Peroxide Dyads from Natural Artemisinin and Synthetic Perorthoesters and Endoperoxides

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.

artemisinin - photochemistry - singlet oxygen - peroxides - dyads

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 

11

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).

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).

13 Jin HX. Liu HH. Zhang Q. Wu YK. J. Org. Chem.  2005,  70:  4240 

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

16 Schmidt RR. Hoffmann M. Tetrahedron Lett.  1982,  23:  409