Stereoselective total synthesis of achaetolide from l-malic acid

Article abstract of DOI:10.1055/s-0030-1260174

A convergent total synthesis of achaetolide is described. The key steps include a Horner-Wadsworth-Emmons olefination, CBS reduction to install the stereochemistry at the C9 center, ste-reoselective vinylation to introduce the chiral center at C6, and finally- a ring-closing metathesis (RCM) reaction to construct the ten-membered lactone of the molecule. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1260174

PAPER
3343
Stereoselective Total Synthesis of Achaetolide from L-Malic Acid
Stereoselective
T
o
o
tal Synthesis
w
of
A
chaetolide ravaram Sabitha,* Rangavajjula Srinivas, Jhillu S. Yadav1
Division of Organic Chemistry, Indian Institute of Chemical Technology (CSIR), Hyderabad 500 607, India
Fax +91(40)27160512; E-mail: gowravaramsr@yahoo.com; E-mail: sabitha@iict.res.in
Received 6 June 2011; revised 22 July 2011
(Scheme 2). Accordingly, the primary hydroxyl group in
5 was protected as TBS ether 6 followed by protection of
secondary hydroxyl group as TIPS ether 7. Next, the ester
group in 7 was converted into b-ketophosphonate 8 by
Abstract: A convergent total synthesis of achaetolide is described.
The key steps include a Horner–Wadsworth–Emmons olefination,
CBS reduction to install the stereochemistry at the C9 center, ste-
reoselective vinylation to introduce the chiral center at C6, and
finally a ring-closing metathesis (RCM) reaction to construct the treatment with diethyl methylphosphonate in the presence
ten-membered lactone of the molecule.
of n-BuLi.9 The b-ketophosphonate 8 was treated with n-
hexanal in the presence of Ba(OH)2·8H2O10 in wet THF
Key words: macrocycles, metathesis, stereoselective synthesis,
reduction, olefination
(THF–H2O, 9:1) to give enone 9 with E-selectivity in
good yield (80%). A reagent-controlled reduction of
enone was now required. The (R)-Me-CBS reagent11 was
found to give excellent selectivity in setting the desired
configuration at C-4, leading to the allylic alcohol 10
(72%, dr 19:1). Reduction of double bond was achieved
using PtO2 in EtOAc at room temperature to afford the
saturated compound 11 and the free hydroxyl group was
protected as PMB ether 12 using PMB imidate in toluene
in the presence of copper triflate. TBS group was selec-
tively removed by exposing to catalytic CSA in CH2Cl2–
MeOH (4:1) to give primary alcohol 13, which was oxi-
dized to aldehyde by using IBX in DMSO–CH2Cl2. Ste-
reoselective vinylation of aldehyde with in situ generated
vinylmagnesium bromide afforded the corresponding al-
lylic alcohols as a mixture of diastereomers 14a and 14b
(anti/syn = 85:15) in 88% overall yield and these diaste-
reomers were separated by silica gel chromatography. The
major diastereomer 14a (as predicted by the Felkin–Anh12
model) had the required stereochemistry. The free hy-
droxyl group was protected as its TIPS ether 15 and fol-
lowed by deprotection of PMB group using DDQ yielded
the diol fragment 3.
Achaetolide (1, Figure 1), a new ten-membered lactone
was isolated in 1983 by Bodo et al.2 from the fermentation
broth of Achaetomium cristalliferum, Ophiobolus sp. Its
absolute stereochemistry (3S,6R,7S,9R) was established
in 2009 by Takada et al.3 using extensive NMR and GC
analyses and by an extended Mosher method. Polyhy-
droxylated 10-membered macrolides4 exhibit potent bio-
logical activities (cholesterol biosynthesis inhibition
activity, antimicrofilament activity, and phytotoxicity,
etc.); therefore, this class of lactones has received special
attention over recent years.5 So far four total syntheses
have appeared recently.6 Because of its interesting struc-
ture and our continued interest on the synthesis of mac-
rolides,7 we herein report a stereoselective total synthesis
of achaetolide by a convergent strategy wherein L-malic
acid was used as the common starting material for access-
ing both the advanced intermediates for use in total syn-
thesis.
10
O
1
2
9
8
7
O
5
3
HO
OH
HO
6
4
OH
achaetolide (1)
achaetolide (1)
O
O
OH
Figure 1 Structure of archaetolide (1)
OH
2
The retrosynthetic strategy for achaetolide (1) is shown in
Scheme 1. The final assembly of 1 by this route consists
of coupling the fragment 3 with acid fragment 4 via an es-
terification and ring-closing metathesis of 2. Fragment 3
and 4 can be prepared from L-malic acid.
OH OTIPS
OTBS
COOH
OTIPS
The synthesis of fragment 3 started from the known diol
5, which was conveniently prepared from L-malic acid8
4
3
SYNTHESIS 2011, No. 20, pp 3343–3349
Advanced online publication: 16.08.2011
x
x.
x
x
.
2
0
1
1
L-malic acid
DOI: 10.1055/s-0030-1260174; Art ID: Z58411SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Retrosynthetic analysis for the synthesis of 1

3344
G. Sabitha et al.
PAPER
OH
O
ref. 12
OH
O
O
a
a
ref. 7
L-malic acid
OTBS
HO
OBn
HOOC
L-malic acid
OR
OH
OMe
O
16
OTBS
5
OTBS
b
c
CH2OH
COOH
OR
O
O
P
OBn
c
TBSO
TBSO
17 R = H
18 R = TBS
19
4
OEt
OEt
OMe
8 R = TIPS
6 R = H
7 R = TIPS
Scheme 3 (a) (i) Me3S(O)I, n-BuLi, THF, 2 h, 80%, (ii) TBSCl,
imidazole, DMAP, CH2Cl2, 0 °C, 6 h, 90%; (b) Li, naphthalene,
–10 °C, 4 h, 65%; (c) (i) DMP, CH2Cl2, 0 °C to r.t, 1 h, (ii) NaH2PO4,
NaClO2, DMSO, 30 min, 70%.
b
OR
O
d
e
TBSO
9 R = TIPS
OR
Next, it was attempted to couple the two fragments in or-
der to construct a 10-membered ring by RCM reaction.
Accordingly, the Yamaguchi protocol (DCC and
DMAP)15 was explored to afford diene ester 20 in 78%
yield (Scheme 4). It is important to note that the RCM re-
action did not proceed when either one hydroxyl group or
two hydroxyl groups were protected as silyl ethers. There-
fore, the deprotection of three silyl groups was studied
under different conditions. The starting material decom-
posed on removal of silyl groups using TBAF in THF.
However, desilylation was achieved using HF·Py to fur-
nish triol 2 in 42% yield.
OH
f
TBSO
10 R = TIPS
OR
OR1
h
TBSO
g
11 R = TIPS, R1 = H
12 R = TIPS, R1 = PMB
OR
OPMB
i
HO
13 R = TIPS
OR
OH OTIPS
OTBS
OPMB
j
+
COOH
OTIPS
4
3
OR1
a
14a and 14b R = TIPS, R1 = H
dr = 8.5:1.5 (anti/syn)
O
OR1
OR
TBSO
OTIPS
O
OR
OTIPS
15 R = TIPS, R1 = PMB
3 R = TIPS, R1 = H
20
k
Scheme 2 (a) TBSCl, Et3N, DMAP, CH2Cl2, 0 °C, 2 h, 90%; (b)
TIPSOTf, 2,6-lutidine, CH2Cl2, –78 °C, 30 min, 85%; (c)
MeP(O)(OEt)2, n-BuLi, THF, –78 °C, 2 h, 75%; (d) (i) Ba(OH)2,
THF, 1 h, (ii) n-hexanal, THF–H2O (9:1), 30 min, 80%; (e) (R)-CBS,
Me2S·BH3, THF, 0 °C, 1 h, 72%; (f) PtO2, EtOAc, 2 h, 95%; (g)
PMB-imidate, Cu(OTf)2, toluene, 12 h, 85%; (h) CSA (cat.), CH2Cl2–
MeOH (4:1), 30 min, 54%; (i) (i) IBX, DMSO, CH2Cl2, 2 h, 82%, (ii)
CH2=CHMgBr, THF, –78 °C, 10 min, 88% (dr 85:15); (j) TIPSOTf,
2,6-lutidine, –78 °C, 30 min, 78%; (k) DDQ, CH2Cl2–H2O (9:1), 1 h,
62%.
c
b
decomposed
O
HO
OH
O
d
1
OH
2
The preparation of acid fragment 4 starts with the epoxide
16 (Scheme 3), which is readily prepared from L-malic ac-
id.13 Opening of epoxide 16 using trimethylsulfonium
iodide14 in the presence of n-BuLi in anhydrous THF at
–10 °C provided the secondary allylic alcohol 17 in 80%
yield, which was protected as its TBS ether 18. After de-
benzylation, the free alcohol 19 was then oxidized by
DMP in CH2Cl2 to afford the corresponding aldehyde,
which was oxidized to the acid fragment 4 with NaClO2 in
the presence of NaH2PO4⋅2H2O and 2-methylbut-2-ene in
70% yield over two steps.
Scheme 4 (a) DCC, DMAP, 0 °C, 6 h, 78%; (b) TBAF, THF, 2 h;
(c) HF·Py, 24 h, 42%; (d) Grubbs’ second generation catalyst,
CH2Cl2, reflux, 6 h, 54%.
The ring-closing metathesis reaction using Grubbs’ sec-
ond-generation catalyst16was performed on compound 2
in CH2Cl2 at reflux temperature for six hours to afford the
target molecule 1 in 54% yield. The physical and spectro-
scopic data of our synthetic sample 1 were identical to
those of the reported natural and synthetic products.
Synthesis 2011, No. 20, 3343–3349 © Thieme Stuttgart · New York

PAPER
Stereoselective Total Synthesis of Achaetolide
3345
ESI-MS: m/z = 405 [M]+.
In conclusion, a stereoselective synthesis of archaetolide
(1) was accomplished by means of a versatile strategy,
wherein both the intermediates are derived from the inex-
pensive starting material, L-malic acid.
Diethyl (S)-5-(tert-Butyldimethylsilyloxy)-2-oxo-4-(triisopro-
pylsilyloxy)pentylphosphonate (8)
Diethyl methylphosphonate (4.13 g, 27.18 mmol) was dissolved in
anhyd THF (50 mL) under a N2 atmosphere, and to this was added
n-BuLi (1.6 M in n-hexane, 15 mL, 24.46 mmol) dropwise at
–78 °C over 10 min and the reaction was stirred at the same temper-
ature for 1 h. Compound 7 (5.5 g, 13.59) in THF (10 mL) was intro-
duced into the reaction mixture slowly over a period of 10 min
under N2. The resulting mixture was stirred for 1 h at the same tem-
perature and then warmed to r.t. before quenching with sat. aq
NH4Cl (15 mL) at 0 °C. The product was extracted with EtOAc
(2 × 50 mL), the combined organic extracts were washed with H2O
(20 mL), brine (20 mL), and dried (Na2SO4). The solvent was re-
moved under vacuum and the residue was purified by column chro-
matography (EtOAc–hexane, 45%) to afford 8; yield: 5.3 g (75%);
yellow liquid; Rf = 0.4 (EtOAc–hexane, 50%); [a]D –8.3 (c 1.0,
CHCl3).
IR (neat): 2929, 2864, 1717, 1466, 1257, 1028, 837 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.29–4.21 (m, 1 H), 4.16–4.02 (m,
4 H), 3.61 (dd, J = 4.5, 10.0 Hz, 1 H), 3.42 (dd, J = 7.2, 10.0 Hz, 1
H), 3.05 (dd, J = 13.6, 22.7 Hz, 1 H), 3.0 (dd, J = 12.7, 22.7 Hz, 1
H), 2.89 (dd, J = 5.4, 16.4 Hz, 1 H), 2.7 (dd, J = 5.4, 16.4 Hz, 1 H),
1.32 (t, J = 7.3 Hz, 6 H),1.12–0.95 (m, 21 H), 0.86 (s, 9 H), 0.03 (s,
3 H), 0.01 (s, 3 H).
Reactions were conducted under N2 in anhyd solvents such as
CH2Cl2, THF, and EtOAc. All reactions were monitored by TLC
(silica-coated plates and visualizing under UV light). Petroleum
ether (PE) with a boiling range of 60–80 °C was used. Yields refer
to chromatographically and spectroscopically (1H and 13C NMR)
homogeneous material. Air-sensitive reagents were transferred by
syringe or double-ended needle. Evaporation of solvents was per-
formed at reduced pressure on a Büchi rotary evaporator. 1H and 13
C
NMR spectra of samples in CDCl3 were recorded on Varian FT-200
MHz (Gemini) and Bruker UXNMR FT-300 MHz (Avance) spec-
trometers. Chemical shifts (d) are reported relative to TMS (d = 0.0)
as an internal standard. Mass spectra were recorded under EI condi-
tions at 70 eV on LC-MSD (Agilent technologies) spectrometers.
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 mea-
sured with Jasco DIP-370 Polarimeter.
25
Methyl (S)-4-(tert-Butyldimethylsilyloxy)-3-hydroxybutanoate
(6)
To a stirred solution of 5 (2.5 g, 18.65 mmol) in CH2Cl2 (30 mL)
were added sequentially Et3N (3.13 mL, 22.38 mmol) and TBSCl
(3.0 g, 20.5 mmol) at 0 °C under N2 atmosphere followed by the ad-
dition of a catalytic amount of DMAP. The reaction mixture was
warmed to r.t. and stirred for 2 h. It was quenched with sat. aq
NH4Cl (10 mL) and extracted with CH2Cl2 (20 mL). The CH2Cl2
layer was washed with brine (20 mL), dried (Na2SO4), and concen-
trated in vacuo. Purification of the residue by column chromatogra-
phy (EtOAc–hexane, 10%) gave pure 6; yield: 4.17 g (90%); yellow
liquid; Rf = 0.3 (EtOAc–hexane, 10%); [a]D25 –8.54 (c 1.0, CHCl3).
13C NMR (75 MHz, CDCl3): d = 200.8, 69.7, 66.7, 62.3, 49.1, 44.4,
42.7, 25.8, 18.2, 18.0, 16.2, 12.4, –5.6.
ESI-MS: m/z = 525 [M]+.
(S,E)-1-(tert-Butyldimethylsilyloxy)-2-(triisopropylsilyloxy)un-
dec-5-en-4-one (9)
To a solution of b-ketophosphonate 8 (5.3 g, 10.09 mmol) in THF
(50 mL) was added Ba(OH)2·8H2O (2.3 g, 10.09 mmol, 1.0 equiv),
which was preactivated by heating at 110 °C for 1 h and then dried
under vacuum. The reaction mixture was stirred for 30 min, and
then hexanal (1.2 mL, 10.09 mmol) in THF–H2O (9:1, 20mL) was
added and stirred for 30 min. Upon completion of the reaction, the
mixture was partitioned between sat. aq NH4Cl (25 mL) and EtOAc
(50 mL). The layers were separated and the aqueous phase was ex-
tracted with EtOAc (2 × 50 mL). The combined organic layers were
washed with brine (15 mL), dried (Na2SO4), and concentrated under
reduced pressure. The crude residue was purified by column chro-
matography (EtOAc–hexane, 10%) to furnish 9; yield: 3.8 g (80%);
yellow liquid; Rf = 0.4 (EtOAc–hexane, 10%); [a]D25 –9.76 (c 1.0,
CHCl3).
IR (neat): 3440, 2928, 2857, 1742, 1466, 1441, 1255, 1121, 838,
779 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.30–4.19 (m, 1 H), 3.71–3.62 (m,
4 H), 3.44 (dd, J = 7.3, 9.8 Hz, 1 H), 2.64 (dd, J = 5.4, 15.1 Hz, 1
H), 2.41 (dd, J = 6.4, 15.1 Hz, 1 H), 1.11–1.01 (m, 21 H), 0.89 (s, 9
H), 0.05 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 172.4, 70.4, 60.7, 51.4, 40.1, 25.7,
18.2, 17.4, 12.3, –5.4.
ESI-MS: m/z = 248 [M]+, 271 [M + Na]+.
IR (neat): 2929, 2863, 1465, 1466, 1254, 1115, 836 cm–1.
Methyl (S)-4-(tert-Butyldimethylsilyloxy)-3-(triisopropylsilyl-
oxy)butanoate (7)
1H NMR (300 MHz, CDCl3): d = 6.85–6.71 (m, 1 H), 6.08 (d,
J = 15.8 Hz, 1 H), 4.40–4.29 (m, 1 H), 3.64 (dd, J = 4.5, 9.8 Hz, 1
H), 3.45 (dd, J = 6.4, 10.0 Hz, 1 H), 2.85 (dd, J = 5.8, 15.6 Hz, 1 H),
2.61 (dd, J = 6.2, 15.6 Hz, 1 H), 2.25–2.16 (m, 2 H), 1.38–1.23 (m,
6 H), 1.08–1.02 (m, 21 H), 0.93–0.82 (m, 12 H), 0.04 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 199.0, 147.4, 131.4, 70.0, 67.0,
45.0, 32.3, 31.3, 27.7, 25.8, 22.4, 18.2, 18.0, 13.8, 12.4, –5.5.
To a stirred solution of 6 (4 g, 16.103 mmol) in CH2Cl2 (30 mL) at
0 °C were added sequentially 2,6-lutidine (2.8 mL, 24.15 mmol)
and TIPSOTf (5.2 mL, 19.32 mmol). After 30 min, the reaction was
quenched with sat. aq NH4Cl (10 mL) and the mixture was extracted
with CH2Cl2 (2 × 20 mL). The combined organic layers were
washed with brine (10 mL), dried (Na2SO4), and concentrated in
vacuo. Purification of the residue by column chromatography
(EtOAc–hexane, 5%) afforded pure 7; yield: 5.53 g (85%); yellow
liquid; Rf = 0.7 (EtOAc–hexane, 5%); [a]D25 –14.6 (c 1.0, CHCl3).
ESI-MS: m/z = 471 [M]+.
IR (neat): 2865, 2929, 1743, 1465, 1254, 837, 778, 677 cm–1.
(2S,4S,E)-1-(tert-Butyldimethylsilyloxy)-2-(triisopropylsilyl-
oxy)undec-5-en-4-ol (10)
1H NMR (300 MHz, CDCl3): d = 4.30–4.19 (m, 1 H), 3.71–3.62 (m,
4 H), 3.44 (dd, J = 7.3, 9.8 Hz, 1 H), 2.64 (dd, J = 5.4, 15.1 Hz, 1
H), 2.41 (dd, J = 6.4, 15.1 Hz, 1 H), 1.11–1.01 (m, 21 H), 0.89 (s, 9
H), 0.05 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 172.5, 70.4, 60.7, 51.4, 40.1, 25.7,
18.2, 17.4, 12.3, –5.4.
A flame-dried 100 mL round-bottomed flask was charged with an-
hyd THF (30 mL) and cooled to –20 °C. To this solution was added
(R)-methyl-CBS-oxazaborolidine (1.00 M in toluene, 1.57 mL, 1.57
mmol), followed by Me2S·BH3 (2 M, 1.96 mL, 3.92 mmol). After
stirring for 30 min at this temperature, compound 9 (3.70 g, 7.85
mmol) was added slowly over a period of 10 min at the same tem-
Synthesis 2011, No. 20, 3343–3349 © Thieme Stuttgart · New York

3346
G. Sabitha et al.
PAPER
perature, and the mixture stirred for 30 min at the same temperature.
The reaction mixture was slowly quenched with MeOH (10 mL)
over a period of about 15 min. The mixture was warmed to r.t. and,
after the majority of gas evolution had subsided, the solvent was re-
moved under vacuum. The crude oil was purified by column chro-
matography (EtOAc–hexane, 15%) to afford 10; yield: 2.67 g
(72%); colorless liquid; Rf = 0.7 (EtOAc–hexane, 20%); [a]D
–11.92 (c 1.0, CHCl3).
IR (neat): 3452, 2930, 2863, 1464, 1253, 1115, 838, 777, 676 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.68–5.54 (m, 1 H), 5.42 (dd,
J = 6.0, 15.1 Hz, 1 H), 4.39–4.24 (m, 1 H), 4.12–3.97 (m, 1 H),
3.74–3.64 (m, 1 H), 3.63–3.52 (m, 1 H), 2.06–1.95 (m, 1 H), 1.80–
1.73 (m, 1 H), 1.45–1.23 (m, 6 H), 1.14–1.03 (m, 21 H), 0.94–0.86
(m, 12 H), 0.07 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 133.1, 130.7, 72.1, 69.5, 66.0, 41.5,
32.1, 31.3, 28.8, 25.7, 22.5, 18.1, 18.0, 14.0, 12.3, –5.5.
ESI-MS: m/z = 595 [M]+, 618 [M + Na]+.
(2S,4R)-4-(4-Methoxybenzyloxy)-2-(triisopropylsilyloxy)unde-
can-1-ol (13)
A solution of 12 (2.1 g, 3.52 mmol) in CH2Cl2–MeOH (4:1, 20 mL)
was treated with a catalytic amount of CSA (40 mg, 0.175mmol) at
0 °C. After stirring for 30 min, the reaction mixture was quenched
with sat. aq NaHCO3 (10 mL). The solvent was removed in the ro-
tary evaporator and the residue was extracted with EtOAc (2 × 20
mL). The combined organic layers were washed with H2O (10 mL),
brine (15 mL), dried (Na2SO4), and concentrated in vacuo. The res-
idue was purified by column chromatography (EtOAc–hexane,
20%) to give pure 13; yield: 0.91 g (54%); colorless liquid; Rf = 0.8
(EtOAc–hexane, 30%); [a]D25 –23.65 (c 0.5, CHCl3).
25
IR (neat): 3450, 2930, 2863, 1613, 1512, 1462, 1247, 1041, 882,
819 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.19 (d, J = 8.6 Hz, 2 H), 6.81 (d,
J = 8.4 Hz, 2 H), 4.47 (d, J = 10.9 Hz, 1 H), 4.29 (d, J = 10.9 Hz, 1
H), 3.93–3.82 (m, 1 H), 3.79 (s, 1 H), 3.60–3.40 (m, 3 H), 1.92–1.78
(m, 1 H), 1.75–1.62 (m, 1 H), 1.60–1.19 (m, 12 H), 1.13–0.96 (m,
21 H), 0.89 (t, J = 6.9 Hz, 3 H).
ESI-MS: m/z = 472 [M + Na]+.
(2S,4R)-1-(tert-Butyldimethylsilyloxy)-2-(triisopropylsilyl-
oxy)undecan-4-ol (11)
To a stirred solution of 10 (2.1 g, 4.42 mmol) in EtOAc (50 mL) was
added PtO2 (0.12 g, 0.528 mmol), and the reaction mixture was
stirred under H2 atmosphere for 2 h. The contents were then filtered
over Celite and the crude mixture was concentrated under reduced
pressure. The residue was purified by column chromatography
(EtOAc–hexane, 15%) to give pure 11; yield: 2.38 g (95%); color-
13C NMR (75 MHz, CDCl3): d = 159.5, 130.3, 129.6, 113.7, 76.0,
71.5, 69.8, 67.0, 55.1, 39.8, 33.5, 31.8, 29.7, 29.2, 24.8, 22.6, 18.0,
14.0, 12.5.
ESI-MS: m/z = 481 [M]+, 504 [M + Na]+.
25
less liquid; Rf = 0.7 (EtOAc–hexane, 20%); [a]D –11.08 (c 1.0,
CHCl3).
(3R,4S,6R)-6-(4-Methoxybenzyloxy)-4-(triisopropylsilyl-
oxy)tridec-1-en-3-ol (14)
To an ice-cold solution of 2-(iodoxy)benzoic acid (IBX, 698 mg,
2.49 mmol) in anhyd DMSO (0.7 mL, 9.97 mmol) was added a so-
lution of alcohol 13 (800 mg, 1.663 mmol) in anhyd CH2Cl2 (20
mL). The mixture was stirred at r.t. for 2 h and then filtered through
a Celite pad. The filtrate was concentrated under reduced pressure
and extracted with Et2O (20 mL). The Et2O layer was washed with
H2O (20 mL) and concentrated under vacuum to give the interme-
diate crude aldehyde (650 mg, 82%), which was used directly for
the next reaction. The crude aldehyde (650 mg, 1.69 mmol) was tak-
en in a 50 mL round-bottomed flask and dissolved in anhyd THF
(25 mL) and cooled to –78 °C. To this solution was added vinyl-
magnesium bromide (1.63 mL, 1.63 mmol, 1 M in THF) slowly. Af-
ter stirring for 10 min, the mixture was partitioned between sat. aq
NH4Cl (15 mL) and EtOAc (50 mL). The layers were separated and
the aqueous phase was extracted with EtOAc (2 × 50 mL). The
combined organic layers were washed with brine (2 × 15 mL), dried
(Na2SO4), and concentrated under reduced pressure. The crude res-
idue was purified by column chromatography to furnish the alcohol
product (dr = 85:15). The diastereomeric alcohol was separated by
column chromatography (EtOAc–hexane, 8%) to isolate the re-
quired anti-conformation compound 14; yield: 0.606 g (71%); col-
IR (neat): 3415, 2929, 2861, 1462, 1462, 1253, 1110, 837, 777, 678
cm–1.
1H NMR (500 MHz, CDCl3): d = 4.10–4.00 (m, 1 H), 3.89–3.80 (m,
1 H), 3.72–3.66 (m, 1 H), 3.62–3.55 (m, 1 H), 3.38 (s, 1 H), 1.84–
1.72 (m, 1 H), 1.70–1.60 (m, 1 H), 1.53–1.37 (m, 2 H), 1.36–1.22
(m, 10 H), 1.14–1.00 (m, 21 H), 0.95–0.84 (m, 12 H), 0.07 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 72.8, 68.4, 65.4, 39.8, 38.0, 31.8,
29.7, 29.3, 25.8, 25.6, 22.6, 18.0, 14.0, 12.3, –5.47.
ESI-MS: m/z = 475 [M]+.
(S)-8,8-Diisopropyl-6-[(R)-2-(4-methoxybenzyloxy)nonyl]-
2,2,3,3,9-pentamethyl-4,7-dioxa-3,8-disiladecane (12)
To a stirred solution of alcohol 11 (2.1 g, 4.42 mmol) in anhyd tol-
uene (50 mL) under N2 atmosphere were added 4-methoxybenzyl-
2,2,2-trichloroacetimidate (1.49 g, 5.3 mmol) and then Cu(OTf)2
(159 mg, 0.442 mmol). The mixture was allowed to stir for 12 h, and
then concentrated in vacuo. In order to precipitate the trichloroacet-
amide, the residual oil was taken up in a cyclohexane–CH2Cl2 mix-
ture (3:1) and filtered. The remaining oil was purified by flash
chromatography (EtOAc–hexane, 12%) to give pure 12. The pre-
cipitation procedure was repeated three more times to yield the pure
product 12; yield: 2.23 g (85%); yellow liquid; Rf = 0.75 (EtOAc–
hexane, 20%); [a]D25 –5.47 (c 1.2, CHCl3).
25
orless liquid; dr = 85:15; Rf = 0.4 (EtOAc–hexane, 10%); [a]D
–6.63 (c 1.0, CHCl3).
IR (neat): 3453, 2930, 2863, 1613, 1513, 1462, 1247, 883, 667 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.15 (d, J = 8.3 Hz, 2 H), 6.78 (d,
J = 8.3 Hz, 2 H), 5.86–5.69 (m, 1 H), 5.34–5.11 (m, 2 H), 4.44 (d,
J = 11.3 Hz, 1 H), 4.25 (d, J = 11.3 Hz, 1 H), 4.17–4.07 (m, 1 H),
4.02–3.94 (m, 1 H), 3.77 (s, 3 H), 3.57–3.45 (m, 1 H), 1.78–1.46 (m,
2 H), 1.39–1.16 (m, 12 H), 1.13–0.95 (m, 21 H), 0.89 (t, J = 6.7 Hz,
3 H).
13C NMR (75 MHz, CDCl3): d = 159.0, 136.4, 130.9, 129.0, 116.4,
113.6, 76.3, 75.6, 73.5, 69.4, 55.2, 37.4, 33.5, 31.8, 29.8, 29.3, 24.9,
22.6, 18.1, 14.1, 12.7.
IR (neat): 2930, 2862, 1511, 1463, 1248, 836, 776, 676 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.16 (d, J = 7.91 Hz, 2 H), 6.77
(d, J = 7.91 Hz, 2 H), 4.41 (d, J = 10.8 Hz, 1 H), 4.31 (d, J = 10.83
Hz, 1 H), 3.97–3.86 (m, 1 H), 3.76 (s, 3 H), 3.61–3.52 (m, 2 H),
3.47–3.39 (m, 1 H), 1.90–1.71 (m, 1 H), 1.6–1.41 (m, 1 H), 1.34–
1.18 (m, 12 H), 1.1–0.96 (m, 27 H), 0.92–0.80 (m, 12 H), 0.02 (s, 6
H).
13C NMR (75 MHz, CDCl3): d = 159.3, 133.1, 129.1, 113.5, 75.7,
71.0, 69.6, 68.0, 65.1, 55.2, 40.0, 34.2, 31.8, 29.7, 29.3, 25.9, 25.0,
22.6, 18.2, 14.1, 12.8, –5.4.
ESI-MS: m/z = 507 [M]+, 530 [M + Na]+.
Synthesis 2011, No. 20, 3343–3349 © Thieme Stuttgart · New York

PAPER
Stereoselective Total Synthesis of Achaetolide
3347
(5S,6R)-3,3,8,8-Tetraisopropyl-5-[(R)-2-(4-methoxybenzyl-
oxy)nonyl]-2,9-dimethyl-6-vinyl-4,7-dioxa-3,8-disiladecane (15)
To a stirred solution of 14 (490 mg, 0.966 mmol) in CH2Cl2 (20 mL)
at 0 °C were added sequentially 2,6-lutidine (0.168 mL, 1.449
mmol) and TIPSOTf (0.312 mL, 1.15 mmol). After 30 min, the re-
action was quenched with sat. aq NH4Cl (10 mL), and extracted
with CH2Cl2 (2 × 15 mL). The combined organic layers were
washed with brine (10 mL), dried (Na2SO4), and concentrated in
vacuo. The residue was purified by column chromatography
(EtOAc–hexane, 5%) to give pure 15; yield: 0.500 g (78%); color-
13C NMR (75 MHz, CDCl3): d = 140.5, 137.7, 128.2, 127.5, 114.0,
73.0, 71.4, 68.1, 36.1.
(S)-[5-(Benzyloxy)pent-1-en-3-yloxy](tert-butyl)dimethylsilane
(18)
To a stirred solution of 17 (1.4 g, 18.65 mmol) in anhyd CH2Cl2 (30
mL) were added sequentially imidazole (0.776 g, 11.41 mmol) and
TBSCl (3.0 g, 20.5 mmol) at 0 °C under N2 atmosphere followed by
the addition of a catalytic amount of DMAP. The reaction mixture
was warmed to r.t. and stirred for 6 h. It was quenched with sat. aq
NH4Cl (10 mL) and extracted with CH2Cl2 (20 mL). The CH2Cl2
layer was washed with brine (20 mL), dried (Na2SO4), and concen-
trated in vacuo. Purification of the crude product by column chro-
matography (EtOAc–hexane, 8%) afforded pure 18; yield: 2.1 g
25
less liquid; Rf = 0.8 (EtOAc–hexane, 10%); [a]D –1.94 (c 1.0,
CHCl3).
IR (neat): 2934, 2864, 1513, 1463, 1247, 883, 820, 677 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.17 (d, J = 8.3 Hz, 2 H), 6.79 (d,
J = 8.3 Hz, 2 H), 6.03–5.82 (m, 1 H), 5.25–5.01 (m, 2 H), 4.42 (d,
J = 11.3 Hz, 1 H), 4.29 (d, J = 11.3 Hz, 1 H), 4.18–4.09 (m, 1 H),
4.07–3.99 (m, 1 H), 3.78 (s, 3 H), 3.53–3.37 (m, 1 H), 1.86–1.70 (m,
1 H), 1.66–1.38 (m, 3 H), 1.37–1.15 (m, 10 H), 1.12–0.94 (m, 42 H),
0.89 (t, J = 4.5 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 158.8, 138.2, 131.1, 128.8, 115.9,
113.6, 78.9, 75.8, 75.0, 69.4, 55.2, 39.5, 33.7, 31.8, 29.3, 24.9, 22.6,
17.6, 14.0, 12.9, 12.5, 12.2.
25
(90%); colorless liquid; Rf = 0.6 (EtOAc–hexane, 10%); [a]D
+3.346 (c 1.0, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.35–7.14 (m, 5 H), 5.85–5.68 (m,
1 H), 5.18–5.06 (m, 1 H), 5.03–4.93 (m, 1 H), 4.47 (d, J = 11.89 Hz,
1 H), 4.40 (d, J = 11.89 Hz, 1 H), 4.32–4.22 (m, 1 H), 3.58–3.39 (m,
2 H), 1.85–1.65 (m, 2 H), 0.86 (s, 9 H), 0.02 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 141.6, 138.5, 128.5, 127.8, 113.7,
73.0, 70.7, 66.8, 38.0, 25.8, –4.3, –4.9.
ESI-MS: m/z = 663 [M]+, 664 [M + H]+.
(S)-3-(tert-Butyldimethylsilyloxy)pent-4-en-1-ol (19)
To a stirred solution of naphthalene (4.75 g, 37.09 mmol) in THF
(60 mL) was added Li metal (259 mg, 37.09 mmol) in small pieces.
The reaction mixture was stirred at r.t. under an argon atmosphere
until the Li metal was completely dissolved (3–4 h). The resulting
dark green solution of lithium naphthalenide was cooled to –25 °C
and compound 18 (1.895 g, 6.182 mmol) in THF (5 mL) was added
dropwise over a period of 5 min. The resulting mixture was stirred
for 30 min. The mixture was quenched with sat. aq NH4Cl (10 mL)
and H2O (10 mL) and extracted with EtOAc (3 × 15 mL). The com-
bined extracts were washed with H2O (10 mL) and brine (10 mL),
dried (Na2SO4), and concentrated under reduced pressure. The
crude product was purified by column chromatography over silica
gel (EtOAc–hexane, 15%) to afford 19, yield: 870 mg (65%); col-
orless liquid; Rf = 0.4 (EtOAc–hexane, 20%); [a]D –1.2 (c 1.2,
CHCl3).
1H NMR (300 MHz, CDCl3): d = 5.91–5.74 (m, 1 H), 5.24–5.01 (m,
2 H), 4.40 (s, 1 H), 3.74–3.82 (m, 2 H), 1.78–1.84 (m, 2 H), 0.91 (s,
9 H), 0.09 (s, 3 H), 0.03 (s, 3 H).
(3R,4S,6R)-3,4-Bis(triisopropylsilyloxy)tridec-1-en-6-ol (3)
To a solution of 15 (450 mg, 0.678 mmol) in CH2Cl2/H2O (10:1, 20
mL) was added DDQ (313 mg, 1.37 mmol) at 0 °C and the mixture
was stirred for 1 h. After completion of the reaction, it was
quenched with aq NaHCO3 (5 mL), filtered through a pad of Celite
and washed with CH2Cl2 (2 × 25 mL). The combined filtrates were
concentrated and the residue was purified by column chromatogra-
phy (EtOAc–hexane, 8%) to provide 3; yield: 228 mg (62%); color-
less liquid; Rf = 0.6 (EtOAc–hexane, 10%); [a]D +0.425 (c 0.2,
CHCl3).
IR (neat): 3430, 2925, 2860, 1741, 1464, 883, 680 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.97–5.78 (m, 1 H), 5.26–5.11 (m,
1 H), 4.31 (dd, J = 3.7, 7.74 Hz, 1 H), 4.04–3.95 (m, 1 H), 3.94–3.84
(m, 1 H), 1.79–1.55 (m, 2 H), 1.49–1.20 (m, 12 H), 1.15–0.99 (m,
42 H), 0.89 (t, J = 6.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 139.1, 117.0, 78.7, 76.1, 68.8, 40.1,
38.4, 31.8, 29.7, 29.3, 25.6, 22.6, 18.2, 17.7, 14.1, 12.7, 12.3.
25
25
13C NMR (75 MHz, CDCl3): d = 140.6, 114.3, 73.0, 60.1, 39.2, 25.8,
18.1, –4.4, –5.5.
ESI-MS: m/z = 542 [M]+, 543 [M + H]+.
ESI-MS: m/z = 239 [M + Na]+.
(S)-5-(Benzyloxy)pent-1-en-3-ol (17)
Trimethylsulfonium iodide (9.02 g, 44.204 mmol) was dissolved in
anhyd THF (60 mL) under N2 atmosphere. To this was added n-
BuLi (1.6 M in n-hexane, 24 mL, 38.67 mmol) dropwise over 5 min
at –20 °C and the reaction mixture was stirred at the same tempera-
ture for 30 min. Compound 16 (1.903 g, 11.05 mmol) in THF (10
mL) was then added to the mixture slowly over 5 min at the same
temperature. Then, the mixture was stirred for 30 min at 0 °C, and
then at r.t for 1 h. After completion of the reaction, it was quenched
with H2O (30 mL), and extracted with EtOAc (2 × 50 mL). The
combined organic layers were washed with brine (20 mL), dried
(Na2SO4), the solvent was removed under vacuum, and the residue
was purified by column chromatography (EtOAc–hexane, 25%) to
afford 17; yield: 1.7 g (80%); colorless liquid; Rf = 0.5 (EtOAc–hex-
ane, 30%); [a]D25 +9.98 (c 1.0, CHCl3).
(S)-3-(tert-Butyldimethylsilyloxy)pent-4-enoic Acid (4)
To a stirred solution of 4 (0.84 g, 3.88 mmol) in anhyd CH2Cl2 (20
mL) was added NaHCO3 (0.32 g, 3.88 mmol) at 0 °C. Dess–Martin
periodinane (1.97 g, 4.65 mmol) was added and the reaction mixture
was stirred at r.t. for 1 h. The mixture was quenched with a mixture
of sat. aq NaHCO3 and Na2S2O3 (1:7, 5 mL) at 0 °C and extracted
with CH2Cl2 (3 × 10 mL). The combined organic layers were
washed with H2O (10 mL) and dried (Na2SO4). The solvent was
evaporated and the residue was used directly in the next step. To a
stirred solution of the above aldehyde in t-BuOH–2-methylbut-2-
ene (2:1, 6 mL) were added NaClO2 (0.5 g, 5.55 mmol) and
NaH2PO4·2H2O (0.86 g, 5.55 mmol) [dissolved in H2O (2 mL)] and
stirred for 6 h at r.t. The solvent was removed under reduced pres-
sure and the residue was extracted with EtOAc (2 × 5 mL). The
combined organic layers were washed with brine (5 mL) and dried
(Na2SO4). The solvent was evaporated and the residue was purified
by column chromatography (EtOAc–hexane, 15%) to afford 4;
yield: 0.6 g (70%); yellow liquid; Rf = 0.6 (EtOAc–hexane, 20%);
[a]D25 +1.2 (c 1.2, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.40–7.20 (m, 5 H), 5.91–5.73 (m,
1 H), 5.29–5.18 (m, 1 H), 5.10–5.02 (m, 1 H), 4.49 (s, 2 H), 4.34–
4.24 (m, 1 H), 3.72–3.53 (m, 2 H), 2.87–2.75 (m, 1 H), 1.89–1.68
(m, 2 H).
Synthesis 2011, No. 20, 3343–3349 © Thieme Stuttgart · New York

3348
G. Sabitha et al.
PAPER
IR (neat): 3361, 2926, 2856, 1715 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.92 (dd, J = 15.2, 8.4 Hz, 1 H),
5.39 (d, J = 15.2 Hz, 1 H), 4.76–4.70 (m, 1 H), 4.58–4.49 (m, 2 H),
3.75–3.69 (m, 1 H), 2.76–2.71 (m, 1 H), 2.45–2.40 (m, 1 H), 2.32–
2.38 (m, 1 H), 1.53–1.25(m, 13 H), 0.87 (t, J = 6.4 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 171, 138, 135.2, 75.4, 73.3, 73.3,
67.2, 43.8, 36.9, 36.8, 31.7, 29.4, 29.1, 25.0, 22.6, 14.0.
ESI-MS: m/z = 323 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ Calcd for C16H28O5 + Na: 323.1829;
1H NMR (300 MHz, CDCl3): d = 5.93–5.77 (m, 1 H), 5.30–5.10 (m,
2 H), 4.63–4.48 (m, 1 H), 2.51– 2.40 (m, 2 H), 0.88 (s, 9 H), 0.02 (s,
6 H).
13C NMR (75 MHz, CDCl3): d = 176.0, 139.5, 115.4, 70.6, 42.8,
25.6, 18.0, –4.4, –5.1.
ESI-MS: m/z = 253 [M + Na]+.
(3R,4S,6R)-3,4-Bis(triisopropylsilyloxy)tridec-1-en-6-yl (S)-3-
(tert-Butyldimethylsilyloxy)pent-4-enoate (20)
found: 323.1832.
To a stirred solution of acid 4 (127 mg, 0.552 mmol) in anhyd
CH2Cl2 (15 mL) at 0 °C were added DCC (113 mg, 0.552 mmol)
and a catalytic amount of DMAP. After 10 min, alcohol 3 (200 mg,
0.368 mmol) in anhyd CH2Cl2 (5 mL) was added and stirred at r.t.
for 6 h. The reaction mixture was evaporated and the residue was
purified by column chromatography (EtOAc–hexane, 5%) to afford
20; yield: 0.21 g (78%); colorless liquid; Rf = 0.3 (EtOAc–hexane,
10%); [a]D25 +11.0 (c 0.2, CHCl3).
Acknowledgment
R.S. thanks CSIR, New Delhi for the award of a fellowship.
References
(1) Visiting Professor, King Saud University, P.O. Box 2455,
Riyadh 11451, Saudi Arabia.
(2) Bodo, B.; Molho, L.; Davoust, D.; Molho, D.
IR (neat): 2930, 2863, 1735, 1252, 777, 679 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.95–5.72 (m, 2 H), 5.26–4.96 (m,
4 H), 4.92–4.78 (m, 1 H), 4.61–4.44 (m, 1 H), 4.18–4.0 (m, 1 H),
3.94–3.82 (m, 1 H), 2.55–2.30 (m, 2 H), 1.83–1.69 (m, 1 H), 1.65–
1.44 (m, 3 H), 1.32–1.16 (m, 10 H), 1.11–0.93 (m, 36 H), 0.88–0.77
(m, 18 H).
13C NMR (75 MHz, CDCl3): d = 170.3, 140.1, 138.0, 116.5, 114.4,
78.6, 74.7, 72.0, 70.8, 43.7, 38.9, 34.5, 31.7, 29.4, 29.0, 25.7, 25.6,
25.0, 18.1, 14.0, 12.9, 12.4, –4.49, –5.0.
Phytochemistry 1983, 22, 447.
(3) Tayone, W. C.; Shindo, S.; Murakami, T.; Hashimoto, M.;
Tanaka, K.; Noboru Takada, N. Tetrahedron 2009, 65,
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(4) (a) Fuchser, J.; Zeeck, A. Liebigs Ann./Recueil 1997, 87.
(b) Grabley, S.; Granzer, E.; Hütter, K.; Ludwig, D.; Mayer,
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(e) Ayer, W. A.; Sun, M.; Browne, L. M.; Brinen, L. S.;
Clardy, J. J. Nat. Prod. 1992, 55, 649. (f) Ratnayake, A. S.;
Yoshida, W. Y.; Mooberry, S. L.; Hemscheidt, T. Org. Lett.
2001, 3, 3479. (g) Fürstner, A.; Radkowski, K. Chem.
Commun. 2001, 671. (h) Fürstner, A.; Radkowski, K.;
Wirtz, C.; Goddard, R.; Lehmann, C. W.; Mynott, R. J. Am.
Chem. Soc. 2002, 124, 7061.
ESI-MS: m/z = 778 [M + Na]+.
(3R,4S,6R)-3,4-dihydroxytridec-1-en-6-yl (S)-3-Hydroxypent-
4-enoate (2)
To a solution of compound 20 (0.19 g, 0.251 mmol) in THF (5 mL)
was added HF·Py complex (70%, 0.3 mL) at 0 °C, and the mixture
was stirred at r.t. for 24 h. The mixture was then cautiously poured
into aq NaHCO3 (5 mL) and extracted with EtOAc (2 × 10 mL). The
combined extracts were washed with H2O (5 mL) and brine (5 mL),
dried (Na2SO4), and concentrated in vacuo. The residue was puri-
fied by column chromatography on silica gel (EtOAc–hexane, 50%)
to afford pure 2; yield: 34 mg (42%); colorless liquid; Rf = 0.3
(EtOAc–hexane, 50%); [a]D25 –16.5 (c 0.5, MeOH).
(5) Dräger, G.; Kirschning, A.; Thiericke, R.; Zerlin, M. Nat.
Prod. Rep. 1996, 13, 365.
(6) (a) Chandrasekhar, S.; Balaj, S. V.; Rajesh, G. Tetrahedron
Lett. 2010, 51, 5164. (b) Das, T.; Rajib, B.; Samik, N.
Tertrahedron: Asymmetry 2010, 21, 2206. (c) Srihari, P.;
Kumaraswamy, B.; Sankar, P.; Ravishashidhar, V.; Yadav,
J. S. Tetrahedron Lett. 2010, 51, 6174. (d) Rao, S. K.;
Amit Kumar, C.; Ghosh, S. Synlett 2010, 3078.
IR (neat): 3379, 2921, 2853, 1459, 1031, 926 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.95–5.77 (m, 2 H), 5.34–5.06 (m,
5 H), 4.61–4.47 (m, 1 H), 4.1–4.0 (m, 1 H), 3.68–3.54 (m, 1 H), 3.17
(br, 3 H, OH), 2.6–2.4 (m, 2 H), 1.63–1.52 (m, 4 H), 1.35–1.19 (m,
10 H), 0.93–0.79 (t, J = 6.8 Hz, 3 H).
(7) (a) Sabitha, G.; Yadagiri, K.; Swapna, R.; Yadav, J. S.
Tetrahedron Lett. 2009, 50, 5417. (b) Sabitha, G.; Padmaja,
P.; Reddy, N. P.; Jadav, S. S.; Yadav, J. S. Tetrahedron Lett.
2010, 51, 6166. (c) Sabitha, G.; Srinivas, C.; Maruthi, C.;
Yadav, J. S. Helv. Chim. Acta 2010, 93, 1634. (d) Sabitha,
G.; Reddy, T. R.; Srinivas, C.; Yadav, J. S. Helv. Chim. Acta
2011, 94, 224. (e) Sabitha, G.; Reddy, T. R.; Ramesh, M.;
Srinivas, C.; Yadav, J. S. Bull. Chem. Soc. Jpn. 2011, 84,
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(8) (a) Saito, S.; Ishikawa, T.; Kuroda, A.; Koga, K.; Moriwake,
T. Tetrahedron 1992, 48, 4067. (b) Boukouvalas, J.; Fortier,
G.; Radu, I.-I. J. Org. Chem. 1998, 63, 916.
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13C NMR (75 MHz, CDCl3): d = 172.9, 138.9, 136.0, 117.3, 115.4,
75.8, 72.3, 69.9, 69.2, 41.8, 36.5, 34.8, 31.7, 29.3, 29.1, 25.4, 22.6,
14.1.
ESI-MS: m/z = 351 [M + Na]+.
(3S,6R,7S,9R,E)-9-Heptyl-3,6,7-trihydroxy-2,3,6,7,8,9-hexahy-
drooxecin-1-one (Achaetolide, 1)
To a solution of 2 (30 mg, 0.9 mmol) in anhyd CH2Cl2 (60 mL) was
added Grubbs’ second-generation catalyst (8 mg, 10 mol%) and the
solution was refluxed for 6 h. The solution was evaporated and the
content of the flask was directly loaded onto a silica gel column and
purified by column chromatography (EtOAc–hexane, 60%) to af-
ford 1; yield: 14 mg (54%); colorless liquid; Rf = 0.8 (EtOAc–hex-
ane, 60%); [a]D25 –27 (c 0.5, MeOH).
IR (neat): 3452, 2926, 2856, 1710, 1161 cm–1.
Synthesis 2011, No. 20, 3343–3349 © Thieme Stuttgart · New York

PAPER
Stereoselective Total Synthesis of Achaetolide
3349
(10) (a) Alvarez-Ibarra, C.; Arias, S.; Banon, G.; Fernandez, M.;
Rodriguez, V.; Sinisterra, V. J. J. Chem. Soc., Chem.
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