Total synthesis of amphidinolactone A

Article abstract of DOI:10.1016/j.tetasy.2012.04.019

A convergent total synthesis of amphidinolactone A has been achieved, the longest linear sequence being 17 steps with 15.2% overall yield, using a ring-closing metathesis reaction as the macrolactonization step. The RCM precursor was obtained by the union

Full text of DOI:10.1016/j.tetasy.2012.04.019

Tetrahedron: Asymmetry 23 (2012) 709–715
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Tetrahedron: Asymmetry
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Total synthesis of amphidinolactone A
⇑
Tapas R. Pradhan, Debendra K. Mohapatra
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A convergent total synthesis of amphidinolactone A has been achieved, the longest linear sequence being
17 steps with 15.2% overall yield, using a ring-closing metathesis reaction as the macrolactonization step.
The RCM precursor was obtained by the union of acid and alcohol fragments derived from (R)-epichloro-
hydrin and propane-1,3-diol, respectively. The side chain was incorporated following a Wittig reaction to
exclusively obtain the cis-isomer.
Received 19 April 2012
Accepted 27 April 2012
Available online 8 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Amphidinolactone A 1 is a cytotoxic 13-membered macrolide,
and was isolated by Kobayashi et al. in 2007 from symbiotic dino-
flagellate Amphidinium sp. (Y-25) separated from Okinawa, a mar-
ine acoel flatworm Amphiscolops sp.1 The relative and absolute
stereochemistry of amphidinolactone A 1 (Fig. 1) have been deter-
mined on the basis of extensive spectroscopical analysis and its to-
tal synthesis by Kobayashi et al.2 Recently, we reported a concise
and efficient total synthesis3 of amphidinolactone A via a stereose-
lective intramolecular Nozaki–Hiyama–Kishi reaction.
As per the retrosynthetic analysis of amphidinolactone A 1
outlined in Scheme 1, aldehyde 2 could be obtained through a
ring-closing metathesis reaction of 5, which in turn could be
assembled by esterification of acid 6 with alcohol 7. Acid fragment
6 was expected to be obtained by following our earlier synthesis.
Alcohol fragment 7, which is one carbon more than the earlier
synthesis, could be derived from propane-1,3-diol 9.
The synthesis of acid fragment 6 started from the known chiral
epoxide 8, which was prepared from racemic epichlorohydrin by
using Jacobsen’s hydrolytic kinetic resolution protocol.7 Epoxide 8
upon treatmentwith lithium acetylide prepared from TBS-protected
alkyne 10 using n-BuLi in THF at ꢀ78 °C afforded 11 in 92% yield.8
Epoxidation of the resulting chlorohydrin 11 was then achieved
smoothly with NaH in THF at 0 °C to obtain 12 in 91% yield. Partial
hydrogenation was achieved with Lindlar’s catalyst9 to furnish the
Z-olefin derivative 13 in 96% yield. One-carbon homologation10 with
dimethyl sulfonium methylide at ꢀ10 °C afforded allylic alcohol 14
in 85% yield. Protection of the secondary hydroxyl group as its PMB
ether followed by desilylation with p-TsOH in MeOH at room tem-
perature gave primary alcohol 15 in 81% yield over two steps. Treat-
ment of the resulting primary hydroxyl group with TEMPO11 and
BAIB furnished the corresponding aldehyde which upon further oxi-
dation under Pinnick12 conditions furnished acid fragment 6 in 89%
yield over two steps (Scheme 2).
OH
OH
O
O
Figure 1. Structure of amphidinolactone A 1.
We were interested in exploring our observations on the pro-
tecting group directed intramolecular ring-closing metathesis
reaction toward the synthesis of macrolides.4,5 In this respect, we
have recently reported the synthesis of the macrolactone core of
amphidinolactone A.6 Herein we report the total synthesis of
amphidinolactone A following a ring-closing meta-thesis reaction
as the key step.
The synthesis of fragment 7 started with propane-1,3-diol 9 by
monosilylation, Swern oxidation, and vinyl Grignard addition to ob-
tain 16 in 68% yield over three steps.13 Sharpless enantioselective
epoxidation14 using
D
-(ꢀ)-diisopropyltartrate as the chiral source
and interrupting the reaction after 24 h at ꢀ20 °C in the presence
of t-BuOOH and Ti(i-PrO)4, furnished (2S,3R)-17 {½a D25
¼ ꢀ6:4 (c
ꢁ
1.2, CHCl3)} in 42% yield. The enantiomeric purity of (2S,3R)-17
(94% ee) was ascertained by the HPLC analysis. Epoxide 17 was trea-
ted with dimethyl sulfonium methylide at ꢀ10 °C in THF to obtain
⇑
Corresponding author. Tel.: +91 40 27193128; fax: +91 40 27160512.
E-mail addresses: dkm_77@yahoo.com, mohapatra@iict.res.in (D.K. Mohapatra).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.04.019

710
T. R. Pradhan, D. K. Mohapatra / Tetrahedron: Asymmetry 23 (2012) 709–715
OH
OH
O
O
amphidinolactone A 1
OPG
OPG
OPG
O
O
OPG
O
O
H
O
4. PG = H
5. PG = PMB
OTBDPS
2. PG = MOM
PPh3
OPMB
OH
3
TBDPSO
OH
O
OPMB
OH
7
9
6
8
HO
Cl
O
Scheme 1. Retrosynthetic analysis of amphidinolactone A 1.
allylic alcohol 18, which upon selective protection as its PMB ether
with PMB-Br in the presence of NaH in THF at 0 °C afforded 7 in 79%
yield (Scheme 3).
The hydroxyl groups were then protected as the MOM-ether
with MOM-Cl in the presence of DIPEA and a catalytic amount of
DMAP in CH2Cl2 at room temperature to afford bis-MOM ether 2
in 96% yield. Cleavage of the TBDPS ether linkage was achieved
smoothly by using TBAF in THF at room temperature to obtain pri-
mary alcohol 20 in 91% yield. Oxidation of the primary alcohol
group present in 20 with the Dess–Martin periodinane,19 followed
by Wittig reaction to introduce the side chain with triphenylphos-
phonium salt of Z-1-iodohex-3-ene in the presence of nBuLi at
ꢀ15 °C furnished 21 in 69% yield over two steps. Finally, MOM
ethers were unmasked by treating 21 with trimethylsilyl chloride
(TMSCl) in methanol to obtain amphidinolactone A 1 in 74% yield.
The spectroscopic and analytical data were in good agreement with
the reported values.1
With acid 6 and alcohol 7 in hand, the stage was set for a com-
bination of two components and the formation of the macrocycle
through a ring-closing metathesis reaction. As per our earlier re-
ports,6 we followed the EDCI and DMAP in CH2Cl2 conditions15
for the coupling reaction. In this case, the yield was only 70–75%
and the reaction time was long. However, better results were
achieved by uniting both the coupling partners following Yamagu-
chi conditions.16 Activation of acid 6 with 2,4,6-trichlorobenzoyl
chloride in the presence of Et3N and DMAP under high dilution
conditions afforded triene ester 5 in 90% yield (Scheme 4). The
di-PMB protected ester 5 was then treated with DDQ17 in CH2Cl2/
H2O (9:1) to obtain diol 4 in 93% yield. Treatment of diol 4 with
Grubbs II generation catalyst18 in refluxing CH2Cl2 under high dilu-
tion (0.001 M) conditions furnished smoothly the required 13-
membered lactone ring system 19 present in amphidinolactone A
1 in 78% yield. The geometry (trans) of the newly formed double
bond was established by its coupling constant; one of the olefinic
proton signals appeared at d 5.60 ppm as a doublet of a doublet
(Jtrans coupling constant 15.9 Hz) and other olefinic proton signals
appeared at their respective chemical shifts. The spectroscopic
and analytical data were in good agreement with the constitution
and configuration of the assigned structure for 19.
3. Conclusions
In conclusion, we have accomplished the total synthesis of
amphidinolactone A 1 in 17 steps (longest linear sequence) with
15.2% overall yield. The coupling partners’ acid 6 and alcohol 7 have
been synthesized from commercially available starting materials in
a concise manner. The present synthesis involves an efficient ring-
closing metathesis reaction as the crucial macrolactonization step
for the construction of the 13-membered lactone ring as well as
the total synthesis of amphidinolactone A.

T. R. Pradhan, D. K. Mohapatra / Tetrahedron: Asymmetry 23 (2012) 709–715
711
prior to use: THF, toluene, and t-butyl methyl ether from Na and
benzophenone; CH2Cl2, DMSO from CaH2; MeOH from Mg cake.
Commercial reagents were used without purification. Column
chromatography was carried out by using silica gel (60–120 mesh)
unless otherwise mentioned. Analytical thin layer chromatography
(TLC) was run on Merck Silica Gel 60 F254 precoated plates
OTBS
a
Cl
O
8
10
Cl
O
(250
l
m thickness). Optical rotations [
a]
were measured on a
b
D
c
Perkin–Elmer 343 polarimeter and are given in 10ꢀ1 deg cm2 gꢀ1
.
OH
Infrared spectra were recorded in CHCl3/neat (as mentioned) and
reported in wave number (cmꢀ1). Mass spectroscopic data were
obtained using MS (EI) ESI and HRMS mass spectrometers. 1H
NMR spectra were recorded at 200, 300, 400, 500 and 13C NMR
spectra at 50, 75, 100 MHz in CDCl3 solution unless otherwise
mentioned. Chemical shifts are given in ppm downfield from tetra-
methylsilane and coupling constants (J) are reported in Hertz (Hz).
The following abbreviations are used to designate signal multiplic-
ity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet,
br = broad.
OTBS
12
OTBS
11
OH
O
d
e
OTBS
OTBS
13
14
4.1.1. 5-(tert-Butyldiphenylsilyloxy)pent-1-en-3-ol 16
Vinyl magnesium bromide (51.3 mL, 51.28 mmol) (1 M solu-
tion in THF) was added dropwise to a solution of CuI (0.49 g,
2.56 mmol) in THF (30 mL) at –20 °C. The mixture was stirred
for 30 min. and aldehyde (8.0 g, 25.64 mmol) in THF (50 mL)
was added dropwise to the above mixture at the same temper-
ature. After 2 h, the reaction (monitored by TLC) was quenched
with a saturated NH4Cl solution (75 mL) and diluted with ethyl
acetate (50 mL). The organic layer was separated and the aque-
ous layer extracted with ethyl acetate (3 ꢂ 75 mL). The combined
organic layer was washed with brine (2 ꢂ 100 mL), dried over
anhydrous Na2SO4 and concentrated under reduced pressure to
give the crude mass. Purification by flash column chromatogra-
phy over silica gel (ethyl acetate/hexane = 1:9) afforded the de-
sired allyl alcohol (7.4 g, 85%) as a colorless liquid. IR (neat)
OPMB
OPMB
OH
g
f
OH
O
15
6
Scheme 2. Reagents and conditions: (a) n-BuLi, BF3ꢃ(OEt)2, 10, ꢀ78 °C, 1 h, 92%; (b)
NaH, THF, 0 °C, 1 h, 91%; (c) H2, Pd/C on CaCO3, quinoline, rt, 2 h, 96%; (d) Me3SI,
n-BuLi, THF, ꢀ10 °C, 2 h, 85%; (e) PMB-Br, NaH, THF, 4 h, 91%; (f) p-TsOH, MeOH,
0 °C-rt, 1 h, 89%; (g) (i) TEMPO, BAIB, CH2Cl2, 30 min, (ii) NaClO2, NaH2PO4,
2-methyl-2-butene, t-BuOH, H2O, 2 h, 89% (over two steps).
3432, 2936, 2860, 1613, 1513, 1469, 1427, 1106 cmꢀ1 1H NMR
;
4. Experimental
(300 MHz, CDCl3): d 7.70–7.59 (m, 4H), 7.45–7.30 (m, 6H), 5.84
(m, 1H), 5.28 (d, J = 17.0 Hz, 1H), 5.08 (d, J = 10.4 Hz, 1H), 4.39
(br s, 1H), 3.94–3.74 (m, 2H), 2.89 (m, 1H), 1.83–1.66 (m, 2H)
1.06 (s, 9H) ppm; 13C NMR (75 MHz, CDCl3) d 140.5, 135.5,
133.0, 129.8, 127.7, 114.2, 72.0, 62.5, 38.3, 29.6, 26.7,
4.1. General methods
All reactions were performed under inert atmosphere of argon
unless mentioned. All glassware apparatus used for the reactions
are perfectly oven/flame dried. Anhydrous solvents were distilled
19.0 ppm; HRMS (ESI): m/z calcd for
363.1756; found 363.1750.
C
21H28NaO2Si [M+Na]+
ref. 13
TBDPSO
HO
OH
OH
16
9
O
TBDPSO
c
b
OH
17
OH
OPMB
d
TBDPSO
TBDPSO
OH
OH
18
7
Scheme 3. Reagents and conditions: (a)
D-(ꢀ)-DIPT, Ti(i-PrO)4, tBuOOH, CH2Cl2, ꢀ25 °C, 24 h, 42%; (b) Me3SI, nBuLi, THF, ꢀ20 °C, 1 h, 86%; (c) PMB-Br, NaH, THF, rt, 4 h, 79%.

712
T. R. Pradhan, D. K. Mohapatra / Tetrahedron: Asymmetry 23 (2012) 709–715
OPMB
OPG
OPMB
a
TBDPSO
OH
O
O
OPG
OTBDPS
OTBDPS
OH
O
6
7
5. PG = PMB
OH
OH
OH
O
b
c
O
OH
O
O
19
4
OTBDPS
OMOM
OMOM
OMOM
OMOM
OTBDPS
O
d
e
O
O
H
O
O
20
2
OH
OMOM
OH
OMOM
f
g
O
O
O
O
21
amphidinolactone A 1
Scheme 4. Reagents and conditions: (a) 2,4,6-Trichlorobenzoyl chloride, DMAP, Et3N, toluene, 0 °C to rt, 6 h, 92%; (b) DDQ, CH2Cl2/H2O (9:1), 0 °C, 2 h, 93%; (c) Grubbs II
generation, CH2Cl2, reflux, 9 h, 78%; (d) MOMCl, DIPEA, DMAP, CH2Cl2, 0 °C to rt, 24 h, 96%; (e) (1) TBAF, THF, 0 °C-rt, 6 h, 91%; 2. DMP, CH2Cl2, 0 °C to rt, 3 h, 92%; (f) Wittig salt
3, nBuLi, THF, ꢀ15 °C, 4 h, 75%; (g) TMSCl, MeOH, 40 °C, 3 h, 74%.
4.1.2. (R)-3-(tert-Butyldiphenylsilyloxy)-1-((S)-oxiran-2-yl) pro-
pan-1-ol 17
1.88–1.71 (m, 2H) 1.06 (s, 9H) ppm; 13C NMR (75 MHz, CDCl3) d
135.5, 133.0, 129.8, 127.8, 69.4, 62.2, 54.3, 44.5, 35.4, 26.8,
At first, 4 Å molecular sieves (4.2 g) and CH2Cl2 (50 mL) were
placed in a two-necked 250 mL round bottomed flask, followed
by the addition of Ti(OiPr)4 (0.62 mL, 2.01 mmol) and (ꢀ)-diisopro-
pyltartrate (0.55 mL, 2.67 mmol) at –25 °C under nitrogen and the
resulting mixture was stirred for 30 min. The allylic alcohol 16
(7.0 g, 20.59 mmol) was then added and stirred for 30 min, after
which tBuOOH (1.7 mL, 11.32 mmol) (6.5 M in toluene) was added
over 20 min at the same temperature. Then the reaction mixture
was stirred for 12 h at the same temperature and then kept in a
freezer without stirring for 1 day. The reaction progress was
checked by TLC to monitor the resolution of the racemic alcohol.
The reaction was then quenched with a saturated sodium sulfate
solution (15 mL). Diethyl ether (30 mL) was added and the result-
ing mixture stirred for 3 h at room temperature. The reaction mix-
ture was filtered through a pad of Celite and concentrated under
vacuum. The residue was purified by column chromatography
(ethyl acetate/hexane = 3:17) to give epoxide 17 (3.04 g, 42%) as
19.0 ppm; HRMS (ESI): m/z calcd for C
21H28NaO3Si [M+Na]+
379.1700; found 379.1675.
4.1.3. (3S,4R)-6-(tert-Butyldiphenylsilyloxy)hex-1-ene-3,4-diol
18
A stirred solution of trimethylsulfonium iodide (predried by an
azeotropic method using dry toluene) (2.57 g, 12.6 mmol) in THF
(25 mL) was cooled to ꢀ20 °C; nBuLi (4.21 mL, 2.5 M in hexane,
10.5 mmol) was added and stirred for 30 min. After stirring the
reaction mixture for 30 min at ꢀ20 °C, epoxide 17 (1.5 g,
4.21 mmol) in THF (20 mL) was added via syringe over 20 min at
the same temperature. After complete addition, the cooling bath
was removed and the reaction mixture was allowed to warm to
room temperature over 30 min. After stirring at room temperature
for 2 h, the reaction was quenched with saturated ammonium
chloride solution (30 mL) and diluted with ethyl acetate (50 mL).
The organic layer was separated and the aqueous layer extracted
with ethyl acetate (2 ꢂ 50 mL). The combined organic layers were
washed with brine (100 mL), dried over anhydrous Na2SO4, fil-
tered, and concentrated. The residue was purified by silica gel col-
umn chromatography (ethyl acetate/hexane = 1:4) to obtain diol
a colorless liquid. ½a D25
ꢁ
¼ ꢀ6:4 (c 1.2, CHCl3); IR (neat): 3415,
3031, 2923, 2862, 1756, 1455, 1365, 1223, 1084 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): d 7.68–7.62 (m, 4H), 7.43–7.34 (m, 6H), 3.94–
3.81 (m, 3H), 2.95 (q, J = 4.0 Hz, 1H), 2.74–2.68 (m, 2H),

T. R. Pradhan, D. K. Mohapatra / Tetrahedron: Asymmetry 23 (2012) 709–715
713
18 (1.34 g, 86%) as a light yellow liquid. ½a D25
ꢁ
¼ ꢀ5:0 ( 1.8, CHCl3);
70.1, 69.7, 60.1, 55.2, 33.9, 33.4, 32.4, 26.8, 24.7, 19.1 ppm; HRMS
IR (neat): 3424, 2933, 2862, 1641, 1513, 1426, 1106 cmꢀ1; 1H NMR
(300 MHz, CDCl3): d 7.70–7.59 (m, 4H), 7.46–7.31 (m, 6H), 5.85 (m,
1H), 5.31(d, J = 17.2 Hz, 1H), 5.20(d, J = 10.6 Hz, 1H), 4.12 (br s, 1H),
3.96–3.73 (m, 3H), 3.35 (br s, 1H), 2.36 (br s, 1H), 1.91–1.56 (m,
2H), 1.05 (s, 9H) ppm; 13C NMR (75 MHz, CDCl3): d 136.5, 135.5,
132.8, 129.8, 127.7, 116.8, 75.5, 73.9, 62.9, 34.5, 32.8, 26.7,
(ESI): m/z calcd for C
48H60NaO7Si [M+Na]+ 799.4006; found
799.4010.
4.1.6. (R,Z)-((3R,4S)-1-(tert-Butyldiphenylsilyloxy)-4-hydroxy-
hex-5-en-3-yl)-8-hydroxydeca-5,9-dienoate 4
To a stirred solution of di-PMB ether 5 (1.2 g, 1.54 mmol) in
CH2Cl2 (30 mL), was added DDQ (1.05 g, 4.64 mmol) at pH 7 with
phosphate buffer solution (3 mL) at 0 °C. The reaction mixture
was allowed to stir for 2 h at room temperature. After completion
of the reaction (monitored by TLC), it was quenched with saturated
NaHCO3 solution (20 mL). The organic layer was separated and the
aqueous layer extracted with CH2Cl2 (3 ꢂ 40 mL). The combined
organic layer was washed with brine (75 mL), dried over anhy-
drous Na2SO4, and evaporated to give the crude product which
upon purification by silica gel column chromatography (ethyl ace-
tate/hexane = 1:4) afforded the desired diol 4 (770 mg, 93%) as a
19.0 ppm; HRMS (ESI): m/z calcd for
C
22H30NaO3Si [M+Na]+
393.1861; found 393.1857.
4.1.4. (3R,4S)-1-(tert-Butyldiphenylsilyloxy)-4-(4-methoxy-ben-
zyl-oxy)hex-5-en-3-ol 7
To a suspension of NaH (0.130 g, 5.41 mmol, 60% w/v dispersion
in mineral oil) in dry THF (20 mL) was added dropwise a solution of
resulting diol 18 (1.0 g, 2.70 mmol) in THF (10 mL) at 0 °C. The
reaction mixture was then stirred for 45 min at room temperature.
At 0 °C, freshly prepared p-methoxy benzyl bromide (0.54 g,
2.70 mmol) in THF (5 mL) was added and stirred for an additional
4 h at room temperature with frequent monitoring of the progress
of the reaction by TLC. The reaction mixture was quenched with
crushed ice flakes until a clear solution (biphasic) was formed.
The organic layer was separated and the aqueous layer extracted
with ethyl acetate (2 ꢂ 50 mL). The combined organic layers were
washed with water (2 ꢂ 50 mL), brine (75 mL), and dried over
anhydrous Na2SO4. The solvent was removed under reduced pres-
sure and the crude mass was purified by silica gel column chroma-
tography (ethyl acetate/hexane = 1:9) to afford allylic PMB-ether 7
colorless viscous liquid. ½a D25
ꢁ
¼ þ4:2 (c 1.4, CHCl3); IR (neat):
3447, 2930, 2859, 1730, 1637, 1426, 1218, 1107 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): d 7.68–7.58 (m, 4H), 7.45–7.31 (m, 6H), 5.92–
5.75 (m, 2H), 5.54–5.04 (m, 7H), 4.28 (m, 1H), 4.10 (m, 1H),
3.76–3.56 (m, 2H), 2.41–2.18 (m, 4H), 2.17–1.98 (m, 2H), 1.88–
1.77 (m, 2H), 1.76–1.53 (m, 2H), 1.05 (s, 9H) ppm; 13C NMR
(75 MHz, CDCl3): d 173.5, 140.3, 136.1, 135.5, 131.7, 129.6, 127.6,
125.8, 117.0, 114.8, 74.5, 73.9, 72.3, 59.9, 35.1, 33.5, 31.9, 26.7,
26.5, 24.6, 19.0 ppm; HRMS (ESI): m/z calcd for C33H44NaO5Si
[M+Na]+ 559.2850; found 559.2848.
(1.04 g, 79%) as a colorless liquid. ½a D25
¼ þ6:5 (c 1.3, CHCl3); IR
ꢁ
(neat): 3499, 3065, 2936, 2862, 1613, 1512, 1428, 1301, 1247,
4.1.7. (6Z,9R,10E,12S,13R)-13-(2-(tert-Butyldiphenylsilyloxy)-
ethyl)-9,12-dihydroxyoxacyclotrideca-6,10-dien-2-one 19
Grubbs second generation catalyst (101 mg, ca. 0.11 mmol) was
dissolved in dry, deoxygenated CH2Cl2 (200 mL) under an argon
atmosphere. After the solution was heated at reflux, diene 4
(0.6 g, 1.12 mmol) was added slowly via syringe (30 min) in dry,
deoxygenated CH2Cl2 (50 mL) to the reaction mixture. The reaction
mixture was then stirred at reflux for an additional 8 h. After com-
pletion of the reaction (monitored by TLC), the solvent was evapo-
rated under reduced pressure. Purification of the crude residue by
silica gel column chromatography (ethyl acetate/hexane = 3:7)
afforded 19 (443 mg, 78%) (E-isomer only) as a colorless viscous li-
1038, 1069 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.70–7.60 (m,
;
4H), 7.45–7.31 (m, 6H), 7.22–7.16 (m, 2H), 6.85–6.75 (m, 2H),
5.83 (m, 1H), 5.40–5.23 (m, 2H), 4.55 (m, 1H), 4.33 (m, 1H),
3.88–3.73 (m, 6H), 3.68 (m, 1H) 2.74 (br s, 1H), 1.82–1.57 (m,
2H) 1.05 (s, 9H) ppm; 13C NMR (75 MHz, CDCl3) d 159.2, 136.7,
135.53, 135.51, 133.5, 129.8, 129.6, 129.3, 127.7, 127.6, 116.2,
113.8, 81.0, 71.8, 63.0, 55.2, 35.0, 32.0, 26.8, 19.1 ppm; HRMS
(ESI): m/z calcd for
C
30H38NaO4Si [M+Na]+ 513.2432; found
513.2399.
4.1.5. (R,Z)-((3R,4S)-1-(tert-Butyldiphenylsilyloxy)-4-(4-metho-
xy-benzyloxy)hex-5-en-3-yl)8-(4-methoxybenzyloxy)deca-5,9-
dienoate 5
quid. ½a 2D5
ꢁ
¼ ꢀ5:5 (c 1.0, CHCl3); IR (neat): 3424, 2928, 2859, 1734,
1463, 1426, 1378, 1104 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d 7.70–
To a stirred solution of acid 6 (1.0 g, 3.28 mmol) in anhydrous
toluene (20 mL) at 0 °C, Et3N (0.92 mL, 6.58 mmol) followed by
2,4,6-trichlorobenzoyl chloride (0.5 mL, 3.28 mmol) were added
and stirred for 45 min at room temperature. To this resulting solu-
tion, alcohol 7 (0.8 g, 2.19 mmol) and DMAP (0.35 g, 3.28 55 mmol)
separately dissolved in anhydrous toluene (20 mL) were added at
0 °C and then allowed to stir at room temperature for 6 h. The reac-
tion mixture was diluted with ethyl acetate (30 mL) and subse-
quently washed with Na2CO3 (2 ꢂ 25 mL), brine (2 ꢂ 25 mL),
dried over Na2SO4, and the solvent evaporated at 60 reduced pres-
sure to give a colorless oil, which upon purification by silica gel col-
umn chromatography (ethyl acetate/hexane = 1:33) furnished the
desired coupled product 5 (1.5 g, 92%) as a colorless liquid.
7.58 (m, 4H), 7.47–7.31 (m, 6H), 5.60 (dd, J = 15.9, 7.5 Hz, 1H),
5.55–5.42 (m, 2H), 5.32 (m, 1H), 4.82 (m, 1H), 4.32 (m, 1H), 4.11
(m, 1H), 3.82–3.56 (m, 2H), 2.55–2.08 (m, 4H), 2.08–1.80 (m,
3H), 1.61 (m, 1H), 1.43–1.28 (m, 2H), 1.05 (s, 9H) ppm; 13C NMR
(75 MHz, CDCl3): d 172.3, 135.5, 132.8, 131.3, 130.5, 129.9, 127.8,
124.5, 73.3, 73.2, 72.6, 60.0, 35.0, 33.7, 32.4, 26.8, 25.6, 22.9,
19.0 ppm; HRMS (ESI): m/z calcd for
531.2542; found 531.2536.
C
30H40NaO5Si [M+Na]+
4.1.8. (6Z,9R,10E,12S,13R)-13-(2-(tert-Butyldiphenylsilyloxy)-
ethyl)-9,12-bis(methoxymethoxy)oxacyclotrideca-6,10-dien-2-
one 20
To a solution of diol 19 (0.3 g, 0.59 mmol) in dry CH2Cl2 (10 mL)
were added diisopropylethylamine (0.6 mL, 3.54 mmol), DMAP
(cat.), and MOMCl (0.13 mL, 1.77 mmol) sequentially at 0 °C and
the reaction mixture stirred for 24 h at room temperature. After
completion of the reaction (monitored by TLC), it was quenched
with saturated aqueous NaHCO3 solution (20 mL). The organic
layer was separated and the aqueous layer extracted with CH2Cl2
(2 ꢂ 30 mL). The combined organic layer was washed with brine
(30 mL) and dried over Na2SO4. The residue obtained after evapo-
ration of solvent was purified by silica gel column chromatography
(ethyl acetate/hexane = 1:19) to afford the bis-MOM ether 2
½
a 2D5
ꢁ
¼ þ15:2 (c 1.2, CHCl3); IR (neat): 3448, 2931, 2859, 1734,
1612, 1512, 1461, 1246, 1171 cmꢀ1 1H NMR (300 MHz, CDCl3): d
;
7.61 (d, J = 6.1 Hz, 4H), 7.42–7.29 (m, 6H), 7.23–7.14 (m, 4H),
6.86–6.76 (m, 4H), 5.72 (sextet, J = 8.5 Hz, 2H), 5.45–5.33 (m,
2H), 5.31–5.13 (m, 5H), 4.50 (d, J = 9.7 Hz, 2H), 4.32–4.23 (m,
2H), 3.84 (m, 1H), 3.77 (s, 6H), 3.70 (dd, J = 13.4, 6.1 Hz, 1H),
3.67–3.56 (m, 2H), 2.32 (m, 1H), 2.24 (m, 1H), 2.14 (t, J = 7.3 Hz,
2H), 2.05–1.96 (m, 2H), 1.90 (m, 1H), 1.79 (m, 1H), 1.63–1.51 (m,
2H), 1.03 (s, 9H) ppm; 13C NMR (75 MHz, CDCl3): d 172.8, 159.0,
138.6, 135.51, 135.48, 134.9, 133.7, 133.6, 130.4, 130.3, 129.5,
129.2, 127.5, 126.0, 119.1, 117.2, 113.7, 113.6, 80.8, 79.9, 71.8,
(335 mg, 96%) as a colorless liquid. ½a D25
¼ þ44:1 (c 1.2, CHCl3);
ꢁ

714
T. R. Pradhan, D. K. Mohapatra / Tetrahedron: Asymmetry 23 (2012) 709–715
IR (neat): 3451, 2923, 2856, 1741, 1463, 1373, 1101 cmꢀ1; 1H NMR
(300 MHz, CDCl3): d 7.68–7.59 (m, 4H), 7.43–7.29 (m, 6H), 5.56 (m,
1H), 5.41–5.07 (m, 3H), 4.97 (dt, J = 9.1, 3.0 Hz, 1H), 4.71–4.58 (m,
2H), 4.56–4.42 (m, 2H), 4.17 (m, 1H), 3.81 (m, 1H), 3.69–3.57
(m, 2H), 3.36–3.26 (m, 6H), 2.53–1.76 (m, 7H), 1.67 (m, 1H), 1.48
(m, 1H), 1.32 (m, 1H), 1.04 (s, 9H) ppm; 13C NMR (75 MHz, CDCl3):
d 172.7, 136.7, 136.5, 135.6, 131.1, 130.7, 129.5, 127.6, 124.9, 94.0,
93.9, 77.7, 76.0, 70.2, 60.1, 55.7, 55.3, 34.4, 33.8, 31.7, 29.7, 26.8,
25.3, 22.4, 19.1 ppm; HRMS (ESI): m/z calcd for C34H48NaO7Si
[M+Na]+ 619.3067; found 619.3060.
(dd, J = 14.4, 6.8 Hz, 2H), 4.55 (dd, J = 14.4, 6.8 Hz, 2H), 4.17 (m,
1H), 3.92 (m, 1H), 3.39–3.31 (m, 6H), 2.82–2.71 (m, 2H), 2.46–2.15
(m, 7H), 2.12–1.97 (m, 5H), 0.97 (t, J = 7.6 Hz, 3H) ppm; 13C NMR
(75 MHz, CDCl3): d 172.0, 136.5, 132.1, 131.2, 131.0, 130.8, 126.9,
124.9, 124.3, 94.2, 94.0, 76.2, 72.3, 55.8, 55.3, 33.7, 33.3, 31.9,
30.2, 26.8, 52.6, 22.7, 20.6, 14.1 ppm; HRMS (ESI): m/z calcd for
C
24H38NaO6[M+Na]+ 445.2566; found 445.2560.
4.1.11. (6Z,9R,10E,12S,13R)-9,12-Dihydroxy-((2Z,5Z)-octa-2,5-di-
enyl)oxacyclotrideca-6,10-dien-2-one 1
To a stirred solution of bis-MOM ether 21 (10 mg, 0.022 mmol)
in MeOH (3 mL), was added TMSCl (0.01 mL, 0.09 mmol) at 40 °C.
The reaction mixture was stirred at the same temperature for an
additional 3 h. The reaction mixture was cooled to room tempera-
ture and quenched by the addition of solid NaHCO3. The reaction
mixture was filtered through a pad of Celite and washed with
CH2Cl2 (2 ꢂ 5 mL). The filtrate was evaporated under reduced pres-
sure. The crude residue obtained was purified by silica gel column
chromatography (ethyl acetate/hexane = 3:7) to obtain the desired
4.1.9. (6Z,9R,10E,12S,13R)-13-(2-Hydroxyethyl)-9,12-bis-(meth-
oxymethoxy)oxooxacyclotrideca-6,10-dien-2-yl)acetaldehyde 2
To a stirred solution of TBDPS ether 20 (0.14 g, 0.23 mmol) in dry
THF (5 mL) was added TBAF (1 M in THF, 0.58 mL, 0.58 mmol) at
0 °C. The resulting mixture was stirred for an additional 6 h at room
temperature. The reaction mixture was diluted with ethyl acetate
(25 mL) and washed with aqueous NaHCO3 solution (20 mL). The
aqueous layer was then extracted with ethyl acetate (2 ꢂ 20 mL).
The combined organic layer was dried over anhydrous Na2SO4 and
concentrated to afford a light yellow liquid. Purification by silica
gel column chromatography (ethyl acetate/hexane = 2:3) furnished
macrolide 1 (5.5 mg, 74%) as a colorless liquid. ½a D25
¼ ꢀ57:5 (c 0.55,
ꢁ
C6H6); IR (neat): 3444, 2921, 2852, 1741, 1462, 1219 cmꢀ1; 1H NMR
(500 MHz, C6D6): d 5.65 (m, 1H), 5.56 (m, 2H), 5.51 (dd, J = 15.8,
7.6 Hz, 1H), 5.46–5.39 (m, 2H), 5.25 (m, 1H), 5.19 (dd, J = 15.8,
7.6 Hz, 1H), 4.96 (m, 1H), 3.98 (m, 1H), 3.78 (m, 1H), 3.33 (br s,
1H), 2.88–2.75 (m, 2H), 2.64 (m, 1H), 2.47 (m, 1H), 2.37–2.25 (m,
2H), 2.19 (m, 2H), 2.10 (m, 1H), 2.04 (m, 2H), 1.85 (m, 2H), 1.28
(m, 2H), 0.96 (t, J = 7.8 Hz, 3H) ppm; 13C NMR (125 MHz, C6D6): d
171.7, 136.4, 132.2, 131.2, 130.6, 126.7, 125.1, 124.9, 74.0, 73.9,
72.4, 35.9, 32.1, 29.5, 26.0, 25.6, 23.1, 20.9, 14.4 ppm; HRMS (ESI):
m/z calcd for C20H30NaO4 [M+Na]+ 357.2042; found 357.2036.
the primary alcohol (76 mg, 91%) as a colorless liquid. ½a D25
¼ þ59:4
ꢁ
(c 0.7, CHCl3); IR (neat): 3458, 2923, 2852, 1734, 1461, 1376,
1152 cmꢀ1 1H NMR (300 MHz, CDCl3): d 5.63–5.18 (m, 4H), 4.69
;
(dd, J = 6.8, 2.3 Hz, 1H), 4.65–4.56 (m, 3H), 4.55–4.43 (m, 2H), 4.20
(m, 1H), 3.94 (m, 1H), 3.61 (m, 1H), 3.40–3.31 (m, 6H), 2.47–1.70
(m, 7H), 1.66–1.40 (m, 3H) ppm; 13C NMR (75 MHz, CDCl3):
d 173.4, 136.6, 134.2, 131.1, 130.7, 124.6, 95.4, 93.7, 81.0, 75.7,
74.0, 71.7, 60.2, 55.7, 55.3, 33.7, 32.6, 30.5, 26.6, 24.7 ppm;
HRMS (ESI): m/z calcd for C18H30NaO7 [M+Na]+ 381.1889; found
381.1880.
Acknowledgements
To a stirred solution of primary alcohol (50 mg, 0.14 mmol) and
solid anhydrous NaHCO3 (25 mg) in CH2Cl2 (30 mL) at 0 °C was
added Dess–Martin periodinane (89 mg, 0.21 mmol). The resulting
reaction mixture was stirred at 0 °C for 3 h. After completion of the
reaction (monitored by TLC), the mixture was filtered through filter
paper. The filtrate was washed with saturated NaHCO3 solution
(15 mL) and CH2Cl2 (15 mL). The organic layer was separated and
the aqueous layer extracted with CH2Cl2 (3 ꢂ 20 mL). The com-
bined organic layer was dried over anhydrous Na2SO4 and the sol-
vent evaporated under reduced pressure. Purification of the crude
mass by flash chromatography (ethyl acetate/hexane = 1:5) affor-
ded the corresponding aldehyde 2 (45 mg, 92%) as a pale yellow li-
quid, which was used immediately for the next reaction.
We are grateful to Dr. J.S. Yadav, Director, IICT, for his constant
support and encouragement. T.R.P. thanks the Council of Scientific
and Industrial Research (CSIR), New Delhi, India, for the award of
research fellowships. D.K.M. thanks the Council of Scientific and
Industrial Research (CSIR), New Delhi, for a research Grant (P-81-
113) (INSA Young Scientist Award Scheme).
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The triphenylphosphonium salt of Z-1-iodohex-3-ene (240 mg,
0.51 mmol) in THF (5 mL) was stirred at room temperature under
a nitrogen atmosphere until it dissolved completely. To this solu-
tion, was slowly added nBuLi (2.5 M in hexane, 0.2 mL, 0.45 mmol)
at –78 °C. The resulting solution was warmed to 0 °C. After 1 h, the
reaction mixture was again cooled to –78 °C and the above aldehyde
2 (45 mg, 0.13 mmol) in THF (5.0 mL) was slowly added to it. The
mixture was stirred at the same temperature for 4 h. After complete
consumption of the starting material (monitored by TLC), the reac-
tion was quenched with saturated NH4Cl solution (20 mL) and
warmed to room temperature. The organic layer was separated,
and the aqueous layer extracted with ethyl acetate (3 ꢂ 25 mL).
The combined organic layer was washed with brine (40 mL), dried
over Na2SO4, and concentrated. Purification by silica gel column
chromatography (ethyl acetate/hexane = 1:12) afforded the desired
compound 21 (40 mg, 75%) as a colorless liquid. ½a D25
ꢁ
¼ ꢀ10:7 (c 1.4,
CHCl3); IR (neat): 3451, 2925, 2855, 1741, 1457, 1157 cmꢀ1
;
1H
NMR (300 MHz, CDCl3): d 5.64–5.16 (m, 8H), 4.86 (m, 1H), 4.69

T. R. Pradhan, D. K. Mohapatra / Tetrahedron: Asymmetry 23 (2012) 709–715
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