New Products of Artemisinin
J ournal of Natural Products, 1999, Vol. 62, No. 1 57
increasing the polarity to CH3CN-CH2Cl2 (3:7), compounds
71 and 81 were eluted from the column. When 7 was subjected
to treatment with NH3 followed by further workup as described
earlier, there was no formation of 2.
H-13), 1.30 (3H, s, H-15), 1.32 (1H, dd, J ) 5.1, 1.2 Hz, H-2a),
1.69 (1H, m, H-9b), 1.86-1.95 (2H, m, H-1, H-8b), 2.08 (1H, m,
H-7), 2.19 (1H, dd, J ) 9.0, 5.0 Hz, H-2b), 2.51 (1H, dd, J )
5.6, 5.6 Hz, H-3), 3.06 (1H, dq, J ) 7.3 Hz, H-11), 4.53 (1H, d,
J ) 5.4 Hz, H-5), 5.00 (1H, s, OH); 13C NMR, see Table 1; CIMS
m/z 562 (24, 2M+ + 1) with the base peak at 265.
X-Ra y Cr ysta l Str u ctu r e An a lysis of Com p ou n d s 5 a n d
6.9 Crystal data for 5: C15H21NO2; MW 247.34, orthorhombic,
space group P212121(D24)-no.19 from the Laue symmetry and
systematic absences: h00 when h * 2n, 0k0 when k * 2n, 00l
when l * 2n; a ) 8.436(1) Å, b ) 20.552(3) Å, c ) 8.176(1) Å,
V ) 1417.5(5) Å3, Z ) 4, Dc ) 1.159 g cm-3, µ (Cu KR radiation,
λ ) 1.5418 Å) ) 5.7 cm-1; crystal dimensions: 0.16 × 0.20 ×
0.20 mm.
Com p ou n d s 3, 11, a n d 12. Artemisinin (1, 520 mg) was
stirred with a saturated solution of methanolic methylamine
(20 mL) for 22 h. The mixture was further treated as above
for 2 to yield a residue (590 mg) that was chromatographed
on a Si gel (50 g) column using n-hexane-EtOAc (7:3) as
eluent. Compounds 121 then 111 were eluted first followed
by 3 (57 mg), which was obtained as colorless crystals: Rf 0.32
(solvent system A), mp 94.5-95.5 °C; [R]22 -67° (c 0.1, CH2-
D
Cl2); IR (KBr) νmax no NH bands and two double intensity
1
carbonyl bands at 1705 and 1655 cm-1; H NMR δ 1.06 (3H,
d, J ) 6 Hz, H-14), 1.20 (3H, d, J ) 7.0 Hz, H-13), 1.45-1.61
(3H, m, H-2a, H-8a, H-10), 1.72-1.8 (3H, m, H-2b, H-8b, H-9a),
2.06 (2H, m, H-7, H-9b), 2.10 (3H, s, H-15), 2.27-2.38 (1H, m,
H-3a), 2.46-2.56 (1H, m, H-3b), 2.63-2.71 (1H, m, H-1), 3.11
(3H, s, >NMe), 3.32 (1H, dq, J ) 7.1 Hz, H-11), 9.34 (1H, s,
H-5); 13C NMR, see Table 1; EIMS m/z 295(12.2) with the base
peak at 43.
Cr ysta l d a ta for 6: C15H22O5; MW 282.34, monoclinic, space
group C2(C23)-no.5 from Laue symmetry and systematic
absences: hkl when h + k * 2n and the fact that 6 is chiral;
a ) 28.116(3) Å, b ) 6.557(1) Å, c ) 7.928(1) Å, â ) 94.82(1)°,
V ) 1456.4(6) Å3, Z ) 4, Dc ) 1.288 g cm-3, µ(Cu KR radiation)
) 7.5 cm-1; crystal dimensions: 0.10 × 0.12 × 0.60.
Oscillation and Weissenberg photographs yielded prelimi-
nary unit-cell parameters and space group information for each
crystal. Intensity data (1703 +h,+k,+l reflections for 5, 1629
(h,-k,+l nonequivalent reflections for 6) were recorded at 25
°C on an Enraf-Nonius CAD-4 diffractometer [Cu KR radia-
tion, graphite monochromator; ω-2θ scans, θmax ) 75° (scan-
widths: 0.80 + 0.14tanθ for 5, 1.00 + 0.14tanθ for 6]. The
intensities of four reference reflections, monitored every 2 h
during data collection, showed no significant variation (<1%)
throughout. Refined unit-cell parameters were computed from
the diffractometer setting angles for 25 reflections (36°<θ<40°).
The usual Lorentz and polarization corrections were applied
to the intensity data; 1074 and 1288 reflections with I > 3.0σ-
(I) for 5 and 6, respectively, were retained for the structure
analysis and refinement.
Meth yla tion of 2 to 3. Compound 2 (112 mg) was
dissolved in Me2CO (4 mL) following which MeI (1.5 mL) and
anhydrous K2CO3 (67 mg) were added, and the mixture was
stirred at room temperature for 26 h. The reaction mixture
was filtered and the filtrate evaporated to yield 115 mg of
crude product that was crystallized from ether-n-hexane to
yield a compound identical in all aspects with 3, obtained above
(same mp, mixed mp, identical IR and NMR spectra).
Com p ou n d s 4, 13, a n d 14. Artemisinin (1, 710 mg) was
treated with allylamine (2.9 mL), and the mixture was stirred
at room temperature for 70 min. The reaction mixture was
then evaporated in vacuo, and the residue was dissolved in
CH2Cl2 (35 mL), following which Amberlyst 15 (1.0 g) was
added and the suspension stirred for 6 h. More Amberlyst 15
(0.35 g) was added and stirring continued overnight. The
mixture was filtered, and the filtrate was evaporated to yield
650 mg of a yellowish residue that was purified by column
chromatography on Si gel using n-hexane-EtOAc (7:3) as
eluent. Compounds 141 and 131 were eluted first, followed by
4 (217 mg), as colorless crystals: mp 119.5-121 °C; Rf 0.40
(solvent system A); [R]22D -53° (c 0.104, CH2Cl2); IR (KBr) νmax
Both crystal structures were solved by direct methods
(MULTAN11/82). Initial coordinates for all nonhydrogen
atoms were obtained from E-maps. The enantiomer in each
case was chosen to yield the same stereochemistries at C-1
and C-10 as in 1. Positional and thermal parameters of these
atoms (first isotropic and then anisotropic) were adjusted by
means of several rounds of full-matrix least-squares calcula-
tions during which ∑w∆2 [w ) 1/σ2(|Fo|), ∆ ) (|Fo| - |Fc|)] was
minimized. Hydrogen atoms were located in difference Fourier
syntheses, and their positional and isotropic thermal param-
eters were also adjusted in the subsequent least-squares cycles.
An extinction correction, g, was included as a variable during
the later iterations. The parameter refinements converged
(max shift: esd ) 0.03) at R ) ∑||Fo| - |Fc||/∑|Fo| ) 0.035, Rw
1
four carbonyl bands at 1735, 1710, 1700, and 1690 cm-1); H
NMR δ 1.06 (3H, d, J ) 6.0 Hz, H-14), 1.20 (3H, d, J ) 6.8
Hz, H-13), 1.50 (3H, m, H-8a, H-9a, H-10), 1.81 (3H, m, H-2a,
H-2b, H-8b), 2.07 (2H, m, H-1, H-9b), 2.10 (3H, s, H-15), 2.35
(1H, m, H-3a), 2.53 (1H, m, H-3b), 2.68 (1H, m, H-7), 3.30 (1H,
dq, J ) 6.9 Hz, H-11), 4.31 (2H, m, H-1′), 5.12 (1H, br s, H-3′),
5.17 (1H, d, J ) 5.0 Hz, H-3′), 5.75 (1H, m, H-2′), 9.37 (1H, s,
H-5); 13C NMR, see Table 1; EIMS m/z 321(2.4) with the base
peak at 178.
) [∑w(|Fo| - |Fc|)2]1/2 ) 0.049, GOF ) [∑w∆2/(Nobservns
0.049, GOF ) 1.26, g ) 3.5 (7) × 10-6 for 6. Final difference
Fourier syntheses contained no unusual features [∆F (e/Å3)
max:min ) 0.12:-0.10 for 5, 0.18:-0.13 for 6].
-
)
N
param)]1/2 ) 1.29, g ) 6.1(3) × 10-6 for 5, and R ) 0.036, Rw
Com p ou n d 5. The reaction was performed as for the
preparation of 3, but stirring was limited to 4 h only.
Compound 121 was eluted first, without the formation of either
3 or 11.1 Further elution yielded 5 (146 mg) as colorless
Crystallographic calculations were performed by use of the
Enraf-Nonius Structure Determination Package. For all
structure-factor calculations, neutral atom scattering factors,
and their anomalous dispersion corrections were taken from
the literature.10
crystals: mp 156.3-156.9 °C; Rf 0.15 (solvent system A); [R]22
D
-31° (c 0.12, CH2Cl2); IR (KBr) νmax two carbonyl bands at 1715
and 1680 cm-1; 1H NMR δ 0.97 (3H, d, J ) 6.2 Hz, H-14), 1.10
(3H, d, J ) 6.8 Hz, H-13), 1.26 (1H, br dd, J ) 12.0, 5.5 Hz,
H-9a), 1.45-1.50 (2H, m, H-1, H-7), 1.63 (1H, m, H-9b), 1.69
(1H, m, H-10), 1.77 (2H, m, H-8), 1.90 (1H, m, H-2a), 2.15 (1H,
m, H-2b), 2.23 (1H, d, J ) 16.8 Hz, H-5a), 2.33 (2H, m, H-3),
2.45 (1H, m, H-11), 2.79 (1H, d, J ) 16.8 Hz, H-5b), 2.84 (3H,
s, >N-Me); 13C NMR, see Table 1; EIMS m/z 249(73) with the
base peak at 164.
Ack n ow led gm en t. The authors thank Dr. C. D. Hufford,
Department of Pharmacognosy, School of Pharmacy, Univer-
sity of Mississippi, for the 300 MHz 1D and 2D NMR spectra
and Dr. Harry H. S. Fong, Program for Collaborative Research
in the Pharmaceutical Sciences, College of Pharmacy (M/C
877), University of Illinois at Chicago, for CIMS.
Com p ou n d 6. Artemisinin (1, 500 mg) was dissolved in
MeOH (25 mL) then dimethylamine (5 mL) was added, and
the mixture was stirred for 6 h at room temperature. The
reaction mixture was further treated as for 2 to give a residue
that was chromatographed on a column of Si gel (47 g), eluted
with 2% Me2CO in CH2Cl2 to yield 6 (86 mg) as colorless
Refer en ces a n d Notes
(1) Torok, D. S.; Ziffer, H., Meshnick, S. R.; Pan, X.-Q.; Ager, A. J . Med.
Chem. 1995, 38, 5045-5050.
(2) Zeng, M.-Y.; Li, L.-N.; Chen, S.-F.; Li, G.-Y.; Liang, X.-T.; Chen, M.;
Clardy, J . Tetrahedron 1983, 39, 2941-2946.
(3) Yagen, B.; Pu, M. Y.; Yah, H. J . C.; Ziffer, H. J . Chem. Soc., Perkin
Trans. 1 1994, 843-846.
needles: mp 165-167 °C; Rf 0.63 (n-hexane-EtOAc, 1:1); [R]22
D
-114° (c 0.1, CH2Cl2); IR (KBr) νmax 3580 (OH) and 1770 (CO)
1
cm-1; H NMR δ 0.95 (3H, d, J ) 5.1 Hz, H-14), 1.03 (2H, m,
(4) Zhou, W.-S.; Zhang, L.; Fan, Z.-C.; Xu, X.-X. Tetrahedron 1986, 42,
4437-4442.
H-9a, H-10), 1.06 (1H, br s, H-8a), 1.16 (3H, d, J ) 7.3 Hz,