Synlett 2009(9): 1514-1516  
DOI: 10.1055/s-0029-1216740
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Peroxide Dyads from Natural Artemisinin and Synthetic Perorthoesters and Endoperoxides

Axel G. Griesbeck*, Angela Raabe
Organic Chemistry, Department of Chemistry, University of Cologne, Greinstr. 4, 50939 Köln, Germany
Fax: +49(221)4705057; e-Mail: [email protected];
Further Information

Publication History

Received 12 February 2009
Publication Date:
04 May 2009 (online)

Abstract

The hydroxyethyl-substituted bicyclic perorthoesters are building blocks for the coupling with artesunic acid. Peroxides were synthesized in a three-step process from unsaturated aldol adducts by singlet oxygenation and subsequent acid-catalyzed peroxyacetalization. Coupling to artesunic acid by the Mitsonobu method furnised the trioxane dyad in moderate yields. Late introduction of an endoperoxide bridge was achieved from the dehydroartemisinin-sorbinol adduct via photooxygenation.

    References and Notes

  • 1a Klayman DL. Science  1985,  228:  1049 
  • 1b O’Neill PM. Posner GH. J. Med. Chem.  2004,  47:  2945 
  • 1c Zhou WS. Xu XX. Acc. Chem. Res.  1994,  27:  211 
  • 1d Robert A. Dechy-Cabaret O. Cazelles J. Meunier B. Acc. Chem. Res.  2002,  35:  167 
  • 1e Meunier B. Acc. Chem. Res.  2008,  41:  69 
  • 2a Vennerstrom JL. Arbe-Barnes S. Brun R. Charman SA. Chiu FCK. Chollet J. Dong YX. Dorn A. Hunziker D. Matile H. McIntosh K. Padmanilayam M. Tomas JS. Scheurer C. Scorneaux B. Tang YQ. Urwyler H. Wittlin S. Charman WN. Nature (London)  2004,  430:  900 
  • 2b Ellis GL. Amewu R. Sabbani S. Stocks PA. Shone A. Stanford D. Gibbons P. Davies J. Vivas L. Charnaud S. Bongard E. Hall C. Rimmer K. Lozanom S. Jesús M. Gargallo D. Ward SA. O’Neill PM. J. Med. Chem.  2008,  51:  2170 
  • 3 Weissbuch I. Leiserowitz L. Chem. Rev.  2008,  108:  4899 
  • 4 Griesbeck AG. Blunk D. El-Idreesy TT. Raabe A. Angew. Chem. Int. Ed.  2007,  46:  8883 
  • 5 Griesbeck AG. Adam A. Bartoschek A. El-Idreesy TT. Photochem. Photobiol. Sci.  2003,  2:  877 
  • 6 Griesbeck AG. El-Idreesy TT. Bartoschek A. Pure Appl. Chem.  2005,  77:  1059 
  • 7 Posner GH. Chang W. Hess L. Woodard L. Sinishtaj S. Usera AR. Maio W. Rosenthal AS. Kalinda AS. Dángelo JG. Petersen KS. Stohler R. Chollet J. Santo-Tomas J. Snyder C. Rottmann M. Wittlin S. Brun R. Shapiro TA. J. Med. Chem.  2008,  51:  1035 
  • 8 Evans DA. Carreira EM. Tetrahedron Lett.  1990,  31:  4703 
  • 9 Chen KM. Hardtmann GE. Prasad K. Repic O. Shapiro MJ. Tetrahedron Lett.  1987,  28:  155 
  • 10 Evans DA. Chapman KT. Carreira EM. J. Am. Chem. Soc.  1988,  110:  3560 
  • 13 Jin HX. Liu HH. Zhang Q. Wu YK. J. Org. Chem.  2005,  70:  4240 
  • 16 Schmidt RR. Hoffmann M. Tetrahedron Lett.  1982,  23:  409 
11

Typical Photooxygenation Procedure
A solution of 160 mg (0.75 mmol) of the syn-diol 2 CCl4
(30 mL, 5˙10 M in TPP) was irradiated with a 150 W HP mercury lamp, cut-off filter for λ > 370 nm, under constant purging with oxygen. After completion of the reaction (TLC control, KI spot), the solvent was evaporated to give 184 mg of a 76:24 mixture of diastereomeric hydroperoxides 3a.
Major diastereomer: ¹H NMR (300 MHz, CDCl3): δ = 1.24 (t, 3 H, J = 7.2 Hz, CH3CH2), 1.58 (m, 2 H, CH2), 1.72 (s,
3 H, CH3), 2.48 (d, 2 H, J = 6.6 Hz, CH2), 4.05 (m, 1 H, CHOH), 4.14 (q, 2 H, J = 7.2 Hz, CH3CH2), 4.18 (m, 1 H, CHOOH), 4.29 (m, 1 H, CHOH), 5.03 (s, 2 H, C=CH2).
¹³C NMR (75 MHz, CDCl3): δ = 14.1 (CH3CH2), 18.3 (CH3), 38.1 (CH2), 41.5 (CH2), 60.8 (CH2CH3), 68.3 (CHOH), 71.3 (CHOH), 92.7 (CHOOH), 116.7 (CH2=C), 141.0 (CH2=C), 172.2 (C=O).

12

Typical Peroxyacetalization Procedure
A solution of 170 mg (0.7 mmol) of the hydroperoxide 3b in CH2Cl2 (10 mL) was treated with triethylorthopropionate (0.45 mL, 2.1 mmol, 3 equiv) and catalytic amounts of PPTS at r.t. After stirring overnight, sat. NaHCO3 soln was added and the aqueous phase extracted with CH2Cl2 (2 × 10 mL) washed with brine (10 mL) and NaHCO3 soln (10 mL), dried and purified by column chromatography to give 72 mg (38%) of 5a as a colorless oil.
¹H NMR (300 MHz, CDCl3) δ = 0.87 (t, 3 H, J = 7.1 Hz, CH3CH2), 1.21 (t, 3 H, J = 7.2 Hz, CH3CH2O), 1.62 (q, 2 H, J = 7.1 Hz, CH3CH2), 1.79 (s, 3 H, CH3), 1.80 (m, 1 H, CH2), 2.06 (m, 1 H, CH2), 2.38 (m, 1 H, CH2), 2.51 (m, 1 H, CH2), 4.04 (q, 2 H, J = 7.2 Hz, OCH2CH3), 4.17 (d, 1 H, J = 5.4 Hz, CHO), 4.39 (s, 1 H, CHOO), 5.01 (s, 1 H, CH2=C), 5.10 (s, 1 H, CH2=C), 5.22 (m, 1 H, OCHCH2). ¹³C NMR (75 MHz, CDCl3) δ = 6.6 (CH3CH2), 14.2 (CH3CH2O), 19.2 (CH3), 30.6 (CH3CH2), 33.1 (CH2), 42.1 (CH2), 60.5 (OCH2CH3), 66.0 (CHO), 66.6 (OCHCH2), 83.9 (CHOO), 114.3 (OCOO), 115.0 (C=CH2), 141.2 (C=CH2), 170.3 (C=O).

14

Artemisinin and artemisinin derivatives were purchased from Plant Extracts, Xian, China.

15

Spectral Data of 7 (Numbering Corresponds to the Artemisinin Skeleton)
¹H NMR (300 MHz, CDCl3): δ = 0.85 (d, 3 H, J = 7.1 Hz, H9-Me), 0.96 (d, 3 H, J = 5.8 Hz, CH3, H6-Me), 1.03 (m, 1 H, C7), 1.15-1.38 (m, 2 H, 2 × CH, H5a, H6), 1.41 (s, 3 H, CH3, H3-Me), 1.45 (s, 3 H, CH3), 1.69 (s, 3 H, CH3), 1.48-2.09 (m, 12 H, H4, H5, H7, H8a, H8, CH2CH2O, CH2), 2.37 (dt, 1 H, J = 13.7, 3.9 Hz, CH2, H4), 2.65 [m, 5 H, CH, H9, C(=O)CH2CH2C(=O)], 3.94 (m, 1 H, OCH), 4.26 (m, 3 H, OCH2, CHO), 4.86 (s, 2 H, CH2=C, HCOO), 4.99 (s, 1 H, CH2=C), 5.42 (s, 1 H, CH, H12), 5.79 (d, 1 H, J = 9.9 Hz, H10). ¹³C NMR (75 MHz, CDCl3): δ = 12.0 (C9-Me), 19.7 (CH3), 20.2 (C6-Me), 22.0 (C5), 22.8 (CH3CO4), 24.6 (CH2CH2O), 25.9 (C3-Me), 28.9 [C(=O)CH2CH2], 29.0 [C(=O)CH2CH2], 30.9 (C8), 31.8 (C9), 33.7 (CH2), 34.1 (C7), 36.2 (C4), 37.3 (C6), 45.2 (C8a), 51.5 (C5a), 61.0 (OCH2CH2), 61.1 (CHO), 65.5/65.6 (OCHCH2), 80.1 (C12a), 82.9 (CHOO), 91.5 (C12), 92.2 (C10), 104.5 (C3), 113.3 (CH2=C), 114.2 (OCOO), 137.6 (CH2=C), 171.1 (C=O), 172.0 (C=O). IR (film): ν = 2959 (s), 2860 (m), 1737 (s), 1646 (w), 1445 (w), 1377 (m), 1259 (s), 1161 (m), 1098 (s), 1016 (s), 876 (m), 799 (s) cm. ESI-MS: (C30H44O12): m/z = 619.22 g/mol [M + Na]+.