A hydrogen peroxide based access to qinghaosu (artemisinin)

Article abstract of DOI:10.1021/ol2015434

Attachment of H₂O₂ onto the highly hindered quaternary C-12a in an advanced qinghaosu (artemisinin) precursor has been achieved through a facile perhydrolysis of a spiro epoxy ring with the aid of a previously unknown molybdenum species without involving any special equipment or complicated operations. The resultant β-hydroxyhydroperoxide can be further elaborated into qinghaosu, illustrating an entry fundamentally different from the existing ones to this outstanding natural product of great importance in malaria chemotherapy.

Full text of DOI:10.1021/ol2015434

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4212–4215
A Hydrogen Peroxide Based Access to
Qinghaosu (Artemisinin)
Hong-Dong Hao, Yun Li, Wei-Bo Han, and Yikang Wu*
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China
yikangwu@sioc.ac.cn
Received June 9, 2011
ABSTRACT
Attachment of H2O2 onto the highly hindered quaternary C-12a in an advanced qinghaosu (artemisinin) precursor has been achieved through a
facile perhydrolysis of a spiro epoxy ring with the aid of a previously unknown molybdenum species without involving any special equipment or
complicated operations. The resultant β-hydroxyhydroperoxide can be further elaborated into qinghaosu, illustrating an entry fundamentally
different from the existing ones to this outstanding natural product of great importance in malaria chemotherapy.
Qinghaosu (QHS, artemisinin, 1) is a sesquiterpene
endoperoxide discovered by Chinese scientists in the early
1970s (Figure 1).1 Its structure is completely different from
that of traditional antimalarials and shows high potency in
the treatment of even multidrug resistant cases. These
unique features attracted enormous attention from scien-
tific communities worldwide soon after the introduction to
the Western countries by Klayman1c in 1985. Now, the
ACTs (Artemisinin-based Combination Therapies) have
been recommended by the World Health Organization
(WHO) as first-line drugs to battle malaria.
herb that grows in the northern areas does not produce
QHS. And the content of QHS in the herb is rather low.
Even with the high-yielding new Artemesia strains, one
kilogram of dried qinghao leaves can produce, on average,
only ∼8 g of QHS.2 The limited natural supply along with
the academic interest stimulated by the unique structure of
QHS has prompted many elegant studies3À5 on its chemi-
cal synthesis.
Although the molecular architecture of QHS is not so
pretentious among natural products that have already
been synthesized, its synthesis does represent a lasting
challenge over the years. This is because installation of
the peroxy functionality requires stereoselective attach-
ment of a peroxyl/hydroperoxyl group to the sterically
highly congested C-12a position (QHS numbering). De-
spite the enormous efforts3À5 by the investigators around
(1) (a) Liu, J.-M.; Ni, M.-Y.; Fan, J.-F.; Tu, Y.-Y.; Wu, Z.-H.; Wu,
Y.-L.; Chou, W.-S. Acta Chim. Sin. 1979, 37, 129–143. Chem. Abstr.
1980, 92, 94594w. (b) Klayman, D. L. Science 1985, 228, 1049–1055. (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) Robert, A.; Dechy-Cabaret, O.; Cazalles, J. M.;
Meunier, B. Acc. Chem. Res. 2002, 35, 167–174. (f) O’Neill, P. M.;
Posner, G. H. J. Med. Chem. 2004, 47, 2945–2964. (g) Posner, G. H.;
O’Neill, P. M. Acc. Chem. Res. 2004, 37, 397–404. (h) Tang, Y.; Dong,
Y.; Vennerstrom, J. L. Med. Res. Rev. 2004, 24, 425–448. (i) Muraleed-
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814. (j) Li, Y.; Wu, Y.-L. Front. Chem. China 2010, 5, 357–422.
(2) Van Noorden, R. Nature 2010, 466, 672–673.
Figure 1. Strucure of qinghaosu (artemisinin).
To date, all the QHS used in the ACTs is extracted from
a Chinese herb qinghao (wormwood plant, Artemisia
annua) growing in Southern China and Vietnam; the same
r
10.1021/ol2015434
Published on Web 07/15/2011
2011 American Chemical Society

the world over the years, to date it remains impossible to
realize this transformation without recourse to singlet oxy-
gen, ozone (only one case), or Et3SiOOOH5c,6 (short-lived
species generated in situ from Et3SiH and ozone, for
simplified QHS analogues so far). As all the reactions
before and after this step only involve chemistries rather
commonly employed in synthesis and potential alterna-
tives often exist, it is no exaggeration that, in fact, the real
challenge in the synthesis of QHS is the incorporation of a
hydroperoxyl group ontothe C-12a in a “fully” substituted
precursor (i.e., making the O-1/C-12a σ bond).
the synthesis of relatively simple/less hindered organic
peroxides, with the initial bonding of H2O2 to a carbon
framework most commonly via perketal7 formation or
alkylation by a carbocation generated in situ from hydro-
zines8 or alkenes,9 or a ring-opening reaction of epoxides10
(oxiranes) or oxetanes.11 However, because of the large
structural difference between those peroxides derived from
H2O2 and QHS, along with the apparent limitations of
existing protocols, up to now synthesis of QHS using H2O2
has been a “mission impossible”; even the incorporation of
H2O2 onto a cyclohexane-related substrate that is structu-
rallycomplexenough toserve asanadvancedprecursor for
QHS has never been achieved to date.
Hydrogen peroxide (H2O2) is an apparently exploitable
source for peroxy bonds, and it has been employed7À10 in
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During our study on synthesis of organic peroxides using
H2O2 as the source of peroxy bonds, we observed that a
molybdenum species (212) prepared from Na2MoO4 and
glycine could effectively catalyze the perhydrolysis of the
epoxy ring in, for instance, compound 3 (a mixture of the
cis/trans isomers) but did not affect the ketal functionality
in the side chain to any significant extent (Scheme 1). And
the resultant β-hydroxyhydroperoxide 4 could be readily
converted to the corresponding trioxane 513 by treatment
with an acid. As never before had a trioxane so closely
related to QHS been accessed so easily, this result naturally
inspired us to envisage that the long-standing problem of
attaching a hydroperoxyl group to the C-12a in the QHS
framework might be solved just as well in a similar manner.
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Org. Lett., Vol. 13, No. 16, 2011
4213

Before proceeding further with a more complicated sub-
strate, we next looked into the model reaction further for
stereochemical knowledge;should the relative configura-
tion of the epoxy ring make no difference in the perhy-
drolysis, it might be possible to use a mixture of the C-12a
epimers in the synthesis of QHS; the precursor could be
much easier to prepare. Then, we noticed that the reaction
with a mixture of 3a and 3b could never have gone to
completion and the recovered 3 contained only one dia-
stereomer as shown by 1H NMR, which was later assigned
as 3b on the basis of its configurational relation to 3c.14
A separate run with pure 3b also confirmed its practical
inertness to the same perhydrolysis conditions. All of these
observations taken together suggested that the perhydro-
lysis took place with a distinct facial preference and the
attack of H2O2 occurred from the backside of the epoxy
ring with an inversion of the configuration at the C-12a
(QHS numbering). In light of these observations, com-
pound 6 was selected for further studies.
completed in comparable overall yields without isolation/
purification of the intermediate hydroperoxide 7 (like 4,
also not very stable).
Up to this point, it has been experimentally proven that
installation of a hydroperoxyl group onto the C-12a posi-
tion in a fully equipped substrate, a tricky/critical step in
the synthesis of QHS that previously could be completed
only using singlet oxygen (or its like) with difficulty, indeed
can be realized under the conditions readily attainable in
any ordinary synthetic laboratories if a proper catalyst is
employed, although the trioxane 8 is still one ring less
compared with QHS.
Construction of the last ring was achieved under the
16a
PhI(OAc)2/I2 conditions, which in the beginning was
developed for oxidation of ethereal methine carbons in the
synthesis of some steroidal spiroketals. Although no me-
chanistic information on this reaction is available in the
literature, this cyclization appears to be mediated by
radicals. Over the past 20 years, it has found applications
in the synthesis of a range of different natural products16b
(but not related to QHS).
It is interesting to note that, in the original procedure
and most subsequent applications, use of a tungsten lamp
was reported. However, in the present case lamp irradia-
tion did not seem necessary. Under ordinary laboratory
lighting conditions, the cyclization took place smoothly by
stirring the mixture at ambient temperature, providing the
desired product 9 (deoxoQHS, deoxoartemisinin, also a
known5d,f potent antimalarial) in 69% yield.
Scheme 2. H2O2-Based Access to QHS
It may be noteworthy here that such a strategy, i.e. using
a substrate with a nonfunctionalized C-10 CH2 to con-
struct this final ring in the QHS framework, has never been
explored before. Finally, 9 was smoothly converted to
QHS 1 using the literature4b conditions (RuCl3/NaIO4).
Scheme 3. One of the Possible Routes to Epoxide 6
The results with epoxide 6 was rather pleasing. Despite
the significantly increased steric crowding (compared with 3)
causedbythe extra bulky substituentattheC-8ainepoxide
6, the long-sought-after β-hydroxyhydroperoxide 7 still
formed smoothly as anticipated (Scheme 2). And further
exposure of 7 to p-TsOH in CH2Cl2 resulted in a facile
intramolecular ketal exchange reaction, affording the
trioxane 815 in 84% yield. These two steps could be also
(11) Dussault, P. H.; Trullinger, T. K.; Noor-e-Ain, F. Org. Lett.
2002, 4, 4591–4593.
(12) A white powder (mp >200 °C) insoluble in water and many
common organic solvents (such as acetone, CHCl3, CH3CN, THF,
Et2O, DMSO, DMF), with the elemental analysis data (C, H, N, Mo)
fit to the formula of HO2CCH2NH2 HOMo(O2)OMo(O3) 2H2O. Cf.
3
3
also the Supporting Information.
(13) For an optically active C-6 Me analogue (prepared using ozone
to introduce the peroxy band), see ref 5g.
The epoxide 6 can be accessed from, among other pos-
sible alternatives, the known4e aldehyde 10 (Scheme 3, with
4214
Org. Lett., Vol. 13, No. 16, 2011

the relative configuration secured by X-ray crystallographic
analysis of the corresponding ketone 14), which in turn is
readily attainable4e from qinghao acid (artemisinic/arteanuic
acid, 11, which was also the common starting material for
all those singlet oxygen based semisyntheses4), a natural
product present17 in the herb qinghao in significantly
higher contents than QHS and now also accessible18 by
fermentation.19
been realized in a stereoselective manner with remarkable
ease. Such a facile installation of a hydroperoxyl function-
ality onto the C-12a position of the precursor makes it
possible for the first time to construct QHS without re-
course to singlet oxygen (or the like) and thus introduces a
brand-new approach to the synthesis of this important
natural antimalarial agent. Although the present route by
no means is perfect already, the simplicity (i.e., no needs
for special equipments and/or facilities and complicated
operations), facileness, and reproducibility associated with
the key perhydrolysis should provide a useful complement
to the existing methodologies for introducing the peroxy
functionality in QHS and hopefully may facilitate the even-
tualappearance of a large-scale practical synthesis of QHS.
Finally, the knowledge gained from this work may help to
develop a range of trioxanes simpler than but still closely
related to QHS as potential antimalarials.
In summary, with the aid of a novel yet readily prepared
molybdenum species, perhydrolysis of a highly hindered
epoxide specially designed for the synthesis of QHS has
(14) The crystallographic data have been deposited to the Cambridge
Crystallographic Data Center, 12 Union Road, Cambridge CB2 1EZ, U.
K.; e-mail: deposit@ccdc.cam.ac.uk, with the identifying number for
ketone 3c and 14 (the ketone related to ketal 10) being CCDC 823527
and CCDC 823526, respectively. The ORTEP plots are given in the
Supporting Information.
(15) This compound has been obtained previously by sequential
h (methanolysis),
treatment with BF3ÀEt2O/MeOH/PhH/reflux/6
LiAlH4/ Et2O/0 °C/1 h (reduction of aldehyde and ester groups) and
BF3ÀEt2O/ CH2Cl2/0 °C/24 h (ketalization). See: Singh, C.; Chaudhary,
S.; Kanchan, R.; Puri, S. K. Org. Lett. 2007, 9, 4327–4329.
(16) (a) Concepcion, J. I.; Francisco, C, G.; Hernandez, R.; Salazar,
J, A.; Suarez, E. Tetrahedron Lett. 1984, 25, 1953–1956. (b) For a review,
see: Sperry, J.; Liu, Y.-C.; Brimble, M. A. Org. Biomol. Chem. 2010, 8,
29–38.
Acknowledgment. This work was supported by the Na-
tional Basic ResearchProgram ofChina (the 973 Program,
2010CB833200), the National Natural Science Founda-
tion of China (21032002, 20921091, 20672129, 20621062,
20772143), and the Chinese Academy of Sciences (KJCX2.
YW.H08).
(17) The herb qinghao that grows in the northern areas also contains
11.
(18) (a) Martin, V. J. J.; Pitera, D. J.; Withers, S. T.; Newman, J. D.;
Keasling, J. D. Nat. Biotechnol. 2003, 21, 796–802. (b) Ro, D.-K.;
Paradise, E. M.; Ouellet, M.; Fisher, K. J.; Newman, K. L.; Ndungu,
J. M.; Ho, K. A.; Eachus1, 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.
Supporting Information Available. Experimental pro-
cedures and spectral data, 1H and 13C NMR spectra for 6,
7, 8, 9, 10, 12, 13, and 1, cif files for 3c and 14. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(19) It should be mentioned that the route in Scheme 3 is only meant
to show a possible access to this perhydrolysis substrate.
Org. Lett., Vol. 13, No. 16, 2011
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