Dynamic Kinetic Resolution of Phthalides via Asymmetric Transfer Hydrogenation: A Strategy Constructs 1,3-Distereocentered 3-(2-Hydroxy-2-arylethyl)isobenzofuran-1(3H)-one

Article abstract of DOI:10.1021/acs.orglett.5b02394

Dynamic kinetic resolution of phthalides through asymmetric transfer hydrogenation for the construction of 3-(2-hydroxy-2-arylethyl)isobenzofuran-1(3H)-one with 1,3-distereocenters has been developed. This procedure is carried out under a mild condition a

Full text of DOI:10.1021/acs.orglett.5b02394

Letter
pubs.acs.org/OrgLett
Dynamic Kinetic Resolution of Phthalides via Asymmetric Transfer
Hydrogenation: A Strategy Constructs 1,3-Distereocentered 3‑(2-
Hydroxy-2-arylethyl)isobenzofuran-1(3H)‑one
Tanyu Cheng, Qunqun Ye, Qiankun Zhao, and Guohua Liu*
Key Laboratory of Resource Chemistry of Ministry of Education, Shanghai Key Laboratory of Rare Earth Functional Materials,
Shanghai Normal University, Shanghai 200234, P. R. China
S
* Supporting Information
ABSTRACT: Dynamic kinetic resolution of phthalides through asymmetric transfer hydrogenation for the construction of 3-(2-
hydroxy-2-arylethyl)isobenzofuran-1(3H)-one with 1,3-distereocenters has been developed. This procedure is carried out under a
mild condition at 40 °C catalyzed with RuCl[(S,S)-TsDPEN](mesitylene) using HCOOH/Et3N (5:2) as a hydrogen source. A
variety of phthalides are smoothly transferred to provide optically pure phthalides with high yields, excellent enantioselectivities,
and acceptable diastereomeric ratios.
Scheme 1. DKR-ATH of Substituted Ketones
ynamic kinetic resolution through asymmetric transfer
Dhydrogenation (DKR-ATH) as a powerful methodology
can construct two stereocenters for the preparation of various
optically active compounds. To date, most successful examples
use α-substituted ketones as substrates, where well-established
DKR-ATH has led to the formation of various functionalized
alcohols with 1,2-distereocenters such as α-halo alcohols
(Lassaletta’s work, Scheme 1A1),1 α-substituted β-hydroxy
ketones/esters/amides,2 β-amino-α-hydroxy esters,3 and so
on.4,5 In some cases, 1,2-distereocenters can be further inducted
to produce three stereocenters under DKR-ATH process. One
prominent example reported by Johnson and colleagues6 can
provide chiral γ-butyrolactones with three stereocenters
(Johnson’s work, Scheme 1A2).
Despite significant efforts made in the development of DKR-
ATH, it is obvious that DKR-ATH biases to construct chiral
molecule with 1,2-distereocenters. Direct construction of chiral
molecule with 1,3-distereocenters is still difficult to be realized
in DKR-ATH process. Main limitation is due to rapid substrate
racemization at remote β-position of a carbonyl functionality. A
remarkable breakthrough is based on a biocatalytic strategy
developed by Peng’s group,7 where the enzyme ATA-036 as the
efficient catalyst enables an organic transformation of racemic
β-substituted ketone to optically pure molecules with 1,3-
distereocenters. Therefore, learning from biocatalysis in
biochemical processes, developing a DKR-ATH process to
realize an efficient construction of 1,3-distereocenters is highly
desirable; especially, construction of chiral phthalides with 1,3-
distereocenters could be applied potentially to synthesize a
wide range of biologically active compounds, such as γ-amino
alcohols,8 chromanols,9 flavanol9a and so on.10 Phthalides and
their analogues have been reported as showing a wide range of
biological active against several illnesses and physiological
Received: August 19, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02394
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Organic Letters
Letter
conditions, bronchitis, diarrhea, pneumonia, viral infections,
and tuberculosis.11 Therefore, constructing phthalides and
developing their analogues are meaningful work.
Table 1. Optimization of Reaction Conditions for DKR-
ATH of 3-(2-Oxo-2-phenylethyl)isobenzofuran-1(3H)-one
a
On the basis of typically efficient catalyst on various
asymmetric transfer hydrogenation,12,13 some chiral N-sulfony-
lated diamine-based (TsDPEN-based) organometallic com-
plexes have been explored for construction of chiral molecules
with 1,2-distereocenters in DKR-ATH process.6 Recently, we
also find that chiral RuCl[(S,S)-TsDPEN](mesitylene) displays
excellent catalytic efficiency in asymmetric transfer hydro-
genation of β-keto sulfones,14 α-halomethyl ketones,15 and α-
trifluoromethylimines.16 In this contribution, by utilizing the
benefit of RuCl[(S,S)-TsDPEN](mesitylene) on asymmetric
transfer hydrogenation, we realize a DKR-ATH of phthalides to
construct optically pure phthalides with 1,3-distereocenters. As
we envisaged, RuCl[(S,S)-TsDPEN](mesitylene) enables an
efficient DKR-ATH to afford various chiral phthalides with high
yields and excellent enantioselectivities under mild reaction
conditions.
To obtain the highly efficient DKR-ATH of phthalides to
various optically pure phthalides with 1,3-distereocenters, the
optimization of the reaction conditions were performed using
DKR-ATH of 3-(2-oxo-2-phenylethyl)isobenzofuran-1(3H)-
one 1a as a model reaction. On the basis of those extensively
studied chiral TsDPEN-based organometallic complexes in
ATH reaction, four representative organometallic complexes,
AreneRuTsDPEN (Arene = mesitylene and p-cymene, 4a and
4b) and Cp*MTsDPEN (Cp* = pentamethylcyclopentadiene,
M = Rh and Ir, 4c and 4d), were screened to compare their
catalytic performances at first, where the DKR-ATH of 3-(2-
oxo-2-phenylethyl)isobenzofuran-1(3H)-one 1a was carried out
through the use of CH2Cl2 as solvent and HCOOH/Et3N (5:2)
as hydrogen source according to the reported method.4b As
shown in Table 1, it was found that, in the case of 4a as a
catalyst, DKR-ATH of 1a could afford the chiral products of 2a
and 3a with 97% total yield, 99% ee value for 2a, and good dr
value. Such a result was better than that obtained with the
catalysts 4b−4d (Table 1, entry 1 versus entries 2−4),
demonstrating that 4a was the best catalyst in this catalysis
system. Furthermore, the optimization of the polar solvents
confirmed that CH2Cl2 was the optimal reaction solvent (Table
1, entry 1 versus entries 5−10). Moreover, through the further
optimization of amount of 4a and reaction temperature, it was
found that the increased amount of 4a and the enhanced
reaction temperature did not affect the reaction results (Table
1, entries 11 and 13), while the decreased amount of 4a and the
low reaction temperature reduced the total yields (Table 1,
entries 12 and 14). As a result, in the presence of 0.20 mol % of
(S,S)-TsPDEN/[RuCl2(mesitylene)]2 4a, an optimal reaction
condition in this DKR-ATH was the use of HCOOH/Et3N
(5:2) as a hydrogen resource, CH2Cl2 as a solvent at 40 °C of
reaction temperature.
b
c
c
entry cat.
solvent
yield of 2 + 3 (%) ee (%) of 2 dr of 2/3
1
4a
4b
4c
4d
4a
4a
4a
4a
4a
4a
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
i-PrOH
MeOH
DMF
97
92
90
82
90
85
trace
96
82
90
97
92
98
73
99
97
90
76
47
90
-
82/18
80/20
72/28
60/40
60/40
76/24
-
2
3
4
5
6
7
8
98
99
97
99
99
99
88
58/42
53/47
50/50
83/17
80/20
80/20
72/28
9
1,4-dioxane
THF
10
11
12
13
14
d
4a
4a
4a
4a
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
e
f
g
a
1.0 mmol 1a, 2.0 μmol catalyst and 0.5 mL HCOOH/Et3N (5:2)
were added into CH2Cl2 (2.0 mL) and the mixture was stirred at 40
°C for 3 h. Isolated yield. Determined by HPLC analysis using a
chiral stationary phase. Data was obtained by the use of 0.4 mol % of
4a. Data was obtained by the use of 0.1 mol % of 4a. The reaction
temperature was at 50 °C. The reaction temperature was at 30 °C.
b
c
d
e
f
g
postions of Ar group (Table 2, entries 1−13). Moreover, other
Ar groups at 3-position of phthalides (such as naphthyl, thienyl,
and furyl groups) also could be transformed into the
corresponding chiral products with desirable results in this
DKR-ATH process (Table 2, entries 14−16). These observa-
tions indicate that this DKR-ATH was suitable for constructing
a wide scope of chiral phthalides with 1,3-distereocenters.
To determine the synthetic utility and the stereochemistry of
chiral products, the DKR-ATH of 1d was performed on gram-
scale level (Figure 1), where 1.0 g of 1d could be transferred to
4-((S)-1-hydroxy-2-((R)-3-oxo-1,3-dihydroisobenzofuran-1-yl)-
ethyl)benzonitrile 2d with 99% ee (70/30 dr), where its
recrystallization could afford the enantiomerically pure 2d in
68% yield under the above reaction condition. More
importantly, the absolute stereochemistry of 2d could also be
determined as (S,R)-isomer configuration proved by its X-ray
crystallographic analysis as shown in Figure 1. Several works are
studying the catalytic mechanism of the asymmetric hydro-
genation for acetophenone,17 a simple aromatic ketone, with
the catalyst 4b. Herein, we propose that this DKR-ATH
appears to proceed through that similar catalytic cycle (see the
Supporting Information, proposed mechanism).
Having established the efficient DKR-ATH of 3-(2-oxo-2-
phenylethyl)isobenzofuran-1(3H)-one, we further investigated
its general applicability with a series of analogues of 1a. As
shown in Table 2, various phthalides 1a−1p could be
transformed into corresponding chiral alcohols 2 and 3 in
high yields (more than 90%) with excellent enantioselectivity
(more than 99% ee) and good diastereomeric ratios (up to 90/
10 dr) under above optimal reaction condition. It was also
found that electronic and steric properties of substituents at the
Ar group did not affect their enantioselectivities, regardless of
the electro-donating or -withdrawing substituents at 2-,3-,4-
In summary, we find that the further exploration of
RuCl[(S,S)-TsDPEN](mesitylene) enables a highly efficient
DKR-ATH of phthalides for the synthesis of 3-(2-hydroxy-2-
arylethyl)isobenzofuran-1(3H)-ones with 1,3-distereocenters,
B
DOI: 10.1021/acs.orglett.5b02394
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Crystallographic data of compound 2d (CIF)
Table 2. DKR-ATH of 3-Substituted Phthalides Catalyzed by
4a
a
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: ghliu@shnu.edu.cn
Notes
The authors declare no competing financial interest.
b
c
c
entry
2
Ar
yield of 2 + 3 (%) ee (%) of 2 dr of 2/3
ACKNOWLEDGMENTS
■
1
2a
2b
2c
2d
2e
2f
Ph
97
96
96
90
95
96
94
94
95
97
97
93
93
96
94
91
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
82/18
77/23
77/23
74/26
69/31
78/22
80/20
71/29
73/27
71/29
77/23
73/27
90/10
77/23
78/22
70/30
We are grateful to the National Nature Science Foundation of
China (21402120), the Shanghai Science and Technologies
Development Fund (13ZR1458700), CSIRT (IRT1269), the
Shanghai Municipal Education Commission (13CG48, Young
Teacher Training Project), and Shanghai Key Laboratory of
Chemical Biology Fund Project for financial support.
2
4-FPh
3
4-ClPh
4
4-CNPh
4-MePh
4-iPrPh
4-MeOPh
3-FPh
5
6
7
2g
2h
2i
8
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General information, typical experimental procedures,
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Organic Letters
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Org. Lett. XXXX, XXX, XXX−XXX