Stereoselective total synthesis of (+)-synargentolide A

Article abstract of DOI:10.1016/j.tetasy.2010.11.005

The stereoselective synthesis of synargentolide A, a polyhydroxy δ-lactone, has been accomplished from tartaric acid. The key steps in the synthesis involve Keck and Brown allylations and ring closing metathesis.

Full text of DOI:10.1016/j.tetasy.2010.11.005

Tetrahedron: Asymmetry 21 (2010) 2853–2858
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective total synthesis of (+)-synargentolide A
⇑
Kavirayani R. Prasad , Kamala Penchalaiah
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The stereoselective synthesis of synargentolide A, a polyhydroxy d-lactone, has been accomplished from
tartaric acid. The key steps in the synthesis involve Keck and Brown allylations and ring closing
metathesis.
Received 26 October 2010
Accepted 8 November 2010
Available online 7 December 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
hol 57 in 70% yield. Protection of the free alcohol group in 5 as a
MOM ether followed by acetonide deprotection resulted in diol 7
Polyhydroxylated d-lactones are common structural motifs
found ubiquitously in natural products displaying a variety of bio-
logical profiles.1 Synargentolide A 1a is such a lactone isolated
from the acetone extract of the dried aerial parts of Syncolostemon
argenteus of the Southern African genus Syncolostemon, a plant
from the Ongoya forest in the Kwazulu-Natal midlands of South
Africa.2 Synargentolide 1a is structurally similar to anamarine 1c
and the structure of 1b was proposed based on extensive NMR
studies and has been recently revised to be 1a.3 A solitary synthesis
of the putative structure4 and the revised structure3 of synargento-
lide A has appeared recently. We have been involved in the synthe-
sis of bio-active lactones from chiral pool tartaric acid5 and herein
we report a facile synthesis of 1a from tartaric acid.
in 81% yield. Treatment of 7 with TBDMSCl in the presence of
imidazole furnished the silylether which upon reaction with
p-toluenesulphonyl chloride and excess DMAP yielded the tosylate
8 in 94% yield. Next, the TBAF mediated deprotection of the silyl
ether furnished the epoxide which upon treatment with LiAlH4
cleanly resulted in alcohol 9 in 90% yield. Deprotection of the
benzylether in 9 under Li/NH3 conditions resulted in the diol,
which was transformed into the cyclic acetonide 4 in 90% yield
by treatment with 2,2-dimethoxy propane (Scheme 2).
After obtaining the trihydroxy alkene fragment with suitable
protections, the alkene in 4 was elaborated to the
a,b-unsatu-
rated ester 10 in 64% yield via ozonolysis to the aldehyde and
subsequent Wittig olefination. The reduction of the ester 10 with
OAc
OAc
OAc OAc
Me
Me
Me
OAc OAc
O
OAc OAc
O
OAc OAc
anamrine 1c
O
synargentolide A 1b
synargentolide A 1a
O
O
O
published structure
revised structure
DIBAL-H afforded alcohol 11 in almost quantitative yield. Oxida-
tion of 11 with MnO2 followed by Brown’s allylation of the
resulting aldehyde with (+)-Ipc2B-allyl8 furnished the homoal-
lylic alcohol 12 in 52% yield. Acryloylation of 12 furnished ester
3 in 70% yield, which upon RCM with Grubbs 1st generation cat-
alyst9 produced lactone 13 in 85% yield. Deprotection of the ace-
tonide and the MOM ether in 13 with TFA resulted in the
trihydroxy lactone 2, which upon acylation afforded synargento-
lide A 1a in 52% yield. The spectroscopic properties of 1a are in
complete agreement with those reported in the literature
although the specific rotation of our synthetic sample
2. Results and discussion
Our approach for the synthesis of 1a is based on the RCM of
acryloyl ester 3, the formation of which was anticipated by the
elaboration of the appropriately protected homoallylic alcohol 4.
The formation of 4 was envisaged by extension of the primary alco-
hol 6 derived from tartaric acid (Scheme 1).
Accordingly, the oxidation of alcohol 6 prepared from diethyl
tartrate6 gave the aldehyde which upon Keck allylation with allyl-
tributyltin in the presence of MgBr2ÁOEt2 afforded the known alco-
[a
]
D = +66.4 (c 1.0, CHCl3); Lit2
er than that reported for the natural product (Scheme 3).10
[a]D = +40.0 (c 1.1, CHCl3) is high-
⇑
Corresponding author. Tel.: +91 80 22932524; fax: +91 80 23600529.
E-mail address: prasad@orgchem.iisc.ernet.in (K.R. Prasad).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.11.005

2854
K. R. Prasad, K. Penchalaiah / Tetrahedron: Asymmetry 21 (2010) 2853–2858
OH
OAc
O
Me
Me
Me
O
OH OH
O
OAc OAc
O
O
OMOM
3
2
O
O
1a
O
OBn
OBn
O
OH
Me
O
O
tartaric acid
O
OH
O
O
OMOM
4
6
5
Scheme 1. Retrosynthesis for the synthesis of synargentolide A 1a.
i) IBX/EtOAc, Δ, 4h
BnO
BnO
ii) CH2=CHCH2Sn(Bu)3
MgBr2.OEt2, DCM,
OH
ref.6
O
L-diethyl tartrate
O
O
O
OH
6
−78ºC, 2h, 70% (2 steps)
5
i) TBDMSCl, Imidazole,
BnO
i) MOMCl, iPr2NEt, DCM
BnO
DMAP (cat), DMF
0ºC to rt, 3h, 77%
TBSO
HO
0ºC to rt, 12h, 83%
ii) TsCl, DMAP (3eq)
rt, 12h, 94%
TsO
OMOM
ii) PPTS, MeOH, rt, 12h
OH OMOM
81%;
8
7
i) TBAF, THF
BnO
O
i) Li/NH3, THF,−78ºC, 1h, 87%
0ºC to rt, 6h, 86%
Me
Me
ii) MeC(OMe)2Me/ PPTS (cat)
DCM, rt, 2h, 90 %
ii) LiAlH4, THF
O
OMOM
OH OMOM
0ºC to rt, 2h, 90%;
9
4
Scheme 2. Synthesis of the key triol fragment for the synthesis of synargentolide A.
unless otherwise indicated. Unless stated otherwise, all the reac-
tions were performed under inert atmosphere.
3. Conclusion
In conclusion a facile synthesis of bio-active d-lactone synarg-
entolide A has been accomplished from tartaric acid using Keck
and Brown’s allylation strategies as the key reactions. The syn-
thetic sequence is operationally simple and is suitable for the syn-
thesis of a number of derivatives.
4.2. (1S,2R)-1-(Benzyloxy)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-
yl)pent-4-en-2-ol 5
To a stirred solution of 6 (0.50 g, 1.98 mmol) in (7 mL) ethyl ace-
tate was added IBX (1.94 g 6.93 mmol) and refluxed for 4 h. After
the reaction was complete (TLC), it was filtered through a short
pad of Celite and the Celite pad was washed with ethyl acetate
(30 mL). The organic layer was washed with water (10 mL), brine
(10 mL), and dried over Na2SO4. The residue obtained after evapo-
ration of the solvent afforded the crude aldehyde, which was used
in the next step without further purification.
To a solution of the aldehyde obtained above in CH2Cl2 (20 mL),
MgBr2ÁOEt2 (1.02 g, 3.96 mmol) was added at À78 °C under an ar-
gon atmosphere. The reaction mixture was stirred at the same
temperature for 45 min. Allyltributyl tin (0.7 mL, 2.37 mmol) was
then introduced into the reaction mixture dropwise and stirred
for 2 h at À78 °C. After TLC indicated completion of the reaction,
it was quenched by the addition of saturated NH4Cl solution
4. Experimental
4.1. General procedures
Column chromatography was performed on silica gel, Acme
grade 100–200 mesh. TLC plates were visualized either with UV,
in an iodine chamber, or with phosphomolybdic acid spray, unless
otherwise noted. Unless stated otherwise, all reagents were pur-
chased from commercial sources and used without additional puri-
fication. THF was freshly distilled over Na-benzophenone ketyl.
Melting points are uncorrected. Unless stated otherwise, 1H NMR
and 13C NMR spectra were recorded either on a Bruker AC400 or
on a JEOL300 machine in CDCl3 as solvent with TMS as reference

K. R. Prasad, K. Penchalaiah / Tetrahedron: Asymmetry 21 (2010) 2853–2858
2855
O
O
i) O2/O3, DCM, MeOH, NaHCO3, 0ºC, 3h;
Me
Me
CO2Et
(ii) PPh3CHCO2Et, toluene, Δ, 2h
O
O
OMOM
OMOM
64% (2steps)
10
4
i) MnO2, DCM, rt, 18h
O
O
ii) Allyl-B(Ipc)2, ether
Me
Me
DIBAL-H,THF, −78ºC
2h, 98%
−78ºC, 1.5h
O
OMOM
OH
O
OMOM
OH
52% (2 steps)
12
11
OAc
O
i) CH2=CHCOCl,Et3N
0ºC, 1h, 70%
i) 90% aq TFA, 0ºC, 1h
Me
Me
ii) Ac2O, Et3N
O
OAc OAc
1a
O
O
OMOM
13
ii) Grubb's 1st gen cat
CH2Cl2, Δ, 12h, 85%
DMAP (cat)
DCM, 0ºC to rt, 1h,
52% (2 steps)
O
O
Scheme 3. Synthesis of synargentolide A 1a.
(10 mL) and then allowed to warm up to room temperature. It was
then extracted with EtOAc (3 Â 15 mL) and the combined organic
layer was washed with brine (10 mL) and dried over Na2SO4. The
residue obtained after concentration was purified by column chro-
matoghaphy using petroleum ether/ethyl acetate (3:2) as eluent to
furnish homoallylic alcohol 5 (0.41 g) in 70% overall yield in two
1.32 (s, 3H); 13C NMR (100 MHz, CDCl3) 138.4 (Cq), 134.7 (CH),
128.23 (CH), 128.21 (CH), 127.5 (CH), 117.5 (CH2), 108.9 (Cq),
96.2 (CH2), 79.6 (CH), 77.3 (CH), 77.03 (CH), 73.7 (CH2), 66.0
(CH2), 55.9 (CH3), 35.2 (CH2), 26.6 (CH3), 25.7 (CH3); HRMS for
C19H28O5+Na calcd 359.1834; found 359.1830.
To a stirred solution of the MOM ether prepared above (52 mg,
steps as a colorless oil. [
a
]
D = À29.0 (c 2.1, CHCl3); IR (neat) 3465,
0.15 mmol), in MeOH (1 mL), was added PPTS (8 mg, 0.03 mmol).
The reaction mixture was stirred at room temperature for 12 h,
after which NaHCO3 (15 mg) was added and stirred for 10 min.
The reaction mixture was filtered through a short pad of Celite
and the Celite pad was washed with EtOAc (10 mL). Residue ob-
tained after evaporation of the solvent was purified by column
chromatography using petroleum ether/EtOAc (2:3) as eluent to
2985, 2935, 1454, 1380, 1054, 917 cmÀ1
;
1H NMR (300 MHz,
CDCl3) d 7.42–7.20 (m, 5H), 5.74 (ddt, J = 17.4, 10.5, 7.2 Hz, 1H),
5.19–4.91 (m, 2H), 4.89, 4.66 (ABq, J = 11.4 Hz, 2H), 4.40 (dd,
J = 13.8, 6.9 Hz, 1H), 4.05 (dd, J = 8.4, 6.6 Hz, 1H), 3.72
(t, J = 7.8 Hz, 1H), 3.53 (br s, 1H), 3.37 (dd, J = 7.2, 2.4, 1H), 2.45–
2.17 (m, 3H), 1.45 (s, 3H), 1.38 (s, 3H); 13C NMR (75 MHz, CDCl3)
138.1 (Cq), 134.4 (CH), 128.3 (CH), 128.2 (CH), 127.8 (CH), 117.8
(CH2), 109.2 (Cq), 80.2 (CH), 77.4 (CH), 74.0 (CH2), 71.0 (CH), 66.0
(CH2), 38.9 (CH2), 26.5 (CH3), 25.4 (CH3); HRMS for C17H24O4+Na
calcd 315.1572; found 315.1578.
obtain diol 7 (37 mg) in 81% yield as a colorless oil. [
a
]
D = +3.7
(c 4.0, CHCl3); IR (neat) 3430, 2932, 2891, 1101, 1036 cmÀ1
;
1H
NMR (400 MHz, CDCl3) d 7.42–7.20 (m, 5H), 5.83 (ddt, J = 17.1,
10.2, 7.0 Hz, 1H), 5.10 (dd, J = 16.6, 8.6 Hz, 2H), 4.77, 4.59 (ABq,
J = 11.3 Hz, 2H), 4.69, 4.67 (ABq, J = 6.8 Hz, 2H), 3.92–3.80
(m, 2H), 3.63 (d, J = 5.2 Hz, 2H), 3.54 (t, J = 4.7 Hz, 1H), 3.37
(s, 3H), 2.59 (br s, 1H), 2.56–2.45 (m, 1H), 2.44–2.30 (m, 1H), 2.28
(br s, 1H); 13C NMR (100 MHz, CDCl3) 137.6 (Cq), 134.6 (CH), 128.4
(CH), 128.07 (CH), 128.0 (CH), 117.4 (CH2), 96.6 (CH2), 79.6 (CH),
77.1 (CH), 74.1 (CH2), 70.8 (CH), 64.0 (CH2), 55.7 (CH3), 35.2 (CH2);
HRMS for C16H24O5+Na calcd 319.1521; found 319.1519.
4.3. (2S,3R,4R)-3-(Benzyloxy)-4-(methoxymethoxy)hept-6-ene-
1,2-diol 7
To a pre-cooled (0 °C) solution of 5 (0.20 g, 0.68 mmol), in
CH2Cl2 (3 mL) was added DIPEA (0.59 mL, 3.42 mmol), followed
by MOMCl (0.2 mL, 2.73 mmol) under an argon atmosphere. The
reaction mixture was stirred at room temperature for 3 h and after
the reaction was complete (TLC), it was poured into cold water
(15 mL) and extracted with EtOAc (3 Â 10 mL). The organic layer
was washed with brine (5 mL) and dried over Na2SO4. The residue
obtained after concentration was purified by column chromatogra-
phy using petroleum ether/ethyl acetate (4:1) as eluent to yield the
corresponding MOM ether (0.18 g) in 77% yield as a colorless oil.
4.4. (2S,3R,4R)-3-(Benzyloxy)-1-(tert-butyldimethylsilyloxy)-4-
(methoxymethoxy)-2-(p-toluenesulfonyloxy)-hept-6-ene 8
To a pre-cooled (0 °C) solution of 7 (0.37 g, 1.23 mmol) in DMF
(0.5 mL) were added DMAP (30 mg, 0.24 mmol) and imidazole
(0.25 g, 3.72 mmol) followed by TBSCl (0.37 g, 2.46 mmol) under
an argon atmosphere. The reaction mixture was stirred at room
temperature for 12 h. After the reaction was complete (TLC), it
was poured into cold water (20 mL) and extracted with diethyl
ether (2 Â 15 mL). The ether layer was washed with brine
(15 mL) and dried over Na2SO4. Evaporation of the solvent and
purification of the resulting residue by column chromatography
using petroleum ether/EtOAc (85:15) as eluent furnished the TBS
[
a]
D = À46.2 (c 0.8, CHCl3); IR (neat) 2986, 2888, 1370, 1156,
1036 cmÀ1 1H NMR (400 MHz, CDCl3) d 7.38–7.16 (m, 5H), 5.62
;
(ddt, J = 16.8, 9.4, 7.0 Hz, 1H), 5.02–4.89 (m, 2H), 4.77, 4.65 (ABq,
J = 11.8 Hz, 2H), 4.57, 4.53 (ABq, J = 6.9 Hz, 2H), 4.31 (dd, J = 14.0,
7.3 Hz, 1H), 3.97 (dd, J = 8.2, 6.2 Hz, 1H), 3.63 (t, J = 8 Hz, 1H),
3.55 (ddd, J = 10.0, 6.5, 3.6 Hz, 1H), 3.37 (dd, J = 7.0, 3.4 Hz, 1H),
3.28 (s, 3H), 2.52–2.35 (m, 1H), 2.30–2.13 (m, 1H), 1.37 (s, 3H),

2856
K. R. Prasad, K. Penchalaiah / Tetrahedron: Asymmetry 21 (2010) 2853–2858
ether (0.42 g) in 83% yield as a colorless oil. [
a
]
D = +14.7 (c 2.4,
1H NMR
cold water at 0 °C. The reaction mixture was extracted with diethyl
ether (3 Â 15 mL) and the combined ether extracts were washed
with brine (10 mL) and dried over Na2SO4. Residue obtained after
evaporation of solvent was purified by column chromatography
using petroleum ether/EtOAC (7:3) as eluent to obtain 9 (0.58 g)
CHCl3); IR (neat) 3447, 2952, 1471, 1255, 915 cmÀ1
;
(400 MHz, CDCl3) d 7.40–7.21 (m, 5H), 5.85 (ddt, J = 17.1, 10.1,
7.1 Hz, 1H), 5.10 (dd, J = 15.4, 8.6 Hz, 2H), 4.77, 4.64 (ABq,
J = 11.2 Hz, 2H), 4.72, 4.68 (ABq, J = 6.8 Hz, 2H), 3.88 (dd, J = 11.3,
6.2 Hz, 1H), 3.84–3.75 (m, 1H), 3.66 (dd, J = 6.0, 2.5 Hz 1H), 3.63
(dd, J = 9.8, 6.0 Hz, 1H), 3.53 (dd, J = 9.8, 6.9 Hz, 1H) 3.37 (s, 3H),
2.61–2.47 (m, 1H), 2.45–2.13 (m, 2H), 0.89 (s, 9H), 0.05 (s, 6H);
13C NMR (100 MHz, CDCl3) 138.2 (Cq), 134.7 (CH), 128.3 (CH),
128.0 (CH), 127.8 (CH), 117.3 (CH2), 96.6 (CH2), 78.4 (CH), 77.5
(CH), 74.6 (CH2), 70.9 (CH), 64.0 (CH2), 55.8 (CH3), 35.7 (CH2),
25.8 (CH3), 18.1 (Cq), À5.4 (CH3); HRMS for C22H38O5Si+Na calcd
433.2386; found 433.2385.
To a stirred solution of the TBS ether prepared above (0.37 g,
0.89 mmol) in CH2Cl2 (3 mL) were added DMAP (0.33 g,
2.69 mmol), followed by p-TsCl (0.34 g, 1.79 mmol) at room tem-
perature under an argon atmosphere. The reaction mixture was
stirred for 12 h at the same temperature. After completion of the
reaction (TLC), it was poured into water (10 mL) and extracted
with diethyl ether (2 Â 15 mL). The combined organic extracts
were washed with brine (10 mL) and dried over Na2SO4. Evapora-
tion of the solvent followed by column chromatography of the
resulting residue using petroleum ether/EtOAc (85:15) as eluent
in 90% yield as a colorless oil. [
a
]
D = À8.9 (c 0.6, CHCl3); IR (neat)
3480, 2932, 1454, 1097 cmÀ1 1H NMR (400 MHz, CDCl3) d 7.40–
;
7.20 (m, 5H), 5.81 (ddt, J = 17.1, 10.1, 7.0 Hz, 1H), 5.12
(d, J = 16.8 Hz, 1H), 5.08 (d, J = 9.3 Hz, 1H), 4.68 (s, 2H), 4.65
(d, J = 4.1 Hz, 2H), 3.99 (dq, J = 12.7, 6.4 Hz, 1H), 3.92 (dt, J = 11.0,
5.0 Hz, 1H), 3.41 (s, 3H), 3.29 (dd, J = 7.0, 3.6 Hz, 1H), 3.20
(d, J = 4.5 Hz, 1H), 2.62–2.24 (m, 2H), 1.26 (d, J = 6.3 Hz, 3H); 13C
NMR (100 MHz, CDCl3) 138.1 (Cq), 134.6 (CH), 128.3 (CH), 127.9
(CH), 127.7 (CH), 117.6 (CH2), 96.9 (CH2), 83.2 (CH), 77.9 (CH), 73.9
(CH2), 66.8 (CH), 56.0 (CH3), 35.4 (CH2), 19.6 (CH3); HRMS for
C16H24O4+Na calcd 303.1572; found 303.1573.
4.6. (4R,5R)-4-((R)-1-(Methoxymethoxy)but-3-enyl)-2,2,5-
trimethyl-1,3-dioxolane 4
Lithium was added to pre-cooled (À78 °C) liquid NH3 followed
by a THF (2 mL) solution of 9 (75 mg, 0.26 mmol). The reaction
mixture was stirred at the same temperature for 1 h and solid
NH4Cl (50 mg) was added followed by water (20 mL). The reaction
mixture was allowed to return to room temperature and was ex-
tracted with ethyl acetate (3 Â 10 mL). The combined organic layer
was washed with brine (5 mL) and dried over Na2SO4. Evaporation
of the solvent followed by column chromatography of the resulting
residue using petroleum/EtoAc (1:3) as eluent to furnish the diol
yielded 8 (0.47 g) in 94% yield as a colorless oil. [
a]
D = À8.1
(c 0.6, CHCl3); IR (neat) 2950, 1364, 1256, 1176, 913 cmÀ1
;
1H NMR
(400 MHz, CDCl3) d 7.77 (d, J = 8.2 Hz, 2H), 7.36–7.18 (m, 7H),
5.80–5.58 (m, 1H), 5.14–4.89 (m, 2H), 4.79 (dd, J = 9.9, 4.4 Hz,
1H), 4.66, 4.64 (ABq, J = 7.0 Hz, 2H), 4.60, 4.56 (ABq, J = 11.3 Hz,
2H), 3.95 (dd, J = 11.4, 4.4 Hz, 1H), 3.90–3.76 (m, 2H), 3.76 (dd,
J = 10.7, 6.0 Hz, 1H), 3.35 (s, 3H), 2.48–2.34 (m, 4H), 2.34–2.21
(m, 1H), 0.86 (s, 9H), 0.03 (s, 3H), 0.02 (s, 3H); 13C NMR
(100 MHz, CDCl3) 144.5 (Cq), 138.0 (Cq), 134.2 (Cq), 134.0 (CH),
129.6 (CH), 128.2 (CH), 128.0 (CH), 127.7 (CH), 127.6 (CH), 117.7
(CH2), 96.3 (CH2), 82.8 (CH), 77.2 (CH), 76.5 (CH), 74.8 (CH2), 61.4
(CH2), 55.9 (CH3), 35.2 (CH2), 25.7 (CH3), 21.5 (CH3), 18.1 (Cq),
À5.52 (CH3), À5.58 (CH3); HRMS for C29H44O7SSi+Na calcd
587.2475; found 587.2476.
(44 mg) in 87% yield as a colorless oil. [
a]
D = À59.8 (c 3.5, CHCl3);
IR (neat) 3429, 2969, 1149, 1028 cmÀ1 1H NMR (400 MHz, CDCl3)
;
d 5.81 (ddt, J = 17.1, 10.0, 6.9 Hz, 1H), 5.15 (dd, J = 18.6, 1.5 Hz, 1H),
5.10 (dd, J = 11.4, 1.2 Hz, 1H), 4.71 (ABq, J = 6.6 Hz, 2H), 3.82 (dq,
J = 6.6, 3.3 Hz, 1H), 3.76 (dt, J = 12.6, 6.6 Hz, 1H), 3.42 (s, 3H),
3.34 (dd, J = 6.3, 3 Hz, 1H), 2.69 (br s, 1H), 2.41 (dd, J = 7.2,
1.2 Hz, 1H), 2.39 (dd, J = 7.5, 1.2 Hz, 1H), 1.27 (d, J = 6.6 Hz, 3H);
13C NMR (100 MHz, CDCl3) 134.0 (CH), 117.9 (CH2), 96.8 (CH2),
77.7 (CH), 76.0 (CH), 67.9 (CH), 55.9 (CH3), 35.9 (CH2), 19.0
(CH3); HRMS for C9H18O4+Na calcd 213.1103; found 213.1101.
To a solution of the diol prepared above (0.1 g, 0.52 mmol) in
CH2Cl2 (2 mL) were added PPTS (26 mg, 0.10 mmol) followed by
2,2-dimethoxy propane (0.12 mL, 1.05 mmol) at room temperature
under an argon atmosphere. The reaction mixture was stirred at
room temperature for 24 h and after the reaction was complete
(TLC), NaHCO3 (30 mg) was added and stirred for 10 min. It was
then filtered through a short pad of Celite, and the Celite pad
was washed with CH2Cl2 (10 mL). Evaporation of solvent followed
by column chromatography using petroleum ether/EtOAc (7:3) as
4.5. (2R,3R,4R)-3-(Benzyloxy)-4-(methoxymethoxy)hept-6-en-
2-ol 9
To a solution of 8 (0.48 g, 0.85 mmol) in THF (3 mL) was added
TBAF (1.4 mL, 1.27 mmol) at 0 °C dropwise under an argon atmo-
sphere. The reaction mixture was stirred at room temperature for
6 h. After the reaction was complete (TLC), it was poured into cold
water (10 mL) and extracted with diethyl ether (3 Â 15 mL). Com-
bined ether extracts were washed with brine (15 mL) and dried
over Na2SO4. Evaporation of solvent followed by column chroma-
tography of the resulting residue using petroleum ether/EtoAc
(4:1) as eluent furnished the epoxide (0.20 g) in 86% yield as a col-
eluent yielded 4 (0.11 g) in 90% as a colorless oil. [
(c 1.3, CHCl3); IR (neat) 2983, 2935, 2894, 1650, 1540, 1376, 1247,
1218, 1100, 1079, 1039, 1026, 916, 859 cmÀ1 1H NMR (400 MHz,
a]D = +76.5
orless oil. [
a]
D = À3.9 (c 1.5, CHCl3); IR (neat) 2927, 1102, 1039,
;
916 cmÀ1 1H NMR (400 MHz, CDCl3) d 7.38–7.08 (m, 5H), 5.66
;
CDCl3) d 5.99–5.83 (m, 1H), 5.11 (dd, J = 11.1, 8.8 Hz, 2H), 4.87,
4.70 (ABq, J = 6.8 Hz, 2H), 4.20 (dt, J = 12.2, 6.1 Hz, 1H), 4.06 (dd,
J = 10, 7.5 Hz, 1H), 3.72 (dd, J = 10.8, 7.5 Hz, 1H), 3.41 (s, 3H), 2.41–
2.27 (m, 1H), 2.26–2.14 (m, 1H), 1.46 (s, 3H), 1.33 (s, 3H), 1.17
(d, J = 6.38 Hz, 3H); 13C NMR (100 MHz, CDCl3) 134.1 (CH), 117.5
(CH2), 108.1 (Cq), 96.4 (CH2), 79.9 (CH), 74.9 (CH), 72.8 (CH), 55.7
(CH3), 36.5 (CH2), 28.4 (CH3), 26.0 (CH3), 16.5 (CH3); HRMS for
(ddt, J = 17.2, 10.1, 7.1 Hz, 1H), 5.06–4.90 (m, 2H), 4.64 (s, 2H),
4.61, 4.46 (ABq, J = 11.7 Hz, 2H), 3.73 (td, J = 6.6, 3.4 Hz, 1H), 3.31
(s, 3H), 3.28 (dd, J = 5.1, 3.5 Hz, 1H), 3.14–2.96 (m, 1H), 2.72 (dd,
J = 5.3, 3.9 Hz, 1H), 2.64 (dd, J = 5.3, 2.6 Hz, 1H), 2.50–2.37
(m, 1H), 2.36–2.24 (m, 1H); 13C NMR (100 MHz, CDCl3) 138.1
(Cq), 134.5 (CH), 128.3 (CH), 127.9 (CH), 127.7 (CH), 117.5 (CH2),
96.4 (CH2), 78.1 (CH), 77.5 (CH), 73.2 (CH2), 55.7 (CH3), 50.8
(CH2), 45.8 (CH), 35.1 (CH2); HRMS for C16H22O4+Na calcd
301.1416; found 301.1414.
C12H22O4+Na calcd 253.1416; found 253.1413.
4.7. (R,E)-Ethyl 5-(methoxymethoxy)-5-((4R,5R)-2,2,5-
To a pre-cooled solution (0 °C) of the epoxide prepared above
(0.65 g, 2.33 mmol) in THF (10 mL) was added LAH (0.18 g,
4.66 mmol) in one portion. The reaction mixture was stirred at
room temperature for 2 h and after the reaction was complete
(TLC), it was quenched by addition of excess EtOAc followed by
trimethyl-1,3-dioxolan-4-yl)pent-2-enoate 10
Ozone was bubbled through a pre-cooled (À78 °C) solution of 4
(107 mg, 0.46 mmol) in a mixture of CH2Cl2/MeOH (4:1, 10 mL),
containing solid NaHCO3 (10 mg) until the pale blue color

K. R. Prasad, K. Penchalaiah / Tetrahedron: Asymmetry 21 (2010) 2853–2858
2857
persisted. Excess ozone was flushed off with oxygen and Me2S
(0.5 mL) was added. The reaction mixture was warmed to 0 °C
and stirred for 3 h. The reaction mixture was concentrated under
reduced pressure and filtered through a short pad of Celite. The
Celite pad was washed with ether (20 mL). Evaporation of the sol-
vent yielded the crude aldehyde which was subjected to the next
reaction without further purification.
To a solution of the crude aldehyde (obtained above), in toluene
(2 mL) was added the ylide Ph3PHC@CHCO2Et (0.24 g, 0.69 mmol)
and refluxed for 2 h. After the reaction was complete (TLC), most
of the solvent was evaporated off and the residue obtained was
purified by column chromatography using petroleum ether/EtOAc
(4:1) as eluent to obtain the unsaturated ester 10 (90 mg) in 64%
layers were washed with brine (5 mL) and dried over Na2SO4.
Evaporation of solvent followed by column chromatography of
the resulting residue with petroleum ether/EtOAc (1:1) as eluent
afforded 12 (57 mg) in 52% overall yield as a colorless oil.
[a]D = +49.3 (c 2.8, CHCl3); IR (neat) 3430, 2981, 2932, 1593,
1377, 1218, 1076, 1028, 916, 857 cmÀ1; 1H NMR (400 MHz, CDCl3)
d 5.87–5.67 (m, 2H), 5.56 (dd, J = 15.5, 6.0 Hz, 1H), 5.12 (d, J =
6.5 Hz, 1H), 5.08 (s, 1H), 4.82, 4.67 (ABq, J = 6.8 Hz, 2H), 4.18 (dt,
J = 12.0, 5.9 Hz, 1H), 4.13 (dd, J = 12.1, 5.9 Hz, 1H), 4.03, (dd,
J = 7.7, 5.7 Hz, 1H), 3.66 (dd, J = 11.5, 7.3 Hz, 1H), 3.38 (s, 3H),
2.37–2.10 (m, 4H), 1.92 (br s, 1H), 1.43 (s, 3H), 1.30 (s, 3H), 1.14
(d, J = 6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) 135.1 (CH), 134.1
(CH), 126.7 (CH), 118.1 (CH2), 108.1 (Cq), 96.3 (CH2), 79.7 (CH),
75.2 (CH), 72.8 (CH), 71.3 (CH), 55.7 (CH3), 41.8 (CH2), 34.8 (CH2),
28.3 (CH3), 25.9 (CH3), 16.3 (CH3); HRMS for C16H28O5+Na calcd
323.1834; found 323.1835.
overall yield as a colorless oil. [
a
]
D = +54.7 (c 1.9, CHCl3); IR (neat)
2984, 2936, 1718, 1654, 1370, 1218, 1099, 1035, 858 cmÀ1
;
1H
NMR (400 MHz, CDCl3) d 7.0 (dt, J = 15.2, 7.4 Hz, 1H), 5.87 (d,
J = 15.6 Hz, 1H), 4.85, 4.63 (ABq, J = 7.2 Hz, 2H), 4.15 (q, 2H),
4.26–4.02 (m, 1H), 4.0 (dd, J = 7.9, 5.8 Hz, 1H), 3.75 (dd, J = 11.1,
6.9 Hz, 1H), 3.36 (s, 3H), 2.51–2.25 (m, 2H), 1.42 (s, 3H), 1.29 (s,
3H), 1.25 (t, J = 7.1 Hz, 3H), 1.15 (d, J = 6.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) 166.0 (Cq), 144.3 (CH), 123.8 (CH), 108.3 (Cq),
96.5 (CH2), 79.8 (CH), 74.4 (CH), 72.7 (CH), 60.2 (CH2), 55.8 (CH3),
34.8 (CH2), 28.1 (CH3), 25.8 (CH3), 16.2 (CH3) 14.1 (CH3); HRMS
for C15H26O6+Na calcd 325.1627; found 325.1629.
4.10. (E,4R,8R)-8-(Methoxymethoxy)-8-((4R,5R)-2,2,5-
trimethyl-1,3-dioxolan-4-yl)octa-1,5-dien-4-yl acrylate 3
To a pre-cooled (0 °C) solution of 12 (0.1 g, 0.33 mmol) in
CH2Cl2 (5 mL) were added Et3N (0.3 mL, 2.33 mmol) followed by
acryloyl chloride (0.13 mL, 1.66 mmol) dropwise under argon
atmosphere. It was stirred at 0 °C for 1 h and after the reaction
was complete (TLC), it was poured into cold water and extracted
with ether (3 Â 10 mL). The combined ether layer was washed
with brine (10 mL) and dried over Na2SO4. Evaporation of the sol-
vent followed by column chromatography of the residue with
petroleum ether/EtOAc (9:1) as eluent furnished the acrylate ester
4.8. (R,E)-5-(Methoxymethoxy)-5-((4R,5R)-2,2,5-trimethyl-1,3-
dioxolan-4-yl)pent-2-en-1-ol 11
To a pre-cooled (À78 °C) solution of the ester 10 (90 mg,
0.29 mmol), in THF (2 mL), was added DIBAL-H (1.8 mL of 1 M
solution in THF, 1.8 mmol) under an argon atmosphere and stirred
for 2 h. After the reaction was complete (TLC), it was quenched
with saturated potassium sodium tartrate (5 mL) and poured into
water (10 mL) and extracted with EtOAc. The combined organic ex-
tracts were washed with brine and dried over Na2SO4. Evaporation
of solvent followed by column chromatography of the resulting
residue with petroleum ether/EtOAc (2:3), as eluent furnished
the allylic alcohol 11 (76 mg) in 98% yield as a colorless oil.
3 (83 mg) in 70% yield as a colorless oil. [
IR (neat) 2981, 2933, 1719, 1540, 1400, 1266, 1189, 1036, 917,
857 cmÀ1 1H NMR (400 MHz, CDCl3) d 6.38 (d, J = 17.2 Hz, 1H),
a]D = +51.3 (c 1.4, CHCl3);
;
6.09 (dd, J = 17.2, 10.4 Hz, 1H), 5.86–5.69 (m, 3H), 5.53
(dd, J = 15.3, 6.7 Hz, 1H), 5.36 (dd, J = 12.8, 6.3 Hz, 1H), 5.08 (dd,
J = 17.4, 10.3 Hz, 2H), 4.83, 4.66 (ABq, J = 6.9 Hz, 2H), 4.16 (dt,
J = 12.2, 6.2 Hz, 1H), 4.02 (dd, J = 8.1, 5.5 Hz, 1H), 3.67 (dq, J = 6.6,
4.2 Hz, 1H), 3.37 (s, 3H), 2.47–2.36 (m, 2H), 2.35–2.13 (m, 2H),
1.44 (s, 3H), 1.31 (s, 3H), 1.14 (d, J = 6.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) 165.3 (Cq), 133.0 (CH), 130.7 (CH2), 130.5 (CH),
129.4 (CH), 128.6 (CH), 118.0 (CH2), 108.1 (Cq), 96.3 (CH2), 79.7
(CH), 74.9 (CH), 73.5 (CH), 72.7 (CH), 55.7 (CH3), 38.9 (CH2), 35.0
(CH2), 28.3 (CH3), 25.9 (CH3), 16.4 (CH3); HRMS for C19H30O6+Na
calcd 377.1940; found 377.1939.
[
a]
D = +57.9 (c 1.5, CHCl3); IR (neat) 3417, 2983, 2925,1449, 1373,
1219 cmÀ1 1H NMR (400 MHz, CDCl3) d 5.89–5.55 (m, 2H), 4.82,
;
4.66 (ABq, J = 6.8 Hz, 2H), 4.17 (dt, J = 11.9, 6.0 Hz, 1H), 4.07
(d, J = 4.8 Hz, 2H), 4.02 (dd, J = 7.0, 5.8 Hz, 1H), 3.73–3.55 (m, 1H),
3.37 (s, 3H), 2.37–1.96 (m, 3H), 1.43 (s, 3H), 1.30 (s, 3H), 1.13 (d,
J = 6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) 132.0 (CH), 127.6
(CH), 108.1 (Cq), 96.4 (CH2), 79.8 (CH), 75.2 (CH), 72.8 (CH), 63.2
(CH2), 55.6 (CH3), 34.8 (CH3), 28.3 (CH3), 25.9 (CH3), 16.3 (CH3);
HRMS for C13H24O5+Na calcd 283.1521; found 283.1532.
4.11. (R)-5,6-Dihydro-6-((R,E)-4-(methoxymethoxy)-4-((4R,5R)-
2,2,5-trimethyl-1,3-dioxolan-4-yl)but-1-enyl)pyran-2-one 13
To a solution of the acrylate ester 3 (46 mg, 0.12 mmol) in
CH2Cl2 (13 mL) was added Grubbs 1st generation catalyst (21 mg,
0.025 mmol) under an argon atmosphere and refluxed for 12 h.
After completion of the reaction, the solvent was evaporated off
and the residue thus obtained was purified by column chromatog-
raphy using petroleum ether/EtOAc (1:1) as eluent to furnish lac-
4.9. (E,4R,8R)-8-(Methoxymethoxy)-8-((4R,5R)-2,2,5-trimethyl-
1,3-dioxolan-4-yl)octa-1,5-dien-4-ol 12
To a solution of the allylic alcohol 11 (76 mg, 0.29 mmol) in
CH2Cl2 (1 mL) was added MnO2 (0.25 g, 2.92 mmol) at room tem-
perature under an argon atmosphere and stirred for 24 h. After
the reaction was complete (TLC), it was filtered through a short
pad of Celite. The Celite pad was washed with CH2Cl2 and the crude
aldehyde obtained after evaporation of solvent was used as such
without further purification in the next step.
To a pre-cooled (À78 °C) solution of (+)-allylB(Ipc)2 (0.5 mL,
0.43 mmol) in ether (2 mL) was added the crude aldehyde obtained
above dissolved in ether (2 ml) under an argon atmosphere. The
reaction mixture was stirred at À78 °C 1.5 h and was quenched
by a solution of phosphate buffer (pH 7) solution (1 mL), MeOH
(1 mL), followed by 30% H2O2 (0.5 mL). After stirring for 30 min,
the reaction mixture was poured into a saturated NaHCO3 solution
and extracted with EtOAc (3 Â 10 mL). The combined organic
tone 13 (36 mg) in 85% yield. [
2983, 2935, 1721, 1380, 1245, 1220, 1151, 1099, 1079, 1031,
817 cmÀ1 1H NMR (400 MHz, CDCl3) d 6.87 (dt, J = 9.3, 4.2 Hz,
a]D = +83.4 (c 1.0, CHCl3); IR (neat)
;
1H), 6.04 (d, J = 9.7 Hz, 1H), 5.93 (dt, J = 14.7, 6.9 Hz, 1H), 5.68
(dd, J = 15.4, 6.3 Hz, 1H), 4.89 (dd, J = 14.8, 6.7 Hz, 1H), 4.85, 4.67
(ABq, J = 6.9 Hz, 2H), 4.20 (dt, J = 12.6, 6.1 Hz, 1H), 4.03 (dd,
J = 7.9, 5.7 Hz, 1H), 3.70 (dq, J = 7.0, 4.4 Hz, 1H), 3.39 (s, 3H),
2.49–2.18 (m, 4H), 1.45 (s, 3H), 1.32 (s, 3H), 1.17 (d, J = 6.4 Hz,
3H); 13C NMR (100 MHz, CDCl3) 163.9 (Cq), 114.5 (CH), 130.4
(CH), 129.6 (CH), 121.6 (CH), 108.2 (Cq), 96.5 (CH2), 79.6 (CH),
77.7 (CH), 75.0 (CH), 72.8 (CH), 55.8 (CH3), 34.8 (CH2), 29.6 (CH2),
28.2 (CH3), 25.9 (CH3), 16.3 (CH3); HRMS for C17H26O6+Na calcd
349.1627; found 349.1627.

2858
K. R. Prasad, K. Penchalaiah / Tetrahedron: Asymmetry 21 (2010) 2853–2858
4.12. Synargentolide 1a
Acknowledgments
To the pre-cooled (0 °C) solution of the lactone 13 (43 mg,
0.13 mmol), was added 90% aq TFA (2 mL) and stirred at room tem-
perature for 1 h. After the reaction was complete (TLC), most of the
TFA was removed under reduced pressure and the residue thus ob-
tained was purified by column chromatography using MeOH/
EtOAc (1:9) as eluent to furnish triol 2, which was subjected to
the next reaction.
To a pre-cooled (0 °C) solution of triol 2 obtained above in
CH2Cl2 (4 mL) was added DMAP (3 mg, .0.026 mmol), triethyl-
amine (0.18 mL, 1.31 mmol) followed by Ac2O (0.1 mL, 1.05 mmol)
under an argon atmosphere. The reaction mixture was stirred at
room temperature for 1 h and after completion of the reaction; it
was poured into cold water and extracted with EtOAc
(3 Â 10 mL). The combined organic layers were washed with brine
(5 mL) and dried over Na2SO4. Evaporation of solvent followed by
column chromatography of the residue using petroleum ether/
EtOAc (2:3) as eluent furnished synargentolide A 1a (25 mg) in
K.R.P. is swarnajayanthi fellow of the Department of Science
and Technology (DST), New Delhi and thanks the DST for funding.
K.P. thanks the council of scientific and industrial research (CSIR),
New Delhi for a senior research fellowship.
References
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Gandi, V. R.; Nidhiry, J. E.; Bhat, K. S. Synthesis 2010, 2521; Prasad, K. R.; Pawar,
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Anbarasan, P. Tetrahedron: Asymmetry 2006, 17, 1146; Prasad, K. R.;
Anbarasan, P. Tetrahedron: Asymmetry 2006, 17, 2465.
6. Al-Hakim, A. H.; Haines, A. H.; Morley, C. Synthesis 1985, 207.
7. Williams, D. R.; Kingler, F. D. Tetrahedron Lett. 1987, 28, 869.
8. Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105, 2092; For a short review
of the application of this reagent see: Ramachandran, P. V.; Reddy, M. V.;
Brown, H. C. Pure Appl. Chem. 2003, 75, 1263.
52% overall yield as a colorless oil. [
D = +40.0 (c 1.1, CHCl3); IR (neat) 2987, 2941, 1739, 1429,
1373, 1222, 1056, 1025, 818 cmÀ1 1H NMR (400 MHz, CDCl3) d
a]D = +66.4 (c 1.0, CHCl3); Lit
[a]
;
6.84 (dt, J = 8.8, 3.9 Hz, 1H), 6.0 (d, J = 9.9 Hz, 1H), 5.80–5.65 (m,
1H), 5.62 (dd, J = 15.5, 5.9 Hz, 1H), 5.17 (td, J = 6.5, 3.1 Hz, 1H),
5.06 (dd, J = 7.4, 3.1 Hz, 1H), 4.95 (dt, J = 12.8, 6.4 Hz, 1H), 4.84
(dt, J = 9.4, 5.8 Hz, 1H), 2.46–2.33 (m, 2H), 2.32–2.21 (m, 2H),
2.13 (s, 3H), 2.03 (s, 3H), 1.99 (s, 3H), 1.16 (d, J = 5.6 Hz, 3H); 13C
NMR (100 MHz, CDCl3) 170.22 (Cq), 170.12 (Cq), 170.0 (Cq),
163.7 (Cq), 144.5 (CH), 131.0 (CH), 128.5 (CH), 121.5 (CH), 77.6
(CH), 73.6 (CH), 69.5 (CH), 67.3 (CH), 33.9 (CH2), 29.5 (CH), 21.0
(CH3), 20.8 (CH3), 20.7 (CH3), 16.1 (CH3); HRMS for C18H24O8+Na
calcd 391.1369; found 391.1369.
9. (a) Grubbs, R. H. Tetrahedron 2004, 60, 7117; (b) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413.
10. The synthetic sample prepared by Sabitha et al. was reported to exhibit a
rotation comparable to that of the natural product, although there was a typo
in the NMR data of the natural product reported by Sabitha et al.,3 Sabitha, G.
Personal communication. Also see Corrigendum to ‘First stereoselective
synthesis of synargentolide
A and revision of absolute stereochemistry’
[Tetrahedron Lett. 2009, 58, 6298–6302]. We consistently observed a higher
rotation for our synthetic sample than that reported for the natural product.
This perhaps might be the result of the better purity of our synthetic sample.