Synthesis of ortho-phenyl substituted MeO-BIPHEP ligand and its application in Rh-catalyzed asymmetric hydrogenation

Article abstract of DOI:10.1016/j.tetasy.2004.05.043

A new BIPHEP-type ligand with phenyl groups at the 3,3′-positions, o-Ph-MeO-BIPHEP 3 was prepared. This ligand afforded excellent enantioselectivities when used in the Rh-catalyzed asymmetric hydrogenation of α-dehydroamino acid derivatives. The strong influence of o-phenyl groups of the ligand on the enantioselectivities of the reaction has been demonstrated by a comparison with its parent ligand MeO-BIPHEP.

Full text of DOI:10.1016/j.tetasy.2004.05.043

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2177–2180
Synthesis of ortho-phenyl substituted MeO-BIPHEP ligand and its
application in Rh-catalyzed asymmetric hydrogenation
Shulin Wu, Minsheng He and Xumu Zhang*
Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA
Received 22 April 2004; accepted 18May 2004
Abstract—A new BIPHEP-type ligand with phenyl groups at the 3,30-positions, o-Ph-MeO-BIPHEP 3 was prepared. This ligand
afforded excellent enantioselectivities when used in the Rh-catalyzed asymmetric hydrogenation of a-dehydroamino acid derivatives.
The strong influence of o-phenyl groups of the ligand on the enantioselectivities of the reaction has been demonstrated by a
comparison with its parent ligand MeO-BIPHEP.
Ó 2004 Published by Elsevier Ltd.
1. Introduction
ious transition metal-catalyzed asymmetric syntheses,
and notably, moisture and air stability. The marked
features of Binap provided great advantage in the
development of atropisomeric bisphosphine ligands. H8-
Binap,8 BIPHEMP,9 MeO-BIPHEP,9 P-Phos,10 SEG-
PHOS,11 TunePhos,12 BisbenzodiodioxanPhos (SYN-
PHOS)13 and TetraMe-BITIANP14 have been reported
through modification of related biaryl phosphines.
While these ligands are effective for many asymmetric
catalytic reactions,15 they are still not efficient for certain
types of reactions and substrates. For example, asym-
metric hydrogenation with Rh-biaryl diphosphine sys-
tems often gives less satisfactory results and has seldom
appeared in the literature. One possible reason is that
the seven-membered chelate rings of these 1,4-diphos-
phines with transition metals are too conformationally
flexible.
The importance of molecular chirality in the fields of
pharmaceuticals, agrochemicals and functional materi-
als has been well recognized. Among various strategies
for making enantiomerically enriched compounds, cat-
alytic asymmetric synthesis mediated by transition metal
complexes provides a powerful method in terms of the
efficiency and atom economy.1 Design and synthesis of
ligands have proven to be one of the most important
subjects in the development of highly enantioselective
transition metal-catalyzed asymmetric reactions.2 Al-
though many effective ligands have been synthesized
over the last few decades, new ligands with unique steric
and electronic properties are still needed to meet the
requirements of diversified reactions and substrates.
Many excellent asymmetric transition metal catalysts
employ C2-symmetric diphosphines as ligands. Devel-
opment of C2-symmetric chiral diphosphine ligands and
their applications to asymmetric reactions have pro-
foundly influenced the direction of chiral ligand design
and research.1;2 Kagan’s DIOP,3 Knowles’s DIPAMP,4
Noyori’s Binap,5 Burk’s DuPhos6 as well as the Trost
ligand7 have become the most significant C2-symmetric
structural motives. The landmark ligand Binap is
remarkable in several aspects: structurally rigid scaffold,
excellent chiral recognition ability, broad utility in var-
The quadrant diagram analysis1b;c of the Rh-MeO-
BIPHEP complexes (Fig. 1) indicates that the orienta-
tion of four P-phenyl groups dictates the chiral envi-
ronment of the metal complex. The two equatorial
equatorial
MeO
MeO
PPh2
PPh2
P
P
Rh
axial
(S)-1
* Corresponding author. Tel.: +1-814-863-5614; fax: +1-814-863-8403;
e-mail: xumu@chem.psu.edu
Figure 1. Quadrant diagram of Rh-MeO-BIPHEP.
0957-4166/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2004.05.043

2178
S.Wu et al./ Tetrahedron: Asymmetry 15 (2004) 2177–2180
OMe
P-phenyl rings exert a greater steric influence on the two
diagonal quadrants while the two axial P-phenyl groups
stay relatively open in the other two quadrants. The
rotation and flexible orientation of the two equatorial P-
phenyl groups can decrease the effectiveness of the chiral
induction. We envisioned that the rotation of the
equatorial phenyl groups could be restricted by intro-
duction of bulky substituents at the 3,30-positions on the
biaryl backbone (Fig. 2). Consequently, better chiral
differentiation would be expected. With this idea in
mind, we recently developed an ortho-substituted BIP-
HEP ligand, o-Ph-hexaMeO-BIPHEP 2,16 and illus-
trated its high enantioselectivities in Rh-catalyzed
asymmetric hydrogenation of some cyclic enamides. The
results prompted us to explore this new type of struc-
tural motif further, and herein we report the concise
synthesis of a new ortho-substituted BIPHEP ligand,
(3,30-diphenyl-6,60-dimethoxybiphenyl-2,20-diyl)-bis(di-
phenylphosphine) (o-Ph-MeO-BIPHEP) (ligand 3) and
its applications in Rh-catalyzed asymmetric hydroge-
nation (Fig. 3).
OMe
OMe
a
b
MeO
HO
88%
97%
P(O)Ph2
P(O)Ph2
OMe
4
5
6
Ph
OMe
OMe
d
MeO
MeO
P(O)Ph2
P(O)Ph2
c
e
69%
40%
91% TfO
Ph
P(O)Ph2
P(O)Ph2
Ph
7
(RS)-9
8
Ph
Ph
f
MeO
MeO
P(O)Ph2
P(O)Ph2
MeO
MeO
P(O)Ph2
P(O)Ph2
+
resolution
Ph
Ph
(S)-9
(R)-9
Ph
Ph
g
MeO
MeO
P(O)Ph2
P(O)Ph2
MeO
MeO
PPh2
86%
PPh2
OMe
Ph
Ph
MeO
Ph
Ph
(S)-9
(S)-3
q
R
R
P
P
MeO
MeO
PPh2
PPh2
MeO
MeO
PPh2
PPh2
Scheme 1. Synthesis of (S)-o-Ph-MeO-BIPHEP. Reagents and condi-
tions: (a) (i) n-BuLi; Ph2PCl; (ii) H2O2. (b) BCl3. (c) NaH, PhN(Tf)2.
(d) PdCl2, dppf, K3PO4, PhB(OH)2. (e) LDA, FeCl3. (f) ()) or (+)-
DTTA. (g) HSiCl3, NBu3.
sub
MeO
Ph
Ph
OMe
Restrict the rotation
of the equatorial P-phenyl groups
(S)-3
(S)-2
racemic bisphosphine oxide 9. The yield was 40% under
unoptimized reaction conditions. The optical resolution
of racemic 9 was carried out in methanol at room tem-
perature. Both isomers can be obtained by using ())-
DTTA [())-(2S,3S)-2,3-O-ditoluoyltartaric acid] or (+)-
DTTA as the resolving reagents. Finally, HSiCl3
reduction of enantiomerically pure 9 in the presence of
tributylamine afforded the desired ligand 3. The con-
figuration of (+)-3 was assigned as S by comparison of
its hydrogenation products with those obtained with its
parent compound, MeO-BIPHEP 1. Unlike the elec-
tron-rich o-Ph-hexaMeO-BIPHEP 2, ligand 3 is an air-
stable solid.
Figure 2. Design of o-Ph-MeO-BIPHEP ligands.
NHAc
COOMe
HOOC
12 91% ee
13 98% ee
Figure 3. Asymmetric hydrogenation of related substrates with Rh-
(S)-3 catalyst.
2. Results and discussion
To evaluate the effectiveness of ligand 3, the Rh-cata-
lyzed asymmetric hydrogenation of a-dehydroamino
acids and their ester derivatives was investigated. Methyl
a-(acetamido)acrylate 10a and methyl (Z)-a-(acetam-
ido)cinnamate 10c were chosen as model substrates to
screen the reaction conditions. The catalyst was gener-
ated in situ by mixing of Rh(NBD)2SbF6 and (S)-3
(1:1.1) in a solvent. The hydrogenation was performed
at room temperature and 4 atm of hydrogen pressure
with a substrate/Rh ratio of 100:1. Complete conversion
of substrates was observed within 24 h. As shown in
Table 1, high (>99% ee) enantioselectivities were
achieved for the hydrogenation of 10a (entries 1, 2, 3
and 7) and even its corresponding acid 10b (entry 9)
under all tested conditions. It seems that changing sol-
vents and H2 pressure have no effect on the enantio-
The synthesis of ligand 3 is outlined in Scheme 1. The
known compound 517 was conveniently prepared from
commercially available 1,4-dimethoxybenzene 4. Thus,
deprotonation of 4 with n-BuLi at 0 °C followed by
quenching with Ph2PCl, oxidation with hydrogen per-
oxide provided phosphine oxide 5 in 97% yield. As the
key step, selective demethylation of 5 with excess BCl3 at
0 °C gave phenol 6, which in turn was transformed to
corresponding triflate 7 with NaH/PhN(Tf)2 in 91%
yield. The ortho-phenyl substituted phosphine oxide 8
was synthesized through the Suzuki coupling of 7 with
phenyl boronic acid using PdCl2 (dppf) as the catalyst.
The lithiation of 8 with LDA followed by an FeCl3-
mediated coupling reaction led to the formation of the

S.Wu et al./ Tetrahedron: Asymmetry 15 (2004) 2177–2180
2179
Table 1. Optimization of reaction conditions for Rh-catalyzed hydrogenation of a-dehydroamino acid derivatives
COOR'
NHAc
COOR'
NHAc
Rh(NBD)2SbF6, L*
H2, solvent, rt
R
R
10
11
Entrya
Ligand
R
R0
H2 pressure (psi)
Solvent
Eeb (%)
1
(S)-3
(S)-3
(S)-3
(S)-3
(S)-3
(S)-3
(S)-3
(S)-3
(S)-3
(S)-3
(S)-1
(S)-1
(S)-1
(S)-1
H
Me 10a
60
60
60
60
60
60
25
25
25
25
25
25
25
25
CH3OH
THF
<99
<99
<99
94
2
H
Me 10a
Me 10a
Me 10c
Me 10c
Me 10c
Me 10a
Me 10c
H 10b
3
H
CH2Cl2
CH3OH
THF
4
Ph
Ph
Ph
H
5
92
97
6
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
7
<99
98
8
Ph
H
9
<99
96
10
11
12
13
14
Ph
H
H 10d
Me 10a
H 10b
25
45
H
Ph
Ph
Me 10c
H 10d
21
36
a See Experimental Section for details. Complete conversions were observed.
b The (S)-configuration was assigned. Enantiomeric excesses (ee) were determined by chiral GC (Chiralsil-VAL III FSOT). The ee values of the acids
were determined from the corresponding methyl esters.
Table 2. Asymmetric hydrogenation of a-dehydroamino acid deriva-
tives catalyzed by Rh-(S)-3 system
selectivity. However, a solvent effect was observed when
10c was employed in the hydrogenation (entries 4–6)
and CH2Cl2 gave the best result among all three given
solvents.
COOR'
NHAc
COOR'
NHAc
Rh(NBD)2SbF6, (S)-3
H2(25 psi), CH2Cl2,rt, 24 h
R
R
10
11
Furthermore, a slight improvement in enantioselectivity
(98%) was observed when the reaction was carried out at
a lower H2 pressure (25 psi) (entry 8). The correspond-
ing acid 10d also gave high ee (96%, entry 10). Thus,
optimized reaction conditions were established. To
demonstrate the importance of the ortho-substituents on
ligand 3, controlled experiments using MeO-BIPHEP 1
were performed on substrates 10a–d under the same
reaction conditions. Compared with the 3,30-substituted
ligand 3, the 3,30-unsubstituted parent ligand MeO-
BIPHEP 1 resulted in a drastic decrease of the ee values
(entries 11–14), which clearly indicates the strong influ-
ence of the o-phenyl groups on ligand 3 on the enantio-
selectivities of the reaction.
Entrya
Substrate
Eeb (%)
1
10a R ¼ H, R0 ¼ CH3
>99
>99
98
2
10b R ¼ H, R0 ¼ H
3
10c R ¼ C6H5, R0 ¼ CH3
4
10d R ¼ C6H5, R0 ¼ H
96
97
5
10e R ¼ p-F–C6H4, R0 ¼ CH3
10f R ¼ p-F–C6H4, R0 ¼ H
10g R ¼ o-Cl–C6H4, R0 ¼ CH3
10h R ¼ o-Cl–C6H4, R0 ¼ H
10i R ¼ m-Br–C6H4, R0 ¼ CH3
10j R ¼ m-Br–C6H4, R0 ¼ H
10k R ¼ 2-Naphthyl, R0 ¼ CH3
10l R ¼ 2-Naphthyl, R0 ¼ H
10m R ¼ i-Propyl, R0 ¼ H
6
98
7
>99
>99
99
8
9
10
11
12
13
99
99
99
>99
COOMe
With the optimal reaction conditions in hand, ligand 3
was used in the hydrogenation of a series of acetyl
derivatives of a-dehydroamino acids 10e–m (Table 2,
entries 5–13). Excellent enantioselectivities (96 to >99%
ee) were observed. These results are comparable to the
best results reported to date. N-Benzoyl derivative 10n
also gave high enantioselectivity (entry 14) as expected.
Asymmetric hydrogenation of a-(acetoamino)acrylates
leads to the formation of valuable natural and unnatural
amino acids. As the milestone reaction in the history of
the development of homogeneous asymmetric catalysis,
it has been extensively studied.1;2a Although a number of
effective chiral phosphine-Rh catalysts have been
developed, high enantioselectivities achieved with ligand
3-Rh complexes are unprecedented because biaryl
diphosphine ligands are generally not very effective in
the Rh-catalyzed hydrogenation of a-(acetoamino)ac-
rylates.18
14
10n
>99
C6H5
NHCOC6H5
a See Experimental Section for details. Complete conversions were
observed.
b The (S)-configuration was assigned. Enantiomeric excesses (ee) were
determined by chiral GC (Chiralsil-VAL III FSOT). The ee values of
the acids were determined on the corresponding methyl esters.
Encouraged by the excellent results observed upon
asymmetric hydrogenation of some cyclic enamides
catalyzed by a Rh-o-Ph-hexaMeO-BIPHEP (ligand 2)
complex,16 we have preliminarily investigated this reac-
tion with ligand 3. Thus, asymmetric hydrogenation of
N-(3,4-dihydro-1-naphthyl)acetamide 12 with the Rh-
(S)-3 catalyst under the reaction conditions established
previously, gave high enantioselectivities (91% ee), albeit
slightly lower than those obtained with ligand 2.

2180
S.Wu et al./ Tetrahedron: Asymmetry 15 (2004) 2177–2180
with Transition Metal Compounds; VCH Verlsgsgesells-
chaft: Weiheim, 1993; Vol. 2, Ligands-References, p 359.
In addition, the ligand 3 system also showed a promising
result for the Rh-catalyzed asymmetric hydrogenation
of itaconic acid derivatives. For example, commercially
available compound 13 can be hydrogenated efficiently
with Rh-(S)-3 at 0 °C in 98% ee.
3. Kagan, H. B.; Dang, T.-P. J.Am.Chem.Soc.
6429.
1972, 94,
4. (a) Knowles, W. S. Angew.Chem,. Int.Ed. 2002, 41, 1998;
(b) Noyori, R.; Takaya, H. Acc.Chem.Res. 1983, 16, 106.
5. (a) Noyori, R. Angew.Chem,. Int.Ed. 2002, 41, 2008; (b)
Noyori, R.; Takaya, H. Acc.Chem.Res. 1990, 23, 345.
6. Burk, M. J.; Gross, M. F.; Harper, T. G. P.; Kalberg, C. S.;
Lee, J. R.; Martinez, J. P. Pure Appl.Chem. 1996, 68, 37.
7. Trost, B. M.; Van Vranken, D. L. Chem.Rev. 1996, 96, 396.
8. (a) Zhang, X.; Mashima, K.; Koyano, K.; Sayo, N.;
Kumobayashi, H.; Akutagawa, S.; Takaya, H. Tetrahe-
dron Lett. 1991, 32, 7283; (b) Zhang, X.; Mashima, K.;
Koyano, K.; Sayo, N.; Kumobayashi, H.; Akutagawa, S.;
3. Conclusion
In conclusion, we have designed and synthesized a new
BIPHEP type ligand o-Ph-MeO-BIPHEP with phenyl
groups at the 3,30-positions. This ligand afforded excel-
lent enantioselectivities in the Rh-catalyzed asymmetric
hydrogenation of a-dehydroamino acid derivatives. The
strong influence of o-phenyl groups of the ligand on the
enantioselectivities of the reaction has been demon-
strated by the comparison with its parent ligand MeO-
BIPHEP. Further investigations of other catalytic
asymmetric reactions with o-BIPHEP-type ligands are
underway and will be reported in due course.
Takaya, H. J.Chem.Soc,. Perkin Trans.1
1994, 2309.
9. (a) Schmid, R.; Broger, E. A.; Cereghtti, M.; Crameri, Y.;
Foricher, J.; Lalonde, M.; Muller, R. K.; Scalone, M.;
Schoettel, G.; Zutter, U. Pure Appl.Chem. 1996, 68, 131;
(b) Schmid, R.; Foricher, J.; Cereghtti, M.; Schonholzer,
P. Helv.Chim.Acta
1991, 74, 370; (c) Schmid, R.;
Cereghtti, M.; Heiser, B.; Schonholzer, P.; Hansen, H.-J.
Helv.Chim.Acta 1988, 71, 897.
10. Pai, C.-C.; Lin, C.-W.; Chen, C.-C.; Chan, A. C. S.;
Wong, W. T. J.Am.Chem.Soc. 2000, 122, 11513.
11. Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.;
Miura, T.; Kumobayashi, H. Adv.Synth.Catal. 2001, 343,
264.
Acknowledgements
12. Zhang, Z.; Qian, H.; Longmire, J.; Zhang, X. J.Org.
Chem. 2000, 65, 6223.
13. (a) Pai, C.-C.; Li, Y.-M.; Zhou, Z.-Y.; Chan, A. C. S.
Tetrahedron Lett. 2002, 43, 2789; (b) Duprat de Paule, S.;
Jeulin, S.; Ratovelomanana-Vidal, V.; Genet, J. P.;
Champion, N.; Dellisb, P. Tetrahedron Lett. 2003, 44, 823.
This work was supported by NIH. We acknowledge a
generous loan of precious metals from Johnson Matthey
Inc.
ꢀ
14. Benincori, T.; Brenna, E.; Sannicolo, F.; Trimarco, L.;
Antognazza, P.; Cesarotti, E. J.Chem.Soc, . Chem.
Commun. 1995, 685.
References and notes
15. For a review, see: McCarthy, M.; Guiry, P. J. Tetrahedron
2001, 57, 3809.
1. (a) Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH:
New York, 2000; (b) Jacobson, E. N.; Pfaltz, A.;
Yamamoto, H. Comprehensive Asymmetric Catalysis I–
III; Springer: New York, 1999; (c) Noyori, R. Asymmetric
Catalysis in Organic Synthesis; John Wiley & Sons: New
York, 1994.
2. (a) Tang, W.; Zhang, X. Chem.Rev. 2003, 103, 3029; (b)
Seyden-Penne, J. Chiral Auxiliaries and Ligands in Asym-
metric Synthesis; Wiley: New York, 1995; (c) Brunner, H.;
Zettlmeier, W. Handbook of Enantioselective Catalysis
16. Tang, W.; Chi, Y.; Zhang, X. Org.Lett. 2002, 4, 1695.
17. Brown, J. M.; Woodward, S. J.Org.Chem. 1991, 56, 6803.
18. For example, it has been reported that asymmetric
hydrogenation of 10b and 10d with [Rh(BINAP)-
(CH3OH)2]ClO4 gave 67% and 84% ee respectively, see:
(a) Myashita, A.; Takaya, H.; Souchi, T.; Noyori, R.
Tetrahedron 1984, 40, 1245; (b) Myashita, A.; Yasuda, A.;
Takaya, H.; Toriumi, T.; Ito, T.; Souchi, T.; Noyori, R.
J.Am.Chem.Soc. 1980, 102, 7932.