Communications
close and are in good agreement with the relevant values
found in acyclic d-xylulose-glycine[7] and dihydroxyace-
tone.[13]
ꢀ
ꢀ
The respective torsion angles around the C4 C5 and C5
C6 bonds in 6 and 8 (Table S2 in the Supporting Information)
are within 4.58 of each other, but the conformations around
the carbonyl group differ significantly. In the 13C NMR
spectrum of crystalline powdered 8 (Figure 1B), two sets of
carbon signals indicate that this compound may exist in two
different conformations. The carbonyl-centered fragment of
molecule 6, including atoms O3, C3, C2, O2, C1, and N, is
virtually planar, with only small (8–108) deviations of the
torsion angles from the staggered/eclipsed conformation.
Similar spatial arrangements for the carbohydrate fragment
were found in acyclic d-xylulose-glycine[7] and dihydroxyace-
tone,[13] as well as the acyclic d-glucose/d-fructose or d-xylose/
d-xylulose intermediates in the xylose/glucose isomerase
active site.[14] Within the enzyme complexes, however, the
periplanar disposition of the O1, O2, and O4 atoms of the
acyclic carbohydrate intermediates is stabilized by coordina-
tion with two metal ions, typically Mg2+ or Mn2+ ions.
Stabilization of the cis conformer in polar environments has
also been detected for a number of a-amino acetone
derivatives[15] and was explained on the basis of s(C H)!
ꢀ
[16]
=
ꢀ
=
s*(C O) and s(C H)!p*(C O) interactions.
Subsequently, we examined the tautomeric composition
of the fructosamine derivatives in D2O/pyridine solutions by
13C NMR spectroscopy. According to the spectral data, the b-
pyranose form predominates in 1–10, 13, and 14 (Table 1),
followed by the b-furanose form and a population of minor
tautomers divided between the a-pyranose, a-furanose, and
acyclic keto tautomers. This tautomeric pattern is character-
istic for both d-fructose and fructosamines derived from
aliphatic amines and amino acids.[6,17] Table 1 provides a
pattern that relates the fructosamine acyclic keto tautomer
population to the nature of the aglycon. d-Fructosamine (1)
and its N-alkyl- or N-carboxyalkyl derivatives are comparable
to common hexoses and hexuloses in displaying less than 1%
of the acyclic tautomer in the equilibrium. N-Aryl-substituted
fructosamines 2, 3, and 4 show a 2–5% tautomeric population
present in the keto form, while addition of the N-methyl
group in 5–7 enhances the acyclic isomer percentage to 9–
11%. This proportion is augmented with an increase in the
size of the N-alkyl substituent, such as those in 8–10. Upon a
further increase, as in fructosamines 11 and 12, an unprece-
dented acyclic keto tautomer proportion of 52–57% is
observed, which dominates over the pyranose and furanose
species. Notably, the aglycon structure does not significantly
influence the relative proportions of the cyclic fructosamine
tautomers, which retain the b-pyranose > b-furanose >
a-furanose > a-pyranose order in aqueous pyridine solutions.
When compared to other known fructosamine structures
that crystallize in the b-pyranose form,[12,18] the crystal
structures of 6 and 8 do not reveal any obvious specific
interactions or steric constraints that would destabilize the
energetically favorable b-pyranose tautomer.
Figure 1. Solid-state 13C NMR spectra and molecular structures of
A) crystalline N-methyl-N-p-tolyl-d-fructosamine (6) and B) crystalline
N-ethyl-N-p-chlorophenyl-d-fructosamine (8).
are shown in Figure 1. In both molecules, the C2–C6 carbon
chain of the carbohydrate portion is in the planar zig-zag
conformation, similar to that found in crystalline d-glucitol.[10]
ꢀ
The C C bond lengths in the fructosyl portion of 6 and 8
(see Table S2 in the Supporting Information) are close to the
respective values in d-fructose and its derivatives[11] (mean of
ꢀ
1.521 ꢀ). The mean distances of the hydroxy C O bonds in 6
(1.426 ꢀ) and 8 (1.432 ꢀ) are longer than the corresponding
bonds in fructopyranoses and are rather closer to the average
values[12] from crystalline d-glucitol derivatives. The C
ꢀ
ꢀ
ꢀ ꢀ
C(OH) C and C C OH valence angles in 6 and 8 (see
Table S2 in the Supporting Information) range from 107.18 to
113.48 (mean of 110.48) and compare well with the average
values[10] found in alditols. The values of the respective
valence angles around the carbonyl C2 atom in 6 and 8 are
We note, however, that the O2 carbonyl oxygen atom in
these molecules is not involved in any heteroatom contacts, in
contrast to the situation in published b-d-fructopyranosyl-
5518
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 5517 –5520