Ru-catalyzed asymmetric hydrogenation of δ-keto Weinreb amides: Enantioselective synthesis of (+)-Centrolobine

Article abstract of DOI:10.1039/c5ob02622a

An efficient asymmetric hydrogenation of δ-keto Weinreb amides catalyzed by a Ru-Xyl-SunPhos-Daipen bifunctional catalyst has been achieved. This method afforded a series of enantio-enriched δ-hydroxy Weinreb amides in good yields (up to 93%) and enantioselectivities (up to 99%). This protocol was successfully applied to the synthesis of the key intermediate of (+)-Centrolobine.

Full text of DOI:10.1039/c5ob02622a

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Ru-Catalyzed Asymmetric Hydrogenation of δ-Keto Weinreb Amides:
Enantioselective Synthesis of (+)-Centrolobine
Mengmeng Zhao,a Bin Lu,a Guangni Ding,a Kai Ren,a Xiaomin Xie,a and Zhaoguo Zhang*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
An efficient asymmetric hydrogenation of δ-keto Weinreb amides catalyzed by Ru-Xyl-SunPhos-Daipen
bifunctional catalyst has been achieved. This method afforded a series of enantioenriched δ-hydroxy
Weinreb amides in good yields (up to 93%) and enantioselectivities (up to 99%). This protocol was
successfully applied to the synthesis of the key intermediate of (+)-Centrolobine.
DOI: 10.1039/x0xx00000x
www.rsc.org/
chiral δ-hydroxy Weinreb amides with high yields and excellent
Introduction
Chiral δ-hydroxy acid derivatives are of particular interest to
synthetic chemists as the key intermediates for natural products
and pharmaceuticals, such as δ-lactones, Ezetimibe, and
Centrolobine.1-3 However, only a few methods are available for
the synthesis of optically pure δ-hydroxy acid derivatives,
including reduction of δ-ketoesters by chiral borane and
asymmetric transfer hydrogenation, and kinetic resolution of
racemic δ-hydroxy esters.4 Furthermore, these synthetic routes
suffered from either poor enantioselectivity or low efficiency. The
development of highly enantioselective, atom-economic and
concise strategies towards the synthesis of δ-hydroxy acid
derivatives remains imperative.
enantioselectivities. Moreover, the efficient asymmetric
hydrogenation was utilized to synthesize the key intermediate of
(+)-Centrolobine.
Figure 1 Ezetimibe and Centrolobine.
Results and discussion
Enantioselective hydrogenation of ketoacid derivatives provides
an efficient and direct method for the synthesis of
enantiomerically pure hydroxy acid derivatives. In the previous
reports, the asymmetric hydrogenation of α-, β-, and γ-ketoesters
catalyzed by Ru complexes has been well-studied.5 However, the
only example of asymmetric hydrogenation of -ketoesters was
catalyzed by Ir complexes to give chiral 1-arylpentane-1,5-diols
rather than δ-hydroxy esters.6 We report herein the asymmetric
hydrogenation of a serious of δ-keto Weinreb amides to afford
Initially, the hydrogenation reaction of methyl 5-oxo-5-
phenylpentanoate (A) was conducted by using [RuCl2 (cymene)]2-
(S)-SunPhos as catalyst in EtOH at 70 oC under 20 atm of H2 based
on the asymmetric hydrogenation of functionalized ketone,5 but
no product was detected after 15 h. Hydrochloric acid or
CeCl3·7H2O, which is usually as additive to enhance the
conversion and enantioselectivity for hydrogenation reactions, did
not improve the outcome (Scheme 1, Eq.1).7 The result may be
attributed to the unstable transition state in which the coordination
of δ-ketoesters with the centre metal of catalyst formed an eight-
membered ring transition state, while a stable six-membered ring
transition state usually formed in the hydrogenation of β-
ketoesters.8 We envision that the introduction of a diamine ligand
to the Ru catalytic system may shield the coordination of the ester
a. School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University,
800 Dongchuan Road, Shanghai 200240, China.
b. Shanghai Institute of Organic Chemistry, 345 Lingling Road, Shanghai 200032,
China. E-mail: zhaoguo@sjtu.edu.cn
Electronic Supplementary Information (ESI) available: Copies of1H and13CNMR
spectra
of
new
compounds,
and
HPLC
chromatograms.
See
DOI:10.1039/x0xx00000x
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Table 1 Ligand screeninga
group of δ-ketoesters and result in the hydrogenation of the
substrates as unfunctionalized ketones. The hydrogenation of A
was then tested using RuCl2[(S)-SunPhos][(S)-Daipen] in i-PrOH
in the presence of t-BuOK based on the reaction conditions for the
hydrogenation of simple ketones (Scheme 1, Eq. 1, 2).9
Unfortunately, the reaction gave only a trace of the desired product
(δ-hydroxy esters) and the corresponding lactone, accompanying
with isopropyl 5-oxo-5-phenylpentanoate as the main product,
while the hydrogenation did not occur in MeOH. Isopropyl 5-oxo-
5-phenylpentanoate (B) was hydrogenated in i-PrOH to afford the
δ-hydroxy product in only 20% yield (Scheme 1, Eq. 3). Then, a
δ-ketoamide (C) was tested for the asymmetric hydrogenation
because amide functional group is usually considered as the
relatively resistant carboxylic acid derivatives and not easy to be
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DOI: 10.1039/C5OB02622A
Entry
Ligand
(S)-SunPhos
(S)-BINAP
(S)-SEGPhos
(S)-C3-TunePhos
L1
Conv.b (%)
eec (%)
88
1
2
3
4
5
6
100
100
73
89
87
100
100
100
81
−13
99
L2
aUnless otherwise stated,all reactions were carried out with a
substrate (0.5 mmol) concentration of 0.25 M in i-PrOH for 15 h.
Substrate/catalyst/t-BuOK
cDetermined by NMR analysis.
=
100/1/5. bDetermined by HPLC.
alcoholyzed.10
Pleasingly,
when
N,N-dimethyl-5-oxo-5-
phenylpentanamide (C) was hydrogenated under the same
conditions, it gave complete conversion of substrate and the
hydrogenated product with 95% yield and 88% ee (Scheme 1, Eq.
4).
Therefore, the δ-keto Weinreb amide (1a), whose reduction
product is the important acylation agent and can be easily
transformed to other useful building blocks, was chosen as the
model substrates to test the asymmetric hydrogenation. Under the
above-mentioned asymmetric hydrogenation conditions, 1a was
hydrogenated completely to give the product (2a) with 88% ee
(Table1, entry 1). Other commercially available chiral bidentate
ligands, such as (S)-BINAP, (S)-SEGPhos, and (S)-C3-TunePhos
were also tested, and similar results were achieved (Table 1,
entries 2−4). The modifications of ligand on P atom always impose
remarkable effects on enantioselectivity in the asymmetric
hydrogenation.11 The hydrogenation was then tested with (R)-4-
Tol-SunPhos (L1, Table 1, entry 5) and (S)-Xyl-SunPhos (L2,
Table 1, entry 6), and the best result was obtained by using L2,
which provided the full conversion of 1a to give the corresponding
alcohol 2a in 99% ee.
Further screening of solvents and bases for the hydrogenation
was summarized in Table 2. Solvents were found to have an
obvious influence on both reactivity and enantioselectivity.
Switching the solvent to other protic solvents, poor results were
observed: both low enantioselectivity and conversion were
observed in methanol, high enantioselectivity but only moderate
conversion were obtained in ethanol (Table 2, entries 1 and 2).
Good results were achieved in dichloromethane, while hardly any
reaction occurred in 1,2-dichloroethane (Table 2, entries 3 and 4).
In addition, the hydrogenation was inefficient in toluene (Table 2,
entry 5). Changing the base to KOH afforded the δ-hydroxy
Weinreb amides with a comparable result to that with t-BuOK as
Scheme 1 Asymmetric hydrogenation of 5-oxo-5-phenylpentanoic acid
derivatives.
2 | J. Name., 2012, 00, 1‐3
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Table 3 Substrate scope a
the base in terms of both conversion and enantioselectivity (Table
2, entry 6). However, when K2CO3 was used as the base, a 98%ee
of 2a with 27% of conversion of 1a was obtained (Table 2, entry
7). Neither potassium bicarbonate nor NEt3 works in this
hydrogenation reaction (Table 2, entries 8 and 9). Potassium
hydroxide was finally chosen as the base for this reaction because
of the lower price and easier handling, and the optimized reaction
conditions were therefore set as follows: RuCl2[(S)-Xyl-
SunPhos][(S)-Daipen] as the catalyst in i-PrOH and KOH as the
base under 10 atm of H2 at 30 oC for 15 h.
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DOI: 10.1039/C5OB02622A
Yieldc
(%)
eed
(%)
Entry
R
Conv.b(%)
1
100
100
100
100
100
100
100
100
100
100
100
100
1a
1b
1c
1d
1e
1f
1
2
C6H5
92
92
91
93
93
93
93
91
91
92
90
91
57
99
99
99
99
99
99
99
99
98
99
99
3
4-MeC6H4
4-OMeC6H4
4-CF3C6H4
4-FC6H4
3
4
5
6
4-ClC6H4
3-MeC6H4
2-MeC6H4
2-OMeC6H4
2-naphthyl
2-thienyl
Et
1g
1h
1i
7
8e
9e
10
11
12
13e
Under the optimized reaction conditions, the asymmetric
hydrogenation of δ-keto Weinreb amides led to a variety of δ-
hydroxy Weinreb amides in high yields with excellent
enantioselectivities. Hydrogenation of substrates bearing either
electron-withdrawing or electron-donating groups at para-or
meta- positions on aryl group afforded the corresponding products
in high ee with full conversion (Table 3, entries 2−7). Among
1j
1k
1l
C6H5CH2
62
9
1m
aUnless otherwise stated, all reactions were carried out under10 atm
of H2 for 15 h at 30 °C using 0.5 mmol of the substrate 1 in i-
PrOH(0.5 M) containing the catalyst RuCl2[(S)-Xyl-SunPhos][(S)-
b
Daipen] and KOH. Substrate/catalyst/base = 100/1/5. Determined
by
NMR
analysis.
cIsolated
yield
by
column
them,
5-(4-Fluorophenyl)-5-hydroxy-N-methoxy-N-
chromatography.dDetermined by HPLC on a ChiralPak column.
eFor 30 h.
methylpentanamide (2e) was obtained with 93% yield and 99%
ee, which is an intermediate for the synthesis of Ezetimibe.2a-d
Absolute configuration of 2e was assigned as (R) on the basis of
the optical rotation of 1-(4-fluorophenyl)pentane-1,5-diol 2e'.6 In
the cases of the substrates possessing ortho- substituents on the
aromatic ring, the reaction time was prolonged to 30 h to achieve
full conversions (Table 3, entries 8 and 9). These results stemmed
from the steric hindrance which decreased the reaction reactivity.
The naphthyl substituted compound 1j was hydrogenated to the
corresponding alcohol in 99% ee (Table 3, entry 10). Meanwhile,
when the aryl group was changed from phenyl to hetero aromatic
groups such as 2-thienyl, the reactions also showed excellent
results and 2k was attained in 90% yield with 99% ee (Table 3,
entry 11). Unfortunately, the reaction of alkyl compound 1l and
1m gave low enantioselectivities, and even lower reactivity of 1m
was observed (Table 3, entries 12 and 13).
Table 2Solvents and bases screeninga
Entry
Solvent
Base
Conv.b (%)
eec (%)
1
2
3
4
5
6
7
8
9
MeOH
EtOH
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
KOH
33
57
2
99
97
--
DCM
100
<5
25
DCE
Toluene
i-PrOH
i-PrOH
i-PrOH
i-PrOH
89
99
98
--
100
27
K2CO3
KHCO3
NEt3
<5
<5
--
aAll reactions were carried out under 10 atm of H2 for 15 h at 30 °C using
0.5 mmol of the substrate 1 in i-PrOH (0.5 M) containing the RuCl2[(S)-
Xyl-SunPhos][(S)-Daipen] and base. Substrate/catalyst/base = 100/1/5.
c
bDetermined by NMR analysis. Determined by HPLC on a ChiralPak
column.
Scheme 2 The synthesis of (+)-Centrolobine.
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To probe the practical utility of this hydrogenation reaction, peak multiplications. HRMS were performed under ESI ionization
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DOI: 10.1039/C5OB02622A
we utilized the reaction to synthesize (+)-Centrolobine which technique on ESI-TOF mass spectrometer. Flash column
shows anti leishmanial activity against Leishmaniaamazonensis chromatography was performed on silica gel (300−400 mesh).
promastigotes, and many catalytic protocols have been reported [α]D values were recorded at the D line of sodium (589 nm) in a 0.5
for the total synthesis of this active drug.2e-g,12 The δ-keto Weinreb dm cell.
amide 1c was prepared in 83% yield via two steps (Scheme 2),13
Preparation of 1a–m.
and then the compound 1c was hydrogenated under the optimized
To the solution of glutaric anhydride (1.0 equiv.) in THF under N2
conditions to give the δ-hydroxy Weinreb amide 2c in 99% ee with
atmosphere was added dropwise to the corresponding Grignard
S/C = 500. Protection of the hydroxy group of compound 2c as the
o
reagent (1.2 equiv.) at 0 C. The solution was warmed to room
TBS ether gave compound 3 in 92% yield without loss of
temperature and stirred for a further 3 hours. The reaction was
enantioselectivity.14 Subsequently, the Weinreb amide 3 was
quenched with 10% HCl, and THF was removed in vacuum. The
o
allowed to be reduced with LiAlH4 at 0 C for 30 min to give δ-
resulting aqueous solution was extracted with DCM. The
hydroxy aldehyde 4 in 95% yield.15 Then (+)-Centrolobine could
combined organic layers were washed with brine, dried (Na2SO4)
be obtained via three steps according to literature procedure.14
and evaporated in vacuum to give white solid as a crude product.
The corresponding acid (1.0 equiv.) was added to N,O-dimethyl
hydroxy amine hydrochloride (1.2 equiv.) in DCM. To this
Conclusions
In conclusion, we have compared the hydrogenation mixture
was
added
1-ethyl-3-(3-
reactivity of different δ-keto acid derivatives and confirmed (dimethylamino)propyl)carbodiimide (1.2 equiv.) at 0 °C, and
that using stable amides as the functionalized group is then Et3N (2.0 equiv.) was added dropwise over 10 min. The ice
essential for the asymmetric hydrogenation of δ-keto acid bath was removed and the temperature maintained at room
derivatives. The asymmetric hydrogenation of δ-keto temperature overnight. The mixture was quenched by water, and
Weinreb amides was achieved with excellent yields and the aqueous phase was extracted with DCM. The combined
enantioselectivities catalyzed by Ru-Xyl-SunPhos-Daipen organic phase was washed with brine, dried (Na2SO4) and
catalyst system. The synthetic utility of this asymmetric evaporated in vacuo and the crude product was purified by column
method was demonstrated by the enantioselective synthesis chromatography to afford the desired compounds 1a–m.
of the key intermediate of (+)-Centrolobine.
N-Methoxy-N-methyl-5-oxo-5-phenylpentanamide (1a).16
Colourless oil; 5.2 g, 85% yield;1H NMR (400 MHz, CDCl3) δ
7.97−7.95 (m, 2H), 7.57−7.50 (m, 1H), 7.48−7.39 (m, 2H), 3.65
(s, 3H), 3.16 (s, 3H), 3.07 (t, J = 7.2 Hz, 2H), 2.54 (t, J = 6.8 Hz,
2H), 2.07 (p, J = 7.2 Hz, 2H);13C NMR (100 MHz, CDCl3) δ 199.6,
173.7, 136.6, 132.7, 128.3, 127.8, 60.9, 37.5, 31.9, 30.7, 18.9.
N-Methoxy-N-methyl-5-oxo-5-(p-tolyl)pentanamide (1b).
Experimental
General methods
Commercially available reagents were used throughout without
further purification beyond that detailed below: DMF and i-PrOH
used in catalyst preparation and hydrogenation were distilled over
calcium hydride. All reactions were carried out under an
atmosphere of nitrogen using standard Schlenk techniques unless
otherwise noted. 1H NMR and 13C NMR spectra were obtained on
1
Colourless oil; 3.1 g, 87% yield; H NMR (400 MHz, CDCl3) δ
7.89−7.83 (m, 2H), 7.26−7.21 (m, 2H), 3.66 (s, 3H), 3.17 (s, 3H),
3.04 (t, J = 7.2 Hz, 2H), 2.54 (t, J = 7.0 Hz, 2H), 2.39 (s, 3H), 2.07
(p, J = 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 199.0, 173.6,
143.2, 134.0, 128.8, 127.7, 60.8, 37.2, 31.7, 30.6, 21.2, 18.8;
HRMS calcd. for C14H19NNaO3[M + Na]+ 272.1263, found:
272.1277.
1
a 400 MHz NMR spectrometer. The chemical shifts of H NMR
were recorded in ppm downfield from tetramethylsilane (TMS)
with the solvent resonance as the internal standard. The chemical
shifts of 13C NMR were recorded in ppm downfield using the
central peak of CDCl3 (77.00 ppm) as the internal standard.
Coupling constants (J) are reported in hertz and refer to apparent
N-Methoxy-N-methyl-5-oxo-5-(4-methoxyphenyl)pentane-
mide (1c). Colourless oil; 4.8 g, 81% yield; 1H NMR (400 MHz,
4 | J. Name., 2012, 00, 1‐3
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CDCl3) δ 7.97−7.94 (m, 2H), 6.94−6.86 (m, 2H), 3.86 (s, 3H), 3.66 (s, 3H), 3.18 (s, 3H), 2.99 (t, J = 7.2 Hz, 2H), 2.54 (t, J = 7.2 Hz,
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DOI: 10.1039/C5OB02622A
(s, 3H), 3.17 (s, 3H), 3.02 (t, J = 7.2 Hz, 2H), 2.54 (t, J = 6.6 Hz, 2H), 2.49 (s, 3H), 2.05 (p, J = 7.2 Hz, 2H); 13C NMR (100 MHz,
2H), 2.06 (p, J = 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 198.2, CDCl3) δ 203.6, 173.6, 137.5, 131.5, 130.8, 130.8, 128.2, 125.4,
173.8, 163.1, 130.0, 129.7, 113.4, 60.9, 55.2, 37.1, 31.8, 30.7, 19.1; 60.8, 40.3, 31.7, 30.6, 20.9, 18.9; HRMS calcd. for
HRMS calcd. for C14H19NNaO4[M + Na]+ 288.1212, found: C14H19NNaO3[M + Na]+: 272.1263, found: 272.1272.
288.1221.
N-Methoxy-N-methyl-5-(2-methoxyphenyl)-5-oxopentana-
N-Methoxy-N-methyl-5-oxo-5-(4-(trifluoromethyl)phenyl)- mide (1i). Light yellow oil; 1.8 g, 75% yield; 1H NMR (400 MHz,
1
pentanamide (1d). Light yellow oil; 2.7 g, 79% yield; H NMR CDCl3) δ 7.67−7.64 (m, 1H), 7.45−7.40 (m, 1H), 7.00−6.92 (m,
(400 MHz, CDCl3) δ 8.09−8.07 (m, 2H), 7.73−7.71 m, 2H), 3.67 2H), 3.88 (s, 3H), 3.65 (s, 3H), 3.16 (s, 3H), 3.05 (t, J= 7.2 Hz,
(s, 3H), 3.18 (s, 3H), 3.11 (t, J = 7.2 Hz, 2H), 2.57 (t, J = 6.8 Hz, 2H), 2.50 (t, J = 7.2 Hz, 2H), 2.02 (p, J = 7.2 Hz, 2H); 13C NMR
2H), 2.09 (p, J = 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ: (100 MHz, CDCl3) δ 201.0, 173.2, 157.7, 132.5, 129.1, 127.4,
198.5, 173.6, 139.2, 133.7 (q, J = 32.2 Hz), 128.1, 125.3 (d, J = 119.6, 110.9, 60.3, 54.6, 42.1, 31.2, 30.2, 18.5; HRMS calcd. for
2.5 Hz), 124.7 (q, J = 270.6 Hz), 60.8, 37.7, 31.7, 30.4, 18.6; C14H19NNaO4[M + Na]+: 288.1212, found: 288.1223.
HRMS calcd. for C14H16F3NNaO3[M + Na]+: 326.0980, found:
N-Methoxy-N-methyl-5-(naphthalen-2-yl)-5-oxopentanam-
1
326.0989.
ide (1j). White solid; 3.0 g, 83% yield; mp 42.9−44.1; H NMR
N-Methoxy-N-methyl-5-oxo-5-(4-fluorophenyl)pentanami-
(400 MHz, CDCl3) δ 8.49 (s, 1H), 8.10−7.81 (m, 4H), 7.60−7.51
1
de (1e). White solid; 2.9 g, 81% yield; mp 58.7−59.5; H NMR (m, 2H), 3.66 (s, 3H), 3.21 (t, J = 7.2 Hz, 2H), 3.18 (s, 3H), 2.60
(400 MHz, CDCl3) δ 8.05−7.96 (m, 2H), 7.15−7.07 (m, 2H), 3.67 (t, J = 6.8 Hz, 2H), 2.14 (p, J = 7.2 Hz, 2H); 13C NMR (100 MHz,
(s, 3H), 3.18 (s, 3H), 3.05 (t, J = 7.2 Hz, 2H), 2.55 (t, J = 6.8 Hz, CDCl3) δ 198.6, 173.1, 134.6, 133.3, 131.6, 128.8, 128.7, 127.5,
2H), 2.07 (p, J = 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 127.5, 126.9, 125.9, 122.9, 60.2, 36.9, 31.2, 30.1, 18.4; HRMS
197.5, 173.3, 164.9 (d, J = 252.5 Hz), 132.8, 130.1 (d, J = 8.7 Hz), calcd. for C17H19NNaO3[M + Na]+: 308.1263, found: 308.1247.
114.9 (d, J = 21.6 Hz), 60.5, 37.1, 31.4, 30.2, 18.5; HRMS calcd.
N-Methoxy-N-methyl-5-oxo-5-(thiophen-2-yl)pentanamide
1
for C13H16FNNaO3[M + Na]+: 276.1012, found: 276.1021.
(1k). Light yellow oil; 2.6 g, 70% yield; H NMR (400 MHz,
N-Methoxy-N-methyl-5-oxo-5-(4-chlorophenyl)pentanami- CDCl3) δ 7.75 (dd, J = 3.6, 1.2 Hz, 1H), 7.61 (dd,J = 4.8, 1.2 Hz,
1
de (1f). White solid; 3.0 g, 83% yield; mp 50.6−51.9; H NMR 1H), 7.12−7.10 (m, 1H), 3.66 (s, 3H), 3.17 (s, 3H), 3.01 (t, J = 7.2
(400 MHz, CDCl3) δ 7.96−7.89 (m, 2H), 7.46−7.39 (m, 2H), 3.67 Hz, 2H), 2.55 (t, J = 7.2 Hz, 2H), 2.08 (p,J = 7.2 Hz, 2H); 13C
(s, 3H), 3.18 (s, 3H), 3.05 (t, J = 7.2 Hz, 2H), 2.56 (t, J = 6.8 Hz, NMR (100 MHz, CDCl3) δ 192.4, 173.3, 143.7, 133.1, 131.6,
2H), 2.07 (p, J = 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 127.7, 60.7, 37.9, 31.6, 30.3, 19.0; HRMS calcd. for
198.3, 173.6, 139.0, 134.9, 129.2, 128.6, 60.9, 37.5, 31.9, 30.5, C11H15NNaO3S [M + Na]+: 264.0670, found: 264.0680.
18.8; HRMS calcd. for C13H16ClNNaO3[M + Na]+: 292.0716,
N-Methoxy-N-methyl-5-oxoheptanamide (1l). Light yellow
oil; 4.4 g, 68% yield; 1H NMR (400 MHz, CDCl3) δ 3.65 (s, 3H),
found: 292.0726.
N-Methoxy-N-methyl-5-oxo-5-(m-tolyl)pentanamide (1g). 3.15 (s, 3H), 2.50−2.34 (m, 6H), 1.89 (p, J = 7.2 Hz, 2H), 1.03 (t,
Light yellow oil; 3.0 g, 83% yield; 1H NMR (400 MHz, CDCl3) δ J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 210.5, 173.5, 60.7,
7.80−7.72 (m, 2H), 7.38−7.29 (m, 2H), 3.66 (s, 3H), 3.17 (s, 3H), 40.8, 35.3, 31.6, 30.4, 18.2, 7.3; HRMS calcd. for C9H17NNaO3[M
3.06 (t, J = 7.2 Hz, 2H), 2.54 (t, J = 6.6 Hz, 2H), 2.39 (s, 3H), 2.07 + Na]+: 210.1106, found: 210.1108.
(p, J = 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 199.3, 173.5,
N-Methoxy-N-methyl-5-oxo-6-phenylhexanamide
(1m).
1
137.7, 136.4, 133.2, 128.0, 127.9, 124.7, 60.6, 37.2, 31.5, 30.4, Yellow oil; 2.5 g, 70% yield; H NMR (400 MHz, CDCl3) δ
20.8, 18.6; HRMS calcd. for C14H19NNaO3[M + Na]+: 272.1263, 7.35−7.29 (m, 2H), 7.28−7.22 (m, 1H), 7.21−7.18 (m, 2H), 3.68
found: 272.1275.
(s, 2H), 3.62 (s, 3H), 3.14 (s, 3H), 2.56 (t, J = 7.2 Hz, 2H), 2.40 (t,
N-Methoxy-N-methyl-5-oxo-5-(o-tolyl)pentanamide (1h). J = 7.2 Hz, 2H), 1.89 (p, J = 7.2 Hz, 2H); 13C NMR (100 MHz,
1
Light yellow oil; 3.1 g, 85% yield; H NMR (400 MHz, CDCl3) δ CDCl3) δ 207.5, 173.6, 134.0, 129.1, 128.3, 126.6, 60.8, 49.7,
7.66−7.64 (m, 1H), 7.37−7.33 (m, 1H), 7.24−7.22 (m, 2H), 3.67
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40.7, 31.8, 30.4, 18.3; HRMS calcd. for C14H19NNaO3[M + Na]+: CDCl3) δ 174.4, 141.7, 136.7, 128.9, 125.7, 73.6, 61V.0ie,w3A8rt.ic6le, 3O2nl.in0e,
DOI: 10.1039/C5OB02622A
272.1263, found: 272.1270.
31.3, 21.0, 20.6; HPLC (Chiralcel OB-H column, hexane/i-PrOH
= 88/12, 0.7 mL/min, 210 nm) t1 = 26.2 min, t2 = 31.4 min; [α]D25
=
Typical Procedure for the Asymmetric Hydrogenation
+28.2 (c 0.58, CH2Cl2); IR (KBr): 3740, 2934, 1730, 1458, 1243,
993, 817, 766, 537 cm−1; HRMS calcd. for C14H21NNaO3[M +
Na]+: 274.1419, found: 274.1424.
To a 25 mL Schlenk tube were added [RuCl2(benzene)]2 (5.0 mg,
0.01 mmol) and (S)-Xyl-SunPhos (17.2 mg, 0.022 mmol). The
tube was vacuumed and purged with nitrogen for three times
before addition of freshly distilled and freeze-and-thaw degassed
DMF (3 mL). The resulting mixture was heated at 100 °C for 10
min. before it was cooled to room temperature, and then (S, S)-
Daipen (6.8 mg, 0.022 mmol) was added under N2. The tube was
vacuumed and purged with nitrogen for three times before it was
heated at 40 °C for 5 h. The solvent was removed under vacuum
to give the catalyst as a yellow solid. The catalyst was dissolved
in degassed i-PrOH (4 mL), and then the solution was equally
charged into four vials which contained 0.5 mmol of substrates,
base (0.025 mmol), and 1 mL of i-PrOH. The vials were then
transferred into 300mL autoclave which is charged with 10 mL i-
PrOH. The autoclaves were purged three times with H2, and the
required pressure of H2 was set. The autoclaves were stirred under
specified reaction conditions. After being cooled to ambient
temperature and careful release of the hydrogen, the autoclaves
were opened and the solvent was evaporated. The reaction
solution was purified by a silica gel column to give the
corresponding hydrogenation products, which was then directly
analyzed by HPLC to determine the enantiomeric excess.
5-Hydroxy-N-methoxy-N-methyl-5-(4-methoxyphenyl)pen-
tanemide (2c). Colourless oil; 122.9 mg, 92% yield, 99% ee; 1H
NMR (400 MHz, CDCl3) δ 7.30−7.26 (m, 2H), 6.89−6.85 (m, 2H),
4.67−4.60 (m, 1H), 3.80 (s, 3H), 3.66 (s, 3H), 3.16 (s, 3H),
2.48−2.43 (m, 2H), 2.26 (d, J = 3.6 Hz, 1H), 1.87−1.69 (m, 4H);
13C NMR (100 MHz, CDCl3) δ 174.1, 158.2, 136.9, 126.7, 113.2,
72.8, 60.7, 54.8, 38.3, 31.6, 31.1, 20.5; HPLC (Chiralcel OB-H
column, hexane/i-PrOH = 80/20, 0.8 mL/min, 210 nm) t1 = 28.4
min, t2 = 34.9 min; [α]2D5 = +29.2 (c 0.80, CH2Cl2); IR (KBr): 3417,
2941, 1728, 1462, 1246, 996, 833, 765, 554 cm−1; HRMS calcd.
for C14H21NNaO4[M + Na]+: 290.1368, found: 290.1372.
5-Hydroxy-N-methoxy-N-methyl-5-(4-(trifluoromethyl)ph-
enyl)pentanamide (2d). Light yellow oil; 142.5 mg, 93% yield,
1
99% ee; H NMR (400 MHz, CDCl3) δ 7.58−7.56 (m, 2H),
7.47−7.45 (m, 2H), 4.74 (s, 1H), 3.65 (s, 3H), 3.19 (s, 1H), 3.16
(s, 3H), 2.47−2.46 (m, 2H), 1.82−1.70 (m, 4H); 13C NMR (100
MHz, CDCl3) δ 174.2, 149.1, 128.9 (q, J = 32.1 Hz), 128.1, 126.0,
124.9 (d, J = 3.1 Hz), 124.1 (q, J = 270.2 Hz), 72.8, 60.9, 38.6,
31.8, 31.08, 20.3; HPLC (Chiralcel OB-H column, hexane/i-PrOH
= 88/12, 0.7 mL/min, 210 nm) t1 = 11.8 min, t2 = 13.1 min; [α]D25
=
5-Hydroxy-N-methoxy-N-methyl-5-phenylpentanamide
(2a). Colorless oil; 109.2 mg, 92% yield, 99% ee; 1H NMR (400
MHz, CDCl3) δ 7.37−7.30 (m, 4H), 7.27−7.22 (m, 1H), 4.69−4.66
(m, 1H), 3.65 (s, 3H), 3.16 (s, 3H), 2.58 (s, 1H), 2.46−2.45 (m,
2H), 1.87−1.73 (m, 4H);13C NMR (100 MHz, CDCl3) δ 174.3,
144.7, 128.1, 127.1, 125.7, 73.7, 61.0, 38.6, 31.9, 31.3, 20.5;
HPLC (Chiralcel OB-H column, hexane/i-PrOH = 80/20, 1.0
mL/min, 210 nm) t1 = 12.4 min, t2 = 15.1 min. [α]2D5 = +26.8 (c
0.54, CH2Cl2); IR (KBr): 3417, 2939, 1731, 1454, 1243, 993, 817,
761, 544 cm−1; HRMS: calcd. for C13H19NNaO3[M + Na]+:
260.1263, found: 260.1275.
+23.9 (c 0.50, CH2Cl2); IR (KBr): 3429, 2948, 1736, 1420, 1328,
1124, 843, 762, 527 cm−1; HRMS calcd. for C14H18F3NNaO3[M +
Na]+: 328.1136, found: 328.1147.
5-Hydroxy-N-methoxy-N-methyl-5-(4-fluorophenyl)penta-
namide (2e). Yellow oil; 119.4 mg, 94% yield, 99% ee; 1H NMR
(400 MHz, CDCl3) δ 7.35−7.29 (m, 2H), 7.05−6.99 (m, 2H),
4.69−4.66 (m, 1H), 3.67 (s, 3H), 3.18 (s, 3H), 2.48−2.45 (m, 3H),
1.81−1.67 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 174.1, 161.5
(d, J = 242.7 Hz), 140.6, 127.1 (d, J = 7.9 Hz), 114.6 (d, J = 21.0
Hz), 72.6, 60.8, 38.5, 31.7, 31.0, 20.3; HPLC (Chiralcel IA-H
column, hexane/i-PrOH = 91/9, 0.5 mL/min, 210 nm) t1 = 33.5
min, t2 = 35.3 min; [α]2D5 = +29.2 (c 0.54, CH2Cl2); IR (KBr): 3409,
2940, 1731, 1423, 1222, 995, 838, 777, 544 cm−1; HRMS calcd.
for C13H18FNNaO3[M + Na]+: 278.1168, found: 278.1168.
1-(4-Fluorophenyl)pentane-1,5-diol(2e').6 LiAlH4 (76.2 mg,
2.0 mmol)was added to 2e (128.0 mg, 0.5mmol) in THF at 25oC.
5-Hydroxy-N-methoxy-N-methyl-5-(p-tolyl)pentanamide
(2b). Colourless oil; 115.5 mg, 92% yield, 99% ee; 1H NMR (400
MHz, CDCl3) δ 7.25−7.23 (m, 2H), 7.15−7.13 (m, 2H), 4.71−4.60
(m, 1H), 3.66 (s, 3H), 3.16 (s, 3H), 2.51−2.42 (m, 2H), 2.33 (s,
3H), 2.27 (s, 1H), 1.86−1.68 (m, 4H); 13C NMR (100 MHz,
6 | J. Name., 2012, 00, 1‐3
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The reaction was stirred for 30 min at room temperature and +44.5 (c 0.70, CH2Cl2); IR (KBr): 3417, 2939, 1730, 1461, 1181,
View Article Online
DOI: 10.1039/C5OB02622A
quenched by addition of 10 ml 5% KHSO4. After aqueous work- 993, 758, 728, 503 cm−1; HRMS calcd. for C14H21NNaO3[M +
up, the pure product was obtained by purification with Na]+: 274.1419, found: 274.1422.
chromatography (80 mg, 80% yield). 1H NMR (400 MHz, CDCl3)
5-Hydroxy-N-methoxy-N-methyl-5-(2-methoxyphenyl)pe-
δ 7.32–7.28 (m, 2H), 7.05–7.00 (m, 2H), 4.66 (t, J = 6.4, 1H), 3.62 ntanamide (2i). Colourless oil; 121.7 mg, 91% yield, 98% ee; 1H
(t, J = 6.4 Hz, 2H), 2.05 (s, 1H), 1.84–1.75 (m, 1H), 1.73–1.65 (m, NMR (400 MHz, CDCl3) δ 7.34−7.32 (m, 1H), 7.25−7.20 (m, 1H),
1H), 1.62–1.53 (m, 2H), 1.51–1.44 (m, 1H), 1.40–1.30 (m, 1H); 7.00−6.83 (m, 2H), 4.92−4.87 (m, 1H), 3.84 (s, 3H), 3.67 (s, 3H),
13C NMR (100 MHz, CDCl3) δ 163.5, 141.6, 127.6(d, J = 8.0
3.17 (s, 3H), 2.78 (d, J = 4.0 Hz, 1H), 2.47 (t, J = 8.0 Hz, 2H),
1.87−1.69 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 174.4, 156.0,
Hz), 115.5(d, J = 21.0 Hz), 73.98, 62.77, 38.9, 32.5, 22.1; HPLC
132.5, 127.8, 126.5, 120.4, 110.1, 69.3, 60.9, 55.0, 36.8, 31.9,
(Chiralcel OD-H column, hexane/i-PrOH = 95/5, 0.8 mL/min, 210
nm) t1 = 31.3 min, t2 = 35.9 min; [α]2D0 = +16.3 (c 0.22, MeOH),
97% ee for R enantiomer [lit.6 [α]2D0 = -24.2 (c 1.0, MeOH), 99%
ee for S enantiomer].
31.4, 20.7; HPLC (Chiralcel OB-H column, hexane/i-PrOH =
70/30, 0.8 mL/min, 210 nm) t1 = 11.1 min, t2 = 17.4 min; [α]D25
=
+21.1 (c 0.79, CH2Cl2); IR (KBr): 3425, 2942, 1730, 1647, 1440,
1240, 995, 757, 499 cm−1; HRMS calcd. for C14H21NNaO4[M +
Na]+: 290.1368, found: 290.1376.
5-Hydroxy-N-methoxy-N-methyl-5-(4-chlorophenyl)penta-
1
namide (2f). Colourless oil; 126.6 mg, 93% yield, 99% ee; H
5-Hydroxy-N-methoxy-N-methyl-5-(naphthalen-2-yl)pent-
anamide (2j). Light yellow oil; 132.0 mg, 92% yield, 99% ee; 1H
NMR (400 MHz, CDCl3) δ 7.85−7.77 (m, 4H), 7.49−7.42 (m, 3H),
4.85−4.82 (m, 1H), 3.61 (s, 3H), 3.14 (s, 3H), 2.45 (s, 2H),
1.93−1.68 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 174.3, 142.3,
133.1, 132.6, 127.8, 127.7, 127.4, 125.8, 125.4, 124.3, 124.0, 73.7,
60.9, 38.4, 31.9, 31.2, 20.5; HPLC (Chiralcel OB-H column,
hexane/i-PrOH = 80/20, 1.0 mL/min, 210 nm) t1 = 17.9 min, t2 =
23.1 min; [α]2D5 = +26.2 (c 0.86, CH2Cl2); IR (KBr): 3413, 2936,
1643, 1417, 1387, 1177, 993, 751, 479 cm−1; HRMS calcd. for
C17H21NNaO3[M + Na]+: 310.1419, found: 310.1426.
NMR (400 MHz, CDCl3) δ 7.29 (s, 4H), 4.69−4.64 (m, 1H), 3.66
(s, 3H), 3.17 (s, 3H), 2.47−2.45 (m, 3H), 1.80−1.67 (m, 4H); 13
C
NMR (100 MHz, CDCl3) δ 174.0, 143.4, 132.1, 127.8, 126.9, 72.5,
60.7, 38.3, 31.6, 30.9, 20.2; HPLC (Chiralcel OB-H column,
hexane/i-PrOH = 88/12, 0.7 mL/min, 210 nm) t1 = 28.1 min, t2 =
31.8 min; [α]2D5 = +27.8 (c 0.66, CH2Cl2); IR (KBr): 3409, 2938,
1730, 1489, 1240, 995, 830, 720, 539 cm−1; HRMS calcd. for
C13H18ClNNaO3[M + Na]+: 294.0873, found: 294.0882.
5-Hydroxy-N-methoxy-N-methyl-5-(m-tolyl)pentanamide
(2g). Colourless oil; 117.2 mg, 93% yield, 99% ee; 1H NMR (400
MHz, CDCl3) δ 7.23−7.20 (m, 1H), 7.19−7.05 (m, 3H), 4.65−4.62
(m, 1H), 3.66 (s, 3H), 3.16 (s, 3H), 2.50−2.40 (m, 3H), 2.34 (s,
3H), 1.82−1.68 (m, 4H); 13C NMR (100 MHz, CDCl3): δ 174.3,
144.7, 137.6, 128.0, 127.8, 126.4, 122.7, 73.6, 61.0, 38.6, 31.9,
31.3, 21.3, 20.6; HPLC (Chiralcel OB-H column, hexane/i-PrOH
5-Hydroxy-N-methoxy-N-methyl-5-(thiophen-2-yl)pentan-
emide (2k). Yellow oil; 110.1 mg, 92% yield, 99% ee; 1H NMR
(400 MHz, CDCl3) δ 7.21−7.20 (m, 1H), 6.97−6.92 (m, 2H),
4.93−4.89 (m, 1H), 3.65 (s, 3H), 3.15 (s, 3H), 3.00 (d, J = 4.0 Hz,
1H), 2.49−2.44 (m, 2H), 1.93−1.69 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ 173.9, 148.9, 126.0, 123.5, 122.9, 69.0, 60.7, 38.5, 31.6,
30.9, 20.3; HPLC (Chiralcel OB-H column, hexane/i-PrOH =
= 88/12, 0.7 mL/min, 210 nm) t1 = 21.5 min, t2 = 28.9 min; [α]D25
=
+25.9 (c 0.71, CH2Cl2); IR (KBr): 3407, 2935, 1729, 1459, 1239,
995, 788, 704 cm−1; HRMS calcd. for C14H21NNaO3[M + Na]+:
274.1419, found: 274.1431.
80/20, 1.0 mL/min, 210 nm) t1 = 15.0 min, t2 = 18.7 min; [α]D25
=
+11.8 (c 0.78, CH2Cl2); IR (KBr): 3393, 2938, 1727, 1440, 1180,
995, 850, 705 cm−1; HRMS calcd. for C11H17NNaO3S [M + Na]+:
266.0827, found: 266.0829.
5-Hydroxy-N-methoxy-N-methyl-5-(o-tolyl)pentanamide
(2h). Colourless oil; 114.8 mg, 91% yield, 99% ee; 1H NMR (400
MHz, CDCl3) δ 7.49−7.47 (m, 1H), 7.23−7.08 (m, 3H), 4.93−4.90
(m, 1H), 3.65 (s, 3H), 3.16 (s, 3H), 2.52−2.46 (m, 3H), 2.32 (s,
3H), 1.87−1.71 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 174.3,
142.9, 134.0, 130.0, 126.7, 125.9, 125.0, 69.9, 61.0, 37.6, 31.9,
31.3, 20.7, 18.9; HPLC (Chiralcel OB-H column, hexane/i-PrOH
5-Hydroxy-N-methoxy-N-methylheptanamide
(2l).17
Colourless oil; 86.5 mg, 92% yield; 1H NMR (400 MHz, CDCl3)
δ 3.67 (s, 3H), 3.53−3.47 (m, 1H), 3.17 (s, 3H), 2.45 (t, J = 6.8 Hz,
2H), 2.07 (s, 1H), 1.80−1.67 (m, 2H), 1.55−1.40 (m, 4H), 0.92 (t,
J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 174.5, 72.1, 60.9,
= 70/30, 0.8 mL/min, 210 nm) t1 = 9.6 min, t2 = 16.4 min; [α]D25
=
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36.2, 31.9, 31.3, 29.8, 20.2, 9.7; [α]2D5 = -0.8 (c 0.71, CH2Cl2); IR hexane/i-PrOH = 98/2, 0.3 mL/min, 210 nm) t1 = 26.1 min, t2 =
View Article Online
DOI: 10.1039/C5OB02622A
(KBr): 3422, 2937, 1651, 1460, 1333, 1179, 993, 607, 500 cm−1.
7-(Methoxy(methyl)amino)-7-oxoheptan-3-yl-4-nitrobenz-
oate (2l'). Yellow oil; 135.9 mg, 95% yield, 3% ee; 1H NMR (400
27.8 min; [α]2D5 = +47.5 (c 1.00, CH2Cl2); HRMS calcd. for
C20H35NNaO4Si [M + Na]+: 404.2233, found: 404.2225.
5-((Tert-butyldimethylsilyl)oxy)-5-(4-methoxyphenyl)-
MHz, CDCl3) δ 8.30−8.25 (m, 2H), 8.23−8.18 (m, 2H), 5.17−5.10 pentanal (4).14, 15 LiAlH4 (16.4 mg, 432.4 μmol)was added to
(m, 1H), 3.66 (s, 3H), 3.16 (s, 3H), 2.46−2.44 (m, 2H), 1.79−1.69 5-((tert-butyldimethylsilyl)oxy)-
N
-methoxy-5-(4-methox-
(m, 6H), 0.95 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ yphenyl)-
N
-methylpentanamide
3
(150.0 mg, 393.1 μmol) in
o
173.8, 164.2, 150.2, 135.9, 130.5, 127.2, 123.6, 123.3, 76.7, 61.0, THF at 0 C. The reaction was stirred for 20 min and
32.9, 31.9, 31.2, 26.7, 20.0, 9.4; HPLC (Chiralcel OB-H column, quenched by addition of 10 ml 5% KHSO4. After aqueous
hexane/i-PrOH = 80/20, 0.8 mL/min, 210 nm) t1 = 15.4 min, t2 = work-up, the pure product was obtained by purification with
1
26.4 min; IR (KBr): 3426, 2968, 1719, 1462, 1276, 1118, 995, chromatography (120.4 mg, 95% yield, 99% ee). H NMR
721, 507 cm−1; HRMS calcd. for C16H21N2NaO6[M + Na]+: (400 MHz, CDCl3) δ 9.71 (t,
J = 1.6 Hz, 1H), 7.21−7.18 (m,
361.1376, found: 361.1377.
2H), 6.87−6.79 (m, 2H), 4.63−4.60 (m, 1H), 3.79 (s, 3H),
2.42−2.36 (m, 2H), 1.75−1.67 (m, 2H), 1.65−1.57 (m, 2H),
5-Hydroxy-N-methoxy-N-methyl-6-phenylhexanamide
(2m). Colourless oil; 116.4 mg, 92% yield, 9% ee; 1H NMR (400 0.87 (s, 9H), 0.01 (s, 3H), -0.16 (s, 3H); 13C NMR (100 MHz,
MHz, CDCl3) δ 7.33−7.27 (m, 2H), 7.25−7.19 (m, 3H), 3.84−3.79 CDCl3) δ 202.5, 158.5, 137.3, 126.9, 113.4, 74.2, 55.1, 43.7,
(m, 1H), 3.67 (s, 3H), 3.18 (s, 3H), 2.81 (dd, J = 13.6, 4.8 Hz, 1H), 40.19, 25.8, 18.2, 1.0, -4.6, -5.0; HPLC (Chiralcel OJ-H
2.69 (dd, J = 13.6, 8.0 Hz, 1H), 2.48−2.44 (m, 2H), 2.10 (d, J = column, hexane/i-PrOH = 98/2, 0.5 mL/min, 226 nm) t1 =
4.0 Hz, 1H), 1.87−1.70 (m, 2H), 1.63−1.49 (m, 2H); 13C NMR 12.7 min, t2 = 14.0 min; [α]2D5 = +52.5 (c 1.00, CH2Cl2).
(100 MHz, CDCl3) δ 174.0, 138.5, 128.9, 127.7, 125.6, 71.5, 60.6,
43.5, 35.7, 31.5, 31.0, 20.1; HPLC (Chiralcel OJ-H column,
Notes and references
(1) A. F. de C. Alcântara, M. R. Souza and D. Piló-Veloso, Fitoterapia, 2000,
hexane/i-PrOH = 88/12, 0.7 mL/min, 210 nm) t1 = 16.8 min, t2 =
18.1 min; [α]2D5 = +0.6 (c 0.70, CH2Cl2); IR (KBr): 3423, 2933,
71, 613.
1728, 1646, 1454, 1179, 992, 746, 504 cm−1; HRMS calcd. for
(2) (a) I. L. De Albuquerque, C. Galeffi, C. G. Casinovi and G. B. Marini-
C14H21NNaO3[M + Na]+: 274.1419, found: 274.1423.
Bettolo, Gazz. Chim. Ital., 1964, 287; (b) C. Galeffi, C. G. Casinovi and
G. B. Marini-Bettoòlo, Gazz. Chim. Ital., 1965, 95; (c) A. Aragao
5-((Tert-butyldimethylsilyl)oxy)-N-methoxy-5-(4-methoxy-
Craveiro, A. da Costa Prado, O. R. Gottlieb and P. C. Welerson de
phenyl)-N-methylpentanamide(3).18
A solution of (R)-5-
Albuquerque, Phytochemistry, 1970, 9, 1869; (d) S. B. Rosenblum, T.
Huynh, A. Afonso, H. R. Davis, N. Yumibe, J. W. Clader and D. A.
Burnett, J. Med. Chem., 1998, 41, 973; (e) W. D. Vaccaro, R. Sher and H.
R. Davis Jr, Bioorg. Med. Chem., 1998, 6, 1429; (f) X.-Y. Fu, T. L.
McAllister, T. K. Thiruvengadam, C.-H. Tann and D. Su, Tetrahedron
Lett., 2003, 44, 801; (g) J. W. Clader, J. Med. Chem., 2003, 47, 1.
hydroxy-N-methoxy-N-methyl-5-(4-methoxyphenyl)pentanami-
de (99% ee, 500.0 mg, 1.9 mmol), imidazole (152.8 mg, 2.3
mmol), and TBSCl (338.3 mg, 2.3 mmol) in DCM (10 mL) was
stirred at room temperature overnight and poured into saturated
NaHCO3. The mixture was stirred vigorously for 30 min. The
layer was separated, and the aqueous layer was extracted with
DCM twice. The combined extracts were dried and concentrated
to give an oil, which was subjected to chromatography (PE/EA =
5/1) to furnish the compound 3 (646.6 mg, 92% yield, 99% ee). 1H
NMR (400 MHz, CDCl3) δ 7.22−7.18 (m, 2H), 6.84−6.80 (m, 2H),
4.63−4.60 (m, 1H), 3.79 (s, 3H), 3.63 (s, 3H), 3.15 (s, 3H), 2.38
(t, J = 6.8 Hz, 2H), 1.74−1.68 (m, 2H), 1.64−1.58 (m, 2H), 0.86
(s, 9H), 0.01 (s, 3H), -0.16 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 174.4, 158.4, 137.6, 126.8, 113.2, 74.4, 61.0, 55.0, 40.5, 32.0,
31.7, 25.8, 20.8, 18.1, -4.7, -5.0; HPLC (Chiralcel OB-H column,
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