Stereospecific total synthesis of (+)-davana acid, (+)-nordavanone and (+)-davanone

Article abstract of DOI:10.1055/S-0029-1218603

A short, total synthesis of (+)-davana acid, (+)-nordavanone and (+)-davanone, which are principle components of davana oil, is described. The notable features are the use of the Evans syn aldol reaction and cyclic ether formation by an intramolecular S_N2 displacement reaction as key steps. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/S-0029-1218603

PAPER
807
Stereospecific Total Synthesis of (+)-Davana Acid, (+)-Nordavanone and
(+)-Davanone
(+)-Davana
Acid,
(
+)-Nordava
w
a
nd(+)-Dava
r
none avaram Sabitha,* M. Nagendra Prasad, M. Bhikshapathi, J. S. Yadav
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27160512; E-mail: gowravaramsr@yahoo.com
Received 4 November 2009; revised 10 November 2009
recent synthesis of (+)-davanone10 also reports the isola-
tion of four diastereomeric davana acid ethyl esters as in-
termediates. Therefore, we undertook the stereospecific
synthesis of these natural products; the results are reported
here.
Abstract: A short, total synthesis of (+)-davana acid, (+)-norda-
vanone and (+)-davanone, which are principle components of da-
vana oil, is described. The notable features are the use of the Evans
syn aldol reaction and cyclic ether formation by an intramolecular
SN2 displacement reaction as key steps.
Key words: Evans aldol, cyclic ether, (–)-linalool, natural product,
davana oil
According to the retrosynthetic analysis depicted in
Scheme 1, compounds 1, 2 and 3 could all be obtained
from the key central intermediate 4, which, in turn, could
be prepared from aldehyde 5 by the Evans syn aldol reac-
tion and cyclic ether formation. Aldehyde 5 could be
made from (–)-linalool (6).
A number of novel sesquiterpenoids1 such as davana acid
(1), nordavanone (2), and davanone (3) have been isolated
from the davana oil of Artemisia pallens, a plant grown in
south India (Figure 1). Davanone 3 was also found in an-
other plant: Tanacetum vulgare.2 The structures of these
compounds were assigned on the basis of spectroscopic
and degradation studies.1c,3 In view of the importance of
davana oil in the perfume industry, A. pallens is under
commercial cultivation in India. Tremendous interest in
the oil has been aroused in the European countries, the
USA and Japan because of its use in the flavouring of
cakes, tobacco and in some costly beverages.4 For this rea-
son, the chemical composition of the davana oil from A.
pallens and has been investigated by a number of research
groups.5
3
O
N
O
2
1
O
H
O
Ph
4
OH
CHO
OMOM
5
6
OH
Scheme 1 Retrosynthetic analysis
O
O
H
O
H
O
davana acid (1)
nordavanone (2)
The synthesis began with commercially available (–)-
linalool (6), which was converted into its methoxymethyl
(MOM) ether 7 using MOM-Cl, and Hunig’s base in
dichloromethane (Scheme 2). Next, a two-step sequence,
comprising chemoselective dihydroxylation11 of the more
electron-rich C–C double bond in compound 7 [OsO4,
K3Fe(CN)6, K2CO3, MeSO2NH2, t-BuOH, H2O] and vici-
nal diol cleavage (NaIO4, H2O, Me2CO) furnished the re-
quired aldehyde 5 in good yield.
O
H
O
davanone (3)
Figure 1
Aldehyde 5 was subjected to the Evans syn aldol12 reac-
tion with the enolate of chiral N-propionyl oxazolidinone
8 to furnish the aldol adduct 9 with high diastereoselectiv-
ity (de 98%) in 87% yield. Subsequent mesylation of the
secondary hydroxy group (MsCl, Et3N, 96%) afforded
mesylate-protected compound 10, which was selectively
MOM-deprotected (HCl, THF, 90%) to give hydroxy me-
sylate 11. On treatment with 2,6-lutidine at 120 °C, 11
rapidly cyclised to the cyclic ether anti,cis-4 as a single
(+)-Davanone is the principle component of davana oil
and exhibits antifungal6 and antispasmodic activities.7
However, in spite of their importance in the perfume in-
dustry, apart from racemic syntheses,8 there have been
few reports9 on the preparation of 1, 2 or 3 (Figure 1). One
SYNTHESIS 2010, No. 5, pp 0807–0810
x
x
.
x
x
.2
0
1
0
Advanced online publication: 11.12.2009
DOI: 10.1055/s-0029-1218603; Art ID: Z23809SS
© Georg Thieme Verlag Stuttgart · New York

808
G. Sabitha et al.
PAPER
O
O
OMOM
OH
N
O
OH
O
O
Ph
CHO
OMOM
8
a
b,c
N
O
e
OMOM
d
9
Ph
5
6
7
O
O
OMs
O
O
N
O
N
O
g
h
N
O
f
1
O
OMOM
10
OH
O
H
O
OMs
Ph
Ph
Ph
4
11
i
j
l
k
k
CHO
3
2
O
O
O
OH
H
H
OH
H
14
12
13
Scheme 2 Reagents and conditions: (a) Hunig’s base, MOM-Cl, CH2Cl2, 0 °C→r.t., 1 h, 88%; (b) OsO4, K3Fe(CN)6, K2CO3, MeSO2NH2, t-
BuOH, H2O; (c) NaIO4, H2O, Me2CO, 80% (over 2 steps); (d) (n-Bu)2BOTf, Et3N, CH2Cl2, –78 °C, 87%; (e) MsCl, Et3N, 0 °C, 0.5 h, 96%; (f)
HCl, THF, r.t., 1 h, 90%; (g) 2,6-lutidine, 120 °C, 1 h, 93%; (h) H2O2, LiOH, H2O–THF, 82%; (i) DIBAL-H, CH2Cl2, –78 °C, 88%; (j) MeMgI,
Et2O, 0 °C, 85%; (k) IBX, DMSO, CH2Cl2, 2 h, 0 °C→r.t; (l) C5H9ZnBr, HMPA, THF, reflux, 78%.
Mass spectra (EI) were recorded at 70 eV on an LC-MSD (Agilent
technologies) spectrometer. Column chromatography was per-
formed on silica gel (60–120 mesh) supplied by Acme Chemical
Co., India. Optical rotations were measured with a JASCO DIP-370
Polarimeter.
isomer in 93% yield through an SN2-type substitution
(Scheme 2).
Hydrolysis of 4 with LiOH and H2O2 in THF–H2O (1:1)
afforded, after an acidic workup, the target davana acid 1
in 82% yield, whereas cleavage of the oxazolidinone in 4
using DIBAL-H provided aldehyde 12 in 88% yield,
which was used immediately for the next reaction. The
Grignard reaction of aldehyde 12 with methylmagnesium
iodide provided secondary alcohol 13 as a diastereomeric
mixture in a ratio of 1:1, which used in the next step with-
out further purification. Oxidation of alcohol 13 with IBX
in DMSO provided (+)-nordavanone (2) in 82% yield. Al-
ternatively, prenylation13 of aldehyde 12 with prenylzinc
bromide in the presence of HMPA in THF, furnished sec-
ondary alcohol 14 as a diastereomeric mixture (1:1) in
78% yield. Alcohol 14 was oxidized with IBX to yield
(+)-davanone (3) in 80% yield. Analytical data for the
synthetic material proved to be identical to those reported
previously.10
(3R)-3-(Methoxymethoxy)-3,7-dimethyl-1,6-octadiene (7)
To a solution of alcohol 6 (5 g, 32.4 mmol) in anhydrous CH2Cl2 (30
mL) at 0 °C, were successively added DIPEA (8.4 mL, 48.6 mmol),
catalytic DMAP (10 mg), and MOM-Cl (3.36 mL, 42.12 mmol).
The mixture was stirred for 3 h at 25 °C then quenched with H2O
(20 mL) and extracted with CH2Cl2 (3 × 15 mL). The organic ex-
tracts were washed with brine (15 mL), dried over anhydrous
Na2SO4 (2 g), and concentrated in vacuo. The crude residue was pu-
rified by column chromatography (EtOAc–hexane, 1:9) to afford
the MOM ether 7.
Yield: 5.6 g (88%); light-yellow oil.
IR (neat): 2975, 2927, 1640, 1449, 1375, 1146, 1036, 922 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.88–5.73 (m, 1 H), 5.21–5.02 (m,
3 H), 4.63 (ABq, J = 6.9 Hz, 2 H), 3.35 (s, 3 H), 2.06–1.92 (m, 2 H),
1.67 (s, 3 H), 1.59 (s, 3 H), 1.58–1.49 (m, 2 H), 1.30 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 142.8, 131.4, 124.3, 114.4, 91.5,
In summary, a concise, asymmetric total synthesis of (+)-
davana acid, (+)-nordavanone and (+)-davanone has been
78.4, 55.2, 40.9, 25.6, 22.8, 22.4, 17.5.
accomplished using the Evans syn aldol reaction and ste- MS (EI): m/z = 221 [M + Na]+.
reospecific cyclic ether formation as key steps.
(4S)-4-Benzyl-3-[(2S,3R,6R)-3-hydroxy-6-(methoxymethoxy)-
2,6-dimethyl-7-octenoyl]-1,3-oxazolan-2-one (9)
Reactions were conducted under N2 in anhydrous solvents. All re-
actions were monitored by TLC (Merck 60 F-254 silica gel plates,
visualized under UV irradiation). n-Hexane (bp 60–80 °C) was
used. Yields refer to chromatographically and spectroscopically (1H
and 13C NMR) homogeneous material. Air-sensitive reagents were
transferred by syringe or double-ended needle. Evaporation of sol-
vents was performed at reduced pressure with a Büchi rotary evap-
orator. IR data were collected on a Perkin-Elmer FTIR-240
spectrophotometer. 1H and 13C NMR spectra of samples in CDCl3
were recorded on Varian FT-200 MHz (Gemini) and Bruker
UXNMR FT-300 MHz (Avance) spectrometers. Chemical shifts (d)
are reported relative to TMS (d = 0.0 ppm) as an internal standard.
To a mixture of 7 (5.2 g, 26.2 mmol) in t-BuOH (50 mL) and H2O
(50 mL) were added K3Fe(CN)6 (25.9 g, 78.6 mmol), K2CO3 (10.8
g, 78.6 mmol), MeSO2NH2 (2.48 g, 26.2 mmol), and OsO4 (1 mL,
4% in H2O) at r.t. The mixture was stirred for 12 h, quenched with
solid Na2SO3 (2 g), and extracted with EtOAc (3 × 30 mL). The
combined organic layers were washed with aq KOH (2 N, 2 × 15
mL) and brine (2 × 20 mL), dried (Na2SO4), filtered, and concen-
trated to give the crude diol, which was used directly in the next step
without further purification. The above crude diol was dissolved in
acetone (15 mL) and NaIO4 (9.9 g, 46.2 mmol) was added. H2O was
added dropwise until the NaIO4 was completely dissolved. The re-
sultant solution was stirred for 1 h and quenched with sat. aq
Synthesis 2010, No. 5, 807–810 © Thieme Stuttgart · New York

PAPER
(+)-Davana Acid, (+)-Nordavanone and (+)-Davanone
809
Na2S2O3 (25 mL). After removing the acetone under reduced pres-
sure, the residue was extracted with EtOAc (3 × 30 mL). The com-
bined organic layers were dried over Na2SO4, concentrated and the
residue was purified by column chromatography to give aldehyde 5
(3.6 g, 80% over 2 steps), which was used for the next reaction im-
mediately.
(1R,4R)-1-(1S)-2-[(4S)-4-Benzyl-2-oxo-1,3-oxazolan-3-yl]-1-
methyl-2-oxoethyl-4-hydroxy-4-methyl-5-hexenyl Methane-
sulfonate (11)
To a solution of 10 (4 g, 8.27 mmol) in THF (20 mL), was added aq
HCl (15%, 10 mL), and the reaction mixture was stirred at r.t. for 1
h. After completion of the reaction, the reaction mixture was ex-
tracted with EtOAc (3 × 20 mL) and the combined organic layers
were washed with H2O (2 × 15 mL), brine (2 × 15 mL), dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The
crude product was purified by column chromatography to afford 11.
To a solution of 4-benzyl-3-propionyl-1,3-oxazolidin-2-one (8;
4.05 g, 17.4 mmol) in anhydrous CH2Cl2 (36 mL), was added di-n-
butylboryl triflate (1 M in CH2Cl2, 17.4 mL, 17.4 mmol) at 0 °C.
The resulting brown solution was stirred for 10 min, then Et3N (5.09
mL, 36.2 mmol) was added (the colour changed from red to light-
yellow during the addition). The mixture was stirred for 1 h at 0 °C
then cooled to –78 °C and a solution of the above aldehyde 5 (2.5 g,
14.5 mmol) in anhydrous CH2Cl2 (10 mL) was added. Stirring was
continued for 1 h at –78 °C, then the reaction mixture was allowed
to warm to 0 °C and stirred for 30 min at this temperature. The re-
action was quenched with pH 7 phosphate buffer (15 mL), MeOH
(50 mL) was added, then the mixture was finally treated with a mix-
ture of MeOH–H2O2 (2:1, 35 mL). The mixture was allowed to
warm to r.t. and stirred for 1 h. Most of the organic solvents were
removed by rotary evaporation and the aqueous layer was extracted
with Et2O (2 × 50 mL). The combined extracts were washed with
sat. NaHCO3 (2 × 10 mL), brine (2 × 10 mL), dried over Na2SO4,
filtered, and concentrated in vacuo. The crude product was purified
by column chromatography (EtOAc–hexane, 3:7) to afford the aldol
product 9.
Yield: 3.2 g (90%); colourless oil; [a]D25 +29.3 (c 1.0, CHCl3).
IR (neat): 3509, 2975, 1776, 1699, 1386, 1354, 1172, 915 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.37–7.15 (m, 5 H), 5.93–5.77 (m,
1 H), 5.29–5.0 (m, 3 H), 4.63–4.51 (m, 1 H), 4.31–4.04 (t,
J = 8.3 Hz, 1 H), 4.13 (dd, J = 2.2, 8.3 Hz, 1 H), 4.03–3.93 (m,
1 H), 3.29 (dd, J = 3.0, 13.5 Hz, 1 H), 3.0 (s, 3 H), 2.74 (dd, J = 9.8,
12.8 Hz, 1 H), 1.85–1.57 (m, 5 H), 1.30 (s, 3 H), 1.23 (d, J = 7.5 Hz,
3 H).
13C NMR (75 MHz, CDCl3): d = 172.9, 153.6, 144.2, 135.1, 129.3,
128.7, 127.1, 112.2, 81.7, 72.6, 66.4, 55.7, 41.6, 38.4, 37.6, 37.0,
28.2, 27.4, 9.4.
MS (EI): m/z = 462 [M + Na]+.
(4S)-4-Benzyl-3-(2S)-2-[(2S,5R)-5-methyl-5-vinyltetrahydro-2-
furanyl]propanoyl-1,3-oxazolan-2-one (4)
25
Yield: 5.1 g (87%); colourless gummy oil; [a]D +18.1 (c 1.0,
A solution of 11 (3 g, 6.8 mmol) in 2,6-lutidine (10 mL) was stirred
under N2 in a 120 °C oil bath until the reaction was complete (mon-
itored by TLC). After cooling to 25 °C, the reaction mixture was di-
luted with EtOAc (100 mL) and washed with aq sat. CuSO4
(2 × 25 mL). The combined organic phases were washed with H2O
(2 × 25 mL), brine (2 × 15 mL), and dried over anhydrous Na2SO4.
The residue was purified by chromatography on silica gel (n-hex-
ane–EtOAc, 8:2) to give 4.
CHCl3).
IR (neat): 3475, 2935, 1780, 1695, 1211 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.35–7.17 (m, 5 H), 5.80 (dd,
J = 17.9, 10.5 Hz, 1 H), 5.18 (m, 1 H), 5.14–5.12 (m, 1 H), 4.70–
4.57 (m, 3 H), 4.23–4.13 (m, 2 H), 3.90–3.80 (m, 1 H), 3.72 (dq,
J = 3.0, 6.9 Hz, 1 H), 3.35 (s, 3 H), 3.28 (dd, J = 13.4, 2.8 Hz, 1 H),
2.72 (dd, J = 13.2, 9.8 Hz, 1 H), 1.93–1.42 (m, 4 H), 1.30 (s, 3 H),
1.24 (d, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 177.1, 153.1, 142.6, 135.0, 129.5,
128.9, 127.4, 114.8, 91.6, 78.5, 71.8, 66.2, 55.4, 55.2, 42.4, 37.8,
37.0, 28.1, 23.2, 10.5.
Yield: 2.17 g (93%); colourless oil; [a]D25 +59.5 (c 1.0, CHCl3).
IR (neat): 2972, 2999, 2876, 1780, 1699, 1210 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.32–7.18 (m, 5 H), 5.83 (dd,
J = 17.5, 10.9 Hz, 1 H), 5.09 (dd, J = 17.5, 1.4 Hz, 1 H), 4.94 (dd,
J = 10.9, 1.4 Hz, 1 H), 4.73–4.67 (m, 1 H), 4.27–4.09 (m, 3 H),
3.94–3.86 (m, 1 H), 3.30 (dd, J = 13.1, 2.9 Hz, 1 H), 2.72 (dd,
J = 13.9, 9.5 Hz, 1 H), 2.09–2.02 (m, 1 H), 1.96–1.90 (m, 1 H),
1.79–1.65 (m, 2 H), 1.26 (s, 3 H), 1.15 (d, J = 7.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 175.1, 153.2, 144.3, 135.5, 129.4,
128.9, 127.3, 111.7, 83.1, 80.8, 66.1, 55.5, 43.3, 37.9, 37.5, 29.6,
26.3, 14.4.
MS (EI): m/z = 428 [M + Na]+.
(1R,4R)-1-(1S)-2-[(4S)-4-Benzyl-2-oxo-1,3-oxazolan-3-yl]-1-
methyl-2-oxoethyl-4-(methoxymethoxy)-4-methyl-5-hexenyl
Methanesulfonate (10)
To a stirred solution of 9 (4.2 g, 10.3 mmol) and Et3N (2.8 mL, 20.6
mmol) in anhydrous CH2Cl2 (25 mL) at 0 °C, was added MsCl (0.96
mL, 12.4 mmol). The mixture was stirred at r.t. for 1 h and extracted
with CH2Cl2 (2 × 25 mL). The extract was washed with H2O (2 × 15
mL) and brine (2 × 15 mL), dried over anhydrous Na2SO4 and con-
centrated under reduced pressure. Purification of the residual oil by
column chromatography (EtOAc–hexanes, 2:8) gave mesylate 10.
MS (EI): m/z = 366 [M + Na]+.
(2S)-2-[(2S,5R)-5-Methyl-5-vinyltetrahydro-2-furanyl]pro-
panoic Acid (1)
H2O2 (30% solution in H2O, 1.32 mL, 11.6 mmol) and LiOH (1 N,
2.9 mL, 2.9 mmol) were added sequentially to a solution of 4 (0.5 g,
1.45 mmol) in THF (20 mL) and H2O (6 mL), and the mixture was
stirred in an ice-water bath. When the reaction was complete (indi-
cated by TLC), aq sat. Na2S2O3 (3 mL) was added, followed by H2O
(20 mL). The mixture was extracted with CH2Cl2 (3 × 6 mL) and the
aqueous phase was acidified to pH 1, extracted with EtOAc (3 × 5
mL), and dried over anhydrous Na2SO4. The organic layer was con-
centrated in vacuo and purified by column chromatography
(EtOAc–hexanes, 4:6) to yield compound 1.
Yield: 4.8 g (96%); colourless oil; [a]D25 +42.7 (c 1.0, CHCl3).
IR (neat): 3097, 2933, 1775, 1699, 1353, 1172, 915 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.36–7.16 (m, 5 H), 5.82 (dd,
J = 17.6, 10.2 Hz, 1 H), 5.28–5.02 (m, 3 H), 4.65–4.52 (m, 3 H),
4.28–4.10 (m, 2 H), 3.96 (dq, J = 3.0, 6.9 Hz, 1 H), 3.35 (s, 3 H),
3.28 (dd, J = 13.0, 2.9 Hz, 1 H), 2.99 (s, 3 H), 2.74 (dd, J = 12.9,
9.5 Hz, 1 H), 1.84–1.56 (m, 4 H), 1.28 (s, 3 H), 1.22 (d, J = 7.1 Hz,
3 H).
13C NMR (75 MHz, CDCl3): d = 172.9, 153.6, 142.1, 135.2, 129.3,
128.8, 127.2, 115.0, 91.5, 81.7, 77.8, 66.5, 55.8, 55.2, 41.5, 38.5,
37.7, 36.1, 27.2, 23.4, 9.4.
Yield: 0.21 g (82%); colourless liquid; [a]D25 +21.3 (c 1.0, CHCl3).
IR (neat): 3400, 2925, 2855, 1711, 1220 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.91 (dd, J = 17.6, 10.4 Hz, 1 H),
5.24 (dd, J = 17.6, 1.6 Hz, 1 H), 5.03 (dd, J = 10.4, 1.6 Hz, 1 H),
MS (EI): m/z = 506 [M + Na]+.
Synthesis 2010, No. 5, 807–810 © Thieme Stuttgart · New York

810
G. Sabitha et al.
PAPER
4.21–4.14 (m, 1 H), 2.60–2.52 (m, 1 H), 2.13–2.04 (m, 1 H), 2.01–
1.90 (m, 1 H), 1.85–1.77 (m, 1 H), 1.72–1.64 (m, 1 H), 1.34 (s,
3 H), 1.15 (d, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 178.6, 143.8, 112.2, 84.0, 80.3,
45.5, 37.6, 29.9, 26.6, 13.2.
tography (EtOAc–hexane, 3:7) to give alcohol 14 as a colourless oil
(0.22 g, 78%). The alcohol 14 (0.15 g, 0.63 mmol) was subjected to
oxidation with IBX and DMSO following the procedure described
above for compound 2, to yield davanone 3.
Yield: 0.118 g (80%); colourless oil; [a]D22 +63.4 (c 0.5, CHCl3).
MS (EI): m/z = 207 [M + Na]+.
IR (neat): 2928, 2853, 1709, 1214, 1030 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.89 (dd, J = 17.2, 10.4 Hz, 1 H),
5.30–5.35 (m, 1 H), 5.18 (dd, J = 17.2, 1.6 Hz, 1 H), 4.96 (dd,
J = 10.4, 1.6 Hz, 1 H), 4.14–4.06 (m, 1 H), 3.32–3.16 (m, 2 H),
2.72–2.64 (m, 1 H), 2.04–1.96 (m, 1 H), 1.93–1.82 (m, 1 H), 1.76–
1.66 [m, 1 H, with overlapping s at 1.73 (3 H)], 1.63–1.51 [m, 1 H,
with overlapping s at 1.60 (3 H)], 1.23 (s, 3 H), 0.99 (d, J = 6.8 Hz,
3 H).
13C NMR (100 MHz, CDCl3): d = 212.3, 144.6, 135.2, 116.0, 111.4,
83.1, 80.8, 51.3, 42.5, 37.4, 30.0, 26.8, 25.6, 18.0, 13.2.
MS (EI): m/z = 259 [M + Na]+.
(3S)-3-[(2S,5R)-5-Methyl-5-vinyltetrahydro-2-furanyl]butan-2-
one (2)
To a cooled (–78 °C) solution of 4 (1.8 g, 5.2 mmol) in CH2Cl2 (20
mL), was added DIBAL-H (1 M in CH2Cl2, 5.72 mL, 5.72 mmol).
The solution was stirred for 15 min at –78 °C and then quenched by
the addition of EtOAc (3 mL). Potassium sodium tartrate (Rochelle
salt; 0.5 M, 50 mL) was added and the mixture was stirred for 1 h at
25 °C. The organic phase was separated and the aqueous phase was
extracted with Et2O (150 mL). The combined organic extracts were
washed with brine (20 mL), dried over Na2SO4, and concentrated in
vacuo. Purification by column chromatography (EtOAc–hexanes,
3:7) gave 12 (0.77 g, 88%) as a light-yellow oil. This aldehyde was
immediately used for the next reaction. To a suspension of Mg Acknowledgment
(57 mg, 2.38 mmol) in anhydrous Et2O (1 mL), MeI (0.15 mL, 2.38
M.N.P. and M.B. thank CSIR, New Delhi for the award of fel-
lowships.
mmol) was added dropwise under a nitrogen atmosphere at 0 °C. It
was allowed to stir for ~1 h at r.t. Aldehyde 12 (0.2 g, 1.19 mmol)
in anhydrous Et2O (1 mL) was then added dropwise at 0 °C and the
mixture was stirred at 25 °C for ~30 min. After completion of the
reaction, sat. aq NH4Cl (5 mL) was added and the mixture was ex-
tracted with EtOAc (3 × 5 mL). The organic layer was washed with
brine (2 × 5 mL), dried over anhydrous Na2SO4 and concentrated
under reduced pressure. Purification by column chromatography
(silica gel; EtOAc–hexanes, 3:7) afforded 13 (0.18 g, 85%) as a yel-
low oil.
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Salemink, C.; Heerma, W.; Verluis, C.; Kloosterman, J.;
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(3) Thomas, A. F.; Thommen, W.; Willhalm, B.; Hagaman, E.
W.; Wenkert, E. Helv. Chim. Acta 1974, 57, 2055.
(4) Husain, A.; Virmani, O. P.; Sharma, A.; Kumar, A.; Misra,
L. N. Major Essential Oil-Bearing Plants in India ; CIMAP:
Lucknow, 1988, 167–181.
(5) (a) Thomas, A. F.; Pitton, G. Helv. Chim. Acta 1971, 1890.
(b) Baslas, R. K. Flavour Ind. 1971, 2, 370.
(6) Vajs, V.; Trifunovic, S.; Janackovic, P.; Sokovic, M.;
Milosavljevic, S.; Tesevic, V. J. Serb. Chem. Soc. 2004, 69,
969.
(7) Perfumi, M.; Paparelli, F.; Cingolani, M. J. Essent. Oil Res.
1995, 7, 387.
(8) (a) Molander, G. A.; Hass, J. Tetrahedron 1999, 55, 617.
(b) Birch, A. J.; Corrie, J. E. T.; Rao, G. S. R. S. Aust. J.
Chem. 1970, 23, 1811. (c) Naegeli, P.; Weber, G.
Tetrahedron Lett. 1970, 959.
(9) (a) Honda, Y.; Ori, A.; Tsuchihashi, G.-I. Chem. Lett. 1987,
1259. (b) Bartlett, P. A.; Holmes, C. P. Tetrahedron Lett.
1983, 24, 1365.
(10) Morrison, K. C.; Litz, J. P.; Scherpelz, K. P.; Dossa, D.;
Vosburg, D. A. Org. Lett. 2009, 11, 2217.
To an ice-cooled solution of 2-(iodooxy)benzoic acid (0.36 g, 1.28
mmol) in anhydrous DMSO (1 mL), was added a solution of alcohol
13 (0.15 g, 0.88 mmol) in anhydrous CH2Cl2 (4 mL). The mixture
was stirred at 25 °C for 2 h and then filtered through a Celite pad
and washed with Et2O (2 × 5 mL). The combined organic filtrates
were washed with H2O (2 × 5 mL) and brine (2 × 3 mL), dried over
anhydrous Na2SO4, and concentrated in vacuo. The crude product
was purified by silica gel column chromatography (EtOAc–hexane,
2:8) to afford nordavanone 2.
Yield: 0.12 g (82%); colourless oil; [a]D22 +14.6 (c 0.5, CHCl3).
IR (neat): 2925, 2854, 1712, 1243 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.89 (dd, J = 17.1, 10.5 Hz, 1 H),
5.19 (dd, J = 17.1, 1.7 Hz, 1 H), 4.98 (dd, J = 10.5, 1.7 Hz, 1 H),
4.15–4.06 (m, 1 H), 2.70–2.59 (m, 1 H), 2.23 (s, 3 H), 2.07–1.97
(m, 1 H), 1.95–1.86 (m, 1 H), 1.80–1.70 (m, 1 H), 1.66–1.52 (m,
1 H), 1.27 (s, 3 H), 1.01 (d, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 212.5, 144.5, 111.4, 83.0, 80.7,
52.6, 37.5, 29.7, 29.6, 26.5, 12.9.
MS (EI): m/z = 205 [M + Na]+.
(2S)-6-Methyl-2-[(2S,5R)-5-methyl-5-vinyltetrahydro-2-furan-
yl]-5-hepten-3-one (3)
(11) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G.
A.; Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.;
Wang, Z.-M.; Xu, D.-Q.; Zhang, X.-L. J. Org. Chem. 1992,
57, 2768.
(12) Evans, D. A.; Bartoli, J.; Shih, T. L. J. Am. Chem. Soc. 1981,
103, 2127.
To a suspension of zinc (0.93 g, 14.28 mmol) in anhydrous THF (10
mL), was added 4-bromo-2-methylbut-2-ene (1.06 g, 7.14 mmol)
and the solution was stirred at 25 °C for 1 h. The solution was treat-
ed with aldehyde 12 (0.2 g, 1.19 mmol) and HMPA (2 mL, 11.9
mmol) and was heated to reflux for 72 h. Sat. aq NH4Cl (4 mL) was
added to the reaction mixture and the solution was diluted with
EtOAc (5 mL), washed with brine (5 mL), dried over Na2SO4, and
concentrated in vacuo. The residue was purified by column chroma-
(13) Hong, B.-C.; Hong, J.-H.; Tsai, Y.-C. Angew. Chem. Int. Ed.
1998, 4, 37.
Synthesis 2010, No. 5, 807–810 © Thieme Stuttgart · New York