A Cu(II)-based strategy for catalytic enantioselective β-borylation of α,β-unsaturated acceptors

Article abstract of DOI:10.1039/c5cc04295j

Cu(I)-based chemistry has flourished over the last decade because of the reliable use of species such as soft acids. However, the unique nature of Cu(ii) catalysts allows the well-documented Cu(I)-based chemistry to be extended. Prominent advantages of th

Full text of DOI:10.1039/c5cc04295j

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Cu(II)-Based strategy for catalytic enantioselective β-borylation of
α,β-unsaturated acceptors
Received 00th January 20xx,
Accepted 00th January 20xx
Lei Zhu, Taku Kitanosono, Pengyu Xu, and Shū Kobayashi*
DOI: 10.1039/x0xx00000x
www.rsc.org/
depends on ligand structures. In contrast to chiral Cu(I) protocols
for enantioselective β-borylation of α,β-unsaturated acceptors,
which have been investigated extensively, chiral Cu(II) catalysis has
not been investigated until recently. We have developed chiral
Cu(II)-catalyzed enantioselective borylation of α,β-unsaturated
acceptors, which proceed well in water.1a,12,13 Unique reactivity and
selectivity are often observed in organic reactions in water. Indeed,
the corresponding Cu(II) chemistry in organic solvents was
unprecedented.
Cu(I)-based chemistry has flourished over the last decade because
of the reliable use of such species as soft acids. However, the
unique nature of Cu(II) catalysts is allowing the well-documented
Cu(I)-based chemistry to be extended. Prominent advantages of
this approach include ease of handling, the avoidance of strong
base, and wider substrate scope in enantioselective β-borylation.
Enantioenriched α-chiral boron derivatives are an important class
of compounds because of their versatile range of applications. Their
C–B linkage can be transferred into C–O, C–N, as well as C–C bonds
through 1,2-migration of intermediary ate complexes with
appropriate nucleophiles, while retaining the integrity of
stereogenic centers.1 In recent years, the Suzuki–Miyaura cross-
coupling reaction has been expanded to include the conversion of
Intrigued by the unique nature of Cu(II) catalysts, which are
distinct from Cu(I) systems, we wanted to extend the range of
Cu(II)-based chemistry to include enantioselective β-borylation of
α,β-unsaturated acceptors (Table 1). We expected that, given the
relatively hard nature of Cu(II) compared with Cu(I), this Lewis acid
could be used to activate carbonyl groups rather than the double
bonds of α,β-unsaturated acceptors. At the outset, we studied
Cu(II) catalysis under the same general conditions developed for
Cu(I)-based strategies. Thus, Cu(OAc)2 was mixed with a phosphine-
based ligand such as BINAP (L1) or Josiphos (L2), which are often
used in Cu(I)-based approaches, with an equimolar amount of
methanol as a proton source. In the presence of the catalysts,
chalcone (1a) was treated with bis(pinacolato)diboron (B2(pin)2, 2)
at room temperature for 12 h, and the crude adduct was treated
with NaBO3 to form a stable alcohol (3a). Whereas the reaction did
not proceed at all by using L1 (entry 1), a moderate yield, albeit
with poor enantioselectivity, was obtained by using L2 (entry 2).
Although a number of reports on Cu(II) complexes have described
the effective combination of Cu(II) salts with bis(oxazolidine) (box),
bis(oxazolinyl)pyridine (pybox), and dibenzylamine ligands, the
reactions generally suffer from moderate yields and
enantioselectivities (entries 3–6). On the other hand, the use of
chiral 2,2ʹ-bipyridine L714 rendered the product in a highly selective
manner (entry 7). In contrast, substituting Cu(I) salt for Cu(II) led to
a significant reduction in the enantioselectivity (entry 8). The
reaction took place with decreased selectivity in methanol and with
low selectivity in acetonitrile (entries 9 and 10). Extensive clustering
of copper(II) acetate species in methanol15 may lead to a reduction
in the number of solvated monomer species, which would cause
chiral induction to be restricted, leading to moderate selectivity.
The best performance of the Cu(II)-L7 complex was achieved when
the reaction was conducted in Et2O (entry 11). It seems that
solvents that do not coordinate Cu(II), such as THF and Et2O,
optically
active
organoboranes
with
retention
of
stereoconfiguration.2 In addition to their chemical importance as
versatile intermediates, boron compounds have been targeted
directly for pharmaceutical applications because they can be used
to generate reversible covalent complexes with carbohydrates,
amino acids, and hydroxamic acids.3
Borylation of alkenes represents one of the most efficient
routes to organoboron compounds. A plethora of approaches have
been developed based on the formation of an isolatable
borylcopper(I) species in situ through σ-bond metathesis between
diboron reagents and Cu(I) salts; this approach was described in
concomitant reports by Hosomi4 and Miyaura5 in 2000. The Cu(I)-
based enantioselective protocols were further embellished through
the use of air-sensitive chiral phosphine-based ligands or N-
heterocyclic carbenes by Yun,6 Hoveyda,7 Shibasaki,8 McQuade,9
Ma,10 and other groups.11 The tendency of Cu(I) to undergo
disproportionation means that this chemistry has required the use
of anhydrous organic solvents and an inert atmosphere. Given the
soft nature of Cu(I), such catalytic systems are highly active for
couplings with sp2 carbon centers, as represented by conjugate
additions through d–π interactions. High catalytic activity is usually
ensured by the addition of a strong base such as NaOtBu and more
than 1 equivalent of alcohol as a proton source, substrate tolerance
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facilitate liberation of monomeric Cu(II) species under dilute for the Cu(acac)2-L7 complex may originate from incomplete
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DOI: 10.1039/C5CC04295J
conditions.
formation of the active 1:1 complex, which may result in diboron
hydrolysis taking place instead of the desired nucleophilic addition
pathway (entry 7). In addition to a high level of enantioselectivity
obtained by using insoluble Cu(OH)2 (entry 8), the remarkable
catalytic activity of insoluble CuO combined with L7 was impressive
and suggestive of heterogeneity of catalyst behavior (entry 9).
Table 1. Cu(II) catalysis for enantioselective β-borylation of chalcone.
Ligand (6 mol%)
Cu(OAc)2 (5 mol%)
MeOH (1 equiv.)
O
O
OH
+ B2(pin)2
solvent, rt, 12 h
then NaBO3
H2O/THF, 3 h
Ph
Ph
Ph
Ph
Table 2. Optimizing the reaction with the Cu(II)-L7 complex.
1a
2
3a
Ligand (6 mol%)
(1.2 equiv)
Cu(II) salt (5 mol%)
MeOH (1 equiv.)
O
Entry
1
2
3
4
Ligand
L1
L2
L3
L4
L5
L6
L7
L7
Solvent Yield (%)[a] Ee (%)[b]
O
OH
+ B2(pin)2
THF
THF
THF
THF
THF
THF
THF
THF
NR
57
50
56
55
36
61
56
82
71
95
–
4
Et2O, rt, 12 h
then NaBO3
H2O/THF, 3 h
Ph
Ph
Ph
Ph
1a
2
3a
56
10
37
–6
81
10
46
13
94
(1.2 equiv)
Entry Ligand Cu(II) salt Yield (%)[a] Ee (%)[b]
5
6
1
2
3
4
5
6
7
8
9
L7
L8
L9
L7
L7
L7
L7
L7
L7
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OMe)2
CuCl2
95
92
31
94
92
4
7
8[c]
9
92
91
L7
L7
L7
MeOH
MeCN
Et2O
NR
trace
68
44
96
–
–
84
81
93
10
11
CuBr2
Cu(acac)2
Cu(OH)2
CuO
[a] Isolated yield of oxidized product. [b] Determined by HPLC analysis.
[c] CuCl was used instead of Cu(OAc)2. NR = no reaction.
[a] Isolated yield of oxidized product. [b] Determined by HPLC analysis.
NR = no reaction. acac = acetylacetonate.
O
O
PPh2
PPh2
P
N
N
N
N
N
N
PPh2
Fe
Bn
Bn
tBu
tBu
tBu
tBu
OMe
HO
OMe
MeO
L1
L4
L2
L3
L8
L9
O
O
Notably, the Cu(II)-based catalyst system was applicable to
various types of α,β-unsaturated acceptors (Scheme 1). Both acyclic
and cyclic enones bearing a range of functional groups reacted
smoothly to afford the corresponding β-borylated products, which
were treated with NaBO3 to provide β-hydroxy ketones 3b–l and 3q
in good to excellent yields with high to excellent enantioselectivities.
α,β-Unsaturated esters also worked well (3m, 3n), with the
sterically unfavored tertiary alcohol 3n, formed from the β,β-
disubstituted ester, being obtained in high yield and with high
enantioselectivity. Furthermore, an α,β-unsaturated amide and an
α,β-unsaturated nitrile were also good substrates, giving 3o and 3p,
respectively. In the case of α,β,γ,δ-unsaturated dienones, it is noted
that only 1,4-addition occurred, affording the corresponding
adducts 3r and 3s; no 1,6-addition products were obtained.
Given that the reaction system in Et2O appeared to be
heterogeneous, we conducted filtration experiments to establish
whether the active catalyst was present in solution or in the solid
state (Scheme 2). Cu(OAc)2, L7, and B2(pin)2 (2) were stirred in Et2O
for 1 h at room temperature, then chalcone (1a) and methanol
were added. The mixture was stirred for a further 2 h at the same
temperature, then filtrated through a 0.2 µm membrane filter. To
this filtrate, benzalacetone (1h), 2, and methanol were added and
the mixture was stirred for 12 h at room temperature. The crude
adducts were then treated with NaBO3 to afford 3a in 92% yield
with 92% ee and 3h in 70% yield with 86% ee. This experiment
strongly suggests that the active species in this asymmetric
borylation exists in solution.
O
O
N
NH HN
N
N
Ph
Ph
N
N
Ph
Ph
iPr
iPr
L5
L6
N
N
tBu
tBu
OH
HO
L7
The role of the Cu(II)-L7 complex was investigated in detail
(Table 2). Mono-protection of the hydroxyl group in L7 with a
methyl group (L8) did not impair the catalytic performance of Cu(II),
whereas bis-protection (L9) resulted in significant inhibition of the
catalytic cycle and serious enantiomeric erosion (entries 2 and 3).
This result suggests that complexation in a tridentate fashion
through N,N,O-type coordination is essential for the catalytic
activity of the Cu(II)-L7 species, which is consistent with
crystallographic representation of a reported CuBr2-L7 complex
adopting a square pyramidal structure.16 A reasonable outcome
that was comparable to that obtained with Cu(OAc)2 (entry 1) was
also achieved when Cu(OMe)2 was used as Cu(II) source (entry 4).
When the interaction between the Cu(II) core and the counterpart
was significantly covalent in nature, the progress of the reaction
appeared to be impeded completely (entries 5 and 6). Based on ESI-
MS analysis, the small decrease in catalytic performance observed
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The solubility of Cu(OAc)2 even with L7 in Et2O is not high, which
indicates that a small amount of the active species works efficiently
in this reaction. Indeed, when we conducted the reaction of 1a with
2 in the presence of 0.005 mol% catalyst, it was found that the
turnover frequency (TOF) reached 31,200 h–1,17 which
demonstrates the remarkably high catalytic performance of this
simple catalyst.
Scheme 2. Filtration experiment.
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DOI: 10.1039/C5CC04295J
O
Ph
Ph
1a
MeOH
solid
Cu(OAc)2
L7
filtration
B2(pin)2
Et2O
Scheme 1. Scope of the reaction with α,β-unsaturated acceptors.
1h
2h
O
Cu(OAc)2 (5 mol%)
L7 (6 mol%)
MeOH (1 equiv)
filtrate
R3
Me
Ph
OH
R1
1h
B2(pin)2
MeOH
R2
R1
R3
R2
Et2O, rt, 12 h
then NaBO3, H2O/THF, 3 h
+
12h
B2(pin)2
OH
O
OH
O
NaBO3
H2O/THF
O
OH
O
OH
Ph
R
R
3b: R = Me: 87% yielda
3d: R = OMe: 92% yielda
96% eeb
Ph
Ph
Me
3a
92% yield, 92% ee
3h
70% yield, 86% ee
93% eeb
3c: R = OMe: 95% yielda
3e: R = Cl: 85% yielda
81% eeb
99% eeb
In conclusion, the exploration of a Cu(II)-based strategy instead
of using conventional Cu(I)-based chemistry led to an increase in
the range of α,β-unsaturated acceptors that are amenable to
catalytic asymmetric β-borylation. The ready availability of Cu(II)
species, coupled with the ease of operating the reaction in the
absence of a strong base, underscore the value of the Cu(II)-based
catalyst over an array of well-documented Cu(I)-based catalysts.
Mechanistic differences between reactions catalyzed by Cu(II) and
Cu(I) species will be discussed in due course.
O
OH
R1
R2
3f: R1 = Me, R2 = F: 87% yielda, 93% eeb
3g: R1 = F, R2 = Cl: 81% yielda, 98% eeb
O
OH
O
OH
O
OH
This work was partially supported by a Grant-in-Aid for Science
Research from the Japan Society for the Promotion of Science (JSPS),
Global COE Program, The University of Tokyo, MEXT, Japan, the
Japan Science and Technology Agency (JST). P.X. thanks the JSPS for
a Research Fellowship for Young Scientists.
OMe
Cl
3h: 76% yielda
3i: 95% yielda
3j: 81% yielda
84% eeb
96% eeb
85% eeb
O
OH
O
OH
O
OH
EtO
Notes and references
3k: 98% yielda
3l: 90% yielda
3m: 70% yielda
1
(a) T. Kitanosono, P. Xu and S. Kobayashi, Chem. Asian J.,
2014, 9, 179–188; (b) J. C. H. Lee, R. McDonald and D. G. Hall,
Nature Chem., 2011, 3, 894–899; (c) C. Solé, A. Tatla, J. A.
Mata, A. Whiting, H. Gulyás and E. Fernández, Chem. Eur. J.,
2011, 17, 14248–14257; (d) H. K. Scott and V. K. Aggarwal,
Chem. Eur. J., 2011, 17, 13124–13132; (e) T. Ohmura, T.
Awano and M. Suginome, J. Am. Chem. Soc., 2010, 132,
13191–13193; (f) D. Imao, B. W. Glasspoole, V. S. Laberge
and C. M. Crudden, J. Am. Chem. Soc., 2009, 131, 5024–
5025; (g) J. L. Stymiest, V. Bagutski, R. M. French and V. K.
Aggarwal, Nature, 2008, 456, 778–782.
81% eeb
93% eeb
89% eeb
O
O
OH
OH
NC
HO Me
Et2N
EtO
3n: 80% yielda
3o: 81% yielda
3p: 86% yielda
89% eeb
93% eeb
81% eeb
O
O
OH
O
OH
nPr
2
(a) J. Ding, T. Rybak and D. G. Hall, Nature Commun. 2014, 5,
5474–5482; (b) L. Li, S. Zhao, A. Joshi-Pangu, M. Diane and M.
R. Biscoe, J. Am. Chem. Soc. 2014, 136, 14027–14030; (c) A.
Bonet, M. Odachowski, D. Leonori, S. Essafi and V. K.
Aggarwal, Nature Chem., 2014, 6, 584–589; (d) G. A.
Molander, S. R. Wisniewski and M. Hosseini-Sarvari, Adv.
Synth. Catal., 2013, 355, 3037–3057; (e) G. A. Molander and
S. R. Wisniewski, J. Am. Chem. Soc., 2012, 134, 16856–16868;
(f) D. L. Sandrock, L. Jean-Gérard, C.-Y. Chen, S. D. Dreher
and G. A. Molander, J. Am. Chem. Soc., 2010, 132, 17108–
17110.
OH
3q: 97% yielda
3r: 82% yielda
90% eeb
3s: 85% yielda
88% eeb
90% eeb
[a] Isolated yield of oxidized product. [b] Determined by HPLC analysis.
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3
(a) S. Lü and J. Wang, Biomarker Res., 2013, 1, 13–22; (b) B. B.
Pappin, M. Kiefel and T. A. Houston, In “Carbohydrates-
Comprehensive Studies on Glycobiology and
View Article Online
DOI: 10.1039/C5CC04295J
Glycotechnology”, C.-F. Chang Ed., 2012, 37–54; (c) M.
Dowlut and D. G. Hall, J. Am. Chem. Soc., 2006, 128, 4226–
4227; (d) M. Groll, C. R. Berkers, H. L. Ploegh, H. Ovaa and G.
Bourenkov, Structure, 2006, 14, 451–456.
H. Ito, H. Yamanaka, J.-I. Tateiwa and A. Hosomi,
Tetrahedron Lett., 2000, 41, 6821–6825.
(a) K. Takahashi, T. Ishiyama and N. Miyaura, J. Organomet.
Chem., 2001, 625, 47–53; (b) K. Takahashi, T. Ishiyama and N.
Miyaura, Chem. Lett., 2000, 982–983.
(a) X. Feng and J. Yun, Chem. Eur. J., 2010, 16, 13609–13612;
(b) X. Feng and J. Yun, Chem. Commun., 2009, 6577–6579; (c)
H. Chea, H.-S. Sim and J. Yun, Adv. Synth. Catal., 2009, 351,
855–858; (d) H.-S. Sim, X. Feng and J. Yun, Chem. Eur. J., 2009,
15, 1939–1943; (e) J.-E. Lee and J. Yun, Angew. Chem. Int. Ed.,
2008, 47, 145–147; (f) S. Mun, J.-E. Lee and J. Yun, Org. Lett.,
2006, 8, 4887–4889.
4
5
6
7
8
J. M. O’Brien, K.-S. Lee and A. H. Hoveyda, J. Am. Chem. Soc.,
2010, 132, 10630–10633.
(a) I.-H. Chen, M. Kanai and M. Shibasaki, Org. Lett., 2010, 12,
4098–4101; (b) I.-H. Chen, L. Yin, W. Itano, M. Kanai and M.
Shibasaki, J. Am. Chem. Soc., 2009, 131, 11664–11665.
J. K. Park, H. H. Lackey, M. D. Rexford, K. Kovnir, M. Shatruk
and D. T. McQuade, Org. Lett., 2010, 12, 5008–5011.
9
10 (a) Z. Niu, J. Chen, Z. Chen, M. Ma, C. Song and Y. Ma, J. Org.
Chem., 2015, 80, 602–608; (b) L. Zhao, Y. Ma, F. He, W. Duan,
J. Chen and C. Song, J. Org. Chem., 2013, 78, 1677–1681; (c) L.
Zhao, Y. Ma, W. Duan, F. He, J. Chen and C. Song, Org. Lett.,
2012, 14, 5780–5783; (d) B. Hong, Y. Ma, L. Zhao, W. Duan, F.
He and C. Song, Tetrahedron: Asymmetry, 2011, 22, 1055–
1062.
11 (a) T. Iwai, Y. Akiyama and M. Sawamura, Tetrahedron:
Asymmetry, 2013, 24, 729–735; (b) D. Hirsch-Weil, K. A.
Abboud and S. Hong, Chem. Commun., 2010, 46, 7525–7527;
For authoritative reviews on boron conjugate additions, see:
(c) A. D. J. Calow and A. Whiting, Org. Biomol. Chem., 2012,
10, 5485–5497; (d) E. Hartmann, D. J. Vyas and M. Oestreich,
Chem. Commun., 2011, 47, 7917–7932; (e) J. A. Schiffner, K.
Müther and M. Oestreich, Angew. Chem. Int. Ed., 2010, 49,
1194–1196.
12 (a) T. Kitanosono, P. Xu, S. Isshiki, L. Zhu and S. Kobayashi,
Chem. Commun., 2014, 50, 9336–9339; (b) T. Kitanosono, P.
Xu and S. Kobayashi, Chem. Commun., 2013, 49, 8184–8186;
(c) G. Stavber and Z. Časar, Appl. Organometal. Chem. 2013,
27, 159–165; (d) S. Kobayashi, P. Xu, T. Endo, M. Ueno and T.
Kitanosono, Angew. Chem. Int. Ed., 2012, 51, 12763–12766;
For a racemic example, see: (e) S. B. Thorpe, J. A. Calderone
and W. L. Santos, Org. Lett., 2012, 14, 1918–1921.
13 Recently, unprecedented catalyses by Cu(0) was also
observed in water, see: T. Kitanosono and S. Kobayashi,
Asian J. Org. Chem., 2013, 2, 961–966.
14 (a) S. Ishikawa, T. Hamada, K. Manabe and S. Kobayashi,
Synthesis, 2005, 2176–2182; (b) C. Bolm, M. Ewald, M. Felder
and G. Schlingloff, Chem. Ber., 1992, 125, 1169–1190; (c) C.
Bolm, M. Zehnder and D. Bur, Angew. Chem. Int. Ed., 1990,
29, 205–207.
15 A. Tsybizova, B. L. Ryland, N. Tsierkezos, S. S. Stahl, J.
Roithová and D. Schröder, Eur. J. Inorg. Chem., 2014, 1407–
1412.
16 (a) M. Kokubo, T. Naito and S. Kobayashi, Tetrahedron 2010,
66, 1111–1118; (b) C. Ogawa, M. Kokubo and S. Kobayashi, J.
Synth. Org. Chem. Jpn. 2010, 68, 718–728; (c) M. Kokubo, T.
Naito and S. Kobayashi, Chem. Lett. 2009, 38, 904–905.
17 TOFs in the reaction of 1a with 2: Cu(OAc)2 in water,1a 12,800
h-1; Cu(OH)2 in water,1a 43,200 h-1; Cu(OH)2 in Et2O, 0.73 h-1.
4 | J. Name., 2012, 00, 1-3
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