Synthesis of Novel Diastereomeric Diphosphine Ligands and Their Applications in Asymmetric Hydrogenation Reactions

Article abstract of DOI:10.1021/ol026817+

(Matrix Presented) Diastereomeric biaryl diphosphine ligands 10 and 11 with added chiral centers on the backbone were synthesized. Substrate-directed asymmetric synthesis occurred in the coupling step of the preparation of the diastereomeric diphosphine oxides. The diastereomeric diphosphine oxides were easily separated by column chromatography with silica gel. Ruthenium catalysts containing these ligands were highly effective in the hydrogenation of 2-(6′-methoxy-2′-naphthyl)propenoic acid and β-ketoesters. The additional chiral centers had a significant influence on the enantioselectivity and activity of the catalysts.

Full text of DOI:10.1021/ol026817+

ORGANIC
LETTERS
2002
Vol. 4, No. 26
4599-4602
Synthesis of Novel Diastereomeric
Diphosphine Ligands and Their
Applications in Asymmetric
Hydrogenation Reactions
Liqin Qiu, Jianying Qi, Cheng-Chao Pai, Shusun Chan, Zhongyuan Zhou,
Michael C. K. Choi, and Albert S. C. Chan*
Open Laboratory of Chirotechnology of the Institute of Molecular Technology for
Drug DiscoVery and Synthesis and Department of Applied Biology and Chemical
Technology, The Hong Kong Polytechnic UniVersity, Hong Kong, China
bcachan@polyu.edu.hk
Received August 29, 2002
ABSTRACT
Diastereomeric biaryl diphosphine ligands 10 and 11 with added chiral centers on the backbone were synthesized. Substrate-directed asymmetric
synthesis occurred in the coupling step of the preparation of the diastereomeric diphosphine oxides. The diastereomeric diphosphine oxides
were easily separated by column chromatography with silica gel. Ruthenium catalysts containing these ligands were highly effective in the
hydrogenation of 2-(6′-methoxy-2′-naphthyl)propenoic acid and â-ketoesters. The additional chiral centers had a significant influence on the
enantioselectivity and activity of the catalysts.
Chiral bidentate phosphines are among the most important
auxiliaries in enantioselective catalysis.1 Although many
effective chiral diphosphine ligands such as BINAP,2 BI-
PHEMP,3 MeO-BIPHEP,3 P-phos,4 tetraMe-bitianp,5a bitinap,5b
bimip,5c biscap,5c SEG-PHOS,6 BIFAP,7 bisbenzodioxan-
Phos,8 and TangPhos9 have been developed, it is important
and necessary to develop new classes of chiral ligands with
novel features to probe new concepts and facilitate practical
applications. An important reason for the need of develop-
(4) (a) Pai, C.-C.; Lin, C.-W.; Lin, C.-C.; Chen, C.-C.; Chan, A. S. C. J.
Am. Chem. Soc. 2000, 122, 11513. (b) Pai, C.-C.; Chan, A. S. C. U.S. Patent
5 886 182, 1999.
(1) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley:
New York, 1994. (b) Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley-
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T.; Noyori, R. J. Am. Chem. Soc. 1980, 102, 7932. (b) Noyori, R.; Takaya,
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Cereghetti, M.; Schonholzer, P. HelV. Chim. Acta 1991, 74, 370. (c) Schmid,
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Demartin, F.; Pilati, T. J. Org. Chem. 1996, 61, 6244. (c) Benincori, T.;
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10.1021/ol026817+ CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/03/2002

hindrance, namely, (S)-[5,5′,6,6′-bis(2R,4R-pentadioxy)]-
(2,2′)-bis(diphenylphosphino)-(1,1′)-biphenyl 10 and (R)-
[5,5′,6,6′-bis(2R,4R-pentadioxy)]-(2,2′)-bis(diphenylphosphino)-
(1,1′)-biphenyl 11. The ligands are highly effective in the
asymmetric hydrogenation of 2-(6′-methoxy-2′-naphthyl)-
propenoic acid and â-ketoesters.
Scheme 1. Synthesis of Ligands.
The synthetic route is shown in Scheme 1.
(2S,4S)-Pentanediol di-p-tosylate 2 was prepared in 80.2%
yield via the reaction of (2S,4S)-pentanediol 1 with p-
toluenesulfonyl chloride in the presence of triethylamine. The
further reaction of compound 2 with catechol in the presence
of K2CO3 in DMSO solvent at room temperature for 72 h
gave (2R,4R)-2,4-dimethyl-3,4-dihydro-2H-1,5-benzodiox-
epine 3 in 41.7% yield. (2R,4R)-7-Bromo-2,4-dimethyl-3,4-
dihydro-2H-1,5-benzodioxepine 4 was subsequently prepared
quantitatively via the bromination of 3 at room temperature
for 24 h. For the preparation of 5, n-butyllithium was added
dropwise to a THF solution containing 4 at -78 °C over 1
h, followed by the addition of chlorodiphenylphosphine to
the resulting mixture. The reaction was continued at room-
temperature overnight to afford 95.5% yield of phosphine 5
that was further oxidized to phosphine oxide 6 with H2O2 in
acetone solution at 0 °C in 97.0% yield. A sequence of ortho-
lithiation/iodination with lithiumdiisopropylamide via a
thermodynamically controlled process gave iododiphosphine
oxide 7 with 59% conversion and 100% selectivity. Dia-
stereomers 8 and 9 were then obtained via Ullmann coupling
of oxide 7 in a combined yield of 80.9%. The molecular
structure of 8 was confirmed by single-crystal X-ray dif-
fraction (Figure 1). Ligands 10 and 11 were obtained in 89.5
ment in this field is that the substrates for asymmetric
catalysis are highly diverse and have different demands for
chiral ligands and corresponding catalysts. As the atropiso-
meric BINAP type ligands are effective for the easy sp2-sp2
axis rotation to change conformation in catalysis,1b much
effort was made to systematically adjust the electronic and
steric effects of the substituents on BINAP or its analogues
to tune their capability of chiral recognition. Chiral diphos-
phine ligand H8-BINAP has been shown to be superior to
BINAP in a series of asymmetric catalytic reactions, due
possibly to the more bulky structure of H8-BINAP.10
Recently, TunaPhos ligands were designed to change the
dihedral angles of the ligands and high ees in the hydrogena-
tion of â-ketoesters were obtained.11 In this communication
we report the development of two novel biaryl ligands with
added chiral centers on the backbone and with high steric
Figure 1. ORTEP drawing of Sax-8.
(8) Pai, C.-C.; Li, Y.-M.; Zhou, Z.-Y.; Chan, A. S. C. Tetrahedron Lett.
2002, 43, 2789.
(9) Tang, W.; Zhang, X. Angew. Chem., Int. Ed. 2002, 41, 1612.
(10) (a) Zhang, X. Y.; Mashima, K.; Koyano, K.; Sayo, N.; Kumobayashi,
H.; Akutagawa, S.; Takaya, H. Tetrahedron Lett. 1991, 32, 7283. (b) Zhang,
X. Y.; Mashima, K.; Koyano, K.; Sayo, N.; Kumobayashi, H.; Akutagawa,
S.; Takaya, H. J. Chem. Soc., Perkin Trans. 1 1994, 2309. (c) Xiao, J. L.;
Nefkens, S. C. A.; Jessop, P. G.; Ikariya, T.; Noyori, R. Tetrahedron Lett.
1996, 37, 2813. (d) Uemura, T.; Zhang, X. Y.; Matsumura, K.; Sayo, N.;
Kumobayashi, H.; Ohta, T.; Nozaki, K.; Takaya, H. J. Org. Chem. 1996,
61, 5510.
and 92.0% yields, respectively, by reducing 8 and 9 with
trichlorosilane and tributylamine in toluene at reflux tem-
perature. Two characteristics of the Ullmann coupling were
noted. First, the coupling reaction was moderately diaste-
reoselective, giving the two diastereomers in unequal amounts.
The Sax-form diastereomer 8 was obtained as the major
product, and its ratio to the Rax-form diasteromer 9 was 7:2.
(11) Zhang, Z.; Qian, H.; Longmire, J.; Zhang, X. J. Org. Chem. 2000,
65, 6223.
4600
Org. Lett., Vol. 4, No. 26, 2002

The reaction of Ru(cymene)Cl2 with ligands 10, S-BINAP,
or ligand 11 gave the corresponding chiral catalysts [RuL-
(p-cymene)Cl]Cl (L ) 10, BINAP, or 11). The asymmetric
hydrogenation of 2-(6′-methoxy-2′-naphthyl)propenoic acid
for the preparation of naproxen,8,12 a popular antiinflamma-
tory drug, was carried out as a model reaction. The
preliminary results are summarized in Table 1.
Table 1. Asymmetric Hydrogenation of
2-(6′-Methoxy-2′-naphthyl)propenoic Acid with
[RuL(p-cymene)Cl]Cl
PH2
T
time conversion
entrya
ligand
10
(psi) (°C) (h)
(%)
% eeb (config)
1
2
500 rt
500 rt
500 rt
800 rt
800 rt
800 rt
1000 rt
4
4
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
46
83 (S)
87 (S)
90 (R)
85 (S)
87 (S)
91 (R)
86 (S)
89 (S)
93 (R)
88 (S)
90 (S)
93 (R)
93 (S)
94 (S)
96 (R)
94 (S)
97 (R)
87 (S)
90 (S)
94 (R)
It was found that [RuCl(p-cymene)11]Cl was more enan-
tioselective than [RuCl(p-cymene)(S-BINAP)]Cl, which
was in turn better than [RuCl(p-cymene)10]Cl in the reac-
tion. These results clearly reveal that the additional chiral
centers on the ligand backbone have a significant effect
on the catalytic enantioselectivity and activity (entries 18,
20). In addition, naproxen was obtained in 96% ee using
[RuCl(p-cymene)11]Cl as a catalyst at 0 °C under 1000 psi
H2, which was an improvement over the Ru[(S)-BINAP]
catalyst system (94% ee) (entries 14, 15). The enantioselec-
tivity was further improved slightly by increasing the reaction
pressure. Up to 97% ee was obtained by using [RuCl(p-
cymene)11]Cl as a catalyst at 0 °C under 1750 psi H2 (entry
17).
S-BINAP
3
11
4
4
10
4
5
S-BINAP
4
6
11
10
4
7
4
8
S-BINAP 1000 rt
4
9
11
10
1000 rt
1600 rt
4
10
11
12
13
14
15
16
17
18
19
20
4
S-BINAP 1600 rt
4
11
10
1600 rt
4
1000
0
0
0
0
0
24
24
24
24
24
S-BINAP 1000
11
10
11
10
1000
2000
1750
When RuLCl2(DMF)n (L ) 10 or 11) catalysts were
applied to the asymmetric hydrogenation of â-ketoesters,5b,8,13
the enantioselectivities for the corresponding products were
also very high and compared favorably with the Ru[(S)-
BINAP]Cl2(DMF)n system (Table 2). These results clearly
showed the great potential of these new ligands in a variety
of useful asymmetric catalytic reactions.
1000 rt
0.5
S-BINAP 1000 rt
11 1000 rt
0.5
0.5
90
36
a Reaction conditions: solvent ) MeOH (2.5 mL); substrate/catalyst )
100:1 (mol/mol); substrate concentration ) 2.0 mg/mL. b The ee values
were determined by chiral HPLC with a Sumichiral OA-2500 column.
In conclusion, two novel diastereomeric biaryl diphosphine
ligands possessing both added chiral centers on the backbone
and high steric hindrance were synthesized. A substrate-
directed asymmetric synthesis occurred in the coupling step
of the diastereomeric diphosphine oxides. In addition, the
results of our asymmetric hydrogenation reactions exhibited
On the basis of this observation, this reaction can be regarded
as a substrate-directed asymmetric synthesis. Second, the two
diastereomers could be easily separated by silica gel column
chromatography using a mixed eluent (100:100:10 CHCl3/
EA/MeOH). This simple separation avoided the generally
tedious and sometimes difficult resolution step.
Table 2. Asymmetric Hydrogenation of â-Ketoesters Catalyzed by RuLCl2(DMF)n
% ee (config)
entrya
R1
Me
R2
R3
Sax-10
99.4 (S)
Rax-11
(S)-BINAP
97.7 (S)
1b
2b
3b
4b
5c
6c
H
H
H
H
H
Cl
Me
Et
99.3 (R)
Me
99.2 (S)
99.4 (R)
98.0 (S)
Me
Bn
Et
99.7 (S)
99.4 (R)
96.1 (S)
ClCH2
Ph
95.1 (R)
96.7 (S)
94.2 (R)
Et
97.7 (R)
82.4 (S)
89.3 (R)
Ph
Et
84.4 (2S,3S)
(13.6% anti)
7.4 (2R,3S)
(86.4% syn)
98.7 (2R,3R)
(34.0% anti)
53.4 (2S,3R)
(66.0% syn)
16.3 (2S,3S)
(10.4% anti)
9.8 (2S,3R)
(89.6% syn)
a Reaction conditions: solvents ) 12.5 µL CH2Cl2 + 987.5 µL MeOH or EtOH; time ) 24 h except for entry 6 (45 h); substrate/[Ru] ) 667:1 (mol/mol)
except for entry 6 (100:1); substrate concentration ) 0.5 mmol/mL; T ) 70 °C except for entry 6 (rt); P ) 50 psi H2 except for entry 6 (1000 psi H2);
complete conversions were obtained in all cases. b The ee values were determined by chiral GC with a WCOT fused silica CP Chirasil-DEX CB column (25
m × 0.25 mm) after converting the products to the corresponding acetyl derivatives. c The ee values were determined by chiral HPLC with a Daicel Chiralcel
1
OD column; ratio of anti to syn products was determined by H NMR.
Org. Lett., Vol. 4, No. 26, 2002
4601

a significant influence of the additional chiral centers on the
enantioselectivity and activity of the catalysts. These findings
accordingly offer a good handle for the development of new
chiral ligands. Further explorations of other applications of
these ligands in asymmetric catalytic reactions are in
progress.
Acknowledgment. We thank the University Grants
Committee Areas of Excellence Scheme (Project AoE P/10-
01), the Hong Kong Polytechnic University ASD Fund, and
the Hong Kong RGC Central Allocation Fund (Project
ERB03) for financial support.
Supporting Information Available: Experimental de-
tails, spectroscopic data, and analytical data for 2-4 and
6-11 and crystallographic data for compound 8 (CIF
format). This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) (a) Ohta, T.; Takaya, H.; Kitamura, M.; Nagai, K.; Noyori, R. J.
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OL026817+
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Org. Lett., Vol. 4, No. 26, 2002