Convenient divergent strategy for the synthesis of TunePhos-type chiral diphosphine ligands and their applications in highly enantioselective Ru-catalyzed hydrogenations

Article abstract of DOI:10.1021/jo702068w

(Chemical Equation Presented) A convenient, divergent strategy for the synthesis of a series of modular and fine-tunable C₃-TunePhos-type chiral diphosphine ligands and their applications in highly efficient Rucatalyzed asymmetric hydrogenations were explored. Up to 97 and 99% ee values were achieved for the enantioselective synthesis of β-methyl chiral amines and α-hydroxy acid derivatives, respectively.

Full text of DOI:10.1021/jo702068w

to the decisive role of chiral ligands for both catalytic activity
and high level of enantioselectivity, considerable efforts have
been devoted to the design and synthesis of a variety of chiral
ligands.3 Inspired by the tremendous success achieved in the
use of Rh- and Ru-BINAP-catalyzed asymmetric reactions,4
many atropisomeric C2-symmetric biaryl diphosphine ligands,
such as H8-BINAP,5 MeO-BIPHEP,6 SEGPHOS,7 P-Phos,8 and
other important biaryl phosphine ligands, have been developed
in the past two decades (Figure 1).3
Convenient Divergent Strategy for the Synthesis
of TunePhos-Type Chiral Diphosphine Ligands
and Their Applications in Highly Enantioselective
Ru-Catalyzed Hydrogenations
Xianfeng Sun,† Le Zhou,‡ Wei Li,† and Xumu Zhang*,†
Department of Chemistry and Chemical Biology &
Pharmaceutical Chemistry, Rutgers, The State UniVersity of
New Jersey, Piscataway, New Jersey 08854-8066, and College
of Science, Northwest A&F UniVersity, Yangling,
Shaanxi 712100, The People’s Republic of China
xumu@rci.rutgers.edu
ReceiVed September 20, 2007
FIGURE 1. Some atropisomeric C2-symmetric biaryl ligands.
Although these atropisomeric biaryl ligands are highly
effective for many asymmetric transformations, the search for
more practical and efficient ligands in terms of ease of
preparation, high enantioselectivity, and high turnover number
(TON) remains an important goal in asymmetric hydrogenation.
Recently, we have developed a novel class of conformation-
ally rigid Cn-TunePhos (Figure 1, n ) 1-6) ligands, by
introducing a bridge with variable length to link the chiral
atropisomeric biaryl groups.9 This family of TunePhos ligands
has proven highly efficient in a variety of asymmetric reac-
tions.10 Apart from optimization in length of these alkyl linkers,
we envision that changes of the phosphorus substituents of
TunePhos ligands are also important structural modifications,
which may endow these new ligands with unique steric and
electronic properties. With respect to the efficient synthesis of
a class of such ligand analogues, the established synthetic routes
from MeO-BIPHEP and its derivatives have some disadvan-
tages, as described in Schmid’s report.6 Specifically, the
phosphinous or phosphinic acid derivatives or the secondary
phosphines have to be synthesized separately in each case
(typically starting from a phosphorus trichloride) which elon-
A convenient, divergent strategy for the synthesis of a series
of modular and fine-tunable C3-TunePhos-type chiral diphos-
phine ligands and their applications in highly efficient Ru-
catalyzed asymmetric hydrogenations were explored. Up to
97 and 99% ee values were achieved for the enantioselective
synthesis of â-methyl chiral amines and R-hydroxy acid
derivatives, respectively.
(2) Noyori, R. Angew. Chem. 2002, 114, 2108; Angew. Chem., Int. Ed.
2002, 41, 2008.
(3) (a) Tang, W.; Zhang, X. Chem. ReV. 2003, 103, 3029. (b) Shimizu,
H.; Nagasaki, I.; Saito, T. Tetrahedron 2005, 61, 5405.
The biological activity of many pharmaceutical compounds,
agrochemicals, flavors, and fragrances is associated with
absolute molecular configuration, which makes the enantiose-
lective synthesis of chiral compounds an important topic.1 The
development of efficient methods to achieve this goal has been
a substantial challenge for chemists in both academia and
industry. Among various strategies, catalytic asymmetric hy-
drogenation mediated by transition metal complexes provides
one of the most practical and powerful routes due to its
remarkable features, including high stereoselectivity, high
reactivity, atom economy, and operational simplicity.2 Owing
(4) Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Tto, I.; Souchi,
T.; Noyori, R. J. Am. Chem. Soc. 1980, 102, 7935.
(5) Zhang, X.; Mashima, K.; Koyano, K.; Sayo, N.; Kumobayashi, H.;
Akutagawa, S.; Takaya, H. Tetrahedron Lett. 1991, 32, 7283.
(6) 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.
(7) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura,
T.; Kumobayashi, H. AdV. Synth. Catal. 2001, 343.
(8) Pai, C.-C.; Lin, C.-W.; Lin, C.-C.; Chen, C.-C.; Chan, A. S. C.; Wong,
W. T. J. Am. Chem. Soc. 2000, 122, 11513.
(9) (a) Zhang, X. U.S. Patent 6521769, 2003 (filed 1999). (b) Zhang,
Z.; Qian, H.; Longmire, J.; Zhang, X. J. Org. Chem. 2000, 65, 6223.
(10) (a) Wu, S.; Wang, W.; Tang, W.; Lin, M.; Zhang, X. Org. Lett.
2002, 4, 4495. (b) Tang, W.; Wu, S.; Zhang, X. J. Am. Chem. Soc. 2003,
125, 9570. (c) Lei, A.; Wu, S.; He, M.; Zhang, X. J. Am. Chem. Soc. 2004,
126, 1626. (d) Wang, C.-J.; Sun, X.; Zhang, X. Angew. Chem. 2005, 117,
5013; Angew. Chem., Int. Ed. 2005, 44, 4933. (e) Wang, C.-J.; Sun, X.;
Zhang, X. Synlett 2006, 1169. (f) Raghunath, M.; Zhang, X. Tetrahedron
Lett. 2005, 46, 7017.
† Rutgers.
‡ Northwest A&F University.
(1) (a) Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York,
2000. (b) Brown, J. M. In ComprehensiVe Asymmetric Catalysis; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Heidelberg, 1999. (c)
Asymmetric Catalysis in Organic Synthesis; Noyori, R., Ed.; Wiley: New
York, 1994.
10.1021/jo702068w CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/03/2008
J. Org. Chem. 2008, 73, 1143-1146
1143

SCHEME 1. Synthesis of Ligandsa
(phosphonic dichlorides), readily formed in situ from intermedi-
ate 5 by the treatment with thionyl chloride, underwent
tetrasubstitution with a wide variety of Grignard reagents to
give compounds 6a-e. Completion of the synthesis of the series
of chiral ligands (Sax,RR)-7a-e was accomplished after reduc-
tion with trichlorosilane and tributylamine in refluxing xylene.
Complete retention of the biphenyl stereochemistry was con-
firmed by 1H NMR analysis and optical rotation measurement.
Several features are highlighted in our new synthetic strategy.
First, the small hindrance of bis(diethyl phosphonate) in
compound 4 facilitated the followed oxidative coupling reaction
to give the desired product 5 in a high yield. This strategy
circumvents the problem in our initial attempt to attach Ar
groups in this step, which led to extremely low homocoupling
yields. For some bulky substituents, even no coupling products
were detected due to high steric hindrance. Second, the
introduction of the synthetically flexible intermediate 5 allows
for the convenient divergent incorporation of various Ar
substituents of the PAr2 moieties in the penultimate step,
avoiding the requisite individual formation of the phosphinic
or phosphinous moieties as described in traditional strategies.3
Third, the chiral linking bridge of the 2,4-pentanediol tether is
very simple and just flexible enough for the chirality transfer
from central-to-axial in the homocoupling reaction with com-
plete diastereodifferentiation without unwanted intermolecular
coupling. This avoids tedious routine resolutions.13 Last, only
five steps are necessary in this procedure, and the overall
synthesis steps are easy to handle.
To test the synthetic utility of these ligands, we have explored
the Ru-catalyzed hydrogenations of allylphthalimides and R-keto
esters. The catalysts RuL*Cl2(DMF)n 8a-e (where L* is the
chiral ligand 7a-e, n ) 2-6) were prepared as reddish brown
solids from [RuCl2(benzene)2]2 and the corresponding 7a-e in
DMF at 100 °C.14 The complexes, thus obtained, were used
directly in the catalytic reactions.
Asymmetric hydrogenation of R-phthalimide ketones and
disubstituted allylphthalimides demonstrates an efficient ap-
proach to access chiral amino alcohols and â-methyl chiral
amines after deprotection.10,15 Chiral amines bearing a â-methyl
group on the chiral center and their derivatives are key structural
elements in both natural products and pharmaceuticals.16 We
initiated our studies by screening catalysts 8a-e on the
asymmetric hydrogenation of the N-2-ethylallylphthalimide. In
the presence of the 8a complex, up to 94% ee and 100%
conversion was observed at 80 °C under 100 atm hydrogen
pressure in 24 h (Table 1, entry 1). A systematic investigation
of the effect of substituents on ligand 7 indicated that the
introduction of somewhat bulky 4-methyl (7b) and 3,5-dimethyl
(7c) groups or much more hindered 3,5-di-tert-butyl (7d) and
4-methoxyl-3,5-di-tert-butyl (7e) groups to P-phenyl rings
dramatically decreased the enantioselectivities (Table 1, entries
2-5).
a Reagents and conditions: (a) DIAD, Ph3P, THF, sonication, 0-35 °C,
1 h; (b) i. Mg, THF, reflux; ii. (EtO)2OPCl, THF, -78 °C to rt; (c) i. LTMP,
THF, -78 °C; ii. FeCl3, THF, -78 °C to rt; (d) i. SOCl2, cat. DMF, reflux
for 30 h; ii. ArMgX, -78 °C; (e) HSiCl3, Bu3N, xylene, reflux.
gates the synthetic route. It could also be difficult to attach bulky
diaryl groups to the phosphorus atoms due to steric hindrance.
Moreover, cumbersome individual resolution procedures have
to be performed for each new derivative in the case of routes
involving the phosphine oxide.6,11
As part of our continued interest in the synthesis and use of
new chiral diphosphine ligands in asymmetric catalysis, we have
developed the idea of using a chiral linker to make enantio-
merically pure TunePhos-type ligands. The designed ligands 7
were first documented by us in the invention disclosure along
with a suggested route of using a chiral linker to control the
formation of biaryl phosphines in 1999.9a Though this attractive
pathway to make 7a was then demonstrated by Chan’s group,
long synthetic routes, moderate yields, and hard modifications
on P-aryl groups restrict their potential applications.12
Herein, a truly general, divergent way to make modular C3-
TunePhos-type of phosphine ligands is discovered (Scheme 1).
The synthetic route was condensed and straightforward: the
chiral bis(bromoether) 3 was prepared by the Mitsunobu reaction
with (2S,4S)-pentanediol and 3-bromophenol. The double Mit-
sunobu reaction proceeded smoothly and afforded 88% yield
of 3 in 1 h under sonication conditions. The phosphate 4 was
conveniently obtained after the generation of bis-Grignard
reagent followed by quenching with diethyl chlorophosphate.
A sequence of thermodynamically controlled ortho-lithiation
with in situ LTMP followed by oxidative homocoupling with
anhydrous ferric chloride afforded bis(diethyl phosphonates) 5
1
in a good yield and >99% diastereoselectivity based on H
To assess the general efficiency of this catalytic system, the
asymmetric hydrogenation reactions were performed on a variety
of substrates using 8a as a catalyst (Table 1, entries 6-12).
NMR analysis. The axial chirality S was assigned when
compared to the data reported in the literature.12 The bis-
(11) (a) Broger, E. A.; Foricher, J.; Heiser, B.; Schmid, R. U.S. Patent
5274125, 1993. (b) Foricher, J.; Heiser, B.; Schmid, R. U.S. Patent 5302738,
1994. (c) Lalonde, M.; Schmid, R. U.S. Patent 5536858, 1996.
(12) (a) Qiu, L.; Wu, J.; Chan, S.; Au-Yeung, T. T.-L.; Ji, J.-X.; Guo,
R.; Pai, C.-C.; Zhou, Z.; Li, X.; Fan, Q.-H.; Chan, A. S. C. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5815. (b) Qiu, L.; Kwong, F. Y.; Wu, J.; Lam,
W. H.; Chan, S.; Yu, W.-Y.; Li, Y.-M.; Guo, R.; Zhou, Z.; Chan, A. S. C.
J. Am. Chem. Soc. 2006, 128, 5955.
(13) Sugimura, T.; Yamada, H.; Inoue, S.; Tai, A. Tetrahedron: Asym-
metry 1997, 8, 649.
(14) Takaya, H.; Akutagawa, S.; Noyori, R. Org. Synth. 1993, 71, 57.
(15) Brunner, H.; Wachter, J.; Schmidbauer, J. Organometallics 1986,
5, 2212.
(16) (a) Lazarevski, G.; Kobrehel, G.; Metelko, B.; Duddeck, H. J.
Antibiot. 1996, 49, 1066. (b) Nicholas, G. M.; Molinski, T. F. Tetrahedron
2000, 56, 2921.
1144 J. Org. Chem., Vol. 73, No. 3, 2008

TABLE 1. Asymmetric Hydrogenation of N-2-Substituted
TABLE 2. Asymmetric Hydrogenation of r-Keto Esters 11a
Allylphthalimides 9a
ee %b
(Sax,RR)-
(S)-C3-
TunePhos
entry
catalyst
sub.
R
prod.
ee %b
config.c
entry sub.
R1
R2
prod.
7c
1
2
3
4
5
6
7
8
9
8a
8b
8c
8d
8e
8a
8a
8a
8a
8a
8a
8a
9a
9a
9a
9a
9a
9b
9c
9d
9e
9f
Et
Et
Et
Et
10a
10a
10a
10a
10a
10b
10c
10d
10e
10f
94
84
72
24
76
95
92
86
66
97
93
94
S (-)
(-)
(-)
(-)
(-)
(-)
(-)
(-)
(+)
(-)
(-)
(-)
1
2
3
4
5
6
7
8
9
11a
11b
11c
11d
11e
11f
11g
11h
11i
Ph
Me 12a
Me 12b
Me 12c
Me 12d
Me 12e
Me 12f
99
98
98
98
96
99
98
98
97
98
97
95
94
93
92
96
96
95
85
96
4-F-C6H4
3-F-C6H4
4-Cl-C6H4
4-Br-C6H4
4-Me-C6H4
4-MeO-C6H4 Me 12g
3-MeOC6H4
2-furyl
Et
nBu
Bn
iBu
tBu
cyclohexyl
cyclopentyl
Cl
Me 12h
Me 12i
10
11
12
10
11j
Ph(CH2)2
Et
12j
9g
9h
10g
10h
a Conversions were >99% as indicated by 1H NMR for all entries. b The
enantiomeric excesses were determined by chiral GC (see the Supporting
Information); the absolute configurations of products were assigned as S
by comparison of the observed optical rotation with reported data.10e
a Complete conversions were indicated by 1H NMR spectroscopy in all
entries. b The enantiomeric excesses were determined by chiral HPLC or
chiral GC (see the Supporting Information). c The absolute configuration
of 10a was assigned by comparison of the observed optical rotation with
reported data.10d
hydrochloride19 was readily accessible via the hydrogenation
of ethyl 2-oxo-4-phenylbutyrate with up to 98% ee (Table 2,
entry 10). To our knowledge, these results represent one of the
highest enantioselectivities yet achieved for the preparation of
optically active R-hydroxy acid derivatives using direct asym-
metric hydrogenations.
In conclusion, we have developed a remarkably versatile route
for the synthesis of a family of C3-TunePhos derivative
diphosphine ligands for highly efficient Ru-catalyzed asym-
metric hydrogenations. These highly enantioselective hydroge-
nation reactions provide facile access to optically active amines
and R-hydroxy acid derivatives, which are very important chiral
building blocks for the synthesis of a variety of natural products
and biologically active molecules. Further exploration of the
general applications of this class of ligands in transition-metal-
catalyzed asymmetric reactions will be reported in due course.
Substrates with a primary n-alkyl substituent such as an ethyl,
n-butyl, or benzyl group at the 2-position of the allylphthalimides
afforded products with high ee values (Table 1, entries 1, 6,
and 7). The enantioselectivities decreased gradually as the steric
hindrance of the substituents in the substrates increased (Table
1, entries 6-9). However, the hydrogenation of a cyclohexyl-
and cyclopentyl-substituted substrates (9f and 9g) still afforded
the desired products in 97 and 93% ee (Table 1, entries 10 and
11). In addition, the electron-deficient 2-chloroallylphthalimide
can also be hydrogenated with good enantioselectivity using
this system (Table 1, entry 12). These enantioselectivities for
the corresponding products were comparable with the results
achieved with Ru[(S)-Cn-TunePhos]Cl2(DMF)n systems.10d
Asymmetric hydrogenation of the corresponding R-keto esters
provides one of the most efficient approaches to enantiomeri-
cally pure R-hydroxy acid derivatives, which are very important
structural motifs in numerous biologically active compounds
and are often utilized as resolving agents.1,17 Optimization
proved that complex 8c showed superior efficiency in the
asymmetric hydrogenation of R-keto esters at room temperature
under low hydrogen pressure.
Experimental Section
Typical Procedure for the Asymmetric Hydrogenations. [Ru-
(benzene)Cl2]2 (5 mg, 0.01 mmol) and chiral ligand 7 (0.021 mmol)
were dissolved in degassed DMF (3 mL) in a Schlenk tube and
heated to 100 °C under N2. After the mixture was cooled to 50 °C,
the solvent was removed under vacuum to give the catalysts as a
reddish brown solid. The catalyst was taken into a glovebox,
dissolved in degassed methanol (16 mL), and distributed equally
among eight vials. To the catalyst solution was added the substrate
(0.25 mmol). The resulting mixture was transferred into an autoclave
and charged with H2 (100 atm for allylphthalimides and 5 atm for
R-keto esters). The autoclave was heated at 80 °C for 24 h for
allylphthalimide substrates or at room temperature for R-keto ester
substrates for 20 h. The autoclave was then cooled to room
temperature, and the H2 was carefully released. The reaction solution
was then evaporated, and the residue was purified by column
chromatography to give the corresponding hydrogenation product,
As shown in Table 2, a variety of R-keto esters were reduced
to form chiral R-hydroxy esters with excellent enantioselectivity
(96-99%). The electronic and steric nature of a substituent on
the phenyl ring of the substrate had little influence on the
enantioselectivity and reactivity of the reaction. The enantio-
meric excesses of 12 were better than those obtained when their
parent ligand C3-TunePhos was used under the same conditions
(Table 2).10e It was noteworthy that, even without acidic
additives,18 ligand 7c showed a marked superiority in selectivity
to BINAP in the hydrogenation of 11. A key intermediate for
the synthesis of ACE inhibitors Benazepril and Delapril
(19) (a) Watthey, J. W. H.; Stanton, J. L.; Desai, M.; Babiarz, J. E.;
Finn, B. M. J. Med. Chem. 1985, 28, 1511. (b) Yanagisawa, H.; Ishihara,
S.; Ando, A.; Kanazaki, T.; Miyamoto, S.; Koike, H.; Iijima, Y.; Oizumi,
K.; Matsushita, Y.; Hata, T. J. Med. Chem. 1988, 31, 422. (c) Ogihara, T.;
Nakamaru, M.; Higaki, J.; Kumahara, Y.; Hamano, Y.; Minamino, T.;
Nakamura, N. Curr. Ther. Res. 1987, 41, 809. (d) Miyake, A.; Itoh, K.;
Oka, Y. Chem. Pharm. Bull. 1986, 34, 2852.
(17) Kinbara, K. Synlett 2005, 732.
(18) Mashima, K.; Kusano, K.; Sato, N.; Matsumura, Y.; Nozaki, K.;
Kumobayashi, H.; Sayo, N.; Hori, Y.; Ishizaki, T.; Akutagawa, S.; Takaya,
H. J. Org. Chem. 1994, 59, 3064.
J. Org. Chem, Vol. 73, No. 3, 2008 1145

which was then directly analyzed by chiral GC (Gamma dex 225)
or chiral HPLC (Chiralpak AD) to determine the enantiomeric
excess.
Supporting Information Available: Complete description of
ligand synthesis, asymmetric hydrogenation, and product charac-
terization together with photocopies of spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank the National Institutes of
Health (GM58832) and Merck & Co., Inc., for the financial
support.
JO702068W
1146 J. Org. Chem., Vol. 73, No. 3, 2008