110
H.-J. Hamann et al. / Tetrahedron Letters 52 (2011) 107–111
3.2. 3-Methoxy-6-propyl-1,2,4,5-tetroxane 9b
Yellow oil (109 mg, 26%), Rf = 0.4 (petroleum ether/Et2O = 98:2).
1H NMR (CDCl3): d [ppm] = 6.12 (s, 1H), 5.61 (t, J = 5.3 Hz, 1H),
3.63 (s, 3H), 1.45–1.57 (m, 4H), 0.94 (t, J = 7.2 Hz, 3H); 13C NMR
(CDCl3): d [ppm] = 115.7, 106.7, 56.1, 29.7, 17.3, 13.7.
Acknowledgments
This investigation received support from the UNDP/World
Bank/WHO Special Program for Research and Training in Tropical
Diseases (TDR). Financial support by Deutsche Forschungsgeme-
inschaft (DFG) is gratifyingly acknowledged as well as donations
of chemicals by Solvay Interox GmbH, Bayer Services GmbH &
Co. OHG, BASF AG and Sasol GmbH. We are indebted to Dr.
Burkhard Ziemer, Christina Knispel, and Dr. Beatrice Braun, Insti-
tute of Chemistry, Humboldt-University Berlin, for carrying out
X-ray crystal analyses.
Figure 3. X-ray structure of tetroxane 9k.27
OOH
O
O
O
O
1.4 eq. BF *OEt
3
2
R
CH(OR )
+
1 3
R
OR
1
CH Cl
OOH
2
2
10
8
11
Supplementary data
Scheme 6. Reaction of cyclohexanone-derived DHP with orthoesters.
Supplementary data (experimental details, X-ray crystal analy-
sis of 7a) associated with this article can be found, in the online
Table 4
3-Alkoxytetroxanes 11 from orthoesters 8 and cyclic gem-DHP 10
Tetroxanes 11/yielda (%)
References and notes
Entry
DHP 10
R
Ortho-formate 8
R1
1
2
3
4
10a
10b
10c
10d
H
H
t-Bu
t-Bu
8a
8b
8a
8b
Me
Et
Me
Et
11a/12
11b/32
11c/16
11d/32
1. Jefford, C. W. Adv. Drug Res. 1997, 29, 271; O’Neill, P. M.; Posner, G. H. J. Med.
Chem. 2004, 47, 2945; Dong, Y. Mini-Rev. Med. Chem. 2002, 2, 113; Borstnik, K.;
Paik, I.-H.; Shapiro, T. A.; Posner, G. H. Int. J. Parasitol. 2002, 32, 1661;
Vennerstrom, J. L.; Fu, H. N.; Ellis, W. Y.; Ager, A. L.; Wood, J. K.; Andersen, S. L.;
Gerena, L.; Milhous, W. K. J. Med. Chem. 1992, 35, 3023; Gelb, M. H. Curr. Opin.
Chem. Biol. 2007, 11, 440; Kim, H. S.; Shibata, Y.; Wataya, Y.; Tsuchiya, K.;
Masuyama, A.; Nojima, M. J. Med. Chem. 1999, 42, 2604; McCullough, K. J.;
Wood, J. K.; Bhattacharjee, A. K.; Dong, Y. X.; Kyle, D. E.; Milhous, W. K.;
Vennerstrom, J. L. J. Med. Chem. 2000, 43, 1246; Wu, Y. L.; Li, Y. Med. Chem. Res.
1995, 5, 569; Jin, H. X.; Zhang, Q.; Kim, H. S.; Wataya, Y.; Liu, H. H.; Wu, Y.
Tetrahedron 2006, 62, 7699; Najjar, F.; Gorrichon, L.; Baltas, M.; Andre-Barres,
C.; Vial, H. Org. Biomol. Chem. 2005, 3, 1612; Ellis, G. L.; Amewu, R.; Hall, C.;
Rimmer, K.; Ward, S. A.; O’Neill, P. M. Bioorg. Med. Chem. Lett. 2008, 18, 1720;
Hamada, Y.; Tokuhara, H.; Masuyama, A.; Nojima, M.; Kim, H. S.; Ono, K.;
Ogura, N.; Wataya, Y. J. Med. Chem. 2002, 45, 1374; Dussault, P. H.; Davies, D. R.
Tetrahedron Lett. 1996, 37, 463.
2. Dong, Y. X.; Matile, H.; Chollet, J.; Kaminsky, R.; Wood, J. K.; Vennerstrom, J. L. J.
Med. Chem. 1999, 42, 1477; Jin, H. X.; Liu, H. H.; Zhang, Q.; Wu, Y. K. Tetrahedron
Lett. 2005, 46, 5767.
3. Kim, H. S.; Tsuchiya, K.; Shibata, Y.; Wataya, Y.; Ushigoe, Y.; Masuyama, A.;
Nojima, M.; McCullough, K. J. J. Chem. Soc., Perkin Trans. 1 1999, 1867.
4. Iskra, J.; Bonnet-Delpon, D.; Begue, J. P. Tetrahedron Lett. 2003, 44, 6309;
Zmitek, K.; Stavber, S.; Zupan, M.; Bonnet-Delpon, D.; Charneau, S.; Grellier, P.;
Iskra, J. Bioorg. Med. Chem. 2006, 14, 7790.
a
Reaction conditions: 1.4 equiv of BF3*OEt2, 10 min.
In summary, we have developed a convenient approach to new
unsymmetric 1,2,4,5-tetroxanes starting from primary geminal
dihydroperoxides. For the first time, hitherto unknown unsym-
metrical alkoxy-substituted 1,2,4,5-tetroxanes were obtained.
Despite the use of quite high amounts of boron trifluoride ether-
ate, most tetroxanes are comparingly stable under these reaction
conditions. The configuration of some tetroxanes was unambigu-
ously assigned by X-ray crystal analysis giving interesting insights
in the configuration and conformation of disubstituted 1,2,4,5-tet-
roxanes. Some of the tetroxanes show notable antimalarial activ-
ity in vitro.
5. Solaja, B. A.; Terzic, N.; Pocsfalvi, G.; Gerena, L.; Tinant, B.; Opsenica, D.;
Milhous, W. K. J. Med. Chem. 2002, 45, 3331.
3. General procedure
6. O’Neill, P. M.; Amewu, R. K.; Nixon, G. L.; ElGarah, F. B.; Mungthin, M.;
Chadwick, J.; Shone, A. E.; Vivas, L.; Lander, H.; Barton, V.; Muangnoicharoen, S.;
Bray, P. G.; Davies, J.; Park, B. K.; Wittlin, S.; Brun, R.; Preschel, M.; Zhang, K. S.;
Ward, S. A. Angew. Chem., Int. Ed. 2010, 49, 5693.
7. Amewu, R.; Stachulski, A. V.; Ward, S. A.; Berry, N. G.; Bray, P. G.; Davies, J.;
Labat, G.; Vivas, L.; O’Neill, P. M. Org. Biomol. Chem. 2006, 4, 4431.
8. Dong, Y. X.; Tang, Y. Q.; Chollet, J.; Matile, H.; Wittlin, S.; Charman, S. A.;
Charman, W. N.; Tomas, J. S.; Scheurer, C.; Snyder, C.; Scorneaux, B.; Bajpai, S.;
Alexander, S. A.; Wang, X. F.; Padmanilayam, M.; Cheruku, S. R.; Brun, R.;
Vennerstrom, J. L. Bioorg. Med. Chem. 2006, 14, 6368; Singh, C.; Malik, H.; Puri, S.
K. Bioorg. Med. Chem. Lett. 2004, 14, 459.
9. Ledaal, T. Acta Chem. Scand. 1967, 21, 1656; Sanderson, J. R.; Paul, K.; Story, P.
R.; Denson, D. D.; Alford, J. A. Synthesis 1975, 159; Sanderson, J. R.; Wilterdink,
R. J.; Zeiler, A. G. Synthesis 1976, 479; Sanderson, J. R.; Zeiler, A. G. Synthesis
1975, 125; Sanderson, J. R.; Zeiler, A. G.; Wilterdink, R. J. J. Org. Chem. 1975, 40,
2239; Milas, N. A.; Harris, S. A.; Panagiotakos, P. C. J. Am. Chem. Soc. 1939, 61,
2430; Dilthey, W.; Inckel, M.; Stephan, H. J. Prakt. Chem. 1940, 154, 219; Schulz,
M.; Kirschke, K.; Hohne, E. Chem. Ber. 1967, 100, 2242; Mccullough, K. J.;
Morgan, A. R.; Nonhebel, D. C.; Pauson, P. L.; White, G. J. J. Chem. Res., Synop.
1980, 34; Adam, W.; Asensio, G.; Curci, R.; Marco, J. A.; Gonzaleznunez, M. E.;
Mello, R. Tetrahedron Lett. 1992, 33, 5833; Sawada, H. Chem. Rev. 1996, 96,
1779; Vennerstrom, J. L.; Dong, Y. X.; Andersen, S. L.; Ager, A. L.; Fu, 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; Zmitek, K.; Stavber, S.; Zupan, M.; Bonnet-Delpon, D.; Iskra, J. Tetrahedron
2006, 62, 1479.
To a stirred solution of 2.0 equiv (5.0 mmol) acetal or orthoester
in 20 mL of dichloromethane 1.0 equiv (2.5 mmol) of dihydroper-
oxide in 10 mL of dichloromethane was added. After 2 min
1.4 equiv (443 lL, 3.5 mmol) BF3*OEt2 was added quickly under
vigorous stirring. After the reaction was complete (TLC) a solution
of 1.00 g potassium carbonate in 10 mL of water was added and the
mixture was stirred vigorously for another hour. The phases were
separated and the aqueous layer extracted three times with 20 mL
of dichloromethane. The combined organic layers were dried (so-
dium sulfate), the solvent evaporated and the crude product sepa-
rated by column chromatography.
3.1. 3-Ethyl-1,2,4,5-tetraoxaspiro[5.5]undecane 5b
Yellow oil (153 mg, 33%), Rf = 0.65 (petroleum ether/
Et2O = 20:1).
1H NMR (CDCl3): d [ppm] = 5.72 (t, 1H, J = 5.4 Hz), 2.25 (m, 2H),
1.40–1.63 (m, 10H), 0.97 (t, 3H, J = 7.7 Hz); 13C NMR (CDCl3): d
[ppm] = 109.1, 108.7, 31.9, 29.9, 25.4, 23.2, 22.2, 21.8, 7.8.