Domino recombinant γ-isomerization and reverse Wacker oxidation of γ-vinyl-γ-butyrolactone: Synthesis of (+)-trans-, (-)- and (+)-disparlures

Article abstract of DOI:10.1002/ejoc.201400021

A domino palladium-catalyzed recombinant γ-isomerization and reverse Wacker oxidation of γ-vinyl-γ-butyrolactone has been explored. The strategy has been used in the stereoselective synthesis of (+)-trans-, (-)- and (+)-disparlures. The synthesis was achieved in seven to eight steps from D-glucono-δ-lactone with overall yields of 19.3, 20.7 and 22.6 %, respectively. Copyright

Full text of DOI:10.1002/ejoc.201400021

FULL PAPER
DOI: 10.1002/ejoc.201400021
Domino Recombinant γ-Isomerization and Reverse Wacker Oxidation of
γ-Vinyl-γ-butyrolactone: Synthesis of (+)-trans-, (–)- and (+)-Disparlures
[a]
[a]
[a]
Venkati Bethi, Pullaiah Kattanguru, and Rodney A. Fernandes*
Keywords: Synthetic methods / Asymmetric synthesis / Cross-metathesis / Palladium / Oxidation / Pheromones
A domino palladium-catalyzed recombinant γ-isomerization
and reverse Wacker oxidation of γ-vinyl-γ-butyrolactone has
been explored. The strategy has been used in the stereo-
selective synthesis of (+)-trans-, (–)- and (+)-disparlures. The
synthesis was achieved in seven to eight steps from D-
glucono-δ-lactone with overall yields of 19.3, 20.7 and
22.6%, respectively.
Introduction
The regioselective transformation of terminal olefins to
carbonyl compounds has drawn considerable synthetic
interest during the past few decades. The palladium-cata-
lyzed Wacker process is a common choice to prepare methyl
ketones from the corresponding olefins.[ This process has
been widely used in industry and synthetic research. The
aldehyde-selective Wacker process has been a major chal-
lenge and considerable efforts have been made to address
this important issue.[ The overall outcome of the Wacker
reaction mainly depends on regioselective hydration of the
olefin followed by oxidation. The Markovnikov and anti-
Markovnikov hydration of terminal olefins lead to the for-
mation of methyl ketones and aldehydes, respectively. In
particular, selective aldehyde formation was observed in the
presence of chelating neighboring functionalities (oxygen,
1]
2]
Figure 1. Structures of disparlures.
In 1970, Bierl identified disparlure as a sex-attractant
pheromone, from the female gypsy moth, Lymantria Dispar
[8]
L. This moth is a harmful pest causing serious forest
[3]
nitrogen or π complexation), or by using various palla-
dium and iron catalysts.[ The heteroatom-directed reverse
Wacker oxidation has been employed in natural product
losses during outbreaks in Europe, Asia and North Amer-
2]
[9]
ica. Iwaki et al. proved the absolute stereochemistry of
disparlure through the synthesis of both enantiomers. A re-
cent study showed that (+)-disparlure (1) and ent-1 have
different binding affinity towards the two pheromone-bind-
[
4]
synthesis. However, this process was rarely studied for γ-
vinyl-γ-butyrolactone to corresponding aldehydes without
[5]
effecting the lactone chiral center. In continuation to our
interest in the application of γ-vinyl-γ-butyrolactone in the
synthesis of natural products,[ recently we studied the re-
combinant inversion of γ-vinyl-γ-butyrolactone by palla-
[10]
ing proteins (PBP1 and PBP2). Disparlure and its stereo-
isomers have been interesting synthetic targets for a long
6]
[11]
time.
[
7]
dium catalysis. Here, we report an efficient domino re-
combinant γ-isomerization and reverse Wacker oxidation of
γ-vinyl-γ-butyrolactone. The developed method was suc-
cessfully used for the synthesis of (+)-trans-, (–)- and (+)-
disparlures (Figure 1).
Results and Discussion
Our investigation began by wanting to generalize the ap-
plications of syn-lactone 4a in various reactions.
lactone 4a can now be prepared easily from d-glucono-δ-
lactone by following a reliable one-pot process. We sub-
[
12]
Syn-
[
6]
[
a] Department of Chemistry, Indian Institute of Technology
jected syn-lactone 4a to the hetero-atom directed reverse
Bombay,
[
4]
Powai, Mumbai 400 076, Maharashtra, India
E-mail: rfernand@chem.iitb.ac.in
Wacker oxidation
with PdCl (10 mol-%) and CuCl
2
(1.5 equiv.) in dimethylformamide (DMF)/H O (7:1) under
2
http://www.chem.iitb.ac.in/~rfernand/default.htm
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201400021.
O gas to give aldehyde 5. This compound after Wittig ole-
2
fination with (isopentyl)triphenylphosphonium bromide (6)
Eur. J. Org. Chem. 2014, 3249–3255
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3249

V. Bethi, P. Kattanguru, R. A. Fernandes
FULL PAPER
and lithium bis(trimethylsilyl)amide (LiHMDS) gave two as the major product (32%) along with syn-lactone 7 in
separable diastereomeric lactones 7 and 8 isolated in 39 and 13% yield (Table 1, Entry 3). This indicates that because O2
6
% yields, respectively (Table 1, Entry 1). The latter re- gas was not bubbled, it suppressed the Wacker oxidation
sulted through Pd-catalyzed domino recombinant γ-isomer- but promoted Pd-catalyzed recombinant γ-isomerization.
ization and reverse Wacker oxidation. The reaction with The reaction was further optimized with PdCl (20 mol-%)
2
2
0 mol-% of PdCl afforded syn-lactone 7 with an improved to give anti-lactone 8 in 51% and 7 in 21% yield, respec-
2
yield of 60% along with isomerized product 8 in 9% yield tively (Table 1, Entry 4). A one-pot β-epimerization fol-
Table 1, Entry 2). Lowary and co-workers[
5a]
earlier re- lowed by Wacker oxidation was attempted with Pd(OAc)
(
2
[
14]
ported a similar reaction to give exclusive syn-aldehyde (20 mol-%; Table 1, Entry 5).
However, though β-epi-
product and did not isolate any γ-isomerization product. merization was observed by formation of a mixture of 4a
Slow isomerization of an aldehyde, such as 5 [with no tert- and 4b by TLC, no aldehyde formation was observed even
butyldimethylsilyl ether (β-OTBDMS) group], is known after a prolonged reaction time. Consequently, the Wittig
without involvement of Pd.[ However, Pd is required for reaction was not attempted. Further attempts to improve
the Wacker process. We became interested in exploring this the yield of the Wittig reaction by using tBuOK (2.5 equiv.),
de novo domino recombinant γ-isomerization and reverse cleanly gave compound 9 (70%; Table 1, Entry 6) obtained
Wacker oxidation. We believed that an interplay of reaction through opening of the lactone. Later, we planned to ana-
conditions could lead predominantly to either compound 7, lyze the reliability of our method by performing the Wacker
through reverse Wacker oxidation as the major product, or oxidation on anti-lactone 4b. Anti-lactone 4b can be ob-
to 8, by a domino recombinant γ-isomerization followed by tained from 4a by a recombinant inversion method devel-
13]
[
7]
reverse Wacker oxidation. To maximize the γ-isomerization, oped by us. A reverse Wacker oxidation by using pre-
we planned to premix 4a with the palladium catalyst and mixed anti-lactone 4b with PdCl (10 mol-%) and CuCl fol-
2
CuCl under a nitrogen atmosphere. To this end, pre-mixed lowed by Wittig reaction delivered 8 (48%) and 7 (11%;
syn-lactone 4a with palladium catalyst (10 mol-%) was Table 1, Entry 7). The reaction yield of 8 was further im-
stirred for 20 min before bubbling O gas. The isolated alde- proved to 64% by increasing the palladium catalyst loading
2
hyde was subjected to Wittig reaction to give anti-lactone 8 from 10 to 20 mol-% (Table 1, Entry 8). This reaction indi-
Table 1. Domino recombinant γ-isomerization and reverse Wacker oxidation of lactones 4a or 4b and subsequent Wittig olefination.
Entry
1
Reaction conditions
(i) PdCl (10 mol-%), CuCl (1.5 equiv.), DMF/H
a, O , 10 h; (ii) 6, LiHMDS, THF, 0 °C, 45 min, then 5, –20 °C, 8 h.
(i) PdCl (20 mol-%), CuCl (1.5 equiv.), DMF/H O (7:1), room temp., 20 min, then
a, O , 8 h; (ii) 6, LiHMDS, THF, 0 °C, 45 min, then 5, –20 °C, 8 h.
(i) 4a, PdCl
Isolated yields
2
2
O (7:1), room temp., 20 min, then
syn-7 (39%)
anti-8 (6%)
syn-7 (60%)
anti-8 (9%)
syn-7 (13%)
anti-8 (32%)
syn-7 (21%)
anti-8 (51%)
4
2
2
3
4
5
6
7
8
2
2
4
2
2
(10 mol-%), CuCl (1.5 equiv.), DMF/H
2
O (7:1), room temp., 20 min, then
O (7:1), room temp., 20 min, then
O
2
, room temp., 10 h; (ii) 6, LiHMDS, THF, 0 °C, 45 min, then 5, –20 °C, 8 h.
(i) 4a, PdCl
2
(20 mol-%), CuCl (1.5 equiv.), DMF/H
2
O
2
, room temp., 8 h; (ii) 6, LiHMDS, THF, 0 °C, 45 min, then 5, –20 °C, 8 h.
(20 mol-%), PPh (80 mol-%), pyridine (0.5 equiv.), THF, 50 °C, 36 h;
ii) CuCl (1.5 equiv.), THF/DMF:H O (3.5:3.5:1), O , room temp., 12 h.
(20 mol-%), CuCl (1.5 equiv.), DMF/H O (7:1), room temp., 20 min, then 4a,
(i) 4a, Pd(OAc)
2
3
(
2
2
–[a]
(i) PdCl
O
2
2
2
, 8 h; (ii) 6, tBuOK (2.5 equiv.), THF, 0 °C, 45 min, then 5, –20 °C, 3 h.
(i) 4b, CuCl (1.5 equiv.), DMF/H O (7:1), O , room temp., 20 min, then PdCl
mol-%), 8 h; (ii) 6, LiHMDS, THF, 0 °C, 45 min, then 5, –20 °C, 8 h.
(i) 4b, CuCl (1.5 equiv.), DMF/H O (7:1), O , room temp., 20 min, then PdCl
20 mol-%), 6 h; (ii) 6, LiHMDS, THF, 0 °C, 45 min, then 5, –20 °C, 8 h.
9 (70%)
2
2
2
2
(10
syn-7 (11%)
anti-8 (48%)
syn-7 (16%)
anti-8 (64%)
2
2
(
[
a] No Wacker oxidation occurred. Only epimerization products were detected by TLC. Therefore the Wittig reaction was not attempted.
THF = tetrahydrofuran.
3250
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3249–3255

Synthesis of Disparlures
cates a probable equilibration between the anti- and syn-
For (+)-disparlure (1) synthesis, the cross-metathesis[15]
lactone through the formation of an intermediate π-allyl of lactone 4a with 1-decene and Grubbs’ second-generation
species. (G-II) catalyst gave 16 in low yield (20%). The use of
With the synthesized lactones 7, 8 and 4a, we aimed to Grubbs–Hoveyda second-generation (GH-II) catalyst, fur-
use them in the synthesis of (–)-disparlure (ent-1), (+)-trans- nished 16 in 45% yield. The cross-metathesis reaction of
disparlure (2) and (+)-disparlure (1), respectively. Our syn- unprotected lactone 14 and 1-decene with G-II catalyst af-
thetic approach for (–)-disparlure (ent-1) and (+)-trans-dis- forded 15 in excellent yield of 90% with calcd. Ͻ10% of Z-
parlure (2) is shown in Scheme 1. syn-Lactone 7 was re- olefin isomer formed. Initial efforts for free hydroxy group
duced with diisobutylaluminium hydride (DIBAL-H) to the silylation as the tert-butyldimethylsilyl (TBS) ether with
lactol and subsequent Wittig olefination with (n-octyl)tri- TBSCl and imidazole were low yielding. Later a suitable
phenylphosphonium bromide and with nBuLi as base, pro- condition was identified with TBSOTf and 2,6-lutidine to
vided the diene that was immediately hydrogenated to pro- give 16 in 86% yield (Scheme 2). Low-temperature DIBAL-
duce 10 in 86% yield (over three steps). Similarly, com- H reduction of the lactone to lactol and subsequent Wittig
pound 8 led to 12 in 83% yield. Alcohol 10 on tosylation reaction with (isopentyl)triphenylphosphonium bromide (6)
to 11 (quantitative), followed by treatment with tetra-n-but- gave the diene, which was immediately hydrogenated by
ylammonium fluoride (TBAF) afforded (–)-disparlure (ent- using Pd(OH) /C in iPrOH to produce saturated alcohol 17
2
2
5
[11m]
1
) in 91% yield, [α]D = –1.6 (c = 1.2, CCl ), ref.
[α]D
=
in 70% yield (over three steps). Conversion of hydroxy
4
–
1.0 (c = 1.7, CCl ). Similarly, alcohol 12 on tosylation pro- group to tosylate (18, 91%) and further in situ TBAF-medi-
4
vided 13 in 94% yield. The latter on TBAF treatment then ated OTBS deprotection resulted in spontaneous displace-
2
5
led to (+)-trans-disparlure (2) in 88% yield, [α] = +25.6 (c ment of the tosyl group to give (+)-disparlure (1) in 90%
D
[
9]
25
25
[11m]
=
0.4, CCl ), ref. [α] = +27.5 (c = 0.5, CCl ). The spec- yield, [α]D = +1.6 (c = 1.1, CCl ), ref.
[α]D = +1.0 (c =
4
D
4
4
troscopic and analytical data of ent-1 and 2 were in good 1.5, CCl ). The analytical and spectroscopic data of 1 were
4
agreement with reported data.[
9]
in excellent agreement with earlier reports.
[11]
Scheme 2. Synthesis of (+)-disparlure. Reagents and conditions:
a) 14, 1-decene (1.5 equiv.), G-II catalyst (2.0 mol-%), CH Cl , re-
flux, 72 h, 15 (90%) or 4a, 1-decene (2.0 equiv.), GH-II catalyst
2.0 mol-%), reflux, 72 h, 16 (45%); (b) 2,6-lutidine (2.0 equiv.),
TBDMSOTf (1.5 equiv.), CH Cl , 0 °C to room temp., 2 h, 16
86%); (c) (i) DIBAL-H (1.5 equiv.), Et O, –78 °C, 1 h;
(4.0 equiv.), nBuLi (4.0 equiv.),
(
2
2
(
2
2
(
(
2
–
3 2 2 3 2
ii) Br Ph CH CH(CH )
P+CH
toluene, 0 °C, 30 min, lactol, 0 °C to room temp., 3 h; (iii) H
Pd(OH) /C, iPrOH, room temp., 6 h, 70% (over 3 steps);
d) DMAP (2.5 equiv.) pTsCl (2.0 equiv.), CH Cl , 0 °C, 1 h, room
temp., 5 h, 91%; (e) TBAF (3.4 equiv.), THF, 0 °C to room temp.,
h, 90%.
2
,
2
(
2
2
5
Scheme 1. Synthesis of (–)-disparlure and (+)-trans-disparlure. Rea-
gents and conditions: (a) (i) DIBAL-H (1.5 equiv.), Et O, –78 °C,
(2.0 equiv.), THF, nBuLi
2.0 equiv.), 0 °C, 1 h, lactol, 0 °C to room temp., 8 h; (iii) H
Pd(OH) /C, iPrOH, room temp., 3 h, 10 (86%, over 3 steps), 12
83%); (b) 4-Dimethylaminopyridine (DMAP; 4.0 equiv.) TsCl
3.0 equiv.), CH Cl , 0 °C to room temp., 24 h, 11 (quant), 13
2
Conclusions
+
–
1
(
3 2 2 6 3
h; (ii) Ph P CH (CH ) CH Br
2
,
In summary, we have developed de novo an efficient
domino recombinant γ-isomerization and reverse Wacker
oxidation of γ-vinyl-γ-butyrolactone. The developed
method was then used in the stereoselective synthesis of
(+)- and (–)-disparlures and (+)-trans-disparlure. Further
2
(
(
(
(
2
2
94%); (c) TBAF (3.4 equiv.), THF, 0 °C to room temp., 5 h, ent-1
91%), 2 (88%).
Eur. J. Org. Chem. 2014, 3249–3255
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3251

V. Bethi, P. Kattanguru, R. A. Fernandes
FULL PAPER
studies to extend this strategy on larger-ring-size lactones (400 MHz, CDCl
3
/TMS): δ = 5.64–5.59 (m, 1 H), 5.45–5.38 (m, 1
H), 4.31 (td, J = 6.5, 3.1 Hz, 1 H), 4.22–4.19 (m, 1 H), 2.74 (dd, J
17.7, 6.6 Hz, 1 H), 2.42 (dd, J = 17.6, 4.0 Hz, 1 H), 2.38 (t, J =
.8 Hz, 2 H), 1.95 (td, J = 7.1, 1.3 Hz, 2 H), 1.67–1.62 (m, 1 H),
to give useful building blocks for natural products synthesis
are in progress and will be reported in due course.
=
6
0
1
3
.90–0.86 (m, 15 H), 0.071 (s, 3 H), 0.061 (s, 3 H) ppm. C NMR
): δ = 174.9, 133.0, 122.8, 87.5, 71.3, 38.1, 36.5,
0.5, 28.5, 25.5, 22.3, 17.8, –4.8, –4.9 ppm. HRMS: calcd. for
Si + Na]+ 335.2013; found 335.2012.
(
3
[
100 MHz, CDCl
3
Experimental Section
C
17
H
32
O
3
General Information: Flasks were oven or flame dried and cooled
in a desiccator. Dry reactions were carried out under an atmo-
(
4R,5R)-4-(tert-Butyldimethylsilyloxy)-5-(Z)-(5-methylhex-2-enyl)di-
sphere of Ar or N
2
. Solvents and reagents were purified by stan-
hydrofuran-2(3H)-one (7) and (4R,5S)-4-(tert-Butyldimethylsilyl-
oxy)-5-(Z)-(5-methylhex-2-enyl)dihydrofuran-2(3H)-one (8): Reac-
tion conditions were as stated in Table 1, Entry 4: To a stirred solu-
tion of compound 4a (120 mg, 0.495 mmol) in DMF (3.5 mL) and
water (0.5 mL) were added PdCl
%
stirred for 20 min. Then oxygen gas was bubbled through the solu-
tion for 8 h at room temperature. It was then filtered through a
small pad of silica gel and washed with EtOAc. The filtrate was
2 4
washed with water (3ϫ 50 mL), brine, dried (Na SO ) and concen-
trated to give aldehyde 5 (120 mg) as a colorless oil, which was used
dard methods. Thin-layer chromatography was performed with EM
2
50 Kieselgel 60 F254 silica gel plates. The spots were visualized
1
13
4
by staining with KMnO or under UV lamp. H and C NMR
spectra were recorded with a Bruker, AVANCE III 400 spectrome-
ter and the chemical shifts are calculated relative to the tetrameth-
2
(17.6 mg, 0.099 mmol, 20 mol-
) and CuCl (73.6 mg, 0.743 mmol, 1.5 equiv.) and the mixture
1
ylsilane peak at δ = 0.00 pm for H NMR spectra, and relative to
the CDCl
3
peak at δ = 77.00 ppm (t) for 13C NMR spectra. IR
spectra were obtained with a Perkin–Elmer Spectrum One FT–IR
spectrometer and samples were prepared by evaporation from
CHCl
sco P-2000 digital polarimeter. High-resolution mass spectra
HRMS) were obtained by using positive electrospray ionization
and by TOF method.
3
on CsBr plates. Optical rotations were measured with a Ja-
directly in the next reaction.
(
To a stirred suspension of (isopentyl)triphenylphosphonium brom-
ide (6; 307 mg, 0.743 mmol, 1.5 equiv.) in dry THF (10 mL) was
added LiHMDS (1.2 m solution in THF, 0.62 mL, 0.743 mmol,
1
–
added. The reaction mixture was stirred for 8 h and then quenched
with saturated aq. NH Cl solution. The mixture was extracted with
EtOAc (3ϫ 10 mL) and the combined organic layers were washed
with brine, dried (Na SO ) and concentrated. The residue was puri-
fied by silica gel column chromatography with petroleum ether/
EtOAc (9:1) as an eluent to afford 8 (78.9 mg, 51%) as a colorless
oil. Further elution gave 7 (32.5 mg, 21%) as a colorless oil. The
analytical and spectroscopic data for 7 and 8 were the same as
before.
(4R,5R)-4-(tert-Butyldimethylsilyloxy)-5-(Z)-(5-methylhex-2-enyl)di-
hydrofuran-2(3H)-one (7) and (4R,5S)-4-(tert-Butyldimethylsilyl-
oxy)-5-(Z)-(5-methylhex-2-enyl)dihydrofuran-2(3H)-one (8): Reac-
tion conditions were as stated in Table 1, Entry 2: A mixture of
.5 equiv.) at 0 °C and stirred for 45 min. It was then cooled to
20 °C and a solution of aldehyde 5 (120 mg) in THF (5 mL) was
PdCl
2
(30.7 mg, 0.173 mmol, 20 mol-%) and CuCl (129 mg,
O (1 mL) was stirred
4
1.3 mmol, 1.5 equiv.) in DMF (5 mL) and H
2
for 20 min at room temperature. To this mixture was added com-
pound 4a (210 mg, 0.866 mmol) in DMF (2 mL) and oxygen gas
was bubbled through the solution for 8 h. It was then filtered
through a small pad of silica gel and washed with EtOAc. The
filtrate was washed with water (3ϫ 50 mL), brine, dried (Na SO )
2 4
and concentrated to give crude aldehyde 5 (200 mg) as a colorless
2
4
oil, which was used directly in the next reaction.
(
3R,4E,6Z)-3-(tert-Butyldimethylsilyloxy)-9-methyldeca-4,6-dienoic
Acid (9): Reaction conditions were as stated in Table 1, Entry 6:
A mixture of PdCl (29.3 mg, 0.165 mmol, 20 mol-%) and CuCl
122.7 mg, 1.24 mmol, 1.5 equiv.) in DMF (5 mL) and H O (1 mL)
To a stirred suspension of (isopentyl)triphenylphosphonium brom-
ide (6; 430 mg, 1.04 mmol, 1.2 equiv.) in dry THF (15 mL) was
added LiHMDS (1.2 m solution in THF, 0.9 mL, 1.04 mmol,
2
(
2
1
–
.2 equiv.) at 0 °C and stirred for 45 min. It was then cooled to
20 °C and a solution of aldehyde 5 (200 mg) in THF (5 mL) was
was stirred for 20 min at room temperature. To this mixture was
then added compound 4a (0.2 g, 0.825 mmol) in DMF (2 mL) and
oxygen gas was bubbled through the solution for 8 h. The mixture
was then filtered through a small pad of silica gel and washed with
EtOAc. The filtrate was washed with water (3 ϫ 50 mL), brine,
added. The reaction mixture was stirred for 8 h and then quenched
with saturated aq. NH Cl solution. The mixture was extracted with
EtOAc (3ϫ 10 mL) and the combined organic layers were washed
with brine, dried (Na SO ) and concentrated. The residue was puri-
4
2
4
2 4
dried (Na SO ) and concentrated to give crude aldehyde 5 (200 mg)
as a colorless oil, which was used directly in the next reaction.
fied by silica gel column chromatography with petroleum ether/
EtOAc (19:1) as an eluent to afford 8 (24.4 mg, 9%) as a colorless
oil. Further elution gave 7 (162.5 mg, 60%) as a colorless oil.
To a stirred suspension of (isopentyl)triphenylphosphonium brom-
ide (6; 0.852 g, 2.062 mmol, 2.5 equiv.) in dry THF (15 mL) was
added tBuOK (0.231 g, 2.062 mmol, 2.5 equiv.) at 0 °C and stirred
for 45 min. It was then cooled to –20 °C and a solution of aldehyde
Data for 7: [α]25
= +6.1 (c = 0.75, CHCl
957, 2931, 2860, 1779, 1465, 1364, 1259, 1160, 1102, 1085, 1030,
D
3 3
). IR (CHCl ): ν˜ = 3020,
2
9
5
4
2
7
–
1 1
3
51, 897, 840, 668 cm . H NMR (400 MHz, CDCl /TMS): δ =
5
(200 mg) in THF (5 mL) was added. The reaction mixture was
stirred for 3 h and then quenched with saturated aq. NH Cl solu-
tion. The mixture was extracted with EtOAc (3ϫ 10 mL) and the
combined organic layers were washed with brine, dried (Na SO
.61–5.54 (m, 1 H), 5.49–5.43 (m, 1 H), 4.47–4.44 (m, 1 H), 4.35–
.31 (m, 1 H), 2.72 (dd, J = 17.2, 5.3 Hz, 1 H), 2.65–2.58 (m, 1 H),
.45 (dd, J = 17.2, 1.5 Hz, 1 H), 2.42–2.37 (m, 1 H), 1.95 (t, J =
.1 Hz, 2 H), 1.67–1.62 (m, 1 H), 0.91–0.89 (m, 15 H), 0.09 (s, 6
4
2
4
)
and concentrated. The residue was purified by silica gel column
chromatography with petroleum ether/EtOAc (1:1) as eluent to af-
13
H) ppm. C NMR (100 MHz, CDCl
3
): δ = 175.3, 132.1, 123.9,
8
–
3
4.8, 69.3, 39.6, 36.5, 28.5, 26.9, 25.6, 22.3, 22.2, 17.9, –4.6,
25
ford 9 (0.181 g, 70%) as a colorless oil. [α]
CHCl ). IR (CHCl
635, 1467, 1405, 1366, 1168, 1050, 975, 908, 668 cm . H NMR
(400 MHz, CDCl /TMS): δ = 6.51 (dd, J = 15.1, 11.1 Hz, 1 H),
D
= +4.5 (c = 1.5,
+
5.2 ppm. HRMS: calcd. for [C17
35.2012.
32 3
H O Si + Na] 335.2013; found
3
3
): ν˜ = 3475, 3020, 2959, 2928, 2872, 1772, 1719,
–1
1
1
Data for 8: [α]25
= –13.5 (c = 1.5, CHCl
). IR (CHCl
): ν˜ = 3026,
D
3
3
3
2
1
955, 2931, 2859, 1788, 1603, 1496, 1464, 1384, 1362, 1258, 1197,
6.00 (t, J = 11.0 Hz, 1 H), 5.63 (dd, J = 15.1, 6.5 Hz, 1 H), 5.50
167, 1134, 1086, 1005, 922, 838, 779, 699 cm–1
.
1
H NMR (dt, J = 10.8, 7.9 Hz, 1 H), 4.64 (q, J = 6.0 Hz, 1 H), 2.57 (d, J =
3252
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3249–3255

Synthesis of Disparlures
54 2
.0 Hz, 2 H), 2.05 (dd, J = 15.1, 11.1 Hz, 2 H), 1.68–1.61 (m, 1 H), –4.5 ppm. HRMS: calcd. for [C25H O
Si + Na]+ 437.3785; found
6
0
.91–0.89 (m, 15 H), 0.09 (s, 3 H), 0.08 (s, 3 H) ppm. 1 C NMR
): δ = 177.4, 134.0, 132.0, 128.2, 125.9, 70.1, 43.6,
6.8, 28.7, 25.7, 22.3, 22.27, 18.1, –4.4, –5.1 ppm. HRMS: calcd.
3
437.3789.
7R,8R)-8-(tert-Butyldimethylsilyloxy)-2-methyloctadecan-7-yl-4-
methylbenzenesulfonate (11): To a stirred solution of 10 (80 mg,
.193 mmol) in dry CH Cl (5 mL), was added 4-(dimethylamino)-
(100 MHz, CDCl
3
(
3
+
for [C17
32 3
H O Si + Na] 335.2013; found 335.2019.
0
2
2
(4R,5R)-4-(tert-Butyldimethylsilyloxy)-5-(Z)-(5-methylhex-2-enyl)di- pyridine (DMAP; 94.3 mg, 0.772 mmol, 4.0 equiv.) and p-tolu-
hydrofuran-2(3H)-one (7) and (4R,5S)-4-(tert-Butyldimethylsilyl-
oxy)-5-(Z)-(5-methylhex-2-enyl)dihydrofuran-2(3H)-one (8): Reac-
tion conditions were as stated in Table 1, Entry 8: Compounds 7
and 8 were obtained from 4b (150 mg, 0.619 mmol) by a similar
procedure as described in Table 1, Entry 2. This delivered 7
enesulfonyl chloride (110.6 mg, 0.58 mmol, 3.0 equiv.) at 0 °C. The
reaction mixture was slowly warmed to room temperature and
stirred for 24 h. It was then quenched with water (5 mL) and the
solution extracted with CH Cl (3ϫ 10 mL). The combined or-
2
2
ganic layers were washed with water, brine, dried (Na SO ) and
2
4
(
30.9 mg, 16%) and 8 (123.8 mg, 64%) as colorless oils.
concentrated. The residue was purified by silica gel column
chromatography with petroleum ether/EtOAc (99:1) as eluent to
(7R,8R)-8-(tert-Butyldimethylsilyloxy)-2-methyloctadecan-7-ol (10):
2
5
give 11 (109.8 mg, quant.) as a colorless oil. [α]
CHCl ). IR (CHCl ): ν˜ = 2954, 2928, 2856, 1599, 1496, 1464, 1368,
257, 1188, 1177, 1116, 1098, 936, 901, 837, 814, 776, 667 cm . H
NMR (400 MHz, CDCl /TMS): δ = 7.78 (d, J = 8.2 Hz, 2 H), 7.33
d, J = 8.1 Hz, 2 H), 4.34–4.29 (m, 1 H), 3.75–3.71 (m, 1 H), 2.44
s, 3 H), 1.66–1.02 (m, 27 H), 0.90–0.80 (m, 18 H), 0.049 (s, 3 H),
D
= +26.3 (c = 1.0,
To a stirred solution of 7 (114 mg, 0.365 mmol) in dry Et
10 mL) at –78 °C was added DIBAL-H (1.75 m solution in toluene,
.31 mL, 0.547 mmol, 1.5 equiv.) dropwise under a N atmosphere.
2
O
(
0
3
3
–
1 1
1
2
The reaction mixture was stirred for 1 h and then quenched with
saturated aq. Rochelle’s salt solution (3 mL) and stirred vigorously
at room temperature for 1 h. The aqueous layer was separated and
extracted with CH
were washed with water, brine, dried (Na
3
(
(
1
3
0
1
2
–
5
3
.006 (s, 3 H) ppm. C NMR (100 MHz, CDCl ): δ = 144.5, 134.3,
2
Cl
2
(3ϫ 10 mL). The combined organic layers
SO ) and concentrated
29.7, 127.8, 84.9, 72.1, 38.9, 31.9, 30.3, 29.6, 29.5, 29.3, 29.1, 27.9,
7.3, 26.3, 25.7, 25.6, 25.5, 22.7, 22.5, 21.6, 17.9, 14.1, –4.46,
4.8 ppm. HRMS: calcd. for [C32
91.3873.
2
4
to give the corresponding lactol (114 mg), which was used directly
in the next reaction.
+
H
60
O
4
SiS + Na] 591.3874; found
To a stirred suspension of (n-octyl)triphenylphosphonium bromide
(
7S,8R)-8-(tert-Butyldimethylsilyloxy)-2-methyloctadecan-7-yl-4-
(
333 mg, 0.73 mmol, 2.0 equiv.) in dry THF (10 mL) was added
nBuLi (1.6 m solution in hexane, 0.46 mL, 0.73 mmol, 2.0 equiv.) at
°C. The mixture was stirred for 1 h and a solution of the above
methylbenzenesulfonate (13): This compound was prepared from 12
(
35 mg, 0.0844 mmol) by a similar procedure as described for 11,
0
2
5
to give 13 (45.2 mg, 94%) as a colorless oil. [α]
D
= +2.3 (c = 0.8,
lactol (114 mg, 0.362 mmol) in THF (3 mL) was added. It was
warmed to room temperature and stirred for 8 h and then
quenched with saturated aq. NH
tracted with EtOAc (3ϫ 10 mL) and the combined organic layers
were washed with water, brine, dried (Na SO ) and concentrated.
The residue was purified by silica gel column chromatography with
petroleum ether/EtOAc (49:1) as an eluent to afford the diene
(
CHCl
257, 1188, 1177, 1097, 915, 836, 813, 777, 723, 666, 555 cm . H
NMR (400 MHz, CDCl /TMS): δ = 7.79 (d, J = 8.3 Hz, 2 H), 7.32
d, J = 8.1 Hz, 2 H), 4.41 (dt, J = 2.5, 9.0 Hz, 1 H), 3.89–3.86 (m,
3 3
). IR (CHCl ): ν˜ = 2955, 2927, 2856, 1717, 1599, 1466, 1366,
–
1 1
1
4
Cl solution. The mixture was ex-
3
(
2
4
1
H), 2.43 (s, 3 H), 1.58–1.12 (m, 27 H), 0.91–0.81 (m, 18 H), 0.07
1
3
(
s, 6 H) ppm. C NMR (100 MHz, CDCl
3
): δ = 144.3, 134.6,
29.6, 127.8, 88.7, 74.0, 38.8, 38.7, 34.3, 31.9, 29.6, 29.56, 29.5,
9.3, 27.9, 27.7, 27.0, 25.9, 25.7, 25.4, 22.7, 22.6, 21.6, 18.1, 14.1,
4.5, –4.8 ppm. HRMS: calcd. for [C32
SiS + Na]+ 591.3874;
1
2
–
143 mg) as a colorless oil. The diene was immediately used in the
hydrogenation reaction.
60 4
H O
To a stirred solution of diene (143 mg) in propane-2-ol (12 mL) was
added 10% Pd(OH)
found 591.3876.
2 2
on charcoal (20 mg) and stirred under H
(
balloon pressure) atmosphere at room temperature for 3 h. The
cis-(7S,8R)-7,8-Epoxy-2-methyloctadecane, (–)-Disparlure (ent-1):
To a stirred solution of 11 (90 mg, 0.158 mmol) in dry THF (5 mL)
was added TBAF (1.0 m solution in THF, 0.54 mL, 0.537 mmol,
mixture was filtered through a small pad of Celite and washed with
EtOAc and the filtrate concentrated. The residue was purified by
silica gel column chromatography with petroleum ether/EtOAc
2
3.4 equiv.) at 0 °C under an N atmosphere. The reaction mixture
(
97:3) as eluent to give alcohol 10 (130.1 mg, 86% overall) as a was slowly warmed to room temperature and stirred for 5 h. It was
25
colorless oil. [α]
D
= –1.9 (c = 1.0, CHCl
3
). IR (CHCl
3
): ν˜ = 3470,
then quenched with water and extracted with EtOAc (3ϫ 15 mL).
–
1
2
928, 2857, 1464, 1385, 1366, 1255, 1086, 1006, 837, 775, 669 cm . The combined organic layers were washed with water, brine, dried
1
H NMR (400 MHz, CDCl
3
/TMS): δ = 3.51–3.47 (m, 1 H), 3.45–
2 4
(Na SO ) and concentrated. The residue was purified by silica gel
3
0
(
.41 (m, 1 H), 2.13 (d, J = 6.8 Hz, 1 H), 1.56–1.14 (m, 27 H), 0.91– column chromatography with petroleum ether/EtOAc (99:1) as elu-
1
3
25
.85 (m, 18 H), 0.08 (s, 3 H), 0.07 (s, 3 H) ppm. C NMR ent to afford ent-1 (40.6 mg, 91%) as a colorless oil. [α]
D
= –1.6 (c
). IR (CHCl ): ν˜ =
9.57, 29.3, 27.9, 27.6, 27.4, 25.9, 25.2, 25.0, 22.7, 22.6, 18.1, 14.1, 2955, 2926, 2856, 1466, 1385, 1367, 1266, 1170, 1021, 839,
), ref.[
11m]
[α]
D
= –1.0 (c = 1.5, CCl
100 MHz, CDCl
3
): δ = 75.1, 72.6, 39.0, 34.2, 33.9, 31.9, 29.9, 29.6,
= 1.2, CCl
4
4
3
2
–
+
–1 1
4.1, –4.6 ppm. HRMS: calcd. for [C25
found 437.3784.
H
54
O
2
Si + Na] 437.3785; 722 cm . H NMR (400 MHz, CDCl
H), 1.55–1.16 (m, 27 H), 0.89–0.86 (m, 9 H) ppm. C NMR
100 MHz, CDCl ): δ = 57.2, 38.9, 31.9, 29.6, 29.5, 29.3, 27.9, 27.8,
7.79, 27.3, 26.8, 26.6, 22.7, 22.6, 14.1 ppm. HRMS: calcd. for
38O + Na]+ 305.2815; found 305.2812.
3
/TMS): δ = 2.91–2.88 (m, 2
1
3
(
2
3
(
7S,8R)-8-(tert-Butyldimethylsilyloxy)-2-methyloctadecan-7-ol (12):
This compound was prepared from 8 (70 mg, 0.223 mmol) by a
similar procedure as described for 10, to give 12 (77.1 mg, 83%) as
19
[C H
a colorless oil. [α]2
5
= –1.1 (c = 0.8, CHCl
). IR (CHCl
): ν˜ = 3470,
(+)-trans-(7R,8R)-Disparlure (2): This compound was prepared
D
3
3
2
6
954, 2928, 2857, 1465, 1384, 1365, 1258, 1086, 836, 805, 775,
from 13 (30 mg, 0.053 mmol) by a similar procedure as described
–1
1
25
69 cm . H NMR (400 MHz, CDCl
3
/TMS): δ = 3.62–3.56 (m, 2 for ent-1, to afford 2 (13.1 mg, 88%) as a colorless oil. [α]
D
= +25.6
):
ν˜ = 2956, 2927, 2856, 1467, 1384, 1367, 1261, 1169, 1046, 900,
), ref.[ [α]
9]
25
= +27.5 (c = 0.5, CCl
). IR (CHCl
H), 2.14 (d, J = 2.9 Hz, 1 H), 1.53–1.14 (m, 27 H), 0.92–0.84 (m, (c = 0.4, CHCl
3
D
4
3
13
1
8 H), 0.076 (s, 3 H), 0.072 (s, 3 H) ppm. C NMR (100 MHz,
CDCl ): δ = 75.3, 74.7, 39.0, 31.9, 31.8, 30.4, 29.8, 29.6, 29.3, 28.0, 668 cm . H NMR (400 MHz, CDCl
7.6, 27.5, 26.4, 26.2, 26.0, 25.9, 25.8, 22.7, 22.6, 18.1, 14.1, H), 1.57–1.14 (m, 27 H), 0.97–0.82 (m, 9 H) ppm. C NMR
–
1 1
3
3
/TMS): δ = 2.67–2.64 (m, 2
1
3
2
Eur. J. Org. Chem. 2014, 3249–3255
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3253

V. Bethi, P. Kattanguru, R. A. Fernandes
FULL PAPER
(
2
[
100 MHz, CDCl
9.3, 27.9, 27.2, 26.3, 26.0, 22.7, 22.6, 14.1 ppm. HRMS: calcd. for
19
C H
38O + K]+ 321.2554; found 321.2559.
3
): δ = 58.9, 38.9, 32.2, 32.1, 31.9, 29.6, 29.5, 29.4,
To a stirred suspension of (isopentyl)triphenylphosphonium brom-
ide (6; 467 mg, 1.13 mmol, 4.0 equiv.) in dry toluene (10 mL) was
added nBuLi (1.6 m solution in hexane, 0.70 mL, 1.13 mmol,
4
.0 equiv.) at 0 °C. The mixture was stirred for 30 min and a solu-
(
(
4R,5R)-5-[(E)-Hex-1-en-1-yl]-4-hydroxydihydrofuran-2(3H)-one
15): To a stirred and degassed solution of 14 (50 mg, 0.390 mmol)
tion of lactol (100 mg) in toluene (3 mL) was added. It was slowly
warmed to room temperature, stirred for 3 h and then quenched
with saturated aq. NH
EtOAc (3ϫ 10 mL) and the combined organic layers were washed
with water, brine, dried (Na SO ) and concentrated. The residue
was purified by silica gel column chromatography with petroleum
ether/EtOAc (19:1) as eluent to afford the diene (80 mg) as a color-
less oil. The diene was immediately used in the hydrogenation reac-
tion.
and 1-decene (83 mg, 0.585 mmol, 1.5 equiv.) in dry CH
at room temperature was added Grubbs’ second-generation catalyst
6.8 mg, 0.008 mmol, 2.0 mol-%) and the reaction mixture was
2 2
Cl (5 mL)
4
Cl solution. The solution was extracted with
(
2
4
heated to reflux for 72 h. It was then cooled and filtered through
a small pad of silica gel and the filtrate concentrated. The residue
was purified by silica gel column chromatography with petroleum
ether/EtOAc (17:3) as eluent to give 15 (84.4 mg, 90%) as a color-
less oil. [α]2
3
9
5
= +22.0 (c = 0.6, CHCl
). IR (CHCl
): ν˜ = 3453,
D
3
3
018, 2927, 2856, 1771, 1670, 1466, 1327, 1164, 1076, 1014, 967,
To the stirred solution of diene (80 mg) in propane-2-ol (12 mL)
was added 10% Pd(OH)
–1 1
06, 845 cm . H NMR (400 MHz, CDCl
3
/TMS): δ = 6.02–5.94
2
on charcoal (13 mg) and stirred under
(m, 1 H), 5.61–5.54 (m, 1 H), 4.87–4.84 (m, 1 H), 4.47–4.45 (m, 1
2
H (balloon pressure) atmosphere at room temperature for 6 h. The
H), 2.77 (dd, J = 17.6, 5.4 Hz, 1 H), 2.61 (dd, J = 17.6, 1.0 Hz, 1
mixture was filtered through a small pad of Celite and washed with
EtOAc and the filtrate concentrated. The residue was purified by
silica gel column chromatography with petroleum ether/EtOAc
H), 2.15–2.10 (m, 2 H), 1.74 (br. s, 1 H), 1.35–1.26 (m, 12 H), 0.87
13
(
3
t, J = 6.8 Hz, 3 H) ppm. C NMR (100 MHz, CDCl ): δ = 176.4,
1
1
2
38.7, 121.5, 85.4, 69.6, 38.8, 32.3, 31.7, 29.2, 29.1, 29.0, 28.6, 22.5, (97:3) as eluent to give alcohol 17 (82 mg, 70% overall) as a color-
+
25
[11m]
25
3.9 ppm. HRMS: calcd. for [C14
63.1623.
H
24
O
3
+ Na] 263.1623; found
less oil. [α]
3.2, CHCl
366, 1257, 1086, 837, 667 cm . H NMR (400 MHz, CDCl
TMS): δ = 3.51–3.47 (m, 1 H), 3.45–3.39 (m, 1 H), 2.15 (d, J =
D
= –5.6 (c = 0.16, CHCl
3
), ref.
D
[α] = –3.8 (c =
3
). IR (CHCl ): ν˜ = 3460, 2951, 2929, 2857, 1465, 1383,
3
–
1 1
1
3
/
(
4R,5R)-4-(tert-Butyldimethylsilyloxy)-5-[(E)-hex-1-en-1-yl]dihydro-
furan-2(3H)-one (16) from (4a): This compound was prepared from
a (30 mg, 0.124 mmol) and 1-decene (34.8 mg, 0.248 mmol,
.0 equiv.) by using Grubbs–Hoveyda’s second-generation catalyst
6
2
.9 Hz, 1 H), 1.60–1.52 (m, 1 H), 1.50–1.39 (m, 4 H), 1.37–1.15 (m,
4
2
(
13
2 H), 0.92–0.85 (m, 18 H), 0.08 (s, 3 H), 0.07 (s, 3 H) ppm.
): δ = 75.1, 72.6, 38.9, 34.2, 33.9, 31.9,
9.7, 29.62, 29.6, 29.3, 27.9, 27.7, 27.4, 26.2, 26.0, 25.9, 25.2, 22.7,
2.6, 18.1, 14.1, –4.1, –4.6 ppm. HRMS: calcd. for [C25 Si +
C
NMR (100 MHz, CDCl
2
2
3
1.6 mg, 0.0025 mmol, 2.0 mol-%) by a similar procedure as de-
scribed for the preparation of 15, to give 16 (19.8 mg, 45%) as a
54 2
H O
colorless oil. [α]2
5
= +19.6 (c = 0.5, CHCl
). IR (CHCl
): ν˜ = 3021,
+
D
3
3
Na] 437.3791; found 433.3794.
2
9
5
4
1
0
956, 2929, 2857, 1781, 1464, 1314, 1257, 1158, 1092, 1025, 971,
54, 904, 839 cm . H NMR (400 MHz, CDCl /TMS): δ = 5.87–
3
–1
1
(11R,12R)-12-(tert-Butyldimethylsilyloxy)-17-methyloctadecan-11-
yl-4-methylbenzenesulfonate (18): To a stirred solution of alcohol
.80 (m, 1 H), 5.66–5.60 (m, 1 H), 4.74 (dd, J = 17.0, 3.9 Hz, 1 H),
.43–4.41 (m, 1 H), 2.71 (dd, J = 17.2, 5.3 Hz, 1 H), 2.45 (dd, J =
7.2, 1.5 Hz, 1 H), 2.11–2.06 (m, 2 H), 1.41–1.26 (m, 12 H), 0.89–
17 (50 mg, 0.120 mmol) in dry CH
2 2
Cl (2 mL), was added DMAP
(
37 mg, 0.30 mmol, 2.5 equiv.) and p-toluenesulfonyl chloride
.86 (m, 12 H), 0.041 (s, 3 H), 0.036 (s, 3 H) ppm. 1 C NMR
3
(46 mg, 0.240 mmol, 2 equiv.) at 0 °C. The reaction mixture was
slowly warmed to room temperature over 1 h and stirred for 5 h.
It was then quenched with water (5 mL) and the solution extracted
(
100 MHz, CDCl
3
): δ = 175.5, 137.9, 123.3, 86.0, 71.0, 39.7, 32.4,
3
1.8, 29.4, 29.2, 28.7, 25.6, 22.6, 18.1, 14.1, –4.9, –5.0 ppm. HRMS:
+
2 2
with CH Cl (3ϫ 10 mL). The combined organic layers were
calcd. for [C20
H
38
O
3
Si + Na] 377.2488; found 377.2481.
2 4
washed with water, brine, dried (Na SO ) and concentrated. The
(4R,5R)-4-(tert-Butyldimethylsilyloxy)-5-[(E)-hex-1-en-1-yl]dihydro-
residue was purified by silica gel column chromatography with pe-
furan-2(3H)-one (16) from (15): To a stirred solution of 15 (258 mg,
troleum ether/EtOAc (97:3) as an eluent to give 18 (62.5 mg, 91%)
2
5
[11m]
25
1
2
1
.06 mmol) in dry CH
.12 mmol, 2.0 equiv.) and TBDMSOTf (423 mg, 1.60 mmol,
.5 equiv.) at 0 °C. The reaction mixture was stirred at room tem-
2
Cl
2
(5 mL) was added 2,6-lutidine (227 mg, as a colorless oil. [α]D = +26.9 (c = 0.4, CHCl ), ref.
[α] =
D
3
3 3
+24.8 (c = 1.2, CHCl ). IR (CHCl ): ν˜ = 2953, 2928, 2857, 1599,
1464, 1368, 1258, 1188, 1177, 1097, 935, 897, 837, 814, 776,
–
1
1
perature for 2 h. It was then diluted with CH
5 mL). The solution was extracted with CH
the combined organic phases were washed with water, brine, dried
Na SO ) and concentrated. The residue was purified by silica gel
column chromatography with petroleum ether/EtOAc (9:1) as elu-
2
Cl
2
(5 mL) and H
2
O
667 cm . H NMR (400 MHz, CDCl /TMS): δ = 7.78 (d, J =
3
(
2
Cl
2
(3ϫ 20 mL) and
8.2 Hz, 2 H), 7.33 (d, J = 8.1 Hz, 2 H), 4.33–4.29 (m, 1 H), 3.75–
3.71 (m, 1 H), 2.44 (s, 3 H), 1.68–1.11 (m, 27 H), 0.91–0.80 (m, 18
1
3
(
2
4
H), 0.049 (s, 3 H), 0.006 (s, 3 H) ppm. C NMR (100 MHz,
CDCl ): δ = 144.5, 134.3, 129.7, 127.8, 84.9, 72.1, 38.9, 38.6, 31.9,
3
2
5
ent to afford 16 (323 mg, 86%) as a colorless oil. [α]
D
= +19.4 (c
30.3, 29.6, 29.5, 29.3, 29.1, 27.7, 27.4, 27.3, 26.9, 26.3, 26.0, 25.7,
=
0.8, CHCl ). Other analytical data were same as before.
3
25.5, 22.7, 22.6, 22.5, 21.6, 17.9, 14.1, –4.5, –4.8 ppm. HRMS:
60 4
calcd. for [C32H O
SiS + H]+ 569.4060; found 569.4055.
(
7R,8R)-7-(tert-Butyldimethylsilyloxy)-2-methyloctadecan-8-ol (17):
To a stirred solution of 16 (100 mg, 0.282 mmol) in dry Et
10 mL) at –78 °C was added DIBAL-H (1.75 m solution in toluene,
.24 mL, 0.423 mmol, 1.5 equiv.) dropwise under a N atmosphere.
2
O
cis-(7R,8S)-7,8-Epoxy-2-methyloctadecane, (+)-Disparlure (1): This
compound was prepared from 18 (50 mg, 0.088 mmol) by a similar
procedure as described for ent-1, to afford 1 (22.3 mg, 90%) as a
(
0
2
2
5
[11m]
The reaction mixture was stirred for 1 h and then quenched with
saturated aq. Rochelle’s salt solution (3 mL) and stirred vigorously
at room temperature for 1 h. The aqueous layer was separated and
extracted with CH
were washed with water, brine, dried (Na
colorless oil. [α]
1.5, CCl ). IR (CHCl
1260, 1028, 918, 837, 721 cm . H NMR (400 MHz, CDCl
δ = 2.93–2.89 (m, 2 H), 1.60–1.16 (m, 27 H), 0.92–0.82 (m, 9
D
= +1.6 (c = 1.1, CCl
4
), ref.
D
[α] = +1.0 (c =
4
3
): ν˜ = 2951, 2926, 2855, 1466, 1384, 1367,
–
1 1
3
/TMS):
2
Cl
2
(3ϫ 10 mL). The combined organic layers
SO ) and concentrated
1
3
2
4
3
H) ppm. C NMR (100 MHz,CDCl ): δ = 57.3, 38.9, 31.9, 29.5,
to give the corresponding lactol (100 mg), which was used directly
in the next reaction.
29.3, 27.9, 27.83, 27.8, 27.3, 26.8, 26.6, 22.7, 22.6, 14.1 ppm.
HRMS: calcd. for [C19
H
38O + H]+ 283.3001; found 283.3003.
3254
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3249–3255

Synthesis of Disparlures
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the H NMR and C NMR spectra for all com-
pounds.
Kattanguru, J. Org. Chem. 2012, 77, 9357–9360; a provisional
process patent on this work is filed, application no. 1908/
MUM/2012.
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Published Online: April 11, 2014
Eur. J. Org. Chem. 2014, 3249–3255
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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