Efficient Synthesis of exo-Olefinated Deoxoartemisinin Derivatives by Ramberg-Baecklund Rearrangement

Article abstract of DOI:10.1021/jo035505x

10-exo-Bromoalkylidene- and benzylidenedeoxoartemisinins were synthesized from corresponding 10-alkanesulfonyldihydroartemisinin and 10-phenylmethanesulfonyldihydroartemisinin using a highly efficient, mild, and simple Ramberg-Baecklund rearrangement.

Full text of DOI:10.1021/jo035505x

Efficien t Syn th esis of exo-Olefin a ted
Deoxoa r tem isin in Der iva tives by
Ra m ber g-Ba1ck lu n d Rea r r a n gem en t
Sangtae Oh,† In Howa J eong,† and Seokjoon Lee*,‡
Department of Chemistry, Yonsei University, Wonju
220-710, South Korea, and Department of Basic Sciences,
Kwandong University College of Medicine, Gangneung
210-701, South Korea
sjlee@kwandong.ac.kr
Received October 13, 2003
F IGURE 1. Artemisinin and its derivatives.
Abstr act: 10-exo-Bromoalkylidene- and benzylidenedeoxoar-
temisinins were synthesized from corresponding 10-alkane-
sulfonyldihydroartemisinin and 10-phenylmethanesulfo-
nyldihydroartemisinin using a highly efficient, mild, and
simple Ramberg-Ba¨cklund rearrangement.
first synthesized by J ung et al.7 and then by Haynes et
al.8 from artemisinic acid (4) (Figure 1).
Posner et al.9 and Ziffer et al.10 reported simple
semisynthetic methods for the direct conversion of dihy-
droartemisinin (2) to nonacetal analogues (5). We have
also reported the direct substitution reaction between
10R- or 10â-benzenesulfonyldihydroartemisinin and or-
ganozinc reagents derived from allyl, benzyl, phenyl,
vinyl, and n-butyl Grignard reagents for the related 10-
substituted deoxoartemisinin derivatives (5).11 In par-
ticular, when considering the structural peculiarity and
synthetic utility, we were impressed by the report show-
ing that endo-olefinated deoxoartemisinin derivatives (6)
and their dimers synthesized by Posner et al. exhibit a
high antimalarial12 and antitumor activity.3c
The natural sesquiterpene endoperoxide artemisinin
(1), which was isolated from Artemisia annua L.,1 has
become a potential lead compound in the development
of antimalarial2 and recently anticancer agents.3 The
semisynthetic acetal-type artemisinin derivatives (3),
ether and ester derivatives of trioxane lactol dihydroar-
temisinin (2), were developed for their higher antima-
larial efficacy and are now widely used to treat malarial
patients.4 However, because of the instability5 and toxic-
ity6 of all acetal-type derivatives (3), a great deal of
interest has been concentrated on the synthesis of
nonacetal-type artemisinin derivatives (5), which were
Therefore, to search for noble types of artemisinin
analogues with a high activity and synthetic effective-
ness, we decide to synthesize the C-10 exo-olefinated
deoxoartemisinin derivatives (8). In 1994, McChesney et
al. reported the synthesis of 10-exo-methylene deoxoar-
temisinin (7), but their method was very limited.13
* To whom correspondence should be addressed. Tel.: +82-33-649-
7454. Fax: +82-33-641-1074.
† Yonsei University.
‡ Kwandong University College of Medicine.
(1) Klayman. D. L. Science 1985, 228, 1049.
(2) (a) Luo. X.-D.; Shen. C.-C. Med. Res. Rev. 1987, 7, 29. (b) J ung,
M. Curr. Med. Chem. 1994, 1, 35. (c) Haynes, R. K.; Vonwiller, S. C.
Acc. Chem. Res. 1997, 30, 73. (d) Vroman, J . A.; Alvim-Gaston, M.;
Avery, M. A. Curr. Pharm. Design 1999, 5, 101.
In our laboratory, on the basis of the hypothesis that
the C-10 position of the dihydroartemisinin (2), cyclic
hemiacetal, can be regarded as a sugar-anomeric cen-
ter,9 we have developed more effective method for target
compounds (8) by using the Ramberg-Ba¨cklund rear-
rangement of S-glycoside for 1-exo-methylene glycal.14
(3) (a) Beekman. A. C.; Barentsen, A. R. W.; Woerdenbag, H. J .;
Uden, W. V.; Pras, N.; Konings, A. W. T.; El-Feraly, F. S.; Galal, A.
M.; Wikstro¨m, H. V. J . Nat. Prod. 1997, 60, 325. (b) J ung, M. Bioorg.
Med. Chem. Lett. 1997, 7, 1091. (c) Posner, G. H.; Ploypradith, P.;
Parker, M. H.; O’Dowd, H.; Woo, S.-H.; Northrop, J .; Krasavin, M.;
Dolan, P.; Kensler, T. W.; Xie, S.; Shapiro, T. A. J . Med. Chem. 1999,
42, 4275. (d) Li, Y.; Shan, F.; Wu, J .-M.; Wu, G.-S.; Ding, J .; Xiao, D.;
Yang, W.-Y.; Atassi, G.; Le´once, S.; Caignard, D.-H.; Renard, P. Bioorg.
Med. Chem. Lett. 2001, 11, 5. (e) Posner, G. H.; Northrop, J .; Paik,
I.-H.; Borstnik, K.; Dolan, P.; Kensler, T. W.; Xie, S.; Shapiro, T. A.
Bioorg. Med. Chem. 2002, 10, 227. (f) J ung, M.; Lee, S.; Ham, J .; Lee,
K.; Kim, H.; Kim, S. K. J . Med. Chem. 2003, 46, 987. (g) Posner, G.
H.; Paik, I.-H.; Sur, S.; McRiner, A. J .; Borstnik, K.; Xie, S.; Shapiro,
T. A. J . Med. Chem. 2003, 46, 1060. (h) Oh, S.; J eong, I. H.; Shin, W.-
S.; Lee, S. Bioorg. Med. Chem. Lett. 2003, 13, 3665.
(4) (a) Li, Y.; Yu, P.-L.; Chen, Y.-X.; Li, L.-Q.; Gai, Y.-Z.; Wang, D.-
S.; Zheng, Y.-P. Kexue Tongbao 1979, 24, 667. (b) Brossi, A.; Venugo-
palan, B.; Gerpe, L.; Yeh, H. J . C.; Flippen-Anderson, J . L.; Buchs, P.;
Luo, X. D.; Milhous, W.; Peters, W. J . Med. Chem. 1988, 31, 645. (c)
Lin, A. J .; Klayman, D. L.; Milhous, W. K. J . Med. Chem. 1987, 30,
2147.
As shown in Scheme 1 and Table 1, the reaction of
dihydroartemisinin (2) with the corresponding thiol
(7) (a) J ung, M.; Li, X.; Bustos, D. A.; ElSohly, H. N.; McChesney,
J . D. Synlett 1990, 743. (b) J ung, M.; Lee, S. Heterocycles 1997, 45,
1055.
(8) Haynes, R. K.; Vonwiller, S. C. Synlett 1992, 481.
(9) (a) Woo, S. H.; Parker, M. H.; Ploypradith, P.; Northrop, J .;
Posner, G. H. Tetrahedron Lett. 1998, 39, 1533. (b) Posner, G. H.;
Parker, M. H.; Northrop, J .; Elias, J . S.; Ploypradith, P.; Xie, S.;
Shapiro, T. A. J . Med. Chem. 1999, 42, 300.
(10) (a) Pu, Y. M.; Ziffer, H. J . Med. Chem. 1995, 38, 613. (b) Ma,
J .; Katz, E.; Ziffer, H. Tetrahedron Lett. 1999, 40, 8543.
(11) Lee, S.; Oh, S. Tetrahedron Lett. 2002, 43, 2891.
(12) O’Dowd, H.; Ploypradith, P.; Xie, S.; Shapiro, T. A.; Posner, G.
H. Tetrahedron 1999, 55, 3625.
(13) Srivastava, R. P.; Sindelar, R. D.; McChesney, J . D. Nat. Prod.
Lett. 1994, 4, 279.
(5) (a) Baker, J . K.; McChesney, J . D.; Chi, H. T. Pharm. Res. 1993,
10, 662. (b) J ung, M.; Lee, S. Bioorg. Med. Chem. Lett. 1998, 8, 1003.
(6) (a) Smith, S. L.; Fishwick, J .; McLean, W. G.; Edwards, G.; Ward,
S. A. Biochem. Pharm. 1997, 53, 5. (b) Genovese, R. F.; Newman, D.
B.; Brewer, T. G. Pharmacol. Biochem. Behav. 2000, 67, 37.
(14) Lough, J . M. In Comprehensive Organic Synthesis; Trost, B.
M., Ed.; Pergamon Press: Oxford, 1991; Vol. 3, Chapter 3.8, p 861.
10.1021/jo035505x CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/06/2004
984
J . Org. Chem. 2004, 69, 984-986

SCHEME 1. Syn th esis of exo-Olefin a ted Deoxoa r tem isin in Der iva tives by Ra m ber g-Ba1ck lu n d
Rea r r a n gem en t
TABLE 1. Syn th esis of Th ioa ceta l Ar tem isin in
Der iva tives fr om Dih yd r oa r tem isin in
TABLE 2. exo-Olefin a tion of C-10-Su bstitu ted Su lfon yl
Dih yd r oa r tem isin in by Mod ified Ra m ber g-Ba1ck lu n d
Rea r r a n gem en t
yieldsa (%)
reactants
products
E/Z ratioa
yieldb (%)
R1
9
10
11
12
11a
11b
12b
11c
12c
11d
11e
11f
13a (R2, H; R3, Br)
50:50
84:16
80:20
92:8
93:7
c
74
76
19
84
15
26
78
d
a
b
c
d
e
f
methyl
ethyl
n-butyl
isopropyl
benzyl
allyl
41
86
74
80
82
70
32
6
10
5
8
11
78
84
95
83
82
96
70
86
91
80
80
97
13b (R2, CH3; R3, Br)
13b (R2, CH3; R3, Br)
13c (R2, n-propyl; R3, Br)
13c (R2, n-propyl; R3, Br)
13d (R2, R3, CH3)
13e (R2, H; R3, phenyl)
13f (R2, vinyl; R3, Br)
70:30
d
a
Isolated yield.
a
b
Isolated ratio. Isolated yield. c Stereochemistry not deter-
d
mined. Product not obtained.
reactants15 in the presence of BF3‚Et2O gave a separable
mixture of major thioacetal dihydroartemisinin (9a -f)
with a C-10R stereochemistry and minor C-10â diaster-
eomers (10a -f), respectively.11,16 The C-10 stereochem-
istry of all those products was confirmed by a coupling
constants between H-9 and H-10 in their 1H NMR
spectra.17 In addition, continuous oxidation reaction of
each purified thioacetal compounds (9a -f and 10a -f)
with H2O2/urea (UHP), trifluoroacetic anhydride (TFAA),
and NaHCO3 produced 10R-substituted sulfonyl dihy-
droartemisinin (11a -f) and 10â derivatives (12a -f),
respectively,18 which will be important precursors for the
synthesis of exo-olefinated deoxoartemisinin derivatives
(8) by modified Ramberg-Ba¨cklund rearrangement con-
ditions.19
First, as shown in Scheme 1 and Table 2, the reaction
between 10R-methanesulfonyl dihydroartemisinin (11a )
and CF2Br2, and KOH/Al2O3 in t-BuOH and methylene
chloride (2:1) at room temperature gave an inseparable
E and Z mixture of 10-bromomethylenedeoxoartemisinin
(13a ) in the same ratio,20 which is the first example of
the deoxoartemisinin with an exo-methylene moiety
formed by intramolecular rearrangement in artemisinin
chemistry. Under the same reaction conditions, the 10R-
ethanesulfonyl dihydroartemisinin (11b) stereoselectively
produced a separable E and Z mixture of 10-(1-bromo-
ethylidene) deoxoartemisinin (13b) (76% yield, E/Z ) 84:
16). Though there was no difference in the chemical shift
of the H-18 in E- and Z-13b, the NOE experiment
between H-18 and H-9 showed that the major product
possessed an E-olefin configuration. However, a similar
reaction of the 10â-isomers (12b and 12c) produced the
corresponding products (13b and 13c) in a very low yield
(19% for 13b and 15% for 13c) because they react at a
lower rate than the 10R-isomers (11b and 11c) as
previously reported.18b
The streoselectivity of exo-olefination was greatly
improved when longer alkyl chains were used. 10-(1-
Bromobutylidene)deoxoartemisinin (13c) with a high
stereoselectivity (E/Z ) 92:8) and yield (84%) was formed
from 10R-n-butanesulfonyl dihydroartemisinin (11c) with
a relatively longer carbon chain than 11a and 11b.
Except for the exo-bromomethylene glycols from the
methanesulfonyl glycosides,20a it is a very rare case that
as in artemisinin chemistry, the bromo-olefinated prod-
ucts could be synthesized from alkanesulfonyl reactants
by a Ramberg-Ba¨cklund rearrangement. The bromo-
alkenylidene analogues (13a , 13b, and 13c) were ex-
pected to have potential synthetic utilities and might be
(15) Methanthiol was not useful as thiol reactant for 9a and 10a ,
so methyl disulfide was used.; Li, P.; Sun, L.; Landry, D. W.; Zhao, K.
Carbohydr. Res. 1995, 275, 179.
(16) Venugopalan, B.; Karnik, P. J .; Bapat, C. P.; Chatterjee, D. K.;
Iyer, N.; Lepcha, D. Eur. J . Med. Chem. 1995, 30, 697.
(17) Pu, Y. M.; Ziffer, H. J . Med. Chem. 1995, 38, 613.
(18) (a) Varma, R. S.; Naicker, K. P. Org. Lett. 1999, 1, 189. (b)
Caron, S.; Do, N. M.; Sieser, J . E. Tetrahedron Lett. 2000, 41, 2299.
(19) Chan, T.-L.; Fong. S.; Li, Y.; Man. T.-O.; Poon, C. D. Chem.
Commun. 1994, 1771.
(20) (a) Murphy, P. V.; McDonnell, C.; Ha¨mig, L.; Paterson, D. E.;
Taylor, R. J . K Tetrahedron: Asymmetry 2003, 14, 79. (b) Griffin, F.
K.; Paterson, D. E.; Taylor, R. J . K. Tetrahedron Lett. 1998, 39, 8179.
(c) Alcaraz, M.-L.; Griffin, F. K.; Murphy, P. V.; Paterson, D. E.; Taylor,
R. J . K. Tetrahedron Lett. 1998, 39, 8183.
J . Org. Chem, Vol. 69, No. 3, 2004 985

SCHEME 2. Syn th esis of 10-Isop r op ylid en e
Deoxoa r tem isin in Usin g Meyer s’ Con d ition
preliminarly antimalarial and antitumoral study as well
as other synthetic applications of the exo-olefinated
derivatives, we have obtained interesting results which
will be reported elsewhere.
Exp er im en ta l Section
Typ ica l P r oced u r e for exo-Olefin a tion by Ra m ber g-
Ba1ck lu n d Rea r r a n gm en t. 10R-Ethanesulfonyldihydroarte-
misinin (11b, 220 mg, 0.61 mmol) was added to a stirred
suspension of alumina-supported potassium hydroxide (KOH/
Al2O3, 3.80 g)19 in CH2Cl2 (45 mL) and tert-butyl alcohol (9 mL)
at 5 °C under nitrogen atmosphere. Dibromodifluoromethane
(CF2Br2, 0.73 mL, 7.7 mmol) was then added dropwise through
a syringe for 5 min with additional stirring for 1 h at room
temperature. After the reaction was complete, the excess solid
reagent (KOH/Al2O3) was removed by suction filtration through
a pad of Celite. The filter residue was washed thoroughly with
dichloromethane, and the combined filtrates were concentrated
under reduced pressure. The crude product was purified by silica
gel column chromatography to give 10-(1-bromoethylidene)-
deoxoartemisinin (13b) as 76% yield.
used to synthesize new multisubstituted deoxoartemisi-
nin derivatives derived from the metalation and succes-
sive addition reaction.
Second, in the case of the secondary alkane-substituted
sulfonyl dihydroartemisinin (11d ), 10-isopropylidene
deoxoartemisinin (13d ) was obtained in a very low yield
(26%) due to steric hindrance of the isopropyl group. To
improve the effectiveness, an alternative method, the
Meyers’ condition was used, as shown in Scheme 2.21
However, this method only gave a synthetic intermediate
14 in a 28% yield and was not useful as a secondary
alkanesulfone precursor.
E-13b: white crystal; mp 104-105 °C; [R]20D -88.2 (c ) 0.034,
CHCl3); IR (KBr pellet) νmax 2949, 2924, 2872, 1634, 1453, 1382,
1096, 1022, 990 cm-1; 1H NMR (300 MHz; CDCl3) δ5.57 (1H, s,
H-12), 3.33 (1H, m, J ) 7.7 Hz, H-9), 2.29 (3H, s, H-18), 1.36
(3H, s, H-14), 1.13 (3H, d, J ) 7.3 Hz, H-16), 0.97 (3H, d, J )
6.0 Hz, H-15) ppm; 13C NMR (75 MHz; CDCl3) δ150.0, 106.5,
102.9, 93.1, 81.2, 50.4, 42.8, 37.6, 36.1, 34.2, 25.5, 25.0, 24.2,
21.7, 19.8, 14.5 ppm; GC/MSD (m/z) retention time 20.69 (min)
374 (M+ + 1), 345, 328, 301, 265, 247 (100). Anal. Calcd for
Finally, unlike the alkanesulfonyl reactants (11a -d ),
the 10R-phenylmethanesulfonyldihydroartemisinin (11e)
with an aromatic sulfonyl group gave separable E- and
Z-isomers of the 10-benzylidenedeoxoartemisinin (13e)
with no bromide in a 78% yield (E/Z ) 70:30). The
stereochemistry of E-13e and Z-13e was determined by
comparing each chemical shift of H-17 (6.43 ppm for E
and 5.45 ppm for Z) and H-9 (3.45 ppm for E and 3.33
ppm for Z) of the two isomers.
C
17H25BrO4: C, 54.70; H, 6.75. Found: C, 54.71; H, 6.70.
Z-13b: white crystal; mp 120-121 °C; [R]20D -63.5 (c ) 0.126,
CHCl3); IR (KBr pellet) νmax 2949, 2924, 2874, 1661, 1451, 1382,
1100, 1026, 986 cm-1; 1H NMR (300 MHz; CDCl3) δ5.57 (1H, s,
H-12), 3.25 (1H, m, J ) 7.5 Hz, H-9), 2.32 (1H, td, J ) 13.9, 3.8
Hz, H-4R), 2.28 (3H, s, H-18), 1.45 (3H, s, H-14), 1.09 (3H, d, J
) 7.5 Hz, H-16), 0.97 (3H, d, J ) 6.0 Hz, H-15) ppm; 13C NMR
(75 MHz; CDCl3) δ149.2, 103.4, 102.2, 92.8, 81.2, 50.5, 43.5, 37.5,
36.2, 34.1, 31.0, 25.4, 25.0, 23.8, 22.5, 19.9, 15.8 ppm; GC/MSD
(m/z) retention time 21.72 (min) 374 (M+ + 1), 345, 328, 301,
265, 247 (100). Anal. Calcd for C17H25BrO4: C, 54.70; H, 6.75.
Found: C, 54.86; H, 6.84.
As for other derivatives, although the allyl precursor
11f was totally consumed, the desired 10-allylidene
deoxoartemisinin (13f) could not be obtained. The forma-
tion of 13f by other reaction conditions deserves further
study.
Ack n ow led gm en t. We are grateful for financial
support from Korea Research Foundation Grant No.
KRF-2002-002-C00056.
In conclusion, for the first time, we have shown that
the exo-bromoalkylidenedeoxoartemisinin (13a -d ) and
the exo-benzylidenedeoxoartemisinin (13e) can be syn-
thesized from the corresponding 10-alkane (11a -d ) and
phenylmethanesulfonyldihydroartemisinin (11e) by a
modified Ramberg-Ba¨cklund rearrangement. From the
Su p p or tin g In for m a tion Ava ila ble: Typical procedure
for sulfonation of thioacetal dihydroartemisinin, exo-olefination
by Ramberg-Ba¨cklund rearrangement, and characterization
data for 11a -f, 12a -f, 13a -e, and 14. This material is
available free of charge via the Internet at http://pubs.acs.org.
(21) Meyers, C. Y.; Malte, A. M.; Matthews, W. S. J . Am. Chem.
Soc. 1969, 91, 7510.
J O035505X
986 J . Org. Chem., Vol. 69, No. 3, 2004