Remote ester group leads to efficient kinetic resolution of racemic aliphatic alcohols via asymmetric hydrogenation

Article abstract of DOI:10.1021/ja510990v

A highly efficient method for kinetic resolution of racemic aliphatic alcohols without conversion of the hydroxyl group has been realized; the method involves hydrogenation mediated by a remote ester group and is catalyzed by a chiral iridium complex. This powerful, environmentally friendly method provides chiral δ-alkyl-δ-hydroxy esters and δ-alkyl-1,5-diols in good yields with high enantioselectivities even at extremely low catalyst loading (0.001 mol %).

Full text of DOI:10.1021/ja510990v

Communication
pubs.acs.org/JACS
Remote Ester Group Leads to Efficient Kinetic Resolution of Racemic
Aliphatic Alcohols via Asymmetric Hydrogenation
Xiao-Hui Yang, Ke Wang, Shou-Fei Zhu, Jian-Hua Xie,* and Qi-Lin Zhou*
State Key Laboratory and Institute of Elemento-organic Chemistry, Collaborative Innovation Center of Chemical Science and
Engineering (Tianjin), Nankai University, Tianjin 300071, China
*
S Supporting Information
Scheme 1. Kinetic Resolutions of Racemic Alcohols
ABSTRACT: A highly efficient method for kinetic
resolution of racemic aliphatic alcohols without conversion
of the hydroxyl group has been realized; the method
involves hydrogenation mediated by a remote ester group
and is catalyzed by a chiral iridium complex. This powerful,
environmentally friendly method provides chiral δ-alkyl-δ-
hydroxy esters and δ-alkyl-1,5-diols in good yields with
high enantioselectivities even at extremely low catalyst
loading (0.001 mol %).
ptically active aliphatic alcohols are common substruc-
O
tures in natural products and are also useful chiral
building blocks for the synthesis of chiral drugs. However,
although considerable attention has been devoted to the
development of efficient methods for the synthesis of optically
active aliphatic alcohols in recent decades, it still remains an
1
open challenge. Catalytic asymmetric hydrogenation of
carbonyl compounds is an effective way to obtain chiral
2
alcohols, but this method is limited to the preparation of chiral
3
alcohols with one aryl group or one bulky alkyl group. For this
reason, a method for the kinetic resolution of readily available
inexpensive racemic aliphatic alcohols would be a valuable
alternative for the preparation of optically active aliphatic
alcohols.
Figure 1. Selected bioactive natural and synthetic compounds
prepared from chiral δ-hydroxy esters or 1,5-diols.
Kinetic resolution of racemic aliphatic alcohols either
enzymatically or by means of artificial chiral catalysts has
been extensively studied. However, as far as we know, all of the
4
Scheme 2. Kinetic Resolution of rac-2 via an Ester
Hydrogenation Catalyzed by (R)-1
reported kinetic resolutions of racemic alcohols involve direct
conversion of the hydroxyl group of one enantiomer of the
substrate into some other functional group and recovery of the
unchanged enantiomer with optical activity. For example, the
most commonly used method, acylative kinetic resolution,
5
involves the transformation of one enantiomer to an ester, and
the well-studied oxidative kinetic resolution method involves an
6
oxidation of one enantiomer to a ketone (Scheme 1a,b). We
recently discovered that the hydroxyl groups generated during
asymmetric hydrogenation of ketones promote the reduction of
7
ester groups in the substrates. On the basis of these results, we
envisioned that introducing a remote ester group into racemic
dialkyl carbinol substrates would facilitate their kinetic
resolution, leaving the hydroxyl groups unchanged in both
enantiomers; we refer to this strategy as ester-hydrogenation-
hydroxy esters and 1,5-diols are versatile building blocks for the
synthesis of natural products and pharmaceuticals. For example,
8
promoted kinetic resolution (EHKR) (Scheme 1c).
We chose racemic δ-alkyl-δ-hydroxy esters as substrates to
Received: October 25, 2014
test the EHKR strategy because optically active δ-alkyl-δ-
©
XXXX American Chemical Society
A
dx.doi.org/10.1021/ja510990v | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Scheme 3. Hydrogenation of Racemic δ-Methyl-δ-
valerolactone (rac-4) with (R)-1
Scheme 4. Enantioselective Syntheses of (+)-Civet and (R)-
Lisofylline
Figure 2. Plots of yields and ee values for the hydrogenation of rac-2a
with (R)-1.
they have been used for, or are potential key intermediates for,
9
the synthesis of chiral drugs such as lisofylline and bioactive
1
0
11
natural products such as aspergillide C, haliclamide,
1
2
13
spinosyn A, and caylobolide A (Figure 1), and the reported
methods for the synthesis of such functionalized chiral aliphatic
alcohols are laborious and lengthy 5or are limited to enzyme-
14
1
catalyzed reductions and acylations.
Racemic δ-alkyl-δ-hydroxy esters rac-2 were hydrogenated in
the presence of Ir−(R)-SpiroPAP ((R)-1), a chiral iridium
complex that has been shown to efficiently catalyze the
16
asymmetric hydrogenation of simple ketones. The reactions
produced chiral δ-alkyl-δ-hydroxy esters (S)-2 and 1,5-diols
(
R)-3 with high enantioselectivities (Scheme 2). The EHKR
method provides a practical and efficient kinetic resolution of
racemic aliphatic alcohols with enantiomeric excess (ee) values
1
7
of up to 99%, stereoselectivity factor (s) values of up to 194,
and turnover numbers of up to 52 000.
the yield of (R)-3a increased to 50% with a slight decrease in
enantioselectivity (94% ee); however, the ee of the recovered
(S)-2a was remarkably increased to 94% with an s value of 120.
Plots of the temporal dependence of the yield and ee of (R)-3a
showed that most of the (R)-2a was reduced to (R)-3a in the
first 30 min, after which time the reaction slowed down (Figure
2). The catalytic kinetic resolution method was highly efficient,
and the catalyst loading could be reduced to 0.001 mol %
without diminishing the yield or ee values of (R)-3a (46%
isolated yield, 52% conversion, turnover number = 52 000, 93%
ee) and recovered (S)-2a (44% isolated yield, 97% ee).
The hydrogenation of racemic ethyl 5-hydroxyhexanoate
rac-2a) was initially performed in EtOH under H (10 atm) at
room temperature with 0.1 mol % catalyst (R)-1 and 4 mol %
BuOK. The conversions and yields were determined by H
NMR analysis and the ee values by chiral HPLC. When the
hydrogenation was stopped after 30 min, the hydrogenated
product (R)-3a was obtained in 46% yield with 96% ee, and
unchanged alcohol (S)-2a was recovered in 54% yield with 77%
ee. After the reaction was continued for an additional 30 min,
(
2
t
1
a
Table 1. EHKR of Racemic 5-Alkyl-5-hydroxypentanoates (rac-2) with Catalyst (R)-1
2
3
b
c
d
c
d
entry
R
time (h)
conv (%)
yield (%)
ee (%)
yield (%)
ee (%)
s
1
2
3
4
5
6
7
8
9
Me (2a)
Et (2b)
1
50
52
52
50
48
53
54
50
53
49
47
44
43
45
49
43
44
45
44
49
94 (S)
95 (S)
96 (S)
95 (S)
90 (R)
98 (R)
99 (R)
97 (R)
94 (R)
94 (R)
46
47
47
48
44
49
50
46
48
47
94 (R)
94 (R)
96 (R)
96 (R)
96 (S)
97 (S)
94 (S)
91 (S)
93 (S)
95 (S)
120
126
194
188
142
194
128
110
94
2
n
Pr (2c)
2
nBu (2d)
iBu (2e)
iPr (2f)
Cy (2g)
2
3
6
5
MeO(CH ) (2h)
1
2
3
Me CHCH(CH ) (2i)
2
2
2 2
1
0
Ph (2j)
0.5
139
a
t
Reaction conditions: 1.0 mmol scale, [substrate] = 0.5 M, [KO Bu] = 0.02 M, 0.1 mol % (R)-1, ethanol (2.0 mL), room temperature (25−30 °C).
b
1
c
d
Determined by H NMR analysis. Isolated yields. Determined by HPLC using a chiral column.
B
dx.doi.org/10.1021/ja510990v | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
The reactions of racemic δ-alkyl-δ-hydroxy esters rac-2b−i
were also evaluated with catalyst (R)-1 (Table 1, entries 2−9).
The size of the δ-alkyl group of rac-2 had little effect on the
enantioselectivity of the reaction; the ee values of chiral 1,5-
diols 3b−i were 91−97% with s values ranging from 94 to 194.
However, a bulky δ-alkyl group lowered the reaction rate (the
required reaction time increased from 1 to 6 h). The ee values
of the recovered (R)- or (S)-2 were 90−99%, and higher
conversion generally led to higher ee values of the recovered
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This project was supported by the National Natural Science
Foundation of China, the National Basic Research Program of
China (973 Program) (2012CB821600), and the “111” Project
of the Ministry of Education of China (B06005).
(
R)- or (S)-2. This method was also efficient for the kinetic
resolution of racemic δ-aryl-δ-hydroxy esters. For example,
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ASSOCIATED CONTENT
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AUTHOR INFORMATION
Corresponding Authors
jhxie@nankai.edu.cn
■
2
(
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qlzhou@nankai.edu.cn
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dx.doi.org/10.1021/ja510990v | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX