Synthesis of Enantiopure γ-Lactones via a RuPHOX-Ru Catalyzed Asymmetric Hydrogenation of γ-Keto Acids

Article abstract of DOI:10.1002/adsc.201801186

A RuPHOX?Ru catalyzed asymmetric hydrogenation of γ-keto acids has been developed, affording the corresponding enantiopure γ-lactones in high yields and with up to 97% ee. The reaction could be performed on a gram scale with a relatively low catalyst loading (up to 10000 S/C) under the indicated reaction conditions and the resulting products can be transformed to several enantiopure building blocks, biologically active compounds and enantiopure drugs. (Figure presented.).

Full text of DOI:10.1002/adsc.201801186

Title: Synthesis of Enantiopure γ-Lactones via a RuPHOX-Ru
Catalyzed Asymmetric Hydrogenation of γ-Keto Acids
Authors: Jing Li, Yujie Ma, Yufei Lu, Yangang Liu, Delong Liu, and
Wanbin Zhang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801186
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10.1002/adsc.201801186
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Synthesis of Enantiopure γ-Lactones via a RuPHOX-Ru
Catalyzed Asymmetric Hydrogenation of γ-Keto Acids
Jing Li,a Yujie Ma,a Yufei Lu,a Yangang Liu,a Delong Liu,a,* and Wanbin Zhanga,b,*
a
Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong
University, 800 Dongchuan Road, Shanghai 200240, P. R. China
School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai
b
200240, P. R. China
Fax: (+)86-21-54743265; Phone: (+)86-21-34207176; E-mail: dlliu@sjtu.edu.cn; wanbin@sjtu.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
asymmetric
oxidation,[6]
hydroboration,[7]
Abstract.
A
RuPHOX-Ru catalyzed asymmetric
hydrogenation of γ-keto acids has been developed, hydrosilylation,[8] transfer hydrogenation,[9] and
enzyme catalysis,[10] etc. Generally, asymmetric
affording the corresponding enantiopure γ-lactones in high
yields and with up to 97% ee. The reaction could be
performed on a gram scale with a relatively low catalyst
loading (up to 10000 S/C) under the indicated reaction
conditions and the resulting products can be transformed to
several enantiopure building blocks, biologically active
compounds and enantiopure drugs.
hydrogenation is undoubtedly an efficient pathway
for the construction of enantiopure γ-lactones because
of its high efficiency, environmental friendliness, and
low economic cost (Scheme 1).[11 14] In 1990, Noyori
-
and co-workers developed an asymmetric
hydrogenation of γ-keto esters by using the BINAP-
Ru catalyst, providing high enantioselectivity for
substrates bearing alkyl groups (Scheme 1, up).[12]
However, harsh reaction conditions (100 atm) and a
long reaction time (110 h) were needed to ensure the
completion of the reaction. Adopting a similar
catalytic system to that mentioned above (except
using RuCl3 as a metal salt), the Vinogradov group
were able to promote the reaction using a somewhat
lower H2 pressure (60 atm) but high reaction
temperature (60 oC).[13a] Although excellent
enantioselectivities were obtained, a long reaction
time was still needed. Sada and Sannicolo carried out
this reaction by using a diphosphine ligand with an
Keywords: Enantiopure γ-lactone; RuPHOX-Ru;
Asymmetric hydrogenation; γ-Keto acid
Introduction
The enantiopure γ-lactone skeleton is present in
numerous natural products, biologically active
compounds and drugs,[1] such as insect pheromones,[2]
(+)-harzialactone A[3] and plakolide A,[4] etc. (Figure
1, up). The enantiopure γ-lactone motif is also found
in important precursors for the synthesis of many
enantiopure drugs. For example, it can be transferred
to several norepinephrine reuptakes inhibiting
antidepressants which treat psychiatric disorders
(Figure1, down).[5]
atropisomeric
biheteroaromatic
backbone.[13b]
Nevertheless, harsh reaction conditions (100 bar) and
a long reaction time (168 h) were also required. In
addition, a solution of HCl in alcohol has been used
in all of the above reactions in order to improve
reaction activities, resulting in corrosion of the
stainless-steel autoclave. Furthermore, the above
reactions often give a mixture of products containing
cyclic γ-lactones and acyclic γ-hydroxy esters, and an
additional cyclization is needed to obtain the uniform
cyclic γ-lactones. Just recently, Ohkuma and co-
workers disclosed a P,N-Ru-complex catalyzed
asymmetric hydrogenation of γ-keto esters, with the
corresponding γ-hydroxy esters as the main products
(including γ-lactones) being obtained in high yields
and excellent enantioselectivities (Scheme 1,
middle).[14] The mixed products were then subjected
to a further lactonization with t-BuOK as a base to
Figure 1. Enantiopure γ-lactones and their transformation
Many methodologies have been reported for the
synthesis of enantiopure γ-lactones, including
1
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10.1002/adsc.201801186
Advanced Synthesis & Catalysis
deliver terminal enantiopure γ-lactones. By using γ-
keto esters as substrates, harsh reaction conditions
and/or an additional cyclization is generally needed
for the synthesis of enantiopure γ-lactones. Therefore,
the development of a reaction system to deliver
enantiopure γ-lactones directly via the use of
alternative substrates, e.g. γ-keto acids, under basic
reaction conditions, is essential.
shown in Table 1, MeOH was first used as a solvent
and the desired product (R)-5-phenyldihydrofuran-
2(3H)-one (enantiopure γ-lactone 2a) was obtained in
poor conversion but with 94% ee (entry 1). The use
of EtOH increased the conversion and provided a
higher enantioselectivity than that of MeOH (entry 2).
When n-PrOH was used as
a
solvent, the
corresponding product 2a was obtained with 96%
conversion and 94% ee (entry 3). The substrate was
fully transformed to the desired product with 94% ee
when the reaction was carried out in i-PrOH (entry 4).
Our group has previously developed a planar
enantiopure ruthenocenyl phosphino-oxazoline-
ruthenium complex (RuPHOX-Ru), which has shown
promising catalytic activity in several asymmetric
reactions.[15-16] Specifically, RuPHOX-Ru has been
employed as an efficient enantiopure catalyst in
several asymmetric hydrogenations with excellent
asymmetric catalytic behavior.[16] Herein, we report
an efficient RuPHOX-Ru catalyzed asymmetric
hydrogenation of γ-keto acids for the synthesis of
enantiopure γ-lactones (Scheme 1, down).
For
comparison,
low
conversion
and
enantioselectivity were observed when n-BuOH was
employed in the above reaction (entry 5).
Table 1. Screening of solvent.[a]
Entry
Solvent
Yield (%)[b]
Ee (%)[c,d]
MeOH
EtOH
13
90
96
>99
89
94
96
94
94
92
1
2
3
4
5
n-PrOH
i-PrOH
n-BuOH
[a]
Conditions: 1a (0.3 mmol), RuPHOX-Ru (1 mol%),
KOH (2.0 equiv), and solvent (3 mL) under 20 bar
hydrogen pressure at RT for 24 h.
[b] Determined by 1H NMR.
[c] Determined by HPLC analysis using the Chiralcel AS-H
column.
[d]
The absolute configuration of 2a was determined as R-
configuration by comparing the specific rotation with
reported data.[9b]
The effect of different bases on the reaction was
then investigated (Table 2). Several strong inorganic
bases were examined (entries 1-4). It was shown that
Table 2. Screening of base.[a]
Entry
Base
Conv (%)[b]
Ee (%)[c,d]
LiOH•H2O
NaOH
KOH
t-BuOK
KOH
50
96
>99
>99
43
90
91
94
92
92
92
-
1
2
3
4
Scheme 1. Asymmetric hydrogenation of γ-aryl keto
acids/esters.
5[e]
6[f]
7
KOH
Et3N
>99
NR[g]
[a]
Using the optimal reaction conditions shown in Table 1
with i-PrOH as a solvent.
Results and Discussion
[b-d] As mentioned in Table 1.
[e] Using 1.0 equiv of base.
Our initial experiments began with the asymmetric
hydrogenation of 4-oxo-4-phenylbutanoic acid (γ-
keto acid 1a) using RuPHOX-Ru as a catalyst. As
[f] Using 3.0 equiv of base.
[g] “NR” means no reaction occurred.
2
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10.1002/adsc.201801186
Advanced Synthesis & Catalysis
reaction with KOH as the base provided the best
result (entry 3). When the amount of KOH was
reduced, a sharp decrease in reaction activity was
observed (entry 5). Additionally, increasing the
amount of KOH did not influence the reaction
outcome (entry 6). To our surprise, no reaction
occurred when an organic base such as Et3N was used
instead of inorganic bases (entry 7). Therefore, KOH
was found to be the most suitable base and was used
in subsequent screening.
The asymmetric hydrogenation of a substrate with an
i-Bu group at the p-position of the phenyl ring also
provided 95% yield and 88% ee (2i). Next, 1 bearing
different electron-withdrawing substituents at the
phenyl ring, was examined. Substrates bearing a F
atom located at the m or p-positions of the phenyl
ring were first examined. A similar trend was
observed for the asymmetric hydrogenation of 1
bearing electron-withdrawing groups and substrates
possessing m-substituents (2j) provided higher ee
values than that of substrates possessing p-
substituents (2k). Subsequently, substrates bearing
electron-withdrawing groups on the m-position of the
phenyl ring were examined, with the desired products
being obtained in excellent yields and approximately
90% ee (2l2n). When the reactions of substrates
bearing two electron-donating groups on the phenyl
ring were carried out, the products were obtained in
high yields and excellent enantioselectivities (2o and
2p). 2p with two t-Bu groups on the phenyl ring was
obtained in quantitative yield and 97% ee. The
reaction of a substrate bearing two electronically
different groups on the phenyl ring was also carried
out, with the hydrogenated products being obtained in
excellent yield and good enantioselectivity (2q).
Finally, a naphthalene substrate also provided its
corresponding product in high yield and
enantioselectivity (2r, up to 96% yield and 89% ee).
Subsequently, we carried out the reaction under a
low hydrogen pressure with the aim of using milder
reaction conditions (Table 3). Similar results were
obtained when the reaction was conducted at a high
hydrogen pressure (entry 1). We thus focused our
attention on screening the reaction conditions using a
low hydrogen pressure. It was found that lowering the
hydrogen pressure had no influence on the
asymmetric behavior of the hydrogenation (entries 2-
4) To our delight, almost the same catalytic behavior
was observed when the hydrogenation was carried
out under 6 bar hydrogen pressure (entry 4). Further
decreasing the hydrogen pressure to 2 bar resulted in
only 45% conversion and 60% ee (entry 5).
Table 3. Screening of hydrogen pressure.[a]
Table 4. Scope of substrates 1.[a]
Entry
H2 (bar)
Conv (%)[b]
Ee (%)[c,d]
50
20
>99
>99
>99
>99
45
93
94
95
96
60
1
2
3
4
5
10
6
2
[a]
Using the optimal reaction conditions shown in Table 1
with i-PrOH as a solvent. [b-d] As mentioned in Table 1.
With the optimized reaction conditions in hand, the
scope of hydrogenation substrates was investigated
(Table 4). Firstly, the asymmetric hydrogenation of
the potassium salt of 1a was carried out under the
optimal reaction conditions in the presence of 1 equiv
of KOH. The desired product 2a was obtained in
quantitative yield and 94% ee. Then, 1 bearing
different electron-donating substituents at the phenyl
ring, was examined. Substrates with a Me group
located at the o, m or p-positions of the phenyl ring
were reduced, with the desired products being
obtained in excellent yields and with ees of
approximately 90% (2b2d). Substrates possessing a
m-Me substituent provided the corresponding
products with higher ee (2c) compared with their o-
and p-substituted counterparts (2b and 2d). We,
therefore, synthesized different substrates with
electron-donating groups at the m-position of the
phenyl ring. To our delight, the desired products were
obtained in quantitative yields and ees higher than
90% were obtained for all of the reactions (2e2h).
[a] Using the optimal reaction conditions shown in Table 1;
Ees were determined by chiral HPLC analysis of 2 using
AS-H and IC-3 column; Absolute configuration of 2 was
determined as R-configuration by comparing the specific
rotation with 2a.
[b] The reaction was carried out using the potassium salt of
1a under the optimal reaction conditions in the presence of
1 equiv of KOH.
3
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10.1002/adsc.201801186
Advanced Synthesis & Catalysis
Experimental Section
Unfortunately, no reaction occurred when several
alkyl substituted keto esters, such as those bearing
methyl, tert-butyl or cyclohexyl groups, were used.
General: All hydrogenation reactions were
performed in an autoclave under an atmosphere of
hydrogen, and the workup was carried out in air.
Solvents were degassed using standard procedures.
Commercially available reagents were used without
further purification. Column chromatography was
performed using 100-200 mesh silica gel. Melting
points were measured with SGW X-4 micro melting
point apparatus and the thermometer was uncorrected.
NMR spectra were recorded on a Varian MERCURY
plus-400 spectrometer with TMS as an internal
standard. Enantioselectivity was measured by a high-
performance liquid chromatography (HPLC) using
Daicel Chiralcel AS-H or IC-3 column with n-
hexane/i-PrOH as eluent.
To examine the efficiency of the catalyst system,
the reaction was carried out on a gram scale with a
low catalyst loading (Scheme 3). Thus, 1a (5.30 g)
was subjected to the optimal reaction conditions
using a 0.01 mol% catalyst dosage (S/C = 10000)
under 50 bar hydrogen pressure. The reaction went to
completion within 72 h at RT, providing the desired
product 2a in 97% yield with somewhat loss of
enantioselectivity (91% ee).
2a can be transformed into several different
enantiopure building blocks, biologically active
compounds, and drugs. For example, 2a could be
reduced to diol 3 in 90% yield and 88% ee, which is
an important building block in organic synthesis.[17]
After aminolysis with aniline, the ring-opening
product 4 of 2a, a valuable N-aryl amide scaffold,
was obtained in good yield and ee.[18] Fluoxetine
General
procedure
for
the
asymmetric
hydrogenation
hydrochloride,
a
selective serotonin reuptake
In a nitrogen-filled glovebox, a hydrogenation tube
was charged with a stirring bar, 1 (0.3 mmol),
RuPHOX-Ru (5.2 mg, 1 mol%), KOH (33.7 mg, 2.0
equiv), PPh3 (1.0 mg, 1 mol%), and MeOH (3 mL)
were then injected into the hydrogenation tube using
a syringe. The hydrogenation tube was then put into
an autoclave. The system was evacuated and filled
with hydrogen 3 times. The autoclave was then
charged with hydrogen to 6 bar hydrogen pressure,
and the reaction mixture was stirred at RT for 24 h.
After releasing the hydrogen, the reaction mixture
was acidified with 3 M HCl solution and extracted
with EtOAc (3  5 mL). The extract was dried over
anhydrous Na2SO4 and concentrated on a rotary
evaporator. The conversion of the substrate was
determined by 1H NMR analysis and the ee value was
determined by HPLC using the Chiralcel AS-H or IC-
3 column.
inhibitor developed by Eli Lilly, was approved by
FDA in 1987.[19] The pivotal step to construct
fluoxetine involves the preparation of the key
intermediate 5 (Scheme 2). Thus, (R)-2a was
dissolved in EtOH, followed by the addition of
hydrazine hydrate in one portion, yielding the key
intermediate 5 in 90% yield and with 99% ee.
The corresponding racemic product 2 was obtained
using NaBH4 as a reductant in MeOH at RT.
Scheme 2. Transformations of (R)-2a
(R)-5-Phenyldihydrofuran-2(3H)-one
(2a)[20]
:
Conclusion
1
Colorless oil (48.2 mg, 99%). H NMR (400 MHz,
CDCl3): δ 7.39–7.30 (m, 5H), 5.48 (t, J = 6.8 Hz, 1H),
2.68–2.58 (m, 3H), 2.23–2.11 (m, 1H); 13C NMR
(100 MHz, CDCl3): δ 176.9, 139.3, 128.7, 128.4,
125.2, 81.2, 30.9, 28.9; HPLC (Chiralcel AS-H, n-
hexane/i-PrOH = 75 : 25, UV = 210 nm, flow rate =
0.8 mL/min) tR1 = 12.98 min (major) and tR2 = 15.07
min (minor); ee = 96%; [α]2D7 = +16.42 (c 0.55,
CHCl3).
In conclusion, we have developed an efficient
RuPHOX-Ru catalyzed asymmetric hydrogenation of
γ-aryl ketone acids, with the corresponding
enantiopure γ-lactones being obtained in 95~99%
yield and with 81~97% ee. The reaction could be
easily performed on a gram scale with a relatively
low catalyst loading (up to 10000 S/C) under the
indicated reaction conditions. The resulting products
can be transformed into several enantiopure building
blocks, biologically active compounds and
enantiopure drugs. The current catalytic system
employing the RuPHOX-Ru complex as an
enantiopure catalyst provides an efficient pathway for
the synthesis of enantiopure γ-lactones and their
derivatives.
(R)-5-(o-Tolyl)dihydrofuran-2(3H)-one
(2b)[14]
:
1
Colorless oil (50.2 mg, 95%). H NMR (400 MHz,
CDCl3): δ 7.32–7.16 (m, 4H), 5.71–5.66 (m, 1H),
2.69–2.60 (m, 3H), 2.31 (s, 3H), 2.15–2.02 (m, 1H);
13C NMR (100 MHz, CDCl3): δ 177.1, 137.5, 134.2,
130.7, 128.1, 126.4, 124.1, 78.8, 29.5, 28.6, 18.9;
4
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10.1002/adsc.201801186
Advanced Synthesis & Catalysis
HPLC (Chiralcel AS-H, n-hexane/i-PrOH = 95 : 5,
UV = 210 nm, flow rate = 0.8 mL/min) tR1 = 16.63
min (major) and tR2 = 18.90 min (minor); ee = 84%;
[α]2D7 = +51.85 (c 0.50, CHCl3).
1H); 13C NMR (100 MHz, CDCl3): δ 176.8, 159.0,
141.0, 136.6, 129.9, 128.5, 128.0, 127.4, 117.6, 114.6,
111.7, 80.9, 70.0, 30.8, 28.8; IR (KBr) cm-1: 2359,
2341, 1778, 1766, 1462, 1261, 1022, 798; HR-MS
(ESI): m/z=291.0997, calcd. for C17H16O3 [M+Na]+:
291.0990; HPLC (Chiralcel IC-3, n-hexane/i-PrOH =
[20]
(R)-5-(m-Tolyl)dihydrofuran-2(3H)-one (2c)
:
1
Colorless oil (50.7 mg, 96%). H NMR (400 MHz,
CDCl3): δ 7.27–7.24 (m, 1H), 7.13–7.09 (m, 3H),
5.47–5.44 (m, 1H), 2.68–2.57 (m, 3H), 2.35 (s, 3H),
2.23–2.13 (m, 1H); 13C NMR (100 MHz, CDCl3): δ
176.9, 139.3, 138.5, 129.1, 128.6, 125.8, 122.2, 81.2,
30.9, 28.9, 21.3; HPLC (Chiralcel AS-H, n-hexane/i-
PrOH = 80 : 20, UV = 210 nm, flow rate = 0.8
mL/min) tR1 = 14.87 min (major) and tR2 = 19.24 min
(minor); ee = 92%; [α]2D7 = +18.69 (c 0.25, CHCl3).
90 : 10, UV = 210 nm, flow rate = 0.8 mL/min) tR1
=
52.80 min (major) and tR2 = 57.05 min (minor); ee =
91%; [α]2D7 = +10.47 (c 0.50, CHCl3).
(R)-5-(3-Propoxyphenyl)dihydrofuran-2(3H)-one
o
(2h): White solid (65.4 mg, 99%). Mp 121–123 C;
1H NMR (400 MHz, CDCl3): δ 7.27–7.23 (m, 1H),
6.85–6.81 (m, 3H), 5.46–5.43 (m, 1H), 4.58–4.49 (m,
1H), 2.67–2.56 (m, 3H), 2.21–2.09 (m, 1H), 1.31 (d,
J = 5.6 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ
176.9, 158.1, 140.9, 129.8, 117.1, 115.4, 112.7, 81.0,
69.8, 30.9, 28.8, 21.9; IR (KBr) cm-1: 2977, 2933,
1781, 1603, 1584, 1489, 1449, 1384, 1373, 788, 699;
HR-MS (ESI): m/z=221.1179, calcd. for C13H16O3
[M+H]+: 221.1178; HPLC (Chiralcel AS-H, n-
hexane/i-PrOH = 75 : 25, UV = 210 nm, flow rate =
0.8 mL/min) tR1 = 13.00 min (major) and tR2 = 15.03
min (minor); ee = 94%; [α]2D7 = +13.58 (c 0.60,
CHCl3).
[20]
(R)-5-(p-Tolyl)dihydrofuran-2(3H)-one (2d)
:
1
Colorless oil (50.2 mg, 95%). H NMR (400 MHz,
CDCl3): δ 7.23–7.11 (m, 4H), 5.48–5.40 (m, 1H),
2.66–2.54 (m, 3H), 2.33 (s, 3H), 2.21–2.07 (m, 1H);
13C NMR (100 MHz, CDCl3): δ 177.0, 138.3, 136.3,
129.4, 125.3, 81.3, 30.9, 29.0, 21.1; HPLC (Chiralcel
AS-H, n-hexane/i-PrOH = 75 : 25, UV = 210 nm,
flow rate = 0.8 mL/min) tR1 = 11.97 min (major) and
tR2 = 14.45 min (minor); ee = 81%; [α]2D7 = +13.85 (c
0.30, CHCl3).
(R)-5-(4-Isobutylphenyl)dihydrofuran-2(3H)-one
(2i): Colorless oil (62.2 mg, 95%). H NMR (400
(R)-5-(3-Methoxyphenyl)dihydrofuran-2(3H)-one
1
1
(2e) [20]: Colorless oil (57.1 mg, 99%). H NMR (400
MHz, CDCl3): δ 7.21 (d, J = 7.6 Hz, 2H), 7.14 (d, J =
7.6 Hz, 2H), 5.47–5.44 (m, 1H), 2.64–2.58 (m, 3H),
2.45 (d, J = 6.8 Hz, 2H), 2.23–2.12 (m, 1H), 1.88–
1.78 (m, 1H), 0.87 (d, J = 6.4 Hz, 6H); 13C NMR
(100 MHz, CDCl3): δ 177.0, 142.1, 136.4, 129.4,
125.1, 81.3, 45.0, 30.8, 30.1, 29.0, 22.3; IR (KBr) cm-
1: 2980, 2931, 1770, 1604, 1585, 1455, 1393, 1361,
786, 699; HR-MS (ESI): m/z=219.1385, calcd. for
C14H18O2 [M+H]+: 219.1385; HPLC (Chiralcel AS-H,
n-hexane/i-PrOH = 75 : 25, UV = 210 nm, flow rate =
0.8 mL/min) tR1 = 9.06 min (major) and tR2 = 10.69
min (minor); ee = 88%; [α]2D7 = +13.74 (c 0.50,
CHCl3).
MHz, CDCl3): δ 7.30–7.24 (m, 1H), 6.88–6.85 (m,
3H), 5.48–5.45 (m, 1H), 3.79 (s, 3H), 2.68–2.58 (m,
3H), 2.23–2.10 (m, 1H); 13C NMR (100 MHz,
CDCl3): δ 176.8, 159.8, 141.1, 129.8, 117.3, 113.8,
110.7, 80.9, 55.2, 30.9, 28.8; HPLC (Chiralcel AS-H,
n-hexane/i-PrOH = 75 : 25, UV = 210 nm, flow rate =
0.8 mL/min) tR1 = 16.63 min (major) and tR2 = 19.85
min (minor); ee = 93%; [α]2D7 = 19.54 (c +0.65,
CHCl3).
(R)-5-(3-Ethoxyphenyl)dihydrofuran-2(3H)-one
1
(2f): Colorless oil (60.6 mg, 98%). H NMR (400
MHz, CDCl3): δ 7.28–7.27 (m, 1H), 6.87–6.84 (m,
3H), 5.49–5.44 (m, 1H), 4.02 (q, J = 6.8, 12.8 Hz,
2H ), 2.66–2.58 (m, 3H), 2.22–2.10 (m, 1H), 1.39 (t,
J = 6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
176.8, 159.2, 140.9, 129.8, 117.2, 114.2, 111.3, 81.0,
63.4, 30.9, 28.8, 14.7; IR (KBr) cm-1: 2972, 2926,
2867, 1779, 1462, 1380, 1373, 879, 715; HR-MS
(ESI): m/z=207.1025, calcd. for C12H14O3 [M+H]+:
207.1021; HPLC (Chiralcel AS-H, n-hexane/i-PrOH
= 75 : 25, UV = 210 nm, flow rate = 0.8 mL/min), tR1
= 16.46 min (major) and tR2 = 19.65 min (minor), ee
= 92%; [α]2D7 = +15.50 (c 0.75, CHCl3).
(R)-5-(3-Fluorophenyl)dihydrofuran-2(3H)-one
1
(2j): Colorless oil (52.4 mg, 97%). H NMR (400
MHz, CDCl3): δ 7.35–7.30 (m, 1H), 7.08–6.97 (m,
3H), 5.50–5.45 (m, 1H), 2.69–2.60 (m, 3H), 2.20–
13
2.11 (m, 1H); C NMR (100 MHz, CDCl3): δ 176.4,
162.9 (d, J = 245.6 Hz), 141.9 (d, J = 7.3 Hz), 130.4
(d, J = 8.1 Hz), 120.7 (d, J = 2.9 Hz), 115.2 (d, J =
20.9 Hz), 112.2(d, J = 22.6 Hz), 80.2, 30.8, 28.6; IR
(KBr) cm-1: 2970, 1720, 1592, 1490, 1451, 1269,
1140, 1024, 911, 789, 694; HR-MS (ESI):
m/z=181.0665, calcd. for C10H9FO2 [M+H]+:
181.0659; HPLC (Chiralcel AS-H, n-hexane/i-PrOH
(R)-5-(3-(Benzyloxy)phenyl)dihydrofuran-2(3H)-
one (2g): White solid (79.7 mg, 99%). Mp 56–58 oC;
1H NMR (400 MHz, CDCl3): δ 7.42–7.35 (m, 4H),
7.33–7.24 (m, 2H), 6.93–6.88 (m, 3H), 5.49–5.44 (m,
1H), 5.05 (s, 2H), 2.67–2.59 (m, 3H), 2.22–2.09 (m,
= 95 : 5, UV = 210 nm, flow rate = 0.8 mL/min) tR1
=
14.40 min (major) and tR2 = 17.50 min (minor); ee =
90%; [α]2D7 = +27.10 (c 0.60, CHCl3).
(R)-5-(4-Fluorophenyl)dihydrofuran-2(3H)-one
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801186
Advanced Synthesis & Catalysis
1
(2k)[20]: Colorless oil (51.9 mg, 96%). H NMR (400
MHz, CDCl3): δ 7.28 (t, J = 6.0 Hz, 2H), 7.04 (t, J =
8.4 Hz, 2H), 5.46–5.43 (m, 1H), 2.68–2.56 (m, 3H),
2.19–2.09 (m, 1H); 13C NMR (100 MHz, CDCl3): δ
176.6, 162.6 (d, J = 245.8 Hz), 135.0 (d, J = 3.1 Hz),
127.2 (d, J = 8.3 Hz), 115.7 (d, J = 21.6 Hz), 80.6,
31.0, 29.0; HPLC (Chiralcel AS-H, n-hexane/i-PrOH
1462, 1217, 1138, 848, 807, 703; HR-MS (ESI):
m/z=191.1069, calcd. for C12H14O2 [M+H]+:
191.1072; HPLC (Chiralcel AS-H, n-hexane/i-PrOH
= 75 : 25, UV =210 nm, flow rate = 0.8 mL/min) tR1
=
10.23 min (major) and tR2 = 13.17 min (minor); ee =
92%; [α]2D7 = +6.92 (c 0.15, CHCl3).
(R)-5-(3,5-Di-tert-butylphenyl)dihydrofuran-
= 98 : 2, UV = 210 nm, flow rate = 0.8 mL/min) tR1
16.82 min (major) and tR2 = 19.60 min (minor); ee =
81%.
=
2(3H)-one (2p): White solid (81.5 mg, 99%). Mp 96–
o
1
98 C; H NMR (400 MHz, CDCl3): δ 7.38 (s, 1H),
7.13 (s, 2H), 5.50–5.46 (m, 1H), 2.67–2.62 (m, 3H),
2.26–2.14 (m, 1H), 1.30 (s, 18H); 13C NMR (100
MHz, CDCl3): δ 177.1, 151.3, 138.3, 122.5, 119.4,
82.1, 34.9, 31.4, 31.0, 29.2; IR (KBr) cm-1: 2962,
2918, 2848, 1781, 1595, 1458, 1437, 1363, 1260, 843,
799, 686; HR-MS (ESI): m/z = 275.2006, calcd. for
C18H26O2 [M+H]+: 275.2011; HPLC (Chiralcel AS-H,
n-hexane/i-PrOH = 90 : 10, UV = 210 nm, flow rate =
0.8 mL/min) tR1 = 7.35 min (major) and tR2 = 8.13
min (minor), ee = 97%; [α]2D7 = +9.91 (c 0.52, CHCl3).
(R)-5-(3-Chlorophenyl)dihydrofuran-2(3H)-one
1
(2l)[9a]: Colorless oil (57.8 mg, 98%). H NMR (400
MHz, CDCl3): δ 7.34–7.29 (m, 3H), 7.23–7.19 (m,
1H), 5.49–5.44 (m, 1H), 2.70–2.61 (m, 3H), 2.20–
2.07 (m, 1H); C NMR (100 MHz, CDCl3): δ 176.4,
141.4, 134.7, 130.1, 128.5, 125.4, 123.2, 80.1, 30.8,
28.7; HPLC (Chiralcel AS-H, n-hexane/i-PrOH = 90 :
13
10, UV = 210 nm, flow rate = 0.8 mL/min) tR1
83.77 min (major) and tR2 = 114.60 min (minor); ee =
=
90%; [α]2D7 = +19.57 (c 0.50, CHCl3).
(R)-5-(3-Fluoro-5-methoxyphenyl)dihydrofuran-
1
2(3H)-one (2q): Colorless oil (60.5 mg, 96%). H
(R)-5-(3-(Trifluoromethyl)phenyl)dihydrofuran-
2(3H)-one (2m): Colorless oil (67.0 mg, 97%). (400
MHz, CDCl3): δ 7.61–7.57 (m, 2H), 7.51–7.48 (m,
2H), 5.54–5.51 (m, 1H), 2.75–2.64 (m, 3H), 2.21–
NMR (400 MHz, CDCl3): δ 6.64–6.54 (m, 3H), 5.45–
5.41 (m, 1H), 3.78 (s, 3H), 2.67–2.60 (m, 3H), 2.19–
13
2.11 (m, 1H); C NMR (100 MHz, CDCl3): δ 176.3,
13
2.11 (m, 1H); C NMR (100 MHz, CDCl3): δ 176.2,
163.7 (d, J = 244.8 Hz), 161.2 (d, J = 10.7 Hz), 142.5
(d, J = 9.4 Hz), 106.6 (d, J = 2.6 Hz), 104.2 (d, J =
23.1 Hz), 101.3 (d, J = 24.9 Hz), 80.2 (d, J = 2.2 Hz),
55.6, 30.7, 28.6; IR (KBr) cm-1: 2972, 1781, 1462,
1379, 1134, 1023, 910, 799, 686; HR-MS (ESI): m/z
= 211.0772, calcd. for C11H11FO3 [M+H]+: 211.0770;
HPLC (Chiralcel AS-H, n-hexane/i-PrOH = 75 : 25,
UV = 210 nm, flow rate = 0.8 mL/min) tR1 = 18.33
min (major) and tR2 = 22.15 min (minor); ee = 89%;
[α]2D7 = +20.00 (c 0.45, CHCl3).
140.4, 131.3, 131.0, 129.3, 128.4, 125.2 (q, J = 3.8,
7.6 Hz ), 122.0 (q, J = 3.9, 7.6 Hz ), 80.1, 30.9, 28.7;
IR (KBr) cm-1: 2954, 1718, 1695, 1610, 1427, 1408,
1328, 1256, 1164, 940, 803, 697; HR-MS (ESI): m/z
= 231.0636, calcd. for C11H9F3O2 [M+H]+: 231.0633;
HPLC (Chiralcel AS-H, n-hexane/i-PrOH = 75 : 25,
UV = 210 nm, flow rate = 0.8 mL/min) tR1 = 9.30 min
(major) and tR2 = 11.20 min (minor); ee = 87%; [α]D27
= +14.38 (c 0.25, CHCl3).
(R)-5-(3-(Trifluoromethoxy)phenyl)dihydrofuran-
2(3H)-one (2n): Colorless oil (70.2 mg, 95%). H
(R)-5-(Naphthalen-2-yl)dihydrofuran-2(3H)-one
1
1
(2r)[9a]: White solid (61.1 mg, 96%). H NMR (400
NMR (400 MHz, CDCl3): δ 7.40 (t, J = 7.6 Hz, 1H),
7.25 (t, J = 7.6 Hz, 1H), 7.19–7.17 (m, 2H), 5.49–
5.47 (m, 1H), 2.72–2.62 (m, 3H), 2.19–2.12 (m, 1H);
13C NMR (100 MHz, CDCl3): δ 176.2, 149.5, 141.7,
130.2, 123.4, 120.7, 120.3 (q, J = 255.2 Hz), 117.8,
80.0, 30.8, 28.6; IR (KBr) cm-1: 2922, 1782, 1492,
1451, 1259, 1216, 1169, 929, 799, 702; HR-MS
(ESI): m/z = 247.0583, calcd. for C11H9F3O3 [M+H]+:
247.0582; HPLC (Chiralcel AS-H, n-hexane/i-PrOH
= 75 : 25, UV = 210 nm, flow rate = 0.8 mL/min) tR1
= 9.62 min (major) and tR2 = 11.70 min (minor); ee =
88%; [α]2D7 = +7.98 (c 0.65, CHCl3).
MHz, CDCl3): δ 7.87–7.79 (m, 4H), 7.49–7.48 (m,
2H), 7.38 (d, J = 8.4 Hz, 1H), 5.70–5.65 (m, 1H),
2.76–2.66 (m, 3H), 2.31–2.20 (m, 1H); 13C NMR
(100 MHz, CDCl3): δ 176.9, 136.6, 133.1, 133.0,
128.8, 128.0, 127.7, 126.5, 126.4, 124.2, 122.8, 81.2,
30.8, 28.8; HPLC (Chiralcel AS-H, n-hexane/i-PrOH
= 90 : 10, UV = 210 nm, flow rate = 0.8 mL/min) tR1
= 15.01 min (major) and tR2 = 19.73 min (minor); ee
= 89%; [α]2D7 = +8.31 (c 0.25, CHCl3).
Gram-scale synthesis of 2a
The gram scale synthesis of 2a was carried out
based on the optimal reaction conditions: 1a (5.30 g,
29.7 mmol), RuPHOX-Ru (1.7 mg, 0.01 mol%),
KOH (3.34 g, 59.5 mmol) in MeOH (20 mL) under
50 bar hydrogenation pressure at RT for 72 hours.
After releasing the hydrogen, the reaction mixture
was acidified with 3 M HCl solution and extracted
with EtOAc (3  50 mL). The extract was dried over
Na2SO4 and concentrated on a rotary evaporator. The
(R)-5-(3,5-Dimethylphenyl)dihydrofuran-2(3H)-
1
one (2o): Colorless oil (55.4 mg, 97%). H NMR
(400 MHz, CDCl3): δ 6.94 (s, 1H), 6.91 (s, 2H),
5.43–5.40 (m, 1H), 2.63–2.56 (m, 3H), 2.29 (s, 6H),
2.20–2.08 (m, 1H); 13C NMR (100 MHz, CDCl3): δ
177.0, 139.3, 138.3, 129.9, 122.9, 81.3, 30.9, 28.9,
21.2; IR (KBr) cm-1: 2918, 2359, 2341, 1714, 1608,
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801186
Advanced Synthesis & Catalysis
crude product was purified by flash column
chromatography (PE/EtOAc = 4/1) to afford 2a as
colorless oil (4.67 g, 97%, 91% ee).
hexane/i-PrOH = 90 : 10, UV = 210 nm, flow rate =
0.8 mL/min) tR1 = 28.30 min (minor) and tR2 = 37.01
min (major); ee = 99%; [α]2D7 = +58.00 (c 0.5, CHCl3).
The synthesis of (R)-1-Phenylbutane-1,4-diol (3)[17]
To a solution of 2a (162.2 mg, 1.0 mmol) in THF
was added LiAlH4 in portions. The reaction was
monitored by TLC for the disapperance of starting
material and was quenched by water. The mixture
was then extracted with EtOAc (3  20 mL). The
organic phase was dried over anhydrous Na2SO4 and
concentrated on a rotary evaporator to afford 3 as a
Acknowledgements
This work was supported by Shanghai Municipal Education
Commission (No. 201701070002E00030) and the National
Natural Science Foundation of China (Nos. 21672142, 21472123
and 21620102003).
1
References
colorless oil (149.6 mg, 90%). H NMR (400 MHz,
CDCl3): δ 7.33 (d, J = 4.4 Hz, 4H), 7.29‒7.23 (m,
1H), 4.73‒4.69 (m, 1H), 3.70‒3.60 (m, 2H), 2.92 (s,
1H), 2.46 (s, 1H), 1.88‒1.82 (m, 2H), 1.72‒1.61 (m,
2H); 13C NMR (100 MHz, CDCl3): δ 144.7, 128.3,
127.3, 125.8, 74.2, 62.6, 36.3, 29.1; HPLC (Chiralcel
OD-H, n-hexane/i-PrOH = 95 : 5, UV = 210 nm, flow
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7.49‒7.47 (m, 2H), 7.35‒7.25 (m, 7H), 7.10 (t, J =
7.2 Hz, 1H), 4.80‒4.78 (m, 1H), 3.41 (brs, 1H),
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(100 MHz, CDCl3): δ 171.9, 144.1, 137.7, 128.9,
128.4, 127.5, 125.7, 124.3, 120.0, 73.5,34.1, 33.9;
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(minor) and tR2 = 8.73 min (major); ee = 90%; [α]2D7 =
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(d, J = 4.4 Hz, 1H), 4.53‒4.48 (m, 1H), 4.13 (s, 2H),
2.10‒2.02 (m, 2H), 1.81‒1.76 (m, 2H); 13C NMR
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126.1, 72.1, 35.5, 30.3; HPLC (Chiralcel AD-H, n-
a
white
1
7
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10.1002/adsc.201801186
Advanced Synthesis & Catalysis
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8
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10.1002/adsc.201801186
Advanced Synthesis & Catalysis
UPDATE
Synthesis of Enantiopure γ-Lactones via a
RuPHOX-Ru Catalyzed Asymmetric
Hydrogenation of γ-Keto Acids
Adv. Synth. Catal. 2018, 360, Page – Page
J. Li, Y. Ma, Y. Lu, Y. Liu, D. Liu,* W. Zhang*
9
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