Communications
DOI: 10.1002/anie.201004467
Fluoro Sugars
Fluorine-Directed Glycosylation**
Christoph Bucher and Ryan Gilmour*
Dedicated to Professor Peter H. Seeberger
Carbohydrates are ubiquitous in nature, ranging from cellular
energy sources to modulators of surface-based molecular
recognition.[1] Unsurprisingly, these functional biomolecules
have been the subject of intense synthesis campaigns culmi-
nating in a vast arsenal of glycosylation methods that are
amenable to the stereocontrolled synthesis of complex
oligosaccharides.[2] Central to virtually all of these strategies
is an intermediary oxonium ion, the conformation of which is
decisive in determining the configuration of the newly formed
anomeric center.[3] However, controlling oxonium ion con-
formation in a predictable manner is challenging,[4] especially
for 2-deoxy sugars where the protecting group regime at C2
cannot be modulated to govern stereoselectivity.[5] Cognisant
of the tendency of organofluorine compounds to adopt
conformations that allow for stabilizing hyperconjugative
and attractive electrostatic interactions,[6] we envisaged that
the transient oxonium ions derived from 2-fluoropyranoses
(I!II) would be intriguing candidates for investigation
(Scheme 1).
pyridinium cations,[8] we postulated that in a gluco-configured
2-fluoro-oxonium ion the polarized C–F bond would orient
towards the electropositive center;[9] in essence, conforma-
tional rigidification would be induced by perturbations in
charge distribution around the anomeric center. Conse-
quently, the 3H4 and/or B2,5 oxonium ion conformers (IV and
V, respectively) would be favored, conceivably leading to a
highly b-selective glycosylation event, complementary to the
often a-selective processes associated with 2-deoxy sugars.[5,10]
Whilst the overall oxonium ion topology would be responsive
to electronic and steric modifications around the ring
periphery, we envisaged that the fluorine atom would exert
a controlling influence over the conformation that would
ultimately be manifested in the selectivity of the subsequent
glycosylation (II!III) (Scheme 1). Herein we present a
ꢀ
preliminary validation of the C F bond as design feature to
control oxonium ion conformation in 2-fluoropyranose deriv-
atives. The consequence of inverting the configuration at C2
(gluco-F!manno-F) is described together with the influence
of weakly versus strongly inductive protecting groups.
Implicit is the realization that fluorineꢀs low steric demand,
high bond strength to carbon, and consequent reactive
inertness render the starting monosaccharides excellent
bioisosteres of 2-deoxy sugars.[11] Moreover, fluorinated
glycostructures continue to play an important role in medi-
cine and pharmaceutical development[12] making this inves-
tigation, and the products described herein, timely.
Consistent with Synder and Lankinꢀs observation of a
{NH-FC} dipole effect in 3-fluoropiperidine derivatives,[7]
together with OꢀHaganꢀs findings pertaining to the conforma-
tional dynamics of protonated b-fluoroazetidinium and ethyl-
Initially, we elected to study a series of perbenzylated
glycosyl trichloroacetimidates (Table 1) owing to the popular-
ity of these systems in preparative glycochemistry,[13] and the
mild conditions required to generate the transitory oxonium
species. Employing isopropyl alcohol as the glycosyl acceptor
1
facilitated reaction analysis by H NMR spectroscopy, whilst
CH2Cl2 was strategically chosen as the reaction medium to
minimize the risk of solvent–oxonium ion complex formation
that may bias the selectivity. To our delight, we observed that
the C2 gluco-configured fluoride (entry 1, Table 1) furnished
the desired isopropyl glycoside in excellent yield and with an
impressive level of diastereocontrol (b/a 57:1). Conversely,
the 2-deoxy glycosyl donor (entry 4, Table 1) gave markedly
reduced selectivities (b/a 6:1), presumably due to the lack of
structural control imparted by the fluorine. Moreover, by
simple configurational inversion at C2 (gluco!manno), the
diastereocontrol was once again substantially eroded giving
results comparable to the 2-deoxy system. Intriguingly, under
the conditions of this comparative study, the commonly used,
perbenzylated glucose derivative (Table 1, entry 5, C2-OBn)
gave levels of induction that again were lower than with the
inital gluco-configured fluoro-glycoside (entry 1, Table 1).
Interestingly, the C2 gem-difluoride derivative was recalci-
Scheme 1. Conformational control in 2-fluoro-oxonium ions.
[*] C. Bucher, Prof. Dr. R. Gilmour
Swiss Federal Institute of Technology (ETH) Zurich
Laboratory for Organic Chemistry
Department of Chemistry and Applied Biosciences
Wolfgang-Pauli-Strasse 10, 8093 Zurich (Switzerland)
E-mail: ryan.gilmour@org.chem.ethz.ch
[**] We gratefully acknowledge generous financial support from the
Alfred Werner Foundation (assistant professorship to R.G.), the
Stipendienfonds der Schweizerischen Chemischen Industrie (doc-
toral fellowship to C.B.), and the ETH Zurich. We thank Prof. Dr.
Dieter Seebach for helpful discussions.
Supporting information for this article is available on the WWW
8724
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 8724 –8728