Application of thiol-olefin co-oxygenation methodology to a new synthesis of the 1,2,4-trioxane pharmacophore

Article abstract of DOI:10.1021/ol0492142

(Chemical Equation Presented) Thiol-olefin co-oxygenation (TOCO) of substituted allylic alcohols generates α-hydroxyperoxides that can be condensed in situ with various ketones to afford a series of functionalized 1,2,4-trioxanes in good yields. Manipulation of the phenylsulfenyl group in 4a allows for convenient modification to the spiro-trioxane substituents, and we describe, for the first time, the preparation of a new class of antimalarial prodrug.

Full text of DOI:10.1021/ol0492142

ORGANIC
LETTERS
2004
Vol. 6, No. 18
3035-3038
Application of Thiol−Olefin
Co-oxygenation Methodology to a New
Synthesis of the 1,2,4-Trioxane
Pharmacophore
Paul M. O’Neill,* Amira Mukhtar,† Stephen A. Ward,‡ Jamie F. Bickley,†
,†
Jill Davies,‡ Mario D. Bachi,§ and Paul A. Stocks†
Department of Chemistry, UniVersity of LiVerpool, P.O. Box 147,
LiVerpool L69 3BX, UK, LiVerpool School of Tropical Medicine, Pembroke Place,
LiVerpool, L3 5QA, UK, and Department of Organic Chemistry, The Weizmann
Institute of Science, RehoVot 76100, Israel
p.m.oneill01@liV.ac.uk
Received April 28, 2004
ABSTRACT
Thiol−olefin co-oxygenation (TOCO) of substituted allylic alcohols generates r-hydroxyperoxides that can be condensed in situ with various
ketones to afford a series of functionalized 1,2,4-trioxanes in good yields. Manipulation of the phenylsulfenyl group in 4a allows for convenient
modification to the spiro-trioxane substituents, and we describe, for the first time, the preparation of a new class of antimalarial prodrug.
The 1,2,4-trioxane pharmcophore 1 (Figure 1) is an important
functional group in medicinal chemistry. It is found in the
recently, artemisinin-derived 1,2,4-trioxane monomers and
dimers have been shown to be potent inhibitors of cancer
cell proliferation.2 A disadvantage with the semisynthetic
compounds described is that their production requires arte-
misinin as starting material. Artemisinin is extracted from
the plant Artemisia annua in low yield, a fact that necessitates
significant crop production. Therefore, there is much need
for the development of new and improved approaches to the
1,2,4-trioxane functionality. Current literature methods for
the synthesis of the 1,2,4-trioxane unit include the reaction
of dioxetanes with carbonyls in the presence of Lewis acids,3
acid-catalyzed cyclization of hydroxyperoxyacetals4 with
olefins and reactions of R-peroxy aldehydes with carbonyl
Figure 1. Numbering system of the basic 1,2,4-trioxane ring system
1 and the antimalarial 1,2,4-trioxane artemether 2.
artemisinin class of antimalarials such as artemether 2 and
artesunate, in which its reaction with heme (or free Fe(II))
generates cytotoxic radicals that cause parasite death.1 More
(1) (a) Posner, G. H.; Meshnick, S. R. Trends Parasitol. 2001, 17, 266.
(b) Hindley, S.; Ward, S. A.; Storr, R. C.; Searle, N. L.; Bray, P. G.; Park,
B. K.; Davies, J.; O’Neill, P. M. J. Med. Chem. 2002, 45, 1052.
(2) Posner, G. H.; Paik, I.-H.; Sur, S.; McRiner, A. J.; Borstnik, K.; Xie,
S.; Shapiro, T. A. J. Med. Chem. 2003, 46, 1060.
(3) Posner, G. H.; Oh, C. H.; Gerena, L.; Milhous, W. K. J. Med. Chem.
1992, 35, 2459.
† University of Liverpool.
‡ Liverpool School of Tropical Medicine.
§ The Weizmann Institute of Science.
(4) Bloodworth, A. J.; Shah, A. Chem. Commun. 1991, 947.
10.1021/ol0492142 CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/28/2004

compounds.5 All these routes provide the trioxane in moder-
ate to low overall yields.
During the course of our recent work on the synthesis of
new antimalarial endoperoxides, we utilized a thiol-olefin
co-oxygenation (TOCO) reaction to generate bicyclic per-
oxides structurally related to yingzhaosu A (Scheme 1,
abstraction from thiophenol produces the R-hydroxyperoxide
7a and regenerates phenylthiyl radical to propagate the
reaction. The R-hydroxyperoxide was subsequently shown
to undergo smooth condensation with cyclohexanone in the
presence of a catalytic amount of tosic acid to generate the
1,2,4-trioxane 4a.7 Figure 2 depicts X-ray crystal structures
for the trioxane 4d and the sulfone generated from 4f.
Scheme 1. 2,3-Dioxabicyclo[3.3.1] Nonane and
1,2,4-Trioxane Synthesis by Thiol-Olefin Co-oxygenation
(TOCO)
reaction 1).6 In this letter we describe how, by replacement
of a terpene with an allylic alcohol, this methodology can
be extended to a new synthesis of functionalized spiro 1,2,4-
trioxanes by a simple one-pot procedure (Scheme 1, reaction
2).
Scheme 2 illustrates the mechanism for the TOCO/
condensation reaction. Phenylthiyl radical, generated from
Figure 2. X-ray structures of sulfide trioxane 4d and sulfone
trioxane 8f.
Scheme 2. Mechanism of the TOCO Reaction and Synthesis
of Spiro-trioxanes
Application of the method described in Scheme 2 to
various combinations of ketones and allylic alcohols afforded
the series of spiro-trioxanes shown in Table 1. Considering
the complex sequence of events that must occur to obtain
the R-hydroxyperoxide intermediate and subsequent carbonyl
(6) (a) Bachi, M. D.; Korshin, E. E. Synlett 1998, 122 (b) Korshin, E.
E.; Hoos, R.; Szpilman, A. M.; Konstantinovski, L.; Posner, G. H.; Bachi,
M. D. Tetrahedron 2002, 58, 2449. (c) For an earlier example of the TOCO
reaction, see: Beckwith, A. L. J.; Wagner, R. D. J. Org. Chem. 1981, 46,
3638.
(7) Synthesis of 8-(4-Chloro-phenylsulfenylmethyl)-8-methyl-6,7,10-
trioxa-spiro[4.5]decane (4d). A two-necked, 250 mL, round-bottomed flask
was charged with a solution of 2-methyl-2-propen-1-ol (200 mg, 0.23 mL,
2.77 mmol) and AIBN (31 mg, 1.89 mmol) in acetonitrile (46 mL). The
reaction vessel was flushed with oxygen for several minutes at 0 °C then
stoppered and kept under a positive pressure of pure oxygen. The reaction
mixture was vigorously stirred and UV irradiated (at 0 °C) using an
externally mounted 100W BLAK-RAY UV lamp at a distance of 5-7 cm,
with simultaneous addition of 4-chlorothiophenol (500 mg, 3.46 mol, 1.25
equiv) in acetonitrile (13 mL) over a period of 30 min. After completion of
the addition, the reaction was left to continue stirring at 0 °C for 4-6 h or
until consumption of starting materials (monitored by TLC). The reaction
vessel was then cooled to -10 °C and flushed with nitrogen, and a solution
of cyclopentanone (780 mg, 0.82 mL, 6.94 mmol) in dichloromethane (13
mL) was added, followed by catalytic amounts (ca. 15 mg) of tosic acid.
The mixture was left stirring at -10 °C, and allowed to warm slowly to
room-temperature overnight. Removal of the solvent in vacuo and purifica-
tion by column chromatography yielded the endoperoxide (4d) as a white
solid (391 mg, 46%). Full spectroscopic and compound characterization is
contained in the Supporting Information. Caution: Since vapors of organic
solvents may form explosive mixtures with oxygen in closed systems, all
such reactions should be conducted behind safety shields. For safety
precautions in working with peroxides, see reference 6b.
thiophenol through initiation with AIBN/hV, attacks the
double bond of the allyl alcohol 3a in a Markovnikov fashion
to generate a tertiary carbon radical 5a. This radical traps
oxygen to form a peroxy radical 6a. Radical hydrogen
(5) (a) Jung, M.; Li, X.; Bustos, D. A.; Elsohly, H. N.; McChesney, J.
D.; Milhous, W. K. J. Med. Chem. 1990, 33, 1516 (b) For a recent review
on trioxane syntheses, see: Bez, G.; Kalita, B.; Sarmah, P.; Barua, N. C.;
Dutta, D. K. Curr. Org. Chem. 2003, 7, 1231
3036
Org. Lett., Vol. 6, No. 18, 2004

Table 1. Trioxanes Synthesized via Intermolecular Trapping of the Hydroxyperoxide Products 7a and 7b of the TOCO Reaction with
Cyclic Ketones
allylic alcohol
ketone
trioxane
yield %
3a
3a
3b
3b
3b
3b
3b
3b
3b
3b
cyclohexanone
cyclopentanone
cyclohexanone
cyclopentanone
cyclobutanone
adamantanone
4-t-Bu-cyclohexanone
1,4-cyclohexadione
cyclohexanone
4a : R1 ) Ph; R2 and R3 ) (CH2)5; Ar ) Ph
68
54
53
46
61
42
80
25
55
66
4b: R1 ) Ph; R2 and R3 ) (CH2)4; Ar ) Ph
4c: R1 ) Me; R2 and R3 ) (CH2)5; Ar ) Ph
4d : R1 ) Me; R2 and R3 ) (CH2)4; Ar ) p-Cl-Ph
4e: R1 ) Me; R2 and R3 ) (CH2)3; Ar ) Ph
4f: R1 ) Me; R2CR3 ) adamantylidene; Ar ) Ph
4g: R1 ) Me; R2CR3 ) 4-t-Bu-cyclohexylidene; Ar)p-Cl-Ph
4h : R1 ) Me; R2CR3 ) 4-oxocyclohexylidene; Ar) Ph
4i: R1 ) Me; R2 and R3 ) (CH2)5; Ar ) p-Cl-Ph
4j: R1 ) Me; R2 and R3 ) (CH2)11; Ar ) p-Cl-Ph
cyclododecanone
condensation, the overall sequence proceeds in good yield.
Byproducts generated from oxidation of thiophenol are
observed in very low yields.
Sulfide trioxanes (4e, 4f, and 4j) and the sulfones (8d and
8f) were tested for antiparasitic activity versus chloroquine-
resistant Plasmodium falciparum (Table 2). All of the
In addition to providing facile access to the trioxane
pharmacophore, the TOCO/carbonyl condensation protocol
generates a methylthiophenyl group in the resulting trioxane.
This functionality has proven to be useful for further
manipulation of the structure to generate chemically diverse
groups. Scheme 3 illustrates the synthesis of a formyl-
substituted trioxane (9b) via thiol oxidation using stoichio-
metric mCPBA followed by exposure of the sulfoxide 9a to
Pummerer conditions.8 The resultant carbonyl group in 9b
readily undergoes numerous condensation and nucleophilic
substitution reactions, imparting a high degree of structural
flexibility to a pharmacophore that is of great interest in
current medicinal chemistry.
For example, Wittig reactions on 9b provide vinyl-
substituted trioxane analogues 10a and 10b in excellent yields
(Scheme 3).
These analogues are of interest since they have been shown
to liberate chalcones in biomimetic Fe(II) degradation
reactions (Scheme 4). Chalcones have recently attracted a
Table 2. In Vitro Antimalarial Activity of Spiro-trioxanes
versus K1 Plasmodium falciparuma
trioxane
IC50 (nM) ( mean
4e
4f
4j
8d
314 ( 68
285 ( 54
135 ( 53
90 ( 33
329 ( 42
4 ( 15
8f
artemether
artemisinin
chloroquine
12 ( 20
210 ( 55
a 8d and 8f are the sulfones derived from 4d and 4f (see Table 1),
respectively. Compounds were evaluated using the methods described in
ref 1b.
Scheme 4. Fe(II)-Mediated Trioxane Degradation
analogues display moderate antimalarial activity, with the
exception of trioxane 8d, which exhibits good activity (90
nM). This compound is currently being examined for its in
vivo antimalarial activity versus Plasmodium berghei.
Scheme 3. Synthesis of Chalcone Prodrugs 8a and 8b
great deal of interest as antimalarial parasite cysteine protease
inhibitors. Several chalcone derivatives, including licochal-
cone A and synthetic analogues, have been shown to possess
(8) (a) Arroyo-Gomez, Y.; Rodriguez-Amo, J. F.; Santos-Garcia, M.;
Sanz-Tejedor, M. A. Tetrahedron: Asymmetry 2000, 11, 789. (b) For a
similar Pummerer-type oxidative desulfurization of a â-sulfinyl endoper-
oxide, see: Bachi, M. D.; Korshin, E. E.; Ploos, R.; Szpilman, A. M. J.
Heterocycl. Chem. 2000, 37, 639.
Org. Lett., Vol. 6, No. 18, 2004
3037

good activity both in vitro and in vivo.9,10 Despite the
promising antimalarial activities of chalcone derivatives, a
potential concern with this class of drug is that they might
be expected to react with host proteins, thereby causing
toxicity. In line with this, researchers have shown that in
vitro, licochalcone A readily reacts with sulfur-based biologi-
cal nucleophiles.11 Therefore, a masked prodrug-based ap-
proach to delivering the chalcone selectively to the parasite
would be desirable. Using FeCl2‚4H2O as a mimic of heme
iron(II), we carried out ferrous-mediated degradation of
trioxane 10b and obtained as a major product the chalcone,
11. Scheme 4 outlines two pathways of ferrous-mediated
degradation of 10b. Association of oxygen 2, top half of
Scheme 4, with Fe(II) generates an oxyl radical that can
fragment to generate the observed chalcone in a yield of 45%.
During the iron degradation process, it was noted that
isomerization of the double bond occurs to provide the
thermodynamically more stable trans isomer (JH-H ) 15.8
Hz for a trans-substituted chalcone versus JH-H ) 11.9 Hz
for a cis-substituted chalcone).
The results of our preliminary biomimetic ferrous-mediated
decomposition reactions are significant, since in theory,
similar ferrous-mediated chalcone release within the iron-
rich parasite food vacuole should be accompanied by
concomitant cytotoxic radical generation. Thus, these endo-
peroxide systems may have the capacity to hit the malaria
parasite through two distinctive mechanisms, namely, free-
radical-mediated damage and cysteine protease inhibition.14
The application of these new “trioxane” systems as endo-
peroxide cysteine protease inhibitor (ECPI) prodrugs will be
the focus of future work in this area.
Acknowledgment. We thank the EPSRC (P.ON) (GR/
N65875/01) and BBSRC (P.A.S., P.ON, S.A.W.) (26/
B13581) for financial support of this work. The authors also
thank the EPSRC for a single-crystal diffractometer (GR/
N36851 EPSRC) and NMR facility (GR/M90801). The
authors also thank Dr. E. E. Korshin (Weizmann Institute
of Science) for helpful discussions on the extension of the
TOCO reaction to styryl systems.
Double-bond isomerization has also been noted by
Meunier and co-workers in their biomimetic degradation
studies on the cis-configured endoperoxide antimalarial
artflene.12
An alternative pathway to a primary carbon-centered
radical is also possible from 10b via association of the
endoperoxide oxygen 1 with Fe(II) followed by ester bond
formation and C-C cleavage, and we are currently using
spin trapping techniques to trap these postulated radical
intermediates.13
Note Added after ASAP Posting. The footnote of Table
2 was unclear and compound numbering in the paragraph
below Table 2 was incorrect in the version posted ASAP
July 28, 2004; the corrected version was posted ASAP
August 4, 2004.
Supporting Information Available: Experimental details
1
and characterization data, including H and 13C NMR and
MS data and combustion analysis. This material is available
free of charge via the Internet at http://pubs.acs.org.
(9) Li, R.; Kenyon, G. L.; Cohen, F. E.; Chen, X. W.; Gong, B. Q.;
Dominguez, J. N.; Davidson, E.; Kurzban, G.; Miller, R. E.; Nuzum, E.
O.; Rosenthal, P. J.; McKerrow, J. H. J. Med. Chem. 1995, 38, 5031.
(10) Chen, M.; Theander, T. G.; Christensen, S. B.; Hviid, L.; Zhai, L.;
Kharazmi, A. Anticrob. Agents Chemother. 1994, 38, 1470.
(11) Nadelmann, L.; Tjornelund, J.; Hanse, S. H.; Cornetti, C.; Sidelmann,
J.; Braumann, U.; Christensen, E.; Christensen, S. B. Xenobiotica 1997,
27, 667.
OL0492142
(13) O’Neill, P. M.; Bishop, L. P.; Searle, N. L.; Maggs, J. L.; Storr,
R. C.; Ward, S. A.; Park, B. K., Mabbs, F. J. Org. Chem. 2000, 65,
1578.
(14) O’Neill, P. M.; Stocks, P. A.; Pugh, M. D.; Korshin, E. E.; Ward,
S. A.; Bray, P. G.; Pasini, E.; Davies, J.; Araujo, N.; Verissimo, E.; Bachi,
M. D. Angew. Chem., Int. Ed. 2004, in press.
(12) Cazelles, J.; Robert, A.; Meunier, B. J. Org. Chem. 1999, 64, 6776.
3038
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