Highly enantioselective synthesis of axially chiral biarylphosphonates: Asymmetric suzuki-miyaura coupling using high-molecular-weight, helically chiral polyquinoxaline-based phosphines

Article abstract of DOI:10.1002/anie.201103792

Taking a new turn: An asymmetric Suzuki-Miyaura coupling of 1-bromo-2-naphthalenephosphonic esters with o-methyl-substituted phenylboronic acids proceeds with high enantioselectivity in the presence of high-molecular-weight helically chiral polyquinoxalin

Full text of DOI:10.1002/anie.201103792

Communications
DOI: 10.1002/anie.201103792
Asymmetric Synthesis
Highly Enantioselective Synthesis of Axially Chiral
Biarylphosphonates: Asymmetric Suzuki–Miyaura Coupling Using
High-Molecular-Weight, Helically Chiral Polyquinoxaline-Based
Phosphines**
Takeshi Yamamoto, Yuto Akai, Yuuya Nagata, and Michinori Suginome*
Dedicated to Christian Bruneau on the occasion of his 60th birthday.
Asymmetric synthesis has developed rapidly with the explo-
ration of chiral molecular scaffolds for use as chiral ligands,
reagents, and auxiliaries.[1] Some molecular frameworks such
as 1,1’-binaphthyl are widely recognized as privileged scaf-
folds for chiral sciences and technologies, including not only
asymmetric synthesis, but also chiral recognition and separa-
tion.[2] In addition to those small-molecule-based chiral
scaffolds for asymmetric synthesis, recent efforts have also
been devoted to the development of macromolecular chiral
scaffolds for asymmetric synthesis. The discovery of polymer-
based privileged scaffolds for asymmetric synthesis takes
advantage of the unique properties of macromolecules.[3,4]
However, those reported macromolecular chiral ligands
generally suffer from insufficient enantioselectivity. Only a
DNA system in which the catalyst moieties are introduced
noncovalently has been used to achieve excellent enantiose-
lectivity, eventhough the use of naturally occurring scaffolds
made accessibility to the enantiomeric catalyst difficult.[5]
We have recently established poly(quinoxaline-2,3-diyl)-
based phosphine (PQXphos) as a new macromolecular chiral
ligand for asymmetric hydrosilylation of styrenes.[6–8] In
addition to its high enantioselectivities [up to 97% enantio-
meric excess (ee)] and reusability, the catalyst system
exhibited a highly characteristic switch of enantioselection
because of solvent-dependent inversion of the helical chir-
ality.[6,9] It appears that application of PQXphos to other
Despite the practicality and usefulness of Suzuki–Miyaura
couplings (SMCs) in aryl–aryl bond-forming reactions, only a
few systems for catalytic asymmetric biaryl synthesis through
SMCs have been established.[10–14] In one of the first systems,
reported by Buchwald and co-workers in 2000, 2-dicyclohex-
ylphosphino-2’-dimethylamino-1,1’-binaphthyl
(KenPhos)
was used in the coupling of dialkoxyphosphinyl
(P(O)(OR)2)-substituted naphthyl bromides with ortho-sub-
stituted arylboronic acids to give up to 92% ee. The group of
Uozumi recently reported a highly enantioselective coupling
of the same naphthyl bromide with 2-methoxy-1-naphthyl-
boronic acid, wherein the enantioselectivity of the reaction
was not clearly shown, but was determined only after
crystallization (99% ee).[14] We decided to examine the
coupling of 1-bromo-2-naphthylphosphinates using our poly-
mer-based chiral ligands because the product biarylphosphi-
nates serve as direct precursors for the synthesis of chiral
phosphine ligands, as demonstrated by Buchwald and co-
workers.[10]
The 20 mer-based block copolymers (S,S)-(R)-L1a–d were
prepared by living block copolymerization of a chiral spacer
monomer bearing (R)-2-butoxymethyl side chains and a
phosphorus-containing monomer in the presence of a chiral
initiator, whose chiral group remained at the termini of the
polymer (Figure 1a).[6a,8] In addition, the 1000 mer-based
À
catalytic reactions such as asymmetric C C bond-formation
reactions is highly attractive. We herein report the asymmet-
ric Suzuki–Miyaura cross-coupling to form axially chiral
biaryls by using the high-molecular-weight PQXphos bearing
various diorganophosphorus groups on the helical polymer
backbones.
[*] Dr. T. Yamamoto, Y. Akai, Dr. Y. Nagata, Prof. Dr. M. Suginome
Department of Synthetic Chemistry and Biological Chemistry,
Graduate School of Engineering, Kyoto University
Katsura, Nishikyo-ku, Kyoto 615-8510 (Japan)
E-mail: suginome@sbchem.kyoto-u.ac.jp
Homepage: http://www.sbchem.kyoto-u.ac.jp/suginome-lab/
Prof. Dr. M. Suginome
JST, CREST
Katsura, Nishikyo-ku, Kyoto 615-8510 (Japan
[**] We wish to thank JASCO (Tokyo, Japan) for the vibrational circular
dichroism measurements.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201103792.
Figure 1. PQXphos (S,S)-(R)-L1 and (R)-L2. cy=cyclohexyl, nap=
napthyl.
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Angew. Chem. Int. Ed. 2011, 50, 8844 –8847

high-molecular-weight polymer ligands (R)-L2 were prepared
by living random copolymerization of the chiral and the
phosphorus-containing monomers in a 950:50 ratio using an
achiral organonickel initiator (Figure 1b).[6b,15,16] The 20 mer-
based polymer ligands L1 were finally obtained from their
CHCl3 solution by evaporation, and the 1000 mer-based
ligands L2 were obtained from their toluene solution by
precipitation with MeOH. All polymer ligands possessed pure
right-handed (P) helical structures, as judged by their circular
dichroism (CD) spectra.
The polymer ligands were used in the SMC of dimethox-
yphosphinyl-substituted 1-naphthyl bromide (1a) with o-
tolylboronic acid (2a), a reaction that has been accomplished
by Buchwald et al. with 86% ee using KenPhos at 608C
(Table 1). The coupling proceeded in the presence of (S,S)-
(R)-L1a with a palladium catalyst at 408C, thus affording
higher ee values than at 608C or 808C (entries 1–3). Addi-
tional lowering of the reaction temperature made the reaction
too sluggish. Among the 20 mer-based chiral ligands, (S,S)-
(R)-L1b, which has 3,5-xylyl groups on the phosphorus atom,
showed the highest enantioselectivity (entry 4), whereas the
3,5-bis(trifluoromethyl) derivative showed only a low ee value
(entry 6). We then found that the corresponding 1000 mer-
based PQXphos exhibited higher enantioselectivity: the Ph2P
derivative (P)-(R)-L2a showed higher selectivity than did the
20 mer-based ligand (S,S)-(R)-L1a (entry 7). Furthermore,
the corresponding 3,5-xylyl and 2-naphthyl derivatives
afforded the coupling product with remarkable enantioselec-
tivities (entries 8 and 9), which clearly exceed the selectivity
obtained in the original system. It is interesting to note,
however, that the Cy2P derivative showed only low enantio-
selectivity, in contrast to the original binaphthyl system using
KenPhos.
Several biaryls were synthesized by asymmetric SMC in
the presence of the high-molecular-weight (R)-L2a–d, which
have right-handed helical structures (Table 2). Under the
same reaction conditions as used for 1a, diethoxyphosphinyl
derivative 1b afforded 3a’ with 94% ee in the presence of
polymer ligand (R)-L2c (entry 3). The coupling of 1a with 1-
naphthylboronic acid (2b) was examined with the four
polymer ligands (R)-L2a–d: ligand (R)-L2a bearing the
PPh2 group showed the highest enantioselectivity among the
four (entries 4–7). Notably, the enantioselectivities thus far
shown for both biaryls 3a and 3a’ are higher than those
obtained in the original system using KenPhos as a chiral
ligand. We also examined the asymmetric SMC of 1 with
selected ortho-methyl-substituted phenylboronic acids. The
methoxy-substituted 2c afforded the corresponding coupling
product with high enantioselectivities (entries 8–10). In the
coupling of the dimethyl-substituted 2d and 2e, the 2-
Table 1: Asymmetric Suzuki–Miyaura coupling with PQXphos (S,S)-(R)-
L1a–d and (R)-L2a–d.[a]
Scheme 1. The Suzuki–Miyaura coupling using helically inversed
PQXphos. 1,1,2-TCE=1,1,2-trichloroethane.
Entry
PQXphos
T
[8C]
t
[h]
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
9
(S,S)-(R)-L1a
(S,S)-(R)-L1a
(S,S)-(R)-L1a
(S,S)-(R)-L1b
(S,S)-(R)-L1c
(S,S)-(R)-L1d
(P)-(R)-L2a
(P)-(R)-L2b
(P)-(R)-L2c
(P)-(R)-L2d
80
60
40
40
40
40
40
40
40
40
22
24
180
96
96
108
48
48
48
48
57
70
62
81
74
41
78
69
80
72
71
74
78
86
84
35
83
92
94
40
10
[a] Reaction conditions for entries 1–6: 1a (0.10 mmol), 2a (0.15 mmol),
[Pd2(dba)3] (1.0 mmol), the polymer ligand (4.8 mmol P), and K3PO4
(0.30 mmol) were heated in THF (0.25 mL) and H2O (0.025 mL); for
entries 7–10: 1a (0.10 mmol), 2a (0.15 mmol), [{PdCl(p-allyl)}2]
(1.0 mmol), ligand (4.0 mmol P), and K3PO4 (0.20 mmol) were heated in
THF (0.40 mL) and H2O (0.040 mL). [b] Yield of isolated product.
[c] Determined by HPLC analysis (chiral stationary phase). dba=diben-
zylideneacetone, THF=tetrahydrofuran.
Scheme 2. Possible structures of chiral catalysts and the products that
they generate.
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Communications
Table 2: Asymmetric Suzuki–Miyaura of arylboronic acids with aryl halides with the high-molecular-
the reaction yield was still moder-
ate, the (+)-(R) enantiomer of
biaryl 3d was obtained with
90% ee.
weight PQXphos (P)-(R)-L2a–d.[a]
Finally, it seems important to
note that the stereochemical
course of our system is signifi-
cantly
different
from
that
Entry Halide ArB(OH)2
Product
Ligand Yield ee
[%][b] [%][c]
observed in the Buchwald system
using KenPhos as a chiral ligand.
The structure of (P)-(R)-L2, which
is predicted from the semi-empiri-
cal AM1 calculation of the model
compound,[17] and that of (S)-Ken-
Phos, both of which produce S-
binaphthyl products,[10a] for exam-
ple., (À)-(S)-3b, in the coupling of
naphthylboronic acid with 1, are
shown in Scheme 2. In the
PQXphos, the axial chirality at
the phenyl quinoxaline ring is
induced by the right-handed heli-
cal structure of the poly(quinoxa-
line) backbone, whose helical chir-
ality is in turn induced by the
chiral side chains. Interestingly, in
the coupling of ortho-tolylboronic
acids, our (P)-(R)-L2 ligand
afforded (À)-(S)-3a (94% ee),
whereas (S)-KenPhos gave its
enantiomer (+)-(R)-3a (86% ee),
whose absolute configuration (R)
was determined by a single-crystal
X-ray analysis of a related deriv-
ative.[10b] We separately confirmed
the absolute configuration by its
vibrational circular dichroism
(VCD) spectrum.[18] The mea-
sured VCD spectrum of (À)-3d
was in good agreement with the
calculated VCD spectrum for (S)-
3d, as judged from most of the
1
2
3
1b
1b
1b
L2a
L2b
L2c
75
67
70
86
93
94
2a
2b
(À)-(S)-3a’
4[d]
5[d]
6[d]
7[d]
1a
1a
1a
1a
L2a
L2b
L2c
L2d
42
24
56
68
94
92
90
78
(À)-(S)-3b
(À)-(S)-3c
8
9
10
1a
1a
1a
L2a
L2b
L2c
86
84
78
91
95
94
2c
11
12
13
1a
1a
1a
L2a
L2b
L2c
74
58
78
92
96
98
2d
2e
(À)-(S)-3d
(À)-(S)-3e
14
15
16
17
1a
1a
1a
1c
L2a
L2b
L2c
L2c
88
69
93
78
84
89
94
95
18[d]
1a
2 f
(À)-(S)-3 f
L2c
60
94
[a] Reaction conditions: 1 (0.10 mmol), 2 (0.15 mmol), [{PdCl(p-allyl)}2] (1.0 mmol), polymer ligand
(4.0 mmol P), K3PO4 (0.20 mmol) were heated in THF (0.40 mL) and H2O (0.040 mL) at 408C for 48 h,
unless otherwise noted. [b] Yield of isolated product. [c] Determined by HPLC analysis (chiral stationary
phase). [d] Used 0.20 mmol 2.
naphthyl-substituted ligand (R)-L2c again exhibited the high-
est enantioselectivities of up to 98% ee (entries 11–16). The
optimized reaction conditions could be applied to the
coupling of the naphthyl chloride 1c, which afforded highly
enantioenriched coupling product 3e (entry 17). The chlor-
ine-substituted arylboronic acid 2 f could also be utilized in
the SMC with 1a, thereby giving the corresponding product
carrying a chlorine group for additional functionalization
(entry 18).
The helical sense of the high-molecular-weight PQXphos
(R)-L2b–d was found to be switchable, as observed for (R)-
L2a in our previous report.[6b] We obtained the left-handed
helical polymer ligand (M)-(R)-L2c by heating a 1,1,2-
trichloroethane/THF solution of (P)-(R)-L2c (Scheme 1).
Inversion of the helical sense was complete after 24 hours.
The resultant left-handed helical polymer (M)-(R)-L2c was
used as a ligand in the SMC of 1a with 2d at 408C. Although
major VCD signals.[17] These results indicate that the type of
stereochemical control with PQXphos is significantly differ-
ent from that with KenPhos, probably because of the absence
of the dimethylamino group. In our system, the methyl groups
in 2a and the C5–C8 ring of the naphthyl group of 2b may
serve equally as having steric effects in the stereo-determining
step.
In summary, we have shown that helically chiral PQXphos
serves as a highly enantioselective ligand in the asymmetric
Suzuki–Miyaura coupling reaction to form axially chiral
biarylphosphinic esters. The organic groups on the phospho-
rus atom in the side chains of PQXphos have a considerable
effect on the enantioselectivities of the reactions. The high-
molecular-weight PQXphos bearing bulky P(2-nap)2 groups
successfully underwent solvent-dependent helical inversion,
thus leading to the highly enantioselective production of the
enantiomeric product. Although we have not shown it in this
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2009, 48, 3346; Review: e) A. J. Boersma, R. P. Megens, B. L.
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[7] For an early study on the synthesis and structure of poly(qui-
noxaline-2,3-diyl)s, see: Y. Ito, E. Ihara, M. Murakami, M. Shiro,
J. Am. Chem. Soc. 1990, 112, 6446.
paper, the enantiomeric products can also be obtained using
the enantiomeric polymer catalyst bearing S-configured side
chains. Further optimization of the ligand structure, attempts
at expanding the substrate scope, and utilization of the
polymer-based chiral ligand to other catalytic reactions are
currently being undertaken in this laboratory.
Received: June 3, 2011
Published online: August 4, 2011
[8] For the development of the methods for asymmetric synthesis of
poly(quinoxaline-2,3-diyl)s, see: a) Y. Ito, T. Ohara, R. Shima,
M. Suginome, J. Am. Chem. Soc. 1996, 118, 9188; b) Y. Ito, T.
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Org. Lett. 2002, 4, 351.
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[10] a) J. Yin, S. L. Buchwald, J. Am. Chem. Soc. 2000, 122, 12051;
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Buchwald, J. Am. Chem. Soc. 2010, 132, 11278.
Keywords: asymmetric synthesis · biaryls · cross-coupling ·
.
helical structures · ligand design
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