Concise total synthesis of (+)-disparlure and its trans-isomer using asymmetric organocatalysis

Article abstract of DOI:10.1055/s-0029-1216855

The efficient enantioselective synthesis of (+)-disparlure and its trans-isomer is described. This approach involves tandem asymmetric organocatalytic α-aminoxylation-allylation of an aldehyde and olefin cross metathesis using Grubbs' catalyst as key steps. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1216855

2418
PAPER
Concise Total Synthesis of (+)-Disparlure and its trans-Isomer
Using Asymmetric Organocatalysis
C
oncise Total
u
S
ynthesis of
n
(+)-Disparlu
g
r
e
andIts tra
-
ns-Isom
G
er on Kim*
Department of Chemistry, College of Natural Science, Kyonggi University, San 94-6, Iui-dong, Yeongtong-gu, Suwon 443-760, Korea
Fax +82(31)2499631; E-mail: sgkim123@kgu.ac.kr
Received 25 February 2009; revised 8 April 2009
(–)-disparlure and their trans-isomers based on asymmet-
Abstract: The efficient enantioselective synthesis of (+)-disparlure
ric organocatalysis and olefin cross metathesis.
and its trans-isomer is described. This approach involves tandem
asymmetric organocatalytic a-aminoxylation–allylation of an alde-
hyde and olefin cross metathesis using Grubbs’ catalyst as key
steps.
The retrosynthetic plan for (+)-disparlure (1) is outlined in
Scheme 1. We envisaged that disparlure could be ob-
tained from the diol 3 by stereoselective construction of
an epoxide ring at a late stage. Diol 3 could be derived
from homoallylic alcohol 4 via cross metathesis with 4-
methylpent-1-ene. The key intermediate 4 can be synthe-
sized through a proline-catalyzed tandem asymmetric a-
aminoxylation–allylation of dodecanal (5).6b,7,8
Key words: disparlure, total synthesis, organocatalysis, asymmet-
ric synthesis, olefin cross metathesis
(+)-Disparlure (1) (Figure 1), structurally known as
(7R,8S)-7,8-epoxy-2-methyloctadecane, is the sex-attrac-
tant pheromone emitted by the female gypsy moth, Porth-
etria dispar (L.).1 This gypsy moth is a seriously harmful
pest, causing severe forest losses during outbreaks in Eu-
rope, Asia, and North America. It has been shown that the
(–)-enantiomer antagonizes the effect of (+)-disparlure
and is slightly repellent by itself.2 Both of the enantiomers
bind differently to two pheromone-binding proteins
(PBPs) found in gypsy moth antennae, PBP1 and PBP2.
The (–)-enantiomer has a higher affinity for PBP1, while
the (+)-enantiomer has a higher affinity for PBP2.3 For
these reasons, disparlure has been the target of numerous
syntheses,4,5 in which most of the approaches for the con-
struction of the two asymmetric centers take advantage of
asymmetric epoxidation (AE),5f asymmetric dihydroxyla-
tion (AD),5g,i,l asymmetric chloroallylation,5d chiral stan-
nanes,5c enzymatic procedures,5e,j,k or chiral pool
materials.5a,b,h
HO
8
8
O
HO
3
1
3
PhHNO
HO
O
8
C10H21
H
4
5
Scheme 1 Retrosynthetic analysis
This retrosynthetic concept for (+)-disparlure (1) was put
into practice as depicted in Scheme 2. Homoallylic alco-
hol 4 was prepared in 65% yield from dodecanal (5) and
nitrosobenzene (6) using L-proline as the catalyst fol-
lowed by in situ indium-mediated allylation by a modifi-
cation of the original tandem a-aminoxylation–allylation
reaction.7 This reaction in the solvent dimethyl sulfoxide
did not proceed cleanly; there was formation of a ho-
modimerized aldol as a side product, and the desired prod-
uct 4 was isolated only in 15% yield. However, when the
initial solvent was changed to chloroform, the reaction
proceeded cleanly and the product 4 was isolated in good
yield with a 4:1 diastereoselectivity. The products syn-4
and anti-4 were separated by column chromatography and
showed excellent enantiomeric excesses (98% ee in both
cases). At this stage, we could not define which isomer,
syn or anti, was the major product, so we supposed that the
syn-isomer was the major product according to the litera-
ture;6b,7 however, it was found at the final stage that the
major product was in fact the anti-isomer.9
O
1 (+)-disparlure
O
2 (7S,8S)-trans-isomer
Figure 1
Herein, as part of a program for the synthesis of biologi-
cally active natural products based on asymmetric organo-
catalysis,6 we describe the efficient synthesis of (+)- and
The hydroxy group in homoallylic alcohol 4 was protect-
ed using tert-butyldimethylsilyl triflate to afford 7 in 97%
yield. The phenylamino group in 7 was removed using a
zinc-catalyzed N–O cleavage reaction, which was fol-
lowed by tosylation, to give 9 in 98% yield over two steps.
SYNTHESIS 2009, No. 14, pp 2418–2422
x
x.
x
x
.
2
0
0
9
Advanced online publication: 29.05.2009
DOI: 10.1055/s-0029-1216855; Art ID: F04309SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Concise Total Synthesis of (+)-Disparlure and its trans-Isomer
2419
ONHPh
The conversion of compound 9 into the alkene 10 was
achieved by olefin cross metathesis10 with 4-methylpent-
1-ene in the presence of 5 mol% of Grubbs’ second-gen-
eration catalyst in 84% yield.11 Finally, palladium-cata-
lyzed hydrogenation of 10 followed by treatment with
tetrabutylammonium fluoride gave compound 2 in 96%
yield over two steps. Compound 2 was defined as the
(7S,8S)-trans-isomer of disparlure after comparing the
spectroscopic data and optical rotation of the material
O
N
O
a
b
H21C10
H21C10
65%
Ph
H
97%
OH
5
4
6
dr (anti/syn) 4:1
anti: 98% ee
syn: 98% ee
ONHPh
OH
d
c
H21C10
H
21C10
99%
99%
26
with reported values in the literature5l,12 {[a]D –25.8 (c
OTBDMS
OTBDMS
1.9, CCl4) [Lit.11 [a]D –26.6 (c 0.5, CCl4)]}. From these re-
sults, we were able to establish that the major diastere-
omer in the tandem a-aminoxylation–allylation reaction
was the anti-homoallylic alcohol 4.9 From this synthetic
route, the (7R,8R)-trans-isomer of disparlure was also
prepared from the aldehyde dodecanal (5), using D-pro-
line as catalyst instead of L-proline, in seven steps and
7
8
OTs
OTs
f
e
84%
H
21C10
H
21C10
99%
OTBDMS
OTBDMS
9
10
OTs
H21C10
O
26
50% overall yield {[a]D +26.9 (c 1.0, CCl4) [Lit.12 [a]D
g
H21C10
97%
+27.5 (c 0.5, CCl4)]}.
OTBDMS
11
After becoming aware of anti-homoallylic alcohol 4 as the
major product, we carried out the synthesis of (+)-dispar-
lure (1) using an altered pathway. anti-Homoallylic alco-
hol (4R,5S)-4 was prepared from dodecanal (5) and
nitrosobenzene (6) using the catalyst D-proline followed
by in situ indium-mediated allylation in excellent ee (99%
ee) (Scheme 3). At this stage, we carried out the olefin
cross metathesis of homoallylic alcohol 4 with 4-methyl-
pent-1-ene. Interestingly, under the metathesis conditions,
diol 3 was obtained in 50% isolated yield, which indicates
that N–O bond cleavage accompanied the metathesis re-
action.13,14 Next, palladium-catalyzed hydrogenation of 3
afforded known alcohol 12 in 93% yield, which was con-
verted into (+)-disparlure (1) using the established three-
step, one-pot procedure [MeC(OEt)3, TMSCl, KOH]15 in
2 (7S,8S)
Scheme 2 Stereoselective synthesis of the (7S,8S)-trans-isomer
of disparlure. Reagents and conditions: (a) 1. L-proline (10
mol%), CHCl3, 2. allyl bromide, In, NaI, DMSO; (b) TBDMSOTf,
Et3N, CH2Cl2; (c) Zn, AcOH–EtOH; (d) TsCl, DMAP, CH2Cl2;
(e) 4-methylpent-1-ene, Grubbs II catalyst (5 mol%), CH2Cl2;
(f) 10% Pd/C, H2, hexane; (g) TBAF, THF.
ONHPh
O
N
O
a
b
H21C10
H21C10
Ph
H
67%
50%
OH
5
6
4
dr (anti/syn) 4:1
anti: 99% ee
syn: 98% ee
22
95% yield {[a]D +0.8 (c 0.5, CCl4) [Lit.5c [a]D +0.9 (c
OH
OH
c
1.1, CCl4)]}. (–)-Disparlure could also be prepared from
dodecanal (5) with this synthetic route in six steps and
30% overall yield using the catalyst L-proline in the tan-
H21C10
H21C10
93%
OH
OH
3
12
22
dem a-aminoxylation–allylation reaction {[a]D –0.7 (c
0.5, CCl4) [Lit.5c [a]D –0.9 (c 0.21, CCl4)]}.
d
O
In summary, concise and efficient syntheses of (+)- and
(–)-disparlure and their trans-isomers were accomplished
in high overall yields from commercially available dode-
canal (5). Key steps in the syntheses involved tandem
asymmetric organocatalytic a-aminoxylation–allylation
of the aldehyde, which was shown to be a highly effective
means for preparing chiral diols, and cross metathesis us-
ing Grubbs’ catalyst. Further application of this versatile
strategy to biologically significant molecules of more
structural complexity and diversity is now in progress.
95%
1 (+)-disparlure
Scheme 3 Stereoselective synthesis of (+)-disparlure. Reagents and
conditions: (a) 1. D-proline (10 mol%), CHCl3, 2. allyl bromide, In,
NaI, DMSO; (b) 4-methylpent-1-ene, Grubbs II catalyst (5 mol%),
CH2Cl2; (c) 10% Pd/C, H2, MeOH; (d) 1. MeC(OEt)3, PPTS, toluene,
2. TMSCl, CH2Cl2, 3. KOH, THF.
mesh silica gel 63. Thin-layer chromatography was performed on
EM Reagents 0.25-mm silica gel 60-F plates. Visualization of the
developed chromatogram was performed by fluorescence quench-
ing and anisaldehyde staining. Melting points were determined on a
Thomas Hoover capillary melting point apparatus and are uncor-
rected. 1H and 13C NMR spectra were recorded on Varian Mercury
300 (300 and 75 MHz) and Bruker 400 (400 and 100 MHz) spec-
trometers as noted, and are internally referenced to residual proton
solvent signals. Data for 1H NMR spectra are reported as follows:
chemical shift (d ppm), multiplicity (s = singlet, d = doublet,
t = triplet, q = quartet, m = multiplet), coupling constant (Hz), inte-
All reactions were performed using flame- or oven-dried glassware
under an atmosphere of dry nitrogen. Commercial reagents were
purified prior to use according to the guidelines of Perrin and
Armarego.16 Organic solutions were concentrated under reduced
pressure using a Büchi rotary evaporator. All organic solvents were
distilled prior to use. Chromatographic purification of products was
accomplished using forced-flow chromatography on ICN 60 32–64
Synthesis 2009, No. 14, 2418–2422 © Thieme Stuttgart · New York

2420
S.-G. Kim
PAPER
gration. Data for 13C NMR spectra are reported in terms of chemical
shift. IR spectra were recorded on a Jasco 610 FT-IR spectrometer
using KBr salt plates or as films, and are reported in terms of fre-
quency of absorption (cm–1). Mass spectroscopic data were ob-
tained at the Korea Research Institute of Chemical Technology
Facility. Optical rotations were recorded on a Jasco P-1010 pola-
rimeter (WI lamp, 589 nm). HPLC analysis was performed on a
Shimadzu LC-20A Prominence HPLC system using Chiralcel col-
umns AD (25 cm) and AD guard (5 cm), as noted.
anes, 1:99) to afford compound 7 as a pale yellow oil; yield: 675 mg
(97%).
[a]D26 +12.7 (c 1.0, CHCl3).
IR (KBr): 2926, 2855, 1602, 1496, 1463, 1254 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.21–7.27 (m, 3 H), 6.90–6.97 (m,
3 H), 5.79–5.93 (m, 1 H), 5.02–5.12 (m, 2 H), 3.93–3.98 (m, 1 H),
3.78–3.82 (m, 1 H), 2.22–2.40 (m, 2 H), 1.27–1.69 (m, 18 H), 0.93
(s, 9 H), 0.89 (t, J = 6.9 Hz, 3 H), 0.09 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 149.1, 136.0, 129.1, 121.8, 117.1,
114.6, 86.9, 74.3, 37.9, 32.2, 30.1, 29.9, 29.8, 29.7, 29.6, 26.8, 26.2,
22.9, 18.4, 14.4, –4.0, –4.1.
(4S,5R)-5-(N-Phenylaminooxy)pentadec-1-en-4-ol (4)
To a soln of dodecanal (5; 1.50 mL, 6.0 mmol) and nitrosobenzene
(6; 540 mg, 5.0 mmol) in CHCl3 (3.5 mL), L-proline (60 mg, 0.50
mmol) was added. After being stirred for 4 h at 0 °C, the reaction
mixture was diluted with DMSO (10 mL), which was followed by
the addition of allyl bromide (0.65 mL, 7.5 mmol), NaI (1.12 g, 7.5
mmol), and indium (860 mg, 7.5 mmol) at r.t., and stirring for 1.5 h.
The reaction mixture was quenched with 0.5 M aq HCl (30 mL) and
the aqueous layer was extracted with EtOAc (2 × 40 mL). The com-
bined organic layer was washed with brine (40 mL), dried (anhyd
MgSO4), and concentrated under reduced pressure. The crude resi-
due was purified by flash column chromatography (EtOAc–hex-
anes, 1:9) to afford the title compound (4S,5R)-4 [yield: 870 mg
(52%)] and the more quickly eluting (4R,5R)-isomer [yield: 218 mg
(13%)]. The diastereomeric ratio was determined from the 1H NMR
spectrum of the crude product. The enantiomeric excess of the anti-
and the syn-diastereomer was measured by HPLC analysis after
separation of the isomers using column chromatography.
HRMS: m/z [M+] calcd for C27H49NO2Si: 447.3533; found:
447.3531.
(4S,5R)-4-(tert-Butyldimethylsilyloxy)pentadec-1-en-5-ol (8)
To a soln of 7 (640 mg, 1.4 mmol) in EtOH–AcOH (3:1, 14 mL)
was added Zn powder (910 mg, 14 mmol). The mixture was stirred
for 18 h at r.t., and the resulting suspension was filtered through a
pad of Celite® and concentrated under reduced pressure. The crude
residue was purified by flash column chromatography (EtOAc–hex-
anes, 2:98) to afford compound 8 as a colorless oil; yield: 494 mg
(99%).
[a]D26 +0.50 (c 1.6, CHCl3).
IR (KBr): 3051, 2929, 2856, 1474, 1264 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.75–5.89 (m, 1 H), 5.01–5.09 (m,
2 H), 3.55–3.67 (m, 2 H), 2.14–2.34 (m, 2 H), 2.11 (br s, 1 H), 1.13–
1.52 (m, 18 H), 0.90 (s, 9 H), 0.85 (t, J = 6.9 Hz, 3 H), 0.64 (s, 6 H).
anti-(4S,5R)-4
[a]D26 +33.7 (c 1.0, CHCl3).
13C NMR (75 MHz, CDCl3): d = 135.8, 117.0, 75.3, 74.8, 36.2,
32.13, 32.11, 30.0, 29.83, 29.79, 29.6, 26.3, 26.1, 22.9, 18.3, 14.3,
–4.1, –4.3.
HPLC (Chiralcel AD; i-PrOH–hexanes, 2:98; 1 mL/min): tR
(major) = 11.7 min, tR (minor) = 15.5 min; 98% ee.
IR (KBr): 3414, 3276, 2923, 2853, 1602, 1494, 1466 cm–1.
HRMS: m/z [M+] calcd for C21H44O2Si: 356.3111; found: 356.3091.
1H NMR (300 MHz, CDCl3): d = 7.62 (dd, J = 7.2, 8.7 Hz, 2 H),
6.94–7.00 (m, 3 H), 5.82–5.96 (m, 1 H), 5.11–5.20 (m, 2 H), 4.01
(dt, J = 2.4, 6.0 Hz, 1 H), 3.85–3.90 (m, 1 H), 2.30 (ddd, J = 1.2, 7.2,
8.4 Hz, 2 H), 1.23–1.72 (m, 19 H), 0.88 (t, J = 6.9 Hz, 3 H).
(4S,5R)-4-(tert-Butyldimethylsilyloxy)-5-(p-tolylsulfonyl-
oxy)pentadec-1-ene (9)
To a soln of 8 (303 mg, 0.85 mmol) in CH2Cl2 (7.0 mL) was added
DMAP (830 mg, 6.8 mmol), followed by TsCl (812 mg, 4.3 mmol),
and the mixture was refluxed for 18 h. The reaction mixture was
quenched with sat. NH4Cl soln (15 mL) and the aqueous layer was
extracted with CH2Cl2 (2 × 20 mL). The combined organic layer
was washed with brine (20 mL), dried (anhyd MgSO4), and concen-
trated under reduced pressure. The crude residue was purified by
flash column chromatography (EtOAc–hexanes, 2:98) to afford
compound 9 as a colorless oil; yield: 430 mg (99%).
13C NMR (75 MHz, CDCl3): d = 148.6, 135.3, 129.2, 122.6, 118.0,
115.2, 86.1, 72.5, 37.1, 32.1, 30.0, 29.9, 29.8, 29.6, 28.5, 26.6, 22.9,
14.3.
HRMS: m/z [M+] calcd for C21H35NO2: 333.2668; found: 333.2680.
syn-(4R,5R)-4
HPLC (Chiralcel AD; i-PrOH–hexanes, 2:98; 1 mL/min): tR
(major) = 10.6 min, tR (minor) = 12.9 min; 98% ee.
[a]D26 +16.3 (c 1.0, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.24–7.29 (m, 2 H), 6.94–7.00 (m,
3 H), 5.84–5.95 (m, 1 H), 5.12–5.20 (m, 2 H), 3.82–3.88 (m, 1 H),
3.73–3.79 (m, 1 H), 2.22–2.47 (m, 2 H), 1.18–1.72 (m, 19 H), 0.88
(t, J = 6.3 Hz, 3 H).
IR (KBr): 2958, 2928, 2856, 1599, 1466, 1359, 1263 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.79 (d, J = 8.1 Hz, 2 H), 7.31 (d,
J = 8.1 Hz, 2 H), 5.65–5.79 (m, 1 H), 5.00–5.08 (m, 2 H), 4.45 (dt,
J = 2.4, 9.0 Hz, 1 H), 4.00 (dt, J = 2.1, 6.9 Hz, 1 H), 2.43 (s, 3 H),
2.07–2.25 (m, 2 H), 1.60–1.73 (m, 1 H), 1.40–1.50 (m, 1 H), 1.05–
1.34 (m, 16 H), 0.89 (t, J = 6.6 Hz, 3 H), 0.86 (s, 9 H), 0.06 (s, 3 H),
0.03 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 148.5, 134.9, 129.2, 122.7, 118.0,
115.3, 85.7, 72.9, 38.4, 32.1, 30.0, 29.83, 29.78, 29.69, 29.57, 25.8,
22.9, 14.3.
13C NMR (75 MHz, CDCl3): d = 144.6, 134.7, 134.3, 129.8, 128.1,
117.9, 86.1, 73.8, 39.4, 32.1, 29.8, 29.7, 29.64, 29.55, 29.48, 26.1,
25.3, 22.9, 21.8, 18.3, 14.3, –4.3, –4.4.
(4S,5R)-4-(tert-Butyldimethylsilyloxy)-5-(N-phenylamino-
oxy)pentadec-1-ene (7)
To a soln of (4S,5R)-4 (500 mg, 1.5 mmol) in CH2Cl2 (7.0 mL) at 0
°C was added Et3N (0.42 mL, 3.0 mmol), followed by TBDMSOTf
(0.41 mL, 1.8 mmol), and the mixture was stirred for 30 min. The
reaction mixture was quenched with sat. NH4Cl soln (15 mL) and
the aqueous layer was extracted with CH2Cl2 (2 × 20 mL). The com-
bined organic layer was washed with brine (20 mL), dried (anhyd
MgSO4), and concentrated under reduced pressure. The crude resi-
due was purified by flash column chromatography (EtOAc–hex-
HRMS: m/z [M+] calcd for C28H50O4SSi: 510.3199; found:
510.3196.
(7S,8R)-7-(tert-Butyldimethylsilyloxy)-2-methyl-8-(p-tolylsulfo-
nyloxy)octadec-4-ene (10)
To a soln of 9 (355 mg, 0.69 mmol) in CH2Cl2 (7.0 mL) was added
4-methylpent-1-ene (0.44 mL, 3.5 mmol), followed by Grubbs II
catalyst (29 mg, 0.035 mmol). The reaction mixture was warmed to
Synthesis 2009, No. 14, 2418–2422 © Thieme Stuttgart · New York

PAPER
Concise Total Synthesis of (+)-Disparlure and its trans-Isomer
IR (film): 3290, 3213, 2958, 2916, 2850, 1470 cm–1.
2421
40 °C and stirred for 5 h. The solvent and remaining 4-methylpent-
1-ene were removed under reduced pressure. The crude material
was purified by flash column chromatography (EtOAc–hexanes,
2:98) to afford compound 10 as a colorless oil; yield: 327 mg (84%).
1H NMR (400 MHz, CDCl3): d = 5.35–5.65 (m, 2 H), 3.55–3.70 (m,
2 H), 2.13–2.35 (m, 2 H), 2.10 (br s, 2 H), 1.90–1.98 (m, 2 H), 1.23–
1.68 (m, 19 H), 0.86–0.92 (m, 9 H).
IR (KBr): 2955, 2927, 2856, 1463, 1360, 1264, 1176 cm–1.
13C NMR (100 MHz, CDCl3): d = 133.8, 132.7 (minor), 126.9,
125.7 (minor), 74.03 (minor), 73.97 (minor), 73.8, 73.4, 42.0, 36.5
(minor), 34.6, 31.9, 31.6, 29.7, 29.6, 29.3, 29.2 (minor), 28.6 (mi-
nor), 28.3, 26.0, 22.7, 22.4 (minor), 22.29, 22.26, 14.1.
1H NMR (300 MHz, CDCl3): d = 7.78 (d, J = 8.1 Hz, 2 H), 7.31 (d,
J = 8.1 Hz, 2 H), 5.23–5.46 (m, 2 H), 4.41–4.47 (m, 1 H), 3.92–4.01
(m, 1 H), 2.43 (s, 3 H), 2.00–2.21 (m, 2 H), 1.73–1.92 (m, 2 H),
1.39–1.72 (m, 3 H), 1.04–1.33 (m, 16 H), 0.84–0.96 (m, 18 H), 0.05
(s, 3 H), 0.02 (s, 3 H).
(7R,8S)-2-Methyloctadecane-7,8-diol (12)
To a soln of 3 (162 mg, 0.54 mmol) in MeOH (7 mL) was added
10% Pd/C (0.1 w/w, 16 mg) and the mixture was stirred for 3 h un-
der H2 atmosphere. Then, the Pd/C was filtered off and the reaction
solvent was evaporated under reduced pressure. The residue was
purified by flash column chromatography (EtOAc–hexanes, 15:85)
to afford compound 12 as a white solid; yield: 150 mg (93%).
13C NMR (75 MHz, CDCl3): d = 144.6, 141.0 (minor), 134.8, 132.7,
131.5 (minor), 129.9 (minor), 129.8, 128.2, 128.1 (minor), 126.5,
125.3 (minor), 122.5 (minor), 86.4 (minor), 86.2, 74.3 (minor),
74.1, 42.3, 38.4, 36.8 (minor), 33.0 (minor), 32.1, 29.8, 29.73,
29.68, 29.57, 29.51, 28.8 (minor), 28.6, 28.0 (minor), 27.8, 26.1,
26.0 (minor), 25.4 (minor), 25.3, 22.9, 22.60, 22.55, 21.8, 18.3,
14.3, –4.3, –4.5.
Mp 86–87 °C (Lit.5g 85–88 °C); [a]D22 +1.88 (c 0.5, CHCl3).
IR (film): 3303, 2956, 2915, 2820, 1469 cm–1.
(7S,8R)-7-(tert-Butyldimethylsilyloxy)-2-methyl-8-(p-tolylsulfo-
nyloxy)octadecane (11)
1H NMR (400 MHz, CDCl3): d = 3.58–3.61 (m, 2 H), 2.31 (br s, 1
H), 2.19 (br s, 1 H), 1.15–1.60 (m, 27 H), 0.82–0.91 (m, 9 H).
To a soln of 10 (280 mg, 0.49 mmol) in hexane (5 mL) was added
10% Pd/C (0.1 w/w, 28 mg) and the mixture was stirred for 2 h un-
der H2 atmosphere. Then, the Pd/C was filtered off and the reaction
solvent was evaporated under reduced pressure. The residue was
purified by flash column chromatography (EtOAc–hexanes, 2:98)
to afford compound 11 as a colorless oil; yield: 278 mg (99%).
13C NMR (100 MHz, CDCl3): d = 74.7, 38.9, 31.9, 31.18, 31.15,
29.7, 29.6, 29.3, 27.9, 27.4, 26.3, 26.1, 22.69, 22.64, 22.61, 14.1.
(+)-Disparlure [(7R,8S)-cis-7,8-Epoxy-2-methyloctadecane, 1]
To a soln of 12 (75 mg, 0.25 mmol) in toluene (1.5 mL) was added
triethyl orthoacetate (0.24 mL, 1.25 mmol), followed by PPTS (2
mg). The reaction mixture was warmed to 110 °C and stirred for 1.5
h. The solvent was removed under reduced pressure. The residue
was dissolved in CH2Cl2 (1.5 mL), TMSCl (0.32 mL, 2.5 mmol)
was added, and the mixture was stirred for 15 h at r.t. Then, the sol-
vent was removed under reduced pressure. The residue was purified
by flash column chromatography (EtOAc–hexanes, 1:99) to afford
the acetoxy chloride isomers as a colorless oil. The acetoxy chloride
isomers were dissolved in THF (1.5 mL), which was followed by
the addition of 1 N KOH in MeOH (0.72 mL) and stirring for 2 h at
r.t. Then, the reaction mixture was quenched with H2O (10 mL) and
the aqueous layer was extracted with Et2O (2 × 20 mL). The com-
bined organic layer was washed with brine (20 mL), dried (anhyd
MgSO4), and concentrated under reduced pressure. The crude resi-
due was purified by flash column chromatography (EtOAc–hex-
anes, 2:98) to afford compound 1 as a colorless oil; yield: 67 mg
(95%).
[a]D26 +14.3 (c 1.1, CHCl3).
IR (KBr): 2957, 1463, 1364, 1188, 1176, 1097 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.79 (d, J = 8.4 Hz, 2 H), 7.32 (d,
J = 8.4 Hz, 2 H), 4.45 (dt, J = 2.4, 9.0 Hz, 1 H), 3.86–3.92 (m, 1 H),
2.44 (s, 3 H), 1.05–1.71 (m, 27 H), 0.87–0.95 (m, 18 H), 0.05 (s, 3
H), 0.02 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 144.6, 134.9, 129.8, 128.2, 86.9,
74.5, 39.1, 34.6, 32.2, 29.8, 29.72, 29.65, 29.5, 28.3, 28.1, 27.6,
26.1, 25.4, 22.91, 22.87, 22.8, 21.8, 18.4, 14.3, –4.1, –4.5.
HRMS: m/z [M+] calcd for C32H60O4SSi: 568.3982; found:
568.3987.
(7S,8S)-trans-7,8-Epoxy-2-methyloctadecane (2)
To a soln of 11 (225 mg, 0.40 mmol) in THF (4 mL) was added 1.0
M TBAF in THF (1.6 mL, 1.6 mmol) at 0 °C. After being stirring
for 18 h at r.t., the reaction mixture was quenched with H2O (10 mL)
and the aqueous layer was extracted with Et2O (2 × 20 mL). The
combined organic layer was washed with brine (20 mL), dried (an-
hyd MgSO4), and concentrated under reduced pressure. The crude
residue was purified by flash column chromatography (EtOAc–hex-
anes, 2:98) to afford compound 2 as a colorless oil; yield: 110 mg
(97%).
[a]D22 +0.8 (c 0.5, CCl4) [Lit.5c [a]D +0.9 (c 1.1, CCl4)].
1H NMR (400 MHz, CDCl3): d = 2.88–2.92 (m, 2 H), 1.16–1.60 (m,
27 H), 0.84–0.90 (m, 9 H).
13C NMR (100 MHz, CDCl3): d = 57.2, 38.9, 31.9, 29.7, 29.6, 29.3,
27.9, 27.8, 27.3, 26.9, 26.6, 22.68, 22.61, 22.60, 14.1.
[a]D26 –25.8 (c 1.9, CCl4) [Lit.11 [a]D –26.6 (c 0.5, CCl4)].
Acknowledgment
1H NMR (300 MHz, CDCl3): d = 2.62–2.67 (m, 2 H), 1.17–1.58 (m,
27 H), 0.85–0.91 (m, 9 H).
Generous support from the Korea Research Institute of Chemical
Technology (KRICT) is gratefully acknowledged.
13C NMR (75 MHz, CDCl3): d = 59.1, 39.1, 32.39, 32.36, 32.1,
29.81, 29.77, 29.67, 29.5, 28.1, 27.4, 26.5, 26.3, 22.9, 22.7, 14.3.
References
(7R,8S)-2-Methyloctadec-4-ene-7,8-diol (3)
To a soln of (4R,5S)-4 (450 mg, 1.34 mmol) in CH2Cl2 (14 mL) was
added 4-methylpent-1-ene (0.86 mL, 6.7 mmol), followed by
Grubbs’ catalyst (2nd generation) (56 mg, 0.067 mmol). The reac-
tion mixture was warmed to 40 °C and stirred for 8 h. The solvent
and remaining 4-methylpent-1-ene were removed under reduced
pressure. The crude material was purified by flash column chroma-
tography (EtOAc–hexanes, 15:85) to afford compound 3 as a white
solid; yield: 200 mg (50%).
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2422
S.-G. Kim
PAPER
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Synthesis 2009, No. 14, 2418–2422 © Thieme Stuttgart · New York