Direct, Biomimetic Synthesis of (+)-Artemone via a Stereoselective, Organocatalytic Cyclization

Article abstract of DOI:10.1055/s-0034-1380684

We present a four-step synthesis of (+)-artemone from (-)-linalool, featuring iminium organocatalysis of a doubly diastereoselective conjugate addition reaction. The strategy follows a proposed biosynthetic pathway, rapidly generates stereochemical complexity, uses no protecting groups, and minimizes redox manipulations. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0034-1380684

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 2599–2602
paper
2599
E. D. Nacsa et al.
Paper
Synthesis
Direct, Biomimetic Synthesis of (+)-Artemone via a Stereoselective,
Organocatalytic Cyclization
Eric D. Nacsa
1.
1. SeO2, t-BuOOH
2. prolinol catalyst
Br
Brian C. Fielder
OH
H
O
Zn, Cp2TiCl2
H
O
O
O
Shannon P. Wetzler
Veerasak Srisuknimit
Jonathan P. Litz
Mary J. Van Vleet
Kim Quach
14%
2. SO3•py, DMSO
36%
H
(–)-linalool
lilac aldehyde
(dr 15:1:1:2)
(+)-artemone
(single isomer)
David A. Vosburg*
Department of Chemistry, Harvey Mudd College,
301 Platt Boulevard, Claremont, CA 91711, USA
vosburg@hmc.edu
Received: 07.03.2015
Accepted after revision: 07.04.2015
Published online: 19.05.2015
allylic
oxidation
OH
OH
O
DOI: 10.1055/s-0034-1380684; Art ID: ss-2015-m0145-op
Abstract We present a four-step synthesis of (+)-artemone from (–)-
linalool, featuring iminium organocatalysis of a doubly diastereoselec-
tive conjugate addition reaction. The strategy follows a proposed bio-
synthetic pathway, rapidly generates stereochemical complexity, uses
no protecting groups, and minimizes redox manipulations.
conjugate
addition
Key words natural products, cyclization, terpenoids, total synthesis,
stereoselective synthesis, green chemistry, organocatalysis, biomimet-
ic synthesis
H
O
O
(+)-artemone
Artemone is a sesquiterpene natural product from the
Indian sage Artemisia pallens.1 Some of the other metabo-
lites from this plant have been shown to possess useful me-
dicinal properties,2 though none have yet been disclosed for
artemone. Many related compounds have desirable olfacto-
ry properties.3
The only reported stereoselective syntheses of artemo-
ne are a 20-step route by Honda and co-workers,4 which re-
sults in a 1:2 mixture of artemone and davanone, and our
recent six-step synthesis via a diastereoselective allylic O-
alkylation.5 We sought a shorter route to artemone and
looked for inspiration to the plausible biosynthetic pathway
in Scheme 1,6 an alternative biomimetic approach to our
previous studies on davanone.7 We propose that the final
steps in the biosynthesis of artemone are an allylic oxida-
tion and an intramolecular conjugate addition reaction. The
latter step generates the ring and introduces two new ste-
reocenters in a single operation.
Scheme 1 Proposed biosynthesis of artemone
a stereoselective conjugate addition reaction. We were also
guided by Gaich and Baran’s description of an ideal synthe-
sis9 and aimed to avoid protecting groups and unnecessary
functional group transformations, even being willing to
sacrifice chemical yield for a maximally direct route.
We selected (–)-linalool, an inexpensive monoterpene,
as our starting material (Scheme 2). The selenium dioxide
mediated oxidation of linalool to enal 1 is a known reac-
tion.10 While we never obtained the impressively high yield
(79%) that Sharma and Chand reported for this transforma-
tion, we could reliably access 1 at room temperature or
with microwave heating. Column chromatography readily
separated the enal from residual linalool and the interme-
diate diol.
The conjugate addition step is pivotal, as it establishes
the remaining two stereocenters not already present in lin-
alool. This is a challenging reaction, however, as the tertiary
alcohol is a poor nucleophile and the α-methyl group disfa-
vors enal activation with bulky amines or metal–ligand
complexes. Also, the vast majority of published stereoselec-
Our strategy is similar to that of Naegeli and co-workers,
though their early work lacked stereocontrol, resulting in
an equal mixture of all eight possible stereoisomers.1a,8
Thus, a key element to our synthesis is the identification of
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2599–2602

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E. D. Nacsa et al.
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Synthesis
aldehydes 3a–d were inseparable from each other; further
purification was achieved after the subsequent prenylation
step.
SeO2 (10 mol%)
OH
t-BuOOH
OH
O
microwave
115 °C, 20 min
H
Addition of the γ-prenyl group was most convenient us-
ing Fleury and Ashfeld’s titanium-catalyzed organozinc ad-
dition protocol.13 Despite the fact that this reaction intro-
duced an additional stereocenter, the desired epimeric sec-
ondary alcohols 4a,b could be isolated more readily by
column chromatography than their lilac aldehyde precursor
(3a). The sterically congested alcohols 4a and 4b were oxi-
dized slowly but cleanly to (+)-artemone (5), completing
the synthesis. Our synthetic artemone matched the data of
Honda and co-workers4 and material obtained from our
previous route.5
In conclusion, we have described a very short, biomi-
metic synthesis of (+)-artemone from (–)-linalool using an
organocatalytic cyclization. This route avoids protecting
groups and is redox economic.14 The two-step preparation
of lilac aldehyde (3) is much more direct and atom econom-
ic than Sabitha and co-workers’ eight-step synthesis,15
though our yields and selectivities are more modest.
52%
1
(–)-linalool
Ph
Ph
NaHCO3
hexanes
r.t., 7 d
N
H
OTMS
2 (10 mol%)
Br
H
O
OH
H
O
O
H
Cp2TiCl2 (10 mol%)
Zn, THF, r.t., 1 h
4a,b
17% over 2 steps
lilac aldehydes 3a–d
(anti,cis)/(all others) 3:1
SO3•py
DMSO
CH2Cl2
r.t., 2 d
57%
All reactions, unless otherwise noted, were carried out under an at-
mosphere of argon using oven-dried glassware and magnetic stirring.
Anhydrous hexanes, THF, and CH2Cl2 were obtained from a SolvPure
solvent system using activated alumina. Microwave reactions were
performed with a Biotage Initiator 2.5 system. Reactions were moni-
tored by TLC on glass plates coated with 400-mesh silica gel and visu-
alized using UV radiation and either anisaldehyde or ceric sulfate
stain. Column chromatography was performed using 60-mesh silica
gel. IR spectra were recorded on a Thermo Scientific Nicolet iS5 FT-IR
spectrometer using an iD5 diamond ATR accessory. GC-MS was per-
formed with an Agilent 5975C system using electron-impact ioniza-
H
O
O
(+)-artemone (5)
Scheme 2 Four-step synthesis of (+)-artemone
tive conjugate addition reactions merely offer stereoselec-
tivity at the β-position and not at both the β- and α-car-
bons.11 Our transformation requires stereoselectivity in the
nucleophilic attack as well as the subsequent α-protonation
step.
1
tion. H and 13C NMR spectra were obtained on a Bruker Avance 400
spectrometer at ambient temperature. Chemical shifts are expressed
in ppm (δ) using TMS as the internal standard. For 13C spectra, chemi-
cal shifts are referenced to CDCl3 at 77.0 ppm. Optical rotation mea-
surements were made using a Jasco P-1010 polarimeter. High-resolu-
tion mass spectrometry (HRMS) was performed using a chemical ion-
ization (CI) source on an Agilent 6210 time-of-flight mass
spectrometer.
After screening a number of organic and inorganic
catalysts known to activate enals, we established that
Jørgensen–Hayashi catalyst 212 (Scheme 2) conferred the
greatest selectivity in this reaction. Other optimal parame-
ters included a nonpolar solvent such as hexanes or cyclo-
hexane, performing the reaction at room temperature, and
the addition of sodium bicarbonate. Our most selective con-
ditions provided diastereomeric ratios of up to 5:1 for the
desired anti,cis-lilac aldehyde (3) versus the sum of the oth-
er three (anti,trans, syn,trans, and syn,cis) lilac aldehydes
that are also products of this reaction; however, this level of
selectivity was only observed early in the reaction. To ob-
tain useful amounts of product, prolonged exposure to the
catalyst was necessary and resulted in degraded stereose-
lectivity. We found the most practical balance of selectivity
and yield required one week at room temperature. These
conditions were 65–75% stereoselective for the desired
anti,cis-lilac aldehyde (3a). Column chromatography re-
moved unconverted enal 1 and residual catalyst 2, but lilac
(3R,6E)-8-Oxolinalool (1)
Depending on the time available and scale required, hydroxyenal 1
was prepared by either a conventional or a microwave procedure.
Conventional Procedure: (–)-Linalool (7.13 g, 46 mmol) was dissolved
in CH2Cl2 (10 mL). Separately, SeO2 (554.8 mg, 5.00 mmol) and 70% aq
t-BuOOH (41.0 mL, 38.6 g, 300 mmol) were added to CH2Cl2 (85 mL)
in a round-bottom flask. To the resulting cloudy mixture, the (–)-lin-
alool solution was added. The reaction mixture was stirred at r.t. for 7
d, and then diluted with additional CH2Cl2 (105 mL). The organic layer
was washed successively with 2.0 M KOH (105 mL), water (105 mL),
and brine (105 mL), then dried (MgSO4), filtered, and concentrated.
The crude product was purified using flash chromatography (hex-
anes–EtOAc, 5:1) to afford hydroxyenal 1 as a slightly yellow oil;
yield: 1.22 g (16%).
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E. D. Nacsa et al.
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Synthesis
Microwave Procedure: To a microwave vial were added SeO2 (53.3 mg,
0.48 mmol) and 70% aq t-BuOOH (3.96 mL, 3.7 g, 28.8 mmol), fol-
lowed by a solution of (–)-linalool (0.73 g, 4.8 mmol) in anhydrous
CH2Cl2 (9 mL). The vial was sealed and the reaction mixture was
stirred under microwave irradiation (250 W) at 115 °C for 20 min. The
two-layer reaction mixture was diluted with CH2Cl2 (20 mL) and
washed with 2.0 M KOH (20 mL), deionized water (20 mL), and brine
(20 mL). The organic layer was dried (MgSO4), filtered, and concen-
trated. The crude product was purified using flash chromatography
(hexanes–EtOAc, 5:1) to afford hydroxyenal 1 as a slightly yellow oil;
yield: 0.42 g (52%).
flash chromatography (hexanes–EtOAc, 50:1 → 25:1) to afford 28.1
mg of artemol 4a and 20.9 mg of artemol 4b (17% combined two-step
yield from 1) as clear, colorless oils.
Alcohol 4a
[α]D23 +9.2 (c 1.7, CHCl3); Rf = 0.41 (hexanes–EtOAc, 5:1).
IR: 3466 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 5.98 (m, 1 H), 5.91 (dd, J = 11, 17 Hz, 1
H), 5.18 (dd, J = 1.6, 17 Hz, 1 H), 5.04 (app s, 1 H), 5.00 (dd, J = 1.5, 6.4
Hz, 1 H), 4.97 (dd, J = 1.6, 11 Hz, 1 H), 3.93 (m, 1 H), 3.73 (d, J = 3.9 Hz,
1 H), 1.57–1.98 (m, 5 H), 1.29 (s, 3 H), 1.08 (s, 3 H), 1.06 (s, 3 H), 0.88
(d, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 146.0, 144.5, 112.1, 111.5, 82.8, 82.5,
76.7, 41.9, 38.9, 38.0, 29.7, 26.4, 24.8, 23.9, 11.3.
[α]D23 –12.0 (c 1.0, CHCl3); Rf = 0.56 (hexanes–EtOAc, 4:1).
IR: 3458, 1739, 1685, 1640 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 9.39 (s, 1 H), 6.50 (dt, J = 1.3, 7.4 Hz, 1
H), 5.93 (dd, J = 11, 17 Hz, 1 H), 5.26 (dd, J = 1.0, 17 Hz, 1 H), 5.13 (dd,
J = 1.0, 11 Hz, 1 H), 2.37–2.44 (m, 2 H), 1.66–1.76 (m, 2 H), 1.74 (s, 3
H), 1.60 (br s, 1 H), 1.34 (s, 3 H).
HRMS: m/z [M + H+] calcd for C15H27O2: 239.2006; found: 239.2001.
Alcohol 4b
13C NMR (100 MHz, CDCl3): δ = 195.3, 155.1, 144.2, 138.9, 112.2, 72.6,
Rf = 0.63 (hexanes–EtOAc, 5:1).
40.1, 27.9, 23.7, 8.9.
1H NMR (400 MHz, CDCl3): δ = 5.94 (dd, J = 11, 17 Hz, 1 H), 5.87 (dd,
J = 11, 17 Hz, 1 H), 5.20 (dd, J = 1.6, 17 Hz, 1 H), 5.01 (dd, J = 1.6, 11 Hz,
1 H), 4.95–4.98 (m, 2 H), 4.34 (d, J = 6.8 Hz, 1 H), 3.97 (ddd, J = 5.1, 9.7,
9.7 Hz, 1 H), 3.22 (app t, J = 6.8 Hz, 1 H), 1.99 (m, 1 H), 1.89 (m, 1 H),
1.67–1.76 (m, 2 H), 1.48–1.57 (m, 1 H), 1.30 (s, 3 H), 1.06 (s, 3 H), 1.05
(s, 3 H), 0.86 (d, J = 6.9 Hz, 3 H).
HRMS: m/z [M + H+] calcd for C10H17O2: 169.1223; found: 169.1225.
2-(5-Methyl-5-vinyltetrahydrofuran-2-yl)propionaldehyde (Lilac
Aldehydes, 3a–d)
To hydroxyenal 1 (201.5 mg, 1.20 mmol) were added hexanes (10
mL), organocatalyst 2 (5.5 mg/mL in hexanes, 7.04 mL, 0.12 mmol),
and NaHCO3 (303.5 mg, 3.61 mmol). The reaction mixture was stirred
at r.t. for 7 d, then was diluted with hexanes (20 mL). The solution was
washed with 1 M HCl (2 × 20 mL), sat. aq NaHCO3 (20 mL), and brine
(20 mL). The organic layer was dried (MgSO4), concentrated, and puri-
fied using flash chromatography (hexanes–EtOAc, 20:1) to provide an
anti,cis-enriched mixture of lilac aldehydes (3a–d); yield: 54.3 mg
(27%). Although chromatography did not separate 3a from its diaste-
reomers, it did remove residual traces of organocatalyst 2 which oth-
erwise promoted undesired diastereomeric equilibration to give
equal amounts of 3a–d. The diastereomeric mixture (typically con-
taining 65–75% 3a) was carried on through the next step.
13C NMR (100 MHz, CDCl3): δ = 146.6, 144.2, 111.5, 111.2, 83.5, 83.1,
77.2, 42.7, 41.0, 37.3, 31.3, 27.0, 25.2, 21.5, 17.6.
(2S)-4,4-Dimethyl-2-[(2S,5R)-5-methyl-5-vinyltetrahydrofuran-2-
yl]hex-5-en-3-one (anti,cis-Artemone, 5)
A solution of artemol (4a; 26.9 mg, 0.113 mmol) in CH2Cl2–DMSO
(4:1, 1 mL) was stirred for 2 min at r.t., followed by 7 min at 0 °C. Et3N
(0.14 mL, 1.03 mmol) and sulfur trioxide–pyridine complex (119 mg,
0.749 mmol) were added and the reaction mixture was allowed to
warm to r.t. The solution changed from pale yellow to deep red. After
2 d, the reaction was quenched with sat. aq NaHCO3 (1 mL) and the
mixture was extracted with hexanes–Et2O (2:1, 3 × 1 mL). The organic
layers were combined, washed with brine (3 × 1 mL), dried (MgSO4),
and concentrated. Flash chromatography (hexanes–EtOAc, 40:1 →
10:1) afforded (+)-artemone (5) as a clear, pale yellow oil; yield: 15.3
mg (57%).
Rf = 0.49 (hexanes–EtOAc, 5:1).
IR: 1727 cm–1
.
1H NMR (400 MHz, CDCl3): δ (characteristic peaks) = 9.81 (d, J = 2.5
Hz, 1 H, 3a –CHO), 9.80 (d, J = 1.3 Hz, 1 H, 3b –CHO), 9.79 (d, J = 2.3 Hz,
1 H, 3c –CHO), 9.77 (d, J = 1.5 Hz, 1 H, 3d –CHO), 1.16 (d, J = 7.0 Hz, 3
H, 3d CHCH3), 1.12 (d, J = 7.0 Hz, 3 H, 3b CHCH3), 1.08 (d, J = 7.0 Hz, 3
H, 3c CHCH3), 1.05 (d, J = 7.0 Hz, 3 H, 3a CHCH3).
[α]D23 +49.4 (c 0.7, CHCl3); Rf = 0.82 (hexanes–EtOAc, 4:1).
IR: 1709, 1634 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 5.99 (dd, J = 11, 17 Hz, 1 H), 5.90 (dd,
J = 11, 17 Hz, 1 H), 5.20 (dd, J = 0.9 Hz, 17 Hz, 1 H), 5.17 (dd, J = 1.0, 11
Hz, 1 H), 5.15 (dd, J = 1.6, 17 Hz, 1 H), 4.94 (dd, J = 1.6, 11 Hz, 1 H),
4.13 (dt, J = 5.9, 8.7 Hz, 1 H), 3.05 (dq, J = 8.5, 6.9 Hz, 1 H), 1.97 (m, 1
H), 1.88 (m, 1 H), 1.73 (m, 1 H), 1.61 (m, 1 H), 1.26 (s, 3 H), 1.24 (s, 3
H), 1.23 (s, 3 H), 0.94 (d, J = 6.8 Hz, 3 H).
HRMS: m/z [M + H+] calcd for C10H17O2: 169.1223; found: 169.1229.
4,4-Dimethyl-2-(5-methyl-5-vinyltetrahydrofuran-2-yl)hex-5-en-
3-ol (Artemols, 4a,b)
Zinc dust (56.3 mg, 0.861 mmol) and Cp2TiCl2 (8.2 mg, 0.033 mmol)
were added to THF (5 mL). The flask was sealed under nitrogen. Upon
stirring for 10 min, the reaction color progressed from blood red to
green. In a separate vial, the above mixture of 3a–d (54.0 mg, 0.321
mmol) and 3,3-dimethylallyl bromide (0.11 mL, 143.5 mg, 0.963
mmol) were dissolved in THF (1 mL). This solution was then added to
the reaction mixture. After 1 h, sat. aq NH4Cl (10 mL) and Et2O (10 mL)
were added. The reaction mixture was extracted with Et2O (3 × 10
mL). The organic layers were combined, washed with brine (30 mL),
dried (MgSO4), and concentrated. The residue was then purified using
13C NMR (100 MHz, CDCl3): δ = 215.6, 144.8, 142.3, 114.2, 111.0, 82.6,
80.8, 51.4, 46.0, 37.5, 29.3, 26.4, 23.2, 23.1, 15.2.
Acknowledgment
This work was supported by a Camille and Henry Dreyfus Foundation
Faculty Startup Award, a Henry Dreyfus Teacher-Scholar Award, the
Sherman Fairchild Foundation, the Baker Foundation, Merck/AAAS,
the Harvey Mudd College Department of Chemistry, and the Christian
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2599–2602

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E. D. Nacsa et al.
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Scholars Foundation. We thank Dr. Richard W. Kondrat and Ronald B.
New at the University of California, Riverside for exact mass measure-
ments, Israel Sanchez for experimental support, and Jason S. Kings-
bury for helpful comments on the manuscript.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2599–2602