Asymmetric synthesis of a 12-membered macrolactone core and a 6-epi analogue of amphidinolide W from 4-pentenoic acid

Article abstract of DOI:10.1016/j.tetasy.2012.07.006

A flexible and efficient asymmetric route to the synthesis of a 12-membered macrolactone core and a 6-epi analogue of amphidinolide W has been accomplished from commercially available 4-pentenoic acid. The successful generation of stereocenters was achieved by utilizing an Evans' chiral auxiliary-based alkylation and aldol reaction. Other key reactions such as a Julia-Kocienski olefination, Kita's macrolactonization, ring closing metathesis (RCM) reaction, and Yamaguchi's esterification were significant for the construction of the macrolactone cores.

Full text of DOI:10.1016/j.tetasy.2012.07.006

Tetrahedron: Asymmetry 23 (2012) 1170–1185
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis of a 12-membered macrolactone core and a 6-epi
analogue of amphidinolide W from 4-pentenoic acid
Bhaskar Chatterjee a, Dhananjoy Mondal a,b, Smritilekha Bera a,b,
⇑
a Division of Organic Chemistry, National Chemical Laboratory, Pune 411008, India
b School of Chemical Sciences, Central University of Gujarat, Gandhinagar 382030, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 May 2012
Accepted 12 July 2012
A flexible and efficient asymmetric route to the synthesis of a 12-membered macrolactone core and a 6-
epi analogue of amphidinolide W has been accomplished from commercially available 4-pentenoic acid.
The successful generation of stereocenters was achieved by utilizing an Evans’ chiral auxiliary-based
alkylation and aldol reaction. Other key reactions such as a Julia–Kocienski olefination, Kita’s macrolact-
onization, ring closing metathesis (RCM) reaction, and Yamaguchi’s esterification were significant for the
construction of the macrolactone cores.
Ó 2012 Elsevier Ltd. All rights reserved.
OH
1. Introduction
R1
R2
Naturally occurring marine microorganisms serve as a limitless
source of diverse and highly complex secondary metabolites exhib-
iting a wide range of biological activities, such as cytotoxicity, anti-
viral and anti-fungal properties.1–6 Amphidinolides represent a
group of structurally unique naturally occurring marine macrolides
that have gained attention from medicinal chemists. Since 1986,
Kobayashi et al. have isolated more than 30 novel metabolites
belonging to the ‘amphidinolide’ class from marine dinoflagellates
of the genus Amphidinium sp.7 Many of the amphidinolides exhibit
potent cytotoxic properties against various cancer cell lines in the
standard assays. Despite their common origin and uniform activity
profile, the interesting structural architecture, and biological activ-
ity (mainly anti-tumor properties) and limited natural abundance
of this family of macrolides remain a great challenge to the syn-
thetic organic chemists.8 Amphidinolide W 1, a 12-membered
macrolide isolated by Kobayashi et al. in 2002, shows potent cyto-
toxicity against murine lymphoma L1210 cells in vitro with an IC50
O
*
O
O
Me
Amphidinolide W 1: R1 = H, R2 = Me
(revised)
Amphidinolide W 2: R1 = Me, R2 = H
(proposed)
8
10
OBn
OBn
11
6
9
Me
Me
O
O
*
5
*
2
1
O
MEMO
TBSO
O
Me
Me
6-epi-3 4
macrolactone core 3
value of 3.9 l
g/mL.9 It is structurally unique; being the first and
Figure 1. Structures of amphidinolide W (1 and 2), macrolactone core 3 and 6-epi
analogue 4.
only member in the family which lacks an exomethylene unit. Ex-
cited by the interesting structural features in combination with its
fascinating biological activity, we envisaged developing a poten-
tially useful synthetic method toward the synthesis of amphidino-
lide W (Fig. 1). In this synthesis, the greatest challenge is to
eliminate the risk of epimerization during the esterification and/
or macrolactonization step and control the stereochemistries con-
cerning the formation of the double bond in the D9,10 position
associated with other stereogenic centers, present in the
molecules.
The synthesis of the 12-membered macrolactone core 3 of
amphidinolide W 1 has recently been reported by us,10 while the
total synthesis of amphidinolide W with its structural revision
was deduced earlier11 when Ghosh et al. reported the stereochem-
ical inversion at the C-6 center of the proposed amphidinolide W 2
that is, the 6-epimer of revised amphidinolide W 1. In their syn-
thetic efforts, a well established cross metathesis and Yamaguchi’s
⇑
Corresponding author. Fax: +91 (079) 23260076.
E-mail address: lekha026@yahoo.com (S. Bera).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.07.006

B. Chatterjee et al. / Tetrahedron: Asymmetry 23 (2012) 1170–1185
1171
lactonisation approach resulted in the synthesis of the proposed
amphidinolide W 2 along with its C2-epimer; however major dis-
crepancies in the observed NMR data of proposed amphidinolide
W 2 by Kobayashi et al.,7 compelled them to synthesize the revised
amphidinolide W 1. A comprehensive analysis of the spectroscopic
data of the revised amphidinolide W 1 finally revealed it to be a
naturally occurring compound.
Herein we report a full account of an efficient and successful
synthesis of a 12-membered macrolactone core 3 along with its
6-epi analogue 4 of amphidinolide W 1. Our study could also be
useful in investigating the structure-activity relationship of these
series of isomeric molecules (Fig. 1).
planned to be generated from the chiral auxiliary assisted Evans’
alkylation. The remaining C11 center could be achieved from
D-
mannitol.12,13 Our retrosynthesis illustrates that common to both
syntheses is fragment 7, which could be easily prepared from an
achiral and commercially abundant material, 4-pentenoic acid 8.
The total synthesis of amphidinolide W could be achieved by
assembling the diene fragment with the macrolactone cores 3
and 4 after removal of the O-benzyl group. This could be achieved
by using Lewis acid conditions14a,b,c such as: (1) TiCl4 in CH2Cl2 or
(2) BCl3 or BBr3 in CH2Cl2 which would sustain the olefin as well as
the lactone functionality. Thus, it was envisioned that the side
chain could be stitched in both of the macrolactone cores 3 and
4 in a straightforward manner to complete the total synthesis of
amphidinolide W14 (Fig. 2).
2. Results and discussion
In order to validate our strategy, the synthesis of fragment 7
was chosen as the initial target for our investigation. Thus, for
the asymmetric Evans’ alkylation, the required N-pentenoyl oxazo-
lidinone 12 was prepared via N-acylation of the easily available
(4S)-4-benzyloxazolidin-2-one 11 using a mixed anhydride, ob-
tained from 4-pentenoic acid 8 and pivaloyl chloride in the pres-
ence of lithium chloride and Et3N in THF.15 The presence of
lithium chloride was essential for acylation, possibly due to the
chelating ability of the lithium ion, which results in the activation
of the acid anhydride. Next, the Evans’ alkylation was accom-
plished with oxazolidinone 12 and CH3I in the presence of NaH-
MDS at ꢀ78 °C offering 13 with good yield (85%) and high
diastereoselectivity (17:1).10,16 The diastereomeric purity was as-
sessed on the basis of 1H and 13C NMR spectroscopy. The stereo-
chemical outcome could be ascertained by hydrolyzing 13 into
the corresponding known acid 1717 and comparing its analytical
2.1. Retrosynthetic analysis and strategy
The central goal was the synthesis of macrolactone cores 3 and
4 containing four stereogenic centers and one
D
9,10E-alkene. Retro-
synthetically, the construction of the architectural frame of macro-
lactone core 3 could be primed via the highly stereoselective Julia–
Kocienski olefination of fragments 6, and subsequently invoking
Kita’s protocol for the macrolactonization of fragment 5, whereas
for the 6-epi analogue 4, Yamaguchi esterification on fragment 10
and a ring closing metathesis reaction (RCM) of the key fragment 9
were implemented.
The salient feature of this synthesis is the dibutyl boron triflate
(Bu2BOTf) mediated highly stereocontrolled Evans’ syn-aldol reac-
tion using an oxazolidinone based chiral auxiliary which was ex-
pected to fix the C5 and C6 centers whereas the C2 center was
OH
Julia-Kocienski olefination
OTBS
8
10
OBn
11
6
OH
O
9
Me
Me
O
O
5
BnO
2
1
OH
TBSO
O
O
O
Me
Me
Me
Me
3
5
Kita's macrocyclization
Amphidinolide W
revised 1
O
O
OTBS
Evans alkylation
Evans aldol
HO
H
OH
OBn
OBn
Me
Me
Me
7
Me
6
4-pentenoic acid 8
OBn
Evans Aldol
OH
OH
Me
O
OBn
Me
Me
OMEM
O
9
10
Yamaguchi esterification
Ring Closing Metathesis
OBn
Me
O
Me
O
O
O
O
MEMO
Me
Me
Amphidinolide W
4
proposed 2
Figure 2. Disconnection approach of macrolactone core 3 and its 6-epi analogue 4.

1172
B. Chatterjee et al. / Tetrahedron: Asymmetry 23 (2012) 1170–1185
data with reported values [literature ½a D25
ꢁ
¼ þ10:5 (c 1.0, CHCl3),
O
O
O
observed ½a 2D5
¼ þ9:9 (c 1.0, CHCl3)]. The oxazolidinone derivative
ꢁ
a
13 was smoothly cleaved with lithium aluminium hydride18 in
Et2O to furnish alcohol 14, which was difficult to purify due to
its volatile nature. Therefore, the crude residue was benzylated
to afford the benzylated derivative 15 in 86% yield over two steps,
after chromatographic purification on silica gel. Next, aldehyde 7
as a common precursor, required for the synthesis of both frag-
ments 3 and 4, was derived from 15 via hydroboration–oxidation
using BH3ꢂSMe2 and H2O2 in NaOH followed by oxidation with
Dess–Martin periodinane19 in CH2Cl2 (Scheme 1). When the proce-
dure for the synthesis of 7 was established, we next concentrated
on the stereoselective Evans’ aldol reaction in both of the strategies
for the preparation of macrolactone cores 3 and 4.
b
N
O
OH
4-pentenoic acid 8
O
Bn
HN
O
12
11
Bn
O
O
d
OR
N
O
Me
Me
c
Bn
14: R = H
e
13
15: R = Bn
With aldehyde 7 in hand, we next focused our attention on the
generation of the C5 and C6 centers of macrolactone 4. Oxazolidi-
none 18 was prepared first from (4S)-4-benzyloxazolidin-2-one 11,
with a mixed anhydride generated from a mixture of 5-hexenoic
acid and pivaloyl chloride using a similar method to that described
in Scheme 1. Our next concern was the Evans’ aldol reaction20 be-
tween oxazolidinone 18 and aldehyde 7. Upon subjecting the two
components to Evans’ syn aldol reaction conditions using Bu2BOTf,
i-Pr2EtN in CH2Cl2 at ꢀ78 °C, we produced the syn aldol product 19
in 72% yield after chromatographic purification. The diastereose-
lectivity was very high (>97%). The stereoselectivity of 19 was as-
sumed on the basis of literature precedent21 and the syn
relationship of the newly-generated homoallyl and hydroxyl ste-
reocenters in 19 was corroborated by the small vicinal coupling
constant (3JH2,H3 = 3.90 Hz)22 while the unambiguous stereochemi-
cal assignments were confirmed at a later stage through chemical
modification. After installation of the stereogenic centers, the aux-
iliary was reductively cleaved using sodium borohydride in aque-
ous THF medium at room temperature to produce the diol 20 in
87% yield.23 With the aim of obtaining one of the key fragments
10 for the synthesis of macrolactone core 4, the primary alcohol
of 20 was deoxygenated via selective tosylation of the primary
alcohol followed by reduction of the resulting tosyl ester using lith-
ium aluminium hydride in 92% yield (Scheme 2).
f
O
OBn
OBn
O
g
OH
HO
H
Me
17
Me
Me
16
7
Scheme 1. Reagents and conditions: (a) Pivaloyl chloride, LiCl, Et3N, 89%; (b) CH3I,
NaHMDS, ꢀ78 °C, 85%; (c) LiOOH, THF, H2O, 92%; (d) LiAlH4, ether, 0 °C; (e) NaH,
BnBr, THF, 0 °C to rt; 86% over two steps; (f) BH3.SMe2, THF, 0 °C, NaOH (10%), H2O2
(30%), 88%; (g) Dess–Martin periodinane, CH2Cl2, rt, 94%.
lation under Birch reduction conditions26 (Li in liquid NH3, ꢀ78 °C)
followed by silylation to obtain the prerequisite compound 23. The
spectroscopic data and specific rotation values were in complete
agreement with the reported ones {lit.11
½
a 2D5
ꢁ
¼ ꢀ10:0 (c 2.5,
CHCl3), observed ½a D25
¼ ꢀ9:8 (c 0.6, CHCl3)} (Scheme 3). This justi-
ꢁ
fied the previous statement regarding the syn relationship between
the homoallyl and hydroxyl groups of adduct 19.
After the assignment of the stereocenters present in compound
10, our next task was to make acid 26 for the pivotal esterification
step. The newly-generated secondary hydroxyl group of 10 was
protected as its MEM-ether 24,27 which on dissolving metal med-
iated selective debenzylation26 using Li in liquid NH3 at ꢀ78 °C fur-
nished the primary alcohol 25 in good overall yield. Oxidation of
the primary hydroxyl group in 25 with pyridinium dichromate
(PDC) in DMF afforded acid 2628 in moderate yield as shown in
Scheme 4.
Our next task was the study of the crucial Yamaguchi’s esterifi-
cation followed by the formation of fragment 9 for the ring closing
metathesis reaction. For this, we needed to couple 26 with 29,
which was designed in such a manner that it consisted of the olefin
At this stage, it was necessary to confirm the stereochemistry of
the newly generated centers at the C2 and C3 positions of adduct
19 which were investigated by transforming compound 10 into
compound 23.11 For this endeavor, compound 10 was subjected
to oxidation with 2-iodoxybenzoic acid (IBX)24 to give ketone 21
where the carbonyl group was protected as a ketal using ethylene
glycol and a catalytic amount of p-toluenesulfonic acid in refluxing
benzene to give 22.25 As per our requirement, the benzyl ether 22
was transformed into silyl ether in two steps via selective debenzy-
O
O
OH
O
O
O
OBn
6
2
OBn
O
N
a
1
3
O
N
+
H
Me
Me
Bn
19
7
18
Bn
b
OH
OH
Me
c, d
OBn
HO
OBn
Me
Me
10
20
Scheme 2. Reagents and conditions: (a) Bu2BOTf, i-Pr2NEt, CH2Cl2, ꢀ78 to 0 °C, 72%; (b) NaBH4, THF–H2O, rt, 87%; (c) TsCl, Et3N, DMAP, CH2Cl2, rt, 89%; (d) LiAlH4, THF, reflux,
92%.

B. Chatterjee et al. / Tetrahedron: Asymmetry 23 (2012) 1170–1185
1173
OH
O
Me
Me
a
OBn
b
OBn
Me
Me
10
21
O
O
O
O
Me
Me
OTIPS
c, d
OBn
Me
Me
23
22
Scheme 3. Reagents and conditions: (a) IBX, DMSO, rt, 90%; (b) ethylene glycol, p-TSA, benzene, reflux, 74%; (c) Li-metal, liq. NH3, THF, ꢀ78 °C, 73%; (d) TIPS-Cl, imidazole,
DMAP, CH2Cl2, rt, 89%.
The next critical aspect was assembling acid 26 with alcohol 29,
for which various conditions were investigated (i. DCC, DMAP,
CH2Cl2; ii. EDC, DMAP, CH2Cl2) but none provided the desired re-
sults. Instead, some rearranged, uncharacterizable, and intractable
mixtures of compounds were obtained. Eventually, the required
coupled product 9 was obtained in 75% yield following Yamagu-
chi’s esterification protocol30 using 2,4,6-trichlorobenzoyl chloride,
triethylamine, and DMAP in THF at 0 °C to room temperature. The
product was present along with the trace amounts of the other iso-
mer (<5%), which was conveniently separated by flash column
chromatography. This diene compound 9 was well placed for the
macrocyclization reaction by applying the highly-productive and
established RCM reaction.31,32 With the advent of efficient cata-
lysts, the ring-closing metathesis (RCM) reaction has emerged as
a powerful process for the cyclization of dienes. Thus, we applied
this method to the diene derivative 9 with the use of 1st generation
Grubbs’ catalyst33 to obtain the 12-membered macrocyclic ring but
this reaction was unsuccessful. However, a 2nd generation Grubbs
catalyst34 in benzene under refluxing conditions gave the 6-epi-12-
membered macrolide 4 as a mixture of E- and Z-isomers (2:1) in a
combined 58% yield (Scheme 6). Separation of the two isomers by
applying typical chromatographic techniques such as flash silica
gel column chromatography and high performance liquid chroma-
tography (HPLC) and enhancement in the selectivity under thor-
ough investigation did not provide much success. With regard to
the augmentation of selectivity, we tried manipulations of the hy-
droxyl protecting groups in the middle of the synthetic strategy.
Fragment 26 was used with a TBDMS ether instead of MEM ether
and also with an unmasked secondary hydroxyl group to produce
several derivatives of 9. It was found that none of these cases led
OMEM
OH
Me
Me
OBn
OBn
a
c
Me
Me
24
10
b
OMEM
OMEM
O
Me
Me
OH
OH
Me
Me
25
26
Scheme 4. Reagents and conditions: (a) MEMCl, i-Pr2NEt, CH2Cl2, rt, 78%; (b) Li-
metal, liq. NH3, THF, 83%; (c) PDC, DMF, rt, 77%.
moiety for the RCM as well as hydroxyl group for Yamaguchi’s
esterification. At this point, we decided to use the D-mannitol de-
rived allylic alcohol 2912,13 (Scheme 5), which would not only help
us to study the stereochemical courses of the reactions leading to
the macrocycle, but also would act as a surrogate to the side chain
implantation for the total synthesis of amphidinolide W. Thus
diisopropylidenation of D-mannitol followed by oxidative cleavage
with sodium metaperiodate provided aldehyde 27 in good yields.
Subsequent one carbon Wittig homologation followed by concom-
itant acetonide deprotection under mild acidic conditions afforded
diol 28. The latter upon selective benzylation with dibutyltin oxide
furnished allylic alcohol 29. The product was fully characterized
from its 1H and 13C NMR spectra and comparison of the specific
rotation value with the reported ones {lit.29
½
a 2D5
ꢁ
¼ ꢀ5:9 (c 0.5,
CHCl3), observed ½a D25
¼ ꢀ5:4 (c 0.7, CHCl3)} completely justified
ꢁ
OMEM
O
the structure without any ambiguity (Scheme 5).
a
Me
OBn
OH
+
Yamaguchi's
esterification
OH
Me
Me
O
OH OH
a
29
26
H
OH
OH
O
HO
b,c
OBn
OBn
O
OH OH
27
O
Me
MEMO
D-mannitol
b
O
O
Me
d
OBn
Me
OH
29
OMEM
O
OH
28
4: E
4a:
9
Z (E:Z = 2:1)
Scheme 5. Reagents and conditions: (a) (i) (CH3)2C(OMe)2, SnCl2, 53%; (ii) NaIO4,
CH2Cl2, 76%; (b) Ph3P@CH2, THF, 0 °C; (c) p-TSA, MeOH, rt, 49% over two steps; (d)
Bu2SnO, BnBr, TBAI, toluene, reflux, 84%.
Scheme 6. Reagents and conditions: (a) 2,4,6-trichlorobenzoyl chloride, Et3N,
DMAP, THF, 0 °C to rt, 75%; (b) Grubbs’ 2nd generation, benzene, reflux, 58%
combined yield.

1174
B. Chatterjee et al. / Tetrahedron: Asymmetry 23 (2012) 1170–1185
to an improved selectivity for the RCM reaction. In spite of the suc-
cessful ring closing metathesis reaction, the diastereoisomeric sep-
aration problem inhibited the total synthesis of the macrolide;
however, we believe that this synthetic methodology could be used
for the total synthesis of this natural product and other macrolides
for structure–activity relationship studies (SAR).
taking an account of the basicity of the two-carbon Wittig stabi-
lized ylide which abstracts the highly acidic -proton to the alde-
hyde due to the electron withdrawing nature of the MOM-ether
a
and/or the aldehyde groups present in 34.
The hydroxyl protecting group was replaced from MOM to TBS
upon treatment with TBSOTf and 2,6-lutidine in CH2Cl2 to give
compound 37. The oxazolidinone was disconnected from com-
pound 37 using LiBH4 in EtOH and the THF mixture to afford alco-
hol 38 in 83% yield. The primary hydroxyl group of 38 was oxidized
with PDC to an aldehyde with subsequent Wittig homologation
thus providing the expected (E)-a,b-unsaturated ester 39 as the
major product in 78% yield along with a small amount of the (Z)-
isomer (Scheme 8).
Difficulties during the synthesis of macrolide 4 and also the
structural revision of the amphidinolide W 2 motivated us to en-
sure a successful synthesis of macrolide 3, which in turn would
lead to the total synthesis of amphidinolide W 1 through the re-
quired modification of our earlier described route. Modifications
were made to the above stated synthetic strategy, where at first,
the
D
9,10E-alkene was synthesized followed by macrolactonization.
At the onset of our program to synthesize macrolactone 3, we
performed the Evans’ syn aldol reaction of aldehyde 7, with oxazo-
lidinone derivative 3015a using Bu2B(OTf) at ꢀ78 °C to afford the
desired Evans’ syn isomer 31 in moderate yield (75%) and with high
diastereoselectivity (19:1).10,20 The compound and its diastereolec-
tivity were confirmed from the spectroscopic data. The relative ste-
reochemistry of the newly generated stereocenters was initially
predicted through the literature precedent20 and further confirma-
tion of the absolute configuration was achieved in the latter part of
the synthesis. To continue our strategy, the secondary hydroxyl
group in 31 was protected as its MOM ether 32 with MOM–Cl
and Hunig’s base in 91% yield. Subsequent removal of the oxazolid-
inone ring was achieved with lithium borohydride (generated
in situ from a mixture of LiCl and NaBH4)35 in an ethanol and
Before moving further ahead, we decided to establish the con-
figurations of the two newly generated stereogenic centers in 31.
For this, 39 was converted into its Mosher ester derivative36,37
via desilylation with HF-Py in Py/THF at room temperature38 fol-
lowed by esterification with (R)- and (S)-MTPA acid using DCC
and DMAP in anhydrous CH2Cl2 at room temperature to afford
the (R)-MTPA ester 40 and (S)-MTPA ester 41, respectively
(Scheme 9). The
D
d = (dS ꢀ dR) ꢃ 1000 values were calculated for
as many protons as possible from the 1H NMR spectrum of 40
and 41 (Table 1). By constructing a molecular model of the com-
pound in question and assigning the
uniformly as shown in Figure 3, the absolute stereochemistry of
C5-center was determined to be (R)-configured.
D
d = (dS ꢀ dR) ꢃ 1000 values
After determining the stereochemistry of the C5-center, we pro-
ceeded to determine the configuration of the adjacent methyl
group in 39 by turning 38 into its isopropylidene derivative 42
where NOESY correlations witnessed the syn-alignment of the
two adjacent chiral centers (Scheme 10). For instance the b-pro-
tons H1 and H2 showed significant nOe interactions in 42, thus
establishing the stereochemistry of the methyl center also to be
(R)-configured.
THF mixture to afford alcohol 33. Elaboration of 33 to the
a,b-
unsaturated ester 36 was planned in a two-step sequence. Alcohol
33 was first oxidized to aldehyde 34 with IBX and subsequent Wit-
tig olefination resulted in an unexpected
a,b-unsaturated aldehyde
35 as an exclusive product instead of the desired Wittig product 36
(Scheme 7). The formation of the a,b-unsaturated aldehyde 35 was
confirmed from its spectroscopic data. The 1H NMR data of the
unexpected compound 35 showed an aldehydic proton at d
After the successful installation of the C5, C6, and C2 stereocen-
ters of the macrolactone core 3, our next aim was to incorporate a
9.38 ppm as
a singlet and an olefinic proton resonating at
6.48 ppm as a triplet and thus proved the formation of the unsat-
urated aldehyde 35; the mass spectrum at m/z 269.21 (M+Na)+ also
confirmed this. This observed phenomenon could be explained by
C11 stereocenter in addition to the
obtaining the
9,10(E)-alkene, the Julia–Kocienski reaction was
thought to be appropriate. A one step reduction of unsaturated es-
D
9,10(E)-alkene. With the aim of
D
O
O
O
O
O
OH
a
O
N
H
OBn
O
N
OBn
+
Me
Me
Me
31
Bn
7
Bn
30
O
OMOM
O
OMOM
b
c
O
N
OBn
OBn
HO
Me
32
Me
Me
Me
Bn
33
OMOM
OBn
O
Me
e
Me
d
OBn
O
35
Me
Me
34
OMOM
e
EtO2C
OBn
Me
Me
36
Scheme 7. Reagents and conditions: (a) Bu2BOTf, DIPEA, 0 °C, CH2Cl2, ꢀ78 °C, 75%; (b) MOM-Cl, i-Pr2NEt,CH2Cl2, 0 °C to rt, 91%; (c) LiBH4, EtOH, THF, 0 °C to rt, 86%; (d) IBX,
DMSO, rt, 93%; (e) Ph3P@CHCO2Et benzene, rt, 70%.

B. Chatterjee et al. / Tetrahedron: Asymmetry 23 (2012) 1170–1185
1175
O
O
OTBS
O
OH
O
OBn
O
N
a
OBn
O
N
Me
37
Me
Me
Me
Bn
Bn
31
OTBS
O
OTBS
c, d
b
EtO
OBn
HO
OBn
Me
Me
Me
Me
39
38
Scheme 8. Reagents and conditions: (a) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C to rt, 95%; (b) LiBH4, EtOH/THF, 0 °C to rt, 83%; (c) PDC, CH2Cl2, rt, 81%; (d) Ph3P@CHCO2Et, benzene,
rt, 78%.
O
OMTPA (R)
EtO
OBn
O
OTBS
Me
Me
9
3
7
a, b
40
8
4
1
O
5
6
OMTPA (S)
EtO
OBn
2
Me
Me
EtO
OBn
39
Me
Me
41
Scheme 9. Reagents and conditions: (a) HF–Py, Py, THF, 0 °C to rt, 73%; (b) (R or S)-MTPA acid, DCC, DMAP, CH2Cl2, rt, 73% for (R)-isomer and 76% for (S)-isomer.
OMTPA
O
_ 120)
ter 39 to alcohol 6 with LiAlH4 produced an inseparable mixture of
saturated 6 and allylic alcohol derivatives. In order to circumvent
the purification issue, we planned to perform a two-step reaction.
Accordingly, the chemoselective reduction of the double bond in
39 with NiCl2/NaBH439 in MeOH at 0 °C was carried out to give sat-
urated ester 43, which upon reduction with lithium aluminium hy-
dride in THF provided the pure saturated alcohol 6 in 89% yield.
The Mitsunobu substitution40 of the primary alcohol of 6, by 1-
phenyl-1H-tetrazole-5-thiol (PTSH) followed by oxidation41 pro-
(
(+60)
9
_ 20)
11
(+20)
10
(
_ 50)
4
(
3
12
CH3
8
6
7
1
Ph
O
O
5
2
CH
13
3
CH
14
(_ 120)
3
(_ 60)
(+30)
H
Figure 3. Projection of the MTPA ester to determine the stereochemistry of C5-
center of 39.
vided sulfone 44 in good yields. The key
tion with the appropriate stereocenter at C11 was accomplished
as shown in Scheme 11. At this point, the -mannitol derived alde-
D
9,10(E)-alkene installa-
OTBS
D
O
O
Me
H2
hyde 27 was selected as discussed earlier for further side chain
extension of macrolide 3 in support of the total synthesis of amphi-
dinolide W. Although the Julia–Kocienski42,43 olefination with a
variety of conditions was exhaustively investigated, the best re-
sults were found using KHMDS in DME at ꢀ60 °C with (2R)-2,3-iso-
propylidene glyceraldehyde 27 to produce the desired olefin 45 in
82% yield with exclusive E-selectivity (Scheme 11). The confirma-
tion of E-selectivity was achieved from the 1H NMR spectra where-
in the two olefin protons resonated at d 5.43 and 5.76 ppm with a
coupling constant of J = 15.3 Hz.
3
a, b
HO
Me
2
Me
H1 Me
OBn
OBn
38
42
H2
Me
OBn
Me
O
3
Me
2
H1
O
Me
For the crucial macrolactonization, the isopropylidine group of
45 was cleaved selectively under mild Lewis acid conditions
(Zn(NO3)2ꢂ6H2O, CH3CN),44 which proved to be the most suitable
among the traditional reaction conditions45 (FeCl3ꢂSiO2, CHCl3;
CeCl3ꢂ7H2O; oxalic acid, CH3CN, rt; BiCl3, CH3CN, or CH2Cl2;
nOe correlations between H1
and H2 protons in 42
Scheme 10. Reagents and conditions: (a) TBAF, THF, rt, 90%; (b) 2,2-dimethoxy
propane, acetone, p-TSA, rt,74%.
Table 1
Calculation of
D
d values for (S)- and (R)-MTPS ester [(dS ꢀ dR) ꢃ 1000 values] from 1H NMR spectrum
Protons
H-3
H-2
H-10
4.40
4.38
+20
H-11
4.10
4.12
ꢀ20
H-9
3.17
3.11
+60
H-4
2.56
2.61
ꢀ50
H-13
0.93
0.99
ꢀ60
H-14
0.83
0.80
+30
dS
dR
6.69
6.81
5.63
5.75
D
d
ꢀ120
ꢀ120

1176
B. Chatterjee et al. / Tetrahedron: Asymmetry 23 (2012) 1170–1185
O
OTBS
O
OTBS
a
EtO
EtO
b
OBn
OBn
Me
Me
Me
Me
Me
43
39
OTBS
c, d
HO
OBn
Me
OTBS
6
OTBS
OBn
e
OBn
O
Ph
Me
Me
Me
Me
S
CHO
N
N
N
O
O
N
O
44
O
45
O
27
Scheme 11. Reagents and conditions: (a) NiCl2, NaBH4, MeOH, 0 °C, 98%; (b) LiAlH4, THF, 0 °C, 89%; (c) PTSH, DIAD, Ph3P, THF, 0 °C, 89%; (d) (NH4)6Mo7O24ꢂ4H2O, H2O2, EtOH,
0 °C to rt, 92%; (e) KHMDS, DME, ꢀ60 °C, 82%.
CuCl2ꢂ2H2O; pyridinium p-toluensulfonate, EtOH) followed by
selective Birch reduction of 46 to produce triol 47 in good overall
yield. The dibutyl tin oxide (Bu2SnO) mediated selective protection
of the homo allylic primary hydroxyl as its benzyl ether 48 fol-
lowed by selective oxidation of the remaining primary hydroxyl
to the seco acid 5 was achieved via a two-step protocol. Oxidation
with BAIB in the presence of TEMPO46 to the aldehyde and further
we decided to work out the Yamaguchi’s esterification condi-
tions.30 Therefore, the seco acid 5 was treated with 2,4,6-trichloro-
benzoyl chloride, DIPEA and DMAP and it produced an inseparable
mixture of products 3 and 3a (1:1) in 55% combined yield, possibly
due to epimerization at the C-2 center. The rationalization for the
stereochemistry was obtained from the corresponding 1H and 13C
NMR spectra. Both spectra witnessed the formation of a diastereo-
meric mixture of the compounds 3 and 3a which could not be sep-
arated even by flash column chromatography. This intricate nature
of the substrate to the lactonisation due to the intrinsic lability at
the C-2 center prompted us to investigate other possible routes to
its synthesis. We made an attempt to study Kita’s lactonisation
47
Pinnick oxidation with NaClO2 in the presence of an NaH2PO4
buffer furnished acid 5. The oxidation process went smoothly with-
out giving any over oxidation products for the secondary allylic hy-
droxyl group. The spectroscopic and analytical data supported the
synthesized compound. Setting the stage for the key lactonization,
OTBS
OTBS
OTBS
a
b
O
H
OBn
OBn
Me
Me
Me
Me
Me
Me
OH
OH
45
47
O
HO
HO
46
O
c
OBn
TBSO
TBSO
Me
O
f
OH
O
OH
Hb
d, e
Me
Me
Kita's
Me
Me
O
protocol
OBn
48
Ha
Me
TBSO
OBn
HO
HO
5
3
Yamaguchi's
protocol
g
nOe effect between
OBn
O
Ha and Hb protons
3:
X = Me, Y = H
O
3a:X = H, Y = Me
3:3a =1:1
2
Me
Y
X
TBSO
Scheme 12. Reagents and conditions: (a) Zn(NO3)2ꢂ6H2O, CH3CN, 50 °C, 74%; (b) Li, liq.NH3, ꢀ78 °C, 78%; (c) Bu2SnO, BnBr, TBAI, toluene, reflux, 84%; (d) PhI(OAc)2, TEMPO,
CH2Cl2, rt, 92%; (e) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH/H2O (3:1), 87%; (f) (i) EtOC„CH, [{Ru(p-cymene)Cl2}2], toluene, 0 °C to rt, 30 min; (ii) camphorsulfonic acid
(CSA), toluene, rt to 50 °C, 2 h, 42%; (g) 2,4,6-trichlorobenzoyl chloride, DIPEA, THF, rt; DMAP, benzene, 80 °C, 55% combined yield.

B. Chatterjee et al. / Tetrahedron: Asymmetry 23 (2012) 1170–1185
1177
protocol. When the lactonization was performed under the condi-
tions described by Kita et al.,48,49 it produced the single desired
macrolactone derivative 3 in 42% yield, thus explaining the ab-
sence of epimerization at the C-2 center. The remaining mass
was accounted for by an intractable mixture of products and 35%
starting material. Its elemental analysis, mass, and NMR studies as-
signed the structure of the compound while the NOESY experiment
showed considerable nOe interactions between Ha and Hb protons
and supported the stereochemical identifications for the desired
isomer. The minimum energy diagram of 310 also unambiguously
supported the significant NOE effects between the Ha and Hb pro-
tons in 3. These findings not only resolved the possible drawback of
the Yamaguchi’s lactonization (Scheme 12) but could also be ap-
plied to the highly diastereoselective formation of related bioactive
macrolactone compounds.
urated NH4Cl (20 mL) and the two layers were separated. The
aqueous layer was extracted twice with EtOAc (2 ꢃ 50 mL), and
the combined organic layers were dried over Na2SO4 and concen-
trated to afford a residue which was purified by flash silica gel
chromatography using EtOAc/light petroleum (1:19) yielding 13
(4.5 g, 85%) as a colorless liquid. ½a D25
¼ þ77:2 (c 1.0, CHCl3); IR
ꢁ
(CHCl3) cmꢀ1 2931, 1781, 1697, 1650, 1496, 1454, 1110, 750; 1H
NMR (200 MHz, CDCl3): d 1.23 (d, 3H, J = 6.9 Hz), 2.18 (m, 1H),
2.47 (m, 1H), 2.75 (dd, 1H, J = 9.6, 13.4 Hz), 3.27 (dd, 1H, J = 3.3,
13.4 Hz), 3.82 (m, 1H), 4.15–4.18 (m, 2H), 4.65 (m, 1H), 5.0–5.11
(m, 2H), 5.78 (m, 1H), 7.13–7.37 (m, 5H); 13C NMR (50 MHz,
CDCl3): d 17.0, 37.4, 37.6, 37.9, 55.3, 65.9, 117.0, 127.3, 128.9
(ꢃ 2), 129.4 (ꢃ 2), 135.3, 135.5, 152.9, 176.3; EIMS: (M+Na)+ calcd
for C16H19NNaOþ 296.13. Found: 296.19; Anal. Calcd for
3
C16H19NO3: C, 70.31; H, 7.01; N, 5.12. Found: C, 70.12; H, 6.86; N,
5.02.
3. Conclusions
4.1.2. (S)-2-Methylpent-4-enoic acid 17
To a solution of imide 13 (0.5 g, 1.8 mmol) in THF/H2O (1/1,
10 mL) at 0 °C, 30% H2O2 solution (0.82 mL, 7.2 mmol) was added
followed by the addition of LiOH.H2O (0.15 g, 3.6 mmol) and stir-
red for 1 h. After completion of the reaction (monitored by TLC),
THF was removed in vacuum and the residue was diluted with
EtOAc (10 mL) and acidified with 1 M HCl to pH ꢄ1. The aqueous
layer was extracted with EtOAc (3 ꢃ 15 mL), and the combined or-
ganic layer was dried over Na2SO4 and concentrated. Purification
by silica gel column chromatography (EtOAc/light petroleum,
In conclusion, a successful synthesis of the 12-membered
macrolactone core 3 and its 6-epi analogue 4 of amphidinolide
W have been described from achiral, inexpensive, and commer-
cially available 4-pentenoic acid 8 while exploring a variety of
important reaction conditions. The synthesis features a highly
stereo and regioselective incorporation of the stereogenic centers
utilizing Evans’ asymmetric alkylation and aldol reactions. For
the construction of the 12-membered lactone of the 6-epi ana-
logue 4 of amphidinolide W, Yamaguchi’s esterification gave
the suitably-substituted diene precursor for the ring closing
metathesis reaction (RCM) in a linear nine-step sequence. In an-
other approach for the 12-membered macrolactone core 3, a
highly stereoselective Julia–Kocienski olefination for the con-
3:7) provided acid 17 (0.192 g, 92%) as a clear liquid. ½a D25
¼ þ9:9
ꢁ
(c 1.0, CHCl3); 1H NMR (200 MHz, CDCl3):
d 1.21 (d, 3H,
J = 6.9 Hz), 2.19 (m, 1H), 2.46 (m, 1H), 2.56 (sextet, 1H,
J = 6.9 Hz), 5.06–5.11 (m, 2H), 5.78 (m, 1H); 13C NMR (50 MHz,
CDCl3):d 16.3, 37.5, 39.2, 117.2, 135.1, 182.8; EIMS: (M+Na)+ calcd
struction of the
D
9,10E-alkene was performed. The final lactoniza-
for C6H10NaOþ 137.06. Found: 137.11+; Anal. Calcd for C6H10O2: C,
2
tion using Kita’s protocol, which selectively produced the
required isomer thus overcoming the difficulty encountered in
63.14; H, 8.83. Found: C, 62.98; H, 8.96.
the Yamaguchi’s lactonization is also
a promising approach.
4.1.3. (S)-(2-Methylpent-4-enyloxy)methylbenzene 15
These synthetic methods will help synthesize related macrolides.
In turn, these products could be useful in the studies of thera-
peutics based on the structure activity relationship (SAR) of iso-
meric molecules.
To a solution of LiAlH4 (2.5 g, 66.0 mmol) in ether (40 mL) at
0 °C, compound 13 (12.0 g, 43.9 mmol) in ether (80 mL) was added
dropwise and stirred for 1 h. The reaction mixture was quenched
by the addition of a saturated solution of Na2SO4, filtered and the
residue was washed with ether, dried over Na2SO4, and concen-
trated to obtain a residue 14, which was directly benzylated with-
out further purification. The crude residue was dissolved in THF
(150 mL) and NaH (2.1 g, 87.9 mmol) was added in small portions
at 0 °C and stirred for 30 min. Next, BnBr (7.9 mL, 65.9 mmol) was
added followed by the addition of a catalytic amount of TBAI and
the reaction mixture was warmed to room temperature and stirred
for 2 h. The reaction was quenched with ice cold water, diluted
with EtOAc, and the layers were separated out and the aqueous
layer was extracted twice with EtOAc (2 ꢃ 50 mL), washed with
brine, dried over Na2SO4, and concentrated under reduced pressure
to afford a residue which was chromatographed on silica gel elut-
ing with EtOAc/light petroleum (1:19) to provide 15 (7.2 g, 86%
over two steps) as a clear liquid. IR (CHCl3) cmꢀ1 2927, 1648,
1385, 1044, 836; 1H NMR (200 MHz, CDCl3): d 0.93 (d, 3H,
J = 6.5 Hz), 1.83–1.94 (m, 2H), 2.22 (m, 1H), 3.26 (dd, 1H, J = 6.3,
8.9 Hz),, 3.31 (dd, 1H, J = 6.3, 8.9 Hz), 4.48 (s, 2H), 4.97–5.01 (m,
2H), 5.76 (m, 1H), 7.23–7.31 (m, 5H); 13C NMR (50 MHz, CDCl3):
d 16.9, 33.5, 38.1, 73.0, 75.2, 116.0, 127.4, 127.5 (ꢃ 2), 128.3
(ꢃ 2), 136.9, 138.8; EIMS: (M+Na)+ calcd for C13H18NaO+ 213.13.
Found: 213.17; Anal. Calcd for C13H18O: C, 82.06; H, 9.53. Found:
C, 81.84; H, 9.29.
4. Experimental
4.1. General methods
1H and 13C NMR chemical shifts are reported in ppm downfield
from tetramethylsilane and coupling constants (J) are reported in
Hertz (Hz). The following abbreviations are used to designate sig-
nal multiplicity: s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet, br = broad. Column chromatography was carried
out using silica gel (60–120 mesh). Specific rotations ½a D25
ꢁ
are given
in 10ꢀ1 degcm2 gꢀ1. Infrared spectra were recorded in CHCl3/neat
(as mentioned) and reported in wave number (cmꢀ1). Yields are gi-
ven after purification, unless stated otherwise. When reactions
were performed under anhydrous conditions, the mixtures were
maintained under nitrogen. Compounds were named following IU-
PAC rules as applied by Beilstein-Institute AutoNom software for
systematic names in organic chemistry.
4.1.1. (S)-4-Benzyl-3-((S)-2-methylpent-4-enoyl)oxazolidin-2-
one 13
A solution of 12 (5.0 g, 19.3 mmol) in THF (50 mL) was cooled to
ꢀ78 °C and NaHMDS (29.0 mL, 29.0 mmol, 1 M in THF) was added
dropwise and stirred for 1 h, followed by the dropwise addition of
methyl iodide (4.8 mL, 77.2 mmol), maintaining the temperature
at -78 °C. After stirring for 1 h, the reaction was quenched with sat-
4.1.4. (S)-5-Benzyloxy-4-methylpentanal 7
To a solution of compound 15 (7.0 g, 36.8 mmol) in THF (40 mL)
at 0 °C was added BH3.SMe2 (4.6 mL, 47.9 mmol) dropwise and

1178
B. Chatterjee et al. / Tetrahedron: Asymmetry 23 (2012) 1170–1185
stirred for 5 h, then slowly quenched by the simultaneous addition
of 10% NaOH solution (20 mL) and 30% H2O2 solution (7 mL). The
mixture was then stirred at rt for 16 h, extracted with EtOAc
(3 ꢃ 30 mL), dried over Na2SO4, concentrated under reduced pres-
sure, and purified by silica gel column chromatography eluting
with EtOAc/light petroleum (1:4) to give alcohol 16 (6.75 g, 88%)
as a clear oil. IR (CHCl3) cmꢀ1 3370, 2928, 1610, 1210, 748; 1H
NMR (200 MHz, CDCl3): d 0.93 (d, 3H, J = 6.8 Hz), 1.16 (m, 1H),
1.49–1.59 (m, 3H), 1.78 (m, 1H), 2.07 (br s, 1H), 3.27 (dd, 2H,
J = 2.4, 6.4 Hz), 3.56 (t, 2H, J = 6.5 Hz), 4.47 (s, 2H), 7.28–7.32 (m,
5H); 13C NMR (50 MHz, CDCl3): d 17.1, 29.7, 30.0, 33.2, 62.8, 73.0,
added at room temperature. After stirring overnight, it was
quenched with a saturated solution of NH4Cl (15 mL) and diluted
with ethyl acetate; the layers were separated and the aqueous
layer was extracted twice with EtOAc (2 ꢃ 20 mL). The combined
organic layers were dried over Na2SO4 and concentrated to afford
a residue which was chromatographed on a silica gel column using
EtOAc/light petroleum (1:3) as eluent to provide diol 20 (3.1 g,
87%) as a colorless viscous liquid. ½a D25
¼ þ7:5 (c 0.9, CHCl3); IR
ꢁ
(CHCl3) cmꢀ1: 3368, 2928, 1648, 1452, 1252, 1115, 835, 697; 1H
NMR (200 MHz, CDCl3): d 0.95 (d, 3H, J = 6.6 Hz), 1.05–1.21 (m,
1H), 1.36–1.55 (m, 4H), 1.58–1.83 (m, 3H), 1.98–2.19 (m, 2H),
2.72 (br s, 2H), 3.29 (dd, 2H, J = 1.5, 6.2 Hz), 3.66–3.83 (m, 3H),
4.48 (s, 2H), 4.93–5.05 (m, 1H), 5.65–5.86 (m, 1H), 7.28–7.34 (m,
5H); 13C NMR (50 MHz, CDCl3): d 17.3, 24.0, 30.3, 30.7, 31.7, 33.5,
43.2, 64.2, 73.0, 75.3, 75.7, 114.8, 126.8, 127.4, 127.5, 128.2 (ꢃ 2),
75.7, 127.5, 128.3, 138.5; EIMS: (M+Na)+ calcd for C13H20NaOþ
2
231.14. Found: 231.23; Anal. Calcd for C13H20O2: C, 74.96; H,
9.68. Found: C, 74.89; H, 9.45.
To a solution of alcohol 16 (6.5 g, 31.3 mmol) in CH2Cl2 (35 mL),
was added Dess–Martin periodinane (19.9 g, 46.9 mmol) at room
temperature and stirred for 1 h. The reaction mixture was diluted
with H2O (15 mL) and CH2Cl2 (15 mL) and filtered. The aqueous
phase was extracted with CH2Cl2 (2 ꢃ 20 mL) and the combined or-
ganic layers were washed with NaHCO3, brine, dried over Na2SO4,
and concentrated. The crude residue was purified by silica gel
chromatography (EtOAc/light petroleum, 1:9) to afford aldehyde
7 (6.1 g, 94%) as a colorless liquid. 1H NMR (200 MHz, CDCl3): d
0.94 (d, 3H, J = 6.5 Hz), 1.43–1.59 (m, 2H), 1.72–1.90 (m, 2H),
2.44 (m, 1H), 3.29 (d, 2H, J = 6.1 Hz), 4.47 (s, 2H), 7.31 (m, 5H),
9.74 (t, 1H, J = 1.74 Hz).
138.4 (ꢃ 2); EIMS: (M+Na)+ calcd for C19H30NaOþ 329.21. Found:
3
329.48; Anal. Calcd for C19H30O3: C, 74.47; H, 9.87. Found: C,
74.25; H, 9.92.
4.1.7. (2S,5R,6S)-1-(Benzyloxy)-2,6-dimethyldec-9-en-5-ol 10
At first, Et3N (2.5 mL, 17.7 mmol), p-toluenesulfonyl chloride
(2.52 g, 13.2 mmol), and DMAP (catalytic amount) were sequen-
tially added to a stirred solution of 20 (2.7 g, 8.8 mmol) in CH2Cl2
(40 mL) at 0 °C. The reaction mixture was stirred at room temper-
ature for 20 h (completion of the reaction was monitored by TLC),
then quenched with ice, diluted with CH2Cl2 (20 mL) and H2O
(20 mL). The aqueous layer was extracted twice with CH2Cl2
(2 ꢃ 25 mL), washed with brine, then dried over anhydrous
Na2SO4, concentrated and purified by silica gel column chromatog-
raphy (EtOAc/light petroleum, 1:5) to afford a mono tosyl ester
(3.6 g, 7.85 mmol, 89%) which was dissolved in THF (30 mL) after
which LiAlH4 (0.45 g, 11.8 mmol) was added at room temperature
and refluxed for 3 h. The reaction was quenched with a saturated
solution of Na2SO4, then filtered through a pad of Celite, washed
with EtOAc. The organic layer was dried over Na2SO4 and concen-
trated. The residue was chromatographed on a silica gel column
(EtOAc/light petroleum, 1:6), to yield 10 (2.1 g, 92%) as a colorless
4.1.5. (S)-4-Benzyl-3-((2S,3R,6S)-7-(benzyloxy)-2-(but-3-enyl)-3-
hydroxy-6-methylheptanoyl)oxazolidin-2-one 19
To an ice-cooled stirred solution of compound 18 (2.0 g,
7.3 mmol) in CH2Cl2 (15 mL), dibutylboron triflate (8.1 mL, 1 M in
CH2Cl2, 8.1 mmol) was added dropwise such that the internal tem-
perature was maintained at 0 °C. After 10 min, i-Pr2NEt (1.6 mL,
8.8 mmol) was added and stirring was continued for another
30 min at the same temperature. The reaction mixture was then
cooled to ꢀ78 °C and aldehyde 7 (1.5 g, 7.3 mmol) in CH2Cl2
(10 mL) was added dropwise and allowed to stir for another 1 h,
then warmed to 0 °C and stirred for another 1 h. At the end, it
was quenched slowly with a phosphate buffer (8.1 mL, pH 7.0),
MeOH (16.2 mL) and then with a mixture of 30% H2O2 and MeOH
(1:2), (24.3 mL). After stirring at rt for 1 h, the reaction mixture
was diluted with CH2Cl2 (20 mL). The layers were separated out
and the aqueous layer was extracted with CH2Cl2 (2 ꢃ 20 mL).
The combined organic layers were dried over anhydrous Na2SO4
and concentrated. The residue thus obtained was purified by flash
silica gel chromatography (EtOAc/light petroleum, 1:6) to furnish
liquid. ½a 2D5
ꢁ
¼ þ5:0(c 1.5, CHCl3); IR (CHCl3) cmꢀ1: 3374, 2930,
1650, 1461, 1215, 836; 1H NMR (200 MHz, CDCl3): d 0.89 (d, 3H,
J = 6.8 Hz), 0.95 (d, 3H, J = 6.7 Hz), 1.07–1.40 (m, 8H), 1.69–2.18
(m, 3H), 3.24–3.42 (m, 3H), 4.48 (s, 2H), 4.91–5.05 (m, 2H), 5.67–
5.90 (m, 1H), 7.27–7.33 (m, 5H); 13C NMR (75 MHz, CDCl3): d
15.4, 17.5, 30.3, 31.0, 31.1, 31.5, 33.7, 38.3, 73.1, 75.8, 76.3,
114.5, 127.4, 127.5 (ꢃ 2), 128.3 (ꢃ 2), 138.8, 139.9; EIMS:
(M+Na)+ calcd for C19H30NaOþ 313.21. Found: 313.28; Anal. Calcd
2
for C19H30O2: C, 78.57; H, 10.41. Found: C, 78.66; H, 10.52.
aldol product 19 (2.52 g, 72%) as
a thick viscous liquid.
½
a 2D5
ꢁ
¼ þ29:0(c 1.2, CHCl3); IR (CHCl3) cmꢀ1: 3498, 2930, 1780,
4.1.8. (2S,6S)-1-(Benzyloxy)-2,6-dimethyldec-9-en-5-one 21
To a solution of the deoxy compound 10 (0.15 g, 0.52 mmol) in
DMSO (4 mL), IBX (0.29 g, 1.0 mmol) was added at room tempera-
ture. After stirring for 2 h, the reaction mixture was diluted with
water (15 mL), filtered and the filtrate was extracted with Et2O
(3 ꢃ 15 mL). The organic layer was washed with NaHCO3 solution,
brine, dried (over Na2SO4), and concentrated. The crude product
was purified on silica gel column eluting with EtOAc and light
petroleum (1:19) to provide ketone 21 (0.134 g, 90%) as a colorless
oil. 1H NMR (200 MHz, CDCl3): d 0.93 (d, 3H, J = 6.6 Hz), 1.06 (d, 3H,
J = 7.0 Hz), 1.25–1.46 (m, 3H), 1.70–1.78 (m, 2H), 1.95–2.07 (m,
2H), 2.43–2.58 (m, 3H), 3.29 (d, 2H, J = 6.0 Hz), 4.48 (s, 2H), 4.93–
5.04 (m, 2H), 5.62–5.87 (m, 1H), 7.29–7.33 (m, 5H); 13C NMR
(50 MHz, CDCl3): d 16.4, 17.1, 27.7, 31.4, 32.0, 33.1, 38.9, 45.5,
73.1, 75.6, 115.1, 127.5, 127.6 (ꢃ 2), 128.3 (ꢃ 2), 138.1,
1692, 1645, 1478, 1386, 1028, 699; 1H NMR (200 MHz, CDCl3): d
0.95 (d, 3H, J = 6.6 Hz), 1.12–1.2 (m, 1H), 1.44–1.83 (m, 6H),
1.92–2.03 (m, 1H), 2.06–2.16 (m, 2H), 2.66 (dd, 1H, J = 10.2,
13.1 Hz), 3.20–3.40 (m, 3H), 3.72–3.85 (m, 1H), 4.09–4.16 (m,
3H), 4.48 (s, 2H), 4.60–4.75 (m, 1H), 4.95–5.08 (m, 2H), 5.70–5.88
(m, 1H), 7.23–7.33 (m, 10H); 13C NMR (50 MHz, CDCl3): d 17.3,
26.1, 30.1, 31.2, 31.8, 33.4, 38.0, 47.3, 55.6, 65.9, 73.0, 75.6, 76.4,
115.5, 127.4 (ꢃ 2), 127.5 (ꢃ 2), 128.3 (ꢃ 2), 129.0 (ꢃ 2), 129.3
(ꢃ 2), 135.3, 137.8, 138.7, 153.5, 175.6; EIMS: (M+Na)+ calcd for
C
29H37NaOþ 502.26. Found: 502.37; Anal. Calcd for C29H37NO5: C,
5
72.62; H, 7.78; N, 2.92. Found: C, 72.77; H, 7.65; N, 2.89.
4.1.6. (2R,3R,6S)-7-(Benzyloxy)-2-(but-3-enyl)-6-methylheptane-
1,3-diol 20
To a stirred solution of compound 19 (5.6 g, 11.7 mmol) in a
THF/H2O (3:1, 30 mL) mixture, NaBH4 (1.8 g, 46.8 mmol) was
138.7, 214.4; EIMS: (M+Na)+ calcd for C19H28NaOþ 311.20. Found:
2
311.54.

B. Chatterjee et al. / Tetrahedron: Asymmetry 23 (2012) 1170–1185
1179
4.1.9. 2-((S)-4-(Benzyloxy)-3-methylbutyl)-2-((S)-hex-5-en-2-
yl)-1,3-dioxalane 22
raphy (EtOAc/light petroleum, 1:9) furnished MEM protected
compound 24 (1.78 g, 78%) as a colorless liquid. ½a D25
¼ ꢀ7:0 (c
ꢁ
A mixture of ketone 21 (0.1 g, 0.35 mmol), ethylene glycol
(0.4 mL, 6.9 mmol) and p-TSA (catalytic amount) in dry benzene
(20 mL) was heated at reflux for 4 h using a Dean–Stark apparatus.
Upon completion of the reaction (monitored by TLC), it was
washed with 5% NaHCO3 solution, water, brine and dried (over
Na2SO4). The organic layer was then concentrated to a residue,
which upon silica gel column purification (EtOAc/light petroleum,
1:19) afforded 22 (0.085 g, 74%) as a colorless liquid. 1H NMR
1.0, CHCl3); IR (CHCl3) cmꢀ1: 2928, 1647, 1454, 1060, 773, 697;
1H NMR (300 MHz, CDCl3): d 0.88 (d, 3H, J = 6.9 Hz), 0.95 (d, 3H,
J = 6.7 Hz), 1.11–1.27 (m, 3H), 1.43–1.48 (m, 2H), 1.52–1.63 (m,
2H), 1.72–1.78 (m, 2H), 1.92–2.04 (m, 1H), 3.25 (dd, 1H, J = 6.6,
8.8 Hz), 3.33 (dd, 1H, J = 5.9, 8.8 Hz), 3.38 (s, 3H), 3.40–3.44 (m,
1H), 3.50–3.53 (m, 2H), 3.68–3.73 (m, 2H), 4.49 (s, 2H), 4.72
(ABq, 2H, J = 7.1 Hz), 4.94 (d, 1H, J = 10.4 Hz), 5.0 (d, 1H,
J = 17.0 Hz), 5.70–5.86 (m, 1H), 7.28–7.33 (m, 5H); 13C NMR
(75 MHz, CDCl3): d 14.7, 17.5, 27.5, 29.9, 31.7, 31.9, 33.8, 35.4,
59.0, 67.2, 71.9, 73.1, 75.8, 82.2, 94.9, 114.5, 127.5 (ꢃ 3), 128.3
(200 MHz, CDCl3):
d 0.91 (d, 3H, J = 6.9 Hz), 0.94 (d, 3H,
J = 6.7 Hz), 1.09–1.18 (m, 1H), 1.34–1.48 (m, 1H), 1.57–1.77 (m,
6H), 1.90–2.04 (m, 1H), 2.08–2.22 (m, 1H), 3.23 (dd, 1H, J = 6.6,
9.1 Hz), 3.32 (dd, 1H, J = 6.0, 9.1 Hz), 3.91 (s, 4H), 4.49 (s, 2H),
4.90–5.05 (m, 2H), 5.70–5.92 (m, 1H), 7.24–7.34 (m, 5H); 13C
NMR (50 MHz, CDCl3): d 14.1, 17.4, 27.0, 30.4, 31.3, 32.0, 33.8,
39.1, 65.1, 65.2, 73.0, 75.9, 114.0, 114.4, 127.4, 127.5 (ꢃ 2), 128.3
(ꢃ 2), 138.9 (ꢃ 2); EIMS: (M+Na)+ calcd for C23H38NaOþ 401.27.
4
Found: 401.37; Anal. Calcd for C23H38O4: C, 72.98; H, 10.12. Found:
C, 73.11; H, 9.98.
4.1.12. (2S,5R,6S)-5-((2-Methoxyethoxy)methoxy)-2,6-dimethyl-
dec-9-en-1-ol 25
(ꢃ 2), 138.9, 139.0; EIMS: (M+Na)+ calcd for C21H32NaOþ 355.22.
3
Found: 355.57; Anal. Calcd for C21H32O3: C, 75.86; H, 9.70. Found:
C, 75.69; H, 9.61.
To a vigorously stirred solution of ammonia (15 mL) at ꢀ78 °C,
lithium (0.19 g, 26.5 mmol) was added. A deep blue color appeared
within 5 min and after 30 min the benzylated derivative 24 (1.0 g,
2.6 mmol) in THF (10 mL) was added dropwise. The solution was
stirred for 1 h, and then quenched with solid NH4Cl, until the blue
color disappeared. Ammonia was allowed to evaporate completely
and the residue was diluted with H2O (15 mL) and extracted with
EtOAc (3 ꢃ 20 mL). The combined extracts were dried over Na2SO4,
concentrated, and purified on a silica gel column using EtOAc/light
petroleum (2:3) to produce 25 (0.63 g, 83%) as a colorless liquid.
4.1.10. ((S)-4-(2-((S)-Hex-5-en-2-yl)-1,3-dioxolan-2-yl)-2-methyl-
butoxy)triisopropylsilane 23
A small piece of lithium was added to a pre-condensed stirred
solution of ammonia (10 mL) at -78 °C until a deep blue color
persisted. After 30 min, compound 22 (0.060 g, 0.18 mmol) in
THF (5 mL) was added dropwise to this solution. The reaction
mixture was stirred for 1 h at this temperature, and then
quenched with solid NH4Cl, until the blue color disappeared.
Ammonia was allowed to evaporate completely and the residue
was diluted with H2O (5 mL) and extracted with EtOAc
(3 ꢃ 10 mL). The combined extracts were dried over Na2SO4, con-
centrated, and purified on silica gel column using EtOAc/light
petroleum (1:6) to produce an alcohol which was used for rgw
next sillyl protection. To a solution of this alcohol (0.025 g,
0.1 mmol) in CH2Cl2 (3 mL), imidazole (0.014 g, 0.2 mmol) was
added at 0 °C followed by TIPS-Cl (0.03 mL, 0.15 mmol) and stir-
red at room temperature for 1 h. It was then diluted with water
(5 mL) and extracted with CH2Cl2 (2 ꢃ 10 mL), washed with
brine, dried over Na2SO4, and concentrated to give a residue,
which was purified by flash silica gel column chromatography
(EtOAc/light petroleum, 1:19), to furnish the TIPS protected com-
½
a 2D5
ꢁ
¼ þ15:4 (c 1.0, CHCl3); IR (CHCl3) cmꢀ1: 3375, 2929, 1646,
1459, 1254, 1075, 757, 698; 1H NMR (200 MHz, CDCl3): d 0.88 (d,
3H, J = 7.0 Hz), 0.92 (d, 3H, J = 7.0 Hz) 1.04–1.21 (m, 2H), 1.38–
1.61 (m, 5H), 1.68–1.80 (m, 1H), 1.92–2.18 (m, 2H), 2.43 (br s,
1H), 3.39 (s, 3H), 3.43–3.46 (m, 3H), 3.54–3.58 (m, 2H), 3.68–
3.85 (m, 2H), 4.74 (ABq, 2H, J = 7.1 Hz), 4.92–5.06 (m, 2H), 5.68–
5.92 (m, 1H); 13C NMR (50 MHz, CDCl3): d 14.3, 16.6, 27.2, 29.2,
31.5, 31.6, 35.2, 35.8, 58.9, 67.0, 67.7, 71.7, 82.4, 94.8, 114.3,
138.7; EIMS: (M+Na)+ calcd for C16H32NaOþ 311.22. Found:
4
311.18; Anal. Calcd for C16H32O4: C, 66.63; H, 11.18. Found: C,
66.82; H, 11.02.
4.1.13. (2S,5R,6S)-5-((2-Methoxyethoxy)methoxy)-2,6-dimethyl-
dec-9-enoic acid 26
pound 23 (0.036 g, 89%) as a colorless liquid. ½a D25
¼ ꢀ9:8 (c 0.6,
ꢁ
To a solution of compound 25 (0.5 g, 1.74 mmol) in DMF (8 mL),
PDC (3.3 g, 8.7 mmol) was added and stirred at room temperature
overnight. The reaction mixture was diluted with H2O (25 mL) and
extracted with ether (3 ꢃ 25 mL). The combined extracts were
dried over Na2SO4 and concentrated to a residue. Silica gel column
purification using EtOAc and light petroleum (1:1) as eluent pro-
CHCl3); 1H NMR (500 MHz, CDCl3): d 0.90 (d, 3H, J = 6.5 Hz), 0.92
(d, 3H, J = 7.0 Hz), 1.04–1.07 (m, 21H), 1.11–1.19 (m, 2H), 1.45–
1.55 (m, 2H), 1.62–1.75 (m, 4H), 1.92–2.00 (m, 1H), 2.12–2.21
(m, 1H), 3.47 (dd, 1H, J = 6.4, 9.6 Hz), 3.52 (dd, 1H, J = 5.8,
9.6 Hz), 3.90–3.93 (m, 4H), 4.94 (d, 1H, J = 10.3 Hz), 5.01 (d,
1H, J = 17.1 Hz), 5.75–5.86 (m, 1H); 13C NMR (125 MHz, CDCl3):
d 11.8 (ꢃ 3), 13.7, 16.6, 17.8 (ꢃ 6), 26.4, 30.1, 31.3, 31.7, 36.1,
38.9, 64.9, 65.0, 68.4, 113.8, 114.1, 138.8; EIMS: (M+Na)+ calcd
vided the acid 26 (0.4 g, 77%) as a colorless liquid. ½a D25
¼ þ23:2
ꢁ
(c 0.8, CHCl3); IR (CHCl3) cmꢀ1: 2928, 1710, 1645, 1462, 1382,
1070, 837; 1H NMR (200 MHz, CDCl3): d 0.87 (d, 3H, J = 6.8 Hz),
1.20 (d, 3H, J = 7.0 Hz), 1.42–1.52 (m, 4H), 1.65–2.21 (m, 5H),
2.37–2.55 (m, 1H), 3.39 (s, 3H), 3.44 (m, 1H), 3.52–3.57 (m, 2H),
3.68–3.78 (m, 2H), 4.73 (ABq, 2H, J = 7.2 Hz), 4.91–5.05 (m, 2H),
5.66–5.90 (m, 1H); 13C NMR (50 MHz, CDCl3): d 14.4, 17.1, 27.4,
29.6, 31.6, 31.9, 35.2, 39.3, 59.0, 67.2, 71.8, 81.5, 94.8, 114.6,
for
23H46O3Si: C, 69.29; H, 11.63. Found: C, 69.07; H, 11.89.
C
23H46NaO3Si+ 421.31. Found: 421.44; Anal. Calcd for
C
4.1.11. (8R,11S)-8-((S)-Hex-5-en-2-yl)-11-methyl-14-phenyl-
2,5,7,13-tetraoxotetradecane 24
To a solution of compound 10 (1.75 g, 6.04 mmol) in CH2Cl2
(12 mL), i-Pr2NEt (2.1 mL, 12.1 mmol) and MEM-Cl (1.0 mL,
9.1 mmol) were added at 0 °C and stirred overnight at room tem-
perature. After completion (monitored by TLC), it was quenched
with ice, diluted with H2O (10 mL), and extracted with CH2Cl2
(2 ꢃ 15 mL). The combined organic layer was washed with brine
and dried over anhydrous Na2SO4. The organic layer was concen-
trated to a give a residue, which upon silica gel column chromatog-
138.8, 182.5; EIMS: (M+Na)+ calcd for C16H30NaOþ 325.20. Found:
5
325.31; Anal. Calcd for C16H30O5: C, 63.55; H, 10.00. Found: C,
63.34; H, 10.22.
4.1.14. (S)-1-(Benzyloxy)but-3-en-2-ol 29
A solution of the (S)-but-3-en-1,2-diol 28 (1.0 g, 11.4 mmol),
prepared from
(4.2 g, 17.0 mmol) in toluene (35 mL) and refluxed for 4 h using a
D
-mannitol13 was treated with dibutyltin oxide

1180
B. Chatterjee et al. / Tetrahedron: Asymmetry 23 (2012) 1170–1185
Dean–Stark apparatus. After cooling at room temperature, benzyl
bromide (2.0 mL, 17.0 mmol) and TBAI (catalytic) were added
and refluxed for 2 h. The reaction mixture was diluted with CH2Cl2
(30 mL), washed with 10% NaHCO3 solution (2 ꢃ 20 mL), water,
brine, dried (over Na2SO4) and then concentrated. The residue
was purified on silica gel column chromatography using EtOAc
and light petroleum (1:6) to provide 29 (1.7 g, 84%) as a light yel-
457.45; Anal. Calcd for C25H38O6: C, 69.10; H, 8.81. Found: C,
69.23; H, 8.97.
4.1.17. (S)-4-Benzyl-3-((2S,3R,6S)-7-(benzyloxy)-3-hydroxy-2,6-
dimethylheptanoyl)oxazolidin-2-one 31
Using the same procedure as described for the synthesis of 19,
compound 31 was obtained as a thick viscous liquid from oxazolid-
inone 30 and aldehyde 7. Purification was performed by flash silica
gel chromatography eluting with EtOAC and light petroleum (1:5)
low liquid. ½a 2D5
ꢁ
¼ ꢀ5:4 (c 0.7, CHCl3); 1H NMR (200 MHz, CDCl3): d
2.42 (br s, 1H), 3.36 (dd, 1H, J = 7.9, 9.6 Hz), 3.54 (dd, 1H, J = 3.5,
9.6 Hz), 4.28–4.40 (m, 1H), 4.57 (s, 2H), 5.19 (d, 1H, J = 10.5 Hz),
5.36 (d, 1H, J = 17.3 Hz), 5.74–5.94 (m, 1H), 7.30–7.35 (m, 5H);
13C NMR (50 MHz, CDCl3): d 71.4, 73.3, 74.0, 116.3, 126.8, 127.7
(ꢃ 2), 128.4 (ꢃ 2), 136.6, 137.7; EIMS: (M+Na)+ calcd for
to furnish aldol product 31 (4.2 g, 75%). ½a D25
¼ þ42:0 (c 1.9, CHCl3);
ꢁ
IR (CHCl3): 3506, 2931, 2860, 1781, 1697, 1454, 1210, 1015, 749;
1H NMR (200 MHz, CDCl3): d 0.95 (d, 3H, J = 6.6 Hz), 1.25 (d, 3H,
J = 7.1 Hz), 1.48–1.59 (m, 4H), 1.79 (m, 1H), 2.76 (dd, 1H, J = 9.5,
13.2 Hz), 2.90 (br s, 1H), 3.21–3.34 (m, 3H), 3.74 (dq, 1H, J = 2.5,
7.1 Hz), 3.91 (m, 1H), 4.13–4.21 (m, 2H), 4.48 (s, 2H), 4.67 (m,
1H), 7.22–7.33 (m, 10H); 13C NMR (50 MHz, CDCl3): d 10.3, 17.1,
29.8, 31.1, 33.3, 37.5, 41.9, 54.9, 65.9, 71.6, 72.7, 75.5, 127.2
(ꢃ 2), 127.3, 127.4, 128.1 (ꢃ 2), 128.7 (ꢃ 2), 129.2 (ꢃ 2), 134.9,
C11H14NaOþ 201.09. Found: 201.29; Anal. Calcd for C11H14O2: C,
2
74.13; H, 7.92. Found: C, 74.35; H, 7.76.
4.1.15. (2S,5R,6S)-((S)-1-(Benzyloxy)but-3-en-2-yl)-5-((2-methoxy-
ethoxy)methoxy)-2,6-dimethyldec-9-enoate 9
138.5, 152.7, 177.1; EIMS: (M+Na)+ calcd for C26H33NaOþ 462.23.
5
At first, 2,4,6-trichlorobenzoyl chloride (0.22 mL, 1.4 mmol) was
added to a stirred solution of acid 26 (0.28 g, 0.93 mmol) and i-
Pr2NEt (0.33 mL, 1.86 mmol) in THF (10 mL), at 0 °C. After 1 h, alco-
hol 29 (0.182 g, 1.02 mmol) and DMAP (0.17 g, 1.4 mmol) in THF
(5 mL) were added and the reaction mixture was warmed to room
temperature and stirred for 6 h. The reaction mixture was
quenched with a saturated NaHCO3 solution (10 mL) and the aque-
ous layer was extracted with EtOAc (2 ꢃ 15 mL). The combined or-
ganic layers were dried over Na2SO4 and concentrated. Purification
by flash silica gel chromatography (EtOAc/light petroleum, 1:9)
Found: 462.16; Anal. Calcd for C26H33NO5: C, 71.05; H, 7.57; N,
3.19. Found: C, 70.95; H, 7.39; N, 3.08.
4.1.18. (S)-4-Benzyl-3-((2S,3R,6S)-7-(benzyloxy)-3-(methoxy-
methoxy)-2,6-dimethylheptanoyl)oxazolidin-2-one 32
To a solution of aldol product 31 (1.0 g, 2.3 mL) in CH2Cl2
(10 mL), i-Pr2NEt (1.6 mL, 9.1 mmol) and MOM-Cl (0.35 mL,
4.5 mmol) were added simultaneously at 0 °C. The reaction mix-
ture was then stirred overnight at room temperature, quenched
with ice and water, and extracted with CH2Cl2 (2 ꢃ 10 mL). The
combined extracts were dried (over Na2SO4), concentrated, and
purified on a silica gel column using EtOAc and light petroleum
yielded 9 (0.32 g, 75%). ½a D25
¼ þ13:2 (c 1.0, CHCl3); IR (CHCl3)
ꢁ
cmꢀ1: 2930, 1724, 1650, 1382, 1255, 1026, 773, 621; 1H NMR
(200 MHz, CDCl3):
d 0.83 (d, 3H, J = 6.8 Hz), 1.18 (d, 3H,
J = 7.0 Hz), 1.38–1.48 (m, 4H), 1.65–1.83 (m, 3H), 1.96–2.14 (m,
2H), 2.43–2.52 (m, 1H), 3.38 (s, 3H), 3.39–3.44 (m, 1H), 3.50–
3.57 (m, 4H), 3.67–3.73 (m, 2H), 4.55 (ABq, 2H, J = 12.0 Hz), 4.70
(ABq, 2H, J = 7.1 Hz), 4.90–5.04 (m, 2H), 5.20–5.37 (m, 2H), 5.48–
5.55 (m, 1H), 5.70–5.92 (m, 2H), 7.31–7.33 (m, 5H); 13C NMR
(50 MHz, CDCl3): d 14.3, 17.3, 27.3, 29.7, 31.6, 31.8, 35.1, 39.6,
58.9, 67.1, 71.3, 71.7, 72.6, 73.0, 81.3, 94.6, 114.4, 117.8, 127.5
(ꢃ 2), 127.6, 128.3 (ꢃ 2), 133.5, 137.9, 138.7, 175.5; EIMS:
(1:9) to give 32 (0.99 g, 91%) as a clear liquid. ½a D25
¼ þ58:3 (c
ꢁ
1.2, CHCl3); IR (CHCl3): 2928, 1780, 1699, 1454, 1381, 1209,
1098, 1031, 750; 1H NMR (200 MHz, CDCl3): d 0.95 (d, 3H,
J = 6.6 Hz), 1.23 (d, 3H, J = 7.1 Hz), 1.50–1.80 (m, 5H), 2.75 (dd,
1H, J = 9.8, 13.3 Hz), 3.26–3.34 (m, 6H), 3.79 (m, 1H), 3.96 (m,
1H), 4.12 (d, 2H, J = 4.6 Hz), 4.48 (s, 2H), 4.52–4.63 (m, 3H), 7.21–
7.32 (m, 10H); 13C NMR (50 MHz, CDCl3): d 11.4, 17.2, 29.4, 29.7,
30.1, 33.6, 37.7, 41.4, 55.95, 65.98, 72.9, 75.6, 79.3, 96.4, 127.3
(ꢃ 2), 127.4, 127.5, 128.3 (ꢃ 2), 128.9 (ꢃ 2), 129.4 (ꢃ 2), 135.4,
(M+Na)+ calcd for C27H42NaOþ 485.29. Found: 485.38; Anal. Calcd
6
for C27H42O6: C, 70.10; H, 9.15. Found: C, 70.25; H, 9.38.
138.7, 153.1, 174.8; EIMS: (M+Na)+ calcd for C28H37NaOþ 506.25.
6
Found: 506.42; Anal. Calcd for C28H37NO6: C, 69.54; H, 7.71; N,
2.90. Found: C, 69.42; H, 7.59; N, 2.76.
4.1.16. (3S,6R,7S,12S)-12-(Benzyloxymethyl)-6-(2-mehtoxyeth-
oxy)methoxy-3,7-dimethyloxacyclododec-10-en-2-one 4 and 4a
A solution of ester 9 (0.17 g, 0.37 mmol) and Grubbs’ second
generation catalyst (0.032 g, 0.037 mmol) in dry benzene (70 mL)
was degassed under an argon atmosphere and refluxed for 24 h.
After completion of the reaction (monitored by TLC), the solvent
was evaporated and the residue was chromatographed on flash sil-
ica gel column using EtOAc and light petroleum (1:24) to yield 4
and 4a (0.092 g, combined yield 58%) as an inseparable mixture
4.1.19. (2R,3R,6S)-7-(Benzyloxy)-3-(methoxymethoxy)-2,6-
dimethylheptan-1-ol 33
At first, LiCl (0.156 g, 6.63 mmol)) and NaBH4 (0.252 g,
6.63 mmol) were taken in a mixture of absolute ethanol (25 mL)
and THF (8 mL) and vigorously stirred for 1 h at room temperature.
A solution of aldol product 32 (0.8 g, 1.7 mmol) in THF, (8 mL) was
then added dropwise and the mixture was then stirred for 6 h at
room temperature. The mixture was quenched with a saturated
solution of NH4Cl (10 mL) and extracted with EtOAc (3 ꢃ 15 mL).
The combined organic layers were dried over Na2SO4, concentrated
and the residue was purified on silica gel column using EtOAc/light
petroleum (1:5) to afford 33 (0.44 g, 86%) as a colorless liquid.
of E- and Z- (2:1) isomers as a colorless liquid. IR (CHCl3) cmꢀ1
:
2927, 1723, 1601, 1370, 1116, 1028; 1H NMR (200 MHz, CDCl3):
d 0.90 (d, 1H, J = 6.6 Hz), 0.96 (d, 2H, J = 6.6 Hz), 1.10 (d, 1H,
J = 7.1 Hz), 1.16 (d, 2H, J = 7.1 Hz), 1.58–1.72 (m, 5H), 2.08–2.14
(m, 3H), 2.26–2.40 (m, 1H), 2.60–2.72 (m, 1H), 3.38 (s, 3H), 3.47–
3.61 (m, 5H), 3.65–3.72 (m, 2H), 4.48–4.60 (m, 2H), 4.65–4.75
(m, 2H), 4.98–5.22 (m, 1H), 5.31–5.65 (m, 2H), 7.25–7.35 (m,
5H); 13C NMR (125 MHz, CDCl3): d 14.0 (ꢃ 2), 15.2 (ꢃ 2), 18.3/
22.8, 26.2/28.7, 30.3/31.9, 34.7/35.1, 36.6/36.9, 39.9 (ꢃ 2), 59.1
(ꢃ 2), 67.1/67.3, 71.5/71.6, 71.8 (ꢃ 2), 72.4 (ꢃ 2), 73.1 (ꢃ 2), 81.7
(ꢃ 2), 94.3 (ꢃ 2), 126.1/126.6, 127.6 (ꢃ 2), 127.7 (ꢃ 2), 128.4
(ꢃ 2), 129.6 (ꢃ 2), 130.8 (ꢃ 2), 132.4 (ꢃ 2), 138.1 (ꢃ 2), 175.4/
½
a 2D5
ꢁ
¼ ꢀ28:3 (c 1.2, CHCl3); IR (CHCl3): 3437, 2926, 1736, 1496,
1454, 1208, 1147, 1098, 918, 698; 1H NMR (200 MHz, CDCl3): d
0.75 (d, 3H, J = 7.0 Hz), 0.88 (d, 3H, J = 6.7 Hz), 1.35–1.56 (m, 4H),
1.69–1.86 (m, 2H), 2.39 (br s, 1H), 3.21 (dd, 2H, J = 2.4, 6.3 Hz),
3.33 (s, 3H), 3.41–3.64 (m, 3H), 4.42 (s, 2H), 4.58 (s, 2H), 7.23–
7.27 (m, 5H); 13C NMR (50 MHz, CDCl3): d 10.6, 17.1, 28.8, 29.95,
33.6, 37.8, 55.9, 65.2, 72.99, 75.7, 79.9, 96.7, 127.4 (ꢃ 2), 127.5,
175.6; EIMS: (M+Na)+ calcd for C25H38NaOþ 457.26. Found:
128.3 (ꢃ 2), 138.7; EIMS: (M+Na)+ calcd for C18H30NaOþ 333.20.
6
6

B. Chatterjee et al. / Tetrahedron: Asymmetry 23 (2012) 1170–1185
1181
Found: 333.11; Anal. Calcd for C18H30O4: C, 69.64; H, 9.74. Found:
C, 69.54; H, 9.63.
4.1.23. (4R,5R,8S,E)-Ethyl-9-(benzyloxy)-5-(tert-butyldimethyl-
silyloxy)-4,8-dimethylnon-2-enoate 39
Alcohol 38 (3.0 g, 7.9 mmol) was dissolved in CH2Cl2 (25 mL)
and PDC (5.9 g, 15.7 mmol) was added at room temperature. The
mixture was then stirred overnight and filtered off. The filtrate
was concentrated to a residue, which was purified on a silica gel
column (EtOAc/light petroleum, 1:9) to produce the aldehyde
(2.4 g, 81%) as a colorless liquid. A solution of the above aldehyde
(2.4 g, 6.3 mmol) and (carbethoxymethylene)triphenyl phosphor-
ane (4.4 g, 12.7 mmol) in dry benzene (20 mL) was stirred at room
temperature for 24 h. The reaction was monitored by TLC and after
completion, the solvent was removed in vacuum and the residue
was purified by flash silica gel column chromatography eluting
with EtOAc and light petroleum (1:24) to afford pure Wittig (E)-
4.1.20. (S,E)-7-(Benzyloxy)-2,6-dimethylhept-2-enal 35
Alcohol 33 (0.35 g, 1.1 mmol) was dissolved in DMSO (4 mL)
and then IBX (0.38 g, 1.4 mmol) was added at room temperature
and stirred overnight. The reaction mixture was quenched with
H2O and filtered off. The filtrate was extracted with ether
(2 ꢃ 15 mL), then dried over Na2SO4, and concentrated. The residue
was purified on a silica gel column (EtOAc/light petroleum, 1:9) to
produce aldehyde 34 (0.32 g, 93%) as a colorless liquid. To a solu-
tion of the aldehyde 34 (0.32 g, 1.04 mmol) in dry benzene
(8 mL), (carbethoxymethylene)triphenyl phosphorane (0.72 g,
2.08 mmol) was added at room temperature. It was then stirred
overnight, concentrated and the residue was purified by flash silica
gel column chromatography (EtOAc/light petroleum, 1:49) to af-
ford the eliminated product 35 (0.18 g, 70%) as a colorless liquid.
1H NMR (200 MHz, CDCl3): d 0.97 (d, 3H, J = 6.7 Hz), 1.36 (m, 1H),
1.65(m, 1H), 1.73 (s, 3H), 1.82 (m, 1H), 2.30–2.42 (m, 2H), 3.32
(d, 2H, J = 6.1 Hz), 4.51 (s, 2H), 6.48 (t, 1H, J = 7.3 Hz), 7.30–7.35
(m, 5H), 9.38 (s, 1H); EIMS: (M+Na)+ calcd for C16H22NaO2
269.15. Found: 269.21.
isomer 39 (2.2 g, 78%) as a colorless liquid. ½a D25
¼ þ20:8 (c 0.9,
ꢁ
CHCl3); IR (CHCl3): 2956, 2930, 2857, 1721, 1652, 1462, 1366,
1257, 1180, 1098, 836, 774; 1H NMR (200 MHz, CDCl3): d 0.03 (s,
6H), 0.88 (s, 9H), 0.92 (d, 3H, J = 6.7 Hz), 1.01 (d, 3H, J = 6.9 Hz),
1.28 (t, 3H, J = 7.1 Hz), 1.39–1.78 (m, 5H), 2.45 (m, 1H), 3.23 (dd,
1H, J = 6.3, 9.0 Hz), 3.30 (dd, 1H, J = 6.3, 9.0 Hz), 3.59 (m, 1H),
4.18 (q, 2H, J = 7.1 Hz), 4.48 (s, 2H), 5.78 (dd, 1H, J = 1.3, 15.8 Hz),
6.99 (dd, 1H, J = 7.3, 15.8 Hz), 7.28–7.33 (m, 5H); 13C NMR
(50 MHz, CDCl3): d ꢀ4.5, ꢀ4.2, 13.7, 14.3, 17.2, 18.1, 25.9 (ꢃ 3),
29.2, 31.5, 33.6, 41.3, 60.1, 72.99, 75.3, 75.7, 120.7, 127.4 (ꢃ 2),
127.5, 128.3 (ꢃ 2), 138.7, 152.1, 166.6; EIMS: (M+Na)+ calcd for
4.1.21. (S)-4-Benzyl-3-((2S,3R,6S)-7-(benzyloxy)-3-(tert-butyldi-
methylsilyloxy)-2,6-dimethylheptanoyl)oxazolidin-2-one 37
To a stirred solution of aldol product 31 (5.0 g, 11.4 mmol) in
CH2Cl2 (20 mL), 2,6-lutidine (2.64 mL, 22.7 mmol) was added fol-
lowed by TBS-OTf (3.9 mL, 17.0 mmol) at 0 °C. The reaction mix-
ture was stirred for 30 min, then quenched with ice, diluted with
water (5 mL) and extracted with CH2Cl2 (2 ꢃ 20 mL). The combined
organic layer was washed with 1 M HCL (2 ꢃ 15 mL), brine, dried
over Na2SO4, and concentrated to a residue which was purified
on a silica gel column using EtOAc and light petroleum (1:19) as
eluent to provide the TBS protected aldol compound 37 (5.95 g,
C26H44NaO4Si 471.29. Found: 471.20; Anal. Calcd for C26H44O4Si:
C, 69.59; H, 9.88. Found: C, 69.44; H, 9.69.
4.1.24. (4R,5R,8S,E)-Ethyl-9-(benzyloxy)-4,8-dimethyl-5-((R)-3,
3,3-trifluoro-2-methoxy-2-phenylpropanoyloxy)non-2-enoate
40 [(R)-MTPA ester]
To a solution of Wittig compound 39 (0.050 g, 0.112 mmol) in
THF (2 mL) at 0 °C, HF-pyridine in pyridine/THF mixture [prepared
from a stock solution containing 42 mL, HF-pyridine (70% HF),
114 mL pyridine and 200 mL THF] (2.0 mL) was added and the
resulting solution was warmed to room temperature. After stirring
overnight, the reaction was diluted with EtOAc and quenched by
the careful addition of a saturated NaHCO3 solution. The layers
were separated and the aqueous layer was extracted with EtOAc
(3 ꢃ 10 mL). The combined layers were washed with brine, dried
over Na2SO4, and concentrated in vacuum to afford a residue which
was purified by flash column chromatography (EtOAc/light petro-
leum, 1:6) to give the secondary alcohol (0.027 g, 73%) as a color-
less liquid. The corresponding (R)-MTPA acid (0.011 g,
0.045 mmol), the resulting secondary alcohol (0.010 g, 0.03 mmol),
DCC (0.012 g, 0.06 mmol), and DMAP (0.002 g, 0.015 mmol) were
taken in CH2Cl2 (2 mL) and stirred for 12 h at room temperature.
The reaction mixture was filtered, concentrated, and purified by
flash silica gel column using EtOAc and light petroleum (1:19) to
yield 40 (0.012 g, 73%) as a colorless liquid. 1H NMR (200 MHz,
CDCl3): d 0.80 (d, 3H, J = 6.7 Hz), 0.99 (d, 3H, J = 6.9 Hz), 1.22 (t,
3H, J = 7.1 Hz), 1.49–1.62 (m, 5H), 2.61 (m, 1H), 3.09 (dd 1H,
J = 6.2, 9.3 Hz), 3.13 (dd, 1H, J = 6.3, 9.3 Hz), 3.44 (s, 3H), 4.12 (q,
2H, J = 7.1 Hz), 4.38 (s, 2H), 5.02 (dt, 1H, J = 4.9, 7.7 Hz), 5.75 (dd,
1H, J = 1.3, 15.8 Hz), 6.81 (dd, 1H, J = 7.3, 15.8 Hz), 7.19–7.31 (m,
95%) as a colorless viscous liquid. ½a D25
¼ þ28:4 (c 1.1, CHCl3); IR
ꢁ
(CHCl3): 2929, 1783, 1704, 1454, 1382, 1209, 1104, 837; 1H NMR
(200 MHz, CDCl3): d ꢀ0.02 (s, 3H), 0.02, (s, 3H), 0.87 (s, 9H), 0.93
(d, 3H, J = 6.4 Hz), 1.20 (d, 3H, J = 7.0 Hz), 1.45–1.75 (m, 5H), 2.75
(dd, 1H, J = 9.6, 13.3 Hz), 3.23–3.30 (m, 3H), 3.84 (m, 1H), 4.01–
4.14 (m, 3H), 4.47 (s, 2H), 4.55 (m, 1H), 7.22–7.33 (m, 10H); 13C
NMR (50 MHz, CDCl3): d ꢀ4.9, ꢀ4.2, 11.5, 17.1, 18.0, 25.6 (ꢃ 2),
25.8 (ꢃ 2), 28.6, 32.7, 33.7, 37.5, 42.6, 55.7, 65.9, 72.9, 75.8, 127.2
(ꢃ 2), 127.3, 127.5, 128.2 (ꢃ 2), 128.9 (x2), 129.4 (ꢃ 2), 135.4,
138.7, 153.0, 175.2; EIMS: (M+Na)+ calcd for C32H47NNaO5Si
576.31. Found: 576.46; Anal. Calcd for C32H47NO5Si: C, 69.40; H,
8.55; N, 2.53. Found: C, 69.26; H, 8.38; N, 2.42.
4.1.22. (2R,3R,6S)-7-(Benzyloxy)-3-(tert-butyldimethylsilyloxy)-
2,6-dimethylheptan-1-ol 38
Using the same procedure as described for the synthesis 33,
compound 38 (3.2 g, 83%) was obtained as a colorless liquid from
compound 37. ½a 2D5
¼ ꢀ1:95 (c 0.8, CHCl3); IR (CHCl3): 3430,
ꢁ
2955, 2929, 1471, 1361, 1253, 1096, 836, 774; 1H NMR
(400 MHz, CDCl3): d 0.07 (s, 3H), 0.09 (s, 3H), 0.81 (d, 3H,
J = 7.0 Hz), 0.89 (s, 9H), 0.95 (d, 3H, J = 6.7 Hz), 1.05 (m, 1H),
1.45–1.55 (m, 3H), 1.75 (m, 1H), 1.92 (m, 1H), 2.38 (br s, 1H)
3.26 (dd, 1H, J = 6.4, 8.9 Hz), 3.32 (dd, 1H, J = 6.3, 8.9 Hz), 3.51
(dd, 1H, J = 5.2, 10.6 Hz), 3.67 (dd, 1H, J = 8.4, 10.6 Hz), 3.75 (m,
1H), 4.50 (s, 2H), 7.29–7.34 (m, 5H); 13C NMR (100 MHz, CDCl3):
d ꢀ4.5, ꢀ4.3, 11.6, 17.1, 18.0, 25.8 (ꢃ 3), 29.9, 30.2, 33.6, 39.4,
66.0, 73.0, 75.7, 75.8, 127.4 (ꢃ 2), 127.5, 128.3 (ꢃ 2), 138.7;
EIMS: (M+Na)+ calcd for C22H40NaO3Si+ 403.26. Found: 403.25;
Anal. Calcd for C22H40O3Si: C, 69.42; H, 10.59. Found: C, 69.24; H,
10.38.
8H), 7.42–7.46 (m, 2H); EIMS: (M+Na)+ calcd for C30H37F3NaOþ
6
573.24. Found: 573.55; Anal. Calcd for C30H37F3O6: C, 65.44; H,
6.77. Found: C, 65.87; H, 6.90.
4.1.25. (4R,5R,8S,E)-Ethyl-9-(benzyloxy)-4,8-dimethyl-5-((S)-3,
3,3-trifluoro-2-methoxy-2-phenylpropanoyloxy)non-2-enoate
41 [(S)-MTPA ester]
Using the same procedure as described for the synthesis of
MTPA ester 40, compound 41 (0.013 g, 76%) was obtained as a col-

1182
B. Chatterjee et al. / Tetrahedron: Asymmetry 23 (2012) 1170–1185
orless liquid from compound 39. 1H NMR (200 MHz, CDCl3): d 0.83
(d, 3H, J = 6.7 Hz), 0.93 (d, 3H, J = 6.9 Hz), 1.20 (t, 3H, J = 7.1 Hz),
1.34–1.49 (m, 2H), 1.59–1.73 (m, 3H), 2.56 (m, 1H), 3.17 (d, 2H,
J = 6.2 Hz), 3.44 (s, 3H), 4.10 (q, 2H, J = 7.1 Hz), 4.40 (s, 2H),
5.03 (dt, 1H, J = 4.8, 7.8 Hz), 5.63 (dd, 1H, J = 1.3, 15.8 Hz), 6.69
(dd, 1H, J = 7.5, 15.8 Hz), 7.19–7.31 (m, 8H), 7.44–7.48 (m, 2H);
(1:4) to provide 6 (1.45 g, 89%) as a colorless oil. ½a D25
¼ þ4:3 (c
ꢁ
1.3, CHCl3); IR (CHCl3): 3379, 3019, 2930, 1604, 1215, 1075, 757,
668; 1H NMR (200 MHz, CDCl3): d 0.02 (s, 6H), 0.82 (d, 3H,
J = 6.7 Hz), 0.87 (s, 9H), 0.92 (d, 3H, J = 6.8 Hz), 1.04–1.44 (m, 8H),
1.58–1.74 (m, 3H), 3.24 (dd, 1H, J = 6.5, 9.0 Hz), 3.30 (dd, 1H,
J = 6.2, 9.0 Hz), 3.48 (m, 1H), 3.61 (t, 2H, J = 6.6 Hz), 4.49 (s, 2H),
7.28–7.34 (m, 5H); 13C NMR (50 MHz, CDCl3): d ꢀ4.5, ꢀ4.2, 14.3,
17.2, 18.1, 25.9 (ꢃ 3), 28.5, 29.8, 30.7, 30.95, 33.7, 37.4, 63.3,
73.0, 75.9 (ꢃ 2), 127.4 (ꢃ 2), 127.5, 128.3 (ꢃ 2), 138.7;
EIMS: (M+Na)+ calcd for C24H44NaO3Si+ 431.29. Found: 431.36;
Anal. Calcd for C24H44O3Si: C, 70.53; H, 10.85. Found: C, 70.37; H,
10.66.
EIMS: (M+Na)+ calcd for C30H37F3NaOþ 573.24. Found: 573.55;
6
Anal. Calcd for C30H37F3O6: C, 65.44; H, 6.77. Found: C, 65.89; H,
6.70.
4.1.26. (4R,5R)-4-((S)-4-(Benzyloxy)-3-methylbutyl)-2,2,5-trimeth-
yl-1,3-dioxane 42
To a solution of 38 (0.2 g, 0.53 mmol), in THF (4 mL) at 0 °C was
added TBAF (0.8 mL, 1 M in THF, 0.8 mmol). After stirring for
30 min, the reaction was quenched with a saturated solution of
NH4Cl and diluted with EtOAc. The layers were separated and the
aqueous layer was extracted with EtOAc (2 ꢃ 15 mL), dried over
Na2SO4, concentrated to a residue and purified on silica gel column
(EtOAc/light petroleum, 2:3) to yield a diol compound (0.126 g,
90%) as a colorless liquid. A solution of the above diol (0.1 g,
0.4 mmol) was treated with 2,2-dimethoxy propane (0.07 mL,
0.6 mmol) and p-TSA (catalytic) in acetone (5 mL). The solution
was stirred overnight at room temperature, then quenched with
a saturated solution of NaHCO3, extracted with ethyl acetate
(2 ꢃ 15 mL), dried over Na2SO4, and concentrated. The crude resi-
due was purified on a silica gel column (EtOAc/light petroleum,
1:19) to provide the acetonide protected compound 42 (0.085 g,
74%) as a clear liquid. 1H NMR (400 MHz, CDCl3): d 0.95 (d, 3H,
J = 6.7 Hz), 1.05 (d, 3H, J = 7.0 Hz), 1.13 (m, 1H), 1.29–1.34 (m,
2H), 1.38 (s, 3H), 1.42 (s, 3H), 1.47–1.54 (m, 2H), 1,78 (m, 1H),
3.26 (dd, 1H, J = 6.6, 8.9 Hz), 3.32 (dd, 1H, J = 6.4, 8.9 Hz), 3.58 (d,
1H, J = 11.6 Hz), 3.87 (dt, 1H, J = 2.3, 6.7 Hz), 4.07 (d, 1H,
J = 11.6 Hz), 4.49 (s, 2H), 7.28–7.33 (m, 5H).
4.1.28. 5-((4R,5R,8S,)-9-(Benzyloxy)-5-(tert-butyldimethylsilyl-
oxy)-4,8-dimethylnonylsulfonyl)-1-phenyl-1H-tetrazole 44
At first, DIAD (1.0 mL, 5.1 mmol) was added to a solution of 6
(1.3 g, 3.2 mmol), triphenylphosphine (1.5 g, 5.7 mmol) and 1-phe-
nyl-1H-tetrazole-5-thiol (1.14 g, 6.4 mmol) in THF (20 mL) at 0 °C.
After stirring for 1 h, the reaction was quenched with brine and the
aqueous layer was extracted with EtOAc (2 ꢃ 20 mL), dried (over
Na2SO4), and concentrated. Purification by flash silica gel column
chromatography (EtOAc/light petroleum, 1:19) yielded a sulfide
(1.6 g, 89%) as a clear oil. The above intermediate sulfide (1.6 g,
2.8 mmol) was dissolved in EtOH (20 mL) and cooled to 0 °C. In a
separate flask were mixed 30% H2O2 (3.2 mL, 28.0 mmol) and
ammonium molybdate tetrahydrate (0.348 g, 0.28 mmol), produc-
ing a bright yellow solution that was added via syringe to the reac-
tion flask. The reaction was stirred overnight and then quenched
by the addition of water (10 mL), and extracted with EtOAc
(2 ꢃ 20 mL). The organic layers were dried over Na2SO4 and con-
centrated to afford a residue which was purified on a flash silica
gel column eluting with EtOAc/light petroleum, (1:19) to furnish
sulfone 44 (1.55 g, 92%) as a colorless liquid. ½a D25
¼ þ1:5 (c 1.2,
ꢁ
CHCl3); IR (CHCl3): 2929, 1596, 1497, 1344, 1152, 1045, 836,
761; 1H NMR (200 MHz, CDCl3): d 0.02 (s, 6H), 0.82–0.86 (m,
12H), 0.92 (d, 3H, J = 6.9 Hz), 1.03 (m, 1H), 1.25–1.48 (m, 6H),
1.63–1.76 (m, 2H), 1.95 (m, 1H), 3.19–3.32 (m, 2H), 3.49 (m, 1H),
3.68 (t, 2H, J = 7.8 Hz), 4.48 (s, 2H), 7.30 (m, 5H), 7.59–7.71 (m,
5H); 13C NMR (50 MHz, CDCl3): d ꢀ4.4, ꢀ4.1, 13.9, 17.2, 18.1,
20.4, 25.9 (ꢃ 3), 29.9, 30.7, 31.3, 33.7, 37.2, 56.2, 72.99, 75.5,
75.8, 125.0 (ꢃ 2), 127.4 (ꢃ 2), 127.5, 128.3 (ꢃ 2), 129.7 (ꢃ 2),
131.3, 133.1, 138.7, 153.5; EIMS: (M+Na)+ calcd for
4.1.27. (4R,5R,8S,)-9-(Benzyloxy)-5-(tert-butyldimethylsilyloxy)-
4,8-dimethylnonan-1-ol 6
The Wittig E-isomer 39 (1.95 g, 4.34 mmol) was dissolved in
MeOH (15 mL) and NiCl2.6H2O (0.26 g, 1.1 mmol) was added in
one portion. The reaction mixture was then cooled to 0 °C and
NaBH4 (0.66 g, 17.4 mmol) was added in small portions to avoid
a vigorous reaction. Stirring was continued at 0 °C for 30 min, then
diluted with CH2Cl2 (10 mL) and quenched with saturated NH4Cl
(15 mL). The layers were separated out and the aqueous layer
was extracted with CH2Cl2 (2 ꢃ 20 mL). The combined organic lay-
ers were dried over anhydrous Na2SO4, concentrated, and purified
on a silica gel column (EtOAc/light petroleum, 1:19) to yield the
C
C
31H48N4O4NaSSi+ 623.30. Found: 623.39; Anal. Calcd for
31H48N4O4SSi: C, 61.96; H, 8.05; N, 9.32. Found: C, 61.82; H,
7.97; N, 9.16.
saturated ester 43 (1.93 g, 98%) as a colorless liquid. ½a D25
ꢁ
¼ þ4:2
4.1.29. ((2S,5R,6R,E)-1-(Benzyloxy)-10-((S)-2,2-dimethyl-1,3-
dioxolan-4-yl)-2,6-dimethyldec-9-en-5-yloxy)(tert-butyl)di-
methylsilane 45
(c 0.9, CHCl3); IR (CHCl3): 3019, 2930, 1726, 1462, 1215, 755,
669; 1H NMR (200 MHz, CDCl3): d 0.02 (s, 6H), 0.82 (d, 3H,
J = 6.6 Hz), 0.87 (s, 9H), 0.92 (d, 3H, J = 6.8 Hz), 1.04 (m, 1H), 1.24
(t, 3H, J = 7.1 Hz), 1.32–1.50 (m, 5H), 1.69–1.83 (m, 2H), 2.18–
2.38 (m, 2H), 3.18–3.33 (m, 2H), 3.49 (m, 1H), 4.10 (q, 2H,
J = 7.1 Hz), 4.48 (s, 2H), 7.28–7.33 (m, 5H); 13C NMR (50 MHz,
CDCl3): d ꢀ4.4, ꢀ4.1, 13.8, 14.3, 17.2, 18.2, 26.0 (ꢃ 3), 28.2, 29.8,
30.9, 32.7, 33.7, 37.0, 60.1, 73.0, 75.7, 75.8, 127.4 (ꢃ 2), 127.5,
128.3 (ꢃ 2), 138.7, 173.8; EIMS: (M+Na)+ calcd for C26H46NaO4Si+
473.30. Found: 473.43; Anal. Calcd for C26H46O4Si: C, 69.28; H,
10.29. Found: C, 69.13; H, 10.09.
To a solution of the sulfone 44 (0.5 g, 0.83 mmol) in 1,2-dime-
thoxy ethane (20 mL) at ꢀ60 °C, was added KHMDS (2.5 mL,
0.5 M in toluene, 1.25 mmol). The yellow solution was then stirred
for 30 min after which the aldehyde 27 (0.22 g, 1.7 mmol) in DME
(6 mL) was introduced slowly via a syringe and stirred at ꢀ60 °C
for 2 h. The reaction was warmed to 0 °C and then quenched with
a saturated solution of NH4Cl (10 mL). The layers were separated
and the aqueous layer was extracted with EtOAc (2 ꢃ 20 mL). The
combined organic layers were washed with brine, dried over
Na2SO4 and concentrated to a residue. Purification on flash silica
gel column using EtOAc/light petroleum, (1:49) as eluent, afforded
Next, LiAlH4 (0.23 g, 6.0 mmol) was added to a stirred solution
of ester 43 (1.8 g, 4.0 mmol) in THF (25 mL) at 0 °C. After 1 h, the
reaction was quenched with a saturated solution of Na2SO4 and fil-
tered. The residue was washed with EtOAc (3 ꢃ 25 mL) and the fil-
trate was dried (over Na2SO4) and concentrated. The crude residue
was purified on a silica gel column using EtOAc/light petroleum
Julia product 45 (0.344 g, 82%) as a colorless liquid. ½a D25
¼ þ17:9 (c
ꢁ
2.2, CHCl3); IR (CHCl3): 2929, 1591, 1455, 1379,1252, 1061, 836,
773, 697; 1H NMR (400 MHz, CDCl3): d 0.00 (s, 3H), 0.01 (s, 3H),
0.79 (d, 3H, J = 6.7 Hz), 0.86 (s, 9H), 0.92 (d, 3H, J = 6.8 Hz), 1.00

B. Chatterjee et al. / Tetrahedron: Asymmetry 23 (2012) 1170–1185
1183
(m, 1H), 1.16 (m, 1H), 1.37 (s, 3H), 1.41 (s, 3H), 1.43–1.52 (m, 4H),
1.71 (m, 1H), 1.93–2.01 (m, 2H), 2.08 (m, 1H), 3.23 (dd, 1H, J = 6.6,
9.0 Hz), 3.30 (dd, 1H, J = 6.2, 9.0 Hz), 3.48 (m, 1H), 3.53 (t, 1H,
J = 8.0 Hz), 4.04 (dd, 1H, J = 6.1, 8.0 Hz), 4.45 (m, 1H), 4.49 (s, 2H),
5.41 (dd, 1H, J = 8.0, 15.3 Hz), 5.76 (dt, 1H, J = 6.8, 15.3 Hz), 7.32–
7.37 (m, 5H); 13C NMR (100 MHz, CDCl3): d ꢀ4.5, ꢀ4.2, 14.1,
17.2, 18.1, 25.9 (ꢃ 3), 26.7, 29.9, 30.3, 30.7, 31.8 (ꢃ 2), 33.7, 37.1,
69.5, 72.97, 75.8, 75.9, 77.4, 108.97, 127.0, 127.4, 127.5 (ꢃ 2),
128.3 (ꢃ 2), 136.3, 138.8; EIMS: (M+Na)+ calcd for C30H52NaO4Si+
527.35. Found: 527.47; Anal. Calcd for C30H52O4Si: C, 71.38; H,
10.38. Found: C, 71.14; H, 10.22.
Stark apparatus. After cooling it to room temperature, benzyl bro-
mide (0.08 mL, 0.64 mmol) and TBAI (catalytic) were added and re-
fluxed for 2 h. After completion (monitored by TLC), the reaction
was diluted with CH2Cl2 (15 mL) and washed with 10% NaHCO3
solution, water, brine, dried (over Na2SO4) and then concentrated.
Purification of the residue by silica gel column chromatography
using EtOAc and light petroleum (3:7) provided 48 (0.166 g, 84%)
as a clear liquid. ½a D25
¼ þ10:8 (c 1.3, CHCl3); IR (CHCl3): 3392,
ꢁ
2928, 1619, 1384, 1252, 1045, 835, 772; 1H NMR (400 MHz,
CDCl3): d 0.01 (s, 3H), 0.02 (s, 3H), 0.80 (d, 3H, J = 6.7 Hz), 0.87 (s,
9H), 0.89 (d, 3H, J = 6.8 Hz), 1.00 (m, 1H), 1.16 (m, 1H), 1.32–1.45
(m, 5H), 1.48–1.55 (m, 3H), 1.98–2.07 (m, 2H), 3.33–3.44 (m,
3H), 3.48–3.50 (m, 2H), 4.29 (m, 1H), 4.56 (s, 2H), 5.42 (dd, 1H,
J = 6.6, 15.5 Hz), 5.74 (dt, 1H, J = 6.9, 15.5 Hz), 7.29–7.35 (m, 5H);
4.1.30. (2S,7R,8R,11S,E)-12-(Benzyloxy)-8-(tert-butyldimethyl-
silyloxy)-7,11-dimethyldodec-3-ene-1,2-diol 46
13C NMR (100 MHz, CDCl3):
d
ꢀ4.5, ꢀ4.2, 14.0, 16.5, 18.1,
A solution of 45 (0.65 g, 1.3 mmol) in acetonitrile (20 mL) was
treated with Zn(NO3)2.6H2O (7.6 g, 25.8 mmol) and heated to
50 °C. After 6 h (TLC showed complete disappearance of starting
material), the reaction was quenched with a saturated solution of
NaHCO3 and extracted with EtOAc (3 ꢃ 20 mL). The organic layer
was dried (over Na2SO4), concentrated and purified on a silica gel
column (EtOAc/light petroleum, 3:7) giving diol 46 (0.44 g, 74%)
25.9 (ꢃ 3), 29.1, 30.3, 30.8, 31.9, 35.9, 36.5, 68.3, 71.4, 73.3, 74.4,
75.5, 127.8 (ꢃ 2), 127.9, 128.1 (ꢃ 2), 128.5, 134.1, 137.9;
EIMS: (M+Na)+ calcd for C27H48NaO4Si+ 487.32. Found: 487.43;
Anal. Calcd for C27H48O4Si: C, 69.78; H, 10.41. Found: 69.57; H,
10.24.
as a colorless liquid. ½a D25
¼ þ11:2 (c 1.0, CHCl3); IR (CHCl3):
ꢁ
4.1.33. (2S,5R,6R,11S,E)-12-(Benzyloxy)-5-(tert-butyldimethyl-
silyloxy)-11-hydroxy-2,6-dimethyldodec-9-enoic acid 5
3369, 2928, 1602, 1454, 1384, 1252, 1114, 835, 772; 1H NMR
(500 MHz, CDCl3): d 0.00 (s, 3H), 0.01 (s, 3H), 0.80 (d, 3H,
J = 6.6 Hz), 0.86 (s, 9H), 0.92 (d, 3H, J = 6.8 Hz), 1.01 (m, 1H), 1.15
(m, 1H), 1.21–1.33 (m, 3H), 1.45–1.52 (m, 4H), 1.70 (m, 1H), 1.98
(m, 1H), 2.08 (m, 1H), 3.22–3.31 (m, 2H), 3.44–3.48 (m, 2H), 3.60
(m, 1H), 4.17 (m, 1H), 4.49 (s, 2H), 5.43 (dd, 1H, J = 6.6, 15.5 Hz),
5.74 (dt, 1H, J = 6.7, 15.5 Hz), 7.28–7.33 (m, 5H); 13C NMR
(125 MHz, CDCl3): d ꢀ4.4, ꢀ4.1, 14.1, 17.1, 18.2, 25.9 (ꢃ 3), 29.8,
30.4, 30.8, 31.99, 33.6, 36.8, 66.6, 73.0, 73.2, 75.7, 76.0, 127.4
(ꢃ 2), 127.5, 128.3 (ꢃ 2), 128.4, 134.5, 138.8; EIMS: (M+Na)+ calcd
At first, PhI(OAc)2 (0.115 g, 0.36 mmol) was added to a solution
of diol 48 (0.11 g, 0.24 mmol) and TEMPO (0.004 g, 0.024 mmol) in
CH2Cl2 (3 mL). The reaction was stirred for 3 h at room tempera-
ture, then quenched with a 10% solution of Na2S2O3 (5 mL), and ex-
tracted with CH2Cl2 (3 ꢃ 10 mL). The organic layer was washed
with aqueous NaHCO3, water and dried over Na2SO4. Concentra-
tion and purification by silica gel column chromatography (EtOAc
and light petroleum, 1:4) afforded an aldehyde (0.1 g, 92%) as a
clear oil. Next, NaClO2 (0.078 g, 0.87 mmol) was added to a solu-
tion of the above intermediate aldehyde (0.1 g, 0.22 mmol), 2-
methyl-2-butene (0.023 mL, 0.22 mmol) and NaH2PO4 (0.1 g,
0.87 mmol) in t-butanol and water (3:1), (4 mL) at 0 °C. After stir-
ring for 3 h, the reaction was diluted with water (5 mL) and ex-
tracted with EtOAc (3 ꢃ 15 mL). The combined organic layers
were dried (over Na2SO4), concentrated and purified by flash silica
gel chromatography using EtOAc and light petroleum, (2:3) as elu-
ent, to furnish the seco acid 5 (0.09 g, 87%) as a colorless liquid.
for
27H48O4Si: C, 69.78; H, 10.41. Found: C, 69.61; H, 10.22.
C
27H48NaO4Si+ 487.32. Found: 487.42; Anal. Calcd for
C
4.1.31. (2S,7R,8R,11S,E)-8-(tert-Butyldimethylsilyloxy)-7,11-dimeth-
yldodec-3-ene-1,2,12-triol 47
To a vigorously stirred solution of ammonia (10 mL) at ꢀ78 °C,
small pieces of lithium (0.047 g, 6.7 mmol) were added and stirred
for 5 min until the deep blue color appeared. After stirring for
30 min at ꢀ78 °C, diol 46 (0.31 g, 0.67 mmol) in THF (10 mL) was
added dropwise and stirred for another 1 h, and then quenched
with solid NH4Cl until the blue color disappeared. Ammonia was
allowed to evaporate completely and the residue was diluted with
H2O (10 mL) extracted with EtOAc (2 ꢃ 20 mL). The combined ex-
tracts were dried over Na2SO4, concentrated and purified on silica
gel column using EtOAc/light petroleum (3:1) as eluent to produce
½
a 2D5
ꢁ
¼ þ20:0 (c 1.1, CHCl3); IR (CHCl3): 3393, 2928, 1708, 1619,
1462, 1384, 1252, 1070, 835, 773; 1H NMR (400 MHz, CDCl3): d
0.00 (s, 3H), 0.02 (s, 3H), 0.80 (d, 3H, J = 6.7 Hz), 0.86 (s, 9H), 1.17
(d, 3H, J = 7.1 Hz), 1.27–1.46 (m, 6H), 1.49–1.54 (m, 2H), 1.69 (m,
1H), 1.93–2.10 (m, 2H), 2.42 (m, 1H), 3.37 (m, 1H), 3.48–3.51 (m,
2H), 4.29 (m, 1H), 4.56 (s, 2H), 5.42 (dd, 1H, J = 6.7, 15.5 Hz), 5.74
(dt, 1H, J = 6.7, 15.5 Hz), 7.31–7.35 (m, 5H); 13C NMR (100 MHz,
CDCl3): d ꢀ4.4, ꢀ4.3, 14.4, 16.9, 18.1, 22.7, 25.9 (ꢃ 3), 30.3, 30.8,
31.7, 37.0, 39.3, 71.4, 73.3, 74.3, 75.3, 127.8 (ꢃ 2), 127.9, 128.0
(ꢃ 2), 128.5, 134.1, 137.9, 181.6; EIMS: (M+Na)+ calcd for
triol 47 (0.195 g, 78%) as a colorless liquid. ½a D25
¼ þ3:8 (c 1.2,
ꢁ
CHCl3); IR (CHCl3): 3370, 2928, 1619, 1461, 1383, 1252, 1039,
835, 772; 1H NMR (400 MHz, CDCl3): d 0.01 (s, 3H), 0.02 (s, 3H),
0.80 (d, 3H, J = 6.7 Hz), 0.87 (s, 9H), 0.89 (d, 3H, J = 6.8 Hz), 0.99
(m, 1H), 1.16 (m, 1H), 1.36 (m, 1H), 1.44–1.55 (m, 5H), 1.98–2.11
(m, 2H), 2.20 (br s, 3H), 3.42–3.50 (m, 4H), 3.62 (m, 1H), 4.18 (m,
1H), 5.44 (dd, 1H, J = 6.7, 15.5 Hz), 5.73 (dt, 1H, J = 6.9, 15.5 Hz);
13C NMR (100 MHz, CDCl3): d ꢀ4.5, ꢀ4.1, 13.9, 16.4, 18.1, 25.9
(ꢃ 3), 28.9, 30.1, 30.9, 31.98, 35.8, 35.9, 66.5, 68.4, 73.1, 75.2,
128.6, 134.3; EIMS: (M+Na)+ calcd for C20H42NaO4Si+ 397.27.
Found: 397.35; Anal. Calcd for C20H42O4Si: C, 64.12; H, 11.30.
Found: C, 64.34; H, 11.15.
C
27H46NaO5Si+ 501.30. Found: 501.342; Anal. Calcd for C27H46O5Si:
C, 67.74; H, 9.68. Found: C, 67.56; H, 9.53.
4.1.34. Compounds 3 and 3a
To a solution of the seco acid 5 (0.032 g, 0.07 mmol) in THF
(5 mL), i-Pr2NEt (0.5 mL, 2.7 mmol) and 2,4,6-trichlorobenzoyl
chloride (0.21 mL, 1.33 mmol) were added and stirred overnight
at room temperature. Next, it was diluted with benzene (15 mL)
and added slowly to a solution of DMAP (0.4 g, 3.33 mmol) in ben-
zene (70 mL) at 80 °C by syringe pump over a period of 10 h. The
mixture was stirred for another 1 h and then quenched by the
addition of a saturated NaHCO3 solution, extracted with EtOAc
(2 ꢃ 20 mL), dried over Na2SO4 and concentrated. It was purified
on a flash silica gel column eluting with EtOAc/light petroleum
4.1.32. (2S,5R,6R,11S,E)-12-(Benzyloxy)-5-(tert-butyldimethyl-
silyloxy)-2,6-dimethyldodec-9-ene-1,11-diol 48
A solution of triol 47 (0.16 g, 0.43 mmol) and Bu2SnO (0.16 g,
0.64 mmol) in toluene (20 mL) was refluxed for 4 h using a Dean-

1184
B. Chatterjee et al. / Tetrahedron: Asymmetry 23 (2012) 1170–1185
K.; Schneekloth, J. S. Jr.; Kuramochi, K.; Crews, C. M. Org. Lett. 2006, 8, 427–430;
(g) Hangyou, M.; Ishiyama, H.; Takahashi, Y.; Kobayashi, J. Org. Lett. 2009, 11,
5046–5049; (h) Ko, H. M.; Lee, C. W.; Kwon, H. K.; Chung, H. S.; Choi, S. Y.;
(1:49) to yield an inseparable mixture of products 3 and 3a (1:1)
(0.017 g, 55% combined yield) as a colorless liquid. 1H NMR
(400 MHz, CDCl3): d 0.01 (s, 6H), 0.84 (d, 3H, J = 6.7 Hz), 0.87 (s,
9H), 1.18 (d, 1.5H, J = 6.9 Hz), 1.20 (d, 1.5H, J = 6.9 Hz) 1.38–1.53
(m, 7H), 1.77 (m, 1H), 2.14 (m, 1H), 2.28 (m, 1H), 3.28 (m, 1H),
3.53 (m, 1H), 3.59 (m, 1H), 4.58 (ABq, 2H, J = 12.3 Hz), 5.44–5.55
(m, 2H), 5.91 (ddd, 1H, J = 6.2, 9.4, 15.3 Hz), 7.30–7.36 (m, 5H);
13C NMR (100 MHz, CDCl3): ꢀ4.9, ꢀ4.4, 17.5, 17.9/18.2, 20.1/20.9,
25.9 (ꢃ 3), 28.3, 29.7/30.1, 30.3, 33.2, 34.0, 41.6/46.4, 70.6, 72.4,
73.1, 74.0, 127.4, 127.5, 127.6 (ꢃ 2), 128.2, 128.4, 138.1, 138.3,
175.5; EIMS: (M+Na)+ calcd for C27H44NaO4Si 483.29. Found:
483.24; Anal. Calcd for C27H44O4Si: C, 70.39; H, 9.63. Found: C,
70.44; H, 9.56.
´
Chung, Y. K.; Lee, E. Angew. Chem., Int. Ed. 2009, 48, 2364–2366; (i) Rodriguez-
Escrich, C.; Urpí, F.; Vilarrasa, J. Org. Lett. 2008, 10, 5191–5194.
9. Shimbo, K.; Tsuda, M.; Izui, N.; Kobayashi, J. J. Org. Chem. 2002, 67, 1020–
1023.
10. Mohapatra, D. K.; Chatterjee, B.; Gurjar, M. K. Tetrahedron Lett. 2009, 50, 755–
758.
11. (a) Ghosh, A. K.; Gong, G. J. Am. Chem. Soc. 2004, 126, 3704–3705; (b) Ghosh, A.
K.; Gong, G. J. Org. Chem. 2006, 71, 1085–1093.
12. Kierstead, R. W.; Faraone, A.; Mennona, F.; Mullin, J.; Guthrie, R. W.; Crowley,
H.; Simko, B.; Blaber, L. C. J. Med. Chem. 1983, 26, 1561–1569.
13. (a) Veyrieres, A. J. Chem. Soc., Perkin Trans. 1 1981, 1626–1629; (b) David, S.;
Hanessian, S. Tetrahedron 1985, 41, 643–663; (c) Boons, G-J.; Castle, G. H.;
Clase, J. A.; Grice, P.; Ley, S. V. Synlett 1993, 913–914.
14. (a) Gurjar, M. K.; Nagaprasad, R.; Ramana, C. V. Tetrahedron Lett. 2003, 44,
2873–2875; (b) Gurjar, M. K.; Nagaprasad, R.; Ramana, C. V.; Karmakar, S.;
Mohapatra, D. K. Arkivoc 2005, 237–257; (c) Couladouros, E. A.; Mihou, A. P.;
Bouzas, E. A. Org. Lett. 2004, 6, 977–980; (d) Va, P.; Roush, W. R. Tetrahedron
2007, 63, 5768–5796; (e) Fürstner, A.; Flügge, S.; Larionov, O.; Takahashi, Y.;
Kubota, T.; Kobayashi, J. Chem. Eur. J. 2009, 15, 4011–4029; (f) Fürstner, A. Isr. J.
Chem. 2011, 51, 329–345.
15. (a) Ho, G. J.; Mathre, D. J. J. Org. Chem. 1995, 60, 2271–2273; (b) Powell, N. A.;
Roush, W. R. Org. Lett. 2001, 3, 453–456; (c) Kamenecka, T. M.; Danishfesky, S.
Angew. Chem., Int. Ed. 1998, 37, 2995–2998.
16. Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982, 104, 1737–
1739.
17. (a) Riley, R. G.; Silverstein, R. M.; Moser, J. C. Science 1974, 183, 760–762; (b)
Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett. 1987, 28, 6141–6144.
18. Crimmins, M. T.; Mahony, R. O. ’. J. Org. Chem. 1989, 54, 1157–1161.
19. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156; (b) Dess, D. B.;
Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–7287.
20. Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127–
2129.
21. (a) Heathcock, C. H.; Pirrung, M. C.; Sohn, J. E. J. Org. Chem. 1979, 44, 4294–
4299; (b) Sulikowski, G. A.; Lee, W.-M.; Jin, B.; Wu, B. Org. Lett. 2000, 2, 1439–
1442.
22. Bauer, M.; Maier, M. E. Org. Lett. 2002, 4, 2205–2208.
23. Evans, D. A.; Rieger, D. L.; Jones, T. K.; Kaldor, S. W. J. Org. Chem. 1990, 55, 6260–
6268.
24. Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019–8022.
25. (a) Taber, D. F.; Jiang, Q.; Chen, B.; Zhang, W.; Campbell, C. L. J. Org. Chem. 2002,
67, 4821–4827; (b) Jiang, X.; Covey, D. F. J. Org. Chem. 2002, 67, 4893–
4900.
26. Crich, D.; Dudkin, V. J. Am. Chem. Soc. 2002, 124, 2263–2266.
27. Corey, E. J.; Gras, J-L.; Ulrich, P. Tetrahedron Lett. 1976, 23, 809–812.
28. Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 399–402.
29. RamaRao, A. V.; Bose, D. S.; Gurjar, M. K.; Ravindranathan, T. Tetrahedron 1989,
45, 7031–7040.
30. (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc.
Jpn. 1979, 52, 1989–1993; (b) Paterson, I.; Chen, D. Y-K.; Acena, J. L.; Franklin, A.
S. Org. Lett. 2000, 2, 1513–1516.
31. (a) Murga, J.; Falomir, E.; Garc´ıa-Fortanet, J.; Carda, M.; Marco, J. A. Org. Lett.
2002, 4, 3447–3449; (b) Hanessian, S.; Giroux, S.; Buffat, M. Org. Lett. 2005, 7,
3989–3992; (c) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed.
2005, 44, 4490–4527; (d) Gradillas, A.; Perez-Castells, J. Angew. Chem., Int. Ed.
2006, 45, 6086–6101; (e) Xuan, R.; Oh, H.; Lee, Y.; Kang, H. J. Org. Chem. 2008,
73, 1456–1461.
4.1.35. (3S,6R,7R,12S,E)-12-(Benzyloxymethyl)-6-(tert-butyldi-
methylsilyloxy)-3,7-dimethyloxacyclododec-10-en-2-one 3
Ethoxyacetylene (0.03 mL, 40% in hexane, 0.14 mmol) was
added to a solution of the seco acid 5 (0.045 g, 0.094 mmol) and
[{RuCl2(p-cymene)}2] (1.2 mg, 0.0018 mmol) in toluene (8 mL) at
0 °C. The resulting mixture was warmed to room temperature
and stirred for another 30 min. The dark red solution was then fil-
tered through a pad of silica gel, and the silica gel was washed with
dry Et2O (60 mL) under a nitrogen atmosphere. The filtrate was
then concentrated under reduced pressure. The crude ethoxyvinyl
ester was dissolved in toluene (5 mL) and added to a solution of
CSA (2.2 mg, 0.0094 mmol) in toluene (20 mL) and heated to
50 °C for 2 h. The mixture was filtered through a pad of silica gel
and concentrated to afford a residue which was purified by flash
silica gel chromatography eluting with EtOAc and light petroleum,
(1:49) to give lactone 3 (0.018 g, 42%) as a colorless liquid.
½
a 2D5
ꢁ
¼ þ29:0 (c 0.6, CHCl3); IR (CHCl3): 2929, 1722, 1598, 1384,
1255, 1115, 1026, 772, 618; 1H NMR (500 MHz, CDCl3): d 0.01 (s,
6H), 0.85 (d, 3H, J = 6.7 Hz), 0.87 (s, 9H), 1.18 (d, 3H, J = 6.9 Hz),
1.36–1.42 (m, 2H), 1.49–1.57 (m, 5H), 1.75 (m, 1H), 2.14 (m, 1H),
2.26 (m, 1H), 3.28 (m, 1H), 3.57 (dd, 1H, J = 4.4, 10.8 Hz), 3.61
(dd, 1H, J = 6.7, 10.8 Hz), 4.58 (ABq, 2H, J = 12.4 Hz), 5.44–5.53
(m, 2H), 5.91 (ddd, 1H, J = 6.2, 9.4, 15.5 Hz), 7.28–7.35 (m, 5H);
13C NMR (125 MHz, CDCl3): d ꢀ4.9, ꢀ4.4, 17.5, 17.8, 18.2, 26.0
(ꢃ 3), 28.4, 30.2, 30.4, 33.3, 34.1, 41.7, 70.7, 72.4, 73.2, 74.0,
127.4 (ꢃ 2), 127.5, 127.6 (ꢃ 2), 128.4, 138.2, 138.3, 175.4;
EIMS: (M+Na)+ calcd for C27H44NaO4Si+ 483.29. Found: 483.24;
Anal. Calcd for C27H44O4Si: C, 70.39; H, 9.63. Found: C, 70.34; H,
9.55.
32. (a) Grubbs, R. H.; Pine, S. H. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Paquette, L. A., Eds.; Permagon: New York, 1997; Vol. 5,. Chapter 9.3
(b) Schrock, R. R. in The Strem Chemiker 1992, XIV(1), 1–6; (c) Ivin, K. J.; Mol, J. C.
Olefin Metathesis and Metathesis Polymerization; Academic Press: San Deigo,
1997.
33. Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew. Chem., Int. Ed. Engl.
1995, 34, 2039–2041.
34. (a) Scholl, M.; Trnka, T. M.; Morgan, J. P.; Grubbs, R. H. Tetrahedron Lett. 1999,
40, 2247–2250; (b) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953–956.
Acknowledgments
BC thanks UGC, New Delhi, India, for financial assistance
and authors immensely acknowledge Dr. Mukund K. Gurjar and
Dr. Debendra K. Mohapatra for their kind support for this
synthesis.
35. Crimmins, M. T.; Choy, A. L. J. Org. Chem. 1997, 62, 7548–7549.
36. (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512–519; (b) Sullivan, G.
R.; Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973, 38, 2143–2147.
37. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113,
4092–4096.
38. Nicolaou, K. C.; Ray, M.; Finlay, V.; Ninkovic, S.; Sarabia, F. Tetrahedron 1998, 54,
7127–7166.
39. Kido, F.; Tsutsumi, K.; Maruta, R.; Yoshikoshi, A. J. Am. Chem. Soc. 1979, 101,
6420–6424.
References
1. Poore, G. C. B.; Wilson, G. D. F. Nature 1993, 361, 597–598.
2. de Vries, D. J.; Hall, M. R. Drug Dev. Res. 1994, 33, 161–173.
3. Cowan, D. A. Trends Biotechnol. 1997, 15, 129–131.
4. Jaspers, M. In Drug Discovery Techniques; Harvey, A. L., Ed.; Wiley, 1998; pp 65–
84.
5. Harvey, A. Drug Discovery Today 2000, 5, 294–300.
6. Staley, J. T.; Gosink, J. J. Annu. Rev. Microbiol. 1999, 53, 189–215.
7. (a) Kobayashi, J.; Tsuda, M. Nat. Prod. Rep. 2004, 21, 77–93; (b) Kobayashi, J.;
Shimbo, K.; Kubota, T.; Tsuda, M. Pure Appl. Chem. 2003, 75, 337–342.
8. (a) Marshall, J. A.; Schaff, G.; Nolting, A. Org. Lett. 2005, 7, 5331–5333; (b) Jin, J.;
Chen, Y.; Wu, J.; Dai, W. Org. Lett. 2007, 9, 2585–2588; (c) Kim, C. H.; An, H. J.;
Shin, W. K.; Yu, W.; Woo, S. K.; Jung, S. K.; Lee, E. Angew. Chem., Int. Ed. 2006, 45,
8019–8021; (d) Lepage, O.; Kattnig, E.; Furstner, A. J. Am. Chem. Soc. 2004, 126,
15970–15971; (e) Va, P.; Roush, W. R. Org. Lett. 2007, 9, 307–310; (f) Mandal, A.
40. Mitsunobu, O. Synthesis 1981, 1–28.
41. Schultz, H. S.; Freyermuth, H. B.; Buc, S. R. J. Org. Chem. 1963, 28, 1140–
1142.
42. Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998, 26–
28.
43. Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563–2585.
44. Takeuchi, T.; Kuramochi, K.; Kobayashi, S.; Sugawara, F. Org. Lett. 2006, 8,
5307–5310.

B. Chatterjee et al. / Tetrahedron: Asymmetry 23 (2012) 1170–1185
1185
45. (a) Saravanan, P.; Chandrasekhar, M.; Anand, R. V.; Singh, V. K. Tetrahedron Lett.
1998, 39, 3091–3092; (b) Kim, K. S.; Song, Y. H.; Lee, B. H.; Hahn, C. S. J. Org.
Chem. 1986, 51, 404–407; (c) Xiao, X.; Bai, D. Synlett 2001, 535–537; (d)
Swamy, N. R.; Venkateswarlu, Y. Tetrahedron Lett. 2002, 43, 7549–7552.
46. De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem.
1997, 62, 6974–6977.
47. Sasaki, M.; Inoue, M.; Tachibana, K. J. Org. Chem. 1994, 59, 715–717.
48. Kita, Y.; Maeda, H.; Omori, K.; Okuno, T.; Tamura, Y. J. Chem. Soc., Perkin Trans. 1
1993, 2999–3005.
49. Trost, B. M.; Chilsom, J. D. Org. Lett. 2002, 4, 3743–3745.