Synthesis of antimalarial 1,2,4-trioxanes via photooxygenation of a chiral allylic alcohol

Article abstract of DOI:10.1021/ol026916n

(equation presented) Photooxygenation of the chiral allylic alcohol 4-methyl-3-penten-2-ol (3) in nonpolar solvents and subsequent Lewis acid-catalyzed peroxyacetalization afforded a series of monocyclic and spirobicyclic 1,2,4-trioxanes (5, 6). Two products show significant anti-Malaria activity against Plasmodium falciparum when compared with chloroquine.

Full text of DOI:10.1021/ol026916n

ORGANIC
LETTERS
2
002
Vol. 4, No. 24
193-4195
Synthesis of Antimalarial 1,2,4-Trioxanes
via Photooxygenation of a Chiral Allylic
Alcohol
4
,†
†
†
‡
Axel G. Griesbeck,* Tamer T. El-Idreesy, Maren Fiege, and Reto Brun
Institute of Organic Chemistry, UniVersity of Cologne, Greinstr. 4,
D-50939 K o¨ ln, Germany, and Swiss Tropical Institute, Socinstr. 57,
CH-4002 Basel, Switzerland
griesbeck@uni-koeln.de
Received September 17, 2002
ABSTRACT
Photooxygenation of the chiral allylic alcohol 4-methyl-3-penten-2-ol (3) in nonpolar solvents and subsequent Lewis acid-catalyzed
peroxyacetalization afforded a series of monocyclic and spirobicyclic 1,2,4-trioxanes (5, 6). Two products show significant anti-Malaria activity
against Plasmodium falciparum when compared with chloroquine.
The search for efficient nontoxic drugs against several forms
of Malaria is an important topic in medicinal chemistry,
especially for those parasites that have developed multidrug
resistance in recent times and are especially harmful such
peroxides (dioxetanes, endoperoxides) to carbonyl com-
6
pounds and (b) peroxyacetalization of â-hydroperoxyalco-
7
hols (Scheme 1).
1
as Plasmodium falciparum. A promising new lead structure
is the 1,2,4-trioxane ring peroxide, which occurs in natural
anti-Malaria active terpenoids such as artemisinin (or qing-
haosu) and its analogues as well as the 1,2-dioxane structure
Scheme 1
2
found in yinghaosu A and C. There has been intensive effort
3
4
in the total synthesis, in the synthesis of derivatives, and
5
in the elucidation of the peroxide-specific mode of action.
For the synthesis of the 1,2,4-trioxane skeleton, two major
paths are applicable: (a) acid-catalyzed addition of cyclic
†
University of Cologne.
Swiss Tropical Institute.
‡
(
1) World Health Organization expert committee on malaria: W. H. O.
Technol. Rep. Ser. 2000, 892 i-V, 1-74.
2) Jefford, C. W. In AdVances in Drug Research; Testa, B., Meyer, A.
U., Eds.; Academic Press: New York 1997; Chapter 7, p 29.
(
The latter approach appears to be especially attractive since
â-hydroperoxyalcohols are available by singlet oxygen
(
3) Schmid, G.; Hofheinz, W. J. Am. Chem. Soc. 1983, 105, 624-625.
Zhou, W.-S.; Xu, X. X, Acc. Chem. Res. 1994, 27, 211-216. Haynes, R.
K.; Vonviller, S. C. Acc. Chem. Res. 1997, 30, 73-79. Bachi, M. D.;
Korshin, E. E. Synlett 1998, 122-124.
(5) Wu, Y. Acc. Chem. Res. 2002, 35, 255-259. Posner, G. H.; Northrop,
J.; Paik, I. H.; Borstnik, K.; Dolan, P.; Kensler, T. W.; Xie, S.; Shapiro, T.
A. Bioorg. Med. Chem. 2002, 10, 227-232.
(4) McCullough, K. J.; Nojima, M. Curr. Org. Chem. 2001, 5, 601-
6
36.
1
0.1021/ol026916n CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/26/2002

8
photooxygenation of allylic alcohols. Furthermore, this way
enables the introduction of a wide variety of functional
groups at the level of the nonperoxidic starting materials.
In the course of our recent work on the photoinduced
electron-transfer oxygenation of alkenes, we observed the
formation of 1,2-dioxanes by trapping of arylated alkene
Scheme 3
9
radical cations with triplet oxygen. Surprisingly, this reaction
was also observed with prenol (2-methyl-2-buten-4-ol, 1).
When irradiated in acetonitrile in the presence of catalytic
amounts of 9,10-dicyanoanthracene (DCA) and oxygen, the
1
,2,4-trioxane 2 was formed in low yield (Scheme 2). A
vironmentally more friendly approach, we have recently
developed the polystyrene (PS) microcontainer photooxy-
1
3
genation for the ene reaction of 3. In this solvent-free
approach, the diastereoselectivity drops remarkably in com-
Scheme 2
4
parison to the reaction in CCl due to the high (protic)
substrate concentration. With this efficient source of â-hy-
droperoxyalcohol 4 in hand, we investigated the peroxy-
acetalization with a series of carbonyl components. Boron
trifluoride etherate turned out to be the most efficient Lewis
acid catalyst, and the trans-5,6-disubstituted trioxanes 5 were
formed in good yields (Scheme 4). The corresponding
plausible mechanism for this unusual transformation is the
one-electron oxidation of 1 followed by deprotonation,
oxygen trapping, and subsequent addition of neutral 1 to give
the radical cation of 2, which is eventually reduced. Albeit
an interesting transformation, other allylic alcohols did not
show this behavior and the activity against the P. falciparum
parasite is marginal (Table 2). Thus, we proposed to develop
a qualitative structure-activity relationship by variation of
the trioxane structure 2. From extensive model studies
Scheme 4
10
performed by Jefford et al., it became clear that homolytic
cleavage of the acetal carbon-carbon bond, induced by
single-electron reduction of the peroxy linkage, might be
responsible for the biological activity of 1,2,4-trioxanes.
Obviously, this path is not available for 2 because it would
result in the formation of a vinylic radical. As an alternative
to more promising compounds, the singlet oxygen photo-
oxygenation of allylic alcohol 3 was investigated. The
diastereoselectivity of this ene reaction is remarkably high
in unpolar solvents and drops when protic solvents are used
products derived from the minor (erythro) diastereoisomeric
hydroperoxyalcohol 4 could no longer be detected in the
purified trioxanes from the hydroperoxide mixture obtained
from photooxygenation in CCl . To unambiguously prove
4
the relative configuration of these products, a 73:27 mixture
of diastereoisomers 4 (from the photooxygenation in MeOH)
was treated with acetone/BF and a trans/cis mixture of 5a
3
(
Scheme 3).11
isolated (Scheme 5). The J coupling constants clearly
3
HH
This threo-selectivity is rationalized in terms of the
“
hydroxy-directing effect” which is strongly influenced by
12
competing hydrogen-bond acceptors. To evaluate an en-
Scheme 5
(6) Jefford, C. W.; Jaggi, D.; Boukouvalas, J.; Kohmoto, S. J. Am. Chem.
Soc. 1983, 105, 6497-6498. Jefford, C. W.; McGoran, E. C.; Boukouvalas,
J.; Richardson, G.; Robinson, B. L.; Peters, W. HelV. Chim. Acta 1988, 71,
1
805-1812.
(
7) Singh, C. Tetrahdron Lett. 1990, 31, 6901-6902. O’Neill, P. M.;
Pugh, M.; Davies, J.; Ward, S. A.; Park, B. K. Tetrahedron Lett. 2001, 42,
4
569-4571.
8) Further approaches: Dussault, P. H.; Davies, D. R. Tetrahedron Lett.
(
1
996, 37, 463-466. Bloodworth, A. J.; Hagen, T.; Johnson, K. A.; LeNoir,
I.; Moussy, C. Tetrahedron Lett. 1997, 38, 635-638. O’Neill, P. M.; Pugh,
M.; Davies, J.; Ward, S. A.; Park, B. K. Tetrahedron Lett. 2001, 42, 4569-
4
5
8
indicated that the major diastereoisomer (3JHH ) 9.5 Hz) has
the trans configuration (from threo-4), and the minor
571.
(9) Griesbeck, A. G.; Sadlek, O.; Polborn, K. Liebigs Ann. 1996, 545-
49.
(
10) Posner, G. H.; Oh, C. H. J. Am. Chem. Soc. 1992, 114, 8328-
329. Jefford, C. W.; Jaggi, D.; Kohmoto, S.; Timari, G.; Bernardinelli,
(12) Adam, W.; Prein, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 477-
G.; Canfield, C. J.; Milhous, W. K. Heterocycles 1998, 49, 375-383.
494.
Jefford, C. W. Curr. Med. Chem. 2001, 8, 1803-1826.
(13) Griesbeck, A. G.; Bartoschek, A. Chem. Commun. 2002, 1594-
1595.
(11) Adam, W.; Nestler, B. J. Am. Chem. Soc. 1992, 114, 6549-6550.
4194
Org. Lett., Vol. 4, No. 24, 2002

diastereoisomer (3JHH ) 5.4 Hz) has the cis configuration
from erythro-4). The peroxyacetalization with 2-butanone
As an extension of our work, we also investigated the
Lewis-acid-catalyzed peracetalization of 4 with aldehydes
(Scheme 7). In these cases, however, inseparable mixtures
(
resulted in a 80:20 mixture of diastereoisomers 5e (both 5,6-
3
trans with JHH ) 9.6 Hz) with the ethyl group in an
equatorial position in the major component (cf. Scheme 6).
Scheme 7
Scheme 6
Instead of ketones, acetals or ortho esters can also be used
for the peroxyacetalization. For synthesis of the spirobicyclic
product 5c, the alternative transacetalization using an excess
of cyclopentanone diethyl acetal could be applied with 71%
yield. More interestingly, the combination of 4 and triethyl-
of 1,2,4-trioxanes 6 and aldehyde trimers were obtained in
good yields (ca. 40-50% trimer content; total yields are
given in Scheme 7). Only one diastereoisomer was detected
for all three 1,2,4-trioxanes 6a-c with cis configurations of
the substituents at C(3) and C(5).
orthoacetate in the presence of BF
3
led to the formation of
The anti-Malaria activities were tested against the K1 strain
of P. falciparum and revealed that, in comparison with the
standard drug chloroquine, appreciable effects could be
detected with the simple acyclic 1,2,4-trioxane 5b; even
better results were obtained with the spirobicyclic compound
5c (Table 2), whereas the 3-vinyl derivative 2 was nearly
inactive.
the cyclic perortho ester 5f in good yields (75%%) and low
diastereoselectivity (approximately 54:46, both 5,6-trans
diastereoisomers). To the best of our knowledge, compound
5f is the first perortho ester with a 1,2,4-trioxane substructure
described in the literature. The structures of all new mono-
and spirobicyclic 1,2,4-trioxanes were unambiguously proven
14
by NMR and MS analyses. Especially informative were
1
3
the C NMR shifts of the peroxyacetal carbons C(3) (102-
03 ppm) for the 3,3’-bisalkylated compounds 5a,b,d, which
were strongly low-field shifted for not only the perortho ester
f but, surprisingly, also for the cyclopentano-spiroannulated
1
Table 2. Activities of Synthetic 1,2,4-Trioxanes against the K1
Strain of Plasmodium falciparuma
5
compound
rac-2
rac-5b
rac-5c
chloroquine
artemisinine
activity
trioxane 5c (Table 1; data for 5e is for the major diastereo-
isomer).
1762
276
178
65
Table 1. 13C NMR Shifts of the 1,2,4-Trioxanes 5a-f
1.2
C(3)
C(5)
C(6)
a
All values are the mean of two independent assays and given in ng/
5
5
5
5
5
5
a
b
c
d
e
f
102.3
106.0
114.7
102.8
104.1
113.8
66.2
65.8
68.4
65.6
66.3
66.1
88.4
88.4
88.6
88.8
88.8
87.8
mL.
These activities are still 2 orders of magnitude weaker than
the potent artemisinin derivatives. The synthetic approach
is remarkably simple and uses easily available starting
materials. Furthermore, the structural flexibility is high, and
currently a series of other allylic alcohols and carbonyl
compounds are being applied.
5,16
An analogous approach has been developed by Singh et
al. using the photooxygenation of the terpene alcohol
geraniol.15 They report relatively high activities against P.
falciparum, with one compound exceeding the chloroquine
value.
Acknowledgment. Financial support by the Deutsche
Forschungsgemeinschaft (Project Gr-881/10-1), the Fonds
der Chemischen Industrie, and the UNDP/World Bank/WHO
Special Program for Research and Training in Tropical
Diseases (TDR) is greatly acknowledged.
(
14) Representative experimental procedure for 5e. To a solution of 1.0
g of 4 (7.6 mmol) in 20 mL of diethyl ether were added at room temperature
an excess of 2-butanone (5 g, 70 mmol) and a catalytic amount of BF3-
XEt2O (0.2 mL). After stirring for 12 h at rt, the solution was diluted with
OL026916N
2
5 mL of ether, washed with brine and water, and dried over MgSO4.
Solvent evaporation and column chromatography yielded 1.1 g (77%) of
5
e.
(
(16) O’Neill, P. M.; Miller, A.; Bishop, L. P. D.; Hindley, S.; Maggs, J.
L.; Ward, S. A.; Roberts, S. M.; Scheinmann, F.; Stachulski, A. V.; Posner,
G. H.; Park, B. K. J. Med. Chem. 2001, 44, 58-68.
15) Singh, C.; Gupta, N.; Puri, S. K. Bioorg. Med. Chem. Lett. 2002,
1
2, 1913-1916.
Org. Lett., Vol. 4, No. 24, 2002
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