Asymmetric synthesis of (E)- and (Z)-3,7-dimethyl-2-octene-1,8-diol and callosobruchusic acid

Article abstract of DOI:10.1016/j.tetasy.2004.01.032

Both enantiomers and regioisomers of (E)- and (Z)-3,7-dimethyl-2-octene-1, 8-diol and callosobruchusic acid, which have important biological activity were synthesized by enzymatic transesterification of primary alcohols (E)- and (Z)-10.

Full text of DOI:10.1016/j.tetasy.2004.01.032

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 963–970
Asymmetric synthesis of (E)- and (Z)-3,7-dimethyl-2-
octene-1,8-diol and callosobruchusic acid
S. Nanda and A. Ian Scott*
Center for Biological NMR, Department of Chemistry, Texas A&M University, PO Box 30012, College Station, TX 77842-3012, USA
Received 12 December 2003; accepted 22 January 2004
Abstract—Both enantiomers and regioisomers of (E)- and (Z)-3,7-dimethyl-2-octene-1,8-diol and callosobruchusic acid, which have
important biological activity were synthesized by enzymatic transesterification of primary alcohols (E)- and (Z)-10.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
1 and 2 could be constructed from nerol (Scheme 1). To
fix the methyl stereocenter we adopted an enzymatic
transesterification reaction with an active ester.
(E)-3,7-Dimethyl-2-octene-1,8-diol 1 has been identified
as a major component in the secretion products of the
monarch butterfly, Danaus chrysippus, which is an old
world member of the subfamily Danaine.1 The low
availability of the diol in butterflies, makes it difficult to
evaluate its biological activity. However the structurally
similar (E)-3,7-dimethyl-2-octene-1,8-dioic acid (callos-
obruchusic acid, 2) acts as a pheromone of the azuki
bean weevil, Callosbruchus chinensis SL2 and was found
to display specific activity as a sex pheromone in both
enantiomeric forms, therefore attracting much attention
for bioassay applications in pest control. There are
already some reports regarding the total synthesis of the
two title compounds, which involve both a chemical and
biochemical approach.3 In our study of diterpene cyc-
lases (mainly taxadiene synthase)4 we are in constant
need of several structurally modified geranyl-geraniols
(GGOH), for example, the enantiomers of 7,8-dihydro
GGOH. A logical disconnection of 7,8-dihydro GGOH
leads to diol (E)-1 and (Z)-1 in both enantiomeric forms.
Herein we report the asymmetric total synthesis of
compounds 1 and 2 in both regioisomeric forms.
Our synthesis for the (E)-isomer started from prenol.
The hydroxy group was protected as its p-methoxy-
benzyl ether to give 3 in 95% yield. Selective allylic
oxidation with SeO2/TBHP followed by reduction with
NaBH4 afforded compound 4 in 65% yield. The hydro-
xyl group in 4 was converted to bromide by PBr3, and
the crude bromide then coupled with the copper enolate
of ethyl acetate5 at )110 ꢁC to yield ester 5. Reduction of
the ester with LAH, conversion of the alcohol func-
tionality to a bromide, and successive coupling with an
enolate generated previously from ethyl propionate at
)110 ꢁC, yielded ester 7. The yield for the coupling
reaction of copper enolate generated from ethyl propi-
onate was low (15%). Changing the base from LDA to
LHMDS or KHMDS or altering the solvent (DMF,
ether) and temperature proved to have little effect on
improving the yield. At this stage we have decided to
reach the propionate ester moiety via an alternative
method through diethyl methylmalonate coupling.
Alcohol 6 was converted to the iodo compound 8 by
treatment with I2/triphenylphosphine/imidazole.6 Cou-
pling of 8 with diethyl methylmalonate in DMF at
100 ꢁC afforded the dialkylated malonate derivative 9 in
95% yield.7 Selective hydrolysis and decarboxylation of
9 was achieved by treatment with NaCN/DMSO and
H2O to yield 7 in 60% yield.8 Reduction with LAH
afforded alcohol 10 in 90% yield (Scheme 2).
2. Results and discussion
We planned to bring the (E)-double bond geometry in 1
and 2 starting from prenol, whereas the (Z) geometry in
The (Z)-isomer of 10 was prepared by following the
above reaction sequences starting from (Z)-6, which was
prepared in high yield from nerol as reported earlier.9
* Corresponding author. Tel.: +1-979-845-4032; fax: +1-979-845-5992;
e-mail: scott@mail.chem.tamu.edu
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.01.032

964
S. Nanda, A. I. Scott / Tetrahedron: Asymmetry 15 (2004) 963–970
OH
both enantiomers of 7,8-dihydro GGOH
Y
HO
X
HO
OP
OH
Y
Y = H2, (E)- 1
Y = O, (E)- 2
Y
Y
OH
Y = H2, (Z)- 1
Y = O, (Z)- 2
OH
prenol
nerol
OH
Scheme 1. Synthesis plan for 7,8-dihydro GGOH.
b
c
HO
OP
OP
OPMB
EtO2C
P = H
3, P = PMB
4
a
5
d
e
HO
OPMB
EtO2C
OPMB
6
7
f
g
I
OPMB
EtO2C
CO2Et
OPMB
9
8
h
i
HO
OPMB
EtO2C
OPMB
10
7
Scheme 2. Reagents and conditions: (a) NaH, PMB-Cl; (b) SeO2, TBHP, DCM, NaBH4/MeOH; (c) PBr3, EtOAc, LDA, CuI; (d) LiAlH4; (e) PBr3,
EtCO2Et, LDA, CuI; (f) I2/triphenylphosphine/imidazole, CH3CN/ether (1:3); (g) NaH, MeCH(CO2Et)2, DMF; (h) NaCN, DMSO/H2O; (i) LAH.
With both regioisomers of 10 in hand, the next step was
to install the methyl stereocenter adjacent to the hy-
droxymethyl group. For this purpose we decided to
employ lipase catalyzed transesterification of alcohol 10
with active esters, as acyl donors. For the above studies,
a set of lipases [Pseudomonas fluorescencs (PFL), Can-
dida antarctica (CAL-B), Candida rugosa (CRL), Por-
cine pancreas (PPL), wheat germ (WGL), and Rhizopus
niveus (RNL)] was chosen. Vinyl acetate, isopropenyl
acetate, ethyl acetate, and 3,5-dioxomethylhexanoate10
were selected for the active ester. In all the transesteri-
fication experiments, tert-butylmethyl ether (containing
0.1% water) was used as the solvent (except in case of
3,5-dioxomethylhexanoate). We have also carried out
the transesterification at two different temperatures (25
and 0 ꢁC) to observe any temperature dependence on
chemical yield and enantiomeric excess. A careful
screening of all the lipases revealed that CRL, WGL,
and RNL showed little activity (both optical and
chemical yields were low) toward the transesterification

S. Nanda, A. I. Scott / Tetrahedron: Asymmetry 15 (2004) 963–970
Table 1. Lipase catalyzed transesterification of (E)-10a
965
Entry
Lipasea
Acyl donorb
Temp
(0 ꢁC)
Time (h)
(S)-Esterc
(R)-Alcoholc
Conversion Ed
(c)d
Yield (%) Eep
Yield(%) Ees
1
2
3
4
5
6
7
8
9
PPL
PPL
Ethyl acetate
Ethyl acetate
25
0
12
18
10
14
12
16
4
40
32
46
45
42
44
40
38
46
88
91
89
92
82
86
88
92
95
39
30
43
42
44
40
32
44
45
82
90
88
90
88
80
90
91
93
48.2
49.7
49.6
49.4
51.7
48.2
50.5
49.7
49.4
40
64
PFL
PFL
Isopropenyl acetate
Isopropenyl acetate
Ethyl acetate
25
0
49.4
74.2
29
PFL
PFL
25
0
Ethyl acetate
Ethyl acetate
32.4
45.1
77.5
CAL-B
CAL-B
CAL-B
25
0
Ethyl acetate
3,5-Dioxomethyl hexanoate
9
25
8
132
a Weight equivalent (1:1.2, with alcohol 10) of lipase was used.
b Alcohol 10 (1 equiv) and acylating agent (2 equiv) were used.
25
D
c Eeꢀs were determined by NMR and the ½aꢀ value.
d E ¼ ln½1 ꢁ cð1 þ eepÞꢀ= ln½1 ꢁ cð1 ꢁ eepÞꢀ, where eep ¼ pdt. Ee; c ¼ ees=ðees þ eepÞ.16
reaction with all the acylating agents employed, whereas
other sets, for example, PPL/vinyl acetate, isopropenyl
acetate, and 3,5-dioxomethylhexanoate (25 and 0 ꢁC);
PFL/vinylacetate, 3,5-dioxomethylhexanoate (25 and
0 ꢁC); CAL-B/vinyl acetate, isopropenyl acetate (25 and
0 ꢁC) also showed disappointing results. The remaining
sets showed good to excellent chemical and optical yield
as listed in Table 1. From Table 1 it can be seen that the
CAL-B/3,5-dioxomethylhexanoate combination pro-
vided the optimal result. High chemical yield (46% for
the ester and 45% for the alcohol) and excellent optical
yield (E ¼ 132) was observed, whereas the other systems
also provided good yields. Reactions carried out at low
temperature (0 ꢁC) took a little longer reaction time but
showed more enantioselectivity (entries 2, 4, and 6). For
the corresponding (Z)-isomers of 10 we applied the same
conditions and observed almost similar results both in
terms of enantiomeric excess and chemical yield. The
only noticeable difference was that the (Z)-isomer took a
longer reaction time (3–4 h) when compared to its (E)-
counterpart. For the enantiopreference of lipases toward
transesterification of primary alcohols (not containing O
at the stereocenter), it was reported that the (S)-enan-
tiomer was acylated in most of the cases.11 We observed
the same trend in case of (E)- and (Z)-10. The absolute
configuration was determined by removal of para-
methoxybenzyl group and determining the specific
rotation value of the obtained diol.3 The enantioselec-
tivity of the enzymatic process was determined with the
help of NMR by making the chiral derivatized agent
with ortho-fluoroaryl lactic acid (FAC).12 In that process
the slow reacting (R)-enantiomer and fast reacting (S)-
enantiomer, (released from (S)-ester) were derivatized
with (R)-FAC (EDCIÆHCl/DMAP), with their 1H NMR
spectra was recorded at room temperature. The methyl
signal (doublet, adjacent to hydroxymethyl group)
showed different chemical shift values (d, near 0.9 ppm)
in the diastereomeric pairs. By measuring their integral
ratio, eeꢀs were measured. With the exception of the
methyl signal, other protons did not exhibit visible
separation in the diastereomeric pair, hence the deter-
mination of the absolute configuration could not be
assigned by this analysis. Finally the para-methoxy-
benzyl group was deprotected from (R)-11, 12 by using
DDQ13 to afford (R)-(E)-1 and (Z)-1. This on Jonesꢀ
oxidation yielded (R)-callosobruchusic acid in both
regioisomeric forms. (S)-13 and 14 were deacylated by
hydrolytic removal with K2CO3 or reduction with LAH,
followed by removal of para-methoxybenzyl group to
give (S)-(E)-1 and (Z)-1. Finally Jonesꢀ oxidation of (S)-
(E)-1 and (Z)-1 furnished (S)-callosobruchusic [(E)-2
and (Z)-2] acid in both regioisomeric forms (Scheme 3).
3. Conclusion
An efficient chemo-enzymatic asymmetric synthesis of
3,7-dimethyl-2-octene-1,8-diol and callosobruchusic
acid has been achieved in 9% overall yield starting from
easily available building blocks. Both enantiomers of
diol (E)-1 and (Z)-1 were further employed for the total
synthesis of 7,8-dihydro GGOH, needed for our study
on diterpene cyclase pathway evaluation.
4. Experimental
Unless otherwise stated, materials were obtained from
commercial suppliers and used without further purifi-
cation. THF and diethylether were distilled from sodium
benzophenone ketyl. Dimethylformamide (DMF) and
dimethylsulfoxide (DMSO) were distilled from calcium
hydride. Lipase (from C. rugosa, type VII, 1440 lg of
protein), lipase (from P. pancreas, type II, 6 lg of pro-
tein), lipase AK (from P. fluorescens), lipase (from
C. antarctica immobilized on acrylic resin), lipase (from
R. niveus), lipase (from wheat germ, type I, 8.2 lg of
protein) were obtained from Sigma and used as ob-
tained. Reactions were monitored by thin-layer chro-
matography (TLC) carried out on 0.25 mm silica gel
plates (Merck) with UV light, ethanolic vanillin and
phosphomolybdic acid/heat as developing agents. Silica
gel 100–200 mesh was used for column chromatography.
Yields refer to chromatographically and spectroscopi-
cally homogeneous materials unless otherwise stated.
NMR spectra were recorded on Bruker 500 MHz spec-
trometers at 25 ꢁC in CDCl3 using TMS as the internal
standard. Chemical shifts are shown in d. 13C NMR
spectra were recorded with a complete proton decou-
pling environment. The chemical shift value is listed as
1
dH and dC for H and 13C, respectively. CHN analysis

966
S. Nanda, A. I. Scott / Tetrahedron: Asymmetry 15 (2004) 963–970
HO
OPMB
(R)
E; 11
lipase
Z; 12
(E) and (Z) - 10
+
active ester
R
O
OPMB
(S)
O
E; 13
Z; 14
DDQ
Jones
HO
(R)-11 and 12
(R)- (-) E-2, Z-2
(S)-(-) E-1, Z-1
OH
(R)-(+) E-1, Z-1
K2CO3
DDQ
HO
(S)- 13 and 14
OPMB
or LAH
(S)- 11, 12
O
Jones
HO
O
OH
(S)- (+) E-2, Z-2
Scheme 3. Asymmetric total synthesis of the two title compounds.
was performed in the elemental analysis laboratory at
the Department of Chemistry, TAMU. Optical rota-
tions were measured on a JASCO Dip 360 digital
polarimeter.
thane (60 mL) was prepared. To this solution was added
slowly 1-methoxy-4-(3-methyl-but-2-enyloxymethyl)-
benzene (11 g, 53 mmol). The reaction mixture was then
stirred for 2 days at room temperature, after which it
was diluted with ether (200 mL), washed with aq NaOH,
aq sodium bisulfite, and brine. The organic layer was
dried over Na2SO4 and evaporated to afford the crude
product containing the allylic alcohol as well as the
aldehyde. The crude was then dissolved in 95% EtOH
(150 mL), and NaBH4 (2 g) added to it at 0 ꢁC with the
reaction mixture stirred overnight. Removal of ethanol
afforded a solid residue, which was partitioned between
water and ether. The organic layer was washed with
brine and dried over Na2SO4. Evaporation and purifi-
cation through flash chromatography (3:1, hexane/
4.1. 1-Methoxy-4-(3-methyl-but-2-enyloxymethyl)-ben-
zene 3
3-Methyl-but-2-en-1-ol (5 g, 58 mmol) was taken in THF
(60 mL) at 0 ꢁC, NaH (2.8 g, 69 mmol, 60% in mineral
oil) was added portionwise to it followed by the addition
of tetra-n-butyl ammonium iodide (catalytic). The
solution was allowed to attain room temperature for 1 h.
4-Methoxybenzyl chloride (10.8 g, 69 mmol) was added
to the solution and heated to reflux for 6 h. Afterwards,
cold water was added to it and extracted with ether. The
organic layer was washed with brine and dried over
Na2SO4. Evaporation of the organic layer yielded 11.3 g
of product (95%). 1H and 13C NMR spectra of this
material were compared closely with those of the liter-
ature14 and found similar. The product was used for the
next step without further purification.
1
EtOAc) yielded compound 4 (7.1 g, 65%). H and 13C
NMR spectra of this material was compared closely
with that of literature15 and found similar.
4.3. (E)-6-(4-Methoxy-benzyloxy)-4-methyl-hex-4-enoic
acid ethyl ester 5
To a solution of EtOAc (2.6 mL, 29.5 mmol) and
cuprous iodide (11.2 g, 59 mmol) in THF (100 mL) at
)110 ꢁC (dry ice/ether bath) was added a solution of
4.2. (E)-4-(4-Methoxy-benzyloxy)-2-methyl-but-2-
en-1-ol 4
n
LDA [made by the addition of BuLi (15 mL, 2.0 M in
hexane, 29.6 mmol) to a solution of diisopropylamine
(4.3 mL, 29.6 mmol) in THF (30 mL) at 0 ꢁC and stirred
for 30 min] via cannula. The reaction mixture was
A solution of TBHP (35 mL, 70% aq), salicylic acid (1 g,
7.25 mmol), and SeO2 (0.22 g, 2 mmol) in dichlorome-

S. Nanda, A. I. Scott / Tetrahedron: Asymmetry 15 (2004) 963–970
967
allowed to warm to )30 ꢁC over 2 h, followed by the
addition of 1-((E)-4-bromo-3-methyl-but-2-enyloxy-
methyl)-4-methoxy-benzene (generated from 4, 4.25 g,
15 mmol) in THF (20 mL). Afterwards, the reaction
mixture was stirred for 1 h at )30 ꢁC. The mixture was
then quenched by the addition of saturated NH4Cl and
allowed to warm to room temperature at which point it
was extracted with ether. The combined organic layer
was washed with brine, dried over Na2SO4, and evap-
orated. Purification by flash chromatography (19:1,
hexane/EtOAc) afforded ester 5 as a clear oil (3 g, 70%).
dH: 7.3 (d, J ¼ 8:7 Hz, 2H), 6.9 (d, J ¼ 8:7 Hz, 2H), 5.4
(m, 1H), 4.45 (s, 2H), 4.15 (q, J ¼ 7:0 Hz, 2H), 4.05 (d,
J ¼ 7:2 Hz, 2H), 3.8 (s, 3H), 2.48 (m, 2H), 2.4 (m, 2H),
1.7 (s, 3H), 1.28 (t, J ¼ 7:0 Hz, 3H). dC: 173.4, 159.1,
138.8, 130.7, 129.4, 121.2, 113.7, 72.3, 66.6, 60.6, 55.3,
34.6, 32.9, 16.7, 14.5. Anal. Calcd for C17H24O4: C,
69.84; H, 8.27. Found: C, 69.72; H, 8.39.
(19:1, hexane/EtOAc) to afford 2.88 g of 8 (80% yield).
dH: 7.32 (d, J ¼ 8:7 Hz, 2H), 6.92 (d, J ¼ 8:7 Hz, 2H),
5.45 (m, 1H), 4.47 (s, 2H), 4.06 (d, J ¼ 7:2 Hz, 2H), 3.8
(s, 3H), 3.2 (t, J ¼ 7:0 Hz, 2H), 2.18 (t, J ¼ 7:0 Hz, 2H),
2.0 (m, 2H), 1.7 (s, 3H). dC: 159.3, 138.3, 130.7, 129.7,
122.4, 113.9, 72.0, 66.3, 55.4, 40.1, 31.5, 16.6, 6.6. Anal.
Calcd for C15H21IO2: C, 50.01; H, 5.88. Found: C, 50.15;
H, 5.77%.
4.7. 1-((Z)-6-Iodo-3-methyl-hex-2-enyloxymethyl)-4-
methoxy-benzene
dH: 7.3 (d, J ¼ 8:7 Hz, 2H), 6.88 (d, J ¼ 8:7 Hz, 2H), 5.5
(m, 1H), 4.5 (s, 2H), 4.0 (d, J ¼ 7:2 Hz, 2H), 3.82 (s,
3H), 3.18 (t, J ¼ 7:0 Hz, 2H), 2.2 (t, J ¼ 7:0 Hz, 2H), 2.0
(m, 2H), 1.68 (s, 3H). dC: 159.4, 139.6, 130.7, 129.8,
122.9, 113.6, 72.5, 65.93 55.3, 39.9, 31.4, 15.5, 7.2.
4.4. (E)-6-(4-Methoxy-benzyloxy)-4-methyl-hex-4-en-1-
ol 6
4.8. 2-[(E)-6-(4-Methoxy-benzyloxy)-4-methyl-hex-4-
enyl]-2-methyl-malonicacid diethyl ester 9
Ester 5 (1.1 g, 3.7 mmol) was taken in ether (20 mL) at
0 ꢁC. Lithium aluminium hydride (140 mg, 3.7 mmol)
was then added. The reaction mixture was allowed to
return to room temperature and stirred for a further 2 h.
Excess LAH was quenched with the addition of satu-
rated Na2SO4. The solution was filtered through a Celite
pad and the pad washed with hot EtOAc. The organic
solvent was then evaporated to afford product 6, which
was pure enough for the next step (847 mg, 90%). dH:
7.28 (d, J ¼ 8:7 Hz, 2H), 6.9 (d, J ¼ 8:7 Hz, 2H), 5.45
(m, 1H), 4.46 (s, 2H), 4.05 (d, J ¼ 7:2 Hz, 2H), 3.82 (s,
3H), 3.68 (t, J ¼ 7:0 Hz, 2H), 2.16 (t, J ¼ 7:0 Hz, 2H),
1.75 (m, 2H), 1.7 (s, 3H). dC: 159.3, 140.1, 130.8, 129.7,
121.4, 113.9, 71.9, 66.4, 62.8, 55.5, 36.0, 30.7, 16.6. Anal.
Calcd for C15H22O3: C, 71.97; H, 8.86. Found: C, 71.85;
H, 8.63.
Diethylmethylmalonate (1.4 g, 8 mmol) was taken in
DMF (20 mL) at 0 ꢁC at which point NaH (0.32 g,
8 mmol) was added. The solution was stirred at the same
temperature until hydrogen evolution ceased at which
point iodide 8 (2.9 g, 8.1 mmol) was added dropwise to
it. The reaction mixture was heated at 100 ꢁC for 2 h and
then cooled to room temperature at which point water
was added and extracted with ether. The organic layer
was washed with brine and dried over Na2SO4. Evapo-
ration and purification through flash chromatography
(9:1, hexane/EtOAc) yielded diester 9 (3.2 g, 95%). dH:
7.3 (d, J ¼ 8:7 Hz, 2H), 6.9 (d, J ¼ 8:7 Hz, 2H), 5.4 (m,
1H), 4.47 (s, 2H), 4.2 (q, J ¼ 7:0 Hz, 4H), 4.0 (d,
J ¼ 7:2 Hz, 2H), 3.8 (9s, 3H), 2.2 (t, J ¼ 7:0 Hz, 2H),
1.85 (m, 2H), 1.65 (s, 3H), 1.4 (s, 3H), 1.28 (t,
J ¼ 7:0 Hz, 6H). dC: 172.6, 159.3, 139.8, 129.6, 121.5,
113.9, 71.9, 66.4, 61.3, 55.4, 39.8, 35.2, 22.4, 20.1, 16.3,
14.2, 14.3. Anal. Calcd for C23H34O6: C, 67.96; H, 8.43.
Found: C, 67.88; H, 8.56.
4.5. (Z)-6-(4-Methoxy-benzyloxy)-4-methyl-hex-
4-en-1-ol
It was prepared from nerol–PMB ether as described in
Ref. 9 for benzyloxygeraniol. dH: 7.25 (d, J ¼ 8:7 Hz,
2H), 6.9 (d, J ¼ 8:7 Hz, 2H), 5.55 (m, 1H), 4.5 (s, 2H),
4.0 (d, J ¼ 7:4 Hz, 2H), 3.75 (s, 3H), 3.6 (t, J ¼ 7:0 Hz,
2H), 2.26 (t, J ¼ 7:0 Hz, 2H), 1.78 (s, 3H), 1.70 (m, 2H).
dC: 159.4, 141.9, 130.2, 129.8, 122.0, 114.2, 72.3, 65.6,
61.2, 55.4, 30.1, 27.8, 23.2.
4.9. 2-[(Z)-6-(4-Methoxy-benzyloxy)-4-methyl-hex-4-
enyl]-2-methyl-malonicacid diethyl ester
dH: 7.29 (d, J ¼ 8:7 Hz, 2H), 6.88 (d, J ¼ 8:7 Hz, 2H),
5.46 (m, 1H), 4.45 (s, 2H), 4.16 (q, J ¼ 7:0 Hz, 4H), 3.98
(d, J ¼ 7:4 Hz, 2H), 3.85 (s, 3H), 2.1 (t, J ¼ 7:0 Hz, 2H),
1.86 (m, 2H), 1.72 (s, 3H), 1.4 (s, 3H), 1.4 (s, 3H), 1.25 (t,
J ¼ 7:0 Hz, 6H). dC: 172.5, 159.3, 140.1, 130.7, 129.7,
122.5, 113.9, 70.4, 66.1, 61.3, 55.4, 35.3, 35.2, 23.4, 22.8,
20.1, 19.6, 14.2.
4.6. 1-((E)-6-Iodo-3-methyl-hex-2-enyloxymethyl)-4-
methoxy-benzene 8
Alcohol 6 (2.5 g, 10 mmol) was dissolved in 40 mL (3:1)
ether/CH3CN solution at 0 ꢁC. Imidazole (1.02 g,
15 mmol) was added, followed by I2 (3.8 g, 15 mmol),
and triphenyl phosphine (3.93 g, 15 mmol). The solution
was stirred at room temperature for an additional hour
after which it was filtered, the filtrate evaporated, and
the crude iodide was purified by flash chromatography
4.10. (E)-8-(4-Methoxy-benzyloxy)-2,6-dimethyl-oct-6-
enoic acid ethyl ester 7
A sample of 1.72 g (4.2 mmol) of 9 was taken in 20 mL
DMSO. NaCN (0.41 g, 8.4 mmol) was added followed
by water (0.75 mL, 4.2 mmol). The solution was heated
at 145 ꢁC for 6 h. After that time, water was added to it

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S. Nanda, A. I. Scott / Tetrahedron: Asymmetry 15 (2004) 963–970
and extracted with ether. The organic layer was dried
over Na2SO4 and evaporated. Purification by flash
chromatography (19:1, hexane/EtOAc) yielded ester 7 in
60% yield (0.84 g). dH: 7.3 (d, J ¼ 8:7 Hz, 2H), 6.92 (d,
J ¼ 8:7 Hz, 2H), 5.4 (m, 1H), 4.46 (s, 2H), 4.18 (q,
J ¼ 7:0 Hz, 2H), 4.0 (d, J ¼ 7:2 Hz, 2H), 3.86 (s, 3H),
2.45 (m, 1H), 2.08 (t, J ¼ 7:0 Hz, 2H), 1.68 (s, 3H), 1.4–
1.5 (m, 4H), 1.27 (t, J ¼ 7:0 Hz, 3H), 1.14 (d,
J ¼ 7:2 Hz, 3H). dC: 177.0, 159.3, 140.2, 130.8, 129.6,
121.2, 113.9, 71.9, 66.4, 60.3, 55.4, 39.6, 39.5, 33.5, 25.3,
17.3, 16.3, 14.4. Anal. Calcd for C20H30O4: C, 71.82; H,
9.04. Found: C, 71.66; H, 9.11%.
sealed, and the reaction mixture stirred for the time
listed in Table 1. Afterwards it was filtered and the
filtrate concentrated and purified by preparative TLC on
25
silica (3:1, hexane/EtOAc). ½aꢀ ¼ )3.1 (c 0.98, CHCl3);
D
dH: 7.3 (d, J ¼ 8:7 Hz, 2H), 6.88 (d, J ¼ 8:7 Hz, 2H),
5.40 (m, 1H), 4.46 (s, 2H), 4.05 (d, J ¼ 7:2 Hz, 2H), 3.9
(dd, J ¼ 7:4 Hz, 1.8 Hz, 2H), 3.82 (s, 3H), 2.1 (s, 3H),
2.05 (t, J ¼ 7:0 Hz, 2H), 1.67 (s, 3H), 1.5–1.3 (m, 4H),
1.15 (m, 1H), 0.96 (d, J ¼ 7:0 Hz, 3H). dC: 171.5, 159.3,
140.3, 130.8, 129.6, 121.1, 113.9, 71.9, 69.5, 66.4, 55.4,
39.8, 33.1, 32.6, 25.0, 21.8, 17.0, 16.5. Anal. Calcd
for C20H30O4: C, 71.82; H, 9.04. Found: C, 71.71; H,
8.97.
4.11. (Z)-8-(4-Methoxy-benzyloxy)-2, 6-dimethyl-oct-
6-enoic acid ethyl ester
4.15. Acetic acid (Z)-(S)-8-(4-methoxy-benzyloxy)-2,6-
dimethyl-oct-6-enyl ester
dH: 7.28 (d, J ¼ 8:7 Hz, 2H), 6.9 (d, J ¼ 8:7 Hz, 2H),
5.42 (m, 1H), 4.43 (s, 2H), 4.16 (q, J ¼ 7:0 Hz, 2H), 3.96
(d, J ¼ 7:4 Hz, 2H), 3.82 (s, 3H), 2.46 (m, 1H), 2.06 (t,
J ¼ 7:0 Hz, 2H), 1.72 (s, 3H), 1.35–1.55 (m, 4H), 1.28 (t,
J ¼ 7:0 Hz, 3H), 1.15 (d, J ¼ 7:0 Hz, 3H). dC: 176.9,
159.3, 140.6, 130.8, 129.6, 122.1, 113.8, 71.9, 66.1, 60.4,
55.4, 39.6, 33.7, 32.0, 25.8, 23.5, 17.3, 14.4.
dH: 7.28 (d, J ¼ 8:7 Hz, 2H), 6.9 (d, J ¼ 8:7 Hz, 2H), 5.5
(m, 1H), 4.48 (s, 2H), 4.1 (d, J ¼ 7:2 Hz, 2H), 3.95 (dd,
J ¼ 7:4 Hz, 1.8 Hz, 1H), 3.88 (dd, J ¼ 7:4 Hz, 1.8 Hz,
1H), 3.85 (s, 3H), 2.06 (s, 3H), 2.0 (t, J ¼ 7:0 Hz, 2H),
1.8 (m, 1H), 1.75 (s, 3H), 1.5–1.3 (m, 3H), 1.16 (m, 1H),
0.94 (d, J ¼ 7:0 Hz, 3H). dC: 172.5, 159.3, 141.2, 130.8,
129.7, 122.4, 114.0, 72.0, 69.5, 66.6, 55.8, 39.7, 33.4,
32.7, 25.0, 21.8, 17.6, 16.8.
4.12. (E)-8-(4-Methoxy-benzyloxy)-2,6-dimethyl-oct-
6-en-1-ol 10
4.16. 3,5-Dioxo-hexanoic acid (E)-(S)-8-(4-methoxy-
benzyloxy)-2,6-dimethyl-oct-6-enyl ester
LAH reduction of ester 9 as described above furnished
alcohol 10 in 90% yield. dH: 7.32 (d, J ¼ 8:7 Hz, 2H),
6.91 (d, J ¼ 8:7 Hz, 2H), 5.4 (m, 1H), 4.45 (s, 2H), 4.04
(d, J ¼ 7:2 Hz, 2H), 3.85 (s, 3H), 3.5 (dd, J ¼ 7:4 Hz,
1.8 Hz, 2H), 2.04 (m, 2H), 1.68 (s, 3H), 1.55–1.4 (m, 4H),
1.1 (m, 1H), 0.92 (d, J ¼ 7:0 Hz, 3H). dC: 159.3, 140.6,
130.8, 129.6, 121.0, 113.9, 71.9, 68.5, 66.4, 55.4, 39.9,
35.8, 32.9, 25.1, 16.7, 16.6. Anal. Calcd for C18H28O3: C,
73.93; H, 9.65. Found: C, 73.77; H, 9.42%.
Alcohol (50 mg, 0.17 mmol), lipase (CAL-B, 60 mg), and
acylating agent (3,5-dioxomethylhexanoate, 100 mg)
were put into a small round bottomed flask. The flask
was put into a rotary evaporator (room temperature,
10 Torr) under argon atmosphere. After the reaction
time, DCM was added to it, and filtered with the filtrate
then concentrated. The product ester and the unreacted
(R) alcohol were separated by preparative TLC on silica
(4:1, hexane/EtOAc). dH: 7.3 (d, J ¼ 8:7 Hz, 2H), 6.92
(d, J ¼ 8:7 Hz, 2H), 5.62 (s, 1H), 5.4 (m, 1H), 4.44
(s, 2H), 4.1 (d, J ¼ 7:2 Hz, 2H), 3.98 (m, 2H), 3.82 (s,
3H), 3.35 (s, 2H), 2.1 (s, 3H), 2.06 (t, J ¼ 7:0 Hz, 2H),
1.64 (s, 3H), 1.5–1.35 (m, 4H), 1.18 (m, 1H), 0.96 (d,
J ¼ 7:0 Hz, 3H). dC: 190.3, 187.4, 167.9, 159.3, 140.3,
130.7, 129.6, 121.1, 113.9, 100.7, 71.9, 70.4, 66.4, 55.4,
45.3, 39.8, 33.0, 32.5, 24.9, 24.6, 16.9, 16.6. Anal. Calcd
for C24H34O6: C, 68.88; H, 8.19. Found: C, 68.76; H,
8.13.
4.13. (Z)-8-(4-Methoxy-benzyloxy)-2,6-dimethyl-oct-
6-en-1-ol
dH: 7.34 (d, J ¼ 8:7 Hz, 2H), 6.94 (d, J ¼ 8:7 Hz, 2H),
5.46 (m, 1H), 4.46 (m, 1H), 4.0 (d, J ¼ 7:2 Hz, 2H), 3.85
(s, 3H), 3.45 (dd, J ¼ 7:4 Hz, 1.8 Hz, 2H), 2.08 (t,
J ¼ 7:0 Hz, 2H), 1.8 (s, 3H), 1.6–1.4 (m, 1H), 1.1 (m,
1H), 0.92 (d, J ¼ 7:0 Hz, 3H). dC: 159.4, 141.1, 130.8,
129.6, 121.8, 113.9, 72.0, 68.4, 66.1, 55.5, 35.7, 32.9,
32.3, 25.5, 23.6, 16.7.
4.17. 3,5-Dioxo-hexanoic acid (Z)-(S)-8-(4-methoxy-
benzyloxy)-2,6-dimethyl-oct-6-enyl ester
4.14. Acetic acid (E)-(S)-8-(4-methoxy-benzyloxy)-2,6-
dimethyl-oct-6-enyl ester
dH: 7.32 (d, J ¼ 8:7 Hz, 2H), 6.91 (d, J ¼ 8:7 Hz, 2H),
5.68 (s, 1H), 5.45 (m, 1H), 4.45 (s, 2H), 4.05 (dd,
J ¼ 7:4 Hz, 1.8 Hz, 1H), 4.0 (d, J ¼ 7:2 Hz, 2H), 3.9 (dd,
J ¼ 7:4 Hz, 1.8 Hz, 1H), 3.8 (s, 3H), 3.35 (s, 2H), 2.1 (s,
3H), 2.04 (t, J ¼ 7:0 Hz, 2H), 1.75 (s, 3H), 1.5–1.3 (m,
4H), 1.15 (m, 1H), 0.95 (d, J ¼ 7:0 Hz, 2H). dC: 190.3,
187.4, 167.8, 159.3, 140.8, 130.8, 129.6, 122.0, 114.1,
100.7, 71.9, 70.4, 67.2, 55.4, 45.3, 33.1, 32.5, 32.3, 31.0,
25.4, 24.5, 16.9.
Commercially available anhydrous tert-butylmethyl
ether 5 mL was taken and 0.1% of water added. After
vigorous stirring at room temperature for 30 min the
mixture was allowed to settle. The upper layer (3 mL)
was placed in a resealable sample vial, to which (E)-
alcohol (50 mg, 0.17 mmol), acylating agent (vinyl ace-
tate/isopropenyl acetate/ethyl acetate, 0.35 mmol), and
lipase (60 mg) were successively added. The vial was

S. Nanda, A. I. Scott / Tetrahedron: Asymmetry 15 (2004) 963–970
969
4.18. Release of (S)-alcohols from (S)-esters
3H), 1.49 (m, 1H), 1.23 (d, J ¼ 7:0 Hz, 3H). dC: 191.6,
182.8, 128.9, 115.3, 43.6, 39.3, 32.9, 30.1, 21.5, 17.1.
Anal. Calcd for C10H16O4: C, 59.98; H, 8.05. Found: C,
59.85; H, 8.19.
Method A: Esters were taken in MeOH followed by the
addition of solid K2CO3 (1.5 equiv). The solution was
stirred at room temperature for 1 h. The solution was
filtered and the filtrate evaporated. Water was added to
the residue and extracted with DCM. The final product
was purified by preparative TLC on silica (3:1, hexane/
EtOAc).
4.22. (R)-(E)-Callosobruchusic acid
25
D
CHCl3)}.
20
D
½aꢀ ¼ )10.5 (c 4.2, CHCl3) {lit.2b ½aꢀ ¼ )10.9 (c 7.6,
Method B: Reduction with powdered LAH in ether as
described previously yielded the (S)-alcohol.
4.23. (S)-(Z)-Callosobruchusic acid
25
D
½aꢀ ¼ +11.2 (c 1.5, CHCl3). dH: 5.75 (br s, 1H), 2.55 (m,
4.19. (R)- and (S)-(E)-1 and (Z)-1
1H), 2.25 (t, J ¼ 7:0 Hz, 2H), 2.18 (d, J ¼ 1:2 Hz, 3H),
1.75–1.5 (m, 3H), 1.48 (m, 1H), 1.23 (d, J ¼ 7:0 Hz, 3H).
dC: 191.7, 183.0, 128.8, 115.4, 43.6, 39.3, 32.9, 30.1, 21.4,
17.0.
(R)- and (S)-11 and 12 (100 mg, 0.34 mmol) were taken
in 10 mL DCM/H2O (19:1). DDQ (116 mg, 0.52 mmol)
was added to it and the reaction mixture stirred for 1 h
at room temperature. Afterwards it was filtered, the
filtrate washed with 5% NaHCO3, brine, and dried over
Na2SO4. Evaporation and purification by flash chro-
matography (1:1, hexane/EtOAc) yielded the diols in
75% yield.
4.24. (R)-(Z)-Callosobruchusic acid
25
D
CHCl3)}.
20
D
½aꢀ ¼ )11.5 (c 2.0, CHCl3) {lit.2b ½aꢀ ¼ )11.0 (c 2.0,
25
D
(S)-(E)-1, ½aꢀ ¼ )6.1 (c 3.0, CHCl3). dH: 5.38 (m, 1H),
4.14 (d, J ¼ 7:4 Hz, 2H), 3.45 (m, 2H), 2.0 (t,
J ¼ 7:0 Hz, 2H), 1.68 (s, 3H), 1.65–1.4 (m, 4H), 1.1 (m,
1H), 0.9 (d, J ¼ 7:0 Hz, 3H). dC: 139.6, 123.6, 68.3, 59.3,
39.7, 35.7, 32.6, 24.9, 16.6, 16.2. Anal. Calcd for
C10H20O2: C, 69.72; H, 11.70. Found: C, 69.56; H, 11.57.
Acknowledgements
We thank the Robert. A. Welch Foundation and the
Texas Advanced Technology & Research Program for
financial support.
25
20
(R)-(E)-1, ½aꢀ ¼ +6.7 (c 2.8, CHCl3) {lit.2b ½aꢀ ¼ +6.9
D
D
25
D
(c 3.9, CHCl3)}. (S)-(Z)-1, ½aꢀ ¼ )7.8 (c 2.0, CHCl3) dH:
5.46 (m, 1H), 4.18 (m, 2H), 3.45 (d, J ¼ 7:0 Hz, 2H), 2.1
(m, 2H), 1.8 (s, 3H), 1.7–1.4 (m, 4H), 1.1 (m, 1H), 0.94
(d, J ¼ 7:0 Hz, 3H). dC: 140.2, 124.4, 68.4, 59.1, 35.5,
References and notes
25
32.6, 31.8, 25.2, 23.5, 16.6. (R)-(Z)-1, ½aꢀ ¼ +8.0 (c 1.8,
D
20
D
1. Meinwald, J.; Thompson, W. R.; Eisner, T.; Owen, D. F.
Tetrahedron Lett. 1971, 12, 3485.
CHCl3) {lit.2b ½aꢀ ¼ +8.1 (c 1.6, CHCl3)}.
2. (a) Tanaka, K.; Ohsawa, K.; Honda, H.; Yamamoto, I. J.
Pesticide Sci. 1981, 6, 75; (b) Mori, K.; Ito, T.; Tanaka,
K.; Honda, H.; Yamamoto, I. Tetrahedron 1983, 39, 2303;
(c) Giersch, W.; Schulte-Elte, K. H. Helv. Chim. Acta
1990, 73(3), 733; (d) Gramatica, P.; Giardina, G.; Sper-
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3. Takabe, K.; Mase, N.; Hashimoto, H.; Tsuchiya, A.;
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4. (a) Huang, Q.; Roesner, C. A.; Croteau, R.; Scott, A. I.
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Q.; Wildung, M. R.; Croteau, R.; Scott, A. I. Protein
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A. I. Tetrahedron Lett. 1998, 39, 2033.
4.20. Jones’ oxidation of diols for the synthesis of
2 and 2a
Jonesꢀ reagent was prepared as follows: CrO3 (1.65 g,
0.017 mol) was dissolved in water (2.5 mL). The solution
was cooled at 0 ꢁC and then concentrated H2SO4
(1.45 mL) was added. The water was added up to 7 mL.
Diols (86 mg, 0.5 mmol) were dissolved in 10 mL of
acetone at 0 ꢁC, and freshly prepared Jonesꢀ reagent was
added to it until the orange brown color persisted. The
mixture was stirred at room temperature for 30 min.
After that time, water (10 mL) was added to it and
extracted with ethyl acetate (3 · 10 mL). The organic
layer was dried over Na2SO4. Evaporation and purifi-
cation by flash chromatography yielded 80 mg of the
diacid as a white solid (80% yield).
5. Kuwajima, I.; Doi, Y. Tetrahedron Lett. 1972, 13, 1163.
6. Garegg, P. J.; Samuelson, B. J. Chem. Soc., Perkin. Trans.
1 1980, 2866.
7. Soo Lee, H.; Kim, D. H. Biorg. Med. Chem. 2003, 11,
4685.
8. Deslongchamps, P.; Lamothe, S.; Lin, Ho-shen Can. J.
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9. Chen, Kau-Ming; Semple, J. E.; Joullie, M. M. J. Org.
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4.21. (S)-(E)-Callosobruchusic acid
10. Nanda, S.; Scott, A. I. Unpublished result.
11. Bornscheuer, U. T.; Kazlauskas, R. J. Hydrolases in
Organic Synthesis (Regio- and Stereoselective Biotransfor-
mations); Wiley-VCH: Weinheim, 1999, p 88.
25
D
20
D
½aꢀ ¼ +10.1 (c 0.9, CHCl3) {lit.2b ½aꢀ ¼ +10.5 (c 1.0,
CHCl3)}. dH: 5.7 (br s, 1H), 2.5 (m, 1H), 2.26 (t,
J ¼ 7:0 Hz, 2H), 2.2 (d, J ¼ 1:2 Hz, 3H), 1.8–1.55 (m,

970
S. Nanda, A. I. Scott / Tetrahedron: Asymmetry 15 (2004) 963–970
12. (a) Heumann, A.; Faure, R. J. Org. Chem. 1993, 58, 1276;
(b) Heumann, A.; Loutfi, A.; Ortiz, B. Tetrahedron:
Asymmetry 1995, 6, 1073; (c) Yadav, J. S.; Nanda, S.
Tetrahedron: Asymmetry 2001, 12, 3223.
14. Wennerberg, J.; Olofsson, C.; Frejd, T. J. Org. Chem.
1998, 63, 3595.
15. Hashimoto, M.; Matsumoto, M.; Terashima, S. Tetrahe-
dron 2003, 59, 3019.
13. Horita, K.; Tanaka, T.; Olikawa, Y.; Yonemitsu, O.
Tetrahedron 1986, 42, 3021.
16. Chen, C. S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am.
Chem. Soc. 1982, 104, 7294.