Catalytic Asymmetric [3 + 2] Cycloaddition Reaction between Aurones and Isocyanoacetates: Access to Spiropyrrolines via Silver Catalysis

Article abstract of DOI:10.1021/acs.joc.8b01622

The first enantioselective formal [3 + 2] cycloaddition of aurone analogues with isocyanoacetates was developed via chiral Ag-complex catalysis. A variety of optically enriched spiro-1-pyrrolines were obtained in excellent yields, diastero- and enantioselectivities (up to 99% yield, >20:1 dr, >99% ee). This synthetic approach represents an extremely simple, efficient, and atom-economical method for spiro-1-pyrrolines synthesis.

Full text of DOI:10.1021/acs.joc.8b01622

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Article
Catalytic Asymmetric [3 + 2] Cycloaddition Reaction Between Aurones
and Isocyanoacetates: Access to Spiropyrrolines via Silver Catalysis
Zhi-Peng Wang, Sichuan Xiang, Pan-Lin Shao, and Yun He
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01622 • Publication Date (Web): 11 Jul 2018
Downloaded from http://pubs.acs.org on July 11, 2018
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Catalytic Asymmetric [3 + 2] Cycloaddition Reaction Between
Aurones and Isocyanoacetates: Access to Spiropyrrolines via Silver
Catalysis
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,
,
,
ZhiꢀPeng Wang,† Sichuan Xiang,† PanꢀLin Shao,* † ‡ and Yun He* †
†
School of Pharmaceutical Sciences and Chongqing Key Laboratory of Natural Product Synthesis
and Drug Research, Chongqing University, 55 Daxuecheng South Road, Shapingba, Chongqing
4
01331, People’s Republic of China.
‡
College of Innovation and Entrepreneurship, Southern University of Science and Technology,
Shenzhen 518000, People’s Republic of China.
ABSTRUCT: The first enantioselective formal [3 + 2] cycloaddition of aurone analogues with
isocyanoacetates was developed via chiral Agꢀcomplex catalysis. A variety of optically enriched
spiroꢀ1ꢀpyrrolines were obtained in excellent yields, diasteroꢀ and enantioselectivities (up to 99%
yield, >20:1 dr, >99% ee). This synthetic approach represents an extremely simple, efficient and
atomꢀeconomical method for spiroꢀ1ꢀpyrrolines synthesis.
INTRODUCTION
Spiro heterocyclic compounds are ubiquitous in biologically active natural products and
1
pharmaceutically important compounds, two of the most important classes are spiropyrrolines
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and spiropyrrolidines, which display broad biological activities. In recent decades, the formal [3 +
2] cyclization of electronꢀdeficient olefins with azomethine ylides has emerged as a powerful tool
3
for the construction of such spiropyrrolidine derivatives. In particular, the aurone analogues have
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received extensive attention as dipolarophiles in the construction of spiroheterocycles. In 2016,
Ding and Fu et al. developed the first cyclization of 2ꢀalkylidenebenzofuranꢀ3ꢀone with
azomethine ylides using simple functional ionic liquids as catalysts, accessing highly substituted
5
a
spiropyrrolidine in good yields. Recently, the synthesis of spiropyrrolidine derivatives bearing
four contiguous stereogenic centers was described by Albrecht et al. with moderate
5b
enantioselectivity (Scheme 1). Actually, concerning both the number of stereocenters and
molecular complexities, the stereoselective construction of such privileged scaffold still remains
an important goal in synthetic organic chemistry.
Scheme 1. The application of aurones in the synthesis of spiropyrrolidines.
Owing to the unique reactivity, isocyanoacetates have been explored as versatile building
6
blocks for the construction of heterocyclic compounds, especially in the formal [3 + 2]
7
cycloaddition reaction with olefins. In 2008, Gong and coꢀworkers developed the first cinchona
7
a
alkaloids catalyzed synthesis of dihydropyrroles with αꢀaryl isocyanoacetate and nitroolefins. In
2
011, Escolano group reported the cooperative Brønsted base/Lewis acid cascade catalysis
promoted cycloaddition of isocyanoacetates with α,βꢀunsaturated ketones in moderate yields and
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enantioselectivities. In 2012, Carretero and Adrio et al. disclosed the catalytic asymmetric
formal [3
+
2] cycloaddition of isocyanoacetates with maleimides, using cationic
7c
Au(I)/DTBMꢀsegphos complex as the catalystic system. At the same time, Wang and Xu et al.
developed stereoselective [3 + 2] cycloaddition of αꢀaryl isocyanoacetates with protected
methyleneindolinones to access 3,3´ꢀpyrrolidinyl spirooxindoles catalyzed by cinchona
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alkaloidꢀbased thiourea tertiary amines (Scheme 2). Despite these significant advances, the
enantioselective cycloaddition of isocyanoacetates with aurones has yet to be demonstrated.
Scheme 2. Formal [3 + 2] cyclization of isocyanoacetates with olefins.
RESULTS AND DISCUSSION
Our recent efforts have been devoted to the asymmetric synthesis of nitrogenꢀcontaining
heterocycles, such as pyrrolines and pyrrolidines using functionalized 1,3ꢀdipole enolate derived
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from isocyanoacetates under chiral Brønsted base conditions. In this work, our attention was
drawn to the possibility of the cycloaddition reaction of isocyanoacetates with aurone analogues.
Initial exploration utilized (Z)ꢀ2ꢀbenzylidenebenzofuranꢀ3(2H)ꢀone 1a and methyl
2ꢀisocyanoꢀ3ꢀphenylpropanoate 2a as the model substrates catalyzed by a chiral silver(I) complex
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developed by Dixon group. Although the 1,3ꢀdipole enolate generated from isocyanoacetate
could potentially facilitate a [4 + 3] and/or [3 + 2] Michael/cyclization reaction sequence, our
studies revealed that this approach only led to the [3 + 2] cyclization, affording the spiropyrroline,
and no [4 + 3] annulation product was observed (Scheme 3).
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Scheme 3. Inspiration for the cyclization of isocyanoacetate with aurone analogue.
Encouraged by the preliminary result, we turned our attention to further optimize the [3 + 2]
cyclization conditions. As shown in Table 1, several precatalysts 3 were screened to evaluate their
ability to promote the cycloaddition of 1a and 2a at ambient temperature. To our delight,
precatalyst 3a in combination with Ag
2
O led to high yield and stereoselectivity (entry 1).
afforded better yield, diastereoselectivity and
o
Lowering the temperature to
0
C
a
enantioselectivity (entries 2ꢀ4). Precatalysts 3bꢀe with minor structural modifications were then
screened (entries 5ꢀ8), and 3b afforded the best result (entry 5). Although a chiral silver complex
with (S)ꢀMOP 3f was the optimal catalyst in Gong’s work for the enantioselective cycloaddition of
10
αꢀaryl isocyanoacetates with 2ꢀoxobutenoate esters, 3f with Ag
with poor enantioselectivity (entry 9). Varying the solvent did not benefit the enantioselectivity
entries 10ꢀ14). Thus, we identified the following optimal protocol: reaction of 1a and 2a with a
2
O afforded the desired product
(
2
molar ratio of 1.0:1.2 in the presence of Ag O (10 mol%) and precatalyst 3b (20 mol%) in THF at
o
0
C. It is worth noting that all the reactions were conducted open to air with no need for exclusion
of air or moisture.
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Table 1. Optimization of reaction of aurone analogues with isocyanoacetate.
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entry
3
T( C) solvent yield(%)
dr
ee(%)
78
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3a
3a
3a
3a
3b
3c
3d
3e
3f
25
0
THF
THF
THF
THF
THF
THF
THF
THF
THF
DCM
toluene
EA
90
99
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86
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99
95
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99
98
>20:1
>20:1
>20:1
19:1
90
ꢀ10
ꢀ20
0
90
86
>20:1
>20:1
19:1
93
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ꢀ40
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>20:1
>20:1
>20:1
>20:1
89
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92
0
Et
2
O
84
0
CHCl
3
84
a
b
1
Unless otherwise stated, reactions were run for 12 h. dr ratio determined by H NMR
c
spectroscopy (400 MHz) of the reaction mixture. ee determined by HPLC analysis using a chiral
stationary phase. See Supporting Information for details.
Using this catalytic protocol, a wide range of spiroꢀ1ꢀpyrrolines 4 were prepared as shown in
Scheme 4. The electronic effects of different aryl substituents on aurones were investigated, and
the reaction exhibited good insensitivity to the substitution pattern. Introduction of an
electronꢀdonating or electronꢀwithdrawing group (5ꢀOMe, 5ꢀBr) to the benzofuranone moiety led
to the corresponding products 4bꢀc in almost quantitative yields. The aurone analogues 1 could
2
well tolerate the existence of electronꢀpoor or electronꢀrich phenyl rings as R group, the paraꢀ,
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metaꢀ, or orthoꢀsubstituents did not affect the reaction, and furnished products 4 in excellent yields
4dꢀ4i, albeit the halogen substituents on the paraꢀ and metaꢀposition slightly decreased the
2
enantioselectivity. Moreover, replacement of the R group of the aurone analogues with
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βꢀnaphthyl, 3ꢀindolyl, 3ꢀpyridinyl, 2ꢀfuranyl, 2ꢀthiophenyl and ferrocenyl, respectively, the
reactions could still undergo smoothly to afford the desired products 4jꢀo in almost quantitative
yields and good to excellent diastereoꢀ and enantioselectivities. The conversion from
spiropyrroline 4d to spiropyrrolidine 4d' was easily achieved under a simple reduction condition
3
employing NaCNBH /HOAc without loss of enantioselectivity. The relative and absolute
configuration of 4d was unambiguously established by single crystal Xꢀray analysis of the
1
1
pyrrolidine 4d' (2S,4'S,5'R) (Scheme 4, see Supporting Information for details).
Scheme 4. Substrate scope of aurone analogues.
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The scope of this methodology was then extended to αꢀsubstituted isocyanoacetates 2. This
reaction showed good generality and wide substrate scope. Different substitution patterns on the
isocyanoacetates such as methyl (5a), isopropyl (5b), nꢀbutyl (5c), ester (5d), cyclohexyl (5e) and
allyl (5f) were all well tolerated, funishing the [3 + 2] cyclization products in uniformly high
yields, diastereoꢀ and enantioselectivities, albeit pꢀmethoxyphenyl substituted isocyanoacetate led
to the desired product 5gꢀh with slightly reduced yields and stereoselectivities (Scheme 5).
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Scheme 5. Substrate scope of αꢀsubstituted isocyanoacetates.
Next, the substrate scope of αꢀunsubstituted isocyanoacetate was studied. Unfortunately, the
desired product was obtained in low yield under the standard condition, due to the decomposition
o
of spiropyrroline. To our delight, when the reaction temperature was decreased to ꢀ20 C, the
cycloadducts were obtained in uniformly good yields. As shown in Scheme 6, various aurone
analogues were examined with 2b for the efficient cycloaddition to deliver 6aꢀ6f in high yields,
and excellent enantioselectivities (up to 90% yield, >99% ee). However, the methoxy group on the
benzofuranone moiety led to 6f with a slight erosion of enantioselectivity. Notably, the annulation
highlighted the versatility of this method to prepare spiroꢀ1ꢀpyrroline derivatives possessing three
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contiguous stereocenters. The relative and absolute configuration of 6a was unambiguously
deduced from single crystal Xꢀray diffraction analysis of the corresponding pyrrolidine 6a' (See
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Supporting Information for details).
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Scheme 6. Substrate scope of methyl isocyanoacetate and aurone analogues.
To further explore the synthetic utility of this protocol, a gramꢀscale reaction was also
evaluated. The desired product 4a could be obtained smoothly in 98% yield, >20:1 dr and
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2% ee under the standard condition, without significant loss of the reactivity and
stereoselectivity (Scheme 7).
Scheme 7. Gram scale synthesis of 4a
.
Finally, to validate the application potential of these cycloadducts, we chose product 5f
as a model for transformation. Allylation of the imine on pyrroline moiety was readily
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achieved, providing the diallyl substituted pyrrolidine
7 in excellent yield and good
stereoselectivity. This transformation has the potential to furnish highly substituted
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biologically active pyrrolidine derivatives. The relative configuration of
by its NOE analysis (Scheme 8, see Supporting Information for details).
7 was assigned
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Scheme 8. Transformation of 5f
.
Although the mechanism of these reactions reported here remains to be clarified, a
plausible transitionꢀstate model is depicted in Scheme 9, based on the results from our
experiment and the absolute configuration of the major isomer. In this model, the αꢀproton
of isocyanoacetate is easily deprotonated by the tertiary amine on the precatalyst due to the
activation of Ag(I) chelating to the terminal carbon of the isocyano group. The center metal
Ag(I) could also chelate to the amide nitrogen and the Lewis base phosphorus on
precatalyst. Owing to the hindrance, the ester motif is situated below the bulky phenyl
groups, and then the isocyanoacetate would attack aurone olefin from the Reꢀface,
meanwhile, the oxygen atom of aurone is hydrogenꢀbonded to the precatalyst and
coordinated to Ag(I) to stabilize the transitionꢀstate. Subsequently, a 5ꢀendoꢀdig cyclization
would take place to form the spiropyrroline product with three newly generated
stereocenters.
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Scheme 9. Proposed transitionꢀstate model.
CONCLUSIONS
In summary, we have developed the first enantioselective formal [3 + 2] cycloaddition
reaction of isocyanoacetates with aurone analogues using a chiral Agꢀcomplex catalyst. A
wide variety of isocyanoacetates and aurones with different electronic and steric properties
were well tolerated in this protocol, leading to optically active spiropyrrolines bearing three
contiguous stereogenic centers in excellent yields, diasteroꢀ and enantioselectivities (up to
99% yield, >20:1 dr, >99% ee). Investigations aiming at expanding the application of this
approach to synthesize more promising candidates for drug discovery as well as the
biological evaluation are currently ongoing in our laboratory.
EXPERIMENTAL SECTION
1
13
1
General Information: H and C{ H} NMR spectra were recorded on an Agilent 400M
NMR spectrometer at ambient temperature. Chemical shifts were reported in parts per million
1
(ppm), and the residual solvent peak was used as an internal reference: H (chloroform δ 7.26),
13
1
C{ H} (chloroform δ 77.0). Data are reported as follows: chemical shift, multiplicity (s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet, br = broad), coupling constants (Hz) and
integration. Melting point (M.P.) was obtained on SGW Xꢀ4A. For thin layer chromatography
(TLC), Merck preꢀcoated TLC plates (Merck 60 F254) were used, and compounds were
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visualized with a UV light at 254 nm. High resolution mass spectra (HRMS) were obtained on a
Bruker SolariX 7.0T FTꢀICR mass spectrometer. Optical rotations were recorded on a Rudolph
Autopol I automatic polarimeter. Enantiomeric excesses (ee) were determined by HPLC analysis
on Agilent HPLC units, including the following instruments: pump, G1311C; detector, G1314F;
Enantiomeric excesses (ee) were also determined by HPLC analysis on Acchrom HPLC units,
including the following instruments: pump, 6210; detector, 6410. column, Chiralpak ADꢀH, ODꢀH,
ID.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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0
Unless otherwise noted, all the reactions were carried out in air. Tetrahydrofuran (THF) was
dried and distilled from sodium. Deuterated solvents were purchased from Cambridge Isotope
Laboratories and used as received without further purification. Other chemicals were purchased
from commercial suppliers and used as received without further purification.
14
General procedure for the synthesis of aurones
:
To
a
solution of
benzofuranꢀ3(2
H
)ꢀone (1.0 mmol) and benzaldehyde (1.0 mmol) in dichloromethane (10
mL) was added activated basic aluminum oxide (5.0 mmol) at room temperature with
vigorously stirring. After reaction completion, aluminum oxide was filtered and washed
abundantly with dichloromethane, the filtrate was concentrated to afford crude product,
which was purified by flash chromatography on silica gel (hexanes/ethyl acetate = 20:1) to
give the product 1a as pale yellow solid.
(
f
Z)ꢀ2ꢀBenzylidenebenzofuranꢀ3(2H)ꢀone (1a). 177.8 mg, 80% yield, R = 0.5, (silica gel,
o
1
petroleum ether:EtOAc = 5:1), pale yellow solid, M.P. 89ꢀ90 C. H NMR (400 MHz,
Chloroformꢀd) δ 7.93 (d, J = 7.3 Hz, 2H), 7.81 (d, J = 7.5 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.46 (t,
J = 7.3 Hz, 2H), 7.40 (t, J = 7.1 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H), 6.90 (s,
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H); C{ H} NMR (101 MHz, Chloroformꢀd) δ 184.8, 166.2, 146.9, 136.9, 132.3, 131.5, 129.9,
128.9, 124.7, 123.5, 121.6, 113.0, 112.9.
Z)ꢀ2ꢀBenzylideneꢀ6ꢀmethoxybenzofuranꢀ3(2H)ꢀone (1b). 214.4 mg, 85% yield, R
(
f
= 0.5, (silica
0
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2
3
4
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7
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1
2
3
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8
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0
1
2
3
4
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7
8
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1
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8
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2
3
4
5
6
7
8
9
0
o
1
gel, petroleum ether:EtOAc = 5:1), white scaly solid, M.P. 132ꢀ133 C. H NMR (400 MHz,
Chloroformꢀd) δ 7.90 – 7.88 (m, 2H), 7.69 (t, J = 5.9 Hz, 1H), 7.45 (dd, J = 10.1, 4.6 Hz, 2H),
13
1
7
.40 – 7.36 (m, 1H), 6.81 (s, 1H), 6.76 (dt, J = 8.4, 2.0 Hz, 2H), 3.92 (s, 3H); C{ H} NMR (101
MHz, Chloroformꢀd) δ 183.0, 168.6, 167.5, 147.8, 132.4, 131.3, 129.6, 128.8, 125.8, 114.8, 112.2,
11.9, 96.7, 56.0.
Z)ꢀ2ꢀBenzylideneꢀ6ꢀbromobenzofuranꢀ3(2H)ꢀone (1c). 286.1 mg, 95% yield, R
1
(
f
= 0.3, (silica
o
1
gel, petroleum ether:EtOAc = 10:1), pale yellow solid, M.P. 168ꢀ170 C. H NMR (400 MHz,
Chloroformꢀd) δ 7.88 (d, J = 7.1 Hz, 2H), 7.65 (d, J = 8.1 Hz, 1H), 7.54 (s, 1H), 7.43 (dq, J = 14.3,
13
1
7
.0 Hz, 3H), 7.35 (d, J = 8.1 Hz, 1H), 6.90 (s, 1H); C{ H} NMR (101 MHz, Chloroformꢀd) δ
183.5, 166.1, 146.8, 131.9, 131.6, 131.3, 130.2, 129.0, 127.2, 125.5, 120.7, 116.6, 114.0.
Z)ꢀ2ꢀ(2ꢀChlorobenzylidene)benzofuranꢀ3(2H)ꢀone (1d). 220.7 mg, 86% yield, R = 0.5, (silica
(
f
o
1
gel, petroleum ether:EtOAc = 5:1), pale yellow solid, M.P. 133ꢀ134 C. H NMR (400 MHz,
Chloroformꢀd) δ 8.35 (dd, J = 7.8, 1.6 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.68 – 7.64 (m, 1H), 7.46
(
dd, J = 7.9, 1.2 Hz, 1H), 7.38 (dd, J = 8.7, 7.6 Hz, 2H), 7.32 – 7.29 (m, 2H), 7.23 (t, J = 7.5 Hz,
13
1
1
H); C{ H} NMR (101 MHz, Chloroformꢀd) δ 184.5, 166.2, 147.6, 137.1, 135.9, 132.2, 130.6,
1
30.4, 130.0, 127.0, 124.8, 123.7, 121.5, 112.9, 108.0.
f
(Z)ꢀ2ꢀ(2ꢀMethylbenzylidene)benzofuranꢀ3(2H)ꢀone (1e). 193.7 mg, 82% yield, R = 0.5, (silica
o
1
gel, petroleum ether:EtOAc = 5:1), pale yellow solid, M.P. 101ꢀ102 C. H NMR (400 MHz,
Chloroformꢀd) δ 8.27 – 8.25 (m, 1H), 7.82 (d, J = 7.5 Hz, 1H), 7.67 – 7.63 (m, 1H), 7.34 – 7.20
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(
m, 5H), 7.14 (s, 1H), 2.52 (s, 3H); C{ H} NMR (101 MHz, Chloroformꢀd) δ 184.8, 166.2,
147.0, 139.2, 136.8, 131.2, 130.8, 130.7, 129.8, 126.4, 124.7, 123.4, 121.7, 113.0, 109.9, 20.2.
Z)ꢀ2ꢀ(3ꢀChlorobenzylidene)benzofuranꢀ3(2H)ꢀone (1f). 220.7 mg, 86% yield, R = 0.5, (silica
(
f
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
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3
3
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3
4
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4
4
5
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5
5
5
5
5
5
5
5
6
0
1
2
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4
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9
0
1
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8
9
0
1
2
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7
8
9
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1
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
1
gel, petroleum ether:EtOAc = 5:1), pale yellow solid, M.P. 96ꢀ97 C. H NMR (400 MHz,
Chloroformꢀd) δ 7.91 (s, 1H), 7.78 (t, J = 12.5 Hz, 1H), 7.72 – 7.70 (m, 1H), 7.64 (t, J = 7.7 Hz,
13
1
1
H), 7.38 – 7.32 (m, 3H), 7.22 (t, J = 7.4 Hz, 1H), 6.76 (s, 1H); C{ H} NMR (101 MHz,
Chloroformꢀd) δ 184.6, 166.2, 147.3, 137.1, 134.8, 134.0, 130.9, 130.0, 129.7, 129.6, 124.7, 123.7,
21.4, 113.0, 111.1.
Z)ꢀ2ꢀ(3ꢀMethoxybenzylidene)benzofuranꢀ3(2H)ꢀone (1g). 214.4 mg, 85% yield, R
1
(
f
= 0.4,
o
1
(
silica gel, petroleum ether:EtOAc = 5:1), pale yellow solid, M.P. 116ꢀ117 C. H NMR (400
MHz, Chloroformꢀd) δ 7.81 (d, J = 7.7 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.50 (d, J = 6.7 Hz, 2H),
7
.40 – 7.32 (m, 2H), 7.23 (t, J = 7.5 Hz, 1H), 7.98 – 6.96 (m, 1H), 6.87 (s, 1H), 3.89 (s, 3H);
13
1
C{ H} NMR (101 MHz, Chloroformꢀd) δ 184.8, 166.2, 159.8, 147.0, 136.9, 133.5, 129.8, 124.7,
1
24.3, 123.5, 121.6, 116.5, 115.7, 113.0, 112.9, 55.3.
(
f
Z)ꢀ2ꢀ(4ꢀBromobenzylidene)benzofuranꢀ3(2H)ꢀone (1h). 171.6 mg, 57% yield, R = 0.5, (silica
o
1
gel, petroleum ether:EtOAc = 5:1), pale yellow solid, M.P. 170ꢀ171 C. H NMR (400 MHz,
Chloroformꢀd) δ 7.79 (dd, J = 12.4, 8.1 Hz, 3H), 7.69 – 7.65 (m, 1H), 7.58 (d, J = 8.5 Hz, 2H),
13
1
7
.33 (d, J = 8.3 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H), 6.81 (s, 1H); C{ H} NMR (101 MHz,
Chloroformꢀd) δ 184.6, 166.1, 147.1, 137.0, 132.8, 132.2, 131.2, 124.7, 124.3, 123.7, 121.5, 112.9,
111.5.
(
Z)ꢀ2ꢀ(4ꢀMethoxybenzylidene)benzofuranꢀ3(2H)ꢀone (1i). 229.6 mg, 91% yield, R = 0.5, (silica
f
o
1
gel, petroleum ether:EtOAc = 5:1), pale yellow solid, M.P. 133ꢀ134 C. H NMR (400 MHz,
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Chloroformꢀd) δ 7.91 – 7.87 (m, 2H), 7.81 (dd, J = 7.6, 0.8 Hz, 1H), 7.64 (ddd, J = 8.5, 7.3, 1.4
Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.23 – 7.19 (m, 1H), 7.00 – 6.98 (m, 2H), 6.89 (s, 1H), 3.87 (s,
13
1
3
H); C{ H} NMR (101 MHz, Chloroformꢀd) δ 184.5, 165.8, 161.1, 145.9, 136.5, 133.4, 125.1,
0
1
2
3
4
5
6
7
8
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1
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3
4
5
6
7
8
9
0
1
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8
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124.6, 123.3, 122.0, 114.5, 113.4, 112.9, 55.4.
(
Z)ꢀ2ꢀ(Naphthalenꢀ2ꢀylmethylene)benzofuranꢀ3(2H)ꢀone (1j). 212.4 mg, 78% yield, R
f
= 0.5,
o
1
(
silica gel, petroleum ether:EtOAc = 5:1), yellow solid, M.P. 120ꢀ121 C. H NMR (400 MHz,
Chloroformꢀd) δ 8.30 (s, 1H), 8.06 (dd, J = 8.6, 1.4 Hz, 1H), 7.85 (ddd, J = 14.1, 9.3, 3.4 Hz, 4H),
7
1
1
.67 – 7.63 (m, 1H), 7.54 – 7.49 (m, 2H), 7.36 (d, J = 8.3 Hz, 1H), 7.21 (t, J = 7.4 Hz, 1H), 7.03 (s,
13
1
H); C{ H} NMR (101 MHz, Chloroformꢀd) δ 184.6, 166.1, 147.1, 136.8, 133.7, 133.3, 132.3,
29.9, 128.7, 128.5, 127.72, 127.66, 127.5, 126.6, 124.7, 123.5, 121.7, 113.2, 113.0; HRMS (ESI):
+
m/z calcd. for [C H O , M+H] : 273.0910; found: 273.0916.
1
9
13
2
(
Z)ꢀ2ꢀ((1HꢀIndolꢀ3ꢀyl)methylene)benzofuranꢀ3(2H)ꢀone (1k). 125.4 mg, 48% yield, R
f
= 0.2,
(silica gel, petroleum ether:EtOAc = 3:1), orange solid, M.P. 232ꢀ233 C. H NMR (400 MHz,
DMSOꢀd ) δ 12.11 (br, 1H), 8.26 (d, J = 2.6 Hz, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.75 (t, J = 7.9 Hz,
H), 7.56 (d, J = 8.1 Hz, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.36 (s, 1H), 7.23 (ddd, J = 25.2, 15.5, 7.3
o
1
6
2
1
3
1
Hz, 3H); C{ H} NMR (101 MHz, DMSOꢀd ) δ 182.2, 164.6, 144.6, 136.83, 136.82, 132.7,
6
127.1, 124.3, 123.8, 123.3, 122.7, 121.5, 119.5, 113.6, 112.8, 108.9, 108.0; HRMS (ESI): m/z
+
calcd. for [C17
H
11NNaO
2
, M+Na] : 284.0682; found: 284.0682.
(
f
Z)ꢀ2ꢀ(Pyridinꢀ3ꢀylmethylene)benzofuranꢀ3(2H)ꢀone (1l). 163.0 mg, 73% yield, R = 0.2, (silica
o
1
gel, petroleum ether:EtOAc = 5:1), yellow solid, M.P. 111ꢀ112 C. H NMR (400 MHz,
Chloroformꢀd) δ 9.05 (s, 1H), 8.61 (d, J = 4.1 Hz, 1H), 8.29 (d, J = 7.9 Hz, 1H), 7.82 (d, J = 7.6
Hz, 1H), 7.69 (t, J = 7.7 Hz, 1H), 7.42 – 7.39 (m, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.26 (t, J = 7.4 Hz,
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H), 6.85 (s, 1H); C{ H} NMR (101 MHz, Chloroformꢀd) δ 184.3, 166.2, 152.2, 150.06, 148.0,
137.7, 137.3, 128.6, 124.8, 123.8, 123.7, 121.3, 113.0, 108.8.
Z)ꢀ2ꢀ(Furanꢀ2ꢀylmethylene)benzofuranꢀ3(2H)ꢀone (1m). 178.3 mg, 84% yield, R
(
f
= 0.5, (silica
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
1
gel, petroleum ether:EtOAc = 5:1), yellow solid, M.P. 119ꢀ120 C. H NMR (400 MHz,
Chloroformꢀd) δ 7.79 (d, J = 7.4 Hz, 1H), 7.66 – 7.62 (m, 2H), 7.31 (d, J = 8.3 Hz, 1H), 7.21 (t, J
1
3
1
=
7.4 Hz, 1H), 7.13 (d, J = 3.3 Hz, 1H), 6.89 (s, 1H), 6.60 (d, J = 1.4 Hz, 1H); C{ H} NMR (101
MHz, Chloroformꢀd) δ 184.0, 165.7, 148.8, 145.4, 145.0, 136.7, 124.5, 123.5, 122.0, 117.2, 113.1,
12.9, 101.6.
Z)ꢀ2ꢀ(Thiophenꢀ2ꢀylmethylene)benzofuranꢀ3(2H)ꢀone (1n). 205.4 mg, 90% yield, R
1
(
f
= 0.5,
o
1
(
silica gel, petroleum ether:EtOAc = 5:1), pale yellow solid, M.P. 102ꢀ103 C. H NMR (400
MHz, Chloroformꢀd) δ 7.79 (ddd, J = 7.6, 1.3, 0.5 Hz, 1H), 7.64 (ddd, J = 8.6, 7.3, 1.4 Hz, 1H),
.61 – 7.60 (m, 1H), 7.55 – 7.54 (m, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.23 – 7.19 (m, 1H), 7.17 (s,
7
1
3
1
1H), 7.14 (dd, J = 5.1, 3.7 Hz, 1H); C{ H} NMR (101 MHz, Chloroformꢀd) δ 183.8, 165.6,
45.3, 136.6, 135.6, 133.1, 131.7, 128.1, 124.5, 123.5, 122.2, 113.0, 107.0.
(Z)ꢀ(3ꢀOxoꢀ2(3H)ꢀbenzofuranylidene)methyl]ferrocene (1o). 244.3 mg, 74% yield, R
1
[
f
= 0.4,
o
1
(
silica gel, petroleum ether:EtOAc = 10:1), purple solid, M.P. 150ꢀ151 C. H NMR (400 MHz,
Chloroformꢀd) δ 7.80 (d, J = 7.5 Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 7.18 (t,
1
3
1
J = 7.4 Hz, 1H), 6.89 (s, 1H), 4.86 (s, 2H), 4.54 (s, 2H), 4.17 (s, 5H); C{ H} NMR (101 MHz,
Chloroformꢀd) δ 182.9, 165.4, 146.0, 136.1, 124.5, 123.0, 122.6, 116.4, 112.9, 75.1, 71.8, 71.5,
69.9.
General procedure for the cycloaddition of aurones with αꢀsubstituted isocyanoacetates: THF
2
(1 mL) was added to a 10 mL vial charged with the precatalyst 3b (12.3 mg, 0.02 mmol) and Ag O
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6
o
(
2.3 mg, 0.01 mmol). The mixture was stirred at 0 C for 5 min, then the aurore 1a (22.2 mg, 0.1
mmol) and methyl 2ꢀisocyanoꢀ3ꢀphenylpropanoate 2a (22.7 mg, 0.12 mmol) were added. The
o
reaction mixture was stirred at 0 C until 1a was consumed, and then the reaction mixture was
0
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0
purified by flash chromatography on silica gel directly (eluent, petroleum ether:EtOAc = 5:1, 0.1%
TEA v/v) to afford the product 4a.
Methyl
(2S,4'S,5'R)ꢀ5'ꢀbenzylꢀ3ꢀoxoꢀ4'ꢀphenylꢀ4',5'ꢀdihydroꢀ3Hꢀspiro[benzofuranꢀ2,3'ꢀ
o
pyrrole]ꢀ5'ꢀcarboxylate (4a). White solid, M.P. 58ꢀ59 C, R
f
= 0.2 (silica gel, petroleum ether:
1
EtOAc = 3:2). 40.7mg, 99% yield. H NMR (400 MHz, Chloroformꢀd) δ 7.68 (s, 1H), 7.65 – 7.60
(
m, 2H), 7.38 (dd, J = 6.5, 3.1 Hz, 2H), 7.29 – 7.16 (m, 9H), 7.09 (t, J = 7.5 Hz, 1H), 4.01 (s, 1H),
13
1
3
.62 (s, 3H), 3.08 (d, J = 13.4 Hz, 1H), 2.97 (d, J = 13.4 Hz, 1H); C{ H} NMR (101 MHz,
Chloroformꢀd) δ 197.1, 172.0, 171.4, 160.4, 138.8, 135.8, 132.1, 131.5, 130.2, 128.12, 128.09,
1
26.8, 124.9, 122.9, 120.3, 113.5, 98.3, 86.9, 58.6, 52.2, 44.0; HRMS (ESI): m/z calcd. for
+
25
4 D
[C26H22NO , M+H] : 412.1543; found: 412.1537. Optical Rotation: [α] = +101.64 (c = 2.13,
MeOH). The absolute configuration of 4a was assigned by analogy to 4d'. >20:1 dr. 93% ee.
HPLC condition: Chiralpak ADꢀH column, nꢀhexane/iꢀPrOH = 80:20, flow rate = 1.0 mL/min,
wavelength = 254 nm, t = 11.4 min (major), t = 15.5 min (minor)]
[
R
R
Methyl
(2S,4'S,5'R)ꢀ5'ꢀbenzylꢀ5ꢀmethoxyꢀ3ꢀoxoꢀ4'ꢀphenylꢀ4',5'ꢀdihydroꢀ3Hꢀspiro
o
[
benzofuranꢀ2,3'ꢀpyrrole]ꢀ5'ꢀcarboxylate (4b). White solid, M.P. 81ꢀ82 C, R
f
= 0.3 (silica gel,
1
petroleum ether: EtOAc = 5:1). 43.2 mg, 99% yield. H NMR (400 MHz, Chloroformꢀd) δ 7.68 (s,
1H), 7.49 (d, J = 8.6 Hz, 1H), 7.39 – 7.37 (m, 2H), 7.23 (ddd, J = 20.8, 13.8, 6.4 Hz, 8H), 6.62 (dt,
J = 7.3, 3.6 Hz, 1H), 6.58 (d, J = 1.5 Hz, 1H), 4.00 (s, 1H), 3.87 (s, 3H), 3.61 (s, 3H), 3.07 (d, J =
1
3
1
13.4 Hz, 1H), 2.95 (d, J = 13.4 Hz, 1H); C{ H} NMR (101 MHz, Chloroformꢀd) δ 194.4, 173.9,
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72.1, 168.9, 160.9, 135.9, 132.3, 131.5, 130.2, 128.12, 128.08, 128.0, 126.8, 125.9, 113.3, 112.6,
+
99.1, 96.3, 86.9, 58.4, 56.0, 52.2, 44.0; HRMS (ESI): m/z calcd. for [C27
H
23NNaO
5
, M+Na] :
25
464.1468; found: 464.1469. Optical Rotation: [α]
D
= +103.02 (c = 0.28, MeOH). The absolute
1
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configuration of 4b was assigned by analogy to 4d'. 29:1 dr. 93% ee. [HPLC condition: Chiralpak
R
ADꢀH column, nꢀhexane/iꢀPrOH = 80:20, flow rate = 1.0 mL/min, wavelength = 254 nm, t =16.1
min (major), t = 18.4 min (minor)]
R
Methyl (2S,4'S,5'R)ꢀ5'ꢀbenzylꢀ6ꢀbromoꢀ3ꢀoxoꢀ4'ꢀphenylꢀ4',5'ꢀdihydroꢀ3Hꢀspiro[benzofuranꢀ
o
2
,3'ꢀpyrrole]ꢀ5'ꢀcarboxylate (4c). White solid, M.P. 73ꢀ75 C, R
f
= 0.5 (silica gel, petroleum
1
ether: EtOAc = 5:1). 46.6 mg, 95% yield. H NMR (400 MHz, Chloroformꢀd) δ 7.67 (s, 1H), 7.45
(d, J = 8.2 Hz, 1H), 7.38 (s, 1H), 7.34 – 7.33 (m, 2H), 7.30 – 7.28 (m, 3H), 7.24 – 7.21 (m, 4H),
7.19 – 7.15 (m, 2H), 3.99 (s, 1H), 3.60 (s, 3H), 3.06 (d, J = 13.4 Hz, 1H), 2.93 (d, J = 13.4 Hz,
13
1
1H); C{ H} NMR (101 MHz, Chloroformꢀd) δ 195.9, 171.9, 171.3, 159.8, 135.6, 133.8, 131.8,
131.4, 130.1, 128.3, 128.1, 126.9, 125.6, 119.2, 117.0, 98.9, 87.0, 58.7, 52.3, 44.0; HRMS (ESI):
+
25
m/z calcd. for [C26
100.75 (c = 0.53, MeOH). The absolute configuration of 4c was assigned by analogy to 4d'. 24:1
dr. 94% ee. [HPLC condition: Chiralpak ID column, nꢀhexane/iꢀPrOH = 90:10, flow rate = 1.0
mL/min, wavelength = 254 nm, t =43.1 min (major), t = 56.1 min (minor)]
4 D
H20BrNNaO , M+Na] : 512.0468; found: 512.0471. Optical Rotation: [α] =
+
R
R
Methyl (2S,4'S,5'R)ꢀ5'ꢀbenzylꢀ4'ꢀ(2ꢀchlorophenyl)ꢀ3ꢀoxoꢀ4',5'ꢀdihydroꢀ3Hꢀspiro[benzofuranꢀ
o
2
,3'ꢀpyrrole]ꢀ5'ꢀcarboxylate (4d). White solid, M.P. 70ꢀ71 C, R
f
= 0.4 (silica gel, petroleum
1
ether: EtOAc = 5:1). 44.1 mg, 99% yield. H NMR (400 MHz, Chloroformꢀd) δ 7.73 (s, 1H), 7.69
–
7.66 (m, 1H), 7.65 – 7.61 (m, 2H), 7.38 (dt, J = 6.2, 2.9 Hz, 1H), 7.27 – 7.16 (m, 8H), 7.10 (t, J
= 7.5 Hz, 1H), 4.91 (s, 1H), 3.66 (s, 3H), 3.13 (d, J = 13.3 Hz, 1H), 2.98 (d, J = 13.3 Hz, 1H);
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C{ H} NMR (101 MHz, Chloroformꢀd) δ 196.5, 171.3, 171.2, 160.7, 138.8, 136.4, 135.6, 132.2,
130.3, 129.96, 129.94, 129.2, 128.1, 126.9, 126.2, 125.0, 123.1, 120.2, 113.4, 98.0, 85.9, 52.6,
+
5
2.5, 43.5; HRMS (ESI): m/z calcd. for [C26
H
20ClNNaO
4
, M+Na] : 468.0973; found: 468.0970.
0
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0
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Optical Rotation: [α]
D
= +199.20 (c = 0.40, MeOH). The absolute configuration of 4d was
assigned by analogy to 4d'. 20:1 dr. 97% ee. [HPLC condition: Chiralpak ADꢀH column,
nꢀhexane/iꢀPrOH = 80:20, flow rate = 1.0 mL/min, wavelength = 254 nm, t = 15.6 min (major),
R
R
t = 24.7 min (minor)]
Methyl
(2S,4'S,5'R)ꢀ5'ꢀbenzylꢀ3ꢀoxoꢀ4'ꢀ(oꢀtolyl)ꢀ4',5'ꢀdihydroꢀ3Hꢀspiro[benzofuranꢀ2,3'ꢀ
o
pyrrole]ꢀ5'ꢀcarboxylate (4e). White solid, M.P. 67ꢀ68 C, R
f
= 0.4 (silica gel, petroleum ether:
1
EtOAc = 5:1). 42.1 mg, 99% yield. H NMR (400 MHz, Chloroformꢀd) δ 7.72 (s, 1H), 7.61 (ddd,
J = 7.3, 4.1, 1.3 Hz, 2H), 7.52 (td, J = 4.4, 2.5 Hz, 1H), 7.27 – 7.20 (m, 5H), 7.16 – 7.12 (m, 4H),
7
.08 (t, J = 7.5 Hz, 1H), 4.52 (d, J = 7.7 Hz, 1H), 3.61 (s, 3H), 3.06 (d, J = 13.4 Hz, 1H), 2.97 (d, J
13
1
= 13.4 Hz, 1H), 2.32 (s, 3H); C{ H} NMR (101 MHz, Chloroformꢀd) δ 197.4, 172.4, 171.5,
1
60.9, 138.8, 138.5, 135.9, 131.2, 130.7, 130.5, 130.3, 128.1, 127.8, 126.8, 125.3, 124.9, 122.9,
20.1, 113.5, 98.6, 86.7, 52.7, 52.3, 44.0, 20.4; HRMS (ESI): m/z calcd. for [C27
1
H
4
23NNaO ,
+
25
M+Na] : 448.1519; found: 448.1512. Optical Rotation: [α] = +142.07 (c = 0.58, MeOH). The
D
absolute configuration of 4e was assigned by analogy to 4d'. 20:1 dr. 94% ee. [HPLC condition:
Chiralpak ADꢀH column, nꢀhexane/iꢀPrOH = 90:10, flow rate = 1.0 mL/min, wavelength = 254
R R
nm, t =18.4 min (major), t = 31.4 min (minor)]
Methyl (2S,4'S,5'R)ꢀ5'ꢀbenzylꢀ4'ꢀ(3ꢀchlorophenyl)ꢀ3ꢀoxoꢀ4',5'ꢀdihydroꢀ3Hꢀspiro[benzofuranꢀ
o
2
,3'ꢀpyrrole]ꢀ5'ꢀcarboxylate (4f). White solid, M.P. 54ꢀ55 C, R = 0.4 (silica gel, petroleum ether:
f
1
EtOAc = 5:1). 43.7 mg, 98% yield. H NMR (400 MHz, Chloroformꢀd) δ 7.67 (s, 1H), 7.65 –
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.61 (m, 2H), 7.41 (s, 1H), 7.26 – 7.17 (m, 9H), 7.11 (t, J = 7.5 Hz, 1H), 3.96 (s, 1H), 3.62 (s, 3H),
13
1
3.07 (d, J = 13.3 Hz, 1H), 2.96 (d, J = 13.3 Hz, 1H); C{ H} NMR (101 MHz, Chloroformꢀd) δ
96.8, 171.9, 171.3, 160.3, 139.1, 135.5, 134.1, 134.0, 131.4, 130.2, 129.8, 129.3, 128.4, 128.2,
127.0, 124.9, 123.2, 120.1, 113.5, 97.9, 86.9, 58.0, 52.3, 44.1; HRMS (ESI): m/z calcd. for
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+
25
[
C
26
H20ClNNaO
4 D
, M+Na] : 468.0973; found: 468.0973. Optical Rotation: [α] = +196.70 (c =
0
.39, MeOH). The absolute configuration of 4f was assigned by analogy to 4d'. 18:1 dr. 88% ee.
[HPLC condition: Chiralpak ADꢀH column, nꢀhexane/iꢀPrOH = 90:10, flow rate = 1.0 mL/min,
wavelength = 254 nm, t = 21.0 min (major), t = 31.1 min (minor)]
R
R
Methyl
(2S,4'S,5'R)ꢀ5'ꢀbenzylꢀ4'ꢀ(3ꢀmethoxyphenyl)ꢀ3ꢀoxoꢀ4',5'ꢀdihydroꢀ3Hꢀspiro
o
[
benzofuranꢀ2,3'ꢀpyrrole]ꢀ5'ꢀcarboxylate (4g). Pale yellow solid, M.P. 57ꢀ59 C, R
f
= 0.3 (silica
1
gel, petroleum ether: EtOAc = 5:1). 43.2 mg, 99% yield. H NMR (400 MHz, Chloroformꢀd) δ
7
.67 (s, 1H), 7.63 (t, J = 8.6 Hz, 2H), 7.26 – 7.17 (m, 7H), 7.10 (t, J = 7.5 Hz, 1H), 6.95 (dd, J =
4.3, 1.9 Hz, 2H), 6.81 (dd, J = 8.0, 1.8 Hz, 1H), 3.97 (s, 1H), 3.76 (s, 3H), 3.62 (s, 3H), 3.12 (d, J
13
1
=
13.4 Hz, 1H), 2.98 (d, J = 13.4 Hz, 1H); C{ H} NMR (101 MHz, Chloroformꢀd) δ 197.1,
172.0, 171.4, 160.4, 159.1, 138.9, 135.8, 133.4, 130.2, 129.0, 128.1, 126.8, 124.9, 123.9, 123.0,
120.3, 117.3, 113.5, 113.4, 98.2, 86.9, 58.5, 55.2, 52.3, 43.9; HRMS (ESI): m/z calcd. for
+
25
[
C
27
H
23NNaO
5
, M+Na] : 464.1468; found: 464.1462. Optical Rotation: [α]
D
= +102.03 (c =
0
.59, MeOH). The absolute configuration of 4g was assigned by analogy to 4d'. 30:1 dr. 93% ee.
[HPLC condition: Chiralpak ADꢀH+ODꢀH column, nꢀhexane/iꢀPrOH = 90:10, flow rate = 1.0
mL/min, wavelength = 254 nm, t =43.9 min (major), t = 89.4 min (minor)]
R
R
Methyl
(2S,4'S,5'R)ꢀ5'ꢀbenzylꢀ4'ꢀ(4ꢀbromophenyl)ꢀ3ꢀoxoꢀ4',5'ꢀdihydroꢀ3Hꢀspiro
o
[benzofuranꢀ2,3'ꢀpyrrole]ꢀ5'ꢀcarboxylate (4h). White solid, M.P. 53ꢀ54 C, R
f
= 0.2 (silica gel,
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petroleum ether: EtOAc = 5:1). 48.5 mg, 99% yield. H NMR (400 MHz, Chloroformꢀd) δ 7.67 (s,
1H), 7.65 – 7.61 (m, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.27 – 7.21 (m, 5H), 7.18 (d, J = 6.6 Hz, 3H),
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.11 (t, J = 7.5 Hz, 1H), 3.95 (s, 1H), 3.61 (s, 3H), 3.06 (d, J = 13.3 Hz, 1H), 2.95 (d, J = 13.3 Hz,
0
1
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1
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8
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0
1
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
1
1H); C{ H} NMR (101 MHz, Chloroformꢀd) δ 196.9, 171.9, 171.2, 160.2, 139.0, 135.4, 133.1,
1
31.4, 131.1, 130.1, 128.2, 127.0, 124.9, 123.2, 122.6, 120.2, 113.4, 97.9, 86.8, 57.8, 52.3, 44.1;
+
HRMS (ESI): m/z calcd. for [C H BrNNaO , M+Na] : 512.0468; found: 512.0470. Optical
26 20
4
25
Rotation: [α]
analogy to 4d'. 26:1 dr. 83% ee. [HPLC condition: Chiralpak ADꢀH column, nꢀhexane/iꢀPrOH =
0:10, flow rate = 1.0 mL/min, wavelength = 254 nm, t = 19.8 min (major), t = 20.4 min
minor)]
Methyl
D
= +148.04 (c = 0.46, MeOH). The absolute configuration of 4h was assigned by
9
R
R
(
(2S,4'S,5'R)ꢀ5'ꢀbenzylꢀ4'ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀoxoꢀ4',5'ꢀdihydroꢀ3Hꢀspiro
o
[
benzofuranꢀ2,3'ꢀpyrrole]ꢀ5'ꢀcarboxylate (4i). Pale yellow solid, M.P. 69ꢀ70 C, R
f
= 0.3 (silica
1
gel, petroleum ether: EtOAc = 5:1). 43.2 mg, 99% yield. H NMR (400 MHz, Chloroformꢀd) δ
7
7
=
.68 (s, 1H), 7.65 – 7.60 (m, 2H), 7.30 (d, J = 8.8 Hz, 2H), 7.21 (ddd, J = 10.4, 7.6, 2.2 Hz, 6H),
.09 (t, J = 7.5 Hz, 1H), 6.80 (d, J = 8.8 Hz, 2H), 3.94 (s, 1H), 3.75 (s, 3H), 3.62 (s, 3H), 3.11 (d, J
1
3
1
13.4 Hz, 1H), 2.96 (d, J = 13.4 Hz, 1H); C{ H} NMR (101 MHz, Chloroformꢀd) δ 197.3,
72.1, 171.4, 160.3, 159.4, 138.8, 135.9, 132.6, 130.2, 128.1, 126.8, 124.8, 123.8, 122.9, 120.3,
13.6, 113.4, 98.2, 86.7, 58.0, 55.1, 52.2, 44.0; HRMS (ESI): m/z calcd. for [C27
1
1
5
H23NNaO ,
+
25
M+Na] : 464.1468; found: 464.1480. Optical Rotation: [α]
D
= +107.57 (c = 0.60, MeOH). The
absolute configuration of 4i was assigned by analogy to 4d'. 22:1 dr. 94% ee. [HPLC condition:
Chiralpak ADꢀH column, nꢀhexane/iꢀPrOH = 80:20, flow rate = 1.0 mL/min, wavelength = 254
nm, t
R
=25.8 min (major), t
R
= 34.4 min (minor)]
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Methyl
(2S,4'S,5'R)ꢀ5'ꢀbenzylꢀ4'ꢀ(naphthalenꢀ2ꢀyl)ꢀ3ꢀoxoꢀ4',5'ꢀdihydroꢀ3Hꢀspiro
o
[benzofuranꢀ2,3'ꢀpyrrole]ꢀ5'ꢀcarboxylate (4j). White solid, M.P. 100ꢀ101 C, R
f
= 0.4 (silica gel,
1
petroleum ether: EtOAc = 5:1). 45.2 mg, 98% yield. H NMR (400 MHz, Chloroformꢀd) δ 7.86 (s,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
6
7
8
9
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1
2
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4
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6
7
8
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0
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7
8
9
0
1H), 7.77 (dd, J = 13.7, 4.8 Hz, 4H), 7.59 (dd, J = 7.0, 5.4 Hz, 2H), 7.52 (d, J = 8.5 Hz, 1H), 7.46
(dd, J = 6.0, 3.2 Hz, 2H), 7.26 – 7.16 (m, 6H), 7.05 (t, J = 7.4 Hz, 1H), 4.22 (s, 1H), 3.63 (s, 3H),
1
3
1
3
1
1
.13 – 3.05 (m, 2H); C{ H} NMR (101 MHz, Chloroformꢀd) δ 197.2, 172.2, 171.5, 160.6, 138.9,
35.8, 133.0, 132.8, 131.0, 130.2, 129.8, 128.9, 128.1, 127.5, 127.4, 126.8, 126.3, 126.1, 124.9,
4
23.0, 120.2, 113.4, 98.5, 87.3, 58.9, 52.3, 44.2; HRMS (ESI): m/z calcd. for [C30H23NNaO ,
+
25
M+Na] : 484.1519; found: 484.1518. Optical Rotation: [α]
D
= +193.18 (c = 0.62, MeOH). The
absolute configuration of 4j was assigned by analogy to 4d'. 23:1 dr. 93% ee. [HPLC condition:
Chiralpak ADꢀH column, nꢀhexane/iꢀPrOH = 90:10, flow rate = 1.0 mL/min, wavelength = 254
R R
nm, t =42.0 min (minor), t = 47.1 min (major)]
Methyl (2S,4'S,5'R)ꢀ5'ꢀbenzylꢀ4'ꢀ(1Hꢀindolꢀ3ꢀyl)ꢀ3ꢀoxoꢀ4',5'ꢀdihydroꢀ3Hꢀspiro[benzofuranꢀ
o
2
,3'ꢀpyrrole]ꢀ5'ꢀcarboxylate (4k). Yellow solid, M.P. 118ꢀ120 C, R
f
= 0.4 (silica gel, petroleum
1
ether: EtOAc = 2:1). 44.2 mg, 98% yield. H NMR (400 MHz, Chloroformꢀd) δ 8.26 (s, 1H), 7.77
(
s, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.55 – 7.52 (m, 2H), 7.29 – 7.27 (m, 2H), 7.24 – 7.10 (m, 8H),
7
1
1
.04 (t, J = 7.4 Hz, 1H), 4.48 (s, 1H), 3.61 (s, 3H), 3.25 (d, J = 13.5 Hz, 1H), 2.97 (d, J = 13.5 Hz,
13
1
H); C{ H} NMR (101 MHz, Chloroformꢀd) δ 197.4, 172.1, 171.4, 160.4, 138.7, 136.1, 135.2,
30.2, 128.2, 128.1, 126.7, 125.0, 124.75, 122.8, 122.3, 120.6, 120.0, 119.0, 113.2, 111.0, 105.7,
+
98.1, 85.5, 52.2, 50.3, 44.1; HRMS (ESI): m/z calcd. for [C28
H
22
N
2
NaO
4
, M+Na] : 473.1472;
25
D
found: 473.1472. Optical Rotation: [α]
= +92.16 (c = 0.31, MeOH). The absolute
configuration of 4k was assigned by analogy to 4d'. 8:1 dr. 94% ee. [HPLC condition: Chiralpak
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ADꢀH column, nꢀhexane/iꢀPrOH = 80:20, flow rate = 1.0 mL/min, wavelength = 254 nm, t =51.4
R
R
min (major), t = 63.9 min (minor)]
Methyl
(2S,4'S,5'R)ꢀ5'ꢀbenzylꢀ3ꢀoxoꢀ4'ꢀ(pyridinꢀ3ꢀyl)ꢀ4',5'ꢀdihydroꢀ3Hꢀspiro[benzofuranꢀ
0
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9
0
o
2,3'ꢀpyrrole]ꢀ5'ꢀcarboxylate (4l). White solid, M.P. 72ꢀ73 C, R
f
= 0.2 (silica gel, petroleum ether:
1
EtOAc = 2:1). 40.8 mg, 99% yield. H NMR (400 MHz, Chloroformꢀd) δ 8.63 (s, 1H), 8.51 (d, J
=
4.7 Hz, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.69 (s, 1H), 7.64 (dd, J = 13.4, 7.7 Hz, 2H), 7.26 – 7.10
1
3
1
(
m, 8H), 3.99 (s, 1H), 3.62 (s, 3H), 3.04 (d, J = 13.2 Hz, 1H), 2.97 (d, J = 13.2 Hz, 1H); C{ H}
NMR (101 MHz, Chloroformꢀd) δ 196.6, 171.8, 171.1, 160.1, 152.0, 149.4, 139.1, 138.9, 135.1,
30.1, 128.3, 128.2, 127.1, 125.0, 123.3, 123.1, 120.1, 113.5, 97.8, 86.8, 56.1, 52.4, 44.3; HRMS
1
+
25
(
ESI): m/z calcd. for [C25
= +184.42 (c = 0.46, MeOH). The absolute configuration of 4l was assigned by analogy to 4d'.
6:1 dr. 88% ee. [HPLC condition: Chiralpak ADꢀH column, nꢀhexane/iꢀPrOH = 80:20, flow rate
= 1.0 mL/min, wavelength = 254 nm, t = 17.3 min (major), t = 22.1 min (minor)]
21 2 4 D
H N O , M+H] : 413.1496; found: 413.1494. Optical Rotation: [α]
1
R
R
Methyl
(2S,4'R,5'R)ꢀ5'ꢀbenzylꢀ4'ꢀ(furanꢀ2ꢀyl)ꢀ3ꢀoxoꢀ4',5'ꢀdihydroꢀ3Hꢀspiro[benzofuranꢀ
o
2
,3'ꢀpyrrole]ꢀ5'ꢀcarboxylate (4m). White solid, M.P. 42ꢀ43 C, R
f
= 0.2 (silica gel, petroleum
1
ether: EtOAc = 5:1). 39.7 mg, 99% yield. H NMR (400 MHz, Chloroformꢀd) δ 7.69 – 7.63 (m,
3H), 7.38 – 7.37 (m, 1H), 7.27 – 7.12 (m, 7H), 6.34 (d, J = 3.2 Hz, 1H), 6.28 (dd, J = 3.2, 1.8 Hz,
13
1
1
H), 4.25 (s, 1H), 3.67 (s, 3H), 3.22 (d, J = 13.6 Hz, 1H), 2.97 (d, J = 13.6 Hz, 1H); C{ H}
NMR (101 MHz, Chloroformꢀd) δ 196.8, 171.9, 171.7, 160.0, 146.0, 142.9, 139.0, 135.7, 130.2,
128.1, 126.8, 124.9, 123.0, 120.1, 113.5, 111.3, 110.5, 97.2, 86.0, 52.5, 51.9, 43.5; HRMS (ESI):
+
25
m/z calcd. for [C H NNaO , M+Na] : 424.1155; found: 424.1153. Optical Rotation: [α] =
D
24
19
5
+149.00 (c = 0.30, MeOH). The absolute configuration of 4m was assigned by analogy to 4d'.
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6:1 dr. 96% ee. [HPLC condition: Chiralpak ADꢀH column, nꢀhexane/iꢀPrOH = 90:10, flow rate
= 1.0 mL/min, wavelength = 254 nm, t
R R
= 17.7 min (major), t = 26.5 min (minor)]
Methyl (2S,4'S,5'R)ꢀ5'ꢀbenzylꢀ3ꢀoxoꢀ4'ꢀ(thiophenꢀ2ꢀyl)ꢀ4',5'ꢀdihydroꢀ3Hꢀspiro[benzofuranꢀ
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7
8
9
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9
0
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2
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4
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6
7
8
9
0
f
2,3'ꢀpyrrole]ꢀ5'ꢀcarboxylate (4n). Colorless oil, R = 0.4 (silica gel, petroleum ether: EtOAc =
1
4
:1). 41.3 mg, 99% yield. H NMR (400 MHz, Chloroformꢀd) δ 7.67 (dt, J = 14.1, 5.2 Hz, 3H),
7
.28 – 7.07 (m, 9H), 6.95 (dd, J = 5.0, 3.7 Hz, 1H), 4.38 (s, 1H), 3.68 (s, 3H), 3.22 (d, J = 13.5 Hz,
1
3
1
1H), 2.97 (d, J = 13.5 Hz, 1H); C{ H} NMR (101 MHz, Chloroformꢀd) δ 196.9, 171.6, 171.4,
159.7, 139.0, 135.6, 131.6, 130.2, 130.0, 128.1, 126.9, 126.8, 126.4, 124.9, 123.2, 120.5, 113.9,
+
97.1, 85.9, 53.9, 52.4, 43.9; HRMS (ESI): m/z calcd. for [C24
H
19NNaO
4
S, M+Na] : 440.0927;
2
5
found: 440.0923. Optical Rotation: [α]
D
= +226.86 (c = 0.53, MeOH). The absolute
configuration of 4n was assigned by analogy to 4d'. 26:1 dr. 94% ee. [HPLC condition: Chiralpak
o
ADꢀH column, nꢀhexane/iꢀPrOH = 90:10, 40 C, flow rate = 1.0 mL/min, wavelength = 254 nm, t
R
R
= 18.5 min (major), t = 19.6 min (minor)]
Methyl
(2S,4'S,5'R)ꢀ5'ꢀbenzylꢀ3ꢀoxoꢀ4'ꢀferroceneꢀ4',5'ꢀdihydroꢀ3Hꢀspiro[benzofuranꢀ2,3'ꢀ
o
pyrrole]ꢀ5'ꢀcarboxylate (4o). Brown solid, M.P. 90ꢀ91 C, R
f
= 0.5 (silica gel, petroleum ether:
1
EtOAc = 5:1). 50.9 mg, 98% yield. H NMR (400 MHz, Chloroformꢀd) δ 7.87 – 7.80 (m, 2H),
7.49 (s, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.28 – 7.24 (m, 1H), 7.21 – 7.15 (m, 3H), 7.11 – 7.09 (m,
2H), 4.31 (dd, J = 2.3, 1.2 Hz, 1H), 4.24 (dt, J = 2.3, 1.2 Hz, 1H), 4.19 (td, J = 2.4, 1.2 Hz, 1H),
4.13 (dd, J = 3.5, 2.4 Hz, 1H), 3.97 (s, 1H), 3.69 (s, 3H), 3.62 (s, 5H), 2.87 (d, J = 13.8 Hz, 1H),
1
3
1
2.58 (s, 1H); C{ H} NMR (101 MHz, Chloroformꢀd) δ 198.7, 172.0, 171.8, 159.4, 139.0, 135.9,
130.3, 127.9, 126.6, 124.9, 123.3, 121.1, 113.6, 99.1, 85.9, 79.3, 70.7, 68.8, 68.5, 68.4, 67.4, 54.0,
+
52.4, 43.1; HRMS (ESI): m/z calcd. for [C30
H
25FeNNaO
4
, M+Na] : 542.1025; found: 542.1039.
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5
Optical Rotation: [α]
= +44.58 (c = 0.60, MeOH). The absolute configuration of 4o was
D
assigned by analogy to 4d'. 8:1 dr. 97% ee. [HPLC condition: Chiralpak ADꢀH column,
R R
nꢀhexane/iꢀPrOH = 95:5, flow rate = 1.0 mL/min, wavelength = 254 nm, t =16.6 min (major), t
0
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9
0
1
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9
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5
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8
9
0
= 24.4 min (minor)]
Methyl
(2S,4'S,5'R)ꢀ5'ꢀmethylꢀ3ꢀoxoꢀ4'ꢀphenylꢀ4',5'ꢀdihydroꢀ3Hꢀspiro[benzofuranꢀ2,3'ꢀ
pyrrole]ꢀ5'ꢀcarboxylate (5a). Colorless oil, R = 0.4 (silica gel, petroleum ether: EtOAc = 5:1).
f
1
3
3.2 mg, 99% yield. H NMR (400 MHz, Chloroformꢀd) δ 7.59 (dd, J = 12.4, 4.4 Hz, 2H), 7.52 (s,
1
H), 7.33 (dt, J = 5.1, 3.1 Hz, 2H), 7.21 – 7.19 (m, 3H), 7.14 (d, J = 8.3 Hz, 1H), 7.04 (t, J = 7.4
13
1
Hz, 1H), 4.16 (s, 1H), 3.80 (s, 3H), 1.52 (s, 3H); C{ H} NMR (101 MHz, Chloroformꢀd) δ 197.3,
1
72.7, 171.3, 160.0, 138.8, 132.3, 131.1, 128.1, 127.9, 124.8, 122.9, 120.4, 113.4, 98.4, 83.2, 56.7,
+
52.8, 22.6; HRMS (ESI): m/z calcd. for [C H NNaO , M+Na] : 358.1050; found: 358.1049.
2
0
17
4
25
Optical Rotation: [α]
D
= +44.41 (c = 0.51, MeOH). The absolute configuration of 5a was
assigned by analogy to 4d'. 23:1 dr. 94% ee. [HPLC condition: Chiralpak ODꢀH column,
R R
nꢀhexane/iꢀPrOH = 95:5, flow rate = 1.0 mL/min, wavelength = 254 nm, t =13.6 min (major), t
=
23.6 min (minor)]
Methyl
(2S,4'S,5'R)ꢀ5'ꢀisopropylꢀ3ꢀoxoꢀ4'ꢀphenylꢀ4',5'ꢀdihydroꢀ3Hꢀspiro[benzofuranꢀ
2
5
7
f
,3'ꢀpyrrole]ꢀ5'ꢀcarboxylate (5b). Colorless oil, R = 0.4 (silica gel, petroleum ether: EtOAc =
1
:1). 36.0 mg, 99% yield. H NMR (400 MHz, Chloroformꢀd) δ 7.58 (dd, J = 9.1, 5.7 Hz, 3H),
.39 (dd, J = 6.4, 2.9 Hz, 2H), 7.21 (dd, J = 6.9, 3.5 Hz, 3H), 7.10 – 7.04 (m, 2H), 4.14 (d, J = 9.4
Hz, 1H), 3.84 (s, 3H), 2.20 (dt, J = 13.4, 6.7 Hz, 1H), 1.12 (d, J = 6.7 Hz, 3H), 0.71 (d, J = 6.7 Hz,
13
1
3
H); C{ H} NMR (101 MHz, Chloroformꢀd) δ 197.3, 172.5, 171.4, 159.9, 138.7, 132.7, 131.3,
128.0, 127.7, 124.8, 122.8, 120.3, 113.4, 98.7, 90.4, 57.2, 52.2, 32.9, 19.0, 18.5; HRMS (ESI):
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25
m/z calcd. for [C H NNaO , M+Na] : 386.1363; found: 386.1360. Optical Rotation: [α]
=
22
21
4
D
+144.64 (c = 0.45, MeOH). The absolute configuration of 5b was assigned by analogy to 4d'. 16:1
o
dr. 94% ee. [HPLC condition: Chiralpak ADꢀH column, nꢀhexane/iꢀPrOH = 95:5, 40 C, flow rate
1
1
1
1
1
1
1
1
1
1
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5
5
5
5
5
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8
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5
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9
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2
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5
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7
8
9
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
= 1.0 mL/min, wavelength = 254 nm, t
R R
=17.1 min (major), t = 20.4 min (minor)]
Methyl (2S,4'S,5'R)ꢀ5'ꢀbutylꢀ3ꢀoxoꢀ4'ꢀphenylꢀ4',5'ꢀdihydroꢀ3Hꢀspiro[benzofuranꢀ2,3'ꢀ
pyrrole]ꢀ5'ꢀcarboxylate (5c). Colorless oil, R = 0.2 (silica gel, petroleum ether: EtOAc = 10:1).
f
1
3
2
3
7.4 mg, 99% yield. H NMR (400 MHz, Chloroformꢀd) δ 7.60 – 7.56 (m, 3H), 7.30 (dd, J = 6.5,
.9 Hz, 2H), 7.21 – 7.19 (m, 3H), 7.13 (d, J = 8.3 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 3.91 (s, 1H),
.80 (s, 3H), 1.84 (td, J = 12.6, 4.1 Hz, 1H), 1.72 – 1.64 (m, 1H), 1.61 – 1.52 (m, 1H), 1.29 – 1.18
13
1
(
m, 3H), 0.83 (t, J = 7.2 Hz, 3H); C{ H} NMR (101 MHz, Chloroformꢀd) δ 197.4, 172.6, 171.3,
159.9, 138.8, 132.0, 131.3, 128.0, 127.9, 124.8, 122.8, 120.3, 113.4, 98.2, 86.3, 57.9, 52.4, 37.4,
+
2
7.0, 23.1, 13.9; HRMS (ESI): m/z calcd. for [C23
H24NO
4
, M+H] : 378.1700; found: 378.1703.
2
5
Optical Rotation: [α]
D
= +78.46 (c = 0.50, MeOH). The absolute configuration of 5c was
assigned by analogy to 4d'. 33:1 dr. 97% ee. [HPLC condition: Chiralpak ADꢀH column,
R R
nꢀhexane/iꢀPrOH = 95:5, flow rate = 1.0 mL/min, wavelength = 254 nm, t =20.4 min (major), t
=
25.2 min (minor)]
Methyl
(2S,4'S,5'R)ꢀ5'ꢀ(3ꢀmethoxyꢀ3ꢀoxopropyl)ꢀ3ꢀoxoꢀ4'ꢀphenylꢀ4',5'ꢀdihydroꢀ3Hꢀspiro
o
[
benzofuranꢀ2,3'ꢀpyrrole]ꢀ5'ꢀcarboxylate (5d). White solid, M.P. 52ꢀ54 C, R
f
= 0.3 (silica gel,
1
petroleum ether: EtOAc = 3:1). 40.0 mg, 98% yield. H NMR (400 MHz, Chloroformꢀd) δ 7.60 –
7.54 (m, 3H), 7.29 (dd, J = 6.6, 2.9 Hz, 2H), 7.19 – 7.18 (m, 3H), 7.14 (d, J = 8.3 Hz, 1H), 7.03 (t,
J = 7.5 Hz, 1H), 3.94 (s, 1H), 3.79 (s, 3H), 3.61 (s, 3H), 2.64 (ddd, J = 16.3, 10.7, 5.5 Hz, 1H),
13
1
2.36 (ddd, J = 16.3, 10.8, 5.3 Hz, 1H), 2.12 (dddd, J = 30.0, 13.7, 10.9, 5.4 Hz, 2H); C{ H}
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5
5
5
5
5
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6
NMR (101 MHz, Chloroformꢀd) δ 197.1, 173.4, 171.9, 171.3, 161.0, 138.9, 131.4, 131.1, 128.2,
128.1, 124.8, 122.9, 120.2, 113.5, 98.0, 85.0, 57.9, 52.7, 51.6, 32.2, 29.5; HRMS (ESI): m/z calcd.
+
25
6 D
for [C23H22NO , M+H] : 408.1442; found: 408.1439. Optical Rotation: [α] = +149.47 (c =
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
0.52, MeOH). The absolute configuration of 5d was assigned by analogy to 4d'. 34:1 dr. 96% ee.
o
[
HPLC condition: Chiralpak ODꢀH column, nꢀhexane/iꢀPrOH = 90:10, 40 C, flow rate = 1.0
mL/min, wavelength = 254 nm, t =12.5 min (major), t = 28.2 min (minor)]
R
R
Methyl
(2S,4'S,5'R)ꢀ5'ꢀcyclohexylꢀ3ꢀoxoꢀ4'ꢀphenylꢀ4',5'ꢀdihydroꢀ3Hꢀspiro[benzofuranꢀ
2
1
1
f
,3'ꢀpyrrole]ꢀ5'ꢀcarboxylate (5e). Colorless oil, R = 0.2 (silica gel, petroleum ether: EtOAc =
1
0:1). 38.7 mg, 96% yield. H NMR (400 MHz, Chloroformꢀd) δ 7.60 – 7.56 (m, 2H), 7.54 (s,
H), 7.39 (dd, J = 7.4, 2.2 Hz, 2H), 7.22 – 7.20 (m, 3H), 7.12 (d, J = 8.7 Hz, 1H), 7.05 (t, J = 7.5
Hz, 1H), 4.12 (s, 1H), 3.82 (s, 3H), 2.13 (d, J = 7.2 Hz, 1H), 1.84 – 1.79 (m, 2H), 1.55 (dd, J =
13
1
2
3.7, 12.4 Hz, 2H), 1.21 – 1.15 (m, 3H), 1.00 (dddd, J = 18.3, 15.6, 9.5, 3.3 Hz, 3H); C{ H}
NMR (101 MHz, Chloroformꢀd) δ 197.4, 172.6, 171.4, 159.5, 138.7, 132.6, 131.3, 127.9, 127.7,
124.8, 122.8, 120.3, 113.4, 98.5, 90.1, 57.2, 52.2, 43.0, 29.4, 28.4, 26.5, 26.3, 26.1; HRMS (ESI):
+
25
4 D
m/z calcd. for [C25H26NO , M+H] : 404.1856; found: 404.1857. Optical Rotation: [α] =
+
168.75 (c = 0.37, MeOH). The absolute configuration of 5e was assigned by analogy to 4d'. 17:1
dr. 97% ee. [HPLC condition: Chiralpak ADꢀH column, nꢀhexane/iꢀPrOH = 90:10, flow rate = 1.0
mL/min, wavelength = 254 nm, t =13.8 min (major), t = 31.1 min (minor)]
R
R
Methyl
(2S,4'S,5'R)ꢀ5'ꢀallylꢀ3ꢀoxoꢀ4'ꢀphenylꢀ4',5'ꢀdihydroꢀ3Hꢀspiro[benzofuranꢀ2,3'ꢀ
o
pyrrole]ꢀ5'ꢀcarboxylate (5f). White solid, M.P. 61ꢀ63 C, R
f
= 0.2 (silica gel, petroleum ether:
1
EtOAc = 5:1). 35.8 mg, 99% yield. H NMR (400 MHz, Chloroformꢀd) δ 7.58 (dd, J = 10.2, 5.2
Hz, 3H), 7.31 (dd, J = 6.5, 2.9 Hz, 2H), 7.21 (dd, J = 4.9, 1.5 Hz, 3H), 7.12 (d, J = 8.3 Hz, 1H),
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6
7
8
9
7
.04 (t, J = 7.5 Hz, 1H), 5.88 – 5.77 (m, 1H), 5.06 (s, 1H), 5.03 (d, J = 3.9 Hz, 1H), 3.98 (s, 1H),
13
1
3.77 (s, 3H), 2.56 (dd, J = 13.7, 7.7 Hz, 1H), 2.46 (dd, J = 13.8, 6.6 Hz, 1H); C{ H} NMR (101
MHz, Chloroformꢀd) δ 197.2, 172.0, 171.3, 160.5, 138.8, 132.5, 131.9, 131.3, 128.1, 128.0, 124.8,
122.9, 120.2, 118.6, 113.4, 98.2, 86.3, 57.6, 52.4, 42.0; HRMS (ESI): m/z calcd. for
1
1
1
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1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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3
3
3
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4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
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6
7
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9
0
1
2
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0
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7
8
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0
1
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8
9
0
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9
0
+
25
22 4 D
[C H19NNaO , M+Na] : 384.1206; found: 384.1203. Optical Rotation: [α] = +93.03 (c = 0.55,
MeOH). The absolute configuration of 5f was assigned by analogy to 4d'. 29:1 dr. 94% ee. [HPLC
condition: Chiralpak ID column, nꢀhexane/iꢀPrOH = 80:20, flow rate = 1.0 mL/min, wavelength =
254 nm, t
R R
=27.0 min (minor), t = 30.6 min (major)]
Methyl
(2S,4'S,5'S)ꢀ5'ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀoxoꢀ4'ꢀphenylꢀ4',5'ꢀdihydroꢀ3Hꢀspiro
o
[
benzofuranꢀ2,3'ꢀpyrrole]ꢀ5'ꢀcarboxylate (5g). White solid, M.P. 73ꢀ75 C, R
f
= 0.3 (silica gel,
1
petroleum ether: EtOAc = 5:1). 38.5 mg, 90% yield. H NMR (400 MHz, Chloroformꢀd) δ 7.84 (s,
1H), 7.57 (d, J = 7.8 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.02 (t, J = 7.0 Hz, 2H), 6.94 (t, J = 7.4 Hz,
3H), 6.86 (d, J = 8.8 Hz, 2H), 6.76 (d, J = 7.4 Hz, 2H), 6.72 (d, J = 8.9 Hz, 2H), 4.66 (s, 1H), 3.80
13
1
(
s, 3H), 3.77 (s, 3H); C{ H} NMR (101 MHz, Chloroformꢀd) δ 197.5, 172.3, 171.4, 162.0, 159.2,
138.6, 132.1, 131.9, 128.5, 128.2, 127.3, 127.2, 124.7, 122.7, 120.2, 113.4, 113.2, 98.6, 89.9, 58.2,
+
55.2, 53.2; HRMS (ESI): m/z calcd. for [C H NO , M+H] : 428.1492; found: 428.1495. Optical
2
6
22
5
25
Rotation: [α]
D
= +251.24 (c = 0.40, MeOH). The absolute configuration of 5g was assigned by
analogy to 4d'. 5:1 dr. 85% ee. [HPLC condition: Chiralpak ADꢀH column, nꢀhexane/iꢀPrOH =
0:10, flow rate = 1.0 mL/min, wavelength = 254 nm, t =27.6 min (minor), t = 42.3 min
(major)]
9
R
R
Methyl (2S,4'S,5'S)ꢀ4'ꢀ(4ꢀbromophenyl)ꢀ5'ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀoxoꢀ4',5'ꢀdihydroꢀ3Hꢀspiro
o
[benzofuranꢀ2,3'ꢀpyrrole]ꢀ5'ꢀcarboxylate (5h). White solid, M.P. 84ꢀ86 C, R
f
= 0.3 (silica gel,
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5
5
5
5
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6
1
petroleum ether: EtOAc = 5:1). 39.5 mg, 78% yield. H NMR (400 MHz, Chloroformꢀd) δ 7.83 (s,
1H), 7.58 – 7.51 (m, 2H), 7.09 – 7.02 (m, 3H), 6.96 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 8.8 Hz, 2H),
13
1
6
.75 (d, J = 8.9 Hz, 2H), 6.62 (d, J = 8.5 Hz, 2H), 4.60 (s, 1H), 3.80 (s, 3H), 3.78 (s, 3H); C{ H}
NMR (101 MHz, Chloroformꢀd) δ 197.2, 172.2, 171.2, 161.8, 159.4, 138.9, 133.5, 131.1, 130.4,
28.2, 128.0, 124.8, 123.0, 121.8, 120.1, 113.4, 113.3, 98.1, 89.7, 57.5, 55.3, 53.3; HRMS (ESI):
0
1
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0
1
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9
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0
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8
9
0
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6
7
8
9
0
1
+
25
m/z calcd. for [C H BrNO , M+H] : 506.0598; found: 506.0597. Optical Rotation: [α] =
D
26 21
5
+
253.39 (c = 0.53, MeOH). The absolute configuration of 5h was assigned by analogy to 4d'. 5:1
dr. 90% ee. [HPLC condition: Chiralpak ADꢀH column, nꢀhexane/iꢀPrOH = 90:10, flow rate = 1.0
mL/min, wavelength = 254 nm, t =20.9 min (major), t = 33.5 min (minor)]
R
R
General procedure for the cycloaddition of aurones with αꢀunsubstituted isocyanoacetate:
THF (1 mL) was added to a 10 mL vial charged with the precatalyst 3b (12.3 mg, 0.02 mmol) and
o
Ag
2
O (2.3 mg, 0.01 mmol). The mixture was stirred at ꢀ20 C for 5 min, then the aurore 1a (22.2
mg, 0.1 mmol) and methyl isocyanoacetate 2b (11.9 mg, 0.12 mmol) were added. The reaction
o
mixture was stirred at ꢀ20 C until 1a was consumed, and then the reaction mixture was purified
by flash chromatography on silica gel directly (eluent, petroleum ether:EtOAc = 5:1, 0.1% TEA
v/v) to afford the product 6a.
Methyl
(2S,4'S,5'R)ꢀ3ꢀoxoꢀ4'ꢀphenylꢀ4',5'ꢀdihydroꢀ3Hꢀspiro[benzofuranꢀ2,3'ꢀpyrrole]ꢀ5'ꢀ
f
carboxylate (6a). Colorless oil, R = 0.2 (silica gel, petroleum ether: EtOAc = 5:1). 26.7 mg, 83%
1
yield. H NMR (400 MHz, Chloroformꢀd) δ 7.60 (d, J = 7.7 Hz, 1H), 7.50 (dd, J = 9.2, 5.1 Hz,
2H), 7.19 – 7.16 (m, 5H), 7.03 (t, J = 7.5 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 5.22 (dd, J = 7.9, 2.9
13
1
Hz, 1H), 4.12 (d, J = 8.0 Hz, 1H), 3.77 (s, 3H); C{ H} NMR (101 MHz, Chloroformꢀd) δ 197.5,
171.3, 170.1, 161.7, 138.7, 132.1, 129.2, 128.3, 127.9, 124.5, 122.8, 120.4, 113.3, 98.0, 79.7, 54.4,
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+
5
2.7; HRMS (ESI): m/z calcd. for [C H NNaO , M+Na] : 344.0893; found: 344.0892. Optical
1
9
15
4
25
Rotation: [α]
D
= +39.6 (c = 0.50, MeOH). The absolute configuration of 6a was assigned by
analogy to 6a'. 7:1 dr. 95% ee. [HPLC condition: Chiralpak ADꢀH column, nꢀhexane/iꢀPrOH =
90:10, flow rate = 1.0 mL/min, wavelength = 254 nm, t =30.0 min (major), t = 31.7 min
minor)]
Methyl
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0
R
R
(
(2S,4'S,5'R)ꢀ4'ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀoxoꢀ4',5'ꢀdihydroꢀ3Hꢀspiro[benzofuranꢀ2,3'ꢀ
f
pyrrole]ꢀ5'ꢀcarboxylate (6b). Colorless oil, R = 0.1 (silica gel, petroleum ether: EtOAc = 5:1).
1
3
0.9 mg, 88% yield. H NMR (400 MHz, Chloroformꢀd) δ 7.60 (d, J = 7.8 Hz, 1H), 7.54 – 7.50
(
m, 2H), 7.13 (d, J = 8.7 Hz, 2H), 7.04 (t, J = 7.5 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.72 (d, J =
8
.7 Hz, 2H), 5.14 (dd, J = 8.1, 2.9 Hz, 1H), 4.07 (d, J = 8.1 Hz, 1H), 3.77 (s, 3H), 3.70 (s, 3H);
13
1
C{ H} NMR (101 MHz, Chloroformꢀd) δ 197.7, 171.3, 170.2, 161.8, 159.2, 138.8, 130.4, 124.5,
1
23.8, 122.8, 120.4, 113.8, 113.3, 97.9, 79.7, 55.1, 53.9, 52.8; HRMS (ESI): m/z calcd. for
+
25
5 D
[C20H18NO , M+H] : 352.1179; found: 352.1177. Optical Rotation: [α] = +70.2 (c = 0.31,
MeOH). The absolute configuration of 6b was assigned by analogy to 6a'. 9:1 dr. 98% ee. [HPLC
condition: Chiralpak ADꢀH column, nꢀhexane/iꢀPrOH =80:20, flow rate = 1.0 mL/min,
wavelength = 254 nm, t =20.5 min (major), t = 24.3 min (minor)]
R
R
Methyl
(2S,4'S,5'R)ꢀ4'ꢀ(4ꢀbromophenyl)ꢀ3ꢀoxoꢀ4',5'ꢀdihydroꢀ3Hꢀspiro[benzofuranꢀ2,3'ꢀ
f
pyrrole]ꢀ5'ꢀcarboxylate (6c). Colorless oil, R = 0.1 (silica gel, petroleum ether: EtOAc = 5:1).
1
3
2.8 mg, 82% yield. H NMR (400 MHz, Chloroformꢀd) δ 7.61 (d, J = 7.7 Hz, 1H), 7.57 – 7.51
(m, 2H), 7.34 (d, J = 8.3 Hz, 2H), 7.10 – 7.05 (m, 3H), 6.95 (d, J = 8.4 Hz, 1H), 5.15 (dd, J = 8.0,
13
1
2
.9 Hz, 1H), 4.07 (d, J = 8.0 Hz, 1H), 3.78 (s, 3H); C{ H} NMR (101 MHz, Chloroformꢀd) δ
197.1, 171.2, 169.8, 161.5, 139.0, 131.6, 131.2, 130.9, 124.6, 123.1, 122.1, 120.3, 113.3, 97.7,
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