An unexpected ruthenium complex and its unique behavior as catalyst in dynamic kinetic resolution of secondary alcohols

Article abstract of DOI:10.1039/b811627j

A ruthenium complex was accidentally synthesized and its unique catalytic behavior in dynamic kinetic resolution of various types of secondary alcohols, particularly for those bearing additional functional groups, is described. The Royal Society of Chemis

Full text of DOI:10.1039/b811627j

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An unexpected ruthenium complex and its unique behavior as catalyst in
dynamic kinetic resolution of secondary alcoholswz
Qihui Chen and Chengye Yuan*
Received (in Cambridge, UK) 8th July 2008, Accepted 28th July 2008
First published as an Advance Article on the web 17th September 2008
DOI: 10.1039/b811627j
A ruthenium complex was accidentally synthesized and its
unique catalytic behavior in dynamic kinetic resolution of
various types of secondary alcohols, particularly for those
bearing additional functional groups, is described.
Enantiomerically pure compounds are of great importance in
pharmaceutical, agrochemical and other fine chemical industries.
In the last decades, many asymmetric transformations have been
Fig. 1 Ruthenium complexes used in racemization during DKR.
coordination site. Additionally, for these secondary alcohols
developed for the preparation of enantiomerically pure com-
bearing sulfonyl or phosphonate moiety, they easily coordinate
pounds by employing chiral transition-metal complexes, enzymes
to ruthenium, therefore, none of the reported catalysts can operate
or organocatalysts.1 However, direct resolution of racemic
mixtures is still the most popular method to prepare enantiomeri-
cally pure compounds in industry.2 Enzymatic kinetic resolutions
are usually very efficient in stereoselectivity, but they have an
intrinsic limitation: not more than 50% of the enantiomer could
be resolved. Dynamic kinetic resolution (DKR), in which an
in situ racemization of an undesired enantiomer is coupled with
kinetic resolution (KR), may be the best way to overcome this
limitation.3 A number of Rh, Ir, and Ru complexes have been
studied for the racemization of secondary alcohols.4 However,
only very few of them have been successfully incorporated in
chemoenzymatic kinetic resolution (Fig. 1).5 In 1997, the Backvall
group first reported an efficient process for DKR by combining
ruthenium complex 1 with Candida antarctica lipase B (CALB).5a
Later, the Park and Kim group developed a new type of
ruthenium complex 2a, which substantially improved the
efficiency of DKR.5b,c A very active racemization catalyst 2b
which remarkably reduced the reaction time of DKR was intro-
duced by the Backvall group.5d,e Recently, the Park and Kim
group has initiated a mild and reusable system of DKR with
catalysts 2c and 2d.5f,g However, to the best of our knowledge,
catalyst 1 needs harsh conditions, while catalyst 2a and 2b require
strong base tBuOK, in addition, catalysts can not be reused;
catalysts 2c and 2d make the DKR more smoothly, however, only
secondary alcohols without functional groups have been studied.
Furthermore, for catalysts 2a to 2d, a good leaving group such as
a chlorine atom is usually essential, which can easily provide a
smoothly and efficiently.6 For these reasons, synthesis of a novel
and more effective and highly compatible racemization catalyst
for the DKR process is a major challenge. Herein we wish to
report a synthetic protocol leading to cyclopentadienyl benzoyl
ruthenium(II) complex 3, which bears a unique metallic spiro
structure. It is interesting to note that, with the aid of this
complex, some optically active secondary alcohols were racemized
smoothly. In the meantime, while the reaction system was coupled
with lipase, a typical and effective DKR of various type of
secondary alcohols was achieved.
Cyclopentadienyl benzoyl ruthenium(II) complex 3z was acci-
dentally synthesized by the reaction of Ru3(CO)12 with penta-
phenylcyclopenta-2,4-dienol with 41% yield. This reaction
incredibly includes oxidative addition and activation of a
carbon–hydrogen bond, as well as functionalization of the
benzene ring. A tentative mechanism is postulated as shown in
Scheme 1.7 The structure of ruthenium complex 3 was confirmed
by an X-ray diffraction study. A detailed study of this reaction
mechanism is being carried out in our group. The reaction
involved in the preparation of ruthenium complex 3 is interesting
State Key Laboratory of Bio-organic and Natural Products
Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 354 Feng-lin Rd., Shanghai, 200032, China.
E-mail: yuancy@mial.sioc.ac.cn; Tel: +8654925120
w Electronic supplementary information (ESI) available: Experimental
procedures. CCDC reference number 682225. For ESI and crystallo-
zgraphic data in CIF or other electronic format see DOI: 10.1039/
b811627j
z Moiety formula: C38H24O3RuC7H8, formula weight: 721.78, space
group: P21/c, cell: a = 11.9868(19), b = 16.875(3), c = 17.706(3), b =
104.126(3), temperature: 293 K, Dc: 1.380 g cmꢀ3, Z: 4. Data
completeness = ratio = 0.997, y(max) = 26.000, R (reflections) =
0.0714 (3636), wR2 (reflections) = 0.2022 (6797), S = 0.950.
Scheme 1 Synthesis of ruthenium complex 3.
Chem. Commun., 2008, 5333–5335 | 5333
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because it may include a novel method to functionalize the
carbon–hydrogen bond that is a topic of current interest in
organometallic chemistry.
As far as we are aware, most reported ruthenium complexes
used in the DKR process, as a rule, contain a good leaving
group such as a chloride or bromide,5b–g or appear unstable and
lead to an activated ruthenium intermediate that contains 16
coordinated electrons.5a Our experimental results on ruthenium
complex 3 are very intriguing, since it does not meet with the
general structural requirements of previous reported racemiza-
tion catalysts. Additionally, complex 3 is stable in air until the
temperature reaches 285 1C. However, as we have found even at
room temperature, a mixture of 5% ruthenium complex 3 and
one equivalent of potassium phosphate was sufficient to race-
mize (S)-1-phenylethanol within 6 h (Scheme 2). After racemiza-
tion, the catalyst can be recovered and reused.8
Scheme 2 Racemization of (S)-1-phenylethanol.
Scheme 3 DKR of 1-phenylethanol.
ruthenium complex 3 was allowed to couple with CALB in the
presence of an alcohol and an acyl donor. We are aware that
many metal complexes are known to catalyze fast racemization of
alcohols, but upon their combination with an enzyme, catalytic
kinetic resolutions are usually not trivial.4,5 Our initial attempts to
We were surprised by this unusual racemization catalysis,
which encouraged us to study what would happen when
Table 1 DKR of various secondary alcohols
Entry
1
Substrate (1a–11a)
CALB/mg
10
Time/h
10
Temp./1C
Product (1b–11b)
Yield (%)ab
94 (97)
ee (%)
99c
25
2
3
10
10
10
10
25
25
92 (96)
90 (90)
98c
99c
4
5
10
6
20
20
25
50
95 (99)d
90 (92)
99d
99c
6
7
4
6
20
20
50
50
92 (95)
92 (95)
96c
92c
8
9
20
50
20
20
25
25
99f
94f
97e
94d,i
10
11
80
80
20
20
25
25
80f,g
92c
88f,g
495h
a
b
Isolated yield. Numbers in parentheses were determined by GC or HPLC. Determined by GC with chiral column. Determined by HPLC
c
d
e
with chiral column. From GC with chiral column of the hydrolyzed product. The amount of catalyst was increased to 9%. The amount of
K3PO4 was reduced to 10%. From the 31P NMR of the hydrolyzed product. The absolute configuration of 9b was determined by comparison of
ref. 6a.
f
g
h
i
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combine ruthenium complex 3 with an enzymatic kinetic resolu-
tion were unsuccessful. It was supposed that these unsuccessful
trials might be due to the presence of a trace amount of water in
this system. As expected, after addition of 4 A molecular sieves to
the reaction system, an acetate of 1-phenylethanol was obtained
in 10 h with 97% yield and 99% ee (Scheme 3).
with the racemization process, this is probably due to the presence
of an intramolecular hydrogen transfer in racemization.5e
In summary, we have introduced a new ruthenium complex 3
that bears a unique metallic spiro structure. This new ruthenium
complex was successfully used as a powerful catalyst in DKR of
secondary alcohols under mild conditions in a short reaction time,
particularly for those alcohols that had additional functional
groups. In these reactions, higher chemical yields and excellent
enantioselectivities were achieved. Further detailed investigations
in connection to the reaction mechanism of this catalytic racemi-
zation process will be undoubtedly helpful to the design of new
and more effective ruthenium complexes as powerful catalysts in
the DKR processes in the quest for optically pure compounds.
Helpful discussion from Professor J.-B. Chen is heartily
grateful. This Project was financially supported by the Chinese
Academy of Sciences, and the National Natural Science
Foundation of China (Grant No. 20672132 and 20872165).
To study the scope of the application of this unusual ruthe-
nium complex 3, a variety of substrates was prepared and
examined (Table 1). As indicated in Table 1, our catalyst system
displayed a high efficiency towards benzylic alcohols (Table 1,
entries 1–4), 1-phenylethanol, 1-(4-methylphenyl)ethanol, and
1-(4-fluorophenyl)ethanol. These alcohols were successfully
converted to (S)-aceta-tes in 10 h with high chemical yields
and excellent enantioselectivities (Table 1, entries 1–3). Besides,
the electronic effect on the reaction involving benzylic alcohols
was not obvious. A naphthyl derivative also gave excellent
results, but a longer reaction time (up to 20 h) was needed
(Table 1, entry 4). For aliphatic alcohols, heating at 50 1C and a
lesser amount of CALB were required for satisfactory results
concerning both yields and enantioselectivities (Table 1, entries
5–6). Hydroxyl compounds bearing an additional functional
group worked very well with this complex 3. For 4-phenylbut-
3-en-2-ol, with less CALB and higher temperature, the expected
product was obtained with 95% chemical yield and 92% ee.
(Table 1, entry 7). 3-Hydroxybutyric acid tert-butyl ester was
successfully transformed to the corresponding (S)-acetate with
high yield and excellent enantioselectivity (Table 1, entry 8). The
(S)-acetate of p-chlorophenylsulfonylpropan-2-ol was obtained
in 94% chemical yield and 94% ee (Table 1, entry 9). As for
a-hydroxylalkylphosphonate and b-hydroxylalkylphosphonate,
the corresponding acetoxyphosphonates were also obtained in
high chemical yields and excellent enantioselectivities (Table 1,
entries 10–11). Overall, our catalyst works well with those
secondary alcohols that contain additional functional groups.
It is worthy to note that, for substrates 7a, 9a, 10a, it was
reported that when catalyst 1 or 2b was used, oxidation usually
occurred;5e,6 while our catalyst had not such drawbacks.
Notes and references
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our catalyst 3, so an alternative hydrogen transfer was involved in
racemization. As shown in Scheme 4, a mechanism of racemiza-
tion was tentatively proposed, that was supported by followed
experimental evidence: the catalyst is reusable; the K3PO4 is not
active enough to produce alcoholic minus-ion directly; only a
catalytic amount of K3PO4 is needed to catalyze DKR of alcohols
with phosphonate; acetone achieved by DKR does not interfere
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¨
7 When 4 A molecular sieve was added to the reaction, the yield was
increased dramatically up to 16% in general. It is indirect experi-
mental evidence showing that water molecules were formed in this
reaction.
8 Catalyst can be recovered with 90% yield after racemization and
the recovered catalyst can be used with same activity.
Scheme 4 A tentative mechanism for racemization.
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