precursor to artemisinin (1).7,9 Natural 3 has also been
converted chemically into semisynthetic 1.7i
With the broader aim of identifying new methods for
accessing artemisinin-derived antimalarial compounds, we
targeted the chemical synthesis of (+)-dihydro-epi-deoxyarte-
annuin B (3). We initiated our studies with silyloxymenthone
4a, prepared from (-)-isopulegol in three steps: diastereo-
selective hydroboration,15 selective monosilylation, and
Swern oxidation.7k
Coupling of silyloxymenthone 4a with allyl iodide 7 (the
Stork-Jung reagent)16 was more challenging than may be
apparent at first glance (Table 1). An attempt at alkylation
Figure 1. (-)-Artemisinin (1), (-)-dihydroartemisinic acid (2),
(+)-dihydro-epi-deoxyarteannuin B (3), and building block 4a.
and further develop this potent weapon in the fight against
malaria.9 The most daunting challenge associated with the
synthesis of artemisinin is the endoperoxide bridge, a feature
that challenges our assumptions regarding the stability of
such species. Artemisinin has stimulated considerable re-
search in the synthesis of endoperoxides, several of which
show promise as potential malaria treatments.10 Artemisinin
shows selective cytotoxicity against iron-rich cancer cells,
and it is now emerging as a lead compound for cancer
research.11
Table 1. Allylation of Menthone and Silyloxymethone 4a18
(+)-Dihydro-epi-deoxyarteannuin B (3), also a natural
isolate of Artemisia annua,12 plays a central role in our long-
term efforts to develop efficient synthetic approaches to
artemisinin. Barriault and Deon prepared ent-(3) through an
elegant application of the tandem oxy-Cope/transannular ene
reaction en route to ent-(+)-arteannuin M.13 Both artemisinin
and 3 arise from nonenzymatic autoxidation of dihydro-
artemisinic acid (2), a related sesquiterpene isolated from
Artemisia annua14 that has emerged as a key chemical
entry
Z
R-X
additive(s)
none
none
HMPA
HMPA, Et2Zn
HMPA, Et2Zn
HMPA
yield (%)
1
2
3
4
5
6
7
H
allyl bromide
1717a
5317b
53
OBn
H
7
allyl iodide
allyl iodide
allyl iodide
H
∼80a
OTIPS
OTIPS
OTIPS
80
(8) (a) Posner, G. H.; Paik, I.-H.; Chang, W.; Borstnik, K.; Sinishtaj, S.;
Rosenthal, A. S.; Shapiro, T. A. J. Med. Chem. 2007, 50, 2516-2519.
Reviews on artemisinin and related compounds: (b) Dhingra, K. V.; Rao,
V.; Narasu, M. L. Life Sci. 2000, 66, 279-300. (c) Haynes, R. K.; Vonwiller,
S. C. Acc. Chem. Res. 1997, 30, 73-79. (d) Vroman, J. A.; Alvim-Gaston,
M.; Avery, M. A. Curr. Pharm. Des. 1999, 5, 101-138. (e) Posner, G. H.;
O’Neill, P. M. Acc. Chem. Res. 2004, 37, 397-404.
7
7
45
89
HMPA, Et2Zn
a Estimated by H NMR spectroscopy.
1
(9) For example, a combination of biosynthetic engineering and chemical
synthesis is at the heart of the combined venture between the Gates
Foundation and One World Health for lowering the cost of artemisinin.
See: Ro, D. K.; Paradise, E. M.; Ouellet, M.; Fisher, K. J.; Newman, K.
L.; Ndungu, J. M.; Ho, K. A.; Eachus, R. A.; Ham, T. S.; Kirby, J.; Chang,
M. C. Y.; Withers, S. T.; Shiba, Y.; Sarpong, R.; Keasling, J. D. Nature
2006, 440, 940-943 and references cited therein.
(10) (a) Posner, G. H.; Jeon, H. B.; Parker, M. H.; Krasavin, M.; Paik,
I.-H.; Shapiro, T. A. J. Med. Chem. 2001, 44, 3054-3058. (b) Posner, G.
H.; Cumming, J. N.; Krasavin, M. Carbon-Centered Radicals and Rational
Design of New Antimalarial Peroxide Drugs. In Biomedical Chemistry:
Applying Chemical Principles to the Understanding and Treatment of
Disease; Torrence, P. F., Ed.; Wiley-Interscience: New York, 2000; pp
289-309. (c) Vennerstrom, J. L.; Arbe-Barnes, S.; Brun, R.; Charman, S.
A.; Chiu, F. C. K.; Chollet, J.; Dong, Y.; Dorn, A.; Hunziker, D.; Matile,
H.; McIntosh, K.; Padmanilayam, M.; Tomas, J. S.; Scheurer, C.; Scorneaux,
B.; Tang, Y.; Urwyler, H.; Wittlin, S.; Charman, W. N. Nature 2004, 430,
900-904. (d) Tang, Y.; Dong, Y.; Vennerstrom, J. L. Med. Res. ReV. 2004,
24, 425-448.
(11) Singh, N. P.; Lai, H. C. Anticancer Res. 2004, 24, 2277-2280.
(12) (a) Brown, G. D. J. Nat. Prod. 1992, 55, 1756-1760. (b) Sy, L.-
K.; Brown, G. D.; Haynes, R. Tetrahedron 1998, 54, 4345-4356. (c) Sy,
L.-K.; Cheung, K.-K.; Zhu, N.-Y.; Brown, G. D. Tetrahedron 2001, 57,
8481-8493. (d) Sy, L.-K.; Brown, G. D. Phytochemistry 2001, 58, 1159-
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(13) Barriault, L.; Deon, D. H. Org. Lett. 2001, 3, 1925-1927.
(14) (a) Wallaart, T. E.; Pras, N.; Quax, W. J. J. Nat. Prod. 1999, 62,
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908.
of 4a (Z ) OTIPS) under standard conditions yielded 6a in
only 45% yield (entry 6). Similar alkylations of menthone
(4, Z ) H) are also problematic (entries 1 and 3).17
We suspect that, upon treatment with strong base, A1,2-
strain favors a conformation for enolate 5 in which the
flanking alkyl substitutents adopt pseudoaxial orientations,
shielding the top and bottom faces (Table 1). Noyori’s
(15) Schulte-Elte, K. H.; Ohloff, G. HelV. Chim. Acta 1967, 50, 153.
(16) (a) Stork, G.; Jung, M. E. J. Am. Chem. Soc. 1974, 96, 3682-
3684. (b) Stork, G.; Jung, M. E.; Colvin, E.; Noel, Y. J. Am. Chem. Soc.
1974, 96, 3684-3686. (c) Singletary, J. A.; Lam, H.; Dudley, G. B. J. Org.
Chem. 2005, 70, 739-741.
(17) (a) Nakashima, K.; Imoto, M.; Sono, M.; Tori, M.; Nagashima, F.;
Asakawa, Y. Molecules 2002, 7, 517-527. For other representative
alkylations of menthone and its derivatives, see: (b) Reference 7a: 62%,
6:1 dr. (c) Halterman, R. L.; Crow, L. D. Tetrahedron Lett. 2003, 44, 2907-
2909. (d) Avery, M. A.; Gao, F.; Chong, W. K. M.; Hendrickson, T. F.;
Inman, W. D.; Crews, P. Tetrahedron 1994, 50, 957-972.
(18) See the Supporting Information for experimental procedures and
data.
2840
Org. Lett., Vol. 9, No. 15, 2007