The stereoselective total syntheses of pectinolides A, B, and C

Article abstract of DOI:10.1016/j.tetasy.2014.09.009

The stereoselective total synthesis of pectinolide B has been accomplished for the first time along with total syntheses of pectinolides A and C. MacMillan α-hydroxylation and Sharpless asymmetric dihydroxylation reactions are involved in generating the three stereogenic centers. Other important transformations in the synthesis are Z-selective Still-Gennari olefination, selective benzylation of the homoallylic alcohol, and a one-pot MOM deprotection followed by lactonization leading to all three pectinolides A-C being synthesized from a common intermediate. Pectinolides A, B, and C were synthesized from n-hexanal in 19, 20, and 18 steps with overall yields of 8.8%, 6.72%, and 9.2%, respectively.

Full text of DOI:10.1016/j.tetasy.2014.09.009

Tetrahedron: Asymmetry 25 (2014) 1409–1417
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
The stereoselective total syntheses of pectinolides A, B, and C
Udugu Ramulu, Dasari Ramesh, Sudina Purushotham Reddy, Singanaboina Rajaram,
⇑
Katragadda Suresh Babu
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 August 2014
Accepted 24 September 2014
The stereoselective total synthesis of pectinolide B has been accomplished for the first time along with
total syntheses of pectinolides A and C. MacMillan a-hydroxylation and Sharpless asymmetric dihydroxy-
lation reactions are involved in generating the three stereogenic centers. Other important transforma-
tions in the synthesis are Z-selective Still–Gennari olefination, selective benzylation of the homoallylic
alcohol, and a one-pot MOM deprotection followed by lactonization leading to all three pectinolides
A–C being synthesized from a common intermediate. Pectinolides A, B, and C were synthesized from
n-hexanal in 19, 20, and 18 steps with overall yields of 8.8%, 6.72%, and 9.2%, respectively.
Ó 2014 Elsevier Ltd. All rights reserved.
OR1
1. Introduction
6'
2'
1'
4'
3'
6
5
4
3
5'
7'
Natural products containing the d-lactone moiety have
attracted considerable synthetic interest in recent years1 due
to their interesting structure features and biological activities.
OR2
O
1
2
O
1
2
3
R1 = R2 = Ac
R1 = Ac, R2 = H
R1 = H, R2 = Ac
Pectinolides A–C (Fig. 1) are d-lactones, which possess
a
6-substituted 5,6-dihydro- -pyrone skeleton that can be isolated
a
from the Mexican shrub Hyptis pectinata of the Lamiaceae
Figure 2.
family.2 These compounds have shown significant cytotoxic
(ED50 <4 lg/mL) and antimicrobial activities. Pectinolides A–C
possess three stereogenic centers, which include one d-lactone
skeleton. As a consequence of the central role played by this
lactone ring system, a few reports have recently been devised
for the asymmetric synthesis of pectinolides
(Fig. 2).
properties and structural features of pectinolides we were
encouraged to synthesize these natural products. To the best of
our knowledge, there are no reports on the synthesis of pectinolide
B 2. Herein we report the first total synthesis of 2 and synthetic
details that have led to the linear syntheses of pectinolides A–C,
using n-hexanal as a starting material.
A
and C.3–5
As part of our continuing interests in the total synthesis of bio-
active natural products,6 together with the significant biological
O
O
O
OAc
O
OH
O
OAc
O
OAc
OAc
OH
pectinolide A 1
pectinolide B 2
pectinolide C 3
Figure 1. Structures of pectinolides A–C 1–3.
⇑
Corresponding author. Tel.: +91 40 27191881; fax: +91 40 27160512.
E-mail address: suresh@iict.res.in (K.S. Babu).
http://dx.doi.org/10.1016/j.tetasy.2014.09.009
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

1410
U. Ramulu et al. / Tetrahedron: Asymmetry 25 (2014) 1409–1417
O
The treatment of 8 with the TBSCl and imidazole, afforded dis-
ilylated compound 9 in 97% yield. Selective monodesilylation of
compound 9 with CSA in 1:1 dry CH2Cl2/MeOH gave primary alco-
hol 6 in 85% yield (Scheme 2).
OH
O
1
3
2
Alcohol 6 was oxidized into the corresponding aldehyde using
IBX.8 The thus obtained aldehyde was subjected to Z-selective
Still–Gennari olefination by employing methyl [bis(2,2,2-trifluoro-
ethyl)]phosphonoacetate, NaH in THF to afford cis-olefinic ester 10
in 85% yield.9 Reduction of ester 10 using DIBAL-H at ꢁ78 °C gave
the corresponding aldehyde. The resultant aldehyde underwent
Wittig reaction with triethylphosphonoacetate, NaH in dry THF
to give 11 in 92% yield (Scheme 2).
4
OBn
OTBS
OH
OPMB
OH
5
Ester 11 upon reduction with DIBAL-H at 0 °C gave alcohol 12 in
96% yield. Alcohol 12 upon subsequent PMB ether formation using
the PMB-trichloroacetimidate (derived from PMB-OH)10 and p-
TsOH at 0 °C provided 13 in 90% yield (Scheme 2). Compound 13
was subjected to a Sharpless asymmetric dihydroxylation reaction
OTBS
H
OH
using AD-mix-
a
at 0 °C to furnish diol 5 in 84% yield (95% de).11
O
7
6
The selective protection of diol 5 was next investigated. Treatment
of diol 5 with one equivalent of benzyl bromide in the presence of
NaH provided homoallyl hydroxy protected ether 14 and allyl
hydroxy protected ether 14a in a 97:3 ratio, respectively. The selec-
tively formed ether 14 was confirmed by COSY and HMBC (Fig. 3).12
Benzyl ether 14 was further protected with MOM-Cl in the presence
of DIPEA as a base to give 15 in 97% yield. Deprotection of the PMB
group in 15 with DDQ/CH2Cl2:H2O (9:1) gave 16 in 95% yield.
Primary alcohol 16 was oxidized with Dess–Martin periodinane
in CH2Cl2 to afford the corresponding aldehyde, which was
then subjected to Z-selective Still–Gennari olefination by employ-
ing methyl [bis(2,2,2-trifluoroethyl)]phosphonoacetate, KHMDS
in THF to afford olefinic ester 17 in 86% yield. Simultaneous
Scheme 1. Retrosynthetic analysis of 1, 2, and 3.
2. Results and discussion
The retrosynthetic analysis of 1, 2, and 3 is depicted in Scheme 1.
These target molecules can be easily envisaged from the common
precursor, hydroxyl lactone 4, which can be prepared from 5 by
protecting group manipulation to selectively reveal only the pri-
mary hydroxyl group, followed by Still–Gennari olefination9a and
subsequent lactonization upon O-deprotection.
Intermediate 5 can in turn be obtained from alcohol 6 involving
Wittig Horner olefination, followed by facile transformation reac-
tions. Compound 6 can be obtained from hexanal 7 via MacMillan
OH
3
OTBS
a-hydroxylation.
1
8
6
10
5
4
As shown in Scheme 2, the synthesis of 2 began with hexanal 7
O
9
which, as previously reported,7a was subjected to MacMillan
7
O2
a-hydroxylation using nitrosobenzene and 20 mol % of D-proline
in DMSO, followed by rapid reduction with sodium borohydride
to furnish an unstable anilinoxy compound, which was further
treated with 30 mol % CuSO4ꢀ5H2O in methanol at room tempera-
ture to cleave the O–N bond and provide diol 8 with high enantio-
meric purity (97% ee) in 66% yield.7a
O
HMBC
COSY
Figure 3. HMBC and COSY correlations of compound 14.
OTBS
OH
OR
d
b
H
a
OH
7
8
9
R = TBS
R = H
O
c
6
OTBS
O
OTBS
O
f
e
OMe
OEt
10
11
OTBS
OTBS
OH
OH
h
OR
OPMB
5
R = H 12
R = PMB
g
13
Scheme 2. Reagents and conditions: (a)
D
-proline, nitrosobenzene, DMSO, 20 °C 25 min, EtOH, NaBH4, 3 h, CuSO4ꢀ5H2O, MeOH 12 h, 66%; (b) imidazole, TBDMSCl, CH2Cl2, rt,
6 h, 97%; (c) CSA, 1:1 dry CH2Cl2/MeOH 0 °C to rt, 1 h, 85%; (d) (i) IBX, EtOAc, reflux, 4 h, 92%; (ii) (F3CCH2O)2POCH2COOMe, NaH, dry THF, ꢁ78 °C, 2 h, 85%; (e) (i) DIBAL-H,
CH2Cl2, ꢁ78 °C, 1 h, 82%; (ii) NaH, Triethylphosphonoacetate 0 °C, 2 h, 92%; (f) DIBAL-H, CH2Cl2, 0 °C, 0.5 h, 96%; (g) PMB imidate, PTSA (cat), dry CH2Cl2, 0 °C to rt, 8 h, 90%; (h)
AD-mix-a, MeSO2NH2, t-BuOH/H2O (1:1), 0 °C, 24 h, 84%.

U. Ramulu et al. / Tetrahedron: Asymmetry 25 (2014) 1409–1417
OTBS OBn OTBS OH
1411
b
a
OPMB
+
OPMB
5
14a
minor
14
major
OH
OBn
OTBS
OMOM
OBn
OTBS
OMOM
OBn
d
c
OPMB
OH
15
16
O
OTBS
OMOM
OBn
OH
O
OMe
e
17
O
OBn
4
Scheme 3. Reagents and conditions: (a) NaH, benzylbromide, 0 °C to rt, 8 h, 82%; (b) MOM-Cl, DIEPA, CH2Cl2, 0 °C to rt, 4 h, 97%; (c) DDQ, CH2Cl2/H2O (9:1), rt, 2 h, 95%; (d) (i)
Dess–Martin periodinane, CH2Cl2, 0 °C to rt, 4 h, 92%; (ii) (F3CCH2O)2POCH2COOMe, 18-crown-6, KHMDS, dry THF, ꢁ78 °C, 2 h, 86%; (e) 6 M HCl, 0 °C to rt, 8 h, 75%.
deprotection of TBS and MOM groups in 17, followed by lactoniza-
tion was accomplished in one-pot with 6 M HCl and furnished the
key intermediate 4 in 75% yield (Scheme 3).
Acetylation of 4 with Ac2O in pyridine gave 21 in 96% yield
(Scheme 4).
Debenzylation of 21 gave pectinolide C 3 in 92% yield, using
TiCl4 in CH2Cl2. Acetylation of pectinolide C using Ac2O in pyridine
afforded pectinolide A 1 in 96% yield. The analytical data of 1 and 3
were identical to those reported for the natural products.2a
The stability of pectinolides B 2 and C was investigated. Pectino-
lides B 2 and C 3 were dissolved in CHCl3 and allowed to stand for
7 days at room temperature to determine if the acetate group
underwent migration to provide a mixture of all three pectinolides
and parent diol. However, we did not find any change in pectino-
lides B and C (Tables 1–4).
Finally, secondary alcohol 4 was protected as a MOM-ether with
MOMCl and DIEPA in dry CH2Cl2 to afford 18 in 96% yield. Depro-
tection of the benzyl group in 18 under DDQ conditions provided
19 in 86% yield. Compound 19 upon treatment with Ac2O in
pyridine afforded 20 in 95% yield. Finally, the deprotection of
MOM using TiCl4 in dry CH2Cl2 afforded the final target pectinolide
B 2 in 82% yield. The spectroscopic data (1H NMR, 13C NMR,
and mass) and specific rotation of synthetic pectinolide B are
indistinguishable to those reported data for the natural product.2a
O
O
OMOM
a
O
OMOM
O
b
4
OBn
OH
O
18
19
e
c
O
OAc
O
OMOM
O
OBn
21
20
OAc
f
O
d
OAc
O
g
2
1
OH
3
Scheme 4. Reagents and conditions: (a) MOM-Cl, DIEPA, CH2Cl2, 0 °C to rt, 2 h, 96%; (b) DDQ, CH2Cl2, reflux, 24 h, 86%; (c) Ac2O, pyridine, rt, 2 h, 95%; (d) TiCl4, CH2Cl2, 0 °C to
5 min, 82%; (e) Ac2O, pyridine, rt, 2 h, 96%; (f) TiCl4, CH2Cl2, 0 °C, 10 min, 92%; (g) Ac2O, pyridine, rt, 2 h, 96%.
Table 1
Comparison of specific rotations of compounds 1–3
Natural products
Synthetic products
Lit.2a
Our synthesis
Lit.3
Lit.4
Lit.4
Lit.5
1
2
3
1
2
3
1
1
3
3
+202 (c 0.15,
MeOH)
+89.6 (c 0.57,
MeOH)
+80.99(c 0.76,
MeOH)
+194.5
(c 0.5,
MeOH)
+84.9
(c 0.4,
MeOH)
+75.0
(c 0.4,
MeOH)
+196.8
(c 0.5,
MeOH)
+191.3
(c 0.5,
MeOH)
+72.4
(c 0.5,
MeOH)
+72 (c 0.5,
MeOH)

1412
U. Ramulu et al. / Tetrahedron: Asymmetry 25 (2014) 1409–1417
Table 2
13C NMR data of compounds 1–3 in CDCl3 (75 MHz, d in ppm)
Natural products
Synthetic products
Position
Lit.2a
Our synthesis
Lit.3
Lit.4
Lit.4
Lit.5
1
2
3
1
2
3
1
1
3
3
C-2
C-3
C-4
C-5
162.12
124.99
140.01
64.24
75.04
162.35
124.62
140.48
63.94
163.38
122.26
144.83
63.12
162.1
125.0
139.9
64.2
162.3
124.7
140.5
63.9
162.9
122.6
144.4
63.2
162.1
125.1
139.9
64.2
162.0
125.1
139.9
64.2
162.7
122.8
144.2
63.1
162.5
122.9
144.0
63.1
C-6
74.84
77.65
75.0
74.8
77.8
75.0
75.0
77.8
77.9
C-10
C-20
C-30
C-40
C-50
C-60
C-70
Me-CO-
133.17
126.18
69.42
34.01
27.20
22.40
13.88
170.25
169.78
21.07
122.77
129.24
68.32
36.83
27.43
22.59
13.96
169.85
126.29
133.25
70.28
34.09
27.01
22.33
13.79
170.87
133.1
126.2
69.3
34.0
27.2
22.4
13.9
170.2
169.8
21.1
123.0
138.7
68.5
36.8
27.4
22.6
13.9
169.9
125.8
133.8
70.7
34.2
27.1
22.4
13.9
170.9
133.1
126.2
69.3
34.0
27.2
22.4
13.9
170.3
169.8
21.1
133.1
126.2
69.4
34.0
27.2
22.4
13.8
170.2
169.8
21.0
125.5
134.1
70.9
34.2
27.1
22.4
13.9
171.0
125.3
134.3
71.0
34.2
27.2
22.4
13.9
171.0
MeCO-
20.52
21.05
20.5
21.1
21.1
21.9
20.46
20.4
20.5
20.4
Table 3
1H NMR data of compounds 1–3 in CDCl3 (300 MHz, d in ppm, J in Hz)
Natural products
Our synthesis
Proton
Lit.2a
1
Lit.2a
2
Lit.2a
3
1
2
3
H-3
H-4
H-5
H-6
H-10
H-20
H-30
H-40
6.24 (d, 9.7)
6.22 (d, 9.8)
6.08 (d, 9.8)
6.24 (d, 9.7)
6.22 (d, 9.8)
6.14 (d, 9.8)
7.01 (dd, 9.8, 5.3)
4.17–4.12 (m)
5.31 (dd, 7.2, 3.0)
5.75 (dd, 11.4, 7.3)
5.68 (dd, 11.5, 9.1)
5.52–5.47 (m)
6.96 (dd, 9.7, 5.7)
5.19 (dd, 5.7, 2.9)
5.60 (dd, 8.1, 2.9)
5.73 (dd, 10.5, 8.9)
5.62 (dd, 10.5, 10.1)
5.35 (ddd, 10.1, 7.3, 6.6)
1.70 (m, 2H)
6.98 (dd, 9.8, 5.6)
5.26 (dd, 5.6, 3.0)
5.54 (dd, 8.1, 3.0)
5.64 (ddd, 11.1, 8.1, 0.9)
5.76 (dd, 11.1, 7.3)
4.39 (qd, 7.3, 0.9)
1.60 (m, 2H)
7.01 (dd, 9.8, 5.4)
4.12 (dd, 5.4, 3.0)
5.35 (dd, 8.0, 3.0)
5.82 (dd, 11.2, 8.0)
5.66 (dd, 11.2, 9.2)
5.44 (ddd, 9.2, 6.8, 5.8)
1.68 (m, 2H)
6.96 (dd, 9.7, 5.8)
5.18 (dd, 5.6, 2.9)
5.59 (dd, 8.1, 3.0)
5.73 (dd, 11.2, 8.5)
5.63 (dd, 10.9, 8.3)
5.38–5.32 (m)
1.74–1.65 (m, 1H)
1.58–1.49 (m, 1H)
1.38–1.19 (m, 4H)
6.97 (dd, 9.8, 5.5)
5.27 (dd, 5.5, 3.0)
5.52 (dd, 7.9, 2.8)
5.65 (dd, 11.1, 7.9)
5.76 (dd, 11.4, 7.7)
4.40 (q, 7.0)
1.65–1.57 (m, 1H)
1.52–1.45 (m, 1H)
1.36–1.24 (m, 4H)
1.76–1.57 (m, 2H)
H-50
1.54 (m, 2H)
1.29 (m, 2H)
0.90 (t, 6.9)
2.09 (s)
1.50 (m, 2H)
1.29 (m, 2H)
0.90 (t, 7.0)
2.10 (s)
1.55 (m, 2H)
1.29 (m, 2H)
0.90 (t, 6.9)
—
1.66–1.57 (m, 4H)
H-60
H-70
0.90 (t, 7.0)
2.09 (s)
2.04 (s)
0.91 (t, 7.0)
2.10 (s)
—
0.91 (t, 6.8)
—
2.05 (s)
5-OAc
30-OAc
2.05 (s)
—
2.04 (s)
Table 4
1H NMR data of compounds1–3 in CDCl3 (300 MHz, d in ppm, J in Hz)
Previous synthetic compounds
Proton
Lit.3
1
Lit.4
1
Lit.4
3
Lit.5
3
H-3
6.23 (d, 9.8)
6.24 (d, 9.8)
6.15 (d, 9.8)
6.14 (d, 9.9)
H-4
H-5
H-6
6.93 (dd, 9.8, 6.0)
5.16 (dd, 6.0, 3.0)
5.57 (dd, 8.3, 3.0)
5.71 (dd, 11.3, 8.3)
5.61 (d, 9.8)
5.33 (ddd, 9.8, 7.6, 6.0)
1.46–1.77 (m, 2H)
1.20–1.40 (m, 4H)
6.96 (dd, 9.6, 5.6)
5.17 (dd, 5.7, 2.8)
5.59 (dd, 7.9, 2.8)
5.73 (dd, 11.1, 8.3)
5.62 (dd, 10.7, 8.3)
5.35 (ddd, 13.5, 7.1, 6.6)
1.78–1.52 (m, 2H)
1.36–1.12 (m, 4H)
7.01 (dd, 9.8, 5.3)
4.15 (dd, 5.3, 2.3)
5.30 (dd, 6.0, 2.3)
5.78–5.64 (m, 2H)
7.06 (dd, 9.9, 5.9)
4.18–4.12 (m)
5.29 (d, 5.9)
H-10
H-20
H-30
H-40
H-50
H-60
H-70
5-OAc
30-OAc
5.75–5.66 (m, 2H)
5.51 (ddd, 9.8, 7.5, 6.0)
1.72–1.56 (m, 4H)
5.51 (dd, 7.9, 5.9)
1.74–1.32 (m, 6H)
1.39–1.30 (m, 2H)
0.91 (t, 6.8)
—
0.91 (t, 6.8)
2.09 (s)
2.04 (s)
0.90 (t, 6.8)
2.09 (s)
2.04 (s)
0.90 (t, 6.9)
—
2.04 (s)
2.05 (s)
3. Conclusion
4. Experimental
4.1. General
In conclusion, we have accomplished the first total synthesis of
pectinolide B along with the total syntheses of pectinolide A and
pectinolide C in a stereoselective manner. The key features of the
syntheses involve MacMillan
oxylation, and Z-selective Still–Gennari olefination reactions.
Reactions were monitored by thin-layer chromatography car-
ried out on silica plates (silica gel 60 F254, Merck) using UV-light
and anisaldehyde or b-naphthol for visualization. Column
a-hydroxylation, Sharpless dihydr-

U. Ramulu et al. / Tetrahedron: Asymmetry 25 (2014) 1409–1417
1413
chromatography was performed on silica gel (60–120 mesh) using
hexanes, ethyl acetate, methanol, and chloroform as eluent.
Evaporation of solvents was conducted under reduced pressure
at temperatures less than 45 °C. IR spectra were recorded on a
Perkin–Elmer 683, Nicolet Nexus 670 spectrometer. 1H NMR and
13C NMR spectra were recorded in CDCl3 solvent on a 300 MHz,
400 MHz, and 500 MHz NMR spectrometer. Chemical shifts d and
coupling constants J are given in ppm (parts per million) and Hz
(Hertz) respectively. Chemical shifts are reported relative to
residual solvent as an internal standard for 1H and 13C (CDCl3: d
7.26 ppm for 1H and 77.0 ppm for 13C). Mass spectra were
obtained on Finnigan MAT1020B, micromass VG 70–70H, or LC/
MSD trapSL spectrometer operating at 70 eV using direct inlet
system.
18.2, 14.1, ꢁ4.2, ꢁ4.7, ꢁ5.2, ꢁ5.3 ppm. MS (ESI): HRMS (ESI): calcd
for C18H42O2NaSi2 [M+Na]+ 369.2615; found 369.2611.
4.1.3. (S)-2-(tert-Butyldimethylsilyloxy)hexan-1-ol 6
To a cooled solution (0 °C) of protected diol 9 (8 g, 23.12 mmol)
in a 1:1 mixture of dry CH2Cl2/MeOH (60 mL) was added camphor
sulfonic acid (2.68 g, 15.60 mmol) and the reaction mixture was
stirred at room temperature for 1 h. After completion of the reac-
tion, the mixture was quenched with triethylamine at 0 °C and
the solvent was removed in vacuo without work-up. The crude
compound was purified by column chromatography using
(hexane/ethylacetate) (85:15) as eluent to obtain pure 6 (4.55 g,
85% yield) as a colorless liquid. [a]
25 = +8.8 (c 3.4, CHCl3). IR (neat):
D
3423, 2958, 2931, 2858, 1466, 1253, 1097, 1051, 835, 775 cmꢁ1. 1H
NMR (300 MHz, CDCl3): d = 3.77–3.70 (m, 1H), 3.60–3.54 (m, 1H),
3.47–3.42 (m, 1H), 1.89 (t, J = 6.1 Hz, OH), 1.52–1.46 (m, 2H),
1.36–1.21 (m, 4H), 0.92–0.89 (m, 12H), 0.09 (s, 6H) ppm. 13C
NMR (75 MHz, CDCl3): d = 72.9, 66.2, 33.6, 27.5, 25.8, 22.8, 18.0,
14.0, ꢁ4.5, ꢁ4.6 ppm. MS (ESI): HRMS (ESI): calcd for C12H28O2NaSi
[M+Na]+ 255.1750; found 255.1744.
4.1.1. (S)-Hexane-1,2-diol 8
To a solution of hexanal 7 (6.0 g, 59.90 mmol) and nitroso ben-
zene (6.41 g, 59.90 mmol) in anhydrous DMSO (87 mL) was added
D
-proline (1.37 g, 11.98 mmol) at 20 °C. The mixture was stirred
vigorously for 25 min under nitrogen (the color of the reaction
changed from green to orange red during this time), then cooled
to 0 °C, and diluted with ethanol (150 mL) after which was added
sodium borohydride (4.55 g, 119.8 mmol) slowly at the same tem-
perature. The reaction mixture was stirred at room temperature for
3 h, and then the reaction was quenched by the addition of ice. The
ethanol was evaporated under vacuum and the reaction mixture
was diluted with water (200 mL) and extracted into Et2O
(3 ꢂ 150 mL). The combined organic layers was washed with brine,
dried over Na2SO4, and concentrated in vacuo to give a crude
roduct, which was dissolved in methanol (50 mL) and reacted with
CuSO4ꢀ5H2O (2.99 g, 11.98 mmol). The reaction mixture was stir-
red at rt overnight and then quenched with cold saturated NH4Cl
solution (30 mL). The mixture was filtered on a Celite pad and
washed thoroughly with ethylacetate (100 mL), concentrated,
and extracted into ethyl acetate (3 ꢂ 125 mL). The combined
organic layer was washed with brine, dried over anhydrous Na2-
SO4, and concentrated in vacuo. The crude product was then
purified by using silica gel flash column chromatography (using
hexane/ethylacetate) (40:60) as eluent to give compound 8 as a
brown liquid (4.66 g, Yield 66%). The ee was determined by chiral
4.1.4. (S,Z)-Methyl 4-(tert-butyldimethylsilyloxy)oct-2-enoate
10
To a solution of 6 (4.5 g, 19.40 mmol) in EtOAc (100 mL) was
added IBX (13.6 g, 48.49 mmol) at room temperature and then
refluxed for 4 h. After completion of the reaction, the reaction
was filtered through a short pad of Celite and the Celite pad was
washed with EtOAc (2 ꢂ 50 mL). The organic layer was washed
with a saturated NaHSO3 solution (2 ꢂ 50 mL), brine (1 ꢂ 50 mL),
and dried over anhydrous Na2SO4 and concentrated. The crude res-
idue was purified by column chromatography using (hexane/ethyl-
acetate) (90:10) as eluent to obtain pure aldehyde (4.1 g, 92% yield)
as a colorless liquid.
To a cooled solution (0 °C) of Still–Gennari phosphonate (6.08 g,
19.13 mmol) in dry THF (50 mL), was slowly added NaH (60%)
(0.765 g, 19.13 mmol) and the reaction mixture was stirred for
30 min at same temperature. The reaction mixture was cooled to
ꢁ78 °C and a solution of aldehyde obtained above in THF (30 mL)
was added dropwise and stirred for 2 h. After completion of the
reaction, it was quenched with saturated NH4Cl, and extracted into
ethylacetate. The combined organic layer was washed with brine,
dried over Na2SO4, and concentrated. The residue was purified by
HPLC column: (Chiral PAK IA: 250 ꢂ 4.6 mm, 5
l) mobile phase:
10% isopropanol in n-hexane, Flow rate: 1.0 mL/min, detection:
column chromatography using (hexane/ethylacetate) (94:6) to
210 nm, 97% ee). [
a
]
D
25 = ꢁ24.8 (c 1.3, EtOH) [(Lit.7a = ꢁ22.0 (c 0.9,
25
give product 10 (4.22 g, 85% yield) as a colorless liquid. [
a]
=
EtOH)]. 1H NMR (300 MHz, CDCl3): d = 3.76–3.61 (m, 2H) 3.43
(dd, J = 11.3, 7.5 Hz, 1H), 2.75 (br s, 2OH), 1.50–1.24 (m, 6H), 0.91
(t, J = 6.8 Hz, 3H) ppm.
D
+70.4 (c 2.8, CHCl3). IR (neat): 2955, 2932, 2858, 1726, 1649,
1465, 1254, 1184, 1083, 834, 776 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d = 6.16 (dd, J = 11.7, 8.2 Hz, 1H), 5.69 (dd, J = 11.7, 1.2 Hz, 1H),
5.31–5.26 (m, 1H), 3.71 (s, 3H), 1.57–1.24 (m, 6H), 0.89–0.86 (m,
12H), 0.05 (s, 3H) 0.01 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3):
d = 166.3, 154.3, 116.9, 68.7, 51.2, 37.0, 27.3, 25.8, 22.5, 18.1,
4.1.2. (S)-5-Butyl-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disilade-
cane 9
To a cooled solution (0 °C) of 8 (4 g, 33.9 mmol) in dry CH2Cl2
(100 mL) was added imidazole (6.91 g, 101.7 mmol) and stirred
for 10 min. To this solution, tert-butyldimethylsilyl chloride
(12.26 g, 81.355 mmol) was added and stirred at room tempera-
ture for 6 h. After completion of the reaction, the reaction was
diluted with ice water and extracted into CH2Cl2 (2 ꢂ 100 mL),
organic layer was dried over anhydrous Na2SO4, and concentrated
under reduced pressure. The crude residue was purified by column
chromatography using (hexane/ethylacetate) (97:3) as eluent to
14.0, ꢁ4.6, ꢁ4.9 ppm. HRMS (ESI): calcd for
C15H30O3NaSi
[M+Na]+ 309.1856; found 309.1852.
4.1.5. (S,2E,4Z)-Ethyl 6-(tert-butyldimethylsilyloxy)deca-2,4-
dienoate 11
To a cooled (ꢁ78 °C) stirred solution of compound 10 (4.0 g,
13.98 mmol) in dry CH2Cl2 (60 mL) was added DIBAL-H (1.0 M in
toluene, 14 mL, 13.98 mmol) and the reaction mixture was stirred
for 1 h. After completion of the reaction, the reaction was
quenched with saturated sodium potassium tartrate (30 mL) and
stirred for 0.5 h. The reaction mixture was extracted into CH2Cl2
(3 ꢂ 75 mL). The combined organic phase was washed with
brine, and dried over anhydrous Na2SO4. The solvent was removed
under reduced pressure. The crude residue was purified by column
chromatography using (hexane/ethylacetate) (92:08) as eluent to
obtain the pure aldehyde (2.93 g, 82% yield) as a colorless liquid.
obtain pure
9 (11.3 g, 97% yield) as a colorless liquid.
[
a]
D
25 = ꢁ11.9 (c 2.6, CHCl3). IR (neat): 2955, 2931, 2859, 1467,
1253, 1111, 1069, 835, 775, 665 cmꢁ1 1H NMR (300 MHz, CDCl3):
.
d = 3.69–3.60 (m, 1H), 3.51 (dd, J = 9.8, 5.3 Hz, 1H), 3.40 (dd, J = 9.8,
6.8 Hz, 1H), 1.57–1.48 (m, 2H), 1.43–1.24 (m, 4H), 0.93–0.85 (m,
21H), 0.06 (s, 6H), 0.05 (s, 3H) 0.04 (s, 3H) ppm. 13C NMR
(75 MHz, CDCl3): d = 73.2, 67.5, 34.1, 27.3, 26.0, 25.9, 22.9, 18.4,

1414
U. Ramulu et al. / Tetrahedron: Asymmetry 25 (2014) 1409–1417
To a cooled solution (0 °C) of triethylphosphonate (3.55 g,
4.1.8. (2S,3S,6S,Z)-6-(tert-Butyldimethylsilyloxy)-1-(4-methoxy-
15.85 mmol) in dry THF (30 mL), was slowly added NaH (60%)
(0.589 g, 14.72 mmol) and the reaction mixture was stirred for
30 min at the same temperature. A solution of the aldehyde
obtained above in THF (20 mL) was added dropwise and stirred
for 1 h. The reaction was then quenched with saturated NH4Cl,
and extracted into ethylacetate (2 ꢂ 60 mL). The combined organic
layer was washed with brine, dried over Na2SO4, and concentrated.
The residue was purified by column chromatography using hex-
ane/ethylacetate (95:5) to give product 11 (3.39 g, 92% yield) as
benzyloxy)dec-4-ene-2,3-diol 5
To a solution of AD-mix-a (11.782 g, 11.782 mmol) in t-BuOH/
H2O (1:1) (70 mL) was added methanesulfonamide (0.80 g,
8.415 mmol) at room temperature and stirred for 10 min, and then
cooled to 0 °C, after which was added olefin 13 (3.4 g, 8.415 mmol)
and the entire reaction mixture was stirred vigorously at this tem-
perature for 24 h. After completion of the reaction (as noticed by
TLC), the reaction was quenched with sodium sulfite (11.782 g),
stirring was continued for another 0.5 h, and the reaction mixture
was returned to room temperature. The product was extracted into
EtOAc (3 ꢂ 100 mL), and the combined organic layer was dried
over Na2SO4 and concentrated. The residue was purified by silica
gel column chromatography using hexane/ethylacetate (78:22) as
eluent to obtain diol 5 (3.1 g, 84% yield, 95% de) as a colorless vis-
cous liquid. The de was determined by chiral HPLC column:
colorless liquid. [
a]
25 = +43.3 (c 2.4, CHCl3). IR (neat): 2955, 2932,
D
2858, 1726, 1649, 1465, 1254, 1184, 1083, 834, 776 cmꢁ1
.
1H
NMR (300 MHz, CDCl3): d = 7.56 (dd, J = 15.1, 11.9 Hz, 1H), 6.06
(t, J = 11.3 Hz, 1H), 5.88 (d, J = 15.1 Hz, 1H), 5.79–5.74 (m, 1H),
4.66–4.56 (m, 1H) 4.22 (q, J = 6.8 Hz, 2H) 1.47–1.20 (m, 6H),
0.93–0.80 (m, 12H), 0.05 (s, 3H) 0.01 (s, 3H) ppm. 13C NMR
(75 MHz, CDCl3): d = 166.9, 144.0, 139.0, 125.0, 122.5, 69.0, 60.3,
38.0, 27.3, 25.8, 22.6, 18.1, 14.2, 14.0, ꢁ4.3, ꢁ4.8 ppm. HRMS
(ESI): calcd for 349.2169 C18H34O3NaSi [M+Na]+; found 349.2171.
(HYDRO RP C18: 150 ꢂ 4.6 mm, 5
water, Flow rate: 1.0 ml/min, detection: 210 nm, Ret. Time:
10.860 min, 95% de). [
25 = +5.8 (c 2.3, CHCl3). IR (neat): 3417,
2930, 2858, 1612, 1512, 1463, 1362, 1299, 1248, 1175, 1039,
835, 772, 670, 578 cmꢁ1 1H NMR (300 MHz, CDCl3): d = 7.27–
l) mobile phase: 75% ACN in
a]
D
.
4.1.6. (S,2E,4Z)-6-(tert-Butyldimethylsilyloxy)deca-2,4-dien-1-ol
12
7.21 (m, 2H), 6.88 (d, J = 8.3 Hz, 2H), 5.57 (dd, J = 11.3, 9.0 Hz,
1H), 5.40 (dd, J = 11.3, 9.0 Hz, 1H), 4.47 (d, J = 3.0 Hz, 2H), 4.45–
4.36 (m, 2H), 3.81 (s, 3H), 3.67–3.58 (m, 1H), 3.58–3.52 (m, 1H),
3.48–3.42 (m, 1H), 2.77 (d, J = 3 Hz, OH), 2.65 (d, J = 5.2 Hz, OH),
1.56–1.42 (m, 1H), 1.39–1.16 (m, 5H), 0.94–0.80 (m, 12H), 0.07
(s, 3H), 0.05 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3): d = 159.3,
137.8, 129.6, 129.0, 126.8, 113.8, 73.4, 73.2, 71.0, 68.8, 68.3, 55.2,
38.0, 27.5, 25.8, 22.6, 18.1, 14.1, ꢁ4.3, ꢁ4.9 ppm. HRMS (ESI): calcd
for 461.2694 C24H42O5NaSi [M+Na]+; found 461.2696.
To a cooled (0 °C) stirred solution of compound 11 (3.3 g,
10.12 mmol) in dry CH2Cl2 (50 mL) was added DIBAL-H (1.0 M in
toluene, 20.2 mL, 20.24 mmol) and the reaction mixture was stir-
red for 0.5 h. After completion of the reaction, the reaction was
quenched with saturated sodium potassium tartrate (30 mL) and
stirred for 0.5 h. The reaction mixture was then extracted into CH2-
Cl2 (3 ꢂ 75 mL). The combined organic phase was washed with
brine, and dried over anhydrous Na2SO4. The solvent was removed
under reduced pressure, and the residue was purified by column
chromatography using hexane/ethylacetate (85:15) to give alcohol
4.1.9. (2S,3S,6S,Z)-2-(Benzyloxy)-6-(tert-butyldimethylsilyloxy)-
1-(4-methoxybenzyloxy)dec-4-en-3-ol 14
12 (2.76 g, 96% yield) as colorless liquid. [
IR (neat): 3337, 2956, 2930, 2857, 1652, 1466, 1253, 1081, 836,
775 cmꢁ1 1H NMR (300 MHz, CDCl3): d = 6.54–6.42 (m, 1H),
a]
25 = +10.6 (c 1.5, CHCl3).
D
To a cooled (0 °C) solution of compound 5 (0.8 g, 1.826 mmol) in
dry THF (30 mL) was added NaH (60%) (0.080 g, 2.009 mmol) and
stirred for 10 min. To this mixture, benzylbromide (0.22 mL,
1.826 mmol), was added and stirred at room temperature for
12 h. After completion of the reaction, the reaction was quenched
with cold water (30 mL), extracted into EtOAc (3 ꢂ 70 mL), dried
over Na2SO4, and concentrated under reduced pressure. The crude
product was purified by column chromatography on silica gel
(hexane/ethylacetate 88:12) to give compound 14 (0.790 g, 82%
.
6.00–5.76 (m, 2H), 5.44–5.35 (m, 1H), 4.58–4.47 (m, 1H), 4.27–
4.15 (m, 2H), 1.58–1.16 (m, 6H), 0.93–0.80 (m, 12H), 0.04 (s, 3H)
0.01 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3): d = 136.3, 133.0,
126.4, 126.3, 69.0, 63.4, 38.2, 27.5, 25.4, 22.6, 18.2, 14.1, ꢁ4.3,
ꢁ4.8 ppm. HRMS (ESI): calcd for
C24H38O3NaSi [M+Na]+
307.2064; found 307.2066.
yield) as a colorless liquid. [
3383, 3030, 2954, 2931, 2858, 1612, 1513, 1462, 1362, 1302,
1249, 1175, 1062, 837, 776, 747, 698, 670 cmꢁ1 1H NMR
a]
25 = +25.9 (c 2.2, CHCl3). IR (neat):
D
4.1.7. tert-Butyl((S,6Z,8E)-10-(4-methoxybenzyloxy)deca-6,8-dien-
5-yloxy)dimethylsilane 13
.
To a cooled (0 °C) solution of alcohol 12 (2.7 g, 9.507 mmol) in
dry CH2Cl2 (50 mL) was added PMB imidate (3.4 g, 19.014 mmol)
followed by PTSA (catalytic amount) and the reaction was stirred
at room temperature for 8 h. After completion of the reaction, it
was quenched with triethylamine, diluted with water (50 mL),
and extracted into CH2Cl2 (3 ꢂ 50 mL). The combined organic lay-
ers were washed with brine, dried over Na2SO4, and concentrated
in vacuo. The crude product was purified by column chromatogra-
phy on silica gel (hexane/ethylacetate, 93:7) to give compound 13
(300 MHz, CDCl3): d = 7.36–7.22 (m, 7H), 6.87 (d, J = 8.7 Hz, 2H),
5.58–5.49 (m, 1H), 5.42–5.37 (m, 1H), 4.76 (d, J = 11.3 Hz, 1H),
4.56 (d, J = 11.3 Hz, 1H), 4.51–4.37 (m, 4H), 3.81 (s, 3H), 3.65–
3.47 (m, 3H), 2.68 (d, J = 4.3 Hz, OH), 1.51–1.41 (m, 1H), 1.38–
1.14 (m, 5H), 0.92–0.81 (m, 12H), 0.05 (s, 3H) 0.04 (s, 3H) ppm.
13C NMR (75 MHz, CDCl3): d = 159.2, 138.0, 137.8, 130.0, 129.2,
128.4, 128.0, 127.8, 126.9, 113.7, 81.1, 73.1, 69.3, 68.6, 67.5, 55.2,
37.9, 27.5, 25.8, 22.6, 18.1, 14.1, ꢁ4.3, ꢁ4.9 ppm. HRMS (ESI): calcd
For C31H48O5NaSi [M+Na]+ 551.3163; found 551.3157.
(3.45 g, 90%) as a colorless liquid. [
a
]
25 = ꢁ26.4 (c 2.2, CHCl3). IR
D
(neat): 3003, 2955, 2930, 2856, 1612, 1512, 1464, 1358, 1248,
1175, 1040, 835, 775 cmꢁ1 1H NMR (300 MHz, CDCl3): d = 7.30–
.
4.1.10. (5S,8S,Z)-5-((S)-1-(Benzyloxy)-2-(4-methoxybenzyloxy)
ethyl)-8-butyl-10,10,11,11-tetramethyl-2,4,9-trioxa-10-silado-
dec-6-ene 15
To a cooled (0 °C) solution of secondary allylic alcohol 14
(0.55 g, 1.04 mmol) in dry CH2Cl2 (10 mL) was added N,N-diisopro-
pyl ethylamine (0.9 mL, 5.20 mmol) and stirred at the same
temperature for 10 min. Next, methoxy methyl chloride (0.24 ml,
3.12 mmol) was added and stirred at room temperature for 4 h.
After completion of the reaction, the reaction was quenched with
7.24 (m, 2H), 6.88 (d, J = 8.6 Hz, 2H), 6.48 (dd, J = 14.9, 11.3 Hz,
1H), 5.94 (t, J = 11.1 Hz, 1H), 5.83–5.73 (m, 1H), 5.43–5.34 (m,
1H), 4.56–4.42 (m, 3H), 4.08–4.03 (m, 2H), 3.81 (s, 3H), 1.55–1.20
(m, 6H), 0.93–0.83 (m, 12H), 0.04 (s, 3H) 0.01 (s, 3H) ppm. 13C
NMR (75 MHz, CDCl3): d = 159.2, 136.0, 130.7, 129.6, 129.3,
127.6, 126.6, 113.7, 71.6, 70.0, 68.9, 55.2, 38.1, 27.4, 25.8, 22.6,
18.2, 14.1, ꢁ4.3, ꢁ4.8 ppm. HRMS (ESI): calcd for C24H40O3NaSi
[M+Na]+ 427.2638; found 427.2632.

U. Ramulu et al. / Tetrahedron: Asymmetry 25 (2014) 1409–1417
1415
ice-water and extracted into CH2Cl2 (2 ꢂ 40 mL). The combined
organic phase was washed with brine, and dried over Na2SO4. After
evaporation of the solvent, the crude residue was purified by col-
umn chromatography using hexane/ethylacetate (91:9) as eluent
to afford the desired product 15 (0.578 g, 97a% yield) as colorless
liquid. [
2857, 1723, 1648, 1463, 1393, 1252, 1197, 1151, 1102, 1071,
1037, 833, 774, 697 cmꢁ1 1H NMR (300 MHz, CDCl3): d = 7.35–
a]
25 = +80.2 (c 1.9, CHCl3). IR (neat): 3028, 2953, 2931,
D
.
7.23 (m, 5H), 6.38 (dd, J = 11.6, 8.6 Hz, 1H), 5.95 (d, J = 11.6 Hz,
1H), 5.63 (dd, J = 11.3, 9.0 Hz, 1H), 5.46–5.41 (m, 1H), 5.02 (dd,
J = 8.3, 2.7 Hz, 1H), 4.66 (d, J = 6.7 Hz, 1H), 4.61 (d, J = 12.0 Hz,
1H), 4.55–4.50 (m, 2H), 4.49–4.44 (m, 1H), 4.41 (d, J = 12.0 Hz
1H), 3.68 (s, 3H), 3.29 (s, 3H), 1.42–1.21 (m, 6H), 0.90–0.83 (m,
12H), 0.04 (s, 3H), 0.01 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3):
d = 165.8, 148.6, 139.5, 137.8, 128.2, 128.1, 127.6, 124.9, 121.4,
93.5, 77.3, 73.3, 72.0, 68.8, 55.4, 51.3, 38.4, 27.5, 25.8, 22.7, 18.1,
liquid. [
a]
D
25 = +74.3 (c 1.4, CHCl3). IR (neat): 2930, 2858, 1612,
1513, 1463, 1361, 1300, 1249, 1097, 1035, 835, 773, 698 cmꢁ1
.
1H NMR (300 MHz, CDCl3): d = 7.36–7.21 (m, 7H), 6.87 (d,
J = 8.5 Hz, 2H), 5.61 (dd, J = 11.1, 8.3 Hz, 1H), 5.35 (t, J = 10.8 Hz,
1H), 4.75–4.60 (m, 3H), 4.54–4.34 (m, 5H), 3.81 (s, 3H),
3.74–3.55 (m, 3H), 3.32 (s, 3H), 1.43–1.12 (m, 6H), 0.92–0.77 (m,
12H) 0.04 (s, 3H) 0.02 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3):
d = 159.1, 139.5, 138.4, 130.4, 129.0, 128.2, 127.6, 125.0, 113.7,
93.5, 80.6, 72.9, 70.7, 70.1, 68.7, 55.4, 55.2, 38.4, 27.3, 25.8, 22.6,
18.1, 14.1, ꢁ4.4, ꢁ4.9 ppm. HRMS (ESI): calcd for C33H56O6NSi
[M+NH4]+ 590.3871; found 590.3873.
14.1, ꢁ4.4, ꢁ4.9 ppm. HRMS (ESI): calcd for
C28H50O6NSi
[M+NH4]+ 524.3402; found 524.3400.
4.1.13. (5S,6S)-5-(benzyloxy)-6-((S,Z)-3-hydroxyhept-1-enyl)-5,
6-dihydro-2H-pyran-2-one 4
To a cooled (0 °C) solution of the cis olefinic ester 17 (256 mg,
0.505 mmol) was added 6 N HCl (3 mL) and stirred for 8 h. After
completion of the reaction, the reaction was quenched with satu-
rated NaHCO3 solution at 0 °C and extracted into ethyl acetate
(2 ꢂ 30 mL). The combined organic layer was washed with brine,
dried over anhydrous Na2SO4, and concentrated under reduced
pressure. The crude residue was purified by silica gel column
chromatography using (hexane/ethylacetate) (60:40) as eluent
to obtain pure compound 4 (120 mg, 75% yield) as colorless
4.1.11. (2S,3S,6S,Z)-2-(Benzyloxy)-6-(tert-butyldimethylsilyloxy)-
3-(methoxymethoxy)dec-4-en-1-ol 16
To a cooled (0 °C) solution of 15 (0.507 g, 0.886 mmol) in CH2Cl2
(18 mL) and water (2 mL) was added DDQ (402 mg, 1.772 mmol)
and stirred at room temperature for 2 h. After completion of the
reaction, a saturated NaHCO3 solution was added, and the aqueous
layer was extracted with CH2Cl2 (2 ꢂ 75 mL). The combined
organic extract was dried over anhydrous Na2SO4 and concen-
trated to dryness. Column chromatography of the residue using
(hexane/ethylacetate) (86:14) gave 16 (0.380 g, 95% yield) as a col-
liquid. [
(neat): 3428, 3031, 2955, 2928, 2864, 1724, 1630, 1496, 1457,
1380, 1331, 1253, 1101, 1052, 824, 742, 698 cmꢁ1 1H NMR
a]
25 = +100.0 (c 0.5, CHCl3) (Lit.5 +117, c 0.5, CHCl3). IR
D
orless syrup. [
2862, 1629, 1462, 1394, 1252, 1093, 1038, 838, 774, 696,
601 cmꢁ1 1H NMR (300 MHz, CDCl3): d = 7.36–7.27 (m, 5H), 5.69
a
]
D
25 = +48.1 (c 1.9, CHCl3). IR (neat): 3457, 2941,
.
(300 MHz, CDCl3): d = 7.39–7.30 (m, 5H), 6.88 (dd, J = 9.9, 4.7 Hz,
1H), 6.14 (d, J = 9.9 Hz, 1H), 5.89 (ddd, J = 11.3, 8.4, 0.9 Hz, 1H),
5.79 (ddd, J = 11.3, 8.2, 0.9 Hz, 1H), 5.34 (ddd, J = 8.4, 3.6, 0.9 Hz,
1H), 4.65–4.58 (m, 2H), 4.41 (q, J = 7.0 Hz, 1H), 4.04 (t,
J = 4.0 Hz, 1H), 1.93 (br s, OH), 1.67–1.57 (m, 1H), 1.48–1.40 (m,
1H), 1.38–1.22 (m, 4H), 0.89 (t, J = 7.0 Hz, 3H) ppm. 13C NMR
(75 MHz, CDCl3): d = 162.7, 143.3, 139.0, 137.0, 128.6, 128.2,
127.8, 124.0, 123.2, 75.7, 71.8, 68.8, 68.1, 36.7, 27.5, 22.5,
14.0 ppm. HRMS (ESI): calcd for C19H24O4Na [M+Na]+ 339.1566;
found 339.1561.
.
(dd, J = 11.3, 9.0 Hz, 1H), 5.32 (t, J = 10.5 Hz, 1H), 4.76 (d,
J = 11.6 Hz, 1H), 4.70 (d, J = 6.7 Hz, 1H), 4.65 (d, J = 11.6 Hz, 1H),
4.54 (d, J = 6.7 Hz, 1H), 4.51 (dd, J = 9.8, 4.8 Hz, 1H), 4.43–4.38
(m, 1H), 3.77–3.72 (m, 1H), 3.67–3.62 (m, 1H), 3.52 (q, J = 4.9 Hz,
1H), 3.37 (s, 3H), 2.11 (t, OH), 1.48–1.41 (m, 1H), 1.36–1.19 (m,
5H), 0.91–0.83 (m, 12H), 0.06 (s, 3H), 0.03 (s, 3H) ppm. 13C NMR
(75 MHz, CDCl3): d = 140.1, 138.0, 128.4, 128.0, 127.9, 124.1, 93.5,
81.4, 73.4, 71.8, 68.7, 61.9, 55.5, 38.4, 27.2, 25.8, 22.6, 18.0, 14.0,
ꢁ4.4, ꢁ4.9 ppm. HRMS (ESI): calcd for C25H44O5NaSi [M+Na]+
475.2850; found 475.2844.
4.1.14. (5S,6S)-5-(benzyloxy)-6-((S,Z)-3-(methoxymethoxy)hept-
1-enyl)-5,6-dihydro-2H-pyran-2-one 18
4.1.12. (2Z,4S,5S,6Z,8S)-Methyl 4-(benzyloxy)-8-(tert-butyldi-
methylsilyloxy)-5-(methoxymethoxy)dodeca-2,6-dienoate 17
To a cooled (0 °C) solution of alcohol 16 (327 mg, 0.723 mmol)
in dry DCM (10 mL) was added Dess–Martin reagent (613 mg,
1.446 mmol) and stirred at room temperature for 4 h. After com-
pletion of the reaction, a saturated Na2S2O3 solution was added
and stirring was continued for 10 min. The reaction mixture was
diluted with a saturated NaHCO3 solution and the aqueous layer
was extracted into DCM (3 ꢂ 30 mL), and dried over anhydrous
Na2SO4. After evaporation of the solvent, the crude product was
purified by column chromatography on silica gel (hexane/ethyl
acetate 92:8) to give the corresponding aldehyde (299 mg, 92%
yield), which was used as such for further reaction.
To cooled (0 °C) solution of (F3CCH2O)2POCH2COOMe (329 mg,
1.034 mmol), 18-crown-6 (853 mg, 3.23 mmol) in anhydrous THF
(10 mL) was added KHMDS (0.97 mL, 0.969 mmol) and the reac-
tion mixture was stirred for 30 min at same temperature. The reac-
tion mixture was cooled to ꢁ78 °C, after which a solution of
aldehyde (291 mg, 0.646 mmol) in dry THF (5 mL) was added and
stirred for 2 h at the same temperature. After completion of the
reaction, the reaction was quenched with saturated NH4Cl, and
extracted into ethyl acetate. The combined organic layer was
washed with brine, dried over Na2SO4, and concentrated. The res-
idue was purified by column chromatography using hexane/ethyl
acetate (93:7) to give product 17 (281 mg, 86% yield) as colorless
Compound 18 was prepared by following the procedure
described for 15, (39 mg, 96% yield) as colorless liquid.
[a]
25 = +55.2 (c 1.6, CHCl3). IR (neat): 3031, 2931, 1728, 1458,
D
1379, 1250, 1154, 1098, 1050, 916, 874, 823, 742, 698 cmꢁ1 1H
.
NMR (300 MHz, CDCl3): d = 7.38–7.28 (m, 5H), 6.87 (dd, J = 9.9,
4.8 Hz, 1H), 6.16 (d, J = 9.9 Hz, 1H), 6.00 (ddd, J = 11.3, 9.0, 0.6 Hz,
1H), 5.62-5.57 (m, 1H), 5.24 (ddd, J = 9.0, 3.5, 1.0 Hz, 1H), 4.66 (d,
J = 6.7 Hz, 1H), 4.64–4.57 (m, 2H), 4.48 (d, J = 6.7 Hz, 1H), 4.28–
4.23 (m, 1H), 3.91 (dd, J = 4.9, 3.5 Hz, 1H), 3.33 (s, 3H), 1.68–1.60
(m, 2H), 1.44–1.20 (m, 4H), 0.88 (t, J = 7.0 Hz, 3H) ppm. 13C NMR
(75 MHz, CDCl3): d = 162.6, 142.7, 137.0, 135.0, 128.5, 128.2,
127.7, 126.6, 123.5, 93.5, 75.8, 71.7, 70.3, 68.9, 55.4, 35.1, 27.5,
22.6, 13.9 ppm. HRMS (ESI): calcd for
383.1829; found 383.1825.
C21H28O5Na [M+Na]+
4.1.15. (5S,6S)-5-hydroxy-6-((S,Z)-3-(methoxymethoxy)hept-1-
enyl)-5,6-dihydro-2H-pyran-2-one 19
To a solution of 18 (36 mg, 0.1 mmol) in CH2Cl2 (10 mL) was
added DDQ (227 mg, 1.0 mmol) and stirred at reflux for 24 h. After
completion of the reaction, the reaction was cooled to 0 °C after
which a saturated NaHCO3 solution was added, and the aqueous
layer was extracted with CH2Cl2 (3 ꢂ 30 mL). The combined
organic extract was dried over anhydrous Na2SO4 and concen-
trated to dryness. Column chromatography of the residue using
(hexane/ethylacetate) (60:40) gave 19 (23.2 mg, 86%) as a colorless

1416
U. Ramulu et al. / Tetrahedron: Asymmetry 25 (2014) 1409–1417
liquid. [
a
]
25 = +8.6 (c 0.7, CHCl3). IR (neat): 3403, 2923, 2853, 1726,
extracted into ethylacetate (2 ꢂ 25 mL). The combined organic
phase was washed with brine, and dried over Na2SO4. After evap-
oration of the solvent, the crude residue was purified by column
chromatography using (hexane/ethylacetate) (73:27) as eluent to
afford the desired product 21 (68.5 mg, 96% yield) as colorless
D
1630, 1462, 1378, 1252, 1153, 1094, 1038, 887, 825, 761 cmꢁ1 1H
.
NMR (300 MHz, CDCl3): d = 7.0 (dd, J = 9.7, 5.5 Hz, 1H), 6.14 (d,
J = 9.7 Hz, 1H), 5.85 (dd, J = 11.4, 8.1 Hz, 1H), 5.70–5.65 (m, 1H),
5.21 (ddd, J = 8.0, 2.9, 0.9 Hz, 1H), 4.69 (d, J = 6.8 Hz, 1H), 4.55 (d,
J = 6.8 Hz, 1H), 4.39–4.34 (m, 1H), 4.13–4.08 (m, 1H), 3.35 (s, 3H),
2.82 (br s, OH), 1.75–1.62 (m, 1H), 1.54–1.46 (m, 1H), 1.43–1.22
(m, 4H), 0.91 (t, J = 7.0 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3):
d = 162.9, 144.2, 136.2, 125.3, 122.8, 94.0, 77.3, 71.4, 63.2, 55.4,
35.1, 27.4, 22.5, 14.0 ppm. HRMS (ESI): calcd for C14H22O5Na [M
+ Na]+ 293.1359; found 293.1361.
liquid. [
(neat): 2928, 2863, 1730, 1457, 1374, 1241, 1100, 1053, 1020,
822, 771, 698, 608 cmꢁ1 1H NMR (300 MHz, CDCl3): d = 7.38–
a]
25 = +102.5 (c 0.6, CHCl3) (Lit.5 +107, c 0.5, CHCl3). IR
D
.
7.28 (m, 5H), 6.88 (dd, J = 9.8, 4.8 Hz, 1H), 6.17 (d, J = 9.9 Hz, 1H),
5.93 (ddd, J = 11.1, 8.7, 0.6 Hz, 1H), 5.68–5.63 (m, 1H), 5.43 (ddd,
J = 8.7, 3.5, 1.0 Hz, 1H), 5.40–5.35 (m, 1H), 4.65–4.54 (m, 2H),
3.94 (dd, J = 4.8, 3.5 Hz, 1H), 2.02 (s, 3H), 1.70–1.61 (m, 1H),
1.50–1.42 (m, 1H), 1.34–1.16 (m, 4H), 0.87 (t, J = 7.0 Hz, 3H)
ppm. 13C NMR (75 MHz, CDCl3): d = 170.2, 162.4, 142.6, 137.0,
132.5, 128.5, 128.2, 127.7, 127.3, 123.6, 76.1, 71.6, 69.2, 69.0,
34.1, 27.2, 22.4, 21.1, 13.9 ppm. HRMS (ESI): calcd for C21H26O5Na
[M+Na]+ 381.1672; found 381.1667.
4.1.16. (2S,3S)-2-((S,Z)-3-(Methoxymethoxy)hept-1-en-1-yl)-6-
oxo-3,6-dihydro-2H-pyran-3-yl acetate 20
To a cooled (0 °C) solution of secondary alcohol 19 (16 mg,
0.059 mmol) in pyridine (0.5 mL) was added Ac2O (0.2 mL) and
stirred at room temperature for 2 h. After completion of the reac-
tion, the reaction was diluted with aqueous CuSO4ꢀ5H2O (5 mL)
and extracted into ethylacetate (2 ꢂ 15 mL). The combined organic
phase was washed with brine, and dried over Na2SO4. After evap-
oration of the solvent, the crude residue was purified by column
chromatography using (hexane/ethylacetate) (73:27) as eluent to
afford the desired product 20 (17.5 mg, 95% yield) as colorless
4.1.19. (S,Z)-1-((2S,3S)-3-Hydroxy-6-oxo-3,6-dihydro-2H-pyran-
2-yl)hept-1-en-3-yl acetate 3
To a cooled (0 °C) solution of 21 (39 mg, 0.108 mmol) in dry
CH2Cl2 (5 mL) was added a solution of TiCl4 (0.23 mL, 0.217 mmol)
in dry CH2Cl2 (2 mL) under N2 and the mixture was stirred at the
same temperature for 10 min. After completion of the reaction,
the reaction was quenched with saturated sodium bicarbonate
(10 mL), extracted into CH2Cl2 (3 ꢂ 30 mL). The combined organic
phase was washed with brine and dried over anhydrous Na2SO4.
The solvent was removed under reduced pressure, and the crude
residue was purified by column chromatography on silica gel (hex-
ane/ethylacetate, 65:35) to give pure compound 3 (26.8 mg, 92%)
liquid. [
a]
25 = +66.2 (c 1.2, CHCl3). IR (neat): 2924, 2854, 1739,
D
1462, 1374, 1221, 1153, 1072, 1034, 948, 826, 769 cmꢁ1
.
1H NMR
(300 MHz, CDCl3): d = 6.96 (dd, J = 9.6, 5.6 Hz, 1H), 6.24 (d,
J = 9.6 Hz, 1H), 5.79 (dd, J = 11.3, 8.7 Hz, 1H), 5.64-5.56 (m, 1H),
5.42-5.36 (m, 1H), 5.15 (dd, J = 5.6, 3.0 Hz, 1H), 4.66 (d, J = 6.8 Hz,
1H), 4.51 (d, J = 6.8 Hz, 1H), 4.30–4.21 (m, 1H), 3.35 (s, 3H), 2.10
(s, 3H), 1.73–1.22 (m, 6H), 0.91 (t, J = 6.8 Hz, 3H) ppm. 13C NMR
(75 MHz, CDCl3): d = 169.8, 162.2, 140.1, 135.7, 125.4, 124.9, 93.6,
74.7, 70.4, 64.1, 55.5, 35.0, 27.5, 22.6, 20.5, 13.9 ppm. HRMS
(ESI): calcd for C16H24O6Na [M+Na]+ 335.1465; found 335.1467.
as a colorless liquid. [
0.76, MeOH). IR (neat): 3417, 2928, 2859, 1727, 1631, 1461,
1374, 1244, 1153, 1088, 1041, 958, 825, 763, 607, 545 cmꢁ1 1H
a]
25 = +75.0 (c 0.4, MeOH) (Lit.2 +80.9, c
D
.
NMR (300 MHz, CDCl3): d = 7.01 (dd, J = 9.8, 5.3 Hz, 1H), 6.14 (d,
J = 9.8 Hz, 1H), 5.75 (dd, J = 11.4, 7.3 Hz, 1H), 5.68 (dd, J = 11.5,
9.1 Hz, 1H), 5.52–5.47 (m, 1H), 5.31 (dd, J = 7.2, 3.0 Hz, 1H), 4.17–
4.12 (m, 1H), 2.99 (br d, J = 7.0 Hz, OH), 2.05 (s, 3H), 1.76–1.57
(m, 2H), 1.38–1.27 (m, 4H), 0.91 (t, J = 6.8 Hz, 3H) ppm. 13C NMR
(75 MHz, CDCl3): d = 170.9, 162.9, 144.4, 133.8, 125.8, 122.6, 77.8,
70.7, 63.2, 34.2, 27.1, 22.4, 21.1, 13.9 ppm. HRMS (ESI): calcd for
4.1.17. (2S,3S)-2-((S,Z)-3-Hydroxyhept-1-enyl)-6-oxo-3,6-dihydro-
2H-pyran-3-yl acetate 2
To a cooled (0 °C) solution of 20 (12 mg, 0.038 mmol) in dry
CH2Cl2 (3 mL) was added
a solution of TiCl4 (0.013 mL,
0.076 mmol) in dry CH2Cl2 (0.5 mL) under N2 and the mixture
was stirred at the same temperature for 5 min. After completion
of the reaction, the reaction was quenched with saturated sodium
bicarbonate (5 mL), and extracted into CH2Cl2 (3 ꢂ 15 mL). The
combined organic phase was washed with brine, and dried over
anhydrous Na2SO4. The solvent was removed under reduced pres-
sure, and the crude residue was purified by column chromatogra-
phy on silica gel (hexane/ethylacetate, 65:35) to give pure
C14H20O5Na [M+Na]+ 291.1202; found 291.1200.
4.1.20. (S,Z)-1-((2S,3S)-3-Acetoxy-6-oxo-3,6-dihydro-2H-pyran-
2-yl)hept-1-en-3-yl acetate 1
To a cooled (0 °C) solution of secondary alcohol 3 (20 mg,
0.0746 mmol) in pyridine (0.3 mL) was added Ac2O (0.2 mL) and
stirred at room temperature for 2 h. After completion of the reac-
tion, the reaction was diluted with aqueous CuSO4 (5 mL) and
extracted into ethyl acetate (2 ꢂ 25 mL). The combined organic
phase was washed with brine, and dried over Na2SO4. After evap-
oration of the solvent, the crude residue was purified by column
chromatography using (hexane/ethylacetate) (82:18) as eluent to
afford the desired product 1 (22.2 mg, 96% yield) as a colorless
compound
[a]
D
2
(8.8 mg, 86% yield) as
a
colorless liquid.
25 = +84.9 (c 0.4, MeOH) (Lit.2 +89.6, c 0.57, MeOH). IR (neat):
3448, 2922, 2852, 1741, 1462, 1375, 1224, 1073, 1031, 947, 827,
768 cmꢁ1 1H NMR (300 MHz, CDCl3): d = 6.97 (dd, J = 9.8, 5.5 Hz,
.
1H), 6.22 (d, J = 9.8 Hz, 1H), 5.76 (dd, J = 11.4, 7.7 Hz, 1H), 5.65
(dd, J = 11.1, 7.9 Hz, 1H) 5.52 (dd, J = 7.9, 2.8 Hz, 1H), 5.27 (dd,
J = 5.5, 3.0 Hz, 1H), 4.40 (q, J = 7.0 Hz, 1H), 2.10 (s, 3H), 1.65–1.57
(m, 1H), 1.52–1.45 (m, 1H), 1.36–1.24 (m, 4H), 0.91 (t, J = 7.0 Hz,
3H) ppm. 13C NMR (75 MHz, CDCl3): d = 169.9, 162.3, 140.5,
138.7, 124.7, 123.0, 74.8, 68.5, 63.9, 36.8, 27.4, 22.6, 20.5,
13.9 ppm. HRMS (ESI): calcd for C14H20O5Na [M+Na]+ 291.1202;
found 291.1203.
liquid. [
(neat): 2957, 2922, 2854, 1739, 1372, 1224, 1073, 1030, 952,
825, 769, 605 cmꢁ1 1H NMR (300 MHz, CDCl3): d = 6.96 (dd,
a]
25 = +194.5 (c 0.5, MeOH). (Lit.2 +202, c 0.15, MeOH). IR
D
.
J = 9.7, 5.8 Hz, 1H), 6.24 (d, J = 9.7 Hz, 1H), 5.73 (dd, J = 11.2,
8.5 Hz, 1H), 5.63 (dd, J = 10.9, 8.3 Hz, 1H), 5.59 (dd, J = 8.1, 3.0 Hz,
1H), 5.38–5.32 m, 1H), 5.18 (dd, J = 5.6, 2.9 Hz, 1H), 2.09 (s, 3H),
2.04 (s, 3H) 1.74–1.65 (m, 1H), 1.58–1.49 (m, 1H), 1.38–1.19 (m,
4H), 0.90 (t, J = 7.0 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3):
d = 170.2, 169.8, 162.1, 139.9, 133.1, 126.2, 125.0, 75.0, 69.3, 64.2,
34.0, 27.2, 22.4, 21.1, 20.4, 13.9 ppm. HRMS (ESI): calcd for C16H22-
O6Na [M+Na]+ 333.1308; found 333.1310.
4.1.18. (S,Z)-1-((2S,3S)-3-(Benzyloxy)-6-oxo-3,6-dihydro-2H-
pyran-2-yl)hept-1-en-3-yl acetate 21
To a cooled (0 °C) solution of secondary alcohol 17 (63 mg,
0.2 mmol) in pyridine (0.5 mL) was added Ac2O (0.3 mL) and stir-
red at room temperature for 2 h. After completion of the reaction,
the reaction was diluted with aqueous CuSO4ꢀ5H2O (5 mL) and

U. Ramulu et al. / Tetrahedron: Asymmetry 25 (2014) 1409–1417
1417
Tetrahedron Lett. 2012, 53, 1258–1260; (e) Rajaram, S.; Ramesh, D.; Ramulu,
U.; Prabhakar, P.; Venkateswarlu, Y. Helv. Chim. Acta 2014, 97, 112–121; (f)
Babu, D. C.; Rao, B.; Ramesh, D.; Swamy, S. R.; Venkateswarlu, Y. Tetrahedron
Lett. 2012, 53, 3633–3636; (g) Prabhakar, P.; Ramesh, D.; Rajaram, S.; Reddy, D.
K.; Venkateswarlu, Y. Helv. Chim. Acta 2011, 94, 1481–1487.; (h) Reddy, S. P.;
Venkateswarlu, Y. Tetrahedron Lett. 2013, 54, 4617–4619.
Acknowledgements
The authors thank the Director, CSIR-Indian Institute of
Chemical Technology for her constant encouragement. This work
was financially supported by ORIGIN project grant CSC-108 from
the Council of Scientific and Industrial Research, New Delhi (India)
under CSIR-Network program. U.R., D.R., S.P.R. and S.R. are thankful
to CSIR-UGC for providing fellowships.
7. (a) Cordova, A.; Sunden, H.; Bogevig, A.; Johansson, M.; Himo, F. Chem. Eur. J.
2004, 10, 3673–3684; (b) Chandrasekhar, S.; Mahipal, B.; Kavitha, M. J. Org.
Chem. 2009, 74, 9531–9534; (c) Mangion, I. K.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2005, 127, 3696–3697; (d) Brown, S. P.; Brochu, M. P.; Sinz, C. J.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 10808–10809.
8. Bartlett, S. L.; Beaudry, C. M. J. Org. Chem. 2011, 76, 9852–9855.
9. (a) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405–4408; (b) Horita, K.;
Sakurai, Y.; Nagasawa, M.; Yonemitsu, O. Chem. Pharm. Bull. 1997, 45, 1558–
1572; (c) Krishna, P. R.; Reddy, P. S. Tetrahedron 2007, 63, 3995–3999.
10. (a) Iversen, T.; Bundle, D. R. J. J. Chem. Soc., Chem. Commun. 1981, 1240–2250;
(b) Wessel, H.-P.; Iversen, T.; Bundle, D. R. J. Chem. Soc., Perkin Trans. 1 1985,
2247–2250; (c) Armstrong, A.; Brakendridge, I.; Jackson, R. F. W.; Kirk, J. M.
Tetrahedron Lett. 1988, 29, 2483–2486.
References
1. For reviews, See: (a) Marco, J. A.; Carda, M.; Murga, J.; Falomir, E. Tetrahedron
2007, 63, 2929–2958; (b) Boucard, V.; Broustal, G.; Campagne, J. M. Eur. J. Org.
Chem. 2007, 225–236.
2. (a) Perda-Miranda, R.; Hernandez, L.; Villavicencio, M. J.; Novelo, M.; Ibarra, P. J.
Nat. Prod. 1993, 56, 583–593; (b) Fragoso-Serrano, M.; Gibbons, S.; Pereda-
Miranda, R. Planta Med. 2005, 71, 278–280.
11. Kolb, H. C.; Nieuwenhze, M. S. V.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483–
2547.
3. Yadav, J. S.; Mandal, S. S. Tetrahedron Lett. 2011, 52, 5747–5749.
4. Sabitha, G.; Das, S. K.; Ankireddy, P.; Yadav, J. S. Tetrahedron Lett. 2013, 54,
1097–1099.
5. Kumar, T. V.; Shankaraih, G.; Babu, K. S.; Rao, J. M. Tetrahedron Lett. 2013, 54,
1397–1400.
6. (a) Ramulu, U.; Ramesh, D.; Rajaram, S.; Reddy, S. P.; Venkatesham, K.;
Venkateswarlu, Y. Tetrahedron: Asymmetry 2012, 23, 117–123; (b) Rajaram, S.;
Ramulu, U.; Ramesh, D.; Prabhakar, P.; Venkateswarlu, Y. Helv. Chim. Acta 2013,
96, 2115–2123; (c) Ramesh, D.; Rajaram, S.; Prabhakar, P.; Ramulu, U.; Reddy,
D. K.; Venkateswarlu, Y. Helv. Chim. Acta 2011, 94, 1226–1233; (d) Ramesh, D.;
Shekhar, V.; Chantibabu, D.; Rajaram, S.; Ramulu, U.; Venkateswarlu, Y.
12. Data for homoallylic ether 14: The selective protection of a benzyl group at C-2
(d 81.1) which is moved to downfield, instead of C-3 (d 67.5) which was
observed upfield in the 13C NMR spectrum, was further supported by the 2D
NMR spectrum of compound 14. The strong HMBC correlations (Fig. 3)
between H2-1, H-3, H2-benzyl (–OCH2–), and H-4/C-2 (d 81.1) confirmed the
benzyl ether position at C-2. The HMBC correlations between H-4, H2-1, and H-
2/C-3 (d 67.5) strongly suggested the free hydroxyl group at the C-3 carbon, in
addition, the position of the OTBS functionality at C-6 was deduced from the
strong HMBC correlations between H-5 and H2-7/C-6 (d 68.6).