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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: griesbeck@uni-koeln.de;
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Publikationsverlauf

Received 12 February 2009
Publikationsdatum:
04. Mai 2009 (online)

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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.

Key words

artemisinin - photochemistry - singlet oxygen - peroxides - dyads

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Typical Photooxygenation Procedure
A solution of 160 mg (0.75 mmol) of the syn-diol 2 CCl4
(30 mL, 5˙10-³ 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).

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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).

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

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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-¹. ESI-MS: (C30H44O12): m/z = 619.22 g/mol [M + Na]+.