Total synthesis of the phytotoxic stagonolides A and B

Article abstract of DOI:10.1016/j.tetasy.2010.01.010

The chemo-enzymatic and covergent synthesis of stagonolide B and the synthesis of stagonolide A, a phytotoxic 10-membered lactone have been achieved starting from d-ribose with overall yields of 25% and 8.7%, respectively. The synthesis contained simple steps in developing three centers' key intermediates, namely the enzymatic (Novozyme-435) resolution of a propargylic alcohol followed by macrolactonization and RCM.

Full text of DOI:10.1016/j.tetasy.2010.01.010

Tetrahedron: Asymmetry 21 (2010) 216–221
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Total synthesis of the phytotoxic stagonolides A and B
Peddikotla Prabhakar, Singanaboina Rajaram, Dorigondla Kumar Reddy, Vanam Shekar,
*
Yenamandra Venkateswarlu
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 003, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 November 2009
Accepted 20 January 2010
The chemo-enzymatic and covergent synthesis of stagonolide B and the synthesis of stagonolide A, a phy-
totoxic 10-membered lactone have been achieved starting from D-ribose with overall yields of 25% and
8.7%, respectively. The synthesis contained simple steps in developing three centers’ key intermediates,
namely the enzymatic (Novozyme-435) resolution of a propargylic alcohol followed by macrolactoniza-
tion and RCM.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
tion of acid intermediate 17 with intermediate 7 followed by RCM.
Intermediate 17 was prepared from 1,4-butanediol.
Stagonospora crisii (a pathogen of Crisium arvense) is a perennial
noxious weed, which produces six phytotoxic metabolites, all
these are usually mentioned as stagonolides. Structurally stagono-
lides A and B are very similar to those of herbarumins, and are phy-
totoxins with potential herbicidal activity isolated from Phoma
herbarum.1 The initial structural and stereochemical assignment
of stagonolide A was established by Berestetskiy et al.2 Stagonolide
B was established by Evidente et al.3 by spectroscopic studies.
Ramana et al.4 further established the structure by total synthesis
and X-ray analysis. Stagonolide A has shown very good phytotoxic
activity compared with the other stagonolides. Herein we report
the chemo-enzymatic and covergent synthesis of stagonolide B
As outlined in Scheme 2, intermediate 7 was prepared from
D-ri-
bose, following the literature procedure.6 The
D
-ribose, protected as
an acetonide and methylated at the anomeric hydroxyl group, was
prepared in one pot to give compound 4 in 91% yield. The compound
4 was reacted with iodine in the presence of triphenyl phosphine
and imidazole at reflux to give iodo compound7 5 in 95% yield, which
was reacted with Zn in ethanol to give a low-boiling Vasell’ interme-
diate8 6 in 89% yield. Compound 6 without purification was reacted
with n-propyl magnesium bromide to give compound 7 (anti/trans:-
syn/cis: 81:19) in 95% yield. The required anti/trans isomer was puri-
fied chromatographically to yield 7 in 79% yield.
The 1,4-butane diol was protected with benzyl bromide to give
benzyl ether 9 in 95% yield; the primary alcohol in the benzyl-pro-
tected butanol 9 was oxidized with pyridinium chlorochromate to
give compound 10 in 92% yield, which was reacted with ethynyl
magnesium bromide in tetrahydrofuran to give racemic propargy-
lic alcohol9 11 in 82% yield. Following the literature procedure, we
carried out the chemo-enzymatic (Novozyme-435) resolution9 of
compound 11 using vinylacetate in diisopropyl ether to give com-
pound (R)-12 (53% yield, 80% ee) and acetylated compound (S)-12
(45% yield, 90%ee). Partial hydrogenation9 of compound (R)-12
using Lindlar catalyst (palladium on CaCO3, poisoned with Pb) in
ethyl acetate gave compound 13 in 86% yield, and the secondary
alcohol in compound 13 was protected with methoxy methyl chlo-
ride10 (MOM-Cl) using N,N-diisopropylethylamine (DIPEA) in
dichloromethane to give compound 14 in 94% yield. The debenzy-
lation11 of compound 14 was carried out with Li–naphthalenide in
dry THF at ꢀ25 °C to give compound 15 in 82% yield, which was
oxidized with IBX acid (2-iodoxy benzoicacid) to afford aldehyde
16 in 94% yield. Oxidation12 of 16 with NaClO2 and NaH2PO4 affor-
ded acid 17 in 98% yield.
and the synthesis of stagonolide A from D-ribose as a chiral source.
OH
OH
OH
O
O
O
HO
O
O
Stagonolide A 1
Stagonolide B 2
2. Results and discussion
The retro synthetic analysis of stagonolides A and B is outlined in
Scheme 1. Stagonolide A was prepared by the esterification of read-
ily available 5-hexenoic acid with intermediate 7 followed by RCM.5
The intermediate 7 was prepared from the Vasella fragmentation of
the D-ribose derivative. Stagonolide B was prepared by the esterifica-
Acid compound 17 was esterified with the previously prepared
compound 7 in the presence of DCC and DMAP in dry dichlorometh-
* Corresponding author. Tel.: +91 40 27193167; fax: +91 40 27160512.
E-mail address: luchem@iict.res.in (Y. Venkateswarlu).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.01.010

P. Prabhakar et al. / Tetrahedron: Asymmetry 21 (2010) 216–221
217
O
HO
O
+
O
O
OH
HO
HO
HO
O
O
O
O
22
7
Stagonolide A
O
OMe
O
O
HO
OH
OH
OH
O
O
O
OH
7
4
O
OMOM
OH
HO
BnO
Stagonolide B
O
17
(R)-12
Scheme 1. Retrosynthesis of stagonolides A and B.
OMe
O
OH
O
O
OMe
a
HO
HO
c
b
I
O
HO
OH
O
O
O
O
O
O
3
4
5
6
HO
d
O
O
7
Scheme 2. Reagents and conditions: (a) 2,2-dimethoxy propane, acetone, HClO4, methanol, 4 h, 91%; (b) I2, PPh3, imidazole, toluene, 2 h, 72%; (c) Zn, EtOH, 90 °C, 89%; (d) n-
propyl magnesium bromide, dry THF, 0 °C, 79%.
ane to give ester compound 18 in 65% yield, which was subjected to
ring closure metathesis (RCM) using Grubbs’ II generation catalyst
to give the protected lactone 19 in 65% (required E-isomer). The
RCM reaction was very smooth and MOM protection did not hinder
the formation of RCM product 19. The removal of the acetonide pro-
tection and MOM-protecting groups was carried out using trifluo-
roacetic acid to give stagonolide B in 90% yield (Scheme 3).
The synthesis of stagonolide A was carried out by esterification5
of 5-hexenoic acid with the previously prepared compound 7 in
the presence of DCC and DMAP to give ester 20 in 95% yield. The
ring closure metathesis (RCM) of compound 20 using Grubbs’ I
generation catalyst led to the protected lactone 21 in 80% yield
(as the required E-isomer). The acetonide-protecting group in com-
pound 21 was carried out using trifluoro acetic acid (TFA) to give
compound 22 in 90% yield, which was oxidized13 with MnO2 to af-
ford stagonolide A 1 in 82% yield (Scheme 4). The physical and
spectroscopic data of synthetically prepared stagonolides A and B
were identical to those of the natural products.
4. Experimental
4.1. General methods
All solvents and reagents were purified by standard techniques.
All column chromatographic separations were performed using sil-
ica gel (Acme’s, 60–120 mesh). The IR spectra were recorded on a
Perkin–Elmer IR-683 spectrophotometer with NaCl optics. Optical
rotations were recorded on a HORIBA SEPA-300 polarimeter,
2 mL cell. 1H and 13C NMR spectra were recorded in CDCl3 solution
on a Varian Gemini 200 and a Brucker Avance 300. Chemical shifts
are reported in parts per million with respect to internal TMS. Cou-
pling constants (J) are quoted in hertz. Mass spectra were recorded
on CEC-21-11013 and Fannigan Mat 1210 double focusing mass
spectrometers operating at a direct inlet system or LC/MSD Trap
SL (Agilent Technologies).
4.1.1. Methyl 2,3-O-(1-methylethylidene)-b-
D-ribofuranoside 4
To a stirred solution of
D
-(ꢀ)-ribose (4.0 g, 26.6 mmol) and 2,2-
3. Conclusion
dimethoxypropane (8 mL, 65.2 mmol) in acetone (25 mL) was
added perchloric acid (aq 70%, 1.6 mL, 18.4 mmol) dropwise at
0 °C and stirred for 2 h at room temperature. Later methanol
(6 mL, 147 mmol) was added and the solution was stirred for 2 h
at room temperature. After completion of the reaction as moni-
In conclusion, we have reported a simple and economic route
for the total synthesis of stagonolides A and B from
overall yields of 25% and 8.7%, respectively.
D-ribose with

218
P. Prabhakar et al. / Tetrahedron: Asymmetry 21 (2010) 216–221
O
a
b
HO
OBn
OBn
OH
OH
OH
16
H
9
10
8
OH
OH
OAc
c
d
BnO
BnO
+
BnO
11
(S)-12
(R)-12
OH
OMOM
e
f
BnO
BnO
BnO
HO
(R)-12
13
14
OMOM
OMOM
OMOM
g
h
HO
i
H
15
MOMO
O
17
O
OMOM
OH
O
O
O
O
O
j
OH
OH
k
l
7 + 17
O
O
O
O
O
18
19
2
Scheme 3. Reagents and conditions: (a) BnBr, NaH, dry THF, 0 °C, 5 h, 95%; (b) PCC, DCM, rt, 1 h, 92%; (c) C2HMgBr, dry THF, 0 °C, 5 h, 82%; (d) vinyl acetate, Novozyme-435,
diisopropyl ether, rt, 2 h, 54%; (e) Lindlar’s catalyst, quinoline, ethyl acetate 2 h, 86%; (f) MOM-Cl, DIPEA, DCM, rt, 4 h, 94%; (g) Li-metal, naphthalene, dry THF, ꢀ25 °C, 4 h,
82%; (h) IBX acid, DMSO, DCM, rt, 4 h, 94%; (i) NaClO2, NaH2PO4ꢃH2O, DMSO, H2O, rt, 1 h, 98%; (j) DCC, DMAP, DCM, rt, 12 h, 65%; (k) Grubbs II, DCM, 45 °C, 12 h, 65%; (l) TFA,
0 °C, 2 h, 90%.
O
O
a
O
O
b
7 + 5-hexenoic acid
O
O
O
O
21
20
HO
HO
O
d
c
O
O
HO
O
O
22
1
Scheme 4. Reagents and conditions: (a) DCC, DMAP, DCM, rt, 12 h, 95%; (b) Grubbs I, DCM, 45 °C, 8 h, 80%; (c) TFA, 0 °C, 2 h, 90%; (d) MnO2, DCM, rt, 12 h, 82%.
tored by TLC, the reaction mixture was neutralized with saturated
NaHCO3 solution (20 mL) and the reaction mixture was filtered.
The filtrate was evaporated under reduced pressure and extracted
with diethylether (3 ꢁ 30 mL). The combined organic layer was
washed with brine solution (20 mL) and dried over anhydrous
Na2SO4 after which the solvent was evaporated under reduced
pressure to give a crude residue, which was purified by silica gel
(60–120 mesh) column using hexane/ethyl acetate (9:1) to obtain
NMR (75 MHz, CDCl3); d 24.6, 26.3, 55.4, 63.9, 81.4, 85.7, 88.3,
109.9 and 112.0; ESI-MS: m/z 227 [M+Na]+.
4.1.2. Methyl 5-deoxy-5-iodo-2,3-O-(1-methylethylidene)-b-D-
ribofuranoside 5
To a stirred solution of compound 4 (6.0 g, 28.4 mmol) in tolu-
ene (100 mL), imidazole (5.8 g, 85.2 mmol) and triphenylphos-
phine (11.2 g, 42.7 mmol) was added iodine (10.1 g, 39.8 mmol)
and stirred at 80 °C for 2 h. After completion of the reaction as
monitored by TLC, the reaction was quenched with a solution of so-
dium thiosulphate pentahydrate (10 mL) and extracted into ethyl
acetate. The organic layer was separated and dried over Na2SO4
and the solvent was removed under reduced pressure to give a
pure compound 4 (6.0 g, 95%) as a yellow liquid. ½a D25
ꢂ
¼ ꢀ94 (c 0.1,
CHCl3); IR (neat): 3452, 2939, 1373, 1209, 1160, 1080 cmꢀ1
;
1H
NMR (300 MHz, CDCl3): d 1.30 (s, 3H), 1.47 (s, 3H), 3.09 (dd,
J = 3.02, 9.80 Hz, 1H), 3.44 (s, 3H), 3.61 (m, 2H), 4.37 (t, J = 3.02,
1H), 4.53 (d, J = 6.03, 1H), 4.78 (d, J = 6.03, 1H), 4.91 (s, 1H); 13C

P. Prabhakar et al. / Tetrahedron: Asymmetry 21 (2010) 216–221
219
crude residue, which was purified by a silica gel (60–120 mesh)
column using hexane/ethyl acetate (9:1) to obtain pure compound
NMR (75 MHz, CDCl3); d 22.5, 40.9, 69.1, 72.9, 127.5, 128.3,
128.4, 138.3 and 202.1; ESI-MS: m/z 179 [M+1]+.
5 (6.7 g, 72%) as a colorless oil: ½a D25
ꢂ
¼ ꢀ68:3 (c 0.1, CHCl3); IR
(neat): 2986, 2935, 1372, 1210, 1194, 1018 cmꢀ1
;
1H NMR
4.1.7. 6-(Benzyloxy)-hex-1-yn-3-ol 11
(300 MHz, CDCl3) d 1.33 (s, 3H), 1.49 (s, 3H), 3.16 (t, J = 10.0 Hz,
1H), 3.29 (dd, J = 9.9, 6.0 Hz, 1H), 3.37 (s, 3H), 4.44 (dd, J = 10.1,
6.0 Hz, 1H), 4.63 (d, J = 5.9 Hz, 1H), 4.77 (d, J = 5.8 Hz, 1H), 5.05
(s, 1H); 13C NMR (75 MHz, CDCl3); d 6.6, 24.9, 26.3, 55.2, 82.9,
85.3, 87.4, 109.6 and 112.6; ESI-MS: m/z 337 [M+Na]+.
To a stirred solution of compound 10 (4.0 g, 22.47 mmol) in dry
THF (50 mL) was added C2HMgBr (3.47 g, 26.89 mmol, 1.6 M solu-
tion) at ꢀ78 °C and stirred for 5 h. After completion of the reaction
as monitored by TLC, the reaction was quenched with saturated
NH4Cl (20 mL) solution and extracted into ethyl acetate
(3 ꢁ 20 mL). The combined organic layer was dried over anhydrous
Na2SO4 and the solvent was removed in vacuo to give a crude res-
idue, which was purified on a silica gel (60–120 mesh) column
using hexane/ethyl acetate (8:2) to afford racemic compound 11
as a pale yellow liquid (3.9 g, 85% yield: IR (neat) 3395, 3282,
4.1.3. (4R,5R)-2,2-Dimethyl-5-vinyl-[1,3]dioxolane-4-
carbaldehyde 6
To a stirred solution of compound 5 (2.0 g, 5.6 mmol) in EtOH
95% (25 mL) was added activated Zn dust (3.0 g, 46.5 mmol) and
stirred for 1 h at reflux. After completion of the reaction as moni-
tored by TLC, the reaction mixture was filtered and the solvent
was evaporated to yield crude aldehyde 6, which was used in the
next step without any further purification.
2106, 1448, 1365, 1092 cmꢀ1 1H NMR (300 MHz, CDCl3): d 1.70–
;
1.91 (m, 4H), 2.46 (d, J = 2.1 Hz, 1H), 2.90 (br d, J = 3.6 Hz, 1H),
3.50–3.60 (m, 2H), 4.2–4.4 (m, 1H), 4.54 (d, J = 12.0 Hz, 1H), 4.58
(d, J = 12.0 Hz, 1H), 7.27–7.36 (m, 5H); 13C NMR (75 MHz, CDCl3)
d 25.3, 35.1, 61.6, 70.0, 72.6, 73.1, 85.2, 127.4, 127.8, 128.2,
138.1; ESI-MS: m/z 205 [M+1]+.
4.1.4. (R)-1-((4R,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-
yl)butan-1-ol 7
To a stirred solution of n-propyl magnesium bromide (1 M solu-
tion) in THF was added compound 6 (950 mg, 6.0 mmol) in dry THF
at 0 °C and stirred for 5 h at the same temperature. After comple-
tion of the reaction as monitored by TLC, the reaction was
quenched with saturated NH4Cl (10 mL), extracted into ethyl ace-
tate, evaporated under reduced pressure, and purified by a silica
gel column (60–120 mesh) using hexane/ethyl acetate (9:1) to ob-
4.1.8. (R)-6-(Benzyloxy)-hex-1-yn-3-ol (R)-12
To a stirred solution of racemic compound 11 (3.8 g, 18.62 mmol)
in diisopropyl ether (50 mL) and vinyl acetate (1.75 mL, 18.97 mmol)
was added Novozyme-435 (1.9 g) at room temperature and stirred
for 2 h. After completion of the reaction as monitored by TLC, the
reaction mixture was filtered through Celite, and the solvent was
evaporated under reduced pressure to give a crude residue, which
was purified by silica gel (60–120 mesh) column using hexane/ethyl
acetate (8:2) to obtain pure compounds (R)-12 (2.0 g, 53% yield, 80%
ee) as a colorless oil and (S)-12 (1.71 g, 45% yield) as a colorless oil.
tain pure compound
¼ þ4:5 (c 0.012, CHCl3): IR (neat): 3465, 1645, 1375,
1096 cmꢀ1 1H NMR (300 MHz, CDCl3): d 0.91 (t, J = 5.66 Hz, 3H),
7 (962 mg, 79%) as a yellow liquid.
½ ꢂ
a 2D5
;
1.32–1.40 (m, 2H), 1.37 (s, 3H), 1.45–1.57 (m, 2H), 1.50 (s, 3H),
1.99 (d, J = 5.28 Hz, 1H), 3.53 (m, 1H), 3.95 (dd, J = 5.28, 6.79 Hz,
1H), 4.52 (t, J = 6.79 Hz, 1H), 5.22–5.36 (m, 2H), 5.94 (m, 1H); 13C
NMR (75 MHz, CDCl3); d 14.1, 18.8, 25.2, 27.1, 27.6, 36.1, 69.2,
79.1, 80.8, 118.9 and 134.4; ESI-MS: m/z 223 [M+Na]+.
Data for (R)-12; ½a D25
ꢂ
¼ þ10:4 (c 0.1, CHCl3): IR (neat) 3395, 3282,
2106, 1448, 1365, 1092 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d 1.70–
1.91 (m, 4H), 2.46 (d, J = 2.1 Hz, 1H), 2.90 (br d, J = 3.6 Hz, 1H),
3.50–3.60 (m, 2H), 4.2–4.4 (m, 1H), 4.54 (d, J = 12.0 Hz, 1H), 4.58
(d, J = 12.0 Hz, 1H), 7.27–7.36 (m, 5H); 13C NMR (75 MHz, CDCl3) d
25.3, 35.1, 61.6, 70.0, 72.6, 73.1, 85.2, 127.4, 127.8, 128.2, 138.1;
ESI-MS: m/z 205 [M+1]+.
4.1.5. 4-(Benzyloxy)butan-1-ol 9
To a stirred suspension of NaH (2.66 g, 110 mmol) in dry THF
(50 mL) was added compound 8 (5.0 g, 55.5 mmol) in dry THF fol-
lowed by benzyl bromide (7.9 mL, 66.04 mmol) at 0 °C and stirred
at room temperature for 5 h. After completion of the reaction as
monitored by TLC, the reaction was quenched with cold water, ex-
tracted into ethyl acetate (3 ꢁ 20 mL), and evaporated under re-
duced pressure to give a crude residue, which was purified by
silica gel (60–120 mesh) column using hexane/ethyl acetate (8:2)
to obtain pure compound 9 (8.8 g, 90%) as a yellow liquid. IR
4.1.9. (R)-6-(Benzyloxy)-hex-1-en-3-ol 13
To a stirred solution of compound (R)-12 (2.0 g, 9.8 mmol) and
quinoline (0.23 mL, 1.9 mmol) in ethylacetate (25 mL) was added
Lindlar’s catalyst (70w/w%) at room temperature and stirred for
2 h under hydrogen atmosphere. After completion of the reaction
as monitored by TLC, the solvent was removed in vacuo to give a
crude residue, which was purified on a silica gel (60–120 mesh)
column using hexane/ethyl acetate (8:2) to afford compound 13
(neat): 3625, 3412, 2401, 1953, 1455, 1215, 1099 cmꢀ1
;
1H NMR
(1.71 g) in 86% yield as a pale yellow liquid. ½a D25
ꢂ
¼ þ18:3 (c
(300 MHz, CDCl3): d 1.64–1.75 (m, 2H), 2.36 (br s, 1H), 3.52 (t,
J = 5.66 Hz, 2H), 3.64 (t, J = 5.85 Hz, 2H), 4.52 (s, 2H), 7.28–7.37
(m, 5H); 13C NMR (75 MHz, CDCl3); d 26.1, 29.2, 61.7, 69.9, 72.5,
127.2, 127.4, 128.1 and 137.9; ESI-MS: m/z 181 [M+1]+.
0.004, CHCl3): IR (neat) 3417, 1643, 1452, 1362, 1099 cmꢀ1 1H
;
NMR (300 MHz, CDCl3): d 1.52–1.76 (m, 4H), 2.30 (br s, 1H), 3.48
(t, J = 5.28 Hz, 2H), 4.12 (q, J = 5.28 Hz, 1H), 5.06 (dt, J = 10.57,
1.51 Hz, 1H), 5.20 (dt, J = 17.3, 1.5 Hz, 1H), 5.83 (m, 1H), 7.24–
7.34 (m, 5H); 13C NMR (75 MHz, CDCl3) d 25.8, 34.3, 70.3, 72.7,
73.0, 114.4, 127.6, 127.7, 128.3, 138.1 and 140.0; ESI-MS: m/z
229 [M+Na]+.
4.1.6. 4-(Benzyloxy)butanal 10
To a stirred solution of the compound 9 (5.0 g, 27.7 mmol) in
dichloromethane (100 mL) was added PCC (12.0 g, 55.8 mmol) at
room temperature and stirred for 1 h. After completion of the reac-
tion as monitored by TLC, the solvent was evaporated under re-
duced pressure to give a crude residue, which was purified on
silica gel (60–120 mesh) column using hexane/ethyl acetate (9:1)
to obtain pure compound 10 (4.5 g, 92% yield) as a pale yellow li-
4.1.10. 1-((4-(Methoxymethoxy)-hex-5-enyloxy)methyl)
benzene 14
To a stirred solution of compound 13 (1.0 g, 4.85 mmol) and DI-
PEA (1.9 mL, 14.72 mmol) in dry DCM (20 mL) was added MOM-Cl
(0.6 mL, 7.5 mmol) at 0 °C and stirred for 2 h at room temperature.
After completion of the reaction as monitored by TLC, water was
added, and the reaction mixture was extracted into DCM (3 ꢁ
20 mL), and dried over anhydrous Na2SO4. The solvent was removed
quid. IR (neat): 3032, 2932, 2865, 1706 cmꢀ1 1H NMR (300 MHz,
;
CDCl3): d 1.90–1.97 (m, 2H), 2.53 (t, J = 6.83 Hz, 2H), 3.50 (t,
J = 5.85 Hz, 2H), 4.48 (s, 2H), 7.28–7.35 (m, 5H), 9.76 (s, 1H); 13C

220
P. Prabhakar et al. / Tetrahedron: Asymmetry 21 (2010) 216–221
in vacuo to give a crude residue, which was purified by silica gel (60–
120 mesh) column using hexane/ethyl acetate (9:1) to afford com-
13C NMR (75 MHz, CDCl3): d 29.9, 30.1, 55.5, 75.9, 93.6, 117.9,
137.7 and 179.3; ESI-MS: m/z 175 [M+1]+.
pound 14 (1.15 g) in 95% yield as a colorless oil. ½a D25
¼ þ53:65 (c
ꢂ
0.01, CHCl3): IR (neat) 2943, 2856, 1642, 1452, 1361, 1099 cmꢀ1
;
4.1.14. (4R)-(R)-1-((4R,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-
4-yl) butyl 4-(methoxymethoxy)hex-5-enoate 18
1H NMR (300 MHz, CDCl3): d 1.53–1.74 (m, 4H), 3.32 (s, 3H), 3.45
(t, J = 5.28 Hz, 2H), 3.96 (q, J = 5.28, 12.08 Hz, 1H), 4.46 (d, J = 6.79,
1H), 4.47 (s, 2H), 4.64 (d, J = 6.79, 1H) 5.14 (br s, 1H), 5.19 (d,
J = 6.79 Hz, 1H), 5.64 (m, 1H), 7.27–7.32 (m, 5H); 13C NMR
(75 MHz, CDCl3): d 25.8, 32.1, 55.3, 70.1, 72.9, 76.9, 93.5, 117.2,
127.4, 127.5, 128.3, 138.5 and 138.6; ESI-MS: m/z 273 [M+Na]+.
To a stirred solution of compound 7 (100 mg, 0.50 mmol), DCC
(123 mg, 0.6 mmol), and DMAP (catalytic) in dry DCM (10 mL) was
added compound 17 (78.1 mg, 0.55 mmol) in dry DCM (5 mL) and
stirred for 12 h at room temperature. After completion of the reac-
tion as monitored by TLC, the solvent was removed under vacuum
to give a crude residue, which was purified by silica gel (60–120
mesh) column using hexane/ethyl acetate (9:1) to afford pure com-
4.1.11. 4-(Methoxymethoxy) hex-5-en-1-ol 15
pound 18 (104 mg) in 65% yield as a pale yellow liquid. ½a D25
¼ þ26:1
ꢂ
To a stirred solution of Li-metal (100 mg, 16.6 mmol) was added
naphthalene (2.04 g, 15.9 mmol) in dry THF (20 mL) and stirred for
90 min at room temperature. Then compound 14 (1.0 g, 0.00 mmol)
in THF was added to the above-mentioned mixture at ꢀ25 °C and
stirred for 2 h at the same temperature. After completion of the reac-
tion as monitored by TLC, the reaction was quenched with saturated
NH4Cl (5 mL), extracted into ethyl acetate (3 ꢁ 20 mL), and dried
over anhydrous Na2SO4. The solvent was removed in vacuo to give
a crude residue, which was purified by silica gel (60–120 mesh) col-
umn using hexane/ethyl acetate (7:3) to afford compound 15
(c 0.02, CHCl3): IR (neat) 3456, 2931, 1738, 1646, 1458, 1375 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d 0.92 (t, J = 7.28 Hz, 3H), 1.30–1.38(m,
2H), 1.58 (m, 1H), 1.66 (m, 1H), 1.83 (q, J = 7.28, 14.5 Hz, 2H) 2.30
(dt, J = 4.16, 7.28 Hz, 2H), 3.34 (s, 3H), 4.00 (q, J = 7.28, 13.5 Hz,
1H), 4.12 (t, J = 7.28 Hz, 1H), 4.47 (d, J = 7.28, 1H), 4.55 (t, J = 6.24,
1H), 4.64 (d, J = 6.24 Hz, 1H), 4.86 (dt, J = 3.12, 7.28 Hz, 1H), 5.17–
5.33 (m, 4H), 5.62–5.68 (m, 1H), 5.71–5.80 (m, 1H); 13C NMR
(75 MHz, CDCl3): d 14.2, 17.9, 25.3, 27.7, 30.3, 33.5, 55.4, 71.6,
76.0, 78.4, 78.8,, 93.6, 108.7, 117.8, 118.2, 133.4, 137.7 and 172.9;
ESI-MS: m/z 379 [M+Na]+.
(492 mg) in 82% yield as a colorless oil. ½a D25
ꢂ
¼ þ29:5 (c 0.01, CHCl3):
IR (neat) 3415, 2933, 1447, 1643, 1097 cmꢀ1
;
1H NMR (300 MHz,
4.1.15. (6E,5R,8S,9S,10R)-4,5,9,10-Tetrahydro-5,8,9-trihydroxy-
10-propyl-3H-oxecin-2(8H)-one 2
CDCl3): d 1.58–1.74 (m, 4H), 1.85 (br s, 1H), 3.36 (s, 3H), 3.64 (t,
J = 6.04 Hz, 2H), 4.02 (q, J = 5.28, 12.8 Hz, 1H), 4.51 (d, J = 6.79, 1H),
4.68 (d, J = 6.79, 1H) 5.17 (br s, 1H), 5.22 (d, J = 7.55 Hz, 1H), 5.67
(m, 1H); 13C NMR (75 MHz, CDCl3): d 28.6, 32.0, 55.4, 62.6, 77.05,
93.6, 117.3 and 138.2; ESI-MS: m/z 161 [M+1]+.
To a solution of compound 18 (60 mg, 0.18 mmol) in dry dichlo-
romethane (50 mL) was added Grubbs’ II generation catalyst
(30.6 mg, 0.036 mmol) and the mixture was degassed thoroughly
under a nitrogen atmosphere, after which the reaction mixture
was refluxed for 12 h. After completion of the reaction as moni-
tored by TLC, the solvent was removed under reduced pressure
to give a crude residue, which was purified by a silica gel (60–
120 mesh) column using hexane/ethyl acetate (9:1) to afford com-
pound 19 (38.5 mg, 65% yield) as a colorless liquid. Thus obtained
compound 19 (35 mg) was reacted with TFA (5 mL) at 0 °C and stir-
red for 2 h. After completion of the reaction, water was added
(5 mL), extracted into ethyl acetate (3 ꢁ 10 mL), and the solvent
was evaporated under reduced pressure to give a crude residue,
which was purified by silica gel (60–120 mesh) column using hex-
ane/ethyl acetate (7:3) to afford pure compound 2 (20.5 mg, 92%
4.1.12. 4-(Methoxymethoxy) hex-5-enal 16
To a suspension of IBX acid (840 mg, 3.0 mmol) in DMSO (2 mL)
and DCM (8 mL), a solution of compound 15 (300 mg, 2.0 mmol) in
DCM was added at room temperature and stirred for 4 h. After
completion of the reaction as monitored by TLC, the reaction was
quenched with saturated NaHCO3 solution (5 mL). The reaction
mixture was filtered through Celite and extracted into ethyl ace-
tate (3 ꢁ 20 mL). The combined organic layer was dried over anhy-
drous Na2SO4, and the solvent was removed in vacuo to give a
crude residue, which was purified by silica gel (60–120 mesh) col-
umn using hexane/ethyl acetate (8:2) to afford compound 16
yield) as a viscous liquid. ½a D25
ꢂ
¼ þ24:5 (c 0.01, CHCl3); IR (neat):
(281 mg) in 94% yield as a colorless oil. ½a D25
ꢂ
¼ þ8:0 (c 0.017,
3409, 2927, 1729, 1560 cmꢀ1
.
1H NMR (300 MHz, CDCl3): d 0.91
CHCl3): IR (neat) 2928, 1705, 1608, 1447, 1097 cmꢀ1
;
1H NMR
(t, J = 7.3 Hz, 3H), 1.21–1.30 (m, 1H), 1.30–1.40 (m, 1H), 1.54 (dd,
J = 4.9, 9.8 Hz, 1H), 1.60 (br s, 1H), 1.82–1.90 (m, 2H), 2.05–2.12
(m, 2H), 2.24 (d, J = 8.4 Hz, 1H), 2.42 (br s, 1H), 2.45 (m, 2H), 3.55
(t, J = 8.5 Hz, 1H), 4.45 (s, 1H), 4.60 (s, 1H), 4.95 (dt, J = 2.5,
9.6 Hz, 1H), 5.62 (d, J = 8.4 Hz, 1H), 5.95 (d, J = 8.4 Hz, 1H). 13C
NMR (75 MHz, CDCl3): d 13.8, 18.1, 27.9, 31.6, 33.8, 68.7, 70.1,
73.4, 73.5, 127.3, 127.4, 176.6. ESI-MS m/z: 267 [M+Na]+.
(300 MHz, CDCl3): d 1.89 (q, J = 6.04, 13.5 Hz, 2H), 2.52 (dt,
J = 1.51, 6.79 Hz, 2H), 3.34 (s, 3H), 4.02 (q, J = 6.04, 13.5 Hz, 1H),
4.47 (d, J = 6.79, 1H), 4.64 (d, J = 6.79, 1H) 5.20 (br s, 1H), 5.24 (d,
J = 5.28 Hz, 1H), 5.65 (m, 1H), 9.76 (s, 1H); 13C NMR (75 MHz,
CDCl3): d 27.8, 39.8, 55.5, 76.1, 93.7, 117.9, 137.7 and 200.9; ESI-
MS: m/z 159 [M+1]+.
4.1.13. 4-(Methoxymethoxy) hex-5-enoic acid 17
4.1.16. (R)-1-((4R,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-
yl)butyl hex-5-enoate 20
To a stirred solution of compound 16 (200 mg, 1.35 mmol) in
DMSO and water (8:2, 10 mL) were added sodium chlorite
(145 mg, 1.61 mmol) and NaH2PO4 (251 mg, 1.61 mmol) and stir-
red at room temperature for 1 h. After completion of the reaction
as monitored by TLC, the reaction mixture was extracted into ethyl
acetate (3 ꢁ 20 mL), and dried over anhydrous Na2SO4. The solvent
was removed in vacuo to give a crude residue, which was purified
by silica gel (60–120 mesh) column using hexane/ethyl acetate
(6:4) to afford compound 17 (182 mg) in 95% yield as a pale yellow
To a stirred solution of compound 7 (100 mg, 0.50 mmol), DCC
(123 mg, 0.6 mmol), and DMAP (catalytic) in dry DCM (10 mL)
was added 5-hexenoic acid (0.071 mL, 0.6 mmol) and stirred for
12 h at room temperature. After completion of the reaction as
monitored by TLC, the solvent was removed under vacuum to give
a crude residue, which was purified by silica gel (60–120 mesh)
column using hexane/ethyl acetate (9:1) to afford compound 20
(133 mg) in 91% yield as a pale yellow liquid. ½a D25
ꢂ
¼ þ28:2 (c 0.1,
liquid. ½a 2D5
ꢂ
¼ þ17:75 (c 0.02, CHCl3): IR (neat) 3435, 2924, 1712,
CHCl3): IR (neat) 2928, 1739, 1641, 1458, 1375, 1167 cmꢀ1
;
1H
1418, 1030 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d 1.88 (q, J = 6.79,
NMR (300 MHz, CDCl3): d 0.92 (t, J = 7.28 Hz, 3H), 1.30–1.38 (m,
2H), 1.58 (m, 1H), 1.66 (m, 1H), 1.83 (q, J = 7.28, 14.5 Hz, 2H)
2.30 (dt, J = 4.16, 7.28 Hz, 2H), 3.34 (s, 3H), 4.00 (q, J = 7.28,
13.5 Hz, 1H), 4.12 (t, J = 7.28 Hz, 1H), 4.47 (d, J = 7.28, 1H), 4.55
13.59 Hz, 2H), 2.45 (t, J = 6.79 Hz, 2H), 3.35 (s, 3H), 4.04 (q,
J = 6.04, 13.5 Hz, 1H), 4.49 (d, J = 6.79, 1H), 4.65 (d, J = 6.79, 1H)
5.20 (d, J = 7.55 Hz, 1H), 5.25 (d, J = 7.55 Hz, 1H), 5.65 (m, 1H);

P. Prabhakar et al. / Tetrahedron: Asymmetry 21 (2010) 216–221
221
(t, J = 6.24, 1H), 4.64 (d, J = 6.24 Hz, 1H), 4.86 (dt, J = 3.12, 7.28 Hz,
1H), 5.17–5.33 (m, 4H), 5.62–5.68 (m, 1H), 5.71–5.80 (m, 1H);
13C NMR (75 MHz, CDCl3): d 14.3, 17.9, 24.0, 25.4, 27.8, 33.2,
33.6, 71.4, 78.4, 78.9, 108.6, 115.6, 118.1, 133.5, 137.5 and 171.8;
ESI-MS: m/z 319 [M+Na]+.
a white solid. ½a D25
ꢂ
¼ ꢀ41:2 (c 0.01, EtOH); IR (KBr): 3409, 2927,
1H NMR (300 MHz, CDCl3): d 0.90
1742, 1705, 1634, 1183 cmꢀ1
.
(t, J = 7.3 Hz, 3H), 1.26–1.34 (m, 1H), 1.38–1.44 (m, 1H), 1.65 (m,
1H), 1.91 (m, 1H), 1.95 (m, 1H), 2.02 (m, 1H), 2.06 (m, 1H), 2.12
(dd, J = 2.5, 14.3 Hz, 1H), 2.42 (dd, J = 2.5, 14.3 Hz, 1H), 2.50 (m,
1H), 3.56 (d, J = 6.3 Hz, 1H), 4.01 (dd, J = 2.5, 14.3 Hz, 1H), 4.62 (t,
J = 6.3 Hz, 1H), 6.20 (m, 1H), 6.40 (m, 1H). 13C NMR (75 MHz,
CDCl3): d 13.9, 18.0, 25.2, 33.6, 34.1, 34.3, 74.6, 76.6, 131.8,
142.9, 174.1 and 199.5. ESI-MS m/z: 249 [M+Na]+.
4.1.17. (6E,8S,9S,10R)-4,5,9,10-Tetrahydro-8,9-dihydroxy-10-
propyl-3H-oxecin-2(8H)-one 22
To a stirred solution of compound 20 (100 mg, 0.33 mmol) in dry
dichloromethane (50 mL) was added Grubbs’ I generation catalyst
(55.6 mg, 0.067 mmol) and the mixture was degassed thoroughly
under a nitrogen atmosphere. The reaction mixture was refluxed
for 8 h. After completion of the reaction as monitored by TLC, the sol-
vent was removed under reduced pressure to give a crude residue.
The residue was purified by silica gel (60–120 mesh) column using
hexane/ethyl acetate (9:1) to afford pure compound 21 (72.4 mg,
80% yield) as a colorless liquid. The above-mentioned compound
21 (70 mg) was reacted with TFA (5 mL) at 0 °C and stirred for 2 h.
After completion of the reaction as monitored by TLC, water was
added (5 mL), extracted into ethyl acetate (3 ꢁ 10 mL), and the sol-
vent was evaporated under reduced pressure to give a crude residue,
which was purified by silica gel (60–120 mesh) column using hex-
ane/ethyl acetate (7:3) to afford pure compound 22 (40.4 mg, 90%
Acknowledgments
The authors P.P., D.K.R., and V.S. are thankful to CSIR, New Delhi,
India, respectively, for the financial support and Dr. J. S. Yadav
Director, Indian Institute of Chemical Technology (IICT), for his
encouragement.
References
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yield) as a colorless low-melting solid; ½a D25
¼ þ12:4 (c 0.5, EtOH);
ꢂ
IR (KBr): 3435, 2928, 2852, 1635, 1456, 1210, 1089 cmꢀ1; 1H NMR
(300 MHz, CDCl3): d 0.90 (t, J = 7.3 Hz, 3H), 1.30–1.22 (m, 3H),
1.45– 1.71 (m, 3H), 2.05–1.78 (m, 3H), 2.21–2.35 (m, 2H), 2.65 (br
s, 1H), 3.42 (d, J = 9.4 Hz, 1H), 4.42 (br s, 1H), 4.94 (td, J = 9.4,
2.4 Hz, 1H), 5.49 (m, 1H), 5.58 (d, J = 15.6 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d 13.6, 18.1, 24.6, 33.4, 33.6, 34.5, 70.1, 73.2,
73.5, 124.8, 130.5, 176.1; ESI-MS: m/z 251 [M+Na]+.
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611–612; (b) Gallos, J. K.; Goga, E. G.; Koumbis, A. E. J. Chem. Soc., Perkin Trans.
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4.1.18. (6E,9R,10R)-4,5–9,10-Tetrahydro-9-hydroxy-10-propyl-
3H-oxecin-2,8-dione 1
To a stirred solution of compound 22 (30 mg, 0.13 mmol) in dry
dichloromethane (10 mL) was added activated MnO2 (22.8 mg,
0.26 mmol) and stirred for 12 h at room temperature. After com-
pletion of the reaction as monitored by TLC, the reaction was fil-
tered through Celite and then the total solvent was evaporated
under reduced pressure to give a crude residue, which was purified
by silica gel (60–120 mesh) column using hexane/ethyl acetate
(8:2) to afford compound 1 (staganolide A) (24 mg, 82% yield) as
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