The stereoselective total synthesis of (-)-achaetolide

Article abstract of DOI:10.1016/j.tetasy.2012.03.010

The stereoselective total synthesis of (-)-achaetolide is described in a convergent manner. Grignard addition, Wittig homologation, acetate aldol and ring closing metathesis reactions were the key steps involved. The required olefinic alcohol fragments were synthesized from a single chiral pool material 2-deoxy-d-ribose and olefinic acid fragment was prepared from acetate aldol reaction. Both the olefinic acid and alcohols were prepared in a concise method.

Full text of DOI:10.1016/j.tetasy.2012.03.010

Tetrahedron: Asymmetry 23 (2012) 547–553
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
The stereoselective total synthesis of (ꢀ)-achaetolide
Pallavi Thakur a, Boyapelly Kumaraswamy a, , Gurram Raji Reddy a, Rakeshwar Bandichhor b,
,
⇑
⇑
Khagga Mukkantii c
a Maithili Life Sciences Pvt. Ltd, Plot No. 146 A, Phase-II, IDA, Mallapur, Hyderabad 500 076, India
b Innovation Plaza, IPD, R&D, Dr. Reddy’s Laboratories Ltd, Survey Nos. 42, 45, 46, and 54, Bachupally, Qutubullapur, R.R. District 500 073, Andhra Pradesh, India
c Institute of Science and Technology, Center for Environmental Science, JNT University, Kukatpally, Hyderabad 500 072, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The stereoselective total synthesis of (ꢀ)-achaetolide is described in a convergent manner. Grignard addi-
tion, Wittig homologation, acetate aldol and ring closing metathesis reactions were the key steps
involved. The required olefinic alcohol fragments were synthesized from a single chiral pool material
Received 7 March 2012
Accepted 21 March 2012
Available online 10 May 2012
2-deoxy-D-ribose and olefinic acid fragment was prepared from acetate aldol reaction. Both the olefinic
acid and alcohols were prepared in a concise method.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
can be obtained by the coupling/esterification of acid 8 with dia-
stereomeric alcohols 9 and 9a by applying two different protocols.
Acid 8 can be obtained from the hydrolysis of compound 10. Imide
10 was prepared by an auxiliary based asymmetric acetate aldol
reaction. Alcohols 9 and 9a were synthesized from commercially
In recent years, 10 membered lactone containing molecules
have attracted the attention of both biologists and chemists due
to their potent biological activities.1 These lactones are secondary
metabolites mainly biosynthesized by fungi, bacteria (antibiotics)
and marine organisms, with only few being produced by plants
or insects (pheromones). This family of natural products displays
a wide range of biological properties, such as antibacterial and
antifungal, phytotoxic activities and the inhibition of cholesterol
biosynthesis.2 A few recently isolated 10-membered macrolides in-
clude achaetolide, herbarumins I–III,3 stagonolides A–I4 and mod-
iolides A and B (Fig. 1).5 In 1983, Bodo et al. reported the
isolation of achaetolide from the culture broth of Achaetomium cri-
salliferum.6 Later on Takada et al. established the stereochemistry
of achaetolide from a different species, Ophiobolus sp.7 Achaetolide
is a 10-membered macrolide with four stereocentres (3S,6R,7S,9R),
three hydroxyl groups and a trans-olefin functionality. The scarce
availability of these natural materials has prompted several syn-
thetic chemists to take up their total synthesis for further evalua-
tion towards biological screening.8 Herein we report a practical
and stereoselective total synthesis of achaetolide from the chiral
available deoxy-D-ribose involving a chiral pool approach using
selective acetonide protection, a seven-carbon Grignard reaction
and a one carbon homologation by selective oxidation and Wittig
reactions.
2. Results and discussion
We began with the synthesis of compounds 9 and 9a from com-
mercially available chiral carbohydrate 2-deoxy-
D-ribose. Protec-
tion of hydroxyl groups of 2-deoxy-
D
-ribose9 with 2,2 dimethoxy
propane under PTSA conditions led to product 11. Grignard addi-
tion with freshly prepared n-heptyl magnesium bromide gave a
diastereomeric mixture 12 and 12a in almost a 1:1 ratio with
92% yield. The diastereomers were separated by flash column chro-
matography and used separately in further reactions (Scheme 2).
We initially focused on the synthesis of 9 and also the synthesis
of C-6 epimer 9a. Compound 12 can be utilized for the synthesis of
9, whereas other isomer 12a can be used for the synthesis of 9a.
Thus, 1,5-diol 12 was subjected to oxidative lactonization in the
presence of BAIB-EMPO to obtain lactone 13.10 Reduction of lac-
tone 13 to lactol 14 by using DIBAL-H was achieved in 85% yield
which upon homologation via 1C-Wittig reaction with methyltri-
phenylphosphonium bromide in the presence of potassium tert-
butoxide yielded olefin 9 (Scheme 3).
precursor 2-deoxy-D-ribose in which C-3 and C-4 stereogenic
centres are correlated with the (6S) and (7R) carbon centres of
the target molecule.
Scheme 1 outlines our retrosynthetic analysis of achaetolide.
We envisioned that the target molecule can be obtained from ester
7 with two terminal olefin moieties by a ring closing metathesis
followed by deprotection of the acetonide group. Ester 7 in turn
After completion of the synthesis of compound 9, we proceeded
further with the other diastereomer 12a for the synthesis of 9a,
which is the C-6 epimer of 9. Accordingly, compound 12a was sub-
jected to a similar sequence of reactions such as 1,5-diol oxidative
⇑
Corresponding authors. Tel.: +91 40 27150243; fax: +91 40 40062330 (B.K.).
E-mail addresses: kumarboyapally@gmail.com (B. Kumaraswamy), rakesh-
warb@drreddys.com (R. Bandichhor).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.03.010

548
P. Thakur et al. / Tetrahedron: Asymmetry 23 (2012) 547–553
OH
4
HO
HO
HO
OH
6
7
3
5
O
O
O
1
8
2
HO
HO
OH
9
O
O
O
herbarumin II 3
achaetolide 1
HO
herbarumin I 2
OH
OH
OH
O
O
O
O
O
O
herbarumin III 4
modiolide A 5
modiolide B 6
Figure 1. Examples of 10-membered macrolides.
O
O
O
O
HO
OH
HO
O
OH
achaetolide 1
O
7
OH
O
HO
OH
O
or
+
C7H15
O
OTBS
C7H15
8
9
O
O
9a
TBSO
O
S
2-deoxy-D-ribose
2-deoxy-D-ribose
N
S
Bn
10
Scheme 1. Retrosynthesis.
lactonization to yield 13a, DIBAL reduction to yield lactol 14a and
then 1C-wittig homologation reaction to afford olefinic alcohol 9a
(Scheme 4).
The newly introduced stereocentre at the 9 position of the tar-
get molecule, or the 6 position of the obtained diastereomers 9 and
9a were compared with previously reported data and confirmed 9
as (9S), and 9a as (9R).8 These two diastereomers were both uti-
lized for the synthesis of the target molecule.
The other key fragment, olefinic acid 8, was synthesized starting
from an auxiliary based asymmetric acetate aldol reaction with N-
acetyl-(4R)-thiazoldinethione 15 and acrolein in the presence of
titanium (IV) chloride and diisopropylethylamine, which afforded
the major required isomer 16.11 The secondary alcohol 16 was
protected as a TBS ether by using TBSCl and 2,6-lutidine to give
compound 10, which was hydrolyzed by using DMAP, water in
DCM to give the desired compound 8 (Scheme 5).12
O
OH
O
OH
2,2-dimethoxy
propane
C7H15MgBr
PTSA, acetone,
12 h, rt, 90%
O
THF, -78 oC, 6 h,92%,
2 isomers,
HO
HO
O
OH
11
O
O
HO
+
O
OH
O
OH
12a
12
Scheme 2. Isolated diastereomers from column chromatography.

P. Thakur et al. / Tetrahedron: Asymmetry 23 (2012) 547–553
549
O
O
HO
O
6
6
DIBAL-H,
BAIB, cat. TEMPO
DCM, 4h, rt, 91%
12
O
DCM, -78 oC, 2 h, 85%
O
O
O
13
14
O
1C-Wittig
CH3PPh3I, KOtBu,
THF, 0 oC- rt, 8 h, 85%
O
OH
9
Scheme 3. Synthesis of olefinic alcohols 9 from 12.
O
O
BAIB, cat. TEMPO
DCM, 4 h, rt, 92%
6
DIBAL-H,
12a
DCM, -78 oC, 2 h, 85%
O
O
13a
HO
O
O
6
1C-Wittig
CH3PPh3I, KOtBu,
O
O
OH
THF, 0 oC- rt, 8 h,82%
O
9a
14a
Scheme 4. Synthesis of olefinic alcohols 9a from 12a.
S
O
N
S
S
S
OH
O
OH
O
Bn
15
CHO
N
S
N
S
+
TiCl4,DIPEA
DCM ,-78 oC,
30 min, 63%
Bn
Bn
16
(8:2)
16a
S
TBSO
TBSO
O
TBSCl, 2,6-lutidine
DMF, rt, 3 h, 92%
N
S
16
10
8
Bn
O
DMAP/H2O
OH
DCM, rt, 14 h, 77%
Scheme 5. Synthesis of olefinic acid.
After the successful preparation of the required fragments 8, 9
and 9a, the remaining step was to couple the two fragments 8, 9
and 8, 9a followed by an RCM strategy. The coupling of the two
fragments 8 and 9a was successfully achieved by treating acid 8
with DCC followed by the addition of alcohol 9a to afford the
diene ester 17. The coupling of acid 8 and alcohol 9 under
Mitsunobu conditions with the inversion of configuration at the
hydroxyl carbon also afforded the same diene ester 17
(Scheme 6).13 Compound 17 was desilylated by using TBAF in tet-
rahydrofuran to afford the free allyl alcohol 7.8 Ring closing
metathesis was attempted directly by exposing substrate 7 to
Grubbs 2nd generation catalyst at reflux in dichloroethane to
yield the product with isopropylidene protection, which upon
treatment with 1 M HCl in THF afforded the desired target mole-
cule, achaetolide.14 The spectroscopic data of the synthetic com-
pound were found to be similar when compared to that of the
natural product.7,8
3. Conclusion
In conclusion, the stereoselective total synthesis of achaetolide
has been achieved. The key reactions involved are the Grignard
addition on lactol, the homologation of the lactol, the acetate aldol
reaction and Grubbs olefin metathesis. The application of this
strategy for the preparation of other analogues in order to investi-
gate their biological activities is currently being pursued.

550
P. Thakur et al. / Tetrahedron: Asymmetry 23 (2012) 547–553
O
O
DCC, DMAP
8
9a
9
+
O
DCM, 6 h,
TBSO
O
0
oC-rt, 90%
17
17
DEAD, TPP,
THF, 0 oC-rt,
10 h, 78%
8
+
O
G-2 (10 mol%)
O
TBAF, THF
rt, 4 h 85%
DCM, reflux
6 h, 61%
O
17
HO
O
7
O
O
1M HCl, THF
55 oC, 6 h, 83%
achaetolide
HO
O
O
18
N
N
Mes
Mes
Cl
Ru
Cl
Ph
Cy3P
2nd generation Grubbs
catalyst (G-2)
Scheme 6. Synthesis of achaetolide.
3,5 syn-diastereomer 12 (4.25 g, 45%), and the more polar (5:5 eth-
ylacetate/hexane) 3, 5 anti-diastereomer 12a (4.44 g, 47%). Overall
yield of isolated products was 92%. Rf = 0.2, 0.1 (60% EtOAc/hex-
4. Experimental
4.1. General
ane). Compound 12. ½a D29
ꢂ
¼ þ8:1 (c 0.45, CHCl3). IR (Neat): 3422,
3320, 2927, 2856, 1654, 1491, 1220, 1055 cmꢀ1
.
1H NMR
The reactions were carried out under N2 in anhydrous solvents
such as CH2Cl2, THF and EtOAc. The THF used was freshly distilled
over benzophenone prior to use. All reactions were monitored by
TLC (silica-coated plates and visualized under UV light). Yields re-
fer to isolated yields. Air-sensitive reagents were transferred by a
syringe or a double-ended needle. 1H and 13C NMR spectra were re-
corded in CDCl3 solution on Brucker Avance 300 spectrometers.
Chemical shifts are reported relative to TMS as an internal stan-
dard. Column chromatography was performed on silica gel (60–
120 mesh) supplied by Acme Chemical Co., India. TLC was per-
formed on Merck 60 F-254 silica gel plates. IR (FT-IR) spectra were
recorded either on KBr pellets or neat as thin film. Optical rotations
were recorded on JASCO DIP-360 digital polarimeter.
(400 MHz; CDCl3): d 4.38 (q, J = 6.2 Hz, 1H), 4.20 (q, J = 6.2 Hz,
1H), 3.85–3.77 (m, 1H), 3.68–3.59 (m, 2H), 3.11 (br s, 1H), 1.88
(br s, 1H), 1.69–1.62 (m, 2H), 1.61–1.52 (m, 2H), 1.49 (s, 3H),
1.48–1.39 (m, 2H), 1.38 (s, 3H), 1.37–1.22 (m, 8H), 0.87 (t,
J = 7.01 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 108.7, 78.0, 77.0,
71.6, 61.6, 37.4, 35.6, 31.8, 29.6, 29.3, 28.0, 25.4 (2C), 22.6, 14.1;
(ESI-MS): m/z 297 (M+Na)+; HRMS: calcd for C15H30NaO4:
297.2041, found: 297.2044. Compound 12a. ½a D29
¼ þ2:5 (c 0.15,
ꢂ
CHCl3). IR (Neat): 3423, 2927, 2856, 1650, 1457, 1379, 1219,
1045 cmꢀ1 1H NMR (400 MHz; CDCl3): d 4.47–4.41 (m, 1H), 4.20
.
(q, J = 6.2 Hz, 1H), 3.86–3.77 (m, 1H), 3.66 (dd, J = 11.0, 6.6 Hz,
1H), 3.60 (dd, J = 11.0, 6.6 Hz, 1H), 2.20 (br s, 2H), 1.84–1.76 (m,
1H), 1.65–1.56 (m, 2H), 1.52–1.46 (m, 2H), 1.45 (s, 3H), 1.37 (s,
3H), 1.35–1.22 (m, 9H), 0.88 (t, J = 7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d 107.7, 77.9, 74.5, 69.4, 61.5, 38.1, 35.7, 31.8,
29.5, 29.2, 28.1, 25.6, 25.4, 22.6, 14.0; (ESI-MS): m/z 313 (M+K)+.
4.1.1. (S)-1-[(4S,5R)-5-(Hydroxymethyl)-2,2-dimethyl-1,3-dioxo
lan-4-yl]nonan-2-ol 12 and (R)-1-[(4S,5R)-5-(hydroxymethyl)-
2,2-dimethyl-1,3-dioxolan-4-yl]nonan-2-ol 12a
A dry flask was charged with Mg turnings (2.4 g, 100.0 mmol)
and a few particles of iodine, heated under nitrogen until the io-
4.1.2. (3aS,6S,7aS)-6-Heptyl-2,2-dimethyldihydro-3aH-
[1,3]dioxolo[4,5-c]pyran-4(6H)-one 13
dine started to sublime.
A solution of n-C7H15Br (18.5 g,
To a solution of 1,5-diol 12 (4 g, 14.6 mmol) in DCM (40 mL) at
0 °C was added iodobenzenediacetate (9.9 g, 30.6 mmol) followed
by TEMPO (228 mg, 1.4 mmol) and the reaction mixture left to stir
at rt for 4 h. After conversion of the diol to lactone was complete,
the reaction mixture was quenched with saturated solution of
sodium thiosulphate (20 mL) and extracted into DCM (3 ꢁ 40 mL).
The combined organic layers were dried over Na2SO4 and evapora-
tion of the solvent led to a crude lactone which was purified on
silica gel (1:9 ethylacetate/hexane) to furnish lactone 13 as a
colourless liquid (3.58 g, 91%). Rf = 0.4 (20% EtOAc/hexane).
103.4 mmol) in dry THF (120 mL) was added dropwise to start a
vigorous exothermic reaction. The reaction was left at reflux for
1 h, until no Mg particles remained in the flask, and then cooled
to 0 °C. Lactol 11 (6 g, 34.5 mmol) in THF (45 mL) was then added
and the solution was left to stand for 6 h, after which it was
quenched with a saturated solution of NH4Cl (30 mL). Next, AcOEt
(120 mL) was added and the separated aqueous phase was ex-
tracted with AcOEt (3 ꢁ 100 mL). The organic phases were dried
over Na2SO4 and concentrated. The crude oil was separated on a
silica gel column (4:6 ethylacetate/hexane) to afford less the polar

P. Thakur et al. / Tetrahedron: Asymmetry 23 (2012) 547–553
551
½
a 2D9
ꢂ
¼ ꢀ35 (c 0.25, CHCl3); IR (Neat): 2983, 2930, 2857, 1747,
1630, 1458, 1260, 1210, 1097 cmꢀ1
.
1H NMR (400 MHz; CDCl3): d
1377, 1267, 1210 cmꢀ1 1H NMR (400 MHz; CDCl3): d 4.70–4.55
.
4.69 (q, J = 7.9 Hz, 1H), 4.55 (d, J = 7.5 Hz, 1H), 4.25–4.16 (m, 1H),
2,42 (ddd, J = 1.41, 8.4, 1.8 Hz, 1H), 1.78–1.65 (m, 2H), 1.64–1.53
(m, 2H), 1.51 (s, 3H), 1.50–1.41 (m, 1H), 1.40 (s, 3H), 1.39–1.20
(m, 8H), 0.88 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) d
170.5, 111.7, 75.5, 72.8, 71.9, 35.0, 34.8, 31.7, 29.2, 29.0, 26.9,
25.3, 24.8, 22.6, 14.0; (ESI-MS): m/z 293 (M+Na); HRMS:
(m, 3H), 2.03 (td J = 15.0, 1.8 Hz, 1H), 1.79–1.65 (m, 2H), 1.63–
1.54 (m, 2H), 1.51 (s, 3H), 1.50–1.39 (m, 1H), 1.38 (s, 3H), 1.35–
1.21 (m, 8H), 0.89 (t, J = 7.0, 3H); 13C NMR (100 MHz, CDCl3): d
168.3, 110.6, 75.1, 72.9, 71.8, 34.8, 33.9, 31.7, 29.2, 29.1, 25.9,
24.8, 23.9, 22.6, 14.0; (ESI-MS): m/z 271 (M+H); HRMS: calcd for
C15H26NaO4: 293.1728, found: 293.1736.
C15H26NaO4: 293.1728, found: 293.1732.
4.1.3. (3aS,6S,7aS)-6-Heptyl-2,2-dimethyltetrahydro-3aH-
[1,3]dioxolo[4,5-c]pyran-4-ol 14
4.1.6. (3aS,6R,7aS)-6-Heptyl-2,2-dimethyltetrahydro-3aH-
[1,3]dioxolo[4,5-c]pyran-4-ol 14a
To a stirred solution of 13 (3.0 g, 11.1 mmol) in dichlorometh-
ane (30 mL) at ꢀ78 °C was added DIBAL (16.60 mL, 16.6 mmol,
1.0 M solution in toluene). The reaction was maintained at
ꢀ78 °C until complete consumption of the starting material oc-
curred (judged by TLC analysis) for 2 h. The reaction was quenched
with a 10 mL saturated aq NH4Cl solution and a 10 mL saturated aq
sodium potassium tartrate solution and the solution was warmed
to rt. The mixture was diluted with dichloromethane (20 mL) and
stirred vigorously for 1 h. After extraction with dichloromethane
(2 ꢁ 30 mL) the combined organic extracts were dried over anhy-
drous sodium sulphate, the solvent was evaporated and the resi-
due was purified by silica gel column chromatography (2:8
ethylacetate/hexane) to afford product 14 (2.56 g, 85%) as a colour-
Compound 14a was prepared according to the procedure de-
scribed for compound 14 starting from compound 13a (3.0 g,
11.1 mmol) and DIBAL (16.60 mL, 16.6 mmol, 1.0 M solution in tol-
uene). Purification by silica gel column chromatography (2:8 ethyl-
acetate/hexane) afforded the pure compound 14a (2.56 g, 85%) as a
colourless oil. Rf = 0.2 (20% EtOAc/hexanes). ½a D29
ꢂ
¼ þ3:1 (c 1.0,
CHCl3); IR (KBr): 3420, 2928, 1460, 1220, 1058 cmꢀ1
;
1H NMR
(300 MHz; CDCl3): d 5.37 (d, J = 1.5 Hz, 1H), 4.34–4.23 (m, 1H),
3.92 (d, J = 5.3 Hz, 1H), 3.85–3.73 (m, 1H), 2.64–2.57 (m, 1H),
1.83 (ddd, J = 14.5, 6.8, 1.3, 1H), 1.57–1.21 (m, 18H), 0.89 (t,
J = 7.0 Hz, 3H). Minor isomer 4.81 (dd, J = 1.09, 2.3 Hz, 1H), 4.06–
4.02 (m, 1H), 3.48 (d, J = 10.9, 1H), 3.35–3.24 (m, 1H). 13C NMR
(75 MHz, CDCl3) d 108.7, 92.4, 73.3, 71.3, 66.3, 35.3, 34.4, 31.7,
29.5, 29.2, 28.1, 26.2, 25.3, 22.6, 14.0; Minor isomer 109.6, 92.9,
73.1, 72.8, 35.7, 34.1, 29.4, 28.0, 26.4; (ESI-MS): m/z 295 (M+Na).
less oil: Rf = 0.3 (20% EtOAc/hexanes). ½a D29
¼ þ43:2 (c 0.55, CHCl3);
ꢂ
IR (KBr): 3428, 2985, 2926, 2856, 1458, 1372, 1218, 1051 cmꢀ1; 1H
NMR (400 MHz; CDCl3): d 4.76 (d, J = 6.6 Hz, 1H), 4.44–4.40 (m,
1H), 3.80 (t, J = 6.2 Hz, 1H), 3.75–3.67 (m, 1H), 3.65–3.43 (br s,
1H), 2.06 (m, 1H), 1.72 (ddd, J = 15.0, 11.9, 4.0 Hz, 1H), 1.62–1.24
(m, 18H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
109.1, 96.3, 76.6, 72.8, 70.6, 35.4, 32.6, 31.7, 29.5, 29.2, 27.9,
25.8, 25.4, 22.6, 14.0; (ESI-MS): m/z 295 (M+Na); HRMS: calcd for
4.1.7. (R)-1-[(4S,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-
yl]nonan-2-ol 9a
Compound 9a was prepared according to the procedure de-
scribed for compound
9 starting from compound 14a (2 g,
7.3 mmol). Purification by silica gel column chromatography (1:9
C15H28NaO4: 295.1885: found: 295.1882.
ethylacetate/hexane) afforded the pure product 3a (1.58 g, 80%
yield) as
a
colourless oil. Rf = 0.4 (20% EtOAc/hexanes).
4.1.4. (S)-1-[(4S,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-
yl]nonan-2-ol 9
½
a 2D9
ꢂ
¼ ꢀ4:2 (c 1.3, MeOH), lit.8b
½
a 3D2
ꢂ
¼ ꢀ3:6 (c 1.0, MeOH); IR
(KBr): 3464, 2927, 2859, 1374 cmꢀ1
;
1H NMR (300 MHz; CDCl3):
To a stirred suspension of methyl triphenylphosphonium bro-
mide (10.5 g, 29.4 mmol) in THF (70 mL) was added potassium
tert-butoxide (2.88 g, 25.7 mmol) at 0 °C and the reaction mixture
was stirred for 20 min at the same temperature and then at room
temperature for 1 h. After the mixture was cooled to 0 °C, a solu-
tion of 14 (2 g, 7.3 mmol) in THF (20 mL) was added and the reac-
tion mixture was stirred at room temperature for 8 h and then
poured carefully into water. The mixture was extracted with ethyl
acetate and the organic layer was dried over anhydrous Na2SO4, fil-
tered and evaporated. The resulting syrup was purified by silica gel
column chromatography (1:9 ethylacetate/hexane) to give com-
pound 9 (1.62 g, 82%) as a colourless liquid. Rf = 0.4 (20% EtOAc/
d 5.83–5.66 (m, 1H), 5.35–5.15 (m, 2H), 4.55–4.38 (m, 2H), 3.85–
3.69 (m, 1H), 4.90 (br s, 1H), 1.64–1.52 (m, 1H), 1.51–1.21 (m,
19H), 0.89 (t, J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 134.2,
118.3, 108.3, 79.6, 74.9, 69.0, 37.8, 37.3, 31.8, 29.5, 29.2, 28.1,
25.7, 25.6, 22.6, 14.0. (ESI-MS): m/z 293 (M+Na); HRMS: calcd for
C16H30NaO3: 293.2087, found: 293.2089.
4.1.8. (S)-1-[(R)-4-Benzyl-2-thioxothiazolidin-3-yl]-3-
hydroxypent-4-en-1-one 16
To a stirred solution of N-acetyl-(4R)-thiazoldinethione 15
(1.0 g, 3.98 mmol) in dry CH2Cl2 (17 mL) at 0 °C under a nitrogen
atmosphere was added dropwise TiCl4 (0.52 mL, 4.76 mmol) and
stirred for 5 min. Next a solution of DIPEA (0.82 mL, 4.76 mmol)
in dry CH2Cl2 (5 mL) was added via cannula. The reaction mixture
was cooled to ꢀ78 °C and continued to stir for 30 min. A solution of
acrolein (0.22 g, 3.98 mmol) in dry CH2Cl2 (6 mL) was then trans-
ferred via cannula to the reaction mixture, which was then stirred
for 30 min at ꢀ78 °C. After completion of the reaction, the reaction
mixture was quenched by the addition of a half-saturated aq NH4Cl
(10 mL) solution while stirring and allowed to return to room tem-
perature and diluted with CH2Cl2 (30 mL). The organic layer was
separated and the aqueous layer was extracted with CH2Cl2
(2 ꢁ 30 mL). The combined organic extracts were washed with
hexanes). ½a 2D7
ꢂ
¼ ꢀ15:2 (c 0.6, CHCl3); lit8a
½
a 3D2
ꢂ
¼ ꢀ14:0 (c 0.2,
CHCl3); IR (KBr): 3464, 2920, 2859, 1045 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): d 5.76 (ddd J = 17.3, 9.8, 7.5 Hz, 1H), 5.20–5.34
(m, 2H), 4.52 (td, J = 7.5, 0.8 Hz, 1H), 4.31 (ddd, J = 9.8, 6.0, 3.7 Hz,
1H), 3.69–3.79 (m, 1H), 3.0 (br s, 1H), 1.23–1.53 (m, 20H), 0.89
(t, J = 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 133.8, 118.6,
108.8, 79.8, 78.4, 71.3, 37.5, 37.2, 31.7, 29.5, 29.2, 28.0, 25.5,
25.4, 22.6, 14.0; (ESI-MS): m/z 293 (M+Na); HRMS: calcd for
C16H30NaO3: 293.2089 (M+Na), found: 293.2081.
4.1.5. (3aS,6R,7aS)-6-Heptyl-2,2-dimethyldihydro-3aH-
[1,3]dioxolo[4,5-c]pyran-4(6H)-one 13a
Compound 13a was prepared according to the procedure de-
scribed for compound 13 starting from compound 12a (4 g,
14.6 mmol). Purification by silica gel column chromatography
(1:9 ethylacetate/hexane) afforded the pure product 13a (3.62 g,
80 mL of
a
half-saturated aq NH4Cl (2 ꢁ 30 mL), water
(2 ꢁ 30 mL), brine (2 ꢁ 30 mL), dried over Na2SO4, filtered and con-
centrated under reduced pressure. The residue was purified by
flash column chromatography on silica gel (100–200 mesh, 20–
25% EtOAc in hexane) to afford less polar minor anti-diastereomer
16a followed by more polar major syn-diastereomer 16 (0.770 g,
62.4%) as a yellow oil. Rf = 0.30 (SiO2, 20% EtOAc in hexane).
92% yield) as
a colourless oil Rf = 0.3 (20% EtOAc/hexane).
½ ꢂ
a 2D9
¼ þ60 (c 0.3, CHCl3); IR (Neat): 3437, 2928, 2857, 1759,

552
P. Thakur et al. / Tetrahedron: Asymmetry 23 (2012) 547–553
½
a 2D7
ꢂ
¼ ꢀ138:2 (c 1.3, CHCl3). IR (Neat) 3481, 2926, 1688, 1496,
quickly. After 15 min of stirring, alcohol 9a (250 mg, 0.925 mmol)
1256, 1160, 1040, 701 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.36–
;
was added as a solution in 10 mL of dichloromethane along with
a small amount of DMAP (10 mg). The cooling bath was removed
and stirring was continued for 6 h. The solution was filtered and
the solvent was removed under reduced pressure. The resulting
oil was purified by column chromatography using (5% ethylacetate
in hexane) to give 17 (402 mg, 90%) as a colourless oil. Rf = 0.4
7.25 (m, 5H), 6.00–5.85 (m, 1H), 5.43–5.30 (m, 2H), 5.17 (dt,
J = 10.5, 1.5 Hz, 1H), 4.70–4.63 (m, 1H), 3.64 (dd, J = 17.3, 3.0 Hz,
1H), 3.44–3.37 (m, 1H), 3.32–3.20 (m, 2H); 3.04 (dd, J = 13.5,
10.5 Hz, 1H), 2.90 (d, J = 11.3 Hz, 1H), 2.80–2.65 (br s, –OH, 1H).
13C NMR (75 MHz, CDCl3): d 201.0, 172.0, 138.7, 136.1, 129.1,
128.6, 126.9, 114.9, 68.3, 68.0, 60.1, 45.2, 36.5, 31.9; MASS (ESIMS)
m/z 330 (M+Na)+.
(SiO2, 1:9 EtOAc in hexane). ½a D30
ꢂ
¼ ꢀ7:3 (c 0.5, MeOH); lit.8b
½
a 2D9
ꢂ
¼ ꢀ6:1 (c 0.33, MeOH); IR (KBr): 3449, 2926, 2856, 1737,
1253 cmꢀ1 1H NMR (300 MHz; CDCl3): d 5.93–5.69 (m, 2H),
;
4.1.9. (S)-1-[(R)-4-Benzyl-2-thioxothiazolidin-3-yl]-3-(tert-
butyldimethylsilyloxy)pent-4-en-1-one 10
5.38–5.19 (m,3H), 5.09–4.92 (m, 2H), 4.56 (q, J = 7.1 Hz, 1H), 4.45
(t, J = 6.7 Hz, 1H), 4.20–4.18 (m, 1H), 2.59–2.48 (m, 2H), 1.68–
1.52 (m, 4H), 1.49 (s, 3H), 1.39 (s, 3H), 1.39–1.19 (m, 10H), 0.92–
0.81 (m, 12H), 0.10 (s, 3H), 0.08 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 170.5, 140.3, 134.1, 118.4, 114.6, 108.3, 79.5, 74.9, 72.2, 70.6,
43.7, 35.2, 34.8, 31.8, 29.7, 29.4, 29.1, 28.2, 25.8, 25.7, 25.0, 22.6,
18.1, 14.0, ꢀ4.5, ꢀ4.9; (ESI-MS): m/z 505 (M+Na+); HRMS: calcd
for C27H50NaO5Si: 505.3320 (M+Na), found: 505.3322.
To a stirred solution of compound 16 (0.70 g, 2.28 mmol) in dry
DMF (10 mL) at 0 °C under a nitrogen atmosphere were added 2,6-
lutidine (0.42 mL, 3.64 mmol) and TBSCl (0.546 g, 3.64 mmol)
sequentially and stirred at room temperature for 3 h. The reaction
mixture was then quenched with saturated NaHCO3 (5 mL). The or-
ganic layer was separated and the aqueous layer was extracted
with EtOAc (3 ꢁ 20 mL). The combined organic extracts were
washed with water (2 ꢁ 20 mL), brine (1 ꢁ 20 mL) and dried over
anhydrous Na2SO4, filtered and concentrated. The residue was
purified by column chromatography on silica gel (5% EtOAc in hex-
ane) to afford compound 10 (0.883 g, 92%) as a yellow oil. Rf = 0.65
4.1.12. (S)-{(R)-1-[(4S,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-
yl]nonan-2-yl} 3-hydroxypent-4-enoate 7
To a stirred solution of compound 17 (400 mg, 0.83 mmol) in
THF (8 mL) at 0 °C, TBAF (1.24 mL, 1.24 mmol, 1 M solution in
THF) was added dropwise at the same temperature. The mixture
was allowed to stir at room temperature for 4 h. The resultant mix-
ture was quenched with water (7 mL) and diluted with diethyl
ether (10 mL). The organic layer was washed with water and then
with brine. The combined organic layers were dried over anhy-
drous Na2SO4, and concentrated under reduced pressure. The resi-
due was purified by chromatography on silica gel (15% EtOAc/
hexane) to give compound 7 (260 mg, 85%) as a yellow liquid.
10% EtOAc in hexane). ½a D25
¼ þ177:5 (c 1.5, CHCl3). IR (Neat): mmax
ꢂ
2931, 2855, 1696, 1645, 1516, 1341, 1252, 1165, 1037, 834 cmꢀ1
.
1H NMR (300 MHz, CDCl3): d 7.40–7.25 (m, 5H, Ar-H), 5.96–5.83
(m, 1H), 5.30–5.20 (m, 2H), 5.09 (d, J = 10.3 Hz, 1H), 4.81–4.74
(m, 1H), 3.69 (dd, J = 16.4, 8.4 Hz, 1H), 3.39–2.27 (m, 2H), 3.21–
2.99 (m, 2H), 2.89 (d, J = 11.5 Hz, 1H), 0.87 (s, 9H), 0.08 (s, 3H),
0.06 (s, 3H). 13C NMR (75 MHz, CDCl3): d 200.9, 171.4, 140.3,
136.5, 129.3, 128.8, 127.1, 114.6, 70.7, 68.6, 46.5, 36.5, 32.1, 25.7,
18.0, ꢀ4.97, ꢀ4.2.;MASS (ESIMS): m/z 444 (M+Na)+.
Rf = 0.4 (SiO2, 2:8 EtOAc in hexane). ½a D28
¼ ꢀ17:2 (c 0.7, CHCl3);
ꢂ
IR (KBr): 3448, 2925, 2858, 1732, 1639, 1376.1
4.1.10. (S)-3-(tert-Butyldimethylsilyloxy)pent-4-enoic acid 2
To a stirred solution of compound 10 (800 mg, 1.90 mmol), H2O
(0.1 mL, 5.70 mmol) and DCM (10 mL) was added DMAP (116 mg,
0.95 mmol) and stirred at rt for 14 h until TLC showed complete
conversion of starting material. The reaction mixture was then di-
luted with ether (20 mL), washed with 1 M HCl (7 mL), water
(7 mL) and brine (5 mL), and dried over anhydrous Na2SO4. After
removal of the solvents, the crude residue was chromatographed
on silica gel (50% EtOAc/hexane) to afford compound 8 (336 mg,
H NMR (300 MHz; CDCl3): d 5.92–5.67 (m, 2H), 5.39–5.09
(m,4H), 5.09–5.00 (m, 1H), 4.55–4.43 (m, 2H), 4.15 (ddd J = 9.1,
6.0, 3.0 Hz, 1H), 2.50(dd, J = 3.8, 1H), 2.47 (dd, J = 8.3 Hz, 1H),
1.70–1.47 (m, 3H), 1.45 (s, 3H), 1.35–1.22 (m, 14H), 0.90 (t,
J = 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 171.8, 138.8, 134.0,
118.5, 115.3, 108.4, 79.4, 74.4, 72.5, 68.9, 41.4, 34.9, 34.6, 31.7,
29.3, 29.1, 28.2, 25.5, 25.1, 22.6, 14.0; (ESI-MS): m/z 391
(M+Na+); HRMS: calcd for C21H36NaO5 391.2455, found: 391.2466.
77%); Rf = 0.2 (SiO2, 6:4 EtOAc in hexane). ½a D28
¼ ꢀ5:2 (c 0.7,
ꢂ
MeOH); lit8b
½
a 2D9
ꢂ
¼ ꢀ4:95 (c 2.0, MeOH); IR (KBr): 3449, 2926,
4.1.13. (3aS,5R,9S,11aR,E)-5-Heptyl-9-hydroxy-2,2-dimethyl-
4,5,8,9-tetrahydro-3aH-[1,3]dioxolo[4,5-d]oxecin-7(11aH)-one
18
2855, 1713, 1464, 1110 cmꢀ1 1H NMR (300 MHz; CDCl3): d 6.16
;
(br s, 1H), 5.84 (ddd, J = 16.6, 10.6, 4.0 Hz, 1H), 5.24 (td, J = 17.4,
1.5 Hz, 1H), 5.07 (td, J = 11.3, 1.5 Hz, 1H), 4.61–4.52 (m, 1H),
2.57–2.38 (m, 2H), 0.88 (s, 9H), 0.06, 0.05 (2s, 6H); 13C NMR
(75 MHz, CDCl3) d 176.3, 139.5, 115.2, 70.6, 43.2, 25.7, 18.1, ꢀ4.4,
ꢀ5.2; (ESI-MS): m/z 231(M+H+).
Ester 7 (90 mg, 0.24 mmol) was dissolved in freshly distilled de-
gassed anhydrous DCM (110 mL) and then treated with Grubbs
catalyst 2nd generation (21 mg, 0.024 mmol) and heated at reflux
for 6 h under an inert atmosphere. The reaction mixture was evap-
orated under reduced pressure to give a brown residue, which was
purified by silica gel column chromatography (20% EtOAc/hexane)
to afford compound 18 (51 mg, 61%) as a light brown liquid;
4.1.11. (S)-{(R)-1-[(4S,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-
yl]nonan-2-yl) 3-(tert-butyldimethylsilyloxy)pent-4-enoate 17
From compounds 8 and 9.
Rf = 0.3 (SiO2, 2:8 EtOAc in hexane). ½a D29
ꢂ
¼ ꢀ31 (c 0.8, CHCl3);
lit.7
½
a 2D4
ꢂ
¼ ꢀ33 (c 0.34, CHCl3); IR (neat)
v
max = 3459, 2928, 2858,
To a solution of 9 (250 mg, 0.925 mmol), 8 (234 mg, 1.02 mmol)
and PPh3 (364 mg, 1.4 mmol) in THF (10 mL) at 0 °C was added
DEAD (0.22 mL, 1.40 mmol). Stirring was continued at 0 °C for
1 h and then at rt for 10 h, after which the solution was concen-
trated and the crude residue was purified on silica gel by column
chromatography using (5% ethylacetate in hexane) to obtain 17
(348 mg, 78%) as a colourless oil. Rf = 0.4 (SiO2, 1:9 EtOAc in
hexane).
1728, 1374, 1054, 771 cmꢀ1 1H NMR (300 MHz; CDCl3): d 5.57
;
(dd, J = 8.8, 16.1 Hz, 1H), 5.43 (dd, J = 7.8, 16.1 Hz, 1H), 4.64 (ddd,
J = 5.7, 9.0, 14.3 Hz, 1H), 4.39 (dd, J = 6.3, 9.0 Hz, 1H), 4.27 (q,
J = 7.9 Hz, 1H), 3.91 (dd, J = 6.0, 10.3 Hz, 1H), 2.67 (dd, J = 7.8,
13.3 Hz, 1H), 2.17 (dd, J = 7.9, 13.4 Hz, 1H), 2.10 (dd, J = 5.8,
10.1 Hz, 1H), 1.48 (m, 1H), 1.44 (d, J = 15.8 Hz, 1H), 1.34 (s, 4H),
1.19 (s, 3H), 1.16–1.08 (m, 10H), 0.79 (t, J = 7.0 Hz, 3H); 13C NMR
(75 MHz; CDCl3): d 170.0, 133.5, 129.6, 108.6, 80.8, 77.3, 74.9,
70.0, 43.8, 38.0, 35.7, 31.7, 29.3, 29.1, 28.0, 25.5, 25.3, 22.6, 14.0;
(ESI-MS): m/z 341 (M+H)+; HRMS m/z calcd for C19H32O5Na
363.2142 (M+Na)+ found 363.2137.
From compounds 8 and 9a.
A solution of acid 8 (234 mg, 1.02 mmol) in 8 mL of dichloro-
methane was cooled to 0 °C. A sample of DCC (286 mg, 1.4 mmol)
was added in several portions and a white precipitate formed

P. Thakur et al. / Tetrahedron: Asymmetry 23 (2012) 547–553
553
26, 338–362; (c) Nicolaou, K. C.; Chen, J. S.; Dalby, S. M. Bioorg. Med. Chem.
2009, 17, 2290–2303; (d) Lu, X.-L.; Xu, Q.-Z.; Liu, X.-Y.; Cao, X.; Ni, K.-Y.; Jiao, B.-
H. Chem. Biodivers. 2008, 5, 1669–1674; (e) Itokawa, H.; Morris-Natschke, S. L.;
Akiyama, T.; Lee, K.-H. J. Nat. Med. 2008, 62, 263–280; (f) Wen, Z.; Guo, Y.-W.;
Yucheng, G. Curr. Med. Chem. 2006, 43, 303–332; (g) Croteau, R.; Kutchan, T. M.;
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Pietra, F. Nat. Prod. Rep. 1997, 453–464.
4.1.14. Achaetolide 1
To a stirred solution of compound 18 (20 mg, 0.06 mmol) in THF
(5 mL) was added aq HCl (1 M, 0.2 mL) and the mixture was stirred
at 55 °C for 6 h when TLC showed complete consumption of start-
ing material. The reaction mixture was then diluted with aq NaOH
(1 N solution, 0.3 mL). The organic layer was dried (anhydrous
Na2SO4) and evaporated and the residue was purified by column
2. (a) Dräger, G.; Kirschning, A.; Thiericke, R.; Zerlin, M. Nat. Prod. Rep. 1996, 13,
365; (b) Longo, L. S., Jr.; Bombonato, F. I.; Ferraz, H. M. C. Quim. Nova 2007, 30,
415.
chromatography (50% EtOAc/hexane) to afford achaetolide
1
(14.5 mg, 83%), Rf = 0.2 (SiO2, 6:4 EtOAc in hexane). ½a D28
ꢂ
¼ ꢀ28 (c
3. (a) Rivero-Cruz, J. F.; Garcia-Aguieee, G.; Cerda-Garcia-Rojas, C. M.; Mata, R.
Tetrahedron 2000, 56, 5337–5344; (b) Rivero-Cruz, J. F.; Martha, M.; Cerda-
Garcia-Rojas, C. M.; Mata, R. J. Nat. Prod. 2003, 66, 511–514.
4. (a) Evidente, A.; Cimmino, A.; Berestetskiy, A.; Mitina, G.; Andolfi, A.; Motta, A.
J. Nat. Prod. 2008, 71, 31–34; (b) Evidente, A.; Cimmino, A.; Berestetskiy, A.;
Andolfi, A.; Motta, A. J. Nat. Prod. 2008, 71, 1897–1901; (c) Yuzikhin, O.; Mitina,
G.; Berestetskiy, A. J. Agric. Food Chem. 2007, 55, 7707–7711.
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Synthesis 2011, 20, 3343–3349.
0.4, MeOH); lit.7
½
a 2D1
ꢂ
¼ ꢀ27 (c 0.52, MeOH); IR(neat)
mmax = 3376,
2928, 2853, 1726, 1462, 1067 cmꢀ1 1H NMR (300 MHz; CD3OD):
;
major conformer d 5.94 (dd, J = 15.3, 8.2, Hz, 1H), 5.72 (dd,
J = 15.3 8.2, Hz, 1H), 4.78–4.64 (m, 2H), 4.47– 4.41 (m, 1H), 3.65
(d, J = 9.4 Hz, 1H), 2.51 (dd, J = 3.8, 11.8 Hz, 1H), 2.50 (dd, J = 3.8,
11.6 Hz, 1H), 2.40–2.31 (m, 1H), 1.88–145 (m, 2H), 1.41 (s, 1H),
1.34–1.24 (m, 10H), 0.89 (t, J = 7.4 Hz, 3H), minor conformer d
5.59 (dd, J = 7.4, 16.8 Hz, 1H), 5.42 (dd, J = 8.8, 16.9 Hz, 1H), 4.48–
4.41 (m, 1H), 4.29 (dd, J = 3.2, 6.9 Hz, 1H), 3.47–3.42 (m, 1H),
2.92 (dd, J = 7.8, 12.3 Hz, 1H), 2.42–2.31 (m, 1H), 2.26 (dd,
J = 8.68, 13.4 Hz, 1H), 1.75–1.65 (m, 1H), 1.57–1.53 (m, 1H), 1.38
(s, 1H); 13C NMR (75 MHz; CD3OD): d 172.3, 172.2, 136.5, 131.7,
131.1, 127.9,78.3, 77.6, 76.7, 74.7, 74.6, 74.5, 71.7, 68.1, 38.3,
38.0, 37.6, 36.1, 33.0, 30.8, 30.6, 30.5, 30.4, 26.9, 26.3, 23.8, 14.4;
(ESI-MS): m/z 323 (M+Na); HRMS m/z calcd for C16H28O5Na
323.1829 (M+Na)+ found 323.1831.
9. Jogireddy, R.; Dakas, P. Y.; Valot, G.; Barluenga, S.; Winssinger, N. Chem. Eur. J.
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Acknowledgments
PT is thankful to Dr. Reddy’s Laboratories Pvt. Ltd for support
and Maithili Life Sciences Pvt. Ltd for financial assistance.
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