Construction of the Erythrinane Core Skeleton via Asymmetric Catalytic Cascade Reaction of Tertiary Enamides

Article abstract of DOI:10.1021/acs.joc.0c01992

We report herein an efficient cascade strategy for the rapid construction of a highly enantioenriched erythrinane core skeleton. Under the sequential catalysis of a chiral Cr(III)(salen)Cl and InCl3, cyclohexanone-derived tertiary enamides undergo an intramolecular enantioselective nucleophilic addition followed by diastereoselective Pictet-Spengler cyclization. This method is highly enantio- and diastereoselective, leading to diverse erythrina alkaloid derivatives as the sole diastereoisomer with up to 98% ee.

Full text of DOI:10.1021/acs.joc.0c01992

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Article
Construction of the Erythrinane Core Skeleton via Asymmetric
Catalytic Cascade Reaction of Tertiary Enamides
Li Zhen, Shuo Tong,* Jieping Zhu, and Mei-Xiang Wang*
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ABSTRACT: We report herein an efficient cascade strategy for the rapid construction of a highly enantioenriched erythrinane core
skeleton. Under the sequential catalysis of a chiral Cr(III)(salen)Cl and InCl3, cyclohexanone-derived tertiary enamides undergo an
intramolecular enantioselective nucleophilic addition followed by diastereoselective Pictet−Spengler cyclization. This method is
highly enantio- and diastereoselective, leading to diverse erythrina alkaloid derivatives as the sole diastereoisomer with up to 98% ee.
the cross-conjugation system within tertiary enamides, there will
be two resonance structures that can be obtained by conjugation
of the long-pair electrons of nitrogen with carbon−carbon
double bond and carbon−oxygen double bond, respectively.
The enabled regulation of the cross-conjugation system by
means of the nature of the EWG on the nitrogen atom as well as
the reaction media could revive and modulate the nucleophil-
icity of tertiary enamides. We have long been interested in
exploring the nucleophilic reaction and synthetic application of
tertiary eamides,7−14 thus demonstrating that tertiary enamides
are unique, shelf-stable, and versatile synthons in organic
synthesis.15 Following the reactivity of the parent enamine with
electrophiles, tertiary enamides generally produce the expected
monofunctionalized products. The reactions are believed to
proceed through an iminium intermediate, followed by
iminium−enamine tautomerization (Scheme 1a). Based on
this hypothesis, we have recently developed a catalytic
asymmetric cascade reaction involving the nucleophilic addition
of tertiary enamides to ketonic carbonyls and the trapping of
acyliminium by a benzene moiety (Scheme 1b). We envisioned
INTRODUCTION
■
The erythrina alkaloids contain a unique tetracyclic spiroamine
scaffold and display remarkable curare-like and hypnotic
activities.1 Many compounds containing the erythrinane
skeleton also possess interesting biological activities, including
sedative, hypotensive, and CNS depressant properties.2 Because
of distinctive molecular structures and diverse pharmacological
activities, these alkaloids are very attractive targets for synthetic
organic chemists. Despite many elegant synthetic methods
documented in the literature,3,4 the catalytic enantioselective
synthesis of erythrina alkaloids and their analogues is rare. In the
synthesis of (+)-dihydro-β-erythroidine, Kristensen and Vital
reported a Pd/(S,S-salen)-catalyzed enantioselective allylation
to produce allyl prolinone, this chiral key intermediate then went
through a 12-step synthetic sequence to finally deliver the
lactonic erythrina alkaloid.5 You’s group developed a Pd(0)-
catalyzed intramolecular dearomative arylation of 5-hydroxyl
indoline, which produces an erythrinane derivative in 31% yield
and 86% ee.6 Nevertheless, the de novo construction of the
erythrinane skeleton allowing structurally diverse modification
in the catalytic enantioselective manner remains a big challenge
and in great demand.
Received: August 18, 2020
As an enamine variant, tertiary enamides are stable
compounds and they show diminished enaminic (nucleophilic)
reactivity because of the electron-withdrawing nature of the N-
acyl group. Therefore, tertiary enamides have long been known
as inert chemicals in organic transformations. However, this
conventional notion has been challenged in recent years. Due to
https://dx.doi.org/10.1021/acs.joc.0c01992
© XXXX American Chemical Society
J. Org. Chem. XXXX, XXX, XXX−XXX
A

The Journal of Organic Chemistry
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Article
Scheme 1. Design of a Catalytic Asymmetric Cascade
Reaction for the Construction of Erythrinane Skeleton
Table 1. Condition Optimization for Enantioselective
Intramolecular Addition of 1a−2a
d
e
entry
cat*
solvent
temp. (°C) time (h) 2a (%)
ee (%)
a
1
cat*-1
cat*-2
cat*-3
cat*-3
cat*-3
cat*-3
cat*-3
cat*-3
cat*-3
cat*-3
cat*-3
xylenes
DCM
benzene
toluene
xylenes
DCM
DCE
CCl4
toluene
toluene
toluene
rt
rt
rt
rt
rt
rt
rt
rt
rt
10
0
12
12
60
12
24
24
24
12
12
18
12
28
35
83
90
86
99
98
86
90
99
trace
25
13
50
77
59
15
40
66
86
94
b
2
c
3
c
4
c
5
c
6
c
7
c
8
f
9
f
10
11
f
g
n.d.
a
b
c
Conditions: 1a (0.2 mmol), cat*-1 (20 mol %), xylenes (6 mL), RT.
Conditions: 1a (0.2 mmol), cat*-2 (10 mol %), DCM, RT.
Conditions: 1a (0.2 mmol), (R,R)-Cr(III)(salen)Cl (0.04 mmol, 0.2
that the use of cyclohexanone-derived tertiary enamides 1
bearing an electron-rich aryl moiety would first lead to the
formation of 5−6 fused ring system 2. Had this been the case, a
cascade intramolecular Pictet−Spengler cyclization could be
expected, leading eventually to ABCD ring-fused erythrinane
core skeleton 3 in a very short synthetic sequence.16
Disconnection of both the C−N bond of amide and enamine
function in 1 would afford phenethylamine 8, cyclohexanone
(9), and 2-oxo-2-arylacetylchloride 10, three simple reagents all
being commercially available (Scheme 1c). We report herein a
catalytic asymmetric reaction cascade involving the nucleophilic
addition of tertiary enamides to ketone carbonyls and the
trapping of acyliminium by Pictet−Spengler cyclization. This
method is highly efficient and enantio- and diastereoselective,
thus leading to diverse erythrina alkaloid derivatives as the sole
diastereoisomers with up to 98% ee.
d
equiv), Na2CO3 (0.04 mmol, 0.2 equiv), solvent (6 mL). Yield of the
isolated product. Measured by chiral-phase high-performance liquid
chromatography (HPLC). 100 mg 4 Å MS was added. n.d. not
determined.
e
f
g
83% yield but with only moderate ee (entry 3). Gratifyingly,
other aromatic solvents such as toluene (entry 4) and xylenes
(entry 5) could dramatically improve both the conversion and
stereoselectivity, with toluene being the best to obtain 2a in 90%
yield with 77% ee. However, switching to halogen-containing
solvents like dichloromethane (DCM, entry 6), 1,2-dichloro-
ethane (DCE, entry 7), and CCl4 (entry 8) diminished the
enantioselectivity. Toluene was chosen for further optimization.
It is noteworthy that the use of 4 Å MS as an additive plays a
decisive role in improving the stereocontrol (entry 9). Evidently,
the ee value of this (R,R)-Cr(III)(salen)Cl-catalyzed cyclization
was further increased to 94% when the reaction was performed
at a lower temperature of 10 °C (entry 10). Nevertheless, further
decreasing the temperature to 0 °C led to a much slower
reaction (entry 11). Overall, the optimum conditions found
consisted of stirring a toluene solution of 1a (c = 0.033 M) at 10
°C in the presence of (R,R)-Cr(III)(salen)Cl (0.2 equiv),
Na2CO3 (0.2 equiv), and 4 Å MS (500 mg/mmol) for 18 h.
Under these conditions, compound 2a was isolated in 99% yield
with 94% ee.
With the optimized conditions in hand, the scope of this
catalytic enantioselective cyclization was briefly examined. As
shown in Scheme 2, tertiary enamides having both an electron-
withdrawing (1b, 1c) or an electron-donating group (1d) on the
aromatic ring afforded the corresponding fused bicyclic product
2b−2d in 86−95% yields and 93−99% ees. Analogously, a
highly enantiopure 2-naphthyl-substituted product 2e was
synthesized in 80% yield and 92% ee. It is worth noting that
4,4-dimethylcyclohexanone and monoprotected cyclohexane-
RESULTS AND DISCUSSION
■
To begin with, condensation between alkyl amine 8 and
cyclohexanone (9) followed by acylation of the resulting imine
afforded tertiary enamide 1a as our starting reagent. Exploring
the reaction of 1a, we first looked at the performance of the
complexation of chiral binol-Ti(OiPr)4 and Pybox with copper,
which were validated in catalyzing the enantioselective addition
of tertiary enamides to ketones.12a,17 Surprisingly, they both
gave low yields of the desired product and low enantioselective
control (Table 1, entries 1−2), indicating that the structure of
enamides may have a great influence on their reactivity. The
combination of (R,R)-Cr(III)(salen)Cl and Na2CO3 were then
tested because in our previous result they also performed well in
the enantioselective addition of tertiary enamides to ketonic
carbonyls.12c Stirring a benzene solution of 1a in the presence of
(R,R)-Cr(III)(salen)Cl (0.2 equiv) and Na2CO3 (0.2 equiv) at
room temperature for 60 h afforded 2a as the only product in
B
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Scheme 2. Scope of Cr(III)(salen)Cl-Catalyzed
Enantioselective Intramolecular Addition of Tertiary
Enamides for the Formation of 5−6 Fused Ring System 2
Table 2. Condition Optimization for Diastereoselective
Pictet−Spengler Cyclization
a
temp.
time
(h)
3a
ee
b
c
entry
cat. (eq)
solv.
tol
tol
(°C)
(%)
(%)
1
2
3
4
5
6
7
8
p-TSA (0.5)
InCl3 (0.5)
BF3·Et2O (0.5) tol
rt
rt
rt
rt
rt
rt
5
5
5
0
−10
0.5
0.5
0.5
0.5
0.5
0.5
3
72
3
18
72
2
20
3
93
93
94
93
92
95
94
93
92
98
AlCl3 (0.5)
InCl3 (0.5)
InCl3 (0.5)
InCl3 (0.5)
InCl3 (0.2)
InCl3 (1.0)
InCl3 (1.0)
InCl3 (1.0)
tol
8
CHCl3
DCM
DCM
DCM
DCM
DCM
DCM
10
35
56
36
51
64
9
10
11
0
a
b
Conditions: 2a (0.2 mmol), catalyst, solvent (6 mL). Yield of the
isolated product. Measured by chiral-phase HPLC.
c
5R, 13bS) and is consistent with erythrina-type alkaloid
(Supporting Information).17
The scope of the diastereoselective Pictet−Spengler cycliza-
tion promoted by InCl3 was next examined. As shown in Scheme
3, tertiary enamides having both an electron-withdrawing (2b,
2c) and electron-donating (2d) group on the aromatic ketones
are compatible with the reaction conditions, affording the
desired products (3b−3d) in good enantiopurities (84−90%
ee) and moderate yield (31−65%). The 2-naphthyl substituted
product 3e was synthesized analogously in 39% yield and 91%
ee. Pleasingly, 4,4-dimethylcyclohexanone-derived 2f partici-
pated in the reaction smoothly to afford the desired erythrina
derivative 3f in 31% yield and 91% ee. When a keto-protected
cyclohexanone (2g) was subjected to the reaction, a diminished
yield of 3g was observed. This was mainly due to the partial
deprotection that occurred spontaneously during the diaster-
eoselective cyclization in the presence of InCl3. However, the
enantioselectivity of 3g was maintained at a high level (96% ee).
Tertiary enamides bearing dihydropyran (2h) and dihydrothio-
pyran (2i) followed the same reaction route to produce the
corresponding heterocyclic product 3h (44% yield, 95% ee) and
3i (47% yield, 86% ee), respectively. Pleasingly, all products
were obtained with high diastereomeric purity. The moderate
yields were mainly attributed to the undesired competitive
dehydration and double bond migration byproduct 4 during the
Pictet−Spengler cyclization (Scheme 3).
The obtained fused tetracyclic compounds 3 not only
resemble the structure of erythrina alkaloids but they are also
invaluable platforms for the synthesis of diverse complicated N-
heterocyclic compounds potentially useful in drug discovery. To
further illustrate the synthetic potential of the present method,
post functionalization of 3a was undertaken. As shown in
Scheme 4, using an excess amount of LiAlH4, chemoselective
lactam reduction of 3a afforded 5 in 90% yield. On the other
hand, α,β-unsaturated lactam 6 was obtained upon dehydration
in the yield of 89%. Finally, the hydrogenation of 6 in the
presence of Pd/C produces 7 as the sole diastereoisomer in 81%
yield.
1,4-dione were also found to be well tolerated to afford the
functionalized enantioenriched products 2f and 2g in good
yields and excellent enantiopurities. In addition, compounds 1h
and 1i bearing dihydropyran (1h) and dihydrothiopyran (1i)
were also suitable substrates, affording the fused bicyclic
products in good yields and excellent ees (2h, 92% yield, 94%
ee; 2i, 66% yield, 99% ee), which highly enriched the diversity of
the heteroskeleton. The absolute configuration of 2a was
determined by X-ray crystallography, and the configurations of
the other 5−6 bicyclic products 2 were assigned accordingly
(Supporting Information).17
During the experiment, we found that further intramolecular
cyclization from 2a to 3a was not going well under the current
catalyst system. To facilitate the sequential diastereoselective
Pictet−Spengler cyclization and thus access the erythrinane core
skeleton, an additional Lewis acid or Brønsted acid was added.
After screening a series of acid promoters and reaction
conditions, InCl3 stood out as the best to afford ABCD ring-
fused erythrinane core skeleton 3a as the sole diastereomer but
only in 35% yield (Table 2, entry 1−6). Evidently, decreasing
the reaction temperature from rt to 5 °C dramatically improved
the yield of 3a from 35 to 56% (entry 7). Lowering the catalyst
loading led to a slower reaction with a diminished yield (entry
8), while the reaction was further accelerated when it was
executed at a higher catalyst loading (entry 9). Overall, the
optimum conditions were to stir a CH2Cl2 solution of 2a (c
0.033 M) in the presence of InCl3 (1 equiv) at 0 °C for 18 h.
Under these conditions, highly enantioenriched 3a was isolated
in 64% yield with excellent enantioselectivity (98% ee) and
diastereoselectivity (>19:1 d.r.). The absolute configuration of
3a was determined by X-ray crystallographic analysis to be (4aR,
C
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Scheme 3. Scope of InCl3-Promoted Diastereoselective
Pictet−Spengler Cyclization
CONCLUSIONS
■
In summary, we have developed an efficient two-step strategy for
the rapid construction of the erythrinane core skeleton from
cyclohexanone-derived tertiary enamides. This method com-
prises a chiral Cr(III)(salen)Cl-catalyzed enantioselective
intramolecular addition of tertiary enamides to ketone carbonyls
with subsequent InCl3-promoted diastereoselective Pictet−
Spengler cyclization processes. The cascade asymmetric double
intramolecular cyclization reactions produce diverse erythrina
alkaloids in moderate yields with good enantioselectivity and
excellent diastereoselectivity. Synthetic application of the
method by transforming the resulting products into various
erythrina-type core skeleton derivatives was also included. The
synthesis of erythrina-type and iboga-type alkaloids based on
this methodology is currently under development in our
laboratory.
EXPERIMENTAL SECTION
■
General Remarks. All chemicals were dried or purified according to
standard procedures prior to use. Flash column chromatography was
performed on silica gel (100−200 mesh). Reactions were monitored
using precoated, glass-backed silica gel plates and visualized by means of
UV irradiation (254 nm) or KMnO4, phosphomolybdic acid. 1H NMR
and 13C NMR spectra were recorded using a JEOL EXC-400 MHz
spectrometer at ambient temperature. 1H frequency is at 400.13 MHz
and 13C frequency is at 100.62 MHz. Chemical shifts are reported in
ppm with either tetramethylsilane or the residual solvent resonance
used as an internal standard. Abbreviations are used in the description
of NMR data as follows: chemical shift (δ, ppm), multiplicity (s =
singlet, d = doublet, t = triplet, m = multiplet), and coupling constant (J,
Hz). Melting points are uncorrected. Infrared spectra were recorded
using an FT-IR spectrometer with KBr discs in the 4000−400 cm−1
region. The high-resolution mass spectra (HRMS) were recorded on a
Q Exactive Orbitrap Mass Spectrometer (Orbitrap). All yields reported
were isolated yields, and ee values were determined by HPLC using
Daicel ADH or ODH chiral columns eluted with a mixture of
isopropanol and hexane at 25 °C. The optical rotation was determined
by a Rudolph Autopol IV Automatic polarimeter. Crystallographic data
were collected on a Rigaku XtaLAB Synergy (Cu) X-ray single crystal
diffractometer.
General Procedure for the Synthesis of Tertiary Enamides 1.
A dichloromethane solution of amine (0.5 M), ketone (0.5 M), and 4 Å
MS (1:1 w/w) was vigorously stirred at 25 °C until the conversion of
amine to imine was completed. The mixture was filtered through a pad
of Celite and washed with DCM. The filtrate was concentrated in vacuo
to give a crude imine product, which was used immediately without
further purification. Under an argon atmosphere, imine (5 mmol) was
dissolved in N,N-dimethylformamide (DMF, 10 mL), and then Et3N
(0.834 ml, 6 mmol, 1.2 equiv) was added. After cooling to −20 °C, acyl
chloride (6 mmol, 1.2 equiv) was added dropwise for 20 min. The
resulting mixture was kept stirring at −20 °C for another 20 min. A
saturated aqueous NaHCO3 solution (20 mL) was added to quench the
reaction at −20 °C. The mixture was extracted with ethyl acetate (3 ×
50 mL) and washed with brine (2 × 50 mL). The organic layer was
dried over anhydrous Na2SO4 and concentrated in vacuo. The residue
was purified by flash column chromatography on silica gel to give the
pure enamide product 1.
Scheme 4. Post Functionalization of 3a
N-(Cyclohex-1-en-1-yl)-N-(3,4-dimethoxyphenethyl)-2-oxo-2-
phenylacetamide (1a). Purified by column chromatography on silica
gel (hexane/AcOEt/Et3N = 20:1:0.5): white solid (687.8 mg, 35%);
m.p. 92−94 °C; IR(KBr) 2933, 2849, 1642, 1516 cm−1; 1H NMR (400
MHz, DMSO-d6): δ 7.68 (t, 1H, J = 7.3 Hz), 7.64 (d, 2H, J = 7.3 Hz),
7.48−7.52 (m, 2H), 6.88 (s, 1H), 6.87 (d, 1H, J = 6.4 Hz), 6.79 (dd, 1H,
J = 8.0, 1.6 Hz), 5.24−5.26 (m, 1H), 3.81 (t, 2H, J = 7.1 Hz), 3.75 (s,
3H), 3.75 (s, 3H), 2.81 (t, 2H, J = 7.1 Hz), 1.98−2.02 (m, 2H), 1.67−
1.71 (m, 2H), 1.40−1.42 (m, 2H), 1.24−1.27 (m, 2H); 13C{1H} NMR
(101 MHz, DMSO-d6): δ 191.5, 165.6, 148.6, 147.5, 135.8, 134.3,
a
Conditions: (a) LiAlH4 (5 equiv), tetrahydrofuran (THF), reflux, 8
h, 90%; (b) MsCl (3.6 equiv), Et3N (7 equiv), DCM, RT, 12 h, 89%;
(c) Pd/C (20% w/w), H2 (1 atm), MeOH, RT, 12 h, 81%, >19:1 d.r.
D
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133.3, 130.76, 128.9, 128.6, 120.9, 112.9, 111.8, 55.6, 55.4, 43.4, 32.6,
26.0, 24.1, 21.7, 20.6; HRMS (ESI-Orbitrap) calcd for C24H28NO4+ [M
+ H]+ 394.2018; found: 394.2013.
N-(3,4-Dimethoxyphenethyl)-2-oxo-2-phenyl-N-(1,4-dioxaspiro-
[4.5]dec-7-en-8-yl)acetamide (1g). Purified by column chromatog-
raphy on silica gel (hexane/AcOEt/Et3N = 20:1:0.5): white solid (1.1 g,
49%); m.p. 113−114 °C; IR(KBr) 2959, 2935, 1641, 1516 cm−1; 1H
NMR (400 MHz, DMSO-d6): δ 7.63−7.66 (m, 1H), 7.57−7.59 (m,
2H), 7.44−7.48 (m, 2H), 6.86−6.88 (m, 2H), 6.75 (dd, 1H, J = 8.2, 1.8
Hz), 5.08−5.10 (m, 1H), 3.78 (t, 2H, J = 7.3 Hz), 3.75−3.76 (m, 4H),
3.71 (s, 3H), 3.71 (s, 3H), 2.76 (t, 2H, J = 7.1 Hz), 2.13−2.14 (m, 2H),
1.86−1.87 (m, 2H), 1.43−1.46 (m, 2H); 13C{1H} NMR (101 MHz,
DMSO-d6): δ 191.3, 165.6, 148.6, 147.5, 135.1, 134.4, 133.3, 130.7,
128.9, 128.7, 126.6, 120.9, 112.8, 111.7, 105.7, 63.8, 55.6, 55.4, 43.5,
N-(Cyclohex-1-en-1-yl)-N-(3,4-dimethoxyphenethyl)-2-(4-fluoro-
phenyl)-2-oxoacetamide (1b). Purified by column chromatography
on silica gel (hexane/AcOEt/Et3N = 20:1:0.5): white solid (904.0 mg,
44%); m.p. 71−72 °C; IR(KBr) 2935, 1643, 1515 cm−1; 1H NMR (400
MHz, DMSO-d6): δ 7.72−7.76 (m, 2H), 7.30−7.35 (m, 2H), 6.90 (d,
1H, J = 8.2 Hz), 6.90 (s, 1H), 6.79 (d, 1H, J = 8.2 Hz), 5.25−5.27 (m,
1H), 3.79 (t, 2H, J = 7.3 Hz), 3.75 (s, 3H), 3.75 (s, 3H), 2.81 (t, 2H, J =
7.1 Hz), 1.98−2.04 (m, 2H), 1.68−1.73 (m, 2H), 1.40−1.46 (m, 2H),
1.25−1.28 (m, 2H); 13C{1H} NMR (101 MHz, DMSO-d6): δ 189.9,
165.4 (d, J = 255.1 Hz), 165.3, 148.6, 147.5, 135.9, 131.7 (d, J = 10.6
Hz), 130.8, 130.1 (d, J = 1.9 Hz), 128.8, 120.8, 116.1 (d, J = 22.2 Hz),
112.9, 111.8, 55.6, 55.4, 43.6, 32.6, 26.1, 24.1, 21.7, 20.7; HRMS (ESI-
+
34.7, 32.5, 30.2, 25.1; HRMS (ESI-Orbitrap) calcd for C26H29NNaO6
[M + Na]+ 474.1887; found: 474.1884.
N-(3,6-Dihydro-2H-pyran-4-yl)-N-(3,4-dimethoxyphenethyl)-2-
oxo-2-phenylacetamide (1h). Purified by column chromatography on
silica gel (hexane/AcOEt/Et3N = 20:1:0.5): white solid (830.4 mg,
42%); m.p. 107−109 °C; IR(KBr) 2922, 1645, 1515 cm−1; 1H NMR
(400 MHz, DMSO-d6): δ 7.70 (t, 1H, J = 7.1 Hz), 7.66 (d, 2H, J = 6.9
Hz), 7.49−7.53 (m, 2H), 6.93 (d, 1H, J = 1.8 Hz), 6.91 (d, 1H, J = 8.2
Hz), 6.81 (dd, 1H, J = 8.2, 1.8 Hz), 5.32−5.33 (m, 1H), 3.86 (t, 2H, J =
7.3 Hz), 3.76−3.77 (m, 2H), 3.75 (s, 3H), 3.75 (s, 3H), 3.53 (t, 2H, J =
5.5 Hz), 2.84−2.86 (m, 2H), 2.11−2.15 (m, 2H); 13C{1H} NMR (101
MHz, DMSO-d6): δ 191.2, 165.6, 148.7, 147.5, 134.5, 133.4, 133.1,
130.6, 129.0, 128.8, 126.9, 121.0, 112.9, 111.8, 63.8, 63.2, 55.6, 55.5,
43.4, 32.6, 26.6; HRMS (ESI-Orbitrap) calcd for C23H25NNaO5+ [M +
Na]+ 418.1625; found: 418.1624.
N-(3,6-Dihydro-2H-thiopyran-4-yl)-N-(3,4-dimethoxyphenethyl)-
2-oxo-2-phenylacetamide (1i). Purified by column chromatography
on silica gel (hexane/AcOEt/Et3N = 20:1:0.5): yellow solid (616.5 mg,
30%); m.p. 107−108 °C; IR(KBr) 2922, 1644, 1515 cm−1; 1H NMR
(400 MHz, DMSO-d6): δ 7.70 (t, 1H, J = 7.3 Hz), 7.64 (d, 2H, J = 7.8
Hz), 7.49−7.52 (m, 2H), 6.93 (s, 1H), 6.92 (d, 1H, J = 8.7 Hz), 6.81 (d,
1H, J = 7.8 Hz), 5.46−5.49 (m, 1H), 3.84 (t, 2H, J = 7.1 Hz), 3.76 (s,
3H), 3.76 (s, 3H), 2.81−2.86 (m, 4H), 2.55−2.58 (m, 2H), 2.29−2.33
(m, 2H); 13C{1H} NMR (101 MHz, DMSO-d6): δ 191.2, 165.6, 148.6,
147.5, 136.7, 134.6, 133.2, 130.6, 129.0, 128.9, 126.5, 120.9, 112.8,
111.7, 55.6, 55.5, 43.7, 32.5, 27.6, 24.5, 24.1; HRMS (ESI-Orbitrap)
calcd for C23H25NNaO4S+ [M + Na]+ 434.1397; found: 434.1398.
General Procedure for (R,R)-Cr(III)(salen)Cl-Catalyzed Enan-
tioselective Synthesis of 2. Under argon protection, enamide 1 (0.2
mmol), (R,R)-Cr(III)(salen)Cl (0.2 equiv, 0.04 mmol, 25.3 mg), 4 Å
MS (100 mg), and Na2CO3 (0.2 equiv, 4.2 mg) were added in dry
toluene (6 mL) and the resulting mixture was stirred at 10 °C. After a
period of time (18−48 h), 4 Å MS was filtered and the reaction was
quenched by saturated NaHCO3 solution. The resulting mixture was
extracted with CH2Cl2 (3 × 10 mL) and washed with brine. The
combined organic layers were dried over anhydrous Na2SO4 and
concentrated in vacuo. The residue was purified by flash column
chromatography to afford pure product 2.
+
Orbitrap) calcd for C24H26FNNaO4 [M + Na]+ 434.1738; found:
434.1736.
2-(4-Bromophenyl)-N-(cyclohex-1-en-1-yl)-N-(3,4-dimethoxy-
phenethyl)-2-oxoacetamide (1c). Purified by column chromatog-
raphy on silica gel (hexane/AcOEt/Et3N = 20:1:0.5): white solid
(708.6 mg, 30%); m.p. 81−83 °C; IR(KBr) 2936, 2933, 1643, 1515
cm−1; 1H NMR (400 MHz, DMSO-d6): δ 7.72 (d, 2H, J = 8.7 Hz), 7.56
(d, 2H, J = 8.7 Hz), 6.89−6.91 (m, 2H), 6.78 (dd, 1H, J = 8.2, 1.4 Hz),
5.23−5.25 (m, 1H), 3.79 (t, 2H, J = 7.3 Hz), 3.75 (s, 3H), 3.75 (s, 3H),
2.80 (t, 2H, J = 6.9 Hz), 1.98−2.02 (m, 2H), 1.69−1.72 (m, 2H), 1.40−
1.45 (m, 2H), 1.24−1.30 (m, 2H); 13C{1H} NMR (101 MHz, DMSO-
d6): δ 190.5, 165.1, 148.6, 147.4, 135.9, 132.3, 132.2, 130.7, 130.5,
129.0, 128.6, 120.9, 112.8, 111.7, 55.5, 55.4, 43.5, 32.6, 26.1, 24.2, 21.8,
+
20.7; HRMS (ESI-Orbitrap) calcd for C24H26BrNNaO4 [M + Na]+
494.0937; found: 494.0936.
N-(Cyclohex-1-en-1-yl)-N-(3,4-dimethoxyphenethyl)-2-oxo-2-(p-
tolyl)acetamide (1d). Purified by column chromatography on silica gel
(hexane/AcOEt/Et3N = 20:1:0.5): white solid (753.0 mg, 37%); m.p.
100−101 °C; IR(KBr) 2932, 1642, 1516 cm−1; 1H NMR (400 MHz,
DMSO-d6): δ 7.53 (d, 2H, J = 8.2 Hz), 7.30 (d, 2H, J = 7.8 Hz), 6.91 (s,
1H), 6.90 (d, 1H, J = 8.0 Hz), 6.78 (dd, 1H, J = 8.0, 1.6 Hz), 5.23−5.25
(m, 1H), 3.80 (t, 2H, J = 7.1 Hz), 3.75 (s, 3H), 3.75 (s, 3H), 2.80 (t, 2H,
J = 7.1 Hz), 2.38 (s, 3H), 1.99−2.02 (m, 2H), 1.68−1.69 (m, 2H),
1.41−1.44 (m, 2H), 1.25−1.28 (m, 2H); 13C{1H} NMR (101 MHz,
DMSO-d6): δ 191.1, 165.8, 148.6, 147.4, 145.0, 135.9, 131.0, 130.8,
129.5, 128.8, 128.7, 120.9, 112.8, 111.7, 55.5, 55.4, 43.3, 32.7, 26.1,
+
24.2, 21.8, 21.3, 20.7; HRMS (ESI-Orbitrap) calcd for C25H29NNaO4
[M + Na]+ 430.1989; found: 430.1988.
N-(Cyclohex-1-en-1-yl)-N-(3,4-dimethoxyphenethyl)-2-(naph-
thalen-2-yl)-2-oxoacetamide (1e). Purified by column chromatog-
raphy on silica gel (hexane/AcOEt/Et3N = 20:1:0.5): white solid
(909.2 mg, 41%); m.p. 115−116 °C; IR(KBr) 2932, 1642, 1515 cm−1;
1H NMR (400 MHz, DMSO-d6): δ 8.20 (s, 1H), 8.06−8.08 (m, 1H),
8.00−8.03 (m, 2H), 7.69−7.75 (m, 2H), 7.62−7.66 (m, 1H), 6.97 (d,
1H, J = 1.8 Hz), 6.92 (d, 1H, J = 8.2 Hz), 6.81 (dd, 1H, J = 8.2, 1.8 Hz),
5.23−5.25 (m, 1H), 3.88 (t, 2H, J = 7.1 Hz), 3.77 (s, 3H), 3.77 (s, 3H),
2.85 (t, 2H, J = 7.1 Hz), 2.01−2.04 (m, 2H), 1.62−1.66 (m, 2H), 1.37−
1.40 (m, 2H), 1.17−1.24 (m, 2H); 13C{1H} NMR (101 MHz, DMSO-
d6): δ 191.5, 165.6, 148.6, 147.3, 135.9, 135.5, 131.9, 131.3, 130.7,
129.7, 129.4, 128.9, 127.9, 127.3, 123.1, 121.0, 112.7, 111.7, 55.5, 55.4,
43.1, 32.6, 26.0, 24.1, 21.8, 20.7; HRMS (ESI-Orbitrap) calcd for
C28H29NNaO4+ [M + Na]+ 466.1989; found: 466.1988.
(S)-1-(3,4-Dimethoxyphenethyl)-3-hydroxy-3-phenyl-4,5,6,7-tet-
rahydro-1H-indol-2(3H)-one (2a). Purified by column chromatog-
raphy on silica gel (hexane/AcOEt = 3:1): white solid (77.9 mg, 99%);
m.p. 143−145 °C; [α]2D5 = −152.0 (c 0.25, CHCl3); ee = 94% (DAICEL
Chiralpak AD-H, hexane/2-propanol = 70/30, λ = 207 nm, flow rate =
0.5 mL/min); IR(KBr) 3374, 2932, 1703, 1681, 1515 cm−1; 1H NMR
(400 MHz, DMSO-d6): δ 7.28−7.32 (m, 2H), 7.23−7.25 (m, 1H), 7.20
(d, 2H, J = 7.3 Hz), 6.86 (d, 1H, J = 8.2 Hz), 6.81 (d, 1H, J = 1.8 Hz),
6.71 (dd, 1H, J = 8.0, 1.6 Hz), 6.02 (s, 1H), 3.73 (s, 3H), 3.70 (s, 3H),
3.55−3.62 (m, 1H), 3.44−3.51 (m, 1H), 2.71 (t, 2H, J = 6.9 Hz), 1.95−
2.04 (m, 3H), 1.53−1.64 (m, 5H); 13C{1H} NMR (101 MHz, DMSO-
d6): δ 178.8, 148.7, 147.4, 140.3, 138.3, 131.2, 127.9, 126.9, 125.3,
120.8, 117.5, 112.9, 112.0, 79.0, 55.6, 55.4, 40.7, 34.5, 22.0, 21.9, 20.5,
N-(3,4-Dimethoxyphenethyl)-N-(4,4-dimethylcyclohex-1-en-1-
yl)-2-oxo-2-phenylacetamide (1f). Purified by column chromatog-
raphy on silica gel (hexane/AcOEt/Et3N = 20:1:0.5): white solid
(927.4 mg, 44%); m.p. 110−111 °C; IR(KBr) 2921, 2848, 1644, 1516
cm−1; 1H NMR (400 MHz, DMSO-d6): δ 7.63−7.69 (m, 3H), 7.47−
7.51 (m, 2H), 6.90 (d, 1H, J = 7.6 Hz), 6.91 (s, 1H), 6.79 (dd, 1H, J =
8.2, 1.8 Hz), 5.14−5.16 (m, 1H), 3.84 (t, 2H, J = 7.1 Hz), 3.75 (s, 3H),
3.75 (s, 3H), 2.82 (t, 2H, J = 6.9 Hz), 2.02−2.06 (m, 2H), 1.48−1.49
(m, 2H), 1.22−1.25 (m, 2H), 0.69 (s, 6H); 13C{1H} NMR (101 MHz,
DMSO-d6): δ 191.2, 165.6, 148.6, 147.5, 134.6, 134.4, 133.2, 130.7,
128.9, 128.7, 128.2, 120.9, 112.9, 111.8, 55.6, 55.4, 43.4, 38.0, 34.6,
−
19.0; HRMS (ESI-Orbitrap) calcd for C24H26NO4 [M − H]−
392.1867; found: 392.1872.
(S)-1-(3,4-Dimethoxyphenethyl)-3-(4-fluorophenyl)-3-hydroxy-
4,5,6,7-tetrahydro-1H-indol-2(3H)-one (2b). Purified by column
chromatography on silica gel (hexane/AcOEt = 3:1): white solid
(71.6 mg, 87%); m.p. 236−237 °C; [α]2D5 = −58.8 (c 0.25, CHCl3); ee =
93% (DAICEL Chiralpak AD-H, hexane/2-propanol = 70/30, λ = 254
nm, flow rate = 0.5 mL/min); IR(KBr) 3364, 2932, 1703, 1682, 1515
+
32.7, 27.7, 27.4, 23.5; HRMS (ESI-Orbitrap) calcd for C26H31NNaO4
[M + Na]+ 444.2145; found: 444.2143.
E
https://dx.doi.org/10.1021/acs.joc.0c01992
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
cm−1; 1H NMR (400 MHz, DMSO-d6): δ 7.19−7.22 (m, 2H), 7.09−
7.13 (m, 2H), 6.86 (d, 1H, J = 8.2 Hz), 6.80 (d, 1H, J = 1.8 Hz), 6.70
(dd, 1H, J = 8.0, 1.6 Hz), 6.09 (s, 1H), 3.72 (s, 3H), 3.70 (s, 3H), 3.57−
3.61 (m, 1H), 3.48−3.51 (m, 1H), 2.71 (t, 2H, J = 6.6 Hz), 1.99−2.07
(m, 3H), 1.54−1.64 (m, 5H); 13C{1H} NMR (101 MHz, DMSO-d6): δ
178.6, 161.3 (d, J = 243.6 Hz), 148.7, 147.4, 138.5, 136.4, 131.1, 127.3
(d, J = 7.8 Hz), 120.8, 117.2, 114.7 (d, J = 22.1 Hz), 112.9, 112.0, 78.5,
55.6, 55.4, 40.6, 34.4, 22.0, 21.9, 20.5, 19.0; HRMS (ESI-Orbitrap)
calcd for C24H25FNO4− [M − H]− 410.1773; found: 410.1775.
(S)-3-(4-Bromophenyl)-1-(3,4-dimethoxyphenethyl)-3-hydroxy-
4,5,6,7-tetrahydro-1H-indol-2(3H)-one (2c). Purified by column
chromatography on silica gel (hexane/AcOEt = 3:1): white solid
(81.2 mg, 86%); m.p. 111−112 °C; [α]2D5 = −128.4 (c 0.25, CHCl3); ee
= 99% (DAICEL Chiralpak AD-H, hexane/2-propanol = 70/30, λ =
254 nm, flow rate = 0.5 mL/min); IR(KBr) 3359, 2931, 1703, 1681,
40.8, 34.8, 34.4, 32.9, 29.0, 28.2, 27.1, 18.4; HRMS (ESI-Orbitrap)
calcd for C26H30NO4− [M − H]− 420.2180; found: 420.2184.
(S)-1′-(3,4-Dimethoxyphenethyl)-3′-hydroxy-3′-phenyl-
3′,4′,6′,7′-tetrahydrospiro[[1,3]dioxolane-2,5′-indol]-2′ (1′H)-one
(2g). Purified by column chromatography on silica gel (hexane/
AcOEt = 3:1): yellow solid (77.7 mg, 86%); m.p. 121−122 °C; [α]D25
=
−57.2 (c 0.25, CHCl3); ee = 96% (DAICEL Chiralpak AD-H, hexane/
2-propanol = 70/30, λ = 254 nm, flow rate = 0.5 mL/min); IR(KBr)
3364, 2925, 1716. 1683, 1515 cm−1; 1H NMR (400 MHz, DMSO-d6):
δ 7.28−7.32 (m, 2H), 7.24−7.26 (m, 1H), 7.21−7.23 (m, 2H), 6.85 (d,
1H, J = 8.2 Hz), 6.79 (d, 1H, J = 1.8 Hz), 6.70 (dd, 1H, J = 8.2, 1.8 Hz),
6.15 (s, 1H), 3.82−3.89 (m, 3H), 3.76−3.80 (m, 1H), 3.71 (s, 3H),
3.70 (s, 3H), 3.55−3.63 (m, 1H), 3.45−3.51 (m, 1H), 2.69 (t, 2H, J =
7.1 Hz), 2.18−2.25 (m, 3H), 1.70−1.78 (m, 3H); 13C{1H} NMR (101
MHz, DMSO-d6): δ 178.7, 148.7, 147.4, 139.8, 137.7, 131.1, 128.1,
127.2, 125.4, 120.8, 114.9, 112.7, 112.0, 107.4, 78.9, 63.8, 63.7, 55.6,
55.3, 41.0, 34.6, 30.6, 30.2, 19.9; HRMS (ESI-Orbitrap) calcd for
C26H28NO6− [M − H]− 450.1922; found: 450.1926.
(S)-1-(3,4-Dimethoxyphenethyl)-3-hydroxy-3-phenyl-3,4,6,7-
tetrahydropyrano[4,3-b]pyrrol-2(1H)-one (2h). Purified by column
chromatography on silica gel (hexane/AcOEt = 3:1): white solid (72.8
mg, 92%); m.p. 121−122 °C; [α]2D5 = −271.2 (c 0.25, CHCl3); ee = 94%
(DAICEL Chiralpak AD-H, hexane/2-propanol = 70/30, λ = 254 nm,
flow rate = 0.5 mL/min); IR(KBr) 3363, 2932, 1717, 1515 cm−1; 1H
NMR (400 MHz, DMSO-d6): δ 7.30−7.33 (m, 2H), 7.26−7.28 (m,
1H), 7.22 (d, 2H, J = 6.9 Hz), 6.87 (d, 1H, J = 7.8 Hz), 6.82 (d, 1H, J =
1.8 Hz), 6.71 (dd, 1H, J = 8.2, 1.8 Hz), 6.28 (s, 1H), 4.10 (dt, 1H, J =
14.7, 2.7 Hz), 3.72−3.76 (m, 3H), 3.73 (s, 3H), 3.70 (s, 3H), 3.60−3.67
(m, 1H), 3.47−3.54 (m, 1H), 2.73 (t, 2H, J = 7.1 Hz), 2.17−2.20 (m,
2H); 13C{1H} NMR (101 MHz, DMSO-d6): δ 178.5, 148.7, 147.5,
139.7, 137.1, 131.0, 128.1, 127.3, 125.2, 120.9, 116.0, 112.9, 112.0, 78.4,
63.4, 61.3, 55.6, 55.4, 40.8, 34.3, 21.6; HRMS (ESI-Orbitrap) calcd for
C23H24NO5− [M − H]− 394.1660; found: 394.1661.
(S)-1-(3,4-Dimethoxyphenethyl)-3-hydroxy-3-phenyl-3,4,6,7-
tetrahydrothiopyrano[4,3-b]pyrrol-2(1H)-one (2i). Purified by col-
umn chromatography on silica gel (hexane/AcOEt = 3:1): white solid
(54.3 mg, 66%); m.p. 163−165 °C; [α]2D5 = −80.8 (c 0.25, CHCl3); ee =
99% (DAICEL Chiralpak AD-H, hexane/2-propanol = 70/30, λ = 254
nm, flow rate = 0.5 mL/min); IR(KBr) 3373, 2928, 1704, 1681, 1515
cm−1; 1H NMR (400 MHz, DMSO-d6): δ 7.30−7.34 (m, 2H), 7.26−
7.28 (m, 1H), 7.22 (d, 2H, J = 7.8 Hz), 6.86 (d, 1H, J = 8.2 Hz), 6.82 (d,
1H, J = 1.4 Hz), 6.71 (dd, 1H, J = 8.2, 1.4 Hz), 6.30 (s, 1H), 3.72 (s,
3H), 3.70 (s, 3H), 3.59−3.66 (m, 1H), 3.47−3.54 (m, 1H), 3.09 (d,
1H, J = 16.5 Hz), 2.77 (t, 2H, J = 5.5 Hz), 2.71 (t, 2H, J = 8.0 Hz), 2.66
(d, 1H, J = 16.5 Hz), 2.35−2.39 (m, 2H); 13C{1H} NMR (101 MHz,
DMSO-d6): δ 177.9, 148.7, 147.5, 139.6, 139.1, 131.0, 128.2, 127.4,
125.3, 120.8, 115.0, 112.8, 111.9, 79.1, 55.6, 55.4, 40.7, 34.4, 24.1, 22.2,
20.4; HRMS (ESI-Orbitrap) calcd for C23H26NO4S+ [M + H]+
412.1577; found: 412.1569.
1
1515 cm−1; H NMR (400 MHz, DMSO-d6): δ 7.48 (d, 2H, J = 8.2
Hz), 7.11 (d, 2H, J = 7.8 Hz), 6.86 (d, 1H, J = 8.2 Hz), 6.80 (d, 1H, J =
1.8 Hz), 6.69 (dd, 1H, J = 8.0, 1.6 Hz), 6.13 (s, 1H), 3.72 (s, 3H), 3.70
(s, 3H), 3.56−3.63 (m, 1H), 3.46−3.51 (m, 1H), 2.69−2.75 (m, 2H),
2.06−2.08 (m, 2H), 1.96−1.99 (m, 1H), 1.59−1.63 (m, 2H), 1.53−
1.54 (m, 3H); 13C{1H} NMR (101 MHz, DMSO-d6): δ 178.3, 148.7,
147.4, 139.7, 138.8, 131.1, 130.9, 127.6, 120.8, 120.2, 117.1, 112.9,
112.0, 78.6, 55.6, 55.4, 40.6, 34.4, 21.9, 21.8, 20.5, 18.9; HRMS (ESI-
−
Orbitrap) calcd for C24H25BrNO4 [M − H]− 470.0972; found:
470.0972.
(S)-1-(3,4-Dimethoxyphenethyl)-3-hydroxy-3-(p-tolyl)-4,5,6,7-
tetrahydro-1H-indol-2(3H)-one (2d). Purified by column chromatog-
raphy on silica gel (hexane/AcOEt = 3:1): white solid (77.4 mg, 95%);
m.p. 91−93 °C; [α]2D5 = −119.6 (c 0.25, CHCl3); ee = 96% (DAICEL
Chiralpak AD-H, hexane/2-propanol = 70/30, λ = 254 nm, flow rate =
0.5 mL/min); IR(KBr) 3359, 2922, 1703, 1681, 1515 cm−1; 1H NMR
(400 MHz, DMSO-d6): δ 7.08−7.11 (m, 4H), 6.86 (d, 1H, J = 8.2 Hz),
6.80 (s, 1H), 6.71 (d, 1H, J = 7.8 Hz), 5.95 (s, 1H), 3.72 (s, 3H), 3.71 (s,
3H), 3.54−3.60 (m, 1H), 3.45−3.50 (m, 1H), 2.70 (t, 2H, J = 6.6 Hz),
2.27 (s, 3H), 1.95−2.03 (m, 3H), 1.53−1.62 (m, 5H); 13C{1H} NMR
(101 MHz, DMSO-d6): δ 178.9, 148.7, 147.4, 138.1, 137.3, 136.0,
131.2, 128.5, 125.2, 120.8, 117.6, 112.9, 112.0, 78.9, 55.6, 55.4, 40.7,
34.5, 22.0, 21.9, 20.6, 20.5, 19.0; HRMS (ESI-Orbitrap) calcd for
C25H28NO4− [M − H]− 406.2024, found: 406.2026.
(S)-1-(3,4-Dimethoxyphenethyl)-3-hydroxy-3-(naphthalen-2-yl)-
4,5,6,7-tetrahydro-1H-indol-2(3H)-one (2e). Purified by column
chromatography on silica gel (hexane/AcOEt = 3:1): white solid
(71.0 mg, 80%); m.p. 203−205 °C; [α]2D5 = −87.2 (c 0.25, CHCl3); ee =
92% (DAICEL Chiralpak AD-H, hexane/2-propanol = 70/30, λ = 254
nm, flow rate = 0.5 mL/min); IR(KBr) 3365, 2930, 1703, 1681, 1515
cm−1; 1H NMR (400 MHz, DMSO-d6): δ 7.85−7.91 (m, 3H), 7.81 (d,
1H, J = 8.2 Hz), 7.48−7.50 (m, 2H), 7.19 (dd, 1H, J = 8.7, 1.4 Hz), 6.86
(d, 1H, J = 8.2 Hz), 6.84 (d, 1H, J = 1.8 Hz), 6.73 (dd, 1H, J = 8.1, 1.7
Hz), 6.24 (s, 1H), 3.71 (s, 3H), 3.70 (s, 3H), 3.61−3.66 (m, 1H), 3.49−
3.56 (m, 1H), 2.75 (t, 2H, J = 6.9 Hz), 1.99−2.11 (m, 3H), 1.54−1.64
(m, 5H); 13C{1H} NMR (101 MHz, DMSO-d6): δ 178.8, 148.7, 147.4,
138.6, 137.9, 132.8, 132.2, 131.2, 127.9, 127.6, 127.4, 126.1, 125.8,
124.0, 123.6, 120.9, 117.6, 112.8, 111.9, 79.3, 55.5, 55.4, 40.8, 34.5,
General Procedure for Diastereoselective Synthesis of
Product 3. Under argon protection, product 2 (0.2 mmol) and
InCl3 (1 equiv, 44.2 mg) were added in dry DCM (6 mL) and the
resulting mixture was stirred at 0 °C. After a period of time, the solvent
was removed in vacuo and the residue was chromatographed on a silica
gel column to give pure product 3.
−
22.04, 21.98, 20.6, 19.2; HRMS (ESI-Orbitrap) calcd for C28H28NO4
[M − H]− 442.2024; found: 442.2025.
(S)-1-(3,4-Dimethoxyphenethyl)-3-hydroxy-5,5-dimethyl-3-phe-
nyl-4,5,6,7-tetrahydro-1H-indol-2(3H)-one (2f). Purified by column
chromatography on silica gel (hexane/AcOEt = 3:1): white solid (404.7
mg, 96%); m.p. 236−237 °C; [α]2D5 = −58.8 (c 0.25, CHCl3); ee = 93%
(DAICEL Chiralpak AD-H, hexane/2-propanol = 70/30, λ = 254 nm,
flow rate = 0.5 mL/min); IR(KBr) 3353, 2952, 1682, 1508 cm−1; 1H
NMR (400 MHz, DMSO-d6): δ 7.27−7.30 (m, 2H), 7.22 (t, 1H, J = 7.3
Hz), 7.16 (d, 2H, J = 6.9 Hz), 6.86 (d, 1H, J = 8.2 Hz), 6.81 (d, 1H, J =
1.8 Hz), 6.71 (dd, 1H, J = 7.8, 1.8 Hz), 5.98 (s, 1H), 3.72 (s, 3H), 3.70
(s, 3H), 3.61−3.66 (m, 1H), 3.47−3.53 (m, 1H), 2.73 (t, 2H, J = 6.9
Hz), 1.97−2.01 (m, 2H), 1.76 (d, 1H, J = 16.5 Hz), 1.34 (t, 2H, J = 6.2
Hz), 1.29 (d, 1H, J = 16.5 Hz), 0.84 (s, 3H), 0.74 (s, 3H); 13C{1H}
NMR (101 MHz, DMSO-d6): δ 179.0, 148.7, 147.4, 140.2, 137.0,
131.2, 127.8, 126.9, 125.1, 120.9, 116.7, 112.9, 112.0, 79.0, 55.6, 55.4,
(S)-1-(2-(4aR,5R,13bS)-5-Hydroxy-11,12-dimethoxy-5-phenyl-
3,4,4a,5,8,9-hexahydro-1H-indolo[7a,1-a]isoquinolin-6(2H)-one
(3a). Purified by column chromatography on silica gel (hexane/AcOEt
= 4:1): white solid (50.4 mg, 64%); m.p. 227−228 °C; [α]2D5 = −33.2 (c
0.25, CHCl3); ee = 98% (DAICEL Chiralpak OD-H, hexane/2-
propanol = 75/25, λ = 207 nm, flow rate = 0.5 mL/min); IR(KBr) 3342,
1
2938, 1678 cm−1; d.r. >19:1; H NMR (400 MHz, chloroform-d): δ
7.48 (d, 2H, J = 6.9 Hz), 7.30−7.38 (m, 3H), 6.93 (s, 1H), 6.64 (s, 1H),
4.15−4.21 (m, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.53−3.60 (m, 1H),
3.02−3.10 (m, 1H), 2.88−2.92 (m, 1H), 2.83−2.87 (m, 1H), 2.50 (s,
1H), 1.98−2.07 (m, 2H), 1.77−1.92 (m, 2H), 1.35−1.37 (m, 2H),
1.21−1.26 (m, 1H), 0.18−0.27 (m, 1H); 13C{1H} NMR (101 MHz,
chloroform-d): δ 173.8, 148.0, 147.5, 140.6, 135.8, 128.2, 127.6, 125.1,
112.2, 109.0, 81.8, 60.3, 56.4, 56.1, 49.5, 36.5, 36.3, 27.2, 24.7, 20.6,
F
https://dx.doi.org/10.1021/acs.joc.0c01992
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
−
1
20.3; HRMS (ESI-Orbitrap) calcd for C24H26NO4 [M − H]−
2936, 1678 cm-1; d.r. >19:1; H NMR (400 MHz, chloroform-d): δ
7.88 (s, 1H), 7.80−7.85 (m, 3H), 7.65 (d, 1H, J = 8.2 Hz), 7.47−7.50
(m, 2H), 6.93 (s, 1H), 6.63 (s, 1H), 4.18−4.24 (m, 1H), 3.88 (s, 3H),
3.87 (s, 3H), 3.56−3.63 (m, 1H), 3.01−3.09 (m, 1H), 2.83−2.93 (m,
2H), 2.20−2.80 (br s, 1H), 1.98−2.07 (m, 2H), 1.78−1.90 (m, 2H),
1.23−1.39 (m, 2H), 1.15−1.19 (m, 1H), 0.18−0.27 (m, 1H); 13C{1H}
NMR (101 MHz, chloroform-d): δ 174.0, 147.9, 147.5, 137.9, 135.7,
133.0, 132.9, 128.5, 127.9, 127.7, 126.8, 126.4, 126.2, 125.4, 125.1,
112.1, 108.8, 81.9, 60.5, 56.3, 56.0, 49.7, 36.6, 36.4, 27.2, 24.7, 20.53,
392.1867; found: 392.1863.
1-(3,4-Dimethoxyphenethyl)-3-phenyl-5,6-dihydro-1H-indol-
2(4H)-one (4). Purified by column chromatography on silica gel
(hexane/AcOEt = 4:1): colorless oil (22.5 mg, 30%); IR(KBr) 2933,
1682, 1515 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 7.57 (d, 2H, J =
7.3 Hz), 7.41−7.44 (m, 2H), 7.33 (t, 1H, J = 7.3 Hz), 6.84 (d, 1H, J =
8.2 Hz), 6.79 (s, 1H), 6.73 (d, 1H, J = 7.3 Hz), 5.96 (t, 1H, J = 4.4 Hz),
3.74−3.78 (m, 2H), 3.70 (s, 3H), 3.70 (s, 3H), 2.73−2.79 (m, 4H),
2.32−2.37 (m, 2H), 1.71−1.77 (m, 2H); 13C{1H} NMR (101 MHz,
DMSO-d6): δ 167.8, 148.6, 147.4, 140.4, 137.8, 131.5, 131.1, 128.6,
128.2, 127.6, 124.3, 120.7, 112.6, 111.9, 111.3, 55.5, 55.3, 33.9, 23.9,
+
20.46; HRMS (ESI-Orbitrap) calcd for C28H30NO4 [M + H]+
444.2169; found: 444.2169.
(4aR,5R,13bS)-5-Hydroxy-11,12-dimethoxy-3,3-dimethyl-5-phe-
nyl-3,4,4a,5,8,9-hexahydro-1H-indolo[7a,1-a]isoquinolin-6(2H)-
one (3f). Purified by column chromatography on silica gel (hexane/
+
23.5, 23.2; HRMS (ESI-Orbitrap) calcd for C24H26NO3 [M + H]+
376.1907; found: 376.1903.
AcOEt = 4:1): white solid (26.1 mg, 31%); m.p. 230−231 °C; [α]D25
=
(4aR,5R,13bS)-5-(4-Fluorophenyl)-5-hydroxy-11,12-dimethoxy-
3,4,4a,5,8,9-hexahydro-1H-indolo[7a,1-a]isoquinolin-6(2H)-one
(3b). Purified by column chromatography on silica gel (hexane/AcOEt
= 4:1): white solid (53.5 mg, 65%); m.p. 238−240 °C; [α]2D5 = −84.8 (c
0.25, CHCl3); ee = 84% (DAICEL Chiralpak OD-H, hexane/2-
propanol = 75/25, λ = 220 nm, flow rate = 0.5 mL/min); IR(KBr) 3329,
2936, 1678, 1508 cm−1; d.r. >19:1; 1H NMR (400 MHz, chloroform-
d): δ 7.43−7.46 (m, 2H), 7.02−7.06 (m, 2H), 6.91 (s, 1H), 6.63 (s,
1H), 4.15−4.18 (m, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.49−3.55 (m,
1H), 3.01−3.09 (m, 1H), 2.86−2.89 (m, 1H), 2.81−2.83 (m, 1H), 2.50
(br s, 1H), 1.90−2.00 (m, 2H), 1.73−1.87 (m, 2H), 1.34−1.43 (m,
2H), 1.24−1.30 (m, 1H), 0.32−0.38 (m, 1H); 13C{1H} NMR (101
MHz, chloroform-d): δ 173.8, 162.6 (d, J = 248.5 Hz), 148.1, 147.6,
136.4, 135.7, 129.4 (d, J = 7.7 Hz), 125.1, 115.1 (d, J = 21.2 Hz), 112.2,
109.0, 81.4, 60.4, 56.4, 56.1, 49.5, 36.6, 36.4, 27.2, 24.8, 20.5; HRMS
−182.4 (c 0.25, CHCl3); ee = 91% (DAICEL Chiralpak OD-H,
hexane/2-propanol = 75/25, λ = 220 nm, flow rate = 0.5 mL/min);
IR(KBr) 3352, 2927, 1681, 1507 cm−1; d.r. >19:1; 1H NMR (400 MHz,
chloroform-d): δ 7.48 (d, 2H, J = 7.3 Hz), 7.32−7.35 (m, 2H), 7.28−
7.30 (m, 1H), 6.79 (s, 1H), 6.55 (s, 1H), 4.28−4.33 (m, 1H), 3.93 (s,
3H), 3.84 (s, 3H), 3.34 (td, 1H, J = 12.5, 5.2 Hz), 3.13−3.22 (m, 1H),
2.81−2.86 (m, 1H), 2.58 (dd, 1H, J = 16.3, 4.8 Hz), 2.34 (s, 1H), 2.01−
2.07 (m, 1H), 1.82−1.90 (m, 1H), 1.25−1.29 (m, 2H), 1.00 (s, 3H),
0.86−0.93 (m, 1H), 0.79 (s, 3H), 0.58 (dd, 1H, J = 14.0, 5.7 Hz);
13C{1H} NMR (101 MHz, chloroform-d): δ 175.9, 148.0, 147.6, 139.1,
136.2, 128.0, 125.2, 112.3, 108.3, 82.9, 61.6, 56.3, 56.0, 46.7, 39.8, 35.6,
34.1, 34.0, 32.3, 29.6, 26.1, 24.8; HRMS (ESI-Orbitrap) calcd for
C26H32NO4+ [M + H]+ 422.2326; found: 422.2325.
(4a′R,5′R,13b′S)-5′-Hydroxy-11′,12′-dimethoxy-5′-phenyl-
1′,2′,4a′,5′,8′,9′-hexahydrospiro[[1,3]dioxolane-2,3′-indolo[7a,1-
a]isoquinolin]-6′ (4′H)-one (3g). Purified by column chromatography
on silica gel (hexane/AcOEt = 4:1): white solid (22.6 mg, 25%); m.p.
229−231 °C; [α]2D5 = −139.2 (c 0.25, CHCl3); ee = 96% (DAICEL
Chiralpak OD-H, hexane/2-propanol = 75/25, λ = 220 nm, flow rate =
0.5 mL/min); IR(KBr) 2935, 1644, 1516 cm−1; d.r. >19:1; 1H NMR
(400 MHz, chloroform-d): δ 7.45 (d, 2H, J = 7.3 Hz), 7.33−7.36 (m,
2H), 7.29−7.31 (m, 1H), 6.96 (s, 1H), 6.56 (s, 1H), 4.33−4.38 (m,
1H), 3.93 (s, 3H), 3.86−3.91 (m, 2H), 3.85 (s, 3H), 3.73−3.82 (m,
2H), 3.38 (td, 1H, J = 12.5, 5.2 Hz), 3.16−3.25 (m, 1H), 3.04−3.09 (m,
1H), 2.64 (dd, 1H, J = 16.3, 4.8 Hz), 2.12 (t, 2H, J = 6.6 Hz), 1.69−1.93
(br s, 1H), 1.69−1.80 (m, 2H), 1.29−1.36 (m, 1H), 1.06 (dd, 1H, J =
13.7, 6.0 Hz); 13C{1H} NMR (101 MHz, chloroform-d): δ 175.2,
147.9, 147.5, 139.07, 134.9, 128.2, 128.1, 127.6, 124.7, 111.9, 108.8,
108.4, 82.8, 64.5, 64.3, 61.1, 56.2, 55.9, 48.4, 35.9, 35.3, 35.0, 30.9, 26.3;
+
(ESI-Orbitrap) calcd for C24H27FNO4 [M + H]+ 412.1919; found:
412.1920.
(4aR,5R,13bS)-5-(4-Bromophenyl)-5-hydroxy-11,12-dimethoxy-
3,4,4a,5,8,9-hexahydro-1H-indolo[7a,1-a]isoquinolin-6(2H)-one
(3c). Purified by column chromatography on silica gel (hexane/AcOEt
= 4:1): white solid (42.5 mg, 45%); m.p. 258−259 °C; [α]2D5 = −165.2
(c 0.25, CHCl3); ee = 86% (DAICEL Chiralpak OD-H, hexane/2-
propanol = 75/25, λ = 220 nm, flow rate = 0.5 mL/min); IR(KBr) 3329,
2931, 1677, 1511 cm−1; d.r. >19:1; 1H NMR (400 MHz, chloroform-
d): δ 7.49 (d, 2H, J = 8.7 Hz), 7.36 (d, 2H, J = 8.2 Hz), 6.90 (s, 1H), 6.63
(s, 1H), 4.09−4.20 (m, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.49−3.56 (m,
1H), 3.01−3.09 (m, 1H), 2.88 (t, 1H, J = 5.3 Hz), 2.82−2.84 (m, 1H),
1.97−2.01 (m, 1H), 1.88−1.94 (m, 1H), 1.71−1.84 (m, 2H), 1.37−
1.40 (m, 2H), 1.24−1.31 (m, 1H), 0.34−0.42 (m, 1H); 13C{1H} NMR
(101 MHz, chloroform-d): δ 173.5, 148.1, 147.5, 139.7, 135.5, 131.4,
129.4, 125.0, 122.3, 112.1, 108.8, 81.5, 60.4, 56.4, 56.0, 49.4, 36.7, 36.3,
+
HRMS (ESI-Orbitrap) calcd for C26H30NO6 [M + H]+ 452.2068;
+
27.2, 24.8, 20.6, 20.5; HRMS (ESI-Orbitrap) calcd for C24H27BrNO4
found: 452.2061.
[M + H]+ 472.1118; found: 472.1119.
(4aS,5R,13bS)-5-Hydroxy-11,12-dimethoxy-5-phenyl-
1,2,4a,5,8,9-hexahydropyrano[4′,3′:2,3]pyrrolo[2,1-a]isoquinolin-
6(4H)-one (3h). Purified by column chromatography on silica gel
(hexane/AcOEt = 4:1): white solid (34.8 mg, 44%); m.p. 226−229 °C;
[α]2D5 = −160.0 (c 0.25, CHCl3); ee = 95% (DAICEL Chiralpak OD-H,
hexane/2-propanol = 75/25, λ = 214 nm, flow rate = 0.5 mL/min);
IR(KBr) 3347, 2926, 1682, 1513 cm−1; d.r. >19:1; 1H NMR (400 MHz,
chloroform-d): δ 7.46 (d, 2H, J = 8.2 Hz), 7.30−7.39 (m, 3H), 6.94 (s,
1H), 6.61 (s, 1H), 4.28−4.33 (m, 1H), 3.90 (s, 3H), 3.86 (s, 3H),
3.57−3.71 (m, 3H), 3.39−3.50 (m, 2H), 3.09−3.17 (m, 1H), 2.94 (t,
1H, J = 6.4 Hz), 2.75 (d, 1H, J = 16.0 Hz), 2.50 (br s, 1H), 2.04−2.17
(m, 2H); 13C{1H} NMR (101 MHz, chloroform-d): δ 174.4, 148.3,
148.0, 139.2, 134.5, 128.44, 128.36, 127.2, 125.2, 112.2, 108.8, 81.0,
65.0, 62.8, 58.9, 56.3, 56.1, 49.8, 36.3, 35.7, 27.0; HRMS (ESI-
Orbitrap) calcd for C23H26NO5+ [M + H]+ 396.1805; found: 396.1804.
(4aR,5R,13bS)-5-Hydroxy-11,12-dimethoxy-5-phenyl-
1,2,4a,5,8,9-hexahydrothiopyrano[4′,3′:2,3]pyrrolo[2,1-a]-
isoquinolin-6(4H)-one (3i). Purified by column chromatography on
silica gel (hexane/AcOEt = 4:1): white solid (38.4 mg, 47%); m.p.
226−228 °C; [α]2D5 = −236.0 (c 0.25, CHCl3); ee = 86% (DAICEL
Chiralpak OD-H, hexane/2-propanol = 75/25, λ = 220 nm, flow rate =
(4aR,5R,13bS)-5-Hydroxy-11,12-dimethoxy-5-(p-tolyl)-
3,4,4a,5,8,9-hexahydro-1H-indolo[7a,1-a]isoquinolin-6(2H)-one
(3d). Purified by column chromatography on silica gel (hexane/AcOEt
= 4:1): purified by column chromatography on silica gel (hexane/
AcOEt = 4:1 to 2:1): white solid (25.3 mg, 31%); m.p. 244−246 °C;
[α]2D5 = −63.2 (c 0.25, CHCl3); ee = 90% (DAICEL Chiralpak OD-H,
hexane/2-propanol = 75/25, λ = 230 nm, flow rate = 0.5 mL/min);
IR(KBr) 3331, 2931, 1678, 1512 cm−1; d.r. >19:1; 1H NMR (400 MHz,
chloroform-d): δ 7.36 (d, 2H, J = 7.8 Hz), 7.16 (d, 2H, J = 7.8 Hz), 6.94
(s, 1H), 6.64 (s, 1H), 4.11−4.20 (m, 1H), 3.88 (s, 3H), 3.86 (s, 3H),
3.52−3.58 (m, 1H), 3.01−3.09 (m, 1H), 2.86−2.91 (m, 1H), 2.81−
2.84 (m, 1H), 2.31−2.51 (br s, 1H), 2.35 (s, 3H), 1.97−2.05 (m, 2H),
1.77−1.91 (m, 2H), 1.35−1.37 (m, 2H), 1.22−1.27 (m, 1H), 0.25−
0.34 (m, 1H); 13C{1H} NMR (101 MHz, chloroform-d): δ 174.1,
148.0, 147.5, 138.0, 137.5, 135.9, 129.0, 127.5, 125.1, 112.2, 109.1, 81.7,
60.4, 56.4, 56.1, 49.5, 36.5, 36.4, 27.3, 24.7, 21.3, 20.6, 20.4; HRMS
+
(ESI-Orbitrap) calcd for C25H30NO4 [M + H]+ 408.2169; found:
408.2172.
(4aR,5R,13bS)-5-Hydroxy-11,12-dimethoxy-5-(naphthalen-2-yl)-
3,4,4a,5,8,9-hexahydro-1H-indolo[7a,1-a]isoquinolin-6(2H)-one
(3e). Purified by column chromatography on silica gel (hexane/AcOEt
= 4:1): white solid (34.6 mg, 39%); m.p. 228−229 °C; [α]2D5 = −74.0 (c
0.25, CHCl3); ee = 91% (DAICEL Chiralpak OD-H, hexane/2-
propanol = 75/25, λ = 254 nm, flow rate = 0.5 mL/min); IR(KBr) 3343,
1
0.5 mL/min); IR(KBr) 3350, 2922, 1680, 1514 cm−1; d.r. >19:1; H
NMR (400 MHz, chloroform-d): δ 7.41 (d, 2H, J = 6.9 Hz), 7.29−7.37
(m, 3H), 7.34 (s, 1H), 6.60 (s, 1H), 4.38−4.44 (m, 1H), 3.91 (s, 3H),
3.86 (s, 3H), 3.38−3.45 (m, 1H), 3.19 (dd, 1H, J = 9.8, 5.7 Hz), 3.10−
G
https://dx.doi.org/10.1021/acs.joc.0c01992
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
3.15 (m, 1H), 2.73−2.77 (m, 2H), 2.60 (td, 1H, J = 11.9, 4.1 Hz),
2.24−2.49 (br s, 1H), 2.24−2.37 (m, 3H), 2.04−2.12 (m, 1H);
13C{1H} NMR (101 MHz, chloroform-d): δ 148.2, 147.6, 139.6, 133.2,
128.4, 126.9, 124.7, 112.1, 109.4, 82.4, 60.3, 56.2, 56.0, 52.4, 36.0, 33.5,
26.9, 25.3, 21.0; HRMS (ESI-Orbitrap) calcd for C23H26NO4S+ [M +
H]+ 412.1577; found: 412.1571.
by flash column chromatography on silica gel (PE/EA = 2:1) to afford
pure product 2h (yield: 74%, 2.16 g; ee: 84%).
Synthetic Procedure for Gram Scale Synthesis of 3h. Under
argon protection, product 2h (5.47 mmol, 2.16 g) and InCl3 (1 equiv,
1.21 g) were added in dry DCM (164 mL) and the resulting mixture
was stirred at 0 °C. After 12 h, the solvent was removed in vacuo and the
residue was chromatographed on a silica gel column eluted with a
mixture of petroleum ether and ethyl acetate (2:1) to give pure product
3h (yield: 1.11 g, 51%; ee: 74%).
Synthesis of 5. To a stirred suspension of LiAlH4 (57 mg, 1.5
mmol) in THF (10 mL) was added 3a (118 mg, 0.3 mmol) and the
resulting mixture was refluxed for 8 h. The solution was cooled to rt and
quenched by successive addition of water (0.2 mL) and 20% aqueous
NaOH solution (0.2 mL) under vigorous stirring. The mixture was
filtered through a pad of Celite, and the white precipitate was washed
several times with THF containing ∼1% of concentrated ammonium
hydroxide. The combined filtrates were concentrated and purified by
flash column chromatography on silica gel (PE/EA = 3:1) to give
product 5. White solid (102.5 mg, 90%); m.p. 241−243 °C; IR(KBr)
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c01992.
■
sı
HPLC data; crystal data; and copies of 1H NMR and 13
NMR spectra of products (PDF)
C
1
2923, 1509 cm−1; H NMR (400 MHz, chloroform-d): δ 7.49−7.78
(m, 2H), 7.13−7.38 (m, 3H), 6.79 (s, 1H), 6.65 (s, 1H), 4.32 (s, 1H),
3.89 (s, 3H), 3.82 (s, 3H), 3.38−3.47 (m, 2H), 3.20−3.28 (m, 1H),
2.71−2.79 (m, 2H), 1.69−1.78 (m, 2H), 1.57−1.64 (m, 2H), 1.20−
1.26 (m, 3H), 1.08−1.11 (m, 1H), 0.84−0.90 (m, 1H); 13C{1H} NMR
(101 MHz, chloroform-d): δ 146.5, 141.7, 139.3, 127.8, 127.1, 127.0,
111.8, 108.9, 91.6, 83.6, 60.4, 56.1, 56.0, 51.2, 40.9, 38.1, 29.3, 24.0,
Crystallographic data for 2a (TX1109-2a) (CIF)
Crystallographic data for 3a (TX1069-3a) (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
+
20.8, 20.3; HRMS (ESI-Orbitrap) calcd for C24H30NO3 [M + H]+
Shuo Tong − MOE Key Laboratory of Bioorganic Phosphorous
and Chemical Biology, Department of Chemistry, Tsinghua
University, Beijing 100084, China; orcid.org/0000-0002-
7982-2546; Email: tongshuo@mail.tsinghua.edu.cn
Mei-Xiang Wang − MOE Key Laboratory of Bioorganic
Phosphorous and Chemical Biology, Department of Chemistry,
Tsinghua University, Beijing 100084, China; orcid.org/
0000-0001-7112-0657; Email: wangmx@
380.2220; found: 380.2210.
Synthesis of 6. To a solution of 3a (157 mg, 0.4 mmol) in CH2Cl2
(5 mL) at 0 °C were added MsCl (165 mg, 111 μL, 1.44 mmol) and
Et3N (283 mg, 389 μL, 2.8 mmol). The solution was stirred at 0 °C for 1
h and allowed to warm to rt and stirred overnight. Water was added, and
the mixture was extracted with CH2Cl2 and washed with brine. The
combined organic phases were dried over anhydrous Na2SO4 and
concentrated in vacuo. Flash chromatography on silica gel (PE/EA =
3:1) affords 6. White solid (133.7 mg, 89%); m.p. 148−150 °C IR(KBr)
2921, 1679, 1510 cm−1; 1H NMR (400 MHz, chloroform-d): δ 7.44−
7.46 (m, 2H), 7.38−7.42 (m, 2H), 7.30−7.34 (m, 1H), 7.21 (s, 1H),
6.71 (s, 1H), 4.23−4.29 (m, 1H), 3.93 (s, 3H), 3.87 (s, 3H), 3.46−3.53
(m, 1H), 3.25 (dd, 1H, J = 14.4, 4.8 Hz), 2.97−3.05 (m, 1H), 2.91 (t,
1H, J = 5.3 Hz), 2.85 (dd, 1H, J = 14.9, 5.7 Hz), 2.49 (d, 1H, J = 12.4
Hz), 2.14 (d, 1H, J = 13.3 Hz), 1.82−1.92 (m, 1H), 1.76 (d, 1H, J = 13.7
Hz), 1.64 (td, 1H, J = 13.2, 4.3 Hz), 1.36−1.49 (m, 1H); 13C{1H} NMR
(101 MHz, chloroform-d): δ 169.2, 157.1, 148.2, 146.7, 131.8, 131.4,
130.6, 129.8, 128.3, 128.0, 127.3, 112.6, 110.6, 64.8, 56.6, 56.0, 41.5,
36.4, 28.5, 27.8, 27.6, 21.5; HRMS (ESI-Orbitrap) calcd for
C24H26NO3+ [M + H]+ 376.1907; found: 376.1903.
mail.tsinghua.edu.cn
Authors
Li Zhen − MOE Key Laboratory of Bioorganic Phosphorous and
Chemical Biology, Department of Chemistry, Tsinghua
University, Beijing 100084, China
Jieping Zhu − Laboratory of Synthesis and Natural Products,
Institute of Chemical Science and Engineering, Ecole
́
́
Polytechnique Federale de Lausanne, EPFL-SB-ISIC-LSPN,
1015 Lausanne, Switzerland; orcid.org/0000-0002-8390-
6689
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c01992
Synthesis of 7. To a two-necked round bottom flask equipped with
a magnetic stirrer were added compound 6 (94 mg, 0.25 mmol), Pd/C
catalyst (18.8 mg, 20% w/w), and CH3OH (5 mL). The reaction
mixture was stirred at room temperature under a hydrogen atmosphere
overnight. The mixture was filtered through Celite, and the filtrate was
evaporated under vacuum. Flash chromatography on silica gel (PE/EA
= 3:1) affords 7. White solid (76.4 mg, 81%); m.p. 91−93; IR(KBr)
2929, 1692, 1508 cm−1; 1H NMR (400 MHz, chloroform-d): δ 7.19−
7.30 (m, 5H), 6.80 (s, 1H), 6.54 (s, 1H), 4.29−4.34 (m, 1H), 3.93 (s,
3H), 3.85 (s, 3H), 3.67 (d, 1H, J = 6.9 Hz), 3.25−3.33 (m, 1H), 3.14−
3.22 (m, 1H), 2.77−2.83 (m, 1H), 2.55 (dd, 1H, J = 16.3, 4.8 Hz), 2.21
(d, 1H, J = 13.7 Hz), 1.56−1.67 (m, 3H), 1.18−1.37 (m, 4H); 13C{1H}
NMR (101 MHz, chloroform-d): δ 177.7, 148.1, 147.5, 135.4, 133.8,
129.7, 128.2, 126.8, 126.8, 112.3, 107.9, 62.2, 56.4, 56.0, 52.0, 42.9,
36.7, 35.3, 26.0, 25.97, 24.1, 21.6; HRMS (ESI-Orbitrap) calcd for
C24H28NO3+ [M + H]+ 378.2064; found: 378.2058.
Synthetic Procedure for Gram Scale Synthesis of 2h. Under
argon protection, enamide 1h (7.37 mmol, 2.91 g), (R,R)-Cr(III)-
(salen)Cl (0.2 equiv, 1.47 mmol, 931.6 mg), 4 Å MS (3.69 g), and
Na2CO3 (0.2 equiv, 154.8 mg) were added in dry toluene (221 mL) and
the resulting mixture was stirred at 10 °C. After 48 h, 4 Å MS was
filtered and the reaction was quenched by saturated NaHCO3 solution.
The resulting mixture was extracted with CH2Cl2 (3 × 30 mL) and
washed with brine. The combined organic layers were dried over
anhydrous Na2SO4 and concentrated in vacuo. The residue was purified
Author Contributions
This manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was received from the National Natural
Science Foundation of China (21901137, 21920102001,
21732004). S.T. also thanks the Thousand Young Talents
Program for support.
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