Unprecedented 3-O-methyl-3-C-trifluoromethyl-d-ribono- (and l-lyxono)-γ-lactones synthesized by nucleophilic trifluoromethylation of d-hexose-derived cyclic ketones

Article abstract of DOI:10.1016/j.jfluchem.2016.05.002

3-O-Methyl-3-C-trifluoromethyl-d-ribono-(and l-lyxono)-γ-lactones have been prepared from protected d-hexoses (gluco, galacto) by multi-step routes from d-glucose. The synthetic strategy includes the following steps: regioselective oxidation, nucleophilic trifluoromethylation with the Ruppert-Prakash reagent of 3-keto hexofuranose derivatives attacked stereoselectively from the less hindered face, protective group manipulations, and regioselective oxidation of a hemiacetalic hydroxyl. Base-catalyzed hydrolysis of two related d-ribonolactones afforded 3-O-Me-3-C-CF₃-d-ribonic acid.

Full text of DOI:10.1016/j.jfluchem.2016.05.002

Accepted Manuscript
Title: Unprecedented
3-O-methyl-3-C-trifluoromethyl-D-ribono- (and
L-lyxono)-␥-lactones synthesized by nucleophilic
trifluoromethylation of D-hexose-derived cyclic ketones
¨
Author: Siwar Ghannay Jihed Brahmi Kaıss Aouadi Moncef
Msadek Jean-Pierre Praly
PII:
S0022-1139(16)30104-X
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2016.05.002
FLUOR 8772
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Revised date:
Accepted date:
24-3-2016
28-4-2016
1-5-2016
¨
Please cite this article as: Siwar Ghannay, Jihed Brahmi, Kaiss Aouadi, Moncef
Msadek, Jean-Pierre Praly, Unprecedented 3-O-methyl-3-C-trifluoromethyl-
D-ribono- (and L-lyxono)-rmgamma-lactones synthesized by nucleophilic
trifluoromethylation of D-hexose-derived cyclic ketones, Journal of Fluorine
Chemistry http://dx.doi.org/10.1016/j.jfluchem.2016.05.002
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Unprecedented 3-O-methyl-3-C-trifluoromethyl-D-ribono-(and L-lyxono)-γ-lactones
synthesized by nucleophilic trifluoromethylation of D-hexose-derived cyclic ketones
Siwar Ghannay,a Jihed Brahmi,a Kaïss Aouadi,a,* Moncef Msadeka and Jean-Pierre Pralyb,*
Université de Monastir, Laboratoire de Synthèse Hétérocyclique, Produits Naturels et
a
Réactivités, Faculté des Sciences de Monastir, Avenue de l’Environnement, 5000 Monastir,
Tunisia.
b
Université de Lyon, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires,
UMR CNRS 5246, Laboratoire de Chimie Organique 2-Glycochimie, Bâtiment Curien, 43
boulevard du 11 Novembre 1918, F-69622 Villeurbanne, France.
*Corresponding author

Graphical abstract
Highlights
 Preparation of 3-CF3 glyconolactones by multi-step routes from D-glucose.
 The introduction of CF3 group was achieved by nucleophilic trifluoromethylation.
 The nucleophilic trifluoromethylation carried out by using Ruppert-Prakash
reagent.
Abstract
3-O-Methyl-3-C-trifluoromethyl-D-ribono-(and L-lyxono)-γ-lactones have been prepared from
protected D-hexoses (gluco, galacto) by multi-step routes from D-glucose. The synthetic
strategy includes the following steps: regioselective oxidation, nucleophilic
trifluoromethylation with the Ruppert-Prakash reagent of 3-keto hexofuranose derivatives
attacked stereoselectively from the less hindered face, protective group manipulations, and
regioselective oxidation of a hemiacetalic hydroxyl. Base-catalyzed hydrolysis of two related
D-ribonolactones afforded 3-O-Me-3-C-CF3-D-ribonic acid.
Keywords:
Nucleophilic
trifluoromethylation/
Lactones/
D-Glucose/
Ketones/
Stereoselectivity

Introduction
Glyconolactones which typically display several hydroxyl groups bound to chiral centers
constitute a valuable family of synthons suitable for diverse chemical modifications and they
have found broad applications as building blocks for the synthesis of various derivatives, such
as C-glycosyl compounds, aza-, thio-, and carbasugars (sugar analogs with a N-, S-, or C-
atom in the ring), L-sugars, natural products, surfactants and related polymers [1]. For
example, α-glucosidase inhibitors 1-deoxynojirimycin (DNJ) and 1-deoxymannojirimycin
(DMJ) are significant bioactive natural products synthesized from L-gulono-1,4-lactone and
D-mannono-1,4-lactone, respectively [2]. We reported previously a multi-step approach from
D-glucose toward analogues of (2S,3R,4S)-4-hydroxyisoleucine, a naturally occurring
insulinotropic amino acid [3]. For this purpose, and as previously shown by Fleet et al. when
exploring the synthesis of sugar-derived amino acids [4], glyconolactones with a free 2-OH
were key intermediates which were converted to the corresponding triflates. Upon treatment
with NaN3, they afforded the corresponding azido derivatives stereospecifically through SN2
displacement [4]. Subsequent catalytic reduction followed by base-catalyzed hydrolysis
delivered the desired amino acids.
We reasoned that the synthetic potential of glyconolactones could be enhanced further by
modifying their C-3 carbon atom. A common mean to achieve this goal involves the
nucleophilic attack of a keto group installed at C-3 [5]. Although this synthetic approach
allowed for the introduction of various groups (for example: methyl [6], dichloromethyl [7],
nitromethyl [8], trifluoromethyl [9a-b], and other [10]), 3-trifluoromethylated glyconolactones
appear to be unprecedented to date. A synthesis of 3-trifluoromethylated -lactones with four
asymmetric centers via sequential [3,3]-Ireland-Claisen rearrangement and iodolactonisation
has been reported [11]. Related multi-step routes giving access to -trifluoromethyl--
lactones have been developed [12].
Owing to its unique properties, the CF3 functionality (high electronegativity, higher energy of
C-F bond, low polarizability combined with a high ionization potential) if present in organic
molecules convey metabolic stability, enhanced binding interactions, lipophilicity, changes in
physical properties with a profound effect on its bioactivity and bioavailability [13]. Found in
many bioactive molecules and commercial drugs/specialities, the CF3 group is a privileged
structural motif in medicinal chemistry and other fields [14,15], so that many strategies
toward trifluoromethyl-containing molecules are being developed nowadays [16]. Actually,
trifluoromethylated amino acids have found innovative and valuable applications in
biochemistry and medicinal chemistry [17]. Because of the hydrophobicity of fluorocarbon

chains, they have the capacity to enhance helical protein stability, increasing the protein-
protein interaction’s (PPIs) selectivity in peptide and protein designs [18]. Fluorinated amino
acids also play an important role in the control of blood pressure, allergies and tumor growth
[19].
We herein describe the synthesis of unprecedented 3-O-methyl-3-C-trifluoromethyl-D-
ribono(and L-lyxono)-1,4-lactones and (2R,3R,4R)-3-O-methyl-3-C-trifluoromethyl-D-ribonic
acid from 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose that might be of interest as
precursors of trifluoromethylated unnatural amino acids.
Result and discussion
As depicted in Scheme 1, our syntheses started from 1,2:5,6-di-O-isopropylidene-α-D-
glucofuranose (diacetone glucose), a cheap commercially available substrate amenable to
regioselective oxidation to afford the 3-oxo derivative 2a [20]. Diacetone glucose was
converted into its D-galacto-configured analog using a known procedure [21]. It has been
reported that nucleophilic trifluoromethylation carried out with CF3SiMe3 (Ruppert-Prakash
reagent) and catalytic TBAF in anhydrous THF occurred stereoselectively on the convex face
of the ketone 2a to afford 1,2:5,6-di-O-isopropylidene-3-C-trifluoromethyl-3-O-
trimethylsilyl-α-D-allofuranose [9a]. In our case, we used 0.5 eq of TBAF (1.0 M solution in
THF) to access directly to the 3-O-unprotected 3a in good yield without isolating the silylated
intermediate. Under our conditions, 2b was readily converted into 1,2:5,6-di-O-
isopropylidene-3-C-trifluoromethyl-α-D-gulofuranose 3b in 82% yield. The O-methylation
[22] of 3a,b and the regioselective acid-catalyzed hydrolysis of the 5,6-O-isopropylidene
acetals in 4a,b afforded the precursors 5a,b in 98 and 90% yields, respectively [23].Their
oxidative cleavage in the presence of NaIO4 delivered the alcohols 6a,b in 72 and 51%,
respectively.
In 1D NOE experiments carried out with a CDCl3 solution of 4a (Figure 1), selective
irradiation of the methoxy group increased significantly the resonances of the 4-H proton
(0.53%), of the methyl groups in position 1 and 5 (0.31% and 0.28%, respectively) and to a
lower extent of the 5-H proton (0.10%). This confirmed that the methoxy group and the 4-H
proton were on the same side, which entailed a (R) configuration at C-3. Similarly, the 1D
NOE experiments carried out for 4b supported the proposed structure (Figure 1). The
nucleophilic attack of the CF3 group on the less hindered face (i.e. to the side opposite to the
1,2-O-isopropylidene acetal) was further confirmed by 2D NMR spectroscopy. The structure
of 6b, unambiguously determined by a single crystal X-ray analysis (Figure 2)[24], showed

also that the nucleophilic addition of the CF3 group occurred from the less hindered face.
These observations are consistent with the literature [9].
The benzylation of the compounds 6a,b afforded the compounds 7a,b which were subjected
to acid-catalyzed hydrolysis to cleave the 1,2-O-isopropylidene acetals. Upon treatment by
bromine [25], simultaneous debenzylation and regioselective oxidation of the hemiacetals
occurred to afford 3-C-trifluoromethyl-D-ribono(L-lyxono)-1,4-lactones 8a,b with free 2-OH
and 5-OH groups (Scheme 1). Also, the tosylation of primary alcohol in 6a with p-toluene
sulfonyl chloride afforded the compound 9a in 98% yield. This latter was subjected to similar
modifications at the 1- and 2-positions to afford 3-C-trifluoromethyl-γ-lactone 10a in 77%
yield. Finally, base-catalyzed hydrolysis of 3-C-trifluoromethyl-D-ribono-1,4-lactones 8a and
10a afforded in good yield 3-O-methyl-3-C-trifluoromethyl-D-ribonic acid 11a (Scheme 1).
On the other hand, the substitution of the alcohol function of compound 6a with iodine
(Garegg’s conditions) afforded the intermediate 12a in 85% yield (Scheme 2). When
subjected to catalytic hydrogenation in the presence of Pd/C (10%) followed by deprotection
of the 1,2-O-isopropylidene acetal and oxidation of the anomeric hemiacetalic alcohol, 12a
afforded the 3-O-methyl-3-C-trifluoromethyl-5-deoxy-D-ribono-1,4-lactone 14a in 38% yield.
A number of heteronuclear couplings between the fluorine nuclei and the neighbouring
hydrogen and carbon atoms can be seen in the NMR spectra of the studied compounds. As
1
expected the CF3 and C-3 carbon resonances appeared as quartets due to the JC,F (285Hz)
2
1
13
and JC,F (28Hz) couplings. In the H and C NMR spectra, the OMe group often appeared
5
4
3
as a quartet due to weak JF,H and JF,C couplings (1.5Hz). A JC,F coupling (2.4 Hz)
appeared for C-2 in 14a. A long-range coupling 4JC,F (2.5 Hz) was often detected for the C-5
signal in D-ribo-, and L-lyxo-configured products, where the CF3 group and C-are syn-(D-
ribo) and trans-diaxially (L-lyxo) disposed.
Conclusion
In conclusion, starting from 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose, a cheap
derivative of D-glucose, we have developed multi-step syntheses toward four 3-O-methyl-3-
C-trifluoromethyl-D-ribono(L-lyxono)-1,4-lactones and 3-O-methyl-3-C-trifluoromethyl-D-
ribonic acid. The stereoselective introduction of CF3 group was achieved by nucleophilic
trifluoromethylation taking place from the convex less hindered face of ketones. The
conversion of γ-lactone with a free 2-OH group into amino-acids being well documented,
further developments of this strategy for synthesizing trifluoromethylated unnatural amino
acids, now under investigation, will be reported in due course.

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Figure 1. 1D NOE enhancements measured for 4a (left) and 4b (right).

Figure 2.ORTEP representation of the crystal structure of compound 6b [24].

Scheme 1: Reagents and conditions (a) PDC, Ac2O, CH2Cl2; (b) CF3SiMe3, THF, TBAF, rt; (c) 1- CH3I, KOH,
Bu4N+Br-, acetone, 0ºC; (d) AcOH/H2O, 60 ºC; (e) 1- NaIO4, H2O, rt; 2- NaBH4, H2O, rt; (f) TsCl, pyridine, rt;
(g) 1- HCl (1N), 70 ºC; 2- Br2, BaCO3, dioxan/H2O, rt; (h) LiOH.H2O, AcOH, rt; (i) BnBr, NaH, DMF, rt.

Scheme 2: Reagents and conditions (a) I2, PPh3, imidazole, toluene, 110 ºC; (b) 1- H2, Pd-C (10%), MeOH,
rt; 2- HCl (1N), 70 ºC; 3- Br2, BaCO3, dioxan/H2O, rt.