Asymmetric synthesis approach of enantiomerically pure spiro-indenoquinoxaline pyrrolidines and spiro-indenoquinoxaline pyrrolizidines

Article abstract of DOI:10.1016/j.tetasy.2015.08.013

An efficient, one-pot, four-component procedure for the synthesis of a small library of novel chiral spiro-indenoquinoxaline pyrrolidines and chiral spiro-indenoquinoxaline pyrrolizidines with high regio-, diastereo- (up to 96 dr), and enantioselectivity (up to 99% ee), through a 1,3-dipolar cycloaddition reaction of azomethine ylides and an optically active cinnamoyl-crotonoyl oxazolidinone is described. This methodology was very simple and was utilized to construct complex products from simple starting materials. The process was carried out in aqueous ethanol as an eco-friendly solvent and in the absence of any Lewis acids catalysts. The oxazolidinone chiral auxiliary was removed through a non-destructive protocol. The reaction mechanism is discussed on the basis of the assignment of the absolute configuration of the cycloadducts and using quantum mechanical calculations. The regio- and stereoselectivity were described on the basis of transition states' stabilities and global and local reactivity indices of the reactants. The results of the theoretical calculations are in agreement with the experimental outcomes.

Full text of DOI:10.1016/j.tetasy.2015.08.013

Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis approach of enantiomerically pure
spiro-indenoquinoxaline pyrrolidines and spiro-indenoquinoxaline
pyrrolizidines
b
Naeimeh Shahrestani a, Farbod Salahi a, Niloofar Tavakoli a, Khosrow Jadidi a, , Mahshid Hamzehloueian ,
⇑
Behrouz Notash a
a Department of Chemistry, Shahid Beheshti University, G.C., Tehran 1983963113, Iran
b Department of Chemistry, Islamic Azad University, Jouybar Branch, Jouybar 47715-195, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient, one-pot, four-component procedure for the synthesis of a small library of novel chiral spiro-
indenoquinoxaline pyrrolidines and chiral spiro-indenoquinoxaline pyrrolizidines with high regio-, dia-
stereo- (up to 96 dr), and enantioselectivity (up to 99% ee), through a 1,3-dipolar cycloaddition reaction
of azomethine ylides and an optically active cinnamoyl–crotonoyl oxazolidinone is described. This
methodology was very simple and was utilized to construct complex products from simple starting mate-
rials. The process was carried out in aqueous ethanol as an eco-friendly solvent and in the absence of any
Lewis acids catalysts. The oxazolidinone chiral auxiliary was removed through a non-destructive proto-
col. The reaction mechanism is discussed on the basis of the assignment of the absolute configuration of
the cycloadducts and using quantum mechanical calculations. The regio- and stereoselectivity were
described on the basis of transition states’ stabilities and global and local reactivity indices of the reac-
tants. The results of the theoretical calculations are in agreement with the experimental outcomes.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 12 December 2014
Revised 14 August 2015
Accepted 18 August 2015
Available online xxxx
1. Introduction
are important types of nitrogen containing heterocyclic
compounds, which have both biological and pharmaceutical
The advantages of asymmetric multicomponent reactions
together with the high level of stereoselectivity attained in some
of these reactions, have forced chemists in industry and in acade-
mia to adopt this new synthesis strategy as a viable option.1
Asymmetric 1,3-dipolar cycloaddition reactions have become a
rapidly growing field of research in organic chemistry. This
approach allows the chirality in a product to be introduced via
attachment and removal of a chiral auxiliary. A number of asym-
metric 1,3-dipolar cycloaddition reactions of azomethine ylides,
where the chirality was located in the dipolarophile using a chiral
auxiliary, are described in the literature.2–4
Asymmetric 1,3-dipolar cycloaddition reactions of azomethine
ylides offer an effective approach to access chiral pyrrolidines
and pyrrolizidines substructures containing three or four new
stereogenic centres that are found in many biologically active com-
pounds,5,6,7a,b particularly for spiro-pyrrolidines that exhibit anti-
convulsion7c potential antileukaemic7d local anaesthetic7e and
antiviral activities.7f In addition, tetracyclic indenoquinoxalines
properties.8 For example, quinoxalines, brimonidine and vareni-
cline (Fig. 1) have been approved by the food and drug administra-
tion for the treatment of glaucoma9a and smoking cessation
therapy,9b,c while NVPBSK805,9d NCGC55879-019e and R(+)
XK469,9f act as potent janus kinase inhibitors, BRCA1 inhibitors
and anti-tumour agents, respectively.
It is expected that joining indenoquinoxaline to a chiral pyrro-
lidine or pyrrolizidine ring through a spiro atom at the C-3 position
could lead to the formation of chiral spiro-indenoquinoxaline
pyrrolidine or spiro-indenoquinoxaline pyrrolizidine systems, thus
providing more opportunities for the development of a wide range
of biologically active compounds. Hence, as a result of the afore-
mentioned reasons and in continuation of our investigations
towards the synthesis of various spiro heterocyclic compounds,10
we herein report, a mild, expeditious, and facile four-component,
one-pot synthesis of novel heterocyclic chiral spiro-indenoquinox-
aline pyrrolidine and spiro-indenoquinoxaline pyrrolizidine
systems with high regio-, diastereo- (>96:4 dr), and enantioselec-
tivity (>99% ee) through a catalyst-free, one-pot, four-component
1,3-dipolar cycloaddition reaction of various amino acid,
L-proline
⇑
Corresponding author. Tel./fax: +98 021 22431661.
E-mail address: k-jadidi@sbu.ac.ir (K. Jadidi).
4, trans-4-hydroxy- -proline 5 or sarcosine 6 with ninhydrin 1,
L
http://dx.doi.org/10.1016/j.tetasy.2015.08.013
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Shahrestani, N.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.08.013

2
N. Shahrestani et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
O
H
N
N
F
F
N
N
H
H
N
N
N
N
N
N
O
CH3
O
N
N
O
O
COOH
Cl
O
NVP-BSK805
R(+)XK469
NCGC55879-01
S
COOH
Br
O
H
N
N
H
N
N
N
N
N
N
N
H
O
NH
N
N
COOH
Varenicline
Brimonidine
Quinacillin
Figure 1. Some biologically important drugs and molecules with a quinoxaline moiety.
O
R1
R1
O
H2N
H2N
OH
OH
(S)
R2
N
O
O
O
1
2
3
X
OH
N
H
COOH
N
H
O
6
4
X = H
5 X = OH
Hc
X
Hb R2
Hc
Hc
R2
Hb
O
O
N
N
N
Ha
O
N
Ha
O
N
N
O
O
N
R1
N
R1
R1
7a-g
R1
7h-i
NaOMe, DMC
CH2Cl2, r.t., 4h
NaOMe, DMC
CH2Cl2, r.t., 4h
X
Hc
Hc
Hc
H
b R2
Hb
N
R2
O
N
O
N
Ha
Ha
O
O
N
N
N
R1
R1
R1
R1
8h-i
8a-g
Scheme 1. Asymmetric synthesis of new chiral spiro-indenoquinoxaline pyrrolidine and spiro-indenoquinoxaline pyrrolizidine 7 and 8.
phenylenediamines 2, and optically active cinnamoyl–crotonoyl
oxazolidinone 3 as mentioned in Scheme 1.
Over the past decade, the understanding of the selectivity beha-
viour in the polar [3+2] cycloaddition reactions has evolved from a
successful interplay between theory and experiment. In this
regard, a theoretical analysis of regio- and stereoselectivity of the
1,3-dipolar cycloaddition reaction of azomethine ylide 10
(Scheme 2) with cinnamoyl–crotonoyl oxazolidinone 3 was carried
out by calculating the relevant transition states and reactivity
indices.
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N. Shahrestani et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
3
O
O
O
O
N
-H2O
H2O
NH2
NH2
OH
OH
EtOH, ref
-H2O
O
N
O
2
1
9
4
COOH
N
H
O
O
O
H2O
N
N
N
N
O
HO
OH
O
OH
-H+
H
N
N
N
N
N
O
O
N
N
N
O
-H2O
O
N
N
N
N
N
N
10
Scheme 2. Mechanism for the formation of azomethine ylide 10 from ninhydrin 1, 1,2-phenylenediammine 2, and
L-proline 4.
Chiral cinnamoyl–crotonoyl oxazolidinone 3 was conveniently
prepared from the corresponding acid chloride [usually obtained
from the acid after treatment with (COCl)2] and chiral oxazolidi-
none after deprotonation with a base such as NaH.11
Various chiral auxiliaries, such as camphorsultam and menthol,
were screened in the reaction but in general no separable diastere-
omeric cycloadducts were obtained and the achieved diastereofa-
cial selectivity was low to moderate.
The one-pot four component reaction was also carried out in
toluene and acetonitrile and it was found that even under refluxing
conditions, there was no improvement in the reaction results. This
was attributed to the poor solubility of the reactant in toluene and
acetonitrile, especially the amino acids.
The structures of the cycloadducts were assigned from their ele-
mental and spectroscopic analyses including IR, 1H NMR, 13C NMR,
and mass spectra data. Thus, the IR spectrum of spiro-indeno-
quinoxaline pyrrolizidine 7a showed two strong peaks around
1779 and 1692 cmꢀ1 indicating the presence of two carbonyl
groups. The observation of two characteristic triplets and one dou-
blet in the 1H NMR spectra of compounds 7 and 8 unambiguously
2. Result and discussion
Herein ninhydrin 1 and phenylenediamine 2 were condensed,
and indenoquinoxaline 9 was formed. Next, after condensation of
an amino acid (cyclic or linear) with 9 and decarboxylation of
amino acid, non-stabilized azomethine ylide 10 was produced
(Scheme 2). The [3+2] cycloaddition of chiral dipolarophile 3 with
azomethine ylide 10 led to the formation of new chiral spiro-inde-
noquinoxaline pyrrolizidine 7, which contains four contiguous
stereogenic centres (Scheme 1). Despite the fact that sixteen differ-
ent stereoisomers could be prepared theoretically, only
diastereoisomer 7 was obtained in high yield and with high enan-
tiomeric purity using this strategy. Finally, in order to explore the
scope and generality of the present strategy, a small library of new
chiral spiro-indenoquinoxaline pyrrolizidines and spiro-indeno-
quinoxaline pyrrolidines 7a–i was synthesized and the results
are summarized in Table 1.
The one-pot, four-component, 1,3-dipolar cycloaddition was
carried out under mild conditions in aqueous ethanol and in the
absence of any catalyst or Lewis acids.
Table 1
New chiral spiro-indenoquinoxaline pyrrolidines and spiro-indenoquinoxaline pyrrolidines 7 and 8
Entry
Amino acid
R1
R2
Product
7
8
20c
20c
Yield (%)
[a
]
Yield (%)
[a]
D
D
1
2
3
4
5
6
7
8
9
4
4
4
4
5
5
5
6
6
H
H
Ph
CH3
Ph
CH3
Ph
Ph
CH3
Ph
CH3
a
b
c
d
e
f
g
h
i
94
96
94
96
92
92
90
82
81
+165.3
+134.7
+164
+136.7
+112
+111.2
+128
+270.7
+273.1
98
97
97
95
83
84
83
96
92
ꢀ18
ꢀ17
CH3
CH3
H
CH3
H
ꢀ23.4
ꢀ20.2
ꢀ14
ꢀ18
ꢀ16.4
ꢀ34
H
H
ꢀ33
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4
N. Shahrestani et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Figure 2. The ORTEP diagram of 7d. Thermal ellipsoids are at 30% probability level.
confirmed the formation of a new pyrrolizidine ring. The pyrrolizi-
dine ring proton attached to the phenyl ring appeared as a triplet at
d 4.32 (Hb). The pyrrolizidine NCH proton appeared as a multiplet
at d 4.98 (Hc), whereas the pyrrolizidine proton attached to the cin-
namoyl oxazolidinone moiety was more deshielded and exhibited
a doublet at d 5.30 (Ha, J = 9 Hz). The aromatic protons appeared as
a multiplet in the region d 6.93–8.27. The off resonance decoupled
13C NMR spectra of 7a exhibited characteristic peaks for the spiro
carbon at 73.2 ppm and carbonyls group attached to the cinnamoyl
oxazolidinone moiety at 165.9 and 172.4 ppm; the signals for all
other carbons were located at appropriate chemical shifts in agree-
ment with the proposed structure.
The formation of the product was confirmed by mass spectra
and elemental analyses. The mass spectrum of 7a showed a peak
at m/z 501 (M-91). The absolute configuration of chiral spiro-inde-
noquinoxaline pyrrolizidine 7d was determined by single-crystal
X-ray analysis as (3ˊR) (spiro carbon C10), (7aˊR) (C21), (1S)
(C22), (2S) (C24) (Fig. 2).12,13
using the analysis of the HMBC spectra. Based on the HMBC spec-
trum, there was no correlation between Hc and the signal of car-
bonyl group, which confirms the presence of a carbonyl group at
C-20 position in 8a (instead of C-10).
The formation of the product was confirmed by mass spectra
and elemental analyses. The mass spectrum of 8a showed a peak
at m/z 448 (m+1).
It is known that chiral cinnamoyl–crotonoyl oxazolidinone, in
the absence of Lewis acids, prefers a low energy Z-conformer of
(S)-cis. The B3lyp/6-31G(d,p) calculations also show that Z-con-
former of 3 is 9.2 Kcal/mol more stable than the U-conformer
(Scheme 3). Thus, on the basis of the absolute configuration of
the four stereogenic centres in the pyrrolizidine ring, it is assumed
that the azomethine ylide approaches from the endo-Si-face of the
dipolarophile as a Z-conformer of (S)-cis (Scheme 4).
O
O
O
Particularly noteworthy is the fact that all of the covalently
attached azomethine ylide auxiliaries require destructive removal.
It was in this context that we initiated studies where our goal was
to develop a recoverable chiral auxiliary. For compounds 7a–i, the
chiral auxiliary was removed easily with sodium methoxide and
dimethyl carbonate in CH2Cl2 and provided access to a variety of
enantiomerically pure products 8a–i in excellent to quantitative
yields (Scheme 1). It should be noted that the auxiliary was recov-
ered from this reaction in high yield.14
The stereochemistry and the structure of resulted cycloadduct
8a were evaluated by using 1H NMR and 13C NMR and also 2D
NMR spectroscopy techniques. The 13C NMR spectrum displayed
29 signals, which were classified into 1 methyl, 3 methylene, 16
methines, and 9 quaternary carbons including a spiro carbon by
the DEPT 135° experiments. In the HMQC spectrum of product
8a, the positions of the three protons (Ha, Hb, and Hc) that were
directly bonded to these carbon atoms (CH) were assigned. The
1H NMR spectrum displayed two signals at d = 3.898 and
d = 4.367 ppm (Hb, Hc respectively) and exhibited a doublet at d
4.571 (Ha, J = 12 Hz); the Hb could be trans to Hc, because of the
absence of any correlation between them in the ROESY spectrum.
This was also confirmed from the weak NOE pattern between
them. In order to determine the exact regioselectivity, the connec-
tivity of the carbons in the molecular structure was obtained by
(
)
S
R2
N
O
R2
N
(
)
S
O
O
U-Conformer of 3
Z-Conformer of 3
Scheme 3. S-cis conformations of 3.
In recent years, 1,3-dipolar cycloaddition reactions have been
the subject of several DFT studies showing that hybrid functionals
such as B3LYP,15 together with the standard 6-31G(d) and 6-31G(d,
p) basis sets, produce satisfactory results.16 Herein, the full geo-
metrical optimization of all structures corresponding to potential
energy minima and also related transition states (TSs) was carried
out using this methodology. No symmetrical restriction was
applied during geometrical optimizations. The nature of stationary
geometries has been characterized by calculating the frequencies
in order to verify that the transition states have only one imaginary
frequency with the corresponding eigenvector involving the for-
mation of the newly created C–C bonds. The electronic structures
of the stationary points and transition structures were studied by
the natural bond orbital (NBO) method.17 Furthermore, harmonic
frequencies, zero-point energies and thermodynamic corrections
were obtained by using analytical force constants. Thermal
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N. Shahrestani et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
5
corrections to enthalpy and entropy values were evaluated at
298.15 K. All calculations were carried out with the Gaussian 09
suite of programs (Scheme 4).18
13.7 kcal/mol for TS 13 and 14.5 kcal/mol for TS 14. Accordingly, it
can be predicted that the 7d regioisomer will be formed preferen-
tially, which is in good agreement with the experimental observa-
tions. These cycloadditions are exothermic by approximately ꢀ18
to ꢀ22.6 kcal/mol. The calculated activation barriers for the endo
approaches are lower than those for the exo approaches (Table 2
and Fig. 4).
The analysis of the geometries at the TSs is given in Figure 3 and
indicates that this reaction takes place along asynchronous pro-
cesses. In an asynchronous cycloaddition reaction, the approach
of the reactants to each other and the new bonds formation in
the TS are asymmetric processes. The synchronicity (Sy) index of
the cycloaddition reactions is estimated by the equation19
(R)
N
(R)
N
N
H
N
N
H
endo
N
(S)
O
N
(S)
O
N
H
(S)
H
O
(S)
O
O
O
n
X
jdBi ꢀ dBa
j
v
Sy ¼ 1 ꢀ ð2n ꢀ 2Þꢀ1
ð1Þ
Scheme 4. Proposed models for endo-Si.
dBa
v
i¼1
The analysis of gas-phase results indicated that the 1,3-dipolar
cycloaddition reaction of dipole 11 with dipolarophile 3 take place
along asynchronous concerted processes. The possible regio- and
stereoisomeric pathways are shown in Scheme 5. Therefore four
TSs, TS 7d, TS 12, TS 13, TS 14 and their corresponding cycload-
ducts were located and characterized. The relative energies are
compiled in Table 2 and Figure 4. The geometries of the TSs are
presented in Figure 3.
where n is the number of bonds directly involved in the reaction
and dBi is the relative variation of the Wiberg bond indices20 for
the bonds in the TS, which is calculated by the equation:
BTi s ꢀ BRi
dBi ¼
ð2Þ
BPi ꢀ BRi
Here, superscript indices P, R, and TS correspond to the product,
reactant, and transition state. The average variation dBav, in Eq. (1)
is determined by:
As shown in Table 2, the activation barriers associated to these
cycloadditions are: 6.5 kcal/mol for TS 7d, 10.3 kcal/mol for TS 12,
H
CH3
O
H
N
N
H
O
N
O
Ts 7d
N
O
H
N
CH3
H
N
O
CH3
7d
N
O
H
CH3
N
42
Ts 12
N
3
CH3
12
21
O
5
+
H3C
CH3
N
H
N
CH3
O
H
11
O
N
CH3
N
O
N
H
3
O
11
CH3
N
Ts 13
Ts 14
O
N
CH3
O
H
N
H
13
N
O
CH3
N
O
H
CH3
N
CH3
14
CH3
Scheme 5. Regio- and stereoisomeric pathways for a 1,3-dipolar cycloaddition reaction between azomethine ylide 11 with crotonoyl oxazolidinone 3.
Table 2
Calculated electronic activation energies Ea, reaction Gibbs free energies
enthalpies
H# and Average Bond Index Changes (dBav), Synchronicities (Sy) at B3lyp/6-31G(d,p), all energies are in kcal/mol
D
G, reaction enthalpies
D
H, reaction energies
D
Erxn, activation Gibbs free energies
D
G#, activation
dBav
D
Structure
D
Erxn
D
H
D
G
Ea
6.5
D
H# G#
D
D
R
Sy
7d
12
13
14
ꢀ19.7
ꢀ21.3
ꢀ18.0
ꢀ22.6
ꢀ19.9
ꢀ21.6
ꢀ18.2
ꢀ22.8
ꢀ4.9
ꢀ6.4
ꢀ3.1
ꢀ8.0
6.8
10.5
14.2
14.7
21.0
24.8
27.0
28.9
0.701
0.489
0.808
0.045
0.46
0.69
0.22
0.85
0.25
0.35
0.23
0.38
10.3
13.7
14.5
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6
N. Shahrestani et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
2.81
2.11
(0.12)
(0.41)
2.57
(0.19)
2.08
Endo
(0.46)
Endo
Ts 7d
CT=0.19
Ts 12
CT=0.26
2.30
(0.32)
2.25
2.90
(0.37)
(0.13)
2.10
(0.42)
Exo
Exo
Ts 13
Ts 14
CT=0.18
CT=0.17
Figure 3. Transition structures corresponding to the regioisomeric and stereoisomeric pathways of the 1,3-dipolar cycloaddition reaction channels. The bond lengths directly
involved in the reaction are given in angstroms. The bond orders are given in parenthesis. Hydrogen atoms have been omitted for the sake of clarity. The charge transfers (CT)
are given in a.u.
Table 3
20
Wiberg bond indices for reactants, transition structures and products indicated in
Scheme 5
15
10
5
Structure
B21,3
B3,42
B5,11
B5,42
B5,21
B11,42
B11,21
7d
12
13
14
3
11
—
—
1.82
—
—
—
0.41
—
0.42
—
0.97
—
0.97
—
—
—
—
0.46
—
0.37
—
0.95
—
—
—
—
0.19
—
0.32
—
0.94
—
—
—
0.12
0
1.13
1.16
1.05
1.20
1.08
0.97
0.95
0.96
0.97
1.42
1.21
1.38
1.19
1.29
0.95
0.96
0.95
0.95
Ts 7d
Ts 12
Ts 13
Ts 14
7d
12
13
14
1.46
1.36
1.44
1.38
0.98
0.98
0.97
0.97
-5
-10
-15
-20
-25
0.13
—
0.91
—
0.93
—
Reactanta TSs
Products
0.94
0.96
Figure 4. Relative energies (kcal/mol) for the reactants, TSs and products for the
four possible reaction channels.
The extent of the asynchronicity of the bond formation in a
cycloaddition reaction can also be measured through the difference
n
X
dBa ¼ nꢀ1 dBi
ð3Þ
v
i¼1
between the lengths of the two
the reaction. The computed synchronicities (Sy) and the
r
bonds that are being formed in
Rs for
D
According to Eq. (1), for a perfectly synchronous process, Sy = 1
and for a fully asynchronous process synchronicity is zero. Based
on Eqs. (2) and (3), early and late transition structures will be char-
acterized by dBav < 0.5 and dBav > 0.5, respectively.19g Wiberg bond
indices for reactants, transition structures and products are shown
in Table 3.
the four possible channels in Table 2 show that the asynchronici-
ties order is Ts 13 > Ts 7d > Ts 12 > Ts 14 which complies with
the stability of the products. The dBavs are in all cases indicative
of an early transition state which is in agreement with the exother-
mic nature of the reactions (Table 2).
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N. Shahrestani et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
7
Table 4
Calculated global properties of dipole 6 and dipolarophile 3 at B3lyp/6-31G(d,p)
Structure
ƐHOMO (eV)
ƐLUMO (eV)
x
(eV)
l
(a.u.)
g
(a.u.)
S (a.u.)
N
Azomethine ylide 11
Cinnamoyl–crotonyl oxazolidinone 3
ꢀ4.44
ꢀ6.75
ꢀ1.39
ꢀ1.36
1.40
1.53
ꢀ0.1071
ꢀ0.1492
0.112
0.198
4.478
2.524
4.68
2.37
Recent studies have shown that the defined global and local
indices in the context of density functional theory are powerful
tools for helping understand the behaviour of 1,3-DC reactions.21
The charge transfer ability of a molecule in its ground state can
be described by the electronic chemical potential, which is defined
as the arithmetic mean of one-electron energies of the frontier
energy gap between HOMO13 and LUMO3 (3.074 eV) is lower
than the LUMO13 and the HOMO3 (5.360 eV). This attests that
the HOMO–LUMO energy gaps (Table 4) also suggest that
the HOMOdipole–LUMOdipolarophile interaction controls the
cycloaddition reactions (normal electron demand reactions).25
The DFT-based reactivity indices such as Fukui functions and
local electrophilicity indices were evaluated on the dipole and
dipolarophile reagents with the aim of describing the experimen-
molecular orbital HOMO and LUMO, eH and eL as
The chemical hardness , which is a measure of the stability of a
system, may be approached in terms of eH and eL as
The global electrophilicity index , which measures the stabiliza-
tion in energy when the system acquires an additional electronic
charge N from the environment, was given the following simple
expression, = (
2/2 ),22 in terms of the electronic chemical
potential and the chemical hardness. On the other hand, the
nucleophilicity index for given system was defined as
N = ƐHOMO ꢀ ƐHOMO (TCE), where ƐHOMO is the HOMO energy of the
nucleophile and ƐHOMO corresponds to the HOMO energy of
l = (eH + eL)/2.
g
22
g
=
eL
ꢀ
eH.
tally observed regioselectivity.24c–g We calculated
a Fukui
x
function for nucleophilic (f+k) and electrophilic (fkꢀ) attacks
through the Mulliken charges analysis using Eqs. (4) and (5),
respectively24h
D
x
l
g
fkþ
¼
qNk þ1
ꢀ
qNk ¼ qNk ꢀ qNk þ1
ð4Þ
a
fkꢀ
¼
qkN
ꢀ
qNk ꢀ1 ¼ qNk ꢀ1 ꢀ qNk
ð5Þ
(TCE)
with k, N,
q and q, corresponding to the index of the atom, the
the tetracyanoethylene (TCE) taken as a reference.23
The calculated global properties and N are shown in
Table 4. The electrophilicity ( ) of 3 is greater than 1.5 eV, so it
number of electrons, the population number and the net charge
stemming from calculations, respectively.
l, g, x
x
The local electrophilicity index, xk, can be measured by
+ 24
+
could be classified as a strong electrophile within the electrophilic-
xk
=
x
fk
.
This expression shows that wherever fk has its
ity scale24a while the azomethine ylide has a large nucleophilicity
maximum value, i.e. at the active site of the electrophile. For polar
cycloaddition reactions the most favourable regioisomeric path-
way corresponds to the bond-formation at the most electrophilic
and nucleophilic sites of the unsymmetrical reactants. Therefore,
the regioselectivity of these cycloaddition reactions can be
value, N = 4.68 eV. The electronic chemical potential,
nucleophilicity index, N of the azomethine ylide 11 is higher
than the cinnamoyl–crotonoyl oxazolidinone while the
l and the
3
electrophilicity of 3 is greater than the 11; therefore during a
polar process a net charge transfer will take place from the
azomethine ylide to the alkene, which is in agreement with the
charge transfer found at the TSs. As shown in Figure 5, the
explained by using the local electrophilicity index
xk, at the more
electrophile reactant together with the nucleophilic Fukui func-
tions, fkꢀ, at the less electrophilic one. In Table 5, the electrophilic,
f+k and nucleophilic, fꢀk , Fukui functions and local electrophilicities
contributions to the respective atomic centres are summarized.
Cinnamoyl–crotonoyl oxazolidinone 3 has the largest elec-
trophilic activation at the C5 carbon atom,
xk = 0.108 eV, whereas
the azomethine ylide 11 has the largest nucleophilic activation at
the C42 carbon atom, fꢀk = 0.120 (see Table 5). Therefore, C5 of
cinnamoyl–crotonoyl oxazolidinone 3 will be the preferred position
for a nucleophilic attack by C42 of the azomethine ylide 11, which is
in good agreement with the experimental observations.
The regioselectivity in the cycloaddition reactions has also been
described in terms of a local hard and soft acid and bases principle,
formulated with density functional theory (DFT).26 The HSAB prin-
ciple indicates that the interaction between A and B is favored
when it occurs through those atoms with approximately equal
softness values. According to chemical potentials and electrophilic-
ity indices, as well as the HOMO–LUMO energy gaps, dipoles and
dipolarophiles are classified as nucleophiles or electrophiles. When
Table 5
Calculated local properties of dipole 13 and dipolarophile 3 at B3lyp/6-31G(d,p)
s+
sꢀ
ꢀ
+
Reactant
Site
fk
xk(eV)
fk
cinnamoyl-crotonoyl
Azomethine ylide 11
3
3
11
11
C5
0.071
0.020
0.025
0.028
0.032
0.027
0.092
0.120
0.108
0.030
0.034
0.039
0.179
0.050
0.112
0.125
0.081
0.068
0.414
0.538
oxazolidinone 3
C11
C21
C42
Figure 5. The HOMO–LUMO energy gaps.
Please cite this article in press as: Shahrestani, N.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.08.013

8
N. Shahrestani et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
atoms i and j of a molecule A (nucleophile) are involved in the for-
mation of a cycloadduct with atoms k and i of another molecule B
solvent was removed under reduced pressure and the crude pro-
duct was purified by column chromatography using n-hexane/
ethyl acetate (70:30) as eluent to afford pure 7a in 94% yield.
(electrophile),
D can be considered as a measure of predominance
of one approach over the other. The reaction path associated with
the lower
D
value will be the preferred one.
4.3. Typical procedure for the preparation of (10R,20S,30R,7a0R)-
methyl10-phenyl-10,20,50,60,70,7a0-hexahydrospiro[indeno[1,2-b]-
quinoxaline-11,30-pyrrolizine]-20-carboxylate 8a
2
2
kl
ij
D
¼ ðsiꢀ ꢀ sþÞ þ ðsjꢀ ꢀ slþÞ
ð6Þ
k
where sis are the appropriate type of atomic softness and they cal-
culated as
To a solution of 7a (609 mg, 1.03 mmol) in CH2Cl2 (5 mL), were
added sodium methoxide (275 mg, 5.15 mmol), and dimethyl car-
bonate (0.42 mL, 5.15 mmol) after which it was stirred at room
sꢁk ¼ fꢁk S
ð7Þ
ð8Þ
temperature for 4 h (the reaction time for trans-4-hydroxy-L-pro-
where S is the global softness and computed as27
line derivatives was 6 h). After the reaction was complete, water
(5 mL) was added and the organic layer was separated. The aque-
ous layer was acidified to ca. pH 7 with hydrochloric acid and
extracted with CH2Cl2. The combined organic layer was dried over
MgSO4, filtered, and concentrated in vacuo. The mixture was chro-
matographed on silica gel by ether–hexane (1/2) to afford pure 8a
in 98% yield and (S)-4-benzyloxazolidin-2-one in 96% yield.
1
S ¼
2
g
Herein, cinnamoyl–crotonoyl oxazolidinone 3 behaves as an
electrophile and azomethine ylide 11 as a nucleophile. The calcu-
kl
ij
lated
D
values for the generation of 7d (0.261) is smaller com-
pared to that for the generation of 12 (0.293) (Table 3). This
observation is in good agreement with the experimental
observation.
4.4. (S)-4-Benzyl-3-((10R,20S,30R,7a0R)-10-phenyl-10,20,50,60,70,7a0-
hexahydrospiro[indeno[1,2-b]quinoxaline-11,30-pyrrolizine]-
20-ylcarbonyl)oxazolidin-2-one 7a
3. Conclusion
In conclusion, we have prepared a small library of new chiral
spiro-indenoquinoxaline pyrrolidines and chiral spiro-indeno-
quinoxaline pyrrolizidines through a one-pot, four-component
reaction between ninhydrin, o-phenylenediamine derivatives,
amino acid, and chiral cinnamoyl–crotonoyl oxazolidinone under
mild reaction conditions in the presence of environmentally
friendly aqueous ethanol as the solvent. The products were
obtained in excellent yields (up to 96%) and with excellent enan-
tiomeric purity (up to 99%). The removal of the chiral auxiliary
was easily achieved without racemization or by-product forma-
tion. The regiochemistry of the cycloaddition has been explained
successfully by using the density functional theory based on global
and local reactivity indices and HSAB principle as well as the anal-
ysis of the activation energies.
H3
Hc
H3
Hb
O
H1
N
H2
H2
N
Ha
O
N
O
N
Yellow oily liquid (550 mg, 94%); IR (KBr) (m
max/cmꢀ1): CO 1779,
1692; 1H NMR (300 MHz, CDCl3): dH (ppm) = 1.60–1.70 (m, 1H, pyr-
rolizine), 1.90–1.99 (m, 2H, pyrrolizine), 2.04–2.15 (m, 2H, pyrroli-
zine), 2.54–2.61 (dd, 1H, J = 13.35, 9 Hz, H3), 2.63–2.68 (m, 1H,
pyrrolizine), 2.94–2.99 (dd, 1H, J = 13.5, 2.7 Hz, H3), 3.25–3.40 (m,
1H, H2), 3.71–3.75 (dd, 1H, H2), 4.17–4.25 (m, 1H, H1), 4.28–4.36
(m, 1H, Hb), 4.95–5.00 (m, 1H, Hc), 5.30 (d, 1H, J = 9 Hz, Ha), 6.93–
8.27 (m, 18H, Arom); 13C NMR (75 MHz, CDCl3): dc (ppm) = 25.3,
27.4, 37.5, 48.5, 52.9, 55.4, 62.7, 65.6, 71.8, 73.2, 122.7, 126.7,
126.9, 128.7, 128.9, 129.1, 129.2, 129.2, 129.7, 129.9, 130.1, 134.8,
139.0, 140.9, 141.8, 142.4, 143.8, 151.9, 152.0, 165.9, 172.4; MS
m/z (%): 501 (M-91) (%48), 434 (%75), 386 (%38), 319 (%56), 218
4. Experimental
4.1. General
Melting points were measured by an Electrothermal 9200 appa-
ratus. IR spectra were recorded on FT-IR 102 MB BOMEM appara-
tus. 1H and 13C, DEPT 135, ROSEY, HMQC and HMBC spectra
were determined on a BRUKER DRX-300 AVANCE spectrometer
at 300.13 and 75.47 MHz, respectively. MS spectra were recorded
on a Shimadzu QP 1100EX mass spectrometer operating at an
ionization potential of 70 eV.
(%50), 131 (%80); [a]
20 = +165.3 (c 0.03, CH2Cl2).
D
4.5. (S)-4-Benzyl-3-((10S,20S,30R,7a0R)-10-methyl-10,20,50,60,70,7a0-
hexahydrospiro[indeno[1,2-b]quinoxaline-11,30-pyrrolizine]-
20-ylcarbonyl)oxazolidin-2-one 7b
4.2. Typical procedure for the preparation of (S)-4-benzyl-3-
((10R,20S,30R,7a0R)-10-phenyl-10,20,50,60,70,7a0-hexahydrospiro-
[indeno-[1,2-b]quinoxaline-11,30-pyrrolizine]-20-ylcarbonyl)-
oxazolidin-2-one 7a
Hc
H3 H3
Hb
O
H1
N
H2
H2
N
Ha
O
N
A
mixture of ninhydrin 1a (0.178 g, 1 mmol) and
O
N
1,2-phenylenediamine 2a (0.108 g, 1 mmol) was stirred for
10 min in ethanol (10 mL). To this solution were added amino acid
4 (0.115 g, 1 mmol) and cinnamoyl oxazolidinone 4a (0.307 g,
1 mmol), after which it was heated at reflux for approximately
20 h (the progress of the reaction was monitored by TLC). The
Yellow solid (508 mg, 96%); IR (KBr) (m
max/cmꢀ1): CO 1779, 1686;
1H NMR (300 MHz, CDCl3): dH (ppm) = 1.36 (d, 3H, J = 6.6 Hz, CH3),
1.87–2.21 (m, 5H, pyrrolizine), 2.57–2.60 (m, 1H, pyrrolizine),
Please cite this article in press as: Shahrestani, N.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.08.013

N. Shahrestani et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
9
2.60–2.64 (dd, 1H, H3), 3.03–3.12 (dd, 1H, H3), 3.03–3.12 (m, 1H,
H2), 3.23–3.28 (m, 1H, H1), 3.72–3.75 (m, 1H, H2), 4.03 (m, 1H,
Hb), 4.33 (m, 1H, Hc), 4.82 (d, 1H, J = 9.6 Hz, Ha), 7.08–8.20 (m,
13H, Ar); 13C NMR (75 MHz, CDCl3): dc (ppm) = 16.1, 26.0, 28.2,
37.8, 41.4, 48.2, 55.9, 61.4, 65.7, 70.8, 73.8, 122.4, 127.7, 127.2,
128.7, 128.8, 129.0, 129.3, 129.9, 130.1, 135.2, 138.6, 142.0, 142.4,
144.2, 151.9, 165.5, 172.5; MS m/z (%): 530(M) (%62), 501 (%38),
434 (%70), 353 (%45), 326 (%78), 218 (%78), 97 (%80);
135.4, 136.9, 141.8, 152.2, 164.8, 172.4; MS m/z (%): 558(M) (%
28), 462 (%75), 382 (%20), 246(%60), 69 (%81); [
0.03, CH2Cl2).
a]
20 = +136.7 (c
D
4.8. (S)-4-Benzyl-3-((10R,20S,30R,60R,7a0R)-60-hydroxy-10-phenyl-
10,20,50,60,70,7a0-hexahydrospiro[indeno[1,2-b]quinoxaline-11,30-
pyrrolizine]-20-ylcarbonyl)oxazolidin-2-one 7e
[a]
20 = +134.7 (c 0.03, CH2Cl2).
D
4.6. (S)-4-Benzyl-3-((10R,20S,30R,7a0R)-7,8-dimethyl-10-phenyl-
10,20,50,60,70,7a0-hexahydrospiro[indeno[1,2-b]quinoxaline-11,30-
pyrrolizine]-20-ylcarbonyl)oxazolidin-2-one 7c
HO
Hc
H3
H3
Hb
O
H1
N
H2
H2
N
Ha
O
N
O
N
Ha
H
3H3
Hb
O
H1
N
H2
H2
Yellow oily liquid (557 mg, 92%); IR (KBr) (m
max/cmꢀ1): CO 1780,
N
Ha
O
1688, OH 3423; 1H NMR (300 MHz, CDCl3): dH (ppm) = 1.65–1.97
(m, 3H, pyrrolizine), 2.45–2.52 (m, 1H, pyrrolizine), 2.54–2.61 (dd,
1H,, J = 13.05, 9.3 Hz, H3), 2.72–2.77 (m, 1H, H3), 2.95–3.03 (m, 1H,
H2), 3.21–3.27 (m, 1H, Hˊ), 3.71–3.74 (m, 1H, H2), 4.13–4.16 (m,
1H, H1), 4.44 (m, 1H, OH), 4.47–4.50 (dd, 1H, Hb), 4.76–4.82 (m,
1H, Hc), 5.28 (d, 1H, J = 9 Hz, Ha), 6.93–8.24 (m, 18H, Ar); 13C NMR
(75 MHz, CDCl3): dc (ppm) = 37.4, 38.1, 52.6, 55.3, 55.4, 63.2, 65.7,
70.8, 71.9, 73.7, 117.6, 119.8, 127.0, 127.2, 128.7, 128.8, 128.9,
129.1, 129.3, 129.3, 129.8, 130.5, 133.7, 134.8, 137.0, 138.5, 140.5,
141.6, 142.2, 143.9, 152.0, 152.2, 161.6, 165.4, 171.8; MS m/z (%):
608 (M) (32%), 524 (50%), 447 (42%), 404 (65%), 217 (60%), 91
N
O
N
Yellow oily liquid (580 mg, 94%); IR (KBr) (m
max/cmꢀ1): CO 1781,
1689; 1H NMR (300 MHz, CDCl3): dH (ppm) = 1.88–2.01 (m, 2H, pyr-
rolizine), 2.05–2.19 (m, 3H, pyrrolizine), 2.25–2.55 (d, 6H, 2CH3),
2.61–2.70 (dd, 1H, H3), 2.93–2.99 (dd, 1H, H3), 3.23–3.31 (m, 1H,
H2), 3.69–3.73 (dd, 1H, H2), 4.11–4.26 (m, 1H, H1), 4.24–4.31 (m,
1H, Hb), 4.93–4.99 (m, 1H, Hc), 5.30 (d, 1H, J = 9.3 Hz, Ha), 6.93–
8.27 (m, 16H, Ar); 13C NMR (75 MHz, CDCl3): dc (ppm) = 20.2,
20.2, 25.4, 27.4, 37.5, 48.5, 52.8, 55.5, 62.7, 65.6, 71.7, 73.4, 122.7,
126.7, 126.9, 128.7, 128.9, 129.1, 129.2, 129.2, 129.7, 129.8, 134.9,
139.1, 139.2, 139.4, 140.7, 140.9, 141.1, 143.8, 151.9, 151.9, 165.9,
172.4; MS m/z (%): 620 (M) (%35), 444 (%63), 416 (%70), 245 (%
(45%), 77; [a]
20 = +112 (c 0.03, CH2Cl2).
D
4.9. (S)-4-Benzyl-3-((10R,20S,30R,60R,7a0R)-60-hydroxy-7,8-dime-
thyl-10-phenyl-10,20,50,60,70,7a0-hexahydrospiro[indeno[1,2-b]
quinoxaline-11,30-pyrrolizine]-20-ylcarbonyl)oxazolidin-2-one 7f
42), 91 (%75); [a]
20 = +164 (c 0.03, CH2Cl2).
D
4.7. (S)-4-Benzyl-3-((10S,20S,30R,7a0R)-10,7,8-trimethyl-10,20,50,60,70
,7a0-hexahydrospiro[indeno[1,2-b]quinoxaline-11,30-pyrrolizine]-
20-ylcarbonyl)oxazolidin-2-one 7d
HO
H3
H3
Hc
Hb
O
H1
N
H2
H2
N
Ha
O
N
Hc
O
H3
H3
Hb
O
N
H1
N
H2
H2
N
Ha
O
N
Yellow solid (580 mg, 92%); IR (KBr) (m
max/cmꢀ1): CO 1781, 1689,
O
N
OH 3424; 1H NMR (300 MHz, CDCl3): dH (ppm) = 1.65–1.93 (m,
4H, pyrrolizine), 2.50–2.53 (d, 6H, 2CH3), 2.71–2.76 (dd, 1H,
J = 8.7, 6 Hz, H3), 2.94–2.96 (m, 1H, H3), 2.97–2.99 (m, 1H, H2),
3.18–3.24 (m, 1H, Hˊ), 3.68–3.72 (m, 1H, H2), 4.07–4.12 (m, 1H,
H1), 4.40–4.47 (dd, 1H, Hb), 4.49–4.52 (m, 1H, OH), 4.73–4.81 (m,
1H, Hc), 5.30 (d, 1H, J = 9 Hz, Ha), 6.92–8.17 (m, 16H, Ar); 13C NMR
(75 MHz, CDCl3): dc (ppm) = 20.2, 20.2, 37.4, 38.2, 52.5, 55.1, 55.5,
63.2, 65.6, 70.8, 71.8, 73.9, 122.2, 126.5, 127.0, 127.1, 128.4,
128.7, 128.7, 129.1, 129.2, 129.7, 130.0, 134.9, 138.7, 139.2, 139.5,
140.5, 140.5, 140.9, 143.7, 151.2, 151.8, 164.4, 171.8; MS m/z (%):
636 (M) (40%), 475 (55%), 433 (40%), 356 (23%), 158 (75%), 77
Yellow solid (533 mg, 96%); IR (KBr) (m
max/cmꢀ1): CO 1780, 1688;
1H NMR (300 MHz, CDCl3): dH (ppm) = 1.35 (d, 3H, J = 6.3 Hz, 3H),
1.82–2.19 (m, 5H, pyrrolizine), 2.48–2.52 (d, 6H, 2CH3), 2.52–2.55
(m, 1H, pyrrolizine), 2.55–2.63 (dd, 1H, H3), 2.98–3.10 (m, 2H, H2,
H3), 3.23–3.28 (m, 1H, H1), 3.70–3.73 (dd, 1H, H2), 3.93 (m, 1H,
Hb), 4.28 (m, 1H, Hc), 4.84 (d, 1H, J = 9.6 Hz, Ha), 7.06–8.16
(m, 13H, Ar); 13C NMR (75 MHz, CDCl3): dc (ppm) = 16.1, 20.2,
20.2, 28.7, 29.8, 38.0, 42.3, 49.2, 55.5, 59.4, 65.7, 69.7, 121.4,
123.8, 125.2, 127.7, 127.8, 128.9, 128.1, 129.9, 130.0, 130.0, 131.9,
(43%); [a]
20 = +111.2 (c 0.03, CH2Cl2).
D
Please cite this article in press as: Shahrestani, N.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.08.013

10
N. Shahrestani et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
4.10. (S)-4-Benzyl-3-((10S,20S,30R,60R,7a0R)-60-hydroxy-10-methyl-
10,20,50,60,70,7a0-hexahydrospiro[indeno[1,2-b]quinoxaline-11,30-
pyrrolizine]-20-ylcarbonyl)oxazolidin-2-one 7g
Yellow oily liquid (408 mg, 81%); IR (KBr) (m
max/cmꢀ1): CO 1785,
1686; 1H NMR (300 MHz, CDCl3): dH (ppm) = 1.40 (d, 3H,
J = 4.5 Hz), 1.87 (S, 3H), 2.57–2.64 (dd, 1H, H3), 3.10–3.13 (m, 1H,
H3), 3.10–3.13 (m, 1H, H2), 3.43–3.47 (m, 1H, Hc), 3.50–3.59 (m,
1H, Hc), 3.50–3.59 (m, 1H, H1), 3.72–3.75 (m, 1H, H2), 4.06 (m, 1H,
Hb), 4.51 (d, 1H, J = 5.7 Hz, Ha), 7.10–8.14 (m, 18H, Ar); 13C NMR
(75 MHz, CDCl3): dc (ppm) = 16.9, 35.2, 36.8, 38.3, 55.5, 59.1, 60.2,
65.7, 120.3, 121.7, 125.5, 127.2, 128.8, 128.6, 128.7, 129.8, 129.9,
130.3, 131.6, 135.9, 138.1, 142.6, 152.3, 165.1, 171.3; MS m/z: 504
HO
Hc
H3
H1
H3
Hb
O
N
H2
H2
N
O
Ha
(M) (24%), 257 (25%), 217 (20%), 91 (32%); [
CH2Cl2).
a]
20 = +283.1 (c 0.03,
D
N
O
N
4.13. Methyl (10R,20S,7a0R,11R)-10-phenyl-10,20,50,60,70,7a0-hexa-
hydrospiro[indeno[1,2-b]quinoxaline-11,30-pyrrolizine]-20-
carboxylate 8a
Yellow solid (490 mg, 90%); IR (KBr) (m
max/cmꢀ1): CO 1779, 1673,
OH 3423; 1H NMR (300 MHz, CDCl3): dH (ppm) = 1.34 (d, 3H,
J = 9.6 Hz, CH3), 1.68–1.76 (m, 1H, pyrrolizine), 2.18–2.57 (m, 3H,
pyrrolizine), 2.60–2.63 (dd, 1H, H3), 2.79–2.84 (dd, 1H, H3), 3.07–
3.12 (m, 1H, H2), 3.18–3.24 (m, 1H, Hˊ), 3.287–3.33 (m, 1H, OH),
3.72–3.75 (m, 1H, H2), 4.03 (m,1H, H1), 4.15–4.21 (dd, 1H, Hb),
4.49–4.53 (m, 1H, Hc), 4.79 (d, 1H, J = 9.3 Hz, Ha), 7.02–8.18 (m,
13H, Ar); 13C NMR (75 MHz, CDCl3): dc (ppm) = 16.1, 37.7, 38.5,
41.3, 54.9, 55.8, 62.1, 65.8, 69.8, 72.1, 74.2, 122.3, 126.7, 127.2,
128.8, 129.0, 129.2, 129.3, 129.7, 129.8, 130.4, 135.1, 138.3, 141.7,
142.2, 144.2, 152.0, 165.0, 171.9; MS m/z (%): 546(M) (35%), 455
Hc
Hb
O
N
O
Ha
N
(66%), 344 (25%), 217 (48%), 91 (80%); [a]
20 = +128 (c 0.03, CH2Cl2).
D
N
4.11. (S)-4-Benzyl-3-((20R,30S,40R)-10-methyl-40-phenylspiro-
[indeno[1,2-b]quinoxaline-11,20-pyrrolidine]-30-ylcarbonyl)-
oxazolidin-2-one 7h
Yellow solid (438 mg, 98%); IR (KBr) (m
max/cmꢀ1): CO 1721; 1H NMR
(300 MHz, CDCl3): dH (ppm) = 1.73–2.18 (m, 4H, pyrrolizine), 2.52–
2.66 (m, 2H, pyrrolizine), 2.85 (S, 3H, OCH3), 3.86–3.93 (dd, 1H, Hb),
4.32–4.40 (m, 1H, Hc), 4.57 (d, 1H, J = 12 Hz, Ha), 7.27–8.34 (m, 13H,
Arom); 13C NMR (75 MHz, CDCl3): dc (ppm) = 28.1, 30.9, 31.6, 47.8,
51.1, 52.8, 73.2, 75.2, 122.3, 127.0, 127.0, 128.0, 128.6, 128.7, 129.0,
129.4, 129.7, 129.9, 130.9, 138.1, 139.9, 142.4, 142.8, 144.1, 153.1,
170.0; MS m/z (%): 448 (M + 1) (24%), 416 (20%), 386 (25%), 285
H3
H3
Hc
Hc
Hb
O
H1
N
H2
H2
N
Ha
O
N
(85%), 256 (48%), 159 (85%), 103 (50%), 77 (30%); [
0.02, CH2Cl2).
a]
20 = ꢀ18 (c
O
D
N
Yellow oily liquid (464 mg, 82%); IR (KBr) (
m
max/cmꢀ1): CO 1784,
4.14. Methyl (10S,20S,7a0R,11R)-10-methyl-10,20,50,60,70,7a0-hexa-
hydrospiro[indeno[1,2-b]quinoxaline-11,30-pyrrolizine]-20-
car boxylate 8b
1686; 1H NMR (300 MHz, CDCl3): dH (ppm) = 1.95 (S, 3H), 2.52–
2.60 (dd, 1H, J = 13.5, 9.3 Hz, H3), 2.97–3.03 (dd, 1H, J = 13.8,
2.7 Hz, H3), 3.12–3.17 (m, 1H, Hc), 3.60–3.65 (m, 1H, Hc), 3.22–
3.75 (dd, 1H, H2), 4.06–4.11 (m, 1H, H1), 4.14–4.209 (dd, 1H, H2),
4.72–4.80 (dd, 1H, Hb), 5.03 (d, 1H, J = 8.7 Hz, Ha), 6.84–8.21 (m,
18H, Ar); 13C NMR (75 MHz, CDCl3): dc (ppm) = 34.2, 37.4, 45.0,
55.5, 60.5, 61.9, 65.7, 74.1, 122.1, 125.7, 126.9, 127.1, 127.8,
128.6, 128.7, 128.8, 128.9, 129.3, 129.6, 129.9, 131.0, 134.9, 138.4,
141.4, 141.6, 142.1, 145.9, 152.1, 153.0, 165.1, 171.3; MS m/z (%):
434 (M-132) (75%), 362 (20%), 317 (33%), 217 (15%), 133 (85%),
Hc
Hb
O
N
O
Ha
N
91 (42%); [a]
20 = +270.7 (c 0.03, CH2Cl2).
D
N
4.12. (S)-4-Benzyl-3-((20R,30S,40S)-10,40-dimethylspiro[indeno-
[1,2-b]quinoxaline-11,20-pyrrolidine]-30-ylcarbonyl)oxazolidin-2-
one 7i
Yellow solid (373 mg, 97%); IR (KBr) (m
max/cmꢀ1): CO 1724; 1H NMR
(300 MHz, CDCl3): dH (ppm) = 1.30 (d, 3H, J = 6.3 Hz), 1.65–1.77 (m,
1H, pyrrolizine), 1.90–1.99 (m, 2H, pyrrolizine), 2.13–2.23 (m, 1H,
pyrrolizine), 2.45–2.49 (m, 2H, pyrrolizine), 2.69–2.80 (dd, 1H,
Hb), 2.91 (S, 3H, OCH3), 3.85–3.90 (m, 1H, Hc), 3.94 (d, 1H,
J = 12 Hz, Ha), 7.53–8.29 (m, 8H, Ar); 13C NMR (75 MHz, CDCl3): dc
(ppm) = 16.8, 28.4, 29.6, 31.6, 41.4, 47.7, 51.0, 72.4, 75.3, 122.3,
126.7, 128.7, 128.9, 129.3, 129.5, 129.9, 130.8, 138.0, 142.4, 142.8,
144.4, 170.5; MS m/z (%): 385(M) (45%), 354 (33%), 326 (66%), 230
H3
H3
O
Hc
Hb
O
Hc
H1
N
H2
H2
N
Ha
O
N
N
(80%), 131 (24%), 91 (88%); [
a
]
20 = ꢀ17 (c 0.02, CH2Cl2).
D
Please cite this article in press as: Shahrestani, N.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.08.013

N. Shahrestani et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
11
6.61 (d, 1H, Ha), 7.07–7.11 (m, 1H, Hc), 7.27–7.74 (m, 13H, Ar); 13C
NMR (75 MHz, CDCl3): dc (ppm) = 40.3, 40.9, 51.2, 53.0, 54.4, 55.8,
62.7, 63.1, 74.5, 122.4, 122.6, 126.5, 127.1, 128.0, 128.4, 128.7,
128.9, 129.1, 129.4, 129.6, 129.8, 130.0, 131.1,137.7, 139.3, 139.4,
142.1, 142.3, 165.1, 170.6; MS m/z (%): 463 (M) (22%), 404 (45%),
4.15. Methyl (10R,20S,7a0R,11R)-7,8-dimethyl-10-phenyl-10,20,50,
60,70,7a0-hexahydrospiro[indeno[1,2-b]quinoxaline-11,30-pyrro-
lizine]-20-carboxylate 8c
328 (75%), 217 (33%), 129 (45%), 91 (55%); [
CH2Cl2).
a]
20 = ꢀ14 (c 0.03,
D
Hc
Hb
N
O
4.18. Methyl (10R,20S,60R,7a0R,11R)-60-hydroxy-7,8-dimethyl-10-
phenyl-10,20,50,60,70,7a0-hexahydrospiro[indeno[1,2-b]quinoxaline-
11,30-pyrrolizine]-20-carboxylate 8f
N
O
Ha
N
HO
Hc
Hb
Yellow solid (458 mg, 97%); IR (KBr) (m
max/cmꢀ1): CO 1720; 1H NMR
O
N
(300 MHz, CDCl3): dH (ppm) = 1.83–2.28 (m, 4H, pyrrolizine), 2.56–
2.69 (m, 2H, pyrrolizine), 2.64 (S, 6H, 2CH3), 2.87 (S, 3H, OCH3),
3.89–3.96 (dd, 1H, Hb), 4.38–4.46 (m, 1H, Hc), 4.60 (d, 1H, J = 12 Hz,
Ha), 7.27–8.34 (m, 11H, Arom); 13C NMR (75 MHz, CDCl3): dc (ppm)
= 20.3, 20.3, 28.1, 31.9, 47.8, 51.1, 52.8, 63.1, 73.2, 75.2, 122.0,122.1,
127.0, 127.8, 127.9, 128.1, 128.2, 128.4, 128.7, 129.2, 129.3, 129.7,
129.9, 130.5, 138.4, 139.2, 139.8, 140.1, 141.3, 141.6, 143.9, 152.3,
163.4, 170.0; MS m/z (%): 476 (M + 1) (22%), 444 (65%), 416 (42%),
Ha
O
N
N
Yellow liquid (408 mg, 84%); IR (KBr) (m
max/cmꢀ1): CO 1748, 3332;
1H NMR (300 MHz, CDCl3): dH (ppm) = 1.27–1.41 (m, 1H, pyrroli-
zine), 2.10 (S, 6H), 1.81–2.21 (m, 4H, pyrrolizine), 2.51–2.68 (m,
1H, pyrrolizine), 2.73 (S, 3H, OCH3), 6.33–6.49 (m, 1H, Hb), 7.09
(d, 1H, Ha), 6.90–7.14 (m, 1H, Hc), 7.26–8.34 (m, 11H, Ar); 13C
NMR (75 MHz, CDCl3): dc (ppm) = 20.1, 20.2, 37.5, 54.3, 55.1, 57.4,
65.6, 70.2, 72.4, 75.3, 122.0, 125.9, 127.1, 127.2, 128.7, 128.8,
128.9, 128.3, 130.5, 131.0, 131.2, 134.5, 135.0, 140.1, 142.2, 153.2,
172.4; MS m/z (%): 490 (M + 1) (25%), 432 (33%), 356 (24%), 157
230 (50%), 131(35%), 77 (68%); [
a]
20 = ꢀ23.4 (c 0.02, CH2Cl2).
D
4.16. Methyl (10S,20S,7a0R,11R)-10,7,8-trimethyl-10,20,50,60,70,7a0-
hexahydrospiro[indeno[1,2-b]quinoxaline-11,30-pyrrolizine]-20-
carboxylate 8d
Hc
(44%), 91 (64%); [
a
]
D
20 = ꢀ18 (c 0.03, CH2Cl2).
4.19. Methyl (10S,20S,60R,7a0R,11R)-60-hydroxy-10-methyl-10,20,50,
60,70,7a0-hexahydrospiro[indeno[1,2-b]quinoxaline-11,30-pyrroli-
zine]-20-carboxylate 8g
Hb
O
N
Ha
O
N
N
HO
Hc
Hb
O
Yellow solid (327 mg, 95%); IR (KBr) (m
max/cmꢀ1): CO 1733; 1H NMR
N
O
(300 MHz, CDCl3): dH (ppm) = 1.29 (d, 3H, J = 6.3 Hz), 1.61–1.96 (m,
2H, pyrrolizine), 2.13–2.28 (m, 2H, pyrrolizine), 2.13 (S, 6H), 2.44–
2.48 (m, 1H, pyrrolizine), 2.64–2.68 (m, 1H, Hb), 2.74 (S, 3H,
OCH3), 3.55–3.70 (m, 1H, Hc), 3.74 (d, 1H, J = 12 Hz, Ha), 7.45–8.28
(m, 6H, Ar); 13C NMR (75 MHz, CDCl3): dc (ppm) = 16.8, 20.2, 20.2,
23.3, 24.9, 26.4, 37.1, 43.6, 45.0, 46.4, 57.3, 67.8, 116.9, 117.8,
120.5, 123, 123.3, 125.8, 126.7, 127.4, 131.1, 137.1, 152.8, 170.0;
MS m/z (%): 413 (M) (16%), 382 (25%), 354 (65%), 131 (35%), 91
Ha
N
N
Yellow liquid (332 mg, 83%); IR (KBr) (m
max/cmꢀ1): CO 1740, 3344;
1H NMR (300 MHz, CDCl3): dH (ppm) = 1.34 (d, 3H, J = 9.6 Hz, CH3),
1.87–2.70 (m, 4H, pyrrolizine) 2.83 (S, 3H, OCH3), 2.71–2.95 (m,
1H, pyrrolizine), 3.63–3.81 (m, 1H, Hb), 5.19–5.22 (m, 1H, Hc),
6.43 (d, 1H, Ha), 7.58–8.24 (m, 8H, Ar); 13C NMR (75 MHz, CDCl3):
dc (ppm) = 16.1, 37.0, 39.2, 55.0, 56.4, 59.7, 65.7, 69.1, 72.7, 75.2,
122.9, 125.7, 127.3, 128.6, 128.9, 129.3, 130.4, 130.8, 131.3, 135.1,
135.6, 141.8, 152.2, 173.5; MS m/z (%): 401 (M) (12%), 344 (28%),
(18%); [
a]
20 = ꢀ20.2 (c 0.03, CH2Cl2).
D
4.17. Methyl (10R,20S,60R,7a0R,11R)-60-hydroxy-10-phenyl-10,20,50,
60,70,7a0-hexahydrospiro[indeno[1,2-b]quinoxaline-11,30-pyrrol-
izine]-20-carboxylate 8e
317 (42%), 217 (60%), 91(75%); [
a
]
D
20 = ꢀ16.4 (c 0.03, CH2Cl2).
4.20. Methyl (30S,40R,11R)-10-methyl-40-phenylspiro[indeno-
[1,2-b]quinoxaline-11,20-pyrrolidine]-30-carboxylate 8h
HO
Hc
Hb
O
N
Ha
O
Hc
Hb
N
Hc
O
N
N
Ha
O
N
Yellow liquid (382 mg, 83%); IR (KBr) (m
max/cmꢀ1): CO 1744, 3341; 1H
NMR (300 MHz, CDCl3): dH (ppm) = 1.27–1.61 (m, 4H, pyrrolizine),
N
3.83 (S, 3H, OCH3), 4.71 (m, 1H, pyrrolizine), 6.43–6.49 (m, 1H, Hb),
Please cite this article in press as: Shahrestani, N.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.08.013

12
N. Shahrestani et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Arvinnezhad, H.; Samadi, S.; Jadidi, K.; Javidan, A.; Notash, B. Tetrahedron Lett.
Yellow liquid (404 mg, 96%); IR (KBr) (m
max/cmꢀ1): CO 1738; 1H
2012, 53, 5148–5150; (d) Mehrdad, M.; Faraji, L.; Jadidi, K.; Eslami, P.; Sureni,
H. Monatsh. Chem. 2011, 142, 917–921; (e) Faraji, L.; Arvinnezhad, H.; Alikami,
N.; Jadidi, K. Lett. Org. Chem. 2010, 7, 472–474; (f) Jadidi, K.; Gharemanzadeh,
R.; Mehrdad, M.; Darabi, H. R.; Khavasi, H. R.; Asgari, D. Ultrason. Sonochem.
2008, 15, 124–128; (g) Jadidi, K.; Moghaddam, M. M.; Aghapoor, K.;
Gharemanzadeh, R. J. Chem. Res. 2007, 71–73; (h) Azizian, J.; Jadidi, K.;
Mehrdad, M.; Sarrafi, Y. Q. Synth. Commun. 2000, 30, 2309–2315; (i) Azizian, J.;
Morady, A. V.; Jadidi, K.; Mehrdad, M.; Sarrafi, Y. Synth. Commun. 2000, 30, 537–
542; (j) Salahi, F.; Taghizadeh, M. J.; Arvinnezhad, H.; Moemeni, M.; Jadidi, K.;
Notash, B. Tetrahedron Lett. 2014, 55, 1515–1518.
NMR (300 MHz, CDCl3): dH (ppm) = 1.99 (S, 3H), 2.93 (S, OCH3),
3.62–3.68 (t, 1H, Hc), 3.82–3.88 (t, 1H, Hc), 4.11 (d, 1H, J = 9.8 Hz,
Ha), 4.36–4.45 (m, 1H, Hb), 7.28–8.44 (m, 13H, Ar); 13C NMR
(75 MHz, CDCl3): dc (ppm) = 35.4, 45.3, 50.9, 51.1, 61.3, 61.8,
121.6, 121.5, 125.1, 126.5, 128.6, 128.7, 128.8, 130.4, 131.4, 131.1,
137.2, 141.7, 142.3, 171.2; MS m/z (%): 379 (M-41) (35%), 217
(80%), 91 (44%), 77 (86%); [
a
]
20 = ꢀ34 (c 0.03, CH2Cl2).
D
11. (a) Sibi, M.; Stanley, L.; Jasperse, C. J. Am. Chem. Soc. 2005, 127, 8276–8277; (b)
Michael, T.; Crimmins, M.; Hamish, S.; Colin, O.; Hughes, C. Org. Synth. 2011, 88,
364–376.
4.21. Methyl (30S,40S,11R)-10,40-dimethylspiro[indeno[1,2-b]
quinoxaline-11,20-pyrrolidine]-30-carboxylate 8i
12. X-ray data for 7d: C35H34N4O3, M = 558.66, Orthorhombic system, space group
P212121, a = 12.287(3), b = 14.033(3), c = 16.500(3) Å; V = 2845.0(11) Å3, Z = 4,
Dcalcd
0.52ꢂ0.23ꢂ0.20 mm. The X-ray diffraction measurement was made on
STOE IPDS 2T diffractometer with graphite monochromated Mo-K radiation.
= 1.304 g , l(Mo-Ka , crystal dimension of
cmꢀ3 ) = 0.084 mmꢀ1
Hc
Hb
N
a
Hc
a
O
The structure was solved by using SHELXS. The Data reduction and structure
refinement was carried out with SHELXL using the X-STEP32 crystallographic
N
O
Ha
13
software package. The non-hydrogen atoms were refined anisotropically by
full matrix least-squares on F2 values to final R1 = 0.0860, wR2 = 0.1250 and S =
1.061 with 383 parameters using 4901 independent reflection (h range = 2.53-
25°). Hydrogen atoms were added in idealized positions. The crystallographic
information file has been deposited with the Cambridge Data Centre, CCDC
1033398.
N
Yellow liquid (330 mg, 92%); IR (KBr) (m
max/cmꢀ1): CO 1737; 1H
13. X-STEP32 Version 1.07b, Crystallographic Package; Stoe
Darmstadt, Germany, 2000.
& Cie GmbH:
NMR (300 MHz, CDCl3): dH (ppm) = 1.44 (S, 3H), 2.11 (S, 3H), 2.85
(S, OCH3), 3.50–3.68 (t, 2H, Hc), 3.75 (d, 1H, J = 9.9 Hz, Ha), 4.27–
4.48 (m, 1H, Hb), 7.27–8.28 (m, 8H, Ar); 13C NMR (75 MHz, CDCl3):
dc (ppm) = 16.1, 36.2, 38.3, 55.3, 60.1, 63.3, 73.0, 121.3, 122.6, 125.1,
126.9, 128.1, 128.4, 128.7, 130.3, 131.8, 131.9, 137.1, 141.8, 173.3;
MS m/z (%): 359 (M) (32%), 317 (20%), 300 (43%), 217 (86%), 91
14. Kanomata, N.; Maruyama, S.; Tomono, K.; Anada, S. Tetrahedron Lett. 2003, 44,
3599–3603.
15. (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652; (b) Lee, C.; Yang, W.; Parr, R.
G. Phys. Rev. B 1988, 37, 785–789.
16. (a) Sarrafi, Y.; Sadatshahabi, M.; Hamzehloueian, M.; Alimohammadi, K.;
Tajbakhsh, M. Synthesis 2013, 45, 2294–2304; (b) Alimohammadi, K.; Sarrafi,
Y.; Tajbakhsh, M.; Yeganegi, S.; Hamzehloueian, M. Tetrahedron 2011, 67,
1589–1597; (c) Sarrafi, Y.; Hamzehloueian, M.; Alimohammadi, K.; Yeganegi, S.
J. Mol. Struct. 2012, 1030, 168–176; (d) Gérard, H.; Chataigner, I. J. Org. Chem.
2013, 78, 9233–9242; (e) Domingo, L. R.; Saéz, J. A.; Zaragozá, R. J.; Arno, M. J.
Org. Chem. 2008, 73, 8791–8799; (f) Boz, E.; Tüzün, N. S. J. Organomet. Chem.
2013, 724, 167–176; (g) Wang, H.; Jain, P.; Antilla, J. C.; Houk, K. N. J. Org. Chem.
2013, 78, 1208–1215; (h) Bentabed-Ababsa, G.; Derdour, A.; Roisnel, T.; Sáez, J.
A.; Pérez, P.; Chamorro, E.; Domingo, L. R.; Mongin, F. J. Org. Chem. 2009, 74,
2120–2133.
(75%); [
a]
20 = ꢀ33 (c 0.03, CH2Cl2).
D
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