1,2,3-Triazole tethered 1,2,4-trioxanes: Studies on their synthesis and effect on osteopontin expression in MDA-MB-435 breast cancer cells

Article abstract of DOI:10.1016/j.ejmech.2019.111908

Artemisinin and its analogs have shown potent anticancer activity in primary cancer cultures and cell lines by inhibiting cancer proliferation, metastasis, and angiogenesis. Despite its apparent compatibility to normal cells and low IC₅₀ values

Full text of DOI:10.1016/j.ejmech.2019.111908

Journal Pre-proof
1,2,3-Triazole tethered 1,2,4-trioxanes: Studies on their synthesis and effect on
osteopontin expression in MDA-MB-435 breast cancer cells
Bala Gangadhar Pasupuleti, Kitboklang Khongsti, Bidyadhar Das, Ghanashyam Bez
PII:
S0223-5234(19)31060-8
DOI:
https://doi.org/10.1016/j.ejmech.2019.111908
EJMECH 111908
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 13 September 2019
Revised Date: 21 November 2019
Accepted Date: 22 November 2019
Please cite this article as: B.G. Pasupuleti, K. Khongsti, B. Das, G. Bez, 1,2,3-Triazole tethered
1,2,4-trioxanes: Studies on their synthesis and effect on osteopontin expression in MDA-MB-435
breast cancer cells, European Journal of Medicinal Chemistry (2019), doi: https://doi.org/10.1016/
j.ejmech.2019.111908.
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Graphical Abstract
1,2,3-Triazole tethered 1,2,4-trioxanes: Studies on their synthesis and effect on
osteopontin expression in MDA-MB-435 breast cancer cells
R
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R1
O
R
O
O
N
R1
N
N
X
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1,2,3-Triazole tethered 1,2,4-trioxanes: Studies on their synthesis and effect on
osteopontin expression in MDA-MB-435 breast cancer cells
Bala Gangadhar Pasupuleti,a Kitboklang Khongsti,b Bidyadhar Dasb* and Ghanashyam Beza*
aDepartment of Chemistry, North-Eastern Hill University, Shillong-793022, Meghalaya, India
bDepartment of Zoology, North-Eastern Hill University, Shillong-793022, Meghalaya, India
ghanashyambez@yahoo.com
Abstract
Artemisinin and its analogs have shown potent anticancer activity in primary cancer cultures and
cell lines by inhibiting cancer proliferation, metastasis, and angiogenesis. Despite its apparent
compatibility to normal cells and low IC50 values in comparison to the commonly used
anticancer drugs, the underlying mechanisms behind their cytotoxic effects are not yet fully
understood. Surprisingly, the efficacy of synthetic 1,2,4-trioxanes against cancer has not been
explored yet. Given the high antitumor activity of artemisinin dimers in comparison to their
monomers, we report here the synthesis of simple 1,2,3-triazole conjugated 1,2,4-trioxanes and
their potential antitumor activity by studying their inhibitory effect on osteopontin (OPN)
expression in MDA-MB-435 breast cancer cells. It may be noted that despite being a strong
marker to identify human tumor metastasis, no study on effect of artemisinin and its synthetic
and semisynthetic derivatives on OPN expression has ever been studied. Although our initial
studies did not notice any straight-line relationship between the number of trioxane units in a
molecule to the extent of inhibition of OPN protein expression, we could observe better results in
some cases in comparison to artemisinin. Although artemisinin did not show appreciable OPN
downregulation in MDA-MB-435 cancer cells, dihydroartemisinin (DHA) and some synthetic
1,2,4-trioxane monomers and dimers showed downregulation of OPN expression. Therefore,
these compounds may act as an anti-metastatic agent in controlling breast cancer cells metastasis.
Keywords: 1,2,4-trioxanes, 1,2,3-triazoles, cancer metastasis, OPN, MDA-MB-435 cells
1

Introduction
Osteopontin (OPN) is a non-collagenous and sialic acid-rich extra cellular glycosylated
phosphoprotein that can be used as a biomarker to determine the oncogenic potential of various
cancers [1,2]. OPN plays crucial roles in cancer cell metastasis and upregulation of OPN
expression can be correlated with enhanced tumor progression and metastasis in a variety of
cancers [3-5]. Since OPN regulates various cell signaling pathways leading to tumor progression
by interacting with its receptor site, its inhibition can block downstream cell signaling pathways
to interrupt tumor cell progression and metastasis.
Since the discovery of anticancer properties of artemisinin by Woerdenberg and coworkers in
1993 [6], various artemisinin derivatives have demonstrated decreased proliferation, increased
level of oxidative stress, induction of apoptosis, and angiogenesis in cancer cells. Given the
dose-dependent toxicity is one of the major concerns in current anticancer therapy, artemisinin
may have benefits as an anticancer agent due to its negligible toxicity even after prolong
exposure till one year [7]. Among the semisynthetic artemisinin derived antitumor compounds
such as arteether, artemether, artesunate (1), and artemisone (2), the last one has shown better
pharmacokinetic profiles including a longer half-life and lower toxicity [8]. It is believed that
replacement of oxygen at C-10 by nitrogen might have removed the possibility of formation of
DHA during metabolic process and hence toxicity is reduced further. Artemether and artesunate
showed very low side effects in pituitary macroadenoma, malignant skin cancer, laryngeal
squamous cell carcinoma, and advanced non-small cell lung [9-11]. They substantially reduced
the tumor size and cancer metastasis with combination chemotherapy [9]. A host of
semisynthetic artemisinin derivatives, both monomers and dimers, were synthesized to observe
that majority of them showed better anticancer activity than the corresponding monomers. Since
various theory on anticancer property of artemisinin derivatives suggest that the endoperoxide
ring is crucial to its activity [12], it is natural to correlate the enhanced activity of the dimers to
the presence of two endoperoxide ring in the same molecule. Although there are many reports on
synthesis of synthetic 1,2,4-trioxanes to evaluate their antimalarial activity, to our surprise, their
anticancer activities have not been explored yet. Since artemisinin as a drug is not cost-effective
due to poor natural abundance and its derivatisation makes it even dearer, we planned to
synthesize some synthetic 1,2,4-trioxanes from readily available starting material by following
simple synthetic protocols and study their plausible antitumor properties.
2

1,2,3-triazoles show diverse pharmacological activities such as antiretroviral, antimicrobial, anti-
inflammatory, anticonvulsant, antiproliferative, etc. [13,14]. Since 1,2,3-triazole moiety acts as
H-bond acceptors of biomolecular targets, they are found in many interesting drugs [15-19]. Due
to their stability against metabolic degradation under a wide pH range [20] and redox conditions
under physiological conditions, they have found immense importance as a linker in the synthesis
of bioconjugates [16,21]. It is already established via various proof of concepts that if two
pharmacophores are linked through appropriate spacers to develop a new drug candidate, both
pharmacophores may interact synergistically to display higher activity [22]. Such concept was
proven in artemisinin and quinine hybrid to achieve enhanced antimalarial effect in comparison
to that of the stoichiometric mixture of artemisinin and quinine [23]. Benoit-Vical and coworkers
[24] also observed better antimalarial activity in trioxaquine, a trioxane-chloroquine hybrid than
the individual precursors. Similar observations were made in the case of artemisinin-primaquine
phosphate and stilbene-chalcone hybrids as well [25,26]. The fact that inhibition of tumor
metastasis in cancer cells by artemisinin and their derivatives has not been tested for OPN
protein expression inspired us to study the synthesis of some 1,2,3-traizole tethered 1,2,4-
trioxanes (Scheme 1) and their effect on OPN protein expression. Only in 2018, the first example
of effect of 1,2,4-trioxanes on OPN expression was carried out by Bai et al. where they observed
decreased OPN level upon treatment of osteoarthritic rat with artesunate (1) [27]. Since synthetic
1,2,4-trioxanes have never been studied for their anticancer activity and 1,2,3-triazoles possess
antiproliferative properties besides being a biocompatible linker, we assumed that both 1,2,3-
triazole and 1,2,4-trioxane cores may act synergistically in a 1,2,3-triazole tethered 1,2,4-
trioxanes to show antitumor activity.
Given the fact that osteopontin (OPN) can act as a marker for identification of metastatic cancer
cells, we synthesized a series of synthetic 1,2,4-trioxanes monomers and two series of 1,2,4-
3

dimers (Figure 1) starting from readily available citronellol with 1,2,3-triazoles as linkers to
study their effect on down regulation of OPN expression in MDA-MB-435 breast cancer cell
lines.
Figure 1.1,2,4-Trioxane for downregulation of OPN expression in breast cancer cell
Results and Discussion
Chemistry
For the synthesis of 1,2,4-trioxanes, we chose citronellol because the diversity points, viz. the
double bond and the hydroxy group are separated by five carbon aliphatic chain (Fig. 1). We
proposed to introduce the 1,2,3-triazole linker in place of the hydroxy group because of its easy
accessibility, physiological stability and the ease of tethering suitable moieties to study their
effect on biological activity. For that purpose, we proposed to convert the trisubstituted double
bond of citronellol to a 1,2,4-trioxane core having a diversity point and the primary hydroxy
group to an azide for the synthesis of 1,2,3-triazole linker (Figure 2).
Figure 2. Proposed 1,2,4-trioxane core
To achieve our objective, citronellol (3) was converted to its tosylated derivative using p-
o
toluenesulfonyl chloride in pyridine at 0-5 C to get desired 3,7-dimethyl-6-octenyl tosylate (4)
[28] in 81% isolated yield (Scheme 1). Then the 3,7-dimethyl-6-octenyl tosylate (4) was
converted to its azide derivative (5) [29] in 78% isolated yield by stirring with two equivalents of
4

o
NaN3 at 40 C overnight in dry DMF. Subsequently, the trisubstituted double bond of 8-azido-
2,6-dimethyloct-2-ene (5) was dihydroxylated with 1.2 equiv of NMO and 10 mol% OsO4 in
acetone/water (8/2) mixture at room temperature to get a diastereomeric pair of 8-azido-2,6-
dimethyloctane-2,3-diol (6) [30] in 87% isolated yields. To achieve the azido tethered 1,2,4-
trioxane compound (7a), we optimized the method (refer to Table S1 in supplementary data)
reported by Yadav and Coworkers [31] by treating 8-azido-2,6-dimethyloctane-2,3-diol (6) with
50% H2O2 (8 equiv.), conc. H2SO4 (0.25 equiv.) in dry CH2Cl2 to form azido tethered
hydroperoxide which upon treatment with p-nitrobenzaldehyde in the presence of p-TsOH
yielded the 1,2,4-trioxane derivative 7a as an inseparable diastereomeric mixture in 68% overall
yield.
The ratio ofdiastereomeric mixture of azido tethered 1,2,4-trioxane (Figure 3) was determined
1
from HNMR data where the protons at C3 (δ 6.04 ppm and δ 5.88 ppm) of 1,2,4-trioxane
nucleus have shown 1:3 ratio in favor of the nitrophenyl group in the equatorial position. While
the p-nitrophenyl group at the equatorial position is devoid of 1,3-diaxial interaction to form the
major diastereomer, its presence in the axial position experiences 1,3-diaxial interaction with the
axial hydrogen at C5 to form the minor diastereomer. The axial orientation of the nitrophenyl
group in the minor diastereomer was also confirmed by downfield shift of the proton [δ 3.77-
3.73 ppm (minor) and δ 3.61-3.57 ppm (major)] at C5 due to diamagnetic field of the phenyl
ring.
Scheme 1. Synthesis of 1,2,4-trioxanes with azide terminal
5

Reaction conditions: a) dry pyridine, p-TsCl, 0-5 oC, 12 h; b) dry DMF, NaN3, 40 oC, overnight;
c) NMO.H2O, OsO4 (10 mol%), acetone/water(8/2), RT, 24 h; d) H2O2, H2SO4, dichloromethane,
0-5 oC, 4 h; e) p-nitrobenzaldehyde, p-TsOH, dry dichloromethane, 0-5 oC-r.t, 12-18 h.
Figure 3. Plausible diastereoselective preference
The optimized reaction conditions were applied to synthesize various azido tethered 1,2,4-
trioxanes by varying the carbonyl counterpart (Scheme 1). The aromatic benzaldehydes bearing
both electron-releasing and electron withdrawing groups on the phenyl ring gave similar yields
under the optimized reaction conditions (7a-m). In contrast, cyclohexanone (7n) and p-chloro
acetophenone (7o) required 1.5 equiv. of p-TsOH to give the optimum yields.
Having synthesized a library of 1,2,4-trioxane derivatives with azide terminal, we proposed to
conjugate the trioxane with acetonide protected
manipulate the solubility of the trioxane by shuttling between protected and unprotected hydroxy
groups. For that purpose, -Fructose derived acetonide derivative (8) [32] was subjected to
D-fructose derived carbohydrate in order to
D
propargylation with propargyl bromide in the presence alkaline solution in the presence of a
phase transfer catalyst, tetrabutylammonium hydrogen sulfate (TBAHS) to get the propargylated
derivative (9), as shown in Scheme 2.
Scheme 2: Propargylation of
D
-Fructose acetonide
6

Scheme 3. Synthesis of 1,2,4-trioxanes bearing carbohydrate moiety
Then the compound 9 was subjected to CuI catalyzed CuAAC reaction with azido-1,2,4-trioxane
derivative, 7n in the presence of L-proline/glycerol [33] to obviate a carbohydrate bearing 1,2,4-
trioxane tethered 1,2,3-triazole, 10l (Scheme 3). The 13C-NMR spectra showed characteristic
signals at
145.30 (–C=CH-Ntriazole) and δ 122.10 ppm (–C=CH-Ntriazole) indicating the
13
formation of 1,4-substituted 1,2,3-triazole. The absence of any peak at ~133 ppm in C-NMR
spectra confirmed that 1,5-disubstituted 1,2,3-triazole regisoisomer is absent. The reaction was
extended to other azido-tethered 1,2,4-trioxanes to synthesize a library 10a-l in good yields.
It is known that many artemesinin dimers have shown better antimalarial and anticancer
properties than the parent artemesinin. For example, the artemisinin ether dimer (Figure 4) was
22 times more cytotoxic than artemesinin and 60 times more than dihydroartemesinin, DHA. It
may be due to the presence of two reactive peroxide centers in the dimer that can behave as
better radical generator viahomolytic cleavage of ether bridges linking to two monomeric units
[34].
Figure 4.Artemisinin dimer
7

With an aim to synthesize 1,2,4-trioxane dimers (12a-l), the reaction between azido tethered
1,2,4-trioxanes with diethynylbenzenewas carried out following our method [33] (Scheme 4).
For example, the product (12e) exhibited a singlet at δ 7.88 ppm integrating four protons
1
representing the symmetrical benzene ring between two 1,2,3-triazole rings in HNMR. A
doublet at δ 7.79 ppm with J value 4.4 Hz integrating two protons represented the protons in the
1,2,3-triazole rings; a muliplet at δ 4.48-4.41 ppm represented the methylene protons attached to
triazole ring. The 13C-NMR spectra also showed the characteristic signals at δ147.3 ppm (–
C=CH-Ntriazole) and δ119.5 ppm (–C=CH-Ntriazole) to prove the formation of 1,4-substituted 1,2,3-
triazole. The absence of any peak at ~133 ppm in 13CNMR spectra confirmed that 1,5-
disubstituted 1,2,3-triazole regisoisomer is absent. Nevertheless, the HRMS also showed a peak
at m/z 945.23 equivalent to (M+Na)+ of the compound 12e. The structures of other compounds
were also confirmed by IR, 1H-NMR, and 13CNMR spectral data shown in experimental section.
Scheme 4. 1,2,4-Trioxane dimers with 1,4-bis(triazolyl)benzene linker
Given the structural rigidity of 1,4-bis(1,2,3-triazolyl)benzene system, we synthesized another
series of 1,2,4-trioxane dimers (13a-i) starting from bispropargylated diethanolamine (refer to
the supplementary materials) by reacting with azido tethered 1,2,4-trioxanes under the same click
conditions (Scheme 5).
8

Scheme 5. 1,2,4-Trioxane dimers with bis(triazolyl)ethylamine linker
Biological Studies
OPN plays a functional role in progression and malignancy of breast cancer [35] and high
expression of OPN is observed in the highly invasive and metastatic human breast cancer cell
lines [36]. To study the effect of 1,2,4-trioxane monomers and dimers on OPN expression,
MDA- MB-435 cells (Fig. 5) were maintained using Dulbecco’s modified Eagle medium
(DMEM) supplemented with 10% fetal bovine serum (FBS), 1x antibiotic mix (penicillin and
streptomycin) at 37 ˚C in a humidified atmosphere of 5% CO2 (Fig. 1A). 1x106 MDA-MB-435
cells were seeded in a 6 cm plate and incubated for 24 h. The cells were then serum starved for
24 h and treated with 50 µM of the 1,2,4-trioxane derivatives for 24 h except for 13a-i (10 µM)
and OPN protein levels were analyzed by western blot.
Figure 5. MDA-MB-435 breast cancer cells maintenance under 40x magnification
9

Upon treatment with 1,2,4-trioxane monomer, a decrease in OPN expression were observed in
case compounds 10g (~ 0.2fold), 10k (~ 0.12 fold), 10d (~ 0.15 fold), and 10e (~ 0.15 fold)
while the rest did not show appreciable changes in their respective OPN expressions as compared
to the control (Fig. 6A-F). Interestingly, the reference compounds artemisinin showed no effect
on OPN expression while DHA and 1,2,3-triazole bearing DHA ether (11) decreased OPN
expression by ~ 0.45 and ~ 0.3fold respectively (Fig. 7A and 7B).
50 µM
10i
50 µM
10l
C
C
10h
10j
10g
10k
OPN
OPN
β-actin
β-actin
A
B
50 µM
C
10d
10b
10f
10a
10c
10e
OPN
β-actin
C
10h
10j
10i
10g
10k
D
C
C
10d
10b
10f
10a
10c
10e
C
10l
E
F
Figure 6. Effect of 1,2,4-trioxane monomers (10a-l) on OPN protein level in MDA-MB-435
breast cancer cells (A, B, C). Effect of monomers (50 µM) on OPN protein level treated for 24 h
and its corresponding densitometric analyses (D, E, F).
10

Figure 7. Effect of artemisinin, DHA and 11 (50 µM) on OPN protein level in MDA-MB-435
breast cancer cells after 24 h treatment and its corresponding densitometric analyses (B).
11

Figure 8. Effect of 1,2,4-trioxane dimers (12a-l) on OPN protein level in MDA-MB-435 breast
cancer cells (A, B, E). Effect of dimers (50 µM) on OPN protein level treated for 24 h and its
corresponding densitometric analyses (C, D, G).
The 1,2,4-trioxane dimers 12a-l showed no alterations in OPN expression level (Fig. 8) at 50 µM
level despite having two 1,2,4-trioxane units in those compounds. Surprisingly, treatment of
MDA-MB-435 cells with 1,2,4-trioxanes 13a-i bearing bis(triazolyl)ethylamine linker showed
significant decrease in OPN expression at 10 µM level, e.g. 13i (~ 0.27 fold), 13d (~ 0.26 fold),
13h (~ 0.15 fold), 13b (~ 0.17 fold), 13e (~ 0.33 fold), 13f (~ 0.11 fold), 13g (~ 0.43 fold), 13c
(~ 0.45 fold) and 13a (~ 0.28 fold) (Figs. 9). The fact that OPN plays a functional role in
progression and malignancy of breast cancer [35] and high expression of OPN is observed in the
highly invasive and metastatic human breast cancer cell lines [36], the compounds such as 10g,
12

11, 13a, 13c, 13d, 13e, 13g, 13i, and DHA may act as an anti-metastatic agent in controlling
MDA-MB-435 breast cancer cells metastasis. We are undertaking further studies to understand
the mechanism and functional sequel involved in this event.
Figure 9. Effect of 1,2,4-trioxane dimers with bis(triazolyl)ethylamine linkers (13a-i) on OPN
protein level in MDA-MB-435 breast cancer cells (A). Effect of dimers (10 µM) on OPN protein
level treated for 24 h and its corresponding densitometric analyses (B).
Conclusion
In summary, we have synthesized three series 1,2,4-trioxanes starting from citranellol. These
trioxanes were used for a preliminary study on downregulation of OPN expression in MDA-MB-
435 breast cancer cells where most of the synthetic 1,2,4-trioxanes were effective against
metastatic cancer. Interestingly, artemisinin hardly showed OPN downregulation in MDA-MB-
435 cells, while dihydroartemisinin and its ether derivative 11 showed promising results. We
found no direct correlation between 1,2,4-trioxane monomers and dimers in affecting OPN
13

downregulation, but more flexible 1,2,4-trioxane dimers (13a-i) showed better activity. The
results suggest that synthetic 1,2,4-trioxanes can be employed against cancer metastasis.
Although artemisinin derived 1,2,4-trioxanes are being used for anticancer studies, we report
here the first study on anticancer properties of synthetic 1,2,4-trioxanes. More studies are
required to understand the mechanism behind downregulation of OPN expression in cancer cell.
Experimental section
Chemistry
Metarials and Methods
Chemicals purchased from the commercial source were used without further purification unless
1
13
otherwise mentioned. H-NMR, and C NMR spectra of the compounds were obtained using a
Brucker Avance 400 MHz machine at 400 MHz and 100 MHz, respectively. Multiplicity of the
peaks is reported as s = singlet, d = doublet, t = triplet, m = multiplet, b = broad. Coupling
constants are presented in the hertz (Hz). LRMS data were recorded by using the ESI method.
3,7-Dimethyl-6-octenyltosylate (4):To a solution of citronellol (10 g, 64.1 mmol), dry pyridine
(61 mL, 769 mmol) was added and stirred for 30 min. Then the temperature was brought down
o
to 0 C and
p
-toluenesulfonyl chloride (18.26 g, 96.15 mmol) was added. Upon completion of
the reaction, the solution was poured into a mixture of ice cold water and HCl (50 mL) and
extracted with ethyl acetate (2 x 50 mL). The organic phase was washed with dilute HCl (50
mL), water (50 mL), saturated aqueous NaHCO3 (50 mL) and brine (50 mL) and dried in
Na2SO4, concentrated in vacuo to give an oil which was purified by column chromatography
(SiO2, Hexane: EtOAc , 9.5: 0.5) to give as an oil in 61% Yield (12.2 g). IR (KBr, cm-1):
υ1599,
1
1362, 1177, 815, 664. HNMR (400 MHz, CDCl3):
δ 7.80 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.8
Hz, 2H), 5.02 (t, J = 8.4 Hz, 1H), 4.09-4.03 (m, 2H), 2.45 (d, J = 2.8 Hz, 3H), 1.98-1.84 (m,
2H), 1.71-1.65 (m, 6H), 1.54-1.40 (m, 2H), 1.26-1.22 (m, 1H), 1.13-1.03 (m, 2H), 0.85-0.79 (m,
3H) ppm. 13CNMR (100 MHz, CDCl3):
δ
144.6, 133.1, 131.4, 129.8, 127.8, 124.3, 69.1, 36.6,
+
35.6, 28.8, 25.7, 25.2, 21.6, 19.0, 17.6 ppm. ESI-MS (m/z): 328 (M++ NH4 ).
8-Azido-2,6-dimethyloct-2-ene (5): To a solution of 3,7-dimethyl-6-octenyl tosylate (12 g,
38.70 mmol) in dry DMF was added NaN3, and stirred at 40 oC. After completion of reaction, the
reaction solution was kept round-bottom flask in refrigerator overnight. The reaction was
14

quenched by adding 50 mL of ice cold water and extracted with ethyl acetate (3 x 50 mL) and
the combined organic layer was concentrated in vacuo to give the crude product as oil. The crude
was purified by column chromatography with hexane as eluent to get the product in 78% yield
(5.5 g). IR (KBr, cm-1):
υ J
2097, 1457, 1379, 1216, 760. 1HNMR (400 MHz, CDCl3): 5.09 (t,
=
7.6 Hz, 1H), 3.30-3.24 (m, 2H), 2.03-1.96 (m, 2H), 1.68 (s, 3H), 1.60 (s, 3H), 1.56-1.53 (m,
13
1H), 1.43-1.30 (m, 2H), 1.23-1.11 (m, 2H), 0.91 (d,
J
= 7.2 Hz, 3H) ppm. CNMR (100 MHz,
CDCl3):
(M+).
δ131.4, 124.4, 49.4, 36.8, 35.6, 29.9, 25.7, 25.3, 19.2, 17.6 ppm. ESI-MS (m/z): 181
8-Azido-2,6-dimethyloctane-2,3-diol(6): To a solution of 8-azido-2,6-dimethyloct-2-ene (5.4 g,
29.83 mmol) in mixture of acetone : water (8:2), NMO.H2O (4.8 g, 35.80 mmol) was added and
stirred at room temperature until NMO.H2O was dissolved. OsO4 (10 mol %) mixture was added
to the solution and stirred at room temperature until starting material got consumed. After
completion of the reaction, a saturated solution of Na2S2O5 (50 mL) was added and extracted
with ethyl acetate (3 x 75 mL), washed with brine (50 mL) and water (3 x 50 mL), and
concentrated in vacuo to get an oily crude which was purified by column chromatography
employing 40% ethyl acetate in hexane. Yield: 87%, (5.6 g). IR (KBr, cm-1):
υ 3420, 2097,
1463, 1382, 1262, 1072, 917. 1HNMR (400 MHz, CDCl3): 3.36-3.24 (m, 3H), 2.46 (d, J = 4.4
Hz, 1H), 2.17 (s, 0.8H), 1.92 (s, 0.2H), 1.69-1.33 (m, 7H), 1.22 (s, 3H), 1.16 (s, 3H), 0.94-0.91
(m, 3H) ppm. 13CNMR (100 MHz, CDCl3):
δ7 8.8, 78.5, 73.2, 73.2, 49.4, 49.4, 35.8, 35.4, 34.0,
33.6, 30.4, 30.2, 29.0, 28.7, 26.5, 26.5, 23.1, 19.4, 19.1 ppm. ESI-MS (m/z): 215 (M+).
o
8-Azido-2-hydroperoxy-2,6-dimethyloctan-3-ol (6a): To an ice-cooled (0-5 C) solution of 8-
azido-2,6-dimethyloctane-2,3-diol (5.5 g, 25.58 mmol), was added 50% H2O2 (5.8 mL, 204.65
mmol) followed by H2SO4 (0.34 mL, 6.3 mmol). After 4 h, the reaction was quenched by adding
ice cold water and extracted with CHCl3 (3 x 50 mL). The organic layer was washed with
saturated solution of NaHSO4 (50 mL) and water (50 mL), and concentrated in vacuo to get an
oily crude product which was used directly for the next reaction.
Typical procedure for synthesis of azido tethered 1,2,4-trioxane monomers: A solution of 4-
o
nitro benzaldehyde (0.218 g, 1.449 mmol) in dry dichloromethane was stirred at 0-5 C for 15
15

min. Then p-TsOH (0.274 g, 1.449 mmol) and 8-azido-2-hydroperoxy-2,6-dimethyloctan-3-ol
crude (0.5 g, 2.17 mmol) were added to the solution sequentially. After completion of reaction,
solvent was evaporated at low temperature and purified by column chromatography (SiO2,
hexane: ethyl acetate, 9:1).
5-(5-Azido-3-methylpentyl)-6,6-dimethyl-3-(4-nitrophenyl)-1,2,4-trioxane(7a):Oil,
86%
1
yields. IR (KBr, cm-1):
υ
2096, 1637, 1533, 1460, 1351, 1262, 1098, 906, 807. HNMR (400
MHz, CDCl3; diastereomeric pairs as major/minor): 8.24-821 (m, 2H), 7.68-761 (m, 2H), 6.04
(s, 0.9H), 5.88 (s, 0.2H), 3.77-3.74 (m, 0.3H), 3.60-3.58 (m, 1.1H), 3.38-3.26 (m, 2H), 1.70-1.38
(m, 6H), 1.36 (s, 3H), 1.25 (s, 3H), 1.21-1.18 (m, 1H), 0.95-0.93 (m, 3H) ppm. 13CNMR (100
MHz, CDCl3; diastereomeric pairs as major/minor): 148.3, 148.1, 147.1, 145.4, 127.5, 127.1,
123.5, 123.5, 100.0, 99.67, 86.3, 86.1, 84.3, 84.1, 81.9, 80.97, 49.3, 35.5, 35.4, 34.0, 33.8, 30.4,
30.2, 26.9, 26.7, 25.4, 25.0, 23.3, 20.3, 19.1, 19.1 ppm. ESI-MS (m/z): 387.15 (M+Na)+.
5-(5-Azido-3-methylpentyl)-3-(2-bromophenyl)-6,6-dimethyl-1,2,4-trioxane(7b): Oil; IR
1
(KBr, cm-1):
MHz, CDCl3; diasteromeric pairs as major/minor):
υ
2931, 2095, 1699, 1464, 1264, 1210, 1159, 1121, 1089, 1041, 757. HNMR (400
7.67-7.57 (m, 1H), 7.55-7.52 (m, 1H),
7.35-7.31 (m, 1H), 7.22-7.17 (m, 1H), 6.25(s, 0.4H), 6.10 (s, 1.1H), 3.76-3.66 (m, 1H), 3.36-3.23
(m, 2H), 1.69-1.38 (s, 10H), 1.27-1.23 (m, 3H), 0.94-0.92 (m, 3H) ppm. 13CNMR (100 MHz,
CDCl3; diastereomeric pairs as major/minor): 138.2, 136.9, 132.9, 132.7, 130.4, 130.2, 128.1,
127.8, 127.5, 127.3, 123.2, 122.9, 100.1, 100.0, 86.1, 85.9, 84.1, 84.0, 81.6, 80.4, 49.4, 49.4,
35.6, 35.5, 33.9, 33.7, 30.4, 30.3, 27.1, 26.9, 25.6, 25.1, 23.4, 20.2, 19.2, 19.2 ppm. ESI-MS
(m/z): 421.23 (M+Na)+.
5-(5-Azido-3-methylpentyl)-3-(4-fluorophenyl)-6,6-dimethyl-1,2,4-trioxane(7c): Oil; IR
(KBr, cm-1):
υ
2968, 2096, 1607, 1464, 1226, 1155, 1101, 1085, 835. 1HNMR (400 MHz,
CDCl3; diasteromeric pairs as major/minor):
7.48-7.41 (m, 2H), 7.07-7.03 (m, 2H), 5.96 (s,
0.3H), 5.78 (s, 0.9H), 3.72-3.62 (m, 1H), 3.35-3.23 (m, 2H), 1.69-1.22 (s, 13H), 0.94-0.92 (m,
13
3H) ppm. CNMR (100 MHz, CDCl3; diastereomeric pairs as major/minor): 164.3, 161.9 (d,
J = 23 Hz), 135.9, 134.0, 128.7, 128.0, 115.3, 115.1, 101.0, 100.5, 86.2, 86.0, 84.2, 84.0, 81.4,
16

80.3, 49.3, 35.5, 35.5, 34.0, 33.8, 30.4, 30.3, 27.1, 26.9, 25.6, 25.2, 23.5, 20.2, 19.1, 19.1 ppm.
ESI-MS (m/z): 360.22 (M+Na)+.
5-(5-Azido-3-methylpentyl)-3-(4-chlorophenyl)-6,6-dimethyl-1,2,4-trioxane(7d): Oil; IR
1
(KBr, cm-1):
CDCl3; diasteromeric pairs as major/minor):
0.9H), 5.78 (s, 0.5H), 3.72-3.60 (m, 1H), 3.35-3.25 (m, 2H), 1.69-1.18 (m, 13H), 0.94-0.92 (m,
3H) ppm. 13CNMR (100 MHz, CDCl3; diastereomeric pairs as major/minor):
134.9, 134.5,
υ
2932, 2098, 1600, 1492, 1262, 1217, 1161, 1087, 1015. HNMR (400 MHz,
7.41-7.38 (m, 2H), 7.35-7.33 (m, 2H), 5.96 (s,
130.9, 129.4, 128.5, 128.5, 128.1, 127.6, 100.9, 100.4, 86.2, 86.0, 84.1, 84.0, 81.5, 80.4, 49.3,
35.6, 35.5, 34.0, 33.9, 30.5, 30.3, 27.0, 26.9, 25.5, 25.1, 23.5, 20.3, 19.2, 19.1 ppm. ESI-MS
(m/z): 376.23 (M+Na)+
5-(5-Azido-3-methylpentyl)-3-(3-bromophenyl)-6,6-dimethyl-1,2,4-trioxane(7e): Oil; IR
1
(KBr, cm-1):
υ
2931, 2095, 1703, 1464, 1371, 1257, 1210, 1161, 1099, 1066, 786. HNMR (400
MHz, CDCl3; diasteromeric pairs as major/minor): 7.63-7.21 (m, 4H), 5.93 (s, 0.8H), 5.76 (s,
0.3H), 3.71-3.60 (m, 1H), 3.37-3.23 (m, 2H), 1.70-1.23 (m, 13H), 0.95-0.93 (m, 3H) ppm.
13CNMR (100 MHz, CDCl3; diastereomeric pairs as major/minor): 142.4, 140.5, 132.1, 131.7,
129.9, 129.7, 129.3, 125.4, 124.9, 124.9, 122.4, 122.4, 100.6, 100.1, 86.2, 86.0, 84.2, 84.0, 81.6,
80.5, 49.3, 35.5, 35.5, 34.0, 33.7, 30.5, 30.3, 27.0, 26.8, 25.5, 25.1, 23.4, 20.2, 19.2, 19.1 ppm.
ESI-MS (m/z): 420.19 (M+Na)+
5-(5-(5-Azido-3-methylpentyl)-6,6-dimethyl-1,2,4-trioxan-3-yl)benzo[d][1,3]dioxole(7f):Oil;
1
IR (KBr, cm-1):
υ
2971, 2870, 2096, 1688, 1489,1449, 1123, 1038, 603. HNMR (400 MHz,
CDCl3; diastereomeric pairs): 6.94-6.91 (m, 2H), 6.78 (d, J = 8 Hz, 1H), 5.95 (s, 2H), 5.90 (s,
1.2H), 5.72 (s, 0.1H), 3.68-3.64 (m, 1H), 3.35-3.24 (m, 2H), 1.69-1.37 (m, 10H), 1.22 (s, 3H),
0.93 (d, J = 6.8 Hz, 3H) ppm. 13CNMR (100 MHz, CDCl3; diastereomeric pairs):
148.0,
147.7, 134.0, 120.2, 107.9, 106.6, 101.1, 100.9, 84.2, 84.0, 81.3, 49.3, 35.5, 33.9, 30.4, 27.0,
25.2, 20.1, 19.1 ppm. ESI-MS (m/z): 386.56 (M+Na)+
4-(5-(5-Azido-3-methylpentyl)-6,6-dimethyl-1,2,4-trioxan-3-yl)phenol (7g): Oil; IR (KBr, cm-
1
1):
υ
3442, 2932, 2098, 1600, 1492, 1262, 1217, 1161, 1087, 1015. HNMR (400 MHz, CDCl3;
17

diasteromeric pairs as major/minor): 7.32-7.27 (m, 2H), 6.71 (m, 2H), 6.05 (br s, 1H,), 5.94 (s,
0.7H), 5.75 (s, 0.4H), 3.71-3.24 (m, 3H), 1.67-1.36 (m, 10H), 1.24 (s, 3H), 0.91 (d, J = 6.4 Hz,
3H) ppm. 13CNMR (100 MHz, CDCl3; diastereomeric pairs as major/minor): 157.76, 156.4,
131.5, 129.5, 128.4, 127.9, 115.3, 115.2, 101.6, 101.1, 86.1, 85.9, 84.2, 84.1, 81.4, 80.2, 49.3,
35.5, 35.5, 34.0, 33.8, 30.5, 30.3, 27.1, 27.0, 25.6, 25.2, 23.5, 20.1, 19.2, 19.1 ppm. ESI-MS
(m/z): 358.45 (M+Na)+
5-(5-Azido-3-methylpentyl)-6,6-dimethyl-3-phenyl-1,2,4-trioxane(7h): Oil; IR (KBr, cm-1):
υ
2930, 2097, 1641, 1463, 1382, 1262, 1162, 1072, 961. 1HNMR (400 MHz, CDCl3; diasteromeric
pairs as major/minor): 7.49-7.44 (m, 2H), 7.38-7.33 (m, 3H), 5.99 (s, 0.4H), 5.81 (s, 0.6H),
3.73-3.64 (m, 1H), 3.36-3.22 (m, 2H), 1.69-1.23 (m, 13H), 0.94-0.89 (m, 3H) ppm. 13CNMR
(100 MHz, CDCl3; diastereomeric pairs as major/minor): 138.1, 134.4, 129.1, 128.7, 128.3,
128.3, 126.7, 126.2, 101.7, 101.1, 86.1, 86.0, 84.1, 84.0, 81.3, 80.2, 49.3, 35.5, 35.5, 34.1, 33.8,
30.4, 30.3, 27.1, 27.0, 25.6, 25.2, 23.5, 20.3, 19.2, 19.1 ppm. ESI-MS (m/z): 342.34 (M+Na)+
5-(5-Azido-3-methylpentyl)-3-(4-methoxyphenyl)-6,6-dimethyl-1,2,4-trioxane(7i): Oil; IR
(KBr, cm-1):
υ
2932, 2873, 2096, 1616, 1518, 1458, 1371, 1264, 1220, 1086, 1068, 833. 1HNMR
(400 MHz, CDCl3; diasteromeric pairs as major/minor): 7.42-7.36 (m, 2H), 6.90-6.87 (m, 2H),
5.95 (s, 0.8H), 5.76 (s, 0.4H), 3.79 (s, 3H), 3.70-3.66 (m, 1H), 3.58-3.22 (m, 2H), 1.82-1.23 (m,
13H), 0.93-0.91 (m, 3H) ppm. 13CNMR (100 MHz, CDCl3; diastereomeric pairs as
major/minor): 160.3, 160.0, 132.2, 130.2, 128.2, 127.6, 113.7, 113.7, 101.5, 101.0, 86.0, 85.9,
84.1, 83.9, 81.1, 80.0, 55.3, 55.2, 49.3, 35.5, 35.5, 33.9, 33.6, 30.5, 30.4, 27.1, 27.0, 25.6, 25.3,
23.6, 20.1, 19.2, 18.8 ppm. ESI-MS (m/z): 372.65 (M+Na)+
5-(5-Azido-3-methylpentyl)-6,6-dimethyl-3-(p-tolyl)-1,2,4-trioxane(7j): Oil; IR (KBr, cm-1):
υ
1
2969, 2931, 2872, 2095, 1617, 1460, 1370, 1263, 1089, 815. HNMR (400 MHz, CDCl3;
diasteromeric pairs as major/minor):
7.38-7.33 (m, 2H), 7.17 (d, J = 8.0 Hz, 2H), 5.96 (s,
0.3H), 5.78 (s, 0.8H), 3.71-3.63 (m, 1H), 3.36-3.22 (m, 2H), 2.34 (s, 3H), 1.69-1.23 (m, 13H),
0.94-0.88 (m, 3H) ppm. 13CNMR (100 MHz, CDCl3; diastereomeric pairs as major/minor):
138.9, 138.5, 137.1, 135.1, 129.0, 128.9, 126.7, 126.1, 101.7, 101.1, 86.0, 85.9, 84.0, 83.9, 81.20,
18

80.1, 49.3, 35.5, 35.5, 34.0, 33.8, 30.4, 30.3, 27.1, 27.0, 25.6, 25.2, 23.5, 21.2, 20.2, 19.1, 18.3
ppm. ESI-MS (m/z): 356.23 (M+Na)+
5-(5-Azido-3-methylpentyl)-6,6-dimethyl-3-(3-nitrophenyl)-1,2,4-trioxane(7k): Oil; IR (KBr,
cm-1):
υ
2932, 2096, 1637, 1533, 1460, 1351, 1262, 1098, 906, 807. 1HNMR (400 MHz, CDCl3;
diasteromeric pairs as major/minor): 8.36-8.31 (m, 1H), 8.23-8.18 (m, 1H), 7.83-7.78 (m, 1H),
7.57-7.55 (m, 1H), 6.04 (s, 0.3H), 5.88 (s, 1H), 3.77-3.73 (m, 1H), 3.65-3.62 (m, 0.4H), 3.37-
3.26 (m, 2H), 1.71-1.29 (m, 10H), 1.22 (s, 3H), 0.95-0.93 (m, 3H) ppm. 13CNMR (100 MHz,
CDCl3; diastereomeric pairs as major/minor): 148.2, 142.4, 140.7, 132.8, 132.4, 129.3, 123.9,
123.6, 121.8, 121.3, 100.0, 99.6, 86.3, 86.1, 84.3, 84.2, 82.0, 80.9, 49.3, 35.5, 35.5, 33.9, 33.7,
30.4, 30.2, 27.0, 26.9, 25.4, 25.1, 23.4 and 20.3, 19.1, 19.1 ppm. ESI-MS (m/z): 387.53
(M+Na)+.
5-(5-Azido-3-methyl)-6,6-dimethyl-3-(napthalen-1-yl)-1,2,4-trioxane(7l): Oil; IR (KBr, cm-1):
1
υ
2932, 2098, 1610, 1601, 1492, 1475, 1262, 1217, 1161, 1087, 1015. HNMR (400 MHz,
CDCl3; diasteromeric pairs as major/minor): 8.22-8.18 (m, 1H), 7.85-7.74 (m, 3H), 7.53-7.43
(m, 3H), 6.67 (s, 0.3H), 6.50 (s, 0.6H), 3.85-3.80 (m, 0.5H), 3.69-3.66 (m, 0.4H), 3.55-3.20 (m,
2H), 1.82-1.22 (m, 13H), 0.91-0.89 (m, 3H) ppm. 13CNMR (100 MHz, CDCl3; diastereomeric
pairs as major/minor):
135.1, 133.9, 133.8, 133.7, 131.1, 131.0, 129.3, 129.1, 128.5, 126.2,
126.1, 125.6, 125.2, 125.1, 124.2 123.9, 123.2, 122.8, 99.1, 86.1, 85.9, 83.9, 83.7, 81.4, 80.3,
49.4, 35.6, 35.5, 34.1, 33.8, 30.5, 30.3, 27.1, 27.0, 25.7, 25.2, 23.4, 20.6, 19.2, 18.9 ppm. ESI-
MS (m/z): 392.49 (M+Na)+.
5-(5-Azido-3-methylpentyl)-3-(furan-2-yl)-6,6-dimethyl-1,2,4-trioxane(7m): Oil; IR (KBr,
cm-1):
υ
2971, 2870, 2096, 1688, 1489,1449, 1123, 1038, 603. 1HNMR (400 MHz, CDCl3;
diastereomeric pairs as major/minor): 7.42-7.40 (m, 1H), 6.46-6.31 (m, 2H), 5.99 (s, 0.5H),
5.86 (s, 0.9H), 3.75-3.72 (m, 0.5H), 3.66-3.63 (m, 1H), 3.35-3.21 (m, 2H), 1.71-1.33 (m, 10H),
1.25 (s, 3H), 0.93-0.91 (m, 3H) ppm. 13CNMR (100 MHz, CDCl3; diastereomeric pairs as
major/minor): 152.6, 151.1, 143.2, 142.9, 110.1, 110.0, 109.1, 108.2, 95.6, 95.3, 85.8, 85.6,
83.6, 83.5, 81.1, 80.4, 49.3, 35.5, 35.5, 33.9, 33.7, 30.4, 30.3, 26.9, 26.8, 25.0, 24.8, 22.8, 20.4,
19.1, 19.1 ppm. ESI-MS (m/z): 332.15 (M+Na)+.
19

4-(5-Azido-3-methylpentyl)-3,3-dimethyl-1,2,5-trioxaspiro[5.5]undecane(7n): Oil; IR (KBr,
1
cm-1):
υ
2935, 2862, 2096, 1449, 1365, 1259, 1100, 950. HNMR (400 MHz, CDCl3): 3.63-
13
3.59 (m, 1H), 3.35-3.25 (m, 2H), 1.66-1.24 (m, 20H), 1.08 (s, 3H), 0.94-0.90 (m, 3H). CNMR
(100 MHz, CDCl3):
106.3, 82.5, 82.3, 78.9, 48.8, 37.7, 35.5, 35.11, 34.8, 33.5, 33.3, 29.8,
29.7, 26.3, 26.1, 25.7, 24.6, 23.4, 23.2, 22.6, 18.7, 18.5 ppm. ESI-MS (m/z): 334.47 (M+Na)+.
5-(5-Azido-3-methylpentyl)-3-(4-chlorophenyl)-3,6,6-trimethyl-1,2,4-trioxane(7o): Oil; IR
1
(KBr, cm-1):
MHz, CDCl3; diastereomeric pairs as major/minor):
υ
2974, 2928, 2871, 2096, 1598, 1488, 1462, 1370, 1248, 1091, 830. HNMR (400
7.45-7.40 (m, 2H), 7.30-7.26 (m, 2H),
3.79-3.75 (m, 0.5H), 3.37-3.23 (m, 2.5H), 1.68-0.87 (m, 19H) ppm. 13CNMR (100 MHz, CDCl3;
diastereomeric pairs as major/minor): 144.6, 144.3, 133.1, 133.0, 128.1, 127.9, 126.6, 126.2,
106.4, 106.1, 84.5, 84.3, 83.8, 83.5, 81.2, 81.1, 49.3, 35.6, 35.4, 34.0, 33.7, 30.4, 30.2, 26.7, 26.5,
26.3, 25.9, 25.4, 23.4, 22.0, 19.8, 19.1 ppm. ESI-MS (m/z): 390.75 (M+Na)+.
Synthesis of 2,2,2
ˈ,2ˈ-tetramethyl-7-(prop-2-yn-1-yloxy)tetrahydrospiro[[1,3]-dioxolo[4,5-c]
pyran-6,4 -[1,3]dioxolane] (9): A 50% NaOH (aq) solution was made by dissolving NaOH
ˋ
(0.83 g) in H2O (0.8 mL). The compound 8 (1.5 g, 5.76 mmol) was dissolved in toluene (5 mL)
and slowly poured over the aqueous solution. Tetrabutylammonium hydrogen bisulphate (0.002
g, 0.0069 mmol) and propargyl bromide (1.2 mL, 11.23 mmol) were added and the stirred gently
for 48 h. After completion of the reaction, the compound was extracted with ethyl acetate and
evaporated under reduced pressure to get the crude product as a yellow oil. Purification using
column chromatography with silica gel and EtOAc/hexane (1:1) as eluent gave pure 9 (0.98 g,
52%) as a pale yellow viscous oil. IR (KBr, cm-1):
1220, 1116, 1084, 1018, 886. 1HNMR (400MHz, CDCl3): 4.54 (dd,
4.44 (dd, = 16.0 Hz, 2.4 Hz, 1H), 4.31 (dd, = 7.6 Hz, 5.4 Hz, 1H), 4.25 (d,
4.20-4.10 (m, 2H), 4.16 (m, 2H), 3.95 (d, = 8.6 Hz, 1H), 3.76 (d, = 7.6 Hz, 1H), 2.44 (t,
2.3 Hz, 0.6H), 2.35 (s, 0.3H), 1.58 (s, 3H), 1.49 (s, 3H), 1.41 (s, 3H), 1.36 (s, 3H) ppm. 13CNMR
(100 MHz, CDCl3): 111.5, 108.6, 103.7, 79.0, 77.1, 74.4, 73.5, 73.4, 71.2, 59.5, 57.8, 27.6,
υ
3291, 2988, 2936, 2115, 1632, 1456, 1383,
= 16.0 Hz, 2.4 Hz, 1H),
= 8.6 Hz, 1H),
J
J
J
J
J
J
J =
δ
26.2, 25.8, 25.4 ppm. ESI-MS (m/z): 299.17 (M+H)+.
20

Typical procedure for 1,2,3-triazole linked 1,2,4-trioxane monomers: A mixture of CuI (2
mg, 1 mol%) and L-proline (1.2 mg, 1 mol%) taken in an oven-dried two-neck round bottom
flask was mixed with glycerol (4 mL) in a bath sonicator for 30 min. Then azido tethered 1,2,4-
trioxane derivative (7a) (0.364 g, 1 mmol) and compound 9 (0.3 g,1 mmol) were added to the
solution and stirred at room temperature. The progress of the reaction was monitored by TLC
and found completed within 5 h. The reaction was quenched by adding water (5 mL) to the
suspension and extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried
over anhydrous Na2SO4 and concentrated the organic layer to afford the crude product. The
crude was purified by column chromatography employing 15% ethyl acetate in hexane as eluent.
1-(5-(6,6-Dimethyl-3-(4-nitrophenyl)-1,2,4-trioxan-5-yl)-3-methylpentyl)-4-((((3aS,4'R, 7aS)
-2,2,2',2'-tetramethyl tetrahydrospiro[[1,3]dioxolo[4,5-c]pyran-6,4'-[1,3]dioxolan]-7-yl)oxy)
methyl)-1
1383, 1220, 1116, 1084, 1018, 886. 1HNMR (400 MHz, CDCl3): 1HNMR (400 MHz, CDCl3):
8.23 (d, = 8.2 Hz, 2H), 7.68-7.62 (m, 2H), 7.55 (s, 1H), 6.05 (s, 0.5H), 5.88 (d, = 12.4 Hz,
0.5H), 5.06 (d, = 12.4 Hz, 1H), 4.82 (d, = 12.4 Hz, 1H), 4.42-4.34 (m, 2H), 4.22 (d, = 6.4
Hz, 1H), 4.13 (d, = 13.6 Hz, 1H), 4.05-4.03 (m, 3H), 3.89 (d, = 8.4 Hz, 1H), 3.75-3.65 (m,
1H), 3.59 (d, = 7.6 Hz, 1H), 2.01-1.98 (m, 1H), 1.78-1.71 (m, 1H), 1.57 (s, 3H), 1.48 (s, 3H),
1.36 (s, 12H), 1.25-1.19 (m, 5H), 1.01-0.98 (m, 3H) ppm. 13CNMR (100 MHz, CDCl3):
H υ 3291, 3123, 2988, 2936,
-1,2,3-triazole(10a): Yield 67%, gum. IR (KBr, cm-1):
J
J
J
J
J
J
J
J
δ
148.26, 148.07, 147.09, 145.30, 145.06, 127.59, 127.13, 123.57, 123.53, 122.18, 112.05, 109.13,
104.28, 100.04, 99.64, 86.30, 86.03, 84.25, 84.13, 81.99, 81.96, 80.96, 80.92, 77.46, 76.52,
73.81, 71.73, 65.19, 60.14, 48.31, 37.24, 37.18, 33.66, 33.25, 30.27, 30.11, 28.20, 26.86, 26.78,
26.51, 26.25, 26.00, 25.81, 25.41, 25.00, 23.99, 23.36, 20.38, 19.03 ppm.Anal. Calcd for
(C32H46N4O11): C 57.99, H 7.00, N 8.45. Found: C 57.95, H 6.95, N 8.50.
1-(5-(3-(2-Bromophenyl)-6,6-dimethyl-1,2,4-trioxan-5-yl)-3-methylpentyl)-4-
((((3aS,4'R,7aS)-2,2,2',2'-tetramethyltetrahydrospiro[[1,3]dioxolo[4,5-c]pyran-6,4'-
[1,3]dioxolan]-7-yl)oxy)methyl)-1
H
-1,2,3-triazole (10b): Gum; IR (KBr, cm-1):
υ 3296, 2981,
1
2932, 2875, 1713, 1642, 1572, 1461, 1246, 1217, 1038, 1022. HNMR (400 MHz, CDCl3):
7.66 (d,
J
= 7.8 Hz, 1H), 7.59-7.51 (m, 2H), 7.33 (t,
J
= 7.6 Hz, 1H), 7.19 (t,
J
= 7.8 Hz, 1H),
6.24 (s, 0.4H), 6.09 (s, 0.6H), 5.04 (d,
J
= 12.4 Hz, 1H), 4.81 (d, J = 12.4 Hz, 1H), 4.43-4.30 (m,
21

2H), 4.20 (d,
1H), 3.74-3.62 (m, 1H), 3.59 (d,
3H), 1.47 (s, 3H), 1.36 (s, 12H), 1.26-1.22 (m, 5H), 0.97 (d,
MHz, CDCl3): 145.10, 144.84, 138.14, 136.84, 132.85, 132.65, 130.46, 130.21, 128.12,
J
= 6.4 Hz, 1H), 4.11 (d,
= 7.4 Hz, 1H), 2.02-1.92 (m, 1H), 1.74-1.65 (m, 1H), 1.56 (s,
= 6.4 Hz, 3H) ppm. 13CNMR (100
J = 12.8 Hz, 1H), 4.05-3.98 (m, 3H), 3.87 (d, J = 8.4 Hz,
J
J
δ
127.48, 123.08, 122.74, 122.25, 111.94, 109.00, 104.24, 100.05, 99.96, 85.95, 85.70, 83.99,
83.80, 81.54, 81.53, 80.37, 80.32, 77.40, 76.35, 73.75, 71.64, 64.99, 60.08, 48.23, 37.17, 37.04,
33.82, 33.53, 30.25, 30.02, 28.15, 26.93, 26.77, 26.56, 26.22, 25.95, 25.55, 25.00, 23.97, 23.41,
20.20, 18.96 ppm. Anal. Calcd for (C32H46BrN3O9): C 55.17, H 6.66, N 6.03. Found: C 55.10, H
6.60, N 6.10.
1-(5-(3-(4-Fluorophenyl)-6,6-dimethyl-1,2,4-trioxan-5-yl)-3-methylpentyl)-4-((((3aS,4'R,
7aS)-2,2,2',2'-tetramethyltetrahydrospiro[[1,3]dioxolo[4,5-c]pyran-6,4'-[1,3]dioxolan]-7-
yl)oxy)methyl)-1
H
1
-1,2,3-triazole (10c):Gum; IR (KBr, cm-1):
υ
3210, 2976, 2912, 2871, 1642,
= 4.8 Hz, 1H), 7.48-7.45 (m, 2H),
= 3.8 Hz, 0.8H), 5.05 (d, = 12.4 Hz, 1H),
= 6.0 Hz, 1H), 4.13 (d, = 13.6 Hz, 1H), 4.05-
= 8.8 Hz, 1H), 3.75-3.65 (m, 1H), 3.59 (d, = 7.4 Hz, 1H), 1.99-1.90 (m,
1H), 1.77-1.63 (m, 1H), 1.57 (s, 3H), 1.48 (s, 3H), 1.39-1.33 (m, 12H), 1.26-1.23 (m, 5H), 1.00-
0.97 (m, 3H) ppm. 13CNMR (100 MHz, CDCl3):
164.49, 162.04, 145.31, 145.07, 133.94,
1421, 1121, 1011. HNMR (400 MHz, CDCl3): 7.52 (d,
7.05 (t, = 8.4 Hz, 2H), 5.96 (s, 0.2H), 5.78 (d,
4.83-4.78 (m, 1H), 4.43-4.34 (m, 2H), 4.22 (d,
3.99 (m, 3H), 3.89 (d,
J
J
J
J
J
J
J
J
δ
128.74, 128.65, 128.18, 128.09, 122.33, 122.14, 115.36, 115.15, 112.07, 109.15, 101.00, 86.13,
85.88, 84.17, 84.03, 81.44, 81.42, 80.31, 80.28, 77.46, 76.56, 73.83, 71.77, 65.22, 60.17, 48.34,
37.26, 37.22, 33.99, 33.73, 30.38, 30.17, 28.20, 26.79, 26.52, 26.26, 26.01, 25.83, 25.57, 25.30,
24.01, 23.56, 20.19, 19.02 ppm. Anal. Calcd for (C32H46FN3O9): C 60.46, H 7.29, N 6.61. Found:
C 60.40, H 7.20, N 6.56.
1-(5-(3-(4-Chlorophenyl)-6,6-dimethyl-1,2,4-trioxan-5-yl)-3-methylpentyl)-4-((((3aS,4'R,
7aS)-2,2,2',2'-tetramethyltetrahydrospiro[[1,3]dioxolo[4,5-c]pyran-6,4'-[1,3]dioxolan]-7-
yl)oxy)methyl)-1
1262, 1217, 1161, 1087, 1015. 1HNMR (400 MHz, CDCl3): 7.52 (s, 1H), 7.42 (d,
2H), 7.34 (d, = 8.0 Hz, 2H), 5.95 (s, 0.2H), 5.79 (d, = 4.2 Hz, 0.8H), 5.05 (d,
= 6.4 Hz, 1H), 4.13 (d, = 13.6 Hz, 1H),
H
-1,2,3-triazole (10d): Gum; IR (KBr, cm-1):
υ
3211, 2989, 2851, 1600, 1492,
= 8.0 Hz,
= 12.4 Hz,
J
J
J
J
1H), 4.83-4.79 (m, 1H), 4.41-4.34 (m, 2H), 4.22 (d,
J
J
22

4.05-3.99 (m, 3H), 3.89 (d,
1.91 (m, 1H), 1.77-1.64 (m, 1H), 1.57 (s, 3H), 1.48 (s, 3H), 1.39-1.33 (m, 12H), 1.26-1.20 (m,
5H), 0.99-0.97 (m, 3H) ppm. 13CNMR (100 MHz, CDCl3):
145.29, 138.56, 136.73, 134.90,
J = 8.6 Hz, 1H), 3.75-3.62 (m, 1H), 3.59 (d, J = 7.4 Hz, 1H), 1.98-
δ
128.51, 128.17, 127.68, 122.19, 112.05, 109.13, 104.30, 100.86, 100.36, 86.13, 85.87, 84.11,
83.96, 81.51, 81.49, 80.42, 80.39, 77.11, 76.56, 73.82, 71.75, 65.19, 60.16, 48.33, 37.24, 37.20,
33.96, 33.70, 30.34, 30.13, 28.20, 26.97, 26.80, 26.53, 26.26, 26.01, 25.83, 25.54, 24.01, 23.50,
20.26, 19.02 ppm. Anal. Calcd for (C32H46ClN3O9): C 58.93, H 7.11, N 6.44. Found: C 58.88, H
7.05, N 6.52.
1-(5-(3-(3-Bromophenyl)-6,6-dimethyl-1,2,4-trioxan-5-yl)-3-methylpentyl)-4-((((3aS,4'R,
7aS)-2,2,2',2'-tetramethyltetrahydrospiro[[1,3]dioxolo[4,5-c]pyran-6,4'-[1,3]dioxolan]-7-
yl)oxy)methyl)-1
1642, 1572, 1461, 1246, 1217, 1038, 1022.1HNMR (400 MHz, CDCl3): 7.63-7.40 (m, 4H),
7.21-7.23 (m, 1H), 5.93 (s, 0.2H), 5.76 (d, = 4.0 Hz, 0.8H), 5.06 (d, = 12.6 Hz, 1H), 4.83-4.79
(m, 1H), 4.41-4.34 (m, 2H), 4.22 (d, = 6.4 Hz, 1H), 4.13 (d, = 13.8 Hz, 1H), 4.05-4.00 (m,
3H),3.89 (d, = 8.6 Hz, 1H), 3.76-3.65 (m, 1H), 3.59 (d, = 7.2 Hz, 1H), 1.98-1.89 (m, 1H),
1.76-1.65 (m, 1H), 1.57 (s, 3H), 1.48 (s, 3H), 1.40-1.33 (m, 12H), 1.25-1.08 (m, 5H), 1.00-0.94
(m, 3H) ppm. 13CNMR (100 MHz, CDCl3):
145.23, 140.46, 140.45, 132.20, 131.83, 129.96,
H υ 3296, 2981, 2932, 2875, 1713,
-1,2,3-triazole (10e): Gum; IR (KBr, cm-1):
J
J
J
J
J
J
δ
129.76, 129.29, 125.47, 124.98, 122.43, 122.35, 122.17, 112.08, 109.16, 104.29, 100.64, 100.17,
86.14, 85.89, 84.17, 84.01, 81.61, 80.57, 80.54, 77.07, 73.82, 71.74, 65.18, 60.15, 48.29, 37.54,
37.27, 33.97, 33.70, 29.95, 29.83, 28.21, 26.82, 26.53, 26.27, 25.99, 25.83, 25.52, 25.31, 24.01,
23.48, 19.06, 18.31 ppm. Anal. Calcd for (C32H46BrN3O9): C 55.17, H 6.66, N 6.03. Found: C
55.11, H 6.60, N 6.10.
1-(5-(3-(Benzo[d][1,3]dioxol-5-yl)-6,6-dimethyl-1,2,4-trioxan-5-yl)-3-methylpentyl)-4-
((((3aS,4'R,7aS)-2,2,2',2'-tetramethyltetrahydrospiro[[1,3]dioxolo[4,5-c]pyran-6,4'-
[1,3]dioxolan]-7-yl)oxy)methyl)-1
2921, 2861, 1643, 1541, 1453, 1248, 1219, 1081, 1039.1HNMR (400 MHz, CDCl3): 7.51 (s,
1H), 6.94-6.87 (m, 2H), 6.74 (d, = 8.0 Hz, 1H), 5.91 (s, 2H), 5.85 (s, 0.6H), 5.68 (d, = 4.6 Hz,
0.6H), 5.01 (d, = 12.4 Hz, 1H), 4.78 (d, = 12.4 Hz, 1H), 4.37-4.30 (m, 2H), 4.18 (d, = 6.6
= 8.6 Hz, 1H), 3.63-3.60 (m, 1H), 3.55
H υ 3289, 2986,
-1,2,3-triazole (10f): Gum; IR (KBr, cm-1):
J
J
J
J
J
Hz, 1H), 4.10-4.05 (m, 1H), 4.01-3.95 (m, 3H), 3.84 (d,
J
23

(d,
J
= 7.4 Hz, 1H), 1.96-1.87 (m, 1H), 1.73-1.60 (m, 1H), 1.53 (s, 3H), 1.44 (s, 3H), 1.36-1.29
= 6.8 Hz, 3H) ppm. 13CNMR (100 MHz, CDCl3):
(m, 12H), 1.23-1.21 (m, 5H), 0.95 (d,
J
δ
148.29, 148.00, 147.66, 145.16, 133.90, 131.93, 122.22, 120.94, 120.20, 111.99, 109.06, 107.86,
106.91, 106.53, 104.25, 101.40, 101.06, 85.92, 85.66, 84.11, 83.95, 81.22, 81.20, 80.06, 80.03,
77.54, 76.43, 73.76, 71.67, 65.05, 60.10, 48.27, 37.18, 37.15, 33.93, 33.66, 30.29, 30.21, 28.14,
26.83, 26.75, 26.21, 25.94, 25.57, 25.55, 25.14, 23.96, 23.55, 20.98, 20.10, 19.01, 18.98 ppm.
Anal. Calcd for (C33H47N3O11): C 59.90, H 7.16, N 6.35. Found: C 59.95, H 7.10, N 6.41.
1-(5-(3-(4-Methoxyphenyl)-6,6-dimethyl-1,2,4-trioxan-5-yl)-3-methylpentyl)-4-((((3aS,4'R,
7aS)-2,2,2',2'-tetramethyltetrahydrospiro[[1,3]dioxolo[4,5-c]pyran-6,4'-[1,3]dioxolan]-7-
yl)oxy)methyl)-1
1461, 1246, 1217, 1038, 1022.1HNMR (400 MHz, CDCl3): 7.55-7.51 (m, 1H), 7.42-7.36 (m,
H υ 3289, 2976, 2924, 1642, 1572,
-1,2,3-triazole (10g): Gum; IR (KBr, cm-1):
2H), 6.89 (d,
1H), 4.82 (d,
J
= 8.4 Hz, 2H), 5.95 (s, 0.5H), 5.77 (d,
J
= 3.4 Hz, 0.5H), 5.05 (d, = 12.4 Hz,
J
J
= 12.4 Hz, 1H), 4.41-4.34 (m, 2H), 4.22 (d,
J
= 8.4 Hz, 1H), 4.13 (d, J = 13.4 Hz,
1H), 4.05-3.99 (m, 3H), 3.88 (d,
Hz, 1H), 1.99-1.87 (m, 1H), 1.76-1.64 (m, 1H), 1.57 (s, 3H), 1.48 (s, 3H), 1.37-1.35 (m, 12H),
1.16-1.08 (m, 5H), 1.00-0.94 (m, 3H) ppm. 13CNMR (100 MHz, CDCl3):
160.34, 160.05,
J = 8.6 Hz, 1H), 3.80 (s, 3H), 3.69-3.65 (m, 1H), 3.59 (d, J = 7.6
δ
145.33, 132.11, 130.17, 128.17, 127.65, 122.29, 122.12, 113.73, 113.70, 112.06, 109.14, 104.31,
101.57, 101.02, 86.02, 85.76, 84.09, 83.93, 81.16, 81.14, 80.01, 79.98, 77.48, 76.56, 73.83,
71.78, 65.24, 60.18, 55.28, 48.36, 37.53, 37.27, 34.02, 33.76, 30.43, 30.32, 29.98, 29.68, 28.20,
27.05, 26.93, 26.82, 26.26, 26.01, 25.64, 25.28, 23.61, 20.18, 19.06, 18.30 ppm. Anal. Calcd for
(C33H49N3O10): C 61.19, H 7.62, N 6.49. Found: C 61.11, H 7.58, N 6.55.
1-(5-(6,6-Dimethyl-3-(
2,2,2',2'-tetramethyltetrahydrospiro[[1,3]dioxolo[4,5-c]pyran-6,4'-[1,3]dioxolan]-7-yl)oxy)
methyl)-1 3276, 2954, 2927, 1635, 1577, 1465,
-1,2,3-triazole (10h): Gum; IR (KBr, cm-1):
1238, 1210, 1029. 1HNMR (400 MHz, CDCl3):
7.55-7.51 (m, 1H), 7.38-7.33 (m, 2H), 7.17 (d,
= 8.0 Hz, 2H), 5.96 (s, 0.5H), 5.78 (d, = 3.4 Hz, 0.5H), 5.05 (d, = 12.4 Hz, 1H), 4.81 (d,
12.4 Hz, 1H), 4.41-4.34 (m, 2H), 4.22 (d, = 8.4 Hz, 1H), 4.13 (d, = 13.4 Hz, 1H), 4.05-3.99
(m, 3H), 3.89 (d, = 8.4 Hz, 1H), 3.69-3.64 (m, 1H), 3.59 (d, = 7.2 Hz, 1H), 2.35 (s, 3H), 1.98-
p-tolyl)-1,2,4-trioxan-5-yl)-3-methylpentyl)-4-((((3aS,4'R,7aS)-
H
υ
ẟ
J
J
J
J =
J
J
J
J
1.88 (m, 1H), 1.76-1.65 (m, 1H), 1.57 (s, 3H), 1.48 (s, 3H), 1.37-1.33 (m, 6H), 1.26-1.07 (m,
24

13
12H), 0.99-0.83 (m, 3H) ppm. CNMR (100 MHz, CDCl3):
δ 145.30, 139.05, 138.62, 137.00,
135.09, 129.01, 126.70, 126.19, 122.15, 112.08, 109.16, 104.30, 101.70, 101.16, 86.05, 85.78,
84.04, 83.87, 81.22, 80.11, 80.08, 77.48, 76.56, 73.83, 71.77, 65.23, 60.17, 48.38, 37.54, 37.24,
34.01, 33.74, 29.85, 29.69, 28.21, 27.04, 26.81, 26.26, 26.00, 25.59, 25.34, 25.18, 23.55, 22.69,
21.29, 19.06, 18.30 ppm. Anal. Calcd for (C33H49N3O9): C 62.74, H 7.82, N 6.65. Found: C
62.81, H 7.76, N 6.60.
1-(5-(6,6-Dimethyl-3-(3-nitrophenyl)-1,2,4-trioxan-5-yl)-3-methylpentyl)-4-((((3aS,4'R,7aS)-
2,2,2',2'-tetramethyltetrahydrospiro[[1,3]dioxolo[4,5-c]pyran-6,4'-[1,3]dioxolan]-7-yl)
oxy)methyl)-1
H
-1,2,3-triazole (10i): Gum; IR (KBr, cm-1):
υ 3291, 2966, 2920, 1652, 1580,
1
1525, 1475, 1370, 1233, 1211, 1023. HNMR (400 MHz, CDCl3): 8.36-8.32 (m, 1H), 8.24-
8.20 (m, 1H), 7.83-7.77 (m, 1H), 7.58-7.52 (m, 2H), 6.04 (s, 0.6H), 5.89 (d,
J
= 3.6 Hz, 0.4H),
= 8.4 Hz, 1H),
= 8.4 Hz, 1H), 3.76-3.61 (m, 1H), 3.59
5.06 (d,
4.13 (d,
J
J
= 12.4 Hz, 1H), 4.82 (d,
J = 12.4 Hz, 1H), 4.40-4.34 (m, 2H), 4.22 (d, J
= 13.4 Hz, 1H), 4.05-4.00 (m, 3H), 3.89 (d,
J
(d,
J
= 7.6 Hz, 1H), 2.00-1.95 (m, 1H), 1.76-1.67 (m, 1H), 1.57 (s, 3H), 1.48 (s, 3H), 1.38-1.36
145.38,
(m, 12H), 1.25-1.08 (m, 5H), 1.01-0.94 (m, 3H) ppm. 13CNMR (100 MHz, CDCl3):
δ
142.34, 140.61, 132.48, 129.41, 124.00, 123.69, 122.14, 121.88, 121.38, 112.08, 109.17, 104.31,
100.11, 99.68, 86.30, 86.08, 84.37, 84.19, 82.04, 80.98, 77.49, 76.58, 73.84, 71.78, 65.27, 60.18,
48.37, 37.55, 37.29, 33.97, 33.84, 30.48, 30.30, 28.23, 26.96, 26.81, 26.28, 26.03, 25.48, 25.06,
23.45, 20.32, 19.02, 18.31 ppm. Anal. Calcd for (C32H46N4O11): C 57.99, H 7.00, N 8.45. Found:
C 57.91, H 6.95, N 8.50.
1-(5-(6,6-dimethyl-3-(napthalen-1-yl)-1,2,4-trioxan-5-yl)3-methylpentyl)-4-(((2,2,2
tetramethyltetrahydrospiro[[1,3]dioxolo[4,5-c]pyran-6,4 -[1,3]dioxolan]-7-yl)oxy)methyl)-
3291, 3123, 2988, 2936, 1632, 1614, 1456,
8.22-8.17 (m, 1H),
ˈ,2ˈ-
ˈ
1
H
-1,2,3-triazole (10j): Gum; IR (KBr, cm-1):
υ
1
1414, 1383, 1220, 1116, 1084, 1018, 886. HNMR (400 MHz, CDCl3):
ẟ
7.86-7.73 (m, 3H), 7.53-7.44 (m, 4H), 6.66 (s, 0.5H), 6.51 (d,
Hz, 1H), 4.80 (d, = 12.4 Hz, 1H), 4.36-4.31 (m, 2H), 4.20 (d,
Hz, 1H), 4.04-3.98 (m, 3H), 3.88 (d, = 8.4 Hz, 1H), 3.85-3.65 (m, 1H), 3.58 (d,
1H), 1.98-1.91 (m, 1H), 1.75-1.69 (m, 1H), 1.56 (s, 3H), 1.48 (s, 3H), 1.44-1.31 (s, 12H), 1.25-
J
= 3.2 Hz, 0.5H), 5.04 (d,
J
= 12.4
J
J = 8.2 Hz, 1H), 4.12 (d,
J
= 13.6
J
J = 7.4 Hz,
1.19 (m, 5H), 1.00-0.96 (m, 3H) ppm. 13CNMR (100 MHz, CDCl3):
δ 145.3, 135.0, 133.9, 133.8,
25

133.6, 131.0, 130.9, 129.2, 129.1, 128.5, 126.2, 126.1, 125.6, 125.2, 125.0, 124.1, 123.8, 123.1,
122.8, 122.1, 112.0, 109.1, 104.3, 99.0, 86.0, 85.8, 83.8, 83.6, 81.4, 81.3, 80.3, 80.2, 77.4, 76.5,
73.8, 71.8, 65.2, 60.2, 48.3, 37.3, 37.1, 34.0, 33.7, 30.4, 30.2, 28.2, 27.0, 27.0, 26.8, 26.2, 26.0,
25.6, 25.1, 23.3, 20.5, 19.1, 19.0 ppm. Anal. Calcd for (C36H49N3O9): C 64.75, H 7.40, N 6.29.
Found: C 64.80, H 7.35, N 6.25.
1-(5-(3-(furan-2-yl)-6,6-dimethyl-1,2,4-trioxan-5-yl)-3-methylpentyl)-4-(((2,2,2
methyltetrahydrospiro[[1,3]dioxolo[4,5-c]pyran-6,4 -[1,3]dioxolan]-7-yl)oxy)methyl)-1
1,2,3-triazole (10k): Gum; IR (KBr, cm-1):
3291, 3123, 2971, 2870, 2096, 1688, 1489,1449,
1123, 1038, 603. 1HNMR (400 MHz, CDCl3): 7.52 (s, 1H), 7.42 (d,
= 5.4 Hz, 1H), 6.47-6.18
(m, 2H), 5.99 (d, = 2.0 Hz, 0.5H), 5.86 (d, = 3.6 Hz, 0.5H), 5.05 (d, = 12.4 Hz, 1H), 4.81
(d, = 12.4 Hz, 1H), 4.41-4.35 (m, 2H), 4.22 (d, = 8.4 Hz, 1H), 4.13 (d, = 13.4 Hz, 1H),
4.05-3.99 (m, 3H), 3.89 (d, = 8.4 Hz, 1H), 3.74-3.61 (m, 1H), 3.58 (d, J = 7.4 Hz, 1H), 1.99-
ˈ,2ˈ-tetra
ˈ
H-
υ
J
J
J
J
J
J
J
J
1.91 (m, 1H), 1.75-1.69 (m, 1H), 1.56 (s, 3H), 1.48 (s, 3H), 1.39-1.33 (m, 12H), 1.27-1.18 (m,
13
5H), 1.00-0.97 (m, 3H) ppm. CNMR (100 MHz, CDCl3):
δ 152.1, 151.4, 144.7, 142.7, 142.5,
121.7, 111.5, 109.6, 109.5, 108.6, 108.6, 107.7, 103.8, 95.1, 94.8, 85.2, 85.0, 83.2, 83.0, 80.7,
79.9, 76.9, 76.2, 73.3, 71.3, 64.6, 59.7, 47.9, 36.7, 36.6, 33.3, 33.2, 30.0, 29.7, 27.6, 26.2, 26.2,
25.9, 25.7, 25.5, 24.5, 24.3, 22.2, 20.0, 18.5, 18.5 ppm. Anal. Calcd for (C30H45N3O10): C 59.29,
H 7.46, N 6.91. Found: C 59.25, H 7.40, N 6.99.
1-(5-(3,3-Dimethyl-1,2,5-trioxaspiro[5.5]undecan-4-yl)-3-methyl pentyl)-4-(((2,2,2
methyltetrahydrospiro[[1,3]dioxolo[4,5-c]pyran-6,4 -[1,3]dioxolan]-7-yl)oxy)methyl)-1
3291, 3123, 2988, 2936, 1383, 1220, 1116, 1084,
= 12.4 Hz, 1H), 4.82 (d,
= 8.4Hz, 1H), 4.13 (d, = 13.4 Hz, 1H), 4.06-4.00
= 8.4 Hz, 1H), 3.65-3.58 (m, 2H), 2.01-1.93 (m, 1H), 1.76-1.71 (m, 1H),
1.64-1.55 (m, 10H), 1.49 (s, 3H), 1.38 (s, 10H), 1.24 (s, 7H), 1.07 (s, 3H), 0.99 (d, = 6.4 Hz,
3H) ppm. 13CNMR (100 MHz, CDCl3):
145.3, 122.1, 112.0, 109.1, 106.9, 104.2, 83.0, 82.8,
ˈ,2ˈ-tetra-
ˈ
H-
1,2,3-triazole (10l): Gum, IR (KBr, cm-1):
υ
1
1018, 886. HNMR (400 MHz, CDCl3): 7.54 (s, 1H), 5.06 (d,
J
J =
12.4 Hz, 1H), 4.41-4.34 (m, 2H), 4.22 (d,
(m, 3H), 3.89 (d,
J
J
J
J
δ
79.5, 77.4, 77.4, 73.8, 71.7, 65.2, 60.1, 48.4, 38.3, 37.3, 36.1, 36.0, 34.08, 33.8, 30.4, 30.2, 29.6,
28.1, 26.8, 26.5, 26.2, 25.9, 25.1, 24.0, 23.7, 23.2, 23.1, 19.1, 19.0 ppm. Anal. Calcd for
(C31H51N3O9): C 61.06, H 8.43, N 6.89. Found: C 61.00, H 8.35, N 6.96.
26

Typical procedure for synthesis of 1,2,3-triazole tethered 1,2,4-trioxane with 1,4-
disubstituted benzene core: A mixture of CuI (2 mg, 1 mol%) and L-proline (1.2 mg, 1 mol%)
taken in an oven-dried two-neck round bottom flask was mixed with glycerol (4 mL) in a bath
sonicator for 30 min. Then azido-1,2,4-trioxane derivative of compound (6a) (0.364 g, 1 mmol)
and 1,4-diethylene benzene (0.126 g, 1 mmol) were added to the solution and stirred at room
temperature. The progress of the reaction was monitored by TLC and found completed within 6
h. The reaction was quenched by adding water (5 mL) to the suspension and extracted with ethyl
acetate (3 × 15 mL). The combined organic layer was dried over anhydrous Na2SO4 and
concentrated the organic layer to afford the crude product. The crude was purified by column
chromatography employing 15% ethyl acetate in hexane as eluent.
1,4-bis(1-(5-(6,6-dimethyl-3-(4-nitrophenyl)-1,2,4-trioxan-5-yl)-3-methylpentyl)-1
H-1,2,3-
triazol-4-yl)benzene (12a): Yield 67%, gum. IR (KBr, cm-1):
υ 3312, 3134, 2972, 2871, 1619,
1
1461, 1531, 1384, 1350, 1192, 1107. HNMR (400MHz, CDCl3): 8.22-8.18 (m, 4H), 7.87 (s,
4H), 7.80 (s, 2H), 7.65-7.58 (m, 4H), 6.02 (s, 0.5H), 5.86 (s, 1.5H), 4.51-4.43 (m, 4H), 3.74-3.55
(m, 2H), 2.06-2.01 (m, 2H), 1.83-1.67 (m, 4H), 1.56-1.50 (m, 4H), 1.36-1.32 (m, 6H), 1.04-1.01
(m, 4H), 0.88-0.80 (m, 6H) ppm. 13CNMR (100 MHz, CDCl3):
δ 148.3, 148.1, 147.3, 147.1,
145.3, 130.3, 127.5, 127.5, 127.1, 126.0, 123.5, 119.5, 100.0, 99.6, 86.3, 86.0, 84.2, 84.1, 81.9,
80.9, 48.4, 37.2, 37.1, 33.9, 33.6, 30.2, 30.0, 26.9, 26.7, 25.4, 25.0, 23.3, 20.3, 19.1, 19.1 ppm.
Anal. Calcd for (C44H54N8O10): C 61.81, H 6.37, N 13.11. Found: C 61.75, H 6.32, N 13.20.
1,4-Bis(1-(5-(3-(2-bromophenyl)-6,6-dimethyl-1,2,4-trioxan-5-yl)-3-methylpentyl)
-1
H-
o
1,2,3-triazol-5-yl)benzene (12b): White solid; Mp: 119-120 C, IR (KBR, cm-1):
υ 3051, 3025,
1
2956, 2926, 2866, 1634, 1492, 1443, 1070, 786. HNMR (400 MHz, CDCl3): 7.88 (s, 4H),
7.78-7.64(m, 4H), 7.58-7.16 (m, 6H), 6.24 (s, 1H), 6.10 (d,
3.76-3.63 (m, 2H), 2.04-1.99 (m, 2H), 1.83-1.37 (m, 18H), 1.26-1.20 (m, 6H), 1.03-1.00 (m, 6H)
ppm. 13CNMR (100 MHz, CDCl3):
147.3, 138.1, 136.9, 132.9, 132.7, 130.5, 130.3, 130.2,
J = 4.4 Hz, 1H), 4.47-4.43 (m, 4H),
δ
128.1, 127.8, 127.5, 127.3, 126.0, 123.2, 122.8, 119.5, 100.1, 100.1, 86.0, 85.7, 84.0, 83.8, 81.6,
80.4, 48.5, 37.3, 37.1, 33.9, 33.6, 30.5, 30.1, 26.9, 26.8, 25.6, 25.1, 23.4, 20.2, 19.2, 19.1 ppm.
Anal. Calcd for (C44H54Br2N6O6): C 57.27, H 5.90, N 9.11. Found: C 57.21, H 5.95, N 9.06.
27

1,4-Bis(1-(5-(3-(4-fluorophenyl)-6,6-dimethyl-1,2,4-trioxan-5-yl)-3-methylpentyl)-1H-1,2,3-
o
triazol-4-yl)benzene (12c): White solid; Mp: 110-113 C, IR (KBr, cm-1):
υ 3315, 3129, 2974,
1
2935, 2870, 1609, 1460, 1192, 1107. HNMR (400 MHz, CDCl3): 7.81 (s, 4H), 7.71 (d,
J =
4.4 Hz, 2H), 7.40-7.33 (m, 4H), 7.00-6.94 (m, 4H), 5.88 (s, 1H), 5.70 (s, 1H), 4.41-4.35 (m, 4H),
3.63-3.61 (m, 1H), 3.59-3.54 (m, 1H), 1.98-1.93 (m, 2H), 1.51-1.27 (m, 8H), 1.25-1.14 (m, 13H),
0.98-0.94 (m, 3H), 0.82-0.75 (m, 6H) ppm. 13CNMR (100 MHz, CDCl3):
Hz), 160.9 (d, = 21.6 Hz), 146.3, 134.7, 132.9, 129.3, 127.7, 127.1, 125.0, 118.4, 114.3, 114.0,
δ 163.3 (d, J = 22.9
J
100.0, 99.5, 85.1, 84.8, 83.1, 83.0, 80.4, 79.2, 47.4, 36.2, 36.2, 33.0, 32.8, 29.1, 28.6, 26.0, 25.8,
24.5, 24.2, 22.5, 21.6, 19.1, 18.0 ppm. Anal. Calcd for (C44H54F2N6O6): C 65.98, H 6.80, N
10.49. Found: C 64.92, H 6.75, N 1056.
1,4-Bis(1-(5-(3-(4-chlorophenyl)-6,6-dimethyl-1,2,4-trioxan-5-yl)-3-methylpentyl)-1H-1,2,3-
o
triazol-4-yl)benzene (12d): White solid; Mp: 146-148 C, IR (KBr, cm-1):
υ 3051, 3025, 2956,
1
2926, 2866, 1634, 1492, 1443, 1070. HNMR (400 MHz, CDCl3): 7.81 (s, 4H), 7.70 (d,
J =
4.8 Hz, 2H), 7.34-7.19 (m, 8H), 5.87 (s, 1H), 5.69 (s, 1H), 4.42-4.34 (m, 4H), 3.63-3.51 (m, 2H),
1.98-1.91 (m, 2H), 1.48-1.21 (m, 24H), 0.95 (d,
= 6.0 Hz, 6H) ppm. 13CNMR (100 MHz,
CDCl3): 146.3, 137.5, 135.7, 133.9, 133.5, 129.3, 127.5, 127.4, 127.1, 126.6, 125.0, 118.4,
J
δ
99.8, 99.3, 85.1, 84.8, 83.1, 82.9, 80.5, 79.3, 47.4, 36.2, 36.2, 32.9, 32.6, 29.3, 29.2, 26.0, 25.8,
25.7, 24.5, 24.1, 22.4, 19.2, 18.0 ppm. Anal. Calcd for (C44H54Cl2N6O6): C 63.38, H 6.53, N
10.08. Found: C 63.32, H 6.48, N 10.15.
1,4-Bis(1-(5-(3-(3-bromophenyl)-6,6-dimethyl-1,2,4-trioxan-5-yl)-3-methylpentyl)-1H-1,2,3-
o
triazol-4-yl)benzene (12e): White solid; M.p: 103-105 C, IR (KBr, cm-1):
υ 3315, 3127, 3090,
1
2970, 2871, 1595, 1441, 1193, 1122. HNMR (400 MHz, CDCl3): 7.88 (s, 4H), 7.79 (d,
J =
4.4 Hz, 2H), 7.62-7.58 (m, 2H), 7.47-7.35 (m, 4H), 7.25-7.20 (m, 2H), 5.92 (s, 1H), 5.75 (s, 1H),
4.48-4.39 (m, 4H), 3.71-3.59 (m, 2H), 2.05-1.20 (m, 26H), 1.02 (d, = 6.4 Hz, 6H) ppm.
13CNMR (100 MHz, CDCl3):
147.3, 142.3, 140.5, 132.2, 131.8, 130.2, 129.9, 129.7, 129.3,
J
δ
126.0, 125.4, 124.9, 122.4, 119.5, 100.6, 100.1, 86.1, 85.8, 84.1, 84.0, 81.6, 80.5, 48.5, 37.3,
37.2, 33.9, 33.6, 30.4, 30.1, 27.0, 26.7, 25.5, 25.1, 23.4, 20.2, 19.1, 19.1 ppm. Anal. Calcd for
(C44H54Br2N6O6): C 57.27, H 5.90, N 9.11. Found: C 57.22, H 5.85, N 9.19.
28