Stereoselective total synthesis of pinolide and its C2 epimer and evaluation of their cytotoxic activity 1

Article abstract of DOI:10.1055/s-0034-1379709

Pinolide, a naturally occurring nonenolide and its C2 epimer have been synthesized using d-mannitol and 1,2-epoxyhex-5-ene as the starting materials. The synthesis involves the Jacobsen's hydrolytic kinetic resolution, Yamaguchi esterification, and intramolecular ring-closing metathesis as the key steps. The 2-epi-pinolide, the C2 epimer of pinolide, has been synthesized for the first time. The cytotoxic activity of the pinolide and 2-epi-pinolide has been studied.

Full text of DOI:10.1055/s-0034-1379709

SYNTHESIS
0
0
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9
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7
8
8
1
1
4
3
7
-
2
1
0
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 653–658
paper
653
P. Jangili et al.
Paper
Synthesis
Stereoselective Total Synthesis of Pinolide and Its C2 Epimer and
Evaluation of Their Cytotoxic Activity1
Paramesh Jangilia
C. Ganesh Kumarb
R
O
Y. Poornachandrab
Biswanath Das*a
R
OH
D-mannitol
O
R
HO
HO
R
S
2
R
O
1
a Natural Products Chemistry Division, CSIR-Indian Institute of
Chemical Technology, Hyderabad 500007, India
biswanathdas@yahoo.com
b Medicinal Chemistry and Pharmacology Division, CSIR-Indian
Institute of Chemical Technology, Hyderabad 500007, India
OH
O
OMOM
O
HO
pinolide: 2S
C-2 epimer: 2R
O
Received: 19.09.2014
Accepted after revision: 19.11.2014
Published online: 11.12.2014
6
HO
HO
HO
5
2
DOI: 10.1055/s-0034-1379709; Art ID: ss-2014-z0574-op
1
O
O
9
HO
OH
OH
O
O
Abstract Pinolide, a naturally occurring nonenolide and its C2 epimer
have been synthesized using D-mannitol and 1,2-epoxyhex-5-ene as
the starting materials. The synthesis involves the Jacobsen’s hydrolytic
kinetic resolution, Yamaguchi esterification, and intramolecular ring-
closing metathesis as the key steps. The 2-epi-pinolide, the C2 epimer
of pinolide, has been synthesized for the first time. The cytotoxic activi-
ty of the pinolide and 2-epi-pinolide has been studied.
(S)-1
(R)-1
Figure 1 Structures of pinolide [(2S)-1] and 2-epi-pinolide [(2R)-1]
In continuation of our work6 on the stereoselective con-
struction of natural products, we proposed that compound
(2S)-1 could be synthesized from the alcohol fragment 2
and the acid fragment (2S)-3 (Scheme 1). Similarly, (2R)-1
can be prepared from the same alcohol 2 and the enantio-
meric acid (2R)-3. The alcohol 2, in turn, can be prepared
from D-mannitol (4) and the acids (2S)-3 and (2R)-3 from
1,2-epoxyhex-5-ene (5).
The synthesis was initiated (Scheme 2) by converting D-
mannitol (4) into the known diol 6 following a reported
method.7 The diol 6 was then treated with dibutyltin oxide
and 4-toluenesulfonyl chloride in triethylamine and subse-
quently with methanolic potassium carbonate to afford the
epoxyalkene 7. The epoxide ring of 7 was then opened with
ethylmagnesium bromide using copper(I) iodide to produce
the required alcohol 2.
Key words pinolide, total synthesis, D-mannitol, 1,2-epoxyhex-5-ene
The ten-membered lactones (nonenolides) are com-
monly isolated from fungal sources.2 These compounds
contain interesting structural features with various stereo-
genic centers and different functionalities. They also pos-
sess important biological properties such as cytotoxic, anti-
bacterial, antifungal, and herbicidal activity.2,3 Pinolide
[(2S)-1], a ten-membered lactone, was isolated4 from the
liquid culture of isolate CO-99 of the fungus Didymella
pinodes, the causal agent of ascochyta blight on pea plants
(Pisum sativum). Herein, we report the stereoselective syn-
thesis of pinolide [(2S)-1] and 2-epi-pinolide [(2R)-1] (Fig-
ure 1); we also studied the cytotoxicity of both the epimers
(2S)-1 and [(2R)-1]. While our work was under progress a
synthesis of (2S)-1 was published using different starting
materials.5 However, the present work is the first report of
the synthesis of 2-epi-pinolide [(2R)-1]. The C2 epimers of
different natural nonenolides have been isolated4 from nat-
ural sources, but 2-epi-pinolide [(2R)-1] is naturally un-
known. This synthesis provides an access to both the epi-
mers (2S)-1 and (2R)-1 to examine and compare their dif-
ferent other biological properties.
The synthesis of the acid fragment (2S)-3 was achieved8
(Scheme 3) from the epoxide 5, which was subjected to hy-
drolytic kinetic resolution9 using Jacobsen’s (R,R)-
(Salen)Co(III) complex and acetic acid to generate the diol
(2S)-8 (96% ee). The diol (2S)-8 was treated with tert-bu-
tyldimethylsilyl chloride and imidazole to protect its pri-
mary hydroxy group as the tert-butyldimethylsilyl ether
(2S)-9. The secondary hydroxy group of (2S)-9 was subse-
quently protected as methoxymethyl (MOM) ether (2S)-10
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 653–658

654
P. Jangili et al.
Paper
Synthesis
HO
HO
by reaction with methoxymethyl bromide and diisopropyl-
ethylamine. Compound (2S)-10 was converted into the de-
sired acid (2S)-3 by treatment with tetrabutylammonium
fluoride to produce the primary alcohol (2S)-11 which was
next oxidized10 with (diacetoxyiodo)benzene and 2,2,6,6-
tetramethylpiperidin-1-yloxyl in acetonitrile–water (2:1).
The enantiomeric acid (2R)-3 was also prepared8 from
the same epoxide 5 (Scheme 3). The latter underwent hy-
drolytic kinetic resolution9 with Jacobsen’s (S,S)-
(Salen)Co(III) complex and acetic acid to furnish the diol
(2R)-8 (96% ee). The diol (2R)-8 was then converted into the
acid (2R)-3 following the similar methods described above,
that is, (i) protection of the primary hydroxy group of (2R)-
8 as TBS ether (2R)-9; (ii) protection of the secondary hy-
droxy group of (2R)-9 as MOM ether (2R)-10; (iii) deprotec-
tion of TBS ether group of (2R)-10 to primary alcohol (2R)-
11, and (iv) oxidation of primary hydroxy group of (2R)-11
to the acid (2R)-3.
2
1
O
OH
O
(2S)-1
(2R)-1
O
O
+
OH
HO
OMOM
O
(2S)-3
(2R)-3
2
O
The alcohol fragment 2 was coupled (Scheme 4) with
the acid fragments (2S)-3 and (2R)-3 separately using 2,4,6-
trichlorobenzoyl chloride, triethylamine, and 4-(dimethyl-
amino)pyridine under the Yamaguchi esterification proto-
col11 to produce the esters (2S)-12 and (2R)-12, respective-
ly. These two esters underwent intramolecular ring-closing
metathesis12 in the presence of Grubbs II catalyst (Figure 2)
to produce the cyclic esters (2S)-13 [from (2S)-12] and (2R)-
13 [from (2R)-12]. Next, the compounds (2S)-13 and (2R)-
13 were subjected to treatment with 4 M hydrochloric acid
in acetonitrile to furnish the desired products, pinolide
[(2S)-1] and 2-epi-pinolide [(2R)-1], respectively. The physi-
cal (optical rotation) and the spectral (1H and 13C NMR and
MS) properties of (2S)-1 were found to be identical to those
reported for the naturally occurring compound.4
The two compounds, pinolide and 2-epi-pinolide were
examined for in vitro cytotoxicity against a panel of three
cancer cell lines: MDA-MB-231 (human breast adenocarci-
noma), HepG2 (human liver carcinoma), and COLO205 (hu-
man colon carcinoma). Doxorubicin was used as the posi-
tive control. MTT assay (according to the method of
Mosmann13) was applied to assess the cytotoxic activity of
D-mannitol
1,2-epoxyhex-5-ene
4
5
Scheme 1 Retrosynthetic analysis of pinolide [(2S)-1] and 2-epi-pino-
lide [(2R)-1]
O
O
O
O
b
a
D-mannitol
HO
OH
O
4
6
7
O
O
O
c
OH
O
OH
2
Scheme 2 Synthesis of the alcohol fragment 2. Reagents and condi-
tions: (a) ref. 7; (b) (i) Bu2SnO, TsCl, Et3N, CH2Cl2, r.t., 30 min; (ii) K2CO3,
MeOH, r.t., 1 h, 75%; (c) EtMgBr, CuI, –20 °C to r.t., 84%.
OR2
d [for (2S)-8]
e [for (2R)-8]
OMOM
i
R1O
O
HO
(2S)-8, (2R)-8 R1 = R2 = H
5
O
f
(2S)-9, (2R)-9 R1 = TBS, R2 = H
(2S)-10, (2R)-10 R1 = TBS, R2 = MOM
(2S)-11, (2R)-11 R1 = H, R2 = MOM
g
h
HO
OMOM
O
(2S)-3, (2R)-3
Scheme 3 Synthesis of the acid fragments (2S)-3 and (2R)-3. Reagents and conditions: (d) (R,R)-(salen)Co(III)OAc (0.5 mol%), distilled H2O (0.45 equiv),
AcOH, THF, 0 °C, 24 h, 46% (96% ee); (e) (S,S)-(salen)Co(III)OAc (0.5 mol%), distilled H2O (0.45 equiv), AcOH, THF, 0 °C, 24 h, 46% (96% ee); (f) TBSCl,
imidazole, THF, r.t., 96%; (g) MOMBr, i-Pr2NEt, CH2Cl2, 45 °C, 100%; (h) TBAF, THF, 0 °C–r.t., 100%; (i) PhI(OAc)2, TEMPO, MeCN–H2O (2:1), r.t., 3 h; 84%.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 653–658

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Synthesis
In conclusion, we have developed a stereoselective total
synthesis of the natural nonenolide, pinolide and its C2 epi-
mer. The synthesis utilized D-mannitol and 1,2-epoxyhex-
5-ene as the starting materials with Jacobsen’s hydrolytic
kinetic resolution, Yamaguchi esterification, and intramo-
lecular ring-closing metathesis as the key steps. This is the
first report of the synthesis of 2-epi-pinolide. The cytotoxic
activity of the synthetic compounds pinolide [(2S)-1] and
2-epi-pinolide [(2R)-1] was evaluated.
j [for (2S)-12]
k [for (2R)-12]
O
O
O
O
l
O
OH
OMOM
O
2
(2S)-12 [from (2S)-3]
(2R)-12 [from (2R)-3]
HO
O
O
m
O
O
NMR spectra were recorded on Gemini 500 MHz and 300 MHz spec-
trometers using CDCl3 as solvent and TMS as internal standard. ESI-
MS were recorded with VG-Autospec micromass. Optical rotations
were measured with a Jasco DIP 360 digital polarimeter. All reactions
were monitored by TLC using silica gel F254 pre-coated plates. Column
chromatography was carried out using silica gel 60–120 mesh (Qing-
dao Marine Chemical, China); PE = petroleum ether.
OMOM
HO
OH
O
O
(2S)-13 [from (2S)-12]
(2R)-13 [from (2R)-12]
(2S)-1 [from (2S)-13]
(2R)-1 [from (2R)-13]
Scheme 4 Coupling of the fragments 2 and (2S)-3, 2 and (2R)-3. Re-
agents and conditions: (j) (2S)-3, 2,4,6-trichlorobenzoyl chloride, Et3N,
DMAP, THF, r.t., 93%; (k) (2R)-3, 2,4,6-trichlorobenzoyl chloride, Et3N,
DMAP, THF, r.t., 91%; (l) Grubbs II catalyst, CH2Cl2, 50 °C, 83%; (m) 4 M
HCl, MeCN, 0 °C to r.t., 8 h, 90%.
(4S,5R)-2,2-Dimethyl-4-[(R)-oxiran-2-yl]-5-vinyl-1,3-dioxolane (7)
To a stirred solution of 6 (1 g, 5.31 mmol) in CH2Cl2 (20 mL), Et3N
(1.48 mL, 10.62 mmol) and Bu2SnO (27.0 mg, 0.10 mmol) were added.
After 5 min, TsCl (1.11 g, 5.84 mmol) was added and the mixture was
stirred for 30 min. The mixture was diluted with CH2Cl2 (10 mL),
washed with H2O (2 × 10 mL) and brine (10 mL), and dried (Na2SO4).
The organic layer was evaporated under reduced pressure and the
residue purified by column chromatography (silica gel, 10% EtOAc–
PE) to give the tosylate as a colorless liquid which was used directly in
the next step.
N
N
Cl
Ru
Cl
Ph
P(Cy)3
A solution of tosylate in MeOH (10 mL) was treated with K2CO3 (1.62
g, 11.78 mmol) and stirred at r.t. for 1 h. The mixture was treated with
aq NH4Cl solution (5 mL). The MeOH was evaporated under reduced
pressure and the residue was extracted with Et2O (3 × 10 mL). The
combined organic layers were washed with H2O (75 mL) and brine
(75 mL), dried (Na2SO4), and evaporated. The residue was purified by
column chromatography (silica gel, 10% EtOAc–PE) to furnish 7 (0.68
g, 75%) as a colorless liquid. [α]D25 –3.1 (c 0.2, CHCl3).
A
Grubbs II catalyst
Figure 2
the two compounds. IC50 values (in μM) are indicated as the
mean ± SD of three independent experiments depicted in
Table 1. The results showed that both the compounds ex-
hibited significant cytotoxic activity against all the three
cancer cell lines. However, pinolide and 2-epi-pinolide ex-
hibited promising activity against MDA-MB-231 cell line
(IC50 values are 9.8 and 11.2 μM, respectively), and good cy-
totoxicity against HepG2 and COLO205 cell lines.
IR (KBr): 2923, 2852, 1597, 1373, 1257, 1177, 1079, 874 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 5.87 (m, 1 H), 5.44 (d, J = 16.0 Hz, 1 H),
5.30 (d, J = 9.0 Hz, 1 H), 4.38 (t, J = 7.0 Hz, 1 H), 3.62 (dd, J = 7.0, 5.0 Hz,
1 H), 3.10 (m, 1 H), 2.83 (m, 1 H), 2.72 (m, 1 H), 1.46 (s, 3 H), 1.44 (s, 3
H).
13C NMR (75 MHz, CDCl3): δ = 134.9, 119.0, 109.7, 80.1, 80.0, 51.2,
44.7, 26.8, 26.6.
MS (ESI): m/z = 171 [M + H]+.
Anal. Calcd for C9H14O3: C, 63.51; H, 8.29. Found: C, 63.42; H, 8.33.
Table 1 Cytotoxicity of Pinolide and 2-epi-Pinolide Against Human
Cancer Cell Lines
(R)-1-[(4R,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)butan-1-ol
(2)
Cell line
IC50 (μM)
A suspension of EtMgBr in THF (30 mL) was prepared from EtBr (0.79
mL, 10.59 mmol) and Mg (0.343 g, 14.12 mmol) in the usual manner.
The suspension was cooled (–20 °C) and CuI (1.0 g, 5.29 mmol) was
added. The mixture was stirred at –20 °C for 15 min. To this cooled
organometallic suspension, a solution of epoxide 7 (0.60 g, 3.53
mmol) in THF (20 mL) was added. The mixture was stirred at this
temperature for 1 h and then gradually brought to r.t. and stirred
overnight. The reaction was quenched by the addition of aq sat. NH4Cl
(10 mL) and extracted with EtOAc. The combined organic layers were
Pinolide [(2S)-1] 2-epi-Pinolide [(2R)-1] Doxorubicin
MDA-MB-231
Hep G2
9.8 ± 0.31
13.2 ± 0.26
15.8 ± 0.14
11.2 ± 0.28
15.2 ± 0.12
14.1 ± 0.22
0.7 ± 0.16
0.6 ± 0.11
0.7 ± 0.09
COLO205
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Synthesis
washed with 5% aq HCl, H2O, and brine and then dried (Na2SO4). Sol-
vent removal under reduced pressure gave a residue that was purified
by column chromatography (silica gel, 0–10% EtOAc–hexane) to af-
ford pure 2 (0.59 g, 84%) as a colorless liquid. [α]D25 +7.1 (c 0.3, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 5.81 (m, 1 H), 5.08–4.91 (m, 2 H), 4.79
(d, J = 7.0 Hz, 1 H), 4.65 (d, J = 7.0 Hz, 1 H), 3.68–3.53 (m, 3 H), 3.39 (s,
3 H) 2.22–2.02 (m, 2 H), 1.69–1.50 (m, 2 H), 0.88 (s, 9 H), 0.02 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 138.9, 115.0, 96.5, 78.0, 65.9, 55.8, 31.1,
1H NMR (300 MHz, CDCl3): δ = 5.78 (m, 1 H), 5.32 (d, J = 16.0 Hz, 1 H),
5.18 (d, J = 9.0 Hz, 1 H), 4.37 (t, J = 7.0 Hz, 1 H), 3.81–3.77 (m, 2 H) 3.64
(dd, J = 7.0, 4.0 Hz, 1 H), 1.50–1.41 (m, 2 H), 1.33 (s, 3 H), 1.31 (s, 3 H),
1.30–1.24 (m, 2 H), 0.82 (t, J = 7.0 Hz, 3 H).
29.8, 26.0, 18.1, –5.2.
MS (ESI): m/z = 275 [M + H]+.
Anal. Calcd C14H30O3Si: C, 61.26; H, 11.02. Found: C, 61.37; H, 11.00.
13C NMR (75 MHz, CDCl3): δ = 136.8, 118.8, 108.7, 83.1, 77.3, 70.1,
34.5, 27.0, 19.1, 13.9.
(S)-2-(Methoxymethoxy)hex-5-en-1-ol [(S)-11]
To a solution of 10 (0.8 g, 2.90 mmol) in THF (10 mL) at 0 °C, was add-
ed 1 M TBAF in THF (3.5 mL). The mixture was stirred for 2 h at r.t.
and then it was diluted with EtOAc and the solution was washed with
H2O (10 mL) and brine (10 mL), dried (Na2SO4), and concentrated un-
der reduced pressure. The residue was purified by column chroma-
tography (silica gel, hexane–EtOAc, 5:2) to give (S)-11 (0.47 g, 100%)
as a colorless liquid. [α]D25 +40.9 (c 0.25, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 5.78 (m, 1 H), 5.08–4.92 (m, 2 H), 4.71
(d, J = 7.0 Hz, 1 H), 4.62 (d, J = 7.0 Hz, 1 H), 3.61–3.48 (m, 3 H), 3.42 (s,
3 H), 3.09 (br s, 1 H), 2.20–2.05 (m, 2 H), 1.68–1.48 (m, 2 H).
MS (ESI): m/z = 223 [M + Na]+.
Anal. Calcd for C11H20O3: C, 65.97; H, 10.07. Found: C, 66.09; H, 10.03.
(S)-Hex-5-ene-1,2-diol [(S)-8]
The catalyst (R,R)-(salen)Co(III)OAc (32 mg, 51 μmol, 0.005 equiv)
was dissolved in (±)-1,2-epoxyhex-5-ene (5, 1.15 mL, 1 g, 10.20
mmol), AcOH (12 μL, 0.21 mmol, 0.02 equiv), and THF (0.5 mL). The
solution was cooled to 0 °C and H2O (0.082 mL, 4.59 mmol, 0.45
equiv) was added in 1 portion. After 24 h, the residual epoxide was
isolated by vacuum transfer into a cooled (–78 °C) receiving flask and
(S)-hex-5-ene-1,2-diol [(S)-8, 0.55 g, 46%] was distilled under re-
duced pressure; 96% ee (chiral chromatography). [α]D25–14.0 (c 0.3,
CHCl3).
13C NMR (75 MHz, CDCl3): δ = 138.1, 115.2, 97.0, 81.3, 65.5, 55.8, 31.0,
29.9.
MS (ESI): m/z = 183 [M + Na]+.
Anal. Calcd for C8H16O3: C, 59.97; H, 10.07. Found: C, 59.86; H, 10.10.
IR (KBr): 3431, 2932, 1640, 1417, 1059 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 5.82 (m, 1 H), 5.11–4.95 (m, 2 H), 3.78–
3.60 (m, 4 H), 3.43 (m, 1 H), 2.28–2.03 (m, 2 H), 1.57–1.42 (m, 2 H).
(S)-2-(Methoxymethoxy)hex-5-enoic Acid [(S)-3]
To a solution of 11 (0.4 g, 2.50 mmol) in MeCN–H2O (2:1, 10 mL) were
added PhI(OAc)2 (1.77 g, 5.50 mmol) and TEMPO (78 mg, 0.50 mmol);
the mixture was stirred at r.t. for 3 h. When the reaction was com-
plete (TLC), the mixture was filtered and extracted with EtOAc (2 × 20
mL). The combined organic phases were dried and concentrated un-
der reduced pressure. The crude residue was purified by column
chromatography (silica gel, hexane–EtOAc 7:3) to give pure (S)-3
(0.36 g, 84%) as a pale yellow liquid. [α]D25 –56.6 (c 0.1, CHCl3).
13C NMR (75 MHz, CDCl3): δ = 138.8, 115.0, 71.4, 66.0, 32.6, 29.9.
MS (ESI): m/z = 139 [M + Na]+.
Anal. Calcd for C6H12O2: C, 62.04; H, 10.41. Found: C, 62.18; H, 10.38.
(S)-1-(tert-Butyldimethylsiloxy)hex-5-en-2-ol [(S)-9]
A mixture of (S)-hex-5-ene-1,2-diol [(S)-8, 0.5 g, 4.31 mmol], TBSCl
(0.65 g, 4.31 mmol), and imidazole (0.29 g, 4.31 mmol) in THF (20 mL)
was stirred for 2 h at r.t. The white precipitate was removed by filtra-
tion and washed with Et2O (30 mL). The combined filtrates were con-
centrated and purified by flash column chromatography (PE–EtOAc,
IR (KBr): 3438, 2925, 2853, 1734, 1640, 1444, 1214, 1036 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 9.48 (br s, 1 H), 5.81 (m, 1 H), 5.16–
4.98 (m, 2 H), 4.76 (d, J = 7.0 Hz, 1 H), 4.68 (d, J = 7.0 Hz, 1 H), 4.17 (t,
J = 7.0 Hz, 1 H), 3.40 (s, 3 H), 2.26–2.19 (m, 2 H), 1.98–1.84 (m, 2 H).
25
10:1) to give (S)-9 (0.95 g, 96%) as a colorless oil. [α]D +4.0 (c 0.2,
CHCl3).
13C NMR (75 MHz, CDCl3): δ = 178.3, 137.5, 116.0, 96.4, 75.0, 56.2,
32.1, 29.2.
MS (ESI): m/z = 197 [M + Na]+.
1H NMR (300 MHz, CDCl3): δ = 5.81 (m, 1 H), 5.10–4.92 (m, 2 H), 3.70–
3.60 (m, 2 H), 3.42 (m, 1 H), 2.26–2.10 (m, 2 H), 1.59–1.47 (m, 2 H),
0.91 (s, 9 H), 0.10 (s, 6 H).
Anal. Calcd for C8H14O4: C, 55.16; H, 8.10. Found: C, 55.26; H, 8.05.
13C NMR (75 MHz, CDCl3): δ = 138.8, 115.0, 71.2, 67.2, 32.0, 30.0, 26.1,
18.1, –5.2.
MS (ESI): m/z = 253 [M + Na]+.
(R)-1-[(4R,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl]butyl (S)-2-
(Methoxymethoxy)hex-5-enoate [(2S)-12]; Typical Procedure
Anal. Calcd for C12H26O2Si: C, 62.55; H, 11.37. Found: C, 62.43; H,
11.42.
To a stirred solution of acid (S)-3 (87 mg, 0.5 mmol) in anhyd THF (5
mL) were added 2,4,6-trichlorobenzoyl chloride (0.094 mL, 0.6 mmol)
and Et3N (0.35 mL, 2.5 mmol), and the contents were stirred at r.t.
When the formation of the mixed anhydride was complete (indicated
by TLC), DMAP (122 mg, 1.0 mmol) and a solution of alcohol 2 (100
mg, 0.5 mmol) in toluene (5 mL) were added and the mixture was
stirred for 3 h at r.t. The reaction was quenched by the addition of H2O
and extracted with EtOAc (3 × 10 mL). The combined organic phases
were washed with sat. NaHCO3 (10 mL) and brine (10 mL), dried
(Na2SO4), and evaporated under reduced pressure. The crude residue
was purified by column chromatography (silica gel, 100–200 mesh,
10% EtOAc–hexane) to afford (2S)-12 (165 mg, 93%) as a colorless liq-
uid. [α]D25 –22.0 (c 0.2, CHCl3).
(S)-5-(But-3-enyl)-8,8,9,9-tetramethyl-2,4,7-trioxa-8-siladecane
[(S)-10]
(S)-1-(tert-Butyldimethylsiloxy)hex-5-en-2-ol [(S)-9, 0.8 g, 3.48
mmol] was dissolved in CH2Cl2 (20 mL) and cooled to 0 °C. i-Pr2NEt
(1.82 mL, 10.40 mmol) was added followed by MOMBr (0.58 mL, 7.10
mmol). The solution was stirred at 0 °C for 0.5 h and then heated un-
der reflux overnight. The mixture was cooled to r.t., acidified with 1
M HCl (10 mL), and extracted with CH2Cl2 (3 × 20 mL). The combined
organic extracts were dried (MgSO4) and the filtrate concentrated in
vacuo. Flash column chromatography (EtOAc–PE, 1:20) yielded (S)-10
(0.95 g, 100%) as a colorless oil. [α]D25 –56.9 (c 0.25, CHCl3).
IR (KBr): 2922, 2852, 1748, 1455, 1256, 1037 cm–1
.
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1H NMR (500 MHz, CDCl3): δ = 5.83 (m, 2 H), 5.40 (d, J = 17.0 Hz, 1 H),
5.27 (d, J = 9.0 Hz, 1 H), 5.19 (m, 1 H), 5.09–4.99 (m, 2 H), 4.69 (d, J =
7.0 Hz, 1 H), 4.65 (d, J = 7.0 Hz, 1 H), 4.30 (t, J = 7.0 Hz, 1 H), 4.13 (dd,
J = 7.0, 5.0 Hz, 1 H), 3.81 (dd, J = 7.0, 6.0 Hz, 1 H), 3.39 (s, 3 H), 2.25–
2.19 (m, 2 H), 1.92–1.80 (m, 2 H), 1.70–1.59 (m, 2 H), 1.41 (s, 6 H),
1.38–1.24 (m, 2 H), 0.92 (t, J = 7.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 172.0, 137.2, 135.8, 118.9, 115.5,
109.4, 96.0, 81.1, 79.4, 74.5, 73.2, 56.0, 33.0, 32.2, 29.4, 26.9, 26.8,
18.4, 13.8.
(R)-1-[(4R,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl]butyl (R)-2-
(Methoxymethoxy)hex-5-enoate [(2R)-12]
Following the typical procedure for (2S)-12 using (2R)-3a (87 mg, 0.5
mmol), anhyd THF (5 mL), 2,4,6-trichlorobenzoyl chloride (0.094 mL,
0.6 mmol), and Et3N (0.35 mL, 2.5 mmol), followed by DMAP (122 mg,
1.0 mmol) and alcohol 2 (100 mg, 0.5 mmol) in toluene (5 mL) afford-
25
ed (2R)-12 (162 mg, 91%) as a colorless liquid. [α]D +5.0 (c 0.1,
CHCl3).
IR (KBr): 2921, 1624, 1384, 1216, 770 cm–1
.
MS (ESI): m/z = 357 [M + H]+.
1H NMR (500 MHz, CDCl3): δ = 5.82 (m, 2 H), 5.40 (d, J = 17.0 Hz, 1 H),
5.27 (d, J = 9.0 Hz, 1 H), 5.18 (m, 1 H), 5.10–4.98 (m, 2 H), 4.70 (d, J =
7.0 Hz, 1 H), 4.65 (d, J = 7.0 Hz, 1 H), 4.31 (t, J = 7.0 Hz, 1 H), 4.12 (dd,
J = 7.0, 5.0 Hz, 1 H), 3.83 (dd, J = 7.0, 6.0 Hz, 1 H), 3.39 (s, 3 H), 2.27–
2.16 (m, 2 H), 1.89–1.79 (m, 2 H), 1.69–1.52 (m, 2 H), 1.41 (s, 3 H),
1.40 (s, 3 H), 1.32–1.20 (m, 2 H), 0.92 (t, J = 7.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 172.1, 137.2, 135.8, 119.2, 115.5,
109.2, 96.2, 81.1, 79.1, 74.9, 73.0, 56.1, 32.7, 32.1, 29.4, 26.9, 26.8,
18.5, 13.9.
Anal. Calcd for C19H32O6: C, 64.02; H, 9.05. Found: C, 63.91; H, 9.10.
(3aR,4R,7S,11aR,E)-7-(Methoxymethoxy)-2,2-dimethyl-4-propyl-
3a,4,7,8,9,11a-tetrahydro-6H-[1,3]dioxolo[4,5-c]oxecin-6-one
[(2S)-13]; Typical Procedure
To a solution of (2S)-12 (100 mg, 0.28 mmol) in degassed anhyd
CH2Cl2 (75 mL) was added Grubbs II catalyst (43 mg, 0.05 mmol) and
the mixture was heated at 50 °C under an argon flow for 12 h. When
the reaction was complete (TLC), most of the solvent was evaporated
and then air was bubbled to decompose the catalyst. The remaining
solvent was evaporated under reduced pressure to afford a dark
brown oily residue that was quickly passed through a short silica gel
column (20% EtOAc–hexane) to give (2S)-13 (76 mg, 83%) as a color-
less liquid. [α]D25 +6.5 (c 0.2, CHCl3).
MS (ESI): m/z = 357 [M + H]+.
Anal. Calcd for C19H32O6: C, 64.02; H, 9.05. Found: C, 63.92; H, 9.08.
(3aR,4R,7R,11aR,E)-7-(Methoxymethoxy)-2,2-dimethyl-4-propyl-
3a,4,7,8,9,11a-tetrahydro-6H-[1,3]dioxolo[4,5-c]oxecin-6-one
[(2R)-13]
IR (KBr): 2924, 1620, 1384, 1260, 1023, 799 cm–1
.
Following the typical procedure for (2S)-13 using (2R)-12 (80 mg,
0.22 mmol) in degassed anhyd CH2Cl2 (75 mL) and Grubbs II catalyst
(34 mg, 0.04 mmol) gave (2R)-13 (61 mg, 83%) as a colorless liquid.
[α]D25 +4.3 (c 0.2, CHCl3).
1H NMR (500 MHz, CDCl3): δ = 5.65 (ddd, J = 15.0, 10.0, 4.0 Hz, 1 H),
5.57 (dd, J = 15.0, 10.0 Hz, 1 H), 5.17 (td, J = 8.0, 2.0 Hz, 1 H), 4.69 (d,
J = 7.0 Hz, 1 H), 4.67 (d, J = 7.0 Hz, 1 H), 4.28 (dd, J = 7.0, 2.0 Hz, 1 H),
4.01 (t, J = 8.0 Hz, 1 H), 3.49 (dd, J = 10.0, 8.0 Hz, 1 H), 3.40 (s, 3 H),
2.41 (m, 1 H), 2.21–2.14 (m, 2 H), 2.03 (m, 1 H), 1.81 (m, 1 H), 1.67–
1.58 (m, 3 H), 1.42 (s, 3 H), 1.39 (s, 3 H), 0.93 (t, J = 7.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 173.2, 136.0, 128.8, 108.7, 95.6, 82.1,
79.4, 73.6, 72.7, 55.7, 34.1, 31.8, 27.2, 26.9, 26.8, 17.9, 13.7.
MS (ESI): m/z = 329 [M + H]+.
IR (KBr): 2925, 1749, 1650, 1458, 1380, 1049, 873 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 5.61 (ddd, J = 15.0, 10.0, 4.0 Hz, 1 H),
5.47 (ddd, J = 15.0, 10.0, 2.0 Hz, 1 H), 5.02 (td, J = 8.0, 4.0 Hz, 1 H), 4.68
(d, J = 7.0 Hz, 1 H), 4.61 (d, J = 7.0 Hz, 1 H), 4.55 (dd, J = 8.0, 7.0 Hz, 1
H), 3.94 (dd, J = 10.0, 8.0 Hz, 1 H), 3.56 (t, J = 10.0 Hz, 1 H), 3.33 (s, 3
H), 2.29 (m, 1 H), 2.18 (m, 1 H), 2.04 (m, 1 H), 1.93 (m, 1 H), 1.84 (m, 1
H), 1.65–1.56 (m, 3 H), 1.42 (s, 3 H), 1.40 (s, 3 H), 0.94 (t, J = 7.0 Hz, 3
H).
Anal. Calcd for C17H28O6: C, 62.17; H, 8.59. Found: C, 62.09; H, 8.57.
Pinolide [(2S)-1]; Typical Procedure
13C NMR (125 MHz, CDCl3): δ = 171.7, 132.0, 129.2, 109.7, 96.8, 80.0,
76.7, 76.6, 76.1, 56.0, 35.5, 30.3, 27.1, 26.8, 23.8, 17.8, 13.9.
MS (ESI): m/z = 329 [M + H]+.
To a solution of compound (2S)-12 (50 mg, 0.15 mmol) in MeCN (10
mL), 4 M aq HCl (1 mL) was added at 0 °C; the mixture was stirred for
8 h at r.t. The mixture was neutralized with aq NaHCO3 (5 mL) and
extracted with EtOAc. The combined organic extracts were washed
with brine and dried (Na2SO4). Evaporation of the solvent followed by
purification of the residue by chromatography (50% hexane–EtOAc)
provided pure pinolide [(2S)-1], 33 mg, 90%] as a white solid. [α]D
–9.8 (c 0.2, CHCl3).
1H NMR (500 MHz, CDCl3): δ = 5.56–5.53 (m, 2 H), 5.01 (td, J = 9.0, 2.5
Hz, 1 H), 4.37 (dd, J = 5.0, 2.5 Hz, 1 H), 3.84 (br t, J = 9.0 Hz, 1 H), 3.45
(t, J = 9.0 Hz, 1 H), 2.92 (br s, 1 H), 2.48–2.38 (m, 2 H), 2.16–1.88 (m, 3
H), 1.73–1.55 (m, 1 H), 1.44–1.25 (m, 2 H), 0.94 (t, J = 7.0 Hz, 3 H).
Anal. Calcd for C17H28O6: C, 62.17; H, 8.59. Found: C, 62.25; H, 8.55.
2-epi-Pinolide [(2R)-1]
25
Following the typical procedure for (2S)-1 using (2R)-12 (30 mg, 0.09
mmol) in MeCN (5 mL) and 4 M aq HCl (0.5 mL) gave (2R)-1 (20 mg,
90%) as a white solid. [α]D25 –6.0 (c 0.25, CD3OD).
IR (KBr): 3496, 2921, 2851, 1715, 1459, 1383, 1219, 1080 cm–1
1H NMR (500 MHz, CD3OD): δ = 5.51–5.30 (m, 2 H), 4.24–4.01 (m, 2
H), 3.67 (br t, J = 9.0 Hz, 1 H), 3.55 (br t, J = 9.0 Hz, 1 H), 2.22–2.13 (m,
2 H), 2.03 (m, 1 H), 1.91 (m, 1 H), 1.75–1.54 (m, 2 H), 1.39–1.26 (m, 2
H), 0.93 (t, J = 7.0 Hz, 3 H).
13C NMR (125 MHz, CD3OD): δ = 175.2, 133.5, 130.1, 77.5, 74.2, 71.6,
70.4, 36.2, 32.8, 25.1, 18.9, 14.4.
MS (ESI): m/z = 245 [M + H]+.
.
13C NMR (125 MHz, CDCl3): δ = 173.2, 132.7, 132.1, 77.0, 74.4, 74.3,
69.8, 33.5, 31.3, 26.6, 17.8, 13.8.
MS (ESI): m/z = 245 [M + H]+.
Anal. Calcd for C12H20O5: C, 59.00; H, 8.25. Found: C, 58.91; H, 8.28.
Anal. Calcd for C12H20O5: C, 59.00; H, 8.25. Found: C, 58.91; H, 8.30.
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Acknowledgment
(4) Cimmino, A.; Andolfi, A.; Fondevilla, S.; Abouzeid, M. A.;
Rubiales, D.; Evidente, A. J. Agric. Food Chem. 2012, 60, 5273.
(5) Yadav, J. S.; Avuluri, S.; Kattela, S. S.; Das, S. Eur. J. Org. Chem.
2013, 6967.
(6) (a) Reddy, P. R.; Lingaiah, M.; Das, B. Synlett 2014, 25, 975.
(b) Maram, L.; Das, B. Synthesis 2014, 46, 1205. (c) Reddy, C. R.;
Das, B. Tetrahedron Lett. 2014, 55, 67.
(7) Yadav, V. K.; Agarwal, D. Chem. Commun. 2007, 5232.
(8) Jangili, P.; Kashanna, J.; Kumar, G. C.; Poornachandra, Y.; Das, B.
Bioorg. Med. Chem. Lett. 2014, 24, 325.
(9) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen,
K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc.
2002, 124, 1307.
The authors thank CSIR and UGC, New Delhi for financial assistance.
They are also thankful to NMR, Mass and IR divisions of CSIR-IICT for
spectral recording.
References and notes
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 653–658