Highly Enantioselective Hydrogenation of Enol Acetates Catalyzed by Ru-TunaPhos Complexes

Article abstract of DOI:10.1021/ol027010k

(Matrix Presented) The chiral disphosphines with tunable dihedral angles (TunaPhos) have been used for asymmetric hydrogenation of enol acetates and dihedral-angle-dependent enantioselectivities were observed. C2-TunaPhos has been proved to be effective for Ru-catalyzed asymmetric hydrogenation of electron-deficient and other enol acetates.

Full text of DOI:10.1021/ol027010k

ORGANIC
LETTERS
2
002
Vol. 4, No. 25
495-4497
Highly Enantioselective Hydrogenation
of Enol Acetates Catalyzed by
Ru−TunaPhos Complexes
4
Shulin Wu, Weimin Wang, Wenjun Tang, Min Lin, and Xumu Zhang*
Department of Chemistry, The PennsylVania State UniVersity, 152 DaVey Laboratory,
UniVersity Park, PennsylVania 16802
xumu@chem.psu.edu
Received October 1, 2002
ABSTRACT
The chiral disphosphines with tunable dihedral angles (TunaPhos) have been used for asymmetric hydrogenation of enol acetates and dihedral-
angle-dependent enantioselectivities were observed. C2-TunaPhos has been proved to be effective for Ru-catalyzed asymmetric hydrogenation
of electron-deficient and other enol acetates.
Catalytic asymmetric synthesis presents one of most powerful
methods for accessing a wide range of enantiomerically
enriched compounds. Design and synthesis of chiral phos-
phine ligands play a central role for the development of
highly enantioselective transition metal-catalyzed asymmetric
lead to dramatic variation of reactivity and enantioselectivity.
For atropisomeric biaryl diphosphines, a small variation of
the dihedral angle of the ligands can have a significant impact
on the reactivity and selectivity of reactions.
Although atropisomeric biaryl diphosphines such as BI-
3
1
1,4
1,5
1,5
reactions. Conformationally rigid and yet tunable ligands
NAP, BIPHEMP, and MeO-BIPHEP have been used
effectively as ligands for many asymmetric catalytic reac-
tions, they are still not efficient for certain substrates. A major
reason is the flexible dihedral angle of these ligands, since
2
are often desired for achieving high enantioselectivities.
However, there is no general solution in dealing with the
many challenging transition metal-catalyzed asymmetric
transformations since enantioselectivities are often substrate
dependent. In fact, subtle changes in conformational, steric,
and or electronic properties of the chiral ligands can often
(3) (a) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura,
T.; Kumobayashi, H. AdV. Synth. Catal. 2001, 343, 264. (b) Casey, C. P.;
Whiteker, G. T.; Melville, M. G.; Petrovich, L. M.; Gavney, J. A.; Powell.
D. R. J. Am. Chem. Soc. 1992, 114, 5535. (c) Casey, C. P.; Whiteker, G.
T. Isr. J. Chem. 1990, 30, 299. (d) Casey, C. P.; Whiteker, G. T. J. Org.
Chem. 1990, 55, 1394.
(4) (a) Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008. (b) Noyori,
R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345.
(
1) (a) Ojima, I., Ed. Catalytic Asymmetric Synthesis; VCH: New York,
2
000. (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,
1
994.
2) (a) Zhou, Y.; Tang, W.; Wang, W.; Li, W.; Zhang, X. J. Am. Chem.
Soc. 2002, 124, 4952. (b) Tang, W.; Zhang, X. Angew. Chem., Int. Ed.
002, 41, 1612. (c) Tang, W.; Chi, Y.; Zhang, X. Org. Lett. 2002, 4, 1695.
d) Li, W.; Zhang, X. J. Org. Chem. 2000, 65, 5871 and references cited
therein.
(5) (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.
(
2
(
1
0.1021/ol027010k CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/13/2002

the sp2-sp2 rotation in these biaryl ligands causes only small
energy change within a wide range of dihedral angle. We
screen the reaction conditions. The anionic dinuclear ruthe-
nium (II) complexes of [NH Me ][{RuCl((S)-Cn-TunaPhos)}
(µ-Cl) ] (n ) 1-6) were prepared according to the literature
method and used as the catalysts. The reactions were carried
out in ethanol at room temperature under 3 atm of hydrogen
pressure with a substrate/Ru ratio of 100:1. As shown in
Table 1, the Ru-TunaPhos catalysts are generally active and
2
2
2
-
have recently developed a novel class of diphosphine ligands
3
6
11
(
Cn-TunaPhos, n ) 1-6) (Figure 1) with tunable dihedral
Table 1. Ligand Screening for Ru-Catalyzed Hydrogenation of
Enol Acetate
Figure 1. Cn-TunaPhos, n ) 1-6.
angles by introducing a bridge with variable length to link
the chiral atropisomeric biaryl groups. Thus, the sp2-sp2
rotation in these biaryl ligands is restricted. The interesting
point is that each of the ligands adopts a small change of
dihedral angle of the chiral backbone. These ligands allow
us to systematically study the influence of dihedral angle of
atropisomeric biaryl diphosphines on the reactivity and
selectivity of asymmetric reactions. As a result, excellent
ligands with high reactivity and enantioselectivity for
particular substrates could be found. We have previously
demonstrated that TunaPhos are excellent ligands for some
asymmetric reactions.6 For example, in Ru-catalyzed asym-
metric hydrogenation of â-keto esters, C4-TunaPhos has
shown the best enantioselectivity (up to 99% ee) among the
TunaPhos ligands. To further expand the applications of the
TunaPhos ligands in asymmetric catalysis, we herein report
our recent studies on asymmetric hydrogenation of enol
acetates catalyzed by Ru-TunaPhos complexes.
entrya
ligand
dihedral angleb (deg)
eec (%)
1
2
3
4
5
6
C1
C2
C3
C4
C5
C6
60
74
77
88
94
95.9
95.9
92.1
88.9
91.9
92.3
106
a
[
NH2Me2][{RuCl[(S)-Cn-TunaPhos]}2(µ-Cl)3] were used as catalysts;
substrate/Ru ) 100:1; all reactions were complete in >99% conversion.
Calculated dihedral angles of Cn-TunaPhos from CAChe MM2 program.
Enantiomeric excesses were determined by chiral GC using a Supelco
b
c
6
chiral select 1000 (0.25 mm × 30 m) column; the configuration of the
,7
product is S.
the reactions were complete in all cases. The obtained
enantioselectivities are particularly interesting. C1- and C2-
TunaPhos possessing smaller dihedral angles gaVe high
enantiomeric excesses (both 95.9%). The enantioselectivity
dropped to 92.1% ee with C3-TunaPhos and reached the
lowest (88.9% ee) with C4-TunaPhos. Further increase of
the dihedral angles led to the increase of enantioselectivities
to 91.6% ee with C5-TunaPhos and 92.3% ee with C6-
TunaPhos. This trend is in contrast to our previous observa-
tions on hydrogenation of â-ketoesters, where C4-TunaPhos
Asymmetric hydrogenation of readily accessible enol
acetates is an attractive alternative to direct hydrogenation
of unfunctionalized ketones. An advantage of enol acetate
substrates is their chelation through secondary donor
group.This chelation is important to achieve high enantiose-
lectivity in hydrogenation. Good to excellent enantioselec-
tivites have been achieved upon asymmetric hydrogenation
of some cyclic and acyclic enol esters with Rh-phosphine
6
showed the best ee. Although it is still unclear why the
TunaPhos ligands provide different trends of ees in the two
types of reactions, the phenomenon indicates that different
reactions may require diphosphines with different dihedral
angles. These results, on the other hand, also reflect the
important design of our TunaPhos ligands.
Further experiments with C1 and C2-TunaPhos ligands
revealed a strong solvent effect in hydrogenation of 1-(2-
naphthyl)-1-(acetyloxy)ethylene (Table 2). The best ee
(97.7%) was achieved when a mixture of ethanol/CH
4:1) was used as the solvent and the Ru-C2-TunaPhos
complex was employed as the catalyst (entry 2). This result
is higher than those obtained with the Rh-PennPhos system
8
complexes. In contrast, hydrogenation of enol acetates
employing Ru-chiral phosphine system is rarely mentioned
9
in the literature. We initiated this study by choosing 1-(2-
naphthyl)-1-(acetyloxy)ethylene10 as the model substrate to
(
6) Zhang, Z.; Qian, H.; Longmire, J.; Zhang, X. J. Org. Chem. 2000,
6
4
5, 6223.
(
1, 3457.
7) Lei, A.; He, M.; Wu, S.; Zhang, X. Angew. Chem., Int. Ed. 2002,
2 2
Cl
(
(
8) For selected examples of asymmetric hydrogenations of simple enol
acetates, see: (a) Li, W.; Zhang, Z.; Xiao, D.; Zhang, X. J. Org. Chem.
000, 65, 3489. (b) Jiang, Q.; Xiao, D.; Zhang, Z.; Cao, P.; Zhang, X.
2
Angew. Chem., Int. Ed. 1999, 38, 516 and the references cited. (c) Boaz,
N. W. Tetrahedron Lett. 1998, 39, 5505. (d) Burk, M. J. J. Am. Chem. Soc.
1
991, 113, 8518. (e) Koenig, K. E.; Bachman, G. L.; Vineyard, B. D. J.
Org. Chem. 1980, 45, 2362.
9) For asymmetric hydrogenation of 1-phenyl-1-(acetyloxy)ethylene with
(10) For the synthesis of enol acetates, see: Larock, R. C. ComprehensiVe
Organic Transformations; VCH: New York, 1989; p 743.
(11) (a) Mashima, K.; Nakanura, T.; Matsuo, Y.; Tani, K. J. Organomet.
Chem. 2000, 607, 51. (b) Ohta, T.; Tonomura, Y.; Nazaki, K.; Takaya, H.;
Mashima, K. Organometallics 1996, 19, 1521. (c) Ikariya, T.; Ishii, Y.;
Kawano, H.; Arai, T.; Saburi, M.; Yoshikawa, S.; Akutagawa, S. J. Chem.
Soc., Chem. Commun. 1985, 922.
(
Ru-BINAP complex, see: Ohta, T.; Miyake, T.; Seido, N.; Kumobayashi,
H.; Takaya, H. J. Org. Chem. 1995, 60, 357. For asymmetric hydrogenation
of 1,1,1-trifluoroalkan-2-one enol acetates, see: Kuroki, Y.; Asada, D.;
Sakamaki, Y.; Iseki, K. Tetrahedron Lett. 2000, 41, 4603.
4496
Org. Lett., Vol. 4, No. 25, 2002

Table 2. Optimization of Reaction Conditions for
Ru-Catalyzed Hydrogenation of Enol Acetate
Table 3. Hydrogenation of Enol Acetates Catalyzed by a
Ru-C2-TunaPhos System
entrya
ligand
solvent
conversion (%)
ee (%)
c
1
2
3
4
5
6
C1
C2
C3
C4
C5
C6
EtOH/CH2Cl2b
EtOH/CH2Cl2b
MeOH
MeOH/CH2Cl2b
EtOH/CH2Cl2b
EtOH/CH2Cl2b
>99
>99
30.3
31.4
>99
>99
92.7
97.7
71.0
75.3
94.0d
95.8e
a
[
NH2Me2][{RuCl[(S)-Cn-TunaPhos]}2(µ-Cl)3] were used as catalysts;
b c
substrate/Ru ) 100:1. v/v ) 4:1. Enantiomeric excesses were determined
by chiral GC using a Supelco chiral select 1000 (0.25 mm × 30 m) column;
d
the configuration of the product is S. The reaction was carried out under
e
a H2 pressure of 10 atm. The reaction was carried out at 50 °C.
(
80.9% ee) 8b and Rh-Et-KetalPhos system (94.5% ee).8a
When methanol was used as the solvent, both the reactivities
and the enantioselectivities decreased dramatically (entries
3
and 4). The hydrogenation did not proceed in pure CH
2
-
Cl , THF, toluene, and even alcoholic CF CF OH. In
2
3
2
addition, small pressure and temperature effects were also
observed (entries 5 and 6).
With the optimized ligand and reaction conditions, several
other enol acetates were examined for hydrogenation with
the Ru-C2-TunaPhos catalyst (Table 3). Hydrogenation of
a
[NH2Me2][{RuCl[(S)-C2-TunaPhos]}2(µ-Cl)3] was used as the catalyst
b
and EtOH/CH2Cl2 (4:1) as the solvent; substrate/Ru ) 100:1. Enantiomeric
excesses were determined by chiral GC using a Supelco chiral select 1000
1-aryl-(acetyloxy) ethylenes with an electron-withdrawing
(0.25 mm × 30 m) column; the configuration of the products is S. c The
reaction was carried out at 50 °C.
substituent on the phenyl ring gave excellent enantioselec-
tivities (entries 2, 3, and 5). For example, hydrogenation of
In conclusion, a series of chiral diphosphines with tunable
dihedral angles have been used for asymmetric hydrogenation
of enol acetates. C2-TunaPhos has been proved to be
effective for Ru-catalyzed asymmetric hydrogenation of
electron-deficient and other enol acetates. Further investiga-
tions of other catalytic asymmetric reactions with the
TunaPhos ligands are underway and progress will be
disclosed in due time.
1
-(4-nitrophenyl)-1-(acetyloxy)ethylene afforded 100% con-
version and 96.6% ee, which was higher than that observed
8d
with Rh-BPE system (90% ee). To our surprise, hydro-
genation of relatively electron-rich substrates such as 1-phen-
yl-1-(acetyloxy) ethylene and 1-(4-methoxyphenyl)-1-(acety-
loxy)ethylene did not occure under the present reaction
conditions. The starting materials were recovered along with
a small amount of hydrogenolysis products. On the other
hand, an electron-rich enol acetate bearing a furyl group gave
a high ee (93.1%) albeit with a moderate conversion. This
result indicates that a secondary interaction between the
oxygen atom in furan and the catalyst might play a role in
this transformation. Interestingly, over 99% ee was also
achieved upon hydrogenation of enol acetate derived from
Acknowledgment. This work was supported by the
National Institute of Health. We acknowledge Johnson
Matthey for a gift of precious metals.
Supporting Information Available: Experimental de-
tails. This material is available free of charge via the Internet
at http://pubs.acs.org.
1-indanone with a prolonged reaction time and at an elevated
temperature (entry 9), which was comparable to the best
result reported in the literature.8b
OL027010K
Org. Lett., Vol. 4, No. 25, 2002
4497