Stereoselective total synthesis of the cytotoxic lactone (-)-spicigerolide

Article abstract of DOI:10.1016/j.tetasy.2011.02.010

A highly stereoselective synthesis of the naturally occurring lactone (-)-spicigerolide has been achieved utilizing OsO₄-catalyzed dihydroxylation, CBS, Lindlar's reductions, Still-Gennari, and Grignard reactions as the key reaction steps.

Full text of DOI:10.1016/j.tetasy.2011.02.010

Tetrahedron: Asymmetry 22 (2011) 493–498
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective total synthesis of the cytotoxic lactone (ꢀ)-spicigerolide
⇑
Gowravaram Sabitha , Chintam Nagendra Reddy, Atla Raju, Jhillu Singh Yadav
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad-500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly stereoselective synthesis of the naturally occurring lactone (ꢀ)-spicigerolide has been achieved
utilizing OsO4-catalyzed dihydroxylation, CBS, Lindlar’s reductions, Still–Gennari, and Grignard reactions
as the key reaction steps.
Received 27 January 2011
Accepted 10 February 2011
Available online 14 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
presence of n-BuLi in THF to furnish alkene 10 in 60% yield. Next,
the OsO4-catalyzed dihydroxylation reaction11 of the terminal al-
Spicigerolide 11 is a member of the polyacetate/pyranone-
containing natural products, isolated from Hyptis spicigera, a plant
which is used in traditional medicine in Mexico to treat gastroin-
testinal disturbances, skin infections, wounds, and insects bites.
This lactone also displays cytotoxic activity in cell tumoral lines.1,2
Other examples of this class of natural products include synargen-
tolide A 2,3 anamarine 3,4 hyptolide 4,5 and synrotolide 56 (Fig. 1),
isolated from the leaves and flowers of an unclassified Hyptis spe-
cies and other botanically related genera. In addition, the common
structural features of the members of this class of compounds have
shown significant medicinal properties.2 Such pharmacological
properties make these lactones interesting synthetic targets.
kene 10 gave diol 12 in 90% yield with high diastereoselectivity
(9:1 dr),12 which was selectively tosylated to give tosylate 13 in
good yield. The –CH2OTs group of 13 was transformed into a
methyl group by LAH in refluxing THF and the free secondary hy-
droxyl group in compound 14 was protected as MOM ether 15
and debenzylation was performed using Li in liquid NH3. The
resulting alcohol 16 was oxidized to the corresponding aldehyde
8 in 85% yield using IBX in DMSO/CH2Cl2 (Scheme 2).
With the required aldehyde 8 in hand, our attention was turned
to couple it with the known alkyne 9 prepared from homopropargy-
lic alcohol as reported.13 However, the reaction of aldehyde 8 with
lithiated alkyne (prepared in situ by treatment of alkyne 9 with n-
BuLi in THF at ꢀ78 °C) failed to give the desired propargyl alcohol
17 (Scheme 3). However, treatment of alkyne 9 with the Grignard re-
agent prepared from ethyl bromide and magnesium, followed by the
addition of aldehyde 8 in dry THF at rt gave very low yields of prod-
uct 17 (ꢁ10%). However, this reaction proceeded smoothly when it
was brought to reflux to afford the alcohol 17 as a 1:1 mixture of dia-
stereomers (determined by chiral HPLC analysis) in 80% overall
yield, which without separation converted into keto compound 18.
Ketone 18 was stereoselectively reduced to the chiral propargyl
alcohol 19 in 80% yield using (S)-CBS catalyst14 with the required
stereoselectivity (9:1 dr).15 The free hydroxyl group was protected
as tri-MOM ether 7 followed by PMB group deprotection. Further
oxidation of the resulting alcohol 20 to its corresponding aldehyde
21 and chain elongation utilizing the Still–Gennari reagent,16
[(F3CCH2O)2–POCH2CO2Me], furnished the corresponding Z-iso-
2. Results and discussion
In a continuation of our interest in the synthesis of bio-active
natural lactones, we have recently reported the total synthesis of
synargentolide7 and anamarine.8 Herein, we report the stereose-
lective total synthesis of (ꢀ)-spicigerolide from chiral pool
L-(+)-
DET and homopropargyl alcohol, constructing a lactone ring via a
Stille–Gennari reaction. So far, three syntheses9 have been re-
ported for the synthesis of (ꢀ)-spicigerolide based on an RCM
strategy.
Retrosynthetic analysis (Scheme 1) revealed that the target
molecule 1 could be obtained from 6 by lactonization and partial
hydrogenation of the triple bond. Compound 6 is accessible from
7 by a Stille–Gennari Wittig reaction, whereas, 7 can be obtained
by coupling of 8 and 9 via a Grignard reaction. Compound 8 could
meric a,b-unsaturated ester 6 exclusively in 80% yield. Removal of
MOM groups and cyclization was easily achieved in one-pot by
refluxing 6 in a mixture of MeOH/CH3CN for 65 h under neutral con-
ditions using CeCl3ꢂ7H2O to give lactone 22.
be made from
L-(+)-DET.
The synthesis of 1 starts with the known aldehyde 11 prepared
from L
-(+)-DET as reported.10 The one carbon extension of aldehyde
11 was accomplished by a Wittig reaction using CH3PPh3+Iꢀ in the
All that remained to complete the synthesis was to acylate the
resulting tetrol 22 and partially reduce the triple bond. Thus, the
tetrol 22 was acylated by acetic anhydride in the presence of
NEt3 and DMAP to furnish the tetra-acetate compound 23. Finally,
⇑
Corresponding author. Tel.: +91 40 27191629; fax: +91 40 27160512.
E-mail address: gowravaramsr@yahoo.com (G. Sabitha).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.02.010

494
G. Sabitha et al. / Tetrahedron: Asymmetry 22 (2011) 493–498
OAc
OAc OAc
OAc OAc
O
O
O
O
OAc OAc
O
OAc OAc
OAc OAc
spicigerolide 1
O
synargentolide 2
anamarine 3
OAc OAc
OH OAc
O
O
O
O
OAc
OAc OH
synrotolide 5
hyptolide 4
Figure 1. Spicigerolide type pyranone polyacetates.
O
OR
O
OR
OAc OAc
O
OPMB
O
OR
O
OR
O
OAc OAc
OR
OR
R = MOM
MeO2C
R = MOM
spicigerolide 1
7
6
O
OH
O
OPMB
CO2Et
CHO
EtO2C
+
OBn
OMOM
OR
O
OH
O
R = MOM
L-(+)-DET
10
9
8
Scheme 1. Retrosynthetic analysis for (ꢀ)-spicigerolide.
partial hydrogenation of the triple bond in 23 was performed using
Lindlar’s catalyst in EtOAc to provide the target lactone, (ꢀ)-spicig-
erolide 1 in 90% yield. The spectroscopic data of synthetic 1
matched with the reported values.9a
4. Experimental
4.1. General
Reactions were conducted under N2 in anhydrous solvents such
as CH2Cl2, THF, and EtOAc. All reactions were monitored by TLC
(silica-coated plates and visualizing under UV light).Light petro-
leum ether (bp 60–80 °C) was used. Yields refer to chromatograph-
ically and spectroscopically (1H, 13C NMR) homogeneous material.
Air-sensitive reagents were transferred by syringe or double-ended
needle. Evaporation of the solvents was performed at reduced
3. Conclusion
In conclusion, we have accomplished the stereoselective total
synthesis of (ꢀ)-spicigerolide. The stereocontrolled CBS reduction
and Still–Gennari reaction are the key steps involved in this
synthesis.
OH
O
O
b, c
f, g
ref 9
a
CO2Et
O
EtO2C
OBn
OBn
OH
L-(+)-DET
O
O
11
10
O
O
O
f, g
d, e
R'
OBn
RO
OBn
OR
O
OR
O
OH
O
R = H
R = MOM
R' = CH2OH
R' = CHO
12;
13;
14;
15;
R = H
R = Ts
R = MOM,
R = MOM,
16;
8;
Scheme 2. Reagents and conditions: (a) CH3PPh3+Iꢀ, n-BuLi, anhydrous THF, ꢀ78 °C to rt, 4 h, 60%; (b) OsO4, NMO, acetone/H2O (1:1), rt, 48 h, 90%, (9:1 dr); (c) TsCl, TEA, n-
Bu2SnO, DMAP, anhydrous CH2Cl2, 0 °C to rt, 1 h, 90%; (d) LAH, anhydrous THF, reflux, 3 h, 80%; (e) MOM–Cl, DIPEA, anhydrous CH2Cl2, 0 °C to rt, 10 h, 95%; (f) Li/liq NH3,
anhydrous THF, ꢀ78 °C, 30 min, 80%; (g) IBX, DMSO, anhydrous CH2Cl2, 0 °C to rt, 20 h, 85%.

G. Sabitha et al. / Tetrahedron: Asymmetry 22 (2011) 493–498
495
O
OH
O
a
OPMB
+
OPMB
O
OR
O
OR
O
OMOM
OR
R = MOM
8
17
9
O
O
O
OH
c
b
OPMB
OPMB
OR
O
OR
O
OR
OR
R = MOM
R = MOM
O
18
19
OR
O
OR
e, f
d
OPMB
OR
O
OR
O
R'
OR
OR
20; R = MOM, R' = CH2OH
R = MOM
7
21;
R = MOM,
R' = CHO
O
OR
OR OR
h, i
g
OR
O
OR
OR
OR
O
O
R = MOM
MeO2C
R = H
22;
23;
6
R = Ac
OAc OAc
j
O
O
OAc OAc
1
Scheme 3. Reagents and conditions: (a) EtMgBr, anhydrous THF, reflux, 2 h, 80%, (1:1 dr); (b) DMP, NaHCO3, anhydrous CH2Cl2, 0 °C to rt, 3 h, 85%; (c) methyl-(S)-CBS-
oxazaborolidine (1.0 M in toluene), catecholborane, anhydrous CH2Cl2, ꢀ78 °C to rt, 3 h, 80%, (9:1 dr); (d) MOM–Cl, DIPEA, anhydrous CH2Cl2, 0 °C to rt, 8 h, 90%; (e) DDQ,
CH2Cl2/H2O (9:1), 0 °C to rt, 2 h, 90%; (f) IBX, DMSO, anhydrous CH2Cl2, 0 °C to rt, 10 h, 80%; (g) NaH, (F3CCH2O)2POCH2COOCH3, anhydrous THF, ꢀ78 °C, 1 h, 80%; (h)
CeCl3ꢂ7H2O, MeOH/CH3CN (1:1), reflux, 65 h, 65%; (i) Ac2O, TEA, DMAP, anhydrous CH2Cl2, 0 °C to rt, 30 min, 90%; (j) Pd/C, CaCO3, H2, quinoline, EtOAc, rt, 1 h, 90%.
pressure on a Buchi rotary evaporator. 1H and 13C NMR spectra of
samples in CDCl3 were recorded on Varian FT-200 MHz (Gemini)
and Bruker UXNMR FT-300 MHz (Avance) spectrometers. Chemical
shifts (d) are reported relative to TMS (d = 0.0) as an internal stan-
dard. Mass spectra were recorded in E1 conditions at 70 eV on LC–
MSD (Agilent technologies) spectrometers. All high resolution
spectra were recorded on QSTAR XL hybrid ms/ms system (Applied
Bio systems/MDS sciex, foster city, USA), equipped with an ESI
source(IICT, Hyderabad). Column chromatography was performed
on silica gel (60–120 mesh) supplied by Acme Chemical Co., India.
TLC was performed on Merck 60 F-254 silica gel plates. Optical
rotations were measured with a JASCO DIP-370 Polarimeter at
25 °C.
(15 mL) was added dropwise and stirred for another 45 min. The
reaction mixture was quenched with saturated NH4Cl solution
(15 mL) at 0 °C and extracted with diethyl ether (2 ꢃ 30 mL). The
combined organic extracts were washed with brine (2 ꢃ 20 mL),
dried over anhydrous Na2SO4, and concentrated in vacuo. The res-
idue was purified by column chromatography (SiO2, ethyl acetate/
hexane, 2:8) to afford pure compound 10 (2.97 g, 60%) as a pale
yellow liquid; ½a D25
ꢄ
¼ þ42:0 (c 1, CHCl3); IR (KBr) 2986, 2928,
2861, 1218, 1038 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d 7.27–7.15
(m, 5H, ArH), 5.81–5.68 (m, 1H), 5.23 (dd, J = 1.5, 18.1 Hz, 1H),
5.12 (dd, J = 1.5, 10.5 Hz, 1H), 4.50 (ABq, J = 8.3, 12.8 Hz, 2H, CH2–
OAr), 4.17–4.10 (m, 1H), 3.79–3.72 (m, 1H), 3.49 (dd, J = 2.2,
5.2 Hz, 2H), 1.34 (s, 6H); 13C NMR (75 MHz, CDCl3): d 137.9,
135.4, 128.3, 127.6, 127.5, 118.3, 109.3, 96.1, 80.5, 79.4, 73.5,
69.3, 27.0 (2 ꢃ C); HRMS calcd for C15H20O3Na: 271.1310; found:
271.1318.
4.1.1. (4S,5S)-4-[(Benzyloxy)methyl]-2,2-dimethyl-5-vinyl-1,3-
dioxolane 10
To a stirred suspension of triphenyl phosphonium methyl io-
dide (16.38 g, 39.9 mmol) in dry THF (30 mL) at ꢀ78 °C, n-BuLi in
hexane (1.6 M, 25 mL, 40 mmol) was added dropwise under an
N2 atmosphere and allowed to return to room temperature. After
45 min, the reaction mixture was again cooled to ꢀ78 °C and the
aldehyde compound 11 (5 g, 20.0 mmol) dissolved in dry THF
4.1.2. (1S)-1-{(4S,5S)-5-[(Benzyloxy)methyl]-2,2-dimethyl-1,3-
dioxolan-4-yl}ethane-1,2-diol 12
At first, NMO (1.81 g, 15.47 mmol) and alkene 10 (2.92 g,
11.77 mmol) were dissolved in 4:1 acetone/H2O (30 mL). Next, a
0.02 M solution of OsO4 in toluene (0.7 mL) was added, and the

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G. Sabitha et al. / Tetrahedron: Asymmetry 22 (2011) 493–498
reaction mixture was stirred for 48 h at rt, then cooled in an ice
bath. The reaction was quenched by the addition of saturated
aqueous Na2SO3 (15 mL). Most of the acetone was removed by ro-
tary evaporation, and the aqueous mixture was extracted with
EtOAc (3 ꢃ 40 mL). The combined extracts were concentrated
under reduced pressure, and the residue was purified by column
chromatography (SiO2, ethyl acetate/hexane, 6:4) to give the cor-
responding diol 12 (2.98 g, 90%) as a viscous liquid with high dia-
stereoselectivity (9:1) determined by chiral HPLC analysis.
94.8, 80.3, 78.3, 73.4, 73.2, 71.2, 55.3, 27.0, 26.8, 16.4; HRMS calcd
for C17H26O5Na: 333.1677; found: 333.1692.
4.1.5. {(4S,5S)-5-[(1S)-1-(Methoxymethoxy)ethyl]-2,2-dimethyl-
1,3-dioxolan-4-yl}methanol 16
To a solution of lithium (0.22 g, 43.8 mmol) in liquid NH3 (25 ml)
was added compound 15 (2 g, 6.45 mmol) in dry THF (15 ml). The
mixture was stirred for 30 min and quenched with solid NH4Cl
(1.36 g). Ammonia was allowed to evaporate and the residual mix-
ture was taken in ether (35 ml) and washed with water (2 ꢃ 10 ml),
brine (1 ꢃ 10 ml), and dried (Na2SO4). Removal of the solvent and
purification by column chromatography (SiO2, ethyl acetate/hex-
ane, 5:5) afforded pure alcohol 16 (1.12 g, 80%) as a colorless liquid.
½
a 2D5
ꢄ
¼ þ31:0 (c 1, CHCl3); IR (KBr) 3428, 2928, 1375, 1214,
1058 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.37–7.27 (m, 5H,
;
ArH), 4.59 (s, 2H, CH2–OAr), 4.02 (m, 1H), 3.80–3.44 (m, 6H),
1.37(s, 3H, CH3), 1.36 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3): d
136.9, 128.5, 128.0, 127.9, 109.3, 79.7, 78.1, 73.8, 72.4, 70.6,
63.8, 26.7 (2 ꢃ C); HRMS calcd for C15H22O5Na: 305.1364; found:
305.1365.
½
a 2D5
ꢄ
¼ þ3:6 (c 1, CHCl3); IR (KBr) 3454, 2985, 2934,1375,
1036 cmꢀ1 1H NMR (300 MHz, CDCl3): d 4.69 (dd, J = 5.4, 12.8 Hz,
;
2H, CH2), 4.02–3.59 (m, 5H), 3.36 (s, 3H, CH3), 1.39 (s, 3H, CH3),
1.38 (s, 3H, CH3), 1.26 (d, J = 5.8 Hz, 3H, CH3); 13C NMR (75 MHz,
CDCl3): 106.3, 92.0, 74.6, 70.8, 69.3, 60.4, 52.7, 24.1, 23.9, 14.0;
HRMS calcd for C10H20O5Na: 243.1208; found: 243.1202.
4.1.3. (1S)-1-{(4S,5S)-5-[(Benzyloxy)methyl]-2,2-dimethyl-1,3-
dioxolan-4-yl}ethan-1-ol 14
A solution of 12 (2.92 g, 10.35 mmol) in dry CH2Cl2 (20 mL),
containing triethylamine (2.1 g, 20.8 mmol), n-Bu2SnO (0.05 g)
and DMAP (0.06 g) were cooled to 0 °C and treated with p-toluene-
sulphonyl chloride (1.97 g, 10.34 mmol). The reaction mixture was
stirred at room temperature for 1 h. It was then diluted with water
and extracted with CH2Cl2. The organic layer was washed with
brine and dried over anhydrous Na2SO4. Removal of solvent under
reduced pressure afforded the unstable crude tosyl compound 13,
which was used for further reaction.
4.1.6. (4R)-6-[(4-Methoxybenzyl)oxy]-4-(methoxymethoxy)-1-
{(4R,5S)-5-[(1S)-1-(methoxymethoxy)ethyl]-2,2-dimethyl-1,3-
dioxolan-4-yl}-2-hexyn-1-one 18
To an ice-cooled solution of 2-iodoxybenzoic acid (2.5 g,
9.25 mmol) in dry DMSO (4.8 mL, 61.43 mmol) was added a solu-
tion of alcohol 16 (1.07 g, 4.86 mmol) in dry CH2Cl2 (15 mL). The
mixture was stirred at room temperature for 2 h and then filtered
through a Celite pad and washed with Et2O (15 mL). The combined
organic filtrates were washed with H2O (2 ꢃ 5 mL) and brine
(5 mL), dried over anhydrous Na2SO4 (2 g), and concentrated in va-
cuo. The unstable crude aldehyde product 8 was used directly in
the next step without purification by column chromatography.
To a suspension of Mg (0.39 g, 16.25 mmol) in anhydrous THF
(50 mL), ethyl bromide (16.14 g, 292 mmol) was added dropwise
under nitrogen atmosphere at 0 °C. It was allowed to stir for
30 min. at room temperature. To this Grignard reagent, alkyne
compound 9 (1.07 g, 4.05 mmol) in anhydrous THF (75 mL) was
added at room temperature. After stirring for 2 h at room temper-
ature, the aldehyde compound 8 (0.9 g, 4.12 mmol) was added to
the reaction mixture and brought to reflux conditions to afford
alcohol 17 as a 1:1 mixture of diastereomers (determined by chiral
HPLC analysis) in approximately 80% yield. The reaction mixture
was quenched with saturated NH4Cl solution (7 mL) and filtered
over a Celite pad. The reaction mixture was extracted with EtOAc
and dried over Na2SO4. The organic layer was concentrated to give
a crude non-separable diastereomeric mixture, which was used for
the next step.
To a stirred suspension of LiAlH4 (0.422 g, 11.1 mmol) in dry
THF (10 mL) at 0 °C was added drop wise a solution of compound
13 (4 g, 9.25 mmol) in dry THF (20 mL). The reaction mixture
was refluxed for 3 h. It was then cooled to 0 °C, diluted with ether
and quenched by the dropwise addition of saturated aqueous
Na2SO4. The solid material was filtered and washed thoroughly
with hot ethyl acetate several times. The combined organic layers
were dried over anhydrous Na2SO4. The solvent was removed un-
der vacuo and the residue was purified by silica gel column chro-
matography (SiO2, ethyl acetate/hexane, 4:6) to afford the
compound 14 (1.96 g, 80%) as a viscous liquid. ½a D25
ꢄ
¼ þ11:8 (c 1,
CHCl3); IR (KBr) 3450, 2983, 1453, 1216, 1085 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): d 7.36–7.22 (m, 5H, ArH), 4.58 (ABq, J = 6.7,
9.0 Hz, 2H, CH2–OAr), 4.09–3.95 (m, 1H), 3.81–3.46 (m, 4H), 1.56
(br s, 1H, OH), 1.39 (s, 3H, CH3), 1.37 (s, 3H, CH3), 1.19 (d,
J = 6.7 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3): d 135.0, 125.6,
125.0, 124.8, 108.0, 79.9, 74.8, 70.7, 68.1, 65.2, 24.4, 24.2, 16.4;
HRMS calcd for C15H22O4Na m/z 289.1415 [M+Na]+; found m/z
289.1422 [M+Na]+.
To a stirred solution of compound 17 (1.58 g, 3.27 mmol) in
CH2Cl2 (10 mL), Dess–Martin periodinate (2.08 g, 4.90 mmol) was
added at 0 °C and stirred for 3 h. After completion of the reaction,
the reaction was quenched with aqueous sodium thio sulfate solu-
tion (4 mL) and saturated aqueous sodium bicarbonate solution
(10 mL). The reaction mixture was extracted with CH2Cl2
(2 ꢃ 10 mL), dried over anhydrous Na2SO4, and concentrated in va-
cuo. The residue was purified by column chromatography (SiO2,
ethyl acetate/hexane, 4:6) to afford 18 (1.25 g, 80%) as a yellow li-
4.1.4. (4S,5S)-4-[(Benzyloxy)methyl]-5-[(1S)-1-
(methoxymethoxy)ethyl]-2,2-dimethyl-1,3-dioxolane 15
To a solution of hydroxyl compound 14 (1.9 g, 7.14 mmol) in
anhydrous DCM (20 mL) at 0 °C under nitrogen, was added iPr2NEt
(1.84 g, 14.26 mmol) dropwise. After 5 min, MOMCl (0.68 mL,
8.44 mmol) was added dropwise. After stirring for 10 h at room
temperature, the reaction mixture was diluted with water, satu-
rated aqueous NH4Cl and brine solution, then dried over anhydrous
Na2SO4. The residue was purified on silica gel column chromatogra-
phy (SiO2, ethyl acetate/hexane, 2:8) to afford pure 15 as a clear col-
quid. ½a 2D5
ꢄ
¼ þ44:0 (c 1, CHCl3); IR (KBr) 2932, 1681, 1459, 1247,
1030 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d 7.20 (d, J = 9.0 Hz, 2H),
6.82 (d, J = 8.3 Hz, 2H), 4.88 (t, J = 7.5 Hz, 1H), 4.76 (m, 4H), 4.41
(s, 2H, CH2-OAr), 4.15 (m, 1H), 3.90–3.80 (m, 2H), 3.79 (s, 3H,
CH3), 3.57 (t, J = 5.2 Hz, 2H), 3.37 (s, 3H, CH3), 3.35 (s, 3H, CH3),
2.07 (m, 2H), 1.44 (s, 3H, CH3), 1.38 (s, 3H, CH3), 1.20 (d,
J = 6.7 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3): d 181.6, 159.0,
130.1, 129.2, 113.9, 110.6, 95.4, 94.6, 83.0, 82.0, 81.2, 81.0, 72.7,
72.1, 65.3, 62.6, 55.8, 55.5, 55.2, 35.2, 26.9, 26.3, 16.2; HRMS calcd
for C25H36O9Na: 503.2257; found: 503.2239.
orless liquid (2.09 g, 90%). ½a D25
ꢄ
¼ ꢀ13 (c 0.3, CHCl3). ½a D25
ꢄ
¼ þ21:5
(c 1, CHCl3); IR (KBr) 2984, 2932, 1373, 1148, 1097 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): d 7.32–7.22 (m, 5H, ArH), 4.64 (dd, J = 5.0,
12.8 Hz, 2H, CH2), 4.55(ABq, J = 8.0, 11.9 Hz, 2H, CH2-OAr), 4.06
(dq, J = 3.2, 7.3, 1H), 3.76–3.62 (m, 3H), 3.59–3.43 (m, 1H), 3.29 (s,
3H, CH3),1.39 (s, 3H, CH3), 1.38 (s, 3H, CH3), 1.20 (d, J = 6.0 Hz, 3H,
CH3); 13C NMR (75 MHz, CDCl3): 137.9, 128.1, 127.5, 127.4, 109.3,

G. Sabitha et al. / Tetrahedron: Asymmetry 22 (2011) 493–498
497
4.1.7. (1S,4R)-6-[(4-methoxybenzyl)oxy]-4-(methoxymethoxy)-
1-{(4S,5S)-5-[(1S)-1-(methoxymethoxy)ethyl]-2,2-dimethyl-1,3-
dioxolan-4-yl}-2-hexyn-1-ol 19
55.4, 37.7, 27.3, 27.0, 15.9; HRMS calcd for
429.2100; found: 429.2085.
C
19H34O9Na:
Catecholborane (1.0 M, 3 mL, 25.21 mmol) was added dropwise
over 30 min to a stirred solution of 18 (1.2 g, 2.50 mmol), methyl
(S)-CBS-oxazaborolidine (1.0 M, 0.12 mL, 0.45 mmol), and pow-
dered 4 Å molecular sieves (0.4 g) in anhydrous CH2Cl2 (10 mL)
at ꢀ78 °C. The mixture was stirred for 3 h at ꢀ78 °C before being
warmed to ꢀ0 °C, and then MeOH (5 mL) was added slowly. The
mixture was slowly warmed to room temperature and concen-
trated. The residue consisting of chiral propargyl alcohol, with
the required diastereoselectivity (9:1 dr), was then purified and
separated by silica gel column chromatography (SiO2, ethyl ace-
tate/hexane, 5:5) to give 19 (0.96 g, 80%) as a colorless viscous li-
4.1.10. Methyl (Z,5R,8S)-5,8-di(methoxymethoxy)-8-{(4S,5S)-5-
[(1S)-1-(methoxymethoxy)ethyl]-2,2-dimethyl-1,3-dioxolan-4-
yl}-2-octen-6-ynoate 6
To an ice-cooled solution of 2-iodoxybenzoic acid (0.36 g,
1.33 mmol) in dry DMSO (0.96 mL, 12.28 mmol) was added a solu-
tion of alcohol 20 (0.5 g, 1.23 mmol) in dry CH2Cl2 (10 mL). The
mixture was stirred at room temperature for 2 h and then filtered
through a Celite pad and washed with Et2O (15 mL). The combined
organic filtrates were washed with H2O (2 ꢃ 5 mL) and brine
(5 mL), dried over anhydrous Na2SO4 (2 g), and concentrated in va-
cuo. The unstable crude aldehyde product was used for further
reaction. In a 50 ml R.B. flask, NaH (0.034 g, 1.41 mmol) was taken
and to it 4 mL of dry THF were added under an N2 atmosphere.
After 5 min, bis-(2,2,2-trifluoroethyl) (methoxy-carbonyl methyl)]
phosphonate (0.36 g, 1.13 mmol) in 2 mL of dry THF was added
at 0 °C. It was then allowed to stir for 30 min. The reaction mixture
was cooled to ꢀ78 °C and the above crude aldehyde 21 (0.39 g,
0.96 mmol) in dry THF (2 mL) was added over a period of 10 min
and the resulting mixture was stirred for 1 h at ꢀ78 °C. The reac-
tion mixture was quenched with saturated NH4Cl (5 mL) and the
product was extracted into ether (2 ꢃ 10 mL). The organic layer
was dried over anhydrous Na2SO4 (2 g) and evaporated in vacuo
(water bath temperature should not exceed 35 °C) and the product
was purified using silica gel column chromatography (SiO2, ethyl
acetate/hexane, 3:7) to afford (Z)-olefin ester 6 (0.35 g, 80%) as a
quid. ½a 2D5
ꢄ
¼ þ18:1 (c 1, CHCl3); IR (KBr) 3447, 2933, 1374, 1152,
1032 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d 7.25 (d, J = 8.0 Hz, 2H),
6.88 (d, J = 8.3 Hz, 2H), 4.80 (d, J = 6.8 Hz, 1H), 4.72 (t, J = 4.8 Hz,
1H), 4.70–4.51 (m, 4H), 4.43 (s, 2H, CH2-OAr), 4.14–3.85 (m, 3H),
3.81 (s, 3H, CH3), 3.61(td, J = 2.2, 6.0 Hz, 2H), 3.38 (s, 3H, CH3),
3.35 (s, 3H, CH3), 2.36 (br s, 1H, OH), 2.05 (m, 2H), 1.44 (s, 3H,
CH3), 1.40 (s, 3H, CH3), 1.27 (d, J = 6.0 Hz, 3H, CH3); 13C NMR
(75 MHz, CDCl3): 159.1, 130.0, 129.1, 113.6, 110.0, 94.7, 94.0,
84.8, 83.8, 80.0, 78.5, 73.7, 72.6, 65.8, 63.9, 62.7, 55.7, 55.5, 55.1,
35.8, 27.2, 27.1, 16.3; HRMS calcd for C25H38O9Na: 505.2413;
found: 505.2392.
4.1.8. (4S,5S)-4-[(1S,4R)-6-[(4-Methoxybenzyl)oxy]-1,4-di(meth
oxymethoxy)-2-hexynyl]-5-[(1S)-1-(methoxymethoxy)ethyl]-
2,2-dimethyl-1,3-dioxolane 7
light yellow liquid. ½a D25
ꢄ
¼ ꢀ1:0 (c 1, CHCl3); IR (KBr) 2943, 1727,
To a solution of hydroxyl compound 19 (0.9 g, 1.86 mmol) in
anhydrous DCM (10 mL) at 0 °C under nitrogen, was added iPr2NEt
(0.48 g, 3.72 mmol) dropwise and after 5 min MOMCl (0.23 mL,
2.85 mmol) was added drop wise. After stirring for 8 h at room
temperature, the reaction mixture was diluted with water, satu-
rated aqueous NH4Cl and brine solution, and then dried over anhy-
drous Na2SO4. The residue was purified on silica gel column
chromatography (SiO2, ethyl acetate/hexane, 4:6) to afford the
1444, 1173, 1032 cmꢀ1 1H NMR (300 MHz, CDCl3): d 6.47–6.32
;
(m, 1H), 5.88 (d, J = 11.5 Hz, 1H), 4.88 (td, J = 1.8, 7.5 Hz, 2H),
4.72–4.38 (m, 6H), 4.15–3.81 (m, 2H), 3.78 (s, 3H, CH3), 3.37 (s,
3H, CH3), 3.36 (s, 3H, CH3), 3.35 (s, 3H, CH3), 3.10 (m, 1H), 2.13–
2.04 (m, 2H, CH2), 1.42 (s, 3H, CH3), 1.41 (s, 3H, CH3), 1.23 (d,
J = 6.4 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3): d 165.1, 144.3,
121.4, 110.4, 95.1, 94.7, 94.0, 80.5, 80.2, 79.6, 77.8, 73.6, 73.2,
67.0, 55.6, 55.4, 53.0, 51.1, 34.5, 27.4, 27.2, 16.2; HRMS calcd for
pure 7 (0.88 g, 90%) as a clear colorless liquid. ½a D25
ꢄ
¼ þ51:0 (c 1,
C22H36O10Na: 483.2206; found: 483.2186.
CHCl3); IR (KBr) 2935, 1373, 1247, 1099, 1033 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): d 7.19 (d, J = 9.0 Hz, 2H), 6.81 (d, J = 8.5 Hz,
2H), 4.87 (dd, J = 6.7, 13.5 Hz, 2H), 4.71–4.46 (m, 6H), 4.40 (s, 2H,
CH2-OAr), 3.90 (m, 3H), 3.79 (s, 3H, CH3), 3.55 (m, 2H),3.37 (s,
3H, CH3), 3.35 (s, 3H, CH3), 3.32 (s, 3H, CH3), 2.0 (m, 2H), 1.41 (s,
3H, CH3), 1.40 (s, 3H, CH3), 1.24 (d, J = 6.7 Hz, 3H, CH3); 13C NMR
(75 MHz, CDCl3): d 159.1, 130.3, 129.2, 113.6, 110.2, 95.0, 94.7,
94.1, 81.6, 80.5, 79.5, 73.6, 73.1, 72.6, 66.9, 65.7, 62.6, 55.6, 55.5,
55.4, 55.1, 35.8, 27.4, 27.2, 15.0; HRMS calcd for C27H42O10Na:
549.2675; found: 549.2657.
4.1.11. (1S,2S)-2-(Acetyloxy)-1-[(1S,2S)-1,2-di(acetyloxy)propyl]-
4-[(2R)-6-oxo-3,6-dihydro-2H-2-pyranyl]-3-butynyl acetate 23
To a stirred solution of compound 6 (0.3 g, 0.65 mmol) in a mix-
ture of MeOH (5 mL) and CH3CN (5 mL) was added CeCl3.7H2O
(cat.) under N2, then the mixture was stirred at rt for 65 h. The mix-
ture was quenched with solid NaHCO3 (0.5 g) and filtered. The sol-
vent was removed and concentrated in vacuo. The crude tetraol
lactone product was obtained as a colorless viscous liquid 22,
which was directly used for the next step without purification by
silica gel column chromatography.
4.1.9. (3R,6S)-3,6-Di(methoxymethoxy)-6-{(4S,5S)-5-[(1S)-1-
(methoxymethoxy)ethyl]-2,2-dimethyl-1,3-dioxolan-4-yl}-4-
hexyn-1-ol 20
Anhydrous Et3N (0.26 g, 2.57 mmol), Ac2O (0.13 g, 1.27 mmol),
and DMAP (20 mg) were added to a solution of tetraol 22 (0.09 g,
0.32 mmol) in anhydrous CH2Cl2 (10 mL) under a nitrogen atmo-
sphere at room temperature. The mixture was stirred at room tem-
perature for 30 min. The solvent was removed under reduced
pressure, and the mixture was purified by silica gel column chro-
matography (SiO2, ethyl acetate/hexane, 4:6) to afford 23 (0.1 g,
To a solution of 7 (0.82 g, 1.55 mmol) in CH2Cl2:H2O (10:1,
10 mL) was added dichlorodicyanoquinone (DDQ) (0.43 g,
1.9 mmol) at 0 °C. The solution was stirred for 2 h. After the reac-
tion was completed, the solution was filtered through a pad of Cel-
ite. The Celite pad was washed with CH2Cl2 (3 ꢃ 20 mL). The
combined filtrate was concentrated, and purification by column
chromatography (SiO2, ethyl acetate/hexane, 5:5) provided 20
80%) as a colorless liquid. ½a D25
ꢄ
¼ ꢀ41:3 (c 1, CHCl3); IR (KBr)
2953, 1739, 1617, 1240, 1023 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d
6.87 (ddd, J = 3.0, 5.0, 9.5 Hz, 1H), 6.05 (m, 1H), 5.83 (m, 1H),
5.44–5.40 (m, 1H), 5.28 (dd, J = 3.4, 8.0 Hz, 1H), 5.20 (ddd, J = 1.0,
3.2, 7.5 Hz, 1H), 5.01 (m, 1H), 2.49 (m, 2H), 2.16 (s, 3H, CH3),
2.13 (s, 3H, CH3), 2.13 (s, 3H, CH3), 2.06 (s, 3H, CH3), 1.20 (d,
J = 6.5 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3): d 170.0, 169.8,
169.6, 169.4, 163.5, 144.6, 126.3, 85.5, 82.1, 72.2, 72.0, 71.1, 71.0,
68.8, 30.0, 21.2, 21.1 (2 ꢃ C), 21.0, 14.8; HRMS calcd for
(0.5 g, 90%) as a colorless liquid. ½a D25
ꢄ
¼ ꢀ60:8 (c 1, CHCl3); IR
(KBr) 3459, 2940, 1216, 1152, 1031 cmꢀ1
;
1H NMR (300 MHz,
CDCl3): d 4.91 (q, J = 3.0, 6.7 Hz, 2H), 4.78–4.47 (m, 6H), 4.15–
3.67 (m, 5H), 3.39 (s, 3H, CH3), 3.38 (s, 3H, CH3), 3.37 (s, 3H,
CH3), 2.0 (m, 2H, CH2), 1.43 (s, 3H, CH3), 1.42 (s, 3H, CH3), 1.24
(d, J = 6.0 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3): d 110.4, 95.2,
94.6, 94.1, 81.4, 80.5, 80.0, 79.6, 72.0, 66.8, 63.8, 59.2, 55.7, 55.6,
C20H24O10Na: 447.1423; found: 447.1434.

498
G. Sabitha et al. / Tetrahedron: Asymmetry 22 (2011) 493–498
4.1.12. (1S,2S,3Z)-2-(Acetyloxy)-1-[(1S,2S)-1,2-di(acetyloxy)pro
pyl]-4-[(2R)-6-oxo-3,6-dihydro-2H-2-pyranyl]-3-butenyl ace
tate [(ꢀ)-spicigerolide] 1
References
1. Pereda-Miranda, R.; Fragoso-Serrano, M.; Cerda-Garcia-Rojas, C. M. Tetrahedron
2001, 57, 47–53.
To a solution of compound 23 (0.06 g, 0.14 mmol) in EtOAc
(5 mL), three drops of quinoline and Lindlar’s catalyst (Pd/BaSO4)
were added and stirred at room temperature under H2 atm for
1 h. After completion of the reaction, the reaction mixture was fil-
tered and the solvent was removed under reduced pressure. The
crude product was purified on silica gel column chromatography
(SiO2, ethyl acetate/hexane, 4:6) to afford compound 1 (0.054 g,
2. Pereda-Miranda, R.; Hernandez, L.; Villavicencio, M. J.; Novelo, M.; Ibarra, P.;
Chai, H.; Pezzuto, J. M. J. Nat. Prod. 1993, 56, 583–593.
3. Collett, L. A.; Davies-Coleman, M. T.; Rivett, D. E. A. Phytochemistry 1998, 48,
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4. Alemany, A.; Marquez, C.; Pascual, C.; Valverde, S.; Martinez-Ripoll, M.; Fayos,
J.; Perales, A. Tetrahedron Lett. 1979, 20, 3583–3586.
5. Achmad, S. A.; Hoyer, T.; Kjaer, A.; Makmur, L.; Norrestam, R. Acta Chem. Scand.
1987, 41B, 599–609.
6. Coleman, M. T. D.; English, R. B.; Rivett, D. E. A. Phytochemistry 1987, 26, 1497–
1499.
7. Sabitha, G.; Gopal, P.; Reddy, C. N.; Yadav, J. S. Tetrahedron Lett. 2009, 50, 6298–
6302.
8. Sabitha, G.; Gopal, P.; Reddy, C. N.; Yadav, J. S. Tetrahedron Lett. 2010, 51, 5736–
5739.
9. (a) Georges, Y.; Ariza, X.; Garcia, J. J. Org. Chem. 2009, 74, 2008–2012; (b)
Falomir, E.; Murga, J.; Carda, M.; Marco, J. A. Tetrahedron Lett. 2003, 44, 539–
541; (c) Falomir, E.; Murga, J.; Ruiz, P.; Carda, M.; Marco, J. A. J. Org. Chem. 2003,
68, 5672–5676.
10. Waanders, P. P.; Thijs, L.; Zwanenburg, B. Tetrahedron Lett. 1987, 28, 2409–
2412.
11. Chandrasekhar, S.; Sudhakar, A. Org. Lett. 2010, 12, 236–238.
12. The diastereomeric excess of the product was determined using a Shimadzu
90%) as a colorless liquid. ½a D25
ꢄ
¼ ꢀ23:4 (c 1.30, CHCl3) lit.9a
½
a 2D5
ꢄ
¼ ꢀ23:0 (c 1.34, CHCl3); IR (KBr) 2925, 1735, 1457, 1374,
1023 cmꢀ1 1H NMR (300 MHz, CDCl3): d 6.90 (ddd, J = 2.6, 5.8,
;
9.8 Hz, 1H), 6.05 (ddd, J = 1.0, 2.4, 10 Hz, 1H), 5.79 (dd, J = 9.3,
10.7 Hz, 1H), 5.51–5.29 (m, 5H), 4.96 (dq, J = 6.3, 8.4 Hz, 1H), 2.50
(dddd, J = 1.0, 4.3, 5.8, 18.6 Hz, 1H), 2.35 (ddt, J = 2.5, 11.0 18.5 Hz,
1H), 2.12 (s, 3H, CH3), 2.12 (s, 3H, CH3), 2.04 (s, 3H, CH3), 2.03 (s,
3H, CH3), 1.20 (d, J = 6.2 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3): d
170.2, 170.1, 170.0,169.9, 163.5, 144.7, 132.7, 128.6, 121.4, 73.7,
71.0, 69.2, 66.9, 66.1, 29.2, 21.0, 20.9, 20.8, 20.7, 16.6; HRMS calcd
for C20H26O10Na: 449.1420; found: 449.1416.
high-performance liquid-chromatography (HPLC) system equipped with
a
1H NMR (500 MHz, CDCl3) data of natural product1: d 6.90 (ddd,
J = 9.7, 5.2, 2.5 Hz, H-4), 6.06 (ddd, J = 9.7, 2.5, 1.3 Hz, H-3), 5.79
(ddd, J = 10.5, 9.5, 0.5 Hz, H-10), 5.49 (ddd, J = 10.5, 9.0, 1.0 Hz, H-
20), 5.40 (ddd, J = 9.0, 9.0, 0.5 Hz, H-30), 5.37 (dd, J = 9.0, 2.1 Hz, H-
40), 5.35 (dddd, J = 11.0, 9.5, 4.5, 1.0 Hz, H-6), 5.30 (dd, J = 8.7,
2.1 Hz, H-50), 4.96 (dq, J = 8.7, 6.2 Hz, H-6’), 2.52 (dddd, J = 18.5,
5.2, 4.5, 1.3 Hz, H-5eq), 2.35 (dddd, J = 18.5, 11.0, 2.5, 2.5 Hz, H-
5ax) 2.12 (s, 6H), 2.04 (s, 3H), 2.03 (s, 3H), 1.19 (d, J = 6.2 Hz,
CH3-70).
chiral HPLC column (Chiralcel OD) and a UV detector at an absorbance of
225 nm. A solvent system of acetonitrile and water (3:7) at a flow rate of
1.0 ml/min was used.
13. Sabitha, G.; Bhaskar, V.; Reddy, S. S. S.; Yadav, J. S. Synthesis 2009, 3285.
14. (a) Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1997, 38, 7511–7514; (b) Hung, D.
T.; Nerenberg, J. B.; Schreiber, S. L. J. Am. Chem. Soc. 1996, 118, 11054–11080.
15. The diastereomeric excess of the product was determined using a Shimadzu
high-performance liquid-chromatography (HPLC) system equipped with
a
chiral HPLC column (Chiralcel OD) and a UV detector at an absorbance of
225 nm. A solvent system of acetonitrile and water (4:6) at a flow rate of
1.0 ml/min was used.
16. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405–4408.
Acknowledgment
C.N.R. and A.R. thanks UGC, New Delhi, for the award of
fellowships.