An enantiodivergent synthesis of both (+)- and (-)-disparlure from (R)-2,3-cyclohexylideneglyceraldehyde

Article abstract of DOI:10.1016/j.tetasy.2011.08.013

Reduction of ketone 3 derived from (R)-2,3-cyclohexylideneglyceraldehyde 1 with some common hydrides took place with syn-selectivity. The resulting major product 4a has been exploited as a common chiral template to prepare both enantiomers Ia,b of disparlure.

Full text of DOI:10.1016/j.tetasy.2011.08.013

Tetrahedron: Asymmetry 22 (2011) 1516–1521
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
An enantiodivergent synthesis of both (+)- and (ꢀ)-disparlure
from (R)-2,3-cyclohexylideneglyceraldehyde
⇑
Akhil Kumar Dubey, Angshuman Chattopadhyay
Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400 085, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 July 2011
Accepted 23 August 2011
Reduction of ketone 3 derived from (R)-2,3-cyclohexylideneglyceraldehyde 1 with some common
hydrides took place with syn-selectivity. The resulting major product 4a has been exploited as a common
chiral template to prepare both enantiomers Ia,b of disparlure.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
due to its easy accessibility on a multi-gram scale, good reactivity
both in aqueous and anhydrous media, and being less prone to
The gypsy moth is a seriously harmful pest, causing severe forest
losses during outbreaks in Europe, Asia, and North America. (+)-
Disparlure Ia (Fig. 1), structurally known as (7R,8S)-7,8-epoxy-2-
methyloctadecane, is the sex-attractant pheromone emitted by
the female gypsy moth, Lymantria dispar.1 It has been shown that
the (ꢀ)-enantiomer Ib antagonizes the effect of (+)-disparlure and
is slightly repellent by itself.2 Both the enantiomers bind differently
to two pheromone-binding proteins (PBP1 and PBP2) that are found
in gypsy moth antennae. Compounds Ia and Ib have higher affinity
for PBP2 and PBP1, respectively.3 Thus, a practical synthesis of both
enantiomers of disparlure in enantiomerically pure form assumes
considerable significance to have a detailed study of their struc-
ture–activity relationship and also for a thorough control of gypsy
moth pests in the forest. Accordingly, efforts have been directed to-
ward the synthesis of both enantiomers Ia and Ib4,5a–l and several
analogues.5m–o Understandably, for the synthesis of both these
enantiomers the prime requisite is to introduce its two stereo-cen-
ters in the linear carbon chain, which has been accomplished in a
different manner by various synthetic groups, viz asymmetric epox-
idation (AE),5f asymmetric dihydroxylation (AD),5g,i,l asymmetric
chloroallylation,5d use of chiral stannanes,5c enzymatic proce-
dures,5e,j,k or through the exploitation of chiral pool materials.5a,b,h
However, owing to their high importance there is a scope for the
development of a new strategy for the efficient synthesis of both
the enantiomers Ia and Ib of disparlure.
polymerization. Furthermore, the higher stability of its ketal
functionality compared to the corresponding acetonide derivative7
enabled us earlier6 to manipulate all the hydroxyls of its alkylation
products selectively. The present work describes our endeavor to
explore the potential of 1 once again to develop a practically viable
strategy for the syntheses of both Ia and Ib.
2. Results and discussion
Retro synthetic analysis (Scheme 1) of both (+)- and (ꢀ)-dispar-
lure I suggested that both these enantiomers could be obtained
from two differently protected forms 10a and 11b of the same
syn diol that could be accessed from 1 through 4a. It needs to be
re-stated that compound 4a had been prepared earlier in good
yield and highly stereo-selective syn reduction of ketone 36k de-
rived from 1 (Table 1, entry A). Now, with a view to developing a
somewhat practical synthesis of disparlure, it was performed un-
der three different operationally simpler procedures using com-
mon hydrides, viz LiAlH4 (Table 1, entry B), NaBH4 (Table 1, entry
C), and LiAlH4/LI8 (Table 1, entry D) and their results are shown
in Table 1.
In all the three cases (Table 1, entries b–d) reduction of 3
yielded 4a in good yields, but with nearly the same degrees of
moderate syn-selectivity. Among the three, LiAlH4 reduction ap-
peared to be most suitable for our purpose as it took place with
the highest yield and best syn-selectivity. Thus, despite achieving
less syn-selectivity compared to a K-selectride reduction,6k the
operationally simpler LiAlH4 reduction of 3 appeared to be prefer-
able in our goal to establish a practical synthesis of Ia and Ib. Fur-
thermore, somewhat less syn-selectivity in this case could be offset
by the easy column chromatographic separation of our desired iso-
mer 4a from the anti-4b compound to obtain a substantial amount
of it in homochiral form.
In our ongoing program regarding the synthesis of bioactive
compounds, we have been exploiting (R)-2,3-cyclohexylideneglyc-
eraldehyde 16a as a useful template for the asymmetric construc-
tion of different structural units during our syntheses of different
biomolecules.6 Compound 1 has various operational advantages
⇑
Corresponding author.
E-mail addresses: achat@apsara.barc.ernet.in, achat@barc.gov.in (A. Chattopad-
hyay).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.08.013

A. K. Dubey, A. Chattopadhyay / Tetrahedron: Asymmetry 22 (2011) 1516–1521
1517
O
O
Ia
Ib
Figure 1. Both enantiomers of disparlure.
OTs
R1
O
OTBDPS
10a
O
O
O
Ib
O
R1
4a
CHO
OTBDMS
R1
OH
1
O
OTs
11b
Ia
R1 = C9H19
Scheme 1. Retro-synthesis of (ꢀ) and (+)-disparlure.
diate 4a, a partially protected 1,2-syn-diol derived from 1.6a As could
be evident here, the partial protection of the syn diol moiety in 4a
enabled us to smoothly obtain another set of partially protected
diols 9a and 11a, the advanced precursors of Ib and Ia, respectively.
Notably, using an LiAlH4 reduction of ketone 3 (Table 1, entry B) the
overall yield of 4a has been considerably increased to 60% in two
practically viable steps (steps ii and iii, Scheme 2) starting from Grig-
nard product 4. Accordingly, the overall yields of Ia and Ib in this
protocol were found to be 10.75% and 13.97%, respectively, which
were comparable with most of the reported approaches.5 The effi-
cacy of the present route was due to many operational advantages
associated with easily available 16a as mentioned earlier and its
being comprised of a series of operationally simple and scaleable
reactions. In view of this, despite the presence of a moderately
syn-selective reduction of ketone 3 (Table 1, entry B), utilizing the
present route has significant advantages to achieve the practical
syntheses of both Ia/Ib, compared to all other reported syntheses.5
Understandably, beginning with the major Grignard product anti-
4b there is a scope to prepare the trans isomers5o of both Ia and Ib
following the same reactions protocol as described here.
Table 1
Hydride reduction of 3
Entry
Hydride
Yield (%)
Stereoselectivity 4a:4b
Reference
6k
A
B
C
D
K-selectride
LiAlH4
NaBH4
95
91.7:8.3
65.8:34.2
62:38
91.3
81.3
85.9
LiAlH4–LiI
63.4:36.6
Silylation of 4a and deketalisation of the resulting silyl-ether 5a
under acidic conditions afforded diol 6a in good yield. This was
converted into epoxide 8a in two steps, viz regioselective tosyla-
tion at its primary hydroxyl and base treatment of the product
7a. The epoxide 8a was treated with 4-methypentylmagnesium
bromide in the presence of copper (I) catalyst to afford the alcohol
9a. This was tosylated which took place quantitatively and the
resulting product 10a was desilylated on treatment with TBAF to
directly afford Ib in good yield whose spectroscopic and rotation
data were found to be in accordance with the reported ones5a
(Scheme 2).
Benzylation of 4a, followed by acid mediated deketalisation of
the resulting 5b afforded diol 6b in good yield. This was converted
into epoxide 8b in two steps, viz regioselective tosylation at its
primary hydroxyl and base treatment of the product 7b. Now, as
carried out earlier for the preparation of 9a, copper (I) catalyzed
reaction of epoxide 8b with 4-methypentylmagnesium bromide
afforded the alcohol 9b. This was silylated upon treatment with
TBDMS-Cl and the resulting product 10b was subjected to hydroge-
nation producing a known alcohol 11a5a following debenzylation at
the C-8 hydroxyl. Next, the hydroxyl of 11a was tosylated, and this
took place quantitatively to yield 11b which was subjected to desi-
lylation on treatment with TBAF to afford Ia in good yield whose
spectroscopic and rotation data were found to be in accordance
with the reported ones (Scheme 2).5a
4. Experimental
Chemicals used as starting materials are commercially available
and were used without further purification. All solvents used for
the extraction and chromatography were distilled twice at atmo-
spheric pressure prior to use. The 1H and 13C NMR spectra were re-
corded with a Bruker Ac-200 (200 MHz) instrument in CDCl3. The
organic extracts were desiccated over dry Na2SO4.
4.1. Reduction of compound 3 with LiAlH4
To a stirred solution of 3 (6.2 g, 0.02 mol) in THF (100 ml) at 0 °C
was added LiAlH4 (760 mg, 0.02 mol) in several portions over a
period of 1 h. The mixture was stirred at 0 °C for 1.5 h until the
reaction was completed (TLC). The reaction was then quenched
by the dropwise addition of aqueous saturated Na2SO4 that
destroyed the excess hydride to form a white precipitate. It was
then filtered through a sintered funnel and washed with EtOAc.
3. Conclusion
A simple route to an enantiodivergent synthesis of both enantio-
mers Ia and Ib of disparlure has been established through the
functional and stereoselective manipulation of a common interme-

1518
A. K. Dubey, A. Chattopadhyay / Tetrahedron: Asymmetry 22 (2011) 1516–1521
IA
R1 = -C9H19
iii (a,b,c)
ii
i
O
O
O
O
O
+
O
O
O
O
O
R1
R1
R1
CHO
R1
OH
O
OH
OH
2
3
4b
1
4a
HO
HO
iv(a)
iv(b)
O
vi
v
TsO
HO
4a
R1
O
R1
R1
OR
OR
OR
6a- R- TBDPS
6b- R- Bn
7a- R- TBDPS
7b- R- Bn
5a- R- TBDPS
5b- R- Bn
OH
O
viii
R1
vii
R1
OR
OR
9a- R- TBDPS
9b- R- Bn
8a- R- TBDPS
8b- R- Bn
OTs
vi
O
ix
9a
R1
OR
Ib
10a
OTBDMS
OTBDMS
OR
x
xi
R1
ix
O
9b
R1
OR1
10b
1
11a,
R = H
Ia
vi
11b, R1 = Ts
Scheme 2. Synthesis of (ꢀ) and (+)-disparlure. Reagents and conditions: (i) Ref. 6k; (ii) Ref. 6k; (iii) (a) LiAlH4, Dry THF, 0 °C, 91%; (b) NaBH4, MeOH, 0 °C, 81%; (c) LiAlH4, LiI,
Et2O, ꢀ40 to ꢀ78 °C, 86%; (iv) (a) TBDPSCl, imidazole, DMAP, Dry CH2Cl2, 95%; (b) PhCH2Br, NaH, Dry THF, 60 °C, 90%; (v) aq TFA (80%), CH2Cl2, 0 °C, 80%; (vi) TsCl, Dry Py,
DMAP, 0 °C, quantitatively; (vii) K2CO3, Dry CH3OH, 85%; (viii) (CH3)2CH(CH2)2CH2MgBr, Cu, Dry THF, ꢀ60 °C, 70%; (ix) TBAF, Dry THF, 0 °C, 75%; (x) TBDMS-Cl, imidazole,
DMAP, Dry CH2Cl2, 90%; (xi) Pd/C, H2 gas, C2H5OH, 85%.
The organic filtrate was washed with water, brine, and dried over
Na2SO4. Solvent removed under reduced pressure afforded the
residue which was purified by column chromatography (silica
gel; 0–15% EtOAc in petroleum ether) to afford pure 4a6k (3.75 g,
yield 59.7%) and 4b6k (1.95 g, yield 31.2%), both as colorless oils.
was removed under reduced pressure. The residue was taken in
CHCl3. The organic solution was washed with water, brine, and
dried over Na2SO4. Solvent removed under reduced pressure to af-
ford the residue which was purified by column chromatography
(silica gel; 0–15% EtOAc in petroleum ether) to afford pure 4a
(3.14 g, yield 50.3%) and 4b (2.0 g, yield 31%).
4.2. Reduction of compound 3 with NaBH4
4.3. Reduction of compound 3 with LiAlH4/LiI
To a stirred solution of 3 (6.2 g, 0.022 mol) in MeOH (50 ml) at
0 °C was added NaBH4 (740 mg, 0.02 mol) in several portions over
a period of 20 min. The mixture was stirred at 0 °C for 2 h. Solvent
To a stirred solution of 3 (3.1 g, 0.011 mol) in diethyl ether
(20 ml) was added LiI (13.4 g, 0.1 mol) and the mixture was stirred

A. K. Dubey, A. Chattopadhyay / Tetrahedron: Asymmetry 22 (2011) 1516–1521
1519
at ꢀ40 °C for 5 min. Then it was cooled to ꢀ78 °C and LiAlH4 (3.8 g,
0.1 mol) was added in several portions over a period of 20 min. The
mixture was stirred at ꢀ78 °C for 30 min and quenched by the
addition of aqueous saturated Na2SO4 that decomposed the excess
hydride to form a white precipitate. It was then filtered through a
sintered funnel and washed with EtOAc. The organic filtrate was
washed with water, brine, and dried over Na2SO4. Solvent removed
under reduced pressure afforded a residue which was purified by
column chromatography (silica gel; 0–15% EtOAc in petroleum
ether) to afford pure 4a (1.7 g, yield 54.5%) and 4b (980 mg, yield
31.4%).
(15 mL) and mixed with solid K2CO3 (1.10 g, 8 mmol). The mixture
was stirred at room temperature for three hours. The solvent was
removed under reduced pressure and the residue was dissolved
in CHCl3. The organic layer was washed successively with water,
5% aqueous HCl, water, brine, and then dried over Na2SO4. Solvent
removal under reduced pressure and column chromatography of
the residue (silica gel, 0–5% EtOAc in hexane) afforded pure com-
pound 8a (1.53 g, yield 85%) as a colorless liquid. ½a D25
¼ ꢀ16:8 (c
ꢁ
0.9, CHCl3); 1H NMR: d 0.89 (t, J = 6.8 Hz., 3H), 1.0–1.5 (m, 27H),
2.44–2.46 (m, 1H), 2.70–2.74 (m, 1H), 3.03–3.07 (m, 1H), 3.33–
3.67 (m, 1H). 7.2–7.4 (m, 6H), 7.6–7.7 (m, 4H). 13C NMR: 14.1,
19.4, 22.7, 24.9, 26.9, 27.0, 29.3, 29.4, 29.5, 31.9, 34.7, 44.8, 55.6,
75.2, 127.40, 127.47, 129.5, 133.9, 134.2, 136.0. Anal. Calcd for
4.4. (2R,3R)-1,2-O-Cyclohexylidene-3-O-tert-butydiphenylsilyl-
tridecane-1,2,3-triol 5a
C29H44O2Si: C, 76.93; H, 9.80. Found: C, 77.19; H, 9.59.
To a stirred solution of 4a (2.5 g, 8.0 mmol) in CH2Cl2 (75 mL)
containing imidazole (0.82 g, 12.01 mmol) were added TBDPSCl
(2.64 g, 9.6 mmol) and a catalytic amount (150 mg) of DMAP. The
mixture was stirred for a further 10 h and then poured in water,
the organic layer separated and the aqueous layer was extracted
with CHCl3. The combined organic extracts were washed with
water, brine, and dried. Solvent removal under reduced pressure
followed by column chromatography of the residue (Silica gel, 0–
10% EtOAc in Hexane) afforded pure 5a (4.19 g, yield 95%), as a col-
4.7. (7R,8R)-2-Methyl-8-O-tert-butyldiphenylsilyl-7,8-
octadecanediol 9a
A Grignard suspension of 1-bromo-4-methylpentane in THF
(50 mL) was prepared from the bromide (1.64 g, 9.94 mmol) and
Mg (0.29 g, 11.92 mmol) in the usual manner. The suspension
was cooled (ꢀ50 °C) and Cu(I) bromide (0.712 g, 4.97 mmol) was
added to it. The mixture was stirred for 15 min. To the resultant
black suspension at ꢀ50 °C was added compound 8a (1.5 g,
3.31 mmol) in THF (40 mL). The mixture was stirred at the same
temperature for 1 h and then overnight at room temperature.
The reaction was quenched by the addition of aqueous saturated
NH4Cl (10 mL) and extracted with EtOAc. The organic layer was
washed with 5% aqueous HCl, water, brine, and then dried over
Na2SO4. Solvent removal under reduced pressure and column chro-
matography of the residue (silica gel, 0–10% EtOAc in hexane)
orless thick oil. ½a D25
ꢁ
¼ þ3:75 (c 0.7, CHCl3); 1H NMR: d 0.88 (t,
J = 6.8 Hz., 3H), 1.0–1.2 (m, 27H), 1.3–1.6 (m, 10H), 3.63–3.78 (m,
2H), 3.86–3.93 (m, 1H), 4.08–4.17 (m, 1H), 7.25–7.43 (m, 6H),
7.67–7.71 (m, 4H). 13C NMR: 14.1, 19.5, 22.7, 23.7, 23.8, 25.0,
25.2, 27.0, 29.3, 29.4, 29.50, 29.58, 29.66, 31.9, 32.7, 34.5, 36.0,
65.2, 74.2, 77.9, 109.7, 127.32, 127.36, 129.4, 134.3, 136.01,
136.07. Anal. Calcd for C35H54O3Si: C, 76.31; H, 9.88. Found: C,
76.57; H, 9.55.
afforded pure 9a (1.24 g, yield 70%) as
a colorless liquid.
½
a 2D5
ꢁ
¼ þ4:7 (c 1.07, CHCl3); 1H NMR: d 0.86 (m, 9H), 0.97–1.52
4.5. (2R,3R)-3-O-tert-Butydiphenylsilyl-tridecane-1,2,3-triol 6a
(m, 36H), 2.2 (br s, 1H), 3.53 (m, 1H), 3.6 (m, 1H). 7.2–7.4 (m,
6H), 7.6–7.7 (m, 4H). 13C NMR: 14.0, 19.5, 22.6, 24.8, 26.0, 27.1,
27.3, 27.8, 29.2, 29.3, 29.4, 29.5, 31.8, 33.4, 33.9, 38.9, 72.7, 76.2,
127.4, 127.6, 129.6, 129.7, 133.5, 134.1, 135.9. Anal. Calcd for
To a stirred and cooled (0 °C) solution of 5a (4 g, 7.26 mmol) in
CH2Cl2 (75 mL) was added 80% aqueous TFA (10 mL) in portions.
After stirring the mixture for 2.5 h for completion of the reaction
(by TLC), NaHCO3 was added to decompose the excess TFA, fol-
lowed by the addition of water. The mixture was extracted with
CHCl3. The combined organic extracts were washed with water
and brine, and dried over Na2SO4. Solvent removal under reduced
pressure followed by column chromatography (silica gel, 5% MeOH
in CHCl3) of the residue afforded pure 6a (2.73 g, yield 80%).
C35H58O2Si: C, 78.00; H, 10.85. Found: C, 78.27; H, 10.62.
4.8. (ꢀ)-Disparlure Ib
To a cooled (0 °C) solution of 9a (1.2 g, 2.23 mmol) in pyridine
(8 mL) containing a catalytic amount (100 mg) of DMAP was
slowly added p-toluenesulfonylchloride (0.51 g, 2.67 mmol). The
mixture was stirred at 0 °C for 9 h. After the completion of the reac-
tion (monitored with TLC), it was quenched by the addition of
water and extracted with CHCl3. The organic layer was washed
successively with 5% aqueous HCl, water, brine, and then dried
over Na2SO4. Removal of solvent under reduced pressure afforded
the crude residue which was quickly purified by passing through
a short silica gel and eluting first with 5% diethyl ether in hexane
to remove unreacted p-toluenesulfonylchloride that was used in
excess and then with 10% EtOAc in hexane to obtain 10a in quan-
titative yield. Compound 10a was found to be unstable on long
standing and hence the majority of it was immediately used for
the next reaction. However, a small portion of it was used for char-
½
a 2D5
ꢁ
¼ ꢀ20 (c 0.8, CHCl3); 1H NMR: d 0.86 (t, J = 6.8 Hz, 3H), 1.0–
1.3 (m, 27H), 1.66 (br s, 2H), 3.5–3.8 (m, 4H), 7.3–7.5 (m, 6H),
7.7–7.9 (m, 4H). 13C NMR: 14.0, 19.4, 22.6, 24.8, 27.0, 29.30,
29.38, 29.4, 31.8, 33.2, 64.3, 73.26, 73.84, 127.5, 127.7, 129.7,
129.8, 133.1, 133.6, 135.7, 135.8. Anal. Calcd for C29H46O3Si: C,
73.99; H, 9.85. Found: C, 74.28; H, 9.62.
4.6. (2R,3R)-1,2-Epoxy-3-O-tert-butyldiphenylsilyl-tridecane-3-
ol 8a
To a cooled (0 °C) solution of 6a (2.7 g, 5.73 mmol) in pyridine
(10 mL) containing DMAP (50 mg) was slowly added p-toluene-
sulfonylchloride (1.093 g, 5.73 mmol) over a period of two hours.
The mixture was stirred at 0 °C for 2 h. After completion of the
reaction (monitored with TLC), it was quenched by the addition
of water and extracted with CHCl3. The organic layer was washed
successively with 5% aqueous HCl, water, brine, and then dried
over Na2SO4. The solvent was removed under reduced pressure
to obtain the crude residue which was quickly purified by passing
through a short silica gel column eluting first with 10% diethyl
ether in hexane and then with 5–15% EtOAc in hexane to obtain
7a in quantitative yield. This was immediately dissolved in MeOH
acterization. ½a D25
ꢁ
¼ þ6:5 (c 2.6, CHCl3); 1H NMR: d 0.84 (m, 9H),
1.0–1.2 (m, 36H), 2.41 (s, 3H), 3.84 (m, 1H), 4.43 (m, 1H), 7.2–7.6
(m, 14H). 13C NMR: 14.0, 19.2, 21.4, 22.5, 22.6, 25.5, 26.9, 27.6,
27.9, 29.2, 29.3, 29.4, 31.8, 38.6, 72.7, 84.4, 127.4, 127.5, 127.6,
127.9, 129.4, 129.5, 129.6, 133.5, 133.7, 134.2, 135.9, 144.0.
To a solution of 10a (1.35 g, 1.95 mmol) in 10 mL of THF was
added TBAF (2.7 mL, 3.9 mmol) at 0 °C under an argon atmosphere.
The reaction mixture was stirred for 4 h at room temperature. After
completion of the reaction (indicated by TLC), it was poured into
water and extracted with ether. The combined ethereal extract

1520
A. K. Dubey, A. Chattopadhyay / Tetrahedron: Asymmetry 22 (2011) 1516–1521
was washed with water and brine and dried over Na2SO4. Evapora-
tion of solvent followed by column chromatography with (0–10%
EtOAc in hexane) yielded pure Ib (0.41 g, yield 75%) a colorless
K2CO3 (1.2 gm, 8.68 mmol). The mixture was stirred at room
temperature for three hours. The solvent was removed under re-
duced pressure and the residue was dissolved in CHCl3. The organic
layer was washed successively with water, 5% aqueous HCl, water,
brine, and then dried over Na2SO4. The solvent was removed under
reduced pressure and column chromatography of the residue (sil-
ica gel, 0–5% EtOAc in hexane) afforded pure compound 8b (1.08 g,
oil. ½a 2D5
ꢁ
¼ ꢀ1:1 (c 1.4, CCl4); lit.5a
½
a 2D5
ꢁ
¼ ꢀ1:0 (c 1.7, CCl4); 1H
NMR: d 0.84–0.87 (m, 9H), 1.15–1.56 (m, 27H), 2.87–2.91 (m,
2H). 13C NMR: 13.9, 22.4, 22.5, 26.5, 26.7, 27.2, 27.7, 27.8, 29.2,
29.4, 31.8, 38.8, 57.0.
yield 85%) as a colorless liquid. ½a D25
ꢁ
¼ þ16:7 (c 1.08, CHCl3); 1H
4.9. (2R,3R)-1,2-O-Cyclohexylidene-3-O-benzyl-tridecane-1,2,3-
triol 5b
NMR: d 0.88 (t, J = 6.8 Hz, 3H), 1.2–1.5 (m, 18H), 2.47–2.50 (m,
1H), 2.7–2.8 (m, 1H), 3.02 (m, 2H), 4.58 (d, J = 11.8 Hz, 1H), 4.84
(d, J = 11.3 Hz, 1H), 7.2–7.4 (m, 5H). 13C NMR: 13.9, 22.5, 25.4,
29.2, 29.5, 31.8, 32.3, 42.9, 54.9, 71.5, 80.4, 127.2, 127.6, 128.1,
138.7. Anal. Calcd for C20H32O2: C, 78.90; H, 10.59. Found: C,
78.70; H, 10.81.
To a suspension of sodium hydride (0.52 g, 50% suspension in
oil, 10.77 mmol) and dry THF (50 ml), 4a (2.8 g, 8.97 mmol) in
dry THF (50 ml) was added dropwise over a period of 10 min under
an argon atmosphere. The mixture was heated at 60 °C for 1 h that
was accompanied with the liberation of H2 gas. The mixture was
cooled to room temperature followed by the addition of benzyl
bromide (1.84 g, 10.77 mmol) in THF (50 ml) to it. The mixture
was stirred for I h and then brought to 60 °C and heated for a fur-
ther 2 h. On completion of the reaction (monitored with TLC), it
was cooled with ice-water, quenched by the addition of water,
and extracted with EtOAc. The organic layer was washed succes-
sively with water, 5% aqueous HCl, water, brine, and then dried
over Na2SO4. Solvent removal under reduced pressure and column
chromatography of the residue (silica gel, 0–10% EtOAc in hexane)
afforded pure compound 5b (3.25 g, yield 90%) as a colorless liquid.
4.12. (7R,8R)-2-Methyl-8-O-benzyl-7,8-octadecanediol 9b
Following the same procedure as reported for the preparation of
9a, (CH3)2CH(CH2)2CH2MgBr, prepared from Mg (0.28 g, 11.82
mmol), 1-bromo-4-methylpentane (1.63 g, 9.85 mmol) in THF
(25 mL) was reacted with Cu(I) bromide (0.72 g, 5.01 mmol) at
ꢀ50 °C. To the resultant black suspension at ꢀ50 °C was added 8b
(1 g, 3.28 mmol) in THF (30 mL). After the usual work up and sol-
vent removal under reduced pressure, the residue was purified by
column chromatography (silica gel, 0–5% EtOAc in hexane) to ob-
tain pure 9b (0.9 g, yield 70%) as a colorless liquid. ½a D25
¼ þ10:3
ꢁ
½
a 2D5
ꢁ
¼ þ16:9 (c 1.5, CHCl3); 1H NMR: d 0.89 (t, J = 6.6 Hz., 3H), 1.2–
(c 1.16, CHCl3); 1H NMR: d 0.87 (m, 9H), 1.2–1.7 (m, 27H), 1.77 (s,
1H), 3.24 (m, 1H), 3.57 (m, 1H), 4.47 (d, J = 12.8 Hz, 1H), 4.66 (d,
J = 11.3 Hz, 1H), 7.2–7.3 (m, 5H). 13C NMR: 14.1, 22.5, 25.1, 25.9,
27.3, 27.8, 29.2, 29.5, 29.8, 30.2, 31.8, 33.4, 38.9, 72.3; 72.6, 82.3,
127.5, 127.7, 128.3, 138.5. Anal. Calcd for C26H46O2: C, 79.94; H,
11.87. Found: C, 79.71; H, 11.69.
1.4 (m, 18H), 1.4–1.6 (m, 10H), 3.42 (m, 1H), 3.65–3.69 (m, 1H),
3.98–4.02 (m, 1H), 4.1–4.2 (m, 1H), 4.63 (d, J = 12.8 Hz, 1H), 4.82
(d, J = 12.8 Hz, 1H), 7.2–7.4 (m, 5H). 13C NMR: 14.0, 22.6, 23.8,
24.0, 25.2, 25.5, 29.2, 29.5, 30.8, 31.8, 34.9, 36.3, 65.7, 72.9, 78.4,
80, 109.8, 127.4, 127.7, 127.9, 128.2, 138.9. Anal. Calcd for
C26H42O3: C, 77.56; H, 10.51. Found: C, 77.71; H, 10.27.
4.13. (7R,8R)-2-Methyl-7-O-tert-butyldimethylsilyl-7,8-
4.10. (2R,3R)-3-O-Benzyl-tridecane-1,2,3-triol 6b
octadecanediol 11a
To a stirred and cooled (0 °C) solution of 5b (3.2 g, 7.95 mmol)
in CH2Cl2 (50 mL) was added 80% aqueous trifluoroacetic acid
(15 mL) in portions. The mixture was stirred for 2.5 h at 0 °C until
its completion (by TLC). Solid NaHCO3 (5 g) was added to it to
decompose the excess TFA, followed by the addition of water.
The mixture was extracted with CHCl3. The combined organic ex-
tract was washed with water and brine, and dried over Na2SO4. Re-
moval of the solvent in vacuum followed by column
chromatography (silica gel, 5% MeOH in CHCl3) of the residue affor-
To a stirred solution of 9b (0.9 g, 2.30 mmol) and tert-butyldi-
methylsilyl chloride (0.41 g, 2.76 mmol) in CH2Cl2 (50 mL) was
added imidazole (0.24 g, 3.45 mmol). The mixture was stirred for
a further 10 h at room temperature and treated with water. The or-
ganic layer was separated and washed with water, brine, and dried.
Solvent removal under reduced pressure afforded the residue
which was purified by column chromatography (silica gel, 0–10%
EtOAc in petroleum ether) to afford compound 10b (1.04 g, yield
90%).
ded pure 6b (2.05 g, yield 80%) as a colorless thick oil. ½a D22
ꢁ
¼ þ4:5
To a solution of 10b (1 g, 1.98 mmol) in ethanol (10 mL) was
added activated 10% Pd/C (50 mg). The reaction mixture was stir-
red under a hydrogen atmosphere (balloon) for 3 h at room tem-
perature. After completion of the reaction (TLC), it was filtered
through a short pad of Celite which was then thoroughly washed
with diethyl ether. Solvent removal under reduced pressure and
column chromatography (silica gel, 0–10% EtOAc in hexane) of
the residue afforded a known 11a (0.69 g, yield 85%) in pure form
(c 2.01, CHCl3); 1H NMR: d 0.88 (t, J = 6.6 Hz., 3H), 1.2–1.4 (m, 18H),
2.09 (s, 2H), 3.64–3.66 (m, 4H), 4.47 (d, J = 12.8 Hz, 1H), 4.68 (d,
J = 11.3 Hz, 1H), 7.2–7.4 (m, 5H). 13C NMR: 14.1, 22.7, 25.3, 29.3,
29.6, 29.9, 30.3, 31.9, 64.0, 72.4; 73.2, 79.9, 127.8, 127.9, 128.4,
138.3. Anal. Calcd for C20H34O3: C, 74.49; H, 10.63. Found: C,
74.75; H, 10.37.
4.11. (2R,3R)-1,2-Epoxy-3-O-benzyl-tridecane-3-ol 8b
as an oil. ½a 2D5
ꢁ
¼ ꢀ4:2 (c 2.8, CHCl3); lit5a
½
a 2D5
ꢁ
¼ ꢀ3:8 (c 3.2, CHCl3);
1H NMR: d 0.06 (s, 6H), 0.87 (m, 9H), 1.2–1.5 (m, 36H), 1.77 (s, 1H),
3.45 (m, 2H). 13C NMR: ꢀ4.6, ꢀ4.1, 14.0, 18.1, 22.5, 22.6, 25.3, 25.9,
27.6, 27.9, 29.3, 29.6, 29.7, 31.9, 33.9, 34.1, 38.9, 72.7; 75.2.
To a cooled (0 °C) solution of 6b (2 g, 6.21 mmol) in pyridine
(10 mL) containing DMAP as a catalyst was added p-toluenesulfo-
nylchloride (1.18 g, 6.21 mmol). The mixture was stirred at 0 °C for
2 h. After completion of the reaction (monitored with TLC), it was
quenched by the addition of water and extracted with CHCl3. The
organic layer was washed successively with 5% aqueous HCl,
water, brine, and then dried. The solvent was removed under re-
duced pressure to obtain the crude residue which was quickly
purified by passing through a short plug of silica gel and eluting
with 5–15% EtOAc in hexane to obtain 7b in quantitative yield. This
was immediately dissolved in MeOH (20 mL) and mixed with solid
4.14. (+)-Disparlure Ia
To a cooled (0 °C) solution of 11a (0.65 g, 1.57 mmol) in pyri-
dine (4 mL) containing DMAP as a catalyst was slowly added p-tol-
uenesulfonylchloride (0.328 g, 1.723 mmol). The mixture was
stirred at 0 °C for 6 h. After completion of the reaction (monitored
with TLC), it was quenched by the addition of water and extracted
with CHCl3. The organic layer was washed successively with 5%

A. K. Dubey, A. Chattopadhyay / Tetrahedron: Asymmetry 22 (2011) 1516–1521
1521
5. (a) Prasad, K. R.; Anbarasan, P. J. Org. Chem. 2007, 72, 3155. and references cited
therein; (b) Koumbis, A. E.; Chronopoulos, D. D. Tetrahedron Lett. 2005, 46, 4353.
and references cited therein; (c) Marshall, J. A.; Jablonowski, J. A.; Jiang, H. J. Org.
Chem. 1999, 64, 2152. and references cited therein; (d) Hu, S.; Jayaraman, S.;
Oehlschlager, A. C. J. Org. Chem. 1999, 64, 3719; (e) Tsuboi, S.; Yamafuji, N.;
Utaka, M. Tetrahedron: Asymmetry 1997, 8, 375; (f) Li, L. H.; Wang, D.; Chan, T. H.
Tetrahedron Lett. 1997, 38, 101; (g) Sinha-Bagchi, A.; Sinha, S. C.; Keinan, E.
Tetrahedron: Asymmetry 1995, 6, 2889; (h) Paolucci, C.; Mazzini, C.; Fava, A. J.
Org. Chem. 1995, 60, 169; (i) Ko, S. Y. Tetrahedron Lett. 1994, 35, 3601; (j) Tsuboi,
S.; Furutani, H.; Ansari, M. H.; Sakai, T.; Utaka, M.; Takeda, A. J. Org. Chem. 1993,
58, 486; (k) Brevet, J.-L.; Mori, K. Synthesis 1992, 1007; (l) Keinan, E.; Sinha, S. C.;
Sinha-Bagchi, A.; Wang, Z.-M.; Zhang, X.-L.; Sharpless, K. B. Tetrahedron Lett.
1992, 33, 6411; (m) Inkster, J. A. H.; Ling, I.; Honson, N. S.; Jacquet, L.; Gries, R.;
Plettner, E. Tetrahedron: Asymmetry 2005, 16, 3773. and references cited therein;
(n) Chen, H.; Gong, V.; Gries, R.; Plettner, E. Bioorg. Med. Chem. 2010, 18, 2920.
and references cited therein; (o) Kim, S. G. Synthesis 2009, 2418. and references
cited therein.
6. (a) Chattopadhyay, A.; Mamdapur, V. R. J. Org. Chem. 1995, 60, 585; (b)
Chattopadhyay, A. J. Org. Chem. 1996, 61, 6104; (c) Chattopadhyay, A.; Dhotare,
B.; Hassarajani, S. A. J. Org. Chem. 1999, 64, 6874; (d) Dhotare, B.; Chattopadhyay,
A. Synthesis 2001, 1337; (e) Dhotare, B.; Chattopadhyay, A. Tetrahedron Lett.
2005, 46, 3103; (f) Dhotare, B.; Goswami, D.; Chattopadhyay, A. Tetrahedron Lett.
2005, 46, 6219; (g) Chattopadhyay, A.; Salaskar, A. J. Chem. Soc., Perkin Trans. 1
2002, 785; (h) Chattopadhyay, A.; Vichare, P.; Dhotare, B. Tetrahedron Lett. 2007,
48, 2871; (i) Chattopadhyay, A.; Goswami, D.; Dhotare, B. Tetrahedron Lett. 2006,
47, 4701; (j) Chattopadhyay, A. Tetrahedron: Asymmetry 1997, 8, 2727; (k)
Dhotare, B.; Salaskar, A.; Chattopadhyay, A. Synthesis 2003, 2571; (l) Dubey, A.
K.; Goswami, D.; Chattopadhyay, A. ARKIVOC 2010, 137; (m) Chattopadhyay, A.;
Goswami, D.; Dhotare, B. Tetrahedron Lett. 2010, 51, 4701; (n) Chattopadhyay,
A.; Tripathy, S. J. Org. Chem. 2011, 76, 5856.
aqueous HCl, water, brine, and then dried. The solvent was
removed under reduced pressure to obtain the crude residue
which was quickly purified by passing through a short silica gel
and eluting first with 5% EtOAc in hexane to remove the p-toluene-
sulfonylchloride that was used in excess and then with (0–10%
EtOAc in hexane) to obtain 11b in quantitative yield.
To a solution of 11b (0.70 g, 1.23 mmol) in THF (5 mL) was
added TBAF (1.4 mL, 2.46 mmol) at 0 °C under an argon atmo-
sphere. The reaction mixture was stirred for 5 h at that tempera-
ture and then for 1 h more at room temperature. It was poured
into water and extracted with diethyl ether. The combined ethereal
extract was washed successively with water, brine, and dried over
Na2SO4. Solvent removal under reduced pressure afforded the res-
idue which was purified by column chromatography (silica gel; 0–
10% EtOAc in hexane) to afford pure Ia (0.26 g, yield 75%).
½
a 2D5
ꢁ
¼ þ1:1 (c 1.7, CCl4); lit.5a
½
a 2D5
ꢁ
¼ þ1:0 (c 1.5, CCl4); 1H NMR:
d 0.84–0.87 (m, 9H), 1.11–1.59 (m, 27H), 2.86–2.90 (m, 2H). 13C
NMR: 14.0, 22.5, 22.6, 26.5, 26.8, 27.2, 27.8, 29.2, 29.5, 31.8, 38.9,
57.1.
References
1. Bierl, B. A.; Beroza, M.; Collier, C. W. Science 1970, 170, 87.
2. Miller, J. R.; Mori, K.; Roelofs, W. L. J. Insect Physiol. 1977, 23, 1447.
3. Plettner, E.; Lazar, J.; Prestwich, E. G.; Prestwich, G. D. Biochemistry 2000, 39,
8953.
7. Jurczak, J.; Pikul, S.; Bauer, T. Tetrahedron 1986, 42, 447.
8. Ghosh, A.; Lei, H. J. Org. Chem. 2002, 67, 8783.
4. For reviews, see: (a) Mori, K.; Tashiro, T. Curr. Org. Synth. 2004, 1, 11; (b) Mori, K.
Acc. Chem. Res. 2000, 33, 102.