Stereocontrolled Synthesis of 2-Fluorinated C-Glycosides

Article abstract of DOI:10.1002/ejoc.201800618

A systematic study of the addition of C-based nucleophiles to fluorinated lactones based on 2-deoxy-2-fluoro-d-pyranoses is disclosed. This high yielding, α-selective process was found to be independent on the nature or configuration [(R)-C(sp³)–F, (S)-C(sp³)–F] of the substituent at C2. Representative, fluorinated analogues of Trehalose, Carminic acid, and the spirocyclic cores of Tofogliflozin and Papulacandin D are also reported. These glycomimics constitute a valuable series of ¹⁹F NMR active probes for application in structural biology.

Full text of DOI:10.1002/ejoc.201800618

A Journal of
Accepted Article
Title: Stereocontrolled Synthesis of 2-Fluorinated C-Glycosides
Authors: Anna Sadurní and Ryan Gilmour
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800618
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10.1002/ejoc.201800618
European Journal of Organic Chemistry
COMMUNICATION
Stereocontrolled Synthesis of 2-Fluorinated C-Glycosides
Anna Sadurní,[a] and Ryan Gilmour*[a,b]
neighbouring groups.[13] Despite the rich body of literature
Abstract:
A
systematic study of the addition of C-based
describing fluoro-C-glycosides and fluoro-carbasugars,[14]
strategies that simultaneously exploit C-glycoside formation and
fluorine installation at C2 appear conspicuously absent from the
glycosylation repertoire. To address this, a systematic study of
the addition of various C-based nucleophiles to fluorinated
lactones based on 2-deoxy-2-fluoro-D-pyranoses is disclosed.
nucleophiles to fluorinated lactones based on 2-deoxy-2-fluoro-D-
pyranoses is disclosed. This high yielding, α-selective process was
found to be independent on the nature or configuration [(R)-C(sp3)-F,
(S)-C(sp3)-F] of the substituent at C2. Representative, fluorinated
analogues of Trehalose, Carminic acid, and the spirocyclic cores of
Tofogliflozin and Papulacandin
D are also reported. These
glycomimics constitute a valuable series of 19F NMR active probes
for application in structural biology.
The diversity of mammalian and bacterial “glycospace” provides
a rich platform from which to design tailored glycomimetics for
applications in medicine.[1] Through relatively modest structural
modifications, the natural role of complex carbohydrates in
molecular recognition events can be harnessed for therapeutic
purposes.[2] Subtle, often single site, alterations are sufficient to
markedly enhance a biological response[3] or even to engage
pathways that elude the native sugars.[4] Of the plethora of
structural modifications employed in glycomimic design,
formation of C-glycosides is arguably one of the most common
(Figure 1). These scaffolds mitigate the intrinsic risk of enzymatic
degradation by replacing the C(sp3)-O bond of the glycosidic link
with a more robust C(sp3)-C(sp3/sp2/sp) bond. A number of
successful pharmaceuticals contain this structural feature,
including a series of SGLT-2 inhibitors such as Dapagliflozin
(1).[5] It is also important to note that the aryl C-glycoside motif is
found in numerous natural products,[6] including Carminic acid
(2) and Papulacandin D (3). Whilst this approach is logical, the
intrinsic challenges associated with the generation of crowded,
often quaternary,[7] stereocentres must be considered.
Figure 1. Selected examples of C-glycosides.
Specifically, benzylated lactones based on D-glucose and D-
galactose were investigated in which the substituent at C2 was
varied (X = F, OBn and H). In the case of the fluorinated
electrophiles, both the gluco- and manno-configured systems
were studied to assess any possible influence of the
configuration on reaction efficiency. The nucleophile series was
composed of simple organometallic species that were either
commercially available or could be easily prepared by simple
halogen-metal exchange (Figure 2, lower).
A second strategy in devising metabolically robust glycomimics
is the strategic OH → F substitution at C2 of pyranoside glycosyl
donors.[8] This seemingly subtle modification introduces several
notable features that include enhanced hydrolytic stability,[9]
retention of the electronegativity intrinsic to the native structure,
and the ability to direct glycosylation selectivity.[3,4,8,10] A classic
bioisostere of the hydroxyl group,[11] fluorine also functions as a
valuable 19F NMR probe[12] (Figure 2, upper) and allows various
physicochemical parameters to be modulated such as
lipophilicity, metabolic stability, and the pKa values of
[a]
[b]
A. Sadurní, Prof. Dr. R. Gilmour
Organisch-Chemisches Institut
Westfälische Wilhelms-Universität Münster
Corrensstraße 40, 48149 (Germany)
E-mail: ryan.gilmour@uni-muenster.de
http://www.uni-muenster.de/Chemie.oc/gilmour/index.html
Prof. Dr. R. Gilmour
Excellence Cluster EXC 1003, Cells in Motion
Westfälische Wilhelms-Universität Münster
Figure 2. An overview of the scope of this study.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201800618
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COMMUNICATION
Preliminary studies to assess the comparative efficiency and
selectivity of additions were performed with lactones L1[15] and
L2 (X = F and OBn, respectively. Table 1). For this purpose,
commercially available organo-lithium reagents were employed
(Nu-1 = sec-BuLi, Nu-2 = n-BuLi and Nu-3 = MeLi).
Reactions were performed in THF at -78 °C for 0.5 h prior to
being quenched, and the α:β ratio of the product was
determined by 19F NMR spectroscopy and NOE experiments
of the crude mixture.[4] Importantly, care must be exercised
during the work-up to prevent epimerisation at C2. This was
observed when utilising MeOH and furnished an inseparable
mixture of gluco- and manno-configured analogues. This
issue could be easily circumvented by performing an aqueous
work up (Full details in the SI).
Table 1. Exploring the effect of C2-substituent and nucleophile on C-
glycosylation.[a]
As is immediately evident from Table 1, the addition of
nucleophiles Nu-1, Nu-2 and Nu-3 to the fluorinated lactone L1
proceeded smoothly to deliver the corresponding products
exclusively as the α-anomer (>20:1, up to 88% yield, entries 1, 2
and 3) irrespective of the substituent at C2. This clear
manifestation of the anomeric effect[16] would prove useful in
subsequent transformations (vide infra). Comparable behaviour
was also observed with the 2-OBn derivative L2 (entries 4, 5
and 6) where the α-anomer predominated and synthetically
useful yields were observed (up to 94%).
Entry
1
Nucleophile
(Nu)
Product
Yield
(%)
Anomeric
α:β ratio[b]
Encouraged by these preliminary results, the nucleophile scope
was extended to include aryl lithium (Nu-4), lithium enolate (Nu-
5) and allyl magnesium species (Nu-6) (Table 2). Moreover,
since L1 and L2 displayed closely similar behaviour in the initial
investigation, 2-deoxy lactones (L3) were evaluated. Since
hydrogen is often substituted by fluorine in molecular editing
processes, this transformation may provide facile access to
another class of bioisosteres.[11] For completeness, the manno-
configured lactone L4 was included in this comparison to assess
the effect of the configuration at C2 on the reaction outcome.
Initially, the independent additions of Nu-4, Nu-5 and Nu-6 to
the 2-deoxy lactone L3 were performed (entries 1, 2 and 3).
[c]
Nu-1
Nu-2
60
70
>20:1
2
3
4
5
6
>20:1
>20:1
Nu-3
Nu-1
Nu-2
Nu-3
88
85
92
94
Whilst employing Nu-5 and Nu-6 delivered the expected
products (α:β>20:1, entries 2 and 3, respectively), double
addition was observed with the aryl lithium Nu-4 (entry 1). In
contrast, the gluco-configured lactone L-1 was smoothly
converted to the expected α-product, irrespective of the
nucleophile employed (entries 4, 5 and 6; 97%, 96% and 90%
yield, respectively). Inverting the configuration of the C2 fluorine
had no effect on selectivity, and again furnished the product
glycosides in good yields (99%, 95%, 91% yield; entries 7, 8 and
9, respectively). The 2-deoxy-galactose derived lactone L-5
proved troublesome under the general condition of the study.
Double addition was observed with Nu-4 (entry 10), where with
Nu-5 and Nu-6, a significant reduction in yield was noted (45%
and 53%, entries 11 and 12, respectively). Reintroducing the
fluorine substituent at C2 was found to significantly enhanced
the reaction efficiency (89%, quant., 94% yield, entries 13, 14
and 15, respectively.)
[c]
>20:1
>20:1
>20:1
[a] Reactions were performed with the specified lactone (LX) (0.1 mmol,
1.0 eq.) and the specified nucleophile (0.11 mmol, 1.1 eq) in 0.58 mL of
THF. The lithium enolate Nu-5 was obtained from tert-butyl acetate and
LHMDS. [b] Selectivity determined by 19F NMR analysis of the crude
reaction mixture; [c] 1:1 mixture of diastereomers with respect to the sec-
butyl moiety.
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10.1002/ejoc.201800618
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COMMUNICATION
[a] Reactions were performed with the specified lactone (LX) (0.1 mmol,
1.0 eq.) and the specified nucleophile (0.11 mmol, 1.1 eq) in toluene:THF
(2:1) or THF. [b] Mixture of product and double addition (d.a.); [c] Mixture
Table 2. Exploring the effect of the lactone on C-glycosylation.[a]
of product and opened form of the product [d] Selectivity determined by 19
NMR analysis of the crude reaction mixture.
F
Having validated this class of fluorinated lactones as competent
electrophiles en route to C-glycosides, a series of natural and
non-natural products were prepared employing L1 as a common
foundation (Scheme 1). In the preparation of a fluorinated
analogue of trehalose (6), L1 was smoothly converted to 4 by
the addition of MeLi at -78 °C in THF. The expected, α-
configured product was isolated in quantitative yield, before
being processed to the disaccharide core. This was achieved by
standard glycosylation conditions employing the TCA donor 5
(TMSOTf, CH2Cl2) to furnish the fluorinated glycomimetic 6
(30%) as a mixture of diastereoisomers (α:β 1.8:1). Next, a
masked analogue of Carminic acid (9) was prepared by
exposure to the appropriate aryl lithium reagent with
concomitant reduction with Et3SiH and BF3•Et2O. This first
fluorinated analogue of Carminic acid 9 was isolated in 80%
yield, again with exclusive β selectivity. By extension, an
addition / deprotection / cyclisation sequence provided an
efficient and α-selective route to compound 11, which is a
structural analogue of the cores of Tofogliflozin (12) and
Papulacandin D (3). Finally, the addition of allyl magnesium
bromide, followed by hydroboration / oxidation generated the
alcohol 14. When exposed to CSA, this material readily cyclised
to furnish the fluorinated spiro-systems 15 further underscoring
the versatility of L1 as a starting material.
Entry
Lactone
Nucleophile
(Nu)
Yield
(%)
Anomeric
α:β ratio[d]
1
2
3
Nu-4
Nu-5
Nu-6
62[b]
99
3(d.a.):1:1
>20:1
>20:1
62
4
5
6
Nu-4
Nu-5
Nu-6
97
90
96
>20:1
>20:1
>20:1
7
8
9
Nu-4
Nu-5
Nu-6
99
95
91
>20:1
>20:1
>20:1
10
11
12
Nu-4
Nu-5
Nu-6
d.a.
45
-
>20:1
>20:1
53[c]
13
14
15
Nu-4
Nu-5
Nu-6
89
quant.
94
>20:1
>20:1
>20:1
Scheme 1. a) MeLi, THF, -78 °C, 30 min. quant. α:β 1:0; b) 4, 5, TMSOTf,
CH2Cl2, -78 °C to r.t. overnight, 30%, αα:αβ 1.8:1; c) n-BuLi, ArBr (see SI),
THF, -78 °C, 1 h, 73%, α:β 1:0; d) Et3SiH, BF3•Et2O, CH2Cl2:MeCN, -10 °C to
r.t., 3h, 80%, α:β 0:1; e) n-BuLi, ArBr (see SI), THF:toluene (1:2), -78 °C, 1 h,
73%, α:β 1:0; f) Et3SiH, BF3•Et2O, MeCN, -40 °C to 0 °C, 2h, 69%, α:β 1:0; g)
Allyl magnesium bromide, THF, -78 °C, 30 min., 96%, α:β 1:0; h) 9-BBN, H2O2
(30% in H2O), NaOH (3 M aq.), overnight, r.t., 50%; i) CSA, dioxane, 80 °C, 8
h, 53%, α:β 1:1.
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10.1002/ejoc.201800618
European Journal of Organic Chemistry
COMMUNICATION
8359;
(d)
N.
A.
Meanwell,
J.
Med.
Chem.
2018,
Motivated by rapid advances in glycobiology, a series of
glycomimetics have been prepared that exploit the stability
advantages of C-glycosides and 2-fluorosugars over the native
systems. This study demonstrates that whilst the OBn → F
substitution at C2 is extremely well tolerated, the fluorinated
lactones more robust towards the addition of organometallic
reagents than the corresponding 2-deoxy lactones. The α-
selectivity observed for the 2-OBn and 2-F sugars can be
exploited in subsequent transformations. In this study, a series
of natural and non-natural product analogues have been
prepared in a stereoselective manner. Exploiting these systems
in the context of chemical biology will be the focus of future
efforts from this laboratory.
DOI:10.1021/acs.jmedchem.7b01788.
[12] H. Chenm, S. Viel, F. Ziarelli, L. Peng, Chem. Soc. Rev. 2013, 42,
7971-7982.
[13] (a) K. Müller, C. Faeh, F. Diederich, Science 2007, 317, 1881-1886; (b)
S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev.
2008, 37, 320-330.
[14] E. Leclerc, X. Pannecoucke, M. Ethève-Quelquejeu, M. Sollogoub,
Chem. Soc. Rev. 2013, 42, 4270-4283.
[15] The fluorinated lactone was prepared according to D. Waschke, Y.
Leshch, J. Thimm, U. Himmelreich, J. Thiem, Eur. J. Org. Chem. 2012,
948-959.
[16] (a) Kirby, A. J. The Anomeric Effect and Related Stereoelectronic
Effects at Oxygen, Springer Verlag, New York, 1982; (b) C. Thiehoff, Y.
P. Rey, R. Gilmour, Isr. J. Chem. 2017, 57, 92-100.
Experimental Section
Full experimental details are provided in the supporting information.
Acknowledgements
This work was supported by the WWU Münster, the Deutsche
Forschungsgemeinschaft (DFG): “Cells in Motion, Cluster of
Excellence” ; and the European Research Council (ERC-2013-
StG Starter Grant to RG - Project number 336376-ChMiFluorS);
Initial Training Network, FLUOR21 (AS), funded by the FP7
Marie Curie Actions of the European Commission (FP7-
PEOPLE-2013-ITN-607787).
Keywords: carbohydrate • fluorine • glycosides • bioisostere •
natural products
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COMMUNICATION
Entry for the Table of Contents
Organofluorine chemistry
Anna Sadurní, Ryan Gilmour*
Page No. – Page No.
Stereocontrolled Synthesis of 2-
Fluorinated C-Glycosides
A study of the addition of C-based nucleophiles to fluorinated lactones based on 2-
deoxy-2-fluoro-D-pyranoses is disclosed. This high yielding, α-selective process
was found to be independent on the nature or configuration of the substituent at C2.
Representative, fluorinated analogues of Trehalose, Carminic acid, and the
spirocyclic cores of Tofogliflozin and Papulacandin D are also reported.
This article is protected by copyright. All rights reserved.