G. Magueur et al. / Journal of Fluorine Chemistry 127 (2006) 637–642
641
5
.2. Difluoromethylenation: general procedure
5.6. 2,3,4,6-Tetrakis-O-benzyl-1-bromo-1-deoxy-1-
trifluoromethyl-D-glucopyranose (12)
Methyllithium (1.6 M (Et O), 2.0 mmol) was slowly added
2
to a À78 8C solution of bromide (1.0 mmol) in THF (7 mL).
Thionyl bromide (1.5 mmol, 310 mg) and pyridine
(1.5 mmol, 79 mg) were successively added at 0 8C to a
solution of compound 11 (1.0 mmol, 618 mg) in CH Cl
2
After 5 min stirring at this temperature, the mixture was
quenched with aqueous NH Cl, extracted with AcOEt, dried
4
2
over MgSO and concentrated under vacuum. The crude was
4
(10 mL). When the reaction was finished (TLC), the mixture
was quenched with aqueous NaHCO (10 mL), extracted with
then purified on silica gel (90/10 cyclohexane/AcOEt) to afford
the corresponding gem-difluoroolefin.
3
AcOEt (5 mL), dried over MgSO and concentrated under
4
vacuum. The crude was then purified on silica gel (90/10
cyclohexane/AcOEt) to afford the corresponding trifluoro-
5
.3. 10,10-Difluoromethylene-deoxoartemisinin (8)
methylated bromide (12) (92%, 626 mg).
1
Yield 78%, a colorless oil. H NMR (CDCl ): d 0.93 (3H, d,
J = 5.7 Hz, H-15), 1.06 (3H, t, J = 7.0 Hz, H-16), 1.41 (3H, s, H-
1
Yield 92%, a yellow oil. H NMR (CDCl ): d 3.76–3.84 (2H,
3
3
m), 3.95 (1H, dd, J = 7.6 and 4.6 Hz), 4.35 (1H, d, J = 4.3 Hz
H-2), 4.43 (1H, dd, J = 10.5 and 4.3 Hz), 4.52–4.91 (9H, m),
13
7.22–7.44 (20H, m, HAr). C NMR (CDCl ): d 67.8 (CH ),
1
5
1
4), 0.79–2.10 (10H, m), 2.35 (1H, m, H-4), 3.23 (1H, m, H-9),
1
3
.3 (1H, s, H-12). C NMR (CDCl ): d 12.9 (d, J = 9.4 Hz, C-
3
3
2
6), 19.9 (C-15), 21.9 (C-8), 24.6 (C-5), 25.5 (C-14), 28.5 (d,
73.39 (CH ), 73.40 (CH ), 74.2 (CH ), 74.6 (CH ), 75.4 (CH),
2 2 2 2
J = 3.9 Hz, C-9), 33.6 (C-7), 35.8 (C-4), 37.1 (C-6), 46.2 (C-8a),
1.3 (C-5a), 80.7 (C-12a), 93.6 (C-12), 104.4 (C-3), 114.5 (dd,
J = 35 and 14 Hz, C-10), 154.9 (dd, J = 286 and 282 Hz, CF ).
77.7 (CH), 83.1 (CH), 83.3 (CH), 92.1 (q, J = 32 Hz, C-CF3),
121.9 (q, J = 286 Hz, CF ), 127.5–128.5 (C ), 136.8 (C ),
5
3
Ar
Ar
1
137.7 (C ), 137.8 (C ), 138.0 (C ). F NMR (CDCl ): d
9
2
Ar
Ar
Ar
3
1
9
F NMR (CDCl ): d À117.0 (dm, J = 80 Hz, 1F, CF ), À98.9
À71.9 (s, 3F, CF3).
3
2
(
H, 7.0. Found: C, 60.1; H, 7.1. a = +81 (c = 0.84, MeOH).
dm, J = 80 Hz, 1F, CF ). Anal. Calcd. for C H F O : C, 60.7;
2 16 22 2 4
D
5.7. 2,6-Anhydro-1-deoxy-1,1-difluoro-3,4,5,7-tetrakis-O-
benzyl-D-gluco-hept-1-enitol (13)
5
.4. 10,10-Difluoromethylene-deoxoartemisitene (9)
Reaction of bromide 12 (184 mg, 0.3 mmol) with methyl-
lithium (5.1 equiv., 1.6N) at À40 8C gave compound 13 as a
colorless oil (142 mg, 91%) after purification on silica gel.
Spectral data of this compound are the same than those reported
in the literature [10b].
1
Yield 73%, a colorless oil. H NMR (CDCl ): d 0.97 (3H, d,
3
J = 5.8 Hz, H-15), 1.41 (3H, s, H-14), 0.80–2.09 (10H, m), 2.33
1H, m, H-4), 5.18 (1H, dm, J = 2.2 Hz, H-16), 5.26 (1H, dm,
(
13
J = 2.2 Hz, H-16), 5.57 (1H, d, J = 1.1 Hz, H-12). C NMR
CDCl ): d 19.8 (C-15), 24.6 (C-5), 25.5 (C-14), 30.9 (C-8),
(
13
3
C NMR (CDCl ): d 68.7 (CH ), 71.0 (CH ), 72.8 (CH ),
3
2
2
2
3
8
1
1
3.8 (C-7), 35.9 (C-4), 37.5 (C-6), 48.1 (C-8a), 50.7 (C-5a),
0.2 (C-12a), 92.3 (dd, J = 2.9 and 1.2 Hz, C-12), 104.0 (C-3),
14.5 (dd, J = 10.6 and 3.1 Hz, C-9), 135.4 (d, J = 6.3 Hz, C-
7
7
1
3.0 (t, J = 2.7 Hz, CH), 73.4 (CH ), 73.6 (CH ), 76.8 (CH),
2 2
7.1 (CH), 82.3 (CH), 112.3 (dd, J = 39 and 13 Hz, C CF2),
27.5–128.5 (C ), 137.4 (C ), 137.7 (C ), 137.9 (C ), 138.1
Ar
Ar
Ar
Ar
6), 153.9 (dd, J = 291 and 284 Hz, CF ), C-10 not observed.
2
19
C ), 153.6 (dd, J = 290 and 278 Hz, CF ). F NMR (CDCl3):
(
Ar 2
1
9
F NMR (CDCl ): d À110.1 (d, J = 58 Hz, 1F, CF ), À99.6
3
2
d À116.8 (dd, J = 74 and 3.3 Hz, 1F, CF ), À99.9 (dd, J = 74
2
(dd, J = 58 and 2.6 Hz, 1F, CF ). Anal. Calcd. for C H F O :
2 16 20 2 4
C, 61.1; H, 6.4. Found: C, 60.4; H, 6.9.
and 1.1 Hz, 1F, CF ).
2
Acknowledgments
5.5. 2,3,4,6-Tetrakis-O-benzyl-1-trifluoromethyl-D-
glucopyranose (11)
Authors thank Professor Philippe Grellier (Museum
National d’Histoire Naturelle) for biological experiments,
and Professor Patrick Rollin (Universit e´ d’Orl e´ ans) for the gift
of carbohydrate. We thank MENRT for a fellowship (G.M.) for
financial support. We are grateful to P.G. Dien, and N.V. Hung
at the Institute of Natural Products (CNST, Hanoi, Vietnam) for
supplying of artemisinin.
CF TMS (1.2 mmol, 170 mg) and TBAF (0.1 mmol, 20 mg)
3
were successively added at 0 8C to a solution of lactone 10
(
1.0 mmol, 548 mg) in THF (7 mL). When the reaction was
finished (TLC), the mixture was quenched with aqueous NaCl
10 mL), extracted with AcOEt (5 mL), dried over MgSO and
(
4
concentrated under vacuum. The crude was then purified on
silica gel (80/20 cyclohexane/AcOEt) to afford the trifluor-
References
omethylated sugar (11) (72%, 444 mg).
1
Colorless oil. H NMR (CDCl ): d 3.68–4.12 (7H, m), 4.42–
3
[1] D.L. Klayman, Science 228 (1985) 1049–1055.
[2] J.-P. B e´ gu e´ , D. Bonnet-Delpon, Drugs Future 30 (2005) 509–518, and
references cited therein.
1
.00 (8H, m), 7.17–7.54 (20H, m, HAr). C NMR (CDCl ): d
3
5
6
7
3
8.0 (CH ), 72.8 (CH), 73.4 (CH ), 75.0 (CH ), 75.9 (CH ),
2
2
2
2
[
3] (a) A. Abouabdellah, J.P. B e´ gu e´ , D. Bonnet-Delpon, J.C. Gantier, N.
Truong Thi Thanh, T. Truong Dinh, Bioorg. Biomed. Chem. Lett. 6 (1996)
6.2 (CH ), 77.4 (CH), 78.6 (CH), 83.4 (CH), 94.4 (q,
2
J = 31 Hz, C-CF ), 122.6 (q, J = 288 Hz, CF ), 127.7–128.5
3
3
2
717–2720;
1
9
(
C ), 138.1 (C ), 138.2 (C ), 138.4 (C ). F NMR (CDCl3):
Ar Ar Ar Ar
(b) T.T. Nga, C. M e´ nage, J.P. B e´ gu e´ , D. Bonnet-Delpon, J.C. Gantier, B.
Pradines, J.C. Doury, T.D. Thac, J. Med. Chem. 21 (1998) 4101–4108;
d À83.4 (s, 3F, CF3).