Reengineering Chemical Glycosylation: Direct, Metal-Free Anomeric O-Arylation of Unactivated Carbohydrates

Article abstract of DOI:10.1002/chem.201804416

To sustain innovation in glycobiology, effective routes to well-defined carbohydrate probes must be developed. For over a century, glycosylation has been dominated by the formation of the anomeric Csp³?O acetal junction in glycostructures. A dissociative mechanistic spectrum spanning S_N1 and S_N2 is frequently operational thereby reducing the efficiency. By reengineering this fundamental process, an orthogonal disconnection allows the acetal to be formed directly from the reducing sugar without the need for substrate pre-functionalisation. The use of stable aryliodonium salts facilitates a formal O?H functionalisation reaction. This allows lactols to undergo mild, metal-free O-arylation at ambient temperature. The efficiency of the transformation has been validated using a variety of pyranoside and furanoside monosaccharides in addition to biologically relevant di- and trisaccharides (up to 85 %). Fluorinated mechanistic probes that augment the anomeric effect were employed. It is envisaged that this strategy will prove expansive for the construction of complex acetals under substrate-based stereocontrol.

Full text of DOI:10.1002/chem.201804416

A Journal of
Accepted Article
Title: Re-Engineering Chemical Glycosylation: Direct, Metal-Free
Anomeric O-Arylation of Unactivated Carbohydrates
Authors: Nicola Lucchetti and Ryan Gilmour
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Re-Engineering Chemical Glycosylation: Direct, Metal-Free Anomeric
O-Arylation of Unactivated Carbohydrates
Dr. Nicola Lucchetti, and Prof. Dr. Ryan Gilmour*
aryl glycosides have been intensively pursued.[12] Predicated on
Abstract: To sustain innovation in glycobiology, effective routes to well-
retrosynthetic analysis of the anomeric C(sp3)−O bond (Figure 1, upper
defined carbohydrate probes must be developed. For over a century,
glycosylation has been dominated by formation of the anomeric C(sp3)−O
centre, disconnection A), a plethora of protocols for aromatic O-
glycosylation has been developed. These strategies traverse the
acetal junction in glycostructures. A dissociative mechanistic spectrum
Umpolung spectrum proceeding via postulated glycosyl cations,[4]
radicals and carbenes (Figure 1, lower centre).[13] Furthermore
spanning SN1 and SN2 is frequently operational thereby complicating
efficiency. By re-engineering this venerable process, an orthogonal
disconnection allows the acetal to be forged directly from the reducing
sugar without the need for substrate pre-functionalisation. Engagement with
stable aryliodonium salts facilitates a formal O−H functionalisation reaction.
This allows lactols to undergo mild, metal-free O-arylation at ambient
temperature. The efficiency of the transformation has been validated using
a variety of pyranoside and furanoside monosaccharides in addition to
biologically relevant di- and tri-saccharides (up to 85%). Fluorinated
mechanistic probes that augment the anomeric effect have been employed.
It is envisaged that this strategy will prove expansive for the construction of
complex acetals under substrate-based stereocontrol.
significant advances in translating chemical glycosylation to a catalysis
paradigm have enriched the field.[4,14]
To complement the existing glycosylation ordnance, it was envisaged
that re-engineering the acetal linkage via strategic disconnection B
(Figure 1, lower) would provide an attractive alternative for aryl
glycoside formation. This O−H functionalisation reaction would
mitigate the need for substrate-pre-functionalisation
/ activation
sequences and allow reducing sugars to be used directly.
A
stereoretentive reaction would also allow chirality encoded at C1 to be
translated to the product. Herein, a direct, metal-free, O-arylation of
mono-, di- and tri-saccharides at the lactol position is validated using
simple aryliodonium salts as the electrophilic partner (Figure 1, lower).
The functional virtuosity of complex carbohydrates is reflected in their
structural diversity.[1] Central to the energy, architectural and molecular
recognition aspects of cell biology, glycostructures continue to provide
a rich source of innovation for the design of novel pharmaceuticals and
materials:[2] This is particularly prominent in phenolic glycosides such
as the antibiotic Vancomycin.[3] However, exploring and harnessing
carbohydrate function is frequently compromised by synthetic
challenges.[4] In contrast to peptides and nucleic acids, the efficiency
with which complex sugars are produced biosynthetically cannot easily
be emulated in a laboratory paradigm. An amalgamation of regio- and
stereo-selectivity complications, further compounded by complex
conformational equilibria, render carbohydrate coupling protocols less
general than the aforementioned biomolecule classes. Whilst advances
in automation have significantly alleviated the synthesis bottleneck,[5]
innovative coupling methods to construct the acetal junction intrinsic
to carbohydrates must be developed in parallel. When considering
glycostructures of translational relevance to medicine, phenolic
glycosides have emerged as venerable blueprints. Exploited for over a
century as anti-inflammatory agents,[6] aryl capped glycosides based on
β-Phlorizin have emerged as powerful and selective SGLT2 inhibitors
for the clinical management of type II diabetes.[7] This motif also
features in Bimosiamose for the treatment of psoriasis and asthma,[8]
a
plenum of myelin-associated glycoprotein (MAG) antagonists,[9] and in
the natural product Rumexoside (Figure 1, top). Indeed, a recent survey
of U.S. FDA approved drugs containing oxygen heterocycles by
Njardarson and co-workers revealed that pyranoses and furanoses are
the top two most frequently employed motifs.[10] Reconciling the pre-
eminence of glycosylated molecules in human medicine with the
dearth of effective strategies for their construction is exemplified by a
recent study by Schepartz and Miller on the rapid O-glycosylation.[11]
Consequently, strategies to facilitate the efficient synthesis of diverse
Figure 1. Top: Examples of pharmaceutically relevant aryl glycosides. Upper
centre: A generic glycostructure indicting the two possible disconnections of the
acetal junction. Lower centre: A conceptual overview of glycosylation strategies
based on strategic disconnection A. Bottom: A conceptual alternative via an O−H
functionalisation exploiting aryliodonium reagents (disconnection B).
[*]
Dr. Nicola Lucchetti, Prof. Dr. Ryan Gilmour
Organisch Chemisches Institut
Westfälische Wilhelms-Universität Münster
Correnstraße 40, 48149 Münster (Germany)
E-mail: ryan.gilmour@uni-muenster.de
Homepage: http://www.uni-muenster.de/Chemie.oc/gilmour/
Aryl-λ3-iodane salts[15,16] have emerged as powerful and versatile
arylating reagents.[17] Pertinent examples include Olofsson’s elegant
functionalisation of diaryliodonium salts to decorate the periphery of
sugars,[18a] and Toste’s diastereoselective acetalisation with chiral
Supporting information for this article is given via a link at the end of the
document.
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diaryliodonium phosphates.[19] Cognisant that these reagents undergo
facile O−H functionalisation of various alcohols, we sought to explore
the competence of aryl iodonium salts for the functionalisation of the
hemi-acetal of unactivated, reducing sugars. As a starting point for this
study, commercially available diphenyliodonium hexafluorophosphate
2a was investigated as a model electrophile for the arylation of 2,3,4,6-
tetra-O-benzylated-D-glucopyranose 1a (Table 1).
Scheme 1. Direct O-Arylation of carbohydrates: Exploring diaryliodonium scope.[a]
Table 1. Direct O-arylation of tetra-O-benzylated-D-glucopyranose 1a using 2a.[a]
Entry
Solvent
toluene
toluene
toluene
toluene
DCE
Base (eq.)
KOtBu (1.5)
K2CO3 (1.5)
NaH (1.5)
Yield [%][b]
1
2
39
0
3
9
4
NaOtBu (1.5)
KOtBu (1.5)
KOtBu (1.5)
KOtBu (1.5)
KOtBu (1.5)
KOtBu (1.5)
<5
21
<5
35
37
43
5
6
CH3CN
CH2Cl2
toluene
toluene
7
8[c]
9[d]
[a] Reactions were performed in toluene on a 0.15 mmol scale at ambient temperature.
The α:β ratio of the products was determined by 1H NMR spectroscopy. The α:β ratios
of the starting materials are provided in the SI.
[a] Standard conditions: 1a (1 eq.) and 2a (1 eq.), 0.09 mmol scale. [b] Isolated yields
following flash column chromatography. [c] T = 40 °C. [d] = [TMPIPh]OTs (2aa)
used as the diaryliodonium salt.
Gratifyingly, arylation of lactol 1a with 2a in the presence of KOtBu
(1.5 equiv.) at ambient temperature in toluene afforded the desired
compound 3a in 39% yield (entry 1). Employing alternative inorganic
bases such as K2CO3, NaH and NaOtBu proved detrimental to reaction
efficiency (entries 2-4). Generally, switching reaction media to CH3CN
or DCE did not improve the outcome (entries 5-7).[20] However,
dichloromethane furnished 3a in a comparable yield to toluene (35%,
entry 7). No change in conversion or in the anomeric composition of
the product (α:β) was observed by elevating the temperature to 40 °C
(entry 8). Furthermore, an excess of arylating agent proved to be
unnecessary and thus a 1:1 stoichiometry was optimal (see SI for
details). In an attempt to improve the reaction efficiency, the optimised
conditions identified in Table 1 were repeated using more electron-rich
diaryliodonium salts. Inspired by studies from Stuart and co-
workers,[17g,21] the 2,4,6-trimethoxyphenyl (TMP) group was exploited
as a prosthetic ligand at the iodine(III) centre. This structural alteration
led to a slight increase in yield (43%, entry 9). With a preliminary
validation of concept having been demonstrated, attention was then
focused on exploring the scope of this transformation (Scheme 1). This
operationally simple protocol was performed at ambient temperature
and the anomeric ratio (α:β) of the products was determined by 1H
NMR (3JHH-coupling constant) analysis. Symmetrical or unsymmetrical
(TMP) diaryliodonium salts were employed as necessary (see SI for
full preparative details). Gratifyingly, the 2,6-disubstituted arenes,
known to facilitate reductive elimination, were well tolerated in the
title transformation and furnished the desired aryl glycosides 3b-e in
good yields (49-85%). As expected, the α-anomers predominated
giving a first indication that the reaction was stereoretentive (vide
infra).
Increasing the steric demand of the arylating reagent had little effect on
the transformation with 3f being formed in 53% yield (α:β = 2.2:1).
Importantly, the method was compatible with the presence of halides
within the aromatic core (3g, 71% yield). This is advantageous for
downstream functionalisation. The 2,6-dichloro derivative underwent
smooth O-arylation to deliver 3h in 68% yield. The scope was not
limited to ortho,ortho'-disubstituted diaryliodonium salts. Indeed, 2,5-
and 2,4-dimethylphenyl ethers were also isolated in good yields (3i,j
both in 63% yields). In view of the importance of the CF3 group in drug
discovery,[22] the 3- and 4-trifluoromethylated derivatives 3k and 3m
were prepared (71% and 80% yield, respectively). Finally, the 4-
nitrophenyl substituted glucose 3l was prepared in 66% yield (α:β =
2.6:1). Having investigated the electrophile scope, a series of reducing
sugars were explored as nucleophilic coupling partners (Scheme 2).
Modifying the protecting group electronics from benzyl (Bn) to p-
methoxybenzyl (PMB) 4b led to comparable yields (66%) but with an
inversion in anomeric ratio (α:β 1:3.3 versus 2:1 for 3c). This single
example is intriguing in that the intrinsic α-selectivity of the lactol is
inverted to favour the β-glycoside. The conformationally restricted
substrate containing a benzylidene acetal was also well tolerated (4c,
71%, α:β 1.5:1), as was the 2-deoxy-system 4d (47%, α:β 1.6:1).
Installation of the sterically more cumbersome α-methly substituent did
not impede the reaction and 4e was isolated in 64% yield.
Epimerisation at C2 to generate the D-mannose system was also well
tolerated and furnished the glycoside 4f in 76% yield (α:β 11:1).
Interestingly, the C4 epimer D-galactose performed slightly less well
with 4g being isolated in 67% (α:β 1.3:1). The D-mannofuranose
species 4h was isolated in 81% yield exclusively as the α-anomer.
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Finally, the L-fucose derivative 4i was obtained in 57% yield, whilst
the arylated D-ribose 4j was obtained in 32% yield (anomeric ratio α:β
= 1:1.1).
the case of a stereoretentive process. Furthermore, 2-fluoro sugars
remain privileged tools for mechanistic enzymology and in
stereoselective
glycosylation.[25]
Interestingly,
classic
trichloroacetimidate activation of 1a with a Lewis acid (TMSOTf)
favours formation of the β-glycoside.[25c] However, with this protocol
the predominant α-composition of the lactol is transmitted to the
product (α:β 2.4:1 versus 2.6:1 for 1k and 4k respectively). In the D-
mannose case 1l → 4l, complete stereoretention was again observed (α
only). This feature of the process was further confirmed with the D-
galactose system: 1m → 4m, α:β 2:1 → 2:1), and finally with the
geminal-difluoro system: 1n → 4n, α → α). Interestingly, the
trichloroacetimidate donor of the latter substrate (1n) is completely
recalcitrant to classic glycosylation conditions[25c] and thus this method
provides a handle to install C2 gem-difluorinated building blocks into
structures of interest. Collectively, these data are consistent with a
mechanistic framework that proceeds via an I(III) intermediate that is
not prone to epimerisation prior to reductive elimination (Scheme 4,
lower).
Scheme 2. O-Arylation of pyranoses and furanoses utilising aryliodonium salt 2c.[a]
Scheme 4. Top: Exploring the stereoretentive nature of the O-arylation using
fluorinated probes to enhance the anomeric effect. Bottom: Tentative mechanism.[a]
[a] Reaction were performed in toluene on a 0.15 mmol scale at ambient temperature.
The α:β ratio was determined by 1H NMR spectroscopy.
To validate this alternative to chemical glycosylation on more complex
glycostructures, a representative O−H functionalisation using 2c was
performed on a biologically relevant di- and tri-saccharide (Scheme 3).
Exposing the lactose derivative 5a to the optimised arylation
conditions at ambient temperature smoothly furnished the desired
glycoside 6a in 73% yield (βα:ββ 1.4:1). Furthermore the trisaccharide
6b, commonly employed in bacterial imaging,[23] was isolated in 57%
yield (ααα:ααβ 1.3:1)
Scheme 3. Extending the O-arylation to more complex carbohydrates.
[a] Reaction were performed in toluene on a 0.15 mmol scale at ambient temperature.
[b] Reaction were performed in toluene on a 0.22 mmol scale at ambient temperature.
The α:β ratio was determined by 1H NMR spectroscopy.
Finally, the utility of the method towards scale-up was explored on a
1.5 g scale (Scheme 5). The desired aryl ether 3a was isolated in an
increased 84% yield upon stirring for 24 h without any erosion in the
anomeric ratio (α:β = 2:1). Global deprotection under hydrogenolysis
conditions (H2, Pd/C, methanol at ambient temperature), furnished 7 in
80% yield.
Scheme 5. Representative scale-up and global deprotection.
Having established a broad substrate scope for the transformation, the
conservation of stereochemistry was interrogated (Scheme 4). To that
end, a series of fluorinated substrates were prepared to augment the
anomeric effect.[24] The presence of the electron withdrawing group at
C2 ensures that the equilibrium favours the α-anomer of the reducing
sugar: This in turn should be mirrored in the product composition in
In summary, a mild, one-pot, procedure for the efficient and scalable
synthesis of O-functionalised carbohydrates is disclosed. Predicated on
a stereoretentive O−H functionalisation of the reducing sugar (lactol)
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this alternative disconnection to conventional glycosylation constitutes
a facile and expansive platform for the preparation of aryl glycosides.
Promoted by easily accessible electrophilic iodine(III) reagents, the
process does not require the classic pre-functionalisation / activation
sequence inherent to classical glycosylation methods. Validated for
both pyranosyl and furanosyl substrates, the reaction is compatible
with a variety of arylating agents and tolerates a range of protecting
groups and substituents. The process is particularly suited to the
synthesis of fluorinated glycostructures where the stereoelectronic
effects of the 2-fluoro substituent can be incorporated into the reaction
design to promote formation of α-configured products. Given the
generality of this enabling technology, we envisage that it will find
application in the preparation of complex acetals in a broader sense.
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This work was supported by the WWU Münster, the DFG (SFB 858,
and Excellence Cluster “Cells in Motion”) and the European Research
Council (ERC-2013-StG Starter Grant to RG).
Keywords: acetal • arylation • fluorine • stereoretention • sugars
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Entry for the Table of Contents
COMMUNICATION
Nicola Lucchetti, Ryan Gilmour*
Page No. – Page No.
Re-Engineering Chemical Glycosylation:
Direct, Metal-Free Anomeric O-Arylation
of Unactivated Carbohydrates
By re-engineering classic glycosylation, an orthogonal disconnection allows the acetal to be
forged directly from the reducing sugar without the need for substrate pre-organisation.
Engagement with stable aryliodonium salts facilitates a formal O−H functionalisation
reaction of the lactol. This constitutes a mild, metal-free O-arylation at ambient temperature.
The efficiency of the transformation has been validated using a variety of pyranoside and
furanoside monosaccharides in addition to biologically relevant di- and tri-saccharides.
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