Design and de Novo Synthesis of 6-Aza-artemisinins

Article abstract of DOI:10.1021/acs.orglett.8b01987

Development of designer natural product variants, 6-aza-artemisinins, enabled us to achieve structural modification of the hitherto unexplored cyclohexane moiety of artemisinin and concise de novo synthesis of the tetracyclic scaffold in just four steps f

Full text of DOI:10.1021/acs.orglett.8b01987

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Design and De Novo Synthesis of 6‑Aza-artemisinins
†
‡
‡
‡
§
‡
Karunakar Reddy Bonepally, Takahisa Hiruma, Haruki Mizoguchi, Kyohei Ochiai, Shun Suzuki,
Hideaki Oikawa,‡ Aki Ishiyama, Rei Hokari, Masato Iwatsuki, Kazuhiko Otoguro, Satoshi Omura,§
§
§
§
̅
,†
and Hiroki Oguri*
†Division of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology, 2-24-16
Nakacho, Koganei, Tokyo 184-8588, Japan
‡
Division of Chemistry, Graduate School of Science, Hokkaido University, North 10 West 8, Kita-ku, Sapporo 060-0810, Japan
§
Research Center for Tropical Diseases, Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo
1
08-8641, Japan
*
S Supporting Information
ABSTRACT: Development of designer natural product variants,
-aza-artemisinins, enabled us to achieve structural modification of
6
the hitherto unexplored cyclohexane moiety of artemisinin and
concise de novo synthesis of the tetracyclic scaffold in just four steps
from the modular assembly of three simple building blocks. This
expeditious catalytic asymmetric synthetic approach generated lead
candidates exhibiting superior in vivo antimalarial activities to
artemisinin.
rtemisinin-based combination therapies (ACTs) have
been consistently successful in reducing the malaria
burden in tropical and subtropical regions. Artemisinin (1), a
have been developed for designing more accessible analogues
with simplified structures.
8
A
Semisynthetic approaches for generating artemisinin de-
rivatives mostly relies on the chemical modification of the
lactone moiety (D-ring) of 1 to produce artesunate (3) and
sesquiterpene lactone bearing an unusual peroxide bridge, is
1
found in Artemisia annua (Figure 1). The therapeutic
9
10
other variants, including 11-aza-analogues exemplified as 5
Figure 1). Due to the absence of functional groups except for
(
the lactone, structural diversification of the other regions,
especially for the cyclohexane ring (C-ring), remains largely
untouched through exploitation of natural products and
11
fermentation-derived substances. In order to achieve the
structural modification of the hitherto unexplored region as
well as concise access to the antimalarial tetracyclic scaffold,
herein, we report the design and concise de novo synthesis of 6-
aza-artemisinins (Figure 2). Installation of nitrogen into the
cyclohexane ring could make a drastic change in the
retrosynthetic disconnections for the concise asymmetric
synthesis. This approach could gain rapid access to a series
of 6-aza-artemisinins with generation of substitutional
variations on the nitrogen.
Figure 1. Artificial synthesis of artemisinins and structure of a fully
synthetic analogue.
We designed 6-aza-artemisinins by replacing a stereogenic
3
sp carbon center at the C6 position of 1 with a nitrogen
(
Figure 2). Installation of the nitrogen could not only allow
deep-seated structural modifications of the cyclohexane ring
but also pave a new path for the modular synthesis. By
exploiting the versatile reactivities of the nitrogen, we
conceived a disconnection into three simple building blocks,
amine, aldehyde, and alkyne. Catalytic asymmetric assembly of
the three components could gain direct access to the chiral
efficacies of 1, coupled with its unusual structure, have
2
prompted chemists to accomplish pioneering total syntheses.
Avery developed a flexible synthetic approach and conducted
3
structure−activity relationship studies, and Cook reported a
4
highly concise synthesis of 1. Recently, the engineered
biosynthesis of artemisinic acid (2) and subsequent chemical
5
,6
conversions allowed artificial synthesis of 1. In addition, fully7
Received: June 25, 2018
synthetic antimalarial peroxides represented by OZ439 (4)
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01987
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Catalytic Asymmetric Synthesis of Tetracyclic
Scaffold 16 in Four Steps from Three Building Blocks
Figure 2. Outline for catalytic asymmetric synthesis of 6-aza-
artemisinins.
ene-yne 7, which possesses all of the framework carbon and
nitrogen atoms of the 6-aza-artemisinins. Next, the precursor 8,
composed of a piperidine ring with a (Z)-vinyl silane moiety
and two contiguous stereogenic centers, would be forged
through diastereo-controlled cyclization of 7 via the metal-
lacyclic intermediate I, followed by protonation. Protecting
group manipulations of 8, installation of peroxide, and cyclic
acetal formations could assemble the tetracyclic scaffold of 6-
aza-artemisinins.
1
5
provided optimal results. Treatment of 13a with “Ti(Oi-
Pr) ”, generated in situ at low temperature in diisopropyl ether,
2
effected the intended cyclization, presumably via metallacyclic
intermediate I (Figure 2) as the temperature was gradually
increased (−78 °C → −20 °C). Subsequent protonation of the
intermediate furnished the desired 14 in 33% yield as the
major product. The relative configurations of crystalline 14
were unambiguously elucidated based on X-ray analysis
(Supporting Information (SI), Figure S2). Thus, Ti(II)-
mediated cyclization of 13a leading to 14 allowed direct
installation of consecutive stereogenic centers (C8 and C9) in
a highly diastereo-controlled manner, despite the modest yield.
The tetracyclic scaffold 16 composed of the trioxane moiety
was then constructed employing a sequential one-pot protocol
The amine building blocks 10a/10b and the aldehyde 12
1
2
were synthesized from the known sulfonamide 9 and
commercially available ethyl levulinate (11), respectively
(Scheme 1).
Scheme 1. Synthesis of Building Blocks
(
Scheme 2). First, treatment of 14 with trifluoroacetic acid
effected removal of the protecting groups and formation of an
ammonium salt (II). Since temporary protection of the amine
was assumed to be required for the subsequent oxidative
conditions, the resulting II was directly subjected to ozonolysis
3
a
using conditions modified from Avery’s protocol. To
minimize the allylic strain of the vinyl silane 14, the substrate
may adopt the conformation (II), and [3 + 2] dipolar
cycloaddition of ozone occurred predominantly at the less-
hindered α-face to generate molozonide (III). Spontaneous
migration of the silyl group allowed simultaneous installation
of aldehyde and trimethylsilyl peroxide (IV). Upon additional
treatment with trifluoroacetic acid, tandem formation of two
cyclic acetals furnished the trioxane 16 in 29% yield from 14.
Accordingly, this approach allowed streamlined access to the
tetracyclic array of 6-aza-artemisinins in a sequence of just four
steps starting from modular assembly of the three building
blocks.
To improve the yield of Ti(II)-mediated cyclization, we
employed the less sterically demanding substrate 13b without
the C9 methyl group to form 17 (Scheme 3). Cu(I)-catalyzed
three-component assembly employing 10b in place of 10a
afforded 13b (94% ee) in 85% yield. Subsequent Ti(II)-
mediated cyclization of 13b proceeded smoothly to produce
the desired 17 in 61% yield along with the C8 epimer (7%
yield). We thus substantially improved the cyclization process
to form 17, relative to the corresponding conversion of the C9-
A four-step synthesis of the tetracyclic scaffold of 6-aza-
artemisinins commenced with Cu-catalyzed condensation of
the three building blocks, 10a, 12, and trimethylsilylacetylene
(
Scheme 2). To establish a catalytic asymmetric synthetic
route, we adopted Carreira’s chiral catalyst CuBr/(R,M)-
13
PINAP for Cu(I)-mediated assembly. Under the optimized
conditions employing only 1 mol % of the chiral catalyst, the
three-component condensation proceeded smoothly at room
temperature to give the ene-yne 13a in 92% yield with
excellent enantioselectivity (93% ee). The use of dimethyl
carbonate as a solvent in the presence of 4 Å molecular sieves
14
was critical for smooth catalytic conversion to furnish 13a.
Next, we explored diastereo-controlled formation of the
piperidine 14, with a syn-stereochemical relationship between
C5 and C8, as well as a 9R-methyl group (Scheme 2). Low-
valent titanium(II)-mediated cyclization of the ene-yne
B
DOI: 10.1021/acs.orglett.8b01987
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Synthesis and Installation of a Substituent of 6-
Aza-artemisinins
substituent at the stereogenic C6 position of 1. Similar
reductive amination of 20/21 with aldehydes provided three
derivatives (23−25) in good yields (>75%). The absolute
configurations of the 6-aza-artemisinins were elucidated based
on X-ray analysis of 27 prepared via acylation with p-
bromobenzoyl chloride (Scheme 3). Thus, several substituents
were installed on the nitrogen at the latest stage of the
synthesis.
In vivo antimalarial activities of 6-aza-artemisinins were
evaluated by Peter’s four-day suppressive test employing a
mouse model infected with rodent malaria P. berghei N strain
(
Figure 3 and SI, Table S2). Although the highly potent in vitro
Figure 3. In vivo antimalarial therapeutic effects of 6-aza-artemisinins
using the P. berghei rodent malaria model. Activities resulting in
average parasitemia reduction were evaluated upon intraperitoneal
administration [dosage 15 mg/kg, once a day for 4 days].
activities made it difficult to prioritize the lead candidates
among the 6-aza-artemisinins (SI, Table S1), the results of
preliminary in vivo experiments produced discernible differ-
ences between selected compounds. Intraperitoneal admin-
istration of 6 bearing N-methyl and C9-methyl groups (dosage
15 mg/kg, once a day for 4 days) exhibited limited efficacy in
parasite clearance under the assay conditions, despite the high
activity in vitro (IC50 = 32 nM for P. falciparum K1 strain, SI,
Table S1). N-Benzylated 23 without the C9 methyl group
showed potent activity (51.5%) greater than that of artemisinin
(1) (23.5%), confirming the significance of the N6 arylalkyl
substituents. More importantly, 24 bearing the N-benzyl and
the C9 methyl group exhibited almost identical or even
superior in vivo therapeutic activity (98.6%) to that of the first-
line drug artesunate (3, 95.5%). The analogues 16 and 25
having either a methoxy or 2-morpholinoethoxy substituent on
the para-position of the benzene ring also exerted potent
inhibitory activities, 82.9% and 69.1%, respectively.
methylated 13a into 14 (33% yield). Alkylation of 17 with
methyl iodide afforded an easily separable 1:1 mixture of
diastereomers 14 and 15 in 94% yield. C9 epimerization of 15
was feasible to give 14 in 81% yield with the recovery of 15
(
17%). This protocol provides a high-yielding alternative route
to the precursor 14 and also enables us to access the C9
epimeric precursor. The resulting precursors 17 and 15 were
subjected to the one-pot conversions to generate 6-aza-
artemisinins: 18 without the C9 methyl group and 19 having
the 9S-methyl group, respectively. The C9 methyl substituent
and its stereochemistry had considerable impacts on the yields
of the trioxane formation. Conversion of the C9-desmethylated
1
7 led to a significant improvement, providing 18 in 49% yield,
compared to the transformation of 14 into 16 (29% yield).
We further performed oral administration of the optimum 6-
aza-artemisinin 24 (SI, Table S3 and Figure S1). Oral
treatment of 24 (dosage 30 mg/kg, once a day for 4 days)
exhibited a potent therapeutic efficacy (95.6%), which is
superior to artemisinin (1, 74.5%) and comparable to
Meanwhile, the corresponding conversion with the C9 epimer
1
5 produced 19 in 7% yield.
With the tetracyclic scaffold 16 in hand, we then modified
the substituent on the nitrogen (Scheme 3). Removal of the p-
methoxy benzyl group in 16 with DDQ liberated the secondary
amine 21. Reductive amination of 21 with formaldehyde gave
rise to 6-aza-artemisinin (6). X-ray analysis of crystalline 6
confirmed the relative configuration of the 6-aza-artemisinins
16
artesunate (3, 97.7%). Thus, we have generated 6-aza-
artemisinins as lead candidates for next-generation artemisinin-
based malaria chemotherapy. Modifications at the C6 position
were demonstrated to have drastic impacts on the antimalarial
activities.
(Scheme 3). Notably, the three-dimensional structure of 6, in
which the N6 methyl group adopts a pseudoequatorial
conformation, is essentially identical to that of 1. Thus, this
approach is capable of accurate emulation of the methyl
In summary, we have designed 6-aza-artemisinins and
developed a catalytic asymmetric synthetic process in just
four steps initiated by the modular assembly of three simple
C
DOI: 10.1021/acs.orglett.8b01987
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
building blocks. This de novo synthetic approach led to the
discovery of a novel scaffold bearing the N-arylalkyl group
generated by the element substitution at the cyclohexane
moiety of 1. We demonstrated that installation of a relatively
large substituent at N6 is acceptable and sometimes intensifies
the activities, which allowed generation of lead candidates
exerting the very potent in vivo antimalarial efficacy greater
than artemisinin (1) and comparable to the first-line
semisynthetic drug artesunate (3). These results underlie the
promising, but still untapped, potential of 6-aza-artemisinins
with manipulatable physical and pharmacological properties.
The next challenge will be the generation of chemical probes
Asian CORE Program, “Asian Chemical Biology Initiative”,
and JSPS A3 Foresight Program.
REFERENCES
■
(1) (a) Enserink, M. Science 2005, 307, 33. (b) White, N. J. Science
2008, 320, 330.
(2) (a) Schmid, G.; Hofheinz, W. J. Am. Chem. Soc. 1983, 105, 624.
b) Ravindranathan, T.; Kumar, M. A.; Menon, R. B.; Hiremath, S. V.
(
Tetrahedron Lett. 1990, 31, 755. (c) Liu, H. J.; Yeh, W. L.; Chew, S. Y.
Tetrahedron Lett. 1993, 34, 4435. (d) Zhou, W.-S.; Xu, X.-X. Acc.
Chem. Res. 1994, 27, 211. (e) Constantino, M. G.; Beltrame, M., Jr; da
Silva, G. V. J.; Zukerman-Schpector, J. Synth. Commun. 1996, 26, 321.
(
2
f) Yadav, J. S.; Thirupathaiah, B.; Srihari, P. Tetrahedron 2010, 66,
005.
3) (a) Avery, M. A.; Chong, W. K. M.; Jennings-White, C. J. Am.
17
for chemical proteomics studies and hybrid molecules to
18
cope with emerging artemisinin-resistant parasites. The
simple molecular design strategy featuring element substitution
of a skeletal carbon center is expected to be generally
(
Chem. Soc. 1992, 114, 974. (b) Avery, M. A.; Gao, F.; Chong, W. K.
M.; Mehrotra, S.; Milhous, W. K. J. Med. Chem. 1993, 36, 4264.
(c) Avery, M. A.; Muraleedharan, K. M.; Desai, P. V.;
Bandyopadhyaya, A. K.; Furtado, M. M.; Tekwani, B. L. J. Med.
Chem. 2003, 46, 4244 and references cited therein.
19
applicable to other intricate scaffolds, which could facilitate
the development of streamlined and versatile chemical
platforms generating natural-product-inspired molecules with-
out substantial structural simplification.
(
(
4) Zhu, C.; Cook, S. P. J. Am. Chem. Soc. 2012, 134, 13577.
5) Paddon, C. J.; Westfall, P. J.; Pitera, D. J.; Benjamin, K.; Fisher,
K.; McPhee, D.; Leavell, M. D.; Tai, A.; Main, A.; Eng, D.; Polichuk,
D. R.; Teoh, K. H.; Reed, D. W.; Treynor, T.; Lenihan, J.; Jiang, H.;
Fleck, M.; Bajad, S.; Dang, G.; Dengrove, D.; Diola, D.; Dorin, G.;
Ellens, K. W.; Fickes, S.; Galazzo, J.; Gaucher, S. P.; Geistlinger, T.;
Henry, R.; Hepp, M.; Horning, T.; Iqbal, T.; Kizer, L.; Lieu, B.; Melis,
D.; Moss, N.; Regentin, R.; Secrest, S.; Tsuruta, H.; Vazquez, R.;
Westblade, L. F.; Xu, L.; Yu, M.; Zhang, Y.; Zhao, L.; Lievense, J.;
Covello, P. S.; Keasling, J. D.; Reiling, K. K.; Renninger, N. S.;
Newman, J. D. Nature 2013, 496, 528.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01987.
Full experimental procedures, NMR spectra, chiral
HPLC analysis, and ORTEP diagrams (PDF)
(
6) (a) Acton, N.; Roth, R. J. J. Org. Chem. 1992, 57, 3610.
b) Levesque, F.; Seeberger, P. H. Angew. Chem., Int. Ed. 2012, 51,
1706. (c) Kopetzki, D.; Levesque, F.; Seeberger, P. H. Chem. - Eur. J.
013, 19, 5450. (d) Turconi, J.; Griolet, F.; Guevel, R.; Oddon, G.;
Villa, R.; Geatti, A.; Hvala, M.; Rossen, K.; Goller, R.; Burgard, A. Org.
Accession Codes
(
́
CCDC 1510941, 1511018, and 1511023 contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
́
2
̈
Process Res. Dev. 2014, 18, 417. (e) Amara, Z.; Bellamy, J. F. B.;
Horvath, R.; Miller, S. J.; Beeby, A.; Burgard, A.; Rossen, K.; Poliakoff,
M.; George, M. W. Nat. Chem. 2015, 7, 489.
(7) Charman, S. A.; Arbe-Barnes, S.; Bathurst, I. C.; Brun, R.;
1
223 336033.
Campbell, M.; Charman, W.; Chiu, F. C. K.; Chollet, J.; Craft, J. C.;
Creek, D. J.; Dong, Y.; Matile, H.; Maurer, M.; Morizzi, J.; Nguyen,
T.; Papastogiannidis, P.; Scheurer, C.; Shackleford, D. M.;
Sriraghavan, K.; Stingelin, L.; Tang, Y.; Urwyler, H.; Wang, X.;
White, K. L.; Wittlin, S.; Zhou, L.; Vennerstrom, J. L. Proc. Natl. Acad.
Sci. U. S. A. 2011, 108, 4400.
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: h_oguri@cc.tuat.ac.jp.
ORCID
(8) (a) 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.; Santo, T. J.; Scheurer,
C.; Scorneaux, B.; Tang, Y.; Urwyler, H.; Wittlin, S.; Charman, W. N.
Nature 2004, 430, 900. (b) O’Neill, P. M.; Amewu, R. K.; Nixon, G.
L.; Bousejra ElGarah, F.; Mungthin, M.; Chadwick, J.; Shone, A. E.;
Vivas, L.; Lander, H.; Barton, V.; Muangnoicharoen, S.; Bray, P. G.;
Davies, J.; Park, B. K.; Wittlin, S.; Brun, R.; Preschel, M.; Zhang, K.;
Ward, S. A. Angew. Chem., Int. Ed. 2010, 49, 5693. (c) Oguri, H.;
Hiruma, T.; Yamagishi, Y.; Oikawa, H.; Ishiyama, A.; Otoguro, K.;
Yamada, H.; Omura, S. J. J. Am. Chem. Soc. 2011, 133, 7096.
Hideaki Oikawa: 0000-0002-6947-3397
Hiroki Oguri: 0000-0001-8007-1631
Notes
The authors declare the following competing financial
interest(s): A patent application on antimalarial 6-aza-
artemisinins has been filed by Tokyo University of Agriculture
&
Technology and Kitasato University.
ACKNOWLEDGMENTS
■
(9) For selected reviews, see: (a) O’Neill, P. M.; Posner, G. H. J.
Med. Chem. 2004, 47, 2945. (b) Chaturvedi, D.; Goswami, A.; Pratim
Saikia, P.; Barua, N. C.; Rao, P. G. Chem. Soc. Rev. 2010, 39, 435.
The authors thank Drs. Timothy N. C. Wells, Jeremy Burrows,
and Didier Leroy of Medicines for Malaria Venture (MMV)
for their invaluable advice and continuous support. The
authors thank Mr. Takashi Matsumoto (Rigaku) and Mr. Ryo
Watanabe (Hokkaido Univ.) for X-ray analysis. This work was
supported in part by the GHIT fund HTLP RFP (2014-001),
JSPS KAKENHI Grant Numbers JP23310156, JP26102702,
and JP16H01135, the Naito Foundation, and the Uehara
Memorial Foundation. This work was inspired by the
international and interdisciplinary environments of the JSPS
(
2
c) Slack, R. D.; Jacobine, A. M.; Posner, G. H. MedChemComm
012, 3, 281.
10) (a) Avery, M. A.; Bonk, J. D.; Chong, W. K. M.; Mehrotra, S.;
(
Miller, R.; Milhous, W.; Goins, D. K.; Venkatesan, S.; Wyandt, C. J.
Med. Chem. 1995, 38, 5038. (b) Torok, D. S.; Ziffer, H.; Meshnick, S.
R.; Pan, X.-Q.; Ager, A. J. Med. Chem. 1995, 38, 5045. (c) Mekonnen,
B.; Weiss, E.; Katz, E.; Ma, J.; Ziffer, H.; Kyle, D. E. Bioorg. Med.
Chem. 2000, 8, 1111. (d) Al-Oqail, M. M.; Galal, A. M.; Ahmad, M.
S.; Al-Fishawi, A. M.; El-Feraly, F. S. Molecules 2003, 8, 901.
D
DOI: 10.1021/acs.orglett.8b01987
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
e) Haynes, R. K.; Wong, H.-N.; Lee, K.-W.; Lung, C.-M.; Shek, L. Y.;
Williams, I. D.; Croft, S. L.; Vivas, L.; Rattray, L.; Stewart, L.; Wong,
V. K. W.; Ko, B. C. B. ChemMedChem 2007, 2, 1464. (f) Singh, A. S.;
Verma, V. P.; Hassam, M.; Krishna, N. N.; Puri, S. K.; Singh, C. Org.
Lett. 2008, 10, 5461. (g) Nguyen Le, T.; De Borggraeve, W. M.;
Grellier, P.; Pham, V. C.; Dehaen, W.; Nguyen, V. H. Tetrahedron
Lett. 2014, 55, 4892. (h) Singh, C.; Verma, V. P.; Hassam, M.; Singh,
A. S.; Naikade, N. K.; Puri, S. K. J. Med. Chem. 2014, 57, 2489.
(
i) Harmse, R.; Wong, H. N.; Smit, F.; Haynes, R. K.; N’Da, D. D.
Curr. Med. Chem. 2015, 22, 3607.
11) (a) Gormisky, P. E.; White, M. C. J. Am. Chem. Soc. 2013, 135,
4052. (b) Zhang, X.; Yang, H.; Tang, P. Org. Lett. 2015, 17, 5828.
12) Kurosawa, W.; Kan, T.; Fukuyama, T. Org. Synth. 2002, 79,
86.
13) Kno
Carreira, E. M. Angew. Chem., Int. Ed. 2004, 43, 5971.
14) The catalytic asymmetric condensation employing toluene as
(
1
(
1
(
̈
pfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.;
(
13
solvent resulted in sluggish reaction. Solvents such as dichloro-
methane or 1,2-dimethoxyethane were suitable for this condensation
attaining high enantioselectivities (>90% ee) but provided 13 with
slightly lower yields compared to the optimum solvent, dimethyl
carbonate.
(
1
(
15) Urabe, H.; Suzuki, K.; Sato, F. J. Am. Chem. Soc. 1997, 119,
0014.
16) Based on comparison of the P values for the oral administration
between artemisinin (1) and 6-aza-artemisinin (24), 24 exhibited
potent therapeutic efficacies greater than that of 1 (P = 0.0245) on
day 4. Comparison between 24 and artesunate (3) showed no
significant difference.
(17) (a) Eckstein-Ludwig, U.; Webb, R. J.; van Goethem, I. D. A.;
East, J. M.; Lee, A. G.; Kimura, M.; O’Neill, P. M.; Bray, P. G.; Ward,
S. A.; Krishna, S. Nature 2003, 424, 957. (b) Wang, J.; Zhang, C. J.;
Chia, W. N.; Loh, C. C. Y.; Li, Z. J.; Lee, Y. M.; He, Y. K.; Yuan, L. X.;
Lim, M. T. K.; Liu, C.; Liew, X.; Lee, Y. Q.; Zhang, J. B.; Lu, N. C.;
Lim, C. T.; Hua, Z. C.; Liu, B.; Shen, H. M.; Tan, K. S. W.; Lin, Q. S.
Nat. Commun. 2015, 6, 10111.
(
18) (a) Straimer, J.; Gnadig, N. F.; Witkowski, B.; Amaratunga, C.;
̈
Duru, V.; Ramadani, A. P.; Dacheux, M.; Khim, N.; Zhang, L.; Lam,
S.; Gregory, P. D.; Urnov, F. D.; Mercereau-Puijalon, O.; Benoit-
Vical, F.; Fairhurst, R. M.; Men
47, 428. (b) Mbengue, A.; Bhattacharjee, S.; Pandharkar, T.; Liu, H.;
́
ard, D.; Fidock, D. A. Science 2015,
3
Estiu, G.; Stahelin, R. V.; Rizk, S. S.; Njimoh, D. L.; Ryan, Y.;
Chotivanich, K.; Nguon, C.; Ghorbal, M.; Lopez-Rubio, J.-J.;
Pfrender, M.; Emrich, S.; Mohandas, N.; Dondorp, A. M.; Wiest,
O.; Haldar, K. Nature 2015, 520, 683.
(19) Bebbington, M. W. P. Chem. Soc. Rev. 2017, 46, 5059.
E
DOI: 10.1021/acs.orglett.8b01987
Org. Lett. XXXX, XXX, XXX−XXX