Spirofused and Annulated 1,2,4-Trioxepane-, 1,2,4-Trioxocane-, and 1,2,4-Trioxonane-Cyclohexadienones: Cyclic Peroxides with Unusual Ring Conformation Dynamics

Article abstract of DOI:10.1002/anie.201807485

C3- or C4-hydroxyalkylated phenols are highly reactive towards peroxidation with oxone, which results in the formation of tertiary C3 hydroperoxides. This reaction can also be performed with photochemically generated singlet oxygen. However, other charact

Full text of DOI:10.1002/anie.201807485

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Accepted Article
Title: Spirofused and annulated 1,2,4-trioxepane-, 1,2,4-trioxocane-,
and trioxonane-cyclohexadienones: Cyclic peroxides with
unusual ring conformation dynamics
Authors: Axel G. Griesbeck, Angelika Eske, Sabrina Ecker, Carolina
Fendinger, Bernd Goldfuss, Matthis Jonen, Jens Lefarth, Jörg
M Neudörfl, and Matthias Spilles
This manuscript has been accepted after peer review and appears as an
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using the Digital Object Identifier (DOI) given below. The VoR will be
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to this Accepted Article as a result of editing. Readers should obtain
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to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201807485
Angew. Chem. 10.1002/ange.201807485
Link to VoR: http://dx.doi.org/10.1002/anie.201807485
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Spirofused and annulated 1,2,4-trioxepane-, 1,2,4-trioxocane-,
and 1,2,4-trioxonane-cyclohexadienones:
Cyclic peroxides with unusual ring conformation dynamics
Angelika Eske, Sabrina Ecker, Carolina Fendinger, Bernd Goldfuss, Matthis Jonen, Jens Lefarth,
Jörg.-M. Neudörfl, Matthias Spilles, and Axel G. Griesbeck*
well as the design of artemisinin dimers, conjugates and dyads.[10]
Recently, also flow photochemistry has been applied in order to
produce larger amounts of artemisinin involving an oxygenation
key step.[11]
Abstract: C-3 or C-4-hydroxyalkyated phenols are highly reactive
towards peroxidation by Oxone and result in the formation of tertiary
C-3 hydroperoxides. This reaction can also be performed with
photochemically generated singlet oxygen. Other characteristic
singlet oxygen reactions do however not proceed with caroate. The
initial formed hydroperoxides are cyclized under Lewis-acid catalysis
with boron-, indium- or iron-based catalysts to give spiroannulated
peroxides 6, 9 which exhibit restricted ring inversion processes
whereas the larger nine-membered ring peroxides 12 are less stable
thermally and show –possibly correlated – also higher ring flexibility
(by NMR analysis).
Scheme 1. The natural sesquiterpene peroxide artemisinin and three
pharmaactive 1,2,4-trioxane (1,2) and 1,2,4-trioxepane (3) derivatives.
Cyclic organic peroxides are Janus-faced compounds: some of
them show uncontrollable and violent behavior, some of them
remarkable strong pharmacological effects.[1] The disreputable
triacetone triperoxide (TATP) is a dangerous and uncontrollable
explosive and an example for the first properties.[2] Artemisinin is
the most popular example for the beneficial properties of cyclic
peroxides.[3] The 2015 Nobel prize in physiology and medicine for
the Chinese scientist Youyou Tu for “discoveries concerning a
novel therapy against Malaria” honored her groundbreaking work
in structure elucidation and investigations of antimalarial activities
of this natural lactone peroxide.[4] The central compound in this
research is the unusual peroxide artemisinin, a structurally
complex tetracyclic sesquiterpene lactone with an endoperoxide
substructure that can be isolated from the leaves of artemisia
annua.[5] Due to its very high antimalarial activities, artemisinin, its
derivatives, and numerous analogs have become important as
antimalarial drugs against multidrug-resistant forms of the plas-
modium falciparum parasite.[6] Recently, several reports also
report on antitumor[7] and ß-cell reactivation relevant in diabetes
therapy of these compounds.[8] This high pharmacological
potential combined with its synthetically challenging structure
have prompted synthetic chemists to design total or partial
synthesis routes to this compound and derivatives thereof[9] as
In the last decade, we have developed a synthetic protocol to a
series of 1,2,4-trioxanes with antimalarial properties similar to the
natural products, e.g. the 1,2,4-trioxane 1.[12] Furthermore, dyads
(additional to hybrids or dimeric structures)[13] composed of
natural artemisinine derivatives and synthetic trioxanes were
realized.[14] In extension to these compound families, we
synthesized a series of ester-substituted 1,2,4-trioxanes (e.g. 2)
that showed remarkable strong glutathione-transferase (GST)
inhibition.[15] The (homo)allylic alcohol / singlet oxygen approach
to allylic hydroperoxides that was used for these processes limits
the reaction to 1,2,4-trioxanes[12] and seven-membered analogs
like compound 3.[16] Another way to allylic hydroperoxides is the
caroate oxidation of phenols that are substituted at C4[17]
a
method that was also used for the synthesis of new
spiroannulated 1,2,4-trioxanes.[18] The process uses as reagent
Oxone®, a triple salt composed of 2KHSO5, KHSO4, and K2SO4,
a remarkably powerful oxidant with the potassium salt of Caro´s
acid (caroate) as the reactive component.[19] The caroate reaction
of phenols occurs at moderate basic conditions (pH = 8) in
aqueous medium. Singlet oxygen was postulated as the reactive
oxygen species in this specific application.[17] This assumption
appears plausible because singlet oxygen 1O2 was already
described as a decomposition product from Caro´s acid either
uncatalyzed or ketone-catalyzed.[20] Thus, this non-photo-
chemical approach to singlet oxygen products appears to be of
general relevance for the synthesis of 1,n-hydroxy hydro-
peroxides from 4-hydroxyalkyl phenols. We first investigated if
this caroate approach really follows a singlet oxygen path and
therefore compared the reactivity of probe molecules from 1O2. As
model substrate, commercial 4-hydroxyethylphenol 4 was applied.
A. Eske (M. Sc.), S. Ecker (M. Sc.), C. Fendinger (B.Sc.),
Prof. Dr. B. Goldfuss, M. Jonen (B. Sc.), J. Lefarth (M. Sc.),
Dr. J.-M. Neudörfl, M. Spilles (B.Sc.), Prof. Dr. A. G. Griesbeck
Department of Chemistry, University of Cologne
Greinstr. 4, 50939 Köln
E-mail: griesbeck@uni-koeln.de
Supporting information for this article is given via a link at the end of
the document.
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The caroate decomposition in aqueous media at pH = 10.5 leads
to the formation of the hydroperoxide 5 in yields between 56 and
76% (in the presence of the lactol as side-product).[21] The
corresponding reaction with photogenerated 1O2 (Sens. =
tetraphenylporphyrin) also resulted in 5. No other typical singlet
oxygen substrates (e.g. limonene, 2,3-dimethyl-2-butene) did
however resulted in the expected 1O2 products under caroate
conditions, making the phenolate (at the given pH) reactivity a
very special case.
Figure 1. 1H-NMR spectra of 6a and 6b in CDCl3.
Scheme 2. Caroate-induced hydroperoxidation of 4-hydroxyethylphenol 4 and
subsequent peroxyacetalization under Lewis-acid catalysis.
Subsequent peroxyacetalization with BF3 or In(OTf)3 as Lewis-
acid catalysts (Lewis acid optimization see SI) delivered the 1,2,4-
trioxepanes 6a-6d in moderate to low yields (Scheme 2). We were
initially surprised by the complexity of the NMR spectra of these
Figure 2. 13C-NMR spectra of 6c and 6d in CDCl3
1
compounds: in the H NMR all cyclohexadienone H´s appeared
with different chemical shifts and also the formally enantiotopic
methyl groups appear at 1.3 and 1.6 ppm (Figure 1). Analogously,
13C NMR signals for all carbon atoms were different (Figure 2).
Temperature-dependent NMR measurements were possible only
until 50°C because of the instability of the cyclic peroxides and no
coalescence effects could be determined. Thus, we speculated
that the actual chemical structures of the products deviate from
the expected 1,2,4-trioxepane ring. Two products could be
crystallized and revealed that also this assumption was incorrect
(Figure 3).[22]
Thus, the expected cyclic ring peroxide structures 6 are actually
the products of the peroxacetalization. The anisochronicity effects
in the NMR spectra are obviously a consequence of slow peroxide
ring inversion, an unusual property that we have not yet observed
in the six-membered 1,2,4-trioxane series.
Figure 3. Structures of spiro-1,2,4-trioxepanes 6c and 6d in the crystal.
In order to explore if this structural behavior also occurs for larger
ring systems, we have applied homologous substrates: the C3-
linked phenol 7[23] is converted into the hydroperoxide 8 in 36%
yield and peroxyacetalization with acetone delivers the 1,2,4-
trioxocane 9a in low yields (6-21%). Again, the two methyl groups
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appear with different chemical shift (Scheme 3) and also other
derivatives show the anisochronicity effects analogous to the
seven-membered ring peroxides 6a-d. Using In(OTf)3 as Lewis
acid, the corresponding eight-membered peroxides 9b and 9c
were also available.
Figure 4. 1H-NMR and 13C-NMR spectra of the 1,2,4-trioxononane 12a in CDCl3
(negative signals CH and CH3).
Scheme 3. Caroate-induced hydroperoxidation of 4-hydroxypropylphenol 7 and
subsequent peroxyacetalization under Lewis-acid catalysis.
This synthetic protocol could not be applied for the generation of
spiro-fused 1,2,4-trioxanes, i.e. the hydroperoxide from the oxone
conversion of 4-hydroxymethylphenol 13 was not formed and
consequently could not be transformed into 1,2,4-trioxanes. An
analogous six-membered peroxide 16 was synthesized via the
uncatalyzed intramolecular peracetal formation from the aldehyde
14 (Scheme 5).
Motivated from the ring structure of the highly unstable triacetone
triperoxide, we envisaged the synthesis also of nine-membered
peroxides, the 1,2,4-trioxononanes: the C4-linked phenol 10[24] is
converted with caroate into the hydroperoxide 11 in 79% yield.
The ferric chloride catalyzed[25] peroxyacetalization with three
ketones delivered the 1,2,4-trioxocanes 12a-12c in low yields
(Scheme 4). From these products, no anisochronicity NMR
effects were detected, e.g. the NMR of the 3,3-dimethyl derivative
12a showed only one methyl signal in 1H and 13C NMR (Figure 4).
Scheme 5. Caroate-induced hydroperoxidation of aldehyde 14 and intra-
molecular 1,2-dioxane (16) formation.
Alternatively to spirofused cyclic peroxides, this approach also
allows the synthesis of annulated peroxides, e.g. the 3-
hydroxymethylated phenol 17[26] was successfully converted into
a seven-membered cyclic peroxide 19 via the corresponding
hydroperoxide 18 (Scheme 6) in 41% overall yield.
Scheme 4. Caroate-induced hydroperoxidation of 4-hydroxybutylphenol 10 and
subsequent peroxyacetalization under Lewis-acid (FeCl3) catalysis.
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In summary, the gain in stabilization, as determined from Gibbs
energy difference between starting materials and products
decreases with increasing ring size. This overall effect is
composed of stabilizing NBO interactions (per-anomeric effect.
dominates for 6-8 membered peroxides) and destabilizing ring
strain that prevail for the nine-membered peroxides 12. These
opposing effects explain unusual thermal stabilities of medium-
sized peroxides (e.g. the artemisinin derivatives) and the
instability of the nine-membered 1,2,4-trioxononanes (e.g. TATP).
Scheme 6. Caroate-induced hydroperoxidation / acetone peroxyacetalization
of 4-methyl-3-hydroxymethylphenol 17.
Figure 5. Structures of the cyclic peroxides 16 and 19 in the crystal.
Comparing the peroxide-containing ring families described in this
communication, it became clear that slow ring conformational
interconversion exists for seven- and eight-membered rings
whereas the nine-membered cyclic peroxides undergo faster ring
movements. This effect does qualitatively also match the stability
features: whereas compounds 6 and 9 (and 19) were stable in
solution (and in solid state for 6c and 6d), the larger ring systems
12 slowly decompose also in solution even when stored at -20°C.
Stabilizing stereoelectronic effects were described by Alabugin
and colleagues to explain the unusual stability of bis-peroxides
(1,2,4,5-tetroxanes).[27] The key stabilizing feature that was
Scheme 7. M062X/6-311++G**-GD3 (PCM, in CHCl3) // B3LYP/6-31G*-GD3BJ
calculated free reaction energies of hydroperoxides to cyclic peroxides and
NBO-calculated (per)anomeric interaction energies..
Keywords: Peroxides • photochemistry • oxygenation •
heterocycles • structures
identified by quantum chemical calculation was
a
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
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A. Eske, S. Ecker, C. Fendinger, B.
Goldfuss, M. Jonen, J. Lefarth, J.-M.
Neudörfl, M. Spilles, A. G. Griesbeck*
Page No. – Page No.
Spirofused and annulated 1,2,4-
trioxepane-, trioxocane-, and
trioxononane cyclohexadienones:
Cyclic peroxides with unusual ring
conformation dynamics
New spirofused and ring-annulated peroxides with unusual conformational
behaviour are available from Oxone-induced peroxidation and peracetalization
of 3- and 4-functionalized phenols. The stability properties enlighten the
dichotomy of cyclic peroxides between medicinal and energetic properties.
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