Synthesis of fluorinated exo-glycals through modified Julia olefination

Article abstract of DOI:10.1002/ejoc.201201719

An efficient synthesis of fluorinated enol ethers derived from carbohydrates is reported. A modified Julia olefination reaction of functionalized lactones with fluorine-substituted sulfones gives the corresponding monofluorinated tri- or tetrasubstituted exo-glycals. An efficient synthesis of fluorinated enol ethers derived from carbohydrates is reported. A modified Julia olefination reaction of functionalized lactones with fluorine-substituted sulfones gives the corresponding monofluorinated tri- or tetrasubstituted exo-glycals.

Full text of DOI:10.1002/ejoc.201201719

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201201719
Synthesis of Fluorinated exo-Glycals through Modified Julia Olefination
Samuel Habib,[a] Florent Larnaud,[b] Emmanuel Pfund,[b] Thierry Lequeux,[b]
Bernard Fenet,[c] Peter G. Goekjian,[a] and David Gueyrard*[a]
Keywords: Fluorine / Enols / Olefination / Carbohydrates / Alkenes
An efficient synthesis of fluorinated enol ethers derived from
ones gives the corresponding monofluorinated tri- or tetra-
carbohydrates is reported. A modified Julia olefination reac- substituted exo-glycals.
tion of functionalized lactones with fluorine-substituted sulf-
preparation of fluoroalkenes by a modified Julia reac-
Introduction
tion,[13] this reaction has been extended by different groups
for the preparation of diversely functionalized di-, tri-, and
tetrasubstituted fluoroalkenes.[14] This reaction proceeds
smoothly from aldehydes or ketones to fluoroalkenes, but
it has not been applied to the olefination of lactones. We
report herein the synthesis of fluorinated exocyclic enol
ethers through the modified Julia olefination of lactones.
The introduction of a fluorine atom into a biologically
active molecule strongly modifies the chemical and physical
properties of the latter. In the specific case of fluorine-sub-
stituted enol ethers, the presence of fluorine additionally
stabilizes the enol ether function and radically alters its elec-
tronic distribution.[1] In the field of carbohydrates, exo-
glycals[2] are an important class of glycomimetics in which
their monohalogenated counterparts[3] have been prepared
for chemical purposes. Monofluorinated exo-glycals[4] have
been studied as probes for glycosyl-processing enzymes,
whereas 6-fluoro-5,6-anhydrocarbohydrates[5] have been in-
vestigated as inactivators of (S)-adenosyl-l-homocysteine
hydrolase. However, these monofluoroenol ethers were pre-
pared through stepwise methods that provide limited struc-
tural flexibility and little generality.
An original route to exo-glycals was recently developed
in our group in Lyon[6] by using modified Julia reagents[7]
on sugar-derived lactones. The reaction was further ex-
tended to the synthesis of tri- and tetrasubstituted enol
ethers.[8] This methodology was used for the preparation of
glycomimetics[9] and chiral ligands for catalysis[10] and for
the total synthesis of bistramide A and its analogues.[11]
Julia olefination has proven to be among the more prom-
ising direct methods for the synthesis of fluoroalkenes.[12]
Since a Caen’s group initial work describing the one-step
Results and Discussion
Fluoroalkyl sulfones were prepared according to a litera-
ture procedure,[15] and their addition to lactones was tested
to prepare exo-glycals. The reaction was first performed
with 2,3,4,6-tetra-O-benzyl-d-gluconolactone and 2-benzo-
thiazolyl fluoromethyl sulfone (Scheme 1). Using our pre-
vious standard conditions,[11] we were gratified to learn that
trisubstituted fluoroalkene 1 could be obtained in 85% iso-
lated yield as an E/Z mixture, with a slight preference for
the E isomer.[16]
[a] Université de Lyon, ICBMS, UMR 5246 – CNRS, Bat. 308 –
Curien (CPE Lyon), Université Claude Bernard Lyon 1,
43 Bd. du 11 Novembre 1918, 69622 Villeurbanne, France
Fax: +33-4-72448109
Scheme 1. Initial attempt under our standard conditions.
E-mail: gueyrard@univ-lyon1.fr
Homepage: http://www.icbms.fr/user/main.asp?num = 150
[b] Laboratoire de Chimie Moléculaire et Thioorganique, UMR
CNRS 6507, FR3038 ENSICAEN Université de Caen Basse-
Normandie,
6 Bd. du Maréchal Juin, 14050 Caen Cedex, France
[c] Centre Commun de Résonnance Magnétique Nucléaire,
Bâtiment Curien,
This result prompted us to explore the scope of this reac-
tion by using various fluoroalkyl sulfones and benzyl ether
protected sugar lactones[17] (Table 1). 2-Benzothiazolyl
fluoromethyl sulfone and 2-deoxy-3,4,6-tri-O-benzyl-d-
gluconolactone gave the corresponding fluorinated exo-
glycal 2 in 82% yield. In contrast to the previous result, the
observed E/Z selectivity was in favor of the Z alkene, and
3 rue Victor Grignard, 69622 Villeurbanne Cedex, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201719.
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Synthesis of Fluorinated exo-Glycals
this showed the influence of the 2-alkoxy group on the rela- in these cases, products 3 and 4 were isolated in good yields.
tive diastereoselectivity. Furanose lactones were tested, and A mixture of E/Z enol ethers was obtained in a 7:3 and
6:4 ratio, respectively. 2-Benzothiazolyl fluoroethyl sulfone
provided similar results, as tetrasubstituted exo-glycals 5–8
were isolated in 60–85% yield. An interesting inversion in
the selectivity was observed: the Z isomers were preferen-
tially obtained for 2-alkoxy-substituted derivatives 5, 7, and
8, whereas the E isomer was favored for deoxy derivative 6.
This illustrates the opposing influences of the electronic ef-
fects of the fluorine atom and the steric effects of the methyl
group.
Table 1. Synthesis of fluorinated exo-glycals from benzyl-protected
sugar lactones.
The stereochemistry of the double bond was established
in compounds 2, 3, 6, and 7 by homonuclear and hetero-
Table 2. Influence of the protecting group.[a]
[a] TES = triethylsilyl, TBDMS = tert-butyldimethylsilyl. [b] Pro-
cedure A: reaction performed with BF3·OEt2; procedure b: reaction
performed without BF3·OEt2.
Figure 1. Observed NOEs for some fluorinated enol ethers.
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D. Gueyrard et al.
SHORT COMMUNICATION
nuclear NOE measurements (Figure 1). The stereochemis- Table 3. Reaction with aminosulfones.[a]
1
try of the remaining compounds could be assigned by H–
1H NOESY experiments or by the combination of the rela-
tive chemical shifts of the signals in the 19F NMR spectra
2
3
and the magnitudes of the JCF and JCF coupling con-
stants (see the Supporting Information).[18]
We next focused on the influence of the protecting
groups on the course of the olefination reaction (Table 2).
Both isopropylidene and silyl ether protecting groups were
tolerated on the lactone, and trisubstituted and tetrasubsti-
tuted glycals 9–16 were obtained in moderate to good
yields. In the case of triethylsilyl ethers 9, 12, 13, and 16,[19]
better yields were obtained without the addition of a Lewis
acid.[20] As in the non-fluorine-substituted case, we noticed
that a tert-butyldimethylsilyl protecting group on the C-2
hydroxy group of the γ-lactone derivative negatively influ-
enced the course of the reaction, and significantly lower
yields were observed for 10 and 14. The stereoselectivity of
the formation of the double bond improved when the reac-
tion was conducted with a silyl ether protecting group, as
in the case of glucopyranose 9 when compared to benzyl-
protected 1. However, the opposite effect was observed for
furanoses 12 and 16, as the selectivity shifted towards the
Z isomer.
[a] TBDMS = tert-butyldimethylsilyl.
Having a straightforward method in hand to access alkyl-
ated exo-glycal derivatives, we investigated the synthesis of
fluorinated neoglycolipid skeletons. The reaction of tetra-
benzylgluconolactone with a benzothiazolyl sulfone con-
taining a fatty acid like hydrocarbon chain gave corre-
sponding fluoroalkene 17 in 53% yield (Figure 2). Better
results were observed when the olefination was performed
with a protected d-ribonolactone; in that case, tetrasubsti-
tuted fluorinated enol ether 18 was obtained in 83% yield.
Again, the steric demand of the alkyl chain appeared to be
significant, as improved Z selectivity was observed in both
cases.
Conclusions
In conclusion, we have developed a fluoroenol ether syn-
thesis by using modified Julia reagents for the preparation
of tri- and tetrasubstituted fluorinated exocyclic enol ethers
from lactones. This general route offers original and conve-
nient access to the synthesis of fluoro C-glycoside and nu-
cleoside analogues. This series of compounds constitutes a
new family of glycomimetics with, for example, potential
biological activities as glycosidase inhibitors.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, spectroscopic data, and copies of
1
the H NMR and 13C NMR spectra of all reported compounds.
Acknowledgments
Financial support from the Ministère de l’Enseignement Supérieur
et de la Recherche (research fellowship to S. H.) is gratefully
acknowledged. We also thank the ERDF (ISCE-chem) for a re-
search fellowship to F. L.
Figure 2. Introduction of long alkyl chains.
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2,3,4,6-tetra-O-benzyl-d-gluconolactone
(96 mg,
0.178 mmol, 1.5 equiv.) and 2-(fluoromethylsulfonyl)benzothi-
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distilled THF (480 μL) at –78 °C. Then, BF3·OEt2 (22 μL,
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–78 °C, diluted with dichloromethane, stirred at room tempera-
ture for 15 min, and extracted with dichloromethane (2ϫ). The
organic layers were combined and washed with brine, dried
with sodium sulfate, and concentrated. The residue was dis-
solved in dry THF (1.2 mL) and DBU (37 μL, 2.0 equiv.) was
added. Stirring was maintained for 1 h, and then the mixture
was concentrated by rotary evaporation and purified by flash
chromatography to afford the desired product (56 mg,
0.100 mmol, 85% yield).
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2
than in the Z isomer; The JCF coupling constants were found
to be consistently lower in the Z isomer than in the E isomer,
whereas the 3JCF coupling constant was found to be ca. 2.5 Hz
in the Z isomer and near zero in the E isomer.[3c] These corre-
lations will be addressed in more detail in an upcoming paper.
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[20] Typical procedure for the synthesis of fluorinated enol ethers
without BF3·OEt2: In a 5 mL round-bottomed flask under an
atmosphere of argon, 2,3,4,6-tetra-O-triethylsilyl-d-glucono-
lactone (104 mg, 0.164 mmol, 1.5 equiv.) and 2-(fluorometh-
ylsulfonyl)benzothiazole (25 mg, 0.109 mmol, 1.0 equiv.) were
dissolved in freshly distilled THF (440 μL) at –78 °C. Then, a
solution of LiHMDS (1 m in THF, 220 μL, 2.0 equiv.) was
added dropwise over 5 min. Stirring was maintained for
45 min, and then the mixture was hydrolyzed at –78 °C, diluted
with dichloromethane, stirred at room temperature for 15 min,
and extracted with dichloromethane (2ϫ). The organic layers
were combined and washed with brine, dried with sodium sulf-
ate, and concentrated. The residue was dissolved in dry THF
(1.1 mL) and DBU (34 μL, 2.0 equiv.) was added. Stirring was
maintained for 1 h, and then the mixture was concentrated by
rotary evaporation and purified by flash chromatography to
afford the desired product (66 mg, 0.102 mmol, 94% yield).
Received: December 20, 2012
Published Online: February 18, 2013
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