Ruthenium-catalyzed asymmetric hydrogenation of 3-oxoglutaric acid derivatives: A study of unconventional solvent and substituent effects

Article abstract of DOI:10.1002/chem.201202614

A series of 3-oxoglutaric acid derivatives have been hydrogenated in different solvents in the presence of [RuCl(benzene)(S)-SunPhos]Cl (SunPhos=(2,2,2′,2′-tetramethyl-[4,4′-bibenzo[d][1,3]dioxole] -5,5′-diyl)bis(diphenylphosphine)). Unlike simple β-keto acid derivatives, these advanced analogues can be readily hydrogenated in uncommon solvents such as THF, CH₂Cl₂, acetone, and dioxane with high enantioselectivities. Two possible catalytic cycles have been proposed to explain the different reactivities of these 1,3,5-tricarbonyl substrates in the tested solvents. The C-2 and C-4 substituents had notable but irregular influence on the reactivity and enantioselectivity of the reactions. More pronounced solvent effects were observed: the ee values increased from around 20 % in EtOH or THF to 90 % in acetone. Inversion of the product configuration was observed when the solvent was changed from EtOH to THF or acetone, and a mixed solvent system can lead to better enantioselectivity than a single solvent. Pronounced solvent effects: 3-Oxoglutaric acid derivatives have been hydrogenated in various solvents with high enantioselectivities (see scheme). Inversions of the product configuration were observed when the solvent was changed. Mixed solvent systems can give better enantioselectivities than a single solvent.

Full text of DOI:10.1002/chem.201202614

FULL PAPER
DOI: 10.1002/chem.201202614
Ruthenium-Catalyzed Asymmetric Hydrogenation of 3-Oxoglutaric Acid
Derivatives: A Study of Unconventional Solvent and Substituent Effects
Wanfang Li,[a] Xiaoming Tao,[a] Xin Ma,[a] Weizheng Fan,[a] Xiaoming Li,[a]
Mengmeng Zhao,[a] Xiaomin Xie,[a] and Zhaoguo Zhang*[a, b]
Abstract: A series of 3-oxoglutaric acid
derivatives have been hydrogenated in
different solvents in the presence
enantioselectivities. Two possible cata-
lytic cycles have been proposed to ex-
plain the different reactivities of these
1,3,5-tricarbonyl substrates in the
tested solvents. The C-2 and C-4 sub-
stituents had notable but irregular in-
fluence on the reactivity and enantiose-
lectivity of the reactions. More pro-
nounced solvent effects were observed:
the ee values increased from around
20% in EtOH or THF to 90% in ace-
tone. Inversion of the product configu-
ration was observed when the solvent
was changed from EtOH to THF or
acetone, and a mixed solvent system
can lead to better enantioselectivity
than a single solvent.
of
(SunPhos=(2,2,2’,2’-tetramethyl-[4,4’-
bibenzo[d][1,3]dioxole]-5,5’-diyl)bis(di-
[RuClACHTUNGTRENNUNG(benzene)(S)-SunPhos]Cl
ACHTUNGTRENNUNG
phenylphosphine)). Unlike simple b-
keto acid derivatives, these advanced
analogues can be readily hydrogenated
in uncommon solvents such as THF,
CH2Cl2, acetone, and dioxane with high
Keywords: asymmetric catalysis
configuration inversion · hydrogen-
ation · ruthenium · solvent effects
·
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
Introduction
good-to-excellent enantioselectivities. In this article, we
report the effects of solvent and substituents on the reaction
by using a wider scope of solvents and substrates.
The asymmetric hydrogenation of ketones represents one of
the most powerful tools for the construction of chiral alco-
hols in both academia and industry.[1] Although mono- and
nonfunctionalized ketones have been hydrogenated with
spectacular enantioselectivities,[2] polyfunctionalized ketones
have remained elusive because the different directing func-
tionalities often compete to coordinate with the central
metal of the catalyst (Scheme 1a).[3] Higher temperatures[4]
or greater steric distinctions[5] enhance the enantioselectivi-
ties in certain cases, but are not always effective. For exam-
ple, 3k and 3l were hydrogenated to 4k and 4l, respectively,
with poor enantioselectivities in the presence of [RuCl-
Scheme 1. Competitive coordination in polyfunctionalized ketones.
ACHTUNGTRENNUNG(benzene)(S)-SunPhos]Cl (Scheme 1b). Bçrner and co-
workers[6] first reported a highly enantioselective hydrogena-
tion of one 3-oxoglutaric acid derivative (X=COOMe, Y=
CONHtBu) by using rhodium and ruthenium complexes;
enantioselectivities of up to 96% were achieved.
Results and Discussion
Initial discovery of asymmetric hydrogenation in THF: We
previously observed that no desired products were obtained
when b-keto-Weinreb and morpholyl amide were hydrogen-
ated in EtOH (Scheme 2). Unexpectedly, parts of 1a and 1b
were alcoholized to yield ethyl acetoacetate (1d) and the
In an earlier study,[7] we realized the asymmetric hydro-
ACHTUNGTRENNUNGgenACHTUNGTRENNUNGation of a series of 3-oxoglutaric acid derivatives with
[a] W. Li, X. Tao, X. Ma, W. Fan, X. Li, M. Zhao, X. Xie, Prof. Z. Zhang
School of Chemistry and Chemical Engineering
Shanghai Jiao Tong University
libACHTNUTGRNEUNG
erated amines poisoned the catalyst.[8] Therefore nonalco-
hol solvents were used instead. We found that THF, an inef-
fective solvent for the hydrogenation of b-keto esters,[9] was
an excellent alternative for the hydrogenation of b-keto
amides.
800 Dongchuan Road, Shanghai 200240 (P.R. China)
Fax : (+86)21-5474-8925
E-mail: zhaoguo@sjtu.edu.cn
On the basis that b-keto amides are more electron rich[10]
1,3-dicarbonyls than b-keto esters, they can preferably be
anchored by ruthenium catalysts even in the presence of a
large excess of the coordinating THF.[11] However, Cerveny
and co-workers reported that methyl acetoacetate can still
[b] Prof. Z. Zhang
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
345 Lingling Road, Shanghai 200032 (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202614.
Chem. Eur. J. 2012, 18, 16531 – 16539
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
16531

strong coordinating nature of the nitrile group,[14] which pro-
hibited the substrates from being captured by the catalyst.[15]
The hydrogenation reactions were slower in CH2Cl2.[6] For
example, the conversions of 3c and 3j were only 65 and
40%, respectively, under the same conditions. However, we
found that 3 f was almost inert in CH2Cl2, but it was readily
hydrogenated with 91.4% ee by adding a catalytic amount
of sulfuric acid (entry 6, Table 1). Protic acids usually act as
accelerators in the asymmetric hydrogenation reactions of
b-keto esters.[16] With the substituted phenyl amides 3g–j,
CH2Cl2 gave much lower ee values than with other solvents.
Acetone is also an acceptable solvent for the hydrogenation
of b-keto esters, but usually the turnover frequency in this
solvent is lower than in ethanol or methanol[9d,17] and a
small amount of water is necessary to achieve an acceptable
conversion.[18] In this work, the carefully dried acetone
seemed to be an all-purpose solvent for most substrates. For
example, the secondary amides 3a–e led to ee values ranging
from 93.3% to 98.5%. The ee value of 4e was >98% in
acetone, which is comparable to that obtained in the enzy-
matic preparation of an important precursor to Atorvasta-
tin.[19] Ethereal solvents were generally ineffective for the
ruthenium-catalyzed asymmetric hydrogenation of simple b-
keto esters.[9d,17] However, dioxane worked well for the hy-
drogenation of the tested substrates (Table 1), affording
comparable enantioselectivities to those obtained in THF.
The presence of substituents on the N-phenyl rings of the
Scheme 2. Alcoholysis of b-keto amides under catalytic conditions.
be readily hydrogenated in THF and that the reaction rate
could be improved by adding a small amount of water or
methanol.[12] Our experiment in carefully dried THF showed
that b-keto ester 1c underwent no conversion, but full con-
version with moderate enantioselectivity was observed by
adding a catalytic amount of a protic acid (Scheme 3).[13]
Scheme 3. Acid-promoted asymmetric hydrogenation of b-keto esters in
THF. Ru-cat.=[RuACHTUNGTRENNUNG(benzene)Cl(S)-SunPhos]Cl.
Solvent effects: To gain an in-depth understanding of the
role of solvents in the hydrogenation reaction, several other
solvents were examined. Like 1a and 1b, 3c and 3 f pro-
duced no hydrogenation products due to alcoholysis in
EtOH. However, we found that in 2-PrOH, 3c can be readi-
ly hydrogenated to afford 4c with 95.1%ee (entry 3,
Table 1) but 3 f was again alcoholized (with <10% conver-
sion and 33.3% ee (entry 6, Table 1). The reactions proceed-
ed well except in acetonitrile. We attributed this to the
amide remarkably influenced the ee values of the hydro
ACHTUNGTRENNUNGgen-
AHCTUNGTREGaNNNU tion products. For example, the more electron-donating
methyl or methoxy groups at the ortho or para positions im-
proved the ee values by 40–50%. Of note, the presence of a
p-trifluoromethyl group on the N-phenyl rings de-
creased the ee drastically from 62.9 to 24.2% in
Table 1. Asymmetric hydrogenation of 3-oxoglutarate acid derivatives in different sol-
vents.[a]
CH2Cl2. Comparing the data in entries 9 and 10 in
Table 1, we reckoned that the coordination ascend-
ency of amide carbonyls over ester carbonyls was
impaired by the strong electron-withdrawing nature
of the trifluoromethyl group, and vice versa, the
higher ee value of 4i relative to 4g in all the tested
solvents (entry 9 vs. entry 7, Table 1) can be attrib-
uted to the greater electron richness of the amide
carbonyls.
To sum up, the optimum solvent for the reaction
is substrate-dependent. With the exception of 3a
and 3 f (entries 1 and 6, Table 1), the ee values
varied considerably in different solvents. For exam-
ple, the diphenylamide 4d (entry 4, Table 1) was
obtained with high ee in THF (98.1%), acetone
(97.9%), and dioxane (97.1%), but with only
53.3% ee in EtOH.
Entry
3
R1, R2
ee [%]
THF[b] EtOH[b]
CH2Cl2 Acetone Dioxane
1
2
3
3a
3b
Et
–(CH2)5–
96.5
95.2
93.4
86.5
97.8
96.7
98.5
98.5
93.3
97.9
98.2
88.3
91.9
89.2
92.4
75.9
97.5
94.7
94.2
97.1
95.5
84.4
76.8
85.4
85.9
54.9
3c –(CH2)2O
(CH2)2– 96.4
N/A (95.1)[c] 92.5[d]
4
5
6
7
8
9
10
3d
3e
3 f
3g
3h
3i
Ph2
Bn2
98.1
89.7
87.3
86.7
93.6
88.2
49.3
53.3
86.8
93.8
92.9
Me, OMe
Ph, H
2,6-Me2Ph, H
p-MeOPh, H
p-CF3Ph, H
N/A (33.3)[c] 91.4[e]
88.4
70.1
90.2
88.6
62.9
64.1
75.6
24.2[f]
3j
[a] All reactions were carried out with 0.5 mmol of substrate in 2.5 mL of solvent at
708C under 20 bar of H2 for 10 h. [Ru(benzene)Cl2]2/ligand/substrate=1:2.1:100. The
AHCTUNGTRENNUNG
Mechanistic proposal: For a deeper understanding
of the solvent effects, two possible reaction path-
ways were proposed in accord with literature data
(Scheme 4). Cycle I is based on the comparatively
well-recognized mechanism for b-keto ester hydro-
genation reactions.[2] However, it does not explain
conversions were 100% unless indicated otherwise. The ee values were determined by
chiral HPLC. [b] Data are quoted from ref. [7]. [c] N/A=No product separated due to
alcoholysis of the reactant, the ee values in the brackets were obtained in 2-PrOH.
After 7 h, the conversions of 3c and 3 f were 100 and <10%, respectively. The alco-
holysis product 1-ethyl-5-isopropyl-3-oxopentanedioate was detected for 3 f. [d] 65%
conversion by 1H NMR. [e] 2 equiv (based on the catalyst) of 0.8m H2SO4 (aq.) were
1
added, otherwise the conversion was very low. [f] 40% conversion by H NMR.
16532
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Chem. Eur. J. 2012, 18, 16531 – 16539

Asymmetric Hydrogenation of 3-Oxoglutaric Acids
FULL PAPER
the product 4 and regenerate the active catalyst A. A similar
process was also proposed by Hamada and co-workers in
their anti-selective asymmetric hydrogenation of a-amino-b-
keto esters by dynamic kinetic resolution.[21]
The catalytic cycle II features the hydrogenation of the
enol double bond. According to this cycle, a protic solvent is
not necessary for the ready hydrogenation of enol-enriched
substrates. Tautomeric shifts in the b-dicarbonyl substrates
are greatly influenced by the solvent[22] and the acidity of
the solution.[23] We believe that the hydrogenation reaction
proceeds through both cycles in protic solvents or in the
presence of protic acids. For example, when the hydrogena-
tion of 3c and 3h was carried out in THF by adding a cata-
lytic amount of sulfuric acid or p-toluenesulfonic acid, the ee
values of 4c and 4h dropped significantly from 96.4 and
93.6% to 79.8 and 73.7% (Table 1, entries 3 and 8), respec-
tively.
Asymmetric hydrogenation of substituted substrates: Next
we extended the substrate scope to the 4,4-disubstituted 3-
oxoglutaric acid derivatives 5a–j. As shown in Table 2, com-
Table 2. Asymmetric hydrogenation of 5a–j.[a]
Entry
5
R1
R2
ee [%]
THF
EtOH
Acetone
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5 f
5g
5h
5i
Et
tBu
Et
Et
Et
Et
Et
Et
Et
Me
Me
–(CH2)2–
–(CH2)3–
–(CH2)4–
Et
ꢀ67.7[b]
ꢀ56.2[b]
77.5[b]
86.2[b]
ꢀ88.1[b]
NR[e]
90.3[f]
49.3
49.1
51.9
80.8
13.2
12.2
nt[c]
44.7
42.9
45.9
16.3
nt[c]
nt[c]
nt[c]
81.8[d]
65.1[d]
NR[e]
87.1
55.3
76.1
Me
–(CH2)2–
–(CH2)3–
–(CH2)4–
56.9
22.7
Scheme 4. Proposed pathways for the asymmetric hydrogenation of 3.
10
5j
tBu
91.8
[a] Reactions were carried out under 20 bar of H2 for 15 h at 708C, S/C=
200. The conversions were 100% unless indicated otherwise. The ee
values were determined by HPLC, the ee values of 6a–e were determined
as their 4-nitrobenzoates. [b] The conversions of 5a–e were 52, 31, 37, 29,
and 52% after 20 h. [c] nt=not detected due to a very low conversion.
[d] The conversions of 5d and 5e were 36 and 45%, respectively.
[e] NR=No reaction, even at a higher temperature and after a prolonged
reaction time. [f] 26 h was required for full conversion.
why 3k and 3l could be hydrogenated in a nonprotic solvent
like THF. Therefore we reconsidered the possibility of the
participation of the enol form in the hydrogenation reac-
tions,[20] which has not been excluded previously.[15d,26]
Substrates 3a–l exist in both the keto and enol forms in
various proportions (see the Supporting Information). As
suggested in cycle II, enol 3 first exchanges the solvent lig-
A
pounds 5a–e were hydrogenated more slowly in THF than
in EtOH. Herein, cycle I in Scheme 4 became advantageous
because fully substituted C-4 disfavors the formation of enol
tautomers. However, the ee values were much higher than
those of the unsubstituted counterparts (3k and 3l). Full
conversions of 5a–e were observed in EtOH but with gener-
ally much lower ee values than in THF. One exception is the
cyclopropyl-substituted substrate 5c, which afforded 6c in a
higher ee in EtOH (entry 3, Table 2). The reactions of esters
mer enol 3’ is also possible), which easily isomerizes to C’ in
which the C=C double bond coordinates to ruthenium in-
stead of the enolic hydroxy group. Such a s!p transforma-
tion does not necessarily require the protonation of the C-3
carbonyl as in cycle I. Then intramolecular enol C=C inser-
tion into the ruthenium hydride takes place to form D’. Fi-
nally, D’ is subjected to s-bond metathesis with hydrogen or
protonolysis with acid (via the enol form of D’) to liberate
Chem. Eur. J. 2012, 18, 16531 – 16539
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16533

Z. Zhang et al.
5a–e were rather slow in acetone and the enantioselectivi-
ties were in between those observed in THF and EtOH. To
our surprise, for several substrates, the products were
formed with opposite configurations in the two solvents.
This apparent anomaly will be discussed later (see Table 4).
The dimethyl-substituted amide 5g (entry 7, Table 2) was
hydrogenated to give 6g with a much higher ee in THF than
in EtOH, whereas the ring-containing amides 5h–j (en-
tries 8–10, Table 2) afforded the products with much lower
ee values. For example, substrate 5j, bearing a five-mem-
bered ring, gave 6j with an equally low ee in THF and
EtOH. However, these ring-containing amides (5h–j) can
be hydrogenated with much higher ee values in acetone. For
5j, the ee increased strikingly from 22.7% in THF and
16.3% in EtOH to 91.8% in acetone. Note that the hydro-
genation activity of the diethyl-substituted ester 5 f was ex-
tremely low in all the tested solvents and essentially no hy-
drogenation product was observed (entry 6, Table 2). Nota-
bly, the rate of reduction of 5 f with NaBH4 was much
slower than that of 5a.
According to the proposed mechanism in Scheme 4, the
low activities of 5k–r in THF are due to the reluctance of
the keto–enol tautomerization. The reactivity of 5k towards
hydrogenation in THF was improved when 4 equivalents of
H2SO4 were added (see footnote in Table 3). In EtOH, the
hydrogenation of 5k–r probably proceeded through cycle I,
as illustrated by the competition experiment shown in
Scheme 5. A 1:1 mixture of 1d and 1e was hydrogenated in
Scheme 5. Relative rates of the asymmetric hydrogenation reactions of
1d and 1e.
The effect of C-2 substitution was also investigated
(Table 3). When Het=NHtBu and R=Me (entry 1, Table 3)
Table 3. Asymmetric hydrogenation of 5k–r.[a]
the presence of 0.5 mol% [RuClACTHNUGRTNEUNG(benzene)(S)-SunPhos]Cl
(20 bar of H2, 708C, EtOH), the timescales of the conver-
1
sions determined by GC and H NMR were as follows: for
1d: 25% in 1 h, 95% in 2 h, 100% in 5 h; for 1e: 1% in
1 h, 5% in 2 h, 100% in 5 h.
Entry
5
R
Het
ee [%]
THF
EtOH
Inversion of chirality induced by different solvents: This
phenomenon has previously been reported in rhodium-cata-
lyzed asymmetric hydrogenation reactions of some dehy-
droamino esters,[24] enol acetates,[25] itaconates,[26] and
ketone-derived hydrazones,[27] but seldom been observed in
ruthenium-catalyzed ketone hydrogenation reactions.[28] Be-
cause the reactivity was higher in EtOH than in THF, we
performed reactions in a mixed solvent of EtOH/THF (8:1,
v/v). The configurations of the major hydrogenation prod-
ucts were the same as those obtained in EtOH, however,
the ee values of 6a and 6e were in between the values ob-
served in THF and EtOH, but higher ee values were found
when the hydrogenation reactions were carried out on 5b
and 5k in a mixed solvent (Table 4). For example, the ee of
6k was 85.2% in the mixed solvent of EtOH/THF, a much
better enantioselectivity than obtained in a pure solvent.[29]
1
2
3
4
5
5
6
7
5k
5l
Me
–(CH2)2–
Me
Me
Et
NHtBu
NHtBu
NMe2
NMeOMe
NMeOMe
NMeOMe
NMeOMe
NMeOMe
ꢀ63.7[b]
ꢀ36.3[c]
NR[d]
NR
NR
NR
52.7
70.7
71.9
97.0
NR
32.5
84.1
91.7[e]
5m
5n
5o
5p
5q
5r
–
–
–
N
NR
NR
[a] The reactions were carried out under 20 bar of H2 for 15 h at 708C. S/
C=200. The conversions were 100% unless indicated otherwise. The ee
values were determined by HPLC, the ee values of 6l–m were deter-
mined as their 4-nitrobenzoates. [b] 37% conversion in 20 h, 100% con-
version was observed in 10 h when 4 equiv (based on catalyst) of 0.8m
H2SO4 (aq.) were added. [c] The reaction was performed under 30 bar of
H2 at 858C for 24 h; [d] NR=No reaction. [e] Quoted from ref. [8].
or R=–(CH2)2– (entry 2, Table 3), different enantiomers
were obtained in THF and EtOH with variable ee values.
Other secondary amides were inert in THF, but they were
easily hydrogenated in EtOH. Comparing 5m and 5n, it was
surprising that the presence of an oxygen atom at the amide
nitrogen increased the ee from 71.9 to 97.0%. As the size of
the ring at C-2 became larger, the ee increased from 32.5 to
91.7% (entries 5–7, Table 3). Like 5 f in Table 1, the diethyl-
substituted Weinreb amide 5o was also totally inert in all
the tested solvents (even NaBH4 reduction failed to produce
6o).
Table 4. Hydrogenation of substrates 5 to 6 in mixed solvents.[a]
Entry
5
ee [%] of 6
EtOH
THF
EtOH/THF=8:1
1
2
3
4
5
5a
5b
5e
5k
5p
ꢀ67.7
ꢀ56.2
ꢀ88.1
ꢀ63.7
49.1
51.9
12.2
52.7
32.5
43.6
59.8
26.7
85.2
35.4[c]
NR[b]
[a] The reactions were performed under 20 bar of H2 for 15 h at 708C. S/
C=200. [b] NR=No reaction. [c] 90% conversion.
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Chem. Eur. J. 2012, 18, 16531 – 16539

Asymmetric Hydrogenation of 3-Oxoglutaric Acids
FULL PAPER
The preparations of substrates 1a–d, 3a–d, 3 f–j, 5b, 5g, 5n, and 5r were
reported in the Supporting Information of our previous letter.[7] The reac-
tion schemes for other new substrates and the data for the derivatives of
some hydrogenation products are provided in the Supporting Informa-
tion.
Conclusions
We have studied the effect of solvent on the enantioselectiv-
ity and reactivity of the asymmetric hydrogenation of a
series of 3-oxoglutaric acid derivatives. As a result of the un-
usual activities observed in some non-protic solvents, a dif-
ferent catalytic cycle involving enol hydrogenation has been
proposed. This new hydrogenation pathway explains why
the 1,3,5-tricarbonyl compounds can be hydrogenated suc-
cessfully in non-protic solvents like THF, CH2Cl2, acetone,
and dioxane. Different amide substrates behaved quite dif-
ferently in the same solvent. In addition, substituents on the
2- or 4-methylenes had a clear influence on the activity and
enantioselectivity of the reaction. Moderate-to-good ee
values were obtained by choosing the right solvent. More
importantly, the solvent induced chiral inversions in the hy-
drogenation of some substituted substrates. Although the
mechanism of the solvent effect, which has puzzled many
physical organic chemists for a long time, has not been eluci-
dated, we believe that our finding of this pronounced sol-
vent effect will help to increase the probability of highly se-
lective hydrogenations of polyfunctionalized ketones.
N-Methoxy-N,2,2-trimethyl-3-oxobutanamide (1e): N-Methoxy-N,2,2-tri-
methyl-3-oxobutanamide (1e’) was prepared by a similar procedure to
that described in the literature[31] and used without purification in the
next step. The crude 1e’ (2.2 g, 13.8 mmol) in THF (5 mL) was added
dropwise to a suspension of NaH (830 mg, 60% dispersed in mineral oil,
21.0 mmol) in THF (20 mL). After 1.5 h, MeI (2.5 mL, 41.0 mmol) was
added dropwise and the mixture was stirred overnight. It was then
poured into 10% aqueous HCl (20 mL) and extracted with ethyl acetate
(4ꢁ5 mL). The combined organic phase was dried over Na2SO4. Column
chromatography (PE/EA=3, Rf =0.4) afforded 1e as
a light-yellow
1
liquid (1.8 g, 75%). H NMR (400 MHz, CDCl3): d=3.58 (s, 3H), 3.19 (s,
3H), 2.08 (s, 3H), 1.32 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=
205.7, 175.2, 60.4, 54.6, 33.0, 25.7, 22.3 ppm; HRMS: calcd for C8H15NO3
[M+H]+: 174.1130; found: 174.1141.
3-Hydroxy-N-methoxy-N,2,2-trimethylbutanamide
(2e):
1H NMR
(400 MHz, CDCl3): d=3.96–3.86 (m, 1H), 3.69 (s, 3H), 3.49 (d, J=
6.0 Hz, 1H), 3.18 (s, 3H), 1.23 (d, J=2.2 Hz, 6H), 1.17 ppm (d, J=
6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=178.7, 73.2, 60.6, 47.0, 33.5,
21.2, 18.9, 17.2 ppm; FTIR (KBr pellet): n˜ =3454, 2977, 2940, 1629, 1464,
1410, 1365, 1163, 1102, 994 cmꢀ1; HRMS: calcd for C8H17NO3 [M+H]+:
176.1287; found: 176.1296.
1-tert-Butyl 5-ethyl 3-oxopentanedioate (3k):[32] The mono-ester of 3-oxo-
glutaric acid was prepared according to a literature procedure[33] and di-
AHCTUNGRETGeNNUN ster formation also by a
known procedure.[34] 1H NMR (400 MHz,
CDCl3) ratio of enol form (ef) and keto form (kf)=20:80: d=12.24 and
12.08 (br, Hef, OH), 5.10 and 5.03 (s, CH=C), 4.20 (q, J=7.1 Hz, 2H),
3.58 and 3.51 (s, Hef, CH2CO), 3.18 and 3.13 (s, Hkf, CH2CO), 1.46 (s, 9H;
Experimental Section
CACTHNUTRGNEUNG
(CH3)3), 1.28 ppm (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
General: All reactions were carried out under an atmosphere of nitrogen
by using standard Schlenk techniques unless otherwise noted. 1H and
13C NMR spectra were obtained on a 400 MHz Varian NMR spectrome-
ter. The 1H chemical shifts were recorded in ppm downfield from tetra-
methylsilane (TMS) with the solvent resonance as the internal standard.
The 13C chemical shifts were recorded in ppm downfield using the central
peak of CDCl3 (77.0 ppm) as the internal standard. Coupling constants
(J) are reported in Hz and refer to apparent peak multiplications. Flash
column chromatography was performed on silica gel (300–400 mesh). IR
(KBr pellet) spectra were recorded with a Perkin–Elmer Spectrum 100
FT-IR spectrometer. Commercially available reagents were used without
further purification except for those detailed below. The solvents used in
catalyst preparation and hydrogenation reactions were pretreated as fol-
lows:[30] THF and dioxane were distilled over sodium benzophenone
ketyl under nitrogen, CH2Cl2 was distilled over calcium hydride, EtOH
was distilled over magnesium under nitrogen, acetone was dried with an-
hydrous CaSO4 for two days and freshly distilled before use, acetonitrile
was dried over P2O5 and distilled before use.
195.8, 166.6, 165.7, 93.2, 91.6, 82.1, 61.3, 61.2, 60.1, 50.1, 48.8, 42.0, 40.8,
27.7, 13.9 ppm.
1-tert-Butyl 5-ethyl 3-hydroxypentanedioate (4k):[35] 1H NMR (400 MHz,
CDCl3): d=4.49–4.34 (m, 1H), 4.17 (q, J=7.1 Hz, 2H), 3.52–3.41 (m,
1H), 2.52 (dd, J=6.3, 2.7 Hz, 2H), 2.46 (d, J=6.3 Hz, 2H), 1.46 (s, 9H),
1.27 ppm (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=171.5,
171.0, 81.0, 64.7, 60.4, 41.6, 40.6, 27.8, 13.9 ppm; FTIR (KBr pellet): n˜ =
3482, 2980, 2935, 1728, 1454, 1398, 1257, 1154, 1042, 956, 843 cmꢀ1
.
1-Benzhydryl 5-ethyl 3-oxopentanedioate (3l): 1H NMR (400 MHz,
CDCl3) ratio of enol form (ef) and keto form (kf)=91:9: d=12.11 and
11.94 (br, Hef, OH), 7.53–7.11 (m, 10H; Ar-H), 6.92 (d, J=9.2 Hz, 1H),
5.31 and 5.11 (s, Hef, CH=C), 4.30–4.04 (m, 2H), 3.72 and 3.57 (s, Hef,
CH2CO), 3.39–3.33 (m, Hkf, CH2CO), 3.23 (s, Hkf, CH2CO), 1.36–
1.12 ppm (m, 3H); 13C NMR (100 MHz, CDCl3): d=195.3, 171.3, 170.8,
166.6, 165.8, 139.5, 128.5, 128.1, 128.0, 127.1, 127.0, 92.2, 91.9, 78.0, 61.4,
48.9, 40.8, 13.9 ppm; FTIR (KBr pellet): n˜ =3436, 3030, 1744, 1714, 1496,
1450, 1407, 1322, 1249, 1146, 1026, 966, 761, 700 cmꢀ1; HRMS: calcd for
C20H20O5 [M+Na]+: 363.1208; found: 363.1216.
Typical procedure for the asymmetric hydrogenation reactions: [Ru-
1-Benzhydryl 5-ethyl 3-hydroxypentanedioate (4l): HPLC (Chiralcel AS-
H column, hexane/iPrOH 90:10, 0.8 mLminꢀ1, 220 nm): t1 =22.6 min, t2 =
33.1 min; 1H NMR (400 MHz, CDCl3): d=7.38–7.26 (m, 10H; Ar-H),
6.91 (s, 1H), 4.51–4.45 (m, 1H), 4.16 (q, J=7.1 Hz, 2H), 3.36 (d, J=
4.1 Hz, 1H), 2.73–2.63 (m, 2H), 2.55–2.52 (m, 2H), 1.28–1.24 ppm (t, J=
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=171.6, 170.5, 139.6, 128.3,
127.8, 127.8, 126.9, 126.8, 77.1, 64.5, 60.5, 40.8, 40.6, 40.5, 13.9 ppm; FTIR
(KBr pellet): n˜ =3470, 2981, 1733, 1495, 1453, 1374, 1268, 1167, 1033, 980,
746, 700 cmꢀ1; HRMS: calcd for C20H22O5 [M+Na]+: 365.1365; found:
365.1369.
ACHTUNGTRENNUNG(benzene)Cl2]2 (6.2 mg, 12.5 mmol) and (S)-SunPhos (18.3 mg, 27.5 mmol)
were added to a 20 mL Schlenk tube. The tube was evacuated and
purged with nitrogen three times before the addition of freshly distilled
and freeze–thaw degassed EtOH/CH2Cl2 (1:1, v/v, 2 mL). The resulting
mixture was heated at 508C for 1 h and then the solvent was removed
under vacuum to give the catalyst as a brownish yellow solid. The solid
was dissolved in degassed solvent (10 mL) and then the solution was div-
ided equally into five vials containing the substrates (1 mmol). A further
3 mL of the selected solvent was added. The vials were placed in an auto-
clave, which was purged three times with H2 and then the required pres-
sure of H2 was set. Then the autoclave was stirred under the specified re-
action conditions. After cooling to ambient temperature and careful re-
lease of the hydrogen, the autoclave was opened and the solvent was re-
moved by evaporation. The enantiomeric excess was determined by
HPLC (derivatized by 4-nitrobenzoyl chloride if needed) after passing
the samples through a short pad of silica gel eluting with petroleum
ether/ethyl acetate.
Ethyl 5-(dibenzylamino)-3,5-dioxopentanoate (3e): Dibenzylamine (7.8 g,
39.6 mmol) was added dropwise to a solution of diethyl 3-oxoglutarate
(10.0 g, 49.4 mmol) and 4-dimethylaminopyridine (DMAP; 600 mg,
4.9 mmol) in toluene (300 mL). After stirring at reflux for 6 h, the solvent
was evaporated and the crude product was purified by silica gel column
chromatography (PE/EA=2, Rf =0.4) to give 3e as a yellow oil (4.5 g,
1
58%). H NMR (400 MHz, CDCl3) ratio of enol form (ef) and keto form
Chem. Eur. J. 2012, 18, 16531 – 16539
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
16535

Z. Zhang et al.
(kf)=52:48: d=7.42–7.11 (m, 10H; Ar-H), 5.35 (s, Hef, CH=CO), 4.62 (s,
2H; BnCH2), 4.42 (s, 2H; BnCH2), 4.16 (dd, J=7.1, 2.4 Hz, 2H; Hef+kf
chloric acid afforded the crude product. Flash column chromatography
(PE/EA=15, Rf =0.3) afforded 5e (5.4 g, 84%) as a light-yellow liquid.
1H NMR (400 MHz, CDCl3): d=4.25–4.07 (m, 4H), 3.50 (s, 2H), 2.22–
2.07 (m, 4H), 1.75–1.61 (m, 4H), 1.31–1.19 ppm (m, 6H); 13C NMR
(100 MHz, CDCl3): d=198.5, 172.7, 166.8, 66.9, 61.6, 61.3, 60.3, 45.7, 32.9,
25.5, 14.1, 14.0, 13.9 ppm.
,
OCH2CH3), 3.79 and 3.65 (s, Hkf, CH2CO) 3.20 (s, Hef, CH2CO), 1.24 ppm
(td, J=7.1, 1.3 Hz, 3H; Hef+kf, OCH2CH3); 13C NMR (100 MHz, CDCl3):
d=197.0, 171.9, 170.4, 168.1, 166.9, 166.8, 136.6, 136.3, 135.8, 135.56,
128.7, 128.6, 128.3, 127.8, 127.8, 127.5, 127.4, 127.2, 126.3, 126.2, 126.1,
88.5, 61.1, 60.9, 50.2, 49.4, 48.6, 48.4, 47.9, 47.5, 41.5, 13.7 ppm; FTIR
(KBr pellet): n˜ =3750, 3418, 3031, 2982, 1734, 1641, 1454, 1385, 1153,
Diethyl 2,2-diethyl-3-oxopentanedioate (5 f): Compound 5 f was prepared
by the procedure of Masamune and co-workers for b-keto esters.[41] Car-
bonyldiimidazole (5.2 g, 37.4 mmol) was added in portions to a solution
of ethyl 2,2-diethylmalonic acid (6.4 g, 34 mmol) in THF (50 mL) and the
mixture was stirred for 1 h. The resultant brown solution was added drop-
wise to a mixture of ethyl potassium malonate (7.5 g, 44.2 mmol), anhy-
drous MgCl2 (4.9 g, 51 mmol), and Et3N (5.2 g, 51 mmol), which had been
previously stirred for 2 h at room temperature. After the addition, the
mixture was stirred at 708C overnight. After cooling, acid treatment, ex-
traction, and column chromatography (PE/EA=10, Rf =0.4) gave 5 f
(5.1 g, 58%). 1H NMR (400 MHz, CDCl3) ratio of enol form (ef) and
keto form (kf)=6:94: d=12.31 (br, 0.05H; OH), 5.12 (s, 0.06H; CH=C),
4.24–4.13 (m, 4H), 3.47 and 3.35(s, 2H; Hkf+ef, CH2CO), 2.04–1.78 (m,
4H), 1.36–1.14 (m, 6H), 0.78 ppm (m, 6H); 13C NMR (100 MHz, CDCl3):
d=199.9, 171.8, 166.8, 64.4, 61.4, 61.3, 61.2, 45.9, 41.6, 24.4, 23.9, 23.7,
14.0, 8.0 ppm; HRMS: calcd for C13H22O5 [M+Na]+: 281.1365; found:
281.1368.
1029, 1146, 1026, 952 cmꢀ1
354.1705; found: 354.1690.
;
HRMS: calcd for C21H23NO4 [M+H]+:
Ethyl 5-(dibenzylamino)-3-hydroxy-5-oxopentanoate (4e):[36] HPLC
(Chiralcel OD-H column, hexane/iPrOH 85:15, 0.8 mLminꢀ1, 220 nm):
1
t1 =17.6 min, t2 =20.8 min; H NMR (400 MHz, CDCl3): d=7.40–7.11 (m,
10H; Ar-H), 4.69–4.43 (m, 4H), 4.56–4.52 (m, 1H), 4.38 (d, J=3.5 Hz,
1H), 4.13 (q, J=7.1 Hz, 2H), 2.73–2.49 (m, 4H), 1.23 ppm (t, J=7.1 Hz,
3H); 13C NMR (100 MHz, CDCl3): d= =171.8, 170.9, 136.4, 135.5, 128.4,
128.1, 127.6, 127.2, 126.9, 125.9, 64.9, 59.9, 49.4, 47.6, 40.6, 38.4, 13.6 ppm;
FTIR (KBr pellet): n˜ =3429, 2980, 2927, 1731, 1632, 1449, 1368, 1265,
1204, 1158, 1029, 951 cmꢀ1
356.1862; found: 356.1845.
;
HRMS: calcd for C21H25NO4 [M+H]+:
Diethyl 2,2-dimethyl-3-oxopentanedioate (5a):[37] Ethyl acetate (8.4 g,
95 mmol) was added dropwise to a mixture of diethyl 2,2-dimethylmalo-
nate (6.0 g, 32 mmol), NaH (60% dispersed in mineral oil; 3.8 g,
95 mmol) in toluene (80 mL) containing several drops of EtOH. The mix-
ture was heated at reflux for 6 h and quenched with 6m aqueous 10%
HCl (100 mL). The organic phase was separated and extracted with
EtOAc (3ꢁ30 mL). The organic phase was combined and dried over
Na2SO4. Flash column chromatography (PE/EA=10, Rf =0.2) afforded
Ethyl 1-(3-morpholino-3-oxopropanoyl)cyclopropanecarboxylate (5h):
Ethyl 1-[3-(tert-butoxy)-3-oxopropanoyl]cyclopropanecarboxylate (5h’;
7.1 g, 28.1 mmol) was heated at reflux together with morpholine (2.5 g,
18.1 mmol) in xylene for 3 h. The solvent was evaporated and column
chromatography (PE/EA=2, Rf =0.4) afforded 5h as
a light-yellow
1
5a as a colorless liquid (4.5 g, 61%). H NMR (400 MHz, CDCl3) ratio of
liquid (5.3 g, 7%). 1H NMR (400 MHz, CDCl3): d=4.16 (dd, J=7.1,
1.1 Hz, 2H), 4.06 (s, 2H), 3.75–3.58 (m, 6H), 3.48–3.36 (m, 2H), 1.60 (d,
J=1.1 Hz, 4H), 1.25 ppm (td, J=7.1, 1.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=199.1, 171.8, 166.2, 81.9, 81.6, 67.8, 46.9, 32.6, 32.5, 30.8, 27.9,
27.7, 25.5 ppm; FTIR (KBr pellet): n˜ =3452, 2878, 2859, 1720, 1646, 1441,
1372, 1338, 1310, 1179, 1115, 1069, 1037, 968 cmꢀ1; HRMS: calcd for
C13H19NO5 [M+H]+: 270.1341; found: 270.1320.
enol form (ef) and keto form (kf)=9:91: d=12.28 (br, Hef, OH), 5.12 (s,
Hef, CH=C), 4.28–4.09 (m, 4H), 3.53 (s, 2H), 1.39 (s, 6H), 1.31–1.21 ppm
(m, 6H); 13C NMR (100 MHz, CDCl3): d=200.3, 172.7, 166.7, 87.6, 61.5,
61.3, 61.2, 61.1, 60.2, 55.8, 45.0, 23.0, 21.6, 13.9, 13.8 ppm.
Ethyl 1-(3-ethoxy-3-oxopropanoyl)cyclopropanecarboxylate (5c):[38] Pre-
pared by the same procedure as 5a with diethyl cyclopropane-1,1-dicar-
boxylate[39] and ethyl acetate. 1H NMR (400 MHz, CDCl3): d=4.18–4.12
(m, 4H), 3.94 (s, 2H), 1.71–1.54 (m, 4H), 1.33–1.21 ppm (m, 6H);
13C NMR (100 MHz, CDCl3): d=198.4, 170.5, 167.6, 61.3, 61.1, 49.0, 34.6,
21.3, 18.9, 14.9, 14.0 ppm; FTIR (KBr pellet): n˜ =3433, 1645, 2611, 1384,
1265, 1138, 741 cmꢀ1; HRMS: calcd for C11H16O5 [M+Na]+: 251.0895;
found: 251.0871.
Compound 5h’ was prepared by the same procedure as used for 5d with
ethyl 1-cyanocyclopropanecarboxylate[42] and tert-butyl bromoacetate.
1H NMR (400 MHz, CDCl3): d=4.18 (q, J=7.2 Hz, 2H), 3.85 (s, 2H),
1.63 and 1.60 (2 s, 4H), 1.47–1.42 (m, 9H), 1.27 ppm (t, J=7.1 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=198.6, 170.3, 166.4, 81.3, 61.0, 50.1, 34.2,
27.6, 21.1, 13.8 ppm; HRMS: calcd for C13H20O5 [M+Na]+: 279.1208;
found: 279.1186.
Ethyl 1-(3-ethoxy-3-oxopropanoyl)cyclobutanecarboxylate (5d): A cata-
lytic amount of MeSO3H (30 mg, 0.3 mmol) was added to freshly activat-
ed zinc dust (5.0 g, 76 mmol, washed sequentially with 5% HCl solution,
EtOH, and diethyl ether, and dried in vacuum) in THF (50 mL). The
mixture was stirred at 808C for 10 min and then tert-butyl 2-cyano-2-
methylbutanoate (4.8 g, 31 mmol) was added in one portion. The mixture
was stirred for another 10 min and then ethyl 2-bromoacetate (10.3 g,
61 mmol) was added dropwise over 2 h. After heating at 808C for anoth-
er 6 h, the residual zinc silt was filtered off before the solvent was evapo-
rated. EtOAc (50 mL) was added and acidified with 10% aqueous HCl
(20 mL) for 1 h. The aqueous phase was extracted with ethyl acetate (3ꢁ
20 mL) and the combined organic phases were washed with saturated
brine and dried over Na2SO4. Flash column chromatography (PE/EA=
10, Rf =0.3) afforded 5d (6.7 g, 90%) as a light-yellow liquid. 1H NMR
(400 MHz, CDCl3): d=4.26–4.09 (m, 4H), 3.48 (t, J=1.0 Hz, 2H), 2.66–
2.36 (m, 4H), 2.09–1.79 (m, 2H), 1.34–1.19 ppm (m, 6H); 13C NMR
(100 MHz, CDCl3): d=197.9, 171.6, 166.8, 61.6, 61.3, 59.2, 44.8, 29.4, 27.5,
15.4, 13.96, 13.90 ppm; FTIR (KBr pellet): n˜ =3432, 2810, 1705, 1629,
Ethyl 1-[3-(diethylamino)-3-oxopropanoyl]cyclobutanecarboxylate (5i):
Compound 5d (2.5 g, 10.3 mmol), diethylamine (754 mg, 10.3 mmol), and
DMAP (126 mg,1.0 mmol) were heated at reflux in toluene (100 mL) for
8 h. The solvent was evaporated and column chromatography (PE/EA=
2, Rf =0.4) afforded 5i as a light-yellow liquid (2.1 g, 75%). 1H NMR
(400 MHz, CDCl3) ratio of enol form (ef) and keto form (kf)=26:74: d=
5.20–5.12 (m, Hef, CH=CO), 4.27–4.14 (m, 2H), 3.61–3.52 (m, 2H), 3.47–
3.21 (m, 4H), 2.68–2.40 (m, 4H), 2.10–1.79 (m, 2H), 1.34–1.20 (m, 3H),
1.21–1.05 ppm (m, 6H); 13C NMR (100 MHz, CDCl3): d=199.5, 176.5,
173.2, 171.7, 170.8, 165.4, 84.8, 61.2, 60.9, 58.8, 52.5, 43.8, 42.4, 41.8, 40.0,
39.8, 29.2, 27.4, 16.0, 15.2, 13.9, 13.74, 13.7, 12.9, 12.5 ppm; FTIR (KBr
pellet): n˜ =3443, 2978, 1715, 1640, 1490, 1462, 1383. 1364, 1272, 1119,
1015, 786 cmꢀ1; HRMS: calcd for C14H23NO4 [M+Na]+: 292.1525; found:
292.1529.
tert-Butyl 1-[3-(diethylamino)-3-oxopropanoyl]cyclopentanecarboxylate
(5j): tert-Butyl 1-[3-(tert-butoxy)-3-oxopropanoyl]cyclopentanecarboxy-
late (5j’; 5.8 g, 18.6 mmol) and Et2NH (1.4 g, 18.6 mmol) were heated at
reflux in xylene (50 mL) for 4 h. The solvent was evaporated and column
chromatography (PE/EA=2, Rf =0.5) afforded 5j as a light-yellow liquid
(4.8 g, 83%). 1H NMR (400 MHz, CDCl3) ratio of enol form (ef) and
keto form (kf)=18:82: d=5.13 (s, Hef, CH=CO), 3.61 (s, 2H; Hkf,
CH2CO), 3.39 (q, J=7.1 Hz, 2H), 3.27 (q, J=7.2 Hz, 2H), 2.21–1.95 (m,
4H), 1.69–1.60 (m, 4H), 1.46 and 1.33 (2 s, 9H), 1.19–1.12 ppm (m, 6H);
13C NMR (100 MHz, CDCl3): d=200.3, 178.3, 172.0, 165.5, 84.3, 81.5,
67.4, 44.8, 42.5, 39.8, 34.0, 32.8, 27.5, 25.4, 24.2, 14.0, 12.6 ppm; HRMS:
calcd for C17H29NO4 [M+Na]+: 334.1994; found: 334.1989.
1429, 1384, 1222, 619 cmꢀ1
265.1052; found: 265.1052.
;
HRMS: calcd for C12H18O5 [M+Na]+:
Ethyl 1-(3-ethoxy-3-oxopropanoyl)cyclopentanecarboxylate (5e):[40] Mag-
nesium turnings (900 mg, 37 mmol) in absolute ethanol (50 mL) were
heated at reflux for 18 h. After the resulting suspension of MgACTHNUTRGNEUNG(OEt)2 was
cooled to room temperature, diethyl 3-oxoglutarate (5.0 g, 25 mmol) was
added through a syringe. Then the solution was heated at reflux for 1 h
and 1,4-dibromobutane (5.4 g, 24.7 mmol) was added in one portion.
After heating at reflux overnight, quenching and extraction with hydro-
16536
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 16531 – 16539

Asymmetric Hydrogenation of 3-Oxoglutaric Acids
FULL PAPER
Compound 5j’ was prepared with tert-butyl 1-cyanocyclopentanecarboxy-
late[43] and tert-butyl bromoacetate by the same procedure as used for 5d.
1H NMR (400 MHz, CDCl3): d=3.41 (s, 2H), 2.20–1.98 (m, 4H), 1.72–
1.59 (m, 4H), 1.46 (s, 9H), 1.45 ppm (s, 9H); 13C NMR (100 MHz,
CDCl3): d=199.1, 171.8, 166.2, 81.9, 81.6, 67.8, 46.9, 32.6, 32.5, 30.8, 27.9,
27.7, 25.5 ppm; FTIR (KBr pellet): n˜ =3443, 2974, 1714, 1644, 1456, 1368,
1273, 1153 846 cmꢀ1; HRMS: calcd for C17H28O5 [M+Na]+: 335.1834;
found: 335.1827.
chloride (1.8 g, 21.8 mmol) was added in one portion. Then the mixture
was stirred overnight, washed with 10% aqueous HCl (20 mL), and ex-
tracted with CH2Cl2 (2ꢁ10mL). The combined organic phases were
dried over anhydrous Na2SO4 and column chromatography (PE/EA=3,
Rf =0.2) afforded 5m (2.7 g, 56%). 1H NMR (400 MHz, CDCl3) ratio of
enol form (ef) and keto form (kf)=10:90: d=12.50 (s, Hef, OH), 5.10 (s,
CH=CO), 4.24–4.13 (m, 2H), 3.46 (d, J=2.0 Hz, 2H), 2.97 (s, 3H), 2.88
(s, 3H), 1.41–1.38 (m, 6H), 1.30–1.24 ppm (m, 3H); 13C NMR (100 MHz,
CDCl3): d=203.0, 171.0, 166.7, 86.4, 61.3, 60.2, 56.1, 44.7, 37.2, 36.9, 25.1,
22.60, 14.0, 13.9 ppm; FTIR (KBr pellet): n˜ =3440, 2933, 1746, 1711,
Ethyl 5-(tert-butylamino)-4,4-dimethyl-3,5-dioxopentanoate (5k): Com-
pound 5b (10.0 g, 38.7 mmol) was stirred in CH2Cl2 (40 mL) and
CF3COOH (20 mL) for 8 h at room temperature. The solvent was evapo-
rated under vacuum to give the crude acid 5-ethoxy-2,2-dimethyl-3,5-di-
oxopentanoic acid (5s; 7.2 g, 92%), which was used directly in the syn-
thesis of the amide. Acid 5s (3 0 g, 14.8 mmol) was dissolved in CH2Cl2
(30 mL) and then EDC·HCl (3.5 g, 18 mmol) and DMAP (180 mg,
1.5 mmol) were added in portions at 08C. Then tBuNH2 (1.3 g, 18 mmol)
in CH2Cl2 (5 mL) was added dropwise. After the addition, the mixture
was stirred at room temperature for 6 h, washed with 10% aqueous HCl,
and extracted with CH2Cl2 (3ꢁ10mL). The combined organic phases
were dried over Na2SO4 and column chromatography (PE/EA=5, Rf =
0.2) afforded 5k (2.4 g, 63%). 1H NMR (400 MHz, CDCl3): d=5.50 (br,
1H; NHtBu), 4.18 (q, 2H; J=7.1 Hz), 3.56 (s, 2H), 1.36 (d, J=2.8 Hz,
6H), 1.33–1.31 (m, 9H), 1.27 ppm (t, J=7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=203.8, 170.1, 167.2, 88.7, 61.2, 57.0, 51.5, 44.8, 28.4,
28.3, 23.5, 21.9, 14.0 ppm; FTIR (KBr pellet): n˜ =3427, 2925, 2346, 1624,
1457, 1127, 621 cmꢀ1; HRMS: calcd for C13H23NO4 [M+Na]+: 280.1525;
found: 280.1523.
1641, 1390, 1320, 1261, 1116, 1025, 620 cmꢀ1
C11H19NO4: 229.1314 [M]+; found: 229.1316.
; HRMS: calcd for
Ethyl 4-ethyl-4-[methoxyACTHNUGRTNEUNG(methyl)carbamoyl]-3-oxohexanoate (5o): The
tert-butyl ester of 5-ethoxy-2,2-diethyl-3,5-dioxopentanoic acid (5t) was
prepared from tert-butyl 2-cyano-2-ethylbutanoate[45] and ethyl bromo-
AHCTUNGERTGaNNUN cetate by the same procedure as used for 5s and used directly for the
hydrolysis with CF3COOH. N,O-Dimethylamine hydrochloride (7.1 g,
73.2 mmol) and EDC·HCl (12.2 g, 63.4 mmol) were added successively to
the crude 5t (4.9 g, 21 mmol) in MeCN (40 mL) at 08C. Then Et3N
(3.2 g, 32.0 mmol) in MeCN (10 mL) was added dropwise over 30 min.
The mixture was stirred for 10 h and then the solvent was evaporated. Fi-
nally, EtOAc (50 mL) and 10% aqueous HCl (50 mL) were added. The
aqueous phase was extracted with EtOAc (3ꢁ15 mL) and the combined
organic phases were washed with saturated brine and dried over Na2SO4.
Column chromatography (PE/EA=3, Rf =0.3) afforded 5o (3.7 g, 64%)
as a colorless oil. 1H NMR (400 MHz, CDCl3): d=4.18 (q, J=7.1 Hz,
2H), 3.59 (s, 3H), 3.37 (s, 2H), 3.19 (s, 3H), 1.97–1.82 (m, 4H), 1.26 (t,
J=7.1 Hz, 3H), 0.78 ppm (t, J=7.6 Hz, 6H); 13C NMR (100 MHz,
CDCl3): d=199.3, 173.1, 166.9, 62.8, 61.0, 60.5, 46.0, 33.1, 22.5, 14.0,
7.5 ppm; FTIR (KBr pellet): n˜ =2977, 2942, 2883, 1747, 1710, 1661, 1460,
1407, 1367, 1311, 1262, 1031, 956 cmꢀ1; HRMS: calcd for C13H23NO5
[M+H]+: 296.1474; found: 296.1475.
Ethyl 3-[1-(tert-butylcarbamoyl)cyclopropyl]-3-oxopropanoate (5l): Com-
pound 5l was prepared by a procedure similar to that reported in the lit-
erature.[44] An aqueous solution (40 mL) of KOH (6.0 g, 107 mmol) was
added dropwise to diethyl cyclopropane-1,1-dicarboxylate (20 g,
107 mmol) in EtOH (120 mL) and the mixture was stirred at room tem-
perature for 5 h. EtOH was evaporated and the aqueous phase was
washed with Et2O (2ꢁ30 mL). Then the water phase was acidified to
pH 3 with 10% aqueous HCl and extracted with EtOAc (3ꢁ60 mL). The
combined organic layers were dried over anhydrous Na2SO4. Evaporation
of the solvent in vacuo afforded the crude acid (14.7 g, 86%) for use in
the next step. SOCl2 (15.2 g, 128 mmol) was added to a solution of this
crude acid (13.5 g, 85.4 mmol) in CH2Cl2 (80 mL) at room temperature.
After stirring at reflux for 1 h, the mixture was evaporated in vacuo to
give the acid chloride as a yellow liquid. The acid chloride was dissolved
in CH2Cl2 (30 mL) and then added dropwise to a solution of tBuNH2
(9.3 g, 127 mmol) and Et3N (12.9 g, 127.4 mmol) in CH2Cl2 (80 mL) at
08C. After stirring at room temperature for 1 h, the reaction mixture was
evaporated and the residue was diluted with EtOAc (100 mL). The mix-
ture was washed with 2% aqueous HCl (3ꢁ50 mL), water (60 mL), and
brine (50 mL), and then dried over anhydrous Na2SO4. Filtration and
evaporation in vacuo provided the crude amide as a light-yellow oil
(11.9 g, 65.7%), which was used without further purification. 1H NMR
(400 MHz, CDCl3): d=4.12 (q, J=7.1 Hz, 2H), 1.67–1.59 (m, 3H), 1.51–
1.45 (m, 2H), 1.40–1.32 (m, 9H), 1.24 (t, J=7.1 Hz, 3H).
Ethyl
3-{1-[methoxyACHTNUGTREN(NGNU methyl)carbamoyl]cyclopropyl}-3-oxopropanoate
(5p):
tert-Butyl-1-(3-ethoxy-3-oxopropanoyl)cyclopropanecarboxylate
(5w) was prepared by the same method as used for 5b from tert-butyl-
cyanocyclopropanecarboxylate and ethyl bromoacetate. 1H NMR
(400 MHz, CDCl3): d=4.17 (d, J=7.2 Hz, 2H), 3.90 (s, 2H), 1.61–1.50
(m, 4H), 1.47–1.44 (m, 9H), 1.26 ppm (t, J=7.1 Hz, 4H); 13C NMR
(100 MHz, CDCl3): d=198.5, 169.4, 167.4, 81.9, 60.9, 48.8, 35.4, 27.7, 20.4,
18.3, 13.9 ppm; HRMS: calcd for C13H20O5 [M+Na]+: 279.1208; found:
279.1200.
The hydrolysis of 5w by the same procedure as 5s gave 1-(3-ethoxy-3-ox-
opropanoyl)cyclopropanecarboxylic acidcrude acid (5u; 7.8 g, 39 mmol)
was dissolved in CHCl3 (50 mL) and carbonyldiimidazole (9.5 g,
58 mmol) was added in portions and the mixture stirred for 30 min. Then
N,O-dimethylamine hydrochloride (5.7 g, 58 mmol) was added in one
portion and the mixture was stirred at room temperature overnight,
washed with aqueous 10% HCl (30 mL), and the organic phase dried
over anhydrous Na2SO4. Column chromatography (PE/EA=4, Rf =0.3)
afforded 5p (6.6 g, 70%). 1H NMR (400 MHz, CDCl3): d=4.17 (q, J=
7.1 Hz, 2H), 3.63 (s, 3H), 3.56 (s, 2H), 3.28 (s, 3H), 1.48–1.28 (m, 4H),
1.26 ppm (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=195.6,
169.1, 166.8, 61.1, 60.9, 47.1, 35.3, 32.8, 28.5, 14.8, 13.9 ppm; FTIR (KBr
pellet): n˜ =3413, 2982, 2937, 1733, 1636, 1376, 1299, 1248, 1167, 1023,
943 cmꢀ1; HRMS: calcd for C11H17NO5: 243.1107 [M]+; found: 243.1106.
This crude amide was hydrolyzed[44] with KOH (3.7 g, 66.4 mmol) in
EtOH/H2O (3:1) to give the 1-(tert-butylcarbamoyl)cyclopropanecarbox-
ylic acid (8.9 g, 87%) as a white solid. 1H NMR (400 MHz, CDCl3): d=
8.27 (s, 1H), 1.65 (m, 4H), 1.34 ppm (s, 9H); 13C NMR (100 MHz,
CDCl3): d=177.3, 168.2, 51.4, 28.7, 26.0, 20.5 ppm.
Ethyl
3-{1-[methoxyACTHUGNETRNNU(G methyl)carbamoyl]cyclobutyl}-3-oxopropanoate
The last step was similar to that used for the synthesis of 5j following the
procedure of Masamune and co-workers.[41] 1H NMR (400 MHz, CDCl3):
d=8.18 (br, 1H; NHtBu), 4.20 (q, J=7.2 Hz, 2H), 3.28 (s, 2H), 1.80 (q,
J=4.5 Hz, 2H), 1.46 (q, J=4.5 Hz, 2H), 1.35 (s, 9H), 1.36–1.32 (m,
10H), 1.28 ppm (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
201.9, 166.59, 166.57, 61.3, 50.8, 44.1, 35.3, 28.4, 18.2, 13.8 ppm; FTIR
(KBr pellet): n˜ =3441, 2985, 1736, 1698, 1447, 1371, 1315, 1248, 1165,
(5q): Compound 5q was prepared by the same procedure as used for 5l
from diethyl cyclobutane-1,1-dicarboxylate.[46] 1H NMR (400 MHz,
CDCl3): d=4.18 (q, J=7.1 Hz, 2H), 3.53 (s, 3H), 3.33 (s, 2H), 3.20 (s,
3H), 2.61–2.43 (m, 4H), 2.02–1.82 (m, 2H), 1.32–1.23 ppm (m, 3H);
13C NMR (100 MHz, CDCl3): d=196.3, 172.5, 166.8, 61.1, 58.8, 44.3, 33.0,
26.9, 15.1, 14.0 ppm; FTIR (KBr pellet): n˜ =3433, 2981, 2933, 1742, 1706,
1658, 1416, 1384, 1330, 1154, 1030, 996 cmꢀ1
; HRMS: calcd for
1099, 1025, 852, 746 cmꢀ1
278.1368; found: 278.1375.
;
HRMS: calcd for C13H21NO4 [M+Na]+:
C12H19NO5: 257.1263 [M]+; found: 257.1264.
Diethyl 3-hydroxy-2,2-dimethylpentanedioate (6a): 1H NMR (400 MHz,
CDCl3): d=4.12–4.20 (m, 4H), 4.16 (d, J=1.5 Hz, 1H), 3.22 (d, J=
4.9 Hz, 1H), 2.45–2.41 (m, 2H), 1.27 (td, J=7.1, 3.3 Hz, 6H), 1.19 ppm
(d, J=5.9 Hz, 6H); 13C NMR (100 MHz, CDCl3): d=176.3, 172.4, 72.3,
Ethyl 5-(dimethylamino)-4,4-dimethyl-3,5-dioxopentanoate (5m): Car-
bonyldiimidazole (3.5 g, 21.7 mmol) was added to 5s (3.9 g, 19.2 mmol) in
CH2Cl2 (40 mL) at room temperature. After 1 h, dimethylamine hydro-
Chem. Eur. J. 2012, 18, 16531 – 16539
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
16537

Z. Zhang et al.
60.4, 46.2, 36.8, 21.0, 20.4, 13.8 ppm; FTIR (KBr pellet): n˜ =3514, 2983,
2940, 1728, 1471, 1448, 1383, 1369, 1304, 1262, 1176, 1134, 1078, 1046,
1026, 862 cmꢀ1; HRMS: calcd for C11H20O5 [M+Na]+: 255.1208; found:
255.1214.
1-tert-Butyl 5-ethyl 3-hydroxy-2,2-dimethylpentanedioate (6b): 1H NMR
(400 MHz, CDCl3): d=4.17 (q, J=7.1 Hz, 2H), 4.14 (m, 1H), 3.21 (d, J=
5.2 Hz, 1H), 2.45–2.40 (m, 2H), 1.45 (s, 9H), 1.27 (t, J=7.1 Hz, 3H),
1.15 ppm (d, J=3.5 Hz, 6H); 13C NMR (100 MHz, CDCl3): d=176.0,
172.8, 81.0, 72.9, 60.8, 46.7, 37.2, 27.9, 21.5, 20.8, 14.1 ppm; FTIR (KBr
pellet): n˜ =3492, 2980, 2937, 1719, 1631, 1467, 1391, 1369, 1301, 1256,
1077, 1046, 1007, 1029, 850 cmꢀ1; HRMS: calcd for C13H24O5 [M+Na]+:
283.1521; found: 283.1522.
Ethyl 5-(tert-butylamino)-3-hydroxy-4,4-dimethyl-5-oxopentanoate (6k):
HPLC (Chiralcel AD-H column, hexane/iPrOH 91:9, 0.6 mLminꢀ1
,
220 nm): t1 =9.7 min, t2 =10.8 min; 1H NMR (400 MHz, CDCl3): d=6.35
(s, 1H), 4.17 (q, J=7.2 Hz, 2H), 4.06 (d, J=3.9 Hz, 1H), 3.96–3.87 (m,
1H), 2.57–2.32 (m, 2H), 1.34–1.31 (m, 9H), 1.27 (t, J=7.2 Hz, 3H), 1.23
(s, 3H), 1.08 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=175.5, 172.8,
73.6, 60.6, 50.6, 45.3, 36.9, 28.5, 24.0, 21.6, 13.9 ppm; FTIR (KBr pellet):
n˜ =3343, 2973, 2934, 1737, 1648, 1543, 1455, 1391, 1366, 1301, 1227, 1179,
1070, 1049, 1027, 920, 614 cmꢀ1; HRMS: calcd for C13H25NO4 [M+Na]+:
282.1681; found: 282.1675.
Ethyl 3-[1-(tert-butylcarbamoyl)cyclopropyl]-3-hydroxypropanoate (6l):
1H NMR (400 MHz, CDCl3): d=7.20 (s, 1H), 4.18 (qd, J=7.1, 2.5 Hz,
2H), 3.91 (d, J=2.7 Hz, 1H), 3.41 (d, J=10.6 Hz, 1H), 2.86–2.59 (m,
2H), 1.43–1.37 (m, 1H), 1.35–1.32 (m, 9H), 1.29 (t, J=7.1 Hz, 3H), 0.97–
Ethyl 1-(3-ethoxy-1-hydroxy-3-oxopropyl)cyclopropanecarboxylate (6c):
1H NMR (400 MHz, CDCl3): d=4.21–4.08 (m, 4H), 3.88–3.80 (m, 1H),
3.36 (d, J=7.7 Hz, 1H), 2.80–2.66 (m, 2H), 1.31–1.19 (m, 6H), 1.22 (m,
2H), 1.00–0.95 ppm (m, 2H); 13C NMR (100 MHz, CDCl3): d=173.4,
171.8, 68.8, 60.2, 60.1, 40.0, 27.1, 13.7, 12.9, 12.4 ppm; FTIR (KBr pellet):
n˜ =3498, 2984, 2938, 1722, 1447, 1395, 1374, 1281, 1262, 1176, 1152, 1075,
1029, 1026, 757 cmꢀ1; HRMS: calcd for C11H18O5 [M+Na]+: 253.1052;
found: 253.1043.
0.81ACHTNUGRTNEUNG
(m, 2H), 0.39–0.35 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=
172.4, 170.8, 73.4, 60.8, 50.6, 38.9, 28.7, 28.4, 14.8, 13.9, 9.6 ppm; FTIR
(KBr pellet): n˜ =3322, 2971, 2934, 1737, 1646, 1552, 1454, 1392, 1366,
1257, 1225, 1161, 1049, 1029, 976, 935, 623 cmꢀ1; HRMS: calcd for
C13H23NO4 [M+H]+: 258.1705; found: 258.1709.
Ethyl 5-(dimethylamino)-3-hydroxy-4,4-dimethyl-5-oxopentanoate (6m):
HPLC (Chiralcel AD-H column, hexane/iPrOH 91:9, 0.6 mLminꢀ1
,
Ethyl 1-(3-ethoxy-1-hydroxy-3-oxopropyl)cyclobutanecarboxylate (6d):
1H NMR (400 MHz, CDCl3): d=4.28 (m, 1H), 4.18 (m, 4H), 3.23 (d, J=
6.5 Hz, 1H), 2.52–2.24 (m, 4H), 2.14–1.84 (m, 2H), 1.34–1.20 ppm (m,
6H); 13C NMR (100 MHz, CDCl3): d=175.6, 172.5, 71.5, 60.8, 60.8, 60.6,
51.0, 40.3, 37.2, 26.9, 26.8, 15.4, 14.2, 14.1, 12.8 ppm; FTIR (KBr pellet):
n˜ =3482, 2983, 1726, 1446, 1372, 1301, 1207, 1170, 1134, 1096, 1032,
1
220 nm): t1 =27.0 min, t2 =31.2 min; H NMR (400 MHz, CDCl3): d=4.28
(d, J=6.6 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 4.14–4.05 (m, 1H), 3.04 (s,
6H), 2.53 (dd, J=6.3, 4.8 Hz, 2H), 1.33 (s, 3H), 1.29 (s, 3H), 1.26 ppm (t,
J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=176.6, 172.2, 75.2, 60.0,
45.0, 37.7, 37.3, 21.7, 21.0, 13.7 ppm; FTIR (KBr pellet): n˜ =3432, 2956,
1733, 1610, 1471, 1378, 1295, 1259, 1173, 1110, 1076, 1045, 800, 643 cmꢀ1
;
857 cmꢀ1
;
HRMS: calcd for C12H20O5 [M+Na]+: 267.1208; found:
HRMS: calcd for C11H21NO4 [M+Na]+: 254.1368; found: 254.1360.
267.1216.
Ethyl 3-hydroxy-3-{1-[methoxy
ACHTUNGTNER(UNGN methyl)carbamoyl]ACHTUNREGTGcNNUN yclopropyl}ACHTUNGTRENNUNGpropano-
Ethyl 1-(3-ethoxy-1-hydroxy-3-oxopropyl)cyclopentanecarboxylate (6e):
1H NMR (400 MHz, CDCl3): d=4.19–4.11 (m, 4H), 4.11–4.07 (m, 1H),
3.33 (d, J=6.5 Hz, 1H), 2.51–2.33 (m, 2H), 2.10–1.99 (m, 2H), 1.94–1.74
(m, 2H), 1.72–1.54 (m, 4H), 1.33–1.19 ppm (m, 6H); 13C NMR
(100 MHz, CDCl3): d=175.7, 171.7, 71.4, 60.0, 59.9, 57.6, 38.1, 32.9, 31.1,
25.0, 13.4 ppm; FTIR (KBr pellet): n˜ =3498, 2966, 2874, 1727, 1449, 1373,
1299, 1233, 1172, 1100, 1027, 950, 861 cmꢀ1; HRMS: calcd for C13H22O5
[M+Na]+: 281.1365; found: 281.1362.
AHCTUNGTREGaNNNU te (6p): HPLC (Chiralcel OD-H column, hexane/iPrOH 93:7,
0.5 mLminꢀ1, 220 nm): t1 =25.2 min, t2 =27.9 min; 1H NMR (400 MHz,
CDCl3): d=4.15 (q, J=7.1 Hz, 2H), 4.00–3.87 (m, 1H), 3.71 (s, 3H), 3.50
(d, J=4.6 Hz, 1H), 3.26 (s, 3H), 2.71–2.49 (m, 2H), 1.26 (t, J=7.1 Hz,
3H), 1.09–0.85 ppm (m, 4H); 13C NMR (100 MHz, CDCl3): d=172.3,
171.1, 70.0, 60.6, 60.5, 39.9, 34.0, 29.5, 13.9, 9.4, 8.7 ppm; FTIR (KBr
pellet): n˜ =3413, 2982, 2937, 1733, 1636, 1423, 1376, 1299, 1248, 1167,
1097, 1023, 943, 622 cmꢀ1
268.1161; found: 268.1155.
;
HRMS: calcd for C11H19NO5 [M+Na]+:
Ethyl 1-(1-hydroxy-3-morpholino-3-oxopropyl)cyclopropanecarboxylate
(6h): HPLC (Chiralcel AD-H column, hexane/iPrOH 90:10,
0.7 mLminꢀ1, 220 nm): t1 =21.9 min, t2 =23.3 min; 1H NMR (400 MHz,
CDCl3): d=4.18–4.13 (m, 1H), 4.11 (q, 7.2 Hz, 2H), 4.04 (d, J=4.5 Hz,
1H), 3.73–3.55 (m, 6H), 3.54–3.47 (m, 2H), 2.82–2.64 (m, 2H), 1.27–1.23
(m, 1H), 1.25–1.21 (m, 3H), 1.18–1.11 (m, 2H), 1.04–0.97 ppm (m, 1H);
13C NMR (100 MHz, CDCl3): d=173.9, 170.9, 67.8, 66.6, 66.4, 60.3, 45.8,
41.7, 37.6, 27.1, 14.0, 12.8, 12.2 ppm; FTIR (KBr pellet): n˜ =3422, 2977,
2909, 2859, 1714, 1628, 1445, 1372, 1331, 1302, 1274, 1232, 1174, 1151,
1116, 1071, 1036, 969, 851, 757, 578 cmꢀ1; HRMS: calcd for C13H21NO5
[M+Na]+: 294.1317; found: 294.1322.
Ethyl 3-hydroxy-3-{1-[methoxy
ACHTUNGTRENUN(NG methyl)carbamoyl]cyclobutyl}propanoate
(6q): HPLC (Chiralcel AD-H column, hexane/iPrOH 91:9, 0.6 mLminꢀ1
,
220 nm): t1 =21.8 min, t2 =23.9 min; 1H NMR (400 MHz, CDCl3): d=
4.43–4.41 (m, 1H), 4.17 (d, J=7.2 Hz, 2H), 3.69 (s, 3H), 3.24 (d, J=
4.0 Hz, 1H), 3.19 (s, 3H), 2.50–2.45 (m, 3H), 2.39–2.25 (m, 2H), 2.16–
2.11 (m, 1H), 1.92 (s, 1H), 1.82–1.70 (m, 1H), 1.26 ppm (t, J=7.1 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=175.8, 172.7, 69.9, 60.4, 52.0, 37.2,
33.2, 28.2, 25.4, 15.4, 13.9 ppm; FTIR (KBr pellet): n˜ =3431, 2946, 1733,
1631, 1375, 1269, 1307, 1295, 1259, 1172, 1048, 992, 555 cmꢀ1; HRMS:
calcd for C12H21NO5 [M+Na]+: 282.1317, found 282.1319.
Ethyl 1-[3-(diethylamino)-1-hydroxy-3-oxopropyl]cyclobutanecarboxylate
(6i): HPLC (Chiralcel AD-H column, hexane/iPrOH 95:5, 0.8 mLminꢀ1
,
1
220 nm): t1 =19.9 min, t2 =26.2 min; H NMR (400 MHz, CDCl3): d=4.59
(d, J=3.1 Hz, 1H), 4.27 (dt, J=9.7, 2.7 Hz, 1H), 4.18 (dt, J=7.1, 6.3 Hz,
2H), 3.47–3.14 (m, 4H), 2.48–2.18 (m, 6H), 1.99–1.80 (m, 2H), 1.31–1.20
(m, 3H), 1.18–1.06 ppm (m, 6H); 13C NMR (100 MHz, CDCl3): d=175.3,
171.1, 70.4, 60.0, 51.1, 41.5, 39.7, 33.6, 27.1, 24.7, 15.1, 13.7, 13.6,
12.5 ppm; FTIR (KBr pellet): n˜ =3418, 2978, 2942, 1722, 1622, 1452,
1383, 1366, 1307, 1256, 1211, 1144, 1081, 949, 880, 614 cmꢀ1; HRMS:
calcd for C14H25NO4 [M+Na]+: 294.1681; found: 294.1684.
Acknowledgements
We thank the National Natural Science Foundation of China, the Science
and Technology Commission of Shanghai Municipality, and the Educa-
tion Commission of Shanghai Municipality for financial support.
tert-Butyl 1-[3-(diethylamino)-1-hydroxy-3-oxopropyl]cyclopentanecar-
boxylate (6j): HPLC (Chiralcel AD-H column, hexane/iPrOH 95:5,
0.8 mLminꢀ1, 220 nm): t1 =13.8 min, t2 =17.9 min; 1H NMR (400 MHz,
CDCl3): d=4.44 (d, J=3.3 Hz, 1H), 4.25–4.16 (m, 1H), 3.51–3.16 (m,
4H), 2.47–2.29 (m, 2H), 2.12–2.00 (m, 1H), 2.01–1.90 (m, 1H), 1.87–1.59
(m, 6H), 1.22–1.07 ppm (m, 6H); 13C NMR (100 MHz, CDCl3): d=175.8,
171.8, 80.3, 72.0, 58.9, 41.9, 40.2, 35.7, 34.2, 30.3, 27.9, 25.7 25.5, 14.1,
12.9 ppm; FTIR (KBr pellet): n˜ =3425, 2971, 2872, 1717, 1623, 1454,
1384, 1366, 1254, 1152, 1081, 850, 619 cmꢀ1; HRMS: calcd for C17H31NO4
[M+Na]+: 336.2151; found: 336.2144.
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 16531 – 16539

Asymmetric Hydrogenation of 3-Oxoglutaric Acids
FULL PAPER
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Received: July 24, 2012
Revised: August 30, 2012
Published online: October 29, 2012
Chem. Eur. J. 2012, 18, 16531 – 16539
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
16539