Communication
ing a wide range of structurally diverse secondary alcohols to
the enantioselective acylation with isopropenyl acetate
(1.5 equiv) in toluene at room temperature.
The DKR of phenylethanol 3a gave enantiopure acylated al-
cohol with an excellent isolated yield (96%) and >99% ee
(Table 2, entry 1) using 2 mol% of 2. An electron-withdrawing
group (CF3) in the para position did not affect the reactivity
and the desired compound was isolated enantiomerically pure
(>99% ee) in 95% yield (entry 2). The presence of either an
electron-donating (OMe) in para or an electron-withdrawing
group (Cl) in meta position resulted in an significant decrease
of the reactivity and 10 or 16 h, respectively, were required to
achieve the acylated enantiomerically pure alcohols (4c and
4d) with full conversion and >99% ee (entries 3 and 4). With
the ortho-methyl phenylethanol 3e a lower reactivity was ob-
served, and 24 h and higher catalyst loading were required to
obtain the protected alcohol in 91% yield and 90% ee
(entry 5). The transformation of a bulkier secondary alcohol
such as the bicyclic alcohol derivative 3g was also possible in
good yield with a slight erosion in the enantiomeric excess
(91%) (entry 6). To our delight, the DKR of 2-chloro-1-phenyl
ethanol (3 f) led to the desired acetate 4 f in 80% yield with an
excellent ee (98%) (entry 7). The DKR for the preparation of
chiral b-halo alcohols, which are important structural elements
for asymmetric catalysis, were known to be difficult to achieve,
mostly involving high temperatures (708C) and long reactions
times (48 h).[13] Different heterocyclic alcohols were well tolerat-
ed, leading to the desired acetates in excellent yields and
enantioselectivities (entries 8 and 9). Aliphatic sec-alcohols
were also subjected to the DKR conditions catalyzed by 2 (en-
tries 10 and 11). In both cases, a lower amount of CAL-B was
required in order to obtain the corresponding enantioenriched
acetates (4j and 4k) with very good yields and reasonably
high enantiomeric excesses (90% ee).[8g]
Scheme 2. Synthesis of cationic complex 2.
We began our study with the racemization of (S)-phenyle-
thanol as a model reaction in the presence of 2 and a base at
room temperature (Table 1). As the usual activation of neutral
Table 1. Racemization of (S)-phenylethanol using 2.[a]
Entry
2 [mol%]
Base [equiv]
3a [% ee][b]
1
2
3
4
5
6
7
8
1
1
1
1
1
1
0.5
0.5
KOtBu (0.05)
–
K2CO3 (1)
K2CO3 (0.25)
K2CO3 (0.1)
K2CO3 (0.1)[c]
K2CO3 (0.25)
K2CO3 (0.1)[d]
0
>99
0
0
5
0
0
0
[a] Reaction conditions: 2 (0.5-1 mol%), (S)-3a (0.25 mmol) and the base
(equiv) were dissolved in toluene (0.5 mL). [b] Determined by HPLC using
Chiralpack OD-H. [c] Reaction time 1.5 h. [d] Reaction time 2 h.
ruthenium complexes involves an alkoxide base, the reaction
was initially conducted in the presence of KOtBu (5 mol%).
This leads to a rapid racemization of the enantiomerically pure
alcohol (to 0% ee) after 1 h (entry 1). A reaction in the absence
of a base resulted in no racemization (entry 2). Then, K2CO3
were selected as the operating base. The amount of K2CO3 can
be lowered to 10 mol% without affecting the racemization
performance, reaching the completely racemic mixture of alco-
hols after 1.5 h (entry 6). It is noteworthy that the catalyst load-
ing was decreased to 0.5 mol%, leading to 0% ee in the pres-
ence of 0.25 or 0.1 mol of K2CO3 after 1 or 2 h, respectively (en-
tries 7 and 8). To our delight, the optimized racemization can
be conducted by using K2CO3 (10%) and a low catalyst loading
(0.5 mol%).
Taking into account the interest in the development of se-
quential reactions,[14] the combination of two or more transfor-
mations that may operate independently represents a powerful
and useful synthetic strategy in organic chemistry. In this con-
text, we set as a target the conversion of ketones into the
enantioenriched protected alcohols via sequential transfer hy-
drogenation reactions. The asymmetric transformation of ke-
tones to chiral acetates by metal-enzyme multicatalysis has
been described using a ruthenium catalyst.[15] However, these
procedures present as main drawbacks the use of H2 as the hy-
drogen source,[15a] the requirement of high temperatures
during long reaction times,[15a,b] or the use of a very unusual
hydrogen source (2,6-dimethylheptan-4-ol).[15b]
Encouraged by the excellent results obtained for the racemi-
zation of phenylethanol (3a), we next tried to link the racemi-
zation with the enzymatic reaction using a lipase (CAL-B). Our
aim at this point was to demonstrate the compatibility of the
racemization conditions and catalyst in a full DKR procedure
using simply one base (K2CO3).[4]
We have recently reported the use of the neutral ruthenium
complex 1 in the catalytic hydrogenation of ketones using
iPrOH as a hydrogen source.[16] With this in mind, we saw the
possibility of combining both hydrogenation processes using
our cationic complex 2. We now describe a transfer hydroge-
nation for the reduction of ketones using a simple and easy to
handle hydrogen source (iPrOH), followed by the lipase-cata-
lyzed DKR of the corresponding secondary alcohols. All this
being performed in the same reaction vessel, eliminates purifi-
cation steps and uses a single catalyst.
A short optimization of the reaction conditions using phe-
nylethanol (4a) as a model substrate was carried out and high-
lighted the compatibility of the cationic 2 with CAL-B. After
optimizing the reaction conditions, the scope of the transfor-
mation was studied using 2 (2–3 mol%) and CAL-B, by subject-
&
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Chem. Eur. J. 2014, 20, 1 – 5
2
ꢃ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!