Synthesis of Chiral Bisphosphines with Tunable Bite Angles and Their Applications in Asymmetric Hydrogenation of β-Ketoesters

Full text of DOI:10.1021/jo000462v

J . Org. Chem. 2000, 65, 6223-6226
6223
Notes
Syn th esis of Ch ir a l Bisp h osp h in es w ith
Tu n a ble Bite An gles a n d Th eir
Ap p lica tion s in Asym m etr ic Hyd r ogen a tion
of â-Ketoester s
Zhaoguo Zhang, Hu Qian, J ames Longmire, and
Xumu Zhang*
Department of Chemistry, The Pennsylvania State
University, University Park, Pennsylvania 16802
F igu r e 1. Chiral atropisomeric bisphosphines.
reactions.5 The correlation of bite angles of chiral chelat-
ing phosphines with the enantioselectivity of a reaction
may provide significant insights for future ligand design
and therefore is of fundamental importance.
xumu@chem.psu.edu
Received March 28, 2000
Chiral atropisomeric biaryl diphosphines such as
BINAP, BIPHEMP, and MeO-BIPHEP are very effective
ligands for many asymmetric reactions.2,3 The sp2-sp2
rotation in these chiral biaryl ligands causes only a small
energy change within a wide range of bite angles with
transition metals. While these ligands have been proven
effective, sometimes they are not efficient for certain
substrates due to the lack of ligand rigidity. To overcome
this drawback, we proposed to introduce a bridge with
variable length to link the diaryl groups so that the new
ligands are rigid with tunable bite angles.4 Ideally, a
change in the bite angle of the metal-ligand complex will
allow highly enantioselective transformation with certain
substrates. We chose MeO-BIPHEP as the starting
compound to make these type of chiral bisphosphines,
which are called TunaPhos ligands (Scheme 1). Enan-
tiomerically pure MeO-BIPHEP was made according to
a reported procedure3 and demethylated to provide
HO-BIPHEP (7) in high yield. Reaction of 7 with alkyl
dihalides in the presence of excess anhydrous K2CO3 in
DMF formed C1-C6TunaPhos ligands (1-6) (Scheme 1).
The dihedral angles of TunaPhos, MeO-BIPHEP, and
BINAP based on a CAChe MM2 calculation are listed in
Table 1. The bite angle (P-metal-P) of CnTunaPhos
with transition metals should increase with an increase
in the dihedral angle. Furthermore, the TunaPhos lig-
ands should be less flexible compared with BINAP and
Although many effective chiral bisphosphines have
been developed, there is no general solution in dealing
with the many challenging transition metal-catalyzed
asymmetric transformations since enantioselectivities are
often substrate-dependent. Subtle changes in geometric,
steric, and/or electronic properties of chiral ligands can
lead to dramatic variations of reactivity and enantiose-
lectivity. Conformationally rigid and yet tunable chiral
ligands offer a great advantage in optimizing the enan-
tioselectivity of a reaction by maximizing the possibility
of a low energy enantiotopic approach of substrates in
the stereochemistry defining step. Recently, we have
developed two conformationally rigid chiral bisphos-
phines1 (BICP and PennPhos) which have been shown
to be effective for several asymmetric reactions. We
envision that a strategy to restrict sp2-sp2 rotation in
chiral biaryl ligands such as BINAP,2 BIPHEMP,3 and
MeO-BIPHEP3 (Figure 1) will be useful in generating
new chiral ligands with tunable bite angles. A closely
related idea has been applied to generate chiral biaryl
compounds with a range of dihedral angles.4 Extensive
studies by several research groups have demonstrated
that changing bite angles of chelating bisphosphines have
a dramatic effect on the reactivity and selectivity of
(1) For PennPhos, see (a) J iang, Q.; J iang, Y.; Xiao, D.; Cao, P.;
Zhang, X. Angew. Chem., Int. Ed. Engl. 1998, 37, 1100-1103. (b) J iang,
Q.; Xiao, D,; Zhang, Z.; Cao, P.; Zhang, X. Angew. Chem., Int. Ed. Engl.
1999, 38, 516. (c) Zhang, Z.; Zhu, G.; J iang, Q.; Xiao, D.; Zhang, X. J .
Org. Chem. 1999, 64, 1774. For BICP, see: (d) Zhu, G.; Cao, P.; J iang,
Q.; Zhang, X. J . Am. Chem. Soc. 1997, 119, 1799. (e) Zhu, G.;
Casalnuovo, A. L.; Zhang, X. J . Org. Chem. 1998, 63, 8100. (f) Zhu,
G.; Zhang, X. J . Org. Chem. 1998, 63, 9590. (g) Cao, P.; Zhang, X. J .
Org. Chem. 1999, 64, 2127. (h) Cao, P.; Zhang, X. J . Am. Chem. Soc.
1999, 121, 7708.
(2) (a) Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345. (b)
Takaya, H.; Ohta, T.; Noyori, R. In Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; VCH: New York, 1993. (c) Noyori, R. Asymmetric
Catalysis in Organic Synthesis; Wiley: New York, 1994.
(3) (a) Schmid, R.; Cereghetti, M.; Heiser, B.; Schonholzer, P.;
Hansen, H.-J . Helv. Chim. Acta 1988, 71, 897. (b) Schmid, R.; Foricher,
J .; Cereghetti, M.; Schonhoizer, P. Helv. Chim. Acta 1991, 74, 370. (c)
Schmid, R.; Broger, E. A.; Cereghetti, M.; Crameri, Y.; Foricehr, J .;
Lalonde, M.; Muller, R. K.; Scalone, M.; Schoettel, G.; Zutter, U. Pure
Appl. Chem. 1996, 68, 131.
(4) (a) Lustenberger, P.; Martinborough, E.; Denti, T. M.; Diederich,
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M.; Hatsuda, M.; Ueda, S.; Oku, A. Tetrahedron: Asymmetry 1996, 7,
2479. (c) Lipshutz, B. H.; Shin, Y.-J . Tetrahedron Lett. 1998, 7017.
(5) (a) Davies, I. W.; Deeth, R. J .; Larsen, R. D.; Reider, P. J .
Tetrahedron Lett. 1999, 40, 1233. (b) Kamer, P. C. J .; Reek, J . N. H.;
van Leeuwen, P. W. N. M. CHEMTECH 1998, 28(9), 27. (c) van der
Veen, L. A.; Boele, M. D. K.; Bregman, F. R.; Kamer, P. C. J .; van
Leeuwen, P. W. N. M.; Goubitz, K.; Fraanje, J .; Schenk, H.; Bo, C. J .
Am. Chem. Soc. 1998, 120, 11616. (d) Meessen, P.; Vogt, D.; Keim, W.
J . Organomet. Chem. 1998, 551, 165. (e) Sakaki, S.; Takeuchi, K.;
Sugimoto, M.; Kurosawa, H. Organometallics 1997, 16, 2995. (f)
Harada, T.; Takeuchi, M.; Hatsuda, M.; Ueda, S.; Oku, A. Tetrahedron:
Asymmetry 1996, 7, 2479. (g) Davies, I. W.; Gerenda, L.; Castonguay,
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Organometallics 1995, 14, 3081. (j) Brown, J . M.; Guiry, P. J . Inorg.
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10.1021/jo000462v CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/19/2000

6224 J . Org. Chem., Vol. 65, No. 19, 2000
Notes
Sch em e 1. Syn th esis of Cn Tu n a P h os Liga n d s
1), enantioselectivity dropped slightly to 97.1% ee with
Ru-C5TunaPhos (5) and 96.5% ee with Ru-C6Tunaphos
(6). This general trend is true for all other substrates
listed in Table 2 (entries 1-7) with only one exception
(the result in entry 5). Overall, the Ru-C4TunaPhos (4)
complex is a superior catalyst compared with other
TunaPhos systems and the results are comparable or
better than those obtained with Ru-BINAP and Ru-
MeO-BIPHEP catalysts under the same conditions (en-
tries 1-7). This observation is consistent with the fact
that C4TunaPhos (4), MeO-BIPHEP and BINAP have
similar dihedral angles (Table 1). Furthermore, the
results with Ru-C3TunaPhos(3) and Ru-C5TunaPhos
(5) are much higher than those obtained with Ru-
C1TunaPhos(1) and are only slightly lower than the
results achieved with Ru-C4TunaPhos (4). This indi-
cates the bite angles of Ru complexes with C3, C4, and
C5TunaPhos may be similar while the Ru-C1TunaPhos
complex has a much smaller bite angle. Using a â-ke-
toester with a substituent at the R-position, syn/anti ratio
about 1:1 was observed with the acyclic substrate in entry
6. However, anti product is dominant with a cyclic
substrate with TunaPhos (1-6), BINAP,7 and MeO-
BIPHEP ligand systems.8
Ta ble 1. Ca lcu la ted Dih ed r a l An gles of Ch ir a l
Bisp h osp h in es
phosphine
1
2
3
4
5
6
MeO-BIPHEP BINAP
87 87
dihedral anglea 60 74 77 88 94 106
(deg)
In conclusion, a series of chiral bisphosphines with
tunable dihedral angles have been made for the first
time and used for Ru-catalyzed asymmetric hydroge-
nation of â-ketoesters. Enantioselectivities with the
Ru-C4TunaPhos(4) catalyst are comparable or better
than those observed with Ru-BINAP and Ru-MeO-
BIPHEP complexes, while enantioselectivities in asym-
metric hydrogenation of â-ketoesters are low with other
catalysts [e.g., Ru-C1TunaPhos(1) and Ru-C6TunaPhos-
(6)]. The current study demonstrates the concept that
changes in ligand dihedral angles indeed cause signifi-
cant variations of enantioselectivity. Future work on
applications of these TunaPhos ligands will focus on
achieving new transition metal-catalyzed enantioselec-
tive reactions and extending the scope of substrates in
many existing enantioselective transformations.
MeO-BIPHEP because the rotation of the sp2-sp2 bond
is restricted.
To establish a correlation of the dihedral angle of
chelating chiral phosphines with enantioselectivity of a
given reaction, a well-studied asymmetric hydrogena-
tion of â-ketoesters was selected.6 It is known that
Ru-BINAP and Ru-MeO-BIPHEP complexes are excel-
lent catalysts for this asymmetric transformation. We
proposed that some TunaPhos ligands will offer compa-
rable enantioselectivities as those achieved with Ru-
BINAP and Ru-MeO-BIPHEP complexes because of
their similar coordination environments. Although varia-
tion of the coordination environments from the BINAP
and MeO-BIPHEP systems using other TunaPhos ligands
may result in lower enantioselectivity for reduction of
â-ketoesters, these TunaPhos ligands may provide a
unique chance for achieving high enantioselectivity for
other reactions.
Exp er im en ta l Section
Gen er a l P r oced u r es. All reactions and manipulations were
performed in
a nitrogen-filled glovebox or using standard
To test this hypothesis, Ru-catalyzed asymmetric
hydrogenation of â-ketoesters with six TunaPhos ligands
(1-6), BINAP and MeO-BIPHEP were performed under
the same reaction conditions (Table 2). These reactions
were performed according to literature procedure in
which the Ru-catalyst was prepared by mixing [Ru-
(benzene)Cl2]2 and a diphosphine ligand in situ in hot
DMF.7 The reaction was carried out under 750 psi of H2
in MeOH at 60 °C for 20 h. While ligands C1-
C6TunaPhos (1-6) showed similar reactivity, the enan-
tioselectivity varied dramatically. For example, methyl
acetoacetate (entry 1) was reduced with ca. 91% ee using
both Ru-C1TunaPhos (1) and Ru-C2TunaPhos (2)
catalysts. The enantioselectivity increased to 97.7%ee
with Ru-C3TunaPhos (3) and reached a maximum of
99.1% ee with Ru-C4TunaPhos (4). With further in-
crease of the dihedral angle of chiral phosphines (Table
Schlenk techniques. All solvents were purified and degassed
before use using the standard procedure. â-Ketoesters were
redistilled and stored under N2. NBu3, HSiCl3, BBr3, and [Ru-
(benzene)Cl2]2 were purchased from Aldrich.
(R)-(6,6-Dim eth oxybip h en yl-2,2′-d iyl)bis(d ip h en ylp h os-
p h in e) [(R)-MeO-BIP HEP ]. To a suspension of (R)-(6,6′-
dimethoxybiphenyl-2,2′-diyl) bis(diphenylphosphine oxide) (46.0
g, 74.9 mmol) in p-xylene (490 mL) were added Bu3N (157 mL,
660 mmol) and HSiCl3 (57.1 g, 420 mmol) at room temperature
under N2. After being stirred at room temperature for 30 min,
the mixture was heated at reflux for 3 h and then cooled to 0 °C
followed by slow addition of 30% aqueous NaOH (350 mL,
degassed). To this mixture was added CH2Cl2 (200 mL, de-
gassed), and the water layer was removed with a cannula. The
organic layer was treated again with degassed 30% aqueous
NaOH, washed with degassed H2O and brine, dried over
Na2SO4, filtered, and evaporated. The residue was heated on
degassed EtOH at 80 °C for 5 min, cooled to 0 °C, and filtered.
The solid product was washed with degassed EtOH and dried
(6) Ager, D. J .; Laneman, S. A. Tetrahedron: Asymmetry 1997, 8,
3327.
(7) (a) Kitamura, M.; Tokunaga, M.; Ohkuma, T.; Noyori, R.
Tetrahedron Lett. 1991, 32, 4163. (b) Kitamura, M.; Tokunaga, M.;
Ohkuma, T.; Noyori, R. Org. Synth. 1993, 71, 1.
(8) (a) Genet, J . P.; Ratovelomanana-Vidal, V.; Cano de Andrade,
M. C.; Pfister, X.; Guerreiro, P.; Lenoir, J . Y. Tetrahedron Lett. 1995,
36, 4801. (b) Genet, J . P.; Pinel, C.; Ratovelomanana-Vidal, V.; Mallart,
S.; Pfister, X.; Bischoff, L.; Cano de Andrade, M. C.; Darses, S.; Galopin,
C.;. Laffitte, J . A Tetrahedron: Asymmetry 1994, 5, 675.

Notes
J . Org. Chem., Vol. 65, No. 19, 2000 6225
Ta ble 2. Ru -Ca ta lyzed Asym m etr ic Hyd r ogen a tion of â-Ketoester sa
a
Hydrogenation was performed as described in the text. All reactions were complete in >99% conversion, and ee’s were determined by
chiral GC.
in vacuo (42.3 g, 97%): [R]23D ) +42.5 (c ) 1.0, CHCl3); 1H NMR
(CDCl3) δ 7.21-7.12 (m, 18H), 7.03-6.95 (m, 4H), 6.70-6.65 (m,
4H), 3.08 (s, 6H); 31P NMR (CDCl3) δ -14.2; 13C NMR(CDCl3) δ
157.5-127.8 (m, Ar-C), 110.7, 54.7.
up to 3.5 equiv of 1,2-dibromoethane was used to force a complete
conversion of the starting material [(R)-(6, 6′-dihydroxybiphenyl-
2,2′-diyl)bis(diphenylphosphine)].
C1Tu n a P h os (1). Prepared as above from (R)-(6, 6′-dihy-
(R)-(6,6′-Dih yd r oxybip h en yl-2,2′-d iyl)bis(d ip h en ylp h os-
p h in e) (7). A solution of (R)-(6,6′-dimethoxybiphenyl-2,2′-diyl)-
bis(diphenylphosphine) [(R)-MeO-BIPHEP] (23.3 g, 40 mmol) in
CH2Cl2 (500 mL) was cooled to -78 °C and bubbled with N2 for
15 min. To this solution was added BBr3 (30.0 g, 120 mmol) via
a syringe over a period of 10 min. The mixture was stirred at
-78 °C for 1 h, and then slowly warmed to room temperature
and stirred overnight. After the mixture was cooled to 0 °C,
degassed water (120 mL) was added slowly and the aqueous
layer was removed via cannula. The organic layer was washed
subsequently with degassed H2O and brine and dried over
Na2SO4. The resulting organic solution was passed through a
pad of neutral Al2O3 and evaporated to dryness to give the
product, which was directly used for the next step (18.7 g,
droxybiphenyl-2,2′-diyl)bis(diphenylphosphine): yield 80%; [R]23
D
1
) -396 (c ) 0.5, CHCl3); H NMR (CDCl3) δ 7.8-7.0 (m, 26H),
5.41 (s, 2H); 31P NMR (CDCl3) δ -9.7; 13C NMR (CDCl3) δ 152.9-
121.0 (m, Ar-C), 101.6; HRMS 567.1672, calcd [M+ + 1]
567.1643.
C2Tu n a P h os (2). Prepared as above from (R)-(6,6′-dihy-
droxybiphenyl-2,2′-diyl)bis(diphenylphosphine): yield 64%; [R]23
D
1
) -294 (c ) 0.5, CHCl3); H NMR (CDCl3) δ 7.8-7.0 (m, 26H),
4.30 (d, 2H, J ) 8.7 Hz), 4.00 (d, 2H, J ) 8.7 Hz); 31P NMR
(CDCl3) δ -8.4; 13C NMR (CDCl3) δ 159.8-122.4 (m, Ar-C), 74.3;
HRMS 581.1816, calcd [M+ + 1] 581.1799.
C3Tu n a P h os (3). Prepared as above from (R)-(6,6′-dihy-
droxybiphenyl-2,2′-diyl)bis(diphenylphosphine): yield 82%; [R]23
D
1
) -225 (c ) 0.5, CHCl3); H NMR (CDCl3) δ 7.5-6.7 (m, 26H),
84%): [R]23 ) -10.4 (c ) 0.5, EtOH); 1H NMR (CD2Cl2) δ 7.3-
4.1-4.0 (m, 4H), 1.68(t, J ) 5.7 Hz, 2H); 31P NMR (CDCl3) δ
-11.7; 13C NMR (CDCl3) δ 157.8-118.8 (m, Ar-C), 72.2, 29.6;
HRMS 595.1922, calcd [M+ + 1] 595.1956.
D
6.8 (m, 26H), 4.27 (s, br, 2H); 31P NMR (CD2Cl2) δ -13.6; 13C
NMR(CD2Cl2) δ 154.9-116.7 (m, Ar-C); HRMS 555.1649, calcd
[M+ + 1] 555.1643.
C4Tu n a P h os (4). Prepared as above from (R)-(6,6′-dihy-
Syn th esis of [(R)-Cn -Tu n a P h os]. Gen er a l P r oced u r e. A
solution of (R)-(6,6′-dihydroxybiphenyl-2,2′-diyl)bis(diphenylphos-
phine) (7) (1.11 g, 2 mmol) in DMF (20 mL) was bubbled with
N2 for 15 min. To this solution was added anhydrous K2CO3 (1.38
g, 10 mmol), and the mixture was stirred at room temperature
for 15 min before bromochloromethane (2.1 mmol) was added
via a syringe. The mixture was stirred at room temperature for
24 h and then heated to 60 °C until completion of the reaction
(48 h). After removal of the solvent, the residue was extracted
with ether, washed with water and brine, and dried over
Na2SO4. The foamy solid obtained after evaporation of solvents
was purified by a silica gel column with CH2Cl2-hexanes (1:3)
as the eluent. C3, C4, C5, C6TunaPhos ligands were made
according to this procedure. For the synthesis of C2TunaPhos,
droxybiphenyl-2,2′-diyl)bis(diphenylphosphine): yield 84%; [R]23
D
1
) -167 (c ) 0.5, CHCl3); H NMR (CDCl3) δ 7.6-6.7 (m, 26H),
4.19 (d, J ) 11.5 Hz, 2H), 3.77(d, J ) 10.4 Hz, 2H), 1.68 (t, J )
10.4 Hz, 2H), 1.55 (d, J ) 11.5 Hz, 2H); 31P NMR (CDCl3) δ
-11.2; 13C NMR (CDCl3) 156.3-115.5 (m, Ar-C), 69.7, 25.5;
HRMS 609.2100, calcd [M+ + 1] 609.2112.
C5Tu n a P h os (5). Prepared as above from (R)-(6,6′-dihy-
droxybiphenyl-2,2′-diyl)bis(diphenylphosphine): yield 55%; [R]23
D
1
) -143 (c ) 0.5, CHCl3); H NMR (CDCl3) δ 7.6-6.9 (m, 26H),
4.3-4.2 (m, 2H), 4.0-3.8 (m, 2H), 1.9-1.4 (m, 6H); 31P NMR
(CDCl3) δ -11.4; 13C NMR (CDCl3) δ 157.0-113.5 (m, Ar-C),
67.2, 26.0, 22.3; HRMS 623.2261, calcd [M+ + 1] 623.2269.
C6Tu n a P h os (6). Prepared as above from (R)-(6,6′-dihy-
droxybiphenyl-2,2′-diyl)bis(diphenylphosphine): yield 55%;

6226 J . Org. Chem., Vol. 65, No. 19, 2000
Notes
[R]23 ) -122 (c ) 0.5, CHCl3); 1H NMR (CDCl3) δ 7.8-6.8
was set to 750 psi. The reactor was placed in an oil bath at 60
°C and stirred for 20 h. The bomb was then cooled to room
temperature and the H2 carefully released. The methanol
solution was removed and the residue dissolved in ether. The
ether solution was washed with H2O and brine and dried over
Na2SO4. The ether solution was passed through a short silica
gel column and concentrated to dryness to give products.
D
(m, 26H), 4.1-4.0 (m, 2H), 3.7-3.6 (m, 2H), 1.9-1.4 (m, 8H);
31P NMR (CDCl3) δ -11.5; 13C NMR (CDCl3) δ 156.5-111.4 (m,
Ar-C), 66.4, 25.9, 24.5; HRMS 637.2413, calcd for [M+ + 1]
637.2425.
Pr oced u r e for th e Asym m etr ic Hyd r ogen a tion Rea c-
tion . To a 10 mL Schlenk tube were added [Ru(benzene)Cl2]2
(10 mg, 0.02 mmol) and diphosphine (0.048 mmol of R-BINAP,
R-MeO-BIPHEP, or C1-C6TunaPhos). The tube was purged
with N2 three times before addition of freshly distilled and
degassed DMF (1 mL). The resulting mixture was heated at 99-
101 °C for 10 min. After the mixture was cooled to 50 °C, the
solvent was removed under vaccum to give the catalysts as an
orange-red solid. This catalyst was taken into a glovebox,
dissolved in degassed methanol (8 mL), and distributed equally
to eight vials (1 mL each). The â-ketoester was added in each
vial and these eight vials was transferred to a Parr bomb. The
bomb was purged three times with H2, and the pressure of H2
Ack n ow led gm en t. This work was supported by the
National Institutes of Health and a Camille and Henry
Dreyfus Teaching Scholar Award. We acknowledge a
generous loan of precious metals from J ohnson Matthey
Inc. and a gift of chiral GC columns from Supelco.
J O000462V