Asymmetric Transfer Hydrogenation of gem-Difluorocyclopropenyl Esters: Access to Enantioenriched gem-Difluorocyclopropanes

Article abstract of DOI:10.1002/anie.202008572

Catalytic enantioselective access to disubstituted functionalized gem-difluorocyclopropanes, which are emerging fluorinated motifs of interest in medicinal chemistry, was achieved through asymmetric transfer hydrogenation of gem-difluorocyclopropenyl este

Full text of DOI:10.1002/anie.202008572

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Asymmetric transfer hydrogenation of gem-difluoro-cyclopropenyl
esters. Access to enantio-enriched gem-difluorocyclopropanes
Authors: Christophe Meyer, Khalil Yamani, Hugo Pierre, Alexis
Archambeau, and Janine Cossy
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202008572
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10.1002/anie.202008572
Angewandte Chemie International Edition
COMMUNICATION
Asymmetric transfer hydrogenation of gem-difluoro-
cyclopropenyl esters. Access to enantio-enriched
gem-difluorocyclopropanes
Khalil Yamani,[a] Hugo Pierre,[a] Alexis Archambeau,[a] Christophe Meyer,*[a] and Janine Cossy*[a]
[a]
K. Yamani, H. Pierre, Dr. A. Archambeau, Dr. C. Meyer, Prof. Dr. J. Cossy
Molecular, Macromolecular Chemistry, and Materials
ESPCI Paris, PSL University, CNRS
10 rue Vauquelin 75005 Paris, France
E-mail: christophe.meyer@espci.fr, janine.cossy@espci.fr
Supporting information for this article is given via a link at the end of the document.
Abstract:
A
catalytic enantioselective access to disubstituted
4-bromo-4,4-difluorocrotonate, followed by radical-induced ring
closure, to afford difluorocyclopropane V.[14] Ring-closure
induced by Michael addition of glycine-derived enolate VI to
N-(difluorobromocrotonyl)oxazolidinone VII was also disclosed
functionalized gem-difluorocyclopropanes, which lie among
emerging fluorinated motifs, was developed by asymmetric transfer
hydrogenation of gem-difluorocyclopropenyl esters, catalyzed by
Noyori-Ikariya (p-cymene)-ruthenium(II) complex, with (N-tosyl-
1,2-diphenylethylenediamine) as chiral ligand and isopropanol as
hydrogen donor. The resulting cis-gem-difluorocyclopropyl esters
were obtained with moderate to high enantiomeric purities (ee = 66-
99%) and post-functionalization reactions enable access to valuable
building blocks incorporating a cis- or trans-gem-difluorocyclopropyl
motif.
to access
-amino acid derivative VIII[15] (Scheme 1A).
Alternatively, chemo-enzymatic processes can be used, as
illustrated by the kinetic resolution of racemic diacetate IX, which
afforded optically active alcohol X and diacetate (–)-IX through a
lipase-catalyzed ester hydrolysis.[16,17] Very recently, the
enantioselective reduction of aryl gem-difluorocyclopropenes XI
into aryl gem-difluorocyclopropanes XII by hydrocupration was
disclosed (Scheme 1C).[18] Herein, we report
a catalytic
enantioselective approach toward disubstituted functionalized
gem-difluorocyclopropanes, capitalizing on the asymmetric
gem-Difluorocyclopropanes have aroused considerable interest
both from a structural standpoint and because of their ability to
participate in various ring-opening reactions.[1,2] Considering the
increasing use of the cyclopropyl fragment in the development of
drug candidates[3] and the unarguable importance of fluorinated
compounds in medicinal chemistry and agrochemistry,[4] it is not
surprising that gem-difluorocyclopropanes are encountered into
bioactive compounds[5] and currently lie among “emerging
fluorinated motifs”.[6] Notorious examples include -amino acid I,
a selective metabotropic glutamate receptor 2 antagonist,[7] the
lysophosphatidic acid receptor 2 antagonist II,[8] the serotonin 2C
receptor antagonist III[9] and zosuquidar,[10] which reached
phase III clinical trials to treat acute myeloid leukemia (Figure 1).
transfer
hydrogenation
of
gem-difluorocyclopropenyl
carboxylates A into gem-difluorocyclopropyl esters B in the
presence of Noyori-Ikariya ruthenium(II) complex and
isopropanol as hydrogen donor (Scheme 1D).
A. Diastereoselective (auxiliary-based) reactions
O
OLi
F
F
BnO
OBn
THF, 78 °C
then Et B, O
DMI, 20 °C
51%
BrF2C
XN*
H
PhN
XN*
N
N
+
H
O
CO2Mes
3
2
CO2Mes
O
iPr
V (de = 92%)
IV
BrF2C
Bn
Ph
F
F
Ph2C=N
EtO2C
H
+
Ph
N
O
DMF, 20 °C
54%
H
LiO
EtO
O
O
YN*
VIII (de > 95%)
F
F
F
F
F
F
VI
VII
O
H
YN*
H
H
O
H
H
H
B. Biocatalytic reactions
OH
HO
F
F
F
F
F
F
SL-25 Lipase
NH2
F
N
(Pseudomonas cepacia)
OAc
I
AcO
OAc
HO
OAc
AcO
+
N
N
N
buffer (pH 7.2), 35 °C
N
(±)-IX
X
( )-IX
(36%, ee > 99%)
F
OMe
NH
O
F
(53%, ee = 48%)
H
H
N
H
N
N
C. Enantioselective hydrocupration
Cu(OAc)2 (5 mol%)
Ph
Cl
O
II
N
III
Pt-Bu2
O
OH Zosuquidar
Pt-Bu2
L* (6 mol%)
iPrOH (2 equiv)
F
F
F
F
Me
O Si
Fe
Figure 1. Examples of bioactive gem-difluorocyclopropanes.
Me
+
*
Ar
Ar
toluene, RT
31-89%
L*
H
XI
XII
n
(4 equiv)
(ee = 12-90%)
D. This work : Catalytic enantioselective transfer hydrogenation
gem-Difluorocyclopropanes are classically synthesized by
cyclopropanation of alkenes with difluorocarbene, which can be
generated from various precursors.[6,11,12] Examples of diastereo-
selective difluorocyclopropanations of alkenes possessing
adjacent stereocenters have been reported,[13] but to date only a
few methods are available for the synthesis of enantio-enriched
gem-difluorocyclopropanes. Diastereoselective auxiliary-based
approaches involve Michael addition of lithium enolate IV
iPr
Ts
Ph
N
Ru
(10-15 mol%)
F
F
F
F
N
Ph
H
OR'
OR'
Me
iPrOH/CH Cl , RT
R
R
A
B
2
2
O
O
Scheme 1. Synthesis of enantio-enriched gem-difluorocyclopropanes.
Mes = 2,4,6-trimethylphenyl, DMI = 1,3-dimethylimidazolidin-2-one.
(derived from
a chiral N-acyl imidazolidinone) to mesityl
1
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10.1002/anie.202008572
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COMMUNICATION
Although hydrogenation of difluorocyclopropenes may appear as
an appealing entry toward difluorocyclopropanes, those latter
strained compounds are prone to ring-cleavage in the presence
of transition metal catalysts,[1,2] in particular under standard
Pd-catalyzed heterogeneous conditions.[19] Nevertheless, the
conjugate reduction of gem-difluorocyclopropenyl ketones into
diastereomeric mixtures of cis- and trans-gem-difluoro-
cyclopropyl ketones was previously accomplished by hydride
transfer from a Hantzsch ester in the presence of an acid
catalyst.[20] Enantioselective transfer hydrogenation of C=O and
C=N bonds, catalyzed by ruthenium complexes possessing a
chiral N-sulfonyl-1,2-diphenylethylenediamine ligand (or related
rhodium and iridium complexes), is a powerful method to access
Worthy of note was the slightly higher enantiomeric purity
determined for ent-2a (ee = 98%) compared to that of 2a (ee =
94%). Although in this case, the difference lies within an
acceptable error range,[26]
a
phenomenon of self-
disproportionation of enantiomers, already reported for scalemic
fluorine-containing compounds, could be suspected.[27] Transfer
hydrogenation of 1a was repeated several times at different
scales and optical purities of 94-96% were consistently
determined for difluorocyclopropane 2a.
The substrate scope of this asymmetric transfer hydrogenation
was examined and variation of the ester substituent was first
studied. Transfer hydrogenation of tert-butyl ester 1b and benzyl
optically enriched alcohols and amines, respectively.[21] However, ester 1c afforded gem-difluorocyclopropanes 2b (79%,
examples of enantioselective transfer hydrogenation of
, -disubstituted electron-deficient olefins with those latter
catalysts are scarce and so far limited to alkylidene-
malononitriles or nitroalkenes.[22] We hypothesized that the high
ring-strain of difluorocyclopropenylcarbonyl compounds could
provide the driving force to achieve the catalytic transfer
hydrogenation of the C=C bond under mild conditions without
jeopardizing the three-membered ring.[24] To test this hypothesis,
gem-difluorocyclopropenyl esters A were selected as substrates
to avoid potential competitive reduction of the carbonyl group
and hence circumvent chemoselectivity issues.
ee = 85%) and 2c (82%, ee = 92%), respectively. The interest of
having esters cleavable under different conditions was
highlighted by the fact that saponification of methyl ester 2a with
LiOH occurred with concomitant epimerization and led to the
trans-gem-difluorocyclopropanecarboxylic acid 5 (81%).[17] The
vicinal fluorine atoms presumably increase the acidity of the
proton at the position of the carbonyl group thereby resulting in
an easy epimerization under alkaline conditions (LiOH), although
no competitive -elimination of fluorine took place.[28] As a
complementary method, tert-butyl ester 2b was cleaved under
acidic conditions (CF3CO2H, CH2Cl2, RT) to provide the cis-gem-
difluorocyclopropanecarboxylic acid 6 (67%) (Scheme 3).
In our initial studies, gem-difluorocyclopropenyl methyl ester 1a,
prepared by slow addition (via syringe pump) of trimethylsilyl
fluorosulfonyldifluoroacetate (TFDA) to methyl phenylpropiolate
(cat. NaF, diglyme, 120°C, 4.5h, 94% yield), was selected as the
test substrate.[23] Cyclopropenyl ester 1a underwent an efficient
hydrogen transfer upon treatment with catalyst (S,S)-[Ru]-I[21a-c]
(10 mol%) in iPrOH/CH2Cl2 (10:1) (RT, 1h), which afforded the
3,3-difluorocyclopropyl ester 2a as a single cis detectable
diastereomer (cis/trans > 96:4, by analysis of the crude product
by 1H and 19F NMR spectroscopy) in 85% yield (4.3 mmol scale
experiment).[25] The enantiomer, ent-2a (83%), was obtained
similarly from 1a using (R,R)-[Ru]-I as the catalyst and an
enantiomeric excess of 94% was determined for 2a by
supercritical fluid chromatography (SFC) on a chiral stationary
phase.[26] Reduction of 2a with DIBAL-H and condensation of the
resulting primary alcohol 3a with p-bromobenzoyl chloride
afforded the crystalline p-bromobenzoate 4 (61%, two steps
from 2a), the absolute configuration of which was assigned by
X-ray diffraction analysis (Scheme 2).
F
F
F
F
(S,S)-[Ru]-I (10-15 mol%)
(cis/trans > 96:4)
Ph
CO2R' iPrOH/CH2Cl2 (10:1), RT, 1h Ph
CO2R'
1b, R' = t-Bu
1c, R' = Bn
2b, R' = t-Bu (79%) (ee = 85%)
2c , R' = Bn (82%) (ee = 92%)
F
F
F
F
LiOH
(trans/cis > 96:4)
(cis/trans > 96:4)
MeCN/H2O (2:1), RT, 2h
81%
Ph
Ph
CO2Me
Ph
Ph
CO2H
CO2H
2a
2b
5
6
F
F
F
F
CF3CO2H
CH2Cl2, RT, 1.5h
67%
CO2t-Bu
Scheme 3. Influence of the ester substituent.
The substituent on the cyclopropene (at C2) was next varied.
The presence of a substituent at the para position on the
aromatic ring in substrates 1d–1g resulted in a slight drop of
enantioselectivity compared to 1a, regardless of the steric or
electronic properties of the substituent, as indicated by the
formation of difluorocyclopropyl esters 2d (ee = 85%), 2e (ee =
92%) and 2f (ee = 83%) possessing a tert-butyl, a fluorine atom
and a methoxy group, respectively. For substrate 1f, a higher
catalyst loading (15 mol%) was required to reach full conversion
presumably because the mesomeric donor p-methoxyphenyl
group attenuates the electrophilicity of C2 and resulted in a
slower reaction compared to 1a. Whereas 2a–2f were formed
with high cis diastereoselectivity, transfer hydrogenation of 1g
possessing an electron-withdrawing p-nitrophenyl group at C2
led to a diastereomeric mixture of cis- and trans-difluoro-
cyclopropanes 2g and 2’g (cis/trans = 80:20) both possessing
the same optical purity.[26] Epimerization of the mixture of 2g/2’g
was purposely achieved by heating in the presence of Et3N
(MeCN, 70 °C, 1h) to produce selectively the more stable trans
diastereomer 2’g (80%, ee = 66%) under thermodynamic control.
TFDA (4.5 equiv)
CO2Me
(added over 4.5h)
F
F
F
F
(S,S)-[Ru]-I (10 mol%)
NaF (10 mol%)
Ph
CO2Me
iPrOH/CH2Cl2 (10:1) Ph
diglyme, 120°C
94%
CO2Me
Ph
1a
2a
RT, 1h
85%
(cis/trans > 96:4)
(ee = 94%)
iPr
Ts
N
Ph
DIBAL-H (3 equiv)
Et2O, 78 °C to RT
Ru
97%
N
Ph
H
Me
p-BrC6H4COCl
Et3N, DMAP
Br
(S,S)-[Ru]-I
F
(R)
F
(S)
F
F
O
OH
CH2Cl2, RT
63%
Ph
Ph
4
3a
O
Scheme 2. Asymmetric transfer hydrogenation of 1a. DIBAL-H = Diisobutyl-
aluminum hydride, DMAP = 4-(Dimethylamino)pyridine.
2
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10.1002/anie.202008572
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Introduction of a fluorine atom or a nitro group at the meta
position of the aromatic ring in substrates 1h and 1i had little
impact on the enantioselectivity compared to 1a, as illustrated
with the isolation of difluorocyclopropanes 2h (71%, ee = 95%)
and 2i (60%, ee = 89%), respectively. The highest
enantioselectivities were observed for substrates 1j and 1k
possessing a bromine atom at the ortho position which afforded
gem-difluorocyclopropyl esters 2j (65%, ee = 97%) and 2k (85%,
ee = 99%). The aromatic ring could also be disubstituted, as
shown with substrate 1l containing a fluorine atom and a cyano
group at the ortho and meta positions, respectively, which led to
cyclopropane 2l (64%, ee = 86%). In this case, the reaction was
carried out in iPrOH/CH2Cl2 (1:1) to ensure complete solubility of
substrate 1l. Transfer hydrogenation of difluorocyclopropenyl
esters substituted by alkyl groups at C2 also proceeded well.
Reduction of substrate 1m, possessing a methyl group at C2,
afforded cis-gem-difluorocyclopropane 2m (86%, ee = 79%) with
lower enantioselection compared to the analogous benzyl ester
2c with a phenyl group at C2 (ee = 92%). However, higher
enantioselectivities were observed for substrates 1n and 1o
possessing a 2-(tert-butyldiphenylsilyloxy)ethyl or a 3-benzyloxy-
propyl group, as illustrated by the formation of difluoro-
cyclopropanes 2n (65%, ee = 90%) and 2o (81%, ee = 90%),
respectively (Scheme 4).[26,29]
(S,S)-[Ru]-I and give rise to enols C and ent-C that would then
tautomerize to cis-difluorocyclopropanes B (major enantiomer)
and ent-B (with proton transfer at C1 on the less hindered face,
opposite to the R group at C2, under kinetic control) (Scheme 5).
F
3
F
iPr
Me
iPr
Me
F
2
1
3
R
2
R
R
CO2R'
2
Ru
H
Ru
H
A
F
NTs
Ph
NTs
Ph
N
N
F
1
3
1
H
O
H
Heq
ax
Heq
ax
iPr
Me
R'O
O
F
Ph
(S,S)-[Ru]-I
Ph
OR'
Ru
TS-I
TS-II
H
NTs
Ph
N
H
H
F
F
F
F
H
R
Ph
H
R
OR'
OR'
OH
(S,S)-[Ru]-II
C
B
ent-C
OH
O
F
F
F
F
iPrOH
(S,S)-[Ru]-I
H
R
H
CO2R'
H
R
H
CO2R'
ent-B
Scheme 5. Face selectivity of the transfer hydrogenation of substrates A.
To demonstrate the synthetic utility of gem-difluorocyclopropyl
esters B, post-functionalization reactions were investigated with
the particular goal of creating nitrogen heterocycles. Ester 2a
was treated with (MeO)MeNH•HCl in the presence of Me3Al,
(toluene, 70°C) to afford the trans-difluorocyclopropyl Weinreb
amide 7 (65%). Subsequent addition of phenylethynyllithium and
condensation of the resulting ynone with N2H4•H2O delivered the
(gem-difluorocyclopropyl)pyrazole 8[32] (42%) (Scheme 6).
F
F
F
F
3
3
(S,S)-[Ru]-I (10 mol%)
2
2
1
1
iPrOH/CH2Cl2 (10:1), RT, 1h
R
CO2R'
F
R
CO2R'
1d 1o
2d 2o
F
F
F
CO2Me
CO2Me
(82%)
2g/2'g
(cis/trans = 80:20)
R"
2d,R" = t-Bu (65%, ee = 85%)
2e, R" = F
(58%, ee = 92%)
2f, R" = OMe (66%, ee = 83%)[a]
O2N
F
F
2g/2'g
2'g (80%, ee = 66%)
Et N, MeCN
3
70°C, 16h
F
F
F
F
(MeO)MeNH.HCl
Me3Al
1.
Li
Ph
THF, -78 °C to RT
N
O
Ph
F
F
Ph
Ph
CO2Me
F
F
toluene, 70 °C
65%
F
F
2. N2H4.H2O
EtOH, RT
42%
NH
2a
7
8
N
MeO
Me
R"
CO2Me
CO2R'
Ph
CO2Me
Scheme 6. Synthesis of gem-difluorocyclopropane 8.
F
Br
CN
2h,R" = F (71%, ee = 95%) 2j, R' = Me (65%, ee = 97%)
2i, R" = NO2 (60%, ee = 89%) 2k, R' = t-Bu (85%, ee = 99%)[b]
2l (64%, ee = 86%)[c]
Construction of a nitrogen heterocycle fused to a difluoro-
cyclopropane was also studied. After reduction of ester 2j, the
primary alcohol was converted into the corresponding mesylate
which was displaced with benzylamine to afford secondary
amine 9 (50%, three steps from 2j). Compound 9 was involved
in an intramolecular Hartwig-Buchwald amination[33] which
provided the gem-difluorocyclopropa[c]quinoline 10 (84%)
(Scheme 7).
F
F
F
F
F
F
BnO
Me
CO2Bn
TBDPSO
CO2Me
CO2Me
2o (81%, ee = 90%)
2m (86%, ee = 79%)
2n (65%, ee = 90%)
Scheme 4. Scope of the asymmetric transfer hydrogenation.
TBDPS = Sit-BuPh2. [a] (S,S)-[Ru]-I (15 mol%). [b] iPrOH/CH2Cl2 (8:1).
[c] iPrOH/CH2Cl2 (1:1).
1. DIBAL-H, Et2O
Although a detailed analysis of the enantioselectivities observed
in the transfer hydrogenation of cyclopropenyl esters A deserves
further studies, previous mechanistic investigations on the
rhodium-catalyzed transfer hydrogenation of enones point
toward a 1,4-addition mechanism rather than a concerted
hydrogenation of the olefin, or migratory insertion of the latter
F
F
Pd(OAc)2 (10 mol%)
BINAP (10 mol%)
Cs2CO3 (2 equiv)
78 °C to RT
2. MsCl, Et3N
CH2Cl2, 0 °C to RT
F
F
F
F
CO2Me
Toluene, reflux
3. BnNH2, K2CO3
DMF, 90 °C
50%
N
NHBn
Br
84%
Br
Bn
2j
9
10
Scheme 7. Synthesis of gem-difluorocyclopropa[c]quinoline 10.
into
a
Rh-H bond.[22d] Hence, dehydrogenation of iPrOH
catalyzed by (S,S)-[Ru]-I would first generate hydride complex
(S,S)-[Ru]-II.[30] Hydride transfer at C2 to Michael acceptors A,[31]
with additional activation of the carbonyl by hydrogen bonding
with the axial proton of the amino group on the ligand, may
preferentially occur through transition state TS-I rather than TS-II
to minimize steric interactions between the gem-difluorinated C3
atom and the p-cymene ligand. This would regenerate
In conclusion, we have demonstrated that gem-difluoro-
cyclopropenyl esters can undergo an efficient enantioselective
transfer hydrogenation from isopropanol catalyzed by Noyori-
Ikarya ruthenium(II) complex. This transformation opens a new
access to enantio-enriched gem-difluorocyclopropyl esters and
to diversely substituted cis- or trans-gem-difluorocyclopropyl
building blocks of interest in medicinal chemistry.
3
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10.1002/anie.202008572
Angewandte Chemie International Edition
COMMUNICATION
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Keywords: Transfer hydrogenation • Small ring systems •
Difluorocyclopropanes • Difluorocyclopropenes •
Enantioselectivity
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4
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Entry for the Table of Contents
iPr
Ts
Ph
N
Ru
(10-15 mol %)
15 examples (58 86%)
N
F
F
F
F
Ph
H
Me
iPrOH/CH2Cl2, RT, 1h
R = Aryl, Me, (CH2)2OTBDPS, (CH2)3OBn; R' = Me, t-Bu, Bn
(cis/trans = 80:20 to
> 96:4 in most cases)
R
CO2R'
R
CO2R'
(ee = 66-99%)
Asymmetric transfer hydrogenation of gem-difluorocyclopropenyl esters using Noyori-Ikarya’s catalyst and isopropanol as the
hydrogen donor enables access to enantio-enriched gem-difluorocyclopropanes (ee = 66-99%) which are emerging fluorinated motifs
of interest in medicinal chemistry.
Institute and/or researcher Twitter usernames: @ESPCI_Paris, @INC_CNRS
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