Mild Functionalization of Tetraoxane Derivatives via Olefin Metathesis: Compatibility of Ruthenium Alkylidene Catalysts with Peroxides

Article abstract of DOI:10.1021/acs.orglett.6b03688

An easy and mild functionalization method of tetraoxane derivatives via olefin metathesis is reported. This reaction offers a new method to afford fully functionalized tetraoxanes in high yields. This method is also utilized in the functionalization of bioactive compounds.

Full text of DOI:10.1021/acs.orglett.6b03688

Letter
pubs.acs.org/OrgLett
Mild Functionalization of Tetraoxane Derivatives via Olefin
Metathesis: Compatibility of Ruthenium Alkylidene Catalysts with
Peroxides
Anupam Jana and Karol Grela*
̇
Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, Zwirki i Wigury 101, 02-089 Warsaw, Poland
*
S Supporting Information
ABSTRACT: An easy and mild functionalization method of
tetraoxane derivatives via olefin metathesis is reported. This
reaction offers a new method to afford fully functionalized
tetraoxanes in high yields. This method is also utilized in the
functionalization of bioactive compounds.
alaria is one of the most threatening diseases in the
tropical and subtropical regions. It is caused by infection
2), olefin metathesis has become a routine process in the
manipulation of C−C double bonds. Nowadays, olefin meta-
M
with parasites of genus Plasmodium and affects billions of people
1
worldwide every year. The natural product, artemisinine (ART,
1), isolated from Chinese medicinal plant Artemisia annua, is
established as the best antimalarial to treat Plasmodium faliparum
2
related infections. The importance of “the isolation and
application of Artemisia annua” has been recognized by the3
award of the Nobel Prize in Medicine for 2015 to Tu Youyou.
4
Due to poor pharmacokinetic properties, high cost, and the
limited bioavailability of artemisinine, its semisynthetic deriva-
Figure 2. Catalysts for olefin metathesis.
tives (Figure 1) are being used against P. faliparum, but
thesis has emerged as a versatile and powerful tool for target-
oriented organic synthesis as well as in biological and material
8
9
science. However, with one exception, this phenomenal
reaction has not yet been used for the functionalization of
peroxides. Due to their instability and highly oxidizing power,
applications of peroxides as substrates for metathesis reaction is a
challenging and rather underrepresented area. On the contrary,
peroxides were used in easy, rapid, and efficient removal of
10
ruthenium residues produced from metathesis reaction.
Figure 1. Antimalarial drugs.
Therefore, in the current study, we decided to explore the
applicability and the generality of functionalization of tetraoxane
substrates via olefin metathesis. As the examples of conducting
emergence of resistance to the most available drugs has
9
metathesis reaction with organic peroxides are rare, in the first
stimulated a search for its replacementssynthetic peroxides
5
phase of our research we sought to explore reactivity of different
organic peroxides toward popular commercial ruthenium olefin
metathesis catalysts in order to reveal potential incompatibility
between Ru catalysts and peroxide substrates.
For this study, we tested the compatibility of two
representative catalysts: Grubbs second-generation catalyst 4
and nitro-Hoveyda−Grubbs catalyst 5 with selected peroxides
such as m-CPBA, benzoyl peroxide, di-tert-butyl peroxide, tert-
hydroperoxide, 1,2,3,4-tetraoxne 9, and hydroperoxide 10. To
check how different peroxide additives influence the catalytic
as potential antimalarial drugs. The search for new drugs has
6
brought renewed attention to 1,2,4,5-tetraoxanes, a class of
peroxides that combine high antimalarial activity with remarkable
chemical stability. However, chemical diversity in this class of
compounds has yet to be developed, as functionalized
tetraoxanes remain relatively unexplored.
Although several approaches have been reported for
6
7
constructing a tetraoxanes, methods for their postsynthetic
functionalization of tetraoxane derivatives are limited in number
6
c−f
and scope.
Therefore, developing practical and general
methods to prepare libraries of such compounds is of
importance. Since 1995, when the first well-defined ruthenium
carbene complexes such as 4 were introduced by Grubbs (Figure
Received: December 10, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03688
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Organic Letters
Letter
1
1
13
activity of these Ru complexes, we used a model cross-
metathesis reaction (CM) of allylbenzene 6 and cis-1,4-
diacetoxy-2-butene 7 (see Table 1). This reaction in the absence
unknown it is supposed that the radicals formed in the
presence of high concentrations of iron(II) accumulated inside
the parasite food vacuole after the digestion of large quantities of
host hemoglobin can alkylate several targets in the parasite,
leading to its death. Among the different types of endoperoxides,
1
1
Table 1. Influence of Peroxy Additives on Model CM Reaction
14
,2,3,4-tetraoxnes have significantly higher stability than their
,2,4-trioxolane or 1,2,4-trioxane counterparts. Dispirotetraox-
anes bearing the adamantyl fragment, which increases stability of
the endoperoxide motif, are characterized by enhanced
15
bioactivity. Some of them showed improved pharmacokinetic
14b
profiles compared to those of ART derivatives. Based on this
analysis, we envisaged tetraoxane 12 as a prototypical substrate
for functionalization via olefin metathesis, leading to new
endoperoxide derivatives (for the synthesis of 1,2,3,4-tetraoxane
substrates, see the Supporting Information). Cross-metathesis of
the tetraoxane-bearing alkene 12 with (Z)-1,4-diacetoxy-2-
butene 7 was chosen to check the feasibility of this trans-
formation (Table 2). At first, tetraoxane 12 was treated with
Table 2. Optimization of Reaction Conditions for the Cross-
Metathesis
a
entry
catalyst
solvent
temp (°C)
yield (%)
1
2
3
4
5
6
4
5
4
5
5
5
CH Cl2
rt
rt
50
87
78
87
90
90
2
CH Cl2
2
a
(MeO) CO
rt
Reaction conditions: allylbenzene (6), (Z)-but-2-ene-1,4-diyl diac-
2
etate (7), additive (0.3 equiv), [Ru] 2.5 mol %, CH Cl , 4 h, rt.
(MeO)
2
CO
rt
2
2
b
Conversion of allylbenzene determined by GC using durene as an
(MeO) CO
45
45
2
internal standard; nr = no reaction.
CH Cl2
2
a
Isolated yield after flash chromatography, E/Z ratio was determined
1
by H NMR spectroscopy.
of any additives proceeds in 85% conversion. Results in Table 1
(
entries 2−6, 12, and 13) show that additives as hydroperoxides
cross-metathesis partner 7 at room temperature in the presence
of 3 mol % of Grubbs catalyst 4 in dichloromethane (DCM)
under an atmosphere of argon for 2 h. The cross-metathesis
product 13 was obtained in 50% yield (Table 2, entry 1) as the
mixture of two geometrical isomers (E/Z = 8:1). To improve the
yield, further optimization was conducted. In the case of Grubbs
II generation catalyst 4, the yield of the reaction was increased
when dimethyl carbonate (DMC) was used as a solvent (entry
and a peroxyacid apparently destroyed both of the Ru catalysts
tested, as no conversion in the model CM reaction was observed.
On the other hand, nitro-Hoveyda−Grubbs catalyst 5 exhibited
some limited catalytic activity in the presence of benzoyl
peroxide (entry 7), though Grubbs carbene 4 was unable to show
any activity in the presence of this additive. Importantly, organic
peroxides like tert-butyl peroxide (entries 8 and 9) and 1,2,3,4-
tetraoxne (entries 10 and 11) had no effect on CM of alkene 6.
We are not attempted to characterize products of oxidation of
Ru catalysts 4 and 5 with peroxides. However, during CM
performed in the presence of additive 10, cyclohexanone
derivative 11 was identified in the reaction mixture. To
characterize better this transformation, we mixed 10 with
catalytic amount of complex 4 (3 mol %) and as result a clean
formation of cycloxexanone 11 (Scheme 1) together with
RuO2. Significantly, 1,2,3,4-tetraoxne 9 was not destroyed by
either 4 or 5 in an analogous experiment.
The fundamental structural functionality within artemisinin
and synthetic highly potent 1,2,4-trioxanes and 1,2,3,4-
tetraoxanes is the endoperoxide bridge. Although the mechanism
of action of artemisinins and other endoperoxides is still
3
). Switching to Hoveyda−Grubbs catalyst 5 instantly increased
12
the yield from 50 to 87% (entry 2), independent of the solvent
used. The yield was further increased when reaction was
conducted at 45 °C (entries 5 and 6).
More tetraoxane substrates were synthesized (see the
Supporting Information) in order to peruse the scope and
limitations study. Thus, in an optimized experimental procedure
a mixture of tetraoxane-derived alkene (1 equiv), cross-partner
1
0
(
3 equiv), and nitro catalyst 5 (3 mol %) were refluxed at 45 °C.
As tetraoxane derivatives are in general thermally unstable, DCM
was used as a solvent for the metathesis reactions due to its low
boiling point. After evaporation of DCM, column chromatog-
raphy over silica gel provided the pure product. A wide range of
CM partners underwent reactions with tetraoxane-bearing
alkenes, leading to diversely substituted tetraoxane derivatives
as shown in Table 3. For example, when the tetraoxane 12 was
refluxed with (Z)-but-2-ene-1,4-diyl diacetate in the presence of
Scheme 1. Decomposition of 10 Promoted by Ru-carbene 4
3
mol % of nitro-Hoveyda−Grubbs catalyst 5 for 2 h, acetate 13
was obtained in 90% yield as a mixture of E- and Z-isomers in an
B
DOI: 10.1021/acs.orglett.6b03688
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Organic Letters
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Table 3. CM Functionalization of Tetraoxanes with Various
Alkenes
Scheme 2. Preparation of a Tetraoxane−Drug Conjugate
a,b
ruthenium catalyst 5. Then, another 5 mol % of the catalyst was
added and the mixture refluxed for another 12 h. The reaction
produced the desired dispiroperoxide drug conjugate 27 in 40%
yield. The purification of the reaction mixture was challenging as
the formed CM product was highly polar and insoluble in most of
the common solvents, and unfortunately, the isolated yield was
low.
To further extend the application of the studied protocol,
other important classes of olefin metathesis transformation, such
8d,e
as self-CM reaction (a.k.a. “dimerization”),
8d,e
ring-closing
8d,e
metathesis (RCM), and enyne metathesis reactions were
investigated (Scheme 3). At first, self-CM reaction was
Scheme 3. Self-CM, RCM, and Enyne Metathesis of
Tetraoxane Derivatives
a
Conditions: CH Cl (nondegassed), 45 °C, catalyst 5 (3 mol %).
2
2
b
Isolated yields after flash chromatography. E/Z ratio was determined
1
c
d
by H NMR spectroscopy or HPLC. With 5 mol % of 5. With 7 mol
%
e
of 5. With 10 mol % 5.
8
:1 ratio. Similarly, when (Z)-1,4-dichlorobut-2-ene was used as
cross-partner, the corresponding product16 was isolated in 87%
yield. Furthermore, when allyl benzene and allylcyclohexane
were employed to react with 12, benzyl- and cyclohexylmethyl-
substituted tetraoxanes 19 and 17 were afforded, respectively.
Tetraoxane 15 also worked well with the cross-partner (Z)-but-
2
-ene-1,4-diyl diacetate and gave product 22 in 78% yield.
Interestingly, CM proceeded efficiently in the case of electron-
poor substrates, such as methyl acrylate, leading to the
corresponding disubstituted α,β-unsaturated ester (E)-23 in
8
9% yield. Notably, CM of the dispiroperoxides 12 and 15 with
attempted. A solution of compound 12 in dichloromethane
was refluxed at 55 °C in the presence of catalyst 5 (2.5 mol %) for
6 h. The expected “dimeric” product 28 containing two
tetraoxane fragments was formed in excellent yield as 2:1 E/Z
mixture. Then the RCM precursor 29 was synthesized from the
corresponding carboxylic acid by an esterification reaction with
hepta-1,6-dien-4-ol in 73% yield. Upon treatment of diene 29
with catalyst 5 (1 mol %), ring-closing metathesis proceeded
smoothly to form cyclopentene derivative 30 in outstanding
yield. Finally, enyne cross-metathesis was studied using
dispiroperoxide 31. Therefore, we focused on the synthesis of
the substrate of enyne metathesis 31. To this end, ester 9 was
reduced by adding lithium aluminum hydride to afford the
corresponding alcohol, which was alkylated by treatment of
propargyl bromide and sodium hydride. The alkylated product
31 was obtained in 50% yield as the only isolable product. The
alkyne 31 was subjected to enyne metathesis with ethylene at 4
atm pressure at 30 °C for 4 h in the presence of catalyst 5 to result
in tetraoxane-embedded diene 32 in 67% yield.
long-chain alkenes such as TBS-protected hex-5-en-1-ol and
methyl dec-9-enoate (9-DA) proceeded efficiently, leading to
corresponding products in good yield. Next, we decided to prove
that this methodology can be used to combine a fragile
dispiroperoxide fragment not only with small molecules like
(
Z)-but-2-ene-1,4-diyl diacetate or acrylate but also with more
elaborate compounds and biomolecules. We were therefore
pleased to see that CM reaction of 12 with estrone derivative
gave product 25 in 67% yield.
Having successfully demonstrated the practicality of tetraox-
ane CM with simpler substrates (Table 3), we decided to apply
the methodology to more complicated compounds of potential
medicinal interest. To do so, we attempted the CM reaction of
16
potentially antimalarial dispiroperoxide 12 with ester 26,
a
distant relative of the fluoroquinolone antibacterial agent
moxifloxacin (Scheme 2). At first, compound 26 and 3 equiv
of tetraoxane derivative 12 were dissolved in dichloromethane
and refluxed at 45 °C for 12 h in the presence of 5 mol % of
C
DOI: 10.1021/acs.orglett.6b03688
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Organic Letters
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In summary, it was found that 1,2,3,4-tetraoxanes, unlike
hydroperoxides and benzoyl peroxide, are fully compatible with
popular Ru olefin metathesis catalysts. As a result, we have
developed an easy and mild functionalization method for
tetraoxane derivatives via olefin metathesis. A number of
peroxide derivatives bearing various substituents were obtained
by self-CM, CM, RCM, and enyne cross-metathesis with
ethylene. We expect that the developed transformation can
serve as a convenient platform for preparing drug conjugates
containing antimalarial peroxide pharmacophore. Due to the
potential utility of the resulting functionalized dispiroperoxides
and the mild conditions employed, we expect this method to be
of utility in medicinal chemistry.
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ASSOCIATED CONTENT
Supporting Information
■
̂
*
S
(
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b03688.
(
b) Yan, X.; Chen, J.; Zhu, Y.-T.; Qiao, C. Synlett 2011, 2011, 2827−
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AUTHOR INFORMATION
Corresponding Author
■
*
Tel: +48-22-8220211 ext 420. Fax: +48-22-8220211. E-mail:
prof.grela@gmail.com.
ORCID
(
9) For a unique example of cross-metathesis with Grubbs catalyst
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12) Ru catalysts are known, in the presence of various oxidants form
́
́
Karol Grela: 0000-0001-9193-3305
Notes
(
2
́
The authors declare no competing financial interest.
(
ACKNOWLEDGMENTS
A.J. and K.G. are grateful to the National Science Centre
Poland) for the NCN MAESTRO Grant No. DEC-2012/04/
A/ST5/00594. The study was carried out at the Biological and
Chemical Research Centre, University of Warsaw, established
within the project cofinanced by European Union from the
European Regional Development Fund under the Operational
Programme Innovative Economy, 2007−2013.
■
(
(
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DOI: 10.1021/acs.orglett.6b03688
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