The Ratio between Endocyclic and Exocyclic Cleavage of Pyranoside Acetals Is Dependent upon the Anomer, the Temperature, the Aglycon Group, and the Solvent

Several cis-fused decalin pyranosides with
intramolecular nucleophiles of high effective molarity
were
studied to determine the ratio between endocyclic and exocyclic
cleavage in specific-acid-catalyzed solvolysis reactions.
The molecular design that allows a differentiation between endo-
or exocyclic cleavage is the symmetry and asymmetry
of the respective oxocarbenium ion intermediates. The synthesis of
the molecular probes involves eight steps from
a known compound, and proceeds via a key intermediate functionalized
with three different oxidation states. A
crystal structure confirmed the relative stereochemistry of the probes.
A quantifiable percentage of endocyclic cleavage
for β-pyranosides was found for all reaction conditions, whereas
α-pyranosides show exclusively exocyclic cleavage.
The percent of endocyclic cleavage for β-pyranosides is
dependent upon the temperature, the aglycon group, and the
solvent. At lower temperatures endocyclic cleavage increases.
The ΔH⧧ and
ΔS⧧ for endocyclic and
exocyclic
cleavage were determined to be 19.2 ± 1.4 kcal/mol and −12.6 ±
6.1 eu, and 22.8 ± 1.1 kcal/mol and 3.7 ± 3.8
eu in methanol, respectively. These values support the theory of
stereoelectronic control in the cleavage of pyranoside
acetals. Pyranosides with phenyl aglycon groups exhibit
significantly lower percentages of endocyclic cleavage
than pyranosides with alkyl aglycon groups. Although an exact
percentage of endocyclic cleavage of pyranosides
in water could not be determined, it appears to be approximately the
same or greater than that which occurs in
methanol. The addition of non-hydrogen-bonding/non-nucleophilic
solvents increased the percent of endocyclic
cleavage. The results are interpreted to support some extent of
nucleophilic assistance in the endocyclic solvolysis
of pyranosides, stereoelectronic control on the site of cleavage, and
the possibility of endocyclic cleavage at the
active site of glycosyl transfer enzymes.