Total synthesis of (+)-synargentolide A

Article abstract of DOI:10.1016/j.tetasy.2012.06.021

The highly stereoselective total synthesis of polyacetate α,β-unsaturated δ-lactone natural product (+)-synargentolide A has been accomplished from inexpensive d-1,5-gluconolactone. Key reactions involved in the synthesis are hydroboration, Wittig olefination, Brown's asymmetric allylation, and a ring closing metathesis reaction. 2012 Elsevier Ltd.

Full text of DOI:10.1016/j.tetasy.2012.06.021

Tetrahedron: Asymmetry 23 (2012) 931–937
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Tetrahedron: Asymmetry
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Total synthesis of (+)-synargentolide A
⇑
J. S. Yadav , B. Thirupathaiah, Vinay K. Singh, V. Ravishashidhar
Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 April 2012
Accepted 13 June 2012
The highly stereoselective total synthesis of polyacetate
synargentolide A has been accomplished from inexpensive
in the synthesis are hydroboration, Wittig olefination, Brown’s asymmetric allylation, and a ring closing
a
,b-unsaturated d-lactone natural product (+)-
-1,5-gluconolactone. Key reactions involved
D
metathesis reaction.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
OAc
OAc
The polyacetate a,b-unsaturated d-lactone ring containing nat-
ural products displays a wide range of biological activities.1 Among
them (+)-synargentolide A 1,2 hyptolide 2,3 spicigerolide 3,4 ana-
marine 4,5 and synrotolide 5,6 were isolated from Syncolostemon
and Hyptis species (Fig. 1) and exhibit cytotoxicity against human
tumor cells, as well as antifungal and antimicrobial activity.7 Due
to their biological activities, these molecules have become interest-
ing synthetic targets for chemists.1c,8 (+)-Synargentolide A can be
isolated from the extracts of Syncolostemon argenteus; the structure
was proposed to be 1b by Davies–Coleman and Rivett2 on the basis
of extensive spectroscopic analysis, but has recently been revised
to be 1a.9 To date, five total syntheses have been reported in the
literature.9,10
OAc OAc
O
OAc OAc
O
O
O
published structure of
revised structure of
synargentolide A 1b
synargentolide A 1a
OAc OAc
OAc OAc
O
O
O
O
OAc
OAc OAc
spicigerolide 3
hyptolide 2
As part of our ongoing research program on the total synthesis
of biologically active lactone containing natural products,11 we
herein report an efficient stereoselective total synthesis of (+)-
synargentolide A from the inexpensive and readily available start-
OAc OAc
OAc OAc
ing material D-1,5-gluconolactone.
O
O
OAc OAc
O
2. Results and discussion
OAc OAc
O
Our retrosynthetic analysis revealed that the target molecule 1a
(Scheme 1) could be obtained via deprotection followed by acyla-
tion of 6, which in turn can be prepared from 7 by acryloylation fol-
lowed by ring-closing metathesis. Compound 7 is accessible from 8
via DIBAL-H reduction, oxidation, and Brown’s asymmetric allyla-
tion. Compound 8 could be constructed by a sequence of reactions
from olefin 9, which in turn could be obtained from the chiral pool
anamarine 4
Figure 1. Polyacetate
synrotolide 5
a
,b-unsaturated d-lactone natural products.
for 1 h to give olefin 9. Compound 9 was subjected to hydrobora-
tion using 9-BBN13c,14 to furnish the primary alcohol 11 in 78%
yield. The primary hydroxy group of compound 11 was protected
as the benzyl ether in the presence of NaH, BnBr, and cat TBAI in
anhydrous THF to afford 12 in 95% yield. Selective deprotection
of the terminal acetonide with PPTS in methanol furnished diol
13. The primary alcohol was converted into the corresponding tos-
ylate and treated with LiAlH4 to give 14 in 85% yield over two
steps. The secondary alcohol of compound 14 was protected as
starting material D-1,5-gluconolactone.
Our synthesis started with
D-1,5-gluconolactone, which was
converted to diol 10 by known protocol.12 Diol 10 was subjected
to reductive elimination13 with iodine-PPh3-imidazole at reflux
⇑
Corresponding author. Tel.: +91 40 27193030; fax: +91 40 27160387.
E-mail addresses: yadavpub@iict.res.in, yadav@iict.res.in (J.S. Yadav).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.06.021

932
J. S. Yadav et al. / Tetrahedron: Asymmetry 23 (2012) 931–937
OAc
O
OAc OAc
O
TBSO
O
O
O
6
O
(+)-synargentolide A 1a
O
O
OEt
TBSO
HO
O
O
TBSO
O
O
H
O
7
8
O
O
O
O
HO
OH
O
OH
D-1,5-gluconolactone
9
Scheme 1. Retrosynthetic analysis of (+)-synargentolide A.
O
O
O
OH
2 steps
HO
TPP, imidazole, I2
OH
O
THF, reflux, 1 h 80%
HO
OH Ref 11
O
O
OH
10
D-1,5-gluconolactone
O
O
9-BBN, THF
rt, 6 h, 78%
OH
O
O
O
O
O
O
11
9
O
PPTS, MeOH
rt, 5 h, 77%
OBn
NaH, Bn-Br, TBAI
THF, rt, 3 h, 95%
O
O
O
12
i. Et3N, Bu2SnO, Ts-Cl
CH2Cl2, rt, 3 h
O
O
OBn
OBn
HO
ii. LiAlH4, THF
rt, 2 h, 85%
HO
HO
O
O
13
14
O
TBSOTf, 2,6-lutidine
CH2Cl2, 0 oC, 30 min, 96%
OBn
TBSO
O
15
Scheme 2. Synthesis of the compound 15.
the TBS ether with TBSOTf and 2,6-lutidine in CH2Cl2 to furnish 15
in 96% yield (Scheme 2).
The cleavage of benzyl ether in 15 using Pd(OH)2 afforded the
primary alcohol 16. Oxidation of 16 under Swern conditions gave

J. S. Yadav et al. / Tetrahedron: Asymmetry 23 (2012) 931–937
933
O
O
20% Pd(OH)2, H2
OBn
OH
THF, 4 h, 90%
TBSO
O
TBSO
O
16
15
O
i. (COCl)2, DMSO
DIBAL-H, 0 oC
TEA, CH2Cl2, -78 oC
OEt
CH2Cl2, 30 min, 89%
ii. Ph3PCHCOOEt,
benzene, reflux
2 h, 93%
TBSO
O
O
8
O
O
i. IBX, 1 h
CH2Cl2: DMSO
OH
ii. (+)-Ipc2B
(CH2CHCH2)
Et2O, -100°C
1h, 85%
TBSO
O
OH
O
TBSO
17
7
O
Grubbs-I, CH2Cl2
reflux, 5 h, 87%
acryloyl-Cl, Et3N
CH2Cl2, 0°C
30 min, 72%
TBSO
O
O
18
O
O
OAc
i. 4 M HCl, THF
rt, 12 h
ii. Ac2O, Et3N, CH2Cl2
rt, 30 min, 61%
TBSO
O
O
OAc OAc
O
6
1a
O
O
Scheme 3. Synthesis of (+)-synargentolide A 1a.
the corresponding aldehyde, which was subjected to C2-Wittig
olefination to yield ,b-unsaturated ester 8 in 93% yield. Reduction
of the ester 8 to allylic alcohol 17 was achieved with DIBAL-H. The
allylic alcohol 17 was oxidized with IBX to furnish an ,b-unsatu-
4. Experimental section
4.1. General
a
a
rated aldehyde, which was allylated with (+)-Ipc2B(allyl) (Brown’s
asymmetric allylation)15 to furnish the required homoallylic alco-
hol 7 as a single diastereomer.16 Acryloylation of 7 with acryloyl
chloride, Et3N in anhydrous CH2Cl2 furnished acrylate 18, which
was subjected to ring closing metathesis (RCM) with Grubbs’ first
generation catalyst17 to furnish lactone 6 in 87% yield. Finally,
the cleavage of the protecting groups in lactone 6 with 4 M HCl
in THF gave trihydroxy lactone, which was acylated in the presence
of Ac2O, Et3N, and cat DMAP to afford (+)-synargentolide A in 61%
yield (Scheme 3). The spectroscopic data and specific rotation of
All reagents were of reagent grade and used without further
purification unless specified otherwise. Solvents for the reactions
were distilled prior to use: THF, toluene, and diethyl ether were
distilled from Na and benzophenone ketyl and CH2Cl2 from CaH2.
All air- and moisture-sensitive reactions were conducted under a
nitrogen atmosphere in flame-dried or oven-dried glassware with
magnetic stirring. The 1H NMR and 13C NMR spectra were recorded
in CDCl3 as the solvent on a 300 MHz spectrometer at ambient
temperature. The coupling constants J are given in Hz. The chemi-
cal shifts are reported in ppm on a scale downfield from TMS as the
internal standard and signal patterns are indicated as follows:
s = singlet, d = doublet, dd = doublet of doublet, t = triplet, td = trip-
let of double, q = quartet, m = multiplet, br = broad. FTIR spectra
were recorded on KBr pellets CHCl3/neat (as mentioned) and re-
ported in wave number (cmꢁ1). Optical rotations were measured
on a digital polarimeter using a 1 mL cell with a 1 dm path length.
For low (MS) and high (HRMS) resolutions, m/z ratios are reported
as values in atomic mass units. Mass analysis was performed in ESI
mode. Column chromatography was carried out using silica gel
(60–120 mesh or 100–200 mesh) packed in glass columns. Techni-
cal grade ethyl acetate and petroleum ether used for column chro-
matography were distilled prior to use.
our synthetic compound 1a ½a D25
¼ þ53:8 (c 0.8, CHCl3), were in
ꢀ
agreement with the data previously reported; Lit.2
[a] = +40 (c
D
9b
1.1, CHCl3); Lit.
[a] = +66.4 (c 1.0, CHCl3).
D
3. Conclusions
In conclusion, we have demonstrated an efficient and straight-
forward strategy for the total synthesis of (+)-synargentolide A,
in a highly stereoselective manner starting from inexpensive and
readily available D-1,5-gluconolactone. The synthesis involves hyd-
roboration, C2-Wittig olefination, Brown’s asymmetric allylation,
and ring closing metathesis as key reactions.

934
J. S. Yadav et al. / Tetrahedron: Asymmetry 23 (2012) 931–937
4.1.1. (4S,41R,5R)-2,2,21,21-Tetramethyl-5-vinyl-4,41-bi(1,3-
dioxolan) 9
3.98–4.08 (m, 2H), 4.12 (dd, J = 7.5, 6.0 Hz, 1H), 4.53 (s, 2H),
7.27–7.38 (m, 5H) ppm. 13C NMR (CDCl3, 75 MHz): d 138.4,
128.3, 127.6, 127.4, 109.5, 108.9, 81.2, 77.5, 76.9, 72.9, 67.6, 67.2,
33.8, 27.2, 26.9, 26.6, 25.2 ppm. ESI-MS: m/z: 359 (M+Na)+ HRMS
(ESI-MS): Anal. calcd for C19H28O5Na (M+Na)+ 359.1829, found
359.1833.
To a stirred solution of diol 10 (10 g, 38.16 mmol) in dry THF
(150 ml) were added triphenylphosphine (30.0 g, 114.50 mmol)
and imidazole (15.6 g, 229.00 mmol) followed by iodine (29.0 g,
114.50 mmol) at 0 °C. The reaction mixture was refluxed for 1 h,
cooled to room temperature, then decanted into saturated aqueous
Na2S2O3 (100 ml) and extracted with ethyl acetate (2 ꢂ 30 mL).
The combined organic phase was washed with saturated aqueous
Na2S2O3 (1 ꢂ 50 mL), saturated aqueous NaHCO3 (1 ꢂ 40 mL), and
with brine (1 ꢂ 30 mL), dried over anhydrous Na2SO4, and the sol-
vent was evaporated under reduced pressure. The crude product
was subjected to flash column chromatography (silica gel, 5%
EtOAc/hexane as an eluent) to afford olefin 9 (6.96 g, 80%) as a col-
4.1.4. (R)-1-((4R,5R)-5-(2-(Benzyloxy)ethyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)ethane-1,2-diol 13
To a stirred solution of 12 (4.1 g, 12.20 mmol) in MeOH (45 mL)
was added PPTS (0.76 g, 3.05 mmol) at 0 °C, stirred for 5 h at room
temperature; then the reaction mixture was quenched with satu-
rated aqueous NaHCO3 (15 mL) at 0 °C. The methanol was evapo-
rated under reduced pressure, and the crude compound was
extracted with ethyl acetate (3 ꢂ 30 mL). The combined organic
phase was washed with brine (1 ꢂ 20 mL), dried over anhydrous
Na2SO4, the solvent was evaporated, and the crude product was
purified by silica gel column chromatography (silica gel, 50%
EtOAc/hexane as an eluent) to obtain the desired product 13
orless oil Rf = 0.5 (silica gel, 10% EtOAc/hexane). ½a D25
¼ ꢁ5:75 (c
ꢀ
3.0, CHCl3). IR (neat) mmax
: 2932, 1379, 1253, 1051, 962,
841 cmꢁ1 1H NMR (CDCl3, 300 MHz): d 1.31 (s, 3H), 1.37 (s, 3H),
.
1.38 (s, 6H), 3.60 (t, J = 7.55 Hz, 1H), 3.83–3.94 (m, 1H), 3.99–
4.11 (m, 2H), 4.26–4.35 (m, 1H), 5.16 (d, J = 10.5 Hz, 1H), 5.38 (d,
J = 17.1 Hz, 1H), 5.81–5.96 (m, 1H) ppm 13C NMR (CDCl3,
75 MHz): d 135.8, 117.1, 109.6, 109.3, 81.0, 80.4, 76.6, 66.9, 26.9,
26.8, 26.6, 25.2 ppm. ESI-MS: m/z: 251 (M+Na).+
(2.78 g, 77%). Rf = 0.5 (silica gel, EtOAc). ½a D25
ꢀ
¼ þ8:7 (c 2.8, CHCl3).
IR (neat) m .
max: 3418, 2932, 1371, 1219, 1079, 772 cmꢁ1 1H NMR
(CDCl3, 300 MHz): d 1.38 (br s, 6H), 1.68 (br s, 1H), 1.87–2.15 (m,
2H), 3.59–3.80 (m, 6H), 4.11 (td, J = 7.0, 4.3 Hz, 1H), 4.53 (s, 2H),
7.29–7.40 (m, 5H) ppm. 13C NMR (CDCl3, 75 MHz): d 137.7,
128.4, 127.8, 127.7, 108.6, 80.7, 77.0, 73.1, 72.7, 67.1, 64.0, 33.7,
27.1, 26.8 ppm. ESI-MS: m/z: 319 (M+Na)+ HRMS (ESI-MS): Anal.
calcd for C16H24O5Na (M+Na)+ 319.1516, found 319.1520.
4.1.2. 2-(4S,41R,5R)-2,2,21,21-Tetramethyl-4,41-bi(1,3-dioxolan)-
5-yl)ethanol 11
At first, 9-BBN (54 mL, 26.97 mmol, 0.5 M in THF) was added
dropwise to a well stirred solution of olefin 9 (4.1 g, 17.98 mmol)
in anhydrous THF (35 mL) at 0 °C and the reaction mixture was
stirred for 6 h at room temperature. Then the reaction mixture
was quenched with 3 M NaOH (10 mL) at 0 °C, followed by the
dropwise addition of 30% H2O2 (15 mL) and the resulting solution
was stirred for 4 h at room temperature. The organic phase was
separated and the aqueous layer extracted with ethyl acetate
(3 ꢂ 20 mL). The combined organic phase was washed with brine
(1 ꢂ 30 mL), dried over anhydrous Na2SO4, and the solvent was
evaporated under reduced pressure. The crude product was sub-
jected to flash column chromatography (silica gel, 20% EtOAc/hex-
ane) to obtain primary alcohol 11 (3.45 g, 78%). Rf = 0.4 (silica gel,
4.1.5. (R)-1-((4R,5R)-5-(2-(Benzyloxy)ethyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)ethanol 14
To a stirred solution of diol 13 (2.55 g, 8.61 mmol) and dibutyl-
tin oxide (0.43 g, 1.72 mmol) in anhydrous DCM (35 mL), was
added Et3N (1.8 mL, 12.91 mmol) dropwise at 0 °C, then the reac-
tion mixture was allowed to warm to room temperature. After
15 min, the reaction mixture was cooled to 0 °C and then p-tolu-
enesulfonylchloride (1.64 g, 8.61 mmol) was added portionwise
and stirred for 3 h at room temperature. After complete consump-
tion of the starting material, the reaction mixture was quenched
with water (15 mL), and extracted with CH2Cl2 (2 ꢂ 15 mL). The or-
ganic phase was washed with brine (20 mL), dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The
resulting monotosylated compound was directly used for the next
step without further purification.
40% EtOAc/hexane). ½a D25
ꢀ
¼ þ15:5 (c 0.8, CHCl3). IR (neat) mmax
:
3446, 2988, 1380, 1215, 1068, 847 cmꢁ1.1H NMR (CDCl3,
300 MHz): d 1.32 (s, 3H), 1.35 (s, 3H), 1.38 (s, 6H), 1.76–1.90 (m,
1H), 1.95–2.07 (m, 1H), 3.56 (t, J = 8.1 Hz, 1H), 3.75–3.82 (m, 2H),
3.86–4.17 (m, 4H) ppm.13C NMR (CDCl3, 75 MHz): d 109.7, 109.1,
81.1, 79.8, 77.1, 67.8, 60.7, 35.9, 27.1, 26.8, 26.5, 25.1 ppm ESI-
MS: m/z: 247 (M+H).+
The monotosylate compound in THF (40 mL) was added drop-
wise to a well stirred suspension of LAH (0.56 g, 14.66 mmol) in
anhydrous THF (10 mL) at 0 °C. The reaction mixture was allowed
to stir for 2 h at room temperature and the reaction mixture was
quenched with a saturated aqueous NH4Cl solution (10 mL) at
0 °C. Next ethyl acetate (50 mL) and water (20 mL) were added,
the organic layer was separated and the aqueous layer was ex-
tracted with ethyl acetate (2 ꢂ 15 mL). The combined organic
phase was washed with brine (1 ꢂ 25 mL), dried over anhydrous
Na2SO4 and concentrated at reduced pressure and the residue
was purified by silica gel column chromatography (silica gel, 12%
EtOAc/hexane as an eluent) to yield compound 14 (2.05 g, 85% over
4.1.3. (4S,41R,5R)-5-(2-(Benzyloxy)ethyl)-2,2,21,21-tetramethyl-
4,41-bi(1,3-dioxolane) 12
Primary alcohol 11 (3.3 g, 13.41 mmol) in dry THF (25 mL) was
added to a stirred solution of 60% NaH (0.8 g, 20.12 mmol) in anhy-
drous THF (10 mL) at 0 °C and stirred for 15 min. Then benzyl bro-
mide (1.6 mL, 13.41 mmol) and a catalytic amount of TBAI were
added at 0 °C and the reaction mixture was allowed to stir at room
temperature for 3 h. After completion of the reaction, the reaction
mixture was quenched with cold water (10 mL). The organic phase
was separated and the aqueous layer extracted with ethyl acetate
(1 ꢂ 15 mL). The combined organic phase was washed with brine
(1 ꢂ 20 mL), dried over anhydrous Na2SO4, the organic solvent
was evaporated, and the crude product was purified by silica gel
column chromatography (silica gel, 5% EtOAc/hexane) to give com-
pound 12 (4.28 g, 95%). Rf = 0.4 (silica gel, 10% EtOAc/hexane).
two steps). Rf = 0.4 (silica gel, 20% EtOAc/hexane). ½a D25
¼ þ20:5 (c
ꢀ
0.8, CHCl3). IR (neat)
mmax: 3442, 2985, 1370, 1240, 1089, 877,
738 cmꢁ1 1H NMR (CDCl3, 300 MHz): d 1.19 (d, J = 6.8 Hz, 3H),
.
1.35 (s, 6H), 1.78–2.05 (m, 2H), 2.26 (br s, 1H), 3.51- 3.71 (m,
3H), 3.76–3.88 (m, 1H), 4.05 (td, J = 8.3, 3.7 Hz, 1H), 4.50 (s, 2H),
7.27–7.35 (m, 5H) ppm. 13C NMR (CDCl3, 75 MHz): d 138.1,
128.3, 127.7, 127.6, 108.3, 84.2, 75.0, 73.0, 67.5, 67.3, 34.5, 27.2,
27.0, 18.9 ppm ESI-MS: m/z: 303 (M+Na)+ HRMS (ESI-MS): Anal.
calcd for C16H24O4Na (M+Na)+ 303.1566, found 303.1576.
½
a 2D5
ꢀ
¼ þ17:6 (c 1.0, CHCl3). IR (neat)
mmax: 2987, 1371, 1216,
1061, 848, 737 cmꢁ1 1H NMR (CDCl3, 300 MHz): d 1.33 (s, 3H),
.
1.35 (s, 3H), 1.38 (s, 3H), 1.40 (s, 3H), 1.78–1.92 (m, 1H), 2.07–
2.21 (m, 1H), 3.52–3.71 (m, 3H), 3.95 (dd, J = 7.5, 5.2 Hz, 1H),

J. S. Yadav et al. / Tetrahedron: Asymmetry 23 (2012) 931–937
935
4.1.6. ((R)-1-((4S,5R)-5-(2-(Benzyloxy)ethyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)ethoxy)(tert-butyl)dimethylsilane 15
steps). Rf = 0.7 (silica gel, 10% EtOAc/hexane). ½a D25
ꢀ
¼ þ22:6 (c 2.3,
CHCl3). IR (neat) mmax: 2933, 1723, 1656, 1371, 1256, 1171, 1078,
To a solution of alcohol 14 (2.0 g, 7.14 mmol) in anhydrous
CH2Cl2 (20 mL), 2,6-lutidine (1.25 mL, 10.71 mmol) was added
and the reaction mixture was stirred at 0 °C under a nitrogen atmo-
sphere. After 5 min, TBSOTf (2.0 mL, 8.56 mmol) was added drop-
wise and stirred at the same temperature for 30 min. After
complete consumption of the starting material, the reaction mix-
ture was quenched with water (8 mL), and extracted with CH2Cl2
(1 ꢂ 15 mL). The organic phase was washed with brine (20 mL),
dried over anhydrous Na2SO4, filtered, and concentrated under re-
duced pressure. The residue was purified by column chromatogra-
phy over silica gel (3% EtOAc/hexane as an eluent) to yield the TBS
protected compound 15 (2.70 g, 96%). Rf = 0.6 (10% EtOAc/hexane).
834, 776 cmꢁ1 1H NMR (CDCl3, 300 MHz): d 0.06 (s, 3H), 0.08 (s,
.
3H), 0.89 (s, 9H), 1.22 (d, J = 5.9 Hz, 3H), 1.29 (t, J = 6.9 Hz, 3H),
1.36, (s, 3H), 1.39 (s, 3H), 2.38–2.47 (m, 1H), 2.63–2.71 (m, 1H),
3.46 (t, J = 6.9 Hz, 1H), 3.74–3.81 (m, 1H), 4.03 (td, J = 7.9, 2.9 Hz,
1H), 4.19 (q, J = 6.9 Hz, 2H), 5.90 (d, J = 15.8 Hz, 1H), 7.01 (dt,
J = 15.8, 6.9 Hz, 1H), ppm. 13C NMR (CDCl3, 75 MHz): d 166.3,
144.7, 123.4, 108.9, 84.2, 78.0, 70.5, 60.1, 37.1, 27.2, 27.1, 25.7,
21.5, 17.9, 14.2, ꢁ4.3, ꢁ4.5 ppm. ESI-MS: m/z: 395 (M+Na)+ HRMS
(ESI-MS): Anal. calcd for C19H36O5NaSi (M+Na)+ 395.2224, found
395.2236.
4.1.9. (E)-4-((4R,5S)-5-((R)-1-(tert-Butyldimethylsilyloxy)ethyl)-
2,2-dimethyl-1,3-dioxolan-4-yl)but-2-en-1-ol 17
To a stirred solution of compound 8 (1.5 g, 4.03 mmol) in dry
CH2Cl2 (20 mL) was added DIBAL-H (8.87 mL, 8.87 mmol, 1.0 M
solution in toluene) at ꢁ78 °C for 10 min. Next, the reaction mix-
ture was stirred for 30 min at 0 °C. After completion of the reac-
½
a 2D5
ꢀ
¼ þ11:7 (c 1.5, CHCl3). IR (neat)
mmax: 2932, 1370, 1254, 1097,
835, 775 cmꢁ1 1H NMR (CDCl3, 300 MHz): d 0.06 (s, 3H), 0.07 (s,
.
3H), 0.89 (s, 9H), 1.21 (d, J = 6.0 Hz, 3H), 1.36, (s, 3H), 1.38 (s,
3H), 1.78–1.88 (m, 1H), 2.02–2.12 (m, 1H), 3.50 (t, J = 7.0 Hz, 1H),
3.56–3.70 (m, 2H), 3.76–3.83 (m, 1H), 3.99–4.07 (m, 1H), 4.52 (s,
2H), 7.27–7.36 (m, 5H) ppm. 13C NMR (CDCl3, 75 MHz): d 138.6,
128.2, 127.5, 127.3, 108.5, 84.9, 76.4, 72.9, 70.0, 67.5, 35.1, 27.3,
27.2, 25.8, 25.6, 21.2, ꢁ4.3, ꢁ4.5 ppm. ESI-MS: m/z: 417 (M+Na)+;
HRMS (ESI-MS): Anal. calcd for C22H38O4NaSi (M+Na)+ 417.2431,
found 417.2443.
tion, the reaction mixture was quenched with
a saturated
sodium potassium tartrate solution (10 mL) and was stirred vig-
orously at room temperature for an additional 1 h after which
the contents were extracted into CH2Cl2 (2 ꢂ 15 mL). The com-
bined organic layers were washed with brine solution (20 mL),
dried over anhydrous Na2SO4, and the solvent removed under re-
duced pressure to afford the crude aldehyde. The crude product
was subjected to flash column chromatography on silica gel (12%
EtOAc/hexane as an eluent) to give allylic alcohol 17 (1.18 g,
4.1.7. 2-((4R,5S)-5-((R)-1-(tert-Butyldimethylsilyloxy)ethyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)ethanol 16
At first, 20% Pd(OH)2 was added to a solution of 15 (2.6 g,
6.60 mmol) in anhydrous THF (25 mL) and stirred for 4 h under a
hydrogen atmosphere. After complete consumption of the starting
material, the reaction mixture was filtered through a pad of Celite
The filtrate was concentrated under reduced pressure and the res-
idue was purified on silica gel using (12% EtOAc-hexane as an elu-
ent) to afford the primary alcohol 16 (1.80 g, 90%) as a colorless
89%) as a clear liquid. Rf = 0.3 (20% EtOAc/hexane). ½a D25
¼ þ8:9
ꢀ
(c 2.7, CHCl3). IR (neat)
mmax: 3429, 2932, 1373, 1256, 1101,
1073, 972, 834, 776 cmꢁ1 1H NMR (CDCl3, 300 MHz): d 0.07 (s,
.
3H), 0.08 (s, 3H), 0.89 (s, 9H), 1.22 (d, J = 5.6 Hz, 3H), 1.36, (s,
3H), 1.39 (s, 3H), 2.25–2.34 (m, 1H), 2.49–2.55 (m, 1H), 3.45 (t,
J = 7.2 Hz, 1H), 3.75–3.82 (m, 1H), 3.97 (td, J = 7.2, 3.2 Hz, 1H),
4.12 (br s, 2H), 5.70–5.83 (m 2H) ppm. 13C NMR (CDCl3,
75 MHz): d 131.5, 128.6, 108.6, 84.2, 79.0, 70.4, 63.6, 37.3,
27.3, 27.2, 25.8, 21.3, 17.9, ꢁ4.2, ꢁ4.5 ppm ESI-MS: m/z: 353
(M+Na)+ HRMS (ESI-MS): Anal. calcd for C17H34O4NaSi (M+Na)+
353.2118, found 353.2119.
liquid. Rf = 0.3 (20% EtOAc/hexane). ½a D25
ꢀ
¼ ꢁ5:8 (c 1.1, CHCl3). IR
(neat)
m
max: 3450, 2935, 1374, 1252, 1082, 834, 775 cmꢁ1 1H
.
NMR (CDCl3, 300 MHz): d 0.07 (s, 3H), 0.08 (s, 3H), 0.88 (s, 9H),
1.22 (d, J = 6.0 Hz, 3H), 1.35, (s, 3H), 1.38 (s, 3H), 1.70–1.85 (m,
1H), 1.91–2.04 (m, 1H), 3.47 (t, J = 6.8 Hz, 1H), 3.69–3.82 (m, 3H),
4.03 (td, J = 9.0, 3.0 Hz, 1H) ppm 13C NMR (CDCl3, 75 MHz): d
108.8, 84.8, 79.3, 70.4, 61.2, 36.8, 27.3, 27.1, 25.8, 21.4, 17.9,
ꢁ4.3, ꢁ4.5 ppm ESI-MS: m/z: 327(M+Na)+ HRMS (ESI-MS): Anal.
calcd for C15H32O4NaSi (M+Na)+ 327.1962, found 327.1968.
4.1.10. (R,E)-7-((4R,5S)-5-((R)-1-(tert-Butyldimethylsilyloxy)-
ethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)hepta-1,5-dien-4-ol 7
Allylic alcohol 17 (0.43 g, 1.30 mmol) in dry DCM (10 mL) was
added dropwise to
a well stirred solution of IBX (0.55 g,
4.1.8. (E)-Ethyl 4-((4R,5S)-5-((R)-1-(tert-butyldimethylsilyloxy)-
ethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-enolate 8
1.95 mmol) in anhydrous DMSO (8 mL) at 0 °C, after which the
reaction mixture was allowed to stir for 1 h at room temperature.
After completion of the reaction (TLC analysis), the reaction mix-
ture was filtered through a pad of Celite and the filtrate was con-
centrated in vacuo to obtain the crude residue, which was
subjected to flash column chromatography using 3% EtOAc/hex-
ane as eluent to furnish the aldehyde, which was used for the
next reaction.
A solution of (+)-IPC2B(allyl) (1.27 mL, 1.27 mmol, 1.0 M solu-
tion in pentane) in anhydrous Et2O (5 mL) was cooled to ꢁ100 °C
after which a solution of the aldehyde (0.38 g, 1.15 mmol) in dry
diethyl ether (10 mL) was added slowly under an N2 atmosphere.
The mixture was stirred at ꢁ100 °C for 1 h and then warmed to
0 °C. The reaction mass was quenched by the dropwise addition
of 30% H2O2 (2 mL) and 1 M NaOH (2 mL). The mixture was di-
luted with ethyl acetate (10 mL) and the layers were separated.
The aqueous layer was extracted with ethyl acetate
(3 ꢂ 10 mL). The combined organic layer was washed with brine
(1 ꢂ 15 mL), dried over anhydrous Na2SO4, filtered, and concen-
trated in vacuo. The crude reaction mixture was purified by
silica gel column chromatography (10% EtOAc/hexane as an elu-
At first, DMSO (1.5 mL, 21.05 mmol) was added slowly to the
well stirred solution of oxalyl chloride (0.91 mL, 10.52 mmol) in
anhydrous CH2Cl2 (5 mL) at ꢁ78 °C. After stirring for 20 min at
ꢁ78 °C, alcohol 16 (1.6 g, 5.26 mmol) in anhydrous CH2Cl2
(15 mL) was added to the above solution. After stirring for 1 h,
Et3N (4.4 mL, 31.56 mmol) was introduced via a syringe. Next,
the reaction mixture was stirred for 30 min at ꢁ78 °C, and then
for 20 min at ꢁ50 °C followed by the addition of water (15 mL).
The organic phase was separated and the aqueous layer was
washed with CH2Cl2 (2 ꢂ 10 mL). The combined organic layer
was dried over anhydrous Na2SO4 and concentrated under reduced
pressure to give the aldehyde as a pale yellow syrup, which was
used for the next step without further purification.
This crude aldehyde was treated with the stabilized C2-Wittig
ylide (3.2 g, 9.40 mmol) in dry benzene at reflux for 2 h. After com-
pletion of the reaction (TLC analysis), benzene was removed under
vacuum, and the crude ester was subjected to column chromatog-
raphy using silica gel (4% EtOAc/hexane as an eluent) to afford
a,b-
unsaturated ester 8 as a colorless liquid. (1.82 g, 93% over two

936
J. S. Yadav et al. / Tetrahedron: Asymmetry 23 (2012) 931–937
ent) to give homoallyl alcohol 7 (0.41 g, 85% over two steps) as a
4.1.13. (2R,3R,4R,E)-7-((R)-6-Oxo-3,6-dihydro-2H-pyran-2-
yl)heap-6-ene-2,3,4-triacetate [(+)-synargentolide A] 1a
To a well stirred solution of compound 6 (0.1 g, 0.25 mmol) in
THF (8 mL) was added 4 M HCl (1.0 mL) solution at 0 °C then the
reaction mixture was warmed to room temperature and stirred
for 12 h. The reaction mixture was quenched with solid NaHCO3
and filtered. The filtrate was removed under reduced pressure to
give the crude trihydroxy lactone, which was used for the next step
without further purification.
colorless liquid. Rf = 0.5 (20% EtOAc/hexane). ½a D25
¼ þ15:8 (c 1.6,
ꢀ
CHCl3). IR (neat) mmax: 3445, 2955, 1374, 1254, 1075, 973, 834,
776 cmꢁ1 1H NMR (CDCl3, 300 MHz): d 0.07 (s, 3H), 0.08 (s,
.
3H), 0.89 (s, 9H), 1.22 (d, J = 6.0 Hz, 3H), 1.36, (s, 3H), 1.39 (s,
3H), 1.69 (br s, 1H), 2.23–2.38 (m, 3H), 2.48–2.57 (m, 1H),
3.47 (t, J = 6.8 Hz, 1H), 3.71–3.84 (m, 1H), 3.95 (td, J = 7.5,
3.0 Hz, 1H), 4.17 (q, J = 6.8 Hz, 1H), 5.11 (s, 1H), 5.15 (d,
J = 6.8 Hz, 1H), 5.58 (dd, J = 15.8, 6.8 Hz, 1H), 5.70–5.91 (m 2H)
ppm. 13C NMR (CDCl3, 75 MHz): d 134.7, 134.3, 127.6, 117.9,
108.6, 84.1, 79.1, 71.6, 70.5, 41.8, 37.2, 27.3, 27.2, 25.8, 21.4,
17.9, ꢁ4.2, ꢁ4.5 ppm ESI-MS: m/z: 393 (M+Na)+ HRMS (ESI-
To a pre-cooled (0 °C) solution of trihydroxy lactone (0.045 g,
0.18 mmol) in anhydrous CH2Cl2 (5 mL) was added triethylamine
(0.15 mL, 1.11 mmol), Ac2O (0.08 mL, 0.93 mmol), followed by
DMAP (2 mg) under a nitrogen atmosphere. The reaction mixture
was then allowed to stir for 30 min at room temperature. After
completion of the reaction (TLC analysis) it was poured into cold
water (5 mL) and extracted with ethyl acetate (3 ꢂ 5 mL). The or-
ganic phase was washed with brine (1 ꢂ 8 mL), and dried over
anhydrous Na2SO4. The organic solvent was then removed under
reduced pressure. The crude product was purified by column chro-
matography on silica gel (15% EtOAc/hexane as the eluent) to give
synargentolide 1a (0.056 g, 61% over two steps) as a colorless oil.
MS): Anal. calcd for
393.2449.
C
20H38O4NaSi (M+Na)+ 393.2431, found
4.1.11. (R,E)-7-((4R,5S)-5-((R)-1-(tert-Butyldimethylsilyloxy)-
ethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)hepta-1,5-dien-4-yl
acrylate 18
Acryloyl chloride (0.11 mL, 1.33 mmol) was added dropwise un-
der N2 atmosphere to a solution of homoallyl alcohol 7 (0.33 g,
0.89 mmol) and Et3N (0.25 mL, 1.78 mmol) in CH2Cl2 (8 mL). The
mixture was stirred at 0 °C for 30 min. After completion of the
reaction (TLC analysis), the reaction mixture was poured into cold
water (5 ml), and extracted with CH2Cl2 (2 ꢂ 5 mL). The organic
phase was washed with brine (1 ꢂ 8 mL), dried over anhydrous
Na2SO4, and the organic solvent was removed under reduced pres-
sure. The crude product was purified by column chromatography
on silica gel (3% EtOAc/hexane as an eluent) to afford acrylate 18
Rf = 0.5 (40% EtOAc/hexane). ½a D25
ꢀ
¼ þ52 (c 0.8, CHCl3). IR (neat)
m
max: 2924, 1736, 1373, 1219, 1055, 1021 cmꢁ1 1H NMR (CDCl3,
.
300 MHz): d 1.19 (d, J = 5.9 Hz, 3H), 2.02 (s, 3H), 2.06 (s, 3H),
2.15 (s, 3H), 2.27–2.34 (m, 2H), 2.39–2.45 (m, 2H), 4.84–4.90 (m,
1H), 4.95–5.02 (m, 1H), 5.09 (dd, J = 6.9, 2.9 Hz, 1H), 5.20 (td,
J = 7.9, 2.9 Hz, 1H), 5.66 (dd, J = 15.8, 5.9 Hz, 1H), 5.69–5.78 (m,
1H), 6.04 (d, J = 9.9 Hz, 1H), 6.86 (dt, J = 9.9, 3.9 Hz, 1H) ppm 13C
NMR (CDCl3, 75 MHz): d 170.2, 170.1, 170.0, 163.7, 144.5, 130.9,
128.4, 121.5, 77.5, 73.6, 69.5, 67.2, 33.9, 29.5, 21.0, 20.8, 20.7,
16.2 ppm ESI-MS: m/z: 391 (M+Na)+ HRMS (ESI-MS): Anal. calcd
for C18H24O8Na (M+Na)+ 391.1363, found 391.1375.
(0.27 g, 72%) as
a
colorless oil. Rf = 0.5 (5% EtOAc/hexane).
max: 1726, 1257, 1189,
½
a 2D5
ꢀ
¼ þ18:7 (c 2.0, CHCl3). IR (neat)
m
1075, 971, 834, 774 cmꢁ1.1H NMR (CDCl3, 300 MHz): d 0.06 (s,
3H), 0.08 (s, 3H), 0.89 (s, 9H), 1.21 (d, J = 6.0 Hz, 3H), 1.36, (s,
3H), 1.38 (s, 3H), 2.23–2.63 (m. 4H), 3.46 (t, J = 6.9 Hz, 1H), 3.70–
3.88 (m, 1H), 3.90–4.22 (m, 1H), 5.02–5.19 (m, 2H), 5.39 (q,
J = 6.4 Hz, 1H), 5.54 (dd, J = 15.4, 6.8 Hz, 1H), 5.65–5.96 (m, 3H),
6.11 (dd, J = 17.1, 10.4 Hz, 1H), 6.40 (d, J = 17.1 Hz, 1H) ppm 13C
NMR (CDCl3, 75 MHz): d 165.3, 133.2, 130.4, 130.1, 130.0, 128.8,
117.8, 108.6, 83.9, 78.8, 73.7, 70.4, 38.9, 37.0, 27.3, 27.2, 25.8,
21.4, 17.9, ꢁ4.2, ꢁ4.5 ppm ESI-MS: m/z: 447 (M+Na)+ HRMS (ESI-
Acknowledgements
B.T, V.K.S thanks the UGC and V.R thanks the CSIR New Delhi,
India, for the award of fellowships. The authors also acknowledge
the partial support of the King Saud University for the Global Re-
search Network for Organic Synthesis (GRNOS)
MS): Anal. calcd for
447.2545.
C
23H40O5NaSi (M+Na)+ 447.2537, found
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ꢀ
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1075, 833, 776 cmꢁ1. 1H NMR (CDCl3, 300 MHz): d 0.06 (s, 3H), 0.08
(s, 3H), 0.89 (s, 9H), 1.22 (d, J = 6.0 Hz, 3H), 1.36 (s, 3H), 1.39 (s, 3H),
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