Asymmetric total synthesis of (-)-rasfonin

Article abstract of DOI:10.1016/j.tet.2012.11.051

An efficient chemoenzymatic asymmetric synthesis of pyranone containing natural product (-)-rasfonin is presented here. Enantioselective enzymatic desymmetrization (EED) and a unique Gluconobacter oxydans mediated oxidative kinetic resolution (OKR) have been successfully employed to install three stereocenters (C_6′, C₇, and C₉) of the target molecule. Stereoselective Achmatowicz reaction of a properly decorated furyl nucleus led to the core pyranone structure of rasfonin. At the late stage of the synthesis Negishi coupling has been used to complete the synthesis.

Full text of DOI:10.1016/j.tet.2012.11.051

Tetrahedron 69 (2013) 1153e1165
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric total synthesis of (ꢀ)-rasfonin
*
Rajib Bhuniya, Samik Nanda
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 August 2012
Received in revised form 9 November 2012
Accepted 14 November 2012
Available online 17 November 2012
An efficient chemoenzymatic asymmetric synthesis of pyranone containing natural product (ꢀ)-rasfonin
is presented here. Enantioselective enzymatic desymmetrization (EED) and a unique Gluconobacter
oxydans mediated oxidative kinetic resolution (OKR) have been successfully employed to install three
0
stereocenters (C6 , C7, and C9) of the target molecule. Stereoselective Achmatowicz reaction of a properly
decorated furyl nucleus led to the core pyranone structure of rasfonin. At the late stage of the synthesis
Negishi coupling has been used to complete the synthesis.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
The external double bond (between C11 and C12) was introduced by
Negishi carbozincation coupling reaction. The crucial ester linkage
0
The protein ras functions as a molecular switch for signal
transduction pathways that control cell growth and differentiation.
Activating mutations in these ras proteins result in constitutive
signaling, thereby stimulating cell proliferation and inhibiting ap-
optosis (programmed cell death), and most significantly, as an
oncogene that is able to induce tumors in animals or cell cultures.
Mutations in the ras family of proto-oncogenes (comprising H-ras,
N-ras, and K-ras) are very common, being found in 20e30% of all
human tumors.1 Therefore the ras-signaling pathway has attracted
considerable attention as a target for anticancer therapy because of
its important role in carcinogenesis. Rasfonin, a new apoptosis in-
ducer in ras dependent Ba/F3-V12 cells, was isolated by Hayakawa
and co-workers from the fermented mycelium of Talaromyces
species 3656-A1 in 2000.2 Recent studies have indicated that
(ꢀ)-rasfonin can selectively destroy ras-dependent cells with an
(between C5 and C1 ) was planned to be constructed by Yamaguchi
esterification reaction of an appropriately substituted acid (A) and
alcohol fragment (B). The required acid and the alcohol fragments
are constructed from the more easily available starting materials.
The alcohol fragment is made by the crucial stereospecific Achma-
towicz reaction of a properly functionalized furyl system. One ster-
0
eocenter in the acid fragment (C6 ) and another stereocenter in the
alcohol fragment (C7) are thought to be constructed byapplying EED
strategy.8 Whereas the remaining stereocenter (C9) in the pyranone
alcohol fragment is planned to be constructed by a novel oxidative
kinetic resolution (OKR) reaction by Gluconobacer oxydans.9
2. Results and discussion
IC50 of 0.16
m
g/mL.3 Ishibashi and co-workers reported that rasfonin
2.1. Synthesis of the acid fragment A
suppressed proliferation of mouse splenic lymphocytes stimulated
with the mitogens concanavalin A and lipopolysaccharide with IC50
For the preparation of acid fragment A the synthesis starts from
ethane-1,2-diol, selective mono protection of the diol with
TBDPSeCl (tert-butylchlorodiphenylsilane) afforded the mono
TBDPS protected ether 1 in 80% yield.10 The primary hydroxyl group
in 1 was converted to its corresponding iodo compound 2 by treat-
ment with TPP (triphenylphosphine), imidazole, and iodine in dry
THF at ꢀ20 ꢁC to room temperature in 94% yield.11 This iodo com-
pound was then coupled with diethyl malonate using sodium hy-
dride as base at 0 ꢁC to afford mono alkylated compound 3 in 72%
yield. Reduction of the diester functionality in compound 3 with LAH
in dry ether furnished the diol 4 in 85% yield. The initial EED reaction
of compound 4 (enzymatic transesterification)8 was optimized by
employing many lipases, and it was found that lipase-AK (Pseudo-
monas fluorescens) provides the best result in terms of both enan-
tioselectivity (ee¼99%) and chemical yield (91%) of the synthesized
values of 0.7 and 0.5 m
g/mL, respectively.4
The first asymmetric total synthesis of rasfonin was reported by
Ishibashi et al. in 2005.5 Later on Boeckman Jr. group reported the
total synthesis of rasfonin by applying asymmetric alkylation re-
action based on a new chiral auxiliary.6 Whereas our work is in
progress another synthesis of rasfonin has been reported by Huang
et al. involving asymmetric conjugate addition of MeMgBr and
Achmatowicz reaction.7 Herein we report the asymmetric synthesis
of rasfonin by a chemoenzymatic approach. The retrosynthetic
analysis of the target molecule rasfonin is presented in Scheme 1.
* Corresponding author. Tel.: þ91 3222 283328; fax: þ91 3222 282252; e-mail
address: snanda@chem.iitkgp.ernet.in (S. Nanda).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.051

1154
R. Bhuniya, S. Nanda / Tetrahedron 69 (2013) 1153e1165
15
9
14
16
11
OH
1
13
OTBDPS
8
10
4'
O
O
OPMB
6
O
O
O
7
2
12
+
5
B
OH
OTBDPS
3
A
O1'
3'
5'
4
7'
6'
OH
8'
O
2'
EED
Achmatowicz
9'
OH
10'
HO
HO
OPMB
O
OTBDPS
OH
OKR
EED
OAc
OAc
HO
OPMB
HO
OPMB
Scheme 1. Retrosynthetic analysis of rasfonin.
monoacetate product 5 (vinyl acetate was used as the acylating
agent whereas diisopropyl ether was chosen as solvent). The initial
optimization results are summarized in Table 1. The absolute con-
figuration of the acetate 5 is established by chemical analogy, as the
stereopreferences for EED reaction of similar 2-substituted 1,3-
propane diol are well known in the literature.8
using Lipase PS-D (Burkholderia cepacia, immobilized on diatomite)
as enzyme in phosphate buffer solution of pH 7.013 to yield the
monoacetate 13 (yield¼86%; ee>99%). The free hydroxy group in
alcohol 13 was protected as its TBDPS (tert-butyldiphenylsilyl)
ether by treatment with imidazole and TBDPSeCl to afford the
TBDPS-protected compound 14 in 89% yield. The acetate func-
tionality was removed by treatment with K2CO3 in MeOH to yield
enantiomerically pure 15 in 92% yield. Swern oxidation of com-
pound 15 afforded the corresponding aldehyde, which upon Wittig
olefination with (1-carbethoxyethylidene)-triphenylphosphorane
afforded the unsaturated ester compound 16 in 88% yield in two
steps. The olefinic unsaturation in compound 16 was reduced by
NiCl2/NaBH4 followed by reduction of the ester functionality with
LAH afforded alcohol 17 (as diastereomeric mixtures; 1:1) in 82%
yield (in two steps; Scheme 3). With this alcohol 17 in our hand we
have explored an OKR reaction (diastereoselecive enzymatic oxi-
dation) reaction by G. oxydans (NCIMB 8035). Thus when a trial
reaction (100 mg scale) was run with a 24 h submerged culture of G.
oxydans in a biphasic solvent (isooctane/water¼1:1), (2S,4S)-acid
18 (the fast reacting diastereomer; yield¼48%) and (2S,4R)-alcohol
19 (slow reacting diastereomer; yield¼45%; de¼98%; Scheme 3)
were obtained after 2 h of incubation in an orbital incubator shaker.
Formation of little amount of aldehyde was also detected during the
course of the reaction. Similar kind of enantioselective oxidation of
racemic 2-phenyl-propan-1-ol with the whole cells of G. oxydans is
earlier documented in the literature.14 But to the best of our
knowledge this is the first example of a biocatalytic diaster-
eoselective oxidative kinetic resolution by G. oxydans. The reaction
was next performed in 10 g scale, and similar product distribution
was obtained. When the oxidation was kept for longer time (more
than 3 h; Table 2), the major product obtained was the acid-18 (82%
yield). For our synthetic exercise we need the (2S,4R) alcohol-19,
hence the oxidation was stopped after 2 h interval. The acid 18 can
be converted back to alcohol 17 by a two-step epimerization re-
action. Thus when acid 18 was refluxed with DBU in THF solvent it
afforded the epimerized acid, which was further reduced with LAH
to furnish the alcohol 17 (88% in two steps). The alcohol 17 then
again can be used in the initial oxidation step. Though alcohol 19
can also be accessed by EED reaction of meso-2,4-dimethylpentane-
1,5-diol.15 But it seems that the precursor meso-2,4-
dimethylglutaric anhydride is difficult to synthesize in large
scale.16 We have initially tried to synthesize the meso-anhydride
but unable to produce it in a large-scale setup. Actually the frac-
tional crystallization step for separating out the meso-anhydride
from the (dl)-anhydride is extremely tedious and needs careful
optimization. As the (dl)-anhydride needs to be thrown out, the
Table 1
EED reaction of 2-(2-(tert-butyldiphenylsilyloxy)ethyl)propane-1,3-diol (4)
Entry
Lipases
Acyl donor
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
Lipase AK-Amano
Lipase AK-Amano
Lipase PS-Amano
Lipase PS-Amano
Lipase A (Amano-6)
Lipase F (AP 15)
Lipase PS-D
Lipase PS-D
Novozym-435
Lipozyme
Rhizopus arrhizus
Candida lipolytica
Vinyl acetate
Isopropenyl acetate
Vinyl acetate
Isopropenyl acetate
Vinyl acetate
Vinyl acetate
Vinyl acetate
Isopropenyl acetate
Vinyl acetate
Vinyl acetate
Vinyl acetate
91
88
80
76
56
62
90
82
40
35
22
20
99
94
82
88
68
72
88
90
46
30
ndc
ndc
9
10
11
12
Vinyl acetate
a
Isolated yield after purification by chromatography.
Determined by chiral-HPLC (CHIRALCEL AS-H of the corresponding benzoyl
b
derivative of monoacetate compound).
c
Not determined.
The free hydroxy group in the monoacetate 5 was protected as its
TBDPS (tert-butyldiphenylsilyl) ether to afford compound 6 in 89%
yield. Acetate group was then deprotected with K2CO3 in MeOH to
yield compound 7 (92%). Oxidation of compound 7 under Swern
condition afforded the corresponding aldehyde 8 in 90% yield.12
Wittig olefination with (1-carbethoxyethylidene)-triphenylphos-
phorane of aldehyde 8 afforded the unsaturated ester compound 9 in
84% yield. Reduction of carboethoxy group by DIBALeH (1 equiv) in
dry DCM solvent at ꢀ78 ꢁC afforded the corresponding unsaturated
aldehyde 10 in 84% yield. HornereWadswortheEmmons olefination
reaction of aldehyde 10 using triethylphosphonoacetate yielded E-
ester 11 in 86% yield. Hydrolysis of 11 with LiOH/THF afforded cor-
responding
a, b-unsaturated acid A in 84% yield (Scheme 2; overall
yield 17% from 1,2-ethane diol).
2.2. Synthesis of the a-pyranone alcohol fragment B
The synthesis starts from prochiral acetic acid 3-acetoxy-2-
methyl-propyl ester (compound 12). Enantioselective enzymatic
desymmetrization (EED) of the diacetate 12 was performed by

R. Bhuniya, S. Nanda / Tetrahedron 69 (2013) 1153e1165
1155
PO
PO
PO
c
PO
e
i
a
d
b
HO
PO
CO2Et
CO2Et
I
OH
PO
OH
OH
OH
2
1
4
3
7
PO
PO
OP
CHO
OH
f
h
g
OP
OAc
OP
OH
5
6
8
OAc
ee = 99%
OHC
OP
EtOOC
HOOC
OP
OP
k
EtO2C
OP
j
10
OP
P = TBDPS
11
OP
OP
9
l
OP
A
Scheme 2. Preparation of the acid fragment. Reagents and conditions: (a) TBDPSeCl, imidazole, dry THF (tetrahydrofuran), 0 ꢁC to rt, 80%; (b) I2, TPP (triphenylphosphine), im-
idazole, dry THF, 94%; (c) CH2(CO2Et)2, NaH, dry THF, 0 ꢁC, 30 min, reflux 12 h, 72%; (d) LiAlH4, dry ether, 0 ꢁC, 85%; (e) vinyl acetate, Lipase-AK, i-Pr2O, 4 A MS, rt, 91%; (f) TBDPSeCl,
ꢀ
imidazole, DMAP (5 mol %), dry DCM (CH2Cl2), 89%; (g) K2CO3, MeOH, rt, 92%; (h) (COCl)2, DMSO, Et3N, dry DCM, ꢀ78 ꢁC; (i) Ph3P(CHMe)CO2Et, dry DCM, 0 ꢁC to rt, 84%; (j)
DIBALeH, dry DCM, ꢀ78 ꢁC, 84%; (k) (EtO)2POCH2CO2Et, NaH, dry THF, 0 ꢁC to rt, 86%; (l) LiOH, THF/H2O (5:1), rt, 84%.
b
c
a
PO
OH
HO
OAc
PO
OAc
AcO
OAc
15
14
13; ee > 99%
12
P = TBDPS
PO
OH
19
e
d
f
PO
PO
OH
COOEt
16
17
PO
OH
O
18
17
g
Scheme 3. A novel oxidative kinetic resolutionbyG. oxydans and EED reaction forthe construction of C9 and C7 stereocenters. Reagentsand conditions: (a)Lipase PS-D, phosphatebuffer
(pH¼7.0), 86%; (b) TBDPSeCl, Im, DMAP (5 mol %), dry DCM, 0 ꢁC tort, 89%; (c) K2CO3, MeOH, rt, 92%; (d) (i) (COCl)2, DMSO, Et3N, dry DCM, ꢀ78 ꢁC; (ii) Ph3P(CMe)CO2Et, dry DCM, 88%; (e)
(i) NiCl2, NaBH4, MeOH, 0 ꢁC to rt, (ii) LAH, dry THF, 0 ꢁC, 82%; (f) G. oxydans, rt, de¼96%, yield¼45%; (g) DBU, dry THF, reflux, 2 h; (ii) LAH, dry ether, rt, 88% (over two steps).
Table 2
Product distribution in the oxidative kinetic resolution of alcohol 17 by G. oxydans
G. Oxydans
PO
PO
OH
PO
OH
PO
OH
CHO
O
aldehyde
18
19
17
P = TBDPS
Time (h)
Yield of 18 (%)a
Yield of 19 (%)
Yield of aldehyde (%)
1
2
3
5
32
48
68
82
28
45
20
15
10
<5
<5
Ndb
a
The reaction is performed in a biphasic medium (water/isooctane¼1:1; subs concentration is 10 g/L) in a rotary shaker. Yields are obtained as isolated yield after
purification.
b
Not detected.
yield of the overall process becomes significantly lower. Whereas in
our case we are able to synthesize the required (2S,4R) alcohol 19
with moderate yield and excellent enantio/diastereo controlled
manner though the synthetic steps are little lengthy. Though al-
cohol oxidases from Acetobacter and Gluconobacter sp. are well
known for their efficiency, but their synthetic utility has not been
explored at all.
a catalytic amount of CSA (camphor sulfonic acid) furnished PMB
and TBDPS protected compound 20 in 86% yield.17 Deprotection of
the TBDPS group was achieved by treating with TBAF/THF18 at room
temperature to afford mono PMB protected compound 21 in 88%
yield. Compound 21 is known in the literature,19 and by comparing
its optical rotation value with our synthesized product the absolute
configuration of alcohol 19 obtained in the diastereoselective en-
zymatic oxidation step was confirmed. Swern oxidation of this al-
cohol 21 afforded the corresponding aldehyde 22 in 90% yield.
The alcohol functionality in compound 19 was then protected as
its PMB ether by treating with PMB-imidate in the presence of

1156
R. Bhuniya, S. Nanda / Tetrahedron 69 (2013) 1153e1165
Addition of 2-lithiofuran to aldehyde 22 at room temperature gave
the compound 23 in 76% yield. Oxidation of the free hydroxy group
under several reaction conditions (Swern, DesseMartin period-
inane, TPAPeNMO, IBX) afforded the ketone product 24 with sub-
afforded our target molecule (ꢀ)-rasfonin (Scheme 5; overall
yield¼2.46% from compound 12 and 5.3% from ethane-1,2-diol).
3. Conclusion
sequent epimerization at the a-carbon (approximately 1:1 mixture
of formation of two epimers have been indicated in 13C NMR
In conclusion we have described an efficient asymmetric syn-
20
analysis). However oxidation with large excess of activated MnO2
thesis of the
a-pyranone-containing natural product, (ꢀ)-rasfonin
afforded the corresponding ketone 24 without any epimerization,
which was immediately converted to alcohol 25 by stereoselective
reduction with L-Selectride21 and 35% aqueous H2O2 at ꢀ78 ꢁC in
85% yield (de >99%). The high diastereoselectivity in the L-Selec-
tride reduction can be explained by invoking FelkineAhn type
transition state in which the PMB containing appendage act as the
largest substituent.21b Stereospecific Achmatowicz reaction22 of 25
with NaHCO3, NaOAc, and NBS (N-bromosuccinimide) afforded
compound 26 (as a mixture of diastereomers as indicated in 1H
NMR analysis) in 90% yield. Oxidation of the lactol functionality in
26 to the corresponding lactone was achieved by PCC (pyridinium
chlorochromate) and the lactone was subsequently reduced ster-
eoselectively, without further purification by Luche reduction23 to
afford the desired alcohol fragment B in 74% yield (over two steps,
Scheme 4, overall yield¼6.7% from compound 12).
in a divergent way. The main highlight of our synthetic strategy is to
access two advanced intermediates in a chemoenzymatic way fol-
lowed by functional group manipulation. A novel oxidative kinetic
resolution catalyzed by G. oxydans has been employed successfully
for the synthesis of one of the intermediate. The other key re-
actions, which have been successfully applied for the total synthesis
of rasfonin are Negishi coupling, Yamaguchi esterification and
stereospecific Achmatowicz reaction.
4. Experimental section
4.1. Materials and methods
Unless otherwise stated, materials were obtained from com-
mercial suppliers and used without further purification. THF and
d
c
OPMB
OPMB
b
a
HO
OPMB
OHC
PO
OPMB
e
19
22
21
20
f
g
OPMB
OPMB
O
O
O
23
25
de >99%
24
OH
O
OH
O
O
OPMB
O
OPMB
HO
h
OH
B
26
O
Scheme 4. Reagents and conditions: (a) PMB-imidate, CSA (5 mol %), cyclohexane/DCM (2:1), 86%; (b) TBAF, dry THF, 0 ꢁC, 88%; (c) (COCl)2, DMSO, Et3N, dry DCM, ꢀ78 ꢁC, 90%; (d)
furan, n-BuLi, dry THF, rt (3 h), 0 ꢁC, 76%; (e) MnO2, dry DCM, 0 ꢁC-rt, 74%; (f) L-Selectride, dry THF, ꢀ78 ꢁC, 85%; (g) CH3COONa$3H2O, NaHCO3, NBS, THF/H2O (4:1), 90%; (h) (i) PCC,
CH3COONa, Celite, dry DCM, 0 ꢁC to rt; (ii) CeCl3$7H2O, NaBH4, dry DCM, anhydrous MeOH, ꢀ78 ꢁC, 74% (over two steps).
2.3. Coupling of acid fragment A and alcohol fragment B for
the total synthesis of (L)-rasfonin
diethyl ether were distilled from sodium benzophenone ketyl.
Dichloromethane (DCM), dimethylformamide (DMF), and dime-
thylsulfoxide (DMSO) were distilled from calcium hydride. Diiso-
propyl ether (DIPE) was refluxed over P2O5 and distilled prior to
use. Vinyl acetate and isopropenyl acetate were freshly distilled
prior to use. Lipase AK (from P. fluorescens), lipase PS (from B.
cepacia), lipase PS-D (immobilized on diatomite), lipase-A (from
Candida antarctica), lipase-F (from Rhizopus oryzae), Novozym-435
(lipase acrylic resin from C. antarctica), and lipozyme (immobilized
from Mucor miehei) were obtained from commercial suppliers and
used as obtained. G. oxydans (NCIMB 8035) was obtained from
NCIMB culture collection and grown as specified in the catalog.
Reactions were monitored by thin-layer chromatography (TLC)
carried out on 0.25 mm silica gel plates with UV light, ethanolic
anisaldehyde, and phosphomolybdic acid/heat as developing
agents. Silicagel 100e200 mesh was used for column chromatog-
raphy. Yields refer to chromatographically and spectroscopically
homogeneous materials unless otherwise stated. NMR spectra were
recorded on 400 and 200 MHz spectrometers at 25 ꢁC in CDCl3
After successful construction ofboth the required fragments A and
B, the remaining task was to couple the two fragments followed by
functional group manipulation. Yamaguchi coupling24 of
a-pyranone
alcohol fragment B with diene acid A afforded compound 27 in 84%
yield. Removal of the PMB group was achieved with DDQ25 to afford
alcohol 27 in 80% yield. In this stage of synthesis we have realized that
the remaining task can be accomplished by performing a successful
CeC cross coupling reaction (sp3esp2) to attach the 2-butenyl side
chain. Therefore the primary hydroxy group in compound 28 was
transformed to its corresponding iodo compound 29 by treatment
with triphenylphosphine (TPP), imidazole, and iodine. Initially iron-
catalyzed [FeCl3 or Fe(acac)3] cross-coupling reaction26 between
iodo compound 29 and vinyl Grignard generated from E-2-
bromobutene was attempted, but with our dismay we could not de-
tect the formation of product 30. Later on lithiated species generated
from E-2-bromobutene and t-BuLi was used as the sp2 coupling
partner.27 Though we were able to isolate compound 30 this time, but
the miserably low yield (<10%) forced us to search for other alter-
natives. Careful optimization was performed to get the best possible
result, and it was found that coupling reaction of the iodo compound
29 with E-2-bromobutene under Negishi condition28 afforded com-
pound 30 in 76% yield. Finally deprotection of the TBDPS groups was
achieved by treating compound 30 with HF/pyridine29 in dry THF
using TMS as the internal standard. Chemical shifts are shown in d.
13C NMR spectra were recorded with a complete proton decoupling
environment. The chemical shift value is listed as dH and dC for 1H
and 13C, respectively. Mass spectroscopic analysis was performed in
the IICT, Hyderabad (TOF analyzer). Optical rotations were mea-
sured on a digital polarimeter. HPLC analysis was performed with
CHIRALPAK AD-H and AS-H (Daicel) columns.

R. Bhuniya, S. Nanda / Tetrahedron 69 (2013) 1153e1165
1157
O
O
OH
O
O
OPMB
b
a
B
A
c
O
O
OP
OP
O
O
28
OP
27
OP
No product
BrMg
Fe(acac)3
O
O
O
O
O
O
I
e
d
O
O
O
OP
OH
OP
O
O
O
30
OP
OH
29
OP
Rasfonin
P = TBDPS
Li
Very low yield of 30
Scheme 5. Synthesis of (ꢀ)-rasfonin. Reagents and conditions: (a) A, Et3N, 2,4,6-trichlorobenzoyl chloride, dry toluene, rt, 1 h, then B, dry toluene, DMAP, rt, 5 h, 84%; (b) DDQ,
DCM/H2O (19:1), 0 ꢁC, 80%; (c) I2, Ph3P, imidazole, dry DCM, 0 ꢁC to rt; 85%; (d) Zn/Cu, dry toluene/dimethylacetamide (19:1), 70 ꢁC, [Pd(PPh3)4] (5 mol %), E-2-bromobutene, 60 ꢁC,
76%; (e) HF/pyridine, dry THF, rt, 48 h, 72%.
4.2. 2-(tert-Butyldiphenylsilyloxy)ethanol (1)
4.4. Diethyl 2-(2-(tert-butyldiphenylsilyloxy)ethyl)malonate (3)
TBDPSO
CO2Et
TBDPSO
OH
CO2Et
Ethane-1,2-diol (1.52 g, 24.2 mmol) was taken in anhydrous THF
(100 mL) and cooled to 0 ꢁC. Imidazole (3.0 g, 44.4 mmol) and
DMAP (catalytic) were added to the reaction mixture followed by
the addition of TBDPSeCl (10.5 mL, 40.3 mmol). The reaction
mixture was allowed to warm at room temperature, after 24 h
water was added to the reaction mixture and it was extracted with
Et2O. The organic layer was washed with brine and dried over
MgSO4. Evaporation of the organic solvent and purification by silica
gel chromatography (3:1; hexane/EtOAc) yielded the mono TBDPS-
protected diol 1 as a liquid, in 80% yield (5.79 g).
Sodium hydride (60% suspension in mineral oil, 640 mg,
16.0 mmol) was taken in 65 mL anhydrous THF, then diethyl mal-
onate (2.56 g, 16 mmol) was added at 0 ꢁC. After 0.5 h, compound 2
(6.54 g, 16 mmol) was added and the reaction mixture was refluxed
for 12 h. After that time water was added at 0 ꢁC and the reaction
mixture was extracted with EtOAc, the organic layer was succes-
sively washed with brine and dried (MgSO4). The organic extract
was evaporated in vacuo and purified by silica gel chromatography
(10:1; hexane/EtOAc) to afford the diethyl malonate derivative 3 in
72% yield (5.09 g) as a clear liquid.
Rf¼0.2 (EtOAc/hexane¼1:3).
Rf¼0.4 (EtOAc/hexane¼1:5).
dH (CDCl3, 200 MHz): 7.75e7.70 (m, 4H), 7.45e7.42 (m, 6H),
3.82e3.70 (m, 4H), 2.32 (t, J¼6.0 Hz, 1H), 1.12 (s, 9H).
IR (film): 2920, 2855, 1742, 1465, 1427 cmꢀ1
.
dH (CDCl3, 200 MHz): 7.68e7.63 (m, 4H), 7.43e7.35 (m, 6H),
4.25e4.11 (m, 4H), 3.77e3.67 (m, 3H), 2.23e2.13 (m, 2H), 1.26 (t,
J¼7.2 Hz, 6H), 1.05 (s, 9H).
4.3. tert-Butyl(2-iodoethoxy)diphenylsilane (2)
dC (CDCl3, 50 MHz): 169.6, 135.5, 133.5, 129.7, 127.7, 61.4, 61.2,
48.7, 31.5, 26.8, 19.2, 14.1.
TBDPSO
I
Ph3P (4.63 g, 17.7 mmol) and imidazole (3.1 g, 45 mmol) were
added to a solution of alcohol 1 (4.5 g, 15 mmol) in dry THF (60 mL).
The suspension was cooled to ꢀ20 ꢁC, and I2 (4 g, 15.8 mmol) was
added to the solution. After being stirred for 30 min, the reaction
mixture was warmed to room temperature, and further stirred for
1.5 h. After that the reaction mixture was cooled to 0 ꢁC, and poured
into saturated aqueous solution of NaHCO3 (50 mL). The mixture
was then extracted with Et2O (2ꢂ60 mL), and the organic extract
was washed with saturated aqueous Na2S2O3 and brine. The or-
ganic extract was dried (MgSO4) and evaporated. The crude iodo
compound was then purified by flash chromatography (40:1;
hexane/EtOAc) to afford 2 in 94% yield (colorless liquid, 5.77 g).
Rf¼0.9 (EtOAc/hexane¼1:10).
4.5. 2-(2-(tert-Butyldiphenylsilyloxy)ethyl)propane-1,3-diol (4)
TBDPSO
OH
OH
LAH (750 mg, 19.7 mmol) was taken in 70 mL dry ether followed
by addition of the malonate derivative 3 (5.8 g, 13.14 mmol) at 0 ꢁC.
After 1 h, saturated solution of Na2SO4 was carefully added to
quench the reaction mixture. Then the reaction solution was fil-
tered by washing with hot Et2O for several times and then it was
concentrated in vacuo. The crude product was purified by flash
chromatography (1:1; hexane/EtOAc) to afford compound 4 as
a thick liquid (4.0 g, yield 85%).
dH (CDCl3, 200 MHz): 7.72e7.68 (m, 4H), 7.46e7.38 (m, 6H), 3.89
(t, J¼6.8 Hz, 2H), 3.24 (t, J¼6.6 Hz, 2H), 1.11 (s, 9H).
Rf¼0.2 (EtOAc/hexane¼1:1).
dC (CDCl3, 50 MHz): 135.6,133.3, 129.9, 127.8, 64.7, 26.8, 19.3, 6.8.
IR (film): 3420, 2925, 2855, 1435 cmꢀ1
.

1158
R. Bhuniya, S. Nanda / Tetrahedron 69 (2013) 1153e1165
dH (CDCl3, 200 MHz): 7.73e7.69 (m, 4H), 7.44e7.42 (m, 6H),
4.8. (S)-4-(tert-Butyldiphenylsilyloxy)-2-((tert-butyldiphe-
3.8e3.72 (m, 6H), 1.95 (m, 1H), 1.65e1.56 (m, 2H), 1.10 (s, 9H).
dC (CDCl3, 50 MHz): 135.6, 133.4, 129.8, 127.8, 65.1, 62.4, 40.2,
31.2, 26.9, 19.2.
nylsilyloxy)methyl)butan-1-ol (7)
TBDPSO
OTBDPS
OH
HRMS (ESI) for C21H30O3NaSi [MþNa]þ, calculated: 381.1862,
found: 381.1858.
4.6. (R)-4-(tert-Butyldiphenylsilyloxy)-2-(hydroxymethyl)bu-
tyl acetate (5)
The acetate group in compound 6 (3.84 g, 5.95 mmol) was
deprotected by adding K2CO3 (410 mg, 2.97 mmol) in MeOH
(25 mL) solvent. After completion of the reaction, as indicated by
TLC, MeOH was evaporated under reduced pressure. The residue
was taken in Et2O, and washed successively with water and brine.
The organic layer was dried with MgSO4 and evaporated under
reduced pressure to afford the crude product. The crude product
was then purified by flash chromatography (3:1; hexane/EtOAc) to
afford compound 7 in 92% yield (3.32 g) as a liquid.
TBDPSO
OH
OAc
Compound 4 (2.04 g, 5.6 mmol) was taken in 25 mL of anhy-
drous DIPE (di-isopropyl ether). Lipase-AK (276 mg) was added to
the reaction mixture, followed by addition of vinyl acetate (0.52 mL,
Rf¼0.3 (EtOAc/hexane¼1:5).
25
[
a
]
D
þ8.89 (c 1.0, CHCl3).
ꢀ
5.6 mmol) and powdered molecular sieves (4 A, 200 m). The re-
IR (film): 3355, 3069, 2905, 1465, 1427 cmꢀ1
.
action mixture was stirred under an argon atmosphere in room
temperature. The progress of the reaction was monitored by TLC
measurement. After 100% conversion, it was filtered on a Celite pad,
washed by ether and evaporated to dryness. The crude product was
purified by flash chromatography (5:1; hexane/EtOAc) to afford the
(R)-mono acetate compound 5 in 91% yield (2.03 g) as a clear liquid.
Rf¼0.4 (EtOAc/hexane¼1:3).
dH (CDCl3, 200 MHz): 7.68e7.65 (m, 8H), 7.41e7.34 (m, 12H),
3.79e3.6 (m, 6H), 2.96e2.9 (m, 1H), 1.61e1.52 (m, 2H), 1.06 (s, 9H),
1.04 (s, 9H).
dC (CDCl3, 50 MHz): 135.6, 133.6, 133.3, 129.8, 129.7, 127.8, 127.7,
66.7, 65.4, 62.2, 40.2, 31.2, 26.9, 19.2.
4.9. (R)-4-(tert-Butyldiphenylsilyloxy)-2-((tert-butyldiphe-
nylsilyloxy)methyl)butanal (8)
[a
]
25 þ20.57 (c 1.0, CHCl3).
D
IR (film): 3400, 2955, 2855, 1745, 1427 cmꢀ1
.
dH (CDCl3, 200 MHz): 7.7e7.66 (m, 4H), 7.46e7.38 (m, 6H),
4.21e4.04 (m, 2H), 3.79e3.73 (m, 2H), 3.61 (d, J¼5.2 Hz, 2H), 2.77
(br, 1H, ꢀOH), 2.1 (m, 1H), 2.07 (s, 3H), 1.67e1.58 (m, 2H), 0.99 (s,
9H).
TBDPSO
OTBDPS
CHO
dC (CDCl3, 50 MHz): 171.6, 135.6, 133.3, 129.8, 127.7, 64.8, 62.8,
62.0, 38.3, 31.2, 26.8, 20.9, 19.1.
Oxalyl chloride (0.4 mL, 4.1 mmol) was taken in dry DCM
(50 mL). Dry DMSO (0.6 mL, 8.1 mmol) was added to the reaction
mixture slowly and the temperature was maintained at ꢀ78 ꢁC.
After 20 min, alcohol 7 (1.61 g, 2.7 mmol) taken in DCM (10 mL) was
added to the reaction mixture. The reaction mixture was kept at
ꢀ78 ꢁC for 50 min. Then Et3N (2.3 mL, 16.2 mmol) was added and
the mixture is allowed to attain room temperature. After that water
was added to it and extracted with DCM, the organic layer was
washed with NaHCO3 solution and brine and dried over MgSO4. The
reaction mixture was evaporated in vacuo to afford the crude al-
dehyde 8 as a clear liquid.
HRMS (ESI) for C23H32O4NaSi [MþNa]þ, calculated: 423.1968,
found: 423.1974.
4.7. (S)-4-(tert-Butyldiphenylsilyloxy)-2-((tert-butyldiphe-
nylsilyloxy)methyl)butyl acetate (6)
TBDPSO
OTBDPS
OAc
Rf¼0.9 (EtOAc/hexane¼1:5).
IR (film): 2925, 1730, 1455, 1405 cmꢀ1
.
Mono acetate compound 5 (1.92 g, 4.8 mmol) was taken in an-
hydrous DCM (25 mL) and cooled to 0 ꢁC. Imidazole (650 mg,
9.5 mmol) and DMAP (catalytic) were added to the reaction mix-
ture followed by the addition of TBDPSeCl (1.5 mL, 5.7 mmol). The
reaction mixture was allowed to warm at room temperature for 3 h,
after which water was added to it and extracted with DCM, the
organic layer was washed with brine and dried over MgSO4. The
organic extract was evaporated in vacuo to give the crude product,
which was purified by silica gel chromatography (10:1; hexane/
EtOAc) to afford compound 6 in 89% yield (2.73 g) as a viscous
liquid.
dH (CDCl3, 200 MHz): 9.49 (s, 1H), 7.68e7.63 (m, 8H), 7.51e7.31
(m, 12H), 3.79 (t, J¼6.6 Hz, 4H), 2.53e2.48 (m, 3H), 1.04 (18H).
dC (CDCl3, 50 MHz): 194.4, 135.6, 133.7, 129.6, 127.7, 61.8, 61.6,
51.1, 31.1, 26.8, 19.2.
4.10. (S,E)-Ethyl-6-(tert-butyldiphenylsilyloxy)-4-((tert-bu-
tyldiphenylsilyloxy)methyl)-2-methylhex-2-enoate (9)
EtO2C
OTBDPS
OTBDPS
Rf¼0.4 (EtOAc/hexane¼1:10).
[a
]
25 þ12.89 (c 1.0, CHCl3).
In an argon atmosphere the crude aldehyde 8 (1.62 g, 2.7 mmol)
was taken in 16 mL of dry DCM. Then a precooled (0 ꢁC) solution of
ylide ((1-carbethoxyethylidene)-triphenylphosphorane) (2.44 g,
6.76 mmol) in DCM was added to the aldehyde solution. The mix-
ture was stirred at 0 ꢁC for 30 min and then warmed to room
temperature and stirred for an additional 24 h. After that water was
added to it and extracted with DCM, the organic layer was washed
with brine and dried over MgSO4. The organic extract was evapo-
rated in vacuo to give the crude product, which was purified by
D
IR (film): 3045, 1750, 1465, 1427 cmꢀ1
dH (CDCl3, 200 MHz): 7.74e7.71 (m, 8H), 7.52e7.43 (m,12H), 4.24
(d, J¼5.8 Hz, 2H), 3.81e3.64 (m, 4H), 2.26e2.18 (m, 1H), 2.04 (s, 3H),
1.77e1.71 (m, 2H), 1.13 (s, 18H).
.
dC (CDCl3, 50 MHz): 171.1, 135.7, 134.0, 133.7, 129.7, 127.8, 64.8,
63.4, 61.8, 37.2, 31.2, 27.0, 21.0, 19.4, 19.3.
HRMS (ESI) for C39H50O4NaSi2 [MþNa]þ, calculated: 661.3145,
found: 661.3149.

R. Bhuniya, S. Nanda / Tetrahedron 69 (2013) 1153e1165
1159
silica gel chromatography (8:1; hexane/EtOAc) to afford the un-
4.13. (S,2E,4E)-8-(tert-Butyldiphenylsilyloxy)-6-((tert-butyldi-
phenylsilyloxy)methyl)-4-methylocta-2,4-dienoic acid, A
saturated ester compound 9, in 84% yield (1.53 g) as a liquid.
Rf¼0.6 (EtOAc/hexane¼1:20).
25 þ4.69 (c 1.06, CHCl3).
HOOC
OTBDPS
OTBDPS
[a]
D
IR (film): 3069, 2925, 2855, 1710, 1465, 1427 cmꢀ1
.
dH (CDCl3, 200 MHz): 7.76e7.62 (m, 8H), 7.39e7.32 (m, 12H),
6.62 (d, J¼10.2 Hz, 1H), 4.27e4.11 (m, 2H), 3.63e3.57 (m, 4H),
2.99e2.94 (m, 1H), 2.04e1.92 (m, 1H), 1.82 (s, 3H), 1.61e1.46 (m,
1H), 1.25 (t, J¼6.0 Hz, 3H), 1.04 (s, 18H).
The unsaturated ester 11 (740 mg, 1.03 mmol) was taken in 6 mL
of THF/water (5:1). LiOH (50 mg, 2.1 mmol) was added to it and the
solution was stirred at room temperature for 48 h. After that time it
was extracted several times with EtOAc. The organic layer was
dried (MgSO4) and evaporated in vacuo to give the crude product,
which was purified by silica gel chromatography (1:1; hexane/
EtOAc) to afford the unsaturated acid A in 84% yield (597 mg) as
a gummy liquid.
dC (CDCl3, 50 MHz): 168.0, 143.3, 135.6, 135.5, 133.8, 133.6, 129.6,
129.2, 127.6, 66.4, 61.7, 60.4, 38.3, 34.2, 26.8, 19.3, 19.2, 14.3, 12.8.
HRMS (ESI) for C42H54O4NaSi2 [MþNa]þ, calculated: 701.3458,
found: 701.3462.
4.11. (S,E)-6-(tert-Butyldiphenylsilyloxy)-4-((tert-butyldiphe-
nylsilyloxy)methyl)-2-methylhex-2-enal (10)
Rf¼0.4 (EtOAc/hexane¼1:5).
[a
]
25 ꢀ2.78 (c 0.25, CHCl3).
D
IR (film): 2922, 2852, 1849, 1755, 1655, 1561, 1459 cmꢀ1
.
OHC
OTBDPS
OTBDPS
dH (CDCl3, 400 MHz): 7.64e7.61 (m, 8H), 7.44e7.34 (m, 13H),
5.79 (d, J¼15.6 Hz, 1H), 5.67 (d, J¼9.6 Hz, 1H), 3.64e3.52 (m, 4H),
2.99e2.94 (m,1H),1.95e1.90 (m,1H),1.74 (s, 3H),1.49e1.43 (m,1H),
1.04 (s, 18H).
dC (CDCl3, 100 MHz): 172.4, 151.8, 144.8, 135.6, 135.5, 135.48,
135.4, 134.1, 133.7, 133.6, 133.5, 129.62, 129.58, 129.55, 127.60,
127.58, 115.0, 66.6, 61.5, 38.2, 34.3, 26.8, 19.2, 19.1, 12.6.
HRMS (ESI) for C42H52O4NaSi2 [MþNa]þ, calculated: 699.3302,
found: 699.3308.
Compound 9 (1.55 g, 2.3 mmol) was taken in dry DCM (15 mL)
and cooled to ꢀ78 ꢁC. A solution of DIBALeH (1 M in DCM, 2.3 mL,
2.3 mmol) was added over 15 min. The reaction mixture was stirred
for a further 2 h at the same temperature then warmed to room
temperature and quenched with dry methanol and stirred for
a further 1.5 h. Then the content of the reaction mixture was
extracted with DCM, brine and dried over MgSO4. The organic ex-
tract was evaporated to dryness to afford the aldehyde 10, which
was directly used for the next step without further purification.
Rf¼0.5 (EtOAc/hexane¼1:20).
4.14. (R)-3-Hydroxy-2-methylpropyl acetate (13)
HO
OAc
dH (CDCl3, 200 MHz): 9.32 (s, 1H), 7.64e7.58 (m, 8H), 7.43e7.31
(m, 12H), 6.25 (dd, J¼10.0, 1.4 Hz, 1H), 3.75e3.57 (m, 4H), 3.12e3.07
(m, 1H), 2.01e1.92 (m, 1H), 1.7 (s, 3H), 1.62e1.5 (m, 1H), 1.0 (s, 18H).
dC (CDCl3, 50 MHz): 195.6, 156.3, 140.5, 135.8, 135.71, 135.67,
133.8, 133.6, 129.96, 129.87, 127.9, 127.86, 66.3, 61.6, 38.7, 27.0, 19.4,
19.3, 9.6.
To a stirred suspension of diacetate 12 (9.08 g) in phosphate
buffer solution (60 mL) of pH 7.0 at 37 ꢁC was added the enzyme
lipase (PSD, 1.3 g). The pH of the suspension was kept constant by
the continuous addition of 0.2 M aqueous NaOH using an automatic
titrator. The reaction was monitored by TLC (hexane/EtOAc; 3:1).
When the desired degree of conversion was reached, the reaction
was quenched by the addition of ether (50 mL) and the layers were
separated. The aqueous layer was further extracted with ether
(3ꢂ25 mL) and the combined extracts were washed with saturated
NaCl solution, dried over MgSO4, and concentrated. The crude re-
action mixture was purified by silica gel chromatography (3:1;
hexane/EtOAc) to give the optically active monoester product 13 as
yellow oil in 86% yield (5.87 gm).
4.12. (S,2E,4E)-Ethyl-8-(tert-butyldiphenylsilyloxy)-6-((tert-
butyldiphenylsilyloxy)methyl)-4-methylocta-2,4-dienoate (11)
EtOOC
OTBDPS
OTBDPS
NaH (63 mg, 1.58 mmol) was taken in 5 mL anhydrous THF, then
triethylphosphonoacetate (0.32 mL, 1.58 mmol) was added at 0 ꢁC.
After 0.5 h, aldehyde (10) (1.05 g, 1.58 mmol) was added and the
reaction mixture was warmed to room temperature. After that time
water was added at 0 ꢁC and the reaction mixture was extracted
with Et2O, the organic layer was successively washed with brine
and dried (MgSO4). The crude product was then purified by flash
chromatography (30:1; hexane/EtOAc) to afford ester 11 in 86%
yield (977 mg) as a clear liquid.
Rf¼0.3 (EtOAc/hexane¼1:3).
25
25
[a
]
ꢀ10.2 (c 1.0, CHCl3), {lit10
[
a]
ꢀ10.0 (c 1.2, CHCl3)}. The
D
D
optical and spectroscopy data are in good agreement with reported
values.
4.15. (S)-3-(tert-Butyldiphenylsilyloxy)-2-methylpropyl ace-
tate (14)
TBDPSO
OAc
Rf¼0.3 (EtOAc/hexane¼1:30).
[
a]
25 þ6.55 (c 1.88, CHCl3).
Mono acetate compound 13 (8.62 g, 65 mmol) was taken in
anhydrous DCM (250 mL) and cooled to 0 ꢁC. Imidazole (8.92 g,
130 mmol) and DMAP (catalytic) were added to the reaction mix-
ture followed by the addition of TBDPSeCl (20 mL, 78.2 mmol). The
reaction mixture was allowed to warm at room temperature for 3 h,
after which water was added to it and extracted with DCM, the
organic layer was washed with brine and dried over MgSO4. The
organic extract was evaporated in vacuo to give the crude product,
which was purified by silica gel chromatography (10:1; hexane/
EtOAc) to afford the TBDPS-protected compound 14 in 89% yield
(21.43 g) as a clear liquid.
D
IR (film): 3069, 2931, 2858, 1713, 1624, 1469, 1427, 1300 cmꢀ1
.
dH (CDCl3, 400 MHz): 7.68e7.64 (m, 8H), 7.45e7.39 (m, 12H),
7.32 (d, J¼15.6 Hz, 1H), 5.83 (d, J¼16.0 Hz, 1H), 5.66 (d, J¼9.6 Hz,
1H), 4.28 (q, J¼7.2 Hz, 2H), 3.65e3.56 (m, 4H), 3.02e3.0 (m, 1H),
1.98e1.96 (m, 1H), 1.77 (s, 3H), 1.49e1.46 (m, 1H), 1.36 (t, J¼7.2 Hz,
3H), 1.08 (s, 18H).
dC (CDCl3, 50 MHz): 167.6, 149.6, 143.5, 135.73, 135.65, 134.3,
133.9, 133.7, 129.75, 127.7, 116.0, 66.8, 61.7, 60.2, 38.3, 34.5, 26.9,
19.3, 19.2, 14.4, 12.7.
HRMS (ESI) for C44H56O4NaSi2 [MþNa]þ, calculated: 727.3615,
found: 727.3611.
Rf¼0.5 (EtOAc/hexane¼1:5).

1160
R. Bhuniya, S. Nanda / Tetrahedron 69 (2013) 1153e1165
[
a
]
25 þ17.04 (c 1.0, CHCl3).
HRMS (ESI) for C25H34O3NaSi [MþNa]þ, calculated: 433.2175,
D
dH (CDCl3, 200 MHz): 7.69e7.64 (m, 4H), 7.41e7.38 (m, 6H),
4.18e4.00 (m, 2H), 3.59 (dd, J¼7.2, 4.0 Hz, 2H), 2.11e2.05 (m, 1H),
2.01 (s, 3H), 1.06 (s, 9H), 0.97 (d, J¼6.8 Hz, 3H).
found: 433.2179.
4.18. (4S)-5-(tert-Butyldiphenylsilyloxy)-2,4-dimethylpentan-
1-ol (17)
dC (CDCl3, 50 MHz): 171.3, 135.8, 133.9, 129.8, 127.8, 66.4, 65.4,
35.4, 27.0, 21.1, 19.5, 13.9.
TBDPSO
OH
4.16. (S)-3-(tert-Butyldiphenylsilyloxy)-2-methylpropan-1-ol
(15)
The unsaturated ester 16 (10.52 g, 25.7 mmol) was taken in
MeOH (100 mL), NiCl2 (6.21 g, 26.15 mmol) was added to the re-
action mixture at 0 ꢁC. The temperature of the reaction was kept at
TBDPSO
OH
The acetate group in compound 14 (24.22 g, 65.2 mmol) was
deprotected by adding K2CO3 (4.53 g, 33 mmol) in MeOH (100 mL)
solvent. After completion of the reaction, as indicated by TLC, MeOH
was evaporated under reduced pressure. The residue was taken in
Et2O, and washed successively with water and brine. The organic
layer was dried with MgSO4 and evaporated under reduced pressure.
The product was purified by flash chromatography (3:1; hexane/
EtOAc) to afford compound 15 in 92% yield (19.73 g) as a liquid.
Rf¼0.3 (EtOAc/hexane¼1:5).
0
ꢁC, after 0.5 h NaBH4 (5.43 g, 141.0 mmol) was added to the re-
action mixture. The reaction mixture was then allowed to warm at
room temperature. After completion of the reaction, as indicated by
TLC, MeOH was evaporated under reduced pressure. The residue
was taken in EtOAc, and washed successively with water and brine.
The organic layer was dried with MgSO4 and evaporated under
reduced pressure.
The crude product was used in the next step without further
purification. LAH (1.46 g, 38.5 mmol) was taken in 120 mL dry ether
then the ester was added at 0 ꢁC. After 1 h, saturated solution of
Na2SO4 was added slowly to quench the reaction mixture. Then the
reaction solution was filtered by washing with hot Et2O at several
times. The reaction mixture was evaporated in vacuo to give the
crude product, which was purified by silica gel chromatography
(3:1; hexane/EtOAc) yielded compound 17, in 82% yield (7.77 g) as
diastereomeric mixture as a colorless liquid (over two steps).
Rf¼0.3 (EtOAc/hexane¼1:5).
[a
]
25 þ3.84 (c 1.1, CHCl3).
D
dH (CDCl3, 200 MHz): 7.71e7.67 (m, 4H), 7.44e7.38 (m, 6H),
3.78e3.57 (m, 4H), 2.61 (br, 1H, eOH), 2.05e1.96 (m, 1H), 1.08 (s,
9H), 0.85 (d, J¼7.0 Hz, 3H).
dC (CDCl3, 50 MHz): 135.6, 133.2, 129.8, 127.8, 68.7, 67.6, 37.3,
26.8, 19.2, 13.2.
4.17. (S,Z)-Ethyl-5-(tert-butyldiphenylsilyloxy)-2,4-
dimethylpent-2-enoate (16)
4.19. Oxidative kinetic resolution of compound 17 by G.
oxydans
TBDPSO
COOEt
The strains of G. oxydans are routinely maintained on GYC solid
medium (glucose 50 g/L, yeast extract 10 g/L, CaCO3 10 g/L, agar
15 g/L, pH¼6.8) at 28 ꢁC. Submerged cultures of G. oxydans were
carried out in a GlyY medium (glycerol 25 g/L, yeast extract 10 g/L,
pH 5.0) into 1 l Erlenmeyer flasks containing 500 mL of medium on
a reciprocal shaker (100 rpm). After 24 h, isooctane is added to the
submerged culture (1:1) to make the required volume. Compound
17 (neat; 10 g/L, 27 mmol) was added directly to the suspension and
stirred well in an orbital shaker (100 rpm). The biotransformations
were monitored periodically by TLC analysis. After 2 h, the reaction
mixture was centrifuged (15,000 rpm) to remove the bacterial cells.
The supernatant was extracted several times with large volume of
EtOAc and the organic layer was dried with MgSO4. The solvent was
evaporated in vacuo and the product was purified through silica gel
column chromatography (3:1; hexane/EtOAc). The isolated yield of
alcohol 19 is 45% (4.5 g) and that of acid 18 is 48% (4.96 g).
Oxalyl chloride (3.6 mL, 41.2 mmol) was taken in dry DCM
(160 mL). Dry DMSO (5.9 mL, 82.4 mmol) was added after main-
taining the reaction temperature at ꢀ78 ꢁC. After 20 min, alcohol 15
(9 g, 27.5 mmol) dissolved in dry DCM was added (40 mL). The
reaction mixture was kept at ꢀ78 ꢁC for 50 min. Then Et3N
(22.9 mL, 164.9 mmol) was added and the solution was allowed to
attain room temperature for a while. After that water was added to
it and extracted with DCM, the organic layer was washed with
NaHCO3 solution and brine and dried over MgSO4. The organic
solvent was evaporated in vacuo to afford the crude aldehyde.
In an argon atmosphere the crude aldehyde was taken with dry
DCM (125 mL). Then a precooled (0 ꢁC) solution of ylide ((1-
carbethoxyethylidene)-triphenylphosphorane) (24.8 g, 68.7 mmol)
in DCM (25 mL) was added to the aldehyde solution. The mixture
was stirred at 0 ꢁC for 30 min and then warmed to room temperature
and stirred for an additional 24 h. After that time water was added to
it and was extracted with DCM, the organic layer was washed with
brine and dried over MgSO4. The organic extract was evaporated in
vacuo to give the crude product, which was purified by silica gel
chromatography (20:1; hexane/EtOAc) yielded the unsaturated ester
compound 16, in 88% yield (9.93 g) as a liquid (over two steps).
Rf¼0.4 (EtOAc/hexane¼1:20).
TBDPSO
OH
Compound 19 (liquid): Rf¼0.3 (EtOAc/hexane¼1:5).
25
[
a
]
þ2.48 (c 1.35, CHCl3).
D
dH (CDCl3, 200 MHz): 7.67e7.62 (m, 4H), 7.44e7.35 (m, 6H),
3.54e3.28 (m, 4H), 1.77e1.57 (m, 2H), 1.50e1.37 (m, 2H), 1.04 (s,
9H), 0.93 (d, J¼6.6 Hz, 3H), 0.87 (d, J¼6.4 Hz, 3H).
dC (CDCl3, 50 MHz): 135.6, 134.0, 129.5, 127.6, 68.8, 68.3, 37.2,
33.2, 26.9, 19.3, 17.9, 17.4.
[a
]
25 þ6.56 (c 1.3, CHCl3).
D
HRMS (ESI) for C23H34O2NaSi [MþNa]þ, calculated: 393.2226,
found: 393.2221.
IR (film): 3049, 2855, 1710, 1680, 1465, 1427 cmꢀ1
.
dH (CDCl3, 200 MHz): 7.70e7.66 (m, 4H), 7.42e7.35 (m, 6H), 6.63
(d, J¼9.8 Hz, 3H), 4.21 (q, J¼7.0 Hz, 2H), 3.58 (d, J¼6.2 Hz, 2H),
2.84e2.7 (m, 1H), 1.83 (s, 3H), 1.33 (t, J¼7.2 Hz, 3H), 1.08 (s, 9H), 1.06
(d, J¼7.0 Hz, 3H).
TBDPSO
OH
O
Compound 18 (liquid): Rf¼0.2 (EtOAc/hexane¼1:1).
dC (CDCl3, 50 MHz): 168.2, 144.5, 135.6, 133.7, 129.7, 128.0, 127.7,
67.8, 60.4, 36.2, 26.8, 19.3, 16.3, 14.3, 12.6.
25
[
a
]
ꢀ8.74 (c 1.32, CHCl3).
D

R. Bhuniya, S. Nanda / Tetrahedron 69 (2013) 1153e1165
1161
dH (CDCl3, 400 MHz): 7.67e7.65 (m, 4H), 7.42e7.36 (m, 6H),
4.22. (2S,4R)-5-(4-methoxybenzyloxy)-2,4-dimethylpentanol
(21)
3.52e3.45 (m, 2H), 2.60e2.51 (m, 1H), 1.54e1.48 (m, 2H), 1.24 (d,
J¼6.6 Hz, 3H), 1.02 (s, 9H), 0.94 (d, J¼6.6 Hz, 3H).
dC (CDCl3, 100 MHz): 182.6, 135.6, 129.5, 129.4, 127.5, 68.7, 37.4,
36.9. 33.5, 26.8, 19.2, 17.6, 16.9.
HO
OPMB
HRMS (ESI) for C23H32O3NaSi [MþNa]þ, calculated: 407.2018,
found: 407.2022.
Compound 20 (1.51 g, 3.064 mmol) was taken in dry THF
(15 mL). TBAF (1 M in THF, 4.6 mL) was added to it at 0 ꢁC and the
reaction mixture was stirred for 3 h at room temperature. After that
time, THF was evaporated, and water (7 mL) was added to it, the
reaction mixture was extracted with EtOAc (2ꢂ30 mL), the organic
layer was washed with NaHCO3 and brine, and dried (MgSO4). The
organic extract was evaporated in vacuo to give the crude product,
which was purified by silica gel chromatography (10:1; hexane/
EtOAc) to afford mono PMB protected alcohol 21 (88% yield,
677 mg) as a thick liquid.
4.20. Preparation of (4S)-5-(tert-butyldiphenylsilyloxy)-2,4-
dimethylpentan-1-ol (17) from acid 18
DBU (0.21 mL, 1.5 mmol) was added to stirred solution of acid 18
(4.96 g, 12.9 mmol) in THF (73 mL). Stirring was continued at
refluxing condition for 1 h and then solvent was evaporated. The
crude epimerized acid was then reduced by LAH reduction. LAH
(492 mg, 12.9 mmol) was taken in 70 mL dry Et2O followed by
addition of the crude acid at 0 ꢁC. After reaching room temperature
the reaction mixture was refluxed for 2 h. After completion of the
reaction, as indicated by TLC, saturated solution of Na2SO4 was
added carefully to quench the reaction mixture. Then the reaction
solution was filtered on a Celite pad, by washing with hot Et2O for
several times and then it was concentrated in vacuo. The crude
product was purified by flash chromatography (3:1; hexane/EtOAc)
to afford compound 17 as colorless liquid (3.92 g, yield 88%, over
two steps).
Rf¼0.4 (EtOAc/hexane¼1:5).
[a
]
25 ꢀ2.4 (c 1.0, CHCl3).
D
IR (film): 3388, 2924, 1611, 1512, 1460 cmꢀ1
.
dH (CDCl3, 200 MHz): 7.24 (d, J¼8.4 Hz, 2H), 6.86 (d, J¼8.4 Hz,
2H), 4.41 (s, 2H), 3.79 (s, 3H), 3.49e3.39 (m, 2H), 3.29e3.2 (m, 2H),
2.03 (br, 1H, ꢀOH), 1.89e1.64 (m, 2H), 1.53e1.4 (m, 1H), 1.28e1.17
(m, 1H), 0.93 (d, J¼6.8 Hz, 3H), 0.89 (d, J¼6.0 Hz, 3H).
dC (CDCl3, 50 MHz): 159.3, 130.9, 129.4, 113.9, 75.8, 72.9, 68.0,
55.5, 37.9, 33.4, 31.2, 18.4, 17.8.
HRMS (ESI) for C15H24O3Na [MþNa]þ, calculated: 275.1623,
found: 275.1626.
4.21. ((2S,4R)-4-((4-Methoxybenzyloxy)methyl)-2-
methylpentyloxy)(tert-butyl)diphenylsilane (20)
4.23. (2S,4R)-5-(4-Methoxybenzyloxy)-2,4-dimethylpentanal
(22)
TBDPSO
OPMB
OPMB
OHC
Oxalyl chloride (0.29 mL, 3.3 mmol) was taken in dry DCM
(10 mL). Dry DMSO (0.47 mL, 6.6 mmol) was added to the solution
and the reaction mixture was cooled at ꢀ78 ꢁC. After 20 min, al-
cohol 21 (550 mg, 2.2 mmol) was added dissolving in dry DCM
(4 mL). The reaction mixture was kept at ꢀ78 ꢁC for 50 min. Then
Et3N (1.83 mL, 13.2 mmol) was added to the reaction mixture and it
was allowed to attain room temperature. After that time water was
added to it and extracted with DCM, the organic layer was washed
with NaHCO3 solution and brine and dried over MgSO4. The organic
extract was evaporated in vacuo to give the crude product, which
was purified by silica gel chromatography (8:1; hexane/EtOAc)
yielded the aldehyde compound 22, in 90% yield (491 mg) as
a liquid.
A solution of 4-methoxybenzyl alcohol (1.24 g, 9 mmol) in 25 mL
of ether was added to a suspension of 60% NaH (0.072 g, 1.8 mmol)
in 10 mL of ether at room temperature. The resulting mixture was
stirred at room temperature for 30 min and cooled to 0 ꢁC. Tri-
chloroacetonitrile (TCA, 1.1 mL, 18 mmol) was added to it and the
reaction mixture was allowed to warm slowly to room temperature
over 6 h. The solution was evaporated to orange syrup, which was
dissolved in anhydrous hexane (40 mL) containing a few drops of
MeOH. This suspension was then shaken vigorously and filtered
through Celite, and the filtrate was concentrated to afford the crude
imidate. The crude imidate (2.3 g, 8.12 mmol) was taken in cyclo-
hexane (20 mL) and a solution of alcohol 19 (1.5 g, 4.06 mmol) in
10 mL of DCM was added. The resulting solution was cooled to 0 ꢁC
and CSA (0.094 g, 0.04 mmol) was added to it. The reaction mixture
was stirred overnight at room temperature, and a white precipitate
of trichloroacetamide developed slowly. The solution was filtered
off, and washed with DCM. The filtrate was washed with NaHCO3
solution, water, and brine. The organic extract was evaporated in
vacuo to give the crude product, which was purified by silica gel
chromatography (20:1; hexane/EtOAc) yielded compound 20 in
86% yield (1.71 g) as a liquid.
Rf¼0.7 (EtOAc/hexane¼1:5).
[a
]
25 ꢀ4.89 (c 1.0, CHCl3).
D
IR (film): 2927, 1705, 1611, 1512, 1461, 1247 cmꢀ1
.
dH (CDCl3, 200 MHz): 9.56 (d, J¼2.4 Hz, 1H, CHO), 7.25 (d,
J¼8.4 Hz, 2H), 6.88 (d, J¼8.4 Hz, 2H), 4.41 (s, 2H), 3.80 (s, 3H),
3.3e3.25 (m, 2H), 2.50e2.42 (m, 1H), 1.96e1.75 (m, 2H), 1.6-1.4 (m,
1H), 1.08 (d, J¼7.0 Hz, 3H), 0.95 (d, J¼6.0 Hz, 3H).
dC (CDCl3, 50 MHz): 205.2, 159.1, 130.6, 129.1, 113.8, 75.1, 72.7,
55.2, 44.2, 35.1, 31.3, 17.6, 14.3.
HRMS (ESI) for C15H22O3Na [MþNa]þ, calculated: 273.1467,
found: 273.1462.
Rf¼0.5 (EtOAc/hexane¼1:10).
[
a]
25 ꢀ8.46 (c 0.9, CHCl3).
D
IR (film): 2921, 1700, 1632, 1451, 1355 cmꢀ1
.
dH (CDCl3, 200 MHz): 7.71e7.67 (m, 4H), 7.44e7.34 (m, 6H), 7.26
(d, J¼8.6 Hz, 2H), 6.88 (d, J¼8.0 Hz, 2H), 4.43 (s, 2H), 3.81 (s, 3H),
3.6e3.47 (m, 2H), 3.44e3.12 (m, 2H), 1.9e1.7 (m, 2H), 1.52e1.4 (m,
1H), 1.3e1.2 (m, 1H), 1.09 (s, 9H), 0.98 (d, J¼6.6 Hz, 3H), 0.93 (d,
J¼6.6 Hz, 3H).
4.24. (2S,4R)-5-(4-Methoxybenzyloxy)-1-(furan-2-yl)-2,4-
dimethylpentan-1-ol (23)
OPMB
O
dC (CDCl3, 50 MHz): 159.0, 135.7, 134.1, 131.0, 129.5, 129.1, 127.6,
113.7, 75.8, 72.6, 68.9, 55.3, 37.8, 33.2, 31.0, 26.9, 19.3, 18.1, 17.9.
HRMS (ESI) for C31H42O3NaSi [MþNa]þ, calculated: 513.2801,
found: 513.2806.
OH
n-Butyllithium (1.34 mL, 2.14 mmol) was added to a solution of
furan (0.16 mL, 2.2 mmol) in dry THF (4 mL) solution in an argon

1162
R. Bhuniya, S. Nanda / Tetrahedron 69 (2013) 1153e1165
atmosphere at room temperature. The reaction mixture was further
stirred at ambient temperature for 3 h, followed by addition of al-
dehyde 22 (500 mg, 2 mmol) at 0 ꢁC. The reaction mixture allowed
to warm room temperature. After that water was added to it and
extracted with Et2O, the organic layer was washed with brine and
dried over MgSO4. The organic extract was evaporated in vacuo to
give the crude product, which was purified by silica gel chroma-
tography (3:1, hexane/EtOAc) afforded compound 23, in 76% yield
(502 mg) as a liquid.
4.27. (2R)-2-((2S,4R)-5-(4-Methoxybenzyloxy)-4-
methylpentan-2-yl)-6-hydroxy-2H-pyran-3(6H)-one (26)
O
OPMB
HO
O
To a mixture of compound 25 (1.32 g, 3.95 mmol) in THF/water
(4:1), NaHCO3 (664 mg, 7.9 mmol), NaOAc (324 mg, 3.95 mmol),
and NBS (704 mg, 3.95 mmol) were added at 0 ꢁC. The reaction
mixture was then allowed to warm at room temperature, after
which water was added to it and extracted with Et2O, the organic
layer was washed with brine and dried over MgSO4. The organic
extract was evaporated in vacuo to give the crude product, which
was purified by silica gel chromatography (5:1; hexane/EtOAc)
yielded the hemi-acetal compound 26 in 90% yield (1.17 g) as a clear
liquid.
4.25. (2S,4R)-5-(4-Methoxybenzyloxy)-1-(furan-2-yl)-2,4-
dimethylpentan-1-one (24)
OPMB
O
O
To a stirred suspension of MnO2 (6.32 g, 71.1 mmol), in dry
CH2C12 (10 mL) was added a solution of 23 (450 mg, 1.37 mmol) in
CH2Cl2 (5 mL) at 0 ꢁC. Stirring was continued for 1 h at room
temperature. Then the reaction mixture was filtered through a pad
of Celite by washing with DCM at several times. The solution was
then evaporated to give a crude residue, which was purified by
column chromatography on silica gel using hexane/EtOAc (20:1, v/
v) as eluent to afford the ketone 24 in 74% yield (331 mg) as a col-
orless liquid.
Rf¼0.6 (EtOAc/hexane¼1:10).
dH (CDCl3, 200 MHz): 7.31e7.26 (m, 2H), 6.93e6.86 (m, 3H), 6.1
(d, J¼10.2 Hz, 1H), 5.58 (d, J¼7.0 Hz, 1H), 4.59e4.47 (m, 1H), 4.44 (s,
2H), 3.82 (s, 3H), 3.48e3.14 (m, 2H), 2.48e2.38 (m, 1H), 1.82e1.73
(m, 2H), 1.38e1.3 (m, 1H), 0.98 (d, J¼7.0 Hz, 3H), 0.96 (d, J¼6.8 Hz,
3H).
Rf¼0.4 (EtOAc/hexane¼1:10).
4.28. (5R,6R)-6-((2S,4R)-5-(4-Methoxybenzyloxy)-4-
methylpentan-2-yl)-5,6-dihydro-5-hydroxypyran-2-one (B)
[a
]
25 þ44.8 (c 1.0, CHCl3).
D
IR (film): 2921, 1715, 1588, 1452, 1365 cmꢀ1
.
dH (CDCl3, 200 MHz): 7.59 (d, J¼1.8 Hz, 1H), 7.27 (d, J¼6.8 Hz,
1H), 7.21e7.15 (m, 2H), 6.94 (d, J¼8.0 Hz, 2H), 6.52 (m, 1H), 4.43 (s,
2H), 3.84 (s, 3H), 3.48e3.24 (m, 3H), 2.03e1.55 (m, 2H), 1.32e1.26
(m, 1H), 1.23 (d, J¼5.6 Hz, 3H), 0.98 (d, J¼6.6 Hz, 3H).
dC (CDCl3, 50 MHz): 193.6, 171.3, 159.2, 146.5, 130.9, 129.3, 117.5,
113.9, 112.3, 72.3, 70.6, 55.4, 39.4, 37.9, 31.6, 17.9, 17.3.
HRMS (ESI) for C19H24O4Na [MþNa]þ, calculated: 339.1572,
found: 339.1575.
O
O
OPMB
OH
To a stirred suspension of PCC (1.36 g, 6.3 mmol), Celite
(971 mg), and anhydrous sodium acetate (516 mg, 6.3 mmol) in
CH2C12 (8 mL) was added a solution of 26 in CH2Cl2 (15 mL) at 0 ꢁC.
The reaction mixture was allowed to attain room temperature.
Stirring was continued for 24 h, and then the reaction mixture was
filtered through Celite-pad by washing with DCM at several times.
The solution was evaporated to give the crude lactone.
4.26. (1R,2S,4R)-5-(4-Methoxybenzyloxy)-1-(furan-2-yl)-2,4-
dimethylpentan-1-ol (25)
OPMB
O
To a cooled (ꢀ78 ꢁC) stirred solution of crude lactone (690 mg,
2.11 mmol) in MeOH (7 mL) was added CeCl3$7H2O (1.57 g,
4.2 mmol). The mixture was stirred at ꢀ78 ꢁC for 20 min, and
NaBH4 (80 mg, 2.11 mmol) was added. The reaction mixture was
then kept at ꢀ78 ꢁC for 3 h. After completion of the reaction, as
indicated by TLC, MeOH was evaporated under reduced pressure.
The residue was taken in EtOAc, and washed successively with
water and brine. The organic layer was dried with MgSO4 and
evaporated under reduced pressure. The residue was purified by
column chromatography on silica gel (10:1; hexane/EtOAc) to
provide compound B (74% yield, 962 mg, over two steps) as a thick
clear liquid.
OH
To a cooled (ꢀ78 ꢁC) stirred solution of ketone 24 (1.32 g,
3.95 mmol) in THF (40 mL) was added L-Selectride (1.0 M solution
in THF, 22 mL, 22 mmol). The mixture was stirred at ꢀ78 ꢁC for
15 min and 35% aqueous H2O2 (10 mL) was added afterward. After
being stirred for 1 h, the mixture was quenched with saturated
aqueous Na2SO3 (20 mL). The resulting mixture was diluted with
H2O and extracted with CH2Cl2 (20 mLꢂ5). The combined extracts
were dried and concentrated in vacuo. The crude residue was pu-
rified by column chromatography on silica gel (8:1; hexane/EtOAc)
to provide compound 25 (85% yield, 1.12 g) as a colorless liquid.
Rf¼0.5 (EtOAc/hexane¼1:5).
Rf¼0.5 (EtOAc/hexane¼1:5).
25
[a
]
25 ꢀ6.3 (c 1.2, CHCl3).
[
a
]
D
ꢀ10.71 (c 0.17, CHCl3).
D
IR (film): 3372, 2921, 1622, 1458, 1375 cmꢀ1
.
IR (film): 3447, 2924, 1718, 1654, 1543, 1509, 1459 cmꢀ1
.
dH (CDCl3, 200 MHz): 7.40e7.27 (m, 3H), 6.92 (d, J¼8.6 Hz, 2H),
6.37e6.24 (m, 2H), 4.56e4.50 (m, 1H), 4.46 (s, 2H), 3.84 (s, 3H),
3.39e3.22 (m, 2H), 2.55e2.44 (br, 1H, ꢀOH), 2.15e2.06 (m, 1H),
1.98e1.85 (m, 1H), 1.76e1.45 (m, 2H), 1.03 (d, J¼7.2 Hz, 3H), 0.97 (d,
J¼6.5 Hz, 3H).
dH (CDCl3, 200 MHz): 7.15 (d, J¼6.0 Hz, 2H), 6.84 (dd, J¼9.4 Hz,
6.0 Hz,1H), 6.78 (d, J¼8.6 Hz, 2H), 6.01 (d, J¼9.6 Hz,1H), 4.33 (s, 2H),
4.15e4.05 (m, 1H), 3.85e3.76 (m, 1H), 3.71 (s, 3H), 3.21e3.10 (m,
2H), 2.24e1.99 (m, 2H), 1.95e1.78 (m, 2H), 1.05 (d, J¼7.4 Hz, 3H),
0.82 (d, J¼6.8 Hz, 3H).
dC (CDCl3, 50 MHz): 159.2, 156.6, 141.7, 130.8, 129.3, 113.9, 110.2,
106.7, 75.6, 72.9, 71.5, 55.4, 37.5, 35.7, 31.1, 18.6, 16.7.
HRMS (ESI) for C19H26O4Na [MþNa]þ, calculated: 341.1729,
found: 341.1724.
dC (CDCl3, 50 MHz): 164.0, 159.2, 144.3, 129.6, 129.3, 123.1, 113.8,
85.4, 76.1, 72.7, 60.4, 55.3, 35.7, 30.6, 16.3, 15.7.
HRMS (ESI) for C19H26O5Na [MþNa]þ, calculated: 357.1678,
found: 357.1681.

R. Bhuniya, S. Nanda / Tetrahedron 69 (2013) 1153e1165
1163
4.29. (2E,4E,6S)-(2R,3R)-2-((2S,4R)-5-(4-Methoxybenzyloxy)-
4-methylpentan-2-yl)-3,6-dihydro-6-oxo-2H-pyran-3-yl-8-
tert-butyldiphenylsilyloxy-6-(tert-butyldiphenylsilyloxy-
methyl)-4-methylocta-2,4-dienoate (27)
dH (CDCl3, 200 MHz): 7.59e7.55 (m, 8H), 7.39e7.18 (m, 13H), 7.01
(dd, J¼6.2, 3 Hz, 1H), 6.18 (d, J¼9.6 Hz, 1H), 5.73 (d, J¼11.6 Hz, 1H),
5.61 (d, J¼8.8 Hz, 1H), 5.39 (dd, J¼6.8, 2.6 Hz, 1H), 4.07 (dd, J¼8.6,
2.8 Hz, 1H), 3.62e3.49 (m, 4H), 3.42e3.31 (m, 2H), 3.01e2.90(m,
1H), 2.65 (br, 1H, eOH), 2.11e2.03 (m, 1H), 1.88e1.85 (m, 1H),
1.77e1.70 (m, 1H), 1.68 (s, 3H), 1.45e1.30 (m, 3H), 1.09 (d, J¼6.2 Hz,
3H), 1.04 (s, 18H), 0.87 (d, J¼5.2 Hz, 3H).
O
O
OPMB
dC (CDCl3, 50 MHz): 166.5, 163.4, 151.8, 145.5, 140.7, 135.7, 135.6,
134.2, 133.8, 133.6, 129.7, 128.3, 127.7, 125.0, 114.1, 83.5, 68.7, 66.7,
61.6, 60.5, 38.4, 34.4, 32.7, 31.0, 26.9, 21.1, 19.3, 19.2, 15.2, 14.3, 12.7.
A 0 ꢁC solution of triphenylphosphine (143 mg, 0.55 mmol),
imidazole (37 mg, 0.55 mmol), and iodine (138 mg, 0.55 mmol) in
CH2Cl2 (6 mL) was stirred under argon atmosphere for 15 min. The
alcohol 28 (160 mg, 0.18 mmol) was dissolved in CH2Cl2 (4 mL) and
added dropwise to the reaction mixture. The reaction mixture was
stirred for 30 min at this temperature then warmed to room tem-
perature. Stirring was continued for 3 h, and then the reaction
mixture was quenched with H2O and extracted with CH2Cl2. The
combined organic layers were washed with Na2S2O3, dried
(MgSO4), and concentrated in vacuo. The crude residue was puri-
fied by column chromatography on silica gel (20:1; hexane/EtOAc)
to provide iodo compound 29 (85% yield, 114 mg) as a liquid.
Rf¼0.7 (EtOAc/hexane¼1:10).
O
OTBDPS
OTBDPS
O
Distilled triethylamine (0.15 mL, 1.095 mmol) was added to
a solution of diene acid A (378 mg, 0.547 mmol, 1.5 equiv) in an-
hydrous toluene (20 mL) at room temperature, followed by distilled
2,4,6-trichlorobenzoyl chloride (0.12 mL, 0.73 mmol) was added
dropwise, and the resulting clear, colorless solution was stirred at
the same temperature. After 1 h, TLC (10% hexanes/EtOAc) showed
complete consumption of diene acid A. Alcohol B (120 mg,
0.365 mmol) in dry toluene (21 mL) was then added, followed by
DMAP (156 mg, 1.28 mmol) to give a white suspension. After
completion of the reaction (5 h), as indicated by TLC, MeOH was
evaporated under reduced pressure and the crude residue was di-
rectly loaded into a silica gel column. The compound was purified
by column chromatography on silica gel (30:1; hexane/EtOAc) to
provide compound 27 (84% yield, 307 mg) as a liquid.
[a
]
25 ꢀ145.4 (c 0.25, CHCl3).
D
IR (film): 3451, 2924, 1719, 1655, 1459 cmꢀ1
.
dH (CDCl3, 200 MHz): 7.57e7.54 (m, 8H), 7.39e7.25 (m,13H), 7.05
(dd, J¼6.4, 3.2 Hz, 1H), 6.16 (d, J¼9.2 Hz, 1H), 5.73 (d, J¼13.4 Hz, 1H),
5.63 (d, J¼9.0 Hz, 1H), 5.29 (dd, J¼6.2, 2.3 Hz, 1H), 4.06 (dd, J¼9.0,
2.6 Hz, 1H), 3.59e3.42 (m, 4H), 3.28e3.13 (m, 2H), 3.03e2.92 (m,
1H), 2.11e2.07 (m, 1H), 1.87e1.80 (m, 1H), 1.66 (s, 3H), 1.43e1.33 (m,
3H), 1.11 (d, J¼6.5 Hz, 3H), 1.02e0.971 (m, 1H), 0.971 (s, 18H), 0.91
(d, J¼6.5 Hz, 3H).
Rf¼0.6 (EtOAc/hexane¼1:10).
[
a]
25 þ8.15 (c 1.45, CHCl3).
D
IR (film): 3446, 3069, 2932, 2858, 1962, 1890, 1727, 1618 cmꢀ1
.
dH (CDCl3, 200 MHz): 7.63e7.54 (m, 8H), 7.39e7.19 (m, 13H), 7.09
(d, J¼6.2 Hz, 2H), 7.04e6.96 (m, 1H), 6.78 (m, 2H), 6.16 (d, J¼9.6 Hz,
1H), 5.69 (d, J¼15.8 Hz, 1H), 5.65e5.56 (m, 1H), 5.35e5.32 (m, 1H),
4.35(s, 2H), 4.11e4.03 (m, 1H), 3.71 (s, 3H), 3.58e3.49 (m, 4H),
3.22e3.06 (m, 2H), 2.98e2.84 (m, 1H), 2.19e2.08 (m, 1H), 1.91e1.81
(m, 2H), 1.67 (d, J¼7.4 Hz, 3H), 1.48e1.32 (m, 2H), 1.02 (d, J¼5.6 Hz,
3H), 0.96 (s, 19H), 0.91 (d, J¼5.2 Hz, 3H).
dC (CDCl3, 50 MHz): 166.5, 163.2, 151.5, 145.2, 141.0, 135.7, 135.6,
134.2, 133.8, 133.7, 129.7, 129.1, 128.3, 127.7, 124.9, 114.7, 83.2, 66.7,
61.6, 61.5, 38.4, 34.4, 31.2, 26.9, 22.3, 19.3, 19.2, 16.4, 15.4, 12.7, 11.6.
HRMS (ESI) for C53H67O6NaISi2 [MþNa]þ, calculated: 1005.3419,
found: 1005.3416.
dC (CDCl3, 50 MHz): 166.5, 163.4, 159.1, 151.6, 145.4, 140.8, 140.7,
135.7, 135.6, 134.2, 133.8, 133.7, 130.7, 129.7, 129.3, 129.0, 128.3,
127.74, 125.0, 113.8, 83.1, 74.8, 72.8, 66.7, 61.9, 61.6, 55.3, 38.4, 34.4,
31.75, 31.1, 30.9, 26.9, 19.2, 18.9, 16.1, 12.7.
4.31. (2E,4E,6S)-(2R,3R)-3,6-Dihydro-2-((E,2S,4R)-4,6-
dimethyloct-6-en-2-yl)-6-oxo-2H-pyran-3-yl-8-tert-butyldi-
phenylsilyloxy-6-(tert-butyldiphenylsilyloxy-methyl)-4-
methylocta-2,4-dienoate (30)
HRMS (ESI) for C61H76O8NaSi2 [MþNa]þ, calculated: 1015.4976,
found: 1015.4972.
4.30. (2E,4E,6S)-(2R,3R)-3,6-Dihydro-2-((2S,4R)-5-iodo-4-
methylpentan-2-yl)-6-oxo-2H-pyran-3-yl-8-tert-butyldiphe-
nylsilyloxy-6-(tert-butyldiphenylsilyloxy-methyl)-4-
methylocta-2,4-dienoate (29)
O
O
O
OTBDPS
OTBDPS
O
O
O
I
To a mixture of compound 29 (150 mg, 0.152 mmol) in dry
toluene, activated ZneCu couple (15 mg, 0.23 mmol) and dime-
thylacetamide (38 mg, 0.44 mmol) were added at 70 ꢁC. The
resulting suspension was vigorously stirred at this temperature for
4 h. The mixture was cooled to 60 ꢁC before Pd(PPh3)4 (9 mg,
O
OTBDPS
OTBDPS
O
0.007 mmol) and E-2-bromobutene (16
mL, 0.152 mmol) were
Compound 27 (320 mg, 0.32 mmol) was taken in 5 mL of DCM/
H2O (19:1). Next, DDQ (109 mg, 0.48 mmol) was added to it in one
portion at 0 ꢁC. The reaction mixture was allowed to warm to room
temperature and further stirred at same temperature for 3 h. The
reaction mixture was then filtered off, and the filtrate was washed
with 5% NaHCO3 solution, water, and brine. The organic layer was
dried (MgSO4) and evaporated. The organic extract was evaporated
in vacuo to give the crude product, which was purified by silica gel
chromatography (3:1, hexane/EtOAc) to afford the pure alcohol 28
in 80% yield (225 mg) as a liquid.
added. After stirring for 1 h at this temperature, the reaction was
quenched with water and the aqueous layer extracted with Et2O.
The combined extracts were dried over MgSO4, filtered, and
evaporated, and the residue purified by flash chromatography
(20:1; hexane/EtOAc) to give compound 30 in 76% yield (106 mg) as
a liquid.
Rf¼0.6 (EtOAc/hexane¼1:10).
[a
]
25 ꢀ152.6 (c 0.25, CHCl3).
D
IR (film): 3465, 2928, 2857, 1721, 1621, 1463, 1381 cmꢀ1
.
dH (CDCl3, 200 MHz): 7.63e7.59 (m, 8H), 7.42e7.34 (m, 13H),
7.04 (dd, J¼9.4, 6.2 Hz,1H), 6.23 (d, J¼9.2 Hz, 1H), 5.76 (d, J¼16.0 Hz,
[
a]
25 þ34.87 (c 0.5, CHCl3).
D

1164
R. Bhuniya, S. Nanda / Tetrahedron 69 (2013) 1153e1165
1H), 5.66 (d, J¼9.6 Hz, 1H), 5.41 (dd, J¼6.0, 2.2 Hz, 1H), 5.09 (q,
J¼6.7 Hz, 1H), 4.14 (dd, J¼9.2, 2.4 Hz, 1H), 3.64e3.45(m, 4H),
2.98e2.92 (m, 1H), 2.17e2.10 (m, 1H), 1.98 (m, 1H), 1.83 (s, 3H),
1.75e1.64 (m, 2H), 1.60 (m, 1H), 1.59 (d, J¼6.5 Hz, 3H), 1.54 (s, 3H),
1.46 (dd, J¼12.6, 10.2 Hz, 1H), 1.25 (ddd, J¼13.8, 9.2, 4.4 Hz, 1H), 1.12
(d, J¼6.5 Hz, 3H), 1.02 (s, 19H), 0.76 (d, J¼6.5 Hz, 3H).
dC (CDCl3, 50 MHz): 166.5, 163.5, 151.4, 145.4, 140.8, 135.8, 135.7,
134.3, 134.0, 133.8, 129.8, 127.8, 125.2, 120.1, 114.9, 83.7, 66.8, 61.7,
61.5, 43.3, 38.5, 34.5, 31.5, 30.2, 27.0, 24.9, 24.3, 19.3, 15.9, 15.6, 12.7,
11.9.
dH (CDCl3, 400 MHz): 7.34 (d, J¼16.0 Hz, 1H), 7.03 (dd, J¼9.4,
6.2 Hz, 1H), 6.21 (d, J¼9.2 Hz, 1H), 5.79 (d, J¼16.0 Hz, 1H), 5.76 (d,
J¼9.8 Hz, 1H), 5.34 (dd, J¼6.2, 2.2 Hz, 1H), 5.10 (q, J¼6.7 Hz, 1H), 4.11
(dd, J¼9.0, 2.2 Hz, 1H), 3.74 (dt, J¼10.4, 5.2 Hz 1H), 3.61 (m, 3H),
2.9e2.85 (m, 1H), 2.15e2.13 (m, 1H), 2.03 (br d, J¼12.0 Hz, 1H), 1.83
(s, 3H),1.77e1.66 (m, 2H),1.62 (m,1H),1.52 (d, J¼6.5 Hz, 3H),1.50 (s,
3H), 1.4 (dd, J¼12.6, 10.2 Hz, 1H), 1.18 (ddd, J¼13.8, 9.2, 4.4 Hz, 1H),
1.15 (d, J¼6.5 Hz, 3H), 1.04 (ddd, J¼13.6, 9.2, 4.0 Hz, 1H), 0.76 (d,
J¼6.5 Hz, 3H).
dC (CDCl3, 100 MHz): 166.2, 163.4, 151.1, 143.5, 140.7, 134.8, 134.3,
124.9, 120.1, 115.1, 83.3, 66.0, 61.6, 60.7, 46.4, 39.8, 39.3, 34.8, 31.4,
27.8, 20.5, 15.9, 15.6, 13.2, 12.7.
HRMS (ESI) for C57H74O6Si2Na [MþNa]þ, calculated: 933.4922,
found: 933.4927.
HRMS (ESI) for C25H38O6Na [MþNa]þ, calculated: 457.2566,
4.32. Unsuccessful attempt for the coupling reaction
found: 457.2561.
The optical and spectroscopy data are in good agreement with
reported values.
4.32.1. By
tert-BuLi
reaction. tert-Butyllithium
(0.34
mL,
L,
0.441 mmol) was added to a solution of E-2-bromobutene (26
m
0.253 mmol) in dry THF (1 mL) solution in an argon atmosphere at
ꢀ78 ꢁC. The reaction mixture was further stirred at ambient tem-
perature for 1 h, followed by addition of compound 29 (250 mg,
0.253 mmol) in dry THF. The reaction mixture was stirred for 2 h at
ꢀ78 ꢁC, then allowed to warm to room temperature and stirred for
15 h. After that water was added to it and extracted with Et2O, the
organic layer was washed with saturated ammonium chloride so-
lution then brine and dried over MgSO4. The organic extract was
evaporated in vacuo to give the crude product, which was purified
by silica gel chromatography (20:1; hexane/EtOAc). Though we
were able to isolate compound 30 but the miserably low yield
(<10%) forced us to go for other alternatives.
Acknowledgements
Financial support from DST-India is gratefully acknowledged
(Grant: SR/S1/OC-55/2009, IRPHA for NMR instrument). One of the
authors R.B. is thankful to CSIR-India for providing research
fellowship.
Supplementary data
Copies of the 1H NMR and 13C NMR spectra for all key in-
termediates and final products with few HPLC chromatograms are
available. Supplementary data associated with this article can be
found in the online version, at http://dx.doi.org/10.1016/
j.tet.2012.11.051.
4.32.2. By using FeCl3. To a solution of compound 29 (250 mg,
0.253 mmol) and anhydrous FeCl3 (10 mg, 0.06 mmol) at 0 ꢁC in THF
(1 mL) was added a premixed solution of TMEDA (0.17 mL,
1.14 mmol) and (E)-1-methyl-1-propenylmagnesium bromide
(which was prepared by addition of Mg (32 mg, 1.32 mmol) and E-
2-bromobutene (0.13 mL, 1.2 mmol) in dry THF (1 mL)) via a syringe
pump at a 5 mL/h rate. Once the addition was completed, the re-
action mixture was warmed to room temperature. After 30 min, the
mixture was quenched by addition of a saturated aqueous solution
of NH4Cl, but with our dismay we could not detect the formation of
product 30.
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O
OH
To a cooled (0 ꢁC) stirred solution of compound 30 (70 mg,
0.076 mmol) in dry THF (3 mL), HF/pyridine (110 L) was added
m
dropwise. The reaction mixture was allowed to warm room tem-
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]
25 ꢀ166.5 (c 1.0, CHCl3), {lit1
[a
]
25 ꢀ170 (c 0.086, MeOH), lit3
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R. Bhuniya, S. Nanda / Tetrahedron 69 (2013) 1153e1165
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