Synthesis of the C8-C16 fragment of amphidinolide R

Article abstract of DOI:10.1016/j.tetasy.2014.10.010

An asymmetric synthesis of the C8-C16 fragment with several stereogenic centers of amphidinolide R, is described. The key reaction, Sharpless asymmetric epoxidation has provided the basis for generation of the required stereocenters. The target fragment was accomplished in a convergent manner in nine steps (longest linear synthesis of the sequence) and 32% overall yield was obtained starting from 2-butene-1,4-diol.

Full text of DOI:10.1016/j.tetasy.2014.10.010

Tetrahedron: Asymmetry 25 (2014) 1532–1536
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of the C8–C16 fragment of amphidinolide R
⇑
Chada Raji Reddy , Palacherla Ramesh, Nagavaram Narsimha Rao
Division of Natural Products Chemistry, 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:
Received 1 October 2014
Accepted 15 October 2014
An asymmetric synthesis of the C8–C16 fragment with several stereogenic centers of amphidinolide R, is
described. The key reaction, Sharpless asymmetric epoxidation has provided the basis for generation of
the required stereocenters. The target fragment was accomplished in a convergent manner in nine
steps (longest linear synthesis of the sequence) and 32% overall yield was obtained starting from
2-butene-1,4-diol.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
for 1b, 2.7
cells (IC50 = 0.67
l
g/mL for 1c) and human epidermoid carcinoma KB
g/mL for 1a, 6.5 g/mL for 1b, 3.9 g/mL for 1c).
l
l
l
Amphidinolides represent one of the largest groups of marine
originated macrolides with diverse and biologically significant sec-
ondary metabolite structures isolated from symbiotic dinoflagel-
lates Amphidinium sp., which were separated from cells of
Okinawan marine flatworms.1 Amphidinolides share a common
feature with one or more exo-methylene units, and a highly oxy-
genated ring ranging in size from 12 to 29 atoms. Due to their scar-
city, studies of structure determination and the assignment of
stereochemistry are serious challenges and subsequent biological
studies have also been very limited. Several members of this family
exhibit cytotoxicity against a variety of National Cancer Institute
(NCI) tumor cell lines as well as human epidermoid carcinoma
KB cells. Consequently, the amphidinolides have become synthetic
targets.2
Although, there are two total synthesis of amphidinolide J,5
there are no reports in literature for the synthesis of amphidinolide
R. During the synthesis of 1c, Cossy et al. have observed the
formation of amphidinolide R as a mixture along with amphidino-
lide J.5b In continuation of our interests in the synthesis of
macrolides,6 we herein report a convergent approach for the syn-
thesis of C8–C16 fragment, a highly functionalized central unit of
amphidinolide R.
HO
OH
Amphidinolide R 1a is a cytotoxic macrolide that is isolated from
the cultured marine dinoflagellate Amphidinium sp., along with
amphidinolide S 1b (Fig. 1).3 The structure of 1a including its
absolute configuration was elucidated on the basis of spectroscopic
data and chemical experiments. It contains four double bonds
including one exomethylene unit, three chiral hydroxyl groups
including one in the lactone linkage, three asymmetric methyl
groups and a total of six stereogenic centers. The structure of 1a
was found to be a 14-membered macrolactone ring with the lactone
linkage at a different location compared to amphidinolide J 1c.4 The
evidence for the absolute stereochemistry of 1a was provided based
on the known stereochemistry of amphidinolide J. Amphidinolide R
showed potent cytotoxicity, compared to its congeners J and S,
O
O
amphidinolide R 1a
O
HO
OH
OH
O
O
O
O
against murine lymphoma L1210 (IC50 = 1.4 lg/mL for 1a, 4.0 lg/mL
amphidinolide S 1b
amphidinolide J 1c
⇑
Corresponding author. Tel.: +91 40 27191885; fax: +91 40 27160512.
E-mail address: rajireddy@iict.res.in (C.R. Reddy).
Figure 1. Structures of amphidinolide R, S and J.
http://dx.doi.org/10.1016/j.tetasy.2014.10.010
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

C.R. Reddy et al. / Tetrahedron: Asymmetry 25 (2014) 1532–1536
1533
be coupled by Horner–Wadsworth–Emmons olefination. Both of
these fragments, 3 and 4, were envisioned from a common
aldehyde intermediate 5, which in turn could be obtained from
2-butene-1,4-diol using a Sharpless asymmetric reaction as one
of the key steps.
2. Results and discussion
In our retrosynthetic plan (Scheme 1) we envisaged a discon-
nection into three fragments, A–C, which can then be combined
using esterification (C1AO bond) followed by
a ring-closing
The synthesis of the aldehyde intermediate 3, (Scheme 2) began
from the epoxy alcohol 6 (readily prepared from 2-butene-1,4-diol
in three steps using a literature protocol).7 By means of regio-
and stereoselective epoxide opening of 6 in the presence of
Me3Al/n-BuLi, diol 7 was obtained in 89% yield.8
metathesis reaction (C7AC8 bond) between A (C8–C16 fragment)
and B (C1–C7 unit) and a late stage installation of the four-carbon
side chain C (C17–C20) through a Julia–Kocienski olefination to
enable the generation of analogs. The synthesis of fragment A
was planned in its protected form 2. Further analysis of 2 revealed
two subunits, aldehyde 3 and b-ketophosphonate 4, which could
Protection of the diol using TBS-Cl/imidazole in CH2Cl2 condi-
tions gave the corresponding bis-TBS ether (94%), which upon deb-
enzylation using hydrogenolysis (10% Pd/C) provided alcohol 8 in
88% yield. Oxidation of alcohol 8 using Parikh–Doering oxidation
(SO3ÁPy, DMSO)9 gave the corresponding aldehyde 5 (a common
intermediate for synthesis of both fragments 3 and 4) in 92% yield.
A one-carbon Wittig methylenation of 5 (Ph3PCH+3BrÀ/KHMDS/
THF/0 °C), followed by selective desilylation (pTSA/MeOH/0 °C)
gave alcohol 9 (70%), which was subjected to Parikh–Doering
oxidation to give the desired aldehyde fragment 3 in 87% yield.
Next, we focused on the synthesis of keto-phosphonate 4,
which was prepared from the aldehyde intermediate 5 in two steps
(Scheme 3). In the first step, aldehyde 5 was treated with dimethyl
methylphosphonate using nBuLi as the base in THF at À78 °C to
obtain a b-hydroxy phosphonate (83%), which was subsequently
oxidized under Dess–Martin periodinane conditions to afford the
desired b-keto phosphonate fragment 4 in 87% yield.
HO
A
OH
16
8
17
C
7
O
O
1
B
1a
TBSO
OTBS
16
8
With both fragments in hand, we concentrated on the coupling
OTBS
of
3 and 4 to complete the synthesis of C8–C16 fragment
2
OH
(Scheme 4). Aldehyde 3 was subjected to a Horner–Wadsworth–
Emmons reaction with b-keto phosphonate 4 in the presence of
Ba(OH)2Á8H2O, which gave
a,b-unsaturated enone 10 in 85% yield.
O
O
Finally, Luche reduction10 of keto functionality in enone 10 using
NaBH4/CeCl3Á7H2O in MeOH at À78 °C furnished syn-product 2 in
good yield (93%) with excellent diastereoselectivity, which com-
O
P
OTBS
MeO
OMe
OTBS
OTBS
3
4
1) dimethyl methylphosphonate
OTBS
n-BuLi, THF, -78 oC, 3 h, 83%
O
2-butene-1,4-diol
5
4
OTBS
2) Dess-Martin periodinane
rt, CH2Cl2, 1 h, 87%
5
Scheme 1. Retrosynthetic analysis of 1a.
Scheme 3. Synthesis of keto-phosphonate 4.
AlMe3, n-BuLi
OH
OH
BnO
O
BnO
CH2Cl2, 0 oC
1 h, 89%
OH
6
7
i) TBS-Cl, imidazole
CH2Cl2, rt, 6 h, 94%
OTBS
SO3.Py
HO
DMSO:CH2Cl2
rt, 2 h, 92%
OTBS
ii) 10% Pd/C, EtOH
rt, 8 h, 88%
8
i) PPh3=CH3 Br
KHMDS, THF
0 oC, 5 h
SO3.Py
OTBS
OH
3
O
DMSO:CH2Cl2
rt, 2 h, 87%
ii) pTSA, MeOH
30 min, 0 oC
OTBS
OTBS
70% (2 steps)
9
5
Scheme 2. Synthesis of aldehyde fragment 3.

1534
C.R. Reddy et al. / Tetrahedron: Asymmetry 25 (2014) 1532–1536
OTBS
4.53 (d, J = 12.1 Hz, 1H), 3.72 (m, 1H), 3.65–3.56 (m, 3H), 3.43
Ba(OH)2, 0 oC
(dd, J = 9.6, 7.6 Hz, 1H), 3.10–3.39 (br s, 2H), 1.80 (m, 1H), 0.85
(d, J = 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 137.7, 128.3,
127.7, 75.3, 73.4, 72.7, 67.4, 37.6, 13.6; HRMS (EI) m/z calcd for
3
4
OTBS
THF:H2O, 2 h, 85%
OTBS
O
10
C
12H19O3 (M+H)+ 211.1334, found 211.1338. The spectroscopic
data were consistent with those reported.3
OTBS
.
NaBH4, CeCl3 7H2O
OTBS
4.1.2. (2R,3R)-2,4-Bis(tert-butyldimethylsilyloxy)-3-methyl-
butan-1-ol 8
MeOH, -78 oC, 1 h, 93%
OTBS
OH
2
To a stirred solution of alcohol 7 (600 mg, 2.85 mmol) in DMF
(5 mL) was added imidazole (1.16 g, 17.1 mmol) followed by
tert-butyl dimethylsilyl chloride (1.71 g, 11.4 mmol) at 0 °C. The
reaction mixture was allowed to warm to room temperature and
stirred for 12 h. After completion of the reaction, the mixture
was diluted by the addition of saturated aqueous NaHCO3
(20 mL) and the aqueous phase was extracted with ether
(2 Â 20 mL). The combined organic layer was washed with brine
(20 mL), dried over Na2SO4, and the organic solvent evaporated
under reduced pressure. The crude residue was purified by flash
column chromatography (hexanes/EtOAc = 95:5) to give TBS-pro-
tected compound (1.17 g, 94%) as a colorless oil.
Scheme 4. Synthesis of C8–C16 fragment of amphidinolide R.
pletes the synthesis of the C8–C16 fragment of amphidinolide R in
good overall yield.
3. Conclusion
In conclusion, we have reported on the synthesis of the C8–C16
fragment of amphidinolide R in nine steps with 32% overall yield.
The key features of the approach are the successful exploitation
of Sharpless asymmetric epoxidation, regioselective methylation
of an epoxide, Horner–Wadsworth–Emmons olefination, and
Luche reduction. The present approach is amicable for scale up
and also facilitates the synthesis of a similar framework present
in amphidinolide J and S.
Palladium on carbon (26.5 mg, 10% w/w) was added to a solu-
tion of the above compound (1.1 g, 2.51 mmol) in EtOH (5 mL)
and the heterogeneous mixture was stirred overnight under a
hydrogen atmosphere. After completion of the reaction, the mix-
ture was filtered through a small pad of Celite and the resulting fil-
trate was concentrated under reduced pressure. The crude product
was purified by flash column chromatography (hexanes/
EtOAc = 80:20) to give compound 8 (769 mg, 88%) as a colorless
4. Experimental
4.1. General
liquid. [a]
27 = +3.1 (c 1.1, CHCl3); IR (KBr): mmax 3435, 2923, 2853,
D
1437, 1280, 1109, 1059, 968, 770 cmÀ1; 1H NMR (300 MHz, CDCl3):
d 3.73 (dd, J = 4.9, 10.0 Hz, 1H), 3.63 (dd, J = 6.6, 10.0 Hz, 1H), 3.55–
3.50 (m, 2H), 3.47 (dd, J = 4.3, 10.0 Hz, 1H), 2.41–2.31 (m, 1H),
1.96–1.88 (m, 1H), 0.90 (s, 18 H), 0.88 (d, J = 6.7 Hz, 3H), 0.12–
0.01 (m, 12H); 13C NMR (75 MHz, CDCl3): d 74.1, 64.4, 64.0, 38.9,
25.8, 18.2, 18.0, 13.0, À4.4, À4.8, À5.4, À5.5; HRMS (EI) m/z calcd
for C17H41O3Si2 (M+H)+ 349.2589, found 349.2592.
1H NMR and 13C NMR spectra were recorded in CDCl3 and ace-
tone-d6 with 300, 500, or 75 and 125 MHz spectrometers at ambi-
ent temperature. Chemical shifts are reported in ppm relative to
TMS as the internal standard. FTIR spectra were recorded on a Per-
kin–Elmer 683 infrared spectrophotometer, neat or as thin films in
KBr. Optical rotations were measured on an Anton Paar MLP 200
modular circular digital polarimeter by using a 2-mL cell with a
path length of 1 dm. Low-resolution MS were recorded on an Agi-
lent Technologies LC-MSD trap SL spectrometer. All of the reagents
and solvents were of reagent grade and used without further puri-
fication unless otherwise stated. Technical-grade EtOAc and hex-
anes used for column chromatography were distilled before use.
THF, when used as solvent for the reactions, was freshly distilled
from sodium benzophenone ketyl. Column chromatography was
carried out on silica gel (60–120 mesh) packed in glass columns.
All reactions were performed under N2 in flame or oven dried
glassware with magnetic stirring.
4.1.3. (2R,3R)-2,4-Bis((tert-butyldimethylsilyl)oxy)-3-methyl-
butanal 5
A
solution of 8 (1.5 g, 2.43 mmol) and i-Pr2NEt (2.9 mL,
16.9 mmol) in 20 mL of 3:1 DMSO at 0 °C was treated with SO3ÁPyr-
idine (1.5 g, 9.6 mmol) and stirred for 2 h at 25 °C. The reaction was
diluted with ether (30 mL), washed sequentially with H2O (20 mL),
saturated aqueous NaHCO3 (20 mL), and saturated aqueous NaCl
(20 mL) and dried (Na2SO4). The crude product was purified by
flash column chromatography (hexanes/EtOAc = 9:1) to give com-
pound 5 (1.37 g, 92%) as a colorless liquid. [
CHCl3); IR (KBr): mmax 2956, 2887, 1736, 1470, 1253, 1092, 955,
836, 773, 668 cmÀ1 1H NMR (500 MHz, CDCl3): d 9.60 (s, 1H),
a]
27 = +2.2 (c 1.09,
D
4.1.1. (2R,3R)-4-(Benzyloxy)-2-methylbutane-1,3-diol 7
;
To a solution of hydroxy epoxide 6 (1.04 g, 5.3 mmol in CH2Cl2
(20 mL) cooled to 0 °C was added n-BuLi (1.6 M solution in hexane,
3.7 mL, 5.9 mmol), and the resultant mixture was stirred at 0 °C for
30 min. To this solution was added trimethyl aluminum (1.0 M
solution in hexane, 16.2 mL, 16.2 mmol) over a period of 5 min,
and the resultant mixture was stirred at 0 °C for 1 h. The reaction
mixture was carefully treated with MeOH and diluted with satu-
rated aqueous potassium sodium tartrate (20 mL) and EtOAc
(50 mL). After being stirred at room temperature for several hours,
the organic layer was separated and washed with brine (20 mL).
The organic layer was dried over Na2SO4, filtered, and concentrated
under reduced pressure. Purification of the residue by flash chro-
matography on silica gel (30% EtOAc/hexane) gave diol 7 (1.00 g,
3.86 (m, 1H), 3.60 (t, J = 9.4 Hz, 1H), 3.41 (dd, J = 4.9, 9.6 Hz, 1H),
2.31–2.19 (m, 1H), 0.93 (s, 9H), 0.87 (d, J = 6.2 Hz, 3H), 0.86 (s,
9H), 0.01–0.06 (m, 12H); 13C NMR (125 MHz, CDCl3): d 204.2,
79.6, 63.0, 40.9, 25.7, 18.2, 13.5, À4.4, À5.1, À5.6; HRMS (EI) m/z
calcd for C17H38O3Si2Na (M+Na)+ 369.2254 found 369.2257.
4.1.4. (2R,3S)-3-(tert-Butyldimethylsilyloxy)-2-methylpent-4-
en-1-ol 9
Methyl triphenylphosphonium bromide (2.64 g, 3.16 mmol)
and a stirrer bar were added to a flask. Anhydrous THF (30 mL)
was added under nitrogen and the resulting suspension was cooled
to À78 °C prior to the addition of KHMDS (7.32 mL, 3.16 mmol,
0.5 M in toluene) in a dropwise fashion. The resulting suspension
was warmed to 25 °C for 1 h and then recooled to À78 °C prior to
the addition of aldehyde 5 (320 mg, 0.92 mmol) in anhydrous
THF (5.0 mL). The reaction was completed within 2 h and then
89%) as a colorless oil. [
a
]
D
27 = À14.4 (c 1.0, CHCl3); IR (KBr): mmax
3281, 3073, 2971, 2859, 1525, 1059, 911 cmÀ1
;
1H NMR
(300 MHz, CDCl3): d 7.37–7.31 (m, 5H), 4.57 (d, J = 12.1 Hz, 1H),

C.R. Reddy et al. / Tetrahedron: Asymmetry 25 (2014) 1532–1536
1535
quenched by the addition of saturated aqueous NH4Cl (20 mL). The
mixture was then extracted with Et2O (2 Â 50 mL), washed
sequentially with H2O (20 mL) and saturated aqueous NaCl
(20 mL), and dried (Na2SO4). Removal of the solvent under reduced
pressure gave a crude olefin, which was used in next step without
further purification.
A solution of the above olefin in MeOH (5 mL) was cooled to
0 °C and pTSA (cat.) was added. The resulting solution was stirred
at 0 °C for 30 min, then diluted with ether (20 mL) after which sat-
urated aqueous NaHCO3 (10 mL) was added. The resulting layers
were separated and washed with brine (10 mL), dried over Na2SO4,
and the solvents were evaporated under reduced pressure. The res-
idue was purified by flash column chromatography (silica gel,
10?20% EtOAc in hexanes) to yield alcohol 9 (148 mg, 70%, two
were then dried over Na2SO4 and concentrated in vacuo to give
crude aldehyde 3, which was used directly in the next step.
To a solution of keto phosphonate 4 (100 mg, 0.20 mmol) in THF
(5 mL) was added Ba(OH)2Á8H2O (79 mg, 0.41 mmol) under N2 and
stirred for 45 min at rt. The reaction mixture was cooled to 0 °C,
after which was slowly added aldehyde 3 in 2 mL of THF/H2O
(40:1) and the mixture was allowed to warm to rt and stirring con-
tinued for 1 h. The reaction mixture was diluted with CH2Cl2
(10 mL), the organic layer was washed with aqueous saturated
NaHCO3 (5 mL), brine (5 mL), dried over Na2SO4 and concentrated
under reduced pressure. The crude product was purified by flash
column chromatography (silica gel, hexanes/EtOAc 1:1) to afford
enone 10 (68 mg, 85%) as a colorless oil. Rf = 0.50 (10% EtOAc in
hexanes). [
a]
27 = +10.1 (c 1.0, CHCl3); IR (KBr): mmax 2932, 2859,
D
steps) as a colorless oil. [
a
]
27 = +26.8 (c 1.34, CHCl3); IR (KBr): mmax
1675, 1428, 1260, 996, 822, 772, 613 cmÀ1 1H NMR (300 MHz,
;
D
3310, 2924, 2854, 1465, 1369, 1110, 1057, 765, 707 cmÀ1; 1H NMR
(300 MHz, CDCl3): d 5.87 (m, 1H), 5.64–5.37 (m, 2H), 4.10 (m, 1H),
3.62 (dd, J = 8.6, 10.5 Hz, 1H), 3.46 (dd, J = 4.3, 10.5 Hz, 1H), 2.02–
1.90 (m, 1H), 0.91 (s, 9H), 0.81 (d, J = 7.1 Hz, 3H), 0.08 (s, 6H); 13C
NMR (125 MHz, CDCl3): d 135.5, 128.3, 72.8, 64.2, 44.3, 26.1,
CDCl3): d 6.87 (m, 1H), 6.47 (dd, J = 8.7, 16.2 Hz, 1H), 5.75–5.66
(m, 1H), 5.14–5.09 (m, 1H), 4.08–4.01 (m, 1H), 3.95 (t, J = 6.5 Hz,
1H), 3.62 (dd, J = 5.4, 9.8 Hz, 1H), 3.51 (dd, J = 5.4, 9.8 Hz, 1H),
2.46–2.38 (m, 1H), 1.95–1.87 (m, 1H), 1.03 (d, J = 6.5 Hz, 3H),
0.92–0.86 (m, 30H), 0.02–0.05 (m, 18H); 13C NMR (125 MHz,
CDCl3): d 200.9, 149.3, 139.0, 125.1, 115.6, 79.4, 77.3, 63.7, 43.7,
40.6, 25.9, 25.7, 18.1, 14.8, 14.6, 13.1, 13.0, À4.7, À4.9, À5.1,
À5.4; HRMS (EI) m/z calcd for C30H63O4Si3 (M+H)+ 571.4029, found
571.4026.
18.3, 14.2, À4.3, À4.9; HRMS (EI) m/z calcd for
C12H27O2Si
(M+H)+ 231.1775 found 231.1772.
4.1.5. Dimethyl (3R,4R)-3,5-bis(tert-butyldimethylsilyloxy)-4-
methyl-2-oxopentylphosphonate 4
To dimethyl methylphosphonate (114 mg, 0.92 mmol), anhy-
drous THF (3 mL) was added under nitrogen. The resulting suspen-
sion was cooled to À78 °C prior to the addition of n-BuLi (0.37 mL,
2.5 M in THF, 0.92 mmol) in a dropwise fashion. The resulting sus-
pension was stirred for 1 h and aldehyde 5 (160 mg, 0.46 mmol) in
anhydrous THF (2.0 mL) was added. After 2 h the reaction was
quenched by the addition of saturated aqueous NH4Cl (5 mL).
The mixture was extracted with Et2O (2 Â 10 mL), washed with
H2O (10 mL) and saturated aqueous NaCl (10 mL), and dried (Na2-
SO4). Removal of the solvent under reduced pressure followed by
flash chromatographic purification provided hydroxy phosphonate
(180 mg, 83%) as a colorless oil.
4.1.7. (6R,7R,8R,11R,12S,E)-7-((tert-Butyldimethylsilyl)oxy)-2,
2,3,3,6,11,14,14,15,15-decamethyl-12-vinyl-4,13-dioxa-3,14-di-
silahexadec-9-en-8-ol 2
A solution of ketone 13 (53 mg, 0.13 mmol) and CeCl3Á7H2O
(31 mg, 0.13 mmol) in MeOH (1.3 mL) was stirred and cooled to
À78 °C, after which NaBH4 (5 mg, 0.13 mmol) was added slowly.
The solution was stirred for 30 min, after which it was warmed
to 0 °C and stirred for another 30 min. The reaction mixture was
quenched with water (2 mL) and EtOAc (5 mL) was added. The
aqueous layer was extracted with EtOAc (2 Â 5 mL). The organic
layers were combined, washed with water (5 mL), brine (5 mL),
and dried (Na2SO4), filtered, and evaporated under reduced pres-
sure. The residue was purified by flash chromatography to afford
To a solution of the above hydroxy phosphonate (180 mg,
0.38 mmol) in 5 mL of CH2Cl2 was added Dess–Martin periodinane
(193 mg, 0.45 mmol). After stirring at room temperature for 1 h,
the reaction was quenched by the addition of a 5:1 solution of sat-
urated aqueous Na2S2O3/NaHCO3. The layers were separated and
the aqueous layer was washed twice with CH2Cl2 (10 mL). The
combined organic extracts were then dried over Na2SO4 and con-
centrated in vacuo. Purification by flash column chromatography
(25% EtOAc in hexanes) provided 154 mg (87%) of ketone 4 as a col-
alcohol 2 (49 mg, 93%) as a clear colorless oil. [
0.65, CHCl3); IR (KBr): mmax 3310, 3066, 2993, 2873, 1455, 1383,
1238, 1025, 944, 755, 698 cmÀ1 1H NMR (300 MHz, CDCl3): d
a]
27 = +19.6 (c
D
;
5.79–5.70 (m, 1H), 5.65 (dd, J = 15.5, 7.7 Hz, 1H), 5.46 (dd,
J = 15.5, 7.7 Hz, 1H), 5.13 (d, J = 17.1 Hz, 1H), 5.05 (d, J = 10.2 Hz,
1H), 4.10–4.05 (m, 1H), 4.01–3.96 (m, 1H), 3.69 (t, J = 3.8 Hz, 1H),
3.61 (dd, J = 10.2, 7.4 Hz, 1H), 3.46 (dd, J = 10.2, 7.4 Hz, 1H), 2.64
(d, J = 6.7 Hz, 1H), 2.33–2.23 (m, 1H), 1.97–1.88 (m, 1H), 0.96 (d,
J = 6.8 Hz, 3H), 0.93 (d, J = 7.1 Hz, 3H), 0.91 (s, 9H), 0.89 (s, 18H),
0.09–0.01 (m, 18H); 13C NMR (75 MHz, CDCl3): d 139.6, 134.2,
132.0, 115.1, 77.7, 77.3, 72.4, 65.0, 43.6, 40.7, 26.3, 26.2, 18.5,
15.5, 13.5, À3.8, À3.9, À4.0; HRMS (EI) m/z calcd for C30H64O4Si3Na
(M+Na)+ 595.4005, found 595.4001.
orless oil. [
a]
27 = +23.4 (c 1.20, CHCl3); IR (KBr): mmax 3024, 2926,
D
2853, 1696, 1471, 1297, 1166, 1056, 824, 770 cmÀ1
;
1H NMR
(300 MHz, CDCl3): d 4.13 (d, J = 4.2 Hz, 1H), 3.79 (d, J = 4.2 Hz,
3H), 3.77 (d, J = 3.4 Hz, 3H), 3.63–3.56 (m, 1H), 3.40 (dd, J = 4.2,
9.3 Hz, 1H), 3.33 (dd, J = 15.3, 20.4 Hz, 1H), 2.99 (dd, J = 15.3,
22.1 Hz, 1H), 2.26–2.17 (m, 1H), 0.94–0.85 (m, 21H), 0.10–0.01
(m, 12H); 13C NMR (75 MHz, CDCl3): d 202.5, 79.8, 63.3, 52.8,
52.7, 40.0, 37.1, 35.3, 25.8, 25.7, 18.3, 18.1, 13.5, À4.8, À5.4,
À5.7; HRMS (EI) m/z calcd for C20H48O6PSi2 (M+H)+ 469.2565,
found 469.2568.
Acknowledgments
P.R. thanks the University Grants Commission-New Delhi for
the award of a fellowship. C.R.R. is grateful to CSIR, New Delhi,
India for financial support as part of XII-five year plan project
under title ORIGIN (CSC-108).
4.1.6. ((6R,7R,11R,12S,E)-7-(tert-Butyldimethylsilyloxy)-2,2,3,3,
6,11,14,14,15,15-decamethyl-12-vinyl-4,13-dioxa-3,14-disila-
hexadec-9-en-8-one) 10
References
To a solution of alcohol 9 (32 mg, 0.14 mmol) in 2 mL of CH2Cl2
was added Dess–Martin periodinane (70 mg, 0.16 mmol). After
stirring at room temperature for 1 h, the reaction was quenched
by the addition of a 5:1 solution of saturated aqueous Na2S2O3/
NaHCO3. The layers were separated and the aqueous layer was
washed twice with CH2Cl2 (10 mL). The combined organic extracts
1. (a) Kobayashi, J.; Tsuda, M. Nat. Prod. Rep. 2004, 21, 77–93; (b) Kobayashi, J. J.
Antibiot. 2008, 61, 271–284; (c) Chakraborty, T. K.; Das, S. Curr. Med. Chem.
2001, 1, 131–149.
2. For representative references, see: (a) Kobayashi, J.; Ishibashi, M. Chem. Rev.
1993, 93, 1753–1769; (b) Kobayashi, J.; Tsuda, M. Nat. Prod. Rep. 2004, 21, 77–
93; (c) Kobayashi, J.; Kubota, T. J. Nat. Prod. 2007, 70, 451–460; (d) Morris, J. C.;

1536
C.R. Reddy et al. / Tetrahedron: Asymmetry 25 (2014) 1532–1536
Phillips, A. J. Nat. Prod. Rep. 2009, 26, 245–265; (e) Fuerstner, A. Isr. J. Chem.
2011, 51, 329–345; (f) Lu, L.; Zhang, W.; Nam, S.; Horne, D. A.; Jove, R.; Carter, R.
Dilipkumar, U.; Reddy, M. D.; Rao, N. N. Org. Biomol. Chem. 2013, 11, 3355–
3364.
G. J. Org. Chem. 2013, 78, 2213–2247.
7. (a) Righi, G.; Pescatore, G.; Boadies, F.; Bonini, C. Tetrahedron 2001, 57, 5649–
5656; (b) Katsuki, T.; Lee, W. M.; Ma, P.; Martin, V. S.; Masamune, S.; Sharpless,
K. B.; Tuddenham, D.; Walker, F. J. J. Org. Chem. 1982, 47, 1373–1378.
8. Sasaki, M.; Tanino, K.; Miyashit, M. Org. Lett. 2001, 3, 1765–1767.
9. Parikh, J. R.; Doering, W. V. E. J. Am. Chem. Soc. 1967, 89, 5505–5507.
10. (a) Luche, L. J. Am. Chem. Soc. 1978, 100, 2226–2227; (b) Prasad, K. R.; Revu, O. J.
Org. Chem. 2014, 79, 1461–1466; (c) Florence, G. J.; Wlochal, J. Chem. Eur. J.
2012, 18, 14250–14254; (d) Mandal, A. K.; Schneekloth, J. S.; Crews, C. M. Org.
Lett. 2005, 7, 3645–3648.
3. Ishibashi, M.; Takahashi, M.; Kobayashi, J. Tetrahedron 1997, 53, 7827–7832.
4. Kobayashi, J.; Sato, M.; Ishibashi, M. J. Org. Chem. 1993, 58, 2645–2646.
5. (a) Williams, D. R.; Kissel, W. S. J. Am. Chem. Soc. 1998, 120, 11198–11199; (b)
Barbazanges, M.; Meyer, C.; Cossy, J. Org. Lett. 2008, 10, 4489–4492.
6. (a) Reddy, C. R.; Dharmapuri, G.; Rao, N. N. Org. Lett. 2009, 11, 5730–5733; (b)
Reddy, C. R.; Rao, N. N.; Sujitha, P.; Kumar, C. G. Eur. J. Org. Chem. 2012, 1819–
1824; (c) Reddy, C. R.; Rao, N. N.; Reddy, M. D. Eur. J. Org. Chem. 2012, 4910–
4913; (d) Reddy, C. R.; Rao, N. N. RSC Adv. 2012, 2, 7724–7734; (e) Reddy, C. R.;
Suman, D.; Rao, N. N. Eur. J. Org. Chem. 2013, 3786–3796; (f) Reddy, C. R.;