Lewis acid catalysed rearrangements of unsaturated bicyclic [2.2.n] endoperoxides in the presence of vinyl silanes; access to novel Fenozan BO-7 analogues

Article abstract of DOI:10.1016/j.tetlet.2005.03.022

Reactions of a series of unsaturated bicyclic [2.2.n] endoperoxides with allyltrimethylsilane in the presence TMSOTf or SnCl₄ provides the cis-configured endoperoxides 9a-12. It is proposed that this novel reaction proceeds via attack of the al

Full text of DOI:10.1016/j.tetlet.2005.03.022

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3029–3032
Lewis acid catalysed rearrangements of unsaturated bicyclic
[2.2.n] endoperoxides in the presence of vinyl silanes;
access to novel Fenozan BO-7 analogues
Paul M. O’Neill,a,* Sarah L. Rawe,a Richard C. Storr,a
Stephen A. Wardb and Gary H. Posnerc
aDepartment of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, UK
bLiverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK
cDepartment of Chemistry, School of Arts and Sciences, The Johns Hopkins University, Baltimore, MD 21218, USA
Received 18 January 2005; revised 25 January 2005; accepted 3 March 2005
Abstract—Reactions of a series of unsaturated bicyclic [2.2.n] endoperoxides with allyltrimethylsilane in the presence TMSOTf or
SnCl4 provides the cis-configured endoperoxides 9a–12. It is proposed that this novel reaction proceeds via attack of the allylsilane
on the carbocation derived from heterolytic cleavage of the endoperoxide bridge. The reaction proceeds with a high degree of dia-
stereoselectivity and we propose that the bulky –CH2SiMe3 substituent adopts an equatorial position in a product-like transition
state. In contrast to Fenozan B0-7, these compounds displayed poor antimalarial activity versus chloroquine-resistant parasites
in vitro.
Ó 2005 Published by Elsevier Ltd.
The increasing resistance of many strains of the Plasmo-
dium falciparum malaria parasite to traditional quinoline
antimalarial drugs such as chloroquine 1 has rendered
these treatments useless in many parts of the world.
The search for new therapies has established that arte-
misinin 2 is a potent antimalarial and several derivatives
are currently used to treat resistant malaria.1 However,
artemisinin and its semi-synthetic derivatives are expen-
sive replacements for chloroquine and alternatives are
being sought. The antimalarial activity of artemisinin
stems from its peroxide bond and currently several
groups around the world are involved in the search for
new synthetic endoperoxide-containing antimalarials,
which to date has resulted in several promising leads,
including Fenozan 3,2 arteflene3 4a, tetraoxanes such
as 4b4 and VennerstromÕs dispiro 1,2,4-trioxolane 4c.5
Recently, Singh et al.6 have also made significant pro-
gress in the design and synthesis of potent endoperox-
ides including the simple dispiro 1,2,4-trioxanes 4d.
F
NEt2
F
H
O
O
H
O
O
O
NH
O
O
O
Cl
N
2
3
1
H
O
O
CF3
O
O
O
O
H
O
CF3
4a
4b
O O
O
O O
O
Ph
R
4d
4c, R = CONHCH2C(Me)2 NH2
As noted above, one of the most promising classes of
synthetic antimalarials to have been prepared to date
are the 1,2,4-trioxane derivatives such as 3 (this
Keywords: Artemisinin; Endoperoxide; Antimalarial.
*
Corresponding author. Tel.: +44 151 794 3553; fax: +44 151 794
3588; e-mail: p.m.oneill01@liv.ac.uk
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.03.022

3030
P. M. O’Neill et al. / Tetrahedron Letters 46 (2005) 3029–3032
TMSOTf
Dye, CH2Cl2
(A)
n Ar
O
CH2Cl2, -78 o
C
O2, hv, <0 o
C
-TMS
OSiMe3
TMSOTf
Ar
O
Ar
Ar
3
O
Ar
n
Ar
Ar
O
O
O
8a: n = 1, Ar=Ph, 65%
7a: n = 1, Ar=Ph
8b:, n=1, Ar= 4-F-C6H4, 74%
8c: n = 2, Ar=Ph, 52%
7b, Ar=p-F-Ph
7b:, n=1, Ar=4-F-P h
7c: n = 2, Ar=Ph
Ar
5
7d: n=2, Ar=4-F-Ph
8d: n=1, Ar= 4-F-C6H4, 55%
SiMe3
(B)
Ar
Ar
TiCl4
Ar
OMe
n
n
Ar
O
Ar
O
n
OH
O
Ar
O OH
Me3Si
and
6a
O
O
O
O
SiMe3
TMS
TMS
9a: n = 1, Ar=Ph
10a: n = 1, Ar= 4-F-C6H4
11: n=2, Ar=Ph
12: n=2, Ar= 4-F-C6H4,
TMS
SiMe3
O
O
O OH
9b: n = 1, Ar=Ph
10b: n = 1, Ar=Ph
6b
Scheme 1. (A) Lewis acid catalysed synthesis of Fenozan 3 and
(B) synthesis of endoperoxide 6b from peroxy acetal 6a.
Scheme 2. Synthesis of endoperoxides 9a–10b.
compound is also known as Fenozan B0-7). These com-
pounds are prepared by the Lewis acid catalysed reac-
tion of the endoperoxide 7b in the presence of
cyclopentanone.7
We were unable to crystallise 9a or 10a although the
proton NMR spectra for both appeared as a single set
of well-defined peaks that were unchanged at low tem-
perature indicating that there was only one conform-
ation in solution.
The mechanism of this transformation is depicted in
Scheme 1A and involves reaction of the peroxycation
5 with cyclopentanone to provide the cis-fused 1,2,4-tri-
oxane 3. We reasoned that the intermediate cation 5
could be trapped with an allylsilane such that the hydro-
peroxysilyl group could cyclise onto the b-silicon-stabi-
lised carbocation intermediate. A close precedent for
the proposed reaction was recently reported by Dussault
et al.8 whereby the peroxy acetal 6a was transformed
into the cyclic 1,2-dioxolane 6b by treatment with allyl-
trimethylsilane as shown in Scheme 1B.
Based on NMR analysis alone, we were unable to deter-
mine unambiguously the relative stereochemistry of
each diastereoisomer. The crystal structures of Fenozan
and related 1,2,4-trioxanes have been reported and the
cyclopentene and peroxide-containing rings have been
shown to be cis fused with an aromatic substituent in
a pseudoequatorial position.7
We suggest that 9a11/b and 10a/b will adopt a similar
geometry and tentatively propose that the diastereomer,
which predominated when catalytic Lewis acid was em-
ployed was that in which the bulkier silyl group adopted
an equatorial position in a product-like transition state
leading to the diastereomer in which this group was
equatorial and on the same face as the pseudoequatorial
aromatic substituent. This assumption seems reasonable
since we were able to obtain a crystal structure of the
The requisite endoperoxides 8a–d were prepared by pho-
tooxygenation of the corresponding 1,3-dienes, 7a–d,
according to the literature methods of Jefford et al.7
and Posner et al.9 in good overall yield (Scheme 2).
Treatment of 8a with a catalytic amount of TMSOTf
in the presence of allyltrimethylsilane led to a rapid
reaction in which the desired endoperoxide 9a was ob-
tained as a single diastereomer in 54% yield. Increasing
the concentration of TMSOTf to 1.1 equiv provided the
product in 48% yield as a mixture of diastereomers
(1:0.7). Similar results were observed when SnCl4 was
employed as Lewis acid.
Table 1. Reaction conditions employed for the synthesis of 9a–10b
endo-
Equivalents of Reaction Product/
Total
time/min diastereomeric yield (%)
ratioa
Peroxide TMSOTf
(or SnCl4)
For endoperoxide 8b, we also observed the formation of
two diastereomeric products in ratios approaching 1:1
when TMSOTf was employed in slight excess. A single
or predominant diastereomer was produced when a cata-
lytic quantity of TMSOTf was used. Further investiga-
tions allowed us to conclude that only the
stoichiometry of the Lewis acid governed the diastereo-
meric outcome of these reactions even when reaction
times were extended.
8a
8a
8a
8b
8b
8b
8b
8b
8c
8d
8d
0.033
1.1
15
15
9a/b, 1:0
9a/b, 1:0.7
9a/b, 1:1
54
48
53
60
—
—
—
60
10
48
27
1.0 SnCl4
0.033
0.033
0.033
0.033
1.1
30
15
10a/b, 1:0.2
10a/b, 1:0.2
10a/b, 1:0.2
6a/b, 1:0.2
10a/b, 1:0.8
11, 1:0
b
b
b
<10
20
45
15
1.1
1.1
40
40
12, 1:0
12, 1:0
0.1
60
In contrast, for the higher homologues 8c and 8d a single
diastereomer was observed even when excess TMSOTf
was employed (Table 1).
a Determined from the proton NMR of the crude products.
b Purified together and isolated in 31% overall yield.

P. M. O’Neill et al. / Tetrahedron Letters 46 (2005) 3029–3032
3031
TMS
and
higher fluorinated homologue 12 (Fig. 1) in which this
O
stereochemistry was observed. Figure 1 shows that the
unsaturated cyclohexene ring and peroxide-containing
ring are cis fused with the aromatic substituent adopting
a pseudoequatorial position.
0.25 eq TMSOTf
0.14 eq DTBP
O
DCM, -78 to -30 o
C
regioisomer
O
O
TMS
3 eq
We propose the mechanism depicted in Scheme 3 to ac-
count for the stereochemical outcome for endoperoxide
12. TMSOTf-promoted cleavage of the endoperoxide
bridge of 12 produces a carbocation that is attacked
by the allylsilane in a chair-like transition state. Cyclis-
ation of the peroxysilyl function onto the b-stabilised
carbocation provides the product 12, as shown, with
the large –CH2SiMe3 substituent in the equatorial
position.
13
Scheme 4. Attempted rearrangement of ascaridole (13).
pentanone, where the regioisomeric cis-fused 1,2,4-
trioxanes are produced in good yield.12
The reaction of endoperoxide 14 also gave unexpected
results. Treatment of 14 with 3 equiv of allyltrimethylsi-
lane gave compounds 15a and 15b as the major products
in 71% isolated yield. A plausible mechanism for this
outcome is depicted in Scheme 5. Heterolytic cleavage
of the endoperoxide 14 provides the allyl cation, which
reacts to produce the intermediate 14a. Cyclisation of
peroxysilyl group onto the b-stabilised cation provides
the product 14b, which subsequently loses a proton to
provide the aromatised hydroperoxy product 15a.
In order to probe the scope of this reaction, we selected
ascaridole 13 and the endoperoxide 14 derived from 1,4-
dimethylnaphthalene. Exposure of 13 to allyltrimethyl-
silane and TMSOTf (1 equiv) led to no reaction, even
after 24 h at À30 °C (Scheme 4). This is in sharp con-
trast to the reaction carried out in the presence of cyclo-
The other product 15b is presumably obtained by loss of
hydrogen peroxide and the trimethylsilyl group from
14a. The results clearly demonstrate that the outcomes
of these reactions are dictated by the nature of the endo-
peroxide substrate. For endoperoxides 8a–d, the inter-
mediate cation is doubly stabilised by the alkene and
aromatic substituents and this permits a favourable
reaction. In contrast, ascaridole is unreactive under
these conditions and as we have seen, the pathway
followed by the endoperoxide 14 is driven by the
thermodynamically favourable aromatisation of the
naphthalene ring.
The compounds 9a–12, described above, were evaluated
for their antimalarial activity against the most lethal and
chloroquine-resistant K1 strain of the P. falciparum
malaria parasite; the results are shown in Table 2. Dis-
appointingly, these endoperoxide derivatives are poor
Figure 1. ORTEP view of 12 taken from its crystal structure.10
O O
H
TMSOTf
8d
O
Ar
Ar
14
O
SiMe3
SiMe3
O
O
OH
-TMS
-H2O2
TMS
14a
H
15b: 51%
H
H
H
O
-TMS
Ar
O
Ar
Ar
O
SiMe3
O
SiMe3
Ar
O
H+
SiMe3
12
Ar = p-F-C6H4
TMS
TMS
O2H
H
15a: 20%
14b
Scheme 5. Rearrangement of 14 to 15a and 15b.
Scheme 3. Proposed mechanism for the transformation of 8d into silyl
endoperoxide 12.

3032
P. M. O’Neill et al. / Tetrahedron Letters 46 (2005) 3029–3032
Table 2. Antimalarial activities of 8c–12
Manzanares, I.; Canfield, C. J.; Fleck, S. L.; Robinson, B.
L.; Peters, W. Helv. Chim. Acta 1995, 78, 647–662.
3. Hofheinz, W.; Burgin, H.; Gocke, E.; Jaquet, C.; Masci-
adri, R.; Schmid, G.; Stohler, H.; Urwyler, H. Trop. Med.
Parasitol. 1994, 45, 261–265.
4. 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, 2357–2361.
5. Vennerstrom, J. L.; Arbe-Barnes, S.; Brun, R.; Charman,
S. A.; Chiu, F. C. K.; Chollet, J.; Dong, Y. X.; Dorn, A.;
Hunziker, D.; Matile, H.; McIntosh, K.; Padmanilayam,
M.; Tomas, J. S.; Scheurer, C.; Scorneaux, B.; Tang, Y.
Q.; Urwyler, H.; Wittlin, S.; Charman, W. N. Nature 2004,
430, 900–964.
Entry
Compound
IC50/nM
1
2
8c
195
82
8d9
9a
3
684
733
4
9b
10a
5
545
788
6
10b
11
7
>1000
>1000
12.3
5.1
8
12
Artemisinin 2
Fenozan 3
9
10
6. Singh, C.; Malik, H.; Puri, S. K. Bioorg. Med. Chem. 2004,
12, 1177–1182.
7. Jefford, C. W.; Velarde, J. A.; Bernardinelli, G.; Bray, D.
H.; Warhurst, D. C.; Milhous, W. K. Helv. Chim. Acta
1993, 76, 2775–2788.
8. 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,
8407–8414.
antimalarials when compared with both Fenozan and
artemisinin with IC50 values exceeding 500 nM in most
cases. The endoperoxide precursors 8c and 8d were also
assayed and shown to have relatively good antimalarial
activity.
9. Posner, G. H.; Tao, X. L.; Cumming, J. N.; Klinedinst,
D.; Shapiro, T. A. Tetrahedron Lett. 1996, 37, 7225–7228.
10. Crystal data for 12: C24H28F2O2Si, M = 414.56, mono-
Summary
˚
clinic, a = 12.4944(9), b = 10.5879(8), c = 17.2697(13) A,
3
U = 2245.6(3) A , T = 100(2) K, space group P21/n, Z = 4,
We have shown for the first time that unsaturated bicy-
clic [2.2.n] endoperoxides can be transformed into silyl
substituted endoperoxides in the presence of allyltri-
methylsilane and TMSOTf. By the use of catalytic quan-
tities of Lewis acid, this reaction has been shown to
proceed with a high degree of diastereoselectivity. The
endoperoxides were shown to have relatively poor anti-
malarial activity, which may be the result of the high
lipophilicity imparted by the presence of the TMS func-
tion (ClogP > 7.25 for compounds 9a–12, artemisinin
ClogP = 2.84). Use of an allylsilane that produces a
product with a silyl group that can be removed under
oxidative conditions will be the focus of future work
in this area.
˚
absorption co-efficient = 0.137 mmÀ1
. Reflections col-
lected = 12,793, independent reflections = 5092 [R(int) =
0.0339]. Final R indices [I > 2r(I)]R1 = 0.0388, wR2 =
0.1070R; indices (all data) R1 = 0.0460, wR2 = 0.1108.
Additional crystallographic data (excluding structure fac-
tors) for the structure 12 have been deposited with the
Cambridge Crystallographic Data Centre (CCDC) as
supplementary publication number CCDC 256341. Copies
of the data can be obtained, free of charge, on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
(fax: +44 1223 336033 or e-mail: deposit@ccdc.
cam.ca.uk).
11. For 9a: 1H NMR (400 MHz, CDCl3): d 7.41 (4H, m, Ar),
7.32 (4H, m, Ar), 7.18 (2H, m, Ar), 6.13 (1H, d,
J = 2.0 Hz, H-5), 4.00 (1H, m, H-3), 3.58 (1H, m, H-4a),
3.26 (1H, d, J7–7 = 17.1 Hz, H-7), 2.95 (1H, d, J7–7
=
17.1 Hz, H-7), 2.27 (1H, m, H-4), 1.38 (1H, m, H-4), 1.16
(1H, dd, J2–3 = 6.1 Hz, J2–2 = 14.1 Hz, H-2), 0.87 (1H, dd,
J2–3 = 8.2 Hz, J2–2 = 14.1 Hz, H-2), 0.01 (9H, s, H-1); 13C
NMR (100 MHz, CDCl3): d 148.8, 139.8, 136.8, 129.1,
129.0 (C5), 128.7, 128.1, 127.0, 126.5, 125.2, 93.0 (C7a),
77.7 (C3) 60.7 (C4a), 51.7 (C7), 42.5 (C4), 25.2 (C2), 0.0
(C1). IR mmax (neat)/cmÀ1 3032, 2957, 1601, 1494, 1447,
1248, 1086, 1074, 860, 837, 752, 699; EIMS m/z = 364 (M+,
0.5), 307 (7), 218 (86), 156 (52), 141 (19), 128 (27), 115 (66),
91 (38), 77 (Ph, 70), 73 (TMS, 100); HRMS (M+) calcd, for
C23H28O2Si 364.18585. Found: 364.18632.
Acknowledgements
The authors thank the EPSRC and Knoll (BASF) for a
studentship to S.R.
References and notes
1. White, N. J. J. Clin. Invest. 2004, 113, 1084–1092.
2. Jefford, C. W.; Kohmoto, S.; Jaggi, D.; Timari, G.;
Rossier, J. C.; Rudaz, M.; Barbuzzi, O.; Gerard, D.;
Burger, U.; Kamalaprija, P.; Mareda, J.; Bernardinelli, G.;
12. Jefford, C. W.; Jaber, A.; Boukouvalas, J. Chem. Commun.
1989, 1916–1919.