Diastereoselective construction of spirocyclic pyrrolidines bearing two quaternary centers via CuII-P, N-Ligand catalyzed 1,3-dipolar cycloaddition

Article abstract of DOI:10.1016/j.tet.2017.01.001

Here, we report a convenient access to diastereoselective synthesis of polysubstituted pyrrolidines bearing a unique spiro quaternary center at the C-2 position and another quaternary center at C-4. The synthesis system, Cu^II/P, N-Ligand-cataly

Full text of DOI:10.1016/j.tet.2017.01.001

Accepted Manuscript
Diastereoselective construction of spirocyclic pyrrolidines bearing two quaternary
II
centers via Cu -P, N-Ligand catalyzed 1,3-dipolar cycloaddition
Li-Wei Tang, Chuan Li, Bao-Jing Zhao, Li Lan, Man Zhang, Zhi-Ming Zhou
PII:
S0040-4020(17)30001-7
10.1016/j.tet.2017.01.001
TET 28371
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 4 November 2016
Revised Date: 30 December 2016
Accepted Date: 2 January 2017
Please cite this article as: Tang L-W, Li C, Zhao B-J, Lan L, Zhang M, Zhou Z-M, Diastereoselective
II
construction of spirocyclic pyrrolidines bearing two quaternary centers via Cu -P, N-Ligand catalyzed
1,3-dipolar cycloaddition, Tetrahedron (2017), doi: 10.1016/j.tet.2017.01.001.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Diastereoselective Construction of
Spirocyclic Pyrrolidines Bearing Two
Quaternary Centers via CuII-P, N-Ligand
catalyzed 1,3-Dipolar Cycloaddition
Leave this area blank for abstract info.
Li-Wei Tang,[a] Chuan Li,[a] Bao-Jing Zhao,[a] Lan Li ,[a] Man Zhang,[a] and Zhi-Ming Zhou*[a,b]
R&D Centre of Pharmaceuticals school of Chemical Engineering and the Environment
Beijing Institute of Technology
5th zhongguancun South Street, Haidian District, Beijing(China)
E-mail: zzm@bit.edu.cn

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Diastereoselective Construction of Spirocyclic Pyrrolidines Bearing Two Quaternary
Centers via CuII-P, N-Ligand catalyzed 1, 3-Dipolar Cycloaddition
Li-Wei Tanga , Chuan Lia , Bao-Jing Zhaoa , Li Lana , Man Zhanga and Zhi-Ming Zhoua, b,
a R&D Centre of Pharmaceuticals school of Chemical Engineering and the Environment, Beijing Institute of Technology. 5th zhongguancun South Street, Haidian
District, Beijing 100081, China
b State Key Laboratory of Explosion Science and Technology, Beijing Institute of Technology. 5th zhongguancun South Street, Haidian District, Beijing 100081,
China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Here, we report a convenient access to diastereoselective synthesis of polysubstituted
pyrrolidines bearing a unique spiro quaternary center at the C-2 positon and another quaternary
center at C-4. The synthesis system, CuII/P, N-Ligand-catalyzed 1, 3-dipolar cycloadditon, by
employing homoserine lactone derived cyclic imino esters as the dipoles and α, α, β-
trisubstituted olefins as the dipolarophlies, provides exo-spiro-pyrrolidines with good yields,
high diastereoselectivities (up to >98:2 dr) and performs well for a broad scope of substrates.
Available online
2016 Elsevier Ltd. All rights reserved
.
Keywords:
spiropyrrolidine
quaternary center
1, 3-Dipolar cycloaddition
spirolactone
strategies[6]. Among the various types of spirocyclic skeletons,
spirocyclic pyrrolidines and spirolactones[7] represent two large
classes of structurally diverse molecules that exhibit wide ranges
of biological activities. Typical examples include drospirenone[8],
spirotryprostatin A and B[9], and fenspiride (Figure 1).
1. Introduction
1, 3-Dipolar cycloaddition has received increasing attention in
recent years, mainly because it provides easy and rapid way to
construct five-membered nitrogen heterocycles, especially highly
substituted pyrrolidines. These compounds are core structural
scaffold in numerous pharmaceuticals, natural alkaloids, and are
fascinating building blocks in organic synthesis[1]. Based on the
principle of biology-oriented synthesis (BIOS)[2], over recent
dacades numerous natural and unnatural products have been
prepared by synthetic routes that incorporate 1, 3-dipolar
cycloaddition reactions as a key steps[3]. As a consequence, these
reactions are now recognized to be extremely important
components in the repertoire of synthetic organic chemist.
N
N
H
O
O
H
H
O
O
N
N
O
O
N
N
MeO
H
H
Spirotryprostatin A
Spirotryprostatin B
Although various methodologies for the synthesis of
quaternary centers have been explored, the construction of
quaternary stereocentres remains a significant challenge[4]. While,
[3+2] cycloaddition has become a powerful tool to introduce at
least one quaternary center, containing five-membered
heterocyclic rings. Moreover, the position of the quaternary
center on the pyrrolidine-ring can easily be controlled by varying
the cycloaddition dipoles and dipolarophiles[5]. Spiro centres, as a
special category of quaternary centres, have always been more
challenging synthetic endeavors for organic chemists, because
they often require synthetic designs that are based on specific
———
O
O
O
O
NH
H
H
N
H
H
H
H
O
H
Drospirenone
Fenspiride
Figure 1. Representative biologically active proline derivatives bearing a
spirocyclic pyrrolidine or spirolactone.
Corresponding author. Tel.: +86-10-6891-2664; e-mail: zzm@bit.edu.cn

2
Tetrahedron
As the spirocyclic pyrrolidine core is the structural
ACCEPTED MANUSCRIPT
centerpiece of a large number of biologically active compounds,
approaches toward their efficient asymmetric synthese have
received considerable attention. The range of compounds
available through the use of the 1, 3-dipolar cycloaddition makes
it one of the most useful and widely utilized reactions in
diversity-oriented synthesis (DOS)[10]. Gong and co-workers
reported, for the first time, the use of asymmetric,
organocatalyzed three-component 1, 3-dipolar cycloaddition for
the synthesis of spiro[pyrrolidin-3, 3'-oxindole] derivatives, using
methyleneindolinones as the dipolarophiles[11]. One year later,
Waldmann’s group have developed the first Lewis acid-catalyzed
system for the enantioselective synthesis of 3, 3'-pyrrolidinyl
spirooxindoles by means of 1, 3-dipolar cycloaddition, using 3-
arylidene- or alkylideneoxindoles[12]. Subsequently, Wang et al.
employed this approach for the preparation of various spiro
pyrrolidine motifs using α, α, β-trisubstituted 2-alkylidene-
ketones as dipolarophiles[13]. In addition, some other excellent
reports have appeared that describe the preparation of spirocyclic
pyrrolidines using cyclic olefins[1a]. In comparison with the use of
various cyclic dipolarophiles, cyclic dipolars molecules have still
not been fully explored in this reaction. In view of the importance
of spirolactones in biologically active molecules, homoserine
lactone derived cyclic imino esters have become popular dipolar
molecules for the assembly of spirocyclic compounds. However,
only a few examples have been reported using this approach for
the preparation of spirocyclic pyrrolidines. Grigg et al. first
reported their utility in the synthesis of spiro pyrrolidine
Table 1. Optimization of the reaction catalytic systems[a]
.
Br
EtOOC
EtOOC
COOEt
COOEt
Lewis/Ligand (10%mol)
O
N
base (10%mol), solvent, r.t.
O
N
H
O
Br
O
1a
2a
3aa
Entry Ligand/Metal
Solvent
DCM
Base
Yield dr
(%)[b] (%)[c]
1
PPh3/CuClO4
PCy3/CuClO4
dppf/CuClO4
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
61
85:15
80:20
90:10
-
2
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
THF
43
3
n.r.
trace
65
4
X-Phos/CuClO4
L1/CuClO4
5
95:5
85:15
95:5
90:10
90:10
-
6
L1/CuBF4
59
7
L1/Cu(ClO4)2·6H2O
L1/Cu(OTf)2
67
8
60
9
L1/Cu(OAc)2·H2O
L1/Zn(OTf)2
57
10
11
12
13
14
15
16
17
18
19
20
21
22
23[d]
24[e]
n.r.
trace
trace
36
L1/Ni(OAc)2·4H2O
L1/Pd(OAc)2
-
-
L1/AgOAc
40:60
98:2
85:15
90:10
90:10
-
derivatives[14]
,
while, Wang’s team subsequently have
L1/Cu(ClO4)2·6H2O
L1/Cu(ClO4)2·6H2O
L1/Cu(ClO4)2·6H2O
L1/Cu(ClO4)2·6H2O
L1/Cu(ClO4)2·6H2O
L1/Cu(ClO4)2·6H2O
L1/Cu(ClO4)2·6H2O
L1/Cu(ClO4)2·6H2O
L1/Cu(ClO4)2·6H2O
L1/Cu(ClO4)2·6H2O
L1/Cu(ClO4)2·6H2O
73
successfully developed the first catalytic asymmetric method for
the construction of spiro-butyrolactone pyrrolidines by CuI-
catalyzed asymmetric 1, 3-dipolar cycloaddition[15]. In 2013,
Wang’s group also reported the first 1, 3-dipolar cycloaddition
reactions of homoserine-lactone-derived cyclic imino esters with
methyleneindolinones, to provide a series of tricyclic spiro[γ-
EtOH
CH3CN
toluene
47
70
57
[Emim]BF4- DIPEA
n.r.
66
butyrolactonepyrrolidin-3, 3'-oxindole] skeletons via
a
THF
THF
THF
THF
THF
THF
Et3N
95:5
95:5
90:10
90:10
98:2
90:10
bifunctional organocatalytic strategy[16]
.
Despite this, the
Pyridine 63
methodology still need more explored. Nevertheless, it is a
greater challenge to control the high diastereoselectivity, in
consideration of the simultaneous creation of two quaternary
centers at the pyrrolidine ring.
DBU
72
70
70
65
K2CO3
DIPEA
DIPEA
As a part of our program into the synthesis of pyrrolidines
containing all-carbon quaternary centers, we describe herein the
first successful catalytic synthese of spiro pyrrolidines bearing
one quaternary center and another unique spiro quaternary center.
These syntheses are catalyzed by copper(II) and employ
homoserine-lactone-derived cyclic imino esters as dipoles, and α,
α, β-trisubstituted olefins as dipolarophiles.
[a] Conditions: 1a (0.2 mmol), 2a (0.2 mmol), Lewis acid (LA) (10
mol%), ligand (L) (10 mol %), and base (10 mol%) in 2.0 mL solvent at room
temperature for 8 h, unless otherwise noted. [b] Isolated yield. [c] dr value
(diastereomeric ratio)=exo/endo, and were determined by 1H NMR
spectroscopy. [d] Reacted at 0oC for 12h. [e] 5 mol% catalyst used.
We next tested PPFA with differernt Lewis acid (10 mol%) as
the catalyst system in the reaction between the cyclic imino ester
1a, and alkylidene malonate 2a, in dry DCM at room temperature
for 8h (Table 1). Except for the low activity of Ni(OAc)2•4H2O
and Pd(OAc)2 as metal precursors (entries 3 and 4, Table 1),
AgOAc salts combined with ligand L1 showed good reactivity
albeit unsatisfactory diastereoselectivity. To our delight, all the
Cu salts were capable of catalyzing the reaction, providing
moderate yields and good diastereoselectivities (entries 6-9,
Table1) and Cu(ClO4)2•6H2O proved to be the most efficient
Lewis acid catalyst, while the reaction did not proceed in the
presence of Zn(OTf)2 (entry 10, Table 1). These results prompted
us to carry out this reaction in other solvents, such as MeCN,
toluene, EtOH and THF. To our delight, the best result was
obtained in THF, while the cycloaddition reaction did not occur
2. Results and discussion
We initiated our studies by evaluating the reaction between
the cyclic aldimino ester 1a, which is readily synthesized from
homoserine lactone hydrobromide and benzaldehyde, with
alkylidene malonate 2a, using Cu(CH3CN)4ClO4/PPh3 as the
catalyst in dichloromethane at room temperature. We found that
the reaction proceeded smoothly and afforded the desired product
in good yield, albeit with moderate diastereoselectivity (entry 1,
Table 1). Subsequently other phosphine ligands were
investigated, and the results of this investigation reveal that N, N-
dimethyl 2-diphenylphosphino-ferrocenylethylamine (PPFA, L1)
afforded the highest yield and the best diastereoselectivity (entry
5, Table 1). Encouraged by these promising results, PPFA was
selected as the ligand of choice for further metal, solvent and
base screening, and the representative results are presented in
-
in 1-butyl-3-methylimidazoliumtetrafluoroborate ([Emim]BF4 )
(entry 18). With the aim of increasing the reaction yield, we next
Table
1.

3
investigated a series of bases. Both organic and inorganic bases
were found to promote this reaction. For example, K2CO3 and
DBU (1,8-diazabicyclo[5.4.0]-undec-7-ene) provided product
3aa in 72% and 70% yields, respectively (entries 21 and 22).
After utilizing a variety of bases, N, N-diisopropylethylamine
(DIPEA) still proved to be the most effective base. Reducing the
temperature from room temperature to 0oC had no obvious effect
on reactivity or diastereoselectivity (entry 23, Table 1).
Furthermore, the catalyst loading was examined. However, the
yield and dr value of 3aa all decreased when the catalyst loading
was reduced to 5 mol% (entry 24). Based on the above results,
the optimal reaction conditions are as follows: 10 mol%
Cu(ClO4)2•6H2O/L1 as the catalyst, dry THF as the solvent, and
10 mol% DIPEA as the base, at room temperature for 8 h.
in high yields and excellent diastereoselectivities (entries 1-13,
ACCEPTED MANUSCRIPT
Table 2). It appears that the position of the substituents on the
aromatic rings, and their electronic properties have a very limited
effect on the diastereoselectivities. The naphthyl derivative of the
cyclic imino ester afforded the corresponding product 3ja in 83%
yield and with the highest diastereoselectivity (entry 2, Table 2).
It is noteworthy that comparable excellent performance, in terms
of diastereoselectivity and reactivity, is still achieved for the
sterically hindered ortho-substituted cyclic imino ester (entry 5,
Table 2), which demonstrated that the substitution pattern had
little effect on the selectivity of this reaction. In addition, the
heteroaromatic 2-furyl imino ester 3l was also a viable substrate
leading to 85% yield of the corresponding product, with dr >98:2
(entry 12, Table 2). Remarkably, the cyclic imino ester 1i,
bearing the powerful electron-withdrawing nitro group on the
phenyl ring, was used as the substrate, the diastereoselectivity of
the product 3ia was 98:2 dr (entry 9, Table 2), while the
methylthio moiety also worked in this transformation; and the
cycloadduct 3ha was obtained with excellent results, even though
the sulfur atom was potentially coordinated to the Cu salt (entry 8,
Table 2). Notably, the cyclic imino ester 1m, derived from trans-
cinnamaldehyde, is also compatible with this reaction, thereby
giving the corresponding product 3ma in 52% yield with high
diastereoselectivity (entry 13, Table 2). Unfortunately, reaction
of the phenylacetaldehyde-derived cyclic imino ester 3k provided
Having established the optimal reaction conditions, we then
investigated a series of representative cyclic imino esters 1. As
shown in Table 2, a wide array of cyclic imino esters derived
from aromatic aldehyde reacted smoothly with alkylidene
malonate 2a to exclusively afford the corresponding exo-adducts,
Table 2. Substrate scope of various cyclic imino esters 1 and arylidene
R2
EtOOC
CuII/PPFA (10%mol)
EtOOC
COOEt
COOEt
O
R1
N
R1
a
complex mixture of products as evidenced by NMR
spectroscopy; small quantities the desired product was only
detected by HRMS (Table 2, entry 11).
DIPEA (10%mol), THF, r.t.
N
O
O
R2
H
O
1
2
exo-3
malonates 2[a].
Entry
R1
Ph
R2
m-Br
Product
3aa
3ba
3ca
3da
3ea
3fa
Yield(%)[b]
dr (%)[c]
We next evaluated the potential of this spiro-cycloaddition
chemistry with respect to alkylidene malonates. This
cycloaddition reaction tolerated all of the examined aryl
aldehyde-derived alkylidene malonates, irrespective of
electronic properties or substituent pattern (entries 14-19, Table
2). The expected adducts (3ab-ag) were isolated in high yields
and with excellent diastereoselectivities.
1
73
76
77
83
86
73
77
85
73
83
trace
85
52
79
81
80
70
74
75
98:2
96:4
95:5
>95:5
98:2
>95:5
96:4
>98:2
98:2
>98:2
-
2
3
o-BrPh
p-ClPh
p-MePh
p-OCH3Ph
2, 4-diFPh
p-BrPh
p-MeSPh
m-NO2Ph
2-naphthyl
PhCH2
2-furyl
PhCH=CH2
Ph
m-Br
m-Br
4
m-Br
Table 3. Substrate scope of cyclic imino esters 1 and various α, α, β-
trisubstituted olefins 4.[a]
5
m-Br
R2
6
m-Br
R4
R3
R1
R3
CuII/PPFA (10%mol)
O
R1
7
m-Br
3ga
3ha
3ia
N
R4
DIPEA (10%mol), THF, r.t.
N
O
O
R2
H
O
8
m-Br
1
4
exo-5
9
m-Br
Entry R1
R2
R3
R4
Product Yield
(%)[b]
10
11
12
13
14
15
16
17
18
19
m-Br
3ja
1
Ph
H
H
H
H
H
CN
CN
5aa
86
80
87
n.r.
77
73
m-Br
3ka
3la
2
p-BrPh
p-MePh
Ph
CN
CN
5ga
5da
5ab
5ac
m-Br
>98:2
98:2
98:2
98:2
>98:2
98:2
98:2
95:5
3
CN
CN
m-Br
3ma
3ab
3ac
3ad
3ae
3af
4
COOEt
CN
COOEt
COOEt
H
5
Ph
Ph
p-Me
2-naphthyl
p-ClPh
m-CF3Ph
o-BrPh
6[c]
Ph
m-Br COOt-Bu
COOt-Bu 5ad
Ph
[a] Conditions: 1 (0.2 mmol), 4 (0.2 mol), Cu(ClO4)2·6H2O (10 mol%),
Ph
and L1 (10 mol %) in THF (2.0 mL) at room temperature for 8h, unless
otherwise noted and the diastereomeric ratios are >98:2. [b] Isolated yield. [c]
dr=90:10.
Ph
Ph
3ag
To further expand the synthetic utility of this method for the
construction of spiro(butyrolactonepyrrolidines) containing two
quaternary centers, other dipolarophiles were also examined
under the optimized reaction conditions. As shown in Table 3,
benzylidene malononitrile proved to be an excellent
[a] Conditions: 1 (0.2 mmol), 2 (0.2 mmol), Cu(ClO4)2·6H2O (10 mol%),
L1 (11 mol %), and DIPEA (10 mol%) in 2.0 mL THF at room temperature,
unless otherwise noted. [b] Isolated yield. [c] Determined by 1H NMR
spectroscopy.

4
Tetrahedron
dipolarophile, affording the desired spiro adducts in good yields
conditions. With 10 mol% Cu(ClO4)2•6H2O/L1 complex as the
ACCEPTED MANUSCRIPT
and with excellent diastereoselectivities. Moreover, to the best of
catalyst, by treatment of 3mmol of 1g and 3mmol of 2a, the
corresponding adduct 3ga in 78% yield and with 97:3 dr.
our knowledge, β-trifluoromethyl benzylidene malonate 4a[17]
,
which has not been reported as a substrate in any kind of
synthesis reaction so far. Unfortunately, the reaction of the cyclic
iminoester with 5b proved to be messy, indicating that the
construction of pyrrolidines with three contiguous quaternary
centers still challenging. Notably, the tri-substituted alkenes 4c,
with three different sbustituents, is also compatible with this
reaction, thereby giving the corresponding product 5ac in 77%
yield and with >98:2 diastereoselectivity (entry 5, Table 3).
Furthermore, the benzylidene malonate 4d, with bulky tert-butyl
ester, also worked well, yielding the product 5ad with high dr
value (90:10).
After recrystallization from a mixed solvent of petroleum
ether and ethyl acetate, a crystal suitable for X-ray diffraction
was obtained[18] and the relative configuration of 3ia was thus
assigned to be exo (Figure 3, upper).
On the basis of our previous work[19], a possible transition
model was proposed to rationalize the reaction stereoselectivity.
As shown in Figure 3 (bottom), the azomethine ylide, generated
from the cyclic imino ester, coordinates to the CuII catalyst in a
distorted tetrahedral geometry. The cycloaddition favors the exo
product, possibly because of the steric repulsion between the
phenyl rings adjacent to the phosphorus atom and the aromatic
ring of alkylidene malonates. Meanwhile, the one face of the
azomethine ylide is shielded by the methyl group on the N,N-
dimethylethylamine. We hypothesize that the group can not
provide sufficiently large steric hindrance to prevent the attack of
the malonateat form the one face, and thus gives malonates the
opportunity to attack from the other face. So we did not get the
excellent stereoselectivity when (R)-PPFA as the ligand in the
reaction. Furthermore, benzylidene malononitrile as the
dipolarophile, led to worse stereoselectivity because of the
smaller CN group. Moreover, we did the 2D NMR studies for
three representative cycloaddition products (3ca, 5ga, 5ac). From
these points of view, we supposed that the absolute configuration
of the cycloaddition product was (2R,4S,5R).
To realize the asymmetric version of the reaction, ligands in
hand as well as some commercially available ones were screened.
(R)-PPFA proved, once again, to be the best ligand, while the
reaction did not proceed in the presence of L7 or L8 (the results
are summarized in Figure 2). We next investigated a variety of
reaction conditions that involved examining the effects the
solvent, metals, and other parameters (see Table S1 in the
Supporting Information). Based on the above results, the optimal
reaction conditions for the asymmetric reactions are identical to
those of their racemic counterparts, with the exception that
enantiomerically pure PPFA is used instead of the racemate.
Under these optimal conditions, exo-3aa and exo-3ad were
obtained with 74.6 and 65.6% ee, respectively. Unfortunately,
when benzylidene malononitrile 4a was used as the
dipolarophile, the desired spiro adduct 5aa was obtained with
low ee (13%).
Figure 3. X-ray structure of 3ia (upper) and proposed transition state for
asymmetric induction (bottom).
Figure 2. Screening the known ligands.
3. Conclusion
In conclusion, we have developed the first copper(II)
catalyzed reaction for synthesis of pyrrolidines bearing a one
To test the synthetic utility of the present spiro-cycloaddition,
3ga was prepared on a gram scale using the optimized reaction

5
quaternary center and one unique spiro quaternary center. This
was achieved via the CuII/PPFA-catalyzed 1, 3-dipolar
cycloaddition reactions of homoserine-lactone-derived cyclic
imino esters with α, α, β-trisubstituted olefins. This method
provides a reliable strategy for exo-selectivity with excellent
diastereoselective construction of polysubstituted pyrrolidines
containing a unique spiro quaternary center at C-2 and another
quaternary center at C-4; the reaction exhibited excellent
diastereoselectivity, and a broad substrate scope. Moreover, the
cycloaddition proceeded in the presence of only 10 mol% of base
under mild conditions. The easy availability of the required
substrates, and the potential bioactivity of the prepared spiro-
butyrolactone pyrrolidine derivatives, makes this methodology
particularly interesting for medicinal chemistry applicatons.
Further investigation of this protocol for the synthesis of
pyrrolidines with all-carbon quaternary stereocenter is underway
in our laboratory.
White solid. Yield = 73 %; mp 122-124 oC; ee = 74.6 %; 1H
ACCEPTED MANUSCRIPT
NMR (500 MHz, CDCl3) δ 7.51-7.40 (3 H, m), 7.34 (4 H, m),
7.26-7.16 (2 H, m), 5.45 (1 H, s), 4.84 (1 H, s), 4.32 (1 H, s),
4.15-4.07 (1 H, dq, J= 10.5, 7.2), 3.91-3.65 (3 H, m), 3.30 (1 H,
dq, J= 10.5, 7.2), 2.58 (1 H, br), 2.46 (2 H, s), 0.89 (3 H, t), 0.71
(3 H, t). 13C NMR (126 MHz, CDCl3) δ 176.99, 170.34, 168.98,
137.32, 136.74, 132.89, 131.18, 130.02, 129.33, 128.47, 128.40,
127.99, 127.40, 122.32, 70.03, 69.18, 66.21, 62.88, 61.72, 61.50,
54.33, 32.15, 29.71, 13.37, 13.24. IR (KBr) ν 1757, 1716, 1454,
1370, 1267, 1183, 1131, 1012, 867, 794, 741, 703, 650, 605, 542
cm-1. HRMS Calcd. For C25H27BrNO6 [M+H]+: 516.10218,
518.10013; found: 516.10122, 518.09960. HPLC (Chiralpak AD-
H column, hexane/2-propanol = 95/5, flow rate = 0.8 mL/min) tR
= 46.8 min, 49.6 min.
+
4.3.2. diethyl 6-oxo-2,4-diphenyl-7-oxa-1-
azaspiro[4.4]nonane-3,3-dicarboxylate (3ab):
o
1
White solid. Yield = 79 %; mp 99-101 C; H NMR (500
MHz, CDCl3) δ 7.45 (2 H, d, J 7.5), 7.33 (7 H, m), 7.23 (1 H, s),
5.37 (1 H, s), 4.88 (1 H, s), 4.22 (1 H, dd, J =15.0, 7.3), 4.04 (1
H, dq, J =10.2, 7.2), 3.79 (1 H, dq, J =10.3, 7.1), 3.63 (2 H, m),
3.31 (1 H, dq, J= 10.4, 7.2), 2.73 (1 H, br), 2.55 (1 H, dt, J =13.5,
6.9), 2.38 (1 H, dt, J =13.1, 6.5), 0.80 (3 H, t), 0.71 (3 H, t). 13C
NMR (126 MHz, CDCl3) δ (126 MHz, CDCl3) 177.50, 170.37,
169.37, 136.90, 135.16, 130.67, 130.12, 128.39, 128.28, 127.97,
127.32, 71.17, 69.24, 68.93, 66.16, 61.57, 61.35, 59.56, 32.59,
13.26, 13.24. IR (KBr) ν 3341, 1771, 1711, 1455, 1367, 1253,
1190, 1151, 1021, 950, 860, 742, 700, 640, 521 cm-1. HRMS
Calcd. For C25H28NO6+ [M+H]+: 438.19166, found: 438.19179.
4. Experimental section
4.1. General methods
All reactions were performed under an atmosphere of either
argon or nitrogen using oven-dried glassware. H NMR spectra
1
were recorded on a Bruker Avance DRX 500 spectrometer in
CDCl3 at Analytical and Testing Center, Beijing Normal
1
University. H chemical shifts are reported in δ ppm relative to
CHCl3 (7.26 ppm), 13C chemical shifts are reported relative to the
central peak of CDCl3 (77.0 ppm). Data are reported either as: s =
singlet, d = doublet, dd = double doublet, t = triplet, q = quartet,
m = multiplet, br = broad, coupling constant(s) in Hz, integration.
High resolution mass spectra (HRMS) experiments were
performed on an Agilent 6540 UHD Accurate-Mass Q-TOF
LC/MS system at Analytical Instrumentation Center, Beijing
University of Chemical Technology. IR spectra were recorded on
a Bruker Alpha-p. Reactions were monitored by thin layer
chromatography (TLC) using silica gel plates. Flash column
chromatography was performed over silica gel (200-300
mesh).The enantiomeric excess (ee) of the products was
determined by HPLC using Daicel Chiralpak AS-H, AD-H and
Chiralcel OD-H columns with 2-propanol/hexane as eluent.
4.3.3. diethyl 6-oxo-2-phenyl-4-(p-tolyl)-7-oxa-1-
azaspiro[4.4]nonane-3,3-dicarboxylate (3ac):
White solid. Yield = 81 %; mp 98-99 oC; 1H NMR (500 MHz,
CDCl3) δ 7.44 (2 H, d), 7.33 (3 H, m), 7.12 (4 H, s), 5.36 (1 H, s),
4.83 (1 H, s), 4.21 (1 H, dd, J =14.8, 7.3), 4.08 (1 H, dq, J =10.7,
7.1), 3.78 (1 H, dq, J =10.7, 7.1), 3.64 (2 H, m), 3.30 (1 H, dq, J
=10.7, 7.2), 2.78 (1 H, br), 2.58 (1 H, quint), 2.38 (1 H, quint),
2.33 (1 H, s), 0.84 (1 H, t), 0.70 (1 H, t). 13C NMR (126 MHz,
CDCl3) δ 177.69, 170.53, 169.39, 137.73, 137.15, 131.90,
130.01, 129.04, 128.28, 128.24, 127.36, 71.04, 69.22, 68.92,
66.16, 61.51, 61.34, 59.29, 32.58, 21.02, 13.30, 13.25. IR (KBr) ν
1771, 1713, 1459, 1368, 1252, 1193, 1174, 1020, 954, 739, 698,
4.2. General procedure for the Cu(II)-catalyzed [3+2] 1, 3-
dipolar cycloaddition reaction.
+
546 cm-1. HRMS Calcd. For C26H30NO6 [M+H]+: 452.20731,
found: 452.20736.
Cu(ClO4)2·6H2O (6.54 mg, 0.02 mmol) and Ligand1 (0.02
mmol) were added under argon to a 10mL Schlenk tube,
containing activated 4Å MS. The freshly distilled anhydrous
THF (1 mL) was added into the tube. After being stirred for 30
min at room temperature, the cyclic imino ester 1 (0.2 mmol),
olefins 2 or 4 (0.2 mmol) and DIPEA (3 ꢀL, 0.02 mmol) were
added subsequently. The reaction mixture was stirred at room
temperature for ambient time. When the reaction was complete as
monitored by TLC, the mixture was passed through a short
column of silica gel and the diastereometric ratio (exo/endo) was
4.3.4. diethyl 4-(naphthalen-2-yl)-6-oxo-2-phenyl-
7-oxa-1-azaspiro[4.4]nonane-3,3-dicarboxylate
(3ad):
o
White solid. Yield = 80 %; mp 177-179 C; ee = 65.6 %; 1H
NMR (500 MHz, CDCl3) δ 7.88-7.73 (4 H, m), 7.55-7.45 (4 H,
m), 7.35 (4 H, m), 5.46 (1 H, s), 5.09 (1 H, s), 4.22 (1 H, dd, J
=15.4, 7.0), 4.06 (1 H, dq, J =10.7, 7.1), 3.80 (1 H, dq, J =10.7,
7.1), 3.64 (1 H, dd, J =13.9, 7.8), 3.57 (1 H, dq, J =10.7, 7.2),
3.32 (1 H, dq, J =10.7, 7.2), 2.61 (1 H, quint), 2.44 (1 H, quint),
0.71 (3 H, t), 0.67 (3 H, t). 13C NMR (126 MHz, CDCl3) δ
177.57, 170.56, 169.42, 137.03, 133.19, 132.65, 132.48, 130.04,
128.32, 128.01, 127.71, 127.44, 127.38, 127.05, 126.45, 71.12,
69.55, 69.07, 66.22, 61.62, 61.42, 59.73, 32.61, 29.71, 13.25,
13.19. IR (KBr) ν 3321, 2923, 1767, 1712, 1369, 1258, 1196,
1153, 1084, 1020, 952, 862, 740, 697, 598, 480 cm-1. HRMS
1
determined by the H NMR spectroscopic analysis of the crude
product. Then the pure adducts was purified by column
chromatography on silica gel (200-300 mesh).
4.3. Characterization data of product
1
All the products were characterized by H NMR, 13C NMR,
+
Calcd. For C29H30NO6 [M+H]+: 488.20731, found: 488.20669.
HRMS (ESI) and IR. The copies of NMR charts were reported in
Supplementary data.
HPLC (Chiralpak AS-H column, hexane/2-propanol = 90/10,
flow rate = 1 mL/min) tR = 15.80 min, 21.22 min.
4.3.1. diethyl 4-(3-bromophenyl)-6-oxo-2-phenyl-7-
oxa-1-azaspiro[4. 4]nonane-3, 3-dicarboxylate
(3aa):
4.3.5. diethyl 4-(4-chlorophenyl)-6-oxo-2-phenyl-7-
oxa-1-azaspiro[4.4]nonane-3,3-dicarboxylate
(3ae):

6
Tetrahedron
ACCEPTED MANUSCRIPT
1
1
Brown oil. Yield = 70 %; H NMR (500 MHz, CDCl3) δ
White solid. Yield = 77 %; mp 153-155oC; H NMR (500
7.43 (2 H, d), 7.33 (6 H, m), 7.18 (1 H, s), 5.35 (1 H, s), 4.88 (1
H, s), 4.27 (1 H, dd, J =15.6, 7.1), 3.99 (1 H, dd, J =15.6, 7.1),
3.79 (2 H, m), 3.67 (1 H, dq, J =10.7, 7.2), 3.31 (1 H, dq, J
=10.7, 7.2), 2.47 (1 H, quint), 2.40 (1 H, quint), 0.89 (3 H, t),
0.71 (3 H, t). 13C NMR (126 MHz, CDCl3) δ 177.21 (s), 170.34
(s), 169.20 (s), 136.90 (s), 134.10 (s), 133.64 (s), 131.54 (s),
131.03 (s), 128.58 (s), 128.35 (s), 128.19 (s), 127.33 (s), 71.03
(s), 69.21 (s), 68.94 (s), 66.18 (s), 58.72 (s), 54.92 (s), 32.31 (s),
29.71 (s), 13.85 (d, J 20.7), 13.30 (d, J 16.5). IR (KBr) ν 1768,
1712, 1464, 1375, 1261, 1183, 1131, 1021, 867, 794, 741, 659,
MHz, CDCl3) δ 7.46 (1 H, dt), 7.40 (2 H, d), 7.37-7.30 (3 H, m),
7.25-7.15 (2 H, m), 5.32 (1 H, s), 4.84 (1 H, s), 4.31-4.23 (1 H,
m), 4.10 (1 H, dq, J =10.7, 7.1), 3.88-3.78 (2 H, m), 3.74 (1 H,
dq, J =10.7, 7.2), 3.40 (1 H, dq, J =10.7, 7.2), 2.65 (1 H, br), 2.46
(1 H, dt, J =14.5, 7.3), 2.42-2.35 (1 H, m), 0.89 (1 H, t), 0.79 (1
H, t). 13C NMR (126 MHz, CDCl3) δ 177.03, 170.16, 168.84,
137.22, 135.63, 134.21, 132.84, 131.52, 131.19, 130.03, 129.23,
128.62, 128.41, 122.33, 70.80, 69.06, 68.12, 66.10, 61.85, 61.76,
58.50, 32.41, 29.70, 13.35, 13.32. IR (KBr) ν 3350, 1754, 1714,
1464, 1370, 1300, 1265, 1188, 1135, 1091, 1013, 857, 783, 742,
+
+
610, 542 cm-1. HRMS Calcd. For C25H27ClNO6 [M+H]+:
699, 644, 600, 412 cm-1. HRMS Calcd. For C25H26BrClNO6
472.15269, found: 472.15288.
[M+H]+: 550.06320, found: 550.06236.
4.3.6. diethyl 6-oxo-2-phenyl-4-(3-(trifluoromethyl)
phenyl)-7-oxa-1-azaspiro[4.4]nonane-3,3-
dicarboxylate (3af):
4.3.10. diethyl 4-(3-bromophenyl)-6-oxo-2-(p-
tolyl)-7-oxa-1-azaspiro[4. 4]nonane-3, 3-
dicarboxylate (3da):
Brown solid. Yield = 74 %; mp 90-91oC; 1H NMR (500 MHz,
CDCl3) δ 7.58 (1 H, t), 7.46 (5 H, m), 7.33 (3 H, m), 5.39 (1 H,
s), 4.98 (1 H, s), 4.29 (1 H, dd, J =15.8, 7.3), 4.11 (1 H, dq, J
=10.7, 7.2), 3.80 (2 H, m), 3.64 (1 H, dq, J =10.8, 7.2), 3.30 (1 H,
dq, J =10.7, 7.2), 2.71 (1 H, br), 2.50-2.36 (2 H, m), 0.83 (3 H, t),
0.71 (3 H, t). 13C NMR (126 MHz, CDCl3) δ 177.01, 170.29,
169.08, 137.03, 136.20, 134.42, 130.69 (q, JCCF =32.3), 129.11,
128.41, 128.36, 127.39, 126.36 (q, J =3.7), 124.80 (q, J =3.7),
123.88 (q, JCF =272.5), 71.02, 69.21, 68.96, 66.17, 61.71, 61.58,
58.84, 32.18, 29.70, 13.22. IR (KBr) ν 3327, 1773, 1710, 1449,
1370, 1328, 1259, 1194, 1156, 1125, 1073, 1020, 865, 811, 741,
White solid. Yield = 83 %; mp 88-90oC; 1H NMR (500 MHz,
CDCl3) δ 7.47-7.42 (1 H, m), 7.36 (1 H, s), 7.29 (2 H, d), 7.22-
7.18 (2 H, m), 7.15 (2 H, d), 5.31 (1 H, s), 4.84 (1 H, s), 4.304.24
(1 H, m), 4.10 (1 H, dq, J =10.7, 7.1), 3.84-3.76 (2 H, m), 3.76-
3.69 (1 H, m), 3.34 (1 H, dq, J =10.7, 7.2), 2.65 (1 H, br), 2.42 (2
H, m), 2.33 (3 H, s), 0.88 (3 H, t), 0.73 (3 H, t). 13C NMR (126
MHz, CDCl3) δ 177.20, 170.37, 169.20, 138.09, 137.50, 133.92,
132.84, 131.04, 129.96, 129.26, 128.94, 128.60, 127.89, 127.21,
122.26, 71.00, 69.17, 68.80, 66.24, 61.65, 61.57, 58.85, 32.27,
21.09, 13.36, 13.23. IR (KBr) ν 1772, 1714, 1565, 1475, 1444,
1368, 1252, 1194, 1078, 1019, 954, 786, 699, 536 cm-1. HRMS
Calcd. For C26H29BrNO6+ [M+H]+: 530.11783, found: 530.11770.
+
700, 654, 525 cm-1. HRMS Calcd. For C26H27F3NO6 [M+H]+:
506.17905, found: 506.17872.
4.3.11. diethyl 4-(3-bromophenyl)-2-(4-
methoxyphenyl)-6-oxo-7-oxa-1-azaspiro[4.
4]nonane-3,3-dicarboxylate (3ea):
4.3.7. diethyl 4-(2-bromophenyl)-6-oxo-2-phenyl-7-
oxa-1-azaspiro[4.4]nonane-3,3-dicarboxylate
(3ag):
White solid. Yield = 86 %; mp 73-75oC; 1H NMR (500 MHz,
CDCl3) δ 7.47-7.40 (2 H, m), 7.34 (2 H, d, J 8.6), 7.22-7.14 (2 H,
m), 6.85 (2 H, m), 5.29 (1 H, s), 4.82 (1 H, s), 4.30-4.22 (1 H, m),
4.17-4.02 (2 H, m), 3.96 (1 H, m), 3.79 (3 H, s), 3.77-3.70 (1 H,
m), 3.36 (1 H, dq, J =10.7, 7.2), 2.75 (1 H, br), 2.57-2.32 (2 H,
m), 0.88 (1 H, t), 0.77 (1 H, t). 13C NMR (126 MHz, CDCl3) δ
177.23, 170.40, 169.23, 159.60, 137.49, 132.85, 131.04, 129.96,
129.24, 128.54, 122.25, 113.66, 70.89, 68.49, 66.21, 65.90,
61.67, 61.57, 58.71, 55.34, 32.34, 13.37. IR (KBr) ν 1765, 1713,
1612, 1566 1513, 1463, 1369, 1245, 1176, 1013, 835, 784, 700,
White solid. Yield = 75 %; mp 180-182oC; H NMR (500
1
MHz, CDCl3) δ7.64 (1 H, m), 7.52 (2 H, d), 7.39-7.27 (5 H, m),
7.15 (1 H, m), 5.75 (1 H, s), 5.31 (1 H, s), 4.24- 4.18 (1 H, m),
3.93-3.82 (2 H, m), 3.67 (1 H, m), 3.47 (1 H, m), 2.84 (1 H, br),
2.43-2.27 (2 H, m), 0.77 (3 H, t), 0.74 (3 H, t). 13C NMR (126
MHz, CDCl3) δ 177.20, 169.51, 168.98, 136.30, 136.16, 133.70,
130.38, 129.16, 128.28, 128.26, 127.29, 126.99, 126.72, 72.46,
68.90, 68.75, 65.86, 61.77, 61.25, 56.16, 34.03, 29.70, 13.27,
13.22. IR (KBr) ν 3325, 1772, 1710, 1470, 1370, 1260, 1191,
1157, 1078, 1023, 863, 757, 743, 698, 603, 508 cm-1. HRMS
Calcd. For C25H27BrNO6+ [M+H]+: 516.10218, found: 516.10152.
549, 510 cm-1. HRMS Calcd. For C26H29BrNO7 [M+H]+:
546.11274, found: 546.11234.
+
4.3.8. diethyl 2-(2-bromophenyl)-4-(3-
bromophenyl)-6-oxo-7-oxa-1-azaspiro[4.4]nonane-
3,3-dicarboxylate (3ba):
4.3.12. diethyl 4-(3-bromophenyl)-2-(2,4-
difluorophenyl)-6-oxo-7-oxa-1-
azaspiro[4.4]nonane-3, 3-dicarboxylate (3fa):
1
1
White solid. Yield = 76 %; mp 129-131oC; H NMR (500
White solid. Yield = 73 %; mp 126-128oC; H NMR (500
MHz, CDCl3) δ 7.63 (1 H, q), 7.57 (1 H, d), 7.46 (1 H, d), 7.41 (1
H, s), 7.36 (1 H, t), 7.31 (1 H, d), 7.21 (1 H, t), 7.18-7.12 (1 H,
m), 5.98 (1 H, s), 4.79 (1 H, s), 4.37 (1 H, dq, J =10.8, 7.1), 4.28
(1 H, dd, J =16.1, 7.3), 4.00-3.87 (2 H, m), 3.74 (1 H, dq, J
=10.7, 7.1), 3.25 (1 H, dq, J =10.7, 7.2), 2.77-2.68 (1 H, m),
2.59-2.52 (1 H, m), 2.39-2.32 (1 H, m), 1.07 (3 H, t), 0.81 (3 H,
t). 13C NMR (126 MHz, CDCl3) δ 177.49, 170.76, 168.39,
139.25, 135.64, 132.97, 132.75, 131.36, 130.18, 130.02, 129.57,
128.79, 127.83, 125.49, 122.10, 69.55, 68.64, 66.57, 66.07,
62.03, 61.43, 57.96, 31.95, 13.56, 13.26. IR (KBr) ν1768, 1713,
1556, 1466, 1438, 1369, 1268, 1179, 1136, 1019, 908, 859, 797,
743, 705, 662, 606, 504, 450 cm-1. HRMS Calcd. For
C25H26Br2NO6+ [M+H]+: 596.01064, found: 596.01027.
MHz, CDCl3) δ 7.60 (1 H, dd), 7.48-7.43 (1 H, m), 7.37 (1 H, s),
7.23 (2 H, m), 6.92 (1 H, m), 6.80 (1 H, ddd, J =10.9, 8.8, 2.5),
5.61 (1 H, s), 4.84 (1 H, s), 4.24 (2 H, m), 3.93-3.81 (3 H, m),
3.49 (1 H, dq, J =10.8, 7.2), 2.71 (1 H, br), 2.59 (1 H, m), 2.49-
2.42 (1 H, m), 0.98 (3 H, t), 0.88 (3 H, t). 13C NMR (126 MHz,
CDCl3) δ 177.24, 170.36, 168.43, 162.70 (dd, JCF = 250.2, 12.3
Hz), 161.03 (dd, JCF = 250.7, 11.8 Hz), 136.22, 132.91, 131.32,
130.36 (dd, JCCCF = 9.7, 5.3), 130.04, 129.76, 122.21, 121.76 (dd,
JCCF = 12.9, 3.9), 111.54 (dd, JCCF = 21.1, 3.5), 103.61 (t, JCCF
=
25.9), 69.76, 68.76, 66.05, 62.21, 61.99, 61.76, 57.92, 32.10,
29.70, 13.45, 13.38. IR (KBr) ν 1754, 1715, 1604, 1503, 1432,
1369, 1264, 1189, 1135, 1098, 1014, 966, 848, 784, 750, 699,
+
641, 614, 500, 443 cm-1. HRMS Calcd. For C25H25BrF2NO6
[M+H]+: 552.08333, 554.08128; found: 552.08340, 554.08159.
4.3.9. diethyl 4-(3-bromophenyl)-2-(4-
chlorophenyl) -6-oxo-7-oxa-1-azaspiro[4.4]nonane-
3, 3-dicarboxylate (3ca):
4.3.13. diethyl 4-(3-bromophenyl)-2-(4-
bromophenyl)-6-oxo-7-oxa-1-azaspiro[4.4]nonane-
3,3-dicarboxylate (3ga):

7
1
White solid. mp 116-118oC; H NMR (500 MHz, CDCl3) δ
4.3.17. diethyl 4-(3-bromophenyl)-2-(furan-2-yl)-
6-oxo-7-oxa-1-azaspiro[4.4]nonane-3,3-
dicarboxylate (3la):
ACCEPTED MANUSCRIPT
7.50-7.41 (3 H, m), 7.37-7.31 (3 H, m), 7.20 (2 H, m), 5.30 (1 H,
d, J = 2.2), 4.83 (1 H, d, J = 1.6), 4.30-4.22 (1 H, m), 4.09 (1 H,
dqd, J = 10.7, 7.1, 1.3), 3.87-3.77 (2 H, m), 3.73 (1 H, dqd, J =
10.7, 7.2, 1.4), 3.40 (1 H, dqd, J = 14.3, 7.2, 2.3), 2.75 (1 H, br),
2.49-2.41 (1 H, m), 2.41-2.33 (1 H, m), 0.88 (3 H, td, J = 7.1,
1.5), 0.78 (3 H, td, J = 7.2, 1.8). 13C NMR (126 MHz, CDCl3) δ
177.06, 170.14, 168.82, 137.24, 136.25, 132.85, 131.35, 131.18,
130.03, 129.22, 122.31, 70.76, 69.03, 68.14, 66.09, 61.85, 61.75,
58.46, 32.42, 13.35, 13.32. IR (KBr) ν 1772, 1715, 1593, 1566,
1475, 1368, 1251, 1194, 1175, 1073, 1010, 1155, 856, 750, 693,
583 cm-1. HRMS Calcd. For C25H26Br2NO6+ [M+H]+: 596.01064,
found: 596.01009.
White solid. Yield = 85 %; mp 99-101oC; 1H NMR (500 MHz,
CDCl3) δ 7.44 (1 H, m), 7.37 (1 H, t), 7.33 (1 H, s), 7.20 (2 H,
m), 6.46 (1 H, d, J =2.8), 6.36 (1 H, dd, J =3.1, 1.8), 5.35 (1 H,
s), 4.85 (1 H, s), 4.28 (1 H, dd, J 15.7, 7.3), 4.16-4.05 (2 H, m),
4.02 (1 H, m), 3.84 (1 H, m), 3.77 (1 H, dq, J =10.7, 7.2), 3.69 (1
H, dq, J =10.7, 7.2), 2.91 (1 H, s), 2.42-2.30 (2 H, m), 0.98 (3 H,
t,), 0.90 (3 H, t). 13C NMR (126 MHz, CDCl3) δ 176.70, 169.86,
168.81, 149.86, 142.35, 137.25, 132.78, 131.10, 130.01, 129.25,
122.29, 110.67, 109.01, 69.66, 69.16, 66.19, 63.31, 62.29, 61.79,
58.18, 32.35, 13.68, 13.48. IR (KBr) ν 1766, 1719, 1566, 1456,
1372, 1267, 1178, 1065, 1016, 856, 738, 700, 559 cm-1. HRMS
Calcd. For C23H25BrNO7+ [M+H]+: 506.08144, found: 506.08122.
4.3.14. diethyl 4-(3-bromophenyl)-2-(4-
(methylthio)phenyl)-6-oxo-7-oxa-1-
azaspiro[4.4]nonane-3,3-dicarboxylate (3ha):
4.3.18. (E)-diethyl 4-(3-bromophenyl)-6-oxo-2-
styryl-7-oxa-1-azaspiro[4.4]nonane-3,3-
dicarboxylate (3ma):
1
Off-white solid. Yield = 85 %; mp 130-132oC; H NMR (500
MHz, CDCl3) δ 7.48-7.41 (1 H, m), 7.35 (3 H, m), 7.25-7.16 (4
H, m), 5.30 (1 H, s), 4.83 (1 H, s), 4.27 (1 H, dd, J =15.6, 7.3),
4.10 (1 H, dq, J =10.8, 7.1), 3.81 (3 H, m), 3.73 (1 H, dq, J
=10.8, 7.2), 3.38 (1 H, dq, J =10.7, 7.2), 2.78 (1 H, br), 2.47 (3 H,
s), 2.41 (2 H, m), 0.88 (2 H, t), 0.76 (2 H, t). 13C NMR (126
MHz, CDCl3) δ 177.10, 170.27, 169.03, 138.85, 137.35, 133.74,
132.84, 131.11, 130.00, 129.25, 127.86, 126.29, 122.29, 70.87,
69.10, 68.48, 66.18, 61.77, 61.66, 58.63, 32.33, 13.36, 13.32. IR
(KBr) ν 1771, 1714, 1595, 1565, 1475, 1441, 1367, 1297, 1251,
1194, 1175, 1078, 1016, 822, 788, 697, 584, 537 cm-1. HRMS
Calcd. For C26H28BrNO6S + H+: 562.08990, 564.08785; found:
562.08978, 564.08818.
Brown oil. Yield = 62 %; 1H NMR (500 MHz, CDCl3) δ 7.46-
7.44 (1 H, m), 7.39 (3 H, m), 7.33 (3 H, m), 7.28-7.25 (1 H, m),
7.20 (2 H, m), 6.63 (1 H, d, J =15.9), 6.37 (1 H, dd, J =15.9, 7.2),
4.81 (1 H, s), 4.71 (1 H, dd, J =7.2, 1.0), 4.32 (1 H, m), 4.13 (1
H, m), 4.08-3.97 (2 H, m), 3.91 (1 H, m), 3.88-3.79 (1 H, m),
3.48-3.36 (1 H, m), 2.34-2.17 (2 H, m), 1.11 (1 H, t), 0.97 (1 H,
t). 13C NMR (126 MHz, CDCl3) δ 177.61, 170.25, 168.84,
137.86, 136.26, 132.89, 131.00, 129.96, 129.23, 128.67, 128.62,
128.58, 127.95, 126.74, 126.56, 124.76, 122.26, 70.52, 69.22,
67.31, 65.96, 61.94, 61.68, 57.03, 34.20, 14.00, 13.46. IR (KBr) ν
2923, 1769, 1716, 1594, 1565, 1475, 1448, 1368, 1263, 1174,
1020, 967, 907, 854, 724, 692, 540 cm-1. HRMS Calcd. For
C27H28BrNO6 + H+: 542.11783, found: 542.11715.
4.3.15. diethyl 4-(3-bromophenyl)-2-(3-
nitrophenyl)-6-oxo-7-oxa-1-azaspiro[4.4]nonane-
3,3-dicarboxylate (3ia):
4.3.19. 6-oxo-2,4-diphenyl-7-oxa-1-
1
azaspiro[4.4]nonane-3, 3-dicarbonitrile (5aa):
White solid. Yield = 73 %; H NMR (500 MHz, CDCl3) δ
1
White solid. Yield = 86 %; ee = 13 %; mp 85-87oC; H NMR
8.35 (1H, t), 8.19 (1H, dd), 7.93 (1H, d), 7.56 (1H, t), 7.48 (1H,
dt), 7.37 (1H, d), 7.26-7.16 (2H, m), 5.32 (1H, s), 4.87 (1H, s),
4.28 (1H, dt, J =8.8, 7.0), 4.13 (1H, dq, J =10.7, 7.1), 3.91-3.73
(3H, m), 3.43 (1H, dq, J =10.8, 7.2), 2.65 (1H, s), 2.43 (2H, m),
0.92 (1H, t), 0.79 (1H, t). 13C NMR (126 MHz, CDCl3) δ 176.92,
169.90, 168.33, 147.98, 139.73, 139.68, 136.90, 136.88, 133.65,
132.94, 131.36, 130.11, 129.33, 129.28, 123.19, 123.17, 122.40,
70.63, 68.93, 67.72, 65.94, 62.06, 61.96, 57.90, 32.75, 13.37. IR
(KBr) ν 3330, 1751, 1720, 1527, 1477, 1443, 1348, 1267, 1191,
1128, 1095, 1017, 895, 866, 787, 744, 686, 648, 600, 438 cm-1.
(500 MHz, CDCl3) δ 7.69 (2 H, dd), 7.60 (2 H, dt), 7.54-7.46 (6
H, m), 5.16 (1 H, s), 4.49 (1 H, s), 4.32-4.21 (1 H, m), 3.75 (1 H,
m), 2.72 (1 H, br), 2.57 (1 H, m), 2.51-2.44 (1 H, m). 13C NMR
(126 MHz, CDCl3) δ 178.50, 132.78, 130.47, 130.31, 129.94,
129.54, 129.47, 129.21, 129.00, 127.48, 127.43, 113.20, 112.70,
68.81, 66.11, 65.44, 59.80, 47.04, 34.52. IR (KBr) ν 1769, 1717,
1594, 1565, 1475, 1444, 1368, 1262, 1196, 1175, 1150, 1078,
1011, 884, 858, 738, 700, 597, 443 cm-1. HRMS Calcd. For
+
C21H18N3O2 [M+H]+: 344.13990, found: 344.13908. HPLC
+
HRMS Calcd. For C25H26BrN2O8 [M+H]+: 561.08725,
(Chiralpak AS-H column, hexane/2-propanol = 90/10, flow rate =
1 mL/min) tR = 44.9 min, 79.5 min.
563.08521; found: 561.08639, 563.08478.
4.3.16. diethyl 4-(3-bromophenyl)-2-(naphthalen-2-
yl)-6-oxo-7-oxa-1-azaspiro[4.4]nonane-3,3-
dicarboxylate (3ja):
4.3.20. 2-(4-bromophenyl)-6-oxo-4-phenyl-7-oxa-1-
azaspiro[4.4]nonane-3,3-dicarbonitrile (5ga):
1
White solid. Yield = 80 %; mp 150-152oC; H NMR (500
1
White solid. mp 144-146oC; H NMR (500 MHz, CDCl3) δ
MHz, CDCl3) δ 7.64-7.56 (6 H, m), 7.51-7.48 (3 H, m), 5.14 (1
H, s), 4.46 (1 H, s), 4.29-4.22 (1 H, m), 3.74-3.67 (1 H, m), 2.72
(1 H, s), 2.61-2.56 (1 H, m), 2.50-2.44 (1 H, m). 13C NMR (126
MHz, CDCl3) δ 178.50, 132.25, 131.90, 130.21, 130.06, 129.60,
129.38, 129.07, 127.43, 124.58, 112.94, 112.49, 68.21, 66.12,
65.43, 59.71, 46.72, 34.46. IR (KBr) ν 3320, 2923, 1761, 1487,
1456, 1376, 1214, 1179, 1073, 1010, 908, 837, 729, 700, 560,
493 cm-1. HRMS Calcd. For C21H16BrN3O2+ [M+H]+: 422.05041,
424.04837; found: 422.04910, 424.04742.
7.90-7.79 (4 H, m), 7.58 (1 H, dd), 7.52-7.44 (3 H, m), 7.40 (1 H,
s), 7.27-7.20 (2 H, m), 5.31 (1 H, s), 4.94 (1 H, s), 4.29 (1 H, dd,
J =15.6, 7.2), 4.17-4.08 (1 H, m), 3.83 (1 H, dt, J =13.5, 6.6),
3.76 (1 H, dq, J =10.7, 7.2), 3.67 (1 H, dq, J =10.7, 7.1), 3.12 (1
H, dq, J =10.7, 7.2), 2.95 (1 H, s), 2.55-2.40 (2 H, m), 0.89 (2 H,
t), 0.47 (1 H, t). 13C NMR (126 MHz, CDCl3) δ 177.16, 170.34,
169.08, 137.41, 134.44, 134.41, 133.16, 133.02, 132.88, 131.12,
130.01, 129.29, 128.08, 127.87, 127.49, 126.28, 126.25, 125.43,
122.31, 71.01, 69.20, 68.97, 66.21, 61.69, 61.63, 58.82, 32.33,
13.37, 13.03. IR (KBr) ν 1771, 1714, 1594, 1565, 1475, 1441,
1368, 1253, 1194, 1177, 1078, 1018, 907, 857, 820, 730, 698,
541, 478 cm-1. HRMS Calcd. For C29H28BrNO6 + H+: 566.11783,
568.11578; found: 566.11722, 568.11586.
4.3.21. 6-oxo-4-phenyl-2-(p-tolyl)-7-oxa-1-
azaspiro[4. 4]nonane-3, 3-dicarbonitrile (5da):
White solid. Yield = 87 %; mp 91-93oC; 1H NMR (500 MHz,
CDCl3) δδ (500 MHz, CDCl3) 7.60 (2 H, dd), 7.57 (2 H, d),
H
7.49 (4 H, m), 7.30 (1 H, s), 5.13 (1 H, s), 4.48 (1 H, s), 4.27 (1
H, dd, J =16.2, 7.2), 3.75 (1 H, td, J =8.0, 5.6), 2.63 (1 H, br),

8
Tetrahedron
ACCEPTED MANUSCRIPT
2.59-2.54 (1 H, m), 2.49-2.44 (1 H, m), 2.42 (1 H, s). 13C NMR
4591-4597; (f) Christoffers, J.; Baro, A. Adv. Synth. Catal. 2005,
347, 1473-1482; (g) Dalpozzo, R.; Bartoli, G.; Bencivenni, G.
Chem. Soc. Rev. 2012, 41, 7247-7290; (h) Das, J. P.; Marek, I.
Chem. Commun. 2011, 47, 4593-4623.
(126 MHz, CDCl3) δ 178.50, 140.36, 130.53, 130.32, 129.90,
129.68, 129.52, 129.46, 129.00, 127.43, 127.28, 113.25, 112.82,
68.81, 66.08, 65.40, 59.79, 47.13, 34.54, 21.33. IR (KBr) ν 3322,
2922, 1755, 1515, 1456, 1377, 1216, 1180, 1082, 1013, 907, 821,
766, 729, 698, 672, 551, 493 cm-1. HRMS Calcd. For
C22H20N3O2+ [M+H]+: 358.15555, found: 358.15535.
5. For selected leading examples of asymmetric construction of
quaternary carbon centers through 1, 3- dipolar cycloaddition, see:
(a) González-Esguevillas, M.; Adrio, J.; Carretero, J. C. Chem.
Commun. 2013, 49, 4649-4651; (b) Walton, M. C.; Yang, Y.-F.;
Hong, X.; Houk, K.; Overman, L. E. Org. Lett. 2015, 17, 6166-
6169; (c) Teng, H.-L.; Huang, H.; Tao, H.-Y.; Wang, C.-J. Chem.
Commun. 2011, 47, 5494-5496; (d) He, Z.; Liu, T.; Tao, H.;
Wang, C.-J. Org. Lett. 2012, 14, 6230-6233; (e) Zhang, Z. M.; Xu,
B.; Xu, S.; Wu, H. H.; Zhang, J. Angew. Chem. Int. Ed. 2016, 55,
6324-6328; (f) Tang, L. W.; Zhao, B. J.; Dai, L.; Zhang, M.;
Zhou, Z. M. Chem. Asian J. 2016, 11, 2470-2477; (g) Reboredo,
S.; Vicario, J. L.; Badía, D.; Carrillo, L.; Reyes, E. Adv. Synth.
Catal. 2011, 353, 3307-3312.
4.3.22. ethyl 3-cyano-6-oxo-2,4-diphenyl-7-oxa-1-
azaspiro[4.4]nonane-3-carboxylate (5ac):
1
Colorless oil. Yield = 77 %; H NMR (500 MHz, CDCl3) δ
7.58-7.48 (m, 2H), 7.44 (dd, J = 6.6, 2.6 Hz, 2H), 7.35-7.25 (m,
6H), 5.12 (s, 1H), 4.48 (s, 1H), 4.16-3.95 (m, 3H), 3.39 (dt, J =
8.9, 7.3 Hz, 1H), 2.72 (d, J = 5.3 Hz, 1H), 2.64-2.53 (m, 1H),
2.38 (dt, J = 14.0, 7.3 Hz, 1H), 0.97 (t, J = 7.1 Hz, 3H). 13C NMR
(126 MHz, CDCl3) δ 178.60, 164.42, 133.93, 131.01, 128.35,
128.19, 128.08, 128.02, 127.46, 126.40, 115.45, 67.55, 64.91,
64.84, 62.26, 58.33, 58.13, 33.63, 12.85. IR (KBr) ν 1763, 1737,
1498, 1457, 1370, 1256, 1215, 1178, 1160, 1094, 1016, 912, 821,
730, 699, 557 cm-1. HRMS Calcd. For C23H22N2O4 + H+:
391.16578, found: 391.16580.
6. For recent reviews about construction of spirocyclics, see: (a)
Kotha, S.; Deb, A. C.; Lahiri, K.; Manivannan, E. Synthesis 2009,
2009, 165-193; (b) Sannigrahi, M. Tetrahedron 1999, 55, 9007-
9071; (c) Marson, C. M. Chem. Soc. Rev. 2011, 40, 5514-5533; (d)
Zheng, Y.; Tice, C. M.; Singh, S. B. Bio. Med. Chem. Lett. 2014,
24, 3673-3682.
7. Bartoli, A.; Rodier, F.; Commeiras, L.; Parrain, J.-L.; Chouraqui,
G. Natural product reports 2011, 28, 763-782.
8. Elger, W.; Beier, S.; Pollow, K.; Garfield, R.; Shi, S. Q.; Hillisch,
A. Steroids 2003, 68, 891-905.
4.3.23. di-tert-butyl 4-(3-bromophenyl)-6-oxo-2-
phenyl-7-oxa-1-azaspiro[4.4]nonane-3,3-
dicarboxylate (5ad):
9. (a) Cui, C.-B.; Kakeya, H.; Osada, H. Tetrahedron 1996, 52,
12651-12666; (b) KONDOH, M.; Cheng-Bin, C.; MAYUMI, T.;
OSADA, H. Biochemical Journal 1998, 333, 543-548.
10. (a) Chen, C.; Li, X.; Schreiber, S. L. J. Am. Chem. Soc. 2003, 125,
10174-10175; (b) Schreiber, S. L. Science 2000, 287, 1964-1969;
(c) Spandl, R. J.; Díaz-Gavilán, M.; O'Connell, K. M.; Thomas, G.
L.; Spring, D. R. The Chemical Record 2008, 8, 129-142; (d)
Burke, M. D.; Schreiber, S. L. Angew. Chem. Int. Ed. 2004, 43,
46-58.
11. Chen, X.-H.; Wei, Q.; Luo, S.-W.; Xiao, H.; Gong, L.-Z. J. Am.
Chem. Soc. 2009, 131, 13819-13825.
12. Antonchick, A. P.; Gerding-Reimers, C.; Catarinella, M.;
Schürmann, M.; Preut, H.; Ziegler, S.; Rauh, D.; Waldmann, H.
Nat. Chem. 2010, 2, 735-740.
13. (a) Liu, T.; Li, Q.; He, Z.; Zhang, J.; Wang, C. Chin. J. Catal.
2015, 36, 68-77; (b) Liu, T.-L.; He, Z.-L.; Tao, H.-Y.; Cai, Y.-P.;
Wang, C.-J. Chem. Commun. 2011, 47, 2616-2618; (c) Liu, T. L.;
He, Z. L.; Li, Q. H.; Tao, H. Y.; Wang, C. J. Adv. Synth. Catal.
2011, 353, 1713-1719; (d) Liu, T.-L.; He, Z.-L.; Wang, C.-J.
Chem. Commun. 2011, 47, 9600-9602; (e) Hong, L.; Wang, R.
Adv. Synth. Catal. 2013, 355, 1023-1052; (f) Li, Q.-H.; Liu, T.-L.;
Wei, L.; Zhou, X.; Tao, H.-Y.; Wang, C.-J. Chem. Commun. 2013,
49, 9642-9644.
14. (a) Grigg, R.; Sarker, M. A. B. Tetrahedron 2006, 62, 10332-
10343; (b) Grigg, R.; Kilner, C.; Sarker, M. A.; de la Cierva, C.
O.; Dondas, H. A. Tetrahedron 2008, 64, 8974-8991.
15. Liu, T. L.; He, Z. L.; Tao, H. Y.; Wang, C. J. Chem. Eur. J. 2012,
18, 8042-6.
1
Colorless oil. Yield = 73 %; H NMR (500 MHz, CDCl3) δ
7.47 (d, J = 7.1 Hz, 1H), 7.40-7.32 (m, 2H), 7.30-7.07 (m, 2H),
5.19 (s, 5H), 4.72 (s, 1H), 4.23-4.12 (m, 1H), 3.79-3.67 (m, 1H),
2.67 (s, 1H), 2.30-2.14 (m, 1H), 1.10 (s, 9H), 0.92 (s, 9H). 13C
NMR (126 MHz, CDCl3) δ 176.57, 167.85, 166.85, 137.44,
136.50, 132.30, 129.84, 128.97, 128.74, 127.16, 126.96, 126.88,
121.31, 81.56, 81.44, 70.64, 67.76, 67.18, 64.94, 57.29, 32.44,
26.51, 26.21. IR (KBr) ν 1774, 1713, 1557, 1477, 1368, 1284,
1256, 1221, 1162, 1143, 1023, 909, 844, 731, 698 cm-1. HRMS
Calcd. For C29H34BrNO6 + H+: 572.16478, 574.16273; found:
572.16407, 574.16254.
Supplementary data
Supplementary data associated with this article
References and notes
1. For recent reviews about 1,3-dipolar cycloaddition reactions of
azomethine ylides, see: (a) Adrio, J.; Carretero, J. C.
Chem.Commun. 2014, 50, 12434-12446; Chem. Commun. 2011,
47, 6784-6794; (b) Maroto, E. E.; Izquierdo, M.; Reboredo, S.;
Marco-Martínez, J.; Filippone, S.; Martín, N. Acc. Chem. Res.
2014, 47, 2660-2670; (c) Moyano, A.; Rios, R. Chem. Rev. 2011,
111, 4703-4832; (d) Stanley, L. M.; Sibi, M. P. Chem. Rev. 2008,
108, 2887-2902; (e) Albrecht, Ł.; Jiang, H.; Jørgensen, K. A.
Angew. Chem. Int. Ed. 2011, 50, 8492-8509; (f) Gothelf, K. V.;
Jørgensen, K. A. Chem. Rev. 1998, 98, 863-910; (g) Engels, B.;
Christl, M. Angew. Chem. Int. Ed. 2009, 48, 7968-7970.
16. Wang, L.; Shi, X.-M.; Dong, W.-P.; Zhu, L.-P.; Wang, R. Chem.
Commun. 2013, 49, 3458-3460.
17. PCT Int. Appl., 2013102655, 11 Jul 2013.
18. CCDC 1509290 (3ga) and CCDC 1509675 (3ia). These data can
be obtained free of charge from The Cambridge Crystallographic
Data Centre.
19. L. Dai, D. Xu, L. W. Tang, Z. M. Zhou, ChemCatChem 2015, 7,
1078–1082.
2. Wetzel, S.; Bon, R. S.; Kumar, K.; Waldmann, H. Angew. Chem.
Int. Ed. 2011, 50, 10800-10826
3. (a) Padwa, A.; Pearson, W. H. Synthetic applications of 1, 3-
dipolar cycloaddition chemistry toward heterocycles and natural
products; John Wiley & Sons, 2003; Vol. 59; (b) Narayan, R.;
Potowski, M.; Jia, Z.-J.; Antonchick, A. P.; Waldmann, H. Acc.
Chem. Res. 2014, 47, 1296-1310.
4. For reviews on the asymmetric construction of all-carbon
quaternary stereocenters, see: (a) Ley, S. V.; Christoffers, J.; Baro,
A. Quaternary stereocenters: challenges and solutions for organic
synthesis; John Wiley & Sons, 2006; (b) Quasdorf, K. W.;
Overman, L. E. Nature 2014, 516, 181-191; (c) Douglas, C. J.;
Overman, L. E. Proceedings of the National Academy of Sciences
of the United States of America 2004, 101, 5363-5367; (d) Corey,
E. J.; Guzman-Perez, A. Angew. Chem. Int. Ed. 1998, 37, 388-401;
(e) Christoffers, J.; Mann, A. Angew. Chem. Int. Ed. 2001, 40,