Copper(I)-Catalyzed Enantioselective Nucleophilic Borylation of Aliphatic Ketones: Synthesis of Enantioenriched Chiral Tertiary α-Hydroxyboronates

Article abstract of DOI:10.1002/anie.201702826

A new method was developed for the first catalytic enantioselective borylation of aliphatic ketones. A variety of substrates reacted efficiently with bis(pinacolato)diboron in the presence of a copper(I)/chiral N-heterocyclic carbene complex catalyst to furnish optically active tertiary α-hydroxyboronates with moderate to high enantioselectivities (up to 94 % ee). Notably, the product could be converted into the chiral tertiary alcohol derivative using a stereospecific boron functionalization process. The theoretical study of the mechanism for the enantioselectivity is also described.

Full text of DOI:10.1002/anie.201702826

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201702826
German Edition: DOI: 10.1002/ange.201702826
Asymmetric Catalysis
Copper(I)-Catalyzed Enantioselective Nucleophilic Borylation of
Aliphatic Ketones: Synthesis of Enantioenriched Chiral Tertiary
a-Hydroxyboronates
Koji Kubota, Shun Osaki, Mingoo Jin, and Hajime Ito*
Abstract: A new method was developed for the first catalytic
enantioselective borylation of aliphatic ketones. A variety of
substrates reacted efficiently with bis(pinacolato)diboron in the
presence of a copper(I)/chiral N-heterocyclic carbene complex
catalyst to furnish optically active tertiary a-hydroxyboronates
with moderate to high enantioselectivities (up to 94% ee).
Notably, the product could be converted into the chiral tertiary
alcohol derivative using a stereospecific boron functionaliza-
tion process. The theoretical study of the mechanism for the
enantioselectivity is also described.
C
hiral a-heteroatom-substituted organoboron compounds
have attracted considerable interest because of their wide
range of potential applications in asymmetric synthesis and
medicinal chemistry.[1] The development of efficient routes
for the preparation of compounds belonging to this structural
class has therefore captured the imagination of several
research groups. The asymmetric addition of a boron nucle-
ophile to a polarized carbon–heteroatom double bond is one
of the most straightforward methods for the synthesis of chiral
a-heteroatom-substituted organoborons.[2–4] For example,
Ellman and co-workers[2a] reported that the copper(I)-cata-
lyzed asymmetric diboration of aldimines in the presence of
a chiral auxiliary gave the corresponding chiral a-amino-
boronates, which are inhibitors of serine protease. The groups
of Fernꢀndez,[3a] Lin,[3b] Liao,[3c] and Morken[3d] independently
reported the catalytic enantioselective borylation of aldi-
mines to afford the corresponding a-aminoboronates with
high enantioselectivity. Most recently, we reported the first
Scheme 1. Umpolung nucleophilic enantioselective borylation of car-
bonyl compounds. THF=tetrahydrofuran.
the synthesis of new pharmacophores and chiral intermedi-
ates for synthesis.[5] The main challenge to the development of
such a method is the fact that ketones exhibit a much smaller
degree of steric contrast between the substituents attached to
their carbonyl group compared with aldehydes.[6] Catalytic
enantioselective addition of aliphatic ketones is extremely
difficult, although this approach can construct a chiral
quaternary carbon center with high enantioselectivity.[6] For
example, to the best of our knowledge, there is only one
example of catalytic enantioselective arylation of aliphatic
ketones to give chiral tertiary alcohols with high enantiose-
lectivity (> 80% ee).[7]
Clark and co-workers conducted a pioneering study of the
catalytic borylation of ketones in 2010, and found that an
achiral N-heterocyclic carbene (NHC)/copper(I) complex
could be used to catalyze the diboration of various ketones
to give the corresponding racemic tertiary a-hydroxyboro-
nates in high yields.[8,9] However, this work has not yet been
extended to the development of an enantioselective pro-
cess.[10,11] Herein, we report for the first time the enantiose-
lective borylation of the aliphatic ketones 4 with 2 in the
presence of a chiral NHC/copper(I) complex catalyst to give
the corresponding chiral tertiary a-hydroxyboronates 5 with
moderate to high enantioselectivities (Scheme 1b).
The results of an extensive optimization study revealed
that 1-cyclohexylethan-1-one (4a) reacted with 2 (1.1 equiv)
in THF at ambient temperature in the presence of CuCl
(5 mol%) and an NHC salt, derived from trans-1-amino-2-
indanol (S,S)-L1 (5 mol%),[12] KOtBu (1.0 equiv), and MeOH
(2.0 equiv) as a proton source, to afford the corresponding
chiral tertiary a-hydroxyboronate (S)-5a in good yield with
high enantioselectivity (Table 1, entry 1). Several other trans-
1-amino-2-indanol-based chiral NHC salts [(S,S)-L2–(S,S)-
L5] were also evaluated, but afforded lower enantioselectiv-
=
enantioselective borylation of a C O double bond (Sche-
me 1a).[4] A series of aldehydes (1) reacted with bis(pinaco-
lato)diboron (2) in the presence of a chiral copper(I) catalyst
to produce the corresponding enantiomerically enriched
a-alkoxyboronates 3. Despite recent advances toward the
development of enantioselective methods for the borylation
of prochiral carbon–heteroatom double bonds, there are
currently no methods available for the synthesis of chiral
tertiary a-hydroxyboronates from ketones. The development
of an efficient method for the enantioselective nucleophilic
borylation of ketones is therefore highly desired to facilitate
[*] Dr. K. Kubota, S. Osaki, M. Jin, Prof. Dr. H. Ito
Division of Applied Chemistry, Graduate School of Engineering
Hokkaido University, Sapporo
Hokkaido, 060-8628 (Japan)
E-mail: hajito@eng.hokudai.ac.jp
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201702826.
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Table 1: Optimization of the reaction conditions.[a]
low enantioselectivities (entries 7–9). The reaction was also
evaluated using chiral bis(phosphine) ligands (entries 10–12).
The use of the bulky (R)-DTBM-SEGPHOS ligand (R)-L10,
which was found to be effective for the enantioselective
borylation of aldehydes,[4] resulted in no reaction (entry 10).
In contrast, chiral ligands bearing electron-donating alkyl
substituents on the phosphine atoms, for example, (R,R)-
QuinoxP* [(R,R)-L11] and (R,R)-Me-Duphos [(R,R)-L12],
provided access to the desired product, but showed poor
enantioselectivities (entries 11 and 12). The nature of the
proton source was also found to be important to the reactivity
and enantioselectivity of this transformation (entries 13–15).
The use of increasingly bulky proton sources such as iPrOH
and tBuOH, instead of MeOH, resulted in lower yields and
enantioselectivities (entries 13 and 14). Furthermore, the
reaction gave a lower yield and enantioselectivity when it
was conducted in the absence of MeOH (entry 15). Although
the borylation proceeded smoothly with only 0.5 equivalents
of KOtBu, we observed a slight decrease in the enantiose-
lectivity (entry 16). Several other alkoxide bases were also
evaluated in this reaction, including NaOtBu and LiOtBu, but
all afforded lower levels of enantioselectivity (entries 17 and
18). To exclude the possibility that this reaction could proceed
by a metal-free mechanism[14] involving the activation of the
diboron reagent by either the Lewis basic KOtBu or the
carbene generated in situ, we conducted the borylation in the
absence of a copper(I) salt (entry 19). The reaction of 4a with
2 in the presence of (S,S)-L1 and no copper afforded a much
lower yield of the desired product (28%) even after an
extended reaction time (48 h). This reaction also resulted in
a lower enantioselectivity (79% ee), thus discounting the
possibility of a metal-free mechanism.
Entry
Ligand
Alcohol
Yield [%][b]
ee [%][c]
1
(S,S)-L1
(S,S)-L2
(S,S)-L3
(S,S)-L4
(S,S)-L5
(S,S)-L6
(R,R)-L7
(R,R)-L8
(R,R)-L9
(R)-L10
(R,R)-L11
(R,R)-L12
(S,S)-L1
(S,S)-L1
(S,S)-L1
(S,S)-L1
(S,S)-L1
(S,S)-L1
(S,S)-L1
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
iPrOH
tBuOH
none
96
50
91
85
84
60
87
65
14
<5
58
99
84
33
86
86
86
72
28
92
35
56
63
67
21
10
3
0
–
1
5
91
83
81
89
84
73
79
2[d]
3
4
5
6
7
8
9
10
11
12
13
14
15
16[e]
17[f]
18[g]
19[h]
MeOH
MeOH
MeOH
MeOH
With the optimized reaction conditions in hand, we
proceeded to evaluate of the substrate scope of this reaction
(Table 2). Methyl ketones bearing a-branched aliphatic rings
(4b–f) reacted smoothly to give the corresponding chiral
tertiary a-hydroxyboronates [(S)-5b–f] with excellent enan-
tioselectivities (88–94% ee). The ethyl ketone 4g also reacted
well under the optimized reaction conditions, but gave a lower
enantioselectivity, thus indicating that the ability of the
catalyst to differentiate between a methyl group and an
a-branched structure was responsible for the high enantiose-
lectivity of this reaction. Various ketones bearing a-branched
linear aliphatic chains (4h–k) were also borylated with high
enantioselectivities (87–90% ee). The current catalytic system
was also effective for the borylation of the b-branched methyl
ketone 4l, thus providing facile access to the corresponding
product (S)-5l with good enantioselectivity (83% ee). The
a-aryl- and b-phenyl-substituted methyl ketones 4m and 4n,
respectively, also reacted to provide the corresponding
borylated products (S)-5m and (S)-5n with good yields and
enantioselectivities. The reaction of butan-2-one (4o), which
represents one of the most challenging substrates for this
method, provided the product (S)-5o with good enantiose-
lectivity (73% ee). Although acetophenone was also bory-
lated under the optimization reaction conditions, the product
decomposed during purification by column chromatography
over silica gel.
[a] Reaction conditions: CuCl (0.025 mmol), ligand (0.025 mmol), 4a
(0.5 mmol), bis(pinacolato)diboron (2) (0.55 mmol), alcohol
(1.0 mmol), and KOtBu (0.5 mmol) in THF (1.0 mL) at room temper-
ature. [b] Determined by NMR spectroscopy. [c] The ee values of (S)-5a
were determined by HPLC analysis after the acylation of the resulting
alcohol. [d] The reaction time was 18 h. [e] KOtBu (0.5 equiv, 0.25 mmol)
was used. [f] NaOtBu (1.0 equiv, 0.5 mmol) was used instead of KOtBu.
[g] LiOtBu (1.0 equiv, 0.5 mmol) was used instead of KOtBu. [h] The
reaction was conducted without CuCl over 48 h.
ities (entries 2–5). The use of the NHC salt (S,S)-L6, bearing
a methoxy group instead of a hydroxy group, also provided
the desired product (60% yield), but with a much lower
enantioselectivity than (S,S)-L1 (entry 6). The C2- and C1-
symmetric NHC salts (R,R)-L7–(R,R)-L9[10a,13] also showed
2
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Table 2: Substrate scope.[a,b]
pounds.[5] With this in mind, we conducted a preliminary
À
investigation of the stereospecific C C bond-forming reac-
tion of the chiral boronates (Scheme 2). The Aggarwal cross-
coupling reaction[15] of the silyl-protected product (S)-7 with
Scheme 2. Stereospecific cross-coupling reaction with benzofuran.
NBS=N-bromosuccinimide, TES=triethylsilyl.
benzofuran proceeded to afford the arylated, chiral tertiary
alcohol (S)-8 with excellent stereospecificity (> 99% es). This
result therefore suggested that the borylation product will
provide attractive synthetic pathways for useful chiral tertiary
alcohols, which could not be synthesized by previous methods.
This copper(I)-catalyzed ketone borylation reaction pre-
sumably goes through the formation of a borylcopper(I)
complex, followed by its 1,2-addition of substrates 4 (see the
Supporting Information for the proposed reaction path-
way).[8,16] Density functional theory (DFT) calculations
(wB97XD/SDDTHF(PCM): Cu and K// wB97XD/6-311G(d)
THF(PCM): other atoms) were used to investigate the mechanism
for the unprecedented high enantioselectivity of the reaction
(Figure 2; see also the Supporting Information for details).
The results revealed that the addition of the (S,S)-L1/
borylcopper(I) complex to 4k would give the transition
states TS1 and TS2, in which the alkoxide anion resulting
from deprotonation of the hydroxy group in (S,S)-L1
coordinates to the copper center to form the bidentate
carbene complex.[12] The calculation also suggested that the
[a] Reaction conditions: CuCl (0.025 mmol), (S,S)-L1 (0.025 mmol), 4
(0.5 mmol), bis(pinacolato)diboron (2) (0.55 mmol), MeOH
(1.0 mmol), and KOtBu (0.5 mmol) in THF (1.0 mL) at room temper-
ature. [b] Yield of isolated product.
The absolute stereochemistry of the borylation product 5a
was determined by X-ray crystallographic analysis of its
acylated derivative 6 (Figure 1). The results of this analysis
confirmed the structure of 6 and revealed that the absolute
configuration of its chiral center was S.
Enantioenriched tertiary a-hydroxyboronates prepared in
the current study could be used as synthetic building blocks
for the preparation of various functionalized chiral com-
Figure 2. DFT calculations (wB97XD/SDDTHF(PCM): Cu and K//wB97XD/
6-311G(d)THF(PCM): other atoms) of the transition states for the (S,S)-
L1/copper(I)-catalyzed enantioselective borylation of the ketone 4k.
Relative G value (kcalmolÀ1) were obtained at 273 K.
Figure 1. Molecular structure of 6 (thermal ellipsoids set at 50%
probability; hydrogen atoms omitted for clarity). DMAP=4-(N,N-
dimethylamino)pyridine.
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carbonyl oxygen atom in the substrate coordinates to the
potassium cation to give a conformationally rigid transition
state. The addition of the complex to the Re-face to give
transition state TS1 would be free from steric congestion
between the copper complex and the substituents of the
substrates, and would therefore afford the S isomer as the
major product. This arrangement is consistent with the
observed absolute configuration of the borylated product
(Figure 1). In contrast, the activation barrier for the addition
of the complex to the Si-face to give TS2 was + 2.98 kcalmolÀ1
higher in energy than that of TS1. This difference in the
activation barrier was attributed to steric congestion between
the isopropyl moiety in the substrate and the aryl group in the
ligand, thereby explaining the observed enantioselectivity of
this reaction. As noted above, (S,S)-L6, bearing a methoxy
group instead of a hydroxy group on its indane ring, resulted
in a lower enantioselectivity (Table 1, entry 6, 20% ee). Thus,
these theoretical and experimental results suggest that the
formation of the bidentate carbene complex as well as the
interaction between the potassium cation and the substrate
are key factors in providing a higher selectivity in this
reaction.
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tions, by using a copper(I)/chiral carbene complex catalyst.
The method provides facile access to chiral tertiary
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À
tertiary alcohol derivative using a C C bond-forming reac-
tion. We therefore believe that this work will provide
a platform for the preparation of useful chiral functionalized
tertiary alcohols which are difficult to access using any other
method.
Acknowledgements
This study was financially supported by the MEXT (Japan)
program (Strategic Molecular and Materials Chemistry
through Innovative Coupling Reactions) of Hokkaido Uni-
versity, as well as the JSPS (KAKENHI Grant Numbers
15H03804 and 15K13633). K.K. would like to thank the JSPS
for their scholarship funding (KAKENHI Grant Number
14J02341). We would also like to thank Noriaki Tokodai and
Dr. Tomohiro Seki for their help analyzing the X-ray
crystallography data.
Conflict of interest
The authors declare no conflict of interest.
Keywords: asymmetric catalysis · borylation · copper · ketones ·
synthetic methods
[12] This type of chiral NHC ligand was originally developed by
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formation of
a bidentate NHC/copper complex as a key
intermediate in their copper-catalyzed arylation reaction. See:
R. Shintani, K. Takatsu, M. Takeda, T. Hayashi, Angew. Chem.
4
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Manuscript received: March 17, 2017
Final Article published: && &&, &&&&
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Communications
Asymmetric Catalysis
K. Kubota, S. Osaki, M. Jin,
H. Ito*
&&&& — &&&&
Copper(I)-Catalyzed Enantioselective
Nucleophilic Borylation of Aliphatic
Ketones: Synthesis of Enantioenriched
Chiral Tertiary a-Hydroxyboronates
Ketone functionalization: The first cata-
lytic enantioselective borylation of
ketones is presented. A variety of aliphatic
ketones reacted efficiently with bis(pina-
colato)diboron in the presence of
a copper(I)/chiral N-heterocyclic carbene
complex to furnish the corresponding
tertiary a-hydroxyboronate esters with
moderate to high enantioselectivities.
6
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