Syntheses of aggregation pheromones of the palm weevils rhyncophorus vulneratus and rphoenicis and of (+)- trans-whiskey lactone

Article abstract of DOI:10.1055/s-0031-1289579

(3S,4S)-3-Methyloctan-4-ol, (4S,5S)-4-methylnonan-5-ol, and (+)-trans-whiskey lactone [(4S,5R)-5-butyl-4-methyldihydrofuran-2(3H)-one] were synthesized stereoselectively by using a radical cyclization reaction as a key step. All three molecules were synthesized from a common cyclic acetal intermediate. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0031-1289579

3894
PAPER
Syntheses of Aggregation Pheromones of the Palm Weevils Rhyncophorus
vulneratus and R. phoenicis and of (+)-trans-Whiskey Lactone
Palm
W
ee
.
vil Pheromon
S
es and trans
-
W
.
hiskey La
cY
tone adav,*a,b C. Venkateshwar Rao,a A. R. Prasad,a Ahmad Al Khazim Al Ghamdib
a
Division of Organic Chemistry I, CSIR, Indian Institute of Chemical Technology, Hyderabad, 500 007, India
Engineer Abdullah Baqshan for Bee Research, King Saud University, Saudi Arabia
Fax +91(40)27160512; E-mail: yadav@iict.res.in
b
Received 6 August 2011; revised 20 September 2011
Structurally simple g-butyrolactones are widespread natu-
rally occurring substances that occur not only as sex pher-
omones,7 but also as key flavor components.8 The
biological activity of these substances is strictly depen-
dent on the absolute configuration of the chiral C-4 carbon
atom attached to the lactone ring. (+)-trans-Whiskey lac-
tone [(4S,5R)-5-butyl-4-methyldihydrofuran-2(3H)-one]
and cis-whiskey lactone [(4S,5S)-5-butyl-4-methyldihy-
drofuran-2(3H)-one] were identified as key aroma com-
ponents of oak-aged alcoholic beverages, such as
whiskey, brandy, or wine.9a The two compounds, which
are originally components of the oak used in barrels for
the alcoholic beverages, are extracted slowly from the oak
barrels into the alcoholic beverage during the maturing
process. The absolute configuration of the natural trans-
and cis-whiskey lactones were confirmed to be (4S,5R)
and (4S,5S), respectively, by Masuda and Nashimura.9b
Although several syntheses of optically active trans-whis-
key lactone 3 have been reported, most use either a
stoichiometric amount of a chiral source as a starting
material10 or require chiral auxiliaries.11
Abstract: (3S,4S)-3-Methyloctan-4-ol, (4S,5S)-4-methylnonan-5-
ol, and (+)-trans-whiskey lactone [(4S,5R)-5-butyl-4-methyldihy-
drofuran-2(3H)-one] were synthesized stereoselectively by using a
radical cyclization reaction as a key step. All three molecules were
synthesized from a common cyclic acetal intermediate.
Key words: alcohols, pheromones, lactones, radical reactions, ste-
reoselective synthesis
Insect pheromones play a major role in pest-control strat-
egies and are considered to be potential useful tools in
integrated pest management, an ecofriendly and environ-
mentally safe agricultural technique that is practiced
worldwide. Palm weevils are obnoxious pests of coconut
and oil palm crops. Most species produce a single isomer
of a methyl-branched secondary alcohol as an aggregation
pheromone. Rochat and co-workers1 isolated and identi-
fied (4S,5S)-4-methylnonan-5-ol (1; Figure 1) as the ma-
jor component of the aggregation pheromone of the male
Rhynchophorus vulneratus, the Asian palm weevil; the
same compound is also a key component of the male pher-
omones of the taxonomically related Metamasous hemi-
pterus (L.), a weevil of the genus Rhynchophornae. R.
phoenicis (F.),2 the African palm weevil, secretes (3S,4S)-
3-methyloctan-4-ol (2), whereas R. cruentatus (F.),3 the
palmetto weevil, secretes (4S,5S)-5-methyloctan-4-ol.
The absolute configuration of the naturally occurring ste-
reoisomer of 4-methylnonan-5-ol (1) was established by
Oehlschlager and co-workers4 to be (4S,5S), and Mori and
co-workers5 synthesized the compound from an epoxy al-
cohol, whereas Gil and co-workers6 prepared it by using
chiral auxiliary units, according to Evans’ method.
As a part of our ongoing work on the synthesis of phero-
mones,12 we stereoselectively synthesized (+)-trans-whis-
key lactone (3) and the palm weevil pheromones (3S,4S)-
3-methyloctan-4-ol (2) and (4S,5S)-4-methylnonan-5-ol
(1) through radical cyclization reactions. Our retrosyn-
thetic analysis is shown in Scheme 1.
O
OH
EtO
1
9
HO
OH
7
4
O
OH
OH
Scheme 1 Retrosynthetic strategy
O
1
2
3
Our synthesis of (4S,5S)-4-methylnonan-5-ol (1), (3S,
4S)-3-methyloctan-4-ol (2), and (+)-trans-whiskey lac-
tone (3) began from the readily available allyl alcohol 4
(Scheme 2). Alcohol 4 gave the epoxy alcohol 5 when
treated under Sharpless asymmetric epoxidation condi-
tions.13 Epoxy alcohol 5 was converted into the corre-
Figure 1 (4S,5S)-4-methylnonan-5-ol (1), (3S,4S)-3-methyloctan-
4-ol (2), and (3) (+)-trans-whiskey lactone (3)
SYNTHESIS 2011, No. 23, pp 3894–3898
x
x.
x
x
.
2
0
1
1
sponding iodide
6
by treatment with diiodine,
Advanced online publication: 27.10.2011
DOI: 10.1055/s-0031-1289579; Art ID: Z77911SS
© Georg Thieme Verlag Stuttgart · New York
triphenylphosphine, and imidazole at 0 °C.14 Dehydro-

PAPER
Palm Weevil Pheromones and trans-Whiskey Lactone
3895
iodination and ring cleavage of iodide 6 by treatment with compound were in complete agreement with those of the
zinc and sodium iodide in refluxing methanol gave the de- natural product.5a
sired chiral allylic alcohol 7.15
Treatment of the cyclic acetal 9 with propane-1,3-dithiol
Treatment of allylic alcohol 7 with N-bromosuccinimide and boron trifluoride etherate19 at 0 °C gave the cyclic
and ethyl vinyl ether in dichloromethane gave the required thioacetal 13, which on treatment with activated Raney
bromo acetal 8.16 As expected, on treatment with tributyl- nickel20 in refluxing methanol gave alcohol 14 in 80%
stannane in refluxing toluene with 2,2¢-azobis(isobuty- yield. Mitsunobu inversion of the free hydroxyl group by
ronitrile) as the radical initiator, acetal 8 underwent a using diethyl azodicarboxylate, triphenylphosphine, and
standard 5-exo trig cyclization to give the cyclic ethyl ac- 4-nitrobenzoic acid gave the target molecule (3S,4S)-3-
etal 9 with a preferential anti-geometry of the resulting methyloctan-4-ol (2). The spectral data and rotation val-
new stereogenic center.17 The absolute stereochemistry of ues matched those of the natural compound.2 The two
the new stereogenic center was confirmed by oxidizing pheromones 1 and 2 exhibited excellent electrophysical
the cyclic acetal with Jones reagent to give (+)-trans- activities in electroactinographic studies.
whiskey lactone (3). The 1H and 13C NMR spectra and op-
tical rotation of 3 matched the reported data for (+)-trans-
S
whiskey lactone.10g
i
ii
O
S
Hydrolysis of ethyl acetal 9 in refluxing 80% acetic acid
gave the lactol 10, which on one-carbon Wittig olefination
afforded the homologated derivative 11 in 85% yield. The
13C NMR spectrum and HPLC data confirmed the homo-
geneity of the new stereogenic center created during the
free-radical cyclization. The double bond was reduced in
the presence of palladium(II) hydroxide under a hydrogen
atmosphere to give the alcohol 12. Mitsunobu inversion18
of the free alcohol 12 gave the desired pheromone 1. The
1H and 13C NMR spectra and the optical rotation of this
OH
OEt
9
13
iii
OH
14
OH
2
Scheme 3 Reagents and conditions: (i) HS(CH2)3SH, BF3·OEt2,
CH2Cl2; (ii) Raney Ni, MeOH, reflux; (iii) DEAD, Ph3P, 4-nitroben-
zoic acid, THF, then K2CO3, MeOH.
To summarize, we have successfully developed a concise,
efficient, and highly stereoselective synthesis of the pher-
omones (4S,5S) 4-methylnonan-5-ol (1) and (3S,4S) 3-
methyloctan-4-ol (2) and of (+)-trans-whiskey lactone (3)
by using radical cyclization as the key step. The two pher-
omones 1 and 2 exhibited excellent electrophysiological
activity in electroactinographic studies, and further field
trials are in progress.
O
i
ii
HO
HO
I
4
5
O
iii
iv
OH
6
7
v
vi
Br
Optical rotations were measured with a Jasco DIP-360 polarimeter
at 20 °C, and IR spectra were recorded on a Perkin-Elmer FT-IR
spectrophotometer. 1H NMR spectra were recorded using a Varian
Gemini (200 MHz), a Varian Inova (500 MHz), or a Bruker Avance
(300 MHz) spectrometer with TMS as an internal standard in
CDCl3. EI mass spectra were recorded on Micromass VG-7070 H.
High-resolution mass spectra were recorded on a VG-7070 H spec-
trometer. Elemental analyses were performed on a Vario EL analyz-
er. Electroactinographic equipment was obtained from Syntech
GmbH (Kirchzarten, Germany). GC-MS studies were performed on
an Agilent Technologies System 6890N. The progress of all the re-
actions was monitored by TLC on glass plates precoated with silica
gel 60 F254 to a thickness of 0.5 mm (Merck). Column chromatog-
raphy was on columns of silica gel 60–120 mesh with EtOAc–hex-
ane as the eluent. All reactions were carried out under an inert
atmosphere unless stated otherwise, following standard syringe–
septa techniques. All the solvents were dried by using the standard
procedures.
O
O
O
OEt
OEt
O
8
9
3
vii
viii
ix
O
OH
11
OH
10
x
OH
12
OH
1
Scheme 2 Reagents and conditions: (i) D-(–)-DIPT, Ti(O-i-Pr)4, t-
BuOOH, CH2Cl2, –20 °C; (ii) I2, Ph3P, imidazole, MeCN–Et2O (1:3);
(iii) Zn, NaI, MeOH, reflux; (iv) NBS, CH2=CHOEt, CH2Cl2; (v)
Bu3SnH, toluene, AIBN, 80 °C; (vi) Jones’s reagent, acetone; (vii)
80% acetic acid, reflux; (viii) Ph3P+Me I–, THF, BuLi, –78 °C; (ix)
Pd(OH)2, H2, MeOH; (x) DEAD, Ph3P, 4-nitrobenzoic acid, then
K2CO3, MeOH.
[(2R,3R)-3-Butyloxiran-2-yl]methanol (5)
A freshly flame-dried, double-necked, round-bottomed flask was
charged with activated 4-Å MS (~5 g) and anhyd CH2Cl2 (150 mL)
at –20 °C. Ti(O-i-Pr)4 (0.358 g, 1.26 mmol) and D-(–)-DIPT (0.355
g, 1.51 mmol) were added and the mixture was stirred for 20 min.
A soln of allylic alcohol 4 (2.88 g, 25.2 mmol) in CH2Cl2 (20 mL)
Synthesis 2011, No. 23, 3894–3898 © Thieme Stuttgart · New York

3896
J. S. Yadav et al.
PAPER
was added, followed after an interval of 20 min by a 3.7 M soln of
t-BuOOH in toluene (13.6 g, 50.5 mmol). Stirring was continued
until the reaction was complete (4 h). The mixture was then warmed
to 0 °C, quenched with H2O (20 mL), and stirred vigorously for 30
min. It was then filtered through a sintered funnel, and the filtrate
was stirred with 20% aq NaOH (5 mL) saturated with solid NaCl.
The biphasic soln was separated and the aqueous layer was extract-
ed with CH2Cl2 (2 × 50 mL). The combined organic extracts were
dried (Na2SO4) and concentrated in vacuo to give a crude residue
that was purified by column chromatography to give a colorless oil;
yield: 2.7 g (85%); [a]D25 +26.87 (c 0.9, CHCl3).
1H NMR (CDCl3, 200 MHz): d = 0.95 (t, J = 6.7 Hz, 3 H), 1.15–
1.60 (m, 9 H), 3.30 (d, J = 4.9 Hz, 2 H), 3.60 (m, 2 H), 3.95 (m, 1
H), 4.70 (m, 1 H), 5.20 (m, 2 H), 5.60–5.80 (m, 1 H).
MS (EI): m/z = 267 [M + 2 H]+.
Anal. Calcd for C11H21BrO2: C, 49.82; H, 7.98; Found: C, 49.30; H,
8.22.
(2R,3S)-2-Butyl-5-ethoxy-3-methyltetrahydrofuran (9)
A soln of Bu3SnH (4.92 g, 16.9 mmol) and a catalytic amount of
AIBN in toluene (5 mL) was added to a soln of bromoacetal 8 (4.5
g, 16.9 mmol) in refluxing anhyd toluene (35 mL) under N2. After
2 h, the soln was cooled to r.t. and passed through a column of silica
gel column to give a colorless oil; yield: 2.82 g (90%).
IR (neat): 3550, 2929, 2860, 1602, 1453, 1276, 1096, 912, 699 cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.95 (t, J = 6.7 Hz, 3 H), 1.10–
1.50 (m, 6 H), 2.80–3.00 (m, 2 H), 3.50–4.00 (m, 2 H).
IR (neat): 2929, 2870, 1606, 1455, 1372, 1097, 991, 795, 697 cm–1.
MS (EI): m/z = 130 [M+].
1H NMR (CDCl3, 200 MHz): d = 0.91 (t, J = 6.7 Hz, 3 H), 1.05 (d,
J = 6.0 Hz, 3 H), 1.19 (t, J = 6.7 Hz, 3 H), 1.25–1.62 (m, 8 H), 2.10
(m, 1 H), 3.28–3.49 (m, 2 H), 3.70 (m, 1 H), 4.90–5.09 (m, 1 H).
Anal. Calcd for C7H14O2: C, 64.58; H, 10.84; Found: C, 64.56; H,
10.81.
MS (EI): m/z = 188 [M+].
(2R,3S)-2-Butyl-3-(iodomethyl)oxirane (6)
Imidazole (3.27 g, 51.9 mmol), I2 (10.5 g, 41.5 mmol), and Ph3P
(10.88 g, 41.5 mmol) were added successively to a soln of alcohol
5 (2.7 g, 20.7 mmol) in 1:3 MeCN–Et2O (100 mL) at 0 °C under N2,
and the mixture was stirred for 20 min. The resulting soln was dilut-
ed with cool Et2O (200 mL) and filtered through a sintered funnel.
The residue was washed with anhyd Et2O (2 × 25 mL) and the com-
bined filtrates were concentrated under reduced pressure. The crude
product was passed through a pad of silica gel to give a colorless liq-
uid; yield: 4.56 g (92%); [a]D25 +6.5 (c 1.5, CHCl3).
IR (neat): 3087, 2921, 1496, 1455, 1092, 1027, 894 cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.95 (t, J = 6.7 Hz, 3 H), 1.10–
1.50 (m, 6 H), 2.80–3.00 (m, 2 H), 3.50–4.00 (m, 2 H).
(4S,5R)-5-Butyl-4-methyldihydrofuran-2(3H)-one [(+)-trans-
Whiskey Lactone] (3)
Jones’s reagent was added dropwise to an ice-cooled soln of cyclic
acetal 9 (400 mg) in acetone (20 mL) at 0 °C until the color of the
reagent persisted. The mixture was then stirred for 1 h at r.t., then
concentrated under reduced pressure to remove acetone. The result-
ing residue was diluted with H2O (10 mL) and extracted with Et2O
(2 × 20 mL). The extracts were dried (Na2SO4), concentrated, and
purified by column chromatography to give a colorless oil; yield:
240 mg (80%); [a]D25 +76.8 (c 1.01, MeOH), {Lit.10g [a]D19 +79 (c
1.04, MeOH)}.
IR (neat): 2933, 1781, 1458, 1211, 1171, 985, 476 cm–1.
MS (EI): m/z = 240 [M+].
1H NMR (CDCl3, 300 MHz): d = 0.95 (t, J = 6.7 Hz, 3 H), 1.14 (d,
J = 6.3 Hz, 3 H), 1.30–1.75 (m, 6 H), 2.20 (m, 2 H), 2.55–2.62 (m,
1 H), 3.99 (dt, J = 4.0, 7.7 Hz, 1 H).
13C NMR (CDCl3, 75 MHz): d = 13.89, 17.65, 22.55, 28.01, 33.5,
36.19, 37.21, 87.56, 176.56.
Anal. Calcd for C7H13IO: C, 35.02; H, 5.46; Found: C, 35.00; H,
5.45.
(3R)-Hept-1-en-3-ol (7)
A mixture of iodo compound 6 (4.5 g, 18.8 mmol), NaI (5.64 g, 37.6
mmol), and freshly activated Zn (2.98 g, 47.0 mmol) in anhyd
MeOH (30 mL) was refluxed for 8 h under N2. The soln was filtered
and the residue was washed with MeOH (2 × 15 mL). The filtrates
were combined and concentrated. The residue was taken up in
EtOAc (30 mL), washed successively with H2O (2 × 10 mL) and
brine (1 × 10 mL), and then dried (Na2SO4). Evaporation of the sol-
vent gave a residue that was purified by column chromatography to
MS (EI): m/z = 156 [M+].
HRMS (EI): m/z calcd for C9H16O2: 156.2265; found: 156.2267.
(4S,5R)-5-Butyl-4-methyltetrahydrofuran-2-ol (10)
A soln of ethyl acetal 9 (1.5 g, 7.5 mmol) in 80% aq AcOH (15 mL)
was refluxed for 4 h then cooled to 0 °C, neutralized with solid
NaHCO3, and extracted with CH2Cl2 (2 × 20 mL). The organic ex-
tracts were washed successively with H2O (2 × 10 mL) and brine
(1 × 10 mL) then dried (Na2SO4), filtered, and concentrated. The
residue was purified by column chromatography to give a colorless
liquid; yield: 0.96 (76%).
1H NMR (CDCl3, 200 MHz): d = 0.95 (d, J = 6.0 Hz, 3 H), 1.06 (t,
J = 6.7 Hz, 3 H), 1.24–1.62 (m, 6 H), 1.70 (m, 1 H), 2.10–2.40 (m,
2 H), 3.45 (m, 1 H), 3.92 (br s, 1 H), 4.85–4.99 (m, 1 H).
25
give a colorless liquid; yield: 1.93 g (90%); [a]D –21.5 (c 1.04,
EtOH) {Lit.21 [a]D21 –21.6 (c 1.02)}.
IR (neat): 3440, 3031, 2862, 1954, 1602, 1493, 1207, 1091 cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.94 (t, J = 6.7 Hz, 3 H), 1.20–
1.41 (m, 4 H), 1.40–1.55 (m, 2 H), 4.05 (q, J = 3.0, 9.3 Hz, 1 H),
5.10–5.25 (dd, J = 8.2, 14.5 Hz, 2 H), 5.80–5.91 (m, 1 H).
MS (EI): m/z = 114 [M+].
GC-MS: m/z = 115 [M + H]+.
MS (EI): m/z = 158 [M+].
(4S,5R)-4-Methylnon-1-en-5-ol (11)
(3R)-3-(2-Bromo-1-ethoxyethoxy)hept-1-ene (8)
t-BuOK (1.41g, 12.6 mmol) was added to Ph3P+Me I– (6.12 g, 15.1
mmol) in anhyd THF (40 mL) under N2 at –78 °C. After 30 min, a
soln of furanol 11 (0.8 g, 5.0 mmol) in anhyd THF (5 mL) was add-
ed from a cannula to the orange-yellow turbid mixture, and the re-
sulting mixture was stirred for 8 h while the temperature increased
to 0 °C. The reaction was then quenched with sat. aq NH4Cl (15
mL). The mixture was filtered through a sintered funnel and the res-
idue was washed with Et2O (3 × 15 mL). The combined organic fil-
trates were washed successively with H2O (25 mL) and brine (25
mL), dried (Na2SO4), and filtered. The residue was purified by col-
NBS (4.34 g, 24.1 mmol) was added to a stirred soln of CH2=CHO-
Et (3.15 g, 43.8 mmol) and allyl alcohol 7 (2.5 g, 21.9 mmol) in an-
hyd CH2Cl2 (20 mL) at 0 °C, and the mixture was stirred until the
reaction was complete (8–9 h). The mixture was washed with suc-
cessively with H2O (2 × 30 mL) and brine (1 × 30 mL) then dried
(Na2SO4), filtered, and concentrated. The residue was purified by
chromatography to give a colorless liquid; yield: 4.7 g (81%).
IR (neat): 2932, 1423, 1114, 1026, 927, 675 cm–1.
Synthesis 2011, No. 23, 3894–3898 © Thieme Stuttgart · New York

PAPER
Palm Weevil Pheromones and trans-Whiskey Lactone
3897
umn chromatography to give a colorless liquid; yield: 0.59 g
g, 3.2 mmol) at r.t. The mixture was immediately cooled in an ice
bath and then BF3·OEt2 (0.045 g, 32 mmol) was added. The mixture
was then allowed to warm to r.t. and, when the reaction was com-
plete, washed successively with H2O (2 × 10 mL), 10% aq KOH (15
mL), and H2O (2 × 10mL) then dried (K2CO3). Evaporation of the
solvent and purification by column chromatography gave a color-
less liquid product; yield: 500 mg (62.5%); [a]D –10.2 (c 1.01,
MeOH).
IR (neat): 3446, 2931, 1457, 1274, 983, 475 cm–1.
1H NMR (CDCl3, 300 MHz): d = 0.92 (t, J = 6.69 Hz, 3 H), 0.95 (d,
J = 6.4 Hz, 3 H), 1.25–1.65 (m, 8 H), 1.80–1.95 (m, 3 H), 2.08–2.19
(m, 1 H), 2.75–2.85 (m, 4 H), 3.40 (m, 1 H), 4.00–4.11 (m, 1 H).
13C NMR (CDCl3, 75 MHz): d = 14.01, 15.8, 22.6, 25.99, 28.1,
30.13, 30.5, 33.4, 35.5, 37.4, 45.64, 75.7.
(76.2%); [a]D25 +18.1 (c 1.3, MeOH).
IR (neat): 3417, 2958, 2932, 2862, 1467, 1233, 1023, 878, 755, 640
cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.88 (d, J = 6.7 Hz, 3 H), 0.95 (t,
J = 6.7 Hz, 3 H), 1.23–1.49 (m, 6 H), 1.6 (m, 1 H), 1.92 (m, 1 H),
2.30 (m, 1 H), 3.38 (m, 1 H), 4.90–5.50 (m, 2 H), 5.68–5.83 (m, 1
H).
13C NMR (CDCl3, 75 MHz): d = 14.06, 15.41, 22.75, 28.09, 33.37,
36.78, 38.64, 75.62, 115.85, 137.57.
MS (EI): m/z = 155 [M – H]+.
GC-MS: m/z = 155 [M – H]+.
25
(4S,5R)-4-Methylnonan-5-ol (12)
GC-MS: m/z 248 [M]+.
10% Pd(OH)2 (50 mg) was added to a soln of enol 11 (500 mg) in
anhyd EtOAc (5 mL), and the mixture was stirred under H2 until the
starting material was completely consumed. The catalyst was re-
moved by filtration through a pad of Celite, and the filtrate was con-
centrated under reduced pressure at low temperature to give a
colorless oil; yield: 470 mg (92.8%); [a]D25 +9.6 (c 0.60, EtO2).
HRMS: m/z calcd for C12H24S2O: 248.4525, found: 248.4521.
(3S,4R)-3-Methyloctan-4-ol (14)
A soln of thioacetal 13 (450 mg 1.8 mmol) in EtOH (15 mL) was
added to activated Raney Ni (900 mg) in EtOH (15 mL), and the
mixture was refluxed under N2 until the starting material was con-
sumed. The mixture was then cooled to r.t., filtered, and purified by
column chromatography to give a colorless liquid; yield: 300 mg
(76.9%); [a]D25 +10.2 (c 1.02, EtO2).
IR (neat): 3370, 2960, 1461, 1317, 1001, 643 cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.80–1.10 (m, 9 H), 1.20–1.82 (m,
9 H), 3.42 (m, 1 H).
IR (neat): 3417, 2958, 2932, 2862, 1467, 1233, 1023, 878, 755, 640
cm–1.
1H NMR (CDCl3, 300 MHz): d = 0.87 (d, J = 6.7 Hz, 3 H), 0.90 (t,
J = 7.1 Hz, 3 H), 0.92 (t, J = 7.1 Hz, 3 H), 1.16–1.52 (m, 11 H),
1.55 (br s, 1 H), 3.35 (m, 1 H).
13C NMR (CDCl3, 75 MHz): d = 14.08, 14.40, 15.2, 20.4, 22.8, 28.3,
33.05, 34.1, 38.55, 75.2.
13C NMR (CDCl3, 50 MHz): d = 12.01, 14.2, 14.89, 22.91, 24.91,
28.6, 33.2, 39.5 and 75.9.
GC-MS: m/z = 143 [M– H]+.
MS (EI): m/z = 157 [M – H]+.
GC-MS: m/z = 157 [M – H]+.
(4S,5S)-4-Methylnonan-5-ol (1)
Anal. Calcd for C9H20O: C, 74.93; H, 13.97; Found: C, 74.85; H,
13.99.
A soln of Ph3P (1.32 g, 5.0 mmol) and DEAD (0.90 g, 5.1 mmol) in
anhyd THF (7 mL) was added to a soln of alcohol 12 (400 mg, 2.5
mmol) in anhyd THF (7 mL) at 0 °C. After 30 min, 4-
O2NC6H4CO2H (0.42 g, 5.05 mmol) was added and the mixture was
stirred until the reaction was complete. The mixture was then
washed with H2O (2 × 20 mL), extracted with EtOAc (2 × 20 mL),
dried (Na2SO4), and concentrated under reduced pressure. The
crude product was purified by flash column chromatography, and
the resulting ester was deprotected by treatment with K2CO3 (0.698
mg, 5.06 mmol) in MeOH (10 mL) at 20 °C for 3 h to give the free
alcohol. Residual solid K2CO3 was filtered off, and the filtrate was
concentrated under reduced pressure to give a residue that was pu-
rified by column chromatography to give a colorless liquid; yield:
250 mg (62.5%); [a]D25 –25.4 (c 1.25, Et2O) {Lit.5a [a]D19 –26.5 (c
88, Et2O)}.
(3S,4S)-3-Methyloctan-4-ol (2)
A soln of Ph3P (0.72 g, 2.7 mmol) and DEAD (0.48 g, 2.7 mmol) in
anhyd THF (7 mL) was added to a soln of alcohol 14 (200 mg, 1.3
mmol) in anhyd THF (7 mL) at 0 °C. After 30 min, 4-
O2NC6H4CO2H (0.46 g, 2.7 mmol) was added and the mixture was
stirred until the reaction was complete. The mixture was then
washed with H2O (2 × 15 mL) and extracted with EtOAc (2 × 20
mL), dried (Na2SO4), and concentrated under reduced pressure. The
crude product was purified by flash column chromatography, and
the resulting ester was deprotected by treatment with K2CO3 (0.38
g, 2.77 mmol) in MeOH (10 mL) at 20 °C for 3 h to give the free
alcohol. Residual solid K2CO3 was filtered off, and the filtrate was
concentrated under reduced pressure to give a residue that was pu-
rified by column chromatography to give a colorless liquid; yield:
120 mg (60%); [a]D25 –20.2 (c 1.1, Et2O) {Lit.2 [a]D19 –20.7 (c 1.01,
Et2O)}.
IR (KBr): 3380, 2980, 2932, 2875, 1461, 1118, 1001, 643 cm–1.
1H NMR (CDCl3, 500 MHz): d = 0.86 (d, J = 6.0 Hz, 3 H), 0.90 (t,
J = 6.78 Hz, 3 H), 0.92 (t, J = 6.72 Hz, 3 H), 1.25–1.42 (m, 10 H),
1.42–1.46 (m, 1 H), 1.55 (br s, 1 H, OH), 3.50 (m, 1 H).
13C NMR (CDCl3, 75 MHz): d = 13.8, 14.1, 14.2, 20.5, 22.85, 28.5,
34.1, 35.8, 38.0, 75.2.
MS (EI): m/z = 158 [M+].
GC-MS: m/z = 158 [M+].
IR (neat): 3380, 2980, 2932, 2875, 1461, 1118, 643 cm–1.
1H NMR (CDCl3, 500 MHz): d = 0.86 (d, J = 6.08 Hz, 3 H), 0.90 (t,
J = 6.78 Hz, 3 H), 0.92 (t, J = 6.72 Hz, 3 H), 1.00–1.16 (m, 1 H),
1.25–1.42 (m, 8 H), 1.55 (br s, 1 H), 3.50 (m, 1 H).
13C NMR (CDCl3, 75 MHz): d = 11.9, 13.2, 14.1, 22.8, 26.1, 28.5,
34.3, 40.0, 74.9.
MS (EI): m/z = 144 [M+].
GC-MS: m/z = 143 [M + 1]+.
Anal. Calcd for C10H22O: C, 75.88; H, 14.01; Found: C, 75.91; H,
14.08.
(2S,3R)-1-(1,3-Dithian-2-yl)-2-methylheptan-3-ol (13)
A soln of cyclic acetal 9 (600 mg, 3.2 mmol), in anhyd CH2Cl2 was
combined with an equimolar amount of propane-1,3-dithiol (0.348
Anal. Calcd for C9H20O: C, 74.93; H, 13.97; Found: C, 74.88; H,
14.03.
Synthesis 2011, No. 23, 3894–3898 © Thieme Stuttgart · New York

3898
J. S. Yadav et al.
PAPER
Okamura, K. Chem. Pharm. Bull. 1992, 40, 2579.
Acknowledgment
(f) Zschage, O.; Hoppe, D. Tetrahedron 1992, 48, 5657.
(g) Ebata, T.; Matsumoto, K.; Yoshikoshi, H.; Koseki, K.;
Kawakami, H.; Okano, K.; Matsushita, H. Heterocycles
1993, 36, 1017. (h) Katsuji, I.; Yoshitake, M.; Katsuki, T.
Tetrahedron 1996, 52, 3905. (i) Hisashi, N.; Katsuji, I.;
Tsutomu, K. Tetrahedron: Asymmetry 1998, 9, 1165.
(11) (a) Bloch, R.; Gilbert, L. J. Org. Chem. 1987, 52, 4603.
(b) Taber, D. F.; Houze, J. B. J. Org. Chem. 1994, 59, 4004.
(c) Pai, Y.-C.; Fang, J.-M.; Wu, S.-H. J. Org. Chem. 1994,
59, 6018. (d) Takahata, H.; Uchida, Y.; Momose, T.
Tetrahedron Lett. 1994, 35, 4123. (e) Takahata, H.; Uchida,
Y.; Momose, T. J. Org. Chem. 1995, 60, 5628.
C.V.R. thanks CSIR, New Delhi for the award of a fellowship. The
authors acknowledge partial support from King Saud University for
Global Research Network for Organic Synthesis (GRNOS).
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Synthesis 2011, No. 23, 3894–3898 © Thieme Stuttgart · New York