HF-Induced Intramolecular C-Arylation and C-Alkylation/Fluorination of 2-Aminoglycopyranoses

Article abstract of DOI:10.1021/acs.orglett.7b00003

Internal C-aryl and C-alkyl glycosides derived from 2-aminoglycopyranoses have been synthesized, exploiting a HF-mediated stereoselective intramolecular glycosylation. These conditions are compatible with acetate protecting groups and allow introduction of aromatics with various electronic distributions at the anomeric position. This strategy also provides straightforward entry to original fluorinated sugar-azacycle hybrids via a tandem internal C-glycosylation/fluorination reaction starting from 2-N-allyl/propargyl glycopyranoses. All cyclizations proceed in a 1,2-cis stereocontrolled manner.

Full text of DOI:10.1021/acs.orglett.7b00003

Letter
pubs.acs.org/OrgLett
HF-Induced Intramolecular C‑Arylation and C‑Alkylation/Fluorination
of 2‑Aminoglycopyranoses
Nicolas Probst,† Amelie Martin,† Jerome Desire,† Agnes Mingot,† Jerome Marrot,‡ Yves Bleriot,*,†
́
́
̂
́
́
̀
́
̂
́
and Sebastien Thibaudeau*,†
́
†IC2MP, UMR-CNRS 7285, Equipe Synthes
‡Institut Lavoisier de Versailles, UMR CNRS 8180, 45 avenue des Etats-Unis, Versailles78035 Cedex, France
̀
e organique, Bat
̂
. B28, 4 rue Michel Brunet, TSA 51106, Poitiers 86073 Cedex 9, France
S
* Supporting Information
ABSTRACT: Internal C-aryl and C-alkyl glycosides derived from
2-aminoglycopyranoses have been synthesized, exploiting a HF-
mediated stereoselective intramolecular glycosylation. These
conditions are compatible with acetate protecting groups and
allow introduction of aromatics with various electronic distributions
at the anomeric position. This strategy also provides straightforward entry to original fluorinated sugar−azacycle hybrids via a
tandem internal C-glycosylation/fluorination reaction starting from 2-N-allyl/propargyl glycopyranoses. All cyclizations proceed
in a 1,2-cis stereocontrolled manner.
C-Aryl glycosides1 are natural products isolated from plants or
intermediate. In this context, synthesis of unprecedented
congeners is of interest as it may eventuate in the discovery
of lead compounds having novel biological activities and
pharmaceutical value. Exploiting the unique reactivity of
organic compounds in superacid, we report herein a general
and straightforward access to rare10 internal 2-N-C-aryl and C-
alkyl (fluorinated) glycosides derived from 2-glycopyranosyl-
amines (Figure 1).
microorganisms that demonstrate a vast array of important
biological activities.2 Among these, internal C-aryl glycosides,
which have been found as ingredients in folk medicines,3
encompass an enzymatically and chemically robust pseudoano-
meric C−C bond and a conformationally locked aglycon
moiety.4 Internal C-aryl glycosides are also naturally occurring5
and constitute a valuable stereocontrolled entry to C-aryl
glycosides.6 Their synthesis usually involves an intramolecular
Friedel−Crafts reaction as the key step. Various Lewis acids and
glycosyl donors bearing different protecting groups and
anomeric leaving groups have been screened to optimize this
process that is able to incorporate either a furanose7 or a
pyranose sugar unit (Figure 1).8 To date, this methodology is
limited to 2-O-aryl glycosides with electron-rich aromatics
bearing OH, SiMe3, CH3, or OCH3 substituents because of the
inherent low electrophilicity9 of the electrophilic sugar-derived
In marked contrast to acids, superacids11 can generate
polycationic superelectrophilic species12 able to react with poor
nucleophiles such as deactivated arenes.13,14 Applied to
carbohydrates, it could allow rapid anomeric arylation in a
stereocontrolled manner through an intramolecular aglycon
delivery provided the arene is already present in the glycosyl
donor. We have previously identified the acetyl as the
protecting group of choice when applying superacid conditions
to carbohydrates.15
As a first approach, the reactivity of the peracetylated N-
benzyl-β-D-2-aminoglucopyranose 1a was examined, and several
superacids were screened (Table 1). HF/SbF5 failed to trigger
the intramolecular C-arylation, even after modulating the
acidity of the medium (Table 1, entries 1 and 2).16 Satisfyingly,
treatment of 1a with neat liquid HF afforded the desired
tricyclic product 2a (41%) along with the fluorinated derivative
3a (Table 1, entry 4).17 Increasing the reaction time failed to
improve the yield of 2a. Use of neat CF3SO3H was unsuccessful
(Table 1, entries 5 and 6). Protonation of the 2-amino group by
HF, thus deactivating the anomeric position, might be
responsible for the observed low conversion. This forced us
to protect the secondary amine as its N-tosyl derivative to
afford compound 1b. Gratifyingly, upon HF treatment, 1b led
exclusively to the formation of the desired product 2b (Table 1
Figure 1. Previously developed methodologies from 2-O-aryl glyco-
sides and the one disclosed herein from 2-N-aryl/alkyl glycosides to
access internal C-aryl glycosides and fluorinated sugar−azacycle
hybrids.
Received: January 4, 2017
© XXXX American Chemical Society
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Letter
Table 1. Intramolecular C-Arylation of 2-Aminoglucosides
conditions (superacid/
temp (°C) /time)
product
c
yield of 2a/
d
entry substrate
ratio 1/2/3
2b (%)
a
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1b
1b
HF/SbF5 /−20/2 h
e
e
f
f
b
HF/SbF5 /−20/2 h
neat HF/−20/2 h
neat HF/−20/24 h
neat HF/−20/48 h
neat TfOH/0/1.5 h
neat HF/−20/0.5 h
1/3/1
f
g
0 /3/1
41
37
f
g
0 /3/1
e
0/1/0
0/1/0
80
88
neat HF/−40/15 min
a
b
HF/SbF5 (mol % SbF5 = 21.6). HF/SbF5 (mol % SbF5 = 13.8).
Ratio determined by H NMR analysis of the reaction crude. Yield
c
d
1
e
obtained after purification by flash column chromatography. Complex
f
g
mixture. Not determined. Traces of starting material were detected.
entry 7). Finally, performing the reaction at −40 °C for 15 min
proved beneficial and produced 2b in excellent 88% yield
(Table 1, entry 8).
The structure of 2b was firmly established by X-ray
crystallography (CCDC no. 1492103) and confirmed a 1,2-cis
arrangement imposed by the stereochemistry of C-2 bearing
the nitrogen-containing nucleophile (Figure 2). These results
Figure 3. Scope of the HF-mediated cyclization applied to 2-N-
benzylaminoglycosides. (a) PhSH/K2CO3, DMF.
which uneventfully afforded the internal C-aryl glucosides 2f−i
in high 76−98% yields. The convenient removal of the nosyl
group was illustrated by the synthesis of the tetrahydroquino-
line 2a from 2f by treatment with thiophenolate (92%).19 We
then moved to more electronically challenging aromatics
bearing a Br, F, CF3, or NO2 substituent. Gratifyingly, along
with the fluorosugar 3j, we were able to isolate the
trifluoromethyl derivative 2j albeit in low yield (23%), a result
that illustrates the superelectrophilic character of the transient
glycosyl cation trapped by poor nucleophiles. The limit of this
methodology was reached with the deactivated p-nitrophenyl
derivative 1k (N-tosyl) that only afforded the fluorosugar 3k
with no trace of the internal C-aryl glycoside (Figure 3).
Haloaromatics 1l−n also cyclized efficiently to afford
tricycles 2l−n′ in excellent yields. Starting from monosacchar-
ide 1n bearing a fluorine atom in meta position on the aromatic
ring, two internal C-aryl glycosides 2n and 2n′ were isolated,
accounting for the low steric demand of the fluorine atom
allowing rotation of the aromatic ring around the CAr−CN
linkage. The generality of our approach regarding the glycosyl
donor configuration was confirmed by briefly examining the D-
galacto- 1o and D-manno-configured 1p derivatives that
respectively furnished the corresponding internal C-aryl
glycosides 2o and 2p in good yields (Figure 3).
Figure 2. ORTEP drawing of compound 2b.
demonstrate the ability of HF to activate the anomeric leaving
group presumably leading to the formation of a transient
glycosyl cation that is next trapped by the aromatic ring.
To define the scope of this process, the optimized cyclization
conditions were applied to a range of 2-N-aryl glycosides,
incorporating aromatics with various electronic distributions.
These compounds were readily prepared by an N-sulfonyla-
tion/N-alkylation or reductive amination/N-sulfonylation
synthetic strategy starting from commercially available 2-
aminoglycosides (Figure 3).18 In most cases, the cyclization
proceeded smoothly, leading to exclusive formation of the 1,2
syn adducts. The inductively activated naphthalene-substituted
derivative 1c was converted to its cyclic counterpart 2c in
almost quantitative yield. The cyclization also readily took place
with a methoxybenzyl substituent (products 2d,e). For
synthetic purposes, we switched to the N-nosyl derivatives
Concerning the mechanism of this reaction, the isolation of
the 1-fluoro sugars 3j and 3k and the identification of the
remaining acetic acid by NMR analysis are in agreement with
B
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an activation of the anomeric acetate by protonation and the
formation of the transient glycosyl oxocarbenium ion A in neat
HF superacid (Scheme 1).20 This oxocarbenium ion can then
mannopyranose series to go to completion demonstrating the
singular reactivity of this monosaccharide.18 Extension to
substituted alkenes with compound 4c bearing a methallyl
group on the nitrogen produced the fluorinated product 5c
(35% yield) along with the elimination product 6c (29% yield).
Formation of the diastereomeric fluorinated pyrrolidines 7d
and 7d′ was observed starting from compound 4d, as
anticipated. The stereochemistry of compounds 5c, 7d, and
7d′ was determined by extensive NMR experiments.18 Finally,
the cyclization/fluorination process was applied to N-propargyl
derivative 4e to cleanly provide the fluoro olefin 8.
Scheme 1. Suggested Mechanism for the Generation of
Fluorinated and C-Aryl Monosaccharides in HF Superacid
In conclusion, we have explored the intramolecular Friedel−
Crafts arylation of 2-aminoglycosides triggered by HF super-
acid, allowing the stereoselective delivery of a set of original
internal 2-amino-C-aryl glycosides in the glucose, galactose, and
mannose series. This reaction was extended further in the N-
allyl and N-propargyl series to furnish fluorinated sugar−
azacycle hybrids. These sugar-based polycyclic compounds with
a central piperidine ring, amenable for further structural
modification, are of interest in a medicinal chemistry context31
in regard to the therapeutic potential of fluorine-containing
molecules and sugar derivatives.
be fluorinated despite the weak nucleophilic character of the
fluoride ions in these conditions.21 Through activation of the
resulting C−F bond, an equilibrium between the fluorinated
product 3 and the cationic intermediate A can be postulated.
The highly electrophilic character of this latter allows its
subsequent and irreversible trapping by the arene to furnish the
internal C-aryl glycoside 2.
Extension of this strategy to 2-N-alkylglycosyl donors
incorporating a CC bond in the substituent at position 2 is
worth investigating as it should provide original fused sugar-
azacycle structures of biological and synthetic interest (Scheme
2).22−24 Related 2-O-alkyl derivatives have been previously
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00003.
X-ray data for compound 2b (CIF)
Experimental procedures, characterization data, and H
and 13C NMR spectra (PDF)
1
Scheme 2. Cyclization/Fluorination Sequence Applied to 2-
Aminoglycosides Bearing an Unsaturated Alkyl Chain at
a
Position 2
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: sebastien.thibaudeau@univ-poitiers.fr.
*E-mail: yves.bleriot@univ-poitiers.fr.
ORCID
Sebastien Thibaudeau: 0000-0002-6246-5829
́
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the CNRS (PICS program) and the ANR (project
OXYCARB ANR-12-BS07-0003-01) for financial support. A.M.
and N.P., respectively, acknowledge the ANR and the
Foundation of the Chemistry of Natural Products of the
French Academy of Sciences for fellowships.
a
Conditions: neat liquid HF, −40 or 0 °C, 1 h.
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D
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