Stereoselective total synthesis of stagonolide-C

Article abstract of DOI:10.1016/j.tetasy.2012.07.015

The highly stereoselective synthesis of a biologically active stagonolide-C has been described. The pivotal functionalities are derived from Barbier allylation, an epoxidation by m-CPBA, a chiral-auxiliary mediated acetate aldol addition, a 1,3-anti-reduction, a Sharpless kinetic resolution, a Yamaguchi macrolactonization, and ring-closing metathesis.

Full text of DOI:10.1016/j.tetasy.2012.07.015

Tetrahedron: Asymmetry 23 (2012) 1186–1197
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective total synthesis of stagonolide-C
⇑
Akkaladevi Venkatesham, Kommu Nagaiah
Division of Organic and Biomolecular Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 067, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 May 2012
Accepted 27 July 2012
The highly stereoselective synthesis of a biologically active stagonolide-C has been described. The pivotal
functionalities are derived from Barbier allylation, an epoxidation by m-CPBA, a chiral-auxiliary mediated
acetate aldol addition, a 1,3-anti-reduction, a Sharpless kinetic resolution, a Yamaguchi macrolactoniza-
tion, and ring-closing metathesis.
Ó 2012 Elsevier Ltd. All rights reserved.
OH
O
OH
O
1. Introduction
O
O
HO
Nonenolides have been isolated as secondary metabolites of
terrestrial and marine organisms, such as bacteria, fungi, and
plants, and exhibit various biological activities including antibacte-
rial, antifungal, phytotoxic, or enzyme-inhibitory effects.1 Their
scarcity coupled with the complexity of the natural material poses
a great challenge for synthetic chemist. Stagonolide A, a new non-
enolide, was first isolated and its chemical and biological charac-
terization from the liquid culture filtrate of Stagonospora cirsii (a
pathogen of Cirsium arvense) was carried out in 2007 by Berestet-
skiy et al.2 In 2008, Evidente et al. reported the isolation of five
new nonenolides from the same fungus, grown in solid culture.3
Considering their origin and structural similarity, these five new
nonenolides were named as stagonolides B–F, and were isolated
and characterized using spectroscopic methods. When tested by
a leaf disk puncture assay at a concentration of 1 mg/mL, these
compounds showed no toxicity to C. arVense or Sonchus arVensis,
whereas stagonolide A was highly toxic. Stagonolide C was isolated
from the same fungus and was proposed as a potential mycoherbi-
cide by causing necrotic lesions on leaves. Stagonolide A and stag-
onolide C 1 were weakly toxic to Colpoda steinii, a protozoan, when
tested at 0.05 mg/mL, with the other stagonolides being nontoxic.
All stagonolides shown in Figure 1 possess some common and
interesting structural features; the olefinic moiety with a well-de-
fined geometry as well as stereochemically pure hydroxyl append-
ages make them very challenging synthetic targets. The first total
synthesis of 1 was reported by Mohapatra et al.4 The target mole-
cule was achieved by assembling the key fragments by using
Sharpless epoxidation and intramolecular ring-closing metathesis
to construct the macrolide trans double bond. Jana et al.5 reported
the synthesis by using a metal–enzyme combined DKR strategy,
RCM. Qiao et al.6 also achieved the total synthesis of the key frag-
O
O
O
HO
HO
O
stagonolide C
stagonolide B
OH
stagonolide A
1
OH
OH
O
O
O
O
O
O
O
stagonolide D
(revised stricture)
stagonolide F
stagonolide E
O
OH
O
HO
O
OH
O
O
HO
OH
O
O
stagonolide I
stagonolide H
stagonolide G
(revised stricture)
Figure 1. Naturally occurring stagonolides.
ment from L-glutamic acid and D-glucono-1,5-lactone, followed by
Julia–Lythgoe olefination and Yamaguchi esterification. Recently
Yadav et al.7 reported a synthesis by using a Prins cyclization along
with alkene rearrangement and ring-closing metathesis as the key
steps. In continuation of our efforts8 toward the total synthesis of
biologically active natural products, we herein report the stereose-
lective total synthesis of stagonolide C 1 by employing a key inter-
⇑
Corresponding author. Fax: +91 40 27160387.
E-mail address: nagaiah@iict.res.in (K. Nagaiah).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.07.015

A. Venkatesham, K. Nagaiah / Tetrahedron: Asymmetry 23 (2012) 1186–1197
1187
mediate 1,3-anti diol by stereoselective epoxidation, chiral auxil-
2.1. Synthesis of alcohol fragment 12 by using D-mannitol
iary mediated aldol reaction, Sharpless kinetic resolution, Yamagu-
chi macrolactonization, and RCM for the construction of the central
nonenolide core with the required E-stereochemistry of the ring
olefin.
The synthesis of the alcohol fragment began with commercial
and inexpensive -mannitol. This was easily converted into (R)-
D
2,3-O-isopropylidene glyceraldehyde9 2 using a well-known proce-
dure. Treatment of (R)-glyceraldehyde 2 with allyl bromide in the
presence of zinc dust and aqueous ammonium chloride in THF at
0 °C to rt afforded the corresponding homoallyl alcohol10 3 as a
major diastereomer in favor of the anti-isomer in 88% yield. The
mixture of homo allylic alcohol 3 was then protected with a tert-
butylphenylsilyl group by using TBDPSCl, and imidazole in DCM
at rt for 12 h to afford an inseparable diastereomeric mixture of
anti and syn (82:18 by LCMS) 4 in 95% yield.11 The diastereomeric
mixture 4, upon treatment with m-CPBA in DCM at 0 °C to rt, pro-
duced the easily separable diastereomeric pair 5 and 5a (Scheme 2).
These pairs were separated by column chromatography to afford
the required diastereomeric pair 5 in 72.2% yield. The diastereo-
meric ratio of 5 was confirmed by LCMS analysis (91:9). According
to previous reports, the formation of the epoxide takes place anti to
the alkoxy group at the homoallylic position. Studies with benzyl
and para-methoxy benzyl groups produced the anti and syn prod-
ucts in a 2:1 ratio.12 The anti, syn ratio mainly depends on the
allylic 1,3 strain of the bulky TBDPS group and the homoallylic
epoxy interaction with m-CPBA.13
2. Results and discussion
Our synthetic approach for the synthesis of stagonolide-C 1 was
envisioned through the retrosynthetic route depicted in Scheme 1.
Accordingly we envisaged that stagonolide-C 1 could be accessed
from ester 29 with two terminal olefin moieties by ring closing
metathesis. Acid 27 and alcohol 19 were identified as the key cou-
pling partners for compound 28. Acid 27 can be prepared from
benzylic ether 24 generated from 1,4-butanediol. Alcohol 19 with
two stereocenters can be obtained from 12. Key intermediate 12
was obtained from 5 by regioselective reductive opening of the
epoxide ring, selective acetonide deprotection, and olefination.
Compound 5 can be prepared by epoxidation, Barbier allylation
of (R)-2,3-O-isopropylideneglyceraldehyde 2, which in turn can
be obtained from commercially available D-mannitol as the start-
ing material in a chiron pool approach. The key segment 12 can
also be achieved from acetate aldol adduct 16 by a 1,3-anti-selec-
tive reduction and a methyl Grignard reaction. Compound 16 can
be obtained by an aldol reaction between acrolein 15 and the tita-
nium enolate of N-acetyl-4-benzyl-thiazolidinethione 14, which in
The major diastereomeric pair 5 was used directly in further
steps. The major 1,3-anti-epoxide 5 underwent regioselective
reductive opening with DIBAL–H in DCM at ꢀ78 °C for 1 h to afford
turn can be prepared from
D-phenylalanine (Scheme 1).
OTBDPS
OTBDPS
OH
OH
OH
OH
O
O
O
O
O
O
1
28
29
OTBDPS
OH
OTBDPS
+
19
O
OH
27
OH
OH
12
BnO
HO
24
OH
S
OH
O
O
O
O
N
S
5
OH
OTBDPS
16
1,4 butane diol
Ph
O
OH
OH
HO
OH
OH
+
NH2
(R)-2-amino-3-
OH
D-mannitol
OH
phenylpropanoic acid
Scheme 1. Retrosynthetic analysis of stagonolide-C.

1188
A. Venkatesham, K. Nagaiah / Tetrahedron: Asymmetry 23 (2012) 1186–1197
OH
OH
O
O
Zn, allyl bromide
Ref 9
HO
O
O
OH
CHO
NH4Cl, THF, rt,
4 h, 88%;
OH
D-mannitol
OH
2
OH
3
O
O
O
O
TBDPSCl, imidazole,
O
m-CPBA, CH2Cl2
O
+
O
O
CH2Cl2, 0 °C to rt,
12 h, 95%;
0 °C to rt, 12 h, 88%.
OTBDPS
5
OTBDPS
4
OTBDPS
5a
82 : 18
91:9
Scheme 2.
sec-alcohol 6 in 82% yield.14 Subsequent silyl deprotection done by
using TBAF in THF at rt furnished 7 as separable diastereomers.
These diastereomers 7 were separated by flash column chromatog-
raphy to afford the major diastereomer 1,3-anti-7a isolated in
82.8% yield along with minor 7b 9.2% (Scheme 3).
In order to confirm the 1,3-syn and 1,3-anti relationships of 7a
and 7b, they were separated and converted into acetonides by
treatment with 2,2-DMP in the presence of cat. PPTS in DCM at
rt for 5 h to obtain the respective 1,3-anti- and 1,3-syn-diols 8a
and 8b both in 90% yield15 (Scheme 4).
O
O
O
O
2,2-DMP, CH2Cl2
PPTS (cat), rt,
5 h, 90%
O
O
OH
7a
OH
8a
major
O
O
O
O
2,2-DMP, CH2Cl2
The syn and anti relative configuration of the hydroxy groups
was confirmed based on Rychnovsky’s analogy. The stereochemis-
try of syn- and anti-1,3-acetonide was confirmed by the 13C NMR
chemical shifts16 of the six-membered acetonide. The 13C NMR
spectra of syn-1,3-diol acetonides 8b show an axial methyl group
around d 29.7 and an equatorial methyl group around d 19.5. 13C
NMR chemical shifts of ketal carbons follow a stereo regular pat-
tern where the syn-diol acetonides resonate above d 98.0, which
was consistent with those found in the chair confirmation, and
which is indicative of a 1,3-syn-diol disposition. Similarly the 13C
NMR spectrum of compound 8a showed the ketal carbon at d
100.0 and the acetonide methyl at d 25.1 and 24.93, thus confirm-
ing it to be an anti-diol in a twist boat confirmation, which is indic-
ative of a 1,3-anti-diol (Fig. 2). The major 1,3-anti-diol 7a was
protected with a tert-butylphenyl silyl group by using TBDPSCl
and imidazole in DCM at rt for 12 h to afford compound 9 in 92%
yield. After examining the deprotection of the acetonide under var-
ious reaction conditions (Table 1), we found that the deprotection
of acetonide could be conducted successfully using PPTS in MeOH
at 50 °C to afford diol 10 in 86% yield.17 Direct conversion of diol 10
to olefin 11 under TPP, imidazole, and iodine in toluene refluxed
for 2 days produced 10% of 11 along with a diiodo compound.
PPTS (cat), rt,
5 h, 90%
OH
OH
O
O
8b
7b
minor
Scheme 4.
The mixture was treated with Zn in DMF and refluxed to afford ole-
fin 11 in 85% yield.18 Removal of both silyl groups with TBAF in THF
at rt gave 1,3-diol 12 in 91% yield (Scheme 5), which proved to be
identical to the literature,19 when looking at the 1H and 13C NMR
data and the specific rotation.
2.2. Synthesis of alcohol fragment 12 by using D-phenylalanine
The synthesis of 12 was also achieved by an alternative method
according to Schemes 6–8. Our synthesis started from chiral auxil-
iary (R)-4-benzyl-thiazolidine-2-thione 13, which was prepared
from commercially available
D-phenylalanine following the re-
ported procedure.20 Compound 13, upon treatment with acetyl
chloride in the presence of n-BuLi at ꢀ78 °C for 1 h, afforded N-
acylated thiazolidinone 14 in 95% yield. Next, we started the syn-
thesis of the key intermediate 16 with an aldol reaction between
O
O
O
DIBAL-H, -78 °C,
CH2Cl2, 1h r, 82%;
O
O
O
TBAF, THF,
rt, 5 h, 92%
O
OTBDPS
OH
OH
TBDPSO
OH
OH
5
7
O
O
O
O
O
O
+
OH
OH
OH
OH
OH
7a
major
7b
minor
7
90 : 10
Scheme 3.

A. Venkatesham, K. Nagaiah / Tetrahedron: Asymmetry 23 (2012) 1186–1197
1189
Table 1
The more polar major syn-diastereomer 16 was easily separated
by flash column chromatography in 74.8% isolated yield along with
minor anti-diastereomer 16a (13.2% isolated yield). The syn-aldol
product 16 showed characteristic 1H NMR chemical shift signals
Removal of the acetonide group in 9 under different conditions
S. No.
Reaction conditions
Yielda (%)
1
2
3
4
5
6
7
8
CSA (0.1 equiv)/MeOH/rt/12 h
CSA (0.1 equiv)/MeOH/50 °C/12 h
p-TsOH (0.1 equiv)/MeOH/rt/6 h
PPTS (0.1 equiv)/MeOH/rt/12 h
PPTS (0.1 equiv)/MeOH/50 °C/12 h
80% aq AcOH (as solvent)/rt/12 h
80% aq AcOH (as solvent)/rt/36 h
50% aq CF3CO2H/CH2Cl2/rt/3 h
No reaction
60
Complex mixture
No reaction
86
55
40
65
for the
a-protons at d 3.66 (dd, J = 17.3, 3.0 Hz, 1H) for the less
shielded proton and at d 3.32 (dd, J = 17.3, 8.6 Hz, 1H) for the more
shielded proton along with other peaks in their respective posi-
tions, which confirmed the product formation. The less polar minor
anti-aldol product 16a showed characteristic 1H NMR chemical
shift signals for the corresponding
a-protons at d 3.62 (dd,
J = 17.3, 8.6 Hz, 1H) for the less shielded proton and at d 3.46–
3.37 (m, 1H) for the more shielded proton (Scheme 6).
Transamidation23 of the b-hydroxy amide 16 with N,O-dim-
ethylhydroxylamine hydrochloride and imidazole in CH2Cl2 for
12 h resulted in the corresponding Weinreb amide 17 in 92% yield.
Grignard reaction of Weinreb amide 17 with methylmagnesium io-
dide in ether at 0 °C to rt for 1 h furnished b-hydroxy ketone 18 in
86% yield24 (Scheme 7).
a
Isolated yield after column chromatography purification.
acrolein 15 and the titanium enolate of N-acetyl-4-benzyl-thiazoli-
dinethione 148f,21 Consequently, the corresponding acetate aldol
adducts 16 and 16a22 were obtained in 88% combined isolated
yield with high diastereoselectivity (16/16a = syn:anti = 85:15).
O
O
OH
O
O
PPTS(cat), MeOH
HO
TBDPSCl, imidazole
CH2Cl2, rt, 12 h, 92%
50 °C, 12 h, 86%
OH
OH
TBDPSO
OTBDPS
TBDPSO
10
OTBDPS
9
i) TPP, I2, imidazole,
toluene,reflux,
48 h, 10%
TBAF, THF
rt, 6h, 91%
ii) Zn, DMF, reflux,
6 h, 85%
TBDPSO
OTBDPS
OH
12
OH
Scheme 5.
O
29.7
Me
13C NMR
O
H
25.1
O
O
O
Me
98.0
O
O
Me
H
H
Me
Me
O
13C NMR
100.0
O
19.5
H
H
O
O
Me
24.93
O
O
O
H
O
H
O
H
8b
Chair conformation
(1,3-syn-diol)
8a
Twist-boat conformation
(1,3-anti-diol)
Figure 2. Characteristic conformations and 13C NMR chemical shift values for 1,3-syn- and anti-diols.
O
S
S
O
ref 20
n-BuLi, THF, 0 °C
OH
S
S
HN
N
H3C
then CH3COCl
1 h, 95%
NH2
(R)-2-amino-3-phenylpropanoic acid
14
13
Ph
Ph
S
OH
O
OH
O
S
TiCl4, DIPEA, CH2Cl2
N
+
N
S
S
-78 °C, 30 min., 88%
acrolein 15
16
syn-isomer
16a
anti-isomer
Ph
Ph
syn 85 : anti 15
Scheme 6.

1190
A. Venkatesham, K. Nagaiah / Tetrahedron: Asymmetry 23 (2012) 1186–1197
The anti-selective reduction of b-hydroxy ketone 18 using tetra-
ded primary alcohol 26 in 90% yield.30 Oxidation of the primary
alcohol 26 with PCC and NaOAc in dry CH2Cl2 at 0 °C to rt for 5 h
furnished the aldehyde in 90% yield. Oxidation of the aldehyde
using NaClO2 and NaH2PO4ꢁ2H2O in t-BuOH/H2O (3:1) and a few
drops of 2-methyl-2-butene at 0 °C to rt for 10 h (Pinnick’s proto-
col) furnished acid 27 in 92% yield (Scheme 10).
methylammonium triacetoxyborohydride25 in the solvent system
CH3CN/AcOH (4:1) at ꢀ20 °C for 5 h afforded the corresponding
1,3-diols 12 and 12a in 80% combined isolated yield with high dia-
stereoselectivity (12/12a = anti:syn = 95:5) as a separable mixture,
from which 76% of the major anti-diol 12 and minor syn-diol 12a
4% was isolated by column chromatography (Scheme 8). The spec-
troscopic and specific rotation data of the compound were in full
agreement with compound 12 prepared in the synthetic route as
shown in Scheme 5. This is a new method for the synthesis of 12
which is an important intermediate.
2.4. Coupling of fragments 19 and 27 for the total synthesis of
stagonolide-C
With the two key fragments 19 and 27 in hand our next task
was to couple the two fragments and conduct the critical RCM
reaction. Carboxylic acid 27 was coupled with alcohol 19 using
Yamaguchi’s protocol (2,4,6-trichlorobenzoyl chloride, Et3N, THF,
DMAP) to afford the dienoic ester 28 in 86% yield.31 Finally depro-
tection of both TBDPS functionalities was achieved by treating
compound 28 with HF/pyridine in pyridine and THF at rt for 8 h
to afford diol 29 in 84% yield.32 Compound 29 upon treatment with
Grubbs 2nd generation catalyst in DCM at reflux for 24 h afforded
target molecule stagonolide-C 1 in 68% yield (Scheme 11). The
structural integrity of the synthetic stagonolide-C 1 with the cor-
rect stereochemistry at the three stereogenic centers was con-
firmed by comparison of its spectroscopic (1H and 13C NMR) data
and specific rotation with literature data for the natural product
OH
OH
OH
OH
OH
O
Me4NHB(OAc)3
+
CH3CN-AcOH
-20 °C, 5 h, 80%
12a (4%)
12
(76 %)
18
Scheme 8.
Allylic alcohol 12 was selectively protected with a TBDPS group
by using 1 equiv of TBDPSCl, imidazole in DCM at 0 °C for 5 h affor-
ded the corresponding 19 and 20, which were obtained in 90%
combined isolated yield with high allylic selectivity26 (19/
20 = 65: 35). The more polar major compound 19 was easily sepa-
rated by flash column chromatography in 58.5% yield along with
minor compound5,27 20 (31.5% yield). Compound 20 could be con-
verted into its starting material 12 by simple desilylation using
TBAF (Scheme 9).
{synthetic: ½a 2D5
ꢂ
¼ þ43:9 (c 1.0, MeOH); Ref. 5: ½a D29
¼ þ44:4 (c
ꢂ
1.0, MeOH)}.
3. Conclusion
We have accomplished the total synthesis of stagonolide C 1
following a convergent approach involving a chiron pool synthesis.
The main highlight of our synthetic strategy involves the Barbier
allylation and subsequent epoxidation with m-CPBA. Chiral-auxil-
iary mediated acetate aldol addition, 1,3-anti-reduction, Sharpless
kinetic resolution, Yamaguchi macrolactonization, and Grubbs’
olefin metathesis reactions. This approach offers high stereoselec-
tivity and readily available inexpensive starting material at low
cost and simple experimental conditions, which makes it a useful
and attractive process for the total synthesis of stagonolide C 1
for biological evaluation.
2.3. Synthesis of the acid fragment
The other key fragment acid was synthesized by starting from
1,4-butane diol, which was protected with NaH and BnBr in the
presence of a catalytic amount of TBAI in THF at rt for 5 h to give
mono-benzyl ether 21 in 90% yield. The primary alcohol of 21
was oxidized with PCC in DCM at rt for 5 h to afford aldehyde 22
in 92% yield. Vinylation of aldehyde 22 using vinyl magnesium bro-
mide in THF, at ꢀ78 °C for 1 h afforded rac-vinyl carbinol 23 in 88%
yield. The rac-vinyl carbinol 23 upon Sharpless kinetic resolution28
using (ꢀ)-DET, Ti(OiPr)4, and TBHP in DCM for 6 h afforded the
enantiomerically enriched allylic alcohol 24 with 97% ee (deter-
mined by chiral HPLC) and 46% yield29, which was separated from
the epoxy product 24a by column chromatography. Protection of
alcohol 24 using TBDPSCl imidazole in DCM at 0 °C to rt for 8 h
afforded TBDPS ether 25 in 95% yield. Subsequent removal of the
benzyl group using DDQ in DCM–H2O (19:1) at reflux for 4 h affor-
4. Experimental
4.1. General
All solvents and reagents were used as received from suppliers.
TLC was performed on Merck Kiesel gel 60, F254 plates with the
OH
O
OH
O
OH
O
S
CH3MgI
NH(Me)OMe·HCl
CH3
N
N
ether, 0 °C to rt
1h., 86%
S
imidazole, CH2Cl2
r.t., 12 h, 92%
16
18
17
OCH3
Ph
Scheme 7.
TBDPSO
OH
OH
OH
OH
OTBDPS
TBDPSCl, imidazole,
CH2Cl2, 0 °C, 5 h, 90%
+
19
12
20
65 : 35
TBAF, THF, rt, 5 h, 95%
Scheme 9.

A. Venkatesham, K. Nagaiah / Tetrahedron: Asymmetry 23 (2012) 1186–1197
1191
O
PCC, DCM,
rt, 5 h, 92%
OH NaH, BnBr, TBAI (cat),
THF, 0 °C to rt, 5 h, 90%
BnO
OBn
HO
1,4-butane diol
H
HO
21
22
OH
OBn
OH
vinyl magnesium bromide,
THF, -78 °C, 1 h, 88%
(-)-DET, Ti(Oi-Pr)4 TBHP,
OBn
24
+
OH
CH2Cl2, 4 Å MS, -20 °C,
6h, 46%
23
OBn
O
24a
OH
OTBDPS
DDQ, DCM:H2O/ 19:1
reflux, 4 h, 90%
TBDPSCl, imidazole
CH2Cl2, rt, 8 h, 95%
OBn
OBn
24
25
(i) PCC, NaOAc, DCM
rt, 5 h, 90%
TBDPSO
OTBDPS
OH
O
OH
(ii) NaClO2, NaH2PO4,
2-methyl-2-butene,
t-BuOH, H2O, 0 °C to rt, 10 h, 92%
27
26
Scheme 10.
OH
OH
OH
HF/pyridine,
pyridine
OH
OTBDPS
OH
OTBDPS
OTBDPS
Grubbs-II, DCM
reflux, 24 h, 68%
O
OTBDPS 2,4,6-trichloro
O
THF, 0 °C to rt,
8 h, 84%
benzoyl chloride
+
O
O
HO
O
Et3N, THF, DMAP,
0 °C rt, 14h, 86%
29
OTBDPS
1
O
27
O
19
28
OTBDPS
O
O
30
Scheme 11.
layer thickness of 0.25 mm. Column chromatography was per-
formed on silica gel (100–200 mesh) using a gradient of ethyl ace-
tate and hexane as the mobile phase. IR spectra were recorded on a
Perkin–Elmer RX-1 FT-IR system. 1H NMR spectroscopic data were
collected at 300, 400, and 500 MHz, while 13C NMR were recorded
at 75, 100, and 125 MHz. 1H NMR spectral data are given as chem-
ical shifts in ppm followed by multiplicity (s—singlet; d—doublet;
t—triplet; q—quartet; m—multiplet), number of protons, and cou-
pling constants. 13C NMR chemical shifts are expressed in ppm.
Optical rotations were measured with a JASCO digital polarimeter.
HRMS spectroscopic data were collected using ORBITRAP high res-
olution mass spectrometer.
30 min. After being stirred for 1 h, the mixture was filtered through
a Celite pad. The filtrate was concentrated under reduced pressure.
The crude product was partitioned between water and ethyl ace-
tate (3 ꢃ 100 m). The combined organic layer was washed with
brine (1 ꢃ 100 mL) dried over anhydrous Na2SO4, and evaporated.
The residue was purified by column chromatography on silica gel
(100–200 mesh, eluent: 20% EtOAc in hexane) to afford
3
(17.46 g, 88%) as a colorless oil. ½a D25
ꢂ
¼ þ8:0 (c 1.3, CHCl3); IR
(neat): mmax 3460, 2988, 2895, 1375, 1215, 1065 cmꢀ1
;
1H NMR
(CDCl3, 400 MHz): d 5.92–5.78 (m, 1H), 5.19–5.09 (m, 2H), 4.05–
3.98 (m, 2H), 3.97–3.89 (m, 1H), 3.82–3.72 (m, 1H), 2.37–2.15
(m, 2H), 2.08 (d, J = 3.4 Hz, 1H), 1.43 (s, 3H), 1.37 (s, 3H); 13C
NMR (100 MHz, CDCl3): d 133.9, 118.3, 117.9, 109.4, 109.0, 78.4,
78.0, 71.5, 70.3, 66.0, 65.1, 38.2, 37.5, 26.6, 26.5, 25.2, 25.2; MASS
(ESIMS): m/z 195 (M+Na)+; HRMS (ESIMS): m/z calcd for
C9H16O3Na (M+Na)+ 195.0997, found 195.0998.
4.1.1. (R)-1-(2,2-Dimethyl-1,3-dioxolan-4-yl)but-3-en-1-ol 3
To a stirred solution of activated zinc (15.08 g, 230.6 mmol) in
100 mL of dry THF was added a solution of (R)-glyceraldehyde 2
(15 g, 115.3 mmol) in 150 mL of dry THF under nitrogen at 0 °C.
After 30 min, allyl bromide (19.97 mL, 230.6 mmol) was added
dropwise over 30 min at 0 °C. The reaction mixture was stirred
for 4 h at room temperature. After completion of the reaction
(monitored by TLC), the reaction was quenched by the slow addi-
tion of a saturated aqueous NH4Cl solution (30 mL) at 0 °C over
4.1.2. (R)-tert-Butyl(1-(2,2-dimethyl-1,3-dioxolan-4-yl)but-3-
enyloxy)diphenylsilane 4
To a stirred solution of alcohol 3 (10 g, 58.13 mmol) in anhy-
drous CH2Cl2 (150 mL) and imidazole (7.90 g, 116.3 mmol) at 0 °C
was added TBDPSCl (18.12 mL, 69.76 mmol) dropwise and stirred

1192
A. Venkatesham, K. Nagaiah / Tetrahedron: Asymmetry 23 (2012) 1186–1197
for 12 h at room temperature. The reaction mixture was quenched
with water and extracted with CH2Cl2 (3 ꢃ 100 mL). The combined
organic layers were washed with brine (1 ꢃ 100 mL), dried over
anhydrous Na2SO4, and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel
(100–200 mesh, eluent: 8% EtOAc in hexane) to afford 4 (22.64 g,
(ESIMS): m/z 429 (M+H)+, 451 (M+Na)+; HRMS (ESI): Calcd for
25H37O4Si (M+H)+ 429.2461, found 429.2441.
C
4.1.5. 1-(2,2-Dimethyl-1,3-dioxolan-4-yl)butane-1,3-diols 7a
and 7b
To an ice-cooled solution of 6 (11 g, 25.70 mmol) in dry THF
(80 mL) was added a 1 M solution of TBAF in THF (51.4 mL,
51.4 mmol) and stirred for 5 h at room temperature. The mixture
was diluted with H2O (20 mL) and extracted with EtOAc
(3 ꢃ 80 mL). The combined organic layer was washed with brine
(1 ꢃ 80 mL) and dried over anhydrous Na2SO4. The solvent was re-
moved under reduced pressure and the crude product was purified
by column chromatography on silica gel (100–200 mesh, 60%
EtOAc–hexane) to give the more polar anti-diol 7a (4.041 g,
82.8%) as a colorless oil and the minor syn-diol 7b (0.449 g, 9.2%)
as a colorless oil.
95%) as a colorless syrupy liquid. ½a D25
¼ þ19:5 (c 1.2, CHCl3); IR
ꢂ
(neat): mmax 3447, 3071, 2933, 2892, 2859, 1638, 1469, 1428,
1371, 1254, 1211, 1153, 1109, 1072, 997, 857, 821, 772, 740,
702, 610, 507 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.73–7.61 (m,
;
4H), 7.55–7.28 (m, 6H), 5.80–5.63 (m, 1H), 4.99–4.84 (m, 2H),
4.02 (q, J = 6.3 Hz, 1H), 3.89–3.80 (m, 2H), 3.78–3.63 (m, 1H),
2.32–1.97 (m, 2H), 1.28 (s, 3H), 1.27 (s, 3H), 1.06 (s, 9H); 13C
NMR (75 MHz, CDCl3): d 136.02, 135.97, 134.0, 133.8, 133.6,
129.71, 129.66, 127.6, 127.5, 127.4, 127.3, 117.5, 117.2, 77.8,
73.6, 72.9, 66.1, 65.3, 38.6, 37.5, 27.0, 26.5, 26.3, 25.4, 25.1, 19.4;
MASS (ESIMS): m/z 433 (M+Na)+; HRMS (ESI): Calcd for
C
25H34O3NaSi (M+Na)+ 433.2174, found 433.2176.
4.1.6. anti-Diol: (1S,3R)-10-((R)-2,2-dimethyl-1,3-dioxolan-4-
yl)butane-1,3-diol 7a
4.1.3. tert-Butyl((S)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-
(oxiran-2-yl)ethoxy)diphenylsilane 5
½
a 2D5
ꢂ
¼ ꢀ4:2 (c 1.0, CHCl3); IR (neat): mmax 3409, 2975, 2929,
1456, 1376, 1255, 1215, 1151, 1063, 971, 852, 514 cmꢀ1 1H
;
To a stirred solution of m-CPBA (21 g, 121.9 mmol) in CH2Cl2
(150 mL) was added a solution of alkene 4 (20 g, 48.78 mmol) in
CH2Cl2 (150 mL) and the mixture was stirred at room temperature
overnight. After dilution with CH2Cl2 (200 mL), a saturated solution
of NaHSO3 (50 mL) was added to the reaction mixture and then it
was washed with saturated NaHCO3 (aq) solution (3 ꢃ 120 mL)
and brine (1 ꢃ 150 mL) solution. The organic layer was dried over
anhydrous Na2SO4, filtered, and concentrated. The residue was
purified by column chromatography on silica gel (100–200 mesh,
eluent: 15% EtOAc in hexane) to afford 5 (14.99 g, 72.2%) as a col-
NMR (500 MHz, CDCl3): d 4.18 (dq, J = 12.4, 5.7 Hz, 1H), 4.07–
3.91 (m, 4H), 2.76 (br s, –OH, 1H), 2.14 (br s, –OH, 1H), 1.63 (t,
J = 5.7 Hz, 2H), 1.42 (s, 3H), 1.36 (s, 3H), 1.26 (d, J = 6.7 Hz, 3H);
13C NMR (75 MHz, CDCl3): d 109.1, 78.3, 69.1, 65.6, 65.5, 40.2,
26.5, 25.2, 23.7; MASS (ESIMS): m/z 213 (M+Na)+; HRMS (ESI):
Calcd for C9H18O4Na (M+Na)+ 213.1102, found 213.1110.
4.1.7. syn-Diol: (1S,3S)-10-((R)-2,2-dimethyl-1,3-dioxolan-4-
yl)butane-1,3-diol 7b
½
a 2D5
ꢂ
¼ þ22:5 (c 0.33, CHCl3); IR (neat): mmax 3417, 2980, 2930,
orless syrup. ½a D25
ꢂ
¼ þ8:5 (c 1.34, CHCl3); IR (neat): mmax 3448,
1455, 1377, 1255, 1215, 1153, 1064, 969, 849, 512 cmꢀ1 1H
;
3049, 2932, 2891, 2858, 1636, 1470, 1427, 1373, 1257, 1213,
NMR (300 MHz, CDCl3): d 4.23–3.90 (m, 5H), 3.11 (br s, –OH,
1H), 1.82–1.51 (m, 2H), 1.43 (s, 3H), 1.36 (s, 3H), 1.25 (d,
J = 6.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 109.1, 78.4, 72.5,
68.9, 65.3, 40.5, 26.5, 25.2, 24.1; MASS (ESIMS): m/z 213
(M+Na)+; HRMS (ESI): calcd for C9H18O4Na (M+Na)+ 213.1102,
found 213.1111.
1109, 1073, 854, 823, 740, 703, 609, 506 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): d 7.74–7.64 (m, 4H), 7.47–7.33 (m, 6H), 4.26–
4.08 (m, 1H), 3.99–3.85 (m, 2H), 3.76–3.58 (m, 1H), 3.07–2.91
(m, 1H), 2.67–2.56 (m, 1H), 2.27 (dd, J = 5.1, 2.6 Hz, 1H), 1.83–
1.57 (m, 2H), 1.30 (s, 6H), 1.06 (s, 9H); 13C NMR (75 MHz, CDCl3):
d
135.93, 135.89, 133.5, 133.4, 129.9, 129.8, 127.7, 127.60,
127.57, 127.5, 109.1, 78.3, 72.2, 66.7, 49.0, 47.4, 37.2, 27.0, 26.9,
26.4, 25.2, 19.4; MASS (ESIMS): m/z 427 (M+H)+, 449 (M+Na)+;
HRMS (ESI): Calcd for C25H34O4NaSi (M+Na)+ 449.2124, found
449.2121.
4.1.8. (4S,6R)-40-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2,2,6-
trimethyl-1,3-dioxane 8a
To a solution of diol 7a (0.1 g, 0.526 mmol) in dry CH2Cl2
(10 mL) was added 2,2-dimethoxy propane (0.077 mL, 0.63 mmol)
and a catalytic amount of PPTS. The homogeneous solution was
stirred for 4 h. Next, a saturated aq NaHCO3 solution (2 mL) was
added and the mixture was extracted with CH2Cl2 (3 ꢃ 10 mL).
The combined organic layer was washed with brine (1 ꢃ 10 mL),
dried over anhydrous Na2SO4, and concentrated. The crude residue
was purified by column chromatography on silica gel (100–200
mesh, 5% EtOAc–hexane) to afford 8a (0.109 g, 90%) as a colorless
4.1.4. (S)-4-(tert-Butyldiphenylsilyloxy)-4-((R)-2,2-dimethyl-
1,3-dioxolan-4-yl)butan-2-ol 6
To a stirred solution of epoxide 5 (14 g, 32.86 mmol) in CH2Cl2
(150 mL) at ꢀ78 °C, a solution of DIBAL-H in toluene (1.0 M,
115.0 mL, 115.0 mmol) was added dropwise and stirred for 1.0 h
at this temperature. The reaction was quenched by the addition
of MeOH (20 mL), followed by a saturated aqueous sodium potas-
sium tartrate solution (100 mL). It was warmed to 0 °C and stirred
for 1 h. The aqueous layer was extracted with CH2Cl2 (3 ꢃ 100 mL)
and washed with brine (1 ꢃ 100 mL), dried and concentrated in va-
cuo. The residue was purified by column chromatography on silica
gel (100–200 mesh, eluent: 20% EtOAc in hexane) to afford 6
liquid. ½a 2D5
¼ ꢀ37:6 (c 1.0, CHCl3); IR (neat): mmax 2986, 2935,
ꢂ
2891, 1453, 1376, 1223, 1180, 1131, 1073, 967, 933, 854,
520 cmꢀ1 1H NMR (300 MHz, CDCl3): d 4.08–3.90 (m, 3H), 3.83–
;
3.68 (m, 2H), 1.85 (ddd, J = 12.8, 9.0, 6.0 Hz, 1H), 1.64 (ddd,
J = 12.8, 9.0, 6.0 Hz, 1H), 1.40 (s, 3H), 1.33 (s, 9H), 1.19 (d,
J = 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 109.2, 100.0, 77.9,
67.8, 67.1, 62.5, 36.1, 26.6, 25.1, 24.93, 24.87, 21.5; MASS (ESIMS):
m/z 253 (M+Na)+; HRMS (ESI): Calcd for C12H22O4Na (M+Na)+
253.1415, found 253.1411.
(11.53 g, 82%) as a colorless syrup. ½a D25
¼ þ13:3 (c 0.64, CHCl3);
ꢂ
IR (neat): mmax 3451, 2962, 2932, 2858, 2077, 1637, 1468, 1427,
1374, 1258, 1213, 1108, 1070, 740, 507 cmꢀ1 1H NMR (300 MHz,
;
CDCl3): d 7.81–7.59 (m, 4H), 7.44–7.33 (m, 6H), 4.22–4.03 (m,
1H), 3.92 (ddd, J = 12.0, 8.3, 6.7 Hz, 1H), 3.84–3.64 (m, 2H), 3.54
(ddd, J = 8.3, 6.7 Hz, 1H), 2.63 (d, J = 2.5 Hz, 1H), 1.63 (dd, J = 8.3,
4.5 Hz, 2H), 1.28 (s, 3H), 1.25 (s, 3H), 1.05 (s, 9H), 0.97 (d,
J = 6.2 Hz, 2H), 0.94 (d, J = 6.3 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d 135.9, 133.4, 133.1, 130.0, 129.91, 129.86, 129.8, 127.7, 109.3,
78.6, 73.8, 67.7, 64.8, 43.9, 27.0, 26.3, 25.3, 23.8, 19.4; MASS
4.1.9. (4S,6S)-40-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2,2,6-
trimethyl-1,3-dioxane 8b
To a solution of diol 7b (0.1 g, 0.526 mmol) in dry CH2Cl2
(10 mL) was added 2,2-dimethoxy propane (0.077 mL, 0.63 mmol)
and a catalytic amount of PPTS. The homogeneous solution was
stirred for 4 h. Next a saturated aq NaHCO3 solution (2 mL) was

A. Venkatesham, K. Nagaiah / Tetrahedron: Asymmetry 23 (2012) 1186–1197
1193
added and the mixture was extracted with CH2Cl2 (3 ꢃ 10 mL). The
combined organic layer was washed with brine (1 ꢃ 10 mL), dried
over anhydrous Na2SO4, and concentrated. The crude residue was
purified by column chromatography on silica gel (100–200 mesh,
5% EtOAc–hexane) to afford 8b (0.109 g, 90%) as a colorless liquid.
in dry toluene (100 mL) iodine (11.31 g, 44.71 mmol) was added
portionwise through a condenser. The reaction mixture was then
refluxed for 2 days. The reaction mixture was quenched with satu-
rated sodium thiosulfate solution (50 mL) and EtOAc (50 mL). The
organic layer was separated and the aqueous layer was extracted
with EtOAc (2 ꢃ 50 mL), water (1 ꢃ 50 mL), brine (1 ꢃ 30 mL),
dried over Na2SO4, filtered, and concentrated in vacuo to give 11
at 10% along with diiodo compound as a black liquid that was used
in the next step without further purification. To a stirred solution
of crude mixture of 11 and a diiodo compound in dry DMF
(40 mL) at room temperature was added Zn dust (1.46 g,
22.34 mmol) and refluxed for 6 h. The mixture was then filtered
through a Celite pad. The filtrate was then partitioned between
water and ether (3 ꢃ 40 mL) The combined organic layer was
washed with brine (1 ꢃ 40 mL) dried over anhydrous Na2SO4,
and evaporated. The residue was purified by column chromatogra-
phy on silica gel (100–200 mesh, eluent: 10% EtOAc in hexane) to
½
a 2D5
ꢂ
¼ þ3:4 (c 3.1, CHCl3); IR (neat): mmax 3450, 2924, 2857, 1733,
1644, 1464, 1393, 1263, 1079, 407 cmꢀ1 1H NMR (500 MHz,
;
CDCl3): d 4.05 (td, J = 7.9, 3.0 Hz, 1H), 4.02–3.94 (m, 1H), 3.90–
3.83(m, 2H), 3.72 (ddd, J = 11.8, 7.9, 3.0 Hz, 1H), 1.73 (dt, J = 13.0,
3.0 Hz, 1H), 1.43 (s, 3H), 1.41 (s, 3H), 1.37 (s, 3H), 1.34 (s, 3H),
1.27–1.20 (m, 1H), 1.12 (d, J = 5.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d 108.8, 98.0, 78.0, 70.3, 66.8, 64.3, 35.4, 29.7, 26.4, 24.8,
21.8, 19.5; MASS (ESIMS): m/z 253 (M+Na)+; HRMS (ESI): Calcd
for C12H22O4Na (M+Na)+ 253.1415, found 253.1405.
4.1.10. (5S,7R)-50-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2,2,7,10,
10-pentamethyl-3,3,9,9-tetraphenyl-4,8-dioxa-3,9-
disilaundecane 9
afford 11 (5.62 g, 85%) as a colorless liquid. ½a D25
¼ þ12:8 (c 0.8,
ꢂ
To a stirred solution of alcohol 7a (3.7 g, 19.47 mmol) in anhy-
drous CH2Cl2 (80 mL) and imidazole (5.29 g, 77.89 mmol) at 0 °C
was added TBDPSCl (12.66 mL, 48.68 mmol) dropwise and stirred
for 8 h at room temperature. The reaction mixture was quenched
with water and extracted with CH2Cl2 (3 ꢃ 80 mL). The combined
organic layers were washed with brine (1 ꢃ 80 mL), dried over
anhydrous Na2SO4, and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel
(100–200 mesh, eluent: 5% EtOAc in hexane) to afford 9 (11.93 g,
CHCl3); IR (neat): mmax 3070, 2930, 2856, 1469, 1426, 1377, 1260,
1106, 1046, 992, 925, 886, 820, 737, 697, 609; 1H NMR
(300 MHz, CDCl3): d 7.72–7.54 (m, 8H), 7.49–7.26 (m, 12H), 5.51
(ddd, J = 17.3, 10.4, 7.3 Hz, 1H), 4.83–4.68 (m, 2H), 4.08–3.99 (m,
1H), 3.83–3.70 (m, 1H), 1.87–1.66 (m, 2H), 1.01 (s, 9H), 0.99 (s,
9H), 0.82 (d, J = 6.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 140.4,
135.91, 135.89, 135.81, 135.78, 134.8, 134.4, 134.3, 129.5, 129.4,
129.3, 127.41, 127.36, 127.3, 114.6, 72.9, 66.9, 48.1, 27.0, 23.3,
19.2, 19.1; MASS (ESIMS): m/z 615 (M+Na)+.
92%) as a colorless syrup. ½a D25
¼ þ13:2 (c 2.0, CHCl3); IR (neat):
ꢂ
mmax 3453, 3068, 2932, 2893, 2858, 1634, 1466, 1427, 1376,
4.1.13. (2R,4S)-Hex-5-ene-2,4-diol 12
1256, 1212, 1108, 1072, 999, 857, 820, 738, 702, 610, 506 cmꢀ1
;
To a stirred solution of 11 (3.6 g, 6.08 mmol) in dry THF (50 mL)
at 0 °C was added a 1 M solution of TBAF in THF (24.32 mL,
24.32 mmol) and stirred for 6 h at room temperature. The mixture
was diluted with H2O (25 mL) and extracted with EtOAc
(3 ꢃ 50 mL). The combined organic layer was washed with brine
(1 ꢃ 50 mL) and dried over anhydrous Na2SO4. The solvent was re-
moved under reduced pressure and the crude product was purified
by column chromatography on silica gel (100–200 mesh, 60%
EtOAc–hexane) to afford 12 (0.642 g, 91%) as a colorless oil.
1H NMR (300 MHz, CDCl3): d 7.76–7.54 (m, 8H), 7.47–7.26 (m,
12H), 4.00–3.80 (m, 2H), 3.78–3.59 (m, 3H), 1.50–1.40 (m, 1H),
1.33 (s, 3H), 1.22 (s, 3H), 1.01 (s, 9H), 0.94 (s, 9H), 0.91–0.78 (m,
1H), 0.63 (d, J = 6.0 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 136.0,
135.9, 135.7, 134.7, 134.3, 129.6, 129.5, 129.4, 127.5, 127.4,
108.9, 78.9, 71.1, 67.1, 65.4, 45.4, 27.0, 26.9, 26.3, 25.2, 23.2,
19.3, 19.1; MASS (ESIMS): m/z 689 (M+Na)+; HRMS (ESI): Calcd
for C41H54O4NaSi2 (M+Na)+ 689.3458, found 689.3435.
½
a 2D5
ꢂ
¼ ꢀ3:2 (c 0.45, CHCl3); IR (neat): mmax 3336, 3084, 2962,
4.1.11. (2R,3S,5R)-3,5-Bis(tert-butyldiphenylsilyloxy)hexane-
1,2-diol 10
2922, 2852, 1459, 1420, 1376, 1299, 1218, 1120, 1080, 1042,
1018, 986, 923, 856.51, 827, 771 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d 5.89 (ddd, J = 17.3, 10.5, 5.2 Hz, 1H), 5.27 (dt, J = 17.3, 1.5 Hz, 1H),
5.12 (dt, J = 10.5, 1.5 Hz, 1H), 4.48–4.38 (m, 1H), 4.19–4.04 (m, 1H),
To a stirred solution of compound 9 (10 g, 15.01 mmol) in
MeOH (60 mL) was added PPTS (0.377 g, 10 mol %) and then heated
at 50 °C overnight. After completion of the reaction, a saturated aq.
NaHCO3 solution (10 mL) was added to the reaction mixture and
then concentrated under reduced pressure and extracted with
CH2Cl2 (3 ꢃ 80 mL). The combined organic layers were washed
with water (1 ꢃ 80 mL), brine (1 ꢃ 80 mL), dried over Na2SO4,
and concentrated. The crude residue was purified by column chro-
matography on silica gel (15% EtOAc/hexane) to give 10 (8.08 g,
3.27 (br s, –OH, 2H), 1.77–1.56 (m, 2H), 1.22 (d, J = 6.3 Hz, 3H); 13
C
NMR (75 MHz, CDCl3): d 140.7, 114.5, 70.6, 65.3, 43.9, 23.7; MASS
(ESIMS): m/z 139 (M+Na)+; HRMS (ESI): Calcd for C6H12O2Na
(M+Na)+ 139.07295, found 139.07317.
Alternatively, to a stirred solution of Me4NHB(OAc)3 (4.58 g,
17.55 mmol) in dry CH3CN (15 mL) and AcOH (5 mL) at ꢀ40 °C un-
der nitrogen atmosphere was added slowly 18 (0.40 g, 3.51 mmol)
in dry CH3CN (5 mL) via cannula. Next, the clear reaction mixture
was continued to stir at ꢀ20 °C for 5 h. After completion of the
reaction, the reaction mixture was quenched with saturated aq.
Rochelle’s salt (10 mL) and EtOAc (20 mL). The organic layer was
separated and the aqueous layer was extracted with EtOAc
(2 ꢃ 20 mL). The combined organic extracts were washed with sat-
urated aq NaHCO3 (2 ꢃ 10 mL), water (2 ꢃ 10 mL), brine
(2 ꢃ 10 mL), dried over Na2SO4, filtered, and concentrated. The res-
idue was purified by column chromatography on silica gel (100–
200 mesh, eluent: 55–60% EtOAc in hexane) to give major anti-diol
12 (0.308 g, 76%) as a colorless oil, and minor syn-diol 12a (0.016 g,
4%) as a colorless oil.
86%) as a colorless liquid. ½a D25
¼ ꢀ3:1 (c 1.05, CHCl3); IR (neat):
ꢂ
mmax 3496, 3070, 2929, 2856, 1469, 1427, 1389, 1189, 1108,
1001, 822, 772, 738, 702, 611 cmꢀ1 1H NMR (300 MHz, CDCl3): d
;
7.73–7.62 (m, 8H), 7.49–7.32 (m, 12H), 4.28–4.17 (m, 1H), 4.09–
4.00 (m, 1H), 3.79 (dd, J = 6.0, 2.2 Hz, 2H), 3.65–3.57 (m, 1H),
3.44 (d, J = 2.2 Hz, 1H), 2.66 (d, J = 3.7 Hz, 1H), 1.74–1.66 (m, 2H),
1.58 (1.09, d, J = 6.3 Hz, 3H), 1.06 (s, 9H), 1.04 (s, 9H); 13C NMR
(75 MHz, CDCl3): d 135.9, 135.8, 135.5, 134.0, 133.9, 133.3, 133.1,
129.8, 129.7, 127.8, 127.7, 127.5, 74.2, 69.2, 68.8, 64.7, 39.9, 27.0,
26.9, 22.6, 19.2, 19.1; MASS (ESIMS): m/z 650 (M+Na)+; HRMS
(ESI): Calcd for C38H50O4NaSi2 (M+Na)+ 649.3145, found 649.3172.
4.1.12. (5R,7S)-2,2,5,10,10-Pentamethyl-3,3,9,9-tetraphenyl-7-
vinyl-4,8-dioxa-3,9-disilaundecane 11
To a refluxing solution of diol 10 (7.0 g, 11.18 mmol), imidazole
(1.90 g, 28 mmol), and triphenylphosphine (11.73 g, 44.71 mmol)
4.1.14. syn-Diol:(2S,4S)-Hex-5-ene-2,4-diol 12a
1H NMR (300 MHz, CDCl3): d 5.88 (ddd, J = 17.2, 10.4, 5.9 Hz, 1H),
5.25 (dt, J = 17.2, 1.4 Hz, 1H), 5.10 (dt, J = 10.4, 1.4 Hz, 1H), 4.45–4.31

1194
A. Venkatesham, K. Nagaiah / Tetrahedron: Asymmetry 23 (2012) 1186–1197
(m, 1H), 4.20–3.99 (m, 1H), 2.96 (br s, –OH, 2H), 1.69–1.59 (m, 2H),
1.22 (d, J = 6.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 140.6, 114.4,
73.7, 68.5, 44.6, 24.0; MASS (ESIMS): m/z 139 (M+Na)+.
4.1.18. (R)-1-((R)-4-Benzyl-2-thioxothiazolidin-3-yl)-3-hydroxy
pent-4-en-1-one
4.1.18.1. Anti-diastereomer 16a.
CHCl3); IR (neat): mmax 3458, 3026, 2924, 1690, 1494, 1453, 1342,
1291, 1257, 1163, 1137, 1042, 999, 925, 772, 748, 702 cmꢀ1 1H
½
a 2D5
ꢂ
¼ ꢀ114:5 (c 0.9,
4.1.15. (R)-1-(4-Benzyl-2-thioxothiazolidin-3-yl)ethanone 14
To a stirred solution of 13 (2.75 g, 13.2 mmol) in dry THF
(30 mL) at 0 °C under a nitrogen atmosphere was added slowly
n-BuLi (6.3 mL, 15.7 mmol, 2.5 M) and stirred for 30 min at the
same temperature. Next, acetyl chloride (1.24 g, 15.7 mmol) was
slowly added at 0 °C and stirred for 1 h. After completion of the
reaction, the reaction mixture was quenched with saturated aq.
NH4Cl (15 mL). The organic layer was separated and the aqueous
layer extracted with EtOAc (3 ꢃ 25 mL). The combined organic lay-
ers were washed with water (2 ꢃ 30 mL), brine (2 ꢃ 30 mL), dried
over Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel
(100–200 mesh, eluent: 5% EtOAc in hexane) to afford 14 (3.13 g,
;
NMR (500 MHz, CDCl3): d 7.41–7.23 (m, 5H), 5.94 (ddd, J = 17.3,
10.5, 5.7 Hz, 1H), 5.45–5.38 (m, 1H), 5.35 (d, J = 17.3, 1.9 Hz, 1H),
5.18 (d, J = 10.5, 1.9 Hz, 1H), 4.65–4.58 (m, 1H), 3.62 (dd, J = 17.3,
8.8 Hz, 1H), 3.46–3.37 (m, 2H), 3.22 (dd, J = 12.4, 2.8 Hz, 1H), 3.12
(br s, –OH, 1H), 3.04 (dd, J = 12.4, 10.5 Hz, 1H), 2.90 (d,
J = 11.5 Hz, 1H); 13C NMR (75 MHz, CDCl3): d 201.4, 172.7, 138.7,
136.2, 129.3, 128.9, 127.2, 115.4, 69.1, 68.2, 45.1, 36.7, 31.9; MASS
(ESIMS): m/z 308 (M+H)+, 330 (M+Na)+.
4.1.19. (S)-3-Hydroxy-N-methoxy-N-methylpent-4-enamide 17
To a stirred solution of 16 (1.6 g, 5.21 mmol) in dry CH2Cl2
(50 mL) at room temperature under a nitrogen atmosphere was
added imidazole (1.77 g, 26.05 mmol) and Weinreb salt (1.51 g,
15.63 mmol) and continued to stir for 12 h at the same tempera-
ture. After completion of the reaction, the reaction mixture was
quenched with saturated aq. NH4Cl (15 mL). The organic layer
was separated and the aqueous layer was extracted with CH2Cl2
(3 ꢃ 50 mL). The combined organic extracts were washed with
water (1 ꢃ 50 mL), brine (1 ꢃ 50 mL), dried over Na2SO4, filtered,
and concentrated. The residue was purified by column chromatog-
raphy on silica gel (100–200 mesh, eluent: 35% EtOAc in hexane) to
95%) as bright yellow crystals. ½a D25
ꢂ
¼ ꢀ210:0 (c 1.0, CHCl3); IR
(neat): mmax 2925, 1701, 1362, 1215, 1018, 701 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): d 7.35–7.21 (m, 5H, Ar-H), 5.37–5.29 (m, 1H),
3.36 (ddd, J = 11.3, 7.5, 0.9 Hz, 1H), 3.21 (dd, J = 13.2, 3.7 Hz, 1H),
3.02 (dd, J = 10.3, 0.9 Hz, 1H), 2.87 (d, J = 11.3 Hz, 1H), 2.78 (s,
3H); 13C NMR (75 MHz, CDCl3): d 201.4, 170.6, 136.4, 129.3,
128.8, 127.1, 68.1, 36.6, 31.7, 27.0; MASS (LCMS): m/z 274 (M+Na)+.
4.1.16. 1-(4-Benzyl-2-thioxothiazolidin-3-yl)-3-hydroxypent-4-
en-1-ones 16 and 16a
afford 17 (0.762 g, 92%) as a colorless liquid. ½a D25
¼ ꢀ28:9 (c 0.55,
ꢂ
To a stirred solution of 14 (2.0 g, 7.96 mmol) in dry CH2Cl2
(40 mL) at 0 °C under a nitrogen atmosphere was added drop-
wise TiCl4 (1.04 mL, 9.56 mmol) and stirred for 5 min. Next, a
solution of DIPEA (1.66 mL, 9.56 mmol) in dry CH2Cl2 (10 mL)
was added via cannula. The reaction mixture was cooled to
ꢀ78 °C and continued to stir for 30 min. Next a solution of acro-
lein 15 (0.44 g, 7.96 mmol) in dry CH2Cl2 (15 mL) was trans-
ferred via cannula to the reaction mixture, which was then
stirred for 30 min at ꢀ78 °C, then slowly warmed to 0 °C, and
stirred for another 30 min. After completion of the reaction,
CHCl3); IR (neat): mmax 3419, 2970, 2935, 1634, 1425, 1387, 1178,
1100, 1037, 994, 925, 780, 678 cmꢀ1 1H NMR (500 MHz, CDCl3):
;
d 5.92 (ddd, J = 17.3, 10.5, 5.5 Hz, 1H), 5.32 (dt, J = 17.3, 1.4 Hz,
1H), 5.16 (dt, J = 10.5, 1.4 Hz, 1H), 4.60–4.54 (m, 1H), 3.79 (br s, –
OH, 1H), 3.69 (s, 3H), 3.20 (s, 3H), 2.72 (d, J = 16.1 Hz, 1H), 2.60
(dd, J = 16.1, 9.1 Hz, 1H); 13C NMR (75 MHz, CDCl3): d 173.2,
139.1, 115.0, 68.8, 61.3, 38.0, 31.8; MASS (ESIMS): m/z 160
(M+H)+, 182 (M+Na)+; HRMS (ESI): Calcd for C7H14O3N (M+H)+
160.09682, found 160.09713.
the reaction mixture was quenched with the addition of
a
4.1.20. (S)-4-Hydroxyhex-5-en-2-one 18
half-saturated aq NH4Cl (20 mL) while stirring and then allowed
to return to room temperature and diluted with CH2Cl2 (60 mL).
The organic layer was separated and the aqueous layer was ex-
tracted with CH2Cl2 (3 ꢃ 60 mL). The combined organic extracts
were washed with half-saturated aq NH4Cl (2 ꢃ 40 mL), water
(2 ꢃ 40 mL), brine (2 ꢃ 40 mL), dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified
by flash column chromatography on silica gel (100–200 mesh,
eluent: 15–20% EtOAc in hexane) to afford the more polar major
syn-diastereomer 16 (1.830 g, 74.8%) as a yellow oil along with
less polar minor anti-diastereomer 16a (0.322 g, 13.2%) as a yel-
low oil.
To a stirred solution of 17 (0.70 g, 4.40 mmol) in dry ether
(20 mL) at 0 °C under a nitrogen atmosphere was slowly added a
solution of methylmagnesium iodide (11 mL, 11 mmol, 1 M solu-
tion in ether). The reaction mixture was continued to stir for 1 h
at room temperature. After completion of the reaction, the reaction
mixture was quenched with saturated aq. NH4Cl (10 mL). The or-
ganic layer was separated and the aqueous layer was extracted
with ether (3 ꢃ 20 mL). The combined organic extracts were
washed with water (1 ꢃ 20 mL), brine (1 ꢃ 20 mL), dried over
Na2SO4, filtered, and concentrated. The residue was purified by col-
umn chromatography on silica gel (100–200 mesh, eluent: 10%
EtOAc in hexane) to yield b-hydroxy ketone 18 (0.431 g, 86%) as
a colorless oil. ½a D25
ꢂ
¼ ꢀ180:0 (c 0.15, CHCl3); 1H NMR (300 MHz,
4.1.17. (S)-1-((R)-4-Benzyl-2-thioxothiazolidin-3-yl)-3-hydroxy
CDCl3): d 5.86 (ddd, J = 17.3, 10.5, 6.0 Hz, 1H), 5.30 (dt, J = 17.3,
1.5 Hz, 1H), 5.15 (dt, J = 10.5, 1.5 Hz, 1H), 4.65–4.48 (m, 1H), 2.96
(br s, –OH, 1H), 2.72–2.65 (m, 2H), 2.20 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 209.0, 138.8, 115.1, 68.5, 49.5, 30.8; MASS
(ESIMS): m/z 137 (M+Na)+.
pent-4-en-1-one
4.1.17.1. Syn-diastereomer 16.
IR (neat): mmax 3437, 3026, 2923, 1690, 1494, 1452, 1342, 1290,
1255, 1163, 1042, 998, 925, 772, 748, 701 cmꢀ1 1H NMR
½
a 2D5
ꢂ
¼ ꢀ166:4 (c 0.8, CHCl3);
;
(300 MHz, CDCl3): d 7.41–7.24 (m, 5H), 5.95 (ddd, J = 17.3, 10.5,
5.2 Hz, 1H), 5.44–5.30 (m, 2H), 5.17 (dt, J = 10.5, 1.4 Hz, 1H),
4.72–4.66 (m, 1H), 3.66 (dd, J = 17.3, 3.0 Hz, 1H), 3.41 (dd,
J = 12.0, 7.5 Hz, 1H), 3.32 (dd, J = 17.3, 8.6 Hz, 1H), 3.23 (dd,
J = 13.2, 3.7 Hz, 1H), 3.05 (dd, J = 13.2, 10.5 Hz, 1H), 2.90 (d,
J = 12.0 Hz, 1H), 2.88–2.77 (br s, –OH, 1H); 13C NMR (75 MHz,
CDCl3): d 201.3, 172.4, 138.7, 136.3, 129.3, 128.8, 127.2, 115.3,
68.6, 68.2, 45.4, 36.7, 32.0; MASS (ESIMS): m/z 308 (M+H)+, 330
(M+Na)+; HRMS (ESI): Calcd for C15H17NO2NaS2 (M+Na)+
330.0602, found 330.0598.
4.1.21. (2R,4S)-4-(tert-Butyldiphenylsilyloxy)hex-5-en-2-ol 19
To a stirred solution of diol 12 (0.50 g, 4.31 mmol) in anhydrous
CH2Cl2 (20 mL) and imidazole (0.35 g, 5.17 mmol) at 0 °C was
added TBDPSCl (1.12 mL, 3.45 mmol) dropwise and stirred for 5 h
at the same temperature. The reaction mixture was quenched with
water and extracted with CH2Cl2 (3 ꢃ 20 mL). The combined or-
ganic layers were washed with water (1 ꢃ 20 mL), brine
(1 ꢃ 20 mL), dried over anhydrous Na2SO4, and concentrated under
reduced pressure. The residue was purified by column chromatog-

A. Venkatesham, K. Nagaiah / Tetrahedron: Asymmetry 23 (2012) 1186–1197
1195
raphy on silica gel (100–200 mesh, eluent: 8% EtOAc in hexane) to
4.1.25. 6-(Benzyloxy)hex-1-en-3-ol 23
afford 19 (0.890 g, 58.5%) as a colorless syrup. ½a D25
ꢂ
¼ ꢀ5:3 (c 1.3,
To a stirred solution of aldehyde 22 (8.0 g, 44.94 mmol) ta-
ken in 100 mL of anhydrous THF, a solution of vinyl magnesium
bromide (1 M solution in THF, 67.41 mL, 67.41 mmol) was
added at ꢀ78 °C. The resulting mixture was stirred at ꢀ78 °C
for 1 h, quenched by the addition of aq NH4Cl solution, and
then warmed to rt. The aqueous layer was separated and ex-
tracted with EtOAc (3 ꢃ 100 mL), and the combined organic
layer was washed with brine (1 ꢃ 100 mL), dried over anhy-
drous Na2SO4, and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel
(100–200 mesh, eluent: 15% EtOAc in hexane) to give 23
(8.147 g, 88%) as a colorless liquid, which was used without
characterization.
CHCl3); IR (neat): mmax 3497, 2924, 2854, 1463, 1427, 1216, 1109,
996, 924, 821, 771, 739, 702, 611 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d 7.79–7.63 (m, 4H), 7.47–7.34 (m, 6H), 5.81 (ddd, J = 17.3, 10.5,
6.0 Hz, 1H), 5.23 (dt, J = 17.3, 1.5 Hz, 1H), 5.06 (dt, J = 10.5, 1.5 Hz,
1H), 4.54–4.38 (m, 1H), 4.24–4.07 (m, 1H), 3.02 (d, J = 2.8 Hz,
1H), 1.73 (ddd, J = 13.7, 9.6, 3.9 Hz, 1H), 1.65–1.54 (m, 1H), 1.12
(d, J = 6.3 Hz, 3H), 1.06 (s, 9H); 13C NMR (75 MHz, CDCl3): d
139.5, 136.0, 135.9, 133.3, 133.2, 129.9, 129.8, 127.7, 127.5,
115.0, 73.8, 64.6, 44.9, 27.0, 23.4, 19.2; MASS (ESIMS): m/z 355
(M+H)+; HRMS (ESI): Calcd for C22H31O2Si (M+H)+ 355.20878,
found 355.20931.
4.1.22. (3S,5R)-5-(tert-Butyldiphenylsilyloxy)hex-1-en-3-ol 20
Compound 20 was obtained (0.480 g, 31.5%) as a colorless li-
4.1.26. (S)-6-(Benzyloxy)hex-1-en-3-ol 24
quid. ½a 2D5
ꢂ
¼ þ5:0 (c 1.4, CHCl3); IR (neat): mmax 3429, 2960, 2858,
To a suspension of powered molecular sieves (4 Å, 800 mg) in
dry CH2Cl2 (80 mL), Ti(OiPr)4 (5.04 mL, 16.95 mmol) and (ꢀ)-
DIPT (4.21 mL, 20.34 mmol) were added sequentially at ꢀ20 °C.
After stirring for 30 min, allyl alcohol 23 (7 g, 33.9 mmol) in
dry CH2Cl2 (80 mL) was added and stirring was continued for an-
other 30 min at the same temperature. Then TBHP (4 M, 4.23 mL,
16.95 mmol) was added and after stirring for another 6 h at the
same temperature, the reaction mixture was quenched by the
addition of water (80 mL). It was then kept at room temperature
and stirred for 30 min. After re-cooling to 0 °C, an aqueous solu-
tion of NaOH (30% w/v, 50 mL saturated with brine) was added
and the mixture was stirred at 0 °C for 1 h. The reaction mixture
was extracted with CH2Cl2 (2 ꢃ 80 mL). The combined organic
extracts were washed with brine (1 ꢃ 80 mL), dried over anhy-
drous Na2SO4, and concentrated in vacuo. The residue was puri-
fied by column chromatography on silica gel (100–200 mesh:
eluent 15% EtOAc/hexane) to give 24 (3.22 g, 46%) as a colorless
1468, 1426, 1378, 1219, 1109, 994, 870, 821, 772, 703, 609,
505 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.70–7.60 (m, 4H), 7.48–
;
7.29 (m, 6H), 5.76 (ddd, J = 17.2, 10.4, 5.5 Hz, 1H), 5.17 (dt,
J = 17.2, 1.6 Hz, 1H), 5.04 (dt, J = 10.4, 1.6 Hz, 1H), 4.44–4.33 (m,
1H), 4.21–4.08 (m, 1H), 2.69 (d, J = 2.3 Hz, 1H), 1.75–1.50 (m,
2H), 1.11 (d, J = 6.3 Hz, 3H), 1.06 (s, 9H); 13C NMR (75 MHz, CDCl3):
d 141.1, 135.93, 135.90, 134.0, 133.5, 129.9, 129.8, 127.8, 127.7,
127.6, 113.9, 69.5, 68.2, 45.1, 27.1, 23.0, 19.3; MASS (ESIMS): m/z
377 (M+Na)+; HRMS (ESI): Calcd for C22H30O2NaSi (M+Na)+
377.1912, found 377.1924.
4.1.23. 4-(Benzyloxy)butan-1-ol 21
To a suspension of NaH (4.44 g, 111.1 mmol, 60% w/v dispersion
in mineral oil) in anhydrous THF (50 mL) was added dropwise a
solution of 1,4-butane diol (10.00 g, 111.1 mmol)) in anhydrous
THF (100 mL) at 0 °C and continued to stir for the next 30 min at
room temperature. At 0 °C, benzyl bromide (13.19 mL,
111.1 mmol) was added and stirred for 4 h at room temperature
with frequent monitoring of the progress of reaction by TLC. The
reaction mixture was quenched by small crushed ice flakes until
a clear solution (biphasic) had formed. The reaction mixture was
then extracted with EtOAc (3 ꢃ 100 mL). The organic extracts were
washed with water (1 ꢃ 100 mL), brine (1 ꢃ 100 mL), and dried
over anhydrous Na2SO4 and concentrated under reduced pressure.
Purification of the crude product by column chromatography on
silica gel (100–200 mesh, eluent: 20% EtOAc/hexane) afforded
mono-protected alcohol 21 (17.9 g, 90%) as a colorless oil. IR (neat):
mmax 3685, 3019, 2946, 2868, 2400, 1519, 1423, 1099, 1045, 929,
syrup. ½a 2D5
¼ þ2:5 (c 1.0, CHCl3); IR (neat): mmax 3416, 3073,
ꢂ
3030, 2929, 2859, 1487, 1451, 1363, 1273, 1205, 1099, 991,
920, 739, 697, 609 cmꢀ1 1H NMR (300 MHz, CDCl3): 7.43–7.23
;
(m, 5H), 5.87 (ddd, J = 17.2, 10.4, 5.9 Hz, 1H), 5.23 (d, J = 17.2,
1.3 Hz, 1H), 5.11 (d, J = 10.4, 1.3 Hz, 1H), 4.52 (s, 2H), 4.20–
4.07 (m, 1H), 3.52 (t, J = 5.9 Hz, 2H), 2.37 (br s, –OH, 1H),
1.81–1.54 (m, 4H); 13C NMR (75 MHz, CDCl3): d 141.0, 138.1,
128.3, 127.62, 127.57, 114.4, 72.9, 72.6, 70.3, 34.2, 25.7; MASS
(ESIMS): m/z 229 (M+Na)+; HRMS (ESI): Calcd for C13H18O2Na
(M+Na)+ 229.1204, found 229.1205.
4.1.27. (S)-(6-(Benzyloxy)hex-1-en-3-yloxy)(tert-butyl)diphenyl
silane 25
848, 757, 669, 626, 413 cmꢀ1 1H NMR (300 MHz, CDCl3) d 7.35–
;
7.20 (m, 5H), 4.49 (s, 2H), 3.60 (t, J = 5.8 Hz, 2H), 3.49 (t,
J = 5.8 Hz, 2H), 2.24 (br s, –OH, 1H), 1.77–1.58 (m, 4H); 13C NMR
(75 MHz, CDCl3): d 138.0, 128.2, 127.5, 127.4, 77.2, 72.7, 70.0,
61.9, 29.6, 26.3; MASS (EIMS): m/z 180 (M)+.
To a stirred solution of alcohol 24 (2.0 g, 9.7 mmol) in anhy-
drous CH2Cl2 (50 mL) and imidazole (1.32 g, 19.41 mmol) at 0 °C
was added TBDPSCl (3.03 mL, 11.65 mmol) dropwise and stirred
for 8 h at room temperature. The reaction mixture was quenched
with water and extracted with CH2Cl2 (3 ꢃ 50 mL). The com-
bined organic layers were washed with water (1 ꢃ 50 mL), brine
(1 ꢃ 50 mL), dried over anhydrous Na2SO4, and concentrated un-
der reduced pressure. Purification by column chromatography
using silica gel (100–200 mesh, 2% EtOAc/hexane) afforded 25
4.1.24. 4-(Benzyloxy)butanal 22
To stirred solution of alcohol 21 (10 g, 55.5 mmol) in dichloro-
methane (150 mL) at 0 °C were added pyridinium chlorochromate
(17.96 g, 83.33 mmol) and Celite (17.96 g) and stirred at room tem-
perature for 5 h. Diethyl ether (100 mL) was added and the reac-
tion mixture was filtered through a small pad of Celite and silica
gel. The filtered cake was washed thoroughly with ether
(2 ꢃ 150 mL) and the filtrate was concentrated under reduced
pressure. After flash column chromatography on silica gel (100–
200 mesh, eluent: 8% EtOAc in hexane) aldehyde 22 (9.09 g, 92%)
was obtained as a colorless liquid. 1H NMR (400 MHz, CDCl3): d
9.76 (t, J = 1.5 Hz, 1H), 7.36–7.17 (m, 5H), 4.46 (s, 2H), 3.47 (q,
J = 5.1 Hz, 2H), 2.53 (td, J = 7.0, 1.5 Hz, 2H), 1.92 (ddd, J = 13.0,
7.0, 6.0 Hz, 2H); 13C NMR (75 MHz, CDCl3): d 201.3, 138.2, 128.4,
127.6, 73.0, 69.0, 41.0, 22.6; MASS (EIMS): m/z 178 (M)+.
(4.09 g, 95%) as a colorless syrup ½a D25
¼ þ16:5 (c 1.0, CHCl3);
ꢂ
IR (neat): mmax 3448, 3069, 2932, 2857, 1642, 1455, 1426,
1392, 1361, 1199, 1108, 1031, 923, 821, 737, 701, 612,
507 cmꢀ1
; d 7.67–7.56 (m, 4H),
1H NMR (300 MHz, CDCl3):
7.41–7.16 (m, 11H), 5.75 (ddd, J = 16.9, 10.4, 6.3 Hz, 1H), 5.01–
4.90 (m, 2H), 4.38 (s, 2H), 4.16 (q, J = 5.2 Hz, 1H), 3.38–3.22
(m, 2H), 1.66–1.41 (m, 4H), 1.05 (s, 9H); 13C NMR (75 MHz,
CDCl3): d 140.6, 138.7, 136.0, 135.6, 134.4, 134.1, 129.6, 128.2,
127.5, 127.4, 114.6, 74.3, 72.6, 70.2, 34.1, 27.3, 24.7, 19.5; MASS
(ESIMS): m/z 467 (M+Na)+; HRMS (ESI): Calcd for C29H36O2NaSi
(M+Na)+ 467.2382, found 467.2398.

1196
A. Venkatesham, K. Nagaiah / Tetrahedron: Asymmetry 23 (2012) 1186–1197
4.1.28. (S)-4-(tert-Butyldiphenylsilyloxy)hex-5-en-1-ol 26
To a stirred solution of 25 (3.0 g, 6.75 mmol) in CH2Cl2–water
(19:1, 40 mL), DDQ (6.135 g, 27.02 mmol) was added and stirred
at reflux for 4 h. Saturated aq. NaHCO3 solution (30 mL) was added
to the reaction mixture and extracted with CH2Cl2 (3 ꢃ 40 mL). The
combined organic layers were washed with water (1 ꢃ 40 mL),
brine 1 ꢃ 40 mL), dried over Na2SO4, and concentrated. The crude
residue was purified by column chromatography on silica gel
(20% EtOAc/hexane) and afforded 26 (2.15 g, 90%) as a colorless
2857, 1734, 1637, 1467, 1426, 1364, 1256, 1109, 1077, 997, 926,
820, 702 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.72–7.55 (m, 8H),
;
7.48–7.27 (m, 12H), 5.83–5.64 (m, 2H), 5.04–4.75 (m, 5H), 4.21
(q, J = 5.6 Hz, 1H), 4.09 (q, J = 6.6 Hz, 1H), 2.22–2.09 (m, 2H),
1.83–1.58 (m, 4H), 1.06 (s, 9H), 1.04 (s, 9H), 1.00 (d, J = 6.0 Hz,
3H); 13C NMR (75 MHz, CDCl3): d 172.8, 140.2, 139.7, 135.94,
135.89, 135.8, 134.1, 134.0, 133.8, 129.6, 129.5, 129.43, 129.37,
127.5, 127.45, 127.36, 127.3, 115.1, 115.0, 73.5, 72.4, 67.8, 44.1,
32.1, 27.0, 26.9, 20.2, 19.2; MASS (ESIMS): m/z 723 (M+H2O)+;
HRMS (ESI): Calcd for C44H56O4NaSi2 (M+Na)+ 727.36093, found
727.36088.
syrupy liquid. ½a D25
¼ þ17:5 (c 1.0, CHCl3); IR (neat): mmax 3686,
ꢂ
3020, 2400, 2362, 1731, 1519, 1427, 1111, 1026, 929, 848, 755,
669, 627, 502 cmꢀ1 1H NMR (500 MHz, CDCl3): d 7.68–7.59 (m,
;
4H), 7.43–7.28 (m, 6H), 5.77 (ddd, J = 16.9, 10.4, 5.8 Hz, 1H),
5.06–4.93 (m, 2H), 4.20 (q, J = 5.8 Hz, 1H), 3.45 (t, J = 5.0 Hz, 2H),
1.56–1.42 (m, 4H), 1.37 (br s, –OH, 1H), 1.06 (s, 9H); 13C NMR
(75 MHz, CDCl3): d 140.3, 136.0, 135.9, 134.2, 133.9, 129.6, 129.5,
127.5, 127.4, 114.6, 74.1, 62.9, 33.7, 27.5, 27.0, 19.3; MASS (ESIMS):
m/z 377 (M+Na)+; HRMS (ESI): Calcd for C22H30O2NaSi (M+Na)+
377.1912, found 377.1911.
4.1.31. (S)-((2R,4S)-40-Hydroxyhex-5-en-2-yl) 4-hydroxyhex-5-
enoate 29
To a stirred solution of 28 (0.8 g, 1.13 mmol) in dry THF (20 mL)
at 0 °C was added pyridine (0.726 mL, 9.08 mmol) and 70% HF-pyr-
idine solution (0.063 mL, 4.54 mmol) under N2 at room tempera-
ture. The resulting solution mixture was allowed to stir for 8 h.
The reaction mixture was quenched with satd NaHCO3 and ex-
tracted with EtOAc (2 ꢃ 25 mL). The combined organic layers were
washed with water (1 ꢃ 15 mL), brine (1 ꢃ 15 mL), dried over
anhydrous Na2SO4, and concentrated under reduced pressure.
Purification by column chromatography using silica gel (100–200
mesh, 40% EtOAc/hexane) afforded 29 (0.217 g, 84%) as a colorless
4.1.29. (S)-4-(tert-Butyldiphenylsilyloxy)hex-5-enoic acid 27
To a stirred solution of alcohol 26 (1.5 g, 4.23 mmol) in CH2Cl2
(50 mL) and NaOAc (1.051 g, 12.71 mmol) at 0 °C were added
PCC (1.370 g, 6.34 mmol) and celite (1.370 g) and stirred at room
temperature for 5 h. Diethyl ether (50 mL) was added and the reac-
tion mixture was filtered through a small pad of Celite and silica
gel. The filtered cake was washed thoroughly with ether
(2 ꢃ 50 mL) and the filtrate was concentrated under reduced pres-
sure to give the crude aldehyde (1.34 g, 90%). The crude aldehyde
was dissolved in t-BuOH–H2O (40 mL, 3:1), cooled to 0 °C, and after
10 min, treated with 2-methyl-2-butene followed by an aq solu-
tion of NaClO2 (0.688 g, 8.46 mmol) and NaH2PO4ꢁH2O (1.17 g,
8.46 mmol) in H2O (10 mL). After 10 h, the reaction mixture was
quenched with KHSO4 (15 mL) and H2O (10 mL) and extracted with
CH2Cl2 (3 ꢃ 40 mL). The combined organic layer was washed with
brine (1 ꢃ 40 mL), dried over anhydrous Na2SO4, filtered, and con-
centrated in vacuo. After flash column chromatography on silica
gel (100–200 mesh, eluent: 30% EtOAc in hexane), 27 (1.36 g,
oil. ½a 2D5
ꢂ
¼ ꢀ28:8 (c 0.5, MeOH); 1H NMR (300 MHz, CDCl3): d 5.98–
5.75 (m, 2H), 5.33–5.02 (m, 5H), 4.24–4.12 (m, 1H), 4.11–4.03 (m,
1H), 2.53–2.32 (m, 2H), 1.99–1.51 (m, 4H), 1.29 (d, J = 6.0 Hz, 3H);
13C NMR (75 MHz, CDCl3): d 174.1, 140.57, 140.59, 114.9, 114.3,
71.8, 68.5, 68.1, 43.8, 31.8, 30.6, 20.8; MASS (ESIMS): m/z
251(M+Na)+; HRMS (ESI): Calcd for C12H20O4Na (M+Na)+
251.1259, found 251.1251.
4.1.32. Stagonolide C 1
To a solution of 29 (80 mg, 0.350 mmol) in dry dichloromethane
(150 mL) was added second generation Grubbs catalyst (30 mg,
0.0350 mmol) and the mixture was degassed under N2 thoroughly.
The reaction mixture was refluxed for 24 h, and the solvent was re-
moved under reduced pressure. The crude residue was purified by
column chromatography on silica gel (5% MeOH/CHCl3) to afford
92%) was obtained as a colorless liquid ½a D25
¼ þ14:5 (c 0.6, CHCl3);
ꢂ
stagonolide C 1 (48 mg, 68%) as a colorless liquid. ½a D25
ꢂ
¼ þ43:9
IR (neat): mmax 3450, 3065, 2934, 2859, 1709, 1647, 1463, 1423,
1265, 1109, 1075, 1031, 927, 822, 742, 701,504 cmꢀ1 1H NMR
;
(c 1.0, MeOH); Lit.5
½
a 2D9
ꢂ
¼ þ44:4 (c 1.0, MeOH); 1H NMR
(300 MHz, CDCl3): d 7.74–7.62 (m, 4H), 7.49–7.31 (m, 6H), 5.76
(ddd, J = 16.8, 10.4, 6.1 Hz, 1H), 5.11–4.97 (m, 2H), 4.28 (q,
J = 5.5 Hz, 1H), 2.37 (dd, J = 13.8, 7.6 Hz, 2H), 1.81 (dd, J = 13.8,
8.3 Hz, 2H), 1.28 (s, 1H), 1.09 (s, 9H); 13C NMR (75 MHz, CDCl3):
d 179.7, 139.6, 135.9, 135.8, 133.9, 133.8, 129.7, 129.5, 127.5,
127.4, 115.3, 73.2, 31.8, 28.9, 27.0, 19.3; MASS (ESIMS): m/z 391
(M+H)+.
(500 MHz, CDCl3): d 5.60 (dd, J = 15.6, 9.3 Hz, 1H), 5.44 (dd,
J = 15.6, 9.3 Hz, 1H), 5.15 (dq, J = 11.0, 6.5 Hz, 1H), 4.18–4.05 (m,
2H), 2.36–2.25 (m, 1H), 2.09–1.98 (m, 3H), 1.89 (dd, J = 13.7,
2.6 Hz, 1H), 1.78 (ddd, J = 13.7, 11.0, 2.6 Hz, 1H), 1.23 (d,
J = 6.4 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 174.4, 135.8, 133.0,
74.4, 72.0, 67.7, 43.3, 34.4, 31.5, 21.3; MASS (ESIMS): m/z 223
(M+Na)+; HRMS (ESI): Calcd for C10H16O4Na (M+Na)+ 223.09408,
found 223.09409.
4.1.30. (S)-((2R,4S)-40-(tert-Butyldiphenylsilyloxy)hex-5-en-2-yl)
4-(tert-butyldiphenylsilyloxy)hex-5-enoate 28
Acknowledgement
To a stirred solution of acid 27 (800 mg, 2.05 mmol) in dry THF
(20 mL) were added 2,4,6-trichlorobenzoyl chloride (0.38 mL,
2.46 mmol) and Et3N (1.43 mL, 10.25 mmol) and the contents were
stirred at ambient temperature. After completion of the mixed
anhydride formation as indicated by TLC, DMAP (500 mg,
4.1 mmol) and a solution of alcohol 19 (725 mg, 2.05 mmol) in
THF (10 mL) were added and the reaction mixture was stirred for
14 h at rt. The reaction was quenched with water and extracted
with ethyl acetate (3 ꢃ 20 mL). The combined organic phase was
washed with saturated NaHCO3 (1 ꢃ 20 mL) and brine
(1 ꢃ 20 mL) solution, dried (Na2SO4), and evaporated under re-
duced pressure. The crude residue was purified by column chroma-
tography on silica gel (100–200 mesh: eluent 20% EtOAc/hexane)
and afforded 28 (1.241 g, 86%) as a colorless syrupy liquid.
A.V. thanks UGC, New Delhi for the award of fellowship and
Director, IICT.
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