Organocatalytic asymmetric one-pot sequential reaction: Synthesis of highly substituted spirocyclohexanepyrazolones with six contiguous stereogenic carbons

Article abstract of DOI:10.1016/j.tet.2014.10.038

An atom-economical synthesis of chiral polyfunctionalized spiropyrazolone derivatives based on the development of a new organocatalytic enantioselective one-pot sequential Michael/Michael/Aldol reaction of 1,3-dicarbonyl compounds with unsaturated pyrazolones and α,β-unsaturated aldehydes has been developed. The notable features of this one-pot sequential process include the generation of up to six consecutive stereogenic carbon centers including one quaternary stereocenter and five tertiary stereocenters with high enantioselectivities (up to 95% ee) and excellent diastereoselectivities (>99:1 d.r.).

Full text of DOI:10.1016/j.tet.2014.10.038

Tetrahedron 70 (2014) 9330e9336
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Organocatalytic asymmetric one-pot sequential reaction: synthesis
of highly substituted spirocyclohexanepyrazolones with six
contiguous stereogenic carbons
,
Ping Sun a, Chang-Yu Meng b, Feng Zhou a, Xin-Sheng Li a, Jian-Wu Xie a
*
a Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry and Life Science, Zhejiang Normal University,
Jinhua 321004, PR China
b Department of Chemistry and Materials, Yulin Normal University, Yulin 537000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 August 2014
Received in revised form 11 October 2014
Accepted 17 October 2014
Available online 22 October 2014
An atom-economical synthesis of chiral polyfunctionalized spiropyrazolone derivatives based on the
development of a new organocatalytic enantioselective one-pot sequential Michael/Michael/Aldol re-
action of 1,3-dicarbonyl compounds with unsaturated pyrazolones and a,b-unsaturated aldehydes has
been developed. The notable features of this one-pot sequential process include the generation of up to
six consecutive stereogenic carbon centers including one quaternary stereocenter and five tertiary
stereocenters with high enantioselectivities (up to 95% ee) and excellent diastereoselectivities (>99:1
d.r.).
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
Despite these advances, organocatalytic asymmetric methods
for the construction of highly substituted pyrazol-3-one derivatives
The construction of complex molecular architectures, especially
those with multiple stereogenic carbon atoms from simple chem-
icals, continues to be a multifaceted endeavor in both academic and
industrial domains.1 The challenge is exacerbated further when
multiple quaternary and tertiary stereocenters are adjacent. Ini-
tially, a strategy must be devised that could plausibly lead to the
target structure. The number of steps and the yield of each trans-
formation determine the efficiency of a successful synthesis. Pyr-
azol-3-one derivatives are an important class of heterocycles in
analytical, dye, biological, and pharmaceutical chemistry.2 For ex-
ample, pyrazolone-based dyes are widely used as analytical re-
agents.3 In particular, the chiral pyrazolone skeleton plays an
important role in a broad biological profile including analgesic,
antibacterial and antifungal activities,4 and anti-inflammatory ef-
fects,5 CCR3 antagonist activity,6 antitumor activity7 and anti-
ischemic effect.8 Therefore, these pyrazol-3-one derivatives have
become targets of interest in the organic synthetic community.
Recently, a few catalytic asymmetric methodologies, which include
asymmetric Michael addition,9 domino MichaeleMichael-aldol
condensation,10 double Michael reaction11 and others,12 have been
developed for the synthesis of this chiral privileged structural
motif.
with multiple contiguous stereogenic carbons still remain largely
unexplored but would be of great importance. Herein we present
such an advance and its direct application in an atom-economical
synthesis of chiral polyfunctionalized spiropyrazolone derivatives
based on the development of a new organocatalytic enantiose-
lective one-pot sequential Michael/Michael/Aldol reaction of 1,3-
dicarbonyl compounds with unsaturated pyrazolones and a,b-un-
saturated aldehydes. The notable features of this one-pot sequen-
tial process include the generation of up to six consecutive
stereogenic carbon centers including one quaternary stereocenter
and five tertiary stereocenters with high enantioselectivities (up to
95% ee) and excellent diastereoselectivities (>99:1 d.r.).
2. Results and discussion
Over the past years, asymmetric domino reactions mediated by
organocatalysts are in a way biomimetic, as this principle is used
very efficiently in the biosynthesis of complex compounds starting
from simple precursors.1,13 In addition, the generation of several
stereocenters mediated by organocatalysts can be accomplished
very easily without the problems. On the basis of our recent re-
sults,14 we hoped to expand our studies to develop an efficient
protocol for accessing functionalized spiropyrazolones with mul-
tiple contiguous stereogenic carbons from 1,3-dicarbonyl com-
pounds. We envisioned that the 1,3-dicarbonyl compounds could
* Corresponding author. Fax: þ86 579 82282610; e-mail address: xiejw@zjnu.cn
(J.-W. Xie).
http://dx.doi.org/10.1016/j.tet.2014.10.038
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

P. Sun et al. / Tetrahedron 70 (2014) 9330e9336
9331
react with the unsaturated pyrazolones, then a further Michael-
aldol reaction with the unsaturated aldehydes to furnish the de-
sired spirocyclic compounds. The proposed synthetic route is de-
scribed in Scheme 1. This one-pot sequential reaction is a three
component consecutive reaction comprising an unsaturated pyr-
and yield (82%) in the presence of 1e (20 mol %) and piperidine
while the reaction time should be extended (Table 1, entry 7).
Various solvents were screened (Table 1, entries 7e12), and ether
turned out to be optimal to give the product in higher enantio-
selectivities and yields (Table 1, entry 11). Subsequently, several
bases were also employed as additives (entries 13e15). It was
found that use of piperidine as additive provided the best results
(entry 11, 85%, >99:1 dr, 87% ee).
azolone 2a, a 1,3-dicarbonyl compound 3a, an a,b-unsaturated al-
dehyde 4a and a simple chiral bifunctional organocatalyst, which is
capable of catalyzing the one-pot sequential reaction. Firstly, the
1,3-dicarbonyl compound 3a adds to the unsaturated pyrazolone 2a
in a Michael-type reaction. Subsequently, the Michael reaction and
intramolecular aldol reaction happen to produce the chiral poly-
functionalized spiropyrazolone derivative 5a.
To test the substrate scope of the one-pot sequential reaction,
the reaction of various unsaturated pyrazolones 2 and
a,b-un-
saturated aldehydes 4 was studied under the optimized conditions
using 20 mol % of bifunctional thiourea 1e as the catalyst. The re-
sults are summarized in Table 2.
As illustrated in Table 2, for the one-pot sequential reaction of
ethyl acetoacetate 3 and unsaturated pyrazolones 2, high diaster-
eoselectivities and enantioselectivities were achieved with
a,b-
unsaturated aldehydes 4 bearing various -aryl substitutions or
b
heteroaryl substitutions (Table 2). It appeared that the substituents’
electronics have a minimal impact on efficiencies, enantiose-
lectivities, and diastereoselectivities of the one-pot sequential re-
action when the ethyl acetoacetate 3 was used as Michael donor.
The position of the substituent (ortho, meta, para) on the aromatic
enal has an effect on both enantioselectivities and diaster-
eoselectivities (Table 2, 5ce5e). High diastereoselectivity and
enantioselectivity were achieved when electron-denoting sub-
Scheme 1. Possible reaction pathway.
stituent on the ortho position (Table 2, 5d), while a,b-unsaturated
aldehydes 4 with electron-withdrawing substituent on the para
position affords the spiropyrazolone derivative 5g with excellent
Bifunctional thioureas 1aee have appeared to be efficient
organocatalysts for asymmetric additions (Fig. 1).15 We envisioned
that the bifunctional organocatalysts 1aee would be efficient
catalysts for the one-pot sequential reaction. Initially, we exam-
ined the feasibility of the proposed one-pot sequential reaction by
choosing the unsaturated pyrazolone (2a), the ethyl acetoacetate
3, and the cinnamaldehyde 4a as the model substrates to react in
the presence of bifunctional organocatalyst 1a in toluene at 10 ꢀC
(Table 1). After the substrate 2a completely disappeared (36 h,
monitored by TLC), the electrophilic (E)-cinnamaldehyde was
then added to the reaction system. However, no product 5a was
obtained, but the pyrazolone derivative IA was isolated in 87%
yield. When achiral piperidine (Pip.) was used as additive, poly-
functionalized spiropyrazolone derivative 5a was obtained with
high diastereoselectivity and good yield, while the ee was very
low (Table 1, entry 1). Then the organocatalysts were screened by
using the piperidine as an additive (Table 1, entries 1e6).When the
reaction was catalyzed by the Takemoto’s catalyst 1b, the chiral
4aa was formed in moderate yield and 47% ee (Table 1, entry 2).
Subsequently, we were pleased to find that the bifunctional
thioureas 1c, 1d, and 1e, which are readily available from natural
cinchona alkaloids, exhibited a good catalytic activity when the
reaction was carried out at 10 ꢀC (entries 3e5). To our surprise, the
organocatalyst 1e, derived from quinine, was proved to be supe-
rior to 1c in this one-pot sequential reaction, and products were
obtained with 50% ee (Table 1, entry 5). By lowing the temperature
to ꢁ20 ꢀC, the enantioselectivity dramatically increased, (73% ee)
results. Interestingly, for the a,b-unsaturated aldehyde 4l having
strong electron-withdrawing substituent on the aryl ring, spi-
ropyrazolone derivative 5l was obtained with excellent enantio-
selectivity in good yield when the reaction was carried out at
ꢁ10 ꢀC. Moreover, using
L
-proline as a additive, the enantiose-
lectivity was also quite satisfying when
b
-alkyl -unsaturated
a,b
aldehyde 4n was applied (Table 2, 5n), and good yield was ob-
served. To extend the scope of the consecutive reaction further,
unsaturated pyrazolones 2bec were utilized as Michael acceptors
in the one-pot sequential reaction in the presence of 1e-Pip. It
appeared that the substituents’ electronics have an impact on ef-
ficiencies, enantioselectivities, but no effect on the diaster-
eoselectivities (Table 2, 5oe5p).
To determine the absolute configuration of spiropyrazolone
derivatives 5, single crystal suitable for X-ray crystallographic
analysis was fortunately obtained from enantiopure 5j that bears
a bromine atom. As shown in Fig. 2, it composes of (C2R, C3R, C4S,
C5R, C6R, C7S) configuration.
Having established the catalytic asymmetric one-pot sequential
reaction of 1,3-dicarbonyl compounds with unsaturated pyr-
azolones and unsaturated aldehydes, the synthetic utilities of
these previously undocumented multi-functionalized spiropyr-
azolone derivatives were further explored (Scheme 2). The ob-
tained chiral polyfunctionalized spiropyrazolone derivatives are
useful intermediates in organic synthesis. The chiral pyran unit is
the core structure in a number of biologically active natural
products and a new heterocyclic pyran ring was constructed easily
from the chiral polyfunctionalized spiropyrazolone 5a. Firstly, the
Knovevenagel condensation happened when the poly-
functionalized spiropyrazolone 5a was treated with malononitrile
in DCM under basic conditions, and the compound 6a was ob-
tained in high yield (95%). Subsequently, the compound 6a was
treated with sodium hydride and the chiral polyfunctionalized
spiropyrazolone 7a, which contained a pyran ring was obtained in
good yield with complete retention of stereochemistry. In addi-
tion, the spiropyrazolone 5a was readily converted to the spi-
ropyrazolone 8a in good yield without any effect on the ee by
elimination of water.
Fig. 1. Bifunctional organocatalysts 1aee.

9332
P. Sun et al. / Tetrahedron 70 (2014) 9330e9336
Table 1
Screening studies of organocatalytic one-pot sequential reaction of the unsaturated pyrazolone (2a) with the ethyl acetoacetate 3 and the cinnamaldehyde 4aa
Entry
Catalyst
Additive
Solvent
Yieldb (%)
Drc
eec(%)
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
1e
1e
1e
1e
1e
1e
1e
1e
1e
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Et3N
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DCM
Toluene
Chloroform
Ether
THF
Ether
75
62
60
63
78
55
82
45
39
83
85
77
68
67
14
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
15
47
10
13
50
14
73
52
45
57
87
26
82
84
79
7d
8d
9d
10d
11d
12d
13e
14
15
Ether
Ether
Na2CO3
a
Unless otherwise noted, reactions performed with 0.1 mmol of 2a, 0.12 mmol of 3, and 20 mol % of 1 in 1 mL solvent, the mixture was stirred at 10 ꢀC. After compound 2a
was disappeared (monitored by TLC), the substrate 4a and 20 mol % piperidine were added, and stirred for 20 min.
b
Isolated yield.
c
Dr was determined by the chiral HPLC analysis.
d
ꢁ20 ꢀC.
e
ꢁ25 ꢀC.
3. Conclusion
(J) are given in Hz. The ESI-HRMS spectrometer was measured with
a Finnigan LCQDECA ion trap mass spectrometer. The optical rota-
tions were measured at 589 nm at 20 ꢀC. The enantiomeric excess
was determined by HPLC analysis on chiral Chiralpak columns. The
commercial grade solvents were dried and purified by standard
procedures as specified in Purification of Laboratory Chemicals.
In summary, we have developed a new and facile methodology
to perform asymmetric organocatalytic one-pot sequential Mi-
chael/Michael/Aldol reaction of 1,3-dicarbonyl compounds with
unsaturated pyrazolones and unsaturated aldehydes. The one-pot
procedure is initiated by a bifunctional thiourea-amine-catalyzed
asymmetric Michael addition, followed by an amine catalyzed
Michael/aldol addition sequence through iminium/enamine acti-
vation modes, to afford the highly substituted spirocyclohex-
anepyrazolones bearing hydroxy, ester, and aldehyde functional
groups in moderate to good yields with perfect atom economy and
high levels of chemo-, regio-, and stereoselectivities. Notably, this
one-pot sequential process include the generation of up to six
consecutive stereogenic carbon centers including one quaternary
stereocenter and five tertiary stereocenters. In addition, the un-
documented multi-functionalized spiropyrazolone derivatives
were readily converted to other complex heterocyclic molecular
architectures. Further efforts toward the development of enantio-
selective approaches as well as the application of this methodology
to the synthesis of architecturally interesting pyrazolone alkaloids
are currently in progress in our laboratory.
4.2. Asymmetric one-pot sequential Michael/Michael/Aldol
reaction
4.2.1. General procedure. The reactions performed with 0.1 mmol
of 2a, 0.12 mmol of 3, and 20 mol % of 1e in 1 mL ether, the mixture
was stirred at ꢁ20 ꢀC. After compound 2a was disappeared (mon-
itored by TLC, about 30 h), substrate 4a and 20 mol % piperidine was
added, and stirred for 20 min. After that, the reaction mixture was
concentrated and the residue was purified by flash chromatography
on silica gel (petroleum ether/ethyl acetate¼5:1) to give 5a.
4.2.2. (5R,6R,7S,8R,9R,10S)-Ethyl-9-formyl-8-hydroxy-1,8-dimethyl-
4-oxo-3,6,10-triphenyl-2,3-diazaspiro[4.5]dec-1-ene-7-carboxylate
(5a). Pale yellow solid, mp: 112.4e113.7 ꢀC; 85% yield; 1H NMR
(600 MHz, CDCl3)
d
(ppm) 9.54 (d, J¼4.6 Hz, 1H), 7.31 (d, J¼7.6 Hz,
2H), 7.28e7.26 (m, 3H), 7.21 (d, J¼7.2 Hz, 2H), 7.18e7.11 (m, 8H),
4.22 (d, J¼12.2 Hz, 1H), 4.17 (d, J¼12.3 Hz, 1H), 4.11 (s, 1H), 3.90 (d,
J¼12.3 Hz, 1H), 3.83e3.75 (m, 3H), 2.18 (s, 3H), 1.45 (s, 3H), 0.72 (t,
4. Experimental section
4.1. General methods
J¼7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3)
d (ppm) 203.2, 174.8,
173.4, 160.4, 137.0, 135.5, 135.4, 129.0, 128.7, 128.6, 128.5, 128.4,
125.9, 120.4, 100.1, 72.1, 61.9, 61.0, 55.2, 50.2, 46.4, 43.8, 27.3, 14.4,
13.5; IR (KBr) cmꢁ1 3421, 3118, 2917, 1728, 1615, 1692, 1180, 757,
The NMR spectra were recorded with tetramethylsilane as the
internal standard. The thin layer chromatography (TLC) was per-
formed on glass-backed silica plates. The column chromatography
was performed using silica gel (160e200 mesh) eluting with ethyl
acetate and petroleum ether. The 1H NMR spectra were recorded at
400 MHz, and the 13C NMR spectra were recorded at 100 MHz.
689; ESI-HRMS: calcd for
C
32H32N2O5þNa 547.2203, found
12
547.2201; [
a
]
D
¼25.0 (c 0.32, CH2Cl2), 87% ee; The enantiomeric
ratio was determined by HPLC on Chiralpak OD column (1.5% 2-
propanol/hexane, 1 mL/min), tmajor¼20.26 min, tminor¼26.05 min.
Chemical shifts (d) are reported in ppm downfield from CDCl3
(
d
¼7.27 ppm) for 1H NMR and relative to the central CDCl3 reso-
4.2.3. (5R,6R,7S,8R,9R,10S)-Ethyl-9-formyl-8-hydroxy-1,8-dimethyl-
4-oxo-3,6-diphenyl-10-(p-Methoxypheny)-2,3-diazaspiro[4.5]dec-1-
nance (
d
¼77.0 ppm) for 13C NMR spectroscopy. Coupling constants

P. Sun et al. / Tetrahedron 70 (2014) 9330e9336
9333
Table 2
Asymmetric one-pot sequential reaction of 1,3-dicarbonyl compounds with unsaturated pyrazolones and unsaturated aldehydesaec
ene-7-carboxylate (5b). Pale yellow solid, mp: 132.1e133.8 ꢀC; 62%
yield. 1H NMR (600 MHz, CDCl3)
d
(ppm) 9.52 (d, J¼4.7 Hz, 1H),
7.36e7.25 (m, 5H), 7.21e7.09 (m, 7H), 6.67 (d, J¼8.7 Hz, 2H), 4.16
(dd, J¼21.3, 12.2 Hz, 2H), 4.09 (s, 1H), 3.89 (d, J¼12.3 Hz, 1H),
3.82e3.72 (m, 3H), 3.66 (s, 3H), 2.17 (s, 3H), 1.43 (s, 3H), 0.71 (t,
J¼7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3)
d (ppm) 203.4, 174.8,
173.5, 160.5, 159.4, 137.1, 135.6, 128.7, 128.6, 128.5, 128.4, 127.2,
125.9, 120.4, 114.3, 100.1, 72.1, 62.1, 61.0, 55.3, 55.2, 50.1, 46.3, 43.0,
27.3, 14.3, 13.5; IR (KBr) cmꢁ1 3420, 2923, 1725, 1686, 1615, 1402,
1180, 757, 624; ESI-HRMS: calcd for C33H34N2O6þNa 577.2308,
Fig. 2. Molecular structure of enantiopure 5j.
Scheme 2. Transformation of spiropyrazolone 5a.

9334
P. Sun et al. / Tetrahedron 70 (2014) 9330e9336
12
found 577.2308; [
a]
¼46.3 (c 0.32, CH2Cl2), 86% ee; The enantio-
61.9, 61.1, 55.3, 50.1, 46.2, 42.9, 27.3, 14.3, 13.5; IR (KBr) cmꢁ1 3408,
D
meric ratio was determined by HPLC on Chiralpak OD column (1.5%
2-propanol/hexane, 1 mL/min), tmajor¼27.68 min, tminor¼40.67 min.
3130, 1719, 1680, 1615, 1399, 1038, 707, 689; ESI-HRMS: calcd for
12
C
32H31FN2O5þNa 562.2109, found 562.2109; [
a]
¼46.3 (c 0.32,
D
CH2Cl2), 84% ee; The enantiomeric ratio was determined by HPLC
on Chiralpak IC column (10% 2-propanol/hexane, 1 mL/min),
tmajor¼7.18 min, tminor¼11.73 min.
4.2.4. (5R,6R,7S,8R,9R,10S)-Ethyl-9-formyl-8-hydroxy-1,8-dimethyl-
4-oxo-3,6-diphenyl-10-(p-tolyl)-2,3-diazaspiro[4.5]dec-1-ene-7-
carboxylate (5c). Pale yellow solid, mp: 127.8e129.2 ꢀC; 87% yield.
1H NMR (600 MHz, CDCl3)
d
(ppm) 9.55 (d, J¼4.7 Hz, 1H), 7.40e7.29
4.2.8. (5R,6R,7S,8R,9R,10S)-Ethyl-10-(4-chlorophenyl)-9-formyl-8-
hydroxy-1,8-dimethyl-4-oxo-3,6-diphenyl-2,3-diazaspiro[4.5]dec-1-
ene-7-carboxylate (5g). Pale yellow solid, mp: 126.3e127.5 ꢀC; 76%
(m, 5H), 7.24e7.09 (m, 7H), 6.98 (d, J¼8.1 Hz, 2H), 4.20 (dd, J¼18.2,
12.2 Hz, 2H), 4.12 (s, 1H), 3.92 (d, J¼12.3 Hz, 1H), 3.81 (m, 3H), 2.20
(d, J¼3.2 Hz, 6H), 1.46 (s, 3H), 0.74 (t, J¼7.1 Hz, 3H); 13C NMR
yield. 1H NMR (600 MHz, CDCl3)
d
(ppm) 9.55 (d, J¼4.5 Hz, 1H),
(150 MHz, CDCl3)
d
(ppm) 203.4, 174.8, 173.5, 160.5, 138.2, 137.1,
7.35e7.27 (m, 5H), 7.23e7.10 (m, 9H), 4.17 (dd, J¼31.6, 12.2 Hz, 2H),
135.6, 132.2, 129.7, 128.7, 128.5, 128.4, 125.8, 120.4, 72.1, 62.0, 61.0,
4.12 (s, 1H), 3.88 (d, J¼12.3 Hz, 1H), 3.78 (m, 3H), 2.17 (s, 3H), 1.45 (s,
55.2, 50.1, 46.4, 43.5, 27.3, 21.1, 14.4, 13.5; IR (KBr) cmꢁ1 3417, 3118,
3H), 0.71 (t, J¼7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3)
d (ppm) 202.8,
1728, 1615, 1692, 1399, 1038, 757, 689,; ESI-HRMS: calcd for
174.7, 173.3, 160.2, 136.9, 135.3, 134.4, 134.1, 129.2, 128.8, 128.6,
128.5, 126.1, 120.3, 100.1, 72.0, 61.8, 61.1, 55.2, 50.1, 46.3, 43.1, 27.3,
14.3, 13.5; IR (KBr) cmꢁ1 3414, 2923, 1731, 1692, 1612, 1402, 1095,
12
C
33H34N2O5þNa 561.2361, found 561.2360; [
a
]
¼27.8 (c 0.32,
D
CH2Cl2), 88% ee; The enantiomeric ratio was determined by HPLC
on Chiralpak OD column (1.5% 2-propanol/hexane, 1 mL/min),
tmajor¼17.88 min, tminor¼23.94 min.
763; ESI-HRMS: calcd for
C
32H31ClN2O5þNa 581.1814, found
12
581.1814; [
a
]
¼53.7 (c 0.32, CH2Cl2), 91% ee; The enantiomeric
D
ratio was determined by HPLC on Chiralpak OD column (1.5% 2-
4.2.5. (5S,6R,7S,8R,9R,10S)-Ethyl-9-formyl-8-hydroxy-1,8-dimethyl-
4-oxo-3,6-diphenyl-10-(o-tolyl)-2,3-diazaspiro[4.5]dec-1-ene-7-
carboxylate (5d). Pale yellow solid, mp: 118.9e120.0 ꢀC; 41% yield.
propanol/hexane, 1 mL/min), tmajor¼21.46 min, tminor¼29.58 min.
4.2.9. (5S,6R,7S,8R,9R,10R)-Ethyl-10-(2-chlorophenyl)-9-formyl-8-
hydroxy-1,8-dimethyl-4-oxo-3,6-diphenyl-2,3-diazaspiro[4.5]dec-1-
ene-7-carboxylate (5h). Pale yellow solid, mp: 113.7e114.6 ꢀC; 46%
1H NMR (600 MHz, CDCl3)
d
(ppm) 9.53 (d, J¼4.7 Hz, 1H), 7.46e7.41
(m, 2H), 7.35e7.27 (m, 4H), 7.20e7.15 (m, 5H), 7.08 (d, J¼7.4 Hz, 1H),
7.02 (t, J¼7.0 Hz, 1H), 6.93 (t, J¼7.4 Hz, 1H), 4.65 (d, J¼11.9 Hz, 1H),
4.23 (d, J¼12.3 Hz,1H), 4.15 (d, J¼1.6 Hz,1H), 3.93 (d, J¼12.3 Hz,1H),
3.86 (ddd, J¼11.9, 4.7, 1.6 Hz, 1H), 3.82e3.75 (m, 2H), 2.51 (s, 3H),
2.07 (s, 3H), 1.43 (s, 3H), 0.73 (t, J¼7.1 Hz, 3H); 13C NMR (150 MHz,
yield. 1H NMR (600 MHz, CDCl3)
d
(ppm) 9.58 (d, J¼4.9 Hz, 1H), 7.44
(d, J¼7.9 Hz, 2H), 7.39e7.29 (m, 5H), 7.23e7.12 (m, 5H), 7.08 (t,
J¼7.3 Hz, 1H), 7.01 (t, J¼7.6 Hz, 1H), 5.11 (d, J¼12.0 Hz, 1H), 4.24e4.13
(m, 2H), 3.97 (d, J¼12.3 Hz, 1H), 3.81e3.70 (m, 2H), 3.68 (dd, J¼12.0,
3.7 Hz, 1H), 2.21 (s, 3H), 1.42 (s, 3H), 0.73 (t, J¼7.1 Hz, 1H); 13C NMR
DCl3)
d (ppm) 203.3, 174.6, 174.1, 160.5, 143.1, 137.2, 135.4, 131.3,
128.8, 128.5, 128.4, 128.0, 127.5, 127.0, 126.0, 120.4, 72.0, 61.7, 61.0,
(150 MHz, CDCl3) d (ppm) 203.4,174.7, 173.8,161.2, 137.1, 135.2,134.0,
57.0, 50.1, 47.3, 38.7, 27.4, 20.5, 14.3, 13.6; IR (KBr) cmꢁ1 3417, 2917,
133.8, 130.3, 129.6, 129.4, 128.9, 128.6, 128.5, 127.8, 126.1, 120.2, 72.0,
1728, 1692, 1615, 1399, 1186, 757, 683; ESI-HRMS: calcd for
61.3, 61.1, 57.2, 50.0, 47.0, 38.7, 27.3, 14.5, 13.5; IR (KBr) cmꢁ1 3418,
12
C
33H34N2O5þNa 561.2360, found 561.2360; [
a
]
D
¼ꢁ60.0 (c 0.32,
3120, 1751, 1691, 1618, 1417, 1181, 767, 683; ESI-HRMS: calcd for
12
CH2Cl2), 95% ee; The enantiomeric ratio was determined by HPLC
on Chiralpak IC column (10% 2-propanol/hexane, 1 mL/min),
tmajor¼16.52 min, tminor¼29.15 min.
C
32H31ClN2O5þNa 581.1814, found 581.1814; [
a
]
¼ꢁ9.3 (c 0.32,
D
CH2Cl2); The major diastereomer: 82% ee; The enantiomeric ratio
was determined by HPLC on Chiralpak IC column (10% 2-propanol/
hexane, 1 mL/min), tmajor¼21.90 min, tminor¼31.86 min. The minor
diastereomer: 80% ee, tmajor¼13.819 min, tminor¼11.512 min.
4.2.6. (5R,6R,7S,8R,9R,10S)-Ethyl-9-formyl-8-hydroxy-1,8-dimethyl-
4-oxo-3,6-diphenyl-10-(m-tolyl)-2,3-diazaspiro[4.5]dec-1-ene-7-
carboxylate (5e). Pale yellow solid, mp: 109.1e110.6 ꢀC; 47% yield.
4.2.10. (5R,6R,7S,8R,9R,10S)-Ethyl-10-(3-chlorophenyl)-9-formyl-8-
hydroxy-1,8-dimethyl-4-oxo-3,6-diphenyl-2,3-diazaspiro[4.5]dec-1-
ene-7-carboxylate (5i). Pale yellow solid, mp: 114.2e115.9 ꢀC; 59%
1H NMR (600 MHz, CDCl3)
d
(ppm) 9.43 (d, J¼4.8 Hz, 1H), 7.42e7.27
(m, 5H), 7.26e7.24 (m,1H), 7.20e7.03 (m, 6H), 6.78 (d, J¼8.1 Hz,1H),
6.71 (t, J¼7.6 Hz, 1H), 5.05 (d, J¼12.3 Hz, 1H), 4.19 (d, J¼12.3 Hz, 1H),
4.13 (d, J¼1.6 Hz,1H), 3.95 (d, J¼12.3 Hz,1H), 3.85 (s, 3H), 3.79e3.75
(m, 1H), 3.73e3.69 (m, 1H), 3.66 (ddd, J¼12.3, 4.8, 1.6 Hz, 1H), 2.15
(s, 3H), 1.42 (s, 3H), 0.72 (t, J¼7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3)
yield. 1H NMR (600 MHz, CDCl3)
d
(ppm) 9.58 (d, J¼4.3 Hz, 1H), 7.31
(q, J¼8.5 Hz, 5H), 7.25 (s, 1H), 7.19e7.08 (m, 8H), 4.17 (dd, J¼16.3,
12.2 Hz, 2H), 4.12 (s, 1H), 3.87 (d, J¼12.3 Hz, 1H), 3.83e3.74 (m, 3H),
2.17 (s, 3H), 1.46 (s, 3H), 0.71 (t, J¼7.1 Hz, 3H); 13C NMR (150 MHz,
d
(ppm) 204.0, 174.9, 174.0, 161.5, 156.5, 137.1, 135.7, 129.3, 129.1,
CDCl3) d (ppm) 202.7, 174.7, 173.2, 160.2, 137.7, 136.8, 135.3, 130.3,
128.8, 128.5, 128.3, 125.8, 123.9, 121.3, 120.4, 110.6, 72.3, 61.7, 60.9,
128.8, 128.7, 128.6, 128.5, 126.1, 120.6, 72.0, 61.6, 61.1, 55.1, 50.0,
56.3, 55.4, 50.2, 46.7, 33.8, 27.4, 13.9, 13.5; IR (KBr) cmꢁ1 3423, 3114,
46.2, 43.4, 27.3, 14.3, 13.5; IR (KBr) cmꢁ1 3426, 3115, 2982, 1728,
1727, 1614, 1697, 1401, 1035, 747, 686; ESI-HRMS: calcd for
1689, 1598, 1400, 1185, 1095, 765, 704, 684; ESI-HRMS: calcd for
12
12
C
33H34N2O5þNa 561.2360, found 561.2359; [
a
]
¼47.9 (c 0.32,
C
18H13NO6þNa 581.1814, found 581.1814;
[
a
]
¼40.5(c 0.32,
D
D
CH2Cl2); The major diastereomer: 85% ee; The enantiomeric ratio
was determined by HPLC on Chiralpak IC column (10% 2-propanol/
hexane, 1 mL/min), tmajor¼9.59 min, tminor¼21.26 min; The minor
diastereomer: 68% ee, tmajor¼13.817 min, tminor¼8.300 min.
CH2Cl2), 82% ee; The enantiomeric ratio was determined by HPLC
on Chiralpak OD column (1.5% 2-propanol/hexane, 1 mL/min),
tmajor¼21.91 min, tminor¼27.10 min.
4.2.11. (5R,6R,7S,8R,9R,10S)-Ethyl-10-(4-bromophenyl)-9-formyl-8-
hydroxy-1,8-dimethyl-4-oxo-3,6-diphenyl-2,3-diazaspiro[4.5]dec-1-
ene-7-carboxylateyield (5j). Pale yellow solid, mp: 136.3e137.2 ꢀC;
4.2.7. (5R,6R,7S,8R,9R,10S)-Ethyl-10-(4-fluorophenyl)-9-formyl-8-
hydroxy-1,8-dimethyl-4-oxo-3,6-diphenyl-2,3-diazaspiro[4.5]dec-1-
ene-7-carboxylate (5f). Pale yellow solid, mp: 135.4e136.9 ꢀC; 63%
83% yield. 1H NMR (600 MHz, CDCl3)
d
(ppm) 9.55 (d, J¼4.5 Hz, 1H),
yield. 1H NMR (600 MHz, CDCl3)
d
(ppm) 9.56 (d, J¼4.6 Hz, 1H),
7.38e7.27 (m, 6H), 7.25e7.02 (m, 8H), 4.17 (dd, J¼24.3, 12.2 Hz, 2H),
4.11 (d, J¼1.5 Hz, 1H), 3.88 (d, J¼12.3 Hz, 1H), 3.83e3.73 (m, 3H),
2.17 (s, 3H), 1.45 (s, 3H), 0.71 (t, J¼7.1 Hz, 3H); 13C NMR (150 MHz,
7.37e7.27 (m, 5H), 7.24e7.10 (m, 7H), 6.86 (t, J¼8.6 Hz, 2H), 4.21 (d,
J¼12.2 Hz, 1H), 4.17e4.10 (m, 2H), 3.89 (d, J¼12.3, 1H), 3.84e3.73
(m, 3H), 2.19 (s, 3H), 1.45 (s, 3H), 0.71 (t, J¼7.1 Hz, 3H); 13C NMR
CDCl3)
d (ppm) 202.7, 174.7, 173.3, 160.2, 136.9, 135.3, 134.6, 132.1,
(150 MHz, CDCl3)
d
(ppm) 203.0, 174.7, 173.3, 163.3, 161.6, 160.3,
128.9,128.6,128.5126.1, 122.6,120.3,100.1, 72.0, 61.7, 61.1, 55.2, 50.1,
136.9, 135.4, 131.2, 128.8, 128.6, 128.5, 126.1, 120.3, 116.0, 115.9, 72.0,
46.31, 43.2, 27.32, 14.4, 13.54; IR (KBr) cmꢁ1 3426, 2982, 1727, 1687,

P. Sun et al. / Tetrahedron 70 (2014) 9330e9336
9335
1598, 1394, 1179, 757, 677,; ESI-HRMS: calcd for C32H31BrN2O5þNa
13.5; IR (KBr) cmꢁ1 3420, 3124, 1731, 1698, 1603, 1456, 1376, 1083,
12
625.1308, found 625.1309; [
a]
¼35.9 (c 0.32, CH2Cl2), 82% ee; The
752, 682; ESI-HRMS: calcd for C27H30N2O5þNa 485.2056, found
D
12
enantiomeric ratio was determined by HPLC on Chiralpak OD col-
umn (1.5% 2-propanol/hexane, 1 mL/min), tmajor¼23.63 min,
tminor¼31.06 min.
485.2047; [
a]
¼503.8 (c 0.32, CH2Cl2), 91% ee; The enantiomeric
D
ratio was determined by HPLC on Chiralpak OD column (1.5% 2-
propanol/hexane, 1 mL/min), tmajor¼14.26 min, tminor¼22.19 min.
4.2.12. (5R,6R,7S,8R,9R,10S)-Ethyl-10-(3-bromophenyl)-9-formyl-8-
hydroxy-1,8-dimethyl-4-oxo-3,6-diphenyl-2,3-diazaspiro[4.5]dec-1-
ene-7-carboxylate (5k). Pale yellow solid, mp: 143.6e145.2 ꢀC; 65%
4.2.16. (5R,6R,7S,8R,9R,10S)-Ethyl-9-formyl-8-hydroxy-1,8-dimethyl-
4-oxo-3,10-diphenyl-6-(m-tolyl)-2,3-diazaspiro[4.5]dec-1-ene-7-
carboxylate (5o). Pale yellow solid, mp: 111.3e113.2 ꢀC; 73% yield.
yield. 1H NMR (600 MHz, CDCl3)
d
(ppm) 9.58 (d, J¼4.4 Hz, 1H),
1H NMR (600 MHz, CDCl3)
d
(ppm) 9.53 (d, J¼4.6 Hz, 1H), 7.31 (m,
7.43e7.27 (m, 7H), 7.16 (d, J¼7.0 Hz, 6H), 7.03 (t, J¼7.9 Hz, 1H), 4.17
(dd, J¼12.0, 10.2 Hz, 2H), 4.12 (s, 1H), 3.87 (d, J¼12.3 Hz, 1H),
3.84e3.73 (m, 3H), 2.17 (s, 3H), 1.46 (s, 3H), 0.71 (t, J¼7.1 Hz, 3H);
5H), 7.20e7.09 (m, 5H), 7.03 (m, 3H), 6.93 (d, J¼7.2 Hz, 1H), 4.18 (d,
J¼12.4 Hz, 2H), 4.10 (d, J¼1.4 Hz, 1H), 3.89 (d, J¼12.3 Hz, 1H), 3.78
(m, 3H), 2.14 (d, J¼17.3 Hz, 6H), 1.44 (s, 3H), 0.72 (t, J¼7.1 Hz, 3H);
13C NMR (150 MHz, CDCl3)
d
(ppm) 202.7, 174.7, 173.2, 160.2, 138.0,
13C NMR (150 MHz, CDCl3)
d (ppm) 203.4, 174.8, 173.6, 160.5, 137.1,
136.8, 135.3, 135.1, 131.7, 130.5, 128.8, 128.7, 128.6, 128.5, 126.1,
120.6, 72.0, 61.7, 61.1, 55.1, 50.0, 46.3, 43.4, 27.3, 14.3, 13.5; IR (KBr)
135.7,135.2,133.7, 129.3,129.0,128.7,128.6,128.5,125.9,120.4, 72.2,
61.9, 61.0, 55.1, 50.2, 46.4, 44.0, 27.3, 21.4, 14.4, 13.5; IR (KBr) cmꢁ1
cmꢁ1 3418, 2983, 1741, 1697, 1604, 1392, 1179, 754, 683; ESI-HRMS:
3417, 2912, 1730, 1615, 1695, 1179, 764, 684; ESI-HRMS: calcd for
12
12
calcd for C32H31BrN2O5þNa 625.1309, found 625.1309; [
a
]
¼48.0
C
33H34N2O5þNa 561.2360, found 561.2360; [
a
]
D
¼81.1 (c 0.32,
D
(c 0.32, CH2Cl2), 84% ee; The enantiomeric ratio was determined by
HPLC on Chiralpak OD column (1.5% 2-propanol/hexane,1 mL/min),
tmajor¼22.83 min, tminor¼29.36 min.
CH2Cl2), 86% ee; The enantiomeric ratio was determined by HPLC
on Chiralpak OD column (1.5% 2-propanol/hexane, 1 mL/min),
tmajor¼16.29 min, tminor¼20.51 min.
4.2.13. (5R,6R,7S,8R,9R,10S)-Ethyl-9-formyl-8-hydroxy-1,8-dimethyl-
10-(4-nitrophenyl)-4-oxo-3,6-diphenyl-2,3-diazaspiro[4.5]dec-1-
ene-7-carboxylate (5l). Pale yellow solid, mp: 148.3e149.6 ꢀC; 72%
4.2.17. (5R,6R,7S,8R,9R,10S)-Ethyl-6-(3-bromophenyl)-9-formyl-8-
hydroxy-1,8-dimethyl-4-oxo-3,10-diphenyl-2,3-diazaspiro[4.5]dec-1-
ene-7-carboxylate (5p). Pale yellow solid, mp: 139.2e141.0 ꢀC; 43%
yield. 1H NMR (600 MHz, CDCl3)
d
(ppm) 9.64 (d, J¼4.0 Hz, 1H), 8.04
yield. 1H NMR (600 MHz, CDCl3)
d
(ppm) 9.53 (d, J¼4.6 Hz, 1H),
(t, J¼10.5 Hz, 2H), 7.42 (m, 2H), 7.30 (m, 3H), 7.21e7.12 (m, 7H), 4.32
(d, J¼12.0 Hz, 1H), 4.18 (d, J¼12.2 Hz, 2H), 3.93e3.87 (m, 2H),
3.84e3.75 (m, 2H), 2.19 (s, 3H), 1.51 (s, 3H), 0.72 (t, J¼7.1 Hz, 3H);
7.51e7.27 (m, 6H), 7.24e6.90 (m, 8H), 4.20 (d, J¼12.2 Hz, 1H), 4.15
(d, J¼12.2 Hz, 1H), 4.02 (s, 1H), 3.92e3.85 (m, 2H), 3.84e3.75 (m,
2H), 2.19 (s, 3H), 1.45 (s, 3H), 0.79 (t, J¼7.1 Hz, 3H); 13C NMR
13C NMR (150 MHz, CDCl3)
d
(ppm) 202.1, 174.6, 173.0, 160.0, 147.7,
(150 MHz, CDCl3) d (ppm) 203.1, 174.4, 173.1, 160.1, 137.9, 136.7,
143.4, 136.7, 135.0, 129.0, 128.7, 126.3, 124.0, 120.1, 119.5, 71.9, 61.6,
135.1, 131.6, 130.1, 130.1, 129.0, 128.8, 128.6, 126.2, 120.7, 72.1, 61.7,
61.2, 55.2, 50.0, 46.2, 43.3, 27.3, 14.4, 13.5; IR (KBr) cmꢁ1 3411, 3118,
61.2, 55.1, 49.9, 45.9, 43.7, 29.8, 27.2, 14.4, 13.6; IR (KBr) cmꢁ1 3433,
1732, 1696, 1611, 1179, 756, 684; ESI-HRMS: calcd for
3113, 1728, 1673, 1601, 1398, 1183, 758, 688; ESI-HRMS: calcd for
12
12
C
32H31N3O7þNa 592.2054, found 592.2053; [
a
]
¼11.7 (c 0.32,
C
16H11NO6þNa 336.0482, found 336.0483; [
a
]
¼13.0 (c 0.32,
D
D
CH2Cl2); The minor diastereomer: 93% ee; The enantiomeric ratio
was determined by HPLC on Chiralpak IC column (10% 2-propanol/
hexane, 1 mL/min), tmajor¼24.16 min, tminor¼39.00 min; The minor
diastereomer: 23% ee, tmajor¼20.985 min, tminor¼16.939 min.
CH2Cl2), 70% ee; The enantiomeric ratio was determined by HPLC
on Chiralpak OD column (1.5% 2-propanol/hexane, 1 mL/min),
tmajor¼23.76 min, tminor¼28.92 min.
4.2.18. (5R,6R,7S,8R,9R,10S)-Ethyl 9-(2,2-dicyanovinyl)-8-hydroxy-
1,8-dimethyl-4-oxo-3,6,10-triphenyl-2,3-diazaspiro[4.5]dec-1-ene-7-
carboxylate (6a). To a solution of 5a (1.0 mmol) and malononitrile
(1.1 mmol) in DCM (10 mL) was added DABCO (1.0 mmol). The
reaction mixture was stirred 30 h. Then flash chromatography
(ethyl acetate/petroleum ether¼1: 3 as eluent) gave 6a as white
4.2.14. (5S,6R,7S,8R,9R,10S)-Ethyl-9-formyl-10-(furan-3-yl)-8-
hydroxy-1,8-dimethyl-4-oxo-3,6-diphenyl-2,3-diazaspiro[4.5]dec-1-
ene-7-carboxylate (5m). Pale yellow solid, mp: 123.5e125.1 ꢀC; 47%
yield. 1H NMR (600 MHz, CDCl3)
d
(ppm) 9.61 (d, J¼4.3 Hz, 1H), 7.39
(d, J¼7.6 Hz, 2H), 7.30 (dd, J¼10.8, 5.1 Hz, 2H), 7.24e7.07 (m, 7H),
6.13 (dd, J¼3.2, 1.8 Hz, 1H), 6.09 (d, J¼3.3 Hz, 1H), 4.38 (d, J¼12.2 Hz,
1H), 4.09 (d, J¼12.3 Hz, 1H), 4.05 (s, 1H), 3.84 (d, J¼12.3 Hz, 1H),
3.81e3.68 (m, 3H), 2.23 (s, 3H), 1.45 (s, 3H), 0.71 (t, J¼7.1 Hz, 3H);
solid, 95% yield. 1H NMR (600 MHz, CDCl3)
d (ppm) 7.48e7.27 (m,
6H), 7.24e7.08 (m, 9H), 7.03 (s, 1H), 4.39 (td, J¼11.4, 1.4 Hz, 1H), 4.28
(dd, J¼15.2, 6.8 Hz, 2H), 3.85e3.73 (m, 4H), 2.10 (s, 3H), 1.36 (s, 3H),
13C NMR (150 MHz, CDCl3)
d
(ppm) 202.6, 174.7, 173.0, 160.7, 150.2,
0.71 (t, J¼7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3)
d (ppm) 174.9,
142.5, 137.2, 135.1, 128.8, 128.5, 128.5, 128.5, 128.4, 125.8, 120.3,
110.7, 108.8, 71.9, 61.1, 60.6, 54.0, 49.9, 45.8, 37.4, 27.1, 14.0, 13.5; IR
(KBr) cmꢁ1; 3411, 3127, 2018, 1701, 1615, 1596, 1395, 1196, 1019, 763,
173.2, 168.3, 159.7, 136.9, 135.2, 135.0, 129.90, 129.3, 129.0, 128.8,
128.6, 126.5, 126.0, 120.3, 111.8, 110.6, 92.3, 71.9, 61.6, 61.3, 49.5,
48.8, 46.9, 46.4, 27.6, 14.2, 13.4; ESI-HRMS: calcd for
695; ESI-HRMS: calcd for
C
30H30N2O6þNa 537.1996, found
C
35H32N4O4þNa 595.2321, found 595.2322.
12
537.1996; [
a
]
D
¼195.0 (c 0.32, CH2Cl2), 90% ee; The enantiomeric
ratio was determined by HPLC on Chiralpak IC column (15% 2-
4.2.19. (4aR,40R,5S,7R,8S,8aR)-Ethyl 3-cyano-2-imino-30,8a-di-
propanol/hexane, 1 mL/min), tmajor¼8.18 min, tminor¼17.99 min.
methyl-50-oxo-10,5,7-triphenyl-10,2,4a,5,50,7,8,8a-octahydrospiro
[chromene-6,40-pyrazole]-8-carboxylate (7a). To a solution of 6a
(1.0 mmol) in dried THF (10 mL) was added sodium hydride
(2.0 mmol) in portions. The reaction mixture was stirred at room
temperature for 5 h, quenched with water (5 mL) and extracted
with ethyl acetate (3ꢂ5 mL). The organic phase was combined and
then dried. Solvent was removed under reduced pressure. Flash
chromatography (ethyl acetate/petroleum ether¼1:4 as eluent)
gave 7a as white solid; mp: 187.2e188.7 ꢀC; 92% yield. 1H NMR
4.2.15. (5R,6R,7S,8R,9R,10R)-Ethyl-9-formyl-8-hydroxy-1,8,10-
trimethyl-4-oxo-3,6-diphenyl-2,3-diazaspiro[4.5]dec-1-ene-7-
carboxylate (5n). Pale yellow solid, mp: 103.6e105.4 ꢀC; 67% yield.
1H NMR (600 MHz, CDCl3)
d
(ppm) 9.83 (d, J¼4.6 Hz, 1H), 7.61e7.59
(m, 2H), 7.36e7.32 (m, 2H), 7.19e7.14 (m, 6H), 3.98 (d, J¼1.9 Hz, 1H),
3.94 (d, J¼12.3 Hz, 1H), 3.81e3.30 (m, 3H), 3.06 (ddd, J¼11.5, 4.6,
1.9 Hz, 1H), 2.97 (d, J¼6.8 Hz, 1H), 2.15 (s, 3H), 1.38 (s, 3H), 0.75 (d,
J¼6.8 Hz, 2H), 0.70 (t, J¼7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3)
(600 MHz, CDCl3) d (ppm) 8.40 (s, 1H), 7.39e7.28 (m, 6H), 7.26e7.07
d
(ppm) 204.6, 174.8, 173.3, 161.1, 137.3, 135.5, 128.9, 128.5, 128.4,
(m, 9H), 4.34 (d, J¼12.6 Hz, 1H), 3.95e3.86 (m, 2H), 3.79 (dd, J¼12.1,
125.7, 119.7, 71.5, 61.4, 60.9, 57.2, 49.8, 45.7, 30.8, 27.4, 14.1, 13.7,
6.3 Hz, 1H), 3.69 (t, J¼10.2 Hz, 2H), 3.47 (d, J¼12.2 Hz, 1H), 2.11 (s,

9336
P. Sun et al. / Tetrahedron 70 (2014) 9330e9336
3H), 1.73 (s, 3H), 1.27 (s, 1H), 0.92 (t, J¼7.1 Hz, 3H); 13C NMR
Supplementary data
(150 MHz, CDCl3)
d (ppm) 173.8, 168.7, 160.4, 156.3, 136.9, 136.0,
135.3, 129.2, 129.0, 128.9, 128.7, 128.4, 126.2, 120.6, 114.1, 81.0, 61.7,
61.0, 60.9, 50.0, 46.1, 45.2, 44.6, 36.6, 26.0, 14.4, 14.0; (KBr) cmꢁ1
3415, 3130, 2843, 2169,1731,1682,1610,1597,1401,1301,1261, 1154,
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.10.038.
1029, 935, 758, 705, 692; ESI-HRMS: calcd for C35H32N4O4þNa
12
595.2321, found 595.2319; [
a
]
¼ꢁ11.3 (c 0.1, CH2Cl2), 94% ee; The
D
References and notes
enantiomeric ratio was determined by HPLC on Chiralpak IC col-
umn (20% 2-propanol/hexane,
tminor¼27.69 min.
1
mL/min), tmajor¼12.86 min,
1. For selected recent reviews, see: (a) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G.
Angew. Chem. 2006, 118, 7292; Angew. Chem., Int. Ed. 2006, 45, 7134; (b)
Chapman, C. J.; Frost, C. G. Synthesis 2007, 1; (c) Grondal, C.; Jeanty, M.; Enders,
D. Nat. Chem. 2010, 2, 167.
4.2.20. (5S,6R,7S,10R)-Ethyl9-formyl-1,8-dimethyl-4-oxo-3,6,10-
triphenyl-2,3-diazaspiro[4.5]deca-1,8-diene-7-carboxylate (8a). To
a solution of 5a (1.0 mmol) in dried toluene (10 mL) was added
a drop of concentrated sulfuric acid (98%). The reaction mixture was
refluxed for 1 h. After that, water (20 mL) was added and extracted
with toluene, then extracted with ethyl acetate (10 mL). The organic
phase was combined and dried. Solvent was removed under re-
duced pressure. Flash chromatography (ethyl acetate/petroleum
ether¼1:4 as eluent) gave 8a as white solid; mp: 98.2e99.3 ꢀC; 75%
2. For an excellent book about the chemistry of pyrazol-3-ones: Varvounis, G. In
Pyrazol-3-ones. Part IV: Synthesis and Applications; Katritzky, A. R., Ed.; Adv.
Heterocyclic Chem.; Academic: 2009; Vol. 98, pp 143e223.
3. Li, Y.; Zhang, S.; Yang, J.; Jiang, S.; Li, Q. Dyes Pigm. 2008, 76, 508.
4. (a) Sujatha, K.; Shanthi, G.; Selvam, N. P.; Manoharan, S.; Perumal, P. T.; Ra-
jendran, M. Bioorg. Med. Chem. Lett. 2009, 19, 4501; (b) Costa, D.; Marques, A. P.;
Reis, R. L.; Lima, J. L. F. C.; Fernandes, E. Free Radic. Biol. Med. 2006, 40, 632; (c)
Bondock, S.; Rabie, R.; Etman, H. A.; Fadda, A. A. Eur. J. Med. Chem. 2008, 43,
2122.
5. Brogden, R. N. Drugs 1986, 32, 60.
ꢁ
6. Pegurier, C.; Collart, P.; Danhaive, P.; Defays, S.; Gillard, M.; Gilson, F.; Kogej, T.;
Pasau, P.; Van Houtvin, N.; Van Thuyne, M.; Van Keulen, B. Bioorg. Med. Chem.
Lett. 2007, 17, 4228.
yield. 1H NMR (600 MHz, CDCl3)
d (ppm) 10.09 (s, 1H), 7.22e7.13 (m,
11H) (m, 11H), 7.11e7.06 (m, 4H), 4.83 (dd, J¼11.5, 1.4 Hz, 1H),
4.38e4.34 (m, 1H), 3.99e3.89 (m, 2H), 3.57 (d, J¼11.5 Hz, 1H), 2.37
(s, 3H), 2.20 (s, 3H), 0.89 (t, J¼7.1 Hz, 3H); 13C NMR (150 MHz,
7. Casas, J. S.; Castellano, E. E.; Ellena; Garcia-Tasende, M. S.; Peres-Paralle, M. L.;
Sanchez, A.; Sanchez-Gonzalez, A.; Sordo, J.; Touceda, A. J. Inorg. Biochem. 2008,
102, 33.
8. Wu, T. W.; Zeng, L. H.; Wu, J.; Fung, K. P. Life Sci. 2002, 71, 2249.
9. (a) Liao, Y.-H.; Chen, W.-B.; Wu, Z.-J.; Du, X.-L.; Cun, L.-F.; Zhang, X.-M.;
Yuan, W.-C. Adv. Synth. Catal. 2010, 352, 827; (b) Liu, L.-P.; Zhong, Y.; Zhang,
P.-P.; Jiang, X.-X.; Wang, R. J. Org. Chem. 2012, 77, 10228; (c) Mazzanti, A.;
Calbet, T.; Font-Bardia, M.; Moyano, A.; Rios, R. Org. Biomol. Chem. 2012, 10,
1645.
CDCl3)
d (ppm) 190.5, 172.6, 172.3, 159.7, 151.3, 136.8, 136.0, 133.3,
128.9, 128.6, 128.5, 127.5, 125.8, 120.4, 100.1, 617, 61.2, 52.0, 47.6,
46.6, 16.4, 14.5, 13.9; IR (KBr) cmꢁ1 3558, 3102, 2840, 2166, 1724,
1692, 1663, 1636, 1613, 1404, 1154, 774, 756, 717; ESI-HRMS: calcd
12
ꢁ
10. (a) Companyo, X.; Zea, A.; Nekane, A.; Alba, R.; Mazzanti, A.; Moyano, A.; Rios,
for C32H30N2O4þNa 529.2103, found 529.2101; [
a
]
¼50.8 (c 0.1,
D
R. Chem. Commun. 2010, 6953; (b) Zea, A.; Nekane, A.; Alba, R.; Mazzanti, A.;
Moyano, A.; Rios, R. Org. Biomol. Chem. 2011, 9, 6519; (c) Zhang, J.-X.; Li, N.-K.;
Liu, Z.-M.; Huang, X.-F.; Geng, Z.-C.; Wang, X.-W. Adv. Synth. Catal. 2013, 355,
797; (d) Liang, J.-Y.; Chen, Q.; Liu, L.-P.; Jiang, X.-X.; Wang, R. Org. Biomol. Chem.
2013, 11, 1441; (e) Alba, A. N. R.; Zea, A.; Valero, G.; Calbet, T.; Font-Bardía, M.;
Mazzanti, A.; Moyano, A.; Rios, R. Eur. J. Org. Chem. 2011, 7, 1318.
CH2Cl2), 90% ee; The enantiomeric ratio was determined by HPLC
on Chiralpak AD-H column (15% 2-propanol/hexane, 1 mL/min),
tmajor¼9.28 min, tminor¼15.28 min.
4.3. Crystallographic data
11. (a) Wu, B.; Chen, J.; Li, M.-Q.; Zhang, J.-X.; Xu, X.-P.; Ji, S.-J.; Wang, X.-W. Eur. J.
Org. Chem. 2012, 7, 1318; (b) Chauhan, P.; Mahajan, S.; Loh, C. C. J.; Raabe, G.;
Enders, D. Org. Lett. 2014, 16, 2954.
12. (a) Tao, Z.-L.; Zhang, W.-Q.; Chen, D.-F.; Adele, A.; Gong, L.-Z. J. Am. Chem. Soc.
2013, 135, 9255; (b) Li, J.-T.; Lian, X.-J.; Liu, X.-H.; Lin, L.-L.; Feng, X.-M. Chem.
dEur. J. 2013, 19, 5134; (c) Yang, Z.-G.; Wang, Z.; Bai, S.; Liu, X.-H.; Lin, L.-L.;
Feng, X.-M. Org. Lett. 2011, 13, 596; (d) Cui, B.-D.; Li, S.-W.; Zuo, J.; Wu, Z.-J.;
Zhang, X.-M.; Yuan, W.-C. Tetrahedron 2014, 1895; (e) Zhang, H.-M.; Lv, H.; Ye, S.
Org. Biomol. Chem. 2013, 11, 6255; (f) Chen, Q.; Liang, J.; Wang, S.; Wang, D.;
Wang, R. Chem. Commun. 2013, 1657.
13. (a) Wasilke, J. C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem. Rev. 2005, 105, 1001;
(b) Tietze, L. F. Chem. Rev. 1996, 96, 115; (c) Enders, D.; Urbanietz, G.; Cassens-
Sasse, E.; Keeß, S.; Raabe, G. Adv. Synth. Catal. 2012, 354, 1481.
14. (a) Xie, J.-W.; Xu, M.-L.; Zhang, R.-Z.; Pan, J.-Y.; Zhu, W.-D. Adv. Synth. Catal.
2014, 356, 395; (b) Guo, Z.-W.; Xie, J.-W.; Chen, C.; Zhu, W.-D. Org. Biomol. Chem.
2012, 10, 847; (c) Fan, L.-P.; Li, P.; Li, X.-S.; Xu, D.-C.; Ge, M.-M.; Zhu, W.-D.; Xie,
J.-W. J. Org. Chem. 2010, 75, 8716.
4.3.1. Crystal data for 5j. C32H31BrN2O5 (603.49), Orthorhombic,
ꢀ
ꢀ
space group p2(1)2(1)2, a¼11.8358(3) A, b¼31.5354(8) A,
3
ꢀ
ꢀ
c¼8.7355(2)
A,
U¼3260.50(14)
A ,
Z¼17,
specimen
0.28ꢂ0.23ꢂ0.11 mm3, T¼296(2) K, SIEMENS P4 diffractometer, ab-
sorption coefficient 1.299 mmꢁ1, reflections collected 28,614, in-
dependent reflections 7415 [R(int)¼0.0497], refinement by Full-
matrix least-squares on F2, data/restraints/parameters 7415/0/362,
goodness-of-fit on F2¼1.050, final R indices [I>2
(I)] R1¼0.1307,
d
wR2¼0.3006, R indices (all data) R1¼0.0917, wR2¼0.2667, largest diff.
ꢀꢁ3
peak and hole 1.491 and ꢁ0.438 e A . CCDC 989289 contains the
supplementary crystallographic data for compound 5j of this paper.
15. For 1,2-diaminohexane-derived bifunctional thioureas see: (a) Okino, T.; Hoa-
shi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672; (b) Okino, T.; Hoashi, Y.;
Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119 For cinchona-
derived bifunctional thioureas, see: (c) Tian, S.; Chen, Y.; Hang, J.; Tang, L.;
McDaid, P.; Deng, L. Acc. Chem. Res. 2004, For pyrrolidine-thiourea see: (d) Cao,
C.-L.; Ye, M.-C.; Sun, X.-L.; Tang, Y. Org. Lett. 2006, 8, 2901.
Acknowledgements
We are grateful for the financial support from the National
Natural Science Foundation of China (21272214).