1,3-Dipolar cycloaddition of C-aryl-N-phenylnitrones to (R)-1-(1-phenylethyl)-3-[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinone s: Synthesis and antimycobacterial evaluation of enantiomerically pure spiroisoxazolidines

Full text of DOI:10.1016/j.ejmech.2009.09.034

European Journal of Medicinal Chemistry 45 (2010) 124–133
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
1,3-Dipolar cycloaddition of C-aryl-N-phenylnitrones to
(R)-1-(1-phenylethyl)-3-[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones:
Synthesis and antimycobacterial evaluation of enantiomerically
pure spiroisoxazolidines
,
b
Raju Suresh Kumar a, Subbu Perumal a , Krithika Arun Shetty ,
*
Perumal Yogeeswari b, Dharmarajan Sriram b
a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Palkalai Nagar, Madurai 625021, 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:
A series of novel enantiomerically pure spiroisoxazolidines were synthesized regioselectively by the
1,3-dipolar cycloaddition of C-aryl-N-phenylnitrones to (R)-1-(1-phenylethyl)-3-[(E)-arylmethylidene]-
tetrahydro-4(1H)-pyridinones. These compounds have been screened for their in vitro activity against
Mycobacterium tuberculosis H37Rv (MTB) using agar dilution method. Among the twenty two
compounds screened, (3S,4S,5R)-3,4-di(4-methylphenyl)-2-phenyl-7-[(R)-1-phenylethyl]-1-oxa-2,7-dia-
Received 28 July 2009
Received in revised form
10 September 2009
Accepted 22 September 2009
Available online 1 October 2009
zaspiro[4.5]decan-10-one (3e) was found to possess the maximum activity with MIC of 3.02 mM, being
2.5 times more potent than the first-line anti-TB drug ethambutol. For comparison, a series of ten
enantiomerically pure spirooxazolines were also screened, among which (4R,5S)-3,4-bis(4-chlor-
Keywords:
1,3-Dipolar cycloadditions
Spiroisoxazolidines
Spiroisoxazolines
Diastereoselective
Antimycobacterial activity
ophenyl)-7-[(R)-1-phenylethyl]-1-oxa-2,7-diazaspiro[4.5]dec-2-en-10-one
ophenyl)-3-(4-chlorophenyl)-7-[(R)-1-phenylethyl]-1-oxa-2,7-diazaspiro[4.5]dec-2-en-10-one
found to display maximum activity with MIC of 3.25 M.
and
(4R,5S)-4-(2-chlor-
were
m
Ó 2009 Published by Elsevier Masson SAS.
1. Introduction
obtained from the cycloaddition of 1,3-dipoles to dipolarophiles
endowed with exocyclic double bonds [11].
The 1,3-dipolar cycloaddition is a versatile reaction for the
construction of five membered ring heterocycles of biological
importance [1]. Among the 1,3-dipoles, nitrones have been
subjected to numerous 1,3-dipolar cycloadditions, ascribable to
their stability and ease of generation [2,3]. The 1,3-dipolar cyclo-
addition of nitrones to alkenes afford isoxazolidines [4,5] with
generation of as many as three new contiguous stereocenters in
a single step [6,7]. These isoxazolidines can be further elaborated
into polyfunctional cyclic or acyclic bioactive compounds with
complete control of relative stereochemistry [8].
Piperidones and their derivatives exhibit anticancer [12], anti-
convulsant [13], anti-inflammatory [14], and local anaesthetic [15]
activities. Recently, we have initiated a research program on the
synthesis of a series of novel heterocycles employing tandem/
domino reactions [16] and/or screened them for antimycobacterial
activities [17,18]. In particular, our recent investigations have
disclosed that hybrid spiroheterocycles incorporating piperidone
ring system in conjunction with other five membered ring systems
such as pyrrolidines, pyrrolothiazoles and pyrrolizines displayed
moderate to good antimycobacterial activities [19]. This prompted
the synthesis of enantiomerically pure spiroisoxazolidines,
comprising piperidone and isoxazolidine rings, by the 1,3-dipolar
cycloaddition of (R)-1-(1-phenylethyl)-3-[(E)-arylmethylidene]te-
trahydro-4(1H)-pyridinones (1) with C-aryl-N-phenylnitrones and
screen them for antimycobacterial activities. It is pertinent to note
that in our earlier study [20], the synthesis of a series of enantio-
merically pure spiroisoxazolines have been described via cycload-
dition of nitrile oxides to 1 (Scheme 2). These spiroisoxazolines [20]
Spiro compounds display pronounced biological activities [9]
and are also used in natural products chemistry for further trans-
formation into more complex heterocycles [10]. They can be
* Corresponding author. Tel./fax: þ91 452 2459845.
E-mail address: subbu.perum@gmail.com (S. Perumal).
0223-5234/$ – see front matter Ó 2009 Published by Elsevier Masson SAS.
doi:10.1016/j.ejmech.2009.09.034

R.S. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 124–133
125
have also been screened in the present work for in vitro anti-
mycobacterial activity to enable a comparison of the activity of
spiroisoxazolidines and spiroisoxazolines and all these results are
presented in this paper.
spiroisoxazolidines 3–5 in moderate yields (Schemes 1). The
enantiomerically pure dipolarophiles (1) were synthesized as
described by us earlier [19]. The data presented in Scheme 1
show that the cycloaddition of (R)-1-(1-phenylethyl)-3-[(E)-
arylmethylidene]tetrahydro-4(1H)-pyridinones (1) with nitrones
Tuberculosis is an infectious disease finding place amongst the
worldwide health threats. The statistics released by World Health
Organization reports that (i) one-third of the world’s population is
currently infected with TB, (ii) in each year 8 million people in
worldwide develop active TB among whom about 1.7 million people
die [21]. Two developments make the resurgence in TB especially
alarming: (i) the pathogenic synergy with HIV resulting in an
enhancement of the overall incidence of TB in HIV-positive patients
[22] and (ii) the emergence of multi-drugresistant TB (MDR-TB) that
resists two or more of the first-line anti-TB drugs, viz. isoniazid,
rifampicin, pyrizinamide, ethambutol, and streptomycin [23–25]. It
is also pertinent to note that in the last five decades, onlya few drugs
have been approved by the Food and Drug Administration (FDA) to
treat TB [26]. This reflects the inherent difficulties associated with
the discovery and clinical testing of new candidates and the lack of
significant pharmaceutical industry research in this area. Hence the
discovery and development of new drugs that effectively combat TB
are accorded a great importance.
2
proceeds regioselectively affording predominantly two
diastereomeric spiroisoxazolidines, 3 and 4, of the same regio-
chemistry arising from the addition of the oxygen of the nitrone
to the
and 2), spiroisoxazolidines 5a and 5b with reversal of the above
regiochemistry, with oxygen added to the -carbon of the ben-
a-carbon of the benzylidene moiety. In two cases (entries 1
b
zylidene, were also obtained in addition to 3 and 4. These results
show that this cycloaddition is very sensitive to the nature of
substituents in the dipolarophile and it is unclear why in two
cases 5 is obtained. It is pertinent to note that in the case of
entries 10 and 11, the spiroisoxazolidines, 3j and 3k, were
obtained as the only product, while 4j and 4k were formed only
in traces and hence their isolation proved difficult. The data
presented in Scheme 1 show that the reaction is stereoselective
as 3 predominates slightly over 4. As 3 and 4 are diastereomers,
they are readily separable affording enantiomerically pure
spiroisoxazolidines.
The spiroisoxazolidines were separated by flash column chro-
matography and their structures are in accord with their 1H, 13C and
2D NMR spectroscopic data as described for 4a. The 1H NMR
spectrum of 4a has two doublets at 4.45 and 4.53 ppm (J ¼ 7.2 Hz)
related by an H,H-COSY correlation assignable to H-3 and H-4
respectively, the J values indicating that H-3 and H-4 are trans to
2. Chemistry
In the present investigation, the 1,3-dipolar cycloaddition of
(R)-1-(1-phenylethyl)-3-[(E)-arylmethylidene]tetrahydro-4(1H)-
pyridinones (1) with nitrones (2) results in the formation of
Scheme 1. Synthesis of spiroisoxazolidines.

126
R.S. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 124–133
Scheme 2. Synthesis of spiroisoxazolines and spirodioxazoles.
each other. These assignments are supported by the HMBC corre-
lations of (i) H-3 with the N-Ph ipso carbon at 149.3 ppm and (ii) H-
4 with the carbonyl carbon at 208.3 ppm (Fig. 1). Further, H-4
shows HMBC correlations with C-3, C-5 and C-6 respectively at
78.8, 86.9 and 57.1 ppm. The C,H-COSY correlation of C-6 assigns
the doublet at 1.98 ppm (J ¼ 13.2 Hz) to H-6ax and the doublet of
doublets at 2.89 ppm (J ¼ 13.2, 2.1 Hz) to H-6eq. Further, H-6 shows
HMBC correlations with (i) methine carbon at 62.6 ppm, (ii) methyl
carbon at 19.0 ppm and (iii) the signal at 50.3 ppm due to C-8. The
C,H-COSY correlation of C-8 assigns the multiplets at 2.37–2.45 and
3.04–3.13 ppm to H-8eq and H-8ax respectively. From the H,H-COSY
correlation of H-8, it is possible to assign the multiplets at 2.37–
2.45 ppm to H-9eq and 3.31–3.42 ppm to H-9ax. The methine and
methyl protons of N-phenylethyl moiety appeared as a quartet at
3.57 ppm and a doublet at 1.23 ppm (J ¼ 6.6 Hz) respectively. The
aromatic protons appear as a multiplet in the range, 6.98–7.56 ppm.
The 1H and 13C chemical shifts of 3a and 4a differ little. In the case
of 3a, the signals for H-3 and H-4 merge and appear as a singlet at
4.55 ppm. The 1H and 13C chemical shifts of 4a and 3a are shown in
Figs. 2 and 3 respectively.
and 13C chemical shifts of 12 are shown in Fig. 6. The structure of 12
determined by X-ray crystallographic study [28] (Fig. 7) provides
unambiguous stereochemical information, which, in turn, estab-
lishes indirectly the complete stereochemistry of 4. As 3 and 4 differ
very little in their chemical shifts, 3 is assigned a mirror image, viz.
enantiomeric relationship, if the configuration of the a-phenylethyl
group is ignored. Thus the stereochemistry of 3 is tentatively
assigned as (3S,4S,5R).
The low stereoselectivity observed in the cycloaddition resulting
in a slightly enhanced formation of 3 relative to 4 suggests that the
energies of activation for the formation of these compounds do not
differ much. The formation of these diastereomers, 3 and 4 of one
regiochemistry and 5 of another is explained by postulating the
reaction of nitrones with two interconvertible diastereomeric
conformers of 1 (Scheme 5).
The slight preference for the diastereomer 3 can be rationalized
by diminished steric hindrance for the reaction of nitrone with the
conformation, 1A than with 1B (Scheme 5) in view of the presence
of the phenyl group near the C]C double bond in 1B. The addition
of nitrone over 1B is also likely to occur from the top side leading to
the axial orientation of oxygen, which is explicable by the
minimum steric hindrance on this side.
The 1H and 13C chemical shifts of all the spiroisoxazolidines 3–5
were also similarly assigned from straightforward considerations.
Selected HMBC correlations and 1H and 13C chemical shifts of the
regioisomer 5a are shown in Fig. 4. The complete stereochemistry
and the configuration at the stereocentres of 5 were determined
from X-ray crystallographic study of a single crystal of 5a [27]
(Fig. 5).
As all compounds belonging to series 3 and 4 were obtained as
viscous liquids, X-ray crystallographic study could not be carried
out. To obtain crystals suitable for X-ray crystallographic structure
determination to deduce the absolute configuration at stereo-
centres of 3, spiroisoxazolidine 3a was reduced with NaBH4
(Scheme 3). However, the alcohol 10 was obtained as a viscous
liquid. Hence the spiroisoxazolidines 3d and 4d were converted
into the corresponding oximes (Scheme 4). While 3d afforded the
oxime 11 as a viscous liquid, 4d furnished good crystals of 12. The
structure of 12 is in agreement with the one- and two-dimensional
NMR spectroscopic data and selected HMBC correlations and 1H
3. Biological results and discussion
The compounds were screened for their in vitro anti-
mycobacterial activity against Mycobacterium tuberculosis H37Rv
(MTB) by agar dilution method for the determination of MIC in
triplicates. The minimum inhibitory concentration (MIC) is
defined as the minimum concentration of compound required to
completely inhibit bacterial growth. The MICs of the synthesized
compounds along with the standard first-line drugs are reported
in Table 1. All the compounds of spiroisoxazolidines showed
promising in-vitro activity with MIC of less than 50
compounds (3e-f, 3h-i, 4e and 4h) inhibited MTB with MIC of
less than 10 M. Compared to the standard anti-TB drug
ethambutol (MIC: 7.64 M), five compounds (3e, 3h, 3i, 4e and
mM. Six
m
m
4h) were found to be more active and all the twentytwo
Fig. 1. Selected HMBC correlations of 4a.
Fig. 2. 1H and 13C chemical shifts 4a.

R.S. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 124–133
127
Fig. 3. 1H and 13C chemical shifts of 3a.
compounds were found to be less active than isoniazid and
rifampicin. (3S,4S,5R)-3,4-Di(4-methylphenyl)-2-phenyl-7-[(R)-
1-phenylethyl]-1-oxa-2,7-diazaspiro[4.5]decan-10-one (3e) was
found to be the most active compound in vitro with MIC of
aryl rings. Although the spiroisoxazolines 7 and the spiroisox-
azolidines 3–5 differ in the number of aryl rings, an examination of
the data in Tables 1 and 2 disclose that both these series are
endowed with almost equal spread of activity.
3.02 mM, being 2.5 times more potent than ethambutol.
An examination of the MIC values of 3 and 4 (Table 1) from
structure–activity point of view reveals that four compounds
belonging to one diastereomeric set, 3, viz. 3e, 3f, 3h and 3i and two
of the other diastereomeric set, 4, viz. 4e and 4h are more active
than the drug ethambutol. The most active candidates in series 3
and 4 are 3e and 4e respectively, which bear a diastereomeric
relationship. It is found that all compounds belonging to 3 and 4
with substituents in the aryl rings display enhanced activity
relative to the unsubstituted ones, among which 3e and 4e bearing
a methyl group at the para-position of both the phenyl rings
resulted in maximum activity. Replacement of the phenyl in the
4. Conclusion
The present investigation describes the synthesis of enantio-
merically pure spiroisoxazolidines by the 1,3-dipolar cycloaddition
of nitrones to enantiomerically pure dipolarophiles. The
spiroheterocycles obtained in the present work display moderate to
good activity against M. tuberculosis MTB. A series of enantiomeri-
cally pure spiroisoxazolines are found to display an almost equal
antimycobacterial activity against MTB. The synthesis and screening
for biological activity of further series of enantiomerically pure
compounds is currently under investigation in our research group.
isoxazolidine ring (MIC of 3a and 4a ¼ 25.58
mM) with the thienyl
M) enhances the activity four-fold,
ring (MIC of 3h and 4h ¼ 6.33
m
5. Experimental
whilst substitution of the phenyl rings with bulky naphthyl ring
does not alter the activity significantly.
The melting points were measured using open capillary tubes
and are uncorrected. 1H, 13C and two-dimensional NMR spectra
were recorded on a Bruker 300 MHz instrument in CDCl3 using TMS
as internal standard. Chemical shifts are given in parts per million
All the compounds belonging to spiroisoxazoline 7 synthesized
in our previous study [19] were also screened for in vitro
antimycobacterial activity against MTB and the MICs along with
standard drugs are given in Table 2. The data in Table 2 show that all
spiroisoxazolines 7 show promising in-vitro activity with MIC of
(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). Elemental analyses were
performed on a Perkin Elmer 2400 Series II Elemental CHNS
analyser. Column chromatography was performed on silica gel
(230–400 mesh) using petroleum ether-ethyl acetate as eluent.
Optical rotation values were measured using an autopol IV auto-
matic polarimeter at sodium D line at 25 ꢀC. Ten fold serial dilutions
of each test compound/drug were prepared and incorporated into
less than 30
and 7f–h) inhibited MTB with MIC of less than 7
found to be more active than the standard anti-TB drug ethambutol
(MIC: 7.64 M). In the spiroisoxazoline series too, compounds with
mM except 7a (MIC: 60.90
mM). Four compounds (7d
m
M and were
m
substituents in the aryl rings display enhanced activity than the
unsubstituted ones. Compounds with Cl substitution in both the
aryl rings display enhanced activity than that with unsubstituted
Fig. 4. Selected HMBC correlations and 1H and 13C chemical shifts of 5a.

128
R.S. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 124–133
J ¼ 13.0 Hz, H-6ax), 2.28–2.32 (m, 1H, H-8eq), 2.35–2.40 (m, 1H, H-
9eq), 2.97 (dd, 1H, J ¼ 13.0, 2.0 Hz, H-6eq), 3.15–3.17 (m, 1H, H-8ax),
3.34–3.44 (m, 1H, H-9ax), 3.56 (q,1H, J ¼ 7.0 Hz, CH), 4.55 (s, 2H, H-3
and H-4), 6.83–7.54 (m, 20H, aromatic). 13C NMR (75 MHz, CDCl3):
dC 18.2, 38.6, 50.7, 56.8, 58.5, 62.5, 78.2, 86.8, 117.7, 122.3, 123.2,
125.5,127.0,127.2,127.4,128.1,128.4,128.5,128.7,129.5, 137.0,139.7,
142.7, 149.4, 208.1.
5.1.2. (3R,4R,5S)-2,3,4-Triphenyl-7-[(R)-1-phenylethyl]-1-oxa-2,7-
diazaspiro[4.5]decan-10-one (4a)
Viscous liquid; [
C33H32N2O2: C, 81.12; H, 6.60; N, 5.73; Found: C, 81.18; H, 6.65; N,
5.68. IR (CHCl3): 896, 1264, 1427, 1720, 2310, 2982 cmꢁ1 1H NMR
a
]D ¼ ꢁ27.0 (c 0.19, CHCl3); Anal. Calcd for
;
(300 MHz, CDCl3): dH 1.23 (d, 3H, J ¼ 6.6 Hz, CH3), 1.98 (d, 1H,
J ¼ 13.2 Hz, H-6ax), 2.37–2.45 (m, 2H, H-8eq and H-9eq), 2.89 (dd,1H,
J ¼ 13.2, 2.1 Hz, H-6eq), 3.04–3.13 (m, 1H, H-8ax), 3.31–3.42 (m, 1H,
H-9ax), 3.57 (q, 1H, J ¼ 6.6 Hz, CH), 4.45 (d, 1H, J ¼ 7.2 Hz, H-3), 4.53
(d, 1H, J ¼ 7.2 Hz, H-4), 6.98–7.56 (m, 20H, aromatic). 13C NMR
(75 MHz, CDCl3): dC 19.0, 38.6, 50.3, 57.1, 58.6, 62.6, 78.8, 86.9, 117.8,
123.3, 125.5, 127.0, 127.3, 127.8, 128.2, 128.4, 128.5, 128.7, 128.8,
129.5, 137.2, 139.7, 143.0, 149.3, 208.3.
Fig. 5. ORTEP diagram of 5a.
5.1.3. (1R,4R,5R)-1,3,4-Triphenyl-7-[(R)-1-phenylethyl]-2-oxa-3,7-
diazaspiro[4.5]decan-10-one (5a)
Middlebrook 7H11 agar medium with OADC Growth Supplement.
Inoculum of M. tuberculosis H37Rv was prepared 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 10ꢁ2 to give a concentration of approximately 107 cfu/mL.
Colorless solid; [
C33H32N2O2: C, 81.12; H, 6.60; N, 5.73; Found: C, 81.07; H, 6.55; N,
5.69. IR (KBr): 890, 1263, 1435, 1721, 2305, 2989 cmꢁ1 1H NMR
a
]D ¼ ꢁ41.5 (c 0.26, CHCl3); Anal. Calcd for
;
(300 MHz, CDCl3): dH 1.24 (d, 3H, J ¼ 6.6 Hz, CH3), 1.70 (d, 1H,
J ¼ 11.8 Hz, H-6ax), 1.73–1.99 (m, 3H, H-8eq, H-9ax and H-9eq), 2.77–
2.87 (m, 1H, H-8ax), 3.19 (dd, 1H, J ¼ 11.8, 3.0 Hz, H-6eq), 3.44 (q, 1H,
J ¼ 6.6 Hz, CH), 4.99 (s, 1H, H-4), 6.27 (s, 1H, H-1), 6.92–7.62 (m,
20H, aromatic). 13C NMR (75 MHz, CDCl3): dC 18.8, 41.2, 50.6, 56.8,
63.5, 68.4, 79.0, 79.4, 116.1, 122.4, 127.2, 127.3, 128.2, 128.3, 128.4,
128.6, 128.7, 129.4, 133.6, 134.1, 138.4, 142.9, 149.7, 207.1.
A 5 mL 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 defined as the
minimum concentration of compound required to give complete
inhibition of bacterial growth.
5.1.4. (3S,4S,5R)-3-(4-Methylphenyl)-2,4-diphenyl-7-[(R)-1-
phenylethyl]-1-oxa-2,7-diazaspiro[4.5]decan-10-one (3b)
5.1. Cycloaddition of C-aryl-N-phenylnitrones with 1-[(R)-1-
phenylethyl]-3-[(E)-arylmethylidene]tetrahydro-4(1H)-
pyridinones: general procedure
Viscous liquid; [
C34H34N2O2: C, 81.24; H, 6.82; N, 5.57; Found: C, 81.19; H, 6.88; N,
5.53. IR (CHCl3): 898, 1261, 1430, 1722, 2308, 2985 cmꢁ1 1H NMR
a
]D ¼ þ23.5 (c 0.19, CHCl3); Anal. Calcd for
;
(300 MHz, CDCl3): dH 1.20 (d, 3H, J ¼ 6.8 Hz, CH3), 1.84 (d, 1H,
J ¼ 12.9 Hz, H-6ax), 2.30 (s, 1H, CH3), 2.34–2.44 (m, 2H, H-8eq and H-
9eq), 2.96 (dd, 1H, J ¼ 12.9, 2.7 Hz, H-6eq), 3.11–3.16 (m, 1H, H-8ax),
3.33–3.44 (m, 1H, H-9ax), 3.56 (q, 1H, J ¼ 6.8 Hz, CH), 4.52 (s, 2H, H-
3, H-4), 6.94–7.56 (m, 19H, aromatic). 13C NMR (75 MHz, CDCl3): dC
18.2,21.1, 38.9, 50.7, 56.8, 58.5, 62.5, 78.1, 86.7, 117.7, 120.9, 123.1,
127.1, 127.3, 127.4, 128.1, 128.3, 128.5, 128.8, 129.1, 129.4, 136.7, 137.3,
142.7, 149.5, 208.1.
A
mixture of [(R)-1-phenylethyl]-3-[(E)-arylmethylidene]te-
trahydro-4(1H)-pyridinone 1 (1 mmol) and nitrone 2 (1.2 mmol) in
toluene (25 ml) was refluxed for 10–16 h. The progress of the
reaction was monitored by TLC and after completion of the reac-
tion, the solvent was evaporated in vacuo and the residue subjected
to flash column chromatography on silica gel using pet ether-ethyl
acetate (10:1 v/v) as eluent.
5.1.1. (3S,4S,5R)-2,3,4-Triphenyl-7-[(R)-1-phenylethyl]-1-oxa-2,7-
5.1.5. (3R,4R,5S)-3-(4-Methylphenyl)-2,4-diphenyl-7-[(R)-1-
diazaspiro[4.5]decan-10-one (3a)
phenylethyl]-1-oxa-2,7-diazaspiro[4.5]decan-10-one (4b)
Colorless solid; [
C33H32N2O2 : C, 81.12; H, 6.60; N, 5.73; Found: C, 81.16; H, 6.54; N,
5.79. IR (CHCl3): 892, 1261, 1430, 1716, 2307, 2986 cmꢁ1 1H NMR
(300 MHz, CDCl3): dH 1.21 (d, 3H, J ¼ 7.0 Hz, CH3), 1.85 (d, 1H,
a
]D ¼ þ18.7 (c 0.23, CHCl3); Anal. Calcd for
Viscous liquid; [
C34H34N2O2: C, 81.24; H, 6.82; N, 5.57; Found: C, 81.20; H, 6.75; N,
5.50. IR (CHCl3): 896, 1260, 1431, 1718, 2308, 2981 cmꢁ1 1H NMR
a
]
¼ ꢁ36.5 (c 0.22, CHCl3); Anal. Calcd for
D
;
;
Scheme 3. Reduction of spiroisoxazolidines.

R.S. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 124–133
129
Scheme 4. Oximation of spiroisoxazolidines 3d and 4d.
(300 MHz, CDCl3): dH 1.23 (d, 3H, J ¼ 6.8 Hz, CH3), 1.98 (d, 1H,
J ¼ 13.2 Hz, H-6ax), 2.30 (s, 1H, CH3), 2.35–2.45 (m, 2H, H-8eq and
H-9eq), 2.88 (dd, 1H, J ¼ 13.2, 1.8 Hz, H-6eq), 3.06–3.10 (m, 1H, H-
8ax), 3.30–3.41 (m, 1H, H-9ax), 3.57 (q, 1H, J ¼ 6.8 Hz, CH), 4.47
(d, 1H, J ¼ 7.5 Hz, H-3), 4.51 (d, 1H, J ¼ 7.5 Hz, H-4), 6.98–7.28
(m, 19H, aromatic). 13C NMR (75 MHz, CDCl3): dC 19.0, 21.2, 38.6,
50.4, 57.2, 58.6, 62.6, 78.6, 86.8, 117.8, 123.2, 127.0, 127.1, 127.2,
127.3, 128.2, 128.3, 128.5, 129.4, 129.5, 136.6, 137.3, 137.4, 143.0,
149.4, 208.4.
(300 MHz, CDCl3): dH 1.25 (d, 3H, J ¼ 6.6 Hz, CH3), 1.83 (d, 1H,
J ¼ 12.9 Hz, H-6ax), 2.30 (s, 1H, CH3), 2.35–2.44 (m, 2H, H-8eq and H-
9eq), 2.94 (dd, 1H, J ¼ 12.9, 1.8 Hz, H-6eq), 3.09–3.21 (m, 1H, H-8ax),
3.39 (td, 1H, J ¼ 12.0, 6.0 Hz, H-9ax), 3.60 (q, 1H, J ¼ 6.6 Hz, CH), 4.42
(d, 1H, J ¼ 7.5 Hz, H-3), 4.51 (d, 1H, J ¼ 7.5 Hz, H-4), 6.99–7.29
(m, 18H, aromatic). 13C NMR (75 MHz, CDCl3): dC 18.1, 21.2, 38.8,
50.7, 56.7, 57.9, 62.4, 78.3, 86.5, 117.7,123.3,127.0,127.4,128.2, 128.5,
128.8, 129.1, 129.4, 130.8, 133.2, 135.7, 136.2, 137.6, 142.7, 149.3,
207.9.
5.1.6. (1R,4R,5R)-4-(4-Methylphenyl)-1,3-diphenyl-7-[(R)-1-
phenylethyl]-2-oxa-3,7-diazaspiro[4.5]decan-10-one (5b)
5.1.8. (3R,4R,5S)-4-(4-Chlorophenyl)-3-(4-methylphenyl)-2-
phenyl-7-[(R)-1-phenylethyl]-1-oxa-2,7-diazaspiro[4.5]decan-10-
one (4c)
Viscous liquid; [
C34H34N2O2: C, 81.24; H, 6.82; N, 5.57; Found: C, 81.29; H, 6.89; N,
5.51. IR (CHCl3): 892, 1260, 1438, 1719, 2301, 2985 cmꢁ1 1H NMR
a
]
¼ ꢁ48.8 (c 0.23, CHCl3); Anal. Calcd for
D
Viscous liquid; [
C34H33ClN2O2: C, 76.03; H, 6.19; N, 5.22; Found: C, 76.10; H, 6.14; N,
5.28. IR (CHCl3): 892, 1261, 1430, 1718, 2309, 2986 cmꢁ1 1H NMR
a]
¼ ꢁ44.0 (c 0.23, CHCl3); Anal. Calcd for
D
;
(300 MHz, CDCl3): dH 1.20 (d, 3H, J ¼ 6.6 Hz, CH3), 1.74–1.99 (m, 4H,
H-6ax, H-8eq, H-9ax and H-9eq), 2.34 (s, 1H, CH3), 2.82–2.96 (m, 2H,
H-8ax and H-6eq), 3.42 (q, 1H, J ¼ 6.6 Hz, CH), 4.87 (s, 1H, H-4), 6.13
(s, 1H, H-1), 6.84–7.44 (m, 19H, aromatic). 13C NMR (75 MHz,
CDCl3): dC 17.8, 21.2, 41.3, 48.8, 57.6, 63.4, 68.3, 78.5, 79.9, 116.1,
122.1, 127.1, 127.3, 127.7, 128.0, 128.2,128.5, 128.7,128.8, 129.3, 133.6,
135.5, 138.0, 143.9, 150.1, 207.1.
;
(300 MHz, CDCl3): dH 1.27 (d, 3H, J ¼ 6.6 Hz, CH3), 1.90 (d, 1H,
J ¼ 13.0 Hz, H-6ax), 2.31 (s, 1H, CH3), 2.35–2.46 (m, 2H, H-8eq and H-
9eq), 2.85 (d, 1H, J ¼ 13.0 Hz, H-6eq), 3.05–3.21 (m, 1H, H-8ax), 3.33–
3.44 (m, 1H, H-9ax), 3.56 (q, 1H, J ¼ 6.6 Hz, CH), 4.37 (d, 1H,
J ¼ 7.2 Hz, H-3), 4.50 (d, 1H, J ¼ 7.2 Hz, H-4), 7.01–7.30 (m, 18H,
aromatic). 13C NMR (75 MHz, CDCl3): dC 19.0, 21.2, 38.6, 50.3, 57.4,
57.8, 62.7, 78.7, 86.6, 117.9, 123.4, 127.1, 127.2, 127.3, 128.2, 128.5,
128.8, 129.1, 129.4, 133.1, 135.9, 136.2, 137.6, 143.0, 149.2, 208.1.
5.1.7. (3S,4S,5R)-4-(4-Chlorophenyl)-3-(4-methylphenyl)-2-
phenyl-7-[(R)-1-phenylethyl]-1-oxa-2,7-diazaspiro[4.5]decan-10-
one (3c)
5.1.9. (3S,4S,5R)-4-(4-Methylphenyl)-2,3-diphenyl-7-[(R)-1-
Viscous liquid; [
C34H33ClN2O2: C, 76.03; H, 6.19; N, 5.22; Found: C, 76.09; H, 6.25; N,
5.17. IR (CHCl3): 890, 1265, 1434, 1720, 2309, 2980 cmꢁ1 1H NMR
a
]
¼ þ17.5 (c 0.18, CHCl3); Anal. Calcd for
phenylethyl]-1-oxa-2,7-diazaspiro[4.5]decan-10-one (3d)
D
Viscous liquid; [
a
]D ¼ þ20.7 (c 0.24, CHCl3); Anal. Calcd for
;
C34H34N2O2: C, 81.24; H, 6.82; N, 5.57; Found: C, 81.19; H, 6.86; N,
Fig. 6. Selected HMBC correlations and 1H and 13C chemical shifts of 12.

130
R.S. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 124–133
(300 MHz, CDCl3): dH 1.24 (d, 3H, J ¼ 6.9 Hz, CH3), 2.01 (d, 1H,
J ¼ 13.1 Hz, H-6ax), 2.31 (s, 1H, CH3), 2.35–2.45 (m, 2H, H-8eq and H-
9eq), 2.89 (dd, 1H, J ¼ 13.1, 2.4 Hz, H-6eq), 3.01–3.12 (m, 1H, H-8ax),
3.31–3.41 (m, 1H, H-9ax), 3.59 (q, 1H, J ¼ 6.9 Hz, CH), 4.46–4.51
(m, 2H, H-3, H-4), 7.05–7.54 (m, 19H, aromatic). 13C NMR (75 MHz,
CDCl3): dC 18.8, 21.0, 38.6, 50.2, 57.2, 58.2, 62.5, 78.6, 86.9, 117.7,
122.3, 126.9, 127.2, 127.3, 127.7, 128.1, 128.5, 128.6, 129.0, 129.3,
134.0, 136.9, 139.7, 143.2, 149.4, 208.3.
5.1.11. (3S,4S,5R)-3,4-Di(4-methylphenyl)-2-phenyl-7-[(R)-1-
phenylethyl]-1-oxa-2,7-diazaspiro[4.5]decan-10-one (3e)
Viscous liquid; [
C35H36N2O2: C, 81.36; H, 7.02; N, 5.42; Found: C, 81.30; H, 7.07; N,
5.37. IR (CHCl3): 892, 1261, 1430, 1716, 2304, 2985 cmꢁ1 1H NMR
a]
¼ þ13.5 (c 0.22, CHCl3); Anal. Calcd for
D
;
(300 MHz, CDCl3): dH 1.21 (d, 3H, J ¼ 6.6 Hz, CH3), 1.87 (d, 1H,
J ¼ 12.8 Hz, H-6ax), 2.30 (s, 1H, CH3), 2.31 (s, 1H, CH3), 2.33–2.42
(m, 2H, H-8eq and H-9eq), 2.99 (dd, 1H, J ¼ 12.8, 2.1 Hz, H-6eq), 3.06–
3.15 (m, 1H, H-8ax), 3.30–3.41 (m, 1H, H-9ax), 3.54 (q, 1H, J ¼ 6.6 Hz,
CH), 4.46–4.52 (m, 2H, H-3, H-4), 6.97–7.30 (m, 18H, aromatic). 13C
NMR (75 MHz, CDCl3): dC 18.3, 21.0, 21.2, 39.0, 50.7, 56.9, 58.3, 62.5,
77.9, 86.6, 117.6, 123.0, 126.9, 127.1, 127.4, 128.1, 128.5, 128.6, 129.0,
129.3, 129.4, 133.8, 136.7, 137.3, 143.0, 149.6, 208.1.
5.1.12. (3R,4R,5S)-3,4-Di(4-methylphenyl)-2-phenyl-7-[(R)-1-
phenylethyl]-1-oxa-2,7-diazaspiro[4.5]decan-10-one (4e)
Fig. 7. ORTEP diagram for 12.
Viscous liquid; [
C35H36N2O2: C, 81.36; H, 7.02; N, 5.42%; Found: C, 81.40; H, 7.08; N,
5.47. IR (CHCl3): 896, 1265, 1427, 1720, 2310, 2981 cmꢁ1 1H NMR
a]
¼ ꢁ34.0 (c 0.18, CHCl3); Anal. Calcd for
D
5.63. IR (CHCl3): 894, 1262, 1430, 1718, 2309, 2983 cmꢁ1
;
1H NMR
;
(300 MHz, CDCl3): dH 1.21 (d, 3H, J ¼ 6.8 Hz, CH3), 1.87 (d, 1H,
J ¼ 12.9 Hz, H-6ax), 2.25–2.44 (m, 5H, CH3, H-8eq and H-9eq), 3.00
(dd, 1H, J ¼ 12.9, 2.4 Hz, H-6eq), 3.07–3.16 (m, 1H, H-8ax), 3.31–3.41
(m, 1H, H-9ax), 3.54 (q, 1H, J ¼ 6.8 Hz, CH), 4.50 (d, 1H, J ¼ 7.8 Hz, H-
4), 4.54 (d, 1H, J ¼ 7.8 Hz, H-3), 6.98–7.30 (m, 19H, aromatic). 13C
NMR (75 MHz, CDCl3): dC 18.4, 21.0, 39.0, 50.7, 56.9, 58.3, 62.6, 78.1,
86.7, 117.6, 123.1, 127.0, 127.2, 127.4, 127.7, 128.1, 128.5, 128.6, 129.1,
129.4, 133.7, 136.9, 139.8, 143.0, 149.6, 208.1.
(300 MHz, CDCl3): dH 1.24 (d, 3H, J ¼ 6.8 Hz, CH3), 2.01 (d, 1H,
J ¼ 13.1 Hz, H-6ax), 2.30 (s, 1H, CH3), 2.31 (s, 1H, CH3), 2.33–2.45
(m, 2H, H-8eq and H-9eq), 2.88 (dd, 1H, J ¼ 13.1, 2.4 Hz, H-6eq), 3.01–
3.12 (m, 1H, H-8ax), 3.30–3.40 (m, 1H, H-9ax), 3.59 (q, 1H, J ¼ 6.8 Hz,
CH), 4.43–4.48 (m, 2H, H-3, H-4), 6.98–7.27 (m, 18H, aromatic). 13C
NMR (75 MHz, CDCl3): dC 18.9, 21.1, 21.2, 38.6, 50.2, 57.2, 58.2, 62.5,
78.4, 86.9, 117.7, 123.1, 127.0, 127.2, 127.3, 128.2, 128.5, 129.0, 129.3,
129.4, 134.1, 136.7, 136.8, 137.3, 143.2, 149.5, 208.4.
5.1.10. (3R,4R,5S)-4-(4-Methylphenyl)-2,3-diphenyl-7-[(R)-1-
5.1.13. (3S,4S,5R)-4-(2-Chlorophenyl)-2,3-diphenyl-7-[(R)-1-
phenylethyl]-1-oxa-2,7-diazaspiro[4.5]decan-10-one (4d)
phenylethyl]-1-oxa-2,7-diazaspiro[4.5]decan-10-one (3f)
Viscous liquid; [
C34H34N2O2: C, 81.24; H, 6.82; N, 5.57; Found: C, 81.20; H, 6.77; N,
5.54. IR (CHCl3): 894, 1266, 1436, 1721, 2307, 2989 cmꢁ1 1H NMR
a
]D ¼ ꢁ25.8 (c 0.21, CHCl3); Anal. Calcd for
Viscous liquid; [
C33H31ClN2O2: C, 75.78; H, 5.97; N, 5.36; Found: C, 75.72; H, 5.93; N,
5.42. IR (CHCl3): 895, 1267, 1432, 1716, 2304, 2982 cmꢁ1 1H NMR
a
]
¼ þ18.5 (c 0.21, CHCl3); Anal. Calcd for
D
;
;
Scheme 5. Formation of spiroisoxazolidines.

R.S. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 124–133
131
Table 1
(300 MHz, CDCl3):dH 1.16 (d, 3H, J ¼ 6.6 Hz, CH3), 2.03 (d, 1H,
J ¼ 12.9 Hz, H-6ax), 2.31 (s, 1H, CH3), 2.37–2.48 (m, 2H, H-8eq and H-
9eq), 2.77 (d, 1H, J ¼ 12.9 Hz, H-6eq), 3.02–3.12 (m, 1H, H-8ax), 3.23–
3.37 (m, 1H, H-9ax), 3.58 (q, 1H, J ¼ 6.6 Hz, CH), 4.49 (d, 1H,
J ¼ 6.3 Hz, H-3), 5.24 (d, 1H, J ¼ 6.3 Hz, H-4), 7.09–7.39 (m, 18H,
aromatic). 13C NMR (75 MHz, CDCl3):dC 17.8, 21.2, 38.6, 50.7, 54.0,
55.8, 62.3, 78.4, 86.5, 117.7, 120.9, 123.2, 126.6, 127.0, 127.1, 127.4,
128.1, 128.3, 128.5, 128.8, 129.4, 129.7, 135.8, 136.4, 137.4, 142.7,
149.0, 207.3.
Anti-tubercular activity of spiroisoxazolidines 3–5 against MTB.
Comp
MIC (
3
mM)
4
5
a
b
c
d
e
f
g
h
25.58
49.74
23.27
24.89
3.02
5.98
11.64
6.33
25.58
49.74
11.64
12.43
6.06
23.90
11.64
6.33
24.57
–
25.58
24.89
–
–
–
–
–
–
5.1.16. (3R,4R,5S)-4-(2-Chlorophenyl)-3-(4-methylphenyl)-2-
phenyl-7-[(R)-1-phenylethyl]-1-oxa-2,7-diazaspiro[4.5]decan-10-
one (4g)
i
j
k
6.15
23.20
22.62
–
–
–
–
Viscous liquid; [
C34H33ClN2O2: C, 76.03; H, 6.19; N, 5.22; Found: C, 76.10; H, 6.14; N,
5.26. IR (CHCl3): 891, 1261, 1432, 1720, 2311, 2982 cmꢁ1 1H NMR
a
]
¼ ꢁ41.0 (c 0.26, CHCl3); Anal. Calcd for
D
Isoniazid
Rifampicin
Ciprofloxacin
Ethambutol
0.36
0.12
4.71
7.64
;
(300 MHz, CDCl3):dH 1.15 (d, 3H, J ¼ 6.3 Hz, CH3), 2.23 (d, 1H,
J ¼ 12.6 Hz, H-6ax), 2.48–2.58 (m, 2H, H-8eq and H-9eq), 2.67 (d, 1H,
J ¼ 12.6 Hz, H-6eq), 2.87–3.00 (m, 1H, H-8ax), 3.13–3.27 (m, 1H, H-
9ax), 3.44 (q, 1H, J ¼ 6.3 Hz, CH), 4.48 (d, 1H, J ¼ 6.2 Hz, H-3), 5.18 (d,
1H, J ¼ 6.2 Hz, H-4), 6.99–7.54 (m, 18H, aromatic). 13C NMR
(75 MHz, CDCl3):dC 19.4, 21.2, 38.4, 50.3, 54.5, 56.5, 62.8, 78.7, 86.7,
117.5, 120.8, 122.3, 123.1, 128.5, 127.0, 127.2, 128.2, 128.5, 128.7,
128.8, 129.4, 129.6, 131.6, 136.5, 137.4, 143.9, 149.1, 207.3.
(300 MHz, CDCl3): dH 1.17 (d, 3H, J ¼ 6.6 Hz, CH3), 2.03 (d, 1H,
J ¼ 12.6 Hz, H-6ax), 2.35–2.56 (m, 2H, H-8eq and H-9eq), 2.78 (d, 1H,
J ¼ 12.6 Hz, H-6eq), 3.02–3.13 (m, 1H, H-8ax), 3.23–3.38 (m, 1H, H-
9ax), 3.59 (q, 1H, J ¼ 6.6 Hz, CH), 4.52 (d, 1H, J ¼ 6.6 Hz, H-3), 5.27 (d,
1H, J ¼ 6.6 Hz, H-4), 7.00–7.56 (m, 19H, aromatic). 13C NMR
(75 MHz, CDCl3): dC 17.8, 38.6, 50.7, 54.0, 55.8, 62.3, 78.6, 86.6, 117.7,
122.3, 123.3, 125.5, 126.7, 127.0, 127.2, 127.4, 128.1, 128.5, 128.7,
128.8, 129.6, 131.6, 135.7, 139.5, 142.7, 149.0, 207.2.
5.1.17. (3S,4S,5R)-2,3-Diphenyl-7-[(R)-1-phenylethyl]-4-(2-
thienyl)-1-oxa-2,7-diazaspiro[4.5]decan-10-one (3h)
Viscous liquid; [
C31H30N2O2S: C, 75.27; H, 6.11; N, 5.66; Found: C, 75.22; H, 6.15; N,
5.60. IR (CHCl3): 890, 1268, 1430, 1715, 2309, 2986 cmꢁ1 1H NMR
a
]D ¼ þ19.0 (c 0.21, CHCl3); Anal. Calcd for
5.1.14. (3R,4R,5S)-4-(2-Chlorophenyl)-2,3-diphenyl-7-[(R)-1-
phenylethyl]-1-oxa-2,7-diazaspiro[4.5]decan-10-one (4f)
;
(300 MHz, CDCl3):dH 1.26 (d, 3H, J ¼ 6.8 Hz, CH3), 2.01 (d, 1H,
J ¼ 12.9 Hz, H-6ax), 2.17–2.40 (m, 2H, H-8eq and H-9eq), 3.13–3.17
(m, 2H, H-6eq, H-8ax), 3.35 (td, 1H, J ¼ 12.3, 5.7 Hz, H-9ax), 3.54
(q, 1H, J ¼ 6.6 Hz, CH), 4.49 (d, 1H, J ¼ 8.4 Hz, H-3), 4.96 (d, 1H,
J ¼ 8.4 Hz, H-4), 6.85–7.57 (m, 18H, aromatic). 13C NMR (75 MHz,
CDCl3): dC 18.7, 39.1, 50.5, 54.0, 56.7, 62.8, 78.9, 86.1, 118.0, 123.6,
124.8, 126.9, 127.0, 127.4, 127.5, 128.0, 128.2, 128.5, 128.7, 128.8,
138.8, 138.9, 142.8, 149.4, 207.0.
Viscous liquid; [
C33H31ClN2O2: C, 75.78; H, 5.97; N, 5.36; Found: C, 75.74; H, 6.03; N,
5.30. IR (CHCl3): 890, 1264, 1432, 1718, 2308, 2985 cmꢁ1 1H NMR
a
]D ¼ ꢁ22.0 (c 0.17, CHCl3); Anal. Calcd for
;
(300 MHz, CDCl3): dH 1.16 (d, 3H, J ¼ 6.3 Hz, CH3), 2.23 (d, 1H,
J ¼ 12.6 Hz, H-6ax), 2.47–2.60 (m, 2H, H-8eq and H-9eq), 2.69 (d, 1H,
J ¼ 12.6 Hz, H-6eq), 2.88–3.00 (m, 1H, H-8ax), 3.14–3.27 (m, 1H, H-
9ax), 3.45 (q, 1H, J ¼ 6.3 Hz, CH), 4.51 (d, 1H, J ¼ 6.0 Hz, H-3), 5.21
(d, 1H, J ¼ 6.0 Hz, H-4), 6.99–7.53 (m, 19H, aromatic). 13C NMR
(75 MHz, CDCl3): dC 19.5, 38.4, 50.3, 54.5, 56.6, 62.8, 78.9, 86.8,117.5,
120.1,123.2,126.7,127.0,127.2,127.8,128.2,128.4,128.5,128.7,129.1,
129.7, 135.2, 135.9, 139.6, 143.2, 149.1, 207.3.
5.1.18. (3R,4R,5S)-2,3-Diphenyl-7-[(R)-1-phenylethyl]-4-(2-
thienyl)-1-oxa-2,7-diazaspiro[4.5]decan-10-one (4h)
Viscous liquid; [
C31H30N2O2S: C, 75.27; H, 6.11; N, 5.66; Found: C, 75.32; H, 6.16; N,
5.70. IR (CHCl3): 895, 1264, 1436, 1720, 2309, 2985 cmꢁ1 1H NMR
a
]
¼ ꢁ28.0 (c 0.22, CHCl3); Anal. Calcd for
D
5.1.15. (3S,4S,5R)-4-(2-Chlorophenyl)-3-(4-methylphenyl)-2-
phenyl-7-[(R)-1-phenylethyl]-1-oxa-2,7-diazaspiro[4.5]decan-10-
one (3g)
;
(300 MHz, CDCl3):dH 1.31 (d, 3H, J ¼ 6.6 Hz, CH3), 2.14 (d, 1H,
J ¼ 12.9 Hz, H-6ax), 2.38–2.46 (m, 2H, H-8eq and H-9eq), 3.04–3.15
(m, 2H, H-6eq, H-8ax), 3.30–3.44 (m, 1H, H-9ax), 3.69 (q, 1H,
J ¼ 6.6 Hz, CH), 4.41 (d,1H, J ¼ 8.3 Hz, H-3), 4.96 (d,1H, J ¼ 8.3 Hz, H-
4), 6.93–7.49 (m, 18H, aromatic). 13C NMR (75 MHz, CDCl3):dC 18.6,
38.7, 50.1, 53.8, 56.6, 62.5, 79.6, 86.3, 118.4,122.3,123.8, 125.9, 126.9,
127.0,127.3,127.6,128.5,128.7,128.8,129.1,138.6,139.2,142.6,149.1,
207.5.
Viscous liquid; [
a
]D ¼ þ16.5 (c 0.17, CHCl3); Anal. Calcd for
C34H33ClN2O2: C, 76.03; H, 6.19; N, 5.22; Found: C, 76.08; H, 6.25; N,
5.28. IR (CHCl3): 892, 1264, 1430, 1718, 2309, 2986 cmꢁ1 1H NMR
;
Table 2
Anti-tubercular activity of spiroisoxazolines 7 against MTB.
Comp 7
Ar
Ar0
MIC (mM)
a
b
c
d
e
f
g
h
C6H5
C6H5
C6H5
p-ClC6H4
C6H5
p-ClC6H4
C6H5
p-ClC6H4
C6H5
p-ClC6H4
C6H5
p-ClC6H4
60.90
14.05
14.05
3.25
14.72
6.82
7.03
3.25
27.14
25.25
0.36
5.1.19. (3S,4S,5R)-3-(4-Methylphenyl)-2-phenyl-7-[(R)-1-
phenylethyl]-4-(2-thienyl)-1-oxa-2,7-diazaspiro[4.5]decan-
10-one (3i)
p-ClC6H4
p-ClC6H4
p-CH3C6H4
p-CH3C6H4
o-ClC6H4
o-ClC6H4
1-naphthyl
1-naphthyl
Viscous liquid; [
C32H32N2O2S: C, 75.56; H, 6.34; N, 5.51; Found: C, 75.59; H, 6.39; N,
5.57. IR (CHCl3): 894, 1268, 1438, 1719, 2307, 2986 cmꢁ1 1H NMR
a
]
¼ þ21.0 (c 0.24, CHCl3); Anal. Calcd for
D
;
(300 MHz, CDCl3):dH 1.25 (d, 3H, J ¼ 6.6 Hz, CH3), 2.07 (d, 1H,
J ¼ 13.2 Hz, H-6ax), 2.17–2.40 (m, 5H, CH3, H-8eq, H-9eq), 3.09–3.18
(m, 2H, H-6eq, H-8ax), 3.34 (td, 1H, J ¼ 12.6, 5.7 Hz, H-9ax), 3.53
(q, 1H, J ¼ 6.6 Hz, CH), 4.45 (d, 1H, J ¼ 8.5 Hz, H-3), 4.93 (d, 1H,
J ¼ 8.5 Hz, H-4), 6.84–7.81 (m, 17H, aromatic). 13C NMR (75 MHz,
CDCl3): dC 18.6, 21.2, 39.1, 50.5, 54.0, 56.7, 62.8, 78.7, 85.9, 118.0,
i
j
Isoniazid
Rifampicin
Ciprofloxacin
Ethambutol
0.12
4.71
7.64

132
R.S. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 124–133
120.8, 123.5, 124.7, 125.7, 126.9, 127.0, 127.4, 128.2, 128.5, 128.8,
129.1, 129.4, 137.7, 139.0, 142.8, 149.5, 207.1.
8.18. 1H NMR (300 MHz, CDCl3):dH 1.16 (d, 3H, J ¼ 6.8 Hz, CH3), 1.80
(d, 1H, J ¼ 12.3 Hz, H-6ax), 1.86 (td, 1H, J ¼ 11.4, 2.9 Hz, H-8ax), 2.31
(s, 1H, CH3), 2.45–2.56 (m, 1H, H-9ax), 2.84–2.93 (m, 1H, H-8eq), 2.99
(d, 1H, J ¼ 12.3 Hz, H-6eq), 3.14 (dt, 1H, J ¼ 14.1, 3.0 Hz, H-9eq), 3.35
(q, 1H, J ¼ 6.8 Hz, CH), 4.71 (d, 1H, J ¼ 8.9 Hz, H-4), 4.79 (d, 1H,
J ¼ 8.9 Hz, H-3), 6.92–7.37 (m, 19H, aromatic). 13C NMR (75 MHz,
CDCl3): dC 18.6, 21.1, 23.1, 48.6, 57.0, 59.4, 63.6, 76.2, 83.6, 116.2,
122.0, 126.8, 127.0, 127.4, 127.5, 128.1, 128.4, 128.5, 128.9, 129.8,
133.1, 136.8, 140.7, 143.0, 151.1, 157.3.
5.1.20. (3R,4R,5S)-3-(4-Methylphenyl)-2-phenyl-7-[(R)-1-
phenylethyl]-4-(2-thienyl)-1-oxa-2,7-diazaspiro[4.5]decan-
10-one (4i)
Viscous liquid; [
C32H32N2O2S: C, 75.56; H, 6.34; N, 5.51; Found: C, 75.50; H, 6.38; N,
5.45. IR (CHCl3): 890, 1268, 1431, 1722, 2305, 2983 cmꢁ1 1H NMR
a]
¼ ꢁ32.0 (c 0.19, CHCl3); Anal. Calcd for
D
;
(300 MHz, CDCl3):dH 1.31 (d, 3H, J ¼ 6.9 Hz, CH3), 2.13 (d, 1H,
J ¼ 12.9 Hz, H-6ax), 2.30–2.37 (m, 5H, CH3, H-8eq and H-9eq), 3.02–
3.15 (m, 2H, H-6eq, H-8ax), 3.28–3.41 (m, 1H, H-9ax), 3.64 (q, 1H,
J ¼ 6.9 Hz, CH), 4.38 (d, 1H, J ¼ 8.3 Hz, H-3), 4.93 (d, 1H, J ¼ 8.3 Hz,
H-4), 6.82–7.81 (m, 17H, aromatic). 13C NMR (75 MHz, CDCl3):dC
18.6, 21.2, 38.7, 50.1, 53.8, 56.7, 62.5, 79.4, 86.2, 118.4, 123.7, 124.7,
127.2, 127.4, 127.5, 128.2, 128.5, 129.0, 129.4, 135.5, 136.7, 139.3,
143.2, 149.2, 207.5.
5.2.2. (3R,4R,5S)-4-(4-Methylphenyl)-2,3-diphenyl-7-[(R)-1-
phenylethyl]-1-oxa-2,7-diazaspiro[4.5]decan-10-one oxime (12)
Colorless crystals; [
a
]D ¼ ꢁ32.0 (c 0.19, CHCl3); Anal. Calcd for
C34H35N3O2: C, 78.89; H, 6.81; N, 8.12; Found: C, 78.95; H, 6.77; N,
8.17. 1H NMR (300 MHz, CDCl3):dH 1.21 (d, 3H, J ¼ 6.9 Hz, CH3), 1.87
(d, 1H, J ¼ 12.5 Hz, H-6ax), 2.06 (td, 1H, J ¼ 11.1, 3.2 Hz, H-8ax), 2.32
(s, 1H, CH3), 2.55–2.65 (m, 1H, H-9ax), 2.80 (d, 1H, J ¼ 12.5 Hz, H-
6eq), 2.85–2.91 (m, 1H, H-8eq), 3.14 (dt, 1H, J ¼ 14.1, 3.3 Hz, H-9eq),
3.48 (q, 1H, J ¼ 6.9 Hz, CH), 4.64 (d, 1H, J ¼ 8.5 Hz, H-3), 4.69 (d, 1H,
J ¼ 8.5 Hz, H-4), 6.97–7.35 (m, 19H, aromatic). 13C NMR (75 MHz,
CDCl3): dC 17.1, 21.1, 22.8, 48.2, 57.5, 59.3, 63.0, 76.8, 83.1, 116.8,
122.3, 126.8, 127.2, 127.5, 127.6, 128.0, 128.4, 128.5, 128.8, 129.6,
133.6, 136.8, 140.4, 142.7, 150.5, 157.9.
5.1.21. (3S,4S,5R)-4-(1-Naphthyl)-2,3-diphenyl-7-[(R)-1-
phenylethyl]-1-oxa-2,7-diazaspiro[4.5]decan-10-one (3j)
Viscous liquid; [
C37H34N2O2: C, 82.50; H, 6.36; N, 5.20; Found: C, 82.56; H, 6.43; N,
5.14. IR (CHCl3): 893, 1264, 1431, 1720, 2307, 2986 cmꢁ1 1H NMR
a
]
¼ þ29.0 (c 0.27, CHCl3); Anal. Calcd for
D
;
(300 MHz, CDCl3):dH 1.20 (d, 3H, J ¼ 6.6 Hz, CH3), 1.83 (d, 1H,
J ¼ 13.2 Hz, H-6ax), 2.29–2.38 (m, 1H, H-8eq), 2.43 (dt, J ¼ 12.6,
3.3 Hz, 1H, H-9eq), 2.84 (dd, 1H, J ¼ 13.2, 2.4 Hz, H-6eq), 3.02–3.10
(m, 1H, H-8ax), 3.40–3.48 (m, 1H, H-9ax), 3.51 (q, 1H, J ¼ 6.6 Hz, CH),
4.76 (d, 1H, J ¼ 7.2 Hz, H-4), 5.68 (d, 1H, J ¼ 7.2 Hz, H-3), 7.10–7.84
(m, 22H, aromatic). 13C NMR (75 MHz, CDCl3):dC 19.1, 38.4, 50.3,
52.0, 56.6, 62.2, 79.0, 87.0, 118.2, 123.3, 123.6, 124.9, 125.7, 125.9,
126.6, 126.9, 127.2, 127.5, 127.8, 128.1, 128.3, 128.5, 128.7, 129.5,
132.9, 133.3, 133.8, 139.7, 143.2, 149.2, 208.9.
Acknowledgements
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 under (i) IRHPA programme for the purchase of
a high resolution NMR spectrometer and (ii) FIST programme and
University Grants Commission, New Delhi for funds under the DRS
and ASSIST programmes. RSK thanks CSIR, New Delhi for Senior
Research Fellowship.
5.1.22. (3R,4R,5S)-3-(4-Methylphenyl)-4-(1-naphthyl)-2-phenyl-7-
[(R)-1-phenylethyl]-1-oxa-2,7-diazaspiro[4.5]decan-10-one (3k)
Appendix. Supplementary data
Viscous liquid; [
C38H36N2O2: C, 82.58; H, 6.57; N, 5.07; Found: C, 82.52; H, 6.52; N,
5.13. IR (CHCl3): 891, 1267, 1438, 1721, 2311, 2989 cmꢁ1 1H NMR
a]
¼ þ26.5 (c 0.25, CHCl3); Anal. Calcd for
D
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.ejmech.2009.09.034.
;
(300 MHz, CDCl3):dH 1.16 (d, 3H, J ¼ 6.6 Hz, CH3), 1.83 (d, 1H,
J ¼ 13.0 Hz, H-6ax), 2.25 (s, 1H, CH3), 2.29–2.45 (m, 2H, H-8eq and H-
9eq), 2.83 (dd, 1H, J ¼ 13.0, 2.7 Hz, H-6eq), 3.02–3.12 (m, 1H, H-8ax),
3.40–3.44 (m, 1H, H-9ax), 3.48 (q, 1H, J ¼ 6.6 Hz, CH), 4.73 (d, 1H,
J ¼ 7.4 Hz, H-4), 5.66 (d, 1H, J ¼ 7.4 Hz, H-3), 7.02–7.83 (m, 22H,
aromatic). 13C NMR (75 MHz, CDCl3):dC 19.1, 21.1, 38.4, 50.3, 52.0,
56.6, 62.2, 78.8, 86.9, 118.1, 123.5, 124.9, 125.6, 125.9, 126.5, 126.9,
127.0, 127.2, 127.3, 127.8, 128.1, 128.5, 129.0, 129.3, 129.4, 133.0,
133.4, 133.8, 137.4, 143.2, 149.2, 208.9.
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