Stereoarrayed CF3-Substituted 1,3-Diols by Dynamic Kinetic Resolution: Ruthenium(II)-Catalyzed Asymmetric Transfer Hydrogenation

Article abstract of DOI:10.1002/anie.201600812

CF₃-substituted 1,3-diols were stereoselectively prepared in excellent enantiopurity and high yield from CF₃-substituted diketones by using an ansa-ruthenium(II)-catalyzed asymmetric transfer hydrogenation in formic acid/triethylamine. The intermediate mono-reduced alcohol was also obtained in very high enantiopurity by applying milder reaction conditions. In particular, CF₃C(O)-substituted benzofused cyclic ketones underwent either a single or a double dynamic kinetic resolution during their reduction. Doubling up: A double dynamic kinetic resolution is described for the ansa-ruthenium(II)-catalyzed asymmetric transfer hydrogenation of diketones in formic acid/triethylamine to yield the title compounds, displaying a stereotriad, in excellent stereopurity. The intermediate mono-reduced alcohols were isolated in very high enantiopurity by using milder reaction conditions.

Full text of DOI:10.1002/anie.201600812

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201600812
German Edition: DOI: 10.1002/ange.201600812
Asymmetric Catalysis
Stereoarrayed CF3-Substituted 1,3-Diols by Dynamic Kinetic
Resolution: Ruthenium(II)-Catalyzed Asymmetric Transfer
Hydrogenation
Andrej Emanuel Cotman, Dominique Cahard, and Barbara Mohar*
Abstract: CF3-substituted 1,3-diols were stereoselectively pre-
pared in excellent enantiopurity and high yield from CF3-
substituted diketones by using an ansa-ruthenium(II)-cata-
lyzed asymmetric transfer hydrogenation in formic acid/
triethylamine. The intermediate mono-reduced alcohol was
also obtained in very high enantiopurity by applying milder
reaction conditions. In particular, CF3C(O)-substituted benzo-
fused cyclic ketones underwent either a single or a double
dynamic kinetic resolution during their reduction.
alkyl chains. An ensuing potential application of these
fluorine-containing alcohols would be as organocatalysts in
organic transformations or as ligands in coordination chemis-
try.[3] In particular, CF3-substituted 1,3-diols could offer an
interesting opportunity, however a literature search revealed
very few known related compounds in optically active form.[4]
Clearly, the access to such enantiopure diols is still a challenge
and it has prompted our interest in this research area.
Highlighted in 2006 was our report on the efficient access
to a-substituted a-fluoroalkyl carbinols (monoalcohols) by
asymmetric transfer hydrogenation (ATH) of the correspond-
ing ketones using HCO2H/Et3N mixtures.[5] Our first-gener-
P
rogress towards advanced asymmetric synthetic method-
ologies broadens the access to diversified fluorine-containing
chiral structures with novel properties.[1] For example, the
side-chain of the selective monoamine oxidase A inhibitor,
ation
Noyori-type
chiral
ATH
catalysts
(A;
[RuII(R2NSO2DPEN)(h6-arene)]; R2NSO2DPEN = (S,S)- or
(R,R)-N-(dialkylsulfamoyl)-1,2-diphenylethylenediamine;
Figure 2) enabled the preparation, at 258C, of fluorinated
alcohols in high enantiomeric excesses (94–99%) and yields
(> 98%) by employing a substrate/catalyst molar ratio (S/C)
of 200. Moreover, our recently developed second- and third-
generation ansa-RuII-type complexes (B, C, and D) proved to
be very effective in the ATH of diaryl diketones.[6]
befloxatone, features
a
stereogenic a-trifluoromethyl
hydroxymethyl moiety,[2a] and an a-trifluoromethyl 1,3-gly-
colyl stereotriad is embedded in an intermediate of the NMR
molecular probe, 19F-labeled bafilomycin A1, a vacuolar-type
ATPase inhibitor[2b] (Figure 1). The stereoarrangement in
befloxatone allows formation of strong hydrogen bonds
between the hydroxy group and the enzyme active site,
hence increasing the desirable interaction versus that of the
nonfluorinated isosteric analogue. Indeed, alcohols having
a CF3 substituent in close proximity to the hydroxy function
possess an enhanced Brønsted acid character owing to the
characteristic electron-withdrawing property of perfluoro-
Figure 2. Enantiopure N-R2NSO2-[(S,S)-DPEN]-based ruthenium(II)
complexes.
Figure 1. Examples of chiral CF3-substituted alcohols.
Hereafter, we present our investigation results on the
preparation of CF3-substituted 1,3-diols by employing B and
D, which incorporate respectively enantiopure DPEN-SO2N-
(Me)(CH2)3(h6-Tol) and piperidino-SO2DPEN-(CH2)3(h6-Ph)
conjugate ligands. The advantage of these advanced
ruthenium(II) catalyst designs resides in their enhanced
activity and longevity over that of the first-generation. They
are generated in situ from the shelf-stable m-chlorido
ruthenium(II) dimers upon treatment with the HCO2H/
Et3N medium.
[*] A. E. Cotman, Dr. B. Mohar
National Institute of Chemistry
Hajdrihova 19, 1000 Ljubljana (Slovenia)
E-mail: barbara.mohar@ki.si
Homepage: http://www.ki.si
A. E. Cotman
Faculty of Chemistry and Chemical Technology
University of Ljubljana (Slovenia)
Dr. D. Cahard
UMR CNRS 6014 C.O.B.R.A., UniversitØ et INSA de Rouen
1 rue Tesni›re, 76821 Mont Saint Aignan (France)
Readily prepared in high yields by Claisen condensation
of the aryl ketone with ethyl trifluoroacetate, the basic test
substrate 4,4,4-trifluoro-1-phenyl-1,3-butanedione (1a) was
subjected to ATH in HCO2H/Et3N (5:2) using D. Because of
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201600812.
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the dissymmetry of this activated 1,3-diketone, the reduction
Accordingly, a series of 4,4,4-trifluoro-1-(het)aryl-1,3-
to either the monoalcohol (S)-2a or diol anti-3a was deemed
possible (Scheme 1). Both catalyst loading (S/C = 2000) and
butanediones (1b–h) was screened for this transformation
(Table 1). The corresponding diols anti-3b–h were obtained in
Table 1: The ansa-RuII-catalyzed ATH of various 4,4,4-trifluoro-1-
(het)aryl-1,3-butanediones (1).[a]
(Het)Ar
Cat.
anti/syn[b]
ee [%][b]
Ph (1a)
Ph (1a)
B
D
D
D
D
B
D
D
D
D
97:3
98
98.5:1.5 (>99.9)
98.5:1.5 (>99.9)
98.5:1.5 (>99.9)
98:2 (>99.9)
98:2
98.5:1.5 (>99.9)
98.5:1.5 (>99.9)
99:1 (>99.9)
99:1 (>99.9)
99 (>99.9)
>99 (>99.9)
99 (>99.9)
>99 (>99.9)
98.5
97 (>99.9)
>99 (>99.9)
>99 (>99.9)
>99.9 (>99.9)
o-HO-Ph (1b)[c]
p-MeO-Ph (1c)
p-Cl-Ph (1d)
1-Naph (1e)
1-Naph (1e)
2-Naph (1 f)
2-Furyl (1g)
2-Thienyl (1h)
Scheme 1. The ansa-RuII-catalyzed ATH of 4,4,4-trifluoro-1-phenyl-1,3-
butanedione (1a).
temperature (508C) proved to be crucial for the complete
regioselectivity and high enantioselectivity (up to 96.5% ee
attained) for the CF3C(O) reduction. (S)-4,4,4-Trifluoro-3-
hydroxy-1-phenylbutan-1-one [(S)-2a] was isolated in 99.5%
ee and 82% yield after recrystallization from heptane/
toluene.[7] Applying a S/C = 1000 in HCO2H/Et3N (3:2) at
608C, 4,4,4-trifluoro-1-phenylbutan-1,3-diol (3a) was quanti-
tatively formed in a 98.5:1.5 anti/syn ratio and with 99% ee
[anti-(S,S)]. Recrystallization from hexane/EtOAc led to the
stereopure diol. Noteworthy, (R)-2a was prepared in 93% ee
by a copper(I)-catalyzed asymmetric cross-coupling of 3-oxo-
3-phenylpropionic acid with the hazardous CF3CHN2,[8] while
an enzymatic resolution-based multistep synthesis provided
(R)-2a and anti-3a in 92% ee and 96% de (S,S), respective-
ly.[4a] Nevertheless, to the best of our knowledge no metal-
catalyzed asymmetric reduction has been described so far for
such diketones.
[a] ATH of 1 (1 mmol) was carried out in PhCl (1 mL) with the
ruthenium(II) catalyst (S/C=1000 for D and S/C=100 for B) using
HCO2H/Et3N 3:2 (0.5 mL). Conversion (100%) and anti/syn ratio were
determined by 19F NMR spectroscopy, and the ee values were deter-
mined by chiral-phase HPLC or GC. Yields of isolated product ranged
between 95 and 99%. [b] The anti/syn ratio and ee values given within
parentheses were obtained after recrystallization. [c] Reaction using
HCO2H/Et3N (5:2; 0.5 mL) at 508C. 19F NMR spectroscopy indicated
formation of a side-product in 5 mol%.
> 99.9% ee and high yields (95–99%) upon isolation. The
tabulated results demonstrate the tolerance of aromatic ring
substituents (electron rich or electron poor). The o-hydroxy-
phenyl diketone 1b necessitated, for optimum results, the use
of HCO2H/Et3N (5:2) at 508C because a slightly lower anti/
syn ratio (97:3) and a higher amount of side-products (12%)
resulted otherwise. Selected diketones (1e and 1h) were
reduced as was 1a to the monoalcohols [(S)-2e and (S)-2h}]
which were formed in high enantioselectivity (ꢀ 97% ee) and
virtually quantitative yield.[10] A facile single recrystallization
afforded the stereopure carbinols (S)-2.
As suggested by Noyori et al.[9] and by us[5a] for aryl
ketones and trifluoromethyl ketones, respectively, the stereo-
chemical control is enforced by either a stabilizing CH–p or
CH–F attractive electrostatic interaction. In the present case,
the CH–F interaction overrides the CH–p interaction in the
first step, thus leading to the intermediate formation of (S)-2a
on the way to anti-3a (Figure 3).
Investigating different media for this reduction versus
neat HCO2H/Et3N revealed the beneficial use of a cosolvent,
such as PhCl, EtOAc, or 1,2-dichloroethane, and HCO2H/
Et3N (3:2) as the hydrogen donor (for details see the
Supporting Information).
What precedes clearly demonstrates the new practical and
simple access to a large variety of unknown CF3-substituted
1,3-glycols in high stereopurity by applying the present ansa-
RuII-catalyzed asymmetric reduction.
To explore the substrate scope, we shifted to more rigid
1,3-diketones such as a-CF3C(O)-substituted benzofused
five- to seven-membered cyclic ketones (1i–t). These ketones
are based on 1-indanone, a-tetralone, (thio-) chroman-4-one,
Figure 3. Proposed transition states of the two-step ATH of 1a with D.
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Table 2: The D-catalyzed ATH of selected benzofused cyclic ketones 1 to
the monoalcohols 2.[a]
Table 3: The D-catalyzed ATH of benzofused cyclic ketones 1 to the diols
3.[a]
2[b]
ee [%]
2[c]
1
S/C
t [h]
Conv. [%]
d.r.
ee [%][b]
1
S/C
t [h] d.r.
Yield [%] d.r.
ee [%]
1i
1j
1k
1k
1l
1000
1000
1000
1000[c]
1000
500[c]
500
1000
1000
500
24
24
24
24
24
24
24
18
24
24
24
2.5
24
18
100
100
100
100
95
96:3:1:0
97:3:0:0
91:7:2:0
95:4:1:0
74:18:5:3
96:2:2:0
97:3:0:0
6:3:91:0
0:92:7:1
0:96:1:3
0:93:7:0
0:95:5:0
2:86:10:3
10:90:0:0
98 (>99.9)
>99 (>99.9)
99.5
99.5
96.5
>99.9
98.5 (>99.9)
99.5
>99.9
>99.9
>99.9
>99.9
>99.9
73
1i
1j
1l
2000
2000
26 96:4
26 96:4
97.5
97.5
>99.9
>99
72
90
92
84
88
70
51
>99:9
99.5
>99:1 >99.9
>99:1 >99.9
>99:1 >99.9
>99:1 >99
1000[d] 15 97:3
1m 2000
1o 1000
1s
30 98:2
20 89:11
20 86:14
1l
>99
100
100
100
>99
95
2000
75
99:1
64
1m
1n
1o
1p
1q
1r
1s
1t
[a] ATH of 1 (1.0 mmol) was carried out at 408C in PhCl (1 mL) using D
with HCO2H/Et3N (5:2; 0.5 mL). 100% conversion. Yields of isolated
products ranged between 94 and 100%. Conversion and d.r. values were
determined by 19F NMR spectroscopy. The ee values were determined by
chiral-phase HPLC. [b] Crude reaction mixture. [c] After recrystallization.
[d] EtOAc (1 mL) was used as cosolvent.
1000
100
1000
500
100[f]
100
100
[a] ATH of 1 (1.0 mmol) was carried out at 608C in PhCl (1 mL) using D
with HCO2H/Et3N (3:2; 0.5 mL). Conversions and d.r. values were
determined by 19F NMR spectroscopy. The ee values of the major
diastereomer were determined by chiral-phase HPLC and the d.r. values
correspond to the ratios of the four signals, going in an upfield direction,
corresponding to the diastereomers. Yields of isolated products were 1–
4% lower than conversion. [b] The ee values within parentheses were
obtained after recrystallization (d.r. >99.9 for all). [c] EtOAc used as
a cosolvent. [f] 19F NMR spectroscopy indicated the formation of side-
products in 23 mol%.
and 1-suberone. A dynamic kinetic resolution (DKR) was
expected to occur in these cases.[11] Thus, the reduction was
conducted at 408C by employing D with a S/C = 2000 in
HCO2H/Et3N (5:2) and PhCl as cosolvent (Table 2). To favor
the formation of the diol 3, the reaction temperature was
increased to 608C and a higher catalyst loading was used
(Table 3).
Interestingly, racemic 2-trifluoroacetyl-1-indanone (1i)
was reduced quantitatively to the corresponding monoalcohol
2i with a d.r. value of 96:4 [97.5% ee for (2S,1’S)-2i;
Scheme 2], hence validating the occurrence of a DKR. The
absolute configuration was assigned by analogy to that of
(2S*,1’S*)-2s as determined by X-ray analysis.[12] This stereo-
chemistry can be rationalized by the attack of the ruthenium-
(II) hydride on the CF3C(O) re-face, and formation of the
equilibrium mixture wherein (2S,1’S)-2i is predominant.
Notably, heating the stereopure (2S,1’S)-2i at 408C in
a mixture of HCO2H/Et3N (5:2) and PhCl, in the absence of
D resulted in a 96:4 mixture of (2S,1’S)-2i and (2R,1’S)-2i.
This d.r. value was attained within 25 minutes and remained
constant after several days of heating, while in HCO2H/Et3N
(3:2) and PhCl the same equilibrium was established within
10 minutes at 408C. A d.r. value of 94:6 resulted from heating
at 608C.
Though the ATH of the 7-OH-substituted 1l or the 7-
NHAc-substituted 1m led to high diastereo- and enantiose-
lectivities, the former performed better with a higher catalyst
loading (S/C = 1000) and with EtOAc as a cosolvent. Also,
five-membered benzofused cyclic ketones (1i–m) afforded
better results than their six-membered homologues (1o and
1s). Here as well, recrystallization of the 1-indanone-derived
monoalcohol allowed isolation of the stereopure compounds
(2S,1’S)-2.
When targeting diols (3) with the three contiguous
stereocenters, the formation of 23 stereoisomers are theoret-
ically possible. However, we were delighted to confirm by
19F NMR spectroscopy the formation in all cases of one major
diastereomer (86–97% yield) in greater than or equal to
99% ee, except for the seven-membered cyclic compound 1t,
which led to a product with only 73% ee (Table 3). The
indicated d.r. value corresponds to the ratios of the four
19F NMR signals, going in an upfield direction, corresponding
to the diastereomers. X-ray analyses of 3j and 3s revealed
their (1S,2S,1’S) absolute configuration.[12] This data demon-
strates the manifestation of a second DKR whereby the
methine configuration (in the cycle) of 2 en route to 3 is
inverted (Scheme 2 for 3i).[13]
The created stereochemistry at the benzylic carbon (C1) is
governed by the handedness of D (see Figure 3), while the C2
configuration is impacted by outwards orientation of the
peripheral CH(OH)CF3 group, thus minimizing the steric
interference in the second transition state.
Scheme 2. Consecutive ATH/DKRs of 2-trifluoroacetyl-1-indanone (1i)
using D at 608C.
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The ATH of 1k and 1l needed EtOAc as a cosolvent to
In conclusion, we have presented a new, efficient, and
achieve the maximum diastereo- and enantioselectivities, and
the latter required a higher catalyst loading (S/C = 500) for
complete conversion (for a comprehensive study see the
Supporting Information). Here as well, the five-membered
benzofused cyclic ketones (1i–n) outperformed their six-
membered cyclic higher homologues (1o–t). And for the 4-
chromanone-derived substrate 1r, minimizing the side-prod-
uct formation necessitated the use of S/C = 100.
practical ansa-RuII-catalyzed enantio- and diastereoselective
ATH to the carbinols 2 and 3. The latter are formed by an
unprecedented double ATH/DKR in the case of CF3C(O)-
substituted benzofused cyclic ketones. The present method-
ology definitely expands and enriches the area of fluorine
research, and the generated compounds, having excellent
enantiopurity, may be further elaborated to increase molec-
ular complexity.
Moreover, access to the complementary syn diols syn-3
was demonstrated on two representative cases starting from
the stereopure monoalcohols 2 and resorting to the antipode
ent-D for the ATH of the aroyl function (Scheme 3). Thus, the
Acknowledgments
This work was supported by the Slovenian Research Agency
(grant P1-0242), and by the French-Slovenian research
collaboration Proteus. We are also grateful to Dr. Michel
Stephan from PhosPhoenix SARL, France, for very helpful
discussions and for providing ruthenium catalysts.
Keywords: alcohols · asymmetric catalysis · enantioselectivity ·
kinetic resolution · ruthenium
How to cite: Angew. Chem. Int. Ed. 2016, 55, 5294–5298
Angew. Chem. 2016, 128, 5380–5384
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afforded the stereoisomers (1R,3S)-3a [anti/syn = 2:98,
> 99.9% ee (syn)] and (1R,2R,1’S)-3i [d.r. = 0:0:97.5:2.5,
> 99.9% ee (major)], respectively. Interestingly, (1S,2R,1’S)-
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(2S,1’S)-2i on a 4 gram scale using D and ent-D yielded the
corresponding diastereomeric diols (1S,2S,1’S)-3i (d.r. =
96.5:3:0.5:0; > 99.9% ee) and (1R,2R,1’S)-3i (d.r. =
0:0:97.5:2.5; > 99.9% ee), and upon recrystallization the
stereopure compound was obtained.
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[10] ATH of 1e and 1h led to (S)-2e (97% ee) and (S)-2h (98% ee),
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recrystallization from heptane (96% yield).
nide], and 1448690 [for (1S,2R,1’S)-3i] contain the supplemen-
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[12] CCDC 1447877 [for (2S*,1’S*)-2s], 1447876 [for (1S,2S,1’S)-3j],
1447875 [for (1S,2S,1’S)-3s], 1448691 [for (1R,2R,1’S)-3i aceto-
[13] Notably, taking however into account the relative group prior-
ities according to the CIP stereochemistry rules, an S absolute
configuration for the methine of the cycle is encountered in both
compounds.
Received: January 24, 2016
Published online: March 22, 2016
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Angew. Chem. Int. Ed. 2016, 55, 5294 –5298