Conformational Plasticity in Glycomimetics: Fluorocarbamethyl‐L‐idopyranosides Mimic the Intrinsic Dynamic Behaviour of Natural Idose Rings

Abstract

Sugar function, structure and dynamics are intricately correlated. Ring flexibility is intrinsically related to biological activity; actually plasticity in L-iduronic rings modulates their interactions with biological receptors. However, the access to the experimental values of the energy barriers and free-energy difference for conformer interconversion in water solution has been elusive. Here, a new generation of fluorine-containing glycomimetics is presented. We have applied a combination of organic synthesis, NMR spectroscopy and computational methods to investigate the conformational behaviour of idose- and glucose-like rings. We have used low-temperature NMR spectroscopic experiments to slow down the conformational exchange of the idose-like rings. Under these conditions, the exchange rate becomes slow in the (19) F NMR spectroscopic chemical shift timescale and allows shedding light on the thermodynamic and kinetic features of the equilibrium. Despite the minimal structural differences between these compounds, a remarkable difference in their dynamic behaviour indeed occurs. The importance of introducing fluorine atoms in these sugars mimics is also highlighted. Only the use of (19) F NMR spectroscopic experiments has permitted the unveiling of key features of the conformational equilibrium that would have otherwise remained unobserved.

Fluoro‐Carba‐Sugars are Glycomimetic Activators of the glmS Ribozyme

“…Also, idosamine possesses increased flexibility that leads to two interchanging chair conformations. Recent studies revealed that gem ‐difluoro‐carbamethyl‐ l ‐idopyranosides mimic this natural behavior, which confirms our findings on mono ‐fluoro‐carba‐ l ‐idosamine . The influence of the phosphate at C6 on activity is evident (Figure ), and is also reflected by the comparison of 18 and 1 .…”

“…Thus, the coupling constants of 14 and 2 are significantly higher than the calculated values for methyl β‐ l ‐idopyranoside ( 3 J H3‐H4 = 3 J H3‐H2 =3.0 Hz) in the favored 1 C 4 conformation . Similar conformational flexibility could already be demonstrated for the gem ‐difluorocarba‐sugar analog of methyl‐β‐ l ‐idopyranoside . For both 14 and 2 a strong NOE correlations between H2 and H4 as well as between H1 and H5 were observed, indicating a rapid 1 C 4 ↔ 4 C 1 exchange that is not distinguishable on the NMR timescale at room temperature.…”

“…The mono‐fluorinated cyclohexanone 10 was isolated in moderate yield (46 %) as a single diastereomer. In comparison, synthetic routes towards gem ‐difluorocarba‐sugar analogs of α‐ d ‐glucose, α‐, or β‐ d ‐galactose, α‐, or β‐ d ‐mannose, and β‐ l ‐idose have already been described. As far as mono ‐fluorinated carbapyranoses are concerned, however, 5‐fluoro‐(+)‐MK7607 and its C1‐epimer, the unsaturated carba analogs of galactose, are the only representatives described until now .…”

“…Similar binding to the catalytic core assumed, the introduction of fluorine seems to add steric load to the ligand, which neglects potential attracting properties of fluorine as for instance hydrogen acceptor . That fluorination drastically reduces effectivity is rather surprising, as recent studies on fluorinated pseudo‐sugars showed improved capabilities in resembling their natural counterparts compared to their respective unmodified carba analogs . However, in the case of the glmS ribozyme, the ligand binding pocket imposes high steric demands that obviously conflict with possible attracting interactions of newly introduced modifications.…”

Recent Advances in NMR Studies of Carbohydrates

“…Conformation equilibrium of xyloside and n-deoxy-n-fluoro-substituted derivatives, bearing naphthyl aglycone, has been explored by R€ onnols et al [105]. Recently, Unione et al [106] investigated the conformational behavior of idose and glucose-like rings by low-temperature NMR experiments. At low temperature, the conformational exchange rate of idose-like rings becomes slow in the 19 F NMR spectroscopic chemical shift timescale.…”