Stereoselective synthesis of ophiocerins A and C

Article abstract of DOI:10.1016/j.tetasy.2011.06.015

An efficient synthesis of ophiocerins A and C has been achieved via a common intermediate. The stereogenic centers were generated by means of Jacobsen's hydrolytic kinetic resolution and Sharpless kinetic resolution.

Full text of DOI:10.1016/j.tetasy.2011.06.015

Tetrahedron: Asymmetry 22 (2011) 1212–1217
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective synthesis of ophiocerins A and C
⇑
Krishanu Show, Priti Gupta, Pradeep Kumar
Organic Chemistry Division, National Chemical Laboratory, Pune 411008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of ophiocerins A and C has been achieved via a common intermediate. The stere-
ogenic centers were generated by means of Jacobsen’s hydrolytic kinetic resolution and Sharpless kinetic
resolution.
Received 26 May 2011
Accepted 14 June 2011
Available online 19 July 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
OH
O
OH
O
OH
OH
During the search for new bioactive metabolites from freshwa-
ter fungi, Shearer et al. isolated ophiocerins A–C 1–3 (three diaste-
reomeric tetrahydropyran derivatives) and ophiocerin D 4, an
isocrotonyl derivative of tetrahydropyran from the freshwater
aquatic fungi Ophioceras venezuelense (Magnaporthaceae).1,2 The
absolute stereochemistry of 1–4 (Fig. 1) was assigned through cir-
cular dichroism spectroscopy by the exciton chirality method.3,4
The substituted tetrahydropyran moiety5 is found in a number of
natural products that show excellent biological activities.6 Due to
the interesting array of substituents on the tetrahydropyran ring,
the ophiocerins have attracted considerable amount of interest
from synthetic organic chemists worldwide.7,8
Kang and co-workers described the synthesis of ophiocerins
A–C from chiral pool starting materials such as carbohydrate and
(R)-(ꢀ)-4-penten-2-ol,8 while Yadav et al. reported the synthesis
of ophiocerins A and B using tartaric acid7c and chiral epoxides7a
as the starting materials.
As part of our ongoing research program aimed at developing
enantioselective syntheses of naturally occurring bioactive
compounds,9 we became interested in developing a new route to
ophiocerins A and C. Herein we report a new and highly enantiose-
lective total synthesis of ophiocerin A and C via a common
intermediate, starting from an achiral starting material using
Jacobsen hydrolytic kinetic resolution10,11 and Sharpless kinetic
resolution12 as the key steps.
ophiocerin A 1
ophiocerin B 2
OH
OH
OH
O
OH
O
O
O
ophiocerin C 3
ophiocerin D 4
Figure 1. Structures of ophiocerins A-D 1–4.
obtained by base induced cyclization of tosylate 16 which in turn
could be obtained from epoxide 11 via epoxide opening, acetonide
protection followed by olefinic oxidation, subsequent reduction,
and tosylation. Epoxide 11 could be obtained via Sharpless kinetic
resolution of racemic allylic alcohol 10, which in turn could be ob-
tained from propylene oxide 5. Similarly, ophiocerin C could be
synthesized from epoxide 17 using a similar sequence of reactions.
Epoxide 17 could be obtained from allylic alcohol 12 via a
Sharpless epoxidation which in turn could be obtained from allylic
alcohol 10 by Sharpless kinetic resolution.
As illustrated in Scheme 2, the synthesis of ophiocerins A and C
started from the commercially available propylene oxide 5, which
was subjected to Jacobsen‘s hydrolytic kinetic resolution using an
(R,R)-salen-Co(III)-OAc catalyst to give (R)-propylene oxide (R)-5
as a single isomer,10a which was easily isolated from the more po-
lar diol 6 by distillation. (R)-Propylene oxide (R)-5 was treated with
vinylmagnesium bromide in the presence of CuI to give the homo-
allylic alcohol 7 in good yield.
2. Results and discussion
Our synthetic approach for the synthesis of ophiocerins A and C
was envisioned via the retrosynthetic route as shown in Scheme 1.
The allylic alcohol 10 was visualized as a common intermediate for
the synthesis of both ophiocerins A and C. Ophiocerin A 1 would be
Compound 7 was subjected to epoxidation with m-CPBA fol-
lowed by TBS protection to afford diastereomeric epoxide 9 in
⇑
Corresponding author. Tel.: +91 20 25902050; fax: +91 20 25902629.
E-mail address: pk.tripathi@ncl.res.in (P. Kumar).
95% yield. Epoxide
9 was then treated with an excess of
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.06.015

K. Show et al. / Tetrahedron: Asymmetry 22 (2011) 1212–1217
1213
OH
O
OH
OH
O
TBSO
OH
OTs
O
16
O
11
ophiocerin A
1
TBSO
OH
OTBS
O
O
OH
O
9
5
TBSO
OH
OH
10
TBSO
OH
O
ophiocerin C
17
12
3
Scheme 1. Retrosynthetic analysis of ophiocerins A and C.
Sharpless asymmetric kinetic resolution conditions12 provided
the chiral epoxy alcohol 11 in 48% yield and >99% de and chiral
allylic alcohol 12 in 42% yield and 98% de (determined from the
1H and 13C NMR).
OH
O
O
a
OH
OH
+
5
5
(R)-
6
For the synthesis of ophiocerin A, epoxide 11 was opened with
an excess of dimethylsulfonium methylide to furnish diol 13 in 70%
yield. Treatment of diol 13 with 2,2-dimethoxypropane in the pres-
ence of a catalytic amount of pyridinium 4-toluenesulfonate in
acetone gave compound 14 in 80% yield, which upon olefinic
oxidation using OsO4 and NaIO4 followed by subsequent reduction
OH
O
O
b
c
syn:anti (1.2 : 1)
7
(R)-5
8
14
OTBS
with NaBH4 afforded alcohol 15 in 75% yield. Treatment of 15
TBSO
OH
O
e
d
with tosyl chloride followed by desilylation with tetrabutylammo-
nium fluoride gave the secondary alcohol 16. The base-induced
cyclization of 16 with potassium tert-butoxide in diethyl ether at
9
10
0 °C, and the subsequent deprotection of acetonide using
a
TBSO
OH
catalytic amount of 4-toluenesulfonic acid in methanol furnished
TBSO
OH
f
ophiocerin A (1) in 92% yield (Scheme 3). ½a D25
¼ ꢀ23:4 (c 0.1,
ꢁ
+
CH2C12); lit.1½a D25
¼ ꢀ24:0 (c 0.1, CH2Cl2). The physical and spec-
ꢁ
O
11
12
troscopic data of 1 were in full agreement with the literature data.
For the synthesis of ophiocerin C 3, the allylic alcohol 12 obtained
by the chiral resolution of 10 was subjected to a Sharpless asymmet-
ric epoxidation9g,h,12 to give epoxide 17 in 60% yield as a single
diastereomer, which was converted into ophiocerin C 3 following
the same sequence of reactions as described for 1 (Scheme 4). Thus
as shown in Scheme 4, epoxide 17 was opened with an excess of
dimethylsulfonium methylide to furnish diol 18 in 72% yield.
Treatment of diol 18 with 2,2-dimethoxypropane in the presence
of a catalytic amount of pyridinium 4-toluenesulfonate in acetone
afforded compound 19 in 85% yield, which upon olefinic oxidation
followed by subsequent reduction gave alcohol 20 in 78% yield.
Treatment of 20 with tosyl chloride followed by desilylation gave
Scheme 2. Reagents and conditions: (a) (R,R)-salen-Co(III)-OAc (0.5 mol %), distd
H2O (0.55 equiv), 0 °C,14 h, (45% for (R)-5, 43% for 6; (b) vinylmagnesium bromide,
THF, CuI, ꢀ20 °C, 89%, 12 h; (c) m-CPBA, CH2Cl2, 0 °C to rt, 10 h, 96%; (d) TBDMSCl,
imidazole, CH2Cl2, 0 °C to rt, 4 h, 95%; (e) (CH3)3S+ Iꢀ, n-BuLi, THF, ꢀ20 °C, 70%; (f)
(ꢀ)-DIPT, Ti(O-iPr)4, TBHP, dry CH2Cl2, molecular sieves, 4 Å, ꢀ20 °C, 18 h, 48% for
11 and 42% for 12.
dimethylsulfonium methylide13 (generated from trimethylsulfoni-
um iodide and n-BuLi) to give allylic alcohol 10 in 70% yield, which
is a common intermediate for the synthesis of both ophiocerins A
and C. Thus, the treatment of 10 with titanium tetraisopropoxide
and tert-butylhydroperoxide in the presence of (ꢀ)-DIPT under
TBSO
OH
TBSO
OH
TBSO
O
b
a
O
11
13
OH
O
O
14
OH
HO
TBSO
O
OH
e
d
c
OTs
OH
O
O
O
15
16
1
ophiocerin A
Scheme 3. Reagents and conditions: (a) (CH3)3S+Iꢀ, n-BuLi, THF, ꢀ20 °C, 70%; (b) 2,2-DMP, PPTS, dry CH3COCH3, 40 °C,8 h, 80%; (c) (i) OsO4, NaIO4, Et2O–H2O, 24 h, rt; (ii)
NaBH4, MeOH, rt, 0.5 h, 75%; (d) (i)TsCl, NEt3, DMAP (cat.), 3 h; (ii) TBAF, THF, 2 h, 85%; (e) (i) t-BuOꢀK+, Et2O, 2 h; (ii) p-TSA, MeOH, rt, 2 h, 92%.

1214
K. Show et al. / Tetrahedron: Asymmetry 22 (2011) 1212–1217
OH
4.3. Preparation of (R)-pent-4-en-2-ol 7
TBSO
TBSO
OH
TBSO
OH
b
a
A round bottomed flask was charged with copper (I) iodide
(3.28 g, 17.2 mmol), gently heated under vacuum, and slowly
cooled with a flow of argon, after which dry THF (40 mL) was
added. This suspension was cooled to –20 °C and vigorously
stirred, and vinylmagnesium bromide (1 M in THF, 345 mL,
344.8 mmol) was injected into it. A solution of propylene oxide
(R)-5 (10 g, 172.18 mmol) in THF (20 mL) was added slowly to
the above reagent, and the mixture was stirred at –20 °C for
12 h. The reaction mixture was quenched with a saturated aqueous
solution of NH4Cl. The organic layer was washed with brine, dried
(Na2SO4), and concentrated to afford the crude homo allylic
alcohol, which upon distillation provided alcohol 7 (13.2 g, 89%)
O
17
18
12
OH
TBSO
O
TBSO
O
c
d
OH
O
O
O
19
20
OH
O
OH
OH
e
f
OTs
O
3
as a colorless liquid (bp 115 °C, lit15 bp 115 °C). ½a D25
¼ ꢀ9:1 (c
ꢁ
21
3.0, Et2O); {lit.15
½
a 2D5
ꢁ
¼ ꢀ9:8 (c 3.1, Et2O)}; IR (CHCl3, cmꢀ1): mmax
ophiocerin C
3467, 3089, 2998, 2920, 1528, 1487, 1412, 1235, 1051, 994; 1H
NMR (200 MHz, CDCl3): d 5.78–5.85 (m, 1H), 5.14 (d, J = 6.6 Hz,
1H), 5.10 (d, J = 2.4 Hz, 1H), 3.80–3.86 (m, 1H), 2.22–2.38 (m,
2H), 1.82 (s, 1H), 1.18 (d, J = 6.1 Hz, 3H); 13C NMR (50 MHz, CDCl3):
d 134.6, 116.6, 66.5, 43.2, 22.1.
Scheme 4. Reagents and conditions: (a) (ꢀ)-DIPT, Ti(O-iPr)4, TBHP, dry CH2Cl2,
molecular sieves, 4 Å, ꢀ20 °C, 8 days, 60%; (b) (CH3)3S+Iꢀ, n-BuLi, THF, ꢀ20 °C, 72%;
(c) 2,2-DMP, PPTS, dry CH3COCH3, 40 °C, 8 h, 85%; (d) (i) OsO4, NaIO4, Et2O-H2O,
24 h, rt; (ii) NaBH4, MeOH, rt, 0.5 h, 78%; (e) (i) TsCl, NEt3, DMAP (cat.), 3 h; (ii) TBAF,
THF, 2 h, 82%; (f) (i) t-BuOꢀK+, Et2O, 2 h; (ii) p-TSA, MeOH, rt, 2 h, 90%.
4.4. Preparation of (2R)-1-(oxiran-2-yl)propan-2-ol 8
the secondary alcohol 21, which upon base-induced cyclization
with potassium tert-butoxide in diethyl ether at 0 °C, and subse-
quent deprotection of the acetonide using a catalytic amount of 4-
toluenesulfonic acid in methanol furnished ophiocerin C 3 in 90%
To a stirred solution of olefin 7 (3 g, 34.9 mmol) in CH2Cl2
(25 mL) at 0 °C was added m-CPBA (50%) (14.43 g, 41.8 mmol).
The reaction mixture was stirred at room temperature for 10 h
and quenched with a saturated NaHCO3 solution, extracted with
CH2Cl2, washed with saturated NaHCO3 and brine, dried (Na2SO4),
concentrated, and purified by silica gel column chromatography
using pet ether/EtOAc (9:1) as eluent to yield epoxide 8 (3.41 g,
96%) as a colorless liquid in a diastereomeric mixture (1.2:1).
yield (Scheme 4). ½a D25
ꢁ
¼ þ43:4 (c 0.1, CH2Cl2); lit.1
½
a 2D5
ꢁ
¼ þ45:0
(c 0.1, CH2Cl2). The physical and spectroscopic data of 3 were in full
agreement with the literature data.
3. Conclusion
½
a 2D5
ꢁ
¼ ꢀ10:85 (c 0.86, CHCl3); IR (CHCl3, cmꢀ1): mmax 3465, 3180,
2987, 2923, 2855, 1452, 1398, 1243, 1201, 1201, 984, 888; 1H
NMR (200 MHz, CDCl3): d 4.06–4.10 (m, 1H), 3.02–3.05 (m, 1H),
2.81–2.84 (m, 1H), 2.52–2.54 (m, 1H), 1.82–1.86 (m, 1H), 1.71–
1.74 (m, 1H), 1.18 (d, J = 6.3 Hz, 3H); 13C NMR (50 MHz, CDCl3): d
66.5, 66.3, 49.6, 49.3, 47.2, 46.3, 42.9, 42.3, 25.7, 24.2 (both the
diastereomers).
In conclusion, we have accomplished total synthesis of both
ophiocerins A and C via a common intermediate using Jacobsen
hydrolytic kinetic resolution and Sharpless kinetic resolution as
the key steps and as a source of chirality. The generality of the
method shown has significant potential for further extension to
other isomers and related compounds. Further studies are in cur-
rently progress.
4.5. Preparation of tert-butyldimethyl(((2R)-1-(oxiran-2-
4. Experimental
4.1. General
yl)propan-2-yl)oxy)silane 9
To a stirred solution of alcohol 8 (12 g, 117.6 mmol) in CH2Cl2
(50 mL) was added imidazole (16.0 g, 235.0 mmol). To this solution
t-butyldimethylchlorosilane (21.26 g, 141.0 mmol) was added at
0 °C and reaction was stirred at room temperature for 4 h. The
reaction mixture was quenched with a saturated aqueous solution
of NH4Cl and extracted with CH2Cl2 (3 ꢂ 50 mL). The extract was
washed with brine, dried (Na2SO4), and concentrated. Silica gel col-
umn chromatography of the crude product using pet ether/EtOAc
(19:1) as eluent provided compound 9 (24.16 g, 95%) as a colorless
liquid. IR (CHCl3, cmꢀ1): mmax 3060, 2985, 2903, 1885, 1472, 1420,
1377, 1289, 1101, 1005, 938, 898, 760; 1H NMR (500 MHz, CDCl3):
d 4.03–4.10 (m, 1H), 3.03–3.06 (m, 1H), 2.79–2.83 (m, 1H), 2.44–
2.54 (m, 1H), 1.67–1.75 (m, 1H), 1.49–1.55 (m, 1H), 1.18 (d,
J = 6.3 Hz, 3H), 0.88 (s, 9H), 0.03 (s, 3H), 0.02 (s, 3H); 13C NMR
(125 MHz, CDCl3): d 66.5, 66.3, 49.7, 49.1, 47.8, 46.5, 42.8, 42.4,
25.9, 24.6, 17.2, ꢀ3.6, ꢀ4.3, ꢀ4.8, ꢀ5.2. ((both the diastereomers).
All reactions were carried out under argon or nitrogen in oven-
dried glassware using standard gas-light syringes, cannulas, and
septa. Solvents and reagents were purified and dried by standard
methods prior to use. Optical rotations were measured at room
temperature. IR spectra were recorded on an FT-IR instrument.
1H NMR spectra were recorded on 200 MHz, 400 MHz, and
500 MHz and are reported in parts per million (d) downfield rela-
tive to CDCl3 as the internal standard and 13C NMR spectra were re-
corded at 50 MHz, 100 MHz, and 125 MHz and assigned in parts
per million (d) relative to CDCl3. Mass spectra were obtained with
TSQ 70, Finningen MAT spectrometer. Column chromatography
was performed on silica gel (100–200 and 230–400 mesh) using
a mixture of petroleum ether and ethyl acetate as the eluent. Ele-
mental analyses were carried out on a Carlo Erba CHNSO analyzer.
4.2. Preparation of (R)-propylene oxide (R)-5
4.6. Preparation of (5R)-5-((tert-butyldimethylsilyl)oxy)hex-1-
en-3-ol 10
The racemic propylene oxide 5 was resolved to (R)-propylene
oxide (R)-5 in high enantiomeric excess by the hydrolytic kineticres-
To a stirred solution of dry THF was added trimethylsulfonium
iodide (13.91 g, 68.19 mmol) at ꢀ20 °C. The reaction mixture was
stirred for 20 min followed by the addition of n-BuLi (42.6 mL,
olution method following a literature procedure.10b
½
a 2D5
ꢁ
¼ þ11:2
(neat); {lit10b
½ ꢁ
a 2D5
¼ ꢀ11:6 (neat) for (S)-propylene oxide}.

K. Show et al. / Tetrahedron: Asymmetry 22 (2011) 1212–1217
1215
1.6 M, 68.19 mmol). After 40 min, epoxide 9 (2.94 g, 13.61 mmol)
in THF was added dropwise. The reaction mixture was stirred at
ꢀ20 °C for 3 h and quenched by a saturated solution of ammonium
chloride. The two phases were separated and the aqueous phase
was extracted with EtOAc (3 ꢂ 50 mL). The combined organic lay-
ers were washed with water (2 ꢂ 50 mL), brine, dried over Na2SO4,
and concentrated. The residual oil was purified by silica gel column
chromatography using pet ether/EtOAc (7:3) as eluent to furnish
the allylic alcohol 10 (2.19 g, 70%) as a colorless oil. IR (CHCl3,
cmꢀ1): mmax 3415, 3018, 2950, 2963, 2865, 1624, 1427, 1465,
1348, 1262, 1057, 947; 1H NMR (200 MHz, CDCl3): d 5.94–5.76
(m, 1H), 5.29–5.04 (m, 2H), 4.43–4.04 (m, 2H), 1.67–1.55 (m,
2H), 1.24–1.17 (m, 3H), 0.89 (s, 9H), 0.08 (s, 6H); 13C NMR
(50 MHz, CDCl3): d 141.1, 140.7, 114.0, 113.8, 72.2, 69.6, 69.4,
67.1, 45.9, 44.4, 25.7, 24.5, 23.0, 17.9, ꢀ3.9, ꢀ4.4, ꢀ4.9, ꢀ5.0 (both
the diastereomers).
chloride. The two phases were separated and the aqueous phase
was extracted with EtOAc (3 ꢂ 50 mL). The combined organic lay-
ers were washed with water (2 ꢂ 50 mL), brine, dried over Na2SO4,
and concentrated. The residual oil was purified by silica gel column
chromatography using pet ether/EtOAc (7:3) as eluent to furnish
diol 13 (0.22 g, 70%) as a colorless oil. ½a D25
¼ ꢀ11:3 (c 1.2, CHCl3);
ꢁ
IR (CHCl3, cmꢀ1): mmax 3381, 2930, 1681, 1600, 1410, 1297, 1091,
926, 835, 727; 1H NMR (200 MHz, CDCl3): d 5.93–5.79 (m, 1H),
5.39–5.21 (m, 2H), 4.15–4.05 (m, 2H), 3.86–3.78 (m, 1H), 2.75 (br
s, 2H), 1.64–1.56 (m, 2H), 1.20 (d, J = 6.2 Hz, 3H), 0.91 (s, 9H),
0.13 (s, 3H), 0.12 (s, 3H); 13C NMR (50 MHz, CDCl3): d 136.4,
116.7, 75.4, 74.1, 70.1,39.6, 25.8, 24.5, 17.9, ꢀ3.9, ꢀ4.9; ESI[MS]:
283.10 [M++Na]; Anal. Calcd For C13H28O3Si; C, 59.95; H, 10.84;
Found: C, 59.80; H, 10.61.
4.9. Preparation of tert-butyl-(((R)-1-((4R,5S)-2,2-dimethyl-5-
vinyl-1,3-dioxolan-4-yl)-propan-2-yl)oxy) dimethylsilane 14
4.7. Preparation of (1R,3R)-3-((tert-butyldimethylsilyl)oxy)-1-
((S)-oxiran-2-yl)butan-1-ol 11 and (3S,5R)-5-((tert-butyldimeth
ylsilyl)oxy)-hex-1-en-3-ol 12
At first, 2,2-DMP (1.2 mL, 9.6 mmol) and PPTS (115 mg,
0.5 mmol) were added to a solution of diol 13 (1.25 g, 4.8 mmol)
in acetone (30 mL), and the mixture was stirred at reflux for 8 h.
The reaction was then quenched with satd aq NaHCO3 (20 mL).
The aqueous layer was extracted with CH2Cl2 (2 ꢂ 20 mL) and
the combined organic layers were dried over Na2SO4 and concen-
trated under reduced pressure. The crude product was purified
by silica gel column chromatography using pet-ether/EtOAc
Toa mixture of 4 Åmolecularsieves (1.0 g)and Ti(O-iPr)4 (2.7 mL,
9.086 mmol) in dry CH2Cl2 (60 mL), (ꢀ)-DIPT (2.08 mL,9.912 mmol)
was added dropwise over 10 min at ꢀ20 °C. The mixture was stirred
for 20 min at ꢀ20 °C and a solution of 10 (1.9 g, 8.26 mmol) in dry
CH2Cl2 (40 mL) was added over 10 min. The reaction mixture was
stirred for an additional 30 min at ꢀ20 °C after which TBHP
(3.8 mL, 5 M solution in decane, 20.65 mmol) was added dropwise
over 15 min. The reaction mixture was kept at ꢀ20 °C by a constant
temperature bath and after 18 h the reaction was warmed to room
temperature, and quenched with saturated Na2SO4 (30 mL). The
mixture was then stirred vigorously for 2 h. The two phases were
separated and the aqueous phase was extracted with CH2Cl2
(5 ꢂ 30 mL). The combined organic layers were dried over sodium
sulfate, filtered, and concentrated to dryness. The crude product
was then purified by flash chromatography on silica gel using pet
ether/EtOAc (95:5) as eluent to give chiral hydroxy olefin 12 (0.8 g,
42% yield, based on 45.4% conversion) as a colorless oil. Further elu-
tion with pet ether/EtOAc (4:1) gave epoxide 11 as a colorless oil
(0.97 g, 48% yield, based on 54.6% conversion).
(19:1) to give 14 (1.15 g, 80%) as a pale yellow oil. ½a D25
¼ ꢀ2:35
ꢁ
(c 0.34, CHCl3); IR (CHCl3, cmꢀ1): mmax 2857, 1732, 1644, 1463,
1378, 1257, 1173, 1053, 898, 810; 1H NMR (200 MHz, CDCl3): d
5.90–5.72 (m, 1H), 5.35–5.22 (m, 2H), 4.53–4.46 (m, 1H), 4.31–
4.21 (m, 1H), 3.99–3.90 (m, 1H), 1.80–1.68 (m, 2H), 1.49 (s, 3H),
1.36 (s, 3H), 1.16 (d, J = 6.2 Hz, 3H), 0.89 (s, 9H), 0.06 (s, 6H); 13C
NMR (50 MHz, CDCl3): d 134.5, 118.4, 108.1, 79.8, 75.2, 66.0,
40.1, 28.3, 25.8, 25.6, 23.4, 18.0, ꢀ4.4, ꢀ4.8; Anal. Calcd for
C16H32O3Si C, 63.95; H, 10.73; Found: C, 63.81; H, 10.62.
4.10. Preparation of ((4S,5R)-5-((R)-2-(tert-butyldimethylsilyl
oxy)propyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol 15
A solution of 14 (156 mg,0.052 mmol) in Et2O (25 mL) was
added to a saturated aqueous solution of NaIO4 (15 mL) containing
OsO4 (40 mg, 0.17 mmol), and this mixture was stirred at room
temperature for 24 h. The mixture was diluted with Et2O (15 mL)
and H2O (15 mL), and the organic layer was dried (Na2SO4), fil-
tered, and concentrated. The residue was redissolved in MeOH
(10 mL), and NaBH4 (60 mg) was added. After 30 min the mixture
was concentrated, and the residue was partitioned between Et2O
(50 mL) and H2O (20 mL). The organic layer was dried (Na2SO4), fil-
tered, and concentrated, and the residue was purified by silica gel
column chromatography using pet ether/ethylacetate (19:1) as
Data for 11. ½a 2D5
ꢁ
¼ ꢀ28:2 (c 0.5, CHCl3); IR (CHCl3, cmꢀ1): mmax
3422, 2957, 2930, 2857, 1674, 1595, 1460, 1410, 1298, 1075, 1005,
963, 836; 1H NMR (200 MHz, CDCl3): d 4.18–4.00 (m, 1H), 3.75–
3.64 (m, 1H),3.44 (br s, 1H), 2.97–2.91 (m, 1H), 2.79–2.78 (m,
1H), 2.77 (m, 1H), 1.77–1.68 (m, 2H), 1.22 (d, J = 6.2 Hz, 3H), 0.90
(s, 9H), 0.11 (s, 6H); 13C NMR (125 MHz, CDCl3): d 70.5, 69.3,
54.3, 45.1, 42.6, 25.7, 24.3, 17.8, ꢀ3.9, ꢀ4.9; ESI[MS]: 269.07
[M++Na]; Anal. Calcd for C12H26O3Si; C, 58.49; H, 10.63; Found: C,
58.60; H, 10.51.
Data for 12. ½a 2D5
ꢁ
¼ ꢀ30:3 (c 1.1, CHCl3); IR (CHCl3, cmꢀ1): mmax
3450, 3018, 2950, 2930, 2865, 1624, 1427, 1465, 1350, 1262, 1057,
947; 1H NMR (200 MHz, CDCl3): d 5.93–5.79 (m, 1H), 5.32–5.05 (m,
2H), 4.45–4.42 (m, 1H), 4.22–4.18 (m, 1H), 1.69–1.61 (m, 2H), 1.24
(d, J = 6.2 Hz, 3H), 0.90 (s, 9H), 0.10 (s, 6H); 13C NMR (50 MHz, CDCl3):
d 141.1, 113.8, 69.6, 67.2, 44.4, 25.8, 23.0, 17.9, ꢀ4.4, ꢀ5.0; Anal. Calcd
for C12H26O2Si C, 62.55; H, 11.37; Found: C, 62.48; H, 11.41.
eluent to give 15 (119 mg, 75%) as
a
colorless liquid.
½
a 2D5
ꢁ
¼ ꢀ12:2 (c 1.2, CHCl3); IR (neat, cmꢀ1): mmax 3465, 2913,
1456, 1252, 1049, 834; 1H NMR (200 MHz, CDCl3): d 4.31–4.11
(m, 2H), 4.07–3.90 (m, 1H), 3.65–3.53 (m, 2H), 1.88–1.75 (m,
2H), 1.47 (s, 3H),1.36 (s, 3H),1.19 (d, J = 6.2 Hz, 3H), 0.89 (s, 9H),
0.07 (s, 6H); 13C NMR (50 MHz, CDCl3): d 109.0, 78.5, 72.5, 66.5,
63.6, 42.0, 30.9, 26.6, 25.8, 24.4, 17.8, ꢀ3.9, ꢀ4.8; Anal. Calcd for
4.8. Preparation of (3S,4R,6R)-6-(tert-butyldimethylsilyloxy)
C15H32O4Si: C, 59.17; H, 10.59; Found: C, 59.08; H, 10.43.
hept-1-ene-3,4-diol 13
4.11. Preparation of ((4S,5R)-5-((R)-2-hydroxypropyl)-2,2-dim
To a stirred solution of dry THF was added trimethylsulfonium
iodide (1.23 g, 6.05 mmol) at ꢀ20 °C. The reaction mixture was
stirred for 20 min after which was added n-BuLi (3.8 mL, 1.6 M,
6.05 mmol). After 40 min, epoxide 11 (0.3 g, 1.21 mmol) in THF
was added dropwise. The reaction mixture was stirred at ꢀ20 °C
for 3 h and then quenched by a saturated solution of ammonium
ethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate 16
At first, Et3N (1.0 mL, 7.2 mmol) and DMAP (44 mg, 0.4 mmol)
were added to a solution of alcohol 15 (1.10 g, 3.6 mmol) in CH2Cl2
(10 mL) at rt, and the mixture was stirred for 10 min. Next, TsCl
(0.9 g, 4.8 mmol) was added and stirring was continued at rt for

1216
K. Show et al. / Tetrahedron: Asymmetry 22 (2011) 1212–1217
3 h. The reaction was quenched with satd aq NH4Cl (20 mL), and
the mixture was extracted with CH2Cl2 (5 ꢂ 15 mL). The combined
organic layers were washed with H2O and brine, then dried
(Na2SO4), and concentrated under reduced pressure. The crude tos-
ylate product was used in the next step without further
purification.
ether–EtOAc (95:5) as eluent to give chiral hydroxy olefin 17
(0.32 g, 60% yield) as a colorless liquid. ½a D25
¼ ꢀ18:1 (c 3.2,
ꢁ
CHCl3); 1H NMR (200 MHz, CDCl3): d 4.28–4.14 (m, 1H), 3.83–
3.74 (m, 1H), 3.01–2.95 (m, 1H), 2.81–2.76 (m, 1H), 2.74–2.70
(m, 1H), 1.82–1.55 (m, 2H), 1.21 (d, J = 6.2 Hz, 3H), 0.89 (s, 9H),
0.09 (s, 6H); 13C NMR (50 MHz, CDCl3): d 68.3, 66.1, 55.6, 44.5,
42.1, 25.8, 23.5, 17.9, ꢀ4.5, ꢀ5.0; Anal. Calcd for C12H26O3Si: C,
58.49; H, 10.63; Found: C, 58.41; H, 10.55.
A 1 M solution of TBAF in THF (5.2 mL, 5.23 mmol) was added to
a stirred soln of crude tosylate (1.6 g, 3.49 mmol) in dry THF
(10 mL) at rt, and the mixture was stirred for 2 h. The reaction
was quenched with satd aq NH4Cl (20 mL), and the mixture was
extracted with CH2Cl2 (3 ꢂ 15 mL). The combined organic layers
were washed with H2O and brine then dried (Na2SO4) and concen-
trated in vacuo. The crude product was purified by silica gel col-
umn chromatography using pet-ether/EtOAc (5:1) as eluent to
4.14. Preparation of (3S,4S,6R)-6-(tert-butyldimethylsilyloxy)
hept-1-ene-3,4-diol 18
Compound 18 was synthesized using the same procedure as de-
scribed for compound 13. ½a D25
ꢁ
¼ ꢀ28:6 (c 0.8, CHCl3); 1H NMR
give 16 (1.05 g, 85%) as a light yellow oil. ½a D25
¼ ꢀ6:0 (c 0.43,
ꢁ
CHCl3); IR (neat, cmꢀ1): mmax 3455, 2903, 1445, 1185, 790; 1H
(200 MHz, CDCl3): d 5.95–5.78 (m, 1H), 5.40–5.20 (m, 2H), 4.29–
4.20 (m, 1H), 3.91–3.85 (m, 2H), 2.77 (br s, 2H), 1.83–1.69 (m,
1H), 1.59–1.48 (m, 1H), 1.24 (d, J = 6.2 Hz, 3H), 0.89 (s, 9H), 0.09
(s, 6H); 13C NMR (50 MHz, CDCl3): d 137.6, 117.1, 76.4, 71.0,
67.4, 40.0, 25.7, 22.7, 17.9, ꢀ4.5, ꢀ5.1 Anal. Calcd For C13H28O3Si;
C, 59.95; H, 10.84; Found: C, 59.83; H, 10.68.
NMR (200 MHz, CDCl3):
d 7.80 (d, J = 8.2 Hz, 2H), 7.37 (d,
J = 8.2 Hz, 2H), 4.40–4.22 (m, 2H), 4.05–3.88 (m, 3H), 2.46 (s, 3H),
1.73–1.49 (m, 2H), 1.35 (s, 3H),1.32 (s, 3H),1.18 (d, J = 6.2 Hz,
3H); 13C NMR (50 MHz, CDCl3): d 145.0, 132.5, 129.9, 127.9,
109.2, 74.7, 71.8, 68.7, 64.7, 34.0, 29.8, 22.0, 21.6, 19.6; Anal. Calcd
for C16H24O6S: C, 55.80; H, 7.02; Found: C, 55.69; H, 6.99.
4.15. Preparation of tert-butyl-((R)-1-((4S,5S)-2,2-dimethyl-5-
vinyl-1,3-dioxolan-4-yl)propan-2-yloxy)dimethylsilane 19
4.12. Preparation of ophiocerin A 1
Compound 19 was synthesized using the same procedure as de-
A solution of tosylate 16 (90 mg, 0.26 mmol) in dry Et2O (3 mL)
scribed for compound 14. ½a D25
ꢁ
¼ ꢀ16:9 (c 0.4, CHCl3); 1H NMR
was added to
a stirred suspension of t-BuOK (87.85 mg,
(200 MHz, CDCl3): d 5.87–5.70 (m, 1H), 5.39–5.22 (m, 2H), 4.07–
3.99 (m, 1H), 3.92–3.79 (m, 2H), 1.61–1.55 (m, 2H), 1.42 (s, 3H),
1.40 (s, 3H), 1.16 (d, J = 6.2 Hz, 3H), 0.89 (s, 9H), 0.07 (s, 6H); 13C
NMR (50 MHz, CDCl3): d 135.0, 118.9, 108.5, 82.8, 77.1, 65.5,
41.6, 27.4, 26.9, 25.8, 24.6, 18.0, ꢀ4.4, ꢀ4.9 Anal. Calcd for
0.78 mmol) in dry Et2O (5 mL) at 0 °C, and the mixture was stirred
for 2 h at 0 °C. The reaction was quenched with satd aq NH4Cl
(10 mL), and the mixture was extracted with Et2O (4 ꢂ 5 mL).
The combined organic layers were washed with H2O and brine,
then treated with PTSA (3 mg) and MeOH (5 mL) with stirring at
rt for 2 h. The reaction was quenched with satd aq NaHCO3 solu-
tion, and the solvents (MeOH and Et2O) were evaporated under re-
duced pressure. The residue was extracted with CH2Cl2 (3 ꢂ 20 mL)
and the combined organic layers were washed with H2O and brine,
then dried (Na2SO4), and concentrated. The residue was purified by
silica gel column chromatography using pet-ether/EtOAc (4:6) as
eluent to give ophiocerin A 1 (31.7 mg, 92%) as a white solid.
C
16H32O3Si C, 63.95; H, 10.73; Found: C, 63.86; H, 10.63.
4.16. Preparation of ((4S,5S)-5-((R)-2-(tert-butyldimethylsilyl
oxy)propyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol 20
Compound 20 was synthesized using the same procedure as de-
scribed for compound 15.
½
a 2D5
ꢁ
¼ ꢀ22:6 (c 0.2, CHCl3), lit.7c
a 2D5
ꢁ
¼ ꢀ23:4 (c 0.1, CH2Cl2) lit.1½a D25
¼ ꢀ24:0 (c 0.1, CH2Cl2);
ꢁ
½
a 2D7
ꢁ
ꢀ 21:0 (c 0.2, CHCl3); 1H NMR (200 MHz, CDCl3): d 4.08–4.01
½
mp = 62–64 °C;IR (KBr, cmꢀ1): mmax 3401, 2930, 1454, 1389,
1185, 1011; 1H NMR (500 MHz, CDCl3): d 4.10 (m, 1H), 3.83 (ddq,
J = 2.0, 6.4, 11.3 Hz, 1H), 3.71–3.78 (m, 2H), 3.60–3.53 (m, 1H),
1.89 (ddd, J = 2.1, 3.5, 14.3 Hz, 1H), 1.53 (ddd, J = 2.5, 11.0,
13.9 Hz, 1H), 1.16 (d, J = 6.3 Hz, 3H); 13C NMR (125 MHz, CDCl3):
d 67.3, 67.1, 67.0, 65.9, 39.0, 20.8.
(m, 2H), 3.80–3.55 (m, 3H), 1.95 (br s, 1H), 1.61–1.55 (m, 2H),
1.42 (s, 3H), 1.38 (s, 3H),1.16 (d, J = 6.2 Hz, 3H), 0.89 (s, 9H), 0.07
(s, 6H); 13C NMR (50 MHz, CDCl3): d 108.6, 81.5, 73.7, 65.6, 61.9,
42.8, 27.4, 26.9, 25.8, 24.7, 18.0, ꢀ4.4, ꢀ4.9;
4.17. Preparation of ((4S,5S)-5-((R)-2-hydroxypropyl)-2,2-dime
thyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate 21
4.13. Preparation of (1S,3R)-3-(tert-butyldimethylsilyloxy)-1-
((S)-oxiran-2-yl)butan-1-ol 17
Compound 21 was synthesized using the same procedure as de-
scribed for compound 16. ½a D25
ꢁ
¼ þ3:2 (c 0.3, CHCl3); 1H NMR
To a mixture of 4 Å molecular sieves (0.3 g) and Ti(O-iPr)4
(0.7 mL, 2.38 mmol) in dry CH2Cl2 (20 mL), (ꢀ)-DIPT
(0.54 mL,2.60 mmol) was added dropwise over 10 min at ꢀ20 °C.
The mixture was stirred for 20 min at ꢀ20 °C after which a solu-
tion of 12 (0.5 g, 2.17 mmol) in dry CH2Cl2 (20 mL) was added
over 10 min. The reaction mixture was stirred for an additional
30 min at ꢀ20 °C after which TBHP (1.0 mL, 5 M solution in
decane, 5.42 mmol) was added dropwise over 15 min. The reac-
tion mixture was kept at ꢀ20 °C by a constant temperature bath
and after 8 days the reaction was warmed to room temperature,
and quenched with saturated Na2SO4 (15 mL). The mixture was
then stirred vigorously for 2 h. The two phases were separated
and the aqueous phase was extracted with CH2Cl2 (5 ꢂ 20 mL).
The combined organic layers were dried over sodium sulfate, fil-
tered, and concentrated to dryness. The crude product was then
purified by flash chromatography on silica gel using pet
(500 MHz, CDCl3): d 7.79 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.2 Hz,
2H), 4.14–4.11 (m, 2H), 4.09–4.05 (m, 1H), 4.02–3.99 (m, 1H),
3.88–3.85 (m, 1H), 2.47 (s, 3H), 1.71–1.68 (m, 2H), 1.37 (s,
3H),1.31 (s, 3H),1.21 (d, J = J = 6.2 Hz, 3H); 13C NMR (125 MHz,
CDCl3): d 145.1, 132.6, 129.9, 127.9, 109.5, 78.0, 75.3, 68.9, 65.0,
41.0, 27.2, 26.6, 23.8, 21.6.
4.18. Preparation of ophiocerin C 3
Ophiocerin C was synthesized using the same procedure as de-
scribed for ophiocerin A. ½a D25
ꢁ
¼ þ42:4, lit.1
½
a 2D5
ꢁ
¼ þ45:0 (c 0.1,
CH2Cl2); mp = 81–83 °C 1H NMR (200 MHz, CDCl3): d 3.97 (dd,
J = 5.0, 11.3 Hz, 1H), 3.65–3.45 (m, 3H), 3.16 (dd, J = 9.9, 11.0 Hz,
1H), 2.00 (ddd, J = 1.8, 4.3, 12.6 Hz, 1H), 1.38 (ddd, J = 11.1, 11.1,
12.8 Hz, 1H), 1.22 (d, J = 6.2 Hz, 3H); 13C NMR (50 MHz, CDCl3): d
73.3, 72.7,72.2, 69.6, 40.5, 21.2.

K. Show et al. / Tetrahedron: Asymmetry 22 (2011) 1212–1217
1217
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Acknowledgments
K.S. and P.G. thank UGC and CSIR New Delhi for financial assis-
tance. Financial support from DST, New Delhi (Grant No. SR/S1/OC-
44/2009) is gratefully acknowledged.
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