Synthesis and antimalarial assessment of a new series of orally active amino-functionalized spiro 1,2,4-trioxanes (1)

Article abstract of DOI:10.1021/jm100678p

Keto-trioxanes 7a-d, easily accessible in two steps from allylic alcohols 5a-d, underwent reductive amination with substituted anilines to furnish amino-functionalized trioxanes 8a-i, 9a-i, 10a-i, and 11a-i. All these new trioxanes were assessed for their oral antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice. 2-Naphthalene-based trioxanes 9c and 9i, the most active compounds of the series, provided 100% protection to the malaria-infected mice at 24 mg/kg × 4 days, while the related trioxane 9b and phenanthrene-based trioxane 11e provided a similar level of protection at 48 mg/kg × 4 days. All other trioxanes, except 10c, 10d, and 10g, provided 100% protection at 96 mg/kg × 4 days. In this model, β-arteether provided 100% protection at 48 mg/kg × 4 days and 20% protection at 24 mg/kg × 4 days.

Full text of DOI:10.1021/jm100678p

J. Med. Chem. 2010, 53, 7587–7598 7587
DOI: 10.1021/jm100678p
Synthesis and Antimalarial Assessment of a New Series of Orally Active Amino-Functionalized Spiro
1,2,4-Trioxanes1
Chandan Singh,*,† Mohammad Hassam,† Niraj Krishna Naikade,† Ved Prakash Verma,† Ajit Shankar Singh,† and
Sunil. K. Puri‡
†Division of Medicinal & Process Chemistry and ‡Division of Parasitology, Central Drug Research Institute, Lucknow-226001, India
Received June 4, 2010
Keto-trioxanes 7a-d, easily accessible in two steps from allylic alcohols 5a-d, underwent reductive
amination with substituted anilines to furnish amino-functionalized trioxanes 8a-i, 9a-i, 10a-i, and
11a-i. All these new trioxanes were assessed for their oral antimalarial activity against multidrug-
resistant Plasmodium yoelii nigeriensis in Swiss mice. 2-Naphthalene-based trioxanes 9c and 9i, the most
active compounds of the series, provided 100% protection to the malaria-infected mice at 24 mg/kg ꢀ
4 days, while the related trioxane 9b and phenanthrene-based trioxane 11e provided a similar level of
protection at 48 mg/kg ꢀ 4 days. All other trioxanes, except 10c, 10d, and 10g, provided 100%
protection at 96 mg/kg ꢀ 4 days. In this model, β-arteether provided 100% protection at 48 mg/kg ꢀ
4 days and 20% protection at 24 mg/kg ꢀ 4 days.
Introduction
Malaria affects around 300-500 million people in the
tropical and subtropical areas of the world, with an annual
death toll of around two million.1,2 The malaria situation is
getting worse with the rapid spread of multidrug-resistant
Plasmodium falciparum. Against this background, isolation
of artemisinin 1 as the active principle of the Chinese tradi-
tional drug against malaria, Artemisia annua, was a major
Figure 1. Artemisinin and its derivatives.
breakthrough in malaria chemotherapy.3 Artemisinin owes its
antimalarial activity to the presence of 1,2,4-trioxane sys-
tem and is active against both chloroquinine-sensitive and
chloroquinine-resistant malaria. Artemisinin derivatives, e.g.
artemether2 andarteether 3 (Figure 1), are currently the drugs
of choice for the treatment of malaria caused by multidrug-
resistant P. falciparum.4
Figure 2. Amino-functionalized trioxanes 4a and 4b.
As a part of our endeavor to develop synthetic substitutes
for artemisinin derivatives, we have earlier reported a photo-
oxygenation route for the synthesis of 1,2,4-trioxanes. Prep-
aration of β-hydroxyhydroperoxides by photooxygena-
tion of allylic alcohols and their acid-catalyzed reaction
with aldehydes/ketones are the key steps of this method
(Scheme 1).5 Several of the 1,2,4-trioxanes prepared by this
method had shown significant antimalarial activity in vivo.6,7
We had also extended the methodology for the preparation
of a series of amino-functionalized 1,2,4-trioxanes, i.e. 4a
and 4b (Figure 2), which exhibited moderate level of oral
antimalarial activity against multidrug-resistant P. yoelii
nigeriensis.8 In another series of adamantane-based trioxanes,
we have also observed that the substitution of phenyl ring in
the aryl-vinyl moiety with naphthyl, phenanthren-3-yl, and
fluoren-2-yl leads to major improvement in oral antimalarial
activity.9 On the basis of these observations, we have synthe-
sized and screened a new series of amino-functionalized
Scheme 1
trioxanes 8a-i, 9a-i, 10a-i, and 11a-i, several of which
showed superior oral antimalarial activity profile than that of
β-arteether. A graphical representation of the evolution of our
workon trioxanes resulting in the currentseries ofmolecules is
shown in Figure 3. In this communication, we describe the
details of this study.
Chemistry
Allylic alcohols 5a-d were prepared and photooxyge-
nated using our published procedure9,10 to give β-hydro-
xyhydroperoxides 6a-d, which were condensed in situ with
1,4-cyclohexanedione to furnish keto-trioxanes 7a-d in
*To whom correspondence should be addressed. Phone: þ91 0522
2624273. Fax: þ91 0522 2623405. E-mail: chandancdri@yahoo.com.
r
2010 American Chemical Society
Published on Web 10/11/2010
pubs.acs.org/jmc

7588 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 21
Singh et al.
Figure 3. Graphical depiction of the evolution of our work on trioxanes leading to the current series of amino-trioxanes.
Table 1. Yields of Amino-Functionalized Trioxanes
Most of these diastereomers could not be separated by
chromatography, and activity data was measured on mixture
of diastereomers. The amino-trioxane 9i was separated into
pure diastereomers 9im (more polar) and 9il (less polar),
which were separately evaluated for their antimalarial
activity. Also, trioxanes 8g, 9g, 10g, 10i, 11g, and 11i were
separated into pure diastereomers. However, the pure isomers
in these cases were obtained in very small amounts, and hence
the antimalarial activity was measured on the mixture of
diastereomers.
compd
Ar
R
yield (%)
8a
8b
1-naphthyl
1-naphthyl
phenyl
4-fluorophenyl
4-chlorophenyl
87
78
58
54
64
55
61
48
81
87
66
46
46
62
47
55
60
68
54
66
58
65
72
59
64
65
58
67
82
63
78
74
65
54
72
56
8c
8d
1-naphthyl
1-naphthyl
3,5-dichlorophenyl
4-methylphenyl
4-methoxyphenyl
2-biphenyl
8e
1-naphthyl
1-naphthyl
8f
8g
1-naphthyl
1-naphthyl
8h
3-trifluoromethyl phenyl
4-trifluoromethyl phenyl
phenyl
8i
9a
1-naphthyl
2-naphthyl
Antimalarial Activity
9b
9c
2-naphthyl
2-naphthyl
4-fluorophenyl
4-chlorophenyl
Amino-functionalized trioxanes 8a-i, 9a-i, 10a-i, and
11a-i were initially screened for oral antimalarial activity
against multidrug-resistant P. yoelii nigeriensis in Swiss mice
at a dose of 96 mg/kg ꢀ 4 days using Peter’s procedure.11
Trioxanes which showed 100% protection at 96 mg/kg ꢀ
4 days were further screened at lower doses.12 In this model,
β-arteetherprovided100%and 20%protectionat48mg/kgꢀ
4 days and 24 mg/kg ꢀ 4 days, respectively, by oral route. The
results are summarized in Table 2.
9d
9e
2-naphthyl
2-naphthyl
3,5-dichlorophenyl
4-methylphenyl
4-methoxyphenyl
2-biphenyl
9f
9g
2-naphthyl
2-naphthyl
9h
9i
2-naphthyl
2-naphthyl
3-trifluoromethyl phenyl
4-trifluoromethyl phenyl
phenyl
10a
10b
10c
10d
10e
10f
10g
10h
10i
11a
11b
11c
11d
11e
11f
11g
11h
11i
2-fluorenyl
2-fluorenyl
4-fluorophenyl
4-chlorophenyl
2-fluorenyl
2-fluorenyl
3,5-dichlorophenyl
4-methylphenyl
4-methoxyphenyl
2-biphenyl
2-fluorenyl
2-fluorenyl
Results and Discussion
In our efforts to develop synthetic substitutes for artemisi-
nin derivatives, we had earlier reported a series of phenyl-vinyl
substituted amino-trioxanes, i.e. 4a and 4b.8 These trioxanes
had shown only moderate order of oral antimalarial activity.
In another series of adamantane-based 1,2,4-trioxanes, we
had observed that the replacement of the phenyl group of the
aryl-vinyl moiety with naphthyl, phenanthrenyl, and fluor-
enyl had a major improvement on oral antimalarial activity.9
On the basis of this experience, we first prepared 1- and
2-naphthalene-based trioxanes 8a-i and 9a-i and evaluated
their oral antimalarial activity against multidrug-resistant
P. yoelii nigeriensis in Swiss mice at dose ranging from 24 mg/
kgꢀ 4 days to 96mg/kgꢀ 4 days. Ascan beseen fromTable 2,
all these trioxanes showed 100% protection to the malaria-
infected mice at 96 mg/kg ꢀ 4 days. None of the 1-naphthalene-
based trioxanes showed 100% protection at 48 mg/kg ꢀ
4 days. On the other hand, several of the 2-naphthalene-
based trioxanes showed a better activity profile than that of
β-arteether. Trioxanes 9c and 9i (both the isomers 9im and
2-fluorenyl
2-fluorenyl
2-fluorenyl
3-trifluoromethyl phenyl
4-trifluoromethyl phenyl
phenyl
3-phenanthrenyl
3-phenanthrenyl
3-phenanthrenyl
3-phenanthrenyl
3-phenanthrenyl
3-phenanthrenyl
3-phenanthrenyl
3-phenanthrenyl
3-phenanthrenyl
4-fluorophenyl
4-chlorophenyl
3,5-dichlorophenyl
4-methylphenyl
4-methoxyphenyl
2-biphenyl
3-trifluoromethyl phenyl
4-trifluoromethyl phenyl
48-68% yields. Reductive amination of 7a-d with substi-
tuted anilines using NaBH(OAc)3 furnished the amino-
functionalized trioxanes 8a-i, 9a-i, 10a-i, and 11a-i as
mixture of diastereomers in 46-87% yields (Table 1). All
the reductive amination reactions also furnished the corre-
sponding hydroxy-functionalized trioxanes 12a-d as mixture
of diastereomers in 10-14% yields (Scheme 2).

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 21 7589
Scheme 2a
a Reagents and conditions: (a) hν, O2, methylene blue, CH3CN, -10 to 0 °C, 4-6 h; (b) 1,4-cyclohexadione, p-TSA, CH3CN, rt, 6-8 h; (c) RNH2,
NaBH(OAc)3 C6H6, 0 °C, 1 h.
9il), the most active compounds of the series, provided 100%
protection at 24 mg/kg ꢀ 4 days. Because both the diastereo-
mers of 9i (9im and 9il) are equipotent, it appears that the
stereochemical outcome of reductive amination may not be
important for antimalarial activity.14
Trioxane 9b provided 100% protection at 48 mg/kg ꢀ
4 days and 80% protection at 24 mg/kg ꢀ 4 days. Thus,
trioxanes 9b, 9c, and 9i were more active than β-arteether. Log
p values of these highly active trioxanes lie in the range of
5.75-6.51.
Perkin-Elmer FT-IR RXI spectrophotometer. 1H NMR and
13C NMR spectra were recorded on a Bruker DPX-200
(operating at 200 MHz for 1H and at 50 MHz for 13C)
1
or DRX-300 (operating at 300 MHz for H and at 75 MHz
for 13C) spectrometers using CDCl3 as solvent. Tetramethylsi-
lane (0.00 ppm) served as an internal standard in 1H NMR and
CDCl3 (77.0 ppm) in 13C NMR. Chemical shifts are reported in
part per million. Splitting patterns are described as singlet (s),
doublet (d), triplet (t), and multiplet (m). Fast atom bombard-
ment mass spectra (FAB-MS) were obtained on JEOL SX 102
spectrometer using argon/xenon (6 kV, 10 mA) as the FAB gas.
Glycerol or m-nitrobenzyl alcohol was used as matrix. Reac-
tions were monitored on silica gel TLC plates (coated with TLC
grade silica gel, obtained from Merck). Detecting agents used
(for TLC) were: iodine vapors and/or spraying with an aq
solution of vanillin in 10% sulfuric acid followed by heating at
150 °C. Column chromatography was performed over silica gel
(60-120 Mesh) procured from Qualigens (India) and flash silica
gel (230-400 Mesh) procured from Spectrochem (India). All
chemicals and reagents were obtained from Aldrich (USA),
Lancaster (England), or Spectrochem (India) and were used
without further purification. Log p values of the compounds
were calculated using ChemDraw Ultra 7.0 software.
Encouraged by these results, we prepared 2-fluorene and
3-phenanthrene-based trioxanes 10a-i and 11a-i and eval-
uated them for oral antimalarial activity. These trioxanes,
however, were found to be less active than 2-naphthalene-
based trioxanes. None of the fluorene-based trioxanes showed
100% protection at 48 mg/kg ꢀ 4 days. Phenanthrene-based
trioxane 11e provided 100% protection at 48 mg/kg ꢀ 4 days;
related trioxane 11a showed 80% protection at this dose. The
remainder of the trioxanes, with the exception of 10c, 10d, and
10g, showed 100% protection at 96 mg/kg ꢀ 4 days and
partial protection at 48 mg/kg ꢀ 4 days.
Elemental analyses of all the new compounds were recorded
on Vario EL-III C H N S analyzer (Germany), and values were
within 0.5% of the calculated values for all compounds except
8b, 8i, and 8g, and therefore these compounds meet the criteria
of g95% purity. Compounds 8b, 8i, and 9g did not furnish
acceptable elemental analysis. These compounds, however, were
TLC homogeneous and furnished acceptable 1H NMR, 13C
NMR, and HRMS data.
Thus, looking across the series, 2-naphthalene-based triox-
anes were found to be more promising than 1-naphthalene and
3-phenanthrene-based compounds, fluorene-based trioxanes
being the least promising. 2-Naphthalene-based trioxanes 9c
and 9i, the most active compounds of the series, have been
identified for further studies in simian malaria.
Conclusion
General Procedure for Preparation of Keto-trioxanes: Prep-
aration of Trioxane 7a. A slow stream of oxygen was bubbled
into a solution of 5a (1 g, 5.05 mmol) and methylene blue (10 mg)
in CH3CN (50 mL) in a 100 mL double-jacketed round-bottom
flask, maintained below 0 °C by circulating cold ethanol. The
reaction mixture was irradiated with visible light by means of a
tungsten-halogen lamp (500 W). Reaction was complete in 4 h as
observed on TLC. β-Hydroxyhydroperoxide 6a formed in the
reaction was not isolated and reacted in situ with 1,4-cyclohex-
anedione (1.13 g, 10.08 mmol) in the presence of p-TSA (100 mg,
0.58 mmol) for 6 h at rt. Saturated aq NaHCO3 (30 mL) was
added. The aqueous layer was extracted with diethyl ether (2 ꢀ
100 mL), and the combined organic layer was dried over anhyd
Na2SO4 and concentrated under vacuum at rt. The crude
product was purified by column chromatography over silica
gel using EtOAc/hexane (5:95) as eluent to furnish keto-trioxane
7a (0.84 g, 52% yield, based on allylic alcohol 5a as starting
material).
Using keto-trioxanes 7a-d, readily accessible from allylic
alcohols 5a-d in two steps, we have prepared a new series of
amino-functionalized trioxanes 8a-i, 9a-i, 10a-i, and 11a-i
ingoodyields. Severalofthese noveltrioxanes showed activity
profiles comparable with or better than that of β-arteether by
oral route. Trioxanes 9c and 9i, the two most active com-
pounds of the series, are twice as active asβ-arteether. Because
both the diastereomers of 9i (9im and 9il) are equipotent, it
appears that the stereochemical outcome of reductive amina-
tion is not important for antimalarial activity.14
Experimental Section
General. All glass apparatus were oven-dried prior to use.
Melting points were determined on COMPLAB melting point
apparatus and are uncorrected. IR spectra were recorded on a

7590 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 21
Singh et al.
Table 2. In Vivo Oral Antimalarial Activity of Compounds 8a-i, 9a-i, 10a-i, and 11a-i against Multidrug-Resistant P. yoelii nigeriensis in Swiss Mice
a Percent suppression = [(C - T)/C] ꢀ 100; where C = parasitaemia in control group, and T = parasitaemia in treated group. b 100% suppression of
parasitaemia means, number of parasites if present, are below the detection limit.12 (**) Mice that did not develop patent infection until day 28 were
recorded as cured.

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 21 7591
Trioxane 7a. Yield 52%, white solid; mp 82-83 °C. IR (KBr,
furnish amino-functionlized 1,2,4-trioxane 8a as an inseparable
mixture of diastereomers (0.54 g, 87% yield).
1
cm-1) 1598, 1717. H NMR (300 MHz, CDCl3) δ 2.01 (t, 2H,
J = 7.1 Hz), 2.36-2.52 (m, 6H), 3.79 (dd, 1H, J = 11.6 and 2.8
Hz), 3.96 (dd, 1H, J = 11.66 and 10.2 Hz), 5.23 (dd, 1H, J =
10.2 and 2.8 Hz), 5.46 (s, 1H), 5.75 (s, 1H), 7.28-7.31 (m, 1H,
Ar), 7.43-7.55 (m, 3H, Ar), 7.83-7.90 (m, 2H, Ar), 8.00-8.03
(m, 1H, Ar). 13C NMR (75 MHz, CDCl3) δ 27.49 (CH2), 33.20
(CH2), 36.50 (CH2), 36.68 (CH2), 63.25 (CH2), 81.80 (CH),
101.12 (C), 120.23 (CH2), 125.28 (CH), 125.33 (CH), 126.09
(CH), 126.20 (CH), 126.62 (CH), 128.60 (2 ꢀ CH), 131.44 (C),
133.83 (C), 137.02 (C), 143.05 (C), 209.82 (C). FAB-MS (m/z)
324 [M]þ; Anal. Calcd for C20H20O4: C 74.06%, H 6.21%.
Found: C 74.47%, H 6.66%.
Trioxane 8a. Yield 87%, oil; IR (neat, cm-1) 1598, 3423. 1H
NMR (300 MHz, CDCl3) δ 1.38-2.03 (m, 8H), 2.55-2.60 (bm,
1H), 3.37-3.43 (m, 1H), 3.68 (dd, 1H, J = 11.6 and 2.8 Hz), 3.88
(dd, 1H, J = 11.6 and 10.3 Hz), 5.13 (dd, 1H, J = 10.3 and 2.8
Hz), 5.40 (s, 1H), 5.70 (s, 1H), 6.57 (d, 2H, J = 7.7 Hz, Ar), 6.67
(t, 1H, J = 7.3 Hz, Ar), 7.14 (t, 2H, J = 8.5 Hz, Ar), 7.24-7.27
(m, 1H, Ar), 7.35-7.51 (m, 3H, Ar), 7.79-7.86 (m, 2H, Ar),
7.96-7.99 (m, 1H, Ar). 13C NMR (75 MHz, CDCl3) δ 26.80
(CH2), 28.26 (CH2), 28.53 (CH2), 34.34 (CH2), 50.67 (CH),
62.83 (CH2), 81.87 (CH), 102.10 (C), 113.55 (2 ꢀ CH), 117.59
(CH), 120.03 (CH2), 125.38 (CH), 125.57 (CH), 126.17 (CH),
126.26 (CH), 126.66 (CH), 128.64 (2 ꢀ CH), 129.58 (2 ꢀ CH),
131.59 (C), 133.93 (C), 137.36 (C), 143.45 (C), 147.32 (C). FAB-
MS (m/z) 401 [M]þ. HRMS calcd for C26H27NO3, 401.1991;
found, 401.1995; Anal. Calcd for C26H27NO3: C, 77.78%, H,
6.78%, N, 3.49%. Found: C, 77.42%, H, 6.94%, N, 3.38.
Amino-trioxanes 8b-i, 9a-i, 10a-i, and 11a-i were pre-
pared by the above procedure.
Keto-trioxanes 7b-d were prepared from allylic alcohols
5b-d, respectively, by the above procedure.
Trioxane 7b. Yield 54%, white solid; mp 80-81 °C. IR (KBr,
1
cm-1) 1596, 1720. H NMR (300 MHz, CDCl3) δ 2.09 (t, 2H,
J = 7.1 Hz), 2.35-2.70 (m, 6H), 3.89-4.09 (m, 2H), 5.45-5.52
(m, 2H), 5.68 (s, 1H), 7.48-7.56 (m, 3H, Ar), 7.82-7.86 (m, 4H,
Ar). 13C NMR (75 MHz, CDCl3) δ 27.60 (CH2), 33.40 (CH2),
36.62 (CH2), 36.78 (CH2), 63.64 (CH2), 80.63 (CH), 101.35 (C),
117.31 (CH2), 124.54 (CH), 125.56 (CH), 126.63 (CH), 126.72
(CH), 127.81 (CH), 128.41 (CH), 128.58 (CH), 133.26 (C),
133.44 (C), 135.83 (C), 143.24 (C), 209.92 (C). FAB-MS (m/z)
324 [M]þ. Anal. Calcd for C20H20O4: C 74.06%, H 6.21%.
Found: C 74.01%, H 6.54%.
Trioxane 8b. Yield 78%, oil. IR (neat, cm-1) 1587, 3432. 1H
NMR (300 MHz, CDCl3) δ 1.21-1.96 (m, 8H), 2.54-2.58 and
2.73-2.78 (2 ꢀ bm, together integrating for 1H), 3.23-3.34 (m,
1H), 3.67 (dd, 1H, J = 11.8 and 2.7 Hz), 3.86 and 3.93 (2 ꢀ dd,
J = 11.8 and 10.3 Hz respectively, together integrating for 1H,),
5.11 (dd, 1H, J = 10.3 and 2.7 Hz), 5.38 (s, 1H), 5.68 (s, 1H),
6.47-6.52 (m, 2H, Ar), 6.82-6.87 (m, 2H, Ar), 7.22-7.26 (m,
1H, Ar), 7.38-7.51 (m, 3H, Ar), 7.78-7.85 (m, 2H, Ar),
7.94-7.98 (m, 1H, Ar). 13C NMR (75 MHz, CDCl3) δ 26.70
(CH2), 27.25 (CH2), 28.10 (CH2), 28.37 (CH2), 28.63 (CH2),
28.74 (CH2), 32.22 (CH2), 33.12 (CH2), 51.26 (CH), 51.57 (CH),
62.69 (CH2), 63.04 (CH2), 81.78 (CH), 101.92 (C), 114.37 (CH),
114.47 (CH), 115.71 (CH), 116.01 (CH), 120.00 (CH2), 120.04
(CH2), 125.30 (CH), 125.45 (CH), 126.08 (CH), 126.18 (CH),
126.58 (CH), 128.53 (CH), 128.57 (CH), 131.47 (C), 133.82 (C),
137.26 (C), 143.34 (C), 143.63 (C), 155.85 (C, JC-F = 234.9 Hz).
FAB-MS (m/z) 419 [M]þ. HRMS calcd for C26H26FNO3,
419.1897; found, 419.1888.
Trioxane 8c. Yield 58%, white solid; mp 55-56 °C. IR (KBr,
cm-1) 1598, 3406. 1H NMR (300 MHz, CDCl3) δ 1.34-1.99 (m,
8H), 2.55-2.59 and 2.75-2.79 (2 ꢀ bm, together integrating for
1H), 3.26-3.33 (m, 1H), 3.67 (dd, 1H, J = 11.5 and 2.6 Hz), 3.87
and 3.94 (2 ꢀ dd, J = 11.5 and 10.4 Hz, respectively, together
integrating for 1H,), 5.10-5.14 (m, 1H), 5.40 (s, 1H), 5.69 (s,
1H), 6.47 (d, 2H, J = 8.3 Hz, Ar), 7.07 (d, 2H, J = 8.3 Hz, Ar),
7.22-7.25 (m, 1H, Ar), 7.38-7.50 (m, 3H, Ar), 7.78-7.85 (m,
2H, Ar), 7.95-7.98 (m, 1H, Ar). 13C NMR (75 MHz, CDCl3) δ
26.71 (CH2), 27.28 (CH2), 28.05 (CH2), 28.32 (CH2), 28.59
(CH2), 28.71 (CH2), 32.25 (CH2), 33.16 (CH2), 50.73 (CH),
51.06 (CH), 62.79 (CH2), 63.14 (CH2), 81.83 (CH), 101.88 (C),
114.51 (2 ꢀ CH), 120.13 (CH2), 121.92 (C), 125.36 (CH), 125.50
(CH), 126.14 (CH), 126.24 (CH), 126.64 (CH), 128.61 (2 ꢀ CH),
129.34 (2 ꢀ CH), 131.52 (C), 133.88 (C), 137.29 (C), 143.38 (C),
145.89 (C). FAB-MS (m/z) 435 [M]þ. HRMS calcd for
C26H26ClNO3, 435.1601; found, 435.1601. Anal. Calcd for
C26H26ClNO3: C, 71.63%, H, 6.01%, N, 3.21%. Found: C,
71.48%, H, 6.07%, N, 3.04.
Trioxane 7c. Yield 48%, white solid; mp 87-88 °C. IR (KBr,
1
cm-1) 1598, 1717. H NMR (300 MHz, CDCl3) δ 2.06 (t, 2H,
J = 7.1 Hz), 2.35-2.67 (m, 6H), 3.88 (s, 2H), 3.90 (dd, 1H, J =
11.6 and 2.8 Hz), 3.99 (dd, 1H, J = 11.9 and 10.2 Hz), 5.35 (s,
1H), 5.39 (dd, 1H, J = 10.2 and 2.9 Hz), 5.58 (s, 1H), 7.28-7.41
(m, 3H, Ar), 7.52-7.56 (m, 2H, Ar), 7.75 (t, 2H, J = 8.2 Hz, Ar).
13C NMR (75 MHz, CDCl3) δ 27.54 (CH2), 33.38 (CH2), 36.60
(CH2), 36.77 (CH2), 37.07 (CH2), 63.60 (CH2), 80.69 (CH),
101.27 (C), 116.40 (CH2), 120.11 (CH), 120.23 (CH), 123.17
(CH), 125.25 (CH), 125.35 (CH), 127.05 (CH), 127.21 (CH),
137.05 (C), 141.20 (C), 142.13 (C), 143.47 (C), 143.61
(C), 143.84 (C), 209.99 (C). FAB-MS (m/z) 362 [M]þ. Anal.
Calcd for C23H22O4: C 76.22%, H 6.12%. Found: C 76.13%,
H 6.56%.
Trioxane 7d. Yield 68%, white solid; mp 92-93 °C. IR (KBr,
1
cm-1) 1633, 1714. H NMR (300 MHz, CDCl3) δ 2.09 (t, 2H,
J = 7.1 Hz), 2.38-2.54 (m, 6H), 3.93 (dd, 1H, J = 11.9 and 2.9
Hz), 4.04 (dd, 1H, J = 11.9 and 10.2 Hz), 5.50-5.55 (m, 2H),
5.71 (s, 1H), 7.61-7.74 (m, 5H, Ar), 7.86-7.91 (m, 2H, Ar),
8.63-8.71 (m, 2H, Ar). 13C NMR (75 MHz, CDCl3) δ 27.64
(CH2), 33.42 (CH2), 36.66 (CH2), 36.81 (CH2), 63.58 (CH2),
81.04 (CH), 101.36 (C), 117.92 (CH2), 120.78 (CH), 122.76
(CH), 125.18 (CH), 126.58 (CH), 126.99 (CH), 127.12 (CH),
127.76 (CH), 128.95 (CH), 129.14 (CH), 130.34 (C), 130.43 (C),
132.02 (C), 132.46 (C), 136.71 (C) 143.73 (C), 210.00 (C). FAB-
MS (m/z) 374 [M]þ. Anal. Calcd for C24H22O4: C 76.99%, H
5.92%. Found: C 76.53%, H 5.98%.
General Procedure for Reductive Amination of Keto-1,2,4-
trioxanes. Preparation of 8a. To a stirred slurry of sodium
borohydride (0.057 g, 1.5 mmol) in benzene (15 mL) at 0 °C
was added acetic acid (0.88 mL, 15.38 mmol) dropwise over
10 min. The contents were stirred for 3 h at rt to generate sodium
triacetoxyborohydride. The contents were further cooled to
0 °C. Imine generated by the acid-catalyzed (acetic acid) reac-
tion of aniline (0.35 mL, 3.86 mmol) with the keto-trioxane 7a
(0.50 g, 1.54 mmol) in benzene (5 mL) was added dropwise over
20 min to the flask containing sodium triacetoxyborohydride,
and the reaction mixture was stirred at 0 °C for 1 h. Water
(10 mL) was added to the reaction mixtrure. The aqueous layer
was extracted with dichloromethane (2 ꢀ 25 mL). The combined
organic layer was washed with saturated NaHCO3 (2 ꢀ 25 mL),
dried over anhydrous Na2SO4, and concentrated under vacuum
at rt. The crude compound was purified by column chromatog-
raphy over silica gel using EtOAc/hexane (4:96) as eluent to
Trioxane 8d. Yield 54%, white solid; mp 63-65 °C. IR (KBr,
cm-1) 1590, 3401. 1H NMR (300 MHz, CDCl3) δ 1.35-1.94 (m,
8H), 2.55-2.60 and 2.76-2.80 (2 ꢀ bm, together integrating for
1H), 3.28-3.31 (m, 1H), 3.69 (dd, 1H, J = 11.6 and 2.3 Hz), 3.87
and 3.95 (2 ꢀ dd, J = 11.6 and 10.4 Hz respectively, together
integrating for 1H), 5.11-5.15 (m 1H), 5.41 (s, 1H), 5.70 (s, 1H),
6.40 (s, 2H, Ar), 6.62 (s, 1H, Ar), 7.23-7.26 (m, 1H, Ar), 7.41 (t,
1H, J = 7.5 Hz, Ar), 7.48-7.51 (m, 2H, Ar), 7.79-7.87 (m, 2H,
Ar), 7.95-7.98 (m 1H, Ar). 13C NMR (75 MHz, CDCl3) δ 26.68
(CH2), 27.24 (CH2), 27.94 (CH2), 28.24 (CH2), 28.48 (CH2),
28.61 (CH2), 32.19 (CH2), 33.09 (CH2), 50.45 (CH), 50.75 (CH),
62.80 (CH2), 63.14 (CH2), 81.86 (CH), 101.72 (C), 111.32 (2 ꢀ
CH), 116.98 (CH), 120.20 (CH2), 125.37 (CH), 125.49 (CH),

7592 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 21
Singh et al.
126.16 (CH), 126.26 (CH), 126.66 (CH), 128.63 (2 ꢀ CH),
131.52 (C), 133.89 (C), 135.74 (2 ꢀ C), 137.27 (C), 143.35 (C),
148.96 (C). ESI-MS (m/z) 470 [M þ H]þ. HRMS calcd for
C26H25Cl2NO3, 469.1211; found, 469.1214. Anal. Calcd for
C26H25Cl2NO3: C, 66.39%, H, 5.36%, N, 2.98%. Found: C,
66.22%, H, 5.66%, N, 3.16.
(m, 8H, Ar), 7.78-7.85 (m, 2H, Ar), 7.94-7.96 (m, 1H, Ar).
13C NMR (75 MHz, CDCl3) δ 27.20 (CH2), 28.53 (CH2), 28.69
(CH2), 33.07 (CH2), 50.72 (CH), 63.12 (CH2), 81.82 (CH),
101.99 (C), 111.26 (CH), 117.04 (CH), 120.13 (CH2), 125.36
(CH), 125.49 (CH), 126.12 (CH), 126.23 (CH), 126.65 (CH),
127.50 (CH), 128.18 (C), 128.59 (CH), 128.61 (CH), 128.86
(CH), 129.20 (2 ꢀ CH), 129.50 (2 ꢀ CH), 130.70 (CH), 131.51
(C), 133.87 (C), 137.31 (C), 139.56 (C), 143.40 (C), 144.09 (C).
FAB-MS (m/z) 477 [M]þ. HRMS calcd for C32H31NO3,
477.2309; found, 477.2303; Anal. Calcd for C32H31NO3: C,
80.47%, H, 6.54%, N, 2.93%. Found: C, 80.46%, H, 6.92%,
N, 2.80.
Trioxane 8e. Yield 64%, white solid; mp 49-50 °C. IR (KBr,
1
cm-1) 1590, 3401. H NMR (300 MHz, CDCl3) δ 1.35-1.98
(m, 8H), 2.22 (s, 3H), 2.55-2.59 and 2.75-2.79 (2 ꢀ bm,
together integrating for 1H), 3.29-3.36 (m, 1H), 3.67 (dd, 1H,
J = 11.7 and 2.3 Hz), 3.88 and 3.94 (2 ꢀ dd, J = 11.5 and 10.4
Hz, respectively, together integrating for 1H), 5.10-5.13 (m,
1H), 5.40 (s, 1H), 5.69 (s, 1H), 6.50 (d, 2H, J = 8.1 Hz, Ar),
6.96 (d, 2H, J = 8.1 Hz, Ar), 7.21-7.26 (m, 1H, Ar), 7.40 (t, 1H,
J = 7.4 Hz, Ar), 7.47-7.50 (m, 2H, Ar), 7.78-7.85 (m, 2H, Ar),
7.95-7.98 (m, 1H, Ar). 13C NMR (75 MHz, CDCl3) δ 20.59
(CH3), 26.75 (CH2), 27.33 (CH2), 28.23 (CH2), 28.51 (CH2),
28.77 (CH2), 28.89 (CH2), 32.31 (CH2), 33.23 (CH2), 50.91
(CH), 51.25 (CH), 62.79 (CH2), 63.14 (CH2), 81.82 (CH),
102.05 (C), 113.81 (2 ꢀ CH), 120.09 (CH2), 125.35 (CH),
125.52 (CH), 126.13 (CH), 126.22 (CH), 126.63 (CH), 126.75
(C), 128.58 (CH), 130.02 (2 ꢀ CH), 131.52 (C), 133.87 (C),
137.33 (C), 143.42 (C), 145.05 (C). ESI-MS (m/z) 416 [M þ H]þ.
HRMS calcd for C27H29NO3, 415.2147; found, 415.2148. Anal.
Calcd for C27H29NO3: C, 78.04%, H, 7.03%, N, 3.37%. Found:
C, 78.19%, H, 6.54%, N, 3.27%.
Trioxane 8h. Yield 48%, oil. IR (neat, cm-1) 1587, 3432. 1H
NMR (300 MHz, CDCl3) δ 1.37-2.01 (m, 8H), 2.56-2.61 and
2.77-2.81 (2 ꢀ bm, together integrating for 1H), 3.38-3.41 (m,
1H), 3.68 (dd, 1H, J = 11.7 and 2.5 Hz), 3.87 and 3.95 (2 ꢀ dd,
J = 11.7 and 10.3 Hz, respectively, together integrating for 1H),
5.11-5.15 (m, 1H), 5.40 (s, 1H), 5.70 (s, 1H), 6.68 (d, 1H, J = 7.8
Hz, Ar), 6.75 (s, 1H, Ar), 6.88 (d, 1H, J = 7.8 Hz, Ar), 7.18-7.26
(m, 2H, Ar), 7.41 (t, 1H, J = 7.7 Hz, Ar), 7.48-7.51 (m, 2H, Ar),
7.79-7.86 (m, 2H, Ar), 7.96-7.98 (m, 1H, Ar). 13C NMR (75
MHz, CDCl3) δ 26.71 (CH2), 27.28 (CH2), 28.04 (CH2), 28.32
(CH2), 28.58 (CH2), 28.70 (CH2), 32.23 (CH2), 33.12 (CH2)
50.45 (CH), 50.76 (CH), 62.82 (CH2), 63.16 (CH2), 81.89 (CH),
101.85 (C), 109.42 (CH), 113.78 (CH), 116.32 (CH), 120.15
(CH2), 125.38 (CH), 125.53 (CH), 126.17 (CH), 126.26 (CH),
126.66 (CH), 128.62 (2 ꢀ CH), 129.94 (CH), 131.56 (C), 131.88
(C, JC-F = 31.7 Hz), 133.93 (2 ꢀ C), 137.33 (C), 143.43 (C),
147.55 (C). ESI-MS (m/z) 470 [M þ H]þ. HRMS calcd for
C27H26F3NO3, 469.1865; found, 469.1871. Anal. Calcd for
C27H26F3NO3: C, 69.07%, H, 5.58%, N, 2.98%. Found: C,
69.41%, H, 5.78%, N, 2.73.
Trioxane 8f. Yield 55%, white solid; mp 50-51 °C. IR (KBr,
cm-1) 1510, 3431. 1H NMR (300 MHz, CDCl3) δ 1.33-1.97 (m,
8H), 2.56-2.60 and 2.75-2.79 (2 ꢀ bm, together integrating for
1H), 3.24-3.30 (m, 1H), 3.65-3.72 (m, 4H), 3.88 and 3.95 (2 ꢀ
dd, J = 11.5 and 10.4 Hz respectively, together integrating for
1H,), 5.11-5.14 (m, 1H), 5.39 (s, 1H), 5.69 (s, 1H), 6.55 (d, 2H,
J = 8.5 Hz, Ar), 6.75 (d, 2H, J = 8.5 Hz, Ar), 7.22-7.26 (m, 1H,
Ar), 7.40 (t, 1H, J = 7.6 Hz, Ar), 7.45-7.52 (m, 2H, Ar), 7.78-
7.85 (m, 2H, Ar), 7.96-7.98 (m, 1H, Ar). 13C NMR (75 MHz,
CDCl3) δ 26.76 (CH2), 27.33 (CH2), 28.30 (CH2), 28.58
(CH2), 28.85 (CH2), 28.96 (CH2), 32.32 (CH2), 33.24 (CH2),
51.71 (CH), 52.05 (CH), 55.98 (CH3), 62.76 (CH2), 63.13 (CH2),
81.81 (CH), 102.06 (C), 115.16 (2 ꢀ CH), 115.25 (2 ꢀ CH),
120.08 (CH2), 125.34 (CH), 125.51 (CH), 126.12 (CH), 126.21
(CH), 126.62 (CH), 128.57 (2 ꢀ CH), 131.51 (C), 133.86 (C),
137.32 (C), 141.48 (C), 143.41 (C), 152.36 (C). ESI-MS (m/z) 432
[M þ H]þ. HRMS calcd for C27H29NO4, 431.2097; found,
431.2127; Anal. Calcd for C27H29NO4: C, 75.15%, H, 6.77%,
N, 3.25%. Found: C, 75.62%, H, 7.02%, N, 3.70.
Trioxane 8i. Yield 81%, oil. IR (neat, cm-1) 1591, 3413. 1H
NMR (300 MHz, CDCl3) δ 1.32-1.99 (m, 8H), 2.56-2.61 and
2.76-2.80 (2 ꢀ bm, together integrating for 1H), 3.36-3.39
(m, 1H), 3.67 (dd, 1H, J = 11.6 and 2.8 Hz), 3.87 (dd, 1H, J =
11.6 and 10.2 Hz), 5.12-5.15 (m, 1H), 5.39 (s, 1H), 5.69 (s, 1H),
6.52 (d, 2H, J = 8.4 Hz, Ar), 7.24-7.49 (m, 6H, Ar), 7.77-7.85
(m, 2H, Ar), 7.96-7.98 (m, 1H, Ar). 13C NMR (75 MHz,
CDCl3) δ 26.66 (CH2), 27.90 (CH2), 28.16 (CH2), 28.42 (CH2),
28.54 (CH2), 32.19 (CH2), 50.17 (CH), 50.47 (CH), 62.77 (CH2),
63.11 (CH2), 81.83 (CH), 101.77 (C), 101.83 (C), 112.28 (2 ꢀ
CH), 118.44 (C, JC-F = 32.6 Hz), 120.08 (CH2), 125.36 (CH),
125.47 (CH), 126.14 (CH), 126.24 (CH), 126.64 (CH), 126.84
(CH), 126.89 (CH), 128.62 (2 ꢀ CH), 131.50 (C), 133.87
(C), 137.24 (C), 143.30 (C), 149.79 (C). FAB-MS (m/z) 470
[M þ H]þ. HRMS calcd for C27H26F3NO3, 469.1865; found,
469.1860.
Trioxane 8g. This was obtained as oil in 61% yield as a
mixture of diastereomers 8gl and 8gm, which were separated
by column chromatography.
Trioxane (8gl, Less Polar). Oil; IR (neat, cm-1) 1584, 3430. 1H
NMR (300 MHz, CDCl3) δ 1.20-1.92 (m, 8H), 2.42-2.47 (bm,
1H), 3.38-3.44 (m, 1H), 3.64 (dd, 1H, J = 11.9 and 2.9 Hz), 3.84
(dd, 1H, J = 11.6 and 10.4 Hz), 5.10 (dd, 1H, J = 10.2 and 2.6
Hz), 5.38 (s, 1H), 5.68 (s, 1H), 6.69-6.76 (m, 2H, Ar), 7.05-7.08
(m, 1H, Ar), 7.18-7.50 (m, 10H, Ar), 7.78-7.86 (m, 2H, Ar),
7.94-7.97 (m, 1H, Ar)). 13C NMR (75 MHz, CDCl3) δ 26.73
(CH2), 28.08 (CH2), 28.39 (CH2), 32.22 (CH2), 50.54 (CH),
63.75 (CH2), 81.81 (CH), 102.03 (C), 111.21 (CH), 117.04
(CH), 120.08 (CH2), 125.34 (CH), 125.52 (CH), 126.14 (CH),
126.22 (CH), 126.62 (CH), 127.42 (CH), 128.03 (C), 128.57
(CH), 128.61 (CH), 128.92 (CH), 129.14 (2 ꢀ CH), 129.51
(2 ꢀ CH), 130.69 (CH), 131.55 (C), 133.88 (C), 137.28 (C),
Trioxane 9a. Yield 87%, white solid; mp 130-131 °C. IR
(KBr, cm-1) 1505, 3405.; 1H NMR (200 MHz, CDCl3) δ
1.45-2.04 (m, 8H), 2.75-2.79 and 2.81-2.87 (2 ꢀ bm, together
integrating for 1H), 3.40-3.52 (m, 1H), 3.84 (dd, 1H, J = 11.8
and 2.4 Hz), 4.04 (dd, 1H, J = 11.6 and 10.7 Hz), 5.38-5.43 (m,
2H), 5.65(s, 1H), 6.58-6.72 (m, 3H), 7.13-7.25 (m, 2H),
7.50-7.55 (m, 3H), 7.80-7.84 (m, 4H). 13C NMR (50 MHz,
CDCl3) δ 27.41 (CH2), 28.65 (CH2), 28.75 (CH2), 33.32 (CH2),
51.39 (CH), 63.43 (CH2), 80.64 (CH), 80.65 (CH), 102.16 (C),
114.02 (2 ꢀ CH), 117.22 (CH2), 118.02 (CH), 124.68 (CH),
125.59 (CH), 126.59 (CH), 126.69 (CH), 127.84 (CH), 128.47
(CH), 128.55 (CH), 129.61 (2 ꢀ CH), 133.31 (C), 133.52 (C),
136.10 (C), 143.57 (C), 146.85 (C). ESI-MS (m/z) 402 [M þ H]þ.
HRMS calcd for C26H27NO3, 401.1991; found, 401.1992; Anal.
Calcd for C26H27NO3: C, 77.78%, H, 6.78%, N, 3.49%. Found:
C, 77.82%, H, 7.11%, N, 3.12.
139.67 (C), 143.39 (C), 144.11 (C). FAB-MS (m/z) 477 [M]þ
.
Anal. Calcd for C32H31NO3: C, 80.47%, H, 6.54%, N, 2.93%.
Found: C, 80.59%, H, 6.89%, N, 2.84.
Trioxane (8gm, More Polar). Oil; IR (neat, cm-1) 1584, 3430.
1H NMR (300 MHz, CDCl3) δ 1.31-1.99 (m, 8H), 2.65-2.70
(bm, 1H), 3.36-3.42 (m, 1H), 3.66 (dd, 1H, J = 11.6 and 2.4
Hz), 3.93 (dd, 1H, J = 11.3 and 10.3 Hz), 5.09 (dd, 1H, J = 10.3
and 2.4 Hz), 5.39 (s, 1H), 5.67 (s, 1H), 6.69-6.76 (m, 2H, Ar),
7.07-7.09 (m, 1H, Ar), 7.18-7.25 (m, 2H, Ar), 7.34-7.50
Trioxane 9b. Yield 66%, white solid; mp 92-93 °C. IR (KBr,
cm-1) 1634, 3434. 1H NMR (300 MHz, CDCl3) δ 1.43-2.06 (m,
8H), 2.67-2.72 and 2.86-2.90 (2 ꢀ bm, together integrating
for 1H), 3.32-3.39 (bm, 1H), 3.85-3.90 (m, 1H), 3.98 and 4.07
(2 ꢀ dd, J = 11.6 and 10.6 Hz, together integrating for 1H),),
5.42-5.46 (m, 2H), 5.68 (s, 1H), 6.54-6.58 (m, 2H), 6.91

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 21 7593
(t, 2H, J = 8.7 Hz, Ar), 7.50-7.57 (m, 3H, Ar), 7.84-7.87 (m,
4H, Ar). 13C NMR (75 MHz, CDCl3) δ 26.85 (CH2), 27.40
(CH2), 28.26 (CH2), 28.53 (CH2), 28.78 (CH2), 32.45 (CH2),
33.34 (CH2), 51.46 (CH), 51.77 (CH), 63.15 (CH2), 63.44 (CH2),
80.64 (CH), 80.68 (CH), 102.16 (C), 114.52 (CH), 114.62 (CH),
115.84 (CH), 116.13 (CH), 117.15 (CH2), 117.21 (CH2), 124.64
(CH), 125.59 (CH), 126.61 (CH), 126.72 (CH), 127.84 (CH),
128.47 (CH), 128.55 (CH), 133.30 (C), 133.51 (C), 136.06 (C),
143.50 (C), 146.66 (C), 156.04 (C, JC-F = 235.1 Hz). FAB-MS
(m/z) 419 [M]þ. HRMS calcd for C26H26FNO3, 419.1897;
found, 419.1892; Anal. Calcd for C26H26FNO3: C, 74.44%, H,
6.25%, N, 3.34%. Found: C, 74.52%, H, 6.59%, N, 3.16.
Trioxane 9c. Yield 46%, white solid; mp 125-126 °C. IR
(KBr, cm-1) 1594, 3407. 1H NMR (200 MHz, CDCl3) δ
1.36-2.05 (m, 8H), 2.70-2.76 and 2.86-2.92 (2 ꢀ bm, together
integrating for 1H), 3.37-3.43 (m, 1H), 3.91 (dd, 1H, J = 11.9
and 2.9 Hz), 3.97-4.21 (m, 1H), 5.50-5.53 (m, 2H), 5.72 (s, 1H),
6.54 (d, 2H, J = 8.8 Hz, Ar), 7.17 (d, 2H, J = 8.8 Hz, Ar),
7.52-7.61 (m, 3H, Ar), 7.84-7.91 (m, 4H, Ar). 13C NMR
(50 MHz, CDCl3) δ 26.71 (CH2), 27.22 (CH2), 27.97 (CH2),
28.23 (CH2), 28.46 (CH2), 28.55 (CH2), 32.28 (CH2), 33.14
(CH2), 50.62 (CH), 50.88 (CH), 62.96 (CH2), 63.25 (CH2)
80.47 (CH), 101.98 (C), 102.06 (C), 114.44 (2 ꢀ CH), 117.08
(CH2), 121.70 (C), 121.74 (C), 124.50 (CH), 125.43 (CH), 126.49
(CH), 126.59 (CH), 127.72 (CH), 128.36 (CH), 128.44 (CH),
129.24 (2 ꢀ CH), 133.16 (C), 133.38 (C), 135.90 (C), 143.32 (C),
145.88 (C). ESI-MS (m/z) 436 [M þ H]þ. HRMS calcd
for C26H26ClNO3, 435.1601; found, 435.1605. Anal. Calcd
for C26H26ClNO3: C, 71.63%, H, 6.01%, N, 3.21. Found: C,
71.84%, H, 6.49%, N, 3.08%..
Trioxane 9d. Yield 46%, white solid; mp 90-91 °C. IR (KBr,
cm-1) 1591, 3406. 1H NMR (300 MHz, CDCl3) δ 1.49-2.02 (m,
8H), 2.81-2.86 (bm, 1H), 3.39 (m, 1H), 3.85 (dd, 1H, J = 11.7
and 2.9 Hz), 4.03 (dd, 1H, J = 11.7 and 10.3 Hz,), 5.40 (dd, 1H,
J = 10.3 and 2.9 Hz), 5.43 (s, 1H), 5.65 (s, 1H), 6.43 (s, 2H, Ar),
7.36 (s, 1 Hz, Ar), 7.47-7.54 (m, 3H, Ar), 7.81-7.84 (m, 4H,
Ar). 13C NMR (50 MHz, CDCl3) δ 27.32 (CH2), 28.50 (CH2),
28.61 (CH2), 33.22 (CH2), 50.89 (CH), 63.43 (CH2), 80.64 (CH),
101.89 (C), 111.46 (2 ꢀ CH), 117.16 (CH), 117.25 (CH2), 124.61
(CH), 125.58 (CH), 126.62 (CH), 126.73 (CH), 127.84 (CH),
128.47 (CH), 128.57 (CH), 133.30 (C), 133.49 (C), 135.79 (2 ꢀ
C), 136.01 (C), 143.43 (C), 148.87 (C). FAB-MS (m/z) 470
[M þ H]þ. HRMS calcd for C26H25Cl2NO3, 469.1211; found,
469.1211. Anal. Calcd for C26H25Cl2NO3: C, 66.39%, H,
5.36%, N, 2.98%. Found: C, 66.52%, H, 5.71%, N, 2.75.
Trioxane 9e. Yield 62%, white solid; mp 98-99 °C. IR (KBr,
cm-1) 1517, 3411. 1H NMR (300 MHz, CDCl3) δ 1.39-2.03 (m,
8H), 2.23 (s, 3H), 2.62-2.66 and 2.80-2.84 (2 ꢀ bm, respec-
tively, together integrating for 1H), 3.33-3.40 (m, 1H), 3.83 (dd,
1H, J = 11.7 and 2.6 Hz), 3.95 and 4.02 (2 ꢀ dd, J = 11.7 and
10.4 Hz, respectively, together integrating for 1H), 5.38-5.42
(m, 2H), 5.64 (s, 1H), 6.52 (d, 2H, J = 8.1 Hz, Ar), 6.97 (d, 2H,
J = 8.1 Hz, Ar), 7.46-7.53 (m, 3H, Ar), 7.79-7.84 (m, 4H, Ar).
13C NMR (75 MHz, CDCl3) δ 20.58 (CH3), 26.83 (CH2), 27.38
(CH2), 28.29 (CH2), 28.56 (CH2), 28.80 (CH2), 28.89 (CH2),
32.45 (CH2), 33.33 (CH2), 50.94 (CH), 51.26 (CH), 63.11 (CH2),
63.39 (CH2) 80.61 (CH), 102.22 (C), 113.82 (2 ꢀ CH), 117.16
(CH2), 124.62 (CH), 125.54 (CH), 126.56 (CH), 126.67 (CH),
126.76 (C), 127.80 (CH), 128.44 (CH), 128.51 CH), 130.04 (2 ꢀ
CH), 133.26 (C), 133.48 (C), 136.04 (C), 143.48 (C), 145.09 (C).
FAB-MS (m/z) 415 [M]þ. HRMS calcd for C27H29NO3,
415.2147; found, 415.2149. Anal. Calcd for C27H29NO3: C,
78.04%, H, 7.03%, N, 3.37%. Found: C, 78.51%, H, 6.96%,
N, 2.85%.
J = 10.4 and 2.5 Hz), 5.42 (s, 1H), 5.64 (s, 1H), 6.97 (d, 2H, J =
8.8 Hz, Ar), 6.76 (d, 2H, J = 8.8 Hz, Ar), 7.46-7.53 (m, 3H, Ar),
7.79-7.84 (m, 4H, Ar). 13C NMR (75 MHz, CDCl3) δ 27.42
(CH2), 28.92 (CH2), 29.01 (CH2), 33.38 (CH2), 52.10 (CH),
56.05 (CH3), 63.42 (CH2), 80.62 (CH), 102.27 (C), 115.23
(2ꢀCH), 115.32 (2ꢀCH), 117.19 (CH2), 124.64 (CH), 125.57
(CH), 126.58 (CH), 126.69 (CH), 127.82 (CH), 128.46 (CH),
128.53 (CH), 133.28 (C), 133.50 (C), 136.06 (C), 141.56 (C),
143.50 (C), 152.43 (C). FAB-MS (m/z) 431 [M]þ. HRMS calcd
for C27H29NO4, 431.2097; found, 431.2123. Anal. Calcd for
C27H29NO4: C, 75.15%, H, 6.77%, N, 3.25. Found: C, 75.25%,
H, 6.93%, N, 3.17%.
Trioxane 9g. This was obtained as a white solid in 55% yield
as a mixture of diastereomers 9gl and 9gm, which were separated
by column chromatography.
Trioxane (9gl, Less Polar). Melting point 87-88 °C. IR (KBr,
cm-1) 1594, 3405. 1H NMR (300 MHz, CDCl3) δ 1.25-1.98 (m,
8H), 2.48-2.52 (bm, 1H), 3.39-3.45 (m, 1H), 3.77 (dd, 1H, J =
11.8 and 2.9 Hz), 3.89 (dd, 1H, J = 11.8 and 10.2 Hz,),
5.34-5.38 (m, 2H), 5.60 (s, 1H), 6.70-6.75 (m, 2H, Ar),
7.06-7.08 (m, 1H, Ar), 7.18-7.24 (m, 1H, Ar), 7.28-7.49 (m,
8H, Ar), 7.76-7.80 (m, 4H, Ar). 13C NMR (75 MHz, CDCl3) δ
26.80 (CH2), 28.13 (CH2), 28.42 (CH2), 32.36 (CH2), 50.58
(CH), 63.05 (CH2), 80.61 (CH), 102.19 (C), 111.21 (CH),
117.04 (CH), 117.18 (CH2), 124.62 (CH), 125.55 (CH), 126.55
(CH), 126.66 (CH), 127.42 (CH), 127.80 (CH), 128.02 (C),
128.43 (CH), 128.50 (CH), 128.93 (CH), 129.14 (2 ꢀCH),
129.52 (2 ꢀ CH), 130.71 (CH), 133.25 (C), 133.46 (C), 135.99
(C), 139.70 (C), 143.49 (C), 144.15 (C). FAB-MS (m/z) 477 [M]þ.
HRMS calcd for C32H31NO3, 477.2304; found, 477.2320.
Trioxane (9gm, More Polar). Melting point 98-99 °C. IR
(KBr, cm-1) 1599, 3415. 1H NMR (300 MHz, CDCl3) δ
1.30-1.99 (m, 8H), 2.68-2.72 (bm, 1H), 3.37-3.47 (m, 1H),
3.80 (dd, 1H, J = 11.8 and 2.9 Hz), 3.99 (dd, 1H, J = 11.8 and
10.4 Hz,), 5.34-5.38 (m, 2H), 5.62 (s, 1H), 6.70-6.77 (m, 2H,
Ar), 7.07-7.09 (m, 1 Hz, Ar), 7.18-7.24 (m, 1H, Ar), 7.30-
7.51(m, 8H, Ar), 7.78-7.81 (m, 4H, Ar). 13C NMR (75 MHz,
CDCl3) δ 27.17 (CH2), 28.50 (CH2), 28.62 (CH2), 33.06 (CH2),
50.63 (CH), 63.22 (CH2), 80.47 (CH), 102.08 (C), 111.19 (CH),
116.95 (CH), 116.98 (CH2), 124.53 (CH), 125.47 (CH), 126.49
(CH), 126.60 (CH), 127.42 (CH), 127.74 (CH), 128.11 (C),
128.38 (CH), 128.44 (CH), 128.82 (CH), 129.13 (2 ꢀ CH),
129.44 (2 ꢀ CH), 130.65 (CH), 133.19 (C), 133.41 (C), 135.93
(C), 139.56 (C), 143.35 (C), 144.12 (C). FAB-MS (m/z) 477 [M]þ.
HRMS calcd for C32H31NO3, 477.2304; found, 477.2320.
Trioxane (9h). Yield 60%, oil. IR (neat, cm-1) 1608, 3422. 1H
NMR (200 MHz, CDCl3) δ 1.47-2.03 (m, 8H), 2.63-2.69 and
2.82-2.88 (2 ꢀ bm, together integrating for 1H), 3.42 (bm, 1H),
3.84 (dd, 1H, J = 11.4 and 2.3 Hz), 4.04 (dd, 1H, J = 11.4 and
10.8 Hz), 5.41-5.43 (m, 2H), 5.65 (s, 1H), 6.69-6.77 (m, 2H,
Ar), 6.88-6.92 (m, 1H, Ar), 7.19-7.27 (m, 1H, Ar), 7.46-7.54
(m, 3H, Ar), 7.80-7.84 (m, 4H, Ar). 13C NMR (75 MHz,
CDCl3) δ 26.95 (CH2), 27.50 (CH2), 28.24 (CH2), 28.52 (CH2),
28.76 (CH2), 28.85 (CH2), 32.56 (CH2), 33.44 (CH2), 50.61
(CH), 50.91 (CH), 63.35 (CH2), 63.63 (CH2), 80.81 (CH),
102.25 (C), 109.61 (CH), 113.98 (CH), 116.51 (CH), 117.44
(CH2), 122.11 (CH), 124.81 (CH), 125.76 (CH), 126.83 (CH),
126.93 (CH), 128.04 (CH), 128.68 (CH), 128.77 (CH), 130.16
(C), 132.04 (C, JC-F = 31.5 Hz), 133.48 (C), 136.19 (2 ꢀ C),
143.59(C), 147.73 (C). ESI-MS (m/z) 470 [M þ H]þ. HRMS
calcd for C27H26NF3O3, 469.1865; found, 469.1830; Anal. Calcd
for C27H26NF3O3: C, 69.07%, H, 5.58%, N, 2.98. Found: C,
69.31%, H, 5.64%, N, 2.73%.
Trioxane 9i. This was obtained as oil in 68% yield as a mixture
of diastereomers 9il and 9im, which were separated by column
chromatography.
Trioxane 9f. Yield 47%, white solid; mp 92-93 °C. IR (KBr,
cm-1) 1590, 3399. 1H NMR (300 MHz, CDCl3) δ 1.39-2.03 (m,
8H), 2.62-2.66 and 2.80-2.84 (2 ꢀ bm, respectively, together
integrating for 1H), 3.26-3.34 (m, 1H), 3.74 (s, 3H), 3.83 (dd,
1H, J = 11.6 and 2.5 Hz), 3.95 and 4.02 (2 ꢀ dd, J = 11.6 and,
10.4 Hz, respectively, together integrating for 1H), 5.39 (dd, 1H,
1
Trioxane (9il, Less Polar). IR (neat, cm-1) 1607, 3412. H
NMR (300 MHz, CDCl3) δ 1.47-2.05 (m, 8H), 2.81-2.86 (bm,
1H), 3.39-3.48 (m, 1H), 3.84 (dd, 1H, J = 11.7 and 2.7 Hz), 4.03
(dd, 1H, J = 11.7 and 10.2 Hz,), 5.37-5.43 (m, 2H), 5.65 (s, 1H),

7594 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 21
Singh et al.
6.57 (d, 2H, J = 8.4 Hz, Ar), 7.38 (d, 2H, J = 8.4 Hz, Ar),
7.46-7.53 (m, 3H, Ar), 7.80-7.83 (m, 4H, Ar). 13C NMR (75
MHz, CDCl3) δ 27.36 (CH2), 28.57 (CH2), 28.68 (CH2), 33.23
(CH2), 50.64 (CH), 63.44 (CH2), 80.69 (CH), 100.25 (C), 101.95
(C), 112.39 (2 ꢀ CH), 117.23 (CH2), 118.72 (C, JC-F = 32.3 Hz),
124.64 (CH), 125.61 (CH), 126.62 (CH), 126.72 (CH), 126.90
(CH), 126.96 (CH), 127.84 (CH), 128.46 (CH), 128.56 (CH),
133.32 (C), 133.53 (C), 136.06 (C), 143.52 (C), 149.86 (C). ESI-
MS (m/z) 470 [M þ H]þ. HRMS calcd for C27H26F3NO3,
469.1865; found, 469.1825. Anal. Calcd for C27H26NF3O3: C,
69.07%, H, 5.58%, N, 2.98. Found: C, 69.45%, H, 5.91%, N,
2.69%.
integrating for 1H), 3.31-3.40 (m, 1H), 3.82 (dd, 1H, J = 11.6
and 2.8 Hz), 3.89 (s, 2H), 3.94 and 4.02 (2 ꢀ dd, J = 11.6 and
10.5 Hz, respectively, together integrating for 1H), 5.31-5.34
(m, 2H), 5.56 (s, 1H), 6.51 (d, 2H, J = 8.8 Hz, Ar), 7.09 (d, 2H,
J = 8.8 Hz, Ar), 7.28-7.42 (m, 3H, Ar), 7.53-7.56 (m, 2H, Ar),
7.73-7.79 (m, 2H, Ar). 13C NMR (75 MHz, CDCl3) δ 26.77
(CH2), 28.12 (CH2), 28.38 (CH2), 32.39 (CH2), 37.14 (CH2),
50.77 (CH), 63.11 (CH2), 63.39 (CH2), 80.74 (CH), 102.10 (C),
114.53 (2 ꢀ CH), 116.25 (CH2), 120.12 (CH), 120.26 (CH),
121.99 (CH), 123.24 (CH), 125.30 (CH), 125.44 (CH), 127.09
(CH), 127.22 (CH), 129.36 (2 ꢀ CH), 137.26 (C), 141.32 (C),
142.10 (C), 143.68 (C), 143.78 (C), 143.85 (C), 145.90 (C). FAB-
MS (m/z) 474 [M þ H]þ. HRMS Calcd for C29H28ClNO3,
473.1758; found, 473.1759. Anal. Calcd for C29H28ClNO3: C,
73.48%, H, 5.95%, N, 2.96%. Found: C, 73.97%, H, 5.99%, N,
2.93%.
Trioxane 10d. Yield 65%, white solid; mp 183-184 °C. IR
(KBr, cm-1) 1592, 3406. 1H NMR (300 MHz, CDCl3) δ
1.46-2.05 (m, 8H), 2.65-2.70 and 2.84-2.89 (2 ꢀ bm, together
integrating for 1H), 3.36-3.38 (m, 1H), 3.86 (dd, 1H, J = 11.9
and 2.7 Hz), 3.93 (s, 2H), 3.97 and 4.05 (2 ꢀ dd, J = 11.9 and
10.5 Hz, respectively, together integrating for 1H), 5.35-5.37
(m, 2H), 5.59-5.60 (2 ꢀ s, together integrating for 1H), 6.45 (d,
2H, J = 1.6 Hz, Ar), 6.66-6.67 (m, 1H, Ar), 7.32-7.45 (m, 3H,
Ar), 7.56-7.60 (m, 2H, Ar), 7.76-7.82 (m, 2H, Ar). 13C NMR
(75 MHz, CDCl3) δ 26.73 (CH2), 27.29 (CH2), 27.99 (CH2),
28.28 (CH2), 28.51 (CH2), 28.63 (CH2), 32.34 (CH2), 33.23
(CH2), 37.14 (CH2), 50.48 (CH), 50.79 (CH), 63.12 (CH2),
63.40 (CH2), 80.75 (CH), 101.85 (C), 101.91 (C), 111.33 (2 ꢀ
CH), 116.37 (CH2), 117.00 (CH), 120.14 (CH), 120.28 (CH),
123.24 (CH), 125.31 (CH), 125.43 (CH), 127.10 (CH), 127.24
(CH), 135.76 (2 ꢀ C), 137.26 (C), 141.31 (C), 142.12 (C), 143.68
(2 ꢀ C), 143.86 (C), 148.96 (C). FAB-MS (m/z) 507 [M]þ.
HRMS calcd for C29H27Cl2NO3, 507.1368; found, 507.1388.
Anal. Calcd for C29H27Cl2NO3: C, 68.51%, H, 5.35%, N,
2.75%. Found: C, 68.97%, H, 5.43%, N, 2.79%.
Trioxane 10e. Yield 72%, white solid; mp 95-96 °C. IR (KBr,
cm-1) 1598, 3427. 1H NMR (300 MHz, CDCl3) δ 1.39-2.02 (m,
8H), 2.23 (s, 3H), 2.61-2.65 and 2.79-2.83 (2 ꢀ bm, together
integrating for 1H), 3.34-3.39 (m, 1H), 3.79-3.84 (m, 1H),
3.88 (s, 2H), 3.94 and 4.01 (2 ꢀ dd, J = 11.5 and 10.5 Hz,
respectively, together integrating for 1H), 5.31-5.34 (m, 2H),
5.56 (s, 1H), 6.52 (d, 2H, J = 8.2 Hz, Ar), 6.97 (d, 2H, J =
8.2 Hz, Ar), 7.28-7.41(m, 3H, Ar), 7.51-7.56 (m, 2H, Ar),
7.72-7.78 (m, 2H, Ar). 13C NMR (75 MHz, CDCl3) δ 20.58
(CH3), 26.82 (CH2), 27.38 (CH2), 28.30 (CH2), 28.57 (CH2),
28.82 (CH2), 28.92 (CH2) 32.46 (CH2), 33.37 (CH2), 37.14
(CH2), 50.96 (CH), 51.30 (CH), 63.11 (CH2), 63.39 (CH2),
80.72 (CH), 102.19 (C), 113.83 (2ꢀCH), 116.20 (CH2), 116.31
(CH2), 120.11 (CH), 120.26 (CH), 123.24 (CH), 125.29 (CH),
125.44 (CH), 126.79 (C), 127.08 (CH), 127.20 (CH), 130.04
(2ꢀCH), 137.35 (C), 141.34 (C), 142.08 (C), 143.69 (C), 143.84
(2 ꢀ C), 145.08 (C). FAB-MS (m/z) 453 [M]þ. HRMS calcd
for C30H31NO3, 453.2304; found, 453.2265. Anal. Calcd
for C30H31NO3: C, 79.44%, H, 6.89%, N, 3.09%. Found: C,
79.94%, H, 6.93%, N, 3.13%.
Trioxane 10f. Yield 59%, white solid; mp 150-151 °C. IR
(KBr, cm-1) 1595, 3429. 1H NMR (300 MHz, CDCl3) δ
1.34-2.01 (m, 8H), 2.61-2.66 and 2.79-2.84 (2 ꢀ bm, together
integrating for 1H), 3.26-3.36 (m, 1H), 3.73 (s, 3H), 3.79-3.84
(m, 1H), 3.87 (s, 2H), 3.93 and 4.01 (2 ꢀ dd, J = 11.7 and 10.5
Hz, respectively, together integrating for 1H), 5.31-5.33 (m,
2H), 5.56 (s, 1H), 6.56 (d, 2H, J = 8.9 Hz, Ar), 6.76 (d, 2H, J =
8.9 Hz, Ar), 7.27-7.41 (m, 3H, Ar), 7.51-7.56 (m, 2H, Ar),
7.71-7.77 (m, 2H, Ar). 13C NMR (75 MHz, CDCl3) δ 26.79
(CH2), 27.34 (CH2), 28.33 (CH2), 28.60 (CH2), 28.86 (CH2),
28.95 (CH2), 32.45 (CH2) 33.37 (CH2), 37.09 (CH2), 51.70 (CH),
52.03 (CH), 55.98 (CH3), 63.06 (CH2), 63.36 (CH2), 80.65 (CH),
102.18 (C), 102.27 (C), 115.15 (2 ꢀ CH), 115.23 (2 ꢀ CH), 116.19
(CH2), 116.27 (CH2), 120.09 (CH), 120.23 (CH), 123.19 (CH),
Trioxane (9im, More Polar). IR (neat, cm-1) 1607, 3412. 1H
NMR (300 MHz, CDCl3) δ 1.50-2.04 (m, 8H), 2.63-2.67 (bm,
1H), 3.44-3.51 (m, 1H), 3.85 (dd, 1H, J = 11.9 and 3.1 Hz), 3.96
(dd, 1H, J = 11.9 and 10.2 Hz,), 5.39-5.43 (m, 2H), 5.65 (s, 1H),
6.57 (d, 2H, J = 8.4 Hz, Ar), 7.38 (d, 2H, J = 8.4 Hz, Ar),
7.47-7.54 (m, 3H, Ar), 7.80-7.83 (m, 4H, Ar). 13C NMR (75
MHz, CDCl3) δ 26.81 (CH2), 28.06 (CH2), 28.33 (CH2), 32.37
(CH2), 50.33 (CH), 63.18 (CH2), 80.72 (CH), 102.04 (C), 112.41
(2 ꢀ CH), 117.18 (CH2), 124.67 (CH), 125.62 (CH), 126.63
(CH), 126.74 (CH), 126.99 (2 ꢀ CH), 127.86 (CH), 128.47 (CH),
128.57 (CH), 133.33 (C), 133.54 (2 ꢀ C), 136.03 (2 ꢀ C), 143.55
(C), 149.85 (C). ESI-MS (m/z) 470 [M þ H]þ. HRMS calcd
for C27H26F3NO3, 469.1865; found, 469.1825. Anal. Calcd
for C27H26NF3O3: C, 69.07%, H, 5.58%, N, 2.98. Found: C,
69.51%, H, 5.95%, N, 2.65%.
Trioxane 10a. Yield 54%, white solid; mp 135-140 °C. IR
(KBr, cm-1) 1597, 3401. 1H NMR (300 MHz, CDCl3) δ
1.21-2.02 (m, 8H), 2.61-2.66 and 2.79-2.84 (2 ꢀ bm, together
integrating for 1H), 3.35-3.44 (m, 1H), 3.79-3.84 (m, 1H), 3.87
(s, 2H), 3.93 and 4.01 (2 ꢀ dd, J = 11.5 and 10.7 Hz,
respectively, together integrating for 1H), 5.31-5.33 (m, 2H),
5.55 (s, 1H), 6.58 (d, 2H, J = 7.8 Hz, Ar), 6.77 (t, 1H, J = 7.3 Hz,
Ar), 7.15 (t, 2H, J = 7.5 Hz, Ar), 7.29-7.40 (m, 3H, Ar),
7.51-7.55 (m, 2H, Ar), 7.70-7.76 (m, 2H, Ar). 13C NMR (75
MHz, CDCl3) δ 26.80 (CH2), 27.35 (CH2), 28.25 (CH2), 28.51
(CH2), 28.75 (CH2), 28.86 (CH2), 32.44 (CH2), 33.33 (CH2),
37.11 (CH2), 50.58 (CH), 50.90 (CH), 63.09 (CH2), 63.37 (CH2),
80.70 (CH), 102.12 (C), 113.47 (2 ꢀ CH), 116.28 (CH2), 117.46
(CH), 120.10 (CH), 120.24 (CH), 123.21 (CH), 125.28 (CH),
125.41 (CH), 127.07 (CH), 127.19 (CH), 129.54 (2 ꢀ CH), 137.31
(C), 141.31 (C), 142.06 (C), 143.67 (C), 143.82 (2 ꢀ C), 147.38
(C). FAB-MS (m/z) 439 [M]þ. HRMS calcd for C29H29NO3,
439.2147; found, 439.2137. Anal. Calcd for C29H29NO3: C,
79.24%, H, 6.65%; N, 3.19%. Found: C, 79.39%, H, 6.33%,
N, 3.11%.
Trioxane 10b. Yield 66%, white solid; mp 125-126 °C.
1
IR (KBr, cm-1) 1598, 3409. H NMR (300 MHz, CDCl3) δ
1.38-2.00 (m, 8H), 2.60-2.65 and 2.79-2.83 (2 ꢀ bm, together
integrating for 1H), 3.25-3.30 (m, 1H), 3.81 (dd, 1H, J = 11.6
and 2.6 Hz), 3.86 (s, 2H), 3.93 and 4.01 (2 ꢀ dd, J = 11.6 and
10.7 Hz, respectively, together integrating for 1H), 5.30-5.33
(m, 2H), 5.55 (s, 1H), 6.48-6.53 (m, 2H, Ar), 6.86 (t, 2H, J = 8.6
Hz, Ar), 7.22-7.40 (m, 3H, Ar), 7.51-7.55 (m, 2H, Ar),
7.70-7.76 (m, 2H, Ar). 13C NMR (75 MHz, CDCl3) δ 27.77
(CH2), 27.33 (CH2), 28.21 (CH2), 28.48 (CH2), 28.73 (CH2),
28.83 (CH2), 32.43 (CH2), 33.35 (CH2), 37.11 (CH2), 51.91
(CH), 51.67 (CH), 63.10 (CH2), 63.39 (CH2), 80.66 (CH),
80.69 (CH), 102.09 (C), 102.17 (C), 114.40 (CH), 114.50 (CH),
115.80 (CH), 116.09 (CH), 116.31 (CH2), 120.12 (CH), 120.26
(CH), 123.20 (CH), 125.30 (CH), 125.39 (CH), 127.08 (CH),
127.21 (CH), 137.25 (C), 141.29 (C), 142.07 (C), 143.66 (3 ꢀ C),
143.83 (C), 155.91 (C, JC-F = 235.1 Hz). FAB-MS (m/z)
457 [M]þ. HRMS Calcd for C29H28FNO3, 457.2053; found,
457.2047. Anal. Calcd for C29H28FNO3: C, 76.13%, H, 6.17%,
N, 3.06%. Found: C, 76.77%, H, 6.17%, N, 2.93%.
Trioxane 10c. Yield 58%, white solid; mp 160-163 °C. IR
(KBr, cm-1) 1598, 3403. 1H NMR (300 MHz, CDCl3) δ
1.50-2.02 (m, 8H), 2.62-2.65 and 2.80-2.85 (2 ꢀ bm, together

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 21 7595
125.27 (CH), 125.38 (CH), 127.05 (CH), 127.17 (CH), 137.27
(C), 141.29 (C), 141.49 (C), 142.04 (C), 143.65 (2 ꢀ C), 143.80
(C), 152.34 (C). FAB-MS (m/z) 469 [M]þ. HRMS Calcd
for C30H31NO4, 469.2253; found, 469.2247. Anal. Calcd
for C30H31NO4: C, 76.73%, H, 6.65%, N, 2.98%. Found: C,
76.51%, H, 6.81%, N, 3.42%.
Trioxane 10g. This was obtained as a white solid in 64% yield
as a mixture of diastereomers 10gl and 10gm, which were
separated by column chromatography.
5.57 (s, 1H), 6.57 (d, 2H, J = 8.4 Hz, Ar), 7.24-7.42 (m, 5H, Ar),
7.53-7.57 (m, 2H, Ar), 7.72-7.78 (m, 2H, Ar). 13C NMR (75
MHz, CDCl3) δ 27.32 (CH2), 28.55 (CH2), 28.66 (CH2), 33.26
(CH2), 37.16 (CH2), 50.62 (CH), 63.42 (CH2), 80.76 (CH),
101.91 (C), 112.36 (2 ꢀ CH), 116.37 (CH2), 118.65 (C, JC-F
=
32.1 Hz), 120.14 (CH), 120.28 (CH), 123.25 (CH), 125.32 (CH),
125.45 (CH), 126.91 (CH), 126.95 (CH), 127.11 (CH), 127.25
(CH), 137.31 (C), 141.34 (C), 142.14 (C), 143.75 (2 ꢀ C), 143.88
(2 ꢀ C), 149.84 (C). FAB-MS (m/z) 508 [M þ H]þ. HRMS calcd
for C30H28F3NO3, 507.2021; found, 507.2003; Anal. Calcd
for C30H28F3NO3: C, 70.99%, H, 5.56%, N, 2.76%. Found:
C, 71.47%, H, 5.75%, N, 2.44%.
Trioxane (10gl, Less Polar). Melting point 80-81 °C. IR
(KBr, cm-1) 1582, 3406. 1H NMR (300 MHz, CDCl3) δ 1.31-
1.99 (m, 8H), 2.48-2.52 (bm, 1H), 3.39-3.46 (m, 1H), 3.77 (dd,
1H, J = 11.8 and 2.9 Hz), 3.85-3.93 (m, 3H), 5.27-5.30 (m,
2H), 5.53 (s, 1H), 6.70-6.76 (m, 2H, Ar), 7.06-7.08 (m, 1H, Ar),
7.18-7.53 (m, 11H, Ar), 7.69-7.75 (m, 2H, Ar). 13C NMR (75
MHz, CDCl3) δ 26.75 (CH2), 28.09 (CH2), 28.39 (CH2), 32.35
(CH2), 37.09 (CH2), 50.57 (CH), 63.02 (CH2), 80.67 (CH),
102.13 (C), 111.21 (CH), 116.27 (CH2), 117.05 (CH), 120.08
(CH), 120.23 (CH), 123.20 (CH), 125.27 (CH), 125.39 (CH),
127.05 (CH), 127.17 (CH), 127.41 (CH), 127.99 (C), 128.91
(CH), 129.13 (2 ꢀ CH), 129.50 (2 ꢀ CH), 130.70 (CH), 137.24
(C), 139.65 (C), 141.29 (C), 142.03 (C), 143.64 (C), 143.73 (C),
143.79 (C), 144.07 (C). FAB-MS (m/z) 515 [M]þ. HRMS calcd
for C35H33NO3, 515.2460; found, 515.2418. Anal. Calcd for
C35H33NO3: C, 81.52%, H, 6.45%, N, 2.72%. Found: C,
81.71%, H, 6.82%, N, 2.51.
Trioxane (10gm, More Polar). Melting point 128-129 °C. IR
(KBr, cm-1) 1582, 3406. 1H NMR (300 MHz, CDCl3) δ
1.30-1.98 (m, 8H), 2.66-2.72 (bm, 1H), 3.38-3.45 (m, 1H),
3.79 (dd, 1H, J = 11.7 and 2.7 Hz), 3.86 (s, 2H), 3.98 (dd, 1H,
J = 11.7 and 10.7 Hz), 5.27-5.30 (m, 2H), 5.53 (s, 1H),
6.71-6.76 (m, 2H, Ar), 7.07-7.09 (m, 1H, Ar), 7.19-7.54 (m,
11H, Ar), 7.69-7.76 (m, 2H, Ar). 13C NMR (75 MHz, CDCl3)
δ 27.22 (CH2), 28.55 (CH2), 28.68 (CH2), 33.15 (CH2), 37.12
(CH2), 50.76 (CH), 63.30 (CH2), 80.67 (CH), 102.11 (C), 111.29
(CH), 116.23 (CH2), 117.06 (CH), 120.10 (CH), 120.25 (CH),
123.21 (CH), 125.28 (CH), 125.42 (CH), 127.07 (CH), 127.19
(CH), 127.49 (CH), 128.22 (C), 128.86 (CH), 129.19 (2 ꢀ CH),
129.50 (2 ꢀ CH), 130.70 (CH), 137.30 (C), 139.59 (C), 141.32
(C), 142.07 (C), 143.67 (C), 143.72 (C), 143.82 (C), 144.13 (C).
FAB-MS (m/z) 515 [M]þ. HRMS calcd for C35H33NO3,
515.2460; found, 515.2418. Anal. Calcd for C35H33NO3: C,
81.52%, H, 6.45%, N, 2.72%. Found: C, 81.68%, H, 6.46%,
N,2.32%.
Trioxane (10im, More Polar). IR (neat, cm-1) 1617, 3420. 1H
NMR (300 MHz, CDCl3) δ 1.57-2.03 (m, 8H), 2.62-2.67 (bm,
1H), 3.43-3.49 (m, 1H), 3.83 (dd, 1H, J = 11.8 and 2.9 Hz), 3.89
(s, 2H), 3.94 (dd, 1H, J = 11.8 and 10.4 Hz), 5.31-5.36 (m, 2H),
5.56 (s, 1H), 6.57 (d, 2H, J = 8.5 Hz, Ar), 7.28-7.41 (m, 5H, Ar),
7.53-7.57 (m, 2H, Ar), 7.72-7.78 (m, 2H, Ar). 13C NMR
(75 MHz, CDCl3) δ 26.76 (CH2), 28.03 (CH2), 28.29 (CH2),
32.37 (CH2), 37.16 (CH2), 50.29 (CH), 63.15 (CH2), 80.78 (CH),
101.99 (C), 112.37 (2 ꢀ CH), 116.29 (CH2), 119.69 (C, JC-F
=
31.8 Hz), 120.15 (CH), 120.29 (CH), 123.27 (CH), 125.33 (CH),
125.46 (CH), 126.93 (CH), 126.97 (CH), 127.12 (CH), 127.26
(CH), 137.27 (C), 141.34 (C), 142.15 (C), 143.70 (2 ꢀ C), 143.78
(C), 143.88 (C), 149.82 (C). FAB-MS (m/z) 508 [M þ H]þ.
HRMS calcd for C30H28F3NO3, 507.2021; found, 507.2003.
Anal. Calcd for C30H28F3NO3: C, 70.99%, H, 5.56%, N,
2.76%. Found: C, 71.51%, H, 5.81%, N, 2.39%.
Trioxane 11a. Yield 67%, white solid; mp 81-82 °C. IR (KBr,
cm-1) 1639, 3433. 1H NMR (300 MHz, CDCl3) δ 1.40-2.04 (m,
8H), 2.63-2.68 and 2.82-2.86 (2 ꢀ bm, together integrating
for 1H), 3.36-3.42 (m, 1H), 3.82-3.87 (m, 1H), 3.98 and 4.05
(2 ꢀ dd, J = 11.8 and 10.6 Hz, respectively, together integrating
for 1H), 5.44-5.47 (m, 2H), 5.68 (s, 1H), 6.58 (d, 2H, J = 8.1 Hz,
Ar), 6.68 (t, 1H, J = 7.2 Hz, Ar), 7.16 (t, 2H, J = 8.1 Hz, Ar),
7.56-7.74 (m, 5H, Ar), 7.82-7.88 (m, 2H, Ar), 8.67-8.69 (m,
2H, Ar). 13C NMR (75 MHz, CDCl3) δ 26.86 (CH2), 27.45
(CH2), 28.26 (CH2), 28.53 (CH2), 28.78 (CH2), 28.88 (CH2),
32.43 (CH2), 33.32 (CH2), 50.60 (CH), 50.94 (CH), 63.07 (CH2),
63.33 (CH2), 80.04 (CH), 102.19 (C), 102.27 (C), 113.50 (2 ꢀ
CH), 117.51 (CH), 117.77 (CH2), 120.78 (CH), 122.83 (CH),
125.25 (CH), 126.60 (CH), 126.97 (CH), 127.07 (CH), 127.68
(CH), 128.92 (CH), 129.07 (CH), 129.56 (2 ꢀ CH), 130.42 (2 ꢀ
C), 132.00 (C), 132.49 (C), 136.94 (C), 144.04 (C), 147.39 (C).
ESI-MS (m/z) 452 [M þ H]þ. HRMS calcd for C30H29NO3,
451.2147; found, 451.2102. Anal. Calcd for C30H29NO3: C,
79.80%, H, 6.47%, N, 3.10%. Found: C, 79.92%, H, 6.68%,
N, 2.98.
Trioxane 11b. Yield 82%, white solid; mp 96-97 °C. IR (KBr,
cm-1) 1596, 3403. 1H NMR (300 MHz, CDCl3) δ 1.41-1.96 (m,
8H), 2.80-2.85 (bm, 1H), 3.25-3.31 (m, 1H), 3.82 (dd, 1H, J =
11.5 and 2.7 Hz), 4.03 (dd, 1H, J = 11.5 and 10.2 Hz), 5.41-5.46
(m, 2H), 5.66 (s, 1H), 6.47-6.51 (m, 2H, Ar), 6.82-6.88 (m, 2H,
Ar), 7.54-7.72 (m, 5H, Ar), 7.80-7.86 (m, 2H, Ar), 8.66 (bm,
2H, Ar). 13C NMR (75 MHz, CDCl3) δ 27.43 (CH2), 28.75
(CH2), 28.86 (CH2), 33.32 (CH2), 51.69 (CH), 63.33 (CH2),
81.04 (CH), 102.16 (C), 114.44 (CH), 114.54 (CH), 115.80
(CH), 116.09 (CH), 117.79 (CH2), 120.77 (CH), 122.82 (CH),
125.25 (CH), 126.61 (CH), 126.97 (CH), 127.08 (CH), 127.69
(CH), 128.94 (CH), 129.08 (CH), 130.42 (2 ꢀ C), 132.00 (C),
132.48 (C), 136.92 (C), 143.71 (C), 144.00 (C), 155.94 (C, JC-F
= 235.1 Hz). ESI-MS (m/z) 470 [M þ H]þ. HRMS calcd for
C30H28FNO3, 469.2053; found, 469.2028. Anal. Calcd for
C30H28FNO3: C, 76.74%, H, 6.01%, N, 2.98%. Found: C,
76.89%, H, 6.45%, N, 2.75%.
Trioxane 10h. Yield 65%, oil. IR (neat, cm-1) 1599, 3391. 1H
NMR (300 MHz, CDCl3) δ 1.40-1.95 (m, 8H), 2.60-2.65 and
2.79-2.83 (2 ꢀ bm, together integrating for 1H), 3.37-3.40 (m,
1H), 3.72-3.79 (m, 1H), 3.84 (s, 2H), 3.89-4.04 (m, 1H), 5.32
(bm, 2H), 5.53 (s, 1H), 6.66 (d, 1H, J = 7.9 Hz, Ar), 6.76 (s, 1H,
Ar), 6.88 (d, 1H, J = 7.5 Hz, Ar), 7.17-7.25 (m, 1H, Ar),
7.30-7.38 (m, 3H, Ar), 7.49-7.54 (m, 2H, Ar), 7.68-7.78 (m,
2H, Ar). 13C NMR (75 MHz, CDCl3) δ 26.73 (CH2), 27.26
(CH2), 28.03 (CH2), 28.31 (CH2), 28.55 (CH2), 28.64 (CH2),
32.33 (CH2), 33.21 (CH2), 37.09 (CH2), 50.42 (CH), 50.71 (CH),
63.09 (CH2), 63.36 (CH2), 80.73 (CH), 102.01 (C), 109.46 (CH),
113.72 (CH), 116.22 (CH), 116.27 (CH2), 120.09 (CH), 120.24
(CH), 123.21 (CH), 125.28 (CH), 125.40 (CH), 127.07 (CH),
127.20 (CH), 128.54 (CH), 129.91 (CH), 131.83 (C, JC-F = 31.9
Hz), 137.25 (C), 137.28 (C), 141.30 (C), 142.08 (C), 143.67 (C),
143.84 (2 ꢀ C), 147.52(C). FAB-MS (m/z) 507 [M]þ. HRMS
calcd for C30H28F3NO3, 507.2021; found, 507.2030. Anal. Calcd
for C30H28F3NO3: C, 70.99%, H, 5.56%, N, 2.76%. Found: C,
70.81%, H, 5.32%, N, 2.42%.
Trioxane 10i. This was obtained as oil in 58% yield as a
mixture of diastereomers 10il and 10im, which were separated by
column chromatography.
Trioxane 11c. Yield 63%, white solid; mp 60-61 °C. IR (KBr,
cm-1) 1597, 3402. 1H NMR (300 MHz, CDCl3) δ 1.42-2.01 (m,
8H), 2.65-2.70 and 2.85-2.89 (2 ꢀ bm, together integrating for
1H), 3.32-3.42 (m, 1H), 3.88 (dd, 1H, J = 11.9 and 2.9 Hz), 4.01
and 4.08 (2 ꢀ dd, J = 11.9 and 10.4 Hz, respectively, together
1
Trioxane (10il, Less Polar). IR (neat, cm-1) 1617, 3420. H
NMR (300 MHz, CDCl3) δ 1.46-2.04 (m, 8H), 2.81-2.86 (bm,
1H), 3.39-3.46 (m, 1H), 3.83 (dd, 1H, J = 11.8 and 2.8 Hz), 3.89
(s, 2H), 4.02 (dd, 1H, J = 11.8 and 10.5 Hz,), 5.31-5.34 (m, 2H),

7596 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 21
Singh et al.
integrating for 1H), 5.47-5.52 (m, 2H), 5.72 (s, 1H), 6.52 (d, 2H,
J = 8.6 Hz, Ar), 7.13 (d, 2H, J = 8.6 Hz, Ar), 7.61-7.78 (m, 5H,
Ar), 7.86-7.92 (m, 2H, Ar), 8.71-8.72 (m, 2H, Ar). 13C NMR
(75 MHz, CDCl3) δ 27.39 (CH2), 28.61 (CH2), 28.70 (CH2),
33.25 (CH2), 51.06 (CH), 63.31 (CH2), 81.02 (CH), 102.06 (C),
114.52 (2 ꢀ CH), 117.78 (CH2), 120.76 (CH), 121.90 (C), 122.80
(CH), 125.23 (CH), 126.59 (CH), 126.96 (CH), 127.07 (CH),
127.68 (CH), 128.92 (CH), 129.07 (CH), 129.34 (2 ꢀCH),
130.42 (2 ꢀ C), 131.99 (C), 132.47 (C), 136.89 (C), 143.98 (C),
145.93 (C). ESI-MS (m/z) 486 [M þ H]þ. HRMS calcd for
C30H28ClNO3:, 485.1758; found, 485.1768. Anal. Calcd for
C30H28ClNO3: C, 74.14%, H, 5.81%, N, 2.88%. Found: C,
74.35%, H, 6.11%, N, 2.62%.
Trioxane (11gl, Less Polar). Melting point 55-56 °C. IR
(KBr, cm-1) 1582, 3406. 1H NMR (300 MHz, CDCl3) δ
1.32-1.99 (m, 8H), 2.49-2.53 (bm, 1H), 3.41-3.46 (m, 1H),
3.80 (dd, 1H, J = 11.9 and 2.9 Hz), 3.93 (dd, 1H, J = 11.9 and
10.2 Hz), 5.40-5.45 (m, 2H), 5.66 (s, 1H), 6.70-6.76 (m, 2H, Ar),
7.06-7.08 (m, 1H, Ar), 7.18-7.24 (m, 1H, Ar), 7.30-7.43 (m,
5H, Ar),7.56-7.73 (m, 5H, Ar), 7.81-7.88 (m, 2H, Ar),
8.65-8.68 (m, 2H, Ar).; 13C NMR (75 MHz, CDCl3) δ 26.85
(CH2), 28.15 (CH2), 28.46 (CH2), 32.37 (CH2), 50.58 (CH), 63.03
(CH2), 81.02 (CH), 102.24 (C), 111.21 (CH), 117.05 (CH), 117.73
(CH2), 120.80 (CH), 122.84 (CH), 125.27 (CH), 126.62 (CH),
126.98 (CH), 127.08 (CH), 127.44 (CH), 127.69 (CH), 128.05 (C),
128.94(2 ꢀ CH), 129.07 (CH), 129.16 (2 ꢀ CH), 129.54(2 ꢀ CH),
130.44 (CH), 130.73 (2 ꢀ C), 132.01 (C), 132.50 (C), 136.94 (C),
139.72 (C), 144.08 (C), 144.18 (C). ESI-MS (m/z) 528 [M þ H]þ.
HRMS calcd for C36H33NO3, 527.2460; found, 527.2468. Anal.
Calcd for C36H33NO3: C, 81.95%, H, 6.30%, N, 2.65%. Found:
C, 81.51%, H, 6.17%, N, 2.82%.
Trioxane (11gm, More Polar). Melting point 70-71 °C. IR
(KBr, cm-1) 1582, 3406. 1H NMR (300 MHz, CDCl3) δ 1.33-
1.96 (m, 8H), 2.70-2.75 (bm, 1H), 3.38-3.46 (m, 1H), 3.82
(dd, 1H, J = 11.8 and 2.9 Hz), 4.02 (dd, 1H, J = 11.8 and 10.5
Hz), 5.40-5.44 (m, 2H), 5.66 (s, 1H), 6.70-6.76 (m, 2H, Ar),
7.07-7.10 (m, 1H, Ar), 7.18-7.24 (m, 1H, Ar), 7.33-7.46 (m,
5H, Ar), 7.56-7.71 (m, 5H, Ar), 7.81-7.88 (m, 2H, Ar),
8.65-8.68 (m, 2H, Ar). 13C NMR (75 MHz, CDCl3) δ 27.31
(CH2), 28.61 (CH2), 28.73 (CH2), 32.16 (CH2), 50.78 (CH), 63.29
(CH2), 80.96 (CH), 102.18 (C), 111.25 (CH), 117.03 (CH), 117.64
(CH2), 120.77 (CH), 122.84 (CH), 125.24 (CH), 126.61 (CH),
126.97 (CH), 127.08 (CH), 127.50 (CH), 127.68 (CH), 128.20 (C),
128.88 (CH), 128.93 (CH), 129.08 (CH), 129.20 (2 ꢀ CH), 129.53
(2 ꢀ CH), 130.42 (2 ꢀ C), 130.72 (CH), 132.01 (C), 132.49 (C),
136.93 (C), 139.63 (C), 144.01 (C), 144.22 (C). ESI-MS (m/z) 528
[M þ H]þ. Anal. Calcd for C36H33NO3: C, 81.95%, H, 6.30%, N,
2.65%. Found: C, 81.59%, H, 6.45%, N, 2.42%.
Trioxane 11h. Yield 72%, white solid; mp 55-57 °C. IR (KBr,
cm-1) 1570, 3412. 1H NMR (300 MHz, CDCl3) δ 1.40-2.01 (m,
8H), 2.62-2.67 and 2.82-2.87 (2 ꢀ bm, together integrating for
1H), 3.38-3.43 (m, 1H), 3.83 (dd, 1H, J = 11.7 and 2.8 Hz), 3.96
and 4.04 (2 ꢀ dd, J = 11.7 and 10.5 Hz, respectively, together
integrating for 1H), 5.43-5.46 (m, 2H), 5.67 (s, 1H), 6.67 (d, 1H,
J = 8.0 Hz, Ar), 6.75 (s, 1H, Ar), 6.88 (d, 1H, J = 7.6 Hz, Ar),
7.18-7.23 (m, 1H, Ar), 7.58-7.70 (m, 5H, Ar), 7.82-7.88 (m,
2H, Ar), 8.66-8.68 (m, 2H, Ar). 13C NMR (75 MHz, CDCl3) δ
26.78 (CH2), 27.37 (CH2), 28.05 (CH2), 28.34 (CH2), 28.60
(CH2), 28.70 (CH2), 32.35 (CH2), 33.25 (CH2), 50.42 (CH),
50.76 (CH), 63.10 (CH2), 63.36 (CH2), 81.04 (CH), 102.03 (C),
109.38 (CH), 113.79 (CH), 116.30 (CH), 117.84 (CH2), 120.79
(CH), 122.83 (CH), 125.25 (CH), 126.62 (CH), 127.00 (CH),
127.11 (CH), 127.72 (CH), 128.96 (CH), 129.11 (CH), 129.95 (C)
130.40 (C), 131.66 (C), 131.87 (C, JC-F = 31.8 Hz), 132.02 (C),
132.49 (C), 136.90 (C), 143.96 (C), 147.52 (C). ESI-MS (m/z) 520
[M þ H]þ. HRMS calcd for C31H28F3NO3, 519.2021; found,
519.2027. Anal. Calcd for C31H28F3NO3: C, 71.66%, H, 5.43%;
N, 2.70%. Found: C, 71.22%, H, 5.82%; N, 2.66%.
Trioxane 11d. Yield 78%, white solid; mp 70-71 °C. IR (KBr,
cm-1) 1590, 3406. 1H NMR (300 MHz, CDCl3) δ 1.39-1.98 (m,
8H), 2.65-2.68 and 2.84-2.88 (2 ꢀ bm, together integrating for
1H), 3.33 (bm, 1H), 3.84-3.89 (m, 1H), 3.98 and 4.06 (2 ꢀ dd,
J = 11.7 and 10.3 Hz, respectively, together integrating for 1H),
5.46-5.50 (m, 2H), 5.71 (s, 1H), 6.43 (s, 2H, Ar), 6.65 (s, 1H,
Ar), 7.59-7.77 (m, 5H, Ar), 7.85-7.91 (m, 2H, Ar), 8.69-8.72
(m, 2H, Ar). 13C NMR (75 MHz, CDCl3) δ 26.78 (CH2), 27.37
(CH2), 27.99 (CH2), 28.29 (CH2), 28.51 (CH2), 28.62 (CH2),
32.31 (CH2), 33.20 (CH2), 50.48 (CH), 50.79 (CH), 63.08 (CH2),
63.34 (CH2), 81.03 (CH), 101.90 (C), 111.34 (2 ꢀ CH), 117.01
(CH), 117.81 (CH2), 120.79 (CH), 122.82 (CH), 125.24 (CH),
126.62 (CH), 126.99 (CH), 127.11 (CH), 127.72 (CH), 128.96
(CH), 129.10 (CH), 130.41 (2 ꢀ C), 132.02 (C), 132.50 (C),
135.77 (2 ꢀ C), 136.89 (C),143.97 (C), 148.98 (C). ESI-MS (m/z)
520 [M þ H]þ. Anal. Calcd for C30H27Cl2NO3: C, 69.23%, H,
5.23%, N, 2.69%. Found: C, 69.41%, H, 5.61%, N, 2.52%.
Trioxane 11e. Yield 74%, white solid; mp 63-64 °C. IR (KBr,
cm-1) 1594, 3421. 1H NMR (300 MHz, CDCl3) δ 1.24-2.02 (m,
8H), 2.22 (s, 3H), 2.62-2.67 and 2.81-2.85 (2 ꢀ bm, together
integrating for 1H), 3.33-3.40 (m, 1H), 3.81-3.86 (m, 1H), 3.96
and 4.04 (2 ꢀ dd, J = 11.7 and 10.3 Hz, respectively, together
integrating for 1H), 5.42-5.47 (m, 2H), 5.67 (s, 1H), 6.51 (d, 2H,
J = 7.9 Hz, Ar), 6.96 (d, 2H, J = 7.9 Hz, Ar), 7.56-7.73 (m, 5H,
Ar), 7.81-7.87 (m, 2H, Ar), 8.66-8.68 (m, 2H, Ar). 13C NMR
(75 MHz, CDCl3) δ 20.59 (CH3), 26.82 (CH2), 27.41 (CH2),
28.24 (CH2), 28.52 (CH2), 28.77 (CH2), 28.88 (CH2), 32.42
(CH2), 33.33 (CH2), 50.89 (CH), 51.25 (CH), 63.04 (CH2),
63.31 (CH2), 80.97 (CH), 102.22 (C), 102.31 (C), 113.81 (2 ꢀ
CH), 117.58 (CH2), 117.75 (CH2), 120.73 (CH), 122.81 (CH),
125.21 (CH), 126.58 (CH), 126.76 (CH), 126.95 (CH), 127.05
(CH), 127.66 (CH), 128.90 (CH), 129.06 (CH), 130.02 (2 ꢀ CH),
130.39 (2 ꢀ C), 131.96 (C), 132.43 (C), 136.87 (C), 143.94 (C),
145.03 (C). ESI-MS (m/z) 466 [M þ H]þ. HRMS calcd for
C31H31NO3, 465.2304; found, 465.2282; Anal. Calcd for
C31H31NO3: C, 79.97%, H, 6.71%, N, 3.01%. Found: C,
79.89%, H, 6.98%, N, 2.97%.
Trioxane 11f. Yield 65%, white solid; mp 110-111 °C. IR
(KBr, cm-1) 1593, 3412. 1H NMR (300 MHz, CDCl3) δ
1.42-2.02 (m, 8H), 2.80-2.85 (bm, 1H), 3.26-3.34 (m, 1H),
3.72(s, 3H), 3.83 (dd, 1H, J = 11.8 and 2.8 Hz), 4.04 (dd, 1H,
J = 11.8 and 10.5 Hz), 5.42-5.47 (m, 2H), 5.67 (s, 1H), 6.56 (d,
2H, J = 8.8 Hz, Ar), 6.76 (d, 2H, J = 8.8 Hz, Ar), 7.56-7.74 (m,
5H, Ar), 7.82-7.88 (m, 2H, Ar), 8.66-8.68 (m, 2H, Ar). 13C
NMR (75 MHz, CDCl3) δ 27.46 (CH2), 28.90 (CH2), 29.01
(CH2), 33.34 (CH2), 52.08 (CH), 56.02 (CH3), 63.31 (CH2),
81.04 (CH), 102.25 (C), 115.23 (2 ꢀ CH), 115.29 (2 ꢀ CH),
117.74 (CH2), 120.78 (CH), 122.82 (CH), 125.25 (CH), 126.59
(CH), 126.95 (CH), 127.05 (CH), 127.65 (CH), 128.91 (CH),
129.05 (CH), 130.43 (2 ꢀ C), 131.99 (C), 132.48 (C), 136.95 (C),
141.58 (C), 144.06 (C), 152.42 (C). ESI-MS (m/z) 482 [M þ H]þ.
HRMS calcd for C31H31NO4, 481.2253; found, 481.2247. Anal.
Calcd for C31H31NO4: C, 77.31%, H, 6.49%, N, 2.91%. Found:
C, 77.53%, H, 6.89%, N, 3.21%.
Trioxane 11i. This was obtained as oil in 56% yield as a
mixture of diastereomers 11il and 11im, which were separated by
column chromatography.
1
Trioxane (11il, Less Polar). IR (neat, cm-1) 1589, 3413. H
NMR (300 MHz, CDCl3) δ 1.45-2.02 (m, 8H), 2.87-2.91 (bm,
1H), 3.42-3.43 (m, 1H), 3.89 (dd, 1H, J = 11.8 and 2.8 Hz), 4.09
(dd, 1H, J = 11.8 and 10.3 Hz,), 5.48-5.52 (m, 2H), 5.73 (s, 1H),
6.58 (d, 2H, J = 8.5 Hz, Ar), 7.41 (d, 2H, J = 8.5 Hz, Ar),
7.61-7.78 (m, 5H, Ar). 7.86-7.93 (m, 2H, Ar), 8.70-8.72
(m, 2H, Ar). 13C NMR (75 MHz, CDCl3) δ 27.36 (CH2),
28.51 (CH2), 28.61 (CH2), 33.21 (CH2), 50.56 (CH), 63.33
(CH2), 81.05 (CH), 101.96 (C), 112.34 (2ꢀCH), 117.82
(CH2), 118.77 (C, JC-F = 32.4 Hz), 120.78 (CH), 122.81 (CH),
123.45 (C), 125.24 (CH), 126.61 (CH), 126.88 (CH), 126.93 (CH),
126.98 (CH), 127.10 (CH), 127.72 (CH), 128.96 (CH), 129.10
Trioxane 11g. This was obtained as a white solid in 54% yield
as a mixture of diastereomers 11gl and 11gm, which were
separated by column chromatography.

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 21 7597
(CH), 130.41 (C), 130.45 (C), 132.02 (C), 132.50 (C), 136.90 (C),
143.96 (C), 149.84 (C). ESI-MS (m/z) 520 [M þ H]þ. HRMS
calcd for C31H28F3NO3, 519.2021; found, 519.2016; Anal. Calcd
for C31H28F3NO3: C, 71.66%, H, 5.43%, N, 2.70%. Found: C,
71.93%, H, 4.96%, N, 2.60%.
117.70 (CH2), 120.64 (CH), 122.75 (CH), 125.15 (CH), 126.52
(CH), 126.89 (CH), 126.98 (CH), 127.57 (CH), 128.83 (CH),
128.99 (CH), 130.31 (2 ꢀ C), 131.87 (C), 132.36 (C), 136.81 (C),
143.87 (C). ESI-MS (m/z) 394 [M þ NH4]þ. HRMS calcd for
C24H24O4, 376.1675; found, 376.1676.
Trioxane (11im, More Polar). IR (neat, cm-1) 1685, 3415. 1H
NMR (300 MHz, CDCl3) δ 1.28-2.06 (m, 8H), 2.68-2.72 (bm,
1H), 3.44-3.47 (m, 1H), 3.87-3.92 (m, 1H), 4.01 (dd, 1H, J =
11.8 and 10.4 Hz,), 5.48-5.52 (m, 2H), 5.72 (s, 1H), 6.58 (d, 2H,
J = 8.4 Hz, Ar), 7.41 (d, 2H, J = 8.4 Hz, Ar), 7.61-7.78 (m, 5H,
Ar). 7.86-7.92 (m, 2H, Ar), 8.66-8.74 (m, 2H, Ar). 13C NMR
(75 MHz, CDCl3) δ 26.77 (CH2), 27.97 (CH2), 28.24 (CH2), 32.31
(CH2), 50.23 (CH), 63.05 (CH2), 80.99 (CH), 102.00 (C), 112.32
(2 ꢀ CH), 117.64 (CH2), 118.81 (C, JC-F = 32.3 Hz), 120.75
(CH), 122.80 (CH), 123.33 (C), 125.23 (CH), 126.59 (CH), 126.87
(CH), 126.97 (2 ꢀ CH), 127.08 (CH), 127.70 (CH), 128.93 (CH),
129.08 (CH), 130.39 (C), 130.44 (C), 132.00 (C), 132.48 (C),
136.86 (C), 143.99 (C), 149.78 (C). ESI-MS (m/z) 520 [M þ H]þ.
Anal. Calcd for C31H28F3NO3: C, 71.66%, H, 5.43%, N, 2.70%.
Found: C, 71.78%, H, 5.68%, N, 2.43%.
Acknowledgment. M.H., N.K.N., V.P.V., and A.S.S. are
thankful to the University Grant Commission (UGC) and
Council of Scientific and Industrial Research (CSIR), New Delhi,
for the awards of Senior Research Fellowship.
Supporting Information Available: 1H NMR and 13C NMR
Spectra of trioxanes 7a-d, 8a-i, 9a-i, 10a-i, and 11a-i. This
material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) CDRI Communication no. 7560.
(2) World Health Organization 10 Facts on Malaria. www.who.int/
features/factfiles/malaria.
Trioxane 12a. Yield 14% yield, oil. IR (neat, cm-1) 1587,
3425. 1H NMR (300 MHz, CDCl3) δ 1.48-1.82 (m, 7H),
2.33-2.58 (m, 2H), 3.62-3.81 (m, 2H) 3.86-3.96 (m, 1H),
5.11 (dd, 1H, J = 10.3 and 2.2 Hz), 5.38 (s, 1H), 5.68 (s, 1H),
7.23 (d, 1H, J = 7.3 Hz, Ar), 7.38 (t, 1H, J = 7.5 Hz, Ar),
7.43-7.51 (m, 2H, Ar), 7.76-7.83 (m, 2H, Ar), 7.96 (d, 1H, J =
7.6 Hz, Ar). 13C NMR (75 MHz, CDCl3) δ 25.02 (CH2), 25.51
(CH2), 29.96 (CH2), 30.13 (CH2), 30.38 (CH2), 30.50 (CH2),
30.78 (CH2), 31.49 (CH2), 62.63 (CH2), 63.00 (CH2), 67.79
(CH), 68.30 (CH), 81.67 (CH), 102.02 (C), 119.83 (CH2),
125.24 (CH), 125.35 (CH), 125.99 (CH), 126.10 (CH), 126.52
(CH), 128.45 (CH), 128.49 (CH), 131.35 (C), 133.72 (C), 137.19
(C), 143.27 (C). ESI-MS (m/z) 326 [M]þ. HRMS calcd for
C20H22O4, 326.1518; found, 326.1519.
Trioxane 12b. Yield 12%, white solid; mp 105-106 °C. IR
(KBr, cm-1) 1595, 3425. 1H NMR (200 MHz, CDCl3) δ
1.37-2.17 (m, 8H), 2.37-2.42 (m, 1H), 3.80-3.96 (m, 2H),
4.01 (dd, 1H, J = 11.7 and 10.4 Hz), 5.38-5.42 (m, 2H), 5.65 (s,
1H), 7.46-7.55 (m, 3H, Ar), 7.80-7.84 (m, 4H, Ar). 13C NMR
(75 MHz, CDCl3) δ 25.35 (CH2), 30.43 (CH2), 30.60 (CH2),
31.20 (CH2), 63.28 (CH2), 67.78 (CH), 68.29 (CH), 80.77 (CH),
102.46 (C), 117.28 (CH2), 124.80 (CH), 125.72 (CH), 126.76
(CH), 126.87 (CH), 128.01 (CH), 128.65 (CH), 128.71 (CH),
133.43 (C), 133.65 (C), 136.20 (C), 143.65 (C). ESI-MS (m/z) 327
[M þ H]þ. HRMS calcd for C20H22O4, 326.1518; found,
326.1520.
Trioxane 12c. Yield 10%, white solid; mp 150-151 °C. IR
(KBr, cm-1) 1596, 3411. 1H NMR (300 MHz, CDCl3) δ
1.53-2.10 (m, 8H), 2.35-2.43 and 2.58-2.62 (2 ꢀ m, together
integrating for 1H), 3.78-3.85 (m, 2H), 3.87 (s, 2H), 3.95 and
3.97 (2 ꢀ dd, J = 11.7 and 2.8 Hz, together integrating for 1H),
5.28-5.32 (m, 2H), 5.54 (s, 1H), 7.23-7.40 (m, 3H, Ar),
7.51-7.55 (m, 2H, Ar), 7.70-7.76 (m, 2H, Ar). 13C NMR (75
MHz, CDCl3) δ 25.16 (CH2), 30.25 (CH2), 30.42 (CH2), 31.02
(CH2), 37.13 (CH2), 63.07 (CH2), 68.11 (CH), 80.72 (CH),
102.22 (C), 116.20 (CH2), 120.11 (CH), 120.26 (CH), 123.23
(CH), 125.29 (CH), 125.43 (CH), 127.08 (CH), 127.19 (CH),
137.34 (C), 141.34 (C), 142.07 (C), 143.69 (C), 143.83 (2 ꢀ C).
ESI-MS (m/z) 364 [M]þ. HRMS calcd for C23H24O4, 364.1675;
found, 364.1665. Anal. Calcd for C23H24O4: C, 75.80%, H,
6.64%. Found: C, 75.31%, H, 6.24%.
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New orally active spiro 1,2,4-trioxanes with high antimalarial potency.
Trioxane 12d. Yield 13%, oil. IR (neat, cm-1) 1656, 3428. 1H
NMR (300 MHz, CDCl3) δ 1.63-2.00 (m, 8H), 2.42-2.47 and
2.66-2.67 (2 ꢀ m, together integrating for 1H), 3.82-3.89 (m,
2H), 3.99-4.06 (m, 1H), 5.45-5.50 (m, 2H), 5.69 (s, 1H),
7.59-7.76 (m, 5H, Ar), 7.84-7.90 (m, 2H, Ar), 8.70-8.72 (m,
2H, Ar). 13C NMR (75 MHz, CDCl3) δ 25.14 (CH2), 25.64
(CH2), 30.11 (CH2), 30.28 (CH2), 30.54 (CH2), 30.63 (CH2),
30.93 (CH2), 31.62 (CH2), 62.91 (CH2), 63.25 (CH2), 67.93
(CH), 68.46 (CH), 80.89 (CH), 102.12 (C), 117.58 (CH2),

7598 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 21
Singh et al.
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trioxaspiro[5,5]undecanes against multidrug-resistant Plasmodium yoe-
lii nigeriensis in mice. J. Med. Chem. 2006, 49, 2794–2803. (i) Singh,
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antimalarial efficacy test: The blood schizonticidal activity of the test
compounds was evaluated in rodent model using multidrug-resistant
(MDR) strain of Plasmodium yoelii nigeriensis. The colony bred Swiss
mice of either sex (20 ( 2 g) were inoculated intraperitoneally with 1 ꢀ
106 P. yoelii nigeriensis (MDR) parasites on day zero, and treatment was
administered to a group of five mice at each dose, from day 0 to 3, in two
divided doses daily. The drug dilutions of compounds 8a-i, 9a-i,
10a-i, and 11a-i were prepared in groundnut oil so as to contain the
required amount of the drug (1.2 mg for a dose of 96 mg/kg, 0.6 mg for a
dose of 48 mg/kg, 0.3 mg for a dose of 24 mg/kg, and 0.15 mg for a dose
of 12 mg/kg) in 0.1 mL and administered orally for each dose.
Parasitaemia level were recorded from thin blood smears on day 4
and subsequently twice a week until day 28. The animals which did not
develop patent infection until day 28 were recorded as cured.13 Mice
treated with β-arteether served as positive control.
(12) (a) 100% protection means none of the treated mice developed
patent infection during the 28 days observation period and hence
were recorded as cured. Similarly, 20% protection means only one
out of five mice was cured. (b) 100% suppression of parasitemia
means no parasites were detected in 50 oil immersion microscopic
fields (parasites if at all present are below the detection limit). The
parasites present below the detection limit can multiply and
eventually can be detected during observation on subsequent days.
In such cases, though, the drug is providing near 100% suppression
of the parasitaemia on day 4 but will not provide full protection to
the treated mice in the 28 day survival assay. Multidrug-resistant
Plasmodium yoelii nigeriensis used in this study is resistant to
chloroquine, mefloquine, and halofantrine.
€
€
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peroxides and perorthoester with 1,2,4-trioxane structures. Angew.
Chem., Int. Ed. 2007, 46, 8883–8886. (m) Ramirez, A. P.; Thomas,
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Expl. Parasitol. 2000, 94, 8–14.
(14) The fact that both the diastereomers are equipotent could be a
coincidence, as in another series of structurally related amino-
trioxanes we have observed, that while some of the pairs of
diastereomers show similar level of activity, others show significant
difference.15
€
€
A. G.; Neudorfl, J.; Horauf, A.; Specht, S.; Raabe, A. Antimalarial
peroxide dyads from natural artemisinin and hydroxyalkylated 1,2,4-
trioxanes. J. Med. Chem. 2009, 52, 3420–3423.
(8) (a) Singh, C.; Malik, H. Protection of the carbonyl group as 1,2,4-
(15) Malik, H. Ph. D. Thesis. Jawaharlal Nehru University, New Delhi,
2005.
trioxane and its regeneration under basic conditions. Org. Lett.