1,3-Dipolar cycloaddition of nitrile oxides to (R)-1-(1-phenylethyl)-3,5- bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones: Synthesis and antimycobacterial evaluation of novel enantiomerically pure di- and trispiroheterocycles

Article abstract of DOI:10.1016/j.tetasy.2010.03.054

Enantiomerically pure (R)-(1-phenylethyl)-3,5-bis[(E)-arylmethylidene] tetrahydro-4(1H)-pyridinones were synthesized for the first time, and their 1,3-dipolar cycloaddition with nitrile oxides affording di- and trispiroheterocycles regio- and stereoselectively in moderate yields was investigated. These compounds were evaluated against Mycobacterium tuberculosis H37Rv (MTB) and multi-drug-resistant M. tuberculosis (MDR-TB). Among the compounds screened, the dispiroheterocycle, namely, (5R,6R,10S)-3,9-bis(4- chlorophenyl)-10-(2,4-dichlorophenyl)-14-[(E)-(2,4-dichlorophenyl)methylidene] -12-[(R)-1-phenylethyl]-1,4,7-trioxa-2,8,12-tri-azadispiro[4.0.4.4]tetradeca-2, 8-diene 5m was found to possess the maximum activity with MIC of 0.49 μM against MTB, being 9.6 and 15.6 times more potent than ciprofloxacin and ethambutol, respectively. Against MDR-TB, 5m displayed maximum activity with an MIC of 0.49 μM, with it thus being more active than rifampicin, isoniazid, ciprofloxacin and ethambutol by 7.8, 23, 77 and 124 times, respectively.

Full text of DOI:10.1016/j.tetasy.2010.03.054

Tetrahedron: Asymmetry 21 (2010) 1315–1327
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
1,3-Dipolar cycloaddition of nitrile oxides to (R)-1-(1-phenylethyl)-3,5-bis[(E)-
arylmethylidene]tetrahydro-4(1H)-pyridinones: synthesis and antimycobacte-
rial evaluation of novel enantiomerically pure di- and trispiroheterocycles
b
Raju Suresh Kumar a, Stephen Michael Rajesh a, Subbu Perumal a, , Perumal Yogeeswari ,
*
Dharmarajan Sriram b
a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, India
b Medicinal Chemistry & Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science, Pilani, Hyderabad Campus, Jawahar Nagar,
Hyderabad 500 078, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantiomerically pure (R)-(1-phenylethyl)-3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones
were synthesized for the first time, and their 1,3-dipolar cycloaddition with nitrile oxides affording di-
and trispiroheterocycles regio- and stereoselectively in moderate yields was investigated. These com-
pounds were evaluated against Mycobacterium tuberculosis H37Rv (MTB) and multi-drug-resistant M.
tuberculosis (MDR-TB). Among the compounds screened, the dispiroheterocycle, namely, (5R,6R,10S)-
3,9-bis(4-chlorophenyl)-10-(2,4-dichlorophenyl)-14-[(E)-(2,4-dichlorophenyl)methylidene]-12-[(R)-1-
phenylethyl]-1,4,7-trioxa-2,8,12-tri-azadispiro[4.0.4.4]tetradeca-2,8-diene 5m was found to possess the
Received 22 February 2010
Accepted 29 March 2010
Available online 2 June 2010
Dedicated to Professor Henri B. Kagan on his
80th birthday
maximum activity with MIC of 0.49
floxacin and ethambutol, respectively. Against MDR-TB, 5m displayed maximum activity with an MIC of
0.49 M, with it thus being more active than rifampicin, isoniazid, ciprofloxacin and ethambutol by 7.8,
23, 77 and 124 times, respectively.
lM against MTB, being 9.6 and 15.6 times more potent than cipro-
Keywords:
1,3 dipolar cycloaddition
Nitrile oxide
Spiroisoxazolines
Dioxazoles
Antitubercular activity
l
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
The World Health Organization estimates that 2 billion people
(about one-third of the world population) are infected with Myco-
bacterium tuberculosis, among which 8 million develop active
tuberculosis (TB) and nearly 2 million die each year, especially in
developing countries.15 Furthermore, the rising number of people
who contract TB, because their immune systems are compromised
by immunosuppressive drugs or substance abuse or HIV/AIDS, is a
great impediment to TB control and prevention. Further, the devel-
opment and spread of multidrug- and extensively drug-resistant
tuberculosis (MDR/XDR-TB) have the potential to paralyze TB care
programmes posing a serious threat to industrialized nations
where individual care and treatment costs and larger social and
economic disruptions could become major public policy issues.16
In the last 50 years, only a few drugs have been approved by the
Food and Drug Administration (FDA) to treat TB, which reflects
the difficulties in the discovery and clinical testing of new candi-
dates and the lack of pharmaceutical industry research in this area.
Hence, the discovery of fast-acting new drugs to effectively cure
TB, including MDRTB, is imperative.
1,3-Dipolar cycloaddition reactions afford complex heterocycles
with multiple stereocentres, which are useful in the construction of
many natural products and pharmaceuticals.1 The 1,3-dipolar
cycloaddition of nitrile oxides to alkenes and a,b-unsaturated car-
bonyl compounds affords isoxazolines,2 spiroisoxazolines3 and
dioxazoles.3 Isoxazolines exhibit antibacterial,4 antiplatelet,5 anti-
viral6 and anticonvulsant7 activities, while compounds incorporat-
ing the spiroisoxazoline sub-structure have stimulated much
interest in medicinal and biological chemistries.8–11 Some natu-
rally occurring spiroisoxazolines, such as araplysillins, inhibit
ATP-ase enzymes,9 while agelorin is active against pathogens such
as Bacillus subtilis and Micrococcus lutens,10 zamamistatin exhibits
significant antibacterial activity against Rhodospirilium salexigens11
and aerothionin displays antimycobacterial activity.12 Functional-
ized piperidines occur with great regularity in the natural product
arena, in addition to being important as pharmaceuticals.13 Over
the last 10 years, a multitude of piperidine-containing compounds
have entered into preclinical and clinical trials.14
The biological importance of isoxazolines, spiro heterocycles
and piperidines and our ongoing research programme on the con-
struction of novel heterocycles17 led us to recently investigate the
1,3-dipolar cycloaddition of 1-methyl-3,5-bis[(E)-arylmethyli-
* Corresponding author. Tel./fax: +91 452 2459845.
E-mail address: subbu.perum@gmail.com (S. Perumal).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.03.054

1316
R. S. Kumar et al. / Tetrahedron: Asymmetry 21 (2010) 1315–1327
dene]tetrahydro-4(1H)-pyridinones.18 This work led to the chemo-
selective formation of monospiro-isoxazolines from 1-methyl-3,5-
bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones via a tandem
azomethine ylide and nitrile oxide cycloadditions–cycloreversion
sequence.18 In our earlier studies,19,20 we have reported the
synthesis and anti-tubercular evaluation of a series of enantiome-
rically pure spiroisoxazolines via cycloaddition of nitrile oxides to
(R)-1-(1-phenylethyl)-3-[(E)-arylmethylidene]tetrahydro-4(1H)-py-
ridinones. Herein, we report the results of our investigations on the
1,3-dipolar cycloaddition of nitrile oxides to (R)-(1-phenylethyl)-
3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones 2, which
has three dipolarophilic functionalities, with a view to (i) obtaining
enantiomerically pure spiroheterocycles, (ii) screening for their anti-
tubercular activity and (iii) investigating their structure–activity as-
pects. It should be noted that this is the first report on the synthesis
and the cycloaddition of the chiral dipolarophiles 2. This study also
discloses that the group attached to the nitrogen of the dipolaro-
phile influences the reactivity of the above dipolarophiles and the
product selectivity of the cycloaddition.
2. Results and discussion
Enantiomerically pure (R)-(1-phenylethyl)-3,5-bis[(E)-aryl-
methylidene]tetrahydro-4(1H)-pyridinones 2a–g were synthesized
for the first time in good yields (78–85%) by the reaction of (R)-1-(1-
phenylethyl)tetrahydro-4(1H)-pyridinone 1 with aromatic alde-
hydes in the presence of ethanolic sodium hydroxide (30%)
(Scheme 1). All the seven (R)-(1-phenylethyl)-3,5-bis[(E)-arylmeth-
ylidene]tetrahydro-4(1H)-pyridinones (2a–g) are new and their
structures are in accordance with their one and two-dimensional
NMR spectroscopic data. The structure of 2 was also further con-
firmed by X-ray crystallographic studies of single crystals of 2b21
(Fig. 1) and 2d (Fig. 2). These studies show that (i) the configuration
of the arylidene C@C bond of 2 is (E), (ii) the heterocyclic ring adopts
an envelope conformation and (iii) 2b and 2d adopt different nitro-
Figure 1. ORTEP diagram of 2b.
gen invertomers (the lone pair on nitrogen and the a-phenylethyl
group interchanging their orientations in these structures), presum-
ably ascribable to the differences in their crystal packing.
O
N
O
N
NaOH (30%)
EtOH
Ar
Ar
+
2 ArCHO
R
R
H
H
H3C
Ph
Ph
H3C
1
2
Entry
Comp
2a
Ar
Yield (%)
Figure 2. ORTEP diagram of 2d.
1
2
3
4
5
6
7
C6H5
80
83
79
85
84
82
78
2b
p-ClC6H4
p-MeC6H4
o-ClC6H4
o-BrC6H4
o,p-Cl2C6H3
1-Naphthyl
dinones 2 (Scheme 2 and Table 1) led to the formation of (i) spiro
dioxazoles 4 and 5, the former predominating, in 24–30 and 14–
20% yields, respectively, arising from the nitrile oxide addition to
one C@C and C@O bonds; (ii) and a dispiro compound 6 (2–3%),
only in three cases, arising from the addition to both C@C bonds
and (iii) a trispiro compound 7 (6–10%), only when the aryl ring
in 2 bears ortho substituents, such as o-ClC6H4 and o,p-Cl2C6H3,
arising from the addition to C@O and both the C@C bonds. All of
the cycloadducts 4–7 were separated through flash column chro-
matography using petroleum ether–ethyl acetate as eluent. The
reaction proceeds regio- and stereoselectively with the oxygen of
2c
2d
2e
2f
2g
Scheme 1. Synthesis of dipolarophiles.
the nitrile oxide preferentially adding only to the a-carbon of the
benzylidene moiety affording predominantly the stereoisomer 4
in all the cases.
The 1,3-dipolar cycloaddition of nitrile oxide, generated in situ
from benzohydroximoyl chloride 3 and triethylamine to (R)-(1-
phenylethyl)-3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyri-

R. S. Kumar et al. / Tetrahedron: Asymmetry 21 (2010) 1315–1327
1317
Ar'
Ar
H
Ar
S
R
Ar'
N
H
Ar
Me
H
O
N
O
S
Ar
N
N
H
Me
O
R
O
R
Ar
Ar
R
Ph
O
Ph
R
N
S
N
O
O
N
4
5
R
Ar'
H
H3C
Ar'
Ph
Et3N
2
Ar'
Benzene, rt
O
N
N
N
O
H
O
Cl
OH
O
O
Ar'
Ar'
O
O
N
N
N
R
R
S
S
R
Ar'
Ar
Ar
N
Ar'
Ar'
3
Ar
N
H
Ar
H
Ph
H3C
H
H3C
R
Ph
R
6
7
Scheme 2. Synthesis of di- and trispiro cycloadducts.
Table 1
Synthesis of di- and trispiro cycloadducts from 2
Entry
Compd
Ar
Ar0
Yield (%)
4
5
6a
7
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
C6H5
C6H5
C6H5
p-ClC6H4
C6H5
p-ClC6H4
p-(CH3)2CHC6H4
C6H5
p-ClC6H4
C6H5
p-ClC6H4
C6H5
p-ClC6H4
C6H5
p-ClC6H4
p-(CH3)2CHC6H4
C6H5
30
26
30
25
25
25
29
26
24
25
24
26
24
25
28
25
25
15
18
17
20
18
16
15
14
15
16
14
14
15
15
14
16
15
2
—
—
—
—
—
—
—
8
10
7
10
6
8
8
—
—
—
—
—
—
—
—
—
3
—
—
3
—
—
—
—
—
—
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-MeC6H4
p-MeC6H4
o-ClC6H4
o-ClC6H4
o-BrC6H4
o-BrC6H4
o,p-Cl2C6H3
o,p-Cl2C6H3
o,p-Cl2C6H3
1-Naphthyl
1-Naphthyl
1-Naphthyl
p-ClC6H4
p-(CH3)2CHC6H4
a
Figure 3. ORTEP diagram of 4l.
Stereochemistry of 6 was not established.
The structures of the cycloadducts were characterized by one-
and two-dimensional NMR spectroscopic data. The structures of
4, 5 and 7 were further confirmed by X-ray crystallographic stud-
ies22,23 (Figs. 3–5). The stereochemistry of 6 was not established
unambiguously, as it formed in very small amounts from which
suitable crystals could not be obtained.
The diastereomers 4 and 5, bearing an enantiomeric relation-
ship, (if one ignores the configuration of the a-phenylethyl group)
are formed by the cycloaddition of nitrile oxide to C@C bonds of
both dibenzylidene functions, one in each case, and the C@O bond
(Scheme 3). The 1H and 13C chemical shifts of 4d and 5d differed a
little (Table 2) thus showing that the environments of the carbons
and hydrogens of these compounds do not differ much. The forma-
tion of 5 to a slightly lesser extent than 4 may presumably be as-
cribed to the possible greater steric interaction between the aryl
at the 10-position of the isoxazoline with the methyl of the
phenylethyl in 5 than the interaction between the 10-aryl and
hydrogen of the -phenylethyl in 4 (Scheme 3). This is likely to in-
a-
a
Figure 4. ORTEP diagram of 5d.
crease the free energy of activation for the formation of 5 and slow
down its formation relative to its diastereomer 4. A similar influ-
ence of these interactions on the stereoselectivity has been invoked
in the nitrile oxide cycloaddition of (R)-1-(1-phenylethyl)-3-[(E)-
arylmethylidene]tetrahydro-4(1H)-pyridinones.19
With a view to finding the order of occurrence of the cycloaddi-
tion of nitrile oxide to the C@C and C@O bonds leading to the for-
mation of the di- and trispiro compounds, the reaction was

1318
R. S. Kumar et al. / Tetrahedron: Asymmetry 21 (2010) 1315–1327
intercepted at early stages before completion of the reaction at
30 min and 1 h whereupon the reaction mixture failed to afford
either monospiro-isoxazoline or dioxazole thus suggesting that
they might have undergone further reaction very rapidly affording
4–7. Hence it was not possible to infer whether the isoxazoline or
dioxazole or both are the initially formed intermediates, which un-
dergo further cycloaddition to afford the di- or trispiro products.
As the dioxazole ring and one of the isoxazoline rings of the tri-
spiro product 7 have the same absolute configurations as the cor-
responding rings of the dispiro product 5 (Scheme 2), it appeared
that 7 might result from further cycloaddition to 5. To confirm this,
the reaction of 5 with a nitrile oxide was performed in a separate
experiment under the same reaction conditions as those of the
overall reaction. This reaction furnished 7, suggesting its formation
from 5.
A comparison of the results of the cycloaddition of nitrile oxide
to 3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones with
(i) N-Me group 818 and (ii)
a-phenylethyl group 2 is noteworthy.
The cycloaddition of 2 bearing an N- -phenylethyl group afforded
a
only di- and trispiro cycloadducts, whilst the reaction of 8 bearing
N-Me afforded only mono- and dispiro products (Scheme 4). The
cycloaddition of 2 also shows that the mono spiro product is very
reactive towards further cycloaddition, as has been already alluded
to, which explains its non-isolation from the reaction mixture. In
Figure 5. ORTEP diagram of 7i.
Ar'
Ar
Ar
R
H
.
.
Ar
10
H
N
O
S
+
Me
N
Me
2
Ar' C N O-
N
H
O
R
O
R
Ph
S
N
A
Ph
O
4
Ar'
Ar
Ar
Ar
Ar'
N
.
.
H
S
10
Ar
Me
+
Me
2
Ar' C N O-
H
N
N
H
O
R
O
R
R
Ph
O
R
N
Ph
B
O
Ar'
Ar
5
indicates the direction of approach of nitrile oxide
Scheme 3. Formation of diastereomeric dispiro cycloadducts 4 and 5.
Table 2
Comparison of 1H and 13C chemical shifts of 4d and 5d
Nuclei
Chemical shift d (ppm)
Nuclei
1H
13C
4d
5d
4d
19.8
64.2
56.8
52.4
5d
15.2
63.4
56.5
52.5
CH3
CH
0.75, d, J = 6.6 Hz
3.07–3.11, m
4.76, s
2.65, d, J = 11.9 Hz
3.02, d, J = 11.9 Hz
2.72, d, J = 12.5 Hz
3.67, d, J = 12.5 Hz
6.92–7.74, doublets and multiplets
1.07, d, J = 6.6 Hz
3.31, q, J = 6.6 Hz
4.72, s
2.69, d, J = 11.9 Hz
2.80, d, J = 11.9 Hz
3.00, d, J = 12.2 Hz
3.67, d, J = 12.2 Hz
6.85–7.72, doublets and multiplets
CH3
CH
H-10
H-11a
C-10
C-11
H-11b
H-13a
49.1
46.7
C-13
H-13b
H-15 and aromatic protons
158.0
158.2
115.4
89.8
158.2
158.3
115.4
89.9
C-3
C-9
C-5
C-6

R. S. Kumar et al. / Tetrahedron: Asymmetry 21 (2010) 1315–1327
1319
Table 3
the case of aryl rings bearing o-halogens, the dispiro products are
Minimum inhibitory concentrations
(l
M) of compounds 2, 4,
5
and
7
against
also significantly reactive to afford trispiro products, while it is
not so in the case of the corresponding 8. Presumably, the variation
in the group linked to the nitrogen of the piperidone rings, such as
mycobacterial species against MTBa and MDR-TBb
Compd
2
4
5
7
N-methyl and N-a-phenylethyl in 8 and 2, respectively, could alter
MTB
MTB
MDR-
TB
MTB
MDR-
TB
MTB MDR-
TB
the conformation of the piperidone ring which in turn could influ-
ence the extent of transannular/homoconjugative interactions of
the nitrogen with the carbonyl/benzylidene functionality, thereby
affecting the reactivity and/or product selectivity. A similar influ-
ence of the substituent linked to nitrogen on the product selectiv-
c
c
c
c
c
c
c
c
c
c
c
c
c
c
c
c
c
c
c
c
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
65.88 20.24
27.88 9.10
30.67 4.56
13.94 4.14
23.26
6.05
—
—
—
—
—
—
—
—
40.47
4.56
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
c
c
c
c
18.20
2.06
c
1.03
c
c
c
c
—
—
—
c
ity has been observed in the reaction of N-methyl and N-
a-
9.68
2.42
8.75
9.10
4.14
8.06
7.40
1.03
0.49
14.89
8.70
0.99
15.59
2.42
c
c
phenylethyl piperidones with (E)-4-arylbut-3-en-2-ones in the
13.03 8.75
—
—
—
—
c
c
—
—
—
—
—
—
—
—
—
—
4.56
2.06
8.06
3.71
2.06
0.95
7.44
4.36
1.98
15.59
3.88
3.44
3.50
3.14
presence of
obtained.24
L-proline wherein different product selectivities were
c
2.06
c
c
—
—
c
c
—
2.1. Biological results and discussion
1.03
0.95
0.53
0.49
1.78 1.78
0.80 1.60
c
c
c
—
—
—
—
6.24
—
—
—
—
The dipolarophiles 2 and the cycloadducts 4, 5 and 7 were
screened for their in vitro antimycobacterial activity against MTB
and MDR-TB using an agar dilution method for the determination
of MIC in duplicate. The MDR-TB clinical isolate was resistant to
the first line anti-TB drugs, isoniazid, rifampicin and ethambutol.
The MIC is defined as the minimum concentration of compound re-
quired to inhibit 99% of bacterial growth, and the MIC values of the
compounds synthesized along with the standard drugs for compar-
ison are presented in Table 3.
c
c
c
c
c
c
—
—
c
0.99
0.99
c
c
c
q
—
—
—
Rifampicin
Isoniazid
Ciprofloxacin
Ethambutol
0.12 3.80
0.36 11.38
4.71 37.73
7.64 61.18
a
b
c
MTB: Mycobacterium tuberculosis.
MDR-TB: Multi-drug-resistant Mycobacterium tuberculosis.
Not tested.
The dipolarophiles (R)-(1-phenylethyl)-3,5-bis[(E)-arylmethyli-
dene]tetrahydro-4(1H)-pyridinones 2 afford MIC ranging from
Subsequently, compounds with MIC <2.5
against MDR-TB and the compounds inhibited MDR-TB with MIC
ranging from 0.49 to 2.42 M. All the nine compounds screened
were found to be more active than rifampicin (MIC: 3.80 M), iso-
M) and etham-
M). As in the case of MTB, compound 5m
lM were evaluated
6.05–65.88 lM, amongst which compound 2g with an MIC of
6.05
l
M was found to be more active than ethambutol (MIC of
l
7.64
lM) against MTB. The activity of the dipolarophiles 2 is influ-
l
enced by the substituents on the aryl ring, the order being o,p-
dichlorophenyl > 1-naphthyl > o-chlorophenyl > o-bromophenyl >
p-chlorophenyl > p-tolyl > phenyl indicating that the halogen in the
ortho position and the presence of two halogens enhance the
activity. It is found that lipophilicity also enhances the activity as
seen from the order 1-naphthyl > p-tolyl > phenyl.
niazid (MIC: 11.38
butol (MIC: 61.18
lM), ciprofloxacin (MIC: 37.73 l
l
displayed the maximum activity in vitro with an MIC of 0.49 lM
against MDR-TB also, being 7.8, 23.2, 77.0 and 124.9 times more
potent than rifampicin, isoniazid, ciprofloxacin and ethambutol,
respectively.
In the first phase of screening against MTB, all of the diastereo-
meric cycloadducts 4 and 5 showed good to excellent in vitro activ-
The trispiro cycloadducts 7h–n showed good activity with MIC
ranging from 0.80 to 6.24
than ethambutol (MIC: 7.64
<4 M and are more potent than ciprofloxacin (MIC: 4.71
Among the trispiro compounds, 7m was found to be the most ac-
tive in vitro with an MIC of 0.80 M against MTB and was 5.9
and 9.6 times more potent than ciprofloxacin and ethambutol,
respectively. Against MDR-TB, 7m had an MIC of 1.60 M, being
l
M against MTB and are more potent
M). Six compounds 7g–m have MIC
M).
ity with MIC ranging from 0.49 to 40.47
4c, 4d, 4h, 4i, 4k–p, 5b, 5d, 5f, 5i, 5k–m and 5p inhibited MTB with
lM. Eighteen compounds
l
l
l
MIC of less than 7.5
ambutol (MIC: 7.64
l
M being more potent than the standard, eth-
l
M). Sixteen compounds 4c, 4d, 4h, 4i, 4k–m,
l
4o, 4p, 5b, 5d, 5f, 5i, 5l, 5m and 5p were found to be more active
against MTB than ciprofloxacin (MIC: 4.71 M). Compound 5m
was found to be the most active in vitro with an MIC of 0.49
against MTB and was 9.6 and 15.6 times more potent than cipro-
floxacin and ethambutol, respectively.
l
l
lM
2.4, 7.1, 23.5 and 38.2 times more potent than rifampicin, isoniazid,
ciprofloxacin and ethambutol, respectively.
Ar'
3
Ar'
Ar
Ar
H
9
H
7
4
5
Ar
12N
15
10
N
N
8
N 2
H3C
6
10
11
8
O
H3C
O7
5
H
1
O
9
O
14
H
H
13
4
O
6
11
3 Ar'
Ar
H
1
O
Ar'
Cl
OH
Ar
2
H
N
N
Ar
Ar
9
10
Ar'
Ar'
N
Et3N C6H6
rt, 10 h
Ar
H
9
3
H
CH3
4
Ar
12N
8
15 10
9
N 2
N
8
6
O 14
8
N
11
5
N
H3C
O
H3C
O7
5
1
O
14
7
13
6
1
10
Ar
Ar'
O
N
11H
4
O
3
Ar'
11
12
Scheme 4. Cycloaddition of nitrile oxide to 1-methyl-3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones 8.

1320
R. S. Kumar et al. / Tetrahedron: Asymmetry 21 (2010) 1315–1327
In general, against MTB, some compounds belonging to the dia-
NaOH (30 mL, 30%) was stirred at room temperature for 10 min.
The separated solid was filtered and crystallized from alcohol to
give 2 in good yield (78–85%).
stereomer series 4 showed better activity than series 5 and the re-
verse is true for some other compounds. A comparison of the
antimycobacterial activity of the cycloadducts formed from the
cycloaddition of monoarylidine dipolarophiles reported earlier20
and that from the bisarylidene dipolarophiles of the present study
over nitrile oxides shows that the latter cycloadducts, the isoxazo-
lines, are endowed with higher potency than the cycloadducts
from monoarylidene compounds.
4.2.1.1. (R)-(1-Phenylethyl)-3,5-bis[(E)-phenylmethylidene]tet-
rahydro-4(1H)-pyridinone 2a. Obtained as pale yellow crystals,
(0.745 g, 80%); mp = 112–113 °C; [
a
]
D = +10.5 (c 0.20, CHCl3); IR
(KBr)
m
max: 1673, 1621, 1596 cmꢀ1
.
1H NMR (300 MHz, CDCl3): dH
1.32 (d, 3H, J = 6.6 Hz, CH3), 3.72 (q, 1H, J = 6.6 Hz, CH), 3.82 (d, 2H,
J = 15.0 Hz, 2-CH2 and 6-CH2), 3.91 (d, 2H, J = 15.0 Hz, 2-CH2 and 6-
CH2), 7.16–7.40 (m, 15H, aromatic), 7.82 (s, 2H, H-7 and H-8). 13C
NMR (75 MHz, CDCl3): dC 19.3, 51.4, 62.0, 127.1, 127.3, 128.2,
128.3, 128.7, 130.1, 133.5, 135.1, 136.4, 142.4, 188.0. Anal. Calcd for
3. Conclusions
The present investigation describes the synthesis of enantiome-
rically pure new (R)-(1-phenylethyl)-3,5-bis[(E)-arylmethylidene]
tetrahydro-4(1H)-pyridinones and their 1,3-dipolar cycloaddition
with nitrile oxides performed for the first time to afford enantio-
merically pure novel di- and trispiroheterocycles. The present
work also discloses that the product selectivity of the cycloaddition
is mediated by the group linked to the nitrogen of the dipolaro-
philes. The di- and trispiroheterocycles displayed good to excellent
in vitro activity against M. tuberculosis H37Rv (MTB) and multi-
drug-resistant M. tuberculosis (MDR-TB).
C27H25NO: C, 85.45; H, 6.64; N, 3.69. Found: C, 85.52; H, 6.53; N, 3.78.
4.2.1.2. 3,5-Bis[(E)-(4-chlorophenyl)methylidene]-1-[(R)-1-phen-
ylethyl]tetrahydro-4(1H)-pyridinone (2b). Obtained as yellow
crystals; (0.910 g, 83%); mp = 139–140 °C; [
a]
D = +21.0 (c 0.20,
CHCl3); IR (KBr)
m
max: 1688, 1612, 1583 cmꢀ1
.
1H NMR (300 MHz,
CDCl3): dH 1.32 (d, 3H, J = 6.8 Hz, CH3), 3.70 (q, 1H, J = 6.8 Hz,
CH), 3.77 (d, 2H, J = 15.5 Hz, 2-CH2 and 6-CH2), 3.85 (d, 2H,
J = 15.5 Hz, 2-CH2 and 6-CH2), 7.18–7.34 (m, 13H, aromatic), 7.72
(s, 2H, H-7 and H-8). 13C NMR (75 MHz, CDCl3): dC 19.4, 51.4,
62.1, 127.3, 127.4, 128.4, 128.8, 131.4, 133.6, 133.9, 134.9, 135.3,
142.3, 187.8. Anal. Calcd for C27H23Cl2NO: C, 72.32; H, 5.17; N,
3.12. Found: C, 72.43; H, 5.26; N, 3.19.
4. Experimental
4.1. General methods
Melting points were taken using open capillary tubes and are
uncorrected. 1H, 13C and two-dimensional NMR spectra were re-
corded on a Bruker 300 MHz instrument in CDCl3 using TMS as an
internal standard. Chemical shifts are given in parts per million (d-
scale) and the coupling constants are given in Hertz. IR spectra were
recorded on a JASCO FT IR instrument (KBr pellet in case of solids and
CHCl3 in case of liquids). Single crystal X-ray data set for 4l was col-
4.2.1.3.
phenylethyl]tetrahydro-4(1H)-pyridinone 2c. Obtained as yel-
low crystals; (0.790 g, 79%); mp = 103–104 °C; [ D = +13.0 (c 0.20,
CHCl3); IR (KBr)
max: 1679, 1627, 1590 cmꢀ1 1H NMR (300 MHz,
CDCl3): dH 1.33 (d, 3H, J = 6.6 Hz, CH3), 2.37 (s, 6H, CH3), 3.73 (q,
1H, J = 6.6 Hz, CH), 3.81 (d, 2H, J = 15.5 Hz, 2-CH2 and 6-CH2), 3.90
(d, 2H, J = 15.5 Hz, 2-CH2 and 6-CH2), 7.15–7.26 (m, 13H, aromatic),
7.77 (s, 2H, H-7 and H-8). 13C NMR (75 MHz, CDCl3): dC 19.4, 21.4,
51.6, 62.1, 127.1, 127.4, 128.3, 129.2, 130.3, 132.4, 132.8, 136.4,
139.1, 142.5, 188.2. Anal. Calcd for C29H29NO: C, 85.47; H, 7.17; N,
3.44. Found: C, 85.58; H, 7.08 ; N, 3.53.
3,5-Bis[(E)-(4-methylphenyl)methylidene]-1-[(R)-1-
a]
m
.
lected on Enraf–Nonius (CAD4) diffractometer with Mo
Ka
(k = 0.71073 Å) radiation. Scan range was 2.02° 6 h 6 24.97°. The
X-ray diffraction data of 5d was collected on CCD area detector with
Mo
1.39° 6 h 6 26.12°. The single crystal X-ray data set for 7i was col-
lected on a Bruker Kappa X8 APPEX II diffractometer with Mo K
Ka (k = 0.71073 Å) radiation and the scan range was
a
4.2.1.4.
phenylethyl]tetrahydro-4(1H)-pyridinone 2d. Obtained as yel-
low crystals; (0.935 g, 85%); mp = 85–86 °C; [ D = +12.0 (c 0.20,
CHCl3); IR (KBr)
max: 1673, 1617, 1600 cmꢀ1 1H NMR (300 MHz,
3,5-Bis[(E)-(2-chlorophenyl)methylidene]-1-[(R)-1-
(k = 0.71073 Å) radiation. The scan range was 2.22° 6 h 6 33.00°.
Elemental analyses were performed on a Perkin Elmer 2400 Series
II Elemental CHNS analyzer. Column chromatography was per-
formed on silica gel (230–400 mesh) using petroleum ether–ethyl
acetate as eluent. Optical rotation values were measured using an
autopol IV automatic polarimeter at sodium D line at 25 °C. Tenfold
serial dilutions of each test compound/drug were prepared and
incorporated into Middlebrook 7H11 agar medium with OADC
Growth Supplement. Inoculum of M. tuberculosis H37Rv was pre-
pared from fresh Middlebrook 7H11 agar slants with OADC Growth
Supplement adjusted to 1 mg/mL (wet weight) in Tween 80 (0.05%)
saline diluted to 10ꢀ2 to give a concentration of approximately
a]
m
.
CDCl3): dH 1.17 (d, 3H, J = 6.6 Hz, CH3), 3.66 (q, 1H, J = 6.6 Hz,
CH), 3.72 (d, 2H, J = 14.7 Hz, 2-CH2 and 6-CH2), 3.83 (d, 2H,
J = 14.7 Hz, 2-CH2 and 6-CH2), 7.01–7.43 (m, 13H, aromatic), 8.00
(s, 2H, H-7 and H-8). 13C NMR (75 MHz, CDCl3): dC 19.6, 51.0,
60.3, 126.2, 127.0, 127.2, 128.1, 129.7, 129.8, 130.2, 133.5, 134.5,
134.6, 134.9, 142.8, 187.8. Anal. Calcd for C27H23Cl2NO: C, 72.32;
H, 5.17; N, 3.12. Found: C, 72.41; H, 5.10; N, 3.24.
4.2.1.5.
phenylethyl]tetrahydro-4(1H)-pyridinone 2e. Obtained as pale
yellow crystals; (1.100 g, 84%); mp = 100–101 °C; [ D = +14.0 (c
0.20, CHCl3); IR (KBr)
max: 1674, 1615, 1608 cmꢀ1 1H NMR
3,5-Bis[(E)-(2-bromophenyl)methylidene]-1-[(R)-1-
107 cfu/mL. A 5-
lL amount of bacterial suspension was spotted into
7H11 agar tubes containing 10-fold serial dilutions of drugs per mL.
The tubes were incubated at 37 °C, and final readings were recorded
after 28 days. The minimum inhibitory concentration (MIC) is de-
fined as the minimum concentration of compound required to give
complete inhibition of bacterial growth.
a]
m
.
(300 MHz, CDCl3): dH 1.17 (d, 3H, J = 6.6 Hz, CH3), 3.63–3.72 (m,
3H, CH, 2-CH2 and 6-CH2), 3.81 (d, 2H, J = 15.6 Hz, 2-CH2 and 6-
CH2), 6.93–7.63 (m, 13H, aromatic), 7.94 (s, 2H, H-7 and H-8).
13C NMR (75 MHz, CDCl3): dC 19.7, 50.9, 60.3, 125.0, 126.9, 127.0,
127.2, 128.1, 130.0, 130.2, 132.9, 134.3, 135.4, 137.0, 142.9,
187.7. Anal. Calcd for C27H23Br2NO: C, 60.36; H, 4.31; N, 2.61.
Found: C, 60.47; H, 4.38; N, 2.50.
4.2. Preparation of (R)-(1-phenylethyl)-3,5-bis[(E)-
arylmethylidene]tetrahydro-4(1H)-pyridinone 2a–g
4.2.1. General procedure
A mixture of (R)-(1-phenylethyl)tetrahydro-4(1H)-pyridinone 1
(1 mmol) and the appropriate aldehyde (2 mmol) in alcoholic
4.2.1.6. 3,5-Bis[(E)-(2,4-dichlorophenyl)methylidene]-1-[(R)-1-
phenylethyl]tetrahydro-4(1H)-pyridinone 2f. Obtained as a yel-

R. S. Kumar et al. / Tetrahedron: Asymmetry 21 (2010) 1315–1327
1321
low solid; (1.040 g, 82%); mp = 113–114 °C; [
a
]
D = +17.0 (c 0.20,
127.5, 127.8, 128.0, 128.1, 128.4, 128.5, 128.6, 128.7, 128.8,
129.7, 130.8, 131.5, 134.1, 135.6, 141.1, 158.9, 159.0. Anal. Calcd
for C41H35N3O3: C, 79.72; H, 5.71; N, 6.80. Found: C, 79.82; H,
5.64; N, 6.69.
CHCl3); IR (KBr)
m
max: 1670, 1612, 1581 cmꢀ1
.
1H NMR (300 MHz,
CDCl3): dH 1.19 (d, 3H, J = 6.8 Hz, CH3), 3.64 (q, 1H, J = 6.8 Hz,
CH), 3.67 (d, 2H, J = 15.5 Hz, 2-CH2 and 6-CH2), 3.78 (d, 2H,
J = 15.5 Hz, 2-CH2 and 6-CH2), 6.93–7.45 (m, 11H, aromatic), 7.90
(s, 2H, H-7 and H-8). 13C NMR (75 MHz, CDCl3): dC 19.6, 50.9,
60.5, 126.7, 127.1, 127.2, 128.2, 129.7, 130.8, 131.9, 133.5, 134.9,
135.1, 135.7, 142.6, 187.4. Anal. Calcd for C27H21Cl4NO: C, 62.69;
H, 4.09; N, 2.71. Found: C, 62.79; H, 4.16; N, 2.60.
4.3.1.3. 3,4,10,11-Tetraphenyl-13-[(R)-1-phenylethyl]-1,8-dioxa-
2,9,13-triazadispiro[4.1.4.3]tetradeca-2,9-dien-6-one
6a. Obtained as a white solid; (0.010 g, 2%); mp = 202–203 °C;
[a
]
D = ꢀ135.0 (c 0.10, CHCl3); IR (KBr)
mmax: 1592, 1494, 1406,
1346, 1090, 837, 752 cmꢀ1 1H NMR (300 MHz, CDCl3): dH 0.98
;
4.2.1.7.
ethyl]tetrahydro-4(1H)-pyridinone 2g. Obtained as a pale yellow
solid; (0.920 g, 78%); mp = 128–129 °C; [ D = +50.0 (c 0.20, CHCl3);
IR (KBr)
max: 1678, 1612, 1580 cmꢀ1 1H NMR (300 MHz, CDCl3):
dH 1.07 (d, 3H, J = 6.6 Hz, CH3), 3.63 (q, 1H, J = 6.6 Hz, CH), 3.74
(d, 2H, J = 15.3 Hz, 2-CH2 and 6-CH2), 3.85 (d, 2H, J = 15.3 Hz, 2-
CH2 and 6-CH2), 6.85–8.10 (m, 19H, aromatic), 8.51 (s, 2H, H-7
and H-8). 13C NMR (75 MHz, CDCl3): dC 19.3, 51.5, 60.9, 124.7,
124.9, 126.2, 126.5, 126.9, 127.2, 127.9, 128.1, 128.5, 129.2,
131.9, 132.2, 133.4, 135.0, 135.6, 142.4, 188.0. Anal. Calcd for
3,5-Bis[(E)-1-naphthylmethylidene]-1-[(R)-1-phenyl-
(d, 3H, J = 6.8 Hz, CH3), 2.22 (d, 1H, J = 12.6, Hz, H-12a or H-14a),
2.34 (d, 1H, J = 13.2 Hz, H-12a or H-14a), 2.75–2.84 (m, 2H, H-
12b and H-14b), 3.34 (q, 1H, J = 6.8 Hz, CH), 5.29 (s, 1H, H-4 or
H-11), 5.31 (s, 1H, H-4 or H-11), 6.85–7.59 (m, 25H, aromatic).
13C NMR (75 MHz, CDCl3): dC 17.0, 53.8, 54.7, 56.1, 56.2, 62.4,
90.0, 127.1, 127.5, 128.0, 128.2, 128.3, 128.4, 128.5, 128.9, 129.0,
129.9, 133.3, 140.0, 159.0, 159.1, 199.3. Anal. Calcd for
a]
m
.
C41H35N3O3: C, 79.72; H, 5.71; N, 6.80. Found: C, 79.63; H, 5.79;
N, 6.72.
C
2.84.
35H29NO: C, 87.65; H, 6.09; N, 2.92. Found: C, 87.77; H, 6.17; N,
4.3.1.4. (5S,6S,10R)-3,9-Bis(4-chlorophenyl)-10-phenyl-12-[(R)-
1-phenylethyl]-14-[(E)-phenylmethylidene]-1,4,7-trioxa-2,8,12-
triazadispiro[4.0.4.4]tetradeca-2,8-diene 4b. Obtained as a vis-
4.3. Cycloaddition of nitrile oxide to [(R)-1-phenylethyl]-3,5-
bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinone
cous liquid; (0.140 g, 26%); [
m
a
]
D = ꢀ154.0 (c 0.22, CHCl3); IR (CHCl3)
max: 1622, 1596, 1497, 1359, 1084, 1018, 837 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): dH 0.59 (d, 3H, J = 6.6 Hz, CH3), 2.54–2.63 (m,
2H, H-11a and H-13a), 2.91–2.95 (m, 1H, CH), 3.00 (d, 1H,
J = 11.7 Hz, H-11b), 3.68 (d, 1H, J = 12.3 Hz, H-13b), 4.73 (s, 1H,
H-10), 6.94–7.69 (m, 24H, aromatic and H-15). 13C NMR
(75 MHz, CDCl3): dC 19.0, 48.2, 51.4, 56.6, 63.3, 88.9, 114.9, 120.2,
126.1, 126.2, 126.3, 126.6, 127.1, 127.2, 127.3, 127.4, 127.6,
127.7, 127.9, 128.1, 128.9, 132.8, 134.0, 134.8, 136.7, 142.7,
157.1, 157.4. Anal. Calcd for C41H33Cl2N3O3: C, 71.72; H, 4.84; N,
6.12. Found: C, 71.84; H, 4.75; N, 6.20.
4.3.1. General procedure
To a solution of [(R)-1-phenylethyl]-3,5-bis[(E)-arylmethyli-
dene]tetrahydro-4(1H)-pyridinone
2
(1 mmol) in benzene
(20 mL), benzohydroximoyl chloride (4 mmol) was added and the
mixture was stirred at room temperature. A solution of triethyl-
amine (4 mmol) in benzene (5 mL) was added dropwise to the
above mixture and the stirring was continued for 10 h. The pro-
gress of the reaction was monitored by thin-layer chromatography
with petroleum ether–ethyl acetate (4:1 v/v mixture) as eluent.
After completion of the reaction as evident from TLC, the resulting
mixture was filtered to remove the triethylamine hydrochloride,
the solvent was evaporated in vacuo and the residue was subjected
to flash column chromatography on silica gel (10:1 petroleum
ether–ethyl acetate).
4.3.1.5. (5R,6R,10S)-3,9-Bis(4-chlorophenyl)-10-phenyl-12-[(R)-
1-phenylethyl]-14-[(E)-phenylmethylidene]-1,4,7-trioxa-2,8,12-
triazadispiro[4.0.4.4]tetradeca-2,8-diene 5b. Obtained as a vis-
cous liquid; (0.098 g, 18%); [
m
a
]
D = +198.0 (c 0.16, CHCl3); IR (CHCl3)
max: 1628, 1594, 1496, 1351, 1093, 1018, 834 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): dH 0.97 (d, 3H, J = 6.6 Hz, CH3), 2.74–2.83 (m,
2H, H-11a and H-11b), 3.03 (d, 1H, J = 12.3 Hz, H-13a), 3.32 (q,
1H, J = 6.6 Hz, CH), 3.68 (d, 1H, J = 12.3 Hz, H-13b), 4.77 (s, 1H, H-
10), 6.93–7.74 (m, 24H, aromatic and H-15). 13C NMR (75 MHz,
CDCl3): dC 14.7, 46.8, 51.9, 57.2, 62.9, 90.0, 115.8, 121.1, 127.0,
127.1, 127.4, 127.6, 128.0, 128.1, 128.3, 128.4, 128.6, 128.7,
128.8, 129.0, 130.4, 133.7, 135.4, 135.7, 137.8, 140.8, 158.2,
158.4. Anal. Calcd for C41H33Cl2N3O3: C, 71.72; H, 4.84; N, 6.12.
Found: C, 71.63; H, 4.91; N, 6.22.
4.3.1.1. (5S,6S,10R)-3,9,10-Triphenyl-12-[(R)-1-phenylethyl]-14-
[(E)-phenylmethylidene]-1,4,7-trioxa-2,8,12-triazadispi-
ro[4.0.4.4]tetradeca-2,8-diene 4a. Obtained as a viscous liquid;
(0.145 g, 30%); [
a]
D = ꢀ102.0 (c 0.19, CHCl3); IR (CHCl3) mmax
:
1623, 1596, 1498, 1357, 1096, 1018, 839 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): dH 0.69 (d, 3H, J = 6.6 Hz, CH3), 2.66 (d, 1H,
J = 11.7 Hz, H-11a), 2.75 (d, 1H, J = 12.3 Hz, H-13a), 3.02–3.10 (m,
2H, H-11a and CH), 3.73 (d, 1H, J = 12.3 Hz, H-13b), 4.87 (s, 1H,
H-10), 7.02–7.83 (m, 26H, aromatic and H-15). 13C NMR
(75 MHz, CDCl3): dC 20.1, 49.2, 52.6, 57.7, 64.3, 89.7, 115.5, 122.8,
126.8, 127.0, 127.1, 127.3, 127.4, 127.5, 127.9, 128.2, 128.4,
128.5, 128.6, 128.7, 128.8, 128.9, 129.7, 130.3, 131.5, 134.2,
135.3, 143.9, 158.8, 159.2. Anal. Calcd for C41H35N3O3: C, 79.72;
H, 5.71; N, 6.80. Found: C, 79.63; H, 5.78; N, 6.69.
4.3.1.6.
(5S,6S,10R)-10-(4-Chlorophenyl)-14-[(E)-(4-chloro-
phenyl)methylidene]-3,9-diphenyl-12-[(R)-1-phenylethyl]-
1,4,7-trioxa-2,8,12-triazadispiro[4.0.4.4]tetradeca-2,8-diene
4c. Obtained as a viscous liquid; (0.135 g, 30%); [
0.18, CHCl3); IR (CHCl3) max: 1626, 1591, 1490, 1351, 1089,
1019, 837 cmꢀ1 1H NMR (300 MHz, CDCl3): dH 0.78 (d, 3H,
a]D = ꢀ118.0 (c
m
;
4.3.1.2. (5R,6R,10S)-3,9,10-Triphenyl-12-[(R)-1-phenylethyl]-14-
[(E)-phenylmethylidene]-1,4,7-trioxa-2,8,12-triazadispi-
ro[4.0.4.4]tetradeca-2,8-diene 5a. Obtained as a viscous liquid;
J = 6.5 Hz, CH3), 2.68 (d, 1H, J = 11.9 Hz, H-11a), 2.79 (d, 1H,
J = 11.9 Hz, H-13a), 3.01 (d, 1H, J = 11.9 Hz, H-11b), 3.11 (q, 1H,
J = 6.5 Hz, CH), 3.64 (d, 1H, J = 11.9 Hz, H-13b), 4.83 (s, 1H, H-10),
6.93 (d, 2H, J = 8.4 Hz, aromatic), 6.99–7.06 (m, 4H, aromatic),
7.11 (d, 2H, J = 8.4 Hz, aromatic), 7.18–7.31 (m, 6H, aromatic and
H-15), 7.37–7.54 (m, 8H, aromatic), 7.78–7.81 (m, 2H, aromatic).
13C NMR (75 MHz, CDCl3): dC 19.8, 49.0, 52.5, 56.9, 64.1, 89.6,
115.1, 122.5, 126.9, 127.3, 127.4, 127.6, 127.9, 128.1, 128.2,
128.3, 128.4, 128.5, 128.6, 129.9, 130.0, 130.1, 130.9, 131.7,
132.7, 133.4, 133.5, 133.9, 143.3, 158.7, 158.8. Anal. Calcd for
(0.073 g, 15%); [
a]
D = +180.0 (c 0.19, CHCl3); IR (CHCl3) mmax
:
1629, 1592, 1494, 1348, 1096, 1015, 831 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): dH 0.98 (d, 3H, J = 6.8 Hz, CH3), 2.72–2.84 (m,
2H, H-11a and H-11b), 3.11 (d, 1H, J = 12.2 Hz, H-13a), 3.34 (q,
1H, J = 6.8 Hz, CH), 3.62 (d, 1H, J = 12.2 Hz, H-13b), 4.84 (s, 1H, H-
10), 6.94–7.79 (m, 26H, aromatic and H-15). 13C NMR (75 MHz,
CDCl3): dC 14.8, 46.8, 52.0, 57.2, 62.9, 89.8, 115.4, 123.4, 127.0,

1322
R. S. Kumar et al. / Tetrahedron: Asymmetry 21 (2010) 1315–1327
C41H33Cl2N3O3: C, 71.72; H, 4.84; N, 6.12. Found: C, 71.83; H, 4.73;
N, 6.19.
(d, 2H, J = 8.4 Hz, aromatic), 7.71 (d, 2H, J = 8.1 Hz, aromatic). 13C
NMR (75 MHz, CDCl3): dC 19.8, 23.7, 34.0, 34.2, 48.5, 52.6, 57.0,
63.4, 89.5, 114.8, 120.0, 125.8, 126.6, 126.7, 127.1, 127.3, 127.5,
128.3, 128.4, 129.9, 131.1, 132.9, 133.3, 133.6, 133.9, 143.6,
151.0, 153.0, 158.5, 158.9. Anal. Calcd for C47H45Cl2N3O3: C,
73.24; H, 5.88; N, 5.45. Found: C, 73.32; H, 5.79; N, 5.38.
4.3.1.7.
(5R,6R,10S)-10-(4-Chlorophenyl)-14-[(E)-(4-chloro-
phenyl)methylidene]-3,9-diphenyl-12-[(R)-1-phenylethyl]-
1,4,7-trioxa-2,8,12-triazadispiro[4.0.4.4]tetradeca-2,8-diene
5c. Obtained as a viscous liquid; (0.078 g, 17%); [
0.19, CHCl3); IR (CHCl3) max: 1630, 1596, 1490, 1357, 1095,
1016, 833 cmꢀ1 1H NMR (300 MHz, CDCl3): dH 1.05 (d, 3H,
a]D = +180.0 (c
m
4.3.1.11. (5R,6R,10S)-10-(4-Chlorophenyl)-14-[(E)-1-(4-chloro-
phenyl)methylidene]-3,9-di(4-isopropylphenyl)-12-(1-phenyl-
ethyl)-1,4,7-trioxa-2,8,12-triazadispiro[4.0.4.4]tetradeca-2,8-
;
J = 6.6 Hz, CH3), 2.65 (d, 1H, J = 11.8 Hz, H-11a), 2.81 (d, 1H,
J = 11.8 Hz, H-11b), 3.00 (d, 1H, J = 12.3 Hz, H-13a), 3.32 (q, 1H,
J = 6.6 Hz, CH), 3.66 (d, 1H, J = 12.3 Hz, H-13b), 4.70 (s, 1H, H-10),
6.85–7.75 (m, 24H, aromatic and H-15). 13C NMR (75 MHz, CDCl3):
dC 14.9, 46.5, 52.7, 56.6, 63.1, 90.0, 115.2, 120.8, 126.6, 127.1, 127.6,
127.8, 128.1, 128.3, 128.5, 128.7, 128.9, 129.3, 130.2, 131.4, 132.3,
133.6, 133.8, 134.0, 136.0, 138.2, 141.3, 158.6, 158.9. Anal. Calcd
for C41H33Cl2N3O3: C, 71.72; H, 4.84; N, 6.12. Found: C, 71.82; H,
4.77; N, 6.03.
diene 5e. Obtained as
D = +188.0 (c 0.19, CHCl3); IR (CHCl3)
1358, 1092, 1016, 832 cmꢀ1 1H NMR (300 MHz, CDCl3): dH 1.07
a
viscous liquid; (0.090 g, 18%);
[a]
m
max: 1628, 1595, 1495,
;
(d, 3H, J = 6.6 Hz, CH3), 1.16 (d, 6H, J = 6.9 Hz, CH(CH3)2), 1.24 (d,
6H, J = 6.6 Hz, CH(CH3)2), 2.63 (d, 1H, J = 11.7 Hz, H-11a), 2.78–
2.97 (m, 3H, H-11b and CH(CH3)2), 3.09 (d, 1H, J = 12.0 Hz, H-
13a) 3.33 (q, 1H, J = 6.6 Hz, CH), 3.54–3.58 (m, 1H, H-13b), 4.76
(s, 1H, H-10), 6.91–6.97 (m, 2H, aromatic), 7.00 (d, 2H, J = 8.1 Hz,
aromatic), 7.07 (d, 2H, J = 8.1 Hz, aromatic), 7.19 (d, 2H, J = 8.7 Hz,
aromatic), 7.23–7.26 (m, 10H, aromatic and H-15), 7.39 (d, 2H,
J = 8.1 Hz, aromatic), 7.69 (d, 2H, J = 8.1 Hz, aromatic). 13C NMR
(75 MHz, CDCl3): dC 15.2, 23.7, 33.9, 34.2, 46.8, 52.8, 56.6, 63.3,
89.5, 114.7, 120.0, 125.8, 126.6, 126.7, 127.1, 127.4, 127.9, 128.1,
128.4, 128.5, 129.9, 130.1, 131.5, 132.8, 133.4, 133.7, 133.9,
141.3, 150.9, 153.0, 158.7, 159.0. Anal. Calcd for C47H45Cl2N3O3:
C, 73.24; H, 5.88; N, 5.45. Found: C, 73.11; H, 5.79; N, 5.53.
4.3.1.8. (5S,6S,10R)-3,9,10-Tris(4-chlorophenyl)-14-[(E)-(4-chlo-
rophenyl)methylidene]-12-[(R)-1-phenylethyl]-1,4,7-trioxa-
2,8,12-triazadispiro[4.0.4.4]tetradeca-2,8-diene 4d. Obtained as
a white solid; (0.125 g, 25%); mp = 189–190 °C; [
0.15, CHCl3); IR (KBr) max: 1627, 1598, 1492, 1353, 1093, 1014,
835 cmꢀ1 1H NMR (300 MHz, CDCl3): dH 0.75 (d, 3H, J = 6.6 Hz,
a]
D = ꢀ138.0 (c
m
;
CH3), 2.65 (d, 1H, J = 11.9 Hz, H-11a), 2.72 (d, 1H, J = 12.5 Hz, H-
13a), 3.02 (d, 1H, J = 11.9 Hz, H-11b), 3.07–3.11 (m, 1H, CH), 3.67
(d, 1H, J = 12.5 Hz, H-13b), 4.76 (s, 1H, H-10), 6.92 (d, 2H,
J = 8.4 Hz, aromatic), 7.00–7.03 (m, 4H, aromatic), 7.12 (d, 2H,
J = 8.4 Hz, aromatic), 7.23 (d, 2H, J = 8.4 Hz, aromatic), 7.26–7.29
(m, 6H, aromatic and H-15), 7.40 (d, 2H, J = 8.7 Hz, aromatic),
7.45 (d, 2H, J = 8.7 Hz, aromatic), 7.74 (d, 2H, J = 8.7 Hz, aromatic).
13C NMR (75 MHz, CDCl3): dC 19.8, 49.1, 52.4, 56.8, 64.2, 89.8,
115.4, 120.9, 126.6, 127.3, 127.4, 127.9, 128.3, 128.4, 128.5,
128.7, 128.9, 129.0, 129.9, 130.5, 132.3, 133.3, 133.6, 134.2,
136.1, 137.9, 143.3, 158.0, 158.2. Anal. Calcd for C41H31Cl4N3O3:
C, 65.18; H, 4.14; N, 5.56. Found: C, 65.25; H, 4.01; N, 5.64.
4.3.1.12.
(5S,6S,10R)-10-(4-Methylphenyl)-14-[(E)-(4-methyl-
phenyl)methylidene]-3,9-diphenyl-12-[(R)-1-phenylethyl]-
1,4,7-trioxa-2,8,12-triazadispiro[4.0.4.4]tetradeca-2,8-diene
4f. Obtained as a viscous liquid; (0.118 g, 25%); [
0.19, CHCl3); IR (CHCl3) max: 1626, 1590, 1492, 1352, 1091,
1011, 839 cmꢀ1 1H NMR (300 MHz, CDCl3): dH 0.72 (d, 3H,
a]
D = ꢀ160.0 (c
m
;
J = 6.6 Hz, CH3), 2.30 (s, 3H, CH3), 2.33 (s, 3H, CH3), 2.65 (d, 1H,
J = 11.7 Hz, H-11a), 2.77 (d, 1H, J = 12.3 Hz, H-13a), 3.03–3.12 (m,
2H, CH and H-11b), 3.71 (d, 1H, J = 12.3 Hz, H-13b), 4.83 (s, 1H,
H-10), 6.90–7.83 (m, 24H, aromatic and H-15). 13C NMR
(75 MHz, CDCl3): dC 20.1, 21.1, 21.2, 49.1, 52.6, 57.3, 64.2, 89.7,
115.6, 122.8, 127.0, 127.4, 127.5, 128.2, 128.4, 128.5, 128.6,
128.8, 128.9, 129.5, 129.6, 131.1, 131.5, 132.4, 137.3, 137.5,
143.9, 158.8, 159.2. Anal. Calcd for C43H39N3O3: C, 79.97; H, 6.09;
N, 6.51. Found: C, 80.10; H, 6.00; N, 6.63.
4.3.1.9. (5R,6R,10S)-3,9,10-Tris(4-chlorophenyl)-14-[(E)-(4-chlo-
rophenyl)methylidene]-12-[(R)-1-phenylethyl]-1,4,7-trioxa-
2,8,12-triazadispiro[4.0.4.4]tetradeca-2,8-diene 5d. Obtained as
colourless
D = +202.0 (c 0.18, CHCl3); IR (KBr)
1355, 1097, 1014, 837 cmꢀ1
crystals;
(0.100 g,
20%);
mp = 195–196 °C;
[a
]
mmax: 1631, 1598, 1492,
;
1H NMR (300 MHz, CDCl3): dH 1.07
4.3.1.13.
(5R,6R,10S)-10-(4-Methylphenyl)-14-[(E)-(4-methyl-
(d, 3H, J = 6.6 Hz, CH3), 2.69 (d, 1H, J = 11.9 Hz, H-11a), 2.80 (d,
1H, J = 11.9 Hz, H-11b), 3.00 (d, 1H, J = 12.2 Hz, H-13a) 3.31 (q,
1H, J = 6.6 Hz, CH), 3.67 (d, 1H, J = 12.2 Hz, H-13b), 4.72 (s, 1H, H-
10), 6.85–7.31 (m, 16H, aromatic and H-15), 7.38–7.41 (m, 4H, aro-
matic), 7.72 (d, 2H, J = 8.7 Hz, aromatic). 13C NMR (75 MHz, CDCl3):
dC 15.2, 46.7, 52.5, 56.5, 63.4, 89.9, 115.4, 120.9, 126.7, 127.3,
127.7, 127.9, 128.2, 128.3, 128.6, 128.7, 128.9, 129.0, 130.1,
131.0, 132.2, 133.6, 133.7, 134.1, 136.0, 138.0, 141.0, 158.2,
158.3. Anal. Calcd for C41H31Cl4N3O3: C, 65.18; H, 4.14; N, 5.56.
Found: C, 65.07; H, 4.23; N, 5.63.
phenyl)methylidene]-3,9-diphenyl-12-[(R)-1-phenylethyl]-
1,4,7-trioxa-2,8,12-triazadispiro[4.0.4.4]tetradeca-2,8-diene
5f. Obtained as a viscous liquid; (0.075 g, 16%); [
0.19, CHCl3); IR (CHCl3) max: 1633, 1594, 1490, 1352, 1094,
1016, 835 cmꢀ1 1H NMR (300 MHz, CDCl3): dH 1.00 (d, 3H,
a]D = +180.0 (c
m
;
J = 6.6 Hz, CH3), 2.33 (s, 3H, CH3), 2.34 (s, 3H, CH3), 2.74 (d, 1H,
J = 12.0 Hz, H-11a), 2.79 (d, 1H, J = 12.0 Hz, H-11b), 3.09 (d, 1H,
J = 12.0 Hz, H-13a), 3.34 (q, 1H, J = 6.6 Hz, CH), 3.65 (d, 1H,
J = 12.0 Hz, H-13b), 4.80 (s, 1H, H-10), 6.88–7.81 (m, 24H, aromatic
and H-15). 13C NMR (75 MHz, CDCl3): dC 15.3, 21.1, 21.2, 47.0, 52.3,
56.9, 63.1, 89.7, 115.5, 122.7, 126.8, 126.9, 127.0, 127.4, 127.9,
128.0, 128.2, 128.3, 128.5, 128.8, 128.9, 129.0, 129.6, 130.1,
130.5, 131.0, 131.5, 132.6, 137.2, 137.3, 141.3, 158.8, 159.3. Anal.
Calcd for C43H39N3O3: C, 79.97; H, 6.09; N, 6.51. Found: C, 80.08;
H, 6.18; N, 6.40.
4.3.1.10. (5S,6S,10R)-10-(4-Chlorophenyl)-14-[(E)-1-(4-chloro-
phenyl)methylidene]-3,9-di(4-isopropylphenyl)-12-(1-phenyl-
ethyl)-1,4,7-trioxa-2,8,12-triazadispiro[4.0.4.4]tetradeca-2,8-
diene 4e. Obtained as
D = ꢀ156.0 (c 0.21, CHCl3); IR (CHCl3)
1356, 1091, 1016, 837 cmꢀ1 1H NMR (300 MHz, CDCl3): dH 0.78
a
viscous liquid; (0.128 g, 25%);
[a
]
m
max: 1623, 1597, 1495,
;
4.3.1.14.
(5S,6S,10R)-3,9-Bis(4-chlorophenyl)-10-(4-methyl-
(d, 3H, J = 6.6 Hz, CH3), 1.18 (d, 6H, J = 6.9 Hz, CH(CH3)2), 1.24 (d,
6H, J = 6.9 Hz, CH(CH3)2), 2.66 (d, 1H, J = 11.7 Hz, H-11a), 2.81–
2.99 (m, 4H, H-13a, H-11b and CH(CH3)2), 3.08–3.20 (m, 1H, CH),
3.60 (d, 1H, J = 12.0 Hz, H-13b), 4.80 (s, 1H, H-10), 6.92 (d, 2H,
J = 8.4 Hz, aromatic), 6.99–7.27 (m, 16H, aromatic and H-15), 7.44
phenyl)-14-[(E)-(4-methyl-phenyl)methylidene]-12-[(R)-1-
phenylethyl]-1,4,7-trioxa-2,8,12-triazadispiro-[4.0.4.4]tetra-
deca-2,8-diene 4g. Obtained as a viscous liquid; (0.150 g, 29%);
[a]
D = ꢀ103.0 (c 0.20, CHCl3); IR (CHCl3)
mmax: 1620, 1586, 1499,
1356, 1098, 1015, 832 cmꢀ1 1H NMR (300 MHz, CDCl3): dH 0.69
;

R. S. Kumar et al. / Tetrahedron: Asymmetry 21 (2010) 1315–1327
1323
(d, 3H, J = 6.6 Hz, CH3), 2.31 (s, 3H, CH3), 2.34 (s, 3H, CH3), 2.62 (d,
1H, J = 11.7 Hz, H-11a), 2.69 (d, 1H, J = 12.6 Hz, H-13a), 3.01–3.07
(m, 2H, CH and H-11b), 3.74 (d, 1H, J = 12.6 Hz, H-13b), 4.77 (s,
1H, H-10), 6.91 (d, 2H, J = 8.4 Hz, aromatic), 6.95 (d, 2H,
J = 8.4 Hz, aromatic), 7.03–7.05 (m, 4H, aromatic), 7.20 (d, 2H,
J = 8.4 Hz, aromatic), 7.24–7.26 (m, 6H, aromatic and H-15), 7.39
(d, 2H, J = 8.4 Hz, aromatic), 7.48 (d, 2H, J = 8.4 Hz, aromatic),
7.74 (d, 2H, J = 8.4 Hz, aromatic). 13C NMR (75 MHz, CDCl3): dC
20.0, 21.1, 21.2, 49.2, 52.4, 57.2, 64.3, 89.8, 116.0, 121.3, 127.1,
127.2, 127.4, 127.9, 128.2, 128.3, 128.6, 128.7, 128.9, 129.1,
130.7, 132.1, 135.7, 137.4, 137.7, 137.8, 143.8, 158.1, 158.4. Anal.
Calcd for C43H37Cl2N3O3: C, 72.26; H, 5.22; N, 5.88. Found: C,
72.12; H, 5.30; N, 5.82.
mp = 196–197 °C; [
a
]
D = ꢀ122.0 (c 0.10, CHCl3); IR (KBr) mmax
:
1596, 1492, 1403, 1344, 1093, 835, 757 cmꢀ1
;
1H NMR (300 MHz,
CDCl3): dH 1.04 (d, 3H, J = 6.8 Hz, CH3), 2.24–2.33 (m, 2H, H-12a
and H-14a), 2.73 (dd, 1H, J = 13.4, 2.3 Hz, H-12b or H-14b), 2.84
(dd, 1H, J = 13.5, 2.1 Hz, H-12b or H-14b), 3.44 (q, 1H, J = 6.8 Hz,
CH), 5.99 (s, 1H, H-4 or H-11), 6.01 (s, 1H, H-4 or H-11), 6.99–
7.57 (m, 23H, aromatic). 13C NMR (75 MHz, CDCl3): dC 18.1, 51.8,
52.1, 53.9, 54.9, 62.6, 89.1, 127.0, 127.4, 127.5, 128.0, 128.6,
129.5, 129.9, 130.2, 130.5, 130.7, 131.4, 131.7, 133.8, 134.0,
141.2, 158.8, 159.0, 197.1. Anal. Calcd for C41H33Cl2N3O3: C,
71.72; H, 4.84; N, 6.12. Found: C, 71.82; H, 4.73; N, 6.21.
4.3.1.19. (4R,5S,6R,11R,15S)-4,15-Bis(2-chlorophenyl)-3,9,14-tri-
phenyl-17-[(R)-1-phenylethyl]-1,7,10,12-tetraoxa-2,8,13,17-tet-
raazatrispiro[4.0.4.3]octadeca-2,8,13-triene 7h. Obtained as a
4.3.1.15.
(5R,6R,10S)-3,9-Bis(4-chlorophenyl)-10-(4-methyl-
phenyl)-14-[(E)-(4-methyl-phenyl)methylidene]-12-[(R)-1-
phenylethyl]-1,4,7-trioxa-2,8,12-triazadispiro-[4.0.4.4]tetra-
deca-2,8-diene 5g. Obtained as a viscous liquid; (0.080 g, 15%);
white solid; (0.043 g, 8%); mp = 210–211 °C; [
CHCl3); IR (KBr) max: 1598, 1475, 1446, 1403, 1349, 1072, 910,
765 cmꢀ1 1H NMR (300 MHz, CDCl3): dH 1.12 (d, 3H, J = 6.6 Hz,
a]D = +24.0 (c 0.10,
m
;
[
a
]
D = +196.0 (c 0.18, CHCl3); IR (CHCl3)
m
max: 1635, 1604, 1495,
CH3), 2.23 (d, 1H, J = 13.2 Hz, H-16a or H-18a), 2.24 (d, 1H,
J = 13.5 Hz, H-16a or H-18a), 2.60–2.67 (m, 2H, H-16b and H-
18b), 3.61 (q, 1H, J = 6.6 Hz, CH), 5.44, (s, 1H, H-4 or H-15), 5.46
(s, 1H, H-4 or H-15), 6.91–7.47 (m, 28H, aromatic). 13C NMR
(75 MHz, CDCl3): dC 19.0, 52.0, 52.1, 52.2, 52.4, 62.5, 90.7, 90.8,
114.2, 120.5, 126.7, 126.8, 127.1, 127.2, 127.6, 127.9, 128.0,
128.1, 128.4, 129.3, 129.4, 129.6, 129.9, 130.0, 130.4, 130.5,
130.8, 131.6, 133.8, 133.9, 142.6, 158.4, 158.5, 161.5. Anal. Calcd
for C48H38Cl2N4O4: C, 71.55; H, 4.75; N, 6.95. Found: C, 71.42; H,
4.83; N, 6.85.
1352, 1097, 1015, 834 cmꢀ1 1H NMR (300 MHz, CDCl3): dH 0.98
;
(d, 3H, J = 6.6 Hz, CH3), 2.35 (s, 3H, CH3), 2.36 (s, 3H, CH3), 2.73–
2.81 (m, 2H, H-11a and H-11b), 3.01 (d, 1H, J = 11.7 Hz, H-13a),
3.33 (q, 1H, J = 6.6 Hz, CH), 3.71 (d, 1H, J = 11.7 Hz, H-13b), 4.73
(s, 1H, H-10), 6.99–7.72 (m, 22H, aromatic and H-15). 13C NMR
(75 MHz, CDCl3): dC 15.3, 21.1, 21.2, 47.1, 52.4, 56.9, 63.1, 89.9,
115.9, 121.2, 127.0, 127.2, 127.9, 128.0, 128.3, 128.7, 128.8,
128.9, 129.1, 129.4, 129.7, 130.6, 132.5, 135.8, 137.5, 137.6,
141.1, 158.2, 159.2. Anal. Calcd for C43H37Cl2N3O3: C, 72.26; H,
5.22; N, 5.88. Found: C, 72.36; H, 5.30; N, 5.77.
4.3.1.20.
(5S,6S,10R)-10-(2-Chlorophenyl)-3,9-bis(4-chloro-
4.3.1.16.
(5S,6S,10R)-10-(2-Chlorophenyl)-14-[(E)-(2-chloro-
phenyl)-14-[(E)-(2-chlorophenyl)methylidene]-12-[(R)-1-phen-
phenyl)methylidene]-3,9-diphenyl-12-[(R)-1-phenylethyl]-
ylethyl]-1,4,7-trioxa-2,8,12-triazadispiro[4.0.4.4]tetradeca-2,8-
1,4,7-trioxa-2,8,12-triazadispiro[4.0.4.4]tetradeca-2,8-diene
diene 4i. Obtained as a viscous liquid; (0.120 g, 24%); [
a
]
D = ꢀ151.0
4h. Obtained as a viscous liquid; (0.120 g, 26%); [
0.17, CHCl3); IR (CHCl3) max: 1628, 1597, 1495, 1350, 1088,
1011, 832 cmꢀ1 1H NMR (300 MHz, CDCl3): dH 0.59 (d, 3H,
a
]D = ꢀ142.0 (c
(c 0.23, CHCl3); IR (CHCl3) max: 1629, 1592, 1496, 1357, 1086, 1019,
m
m
836 cmꢀ1; 1H NMR (300 MHz, CDCl3): dH 0.49 (d, 3H, J = 6.5 Hz, CH3),
2.51 (d, 1H, J = 12.0 Hz, H-11a), 2.59 (d, 1H, J = 12.0 Hz, H-13a), 2.88
(q, 1H, J = 6.5 Hz, CH), 3.09 (d, 1H, J = 12.0 Hz, H-11b), 3.62 (d, 1H,
J = 12.0 Hz, H-13b), 5.45 (s, 1H, H-10), 6.76–7.73 (m, 22H, aromatic
and H-15). 13C NMR (75 MHz, CDCl3): dC 20.0, 49.7, 52.2, 52.8, 64.5,
90.0, 115.5, 121.2, 126.1, 126.7, 126.9, 127.2, 127.3, 128.2, 128.3,
128.6, 128.8, 128.9, 129.0, 129.2, 129.4, 129.8, 130.2, 130.7, 131.0,
132.3, 133.3, 133.8, 135.2, 136.1, 137.7, 143.4, 157.9, 159.4. Anal.
Calcd for C41H31Cl4N3O3: C, 65.18; H, 4.14; N, 5.56. Found: C,
65.30; H, 4.05; N, 5.62.
;
J = 6.3 Hz, CH3), 2.63 (d, 1H, J = 12.8 Hz, H-11a), 2.69 (d, 1H,
J = 11.6 Hz, H-13a), 2.98 (q, 1H, J = 6.3 Hz, CH), 3.17 (d, 1H,
J = 11.6 Hz, H-11b), 3.69 (d, 1H, J = 12.8 Hz, H-13b), 5.57 (s, 1H,
H-10), 6.84–7.83 (m, 24H, aromatic and H-15). 13C NMR
(75 MHz, CDCl3): dC 20.1, 49.7, 52.3, 52.9, 64.5, 89.8, 115.2, 122.8,
126.0, 126.6, 126.7, 127.1, 127.2, 127.3, 128.2, 128.3, 128.5,
128.6, 128.7, 128.9, 129.2, 129.7, 130.0, 130.2, 130.8, 131.3,
131.4, 132.7, 133.5, 133.8, 135.2, 143.5, 158.5, 160.2. Anal. Calcd
for C41H33Cl2N3O3: C, 71.72; H, 4.84; N, 6.12. Found: C, 71.83; H,
4.76; N, 6.05.
4.3.1.21.
(5S,6S,10R)-10-(2-Chlorophenyl)-3,9-bis(4-chloro-
phenyl)-14-[(E)-(2-chlorophenyl)methylidene]-12-[(R)-1-phen-
4.3.1.17.
(5R,6R,10S)-10-(2-Chlorophenyl)-14-[(E)-(2-chloro-
ylethyl]-1,4,7-trioxa-2,8,12-triazadispiro[4.0.4.4]tetradeca-2,8-
phenyl)methylidene]-3,9-diphenyl-12-[(R)-1-phenylethyl]-
1,4,7-trioxa-2,8,12-triazadispiro[4.0.4.4]tetradeca-2,8-diene
diene 5i. Obtained as
D = +186.0 (c 0.21, CHCl3); IR (CHCl3)
1358, 1088, 1017, 835 cmꢀ1 1H NMR (300 MHz, CDCl3): dH 0.89
a
viscous liquid; (0.075 g, 15%);
[a
]
m
max: 1628, 1598, 1493,
5h. Obtained as a viscous liquid; (0.064 g, 14%); [
0.21, CHCl3); IR (CHCl3) max: 1624, 1595, 1496, 1354, 1082,
1015, 834 cmꢀ1 1H NMR (300 MHz, CDCl3): dH 0.87 (d, 3H,
a]
D = +182.0 (c
;
m
(d, 3H, J = 6.9 Hz, CH3), 2.81 (d, 1H, J = 11.7 Hz, H-11a), 2.89–2.96
(m, 2H, H-11b and H-13a), 3.35 (q, 1H, J = 6.9 Hz, CH), 3.68 (d,
1H, J = 12.6 Hz, H-13b), 5.50 (s, 1H, H-10), 6.95–7.52 (m, 20H, aro-
matic and H-15), 7.73 (d, 2H, J = 8.4 Hz, aromatic). 13C NMR
(75 MHz, CDCl3): dC 19.9, 49.8, 51.5, 52.9, 64.3, 90.8, 115.8, 121.0,
124.8, 126.2, 126.6, 127.2, 127.4, 128.0, 128.2, 128.3, 128.4,
128.6, 128.9, 129.1, 129.3, 129.6, 129.9, 130.1, 130.6, 131.4,
132.1, 133.5, 133.7, 136.3, 137.6, 143.2, 157.5, 159.7. Anal. Calcd
for C41H31Cl4N3O3: C, 65.18; H, 4.14; N, 5.56. Found: C, 65.28; H,
4.22; N, 5.49.
;
J = 6.6 Hz, CH3), 2.80 (d, 1H, J = 11.7 Hz, H-11a), 2.88–2.97 (m, 2H,
H-11b and H-13a), 3.34 (q, 1H, J = 6.6 Hz, CH), 3.66 (d, 1H,
J = 12.3 Hz, H-13b), 5.51 (s, 1H, H-10), 6.94–7.75 (m, 24H, aromatic
and H-15). 13C NMR (75 MHz, CDCl3): dC 19.8, 49.7, 51.2, 52.9, 64.4,
90.5, 115.4, 121.1, 124.6, 126.3, 126.7, 127.0, 127.3, 128.1, 128.2,
128.3, 128.5, 128.7, 128.9, 129.1, 129.4, 129.6, 129.9, 130.1,
130.4, 131.2, 132.5, 133.7, 133.9, 136.0, 137.4, 143.1, 157.4,
159.7. Anal. Calcd for C41H33Cl2N3O3: C, 71.72; H, 4.84; N, 6.12.
Found: C, 71.84; H, 4.77; N, 6.20.
4.3.1.22.
(4R,5S,6R,11R,15S)-4,15-Bis(2-chlorophenyl)-3,9,14-
4.3.1.18.
4,11-Bis(2-chlorophenyl)-3,10-diphenyl-13-[(R)-1-
tris(4-chlorophenyl)-17-[(R)-1-phenylethyl]-1,7,10,12-tetraoxa-
2,8,13,17-tetraazatrispiro[4.0.4.0.4.3]octade-ca-2,8,13-triene
7i. Obtained as colourless crystals; (0.060 g, 10%); mp = 176–
phenylethyl]-1,8-dioxa-2,9,13-triazadispiro[4.1.4.3]tetradeca-
2,9-dien-6-one 6h. Obtained as a white solid; (0.014 g, 3%);

1324
R. S. Kumar et al. / Tetrahedron: Asymmetry 21 (2010) 1315–1327
177 °C; [
a
]
D = +16.0 (c 0.10, CHCl3); IR (KBr)
m
max: 1596, 1492,
ethyl)-1,4,7-trioxa-2,8,12-triazadispiro[4.0.4.4]-tetradeca-2,8-
diene 4k. Obtained as viscous liquid; (0.112 g, 24%);
D = ꢀ120.0 (c 0.21, CHCl3); IR (CHCl3) max: 1627, 1594, 1493,
1359, 1085, 1014, 837 cmꢀ1 1H NMR (300 MHz, CDCl3): dH 0.60
1403, 1344, 1093, 887, 835, 757 cmꢀ1
;
1H NMR (300 MHz, CDCl3):
a
dH 1.11 (d, 3H, J = 6.6 Hz, CH3), 2.18 (d, 1H, J = 13.2 Hz, H-16a or H-
18a), 2.20 (d, 1H, J = 13.5 Hz, H-16a or H-18a), 2.60–2.68 (m, 2H, H-
16b and H-18b), 3.57 (q, 1H, J = 6.6 Hz, CH), 5.36 (s, 1H, H-4 or H-
15), 5.38 (s, 1H, H-4 or H-15), 6.84 (d, 1H, J = 7.8 Hz, aromatic), 6.91
(d, 1H, J = 7.5 Hz, aromatic), 6.96 (d, 1H, J = 7.5 Hz, aromatic), 7.00–
7.42 (m, 22H, aromatic). 13C NMR (75 MHz, CDCl3): dC 18.9, 52.0,
52.1, 52.2, 52.3, 62.5, 90.9, 91.0, 114.4, 118.8, 126.3, 126.9, 127.2,
127.3, 127.5, 127.8, 127.9, 128.0, 128.7, 128.8, 129.6, 129.7,
130.0, 130.1, 130.2, 130.3, 130.4, 133.7, 133.8 , 135.9, 138.3,
142.3, 157.5, 157.6, 160.6. Anal. Calcd for C48H35Cl5N4O4: C,
63.42; H, 3.88; N, 6.16. Found: C, 63.53; H, 3.81; N, 6.27.
[a]
m
;
(d, 3H, J = 6.5 Hz, CH3), 2.59–2.68 (m, 2H, H-11a and H-13a), 2.97
(q, 1H, J = 6.5 Hz, CH), 3.18 (d, 1H, J = 11.4 Hz, H-11b), 3.70 (d,
1H, J = 12.6 Hz, H-13b), 5.51 (s, 1H, H-10), 6.91–7.31 (m, 13H, aro-
matic and H-15), 7.40 (d, 2H, J = 8.4 Hz, aromatic), 7.48 (d, 2H,
J = 7.8 Hz, aromatic), 7.56 (d, 2H, J = 8.4 Hz, aromatic), 7.70–7.77
(m, 3H, aromatic). 13C NMR (75 MHz, CDCl3): dC 19.9, 49.5, 52.3,
55.8, 64.5, 90.1, 115.5, 121.3, 124.1, 126.4, 126.6, 126.7, 127.2,
127.4, 127.9, 128.1, 128.2, 128.3, 128.6, 128.9, 129.7, 130.3,
130.8, 132.5, 133.2, 134.0, 135.1, 136.1, 137.7, 143.3, 157.9,
159.7. Anal. Calcd for C41H31Br2Cl2N3O3: C, 58.32; H, 3.70; N,
4.98. Found: C, 58.41; H, 3.59; N, 4.89.
4.3.1.23. (5S,6S,10R)-10-(2-Bromophenyl)-14-[(E)-1-(2-bromo-
phenyl)methylidene]-3,9-diphenyl-12-(1-phenylethyl)-1,4,7-
trioxa-2,8,12-triazadispiro[4.0.4.4]tetradeca-2,8-diene
4j. Obtained as a viscous liquid; (0.108 g, 25%); [
0.18, CHCl3); IR (CHCl3) max: 1626, 1595, 1492, 1354, 1083,
1015, 833 cmꢀ1 1H NMR (300 MHz, CDCl3): dH 0.62 (d, 3H,
J = 6.8 Hz, CH3), 2.62–2.70 (m, 2H, H-11a and H-13a), 2.99 (q, 1H,
J = 6.8 Hz, CH) 3.18 (d, 1H, J = 10.5 Hz, H-11b), 3.69 (d, 1H,
J = 12.3 Hz, H-13b), 5.56 (s, 1H, H-10), 6.88–7.83 (m, 24H, aromatic
and H-15). 13C NMR (75 MHz, CDCl3): dC 20.0, 49.5, 52.4, 55.8, 64.4,
89.9, 115.1, 122.9, 124.1, 126.4, 126.6, 127.0, 127.1, 127.3, 127.4,
127.8, 128.2, 128.3, 128.4, 128.5, 128.7, 128.8, 129.5, 130.0,
130.4, 130.9, 131.1, 131.4, 132.5, 133.1, 134.4, 135.3, 143.5,
158.5, 160.5. Anal. Calcd for C41H33Br2N3O3: C, 63.50; H, 4.29; N,
5.42. Found: C, 63.58; H, 4.18; N, 5.50.
4.3.1.27. (5R,6R,10S)-10-(2-Bromophenyl)-14-[(E)-1-(2-bromo-
phenyl)methylidene]-3,9-di(4-chlorophenyl)-12-(1-phenyl-
ethyl)-1,4,7-trioxa-2,8,12-triazadispiro[4.0.4.4]tetradeca-2,8-
a]
D = ꢀ140.0 (c
m
;
diene 5k. Obtained as
D = +196.0 (c 0.21, CHCl3); IR (CHCl3)
1356, 1088, 1017, 835 cmꢀ1 1H NMR (300 MHz, CDCl3): dH 0.86
a
viscous liquid; (0.066 g, 14%);
[a]
m
max: 1627, 1595, 1498,
;
(d, 3H, J = 6.8 Hz, CH3), 2.65–2.96 (m, 3H, H-11a, H-11b and H-
13a), 3.35 (q, 1H, J = 6.8 Hz, CH), 3.66 (d, 1H, J = 12.0 Hz, H-13b),
5.47 (s, 1H, H-10), 6.95–7.75 (m, 22H, aromatic and H-15). 13C
NMR (75 MHz, CDCl3): dC 20.1, 48.0, 50.6, 55.4, 63.0, 90.2, 115.6,
118.5, 121.2, 124.1, 126.4, 126.5, 127.0, 127.1, 127.2, 127.6,
128.1, 128.3, 128.6, 128.7, 128.9, 129.1, 129.3, 129.4, 129.7,
130.9, 131.1, 131.4, 132.7, 133.1, 134.4, 137.6, 143.4, 157.8,
159.9. Anal. Calcd for C41H31Br2Cl2N3O3: C, 58.32; H, 3.70; N,
4.98. Found: C, 58.43; H, 3.79; N, 4.87.
4.3.1.24. (5R,6R,10S)-10-(2-Bromophenyl)-14-[(E)-1-(2-bromo-
phenyl)methylidene]-3,9-diphenyl-12-(1-phenylethyl)-1,4,7-
trioxa-2,8,12-triazadispiro[4.0.4.4]tetradeca-2,8-diene
5j. Obtained as a viscous liquid; (0.070 g, 16%); [
0.21, CHCl3); IR (CHCl3) max: 1630, 1589, 1496, 1354, 1081,
1018, 835 cmꢀ1 1H NMR (300 MHz, CDCl3): dH 0.88 (d, 3H,
J = 6.9 Hz, CH3), 2.80 (d, 1H, J = 11.8 Hz, H-11a), 2.90 (d, 1H,
J = 11.8 Hz, H-11b), 2.99 (d, 1H, J = 12.5 Hz, H-13a), 3.36 (q, 1H,
J = 6.9 Hz, CH), 3.64 (d, 1H, J = 12.5 Hz, H-13b), 5.53 (s, 1H, H-10),
6.98–7.67 (m, 22H, aromatic and H-15), 7.77 (d, 2H, J = 6.9 Hz, aro-
matic). 13C NMR (75 MHz, CDCl3): dC 14.8, 47.9, 50.9, 55.5, 63.0,
90.1, 115.1, 122.8, 124.3, 126.3, 126.9, 127.0, 127.1, 127.3, 127.9,
128.0, 128.1, 128.2, 128.3, 128.4, 128.5, 129.0, 129.4, 130.0,
130.7, 131.0, 131.4, 131.5, 132.6, 133.3, 134.1, 135.7, 140.5,
158.5, 160.7. Anal. Calcd for C41H33Br2N3O3: C, 63.50; H, 4.29; N,
5.42. Found: C, 63.60; H, 4.21; N, 5.36.
4.3.1.28. 4,11-Bis(2-bromophenyl)-3,10-bis(4-chlorophenyl)-13-
(1-phenylethyl)-1,8-dioxa-2,9,13-triazadispiro[4.1.4.3]tetra-
deca-2,9-dien-6-one 6k. Obtained as a white solid; (0.014 g, 3%);
a]D = +186.0 (c
m
;
mp = 190–191 °C; [
a
]
D = ꢀ130.0 (c 0.10, CHCl3); IR (KBr) mmax
:
1598, 1495, 1403, 1347, 1096, 834, 754 cmꢀ1
;
1H NMR (300 MHz,
CDCl3): dH 1.05 (d, 3H, J = 6.6 Hz, CH3), 2.23–2.36 (m, 2H, H-12a
and H-14a), 2.70 (dd, 1H, J = 13.2, 2.1 Hz, H-12b or H-14b), 2.80
(dd, 1H, J = 13.5, 2.1 Hz, H-12b or H-14b), 3.43 (q, 1H, J = 6.6 Hz,
CH), 5.94 (s, 1H, H-4 or H-11), 5.96 (s, 1H, H-4 or H-11), 6.88–
7.62 (m, 21H, aromatic). 13C NMR (75 MHz, CDCl3): dC 18.2, 51.9,
54.5, 54.8, 55.0, 62.6, 89.0, 124.8, 125.3, 126.4, 127.1, 127.4,
128.0, 128.1, 128.7, 129.0, 129.9, 130.4, 130.6, 133.3, 136.2,
141.3, 158.0, 158.2, 196.5. Anal. Calcd for C41H31Br2Cl2N3O3: C,
58.32; H, 3.70; N, 4.98. Found: C, 58.44; H, 3.80; N, 4.86.
4.3.1.25. (4R,5S,6R,11R,15S)-4,15-Bis (2-bromophenyl)-3,9,14-
triphenyl-17-(1-phenyl-ethyl)-1,7,10,12-tetraoxa-2,8,13,17-tet-
raazatrispiro[4.0.4.0.4.3]octadeca-2,8,13-triene 7j. Obtained as
4.3.1.29.
(4R,5S,6R,11R,15S)-4,15-Bis(2-bromophenyl)-3,9,14-
tri(4-chlorophenyl)-17-(1-phenylethyl)-1,7,10,12-tetraoxa-
2,8,13,17-tetraazatrispiro[4.0.4.0.4.3]octadeca-2,8,13-triene
7k. Obtained as colourless crystals; (0.055 g, 10%); mp = 179–
a white solid; (0.035 g, 7%); mp = 168–169 °C; [
0.10, CHCl3); IR (KBr) max: 1598, 1494, 1406, 1343, 1097, 883,
834, 758 cmꢀ1 1H NMR (300 MHz, CDCl3): dH 0.65 (d, 3H,
a]D = +14.0 (c
m
180 °C; [
a
]
D = +20.0 (c 0.10, CHCl3); IR (KBr)
mmax: 1598, 1494,
;
1406, 1348, 1091, 884, 838, 758 cmꢀ1
;
1H NMR (300 MHz, CDCl3):
J = 6.8 Hz, CH3), 2.35 (d, 1H, J = 11.4 Hz, H-16a or H-18a), 2.75 (d,
1H, J = 11.7 Hz, H-16a or H-18a), 3.03–3.14 (m, 2H, H-16b and H-
18b), 3.39 (q, 1H, J = 6.8 Hz, CH), 5.57 (s, 1H, H-4 or H-15), 5.60
(s, 1H, H-4 or H-15), 6.92–7.74 (m, 28H, aromatic). 13C NMR
(75 MHz, CDCl3): dC 19.8, 48.1, 51.5, 55.7, 56.0, 63.0, 90.5, 90.6,
115.3, 122.5, 124.1, 126.2, 126.7, 126.8, 127.2, 127.5, 127.9,
128.1, 128.2, 128.4, 128.7, 128.8, 129.0, 129.6, 130.2, 130.5,
130.9, 131.0, 131.3, 131.4, 132.5, 132.6, 133.2, 134.9, 135.4,
143.3, 158.2, 160.8, 161.0. Anal. Calcd for C48H38Br2N4O4: C,
64.44; H, 4.28; N, 6.26. Found: C, 64.56; H, 4.19; N, 6.34.
dH 0.64 (d, 3H, J = 6.6 Hz, CH3), 2.34 (d, 1H, J = 11.4 Hz, H-16a or H-
18a), 2.77 (d, 1H, J = 11.7 Hz, H-16a or H-18a), 3.03–3.18 (m, 2H, H-
16b and H-18b), 3.41 (q, 1H, J = 6.6 Hz, CH), 5.58 (s, 1H, H-4 or H-
15), 5.62 (s, 1H, H-4 or H-15), 6.93–7.78 (m, 25H, aromatic). 13C
NMR (75 MHz, CDCl3): dC 19.0, 48.1, 52.2, 54.9, 56.0, 62.5, 90.5,
90.7, 114.9, 122.4, 124.0, 126.4, 126.8, 126.9, 127.2, 127.7, 127.9,
128.1, 128.2, 128.5, 128.7, 128.8, 129.2, 129.6, 130.2, 130.5,
130.9, 131.1, 131.3, 131.4, 132.5, 132.9, 133.4, 134.9, 135.4,
143.5, 158.4, 160.9, 161.2. Anal. Calcd for C48H35Br2 Cl3N4O4: C,
57.77; H, 3.53; N, 5.61. Found: C, 57.90; H, 3.62; N, 5.69.
4.3.1.26. (5S,6S,10R)-10-(2-Bromophenyl)-14-[(E)-1-(2-bromo-
4.3.1.30.
(5S,6S,10R)-10-(2,4-Dichlorophenyl)-14-[(E)-(2,4-
phenyl)methylidene]-3,9-di(4-chlorophenyl)-12-(1-phenyl-
dichlorophenyl)methylidene]-3,9-diphenyl-12-[(R)-1-phenyl-

R. S. Kumar et al. / Tetrahedron: Asymmetry 21 (2010) 1315–1327
1325
ethyl]-1,4,7-trioxa-2,8,12-triazadispiro[4.0.4.4]tetradeca-2,8-
diene 4l. Obtained as a white solid; (0.113 g, 26%); mp = 167–
4.3.1.34. (5R,6R,10S)-3,9-Bis(4-chlorophenyl)-10-(2,4-dichloro-
phenyl)-14-[(E)-(2,4-dichlorophenyl)methylidene]-12-[(R)-1-
phenylethyl]-1,4,7-trioxa-2,8,12-triazadispiro[4.0.4.4]tetra-
deca-2,8-diene 5m. Obtained as a viscous liquid; (0.072 g, 15%);
168 °C; [
a]
D = ꢀ155.0 (c 0.20, CHCl3); IR (KBr)
mmax: 1625, 1598,
1490, 1357, 1091, 1018, 837 cmꢀ1
;
1H NMR (300 MHz, CDCl3): dH
0.68 (d, 3H, J = 6.6 Hz, CH3), 2.65 (d, 1H, J = 13.1 Hz, H-11a), 2.71
(d, 1H, J = 11.6 Hz, H-13a), 3.05 (q, 1H, J = 6.6 Hz, CH), 3.10 (d, 1H,
J = 11.6 Hz, H-13b), 3.62 (d, 1H, J = 13.1 Hz, H-11b), 5.47 (s, 1H,
H-10), 6.82–7.58 (m, 20H, aromatic and H-15), 7.81 (d, 2H,
J = 6.9 Hz, aromatic). 13C NMR (75 MHz, CDCl3): dC 19.7, 49.6,
52.2, 52.5, 64.4, 89.7, 114.9, 122.6, 125.6, 126.4, 127.1, 127.2,
127.3, 127.4, 127.6, 127.9, 128.3, 128.6, 128.9, 129.2, 129.5,
130.3, 130.9, 131.3, 131.6, 132.0, 133.9, 134.5, 134.6, 135.7,
143.2, 158.6, 159.9. Anal. Calcd for C41H31Cl4N3O3: C, 65.18; H,
4.14; N, 5.56. Found: C, 65.07; H, 4.23; N, 5.49.
[
a
]
D = +185.5 (c 0.21, CHCl3); IR (CHCl3)
mmax: 1636, 1596, 1490,
1359, 1091, 1010, 834 cmꢀ1 1H NMR (300 MHz, CDCl3): dH 0.99
;
(d, 3H, J = 6.3 Hz, CH3), 2.74–2.86 (m, 2H, H-11a and H-11b), 2.90
(d, 1H, J = 12.5 Hz, H-13a), 3.31 (q, 1H, J = 6.3 Hz, CH), 3.72 (d, 1H,
J = 12.5 Hz, H-13b), 5.37 (s, 1H, H-10), 6.59–7.73 (m, 20H, aromatic
and H-15). 13C NMR (75 MHz, CDCl3): dC 15.4, 47.9, 51.3, 52.0, 63.6,
90.0, 115.2, 120.9, 125.8, 126.3, 126.8, 127.3, 127.8, 127.9, 128.2,
128.3, 128.4, 128.9, 129.0, 129.4, 129.7, 130.6, 131.1, 131.5,
131.9, 132.1, 134.2, 134.6, 134.8, 135.5, 136.3, 137.8, 140.4,
158.0, 159.6. Anal. Calcd for C41H29Cl6N3O3: C, 59.73; H, 3.55; N,
5.10. Found: C, 59.86; H, 3.46; N, 5.19.
4.3.1.31.
(5R,6R,10S)-10-(2,4-Dichlorophenyl)-14-[(E)-(2,4-
dichlorophenyl)methylidene]-3,9-diphenyl-12-[(R)-1-phenyl-
4.3.1.35.
(4R,5S,6R,11R,15S)-3,9,14-Tris(4-chlorophenyl)-4,15-
ethyl]-1,4,7-trioxa-2,8,12-triazadispiro[4.0.4.4]tetradeca-2,8-
bis(2,4-dichloro-phenyl)-17-[(R)-1-phenylethyl]-1,7,10,12-tet-
raoxa-2,8,13,17-tetraazatrispiro[4.0.4.0.4.3]octadeca-2,8,13-tri-
ene 7m. Obtained as a white solid; (0.045 g, 8%); mp = 198–
diene 5l. Obtained as
D = +191.0 (c 0.18, CHCl3); IR (KBr)
1357, 1096, 1019, 836 cmꢀ1 1H NMR (300 MHz, CDCl3): dH 1.01
a
viscous liquid; (0.061 g, 14%);
[
a]
m
max: 1635, 1594, 1495,
;
199 °C; [a]D = +12.0 (c 0.10, CHCl3); IR (KBr) mmax: 1596, 1494,
(d, 3H, J = 6.6 Hz, CH3), 2.77–2.85 (m, 2H, H-11a and H-11b), 2.94
(d, 1H, J = 12.5 Hz, H-13a), 3.32 (q, 1H, J = 6.6 Hz, CH), 3.70 (d, 1H,
J = 12.5 Hz, H-13b), 5.43 (s, 1H, H-10), 6.85–7.80 (m, 22H, aromatic
and H-15). 13C NMR (75 MHz, CDCl3): dC 15.6, 47.9, 51.5, 52.1, 63.6,
89.8, 114.9, 122.6, 125.5, 126.7, 127.1, 127.2, 127.3, 127.4, 127.5,
127.8, 127.9, 128.2, 128.3, 128.5, 128.7, 129.4, 129.7, 130.2,
131.1, 131.2, 131.6, 132.3, 134.1, 134.4, 134.8, 135.6, 140.6,
158.6, 160.2. Anal. Calcd for C41H31Cl4N3O3: C, 65.18; H, 4.14; N,
5.56. Found: C, 65.30; H, 4.04; N, 5.63.
1471, 1403, 1344, 1093, 846, 796 cmꢀ1; 1H NMR (300 MHz, CDCl3):
dH 1.16 (d, 3H, J = 6.6 Hz, CH3), 2.17–2.21 (m, 2H, H-16a and H-
18a), 2.55 (d, 1H, J = 13.5 Hz, H-16b or H-18b), 2.67 (d, 1H,
J = 13.2 Hz, H-16b or H-18b), 3.57 (q, 1H, J = 6.6 Hz, CH), 5.28 (s,
1H, H-4 or H-15), 5.31 (s, 1H, H-4 or H-15), 6.74 (d, 1H,
J = 8.4 Hz, aromatic), 6.82 (d, 1H, J = 8.4 Hz, aromatic), 6.93–7.26
(m, 17H, aromatic), 7.35 (d, 2H, J = 8.7 Hz, aromatic), 7.42–7.45
(m, 2H, aromatic). 13C NMR (75 MHz, CDCl3): dC 18.8, 51.5, 51.7,
52.0, 52.5, 62.7, 90.7, 90.8, 114.3, 118.6, 125.9, 127.1, 127.5,
127.7, 127.8, 127.9, 128.1, 128.8, 128.9, 129.9, 130.0, 130.9,
131.1, 134.3, 134.5, 134.9, 135.0, 136.1, 138.5, 142.4, 157.2,
157.3, 160.7. Anal. Calcd for C48H33Cl7N4O4: C, 58.95; H, 3.40; N,
5.73. Found: C, 58.83; H, 3.47; N, 5.64.
4.3.1.32.
(4R,5S,6R,11R,15S)-4,15-Bis(2,4-dichlorophenyl)-
3,9,14-triphenyl-17-[(R)-1-phenylethyl]-1,7,10,12-tetraoxa-
2,8,13,17-tetraazatrispiro[4.0.4.0.4.3]octadeca-2,8,13-triene
7l. Obtained as a white solid; (0.030 g, 6%); mp = 192–193 °C;
[
a
]
D = +18.0 (c 0.10, CHCl3); IR (KBr)
m
max: 1593, 1496, 1475,
4.3.1.36.
(5S,6S,10R)-10-(2,4-Dichlorophenyl)-14-[(E)-1-(2,4-
1405, 1341, 1097, 842, 794 cmꢀ1 1H NMR (300 MHz, CDCl3):
;
dichlorophenyl)methylidene]-3,9-di(4-isopropylphenyl)-12-(1-
phenylethyl)-1,4,7-trioxa-2,8,12-triazadispiro[4.0.4.4]tetra-
deca-2,8-diene 4n. Obtained as a viscous liquid; (0.120 g, 25%);
dH 1.16 (d, 3H, J = 6.5 Hz, CH3), 2.21 (d, 1H, J = 13.2 Hz, H-16a
or H-18a), 2.22 (d, 1H, J = 13.2 Hz, H-16a or H-18a), 2.56 (d,
1H, J = 13.2 Hz, H-16b or H-18b), 2.65 (d, 1H, J = 13.2 Hz, H-16b
or H-18b), 3.60 (q, 1H, J = 6.5 Hz, CH), 5.35 (s, 1H, H-4 or H-
15), 5.39 (s, 1H, H-4 or H-15), 6.79 (d, 1H, J = 8.4 Hz, aromatic),
6.87 (d, 1H, J = 8.7 Hz, aromatic), 6.91–7.43 (m, 24H, aromatic).
13C NMR (75 MHz, CDCl3): dC 18.9, 51.8, 52.0, 52.1, 52.6, 62.7,
90.6, 90.7, 114.1, 120.3, 126.7, 126.8, 127.0, 127.6, 128.1,
128.2, 128.5, 129.4, 129.5, 129.8, 129.9, 131.1, 131.3, 131.7,
134.4, 134.5, 134.6, 134.7, 142.7, 158.3, 161.5. Anal. Calcd for
[a
]
D = ꢀ170.0 (c 0.19, CHCl3); IR (CHCl3)
mmax: 1624, 1596, 1495,
1354, 1094, 1018, 835 cmꢀ1 1H NMR (300 MHz, CDCl3): dH 0.68
;
(d, 3H, J = 6.6 Hz, CH3), 1.19 (d, 6H, J = 6.9 Hz, CH(CH3)2), 1.25 (d,
6H, J = 6.9 Hz, CH(CH3)2), 2.62–3.10 (m, 6H, H-11a, H-13a, H-13b,
CH and CH(CH3)2), 3.60 (d, 1H, J = 12.6 Hz, H-11b), 5.43 (s, 1H, H-
10), 6.81–7.56 (m, 18H, aromatic and H-15), 7.72 (d, 2H,
J = 8.4 Hz, aromatic). 13C NMR (75 MHz, CDCl3): dC 19.7, 23.6,
23.7, 34.1, 34.2, 49.6, 52.2, 52.6, 64.4, 89.6, 114.6, 120.1, 120.3,
125.4, 125.5, 126.4, 126.6, 126.8, 126.9, 127.2, 127.3, 127.6,
128.3, 129.2, 129.4, 130.9, 131.5, 131.7, 132.1, 132.2, 133.8,
134.3, 134.5, 135.7, 143.2, 151.3, 152.8, 158.6, 159.8. Anal. Calcd
for C47H43Cl4N3O3: C, 67.23; H, 5.16; N, 5.00. Found: C, 67.33; H,
5.27; N, 5.09.
C
48H36Cl4N4O4: C, 65.91; H, 4.15; N, 6.41. Found: C, 65.82; H,
4.26; N, 6.50.
4.3.1.33. (5S,6S,10R)-3,9-Bis(4-chlorophenyl)-10-(2,4-dichloro-
phenyl)-14-[(E)-(2,4-di-chlorophenyl)methylidene]-12-[(R)-1-
phenylethyl]-1,4,7-trioxa-2,8,12-triazadispiro[4.0.4.4]tetra-
deca-2,8-diene 4m. Obtained as a white solid; (0.115 g, 24%);
4.3.1.37.
(5R,6R,10S)-10-(2,4-Dichlorophenyl)-14-[(E)-1-(2,4-
mp = 172–173 °C; [
a
]
D = ꢀ168.0 (c 0.18, CHCl3); IR (KBr) mmax
:
dichlorophenyl)methylidene]-3,9-di(4-isopropylphenyl)-12-
(1-phenylethyl)-1,4,7-trioxa-2,8,12-triazadispiro[4.0.4.4]tetra-
deca-2,8-diene 5n. Obtained as a viscous liquid; (0.073 g, 15%);
1626, 1599, 1490, 1351, 1096, 1015, 837 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): dH 0.67 (d, 3H, J = 6.3 Hz, CH3), 2.61 (d, 1H,
J = 12.6 Hz, H-11a), 2.68 (d, 1H, J = 12.0 Hz, H-13a), 3.00–3.04 (q,
1H, J = 6.3 Hz, CH), 3.10 (d, 1H, J = 12.0 Hz, H-13b), 3.63 (d, 1H,
J = 12.6 Hz, H-11b), 5.41 (s, 1H, H-10), 6.81–7.76 (m, 20H, aromatic
and H-15). 13C NMR (75 MHz, CDCl3): dC 19.6, 49.6, 52.1, 52.4, 64.5,
89.9, 115.2, 121.1, 125.9, 126.3, 126.5, 127.2, 127.4, 127.7, 128.4,
128.5, 128.8, 129.0, 129.1, 129.2, 129.6, 130.8, 130.9, 131.5,
131.7, 131.8, 134.0, 134.6, 134.8, 135.7, 136.4, 137.8, 143.0,
158.0, 159.1. Anal. Calcd for C41H29Cl6N3O3: C, 59.73; H, 3.55; N,
5.10. Found: C, 59.64; H, 3.66; N, 5.01.
[a
]
D = +190.5 (c 0.20, CHCl3); IR (CHCl3)
mmax: 1631, 1593, 1494,
1357, 1095, 1014, 836 cmꢀ1 1H NMR (300 MHz, CDCl3): dH 1.00
;
(d, 3H, J = 6.8 Hz, CH3), 1.13 (d, 6H, J = 6.9 Hz, CH(CH3)2), 1.24 (d,
6H, J = 6.6 Hz, CH(CH3)2), 2.78–2.98 (m, 5H, H-11a, H-11b, H-13a
and CH(CH3)2), 3.32 (q, 1H, J = 6.8 Hz, CH), 3.67 (d, 1H,
J = 12.3 Hz, H-13b), 5.39 (s, 1H, H-10), 6.96–7.52 (m, 17H, aromatic
and H-15), 7.70 (d, 2H, J = 8.1 Hz, aromatic), 8.02 (d, 1H, J = 8.1 Hz,
aromatic). 13C NMR (75 MHz, CDCl3): dC 15.6, 23.6, 23.7, 34.2, 34.3,
47.9, 51.5, 52.2, 63.6, 89.6, 114.6, 120.1, 125.4, 126.5, 126.6, 126.8,

1326
R. S. Kumar et al. / Tetrahedron: Asymmetry 21 (2010) 1315–1327
127.0, 127.1, 127.2, 127.8, 128.0, 128.1, 129.3, 129.6, 130.3, 131.1,
131.2, 131.7, 132.4, 132.5, 134.0, 134.3, 134.8, 135.5, 140.7, 151.2,
152.8, 158.6, 160.1. Anal. Calcd for C47H43Cl4N3O3: C, 67.23; H,
5.16; N, 5.00. Found: C, 67.35; H, 5.23; N, 5.11.
H-10), 6.01 (d, 2H, J = 7.5 Hz, aromatic), 6.86–8.02 (m, 25H, aro-
matic and H-15), 8.38 (d, 1H, J = 8.4 Hz, aromatic). 13C NMR
(75 MHz, CDCl3): dC 19.8, 50.0, 51.5, 52.4, 64.0, 90.6, 116.0, 121.3,
124.0, 124.1, 124.8, 125.5, 125.7, 126.0, 126.4, 126.7, 126.8,
126.9, 127.1, 127.2, 127.4, 127.8, 127.9, 128.2, 128.4, 128.5,
128.8, 129.0, 129.3, 130.6, 131.5, 131.6, 131.8, 132.7, 133.3,
134.0, 135.8, 137.8, 143.4, 158.3, 159.7. Anal. Calcd for
4.3.1.38.
(4R,5S,6R,11R,15S)-4,15-Bis(2,4-dichlorophenyl)-
3,9,14-tri(4-isopropyl-phenyl)-17-(1-phenylethyl)-1,7,10,12-tet-
raoxa-2,8,13,17-tetraazatrispiro[4.0.4.0.4.3]-octadeca-2,8,13-
triene 7n. Obtained as a white solid; (0.046 g, 8%); mp = 192–
C49H37Cl2N3O3: C, 74.81; H, 4.74; N, 5.34. Found: C, 74.90; H,
4.67; N, 5.43.
193 °C; [a]D = +16.0 (c 0.10, CHCl3); IR (KBr) mmax: 1598, 1496,
1472, 1406, 1347, 1092, 847, 791 cmꢀ1; 1H NMR (300 MHz, CDCl3):
dH 1.06 (d, 3H, J = 6.6 Hz, CH3), 1.22 (d, 6H, J = 6.9 Hz, CH(CH3)2),
1.27–1.29 (m, 12H, CH(CH3)2), 2.17–3.03 (m, 7H, H-16a, H-16b,
H-18a, H-18b and CH(CH3)2), 3.56 (q, 1H, J = 6.6 Hz, CH), 5.34 (s,
1H, H-4 or H-15), 5.38 (s, 1H, H-4 or H-15), 6.87–8.05 (m, 23H, aro-
matic). 13C NMR (75 MHz, CDCl3): dC 18.5, 23.7, 23.8, 24.0, 33.5,
33.8, 34.3, 49.8, 51.7, 52.2, 52.6, 62.8, 90.4, 90.5, 114.2, 121.6,
125.1, 126.1, 126.5, 126.6, 126.8, 126.9, 127.1, 127.2, 127.3,
127.6, 128.1, 128.2, 129.7, 130.3, 130.8, 134.4, 134.6, 135.7,
144.8, 150.9, 154.7, 155.0, 157.4, 157.9, 160.7. Anal. Calcd for
4.3.1.42. (5R,6R,10S)-3,9-Bis(4-chlorophenyl)-10-(1-naphthyl)-
14-[(E)-1-naphthylmethylidene]-12-[(R)-1-phenylethyl]-1,4,7-
trioxa-2,8,12-triazadispiro[4.0.4.4]tetradeca-2,8-diene
5p. Obtained as a viscous liquid; (0.078 g, 16%); [
0.19, CHCl3); IR (CHCl3) max: 1628, 1595, 1494, 1359, 1091,
1018, 839 cmꢀ1 1H NMR (300 MHz, CDCl3): dH 0.62 (d, 3H,
a]D = +212.0 (c
m
;
J = 6.9 Hz, CH3), 2.81–3.02 (m, 4H, H-11a, H-11b, H-13a and CH),
3.52 (d, 1H, J = 12.3 Hz, H-13b), 5.77 (s, 1H, H-10), 6.25 (d, 2H,
J = 7.2 Hz, aromatic), 6.97–8.02 (m, 25H, aromatic and H-15), 8.33
(d, 1H, J = 8.7 Hz, aromatic). 13C NMR (75 MHz, CDCl3): dC 19.8,
47.0, 51.2, 51.9, 62.4, 90.7, 116.0, 121.2, 123.8, 124.4, 125.1,
125.4, 126.0, 126.1, 126.4, 126.6, 126.8, 127.1, 127.2, 127.7,
127.8, 128.0, 128.2, 128.3, 128.4, 128.8, 129.0, 129.2, 130.1,
131.7, 132.0, 132.3, 132.4, 133.4, 134.1, 135.8, 137.8, 140.3,
158.3, 159.9. Anal. Calcd for C49H37Cl2N3O3: C, 74.81; H, 4.74; N,
5.34. Found: C, 74.70; H, 4.82; N, 5.24.
C57H54Cl4N4O4: C, 68.40; H, 5.44; N, 5.60. Found: C, 68.28; H,
5.35; N, 5.68.
4.3.1.39. (5S,6S,10R)-10-(1-Naphthyl)-14-[(E)-1-naphthylmethy-
lidene]-3,9-diphenyl-12-[(R)-1-phenylethyl]-1,4,7-trioxa-
2,8,12-triazadispiro[4.0.4.4]tetradeca-2,8-diene 4o. Obtained as
a viscous liquid; (0.125 g, 28%); [
a]
D = ꢀ157.5 (c 0.17, CHCl3); IR
(CHCl3)
m
max: 1629, 1592, 1496, 1355, 1094, 1019, 838 cmꢀ1
;
1H
4.3.1.43.
(5S,6S,10R)-3,9-Bis(4-isopropylphenyl)-10-(1-naph-
NMR (300 MHz, CDCl3): dH 0.23 (d, 3H, J = 5.4 Hz, CH3), 2.62 (d,
1H, J = 12.6 Hz, H-11a), 2.69 (d, 1H, J = 11.6 Hz, H-13a), 2.79 (q,
1H, J = 5.4 Hz, CH), 3.26 (d, 1H, J = 11.6 Hz, H-13b), 3.56 (d, 1H,
J = 12.6 Hz, H-11b), 5.90 (s, 1H, H-10), 6.04 (d, 2H, J = 7.2 Hz, aro-
matic), 6.86–7.99 (m, 27H, aromatic and H-15), 8.43 (d, 1H,
J = 8.7 Hz, aromatic). 13C NMR (75 MHz, CDCl3): dC 19.9, 50.0,
51.6, 52.4, 64.0, 90.3, 115.7, 122.9, 124.2, 124.8, 125.5, 125.6,
125.9, 126.3, 126.6, 126.8, 126.9, 127.1, 127.2, 127.3, 127.8,
127.9, 128.1, 128.4, 128.5, 128.6, 128.7, 128.9, 129.2, 129.8,
130.5, 131.0, 131.5, 131.6, 131.7, 132.2, 132.7, 133.3, 134.0,
143.5, 158.9, 160.5. Anal. Calcd for C49H39N3O3: C, 81.98; H, 5.48;
N, 5.85. Found: C, 81.87; H, 5.55; N, 5.76.
thyl)-14-[(E)-1-(1-naphthyl)methylidene]-12-(1-phenylethyl)-
1,4,7-trioxa-2,8,12-triazadispiro[4.0.4.4]tetradeca-2,8-diene
4q. Obtained as a viscous liquid; (0.125 g, 25%); [
0.19, CHCl3); IR (CHCl3) max: 1625, 1597, 1495, 1358, 1095,
1017, 834 cmꢀ1 1H NMR (300 MHz, CDCl3): dH 0.23 (d, 3H,
a]
D = ꢀ172.0 (c
m
;
J = 6.9 Hz, CH3), 1.12 (dd, 6H, J = 6.9, 1.8 Hz, CH(CH3)2), 1.26 (d,
6H, J = 6.9 Hz, CH(CH3)2), 2.67 (d, 1H, J = 11.6 Hz, H-11a), 2.72–
2.81 (m, 2H, H-13a and CH), 2.91–3.00 (m, 2H, CH), 3.23 (d, 1H,
J = 11.6 Hz, H-11b), 3.53 (d, 1H, J = 12.9 Hz, H-13b), 5.86 (s, 1H,
H-10), 6.03 (d, 2H, J = 7.5 Hz, aromatic), 6.86–7.07 (m, 8H, aro-
matic), 7.26–7.85 (m, 15H, aromatic and H-15), 7.98 (d, 2H,
J = 8.7 Hz, aromatic), 8.42 (d, 1H, J = 8.7 Hz, aromatic). 13C NMR
(75 MHz, CDCl3): dC 19.9, 23.6, 23.7, 34.1, 34.3, 50.0, 51.7, 52.5,
63.9, 90.2, 115.4, 120.4, 124.2, 124.3, 124.8, 125.5, 125.6, 125.9,
126.2, 126.3, 126.6, 126.7, 126.9, 127.1, 127.2, 127.3, 127.7,
127.9, 128.0, 128.3, 128.4, 129.1, 131.2, 131.6, 131.8, 132.4,
132.7, 133.3, 134.0, 143.6, 150.7, 152.8, 158.9, 160.4. Anal. Calcd
for C55H51N3O3: C, 82.37; H, 6.41; N, 5.24. Found: C, 82.45; H,
6.30; N, 5.18.
4.3.1.40.
(5R,6R,10S)-10-(1-Naphthyl)-14-[(E)-1-naphthylme-
thylidene]-3,9-diphenyl-12-[(R)-1-phenylethyl]-1,4,7-trioxa-
2,8,12-triazadispiro[4.0.4.4]tetradeca-2,8-diene 5o. Obtained as
a viscous liquid; (0.063 g, 14%); [
a
]
D = +196.0 (c 0.19, CHCl3); IR
(CHCl3)
m
max: 1627, 1598, 1494, 1356, 1092, 1016, 835 cmꢀ1
;
1H
NMR (300 MHz, CDCl3): dH 0.68 (d, 3H, J = 6.6 Hz, CH3), 2.57–2.80
(m, 4H, H-11a, H-11b, H-13a and CH), 3.55 (d, 1H, J = 12.0 Hz, H-
13b), 5.80 (s, 1H, H-10), 6.04 (d, 2H, J = 7.2 Hz, aromatic), 6.96–
8.30 (m, 28H, aromatic and H-15). 13C NMR (75 MHz, CDCl3): dC
19.9, 47.1, 51.2, 51.8, 62.4, 90.4, 115.8, 121.7, 123.0, 124.3, 124.6,
125.0, 125.9, 126.3, 126.7, 126.9, 127.2, 127.3, 127.5, 127.8,
127.9, 128.5, 128.6, 128.9, 129.2, 129.4, 129.8, 131.8, 132.2,
132.3, 132.4, 133.3, 134.0, 137.8, 142.3, 158.2, 159.9. Anal. Calcd
for C49H39N3O3: C, 81.98; H, 5.48; N, 5.85. Found: C, 81.88; H,
5.41; N, 5.76.
4.3.1.44.
(5R,6R,10S)-3,9-Bis(4-isopropylphenyl)-10-(1-naph-
thyl)-14-[(E)-1-(1-naphthyl)methylidene]-12-(1-phenylethyl)-
1,4,7-trioxa-2,8,12-triazadispiro[4.0.4.4]tetradeca-2,8-diene
5q. Obtained as a viscous liquid; (0.075 g, 15%); [
0.19, CHCl3); IR (CHCl3) max: 1627, 1594, 1498, 1356, 1095, 1019,
836 cmꢀ1 1H NMR (300 MHz, CDCl3): dH 0.63 (d, 3H, J = 6.6 Hz,
a]D = +202.0 (c
m
;
CH3), 1.10 (d, 6H, J = 6.9 Hz,CH(CH3)2), 1.28 (d, 6H, J = 7.2 Hz,
CH(CH3)2), 2.75–3.03 (m, 6H, H-11a, H-11b, H-13a, CH and
CH(CH3)2), 3.43 (d, 1H, J = 11.7 Hz, H-13b), 5.80 (s, 1H, H-10), 6.31
(d, 2H, J = 6.3 Hz, aromatic), 6.94–7.87 (m, 22H, aromatic and H-
15), 7.95 (d, 1H, J = 8.1 Hz, aromatic), 8.03 (d, 2H, J = 8.1 Hz, aro-
matic), 8.38 (d, 1H, J = 8.4 Hz, aromatic). 13C NMR (75 MHz, CDCl3):
dC 19.8, 23.6, 23.7, 34.2 34.3, 47.1, 51.3, 52.1, 62.3, 90.3, 115.3,
120.2, 124.0, 124.7, 125.1, 125.5, 125.8, 125.9, 126.2, 126.3, 126.6,
126.7, 127.0, 127.3, 127.7, 128.0, 128.3, 128.5, 128.8, 130.4, 130.6,
131.7, 132.3, 132.4, 132.9, 133.4, 134.1, 140.6, 150.7, 152.9, 155.1,
159.1, 160.6. Anal. Calcd for C55H51N3O3: C, 82.37; H, 6.41; N, 5.24.
Found: C, 82.28; H, 6.30; N, 5.16.
4.3.1.41. (5S,6S,10R)-3,9-Bis(4-chlorophenyl)-10-(1-naphthyl)-
14-[(E)-1-naphthylmethylidene]-12-[(R)-1-phenylethyl]-1,4,7-
trioxa-2,8,12-triazadispiro[4.0.4.4]tetradeca-2,8-diene
4p. Obtained as a viscous liquid; (0.122 g, 25%); [
0.21, CHCl3); IR (CHCl3) max: 1627, 1599, 1494, 1356, 1091,
1014, 836 cmꢀ1 1H NMR (300 MHz, CDCl3): dH 0.20 (d, 3H,
a]
D = ꢀ169.5 (c
m
;
J = 6.5 Hz, CH3), 2.57 (d, 1H, J = 12.6 Hz, H-11a), 2.66 (d, 1H,
J = 11.3 Hz, H-13a), 2.76 (q, 1H, J = 6.5 Hz, CH), 3.26 (d, 1H,
J = 11.3 Hz, H-11b), 3.57 (d, 1H, J = 12.6 Hz, H-13b), 5.84 (s, 1H,

R. S. Kumar et al. / Tetrahedron: Asymmetry 21 (2010) 1315–1327
1327
4.3.2. X-ray crystallographic determination of 5d
References
The unit cell was measured by centreing 2828 reflections and
refined by full-matrix least-square on F2. Empirical formula
C
1. (a) Kozikowski, A. P.; Stein, P. D. J. Am. Chem. Soc. 1982, 104, 4023–4024; (b)
Martin, S. F.; Dappen, M. S.; Dupre, B.; Murphy, C. J.; Colapret, J. A. J. Org. Chem.
1989, 54, 2209–2216; (c) Curran, D. P. J. Am. Chem. Soc. 1983, 105, 5826–5833;
(d) Jager, V.; Muller, I. Tetrahedron 1985, 41, 3519–3528.
2. (a)1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York, 1984;
(b) Gothelf, K. V.; Jorgensen, K. A. Chem. Rev. 1998, 98, 863–910.
3. Nair, V.; Radhakrishnan, K. V.; Sheela, K. C.; Rath, N. P. Tetrahedron 1999, 55,
14199–14210.
4. Kang, Y. K.; Shin, K. J.; Yoo, K. H.; Seo, K. J.; Hong, C. Y.; Lee, C.; Park, S. Y.; Kim,
D. J.; Park, S. W. Bioorg. Med. Chem. Lett. 2000, 10, 95–99.
5. Xue, C.; Roderick, J.; Mousa, S.; Olson, R. E.; DeGrado, W. F. Bioorg. Med. Chem.
Lett. 1998, 08, 3499–3504.
6. Diana, G. D.; McKinlay, M. A.; Brisson, C. J.; Zalay, E. S.; Miralles, J. V.; Salvador,
U. J. J. Med. Chem. 1985, 28, 748–752.
7. Lepage, F.; Tombert, F.; Cuvier, G.; Marivain, A.; Gillardin, J. M. Eur. J. Med. Chem.
1992, 27, 581–593.
8. (a) Howe, R. K.; Shelton, B. R. J. Org. Chem. 1990, 55, 4603–4607; (b) De Amici,
M.; De Micheli, M.; Misani, V. Tetrahedron 1990, 46, 1975–1986.
9. Faulkner, J. Nat. Prod. Rep. 2001, 18, 1–49.
10. Konig, G. M.; Wright, A. D.; Sticher, O. J. Nat. Prod. 1990, 53, 1615–1618.
11. Takada, N.; Watanabe, R.; Suenaga, K.; Yamada, K.; Ueda, K.; Kita, M.; Uemura,
D. Tetrahedron Lett. 2001, 42, 5265–5267.
12. Encarnacion-Dimayuga, R.; Ramirez, M. R.; Luna-Herrera, J. Pharm. Biol. 2003,
41, 384–387.
13. (a) Laschat, S.; Dickner, T. Synthesis 2000, 1781–1813; (b) Weintraub, P. M.;
Sabol, J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59, 2953–2989; (c)
Buffat, M. G. P. Tetrahedron 2004, 60, 1701–1729.
14. Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679–3681.
15. www.who.int/tb/publications/2007/factsheet.
16. http://www3.niaid.nih.gov/topics/tuberculosis/Research/PDF/MDRXDRTB
ResearchAgenda060607_tagged.pdf (June 2007).
17. (a) Suresh Kumar, R.; Perumal, S. Tetrahedron Lett. 2007, 48, 7164–7168; (b)
Ranjith Kumar, R.; Perumal, S. Tetrahedron 2007, 63, 7850–7857; (c)
Karthikeyan, S. V.; Perumal, S. Tetrahedron Lett. 2007, 48, 2261–2265; (d)
Kamal Nasar, M.; Ranjith Kumar, R.; Perumal, S. Tetrahedron Lett. 2007, 48,
2155–2158; (e) Savitha Devi, N.; Perumal, S. Tetrahedron Lett. 2007, 48, 5627–
5629.
18. Ranjith Kumar, R.; Perumal, S. Tetrahedron 2007, 63, 12220–12231.
19. Suresh Kumar, R.; Perumal, S.; Kagan, H. B.; Guillot, R. Tetrahedron: Asymmetry
2007, 18, 170–180.
41H31Cl4N3O3; formula weight 755.49; crystal system Orthorhom-
bic; space group ‘P2(1)2(1)2(1)’. The unit cell dimensions are
a = 7.8663(11) Å, b = 14.429(2) Å, c = 31.819(4) Å, = 90.00°,
b = 90.00°,
= 90.00°, V = 3611.5(9) Å3, Z = 4, Dcalcd = 1.389 Mg/m3,
= 0.372 mmꢀ1, T = 293(2) K, F(0 0 0) = 1560. The reflections col-
lected were 6370 of which 2894 unique [Rint = 0.1855]; 2828
I > 2 (I), R1 = 0.0841 and R2 = 0.0672 for 2828 [I > 2 (I)] and
a
c
l
r
x
r
R1 = 0.900, wR2 = 0.900 for all (6370) intensity data. Goodness of
fit = 0.900. CCDC number is 664285. Copies of the data can be ob-
tained, free of charge, on application to CCDC, 12 Union Road, Cam-
bridge CB2 1EZ, UK [fax: +44(0) 1223 336033 or email:
deposit@ccdc.cam.ac.uk].
4.3.3. X-ray crystallographic determination of 7i
The unit cell was measured by centreing 9833 reflections and
refined by full-matrix least-square on F2. Empirical formula
C
49H36Cl8N4O4; formula weight 1028.42; crystal system triclinic;
space group ‘P1’. The unit cell dimensions are a = 11.5285(10) Å,
b = 13.7808(13) Å, c = 14.8366(14) Å, = 87.451(2)°, b = 83.619
(2)°,
= 83.245(2)°, V = 2325.1(4) Å3, Z = 2, Dcalcd = 1.469 Mg/m3,
= 0.535 mmꢀ1, T = 100(1) K, F(0 0 0) = 1052. The reflections col-
lected were 28258 of which 20449 unique [Rint = 0.0890]; 9833
I > 2 (I), R1 = 0.1572 and R2 = 0.1405 for 9833 [I > 2 (I)] and
a
c
l
r
x
r
R1 = 1.012, wR2 = 1.012 for all (28258) intensity data. Goodness of
fit = 1.012. CCDC number is 664286. Copies of the data can be ob-
tained, free of charge, on application to CCDC, 12 Union Road, Cam-
bridge CB2 1EZ, UK [fax: +44(0) 1223 336033 or email:
deposit@ccdc.cam.ac.uk].
Acknowledgements
20. Suresh Kumar, R.; Perumal, S.; Arun Shetty, K.; Yogeeswari, P.; Sriram, D. Eur. J.
Med. Chem. 2010, 45, 124–133.
21. Suresh, J.; Suresh Kumar, R.; Perumal, S.; Natarajan, S. Acta Crystallogr., Sect. C
2007, C63, o315–o318.
22. Mahalakshmi, S.; Suresh Kumar, R.; Perumal, S.; Sivakumar, V.; Suresh, J. Acta
Crystallogr., Sect. E 2008, C64, o199–o200.
23. Copies of the data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: +44(0) 1223 336033 or email:
deposit@ccdc.cam.ac.uk].
S.P. thanks the Department of Science and Technology, New
Delhi, for funding for a major research project (No. SR/S1/OC-70/
2006) and for funds from (i) IRHPA program used for the purchase
of a high resolution NMR spectrometer and (ii) FIST program and
the University Grants Commission, New Delhi, for (i) funds under
the DRS and ASIST programs and (ii) for funding for a major re-
search project [F. No. 36–155/2008(SR)]. R.S.K. thanks CSIR, New
Delhi, for Senior Research Fellowship and S.M.R. thanks UGC,
New Delhi, for Junior Research Fellowship.
24. Srinivasan, M.; Perumal, S. Tetrahedron 2007, 63, 2865–2874.