Synthesis of cis- and trans -davanoids: Artemone, hydroxydavanone, isodavanone, and nordavanone

Article abstract of DOI:10.1055/s-0033-1338429

A concise and versatile synthesis of both cis and trans diastereomers of the natural products artemone, hydroxydavanone, isodavanone, and nordavanone has been accomplished. The preparation of trans-davanone is also described. Each synthesis is six to eight steps from geranyl acetate, with differentiation between cis and trans products occurring through a diastereoselective cyclization prior to derivatization. Many of these compounds are minor components of davana oil and have now been synthesized for the first time. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1338429

PAPER
▌1541
paper
Synthesis of cis- and trans-Davanoids: Artemone, Hydroxydavanone,
Isodavanone, and Nordavanone
Synthesis of cis- and trans-Davanoids
Kanny K. Wan, Corwyn D. Evans-Klock, Brian C. Fielder, David A. Vosburg*
Department of Chemistry, Harvey Mudd College, 301 Platt Boulevard, Claremont, CA 91711, USA
Fax +1(909)6077577; E-mail: vosburg@hmc.edu
Received: 19.02.2013; Accepted after revision: 27.03.2013
This paper is dedicated to Prof. Christopher T. Walsh on the occasion of his retirement in 2013.
H
O
H
O
O
O
Abstract: A concise and versatile synthesis of both cis and trans
diastereomers of the natural products artemone, hydroxydavanone,
isodavanone, and nordavanone has been accomplished. The prepa-
ration of trans-davanone is also described. Each synthesis is six to
eight steps from geranyl acetate, with differentiation between cis
and trans products occurring through a diastereoselective cycliza-
tion prior to derivatization. Many of these compounds are minor
components of davana oil and have now been synthesized for the
first time.
cis-davanone
cis-artemone
H
O
H
O
O
O
trans-davanone
cis-isodavanone
Key words: davanone, terpenoids, total synthesis, stereoselective
synthesis, green chemistry, asymmetric allylic O-alkylation
H
O
H
O
O
O
OH
Davana oil, the essential oil of the Indian sage Artemisia
pallens, contains over 30 terpenoid natural products (Fig-
ure 1).1 The most abundant of these is cis-davanone,2
which is reported to have antifungal,3 antispasmodic,4 and
antibacterial5 properties. Indeed, cis-davanone has been
the target of several synthetic studies.6 Other davanoids
(compounds with structures related to davanone) have re-
cis-hydroxydavanone
cis-nordavanone
H
O
H
O
O
O
OH
OEt
cis-davana acid ethyl ester
trans-hydroxydavanone
ceived much less attention in synthetic and bioactivity Figure 1 Structures of davanoids mentioned in this article that are
found in davana oil from Artemesia pallens. Of these, only davanone
studies, perhaps due to their relative scarcity in davana
oil.1
and hydroxydavanone are known to naturally occur in both cis and
trans forms.1
Among the davanoids that have never before been pre-
pared stereoselectively (if at all) are trans-davanone,
than the only previous stereoselective route, a 20-step
trans-nordavanone, trans-artemone, cis- and trans-hy-
achievement by Honda et al.6e A nonstereoselective prep-
droxydavanone, and cis- and trans-isodavanone. The
aration of artemones has been reported by Naegeli et al.8
most compelling target among these is cis-hydroxydava-
none, whose antifungal activity is four-fold greater than
ClMg
that of davanone against a range of fungi.3 Driven by the
possibility of discovering more potent antifungal agents
and the lack of stereoselective syntheses of many of these
compounds, we adapted our enantioselective seven-step
synthesis of cis-davanone6g to these other davanoids.
H
O
H
O
O
O
OEt
cis-davana acid ethyl ester (1)
THF, –78 °C
49%
cis-artemone (3)
ClMg
H
O
H
O
O
O
We previously reported five-step syntheses of cis- and
trans-davana acid ethyl esters (1 and 2) using Pd2dba3 and
either C3-(S)-TunePhos or C3-(R)-TunePhos, respective-
ly.6g These esters were treated with prenylmagnesium
chloride to produce cis- and trans-artemone directly (3
and 4, see Scheme 1). The γ-prenylated products 3 and 4
did not undergo a second Grignard addition to the ketone,
as Baran et al. observed for a similar reaction.7 Our six-
step synthesis of cis-artemone (3) is significantly shorter
OEt
trans-davana acid ethyl ester (2)
THF, –78 °C
65%
trans-artemone (4)
Scheme 1 Preparation of cis- and trans-artemone
In order to prepare other davanoids, cis and trans esters 1
and 2 were converted into the corresponding Weinreb
amides 56g and 6, respectively (Scheme 2). From these
Weinreb amides, cis- and trans-nordavanone (7 and 8)
were readily generated with methylmagnesium chloride.
Likewise, trans-davanone (9) was obtained after reaction
of 6 with prenylmagnesium chloride.
SYNTHESIS 2013, 45, 1541–1545
Advanced online publication: 24.04.2013
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8
1
1
4
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DOI: 10.1055/s-0033-1338429; Art ID: SS-2013-M0146-OP
© Georg Thieme Verlag Stuttgart · New York

1542
K. K. Wan et al.
PAPER
H
O
H
O
R
MeMgCl
O
O
OHC
OMe
O
P
N
THF, 0 °C
82%
Me
Li
OMe
OMe
H
O
O
P
12: R = H or
15: R = OTBS
O
5
cis-nordavanone (7)
OMe
OMe
5
Ba(OH)2
THF–H2O, 0 °C
THF, –78 to 0 °C
91%
MeONHMe•HCl
H
O
H
O
O
O
MeMgCl
i-PrMgCl
10
OMe
N
2
THF, 0 °C
99%
THF, –20 °C
79%
H
O
Me
O
R
6
trans-nordavanone (8)
ClMg
cis-isodavanone (13): R = H (96%)
cis-hydroxydavanone (16): R = OH (60%)
H
O
O
R
THF, r.t.
53%
OHC
O
trans-davanone (9)
Li
P
OMe
OMe
H
O
O
P
12: R = H or
15: R = OTBS
O
Scheme 2 Synthesis of cis-nordavanone, trans-nordavanone, and
trans-davanone
OMe
OMe
6
Ba(OH)2
THF–H2O, 0 °C
THF, –78 to 0 °C
68%
11
Previously, the nordavanones had been synthesized non-
stereoselectively by Thomas and Ozainne as a complex
mixture of eight stereoisomers.9 The only reported ste-
reoselective synthesis of cis-nordavanone (7) was by
Sabitha et al. in 2010.6h We are the first to report the ste-
reoselective syntheses of trans-nordavanone (8) and
trans-davanone (9).10
H
O
O
R
trans-isodavanone (14): R = H (94%)
trans-hydroxydavanone (17): R = OH (53%)
Scheme 3 Synthesis of cis- and trans-isodavanones and hydroxy-
davanones
The α,β-unsaturated isodavanones and hydroxydavanones
were prepared using Horner–Wadsworth–Emmons reac-
tions. First, the Weinreb amides 5 and 6 were treated with
dimethyl lithiomethylphosphonate to give ketophospho-
nates 10 and 11, respectively (Scheme 3). Condensation
of 10 and 11 with isobutyraldehyde (12) was facile using
barium hydroxide in wet THF,11 resulting in cis- and
trans-isodavanone (13 and 14), respectively. To our great
delight, these same aqueous basic conditions with the
known TBS-protected aldehyde 1512 directly produced
cis- and trans-hydroxydavanone (16 and 17), convenient-
ly removing the silyl group following condensation.13
These are the first stereoselective preparations of the iso-
davanones and hydroxydavanones; the longest linear se-
quence to each of these four davanoids from geranyl
acetate requires only eight steps (Scheme 4). Neither cis-
hydroxydavanone (16) nor trans-hydroxydavanone (17)
has ever been synthesized previously, and the only report-
ed synthesis of isodavanones is the complex mixture of
stereoisomers obtained by Ohloff and Giersch on their
way to davanone.6b
O
O
3 steps
AcO
AcO
H
geranyl acetate
(er 8:1)
thiazolium
catalysis
palladium
catalysis
H
O
OH
O
O
AcO
OEt
OEt
trans-davana acid ethyl ester (2)
(trans/cis 12:1)
(anti/syn 5:1)
2 steps
H
O
O
P
H
O
1 step
O
O
OH
OMe
OMe
11
trans-hydroxydavanone (17)
Scheme 4 Overview of the eight-step synthesis of trans-hydroxy-
davanone
In conclusion, we have built upon our recent synthesis of
cis-davanone6g to selectively prepare nine other dava-
noids. This is the first systematic approach to any of the
trans-davanoids. All five trans isomers plus cis-isodava-
none (13) and cis-hydroxydavanone (16) have now been
made stereoselectively14 for the first time. Each synthesis
avoids separate protecting group steps along its longest
linear path, maintains redox economy,15 and is shorter
than any previous stereoselective route. In the cases of
trans-davanone (9) and cis- and trans-artemone (3 and 4),
all of the carbons in our synthetic sesquiterpene products
ultimately derive from intact prenyl units. Preliminary an-
tifungal screens indicate that cis-isodavanone and trans-
hydroxydavanone have promising bioactivity,16 and we
are eager to fully test and report the antifungal properties
of all of these davanoids in due course.
Synthesis 2013, 45, 1541–1545
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of cis- and trans-Davanoids
1543
All reactions, unless otherwise noted, were carried out under an at-
mosphere of argon using oven-dried glassware and magnetic stir-
ring. Anhyd CH2Cl2 and THF were obtained from a SolvPure anhyd
solvent system using activated Al2O3. Reactions were monitored
with TLC on glass plates coated with mesh 400 silica gel and visu-
alized using UV and either anisaldehyde or Ce(SO4)2 stain. Column
chromatography was performed using mesh 60 silica gel. IR spectra
were recorded on a Thermo Scientific Nicolet iS5 FT-IR spectrom-
eter using an iD5 diamond ATR accessory. GC-MS was performed
(dd, J = 11, 2 Hz, 1 H), 4.07 (td, J = 8, 7 Hz, 1 H), 3.05 (qd, J = 8,
7 Hz, 1 H), 1.92–2.01 (m, 1 H), 1.80–1.90 (m, 1 H), 1.60–1.73 (m,
2 H), 1.26 (s, 3 H) with overlappings at 1.25 (s, 3 H), 1.22 (s, 3 H),
0.95 (d, J = 7 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 216.0, 144.1, 142.8, 114.5, 111.6,
83.1, 81.2, 51.8, 46.3, 37.4, 30.1, 29.2, 27.3, 23.5, 15.4.
HRMS (CI): m/z calcd for C15H25O2: 237.1849; found: 237.1847
[MH+].
with an Agilent 5975C using electron impact ionization. 1H and 13
C
(2S)-N-Methoxy-N-methyl-2-[(2S,5S)-5-methyl-5-vinyltetrahy-
drofuran-2-yl]propanamide (6)
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, chemical shifts
are referenced to CDCl3 at 77.0 ppm. Optical rotation measure-
ments were made using a Jasco P-1010 polarimeter. High-resolu-
tion mass spectrometry (HRMS) was performed using either an
electron ionization (EI) source on a double-focusing, magnetic sec-
tor mass spectrometer, or a chemical ionization (CI) source on a
time-of-flight mass spectrometer.
The HCl salt of N,O-dimethylhydroxylamine (4.10 g, 42.0 mmol)
was added to a solution of 2 (849 mg, 4.00 mmol) in THF (108 mL).
Upon cooling the stirred solution to –20 °C in a NaCl/ice bath, a 2.0
M solution of isopropylmagnesium chloride was added dropwise
(55.8 mL, 84.0 mmol). After 50 min, the reaction was quenched
with sat. aq NH4Cl (100 mL), and extracted with Et2O (4 × 50 mL).
The combined Et2O layers were washed with brine (150 mL), dried
(MgSO4), and concentrated. The crude product was purified by
flash chromatography (5:1 hexanes–EtOAc) to afford trans
Weinreb amide 6 (720 mg, 3.17 mmol, 79%) as a colorless oil; Rf =
0.15 (hexanes–EtOAc, 3:1); [α]D24 +7.6 (c 1.39, CHCl3).
Ethyl (2S)-2-[(2S,5S)-5-Methyl-5-vinyltetrahydrofuran-2-
yl]propanoate (trans-Davana Acid Ethyl Ester, 2)
Following the procedure of Morrison et al.,6g trans-davana acid eth-
yl ester (2)17 was obtained as a colorless oil (66%); Rf = 0.75 (hex-
anes–EtOAc, 3:1); [α]D23 +15 (c 0.31, CHCl3).
IR (ATR): 1660 cm–1.
1H NMR (400 MHz, CDCl3): δ = 5.84 (dd, J = 17, 11 Hz, 1 H), 5.17
(dd, J = 17, 2 Hz, 1 H) 4.96 (dd, J = 11, 2 Hz, 1 H), 4.14–4.22 (m,
1 H), 3.72 (s, 3 H), 3.21 (s, 3 H), 3.06 (m, 1 H), 1.96–2.02 (m, 1 H),
1.86–1.96 (m, 1 H), 1.67–1.79 (m, 2 H), 1.29 (s, 3 H), 1.08 (d, J =
7 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 210.8, 143.6, 111.4, 82.7, 79.9,
61.4, 40.7, 37.1, 29.2, 28.6, 27.0, 13.2.
IR (ATR): 1734 cm–1.
1H NMR (400 MHz, CDCl3): δ = 5.84 (dd, J = 17, 10 Hz, 1 H), 5.18
(dd, J = 17, 2 Hz, 1 H), 4.98 (dd, J = 10, 2 Hz, 1 H), 4.18 (m, 1 H),
4.16 (d, J = 7 Hz, 2 H), 2.59 (dq, J = 7, 7 Hz, 1 H), 1.83–1.99 (m, 2
H), 1.65–1.75 (m, 2 H), 1.30 (s, 3 H), 1.26 (t, J = 7 Hz, 3 H), 1.12
(d, J = 7 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 175.0, 143.6, 111.31, 83.0, 79.8,
60.3, 45.0, 36.9, 28.2, 27.0, 14.2, 12.8.
HRMS (CI): m/z calcd for C12H22NO3: 228.1594; found: 228.1596
[MH+].
HRMS (EI): m/z [M+] calcd for C12H20O3: 212.1412; found:
212.1418.
(3S)-3-[(2S,5R)-5-Methyl-5-vinyltetrahydrofuran-2-yl]butan-2-
one (cis-Nordavanone, 7)
MeMgCl (0.88 mL, 2.64 mmol, 3.0 M in THF) was added dropwise
over 5 min to a solution of cis Weinreb amide 5 (95.8 mg, 0.440
mmol) in THF (8.36 mL) at 0 °C. The resulting solution was stirred
at 0 °C for 3 h. Additional MeMgCl (0.59 mL, 1.76 mmol) was add-
ed to the reaction mixture to achieve full conversion. The mixture
was stirred at 0 °C for another 90 min, and then it was quenched
with cold, sat. aq NH4Cl (20 mL). The resulting mixture was ex-
tracted with CH2Cl2 (3 × 30 mL). The combined organic extracts
were washed with brine (30 mL), dried (MgSO4), and concentrated.
The crude product was purified by flash chromatography (50:1 hex-
anes–Et2O) to give cis-nordavanone (7) as a colorless oil (63.1 mg,
0.346 mmol, 82%); Rf = 0.57 (hexanes–EtOAc, 2:1); [α]D24 +43.3 (c
1.0, CHCl3).
(2S)-4,4-Dimethyl-2-[(2S,5R)-5-methyl-5-vinyltetrahydrofu-
ran-2-yl]hex-5-en-3-one (cis-Artemone, 3)
Prenylmagnesium chloride was generated by adding 1-chloro-3-
methylbut-2-ene (0.45 mL, 4.022 mmol) dropwise over ca. 3 min to
a stirred suspension of Mg turnings (542 mg, 22.3 mmol) in THF
(8.15 mL) at r.t. After stirring for 10 min, the liquid portion was can-
nulated into a stirred solution of 1 (75.1 mg, 0.35 mmol) in THF
(1.63 mL) at –78 °C over 15 min, followed by a THF rinse (0.5 mL).
This mixture was stirred at –78 °C for 21 h before it was quenched
with brine (25 mL). The resulting mixture was extracted with Et2O
(3 × 15 mL), washed with brine (20 mL), dried (MgSO4), and con-
centrated. The crude product was purified by flash chromatography
(hexanes → 10:1 hexanes–Et2O) to afford 3 (41 mg, 0.17 mmol,
49%) as a yellow oil; Rf = 0.82 (hexanes–EtOAc, 3:1); [α]D25 +36.9
(c 1.0, CHCl3).
IR, 1H NMR, 13C NMR, and GC-MS (EI) data match published val-
ues.6h
IR, GC-MS (EI), and 1H NMR data match published values.8
13C NMR (100 MHz, CDCl3): δ = 216.0, 145.2, 142.8, 114.6, 111.4,
(3S)-3-[(2S,5S)-5-Methyl-5-vinyltetrahydrofuran-2-yl]butan-2-
one (trans-Nordavanone, 8)
81.3, 51.8, 46.4, 37.9, 30.7, 29.7, 26.8, 23.6, 23.5, 15.6.
Using the same procedure as for the cis compound, trans Weinreb
amide 6 (76.6 mg, 0.337 mmol) was converted into trans-nordava-
none (8). The crude mixture was purified by flash chromatography
(4:1 hexanes–EtOAc) to afford 8 as a colorless oil (60.9 mg, 0.334
mmol, 99%); Rf = 0.50 (hexanes–EtOAc, 4:1); [α]D24 +28.8 (c 4.6,
CHCl3).
(2S)-4,4-Dimethyl-2-[(2S,5S)-5-methyl-5-vinyltetrahydrofu-
ran-2-yl]hex-5-en-3-one (trans-Artemone, 4)
Using the same procedure as for the cis compound, trans ester 2
(98.8 mg, 0.465 mmol) was converted into trans-artemone (4). The
crude mixture was purified by flash chromatography (50:1 hex-
anes–Et2O → Et2O) to afford 4 (71.8 mg, 0.304 mmol, 65%) as a
IR (ATR): 1714, 1626 cm–1.
25
1H NMR (400 MHz, CDCl3): δ = 5.82 (dd, J = 18, 11 Hz, 1 H), 5.15
(dd, J = 17, 2 Hz, 1 H) 4.97 (dd, J = 11, 2 Hz, 1 H), 4.03–4.11 (m,
1 H), 2.58–2.70 (m, 1 H), 2.21 (s, 3 H), 1.94–2.04 (m, 1 H), 1.84–
1.91 (m, 1 H), 1.67–1.75 (m, 1 H), 1.59–1.67 (m, 1 H), 1.29 (s, 3 H),
1.08 (d, J = 7 Hz, 3 H).
colorless oil; Rf = 0.85 (hexanes–EtOAc, 3:1); [α]D +39.6 (c 1.0,
CHCl3).
IR (ATR): 1711, 1635 cm–1.
1H NMR (400 MHz, CDCl3): δ = 5.98 (dd, J = 17, 11 Hz, 1 H), 5.79
(dd, J = 18, 11 Hz, 1 H), 5.19 (dd, J = 16, 1 Hz, 1 H), overlapping
with 5.16 (dd, J = 10, 1 Hz, 1 H), 5.11 (dd, J = 17, 2 Hz, 1 H), 4.94
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1541–1545

1544
K. K. Wan et al.
PAPER
13C NMR (100 MHz, CDCl3): δ = 221.9, 143.7, 111.5, 83.2, 80.5,
IR (ATR): 1714, 1642 cm–1.
52.8, 36.9, 29.7, 29.3, 27.3, 12.9.
1H NMR (400 MHz, CDCl3): δ = 5.81 (dd, J = 17, 11 Hz, 1 H), 5.12
(dd, J = 17, 2 Hz, 1 H), 4.97 (dd, J = 11, 2 Hz, 1 H), 3.98 (m, 1 H),
3.81 (s, 3 H), 3.79 (s, 3 H), 3.49 (dd, J = 23, 14 Hz, 1 H), 3.18 (dd,
J = 22, 14 Hz, 1 H), 2.91 (m, 1 H), 1.99–2.07 (m, 1 H), 1.82–1.93
(m, 1 H), 1.71–1.80 (m, 1 H), 1.63–1.71 (m, 1 H), 1.32 (s, 3 H), 1.05
(d, J = 7 Hz, 3 H).
HRMS (CI): m/z calcd for C11H19O2: 183.1380; found: 183.1381
[MH+].
(2S)-6-Methyl-2-[(2S,5S)-5-methyl-5-vinyltetrahydrofuran-2-
yl]hept-5-en-3-one (trans-Davanone, 9)
1-Chloro-3-methylbut-2-ene (0.60 mL, 5.3 mmol) was added drop-
wise over ca. 3 min to a suspension of Mg turnings (25.60 g, 1.05
mol) and 1,2-dibromoethane (0.2 mL) in THF (34.6 mL) at r.t.
When the mixture became warm, the reaction flask was immediate-
ly cooled to 0 °C. The mixture was stirred for 15 min and 4 mL of
this mixture was added to a solution of trans Weinreb amide 6 (15.3
mg, 0.067 mmol) in THF (4.0 mL) over 5 min at r.t. After 2 h, the
reaction was quenched with brine (15 mL) and extracted with Et2O
(3 × 15 mL). The combined Et2O extracts were washed with brine
(30 mL), dried (MgSO4), and concentrated. The crude mixture was
purified by flash chromatography (hexanes → 40:1 hexanes–Et2O)
to afford trans-davanone (9) as a colorless film (8.4 mg, 0.036
mmol, 53%); Rf = 0.71 (hexanes–EtOAc, 4:1); [α]D23 +30.0 (c 0.59,
CHCl3).
13C NMR (100 MHz, CDCl3): δ = 205.8, 143.8, 111.8, 83.8, 81.7,
53.4, 53.3, 43.3, 42.1, 36.9, 30.4, 27.6, 13.2.
HRMS (CI): m/z calcd for C13H24O5P: 291.1356; found: 291.1364
[MH+].
(4E,2S)-2-[(2S,5R)-5-Methyl-5-vinyltetrahydrofuran-2-yl]-6-
methylhept-4-en-3-one (cis-Isodavanone, 13)
Activated Ba(OH)2 (110.0 mg, 0.64 mmol)11 was added to a solu-
tion of cis-ketophosphonate 10 (116.1 mg, 0.400 mmol) in THF (1.2
mL), and the mixture was stirred vigorously at r.t. for 30 min. It was
then cooled to 0 °C, and a solution of isobutyraldehyde (12; 73 μL,
0.80 mmol) in THF–H2O (40:1, 1.20 mL) was then added. The re-
action mixture was stirred at 0 °C and rapidly formed a colorless
gel. The gel was broken up with a spatula, and the mixture was
stirred for an additional 30 min. The reaction was then quenched
with CH2Cl2/sat. aq NaHCO3 (1:1, 4 mL). The resulting mixture
was extracted with CH2Cl2 (3 × 5 mL), the combined CH2Cl2 layers
were washed with brine (10 mL), dried (MgSO4), and concentrated.
The crude product was purified by flash chromatography (50:1 hex-
anes–Et2O) to provide cis-isodavanone (13) as a clear oil (90.7 mg,
0.384 mmol, 96%); Rf = 0.42 (hexanes–EtOAc, 6:1); [α]D24 +20.9 (c
1.0, CHCl3).
IR (ATR): 1715 cm–1.
1H NMR (400 MHz, CDCl3): δ = 5.83 (dd, J = 17, 11 Hz, 1 H), 5.35
(m, 1 H), 5.16 (dd, J = 17, 2 Hz, 1 H), 4.98 (dd, J = 11, 2 Hz, 1 H),
4.07 (m, 1 H), 3.27 (m, 2 H), 2.72 (m, 1 H), 2.00 (m, 1 H), 1.88 (m,
1 H), 1.66–1.78 (m, 1 H) with overlappings at 1.77 (3 H), 1.56–1.65
(m, 1 H) with overlappings at 1.64 (3 H), 1.28 (s, 3 H), 1.03 (d, J =
8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 212.2, 143.7, 135.5, 116.2, 111.5,
83.1, 80.7, 51.3, 42.9, 36.9, 29.4, 27.3, 25.9, 18.2, 13.0.
IR (ATR): 1693, 1670, 1672 cm–1.
HRMS (CI): m/z calcd for C15H25O2: 237.1849; found: 237.1857
1H NMR (400 MHz, CDCl3): δ = 6.85 (dd, J = 16, 7 Hz, 1 H), 6.16
(dd, J = 17, 2 Hz, 1 H), 5.90 (dd, J = 17, 11 Hz, 1 H), 5.18 (dd, J =
17, 2 Hz, 1 H), 4.97 (dd, J = 11, 2 Hz, 1 H), 4.23 (m, 1 H), 2.98 (m,
1 H), 2.48 (m, 1 H), 1.94–2.03 (m, 1 H), 1.84–1.93 (m, 1 H), 1.71–
1.79 (m, 1 H), 1.60–1.70 (m, 1 H), 1.26 (s, 3 H), 1.08 (s, 3 H), 1.07
(s, 3 H), 1.04 (s, 3 H).
[MH+].
Dimethyl {(3S)-3-[(2S,5R)-5-Methyl-5-vinyltetrahydrofuran-2-
yl]-2-oxobutyl}phosphonate (10)
n-BuLi (1.5 mL, 2.64 mmol, 1.75 M in hexanes) was added drop-
wise to a solution of dimethylmethyl phosphonate (0.33 mL, 0.44
mmol) in THF (6.23 mL) at –78 °C over 2 min. After stirring at –78
°C for 35 min, a solution of cis Weinreb amide 5 (100.8 mg, 0.44
mmol) in THF (1.56 mL) was added via cannula over 2 min, fol-
lowed by a THF rinse (0.2 mL). After 1 h, the reaction was allowed
to warm to 0 °C and quenched with ice and sat. aq NH4Cl (4 mL).
The resulting mixture was extracted with EtOAc (3 × 40 mL), the
combined Et2O layers were washed with brine (50 mL), dried
(MgSO4), and concentrated. The crude product was purified via
flash chromatography (1:1 hexanes–EtOAc) to obtain cis-ketophos-
phonate 10 as a yellow oil (116.1 mg, 0.40 mmol, 91%); Rf = 0.16
(hexanes–EtOAc, 1:1); [α]D23 +127.1 (c 1.0, CHCl3).
13C NMR (100 MHz, CDCl3): δ = 203.5, 154.0, 145.1, 127.5, 111.8,
83.3, 80.9, 49.4, 38.0, 31.4, 29.6, 27.0, 21.8, 21.7, 13.5.
HRMS (CI): m/z calcd for C15H25O2: 237.1849; found: 237.1852
[MH+].
(4E)-(2S)-2-[(2S,5S)-5-Methyl-5-vinyltetrahydrofuran-2-yl]-6-
methyl-4-hepten-3-one (trans-Isodavanone, 14)
Following the same procedure as for the cis compound, trans-keto-
phosphonate 11 (137.0 mg, 0.472 mmol) was converted into trans-
isodavanone (14) as a clear oil (105.0 mg, 0.444 mmol, 94%); Rf =
0.56 (hexanes–EtOAc, 6:1); [α]D24 +17.5 (c 2.4, CHCl3).
IR (ATR): 1693, 1669, 1627 cm–1.
IR (ATR): 1714 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.85 (dd, J = 16, 7 Hz, 1 H), 6.16
(dd, J = 17, 2 Hz, 1 H), 5.83 (dd, J = 17, 11 Hz, 1 H), 5.16 (dd, J =
17, 2 Hz, 1 H), 4.96 (dd, J = 11, 2 Hz, 1 H), 4.16 (m, 1 H), 2.97 (dq,
J = 7, 7 Hz, 1 H), 2.47 (m, 1 H), 1.91–1.99 (m, 1 H), 1.82–1.91 (m,
1 H), 1.65–1.75 (m, 2 H), 1.29 (s, 3 H), 1.07 (d, J = 7 Hz, 6 H), 1.06
(d, J = 7 Hz, 3 H).
1H NMR (400 MHz, CDCl3): δ = 5.92 (dd, J = 17, 11 Hz, 1 H), 5.12
(dd, J = 17, 2 Hz, 1 H), 4.97 (dd, J = 11, 2 Hz, 1 H), 3.95 (m, 1 H),
3.80 (s, 3 H), 3.78 (s, 3 H), 3.52 (dd, J = 23, 14 Hz, 1 H), 3.17 (dd,
J = 22, 14 Hz, 1 H), 2.91 (m, 1 H), 1.99–2.08 (m, 1 H), 1.87–1.96
(m, 1 H), 1.69–1.78 (m, 1 H), 1.56–1.68 (m, 1 H), 1.26 (s, 3 H), 1.04
(d, J = 7 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 202.7, 153.5, 143.6, 126.8, 111.3,
82.9, 79.9, 48.9, 37.1, 31.1, 28.5, 27.0, 21.32, 21.28, 12.5.
13C NMR (100 MHz, CDCl3): δ = 205.9, 144.8, 111.9, 83.8, 81.9,
53.4, 52.9, 43.1, 41.8, 37.7, 30.8, 26.9, 13.2.
HRMS (CI): m/z calcd for C15H25O2: 237.1849; found: 237.1851
HRMS (CI): m/z calcd for C13H24O5P: 291.1356; found: 291.1355
[MH+].
[MH+].
(4E,2S)-6-Hydroxy-6-methyl-2-[(2S,5R)-5-methyl-5-vinyltetra-
hydrofuran-2-yl]hept-4-en-3-one (cis-Hydroxydavanone, 16)
Activated Ba(OH)2 (134.7 mg, 0.78 mmol)11 was added to a solu-
tion of cis-ketophosphonate 10 (152.6 mg, 0.525 mmol) in THF (1.6
mL), and the mixture was stirred vigorously at r.t. for 30 min. It was
then cooled to 0 °C, and a solution of aldehyde 1512 (211.1 mg,
1.033 mmol) in THF–H2O (40:1, 1.6 mL) was added. The reaction
Dimethyl {(3S)-3-[(2S,5S)-5-Methyl-5-vinyltetrahydrofuran-2-
yl]-2-oxobutyl}phosphonate (11)
Employing the same procedure as for the cis compound, trans
Weinreb amide 6 (127.0 mg, 0.53 mmol) was converted into trans-
ketophosphonate 11 as a yellow oil (104.6 mg, 0.36 mmol, 68%);
Rf = 0.16 (hexanes–EtOAc, 1:1); [α]D24 +83.8 (c 4.4, CHCl3).
Synthesis 2013, 45, 1541–1545
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of cis- and trans-Davanoids
1545
mixture was stirred at 0 °C and it immediately formed an orange
heterogeneous mixture. The mixture was stirred for an additional 90
min, and then warmed to r.t. and stirred for 3 h. The reaction was
then quenched with CH2Cl2/sat. aq NaHCO3 (1:1, 4 mL) and the re-
sulting mixture was extracted with CH2Cl2 (6 × 5 mL). The com-
bined organic extracts were washed with brine (10 mL), dried
(MgSO4), and concentrated. The crude product was purified by
flash chromatography (50:1 → 5:1 hexanes–Et2O) to obtain cis-hy-
droxydavanone (16) as a yellow oil (79.7 mg, 0.316 mmol, 60%);
Rf = 0.16 (hexanes–EtOAc, 5:1); [α]D24 +35.8 (c 1.69, CHCl3).
References
(1) Misra, L. N.; Chandra, A.; Thakur, R. S. Phytochemistry
1991, 30, 549.
(2) Sipma, G.; van der Waal, B. Rec. Trav. Chim. Pays-Bas
1968, 87, 715.
(3) Vajs, V.; Trifunovic, S.; Janackovic, P.; Sokovic, M.;
Milosavljevic, S.; Tesevic, V. J. Serb. Chem. Soc. 2004, 69,
969.
(4) Perfumi, M.; Paparelli, F.; Cingolani, M. L. J. Essent. Oil
Res. 1995, 7, 387.
IR (ATR): 3443, 1680, 1630 cm–1.
(5) Schmidt, E.; Bail, S.; Friedl, S. M.; Jirovetz, L.; Buchbauer,
G.; Wanner, J.; Denkova, Z.; Slavchev, A.; Stoyanova, A.;
Geissler, M. Nat. Prod. Commun. 2010, 5, 1365.
(6) (a) Naegeli, P.; Weber, G. Tetrahedron Lett. 1970, 959.
(b) Ohloff, G.; Giersch, W. Helv. Chim. Acta 1970, 53, 841.
(c) Birch, A. J.; Corrie, J. E. T.; Subba Rao, G. S. R. Aust. J.
Chem. 1970, 23, 1811. (d) Bartlett, P. A.; Holmes, C. P.
Tetrahedron Lett. 1983, 24, 1365. (e) Honda, Y.; Ori, A.;
Tsuchihashi, G. Chem. Lett. 1987, 1259. (f) Molander, G.
A.; Haas, J. Tetrahedron 1999, 55, 617. (g) Morrison, K. C.;
Litz, J. P.; Scherpelz, K. P.; Dossa, P. D.; Vosburg, D. A.
Org. Lett. 2009, 11, 2217. (h) Sabitha, G.; Prasad, M. N.;
Bhikshapathi, M.; Yadav, J. S. Synthesis 2010, 807.
(7) (a) Baran, P. S.; Shenvi, R. A.; Mitsos, C. A. Angew. Chem.
Int. Ed. 2005, 44, 3714. In our case and in Baran’s,
neighboring Lewis basic groups may stabilize the tetrahedral
intermediate and prevent a second Grignard addition.
Double prenylation (likely γ and then α) of esters has been
observed for simpler esters: (b) Inaba, T.; Aoki, H.;
Watanabe, S.; Sakamoto, M.; Fujita, T. J. Chem. Tech.
Biotechnol. 1991, 52, 407. It is possible that α-prenylation is
preferred for steric reasons on congested carbonyls, as in
Inaba’s presumed γ-prenyl ketone intermediates and our
Weinreb amide 6. Molander also observed α-prenylation of
a Weinreb amide with a Grignard reagent; see ref. 6f.
(8) Naegeli, P.; Klimes, J.; Weber, G. Tetrahedron Lett. 1970,
5021.
1H NMR (400 MHz, CDCl3): δ = 6.93 (d, J = 16 Hz, 1 H), 6.43 (d,
J = 16 Hz, 1 H), 5.91 (dd, J = 17, 11 Hz, 1 H), 5.19 (dd, J = 17, 2
Hz, 1 H), 4.98 (dd, J = 11, 2 Hz, 1 H), 4.24 (m, 1 H), 2.95 (m, 1 H),
1.97–2.07 (m, 1 H), 1.87–1.95 (m, 1 H), 1.72–1.82 (m, 1 H), 1.59–
1.71 (m, 1 H), 1.40 (s, 6 H), 1.28 (s, 3 H), 1.05 (d, J = 7 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 203.3, 152.9, 145.0, 125.6, 111.9,
83.5, 80.9, 71.2, 50.3, 38.0, 29.8, 29.7, 26.9, 13.5.
HRMS (CI): m/z calcd for C15H25O3: 253.1798; found: 253.1803
[MH+].
(4E,2S)-6-Hydroxy-6-methyl-2-[(2S,5S)-5-methyl-5-vinyltetra-
hydrofuran-2-yl]hept-4-en-3-one (trans-Hydroxydavanone, 17)
Following the same procedure as for the cis compound, trans-keto-
phosphonate 11 (175 mg, 0.602 mmol) was converted into trans-hy-
droxydavanone (17). Following flash chromatography (50:1
hexanes–Et2O → Et2O), 17 was obtained as a yellow oil (80.0 mg,
0.317 mmol, 53%); Rf = 0.36 (hexanes–EtOAc, 3:1); [α]D24 +14.7 (c
0.49, CHCl3).
IR (ATR): 3446, 1667, 1629 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.92 (d, J = 16 Hz, 1 H), 6.44 (d,
J = 16 Hz, 1 H), 5.84 (dd, J = 17, 11 Hz, 1 H), 5.17 (dd, J = 17, 2
Hz, 1 H), 4.98 (dd, J = 11, 2 Hz, 1 H), 4.19 (m, 1 H), 2.96 (m, 1 H),
1.94–2.02 (m, 1 H), 1.84–1.93 (m, 1 H), 1.72–1.81 (m, 1 H), 1.66–
1.71 (m, 1 H), 1.41 (s, 6 H), 1.31 (s, 3 H), 1.09 (d, J = 7 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 203.2, 152.7, 144.0, 125.6, 111.7,
83.4, 80.3, 71.4, 50.3, 37.3, 30.0, 29.8, 29.3, 27.5, 12.9.
(9) Thomas, A. F.; Ozainne, M. Helv. Chim. Acta 1974, 57,
2062.
(10) For nonstereoselective syntheses of all davanone
stereoisomers, see references 6a–c.
HRMS (CI): m/z calcd for C15H25O3: 253.1798; found: 253.1802
[MH+].
(11) Patterson, I.; Yeung, K.-S.; Smaill, J. B. Synlett 1993, 774.
(12) Denmark, S. E.; Stavenger, R. A. J. Am. Chem. Soc. 2000,
122, 8837.
Acknowledgment
This work was supported by an Arnold and Mabel Beckman
Scholars Award (to K.K.W.), a Camille and Henry Dreyfus Foun-
dation Faculty Startup Award, the Sherman Fairchild Foundation,
National Science Foundation REU Grant CHE-1005253, the John
Stauffer Charitable Trust, the Harvey Mudd College Department of
Chemistry, and the Christian Scholars Foundation. We thank Dr.
Richard W. Kondrat and Ronald B. New at the University of Cali-
fornia, Riverside for exact mass measurements and Karen C.
Morrison for helpful comments on the manuscript.
(13) Shorter reaction times left the silyl protecting group intact.
(14) All compounds have an 8:1 er derived from an initial
Sharpless asymmetric epoxidation; see ref. 6g.
(15) (a) Richter, J. M.; Ishihara, Y.; Masuda, T.; Whitefield, B.
W.; Llamas, T.; Pohjakallio, A.; Baran, P. S. J. Am. Chem.
Soc. 2008, 130, 17938. (b) Burns, N. Z.; Baran, P. S.;
Hoffmann, R. W. Angew. Chem. Int. Ed. 2009, 48, 2854.
(16) Wan, K. K.; Maloney, K. N., unpublished results.
(17) Bidan, G.; Kossanyi, J.; Meyer, V.; Morizur, J.-P.
Tetrahedron 1977, 2193.
Supporting Information for this article is available online at
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nfomartit
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1541–1545