The preparation of novel chiral auxiliaries SAMIQ/RAMIQ and their application in the asymmetric Michael addition

Article abstract of DOI:10.1016/j.tet.2014.05.049

A pair of novel chiral auxiliaries SAMIQ/RAMIQ was synthesized from l- or d-phenylalanine methyl ester hydrochloride over six steps in 45.8% and 44.4% yield, respectively. The SAMIQ-/RAMIQ-hydrazone methodology was applied for the asymmetric Michael addit

Full text of DOI:10.1016/j.tet.2014.05.049

Tetrahedron 70 (2014) 4602e4610
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The preparation of novel chiral auxiliaries SAMIQ/RAMIQ and their
application in the asymmetric Michael addition
*
Xuan Pan, Zhanzhu Liu
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and
Chinese Academy of Medical Sciences, Beijing 100050, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A pair of novel chiral auxiliaries SAMIQ/RAMIQ was synthesized from L- or D-phenylalanine methyl ester
Received 27 February 2014
Received in revised form 7 May 2014
Accepted 15 May 2014
hydrochloride over six steps in 45.8% and 44.4% yield, respectively. The SAMIQ-/RAMIQ-hydrazone
methodology was applied for the asymmetric Michael addition of ketones to -unsaturated carboxylic
a,b
acid methyl esters, which afforded 3-substituted-5-oxo-alkanoates in moderate to good yield (65e82%)
with excellent enantioselectivity (ee¼95.3%w>99.5%).
Available online 20 May 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Chiral auxiliary
SAMIQ/RAMIQ
Asymmetric Michael addition
1. Introduction
shortcomings, including substrate limitation, low reactivity and the
requirement of highly activated Michael acceptors17e19 and so on,
The asymmetric construction of carbonecarbon bonds or car-
boneheteroatom bonds adjacent to carbonyl group using chiral
auxiliaries is one of the most important strategies in organic syn-
thesis. The commonly used chiral auxiliaries are chiral amino acids
and their derivatives via iminium/enamine methodology. The first
which makes chiral auxiliaries become a significant alternative.
On thebasisof thepreviousstudies, wedesigned andsynthesized
a new type of 1,2,3,4-tetrahydroisoquinoline chiral auxiliaries (S)-2-
amino-3-methoxymethyltetrahydroisoquinoline (SAMIQ) and (R)-
2-amino-3-methoxymethyltetrahydroisoquinoline (RAMIQ), which
combinedthe structural features ofSAMP/RAMPandphenylalanine-
derived auxiliaries (Fig. 1). In addition, these two novel chiral
auxiliaries were studied in the asymmetric Michael addition of ke-
asymmetric a-alkylation of carbonyl group was accomplished by
employing an (S)-proline-based chiral auxiliary.1 Afterward,
phenylalanine-derived auxiliary was also applied in organic syn-
thesis.2,3 Meanwhile, chiral hydrazine proved to be an efficient tool
in asymmetric synthesis,4e7 because the cleavage of hydrazone
could be carried out under various mild conditions to regenerate
the carbonyl functionality.8 The most representative chiral hydra-
zines are (S)-1-amino-2-methoxymethylpyrrolidine (SAMP)9,10 and
(R)-1-amino-2-methoxymethylpyrrolidine (RAMP)11 developed by
Enders et al., which have been applied in a number of important
asymmetric transformations, such as alkylation of aldehydes or
ketones,9 Aldol reaction,12 Michael addition,13 Wittig rearrange-
ment,14 Carroll rearrangement,15 DielseAlder reaction,16 and so on.
Michael addition is one of the most efficient transformations in
organic chemistry, which is usually used to construct CeC bonds.
Organocatalytic Michael addition is, currently, the most efficient
method to obtain versatile 1,4-adducts with excellent enantiose-
lectivities or diastereoselectivities. However, there are still many
tones to a,b-unsaturated carboxylic acid methyl esters.
Fig. 1. Design of novel chiral auxiliaries: SAMIQ/RAMIQ.
2. Results and discussion
The synthetic route of SAMIQ was outlined in Scheme 1. The
overall yield was 45.8% over six steps. Acetylation of L-phenylala-
nine methyl ester hydrochloride (S)-1 afforded (S)-2 in 98% yield.
Compound (S)-2 was reduced by LiBH4 in THF to yield (S)-3 in 87%
* Corresponding author. Tel.: þ86 10 63165253; e-mail address: liuzhanzhu@
imm.ac.cn (Z. Liu).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.05.049

X. Pan, Z. Liu / Tetrahedron 70 (2014) 4602e4610
4603
Table 1
yield, followed by methylation with MeI in the presence of NaH to
Optimization of reaction conditions of asymmetric Michael addition
give (S)-4 as a white solid in 91% yield. The acetyl group of (S)-4 was
removed in 6 N HCl in an almost quantitative yield. Treatment of
(S)-5 with polyoxymethylene in formic acid at 60 ꢀC produced 3-
methoxymethyl tetrahydro-isoquinoline (S)-6 in 82% yield. Nitro-
sation of (S)-6 with NaNO2 and reduction by LiAlH4 resulted in the
chiral auxiliary SAMIQ in 72% yield.
Entry
Solvent
Base
Temperature (ꢀC)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
THF
THF
THF
THF
THF
THF
Et2O
LDA
LDA
LDA
LDA
t-BuONa
n-BuLi
n-BuLi
ꢁ78
ꢁ50
ꢁ30
0
64
45
7
>99.5
>99.5
>99.5
d
No productc
0
No reactiond
d
ꢁ78
78
72
>99.5
>99.5
ꢁ78
a
The overall yield of three steps.
Determined by chiral HPLC analysis of (R)-9a (CHIRALCEL OB-H, 0.5 mL/min,
b
25 ꢀC, hexane/i-PrOH¼95:5).
c
No formation of (S, R)-11a.
(S)-10a was recovered nearly 100%.
d
The enantiomeric excesses of product (R)-9a were determined
by chiral HPLC analysis (CHIRALCEL OB-H, 0.5 mL/min, 25 ꢀC,
hexane/i-PrOH¼95:5). The absolute configuration of (R)-9a was
determined by comparing the specific optical rotation value with
that of literature.13
As can be seen from Table 1, when LDA was used as the base,
product (R)-9a was obtained with greater than 99.5% ee, but raising
the reaction temperature from ꢁ78 ꢀC to ꢁ30 ꢀC resulted in a dra-
matic drop in overall yield from 64% to 7% (entries 1e3). If the re-
action was carried out at 0 ꢀC, there was no formation of compound
(S, R)-11a (entry 4). Changing the base from LDA to t-BuONa led to
a complete loss of reactivity (entry 5). When compound (S)-10a was
metalated with n-BuLi under ꢁ78 ꢀC, the yield was increased to
78%, and the enantiomeric excess of (R)-9a remained greater than
99.5% (entry 6). Thus, n-BuLi was chosen as the optimal base. Ad-
ditionally, Et2O as the solvent was also evaluated, which caused
a slight drop in yield (entry 7). Hence, the optimal condition was
that SAMIQ-hydrazones (R)-10 was metalated with n-BuLi in THF
under ꢁ78 ꢀC for 1 h, followed by addition of 8 for 2 h at the same
temperature.
Scheme 1. Synthesis of SAMIQ and RAMIQ.
RAMIQ was prepared in the same manner starting from
-phenylalanine methyl ester hydrochloride in 44.4% yield.
With the new auxiliaries SAMIQ/RAMIQ in hand, we studied
their application in the asymmetric Michael addition of ketones to
-unsaturated carboxylic acid methyl esters. First, ketones 7 were
transformed into the corresponding SAMIQ-hydrazones (S)-10 by
mixing the chiral auxiliary SAMIQ and ketones 7 at 0 ꢀC overnight
in the presence of AcOH (10 mol %). Compound (S)-10 was depro-
D
a,b
Having established the optimal condition, (R)-9bw(R)-9g were
synthesized according to the standard procedure. The enantiomeric
products (S)-9 were obtained by switching the chiral auxiliary from
SAMIQ to RAMIQ. The racemic products (rac)-9 were also prepared
tonated with base, followed by addition of
a,b-unsaturated car-
via the Michael addition of ketones 7 to a,b-unsaturated carboxylic
boxylic acid methyl esters 8. After purification of the 1,4-adducts (S,
R)-11 by flash chromatography, the chiral auxiliary was removed by
a two-step procedure of acidic hydrolysis to afford product (R)-9
(Scheme 2).
acid methyl esters 8 using t-BuONa as the base. The results are
summarized in Table 2.
As is shown in Table 2, in all cases, the asymmetric Michael
addition of ketones 7 to
a,b-unsaturated carboxylic acid methyl
esters 8 afforded the desired 1,4-adducts 9 over three steps in
moderate to good yield (65%e82%) with excellent enantiose-
lectivity (ee¼95.3%w>99.5%). The substituents on substrates had
little if any effect on the enantiomeric excesses of products 9.
Changing the R-group from phenyl- to naphthyl- led to a slight rise
in overall yield (entries 10e20). Whereas, with the increase in steric
hindrance of R0, the yield fell slightly (entries 1, 4, and 7). In-
terestingly, the overall yield of (R)-9g bearing an electron-
withdrawing group CF3e was only 65% (entry 19).
The proposed mechanism was shown in Fig. 2.20 The SAMIQ-
hydrazone (S)-10 was deprotonated with n-BuLi to generate azae-
nolate, in which the configuration of CeN bond was (Z), and the
lithium atom was chelated with the CH3Oe group. Electrophile 8
attacked on the rigid intermediate from below to result in (S, R)-11
with high diastereoselectivity.
Scheme 2. Asymmetric Michael addition via SAMIQ-/RAMIQ-hydrazone methodology.
3. Conclusion
To identify the optimal reaction condition of the asymmetric
Michael addition of (S)-10 to 8, acetophenone 7a and methyl
crotonate 8a were selected as the model substrates. Reaction
temperatures, bases and solvents were all investigated and the
results are listed in Table 1.
In conclusion, the novel agents SAMIQ and RAMIQ were proven
to be efficient chiral auxiliaries in the asymmetric Michael addition,
which provided a powerful means for the asymmetric formation of
CeC bonds adjacent to CO group. The advantages of SAMIQ and

4604
X. Pan, Z. Liu / Tetrahedron 70 (2014) 4602e4610
Table 2
Synthesis of 9ae9ga
Configurationd
eee (%)
20
Entry
Product
R
R0
Chiral auxiliary
Yield (%)
[a]
D
1
2
3
4
5
6
7
8
(R)-9a
(S)-9a
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
CH3e
CH3e
CH3e
C2H5e
C2H5e
C2H5e
Phenyl
Phenyl
Phenyl
CH3e
SAMIQ
RAMIQ
d
78b
77b
92c
71b
70b
90c
67b
69b
84c
81b
82b
94c
77b
78b
87c
70b
71b
88c
65b
88c
þ9.33
ꢁ9.33
d
R
S
R/S
R
S
R/S
R
S
R/S
R
S
R/S
R
S
R/S
R
S
R/S
R
R/S
>99.5
>99.5
d
(rac)-9a
(R)-9b
(S)-9b
(rac)-9b
(R)-9c
SAMIQ
RAMIQ
d
þ9.25
ꢁ9.00
d
>99.5
95.3
d
SAMIQ
RAMIQ
d
þ2.80
ꢁ2.80
d
>99.5
>99.5
d
(S)-9c
9
(rac)-9c
(R)-9d
(S)-9d
(rac)-9d
(R)-9e
(S)-9e
(rac)-9e
(R)-9f
(S)-9f
Phenyl
10
11
12
13
14
15
16
17
18
19
20
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
SAMIQ
RAMIQ
d
þ9.67
ꢁ9.33
d
>99.5
97.7
d
CH3e
CH3e
C2H5e
C2H5e
C2H5e
Phenyl
Phenyl
Phenyl
CF3e
SAMIQ
RAMIQ
d
þ8.67
ꢁ8.33
d
>99.5
>99.5
d
SAMIQ
RAMIQ
d
þ3.67
ꢁ3.67
d
>99.5
>99.5
d
(rac)-9f
(R)-9g
(rac)-9g
SAMIQ
d
ꢁ9.03
d
>99.5
d
CF3e
a
Unless otherwise noted, all reactions were performed under the optimal condition.
The overall yield of three steps.
The yield of one step.
Determined by comparison of the specific optical rotation with that of literature.
Determined by chiral HPLC analysis (CHIRALCEL OB-H, 0.5 mL/min, 25 ꢀC, hexane/i-PrOH¼95:5).
b
c
d
e
not stated otherwise. Varian Mercury 400 spectrometer (400 MHz,
1H and 100 MHz, 13C) was used to record 1H NMR spectra and 13C
NMR spectra. The data were reported as chemical shift (ppm), in-
tegration, and coupling constant (Hz). High-resolution mass spec-
tra were obtained by Agilent LC/MSD TOF or Thermo Exactive Plus.
Specific optical rotations were recorded on a PerkineElmer in-
strument Model 341LC Polarimeter. Melting points were carried
out on a microscopic melting point apparatus. IR spectra were
obtained by FTIR Microscope Transmission on Thermo Nicolet
5700. Enantiomeric excesses were determined by chiral HPLC
analysis (CHIRALCEL OB-H, 0.5 mL/min, 25 ꢀC, hexane/i-
PrOH¼95:5).
4.2. Compound (S)-2
To a suspension of L-phenylalanine methyl ester hydrochloride
(S)-1 (20.0 g, 92.7 mmol) in CH2Cl2 (400 mL) were added acetyl
chloride (7.9 mL, 111.3 mmol) and Et3N (32.2 mL, 231.8 mmol) drop
wise under argon. The reaction mixture was stirred at 0 ꢀC for 2 h
and poured into water. The organic layer was separated, washed
with brine (250 mL), dried over anhydrous Na2SO4, and concen-
trated under reduced pressure. The residue was purified by column
Fig. 2. Proposed mechanism of asymmetric Michael addition.
RAMIQ were as follows. First, they were easily prepared starting
from or -phenylalanine methyl ester hydrochloride, re-
chromatography (silica gel, PET/EtOAc¼5:1, v/v) to afford com-
L-
D
20
pound (S)-2 (20.0 g, 98%) as a white solid. Mp¼86e88 ꢀC; [
a]
D
spectively, via the same synthetic route. Secondly, both of them
bore a benzene ring chromophore, which facilitated the UV mon-
itoring of the reactions they participated. Thirdly, SAMIQ and
RAMIQ were crystalline solids instead of oily substances, and thus
were more easily handled. The structural modification of these two
novel asymmetric auxiliaries by introducing substituents into the
C-1 site of the tetrahydroisoquinoline moiety and their application
in other asymmetric reactions are in progress in our laboratory and
will be reported in due course.
þ104 (c 1.20, CHCl3); 1H NMR (400 MHz, DMSO-d6)
d 8.33
(d, J¼7.6 Hz,1H), 7.28 (t, J¼7.2 Hz, 2H), 7.22e7.20 (m, 3H), 4.47e4.42
(m, 1H), 3.59 (s, 3H), 3.01 (dd, J¼13.6, 5.6 Hz, 1H), 2.87 (dd, J¼13.6,
9.6 Hz, 1H), 1.79 (s, 3H); 13C NMR (100 MHz, DMSO-d6)
d 172.18,
169.28, 137.24, 128.98 (2C), 128.21 (2C), 126.51, 53.59, 51.76, 36.71,
22.21; HRMS calcd for
222.1127.
C
12H16NO3 [MþH]þ 222.1125, found
4.3. Compound (R)-2
4. Experimental section
4.1. General
Compound (R)-2 was prepared according to the procedure de-
scribed in the synthesis of compound (S)-2. Isolated yield 97% as
20
a white solid. Mp¼85e87 ꢀC; [
a]
ꢁ105 (c 1.20, CHCl3); 1H NMR
D
(400 MHz, DMSO-d6)
d
8.33 (d, J¼7.6 Hz, 1H), 7.27 (t, J¼7.2 Hz, 2H),
All reagents and solvents were pure analytical grade materials
purchased from commercial sources without further purification, if
7.21e7.20 (m, 3H), 4.48e4.42 (m, 1H), 3.58 (s, 3H), 3.00 (dd, J¼13.6,
5.6 Hz, 1H), 2.87 (dd, J¼13.6, 9.2 Hz, 1H), 1.78 (s, 3H); 13C NMR

X. Pan, Z. Liu / Tetrahedron 70 (2014) 4602e4610
4605
(100 MHz, DMSO-d6)
d
172.20, 169.32, 137.26, 128.99 (2C), 128.22
pressure to obtain compound (S)-5 (13.6 g) as a white solid in an
20
(2C), 126.52, 53.61, 51.76, 36.74, 22.21; HRMS calcd for C12H16NO3
almost quantitative yield. Mp¼122e124 ꢀC; [
a
]
D
ꢁ13.3 (c 1.20,
[MþH]þ 222.1125, found 222.1123.
CH3OH); 1H NMR (400 MHz, DMSO-d6)
d 8.45 (s, 2H), 7.34
(t, J¼7.2 Hz, 2H), 7.30e7.26 (m, 3H), 3.44e3.41 (m, 2H), 3.33 (dd,
J¼10.4, 6.0 Hz, 1H), 3.27 (s, 3H), 3.08 (dd, J¼13.2, 4.8 Hz, 1H), 2.83
(dd, J¼13.2, 9.2 Hz, 1H), 2.59 (t, J¼4.8 Hz, 1H); 13C NMR (100 MHz,
4.4. Compound (S)-3
To a solution of compound (S)-2 (19.9 g, 90.0 mmol) in THF
(300 mL) was added LiBH4 (2.97 g, 135.0 mmol) at 0 ꢀC and then the
reaction mixture was stirred for 4 h at this temperature. The re-
action was quenched with aqueous NaOH. After filtration, the or-
ganic solvent was evaporated under reduced pressure to give the
crude product. Purification by column chromatography (silica gel,
DMSO-d6) d 136.41, 129.17 (2C), 128.59 (2C), 126.79, 70.08, 58.43,
51.54, 34.91; HRMS calcd for C10H16NO [MþH]þ 166.1226, found
166.1227.
4.9. Compound (R)-5
CH2Cl2/CH3OH¼50:1, v/v) afforded compound (S)-3 (15.1 g, 87%) as
Compound (R)-5 was prepared according to the procedure de-
scribed in the synthesis of compound (S)-5. Isolated yield nearly
20
a white solid. Mp¼92e94 ꢀC; [
a]
ꢁ20.8 (c 1.20, CHCl3); 1H NMR
D
(400 MHz, DMSO-d6)
d
7.69 (d, J¼8.0 Hz, 1H), 7.26 (t, J¼7.6 Hz, 2H),
100% as a white solid. Mp¼123e125 ꢀC; [
a
]
20 þ13.3 (c 1.20, CH3OH);
D
7.21e7.17 (m, 3H), 4.75 (br s, 1H), 3.92e3.83 (m, 1H), 3.36e3.28
(m, 2H), 2.82 (dd, J¼13.6, 5.6 Hz, 1H), 2.59 (dd, J¼13.6, 8.4 Hz, 1H),
1H NMR (400 MHz, DMSO-d6)
d
8.43 (s, 2H), 7.32 (t, J¼7.2 Hz, 2H),
7.28e7.24 (m, 3H), 3.42e3.39 (m, 2H), 3.32 (dd, J¼10.4, 6.0 Hz, 1H),
3.25 (s, 3H), 3.06 (dd, J¼13.2, 4.8 Hz, 1H), 2.81 (dd, J¼13.2, 9.2 Hz,
1.74 (s, 3H); 13C NMR (100 MHz, DMSO-d6)
d 168.80, 139.30, 129.05
(2C), 128.07 (2C), 125.86, 62.58, 52.40, 36.62, 22.73; HRMS calcd for
1H), 2.57 (t, J¼4.8 Hz, 1H); 13C NMR (100 MHz, DMSO-d6)
d 136.41,
C
11H16NO2 [MþH]þ 194.1176, found 194.1173.
129.17 (2C), 128.59 (2C), 126.79, 70.08, 58.43, 51.54, 34.91; HRMS
calcd for C10H16NO [MþH]þ 166.1226, found 166.1226.
4.5. Compound (R)-3
4.10. Compound (S)-6
Compound (R)-3 was prepared according to the procedure de-
scribed in the synthesis of compound (S)-3. Isolated yield 89% as
A mixture of compound (S)-5 (13.0 g, 64.5 mmol) and poly-
oxymethylene (2.06 g, 64.5 mmol) in formic acid (35 mL) was
heated to 60 ꢀC and stirred for 20 h. The reaction mixture was
neutralized with saturated aqueous NaHCO3 and extracted with
CH2Cl2 (100 mLꢂ6). The combined organic layer was washed with
brine (250 mL), dried over anhydrous Na2SO4, and concentrated
under reduced pressure. Purification by column chromatography
20
a white solid. Mp¼93e95 ꢀC; [
a
]
D
þ19.2 (c 1.20, CHCl3); 1H NMR
(400 MHz, DMSO-d6)
d
7.72 (d, J¼8.0 Hz, 1H), 7.25 (t, J¼7.6 Hz, 2H),
7.22e7.14 (m, 3H), 4.79 (br s, 1H), 3.96e3.88 (m, 1H), 3.37e3.32
(m, 2H), 2.84 (dd, J¼13.6, 5.6 Hz, 1H), 2.62 (dd, J¼13.6, 8.4 Hz, 1H),
1.76 (s, 3H); 13C NMR (100 MHz, DMSO-d6)
d 168.90, 139.32, 129.09
(2C), 128.09 (2C), 125.89, 62.62, 52.46, 36.66, 22.75; HRMS calcd for
C
11H16NO2 [MþH]þ 194.1176, found 194.1173.
(silica gel, CH2Cl2/CH3OH¼50:1, v/v) generated compound (S)-6
20
(9.4 g, 82%) as yellow oil. [
a
]
ꢁ72.5 (c 1.20, CHCl3); 1H NMR
D
4.6. Compound (S)-4
(400 MHz, DMSO-d6) d 7.10e7.01 (m, 4H), 3.90 (s, 2H), 3.38 (dd,
J¼9.2, 5.6 Hz, 1H), 3.34 (dd, J¼9.2, 5.6 Hz, 1H), 3.30 (s, 3H),
To a suspension of NaH (60% in oil, 3.1 g, 77.7 mmol) in THF
(300 mL) was added compound (S)-3 (15.0 g, 77.7 mmol). After 1 h,
a solution of CH3I (7.26 mL, 116.6 mmol) in THF (100 mL) was added
drop wise and the reaction mixturewas stirred at 0 ꢀC overnight. The
reaction was quenched with methanol, and concentrated under
reduced pressure. The residue was purified by column chromatog-
3.04e2.98 (m, 1H), 2.66 (dd, J¼15.6, 3.6 Hz, 1H), 2.45 (dd, J¼15.6,
10.8 Hz,1H); 13C NMR (100 MHz, DMSO-d6)
d 135.75, 134.18,128.92,
125.93, 125.73, 125.42, 75.90, 58.33, 52.52, 47.38, 31.32; HRMS calcd
for C11H16NO [MþH]þ 178.1226, found 178.1227.
4.11. Compound (R)-6
raphy (silica gel, CH2Cl2/CH3OH¼50:1, v/v) to give compound (S)-4
20
(14.6 g, 91%) as a white solid. Mp¼89e91 ꢀC; [
a
]
ꢁ29.7 (c 1.20,
Compound (R)-6 was prepared according to the procedure de-
scribed in the synthesis of compound (S)-6. Isolated yield 85% as
D
CHCl3); 1H NMR (400 MHz, DMSO-d6)
d
7.81 (d, J¼8.4 Hz,1H), 7.27 (t,
J¼7.6 Hz, 2H), 7.20e7.18 (m, 3H), 4.07e4.01 (m, 1H), 3.27e3.21 (m,
yellow oil. [
a]
20 þ70.8 (c 1.20, CHCl3); 1H NMR (400 MHz, DMSO-d6)
D
2H), 3.25 (s, 3H), 2.77 (dd, J¼13.6, 5.6 Hz,1H), 2.64 (dd, J¼13.6, 8.0 Hz,
d
7.09e7.02 (m, 4H), 3.91 (s, 2H), 3.56 (br s, 1H), 3.39 (dd, J¼9.2,
1H), 1.75 (s, 3H); 13C NMR (100 MHz, DMSO-d6)
d
168.64, 138.81,
5.6 Hz, 1H), 3.35 (dd, J¼9.2, 5.6 Hz, 1H), 3.29 (s, 3H), 3.07e3.00
(m, 1H), 2.67 (dd, J¼16.0, 3.6 Hz, 1H), 2.47 (dd, J¼16.0, 10.8 Hz, 1H);
128.99 (2C), 128.10 (2C), 125.98, 73.35, 58.16, 49.77, 36.87, 22.62;
HRMS calcd for C12H18NO2 [MþH]þ 208.1332, found 208.1341.
13C NMR (100 MHz, DMSO-d6)
d 135.38, 134.04, 128.91, 125.96,
125.81, 125.48, 75.65, 58.34, 52.49, 47.20, 31.12; HRMS calcd for
4.7. Compound (R)-4
C
11H16NO [MþH]þ 178.1226, found 178.1226.
Compound (R)-4 was prepared according to the procedure de-
4.12. (S)-2-Amino-3-methoxymethyltetrahydroisoquinoline
scribed in the synthesis of compound (S)-4. Isolated yield 89% as
(SAMIQ)
20
a white solid. Mp¼89e91 ꢀC; [
a
]
þ28.7 (c 1.20, CHCl3); 1H NMR
D
(400 MHz, DMSO-d6)
d
7.83 (d, J¼8.0 Hz, 1H), 7.27 (t, J¼7.2 Hz, 2H),
Compound (S)-6 (9.0 g, 50.6 mmol) was dissolved in 2 N HCl
(50.6 mL), and NaNO2 (5.24 g, 75.9 mmol) was added to the mix-
ture. After 1 h, the reaction mixture was extracted with CH2Cl2
(100 mLꢂ3) and the combined organic layer was concentrated
under reduced pressure to afford the crude product. To a solution of
the crude product in THF (250 mL) was added LiAlH4 (3.85 g,
101.2 mmol) slowly and the reaction mixture was stirred at 0 ꢀC
overnight. The reaction was quenched with aqueous NaOH. After
filtration, the organic solvent was evaporated under reduced
pressure to give the crude product. Recrystallization from ethanol
led to the chiral auxiliary SAMIQ (7.0 g, 72%) as a white solid.
7.20e7.16 (m, 3H), 4.08e4.00 (m, 1H), 3.27e3.21 (m, 2H), 3.24
(s, 3H), 2.77 (dd, J¼13.6, 5.6 Hz, 1H), 2.66 (dd, J¼13.6, 8.0 Hz, 1H),
1.75 (s, 3H); 13C NMR (100 MHz, DMSO-d6)
d 168.65, 138.82, 129.01
(2C), 128.11 (2C), 125.98, 73.36, 58.16, 49.79, 36.88, 22.62; HRMS
calcd for C12H18NO2 [MþH]þ 208.1332, found 208.1331.
4.8. Compound (S)-5
Compound (S)-4 (14.0 g, 67.6 mmol) was refluxed in 6 N HCl
(90 mL) for 24 h. The solvent was evaporated under reduced

4606
X. Pan, Z. Liu / Tetrahedron 70 (2014) 4602e4610
20
Mp¼156e158 ꢀC; [
a
]
ꢁ28.5 (c 0.20, CHCl3); IR:
n
¼3530, 2890,
1.1 mmol) in THF (10 mL) was added to the mixture, and then the
reaction mixture was stirred for 2 h at this temperature. The re-
action was quenched with aqueous NH4Cl and extracted with
EtOAc (50 mLꢂ3). The combined organic layer was washed with
brine (100 mL), dried over anhydrous Na2SO4, and concentrated
under reduced pressure. The residue was purified by flash chro-
matography (silica gel, PET/EtOAc¼20:1, v/v) to afford compound
D
1612, 1585, 1498, 1454, 1120, 1065, 747, 609 cmꢁ1
;
1H NMR
(400 MHz, DMSO-d6)
d
7.17e7.12 (m, 3H), 7.10 (d, J¼8.8 Hz, 1H), 4.08
(d, J¼15.2 Hz, 1H), 3.93 (d, J¼15.2 Hz, 1H), 3.68 (dd, J¼10.0, 6.0 Hz,
1H), 3.46 (dd, J¼10.0, 4.8 Hz, 1H), 3.31 (s, 3H), 3.19e3.13 (m, 1H),
2.90 (dd, J¼16.8, 4.4 Hz, 1H), 2.73 (dd, J¼16.8, 9.2 Hz, 1H); 13C NMR
(100 MHz, DMSO-d6)
d 132.58, 132.18, 128.32, 126.64, 126.35,
125.91, 72.74, 59.75, 58.44, 57.61, 29.79; HRMS calcd for C11H17N2O
(S, R)-11a (343 mg, 87%) as pale yellow oil with high di-
20
[MþH]þ 193.1335, found 193.1335.
astereomeric excesses according to 1H NMR and 13C NMR. [
a]
D
þ59.0 (c 0.20, CHCl3); 1H NMR (400 MHz, CDCl3)
d 7.72e7.70
4.13. (R)-2-Amino-3-methoxymethyltetrahydroisoquinoline
(m, 2H), 7.42e7.37 (m, 3H), 7.19e7.12 (m, 3H), 7.02 (d, J¼6.8 Hz,
1H), 3.88 (d, J¼15.2 Hz, 1H), 3.79e3.76 (m, 2H), 3.64 (s, 3H),
3.42e3.41 (m, 2H), 3.39 (s, 3H), 3.17 (dd, J¼13.6, 9.2 Hz, 1H),
3.08e2.99 (m, 2H), 2.82 (dd, J¼13.2, 4.0 Hz, 1H), 2.29e2.20
(m, 3H), 0.82 (d, J¼6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3)
(RAMIQ)
RAMIQ was prepared according to the procedure described in
the synthesis of SAMIQ. Yield 68% as
a
white solid.
20
Mp¼156e158 ꢀC; [
a
]
þ29.0 (c 0.20, CHCl3); IR:
n
¼3535, 2890,
d 173.38, 169.25, 137.83, 134.40, 133.93, 129.66, 128.71, 128.67 (2C),
D
1610, 1585, 1499, 1454, 1123, 1061, 748, 610 cmꢁ1
;
1H NMR
127.39 (2C), 126.62, 126.43, 125.87, 75.29, 61.09, 59.33, 56.89,
51.63, 41.38, 34.58, 31.90, 28.74, 19.50; HRMS calcd for C24H31N2O3
[MþH]þ 395.2329, found 395.2337.
(400 MHz, DMSO-d6)
d
7.17e7.14 (m, 3H), 7.10 (d, J¼8.8 Hz,1H), 4.09
(d, J¼15.2 Hz, 1H), 3.94 (d, J¼15.2 Hz, 1H), 3.68 (dd, J¼10.0, 6.0 Hz,
1H), 3.45 (dd, J¼10.0, 4.8 Hz, 1H), 3.31 (s, 3H), 3.17e3.13 (m, 1H),
2.90 (dd, J¼17.2, 4.8 Hz, 1H), 2.73 (dd, J¼17.2, 9.6 Hz, 1H); 13C NMR
4.17. Compound (R, S)-11a
(100 MHz, DMSO-d6)
d 132.58, 132.14, 128.32, 126.65, 126.35,
125.91, 72.73, 59.74, 58.44, 57.58, 29.79; HRMS calcd for C11H17N2O
Compound (R, S)-11a was prepared according to the general
[MþH]þ 193.1335, found 193.1336.
procedure in 85% yield as pale yellow oil. [
a
]
D
20 ꢁ61.0 (c 0.20, CHCl3);
1H NMR (400 MHz, CDCl3)
d
7.72e7.70 (m, 2H), 7.40e7.39 (m, 3H),
4.14. Compound (S)-10a (general procedure)
7.16e7.12 (m, 3H), 7.02 (d, J¼6.8 Hz, 1H), 3.88 (d, J¼15.2 Hz, 1H),
3.79e3.76 (m, 2H), 3.64 (s, 3H), 3.42e3.35 (m, 2H), 3.39 (s, 3H), 3.17
(dd, J¼13.6, 9.2 Hz, 1H), 3.05e3.03 (m, 2H), 2.83 (dd, J¼14.0, 3.2 Hz,
1H), 2.29e2.20 (m, 3H), 0.82 (d, J¼6.0 Hz, 3H); 13C NMR (100 MHz,
To a solution of acetophenone 7a (1.4 mL, 12.0 mmol) in toluene
(20 mL) was added chiral auxiliary SAMIQ (1.93 g, 10.0 mmol) and
AcOH (0.06 mL, 1.0 mmol) at 0 ꢀC, and then the reaction mixture
was stirred at the temperature overnight. The reaction was neu-
tralized with saturated aqueous NaHCO3 and extracted with EtOAc
(50 mLꢂ3). The combined organic layer was washed with brine
(100 mL), dried over anhydrous Na2SO4, and concentrated under
reduced pressure. Purification by column chromatography (silica
gel, PET/EtOAc¼40:1, v/v) gave compound (S)-10a (2.88 g, 98%) as
CDCl3) d 173.37,169.25,137.73,134.34,133.87,129.65,128.68,128.66
(2C), 127.36 (2C), 126.60, 126.40, 125.85, 75.27, 61.04, 59.32, 56.85,
51.63, 41.32, 34.49, 31.89, 28.69, 19.45; HRMS calcd for C24H31N2O3
[MþH]þ 395.2329, found 395.2322.
4.18. Compound (R)-9a (general procedure)
colorless oil. [
a
]
20 þ34.3 (c 0.30, CHCl3); 1H NMR (400 MHz, CDCl3)
Compound (S, R)-11a (300 mg, 0.76 mmol) was refluxed in CH3I
(3 mL) for 48 h and then the solvent was evaporated under reduced
pressure. The residue was dissolved in 3 N HCl (4 mL) and n-pen-
tane (15 mL) and stirred for 0.5 h. Separation of the organic layer
and concentration under reduced pressure yielded the final prod-
D
d
7.79 (d, J¼6.0 Hz, 1H), 7.78 (d, J¼7.2 Hz, 1H), 7.37 (t, J¼6.6 Hz, 1H),
7.36 (d, J¼6.6 Hz, 2H), 7.16e7.10 (m, 3H), 7.00 (d, J¼7.2 Hz, 1H), 4.00
(d, J¼15.4 Hz,1H), 3.90 (d, J¼15.4 Hz,1H), 3.71 (dt, J¼7.8, 4.7 Hz,1H),
3.45e3.44 (m, 1H), 3.42 (d, J¼7.0 Hz, 1H), 3.36 (s, 3H), 3.12 (dd,
J¼16.2, 8.6 Hz, 1H), 3.01 (dd, J¼16.2, 3.8 Hz, 1H), 2.44 (s, 3H); 13C
uct (R)-9a (151 mg, 90%) as colorless oil. [
a
]
20 þ9.33 (c 0.30, CHCl3);
D
NMR (100 MHz, CDCl3)
d
164.35, 139.12, 134.45, 134.08, 129.68,
1H NMR (400 MHz, CDCl3)
d
7.97 (d, J¼7.6 Hz, 2H), 7.56 (t, J¼7.6 Hz,
128.84, 128.46 (2C), 126.69 (2C), 126.54, 126.39, 125.85, 74.99,
60.90, 59.40, 56.03, 30.95, 15.88; HRMS calcd for C19H23N2O
[MþH]þ 295.1805, found 295.1807.
1H), 7.46 (t, J¼7.6 Hz, 2H), 3.67 (s, 3H), 3.11 (dd, J¼16.4, 6.0 Hz, 1H),
2.84 (dd, J¼16.4, 7.6 Hz, 1H), 2.72e2.64 (m, 1H), 2.44 (dd, J¼15.2,
6.8 Hz, 1H), 2.32 (dd, J¼15.2, 6.8 Hz, 1H), 1.05 (d, J¼6.4 Hz, 3H); 13
C
NMR (100 MHz, CDCl3)
d 199.37, 173.18, 137.24, 133.22, 128.77 (2C),
4.15. Compound (R)-10a
128.29 (2C), 51.65, 45.02, 41.07, 27.03, 20.31; HRMS calcd for
C
13H17O3 [MþH]þ 221.1172, found 221.1171.
Compound (R)-10a was prepared according to the general pro-
cedure in 98% yield as colorless oil. [
20
a
]
ꢁ35.0 (c 0.30, CHCl3); 1H
4.19. Compound (S)-9a
D
NMR (400 MHz, CDCl3)
d
7.78 (d, J¼6.0 Hz, 1H), 7.78 (d, J¼7.2 Hz,
1H), 7.37e7.36 (m, 3H), 7.16e7.10 (m, 3H), 7.00 (d, J¼6.8 Hz, 1H),
4.00 (d, J¼15.2 Hz, 1H), 3.90 (d, J¼15.2 Hz, 1H), 3.71 (dt, J¼8.0,
4.8 Hz, 1H), 3.46e3.44 (m, 1H), 3.42 (d, J¼7.2 Hz, 1H), 3.36 (s, 3H),
3.12 (dd, J¼16.0, 8.8 Hz, 1H), 3.02 (dd, J¼16.0, 4.0 Hz, 1H), 2.43
Compound (S)-9a was prepared according to the general pro-
20
cedure in 93% yield as colorless oil. [
NMR (400 MHz, CDCl3)
a
]
D
ꢁ9.33 (c 0.30, CHCl3); 1H
d
7.97 (d, J¼7.2 Hz, 2H), 7.56 (t, J¼7.2 Hz,1H),
7.46 (t, J¼7.2 Hz, 2H), 3.67 (s, 3H), 3.11 (dd, J¼16.0, 6.0 Hz, 1H), 2.84
(dd, J¼16.0, 7.6 Hz, 1H), 2.72e2.64 (m, 1H), 2.44 (dd, J¼15.2, 6.8 Hz,
1H), 2.32 (dd, J¼15.2, 6.8 Hz, 1H), 1.05 (d, J¼6.8 Hz, 3H); 13C NMR
(s, 3H); 13C NMR (100 MHz, CDCl3)
d 164.29, 139.09, 134.43, 134.05,
129.65, 128.82, 128.43 (2C), 126.66 (2C), 126.51, 126.36, 125.83,
74.96, 60.87, 59.38, 56.00, 30.93, 15.84; HRMS calcd for C19H23N2O
[MþH]þ 295.1805, found 295.1807.
(100 MHz, CDCl3)
d 199.42, 173.22, 137.27, 133.25, 128.81 (2C),
128.32 (2C), 51.70, 45.06, 41.11, 27.07, 20.34; HRMS calcd for
C
13H17O3 [MþH]þ 221.1172, found 221.1172.
4.16. Compound (S, R)-11a (general procedure)
4.20. Compound (rac)-9a (general procedure)
To a solution of compound (S)-10a (294 mg, 1.0 mmol) in THF
(10 mL) was added n-BuLi (0.5 mL, 2.2 M) drop wise under
ꢁ78 ꢀC. After 1 h, the solution of methyl crotonate 8a (0.12 mL,
To a solution of acetophenone 7a (0.58 mL, 5.0 mmol) in THF
(25 mL) were added t-BuONa (517 mg, 5.5 mmol) and methyl

X. Pan, Z. Liu / Tetrahedron 70 (2014) 4602e4610
4607
crotonate 8a (0.58 mL, 5.5 mmol) at 0 ꢀC. The reaction mixture was
stirred for 2 h. The reaction was quenched with saturated aqueous
NaHCO3 and extracted with EtOAc (100 mLꢂ3). The combined or-
ganic layer was washed with brine (200 mL), dried over anhydrous
Na2SO4, and concentrated under reduced pressure. Purification by
column chromatography (silica gel, PET/EtOAc¼40:1, v/v) gave
compound (rac)-9a (1.02 g, 92%) as colorless oil. 1H NMR (400 MHz,
42.55, 38.23, 33.16, 27.08, 11.33; HRMS calcd for C14H19O3 [MþH]þ
235.1329, found 235.1324.
4.25. Compound (rac)-9b
Compound (rac)-9b was prepared according to the general
procedure in 90% yield as colorless oil. 1H NMR (400 MHz, CDCl3)
CDCl3)
d
7.97 (d, J¼7.6 Hz, 2H), 7.56 (t, J¼7.6 Hz,1H), 7.46 (t, J¼7.6 Hz,
d
7.97 (d, J¼7.6 Hz, 2H), 7.55 (t, J¼7.6 Hz, 1H), 7.46 (t, J¼7.6 Hz, 2H),
2H), 3.67 (s, 3H), 3.11 (dd, J¼16.4, 6.0 Hz, 1H), 2.85 (dd, J¼16.4,
7.2 Hz, 1H), 2.72e2.64 (m, 1H), 2.44 (dd, J¼15.2, 6.8 Hz, 1H), 2.32
(dd, J¼15.2, 6.8 Hz, 1H), 1.06 (d, J¼6.4 Hz, 3H); 13C NMR (100 MHz,
3.67 (s, 3H), 3.07 (dd, J¼16.8, 6.8 Hz, 1H), 2.95 (dd, J¼16.8, 6.8 Hz,
1H), 2.55e2.47 (m, 1H), 2.43e2.39 (m, 2H), 1.50e1.41 (m, 2H), 0.99
(t, J¼7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 199.72,173.52,137.36,
CDCl3)
d
199.38, 173.19, 137.25, 133.23, 128.78 (2C), 128.30 (2C),
133.21, 128.79 (2C), 128.31 (2C), 51.68, 42.56, 38.24, 33.16, 27.09,
51.67, 45.03, 41.08, 27.04, 20.32; HRMS calcd for C13H17O3 [MþH]þ
11.34; HRMS calcd for C14H19O3 [MþH]þ 235.1329, found 235.1324.
221.1172, found 221.1172.
4.26. Compound (S, R)-11c
4.21. Compound (S, R)-11b
Compound (S, R)-11c was prepared according to the general
Compound (S, R)-11b was prepared according to the general
procedure in 75% yield as yellow oil. [
a
]
20 þ101 (c 0.20, CHCl3); 1H
D
procedure in 80% yield as yellow oil. [
NMR (400 MHz, CDCl3)
a
]
20 þ21.0 (c 0.20, CHCl3); 1H
NMR (400 MHz, CDCl3)
d
7.58e7.55 (m, 2H), 7.41e7.39 (m, 3H),
D
d
7.71 (dd, J¼6.4, 1.6 Hz, 2H), 7.39e7.34
7.18e7.15 (m, 6H), 7.00 (d, J¼7.2 Hz, 1H), 6.95e6.92 (m, 2H), 3.77 (d,
J¼15.2 Hz,1H), 3.73 (dd, J¼13.6, 10.4 Hz,1H), 3.67 (d, J¼15.2 Hz,1H),
3.61 (s, 3H), 3.37e3.35 (m, 1H), 3.32e3.28 (m, 2H), 3.25 (s, 3H),
3.03e2.99 (m, 2H), 2.81 (dd, J¼16.4, 10.8 Hz, 1H), 2.66 (dd, J¼16.0,
(m, 3H), 7.15e7.14 (m, 3H), 7.02 (d, J¼6.4 Hz, 1H), 3.89 (d, J¼14.8 Hz,
1H), 3.81e3.78 (m, 2H), 3.64 (s, 3H), 3.42e3.41 (m, 2H), 3.40 (s, 3H),
3.23 (dd, J¼12.0, 9.2 Hz, 1H), 3.08e2.98 (m, 2H), 2.80 (dd, J¼14.0,
5.2 Hz, 1H), 2.33 (dd, J¼14.0, 4.0 Hz, 1H), 2.19e2.14 (m, 2H),
1.25e1.17 (m, 2H), 0.79 (t, J¼7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
8.4 Hz, 1H), 2.61 (d, J¼6.8 Hz, 1H), 2.56 (dt, J¼10.0, 2.4 Hz, 1H); 13
C
NMR (100 MHz, CDCl3)
d 172.74, 168.66, 142.35, 137.79, 134.42,
d
173.76, 169.37, 137.88, 134.40, 133.93, 129.57, 128.71, 128.61 (2C),
133.92, 129.61, 128.72, 128.64 (2C), 128.47 (2C), 127.92 (2C), 127.52
(2C), 127.06, 126.60, 126.44, 125.86, 74.81, 60.80, 59.13, 56.70, 51.78,
41.06, 39.83, 34.04, 32.33; HRMS calcd for C29H33N2O3 [MþH]þ
457.2486, found 457.2482.
127.40 (2C), 126.57, 126.41, 125.85, 75.12, 61.07, 59.30, 56.91, 51.62,
38.12, 34.52, 32.34, 31.89, 25.98, 10.74; HRMS calcd for C25H33N2O3
[MþH]þ 409.2486, found 409.2488.
4.22. Compound (R, S)-11b
4.27. Compound (R, S)-11c
Compound (R, S)-11b was prepared according to the general
Compound (R, S)-11c was prepared according to the general
procedure in 78% yield as yellow oil. [
a
]
20 ꢁ20.0 (c 0.20, CHCl3); 1H
procedure in 77% yield as yellow oil. [
NMR (400 MHz, CDCl3)
a
]
20 ꢁ102 (c 0.20, CHCl3); 1H
D
D
NMR (400 MHz, CDCl3)
d
7.70 (dd, J¼8.0, 2.8 Hz, 2H), 7.40e7.38
d
7.57e7.55 (m, 2H), 7.40e7.39 (m, 3H),
(m, 3H), 7.16e7.13 (m, 3H), 7.02 (d, J¼6.8 Hz, 1H), 3.89 (d, J¼15.2 Hz,
1H), 3.82e3.78 (m, 2H), 3.64 (s, 3H), 3.42e3.41 (m, 2H), 3.40 (s, 3H),
3.24 (dd, J¼12.6, 4.0 Hz, 1H), 3.04e3.02 (m, 2H), 2.80 (dd, J¼13.6,
5.2 Hz, 1H), 2.33 (dd, J¼13.6, 4.0 Hz, 1H), 2.19e2.11 (m, 2H),
1.33e1.17 (m, 2H), 0.79 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
7.19e7.14 (m, 6H), 7.00 (d, J¼7.2 Hz, 1H), 6.94e6.93 (m, 2H), 3.77 (d,
J¼14.4 Hz,1H), 3.71 (dd, J¼13.6,10.4 Hz,1H), 3.67 (d, J¼14.4 Hz,1H),
3.61 (s, 3H), 3.37e3.35 (m, 1H), 3.31e3.28 (m, 2H), 3.25 (s, 3H),
3.03e2.99 (m, 2H), 2.81 (dd, J¼16.4, 10.8 Hz, 1H), 2.66 (dd, J¼16.0,
8.4 Hz, 1H), 2.61 (d, J¼6.8 Hz, 1H), 2.56 (dt, J¼8.4, 2.4 Hz, 1H); 13C
d
173.79, 169.41, 137.90, 134.42, 133.95, 129.60, 128.73, 128.63 (2C),
NMR (100 MHz, CDCl3) d 172.73, 168.64, 142.35, 137.79, 134.42,
127.43 (2C), 126.60, 126.43, 125.87, 75.14, 61.08, 59.32, 56.93, 51.65,
38.14, 34.55, 32.37, 31.92, 26.00, 10.76; HRMS calcd for C25H33N2O3
[MþH]þ 409.2486, found 409.2496.
133.92, 129.59, 128.71, 128.62 (2C), 128.46 (2C), 127.91 (2C), 127.50
(2C), 127.05, 126.59, 126.43, 125.85, 74.81, 60.79, 59.12, 56.70, 51.77,
41.05, 39.82, 34.03, 32.33; HRMS calcd for C29H33N2O3 [MþH]þ
457.2486, found 457.2474.
4.23. Compound (R)-9b
4.28. Compound (R)-9c
Compound (R)-9b was prepared according to the general pro-
20
cedure in 91% yield as colorless oil. [
NMR (400 MHz, CDCl3)
a]
þ9.25 (c 0.40, CHCl3); 1H
Compound (R)-9c was prepared according to the general pro-
D
d
7.97 (d, J¼7.6 Hz, 2H), 7.55 (t, J¼7.6 Hz,1H),
cedure in 91% yield as a white solid. Mp¼79e81 ꢀC; [
a
]
20 þ2.80 (c
D
7.46 (t, J¼7.6 Hz, 2H), 3.67 (s, 3H), 3.07 (dd, J¼16.8, 6.8 Hz, 1H), 2.95
(dd, J¼16.8, 6.8 Hz, 1H), 2.55e2.47 (m, 1H), 2.43e2.39 (m, 2H),
1.50e1.41 (m, 2H), 0.99 (t, J¼7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
0.25, CHCl3); 1H NMR (400 MHz, CDCl3)
d
7.92 (d, J¼7.6 Hz, 2H), 7.54
(t, J¼7.2 Hz, 1H), 7.44 (t, J¼7.6 Hz, 2H), 7.31e7.27 (m, 4H), 7.20 (t,
J¼7.6 Hz, 1H), 3.92e3.85 (m, 1H), 3.59 (s, 3H), 3.40 (dd, J¼16.8,
7.2 Hz, 1H), 3.34 (dd, J¼16.8, 7.2 Hz, 1H), 2.82 (dd, J¼15.6, 7.2 Hz,
1H), 2.69 (dd, J¼15.6, 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
199.73, 173.52, 137.36, 133.21, 128.79 (2C), 128.31 (2C), 51.68,
42.55, 38.23, 33.16, 27.08, 11.33; HRMS calcd for C14H19O3 [MþH]þ
235.1329, found 235.1328.
d 198.34, 172.51, 143.54, 137.10, 133.32, 128.84 (2C), 128.80 (2C),
128.28 (2C), 127.53 (2C), 127.03, 51.80, 44.76, 40.79, 37.71; HRMS
4.24. Compound (S)-9b
calcd for C18H19O3 [MþH]þ 283.1329, found 283.1324.
Compound (S)-9b was prepared according to the general pro-
4.29. Compound (S)-9c
20
cedure in 92% yield as colorless oil. [
NMR (400 MHz, CDCl3)
7.46 (t, J¼7.2 Hz, 2H), 3.65 (s, 3H), 3.07 (dd, J¼16.4, 6.8 Hz, 1H), 2.95
(dd, J¼16.4, 6.8 Hz, 1H), 2.53e2.47 (m, 1H), 2.45e2.35 (m, 2H),
1.51e1.41 (m, 2H), 0.93 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
a
]
ꢁ9.00 (c 0.40, CHCl3); 1H
D
d
7.97 (d, J¼7.2 Hz, 2H), 7.56 (t, J¼7.2 Hz,1H),
Compound (S)-9c was prepared according to the general pro-
cedure in 91% yield as a white solid. Mp¼78e80 ꢀC; [
a
]
20 ꢁ2.80 (c
D
0.25, CHCl3); 1H NMR (400 MHz, CDCl3)
d
7.91 (d, J¼7.6 Hz, 2H), 7.54
(t, J¼7.6 Hz, 1H), 7.43 (t, J¼7.6 Hz, 2H), 7.31e7.26 (m, 4H), 7.20 (t,
J¼7.6 Hz, 1H), 3.92e3.85 (m, 1H), 3.58 (s, 3H), 3.40 (dd, J¼16.8,
d
199.73, 173.52, 137.36, 133.21, 128.79 (2C), 128.31 (2C), 51.68,

4608
X. Pan, Z. Liu / Tetrahedron 70 (2014) 4602e4610
7.2 Hz, 1H), 3.34 (dd, J¼16.8, 7.2 Hz, 1H), 2.82 (dd, J¼15.6, 7.2 Hz,
1H), 2.69 (dd, J¼15.6, 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
4.34. Compound (R, S)-11d
d
198.34, 172.50, 143.54, 137.10, 133.31, 128.83 (2C), 128.80 (2C),
Compound (R, S)-11d was prepared according to the general
20
128.28 (2C), 127.52 (2C), 127.02, 51.79, 44.75, 40.78, 37.70; HRMS
procedure in 92% yield as pale yellow oil. [
a]
ꢁ48.0 (c 0.30,
D
calcd for C18H19O3 [MþH]þ 283.1329, found 283.1321.
CHCl3); 1H NMR (400 MHz, CDCl3)
d 8.15 (s, 1H), 7.94e7.90 (m, 2H),
7.86e7.83 (m, 2H), 7.50 (dd, J¼6.4, 3.2 Hz, 2H), 7.17e7.14 (m, 3H),
7.04 (d, J¼6.8 Hz, 1H), 3.92 (d, J¼15.2 Hz, 1H), 3.85e3.81 (m, 2H),
3.65 (s, 3H), 3.47e3.45 (m, 2H), 3.42 (s, 3H), 3.26 (dd, J¼13.6, 9.2 Hz,
1H), 3.08e3.06 (m, 2H), 2.96 (dd, J¼13.6, 4.0 Hz, 1H), 2.37e2.23
4.30. Compound (rac)-9c
(m, 3H), 0.85 (d, J¼6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 173.36,
Compound (rac)-9c was prepared according to the general
procedure in 84% yield as a white solid. Mp¼78e80 ꢀC; 1H NMR
168.95, 135.12, 134.41, 134.12, 133.93, 133.29, 128.91, 128.74, 128.34,
127.85, 127.30, 126.89, 126.65, 126.45 (2C), 125.90, 124.86, 75.34,
61.17, 59.38, 56.97, 51.66, 41.43, 34.57, 31.92, 28.97, 19.59; HRMS
calcd for C28H33N2O3 [MþH]þ 445.2486, found 445.2480.
(400 MHz, CDCl3)
d
7.91 (d, J¼7.2 Hz, 2H), 7.52 (t, J¼7.2 Hz, 1H), 7.41
(t, J¼7.2 Hz, 2H), 7.30e7.24 (m, 4H), 7.18 (t, J¼7.2 Hz, 1H), 3.92e3.85
(m, 1H), 3.57 (s, 3H), 3.39 (dd, J¼16.8, 7.2 Hz, 1H), 3.32 (dd, J¼16.8,
7.2 Hz, 1H), 2.81 (dd, J¼15.6, 7.2 Hz, 1H), 2.69 (dd, J¼15.6, 7.2 Hz,
1H); 13C NMR (100 MHz, CDCl3)
d 198.22, 172.39, 143.47, 137.01,
4.35. Compound (R)-9d
133.22, 128.74 (2C), 128.71 (2C), 128.18 (2C), 127.45 (2C), 126.93,
51.68, 44.65, 40.68, 37.61; HRMS calcd for C18H19O3 [MþH]þ
283.1329, found 283.1321.
Compound (R)-9d was prepared according to the general pro-
20
cedure in 95% yield as a white solid. Mp¼35e37 ꢀC; [
a]
þ9.67
D
(c 0.30, CHCl3); 1H NMR (400 MHz, CDCl3)
d 8.49 (s, 1H), 8.03 (dd,
J¼8.8, 1.6 Hz, 1H), 7.96 (d, J¼8.0 Hz, 1H), 7.87 (t, J¼8.8 Hz, 2H), 7.59
(dt, J¼7.2, 1.2 Hz, 1H), 7.54 (dt, J¼7.2, 1.2 Hz, 1H), 3.68 (s, 3H), 3.23
(dd, J¼16.4, 6.0 Hz, 1H), 2.96 (dd, J¼16.4, 7.6 Hz, 1H), 2.78e2.70
(m, 1H), 2.48 (dd, J¼15.2, 6.4 Hz, 1H), 2.36 (dd, J¼15.2, 6.4 Hz, 1H),
4.31. Compound (S)-10d
Compound (S)-10d was prepared according to the general pro-
cedure in 96% yield as a yellow solid. Mp¼106e108 ꢀC; [
a
]
20 þ5.00
D
1.09 (d, J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 199.29, 173.18,
(c 0.30, CHCl3); 1H NMR (400 MHz, CDCl3)
d 8.10 (s, 1H), 8.08 (dd,
135.72, 134.53, 132.68, 129.98, 129.74, 128.59 (2C), 127.90, 126.90,
124.03, 51.64, 45.04, 41.09, 27.18, 20.34; HRMS calcd for C17H19O3
[MþH]þ 271.1329, found 271.1336.
J¼8.8, 1.6 Hz, 1H), 7.86 (dd, J¼5.6, 3.2 Hz, 1H), 7.82e7.81 (m, 1H),
7.79 (d, J¼8.4 Hz, 1H), 7.47 (dd, J¼6.0, 3.2 Hz, 2H), 7.17e7.10 (m, 3H),
7.01 (d, J¼7.2 Hz,1H), 4.04 (d, J¼15.2 Hz,1H), 3.95 (d, J¼15.2 Hz,1H),
3.77e3.74 (m, 1H), 3.51e3.45 (m, 2H), 3.37 (s, 3H), 3.15 (dd, J¼16.4,
10.0 Hz, 1H), 3.04 (dd, J¼16.4, 3.6 Hz, 1H), 2.54 (s, 3H); 13C NMR
4.36. Compound (S)-9d
(100 MHz, CDCl3)
d 163.83, 136.46, 134.42, 134.11, 134.05, 133.21,
Compound (S)-9d was prepared according to the general pro-
128.83,128.75,127.92,127.79,126.79,126.58,126.52,126.38,126.35,
125.83, 124.08, 74.98, 60.93, 59.38, 56.07, 30.95, 15.72; HRMS calcd
for C23H25N2O [MþH]þ 345.1961, found 345.1960.
20
cedure in 93% yield as a white solid. Mp¼35e37 ꢀC; [
a]
ꢁ9.33
D
(c 0.30, CHCl3); 1H NMR (400 MHz, CDCl3)
d 8.48 (s, 1H), 8.02 (dd,
J¼8.4, 1.6 Hz, 1H), 7.95 (d, J¼8.0 Hz, 1H), 7.86 (t, J¼8.4 Hz, 2H), 7.58
(dt, J¼7.2, 1.2 Hz, 1H), 7.53 (dt, J¼7.2, 1.2 Hz, 1H), 3.68 (s, 3H), 3.23
(dd, J¼16.4, 6.0 Hz, 1H), 2.96 (dd, J¼16.4, 7.6 Hz, 1H), 2.78e2.70
(m, 1H), 2.48 (dd, J¼15.2, 6.4 Hz, 1H), 2.36 (dd, J¼15.2, 6.4 Hz, 1H),
4.32. Compound (R)-10d
1.09 (d, J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 199.27, 173.17,
Compound (R)-10d was prepared according to the general
20
procedure in 96% yield as a yellow solid. Mp¼106e108 ꢀC; [
a]
135.70, 134.52, 132.67, 129.96, 129.73, 128.57 (2C), 127.88, 126.88,
124.01, 51.62, 45.02, 41.07, 27.16, 20.32; HRMS calcd for C17H19O3
[MþH]þ 271.1329, found 271.1331.
D
ꢁ5.33 (c 0.30, CHCl3); 1H NMR (400 MHz, CDCl3)
d 8.11 (s, 1H), 8.07
(dd, J¼8.4,1.6 Hz,1H), 7.88 (dd, J¼6.0, 3.6 Hz,1H), 7.84e7.82 (m,1H),
7.80 (d, J¼8.8 Hz, 1H), 7.49 (dd, J¼6.0, 3.6 Hz, 2H), 7.18e7.11 (m, 3H),
7.02 (d, J¼7.2 Hz,1H), 4.04 (d, J¼15.2 Hz,1H), 3.96 (d, J¼15.2 Hz,1H),
3.79e3.74 (m, 1H), 3.52e3.45 (m, 2H), 3.38 (s, 3H), 3.15 (dd, J¼16.4,
9.2 Hz, 1H), 3.04 (dd, J¼16.4, 3.6 Hz, 1H), 2.55 (s, 3H); 13C NMR
4.37. Compound (rac)-9d
Compound (rac)-9d was prepared according to the general
procedure in 94% yield as a white solid. Mp¼34e36 ꢀC; 1H NMR
(100 MHz, CDCl3)
d 163.91, 136.52, 134.48, 134.15, 134.10, 133.25,
(400 MHz, CDCl3)
d
8.46 (s, 1H), 8.01 (dd, J¼8.8, 1.6 Hz, 1H), 7.93
128.87, 128.80, 127.97, 127.84, 126.84, 126.62, 126.56, 126.43, 126.40,
125.87, 124.13, 75.04, 60.98, 59.44, 56.12, 30.99, 15.79; HRMS calcd
for C23H25N2O [MþH]þ 345.1961, found 345.1959.
(d, J¼8.0 Hz, 1H), 7.83 (t, J¼8.8 Hz, 2H), 7.55 (dt, J¼6.8, 1.2 Hz, 1H),
7.50 (dt, J¼6.8, 1.2 Hz, 1H), 3.66 (s, 3H), 3.21 (dd, J¼16.4, 6.0 Hz, 1H),
2.94 (dd, J¼16.4, 7.6 Hz, 1H), 2.78e2.70 (m, 1H), 2.47 (dd, J¼15.2,
6.8 Hz, 1H), 2.34 (dd, J¼15.2, 6.8 Hz, 1H), 1.08 (d, J¼6.8 Hz, 3H); 13
C
4.33. Compound (S, R)-11d
NMR (100 MHz, CDCl3) d 199.07, 173.01, 135.55, 134.53, 132.53,
129.60, 129.52, 128.43 (2C), 127.75, 126.75, 123.87, 51.47, 44.87,
40.91, 27.01, 20.19; HRMS calcd for C17H19O3 [MþH]þ 271.1329,
found 271.1357.
Compound (S, R)-11d was prepared according to the general
20
procedure in 89% yield as pale yellow oil. [
a
]
D
þ48.3 (c 0.30,
CHCl3); 1H NMR (400 MHz, CDCl3)
d
8.16 (s, 1H), 7.95e7.90 (m, 2H),
7.86e7.82 (m, 2H), 7.49 (dd, J¼6.0, 3.2 Hz, 2H), 7.18e7.13 (m, 3H),
7.03 (d, J¼6.8 Hz, 1H), 3.92 (d, J¼14.8 Hz, 1H), 3.85e3.82 (m, 2H),
3.64 (s, 3H), 3.51e3.46 (m, 2H), 3.41 (s, 3H), 3.26 (dd, J¼12.4, 8.4 Hz,
1H), 3.08e3.07 (m, 2H), 2.97 (dd, J¼13.2, 4.0 Hz, 1H), 2.34e2.23
4.38. Compound (S, R)-11e
Compound (S, R)-11e was prepared according to the general
procedure in 88% yield as yellow oil. [
a
]
20 þ121 (c 0.20, CHCl3); 1H
D
(m, 3H), 0.85 (d, J¼6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
173.29,
NMR (400 MHz, CDCl3)
d
8.12 (s, 1H), 7.93e7.89 (m, 2H), 7.84e7.82
168.86,135.05,134.35,134.07,133.88,133.24,128.85,128.68,128.28,
127.79, 127.25, 126.83, 126.59, 126.40 (2C), 125.84, 124.82, 75.28,
61.13, 59.31, 56.93, 51.58, 41.37, 34.52, 31.85, 28.92, 19.54; HRMS
calcd for C28H33N2O3 [MþH]þ 445.2486, found 445.2494.
(m, 2H), 7.49 (dd, J¼6.0, 3.2 Hz, 2H), 7.16e7.11 (m, 3H), 7.02
(d, J¼6.8 Hz, 1H), 4.05 (d, J¼15.2 Hz, 1H), 3.87 (d, J¼15.2 Hz, 1H),
3.75 (dd, J¼8.4, 3.6 Hz, 1H), 3.58 (s, 3H), 3.50e3.43 (m, 2H), 3.38 (s,
3H), 3.21e3.13 (m, 2H), 3.09e2.99 (m, 2H), 2.34e2.14 (m, 3H),

X. Pan, Z. Liu / Tetrahedron 70 (2014) 4602e4610
4609
1.34e1.22 (m, 2H), 0.85 (d, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
4.43. Compound (S, R)-11f
d
172.71, 169.09, 134.52, 134.11, 133.28, 129.67, 128.89, 128.85,
128.48, 128.40, 128.25, 127.84, 127.25, 126.85,126.57, 126.42,125.88,
124.95, 74.82, 60.97, 59.32, 57.25, 51.58, 38.28, 35.21, 32.77, 31.00,
26.75, 11.23; HRMS calcd for C29H35N2O3 [MþH]þ 459.2642, found
459.2653.
Compound (S, R)-11f was prepared according to the general
procedure in 78% yield as yellow oil. [
NMR (400 MHz, CDCl3)
a
]
20 þ124 (c 0.20, CHCl3); 1H
D
d
8.09 (s, 1H), 7.92 (dd, J¼6.4, 2.8 Hz, 1H),
7.87e7.84 (m, 2H), 7.75 (d, J¼8.8 Hz,1H), 7.52 (dd, J¼6.0, 3.2 Hz, 2H),
7.19e7.15 (m, 6H), 7.01 (d, J¼7.2 Hz, 1H), 6.94e6.93 (m, 2H),
3.83e3.78 (m, 2H), 3.71 (d, J¼15.2 Hz, 1H), 3.63 (s, 3H), 3.57e3.46
(m, 2H), 3.35e3.32 (m, 2H), 3.27 (s, 3H), 3.16 (dd, J¼13.2, 4.0 Hz,
1H), 3.02 (dd, J¼16.8, 3.2 Hz, 1H), 2.83 (dd, J¼16.8, 10.0 Hz, 1H), 2.71
(dd, J¼15.6, 8.8 Hz, 1H), 2.61 (dd, J¼15.6, 6.4 Hz, 1H); 13C NMR
4.39. Compound (R, S)-11e
Compound (R, S)-11e was prepared according to the general
procedure in 88% yield as yellow oil. [
NMR (400 MHz, CDCl3)
a
]
20 ꢁ120 (c 0.20, CHCl3); 1H
D
(100 MHz, CDCl3)
d 172.69, 168.27, 142.41, 135.08, 134.40, 134.07,
d
8.12 (s, 1H), 7.93e7.88 (m, 2H), 7.84e7.82
133.90, 133.26, 128.90, 128.70, 128.46 (2C), 128.28, 127.89 (2C),
127.84, 127.62, 127.38, 127.05, 126.84, 126.58, 126.41, 125.85, 124.98,
74.79, 60.85, 59.11, 56.76, 51.76, 40.99, 39.99, 34.06, 32.28; HRMS
calcd for C33H35N2O3 [MþH]þ 507.2642, found 507.2654.
(m, 2H), 7.49 (dd, J¼6.0, 3.2 Hz, 2H), 7.16e7.10 (m, 3H), 7.02
(d, J¼6.8 Hz, 1H), 4.05 (d, J¼15.2 Hz, 1H), 3.87 (d, J¼15.2 Hz, 1H),
3.74 (dd, J¼8.4, 3.6 Hz, 1H), 3.58 (s, 3H), 3.55e3.43 (m, 2H), 3.38
(s, 3H), 3.21e3.13 (m, 2H), 3.08e2.99 (m, 2H), 2.34e2.14 (m, 3H),
1.36e1.29 (m, 2H), 0.85 (d, J¼7.6 Hz, 3H); 13C NMR (100 MHz,
4.44. Compound (R, S)-11f
CDCl3)
d 173.70, 169.08, 135.30, 134.52, 134.10, 134.03, 133.27,
129.66, 128.88, 128.84, 128.24, 127.84, 127.24, 126.85, 126.56, 126.41,
125.87, 124.94, 74.82, 60.97, 59.32, 57.25, 51.58, 38.28, 35.21, 32.77,
31.00, 26.75, 11.23; HRMS calcd for C29H35N2O3 [MþH]þ 459.2642,
found 459.2650.
Compound (R, S)-11f was prepared according to the general
procedure in 80% yield as yellow oil. [
NMR (400 MHz, CDCl3)
a
]
20 ꢁ123 (c 0.20, CHCl3); 1H
D
d
8.09 (s, 1H), 7.92 (dd, J¼6.4, 2.8 Hz, 1H),
7.87e7.84 (m, 2H), 7.75 (d, J¼8.4 Hz,1H), 7.52 (dd, J¼6.4, 3.2 Hz, 2H),
7.18e7.14 (m, 6H), 7.02e6.86 (m, 3H), 3.83e3.78 (m, 2H), 3.71 (d,
J¼14.8 Hz, 1H), 3.63 (s, 3H), 3.57e3.42 (m, 2H), 3.35e3.32 (m, 2H),
3.27 (s, 3H), 3.16 (dd, J¼13.6, 4.4 Hz, 1H), 3.03 (dd, J¼16.0, 3.2 Hz,
1H), 2.83 (dd, J¼16.0, 10.4 Hz, 1H), 2.71 (dd, J¼15.6, 8.4 Hz, 1H), 2.61
4.40. Compound (R)-9e
Compound (R)-9e was prepared according to the general pro-
20
cedure in 91% yield as colorless oil. [
NMR (400 MHz, CDCl3)
a]
þ8.67 (c 0.30, CHCl3); 1H
(dd, J¼15.6, 6.4 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 172.73, 168.31,
D
d
8.51 (s, 1H), 8.04 (dd, J¼8.8, 1.6 Hz, 1H),
142.44, 135.11, 134.43, 134.10, 133.93, 133.29, 128.93, 128.74, 128.64,
128.49, 128.31, 127.93, 127.87, 127.65, 127.40, 127.08, 126.87, 126.60,
126.44, 126.42, 125.87, 125.01, 74.82, 60.87, 59.14, 56.78, 51.80,
41.03, 40.02, 39.09, 32.31; HRMS calcd for C33H35N2O3 [MþH]þ
507.2642, found 507.2637.
7.98 (d, J¼7.6 Hz, 1H), 7.88 (t, J¼8.8 Hz, 2H), 7.60 (dt, J¼6.8, 1.2 Hz,
1H), 7.55 (dt, J¼6.8, 1.2 Hz, 1H), 3.66 (s, 3H), 3.22 (dd, J¼16.4, 6.8 Hz,
1H), 3.08 (dd, J¼16.4, 6.8 Hz, 1H), 2.61e2.55 (m, 1H), 2.47
(dd, J¼15.6, 6.0 Hz, 1H), 2.43 (dd, J¼15.6, 7.2 Hz, 1H), 1.56e1.43
(m, 2H), 0.96 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 199.65,
173.54, 135.76, 134.66, 132.74, 130.00, 129.79, 128.61 (2C), 127.94,
126.93, 124.10, 51.68, 42.63, 38.26, 33.25, 27.12, 11.37; HRMS calcd
for C18H21O3 [MþH]þ 285.1485, found 285.1489.
4.45. Compound (R)-9f
Compound (R)-9f was prepared according to the general pro-
cedure in 93% yield as a white solid. Mp¼89e91 ꢀC; [
a
]
20 þ3.67 (c
D
0.30, CHCl3); 1H NMR (400 MHz, CDCl3)
d
8.42 (s,1H), 7.97 (dd, J¼8.8,
4.41. Compound (S)-9e
4.0 Hz, 1H), 7.92 (d, J¼8.0 Hz, 1H), 7.84 (d, J¼8.8 Hz, 2H), 7.57 (t,
J¼6.8 Hz,1H), 7.52 (t, J¼6.8 Hz,1H), 7.30e7.29 (m, 4H), 7.21e7.17 (m,
1H), 3.98e3.91 (m,1H), 3.59 (s, 3H), 3.52 (dd, J¼16.8, 7.2 Hz,1H), 3.45
(dd, J¼16.8, 7.2 Hz,1H), 2.86 (dd, J¼15.6, 7.2 Hz,1H), 2.73 (dd, J¼15.6,
Compound (S)-9e was prepared according to the general pro-
20
cedure in 92% yield as colorless oil. [
a
]
ꢁ8.33 (c 0.30, CHCl3); 1H
D
NMR (400 MHz, CDCl3)
d
8.50 (s, 1H), 8.04 (dd, J¼8.8, 1.6 Hz, 1H),
7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 198.21, 172.48, 143.54,
7.97 (d, J¼8.0 Hz, 1H), 7.88 (t, J¼8.8 Hz, 2H), 7.59 (dt, J¼6.8, 1.2 Hz,
1H), 7.55 (dt, J¼6.8, 1.2 Hz, 1H), 3.66 (s, 3H), 3.22 (dd, J¼16.4, 6.8 Hz,
1H), 3.07 (dd, J¼16.4, 6.8 Hz, 1H), 2.61e2.55 (m, 1H), 2.48 (dd,
J¼15.6, 6.0 Hz, 1H), 2.42 (dd, J¼15.6, 7.2 Hz, 1H), 1.56e1.43 (m, 2H),
135.72, 134.36, 132.63, 129.93, 129.72, 128.80 (2C), 128.63, 128.59,
127.90, 127.51 (2C), 126.99,126.92, 123.97, 51.75, 44.77, 40.75, 37.82;
HRMS calcd for C22H21O3 [MþH]þ 333.1485, found 333.1488.
0.96 (t, J¼7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 199.65, 173.53,
4.46. Compound (S)-9f
135.75, 134.66, 132.73, 130.00, 129.79, 128.61 (2C), 127.94, 126.92,
124.10, 51.65, 42.62, 38.25, 33.34, 27.11, 11.36; HRMS calcd for
Compound (S)-9f was prepared according to the general pro-
C
18H21O3 [MþH]þ 285.1485, found 285.1482.
cedure in 93% yield as a white solid. Mp¼88e90 ꢀC; [
a
]
20 ꢁ3.67 (c
D
0.30, CHCl3); 1H NMR (400 MHz, CDCl3)
d
8.42 (s,1H), 7.97 (dd, J¼8.8,
4.42. Compound (rac)-9e
4.0 Hz, 1H), 7.92 (d, J¼8.0 Hz, 1H), 7.84 (d, J¼8.8 Hz, 2H), 7.57 (t,
J¼6.8 Hz,1H), 7.52 (t, J¼6.8 Hz,1H), 7.30e7.29 (m, 4H), 7.21e7.17 (m,
1H), 3.98e3.91 (m,1H), 3.59 (s, 3H), 3.52 (dd, J¼16.8, 7.2 Hz,1H), 3.45
(dd, J¼16.8, 7.2 Hz,1H), 2.86 (dd, J¼15.6, 7.2 Hz,1H), 2.73 (dd, J¼15.6,
Compound (rac)-9e was prepared according to the general
procedure in 87% yield as colorless oil. 1H NMR (400 MHz, CDCl3)
d
8.51 (s, 1H), 8.04 (dd, J¼8.4, 1.6 Hz, 1H), 7.98 (d, J¼8.0 Hz, 1H), 7.88
7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 198.19, 172.46, 143.53,
(t, J¼8.4 Hz, 2H), 7.60 (t, J¼7.2 Hz, 1H), 7.55 (t, J¼7.2 Hz, 1H), 3.66
(s, 3H), 3.22 (dd, J¼16.4, 6.8 Hz, 1H), 3.08 (dd, J¼16.4, 6.8 Hz, 1H),
2.61e2.55 (m, 1H), 2.48 (dd, J¼15.2, 6.0 Hz, 1H), 2.42 (dd, J¼15.2,
6.0 Hz, 1H), 1.56e1.44 (m, 2H), 0.96 (t, J¼7.6 Hz, 3H); 13C NMR
135.70, 134.34, 132.61, 129.92, 129.71, 128.79 (2C), 128.61, 128.58,
127.89,127.50 (2C),126.98,126.91,123.95, 51.73, 44.75, 40.73, 37.80;
HRMS calcd for C22H21O3 [MþH]þ 333.1485, found 333.1492.
(100 MHz, CDCl3)
d
199.53, 173.43, 135.67, 134.56, 132.64, 129.91,
4.47. Compound (rac)-9f
129.70,128.52 (2C),127.85,126.83,124.00, 51.57, 42.52, 38.16, 33.24,
27.03, 11.28; HRMS calcd for C18H21O3 [MþH]þ 285.1485, found
285.1493.
Compound (rac)-9f was prepared according to the general
procedure in 88% yield as a white solid. Mp¼89e91 ꢀC; 1H NMR

4610
X. Pan, Z. Liu / Tetrahedron 70 (2014) 4602e4610
(400 MHz, CDCl3)
d
8.37 (s, 1H), 7.93 (dd, J¼8.8, 4.0 Hz, 1H), 7.85 (d,
J¼8.0 Hz, 1H), 7.92 (d, J¼8.8 Hz, 1H), 7.89 (d, J¼8.8 Hz, 1H), 7.63 (dt,
J¼6.8, 1.2 Hz, 1H), 7.58 (dt, J¼6.8, 1.2 Hz, 1H), 3.69 (s, 3H), 3.67e3.61
(m, 1H), 3.48 (dd, J¼17.6, 4.4 Hz, 1H), 3.40 (dd, J¼17.6, 8.0 Hz, 1H),
2.75 (dd, J¼16.0, 6.0 Hz, 1H), 2.59 (dd, J¼16.0, 6.0 Hz, 1H); 13C NMR
J¼7.6 Hz, 1H), 7.76 (d, J¼8.8 Hz, 2H), 7.50 (t, J¼7.6 Hz, 1H), 7.45 (t,
J¼7.6 Hz, 1H), 7.29e7.24 (m, 4H), 7.19e7.14 (m, 1H), 3.98e3.91 (m,
1H), 3.54 (s, 3H), 3.48 (dd, J¼16.8, 6.8 Hz, 1H), 3.41 (dd, J¼16.8,
6.8 Hz, 1H), 2.84 (dd, J¼15.6, 6.8 Hz, 1H), 2.70 (dd, J¼15.6, 6.8 Hz,
(100 MHz, CDCl3)
d 195.83, 171.30, 136.02, 133.74, 132.67, 130.14,
1H); 13C NMR (100 MHz, CDCl3)
d
197.97, 172.29, 143.43, 135.51,
129.85, 129.01, 128.92, 128.04, 127.21, 123.84, 52.36, 36.89, 36.33,
36.06, 33.27; HRMS calcd for C17H16O3F3 [MþH]þ 325.1046, found
325.1042.
134.17, 132.43, 129.74, 129.54, 128.63 (2C), 128.45, 128.40, 127.72,
127.38 (2C), 126.82, 126.74, 123.77, 51.53, 44.57, 40.56, 37.63; HRMS
calcd for C22H21O3 [MþH]þ 333.1485, found 333.1484.
Acknowledgements
4.48. Compound (S, R)-11g
This research was financially supported by Beijing Key Labora-
tory of Active Substance Discovery and Druggability Evaluation.
Compound (S)-11g was prepared according to the general pro-
cedure in 74% yield as yellow oil. [
(400 MHz, CDCl3)
a
]
20 þ360 (c 0.20, CHCl3); 1H NMR
D
d
8.16 (s, 1H), 7.93e7.90 (m, 2H), 7.87e7.83 (m,
Supplementary data
2H), 7.51 (dd, J¼6.4, 3.2 Hz, 2H), 7.17e7.13 (m, 3H), 7.02 (d, J¼7.2 Hz,
1H), 4.05 (d, J¼15.2 Hz, 1H), 3.78e3.76 (m, 2H), 3.66 (s, 3H),
3.44e3.42 (m, 2H), 3.41 (s, 3H), 3.39e3.35 (m, 1H), 3.20e3.15 (m,
2H), 3.08e3.05 (m, 1H), 2.69e2.64 (m, 1H), 2.62e2.57 (m, 1H), 2.47
Full experimental detail, 1H NMR spectra, 13C NMR spectra, IR
spectra, HPLC. Supplementary data associated with this article can
be found in the online version, at http://dx.doi.org/10.1016/
j.tet.2014.05.049.
(dd, J¼16.8, 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 171.31, 166.68,
134.43, 134.31, 134.21, 133.67, 133.24, 128.94, 128.83, 128.56, 127.89,
127.29, 127.11, 126.69, 126.60, 126.38, 125.94, 124.80, 75.18, 60.90,
59.28, 57.15, 55.33, 52.27, 33.16, 31.22, 29.32, 27.00; HRMS calcd for
References and notes
C
28H30F3N2O3 [MþH]þ 499.2203, found 499.2205.
1. Yamada, S.; Hiroi, K.; Achiwa, K. Tetrahedron Lett. 1969, 48, 4233e4236.
2. Meyers, A. I.; Williams, D. R.; Druelinger, M. J. Am. Chem. Soc. 1976, 98,
3032e3033.
4.49. Compound (R)-9g
3. Meyers, A. I.; Williams, D. R. J. Org. Chem. 1978, 43, 3245e3247.
4. Corey, E. J.; Enders, D. Tetrahedron Lett. 1976, 3e6.
5. Corey, E. J.; Enders, D. Tetrahedron Lett. 1976, 11e14.
6. Enders, D.; Dahmen, W.; Dederichs, E.; Weuster, P. Synth. Commun. 1983, 3,
1235e1242.
Compound (R)-9g was prepared according to the general pro-
cedure in 92% yield as a white solid. Mp¼95e97 ꢀC; [
a
]
20 ꢁ9.03 (c
D
0.30, CHCl3); 1H NMR (400 MHz, CDCl3)
d 8.46 (s, 1H), 8.01 (dd,
J¼8.8, 1.6 Hz, 1H), 7.95 (d, J¼8.0 Hz, 1H), 7.88 (d, J¼8.8 Hz, 1H), 7.86
(d, J¼8.8 Hz, 1H), 7.60 (dt, J¼7.2, 1.2 Hz, 1H), 7.55 (dt, J¼7.2, 1.2 Hz,
1H), 3.68 (s, 3H), 3.66e3.61 (m, 1H), 3.46 (dd, J¼17.6, 4.4 Hz, 1H),
3.38 (dd, J¼17.6, 8.0 Hz, 1H), 2.74 (dd, J¼16.0, 6.0 Hz, 1H), 2.59 (dd,
7. Stork, G.; Benaim, J. J. Am. Chem. Soc. 1971, 93, 5938e5939.
8. Enders, D.; Peters, R.; Wortmann, L. Acc. Chem. Res. 2000, 157e169.
9. Enders, D.; Eichenauer, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 549e550.
10. Enders, D.; Eichenauer, H. Tetrahedron Lett. 1977, 191e194.
11. Enders, D.; Eichenauer, H. Chem. Ber. 1979, 112, 2933e2960.
12. Eichenauer, H.; Friedrich, E.; Lutz, W.; Enders, D. Angew. Chem., Int. Ed. Engl.
1978, 17, 206e207.
13. Enders, D.; Papdopoulos, K. Tetrahedron Lett. 1983, 24, 4967e4970.
14. Enders, D.; Backhaus, D.; Runsink, J. Tetrahedron 1996, 52, 1503e1528.
15. Enders, D.; Knopp, M.; Schiffers, R.; Raabe, G. Angew. Chem., Int. Ed. Engl. 1995,
34, 2278e2280.
J¼16.0, 6.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 195.75, 170.99,
135.95, 133.67, 132.60, 130.07, 129.79, 128.95, 128.84, 127.97, 127.14,
123.77, 52.27, 36.81, 36.26, 35.99, 33.20; HRMS calcd for C17H16O3F3
[MþH]þ 325.1046, found 325.1043.
16. Beaudegnies, R.; Ghosez, L. Tetrahedron: Asymmetry 1994, 5, 557e560.
17. Cao, C. L.; Sun, X. L.; Zhou, J. L.; Tang, Y. J. Org. Chem. 2007, 72, 4073e4076.
18. Chowdhury, R.; Ghosh, S. K. Org. Lett. 2009, 15, 3270e3273.
19. Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Tanaka, F.; Barbas, C. F. Syn-
thesis 2004, 9, 1509e1521.
4.50. Compound (rac)-9g
Compound (rac)-9g was prepared according to the general
procedure in 88% yield as a white solid. Mp¼95e97 ꢀC; 1H NMR
20. Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D. Tetrahedron 2002, 58,
(400 MHz, CDCl3)
d
8.48 (s, 1H), 8.03 (dd, J¼8.8, 1.6 Hz, 1H), 7.98 (d,
2253e2329.