Synthesis and study of the antimalarial cardamom peroxide

Article abstract of DOI:10.1016/j.tet.2018.03.045

A full account of our previously disclosed synthesis of the monoterpene dimer cardamom peroxide is reported. Inspired by hypotheses regarding the potential biosynthetic origins of this natural product, several unproductive routes are also reported. The ch

Full text of DOI:10.1016/j.tet.2018.03.045

Accepted Manuscript
Synthesis and study of the antimalarial cardamom peroxide
Xirui Hu, Pharath Lim, Rick M. Fairhurst, Thomas J. Maimone
PII:
S0040-4020(18)30310-7
10.1016/j.tet.2018.03.045
TET 29385
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 4 February 2018
Revised Date: 15 March 2018
Accepted Date: 20 March 2018
Please cite this article as: Hu X, Lim P, Fairhurst RM, Maimone TJ, Synthesis and study of the
antimalarial cardamom peroxide, Tetrahedron (2018), doi: 10.1016/j.tet.2018.03.045.
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Graphical Abstract
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Synthesis and Study of the Antimalarial
Cardamom Peroxide
Xirui Hu, Pharath Lim, Rick M. Fairhurst, and Thomas J. Maimone*

1
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Tetrahedron
journal homepage: www.elsevier.com
Synthesis and Study of the Antimalarial Cardamom Peroxide
Xirui Hu,a Pharath Lim,b,c,d Rick M. Fairhurst,b and Thomas J. Maimonea*
aDepartment of Chemistry, University of California–Berkeley, Berkeley, CA 94720 (USA)
bLaboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD (USA)
cNational Center for Parasitology, Entomology, and Malaria Control, Phnom Penh, Cambodia
dcurrent address: Medical Care Development International, Silver Spring, MD (USA)
ABSTRACT
ARTICLE INFO
Article history:
Received
Received in revised form
Accepted
A full account of our previously disclosed synthesis of the monoterpene dimer cardamom
peroxide is reported. Inspired by hypotheses regarding the potential biosynthetic origins of this
natural product, several unproductive routes are also reported. The chemical reactivity of this
structurally unique metabolite in the presence of iron(II) sources is also reported as is its
antimalarial activity against Plasmodium falciparum clinical isolates from several Cambodian
provinces.
Available online
Keywords:
malaria
2009 Elsevier Ltd. All rights reserved
.
endoperoxide
total synthesis
natural product
1. Introduction
Malaria,
a parasitic disease transmitted by Anopheles
mosquitoes, is prevalent in over 99 countries. More than 3 billion
people are at risk of acquiring this disease worldwide, and an
estimated 445,000 deaths occurred as a result of malaria in 2016.1
Among the five known Plasmodium parasites that cause malaria
in humans, Plasmodium falciparum is associated with the
greatest mortality. Humanity’s fight against malaria dates back to
the 1600s, when Peruvian Indians were observed chewing on
Cinchona bark to stop shivering.2 The Cinchona bark, from
which the early antimalarial drug quinine was isolated, was
introduced into Europe as a treatment for malaria in the early
17th century.3 Driven by the needs of the military and the
colonial powers, antimalarial drug development grew rapidly in
the 20th century. Due to this demand, chloroquine was developed
in 1934 and quickly became the front-line antimalarial drug after
approval in 1946; however, a development of chloroquine
resistance in parasites was observed.4 Sulfadoxine-
pyrimethamine (SP), a combination of antifolates, served briefly
as the successor of chloroquine, but widespread resistance to this
substance also emerged after a period of only 5 years. In 1972,
Tu and coworkers discovered the terpenoid peroxide artemisinin
(2) from the leaves of Artemisia annua,5 a plant used for at least
2000 years for the treatment of fever by Chinese herbal medicine
practitioners. Since then, artemisinin derivatives and artemisinin
combination therapies (ACTs) have served as the front-line
treatment for uncomplicated and severe P. falciparum infections.
In the past decade however, continually growing reports detailing
resistance
Figure 1. Antimalarials containing an oxygen-oxygen bond. A)
selected endoperoxide-containing natural products. B) fully
synthetic molecules inspired by natural products.

2
Tetrahedron
Thus it was our belief that enzymatic assistance would not be
ACCEPTED MANUSCRIPT
needed to dictate the sterochemical course of this reaction. Given
that various monterpenes were isolated alongside 1, and the
observation that the peroxide-forming step in the biosynthesis of
2 is non-enzymatic give credence to these ideas.12, 14 Nevertheless
literature precedent suggested that the 7-endo cyclization would
be challenging and we were congnizant that Mayrargue and
coworkers could not forge the 1,2-dioxepane unit (see 7) from
pinene-derived model peroxide 6 via a radical cyclization that
was competent in forging 1,2-dioxolane and 1,2-dioxane
structures (Figure 2B).15
2. Results and Discussion
2.1. First generation attempt towards the synthesis of (+)-
cardamom peroxide
Initial forays into the construction of the cardamom peroxide
began with attempts to construct dimeric pinane-derived diketone
5 from the terpene chiral pool (Scheme 1).16 A Stetter-type
coupling between enone 9, prepared from pinene via intermediate
peroxide 8,17 and (–)-myrtenal proved unsuccessful under the
mediation of thiazolium salt 10 and base. Also examined, but
found to be unworkable, were the coupling of 9 and (–)-myrtenal
either by Rh-catalyzed hydroacylation or SmI2-mediated
reductive coupling (Scheme 1A).18,19 While bromopinene 11
could be dimerized under reductive, titanocene-mediated
conditions to give 12 (a plausible biogenetic precursor to 1),20
achieving the desired oxidation patterns found in 5 proved
challenging (Scheme 1B). Initial success in forging 5 was
eventually found via the pathway shown in Scheme 1C. First, a
Cu(I)-mediated addition of the Grignard reagent prepared from
11 to enone 9 delivered 1,4-addition product 13 in 48% yield and
as a single isomer after acidic work-up.21 Next, this material
underwent allylic oxidation using selenium dioxide to form an
allylic alcohol which was immediately oxidized with DMP.
While this route provided the first glimpse of 5, the very low
yield encountered in the SeO2 oxidation (12%, unoptimized) was
a bottleneck for material throughput.
Figure 2. Synthetic approaches to 1. A) initial retrosynthesis. B)
studies by Mayrargue and co-workers demonstrates the challenge
in forming the 1,2-dioxepane unit found in 1. (DBPO = Di-tert-
butyl peroxyoxalate)
to derivatives of 2 have surfaced, observations which severely
threaten global malaria control.6
Since the isolation of 2 in the 1970’s, a large number of
endoperoxide-containing natural products of both terpenoid and
polyketide origin have been discovered (Figure 1A).7 While far
from approaching the remarkable low nM potency of 2 and its
congeners, many of these compounds possess significant
antimalarial activity and have thus proven to be attractive targets
for chemical synthesis and the development of peroxidation
methodology.8,9 Moreover, these naturally occurring O–O bond-
containing molecules have also inspired the development of new
synthetic antimalarials such as the ozonide arterolane and the
endoperoxide arteflene which is based on the yingzhaosu A
scaffold (Figure 1B).10,11
Concurrent with these studies, however, we discovered a
superior route to 5 based on the chemistry shown in Scheme 1D.
We opted to immediately dimerize (–)-myrtenal under reductive
coupling conditions, a maneuver which produced triene 14 with
more appropriately placed “handles” for further synthetic
manipulation. While ultimately capable of providing gram
quantities of material, this transformation required significant
optimization under rigorously air- and moisture-free conditions
(Table 1). While reductive coupling methods based on
aluminum22 and chromium23 failed to produce triene 14 (entries 1
and 2), several titanium reagents were applicable to this coupling.
Conditions employing titanium powder as reductant produced a
small amount of 14 with a variety of inseparable non-polar side
products (entry 3).24 Employing stoichiometric quantities of
titanocene dichloride with added reducing agent successfully
produced 14 as a single isomer (entries 4 and 5); however the
catalytic version of this system failed to produce the desired
product (entry 6).25 The use of titanium tetrachloride, instead of
Cp2TiCl2/reductant, favorably improved the yield to 35% (entry
7).26 Synthetically useful yields (51% isolated) were obtained
when the classic McMurry coupling procedure [TiCl3, Zn-Cu
alloy] was employed (entry 8).27 This protocol also featured an
easier workup protocol without the need for cumbersome
removal of titanocene side products. However, due to the high
cost of titanium (III) trichloride, this protocol was not directly
applied in our synthesis, but slightly modified by using less
Cardamom peroxide (1), a structurally interesting terpene
endoperoxide was isolated in 1995 by Clardy and coworkers
from Amomum krevanh fruit (Siam cardamom) (Figure 1).12
Initial in vitro assays indicated that 1 exhibited strong inhibition
of P. falciparum (EC50 = 170 nM), a potency similar to the
synthetic antimalarial arteflene. Cardamom peroxide contains a
rare seven-membered endoperoxide motif (1,2-dioxepane) thus
making it an architecturally and biologically intriguing synthetic
target. This feature combined with interest over its possible
biosynthetic origins led us to target 1 for chemical synthesis. In
2014, we reported a 4-step synthesis of this natural product using
oxygen as the sole sources of all of the oxygen atoms.13 Herein
we provide a full account of our synthetic studies and further
antimalarial evaluation of 1 against P. falciparum clinical isolates
from several regions of Cambodia.
Retrosynthetically, we envisioned that 1 might be produced
first in nature as diperoxide 3 and then chemoselectively reduced
(Figure 2A). We viewed 3 as the result of a 7-endo-trig
cyclization of either a peroxy radical or peroxide precursor (see 4)
followed by oxygenation of the resulting α-keto radical or
enolate respectively. Enone 4 in turn could come from an air
oxidation process of diketone 5, which appears to be the product
of a pinane-type monoterpene dimerization. We suspected that
from 5, the ketone α-oxygenation event and the 7-endo
cyclization/oxygenation cascade would occur diastereoselectively
as a result of the steric constraints placed by the pinane units.

3
expensive titanium (IV) tetrachloride and higher equivalents of
ACCEPTED MANUSCRIPT
the
metal
Scheme 1. Synthesis of dimer 5 and failed conversion to 3. A) Unsuccessful Stetter approach to 5. B) Unproductive reductive coupling
strategy. C) Successful synthesis of 5. D) Improved synthesis of 5 and failed conversion to 3.
reductant (entry 9). Satisfyingly, the modified procedure offered
an improved yield (62%) on small scale, and could be
reproducibly performed on 3-gram scales in 53% yield. It should
be noted that 14 proved to be quite unstable, decomposing to
complex mixtures via both air oxidation as well as treatment with
mildly acidic CDCl3.
endo cyclization at a rate comparable to epoxide formation or
that the α-peroxidation occurs at the undesired carbonyl first and
then forms the epoxide.38 This former hypothesis is somewhat
corroborated by our later findings (see Figure 6), wherein we
suspect that protonated 4 favors the formation of a peroxy
hemiketal intermediate (see 25) instead of undergoing the 7-endo
cyclization. While ultimately unsuccessful, this work led us to
consider alternative ways of generating radical 4.
With 14 available in substantial quantities, efforts to install the
two oxygens found in 5 were initiated (Scheme 1D). A [4+2]
cycloaddition with singlet oxygen constructed endoperoxide 15,
thus desymmetrizing C2-symmetric dimer 14. Without isolation,
this material was subject to Kornblum-DeLaMare fragmentation
conditions (DBU) thus furnishing dienone 16.28,29 We envisioned
Table 1. (–)-Myrtenal reductive coupling: selected optimization.
that
a
redox-neutral isomerization consisting of
a
γ-
deprotonation/protonation sequence could forge 5 directly from
16.30 After examining a variety of conditions, some of which are
noted in Scheme 1D, we found that simply stirring 16 with DBU
in DCM cleanly-forged 5 within hours at room temperature. We
also noted that after three days of prolonged stirring, 5 converted
to a 3:1 mixture favoring diastereomer 17, wherein the side chain
has epimerized to relieve steric clash with the gem-dimethyl
group of the neighboring pinane ring. With sufficient amounts of
5 and 17 in hand, we were poised to investigate the proposed
tandem peroxidation cascade. Both isomers were then reacted
under standard conditions known to elicit ketone α-peroxidation
(t-BuOK, O2).31-37 Unfortunately, we were unable to isolate any
of diperoxide 3; the major product isolated under these
conditions was determined to be epoxide 18. These findings led
us to speculate that either anion 4 does not undergo an anionic 7-
Entries/Conditionsa
Yield %
1
2
3
4
5
6
AlCl3 (2 equiv), Zn (2 equiv), MeCN (0.1 M)
CrCl2 (4 equiv), HSiCl3 (5 equiv), THF (0.07 M)
Ti0 (30 equiv), TMSCl (30 equiv), DME (0.07 M)
Cp2TiCl2 (1.2 equiv), Mn (2.4 equiv), THF (0.1 M)
Cp2TiCl2 (1.2 equiv), Zn (2.4 equiv), THF (0.1 M)
0
0
<10b
17b
18b
0
Cp2TiCl2 (0.3 equiv), TMSCl (4 equiv), Mn (8
equiv), THF (0.1 M)
7
8
TiCl4 (1.2 equiv), Zn (2.4 equiv), THF (0.1 M)
TiCl3 (11 equiv), Zn-Cu (30 equiv), DME (0.01 M)
35b
51c,d

4
Tetrahedron
9
TiCl4 (10 equiv), Zn-Cu (40 equiv), DME (0.01 M)
62c,d,e
affored 53 % of 14 on a 3g scale. Cp = cyclopentadienyl, DME = 1,2-
ACCEPTED MANUSCRIPT
dimethoxyethane,
THF
=
tetrahydrofuran.
aReaction performed on a 0.1 g scale, conditions detailed in references unless
otherwise stated. bNMR yield, with dibromomethane as internal standard.
cIsolated yield. dMyrtenal was added in two portions over 24 h. eReaction
Scheme 2. Total synthesis of the cardamom peroxide. A) Successful radical-based oxygenation cascade. B) One-pot synthesis of 19
from 14.
2.2. Total synthesis of (+)-cardamom peroxide
catalytic amount of bis(dipivaloylmethanato)-manganese(II)
(Mn(dpm)2).43 In 2000, Magnus and coworkers further
investigated the manganese-catalyzed system, and extended the
substrate scope to α,β-unsaturated ketones44 and nitriles.45
Interestingly, 1,4-reduction of enones46 and reduction of
ketones47 were achieved under oxygen-free conditions with the
same catalyst/reductant combination. Similar conditions were
also recently extended to unactivated olefin reduction.48,49 In
addition, iron-catalyzed hydroperoxidation and hydrations have
been investigated by Kasuga50 and Boger,51,52 utilizing iron(II)
phthalocyanine [FeII(PC)] and iron(III) oxalate [Fe2(ox)3] in the
presence of a strong reductant and oxygen.
Our successful route to 3 (and ultimately 1) commenced with
previously prepared dienone alcohol 16 (Scheme 2A). Rather
than isomerize this material, we oxidized it to dienone 19 with
Dess-Martin periodinane. Alternatively, we also discovered a
one-pot method to construct this material from 14 wherein the
initial single oxygen [4+2] adduct (i.e. 15) was treated with
catalytic Co(II)-salen (20) according to Taylor’s conditions
(Scheme 2B).39 This induced single-electron reduction of the
endoperoxide, presumably generating radical 21 which undergoes
1,5-hydrogen atom abstraction to form ketone 22 and regenerate
the CoII complex. Enone 22 formed in this process, which is
isomeric to 16, could be oxidized in the same flask to directly
deliver 19 in 72% overall yield from 14.
As shown in Table 2, iron-based systems proved inneffective
for the conversion 19→1 (Entries 1-3). The combination of iron
oxalate and NaBH4 appeared unreactive to enone 19 (entry 1),
while conditions utilizing FeII(PC) and NaBH4 proved highly
With a sufficient amount of 19 in hand, extensive studies and
optimization were necessary to realize the tandem radical
hydroperoxidation reaction (19 → 3 or 1). We recognized that if
Table 2. Optimization of the tandem peroxidation reaction.
a
hydrogen atom transfer (HAT), or alternatively
a
hydrometallation/homolytic M–C cleavage event, occurred in a
regio- and chemoselective fashion onto 19, intermediate 4 could
be generated via diastereoselective reaction of an α-keto radical
with 3O2. This reaction requires the formal addition of the
hydrogen atom to occur at the more electron-deficient alkene, a
process we felt could be tuned via the metal-hydride generating
precursor.40 In addition, we felt the steric encombrance provided
by the neighboring pinane ring could dictate the regioselectivity
as well.
Entries/Conditionsa
Yield %
0
1
Fe2(ox)3•6H2O (5.0 equiv), NaBH4 (6.4 equiv),
EtOH/H2O, 0 ºC
2
3
4
5
6
7
FeII(Pc), NaBH4 (3.0 equiv), EtOH, 0 ºC
0
Fe(acac)3, PhSiH3 (2.5 equiv), EtOH, 0 ºC to rt
Co(acac)2, PhSiH3 (2.5 equiv), DCM/i-PrOH, -10 ºC to rt
Mn(dpm)3, PhSiH3 (2.5 equiv), DCM/i-PrOH, -10 ºC
Mn(dpm)3, PhSiH3 (2.5 equiv), DCM/i-PrOH, -10 ºC
0
Our initial screening of metal precatalysts for this tandem
peroxidation reaction began with several reported hydration/
hydroperoxidation conditions (Table 2). In a pioneering 1989
study, Mukaiyama and Isayama achieved hydroperoxidation and
hydration of electron-rich alkenes catalyzed by Co(acac)2 and
employing a mild silane reductant under an oxygen atmosphere.41
In this work the authors reported that electron-deficient olefins,
such as α,β-unsaturated esters, were not reactive to the cobalt-
catalyzed system. This limitation was successfully resolved later
by the same group in 1990,42 by replacing Co(acac)2 with a
6
34
41b
52b
Mn(dpm)3, PhSiH3 (2.5 equiv), t-BuOOH (1.5 equiv),
DCM/i-PrOH, -10 ºC
aReaction performed on a 0.1 mmol scale using 20 mol % of metal catalyst
unless otherwise stated. bPhSiH3 added slowly over 12 h as a solution in
DCM. Pc = Phthalocyanine, ox = oxalate, acac = acetylacetonate, dpm =

5
dipivaloylmethanato.
ACCEPTED MANUSCRIPT
reactive (entry 2). In the latter case, complete consumption of the
starting material was observed after 15 minutes, and a complex
mixture of products was obtained, among which the major
product was identified as the monoterpene derivative nopinone
(39%, GC yield). Under conditions employing Fe(acac)3 and
PhSiH3 (entry 3),53 bisenone 19 did not react at low temperature,
and therefore the reaction mixture was warmed to room
temperature. Complete consumption of starting material was
achieved after 16 hours; however 1 was not formed and
significant quantities of nopinone were again detected.
To our delight, 1 was isolated in the cobalt- and manganese-
catalyzed reactions after reductive workup in 6% and 34% yield,
respectively (entries 4 and 5, Table 2). This finding is in
accordance with the aforementioned superiority of manganese
catalysts for functionalizing electron-deficient olefins.44-47 We
next decided to evaluate other reaction parameters. It was
discovered that the product composition of this tandem reaction
was highly dependent on the concentration of oxygen relative to
reductant. Decreasing the ratio of reductant to oxygen by slow
addition of phenylsilane as a solution in dichloromethane over 12
h increased the yield of 1 to 41% with far fewer side-products
formed (entry 6). Addition of tert-butyl hydroperoxide (TBHP)
further increased the yield to 52% (entry 7), presumably due to
faster oxidation of the Mn(dpm)2 intermediate back to a
functional Mn(III) catalyst, a process that would consume
molecular oxygen otherwise. Under our optimized conditions
(entry 7), nopinone, hydration product 23, and diol 24 side
products were isolated in 9%, 11%, and 13% yields respectively.
Synthetic cardamom peroxide (1) synthesized from (−)-myrtenal
displayed [α]D = +123.2° (c = 0.005 g/mL. hexanes), which is in
performed the reaction 19→1 using stoichiometric amounts of
Mn(dpm)3 and Figure 3. Investigation into the formation of side-
products during the polyoxygenation cascade.
adding PhSiH3 in a single portion (Figure 3). Under these non-
catalytic conditions, 19 was consumed in less than ten minutes
and only a small amount of diperoxide 3 was detected. Notably, a
significant quantitiy of a mystery product tentatively assigned as
peroxyketal 25, which was both unstable and existed as a mixture
1
agreement with the reported value of [α]D
= +111.35°
of two diastereomers as determined by H NMR spectroscopy,
(concentration not reported). The absolute configuration of
synthetic 1 was unambiguously determined by X-ray analysis,
and is opposite to that previously speculated by Clardy and
coworkers.12 Taking the one-pot transformation of 14 to 19 into
account, the entire synthesis of 1 requires only three-steps.
was detected under these conditions. Upon addition of
triphenylphosphine to the crude reaction mixture, 25 and 3 were
consumed and hydration product 23 and 1 could be isolated in
yields of 40% and 9% respectively. Resubjecting the isolated
hydration product 23 to the reaction conditions gave diol 24 in
moderate yield and without the formation of nopinone. The same
maneuver was then employed on a rapidly isolated sample of 25
(as an isomeric mixture). In this case we detected substantial
amounts of nopinone, diol 24, and a variety of decompsition
products. We hypothesize that with sufficient molecular oxygen
in solution and a reduced concentration of silane, the proposed
2.3. Mechanistic studies of the tandem peroxidation reaction
Intrigued by the formation of nopinone and other byproducts
formed in our key tandem peroxidation reaction, we sought to
better understand the mechanisms by which these compounds
may be formed (Figures 3 and 4). In a key experiment, we
Figure 4. Potential mechanism for the polyoxygenation cascade.

6
Tetrahedron
ACCEPTED MANUSCRIPT
peroxyradical intermediate (see 4) is mainly funneled to
diperoxyradical 26 which is the precurosor to 3 (Figure 4). If,
however, 4 is reduced too quickly, peroxyketal 25 is generated,
thus triggering the formation of the downstream side-products
nopinone, 23, and 24, presumably via 27 and 29. The cleavage
pathway from 27 to nopinone may proceed by the well-
documented
β-hydroxy
hydroperoxide
fragmentation
reaction.54,55 If our hypothesis is correct, this pathway should also
produce peroxy ester 28 as a byproduct, a compound we have not
isolated to date. We have, however, observed small amounts
(~5%) of dione 3056 in reactions utilizing the Co(acac)2/PhSiH3
system, conditions which also produce nopinone (Table 2, entry
4). It is plausible this compound comes from reduction of 28 with
concomitant loss of acetic acid, a process likely driven by relief
of steric strain with the gem-dimethyl group of the pinane ring
system. While we have not isolated 30 from reactions employing
the Mn(dpm)3/PhSiH3 system, we found that subjecting isolated
30 to these conditions elicits rapid decomposition, possibly via
enol 31, a species which could in principle undergo further
hydroperoxidation chemistry. These findings suggest a reason
why 28 and 30 evade detection under manganese-based
conditions.
2.4 Reductive activation of (+)-cardamom peroxide
Despite longstanding and ongoing debate over the mechanism of
action of 2 and antimalarial peroxides,57 a pathway involving
iron-induced peroxide O–O bond cleavage has been largely
attributed as a key component contributing to their antimalarial
activity; many associated mechanistic studies have been
reported.58-61 Upon activation by a one-electron reduction,
organic peroxides cleave to produce a metal alkoxide and an
oxygen- centered radical through O-O bond cleavage, the latter
of which initiates various downstream processes, including
radical β-scission. These processes consequently generate
carbon-centered radicals, carbocations, or epoxides depending on
the structural properties of parent peroxide.62 In the case of 2,
primary alkyl radical 32 is formed, while arteflene and arterolane
generate the secondary radicals shown (Figure 5). In order to
examine the reductive activation mode of 1, we treated it with
observed. After 1 was consumed, as
Figure 5. Selected, characterized activation modes of various
O–O bond-containing antimalarials in the presence of FeII
judged by TLC, three major products vinylogous acid 36,
pyranone 37, and furanone 38, were isolated in yields of 20 %, 5-
10 %, and 42 % respectively. The structure of 37 and 38 were
confirmed by X-ray crystallographic analysis. Presumably,
iron(II) chloride approaches the peroxide from the less-hindered
side and leads to an oxygen-centered radical 33 that selectively
cleaves the neighboring carbon-carbonyl bond. Oxidation of the
resulting acyl radical 34 by the iron(III) center would generate
acylium ion 35, which upon addition of water forges the
carboxylic acid moiety found in 36-38. Pyranone 37 and
furanone 38 are then formed via additional dehydrative
iron(II) chloride in
a
water/acetonitrile mixture under
deoxygenated conditions (Figure 6A). Upon addition of the iron
salt, a rapid solution color change of yellow/green to red was
Figure 6. Activation modes of 1 in the presence of various FeII sources.

7
cyclizations. According to the heme alkylation model for
artemisinin
bioactivity,
primary
radical
ACCEPTED MANUSCRIPT
Thailand
Laos
GM Pursat
GM Preah Vihear
IC50 (nM) (range)b
GM Ratanakiri
IC50 (nM) (range)c
Entry
Antimalarial
Source
IC50 (nM) (range)a
Preah
Vihear
613.3 (218.6-1283.3) 502.7 (341.6-1037.1) 339.0 (228.8-502.4)
1
2
3
4
5
6
7
1
this work
ref. 63
ref. 63
ref. 63
ref. 63
ref. 63
ref. 63
Ratanakiri
3.5 (1.2-8.5)
2.3 (0.6-5.9)
2.6 (0.4-10.0)
2.0 (0.4-6.9)
1.9 (0.9-5.6)
1.4 (0.4-4.3)
artesunate
DHA
Cambodia
quinine
252.8 (65.6-544.9)
21.0 (2.5-83.8)
347.8 (38.4-880.2)
16.5 (1.7-55.4)
189.3 (31.4-620.2)
22.2 (4.9-80.5)
251.8 (16.7-682.9)
18.5 (3.6-64.1)
114.8 (23.2-433.0)
21.6 (5.5-72.3)
137.1 (11.8-479.5)
15.7 (4.2-40.2)
Pursat
piperaquine
chloroquine
mefloquine
Vietnam
SyBR-Green method, plate concentration 20000 - 19.5 nM. GM = geometric mean; a sample size for
entries 1-7 = 4, 96, 96, 92, 66, 91, 89; b sample size for entries 1-7 = 3, 86, 85, 87, 83, 85, 86; c sample size
for entries 1-7 = 2, 79, 79, 78, 78, 77, 77. The GM IC50 against the 3D7 strain for entries 1-7: 994.7, 2.1, 2.1,
64.1, 24.0, 21.8, and 16.4 nM respectively.
Me
Me
N
N
Me
H
NEt2
H
O
HO
N
N
O
Me
HO
H
Me
Me
HN
N
H
Me
O
O
N
O
O
Me
Me
N
N
O
H
N
HO
H
H
H
O
O
O
N
O
Me
N
CF3
O
Me
OH
CF3
Cl
Cl
OCO(CH2)2CO2H
artesunate
Cl
chloroquine
MeO
cardamom peroxide (1)
piperaquine
mefloquine
quinine
DHA
Figure 7. Antimalarial activity of 1 against P. falciparum clinical field isolates from three provinces of Cambodia.
32 forms a covalent C–C bond with heme thus inhibiting
hemozoin formation.63 We viewed 34 or 35 as species also
capable of undergoing a similar reaction and thus a biologically
relevant reaction was conducted by treating cardamom peroxide
(1) with hemin dimethyl ester and the intracellular reductant
glutathione (Figure 6B).61 We observed the formation of 38 along
with three major, presumed porphyrin-containing adducts as
judged by thin layer chromatography. Work-up and column
chromatography yielded fractions with masses corresponding to
heme/1 adducts (see 39, m/z = 974.3963, C56H62FeN4O8).
Unfortunately to date, attempts to demetallate these complexes
for NMR characterization have led only to decomposition. In
addition, we have been unable to grow single crystals of 39 for
X-ray diffraction studies. We stress that the structure of 39, both
with respect to the porphyrin attachment point, as well as the
identity of the cardamom peroxide fragment attached, is not
known. 39 represents a tentative structure and our data simply
implies that the two pieces have joined.
distinct provinces of Cambodia: Ratanakiri (eastern region),
Preah Vihear (central), and Pursat (western) (Figure 7).64 With
the exception of piperaquine at the time, a general trend toward
reduced sensitivity in clinical isolates derived from Pursat was
noted. Evaluation of 1 against isolates from these regions is
shown in Figure 7, with mean IC50s of 613.3, 502.7, and 339.0
nM for Pursat, Preah Vihear, and Ratanakiri, respectively. It is
worth noting that while 1 has not been used clinically, it shows a
similar trend with western Cambodian field isolates being the
least sensitive to its effects.65,66
3. Conclusion
In conclusion, we have developed a practical synthesis of the
antimalarial cardamom peroxide in as little as three steps and
without recourse to the use of protecting groups.67 While the
antimalarial activity of 1 proved insufficient for further clinical
consideration, a variety of interesting chemical findings were
unearthed during our synthetic studies concerning both the
potential origins of this natural product and its reactivity in
comparison to related and previously studied endoperoxides. The
ability to construct highly oxygenated terpenes from molecular
oxygen and simple, unfunctionalized terpene fragments holds
much promise for streamlining the chemical synthesis of other
complex natural products. Efforts to extend this concept to other
complex problems in synthesis are underway and will be reported
2.5 Antimalarial evaluation of the cardamom peroxide
Recent reports of increased ACT failure rates have surfaced in
western Cambodia,6 historically an epicenter for antimalarial
drug resistance. A recent study surveyed drug susceptibilities of a
variety of commonly used antimalarials (artesunate, DHA,
quinine, piperaquine, chloroquine, and mefloquine) against
patient-derived P. falciparum isolates from three geographically
in
due
course.
.

8
Tetrahedron
4. Experimental section
4.2.2. Keto-enone 5 (and 17): [Procedure 1] A flame-dried 25
ACCEPTED MANUSCRIPT
mL round-bottom flask was charged with ketone 13 (270 mg,
4.1 General
0.95 mmol), 2-hydroxybenzoic acid (14.0 mg, 0.1 mmol), and
DCM (5 mL). SeO2 (11.0 mg, 0.1 mmol) and TBHP (0.57 mL,
3.4 mmol, 6M in decane) was added sequentially. The reaction
mixture was stirred at room temperature for 3 days and then
quenched by the addition of saturated aq. Na2S2O3 (2 mL). The
resulting mixture was extracted by DCM and washed with brine.
Flash column chromatography afforded the allylic alcohol
product (33.0 mg, 0.11 mmol). The alcohol was then dissolved in
DCM (1.1 mL) and DMP (56 mg, 0.132 mmol) and NaHCO3 (10
mg, 0.11 mmol) were added sequentially. The reaction was
monitored by TLC for consumption of starting material,
quenched by the addition of brine, extracted with EtOAc, dried
over Na2SO4, and concentrated in vacuo. Flash column
chromatography gave 5 (30.0 mg, 11% yield from 13) as a
Dry tetrahydrofuran (THF), dichloromethane (DCM), toluene,
hexane, acetonitrile, and diethyl ether were obtained by passing
these previously degassed solvents through activated alumina
columns. Amines and alcohols were distilled from calcium
hydride prior to use. 1,2-Dimethoxyethane (DME) was distilled
from sodium and benzophenone. TiCl4 was distilled prior to use.
(–)-Pinene, (–)-myrtenol, and (–)-myrtenal was purchased from
Sigma Aldrich and used directly without further purification.
Reactions were monitored by thin layer chromatography (TLC)
on Silicycle SiliaplateTM G TLC plates (250 ꢀm thickness, 60 Å
porosity, F-254 indicator) and visualized by UV irradiation and
staining with p-anisaldehyde or potassium permanganate
developing agents. Volatile solvents were removed under
reduced pressure using a rotary evaporator. Flash column
chromatography was performed using Silicycle F60 silica gel
(60Å, 230-400 mesh, 40-63 ꢀm). Proton nuclear magnetic
resonance (1H NMR) and carbon nuclear magnetic resonance
(13C NMR) spectra were recorded on Bruker AV-300, AVB-400,
AV-500, or AV-600 spectrometers operating respectively at 300,
1
colorless oil: H NMR (500 MHz, CDCl3) δ 6.76 (dddd, J = 3.2,
3.2, 1.5, 1.5 Hz, 1H), 3.47 (dd, J = 16.9, 3.4 Hz, 1H), 3.12 – 3.08
(m, 1H), 2.93 (ddd, J = 5.6, 5.6, 1.6 Hz, 1H), 2.70 – 2.61 (m, 2H),
2.60 – 2.54 (m, 1H), 2.54 (dd, J = 16.9, 9.1 Hz, 1H), 2.50 (ddd, J
= 19.9, 3.2, 3.2 Hz, 1H), 2.47 – 2.41 (m, 2H), 2.15 – 2.11 (m,
2H), 2.09 (ddd, J = 6.2, 6.2, 2.0 Hz, 1H), 1.32 (s, 3H), 1.30 (d, J
= 10.6 Hz, 1H), 1.29 (s, 3H), 1.03 (d, J = 9.1 Hz, 1H), 0.88 (s,
3H), 0.74 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 214.0, 197.2,
149.1, 137.0, 52.3, 44.9, 43.3, 40.4, 39.8, 39.8, 39.1, 38.9, 37.6,
34.5, 32.7, 31.3, 26.9, 26.0, 22.2, 21.0. IR (thin film, cm-1) 2922,
1714, 1666, 1615, 1468, 1410, 1369; HRMS (EI) calcd. for
[C20H28O2]: m/z 300.2089, found 300.2089.
1
400, 500, and 600 MHz for H, and 75, 100, 125, and 150 MHz
for 13C. Chemical shifts are reported in parts per million (ppm)
with respect to the residual solvent signal CDCl3 (1H NMR: δ =
7.26; 13C NMR: δ = 77.16). Peak multiplicities are reported as
follows: s = singlet, bs = broad singlet, d = doublet, t = triplet, dd
= doublet of doublets, td = triplet of doublets, m = multiplet. app
= apparent. Melting points were determined using MEl-TEMP™
apparatus and are uncorrected. IR spectra were recorded on a
Nicolet 380 FT-IR spectrometer. High-resolution mass spectra
(HRMS) were obtained by the qb3 mass spectrometry facility at
the University of California, Berkeley (a VG Prospec Micromass
spectrometer for EI). Optical rotations were measured on a
Perkin-Elmer 241 polarimeter. X-ray crystallographic analyses
were performed at the UC Berkeley College of Chemistry X-ray
crystallography facility.
[Procedure 2] A flame-dried round-bottom flask was charged
with DBU (0.6 ml, 3.67 mmol) and DCM (7.2 ml) and then
degassed by bubbling a stream of argon through the solution for
20 min. The resulting mixture was added via cannula to a flame-
dried round-bottom flask charged with 16 (110 mg, 0.367 mmol)
under an argon atmosphere. The reaction mixture was stirred for
3 days at room temperature and then quenched with 1N HCl. The
aqueous phase was extracted with DCM and the combined
organic phase washed with saturated aq. NaHCO3 and brine.
Flash column chromatography (EtOAc/hexanes 1:20) gave
recovered starting material (27 mg, 25 %), and 5 and 17 (60 mg,
55%, 1:3 dr) as a colorless oil. The diastereomeric ratio was
4.2 Experimental procedures and data for synthetic
compounds
1
1
4.2.1. Ketone 13: The procedure was adapted from previous
conditions reported by Lipshutz and co-workers (J. Org. Chem.
1994, 59, 7437.) A flame-dried 100 mL round-bottom flask was
charged with Mg0 turnings (1.25 g) and THF (5 mL). A drop of
dibromoethane was added at 0 ºC followed by a solution of
bromide 11 (0.50 g, 2.5 mmol) in THF (5 mL) added dropwise
over 2 hours at –13 ºC. The reaction was then warmed to room
temperature and stirred for an additional 30 minutes. The
resulting grey solution was transferred to a separate round-
bottom flask pre-charged with CuI (0.524 g, 2.75 mmol), Me2S
(0.5 mL, 13.75 mmol), dry LiCl (117 mg, 2.75 mmol) and THF
(5 mL) at – 78 ºC. The resulting mixture was stirred for 10
minutes, followed by the addition of TMSCl (0.35 mL, 2.75
mmol) and enone 9 (0.30 g, 2 mmol). The reaction was
monitored by TLC analysis, and was quenched by the addition of
saturated aq. NH4Cl (5 mL) after the complete consumption of 9.
The resulting mixture was extracted by EtOAc and washed with
brine. Column Chromatography (EtOAC/hexanes 1:20) gave
ketone 13 (0.27 g, 48% yield) as a colorless oil: Rf=0.28
(DCM:hexane 1:2); 1H NMR (300 MHz, CDCl3) δ 5.18 (ddd, J =
3.0, 3.0, 1.5 Hz, 1H), 2.69 – 2.56 (m, 2H), 2.50 (dd, J = 19.3, 2.4
Hz, 1H), 2.34 (ddd, J = 8.5, 5.6, 5.6 Hz, 1H), 2.29 – 1.90 (m,
11H), 1.31 (s, 3H), 1.26 (s, 3H), 1.12 (m, 2H), 0.85 (s, 3H), 0.80
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 214.8, 147.9, 116.5, 56.5,
45.8, 44.9, 41.9, 41.0, 39.3, 38.8, 38.1, 35.4, 34.1, 31.8, 31.4,
28.7, 27.2, 26.5, 22.2, 21.3.
determined by H NMR: H NMR (600 MHz, CDCl3) δ 6.75
(dddd, J = 3.2, 3.2, 1.5, 1.5 Hz, 1H), 3.20 – 3.17 (m, 1H), 3.15
(dd, J = 16.3, 3.2 Hz, 1H), 2.92 (ddd, J = 5.7, 5.7, 1.6 Hz, 1H),
2.71 – 2.63 (m, 2H), 2.50 (ddd, J = 19.9, 3.2, 3.2 Hz, 1H), 2.48 –
2.40 (m, 4H), 2.15 – 2.10 (m, 2H), 1.96 (ddd, J = 6.2, 6.2, 2.1 Hz,
1H), 1.31 (s, 3H), 1.31 (s, 3H), 1.11 (d, J = 10.9 Hz, 1H), 1.03 (d,
J = 9.2 Hz, 1H), 0.95 (s, 3H), 0.72 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 214.3, 197.3, 149.3, 137.0, 48.7, 44.6, 42.3, 40.4, 39.9,
39.5, 38.3, 37.4, 36.9, 32.7, 31.2, 29.4, 26.4, 26.0, 21.0, 20.0.
4.2.3. Epoxide 18: A flame-dried round-bottom flask was
charged with 5 and 17 (30 mg, 0.1 mmol, mixture of two
diastereomers), THF (4 ml) and tert-butanol (1 ml). The resulting
solution was cooled to – 40 °C and oxygen was bubbled through
the solution for 10 minutes. Potassium tert-butoxide (45 mg, 0.4
mmol) was then added as solid in one portion to the reaction. The
reaction mixture was quenched after 30 minutes by the addition
of 1N aq. HCl, extracted with DCM, and washed with brine.
Column Chromatography (EtOAC/hexanes 1:15 to 1:10) gave
recovered starting material, and 18 (11mg, 35% yield) as a
1
colorless oil: [α]20 +170.6° (c 0.005 g/ml, CHCl3); H NMR
D
(500 MHz, CDCl3) δ 6.93 (dddd, J = 3.1, 3.1, 1.4, 1.4 Hz, 1H),
2.95 (ddd, J = 5.7, 5.7, 1.6 Hz, 1H), 2.78 – 2.62 (m, 3H), 2.52 –
2.50 (m, 2H), 2.47 (ddd, J = 9.2, 5.7, 5.7 Hz, 1H), 2.25 (dddd, J =
6.1, 6.1, 2.9, 2.9 Hz, 1H), 2.16 (dddd, J = 5.7, 5.7, 2.8, 2.8 Hz,
1H), 2.01 (dd, J = 6.0, 6.0 Hz, 1H), 1.58 (d, J = 11.1 Hz, 1H),

9
1.33 (s, 3H), 1.28 (s, 3H), 0.97 (d, J = 9.2 Hz, 1H), 0.85 (s, 3H),
0.77 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 206.5, 189.8, 149.1,
140.8, 67.5, 61.5, 42.8, 40.5, 40.5, 40.4, 39.6, 38.2, 37.5, 33.1,
31.3, 29.9, 26.2, 25.9, 21.6, 21.1; IR (thin film, cm-1) 2935, 1730,
1671, 1611, 1467, 1419, 1370, 1274; HRMS (EI) calcd. for
[C20H26O3]: m/z 314.1882, found 314.1885.
4.2.6. Bisenone 19: Dienone alcohol 16 (816 mg, 2.72 mmol,
ACCEPTED MANUSCRIPT
1.0 equiv) was dissolved in DCM (27 mL) and NaHCO3 (228
mg, 2.72 mmol, 1.0 equiv) and Dess-Martin periodinane (1.5 g,
3.54 mmol, 1.3 equiv) were added sequentially. The resulting
mixture was stirred at room temperature for 1 h (monitored by
TLC for complete consumption of 16). The reaction mixture was
quenched by the addition of 1 N aq. NaOH and extracted with
DCM. The combined organic phases were washed with water and
brine, dried over MgSO4, and purified by flash column
chromatography (gradient 20:1 → 10:1 hexanes/ethyl acetate),
4.2.4. Triene 14: The procedure was adapted from previous
conditions reported by McMurry and co-workers (J. Org. Chem.
1978, 43, 3255.) A flame-dried 1 L three-necked flask equipped
with a large stir bar and reflux condenser was charged with
freshly prepared Zn-Cu couple (44 g, 0.67 mol, 40 equiv). The
system was evacuated and backfilled with argon three times.
DME (600 mL) was added, followed by the dropwise addition of
freshly distilled TiCl4 (24 ml, 200 mmol, 10 equiv) to the rapidly
stirring slurry. After 1 hour of sonication, the mixture was heated
to reflux for 5 hours, cooled to room temperature, and a solution
of myrtenal (3.0 g, 20 mmol, 1 equiv) in 50 mL of degassed
DME was added slowly over 12 hours via syringe pump. After 1
hour of additional sonication, the reaction mixture was heated at
reflux for 48 hours, cooled to room temperature, and filtered
through a pad of Florisil® eluting with diethyl ether. This
filtration was repeated to give a clear solution that was
concentrated in vacuo and purified by flash column
chromatography (200:1 hexanes:Et3N) to afford 14 (1.41 g, 53 %
affording 19 (770 mg, 95 %) as white solid: mp 137.1 − 138.4
°C; [α]20 +27.20° (c 0.005 g/ml, CHCl3); H NMR (500 MHz,
1
D
CDCl3) δ 6.55 (ddd, J = 3.4, 1.8, 1.8 Hz, 1H), 6.00 (s, 1H), 3.05
(dd, J = 5.5, 5.5 Hz, 1H), 2.77 – 2.68 (m, 2H), 2.64 (ddd, J =
19.2, 2.4, 2.4 Hz, 1H), 2.54 – 2.41 (m, 3H), 2.39 (ddd, J = 19.9,
2.9, 2.9 Hz, 1H), 2.21 (dddd, J = 6.1, 6.1, 2.8, 2.8 Hz, 1H), 2.15 –
2.10 (m, 1H), 1.42 (dd, J = 2.9, 2.9 Hz, 1H), 1.40 (s, 3H), 1.35 (s,
3H), 1.08 (d, J = 9.1 Hz, 1H), 0.91 (s, 3H), 0.81 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 198.4, 195.0, 149.7, 145.0, 138.3,
132.8, 48.9, 42.6, 41.3, 40.8, 39.3, 38.4, 37.9, 32.7, 32.3, 31.2,
26.0, 26.0, 22.0, 21.0; IR (thin film, cm-1) 2931, 1705, 1651,
1628, 1465, 1421, 1368; HRMS (EI) calcd. for [C20H26O2]: m/z
298.1933, found 298.1937.
4.2.7. Cardamom peroxide (1), hydration product 23, and diol
24: A flame-dried round-bottom flask was charged with bisenone
19 (30 mg, 0.1 mmol, 1.0 equiv), Mn(dpm)3 (12 mg, 0.02 mmol,
20 mol %), DCM (1.6 mL), and i-PrOH (0.4 mL). Oxygen was
vigorously bubbled through the solution for 5 minutes, followed
by the addition of TBHP (5M in decane, 30 ꢀL, 1.5 equiv). The
solution was cooled to −10 °C under an atmosphere of oxygen,
and PhSiH3 (30 ꢀL, 0.24 mmol, 2.4 equiv) in DCM (1 mL) was
added dropwise over 12 h via syringe pump. After the addition
was complete, a solution of triphenylphosphine (56 mg, 0.21
mmol) in DCM was added dropwise at -10 °C to quench the
hydroperoxide intermediates. The reaction mixture was diluted
with H2O (5 mL) and extracted with DCM (3 × 10 mL). The
combined organic layers were washed with brine, dried over
Na2SO4, filtered through Celite®, and concentrated in vacuo. The
crude mixture was purified by flash column chromatography
(DCM) to afford 1 (18.2 mg, 52%) as a white solid, along with
hydration product 23 (3.5 mg, 11%), diol 24 (4.4 mg, 13%), and
nopinone (9% GC yield using an internal standard of dodecane).
[Note: the reaction afforded 48% of 1 on a 150 mg scale].
yield) as a colorless oil: [α]20 = +31.70° (c 0.010 g/ml, CHCl3);
D
1H NMR (500 MHz, CDCl3) δ 6.14 (s, 2H), 5.53 (m, 2H), 2.62
(ddd, J = 5.7, 5.7, 1.6 Hz, 2H), 2.42 (ddd, J = 8.8, 5.7, 5.7 Hz,
2H), 2.39 (ddd, J = 19.2, 3.0, 3.0 Hz, 2H), 2.32 (ddd, J = 19.2,
2.7, 2.7 Hz, 2H), 2.12 (m, 2H), 1.33 (s, 6H), 1.13 (d, J = 8.8 Hz,
2H), 0.81 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 146.9, 126.4,
123.7, 41.3, 41.2, 37.9, 32.2, 31.6, 26.6, 21.0; IR (thin film, cm-1)
2931, 2360, 1705, 1650, 1628, 1369, 1331; HRMS (EI) calcd. for
[C20H28]: m/z 268.2191, found 268.2191.
4.2.5. Dienone alcohol 16: A flame-dried round-bottom flask
was charged with triene 14 (1.3 g, 4.84 mmol, 1 equiv) and DCM
(145 ml). The solution was cooled to –40 °C and methylene blue
(15 mg, 0.05 mmol, 0.01 equiv) in DCM (1 mL) was added.
Oxygen gas was vigorously bubbled through the solution while
irradiating with a 500 W halogen lamp. After 1 hour, a second
portion of methylene blue (15 mg) in DCM (1 mL) was added
and the irradiation was continued until TLC indicated complete
consumption of the starting material (~2 hours). Nitrogen was
then bubbled through the solution for 30 minutes at which point
DBU (3.7 mL, 24 mmol, 5 equiv) was added dropwise at –40 °C.
The resulting mixture was allowed to gradually warm to –20 °C
and stirred for an additional 4 hours at this temperature. The
reaction mixture was quenched by the addition of 1 N HCl and
extracted with DCM. The combined organic layers were washed
with sat. aq. NaHCO3, H2O, brine, dried over MgSO4, and
concentrated in vacuo. The crude material was purified by
column chromatography (gradient 20:1 → 10:1 hexanes/ethyl
(+)-Cardamom peroxide (1): white solid: mp 154.9 − 156.2 °C;
[α]20 +123.20° (c 0.005 g/ml, hexanes); H NMR (500 MHz,
1
D
CDCl3) δ 4.28 (s, 1H), 4.22 (d, J = 11.3 Hz, 1H), 4.18 (d, J = 8.7
Hz, 1H), 2.78 (dd, J = 18.9, 2.4 Hz, 1H), 2.69 (ddd, J = 18.9, 3.0,
3.0 Hz, 1H), 2.58 (dd, J = 15.4, 8.9 Hz, 1H), 2.46 (dddd, J = 11.0,
5.8, 2.9, 2.9 Hz, 2H), 2.40 (d, J = 11.2 Hz, 1H), 2.41 – 2.35 (m,
1H), 2.30 (dd, J = 6.1, 6.1 Hz, 1H), 2.15 – 2.05 (m, 2H), 1.97 –
1.92 (m, 1H), 1.84 – 1.74 (m, 2H), 1.69 (d, J = 11.2 Hz, 1H), 1.38
(s, 3H), 1.27 (s, 3H), 1.06 (s, 3H), 0.86 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 208.8, 204.5, 84.3, 84.2, 83.3, 49.6, 43.9, 43.3,
42.9, 41.0, 40.7, 39.0, 38.3, 30.7, 27.9, 27.5, 26.9, 26.6, 24.1,
22.5; IR (thin film, cm-1) 3447, 3021, 2909, 1722, 1692, 1441,
1406, 1371; HRMS (ESI) calcd. for [C20H28O5Na]+ (M+Na)+: m/z
371.1829, found 371.1837. Vapor diffusion of an ether solution
of 1 with pentane afforded X-ray quality crystals.
acetate) to afford 16 (816 mg, 56 %) as white solid: mp 118.4 −
1
119.6 °C; [α]20 = +246.02° (c 0.005 g/ml, CHCl3); H NMR
D
(500 MHz, CDCl3) δ 6.76 (dddd, J = 3.3, 3.3, 1.5, 1.5 Hz, 1H),
6.40 (d, J = 0.8 Hz, 1H), 5.11 (d, J = 3.0 Hz, 1H, D2O
exchangeable), 4.66 – 4.62 (m, 1H), 2.94 (ddd, J = 5.7, 5.7, 1.5
Hz, 1H), 2.56 – 2.50 (m, 2H), 2.49 – 2.40 (m, 3H), 2.38 – 2.31
(m, 1H), 2.16 – 2.11 (m, 1H), 2.07 (dddd, J = 6.0, 6.0, 6.0, 2.2
Hz, 1H), 1.95 (dd, J = 14.6, 3.6 Hz, 1H), 1.72 (d, J = 10.0 Hz,
1H), 1.34 (s, 3H), 1.31 (s, 3H), 1.07 (d, J = 9.2 Hz, 1H), 0.75 (s,
3H), 0.69 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 191.2, 168.3,
150.6, 137.3, 120.4, 62.9, 53.5, 40.8, 40.3, 40.2, 40.0, 37.5, 33.8,
32.7, 31.2, 27.4, 26.0, 25.9, 22.7, 21.0; IR (thin film, cm-1) 3421,
2916, 1636, 1591, 1393, 1366; HRMS (EI) calcd. for [C20H28O2]:
m/z 300.2089, found 300.2094.
Hydration product 23: colorless oil; [α]20 = –56.7° (c 0.006
D
1
g/ml, CHCl3); H NMR (500 MHz, CDCl3) δ 6.70 (ddd, J = 3.4,
1.8, 1.8 Hz, 1H), 3.38 (d, J = 15.7 Hz, 1H), 2.99 (ddd, J = 5.7,
5.7, 1.6 Hz, 1H), 2.68 (dd, J = 19.0, 2.4 Hz, 1H), 2.59 (ddd, J =
19.0, 3.2, 3.2 Hz, 1H), 2.53 (dt, J = 20.2, 3.2, 3.2 Hz, 1H), 2.50 –
2.41 (m, 3H), 2.39 (d, J = 15.8 Hz, 1H), 2.22 (dd, J = 6.2, 6.2 Hz,

10
Tetrahedron
1H), 2.15 (dddd, J = 5.9, 3.0, 3.0, 1.2 Hz, 1H), 2.11 (dddd, J =
found 347.1861. Vapor diffusion of an ether solution of 38 with
ACCEPTED MANUSCRIPT
6.1, 6.1, 3.0, 3.0 Hz, 1H), 1.92 (d, J = 11.0 Hz, 1H), 1.36 (s, 3H),
1.35 (s, 3H), 1.02 (d, J = 9.1 Hz, 1H), 0.95 (s, 3H), 0.82 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 210.6, 200.6, 150.4, 138.8, 79.8,
50.0, 43.3, 40.4, 40.3, 39.6, 39.3, 38.6, 37.6, 32.9, 31.2, 27.9,
27.4, 26.0, 22.9, 21.0; IR (thin film, cm-1) 3359, 2924, 1721,
1640, 1613, 1421, 1370; HRMS (EI) calcd. for [C20H28O3]: m/z
316.2038, found 316.2040.
pentane afforded X-ray quality crystals.
1
Pyranone 37: white solid: mp 154.3 – 156.0 °C; H NMR (600
MHz, CD2Cl2) δ 5.27 (s, 1H), 4.98 (dd, J = 9.1, 3.9 Hz, 1H), 2.77
– 2.71 (m, 1H), 2.71 (dd, J = 10.8, 7.6 Hz, 1H), 2.43 – 2.35 (m,
2H), 2.34 – 2.25 (m, 2H), 2.22 (dd, J = 5.8, 5.8 Hz, 1H), 2.14
(ddd, J = 11.0, 7.5, 7.5 Hz, 1H), 1.99 (dddd, J = 5.7, 5.7, 3.3, 3.3
Hz, 1H), 1.90 (ddd, J = 14.6, 3.8, 3.8 Hz, 1H), 1.79 (dd, J = 10.6,
10.6 Hz, 1H), 1.27 (s, 3H), 1.22 (s, 3H), 1.10 (ddd, J = 6.1, 3.8,
3.8 Hz, 1H), 1.05 (s, 3H), 0.95 (s, 3H); IR (thin film, cm-1) 3457,
2997, 2923, 2667, 2365, 1677, 1591, 1367; HRMS (ESI) calcd.
for [C20H27O5]– (M-H)– : m/z 347.1864, found 347.1863. Vapor
diffusion of an ether solution of 37 with pentane afforded X-ray
quality crystals.
Diol 24: white solid (acid sensitive): mp 132.9 – 134.1 °C; [α]20
−33.2° (c 0.010 g/ml, CH2Cl2); H NMR (600 MHz, CD2Cl2) δ
D
1
5.49 (s, 1H), 3.37 (d, J = 15.3 Hz, 1H), 2.78 (ddd, J = 15.8, 10.5,
3.5 Hz, 1H), 2.69 – 2.62 (m, 2H), 2.57 (ddd, J = 19.1, 3.2, 3.2 Hz,
1H), 2.41 (dddd, J = 11.0, 6.2, 6.2, 3.1 Hz, 1H), 2.26 (dddd, J =
10.1, 6.0, 6.0, 1.8 Hz, 1H), 2.21 (dd, J = 6.1, 4.8 Hz, 1H), 2.18 –
2.14 (m, 2H), 2.08 (dddd, J = 6.1, 6.1, 2.9, 2.9 Hz, 1H), 1.99 –
1.90 (m, 2H), 1.85 (d, J = 10.9 Hz, 1H), 1.87 – 1.81 (m, 1H), 1.61
(ddd, J = 16.0, 11.0, 5.2 Hz, 1H), 1.58 (d, J = 10.1 Hz, 1H), 1.35
(s, 3H), 1.22 (s, 3H), 0.90 (s, 3H), 0.72 (s, 3H); 13C NMR (150
MHz, CD2Cl2) δ 213.2, 213.1, 82.5, 80.4, 50.7, 49.0, 43.6, 41.7,
41.1, 39.7, 39.0, 38.3, 28.0, 27.5, 27.3, 26.2, 24.6, 24.3, 22.8,
22.0; IR (thin film, cm-1) 3410, 3005, 2925, 2360, 2341, 1823,
1708, 1463, 1408, 1326; HRMS (ESI) calcd. for [C20H30O4Na]+
(M+Na)+ : m/z 357.2036, found 357.2035.
4.2.9. Reaction of 1 with hemin dimethyl ester: In a nitrogen-
filled glove box, a 20 mL vial was charged with hemin dimethyl
ester (68 mg, 0.1 mmol), 1 (42 mg, 0.12 mmol), and glutathione
(307 mg, 1 mmol). Degassed DMSO (3 mL) was added to the
reaction vial at room temperature. The vial was then removed
from glovebox and stirred at 37 ºC for 8 h. The reaction was
monitored by TLC (MeOH/CHCl3 1:15 and acetone/hexane 1:5,
for the consumption of hemin dimethyl ester and 1, respectively),
and quenched by addition of H2O (10 mL), extracted by DCM
(10 mL × 2) and EtOAc (10 mL × 2). The organic layers were
combined, washed with brine, and dried over Na2SO4. Column
chromatography afforded furanone 38 as the major product,
along with a mixture of three paramagnetic, colored, hemin-
containing products, potentially as the regioisomers of Fe(III)-
PPIX adduct 39: HRMS (ESI) calcd. for [C56H62FeN4O8]+ (M-
Cl)+ : m/z 974.3918, found 974.3963.
4.2.8. Acid 36, pyranone 37, and furanone 38: In a nitrogen-
filled glovebox, 1 (12 mg, 0.03 mmol, 1.0 equiv) was dissolved
in thoroughly degassed acetonitrile (750 ꢀL) and H2O (7 ꢀL, 0.4
mmol, 13.0 equiv). To the resulting solution was added FeCl2
(3.5 mg, 0.028 mmol, 0.8 equiv) in one portion and the resulting
mixture stirred for 45 minutes. After 45 minutes, the resulting red
colored solution was removed from the glovebox, opened to the
air, diluted with DCM (15 mL) and washed with brine (2 × 25
mL). The organic phase was concentrated in vacuo and the crude
material purified by preparative thin layer chromatography (50:6
DCM:MeOH) affording acids 36 (2.5 mg, yield 20 %), 38 (5 mg,
yield 42%), and a small amount of 37 (~ 0.5 − 1.0 mg, yield 5 −
10 %).
4.3 In-vitro drug susceptibility of Cardamom Peroxide
4.3.1. Culture-adaptation and maintenance of P. falciparum: All
parasite samples were collected from patients in Cambodia under
protocols approved by Cambodia’s National Ethics Committee
for Health Research, and the National Institute of Allergy and
Infectious Diseases (NIAID) institutional review board (NIH).
All protocol subjects provided written informed consent. Culture-
adaptation of parasites was accomplished by thawing
cryopreserved material containing infected red blood cells
(iRBCs) that had been mixed with glycerolyte. Parasites were
maintained in fresh human blood (O+) and Hepes buffered RPMI
media containing 10% O+ human serum (heat inactivated and
pooled). Cultures were placed in modular incubators and gassed
with 5% O2/5% CO2/balance N2 gas and incubated in a 37 ºC
incubator.
Acid 36: white foam (unstable over extended periods in CDCl3,
converts to 37 and 38); [α]20 +48.0° (c 0.001 g/ml, CH2Cl2); H
1
D
NMR (600 MHz, CD2Cl2) δ 5.25 (d, J = 0.8 Hz, 1H), 4.48 – 4.40
(m, 1H), 2.98 (ddd, J = 10.4, 7.6, 0.8 Hz, 1H), 2.91 (d, J = 11.0
Hz, 1H), 2.83 (dd, J = 18.1, 6.7 Hz, 1H), 2.73 (dd, J = 18.1, 7.9
Hz, 1H), 2.73 – 2.68 (m, 1H), 2.50 – 2.43 (m, 1H), 2.26 (ddd, J =
11.1, 7.9, 7.9 Hz, 1H), 2.26 – 2.21 (m, 1H), 2.10 (d, J = 11.2 Hz,
1H), 2.02 – 1.96 (m, 2H), 1.80 – 1.69 (m, 2H), 1.26 (s, 3H), 1.24
(s, 3H), 1.02 (s, 3H), 0.89 (s, 3H); 13C NMR (125 MHz, CD2Cl2)
δ 206.0, 199.0, 192.8, 102.9, 96.7, 68.2, 50.3, 44.7, 43.9, 40.3,
40.0, 39.0, 38.0, 37.4, 30.6, 26.9, 25.8, 24.7, 23.7, 18.0; IR (thin
film, cm-1) 3061, 2926, 2349, 1724, 1598, 1548, 1484, 1379;
HRMS (ESI) calcd. for [C20H27O5]– (M-H2O-H)− : m/z 347.1864,
found 347.1863.
Furanone 38: white solid: mp 147.5 – 149.8 °C; [α]20D +77.50° (c
0.002 g/ml, CH2Cl2); 1H NMR (600 MHz, CDCl3) δ 5.30 (s, 1H),
4.50 (dd, J = 9.7, 4.3 Hz, 1H), 2.95 (dd, J = 10.6, 7.7 Hz, 1H),
2.73 (dddd, J = 14.8, 9.8, 2.8, 2.8 Hz, 1H), 2.49 (dddd, J = 10.3,
7.8, 7.8, 7.7 Hz, 1H), 2.43 (dd, J = 15.8, 7.2 Hz, 1H), 2.34 (dd, J
= 15.8, 8.0 Hz, 1H), 2.30 (ddd, J = 11.3, 7.8, 7.8 Hz, 1H), 2.26
(ddddd, J = 11.9, 6.2, 3.0, 3.0, 2.3 Hz, 1H), 2.15 (d, J = 11.3 Hz,
1H), 2.03 – 1.97 (m, 2H), 1.83 – 1.74 (m, 2H), 1.27 (s, 3H), 1.25
(s, 3H), 1.03 (s, 3H), 0.93 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
206.0, 192.5, 176.9, 102.8, 96.5, 67.9, 50.0, 44.3, 43.4, 39.9,
39.5, 38.7, 38.6, 34.8, 30.4, 26.8, 25.5, 24.4, 23.6, 17.5; IR (thin
film, cm-1) 3849, 3105, 2997, 2924, 2361, 1682, 1587, 1484,
1368; HRMS (ESI) calcd. for [C20H27O5]– (M-H)− : m/z 347.1864,
4.3.2. Antimalarial drug preparation: Stock solutions of
cardamom peroxide were prepared in DMSO. Two-fold serial
dilutions of stock solutions were prepared in culture water. Final
drug concentrations ranged from 19.5 – 20,000 nM. Fifty µl of
each diluted drug solution were added in duplicate to 96-well,
flat-bottomed plates (Costar 3595, Corning, Lowell, MA). The
drug-coated plates were prepared freshly before use. The quality
of each batch of plates was validated by measuring the
antimalarial drug responses of the P. falciparum 3D7 line.
4.3.3. In-vitro drug susceptibility assay: In-vitro drug
susceptibility was measured using the SYBR Green I method as
previously described (see: Bacon, D. J.; Latour, C.; Lucas, C.;
Colina, O.; Ringwald, P.; Picot, S. Antimicrob. Agents
Chemother. 2007, 51, 1172-1178.). Briefly, synchronized rings
were grown in the presence of different concentrations of drugs
in duplicate wells of drug-coated, clear-bottom, 96-well plates
(Costar 3595, Corning, Lowell, MA), at 1% hematocrit, 1%
starting parasitemia and 200 ꢀl of 0.5% Albumax culture media.

11
2010, 39, 435. (d) Schwikkard, S.; van Heerden, F. R. Nat.
Each plate included two drug-free wells as negative controls for
each drug. Plates were placed in a vacuum chamber and gassed
with 5% O2/5% CO2/balance N2 gas and incubated in a 37 ºC
incubator for 72 hours, and subsequently frozen and kept at -20
ºC until the measurement of SYBR Green. Growth at 72 hours
was measured by SYBR Green I (Invitrogen) staining of parasite
DNA. Relative Fluorescence Units (RFU) was measured at an
excitation of 485nm and emission of 530nm on a FLUOstar
OPTIMA instrument (BMG Labtech, Cary, NC) and analyzed
using World Wide Antimalarial Resistance Network (WWARN)
ACCEPTED MANUSCRIPT
Prod. Rep. 2002, 19, 675-692. (e) Kaur, M.; Jain, M.; Kaur, T.;
Jain, R. Bioorg. Med. Chem. Lett. 2009, 17, 3229-3256. (f)
Dembitsky, V. M. J. Mol. Genet. Med. 2015, 9, 163.
8.
For total syntheses of the strucutres shown in Figure 1A, see:
(a) Schimid, G.; Hofheinz, W. J. Am. Chem. Soc. 1983, 105,
624–625. (b) Xu, X. X.; Zhu, J.; Huang, D. Z.;Zhou, W. S.
Tetrahedron 1986, 42, 819–828. (c) Avery, M. A.; Chong,W.
K. M.; White, C. J. J. Am. Chem. Soc. 1992, 114, 974–979. (d)
Avery, M. A.; White, C. J.; Chong, W. K. M. Tetrahedron Lett.
1987, 28, 4629–4632. (e) Liu, H. J.; Yeh, W. L.; Chew, S. Y.
Tetrahedron Lett. 1993, 34,4435–4438. (f) Constantino, M. G.;
Beltrame, M., Jr.; da Silva, G. V. J. Synth. Commun. 1996, 26,
321–329. (g) Yadav, J. S.; Babu, R. S.; Sabitha, G.
Tetrahedron Lett. 2003, 44, 387–389. (h) Yadav, J. S.;
Thirupathaiah, B.; Srihari, P. Tetrahedron 2010, 66, 2005–
2009. (i) Zhou,W.-S.; Xu, X.-X. Acc. Chem. Res. 1994, 27,
211–216. (j) Zhu, C.; Cook, S. P. J. Am. Chem. Soc. 2014, 134,
13577-13579. (k) Hilf, J. A.; Witthoft, L. W.; Woerpel, K. A. J.
Org. Chem. 2015, 80, 8262-8267. (l) Xu, X.-X.; Dong, H.-Q.
Tetrahedron Lett. 1994, 35, 9429-9432. (m) Szpilman, A. M.;
Korshin, E. E.; Rozenberg, H.; Bachi, M. D. J. Org. Chem.
2005, 70, 3618-3632. (n) Xu, X.-X.; Zhu, J.; Huang, D.-Z.;
Zhou, W.-S. Tetrahedron Lett, 1991, 32, 5785-5788. (o) Li, Q.;
Zhao, K.; Peuronen, A.; Rissanen, K.; Enders, D.; Tang, Y. J.
IVART
analysis
(http://www.wwarn.org/tools-
resources/toolkit/analyse/ivart). The IC50, defined as the drug
concentration at which the SYBR Green I signal was 50% of that
measured from drug-free control wells, was calculated from
IVART software to fit the concentration-inhibition data (see:
Woodrow, C. J. et al. Antimicrob. Agents Chemother. 2013, 57,
3121–3130).
4.4 X-ray crystallographic data
Crystallographic data for structures 1, 3, 37, and 38 have been
deposited with the Cambridge Crystallographic Data Centre.
Copies of the data can be obtained free of charge from
http://www.ccdc.cam.ac.uk/products/csd/request/
(CDCC
#1003088 for 1, #1003087 for 3, #1003085 for 37, and #1003086
for 38).
Am.
Chem.
Soc.
2018,
just
accepted,
DOI:
10.1021/jacs.7b12903
9.
For reviews on the synthesis of endoperoxides, see: (a)
Korshin, E. E.; Bachi, M. D. in Synthesis of Cyclic Peroxides,
Patai’s Chemistry of Functional Groups, Online, Wiley, 2009,
1-117. (b) Dussault, P. Synlett 1995, 997.
Acknowledgments
Financial support is provided by the NIH (GM116952 to T. J.
M.). T.J.M. is a Cottrell Scholar and acknowledges unrestricted
support from Novartis, Bristol-Myers Squibb, Amgen, and Eli
Lilly. X. H. thanks Bristol-Myers Squibb and Amgen for
graduate fellowships. We are grateful to Dr. Hasan Celik for
NMR assistance wherein NIH grant GM68933 is acknowledged.
Dr. Antonio Dipasquale is acknowledged for X-ray
crystallographic analysis wherein support from NIH Shared
Instrument Grant (S10-RR027172) is also acknowledged. This
work was party supported by the Intramural Research Program of
the NIAID, NIH.
10. (a) Slack, R. D,; Jacobine, A. M.; Posner, G. H., Med. Chem.
Commun. 2012, 3, 281-297. (b) Schlitzer, M., ChemMedChem
2007, 2, 944-986. (c) Hofheinz, W.; Burgin, H.; Gocke, E.;
Jaquet, C.; Masciadri, R.; Schmid, G.; Stohler, H.; Urwyler, H.
Trop. Med. Parisitol. 1994, 45, 261-265.(d) Vennerstrom, J. L.
et. al. Nature, 2004, 430, 900-904.
11. For recent examples of non-peroxidic antimalarials, see: (a)
Flannery, E. L.; Chatterjee, A. K.; Winzeler, E. A., Nat. Rev.
Microbiol. 2013, 11, 849–862. (b) Baragana, B. et al. Nature,
2015, 522, 315-320. (c) Kato, N.; Comer, E.; Sakata-Kato, T.;
Sharma, A.; Sharma, M.; Maetani, M.; Bastien, J.; Brancucci,
N. M.; Bittker, J. A.; Corey, V.; Clarke, D.; Derbyshire, E. R.;
Dornan, G. L.; Duffy, S.; Eckley, S.; Itoe, M. A.; Koolen, K.
M.; Lewis, T. A.; Lui, P. S.; Lukens, A. K.; Lund, E.; March,
S.; Meibalan, E.; Meier, B. C.; McPhail, J. A.; Mitasev, B.;
Moss, E. L.; Sayes, M.; Van Gessel, Y.; Wawer, M. J.;
Yoshinaga, T.; Zeeman, A. M.; Avery, V. M.; Bhatia, S. N.;
Burke, J. E.; Catteruccia, F.; Clardy, J. C.; Clemons, P. A.;
Dechering, K. J.; Duvall, J. R.; Foley, M. A.; Gusovsky, F.;
Kocken, C. H.; Marti, M.; Morningstar, M. L.; Munoz, B.;
Neafsey, D. E.; Sharma, A.; Winzeler, E. A.; Wirth, D. F.;
Scherer, C. A.; Schreiber, S. L., Nature 2016, 538, 344-349. (d)
Cowell, A. N. et al. Science, 2018, 359, 191-199.
References and notes
1.
2.
World Health Organization, World Malaria Report. World
Health Organization: Geneva, Switzerland, 2017.
Rosenthal, P. J., Antimalarial Chemotherapy: Mechanisms of
Action, Resistance, and New Directions in Drug Discovery.
Humana Press: Totowa, NJ, 2011.
3.
4.
Poser, C. M.; Bruyn, G. W., An Illustrated History of Malaria.
the Parthenon Publishing Group: Carnforth, UK, 1999.
(a) Wellems, T. E.; Plowe, C. V., J. Infect. Dis. 2001, 184,
770-776. (b) Hastings, I. M., Trends Parasitol 2004, 20, 512-
518. (c) Ginsburg, H., Acta Tropica 2005, 96, 16-23.
12. Kamchonwongpaisan, S.; Nilanonta, C.; Tarnchompoo, B.;
Thebtaranonth, C.; Thebtaranonth, Y.; Yuthavong, Y.;
Kongsaeree, P.; Clardy, J., Tetrahedron Lett. 1995, 36, 1821-
1824.
5. (a) Liu, J.-M.; Ni, M.-Y.; Fen, J.-F.; Tu, Y.-Y.; Wu, Z.-H.; Wu,
Y.-L.; Zhou, W.-S., Huaxue Xuebao 1979, 37, 129-143. (b) Tu,
Y. Angew. Chem. Int. Ed. 2016, 55, 10210-10226.
6. (a) Dondorp, A., M. et al. Engl. J. Med. 2009, 361, 455-467. (b)
Ashley, E. A. et. al. New Engl. J. Med. 2014, 371, 411-423. (c)
Imwong, M. et al. Lancet Infect Dis 2017, 17, 491-497. (d)
Imwong, M.; Hien, T. T.; Thuy-Nhien, N. T.; Dondorp, A. M.;
White, N. J., Lancet Infect Dis 2017, 17, 1022-1023. (e) Rossi,
G.; De Smet, M.; Khim, N.; Kindermans, J. M.; Menard, D.,
Lancet Infect Dis 2017, 17, 1233. (f) Lu, F. et al. N. Engl. J.
Med. 2017, 376, 991-993.
13. Hu, X.; Maimone, T. J., J. Am. Chem. Soc. 2014, 136, 5287-
5290.
14. Czechowski, T.; Larson, T. R.; Catania, T. M.; Harvey, D.;
Brown, G. D.; Graham, I. A., Proc. Natl. Acad. Sci. 2016, 113,
15150-15155.
15. Cointeaux, L.; Berrien, J. F.; Mayrargue, J., Tetrahedron Lett.
2002, 43, 6275-6277.
16. Brill, Z. G.; Condakes, M. L.; Ting, C. P.; Maimone, T. J.,
Chem. Rev. 2017, 117, 11753-11795.
7.
(a) Spiteller, G. Free Radic. Biol. Med. 2006, 41, 362. (b)
Dembitsky, V. M.; Gloriozova, T. A.; Poroikov, V. V. Mini
Rev. Med. Chem. 2007, 7, 571. (c) Chaturvedi, D.; Goswami,
A.; Saikia, P. P.; Barua, N. C.; Rao, P. G. Chem. Soc. Rev.
17. Mazzega, M.; Fabris, F.; Cossu, S.; De Lucchi, O.; Lucchini,
V.; Valle, G., Tetrahedron 1999, 55, 4427-4440.
18. Willis, M. C., Chem. Rev. 2010, 110, 725-748.

12
Tetrahedron
ACCEPTED MANUSCRIPT
19.
Nicolaou, K. C.; Ellery, S. P.; Chen, J. S., Angew.
47. Magnus, P.; Fielding, M. R., Tetrahedron Lett. 2001, 42,
Chem. Int. Ed. 2009, 48, 7140-7165.
6633-6636.
20. Barrero, A. F.; Herrador, M. M.; del Moral, J. F.; Arteaga, P.;
Arteaga, J. F.; Dieguez, H. R.; Sanchez, E. M., J. Org. Chem.
2007, 72, 2988-2995.
21. Lipshutz, B. H.; Hackmann, C., J. Org. Chem. 1994, 59, 7437-
7444.
48. (a) Iwasaki, K.; Wan, K. K.; Oppedisano, A.; Crossley, S. W.;
Shenvi, R. A., J. Am. Chem. Soc. 2014, 136, 1300-1303. (b) C.
Obradors, R. M. Martinez, R. A. Shenvi, J. Am. Chem. Soc.,
2016, 138, 4962-4971. (c) King, S. M.; Ma, X.; Herzon, S. B.
J. Am. Chem. Soc. 2014, 136, 6884. (d) Ma, X.; Herzon, S. B.
Chem. Sci, 2015, 6, 6250.
22. Dutta, D. K.; Konwar, D., Tetrahedron Lett. 2000, 41, 6227-
6229.
49. For
mechanistically
related
hydrofunctionalization
23. Baati, R.; Mioskowski, C.; Barma, D.; Kache, R.; Falck, J. R.,
Org. Lett. 2006, 8, 2949-2951.
methodology, see: (a) Waser, J.; Carreira, E. M. J. Am. Chem.
Soc. 2004, 126, 5676. (b) Waser, J.; Carreira, E. M. Angew. Chem.
Int. Ed. 2004, 43, 4099. (c) Waser, J.; Nambu, H.; Carreira, E. M.
J. Am. Chem. Soc. 2005, 127, 8294. (d) Waser, J.; Gaspar, B.;
Nambu, H.; Carreira, E. M. J. Am. Chem. Soc. 2006, 128, 11693.
(e) Gaspar, B.; Carreira, E. M. Angew. Chem. Int. Ed. 2007, 46,
4519. (f) Gaspar, B.; Carreira, E. M. Angew. Chem. Int. Ed. 2008,
120, 5842. (g) Gaspar, B.; Carreira, E. M. J. Am. Chem. Soc. 2009,
131, 13214. (h) Barker, T. J.; Boger, D. L. J. Am. Chem. Soc. 2012,
134, 13588. (i) Tokuyasu, T.; Kunikawa, S.; Masuyama, A.;
Nojima, M. Org. Lett. 2002, 4, 3595. (j) Shigehisa, H.; Aoki, T.;
Yamaguchi, S.; Shimizu, N.; Hiroya, K. J. Am. Chem. Soc. 2013,
135, 10306. (k) Hashimoto, T.; Hirose, D.; Taniguchi, T. Angew.
Chem. Int. Ed. 2014, 53, 2730. (l) Ma, X.; Herzon, S. B. J. Org.
Chem. 2016, 81, 8673. (m) Ma, X.; Herzon, S. B. J. Am. Chem.
Soc. 2016, 138, 8718. (n) Ma, X.; Dang, H.; Rose, J. A.; Rablen,
P.; Herzon, S. B. J. Am. Chem. Soc. 2017, 139, 5998.
24. Furstner, A.; Hupperts, A., J. Am. Chem. Soc. 1995, 117,
4468-4475.
25. Dieguez, H. R.; Lopez, A.; Domingo, V.; Arteaga, J. F.;
Dobado, J. A.; Herrador, M. M.; Quilez del Moral, J. F.;
Barrero, A. F., J. Am. Chem. Soc. 2010, 132, 254-259.
26. Mukaiyama, T.; Sato, T.; Hanna, J., Chem. Lett. 1973, 1041-
1044.
27. (a) Mcmurry, J. E.; Fleming, M. P.; Kees, K. L.; Krepski, L. R.,
J. Org. Chem. 1978, 43, 3255-3266. (b) McMurry, J. E., Chem.
Rev. 1989, 89, 1513-1524.
28. Kornblum, N.; Delamare, H. E., J. Am. Chem. Soc. 1951, 73,
880-881.
29. Yaremenko, I. A.; Vil', V. A.; Demchuk, D. V.; Terent'ev, A.
O. Beilstein J. Org. Chem. 2016, 12, 1647-1748.
30. (a) Nokami, J.; Nishimura, A.; Sunami, M.; Wakabayashi, S.,
Tetrahedron Lett. 1987, 28, 649-650. (b) Atasoy, B.; Balci, M.,
Tetrahedron 1986, 42, 1461-1468.
50. Sugimori, T.; Horike, S.; Tsumura, S.; Handa, M.; Kasuga, K.,
Inorg. Chim. Acta 1998, 283, 275-278.
51. Leggans, E. K.; Barker, T. J.; Duncan, K. K.; Boger, D. L.,
Org. Lett. 2012, 14, 1428-1431.
31. Gersmann, H. R.; Bickel, A. F.; Nieuwenhuis, H. J. W., Proc.
Chem. Soc. 1962, 279.
32. Novkovic, L.; Trmcic, M.; Rodic, M.; Bihelovic, F.; Zlatar, M.;
Matovic, R.; Saicic, R. N., Rsc Advances 2015, 5, 99577-
99584.
52. Sears, J. E.; Boger, D. L., Acc. Chem. Res. 2015, 48, 653-662.
53. (a) Lo, J. C.; Yabe, Y.; Baran, P. S., J. Am. Chem. Soc. 2014,
136, 1304-1307. (b) Lo, J. C.; Gui, J.; Yabe, Y.; Pan, C. M.;
Baran, P. S., Nature 2014, 516, 343-348. (c) Gui, J.; Pan, C.
M.; Jin, Y.; Qin, T.; Lo, J. C.; Lee, B. J.; Spergel, S. H.;
Mertzman, M. E.; Pitts, W. J.; La Cruz, T. E.; Schmidt, M. A.;
Darvatkar, N.; Natarajan, S. R.; Baran, P. S., Science 2015,
348, 886-891. (d) Dao, H. T.; Li, C.; Michaudel, Q.; Maxwell,
B. D.; Baran, P. S., J. Am. Chem. Soc. 2015, 137, 8046-8049.
54. Gu, X.; Zhang, W.; Salomon, R. G., J. Org. Chem. 2012, 77,
1554-1559.
55. A direct Hock-Criegee-type fragmentation of 25 could also
ultimately lead to nopinone and diketone 30, see reference 29.
56. Michon, C.; Djukic, J. P.; Ratkovic, Z.; Pfeffer, M.,
Tetrahedron Lett. 2002, 43, 5241-5243.
57. (a) Golenser, J.; Waknine, J. H.; Krugliak, M.; Hunt, N. H.;
Grau, G. E. Int. J. Parasitol. 2006, 36, 1427. (b) O’Neill, P.
M.; Barton, V. E.; Ward, S. A. Molecules 2010, 15, 1705. (c)
Posner, G. H.; O’Neill, P. M. Acc. Chem. Res. 2004, 37, 397.
58. Posner, G. H.; Cumming, J. N.; Ploypradith, P.; Chang, H. O.,
J. Am. Chem. Soc. 1995, 117, 5885-5886.
59. Wu, W.-M.; Wu, Y.; Wu, Y.-L.; Yao, Z.-J.; Zhou, C.-M.; Li,
Y.; Shan, F., J. Am. Chem. Soc. 1998, 120, 3316-3325.
60. Robert, A.; Cazelles, J.; Meunier, B., Angew. Chem. Int. Ed.
2001, 40, 1954-1957.
61. Robert, A.; Coppel, Y.; Meunier, B., Chem. Commun. 2002,
414-415.
62. For selected examples, see: (a) Posner, G. H.; O’Neill, P. M.,
Acc. Chem. Res. 2004, 37, 397-404. (b) Wu, W.-M.; Wu, Y.;
Wu, Y.-L.; Yao, Z.-J.; Zhou, C.-M.; Li, Y.; Shan, F., J. Am.
Chem. Soc. 1998, 120, 3316-3325. (c) O’Neill, P. M.; Stocks,
P. A.; Pugh, M. D.; Araujo, N. C.; Korshin, E. E.; Bickley, J.
F.; Ward, S. A.; Bray, P. G.; Pasini, E.; Davies, J.; Verissimo,
E.; Bachi, M. D., Angew. Chem., Int. Ed. 2004, 43, 4193-4197.
(d) Tang, Y.; Dong, Y.; Wang, X.; Sriraghavan, K.; Wood, J.
K.; Vennerstrom, J. L., J. Org. Chem. 2005, 70, 5103-5110.
63. Weissbuch, I.; Leiserowitz, L., Chem. Rev. 2008, 108, 4899-
4914.
33. Chumoyer, M. Y.; Danishefsky, S. J., J. Am. Chem. Soc. 1992,
114, 8333-8334.
34. Magnus, P.; Booth, J.; Magnus, N.; Tarrant, J.; Thom, S.;
Ujjainwalla, F., Tetrahedron Lett. 1995, 36, 5331-5334.
35. Nickel, A.; Maruyama, T.; Tang, H.; Murphy, P. D.; Greene,
B.; Yusuff, N.; Wood, J. L., J. Am. Chem. Soc. 2004, 126,
16300-16301.
36. Schottner, E.; Wiechoczek, M.; Jones, P. G.; Lindel, T., Org.
Lett. 2010, 12, 784-787.
37. Gampe, C. M.; Carreira, E. M., Angew. Chem. Int. Ed. 2011,
50, 2962-2965.
38. House, H. O.; Ro, R. S., J. Am. Chem. Soc. 1958, 80, 2428-
2433.
39. Greatrex, B. W.; Jenkins, N. F.; Taylor, D. K.; Tiekink, E. R.,
J. Org. Chem. 2003, 68, 5205-5210.
40. S. W. M. Crossley, C. Obradors, R. M. Martinez, R. A. Shenvi,
Chem. Rev. 2016, 116, 8912-9000.
41. (a) Mukaiyama, T.; Isayama, S.; Inoki, S.; Kato, K.; Yamada,
T.; Takai, T., Chem. Lett. 1989, 449-452. (b) Inoki, S.; Kato,
K.; Takai, T.; Isayama, S.; Yamada, T.; Mukaiyama, T., Chem.
Lett. 1989, 515-518. (c) Isayama, S.; Mukaiyama, T., Chem.
Lett. 1989, 1071-1074. (d) Isayama, S., Bull. Chem. Soc. Jpn.
1990, 63, 1305-1310.
42. Inoki, S.; Kato, K.; Isayama, S.; Mukaiyama, T., Chem. Lett.
1990, 1869-1872.
43. Magnus and coworkers repeated the synthetic procedure to
prepare Mn(dpm)2 in air, but the obtained product was
identified as Mn(dpm)3. The structure of Mn(dpm)3 was
determined by X-Ray analysis. (See references 43-46)
44. Magnus, P.; Payne, A. H.; Waring, M. J.; Scott, D. A.; Lynch,
V., Tetrahedron Lett. 2000, 41, 9725-9730.
45. Magnus, P.; Scott, D. A.; Fielding, M. R., Tetrahedron Lett.
2001, 42, 4127-4129.
46. Magnus, P.; Waring, M. J.; Scott, D. A., Tetrahedron Lett.
2000, 41, 9731-9733.
64. Lim, P. et al. Antimicrob. Agents Chemother. 2013, 57, 5277-
5283.

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65. This is possibly a result of mutations which increase the ability
2014, 505, 50-55. (c) Mbengue, A. et al. Nature, 2015, 520,
683.
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of the parasite to manage oxidative damage. For a recent
discussion, see: Paloque, L.; Ramadani, A. P.; Mercereau-
Puijalon, O.; Augereau, J.-M.; Benoit-Vical, F. Malaria J.
2016, 15, 149.
67. (a) Saicic, R. N. Tetrahedron 2014, 70, 8183-8218. (b) Young,
I. S.; Baran, P. S. Nat. Chem. 2009, 1, 193-205.
66. For recent studies on artemisinin resistance, see: (a) Straimer, J.
et al. Science, 2015, 347, 6220. (b) Ariey, F. et. al. Nature,