Synthesis of spiro-bisperoxyketals

Article abstract of DOI:10.1021/ol800657m

(Chemical Equation Presented) Syntheses of spirocyclic bis-1,2-dioxolanes, bis-1,2-dioxanes, and bis-1,2-dioxepanes are achieved through intramolecular ketalizations of hydroperoxy ketones or intramolecular alkylations of gem-dihydroperoxides. The spirope

Full text of DOI:10.1021/ol800657m

ORGANIC
LETTERS
2008
Vol. 10, No. 12
2401-2404
Synthesis of Spiro-bisperoxyketals
Prasanta Ghorai,† Patrick H. Dussault,*,† and Chunhua Hu‡
Department of Chemistry and Nebraska Center for Materials and Nanoscience,
UniVersity of NebraskasLincoln, Lincoln, Nebraska 68588
pdussault1@unl.edu
Received March 21, 2008
ABSTRACT
Syntheses of spirocyclic bis-1,2-dioxolanes, bis-1,2-dioxanes, and bis-1,2-dioxepanes are achieved through intramolecular ketalizations of
hydroperoxy ketones or intramolecular alkylations of gem-dihydroperoxides. The spiroperoxides have excellent thermal and chemical stability,
and several display promising activity against P. falciparum.
The efficacy of artemisinin (1, Figure 1) against drug-resistant
strains of Plasmodium falciparum, the most lethal form of
malaria, has focused significant attention on the development
of new classes of peroxide-based antimalarials.1,2 Although
artemisinin and derivatives such as artemether (2) are used
clinically, there is a need for new antimalarial agents that
are accessible, stable, inexpensive, and able to achieve
effective cures with limited dosing regimens.
preliminary data regarding their structure, reactivity, and
antimalarial activity.
Several synthetic 1,2,4,5-tetraoxanes, exemplified by 3 and
4 (Figure 1), have demonstrated promising levels of anti-
malarial activity.3–5 We became interested in the antimalarial
potential of analogous tetraoxanes featuring a spiro relation-
ship of the peroxide units. We now report the synthesis of a
series of spiro-linked bisperoxyketals (Figure 2) as well as
Figure 1. Existing peroxide-containing antimalarials.
† Department of Chemistry.
‡ Nebraska Center for Materials and Nanoscience.
(1) Muraleedharan, K. M.; Avery, M. A. ComprehensiVe Medicinal
Chemistry II; Taylor, J. B., Triggle, D. J., Eds.; Elsevier: Oxford, UK, 2006;
Vol. 7, p 765.
We envisaged two complementary approaches to these
targets (Figure 2). Spiroketals 5a-c, which incorporate
tertiary peroxides, would arise through intramolecular ket-
alization, an approach precedented by the facility of corre-
sponding intermolecular reactions.6,7 Spiroketals 6a and 6b
would arise through intramolecular alkylations of gem-
dihydroperoxides.8 While the introduction of cyclic peroxides
through intramolecular nucleophilic substitution has been
(2) Tuteja, R. FEBS J. 2007, 274, 4670
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(3) Tang, Y.; Dong, Y.; Vennerstrom, J. L. Med. Res. ReV. 2004, 24,
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H.-n.; Miller, R. E.; Wesche, D. L.; Kyle, D. E.; Gerena, L.; Walters, S. M.;
Wood, J. K.; Edwards, G.; Holme; A. D.; McLean, W. G.; Milhous, W. K.
J. Med. Chem. 2000, 43, 2753
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P. G.; Davies, J.; Labat, G.; Vivas, L.; O’Neill, P. M. Org. Biomol. Chem.
2006, 4, 4431; erratum, 2007, 5, 708. Terzic´, N.; Opsenica, D.; Milic´, D.;
(6) Zmitek, K.; Zupan, M.; Iskra, J. Org. Biomol. Chem. 2007, 5, 3895
(7) Dussault, P. H.; Lee, I. Q.; Lee, H.-J.; Lee, R. J.; Niu, Q. J.; Schultz,
J. A.; Zope, U. R. J. Org. Chem. 2000, 65, 8407
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Tinant, B.; Smith, K. S.; Milhous, W. K.; Solaja, B. A. J. Med. Chem.
2007, 50, 5118
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10.1021/ol800657m CCC: $40.75
Published on Web 05/14/2008
2008 American Chemical Society

Scheme 1. Syntheses of Spiro-bisperoxyketal 5a-c
Figure 2. Retrosynthetic overview.
mainly explored for five-membered rings,9 sequential inter-
and intramolecular alkylations of gem-dihydroperoxides by
primary 1,n-diiodides has been applied to the synthesis of
1,2,4,5-tetraoxacycles.10 Moreover, we have applied intramo-
lecular alkylations of hydroperoxyacetals to synthesis of
monocyclic alkoxy-1,2-dioxanes.11
The syntheses of tetracyclic spiroketals 5a-c, illustrated
in Scheme 1, were based upon intramolecular ketalization
of a carbonyl group by tertiary hydroperoxides derived from
regioselective Cobalt-mediated dioxygenations of trisubsti-
tuted alkenes.12,13
The synthesis of the tetracyclic spiro-dioxolane (5a) began
with oxidation of 2-cyclohexenylethanol, followed by a Prins
reaction of the resulting aldehyde to generate alcohol 7.14
Cobalt (II)-mediated dioxygenation using O’Neill’s 2,2,6,6-
tetramethylheptane-3,5-dione (THD) ligand proved unsuc-
cessful either for the alcohol or the corresponding ketone13
but could be cleanly accomplished on the corresponding
acetate to produce bis-silyl peroxide 9. Treatment with
i-Bu2AlH achieved chemoselective cleavage of the ester to
afford the secondary alcohol, which was oxidized to furnish
ketone 10a. Acid-promoted desilylation was accompanied
by spontaneous cyclization to afford spiroketal 5a.
For syntheses of the bicyclic peroxyketals 6a and 6b
(Scheme 2), intramolecular perketalization would be disad-
vantaged by the lack of a method for regioselective introduc-
tion of the precursor secondary hydroperoxides. Our ap-
For the syntheses of the six- and seven-membered tetra-
cyclic spirocycles, the Co-mediated bisdioxygenation could
be directly executed on trisubstituted dienones 12b and 12c
(Scheme 1). The resulting tertiary bisperoxy ketones 10b and
10c underwent tandem desilylation and ketalization, as
before, to directly form the tetracyclic spiroketals 5b and
5c.
Scheme 2. Syntheses of Spiro-6a and -6b
(8) A recent report describes synthesis of spiro bisperoxyketals through
intramolecular peroxymercuration of 1,1-dihydroperoxides: Zhang, Q.; Li,
Y.; Wu, Y.-K. Chin. J. Chem. 2007, 25, 1304. We thank a reviewer for
bringing this reference to our attention.
(9) Korshin, E. E., Bachi, M. D. In Chemistry of Peroxides; Rappoport,
Zvi, Ed.; John Wiley & Sons Ltd.: Chichester, UK, 2006; Vol. 2, pp
189-305..
(10) Kim, H-S.; Nagai, Y.; Ono, K.; Begum, K.; Wataya, Y.; Hamada,
Y.; Tsuchiya, K.; Masuyama, A.; Nojima, M.; McCullough, K. J. J. Med.
Chem. 2001, 44, 2357.
(11) (a) Xu, C. Ph.D. Thesis, University of Nebraska-Lincoln, 2006.
(b) Dussault, P. H.; Zope, U. R. J. Org. Chem. 1995, 60, 8218.
(12) Wu, J.-M.; Kunikawa, S.; Tokuyasu, T.; Masuyama, A.; Nojima,
M.; Kim, H.-S.; Wataya, Y. Tetrahedron 2005, 61, 9961
.
(13) O’Neill, P. M.; Hindley, S.; Pugh, M. D.; Davies, J.; Bray, P. G.;
Park, B. K.; Kapu, D. S.; Ward, S. A.; Stocks, P. A. Tetrahedron Lett.
2003, 44, 8135
.
(14) Snider, B. B.; Rodini, D. J.; Kirk, T. C.; Cordova, R. J. Am. Chem.
Soc. 1982, 104, 555.
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Org. Lett., Vol. 10, No. 12, 2008

proach therefore focused on 2-fold intramolecular alkylation
of 1,1- bishydroperoxides. The synthesis of the spiro-
dioxolane 6a began with 2-fold reaction of heptanal with
dilithiated isobutylene to form diol 15a as an inseparable
mixture of syn- and anti-diastereomers. Ozonolysis of the
without decomposition near 132 °C and displayed evidence
of self-accelerating decomposition only upon heating to
nearly 240 °C (DSC); similar behavior was observed for 5c.
Furthermore, 5b was unreactive toward i-Bu2AlH or PPh3
(Scheme 3). Treatment with ferrous bromide resulted in
Scheme 3. Reactivity of Tetracycle 5b
Figure 3. ORTEP plot of 5b at 50% probability; primed atoms are
generated by the symmetry operation -x+3/2, -y+1, z.
bismethanesulfonate (16a) in the presence of excess H2O2
did not furnish the desired gem-1,1-dihydroperoxide but
instead the corresponding ketone, reflecting the influence of
the allylic sulfonates on the regioselectivity of carbonyl oxide
formation.15 The 3,3-bismesyloxy ketone was unstable
toward ꢀ-elimination and was directly reacted with H2O2/I2
or H2O2/H2SO4 to generate a mixture of three diastereomeric
spiro-bicyclic peroxyketals 6a (see Figure 4).6 The result
relatively rapid cleavage to nonperoxidic products. Reduction
by Zn/HOAc occurred over a period of days to furnish a
new, nonperoxidic spiroketal (19). The strongly acidic
conditions of spiroketal formation (Scheme 1) suggests the
spiroketals are also resistant to Hoch/Criegee-type skeletal
rearrangements.16
Although a full analysis of the conformation of the spiro-
bisperoxyketals must await a more detailed study, we
conducted some preliminary experiments on 5b and 6b.
Nonperoxidic 6,6-spiroketals exhibit a preference for isomers
which minimize steric interactions while maximizing the
number of axial anomeric C-O linkages.17 Evidence of both
exo- and endo-anomeric interactions have been observed in
simple six-membered ring peroxides,18 which typically favor
chairlike conformations.19–21 However, the crystal structure
of 5b found one of the two 1,2-dioxanes in a twist-chair
conformation (Figure 3).
In the case of the bicyclic spiroketals 6a and 6b, the
cyclization of a mixture of syn- and anti-precursors was
anticipated to generate three configurational isomers (Figure
4).17,22 The major diasteromer of 6b, which could be isolated
in pure form, displayed only 10 13C signals and was
unchanged upon exposure to strongly acidic conditions
(TsOH·H2O, CH2Cl2). The remaining two diasteromers were
incompletely resolved even by HPLC, but appeared to
undergo equilibration upon prolonged storage or upon
treatment with acid.
Figure 4. Configurational possibilities for 6a and 6b.
presumably reflects formation and spontaneous cyclization
of the intermediate gem-dihydroperoxide.
For the synthesis of the spiro-bis-1,2-dioxane 6b, the
cyclization precursor 18b was prepared through ozonolysis
of bismesyloxyalkene 16b in the presence of excess H2O2
(Scheme 2).6 Reaction of gem-dihydroperoxide 18b with KO-
t-Bu in the presence of 18-crown-6 resulted in the rapid
formation of spiro bis-1,2-dioxane 6b as a mixture of three
diastereomers (see Figure 4). The major diastereomer, which
could be purified by flash chromatography, was a low-
melting solid which slowly yellowed upon storage at room
temperature. The other two diastereomers were incompletely
separated even by HPLC.
Several of the bisperoxyketals were tested against a
chloroquine-resistant strain (NF54) of P. falciparum in
(16) Dussault, P. H.; Lee, H.-J.; Liu, X. Perkins 1 2000, 3006.
(17) Perron, F.; Albizati, K. F. Chem. ReV. 1989, 89, 1617.
(18) Pierrot, M.; El Idrissi, M.; Santelli, M. Tetrahedron Lett. 1989,
30, 461.
(19) Fattorusso, C.; Campiani, G.; Catalanotti, B.; Persico, M.; Basilico,
N.; Parapini, S.; Taramelli, D.; Campagnuolo, C.; Fattorusso, E.; Romano,
A.; Taglialatela-Scafati, O. J. Med. Chem. 2006, 49, 7088
.
(20) Senthilkumar, K.; Kolandaivel, P. Comput. Biol. Chem. 2003, 27,
The tetracyclic spiro-bisperoxyketals 5a-c were stable to
room temperature storage. The tetracyclic spirocycle 5b melts
173
.
(21) Carballeira, L.; Mosquera, R. A.; Rios, M. A. J. Comput. Chem.
1989, 10, 911
(22) Solladie´, G.; Huser, N.; Fischer, J.; Decian, A. J. Org. Chem. 1995,
60, 4988–4990. Francke, W.; Kitching, W. Curr. Org. Chem. 2001, 5, 233
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(15) Bunnelle, W. H. Chem. ReV. 1991, 91, 335.
Org. Lett., Vol. 10, No. 12, 2008
.
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cultures of human red blood cells; the IC50 of artemisinin is
presented for comparison (Table 1). The tetracyclic spiro-
reactivity, and antimalarial activity of this class of compounds
is in progress.23
Acknowledgment. Research was conducted with funding
from the Medicines for Malaria Venture in facilities remod-
eled with support from the NIH (RR016544-01). NMR
spectra were acquired, in part, on spectrometers purchased
with NSF support (MRI 0079750 and CHE 0091975).
Biological assays were conducted by Dr. Sergio Wittlin and
Dr. Matthias Rottman (Swiss Tropical Institute, Basel). We
thank Dr. Christine Ericcson (Wartburg College, IA) for
assistance with DSC and Prof. Jon Vennerstrom (University
of Nebraska Medical Center) for scientific advice.
Table 1. Activity against the NF54 Strain of P. falciparuma
spiroketal
IC50, ng/mL (trials)
5a
5b
5c
6a
6b
1
70 (3)
1508 (4)
>5000 (2)
2483 (4)
126 (4)
2.1 (4)
a Details in the Supporting Information.
Supporting Information Available: Details regarding
preparation, characterization, and antimalarial testing of new
compounds, as well as DSC and crystallographic data for
5b. This material is available free of charge via the Internet
at http://pubs.acs.org.
bis-1,2-dioxepane (5c) and spiro-bis-1,2-dioxane (5b) dem-
onstrated little or no activity. However, the tetracyclic spiro-
bis-1,2-dioxolane (5a) and the bicylic spiro-bis-1,2-dioxane
(6b) displayed relatively strong antimalarial activity, a
significant outcome given the minimal level of skeletal
functionalization.
OL800657M
(23) While we experienced no hazards in the course of this work, any
preparative work with peroxides should be conducted with an awareness
of the potential for spontaneous and exothermic decomposition reactions:
Medard, L. A. Accidental Explosions: Types of ExplosiVe Substances; Ellis
Horwood Ltd.: Chichester, 1989; Vol. 2. Patnaik, P. A. ComprehensiVe
Guide to the Hazardous Properties of Chemical Substances; Van Nostrand
Reinhold: New York, 1992. Shanley, E. S. In Organic Peroxides; Swern,
D., Ed.; Wiley-Interscience: New York, 1970; Vol. 3, p 341. Safety And
Handling Of Organic Peroxides (AS-109); The Society of the Plastics
Industry, Inc.: Washinton, DC, Aug 1999. http://www.Plasticsindustry.Org/
About/Organicperoxide.html.
In conclusion, we have demonstrated new approaches to
spirobisperoxyketals. The successful construction of spiro-
1,2-dioxolane and -1,2-dioxane skeletons through intramo-
lecular nucleophilic displacements should faciliate stereo-
definedsynthesisandstudyofindividualspiroketalstereoisomers.
The ease of the intramolecular peroxyketalizations suggests
potential extensions to other spirocyclic systems, including
perorthoester analogs. Further studies into the synthesis,
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