Synthesis of new chiral diphosphine ligand (BisbenzodioxanPhos) and its application in asymmetric catalytic hydrogenation

Article abstract of DOI:10.1016/S0040-4039(02)00383-0

The new chiral diphosphine ligand [(5,6), (5′,6′)-bis(1,2-ethylenedioxy)biphenyl-2,2′-diyl]bis (diphenylphosphine) (BisbenzodioxanPhos) has been successfully prepared and used in ruthenium-catalyzed asymmetric hydrogenation of 2-(6′-methoxy-2′-naphthyl)propenoic acid and β-keto esters with high enantioselectivity (92.2% and up to 99.5% ee, respectively).

Full text of DOI:10.1016/S0040-4039(02)00383-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2789–2792
Synthesis of new chiral diphosphine ligand (BisbenzodioxanPhos)
and its application in asymmetric catalytic hydrogenation
Cheng-Chao Pai, Yue-Ming Li, Zhong-Yuan Zhou and Albert S. C. Chan*
Open Laboratory of Chirotechnology of the Institute of Molecular Technology for Drug Design and Synthesis,† and Department
of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
Received 19 November 2001; revised 13 February 2002; accepted 21 February 2002
Abstract—The new chiral diphosphine ligand [(5,6), (5%,6%)-bis(1,2-ethylenedioxy)biphenyl-2,2%-diyl]bis(diphenylphosphine) (Bisben-
zodioxanPhos) has been successfully prepared and used in ruthenium-catalyzed asymmetric hydrogenation of 2-(6%-methoxy-2%-
naphthyl)propenoic acid and b-keto esters with high enantioselectivity (92.2% and up to 99.5% ee, respectively). © 2002 Published
by Elsevier Science Ltd.
Atropisomeric C2-symmetric phosphine ligands have
played crucial roles in the development of asymmetric
catalysis.1 Although many chiral diphosphine ligands
have been prepared and applied in asymmetric catalytic
hydrogenation reactions, and excellent results have
been achieved in a number of reactions,2 the design and
development of new chiral diphosphine ligands for
transition metal complex-catalyzed commercially
attractive reactions is still an area of high interest.
shown to be superior to their binaphthyl counterparts
in a series of asymmetric catalytic reactions.3–6 Our
previous studies have shown that chiral ligands bearing
the H8-BINOL structure induced higher enantioselec-
tivity in a series of asymmetric reactions as compared
to BINOL, due possibly to the more bulky structure of
H8-BINOL.7–10 To expand further the scope of these
findings, it is of high interest to design chiral ligands
similar to H8-BINAP but with added functionalities
(Fig. 1).
Among the chiral ligands studied, atropisomeric
diphosphines of the BINAP type have found widest
application in transition metal-catalyzed reactions due
to their spectacular asymmetry-inducing capability.2
The BINAP family of ligands are outstanding in the
asymmetric hydrogenation of 2-arylacrylic acids in
which most other chiral ligands are ineffective. Chiral
diphosphine ligands of the type H8-BINAP have been
Hetero-aromatic compounds have provided a variety of
opportunities for the synthesis of chiral phosphine lig-
ands for asymmetric catalytic reactions, and many new
chiral hetero-aromatic biarylphosphines such as
tetraMe-bitianp,11 bitianp,12 bimip,13 biscap,13 BIB-
FUP,14,15 SEG-PHOS,16 and BIFAPS17 have recently
been reported. In this communication we report the
Figure 1.
Keywords: BisbenzodioxanPhos; hydrogenation; b-keto esters; naproxen.
* Corresponding author. Tel.: 852-2766 5607; fax: 852-2364 9932; e-mail: bcachan@polyu.edu.hk
† University Grants Committee Area of Excellence Scheme in Hong Kong.
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00383-0

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C.-C. Pai et al. / Tetrahedron Letters 43 (2002) 2789–2792
synthesis of a new type of chiral ligand ([(5,6),(5%,6%)-
bis(1,2 - ethylenedioxy)biphenyl - 2,2% - diyl]bis(diphenyl-
phosphine) (BisbenzodioxanPhos, 6)) and the applica-
tion of its ruthenium complexes in two classes of asym-
metric catalytic hydrogenation reactions which are of
commercial interest.
tuning. The synthetic route to compound 6 is outlined
in Scheme 1.18
Compound 1 is commercially available and can be
readily brominated according to a known procedure19
to provide compound 2 in almost quantitative yield.
Lithiation of 2 with n-butyl lithium in THF at −78°C,
followed by the addition of chlorodiphenylphosphine
and subsequent oxidation with hydrogen peroxide pro-
duced phosphine oxide 3. A sequence of ortho-lithia-
tion/iodination20 with LDA via a thermodynamically
controlled process instead of the generally used iodina-
tion with diiodoethane gave product 4 in 75% isolated
BisbenzodioxanPhos bears a bis-benzodioxane struc-
ture, a structural feature similar to that of H8-BINAP.
It is expected to show good reactivity and selectivity in
asymmetric catalytic reactions in which BINAP is
uniquely useful. The dioxane part of the backbone also
offers good opportunities for easy modification and
Scheme 1. The synthetic route to (R)-BisbenzodioxanPhos. (a) Br2, HOAc, rt, 100%; (b) (1) n-BuLi, THF, −78°C (2) ClPPh2,
−78°C to rt (3) H2O2, 0°C, acetone, 93%; (c) (1) LDA, THF, −78°C (2) 1,2-diiodoethane, −78°C to rt, 75%; (d) Cu, DMF, 140°C,
85%; (e) (1) resolution, (−)-DBTA, CH2Cl2:EA:EtOH=1:2:1.7, 7 days (2) NaOH, 44%; (f) HSiCl3, toluene, 140°C, 83%.
Figure 2. The ORTEP drawing of (−)-DBTA·(R)-5.

C.-C. Pai et al. / Tetrahedron Letters 43 (2002) 2789–2792
2791
Table 1. The asymmetric hydrogenation of b-keto esters
yield. The racemic bis(diphenylphosphine oxide) 5 was
obtained in good yield (85.2%) via Ullmann coupling21
of the iodophosphine oxide 4. The enantiomers of 5 can
be resolved using either (−)-2,3-dibenzoyl tartaric acid
or (+)-2,3-dibenzoyl tartaric acid [(−)- or (+)-DBTA] as
the resolving agent. (R)-Phosphine oxide was obtained
when (−)-DBTA was used as the resolving agent. The
structure and the absolute configuration of the complex
was determined by single-crystal X-ray diffraction of
(−)-DBTA·(R)-5 (Fig. 2).
with 7
OH
O
O
O
catalyst, H2
OR2
R1
R1
OR2
Entrya
R1
R2
Conv. (%)
ee (%)
1b
2b
3c
4b
CH3
CH3
CH3
ClCH2
CH3
Et
Bn
Et
100
100
100
100
98.1
99.5
96.9
97.0
The enantiomeric purity of 5 was determined by HPLC
using a chiral column (Daicel AD). The chiral ligand
BisbenzodioxanPhos (6) was obtained with enan-
tiomeric purity of over 99.9% upon the reduction of its
phosphine oxide precursor 5 with trichlorosilane at
140°C.
a The hydrogenation was carried out in 50 ml autoclave; 50 psi of H2;
solvent 2.5 ml (methanol or ethanol); 100 mg of substrate (0.38–0.2
M); 0.5 mg of catalyst 7 (ca. 0.2 mM); the reaction time was 12–24
h; the reaction temperature was 80–90°C; the configuration of
product was R.
b Enantiomeric excess was determined by GC analysis
(CHROMPACK WCOT fused silica 25 M×0.25 MM coating CP
CHIRASIL-DEX CB) after converting the product to the corre-
sponding acetate derivative.
Whether the dioxane units of the ligand may provide
enough steric hindrance to preserve the configuration of
6 and whether racemization may occur during the high
temperature reduction process are interesting questions.
To test if racemization occurred during the high tem-
perature reduction process and to measure the enan-
tiomeric purity of the ligand, the resolved
enantiomerically pure diphosphine 6 was oxidized back
to its diphenylphosphine oxide using H2O2 and the
enantiomeric composition of the oxidized product was
measured. The experimental result clearly showed that
racemization did not occur during the trichlorosilane
reduction step.
c Enantiomeric excess was determined by GC analysis (CHIRALDEX
G-PN) after converting the hydrogenation product to the corre-
sponding acetate derivative.
The asymmetric hydrogenation of 2-(6%-methoxy-2%-
naphthyl)propenoic acid was also studied using 8 as the
catalyst. The naproxen product, a nonsteroidal drug
with anti-inflammatory, analgesic and antipyretic activ-
ity,25–27 was obtained in high ee. The enantiomeric
excess of naproxen obtained using 6 as chiral ligand
compared favorably with that using BINAP as the
chiral ligand under similar reaction conditions (1000 psi
H2 pressure and ambient temperature, entry 2 in Table
2).6,12,23,25,28 It should be noted that this commercially
attractive reaction has been extensively studied in the
past two decades and except for the BINAP type of
ligands, most other ligands proved ineffective. The
development of new catalysts with improved enantiose-
lectivity is therefore highly desirable.
Ru[(R-6)Cl2(DMF)n] (7) and Ru[(R-6)Cl(p-cymene)]Cl
(8) were prepared by using procedures reported by
Windscheif et al. and Mashima et al.,22,23 and the
complexes were characterized by 1H and 31P NMR
spectra. These complexes were used as catalysts for the
subsequent hydrogenation study without further
purification.
The experiments on the hydrogenation of b-keto esters
were carried out in a Parr stainless steel high pressure
reactor under 50 psi H2 pressure at 80–90°C. The
results shown in Table 1 revealed that the new catalyst
was highly enantioselective in this class of reactions.24
The effect of hydrogen pressure on the enantioselectiv-
ity of the reaction is shown in entries 1–4 of Table 2.
Higher hydrogen pressure gave better enantiomeric
excess in the product.
Table 2. The asymmetric hydrogenation of 2-(6%-methoxy-2%-naphthyl)propenoic acid with 8
catalyst, H2
COOH
COOH
MeOH, rt
CH3O
CH3O
H2 pressure (psi)
Entrya
Conversion (%)
eeb (%)
1
2
3
4
1700
1000
500
100
100
100
100
92.2
91.0 (89.0)c
89.2
100
67.4
a Reactions carried out in a 50 ml autoclave; 2.5 ml of methanol as solvent; 5 mg of substrate (8.8 mM); 0.25 mg of catalyst 8 (0.1 mM based
on Ru); ambient reaction temperature (20–25°C).
b The enantiomeric excess was determined by HPLC analysis with a SUMICHIRAL OA-2500 column.
c This reaction was carried out using (S)-BINAP as the ligand under the same reaction conditions.

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C.-C. Pai et al. / Tetrahedron Letters 43 (2002) 2789–2792
In conclusion, we have designed and prepared an effec-
tive chiral atropisomeric ligand BisbenzodioxanPhos
using a convenient synthetic route. This ligand forms
well-defined ruthenium complexes which offer high
enantioselectivities in the catalytic hydrogenation of a
variety of b-keto esters and 2-(6%-methoxy-2%-naph-
thyl)propenoic acid. The application of this new ligand
in other asymmetric catalytic reactions is being studied.
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Acknowledgements
We acknowledge the financial support from the Hong
Kong Polytechnic University ASD and the Hong Kong
Research Grants Council (project number ERB03).
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