Stereoselective total synthesis of decarestrictine O

Article abstract of DOI:10.1016/j.tetasy.2012.06.027

The stereoselective total synthesis of decarestrictine O, a polyketide natural product is described. The synthesis involves MacMillan α-hydroxylation, C₁-Wittig olefination, hydrolytic kinetic resolution and ring closing metathesis (RCM) as key steps. Improved efficiency was achieved by using the DIBAL mediated reductive transformation of trans-dimethyl l-tartrate acetonide into -hydroxy α,β-unsaturated ester in a single step.

Full text of DOI:10.1016/j.tetasy.2012.06.027

Tetrahedron: Asymmetry 23 (2012) 1155–1160
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Tetrahedron: Asymmetry
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Stereoselective total synthesis of decarestrictine O
⇑
Jhillu S. Yadav , K. Anantha Lakshmi, N. Mallikarjuna Reddy, Nipunge Swapnil, A. Ramachandra Prasad
Pheromone Group, CSIR, Indian Institute of Chemical Technology, Hyderabad 500 607, AP, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 May 2012
Accepted 29 June 2012
The stereoselective total synthesis of decarestrictine O, a polyketide natural product is described. The
synthesis involves MacMillan
a-hydroxylation, C1-Wittig olefination, hydrolytic kinetic resolution and
ring closing metathesis (RCM) as key steps. Improved efficiency was achieved by using the DIBAL med-
iated reductive transformation of trans-dimethyl
ester in a single step.
L
-tartrate acetonide into
e-hydroxy a,b-unsaturated
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
leading to different members of the decarestrictine family. Fig. 1
depicts decarestrictine F, and decarestrictines A1, A2, D, N and
O,4,5 which can be isolated via fermentation of decarestrictine F
at pH 1–2.5.
As part of an ongoing research programme aimed at developing
the enantioselective synthesis of biologically active natural prod-
ucts, certain expertise is required in using different sequences of
Decarestrictines are secondary metabolites,1 belonging to the
family of decanolides which are one of the most important classes
of compounds due to their cholesterol inhibiting properties as de-
scribed in cell line tests with HEP-G2 liver cells.2 These properties
are very important in treating coronary diseases, which have high
prevalence all over the world and more importantly in India where
the risk of these diseases is high due to genetic factors and higher
fat food habits. Decarestrictines are ten membered lactones, which
are isolated from various penicillium strains.3 A common polyke-
tide precursor of decanolides undergoes structural modifications
reactions such as MacMillan
a-hydroxylations, hydrolytic kinetic
resolutions, ring closing metathesis and so on. During these stud-
ies, our investigations into the stereoselective total synthesis of
decarestrictine O 4 have become important due to its significant
biological activity. However, only one synthetic approach has been
O
O
O
O
O
O
O
OH
OH
O
O
O
decarestrictine A1
2
decarestrictine A2
3
1
decarestrictine F
O
O
O
O
O
O
HO
OH
OH
HO
OH
HO
OH
OH
OH
decarestrictine O
6
decarestrictine N
4
5
decarestrictine D
Figure 1.
⇑
Corresponding author. Fax: 91 40 27160387.
E-mail address: yadavpub@iict.res.in (J.S. Yadav).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.06.027

1156
J. S. Yadav et al. / Tetrahedron: Asymmetry 23 (2012) 1155–1160
reported so far for decarestrictine O,6 which is a tedious and mul-
tistep (24 steps) synthesis. Herein, a successful, more concise syn-
thetic route (19 steps) for decarestrictine O is reported employing
eliminating an existing much longer process.7 Compound 9 upon
hydrogenation with Pd/C afforded compound 10. Oxidation of alco-
hol 10 with IBX in a DMSO/CH2Cl2 system yielded the correspond-
ing aldehyde which by C1-Wittig olefination afforded ester 11 in
57% yield. The DIBAL-H reduction of ester 11 gave the correspond-
ing alcohol 12 in 93% yield. Alcohol 12 upon oxidation with IBX in a
DMSO/CH2Cl2 system yielded the corresponding aldehyde, which
MacMillan
a-hydroxylation C1-Wittig olefination, hydrolytic ki-
netic resolution and RCM as the key steps.
2. Results and discussion
was subjected to the MacMillan
a-hydroxylation using nitrosoben-
zene and 40 mol % of -Proline in DMSO, followed by reduction
D
Retrosynthetic analysis (Fig. 2) suggested that the target mole-
cule 4 could be obtained from 21 via ring closing metathesis. Com-
pound 21 could in turn be obtained via esterification of compound
15 with relevant acid 20. Alcohol fragment 15 could be obtained
with sodium borohydride to furnish the unstable anilinoxy com-
pound, which was further treated with 30 mol % of CuSO4ꢀ5H2O
in methanol at rt to cleave the O–N bond to provide diol 13 in
47% yield.8 Selective protection of the primary hydroxyl group of
diol 13 with tosyl chloride, triethylamine and a catalytic amount
of dibutyl tinoxide has afforded the tosylate compound 14 in 80%
yield. Tosylated compound 14 was then LiAlH4 reduced with LAH
in dry THF under reflux conditions to afford alcohol 15 in 79%
yield.9
from dimethyl L-tartrate 7 by using Macmillan a-hydroxylation
and C1-Wittig olefination reactions. Acid fragment 20 could be syn-
thesized from 1-butenol by means of Jacobsen’s hydrolytic kinetic
resolution and opening of the corresponding epoxide with
trimethylsulfoniumiodide.
The synthesis started with compound 7, to make
unsaturated ester 9, which was synthesized from trans-dimethyl
tartrate acetonide 8 in a single step as shown in Scheme 1, while
e-hydroxy a,b-
Following the steps shown in Scheme 2, the synthesis of acid
fragment 20 was achieved by Jacobsen’s hydrolytic kinetic resolu-
L
-
O
O
OH
O
OTBS
O
O
O
+
HO
HO
OH
O
OTBS
O
O
OH
20
15
21
4
O
OH
O
OMe
BnO
MeO
O
OH
16
7
Figure 2.
O
OH
O
O
O
b
ref-7
a
OMe
OEt
c
OMe
MeO
HO
MeO
OH
7
O
O
O
O
O
9
8
O
O
O
OEt
OH
e
f
OEt
d
HO
O
O
O
O
O
11
12
10
O
OH
O
OH
O
OH
OTs
OH
h
g
O
O
O
14
15
13
Scheme 1. Reagents and conditions: (a) 2,2-DMP, cat. PTSA, benzene, reflux, 2 h; (b) DIBAL-H, [(EtO)2P(O)CHCO2Et]ꢁNa+, ꢁ78 °C to rt; (c) H2, Pd/C, EtOAc, 3 h; (d) (i) IBX,
DMSO, CH2Cl2, 0 °C to rt, 2 h; (ii) Ph3PCH2, tBuOK, THF, ꢁ10 °C to rt, 2 h; (e) DIBAL-H, ꢁ78 °C to rt, 1 h; (f) (i) IBX, DMSO, CH2Cl2, 0 °C to rt, 2 h; (ii) PhNO,
NaBH4, MeOH, CuSO4.5H2O ꢁ20 °C to rt over two steps; (g) TsCl, Et3N, Dibutyl tin oxide (cat), dry CH2Cl2, 0 °C to rt, 12 h; (h) LiAlH4, THF, reflux, 3 h.
D-proline, DMSO,

J. S. Yadav et al. / Tetrahedron: Asymmetry 23 (2012) 1155–1160
1157
tion of racemic epoxide 16 using the (R,R)-catalyst to give chiral
4. Experimental
4.1. General
epoxide (S)-16. Epoxide 16 was treated with trimethylsulfonium
iodide in the presence of n-BuLi as a base in dry THF at ꢁ20 °C to
provide allyl alcohol 17 in 87% yield.10 The allylic alcohol was sub-
sequently protected as the tert-butyldimethylsillyl ether with
TBSCl and imidazole to afford compound 18 in 81% yield. Deprotec-
tion of the benzyl ether was achieved by using Li/naphthalene in
dry THF at ꢁ20 °C to yield the corresponding alcohol 19. The
resulting alcohol was oxidized to the aldehyde with IBX in a dry
DMSO/CH2Cl2 system, which upon oxidation with NaClO2, NaH2-
PO4 and 2-methyl 2-Butene in t-BuOH/H2O afforded the acid frag-
ment 20 in 89% yield.11
With both the alcohol and acid fragments in hand, the coupling
of these two fragments was successfully achieved by following the
steps in Scheme 3. Thus, esterification of the free OH group of 15
with acid 20 in the presence of DCC and DMAP gave the diene ester
21 in 72% yield. The diene ester was then cyclized by ring closing
metathesis.12 The diene upon treatment with 5 mol % Grubbs II
catalyst under high dilution condition (0.001 M in CH2Cl2), affor-
ded the cyclic ester 22 in 60% yield. Deprotection of the TBS ether
and acetonide group by using PTSA in methanol afforded the target
molecule Decarestrictine O 4 in 65% yield. The physical data of the
synthesized compound 4 are in full agreement with the reported
data in the literature.4,6
All reactions were conducted under N2 in anhydrous solvents
such as CH2Cl2, THF, EtOAc and Et2O. Preparative chromatographic
separations were performed on silica gel (35–75 lm); reactions
were monitored by TLC analysis using silica plates with fluorescent
indicator (254 nm) and visualized with a UV lamp, anisaldehyde or
b-naphthol solution or alkaline KMnO4 solution. All commercially
available reagents were purchased and typically used as supplied.
Optical rotations were measured at an ambient temperature
(25 °C) on CHCl3 solutions with a polarimeter using a 2 ml capacity
cell with 100 mm path length. Infrared spectra were recorded
using a thin film supported between NaCl plates or as a solid
embedded in a KBr disc. 1H and 13C NMR spectra are recorded in
a Fourier transform mode at the field strength specified either on
a Bruker UXNMR FT-300 MHz (avance) or a Varian VXR-unity-
400 MHz spectrometer. Spectra were obtained on CDCl3 solutions
in 5 mm diameter tubes; Chemical shifts in ppm are quoted rela-
tive to the residual signals of chloroform (dH 7.25 ppm or dC
77.0 ppm). Multiplicities in the 1H NMR spectra are described as:
s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet,
br = broad; coupling constants are reported in Hz. For low (MS)
and high (HRMS) resolution mass spectra ion mass/charge (m/z) ra-
tios are reported as values in atomic mass units.
3. Conclusion
4.1.1. (E)-Ethyl 3-((4S,5S)-5-(hydroxymethyl)-2,2-dimethyl-1,3-
dioxolan-4-yl) acrylate 9
In conclusion, the stereoselective total synthesis of Decarestric-
tine O has been achieved in 19 steps. The Macmillan a-hydroxyl-
To trans-dimethyl tartrate acetonide 8 (15 g, 68 mmol) in dry
toluene (100 mL) was added DIBAL-H (80 mL, 1.7 M solution in
ation, C1-Wittig olefination, hydrolytic kinetic resolution and ring
closing metathesis (RCM) are the key steps used in this endeavour.
OH
OTBS
O
a
b
BnO
BnO
BnO
18
16
17
OTBS
O
OTBS
c
d
HO
HO
19
20
Scheme 2. Reagents and conditions: (a) Me3S+Iꢁ, n-BuLi, THF, ꢁ20 °C, 3 h; (b) TBSCl, imidazole, DMAP, CH2Cl2, 0 °C to rt, 2 h, 81%; (c) Li/naphthalene, dry THF, ꢁ20 °C, 3 h, (d)
(i) IBX, DMSO, CH2Cl2, 0 °C to rt, 2 h, (ii) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH, H2O, 6 h.
O
OH
O
O
OTBS
O
a
+
HO
OTBS
O
O
O
O
15
20
21
O
c
b
O
O
HO
OH
O
OTBS
OH
O
22
4
Scheme 3. Reagents and conditions: (a) DCC, DMAP, CH2Cl2, 0 °C to rt; (b) Grubb’s II catalyst, CH2Cl2, reflux, 16 h; (c) PTSA, MeOH, 0 °C to rt, 2 h.

1158
J. S. Yadav et al. / Tetrahedron: Asymmetry 23 (2012) 1155–1160
toluene, 137 mmol) slowly at 0 °C via cannula. The reaction mix-
ture was stirred for 1 h at 0 °C, then cooled to ꢁ78 °C and an-
other 1 equiv of DIBAL (40 mL, 68 mmol) was slowly added,
and stirred for 30 min. Next Horner–Emmons reagent was added,
which was separately prepared from triethylphosphonoacetate
(23.4 g, 104 mmol) and NaH (2.5 g, 104 mmol) in dry toluene
The reaction mixture was left overnight (ꢁ78 °C to rt) and then
quenched with a saturated sodium potassium tartrate solution.
The reaction mixture was then stirred for 2 h and diluted with
water (100 mL). The aqueous layer was extracted with ether.
The organic layer was dried over Na2SO4 and concentrated in va-
cuo. The compound was purified by column chromatography to
afford 9 (6.8 g, 42.5% yield) as a pale yellow liquid. Rf = 0.4 (silica
gel, 60–120 mesh, 20% Hexane/EtOAc); 1H NMR (CDCl3,
300 MHz): d 1.24 (t, J = 6.2 Hz, 3H), 1.36 (s, 3H), 1.39 (s, 3H),
2.52 (br s, OH), 3.33–3.51 (m, 1H), 3.58–3.67 (m, 2H), 4.13–
4.18 (m, 2H), 4.39–4.47 (m, 1H), 5.64–6.01(m, 1H), 6.62–6.77
(m, 1H); 13C NMR (CDCl3, 75 MHz): d 14.2, 26.6, 27.1, 61.4,
4.1.4. 3-((4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)propan-
1-ol 12
To a stirred solution of compound 11 (2 g, 18.5 mmol) in dry
CH2Cl2 was added DIBAL-H (13.6 mL, 1.7 M, 23 mmol) dropwise
at 0 °C. The mixture was then stirred for 1 h at room temperature.
The reaction was monitored by TLC; after completion of the reac-
tion, the reaction mixture was quenched with a saturated sodium
potassium tartrate solution. The reaction mixture then became vis-
cous, and was diluted with CH2Cl2 (20 mL), and stirred for 3 h. The
two layers were separated, and the aqueous layer was washed with
CH2Cl2 twice. The organic layer was dried over Na2SO4, the solvent
was evaporated and the product purified by column chromatogra-
phy to afford 12 (1.6 g, 93%) as a pale yellow liquid. Rf = 0.2 (silica
gel, 60–120 mesh, 30% Hexane/EtOAc); 1H NMR (CDCl3, 300 MHz):
d 1.41 (d, J = 1.51 Hz, 6H), 1.53–1.75 (m, 4H), 3.65–3.71 (m, 3H),
3.96–4.01 (m, 1H), 5.25–5.38 (m, 2H), 5.78–5.84 (m, 1H); 13C
NMR (CDCl3, 75 MHz): d 26.91, 27.21, 28.38, 29.43, 62.60, 80.55,
80.73, 108.71, 119.08, 135.05; IR (neat):
t
3419, 2986,2928,
62.3, 78.6, 81.0, 139.4, 166.7; IR (neat):
t
3453, 2985, 2933,
1374, 1224,1050 cmꢁ1; ½a D25
ꢂ
¼ ꢁ16:2 (c 0.4, CHCl3); ESI-MS: m/z
1727, 1375, 1040 cmꢁ1; ½a D25
ꢂ
¼ ꢁ8:13 (c 1.5, CHCl3); ESI-MS: m/
209 [M+Na]+.
z: 253 [M+Na]+.
4.1.5. (S)-3-((4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxan-4-yl) pro-
pane-1,2-diol 13
4.1.2. Ethyl 3-((4S,5S)-2,2-dimethyl-5-vinyl-1,3-dioxan-4-yl) pro-
panoate 10
To a stirred solution of IBX (3.16 g, 11.29 mmol) dissolved in
DMSO (6 mL) was added compound 12 (1.4 g, 7.5 mmol) in CH2Cl2
(5 mL) at 0 °C. After complete conversion, the reaction mixture was
filtered through a Celite pad, washed with water and extracted
with ether, dried over anhydrous Na2SO4, concentrated in vacuo
and purified by flash column chromatography to afford the corre-
sponding aldehyde.
To a stirred solution of compound 9 (7 g, 30.4 mmol) in EtOAc,
was added 10% Pd/C (catalytic) and stirred under a hydrogen atmo-
sphere for 3 h. Next, the reaction mixture was filtered through a
small Celite pad and concentrated in vacuo. The compound was
purified by flash column chromatography to afford the correspond-
ing ester 10 (6.4 g, 92% yield) as a colourless liquid. 1H NMR (CDCl3,
300 MHz): d 1.23 (t, 3H, J = 6.98 Hz), 1.37 (s, 3H), 1.38 (s, 3H), 1.75–
2.0 (m, 2H), 2.25 (br s, OH), 2.36–2.56 (m, 2H), 3.37–3.64 (m, 1H),
3.70–3.80 (m, 2H), 3.84–3.92 (m, 1H), 4.08–4.15 (q, 2H, J = 7.17 Hz,
14.35 Hz); 13C NMR (CDCl3, 75 MHz): d 14.11, 26.92, 27.18, 27.91,
Next, D-proline (0.187 g, 1.63 mmol) was dissolved in DMSO
(10 mL), and the suspension stirred at room temperature for
10 min. Nitrosobenzene (0.581 g, 5.43 mmol) was then added in
one portion at room temperature, turning the solution green. The
reaction mixture was cooled to ꢁ20 °C, then the aldehyde (1 g,
5.43 mmol) dissolved in DMSO was added. The reaction mixture
was stirred for 2 h, then sodium borohydride and methanol were
added at 0 °C, the reaction mixture was stirred for 1 h, after which
was added CuSO4ꢀ2H2O (0.405 g, 1.63 mmol). The reaction mixture
was then stirred overnight at rt. The reaction mixture was filtered
through a small Celite pad and concentrated in vacuo. The com-
pound was purified by column chromatography to afford 13
(0.52 g, 47%) as a brown liquid. Rf = 0.3 (silicagel, 60–120 mesh,
60%, Hexane/EtOAc); 1H NMR (CDCl3, 300 MHz): d 1.41(s, 6H),
1.56–1.65 (m, 1H), 1.78–1.86 (m, 1H), 3.49–3.55 (m, 1H), 3.65–
3.70 (m, 1H), 3.86–4.07 (m, 3H), 5.25–5.39 (m, 2H), 5.73–5.85
(m, 1H); 13C NMR (CDCl3, 75 MHz): d 28.59, 35.39, 66.0, 68.2,
30.56, 60.43, 61.86, 76.13, 80.98, 108.82, 173.20; IR (neat):
2985, 2933, 1731, 1375, 1219, 1166, 1070, 1040 cmꢁ1
¼ þ20:3 (c 1.26, CHCl3); ESI-MS: m/z: 233 (M+H), 250
(M+NH4)
t 3453,
;
½ ꢂ
a 2D5
4.1.3. Ethyl 3-((4S,5S)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)-
propanoate 11
To a stirred solution of IBX (10.86 g, 38 mmol) dissolved in
DMSO (20 mL) was added compound 10 (6 g, 25.86 mmol) in
CH2Cl2 (20 mL) at 0 °C. After complete conversion, the reaction
mixture was filtered through a Celite pad, washed with water, ex-
tracted with ether, dried over anhydrous Na2SO4, concentrated in
vacuo and purified by flash column chromatography to afford the
corresponding aldehyde.
70.17, 75.16, 115.26, 137.43; IR (neat):
t 3388, 2925, 2855, 1658,
1037 cmꢁ1; ½a 2D5
ꢂ
¼ ꢁ2:5 (c 0.2, CHCl3); ESI-MS: m/z 225 [M+Na]+.
To a stirred solution of Methyltriphenylphosponium iodide in
dry THF was added potassium tert-butoxide at 0 °C. The mixture
was then stirred for 30 min at the same temperature. Next was
added the aldehyde (4 g, 17.4 mmol) dissolved in dry THF and
the reaction mixture was stirred for 1 h at rt. After completion of
reaction, a small amount of water was added and the compound
was extracted with EtOAc, dried over Na2SO4, concentrated in va-
cuo and purified by column chromatography to afford compound
11 (2.15 g, 57%) as a light yellow liquid. Rf = 0.7 (silicagel, 60–120
mesh, 30% Hexane/EtOAc); 1H NMR (CDCl3, 300 MHz): d 1.22 (t,
J = 7.55, 6.79 Hz, 3H), 1.37 (s, 6H), 1.75–1.99 (m, 2H), 2.35–2.54
(m, 2H), 3.64–3.71 (m, 1H), 3.96–4.01 (m, 1H), 4.07–4.14 (q,
J = 6.79 Hz, 7.55 Hz, 2H), 5.22–5.38 (m, 2H), 5.72–5.83 (m, 1H);
13C NMR (CDCl3, 75 MHz): d 14.08, 26.67, 26.82, 27.08, 30.54,
4.1.6. (S)-3-(4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)-2-
hydroxypropyl4-methyl benzenesulfonate 14
To a stirred solution of compound 13 (0.5 g, 2.47 mmol) in dry
CH2Cl2 was added Et3N (0.7 mL), and a catalytic amount of dibutyl-
tin oxide. The reaction mixture was stirred for 15 min, then cooled
to 0 °C, after which was added para-toluene sulfonyl chloride
(0.564 g, 2.97 mmol). The reaction mixture was then stirred over-
night. After completion of the reaction, a few mL of water was
added and the compound extracted with CH2Cl2 and dried over
Na2SO4. The solvent was evaporated and the residue purified by
column chromatography to afford 14 (0.71 g, 80%) as a pale yellow
liquid. Rf = 0.2 (silicagel, 60–120 mesh, 30% Hexane/EtOAc); 1H
NMR (CDCl3, 300 MHz): d 1.29 (s, 6H), 1.48–1.57 (m, 2H), 2.34 (s,
3H), 3.32–3.47 (m, 1H), 3.83–3.99 (m, 3H), 4.57 (m, 1H), 5.12–
5.26 (m, 1H), 5.47–5.89 (m, 2H), 7.46 (m, 2H), 7.75 (m, 2H); 13C
NMR (CDCl3, 75 MHz): d 21.29, 21.57, 30.83, 37.0, 66.97, 71.82,
60.30, 79.42, 82.30, 108.68, 119.07, 134.92, 173.03; IR (neat):
t
3452, 2985, 2927, 1773, 1735, 1180 cmꢁ1; ½a D25
¼ þ18:75 (c 0.8,
ꢂ
CHCl3); ESI-MS: m/z: 229 [M+H].

J. S. Yadav et al. / Tetrahedron: Asymmetry 23 (2012) 1155–1160
1159
74.72, 80.69, 117.20, 127.92, 129.18, 129.87, 138.75, 141.96; IR
20 mL), washed with brine and dried over anhydrous Na2SO4 and
concentrated in vacuo. Purification of the crude compound by col-
umn chromatography afforded TBS ether 18 (3.9 g, 81%) as a col-
ourless oil. Rf = 0.8 (Silicagel, 60–120 mesh, 30% Hexane/EtOAc);
1H NMR (CDCl3, 300 MHz): d 0.04 (s, 3H). 0.05 (s, 3H), 0.89 (s,
9H), 1.75–1.81 (m, 2H), 3.47–3.61 (m, 2H), 4.27–4.33 (m, 1H),
4.42–4.53 (m, 2H), 4.99–5.17 (m, 2H), 5.75–5.86 (m, 1H), 7.33-
7.34 (m, 5H); 13C NMR (CDCl3, 75 MHz): d ꢁ5.0, ꢁ4.39, 18.18,
25.83, 38.08, 66.67, 70.72, 72.96, 113.69, 127.48, 127.65, 128.29,
(neat):
t
3365, 2924, 2851, 1723, 1601, 1174 cmꢁ1; ½a D25
¼ ꢁ65:3
ꢂ
(c 0.4, CHCl3); ESI-MS: m/z 379 [M+Na]+.
4.1.7. (R)-1-((4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)pro-
pan-2-ol 15
At first, LiAlH4 was taken in dry THF at 0 °C, after which was
added to a solution of compound 14 (0.7 g, 2 mmol) dissolved in
THF at 0 °C. The reaction mixture was heated at reflux for 3 h,
and then the reaction was quenched with water and 5 M NaOH
solution. The reaction mixture was then filtered through a Celite
pad. The solvent was evaporated in vacuo. The compound was
purified by column chromatography to afford alcohol 15 (0.29 g,
80% yield) as a pale yellow liquid. Rf = 0.5 (silicagel, 60–120 mesh,
30% Hexane/EtOAc); 1H NMR (CDCl3, 300 MHz): d 1.18 (s, 6H), 1.36
(d, J = 3.77 Hz, 3H), 1.56–1.71 (m, 2H), 3.83–4.06 (m, 3H), 5.17–
5.33 (m, 2H), 5.67–5.79 (m, 1H); 13C NMR (CDCl3, 75 MHz): d
23.54, 26.87, 27.21, 39.19, 65.11, 77.79, 82.27, 108.90, 119.23,
138.47, 141.56; IR (neat):
t
ꢂ
3068, 3032, 2954, 2930, 1725, 1644,
¼ 6:4 (c 0.4, CHCl3); ESI-MS: m/z:
1464, 1254, 1092 cmꢁ1; ½a D25
329 [M+Na]+.
4.1.11. (S)-3-(tert-butyldimethylsilyloxy)pent-4-en-1-ol 19
To stirred solution of naphthalene powder (14.64 g,
a
114.3 mmol) in dry THF (50 mL) was added lithium metal (0.4 g,
57.7 mmol). The mixture was stirred for 3 h at room temperature
then cooled to ꢁ20 °C and compound 18 (3.5 g, 11.43 mmol) in
dry THF (10 mL) was added. After stirring for 2 h at ꢁ20 °C, the
reaction mixture was quenched with a saturated aqueous NH4Cl
solution and extracted with ether (3 ꢃ 30 mL). The organic layer
was washed with water, brine and dried over Na2SO4. The solvent
was evaporated, and the product purified by column chromatogra-
phy to afford the corresponding alcohol 19 (2.1 g, 85.6%) as a col-
ourless oil. 1H NMR (CDCl3, 300 MHz): d 0.06 (s, 3H), 0.09 (s, 3H),
0.90 (s, 9H), 1.66–1.91(m, 2H), 3.67–3.86 (m, 2H), 4.39–4.45 (m,
1H), 5.08–5.25 (m, 2H), 5.79–5.90 (m, 1H); 13C NMR (CDCl3,
75 MHz): ꢁ5.07, ꢁ4.42, 18.09, 25.79, 39.13, 60.06, 73.16, 114.36,
134.73; IR (neat):
t ;
3404, 2961, 2925, 1726, 1376, 1243 cmꢁ1
½
a 2D5
ꢂ
¼ ꢁ12:25 (c 0.4, CHCl3); ESI-MS: m/z 209 [M+Na]+.
4.1.8. (S)-2-(2-(Benzyloxy)ethyl)oxirane 16
The racemic epoxide of 16 (10 g, 56 mmol) and THF (0.5 mL)
were added to (R,R)-Salen-CoIII catalyst (0.17 g, 0.28 mmol) and
the solution was cooled to 0 °C. Then acetic acid (0.1 mL,
1.12 mmol) was added and after 5 min, water (0.5 mL, 30.8 mmol)
was added. After another 5 min, the ice bath was removed and the
reaction mixture was stirred at rt for 24 h. The reaction mixture
was then concentrated in vacuo. The compound was purified by
column chromatography to afford epoxide (S)-16 (4.8 g) as a pale
yellow liquid. Rf = 0.8 (silicagel, 60–120 mesh, 60% Hexane/EtOAc);
1H NMR (CDCl3, 300 MHz): d 1.67–1.78 (m, 1H), 1.82–1.93 (m, 1H),
2.45–2.47 (m, 1H), 2.71–2.74 (m, 1H), 2.98–3.04 (m, 1H), 3.55–3.60
(m, 2H), 4.49 (s, 1H), 7.21–7.28 (m, 5H); 13C NMR (CDCl3, 75 MHz):
d 32.99, 47.13, 50.09, 67.05, 73.10, 127.65, 128.44, 138.30; IR
140.61; IR (neat):
t ;
3355, 2925, 2856, 1735, 1453, 1055 cmꢁ1
½
a 2D5
ꢂ
¼ þ4:7 (c 0.6, CHCl3); ESI-MS: m/z: 239 [M+Na]+.
4.1.12. 3-(tert-Butyldimethyl silyloxy)pent-4-enoic acid 20
To a stirred solution of IBX (8.28 g, 29.58 mmol) in DMSO
(30 mL) was added compound 19 (2.13 g, 9.86 mmol) in CH2Cl2
(10 mL) at 0 °C. After complete conversion, the reaction mixture
was filtered through a Celite pad, washed with water (30 mL), ex-
tracted with ether (3 ꢃ 40 mL), dried over anhydrous Na2SO4, con-
centrated in vacuo and purified by flash column chromatography
to afford the corresponding aldehyde.
(neat):
MS: m/z: 179 [M+H].
t
2922, 2854, 772 cmꢁ1; ½a D25
¼ þ19:2 (c 0.7, CHCl3); ESI-
ꢂ
4.1.9. (S)-5-(Benzyloxy)pent-1-en-3-ol 17
To a stirred solution of dry THF was added trimethylsulfoniumi-
odide (22.9 g, 112.35 mmol) at ꢁ20 °C. The reaction mixture was
stirred for 20 min followed by the addition of n-BuLi (52 mL,
1.6 M, 84.26 mmol). After 40 min, epoxide 16 (5 g, 28 mmol) in
THF was added dropwise. The reaction mixture was stirred at
ꢁ20 °C for 3 h. The reaction mixture was quenched with a satu-
rated solution of NH4Cl. The two phases were separated and the
aqueous layer was extracted with EtOAc. The organic layer was
dried over Na2SO4, the solvent was evaporated and the residue
purified by column chromatography to afford pure allylic alcohol
17 (4.72 g, 87%) as a pale yellow liquid. Rf = 0.4 (silicagel, 60–120
mesh, 30% Hexane/EtOAc); 1H NMR (CDCl3, 300 MHz): d 1.68–
1.75 (m, 2H), 2.70 (br s, OH), 3.56–3.75 (m, 2H), 3.78–3.86 (m,
1H), 4.5 (s, 2H), 5.03–5.10 (m, 2H), 5.73–5.86 (m, 1H), 7.21–7.33
(m, 5H); 13C NMR (CDCl3, 75 MHz): 35.78, 68.75, 70.13, 73.16,
To a stirred solution of the aldehyde (1.0 g, 4.6 mmol) in t-BuOH
(10 mL) were added solutions of 2-methyl-2-butene (10 mL), Na-
ClO2 (0.63 g, 7 mmol) and NaH2PO4 (0.84 g, 7 mmol) in water
(5 mL) and stirred over 6 h at room temperature. The solvent was
removed under reduced pressure and extracted with EtOAc
(3 ꢃ 10 mL). The combined organic layers were washed with brine
(5 mL), dried over Na2SO4 and concentrated in vacuo. The crude
residue was purified by column chromatography to afford acid
20 (0.89 g, 89%) as a light yellow liquid. Rf = 0.2 (Silicagel, 60–120
mesh, 30% Hexane/EtOAc); 1H NMR (CDCl3, 300 MHz): d 0.05 (s,
3H), 0.06 (s, 3H), 0.88 (s, 9H), 2.55 (d, J = 6.79 Hz. 2H), 4.54–4.60
(m, 1H), 5.09–5.28 (m, 2H), 5.79–5.90 (m, 1H); 13C NMR (CDCl3,
75 MHz): d ꢁ5.23, ꢁ4.48, 14.08, 29.64, 42.94, 70.54, 115.32,
139.32, 172.45; IR (neat):
t ;
2925, 2855, 1714, 1464, 835 cmꢁ1
½
a 2D5
ꢂ
¼ þ2:1 (c 0.4, CHCl3); ESI-MS: m/z: 253 [M+Na]+.
117.42, 127.54, 127.60, 128.33, 134.77, 137.85; IR (neat):
t
3425,
3067, 3030, 2922, 2855, 1640, 1363, 1093 cmꢁ1; ½a D25
ꢂ
¼ ꢁ2:1 (c
4.1.13. (S)-((R)-1-((4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-
4yl)propan-2-yl)-3-(tert-butyl dimethyl silyloxy) pent-4-enoate
21
0.6, CHCl3); ESI-MS: m/z: 215 [M+Na]+.
4.1.10. (S)-(5-(Benzyloxy)pent-1-en-3-yloxy)(tert-butyl)dimeth-
ylsilane 18
To a stirred solution of alcohol 15 (0.2 g, 1.07 mmol) in CH2Cl2
(10 mL) were added DCC (0.44 g, 2.15 mmol) and DMAP (0.26 g,
2.15 mmol) at 0 °C followed by compound 20 (0.29 g, 1.3 mmol).
The reaction mixture was then stirred at room temperature for
2–3 h. After completion of reaction, the mixture was filtered
through a Celite pad with ether and the resulting filtrate was evap-
orated in vacuo. The crude residue was purified by column chro-
matography to afford diene ester 21 (0.31 g, 72%) as a colourless
To a solution of 17 (3 g, 15.62 mmol) in dry CH2Cl2 (30 mL) were
added a catalytic amount of DMAP (15 mg) and imidazole (3.18 g,
46.7 mmol) in one portion followed by TBSCl (3.5 g, 23.43 mmol) in
one portion at 0 °C. The resulting mixture was then stirred for 4 h
at rt. After completion of the reaction, the mixture was quenched
by the addition of water (15 mL), diluted with CH2Cl2 (3 x

1160
J. S. Yadav et al. / Tetrahedron: Asymmetry 23 (2012) 1155–1160
oil. Rf = 0.7 (SiO2, 60–120 mesh, 30% Hexane/EtOAc); 1H NMR
(CDCl3, 300 MHz): d 0.04 (s, 3H), 0.05 (s, 3H), 0.86 (s, 9H), 1.26
(d, J = 6.79 Hz, 6H), 1.38 (d, J = 5.28 Hz, 3H), 1.60–1.71 (m, 1H),
1.80–1.89 (m, 1H), 2.37–2.55 (m, 2H), 3.66–3.78 (m, 1H), 3.92–
3.97 (m, 1H), 4.52–4.57 (m, 1H), 4.98–5.04 (m, 2H), 5.18–5.39
(m, 3H), 5.72–5.89 (m, 2H); 13C NMR (CDCl3, 75 MHz): d ꢁ4.94,
ꢁ4.45, 18.11, 20.62, 25.80, 26.92, 27.25, 38.43, 43.83, 68.92,
70.65, 77.23, 82.81, 108.91, 114.62, 119.19, 134.85, 140.21,
pound was purified by column chromatography to afford com-
pound 4 (0.032 g, 65%) as a pale yellow liquid. Rf = 0.2 (silicagel,
60–120 mesh, 60% Hexane/EtOAc); 1H NMR (500 MHz, acetone-
d6): d 1.28 (d, J = 6.7 Hz, 3H), 1.30 (m, 1H), 1.34–1.38 (dd,
J = 3.2 Hz, 15.6 Hz, 1H), 2.24–2.30 (m, 1H), 2.89 (dd, J = 7.9 Hz,
13.3 Hz, 1H), 3.38–3.43 (m, 1H), 4.03 (br s, OH), 4.24 (m, 1H),
4.45 (m, 1H), 4.56 (br s, OH), 5.02 (m, 1H), 5.41 (dd, J = 8.1 Hz,
16.1 Hz, 1H), 5.54 (dd, J = 7.1 Hz, 16.3 Hz, 1H); 13C NMR
(100 MHz, acetone-d6): d 21.18, 39.62, 45.18, 71.46, 73.2, 74.0,
170.32; IR (neat):
t
3083, 2929, 2857, 1737, 1646, 1463, 1373,
1250 cmꢁ1; ½a 2D5
ꢂ
¼ ꢁ5:25 (c 0.4, CHCl3); ESI-MS: m/z: 399 [M+H].
76.88, 131.12, 135.7, 170.63; IR (neat): t 3399, 2924, 1717,
1459 cmꢁ1; ½a 2D5
¼ ꢁ19:6 (c 0.20, CH3OH); ESI-MS: m/z: 239
ꢂ
4.1.14. (3S,5R,9S,11S,E)-9-(tert-Butyl dimethyl silyloxy)-2,2,5-
trimethyl-4,5,8,9-tetrahydro-3-(1,3)dioxolo(4,5)oxecin-7-one
22
[M+Na]+; HRMS m/z [M+Na]+ found 239.0889; calculated
239.0895 for C10H16O5Na.
Grubbs’ II catalyst (0.88 mg, 5 mol %) was dissolved in CH2Cl2
(10 mL) and then added dropwise to a solution of the ester 21
(0.25 g, 0.628 mmol) in 700 mL of CH2Cl2. The reaction mixture
was stirred at reflux at 45 °C for 12 h by which time all the starting
material were consumed (TLC). The solvent was removed in vacuo
and the crude product was purified by silica gel column chroma-
tography to afford compound 22 (0.14 g, 65%) as a colourless oil.
Rf = 0.2 (Silicagel, 60–120 mesh, 10% Hexane/EtOAc); 1H NMR
(CDCl3, 300 MHz): d 0.05 (s, 3H), 0.06 (s, 3H), 0.92 (s, 9H), 1.21
(d, J = 6.23 Hz, 3H), 1.40 (s, 6H), 1.87–2.04 (m, 2H), 2.45 (d,
J = 3.58 Hz, 2H), 3.58–3.65 (m, 1H), 4.06–4.12 (m, 1H), 4.66–4.68
(m, 1H), 4.93–5.0 (m, 1H), 5.59–5.68 (m, 1H), 5.88–5.94 (m, 1H);
13C NMR (CDCl3, 75 MHz): d ꢁ5.16, ꢁ4.95, 18.27, 21.80, 25.76,
26.97, 29.68, 38.56, 45.24, 67.93, 68.99, 81.62, 84.14, 107.89,
Acknowledgements
K.A.L., N.M.R. and N.S. thank UGC and CSIR New Delhi respec-
tively for award of research fellowships.
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t
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