Synthesis of Non-symmetrical Dispiro-1,2,4,5-Tetraoxanes and Dispiro-1,2,4-Trioxanes Catalyzed by Silica Sulfuric Acid

Article abstract of DOI:10.1021/acs.joc.1c01258

A novel protocol for the preparation of non-symmetrical 1,2,4,5-tetraoxanes and 1,2,4-trioxanes, promoted by the heterogeneous silica sulfuric acid (SSA) catalyst, is reported. Different ketones react under mild conditions with gem-dihydroperoxides or peroxysilyl alcohols/β-hydroperoxy alcohols to generate the corresponding endoperoxides in good yields. Our mechanistic proposal, assisted by molecular orbital calculations, at the ωB97XD/def2-TZVPP/PCM(DCM)//B3LYP/6-31G(d) level of theory, enhances the role of SSA in the cyclocondensation step. This novel procedure differs from previously reported methods by using readily available and inexpensive reagents, with recyclable properties, thereby establishing a valid alternative approach for the synthesis of new biologically active endoperoxides.

Full text of DOI:10.1021/acs.joc.1c01258

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Article
Synthesis of Non-symmetrical Dispiro-1,2,4,5-Tetraoxanes and
Dispiro-1,2,4-Trioxanes Catalyzed by Silica Sulfuric Acid
Patrícia S. M. Amado, Luís M. T. Frija, Jaime A. S. Coelho, Paul M. O’Neill,* and Maria L. S. Cristiano*
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ABSTRACT: A novel protocol for the preparation of non-
symmetrical 1,2,4,5-tetraoxanes and 1,2,4-trioxanes, promoted by
the heterogeneous silica sulfuric acid (SSA) catalyst, is reported.
Different ketones react under mild conditions with gem-
dihydroperoxides or peroxysilyl alcohols/β-hydroperoxy alcohols
to generate the corresponding endoperoxides in good yields. Our
mechanistic proposal, assisted by molecular orbital calculations, at
the ωB97XD/def2-TZVPP/PCM(DCM)//B3LYP/6-31G(d)
level of theory, enhances the role of SSA in the cyclocondensation
step. This novel procedure differs from previously reported
methods by using readily available and inexpensive reagents, with
recyclable properties, thereby establishing a valid alternative
approach for the synthesis of new biologically active endoperoxides.
this synthetic step, we successfully explored a new methodology
for synthesizing the 1,2,4,5-tetraoxane subunit, involving the use
of readily available and low-cost silica sulfuric acid (SSA) as a
catalyst. Silica-supported catalysts have attracted attention in
recent years due to their promising reactivity and recoverable
and reusable properties, leading to economic and environmental
benefits.20,21 SSA was reported by Azarifar et al.22 as an effective
catalyst for the preparation of gem-dihydroperoxides (DHPs).
Peroxyacetalization is the first step in the most broadly used
method for synthesizing 1,2,4,5-tetraoxanes, which involves the
acid-catalyzed cyclocondensation of a ketone or aldehyde with
an active DHP intermediate prepared in situ. Generally, DHPs
are generated from the reaction of a carbonyl compound with
hydrogen peroxide (30 or 50 wt %) in the presence of a
catalyst.23 It has been reported that several catalysts known to
promote peroxyacetalization of ketones and aldehydes (e.g.,
INTRODUCTION
■
Artemisinin combination therapies have been used as the first-
line treatments against Plasmodium falciparum malaria during
the last decades.1−6 Disturbingly, the rise of resistance to
artemisinin and its semi-synthetic derivatives (ARTs, 1a, Figure
1) in South East Asia and the synthetic limitations of the ART
scaffold have pushed the course of research toward the
development of entirely synthetic endoperoxide-based antima-
larials.7−10 Several classes of synthetic endoperoxides have been
scrutinized in this context, including 1,2-dioxanes, 1,2,4-
trioxanes, 1,2,4-trioxolanes, and 1,2,4,5-tetraoxanes.11−13
Among these classes, 1,2,4-trioxolanes and 1,2,4,5-tetraoxanes
were extensively explored, notably yielding four antimalarial
candidates (ozonides OZ27714 (2a) and OZ43915,16 (2b) and
1,2,4,5-tetraoxanes RKA18217 (3a) and E20918 (3b), Figure 1).
O’Neill’s group reported E209, the newest 1,2,4,5-tetraoxane
antimalarial under development. This candidate displays
superior pharmacokinetic and pharmacodynamic properties,
together with potent nanomolar efficacy against multiple strains
of P. falciparum and Plasmodium vivax, in vitro and in vivo. E209
also shows reduced cross-resistance with the C580Y mutation in
transgenic parasites expressing variant forms of K13, known as
the primary liability for artemisinin resistance.19
MTO,24 iodine (I2),25 Re2O7,26 PMA,27 Bi(OTf)3,28 ClSO3H,29
32
HPA/NaY,30 ADA-MNPs,31 and H3+xPMo12−x+6Mox+5O40
)
can also induce selective cyclocondensation of these inter-
mediates with ketones/aldehydes, generating 1,2,4,5-tetraox-
anes.
Given the attractive properties of SSA, we decided to explore
the potential of silica-supported catalysts to promote the
Notwithstanding the promising properties shown by the novel
antimalarial candidate E209, the synthetic approach to its
preparation demands improvement (Scheme 1). Preparation of
E209 involves a six-step synthesis comprising the generation of
the 1,2,4,5-tetraoxane core present in precursor 6a, which
requires the use of moisture-sensitive catalysts such as Re2O7 or
Bi(OTf)3, affording a maximum yield of around 60% (when
using Bi(OTf)3) (Scheme 1a).18 During attempts to improve
Received: May 30, 2021
Published: July 19, 2021
https://doi.org/10.1021/acs.joc.1c01258
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© 2021 American Chemical Society
10608

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Figure 1. Representative endoperoxide-based antimalarial drugs or candidates. Artemisinin and semi-synthetic derivatives (1a−d); 1,2,4-trioxolanes
OZ277 (2a) and OZ439 (2b); and 1,2,4,5-tetraoxanes RKA182 (3a) and E209 (3b).
Scheme 1. (a) Synthetic Approach and Conditions Used in Previous Preparation of E209 and (b) Improved Conditions Proposed
in This Work and Scope Evaluation of the Methodology
cyclocondensation of the 1,2,4,5-tetraoxane ring. Our method-
ology involves a “two-pot” procedure, whereby the DHP
generated immediately reacts with the partner carbonyl
compound to achieve the cyclocondensation step (Scheme 1b).
RESULTS AND DISCUSSION
■
Preparation of the intermediate DHP 5 followed the method
reported by Azarifar et al.22 with some adjustments. 4-(4-
Oxocyclohexyl)phenyl acetate 4a was reacted with aqueous
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Table 1. Screening of Reaction Parameters for the Formation of 1,2,4,5-Tetraoxane 6a
a
entry
catalyst
none
SiO2
solvent
molar ratio SSA/ST
t (min)
yield (%)
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
48 h
48 h
12 h
60
60
60
60
60
75
75
nr
nr
d
1
d
H2SO4
1
13
48
58
62
53
56
51
53
52
48
52
24
12
nr
SSA-(A)
SSA-(B)
SSA-(C)
SSA-(D)
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
b
SSA-(C)
SSA-(C)
SSA-(C)
SSA-(C)
SSA-(C)
SSA-(C)
SSA-(C)
SSA-(C)
SSA-(C)
SSA-(C)
SSA-(C)
SSA-(C)
SSA-(C)
SSA-(C)
SSA-(C)
SSA-(C)
SSA-(C)
Re2O7
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
CH3CN/CH2Cl2 (1:1)
c
CH2Cl2
CH3CN
75
90
90
c
c
CH3CN/CH2Cl2 (1:1)
c
CH3CO2Et
120
180
48 h
48 h
48 h
60
12 h
60
60
Et2O
DMSO
DMF
nr
nr
1,4-dioxane
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
67
63
62
57
34
11
4618
6118
2
3
0.5
0.1
0.01
120
12 h
60
Bi(OTf)3
120
a
b
c
d
ST: starting material. Formic acid used in the first step instead of SSA-(C). Not anhydrous. 1 equiv of SiO2 or H2SO4; nr = no reaction; SSA-
(A−D): 1, 2, 3, and 4 mL of H2SO4 (>95%), respectively.
Figure 2. Representation of the procedure followed for the preparation of SSA-(A−D) catalysts.
hydrogen peroxide 50% (w/w) in acetonitrile (4:1 molar ratio of
H2O2 to the starting ketone) in the presence of the SSA catalyst
at room temperature (Table 1). A solvent extraction workup was
followed to remove excess H2O2, intended for safety purposes
and optimization in the overall yield.
Concerning the preparation of the SSA catalysts, different
proportions of sulfuric acid were used [SSA-(A−D): 1, 2, 3, and
4 mL of H2SO4 (>95%), respectively]. The procedure for
preparing each catalyst was identical (Figure 2) and is described
in detail in the Experimental and Computational Details section.
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Figure 3. (A) Molarity of H2SO4 in SSA-(A−D). Bars represent the mean values of molarity of H2SO4 triplicates SD; (B) reusability of SSA-(C) in
the generation of 6a (the red line corresponds to the molarity of H2SO4 in 1 g of SSA in each run); and (C) Pearson correlation coefficient between the
yield of each run and the molarity of H2SO4 in 1 g of SSA.
The molarity of sulfuric acid adsorbed on the silica gel was
determined by acid−base titration. The results, summarized in
Figure 3A, indicate that the amount of H2SO4 adsorbed by silica
appears to be directly proportional to the amount of H2SO4
added to both SSA-(A) and SSA-(B) (3.85 0.04 and 6.10
0.03 mmol in 1 g of SSA, respectively) in contrast to what was
observed with SSA-(C) and SSA-(D) (7.54 0.04 and 8.40
0.04 mmol in 1 g of SSA), demonstrating a saturation tendency
on the silica gel surface after continuous addition of H2SO4.
The reaction of the crude DHP with 2-adamantanone 4b, in
the presence of SSA catalyst, was selected as the model to find
the optimized reaction conditions for the cyclocondensation
step. The factors analyzed were the nature of the solvent as well
as the amount and the type of the catalyst, namely, the ratio of
H2SO4/SiO2 (SSA-(A−D)) (see Table 1). Analysis of the data
shows that when using a 2:1 molar ratio of SSA-(C) to 4-(4-
oxocyclohexyl)phenyl acetate 4a, in anhydrous dichloro-
methane, at room temperature, p-(dispiro[cyclohexane-1,3′-
[1,2,4,5]tetraoxane-6′,2″-tricyclo[3.3.1.13,7]decan]-4yl)phenyl
acetate 6a is selectively produced with the highest observed yield
(67%), after 60 min (Table 1, entry 19). Increasing the reaction
time (12 h) (Table 1, entry 20) and using a higher molar ratio of
SSA-(C) (3 equiv, Table 1, entry 21) did not improve the
efficacy of the model reaction. SSA-(C) seemed to outperform in
efficiency compared to the other SSA batches, in the same
equivalency (Table 1, entries 4−7). Conduction of the model
reaction using silica gel, or in the absence of catalyst, did not lead
to 6a, even when extending the reaction time for 48 h, showing
the importance of SSA for the reaction’s success (Table 1,
entries 1 and 2). Reaction with H2SO4 (1 equiv) afforded the
desired 1,2,4,5-tetraoxane 6a, though in a much lower yield than
using the silica-supported-H2SO4 catalyst (Table 1, entry 3).
Solvent effects were also investigated. As shown from the data
presented in Table 1, anhydrous dichloromethane is the most
efficient solvent. The reaction failed when solvents dimethyl
sulfoxide (DMSO) and dimethylformamide (DMF) were used
(Table 1, entries 16 and 17). This observation is explained by
the hygroscopic nature of these solvents. The presence of
moisture in the reaction mixture could entail the following
results: (1) water may affect the SiO2−H2SO4 ⇔ SiO2−H2O
conversion equilibrium, altering the catalytic capabilities of SSA
by adsorbing on its surface, interfering with the cyclo-
condensation step, and also promoting the hydrolysis of the
intermediate DHP with the regeneration of the corresponding
starting ketone, and (2) water itself may also hydrolyze the
DHP, thus regenerating to its starting ketone. Even though
DMSO and DMF had a commercial purity of >98%, these
solvents were not freshly distilled prior to use. The use of
ethereal solvents such as diethyl ether or 1,4-dioxane strongly
inhibited the ability of SSA to promote cyclocondensation to the
tetraoxane core (Table 1, entries 15 and 18). The yield
decreased considerably when the reaction was performed under
non-anhydrous conditions (Table 1, entries 11−14), revealing
that anhydrous conditions favor the cyclocondensation of the
1,2,4,5-tetraoxane core by avoiding decomposition of the DHP
to its starting material. The cyclocondensation was achieved
even with minimal amounts of SSA-(C), such as 0.01 equiv,
although with 11% yield (Table 1, entry 24), demonstrating its
catalytic capacity.
A series of 1,2,4,5-tetraoxanes 6a−g were synthesized using
the optimal conditions (Table 1, entry 19), thereby demonstrat-
ing the methodology’s tolerance to a range of functional groups
and structural features (Table 2). We also applied the
methodology to the synthesis of non-symmetrical 1,2,4,5-
tetraoxanes, and, under heterogeneous conditions, the required
compounds were generated with yields ranging from 5 to 67%.
The reactions, performed in the presence of 2 equivalents of
SSA-(C) and using excess of the second ketone (1.5 mmol)
relatively to the starting one, were usually completed in the
period of 1−6 h. Homodimeric byproducts were occasionally
formed during the cyclocondensation step, especially during the
preparation of 6g. The symmetric 1,2,4,5-tetraoxane byproduct
could be differentiated by thin-layer chromatography (TLC)
and was obtained in lower proportion for ketones in which both
structures varied substantially between each other, in polarity or
composition. These circumstances could be avoided by isolating
the DHP through column chromatography and then reacting it
with excess of the second ketone (2 mmol) in the cyclo-
condensation step. 1,2,4,5-Tetraoxane 6e was generated in a
very low yield (5%), which may be ascribed to the use of a very
bulky ketone, 2-adamantanone 4b, which preferentially under-
goes a Baeyer−Villiger rearrangement during the cyclo-
condensation step, originating its corresponding lactone. In
fact, 4-oxahomoadamantan-5-one was isolated in a higher
amount than the desired 1,2,4,5-tetraoxane 6e. Hydroperox-
idation of aromatic aldehyde 4c was achieved easily with SSA-
(C) during the first step. Although cyclocondensation with 4b
was observed, the DHP decomposed back to 4c, suggesting
some instability of the DHP in the reaction medium. An attempt
to generate the corresponding tetraoxane from 4,4-difluorocy-
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Table 2. Scope Evaluation in the SSA-Promoted Formation of 1,2,4,5-Tetraoxanes
Scheme 2. Conditions for One-Pot Synthesis of 1,2,4,5-Tetraoxanes Using SSA-(C)
clohexanone (4d) and 4b was disrupted during purification. It
appears that strong electron-withdrawing groups close to the
tetraoxane ring, such as the fluorine, favor its instability,
promoting decomposition (Table 2).
A one-pot approach to synthesize 1,2,4,5-tetraoxanes was also
carried out in order to understand if the performance would
match the two-step protocol. The procedure involved addition
of 2 equivalents of SSA-(C) and 50% aqueous H2O2 (4 mmol)
to a solution of the starting ketone (1.0 mmol) in acetonitrile.
After consumption of the starting material, 2-adamantanone
(1.5 mmol) was added, and the final mixture left for stirring
overnight (Scheme 2). Under these conditions, the desired
1,2,4,5-tetraoxane was obtained in poor yields (8%). Evapo-
ration of the solvent after the peroxidation step was not
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Figure 4. Free energy profile for the formation of 1,2,4,5-tetraoxane 6g promoted by SSA [modeled by two molecules of Si(OH)3(SO3H)]. DFT
calculations were performed at the ωB97XD/Def2-TZVPP/PCM(DCM)//B3LYP/6-31G(d) level of theory (energy values in kcal mol−1).
considered because it would lead to a dangerous concentration
of free hydrogen peroxide, highly explosive.
(DFT) calculations at the ωB97XD/def2-TZVPP/PCM-
(DCM)//B3LYP/6-31G(d) level of theory. 2-Adamantanone
(4b) and 1,1-cyclohexanediyl dihydroperoxide (5g) were
selected as model substrates, and two molecules of Si-
(OH)3(SO3H) were considered to mimic the SSA. Calculations
predict a thermodynamically favored process, globally. The
proposed mechanism involves protonation of the carbonyl
group of 4b by SSA; followed by 1,2-addition of a hydroperoxide
of 5g to the protonated ketone, with concomitant proton
abstraction by SSA, via TS1 (11.4 kcal mol−1); then, protonation
of the hydroxyl moiety by SSA; and, finally, a SN1-type reaction
to form the 1,2,4,5-tetraoxane 6g. The SN1 reaction occurs via
water dissociation (TS2, rate-limiting step, 12.4 kcal mol−1) to
form a tertiary carbocation that reacts with the second
hydroperoxide of 5g (TS3, 10.5 kcal mol−1), generating 6g
after proton abstraction by SSA. The calculations also suggest
that all steps are reversible, except the last one (TS3), the
dissociation of the product 6g from SSA-H2O being
thermodynamically favored.
Inspired by the results obtained for the synthesis of 1,2,4,5-
tetraoxanes, we decided to evaluate the SSA catalyst’s potential
in the cyclocondensation process to generate 1,2,4-trioxanes.
Two methods were used: (A) hydroperoxysilylation of allylic
alcohols 7a−b, followed by cyclocondensation to 1,2,4-
trioxanes, in the presence of SSA. The 1,2,4-trioxane moiety
(8a−f) could be easily constructed in moderate yields (38−68%,
Table 3), through a milder approach, in the sequence of a
Co(II)-mediated peroxysilylation of allylic alcohols (through a
Isayama and Mukaiyama hydroperoxysilylation33,34); and (B)
perhydrolysis of spiro-oxiranes, followed by cyclocondensation
The recycling properties of SSA were also thoroughly
analyzed. Following each run of the cyclocondensation step of
6a, SSA-(C) was removed from the reaction mixture by filtration
and rinsed several times with dichloromethane to remove the
contaminants adsorbed on the surface of SSA and subsequently
dried in a vacuum oven at 60 °C for 24 h. The recovered SSA-
(C) was reused in the next run. Analysis of the results displayed
in Figure 3B shows that the catalyst SSA-(C) can be used up to 2
times with only a slight loss in the yield of 6a (67−62%). When
using the catalyst in the synthesis of 6a for five consecutive times,
we observed that the yield decreases considerably from the third,
fourth, and fifth runs (41, 27, and 12%, respectively), which is
probably due to the gradual catalyst contamination by the
starting materials and byproducts and the slow loss of H2SO4.
The amount of sulfuric acid loaded on the recovered SSA-(C)
was also evaluated using the acid−base titration method to
better understand the molarity exchanges that occurred during
the reaction and recovery process of the compound. Figure 3B
shows that the molarity of H2SO4 on the silica surface decreases
in the recovered catalyst with each run (run 1: 7.54 0.04; run
2: 4.20 0.08; run 3: 3.17 0.06; run 4: 1.14 0.05; and run 5:
0.53 0.01 mmol in 1 g of SSA), and this decrease is directly
related to the yield of the corresponding run’s yield (Figure 3C, r
= 0.921, p < 0.001).
Mechanistic Study for the Formation of 1,2,4,5-
Tetraoxanes. A proposed mechanism for the formation of
1,2,4,5-tetraoxanes is provided in Figure 4. The role of SSA as an
acid promoter was investigated by density functional theory
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Table 3. Hydroperoxysilylation of Allylic Alcohols, Followed by SSA-Mediated Cyclocondensation to 1,2,4-Trioxanes
Table 4. Perhydrolysis of Spiro-oxiranes, Followed by SSA-Mediated Cyclocondensation to 1,2,4-Trioxanes
a
Reaction time (step 1/step 2, hours).
to 1,2,4-trioxanes, through reaction with the corresponding
ketones, at room temperature, in the presence of SSA. We also
explored SSA as a potential catalyst for the perhydrolysis step
since it has been previously reported as a promoter in the
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alcoholysis and hydrolysis of epoxides35 and regioselective ring
opening of epoxides by the thiocyanate anion to yield
thiocyanohydrins.36 Perhydrolysis of spiro-oxiranes 9a−b was
achieved with SSA in the presence of ethereal H2O2. A simple
solvent extraction workup was performed to remove the excess
H2O2, and the crude β-hydroperoxy alcohols were used
immediately in the next step without further purification.
Subsequent cyclocondensation with the corresponding ketones
yielded the 1,2,4-trioxanes 10a−b in reasonable yields (47−
63%, Table 4). These results highlight the versatility of SSA for
promoting selective cyclocondensation to different six-mem-
bered endoperoxide core structures.
Safety. Organic peroxides are potentially hazardous compounds
(inflammable and explosive) and must be handled carefully: (1) a safety
shield should be used for all reactions involving H2O2 and (2) direct
exposure to strong heat or light, mechanical shock, oxidizable organic
materials, or transition metal ions should be avoided.
Computational Details. DFT calculations were performed using
the Gaussian 09 software package37 and structural representations were
generated with CYLview.38 All the geometry optimizations were carried
out using the standard B3LYP functional and the valence double-zeta 6-
31G(d) basis set. All of the optimized geometries were verified by
frequency computations as minima (zero imaginary frequencies) or
transition states (a single imaginary frequency corresponding to the
desired reaction coordinate). Single-point energy calculations on the
optimized geometries were then evaluated using the long-range
corrected hybrid functional ωB97XD developed by Chai and Head-
Gordon39 and the valence triple-zeta Def2-TZVPP basis set with
solvent effects (dichloromethane) calculated by means of the
polarizable continuum model initially devised by Tomasi and co-
workers,40−43 with radii and non-electrostatic terms of the SMD
solvation model, developed by Truhler and co-workers.44 The free
energy values presented along the manuscript and Supporting
Information were derived from the electronic energy values obtained
at the ωB97XD/Def2-TZVPP//B3LYP/6-31G(d) level, including
solvent effects, and corrected by using the thermal and entropic
corrections based on structural and vibration frequency data calculated
at the B3LYP/6-31G(d) level.
CONCLUSIONS
■
The cyclocondensation of a representative library of ketones
with DHPs or silyl peroxysilyl alcohols/β-hydroperoxy alcohols
to afford the corresponding unsymmetrical 1,2,4,5-tetraoxanes
or 1,2,4-trioxanes, mediated by the SSA catalyst, was system-
atically investigated. The elementary steps governing the
cyclocondensation pathway were investigated through molec-
ular orbital calculations, using the DFT method, at the
ωB97XD/def2-TZVPP/PCM(DCM)//B3LYP/6-31G(d)
level of approximation. The results support a mechanistic
proposal that highlights the catalytic role of SSA, where initial
protonation of the ketone carbonyl group by SSA emerges as a
key step in the mechanism. This novel approach involving the
silica-supported catalyst offers several advantages, namely,
tolerance to a wide range of reagents. In addition, easy
preparation, recyclability, and eco-friendly properties of the
SSA catalyst are features that make this method an appealing
tool in broadening the design of new biologically active
endoperoxides. This improved methodology was successfully
applied to the preparation of p-(dispiro[cyclohexane-1,3′-
[1,2,4,5]tetraoxane-6′,2″-tricyclo[3.3.1.13,7]decan]-4-yl)-phe-
nyl acetate, an instrumental 1,2,4,5-tetraoxane intermediate
scaffold for the synthesis of the antimalarial candidate E209.
Statistical Analysis. The values in this study are expressed as
means standard deviation (SD). The Shapiro−Wilk test was used for
verification of the normality of the data. Graphics and statistical analysis
were generated with manual R scripts in RStudio (version 1.4.1106)
using ggplot2 libraries for the graphic figures.
General Procedure for Preparation of SSA. The general
procedure was adapted from Roy and Mukhopadhyay45 with slight
modifications. To a slurry of silica gel (10 g, 230−400 mesh, pore size
60 Å) in dry diethyl ether (50 mL) was added concentrated H2SO4
(>95%, 3 mL) under strong stirring for 30 min at 0 °C. The solvent was
evaporated under reduced pressure, resulting in free-flowing SSA that
was dried in vacuo for 24 h. Then, it was heated at 120 °C for 3 h (using a
hot plate), affording the catalyst SSA-(C). The prepared catalyst was
stored inside in a desiccator. The molarity of sulfuric acid adsorbed on
the silica gel was determined by the acid−base titration method.
Purified water (10 mL) was added to 0.01 g of SSA, and the mixture was
stirred for 1 h at room temperature. The suspension was then titrated
with a solution of NaOH (0.0025 M).
EXPERIMENTAL AND COMPUTATIONAL DETAILS
■
Chemicals. All reagents and solvents used were of analytical grade
and were used without further purification. 2-Adamantanone (4b), 4,4-
difluorocyclohexanone (4d), and 2-methylprop-2-en-1-ol (7b) were
purchased and used without additional purification. When necessary,
solvents were freshly distilled from appropriate drying agents prior to
use. Analytical TLC was carried out using TLC Silica gel 60 F254
aluminum sheets (AL TLC 20 × 20). Column chromatography was
carried out using technical grade Silica Gel 60 (0.04−0.063 mm).
Procedure for Catalyst Regeneration. Following the cyclo-
condensation process with SSA, the catalyst was filtered out of the
reaction mixture and washed several times with dichloromethane to
remove any remaining organic contaminants (5 × 25 mL). Drying in a
vacuum oven at 60 °C for 24 h regenerates the catalyst.
General Procedure 1: Synthesis of 1,2,4,5-Tetraoxanes (6a−
g). Step 1: Carbonyl compound 1 (1 mmol) was dissolved in
acetonitrile (3 mL) and SSA-(C) (2 mmol) was added to the mixture.
Hydrogen peroxide 50 wt % in H2O (4 mmol) was slowly added over an
ice bath, and then the mixture was left to stir at room temperature until
consumption of the starting material. To this mixture was added
distilled water, and then the catalyst was filtered and rinsed with
CH2Cl2. The filtrate was extracted with CH2Cl2 (3 × 30 mL), dried over
with MgSO4, and concentrated under reduced pressure, at low
temperature (30−35 °C), to obtain the DHP semi-crude, which was
used immediately, without further purification. Step 2: The DHP semi-
crude was dissolved in anhydrous CH2Cl2 (5 mL), followed by addition
of the second carbonyl compound 2 (1.5 mmol). The mixture was
cooled over an ice bath prior to addition of SSA-(C) (2 mmol). The
mixture was then warmed and left to stir at room temperature until
consumption of the starting material. The resulting solution was then
filtered, rinsed with CH2Cl2, and concentrated under reduced pressure.
The residue was purified by flash chromatography using an EtOAc−
hexane gradient (unless specified differently) to afford pure 1,2,4,5-
tetraoxanes.
1
Analytical Equipment. H and 13C nuclear magnetic resonance
(NMR) spectra were recorded using a Bruker AMX400 spectrometer or
a 500 MHz JEOL system equipped with a Royal HFX probe, in
solution, using the deuterated solvents described in each experimental
procedure. The chemical shifts (δ) are described in parts per million
(ppm) downfield from an internal standard of tetramethylsilane.
Melting points (°C) were obtained on an SMP30 melting point
apparatus and are uncorrected. High-resolution mass spectrometry
(HRMS) was recorded using the analytical services within the
Chemistry Department at the University of Liverpool (UoL) and
within the Centre of Marine Sciences (CCMar). HRMS was conducted
on a VG analytical 7070E machine, a Frisons TRIO mass spectrometer,
or an Agilent QTOF 7200 using chemical ionization (CI) or
electrospray (ESI) (UoL) and on a Thermo Scientific high-resolution
mass spectrometer (HRMS), model Orbitrap Elite, capable of MSn, n
up to 10 (CCMar). Elemental analysis (% C, % H, % N, and % S where
specified) were determined by the University of Liverpool Micro-
analysis Laboratory.
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General Procedure 2: Synthesis of 1,2,4-Trioxanes (8a−f) via
Hydroperoxysilylation of Allylic Alcohols Followed by Cyclo-
condensation to 1,2,4-Trioxane. Step 1: Hydroperoxysilylation of
Allylic Alcohols. Procedure as described by O’Neill et al.46 To a
solution of allylic alcohol (1 mmol) in 1,2-dichloroethane (DCE) (10
mL) was added Co(thd)2 (0.03 mmol) at room temperature, and the
solution was allowed to stir while bubbling with oxygen. After a couple
of minutes, triethylsilane (2 mmol) was added, and the reactants were
allowed to react under an oxygen atmosphere. The original purple/
brown solution became green and the reaction was followed by TLC
until completion. The reaction mixture was then filtered through a plug
of Celite in a sinter funnel under pressure. The Celite was washed with
ethyl acetate and the resulting filtrate was then concentrated under
reduced pressure to give the semi-crude peroxysilyl alcohol, which was
used immediately in the next step without further purification. Step 2:
Cyclocondensation of the Peroxysilyl Alcohol to 1,2,4-Trioxanes.
The peroxysilyl alcohol semi-crude (1 mmol) and the carbonyl
compound (1.5 mmol) were dissolved in anhydrous dichloromethane
(5 mL). The mixture was cooled below 5 °C and then SSA-(C) (2
mmol) was added. The mixture was then warmed and left to stir at
room temperature until completion of the reaction (usually 30−60
min). The resulting solution was then filtered, rinsed with dichloro-
methane, and concentrated under reduced pressure. Purification by
flash chromatography using a mixture of EtOAc/n-hexane (unless
specified differently) afforded the pure product.
then cooled to room temperature and treated dropwise, over 2 min,
with a solution (2 mL) of the corresponding ketone (1 mmol) and then
left to stir under reflux (using an oil bath) overnight or until completion
of the reaction. The mixture was cooled to room temperature and then
quenched with water. The aqueous layer was extracted with ethyl
acetate (3 × 15 mL), and the combined organic layers were dried over
anhydrous MgSO4, filtered, and concentrated under vacuum.
Purification by flash chromatography using an EtOAc-hexane gradient
(unless specified differently) afforded the pure spiro-epoxide.
4-(4-Oxocyclohexyl)phenyl Acetate (4a). The procedure was
adapted from by O’Neill et al.18 with slight modifications. To a stirred
solution of 4-(4-hydroxyphenyl)cyclohexanone (2.00 g, 10.51 mmol)
and triethylamine (2.90 mL, 20.8 mmol) in anhydrous dichloro-
methane (20 mL) was added acetic anhydride (3.00 mL, 31.74 mmol),
dropwise, at 0 °C. The reaction mixture was then allowed to warm to
room temperature and stirred for 3 h until the completion of the
reaction. The final reaction mixture was washed with water (3 × 20
mL), sodium bicarbonate (3 × 20 mL), and brine (20 mL). The organic
layer was dried with MgSO4, filtered, and then concentrated under
reduced pressure. Recrystallization of the solid residue from acetone
afforded the ester (2.20 g, 90% yield) as a white solid. mp 101−103 °C.
Spectral data are in accordance with that reported in the literature.18 1H
NMR (400 MHz, CDCl3): δ 7.25 (d, J = 8.5 Hz, 2H), 7.04 (d, J = 8.6
Hz, 2H), 3.08−2.98 (m, 1H), 2.50 (dd, J = 10.6, 4.6 Hz, 4H), 2.29 (s,
3H), 2.22 (dt, J = 14.6, 3.0 Hz, 2H), 1.93 (dt, J = 22.7, 10.6 Hz, 2H)
ppm. 13C{1H} NMR (101 MHz, CDCl3): δ 210.9, 169.6, 149.2, 142.3,
127.7, 121.6, 42.2, 41.3, 34.0, 21.1 ppm. HRMS (ESI+, m/z) calcd
C14H16O3Na (M + Na)+, 255.0992; found, 255.0992.
3-Acetylphenyl Acetate (4c). This compound was synthesized
following the procedure described previously by O’Neill et al.18 using
3′-hydroxyacetophenone. Colorless solid (1.12 g, 86% yield). Spectral
data are in accordance with that reported in the literature.48 1H NMR
(500 MHz, CDCl3): δ 7.83 (ddd, J = 7.8, 1.6, 1.1 Hz, 1H), 7.67 (t, J =
2.0 Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.30 (ddd, J = 8.0, 2.4, 1.0 Hz,
1H), 2.60 (s, 3H), 2.32 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3): δ
197.1, 169.4, 151.0, 138.6, 129.8, 126.6, 125.9, 121.6, 26.8, 21.2. HRMS
(ESI+, m/z) calcd for C10H10O3Na (M + Na)+, 201.05222; found,
201.05185.
p-(Dispiro[cyclohexane-1,3′-[1,2,4,5]tetraoxane-6′,2″-tricyclo-
[3.3.1.13,7]decan]-4-yl)-phenyl Acetate (6a). This compound was
synthesized in accordance with general procedure 1 using 4-(4-
oxocyclohexyl)phenyl acetate 4a (for the peroxidation step) and 2-
adamantanone 4b (for the cyclocondensation step). Purification by
flash chromatography (EtOAc: n-hexane, 2.5:97.5, v/v) provided a
white solid (278 mg, 67% yield). mp 195−197 °C. Spectral data are in
accordance with that reported in the literature.18 1H NMR (500 MHz,
CDCl3): δ 7.15 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.5 Hz, 2H), 3.35−2.94
(m, 2H), 2.54 (tt, J = 12.0, 3.7 Hz, 1H), 2.22 (s, 3H), 2.08−1.66 (m,
14H), 1.65−1.49 (m, 6H). 13C{1H} NMR (126 MHz, CDCl3): δ 169.8,
149.0, 143.5, 127.9, 121.5, 110.6, 107.6, 43.2, 37.0, 34.4, 33.3, 32.0,
30.2, 29.8, 27.2, 21.3. HRMS (ESI+, m/z) calcd C24H30O6Na (M +
Na)+, 437.19346; found, 437.19229.
Preparation of the Co(thd)2·H2O Catalyst. Procedure as
described by O’Neill et al.46 To an aq. solution (95 mL) of NaOH
(0.43 g, 10 mmol) and 2,2,6,6-tetramethyl-3,5-heptanedione (thd) (4.0
mL, 19.17 mmol) was slowly added a solution (15 mL) of cobalt(II)
chloride (1.34 g, 10.35 mmol). After stirring for 3 h at 60 °C (using an
oil bath), and filtering, the product was washed with water and stored
under reduced pressure as a purple powder (3.55 g, 40%). The prepared
catalyst was stored inside in a desiccator.
General Procedure 3: Synthesis of 1,2,4-Trioxanes (10a and
10b) via Perhydrolysis of Spiro-oxiranes Followed by Cyclo-
condensation to 1,2,4-Trioxanes. Step 1: To a spiro-oxirane (1
mmol) solution of MgSO4-dried H2O2−Et2O (15 mL, see note below),
SSA-(C) (2 mmol) was added at 0 °C. The reaction mixture was then
allowed to warm at room temperature and stirred until completion
(usually 1 h). The reaction mixture was then washed with water (1 ×
100 ml) and brine (1 × 100 mL). The combined aqueous layers were
extracted with CH2Cl2 (2 × 75 mL). The combined organic layers were
concentrated under vacuum, affording the β-hydroperoxy alcohol crude,
which was immediately used in the next step without any further
purification. Step 2: Cyclocondensation of the β-Hydroperoxy
Alcohol to 1,2,4-Trioxanes. The β-hydroperoxy alcohol semi-crude
(1 mmol) and the carbonyl compound (1.5 mmol) were dissolved in
anhydrous dichloromethane (5 mL). The mixture was cooled to below
5 °C and then SSA-(C) (2 mmol) was added. The mixture was then
warmed and left to stir at room temperature until completion or the
reaction (usually 30−60 min). The resulting solution was then filtered,
rinsed with dichloromethane, and concentrated under vacuum.
Purification by flash chromatography using a EtOAc−hexane gradient
(unless specified differently) afforded the pure 1,2,4-trioxane
compound.
Method to Dry H2O2−Et2O. Procedure as described by Sabbani et
al.47 At 0 °C, hydrogen peroxide (H2O2, 42 mL, 50 wt % in H2O) was
dissolved in anhydrous diethyl ether (395 mL). Constant stirring was
carried out to add anhydrous MgSO4 until a thick white slurry sank to
the bottom of the flask. The supernatant was then decanted and dried
with anhydrous MgSO4 and filtered again, producing an ethereal
solution of H2O2 with a concentration of approximately 1.5 M. The
solution was used immediately thereafter. The solution cannot be
stored for later use due to safety hazards.
p-(7,8,15,16-Tetraoxa-3-dispiro[5.2.5.2]hexadecyl)phenyl Ace-
tate (6b). This compound was synthesized in accordance with general
procedure 1 using 4a (for the peroxidation step) and cyclohexanone
(for the cyclocondensation step). Purification by flash chromatography
(EtOAc/n-hexane, 2.5:97.5, v/v) provided a white solid (207 mg, 57%
yield). mp 93−95 °C. 1H NMR (500 MHz, CDCl3): δ 7.20 (d, J = 8.5
Hz, 2H), 6.98 (d, J = 8.5 Hz, 2H), 3.25 (s, 1H), 2.59 (tt, J = 12.0, 3.7 Hz,
1H), 2.32 (d, J = 22.7 Hz, 1H), 2.27 (s, 3H), 1.87−1.55 (m, 13H),
1.53−1.39 (m, 3H). 13C{1H} NMR (126 MHz, CDCl3): δ 169.8, 149.0,
143.5, 127.9, 121.5, 108.5, 107.7, 43.2, 31.9, 31.7, 29.6, 25.5, 22.4, 21.2.
HRMS (ESI+, m/z) calcd C20H26O6Na (M + Na)+, 385.16216; found,
385.16165.
General Procedure 4: Corey−Chaykovsky Epoxidation. The
procedure was adapted from Sabbani et al.47 with slight modifications. A
suspension of potassium tert-butoxide (1.5 mmol) in anhydrous 1,2-
dimethoxyethane or tetrahydrofuran (5 mL) was treated with
trimethylsulfoxonium iodide (1.5 mmol), and the mixture was stirred
at reflux (using an oil bath) under nitrogen for 2 h. The mixture was
2-(Dispiro[cyclohexane-1,3′-[1,2,4,5]tetraoxane-6′,2″-tricyclo-
[3.3.1.13,7]decan]-4-yl)-1,3-isoindolinedione (6c). This compound
was synthesized in accordance with general procedure 1 using 2-(4-
oxocyclohexyl)isoindoline-1,3-dione (for the peroxidation step) and 4b
(for the cyclocondensation step). Purification by flash chromatography
(EtOAc/n-hexane, 5:95, v/v) provided a white solid (268 mg, 63%
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yield). mp 174−176 °C. 1H NMR (500 MHz, CDCl3): δ 7.84 (dd, J =
5.4, 3.0 Hz, 2H), 7.70 (dd, J = 5.4, 3.0 Hz, 2H), 4.22 (tt, J = 12.5, 3.8 Hz,
1H), 3.25 (br d, 2H), 2.55 (s, 2H), 2.15−1.84 (m, 8H), 1.79−1.61 (m,
10H). 13C{1H} NMR (126 MHz, CDCl3): δ 168.2, 134.0, 132.0, 123.3,
110.7, 106.7, 49.8, 37.0, 34.4, 33.2, 31.2, 30.2, 29.0, 27.2, 25.6, 24.8.
HRMS (ESI+, m/z) calcd C24H27NO6Na (M + Na)+, 448.17306;
found, 448.17273.
2-(7,8,15,16-Tetraoxa-3-dispiro[5.2.5.2]hexadecyl)-1,3-isoindoli-
nedione (6d). This compound was synthesized in accordance with
general procedure 1 using 2-(4-oxocyclohexyl)isoindoline-1,3-dione
(for the peroxidation step) and cyclohexanone (for the cyclo-
condensation step). Purification by flash chromatography (EtOAc/n-
hexane, 5:95, v/v) provided a white solid (175 mg, 47% yield). mp
177−179 °C. 1H NMR (500 MHz, CDCl3): δ 7.82 (dd, J = 5.4, 3.0 Hz,
2H), 7.69 (dd, J = 5.5, 3.0 Hz, 2H), 4.21 (tt, J = 12.5, 3.8 Hz, 1H), 3.30
(s, 1H), 2.53 (s, 2H), 2.30 (d, J = 31.9 Hz, 2H), 1.90 (s, 1H), 1.79−1.61
(m, 6H), 1.60−1.42 (m, 6H). 13C{1H} NMR (126 MHz, CDCl3): δ
168.2, 134.0, 132.0, 123.3, 108.6, 106.9, 49.7, 31.9, 31.2, 29.6, 28.8,
25.5, 24.7, 22.3, 21.9. HRMS (ESI+, m/z) calcd C20H23NO6Na (M +
Na)+, 396.14176; found, 396.14148.
Dispiro[cyclohexane-1,3′-[1,2,4,5]tetraoxane-6′,2″-tricyclo-
[3.3.1.13,7]decan]-4-one (6e). This compound was synthesized in
accordance with general procedure 1 using 4b (for the peroxidation
step) and 1,4-cyclohexanedione (for the cyclocondensation step).
Purification by flash chromatography (EtOAc/n-hexane, 2.5:97.5, v/v)
provided a white solid (14.7 mg, 5% yield). mp 156−158 °C. Spectral
data are in accordance with that reported in the literature.49 1H NMR
(500 MHz, CDCl3): δ 3.20 (br s, 1H), 2.72 (s, 2H), 2.48 (br d, 4H),
2.10−1.86 (m, 9H), 1.82−1.59 (m, 6H). 13C{1H} NMR (126 MHz,
CDCl3): δ 209.4, 111.1, 106.7, 37.0, 36.5, 35.7, 34.4, 33.2, 30.5, 30.2,
28.0, 27.1. HRMS (ESI+, m/z) calcd C16H22O5Na (M + Na)+,
317.13594; found, 317.13599.
Ethyl Dispiro[cyclohexane-1,3′-[1,2,4,5]tetraoxane-6′,2″-tricyclo-
[3.3.1.13,7]decane]-4-carboxylate (6f). This compound was synthe-
sized in accordance with general procedure 1 using 2-ethyl 4-
oxocyclohexanecarboxylate (for the peroxidation step) and 4b (for
the cyclocondensation step). Purification by flash chromatography
(EtOAc/n-hexane, 1:99, v/v) provided a white solid (178 mg, 51%
yield). mp 67−69 °C. Spectral data are in accordance with the reported
in the literature.50 1H NMR (500 MHz, CDCl3): 4.12 (q, J = 7.1 Hz,
2H), 3.02 (br d, J = 118.6 Hz, 2H), 2.41−2.34 (m, 1H), 2.08−1.60 (m,
19H), 1.50 (s, 1H), 1.23 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (126 MHz,
CDCl3): δ 174.8, 110.6, 107.3, 60.5, 41.8, 39.4, 37.0, 34.4, 33.2, 30.2,
30.2, 28.3, 27.1, 24.8, 23.9, 14.3. HRMS (ESI+, m/z) calcd C19H28O6Na
(M + Na)+, 375.17781; found, 375.17725.
Dispiro[cyclohexane-1,3′-[1,2,4,5]tetraoxane-6′,2″-tricyclo-
[3.3.1.13,7]decane] (6g). This compound was synthesized in
accordance with general procedure 1 using cyclohexanone (for the
peroxidation step) and 4b (for the cyclocondensation step).
Purification by flash chromatography (n-hexane, 100%, v/v) provided
a white solid (179 mg, 64% yield). mp 57−59 °C. Spectral data are in
accordance with that reported in the literature.28 1H NMR (500 MHz,
CDCl3): δ 3.17 (s, 1H), 2.30 (s, 2H), 2.04−1.44 (m, 21H). 13C{1H}
NMR (126 MHz, CDCl3): δ 110.4, 108.1, 37.1, 37.1, 34.4, 33.3, 33.2,
31.9, 30.2, 29.7, 27.2, 25.5, 22.4. HRMS (MALDI-TOF, m/z) calcd for
C16H24O4K (M + K)+, 318,1311; found, 318.3302.
Cyclohex-1-enyl-methanol (7a). The procedure was adapted from
Kwiatkowski and Alexanian51 with slight modifications. 1-Cyclohexene-
1-carboxylic acid (1 g, 7.93 mmol) in diethyl ether (40 mL) was added
dropwise to a suspension of LiAlH4 (0.57 g, 23.78 mmol) in anhydrous
ether at 0 °C (5 mL). The reaction mixture was stirred at 0 °C for 60
min and then successively quenched with H2O (10 mL) and NaOH (6
M, 10 mL) allowing it to warm to room temperature while stirring.
Anhydrous Na2SO4 (2 g) was added, and the mixture was stirred for 30
min, filtered over a pad of Celite, and washed with EtOAc (3 × 30 mL).
The combined organic layers were concentrated under reduced
pressure to afford the desired product as a colorless oil (0.81 g, 91%
yield). Spectral data are in accordance with that reported in the
literature.51 1H NMR (400 MHz, CDCl3): δ 5.71−5.65 (m, 1H), 3.97
(s, 2H), 2.03 (dd, J = 7.0, 4.3 Hz, 4H), 1.67−1.56 (m, 4H). 13C{1H}
NMR (101 MHz, CDCl3): δ 137.6, 123.1, 67.7, 25.6, 24.9, 22.5, 22.4.
HRMS (CI, m/z) calcd for C7H14N (M + NH4)+, 112.1121; found,
112.1124.
2-(7,8,15-Trioxa-12-dispiro[5.2.5.2]hexadecyl)-1,3-isoindoline-
dione (8a). This compound was synthesized in accordance with general
procedure 2 using 7a and 2-(4-oxocyclohexyl)isoindoline-1,3-dione.
Purification by flash chromatography (EtOAc/n-hexane, 5:95, v/v)
followed by recrystallization with acetone provided a white solid (171
mg, 46% yield). 1H NMR (400 MHz, CDCl3): δ 7.85−7.79 (m, 2H),
7.73−7.68 (m, 2H), 4.19 (ddt, J = 12.2, 9.8, 3.9 Hz, 1H), 3.66 (s, 2H),
3.11−2.21 (m, 3H), 2.04−1.23 (m, 15H). 13C{1H} NMR (101 MHz,
CDCl3): δ 168.2, 168.1, 133.9, 133.8, 132.0, 123.1, 100.9, 100.7, 77.9,
77.7, 66.4, 66.0, 50.0, 49.9, 25.9, 25.2, 21.3. Duplicate peaks on 13C{1H}
NMR is due to the mixture of isomers cis or trans. HRMS (ESI+, m/z)
calcd C21H25NO5Na (M + Na)+, 394.1625; found, 394.1626. Anal.
Calcd for C21H25NO5: C, 67.91; H, 6.78; N, 3.77. Found: C, 67.51; H,
7.03; N, 3.58.
tert-Butyl 7,8,16-Trioxa-3-aza-3-dispiro[5.2.5.2]hexadecane-
carboxylate (8b). This compound was synthesized in accordance
with general procedure 2 using 7a and 1-boc-4-piperidone. Purification
by flash chromatography (EtOAc/n-hexane, 5:95, v/v) provided a
1
white solid (124 mg, 38% yield). H NMR (400 MHz, CD3CN): δ
3.87−3.48 (m, 2H), 3.48−3.26 (m, 4H), 2.27 (dd, J = 12.0, 5.4 Hz,
1H), 1.93 (d, J = 1.7 Hz, 22H). 13C{1H} NMR (101 MHz, CD3CN): δ
154.9, 100.9, 79.6, 78.3, 66.0, 40.8, 30.5, 32.2, 34.5, 28.1, 26.1, 21.6.
HRMS (ESI+, m/z) calcd C17H29NO5Na (M + Na)+, 350.1938; found,
350.1942.
Ethyl 7,8,15-Trioxa-12-dispiro[5.2.5.2]hexadecanecarboxylate
(8c). This compound was synthesized in accordance with general
procedure 2 using 7a and ethyl 4-oxocyclohexanecarboxylate.
Purification by flash chromatography (EtOAc/n-hexane, 2.5:97.5, v/
v) provided a colorless oil (119 mg, 40% yield). 1H NMR (400 MHz,
CDCl3): δ 4.12 (qd, J = 7.1, 5.4 Hz, 2H), 3.84−3.34 (m, 2H), 2.86−
2.30 (m, 2H), 1.93−1.27 (m, 17H), 1.24 (td, J = 7.1, 5.6 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3): δ 175.0, 174.9, 101.4, 101.3, 77.7,
77.6, 66.2, 65.9, 60.3, 60.3, 42.2, 41.7, 32.9, 29.9, 25.9, 25.9, 24.8, 24.4,
21.3, 14.2. Duplicate peaks on 13C{1H} NMR is due to the mixture of
isomers cis or trans. HRMS (ESI+, m/z) calcd for C16H26O5Na (M +
Na)+, 321.1672; found, 321.1676.
2-(3,3-Dimethyl-1,2,5-trioxa-9-spiro[5.5]undecyl)-1,3-isoindoli-
nedione (8d). This compound was synthesized in accordance with
general procedure 2 using 2-methylprop-2-en-1-ol (7b) and 2-(4-
oxocyclohexyl)isoindoline-1,3-dione. Purification by flash chromatog-
raphy (EtOAc/n-hexane, 5:95, v/v) provided a white solid (205 mg,
62% yield). 1H NMR (400 MHz, CDCl3): δ 7.82 (m, 2H), 7.70 (td, J =
5.4, 3.0 Hz, 2H), 4.20 (tt, J = 12.4, 4.0 Hz, 1H), 3.69 (m, 2H), 3.18−
2.37 (m, 3H), 1.84−1.03 (m, 11H). 13C{1H} NMR (101 MHz,
CDCl3): δ 168.2, 168.1, 133.9, 133.8, 132.0, 123.1, 100.7, 100.6, 76.9,
67.0, 66.6, 49.9, 33.3, 27.4, 25.5, 25.1, 22.3. Duplicate peaks on 13C{1H}
NMR, it is due to the mixture of isomers cis or trans. HRMS (ESI+, m/
z) calcd for C18H21NO5Na (M + Na)+, 354.1312; found, 354.1317.
Anal. Calcd for C18H21NO5: C, 65.24; H, 6.39; N, 4.23. Found: C,
65.14; H, 6.37; N, 4.22.
tert-Butyl 3,3-Dimethyl-1,2,5-trioxa-9-aza-9-spiro[5.5]undecane-
carboxylate (8e). This compound was synthesized in accordance with
general procedure 2 using 7b and 1-boc-4-piperidone. Purification by
flash chromatography (EtOAc/n-hexane, 5:95, v/v) provided a white
1
solid (189 mg, 58% yield). mp 69−70 °C. H NMR (400 MHz,
CDCl3): δ 3.96−3.57 (m, 2H), 3.56−3.20 (m, 4H), 2.42−1.71 (m,
3H), 1.59−1.02 (m, 16H). 13C{1H} NMR (101 MHz, CDCl3): δ 154.6,
100.4, 80.0, 77.2, 66.6, 40.3, 34.4, 28.4, 22.6. HRMS (ESI+, m/z) calcd
C14H25NO5Na (M + Na)+, 310.1625; found, 310.1627.
Ethyl 3,3-Dimethyl-1,2,5-trioxa-9-spiro[5.5]undecane-
carboxylate (8f). This compound was synthesized in accordance
with general procedure 2 using 7b and ethyl 4-oxocyclohexanecarbox-
ylate. Purification by flash chromatography (EtOAc/n-hexane, 2.5:97.5,
v/v) provided a colorless oil (176 mg, 68% yield). Spectral data are in
accordance with that reported in the literature.52 1H NMR (400 MHz,
CDCl3): δ 4.12 (d, J = 7.1 Hz, 2H), 3.91−3.36 (m, 2H), 2.85−2.28 (m,
2H), 1.94−1.68 (m, 5H), 1.61−1.27 (m, 6H), 1.27−1.22 (m, 3H),
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1.21−1.06 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3): δ 175.9, 174.9,
101.2, 101.1, 77.0, 76.9, 66.7, 66.5, 60.3, 60.3, 42.1, 41.7, 35.2, 27.1,
26.4, 26.1, 24.8, 24.4, 22.3, 14.2, 14.2. Duplicate peaks on 13C{1H}
NMR is due to the mixture of isomers cis or trans. HRMS (ESI+, m/z)
calcd C13H22O5Na (M + Na)+, 281.1359; found, 281.1361.
Algarve, P-8005-039 Faro, Portugal; orcid.org/0000-
0002-9447-2855; Email: mcristi@ualg.pt
Authors
Patrícia S. M. Amado − Center of Marine Sciences (CCMAR),
University of Algarve, P-8005-039 Faro, Portugal;
Department of Chemistry and Pharmacy, FCT, University of
Algarve, P-8005-039 Faro, Portugal; Department of
Spiro[adamantane-2,2′-oxirane] (9a). This compound was
synthesized in accordance with general procedure 4 using 4b and 1,2-
dimethoxyethane as the solvent. Purification by flash chromatography
(EtOAc/n-hexane, 1:99, v/v) provided a white solid (0.91 g, 83%
yield). mp 176−178 °C. Spectral data are in accordance with that
reported in the literature.47 1H NMR (400 MHz, CDCl3): δ 2.64 (s,
2H), 2.05−1.75 (m, 12H), 1.40 (t, J = 3.1 Hz, 2H). 13C{1H} NMR (101
MHz, CDCl3): δ 64.6, 54.8, 37.1, 36.9, 35.9, 35.1, 27.1, 27.0. HRMS
(CI, m/z) calcd for C11H17O (M + H)+, 165.1274; found, 165.1275.
tert-Butyl 1-Oxa-6-azaspiro[2.5]octane-6-carboxylate (9b). This
compound was synthesized in accordance with general procedure 4
using 1-boc-4-piperidone and 1,2-dimethoxyethane as the solvent.
Purification by flash chromatography (EtOAc/n-hexane, 5:95, v/v)
provided a white solid (1.85 g, 58% yield). mp 50−52 °C. Spectral data
are in accordance with that reported in the literature.47 1H NMR (400
MHz, CDCl3): δ 3.72 (s, 2H), 3.43 (ddd, J = 13.3, 9.4, 3.7 Hz, 2H), 2.69
(s, 2H), 1.80 (td, J = 9.4, 4.7 Hz, 2H), 1.48 (s, 9H), 1.44 (d, J = 4.9 Hz,
2H). 13C{1H} NMR (101 MHz, CDCl3): δ 154.8, 79.8, 57.2, 53.8, 42.6,
33.0, 28.4. HRMS (ESI+, m/z) calcd for C11H19NO3Na (M + Na)+:
236.1257; found 236.1256.
2-(Dispiro[cyclohexane-1,3′-[1,2,4]trioxane-6′,2″-tricyclo-
[3.3.1.13,7]decan]-4-yl)-1,3-isoindolinedione (10a). This compound
was synthesized in accordance with general procedure 3 using
spiro[adamantane-2,2′-oxirane] (9a) and 2-(4-oxocyclohexyl)-
isoindoline-1,3-dione. Purification by flash chromatography (EtOAc/
n-hexane, 5:95, v/v) followed by recrystallization with acetone provided
a white solid (199 mg, 47% yield). 1H NMR (400 MHz, CDCl3): δ 7.83
(dd, J = 5.5, 3.0 Hz, 2H), 7.70 (dd, J = 5.5, 3.0 Hz, 2H), 4.20 (tt, J = 12.4,
4.0 Hz, 1H), 4.04−2.88 (m, 2H), 2.77−2.00 (m, 5H), 1.94−1.38 (m,
17H). 13C{1H} NMR (101 MHz, CDCl3): δ 168.2, 133.9, 132.0, 123.1,
100.7, 81.4, 63.8, 49.9, 37.8, 33.7, 32.0, 27.5, 27.4, 24.7. HRMS (ESI+,
m/z) calcd C25H29NO5Na (M + Na)+, 446.1938; found, 446.1925.
tert-Butyl Dispiro[piperidine-4,3′-[1,2,4]trioxane-6′,2″-tricyclo-
[3.3.1.13,7]decane]-1-carboxylate (10b). This compound was synthe-
sized in accordance with general procedure 3 using tert-butyl 1-oxa-6-
azaspiro[2.5]octane-6-carboxylate (9b) and 4b. Purification by flash
chromatography (EtOAc/n-hexane, 4:96, v/v) provided a white solid
(239 mg, 63% yield). mp 74−76 °C. Spectral data are in accordance
with that reported in the literature.47 1H NMR (400 MHz, CDCl3): δ
3.75 (br s, 3H), 3.53−2.36 (m, 4H), 2.21−1.62 (m, 14H), 1.58−1.47
(m, 3H), 1.46−1.43 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3): δ
154.8, 104.6, 79.6, 75.7, 65.3, 39.3, 37.1, 34.9, 33.4, 28.5, 27.1, 27.1,
27.0. HRMS (ESI+, m/z) calcd C21H33NO5Na (M + Na)+, 402.2251;
found, 402.2254.
Chemistry, University of Liverpool, L69 7ZD Liverpool, U.K.
Luís M. T. Frija − Centro de Química Estrutural (CQE),
Instituto Superior Técnico, University of Lisbon, 1049-001
Lisbon, Portugal; orcid.org/0000-0003-3252-3482
Jaime A. S. Coelho − Centro de Química Estrutural (CQE),
̂
Faculdade de Ciencias, University of Lisbon, 1749-016 Lisbon,
Portugal; orcid.org/0000-0002-7459-0993
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01258
Author Contributions
P.S.M.A. conceived the original working hypothesis and wrote
the first draft of the manuscript. P.S.M.A. performed the
synthesis and other experiments. L.M.T.F. and J.A.S.C.
projected the reaction mechanisms, performed the computa-
tions, and analyzed the data. P.M.O. and M.L.S.C. supervised the
research and validated the work. All authors co-wrote the final
version of the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partially supported by the Fundaca
̧
o
̃
para a
̂
Ciencia e Tecnologia (FCT), Portugal, through projects UID/
MULTI/04326/2019 (CCMAR), UIDB/00313/2020 (CQC),
and UIDB/00100/2020 (CQE) and from the operational
programmes CRESC Algarve 2020 and COMPETE 2020
through project EMBRC.PT ALG-01-0145-FEDER-022121.
P.S.M.A., L.M.T.F., and J.A.S.C. thank FCT for Grant SFRH/
BD/130407/2017, Work contract no. IST-ID/115/2018, and
Scientific Employment Stimulus 2020/02383/CEECIND,
respectively. DFT calculations were conducted in the computa-
tional facility of the Bioorganic Chemistry Group at
iMed.ULisboa (UID/DTP/04138/2019).
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* Supporting Information
The Supporting Information is available free of charge at
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̊
Copies of 1H, 13C{1H} NMR, and HRMS spectra for all
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AUTHOR INFORMATION
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Corresponding Authors
Paul M. O’Neill − Department of Chemistry, University of
Liverpool, L69 7ZD Liverpool, U.K.; orcid.org/0000-
0003-4338-0317; Email: pmoneill@liverpool.ac.uk
Maria L. S. Cristiano − Center of Marine Sciences (CCMAR),
University of Algarve, P-8005-039 Faro, Portugal;
Department of Chemistry and Pharmacy, FCT, University of
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