A short and efficient synthetic strategy for the total syntheses of (S)-(+)- and (R)-(-)-Plakolide A

Article abstract of DOI:10.1002/ejoc.200700401

Concise and efficient total syntheses of anticancer agents (S)-(+)-Plakolide A and (R)-(-)-Plakolide A were accomplished in eight steps and an overall yield of 39 % starting from geraniol. The key steps in our strategy are Sharpless asymmetric epoxidation, double elimination, and Stille coupling reactions. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700401

FULL PAPER
DOI: 10.1002/ejoc.200700401
A Short and Efficient Synthetic Strategy for the Total Syntheses of
S)-(+)- and (R)-(–)-Plakolide A
(
[a]
[a]
[a]
Debendra K. Mohapatra,* Chinmoy Pramanik, Mukund S. Chorghade, and
Mukund K. Gurjar[
a]
Keywords: Inhibitors / Epoxidation / Olefination / Cross-coupling
Concise and efficient total syntheses of anticancer agents (S)-
+)-Plakolide A and (R)-(–)-Plakolide A were accomplished in
epoxidation, double elimination, and Stille coupling reac-
tions.
(
eight steps and an overall yield of 39% starting from gera-
niol. The key steps in our strategy are Sharpless asymmetric
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Introduction
So far only one total synthesis of Plakolide A on the
basis of the self-reproduction method developed by Seebach
has been reported in the literature. The interesting phar-
macological activity and unique structural features
prompted us to devise a new, short, and efficient strategy
Plakolide A is an α-exomethylene-γ-disubstituted-γ-lac-
tone isolated recently from a shallow-water marine sponge
of the genus plakortis collected from La Palma Islands, and
it was found to exhibit inducible nitric oxide synthase
[2b]
(
0
iNOS) activity in a cell-based assay (IC
.2 µgmL ). It exhibited 72 h cytotoxicity against the
value of
5
0
–
1 [1]
cultured P-388 marine lymphoma and A-549 human lung
adenocarcinoma cell lines with IC values of 1.1 and
5
0
–
1
5
.0 µgmL , respectively. It also showed cytotoxicity against
PANC-1 human pancreatic carcinoma and NCI/ADR hu-
man breast carcinoma cell lines with IC values of 3.8 and
5
0
–
1
3
.7 µgmL , respectively. Persuasive data mainly based
upon extensive investigation of the structure by its synthe-
sis, specific rotation, and CD spectrum led to the revision
of the stereochemistry of the lactone at C4.[2a]
Figure 1. (S)-(+)-Plakolide A and (R)-(–)-Plakolide A.
Figure 2. Retrosynthetic analysis of (S)-(+)-Plakolide A (1).
for the total syntheses of both (S)-(+)- and (R)-(–)-Plakol-
[
a] Division of Organic Chemistry: Technology, National Chemical ide A starting from the simple and readily available geraniol
Laboratory
(
Figure 1).
Pune 411008, India
Our retrosynthetic strategy is outlined in Figure 2. The
Fax: +91-20-25902629
E-mail: dk.mohapatra@ncl.res.in
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
target molecule was anticipated to be derived from vinyl
stannane derivative 5 via a lactol that could be obtained
Eur. J. Org. Chem. 2007, 5059–5063
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5059

D. K. Mohapatra, C. Pramanik, M. S. Chorghade, M. K. Gurjar
FULL PAPER
Scheme 1. Synthesis of (S)-(+)-Plakolide A (1). Reagents and conditions: (a) -(+)-DIPT, Ti(OiPr)
4
, TBHP, MS 4 Å, CH
, NMO, acetone/water (1:4), room temp., 12 h,
, CH Cl , 1 h; (2) PDC, CH Cl , 4 h, 84% over
, LiCl, CuCl, DMSO, room temp. to 60 °C, 26 h, 83% for 3 and 9% for 13; (h) (1) LDA, THF, –78 °C, 15 min,
2) Eschenmoser’s salt, –78 °C to room temp., 6 h, (3) CH I, CH OH, room temp., 18 h, 82%.
2 2
Cl , –23 °C,
6
h, 95%; (b) PPh
3 4 4
, CCl , reflux, 6 h, 93%; (c) n-BuLi, THF, –40 °C, 1 h, 85%; (d) OsO
9
2%; (e) Bu SnH, AIBN, toluene, 110 °C, 6 h, 90%; (f) (1) silica gel supported NaIO
3
4
2
2
2
2
3 4
two steps; (g) 4, Pd(PPh )
(
3
3
from propargyl alcohol 6. Alcohol 6 could be obtained DMSO. The products were easily separated by flash
from epoxy alcohol 7 in two discrete steps, namely chlorina- chromatography on silica gel. Finally, treatment of the
[
11]
tion followed by a double elimination reaction. Epoxy (E,E)-3 with LDA and Eschenmoser’s salt furnished (S)-
alcohol 7 could be generated by Sharpless epoxidation of (+)-Plakolide A (1). Product 1 exhibited spectroscopic and
geraniol.
physical properties identical to those of an authentic sam-
25
ple; the sign of optical rotation was different {[α] = +43.2
D
[
1]
25
(
c = 1.5, MeOH), ref. [α] = –41.0 (c = 0.12, MeOH)}.
D
Results and Discussion
This reconfirmed the observation of Matsuo et al. that nat-
ural Plakolide A is not (S)-(+)-Plakolide A (1) but rather
Our synthesis of the main core commenced with com-
mercially available geraniol, which was subjected to
Sharpless asymmetric epoxidation to yield epoxide 7 {[α]
[
2]
(R)-(–)-Plakolide A (2).
With the exact same approach, the natural enantiomer
2
5
D
(R)-(–)-Plakolide A (2) was synthesized from geraniol as
[3]
25
=
–5.1 (c = 3.0, CHCl ), ref. [α] = –5.3 (c = 3.0, CHCl )}
3 D 3
well by using -(–)-DIPT for the Sharpless epoxidation and
[4]
[5]
in Ն95% ee (Scheme 1). Chlorination with refluxing
following the same protocol to that described in Scheme 1.
CCl and PPh gave chloroepoxide 8. A double elimination
4
3
25
We arrived at (R)-(–)-Plakolide A (2) {[α] = –42.4 (c =
[
6]
D
reaction effected by treatment with nBuLi in THF at
40 °C furnished propargyl alcohol 6 in 79% overall yield.
[
1]
25
1
.2, MeOH), ref. [α] = –41.0 (c = 0.12, MeOH)}in eight
D
–
steps with an overall 41% yield.
Dihydroxylation of olefin 6 with OsO and NMO in ace-
4
tone and water at ambient temperature gave triol 9 as a
diastereomeric mixture (1:1) in 92% yield. Required vinyl
stannane 10 (1:1 diastereomeric mixture) was easily ob-
[7]
tained from 9 by radical hydrostannylation. Oxidative
[
8]
Conclusions
cleavage of the diol with the use of NaIO -impregnated
4
silica gel in dichloromethane and treatment of the resulting
lactol with PDC in the same pot afforded required lactone
Starting from readily available geraniol and following a
1
13
5
in 84% overall yield. Its H- and C-NMR spectra were practical sequence of reactions, we developed efficient syn-
in good agreement with the assigned structure; elemental thetic routes to enantiopure (S)-(+)-Plakolide A (1) and
analysis confirmed the chemical composition of 5. (R)-(–)-Plakolide A (2). In terms of brevity and efficiency,
With lactone vinyl stannane 5 in hand, vinyl iodide side the described methods compare well with the reported
chain 4 was constructed from nonan-1-al by Takai ole- route, and they are expected to be attractive alternatives
[
9]
fination.
Subsequent coupling of these entities was to the existing method for the total synthesis of the title
achieved through a cuprous chloride accelerated Stille compounds. The obvious and noteworthy advantages of
coupling under conditions reported by Corey and co- our protocol lie in high overall yields, ready access to the
[
10]
workers.
The expected coupled products (E,E)-3 and disubstituted γ-lactone moiety with high enantioselectivity,
(
E,Z)-13 were obtained in a 9:1 ratio by using Pd(PPh ) in and various possibilities of side chain modifications.
3
4
5060
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5059–5063

Total Syntheses of (S)-(+)- and (R)-(–)-Plakolide A
5
5.6 mmol) dropwise, and the mixture was allowed to stir for an
additional 1 h. The mixture was quenched with an aqueous solu-
tion of NH Cl (20 mL), and THF was removed under reduced
pressure. The aqueous layer was extracted with ethyl acetate
2ϫ50 mL), dried with Na SO , and concentrated. The residue was
Experimental Section
General Remarks: Air- and/or moisture-sensitive reactions were
carried out in anhydrous solvents under an atmosphere of argon in
oven/flame-dried glassware. All anhydrous solvents were distilled
prior to use: THF, benzene, toluene, and diethyl ether from Na and
benzophenone; CH Cl from CaH ; MeOH, EtOH from Mg cake.
2 2 2
Commercial reagents were used without purification. Column
4
(
2
4
purified by silica gel column chromatography (ethyl acetate/light
petroleum ether, 3:97) to afford propargyl alcohol derivative 6
(
f
2.2 g, 85%) as a colorless liquid. R = 0.5 (ethyl acetate/light petro-
chromatography was carried out by using silica gel (60–120 mesh).
25
1
leum ether, 1:19). [α]
200 MHz, CDCl ): δ = 5.15 (t, J = 7.2 Hz, 1 H), 2.43 (s, 1 H),
.17 (m, 2 H), 1.7 (m, 2 H), 1.65 (s, 3 H), 1.49 (s, 3 H) ppm.
D 3
= –13.24 (c = 0.65, CHCl ). H NMR
2
–1 1
Specific optical rotations [α]
D
are given in 10–1 °cm g . H and
(
2
3
1
3C NMR chemical shifts are reported in ppm downfield from tet-
ramethylsilane. The following abbreviations are used to designate
signal multiplicity: s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet, br. = broad.
13
C
NMR (50 MHz, CDCl
3
): δ = 132.3, 123.8, 87.7, 71.4, 68.1, 43.2,
2
2
9.8, 25.7, 23.5, 17.7 ppm. IR (liquid film, CHCl
3
): ν˜ = 3398, 3308,
–1
110, 1672, 1451, 1376, 1121, 908 cm . C10
H16O (152.23): calcd.
(
2S,3S)-3-Methyl-3-[(4-methylpent-3-enyl)oxiran-2-yl]methanol (7): C 78.90, H 10.60; found C 79.06, H 10.78.
A stirred mixture of activated 4 Å molecular sieves (5.0 g) and
dichloromethane (30 mL) was cooled to –10 °C. -(+)-Diisopropyl
tartrate (0.86 mL, 4.1 mmol), freshly distilled titanium isopropox-
ide (1.20 mL, 4.1 mmol), and tert-butyl hydroperoxide (5  in dec-
ane, 9.72 mL, 48.6 mmol) were added sequentially. After stirring
for 10 min, the mixture was cooled to –23 °C and freshly distilled
geraniol (5.0 g, 32.4 mmol) in dichloromethane (10 mL) was added
at a rate sufficient to ensure that the temperature remained below
(
6S)-2,6-Dimethyloct-7-yne-2,3,6-triol (9): Osmium tetroxide (cata-
lytic) was added to a stirred mixture of carbinol 6 (2.20 g,
1
2
stirred overnight at room temp. After completion of the reaction,
it was quenched with a saturated solution of sodium sulfite
(
removed under reduced pressure, and the aqueous layer was ex-
tracted with ethyl acetate (3ϫ50 mL). The combined organic layers
2 4
were dried with Na SO and concentrated in vacuo to leave a resi-
due, which on silica gel column chromatography (ethyl acetate/light
4.5 mmol) and NMO (50 % aqueous solution, 6.77 mL,
8.9 mmol) in acetone/water (1:4, 10 mL) at 0 °C. The mixture was
10 mL). The mixture was stirred vigorously for 1 h. Acetone was
–20 °C. The mixture was stirred at –23 °C for an additional 6 h and
water (10 mL) was then added with vigorous stirring. After 30 min,
aqueous NaOH (3 , 20 mL) was added, and the mixture was
stirred at room temp. for an additional 30 min and filtered through
Celite. The filtrate was stirred vigorously with 10% citric acid
petroleum ether, 7:3) furnished 9 (1:1 diastereomeric mixture)
1
(
(
2.6 g, 92%) as a viscous liquid. R
200 MHz, CDCl
f
= 0.3 (ethyl acetate). H NMR
(30 mL) at room temp. for 2 h. After the organic layer was sepa-
3
): δ = 3.44 (m, 1 H), 2.46 (s, 1 H), 2.01–1.69 (m,
H), 1.54 (s, 1.5 H), 1.53 (s, 1.5 H), 1.24 (s, 3 H), 1.20 (s, 1.5 H),
rated, the aqueous layer was extracted with dichloromethane
4
1
7
2
1
9
(
(
2ϫ50 mL). The combined organic layer was washed with brine
40 mL), dried with Na SO , and concentrated in vacuo. Bulb-to-
1
3
.19 (s, 1.5 H) ppm. C NMR (50 MHz, CDCl
8.8/78.1, 73.3, 71.7/71.4, 67.5, 40.9/40.2, 30.5/29.5, 26.7, 26.4/26.4,
3.4/23.3 ppm. IR (liquid film, CHCl ): ν˜ = 3397, 3307, 2109, 1452,
(186.25): calcd. C 64.49, H
3
): δ = 88.0/87.6,
2
4
bulb distillation (100 °C, 0.1 Torr) of the crude product yielded ep-
oxide 7 (5.24 g, 95%) as a colorless liquid. R = 0.6 (ethyl acetate/
3
f
–
1
374, 1167, 1071, 945 cm . C10
.74; found C 64.56, H 9.82.
18 3
H O
light petroleum ether, 3:7). [α]2
200 MHz, CDCl ): δ = 5.07 (t, J = 7.08 Hz, 1 H), 3.81 (dd, J =
2.13, 4.29 Hz, 1 H), 3.66 (dd, J = 12.13, 6.70 Hz, 1 H), 2.96 (dd,
J = 6.70, 4.29 Hz, 1 H), 2.07 (dt, J = 7.59, 7.08 Hz, 2 H), 1.69 (m,
5
1
D
3
= –5.1 (c = 3.0, CHCl ). H NMR
(
1
3
(6S,E)-2,6-Dimethyl-8-(tributylstannyl)oct-7-ene-2,3,6-triol (10): To
a stirred solution of 9 (2.4 g, 12.9 mmol) in toluene (30 mL) was
1
H), 1.68 (s, 3 H), 1.61 (s, 3 H), 1.48 (m, 1 H), 1.30 (s, 3 H) ppm.
added nBu SnH (4.0 mL, 15.5 mmol) and AIBN (30 mg) at room
3
1
3
C NMR (50 MHz, CDCl
3
): δ = 132.0, 123.4, 63.1, 61.3, 61.1, temp. The reaction mixture was degassed with argon and gently
3
1
7
8.5, 25.7, 23.7, 17.6, 16.7 ppm. IR (liquid film, CHCl
3
): ν˜ = 3418,
heated at reflux with stirring for 6 h. The solvent was removed, and
the residue was purified by silica gel column chromatography (ethyl
acetate/light petroleum ether, 2:3) to give 10 (1:1 diastereomeric
–1
672, 1452, 1384, 1094, 864 cm . C10
0.60, H 10.58; found C 70.82, H 10.46.
H O (170.25): calcd. C
18 2
mixture) (5.5 g, 90%) as a colorless liquid. R
f
= 0.6 (ethyl acetate/
light petroleum ether, 7:3). H NMR (200 MHz, CDCl ): δ = 6.12
d, J = 19.3 Hz, 0.5 H), 6.12 (d, J = 19.3 Hz, 0.5 H), 6.0 (d, J =
(
(
(
(
2R,3S)-3-(Chloromethyl)-2-methyl-2-(4-methylpent-3-enyl)oxirane
1
8): A stirred mixture of epoxy alcohol 7 (4.2 g, 24.7 mmol), PPh
7.76 g, 29.6 mmol), and NaHCO (0.42 g, 10 wt.-%) in CCl
3
3
(
3
4
1
2
9.3 Hz, 0.5 H), 5.95 (d, J = 19.3 Hz, 0.5 H), 3.35 (dd, J = 6.9,
.3 Hz, 0.5 H), 3.35 (dd, J = 6.8, 2.1 Hz, 0.5 H), 1.88–1.57 (m, 4
50 mL) was heated at reflux, under a nitrogen atmosphere, for 6 h.
was removed under reduced
After completion of the reaction, CCl
pressure, and the residue was purified by silica gel column
chromatography (ethyl acetate/light petroleum ether, 4:96) to fur-
4
H), 1.54–1.25 (m, 18 H), 1.19 (s, 1.5 H), 1.18 (s, 1.5 H), 1.14 (s, 1.5
H), 1.12 (s, 1.5 H), 0.93 (s, 1.5 H), 0.89 (s, 1.5 H), 0.89 (t, J =
1
3
7
3
.48 Hz, 9 H) ppm. C NMR (50 MHz, CDCl ): δ = 154.7/154.2,
nish epoxy chloride 8 (4.3 g, 93%) as a colorless liquid. R
f
= 0.5
= +9.95 (c = 2.9,
3 3
CHCl ). H NMR (200 MHz, CDCl ): δ = 5.08 (t, J = 7.1 Hz, 1
25
123.8/123.3, 79.1/78.5, 74.6/73.2, 39.3/38.8, 29.3/29.2, 29.1, 28.9,
27.8/27.8, 27.2, 26.5/26.4, 26.1/26.0, 23.2/23.1, 13.7, 9.5 ppm. IR
(ethyl acetate/light petroleum ether, 1:9). [α]
D
1
(
9
liquid film, CHCl
3
): ν˜ = 3393, 1641, 1599, 1463, 1376, 1166, 1071,
H), 3.69 (dd, J = 11.4, 5.8 Hz, 1 H), 3.41 (dd, J = 11.4, 7.3 Hz, 1
H), 3.01 (dd, J = 7.3, 5.8 Hz, 1 H), 2.09 (dt, J = 7.5, 7.1 Hz, 2 H),
1
–
1
94 cm . C22H O Sn (477.31): calcd. C 55.36, H 9.70; found C
46 3
1
3
55.49, H 9.88.
.68 (m, 1 H), 1.68 (s, 3 H), 1.44 (m, 1 H), 1.32 (s, 3 H) ppm.
C
NMR (50 MHz, CDCl
3
): δ = 132.0, 123.2, 61.7, 61.3, 42.0, 38.2,
): ν˜ = 1653, 1451,
17ClO (188.69): calcd.
(
(
S,E)-5-Methyl-5-[2-(tributylstannyl)vinyl]dihydrofuran-2(3H)-one
5): To a vigorously stirred suspension of silica gel supported
25.5, 23.6, 17.5, 16.1 ppm. IR (liquid film, CHCl
3
–1
1385, 1263, 1113, 1072, 914, 860 cm . C10
H
NaIO
4
reagent (12.0 g) in CH
2
Cl
2
(50 mL) was added a solution of
Cl (20 mL). After completion of
C 63.65, H 9.00; found C 63.78, H 9.14.
triol 10 (2.0 g, 4.2 mmol) in CH
2
2
(
S)-3,7-Dimethyloct-6-en-1-yn-3-ol (6): To a stirred solution of ep-
the reaction, PDC (2.02 g, 5.4 mmol) was added at 0 °C. The reac-
tion mixture was stirred at room temp. for an additional 4 h period
and filtered through a pad of silica gel, which was washed with
oxy chloride 8 (3.5 g, 18.5 mmol) in dry THF (25 mL) at –40 °C,
under an argon atmosphere, was added nBuLi (34.77 mL,
Eur. J. Org. Chem. 2007, 5059–5063
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5061

D. K. Mohapatra, C. Pramanik, M. S. Chorghade, M. K. Gurjar
FULL PAPER
CH
gel column chromatography (ethyl acetate/light petroleum ether, solution (20 mL) and ethyl acetate (50 mL). The aqueous layer was
:19) of the residue afforded lactone 5 (1.4 g, 84% over two steps) extracted with ethyl acetate (2ϫ25 mL). The combined organic
as a colorless liquid. R = 0.4 (ethyl acetate/light petroleum ether, layer was dried with Na SO , and solvent was removed in vacuo
2
Cl
2
(2ϫ50 mL), and the solvent was then evaporated. Silica
to give a solid residue that was washed with an aqueous NaHCO
3
1
f
2
4
:9). [α]2
5
= –8.17 (c = 1.0, CHCl
). H NMR (200 MHz, CDCl
1
):
to afford a crude residue, which on purification by silica gel column
chromatography (ethyl acetate/light petroleum ether, 1:19) fur-
1
D
3
3
δ = 6.27 (d, J = 19.3 Hz, 1 H), 5.92 (d, J = 19.3 Hz, 1 H), 2.52 (dt,
J = 6.8, 2.2 Hz, 2 H), 2.28–1.97 (m, 2 H), 1.60–1.21 (m, 18 H), 0.90
nished 1 (0.26 g, 82%) as a colorless liquid. R
f
= 0.3 (ethyl acetate/
= +43.2 (c = 1.5, MeOH). 1
3
): δ = 6.22 (dd, J = 15.1, 10.1 Hz, 1 H),
m, 14 H) ppm. 13C NMR (50 MHz, CDCl
): δ = 176.5, 148.6, light petroleum ether, 1:9). [α]
27.0, 86.6, 33.8, 29.0, 28.7, 27.1, 26.3, 13.6, 9.4 ppm. IR (liquid NMR (200 MHz, CDCl
25
H
(
1
3
D
–
1
film, CHCl
3
): ν˜ = 1768, 1463, 1377, 1262, 1143, 1073, 992 cm .
C H O Sn (415.20): calcd. C 54.96, H 8.70; found C 55.14, H
19 36 2
6.23 (t, J = 2.7 Hz, 1 H), 5.99 (dd, J = 15.0, 10.1, Hz, 1 H), 5.76
(dt, J = 15.0, 6.8 Hz, 1 H), 5.61 (d, J = 15.2 Hz, 1 H), 5.61 (t, J =
2.4 Hz, 1 H), 2.93 (dt, J = 16.6, 2.6 Hz, 1 H), 2.79 (dt, J = 16.6,
8.93.
2
.6 Hz, 1 H), 2.07 (dt, J = 7.2, 6.9 Hz, 2 H), 1.53 (s, 3 H), 1.40–
(
(
S)-5-[(1E,3E)-Dodeca-1,3-dienyl]-5-methyldihydrofuran-2(3H)-one
3) and (S)-5-[(1E,3Z)-Dodeca-1,3-dienyl]-5-methyldihydrofuran-
1
3
1
.25 (m, 12 H), 0.88 (t, J = 6.5 Hz, 3 H) ppm. C NMR (50 MHz,
): δ = 169.78, 137.37, 135.31, 132.20, 129.67, 128.68, 122.26,
2.37, 40.79, 32.65, 31.85, 29.42, 29.23, 29.18, 29.09, 27.10, 22.64,
4.08 ppm. IR (liquid film, CHCl ): ν˜ = 1762, 1664, 1624, 1458,
377, 1281, 1051, 990, 940 cm . C18 (276.41): calcd. C 78.21,
CDCl
3
2
(3H)-one (13): A 50-mL two-necked round-bottom flask was
charged with LiCl (0.59 g, 13.8 mmol) and flame dried under high
vacuum. With cooling, Pd(PPh (0.27 g, 0.23 mmol) and CuCl
1.27 g, 13.8 mmol) were added, and the mixture was degassed (4ϫ)
8
1
1
3
3 4
)
–
1
28 2
H O
(
H 10.21; found C 78.36, H 10.42.
under high vacuum with an Ar purge. DMSO (20 mL) was intro-
duced with concomitant stirring, followed by the addition of vinyl
iodide 4 (0.60 g, 2.3 mmol) and vinyl stannane 5 (1.40 g, 3.4 mmol).
The resulting mixture was rigorously degassed (4ϫ) under high vac-
uum with an Ar purge. The reaction mixture was stirred at room
temp. for 2 h, and then heated to 60 °C for 24 h. After completion
of the reaction, as monitored by TLC, the reaction mixture was
cooled, diluted with ethyl acetate (50 mL), and washed with a mix-
ture of brine (40 mL) and 5% aqueous NH OH (20 mL). The aque-
4
ous layer was further extracted with ethyl acetate (2ϫ50 mL), and
the combined organic layers were washed with water (50 mL) and
then brine (50 mL), dried with Na SO , and concentrated. The
2 4
(2R,3R)-3-Methyl-3-[(4-methylpent-3-enyl)oxiran-2-yl)methanol
(Enantiomer of 7): The same procedure as that for 7 starting from
geraniol (6.0 g, 38.9 mmol) gave the enantiomer of 7 (6.5 g, 98%)
as a colorless oil. [α]
(170.25): calcd. 70.60, H 10.58; found C 70.82, H 10.46.
2
5
D 3 18 2
= +5.2 (c = 1.65, CHCl ). C10H O
(
(
2S,3R)-3-(Chloromethyl)-2-methyl-2-(4-methylpent-3-enyl)oxirane
Enantiomer of 8): The same procedure as that for 8 starting from
the enantiomer of 7 (5.5 g, 32.3 mmol) furnished the enantiomer
25
of 8 (5.6 g, 91%) as a colorless liquid. [α]
CHCl ). C10 17ClO (188.69): calcd. C 63.65, H 9.00; found C
3.78, H 9.14.
D
= –10.26 (c = 2.1,
3
H
6
crude product was purified by flash silica gel column chromatog-
raphy (benzene/light petroleum ether, 1:1) to obtain (E,E)-3
(
R)-3,7-Dimethyloct-6-en-1-yn-3-ol (Enantiomer of 6): The same
procedure as that for 6 starting from the enantiomer of 8 (3.8 g,
20.1 mmol) furnished the enantiomer of 6 (2.6 g, 84%) as a color-
less liquid. [α]D = +12.64 (c = 2.1, CHCl ). C H O (152.23):
(0.496 g, 83%) and (E,Z)-13 (0.054 g, 9%) as colorless liquids. R
f
2
5
=
–
0.5 (benzene/light petroleum ether, 4:1). Data for (E,E)-3: [α]
D
=
2
5
1
2.42 (c = 1.0, CHCl
3
). H NMR (200 MHz, CDCl
3
): δ = 6.14 (dd,
3
10 16
calcd. C 78.90, H 10.60; found C 79.06, H 10.78.
J = 15.2, 10.1 Hz, 1 H), 5.92 (dd, J = 15.0, 10.1 Hz, 1 H), 5.67 (dt,
J = 15.0, 6.8 Hz, 1 H), 5.51 (d, J = 15.2 Hz, 1 H), 2.54–2.45 (m, 2
H), 2.20–1.93 (m, 4 H), 1.45 (s, 3 H), 1.30 (m, 2 H), 1.17–1.26 (br.
m, 12 H), 0.81 (t, J = 6.5 Hz, 3 H) ppm. 13C NMR (50 MHz,
CDCl
2
(
6R)-2,6-Dimethyloct-7-yne-2,3,6-triol (Enantiomer of 9). The same
procedure as that for 9 starting from the enantiomer of 6 (3.2 g,
1.0 mmol) afforded the enantiomer of 9 (3.6 g, 93%) as colorless
oil. C10 (186.25): calcd. C 64.49, H 9.74; found C 64.56, H
.82.
2
3
): δ = 176.5, 137.0, 132.0, 129.4, 128.8, 85.2, 34.4, 32.7, 31.9,
18 3
H O
9.5, 29.3, 29.2, 29.1, 28.9, 26.7, 22.7, 14.1 ppm. IR (liquid film,
9
CHCl
3
): ν˜ = 3020, 1768, 1658, 1523, 1457, 1420, 1378, 1073, 992,
–1
25
(6R,E)-2,6-Dimethyl-8-(tributylstannyl)oct-7-ene-2,3,6-triol (Enanti-
omer of 10): The same procedure as that for 10 starting from the
enantiomer of 9 (2.0 g, 10.7 mmol) gave the enantiomer of 10 (1:1
diastereomeric mixture; 4.7 g, 91 %) as a colorless liquid.
9
29, 669 cm . Data for (E,Z)-13: [α]
D
= +9.37 (c = 0.65, CHCl
3
).
1
H NMR (200 MHz, CDCl
3
): δ = 6.52 (dd, J = 15.3, 11.0 Hz, 1
H), 5.94 (t, J = 10.0 Hz, 1 H), 5.67 (d, J = 15.4 Hz, 1 H), 5.5 (dt,
J = 10.8, 7.6 Hz, 1 H), 2.58 (m, 2 H), 2.25–2.08 (m, 4 H), 1.53 (s,
3
(
9
1
22 46 3
C H O Sn (477.31): calcd. C 55.36, H 9.70; found C 55.49, H
H), 1.42–1.25 (m, 14 H), 0.88 (t, J = 6.4 Hz, 3 H) ppm. IR
9.88.
CHCl ): ν˜ = 3019, 1770, 1651, 1460, 1419, 1378, 1289, 1141, 1073,
3
87, 949, 932, 667 cm–1. C17
H
O
(264.40): calcd. C 77.22, H (R,E)-5-Methyl-5-[2-(tributylstannyl)vinyl]-dihydrofuran-2(3H)-one
(Enantiomer of 5): The same procedure as that for 5 starting from
28
2
0.67; found C 77.04, H 10.82.
the enantiomer of 10 (2.8 g, 5.9 mmol) furnished the enantiomer
(
(
S)-(+)-Plakolide A (1): To a stirred solution of diisopropylamine
0.17 mL, 1.3 mmol) in anhydrous THF (20 mL) at –20 °C was
2
5
D 3
of 5 (2.03 g, 83%) as a colorless oil. [α] = +9.55 (c = 1.3, CHCl ).
19 36 2
C H O
Sn (415.20): calcd. C 54.96, H 8.70; found C 55.14, H
added nBuLi (1.6  in hexane, 0.78 mL, 1.3 mmol). The solution
was stirred for 15 min whilst the cooling bath was maintained at
8.93.
–
78 °C. Lactone 3 (0.3 g, 1.1 mmol) in THF (5 mL) was added, and
(R)-5-[(1E,3E)-Dodeca-1,3-dienyl]-5-methyldihydrofuran-2(3H)-one
(Enantiomer of 3) and (R)-5-[(1E,3Z)-Dodeca-1,3-dienyl]-5-methyl-
dihydrofuran-2(3H)-one (Enantiomer of 13): The same procedure as
that for 3 starting from the enantiomers of 5 (1.18 g, 2.85 mmol)
and 4 (0.5 g, 1.9 mmol) afforded the enantiomers of 3 (0.42 g, 84%)
and 13 (0.045 g, 9%), respectively, as colorless liquids. (E,E) Iso-
the reaction mixture was stirred for 15 min followed by the addition
of dimethyl(methylene)ammonium iodide (0.44 g, 2.4 mmol) in
THF (5 mL). The reaction mixture was stirred for 6 h and grad-
ually warmed to room temp. The solvent was removed under re-
duced pressure, and the residue was dissolved in methanol (10 mL).
To this solution was added an excess amount of methyl iodide
2
5
25
mer: [α]
(c = 1.4, CHCl
found C 77.04, H 10.82.
D 3 D
= +2.68 (c = 1.8, CHCl ). (E,Z) Isomer: [α] = –10.74
(0.17 mL, 2.8 mmol), and the resulting mixture was stirred at room
3
). C17
H
28
O
2
(264.40): calcd. C 77.22, H 10.67;
temp. for 18 h. The solvent was removed under reduced pressure
5062
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5059–5063

Total Syntheses of (S)-(+)- and (R)-(–)-Plakolide A
R)-(–)-Plakolide A (2). The same procedure as that for 1 starting
(
[3] a) Y. Gao, R. M. Hanson, J. M. Klunder, S. Y. Ko, H. Masa-
mune, R. B. Sharpless, J. Am. Chem. Soc. 1987, 109, 5765–
5780; b) M. Hashimoto, H. Harigaye, M. Yamagiya, H. Shirah-
ama, J. Org. Chem. 1991, 56, 2299–2311.
from the enantiomer of 3 (0.2 g, 0.76 mmol) gave 2 (0.17 g, 83%
yield) as a colorless liquid. [α]2
5
1
D
3
= –42.4 (c = 1.2, CH OH). H
NMR (200 MHz, CDCl
.23 (t, J = 2.7 Hz, 1 H), 5.98 (dd, J = 15.0, 10.1 Hz, 1 H), 5.76
dt, J = 15.0, 6.9 Hz, 1 H), 5.6 (d, J = 15.1 Hz, 1 H), 5.60 (t, J =
3
): δ = 6.21 (dd, J = 15.1, 10.1 Hz, 1 H),
[
[
[
4] The enantiomeric purity of compound 7 was estimated
95%ee) by HPLC analysis of its TBDPS ether by using a chi-
ral OD column (0.2 % IPA/light petroleum ether, flow rate
6
(
(
2.5 Hz, 1 H), 2.92 (dt, J = 16.6, 2.5 Hz, 1 H), 2.78 (dt, J = 16.6,
2.5 Hz, 1 H), 2.07 (dt, J = 7.3, 6.9 Hz, 2 H), 1.53 (s, 3 H), 1.38–
1
.25 (m, 12 H), 0.88 (t, J = 6.4 Hz, 3 H) ppm. 13C NMR (50 MHz,
–1
0.5 mLmin , λ = 220 nm).
5] a) R. Aneja, A. P. Davis, P. Knaggs, Tetrahedron Lett. 1974, 15,
67–70; b) C. R. Haylock, L. D. Melton, K. N. Slessor, A. S.
Tracey, Carbohydr. Res. 1971, 16, 375–382; c) J. B. Lee, T. J.
Nolan, Can. J. Chem. 1966, 44, 1331.
CDCl
3
): δ = 169.53, 137.32, 135.41, 132.28, 129.73, 128.80, 122.19,
2.80, 40.90, 32.74, 31.94, 29.52, 29.32, 29.26, 29.18, 27.21, 22.72,
4.19 ppm. IR (liquid film, CHCl ): ν˜ = 1766, 1660, 1463, 1279,
(276.41): calcd. C 78.21, H 10.21; found
8
1
1
6] a) S. Takano, K. Samizu, T. Sugahara, K. Ugasawara, J. Chem.
Soc. Chem. Commun. 1989, 1344–1345; b) J. S. Yadav, P. K.
Deshpande, G. V. M. Sharma, Tetrahedron 1990, 46, 7033–
3
–1
28 2
105, 1051 cm . C18H O
C 78.36, H 10.42.
7046.
Supporting Information (see footnote on the first page of this arti-
[7] a) E. J. Corey, R. H. Wollenberg, J. Org. Chem. 1975, 40, 2265–
1
13
cle): H- and C-NMR spectra of all compounds.
2266; b) M. E. Jung, L. A. Light, Tetrahedron Lett. 1982, 23,
3851–3854.
[
[
8] Y.-L. Zhong, T. K. M. Shing, J. Org. Chem. 1997, 62, 2622–
Acknowledgments
2624.
9] a) K. Takai, K. Nitta, K. Utimoto, J. Am. Chem. Soc. 1986,
1
08, 7408–7410; b) T. Okazoe, K. Takai, K. Utimoto, J. Am.
C. P. thanks Council of Scientific and Industrial Research (CSIR),
New Delhi for the financial assistance in the form of a research
fellowship.
Chem. Soc. 1987, 109, 951–953; c) D. A. Evans, W. C. Black, J.
Am. Chem. Soc. 1993, 115, 4497–4513.
[
10] X. Han, B. M. Stoltz, E. J. Corey, J. Am. Chem. Soc. 1999, 121,
7
600–7605.
[
[
1] S. P. Gunasekara, R. A. Isbrucker, R. E. Longley, A. E.
[11] a) J. Schreiber, H. Maag, N. Hashimoto, A. Eschenmoser, An-
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6
Received: May 3, 2007
Published Online: August 7, 2007
Eur. J. Org. Chem. 2007, 5059–5063
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5063