Highly (Z)-Diastereoselective Synthesis of Trifluoromethylated exo-Glycals via Photoredox and Copper Catalysis

Article abstract of DOI:10.1021/acs.orglett.8b02891

Highly (Z)-diastereoselective approaches for the synthesis of trifluoromethylated exo-glycals by copper and photoredox catalysis are described. These complementary reactions are applicable to a wide range of methylene exo-glycals generated from the corresponding pyranoses and furanoses and give trifluoromethylated compounds under mild conditions in moderate to good yields. DFT calculations have allowed a rationalization of the observed (Z)-stereoselectivity.

Full text of DOI:10.1021/acs.orglett.8b02891

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Highly (Z)‑Diastereoselective Synthesis of Trifluoromethylated exo-
Glycals via Photoredox and Copper Catalysis
†
†
†
†
‡
́
́
́
̂
Christophe J.-M. Frederic, Jerome Cornil, Mathilde Vandamme, Lidia Dumitrescu, Abdellatif Tikad,
§
,†
́
̈
Raphael Robiette, and Stephane P. Vincent*
†
́
Universite de Namur, Laboratoire de Chimie Bio-Organic (CBO), rue de Bruxelles 61, 5000 Namur, Belgium
‡
́
́
́
̀
Laboratoire de Chimie Moleculaire et Substances Naturelles, Faculte des Sciences, Universite Moulay Ismail, Zitoune, Meknes
1120, Morocco
§
́
Universite Catholique de Louvain, Institute of Condensed Matter and Nanosciences, Place Louis Pasteur 1, 1348
Louvain-la-Neuve, Belgium
S
* Supporting Information
ABSTRACT: Highly (Z)-diastereoselective approaches for the syn-
thesis of trifluoromethylated exo-glycals by copper and photoredox
catalysis are described. These complementary reactions are applicable
to a wide range of methylene exo-glycals generated from the
corresponding pyranoses and furanoses and give trifluoromethylated
compounds under mild conditions in moderate to good yields. DFT
calculations have allowed a rationalization of the observed (Z)-
stereoselectivity.
exo-Glycals, such as the molecule 1-(Z),1 have been recognized
as important structural motifs for the inhibition of enzymes,
which include glycosidases and glycosyltransferases.2 In this
context, our group has reported several methods for preparing
phosphono-exo-glycals 2-(Z,E) (Figure 1) which could inhibit
UDP-glactopyranose mutase (UGM) and galactofuranosyl-
transferases 1 and 2 (Glf Ts).3−6 These enzymes are involved
in the biosynthesis of the Mycobacterium tuberculosis cell wall,
the causative agent of tuberculosis, and are validated targets for
the development of antitubercular drugs.7−10 The presence of
several fluorine atoms in close proximity within the scaffold of
the inhibitor (e.g., CF3−CF2, CF3 etc.) could likely greatly
enhance the affinity of the ligand for the host enzyme.11−13
Several nucleophilic,14−17 electrophilic,18−21 and radical
methods for C−CF3 bond formation have been described,22−24
including a variety of transition-metal-catalyzed25−27 and
photoredox28,29 approaches that directly form a Csp2−CF3
bond. It is noteworthy that the photoredox trifluoromethyla-
tion of enol ether or esters to generate α-trifluoromethylated
ketones was recently reported.30−32 However, for the
modification of carbohydrates, only one procedure of endo-
glycal trifluoromethylation is currently available (Figure 1).33
Moreover, beyond their interest as inhibitor scaffolds and key
intermediates in many synthetic applications, we were
interested in constructing exo-glycals such as 5 because the
synthetic method has to work stereoselectively on highly
functionalized molecules.
Herein, we describe the synthesis of trifluoromethylated exo-
glycals via photoredox and copper catalysis, two complemen-
tary methods. The stereoselectivity and the scope of this
transformation with regard to substrates and reaction
conditions will be discussed and the stereoselectivity
rationalized by DFT calculations.
We initiated this study by examining the copper-catalyzed
trifluoromethylation of the 1-methylidene-2,3,5-tri-O-benzyl-D-
arabinofuranoside 4a with Togni reagent 3a as the CF3 source
based on the methodologies developed by Gouverneur and
Sodeoka (Table 1).34,35 When the reaction was performed in
Received: September 10, 2018
Figure 1. exo-Glycals designed as enzyme inhibitors.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02891
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Organic Letters
Letter
Table 1. Optimization of the Copper-Catalyzed
Trifluoromethylation of 4a
Table 2. Optimization of Trifluoromethylation Reaction via
Photoredox Catalysis
a
a
b
entry
catalyst
solvent
time (h)
temp (°C)
yield (%)
c
1
2
3
4
5
6
CuCl
MeOH
i-PrOH
CDCl3
CDCl3
CDCl3
CHCl3
1
3
24
0.5
1
70
70
60
5
23
46
73 (64)
74
71
c
CuCl
CuI
CuI
CuI
CuI
d
e
120
d
CF3
120
b
entry
1
source
solvent
DMF
additive
catalyst
yield (%)
31
d
0.5
120
3b
[Ru(bpy)3]
(PF6)2
a
Reaction conditions: 4a (0.10 mmol), Togni reagent 3a (1.2 equiv),
copper catalyst (10 mol %), solvent (1 mL), argon atmosphere.
2
3
4
5
6
7
8
3b
3b
3b
3b
3b
3b
3b
3b
3a
3c
3c
DCM
[Ru(bpy)3]
(PF6)2
[Ru(bpy)3]
(PF6)2
[Ru(bpy)3]
(PF6)2
[Ru(bpy)3]
(PF6)2
[Ru(bpy)3]
(PF6)2
[Ru(bpy)3]
(PF6)2
[Ru(bpy)3]
(PF6)2
[Ru(bpy)3]
(PF6)2
[Ru(bpy)3]
(PF6)2
[Ru(bpy)3]
(PF6)2
[Ru(bpy)3]
(PF6)2
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
0
0
b
Yields determined by 19F NMR using hexafluorobenzene as an
c
d
internal standard. 20 mol %. Under microwave irradiations.
Isolated yield.
Toluene
THF
e
0
CH3CN
t-BuOH
DMSO
DMA
0
MeOH or i-PrOH in the presence of 20 mol % of CuCl, the
desired compound 5a-(Z) was obtained in 5 and 23% yield,
respectively (entries 1 and 2). This poor yield can be explained
by the generation of adduct 6 resulting from the solvent
addition on the anomeric carbon during the reaction. The
7
46
c
formation of 6 could be avoided using the conditions
58 (56)
36
́
developed by Szabo et al. and copper iodide (10 mol %)
d
9
DMA
58
2
in deuterated chloroform under microwave irradiation, giving
access to trifluoromethylated exo-glycal 5a-(Z) in 64% isolated
yield with an excellent Z-selectivity (entry 4). Neither the use
of nondeuterated chloroform nor the increase in reaction time
affected the yield (entries 5 and 6).
10
11
DMA
DMA
66
46
63
e
Encouraged by these results, we turned our attention to
photoredox-catalyzed trifluoromethylation28,29,33 in order to
compare the two methodologies. 1-Methylidene-2,3,5-tri-O-
benzyl-D-arabinofuranoside 4a was used as the model substrate
to investigate the reaction conditions. Under blue LED
irradiation, the influence of several parameters was evaluated:
mainly the trifluoromethylating reagent, the solvent, and the
catalyst (Table 2). In the presence of Umemoto reagent 3b in
DMF with [Ru(bpy)3](PF6)2 as photocatalyst, the product 5a-
(Z) was obtained in 31% yield in 2.5 h (entry 1). The study of
the solvent effect showed that the yields were considerably
better in highly polar solvents, such as DMSO and DMA
(entries 1−8). Then different CF3 sources, including Togni
reagent 3a and Umemoto reagent 3c, were investigated. While
only traces of 5a-(Z) were observed when 3a was employed
(entry 10), the use of Umemoto reagent 3c afforded 5a-(Z) in
66% (entry 11). Using only 1.5 equiv of reagent 3c
considerably reduced the reactivity (entry 12). The compar-
ison of classical photocalysts revealed that fac-Ir(ppy)3 was the
best choice to perform this trifluoromethylation (entry 14).
Increasing the reaction time (entry 9) or adding a base as
additive (entries 15 and 16) did not improve the reaction
efficiency. Importantly, the photocatalyst and blue LED
irradiation were both crucial for the success of this reaction
(entries 17 and 18). Thus, the optimal conditions were as
follows: fac-Ir(ppy)3 (1.2 mol %), Umemoto reagent 3c (2.05
equiv) in DMA under blue LED irradiation for 2.5 h at room
temperature.
12
DMA
13
14
15
16
17
3b
3c
3c
3c
3c
3c
DMA
DMA
DMA
DMA
DMA
DMA
c
86 (83)
K2HPO4
DIPEA
48
23
0
f
18
fac-Ir(ppy)3
0
a
Reaction conditions: 4a (0.10 mmol), CF3 source (2.05 equiv),
photocatalyst 1.2 mol %), solvent (1 mL), argon atmosphere, Kessil
b
H150-blue LED light source of 34W, 2.5 h. Yields determined by 19
F
c
NMR using hexafluorobenzene as an internal standard. Isolated yield.
16 h. 1.5 equiv of CF3 source. In the dark.
d
e
f
(paths A and B, Scheme 1), the scope of this transformation
was examined with various methylene exo-glycals 4. The
starting enol ethers 4a−j could be easily obtained in 60−75%
yield by methylenation of the corresponding lactone using the
Petasis reagent.37,38 The results, gathered in Scheme 1, show
that in all cases satisfactory yields were obtained by the two
technologies. The two reactions were found to be general as
satisfactory and comparable results were obtained with various
protective groups on the sugar ring (Ac, TBS, or Bn) and
different ring sizes (furanoses and pyranoses). However, in
most cases photoredox catalysis was found to be more efficient,
likely because of the milder reaction conditions required, as
compared to the Cu-catalyzed trifluoromethylations. Indeed,
the latter reaction was carried out in chloroform at 120 °C
under microwave irradiation, inducing probably a partial
degradation of the enol ethers 4. However, the effect of the
Having established the optimal reaction conditions for the
trifluoromethylation via copper and photoredox catalyses
B
DOI: 10.1021/acs.orglett.8b02891
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Letter
Scheme 1. Substrate Scope of the Trifluoromethylation of
Several exo-Glycals
Scheme 2. Hypothetical Mechanism of the
Trifluoromethylation via Copper (Path A) and Photoredox
a b
,
Catalysis (Path B)
fac-IrIII(ppy)3 into its excited state, fac-IrIII(ppy)3*, which
reacts with the Umemoto reagent 3c to afford the CF3 radical.
Subsequent addition of this species on 4 forms the compound
9, which is oxidized by fac-IrIV(ppy)3 to produce oxocarbenium
10. In 2014, Qing et al. reported a stereoselective
trifluoromethylation of styrenes using the ability of excited
photocatalysts to take part in single-electron transfers as well as
in triplet−triplet energy transfers (TTETs).39 Such TTETs
might also contribute to the stereoselectivity observed in our
study.
As previously mentioned, both methods afford the desired
compounds 5 with a high Z-stereoselectivity. In order to obtain
a clear understanding of the origin of this high stereoselectivity,
we set up a computational study. Calculations were carried out
at the B3LYP-D3/6-311+G**//B3LYP-D3/6-31+G* level of
theory, including a continuum description of THF as the
solvent (see the SI for computational details). We have first
explored the relative energy of E and Z isomers of the model
exo-glycals 5k and 5l (Figure 2). The obtained results indicate
that the Z exo-glycal 5k is more stable than its E isomer by 1.1
kcal/mol.
a
Reaction conditions: 4a (1 equiv), CF3 source (2.05 equiv),
photocatalyst 1.2 mol %), solvent (1 mL), under argon atmosphere,
b
Kessil H150-blue LED light source of 34W, 2.5 h. Isolated yield.
c
Bis-trifluoromethylation observed.
ligands of the Copper catalyst have not been investigated,
which could lead to milder conditions being found. Very
interestingly, the two reactions were found to be highly
diastereoselective since, for all screened carbohydrates (4a−j),
the sole isolated diastereomer always displays a Z config-
uration. Structural proof of all products (5a−j) has been
accomplished by 1D homonuclear NOE analyses that
systematically showed a NOE effect between the H-2 proton
of the carbohydrate ring and the exo-methylene proton H-1′
(Scheme 1).
Interestingly, the alkoxy group plays a determinant role in
this thermodynamic selectivity as shown by the results on exo-
glycal 5l, missing the alkoxy group, for which the E isomer is
now the most stable one (by 1.5 kcal/mol).
On the basis of these results and related studies,33,34
a
plausible mechanism is proposed in Scheme 2. For path A
(copper catalysis), it is reasonable to invoke that Togni reagent
3a is activated by CuCl via single-electron transfer generating
7. The CF3 radical is then released and can react with 4 to give
9, which is oxidized by a CuII species or 3a to generate 10.
Deprotonation of 10 leads to 5-(Z), whereas in the presence of
a nucleophile (for instance, ROH, see Table 1), the addition
on the carbocationic species is observed. For path B
(photoredox catalysis), the blue LED irradiation transforms
Figure 2. Computed relative energy (kcal/mol) of model exo-glycals.
C
DOI: 10.1021/acs.orglett.8b02891
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Organic Letters
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The observed stereoselectivity may thus be the result of a
thermodynamic equilibrium favoring the most stable Z isomer.
However, the stereoselectivity of trifluoromethylated exo-glycal
formation may also be determined along the reaction pathway
(kinetic selectivity). Accordingly, we performed a conforma-
tional analysis of the oxonium intermediates 10k and 10l.
Indeed, according to our postulated mechanism (see Scheme
2), the selectivity-determining step in the formation of 5 could
be the last step, the deprotonation of the oxonium
intermediates 10. Such an elimination requires that the C3−
H bond which is broken is parallel to the empty p orbital on
C2 (Figure 3) for stereoelectronic reasons. The computed
Figure 4. Rationale for observed Z selectivity with stabilizing (green)
and destabilizing (red) interactions (dipoles were obtained at the
B3LYP-D3/6-31+G* level of theory, and hydrogen bond interactions
were analyzed using NCI plot41 (see the Supporting Information for
details)).
sponding pyranoses and furanoses. The photoredox catalysis is
in general more efficient due to the milder conditions used
compared to the Cu-catalyzed reaction. Both methods afford
the desired compounds in moderate yield but with high Z-
stereoselectivity, which could be rationalized by computational
studies. Further studies are still required to answer to the
challenging question of generating, in a stereoselective manner
and high yield, tetrasubstituted CF3-containing enol ethers and
other ethylenic compounds. Work is in progress in our
laboratories to answer this important question.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02891.
Figure 3. Conformational analysis of 10k,l.
Experimental procedures and NMR spectra as well as
computational details (PDF)
conformational profile of 10k shows that the lower lying
conformers present the trifluoromethyl group on the same side
as the endocyclic oxygen atom (O1−C2−C3−C4 dihedral
angle close to 0 deg), i.e., those which will lead to the Z exo-
glycal after deprotonation and formation of the double bond. A
high Z kinetic selectivity is thus predicted for 5k. It is
interesting to note that, here again, the alkoxy group plays an
important role in determining selectivity since in absence of an
alkoxy group at the 2-position 10l no or a very low selectivity is
predicted. Indeed, in the latter case, the conformers leading to
E and Z exo-glycal are almost isoenergetic (<0.5 kcal/mol
difference).
AUTHOR INFORMATION
Corresponding Author
■
*Fax: (+32)81-72-45-17. E-mail: stephane.vincent@unamur.be
ORCID
̈
Raphael Robiette: 0000-0002-3449-565X
́
Stephane P. Vincent: 0000-0001-6258-9058
Notes
The authors declare no competing financial interest.
Thus, our calculations indicate that the Z isomer of 5 is the
most favored product from both a thermodynamic and a
kinetic point of view. A detailed electronic and structural
analysis of exo-glycals 5k,l and oxonium ions 10k,l (see the SI
for full results) reveals that this can be accounted for by the
stabilization of the Z isomer/conformer by hydrogen-bonding
interactions between the olefinic hydrogen atom and the
oxygen atom of the ether substituent. Furthermore, the E
isomer/conformer is destabilized by steric interactions
between the CF3 and the ether substituent, despite dipole−
dipole interactions which favor the E isomer/conformer as
compared to the Z one (Figure 4).40
ACKNOWLEDGMENTS
This work was funded by the F.R.S.-FNRS (Mandat de Charge
de recherche to A.T. and FRFC Nrant No. 2.4.625.08.F and
F.R.I.A. fellowship to C.J.-M.F.). R.R. is a Maitre de recherches
of the F.R.S.-FNRS. Computational resources have been
■
́
̂
́
provided by the Universite catholique de Louvain (CISM/
́
́
UCL) and the Federation Wallonie Bruxelles (CECI) funded
by the F.R.S.-FNRS under Convention No. 2.5020.11.
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