could therefore
be caused by a somewhat higher population of the tg
conformer in these compounds.
Table 1. Rate Constants Determined by Polarimetry at 74 °C
in 2.0 M HCla
a Rate constants are the average of four independent experiments. Values
In conclusion, we have prepared and hydrolyzed four
modified glycopyranosides and compared their rates of acid-
catalyzed hydrolysis. We have thereby demonstrated, that
an electronic rather than a steric effect of remote substituents
on glycosides dictates their rates of hydrolysis.
relative to glucoside 1 given as kobs,rel
.
calculated rate constants obtained from kinetic parameters
measured by Overend et al.2 From Table 1, it can been seen
that only a slight change in rate of hydrolysis occurs by
incorporation of an additional methyl group in the 4-position,
i.e., the galactoside 6 is still the most reactive of the pair of
4-C-glycosides 5/6.
Removal of the 4-hydroxyl group from the modified
glycosides 5/6 resulted in a great rate enhancement, which
is known to be a result of deoxygenation (vide supra).7 In
addition, the gluco-configured glycoside (10) reacts slightly
faster than its galacto-configured isomer (8).
Acknowledgment. We acknowledge the financial support
of the SNF and the Lundbeck Foundation.
Supporting Information Available: Experimental details
for the synthesis and data for the hydrolysis experiments,
including representative progress curves. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL030081E
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