Diastereo- and Enantioselective Synthesis of Fluorine Motifs with Two Contiguous Stereogenic Centers

Article abstract of DOI:10.1021/jacs.8b08778

The synthesis of chiral fluorine containing motifs, in particular, chiral fluorine molecules with two contiguous stereogenic centers, has attracted much interest in research due to the limited number of methods available for their preparation. Herein, we report an atom-economical and highly stereoselective synthesis of chiral fluorine molecules with two contiguous stereogenic centers via azabicyclo iridium-oxazoline-phosphine-catalyzed hydrogenation of readily available vinyl fluorides. Various aromatic, aliphatic, and heterocyclic systems with a variety of functional groups were found to be compatible with the reaction and provide the highly desirable product as single diastereomers with excellent enantioselectivities.

Full text of DOI:10.1021/jacs.8b08778

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Article
Diastereo- and Enantioselective Synthesis of Fluorine
Motifs with Two Contiguous Stereogenic Centers
Sudipta Ponra, Wangchuk Rabten, Jianping Yang, Haibo Wu, Sutthichat Kerdphon, and Pher G. Andersson
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Diastereo- and Enantioselective Synthesis of Fluorine Motifs
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Sudipta Ponra, Wangchuk Rabten, Jianping Yang, Haibo Wu, Sutthichat Kerdphon and Pher G. Anders-
son*
Department of Organic Chemistry, Stockholm University, Svante Arrhenius väg 16C, SE-10691 Stockholm, Sweden.
ABSTRACT: The synthesis of chiral fluorine-containing motifs, in particular chiral fluorine molecules with two contiguous stere-
ogenic centers have been attracting much interest in research due to the limited number of methods available for their preparation.
Herein, we report an atom economical and highly stereoselective synthesis of chiral fluorine molecules with two contiguous stereo-
genic centers via azabicyclo iridium-oxazoline-phosphine-catalyzed hydrogenation of readily available vinyl-fluorides. Various ar-
omatic, aliphatic and heterocyclic systems with a variety of functional groups were found to be compatible to the reaction and pro-
vides the highly desirable product as single diastereomers and excellent enantioselectivities.
INTRODUCTION
asymmetric hydrogenation of tetra-substituted vinyl fluorides
would enable enantioselective generation of two contiguous
stereogenic centers containing the fluorine atom at one of the
stereo-centers, in one simple step.20 Cognizant of the aforesaid
limitations, we set out to develop a general, simple and effi-
cient atom economical protocol, for the highly diasteroselec-
tive and enantioselective synthesis of chiral fluorine com-
pounds containing two stereogenic centers (Scheme 1).
Fluorine, on the basis of its unique special properties holds an
esteemed position in modern research1 and plays an important
role in agrochemical,2 pharmaceutical,1b,c material sciences,3
biochemistry1b-d, 4 and medicinal chemistry.1b-d, 5 Approximate-
ly 30% of all agrochemicals and almost 20% of all pharmaceu-
ticals contain a fluorine atom. Despite being an exceptional
pharmacological modulator, selective introduction of fluorine
into organic molecules presents difficulties. Indeed, the few
numbers in nature of biosynthesized natural molecules con-
taining fluorine6, 7 arguably proves the troubles concerned with
the installation of the fluorine atom. The asymmetric introduc-
tion of fluorine thus relies on synthetic organic chemistry and
has become one of the most desired and sought-after enlarge-
ments in the toolbox of fluorination chemistry.8 However, gen-
eral stereoselective fluorination methods for the access of ver-
satile fluorinated building blocks is still narrow and restricts
the availability of structurally diverse fluorinated molecules.
Drugs such as dexamethasone, fluticasone propionate or
fluorothalimolide analogue containing a chiral fluorine carbon
atom with another adjacent chiral center, represents another
major challenge since they require enantioselective generation
of an asymmetric fluorinated molecule with two contiguous
asymmetric centers. Recent progress in this area, has expanded
the availability of fluorinated molecule with two contiguous
chiral centers.8a,b,h,k,m,t-v, 9 However, the repertoire of asymmet-
ric methodologies is still limited and either requires high cata-
lyst loadings,8f, 9a, 10 a mixture of catalysts,10b, 11 sophisticated
reaction conditions,12 multi steps10e, 13 or offer borderline dias-
teroselectivity10g, 14 and enantioselectivity10b,c, 15 resulting in a
mixtures of products.16
Scheme 1. Atom economical stereoselective preparation of
asymmetric fluorine motifs.
RESULTS AND DISCUSSION
The initial investigation focused on the hydrogenation of the inac-
tivated tetra-substituted vinyl-fluoride (E)-diethyl 2-fluoro-3-
phenylmaleate 1a using various N,P-iridium complexes with the
aim to achieve high reactivity, high enantioselectivity but avoid-
ing defluorination which is a common side product in this reac-
tion. Based on previous experience of N,P-iridium catalyzed
asymmetric hydrogenation of tetra-substituted olefins,20a,b we first
choose the bicyclic iridium-N,P complex containing either the
thiazole or oxazoline ring for our current study (Table 1). When
N,P-iridium complex A bearing the thiazole moiety was used, on-
ly 3% of the starting material was consumed to provide the antici-
pated product 2a. A comparable result of 11% conversion of the
starting material 1a, was obtained by changing the basic heterocy-
cle of the N,P-iridium complex from thiazole to oxazoline (B). A
decrease in the steric hindrance around the phosphorus center of
the oxazoline moiety (C) failed to give any conversion to the de-
sired product. Unexpectedly and gratifyingly, replacing the bulki-
er di-phenyl with the less sterically demanding iso-propyl group
on the oxazoline ring (D) resulted in the successful hydrogenation
of 1a in 46% conversion with complete diastereoselectivity
(>99%) and excellent enantiomeric excess (>99%). Interestingly,
negligible defluorinated product 3a (12%) was observed, which is
a common and hitherto unsolved problem in hydrogenations of
vinyl fluorides.19b Further optimization of the ligand led to oxazo-
line N,P-iridium complex E containing 2,4-di-MePh substituent
on phosphorus which gave slightly better result than complex D.
In asymmetric catalysis, enantioselective hydrogenation is one
of the most fundamental and atom economical processes in
organic chemistry.17 Steric hindrance by substituents and also
difficulties in the differentiation of the prochiral faces of the
fully substituted olefin by the catalyst makes tetra-substituted
olefins very challenging substrates for hydrogenation.18 In ad-
dition, defluorination and the unpredictable behavior of the
fluorine molecule, makes tetra-substituted vinyl-fluorides even
more challenging substrates for hydrogenation.19 However, the
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To further increase the steric hindrance around phosphorus the
Table 2. Optimization of hydrogenation of tetra-substituted
vinyl fluoride 4
ortho methyl group was changed to an ortho ethyl group and af-
forded new oxazoline N,P-iridium complex F. This complex pro-
vided superior result: (96% conversion) under the same reaction
conditions with only 8% de-F and perfect diastereoselectivity
(>99% dr) and enantioselectivity (>99% ee).
1
2
3
4
Me
F
Me
F
Ir-catalyst (F)
Me
* *
+
R
CH2Cl2, 24h
R
R
5
6
7
Me
Me
4a, R = CO2Et
4b, R = CH2OH
Me
6
5
Table 1. Evaluation of N,P-iridium catalysts in the asymmet-
ric hydrogenation of 1aa
de-F (6) ee (%)b
Conversion (%)
Substrate H2 (bar)
Yield (% of 5)
Catalyst (mol%)
Entry
8
9
0
0
0
0
0
0
0
0
0
0
97
97
98
97
98
98
96
97
96
97
94
99
92
99
90
99
71
99
65
99
4a
4b
4a
4b
4a
4b
4a
4b
4a
4b
100
100
50
91
98
88
98
86
97
68
76
60
65
1.0
1.0
1.0
1.0
1.0
1.0
0.5
0.5
1.0
1.0
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
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50
20
20
20
20
10
10
a Reaction conditions: 0.05 mmol of 4, catalyst F, 0.5 mL CH2Cl2,
1
24h, r.t. The conversion was determined by H-NMR. Yields are
b
isolated yield. Enantiomeric excess was determined by SFC or
chiral GC/MS using chiral stationary phases.
a
With the optimized reaction conditions established, we evaluated
various (E)-2-fluoro-maleate substrates 1 (Table 3) having differ-
ent substituents. A large number of di-esters were successfully
hydrogenated to generate the desired products 2a to 2p in mostly
excellent conversion (0-16% de-F) with perfect diastereoselectivi-
ties and enantioselectivities. The (E)-2-fluoro-maleate substrates
having different ester groups (Me, Et, Bn) resulted in full conver-
sions and very high stereoselectivities. Replacing phenyl with the
2-naphthyl or 2-thienyl substituent yielded 2d or 2e in excellent
conversion (99%) and ee (>99%) along with a very small quantity
of de-F by-product. Heterocyclic substrates having dimethyl sub-
stituents at the ortho position of the hetero atom did not affect the
enantioselectivity (>99% ee). Having two-methyl groups on the
heterocycle decreased the conversion to 50%, probably due to ste-
ric hindrance. This was easily overcome by increasing the catalyst
loading to 2 mol% which restored 99% conversion (2f with ~10%
de-F and 2g with ~6% de-F). Electron-donating or electron-
withdrawing substituents in the aromatic ring were well tolerated.
The electron-donating methoxy substituent furnished 4-
methoxyphenyl-2-fluoro-succinate 2h in 99% conversion (~7%
de-F). Similarly, electron-withdrawing substituents (F and CF3)
on the aromatic ring produced 2i or 2j in excellent enantioselec-
tivities (>99%ee). However, a higher catalyst loading was re-
quired to overcome the electron-withdrawing character of the sub-
stituents (F: 2 mol% and CF3: 4 mol%). Also, for diethyl 2-(3,4-
dimethylphenyl)-3-fluorosuccinate 2k a catalyst loading of 2
mol% was required to attain excellent conversion (99%) and en-
antiomeric excesses (>99% ee) with small amount of de-F by-
product (~7%). Interestingly, substrates having aliphatic substitu-
ents can be hydrogenated in high levels of stereoselectivity albeit
in lower yield (27% conversion with 15% de-F) and inferior
enatioselectivity (87% ee) as was observed for diethyl 2-fluoro-3-
methylmaleate substrate using catalyst F. Catalyst A was used to
hydrogenate diethyl 2-fluoro-3-methylmaleate to give 2l in 96%
ee without any generation of de-F product (0%). Similarly, vari-
ous aliphatic substituted 3-fluoromaleates reacted sluggishly un-
der the optimal reaction conditions but with excellent enantiose-
lectivity. For ethyl-3-fluoromaleate or iso-propyl-3-fluoromaleate,
Reaction conditions: 0.05 mmol of substrate, 1 mol% catalyst,
0.5 mL toluene. The conversion was determined by 1H-NMR and
the enantiomeric excess was determined by GC/MS using chiral
stationary phases.
After successfully optimizing the new and effective catalyst F for
the hydrogenation of vinyl fluoride 1a, we turned to optimizing
the other reaction parameters (Table 2). For this purpose two dif-
ferent substrates (E)-ethyl 2-fluoro-3-p-tolylbut-2-enoate (4a) and
(E)-2-fluoro-3-p-tolylbut-2-en-1-ol (4b) were selected (see Sup-
porting Information for details). A promising result of 94% con-
version and full conversion for 4b was obtained without generat-
ing any de-F, with excellent diastereoselectivity (>99%) and enan-
tioselectivity (97% ee) using 1.0 mol% catalyst F (entries 1 and
2). For both substrates 4a and 4b, a gradual decrease in the H2
pressure from 100 bar (entries 1 and 2) to 50 bar (entries 3 and 4)
to 20 bar (entries 5 and 6) using 1 mol% catalyst F, was effective
in terms of conversion and de-F. Decreasing the H2 pressure did
not have any negative effect on either the enantioselectivity (98%
ee) or the diastereoselectivity. However, a decrease in the catalyst
loading for substrate 4a from 1.0 mol% (entry 5) to 0.5 mol% (en-
try 7) at 20 bar of H2 pressure, significantly decreased the conver-
sion (71%). Further lowering the H2 pressure to 10 bar using 1
mol% of catalyst F (entry 9) lowers the conversion (65%). Simi-
larly, for substrate 4b a significantly lower quantity of desired
product 5b (76% yield) was observed when decreasing in catalyst
loading from 1 mol% to 0.5 mol% at 20 bar H2 pressure, probably
due to the formation of undesired side products (entry 8), which
could be, either indene derivative formed by Friedel-Crafts alkyla-
tion21 or ether derivative formed by the dimerization of the alco-
hol.22 A H2 pressure of 10 bar using 1 mol% of catalyst F afforded
5b in 65% yield along with 30% side products, without any de-F
(entry 10). Hence, an optimization study for both substrates 4a
and 4b confirmed that 20 bar H2 pressure with 1 mol% catalyst F
are most suitable in terms of stereoselectivity, conversion and de-
F (entries 5 and 6).
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using catalyst A, the products diethyl 2-ethyl-3-fluorosuccinate
conditions. The substrates containing one ester group such as 4a
and 4c could be successfully hydrogenated to afford 5a and 5c in
good yield: excellent diasteroselectivity (>99%) and enantioselec-
tivity (98% ee) without any de-F. The more sterically hindered
2m (97% ee) or 2-fluoro-3-isopropylsuccinate 2n were obtained
in excellent ee (>99%) without de-F. Catalyst D (4 mol%) proved
more beneficial for hydrogenation of tert-butyl-3-fluoromaleate
affording diethyl 2-(tert-butyl)-3-fluorosuccinate 2o in 51% con-
version with excellent >99% ee and almost no defluorination (2%
de-F). The aliphatic substrate dimethyl 2-fluoro-3-propylmaleate
was hydrogenated using catalyst F to give dimethyl 2-fluoro-3-
propylsuccinate 2p in 40% conversion and in good enantioselec-
tivity (91% ee). Using the reaction conditions reported here, vari-
ous types of fluoro-maleate were hydrogenated to the correspond-
ing fluoro-succinate in mostly good to excellent yield; exceptional
diastereoselectivities and enantioselectivities (>99%). Most sig-
nificantly with no or very small amounts of de-F being observed,
which emphasizes this catalytic system is very general for the
fluoro-maleate olefins.
1
2
3
4
5
6
7
8
iso-propyl
group
afforded
ethyl
2-fluoro-4-methyl-3-
phenylpentanoate 5d in 42% yield without compromising the dia-
stereoselectivity, enantioselectivity and de-F. Similarly, heterocy-
clic analog ethyl 2-fluoro-3-(thiophen-3-yl)butanoate 5e was ob-
tained in excellent ee (98%). Vinyl-fluorides containing a -
CH2OH functional group is also readily hydrogenated with this
catalytic system to provide 5b or 5f in excellent yields (99%) and
with high enantioselectivity (97% ee) without any detectable de-
fluorinated by-product. The wide scope of this catalytic system
also includes diol vinyl-fluoride affording 2-fluoro-3-
phenylbutane-1,4-diol 5g in 99% yield and 91% ee. Some inda-
none- and tetralone-derived vinyl-fluorides were also investigated.
The two isomers of ethyl-2-(2,3-dihydro-1H-inden-1-ylidene)-2-
fluoroacetate were hydrogenated to the corresponding ethyl 2-
(2,3-dihydro-1H-inden-1-yl)-2-fluoroacetate 5h and 5i in high
yields (99%) and ees (90% and 97% respectively). Ethyl (E)-2-
(3,4-dihydronaphthalen-1(2H)-ylidene)-2-fluoroacetate also pro-
duced the corresponding 5j in excellent yield (99%) and enanti-
oselectivity (>99% ee). Finally, excellent yield (99%) and very
good enantioselectivity (91-93% ee) were achieved for both the
isomers of ethyl-2-fluoro-3-methyl-5-phenylpent-2-enoate afford-
ing 5k and 5l. Again, it should be highlighted that the various tet-
ra-substituted vinyl-fluorides presented in this Table 4 produce a
single diasteromer and did not result in any trace of the defluori-
nated by-product.
9
10
11
12
13
14
15
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18
19
20
21
22
23
24
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49
50
51
52
53
54
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56
57
58
59
60
Table 3. Hydrogenation of various fluoro-maleate a
Table 4. Hydrogenation of various vinyl-fluoride containing
different functional groups a
a Reaction conditions: 0.05 mmol of substrate, 1 mol% catalyst F,
0.5 mL toluene. The conversion was determined by 1H-NMR.
Yields are isolated hydrogenated product, in some cases contain-
ing small amounts of de-F product. Enantiomeric excess was de-
termined by SFC or GC/MS using chiral stationary phases. b 1.0
mol% catalyst F, 8% de-F by-product, c 1.5 mol% catalyst F, d 2
a Reaction conditions: 0.05 mmol of substrate, 1 mol% catalyst F,
0.5 mL CH2Cl2. Enantiomeric excess was determined by SFC or
GC/MS using chiral stationary phases. b 2 mol% catalyst F.
e
g
mol% catalyst F, 4 mol% catalyst F, f 2 mol% catalyst A,
3
mol% catalyst A, h 4 mol% catalyst D.
To push the boundaries of this highly stereoselective hydrogena-
tion process we also evaluated a number of substrates that would
result in completely aliphatic chiral fluorine molecules with two
contiguous stereogenic centers (Table 5). This protocol was found
To further explore the efficacy of this oxazoline N,P-iridium cata-
lyzed hydrogenation of vinyl-fluorides, different types of sub-
strates 4 containing various functional groups as well as substitu-
ents (Table 4) were evaluated under the hydrogenation reaction
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to be independent of the aliphatic or aromatic nature of the sub-
was observed (13), a chiral molecule with two contiguous stereo-
genic centers, one chiral center containing F and another CF3, was
synthesized.
stituents and various aliphatic vinyl fluorides were efficaciously
hydrogenated in good to excellent yield with excellent diastere-
oselectivity and enantioselectivity. Interestingly, various cyclic or
acyclic primary, secondary and tertiary aliphatic substituents (8a-
8e, 8h and 8i) provided consistent results. Aliphatic substrate
ethyl (E)-3-cyclopropyl-2-fluorobut-2-enoate containing a vinylic
cyclopropane ring was hydrogenated without de-F with the for-
mation of volatile ethyl 3-cyclopropyl-2-fluorobutanoate 8f and a
small amount of ring-opened 2-fluoro-3-methylhexanoate 8g in
74% and 26% yield and excellent ee (97% and 93% respectively).
Cyclopropyl containing 8h and 8i reacted effortlessly without any
ring-opening of the strained three-membered ring. Similarly, ali-
phatic tetra-substituted vinyl-fluoride containing -CH2OH func-
tional group afforded the desired product 8j in 74% yield with
very good ee (94%).
1
2
3
4
5
6
7
8
Scheme 2b. Synthesis of ethyl 2,4,4,4-tetrafluoro-3-
phenylbutanoate.
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Finally, we wanted to demonstrate the usefulness of the hydro-
genated fluoro-succinates as precursors for the synthesis of vari-
ous types of enantiomerically enriched fluorine containing com-
pounds. The two esters in the hydrogenated product 2c can easily
be differentiated by an orthogonal de-protection using Pd-C in
toluene under 1 bar hydrogen pressure to give the desired 4-
ethoxy-3-fluoro-4-oxo-2-phenylbutanoic acid 14 in 90% isolated
yields as well as excellent ee (>99%) (Scheme 3).
Table 5. Hydrogenation of various aliphatic vinyl-fluorides a
HO2C
CO2Et
F
BnO2C
CO2Et
F
H2 (1 bar), Pd-C
Toluene, r.t., 24h
2c
14
90% yield
>99% ee
Scheme 3. Conversion of fluoro-succinates to ethoxy-3-fluoro-4-
oxo-2-phenylbutanoic acid.
We also performed a gram scale control experiment. Pleasingly,
applying 0.5 mol% of catalyst F and scaling up the reaction to 1 g
of starting material (4j), 5j was obtained in similar result (99%
yield, no defluorination, >99% dr and 97% ee) (Scheme 4). Ac-
cordingly, this Ir-catalyzed hydrogenation reaction was confirmed
to be particularly robust solution for the large scale production of
chiral fluorine molecules with two contiguous stereogenic centers
in mild and easy reaction conditions.
a Reaction conditions: 0.05 mmol of substrate, 1 mol% catalyst F,
b
0.5 mL CH2Cl2. 8c was obtained as mixture with 12% de-
fluorinated product. c Ethyl-2-fluoro-3-methylhexanoate (8g) was
obtained as side product (26% yield, >99% dr, 93% ee). The con-
1
version was determined by H-NMR. Enantiomeric excess was
determined by GC/MS using chiral stationary phases.
Notably, this method is also amenable for (3-fluorobut-2-en-2-
yl)benzene 10 and the hydrogenated product 11 was obtained in
55% yield and excellent ee (96%) with complete diasteroselectivi-
ty, where the chiral center containing fluorine is not α- to the car-
bonyl or the alcohol functional group (Scheme 2a).
Scheme 4. Gram-scale production of chiral fluorine molecules
with two contiguous stereogenic centers.
On the basis of computional23 and experimental studies24 the en-
antioselectivity of the reaction has been found to depend on the
steric interactions between substrate olefin and co-ordination
sphere around the catalyst F. The olefin coordinates vertically
trans to phosphorus, and from the perspective of the olefin the
area around the iridium can be divided into four quadrants as pre-
sented in Scheme 5b and 5c. The isopropyl group on the oxazo-
line ring occupies quadrant i, which becomes sterically hindered
quadrant. The o-EtPh groups on the phosphorus partially occupy
quadrant iv, which therefore becomes semi-hindered quadrant.
The other quadrants (ii and iii) do not have any significant parts of
the ligand pointing toward the incoming alkene and considered to
be open quadrants. For the tetrasubstituted vinylflourides, the ole-
fin (4d) is placed trans to phosphorus in such a way that the
smallest substituents (F) occupy the hindered quadrant i give the
Scheme 2a. Atom economical preparation of 3-fluorobutan-2-
yl)benzene.
Another interesting vinyl-fluoride 12 containing the CF3 function-
al group could also be hydrogenated under these developed cata-
lytic conditions with excellent diasteroselectivity and without any
de-F (Scheme 2b). Although a lower yield and enantioselectivity
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O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308. (e) Wang, J.; Sanchez-
Rosello, M.; Aceña, J. L.; Pozo, C. d.; Sorochinsky, A. E.; Fustero, S.;
Soloshonok, V. A.; Liu, H. Chem. Rev. 2013, 114, 2432.
most sterically favored arrangement (Scheme 5d). The other ar-
rangements are sterically unfavoured. So according to this model
the predicted absolute configuration of the hydrogenated product
5d would be 2R,3R. This absolute configuration was confirmed by
transformation into the known allylic alcolhol.25
1
2
3
4
5
6
7
8
2. Jeschke, P. ChemBioChem, 2004, 5, 570.
3. Hung, M. H.; Farnham, W. B.; Feiring, A. E.; Rozen, S. in Fluoro-
polymers: Synthesis Vol. 1 (eds Hougham, G., Cassidy, P. E., Johns,
K. & Davidson, T.) 51–66 (Plenum, 1999).
(a)
(c)
(b)
H
i
ii
i
ii
Et
Open
Hindered
4. (a) Smart, B. E. J. Fluorine Chem. 2001, 09, 3. (b) Ametamey, S.
M.; Honer, M.; Schubiger, P. A. Chem. Rev. 2008, 108, 1501. (c)
Yerien, D. E.; Bonesi, S.; Postigo, A. Org. Biomol. Chem. 2016, 14,
8398.
R2
R1
P
F
Et
N
P
R2 Ir
H
F
N
O
N
Semi-
hindered
R
Open
R1
H
iii
iv
R
iii
iv
H
9
(R)-F
Schematic 3D
quadrant model
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
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58
59
60
5. For selected references (a) Bohm, H.-J.; Banner, D.; Bendels, S.;
Kansy, M.; Kuhn, B.; Muller, K.; ObstSander, U.; Stahl, M. ChemBi-
oChem 2004, 5, 637. (b) Isanbor, C.; O’Hagan, D. J. Fluorine Chem.
2006, 127, 303. (c) Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013.
(d) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359. (e) Hunter, L.
Beilstein J. Org. Chem. 2010, 6, 38. (f) Gillis, E. P.; Eastman, K. J.;
Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. J. Med. Chem. 2015,
58, 8315.
(e)
Sterically unfavored
(f) Sterically unfavored
Sterically unfavored
(d)Sterically favored
(g)
i
i
i
i
ii
ii
ii
ii
F
CO2Et
EtO2
C
F
F
CO2Et
EtO2
C
F
iii
iii
iii
iii
iv
iv
iv
iv
F
CO2Et
(R)
EtO2
C
F
(R)
(S)
(S)
(S)
(R)
(S)
(R)
F
CO2Et
EtO2
C
F
6. (a) Gribble, G. W. in Progress in the Chemistry of Organic Natural
Products Vol. 68 (eds Herz, W.; Kirby, G. W.; Moore, R. E.; Steglich,
W.; Tamm, C.) 1–498 (Springer, 1996). (b) Gribble, G. W. in Pro-
gress in the Chemistry of Organic Natural Products Vol. 91 (eds
Kinghord, A. D.; Falk, H.; Kobayashi, J.) 1–613 (Springer, 2009).
Scheme 5. Determination of absolute configuration of olefin 4d.
CONCLUSION:
In conclusion, we have developed a new azabicyclo iridium-
oxazoline-phosphine-complex, which is very selective and effi-
cient in the hydrogenation of tetra-substituted vinyl-fluorides. The
reaction enables a simple, yet highly stereoselective preparation of
chiral fluorine molecules with two contiguous stereogenic centers.
The developed protocol has an exceptionally wide substrate scope
and is equally effective for various aromatic and aliphatic tetra-
substituted vinyl-fluorides, providing chiral fluoro-alkanes in ex-
cellent yield, diasteroselectivity and enantioselectivity. In addi-
tion, another major improvement of this simple but unique cata-
lytic hydrogenation process, is that it significantly overcomes the
problems of defluorination.
7. Walker, M. C.; Chang, M. C. Y. Chem. Soc. Rev. 2014, 43, 6527.
8. For selected references (a) Ma, J.-A.; Cahard, D. Chem. Rev. 2008,
108, PR1. (b) Babbio, C.; Gouverneur, V. Org. Biomol. Chem. 2006,
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45, 2172. (d) Pihko, P. M. Angew. Chem., Int. Ed. 2006, 45, 544. (e)
Brunet, V. A.; O’Hagan, D. Angew. Chem., Int. Ed. 2008, 47, 1179.
(f) Ueda, M.; Kano, T.; Maruoka, K. Org. Biomol. Chem. 2009, 7,
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Chem. Soc. Rev. 2010, 39, 558. (h) Zheng, Y.; Ma, J.-A. Adv. Synth.
Catal. 2010, 352, 2745. (i) Furuya, T.; Kamlet, A. S.; Ritter, T.
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Org. Chem. 2011, 831. (l) Hollingworth, C.; Gouverneur, V. Chem.
Commun. 2012, 48, 2929. (m) Liang, T.; Neumann, C. N.; Ritter, T.
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V.; Fernandes, T. A.; Santiago, C. B.; Talbot, E. P. A.; Sigman, M. S.;
McKenna, J. M.; Toste, F. D. Chem. Sci. 2017, 8, 2890. (o)
Hiramatsu, K.; Honjo, T.; Rauniyar, V.; Toste, F. D. ACS
Catal. 2016, 6, 161. (p) He, Y.; Yang, Z.; Thornbury, R. T.; Toste, F.
D. J. Am. Chem. Soc. 2015, 137, 12207. (q) Zi, W.; Wang, Y.-M.;
Toste, F. D. J. Am. Chem. Soc. 2014, 136, 12864. (r) Pupo, G. Ibba,
F.; Ascough, D. M. H. Vicini, A. C.; Ricci, P.; Christensen, K. E.;
Pfeifer, L.; Morphy, J. R.; Brown, J. M.; Paton, R. S.; Gouverneur, V.
Science 2018, 360, 638. (s) Banik, S. M.; Mennie, K.; Jacobsen, E.
N. J. Am. Chem. Soc. 2017, 139, 9152. (t) Woerly, E. M.; Banik, S.
M.; Jacobsen, E. N. J. Am. Chem. Soc. 2016, 138, 13858. (u) Witten,
M. R.; Jacobsen, E. N. Org. Lett. 2015, 17, 2772.
ASSOCIATED CONTENT
The Supporting Information is available free of charge via the In-
ternet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Pher.Andersson@su.se
Author Contributions
S.P. and W.R. contributed equally.
Notes
The authors declare no competing financial interest.
9. (a) Zhu, Y.; Han, J.; Wang, J.; Shibata, N.; Sodeoka, M.; So-
loshonok, V. A.; Coelho, J. A. S.; Toste, F. D. Chem. Rev. 2018,
118, 3887. (b) Yang, X.; Wu, T.; Phipps, R. J.; Toste, F. D. Chem.
Rev. 2015, 115, 826. (c) Cahard, D.; Bizet, V. Chem. Soc. Rev. 2014,
43, 135.
ACKNOWLEDGMENT
The Swedish Research Council (VR) and Stiftelsen Olle Engkvist
Byggmästare supported this work. S.P. thanks the Knut and Alice
Wallenberg foundation for his fellowship and Dr. Thishana Singh,
School of Chemistry and Physics, University of Kwazulu-Natal,
South Africa for proof reading and editing the manuscript.
10. (a) Bruns, S.; Haufe, G. J. Fluorine Chem. 2000, 104, 247. (b)
Haufe, G.; Bruns, S.; Runge, M. J. Fluorine Chem. 2001, 112, 55. (c)
Haufe, G.; Bruns, S. Adv. Synth. Catal. 2002, 344, 165. (d) Huang,
Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2005, 127, 15051. (e) Wang, H.-F.; Cui, H.-F.; Chai, Z.; Li, P.;
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ASYMMETRIC HYDROGENATION
R1 = Ar, Aliphatic, CF3
R2 = Ar, Aliphatic,
o-EtPh
R2
R1
R3
F
R2
R3
F
o-EtPh
Ir-N,P catalyst
H2 r.t.
P
*
*
N
Ir(COD)
N
R1
,
BArF
CO2R, CH2OH
R3 = CO2R, CH2OH, Me
>99% dr
O
Up to >99% ee
>40 examples
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R1
R2
F
R1
R
R2
F
Ir-N,P catalyst
H2, r.t.
*
*
R
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Me
F
Me
F
Ir-catalyst (F)
Me
* *
+
R
CH2Cl2, 24h
R
R
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Me
4a, R = CO2Et
4b, R = CH2OH
Me
Me
6
5
ee (%)b
Conversion (% of 5)a
5:6 (%)
Substrate
H2 (bar)
Catalyst (mol%)
Entry
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
97
97
98
97
98
98
96
97
96
97
94 (100)
99 (100)
92 (100)
99 (100)
90 (100)
99 (100)
71 (100)
99 (79)
4a
4b
4a
4b
4a
4b
4a
4b
4a
4b
100
100
50
50
20
20
20
20
10
10
1.0
1.0
1.0
1.0
1.0
1.0
0.5
0.5
1.0
1.0
1.
2.
3.
4.
5.
6.
7.
8.
65 (100)
99 (70)
9.
10.
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BnO2C
CO2Et
F
HO2C
CO2Et
F
H2 (1 bar), Pd-C
Toluene, r.t., 24h
14
2c
90% yield
>99% ee
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