Enantioselective routes to both enantiomers of aryl alcohols with a single catalyst antipode: Ru and Os transfer hydrogenation catalysts

Article abstract of DOI:10.1021/ol016641w

Figure presented The kinetic resolution of secondary aryl alcohols has been investigated. When (CyRuCl₂)₂, (1R,2S)-(+)-cis-1-amino-2-indanol, and KOH or ^tBuOK (catalyst 1) were combined in the presence of (±)-alcohols, ee's > 90% were generally observed. When applied to the kinetic resolution of (±)-indanol and (±)-tetralol, ee's = 99% (R) were observed. In addition, the asymmetric transfer hydrogenation of ketones was investigated with a catalyst, 2, generated in situ from (CyOsCl₂)₂, (1R,2S)-(+)-cis-1-amino-2-indanol, and ^tBuOK, yielding ee's of up to 98% (S).

Full text of DOI:10.1021/ol016641w

ORGANIC
LETTERS
2
001
Vol. 3, No. 23
703-3706
Enantioselective Routes to Both
Enantiomers of Aryl Alcohols with a
Single Catalyst Antipode: Ru and Os
Transfer Hydrogenation Catalysts
3
J. W. Faller* and Adrien R. Lavoie
Department of Chemistry, Yale UniVersity, New HaVen, Connecticut 06520
jack.faller@yale.edu
Received August 23, 2001
ABSTRACT
The kinetic resolution of secondary aryl alcohols has been investigated. When (CyRuCl
2
)
2
, (1R,2S)-(+)-cis-1-amino-2-indanol, and KOH or
BuOK (catalyst 1) were combined in the presence of (±)-alcohols, ee’s > 90% were generally observed. When applied to the kinetic resolution
of (±)-indanol and (±)-tetralol, ee’s ) 99% (R) were observed. In addition, the asymmetric transfer hydrogenation of ketones was investigated
t
t
2 2
with a catalyst, 2, generated in situ from (CyOsCl ) , (1R,2S)-(+)-cis-1-amino-2-indanol, and BuOK, yielding ee’s of up to 98% (S).
The development of new and original chiral catalysts often
proceeds via modification of chiral auxiliaries in order to
improve the transfer of chirality to substrate. However, once
an enantioselective catalyst is discovered, it is often desirable
to enhance the scope of the system to allow the production
of both enantiomers of the product in high enantiomeric
purity. Such a transformation is usually accomplished by
employing the opposite enantiomer of the catalyst, which is
often obtained using the enantiomeric ligand in a transition
metal catalyst. However, in cases where only one antipode
This approach exploits the favorable selectivity for a given
reaction by proper manipulation of equilibrium conditions
for a reversible reaction (See Figure 1). Given that a reaction
1
of the ligand is available, this approach is not an option.
An ideal situation in this case would be the development
of a methodology that could use the same catalyst to produce
either enantiomer of the product in high ee. Kinetic resolu-
Figure 1. Equilibria between the kinetic and thermodynamic
products for this investigation (R ) aryl).
2
tion can provide an alternative route to the other antipode.
is thermodynamically favored and that the relative difference
in rates (taken as a ratio ) kfast/kslow ) krel) is significant,
then one enantiomer can selectively react with the chiral
catalyst and induce an asymmetric transformation.3 In an
(
(
1) Palmer, M.; Walsgrove, T.; Wills, M. J. Org. Chem. 1997, 62, 5226.
2) Reviews on chemical kinetic resolution: (a) Kagan, H. B.; Fiaud, J.
C. Top. Stereochem. 1988, 18, 249. (b) Brown, J. M. Chem. Ber. 1989, 25,
76. (c) Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn.
995, 68, 36.
2
1
,4
1
0.1021/ol016641w CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/17/2001

ideal case, an ee ) 100% can be obtained with a conversion
of 50%. Thus, an asymmetric transfer hydrogenation catalyst
should be capable of dehydrogenation, as well as hydrogena-
tion, and should be able to be used in this manner.
Asymmetric hydrogenations and dehydrogenations using
different catalysts have been reported,5 but Ru catalysts that
(S)-aryl alcohols from aryl ketones. Since there are numerous
methods to reduce the ketones to the racemic alcohols, we
sought to use it as a dehydrogenation catalyst in kinetic
resolutions to prepare the (R)-aryl alcohols.
The results of kinetic resolutions of some chiral alcohols
(as depicted in Figure 3) using catalyst 1 are shown in Table
,6
5
a,6a
have been reported by Noyori effect both reactions.
We
report here that a different system developed by Palmer et
1
al. for hydrogenations that used Ru catalysts derived from
amino alcohols can also be used for kinetic resolutions.
Although both enantiomers of amino-2-indanol are available,
our studies demonstrate the generally unappreciated notion
that a single catalyst can provide a route to both antipodes
of a product.
For our investigation, the system of choice involved the
resolution of racemic R- and â-aryl alcohols because the
oxidation of benzylic alcohols is thermodynamically favored
over reduction relative to the oxidation of aliphatic alcohols
4
(
Figure 2). This suggested to us that the kinetic resolution
Figure 3. (()-Aryl alcohols tested for kinetic resolution by
dehydrogenation catalysis.
7
1
. Notably, most of the examples provide products with
enantiomeric purities in excess of 90%. Furthermore, both
tetralol, (()-6, and indanol, (()-7, were resolved to yield a
single enantiomer in extremely high ee. For (()-7 the
resolution was facile, thus producing the (R)-alcohol with
Figure 2. Net reaction for the kinetic resolution of (()-aryl
alcohols.
9
9% ee in 1 h (conv ) 65%, +25 °C). A similar result was
of aryl alcohols with a chiral Ru catalyst (shown by Palmer
et al. to reduce ketones to alcohols in high ee) could be
effective. This catalyst (1), derived from the readily available
1
observed for the resolution of (()-6, where the (R)-alcohol
was produced with nearly ideal results (99% ee, conv )
5
1%).
p-cymene ruthenium complex, (CyRuCl
2 2
) , and (1R,2S)-(+)-
cis-1-amino-2-indanol, with addition of an appropriate base
t
5-7
such as KOH or BuOK was thus employed.
This
hydrogenation catalyst often provides an excellent route to
Table 1. Data for Kinetic Resolution of (()-Alcohols with
Catalyst 1 That Yield (R)-Alcohols in Excess
(
3) Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda, M.;
Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237.
4) Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. AdV. Synth. Catal. 2001,
43, 5.
5) For Noyori’s highly enantioselective example of kinetic resolution
substratea,7
time (h)
°C
% conv
% ee
krelb,c
(
(()-3
(()-5
(()-6
29
19
24
1
360
19
18
24
18
24
25
25
25
25
0
61
69
59
65
54
51
61
69
57
35
90
87
97
99
90
99
89
92
81
41
>10
>5
3
(
>20
>15
>20
>100
>10
>7
with ArRuClTsdpen, see: (a) Hashiguchi, S.; Fujii, A.; Haack, K.-J.;
Matsumura, K.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. Engl. 1997,
(()-7
3
6, 288. For other selected kinetic resolution examples, see: (b) Nishiba-
yashi, Y.; Takei, I.; Uemura, S.; Hidai, M. Organometallics 1999, 18, 2291.
c) Persson, B. A.; Larsson, A. L. E.; Le Ray, M.; Backvall, J.-E. J. Am.
Chem. Soc. 1999, 121, 1645. (d) Kitamura, M.; Ohkuma, T.; Tokunaga,
M.; Noyori, R. Tetrahedron: Asymmetry 1990, 1, 1. (e) Vedejs, E.; Mackay,
J. A. Org. Lett. 2001, 3, 535.
(()-3d
(()-6
(()-8
(()-9
0
(
25
25
25
25
(()-10
(()-11
∼10
(6) For selected examples of highly enantioselective and catalytic ketone
∼11
hydrogenation, see: (a) Mikami, K.; Korenaga, T.; Terada, M.; Ohkuma,
T.; Pham, T.; Noyori, R. Angew. Chem., Int Ed. 1999, 38, 495. (c) Doucet,
H.; Ohkuma, T.; Murata, K.; Yokozawa, T.; Kozawa, M.; Katayama, E.;
England, A. F.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. 1998, 37,
703. (e) Petra, D. G. I.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.;
Goubitz, K.; Van Loon, A. M.; de Vries, J. G.; Schoemaker, H. E. Eur. J.
Inorg. Chem. 1999, 2335. (f) Faller, J. W.; Lavoie, A. R. Organometallics
a
The substrate-to-metal ratio was 5.5:1.0, and all reactions used 2 mL
t
of 0.1 M BuOK/2-propanol. All reactions employed a (CyRuCl2)2/ligand
mole ratio of 1.0:4.0.1 krel is defined by the ratio of the rate constants
where kA/kB ) ln[(1 - C)(1 - ee)]/ln[(1 - C)(1 + ee)], where C is the
fraction of consumption of racemate, ee is % ee/100, and A and B refer to
the concentrations of the fast and slow reacting enantiomers, respectively.
Sharpless et al. have noted that for practical purposes a krel > 100 is
b
1
2
001, 20, in press.
7) Strem Chemicals has recently begun to market a CATHy catalyst
3
c
(
essentially the same as ∞. Determined from the final conversion and ee.
d
system that is derived from (Cp*RhCl2)2 and enantiopure cis-1-amino-2-
indanol.
At 5.7 days, conv ) 50% and ee ) 88% (R).
3704
Org. Lett., Vol. 3, No. 23, 2001

To expand the scope of this system, an investigation into
the electronic effects of the substrates was undertaken. The
highest level of enantioenrichment was observed for the
substrates bearing electron-donating para substituents. The
results (Table 1, alcohols 3, 8-11) suggest that a strongly
N-H interaction. These authors have referred to the impor-
tant Ru-N-H moiety as an example of metal-ligand
bifunctional catalysis. Others have expanded upon Noyori’s
work and have provided mass spectrometry evidence for a
proposed active catalyst with a metal-centered hydride.1
Both of these proposals suggest that a N-H moiety could
be a prerequisite for an effective catalyst in asymmetric
transfer hydrogenation reactions. Although this is frequently
8
1b
3
electron-withdrawing substituent (such as -CF ) disfavors
the oxidation of alcohols to ketones, whereas electron-
donating substituents (such as -OMe and -Me) lead to high
substrate conversion and thus higher ee. Such results are
2
the case, it should be noted that various aprotic sp nitrogen
5
a,6f
12
confirmed by the observation by our group and others
ligands have also been employed.
that (for the reduction of ketones to alcohols) electron-
withdrawing substituents lead to lower ee’s relative to
electron-donating substituents.
Additionally, the catalyst generated in-situ from (CyOs-
t
Cl ) , (1R,2S)-(+)-cis-1-amino-2-indanol, and BuOK was
2 2
screened for the asymmetric transfer hydrogenation of
While the reduction of ketones with 1 has been found to
preferentially produce (S)-alcohols, the reverse process
dehydrogenates (S)-alcohols and provides a route to the (R)-
alcohols. Therefore, it should be noted that both enantiomers
can be obtained with high leVels of enantioenrichment from
a single enantiomer of the catalyst. This methodology
represents a highly efficient protocol that can be implemented
into synthetic applications where precise control over the
stereochemistry of alcohols is desired.
The observation of (R)-stereocenters in this series of kinetic
resolutions (as opposed to the reduction of ketones) can be
rationalized as a function of the complimentary stereochem-
istry of the (S)-alcohol with 1. Since the catalyst produces
the (S)-alcohol (from acetophenone), it is requisite that the
chirality of the metal center is matched with that product. It
is this “matched” interaction that leads to a preferred
oxidation of the (S)-product to an achiral ketone.Where
energetic considerations are concerned, the transition state
ketones. As shown in Table 2 the catalyst was highly
Table 2. Asymmetric Transfer Hydrogenation Results for
Various Ketones with the Catalyst System Prepared in Situ from
a
2 2
(CyOsCl ) and (1R,2S)-(+)-cis-1-Amino-2-indanol (Catalyst 2)
substrateb
base
°C
time (h)
% conv
% ee
(()-3
KOH
-24
-24
-24
-24
+25
-24
24
24
48
48
12
48
87
86
80
77
84
37
91
92
94
89
97
98
t
(()-3
(()-4
(()-5
(()-6
BuOK
BuOK
BuOK
BuOK
t
t
t
tBuOK
(()-7
a
The substrate to metal ratio was 100:1, and all reactions used 2 mL of
.1 M base/2-propanol. All configurations were (S). b All reactions employed
0
a (CyOsCl2)2/ligand mole ratio of 1.0:4.0.
enantioselective, yielding ee’s that were generally >90%. It
should be noted that for the reduction of 1′-tetralone and
energy for the diastereotopic interaction between 1 and the
q
(S)-alcohol (∆G
S
) is less than that for the interaction with
q
4
1
′-indanone, the corresponding alcohols were obtained with
R
the (R)-alcohol (∆G ). As such, the degree of enantio-
ee’s ) 97% and 98% (S), respectively. However, when the
osmium catalyst was applied to reactions with higher
substrate loadings (over longer time periods), the ee’s were
enrichment is directly proportional to the difference in
transition state energies (∆G ) between the two interactions.
Our optimization of reaction conditions also took into
q
9
slightly diminished.
account the choice of base. We investigated 0.1 M solutions
t
(
in 2-propanol) of KOH, BuOK, and NEt
3
. While there were
not large differences in activity when the catalyst was
t
t
activated with KOH or BuOK, it was determined that BuOK
was slightly advantageous (at 25 °C) as determined by
9
comparison of the krel values. Inferior results were obtained
upon use of NEt with <1% conversion of (()-1-phenyl-
3
ethanol to acetophenone. Furthermore, it should be noted
that the attempted kinetic resolution of (()-1-(1′-naphthyl)-
ethanol was particularly sluggish.9
,10
The source of the transferred hydrogen atom in similar
systems has been attributed to a metal-centered hydride.
Perhaps the most widely accepted theory is that a nitrogen
atom as well as the metal is intimately involved in the hydride
Figure 4. The generation of catalyst 2 (in situ) for the asymmetric
hydrogenation of ketones.
11
transfer process. Noyori and co-workers have suggested
that the transferred hydride originates from an intimate Ru-
In conclusion, we have expanded the scope of catalyst 1
to include the highly effective kinetic resolution of (()-aryl
(
8) One measure of the electronic effects is the Hammett σ constant:
OMe, -0.268; Me, -0.170; H, 0.000; F, +0.062; CF3, +0.54. McDaniel,
D. H.; Brown, H. C., J. Org. Chem. 1958, 23, 420.
(11) (a) Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R.
Angew. Chem., Int. Ed. Engl. 1997, 36, 285. (b) Kenny, J. A.; Versluis, K.;
Heck, A. J. R.; Walsgrove, T.; Wills, M. Chem. Commun. 2000, 99-100.
(12) Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1995, 36, 9153.
(
9) See Supporting Information.
(10) Conversion ) 15%, ee ) 14% (R) at 3 days. Conversion ) 25%,
ee ) 33% (R) at 20 days.
Org. Lett., Vol. 3, No. 23, 2001
3705

alcohols. In most cases, ee’s > 90% have been obtained with
ee’s of 99% in some cases. When the same catalyst was
applied to the kinetic resolution of para substituted (()-aryl
alcohols, a trend was observed in which the electron-
withdrawing substituents led to reduced ee’s in comparison
to electron-donating groups. In addition, the asymmetric
A.L. would like to thank Dr. Jonathan Parr for helpful
discussions in addition to the generous gift of (CyOsCl ) .
2
2
Supporting Information Available: Experimental meth-
ods, determination of ee’s, results for the determination of
optimization conditions, and additional asymmetric osmium
hydrogenation results. This material is available free of
charge via the Internet at http://pubs.acs.org.
transfer hydrogenation of ketones with (CyOsCl
2
)
2
, (1R,2S)-
+)-cis-1-amino-2-indanol, and BuOK was investigated,
yielding ee’s of up to 98%.
t
(
Acknowledgment. This work was financially supported
by the National Science Foundation (Grant No. CHE0092222).
OL016641W
3706
Org. Lett., Vol. 3, No. 23, 2001