Synthesis of planar chiral [2.2]paracyclophane-based bisoxazoline ligands bearing no central chirality and application to Cu-catalyzed asymmetric O-H insertion reaction

Article abstract of DOI:10.1039/c5ob00452g

C₂-symmetric planar chiral [2.2]paracyclophane-based bisoxazoline ligands, characterized by the inserted benzene spacer, which has a sterically demanding substituent, were synthesized and it was shown that up to 80% ee was obtained for the Cu-catalyzed O-H insertion reaction of α-diazo esters without the aid of the central chirality.

Full text of DOI:10.1039/c5ob00452g

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Synthesis of planar chiral [2.2]paracyclophane-
based bisoxazoline ligands bearing no central
chirality and application to Cu-catalyzed
asymmetric O–H insertion reaction†
Cite this: DOI: 10.1039/c5ob00452g
Received 6th March 2015,
Accepted 17th March 2015
DOI: 10.1039/c5ob00452g
www.rsc.org/obc
Shinji Kitagaki,*a Kenta Sugisakab and Chisato Mukaib
C2-symmetric planar chiral [2.2]paracyclophane-based bisoxa- central and planar ones (5)5 have been developed. To the best
zoline ligands, characterized by the inserted benzene spacer, of our knowledge, however, no BOX ligands possessing only a
which has a sterically demanding substituent, were synthesized planar chirality have so far been reported.6,7
and it was shown that up to 80% ee was obtained for the Cu-cata-
Substituted [2.2]paracyclophanes have been used as the
lyzed O–H insertion reaction of α-diazo esters without the aid of planar chiral ligands in a variety of asymmetric reactions8,9
the central chirality.
since the emergence of [2.2]PHANEPHOS, 4,12-bis(diphenyl-
phosphono)[2.2]paracyclophane (Fig. 2, left), which shows
excellent enantioselectivities during the Rh-catalyzed hydro-
genation of dehydroamino acids.10 Although [2.2]paracyclo-
phanes (pCps) possess many characteristic features such as
configurational stability and diversity of possible chiral struc-
tures, the potential ability of this planar chiral backbone for
asymmetric induction has not yet been sufficiently demon-
strated. We now report the development of the pCp-based
BOX, characterized by the inserted benzene spacer, which
enabled the planar chirality to effectively control the asym-
metric induction during the Cu-catalyzed O–H insertion reac-
tion of α-diazo esters.
Chiral bisoxazoline (BOX) compounds are one of the most
prevalent ligands that could be applied to diverse metal-cata-
lyzed asymmetric reactions due to their easy preparation from
the readily available chiral amino alcohols and high reliability
for asymmetric induction.1 Besides BOX ligands containing
only the central chirality, such as simple t-Bu-BOX (1: R = t-Bu,
Fig. 1), Ph-BOX (1: R = Ph), and PyBOX (2), the ligands made
by combining the central and axial chiralities (32 and 43,4) or
We have been interested in the pseudo-ortho-substituted
aryl-pCp as a catalyst scaffold that has no additional chiral
source and that is expected to provide an efficient asymmetric
environment different from the known functionalized pCps.
Our design concept is as follows: (1) one or two spacer aryl
groups are connected to the pseudo-ortho position of the pCp
backbone and two functionalized groups are located on
the spacer at the meta position or directly on the backbone,
(2) the backbone would provide the inherent conformational
rigidity,8,9,11 and (3) the spacer would offer not only the
Fig. 1 Box ligands.
aFaculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku,
Nagoya 468-8503, Japan. E-mail: skitagak@meijo-u.ac.jp; Fax: +81 52 834 8090;
Tel: +81 52 839 2657
bDivision of Pharmaceutical Sciences, Graduate School of Medical Sciences,
Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
†Electronic supplementary information (ESI) available: Experimental details,
1H and 13C NMR spectra, and HPLC data. See DOI: 10.1039/c5ob00452g
Fig. 2 Pseudo-ortho-substituted pCp ligand and catalyst.
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Scheme 1
Fig. 3 [2.2]Paracyclophane-based BOXs.
conformational flexibility that makes the distance between the
two functional groups suitable for performing, but also a steric
or electronic element based on the aryl group itself and/or its
characteristic substituent, which interacts with the substrate
and/or the reactant. In a previous paper, we reported that the
single spacer in the pCp-based a phosphine-phenol catalyst
(Fig. 2, right) was crucial for higher efficiency and enantio-
selectivity of the aza-Morita–Baylis–Hillman reaction.12 Next, we
envisaged that the planar chirality of the BOX ligand bearing
the pCp backbone could highly control the enantioselection of
the metal-catalyzed asymmetric reaction without the aid of the
central chirality. Thus, we designed the C2-symmetric BOX 6 in
which two achiral oxazoline units were located at the meta-posi-
tion of the spacer aryl group at whose para-position a bulky sub-
stituent R as the stereocontrol element was present, along with
9 having a single spacer and 10 bearing no spacer (Fig. 3).
Scheme 2
The synthesis of BOX ligands 6 having different steric fea-
tures was conducted based on the Suzuki–Miyaura coupling of
bromocyclophanyl triflate 813 with arylboronic acid 7 bearing
an oxazolinyl group and a stereocontrol element R (Fig. 3). The
preparation of 7 started with the oxazoline ring formation
from m-bromobenzoic acid (11) (Scheme 1). Borylation via
the lithium–bromine exchange of the resulting 12a produced
the unsubstituted m-oxazolinylphenylboronic acid 7a. The
aryl-substituted boronic acids 7b–d were obtained by the
Ru-catalyzed arylation14 of 12a and subsequent borylation. The
isopropyl-substituted 7e was prepared from 2-bromocumene
(13) as shown in Scheme 2. The carboxylation of 13 followed
by bromination produced the benzoic acid derivative 15, which
was converted into 7e according to the aforementioned pro-
cedure for the preparation of 7a from 11. The coupling of 7a–e
and (Sp)-8 under the influence of Pd(PPh3)4 afforded the
desired bisoxazolines (Sp)-6a–e in good yields (Scheme 3).
With the designed ligands in hand, our endeavors turned
to their application to the catalytic asymmetric reaction. The
Cu-catalyzed O–H insertion reaction of α-diazo esters is useful
Scheme 3
for the construction of α-alkoxycarbonyl compounds.15 The
highly enantioselective version of this reaction has recently
been accomplished using bisazaferrocene,16 the spiro-BOX
4,6b,17 or an imidazoindolephosphine ligand.18 The develop-
ment of an alternative ligand, however, is still desirable
for this type of reaction, as more versatile BOXs 1–3 are not
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suitable at all.16,17 In this context, we first chose the insertion
reaction of methyl α-diazophenylacetate (16) into the O–H
bond of ethanol as a benchmark reaction for our ligands. The
use of 5 mol% of a Cu salt, 6 mol% of the BOX ligand, 6 mol%
of NaBArF as an additive, and MS 5 Å in dichloromethane was
set as the standard conditions with reference to Zhou’s pro-
cedure using 4.17a After mixing them at room temperature for
4 h, ethanol and α-diazo ester 16 were successively added at
40 °C to the mixture, which was stirred until 16 was completely
consumed. When the phenyl-substituted ligand (Sp)-6b and
CuPF6(CH3CN)4 as a copper source were used, the desired
methyl α-ethoxyphenylacetate (17) was obtained in 87% yield
and 67% ee with the S configuration being preferred, although
the absence of MS 5 Å dramatically decreased the enantio-
selectivity (Table 1, entries 1 and 2). Other copper sources were
examined for the reaction using (Sp)-6b, and it turned out that
Cu(OTf)2 was the best source among those examined (entries
2–5). Surprisingly, the use of both MS 4 Å and 3 Å instead of 5 Å
resulted in a significant decrease in enantioselectivity (entries
6 and 7).19 The reaction in chloroform or dichloroethane gave
the insertion product 17 in lower yield and ee (entries 8 and 9).
Under the conditions established for the Cu-catalyzed O–H
insertion using ligand (Sp)-6b, the application of other BOX
ligands was explored. When the unsubstituted ligand (Sp)-6a
was used, the enantioselectivity of the product dramatically
decreased as expected (entry 10). Ligands (Sp)-6c and (Sp)-6e,
Table 2 BOX (Sp)-6-Cu-catalyzed intramolecular aliphatic O–H inser-
tion of 18a
Entry
Ligand
Time (h)
Yieldb (%)
eec (%)
1
2
3
(Sp)-6b
(Sp)-6c
(Sp)-6e
4.5
4.5
2.5
63
63
83
61
55
32
a All reactions were performed with ligand (0.012 mmol), Cu(OTf)2
(0.010 mmol), NaBArF (0.012 mmol), MS 5 Å (300 mg), and diazo ester
(0.20 mmol) in CH2Cl2 (total 2 mL) unless otherwise noted. b Isolated
yield. c Determined by HPLC analysis (Daicel CHIRALPAK AS-H).
characterized by the horizontal extension of the substituent on
the spacer, showed a lower selectivity while the vertically
extended ligand (Sp)-6d exhibited an ee similar to (Sp)-6b
(entries 11–13). The significance of the two-spacer benzene
rings was confirmed as follows. The removal of one of the two
spacers from (Sp)-6b led to a decrease in the enantioselectivity
with the opposite sense (entry 5 vs. 15). The use of ligand (Sp)-
10, whose oxazoline functionality was directly connected to the
pCp backbone, also resulted in a lower level of asymmetric
induction (46% ee) in the opposite sense (entry 16). These
results suggest that the lack of spacer(s) leads to the construc-
tion of the asymmetric environment quite different from that
of (Sp)-6 having two spacers.
Table 1 BOX (Sp)-6-Cu-catalyzed intermolecular aliphatic O–H inser-
tion of 16a
We next turned our attention to the applicability of the
present protocol to systems other than the intermolecular ali-
phatic O–H insertion. As with the intermolecular version, the
phenyl-substituted ligand (Sp)-6b showed a higher selectivity
than the m-xylyl-substituted (Sp)-6c and isopropyl-substituted
(Sp)-6e for the intramolecular aliphatic O–H insertion using
α-diazo ester 1817d (Table 2). On the other hand, for the inter-
Time
(h)
Yieldb
(%)
eec
(%)
Entry
Ligand
[Cu]
1d
2
3
4
5
(Sp)-6b
(Sp)-6b
(Sp)-6b
(Sp)-6b
(Sp)-6b
(Sp)-6b
(Sp)-6b
(Sp)-6b
(Sp)-6b
(Sp)-6a
(Sp)-6c
(Sp)-6d
CuPF6(MeCN)4
CuPF6(MeCN)4
CuCl
7
7
2
3
1.5
3.5
2
2
3
6
2
4
2
0.75
0.5
9
81
87
85
92
86
83
89
71
53
76
84
88
87
91
85
77
14
67
57
54
76
5
CuCl2
Table 3 BOX (Sp)-6-Cu-catalyzed intermolecular aromatic O–H inser-
tion of 20a
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
6e
7f
8g
9h
10
11
12
13
14
15
16
7
60
44
15
40
72
48
18
−54
−46
Entry
Ligand
Time (h)
Yieldb (%)
eec (%)
(Sp)-6e
(Sp)-9a (R = H)
(Sp)-9b (R = Ph)
(Sp)-10
1
2
3
(Sp)-6b
(Sp)-6c
(Sp)-6e
2
2
1
73
65
66
61
39
80
a All reactions were performed with ligand (0.012 mmol), [Cu]
(0.010 mmol), NaBArF (0.012 mmol), MS (300 mg), EtOH
(1.0 mmol), and diazo ester (0.20 mmol) in CH2Cl2 (total 2 mL) unless
otherwise noted. b Isolated yield. c Determined by HPLC analysis
(Daicel CHIRALCEL OD-H). d Without MS 5 Å. e MS 4 Å was used
instead of MS 5 Å. f MS 3 Å was used instead of MS 5 Å. g Performed in
CHCl3. h Performed in (CH2Cl)2.
a All reactions were performed with ligand (0.012 mmol), CuCl
(0.010 mmol), NaBArF (0.012 mmol), MS (300 mg), PhOH
(1.0 mmol), and diazo ester (0.20 mmol) in CH2Cl2 (total 2 mL) unless
otherwise noted. CuCl was used as a Cu source, according to Zhou’s
procedure.17a b Isolated yield. c Determined by HPLC analysis (Daicel
CHIRALCEL OD-H).
5
Å
5
Å
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molecular phenolic O–H insertion reaction of ethyl α-diazopro-
pionate (20),17a (Sp)-6e was superior to (Sp)-6b during the enan-
tioselection, achieving an 80% ee (Table 3).
M. Ogasawara and T. Hayashi, J. Org. Chem., 1999, 64,
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7 For an example of the planar chiral oxazoline ligand which
has no central chirality, see: S.-L. You, Y.-G. Zhou,
X.-L. Hou and L.-X. Dai, Chem. Commun., 1998, 2765–
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8 (a) J. Paradies, Synthesis, 2011, 3749–3766; (b) R. Gleiter
and H. Hopf, Modern Cyclophane Chemistry, Wiley-VCH,
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9 For recent examples of [2.2]paracyclophane-based ligands,
see: (a) Z. Niu, J. Chen, Z. Chen, M. Ma, C. Song and Y. Ma,
J. Org. Chem., 2015, 80, 602–608; (b) M. Busch, M. Cayir,
M. Nieger, W. R. Thiel and S. Bräse, Eur. J. Org. Chem.,
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11 S. Kitagaki, T. Ueda and C. Mukai, Chem. Commun., 2013,
49, 4030–4032.
Conclusions
In summary, we synthesized novel C2-symmetric planar chiral
BOX ligands based on the pCp bearing no central chirality and
demonstrated that the bulky substituent on the spacer
benzene ring played an important role to realize a high level of
single planar chirality-controlled asymmetric induction (up to
80% ee). Further investigation of the scope and limitation of
this Cu-catalyzed insertion reaction and application of the
planar chiral ligands in other catalytic asymmetric reactions
are currently underway.
Acknowledgements
This work was supported by JSPS KAKENHI grant number
24590006. The authors thank Dr Naoko Takenaga for technical
support.
12 S. Kitagaki, Y. Ohta, R. Takahashi, M. Komizu and
C. Mukai, Tetrahedron Lett., 2013, 54, 384–386.
13 S. Kitagaki, Y. Ohta, S. Tomonaga, R. Takahashi and
C. Mukai, Tetrahedron: Asymmetry, 2011, 22, 986–991.
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