Synthesis and anti-malarial activity of yingzhaosu A analogues from unsaturated hydroperoxy acetals

Article abstract of DOI:10.1016/S0040-4039(00)00372-5

Ozonolysis of a vinyl ether 2, prepared from dihydrocarvone 1 (a 1:4 mixture of cis- and trans-isomer), in methanol gave two isomeric unsaturated hydroperoxy acetals cis- and trans-3. Iodonium ion- or ozone-mediated cyclizations of the hydroperoxide cis-3 gave the corresponding yingzhaosu A analogues 4 and 6 in moderate yields. The peroxide 8, obtained by the Ag₂O- mediated methylation of 6, showed notable anti-malarial activity in vitro (IC₅₀=1.0 x 10^-7 M). (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00372-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3145–3148
Synthesis and anti-malarial activity of yingzhaosu A analogues
from unsaturated hydroperoxy acetals
Takahiro Tokuyasu,a Araki Masuyama,a Masatomo Nojima,a,∗ Hye-Sook Kim b and
Yusuke Wataya b,∗
aDepartment of Materials Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565, Japan
bFaculty of Pharmaceutical Sciences, Okayama University, Tsushima-naka 1-1-1, Okayama 700, Japan
Received 27 January 2000; revised 23 February 2000; accepted 25 February 2000
Abstract
Ozonolysis of a vinyl ether 2, prepared from dihydrocarvone 1 (a 1:4 mixture of cis- and trans-isomer), in
methanol gave two isomeric unsaturated hydroperoxy acetals cis- and trans-3. Iodonium ion- or ozone-mediated
cyclizations of the hydroperoxide cis-3 gave the corresponding yingzhaosu A analogues 4 and 6 in moderate yields.
The peroxide 8, obtained by the Ag2O-mediated methylation of 6, showed notable anti-malarial activity in vitro
(IC50=1.0×10−7 M). © 2000 Elsevier Science Ltd. All rights reserved.
Since malaria parasites are rapidly developing resistance to the most commonly used chemotherapeutic
alkaloidal drugs, the anti-malarial properties of non-alkaloidal compounds such as artemisinin and the
related endoperoxides have attracted considerable attention.1,2 As part of our interest in the synthesis
of novel peroxide anti-malarial analogues, we considered the possibility of the electrophile-mediated
cyclization of unsaturated hydroperoxy acetals such as 3 as an attractive method of producing derivatives
of yingzhaosu A (Scheme 1).
Selective monoozonolysis of the electron-rich vinyl ether group of the diene 2, prepared from the com-
mercially available dihydrocarvone 1 (a 1:4 mixture of cis- and trans-isomer) by the Horner–Emmons
reaction, in methanol3 gave two isomeric hydroperoxides cis-3 (11%) and trans-3 (49%), which could be
separated by column chromatography on silica gel. The structures of two hydroperoxides determined by
the HH, CH COSY and NOE measurements suggested that trapping of the carbonyl oxide intermediates
by methanol occurs selectively from the direction anti to the methyl group (Scheme 1).
Reflecting the difference of the structures, two isomeric hydroperoxides, cis- and trans-3, react
with bis(collidine)iodine(I) hexafluorophosphate (BCIH)4 by different pathways (Schemes 1 and 2).
Thus, the reaction of cis-3 gave the iodomethyl-substituted 2,3-dioxabicyclo[3.3.1]nonane 45 (a 5:2
mixture of two isomers; 26%) together with a complex mixture of unidentified oligomeric products.
In contrast, the reaction of the isomeric trans-3 under the same conditions resulted in the formation of
∗
Corresponding authors.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00372-5
tetl 16652

3146
Scheme 1.
the ketone 5 derived from novel migration of the methoxy group (29%) (Scheme 2).6 Consistent with
the intramolecular migration of the methoxy group, the reaction of trans-3 in the presence of 2 equiv. of
CD3OD provided the ketone 5 (23% yield), which did not contain any deuterium in the methoxy group.
Scheme 2.
3
Treatment of cis-3 with ozone in trifluoroethanol (TFE)-CH2Cl2 gave the expected hydroperoxy-
substituted yingzhaosu A analogue 6 in 42% yield (a single isomer).7 From the reaction of trans-3 in
AcOH–CH2Cl2, however, the ketone 7 was obtained in 68% yield (Scheme 3). Surprisingly, the reaction
of cis-3 in AcOH or the reaction of trans-3 in TFE resulted in the formation of complex mixtures of
products. The reason is obscure. Ag2O-Promoted methylation of the hydroperoxide 6 with MeI proceeded
well providing the corresponding methylated product 8 in 53% yield. PM3 calculations suggested that
the 1,2-dioxane ring in 8 adopts a boat form. By the HH, CH COSY and NOE measurements, the
methyldioxy group was determined to occupy the endo position.
Scheme 4 illustrates the mechanism of formation of the hydroperoxide 6. TFE assists the cyclization
of the carbonyl oxide intermediate; solvation of the carbonyl oxide moiety enhances the electrophilicity,
thereby suppressing the [3+2] cycloaddition with the co-produced formaldehyde and facilitating the
intramolecular capture by the hydroperoxy group.3 In accordance with this, the reaction in aprotic
solvents such as ether resulted in the formation of a complex mixture of unidentified products.
Ozonolysis of a diene 9 in methanol gave a 1:1 mixture of two unsaturated hydroperoxy acetals, cis-
and trans-10 (67% yield), which could not be separated by column chromatography on silica gel (Scheme
5). The reaction with BCIH gave the expected bicyclic peroxide 11 (a 3:2 mixture of two isomers; 52%

3147
Scheme 3.
Scheme 4.
yield based on cis-10) together with a ketone 12 (84% based on trans-10). From the ozonolysis of 10 in
TFE–CH2Cl2, the bicyclic peroxide 13 (34%; a single isomer) and a ketone 14 (84%) were obtained. The
similar trend was observed for the ozonolysis in AcOH–CH2Cl2.
Scheme 5.
In a preliminary study of the anti-malarial activities of the derived cyclic peroxides against
P. falciparum,8 compound 8 provided IC50 value of 1.0×10−7 M which are approximately a tenth of the
anti-malarial potency of artemisinin (IC50=7.8×10−9 M). Moreover, the selectivity determined by the
comparison with the 50% inhibitory concentration against mouse mammary FM3A cells (3.3×10−5 M)

3148
was as high as 330, suggesting that this type of cyclic peroxides would be the promising candidate of
anti-malarial drugs with low toxicity.
Acknowledgements
This work was supported in part by a Grant-in-Aid for Scientific Research on Priority Areas (10153238
and 10166211) from the Ministry of Education, Science, Culture and Sports of Japan.
References
1. (a) Zhou, W.-S.; Xu, X.-X. Acc. Chem. Res. 1994, 27, 211. (b) Haynes, R. K.; Vonwiller, S. C. Acc. Chem. Res. 1997, 30, 73.
(c) Robert, A.; Meunier, B. Chem. Soc. Rev. 1998, 27, 273. (d) Meshnick, S. R.; Jefford, C. W.; Posner, G. H.; Avery, M. A.;
Peters, W. Parasitology Today 1996, 12, 79.
2. Yingzahosu A analogues: (a) O’Neill, P. M.; Searle, N. L.; Raynes, K. J.; Maggs, J. L.; Ward, S. A.; Storr, R. C.; Park, B. K.;
Posner, G. H. Tetrahedron Lett. 1998, 39, 6065. (b) Balci, M. D.; Korshin, E. E. Synlett 1998, 122. (c) Cazelles, J.; Robert,
A.; Meunier, B. J. Org. Chem. 1999, 64, 6776.
3. Ushigoe, Y.; Torao, Y.; Masuyama, A.; Nojima, N. J. Org. Chem. 1997, 62, 4949.
4. Rousseau, G.; Homsi, F. Chem. Soc. Rev. 1997, 26, 453.
5. 1-Methoxy-4-iodomethyl-4,8-dimethyl-2,3-dioxabicyclo[3.3.1]nonane
4 (major isomer): mp 95–97°C (from ethyl
acetate/hexane); 1H NMR δ 0.91 (d, J=6.2 Hz, 3H), 1.2–2.0 (m, 6H), 1.36 (s, 3H), 2.3–2.6 (m, 2H), 3.31 (d, J=10.9 Hz)+3.65
(d, J=10.9 Hz) (2 H), 3.43 (s, 3H); 13C NMR δ 11.49 (CH2), 13.91 (CH3), 25.29 (CH3), 25.39 (CH2), 29.27 (CH2), 30.86
(CH2), 38.12 (CH), 39.89 (CH), 49.56 (CH3), 81.85 (C), 104.89 (C). Anal. calcd for C11H19IO2: C, 40.51; H, 5.87; I, 38.91.
Found: C, 40.45; H, 5.77; I, 38.99.
6. Halonium ion mediated migration of an alkoxy group in acetals is known: Harding, K. E.; Tiner, T. H. In Comprehensive
Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, 1991; Vol. 4, Chapter 1.9.
7. 1-Methoxy-4,8-dimethyl-2,3-dioxabicyclo[3.3.1]nonan-4-yl hydroperoxide 6: mp 161–163°C (from ethyl acetate/hexane);
1H NMR δ 0.81 (d, J=4.9 Hz, 3H), 1.2–1.8 (m, 6H), 1.39 (s, 3H), 2.2–2.4 (m, 2H), 3.35 (s, 3H), 8.50 (s, 1H); 13C NMR δ
13.71 (CH3), 20.65 (CH3), 23.51 (CH2), 29.18 (CH2), 30.59 (CH2), 39.73 (CH), 40.20 (CH), 49.26 (CH3), 105.34 (C) 110.03
(C). Anal. calcd for C10H18O5: C, 55.03; H, 8.31. Found: C, 54.95; H, 8.18. 1-Methoxy-4,8-dimethyl-4-(methyldioxy)-2,3-
dioxabicyclo[3.3.1]nonane 8: oil; 1H NMR δ 0.84 (d, J=6.3 Hz, 3H), 1.1–1.3 (m, 3H), 1.37 (s, 3H), 1.6–1.8 (m, 3H), 2.2–2.4
(m, 2H), 3.36 (s, 3H), 3.92 (s, 3H); 13C NMR δ 13.75, 20.87, 23.60, 28.92, 30.62, 40.02, 40.27, 49.18, 63.99, 105.12, 109.26.
Anal. calcd for C11H20O5: C, 56.88; H, 8.68. Found: C, 56.88; H, 8.60.
8. Kim, H.-S.; Shibata, Y.; Wataya, Y.; Tsuchiya, K.; Masuyama, A.; Nojima, M. J. Med. Chem. 1999, 42, 2604.