Highly Enantioselective Ruthenium-Catalyzed Reduction of Ketones Employing Readily Available Peptide Ligands

Article abstract of DOI:10.1002/chem.200305553

Highly efficient and selective catalysts for the asymmetric reduction of aryl alkyl ketones under hydrogen-transfer conditions (2-propanol) were obtained by combining a novel class of pseudo-dipeptide ligands with [{RuCl ₂(p-cymene)}₂]. A library of 36 dipeptide-like ligands was prepared from N-Boc-protected α-amino acids and the enantiomers of 2-amino-1-phenylethanol and 1-amino-2-propanol. The catalyst library was evaluated with the reduction of acetophenone and excellent enantioselectivity of 1-phenylethanol was obtained with several of the novel catalysts. A ligand based on the combination of N-Boc-L-alanine and (S)-1-amino-2-propanol (ligand A-(S)-4) was found to be particular effective. When the situ formed ruthenium complex of this ligand was employed as the catalyst in the hydrogen-transfer reaction of various aryl alkyl ketones, the corresponding alcohol products were achieved in excellent enantioselectivity (up to 98% ee).

Full text of DOI:10.1002/chem.200305553

FULL PAPER
Highly Enantioselective Ruthenium-Catalyzed Reduction of Ketones
Employing Readily Available Peptide Ligands
Anders B˘gevig, Isidro M. Pastor, and Hans Adolfsson*[a]
Abstract: Highly efficient and selective
catalysts for the asymmetric reduction
of aryl alkyl ketones under hydrogen-
transfer conditions (2-propanol) were
obtained by combining a novel class of
The catalyst library was evaluated with
the reduction of acetophenone and ex-
cellent enantioselectivity of 1-phenyle-
thanol was obtained with several of the
novel catalysts. A ligand based on the
combination of N-Boc-l-alanine and
(S)-1-amino-2-propanol (ligand A-(S)-
4) was found to be particular effective.
When the situ formed ruthenium com-
plex of this ligand was employed as the
catalyst in the hydrogen-transfer reac-
tion of various aryl alkyl ketones, the
corresponding alcohol products were
achieved in excellent enantioselectivity
(up to 98% ee).
pseudo-dipeptide
ligands
with
[{RuCl2(p-cymene)}2].
A
library of
36 dipeptide-like ligands was prepared
from N-Boc-protected a-amino acids
and the enantiomers of 2-amino-1-
phenylethanol and 1-amino-2-propanol.
Keywords: amino acids
¥ amino
alcohols ¥ asymmetric catalysis ¥
hydrogen transfer ¥ ruthenium
Introduction
several of the ruthenium complexes were able to selectively
catalyze the reduction reaction, we found that the catalyst
based on ligand 1 was particularly effective, giving the prod-
uct alcohol (1-phenylethanol) in high yield and enantioselec-
tivity.
The enantioselective reduction of ketones to secondary alco-
hols is an important functional group transformation. This
rather simple transformation is extensively employed in
small-scale laboratory experiments as well as in large-scale
industrial applications. The transition-metal-catalyzed hy-
drogen-transfer protocol represents a proficient and particu-
larly mild route towards the formation of chiral secondary
alcohols.[1,2] The introduction of catalysts based on rutheni-
um complexes with chiral amino alcohol or diamine ligands,
in combination with 2-propanol or formic acid as a hydride
source, render this process highly selective and efficient.[3]
We have recently introduced catalysts based on pseudo-di-
peptide ligands for the enantioselective ruthenium-catalyzed
transfer hydrogenation of aryl alkyl ketones in 2-propa-
nol.[4,5] A library of novel ™dipeptide∫ ligands was efficiently
formed combining N-Boc-protected a-amino acids with a
number of vicinal amino alcohols obtained from the corre-
sponding natural and unnatural amino acids. These ligands
were combined with a proper ruthenium(ii) source (i.e.
[{RuCl2(arene)}2]) and the complexes formed were screened
as catalysts for the reduction of acetophenone. Although
This catalyst was successfully employed in the reduction
of a number of aryl alkyl ketones, and enantioselectivity of
up to 96% was obtained. Furthermore, we found that the
product configuration was determined by the stereocenter
present in the amino acid part of the ™dipeptide∫ ligand.
Using catalysts based on natural amino acids gave products
of S configuration and the opposite enantiomer was ob-
tained when d-amino acids were employed. The simplicity
of the ligand structure in combination with the ready availa-
bility and low cost of a-amino acids render this system
highly attractive. A disadvantage with this novel class of cat-
alysts is that the ketone reduction only works using secon-
dary alcohols as hydrogen donors. In efforts towards finding
catalysts which would also tolerate formic acid as the hydro-
gen source, we examined various derivatives of the ™dipep-
tide∫ ligands; but unfortunately no such catalyst could be
developed. One of the compounds we examined, however,
turned out to be more efficient and selective in comparison
[a]Dr. A. B˘gevig, Dr. I. M. Pastor, Dr. H. Adolfsson
Department of Organic Chemistry
The Arrhenius Laboratory, Stockholm University
SE-10691 Stockholm (Sweden)
Fax : (+46)8-154908
E-mail: hansa@organ.su.se
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DOI: 10.1002/chem.200305553
Chem. Eur. J. 2004, 10, 294 302

294 302
to the first-generation catalysts when the reaction was per-
formed in 2-propanol. Here we present the preparation and
evaluation of a novel class of pseudo-symmetric peptide-like
ligands that, when combined with [{RuCl2(p-cymene)}2],
result in catalysts exhibiting superior activity and selectivity
in ketone reductions.
The successful construction of a library of compounds
relies on efficient and selective synthetic procedures that
allow the formation of the desired targets in high yield and
purity.[6,7] Thus, to obtain a library of ligands with the funda-
mental structural features of V-(S)-3, a number of N-Boc-
protected amino acids were coupled with the amino alcohols
(3 and 4) by using isobutyl chloroformate in the presence of
N-methylmorpholine (NMM).[8] This protocol was previous-
ly employed in the formation of our first-generation ligand
library; however, when this reaction was reexamined we
found that two factors turned out to be of crucial impor-
tance for obtaining the pseudo-dipeptides of high purity;
1) full conversion of the Boc-protected amino acid to the
mixed anhydride, and 2) exact stoichiometry of the reac-
tants. In the first case, it was found necessary to extend the
time allowed for isobutyl chloroformate to react with the
amino acid, forming the mixed anhydride intermediate. Sec-
ondly, excess of either the amino alcohol or the coupling re-
agent should be avoided. We found that any residual cou-
pling reagent effectively reacted with the amino alcohol
upon its addition. The separation of the obtained N-isobu-
tylcarbamate-protected amino alcohol from the desired cou-
pling product turned out to be less straightforward. On the
other hand, the need for purification of the ligands is more
cosmetic than absolutely necessary, since the byproducts act
as very poor ligands relative to the pseudo-dipeptide (vide
infra).
Results and Discussion
Preparation and evaluation of the catalyst library: Encour-
aged by the results we obtained using our first-generation li-
gands in the ruthenium-catalyzed transfer hydrogenation of
ketones,[4] we decided to investigate how structural changes
in the amino alcohol part of the ligand would affect the ac-
tivity and selectivity of the catalyst. One obvious structural
variation is of course to employ ligands that contain secon-
dary alcohols instead of the primary hydroxyl functionality
present in the initial ligand system. Hence, we prepared
ligand V-(S)-3 starting from N-Boc-protected l-valine and
(S)-2-amino-1-phenylethanol ((S)-3) (Scheme 1). Employing
By employing the synthetic method described above, a li-
brary of 36 pseudo-dipeptides was prepared (Scheme 2 and
Table 1), and these ligands were evaluated using the reduc-
tion of acetophenone as the model reaction. The reductions
were carried out by using the following conditions: sub-
strate/ruthenium/ligand/base in a 100:1:1.1:5 ratio, with 0.2m
concentration of acetophenone in 2-propanol. The catalyst
was prepared by drying a mixture of [{RuCl2(p-cymene)}2]
(0.5 mol%), the ™dipeptide∫-ligand (1.1 mol%), and NaOH
(5 mol%) under vacuum for 15 30 minutes followed by ad-
dition of oxygen-free 2-propanol. The color of the obtained
mixtures varied from yellow to purple, depending on the
ligand employed. After 10 minutes, the substrate was added
and the reaction progress was monitored by analyzing small
samples using GLC methods. The results obtained after a
two hour reaction time with the library of catalysts are pre-
sented in Table 1 and Figure 1. The catalytic activity varied
significantly, with conversions ranging from 17 up to 93%
depending on the structure of the ligand/catalyst. It is impor-
tant to point out that under these reversible reaction condi-
tions, the maximum theoretical conversion is limited to
96%.[9] One factor which seemed to govern the extent of
conversion was the relative size of the side chains present in
the ligand. Hence, ligands based on tLeu, containing the
more sterically-demanding tert-butyl-group, were considera-
bly less active relative to ligands that contained smaller side
chains. An even more pronounced effect on the catalytic ac-
tivity is clearly visible when comparing ligands of different
stereochemistry. Out of the 36 ligands present in the library,
all but four compounds contain two stereogenic centers;
consequently two diastereomers were formed when each of
the amino alcohols were employed. Taking the relative con-
Scheme 1.
this ligand in the ruthenium-catalyzed reduction of aceto-
phenone under hydrogen-transfer conditions resulted in the
formation of 1-phenylethanol in 91% conversion and
93% ee after two hours. This should be compared to the
result obtained with the analogous ligand 2, which gave ap-
proximately the same enantioselectivity but significantly
lower conversion when used in the same reaction. With this
result in hand, we decided to prepare a library of ligands
based on N-Boc-protected a-amino acids and the commer-
cially available 2-amino-1-phenylethanols (R)-3 and (S)-3
and 1-amino-2-propanols (R)-4 and (S)-4 (Schemes 1 and 2).
Scheme 2.
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H. Adolfsson et al.
FULL PAPER
Table 1. Ligand library screening. Ru-catalyzed hydrogen-transfer of acetophenone to 1-phenylethanol in 2-
propanol.[a,b]
cohol in excellent enantioselec-
tivity (>90%), whereas using
the mismatched ligand combi-
nation resulted in a considera-
bly lower ee of 1-phenylethanol.
In line with our previous obser-
vations, the configuration of the
product alcohol is determined
by the absolute configuration of
the amino acid part of the
ligand. Thus, catalysts based on
N-Boc amino acid (R=)
l-AA
predominantly
gave
l-Ala (Me)
l-Val (iPr)
d-Val (iPr)
l-Leu (iBu)
l-Ile ((S)-sBu)
l-tLeu (tBu)
l-Phe (Bn)
l-PhGly (Ph)
Gly (H)
A-(R)-3
25% conv.
60% ee (S)
A-(S)-3
91% conv.
92% ee (S)
A-(R)-4
23% conv.
59% ee (S)
A-(S)-4
90% conv.
96% ee (S)
products of S configuration and
the use of ligands based on d-
AA resulted in the formation
of the R alcohol as the major
enantiomer. The only excep-
tions were observed with cata-
lysts derived from l-PhG,
whereby a small excess of the
R-configured product was ob-
tained when the mismatched li-
gands were used. The glycine-
derived ligands possess only
one stereogenic center and,
therefore, the sole influence of
this chiral center is displayed
when catalysts based on these
compounds are employed in the
reduction reaction. In agree-
ment with the observation that
the l-configured amino acids
predominantly give S alcohols,
the combination of glycine and
S-amino alcohols resulted in li-
gands that favored the same
product stereoisomer. Catalysts
based on the antipodes of these
ligands naturally favored the
formation of the product R al-
cohol.
V-(R)-3
43% conv.
40% ee (S)
V-(S)-3
91% conv.
93% ee (S)
V-(R)-4
55% conv.
34% ee (S)
V-(S)-4
90% conv.
96% ee (S)
d-V-(R)-3
92% conv.
93% ee (R)
d-V-(S)-3
43% conv.
38% ee (R)
d-V-(R)-4
90% conv.
96% ee (R)
d-V-(S)-4
48% conv.
36% ee (R)
L-(R)-3
30% conv.
20% ee (S)
L-(S)-3
87% conv.
84% ee (S)
L-(R)-4
17% conv.
36% ee (S)
L-(S)-4
81% conv.
95% ee (S)
I-(R)-3
43% conv.
37% ee (S)
I-(S)-3
93% conv.
94% ee (S)
I-(R)-4
30% conv.
31% ee (S)
I-(S)-4
85% conv.
97% ee (S)
tL-(R)-3
30% conv.
35% ee (S)
tL-(S)-3
57% conv.
88% ee (S)
tL-(R)-4
25% conv.
31% ee (S)
tL-(S)-4
69% conv.
92% ee (S)
F-(R)-3
24% conv.
28% ee (S)
F-(S)-3
86% conv.
95% ee (S)
F-(R)-4
41% conv.
29% ee (S)
F-(S)-4
36% conv.
97% ee (S)
PhG-(R)-3
55% conv.
24% ee (R)
PhG-(S)-3
92% conv.
92% ee (S)
PhG-(R)-4
3% conv.
46% ee (R)
PhG-(S)-4
89% conv.
94% ee (S)
Out of the 36 entries de-
scribed in Table 1, ligands
based on N-Boc-protected ala-
nine, valine, or isoleucine and
(S)-1-amino-2-propanol ((S)-4)
gave superior catalysts with
regard to conversion and selec-
tivity.
G-(R)-3
89% conv.
76% ee (R)
G-(S)-3
85% conv.
76% ee (S)
G-(R)-4
81% conv.
72% ee (R)
G-(S)-4
77% conv.
69% ee (S)
[a]For conditions, see scheme above table and the Experimental Section. [b]Conversion and enantioselectivi-
ty were determined by GLC methods (CP Chirasil DEXCB).
figuration into account, ligands prepared from l-amino acids
(l-AA) and (S)-amino alcohols generated ruthenium com-
plexes of high catalytic activity, whereas use of the corre-
sponding diastereomeric ligands resulted in poor catalysts.
This matched/mismatched behavior was further accentuated
when the stereochemical outcome of the reaction was taken
into account. As seen in Figure 1, catalysts generated from
l-AA and (S)-amino alcohols generally gave the product al-
Important factors influencing the catalytic system: Although
several catalysts derived from the ligand library were able to
reduce acetophenone to 1-phenylethanol with very high
enantioselectivity, we chose to continue our studies with
ligand A-(S)-4. The ruthenium complex of this particular
ligand proved to be among the most active catalysts, in fact
we observed 76% conversion (97% ee) after only 30 mi-
nutes reaction time.[10] In order to find the optimum reaction
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Ruthenium-Catalyzed Reduction of Ketones
294 302
was severely reduced (Figure 2). We obtained the highest
conversion when the substrate was added after 10 minutes.
It should be noted that regardless of the catalytic activity,
the enantioselectivity remained high in all cases (97% ee
after 30 min reaction time).
All of the above reactions were conducted at ambient
temperature. In contrast to ruthenium-catalyzed transfer hy-
drogenations with phosphine-based metal precursors (e.g.,
[RuCl2(PPh3)3]), the systems based on RuII(arene) com-
plexes typically perform best at room temperature. Howev-
er, in a recent study Lutsenko and Moberg reported on sig-
nificant rate improvements for the transfer hydrogenation of
acetophenone at elevated temperatures by using the Noyori
catalyst (i.e., [RuII(p-cymene)(R,R)-TsDPEN]).[11] The reac-
tions were performed by using microwave irradiation and
resulted in high yields of the alcohol product in less than
10 minutes reaction time. The stereoselectivity was unfortu-
nately rather poor with ee values ranging from 48 to 82%.
To investigate how the novel catalytic system employing ™di-
peptide∫ ligands behaved under different reaction tempera-
tures, we performed a number of experiments using either
conventional heating or microwave irradiation (Table 2).
Figure 1. Enantiomeric excess of 1-phenylethanol obtained using catalysts
derived from the ligands described in Table 1. The positive numbers refer
to the formation of S isomer in excess, and the negative numbers to the
R isomer.
conditions for ketone reductions with this catalyst, we con-
ducted a series of experiments in which different parameters
were varied. This resulted in a number of crucial observa-
tions. 1) The amount of base necessary for efficient catalyst
formation was found to be three equivalents. Using less than
three equivalents of NaOH resulted in low conversion, and
below two equivalents of base, the catalytic activity was
completely lost. 2) The ligand/ruthenium ratio was varied
and we found an optimum value around 1, which indicates
that a 1:1 complex is the active catalyst. Lower amounts of
ligand gave significantly lower conversion and the use of
more than one equivalent versus ruthenium resulted in a
minor drop of the catalytic activity. 3) Most importantly, we
discovered that the lifetime of the active catalyst was limit-
ed. The typical reaction setup involves mixing the ligand
with the ruthenium precursor and NaOH in 2-propanol
under oxygen-free conditions, followed by addition of the
substrate. If the delay time between substrate addition and
catalyst formation was too long, the activity of the system
Table 2. Catalytic hydrogen transfer of acetophenone in 2-propanol by
[{RuCl2(p-cymene)}2]and A-( S)-4 at elevated temperatures.[a]
[b]
T [8C]
t [min]Yield [%]
ee [%][c]
1[d]
2[d]
3[e]
4[e]
5[e]
6[e]
7[e]
60
60
60
75
90
9
30
4
3
2.5
92
95
92
95
94
93
87
78
93
63
78
88
90
87
120
150
2.5
2
[a]Reaction conditions: acetophenone (1 eq, 0.2 m in 2-propanol),
[{RuCl2(p-cymene)}2](0.5 mol%), A-( S)-4 (1.1 mol%) and NaOH
(5 mol%). [b]Determined by GLC. [c]Enantiomeric excess ( ee) was de-
termined by GLC (CP Chirasil DEXCB). [d]Conventional heating using
an oil bath. 7 minutes pre-stirring of catalyst mixture prior to substrate
addition. [e]Microwave irradiation using an Emry×s TM Creator, program-
med at constant temperature. No pre-stirring of catalyst mixture.
Reactions performed at 608C using either an oil bath or
microwave heating resulted in moderate to high yields and
good enantioselectivity within
a short period of time
(Table 2, entries 1 and 3). Extending the reaction time under
conventional heating did not improve the chemical yield
and further resulted in a small drop of the ee (entry 2). Per-
forming the reductions at higher temperatures resulted in
shorter reaction times, but unfortunately with the cost of
lower enantioselectivity (entries 4 7). Thus if time is crucial,
the reactions can be performed at higher temperature
(608C) without significant loss of stereoselectivity.
As stated above, some of the ligands presented in Table 1
contained up to 10% of a byproduct that formed in the pep-
tide coupling step, namely the N-isobutylcarbamate-protect-
ed amino alcohol. The presence of this byproduct did not se-
verely hamper the performance of the catalytic system, but
a small decrease in conversion and enantioselectivity was
detected. Performing the reduction of acetophenone under
hydrogen-transfer conditions with these byproducts (e.g., 5
Figure 2. The effect of delaying the time of substrate addition. Conver-
sion of acetophenone obtained after 30 minutes.
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H. Adolfsson et al.
FULL PAPER
or 6) as ligands resulted in low conversion (<17% after 2 h)
and poor enantioselectivity (up to 17% ee of the R isomer)
of the secondary alcohol formed.
Without exception, all substrates presented in Table 3
were reduced with excellent enantio-face selectivity
(94% ee or better) by using this novel catalytic system. Re-
garding the catalytic activity, increased size of the alkyl
group of the ketone effectively leads to lower isolated yields
and the following trend was observed: 75% for acetophe-
none (entry 1), 67% for propiophenone (entry 2), 14% for
isopropyl phenyl ketone (entry 3), and the sterically-hin-
dered tert-butyl phenyl ketone completely failed to react.
Theoretically, the yields should be similar for the four ke-
tones, since their reduction potentials and, therefore, also
the reaction equilibrium constants are similar. Hence, the
observed decrease in reactivity is best explained by in-
creased steric interactions between the substrate and the
catalyst. The reduction of methoxy-substituted acetophe-
nones followed the predicted pattern. The 2- and 4-methoxy
substituted phenyl ethanols were isolated in moderate
yields, whereas the reduction of the 3-substituted methoxy-
acetophenone gave a significantly better yield (entries 4 6).
This can be attributed to electronic effects, although steric
hindrance or possibly catalyst deactivation by substrate co-
ordination could be responsible for the low activity observed
for the 2-methoxy derivative. Steric hindrance was most
probably the reason for the low yield obtained with 2-meth-
ylacetophenone (entry 7). 3-Fluoroacetophenone was con-
verted to the corresponding secondary alcohol in good yield
(entry 8). The reduction of 1-tetralone gave the secondary
alcohol in 47% yield (entry 9), and 2-acetonaphthone was
reduced in excellent yield (entry 10). In the ligand optimiza-
tion study on the model compound acetophenone, several li-
gands, when combined with the ruthenium(ii) precursor, re-
sulted in catalysts with similar properties (Table 1). Howev-
er, for other substrates more substantial differences were
observed. This was evident when the ligand I-(S)-4 was used
in the reduction of 3-fluoroacetophenone; this resulted in
considerably lower conversion to the secondary alcohol
(68% after 30 min in comparison to 91% when ligand A-
(S)-4 is used). As expected when using a ligand derived
from a natural amino acid, all products in Table 2 were ob-
tained with the S isomer as the major enantiomer.
Scope of the system: The scope of the catalytic system was
investigated using a number of ketone substrates with
[{RuCl2(p-cymene)}2]and ligand A-( S)-4 as the catalyst. The
results are presented in Table 3.
Table 3. Ru-catalyzed hydrogen transfer of aryl alkyl ketones in the pres-
ence of ligand A-(S)-4.[a]
[b]
Substrate
t [min]Yield [%]
ee [%][c]
96 (S)
1
2
3
4
5
90
150
180
210
90
75
67
14
49
85
98 (S)
96 (S)
94 (S)
97 (S)
6
210
59
94 (S)
Nature of the catalyst: The gradual loss of catalytic activity
observed using this system was initially believed to originate
from slow catalyst decomposition due to ligand degradation.
Since the ligands contain a secondary alcohol, which can un-
dergo oxidation to the corresponding ketone, a less active
complex could be the result of such a transformation. There-
fore, ketone 7, corresponding to the oxidized ligand A-(S)-4,
was prepared separately by means of a Swern oxidation[12]
of A-(rac)-4.[13]
7
210
90
37
87
47
96
97 (S)
96 (S)
96 (S)
97 (S)
8
9
180
90
10
[a]Reaction conditions: ketone (1 eq, 0.2 m in 2-propanol), [{RuCl2-
(p-cymene)}2](0.5 mol%), A-( S)-4 (1.1 mol%) and NaOH (5 mol%).
All reactions were performed at ambient temperature. [b]Isolated yields.
[c]Enantiomeric excess ( ee) and absolute configuration was determined
by GLC (CP Chirasil DEXCB).
When this compound was employed as the ligand in the
reduction of acetophenone, the reaction reached 69% con-
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Ruthenium-Catalyzed Reduction of Ketones
294 302
version and 85% ee after 2 h. This result clearly indicates
that ligand oxidation is not the major deactivating path of
the system. Another possibility for the observed decreased
activity could be the formation of catalytically inert rutheni-
um complexes. The ™dipeptides∫ are potential tridentate li-
gands, and, therefore, a number of structurally-different
metal complexes can be formed.[14,15] Assuming that the hy-
drogen-transfer step occurs following the mechanism pro-
posed by Noyori,[16,17] a 16-electron ruthenium complex
needs to be present prior to the formation of the active
ruthenium hydride. This 16-electron complex can be formed
if only two out of the three available donors of the dipeptide
ligand are coordinated to the metal center. Hence, if the ini-
tially formed, catalytically active ruthenium complex is rear-
ranged into other complexes over time, these new species
could have different catalytic properties. As seen above, the
activity of the catalyst is rather sensitive towards the struc-
ture of the ligand (see Table 1 and Figure 1). In cases in
which the ™wrong∫ diastereomer of the ligand was em-
ployed, very low conversion and low enantioselectivity was
obtained. A possible explanation could be that these mis-
matched ligands favor the formation of such inactive com-
plexes. The matched ligands on the other hand, could, due
to favorable steric interactions, significantly decrease the
rate of such processes. The activity and selectivity obtained
using either the matched or the mismatched ligand can also
be explained by the inherent pseudo-symmetry of the li-
gands (Figure 3). In the matched cases, the combination of
Conclusion
In conclusion, we have designed a novel, highly efficient and
structurally very simple catalytic system for the enantiose-
lective reduction of aryl alkyl ketones under hydrogen-trans-
fer conditions. The catalytic system is based on ruthenium
complexes of modular pseudo-symmetric ™dipeptide∫ li-
gands. The ligands were prepared in a straightforward reac-
tion by coupling N-Boc-protected amino acids to commer-
cially available 1-substituted aminoethanols. In accordance
with our previously developed system, the amino acid part
of the ligand dictates the stereochemical outcome of the re-
duction reaction. This efficiently allows for the formation of
either of the product enantiomers, since both isomers of the
ligands are readily available.
Experimental
General procedure for the ligand preparation: The Boc-protected amino
acids were dissolved in dry THF at À158C and N-methylmorpholine
(NMM; 1.1 equiv) and isobutyl chloroformate (1.0 equiv) were added to
form the mixed anhydride. After 45 min to 3 h the amino alcohol
(0.95 equiv) was added, and the reaction was allowed to reach room tem-
perature. After >3 h the reaction mixture was filtered through a plug of
silica, and the filtrate was evaporated to give the crude product. The
crude ligand could either be used directly without any significant de-
crease in catalytic activity of the hydrogen-transfer reaction, or simply be
purified by recrystallization. The ligands were isolated in yields varying
from 30 to 95%.
A-(R)-3 (Boc-l-Ala-(R)-Ph): 1H NMR (400 MHz, CDCl3): d=1.33 (d,
3J=7.2 Hz, 3H), 1.42 (s, 9H), 3.34 (m, 1H), 3.67 (m, 1H), 4.13 (brs, 1H),
4.82 (m, 1H), 5.13 (d, 3J=6.8 Hz, 1H), 6.75 (s, 1H), 7.25 7.35 ppm (m,
5H); 13C NMR (100 MHz, CDCl3): d=18.7, 28.5 (3C), 47.6, 50.6, 73.5,
80.6, 126.1, 128.1, 128.7, 141.8, 155.8, 174.2 ppm; MS: m/z [M+K]+ calcd
for C16H24N2KO4: 347.137; found: 347.132.
A(S)3 (Boc-l-Ala-(S)-Ph): 1H NMR (300 MHz, CDCl3): d=1.26 (d, 3J=
7.2 Hz, 3H), 1.38 (s, 9H), 3.25 (ddd, 3J=5.4, 8.1 Hz, 2J=13.5 Hz, 1H),
3.60 (ddd, 3J=3.5, 6.7 Hz, 2J=13.8 Hz, 1H), 4.11 (m, 1H), 4.4 (brs, 1H),
4.77 (m, 1H), 5.54 (m, 1H), 7.08 (m, 1H), 7.19 7.37 ppm (m, 5H);
13C NMR (75 MHz, CDCl3): d=18.7, 28.4 (3C), 47.4, 50.4, 72.8, 80.2,
126.0 (2C), 127.8, 128.5 (2C), 141.8, 155.8, 174.2 ppm.
Figure 3. Schematic representation of the ligands in Table 1.
l-amino acids with (S)-amino alcohols, the ligands possess
pseudo-C2-symmetry, which could reduce the number of
possible catalytically active complexes. In the mismatched
cases, however, the pseudo-meso configuration of the li-
gands will open up for the formation of a significantly
higher number of complexes.
We have not yet been able to isolate or spectroscopically
identify any of the possible complexes, but additional inves-
tigations are currently being performed. Another piece of
information regarding the nature of the catalyst was found
when A-(rac)-4 was employed as ligand(s) under standard
conditions. In this experiment we obtained 1-phenylethanol
in 80% conversion and 92% ee (S) after two hours. A closer
inspection of the conversion and enantiomeric excess after
30 minutes showed that these numbers are the arithmetic
mean values of reactions performed with the individual li-
gands (A-(S)-4 and A-(R)-4). This result indicates that the
catalysts formed in this system seem to operate totally inde-
pendent of each other; this supports a model of the active
catalyst being a 1:1 RuÀL complex.
A-(R)-4 (Boc-l-Ala-(R)-Me): 1H NMR (400 MHz, CDCl3): d=1.14 (d,
3
3J=6.4 Hz, 3H), 1.33 (d, J=7.2 Hz, 3H), 1.40 (s, 9H), 3.11 (m, 1H), 3.35
(m, 1H), 3.54 (brs, 1H), 3.87 (m, 1H), 4.14 (m, 1H), 5.40 (m, 1H),
6.98 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=18.7, 20.8, 28.5 (3C),
47.1, 50.6, 67.1, 80.5, 156.0, 174.0 ppm.
A-(S)-4 (Boc-l-Ala-(S)-Me): 1H NMR (300 MHz, CDCl3): d=1.17 (d,
3J=6.0 Hz, 3H), 1.36 (d, 3J=6.9 Hz, 3H), 1.44 (s, 9H), (OH missing),
3.13 (ddd, 3J=6.0, 7.5 Hz, 2J=13.5 Hz, 1H), 3.45 (ddd, 3J=3.3, 6.6 Hz,
2J=13.8 Hz, 1H), 3.86 (brs, 1H; OH), 3.92 (m, 1H), 4.15 (m, 1H), 5.09
(d, 3J=6.6 Hz, 1H), 6.65 ppm (brs, 1H); 13C NMR (100 MHz, CDCl3):
d=18.6, 20.7, 28.5 (3C), 47.2, 50.5, 67.0, 80.5, 156.0, 174.0 ppm; MS: m/z
[M+Na]+ calcd for C11H22N2NaO4: 269.148; found: 269.140.
V-(R)-3 (Boc-l-Val-(R)-Ph) and d-V-(S)-3 (Boc-d-Val-(S)-Ph): 1H NMR
(300 MHz, CDCl3): d=0.89 0.97 (m, 6H), 1.43 (s, 9H), 2.14 (m, 1H),
3.25 (d, 3J=3.0 Hz, 1H), 3.34 (m, 1H), 3.71 (m, 1H), 3.88 (m, 1H), 4.85
(m, 1H), 5.02 (brs, 1H), 6.43 (brs, 1H), 7.27 7.36 ppm (m, 5H);
13C NMR (75 MHz, CDCl3): d=18.3, 19.5, 28.5 (3C), 31.2, 47.6, 60.4,
73.4, 80.1, 126.1 (2C), 127.9, 128.6 (2C), 142.0, 156.3, 173.2 ppm.
V-(S)-3 (Boc-l-Val-(S)-Ph) and d-V-(R)-3 (Boc-d-Val-(R)-Ph): 1H NMR
3
3
(300 MHz, CDCl3): d=0,89 (d, J=6.3 Hz, 3H), 0.93 (d, J=6.3 Hz, 3H),
1.43 (s, 9H), 2.08 (m, 1H), 3.32 (ddd, 3J=5.1, 8.1 Hz, 2J=14.1 Hz, 1H),
3
2
3.46 (brs, 1H; OH), 3.72 (ddd, J=3.6, 7.2 Hz, J=14.1 Hz, 1H), 3.84 (m,
1H), 4.84 (dd, 3J=3.0, 7.8 Hz, 1H), 5.07 (m, 1H), 6.46 (brs, 1H), 7.27
7.38 ppm (m, 5H); 13C NMR (75 MHz, CDCl3): d=18.2, 19.5, 28.5 (3C),
299
Chem. Eur. J. 2004, 10, 294 302
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¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

H. Adolfsson et al.
FULL PAPER
31.0, 47.6, 60.6, 73.1, 80.3, 126.1 (2C), 128.0, 128.7 (2C), 141.8, 156.4,
173.1 ppm; MS: m/z [M+Na]+ calcd for C18H28N2NaO4: 359.195; found:
359.189.
3.89 (m, 1H), 4.08 (m, 1H), 5.32 (m, 1H), 6.88 (m, 1H), 7.24 7.36 ppm
(m, 5H); 13C NMR (100 MHz, CDCl3): d=20.8, 22.3, 23.1, 24.9, 28.5
(3C), 41.4, 47.3, 53.6, 67.0, 80.5, 156.2, 173.9 ppm.
V-(R)-4 (Boc-l-Val-(R)-Me) and d-V-(S)-4 (Boc-d-Val-(S)-Me):
1H NMR (400 MHz, CDCl3): d=0,93 (d, 3J=6.8 Hz, 3H), 0.97 (d, 3J=
I-(R)-3 (Boc-l-Ile-(R)-Ph): 1H NMR (400 MHz, CDCl3): d=0.91 (m,
6H), 1.08 (m, 1H), 1.41 (s, 9H), 1.47 (m, 1H), 1.84 (m, 1H), 3.32 (m,
1H), 3.69 (ddd, 3J=3.5, 7.0 Hz, 2J=14.1 Hz, 1H), 3.92 (dd, 3J=6.6,
3
7.2 Hz, 3H), 1.18 (d, J=6.0 Hz, 3H), 1.44 (s, 9H), 2.15 (m, 1H), 2.56 (d,
3J=4.0 Hz, 1H; OH), 3.13 (ddd, 3J=5.6, 8.0 Hz, 2J=13.6 Hz, 1H), 3.45
(ddd, 3J=3.2, 6.4 Hz, 2J=13.6 Hz, 1H), 3.86 (dd, 3J=6.4, 8.0 Hz, 1H),
3.92 (m, 1H) 5.00 (m, 1H), 6.38 ppm (m, 1H); 13C NMR (75 MHz,
CDCl3): d=18.2, 19.5, 20.9, 28.5 (3C), 30.9, 47.6, 60.6, 67.4, 80.3, 156.4,
172.9 ppm; MS: m/z [M+Na]+ calcd for C13H26N2NaO4: 297.179; found:
297.181.
8.6 Hz, 1H), 4.82 (dd, J=3.4, 8.2 Hz, 1H), 5.15 (d, J=8.8 Hz, 1H), 6.68
(m, 1H), 7.27 7.36 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=11.6,
15.8, 24.9, 28.5 (3C), 37.3, 47.6, 59.7, 73.6, 80.3, 126.1 (2C), 128.0, 128.7
(2C), 141.8, 156.2, 173.1 ppm.
3
3
1
I-(S)-3 (Boc-l-Ile-(S)-Ph): H NMR (300 MHz, CDCl3): d=0.88 (m, 6H),
1.08 (m, 1H), 1.41 (s, 9H), 1.50 (m, 1H), 1.78 (m, 1H), 3.31 (m,
1H), 3.65 (ddd, 3J=3.5, 7.0 Hz, 2J=14.1 Hz, 1H), 3.91 (m, 1H), 4.12
(brs, 1H; OH), 4.81 (m, 1H), 5.35 (m, 1H), 6.90 (m, 1H), 7.22 7.36 ppm
(m,1H); 13C NMR (75 MHz, CDCl3): d=11.5, 15.7, 24.9, 28.5 (3C), 37.2,
47.6, 59.8, 73.0, 80.3, 126.0 (2C), 127.9, 128.7 (2C), 141.8, 156.3,
174.2 ppm; MS: m/z [M+K]+ calcd for C19H30KN2O4: 389.184; found:
389.192.
V-(S)-4 (Boc-l-Val-(S)-Me) and d-V-(R)-4 (Boc-d-Val-(R)-Me):
1H NMR (300 MHz, CDCl3): d=0.88 (m, 6H) 1.10 (d, 3J=5.9 Hz, 3H),
1.36 (s, 9H), 1.98 (m, 1H), 3.01 (m, 1H), 3.36 (m, 1H), 3.88 (m, 2H), 4.5
(brs, 1H; OH), 5.60 (d, 3J=8.1 Hz, 1H), 7.26 ppm (m, 1H); 13C NMR
(75 MHz, CDCl3): d=18.4, 19.5, 20.7, 28.5 (3C), 31.1, 47.1, 60.5, 66.7,
80.0, 156.5, 173.2 ppm.
F-(R)-3 (Boc-l-Phe-(R)-Ph): 1H NMR (300 MHz, CDCl3): d=1.32 (s,
9H), 2.96 (m, 2H), 3.0 (brs, 1H; OH), 3.08 (m, 1H), 3.51 (m, 1H), 4.26
(m, 1H), 4.54 (m, 1H), 5.11 (br s, 1H), 6.31 (brs, 1H), 7.13 7.29 ppm (m,
10H); 13C NMR (75 MHz, CDCl3): d=28.5 (3C), 39.1, 47.6, 56.4, 73.4,
80.6, 126.0 (2C), 127.2, 128.0, 128.7 (2C) 128.9 (2C), 129.6 (2C), 137.0,
141.6, 155.7, 172.4 ppm; MS: m/z [M+K]+ calcd for C22H28N2KO4:
423.169; found: 423.164.
F-(S)-3 (Boc-l-Phe-(S)-Ph): 1H NMR (300 MHz, CDCl3): d=1.37 (s,
9H), 3.00 (m, 2H), 3.20 (m, 1H), 3.58 (m, 2H), 4.32 (m, 1H), 4.73 (dd,
3J=3.6, 8.1 Hz, 1H), 5.23 (d, 3J=8.1 Hz, 1H), 6.52 (brs, 1H), 7.16
7.36 ppm (m, 10H); 13C NMR (75 MHz, CDCl3): d=28.5 (3C), 38.8, 47.7,
56.4, 73.1, 80.6, 126.0 (2C), 127.2, 128.0, 128.7 (2C), 128.9 (2C), 129.5
(2C), 136.9, 141.7, 155.8, 172.7 ppm.
F-(R)-4 (Boc-l-Phe-(R)-Me): 1H NMR (300 MHz, CDCl3): d=1.08 (d,
3J=6.6 Hz, 3H), 1.39 (s, 9H), 2.64 (brs, 1H), 2.96 (m, 1H), 3.03 (d, 3J=
7.5 Hz, 1H), 3.31 (ddd, 3J=3.0, 6.6 Hz, 2J=13.5 Hz 1H), 3.71 (m, 1H),
4.31 (m, 1H) 5.25 (d, 3J=7.8 Hz, 1H), 6.41 (m, 1H), 7.19 7.32 ppm (m,
5H); 13C NMR (75 MHz, CDCl3): d=20.7, 28.5 (3C), 39.0, 47.2, 56.4,
67.1, 80.5, 127.2, 128.9 (2C), 129.5 (2C), 137.0, 155.8, 172.5 ppm; MS: m/
z [M+Na]+ calcd for C17H26N2NaO4: 345.179; found: 345.191.
F-(S)-4 (Boc-l-Phe-(S)-Me): 1H NMR (300 MHz, CDCl3): d=1.06 (d,
3J=6.3 Hz, 3H), 1.37 (s, 9H), 3.00 (m, 3H), 3.22 (brs, 1H), 3.34 (m, 1H),
3.80 (m, 1H), 4.33 (m, 1H) 5.37 (d, 3J=8.4 Hz, 1H), 6.68 (m, 1H), 7.17
7.30 ppm (m, 5H); 13C NMR (75 MHz, CDCl3): d=20.7, 28.5 (3C), 38.9,
47.2, 56.3, 66.8, 80.5, 127.1, 128.8 (2C), 129.5 (2C), 137.0, 155.9,
172.5 ppm.
I-(R)-4 (Boc-l-Ile-(R)-Me): 1H NMR (300 MHz, CDCl3): d=0.91 (m,
6H), 1.18 (d, 3J=8.0 Hz, 3H), 1.22 (m, 2H), 1.44 (s, 9H), 1.89 (m, 1H),
2.66 (d, 4.0 Hz, 1H), 3.13 (ddd, 3J=5.7, 8.1 Hz, 2J=13.5 Hz, 1H), 3.44
(ddd, 3J=3.3, 6.6 Hz, 2J=13.5 Hz, 1H), 3.88 (dd, 3J=6.6, 8.1 Hz, 1H),
3.93 (m, 1H), 5.01 (m, 1H), 6.43 ppm (m, 1H); 13C NMR (75 MHz,
CDCl3): d=11.5, 15.8, 20.9, 25.0, 28.5 (3C), 37.2, 47.1, 59.9, 67.4, 80.3,
156.3, 172.9 ppm.
I-(S)-4 (Boc-l-Ile-(S)-Me): 1H NMR (300 MHz, CDCl3): d=0.92 (m,
6H), 1.11 (m, 1H), 1.17 (d, 3J=8.0 Hz, 3H), 1.43 (s, 9H), 1.51 (m, 1H),
3
2
1.85 (m, 1H), 3.06 (brs, 1H; OH), 3.06 (ddd, J=5.4, 8.1 Hz, J=13.5 Hz,
1H), 3.47 (ddd, 3J=3.3, 6.6 Hz, 2J=13.8 Hz, 1H), 3.88 (m, 1H), 3.93 (m,
1H), 5.14 (d, 3J=7.8 Hz, 1H), 6.59 ppm (m, 1H); 13C NMR (75 MHz,
CDCl3): d=11.5, 15.8, 20.9, 25.0, 28.5 (3C), 37.1, 47.3, 59.9, 67.1, 80.4,
156.3, 172.9 ppm; MS: m/z [M+Na]+ calcd for C14H28N2NaO4: 311.195;
found: 311.200.
G-(R)-3 (Boc-Gly-(R)-Ph) and G-(S)-3 (Boc-Gly-(S)-Ph): 1H NMR
(300 MHz, CDCl3): d=1.38 (s, 9H), 3.21 3.28 (m, 1H), 3.55 3.64 (m,
1H), 3.71 (s, 2H), 4.46 (brs, 1H), 4.74 (dd, 3J=3.0 Hz, 8.4 Hz, 1H), 5.69
(brs, 1H), 7.07 (brs, 1H), 7.20 7.36 ppm (m, 5H); 13C NMR (75 MHz,
CDCl3): d=28.5 (3C), 44.3, 47.4, 73.0, 80.5, 126.1 (2C), 127.9, 128.7 (2C),
141.9, 156.5, 171.0 ppm; MS: m/z [M+Na]+ calcd for C15H22N2NaO4:
317.148; found: 317.148.
G-(R)-4 (Boc-Gly-(R)-Me) and G-(S)-4 (Boc-Gly-(S)-Me): 1H NMR
(300 MHz, CDCl3): d=1.13 (d, 3J=6.0 Hz, 1H), 1.40 (s, 9H), 3.02 3.11
(m, 1H), 3.35 3.42 (m, 1H), 3.71 (d, 3J=5.7 Hz, 2H), 3.85 (m, 1H), 5.72
(brs, 1H), 7.06 ppm (brs, 1H); 13C NMR (75 MHz, CDCl3): d=20.8, 28.5
(3C), 44.4, 47.0, 67.0, 80.5, 156.6, 171.0 ppm.
PhG-(R)-3 (Boc-l-PhGly-(R)-Ph): 1H NMR (300 MHz, CDCl3): d=1.41
(s, 9H), 2.96 (brs, 1H), 3.31 (ddd, 3J=5.7, 7.5 Hz, 2J=14.1 Hz, 1H), 3.72
(ddd, 3J=3.6, 6.9 Hz, 2J=14.1 Hz, 1H), 4.77 (dd, 3J=3.6, 7.5 Hz, 1H),
5.10 (brs, 1H), 5.72 (d, 3J=7.2 Hz, 1H), 6.23 (brs, 1H), 7.21 7.38 ppm
(m, 10H); 13C NMR (75 MHz, CDCl3): d=28.5 (3C), 47.5, 58.7, 72.8,
80.5, 126.1 (2C), 127.4 (2C), 127.9, 128.5 128.6 (2C), 129.2 (2C), 138.3,
141.8, 155.6, 171.4 ppm.
L-(R)-3 (Boc-l-Leu-(R)-Ph): 1H NMR (400 MHz, CDCl3): d=0.92 (m,
3
6H), 1.42 (s, 9H), 1.45 (m, 1H), 1.60 (m, 2H), 3.33 (ddd, J=5.2, 8.0 Hz,
2J=13.6 Hz, 1H), 3.59 (brs, 1H), 3.67 (ddd, 3J=3.3, 7.0 Hz, 2J=13.6 Hz,
3
1H), 4.08 (brs, 1H), 4.82 (m, 1H), 4.98 (d, J=8.0 Hz, 1H), 6.71 (s, 1H),
7.24 7.36 ppm (m, 5H); 13C NMR (75 MHz, CDCl3): d=22.2, 23.1, 24.9,
28.5 (3C), 41.7, 47.6, 53.5, 73.4, 80.3, 126.1 (2C), 127.9, 128.6 (2C), 142.0,
156.2, 174.3 ppm; MS: m/z [M+K]+ calcd for C19H30N2KO4: 389.184;
found: 389.233.
L-(S)-3 (Boc-l-Leu-(S)-Ph): 1H NMR (400 MHz, CDCl3): d=0.90 (m,
PhG-(S)-3 (Boc-l-PhGly-(S)-Ph): 1H NMR (300 MHz, CDCl3): d=1.37
(s, 9H), 3.27 (ddd, 3J=5.7, 7.5 Hz, 2J=13.5 Hz, 1H), 3.55 (ddd, 3J=4.0,
6.6 Hz, 2J=13.5 Hz, 1H), 3.99 (brs, 1H), 4.73 (dd, 3J=3.6, 7.5 Hz, 1H),
5.22 (brs, 1H), 6.00 (d, 3J=7.2 Hz, 1H), 6.83 (brs, 1H), 7.17 7.30 ppm
(m, 10H); 13C NMR (75 MHz, CDCl3): d=28.5 (3C), 47.5, 58.7, 72.8,
80.5, 126.1 (2C), 127.4 (2C), 127.9, 128.5, 128.6 (2C), 129.2 (2C), 138.3,
141.8, 155.6, 171.4 ppm; MS: m/z [M+Na]+ calcd for C21H26N2NaO4:
393.179; found: 393.169.
PhG-(R)-4 (Boc-l-PhGly-(R)-Me): 1H NMR (300 MHz, CDCl3): d=1.37
(s, 9H), 2.99 (brs, 1H), 3.10 (ddd, 3J=5.7, 7.5 Hz, 2J=13.5 Hz, 1H), 3.32
(ddd, 3J=3.6, 6.6 Hz, 2J=13.5 Hz, 1H), 3.82 (m, 1H), 5.17 (brs, 1H),
5.86 (d, 3J=6.3 Hz, 1H), 6.73 (brs, 1H), 7.25 7.37 ppm (m, 5H);
13C NMR (75 MHz, CDCl3): d=20.8, 28.5 (3C), 47.3, 59.0, 67.1, 80.5,
127.4 (2C), 128.5, 129.2 (2C), 138.3, 155.6, 171.4 ppm.
3
6H), 1.41 (s, 9H), 1.45 (m, 1H), 1.58 (m, 2H), 3.26 (ddd, J=5.2, 8.0 Hz,
2J=13.6 Hz, 1H), 3.50 (brs, 1H), 3.66 (ddd, 3J=3.6, 8.0 Hz, 2J=13.6 Hz,
3
1H), 4.07 (brs, 1H), 4.81 (m, 1H), 5.17 (d, J=8.0 Hz, 1H), 6.88 (s, 1H),
7.24 7.36 ppm (m, 5H); 13C NMR (100 MHz, CDCl3): d=22.2, 23.1, 24.9,
28.5 (3C), 41.5, 47.7, 53.5, 73.0, 80.5, 126.1 (2C), 127.9, 128.7 (2C), 141.9,
156.2, 174.1 ppm.
L-(R)-4 (Boc-l-Leu-(R)-Me): 1H NMR (400 MHz, CDCl3): d=0.90 (m,
6H), 1.13 (d, 3J=5.6 Hz, 3H), 1.40 (s, 9H), 1.45 (m, 1H), 1.60 (m, 2H),
3.13 (m, 1H), 3.33 (m, 1H), 3.59 (brs, 1H), 3.87 (m, 1H), 4.09 (brs, 1H),
5.32 (d, 3J=6.4 Hz, 1H), 7.07 (s, 1H), 7.24 7.36 ppm (m, 5H); 13C NMR
(100 MHz, CDCl3): d=20.8, 22.2, 23.1, 24.9, 28.5 (3C), 41.6, 47.1, 53.6,
67.2, 80.3, 156.2, 173.9 ppm; MS: m/z [M+K]+ calcd for C14H28N2KO4:
327.169; found 327.165.
L-(S)-4 (Boc-l-Leu-(S)-Me): 1H NMR (400 MHz, CDCl3): d=0.90 (m,
6H), 1.15 (d, 3J=5.6 Hz, 3H), 1.42 (s, 9H), 1.47 (m, 1H), 1.64 (m, 2H),
3.02 (m, 1H), 3.03 (m, 1H), 3.45 (ddd, 3J=3.0, 6.8 Hz, 2J=14.0 Hz, 1H),
PhG-(S)-4 (Boc-l-PhGly-(S)-Me): 1H NMR (300 MHz, CDCl3): d=1.37
(s, 9H), 2.99 (brs, 1H), 3.10 (ddd, 3J=5.7, 7.5 Hz, 2J=13.5 Hz, 1H), 3.32
(ddd, 3J=3.6, 6.6 Hz, 2J=13.5 Hz, 1H), 3.82 (m, 1H), 5.17 (brs, 1H),
300
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 294 302

Ruthenium-Catalyzed Reduction of Ketones
294 302
5.86 (d, 3J=6.3 Hz, 1H), 6.73 (brs, 1H), 7.25 7.37 ppm (m, 5H);
13C NMR (75 MHz, CDCl3): d=20.7, 28.5 (3C), 47.2, 58.7, 66.8, 80.4,
127.4 (2C), 128.4, 129.0 (2C), 138.3, 155.7, 171.5 ppm; MS: m/z [M+K]+
calcd for C16H24N2NKO4: 347.137; found: 347.146.
tL-(R)-3 (Boc-l-tLeu-(R)-Ph): 1H NMR (400 MHz, CDCl3): d=0.97 (s,
9H), 1.38 (s, 9H), 3.28 (m, 1H), 3.62 (ddd, 3J=3.2, 6.4 Hz, 2J=14.0 Hz,
1H), 3.89 (m, 1H), 4.77, (dd, 3J=3.2, 8.0 Hz, 1H), 5.54 (d, 3J=9.2 Hz,
1H), 6.99 (m, 1H), 7.20 7.33 ppm (m, 5H); 13C NMR (100 MHz, CDCl3):
d=26.8 (3C), 28.5 (3C), 34.7, 47.5, 62.6, 73.4, 80.1, 126.1 (2C), 127.9,
128.6 (2C), 142.0, 156.3, 172.3 ppm.
General procedure for the hydrogen-transfer reaction under microwave
irradiation: [{RuCl2(p-cymene)}2](0.005 mmol), and acetophenone
(1 mmol) were added to a solution of ligand A-(S)-4 (0.011 mmol) and
NaOH (0.05 mmol) in 2-propanol (5 mL). The reaction mixture was
heated in the microwave cavity according to times and temperatures re-
ported in Table 2. After cooling, the reaction mixture was quenched with
NH4Cl (1 mL, aq. sat.), extracted with EtOAc (1 mL) and passed through
a pad of silica. The resulting solution was analyzed by GLC (CP Chirasil
DEXCB).[18]
tL-(S)-3 (Boc-l-tLeu-(S)-Ph): 1H NMR (400 MHz, CDCl3): d=0.93 (s,
3
2
9H), 1.40 (s, 9H), 3.27 (ddd, J=4.8, 8.8 Hz, J=13.6 Hz, 1H), 3.62 (ddd,
3J=3.2, 6.8 Hz, J=14.0 Hz, 1H), 3.89 (d, J=8.8 Hz, 1H), 4.80, (dd, J=
3.2, 8.4 Hz, 1H), 5.55 (d, 3J=9.2 Hz, 1H), 6.98 (m, 1H), 7.20 7.33 ppm
(m, 5H); 13C NMR (100 MHz, CDCl3): d=26.7 (3C), 28.5 (3C), 34.5,
47.6, 62.7, 73.0, 80.2, 126.1 (2C), 127.9, 128.6 (2C), 141.9, 156.5,
172.5 ppm; MS: m/z [M+Na]+ calcd for C19H30N2NaO4: 373.210; found:
373.218.
2
3
3
Acknowledgement
This work was supported by the Swedish Research Council, The Carl
Trygger Foundation, and the Wenner Gren Foundation. We are grateful
to Personal Chemistry AB Uppsala, Sweden for providing the microwave
equipment, Emry×sTM Creator.
tL-(R)-4 (Boc-l-tLeu-(R)-Me): 1H NMR (400 MHz, CDCl3): d=0.96 (s,
9H), 1.13 (d, 3J=6.0 Hz, 3H), 1.38 (s, 9H), 3.11 (ddd, 3J=6.0, 7.6 Hz,
2J=13.6 Hz, 1H), 3.35 (ddd, 3J=3.2, 6.4 Hz, 2J=13.6 Hz, 1H), 3.78 3.93
(m, 2H), 5.47 (m, 1H), 7.05 ppm (m, 1H); 13C NMR (100 MHz, CDCl3):
d=20.9, 26.8 (3C), 28.5 (3C), 34.5, 47.0, 62.7, 67.3, 80.0, 156.4,
172.2 ppm.
[1]For reviews, see: a) U. Matteoli, P. Frediani, M. Bianchi, C. Botte-
ghi, S. Gladiali, J. Mol. Catal. 1981, 12, 265 319; b) G. Zassinovich,
G. Mestroni, S. Gladiali, Chem. Rev. 1992, 92, 1051 1069; c) J.-E.
B‰ckvall, R. L. Chowdhury, U. Karlsson, G. Z. Wang in Perspectives
in Coordination Chemistry (Eds.: A. F. Williams, C. Floriani, A. E.
Merbach), Helvetica Chimica Acta, Basel, 1992, pp. 463 486;
d) C. F. de Graauw, J. A. Peters, H. van Bekkum, J. Huskens, Synthe-
sis 1994, 1007 1017; e) R. Noyori, S. Hashiguchi, Acc. Chem. Res.
1997, 30, 97 102; f) M. J. Palmer, M. Wills, Tetrahedron: Asymmetry
1999, 10, 2045 2061; g) J.-E. B‰ckvall, J. Organomet. Chem. 2002,
652, 105 111; h) K. Everaere, A. Mortreux, J.-F. Carpentier, Adv.
Synth. Catal. 2003, 345, 67 77; i) H.-U. Blaser, C. Malan, B. Pugin,
F. Spindler, H. Steiner, M. Studer, Adv. Synth. Catal. 2003, 345,
103 151.
[2]a) D. M¸ller, G. Umbricht, B. Weber, A. Pfaltz, Helv. Chim. Acta
1991, 74, 232 240; b) J.-P. GenÜt, V. Ratovelomanana-Vidal, C.
Pinel, Synlett 1993, 478 480; c) P. Gamez, F. Fache, M. Lemaire, Tet-
rahedron: Asymmetry 1995, 6, 705 718; d) D. A. Evans, S. G.
Nelson, M. R. Gagnÿ, A. R. Muci, J. Am. Chem. Soc. 1993, 115,
9800 9801; e) Y. Jiang, Q. Jiang, X. Zhang, J. Am. Chem. Soc. 1998,
120, 3817 3818; f) Y. Nishibayashi, I. Takei, S. Uemura, M. Hidai,
Organometallics 1999, 18, 2291 2293.
tL-(S)-4 (Boc-l-tLeu-(S)-Me): 1H NMR (400 MHz, CDCl3): d=0.96 (s,
3
9H), 1.12 (d, J=6.4 Hz, 3H), 1.38 (s, 9H), 3.02 (m, 1H), 3.35 (ddd, 3J=
3.2, 6.4 Hz, 2J=14.0 Hz, 1H), 3.84 3.90 (m, 2H), 5.49 (d, 3J=9.2 Hz,
1H), 7.03 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=20.8, 26.8
(3C), 28.5 (3C), 34.4, 47.2, 62.9, 66.8, 80.1, 156.5, 172.3 ppm; MS: m/z
[M+K]+ calcd for C14H28N2KO4: 327.169; found: 327.175.
(R)-N-isobutoxycarbonyl-2-amino-1-phenylethanol
(5):
1H NMR
(300 MHz, CDCl3): d=0.91 (d, 3J=6.9 Hz, 6H), 1.90 (m, 1H), 3.03 (brs,
1H), 3.29 (ddd, 3J=5.4, 8.4 Hz, 2J=13.8 Hz, 1H), 3.53 (ddd, 3J=3.3,
6.9 Hz, 2J=14.1 Hz, 1H), 3.84 (d, 3J=6.6 Hz, 2H), 4.82 (m, 1H),
5.13 ppm (brs, 1H); 13C NMR (100 MHz, CDCl3): d=19.2 (2C), 28.2,
48.7, 71.5, 73.8, 126.1 (2C), 127.7, 128.1 (2C), 141.9, 157.9 ppm.
(R)-N-isobutoxycarbonyl-1-amino-2-propanol (6): 1H NMR (300 MHz,
CDCl3): d=0.91 (d, 3J=6.9 Hz, 6H), 1.18 (d, 3J=6.6 Hz, 3H), 1.89 (m,
1H), 2.43 (brs, 1H), 3.04 (ddd, 3J=6.0, 7.5 Hz, 2J=13.5 Hz, 1H), 3.31
3
2
3
(ddd, J=3.0, 6.6 Hz, J=14.1 Hz, 1H), 3.83 (d, J=7.2 Hz, 2H), 3.90 (m,
1H), 5.13 ppm (brs, 1H); 13C NMR (100 MHz, CDCl3): d=19.2 (2C),
20.8, 28.2, 48.5, 67.5, 71.4, 157.8 ppm.
[3]a) S. Hashiguchi, A. Fujii, J. Takehara, T. Ikariya, R. Noyori, J. Am.
Chem. Soc. 1995, 117, 7562 7563; b) A. Fujii, S. Hashiguchi, N. Ue-
matsu, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 1996, 118, 2521
2522; c) D. A. Alonso, D. Guijarro, P. Pinho, O. Temme, P. G. An-
dersson, J. Org. Chem. 1998, 63, 2749 2751; d) D. A. Alonso,
S. J. M. Nordin, P. Roth, T. Tarnai, P. G. Andersson, M. Thommen,
U. Pittelkow, J. Org. Chem. 2000, 65, 3116 3122; e) S. J. M. Nordin,
P. Roth, T. Tarnai, D. A. Alonso, P. Brandt, P. G. Andersson, Chem.
Eur. J. 2001, 7, 1431 1436; f) M. Palmer, T. Walsgrove, M. Wills, J.
Org. Chem. 1997, 62, 5226 5228; g) M. Wills, M. Gamble, M.
Palmer, A. Smith, J. Studley, J. Kenny, J. Mol. Catal. A 1999, 146,
139 148; h) M. J. Palmer, J. A. Kenny, T. Walsgrove, A. M. Kawa-
moto, M. Wills, J. Chem. Soc. Perkin Trans. 1 2002, 416 427; i) M.
Watanabe, K. Murata, T. Ikariya, J. Org. Chem. 2002, 67, 1712
1715; j) K. Everaere, J.-F. Carpentier, A. Mortreux, M. Bulliard, Tet-
rahedron: Asymmetry 1998, 9, 2971 2974; k) K. Everaere, J.-F. Car-
pentier, A. Mortreux, M. Bulliard, Tetrahedron: Asymmetry 1999,
10, 4083 4086; l) K. Everaere, J.-F. Carpentier, A. Mortreux, M.
Bulliard, Tetrahedron: Asymmetry 1999, 10, 4663 4666; m) K. Ever-
aere, A. Mortreux, M. Bulliard, J. Brussee, A. van der Gen, G. Now-
ogrocki, J.-F. Carpentier, Eur. J. Org. Chem. 2001, 275 291; n) K.
Everaere, N. Franceschini, A. Mortreux, J.-F. Carpentier, Tetrahe-
dron Lett. 2002, 43, 2569 2571; o) C. Bubert, J. Blacker, S. M.
Brown, J. Crosby, S. Fitzjohn, J. P. Muxworthy, T. Thorpe, J. M. J.
Williams, Tetrahedron Lett. 2001, 42, 4037 4039; p) Y. Ma, H. Liu,
L. Chen, J. Zhu, J. Deng, Org. Lett. 2003, 5, 2103 2106; q) J. Solei-
mannejad, A. Sisson, C. White, Inorg. Chim. Acta 2003, 352, 121
128; r) M. Aitali, S. Allaoud, A. Karim, C. Meliet, A. Mortreux, Tet-
rahedron: Asymmetry 2000, 11, 1367 1374; s) B. Mohar, A. Valleix,
N-(N’-Boc-l-alaninyl)-1-amino-2-propanone
(7):
Oxalyl
chloride
(1.1 mmol, 96 mL) dissolved in CH2Cl2 (2.5 mL) was placed in a flask
equipped with a stirrer and a septum under N2 (using a needle connected
to a dry nitrogen supply). The flask was cooled to À788C, and a solution
of DMSO (2.4 mmol, 176 mL) in CH2Cl2 (0.5 mL) was added with syringe
and needle over 5 min followed by 10 min of stirring. A solution of the
amido alcohol (1 mmol, 0.246 g) in CH2Cl2 (1.0 mL) was then added over
5 min. The resulting mixture was stirred for 15 min and triethylamine
(5 mmol, 0.464 mL) was added at À788C over 5 min. The cooling bath
was removed and when the mixture reached room temperature, water
(3 mL) was added. After 10 min of stirring the phases were separated,
the aqueous phase was extracted with CH2Cl2 (2î10 mL), and the com-
bined organic phases evaporated to dryness. Yield: 199 mg, 80%;[12]
1H NMR (300 MHz, CDCl3): d=1.34 (d, 3J=7.2 Hz, 1H), 1.41 (s, 9H),
2.16 (s, 3H), 4.10 (d, 3J=4.8 Hz, 2H), 4.20 (m, 1H), 5.17 (brs, 1H),
6.97 ppm (brs, 1H); 13C NMR (75 MHz, CDCl3): d=18.7, 27.5, 28.5
(3C), 59.9, 50.3, 80.3, 155.6, 173.1, 203.1 ppm.
General procedure for the hydrogen-transfer reaction: Ligand
(0.011 mmol),
[{RuCl2(p-cymene)}2](0.005 mmol)
and
NaOH
(0.05 mmol) were dried under vacuum for 30 min and dissolved in 2-
propanol (5 mL) in a dry Schlenck tube under an inert atmosphere (N2).
The solution was stirred for 15 min and the ketone (1 mmol) added. The
reaction mixture was stirred at ambient temperature. Samples were taken
at different time intervals and either quenched with NH4Cl (1 mL, aq.
sat.), extracted with EtOAc (1 mL), passed through a pad of silica, and
washed with EtOAc; or directly passed through a pad of silica. The re-
sulting solution was analyzed by GLC (CP Chirasil DEXCB).[18]
301
Chem. Eur. J. 2004, 10, 294 302
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¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

H. Adolfsson et al.
FULL PAPER
J.-R. Desmurs, M. Felemez, A. Wagner, C. Mioskowski, Chem.
Commun. 2001, 2572 2573; t) D. Sterk, M. S. Stephan, B. Mohar,
[9]H. Adkins, R. M. Elofson, A. G. Rossow, C. C. Robinson, J. Am.
Chem. Soc. 1949, 71, 3622 3629.
œ
Tetrahedron: Asymmetry 2002, 13, 2605 2608.
[10]The reduction of acetophenone with other prominent ligands report-
ed in Table 1 resulted in the following conversion and enantioselec-
tivity after 30 minutes reaction time: V-(S)-4, 65% conv. 97% ee; I-
(S)-4, 72% conv. 97% ee.
[4]a) I. M. Pastor, P. V‰stil‰, H. Adolfsson, Chem. Commun. 2002,
2046 2047; b) I. M. Pastor, P. V‰stil‰, H. Adolfsson, Chem. Eur. J.
2003, 9, 4031 4045.
[5]For other examples of amino acid based ligands in the transfer hy-
drogenation of ketones, see: a) T. Ohta, S. Nakahara, Y. Shigemura,
K. Hattori, I. Furokawa, Chem. Lett. 1998, 491 492; b) T. Ohta, S.
Nakahara, Y. Shigemura, K. Hattori, I. Furokawa, Appl. Organomet.
Chem. 2001, 15, 699 709; c) D. Carmona, F. J. Lahoz, R. Atencio,
L. A. Oro, M. P. Lamata, F. Viguri, E. San Josÿ, C. Vega, J. Reyes, F.
JoÛ, ç. KathÛ, Chem. Eur. J. 1999, 5, 1544 1564; d) ç. KathÛ, D.
Carmona, F. Viguri, C. D. Remacha, J. Kovµcs, F. JoÛ, L. A. Oro, J.
Organomet. Chem. 2000, 593 594, 299 306; e) D. Carmona, M. P.
Lamata, F. Viguri, I. Dobrinovich, F. J. Lahoz, L. A. Oro, Adv.
Synth. Catal. 2002, 344, 499 502; f) D. Carmona, M. P. Lamata,
L. A. Oro, Eur. J. Inorg. Chem. 2002, 2239 2251; g) J. W. Faller,
A. R. Lavoie, Organometallics 2001, 20, 5245 5247; h) H. Y. Rhyoo,
Y.-A. Yoon, H.-J. Park, Y. K. Chung, Tetrahedron Lett. 2001, 42,
5045 5048; i) H. Y. Rhyoo, H.-J. Park, Y. K. Chung, Chem.
Commun. 2001, 2064 2065; j) H. Y. Rhyoo, H.-J. Park, W. H. Suh,
Y. K. Chung, Tetrahedron Lett. 2002, 43, 269 272.
[11]S. Lutsenko, C. Moberg, Tetrahedron: Asymmetry 2001, 12, 2529
2532.
[12]D. Swern, K. Omura, Tetrahedron 1978, 34, 1651 1660.
[13]A-( rac)-4 is the 1:1 diastereomeric mixture of ligands A-(S)-4 and
A-(R)-4. This compound was prepared from l-alanine and racemic
1-amino-2-propanol.
[14]K. Severin, R. Bergs, W. Beck, Angew. Chem. 1998, 110, 1722 1743;
Angew. Chem. Int. Ed. 1998, 37, 1634 1654.
[15]For structural examples of [Ru II(h6-arene)(peptide)]complexes, see:
a) W. S. Sheldrick, S. Heeb, J. Organomet. Chem. 1989, 377, 357
366; b) R. Kr‰mer, M. Maurus, R. Bergs, K. Polborn, K. S¸nkel, B.
Wagner, W. Beck, Chem. Ber. 1993, 126, 1969 1980; c) R. Kr‰mer,
M. Maurus, K. Polborn, K. S¸nkel, C. Robl, W. Beck, Chem. Eur. J.
1996, 2, 1518 1526.
[16]a) K.-J. Haack, S. Hashiguchi, A. Fujii, T. Ikariya, R. Noyori,
Angew. Chem. 1997, 109, 297 300; Angew. Chem. Int. Ed. Engl.
1997, 36, 285 288; b) M. Yamakawa, H. Ito, R. Noyori, J. Am.
Chem. Soc. 2000, 122, 1466 1478; c) R. Noyori, M. Yamakawa, S.
Hashiguchi, J. Org. Chem. 2001, 66, 7931 7944.
[17]For other recent mechanistic discussions, see: a) D. A. Alonso, P.
Brandt, S. J. M. Nordin, P. G. Andersson, J. Am. Chem. Soc. 1999,
121, 9580 9588; b) D. G. I. Petra, J. N. H. Reek, J.-W. Handgraaf,
E. J. Meijer, P. Dierkes, P. C. J. Kamer, J. Brussee, H. E. Schoemak-
er, P. W. N. M. van Leeuwen, Chem. Eur. J. 2000, 6, 2818 2829;
c) O. P‡mies, J.-E. B‰ckvall, Chem. Eur. J. 2001, 7, 5052 5058;
d) C. P. Casey, J. B. Johnson, J. Org. Chem. 2003, 68, 1998 2001;
e) J. B. Johnson, J.-E. B‰ckvall, J. Org. Chem. 2003, 68, 7681 7684;
f) J.-W. Handgraaf, J. N. H. Reek, E. J. Meijer, Organometallics 2003,
22, 3150 3157.
[6]For selected reviews on high throughput strategies for catalyst dis-
covery, see: a) K. D. Shimizu, M. L. Snapper, A. H. Hoveyda, Chem.
Eur. J. 1998, 4, 1885 1889; b) J. F. Traverse, M. L. Snapper, Drug
Discovery Today 2002, 7, 1002 1012.
[7]For examples of amino acid-based libraries used in catalysis, see:
a) M. S. Sigman, E. N. Jacobsen, J. Am. Chem. Soc. 1998, 120, 4901
4902; b) B. R. Sculimbrene, S. J. Miller, J. Am. Chem. Soc. 2001, 123,
10125 10126; c) B. M. Cole, K. D. Shimizu, C. A. Krueger, J. P.
Harrity, M. L. Snapper, A. H. Hoveyda, Angew. Chem. 1996, 108,
1776 1779; Angew. Chem. Int. Ed. Engl. 1996, 35, 1668 1671;
d) C. A. Krueger, K. W. Kuntz, C. D. Dzierba, W. G. Wirschun, J. D.
Gleason, M. L. Snapper, A. H. Hoveyda, J. Am. Chem. Soc. 1999,
121, 4284 4285; e) J. R. Porter, W. G. Wirschun, K. W. Kuntz, M. L.
Snapper, A. H. Hoveyda, J. Am. Chem. Soc. 2000, 122, 2657 2658.
[8]A. I. Meyers, F. X. Tavares, J. Org. Chem. 1996, 61, 8207 8215.
[18]For GLC conditions and retention times, see; ref. [4b.]
Received: September 19, 2003 [F5553]
302
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Chem. Eur. J. 2004, 10, 294 302