Studies directed towards the total synthesis of koshikalide: Stereoselective synthesis of the macrocyclic core

Article abstract of DOI:10.1016/j.tetasy.2013.07.002

The stereoselective synthesis of the macrolactone core of the natural product koshikalide is described. Starting with readily available 1,4-butanediol and malic acid as synthons, our synthetic strategy involved the reiterative application of Gilman's reaction, Swern oxidation and Sharpless asymmetric epoxidation to establish the required stereocentres. Other key steps in the synthesis include Negishi cross coupling and Horner-Wadsworth-Emmons (HWE) reactions for construction of the main fragments. The 14-membered lactone ring was prepared by a selective Mitsunobu macrolactonization approach.

Full text of DOI:10.1016/j.tetasy.2013.07.002

Tetrahedron: Asymmetry 24 (2013) 1010–1022
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Studies directed towards the total synthesis of koshikalide:
stereoselective synthesis of the macrocyclic core
⇑
Arramshetti Venkanna, Eppakayala Sreedhar, Bandi Siva, Katragadda Suresh Babu ,
Kothakonda Rajendra Prasad, Janaswamy Madhusudana Rao
⇑
Division of Natural Product Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The stereoselective synthesis of the macrolactone core of the natural product koshikalide is described.
Starting with readily available 1,4-butanediol and malic acid as synthons, our synthetic strategy involved
the reiterative application of Gilman’s reaction, Swern oxidation and Sharpless asymmetric epoxidation
to establish the required stereocentres. Other key steps in the synthesis include Negishi cross coupling
and Horner–Wadsworth–Emmons (HWE) reactions for construction of the main fragments. The 14-mem-
bered lactone ring was prepared by a selective Mitsunobu macrolactonization approach.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 10 June 2013
Accepted 3 July 2013
Available online 10 August 2013
1. Introduction
Strategically, the most challenging problem is the construction
of the lactone ring system as well as the structural moiety possess-
Marine cyanobacterium has been recognized as an important
source of pharmacologically unique bioactive natural products
with novel architectures and functionalities. Recently, Iwasaki
et al. reported the isolation of a novel macrolide kloshikalide 1,1a
from the marine cyanobacterium Lyngbya sp. The gross structure
and relative stereochemistry were determined by extensive NMR
studies, which clearly indicated that koshikalide 1 is a 14-mem-
bered macrolide containing two unusually Z-configured disubsti-
tuted olefins with methyl groups at the C3 and C6 positions.
Koshikalide 1 was found to be weakly cytotoxic against HeLaS3
ing the asymmetric centres bearing a methoxy group and cis-ori-
ented methyl groups. Our group has recently reported on the
facile construction of functionalized lactone rings in the total syn-
thesis of macrolides.1b–d In continuation of our focus on the syn-
thesis of bioactive macrolides, we herein report our approach
towards the stereoselective construction of the macrolactone core
segment of koshikalide 1.
2. Results and discussion
cells, with an IC50 value of 42 lg/mL. To date, no total synthesis
The retrosynthetic analysis of 1 is outlined in Scheme 1. As indi-
cated, our initial disconnections of the target molecule involved a
cleavage of the double bond at C9–C10 as well as the ester linkage
to give 3 and 4. The requisite olefin fragment 3, could, in turn be
of this compound has been reported. The presence of two stereo-
genic centres and a network of diverse and distributed functional-
ities on its novel framework, together with its potential bioactivity,
make koshikalide 1 a challenging and attractive synthetic objective
(see Fig. 1).
accessed from L-malic acid 5 through Wittig and Sharpless asym-
metric reactions to install the required stereochemistry and open-
ing of the epoxide with Zn in ethanol under refluxing conditions.
On the other hand, the acid fragment 4 could be prepared through
Cu mediated cross coupling between 6 and 7. Fragment 6 could be
elaborated by starting from readily available 1,4-butane diol 8 by
selective functional group manipulations.
OH
O
13
1
OMe
11
O
3
9
2.1. Synthesis of fragment 3
5
The preparation of fragment 3 was straightforward and accom-
plished from readily available
L
-malic acid 5. As shown in Scheme 2,
Figure 1. Structure of koshikalide 1.
the trihydroxy derivative of
L
-malic acid 92 was converted into the
corresponding acetonide 10,3 followed by Swern oxidation4
and then Wittig olefination of the resulting aldehyde with
Ph3P@CHCO2Et to furnish the unsaturated ester 115 in 92% overall
⇑
Corresponding authors. Tel.: +91 40 27191881; fax: +91 40 27160512.
E-mail addresses: suresh@iict.res.in, sureshiict@yahoo.co.uk (K.S. Babu).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.07.002

A. Venkanna et al. / Tetrahedron: Asymmetry 24 (2013) 1010–1022
1011
OH
OMe
OH
L-malic acid
OTBS
TBSO
O
5
O
3
OMe
O
X
OMe
+
O
O
O
EtO
+
PMBO
HO
OEt
7
6
X=Cl, Br
1
2
4
OH
8
Scheme 1. Retrosynthetic analysis of koshikalide 1.
O
O
O
a
c
b
d
O
O
9
O
CO2Me
OH
OH
12
10
11
O
O
e
O
OH
g
f
O
O
OMe
O
O
OH
O
I
O
13
O
14
15
16
HO
OMe
h
i
OH
OMe
HO
TBSO
17
3
Scheme 2. Reagents and conditions: (a) 2,2 DMP, PTSA, dry DCM, 0 °C–rt, 4 h, 98%; (b) (i) (COCl)2, dimethyl sulfoxide (DMSO), Et3N, CH2Cl2, –78 °C, 1 h; (ii) Ph3P@CHCO2Et,
C6H6, 0 °C–rt, 12 h, 91% for two steps; (c) diisobutylaluminum hydride (DIBAL-H), CH2Cl2, –15 °C, 30 min, 95%; (d) Ti(OiPr)4, (ꢀ)-DET, 4 Å MS and t-BuOOH, dry DCM, –20 °C,
12 h, 96%; (e) TPP, I2, imidazole, dry DCM, 0 °C–rt, 4 h, 96%; (f) Zn, NaI, MeOH, reflux, 8 h, 96%; (g) NaH, MeI, Dry THF, 0 °C–rt, 2 h, 98%; (h) (ꢀ)-camphor-10-sulfonic acid (CSA),
MeOH, 0 °C–rt, 4 h, 94%; (i) TBSCl, imidazole, dry DCM, 0 °C–rt, 92%.
yield (three steps). Reduction of ester 11 with DIBAL-H in dichloro-
methane at ꢀ15 °C furnished the allylic alcohol 12,6 which was
then subjected to a Sharpless asymmetric epoxidation7 reaction
with Ti(OiPr)4, (ꢀ)-DET and t-BuOOH to obtain the (R,R)-epoxy
alcohol 13 in 96% yield with excellent 97% de (determined by chiral
HPLC). The primary hydroxyl group present in 13 was converted
into its corresponding iodide with TPP and I2 to give 148 in 89%
yield. The opening of the epoxide ring of 14 with Zn in ethanol un-
der refluxing conditions yielded the secondary allylic alcohol 15,9
and subsequent methylation using MeI/NaH10 afforded 16 in 98%
yield. Finally, removal of the acetonide protecting group with
(ꢀ)-camphor-10-sulfonic acid,11 and selective protection of the
resulting diol furnished the required product 312 in 92% yield.
using Me2CuLi to afford 2416 in 96% yield. Deprotection of the PMB
ether20 with DDQ, followed by Dess–Martin oxidation, gave alde-
hyde 2521 in 98% yield.
At this stage, we planned for a Wittig olefination reaction22 with
Ph3P+CH3Iꢀ under basic conditions to afford fragment 4. However,
the reaction yielded the rearranged product 26, in which the dou-
ble bond was isomerized from C2–C3 to C3–C4. Several tactical
operations on 25 using C1-Wittig reagents under various basic con-
ditions failed to give the desired product 4 and led to the formation
of the isomerized product 26 in 82% yield.
2.3. Synthesis of the seco acid
Originally, we planned to prepare 1 by esterification of 3 and 4,
followed by elaboration of the resulting product according to the
established route via RCM (Scheme 1). Despite considerable exper-
imentation, compound 4 was not obtained due to isomerization of
the Z-double bond. In view of these discouraging results, we
decided to revise our synthetic approach to prepare the basic mac-
rocyclic framework by elaborating aldehyde 25 into seco-acid 32
and then making the target compound (Scheme 4). To this end,
aldehyde 25 was subjected to a Horner–Wadsworth–Emmons
(HWE) reaction with a b-ketophosponate23 using Ba(OH)2ꢁ8H2O,
THF/H2O (40:1) to afford 2724 in 86% yield. Subsequent Corey–Bak-
shi–Shibata (CBS) reduction of 2725 gave the secondary alcohol in
85% yield with excellent diastereoselectivity (dr >96:4, determined
by chiral HPLC). The resultant alcohol was O-methylated using
methyl triflate and a proton sponge to afford 28 in 98% yield.26
Methylation under basic conditions such as NaH/MeI yielded the
double bond isomerization product. Deprotection of the acetonide
group27 in 28 with CSA in methanol, followed by selective
protection of the primary alcohol with TrCl gave 2928 in 94% yield.
2.2. Synthesis of the C1–C10 fragment 4
The synthesis of 4 started from the readily available 1,4-butane-
diol 8 (Scheme 3), which was selectively protected as a PMB ether
using PMBBr, NaH and a catalytic amount of TBAI in dry DMF to af-
ford 1813 in 89% yield. The resultant alcohol 18 was oxidized under
Swern conditions to give aldehyde 19.4 Next, the Corey–Fuchs
reaction of aldehyde 19 yielded the dibromo olefin compound
2014 in 82% yield, which was then treated with n-BuLi and ethyl-
chloroformate at ꢀ78 °C to give ester 21.15 The required (Z)-geom-
etry of the allylic bromide 6 was achieved by the conjugate
addition of Me2CuLi to hexynoate 21, which exclusively gave the
(Z)-hexenoate 2216 in 96% yield. Subsequent reduction with DI-
BAL-H17 followed by bromination using Corey’s procedure afforded
the desired bromide 618 in 86% yield (overall yield 92% over two
steps). Bromide 6 was treated with ethyl propiolate 7 by using a
CuI-mediated cross-coupling reaction to give the coupled product
2319 in 89% yield, which was again subjected to Gillman’s reaction

1012
A. Venkanna et al. / Tetrahedron: Asymmetry 24 (2013) 1010–1022
a
O
c
OH
b
OH
PMBO
HO
PMBO
19
H
8
18
O
OEt
Br
f
e
d
PMBO
OEt
PMBO
Br
21
PMBO
20
22
O
O
OEt
EtO
X
O
h
g
PMBO
PMBO
PMBO
6
24
23
X = Cl, Br
O
EtO
O
EtO
26
i
j
isomerized product
O
H
O
EtO
25
x
4
expected product
Scheme 3. Reagents and conditions: (a) PMBBr, NaH, TBAI, dry DMF, 0 °C–rt, 12 h, 89%; (b) (COCl)2, dimethyl sulfoxide (DMSO), Et3N, CH2Cl2, ꢀ78 °C, 1 h; (c) CBr4, TPP,
CH2Cl2, ꢀ15 °C–rt, 1 h, 82%; (d) n-BuLi, ethyl chloroformate, dry THF, 2 h, ꢀ78 °C–rt, 92%; (e) CuI, MeLi, dry THF, pH 7 buffer, ꢀ78 °C, 30 min, 96%; (f) (i) diisobutylaluminum
hydride (DIBAL-H), CH2Cl2, –15 °C, 30 min, 95%; (ii) LiX (X = Cl, Br), s-collidine, methanesulfonyl chloride, dry DMF, 0 °C, 2 h, 86%; (g) 7, CuI, NaI, K2CO3, N,N-
dimethylformamide (dry DMF), rt, 4 h, 89%; (h) CuI, MeLi, dry THF, pH 7 buffer, ꢀ78 °C, 30 min, 96%; (i) (i) DDQ, pH 7 buffer, DCM, 0 °C–rt, 1 h, 89%; ii. DMP, NaHCO3, 0 °C–rt,
98%; (j) t-BuOꢀK+, Ph3P+CH3Iꢀ, dry THF, ꢀ15 °C–rt, 2 h, 82%.
O
O
EtO
EtO
O
OMe
a
O
O
b
25
O
O
28
O
27
HO
OMe
OH
TrO
O
30a
isomerized product
EtO
OH
OMe
d
c
O
TrO
HO
29
OH
OMe
X
TrO
e
30
expected product
O
HO
HO
OR
OMe
OH
OMe
f
TrO
TrO
31
R = TES
32
Scheme 4. Reagents and conditions: (a) Ba(OH)2ꢁ8H2O, THF/H2O (40:1), 89%; (b) (i) (S)-CBS, BH3ꢁDMS, dry THF, –78 °C–rt, 2 h, 85%; (ii) Me3OBF4/proton sponge, dry DCM,
30 min, 98%; (c) (i) (ꢀ)-camphor-10-sulfonic acid (CSA), MeOH, 0 °C–rt, 4 h, 92%; (ii) TrCl, pyridine, dry DCM, 0 °C–rt, 4 h, 89%; (d) LiOH, THF/MeOH/H2O (2:2:1), 2 h, 98%; (e)
(i) TESCl, imidazole, dry DCM, 0 °C–rt, 92%; (ii) diisobutylaluminum hydride (DIBAL-H), CH2Cl2, ꢀ15 °C, 30 min, 93%; (f) (i) DMP, NaHCO3, 0 °C–rt, 1 h, 98%; (ii) 2-methyl-2-
butane(M2B), NaClO2, tert-butanol/H2O, 89%; (iii) TBAF, 0 °C–rt, 2 h, 89%.

A. Venkanna et al. / Tetrahedron: Asymmetry 24 (2013) 1010–1022
1013
Saponification29 of 29 using standard protocols, KOH/THF/MeOH,
LiOH, etc., again led to the formation of isomerized product 30a, in-
stead of the expected compound 30. Several efforts to saponify 29
were found to be unsuccessful even with mild methods and in all
cases, the scrambled double bond product 30a was observed as a
major product (Scheme 4).
In order to overcome this hurdle, a five-step reaction sequence
consisting of a protection and reduction/oxidation strategy was
employed. Thus, the secondary hydroxyl group in 29 was protected
as a TES30 group and reduction with DIBAL-H yielded 31 in 93%
yield. Sequential oxidations30a in 31 (Dess–Martin and Pinnick oxi-
dation) followed by the removal of the TES group with TBAF31 led
to the required seco-acid 32 in 89% yield.
with 98% yield. This was then selectively mono reduced with BH3-
ꢁDMS and NaBH4(cat) in dry THF to give 34 in 89% yield, followed
by mono protection of 34 with n-Bu2SnO, PMBCl in toluene to af-
ford 35 in 80% yield (Scheme 6).
With compound 6 in hand, we designed our synthetic opera-
tions in a step wise fashion to implement the Mitsunobu macrol-
actonization. Thus, fragment 6 was subjected to Negishi cross
coupling reaction34 with (Z)-(4-((tetrahydro-2H-pyran-2-yl)zin-
c(II) bromide34 in the presence of 2.5 mol % of [Pd2(dba3)] and
tri-2-furylphosphine (10 mol %) to give 37 (P98% pure) in 82%
yield (the cis-orientation of the double bond was determined by
NOESY experiments). Deprotection of the PMB group in 37 fol-
lowed by DMP oxidation provided the aldehyde in quantitative
yield, which was further elaborated through Horner–Wads-
worth–Emmons (HWE)24 homologation with b-ketophosponate
3633 to give 38 in 92% yield. Removal of the THP35 deprotection
in 38 followed by Dess–Martin oxidation led to an aldehyde, which
was then transformed into the carboxylic acid 39 using standard
Pinnick oxidation conditions.30 Deprotection of the TBDPS group
in 39 with TBAF furnished the required seco-acid 40 in 89% yield.36
Finally, lactonization of this seco-acid 40 under Mitsunobu condi-
tions37 (DIAD, PPh3, degassed PhH) yielded the core lactone moiety
41 in 56% yield (Scheme 7). The stereostructure of 41 was deter-
mined on the basis of a thorough analysis of its spectroscopic char-
acteristics, particularly the COSY and NOE data (in the NOESY
spectra, correlations between Me-3/H-2 and Me-6/H-5 were ob-
served). All of the intermediate products were also well character-
ized using the NMR and mass spectra techniques.
2.4. Synthesis of the lactone core
Having successfully accomplished the synthesis of seco-acid
fragment 32 with the required stereocentres, we next focused
our attention on obtaining the lactone core. The seco-acid 32 was
subjected to Yamaguchi macrolactonization32 using 2,4,6-trichlo-
robenzoyl chloride, Et3N, and DMAP in toluene to afford the de-
sired macrolactone 33. However, the reaction yielded the double
bond scrambled product 33a, instead of required 33 and again
turned out to be another failure due to the isomerization of the
Z-double bond from C2–C3 to (E)-C3–C4. This isomerization was
attributed to the deprotonation of the active methylene between
the two unstable, strained Z-double bonds (Scheme 5).
At this point, we decided to investigate nonbasic macrolacton-
ization using Mitsunobu reaction. In order to obtain the correct
stereochemistry at C-13 after the Mitsunobu reaction, the corre-
sponding b-ketophosphonate fragment 3633 was prepared from
3. Conclusion
By utilizing high yielding chemical transformations, we have
developed a stereoselective and convergent approach towards
commercially available D-malic acid (Scheme 6), which was then
converted into the corresponding diester with BF3ꢁEt2O, MeOH
OTr
O
OMe
O
O
HO
a
33a
OH
OMe
TrO
isomerized product
OTr
32
O
OMe
O
X
33
expected product
Scheme 5. Reagents and conditions: (a) 2,4,6-Trichlorobenzoyl chloride, Et3N, DMAP, dry toluene, 60 °C, 12 h, 58%.
OH
O
O
P
OH
O
OH
O
c
a
b
PMBO
D-malic acid
PMBO
HO
O
O
O
O
36
R=TBDPS
34
35
Scheme 6. Reagents and conditions: (a) (i) BF3ꢁEt2O, MeOH 0 °C–rt, 12 h, 98%; (ii) BH3ꢁDMS, NaBH4 (cat) dry THF 89%; (b) n-Bu2SnO, PMBCl, toluene 110 °C, 12 h, 80%; (c) (i)
TBDPSCl, imidazole, dry DMF 0 °C–rt, 6 h, 96%; (ii) n-BuLi, dimethylphosphonate, dry THF, ꢀ78 °C, 1.5 h, 75%.

1014
A. Venkanna et al. / Tetrahedron: Asymmetry 24 (2013) 1010–1022
H
THPO
OTHP
BrZn
THPO
X
OR
O
a
36, b
PMBO
PMBO
PMBO
H
6
37
38
R=TBDPS
X=Cl, Br
O
HO
OPMB
O
OR
O
c
e
O
PMBO
O
39 R=TBDPS
40 R=H
d
41
Scheme 7. Reagents and conditions: (a) [Pd2(dba3)], tri-2-furylphosphine (TFP), dry DMF, 0 °C–rt, 1 h, 82%; (b) (i) DDQ, pH 7 buffer, DCM, 0 °C–rt, 1 h, 87%; (ii) DMP, NaHCO3,
0 °C–rt, 1 h, 98%; (iii) 36, Ba(OH)2ꢁ8H2O, THF/H2O (40:1), 4 h, 92%; (c) (i) (ꢀ)-camphor-10-sulfonic acid (CSA), MeOH, 0 °C–rt, 4 h, 92%; (ii) DMP, NaHCO3, 0 °C–rt, 1 h, 98%; (iii)
2-methyl-2-butane, NaClO2, tert-butanol/H2O, 89%; (d) TBAF, THF, 0 °C–rt, 6 h, 89%; (e) PPh3, DIAD, Dry THF, 0 °C–rt, 12 h, 56%.
the synthesis of the macrolactone segment of koshikalide, a cyto-
toxic macrolide. Initial retrosynthetic analysis on 1 identified two
key fragments 3 and 4; while the former was assembled relatively
easily, the latter presented considerable problems due to the
migratory aptitude of the double bond, which necessitated a devi-
ation for our model study. The preparation of the koshikalide core
serves a dual purpose of providing an advanced intermediate to-
wards the synthesis of koshikalide and an entry into an array of
washed with brine and dried over anhydrous Na2SO4. Removal of
the solvent gave a crude product, which was purified by column
chromatography (2% MeOH in chloroform) to afford 10 (2.699 g,
98%) as a colourless oil. ½a D25
ꢂ
¼ ꢀ1:6 (c 1.5, MeOH). 1H NMR
(300 MHz, CDCl3): d = 4.32–4.19 (m, 1H), 4.08–4.01 (m, 1H), 3.76
(t, J = 6.9 Hz, 2H), 3.55 (t, J = 7.5 Hz, 1H), 1.82–1.75 (m, 2H), 1.40
(s, 3H), 1.34 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3): d = 108.9,
74.8, 69.3, 60.2, 35.5, 26.7, 25.5 ppm. ESI-MS: m/z = 169 [M+Na]+.
analogues through the attachment of various side chains at C14
.
4.3. (S,E)-Methyl 4-(2,2-dimethyl-1,3-dioxolan-4-yl)but-2-enoate
11
4. Experimental
4.1. General
Under an inert atmosphere at ꢀ78 °C, DMSO (4.3 mL,
61.6 mmol) was added dropwise to a solution of oxalyl chloride
(2.7 mL, 30.8 mmol) in dichloromethane (35 mL). After stirring
for 15 min, a solution of 10 (3.0 g, 20.5 mol) in dichloromethane
(20 mL) was added dropwise. After stirring for 25 min, triethyl-
amine (20 mL, 143.6 mmol) was added and the reaction was stir-
red for an additional 20 min. After completion (monitored by
TLC), the reaction mixture was warmed to room temperature,
quenched with water (35 mL) and extracted with dichlorometh-
ane. The organic layer was washed with brine and dried over anhy-
drous Na2SO4. Removal of the solvent afforded 2-(2,2-dimethyl-
1,3-dioxolan-4-yl)acetaldehyde, which was used for the next reac-
tion without further purification.
To a stirred solution of the above aldehyde (2.5 g, 17.3 mmol) in
benzene (30 mL) was added phosphine ester (6.041 g, 20.8 mmol).
The resultant mixture was allowed to stir at room temperature for
12 h (monitored by TLC). The solvent was removed under vacuum
to give the crude product which was purified by flash column chro-
matography (20% ethyl acetate hexane) to afford 11 (3.38 g, 91%)
1H NMR and 13C NMR spectra were recorded either in CDCl3 or
in MeOH-d4 solvent on 300, 500 or 75 MHz spectrometer at ambi-
ent temperature. Chemical shifts d is given in ppm, coupling con-
stants J are in Hz. The chemical shifts are reported in ppm on a
scale downfield from TMS as the internal standard and signal pat-
terns are indicated as follows: s, singlet; d, doublet; dd, doublet of
doublet; t, triplet; m, multiplet; br s, broad singlet. FTIR spectra
were recorded as thin films on KBr or neat. Optical rotations were
measured on a digital polarimeter using a 1 mL cell with a 1 dm
path length. For low (MS) and high (HRMS) resolution, m/z ratios
are reported as values in atomic mass units. All of the reagents
and solvents were of reagent grade and used without further puri-
fication unless specified otherwise. Technical grade ethyl acetate
and hexane used for column chromatography were distilled prior
to use. Tetrahydrofuran (THF), when used as a solvent for the
reactions was freshly distilled from sodium benzophenone ketyl.
Column chromatography was carried out using silica gel
(60–120 mesh and 100–200 mesh) packed in glass columns.
Ba(OH)2ꢁ8H2O vacuum dried at 110–120 °C. Column chromatogra-
phy was carried out using silica gel (60–120 mesh and 100–
200 mesh) packed in glass columns. All reactions were performed
under an atmosphere of nitrogen in flame or oven-dried glassware
with magnetic stirring.
as coloured oil. ½a D25
ꢂ
¼ ꢀ17:1 (c 1.7, CHCl3). 1H NMR (300 MHz,
CDCl3): d = 6.94–6.81 (m, 1H), 5.86 (dt, J = 15.7 Hz, 1H), 4.17 (q,
J = 7.1 Hz, 3H), 4.02 (t, J = 6.3 Hz, 1H), 3.54 (t, J = 6.6 Hz, 1H),
2.56–2.35 (m, 2H), 1.39 (s, 3H), 1.32 (s, 3H), 1.29 (t, J = 6.9 Hz,
3H) ppm. 13C NMR (75 MHz, CDCl3): d = 166.1, 143.6, 123.8,
109.2, 74.1, 68.7, 60.2, 36.3, 26.9, 25.4, 14.1 ppm. ESI-MS: m/
z = 223 [M+Na]+.
4.2. (S)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl) ethanol 10
4.4. (S,E)-4-(2,2-Dimethyl-1,3-dioxolan-4-yl)but-2-en-1-ol 12
To stirred solution of triol 9 (2.0 g, 18.8 mmol) in dry DCM
(30 mL), cooled to 0 °C were added 2,2-DMP (3.93 g, 37.7 mmol)
and a catalytic amount of PTSA, then stirred for 4 h at rt. After com-
pletion of the reaction, it was quenched with sat. NaHCO3 and the
water layer extracted with DCM (2 times). The organic layer was
To a stirred solution of compound 11 (1.4 g, 6.54 mmol) in dry
DCM (20 mL) at ꢀ15 °C was added dropwise DIBAL-H (25% in tol-
uene, 9.28 mL, 16.3 mmol). After stirring for 30 min, the reaction
mixture was quenched with sodium potassium tartarate and

A. Venkanna et al. / Tetrahedron: Asymmetry 24 (2013) 1010–1022
1015
diluted with dichloromethane and then stirred until two clear lay-
ers appeared, after which the organic layer was separated and
washed with brine and dried over sodium sulfate. Removal of the
solvent gave a crude product, which was purified by column chro-
matography (30% ethylacetate hexane) to give alcohol 12 (1.068 g,
1H), 1.76–1.71 (m, 2H), 1.41 (s, 3H), 1.35 (s, 3H) ppm. 13C NMR
(75 MHz, CDCl3): d = 140.1, 114.7, 109.2, 74.8, 71.6, 69.5, 40.4,
26.8, 25.6 ppm. ESI-MS: m/z = 195 [M+Na]+.
4.8. (S)-4-((R)-2-Methoxybut-3-enyl)-2,2-dimethyl-1,3-dioxolane
16
95%) as a colourless oil. ½a D25
ꢂ
¼ ꢀ23:35 (c 1.7, CHCl3). 1H NMR
(300 MHz, CDCl3): d = 5.74–558 (m, 2H), 4.16–3.95 (m, 4H), 3.52
(t, J = 6.8 Hz, 1H), 2.41–2.21(m, 2H), 1.38 (s, 3H), 1.31 (s, 3H)
ppm. 13C NMR (75 MHz, CDCl3): d = 132.2, 126.6, 108.8, 75.1,
68.6, 62.7, 36.4, 26.7, 25.4 ppm. ESI-MS: m/z = 195 [M+Na]+.
To a suspension of sodium hydride (0.329 g, 13.72 mmol, 60%
dispersion in paraffin oil) in dry THF (10 mL) at 0 °C was slowly
added a solution of 15 (1.180 g, 6.86 mmol) in dry THF (10 mL) un-
der nitrogen atmosphere and the mixture was allowed to stir for
30 min. The resultant mixture was cooled to 0 °C and then MeI
was slowly added dropwise and stirred for an additional 1 h. After
completion of the reaction, the mixture was poured into ice-cold
water and extracted with ethyl acetate (2 ꢃ 20 ml). The combined
organic layers were washed with brine, dried over anhydrous Na2-
SO4 and evaporated to dryness to afford the crude product, which
was purified by column chromatography (5% ethyl acetate hexane)
4.5. ((2R,3R)-3-(((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)methyl)
oxiran-2-yl)methanol 13
To a stirred solution of evacuated flame dried powdered 4 Å
molecular sieves (2 g) and (ꢀ)-DET (0.2 mL, 1.04 mmol) in DCM
(20 mL) was slowly added Ti(OPri)4 (0.198 g, 0.69 mmol) at
ꢀ25 °C. The mixture was then allowed to stir for 20 min after
which t-BuOOH (6 M in dacane, 8.9 mL, 53.9 mmol) was added at
the same temperature. After being stirred for 30 min, a solution
of compound 12 (1.2 g, 6.97 mmol) in DCM (10 mL) was added
dropwise. The reaction mixture was stirred for 5 h at –25 °C and
monitored by TLC. After completion, the reaction was quenched
by the addition of aqueous NaOH (30% w/v 7.8 mL) and saturated
with NaCl at 0 °C and continued to stir for an additional 1 h. By
using Celite, the reaction mixture was swirled and the solids were
filtered off and dried over anhydrous Na2SO4. Evaporation of the
filtrate under vacuum yielded the crude product which was puri-
fied by flash column chromatography (45% ethyl acetate in hexane)
to afford 16 (1.25 g, 98%) as a colourless oil. ½a D25
¼ þ7:5 (c 0.16,
ꢂ
CHCl3). 1H NMR (300 MHz, CDCl3): d = 5.69–5.57 (m, 1H), 5.26–
5.15 (m, 2H), 4.11–4.04 (m, 1H), 3.97 (t, J = 7.8 Hz, 1H), 3.65 (t,
J = 13.7 Hz, 1H), 3.50 (t, J = 6.9 Hz, 1H), 3.23 (s, 3H), 1.98–1.90 (m,
1H), 1.66–1.59 (m, 1H), 1.37 (s, 3H), 1.30 (s, 3H) ppm. 13C NMR
(75 MHz, CDCl3): d = 137.8, 117.9, 116.9, 80.1, 72.7, 69.4, 56.0,
38.9, 26.9, 25.7 ppm. ESI-MS: m/z = 209 [M+Na]+.
4.9. (2S,4R)-4-Methoxyhex-5-ene-1,2-diol 17
To a solution of compound 16 (0.550 g, 2.95 mmol) in methanol
(10 mL) was added a catalytic amount of (ꢀ)-camphor-10-sulfonic
acid at 0 °C. After the addition, the reaction temperature was
brought to room temperature and allowed to stir for 4 h. After
4 h, the solvent was evaporated under reduced pressure and di-
luted with ethyl acetate (15 mL). The resultant solution was
washed with sat. NaHCO3 solution. The organic layer was sepa-
rated, dried over anhydrous Na2SO4 and evaporated to dryness.
Purification of the crude residue by silica gel column chromatogra-
phy (20% ethyl acetate in hexane) yielded 17 (0.401 g, 94%) as a
to give 13 (1.259 g, 96%) as a colourless oil. ½a D25
¼ þ15:9 (c 0.86,
ꢂ
CHCl3). 1H NMR (300 MHz, CDCl3): d = 4.23–4.12 (m, 1H), 4.07–
3.99 (m, 1H), 3.92–3.82 (m, 1H), 3.65–3.56 (m, 2H), 2.99–2.93
(m, 1H), 3.09–3.03 (m, 1H), 1.90–1.82 (m, 2H), 1.39 (s, 3H), 1.33
(s, 3H) ppm. 13C NMR (75 MHz, CDCl3): d = 109, 72.8, 68.7, 61.4,
57.7, 52.4, 34.8, 26.7, 25.6 ppm. ESI-MS: m/z = 211 [M+Na]+.
4.6. (S)-4-(((2R,3S)-3-(Iodomethyl)oxiran-2-yl)methyl)-2,2-
dimethyl-1,3-dioxolane 14
colourless oil. ½a D25
ꢂ
¼ þ78:6 (c 0.6, CHCl3). 1H NMR (300 MHz,
To a stirred solution of alcohol 13 (1.8 g, 9.57 mmol) in acetoni-
trile/ether (1:3, 60 mL) at 0 °C under nitrogen were added imidaz-
ole (1.53 g, 23.5 mmol), iodine (4.82 g, 19.05 mmol), and
triphenylphosphine (5.01 g, 19.14 mmol) successively. The mix-
ture was stirred for 20–30 min. After completion of the reaction
(monitored by TLC), the resulting solution was diluted by cool
ether (30 mL) and filtered through Celite. The residue was washed
by ether and the combined filtrate was concentrated at low tem-
peratures to afford a pure iodo product as a colourless liquid. This
was used for the next step without purification.
CDCl3): d = 5.73–5.57 (m, 1H), 5.29–5.18 (m, 1H), 3.91–3.75 (m,
2H), 3.59–3.50 (m, 1H), 3.46–3.37 (m, 1H), 3.31 (s, 3H), 2.63–
2.24 (bs, 1H), 1.80–1.71 (m, 1H), 1.61–1.51 (m, 1H) ppm. 13C
NMR (75 MHz, CDCl3): d = 137.5, 117.8, 82.5, 71.1, 66.5, 55.9,
38.4 ppm. ESI-MS: m/z = 169 [M+Na]+.
4.10. (2S,4R)-1-(tert-Butyldimethylsilyloxy)-4-methoxyhex-
5-en-2-ol 3
To stirred solution of 17 (0.270 g, 1.84 mmol) in dry DCM
(10 mL) was added imidazole (0.277 g, 4.08 mmol), after which
the reaction mixture was allowed to stir for 10 min. The resulting
mixture was then cooled to 0 °C, treated with TBDMSCl (0.331 g,
2.23 mmol) and allowed to stir for an additional 6 h. The mixture
was then quenched with a saturated NaHCO3 solution (10 mL).
The aqueous phase was extracted with Et2O (3 ꢃ 10 mL), washed
with brine and dried over Na2SO4. Evaporation of the solvent gave
a crude product, which was further purified by flash column chro-
matography (12% ethyl acetate hexane) to afford 3 (0.442 g, 92%)
4.7. (R)-1-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)but-3-en-2-ol 15
A mixture of iodo compound 14 (1.25 g, 4.19 mmol), NaI
(0.534 g, 8.35 mmol) and freshly activated zinc (1.565 g,
10.43 mmol) in anhydrous MeOH (20 mL) was refluxed for 8 h un-
der a nitrogen atmosphere. After completion of the reaction, the
mixture was filtered through Celite and the residue was washed
with MeOH. The filtrates were combined and concentrated. The
residue was taken in ethyl acetate (20 mL) and washed with water,
brine and dried over anhydrous sodium sulfate. Evaporation of the
solvent and purification by column chromatography (20% ethyl
acetate in hexane) afforded pure alcohol 15 (0.692 g, 96% yield)
as
a
colourless oil.
½
a 2D5
ꢂ
¼ þ87:5 (c = 0.7, CHCl3). 1H NMR
(300 MHz, CDCl3): d = 5.73–5.58 (m, 1H), 5.29–5.19 (m, 1H),
3.88–3.62 (m, 3H), 3.57–3.42 (m, 2H), 3.28 (s, 3H), 2.99–2.93 (bs,
1H), 1.71–1.60 (m, 2H), 1.92 (s, 9H), 0.07 (s, 6H) ppm. 13C NMR
(75 MHz, CDCl3): d = 137.8, 117.7, 82.0, 70.4, 67.0, 55.9, 38.6,
as
a
colourless oil.
½
a 2D5
ꢂ
¼ þ7:9 (c 0.96, CHCl3). 1H NMR
(300 MHz, CDCl3): d = 5.91–5.75 (m, 1H), 5.26 (dt, J = 17.3 Hz and
1.51 Hz, 1H), 5.09 (dt, J = 17.3 Hz and 1.51 Hz, 1H), 4.34–4.17 (m,
2H), 4.05 (t, J = 6.2 Hz, 1H), 3.55 (t, J = 6.8 Hz, 1H), 2.79–2.74 (bs,
25.8 ppm. HRMS (ESI): calcd For
283.1713; found 283.1687.
C
13H28O3NaSi [M+Na]+

1016
A. Venkanna et al. / Tetrahedron: Asymmetry 24 (2013) 1010–1022
4.11. 4-((4-Methoxybenzyl)oxy)butan-1-ol 18
and dried over Na2SO4. Removal of the solvent led to a crude prod-
uct, which was purified by column chromatography (4% ethyl ace-
tate hexane) to afford 21 (0.701 g, 92%) as a colourless oil. IR (KBr):
To a suspension of sodium hydride was added to a solution of
1,4-butanediol 8 (3.5 g, 38.8 mmol) in dry DMF (60 mL) at 0 °C
and the reaction was allowed to stir for 4 h. Next were added tet-
rabutylammonium iodide (1.4 g, 3.13 mmol) and 1-(bromo-
methyl)-4-methoxybenzene (0.042 mol) after which the mixture
was stirred for an additional 12 h at rt. The mixture was then
poured into ice cold water and extracted with ethyl acetate. The or-
ganic layer was washed with brine and dried over sodium sulfate.
Removal of the solvent gave a crude product, which was purified
by column chromatography (20% ethyl acetate hexane) to afford
18 (7.2 g, 89%) as a colourless oil. 1H NMR (300 MHz, CDCl3):
d = 7.20 (d, J = 8.3 Hz, 2H), 6.82 (d, J = 7.8 Hz, 2H), 3.79 (s, 3H),
3.58 (t, J = 5.29 Hz, 2H), 3.46 (t, J = 5.29 Hz, 2H), 2.41–2.30 (s, br,
1H), 1.71–1.61 (m, 4H) ppm. (NMR 75 MHz, CDCl3): d = 158.9,
129.1, 113.5, 72.4, 69.8, 62.2, 55.0, 29.8, 26.4, ppm. ESI-MS: m/
m
= 2957, 2934, 2867, 1739, 1248, 1104, 773 cmꢀ1 1H NMR
.
(300 MHz, CDCl3): d = 7.19 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.5 Hz,
2H), 4.41 (s, 2H), 4.18 (q, J = 7.2 Hz, 2H), 3.7 9 (s, 3H), 3.5 (t,
J = 5.8 Hz, 2H), 2.45 (t, J = 7.0 Hz, 2H), 1.89–1.79 (m, 2H), 1.31 (t,
J = 7.2 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3): d = 159.0, 153.6,
130.1, 129.1 (2C), 113.6 (2C), 88.5, 72.5 (2C), 67.8, 61.6, 55.0,
27.6, 15.4, 13.8 ppm. ESI-MS: m/z = 299 [M+Na]+.
4.15. (Z)-Ethyl 6-(4-methoxybenzyloxy)-3-methylhex-2-enoate
22
To a two-neck RB flask containing freshly dried CuI (0.438 g,
2.3 mmol) was added dry THF (15 mL), cooled to ꢀ15 °C, and then
methyl lithium (1.6 M in ether, 2.8 mL, 4.1 mmol) was slowly
added dropwise via a cannula. The solution turned from light yel-
low to a white precipitate. The mixture was allowed to stir for
30 min at the same temperature. After 30 min, the mixture was
cooled to ꢀ78 °C after which was added a solution of compound
21 (0.276 g, 1.0 mmol) in dry THF (5 mL). The resultant mixure
was allowed to stir for an additional 30 min. After completion of
the reaction (monitored by TLC), the reaction was quenched with
a buffer solution (pH 7) and sat. NH4Cl and stirred until the appear-
ance of a blue colour, and then extracted with ethyl acetate. The or-
ganic layer was again washed with saturated NH4Cl and the
solvent was evoporated under reduced pressure. The crude product
was purified by column chromatography. (3% Ethyl acetate hex-
ane) to give 22 (0.268 g, 96%) as a colourless oil. IR (KBr):
z = 233 [M+Na]+
.
4.12. 4-((4-Methoxybenzyl)oxy)butanal 19
To a solution of oxalyl chloride (1.0 mL, 23.1 mmol) in dichloro-
methane (25 mL) was added DMSO (3.3 mL, 47.0 mmol) dropwise
under an inert atmosphere at –78 °C. After being stirred for
15 min, a solution of compound 18 (2.5 g, 11.9 mmol) in dichloro-
methane (15 mL) was added dropwise and allowed to stir for
25 min. Next, triethyl amine (13.7 mL, 95.1 mmol) was added
and the reaction was stirred for an additional 20 min. After com-
pletion (monitored by TLC), the reaction mixture was warmed to
room temperature, quenched with water (35 mL), and extracted
with dichloromethane. The organic layer was washed with brine
and dried over anhydrous Na2SO4. Removal of the solvent afforded
19 and this crude product was used for the next reaction without
further purification.
m
= 2936, 2857, 1712, 1513, 1247, 1181, 1037, 823 cmꢀ1 1H NMR
.
(300 MHz, CDCl3): d = 7.21 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.7 Hz,
2H), 5.62 (s, 1H), 4.4 (s, 2H), 4.1 (q, J = 7.2 Hz, 2H), 3.79 (s, 3H),
3.45 (t, J = 6.6 Hz, 2H), 2.67 (t, J = 7.0 Hz, 2H), 1.9 (s, 3H), 1.84 (m,
2H), 1.26 (t, J = 7.1 Hz, 3H) ppm.13
C NMR (75 MHz, CDCl3):
4.13. 1-(5,5-Dibromopent-4-en-1-yl)oxy)methyl)-4-methoxy
benzene 20
d = 166.2, 159.9, 159.0, 130.6, 129.1, 116.3, 113.6, 72.4, 69.9, 59.3,
55.2, 30.1, 28.2, 25.1, 14.2 ppm. ESI-MS: m/z = 315 [M+Na]+.
A solution of TPP (11.9 g, 45.2 mmol) (freshly recrystallized) in
dichloromethane was cooled to ꢀ15 °C after which was added CBr4
(7.3 g, 22.2 mmol) under an N2 atmosphere and then allowed to
stir until the reaction mixture turned light yellow. To this mixture
was added a solution of aldehyde 19 (2.37 g, 11.3 mmol) in dichlo-
romethane and continued stirring for an additional 10 min. After
completion, distilled hexane was added and stirred vigorously for
15 min. The mixture was then filtered through a pad of Celite. Re-
moval of the solvent afforded a crude product. Purification by col-
umn chromatography (2% ethyl acetate hexane) gave 20 (3.38 g,
82%) as light yellow oil. 1H NMR (300 MHz, CDCl3): d = 7.19 (d,
J = 8.8 Hz, 2H), 6.82 (d, J = 7.8 Hz, 2H), 6.37 (t, J = 6.8 Hz, 1H), 4.4
(s, 2H), 3.79 (s, 3H), 3.41 (t, J = 5.9 Hz, 3H), 2.19 (q, J = 6.85 Hz,
2H), 1.70 (m, 2H) ppm. 13C NMR (75 MHz, CDCl3): d = 159.1,
138.0, 130.3, 129.1 (2 C), 113.7 (2C), 96.1, 72.6, 68.7, 55.0, 29.9,
27.9 ppm. ESI-MS: m/z = 387 [M+Na]+.
4.16. (Z)-1-((6-Chloro-4-methylhex-4-enyloxy)methyl)-4-metho
xybenzene 6
To a stirred solution of 22 (1.8 g, 6.16 mmol) in dry DCM
(20 mL) was added DIBAL-H (25% in toluene, 10.9 mL, 15.1 mmol)
dropwise at ꢀ15 °C under a nitrogen atomsphere and then allowed
to stir for 30 min. The reaction mixture was then quenched with
sodium potassium tartarate and diluted with DCM and stirred until
the appearance of two clear layers. The organic layer was sepa-
rated, washed with brine and dried over anhydrous Na2SO4. Re-
moval of the solvent under reduced pressure gave
a crude
product, which was purified by silica gel column chromatography
(10% ethylacetate hexane) to give the corresponding allylic alcohol
(1.54 g, 95%) as a colourless oil. IR (KBr):
m = 3428, 2938, 2868,
1652, 1438, 1123, 904, 812 cmꢀ1 1H NMR (300 MHz, CDCl3):
.
d = 7.20 (d, J = 9.1 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 5.47 (t,
J = 7.5 Hz, 1H), 4.38 (s, 2H), 4.02 (d, J = 7.5 Hz, 2H), 3.79 (s, 3H),
3.39 (t, J = 6 Hz, 2H), 2.18 (t, J = 7.5 Hz, 2H), 1.71 (s, 3H), 1.70–
1.63 (m, 2H) ppm. 13C NMR (75 MHz, CDCl3): d = 159.0, 139.1,
130.2, 129.2, 124.9, 113.6, 72.2, 68.7, 58.5, 55.1, 27.8, 27.4,
23.0 ppm. ESI-MS: m/z = 273 [M+Na]+. This alcohol was used for
the next step.
The procedure of Collington and Meyers was followed. To a
cooled suspension of anhydrous LiCl (0.500 g, 11.2 mmol), the
above alcohol (0.250 g, 1.0 mmol) and s-collidine (1.3 mL,
9.1 mmol) in dry DMF (10 mL) was slowly added dropwise meth-
anesulfonyl chloride (0.2 mL, 2.3 mmol). The resulting slurry mix-
ture was then stirred for 2 h at 0 °C under N2. The reaction mixture
4.14. Ethyl 6-((4-methoxybenzyl)oxy)hex-2-ynoate 21
To a solution of dibromo compound 20 (1 g, 2.77 mmol) in dry
THF (15 mL) was added n-BuLi (1.6 M in hexane; 18.5 mL,
6.2 mmol) drop wise at ꢀ78 °C. After being stirred for 45 min,
the reaction mixture was warmed to room temperature and stirred
for an additional 1 h. To this mixture, a solution of ethyl chlorofor-
mate (1.3 ml, 13.3 mmol) in dry THF was added at ꢀ78 °C, and al-
lowed to stir for 30 min at the same temperature. After completion
of reaction, it was quenched with saturated NH4Cl and extracted
with ethyl acetate. The organic layers were washed with brine

A. Venkanna et al. / Tetrahedron: Asymmetry 24 (2013) 1010–1022
1017
was then poured into ice water (50 mL), and extracted with Et2O
(15 mL ꢃ 3). The combined organic extracts were washed with
sat. CuSO4, sat. NaHCO3, and dried over Na2SO4. The solvent was
evaporated under reduced pressure to afford 5 (0.230 g, 86%),
which was used for the next reaction immediately without
purification.
reaction (monitored by TLC), the reaction mixture was filtered
through Celite. The filtrate was washed with saturated sodium
hydrogen carbonate solution, dried over anhydrous Na2SO4 and
concentrated to afford the crude product. Purification by column
chromatography (8% ethyl acetate in hexanes) gave (2Z,5Z)-ethyl
9-hydroxy-3,6-dimethylnona-2,5-dienoate (0.350 g, 89%) as an
oil. IR (KBr):
m = 1709, 1643, 1445, 1375, 1257, 1159, 1054,
4.17. (Z)-Ethyl 9-((4-methoxybenzyl)oxy)-6-methylnon-5-en-2-
855 cmꢀ1 1H NMR (300 MHz, CDCl3): d = 5.61 (s, 1H), 5.16 (t,
.
ynoate 23
J = 7.1 Hz, 1H), 4.11 (q, J = 14.1 Hz, 2H), 3.59 (t, J = 6.4 Hz, 2H),
3.44–3.34 (m, 2H), 2.20 (t, J = 7.3 Hz, 1H), 1.84 (s, 3H), 1.70 (s,
3H), 1.69–1.60 (m, 2H), 1.27 (t, J = 6.9 Hz, 3H) ppm. 13C NMR
(75 MHz, CDCl3); d = 166.3, 158.9, 136.8, 120.9, 115.8, 62.4, 59.5,
35.8, 32.0, 30.6, 24.6, 23.1, 14.1 ppm. HRMS (ESI): calcd For C13H22-
O3Na [M+Na]+ 249.1466; found 249.1464.
To a suspension of the above alcohol (0.250 g, 1.1 mmol) and
sodium bicarbonate (0.557 g, 6.62 mmol) in dry DCM (10 mL)
was added Dess–Martin periodinane (0.703 g, 1.63 mmol) at 0 °C.
The reaction mixture was stirred for 1 h at rt. After completion of
reaction (monitored by TLC), the reaction was quenched with sat.
sodium thiosulfate and allowed to stir until the solution became
clear. The organic layer was separated and the aq. layer was ex-
tracted with diethyl ether (3 ꢃ 20 mL). The combined organic lay-
ers were washed with satd. NaHCO3, brine, dried over anhydrous
Na2SO4 and evaporated in vacuo to give crude aldehyde 25
(0.242 g, 98%), which was used directly in the next step without
further purification.
To a stirred solution of previously dried salts of CuI (2.3 g,
12.2 mmol), NaI (1.82 g, 10.1 mmol), and K2CO3 (1.2 g, 9.2 mmol)
in dry DMF was added a solution of 6 (1.8 g, 6.7 mmol) and ethyl
propionate (0.789 g, 8.4 mmol) in DMF (30 mL) at 0 °C. The reac-
tion mixture was stirred at room temperature for 4 h, and then
quenched with saturated aqueous ammonium chloride. The aque-
ous layer was extracted with ether (3 ꢃ 50 mL), and the combined
organic layers were washed with brine, dried (Na2SO4) and filtered.
The filtrate was then evaporated under reduced pressure and puri-
fied by silica gel column chromatography (3% ethyl acetate in hex-
anes) to afford 23 (0.199 g, 89%) as a colourless oil. IR (KBr):
m
= 2982, 2858, 2938, 2232, 1709, 1614, 1513, 1365, 1249, 1096,
820, 752 cmꢀ1 1H NMR (300 MHz, CDCl3): d = 7.21 (d, J = 8.5 Hz,
.
2H), 6.82 (d, J = 8.5 Hz, 2H), 5.16 (t, J = 7.0 Hz, 1H), 4.38 (s, 2H),
4.18 (q, J = 7.2 Hz, 2H), 3.79 (s, 3H), 3.37 (t, J = 6.2 Hz, 2H), 3.01
(d, J = 6.6 Hz, 2H), 2.09 (q, 7.5 Hz, 2H), 1.74–1.65 (m, 2H), 1.64 (s,
3H), 1.3 (t, J = 7.2 Hz, 3H) ppm.13C NMR (75 MHz, CDCl3): 150.0,
153.0, 138.6, 130.5, 129.0 (2C), 116.4, 113.6, 96.2, 72.5, 68.9,
61.1, 54.8, 35.9, 27.8, 23.1, 17.7, 14.8 ppm. HRMS (ESI): calcd For
4.20. (3E,5Z)-Ethyl 3,6-dimethyldeca-3,5,9-trienoate 26
C
20H26O4 [M+H]+ 331.1904; found 331.1902.
To a stirred solution of Ph3P+CH3Iꢀ, (0.094 g, 0.42 mol) in dry
toluene was add t-BuOꢀK+ at 0 °C and allowed to stir until the solu-
tion turned yellow. To this mixture, a solution of aldehyde 15
(0.094 g, 4.2 mmol) in dry toluene was slowly added dropwise at
0 °C and stirred for an additional 1 h at the same temperature
and then warmed to ambient temperature. After completion, the
reaction mixture was quenched with water and the aqueous phase
was extracted with diethyl ether, dried over Na2SO4 and concen-
trated under reduced pressure. Purification of the residue by flash
chromatography (3% ethyl acetate hexane) afforded 26 (0.076 g,
82%) as a colourless oil. 1H NMR (300 MHz, CDCl3): d = 5.99 (q,
J = 11.1 Hz, 2H), 5.85–5.66 (m, 1H), 5.06–4.87 (m, 2H), 4.12 (q,
J = 14.1 Hz, 2H), 3.01 (s, 2H), 2.25–2.10 (m, 4H), 1.8 (s, 3H), 1.74
(s, 3H), 1.27 (t, J = 7.17 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3):
d = 171.4, 138.3, 137.8, 124.8, 121.4, 120.6, 114.5, 60.4, 45.5, 39.5,
32.2, 24.0, 16.4, 14.1 ppm. HRMS (ESI): calcd for C14H22O2Na
[M+Na]+ 245.1517; found 245.1527.
4.18. (2Z,5Z)-Ethyl 9-((4-methoxybenzyl)oxy)-3,6-dimethylnona
-2,5-dienoate 24
To a two-neck RB flask containing freshly dried CuI (1.19 g,
6.2 mmol) was added dry THF (25 mL), cooled to ꢀ15 °C. Next
methyl lithium (1.6 M in ether, 7.8 mL, 12.5 mmol) was slowly
added dropwise via a cannula. The solution turned from light yel-
low to a white precipitate. The mixture was allowed to stir for
30 min at the same temperature. After 30 min, the mixture was
cooled to ꢀ78 °C, after which was added a solution of compound
23 (0.9 g, 27.2 mmol) in dry THF (5 mL). The resultant mixure
was allowed to stir for an additional 30 min. After completion of
the reaction (monitored by TLC), the reaction was quenched with
a buffer solution (pH 7) and sat. NH4Cl and stirred until it turned
blue, then extracted with ethyl acetate. The organic layer was again
washed with saturated NH4Cl and the solvent was evaporated un-
der reduced pressure. The crude product was purified by column
chromatography (3% ethyl acetate hexane) to give 24 (0.896 g,
4.21. (2Z,5Z,9E)-Ethyl 12-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-
3,6-dimethyl-11-oxododeca-2,5,9-trienoate 27
95%) as an oil; IR (KBr):
m
= 2972, 2941, 2934, 1719, 1619, 1523,
.
1465, 1219, 1026, 812, cmꢀ1
1H NMR (300 MHz, CDCl3): d = 7.19
To a solution of b-ketophosphonate (2.65 g, 9.9 mmol) in THF
(15 mL) was added Ba(OH)2ꢁ8H2O (2.25 g, 7.11 mmol), pre-acti-
vated by heating in a 110 °C oven for 2 h and then dried under vac-
uum. The reaction mixture was then allowed to stir for 30 min at
rt. To this reaction mixture, was added a solution of aldehyde 25
(1.6 g, 7.1 mmol) in THF/H2O (40:1; 10 mL) and allowed to stir
for 2 h at rt. Upon completion, the reaction mixture was diluted
with a saturated aqueous NH4Cl solution (50 mL) and extracted
with ethyl acetate (2 ꢃ 100 mL). The combined organic layers were
washed with brine, dried over Na2SO4 and concentrated under re-
duced pressure. The crude residue was purified by column chroma-
tography (10% ethyl acetate hexane) to provide the coupled
(d, J = 9.0 Hz, 2H), 6.81 (d, J = 8.3 Hz, 2H), 5.59 (s, 1H), 5.12 (t,
J = 8.5 Hz, 1H), 4.37 (s, 2H), 4.12 (q, J = 7.5 Hz, 2H), 3.78 (s, 3H),
3.42–3.3 (m, 4H), 2.16 (t, J = 6.8 Hz, 1H), 2.06 (t, J = 7.3 Hz, 1H),
1.82 (s, 3H), 1.72–1.62 (m, 5H), 1.27 (t, J = 7.5 Hz, 3H) ppm. 13C
NMR (75 MHz, CDCl3): 166.3, 159.1, 141.0, 138.8, 130.6, 129.1
(2C), 120.7, 115.7, 113.6 (2C), 72.4, 69.5, 59.4, 55.1, 36.0, 31.9,
27.9, 24.6, 16.1, 14.2 ppm. HRMS (ESI): calcd For C21H30O4Na
[M+Na]+ 369.2041; found 369.2028.
4.19. (2Z,5Z)-Ethyl 3,6-dimethyl-9-oxonona-2,5-dienoate 25
To a solution of compound 24 (0.6 g, 1.73 mmol) in dichloro-
methane (9.5 mL) and buffer solution (0.5 mL, pH 7) was added
DDQ (0.393 g, 1.71 mol) at 0 °C. The reaction was then warmed
to room temperature and stirred for 1 h. After completion of the
product 27 (2.3 g, 89%) as a colourless oil. ½a D25
¼ ꢀ6:25(c 0.16,
ꢂ
CHCl3) IR (KBr):
m = 2866, 2763, 1719, 1643, 1445, 1375, 1247,
1129, 657 cmꢀ1
.
1H NMR (300 MHz, CDCl3): d = 6.83–6.69 (m,
1H), 6.05 (d, J = 15.8 Hz, 1H), 5.60 (s, 1H), 5.16 (t, J = 7.3 Hz, 1H),

1018
A. Venkanna et al. / Tetrahedron: Asymmetry 24 (2013) 1010–1022
4.47–4.37 (m, 1H), 4.21–4.06 (m, 3H), 3.49 (t, J = 6.7 Hz, 1H), 3.37
(d, J = 7.1 Hz, 2H), 3.06–2.97 (m, 1H), 2.66–2.56 (m, 1H), 2.34 (q,
J = 14.3 Hz, 2H), 2.17 (t, J = 7.3 Hz, 2H), 1.83 (s, 3H), 1.69 (s, 3H),
1.37 (s, 3H), 1.32 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H) ppm. 13C NMR
(75 MHz, CDCl3): d = 196.8, 165.7, 158.0, 147.1, 135.6, 130.8,
122.6, 116.3, 168.4, 72.0, 59.3, 44.3, 38.1, 32.1, 30.9, 27.0, 25.5,
24.8, 23.3, 16.3, 14.5 ppm. HRMS (ESI): calcd for C21H32O5Na
[M+Na]+ 387.242; found 387.2123.
(0.092 g, 92%) as colourless oil. ½a D25
¼ þ56:8 (c = 0.64, CHCl3). IR
ꢂ
(KBr):
m = 2954, 2866, 2756, 1726, 1495, 1456, 1365, 1243, 1223,
821, 704 cmꢀ1 1H NMR (300 MHz, CDCl3): d = 5.67–5.56 (m, 2H),
.
5.39–5.24 (m, 1H), 5.13 (t, J = 6.9 Hz, 1H), 4.14 (q, J = 14.1 Hz, 2H),
3.98–3.86 (bs, 1H), 3.83–3.71 (m, 1H), 3.65–3.55 (m, 1H), 3.52–
3.42 (m, 1H), 3.40–3.30 (m, 3H), 3.24 (s, 3H), 2.81–2.62 (bs, 1H),
2.25–2.02 (m, 4H), 1.84 (s, 3H), 1.72–1.60 (m, 5H), 1.27 (t,
J = 7.17 Hz, 1H) ppm. 13C NMR (75 MHz, CDCl3): d = 166.4, 159.0,
136.3, 133.9, 129.4, 121.1, 115.7, 79.8, 69.2, 66.7, 59.5, 55.8, 39.1,
4.22. (R,2Z,5Z,9E)-Ethyl 12-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-
11-methoxy-3,6-dimethyldodeca-2,5,9-trienoate 28
38.6, 31.9, 30.3, 24.7, 16.1, 14.2 ppm.
363.2142; found 363.2152.
C
19H32NaO5 [M+Na]+
To a stirred solution of the above diol (0.046 g, 0.13 mmol) in
dry DCM at 0 °C were added TrCl (0.041 g, 0.14 mmol) and pyridine
(0.01 mL, 0.14 mmol) and stirring was continued for 4 h at rt. After
completion, the reaction was quenched with sat. NH4Cl and the
aqueous phase was extracted with DCM (2 ꢃ 20 mL). The com-
bined organic layers were washed with brine, dried over anhy-
drous sodium sulfate and the organic layer concentrated to
afford the crude product. Purification by column chromatography
(10% ethyl acetate hexane) gave 29 (0.070 g, 89%) as a light yellow
A solution of (S)-(ꢀ)-2-methyl-CBS-oxazaborolidine (0.49 mL of
a 1 M solution in toluene, 4.9 mmol) in THF (5 mL) was treated with
BH3ꢁDMS (2.0 M solution in THF) (0.2 mL, 04.1 mmol) at 0 °C for
15 min. A solution of enone 27 (0.150 g, 4.1 mmol) in THF (8 mL)
was then added slowly at ꢀ78 °C and the reaction mixture was stir-
red for 1 h at the same temperature. After the addition of saturated
NH4Cl solution, the aqueous layer was extracted with EtOAc; the
combined organic phases were dried over Na2SO4 and concen-
trated. Purification of the residue by flash chromatography (10%
ethyl acetate hexane) gave (R,2Z,5Z,9E)-ethyl 12-((S)-2,2-di-
methyl-1,3-dioxolan-4-yl)-11-hydroxy-3,6-dimethyldodeca-2,5,9-
oil. ½a 2D5
ꢂ
¼ þ69:3 (c 0.5, CHCl3). IR (KBr):
m
= 3436, 2983, 2936,
2862, 1734, 1645, 1436, 1309, 1139, 859 cmꢀ1
.
1H NMR
(300 MHz, CDCl3): d = 7.47–7.41 (m, 6H), 7.33–7.17 (m, 9H), 5.63
(s, 1H), 5.61–5.49 (m, 1H), 5.31–5.20 (m, 1H), 5.14 (t, J = 7.3 Hz,
1H), 4.13 (q, J = 14.3 Hz, 2H), 4.06 (t, J = 5.6 Hz, 1H), 3.72–3.62
(m, 1H), 3.36 (d, J = 7.1 Hz, 2H), 3.15 (s, 3H), 3.09 (d, J = 5.6 Hz,
2H), 2.96–2.84 (bs, 1H), 2.20–2.03 (m, 4H), 1.81 (s, 3H), 1.68–
1.60 (m, 5H), 1.26 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (75 MHz,
CDCl3): d = 166.3, 158.9, 143.8 (3 C), 136.5, 133.6, 129.8, 128.6 (6
C), 127.7 (6 C), 126.9 (3 C), 121.0, 115.8, 86.4, 79.3, 67.9, 67.3,
59.4, 55.8, 39.2, 32.0, 30.6, 24.7, 16.2, 14.2 ppm. HRMS (ESI): calcd
for C38H46O5Na [M+Na]+ 605.3287; found 605.3236.
trienoate (0.128 g, 85%, dr >96:4) as a colourless oil. ½a D25
¼ þ37:2 (c
ꢂ
1.2, CHCl3). IR (KBr):
m = 2923, 2836, 1728, 1679, 1562, 1421, 1084,
752 cmꢀ1 1H NMR (300 MHz, CDCl3): d = 5.66–5.53 (m, 2H), 5.50–
.
5.39 (m, 1H), 5.09 (t, J = 6.6 Hz, 1H), 4.29–4.16 (m, 2H), 4.11 (q,
J = 14.1 Hz, 2H), 4.01 (t, J = 7.6 Hz, 1H), 3.50 (t, J = 7.5 Hz, 1H), 3.34
(t, J = 6.0 Hz, 1H), 2.30–2.25 (bs, 1H), 2.18–2.03 (m, 4H), 1.84 (s,
3H), 1.80–1.70 (m, 2H), 1.66 (s, 3H), 1.38 (s, 3H), 1.32 (s, 3H), 1.27
(t, J = 7.1 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3): d = 165.8, 158.6,
136.1, 133.3, 130.5, 121.5, 116.1, 108.5, 73.4, 69.7, 69.6, 59.2,
40.6, 39.2, 32.1, 30.5, 27.1, 25.9, 24.9, 16.3, 14.4 ppm. HRMS (ESI):
calcd for C18H30O5Na [M+Na]+ 389.1973; found 389.1942.
4.24. (2Z,5Z,9E,11R,13S)-13-Hydroxy-11-methoxy-3,6-dimethyl-
To a stirred solution of the above alcohol (0.120 g, 0.32 mmol) in
dry CH2Cl2 (10 mL) was added proton sponge™ (0.772 g, 3.6 mmol)
followed by trimethyloxonium tetrafluoroborate (0.436 g,
2.9 mmol) at 0 °C. The resulting solution was stirred at rt for 1 h
and then quenched by the addition of saturated aqueous NaHCO3
(5 mL). The phases were separated and the aqueous phase was ex-
tracted with CH2Cl2 (3 ꢃ 5 mL). The combined organic layers were
dried over Na2SO4, concentrated and purified by flash column chro-
matography (5% ethyl acetate hexane) to yield 28 (0.122 g, 98%) as a
14-(trityloxy)tetradeca-2,5,9-trienoic acid 32
To stirred solution of 29 (0.065 g, 0.11 mmol) in dry DCM (5 mL)
was added imidazole (0.019 g, 0.27 mmol) and stirred for 10 min.
The reaction mixture was then cooled to 0 °C, treated with TESCl
(0.03 mL, 0.16 mmol) and allowed to stir for an additional 5 h at
room temperature. After completion, the reaction was quenched
with sat. NaHCO3. The aqueous phase was extracted with Et2O
(2 ꢃ 10 mL), washed with brine and dried over Na2SO4. Removal
of the solvent gave the crude product, which was purified by flash
column chromatography (4% ethyl acetate hexane) to afford
(2Z,5Z,9E,11R,13S)-ethyl 11-methoxy-3,6-dimethyl-13-(triethylsi-
lyloxy)-14-(trityloxy)tetradeca-2,5,9-trienoate (0.071 g, 92%) as a
colourless oil. This compound was used for the next step.
To a stirred solution of the above TES protected compound
(0.068 g, 0.09 mmol) in dry DCM (20 mL) was added DIBAL-H
(25% in toluene, 0.14 mL, 0.24 mmol) dropwise at ꢀ15 °C. After
being stirred for 30 min, the reaction mixture was quenched with
sodium potassium tartarate, diluted with DCM and stirred until
the appearance of two clear layers. The organic layer was sepa-
rated, washed with brine and dried over sodium sulfate. Removal
of the solvent followed by purification of the crude product by col-
umn chromatography (12% ethyl acetate hexane) yielded the cor-
responding allylic alcohol 31 (0.059 g, 93%) as a colourless oil.
colourless oil. IR (KBr):
m = 3014, 2986, 2936, 2846, 1713, 1462,
1286, 1125, 1095, 742 cmꢀ1. ½a D25
ꢂ
¼ þ85:7 (c 0.8, CHCl3). 1H NMR
(300 MHz, CDCl3): d = 5.64 (s, 1H), 5.59 (t, J = 6.4 Hz, 1H), 5.30 (m,
1H), 5.15 (t, J = 6.9 Hz, 1H), 4.25–4.09 (m, 3H), 4.03 (t, J = 5.8 Hz,
1H), 3.65–3.56 (m, 1H), 3.51 (t, J = 7.5 Hz, 1H), 3.38 (d, J = 7.1 Hz,
2H), 3.22 (s, 3H), 2.22–2.04 (m, 4H), 1.84 (s, 3H), 1.80–1.71 (m,
2H), 1.68 (s, 3H), 1.39 (s, 3H), 1.36 (s, 3H), 1.27 (J = 6.9 Hz, 3H)
ppm. 13C NMR (75 MHz, CDCl3): d = 166.3, 158.9, 136.5, 133.6,
130.0, 121.0, 115.8, 108.2, 79.2, 73.4, 69.8, 59.4, 55.8, 40.3, 39.2,
32.0, 30.5, 26.9, 25.8, 24.7, 16.1, 14.2 ppm. HRMS (ESI): calcd for
C
22H36NaO5 [M+Na]+ 403.2455; found 403.2451.
4.23. (2Z,5Z,9E,11R,13S)-Ethyl 13-hydroxy-11-methoxy-3,6-dim
ethyl-14-(trityloxy) tetradeca-2,5,9-trienoate 29
To a solution of compound 28 (0.115 g, 0.30 mmol) in methanol
(5 mL) at 0 °C was added a catalytic amount of (–)-camphor-10-sul-
fonic acid. The reaction temperature was warmed to room temper-
ature and stirred for 4 h. The reaction mixture was concentrated to
remove methanol and diluted with ethyl acetate. The organic layer
was washed with sat. Na2CO3 solution and the organic layer was
concentrated to afford the crude product. Purification by column
chromatography (30% ethyl acetate in hexane) led the diol
To a suspension of the above primary alcohol (0.055 g,
0.08 mmol) and sodium bicarbonate (0.042 g, 0.54 mmol) in dry
DCM (5 mL) was added Dess–Martin periodinane (0.053 g,
0.12 mmol) at 0 °C. After being stirred for 1 h, the reaction mixture
was quenched with satd. sodium thiosulfate and stirred until the
appearance of a clear solution. The organic layer was separated
and the aq layer was extracted with diethyl ether (2 ꢃ 5 mL). The
combined organic layers were washed with sat. NaHCO3 and brine,

A. Venkanna et al. / Tetrahedron: Asymmetry 24 (2013) 1010–1022
1019
dried over anhydrous Na2SO4 and evaporated in vacuo to give the
crude aldehyde (0.054 g, 98%), which was used directly in the next
step without further purification.
0 °C. After being stirred for 12 h, the solvent was removed under
reduced pressure and dissolved in ethyl acetate. The organic layer
was then washed with a saturated NaHCO3 solution and dried over
Na2SO4. Removal of the solvent afforded the crude product, which
was purified by silica column chromatography (30% ethyl acetate
To a solution of the above aldehyde (0.097 g, 0.16 mmol) and 2-
methyl-2-butene (2.9 mL, 2 M solution in THF) in tert-butanol
(5 mL) was added drop wise a solution of NaH2PO4ꢁH2O (184 mg)
and NaClO2 (184 mg) in H2O (2 mL) at 0 °C. The temperature was
then brought to room temperature. After being stirred for
30 min, the reaction was quenched with water (4 mL) and ex-
tracted with ethyl acetate (3 ꢃ 20 mL). The combined organic lay-
ers were washed with brine, dried over anhydrous Na2SO4 and
evaporated in vacuo. The crude product was purified by flash chro-
matography (20% ethyl acetate hexane) to give the acid (0.043 g,
89%) as a colourless oil.
hexane) to afford (R)-dimethyl malate (1.6 g, 98%). ½a D26
¼ þ11:2
ꢂ
(c 1.12, CH3OH). 1H NMR (300 MHz, acetone-d6): d = 4.56–4.48
(m, 1H), 3.71 (s, 3H), 3.64 (s, 3H), 2.84–2.62 (m, 2H) ppm. 13C
NMR (75 MHz, CDCl3): d = 173.6, 170.9, 67.1, 52.7, 51.9, 38.3 ppm.
To a solution of (R)-dimethyl malate (6 g, 37.0 mmol) in dry THF
(60 mL) was added the BH3ꢁDMS complex (2 M solution in THF
15 mL, 37.0 mmol) at room temperature and the reaction was stir-
red for 30 min. The reaction mixture was then cooled to 0 °C after
which a catalytic amount of NaBH4 (ca. 16 mg) was added under N2
and allowed to stir for an additional 30 min at 0 °C. After being stir-
red, the reaction was slowly warmed to rt and stirring continued
over night. The reaction mixture was quenched with methanol
(15 mL) and then stirred for 0.5 h. The solvent was removed and
the crude product was purified by flash column chromatography
(25% acetone–hexane) to afford 34 (1.2 g, 89%) as a colourless oil.
To a stirred solution of the acid (0.035 g, 0.06 mmol) in THF
(4 mL) was added TBAF (0.02 mL, 1 M solution in THF, 0.07 mmol)
at 0 °C. After completion of the reaction (monitored by TLC), the
reaction was quenched with a saturated NaHCO3 solution and
the aqueous layer was extracted with diethyl ether (3 ꢃ 10 mL).
The combined organic layers were dried over Na2SO4 and concen-
trated under reduced pressure to give a crude product, which was
purified by silica gel column chromatography to give seco-acid 32
½
a 2D5
ꢂ
¼ þ27:9 (c 1.08, CH3OH). 1H NMR (300 MHz, acetone-d6):
d = 4.09–3.99 (m, 1H), 3.82 (t, J = 4.9 Hz, 1H), 3.63 (s, 3H), 3.50 (t,
J = 5.2 Hz, 1H), 2.62–2.51 (m, 1H), 2.42–2.31 (m, 1H) ppm. 13C
NMR (75 MHz, acetone-d6): d = 173.7, 70.6, 67.4, 59.7, 40.2 ppm.
ESI-MS: m/z = 257 [M+Na]+.
(0.026 g, 90%) as colourless oil. ½a D25
¼ þ96:8 (c 0.9, CHCl3). IR
ꢂ
(KBr):
m = 3445, 3385, 2921, 2863, 2752, 1718, 1624, 1532, 1361,
1264, 1092, 773 cmꢀ1 1H NMR (300 MHz, CDCl3): d = 7.44–7.38
.
(m, 6H), 7.33–7.17 (m, 9H), 5.63 (s, 1H), 5.55–5.44 (m, 1H), 5.27–
5.15 (m, 1H), 5.04 (t, J = 6.7 Hz, 1H),4.07–3.97 (m, 1H), 3.70–3.61
(m, 1H), 3.44–3.33 (m, 1H), 3.27–3.18 (m, 1H), 3.14 (s, 3H), 3.05
(d, J = 6.7 Hz, 2H), 2.36–2.25 (m, 1H), 2.18–1.95 (m, 4H), 1.86 (s,
3H), 1.64 (s, 3H), 1.60–1.53 (m, 2H) ppm. 13C NMR (75 MHz,
CDCl3): d = 168.7, 159.1, 143.4 (3C), 136.2, 133.2, 129.0, 128.1
(6C), 127.2 (6C), 126.4 (3C), 121.1, 114.5, 87.1, 79.4, 68.2, 67.8,
55.9, 39.1, 38.2, 32.1, 30.8, 24.8, 18.7 ppm. HRMS (ESI): calcd for
4.27. (R)-Methyl 3-hydroxy-4-(4-methoxybenzyloxy)butanoate
35
A solution of 34 (1.2 g, 8.95 mmol) and dibutyltin oxide (Bu2-
SnO) (3.053 g, 12.24 mmol) in toluene (40 mL) was stirred and re-
fluxed under azeotropic conditions, removing H2O with a Dean–
Stark apparatus for 12 h. After cooling to rt, 4-methoxybenzyl chlo-
ride (13.4 mmol, 2.09 g) and tetrabutylammonium iodide (4.9 g,
13.2 mmol) were added to the reaction mixture, and the whole
reaction mixture was refluxed for 3 h. The reaction mixture was
poured into water and extracted with ethyl acetate. The combined
organic layers were washed with a brine solution, dried over Na2-
SO4 and concentrated under reduced pressure. The resultant resi-
due was purified by silica gel column chromatography (25% ethyl
acetate hexane) to afford 35 (1.8 g, 80%) as a colourless oil.
C
36H42O5Na [M+Na]+ 577.2924; found 577.2876.
4.25. (4E,6Z,10E,12R,14S)-12-Methoxy-4,7-dimethyl-14-(tritylox
ymethyl)oxacyclotetradeca-4,6,10-trien-2-one 33a
To a stirred solution of seco-acid 32 (0.015 g, 0.027 mmol) and
Et3N (0.004 mL, 0.029 mmol) in THF (2 mL) was added 2,4,6-tri-
chlorobenzoyl chloride (0.004 mL, 0.028 mmol) drop wise at 0 °C.
The reaction mixture was stirred at room temperature for 1 h, fol-
lowed by dilution with dry toluene (10 mL) and added dropwise
using a syringe pump over a period of 2 h to a refluxing solution
of DMAP (0.102 g, 0.56 mmol) in dry toluene (25 mL). After the
addition was complete, the mixture was refluxed for 10 h and then
concentrated in vacuum. The residue was dissolved in EtOAc
(15 mL) and washed with saturated NaHCO3, brine, dried over Na2-
SO4, filtered and evaporated. The residue was purified by flash
chromatography on silica gel to give macrolactone 33a (0.008 g,
½
a 2D5
ꢂ
¼ þ29:6 (c = 1.14, CHCl3). 1H NMR (300 MHz, CDCl3):
d = 7.27–7.23 (d, J = 8.9 Hz, 2H), 6.91–6.85 (d, J = 9.1 Hz, 2H),
5.01–4.84 (m, 1H), 4.43 (s, 2H), 3.81 (s, 3H), 3.68 (s, 3H), 3.66–
3.56 (m, 1H), 3.46–3.35 (m, 1H), 2.14–2.04 (m, 1H), 1.78–1.65
(m, 1H) ppm. 13C NMR (75 MHz, CDCl3): d = 171.8, 159.1, 130.0,
129.8, 129.3, 113.8, 113.7, 72.9, 72.7, 67.0, 66.2, 55.1, 38.2 ppm.
ESI-MS: m/z = 277 [M+Na]+.
4.28. (R)-Dimethy-4-(tert-butyldiphenylsilyloxy)-5-(4-methoxy
58%) as a colourless oil. IR (KBr):
m
= 2997, 2865, 2792, 1739,
benzyloxy)-2-oxopentyl phosp-honate 36
1686, 1523, 1392, 1196, 1036, 675 cmꢀ1. ½a D25
¼ þ116:3 (c 0.26,
ꢂ
CHCl3). 1H NMR (300 MHz, CDCl3): d = 7.50–7.42 (m, 6H), 7.34–
7.18 (m, 9H), 6.17–5.95 (m, 2H), 5.67–5.55 (m, 2H), 5.29–5.15
(m, 1H), 3.99–3.85 (m, 1H), 3.74–3.63 (m, 1H), 3.19 (s, 3H), 3.17–
2.99 (m, 3H), 2.39–2.32 (m, 1H), 2.26–2.08 (m, 3H), 1.80 (s, 3H),
1.74 (s, 3H), 1.69–1.58 (m, 2H) ppm. 13C NMR (75 MHz, CDCl3):
d = 168.3, 145.5 (3C), 135.7, 132.5, 129.3, 128.2 (6C), 127.7 (6C),
126.1 (3C), 125.6, 120.7, 86.7, 78.2, 67.7, 67.3, 56.2, 46.4, 41.3,
37.8, 32.6, 30.6, 24.5, 19.6 ppm. HRMS (ESI): calcd for C36H40O4Na
[M+Na]+ 559.2819; found 559.2782.
To a stirred solution of compound 35 (1.7 g, 6.69 mmol) in dry
DMF (25 mL) was added imidazole (1.0 g, 14.2 mmol) and allowed
to stir for 10 min. The reaction mixture was cooled to 0 °C, treated
with TBDPSCl (2.3 mL, 8.21 mmol) and the whole mixture was stir-
red at room temperature for 6 h. After being stirred, the reaction
was quenched with sat. aq. NaHCO3. The aqueous phase was ex-
tracted with Et2O (3 ꢃ 50 mL), washed with brine and dried over
Na2SO4. Removal of the solvent gave the crude product, which
was purified by flash column chromatography (10% ethyl acetate
hexane) to afford (R)-methyl 3-(tert-butyldiphenyl silyl-oxy)-4-
4.26. (R)-Methyl 3,4-dihydroxybutanoate 34
(4-methoxybenzyloxy)butanoate (3.1 g, 96%). ½a D26
¼ þ8:5 (c 0.64,
ꢂ
CHCl3). 1H NMR (300 MHz, CDCl3): d = 7.67–7.60 (m, 4H), 7.45–
7.28 (m, 6H), 7.18 (d, J = 9.1 Hz, 2H), 7.05 (d, J = 9.1 Hz, 2H),
4.36–4.25 (m, 1H), 4.17 (d, J = 3.8 Hz, 2H), 3.80 (s, 3H), 3.79 (s,
To a solution of the (R)-malic acid (1.5 g, 11.2 mmol) in MeOH
(20 mL) at 0 °C was slowly added BF3ꢁEt2O (0.4 mL) dropwise at

1020
A. Venkanna et al. / Tetrahedron: Asymmetry 24 (2013) 1010–1022
3H), 3.33 (d, J = 6.0 Hz, 2H), 2.60 (d, J = 6.8 Hz, 2H), 1.0 (s, 9H) ppm.
13C NMR (75 MHz, CDCl3): d = 171.2, 159.4, 135.8 (2 C), 133.8,
133.4, 130.1, 130.0 (2C), 129.6, 129.5, 129.1 (2C), 127.5, 127.4,
133.7, 133.5, 73.1, 72.5, 69.2, 66.0, 55.2, 40.0, 26.8 (3C),
19.2 ppm. HRMS (ESI): calcd for C29H36O5NaSi [M+Na]+ 515.2184;
found 515.2158.
2-en-1-yl)oxy)tetrahydro-2H-pyran (0.8 g, 92%) as a colourless
oil. 1H NMR (300 MHz, CDCl3): d = 5.73 (t, J = 5.7 Hz, 1H), 4.59 (t,
J = 2.9 Hz, 1H), 4.20–4.14 (m, 1H), 3.97–3.92 (m, 1H), 3.84–3.78
(m, 1H), 3.52–3.46 (m, 1H), 2.55 (s, 3H), 1.87–1.78 (m, 1H), 1.70–
1.63 (m, 1H), 1.61–1.48 (m, 4H) ppm. 13C NMR (75 MHz, CDCl3):
d = 132.2, 102.0, 98.2, 71.6, 62.1, 33.6, 30.4, 25.3, 19.3 ppm. ESI-
MS: m/z = 291[M+Na]+.
To a solution of (Z)-2-((3-iodobut-2-en-1-yl)oxy)tetrahydro-
2H-pyran (0.295 g, 1.21 mmol) in dry Et2O (3 mL) was added t-BuLi
(1.5 mL, 1.7 M in pentane, 2.1 mmol) slowly (10 min) at ꢀ78 °C.
The resultant solution was stirred for 30 min at ꢀ78 °C. To this
mixture was added a solution of dry ZnBr2 (0.235 g, 1.2 mmol) in
THF (5 mL) via a cannula. The whole mixture was stirred for
15 min at ꢀ78 °C and then warmed slowly to room temperature.
In another flask containing [Pd2(dba3)] (0.024 g, 0.2 mmol) and
tri-2-furylphosphine (0.020 g, 0.1 mmol) was added dry DMF
(5 mL) and the resultant dark green solution was stirred at 23 °C
for 30 min.
To a stirred solution of dimethyl methylphosphonate (1.172 g,
9.13 mmol) in dry THF (15 mL) was added dropwise n-BuLi
(5.9 mL, 1.6 M in hexane, 9.2 mmol) at ꢀ78 °C and mixture was
stirred for 45 min at same temperature. A solution of the above
TBDPS protected compound (0.008 g, 3.11 mmol) in dry THF
(10 mL) was added to the mixture at the same temperature and
stirred for an additional 1.5 h. The reaction was then quenched
with saturated NH4Cl and extracted with ethyl acetate. The organic
layer was washed with brine and dried over Na2SO4. The solvent
was removed to give a residue, which was purified by flash column
chromatography (40% ethyl acetate hexane) to afford 36 (1.16 g,
75%). ½a 2D5
ꢂ
¼ þ15:8 (c 1.21, CHCl3). IR (KBr):
m
= 3070, 3047, 2999,
1716, 1612, 1513, 1253, 1109, 1034, 821, 705, 610 cm–1
.
1H NMR
A solution of 6 (0.420 g, 1.6 mmol) in dry DMF (4 mL) and the
above generated zinc reagent was then introduced via a cannula
at 0 °C. The reaction mixture was stirred for 1 h, and then
quenched with water, extracted with ether (2 ꢃ 20 mL). The com-
bined organic layers were washed with brine and dried over Na2-
SO4. Removal of the solvent gave the crude product, which was
purified by column chromatography (5% etyl acetate hexane) to af-
(300 MHz, CDCl3): d = 7.69–7.64 (m, 4H), 7.44–7.33 (m, 6H), 7.08
(d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 4.37–4.31 (m, 1H), 4.21
(q, J = 14.5 Hz, 2H), 3.79 (s, 3H), 3.72 (s, 3H), 3.70 (s, 3H), 3.36–
3.28 (m, 2H), 3.07–2.77 (m, 4H), 1.02 (s, 9H) ppm. 13C NMR
(75 MHz, CDCl3): d = 199.8, 159.0, 135.8 (2C), 135.7 (2C), 133.9,
133.1, 130.0, 129.7, 129.5, 129.2 (2C), 127.6 (2C), 127.4 (2C),
113.5 (2C), 73.0, 72.6, 68.6, 55.2, 52.9, 48.8, 42.7, 41.0, 26.8 (3C),
19.1. HRMS (ESI): calcd For C31H41O7NaPSi [M+Na]+ 607.2251;
found 607.2251.
ford 37 (0.387 g, 82%) as an oil. IR (KBr):
m = 2940, 2868, 1607,
1512, 1031,772 cm–1 1H NMR (300 MHz, CDCl3): d = 7.26 (d,
.
J = 8.3 Hz, 2H), 6.88 (d, J = 9.0 Hz, 2H), 5.37 (t, J = 6.0HZ 1H), 5.04
(t, J = 7.5 Hz, 1H), 4.62 (t, J = 3.0 Hz, 1H), 4.43 (s, 2H), 4.28–4.20
(m, 1H), 4.05–3.96 (m, 1H), 3.92–3.83 (m, 1H), 3.81 (s, 3H), 3.54–
3.46 (m, 1H), 3.43 (t, J = 6.8 Hz, 2H), 2,78 (d, J = 6.8 Hz, 2H), 2 (t,
J = 6.8 Hz, 2H), 1.87–1.78 (m, 1H), 1.73–1.67 (m, 1H), 1.71 (S, 3H),
1.68 (s, 3H), 1.66–1.59 (m, 4H), 1.58–1.50 (m, 2H) ppm. 13C NMR
(75 MHz, CDCl3): d = 159.0, 140.3, 135.8, 130.5, 129.1 (2C), 122.8,
120.9, 113.6 (2C), 97.8, 72.5, 69.7, 63.3, 62.1, 52.2, 30.6 (2C),
28.2, 27.9, 25.4, 23.5, 23.2, 19.5 ppm. HRMS (ESI): calcd for C24H36-
O4NH4 [M+NH4]+ 406.2952; found 406.2924.
4.29. 2-(((2Z,5Z)-9-((4-Methoxybenzyl)oxy)-3,6-dimethylnona-
2,5-dien-1-yl)oxy)tetrahydro-2H-pyran 37
A solution of Red-Al (3.4 M in toluene, 9.4 ml, 32.1 mmol) in a
two-necked dry flask charged with a magnetic stirring bar, a reflux
condenser, an addition funnel and an argon in/outlet was diluted
with Et2O (15 ml) and the whole mixture was then cooled to
ꢀ78 °C. To this mixture,
a solution of 2-butyn-1-ol (1.5 g,
21.2 mmol, 1.00 equiv) in Et2O (10 mL) was added dropwise via
the addition funnel. After being stirred at ꢀ78 °C for 30 min, the
reaction mixture was allowed to warm to rt (CAUTION: exothermic
after ca. 1 h). After 12 h, a white suspension had formed which was
cooled to 0 °C. A solution of iodine (8.1 g, 32.1 mmol) in THF
(15 ml) was slowly added at ꢀ78 °C. After warming to rt, the mix-
ture was carefully added to a stirred mixture of saturated aqueous
Na2S2O3 (20 mL) and saturated aqueous Rochelle salt (20 mL), fol-
lowed by the addition of ethyl acetate (15 mL). After stirring at rt
for 30 min, two clear phases were obtained which were separated.
The aqueous phase was extracted with ethyl acetate (3 ꢃ 100 mL),
and the combined organic extracts were dried over Na2SO4 and
concentrated under reduced pressure. Purification of the residue
by flash chromatography (25% ethyl acetate hexane) gave (Z)-3-
iodobut-2-en-1-ol (3.7 g, 98%) as a yellow oil. Note: the product
is not stable upon prolonged storage at rt. 1H NMR (300 MHz,
CDCl3): d = 5.75 (t, J = 7.6 Hz, 1H), 4.11 (d, J = 4.9 Hz, 2H), 2.55 (s,
3H) ppm. 13C NMR (75 MHz, CDCl3): d = 134.0, 102.1, 67.2,
33.5 ppm. ESI-MS: m/z = 207 [M+Na]+.
To a solution of compound (Z)-3-iodobut-2-en-1-ol (0.6 g,
3.21 mmol) in dichloromethane (10 mL) was added 3,4-dihydro-
2H-pyran (2.3 mL, 3.32 mmol) and catalytic amount of (–)-cam-
phor-10-sulfonic acid at 0 °C. The reaction temperature was then
increased to room temperature and allowed to stir for 4 h. After
completion (monitored by TLC), the reaction was quenched with
a saturated sodium hydrogen carbonate solution and the organic
layer was dried over sodium sulfate and concentrated to afford
the crude product. The product was purified by column chroma-
tography (10% ethyl acetate in hexane) to give (Z)-2-((3-iodobut-
4.30. (2R,5E,9Z,12Z)-2-(tert-Butyldiphenylsilyloxy)-1-(4-methox
ybenzyloxy)-9,12-dimethyl-14-(tetrahydro-2H-pyran-2-yloxy)
tetradeca-5,9,12-trien-4-one 38
To a stirred solution of PMB ether 37 (0.650 g, 1.6 mmol) in
dichloromethane (10 mL) was added a pH 7 buffer (0.2 mL) and
DDQ (0.380 g, 1.6 mmol) in three portions over 30 min. Upon the
addition of DDQ, the reaction mixture became orange and as
DDQ was consumed the reaction solution became dark green. After
completion of the reaction (monitored by TLC), the reaction mix-
ture was diluted with dichloromethane (20 mL) and sat. NaHCO3
(10 mL) and stirred vigorously for 10 min. The phases were sepa-
rated and the aqueous layer washed with dichloromethane
(3 ꢃ 15 mL). The organic phases were combined, dried over sodium
sulfate and concentrated. The crude oil was purified by silica gel
column chromatography (10% ethyl acetate hexane) to afford
(4Z,7Z)-4,7-dimethyl-9-(tetrahydro-2H-pyran-2-yloxy)nona-4,7-
dien-1-ol (0.399 g, 89%). 1H NMR (300 MHz, CDCl3): d = 5.37 (t,
J = 7 Hz, 1H), 5.11 (t, J = 7 Hz, 1H), 4.64 (t, J = 3.8 Hz, 1H), 4.31–
4.22 (m, 1H), 4.06–3.96 (m, 1H), 3.95–3.84 (m, 1H), 3.64 (t,
J = 6.2 Hz, 2H), 3.56–3.48 (m, 1H), 2.81 (t, J = 6.6 Hz, 2H), 2.16 (t,
J = 8.1 Hz, 2H), 1.88–1.80 (m, 2H), 1.74 (s, 3H), 1.70 (s, 3H), 1.66–
1.50 (m, 6H) ppm. 1H NMR (75 MHz, CDCl3): d = 140.5, 135.8,
122.6, 120.8, 97.9, 63.4, 62.5, 62.3, 30.8, 30.6 (2 C), 27.9, 25.4,
23.5, 23.2, 19.5 ppm. HRMS (ESI): calcd for C16H28O3Na [M+Na]+
291.1823; found 291.1726.
To a suspension of alcohol (4Z,7Z)-4,7-dimethyl-9-(tetrahydro-
2H-pyran-2-yloxy)nona-4,7-dien-1-ol (0.399 g, 1.49 mmol) and

A. Venkanna et al. / Tetrahedron: Asymmetry 24 (2013) 1010–1022
1021
sodium bicarbonate (0.750 g, 8.92 mmol) in dry DCM (10 mL) was
added Dess–Martin periodinane (0.954 g, 0.22 mmol) at 0 °C. The
reaction mixture was stirred for 1 h. After completion, the reaction
was quenched with sat. sodium thiosulfate and stirred until the
appearance of a clear solution. The organic layer was separated
and the aq layer extracted with diethyl ether (3 ꢃ 20 mL). The
combined organic layers were washed with satd. NaHCO3, brine,
dried over anhydrous Na2SO4 and evaporated in vacuo to give
the crude aldehyde (0.388 g, 98%), which was used directly in the
next step without further purification.
m/z = HRMS (ESI): calcd for C40H52O5NaSi [M+Na]+ 663.2293;
found 663.2282.
To a suspension of the above alcohol (0.100 g, 0.15 mmol) and
sodium bicarbonate (0.078 g, 0.92 mmol) in dry DCM (10 mL)
was added Dess–Martin periodinane (0.099 g, 0.21 mol) at rt and
the reaction mixture was allowed to stir for 1 h. After completion
of the reaction (monitored by TLC), it was quenched with sat. so-
dium thiosulfate and stirred vigorously until the appearance of
two layers. The organic layer was separated and the aq layer was
extracted with diethyl ether (3 ꢃ 20 mL). The combined organic
layers were washed with satd. NaHCO3 and brine, and dried over
anhydrous Na2SO4 and evaporated in vacuo to give the crude alde-
hyde (0.097 g, 98%), which was used directly in next step without
further purification.
To a solution of b-keto phosphonate 36 (0.388 g, 1.17 mmol) in
THF (15 mL) was added Ba(OH)2ꢁ8H2O (0.460 g, 1.42 mmol), pre-
activated by heating in a 110 °C oven for 2 h and then dried under
vacuum and the reaction mixture was allowed to stir for 30 min. To
this mixture, was added a solution of the above crude aldehyde
(0.388 g, 1.45 mmol) in THF/H2O (40:1; 10 mL) and stirring contin-
ued for 2 h at rt. Upon completion, the reaction mixture was di-
luted with a saturated aqueous NH4Cl solution (20 mL) and
extracted with ethyl acetate (2 ꢃ 50 mL). The combined organic
layers were washed with brine, dried over Na2SO4 and concen-
trated under reduced pressure. The crude residue was purified by
column chromatography (8% ethyl acetate hexane) to give the cou-
To a solution of the above aldehyde (0.097 g, 0.15 mmol) and 2-
methyl-2-butene (4 mL) in tert-butanol (10 mL) was added drop-
wise a solution of NaH2PO4ꢁH2O (250 mg) and NaClO2 (250 mg)
in H2O (2.5 mL) at 0 °C. The reaction mixture was then allowed
to warm up to rt and stirred for 30 min. After being stirred, the
reaction was poured into water (6 mL) and extracted with ethyl
acetate (3 ꢃ 20 mL). The combined organic layers were washed
with water and brine, dried over anhydrous Na2SO4 and evapo-
rated in vacuo. The crude product was purified by flash chromatog-
raphy (25% ethyl acetate hexane) to give 39 (0.088 g, 89%) as a
pled product 38 (0.844 g, 80%) as a colourless oil. ½a D26
¼ þ17 (c
ꢂ
0.68, CHCl3). IR (KBr):
m = 3102, 2925, 2855, 1726, 1247, 1118,
704 cmꢀ1
.
1H NMR (300 MHz, CDCl3): d = 7.7–6.63 (m, 4H), 7.45–
colourless oil. ½a D25
ꢂ
= +14.25 (c 0.41, CHCl3). IR (KBr):
m
= 3741,
7.31 (m, 6H), 7.09 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.7 Hz, 2H),
6.74–6.61 (m, 1H), 6.04–6.93 (m, 1H), 5.38, J = 7.7 Hz, 1H), 5.08
(t, J = 7.1 Hz, 1H), 4.62 (t, J = 3.5 Hz, 1H), 4.44–4.35 (m, 1H), 4.28–
4.18 (m, 3H), 4.04–3.96 (m, 1H), 3.91–3.82 (m, 1H), 3.79 (s, 3H),
3.55–3.45 (m, 1H), 3.35 (d, , J = 5.1 Hz, 2H), 2.81–2.72 (m, 3H),
2.25–2.14 (m, 4H), 1.86–1.75 (m, 2H), 1.71 (s, 3H), 1.68 (s, 3H),
1.63–1.48 (m, 5H), 1.01 (s, 9H) ppm. 13C NMR (75 MHz, CDCl3):
d = 198.3, 158.9, 146.8, 139.8, 135.7, 134.7, 134.2, 133.4, 130.9,
130.3, 129.6 (2 C), 129.4 6 (2 C), 129.1 6 (2 C), 127.5 6 (2 C),
127.3 6 (2 C), 123.5, 121.3, 113.5 6 (2 C), 97.8, 73.4, 72.5, 69.2,
63.2, 62.1, 55.1, 44.7, 30.8, 30.6, 30.2, 29.5, 26.8 (3 C), 25.4, 23.5,
2923, 2913, 2858, 2746, 1739, 1563, 1460, 1219, 846 cmꢀ1 1H
.
NMR (300 MHz, CDCl3): d = 7.70–7.63 (m, 4H), 7.44–7.38 (m, 2H),
7.37–7.31 (m, 4H), 7.10 (d, J = 8.9 Hz, 2H), 6.81 (d, J = 7.9 Hz, 2H),
6.71–6.61 (m, 1H), 5.99 (d, J = 15.8 Hz, 1H), 5.67 (s, 1H), 5.17 (t,
J = 7.9 Hz, 1H), 4.44–4.38 (m, 1H), 4.26 (q, J = 16.8 Hz, 2H), 3.79
(s, 3H), 3.49–3.41 (m, 2H), 3.36 (d, J = 4.9 Hz, 2H), 2.81–2.74 (m,
1H), 2.47 (t, J = 7.9 Hz, 2H), 2.26–2.20 (m, 1H), 1.90–1.83 (m, 5H),
1.69 (s, 3H), 1.0 (s, 9H) ppm. 13C NMR (75 MHz, CDCl3): d = 198.6,
178.2, 161.4, 159.0, 147.1, 136.2, 136.0 (2C), 135.8, 134.1, 133.4,
131.0, 130.1, 129.6, 129.5, 129.3 (2C), 129.2, 127.6, 127.5 (2C),
127.4, 121.9, 115.3, 113.6 (2C), 77.2, 73.3, 69.2, 55.2, 44.8, 31.9,
31.0, 30.8, 30.3, 26.9 (3C), 22.6, 19.7 ppm. HRMS (ESI): calcd for
23.2, 19.5, 19.2 ppm. HRMS (ESI): calcd for
C45H60O6NaSi
[M+Na]+ 747.40514; found 747.40410.
C
40H50O6NaSi [M+Na]+ 677.3269; found 677.3248.
4.31. (R,2Z,5Z,9E)-13-(tert-Butyldiphenylsilyloxy)-14-(4-metho
4.32. (S,3Z,6Z,10E)-14-((4-Methoxybenzyloxy)methyl)-4,7-di
xybenzyloxy)-3,6-dimethyl-11-oxotetradeca-2,5,9-trienoic acid
39
methyloxacyclotetradeca-3,6,10-triene-2,12-dione 41
To a stirred solution of 39 (0.065 g, 0.099 mmol) in THF (1 mL)
was added TBAF (0.15 mL, 1 M solution in THF, 0.149 mmol) at
0 °C. The reaction mixture was stirred at room temperature for 6 h,
then diluted with EtOAc (5 mL) and poured into water (2 mL). The
aqueous phase was extracted with EtOAc (3 ꢃ 5 mL). The combined
organic phases were washed with brine, dried over anhydrous Na2-
SO4. Removal of the solvent gave the crude product, which was puri-
fied by flash chromatography (30% ethyl acetate hexane) to afford
To a solution of compound 38 (0.150 g, 0.20 mmol) in methanol
(5 mL) was added a catalytic amount of (ꢀ)-camphor-10-sulfonic
acid at 0 °C. The reaction temperature was then warmed to room
temperature and stirring continued for 4 h. After being stirred,
the reaction mixture was concentrated to remove methanol and di-
luted with ethyl acetate. The organic layer was washed with brine,
dried over Na2SO4, and concentrated to afford the crude product.
Purification by column chromatography (15% ethyl acetate in hex-
ane) gave (R,5E,9Z,12Z)-2-(tert-butyldiphenylsilyloxy)-14-hydro-
xy-1-(4-methoxybenzyloxy)-9,12-dimethyltetradeca-5,9,12-trien-
seco-acid 40 (0.034 g, 83%) as a colourless oil. ½a D25
¼ þ4:9 (c 0.25,
ꢂ
CHCl3). IR (KBr):
m = 3304, 2924, 2854, 1730, 1647, 1635, 1462,
1219, 772 cmꢀ1 1H NMR (300 MHz, CDCl3): d = 7.26 (d, J = 9.0 Hz,
.
4-one (0.110 g, 83%) as a colourless oil. ½a D25
ꢂ
= +20.5 (c 0.76, CHCl3).
m = 3216, 3049, 2922, 2933, 2856, 2852, 1729, 1516, 1245,
2H), 6.91–6.81 (m, 3H), 6.12 (d, J = 15.8 Hz, 1H), 5.67 (s, 1H), 5.20
(t, J = 6.9 Hz, 1H), 4.51 (s, 2H), 4.33–4.26 (m, 1H), 3.92–3.82 (m,
2H), 3.80 (s, 3H), 3.76–3.68 (m, 1H), 3.41–3.32 (m, 2H), 2.78–2.71
(m, 1H), 2.36–2.28 (m, 3H), 1.92–1.85 (m, 4H), 1.70 (s, 3H) ppm.
13C NMR (75 MHz, CDCl3): d = 199.3, 169.1, 161.2, 148.2(2C),
136.0, 130.7, 129.4 (3C), 122.0, 115.2, 113.7 (2C), 77.1, 73.0, 67.0,
55.2, 42.7, 31.7, 30.6, 30.2, 29.6, 22.9 ppm. HRMS (ESI): calcd for C24-
H32O6Na [M+Na]+ 439.2186; found 439.2154.
To solution of PPh3 (0.057 g, 0.218 mmol, azeotropically dried
twice with benzene) in dry THF (0.05 M) was added DIAD (0.037 g,
0.187 mmol) at room temperature. The solution was stirred at room
temperature for 30 min. To this solution was added a solution of
seco-acid 40 (0.026 g, 0.063 mmol) in THF (0.003 M) at 0 °C over a
IR (KBr):
871, 722 cmꢀ1 1H NMR (300 MHz, CDCl3): d = 7.67 (t, J = 7.7 Hz,
.
4H), 7.45–7.30 (m, 6H), 7.09 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.5 Hz,
2H), 6.73–6.61 (m, 1H), 6.0 (d, J = 15.8 Hz, 1H), 5.4 (t, J = 6.8 Hz,
1H), 5.09 (t, J = 6.8 Hz, 1H), 4.44–4.35 (m, 1H), 4.23 (q,
J = 16.5 Hz, 2H), 4.11 (d, J = 6.9 Hz, 2H), 3.79 (s, 3H), 3.35 (d,
J = 4.7 Hz, 2H), 2.81–2.71 (m, 4H), 2.29–2.06 (m, 4H), 1.70 (s, 3H),
1.69 (s, 3H), 1.01 (s, 9H) ppm. 13C NMR (75 MHz, CDCl3):
d = 198.4, 159.0, 146.7, 139.2, 135.9 (2 C), 135.8 (2 C), 134.8,
134.1, 133.4, 131.0, 130.3, 129.6, 129.5, 129.1 (2 C), 127.5 (2 C),
127.4 (2 C), 124.0, 123.5, 113.5 (2 C), 73.4, 72.6, 69.3, 58.9, 55.2,
44.9, 30.7, 30.6, 30.2, 26.9, (3 C), 23.5, 23.1, 19.2 ppm. ESI-MS:

1022
A. Venkanna et al. / Tetrahedron: Asymmetry 24 (2013) 1010–1022
16. (a) Cooper, J.; Knight, D. W.; Gallagher, P. T. J. Chem. Soc., Chem. Commun. 1987,
1220–1222; (b) Corey, E. J.; Katzenellenbogen, J. A. J. Am. Chem. Soc. 1969, 91,
1851.
17. Xie, H.; Shao, Y.; Becker, J. M.; Naider, F.; Gibbs, R. A. J. Org. Chem. 2000, 65,
8552–8563.
18. (a) Jin, Y.; Coates, R. M. Chem. Commun. 2006, 2902–2904; (b) Meyers, A. I.;
Collington, E. W. J. Org. Chem. 1971, 36, 3044; (c) Corey, E. J.; Luo, G.; Lin, L. S. J.
Am. Chem. Soc. 1997, 119, 9927.
19. Ivanov, I. V.; Groza, N. V.; Romanov, S. G. L.; Kuhn, H.; Myagkova, G. I.
Tetrahedron 2000, 56, 553–556.
period of 2 h via syringe pump. The resulting mixture was stirred for
an additional 4 h at this temperature and quenched with water. The
aqueous layer was extracted with ethyl acetate. The organic layer
was washed with brine and dried over anhydrous Na2SO4. After re-
moval of the solvent, the crude product was purified by flash column
chromatography (15% ethyl acetate hexane) to afford 41 (0.013 g,
56%) as a colourless oil. ½a D25
ꢂ
¼ ꢀ4:75 (c 0.08, CHCl3). 1H NMR
(300 MHz, CDCl3): d = 7.12 (d, J = 8.3 Hz, 2H), 6.94–6.85 (m, 3H),
6.33 (d, J = 14.8 Hz, 1H), 6.05 (s, 1H), 4.71–4.67 (m, 1H), 4.51 (s,
2H), 4.32–4.27 (m, 1H), 4.11–4.01(m, 1H), 3.97–3.89 (m, 2H),
2.78–2.71 (m, 1H), 2.11–1.99 (m, 4H), 1.90 (s, 3H), 1.80 (s, 3H)
ppm. 13C NMR (75 MHz, CDCl3): d = 199.7, 165.4, 160.9, 149.2,
148.3, 135.2, 130.5, 129.6 (3C), 127.3, 117.5, 113.6 (2C), 75.2, 72.8,
71.6, 55.4, 43.0, 31.8, 30.8, 30.7, 30.4, 23.2 ppm. HRMS (ESI): calcd
for C24H30O5Na [M+Na]+ 421.1985; found 421.1943.
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Acknowledgments
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A.V.K. thanks the Council of Scientific and Industrial Research
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Commission, New Delhi for a research fellowship.
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