An Efficient Chemoenzymatic Synthesis of Dihydroartemisinic Aldehyde

Article abstract of DOI:10.1002/anie.201609557

Artemisinin from the plant Artemisia annua is the most potent pharmaceutical for the treatment of malaria. In the plant, the sesquiterpene cyclase amorphadiene synthase, a cytochrome-dependent CYP450, and an aldehyde reductase convert farnesyl diphosphate (FDP) into dihydroartemisinic aldehyde (DHAAl), which is a key intermediate in the biosynthesis of artemisinin and a semisynthetic precursor for its chemical synthesis. Here, we report a chemoenzymatic process that is able to deliver DHAAl using only the sesquiterpene synthase from a carefully designed hydroxylated FDP derivative. This process, which reverses the natural order of cyclization of FDP and oxidation of the sesquiterpene hydrocarbon, provides a significant improvement in the synthesis of DHAAl and demonstrates the potential of substrate engineering in the terpene synthase mediated synthesis of high-value natural products.

Full text of DOI:10.1002/anie.201609557

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201609557
German Edition: DOI: 10.1002/ange.201609557
Sesquiterpenoids
An Efficient Chemoenzymatic Synthesis of Dihydroartemisinic
Aldehyde
Melodi Demiray, Xiaoping Tang, Thomas Wirth, Juan A. Faraldos, and Rudolf K. Allemann*
Abstract: Artemisinin from the plant Artemisia annua is the
most potent pharmaceutical for the treatment of malaria. In the
plant, the sesquiterpene cyclase amorphadiene synthase, a cyto-
chrome-dependent CYP450, and an aldehyde reductase con-
vert farnesyl diphosphate (FDP) into dihydroartemisinic
aldehyde (DHAAl), which is a key intermediate in the
biosynthesis of artemisinin and a semisynthetic precursor for
its chemical synthesis. Here, we report a chemoenzymatic
process that is able to deliver DHAAl using only the
sesquiterpene synthase from a carefully designed hydroxylated
FDP derivative. This process, which reverses the natural order
of cyclization of FDP and oxidation of the sesquiterpene
hydrocarbon, provides a significant improvement in the syn-
thesis of DHAAl and demonstrates the potential of substrate
engineering in the terpene synthase mediated synthesis of high-
value natural products.
Scheme 1. Top: Current routes to artemisinin. Bottom: One-step ADS-
catalyzed synthesis of dihydroartemisinic aldehyde (DHAAl, 4) from
12-hydroxyfarnesyl diphosphate (7).
The sesquiterpenoid endoperoxide artemisinin (1) is widely
used as a first-line treatment for malaria in combination
therapy.[1] Although elegant organic syntheses of artemisinin
have been published,[2] the worldwide supply of 1 predom-
inantly relies on extraction from the plant Artemisia annua.[3]
The demand for artemisinin is mainly from the developing
world, which requires the drug to be produced at low cost.
Currently the most efficient way to synthesize artemisinin is
to combine biosynthesis with chemical steps. Central to the
biosynthesis of 1 (Scheme 1) is the class I sesquiterpene
cyclase amorphadiene synthase (ADS), which catalyzes the
conversion of (E,E)-farnesyl diphosphate (FDP, 2) into
amorpha-4,11-diene (3). In this complex reaction cascade,
two 6-membered rings, four stereocentres, and two double
bonds are formed with exquisite regio- and stereochemical
control in one step.[4] Dihydroartemisinic aldehyde (DHAAl,
4) can be made from amorpha-4,11-diene (3) either through
a three-step chemical synthesis or by combining a biooxida-
tion with two chemical steps.[5] Compound 4 can then be
converted into 1 chemically or enzymatically in four well-
established steps.[2a,6] It is noteworthy that an elegant semi-
synthetic pathway has been developed that uses ADS and five
other enzymes in yeast to produce artemisinic acid (5), which
is then converted into dihydroartemisinic acid (6) by tran-
sition metal-catalyzed hydrogenation. The pharmaceutical
company Sanofi scaled up this process in 2014 but the
manufacture was discontinued owing to strong market
forces,[7] thus highlighting the need for ecologically friendly,
low-cost alternatives for the production of artemisinin.
Herein, we report a novel chemoenzymatic process that
exploits the substrate promiscuity of ADS to convert the
hydroxylated FDP analogue 7 into the synthetic intermediate
DHAAl (4). In contrast to existing procedures, this process,
which reverses the natural order of cyclization of FDP and
oxidation of the sesquiterpene hydrocarbon, significantly
shortens the synthesis of dihydroartemisinic aldehyde (4), in
that it uses only one enzyme and requires a single oxidation
step that occurs prior to the ADS-catalyzed cyclization to 4.
The process avoids several redox steps after the cyclization
since it bypasses the formation of the intermediate amorpha-
diene (3) altogether (Scheme 1).
Amorphadiene synthase (ADS) catalyzes the Mg2+-de-
pendent conversion of its natural substrate FDP (2; see
Figure S13 in the Supporting Information) along a complex
reaction path that involves isomerization of the 2,3-double
bond from the E to the Z configuration and 1,6-cyclization to
generate a bisabolyl cation (8), followed by a 1,3-hydride shift
from C1 to C7 and 1,10-cyclization to the amorphyl cation (9).
Finally, deprotonation at C12 or C13 generates amorpha-4,11-
diene (3; Scheme 2 and Figures S4,S22,S23).[8]
[*] M. Demiray, Dr. X. Tang, Prof. Dr. T. Wirth, Dr. J. A. Faraldos,
Prof. Dr. R. K. Allemann
School of Chemistry, Cardiff University
Main Building, Park Place, Cardiff CF10 3AT (Great Britain)
E-mail: allemannrk@cf.ac.uk
Many sesquiterpene synthases display some degree of
substrate promiscuity, and are able to convert methylated and
fluorinated farnesyl diphosphate analogues into modified
Homepage: http://blogs.cardiff.ac.uk/allemann
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201609557.
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Scheme 4. Synthesis of 12-hydroxyfarnesyl diphosphate (7) from com-
mercially available farnesyl chloride 10. a) SeO2 (0.3 equiv), salicylic
acid (0.3 equiv), tBuOOH (5 equiv), CH2Cl2, 08C. b) (Bu4N)3HP2O7
(2 equiv), CH3CN, room temperature.
available (11R)-dihydroartemisinic acid (11R)-6 (Figur-
Scheme 2. Synthesis of amorphadiene (3) from FDP (2) in the plant A.
annua.
es S7,S8,S26,S27).[6b,16]
1
The H-NMR spectrum of the purified enzymatic prod-
ucts (Figure 1 and Figures S24, S25) from incubations of 7
terpenoids.[9–11] In this work, we investigated for the first time
the potential of a sesquiterpene synthase to accept a hydroxy-
lated FDP analogue as a substrate. In particular, we asked
whether ADS[11b] could convert 12-hydroxyfarnesyl diphos-
phate (7;[12] Scheme 1) into dihydroartemisinic aldehyde (4)
via a 12-hydroxyamorphyl cation (OH-9; Scheme 3). It is
Figure 1. 1H NMR (500 MHz, CDCl3) of the pentane-extractable prod-
ucts generated by ADS-catalyzed turnover of 7 after silica-gel purifica-
tion, with inserts showing the diagnostic peaks assigned to H12, H2,
11-CH3, and 7-CH3.
with ADS showed the presence of a 3:2 mixture of aldehydes
as clearly revealed by their diagnostic NMR signals at dH
9.62 ppm (1H, d, J = 3.5 Hz, CHO, major) and 9.57 ppm (1H,
d, J = 3.5 Hz, CHO, minor). The identity of the minor product
Scheme 3. The ADS-catalyzed synthesis of 4 from 12-hydroxyfarnesyl
diphosphate (7) and 12-acetoxyfarnesyl diphosphate (13) via carboca-
tions OH-9 and 15, respectively.
1
was determined to be (11R)-4 based on H-NMR data and
comparison with an authentic sample of
4
(Figur-
es S26,S27).[17a] The structure of the major aldehyde was
deduced to be the (11S)-4 epimer based on its diagnostic 1H-
NMR signals at dH 5.27 (s, H2), 1.64 (s, 3-Me), 1.07 (d, J =
6.8 Hz, 11-Me), and 0.87 ppm (d, J = 6.5 Hz, 7-Me), which are
complementary to those of (11R)-4 at dH 5.13 (s, H2), 1.64 (s,
3-Me), 1.06 (d, J = 6.9 Hz, 11-Me), and 0.87 ppm (d, J =
6.5 Hz, 7-Me; Figure 1). In addition, the epimeric nature of
(11R)-4 and (11S)-4 is further supported by the epimerization
of the corresponding esters that is described later in
Scheme 6. Analysis of the NMR sample by GC–MS showed
a 7:2 mixture of (11S)-4 and (11R)-4, in addition to
approximately 10% of a minor product (Figure 2) that we
tentatively propose to be the enol form (12) of aldehyde 4
based on its identical MS spectrum (Figure S3) with that of
(11S)-4. The MS spectra as well as the GC elution times of
known that a-hydroxylated carbocations such as OH-9 can
isomerize under acidic conditions to aldehydes.[13] The
electrophilic nature of terpene synthase chemistry combined
with the inherent reactivity of a-hydroxylated carbocations
such as OH-9 should therefore lead to aldehyde 4.
Diphosphate 7 was synthesized in two steps from com-
mercially available (E,E)-farnesyl chloride (10; Scheme 4).
The short synthesis involved low-temperature acid-catalyzed
selenium dioxide oxidation of 10[14] and diphosphorylation of
the resulting chloride 11[15] (Tables S1,S2 and Figures S13–
1
S16). For H NMR and GC–MS comparison, an authentic
sample of aldehyde 4 was prepared from commercially
2
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Scheme 5. ADS-catalyzed production of (11S)-4 from 13-acetoxyfarne-
syl diphosphate (16) via carbocation 17.
Figure 2. GC chromatogram (TIC) of the pentane-extractable products
from an incubation of diphosphate 7 (blue), 13 (red), and 16 (green)
with ADS. GC peaks were assigned as putative enol 12 (21.24 min),
and aldehydes (11R)-4 (22.29 min), and (11S)-4 (22.48 min).
To further advance this novel chemoenzymatic approach
towards the production of artemisinin, the 2:3 mixture of
(11R) and (11S)-4 was oxidized to the corresponding dihy-
droartemisinic acids (6) in 93% yield (Scheme 6),[2b] and
(11R)-4 (faster) and (11S)-4 are consistent with those
reported previously.[17] The reaction mechanism for the
conversion of FDP to amorphadiene (Scheme 2) suggests
that enol 12 may initially be formed from carbocation OH-9
through deprotonation of either Ha or Hb (path a-b in
Scheme 3) before 12 equilibrates to the observed mixture of
epimers of 4 outside the active site of ADS. However
incubations of diphosphate 7 with ADS in D2O led to the
exclusive production of deuterated (11S)-4 (Figure S10); no
deuterated (11R)-4 was detected by GC–MS. This observa-
tion indicates that only (11S)-4 can be formed via enol 12.
To further investigate the capability of ADS to act on
unnatural substrates, 12-acetoxyfarnesyl diphosphate (13)
was prepared in three steps (32% overall yield) from
known 1-O-THP-protected 12-hydroxyfarnesol[14] (Figur-
es S17,S18) and incubated with ADS. GC–MS analysis
revealed that the same three products were obtained as
from incubations with diphosphate 7 (Figure 2 and Figure S9).
The observation that no vinyl acetate 14 is produced from 13
(Scheme 3) suggests that the enol 12 is not a product of ADS
catalysis but is formed exclusively from (11S)-4 after its
release from the active site. Control experiments excluded the
presence of ester hydrolase activity in our enzyme prepara-
tions (see the Supporting Information). Remarkably, the
incubation of 13-acetoxyfarnesyl diphosphate (16, Fig-
ure S19) with ADS (Scheme 5) yielded (11S)-4 (93%) and
enol 12 (7%; Figure 2 and Figures S5,S6). The absence of
significant amounts of the (11R)-epimer of 4 implies that enol
12 does not revert to (11R)-4 under the reaction conditions
(pH ꢀ 7.5; Scheme 3). These results strongly suggest that only
one pathway operates to yield the observed epimeric mixture
of aldehydes 4. Hence the formation of 4 from 7 (and 13) most
likely proceeds through an oxygen-assisted non-stereospecific
intramolecular [1,2]-hydride shift from carbocation OH-9 (or
15 for 13; paths a and b in Scheme 3). Since the stable vinyl
acetate 14 is not formed from 13-acetoxyfarnesyl diphosphate
(16), deprotonation of 17 via enol 12 to (11S)-4 appears
unlikely. Hence a stereospecific [1,2]-hydride shift of Ha from
carbocation 17 most likely accounts for the exclusive for-
mation of (11S)-4 (path a in Scheme 5) from diphosphate 16.
Scheme 6. Synthesis of dihydroartemisinic acid methyl ester (18).
subsequently converted into the corresponding dihydroarte-
misinic methyl esters (18) in 94% yield (Figure S11).[18]
Treatment of the esters with LDA under kinetic control
resulted in a 1:1 mixture of (11R)- and (11S)-methyl esters
(Figure S28). (11R)-dihydroartemisinic methyl ester is the
desired intermediate for the synthesis of artemisinin.[19]
In conclusion, we have developed an efficient chemo-
enzymatic route to dihydroartemisinic aldehyde (4), a major
intermediate in the production of artemisinin (1), the most
important drug for the treatment of malaria. We have for the
first time shown that hydroxylated FDP analogues can be
accepted as substrates by sesquiterpene synthases. Hence our
work offers a novel “reversed biosynthetic” approach for the
synthesis of functionally diversified hydroxylated terpenoids.
The chemical synthesis of such products is often difficult
owing to the need to make several small rings with high
stereo- and regiocontrol. The relatively high substrate pro-
miscuity and the templating effect of the active site allow
terpene synthases to chaperone unnatural substrates along
well-defined reaction paths to specific products with high
fidelity. This design offers a promising approach for the
production of high-value terpenoids and terpene alkaloids[11a]
that is complementary to conventional synthetic and biosyn-
thetic procedures.
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Biological Sciences Research Council (BBSRC) through
grants (BB/H01683X/1, BB/M022463/1, BB/N012526/1) and
by the Engineering and Physical Sciences Research Council
(EPSRC) through grant EP/M013219/1. We thank Dr.
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Conflict of interest
The authors declare no conflict of interest.
Keywords: artemisinin · chemoenzymatic synthesis ·
sesquiterpenoids · substrate engineering · synthetic biology
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Manuscript received: September 29, 2016
Revised: January 18, 2017
Final Article published: && &&, &&&&
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Communications
Sesquiterpenoids
An offering to Artemis: Amorphadiene
synthase (ADS) from Artemisia annua can
be used to convert 12-hydroxyfarnesyl
diphosphate into dihydroartemisinic
aldehyde, a direct biosynthetic precursor
of the high-value antimalarial drug arte-
misinin.
M. Demiray, X. Tang, T. Wirth,
J. A. Faraldos,
R. K. Allemann*
&&&& — &&&&
An Efficient Chemoenzymatic Synthesis
of Dihydroartemisinic Aldehyde
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!