Ru-catalyzed asymmetric hydrogenation of γ-heteroatom substituted β-keto esters

Article abstract of DOI:10.1021/jo201822k

A series of enantiomerically pure γ-heteroatom substituted β-hydroxy esters were synthesized with high enantioselectivities (up to 99.1% ee) by hydrogenation of γ-heteroatom substituted β-keto esters in the presence of Ru-(S)-SunPhos catalyst. These asymmetric hydrogenations provide key building blocks for a variety of naturally occurring and biologically active compounds.

Full text of DOI:10.1021/jo201822k

Article
pubs.acs.org/joc
Ru-Catalyzed Asymmetric Hydrogenation of γ-Heteroatom
Substituted β-Keto Esters
Weizheng Fan,† Wanfang Li,† Xin Ma,† Xiaoming Tao,† Xiaoming Li,† Ying Yao,† Xiaomin Xie,†
and Zhaoguo Zhang*,†,‡
†School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
‡Shanghai Institute of Organic Chemistry, 345 Lingling Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: A series of enantiomerically pure γ-heteroatom
substituted β-hydroxy esters were synthesized with high
enantioselectivities (up to 99.1% ee) by hydrogenation of γ-
heteroatom substituted β-keto esters in the presence of Ru-
(S)-SunPhos catalyst. These asymmetric hydrogenations
provide key building blocks for a variety of naturally occurring
and biologically active compounds.
substrates being investigated, usually restricted to simple β-alkyl
or aryl substituents. Until recently, several investigations
involved substrates bearing adjacent heteroatoms, such as a
benzyloxyl group,5 an alkoxyl group,6 halogen atoms,7 or
carbonylamino groups,8 in the vicinity of the keto group. Up to
now, γ-heteroatom substituted β-keto esters were still relatively
intractable substrates as the competitive coordinations of
multiple coordinating groups to the catalyst.9a Therefore, the
asymmetric hydrogenation of β-keto esters bearing adjacent
functional coordinating groups is still a challenging work.
Recently, we designed new biaryl phosphine ligands and
explored their applications in ruthenium-catalyzed asymmetric
hydrogenation of various functionalized ketones and their
applications in organic synthesis.9 In this paper, we disclose a
general and highly enantioselective hydrogenation reaction of γ-
heteroatom substituted β-keto esters.
INTRODUCTION
■
Catalytic asymmetric hydrogenation, one of the most practical
and efficient methods for the synthesis of chiral building blocks,
has attracted much attention in both academia and industry.1
Enantiomerically pure γ-heteroatom substituted β-hydroxy
esters are useful building blocks for the synthesis of a variety
of naturally occurring and biologically active compounds.2 In
particular, γ-heteroatom substituted β-hydroxy esters serve as
key precursors of Atorvastatin chiral side-chain,2a Kaneka
alcohol,2b L-(−)-carnitine, and (R)-(−)-GABOB2c,d ((R)-γ-
amino-β-hydroxybutyric acid) (Scheme 1). Accordingly, the
Scheme 1. Selected Pharmaceutical Applications of Optically
Pure γ-Heteroatom Substituted β-Hydroxy Esters
RESULTS AND DISCUSSION
■
In order to systematically study the impact of the adjacent
heteroatoms on asymmetric hydrogenation of γ-heteroatom
substituted β-keto esters, four representative substrates were
screened simultaneously to accelerate the optimization process:
γ-benzyloxyl substituted β-keto ester (1a), the resulting product
of which could be used to synthesize the chiral side-chain of
Stains;2b γ-benzoate substituted β-keto ester (1d), the reduced
product of which is the main precursor of optically pure 3-
hydroxy γ-butyrolactone;10 γ-phenylsulfonyl substituted β-keto
ester (1j), the resulting product of which could be further
transformed into chiral allylic alcohol by reacting with
aldehyde/ketone via Julia reaction;11 γ-N-carbobenzoxy sub-
stituted β-keto ester (1m), the hydrogenated product of which
is a useful intermediate to prepare L-(−)-carnitine and (R)-
(−)-GABOB.2d
search for efficient, highly enantioselective and practical
approaches to synthesize optically pure γ-heteroatom sub-
stituted β-hydroxy esters is of great significance.
The asymmetric hydrogenation of β-keto esters catalyzed by
ruthenium complexes with chiral phosphine ligands has been
extensively studied.3 Following the pioneering work of Noyori’s
use of BINAP (2,2′-bis(diphenylphosphosino)-1,1′-binaphthyl),
many other effective chiral diphosphines have been developed
for this important transformation.4 In contrast, there are limited
Received: September 3, 2011
Published: October 8, 2011
© 2011 American Chemical Society
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a
The catalyst (RuCl(benzene)(S)-SunPhos)Cl was readily
prepared from (RuCl2(benzene))2 and (S)-SunPhos by
refluxing them in degassed ethanol/dichloromethane for 1 h
and then drying them under reduced pressure.9 The
asymmetric hydrogenation was carried out under 20 bar of
H2, 70 °C in EtOH for 16 h with 1 mol % of (RuCl(benzene)-
(S)-SunPhos)Cl. We obtained full conversions and high
enantioselectivities of the desired product 2a (98.2% ee), 2d
(97.3% ee), 2j (97.9% ee), and 2m (97.1% ee) (Table 1, entry
Table 2. Effects of Temperature and Hydrogen Pressure
b
entry
T (°C)/P (bar)
1a
1d
1j
1m
1
2
3
4
5
50/20
70/20
90/20
70/10
70/50
98.2
98.2
98.6
98.1
98.7
96.0
97.3
96.7
96.7
96.9
96.7
97.9
97.2
97.3
97.4
96.9
97.1
97.1
96.8
96.9
Table 1. Asymmetric Hydrogenation of γ-Heteroatom
a
Substituted β-Keto Esters 1 with (RuCl(Benzene)L)Cl
a
All reactions were carried out with a substrate (1.0 mmol)
concentration of 0.4 in EtOH for 18 h, substrate/
M
(RuCl2(benzene))2/(S)-SunPhos =100/0.5/1.1. Conversion: 100%.
b
Values of ee were determined by HPLC on a Chiralpak IB-3 column.
b
entry
ligands
1a
1d
1j
1m
may have a slightly negative influence on the enantioselectivity
(except for 1a, higher ee was observed under 50 bar). In order
to establish general reaction conditions for asymmetric
hydrogenation of γ-heteroatom substituted β-keto esters, we
chose the initial hydrogen pressure of 20 bar and reaction
temperature of 70 °C throughout of this study.
1
2
3
4
(S)-SunPhos
(S)-SegPhos
98.2
98.6
98.7
95.4
97.3
97.6
97.3
92.0
97.9
97.3
96.8
91.0
97.1
97.3
97.5
94.6
(S)-C3-TunePhos
(R)-BINAP
a
All reactions were carried out with a substrate (1.0 mmol)
concentration of 0.4 M in EtOH under 20 bar of H2 and at 70 °C
for 16 h, substrate/(RuCl2(benzene))2/ligand =100/0.5/1.1. Con-
A comparison study with other ruthenium sources was also
carried out (Table 3). The hydrogenation results catalyzed by
b
version: 100%. Values of ee were determined by HPLC on a
Chiralpak IB-3 column.
a
Table 3. Effects of Ruthenium Source
1). Additionally, three commercially available chiral bidentate
ligands, (S)-SegPhos, (S)-C3-TunePhos, and (R)-BINAP, were
also tested under the same reaction conditions (Figure 1).
b
entry
Ru source
1a
1d
1j
1m
1
2
(RuCl2(benzene))2
98.2
99.1
97.3
97.7
97.9
98.2
97.1
91.6
(RuCl2(p-cymene))2
a
All reactions were carried out with a substrate (1.0 mmol)
concentration of 0.4 M in EtOH under 20 bar of H2 and at 70 °C
for 18 h, substrate/Ru/(S)-SunPhos =100/0.5/1.1. Conversion: 100%.
b
Values of ee were determined by HPLC on a Chiralpak IB-3 column.
(RuCl2(benzene))2 were comparable to those obtained with
(RuCl2(p-cymene))2. Although full conversions and high ee
values were obtained with both ruthenium precatalysts, they
showed different enantioselectivities to different substrates. For
1a, 1d, and 1j, (RuCl2(benzene))2 gave lower ee than
(RuCl2(p-cymene))2 did. But for 1m, the trend was reversed:
when the precatalyst (RuCl2(benzene))2 was replaced by
(RuCl2(p-cymene)2, ee dropped from 97.1 to 91.6%. Therefore,
(RuCl2(p-cymene))2 is applied for the hydrogenation of
substrates bearing alkyloxy groups, carboxylate groups, and
arylsulfonyl groups in the vicinity of the keto group, whereas
(RuCl2(benzene))2 for γ-carbamate substituted β-keto esters.
Preliminary studies have shown that complete conversions
and high enantioselectivities could be obtained when the
reaction was carried out at 70 °C in EtOH, under 20 bar of H2
with an appropriate catalyst. Thus, using in situ prepared chiral
Ru-catalysts under the above reaction conditions, a range of γ-
heteroatom substituted β-keto esters were hydrogenated with
complete conversions and high enantioselectivities, as listed in
Table 4. When γ-benzyloxy and γ-tert-butoxy substituted β-keto
esters were hydrogenated, excellent ee values of 2a (99.1%) and
2b (97.9%)13 were obtained (Table 4, entries 1, 2). Substrate
with γ-chloro substituted β-keto ester (1c) was hydrogenated
Figure 1. Structure of chiral bidentate ligands.
Similar results were obtained when (S)-SegPhos and (S)-C3-
TunePhos were used as ligands (Table 1, entries 2, 3).
However, enantioselectivities of all the products, 2a (95.4% ee),
2d (92.0% ee), 2j (91.0% ee), and 2m (94.6% ee), were lower
when (R)-BINAP was employed (Table 1, entry 4).
We next performed the hydrogenation under different
temperatures (50, 70, and 90 °C) at 20 bar of H2 (Table 2,
entries 1−3). All substrates were reduced with high ee values
under selected temperatures, but very close ee values were
observed. Values of ee at 70 °C were only slightly higher than
those under other temperatures (except for 1a, higher ee was
observed at 90 than at 70 °C), which was then selected as the
optimized temperature. The effect of different hydrogen
pressure (10 and 50 bar H2) was then investigated at 70 °C
with (S)-SunPhos (Table 2, entries 4, 5 vs 2). The results of
slightly lower ee values illustrated that lower or higher pressure
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genated to give the reduced products with equally excellent ee
(98.2%) (Table 4, entries 11 and 12).14 However, the
asymmetric hydrogenation of γ-(4-bromophenyl)sulfonyl sub-
stituted β-keto ester (1l) afforded the debromination product
ethyl 4-phenylsulfonyl-3-hydroxybutyrate (2l) in >99% yield
with 97.5% ee (Table 4, entry 13). Noyori et al. had reported
that using electron-withdrawing amino-protecting groups may
reduce the competitive directing effects of the amino group
versus the ester group within one molecule.8,9f,12 Therefore, we
employed electron-withdrawing rather than electron-donating
amino groups in our study. The γ-carbamate substituted β-keto
esters, such as N-Cbz-γ-amino substituted β-keto ester (1m),
and N-Fomc-γ-amino substituted β-keto ester (1n) and N-Boc-
γ-amino substituted β-keto ester (1o), were also hydrogenated
with excellent ee values ranging from 97.1 to 98.0%, in contrast
to the enantioselective hydrogenation of 1o with RuBr2[(S)-
BINAP] in ethanol at 29 °C, in which 2o of 87% ee was
obtained.8
Table 4. Asymmetric Hydrogenation of γ-Heteroatom
Substituted β-Keto Esters
a
b
entry
X
ee/%
99.1
1
2
3
BnO (1a)
tBuO (1b)
c
97.9
95.5
96.5
97.7
99.0
98.6
88.6
64.9
96.9
98.2
98.2
97.5
97.1
97.2
98.0
c
c
Cl (1c)
d
4
Cl (1c)
5
PhCO2 (1d)
AcO (1e)
c
6
c
c
7
TBSO (1f)
8
OH (1g)
9
4-ClC6H4S (1h)
4-ClC6H4SO2 (1i)
PhSO2 (1j)
10
11
12
13
4-MeC6H4SO2 (1k)
4-BrC6H4SO2 (1l)
CbzNH (1m)
FmocNH (1n)
BocNH (1o)
To test the applicability to larger scale preparation of
enantiomerically pure ethyl 4-benzyloxy-3-hydroxybutyrate
(2a) and ethyl 4-phenylsulfonyl-3-hydroxybutyrate (2j), higher
substrate to catalyst ratio hydrogenation reactions were
conducted (Table 5). As shown in Table 5, when the substrate
e
f
14
f
15
f
c
16
a
All reactions were carried out with a substrate (1.0 mmol)
concentration of 0.4 M in EtOH under 20 bar of H2 at 70 °C for
18 h unless otherwise noted. Substrate/(RuCl2(p-cymene))2/(S)-
a
Table 5. Preparative and Scale-Up Experiments
b
SunPhos =100/0.5/1.1. Conversion=100%. Values of ee were
c
determined by HPLC. Values of ee of their p-nitrobenzoates.
d
e
f
Reaction at 90 °C. Debromination was observed. (RuCl(Benzene)-
(S)-SunPhos)Cl as catalyst.
b
c
entry
1
X
S/C
ee/%
BnO (1a)
BnO (1a)
PhSO2 (1j)
PhSO2 (1j)
2000
3000
2000
5000
98.8
98.4
98.1
97.3
under optimized conditions to give 2c with 95.5% ee (Table 4,
entry 3). When the temperature was elevated to 90 °C, the ee
value of 2a was increased to 96.5% (Table 4, entry 4), which
was in compliance with Noyori’s report that higher temper-
atures could impair the competitive directing effects of chloride
atom.9b,12 Our ligand was also fruitful in the asymmetric
hydrogenation of γ-benzonate and γ-acetate substituted β-keto
esters (1d and 1e), giving excellent ee values of 2d (97.7%) and
2e (99.0%), respectively. It was noteworthy that the TBS group
in 1f was removed during the asymmetric hydrogenation, which
afforded the product ethyl 3,4-dihydroxybutyrate with 98.6%
ee. To find out whether the TBS group was lost before or after
the completion of the asymmetric hydrogenation of 1f, a
control test was performed. Hydrogenation of an unprotected
form of 1f (γ-hydroxy β-keto ester, 1g) gave the corresponding
product 2g with only 88.6% ee, which showed that competitive
coordination between the hydroxyl and carboxylic ester group
greatly impaired the enantioselectivity. Thus, we inferred that
the TBS group should be cleaved after the hydrogenation is
completed.
Substrate with γ-sulfide substituted β-keto ester (1h) was
first introduced into asymmetric hydrogenation, which afforded
the corresponding product 2h with a moderate 64.9% ee (Table
4, entry 9). The moderate enantioselectivity of 2h may be
caused by the competitive coordination of the sulfur atom,
which made the coordination of catalyst with ester carbonyl not
so dominant. This was verified by replacing sulfide with a
sulfone group, a weaker coordination group compared to that
of the sulfide: the asymmetric hydrogenation of sulfone 1i
delivered the reduced product 2i with ee up to 96.9% (Table 4,
entry 10). Likewise, substrates with γ-phenlysulfonyl and γ-(4-
methylphenl)sulfonyl substituted β-keto esters were hydro-
d
2
3
4
a
The reactions were carried out with a substrate (20 mmol)
concentration of 0.5 M in EtOH under 20 bar of H2 for 18 h and
b
at 70 °C except where indicated. Conversion: 100%. Molar ratio of
c
substrate/(RuCl(p-cymene)(S)-SunPhos)Cl. Values of ee were
d
determined by HPLC on a Chiralpak IB-3 column. Fifty grams of
substrate was used, and (RuCl(benzene)(S)-TolSunPhos)Cl was used
as a catalyst.
to catalyst ratio increased to 2000 with a substrate
concentration of 0.5 M, the hydrogenation of ethyl 4-
benzyloxy-3-hydroxybutyrate (1a) gave 2a with complete
conversion and excellent enantiomeric excess of 98.8% ee
(Table 5, entry 1). When our ligand (R)-TolSunPhos was
assayed in combination with (RuCl2(p-cymene))2 in the
asymmetric hydrogenation of 1a with a substrate to catalyst
ratio of 3000, complete conversion and excellent enantiose-
lectivity (98.4% ee) were achieved for product 2a (Table 5,
entry 2). Additionally, the asymmetric hydrogenation of ethyl
4-phenylsulfonyl-3-oxobutyrate (1j) with a substrate to catalyst
ratio of 2000 under the same reaction conditions afforded 2j
with complete conversion and excellent enantioselectivity of
98.1% ee (Table 5, entry 3). When we raised the ratio to 5000,
the high ee almost remained. The asymmetric hydrogenation of
1j was realized to afford 2j with complete conversion and high
enantioselectivity up to 97.3% ee (Table 5, entry 4).
To illustrate the utility of hydrogenated product, Kaneka
alcohol was produced starting from compound 2a (Scheme 2).
Claisen condensation was employed, and β-keto esters 3a were
obtained in 75% yield, which were subjected to diastereose-
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a
temperature. After hydrogen evolution ceased, the thick slurry was
allowed to stir for 2 h. Ethyl 4-chloroacetoacetate (50.0 g, 304 mmol)
was then added dropwise within 3 h, and the reaction mixture was
stirred for 16 h. The reaction mixture was carefully added into 5% HCl
solution (200 mL) at 5 °C and extracted with EtOAc (100 mL × 3).
The organic layers were washed with saturated NaHCO3 (60 mL x 2)
and then saturated NaCl (60 mL), dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo. The crude product was purified by
silica gel chromatography (hexanes/ethyl acetate = 8:1) to give 1a
Scheme 2. Synthesis of Kaneka Alcohol 6a
1
(65.3 g, 91%) as a pale yellow oil: H NMR (400 MHz, CDCl3) δ
7.39−7.30 (m, 5H), 4.59 (s, 2H), 4.17 (q, J = 7.2 Hz, 2H), 4.14 (s,
2H), 3.54 (s, 2H), 1.25 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 201.7, 166.9, 136.8, 128.4, 128.0, 127.7, 74.6, 73.3, 61.3,
45.9, 13.9.
Ethyl 4-(tert-Butoxy)-3-oxobutanoate (1b).15 Ethyl 4-chloroa-
cetoacetate (10.0 g, 60.8 mmol) was added dropwise to a stirred
suspension of 60% sodium hydride (3.7 g, 91.0 mmol) and potassium
tert-butoxide (7.5 g, 60.8 mmol) in THF (80 mL) over 30 min. The
reaction was stirred at rt until TLC analysis indicated consumption of
the starting material (∼12 h). The reaction mixture was carefully
added into 5% HCl solution (80 mL) at 5 °C and extracted with
EtOAc (60 mL × 3), and the combined organic layers were washed
with NaHCO3 (50 mL × 2) and then saturated NaCl (50 mL), dried
over anhydrous Na2SO4, and concentrated in vacuo. The residue was
purified by silica gel chromatography (hexanes/ethyl acetate = 8:1) to
give 1b (10.6 g, 86%) as a pale yellow oil. Mixture of keto and enol
a
Reagents: (a) AcOtBu, LDA, THF, −40 °C, 2 h, 75% yield; (b) (1)
Et2BOMe, NaBH4, MeOH/THF, −60 °C, 5 h, (2) H2O2, THF/H2O,
10 °C, 1 h, 86% yield; (c) 2,2-dimethoxypropane, cat. p-TsOH, 96%
yield; (d) (1) 10 bar H2, 10% Pd/C, AcOEt, rt, 5 h, (2) AcCl, pyridine,
DCM, r.t, (3) recrystallization, (4) K2CO3, MeOH, rt, 89% yield.
lective reduction via the Evans−Prasad 1,3-syn diol synthesis to
furnish 4a in 86% yield and 97.2% de.2b Compound 4a was
further protected with 2,2-dimethoxylpropane and followed by
hydrogenolysis of the benzyl protecting group to give Kaneka
alcohol 6a. In order to upgrade the enantiomeric and
diastereomeric purities of 6a, purification was carried out by
acylation of 6a, followed by crystallization of the ester from
hepatane and hydrolysis of the acyl group with potassium
carbonate; upgraded 6a was delivered with >99.5% ee and
>99.5% de in 89% yield.
1
forms: H NMR (400 MHz, CDCl3) δ 11.98 (s, 0.05H), 5.34 (s,
0.06H), 4.19 (q, J = 7.2 Hz, 2H), 4.01 (s, 2H), 3.97 (s, 0.17H), 3.55 (s,
2H), 1.28 (t, J = 7.2 Hz, 3H), 1.23 (s, 0.85H), 1.21 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 203.3, 167.2, 88.1, 74.2, 67.9, 61.1, 59.9, 46.1,
27.2, 27.1, 14.1, 14.0.
4-Ethoxy-2,4-dioxobutyl Benzoate (1d).16 Sodium benzoate
(17.5 g, 121.5 mmol) was added to a solution of ethyl 4-
chloroacetoacetate (10.0 g, 60.8 mmol) in acetic acid (80 mL); the
resulting mixture was heated at 90 °C for 18 h, then cooled to rt The
mixture was diluted with H2O (150 mL) and extracted with EtOAc
(80 mL × 3). The combined organic layers were washed with
saturated NaHCO3 (50 mL × 2) and brine (50 mL), dried over
anhydrous Na2SO4, and concentrated in vacuo to afford the crude
product that was purified by silica gel chromatography (hexanes/ethyl
acetate = 8:1) to provide 1d (6.4 g, 42%) as a pale yellow oil. Mixture
CONCLUSION
■
In conclusion, we have developed a convenient and general
protocol for highly enantioselective synthesis of γ-heteroatom
substituted β-hydroxy esters by asymmetric hydrogenation.
Among all the reduced products, optically pure ethyl 4-
arylsulfonyl-3-hydroxybutyrate was achieved for the first time
through asymmetric hydrogenation. Catalyzed by (RuCl(p-
cymene)(S)-SunPhos)Cl with up to 5000 TON (turnover
number), enantioselectivity of this reduced product remained.
This asymmetric hydrogenation protocol provides a useful
method for constructing important intermediates with multiple
chiral centers; for illustration, Kaneka alcohol (6a) was
synthesized from the hydrogenated product, which could be
used as an important intermediate of statin drugs.
1
of keto and enol forms: H NMR (400 MHz, CDCl3) δ 12.11 (s,
0.09H), 8.09−8.07 (m, 2H), 7.62−7.56 (m, 2H), 7.49−7.45 (m, 2H),
5.28 (s, 0.10H), 5.01 (s, 2H), 4.89 (s, 0.31H), 4.20 (q, J = 7.2 Hz, 2H),
3.58 (s, 2H), 1.26 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
196.8, 166.3, 165.5, 133.4, 129.7, 129.6, 128.8, 128.4, 89.1, 68.1, 62.3,
61.6, 60.3, 46.0, 14.0, 13.9. HRMS: Calculated for C13H14O5 (M +
H)+: 251.0919. Found: 251.0927.
Ethyl 4-Acetoxy-3-oxobutanoate (1e).16 Prepared by treating
ethyl 4-chloroacetoacetate with potassium acetate using the same
procedure for the preparation of 1d to afford 1e (6.1 g, 53%) as a pale
yellow oil. Mixture of keto and enol forms: 1H NMR (400 MHz,
CDCl3) δ 12.04 (s, 0.06H), 5.20 (s, 0.07H), 4.79 (s, 2H), 4.65 (s,
0.37H), 4.21 (q, J = 7.1 Hz, 2H), 3.50 (s, 2H), 2.17 (s, 3H), 1.29 (t, J
= 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 196.6, 169.9, 166.2,
89.3, 68.2, 67.7, 62.0, 61.6, 46.0, 25.9, 20.2, 14.0, 13.9.
EXPERIMENTAL SECTION
■
General Procedures. Commercially available reagents were used
throughout without further purification other than those detailed
below. Methylene chloride was distilled over calcium hydride. Ethanol
was distilled over magnesium under nitrogen. All reactions were
carried out under an atmosphere of nitrogen using standard Schlenk
Ethyl 4-[(tert-Butyldimethylsilyl)oxy]-3-oxobutanoate (1f).
To a solution of ethyl 4-hydroxy-3-oxobutanoate (1.0 g, 6.8 mmol) in
20 mL of DCM were added imidazole (699 mg, 10.3 mmol) and
DMAP (42 mg); the resulting solution was cooled to 0 °C. TBSCl
(1.1 g, 7.5 mmol) in 5 mL of DCM was added portion-wise to the
solution. The reaction was allowed to warm to rt and stirred for an
additional 12 h. The mixture was diluted with DCM (50 mL) and
washed with 1 M HCl (20 mL × 2), saturated NaHCO3 (20 mL × 2),
and brine (20 mL), dried (MgSO4), and concentrated in vacuo. The
residue was purified by silica gel chromatography (hexanes/ethyl
1
techniques or in a nitrogen-filled glovebox, unless otherwise noted. H
NMR spectra were recorded at 400 MHz with TMS as internal
standard. 13C NMR spectra were recorded at 100 MHz and referenced
to the central peak of 77.00 ppm for CDCl3. Coupling constants (J)
are reported in Hz and refer to apparent peak multiplications. Mass
spectroscopy data were collected on an HRMS-EI instrument. Flash
column chromatography was performed on silica gel (300−400 mesh).
[α]D values are given in deg cm2 g−1 and were recorded at the D-line
of sodium (589 nm) at 20 °C.
Ethyl 4-(Benzyloxy)-3-oxobutanoate (1a).2b Benzyl alcohol
(34.5 g, 319 mmol) was added dropwise to a stirred suspension of
60% sodium hydride (26.7 g, 668 mmol) in THF (200 mL);
occasional cooling was required with an ice bath to maintain ambient
1
acetate = 8:1) to provide 1f (1.5 g, 84%) as a colorless oil: H NMR
(400 MHz, CDCl3) δ 4.22 (s, 2H), 4.19 (q, J = 7.1 Hz, 2H), 3.56 (s,
2H), 1.28 (t, J = 7.1 Hz, 3H), 0.92 (s, 9H), 0.09 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 204.1, 167.2, 68.8, 61.2, 45.5, 25.6, 18.1, 14.0,
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−5.7. HRMS: Calculated for C12H24O4Si (M + H)+: 261.1522. Found:
261.1539.
129.7, 129.5, 128.2, 128.0, 95.1, 66.5, 61.43, 61.36, 60.4, 49.2, 21.4,
13.8, 13.7. HRMS: Calculated for C13H16O5S (M + Na)+: 307.0616.
Found: 307.0633.
Ethyl 4-Hydroxy-3-oxobutanoate (1g).17 Pd/C (10%, 0.5 g)
was added to a solution of 1b (5.0 g, 21.2 mmol) in EtOAc (50 mL),
which was placed in a 300 mL autoclave. The autoclave was purged
and then filled with H2 (10 bar). The mixture was stirred at rt for 5 h.
The catalyst was filtrated with a clarifying pad, and the filtrate was
Ethyl 4-[(4-Bromophenyl)sulfonyl]-3-oxobutanoate (1l).18
Compound 4-bromobenzenethiol (7.8 g, 41.0 mmol) was added into a
solution of potassium hydroxide (2.5, 45.0 mmol) in MeOH (100 mL)
at rt and stirred for 0.5 h. Then ethyl 4-chloroacetoacetate (6.2 g, 38.0
mmol) was added, and the mixture was stirred at rt for 6 h. In a
separate flask, (NH4)6Mo7O24·4H2O (4.7 g, 3.8 mmol) was dissolved
in H2O2 (30%, 20 mL) at 0 °C to give a yellow solution. The oxidant
solution was added to the sulfide at 0 °C and stirred for an additional 2
h. The reaction mixture was condensed in vacuo, further diluted with
H2O (30 mL), and then extracted with DCM (30 mL × 2). The
combined organic layers were washed with brine (20 mL), dried over
MgSO4, and concentrated in vacuo to afford the crude product that
was purified by silica-gel column chromatography (PE/EA = 5:1) to
1
condensed in vacuo to give the product 1g (2.8 g, 91%): H NMR
(400 MHz, CDCl3) δ 4.39 (d, J = 3.6 Hz, 2H), 4.22 (q, J = 7.1 Hz,
2H), 3.50 (s, 2H), 3.00 (s, 1H), 1.29 (t, J = 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 202.8, 166.6, 68.3, 61.5, 45.1, 13.8.
Ethyl 4-[(4-Chlorophenyl)thio]-3-oxobutanoate (1h).18 The
4-chlorobenzenethiol (10.8 g, 74.8 mmol) was added into a solution of
potassium hydroxide (4.6 g, 82.0 mmol) in methanol (100 mL) at rt
and stirred for 0.5 h. Then ethyl 4-chloroacetoacetate (11.2 g, 68.0
mmol) was added, and the mixture was stirred at rt for 6 h. The
mixture was filtered, and the filtrate was evaporated in vacuo. The
residue was diluted with DCM (100 mL), washed with 1 M HCl (20
mL), saturated NaHCO3 (20 mL), and brine (20 mL), dried
(MgSO4), and concentrated in vacuo. Purification of the crude
product by flash chromatography (EtOAc/hexanes = 1:30) afforded
1
provide 1l (9.3 g, 71%). Mixture of keto and enol forms: H NMR
(400 MHz, CDCl3) δ 11.86 (s, 0.44H), 7.79−7.70 (m, 4H), 5.20 (s,
0.41H), 4.38 (s, 1.30H), 4.21 (q, J = 7.2 Hz, 2H), 3.93 (s, 0.99H),
3.79−3.69 (m, 1.33H), 1.30 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 191.1, 171.5, 166.1, 163.5, 137.4, 137.2, 132.5, 132.4, 129.9,
129.8, 129.5, 95.5, 66.2, 61.6, 61.5, 60.7, 49.4, 13.93, 13.86. HRMS:
Calculated for C12H13BrO5S (M + Na)+: 370.9565. Found: 370.9579.
Ethyl 4-{[(Benzyloxy)carbonyl]amino}-3-oxobutanoate
(1m).20 To a solution of N-Cbz-glycine (15.0 g, 72 mmol) in THF
was added N,N′-carbonyldiimidazole (12.8 g, 79 mmol), and the
resulting solution was stirred at rt for 4 h. Treatment of potassium
monoethyl malonate (16.5 g, 86 mmol) with magnesium chloride (9.6
g, 100 mmol) and triethyl amine (15.0 mL, 108 mmol) at rt for 4 h
generated the dianion as its magnesium chelate. To this solution was
added the imidazolide solution, and a gummy precipitate began to
form immediately. After the resulting mixture was stirred at rt for 16 h,
the reaction was poured into ice-cold 1 M HCl. Extraction with EtOAc
(100 mL × 2) followed by washing the combined organics with
saturated NaHCO3 (50 mL × 2) and brine (50 mL) and drying over
MgSO4. Evaporation of the solvent gave the crude product, which was
further purified by silica-gel column chromatography (PE/EA = 4:1)
1
1h (15.1 g, 81%). Mixture of keto and enol forms: H NMR (400
MHz, CDCl3) δ 12.12 (s, 0.17H), 7.33−7.24 (m, 4H), 5.10 (s, 0.16H),
4.18 (q, J = 7.1 Hz, 0.15H), 4.17 (q, J = 7.2 Hz, 2H), 3.80 (s, 2H), 3.62
(s, 2H), 3.54 (s, 0.22H), 1.27 (t, J = 7.1, 0.23), 1.25 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 197.3, 166.8, 133.2, 132.4,
131.7, 131.1, 129.2, 129.0, 90.8, 61.4, 60.3, 46.4, 46.3, 43.9, 37.7, 14.0,
13.9.
Ethyl 4-[(4-Chlorophenyl)sulfonyl]-3-oxobutanoate (1i).
Compound 1h (2.9 g, 10.6 mmol) was dissolved in EtOH (30 mL)
and cooled to 0 °C. In a separate flask, (NH4)6Mo7O24·4H2O (2.6 g,
2.1 mmol) was dissolved in 30% H2O2 (10 mL) at 0 °C to give a
yellow solution. The oxidant solution was added to the sulfide. After 2
h, the reaction mixture was condensed in vacuo. The mixture was
further diluted with H2O (30 mL) and extracted with DCM (30 mL ×
2). The combined organic layers were washed with brine (20 mL),
dried over MgSO4, and concentrated in vacuo to afford the crude
product that was purified by silica-gel column chromatography (PE/
EA = 5:1) to provide 1i (2.6 g, 80%). Mixture of keto and enol forms:
1H NMR (400 MHz, CDCl3) δ 11.86 (s, 0.40H), 7.88−7.82 (m, 2H),
7.58−7.53 (m, 2H), 5.20 (s, 0.40H), 4.39 (s, 1.11H), 4.21 (q, J = 7.1
Hz, 2H), 3.93 (s, 0.91H), 3.75 (s, 1.11H), 1.29 (t, J = 7.1 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 191.1, 171.6, 166.3, 163.6, 141.3,
141.0, 136.9, 136.7, 130.0, 129.8, 129.7, 129.5, 95.7, 66.5, 61.84, 61.78,
60.8, 49.5, 14.1, 14.0. HRMS: Calculated for C12H13ClO5S (M + Na)+:
327.0070. Found: 327.0085.
1
to give the desired product 1m (16.7 g, 83%): H NMR (400 MHz,
CDCl3) δ 7.38−7.30 (m, 5H), 5.53 (s, 1H), 5.11 (s, 2H), 4.43−3.94
(m, 4H), 3.48 (s, 2H), 1.27 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 198.6, 166.4, 156.0, 135.9, 128.0, 127.6, 127.5, 66.4, 61.1,
50.2, 45.8.
Ethyl 4-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-3-ox-
obutanoate (1n).20 Prepared from N-Fmoc-glycine and potassium
monoethyl malonate using the same procedure for preparation of 1m;
1
1n (2.9 g, 89%) was obtained as a white solid: H NMR (400 MHz,
Ethyl 3-Oxo-4-(phenylsulfonyl)butanoate (1j).19 To a stirred
suspension of sodium benzenesulfinate (100 g, 608 mmol) and
potassium iodide (10 g, 61 mmol) in EtOH (500 mL) was added
portion-wise ethyl 4-chloroacetoacetate (11.2 g, 68.0 mmol) over 1 h,
and then the mixture was stirred at rt for an additional 30 min. The
mixture was filtered through a pad of Celite, and the filtrate was
concentrated in vacuo. The residue was crystallized from 500 mL of
Et2O/hexanes (1:3) to give the product 1j (122 g, 74%) as a white
solid. Mixture of keto and enol forms: 1H NMR (400 MHz, CD3Cl) δ
11.83 (s, 0.75H), 7.91−7.89 (m, 2H), 7.68−7.64 (m, 1H), 7.57−7.53
(m, 2H), 5.15 (s, 0.74H), 4.37 (s, 0.35H), 4.17 (q, J = 7.2 Hz, 2H),
3.92 (s, 1.80H), 3.74 (s, 0.33H), 1.25 (t, J = 7.2 Hz, 3 H); 13C NMR
(100 MHz, CDCl3) δ 191.1, 171.5, 166.2, 163.8, 138.34, 138.29, 134.3,
134.1, 129.3, 129.1, 128.3, 128.1, 95.4, 66.4, 61.6, 60.6, 49.4, 13.9, 13.8.
HRMS: Calculated for C12H14O5S (M + Na)+: 293.0460. Found:
293.0468.
CDCl3) δ 7.77−7.29 (m, 1H), 5.50 (s, 1H), 4.41−4.18 (m, 1H), 3.49
(s, 1H), 1.28 (t, J = 7.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
198.4, 166.5, 156.1, 143.6, 141.1, 127.5, 127.2, 126.9, 124.9, 119.8,
66.9, 61.5, 50.6, 46.9, 46.2, 13.8. HRMS: Calculated for C21H21NO5
(M + Na)+: 390.1317. Found: 390.1320.
Ethyl 4-[(tert-Butoxycarbonyl)amino]-3-oxobutanoate
(1o).20 Prepared from N-Boc-glycine and potassium monoethyl
malonate using the same procedure for synthesis of 1m; 1o (3.1 g,
1
86%) was obtained as a pale yellow oil: H NMR (400 MHz, CDCl3)
δ 5.18 (s, 1H), 4.21 (q, J = 7.2 Hz, 2H), 4.14 (d, J = 5.4 Hz, 2H), 3.49
(s, 2H), 1.45 (s, 9H), 1.29 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 198.9, 166.6, 155.5, 79.8, 61.5, 50.4, 46.4, 28.1, 13.9.
Typical Procedure for the Asymmetric Hydrogenation. To a
20 mL Schlenk tube were added (RuCl2(benzene))2 (10 mg, 0.020
mmol) or (RuCl2(p-cymene))2 (12 mg, 0.020 mmol) and (S)-
SunPhos (30 mg, 0.044 mmol). The tube was vacuumed and purged
with nitrogen three times before the addition of freshly distilled and
degassed EtOH/DCM (3 mL/3 mL). The resulting mixture was
heated at 50 °C for 1 h and then cooled to rt. The solvent was
removed under vacuum to give the catalyst. This catalyst was dissolved
in degassed ethanol (10 mL) and distributed equally to four vials. The
β-keto esters (1.0 mmol) were added to these vials, separately, and
were transferred to an autoclave. The autoclave was purged with H2
three times, and the pressure of H2 was set to 20 bar. Then the
Ethyl 3-Oxo-4-tosylbutanoate (1k).19 Prepared from sodium p-
toluenesulfinate and ethyl 4-chloroacetoacetate using the same
procedure for preparation of 1j to afford 1k (10.1 g, 81%) as a
1
white solid. Mixture of keto and enol forms: H NMR (400 MHz,
CDCl3) δ 11.85 (s, 0.82H), 7.80−7.75 (m, 2H), 7.37−7.35 (m, 2H),
5.19 (s, 0.83H), 4.35 (s, 0.13H), 4.20 (q, J = 7.1 Hz, 2H), 3.91 (s, 2H),
3.77 (s, 0.14H), 2.46 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 191.2, 171.5, 166.1, 164.0, 145.3, 145.0, 135.4, 135.3,
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autoclave was stirred under specific reaction conditions. After 18 h, the
autoclave was then cooled to room temperature and the H2 was
carefully released. The autoclave was opened, and the ethanol was
evaporated. The enantiomeric excess was determined by HPLC after
passing the residue through a short pad of silica gel column with
petroleum ether and ethyl acetate.
1H), 4.14 (q, J = 7.1 Hz, 2H), 3.63 (d, J = 3.4 Hz, 1H), 3.40−3.32 (m,
2H), 2.61 (d, J = 6.2 Hz, 2H), 2.46 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 170.8, 145.0, 136.1, 129.9, 127.9, 63.0,
61.1, 60.8, 40.4, 21.5, 13.9; HPLC (Chiralcel OD-H column, n-
hexane/i-PrOH = 80:20, 0.5 mL/min, 225 nm) t1 = 21.0 min, t2 = 26.3
min. HRMS: Calculated for C13H18O5S (M + Na)+: 309.0773. Found:
309.0802.
Ethyl 4-{[(Benzyloxy)carbonyl]amino}-3-hydroxybutanoate
(2m).22 1H NMR (400 MHz, CDCl3) δ 7.37−7.30 (m, 5H), 5.25
(s, 1H), 5.11 (s, 2H), 4.17 (q, J = 7.2 Hz, 2H), 4.14−4.11 (m, 1H),
3.45−3.38 (m, 2H), 3.22−3.15 (m, 1H), 2.58−2.39 (m, 2H), 1.27 (t, J
= 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.3, 156.8, 136.3,
128.4, 128.01, 127.96, 67.3, 66.7, 60.8, 45.8, 38.6, 14.0; HPLC
(Chiralcel IB-3 column, n-hexane/i-PrOH = 85:15, 0.5 mL/min, 215
nm) t1 = 18.9 min, t2 = 22.7 min.
Ethyl 4-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-3-hy-
droxybutanoate (2n). 1H NMR (400 MHz, CDCl3) δ 7.77−7.30
(m, 8H), 5.24 (s, 1H), 4.42 (d, J = 6.9 Hz, 2H), 4.23−4.12 (m, 4H),
3.44−3.39 (m, 2H), 3.31−3.06 (m, 1H), 2.53−2.42 (m, 2H), 1.28 (t, J
= 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.5, 156.9, 143.8,
141.2, 127.6, 127.0, 125.0, 119.9, 67.3, 66.7, 60.9, 47.2, 45.8, 38.4, 14.1;
HPLC (Chiralcel AD-H column, n-hexane/i-PrOH = 80:20, 0.5 mL/
min, 220 nm) t1 = 18.0 min, t2 = 20.7 min. HRMS: Calculated for
C21H23NO5 (M + H)+: 370.1654. Found: 370.1663.
Ethyl 4-[(tert-Butoxycarbonyl)amino]-3-hydroxybutanoate
(2o).8 1H NMR (400 MHz, CDCl3) δ 5.00 (s, 1H), 4.17 (q, J =
7.1 Hz, 1H), 4.13−4.09 (m, 1H), 3.52 (d, J = 3.3 Hz, 1H), 3.36−3.22
(m, 1H), 3.15−3.09 (m, 1H), 2.54−2.43 (m, 2H), 1.45 (s, 9H), 1.28
(t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.3, 156.4,
79.4, 67.5, 60.6, 45.4, 38.7, 28.2, 14.0.
Typical Procedure for the Preparation of 3. A 25 mL round
flask was charged with 2b (1 mmol), pyridine (0.4 mL, 5 mmol), 4-
nitrobenzoyl chloride (278 mg, 1.5 mmol), DMAP (6 mg), and
CH2Cl2 (10 mL). The mixture was stirred at 25−30 °C for 6 h,
saturated aqueous NaHCO3 solution (5 mL) was added, and the
organic layer was separated. The organic layer was washed with 1 M
aqueous hydrochloric acid, saturated aqueous NaHCO3 solution, and
brine. The washed organic solution was dried over anhydrous Na2SO4
and concentrated in vacuo to obtain the crude product, which was
purified by column chromatography (PE/EA = 3:1) to give the title
compound (268 mg, 85%).
Ethyl 4-(Benzyloxy)-3-hydroxybutanoate (2a).2b 1H NMR
(400 MHz, CDCl3) δ 7.38−7.27 (m, 5H), 4.57 (s, 2H), 4.28−4.21
(m, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.54−3.46 (m, 2H), 2.97 (d, J = 4.0
Hz, 1H), 2.54 (d, J = 6.4 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 172.1, 137.8, 128.4, 127.8, 127.7, 73.3, 73.1,
67.1, 60.7, 38.2, 14.1; HPLC (Chiralcel IB-3 column, n-hexane/i-
PrOH = 85:15, 0.5 mL/min, 215 nm) t1 = 17.6 min, t2 = 18.9 min.
Ethyl 4-(tert-Butoxy)-3-hydroxybutanoate (2b).15 1H NMR
(400 MHz, CDCl3) δ 4.17 (q, J = 7.2 Hz, 1H), 4.15−4.10 (m, 1H),
3.41−3.32 (m, 2H), 2.93 (d, J = 4.5 Hz, 1H), 2.54−2.52 (m, 2H), 1.27
(t, J = 7.2 Hz, 3H), 1.19 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
172.1, 73.2, 67.5, 64.8, 60.5, 38.4, 27.4, 14.1.
Ethyl 4-Chloro-3-hydroxybutanoate (2c).12 1H NMR (400
MHz, CDCl3) δ 4.30−4.17 (m, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.65−
3.58 (m, 2H), 3.16 (d, J = 5.0 Hz, 1H), 2.69−2.58 (m, 2H), 1.29 (t, J
= 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.2, 163.5, 150.6,
134.8, 130.8, 123.5, 70.6, 61.0, 44.9, 36.2, 14.0.
4-Ethoxy-2-hydroxy-4-oxobutyl Benzoate (2d). 1H NMR
(400 MHz, CDCl3) δ 8.07−8.05 (m, 2H), 7.60−7.56 (m, 1H),
7.56−7.43 (m, 2H), 4.44−4.35 (m, 3H), 4.19 (q, J = 7.2 Hz, 2H), 3.24
(s, 1H), 2.69−2.58 (m, 2H), 1.28 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 171.8, 166.3, 133.0, 129.5(2C), 128.2, 67.5, 66.2, 60.8,
38.1, 13.9; HPLC (Chiralcel IB-3 column, n-hexane/i-PrOH = 92:8,
0.5 mL/min, 215 nm) t1 = 19.0 min, t2 = 21.4 min. HRMS: Calculated
for C13H16O5 (M + H)+: 275.0895. Found: 275.0904.
Ethyl 4-Acetoxy-3-hydroxybutanoate (2e). 1H NMR (400
MHz, CDCl3) δ 4.30−4.25 (m, 1H), 4.22−4.07 (m, 4H), 3.17−3.15
(m, 1H), 2.55−2.53 (m, 2H), 2.10 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 171.6, 170.8, 66.9, 65.9, 60.6, 37.9,
20.5, 13.8. HRMS: Calculated for C8H14O5 (M + Na)+: 213.0739.
Found: 213.0747.
Ethyl 3,4-Dihydroxybutanoate (2g).21 1H NMR (400 MHz,
CDCl3) δ 4.18 (q, J = 7.1 Hz, 2H), 4.17−4.11 (m, 1H), 3.71−3.66 (m,
1H), 3.56−3.50 (m, 1H), 3.42 (d, J = 3.6 Hz, 1H), 2.59−2.43 (m,
3H), 1.28 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.4,
68.6, 65.6, 60.8, 37.9, 14.0.
Likewise, 3c and 3o were prepared from the corresponding alcohols
and 4-nitrobenzoyl chloride.
Ethyl 4-[(4-Chlorophenyl)thio]-3-hydroxybutanoate
(2h). 1H NMR (400 MHz, CDCl3) δ 7.34−7.25 (m, 4H), 4.16 (q,
J = 7.2 Hz, 2H), 4.14−4.08 (m, 1H), 3.22 (d, J = 3.9 Hz, 1H), 3.10−
3.00 (m, 2H), 2.67−2.53 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 171.9, 133.8, 132.4, 130.8, 129.1, 66.5, 60.8,
40.2, 39.8, 14.0; HPLC (Chiralcel AD-H column, n-hexane/i-PrOH =
90:10, 0.6 mL/min, 254 nm) t1 = 20.2 min, t2 = 23.0 min. HRMS:
Calculated for C12H15ClO3S (M + Na)+: 297.0328. Found: 292.0330.
Ethyl 4-[(4-Chlorophenyl)sulfonyl]-3-hydroxybutanoate
(2i). 1H NMR (400 MHz, CDCl3) δ 8.00−7.77 (m, 2H), 7.65−7.39
(m, 2H), 4.65−4.40 (m, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.52 (d, J = 3.7
Hz, 1H), 3.42−3.30 (m, 2H), 2.61 (d, J = 6.2 Hz, 2H), 1.25 (t, J = 7.1
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.0, 140.8, 137.8, 129.6,
129.5, 63.1, 61.3, 61.0, 40.3, 14.0; HPLC (Chiralcel AD-H column, n-
hexane/i-PrOH = 75:25, 0.5 mL/min, 220 nm) t1 = 22.1 min, t2 = 24.1
min. HRMS: Calculated for C12H15ClO5S (M + H)+: 307.0407.
Found: 307.0410.
1-(tert-Butoxy)-4-ethoxy-4-oxobutan-2-yl 4-Nitrobenzoate
(3b). 1H NMR (400 MHz, CDCl3) δ 8.29−8.18 (m, 4H), 5.58−
5.52 (m, 1H), 4.15−4.10 (m, 2H), 3.66−3.55 (m, 2H), 2.88−2.77 (m,
2H), 1.21 (t, J = 7.1 Hz, 3H), 1.17 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 170.1, 163.7, 150.3, 135.4, 130.6, 123.3, 73.3, 71.5, 62.0,
60.5, 36.1, 27.2, 14.0; HPLC (Chiralcel AS-H column, n-hexane/i-
PrOH = 85:15, 0.5 mL/min, 254 nm) t1 = 13.5 min, t2 = 14.7 min.
HRMS: Calculated for C17H23NO7 (M + Na)+: 376.1372. Found:
376.1390.
1-Chloro-4-ethoxy-4-oxobutan-2-yl 4-Nitrobenzoate
(3c). 1H NMR (400 MHz, CDCl3) δ 8.32−8.20 (m, 4H), 5.72−
5.67 (m, 1H), 4.16 (q, J = 7.1 Hz, 2H), 3.93−3.84 (m, 2H), 2.94−2.92
(m, 2H), 1.24 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
169.2, 163.5, 150.6, 134.8, 130.8, 123.5, 70.6, 61.0, 44.9, 36.2, 14.0;
HPLC (Chiralcel AS-H column, n-hexane/i-PrOH = 85:15, 0.5 mL/
min, 254 nm) t1 = 29.3 min, t2 = 31.6 min. HRMS: Calculated for
C13H14ClNO6 (M + H)+: 316.0588. Found: 316.0596.
Ethyl 3-Hydroxy-4-(phenylsulfonyl)butanoate (2j).14 1H
NMR (400 MHz, CDCl3) δ 7.97−7.94 (m, 2H), 7.71−7.67 (m,
1H), 7.62−7.58 (m, 2H), 4.56−4.49 (m, 1H), 4.14 (q, J = 7.1 Hz,
2H), 3.61 (d, J = 3.5 Hz, 1H), 3.43−3.31 (m, 2H), 2.62 (d, J = 6.2 Hz,
2H), 1.24 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.8,
139.2, 134.0, 129.3, 127.9, 63.0, 61.1, 60.9, 40.4, 14.0; HPLC
(Chiralcel IB-3 column, n-hexane/i-PrOH = 85:15, 0.5 mL/min, 215
nm) t1 = 29.7 min, t2 = 31.8 min. HRMS: Calculated for C12H16O5S
(M + H)+: 273.0797. Found: 273.0814.
5-Oxotetrahydrofuran-3-yl 4-Nitrobenzoate (3e−g). The
hydrogenated products of 1e, 1f, and 1g were treated with 1 M HCl
at rt for 8 h to give the same product 4-hydroxydihydrofuran-2(3H)-
1
one, which was further derived to its p-nitrobenzoate derivative 3: H
NMR (400 MHz, CDCl3) δ 8.33−8.20 (m, 4H), 5.76−5.74 (m, 1H),
4.66 (dd, J = 11.3, 4.7 Hz, 1H), 4.58−4.55 (m, 1H), 3.03 (dd, J = 18.6,
6.6 Hz, 1H), 2.84−2.79 (m, 1H); 13C NMR (100 MHz, DMSO) δ
178.7, 167.2, 153.8, 138.1, 134.3, 127.3, 76.1, 75.6, 37.7; HPLC
(Chiralcel AD-H column, n-hexane/i-PrOH = 60:40, 0.5 mL/min, 210
Ethyl 3-Hydroxy-4-tosylbutanoate (2k). 1H NMR (400 MHz,
CDCl3) δ 7.83−7.81 (m, 2H), 7.39−7.37 (m, 2H), 4.51−4.48 (m,
9449
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Article
nm) t1 = 22.3 min, t2 = 27.3 min. HRMS: Calculated for C11H9NO6
(M + H)+: 252.0508. Found: 252.0522.
give a viscous pale yellow oil. Flash chromatography with 40% EtOAc/
hexanes as eluent provided the desired product (25.9 g, 86%) as a
1-[(tert-Butoxycarbonyl)amino]-4-ethoxy-4-oxobutan-2-yl
4-Nitrobenzoate (3o). 1H NMR (400 MHz, CDCl3) δ 8.30−8.19
(m, 4H), 5.57−5.51 (m, 1H), 4.82 (t, J = 5.9 Hz, 1H), 4.17−4.10 (m,
2H), 3.55 (t, J = 5.8 Hz, 2H), 2.84−2.72 (m, 2H), 1.40 (s, 9H), 1.22
(t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.6, 163.8,
155.8, 150.3, 135.1, 130.7, 123.3, 79.4, 71.4, 60.7, 42.8, 36.4, 28.0, 13.9;
HPLC (Chiralcel AD-H column, n-hexane/i-PrOH = 85:15, 0.5 mL/
min, 254 nm) t1 = 31.5 min, t2 = 33.6 min. HRMS: Calculated for
C18H24N2O8 (M + Na)+: 419.1430. Found: 419.1425.
colorless oil. [α]20 = −12.9 (c = 0.83, CHCl3), which was in
D
agreement with the literature data [α]20D = −9.0 (c = 1.10, CHCl3):23a
1H NMR (400 MHz, CDCl3) δ 7.37−7.29 (m, 5H), 4.56 (s, 2H),
4.27−4.20 (m, 1H), 4.10−4.05 (m, 1H), 3.77 (d, J = 2.4 Hz, 1H),
3.47−3.41 (m, 2H), 3.27 (d, J = 1.6 Hz, 1H), 2.43−2.41 (m, 2H),
1.68−1.61 (m, 2H), 1.46 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
171.9, 137.9, 128.4, 127.7 (2C), 81.3, 74.1, 73.3, 70.4, 68.2, 42.5, 38.8,
28.0; HPLC analysis indicated >98.4% ee and >97.2% de (Chiralcel
IB-3 column analysis, flow 0.2 mL/min, i-PrOH/n-hexane = 25:75,
215 nm) (3R,5S) tR = 43.5 min (desired), (3S,5R) tR = 35.0 min,
retention times for the two undetermined isomers are 25.6 and 31.5
min.
Ethyl (S)-4-(Benzyloxy)-3-hydroxybutanoate (2a).2b To a 25
mL Schlenk tube were added (Ru(p-Cymene)Cl2)2 (12 mg, 20 μmol)
and (R)-TolSunPhos (32 mg, 44 μmol). The tube was vacuumed and
purged with nitrogen three times before the addition of freshly distilled
and degassed EtOH/CH2Cl2 (3 mL/3 mL). The resulting mixture was
heated at 50 °C for 1 h and then cooled to rt. The solvent was
removed under vacuum to give the catalyst. The catalyst was dissolved
in degassed ethanol (10 mL). In the meantime, a 300 mL autoclave
was charged with absolute EtOH (90 mL) and 1a (47.3 g, 200.0
mmol). The catalyst solution (via syringe) was introduced into the
autoclave, and the autoclave was closed under N2. H2 (20 bar) was
introduced three times and released each time through a valve into a
ventilated hood. The autoclave was then filled with H2 (20 bar) and
heated to 70 °C (inner temperature), and the contents were stirred for
18 h. The autoclave was cooled to room temperature. TLC analysis
indicated consumption of the starting material. The reaction solution
was concentrated in a rotary evaporator, and the residue was distilled
under reduced pressure to give 2a (43.1 g, 90%) as a colorless oil.
tert-Butyl 2-{(4R,6S)-6-[(Benzyloxy)methyl]-2,2-dimethyl-
1,3-dioxan-4-yl}acetate (5a).2b To a solution of 4a (20.0 g, 64.4
mmol) in acetone (30 mL) were added 2,2-dimethoxpropane (13.4 g,
128.9 mmol) and p-toluenesulfonic acid monohydrate (613 mg, 5 mol
%); the resulting mixture was stirred at rt until TLC analysis indicated
consumption of the starting material (∼4 h). Saturated NaHCO3 (20
mL) was added into the reaction mixture, and the mixture was stirred
for 30 min (pH 6−7). The mixture was concentrated and diluted with
EtOAc (100 mL). The layers were separated, the aqueous layer was
extracted with EtOAc (50 mL × 2), and the combined organic layers
were dried over anhydrous Na2SO4 and concentrated in vacuo. The
residue was purified by silica gel chromatography with 10% EtOAc/
hexanes as eluent to afford 5a (21.6 g, 96%) as a colorless oil: [α]20
=
D
1
−5.8 (c = 0.97, CHCl3); H NMR (400 MHz, CDCl3) δ 7.37−7.28
(m, 5H), 4.57 (q, J = 12 Hz, 2H), 4.32−4.25 (m, 1H), 4.15−4.08 (m,
1H), 3.50 (dd, J = 6.0, 9.6 Hz, 1H), 3.38 (dd, J = 4.6, 9.8 Hz, 1H), 2.43
(dd, J = 7.2, 15.2 Hz, 1H), 2.31 (dd, J = 5.8, 15.0 Hz, 1H), 1.60 (dt, J =
2.4, 13.2 Hz, 1H), 1.47 (s, 3H), 1.44 (s, 9H), 1.40 (s, 3H), 1.25 (q, J =
12.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 170.2, 138.2, 128.3,
127.7, 127.6, 98.8, 80.6, 73.4, 73.3, 68.4, 65.9, 42.7, 33.2, 30.0, 28.1,
19.6.
[α]20 = −10.0 (c = 1.18, EtOH), which was in agreement with the
D
literature data [α]20 = −9.0 (c = 1.18, EtOH).2b HPLC (ChiralPak
D
OD-H column, flow 0.5 mL/min, IPA/n-Hex = 5:95, 215 nm, (S)-2a
t1 = 30.4 min, (R)-2a t2 = 35.2 min): 98.4% ee of the (S)-
configuration.
tert-Butyl (S)-6-(Benzyloxy)-5-hydroxy-3-oxohexanoate
(3a).2b A 2.5 M solution of n-BuLi (237 mL, 590 mmol) was
added at −10 °C within 45 min to a solution of i-Pr2NH (86 mL, 609
mmol) in THF (200 mL). The resulting mixture was stirred 30 min at
0 °C. tert-Butyl acetate (66.0 g, 570 mmol) was added dropwise within
60 min at −40 °C. A solution of 2a (34.0 g, 143 mmol) in THF (200
mL) was added dropwise within 30 min at −40 °C, and the mixture
was stirred for 1 h at −40 °C. After completion of the reaction, H2O
(200 mL) was added to the reaction mixture (without cooling) within
30 min, leading to an inner temperature of 0 °C. The mixture was
concentrated via rotary evaporation and diluted with EtOAc (150
mL); the layers were separated, the aqueous layer was extracted with
EtOAc (100 mL × 2), and the combined organic layers were washed
with saturated NaCl (80 mL), dried over anhydrous Na2SO4, and
concentrated in vacuo. The residue was purified by silica gel
chromatography with hexanes and ethyl acetate (7:1) as eluent to
tert-Butyl 2-[(4R,6S)-6-(Hydroxymethyl)-2,2-dimethyl-1,3-di-
oxan-4-yl]acetate (6a).2b Pd/C (10%, 1.0 g) was added to a
solution of 5a (20 g, 57.0 mmol) in EtOAc (50 mL) in a 300 mL
autoclave. The autoclave was purged with H2 and then filled with H2
(10 bar). The mixture was stirred at constant H2 pressure with cooling
at 25−30 °C inner temperature for 5 h. The catalyst was filtrated with
a clarifying pad, and the filtrate was evaporated in vacuo. The residue
was dissolved in DCM (100 mL), and pyridine (18 mL, 165 mmol)
was added. To the resulting solution, AcCl (5.2 g, 65.9 mmol) was
added dropwise, and then the mixture stirred at rt for 30 min. After
completion of the reaction, the reaction mixture was washed with
saturated aqueous NaHCO3 solution (30 mL × 2) and brine (30 mL),
dried over anhydrous Na2SO4, and concentrated in vacuo. The residue
was crystallized from 50 mL heptane to afford 15.9 g tert-butyl 2-
[(4R,6S)-6-(acetoxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate:
[α]20D = 13.7 (c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 4.32−
4.26 (m, 1H), 4.15−3.99 (m, 3H), 2.45 (dd, J = 15.2, 7.0 Hz, 1H),
2.32 (dd, J = 15.2, 6.1 Hz, 1H), 2.08 (s, 3H), 1.57 (dt, J = 12.8, 2.4 Hz,
1H), 1.47 (s, 3H), 1.45 (s, 9H), 1.39 (s, 3H), 1.37−1.28 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 170.7, 169.9, 98.7, 80.5, 67.0, 66.8, 65.6,
42.4, 32.3, 29.7, 27.9, 20.7, 19.4.
afford 3a (33.0 g, 75%) as a pale yellow oil. [α]20 = +14.0 (c = 1.12,
D
CHCl3), which was in agreement with the literature data [α]20
=
D
+11.2 (c = 0.84, CHCl3):21a 1H NMR (400 MHz, CDCl3) δ 7.34−7.25
(m, 5H), 4.52 (s, 2H), 4.30−4.23 (m, 1H), 3.48−3.40 (m, 2H), 3.37
(s, 2H), 3.26 (s, 1H), 2.71 (d, J = 6.4 Hz, 2H), 1.45 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 203.0, 166.2, 137.8, 128.5, 127.8, 127.7, 73.4,
73.1, 66.7, 51.2, 46.2, 28.0.
To a solution of tert-butyl 2-[(4R,6S)-6-(acetoxymethyl)-2,2-
dimethyl-1,3-dioxan-4-yl]acetate (15.9 g, 52.6 mmol) in MeOH (50
mL) was added K2CO3 (3.6 g, 26.3 mmol); the resulting mixture was
stirred at rt until TLC analysis indicated consumption of the starting
material (∼30 min). The reaction mixture was filtrated, and the filtrate
was concentrated in vacuo. The residue was diluted with EtOAc (50
mL) and extracted. The organic phase was washed with brine (20 mL)
and dried over anhydrous Na2SO4. The solvent was concentrated
under reduced pressure and subjected to the column chromatography
(15% EtOAc in hexanes) to give the Kaneka alcohol 6a (13.2 g, 89%)
tert-Butyl (3R,5S)-6-(Benzyloxy)-3,5-dihydroxyhexanoate
(4a).2b To a solution of 3a (30.0 g, 97.3 mmol) in THF (150 mL)
and MeOH (30 mL) was added Et2BOMe (21.4 g, 107.0 mmol, 50%
in THF), and the solution was stirred for 30 min at rt before being
cooled to −78 °C. NaBH4 (4.1 g, 107.0 mmol) was added portionwise
over 10 min (moderate gas evolution observed). After the solution was
stirred for 4.5 h at −78 °C, 120 mL of 30% aqueous H2O2 was slowly
added to the cold solution via addition funnel. The mixture was
allowed to warm to rt and then stirred for 2 h at rt. The mixture was
concentrated and extracted with EtOAc (100 mL × 3). The combined
layers were washed successively with saturated NaHCO3 (50 mL × 2),
then water (80 mL), saturated Na2S2O3 (80 mL), and saturated NaCl
(80 mL) before being dried over Na2SO4 and concentrated in vacuo to
as a colorless oil. [α]20 = +12.0 (c = 0.94, CHCl3), which was in
D
agreement with the literature data [α]20 = +9.9 (c = 2.0, CHCl3),
D
−6.8 (c = 1.5, MeOH):23b 1H NMR (400 MHz, CDCl3) δ 4.32−4.27
(m, 1H), 4.04−3.99 (m, 1H), 3.65−3.59 (m, 1H), 3.53−3.47 (m, 1H),
9450
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Article
2.45 (dd, J = 15.2, 7.1 Hz, 1H), 2.32 (dd, J = 15.2, 6.1 Hz, 1H), 2.09−
2.06 (m, 1H), 1.52−1.48 (m, 1H), 1.48 (s, 3H), 1.45 (s, 9H), 1.39 (s,
3H), 1.37−1.28 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 170.1, 98.8,
80.6, 69.5, 65.8, 65.7, 42.5, 31.7, 29.8, 28.0, 19.9. Compound 6a was
converted to tert-Butyl (3R,5S)-6-(benzyloxy)-3,5-dihydroxyhexanoate
4a for chiral purity analysis by chiral HPLC. HPLC analysis (Chiralcel
IB-3 column analysis, flow 0.2 mL/min, IPA/n-Hex = 25:75, 215 nm)
indicated >99.5% ee and >99.5% de.
(b) Ratovelomanana-Vidal, V.; Girard, C.; Touati, R.; Tranchier, J.
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P.; Ben Hassine, B.; Genet, J.-P. Adv. Synth. Catal. 2003, 345, 261.
(c) Kitamura, M.; Ohkuma, T.; Inoue, S.; Sayo, N.; Kumobayashi, H.;
Akutagawa, S.; Ohta, T.; Takaya, H.; Noyori, R. J. Am. Chem. Soc.
1988, 110, 629.
(6) (a) Poupardin, O.; Greck, C.; Genet
(b) Korostylev, A.; Andrushko, V.; Andrushko, N.; Tararov, V. I.;
Konig, G.; Borner, A. Eur. J. Org. Chem. 2008, 5, 840. (c) Tararov, V.
̂
, J.-P. Synlett 1998, 11, 1279.
̈
̈
I.; Andrushko, N.; Andrushko, V.; Konig, G.; Spannenberg, A.; Borner,
̈
̈
A. Eur. J. Org. Chem. 2006, 24, 5543.
ASSOCIATED CONTENT
* Supporting Information
■
(7) (a) Junge, K.; Hagemann, B.; Enthaler, S.; Oehme, G.; Michalik,
M.; Monsees, A.; Riermeier, T.; Dingerdissen, U.; Beller, M. Angew.
S
The NMR and/or HPLC data of compounds 1−6. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Chem., Int. Ed. 2004, 43, 5066. (b) Karame,
́
I.; Bellur, E.; Rotzoll, S.;
Langer, P.; Fischer, C.; Holz, J.; Borner, A. Synth. Commun. 2007, 37,
̈
1067. (c) Pai, C.-C.; Lin, C.-W.; Lin, C.-C.; Chen, C.-C.; Chan, A. S.
C.; Wong, W. T. J. Am. Chem. Soc. 2000, 122, 11513. (d) Genet
Pinel, C.; Ratovelomanana-Vidal, V.; Mallart, S.; Pfister, X.; Bischoff,
̂
, J.-P.;
AUTHOR INFORMATION
■
L.; Cano De Andrade, M. C.; Darses, S.; Galopin, C.; Laffitte, J. A.
̃
Corresponding Author
*E-mail: zhaoguo@sjtu.edu.cn.
Tetrahedron: Asymmetry 1994, 5, 675. (e) Zhou, Y.-G.; Tang, W.;
Wang, W. B.; Li, W.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 4952.
(8) Nishi, T.; Kitamura., M.; Ohkuma, T.; Noyori, R. Tetrahedron
Lett. 1988, 29, 6327.
(9) (a) Li, W.; Ma, X.; Fan, W.; Tao, X.; Li, X.; Xie, X.; Zhang, Z.
Org. Lett. 2011, 13, 3876. (b) Sun, Y.; Wan, X.; Wang, J.; Meng, Q.;
Zhang, H.; Jiang, L.; Zhang, Z. Org. Lett. 2005, 7, 5425. (c) Wan, X.;
Sun, Y.; Luo, Y.; Li, D.; Zhang, Z. J. Org. Chem. 2005, 70, 1070.
(d) Wan, X.; Meng, Q.; Zhang, H.; Sun, Y.; Fan, W.; Zhang, Z. Org.
Lett. 2007, 9, 5613. (e) Meng, Q.; Sun, Y.; Ratovelomanana-Vidal, V.;
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China,
the Science and Technology Commission of Shanghai
Municipality, and the Education Commission of Shanghai
Municipality for financial support.
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