A Copper(I)-Catalyzed Enantioselective γ-Boryl Substitution of Trifluoromethyl-Substituted Alkenes: Synthesis of Enantioenriched γ,γ-gem-Difluoroallylboronates

Article abstract of DOI:10.1002/anie.201803663

The first catalytic enantioselective γ-boryl substitution of CF₃-substituted alkenes is reported. A series of CF₃-substituted alkenes was treated with a diboron reagent in the presence of a copper(I)/Josiphos catalyst to afford the c

Full text of DOI:10.1002/anie.201803663

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Accepted Article
Title: A Copper(I)-Catalyzed Enantioselective γ-Boryl Substitution
of Trifluoromethyl-substituted Alkenes: Synthesis of
Enantioenriched γ,γ-gem-Difluoroallylboronates
Authors: Ryoto Kojima, Sota Akiyama, and Hajime Ito
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201803663
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10.1002/anie.201803663
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A Copper(I)-Catalyzed Enantioselective γ-Boryl Substitution of
Trifluoromethyl-substituted Alkenes: Synthesis of
Enantioenriched γ,γ-gem-Difluoroallylboronates
Ryoto Kojima, Sota Akiyama and Hajime Ito*[a]
Abstract: The first catalytic enantioselective γ-boryl substitution of
CF3-substituted alkenes is reported. A series of CF3-substituted
alkenes was treated with a diboron reagent in the presence of a
copper(I)/Josiphos catalyst to afford the corresponding optically active
γ,γ-gem-difluoroallylboronates in high enantioselectivity. The thus
obtained products could be readily converted into the corresponding
difluoromethylene-containing homoallylic alcohols using highly
stereospecific allylation reactions.
powerful approach to generate alcohols. Early studies on the
enantioselective addition of trifluoromethyl nucleophiles (CF3Nu)
to carbonyl compounds have been reported by e.g. Feng,[3]
Mukaiyama,[4] and Shibata[5], and many others.[6] The
enantioselective addition of difluoromethyl nucleophiles
(CHF2Nu) to carbonyl compounds is limited to one case reported
by Hu and co-workers that proceeded in moderate
enantioselectivity (up to 64% ee).[7] Jacobsen has recently
reported
a unique catalytic method for the asymmetric
difluorination of alkenes to generate difluoromethylated
stereocenters.[8]
The selective synthesis of fluorinated compounds is one of the
most important research subjects in pharmaceutical and
agrochemical science, as the molecular properties of substrates
change dramatically upon the introduction of fluorine atom(s).[1]
Similar to the trifluoromethyl group (-CF3), the introduction of the
difluoromethylene (-CF2-) group often induces beneficial effects
to biologically active target molecules, and
a variety of
difluoromethylene-containing drugs and agrochemicals, such as
Tafluprost and Lubiprostone, has been developed (Figure 1).[2] In
the area of pharmaceutical science, the demand for optically
active organic compounds has increased steadily, and
enantioselective difluoromethylation methods have been
developed accordingly.
Figure 1. Representative Bioactive gem-Difluoromethylene-containing
Molecules.
O
O
O
OH
O
H
Scheme 1. Catalytic Enantioselective Synthesis of Allyl Boronates
H
O
HO
HO
HO
C
F
F
Asymmetric copper-catalyzed borylations represent
a
C
O
powerful tool for the synthesis of optically active organoboron
compounds.[9] We and other groups have reported the
asymmetric synthesis of allylboron compounds via the
asymmetric boryl substitution of allylic compounds (Scheme
1a).[10] The allylboration of aldehydes with enantio-enriched
allylboronates generally proceeds in a highly stereospecific
manner.[11] The reaction mechanism should include the
enantioselective addition of a borylcopper intermediate and the β-
elimination of the heteroatom and the copper moiety. In 2011,
F
F
Tafluprost
Lubiprostone
Several approaches have been reported that generate a chiral
center at the same time. For example, the enantioselective
addition of fluorinated nucleophiles to carbonyl compounds is a
[a]
Dr. R. Kojima, S. Akiyama and Prof. Dr. H. Ito
Division of Applied Chemistry and Frontier Chemistry Center,
Faculty of Engineering, Hokkaido University
Kita 13 Nishi 8 Kita-ku, Sapporo, Hokkaido 060-8628 (Japan)
E-mail: hajito@eng.hokudai.ac.jp
Hoveyda
carbene/copper(I)-catalyzed
and
co-workers
reported
borylations
N-heterocyclic
of an α-
(trifluoromethyl)styrene derivative that produce an achiral β,β-
difluorostyrene derivative, wherein the β-fluorine elimination is
involved in the catalytic cycle.[12,13] Recently, Zhou and co-workers
have reported the synthesis of γ,γ-gem-difluoroallylboronates via
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201803663
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COMMUNICATION
iron-catalyzed boryl substitutions.[14,15] However, to the best of our
knowledge, examples for the catalytic enantioselective synthesis
of gem-difluoroallylboronates have not yet been reported. We
anticipated that γ,γ-gem-difluoroallylboronates with a chiral C–B
bond could potentially be synthesized from CF3-substituted
alkenes via a similar mechanism, provided that the addition of the
borylcopper proceeds enantioselectively (Scheme 1b). We
hypothesized that this reaction may offer an efficient pathway to
stereodefined β,β-difluoro homoallylic alcohols. Herein, we report
an enantioselective γ-boryl substitution of CF3-substituted
alkenes with a diboron compound that is catalyzed by a
copper(I)/Josiphos catalyst system, and that provides optically
2[e]
3[f]
4
(R,S)-L1
(R,S)-L1
24
4
<5
84
94
91
89
91
90
80
92
92
97
–
97
46
96
93
–5
–84
84
50
40
–61
(R,S)-L2
2
5
(R,S)-L3
2
6
(R,S)-L4
2
7
(R,S)-Walphos
(R,R)-BenzP*
(R,R)-QuinoxP*
(R)-Segphos
(R,R)-Me-Duphos
(R,S)-L1
1
8
1
9
21
1
active
boronates
gem-difluoroallylboronates.
were converted into
Subsequently,
the corresponding
these
10
11
12[g]
difluoromethylene-containing homoallylic alcohols via allylation
reactions (Scheme 2).
8
2
The reaction between CF3-substituted alkene (E)-1a and
bis(pinacolato)diboron (1.5 equiv) in the presence of a CuCl
complex of the Josiphos-type ligand (R,S)-L1 (5 mol%) and
NaOMe (1.2 equiv) in THF at 30 °C afforded (R)-2a in high yield
(91%) and excellent enantioselectivity (97% ee) (Table 1, entry 1).
Upon decreasing the amount of NaOMe to 10 mol%, the boryl
substitution scarcely proceeded (Table 1, entry 2). The absolute
configuration of the product 2a was determined by single crystal
X-ray structure analysis (Supporting Information p S19–20).
When the reaction was conducted at 0 °C, the yield decreased
slightly (84%, 97% ee; Table 1, entry 3). Several other Josiphos-
type ligands [(R,S)-L2–(R,S)-L4] were also evaluated, but these
afforded (R)-2a in lower enantioselectivity than that obtained in
entry 1 (Table 1, entries 4–6). The use of (R,S)-Walphos also
provided (R)-2a (91% yield), albeit in much lower
enantioselectivity than (R,S)-L1 (entry 7). The reaction was also
evaluated using other types of chiral bisphosphine ligands. The
use of (R,R)-BenzP* and (R,R)-QuinoxP*, which are effective for
enantioselective allylic boryl substitutions,[10] afforded (R)-2a in
lower enantioselectivity than (R,S)-L1 (Table 1, entries 8 and 9).
The use of (R)-Segphos and (R,R)-Me-Duphos also afforded
inferior results (Table 1, entries 10 and 11). Interestingly, the
application of the optimum reaction conditions to (Z)-1a instead of
(E)-1a resulted in a significantly lower enantioselectivity (Table 1,
entry 12).
[a] Reagents and conditions: CuCl (0.013 mmol), ligand (0.013 mmol), (E)-1a
(0.25 mmol), bis(pinacolato)diboron (0.38 mmol), and NaOMe (0.38 mmol) in
THF (0.5 mL) at 30 ºC. [b] NMR yield. The isolated yield is shown in
parentheses. [c] The ee value of (R)-2a was determined by HPLC analysis of
the alcohol derived from the obtained boronate. [d] 0.5 mmol scale. [e] 10 mol%
of NaOMe. [f] T = 0 ºC. [g] (Z)-1a was used as the substrate.
With the optimized conditions in hand, we proceeded to
evaluate the substrate scope of this reaction (Table 2). Substrates
containing a hexyl or methylcyclohexyl group [(E)-1b–c] also
afforded the corresponding products in high yield and excellent
enantioselectivity [(R)-2b: 89% yield, 97% ee; (R)-2c: 90% yield,
96% ee]. The branched CF3-substituted alkene (E)-1d, which is
sterically congested around its C=C bond, also smoothly afforded
the corresponding product (88% yield, 50% ee). Interestingly,
tetra-substituted gem-difluoroallylboronate (R)-2e was not formed,
probably due to the steric hindrance. The CF3-substituted alkenes
(E)-1f–1h, which bear benzyl ether, silyl ether, or prenyloxy
groups also smoothly furnished the corresponding products in
high yield and excellent enantioselectivity [(S)-2f: 65% yield, 97%
ee; (S)-2g: 78% yield, 97% ee; (R)-2h: 76% yield, 96% ee].
Substrate (E)-1i, which contains a chloro group that may engage
in copper(I)-catalyzed boryl substitutions, could also be used
under these conditions, and the formation of side-products was
not detected [(R)-2i: 80% yield, 97% ee].[16] CF3-substituted
alkenes containing phthalimide [(E)-1j] or secondary/tertiary
amino groups [(E)-1k–l] also furnished the target compounds in
high yield and excellent enantioselectivity [(S)-2j: 61% yield, 97%
ee; (S)-2k: 88% yield, 96% ee; (S)-2l: 89% yield, 95% ee]. The
reaction of estrone-type substrate (E)-1m provided (S)-2m in high
yield and excellent diastereoselectivity (90% yield, 96% de).
Table 1. Optimization of the Reaction Conditions for the Copper(I)-Catalyzed
Enantioselective Boryl Substitution of CF3-substituted Alkene (E)-1a.[a]
5 mol% CuCl
5 mol% ligand
(pin)B–B(pin) (1.5 equiv)
F
B(pin)
F
F
F
NaOMe (1.5 equiv)
THF, 30 ºC
Ph
F
Ph
(E)-1a
(R)-2a
PR'2
Me
Table 2. Substrate Scope of the Copper(I)-Catalyzed Enantioselective Boryl
Substitution of CF3-substituted Alkene (E)-1.[a]
R2P
PPh2
Fe
PCy2
Me
Fe
(R,S)-L1: R = Ph, R' = t-Bu
(R,S)-L2: R = Cy, R' = Cy
(R,S)-L3: R = Ph, R' = Cy
(R,S)-L4: R = 3,5-(t-Bu)2-4-OMe-C6H2, R' = Cy
(R,S)-Walphos
Entry
1[d]
Chiral Ligand
Time (h)
2
Yield (%)[b]
91 (85)
ee (%)[c]
97
(R,S)-L1
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10.1002/anie.201803663
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CuCl (5 mol%)
transformation of gem-difluoroallylboronates. For that purpose,
(R)-2a was subjected to an oxidation with NaBO3 or to a
homologation with a halomethyl lithium reagent.[17,18] These
reactions afforded the corresponding alcohol (R)-3 (73%, 97% ee)
and homoallylboronate (R)-4 (66%, 97% ee), respectively.
(R,S)-L1 (5 mol%)
(pin)B–B(pin) (1.5 equiv)
B(pin)
R
F
F
F
F
NaOMe (1.5 equiv)
THF, 30 ºC
R
F
(E)-1
2
B(pin)
Cy
B(pin)
B(pin)
Cy
F
F
F
We then investigated the allylation of carbonyls with gem-
difluoroallylboronate 2 (Table 3). The reaction of (R)-2a with
benzaldehyde, 3-phenylpropionaldehyde, acetaldehyde, and
acetophenone using Aggarwal’s carbonyl allylation conditions[19]
afforded the corresponding homoallylic alcohols [(R,E)-5a–c] in
high stereoselectivity and stereospecificity. The absolute
configuration of the product 5b was confirmed by single crystal X-
ray structure analysis (Supporting Information p S20–21). The
reaction of (S)-2f with benzaldehyde or phenylacetaldehyde,
followed by t-butyldimethylsilyl (TBS) deprotection using
tetrabutylammonium fluoride (TBAF), provided diols (R,E)-6d and
(R,E)-6e, respectively, in high stereoselectivity. Notably, (R,E)-6d
and (R,E)-6e are important depsipeptide and dipeptide isostere
intermediates. Taguchi and co-workers have reported the
diastereoselective synthesis of functionalized (Z)-fluoroalkenes
F
F
Hex
(R)-2b, 1 h
89%, 97% ee
F
(R)-2c, 1 h
90%, 96% ee
(R)-2d[b], 24 h
88%, 50% ee
B(pin)
F
B(pin)
OTBS
B(pin)
OBn
F
F
F
F
F
Ph
(R)-2e, 24 h
trace
(S)-2f, 2 h
65%, 97% ee
(S)-2g, 1 h
78%, 97% ee
B(pin)
F
B(pin)
F
O
3
Cl
F
F
(R)-2h, 2 h
76%, 96% ee
(R)-2i, 2 h
80%, 97% ee
B(pin)
NPhth
B(pin)
NHPh
B(pin)
NMePh
F
F
F
F
F
F
using
a copper(I)-mediated alkyl transfer reaction and a
(S)-2j, 2 h
61%, 97% ee
(S)-2k[c], 2 h
(88%), 96% ee
(S)-2l[c], 1 h
(89%), 95% ee
subsequent oxidation of the primary hydroxyl group of the racemic
(E)-4,4-difluoro-5-hydroxyallylic alcohol derivatives.[20] The
method presented herein represents the first example of an
enantioselective boryl substitution/stereoselective allylation
sequence that should find further applications in synthetic and
medicinal chemistry.
B(pin)
F
O
F
H
H
H
(S)-2m, 2 h
90%, 96% de
O
Table 3. Allylation of Carbonyl Compounds with gem-Difluoroallylboronate 2.[a–
c]
[a] Reagents and conditions: CuCl (0.025 mmol), ligand (0.025 mmol), (E)-1 (0.5
mmol), bis(pinacolato)diboron (0.75 mmol), and NaOMe (0.75 mmol) in THF (1
mL) at 30 ºC. The ee values of 2 were determined by HPLC analysis after
oxidation or esterification. [b] T = 50 ºC. [c] NMR yield of the boronate in the
crude reaction mixture. The alcohol derivative was isolated after oxidation of the
crude reaction mixture [(S)-3k: 78% isolated yield; (S)-3l: 70% isolated yield].
TBS = tert-butyldimethylsilyl. Phth = phthalimide.
1. n-BuLi (1.1 equiv)
THF, –78°C, 15 min
3. Electrophile
(1.5 equiv)
F
F
B(pin)
R
F
R1
R
2. TFAA (1.2 equiv)
30 min.
–78°C to rt
F
HO R2
(R,E)-5
2
F
F
F
F
Ph
Ph
Ph
Ph
CuCl (5 mol%)
(R,S)-L1 (5 mol%)
(pin)B–B(pin) (1.5 equiv)
OH
(R,E)-5a, 86%
E/Z >95:5, 97% ee
OH
B(pin)
F
(R,E)-5b, 65%
E/Z 95:5, 97% ee
(E)-1a
NaOMe (1.5 equiv)
THF, 30 °C, 2 h
F
Ph
F
F
(5.0 mmol)
(R)-2a
88%, 97% ee
(1.34 g)
Ph
(R,E)-5c, 49%
E/Z >95:5, 97% ee
Ph
HO Me
F
NaBO3⋅4H2O
(10 equiv)
THF/H2O, rt, 24 h
ClCH2Br (2.0 equiv)
n-BuLi (1.5 equiv)
THF, –78 °C then rt, 2 h
F
F
F
Ph
OH
Bn
OH
OH
OH
B(pin)
F
(R,E)-6d, 73% (2 steps)[d]
(R,E)-6e, 72% (2 steps)[d]
F
OH
E/Z >95:5, 98% ee
E/Z 89:11, 95% ee
F
Ph
F
Ph
(R)-3, 73%, 97% ee
(R)-4, 66%, 97% ee
[a] Reagents and conditions: 2 (0.25 mmol), n-BuLi (0.28 mmol), TFAA (0.30
mmol), electrophile (0.38 mmol), in THF (2.5 mL); T= –78 °C ® r.t. [b] The E/Z
ratio of the products was determined by 1H NMR spectroscopy and HPLC. [c]
Isolated product yields. The ee values of the products were determined by
HPLC. [d] The product was isolated after treatment with TBAF/THF. TFAA =
trifluoracetic anhydride. TBAF = tetrabutylammonium fluoride.
Scheme 2. Gram-Scale Synthesis of Enantioenriched Chiral gem-
Difluoroallylboronates and Their Subsequent Derivatization.
To demonstrate the synthetic utility of this method, we
investigated a gram-scale synthesis of gem-difluoroallylboronates
(Scheme 2). When the boryl substitution of (E)-1a was carried out
on a 5.0-mmol scale, (R)-2a was obtained in high yield and
excellent enantioselectivity (88%, 97% ee). We also examined the
In conclusion, we have developed the first example of an
enantioselective copper(I)-catalyzed γ-substitution of CF3-
substituted alkenes that provides access to optically active γ,γ-
gem-difluoroallylboronates. The synthetic utility of this
borylation/allylboration procedure manifests in e.g. the modular
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L. Collins, C. M. Wilson, E. L. Myers, V. K. Aggarwal, Angew. Chem., Int.
Ed. 2017, 56, 11700; Angew. Chem. 2017, 129, 11860.
construction of difluoromethylene scaffolds; the enantioenriched
gem-difluoroallylboronates can moreover be readily transformed
into useful secondary products, such as depsipeptide isosteres.
[10] a) H. Ito, S. Ito, Y. Sasaki, K. Matsuura, M. Sawamura, J. Am. Chem.
Soc. 2007, 129, 14856; b) H. Ito, T. Okura, K. Matsuura, M. Sawamura,
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Acknowledgements
The authors would like to thank Prof. T. Seki and T. Sumitani
(Hokkaido University) for their technical assistance with the X-ray
crystallographic analysis. This work was financially supported by
the Japanese Ministry of Education, Culture, Sports, Science and
Technology (MEXT) via the “Program for Leading Graduate
Schools” (Hokkaido University “Ambitious Leaders Program”),
and by the Japan Society for the Promotion of Science via
KAKENHI grants 15H03804 and 18H03907.
[11] a) Boronic Acids: Preparation and Applications in Organic synthesis,
Medicine and Materials, 2nd revised ed.; D. G. Hall, Ed.; Wiley-VCH:
Weinheim, 2011; b) C. Diner, K. J. Szabó, J. Am. Chem. Soc. 2017, 139,
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[12] R. Corberán, N. W. Mszar, A. H. Hoveyda, Angew. Chem., Int. Ed. 2011,
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[13] For selected recent examples on copper(I)-catalyzed defluoroborylation
reactions, see: a) R. Kojima, K. Kubota, H. Ito, Chem. Commun. 2017,
53, 10688; b) H. Sakaguchi, Y. Uetake, M. Ohashi, T. Niwa, S. Ogoshi,
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Keywords: Asymmetric catalysis • Boron • Copper • Fluorine •
Synthetic methods
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10.1002/anie.201803663
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
Ryoto Kojima, Sota Akiyama and Hajime
Ito*
i) n-BuLi
ii) TFAA
cat. Cu/L*
(pin)B–B(pin)
F
F
up to 86% yield
up to E/Z >95:5
up to 100% es
B(pin)
F
F
R1
F
F
R
O
iii)
NaOMe
F
R
R
Page No. – Page No.
HO R2
R1
R2
A Copper(I)-Catalyzed
Enantioselective γ-Boryl Substitution
of Trifluoromethyl-substituted
Alkenes: Synthesis of
Enantioenriched γ,γ-gem-
Difluoroallylboronates
The first catalytic enantioselective γ-boryl substitution of CF3-substituted alkenes
was accomplished by treatment of a series of CF3-substituted alkenes with a
diboron reagent in the presence of a copper(I)/Josiphos catalyst, which afforded the
corresponding optically active γ,γ-gem-difluoroallylboronates in high yield and
enantioselectivity.
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