Synthesis of amorpha-4,11-diene from dihydroartemisinic acid

Article abstract of DOI:10.1016/j.tet.2018.12.050

Amorphadiene is a natural product involved in the biosynthesis of the antimalarial drug artemisinin. A convenient four-step synthesis of amorphadiene, starting from commercially available dihydroartemisinic acid, is reported. The targeted molecule is isolated with an overall yield of 85% on a multi-gram scale in four steps with only one chromatography.

Full text of DOI:10.1016/j.tet.2018.12.050

Accepted Manuscript
Synthesis of amorpha-4,11-diene from dihydroartemisinic acid
Geoffrey Schwertz, Andrea Zanetti, Marllon Nascimento de Oliveira, Mario Andrès
Gomez Fernandez, Fabienne Dioury, Janine Cossy, Zacharias Amara
PII:
S0040-4020(18)31540-0
https://doi.org/10.1016/j.tet.2018.12.050
TET 30036
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 9 November 2018
Accepted Date: 22 December 2018
Please cite this article as: Schwertz G, Zanetti A, Nascimento de Oliveira M, Gomez Fernandez
MarioAndrè, Dioury F, Cossy J, Amara Z, Synthesis of amorpha-4,11-diene from dihydroartemisinic
acid, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2018.12.050.
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ACCEPTED MANUSCRIPT
Synthesis of Amorpha-4,11-diene from Dihydroartemisinic Acid
a,b
a,b
a,b
Geoffrey Schwertz , Andrea Zanetti , Marllon Nascimento de Oliveira , Mario Andrès
a,b
b
a,
b,
Gomez Fernandez , Fabienne Dioury , Janine Cossy *, Zacharias Amara *
a
Laboratoire de Chimie Organique, Institute of Chemistry, Biology and Innovation (CBI),
UMR 8231, ESPCI ParisTech/CNRS/PSL Research University, Paris Cedex 05, France
b
Equipe de Chimie Moléculaire, Laboratoire de Chimie Moléculaire, Génie des Procédés
Chimiques et Energétiques (CMGPCE), EA 7341, Conservatoire national des arts et métiers,
HESAM Université, 2 rue Conté, Paris Cedex 03, France
Abstract: Amorphadiene is a natural product involved in the biosynthesis of the antimalarial
drug artemisinin. A convenient four-step synthesis of amorphadiene, starting from
commercially available dihydroartemisinic acid, is reported. The targeted molecule is isolated
with an overall yield of 85% on a multi-gram scale in four steps with only one
chromatography.
Keywords
Amorphadiene – Artemisinin – Malaria – Elimination – Microwaves
1
. Introduction
Amorphadiene (AD) is produced in plants by cyclization of farnesyl-pyrophosphate by the
1
enzyme amorphadiene synthase (ADS) (Scheme 1). AD is a key intermediate in the
1
,2
biosynthesis of the antimalarial drug artemisinin. In this context, the synthesis of AD has
2
–4
been described using a fermentation route (Amyris process).
However, AD is not yet
commercially available. Herein, we report a short and high-yielding gram-scale synthesis of
AD starting from the commercially available dihydroartemisinic acid, 1, which is an
5
intermediate in the Sanofi process to prepare artemisinin.
1

ACCEPTED MANUSCRIPT
Scheme 1. Semi-synthetic approach for the production of artemisinin (Amyris/Sanofi processes).
With the goal of providing a direct and scalable access to AD from the commercially
available natural product dihydroartemisinic acid, 1, a three-step synthetic procedure, relying
on the carboxylic acid reduction to the corresponding alcohol 2, followed by an
activation/elimination sequence to produce AD, was envisioned (Scheme 2). Bouwmeester et
al. described a similar synthetic approach as ours, starting from artemisinic acid, affording
6
AD with an overall yield of 25%. However, only a generic route was reported without
detailed procedures, scale, and yield for each individual step.
Scheme 2. Formation of amorphadiene, AD, from dihydroartemisinic acid, 1.
2
. Results and discussion
Our attempts for the direct reduction of 1 to 2 focused on the use of lithium aluminium
hydride (LiAlH ) as a reducing agent. The reaction was first tested using 2.0 equivalents of
4
7
LiAlH in anhydrous THF at 0 °C (Table 1, entry 1). However, only moderate conversion of
4
1
was obtained (60%) and alcohol 2 was isolated in only 25% yield after purification. By
increasing the amount of LiAlH in freshly distilled Et O and, after stirring at 23 °C for 2 h,
4
2
alcohol 2 was obtained with a good yield of 85% without purification (Table 1, entry 2). This
2

ACCEPTED MANUSCRIPT
yield was further improved to 95% by stirring the reaction mixture for 24 h (Table 1, entry 3).
Ultimately, we were able to optimize these conditions using 3.0 equivalents of LiAlH in non-
4
distilled Et O at a concentration of 0.29 M (Table 1, entry 4).
2
Table 1. Reduction of 1 to alcohol 2.
[
a]
Entry
LiAlH (equiv)
Solvent
T
t [h]
1
Conversion
ca. 60%
100%
Yield
4
1
2
3
4
2.0
5.0
5.0
3.0
THF (0.18
M
)
0 °C
25%
85%
95%
95%
Et
O (0.07
M
)
0 °C → 23 °C
0 °C → 23 °C
0 °C → 23 °C
2
2
[
b]
Et
Et
O (0.07
O (0.29
M
M
)
)
24
16
100%
2
2
[
b]
100%
[
a] Isolated yields. [b] The reaction was conducted with non-distilled solvent.
Different conditions were then evaluated to attempt direct conversion of 2 into AD.
8
Unfortunately, the direct elimination of the hydroxyl group, using either the Burgess reagent
9
or a one-pot selenide strategy, inspired in the Grieco method, failed to give satisfying results
1
0
even on purified 2 (Scheme 3).
Scheme 3. Attempts for the direct synthesis of AD from alcohol 2.
Alternatively, we considered the activation of the alcohol followed by an elimination.
Alcohol 2 was quantitatively converted to its corresponding mesylate 3 (MsCl, 1.1 equiv;
1
1
Et N, 1.5 equiv; in anhydrous CH Cl , 1 M) (Scheme 4). Bouwmeester et al. reported the
3
2
2
3

ACCEPTED MANUSCRIPT
same transformation of 2 to 3 using pyridine as solvent and base, which however, required
6
purification by column chromatography to isolate pure mesylate 3. We replaced pyridine
with dichloromethane as solvent and used only 1.5 equivalents of base, which afforded pure 3
without further purification.
Scheme 4. Transformation of alcohol 2 to the corresponding mesylate 3.
The elimination of the leaving group and formation of the C=C double bond turned out
to be more challenging than anticipated. Several conditions were attempted based on related
1
2–14
literature procedures (Table 2).
As the direct elimination of the mesylate group failed to
give satisfying results (Table 2, entry 1), 3 was treated with sodium iodide (NaI, 5.0 equiv)
and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 3.0 equiv) in a one-pot reaction, upon which
AD was isolated, after column chromatography, in 35% yield (Table 2, entry 2).
Alternatively, DBU was added only after completion of the Finkelstein reaction using NaI
(2.0 to 10.0 equiv) but yields in AD remained moderate (30–40%; Table 2, entries 3–5).
Table 2. Primary screening experiments for the elimination step.
Base
equiv)
DBU
Additive
(equiv)
Entry
“steps” Solvent
T
t [h]
20
Conversion Yield
(
1
2
3
4
5
–
1
1
2
2
2
THF
DMF
reflux
0%
–
(
3.0)
DBU
3.0)
DBU
3.0)
DBU
5.0)
DBU
5.0)
NaI
(5.0)
NaI
80 °C → 23 °C
48
100%
100%
100%
100%
35%
30%
40%
30%
(
DME
60 °C → reflux 5 then 3
(
(2.0)
NaI
2.5 then
Acetone
Reflux
13
(
(5.0)
NaI
Acetone
THF
Reflux
65 °C
13
(
(10.0)
3.5
4

ACCEPTED MANUSCRIPT
As the one-pot procedure was not high yielding, another method used by Baran et al.
1
5
on a similar scaffold as 3, consisting of isolating the iodo intermediate 4, after reacting 3
with NaI prior to the addition of base was realized (Scheme 5). The substitution of the
mesylate moiety by an iodine proceeded well, affording 4 in yields to 97%.
Scheme 5. Conversion of mesylate 3 into the iodinated intermediate 4.
After isolation, the iodo-compound 4 was reacted with DBU (5.0 equiv) in boiling
acetone and AD was isolated in 45% yield (Table 3, entry 1). It is worth noting that 4-
hydroxy-4-methylpentan-2-one was also isolated from this reaction, which presumably
indicates that a self-condensation of acetone occurred and thus, acetone was not considered as
a relevant solvent to carry out this transformation. In THF, a longer reaction time (24 h
instead of 5 h) was required to achieve full conversion of 4 (Table 3, entry 2) but the yield in
AD remained modest (45%). With these results in hand, we postulated that DBU could
promote undesirable side reactions and we decided to use alternative bases. No conversion
was observed with Et N (5.0 equiv) (Table 3, entry 3), whereas a moderate conversion was
3
recorded with 5.0 equivalents of t-BuOK after 40 h at 65 °C (55%) (Table 3, entry 4). This
result was improved by using microwave irradiation and gratifyingly, a complete conversion
of 4 was obtained after 1 h producing AD in 89% yield (Table 1, entry 5). Reducing the
amount of t-BuOK to 3.0 equiv did not give full conversion of 4 after 1 h in THF (Table 3,
entry 6). By using a freshly prepared solution of t-BuOK in THF (1 M), the excess of base
was reduced to 1.3 equivalents and the reaction time to 0.5 h, affording 1 in an excellent yield
of 96% (Table 3, entry 8). More importantly, it allowed us to increase the concentration in 4
to 0.75 M, which also enabled to scale-up the reaction to 4 g of 4 per batch using a standard
2
0 mL sealed tube.
Because thermal heating is usually preferred over microwave-assisted reaction for
large scale synthesis, we also investigated the preparation of AD using conventional heating.
A moderate conversion (50%) of 4 was achieved when the reaction was performed in tert-
butanol (t-BuOH) at 65 °C (Table 3, entry 9), whereas the iodo intermediate 4 was fully
converted to AD when the reaction was carried out in boiling t-BuOH (Table 3, entry 10).
Ultimately, we were able to perform the elimination with only 2.0 equivalents of t-BuOK (on
5

ACCEPTED MANUSCRIPT
a 6.5 g scale) and to isolate AD in 63% yield (Table 3, entry 11). We found that, in this case,
1
0% of the alcohol 2 was formed along with other unidentified side products (estimated yield
1
based on H NMR).
Table 3. Optimization of the conditions for the elimination step.
Entry
Base (equiv)
DBU (5.0)
DBU (5.0)
Solvent
Acetone
THF
[C]
T [°C]
Reflux
65
Time [h]
Conversion
100%
100%
0%
Yield
[
a]
1
2
3
4
5
6
7
8
9
0.15
0.15
0.15
0.15
0.15
0.15
0.15
0.75
0.15
0.15
1.50
M
5
24
40
40
1
45%
45%
–
[a]
M
M
M
M
M
M
M
M
M
M
Et
N (5.0)
THF
65
3
[
b]
t-BuOK (5.0)
t-BuOK (5.0)
t-BuOK (3.0)
t-BuOK (6.7) (1
t-BuOK (1.3) (1
t-BuOK (5.0)
t-BuOK (5.0)
t-BuOK (2.0)
THF
65
55%
47%
89%
47%
90%
96%
48%
86%
63%
[
c]
[a]
THF
65 (
µW)
100%
55%
[
[
b]
b]
THF
65 (
65 (
65 (
µW)
µW)
µW)
1
M
M
in THF)
in THF)
t-BuOH
0.5
0.5
5
100%
100%
50%
[
a]
[
[
b]
b]
65
90
90
1
1
0
1
t-BuOH
t-BuOH
5
100%
100%
[
a]
3.5
[
a] Isolated yield. [b] Estimated yield based on the GC/MS chromatogram of crude product. [c]
µW =
microwave irradiation.
3
. Conclusion
In summary, a screening of conditions allowed us to secure a straightforward access to the
important terpene, amorphadiene (AD), from commercially available dihydroartemisinic acid
1
(Scheme 6). The most challenging step was the elimination step, which required
considerable optimization. Eventually, 1.3 equiv of t-BuOK (1 M in THF) were sufficient to
achieve full conversion of 4 in 0.5 h and to produce AD in 96% yield. Alternatively, we also
developed a thermal approach in boiling t-BuOH affording AD in 63% yield. It is noteworthy
to mention that alcohol 2 could be transformed in one step to its corresponding bromo
1
6
derivative 5 by employing an Appel bromination (see Experimental Section), however, a
lower yield (35%) was obtained for the elimination step.
6

ACCEPTED MANUSCRIPT
Scheme 6. Synthesis of amorphadiene, AD, from dihydroartemisinic acid, 1.
A reliable and straightforward multi-gram scale synthesis of amorphadiene from
dihydroartemisinic acid has been established with an overall yield of 85%. This will enable
future scale-up and access to this key molecule for studying its transformation into artemisinic
acid and artemisinin derivatives.
4
. Experimental Section
4
.1 General Information
Reagents (Aldrich) were purchased as reagent grade and used without further purification.
Reactions in the absence of air and moisture were performed in oven-dried glassware under
Ar atmosphere. Flash column chromatography was performed using SiO (60 Å, 230–
2
4
00 mesh, particle size 0.040–0.063 mm, Merck) at 23 °C with a head pressure of 0.0–0.5 bar.
The solvent compositions are reported individually in parentheses. Analytical thin layer
chromatography (TLC) was performed on aluminium sheets coated with silica gel 60 F254
(
Merck, Macherey-Nagel) or with silica gel 60 RP-18 F254s (Merck, Macherey-Nagel).
Visualization was achieved using an alkaline aqueous solution of potassium permanganate
KMnO ). Evaporation in vacuo was performed at 25–35 °C and 900–10 mbar. Reported
(
4
yields refer to spectroscopically and chromatographically pure compounds that were dried
1
13
under high vacuum (0.1–0.05 mbar) before analytical characterization. H and C nuclear
magnetic resonance (NMR) spectra were recorded on a Bruker AV 400 spectrometer at
1
13
4
00 MHz ( H) and 101 MHz ( C). Chemical shifts
δ are reported in ppm upfield using the
residual deuterated solvent signals as an internal reference (CDCl3: δH = 7.26 ppm, δC
=
7

ACCEPTED MANUSCRIPT
1
7
7.16 ppm). For H NMR, coupling constants J are given in Hz and the resonance multiplicity
is described as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad). All
spectra were recorded at 298 K. Infrared (IR) spectra were recorded on a Bruker Tensor 27
–
1
FT-IR spectrometer and are reported as wavenumbers ꢀꢁ ꢂ(cm ). High-resolution mass
spectrometry (HRMS) was performed by the Laboratoire de Spectrométrie de Masse from
Sorbonne Université, Paris. Gas Chromatography coupled to Mass Spectrometry (GC/MS)
analysis was performed on a Shimadzu GCMS-QP2010S using an electronic impact (EI)
spectrometer. Low-resolution mass spectra (LRMS) result from ionization by electronic
impact (EI-LRMS). The abundance indicated for each mass number (m/z values) is given in
percentage relative to the strongest peak of 100% abundance (base peak). Melting points were
determined using a Büchi melting point apparatus in open capillaries. Nomenclature follows
the suggestions proposed by the software ChemDraw Professional 2016.
4
4
.2 Synthesis of Amorpha-4,11-diene (AD)
.2.1(R)-2-((1R,4R,4aS,8aS)-4,7-dimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalen-1-
yl)propan-1-ol (2)
A suspension of LiAlH (12.2 g, 321.5 mmol) in Et O (120 mL) was cooled below 0 °C with
4
2
an ice/sodium chloride/water bath and treated over 1.5 h with a solution of dihydroartemisinic
acid (1) (25.0 g, 105.78 mmol) in Et O (250 mL) while maintaining the internal temperature
2
below 7 °C. The mixture was maintained in the cold bath, allowed to warm up to 23 °C,
stirred for 16 h, cooled below 0 °C, and treated dropwise with H O (12.5 mL; 1.0 mL/g of
2
LiAlH ) while maintaining the internal temperature below 5 °C. The mixture was stirred at
4
5
°C for 20 min, treated carefully with a 15% NaOH solution in H O (12.5 mL; 1.0 mL/g of
2
LiAlH ), stirred for 10 min at 5 °C, and treated with H O (37.0 mL; 3.0 mL/g of LiAlH )
4
2
4
while maintaining the internal temperature below 5 °C. Anhydrous MgSO was added to
4
absorb the remaining water and the mixture was filtered. The filtrate was evaporated to afford
2
(22.40 g, 95%) as a white solid.
20
m.p. 83.9–84.3 °C; R = 0.22 (SiO ; petroleum ether/EtOAc 95:05; KMnO ); [α] = –8.8° (c
f
2
4
D
1
1
2
1
6
1
.04, CHCl ); H NMR (400 MHz, CDCl ): δ = 5.21 (br s, 1 H), 3.75 (m, 1 H), 3.52 (m, 1 H),
3
3
.47 (br s, 1 H), 2.08–1.72 (m, 3 H), 1.69–1.57 (m, 3 H), 1.61 (s, 3 H), 1.53 (m, 1 H), 1.41 (m,
H), 1.30–1.14 (m, 2 H), 1.00 (d, J = 6.8 Hz, 3 H), 1.08–0.88 (m, 2 H), 0.86 ppm (d, J =
13
.4 Hz, 3 H), OH signal too weak to be observed; C NMR (101 MHz, CDCl ):
δ = 135.3,
3
20.8, 67.0, 42.8, 42.2, 37.7, 36.8, 35.8, 27.8, 26.8, 26.5, 26.0, 24.0, 20.0, 15.1 ppm; IR
8

ACCEPTED MANUSCRIPT
–
1
(
ATR): ꢀꢁ ꢂ= 3335, 3328, 2920, 2865, 1467, 1451, 1432, 1370, 1025, 991, 955 cm ; HR-ESI-
+
+
MS: m/z: 245.1875 ([M + Na] , calcd for C H ONa : 245.1876); GC/MS: m/z (%): 222 (11,
1
5
26
+
+
[
(
M] ), 191 (14, [M – CH O]), 163 (100, [M – C H O] ), 149 (10), 135 (15), 121 (25), 107
3 3 7
1
7
36), 105 (14). Analytical data correspond to the literature.
4
.2.2(R)-2-((1R,4R,4aS,8aS)-4,7-dimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalen-1-yl)propyl
methanesulfonate (3)
A solution of 2 (18.89 g, 85.0 mmol) in anhydrous CH Cl (85 mL) was cooled to 0 °C,
2
2
treated with Et N (18.4 mL, 127.5 mmol), stirred for 5 min at 0 °C, and treated dropwise with
3
MsCl (7.6 mL, 93.5 mmol) leading to a white precipitate. The mixture was stirred at 23 °C for
2
.5 h and diluted with CH Cl (40 mL). The organic layer was washed with 1
N
HCl (2 ×
2
2
2
0 mL), dried over MgSO , filtered, and evaporated to afford mesylate 3 (25.64 g, quant.) as a
4
white crystalline solid.
m.p. 71.7–73.5 °C; R = 0.24 (SiO ; petroleum ether/EtOAc 95:05; KMnO ); [α] = –9.8° (c
20
f
2
4
D
1
1
.02, CHCl ); H NMR (400 MHz, CDCl ):
δ
= 5.14 (br s, 1 H), 4.29 (dd, J = 9.5, 3.2 Hz, 1
3
3
H), 4.12 (dd, J = 9.5, 6.2 Hz, 1 H), 3.00 (s, 3 H), 2.47 (br s, 1 H), 2.00–1.72 (m, 4 H), 1.69–
1
1
1
.48 (m, 3 H), 1.63 (s, 3 H), 1.40 (m, 1 H), 1.31–1.16 (m, 2 H), 1.04 (d, J = 6.8 Hz, 3 H),
1
3
.02–0.87 (m, 2 H), 0.86 ppm (d, J = 6.5 Hz, 3 H); C NMR (101 MHz, CDCl ):
δ
= 135.9,
3
20.0, 74.1, 42.5, 42.0, 37.4, 37.3, 35.5, 34.6, 27.7, 26.8, 26.3, 25.9, 24.0, 19.8, 15.2 ppm; IR
–
1
(
ATR): ꢀꢁ ꢂ= 2911, 2868, 1449, 1353, 1175, 1110, 953 cm ; HR-ESI-MS: m/z: 323.1650 ([M +
+
+
+
Na] , calcd for C H O SNa : 323.1651); GC/MS: m/z (%): 300 (11, [M] ), 163 (100, [M –
1
6
28
3
+
C H O S] ), 147 (17), 133 (10), 121 (29), 119 (19), 107 (31), 105 (20).
4
9
3
4
.2.3(1R,4R,4aS,8aS)-1-((R)-1-iodopropan-2-yl)-4,7-dimethyl-1,2,3,4,4a,5,6,8a-
octahydronaphthalene (4)
A solution of mesylate 3 (12.03 g, 40.0 mmol) in acetone (80 mL) was treated with NaI
(
18.0 g, 120.1 mmol), stirred at 70 °C for 0.5 h, cooled to 23 °C, diluted with Et O (100 mL)
2
and H O (50 mL). The two layers were separated and the aqueous layer was extracted with
2
Et O (6 × 50 mL). The combined organic layers were washed twice with a Na S O sat.
2
2
2
3
aqueous solution (100 + 50 mL), dried over MgSO , filtered, and evaporated to afford 4
4
(12.33 g, 93%) as a light yellow oil that crystallizes upon cooling in a freezer.
20
1
R = 0.70 (SiO ; hexane; KMnO ); [α]
= –32.0° (c 1.02, CHCl ); H NMR (400 MHz,
f
2
4
D
3
CDCl3):
δ
= 5.17 (br s, 1 H), 3.44 (dd, J = 9.7, 2.5 Hz, 1 H), 3.30 (dd, J = 9.7, 5.4 Hz, 1 H),
9

ACCEPTED MANUSCRIPT
2
2
0
3
1
9
.49 (br s, 1 H), 2.03–1.84 (m, 2 H), 1.79 (m, 1 H), 1.64 (m, 1 H), 1.62 (s, 3 H), 1.59–1.48 (m,
H), 1.41 (m, 1 H), 1.33–1.10 (m, 3 H), 0.99 (d, J = 6.4 Hz, 3 H), 0.97–0.89 (m, 2 H),
1
3
.87 ppm (d, J = 6.5 Hz, 3 H); C NMR (101 MHz, CDCl ):
δ = 135.8, 121.1, 46.0, 42.1,
3
7.7, 35.6, 34.8, 27.7, 26.8, 26.1, 25.9, 24.0, 20.2, 19.9, 19.0 ppm; IR (ATR): ꢀꢁ ꢂ= 2906, 2867,
447, 1433, 1377, 1303, 1291, 1254, 1227, 1191, 1171, 1159, 1110, 1031, 990, 957, 942,
–
1
+
24 cm ; HR-ESI-MS: molecule not ionized in ESI; GC/MS: m/z (%): 332 (4, [M] ), 163
+
(
100, [M – C H I] ), 121 (19), 107 (25), 105 (7).
3
6
4
.2.4(1R,4R,4aS,8aS)-1-((R)-1-bromopropan-2-yl)-4,7-dimethyl-1,2,3,4,4a,5,6,8a-
octahydronaphthalene (5)
A solution of 2 (100 mg, 0.45 mmol) in CH Cl (2.5 mL) was treated with PPh (236 mg,
2
2
3
0
.90 mmol), cooled to 0 °C, treated with CBr (375 mg, 1.13 mmol), stirred at 0 °C for 1 h,
4
and evaporated. The crude was absorbed on SiO and column chromatography (SiO pre-
2
2
treated with hexane/Et N 99:01; hexane) gave 5 (128 mg, quant.) as a colorless oil.
3
20
1
R = 0.60 (SiO ; hexane; KMnO ); [α]
= –16.1° (c 0.94, CHCl ); H NMR (400 MHz,
3
f
2
4
D
CDCl3):
δ = 5.17 (br s, 1 H), 3.61 (dd, J = 9.9, 2.6 Hz, 1 H), 3.49 (dd, J = 9.9, 5.6 Hz, 1 H),
2
.49 (br s, 1 H), 2.02–1.74 (m, 4 H), 1.70–1.48 (m, 3 H), 1.63 (s, 3 H), 1.42 (m, 1 H), 1.35–
.18 (m, 2 H), 1.05 (d, J = 6.5 Hz, 3 H), 1.03–0.90 (m, 2 H), 0.87 ppm (d, J = 6.5 Hz, 3 H);
1
1
3
C NMR (101 MHz, CDCl3):
δ = 135.7, 120.7, 44.2, 42.5, 42.1, 37.6, 35.8, 35.6, 27.7, 26.8,
2
1
6.1, 25.9, 24.0, 19.9, 17.0 ppm; IR (ATR): ꢀꢁ ꢂ= 2907, 2869, 1447, 1435, 1379, 1334, 1306,
–
1
290, 1261, 1236, 1218, 1185, 1159, 1140, 1110, 1075, 1037, 991, 958, 942, 925 cm ; HR-
+
+
ESI-MS: molecule not ionized in ESI; GC/MS: m/z (%): 286 (4, [M] ), 284 (4, [M] ), 163
+
(
100, [M – C H Br] ), 121 (18), 107 (22), 105 (5).
3
6
4
.2.5(1R,4R,4aS,8aR)-4,7-dimethyl-1-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,8a-
octahydronaphthalene (Amorpha-4,11-diene, AD)
Microwave-assisted Approach:
Iodo derivative 4 (11.85 g, 35.7 mmol) was treated with t-BuOK (1
M in THF) (46.4 mL,
4
6.4 mmol), stirred at 65 °C in a microwave oven for 30 min, diluted with Et O (150 mL) and
2
H O (150 mL). The two layers were separated and the aqueous layer was extracted with Et O
2
2
(
4 × 75 mL). The combined organic layers were washed brine, dried over MgSO , filtered,
4
and evaporated. Column chromatography (SiO ; hexane) gave AD (7.03 g, 96%) as a
2
colorless oil.
1
0

ACCEPTED MANUSCRIPT
Thermal Approach:
A solution of iodo derivative 4 (6.46 g, 19.43 mmol) in melted t-BuOH (13 mL) was treated
with t-BuOK (4.4 g, 39.2 mmol), stirred at reflux for 3.5 h, diluted with Et O (60 mL) and
2
H O (60 mL). The two layers were separated and the aqueous layer was further extracted with
2
Et O (4 × 30 mL). The combined organic layers were dried over MgSO , filtered, and
2
4
evaporated. Column chromatography (SiO ; cyclohexane) gave AD (2.52 g, 63%) as a
2
colorless oil.
2
0
R = 0.77 (SiO ; hexane; KMnO ); R = 0.34 (RP-18; MeOH; KMnO ); [α] = –13.9° (c
D
f
2
4
f
4
20
D
1
1
.00, CHCl ) ([18]: [α] = –14.0° (c 0.4, CHCl )); H NMR (400 MHz, CDCl ):
δ
= 5.06 (br
s, 1 H), 4.87 (br s, 1 H), 4.64 (br s, 1 H), 2.55 (br s, 1 H), 2.06–1.83 (m, 3 H), 1.77 (m, 1 H),
.74 (s, 3 H), 1.67 (dq, J = 12.9, 3.5 Hz, 1 H), 1.60 (s, 3 H), 1.59–1.46 (m, 2 H), 1.40 (m, 1
3
3
3
1
1
3
H), 1.35–1.18 (m, 2 H), 0.98 (qd, J = 12.8, 3.4 Hz, 1H), 0.89 ppm (d, J = 6.4 Hz, 3 H); C
NMR (101 MHz, CDCl3): = 148.5, 135.1, 121.3, 110.2, 48.1, 42.3, 38.1, 35.9, 28.3, 26.9,
6.5, 26.3, 24.1, 23.1, 20.3 ppm; IR (ATR): ꢀꢁ ꢂ= 2918, 2866, 1643, 1446, 1376, 1240, 1173,
δ
2
1
2
–
1
139, 1108, 993, 968, 936 cm ; HR-ESI-MS: molecule not ionized in ESI; GC/MS: m/z (%):
+
+
18
04 (45, [M] ), 189 (73, [M – CH ] ), 119 (100). Analytical data correspond to the literature.
3
Acknowledgements
This work was supported by the Bill & Melinda Gates Foundation [OPP1190174]. We would
like to thank Dr. Kai Rossen for his advice and for helpful discussions. We also thank Cédric
Przybylski at the Laboratoire de Spectrométrie de Masse of the Sorbonne Université, Paris,
for HRMS measurements.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at
https://doi.org/
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2
2
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Highlights
•
•
•
•
A direct method for the production of amorpha-4,11-diene.
The multi-step sequence is high yielding, scalable and reproducible.
The multi-step sequence involves only one chromatography.
The last step is accelerated using microwave irradiation.