Total synthesis of synargentolide B

Article abstract of DOI:10.1016/j.tetasy.2015.07.007

A simple and efficient stereoselective synthesis of synargentolide B was achieved by using ethyl (S)-2-hydroxypropanoate as a readily available starting material. The key steps involved in the synthesis are Horner-Wadsworth-Emmons olefination, Sharpless a

Full text of DOI:10.1016/j.tetasy.2015.07.007

Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Total synthesis of synargentolide B
⇑
Udugu Ramulu, Singanaboina Rajaram, Dasari Ramesh, 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:
A simple and efficient stereoselective synthesis of synargentolide B was achieved by using ethyl (S)-2-hy-
droxypropanoate as a readily available starting material. The key steps involved in the synthesis are
Horner–Wadsworth–Emmons olefination, Sharpless asymmetric dihydroxylation, zinc allylation, and
Hoveyda–Grubbs IInd generation catalyzed ring closing metathesis.
Received 28 May 2015
Accepted 14 July 2015
Available online xxxx
Ó 2015 Elsevier Ltd. All rights reserved.
1
. Introduction
Synargentolides A–E 1–5 are a,b-unsaturated d-lactones (Fig. 1),
which possess a polyacetoxy side chain skeleton isolated by Rivett
7
Over the past two decades, naturally occurring polyacetoxy side
and Davies-Coleman et al. from the South African plant
1
chain containing
a,b-unsaturated d-lactones are a growing class of
Syncolostemon argenteus, in 1998. The structures of five a-pyrones
natural products isolated from a wide variety of sources. In partic-
have been established based on spectroscopic, chiroptical, and
chemical evidences. In 1990, Pereda-Miranda et al. reported (6R)-
[(5R,6S)-diacetyloxy-(1S,2R)-dihydroxy-3E-heptenyl]-5,6-dihydro-
2H-pyran-2-one 1 from the leaves of Mexican plant Hyptis oblongi-
folia. Recently, Prasad et al. and Sabitha et al. established the
structure of 1 by the total synthesis of four diastereomers, individ-
ually. The absolute stereochemistry was confirmed by X-ray crystal
structure analysis of the corresponding tetraacetate of 1 by Prasad
ular, ,b-unsaturated d-lactones exhibit cytotoxicity against
a
2
human tumor cells, antifungal and antimicrobial properties. In
addition they inhibit HIV protease, induce apoptosis,4 and anti-
3
5
6
8
9
10
leukemic along with other immunosuppressive properties. Due
to these biological activities and structural features, d-lactones
have attracted the wide attention of a number of synthetic organic
chemists.
O
O
O
2
OAc
OH
O
OAc OAc
OAc
O
OAc
OH
2'
O1
6
3
4
4
'
7
'
5'
1
'
6
'
3'
5
OAc
synargentolide C 3
OH
OAc
OAc
OH
synargentolide A 2
revised structure)
synargentolide B 1
(
O
O
OAc
OAc
OH
O
OAc OAc
O
OH
OH
OH
synargentolide E 5
Figure 1. Structures of synargentolides A–E 1–5.
OH
OAc
synargentolide D 4
⇑
Corresponding author. Tel.: +91 40 27191881; fax: +91 40 27160512.
E-mail address: suresh@iict.res.in (K. Suresh Babu).
http://dx.doi.org/10.1016/j.tetasy.2015.07.007
957-4166/Ó 2015 Elsevier Ltd. All rights reserved.
0
Please cite this article in press as: Ramulu, U.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.07.007

2
U. Ramulu et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
O
O
O
O
OTBS
OH
OAc
O
O
a
OPMB
OPMB
OPMB
OPMB
OAc
OH
O
b
7
O
O
O
OTBS 15
HO
16
OAc
O
OAc
OH
6
OH
1
OAc
O
c
d
O
OH
O
O
OH
OTBS
OH
OTBS
OH
OAc
OEt
OPMB
17
OEt
1
8
OH
O
OAc
O
9
OTBS
8
7
e
OH
Scheme 1. Retrosynthetic analysis of 1.
O
OAc
19
et al. In 2014, Akkewar et al.11 also reported its total synthesis by
using -ribose and -ascorbic acid as starting materials.
Scheme 3. Reagents and conditions: (a) 2,2 dimethoxypropane, PTSA, CH Cl , 0 °C–
2
2
D
L
rt, 2 h, 92%; (b) TBAF, THF, 0 °C–rt, 4 h, 92%; (c) Red-Al, dry THF, 0 °C–rt, 8 h, 80%; (d)
Ac O, triethylamine, CH Cl , DMAP (cat) 0 °C–rt, 6 h, 93%; (e) DDQ, CH Cl /H
9:1), rt, 2 h, 93%.
2
2
2
2
2
2
O
As part of our ongoing research program on the total synthesis
of biologically active d-lactone containing natural products, the
structural features of synargentolide B 1 prompted us to attempt
the synthesis of this molecule. Recently we have accomplished
(
imidazole to give disilyl ether 11 in 88% yield. Reduction of ester
the synthesis of pectinolides A–C,1
pectinolide H,
2a
clonostachydiol,
etc. Herein, we report a simple and efficient
12b
1
1 using DIBAL-H at ꢀ78 °C gave the corresponding aldehyde in
1
2d
12
9
0% yield. The resultant aldehyde underwent a Wittig reaction
approach for the stereoselective total synthesis of synargentolide
B 1 in a concise manner from the inexpensive and readily available
starting material ethyl (S)-2-hydroxypropanoate 9.
with triethylphosphonoacetate, and sodium hydride in dry THF
to give 12 in 89% yield (Scheme 2). Ester 12 was reduced with
DIBAL-H at 0 °C to give alcohol 13 in 96% yield. Allylic alcohol 13
was protected with PMB imidate derived from p-methoxybenzyl
alcohol to provide PMB-ether 14 in 84% yield. Compound 14
was subjected to Sharpless asymmetric dihydroxylation reaction
2
. Results and discussion
14
According to the retrosynthetic analysis as shown in Scheme 1,
using AD-mix-b at 0 °C to furnish diol 7 in 90% yield (dr 97.5:2.5).
the target synargentolide
B
1
can be synthesized by ring
Diol 7 was protected with 2,2-dimethoxy propane in the pres-
ence of p-toluene sulfonic acid to give acetonide protected com-
pound 15 in 92% yield. Next, the di-TBS ethers in 15 were
removed using TBAF in THF to give diol 16 in 92% yield. The triple
bond in 16 was selectively converted into trans-double bond to
closing metathesis of compound 6, which in turn could be obtained
from the compound 7 by zinc allylation, followed by acryloylation.
Intermediate 7 could in turn be prepared from hydroxy ester 8
by Witting–Horner olefination, Sharpless asymmetric dihydroxyla-
tion, followed by other transformation reactions. Compound 8 could
be synthesized starting from ethyl (S)-2-hydroxypropanoate 9.
As shown in Scheme 2, the commercially available alcoholic
1
5
give 17 with Red-Al in dry THF in 80% yield. The secondary diol
in 17 was acetylated with acetic anhydride in the presence of tri-
ethylamine, and DMAP (cat) in dry dichloromethane to afford dia-
cetyl compound 18 in 93% yield (Scheme 3).
2
5
ester 9 was initially protected as its silyl ether 10 [
a
]
D
= ꢀ25.1 (c
)] in 93% yield with TBSCl
and imidazole. The silyl ester 10 was reduced with DIBAL-H
78 °C to give the aldehyde in 84% yield. The thus obtained
aldehyde was treated with ethyl propiolate and LiHMDS in dry
1
3b
2
.5, CHCl
3
) [Lit
= ꢀ21.7 (c 1.17, CHCl
3
The deprotection of the PMB group in 18 with DDQ/H O (9:1)
2
provided primary alcohol 19 in 93% yield. The primary alcohol 19
1
6
ꢀ
was oxidized with IBX in EtOAc at reflux to afford the corre-
sponding aldehyde, which was further subjected to zinc allyla-
2
5
17
THF to give hydroxy ester
8
[
a]
D
= +3.4 (c 2.5, CHCl
3
)
tion
4
by allylbromide, saturated NH Cl in THF to give an
1
3a
13a
[
Lit = +0.8 (c 4.3, CHCl
3
)] in 76% yield (dr 97:3).
The newly
inseparable mixture of 20 in 82% yield (88:12 determined by chiral
HPLC), which was separated by conversion into its acryloylester 6
generated hydroxy group was protected with TBSCl using
O
OH
OTBS
O
OTBS
OEt
a
b
c
OEt
OEt
O
9
8
10
HO
O
O
OTBS
OTBS
OTBS
OH
e
OEt
d
OEt
OTBS
13
12
OTBS 11
OTBS
OH
OTBS
f
OTBS
OPMB
g
OPMB
OH
14
OTBS
OTBS
7
Scheme 2. Reagents and conditions: (a) imidazole, TBSCl, CH
2
Cl
2
, rt, 8 h, 93%; (b) (i) DIBAL-H, CH
Cl
, ꢀ78 °C, 0.5 h, 90%; (ii) NaH, triethylphosphonoacetate 0 °C, 2 h, 89%; (e) DIBAL-H, CH
, 0 °C–rt, 8 h, 84%; (h) AD-mix-b, MeSO NH , t-BuOH/H O (1:1), 0 °C, 36 h, 90%.
2
Cl
2
, ꢀ78 °C, 0.5 h, 84%; (ii) ethyl propiolate, LIHMDS, dry THF, ꢀ78 °C to rt,
3
0
h, 76%; (c) imidazole, TBSCl, CH
°C, 0.5 h, 96%; (f) PMB imidate, PTSA (cat), dry CH
2
Cl
2
, rt, 8 h, 88%; (d) (i) DIBAL-H, CH
Cl
2
2
2
Cl
2
, ꢀ78 °C to
2
2
2
2
2
Please cite this article in press as: Ramulu, U.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.07.007

U. Ramulu et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
3
O
O
OAc
O
OH
OAc
O
O
OAc
O
O
a
b
19
+
OAc
O
OAc
O
OAc
O
20
6
6a
O
O
OAc
O
O
OAc
OH
O
d
c
OAc
O
OAc
OH
21
Synergentolide B
1
Scheme 4. Reagents and conditions: (a) (i) IBX, EtOAc, reflux, 4 h, 87%; (ii) Zn, allylbromide, saturated NH
6%; (c) Hoveyda–Grubbs-II, toluene, 80 °C, 1 h, 92%; (d) PPTS, MeOH, reflux, 6 h, 70%.
4
Cl 0 °C–rt, 9 h, 82%; (b) TEA, acryloylchloride, DCM, 0 °C, 10 min,
6
and 6a in 66% and 9% yields, respectively. The major compound 6
was subjected to ring closing metathesis protocol with
Hoveyda Grubbs-IInd catalyst (10 mol %) in toluene at 80 °C to
Table 2
1
3C NMR data of synargentolide B 1
a
18
Lit9
Lit10
Lit11
Natural product7
Position-C
Our synthesis
25
10
give compound 21 [
D 3
a] = +42.2 (c 0.2, CHCl ) {Lit = +45.5 (c
C-2
C-3
C-4
C-5
C-6
C-1
C-2
C-3
C-4
166.4
121.1
148.6
26.4
166.3
121.1
148.6
26.3
163.73
120.93
145.80
25.52
76.83
74.26
69.50
134.17
126.66
74.97
70.05
166.4
121.1
148.7
26.4
78.9
75.8
166.3
121.2
148.6
26.4
79.0
75.8
0
.46, CHCl )} in 92% yield. Finally, the deprotection of acetonide
3
group in 21 using PPTS in methanol gave the target molecule
synargentolide B 1 in 70% yield (Scheme 4). The physical and spec-
troscopic properties of these compounds were identical to those
reported earlier (Tables 1–3).
78.9
78.9
0
0
0
0
0
0
0
75.7
75.6
71.4
71.3
71.5
71.5
136.5
126.6
76.2
136.4
126.6
76.1
136.6
126.6
76.3
72.1
15.1
136.6
126.7
76.3
72.2
15.2
3
. Conclusion
C-5
C-6
C-7
72.1
72.0
In conclusion, we have reported a simple and efficient approach
15.1
15.2
15.08
for the synthesis of synargentolide B 1 in a stereoselective manner.
The crucial steps involved in the synthesis are the Sharpless asym-
metric dihydroxylation, zinc allylation and ring closing metathesis
for the synthesis of this plant derived natural product.
Ac-CO
Ac-CO
Ac-Me
Ac-Me
172.2
171.9
20.9
172.1
171.8
21.1
170.45
170.29
21.13
20.46
172.2
171.9
20.9
172.2
171.8
21.0
21.0
21.2
21.0
21.1
4
4
. Experimental
UV light). Yields refer to after chromatography and spectroscopi-
1
13
.1. General
cally ( H, C NMR) homogeneous material. Air-sensitive reagents
were transferred by syringe or double-ended needle. Evaporation
of solvents was performed at reduced pressure on a Buchi rotary
2
Reactions were conducted under N in anhydrous solvents such
1
13
as DCM, THF, DMSO, CH
3 2
CN, Et O, toluene, and EtOAc. All reactions
evaporator. H and C NMR spectra were recorded in CDCl
3
solu-
were monitored by TLC (silica-coated plates and visualizing under
tion on Varian Gemini 200 and BruckerAvance 300
a
Table 1
1
H NMR data of synargentolide B 1
Position-H
Lit9
Lit10
Lit11
6.03 (dt, 9.8, 1.5, 1H)
6.95 (ddd, 9.8, 5.3, 3.3, 1H)
2.58 (m, 2H)
4.52 (m, 1H)
3.71 (dd, 6.8, 2.7, 1H)
4.48 (m, 1H)
5.89 (dd, 15.8, 5.3, 1H)
5.81 (dd, 15.8, 6.8, 1H)
5.33 (dd, 6.4, 3.8, 1H)
5.07 (dq, 6.4, 3.8, 1H)
1.21 (d, 6.4, 3H)
2.09 (s, 3H)
Our synthesis
Natural product7
3
4
5
6
6.01 (d, 9.6, 1H)
6.02 (dt, 9.8, 1.5, 1H)
6.95 (ddd, 9.8, 5.2, 3.5, 1H)
2.57 (m, 2H)
4.53 (m, 1H)
3.70 (m, 1H)
6.03 (dt, 9.7, 1.2, 1H)
6.95 (ddd, 9.6, 5.8, 3.0, 1H)
2.57 (m, 2H)
4.52 (m, 1H)
3.70 (m, 1H)
5.97 (m, 9.7, 1H)
7.06 (m, 1H)
2.56 (m, 2H)
4.53 (td, 6.5, 3.2, 1H)
3.65 (m, 1H)
4.31 (m, 1H)
5.94 (ddd, 15.7, 5.8, 0.9, 1H)
5.79 (ddd, 15.7, 6.8, 1.2, 1H)
5.40 (dd, 6.8, 3.5, 1H)
5.04 (m, 1H)
1.20 (d, 6.6, 3H)
2.05 (s, 3H)
6.95 (dt, 9.4, 4.9, 1H)
2.62–2.49 (m, 2H)
4.57–4.50 (m, 1H)
3.76–3.64 (m, 1H)
4.49–4.41 (m, 1H)
5.88 (dd, 15.7, 5.2, 1H)
5.79 (dd, 15.6, 6.6, 1H)
5.31 (dt, 9.9, 3.6, 1H)
5.05 (dq, 10.2, 3.7, 1H)
1.19 (d, 6.5, 3H)
0
1
0
2
4.48 (m, 1H)
4.49 (m, 1H)
0
3
5.88 (dd, 15.6, 5.0, 1H)
5.79 (dd, 15.6, 6.0, 1H)
5.31 (dd, 6.0, 3.8, 1H)
5.05 (dq, 6.6, 3.8, 1H)
1.20 (d, 6.6, 3H)
2.08 (s, 3H)
5.88 (dd, 15.7, 5.2, 1H)
5.79 (dd, 15.6, 6.0, 1H)
5.32 (m, 1H)
5.07 (m, 1H)
1.21 (d, 6.5, 3H)
2.08 (s, 3H)
0
4
5
0
0
6
0
7
Ac-Me
2.07 (s, 3H)
Ac-Me
2.03 (s, 3H)
3.05 (br s, 1H)
2.95 (br s, 1H)
2.04 (s, 3H)
—
—
2.05 (s, 3H)
—
—
2.04 (s, 3H)
—
—
2.01 (s, 3H)
—
—
0
1
2
-OH
-OH
0
Table 3
Comparison of specific rotations of synargentolide B 1
Lit9
26.3 (c 0.2, CHCl
Lit10
Lit11
+27.1 (c 0.2, CH
Our synthesis
Natural product7
+
3
)
+25.6 (c 0.7, CHCl
3
)
2
Cl
2
)
+24.8 (c 0.4, CHCl
3
)
3
+28.8 (c 0.18, CHCl )
Please cite this article in press as: Ramulu, U.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.07.007

4
U. Ramulu et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
spectrometers. Chemical shifts (d) are reported relative to TMS
d = 0.0) as an internal standard. Mass spectra were obtained on
MS-EI, MS-ESI, HRMS mass spectrometers of Agilent Technologies
100 Series. Column chromatography was performed on silica gel
60–120 mesh) supplied by Acme Chemical Co., India. TLC was per-
formed on Merck 60 F-254 silica gel plates. IR (FT-IR) spectra were
recorded either on KBr pellets or neat as thin film or in CHCl
85.5, 77.3, 70.6, 66.9, 61.9, 25.6, 18.8, 17.9, 13.8, ꢀ4.6, ꢀ5.0;
+
(
ESI/MS (m/z): 309 (M+Na) .
1
(
4.1.3. (4R,5S)-Ethyl 4,5-bis(tert-butyldimethylsilyloxy)hex-2-
ynoate 11
To a solution of the ethyl ester compound 8 (5.2 g, 18.18 mmol)
2 2
in dry CH Cl (100 mL) was added imidazole (1.85 g, 27.3 mmol)
3
.
Optical rotations were recorded on JASCO DIP-360 digital
polarimeter at 25 °C.
and the reaction mixture was stirred for 10 min at 0 °C. To this
solution tert-butyldimethylsilyl chloride (3.28 g, 21.8 mmol) was
added at 0 °C, and the mixture was stirred at room temperature
for 8 h. After completion of the reaction, the mixture was diluted
4
.1.1. (S)-Ethyl 2-(tert-butyldimethylsilyloxy)propanoate 10
To a solution of ethyl (S)-2 hydroxypropanoate (9) (6 g,
0.84 mmol) in dry DCM (125 mL) was added imidazole (5.18 g,
6.27 mmol), and the mixture was stirred for 10 min at 0 °C. To
with ice-water and extracted into CH
bined extract was washed with brine, dried over anhydrous
Na SO , and concentrated under reduced pressure. The crude resi-
2
Cl
2
(3 ꢁ 100 mL). The com-
5
7
2
4
this solution tert-butyldimethylsilyl chloride (9.19 g, 61.01 mmol)
was added at 0 °C, and the mixture was stirred at room tempera-
ture for 8 h. After completion of the reaction, the mixture was
diluted with ice-water and extracted into DCM (3 ꢁ 125 mL). The
combined organic extract was washed with brine, dried over anhy-
due was purified by column chromatography using (hexane/ethy-
lacetate) (96:4) to give pure compound 11 (6.33 g, 88%) as a
2
5
ꢀ1
colorless liquid. [
a
]
D
= ꢀ9.1 (c 2.3, CHCl
3 max
); IR (neat, cm ): m
2957, 2931, 2888, 2859, 1739, 2241, 1718, 1473, 1364, 1251,
1116, 837, 779; H NMR (300 MHz, CDCl
1
3
): d 4.22 (q, J = 7.5 Hz,
drous Na
2
SO
4
, and concentrated under reduced pressure. The crude
2H), 4.17 (d, J = 6.0 Hz, 1H), 3.89–3.79 (m, 1H), 1.30 (t, J = 7.5 Hz,
3H), 1.20 (d, J = 6.0 Hz, 3H), 0.91 (s, 9H), 0.89 (s, 9H), 0.16 (s, 3H),
0.12 (s, 3H), 0.10 (s, 3H), 0.08 (s, 3H); C NMR (75 MHz, CDCl ):
3
d 153.4, 87.7, 76.7, 71.7, 68.4, 61.7, 25.8, 25.7, 19.9, 18.1, 18.0,
14.0, ꢀ4.5, ꢀ4.6, ꢀ4.8, ꢀ5.1; ESI/MS (m/z): 423 (M+Na).
residue was purified by column chromatography using hex-
ane/ethyl acetate (98:2) to give pure compound 10 (10.97 g, 93%)
as a colorless liquid. [
1
3
2
5
13b
a
]
D
= ꢀ25.1 (c 2.5, CHCl
3
) [Lit
= ꢀ21.7 (c
ꢀ1
1
1
4
1
.17, CHCl )]; IR (neat, cm ): mmax 2955, 2932, 2897, 2859, 1736,
373, 1257, 1146, 1061, 833, 778; H NMR (300 MHz, CDCl ): d
.30 (q, J = 6.4 Hz, 1H), 4.23–4.12 (m, 2H), 1.39 (d, J = 7.1 Hz, 3H),
.27 (t, J = 6.4 Hz, 3H), 0.90 (s, 9H), 0.10 (s, 3H), 0.07 (s, 3H);
3
1
3
4.1.4. (6R,7S,E)-Ethyl 6,7-bis(tert-butyldimethylsilyloxy)oct-2-
en-4-ynoate 12
1
3
C
NMR (75 MHz, CDCl
5.0, ꢀ5.4; ESI/MS (m/z): 255 (M+Na) .
3
): d 173.9, 68.4, 60.6, 25.6, 21.2, 18.2, 14.1,
To a cooled (ꢀ78 °C) solution of ester compound 11 (5.1 g,
+
ꢀ
2 2
12.75 mmol) in dry CH Cl (75 ml) was added DIBAL-H (1.0 M in
toluene, 12.8 mL, 12.75 mmol) and the reaction was stirred for
0.5 h. After completion of the reaction, the reaction was quenched
with saturated sodium potassium tartrate (30 mL) and stirred for
4
.1.2. (4R,5S)-Ethyl 5-(tert-butyldimethylsilyloxy)-4-hydroxy-
hex-2-ynoate 8
To a cooled (ꢀ78 °C) stirred solution of compound 10 (9.0 g,
0.5 h. The reaction mixture was extracted into CH
(3 ꢁ 75 mL). The combined organic phase was washed with brine,
and dried over anhydrous Na SO , and concentrated in vacuo. The
crude product was purified by column chromatography (hex-
ane/ethylacetate, 93:7) to give the aldehyde (4.08 g, 90%) as a col-
orless oil.
2 2
Cl
3
8.80 mmol) in dry DCM (150 mL) was added DIBAL-H (1.0 M, in
toluene, 38.8 mL, 38.8 mmol) and the reaction mixture was stirred
for 0.5 h. After completion of the reaction, the reaction was
quenched with saturated sodium potassium tartrate (50 mL) and
stirred for 0.5 h. The reaction mixture was extracted into DCM
2
4
(
3 ꢁ 125 mL). The combined organic phase was washed with brine,
To a cooled solution (0 °C) of triethylphosphonoacetate (3.58 g,
16.01 mmol) in dry THF (30 mL), was slowly added NaH (60%)
(0.55 g, 13.87 mmol) and the reaction mixture was stirred for
30 min at the same temperature. A solution of the aldehyde
(3.8 g, 10.67 mmol) obtained above in THF (20 mL) was added
dropwise and stirred for 1 h. After completion of the reaction, it
and dried over anhydrous Na SO . The solvent was removed under
2
4
reduced pressure. The crude residue was purified by column chro-
matography using (hexane/ethyl acetate 95:5) to give the pure
aldehyde (6.12 g, 84%) as a colorless liquid.
To a stirred solution of ethyl propiolate (4.38 g, 44.68 mmol) in
dry THF (30 ml) was added LiHMDS (1.0 M, in hexane, 38.3 ml,
was quenched with saturated NH
etate (3 ꢁ 100 mL). The combined organic layer was washed with
brine, dried over Na SO , and concentrated. The residue was puri-
4
Cl, and extracted into ethylac-
3
ꢀ
8.3 mmol) at ꢀ78 °C and the reaction mixture was stirred at
78 °C for 30 min. The aldehyde (6.0 g, 31.90 mmol) dissolved in
THF (50 ml) was added dropwise to the reaction mixture over
h. Stirring was continued for 2 h. After completion of the reac-
tion, the mixture was quenched with saturated NH Cl (40 mL)
2
4
fied by column chromatography using (hexane/ethylacetate 94:6)
1
to give the product 12 (4.04 g, 89% yield) as a colorless liquid.
2
5
4
[a]
D
= ꢀ11.7 (c 3.0, CHCl
3
). IR (neat): 2957, 2931, 2887, 2858,
and stirred for 0.5 h, then diluted with water. The reaction mixture
was extracted into ethyl acetate (3 ꢁ 125 mL). The combined
organic phase was washed with brine and dried over anhydrous
2213, 1720, 1621, 1472, 1363, 1301, 1258, 1154, 1114, 835,
777 cm
ꢀ
1
1
.
3
H NMR (300 MHz, CDCl ): d = 6.77 (dd, J = 15.8,
1.5 Hz, 1H), 6.18 (d, J = 15.8 Hz, 1H), 4.25–4.18 (m, 3H), 3.84–3.78
(m, 1H), 1.30 (t, J = 7.1 Hz, 3H), 1.19 (d, J = 6.0 Hz, 3H), 0.91 (s,
9H), 0.89 (s, 9H), 0.13 (s, 3H), 0.11 (s, 3H), 0.08 (s, 3H), 0.07 (s,
2 4
Na SO . The solvent was removed under reduced pressure. The
crude residue was purified by column chromatography using (hex-
ane/ethyl acetate) (85:15) to give pure compound 8 (6.93 g, 76%) as
a brown liquid. The de was determined by chiral HPLC column:
1
3
3
3H); C NMR (75 MHz, CDCl ): d = 165.8, 130.1, 125.0, 100.0,
81.5, 71.9, 69.0, 60.7, 25.7, 20.1, 18.1, 18.0, 14.1, ꢀ4.6, ꢀ4.7,
(
ATLANTIS C18: 150 ꢁ 4.6 mm, 5
l) mobile phase: 80% ACN in
ꢀ5.1; ESI/MS (m/z): 449 (M+Na).
WATER, Flow rate: 1.0 ml/min, detection: 210 nm, 94% de).
2
5
13a
[a
]
D
= +3.4 (c 2.5, CHCl
3
) [Lit = +0.8 (c 4.3, CHCl
3
)]; IR (neat,
4.1.5. (6R,7S,E)-6,7-Bis(tert-butyldimethylsilyloxy)oct-2-en-4-
yn-1-ol 13 dot alcohol 13
To a cooled (0 °C) stirred solution of compound 12 (3.9 g,
2 2
9.15 mmol) in dry CH Cl (75 mL) was added DIBAL-H (1.0 M in
toluene, 18.3 mL, 18.30 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
ꢀ
1
cm ):
mmax 3446, 2957, 2932, 2896, 2859, 2240, 1716, 1472,
1
1
4
2
0
464, 1368, 1251, 1093, 837, 778; H NMR (300 MHz, CDCl
3
): d
.37–4.32 (m, 1H), 4.24 (q, J = 7.1, Hz, 2H), 4.03–3.94 (m, 1H),
.50 (br s, 1H), 1.31 (t, J = 7.1 Hz, 3H), 1.26 (d, J = 6.2 Hz, 3H),
.91 (s, 9H), 0.10 (s, 6H); 13C NMR (75 MHz, CDCl
): d 153.2,
3
Please cite this article in press as: Ramulu, U.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.07.007

U. Ramulu et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
5
stirred for 0.5 h. The reaction mixture was extracted into CH
3 ꢁ 75 mL). The combined organic phase was washed with brine,
and dried over anhydrous Na SO . The solvent was removed under
2
Cl
2
4.1.8. (5R,6S)-5-((E)-5-(((4R,5R)-5-((4-Methoxybenzyloxy)meth-
yl)-2,2-dimethyl 1,3 dioxolan-4-yl)ethynyl)-2,2,3,3,6,8,8,9,9-non-
amethyl-4,7-dioxa-3,8-disiladecane 15
(
2
4
reduced pressure, the residue was purified by column chromatog-
To
a
cooled (0 °C) solution of diol compound
7 (2.0 g,
raphy using (hexane/ethylacetate 80:20) to give the alcohol 13
3.717 mmol) in dry CH
2
Cl (40 mL) was added 2,2-dimethoxypro-
2
25
(
3.374 g, 96% yield) as a colorless liquid. [
a
]
D
= ꢀ14.2 (c 3.2,
pane (2.3 ml, 18.60 mmol) and a catalytic amount of PTSA. The
resulting mixture was bought to room temperature and stirred
for 2 h. After completion of the reaction, the mixture was quenched
CHCl ). IR (neat): 3422, 2956, 2931, 2887, 2858, 2213, 1472,
3
ꢀ1 1
1
463, 1362, 1256, 1115, 1042, 836, 777 cm . H NMR (300 MHz,
CDCl
3
): d = 6.20 (dt, J = 15.4, 5.5 Hz, 1H), 5.75 (d, J = 14.4 Hz, 1H),
with saturated NaHCO
(3 ꢁ 50 mL). The combined extract was washed with brine, dried
over anhydrous Na SO , and concentrated under reduced pressure.
3
solution, and extracted into DCM
4
0
0
8
.24–4.16 (m, 3H), 3.81–3.76 (m, 1H), 1.19 (d, J = 6.6 Hz, 3H),
.90 (s, 9H), 0.89 (s, 9H), 0.13 (s, 3H), 0.11 (s, 3H), 0.08 (s, 3H),
.07 (s, 3H); C NMR (75 MHz, CDCl
2.4, 72.2, 68.9, 62.9, 25.8, 25.7, 19.9, 18.2, 18.1, ꢀ4.4, ꢀ4.5,
5.0; ESI/MS (m/z): 407 (M+Na).
2
4
1
3
3
): d = 141.1, 110.4, 91.2,
The crude residue was purified by column chromatography using
(hexane/ethylacetate) (90:10) to give pure compound 15 (1.97 g,
2
5
ꢀ
92%) as a colorless oil. [
a
]
D
= +18.2 (c 1.4, CHCl
3
); IR (neat,
ꢀ1
cm ):
3
1250, 1111, 1037, 833, 777; H NMR (300 MHz, CDCl ): d 7.30–
mmax 2955, 2931, 2888, 2858, 1614, 1514, 1463, 1380,
1
4
2
.1.6. (5R,6S)-5-((E)-5-(4-Methoxybenzyloxy)pent-3-en-1-ynyl)-
,2,3,3,6,8,8,9,9-nonamethyl-4,7-dioxa-3,8-disiladecane 14
To a cooled (0 °C) solution of alcohol compound 13 (3.5 g,
7.22 (m, 2H), 6.87 (d, J = 8.3 Hz, 2H), 4.53 (s, 2H), 4.49 (dd, J = 7.5,
1.5 Hz, 1H), 4.26–4.18 (m, 1H), 4.15–4.09 (m, 1H), 3.88–3.73 (m,
4H), 3.64–3.49 (m, 2H), 1.47 (s, 3H), 1.42 (s, 3H), 1.16 (s, 3H),
0.89 (s, 9H), 0.88 (s, 9H), 0.10 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H),
9
2 2
.11 mmol) in dry CH Cl (60 mL) was added PMB imidate
(
3.86 g, 13.67 mmol) followed by PTSA (catalytic amount) and
1
3
the reaction was stirred at room temperature for 8 h. After comple-
tion of the reaction, it was quenched with triethylamine and
diluted with water (60 mL), and extracted with DCM (3 ꢁ 75 mL).
The combined organic layers was washed with brine, dried over
3
0.06 (s, 3H); C NMR (75 MHz, CDCl ): d 159.2, 129.9, 129.3,
113.7, 110.5, 87.1, 81.4, 80.9, 73.2, 72.0, 68.9, 68.4, 67.4, 55.2,
27.0, 26.2, 25.8, 25.7, 19.5, 18.2, 18.0, ꢀ4.5, ꢀ5.0; ESI/MS (m/z):
601 (M+Na).
Na
by column chromatography on silica gel (hexane/ethylacetate,
8:12) to give compound 14 (3.85 g, 84%) as a brown color liquid.
2 4
SO , and concentrated in vacuo. The crude product was purified
4.1.9. (2S,3R)-5-((4R,5R)-5-((4-Methoxybenzyloxy)methyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)pent-4-yne-2,3-diol 16
8
2
5
ꢀ1
[
1
CDCl
a
]
D
= ꢀ10.5 (c 3.4, CHCl
614, 1515, 1463, 1251, 1112, 1039, 832, 775; H NMR (300 MHz,
): d 7.28–7.23 (m, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.14 (dt,
3
); IR (neat, cm ):
m
max 2956, 2931, 2858,
To a cooled (0 °C) solution of acetonide protected compound 15
(1.8 g, 3.11 mmol) in dry THF (15 mL) was added TBAF (9.3 ml, 1 M
in THF, 9.34 mmol) and stirred for 4 h at room temperature.
After completion of the reaction, the reaction was diluted with
water and extracted into EtOAc (3 ꢁ 50 mL). The combined organic
1
3
J = 15.8, 5.9 Hz, 1H), 5.74 (d, J = 14.8 Hz, 1H), 4.44 (s, 2H), 4.18 (d,
J = 5.9 Hz, 1H), 4.02 (d, J = 6.8 Hz, 1H), 3.80 (s, 3H), 1.19 (d,
J = 6.0 Hz, 3H), 0.90 (s, 9H), 0.89 (s, 9H), 0.13 (s, 3H), 0.11 (s, 3H),
2 4
layer was washed with brine, dried over Na SO , and concentrated
0
1
5
5
.08 (s, 3H), 0.07 (s, 3H); 13C NMR (75 MHz, CDCl
39.0, 130.0, 129.3, 113.8, 111.7, 91.0, 82.6, 72.2, 71.9, 69.5, 68.9,
5.2, 25.8, 25.7, 19.9, 18.2, 18.1, ꢀ4.5, ꢀ4.6, ꢀ5.0. ESI/MS (m/z):
27 (M+Na).
3
): d 159.2,
in vacuum. The crude product was purified by column chromatog-
raphy on silica gel (hexane/ethyl acetate, 40:60) to give pure
2
5
compound 16 (1.0 g, 92%) as a colorless liquid. [
a]
D
= +32.9 (c
ꢀ1
3
1.7, CHCl ); IR (neat, cm ):
mmax 3446, 3073, 3029, 2977,
928, 2871, 1637, 1452, 1078, 928, 741, 669; H NMR (300 MHz,
1
2
4
.1.7. (2R,3R,6R,7S)-6,7-Bis(tert-butyldimethylsilyloxy)-1-(4-
3
CDCl ): d 7.29–7.24 (m, 2H), 6.88 (d, J = 8.5 Hz, 2H), 4.56–4.52
methoxybenzyloxy)oct-4-yne-2,3-diol 7
(m, 3H), 4.31 (dd, J = 3.6, 1.6 Hz, 1H), 4.23–4.19 (m, 1H), 3.86
(dd, J = 6.4, 3.6 Hz, 1H), 3.81 (s, 3H), 3.60 (d, J = 4.3 Hz, 2H),
2
To a solution of AD-mix-b (6.11 g, 6.11 mmol) in t-BuOH/H O
1
3
(
1:1) (40 mL) was added methanesulfonamide (0.425 g,
1.48 (s, 3H), 1.42 (s, 3H), 1.23 (s, 3H); C NMR (75 MHz, CDCl
3
):
4
.36 mmol) at room temperature and stirred for 10 min. The solu-
d
159.2, 129.6, 129.4, 113.8, 110.7, 84.1, 83.3, 80.7, 73.2,
tion was then cooled to 0 °C, olefin 14 (2.2 g, 4.36 mmol) added,
and the entire reaction mixture was stirred vigorously at this tem-
perature for 36 h. After completion of the reaction (as noticed by
TLC), the reaction was quenched with sodium sulfite (6.5 g) and
stirring was continued for another 0.5 h after which the reaction
mixture was brought to room temperature. The product was
extracted into EtOAc (3 ꢁ 75 mL), and the combined organic layer
70.1, 68.7, 67.5, 67.0, 55.2, 26.8, 26.2, 18.2; ESI/MS (m/z): 373
(M+Na).
4.1.10. (2S,3R,E)-5-((4R,5R)-5-((4-Methoxybenzyloxy)methyl)-
2,2-dimethyl-1,3-dioxolan-4-yl)pent-4-ene-2,3-diol 17
To a cooled (0 °C) solution of 16 (0.8 g, 2.285 mmol) in dry THF
(10 mL) was added Red-Al (2.2 ml, 11.428 mmol) and stirred at
room temperature for 12 h. After completion of the reaction, the
was dried over Na
by silica gel column chromatography using (hexane/ethylacetate)
77:23) as eluent to obtain diol 7 (2.11 g, 90% yield, 95% de) as a
colorless viscous liquid. The de was determined by chiral HPLC col-
umn: (XDB C18: 250 ꢁ 4.6 mm, 5 ) mobile phase: 90% ACN in
WATER, Flow rate: 1.0 ml/min, detection: 210 nm, 96% de).
2 4
SO and concentrated. The residue was purified
mixture was quenched with saturated NaHCO
extracted into EtOAC (3 ꢁ 50 mL). The combined organic extract
was washed with brine, dried over anhydrous Na SO , and concen-
3
solution and
(
2
4
l
trated under reduced pressure. The crude residue was purified by
column chromatography using (hexane/ethyl) acetate (45:55) to
2
5
[
1
a
]
D
= ꢀ19.4 (c 3.4, CHCl
3
). IR (neat): 3437, 2929, 2856, 1587,
give pure 17 (0.643 g, 80%) as a colorless gummy liquid.
ꢀ1
1
25
ꢀ1
463, 1282, 1250, 1128, 831, 777 cm
.
H NMR (300 MHz,
[a
]
D
= +9.5 (c 1.1, CHCl
3
); IR (neat, cm ): mmax 3445, 2984, 2931,
CDCl
3
): d = 7.27–7.23 (m, 2H), 6.88 (d, J = 8.7 Hz, 2H), 4.49 (s,
1611, 1514, 1458, 1382, 1302, 1248, 1171, 1079, 1032, 848, 819;
H NMR (30 0 MHz, CDCl ): d 7.28–7.23 (m, 2H), 6.88 (d,
3
J = 8.5 Hz, 2H), 5.83–5.72 (m, 2H), 4.51 (s, 2H), 4.26–4.22 (m, 1H),
1
2H), 4.43 (dd, J = 6.1, 1.2 Hz, 1H), 4.14 (dd, J = 5.0, 1.4 Hz, 1H),
3.83–3.77 (m, 5H), 3.68 (dd, J = 9.6, 4.2 Hz, 1H), 3.59 (dd, J = 9.6,
5.6 Hz, 1H), 1.16 (d, J = 6.1 Hz, 3H), 0.90 (s, 9H), 0.89 (s, 9H), 0.11
4.07–4.02 (m, 1H), 3.91–3.85 (m, 1H), 3.84–3.76 (m, 4H), 3.61–
13
13
(
s, 3H), 0.09 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H); C NMR (75 MHz,
CDCl ): d = 159.3, 129.7, 129.4, 113.8, 86.9, 82.3, 73.3, 72.1, 70.2,
8.4, 63.8, 55.2, 25.8, 25.7, 19.5, 18.2, 18.1, ꢀ4.5, ꢀ4.6 ESI/MS
m/z): 561 (M+Na).
3.51 (m, 2H), 1.43 (s, 6H), 1.08 (d, J = 6.4 Hz, 3H); C NMR
3
3
(75 MHz, CDCl ): d 159.3, 132.5, 130.4, 129.8, 129.4, 113.7, 109.5,
79.9, 78.8, 75.6, 73.2, 69.9, 68.9, 55.2, 26.9, 17.7; ESI/MS (m/z):
375 (M+Na).
6
(
Please cite this article in press as: Ramulu, U.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.07.007

6
U. Ramulu et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
4
2
1
.1.11. (2S,3R,E)-5-((4R,5R)-5-((4-methoxybenzyloxy)methyl)-
,2-dimethyl-1,3-dioxolan-4-yl)pent-4-ene-2,3-diyl diacetate
8
The crude residue was purified by column chromatography using
(hexane/ethylacetate) (80:20) as eluent to obtain pure compound
ꢀ1
20 (232 mg, 82%) as a colorless liquid. IR (neat, cm ):
mmax 3456,
To a cooled (0 °C) solution of diol 17 (520 mg, 1.47 mmol) in
2987, 2923, 1740, 1633, 1372, 1228, 1168, 1059, 978, 878, 765:
H NMR (300 MHz, CDCl ): d 5.93–5.73 (m, 3H), 5.43–5.29 (m,
3
1
CH
2
Cl
2
(15 mL) were added triethylamine (0.83 ml, 5.9 mmol),
acetic anhydride (0.42 mL, 4.43 mmol), and a catalytic amount of
DMAP and stirred at room temperature for 6 h. After completion
1H), 5.20–5.01 (m, 3H), 4.53–4.44 (m, 1H), 3.89–3.80 (m, 1H),
3.73–3.62 (m, 1H), 2.38–2.15 (m, 2H), 2.08 (s, 3H), 2.04 (s, 3H),
13
of the reaction, the reaction was diluted with aqueous NaHCO
5 mL) and extracted into DCM (2 ꢁ 30 mL). The combined organic
phase was washed with brine, and dried over Na SO . After evap-
3
1.44 (s, 3H), 1.42 (s, 3H), 1.20 (d, J = 6.6 Hz, 3H);
C NMR
(
(75 MHz, CDCl ): d 170.3, 169.9, 133.9, 133.5, 127.2, 118.3, 109.1,
3
2
4
82.5, 77.0, 74.4, 70.5, 37.5, 26.9, 26.8, 21.1, 21.0, 15.0; ESI/MS
oration of the solvent, the crude residue was purified by column
chromatography using (hexane/ethylacetate) (75:25) as eluent to
afford the desired product 18 (596 mg, 93% yield) as a colorless liq-
(m/z): 379 (M+Na).
4.1.14. (2S,3R,E)-5-((4R,5R)-5-((R)-1-(Acryloyloxy)but-3-enyl)-
2,2-dimethyl-1,3-dioxolan-4-yl)pent-4-ene-2,3-diyl diacetate 6
To a cooled (0 °C) solution of alcohol 20 (165 mg, 0.463 mmol)
25
uid. [
D 3
a] = +3.2 (c 1.3, CHCl ). IR (neat): 2987, 2937, 1741, 1612,
ꢀ1
1
513, 1458, 1371, 1301, 1246, 1172, 1087, 1032, 820, 760 cm
.
1
H
NMR (300 MHz, CDCl
3
):
d
7.28–7.23 (m, 2H), 6.88 (d,
in dry CH
2
Cl
2
(5 mL) was added triethylamine (0.16 mL,
J = 6.5 Hz, 2H), 5.83–5.65 (m, 2H), 5.38 (dd, J = 6.2, 3.5 Hz, 1H),
1.158 mmol) and acryloyl chloride (0.1 mL, 1.02 mmol) and stirred
at the same temperature for 10 min. After completion, the reaction
was quenched with saturated sodium bicarbonate (5 ml) and
5
3
2
.05–4.97 (m, 1H), 4.52 (s, 2H), 4.25 (dd, J = 8.2, 6.1 Hz, 1H),
.88–3.83 (m, 1H), 3.80 (s, 3H), 3.56–3.51 (m, 2H), 2.07 (s, 3H),
1
3
.02 (s, 3H), 1.43 (s, 3H), 1.42 (s, 3H), 1.14 (d, J = 6.5 Hz, 3H);
): d = 170.3, 169.8, 159.2, 132.2, 129.8,
29.3, 127.4, 113.7, 109.6, 79.9, 78.2, 74.2, 73.2, 70.4, 68.8, 55.2,
C
extracted into CH
was washed with brine, and dried over anhydrous Na
2
Cl
2
(3 ꢁ 15 mL). The combined organic phase
NMR (75 MHz, CDCl
1
2
3
2
SO . The sol-
4
vent was removed under reduced pressure, and the crude residue
was purified by column chromatography on silica gel (hex-
6.9, 26.8, 21.1, 21.0, 14.9. ESI/MS (m/z): 459 (M+Na).
ane/ethyl acetate, 90:10) to give acryl ester compound
6
2
5
4
3
.1.12. (2S,3R,E)-5-((4R,5R)-5-(Hydroxymethyl)-2,2-dimethyl-1,
-dioxolan-4-yl)pent-4-ene-2,3-diyl diacetate 19
(125 mg, 66%) as a colorless liquid. [
a
]
D
= +18.3 (c 0.8, CHCl
3
); IR
ꢀ1
(neat, cm ):
m
max 2921, 2851, 1743, 1619, 1383, 1227, 1067,
1
To a cooled (0 °C) solution of 18 (550 mg, 1.267 mmol) in CH
18 mL) and water (2 mL) was added DDQ (575 mg, 2.534 mmol)
and stirred at room temperature for 2 h. After completion of the
reaction, saturated NaHCO (15 ml) solution was added, and the
aqueous layer was extracted with CH Cl
(2 ꢁ 50 mL). The com-
bined organic extract was washed with brine, dried over anhy-
drous Na SO , and concentrated under reduced pressure. The
2
Cl
2
770; H NMR (300 MHz, CDCl ): d 6.42 (d, J = 17.4 Hz, 1H), 6.10
3
(
(dd, J = 17.2, 10.4 Hz, 1H), 5.92–5.69 (m, 4H), 5.42–5.39 (m, 1H),
5.22–4.98 (m, 4H), 4.40–4.36 (m, 1H), 3.85–3.79 (m, 1H),
2.56–2.30 (m, 2H), 2.09 (s, 3H), 2.04 (s, 3H), 1.42 (s, 3H), 1.41 (s,
3
1
3
2
2
3
3H), 1.18 (d, J = 6.5 Hz, 3H); C NMR (75 MHz, CDCl ): d 170.3,
169.8, 165.3, 132.7, 132.2, 131.5, 128.1, 127.7, 118.4, 109.7, 80.7,
78.7, 74.0, 72.6, 70.5, 35.6, 26.9, 26.8, 21.1, 20.1, 14.8; ESI/MS
(m/z): 431 (M+Na).
2
4
crude residue was purified by column chromatography using (hex-
ane/ethylacetate) (70:30) to give compound 19 (370 mg, 93% yield)
2
5
as a colorless liquid. [
a]
D
= +13.2 (c = 0.3, CHCl
3
). IR (neat): 3445,
4.1.15. (2S,3R,E)-5-((4R,5R)-2,2-Dimethyl-5-((R)-6-oxo-3,6-di-
hydro-2H-pyran-2-yl)-1,3-dioxolan-4-yl)pent-4-ene-2,3-diyl
diacetate 21
2
6
5
987, 2936, 1740, 1633, 1372, 1229, 1167, 1053, 975, 856,
. H NMR (300 MHz, CDCl ): d 5.87–5.71 (m, 2H), 5.42–
3
.32 (m, 1H), 5.11–5.00 (m, 1H), 4.41–4.32 (m, 1H), 3.89–3.74
m, 2H), 3.65–3.52 (m, 1H), 2.08 (s, 3H), 2.05 (s, 3H), 1.44 (s, 6H),
.19 (d, J = 6.4 Hz, 3H).
69.8, 131.9, 128.0, 109.5, 81.0, 80.9, 74.3, 70.3, 60.5, 26.9, 26.8,
1.1, 20.9, 15.0; ESI/MS (m/z): 339 (M+Na).
ꢀ1 1
08 cm
A solution of compound 6 (30 mg, 0.0735 mmol) in dry toluene
(15 mL) was first bubbled with nitrogen flow, after which Hoveyda
Grubbs II generation catalyst (4.6 mg, 0.007 mmol) was added at
once and the resulting mixture was heated under nitrogen at
80 °C for 1 h. After completion of the reaction, the mixture was
cooled to room temperature and the solvent was evaporated in
vacuo. The crude residue was purified by column chromatography
on silica gel (hexane/ethylacetate, 42:58) to give compound 21
(
13
1
1
2
3
C NMR (75 MHz, CDCl ): d = 170.3,
4
.1.13. (2S,3R,E)-5-((4R,5R)-5-(1-Hydroxybut-3-enyl)-2,2-dimeth-
yl-1,3-dioxolan-4-yl)pent-4-ene-2,3-diyl diacetate 20
2
5
To a solution of 19 (330 mg, 1.05 mmol) in EtOAc (10 mL) was
added IBX (882 mg, 3.15 mmol) at room temperature and then
refluxed for 4 h. After completion of the reaction, the reaction
was filtered through a shot pad of Celite and the Celite pad was
washed with EtOAc (2 ꢁ 20 mL). The organic layer was washed
(25.8 mg, 92%) as a colorless liquid. [
a]
D
= +42.2 (c 0.2, CHCl
3
)
1
0
ꢀ1
[Lit = +45.5 (c 0.46, CHCl
3
)]; IR (neat, cm ):
1739, 1609, 1374, 1243, 1067, 977, 816; H NMR (300 MHz,
m
max 2924, 2853,
1
CDCl ): d 6.92 (ddd, J = 8.4, 4.7, 3.8 Hz, 1H), 6.04 (dt, J = 9.9,
3
1.9 Hz, 1H), 5.92–5.82 (m, 2H), 5.41 (dd, J = 5.3, 3.5 Hz, 1H), 5.10–
5.01 (m, 1H), 4.51–4.41 (m, 2H), 3.89 (t, J = 7.1 Hz, 1H), 2.56–2.52
(m, 2H), 2.09 (s, 3H), 2.05 (s, 3H), 1.43 (s, 3H), 1.42 (s, 3H), 1.22
with saturated NaHSO
dried over anhydrous Na
3
solution (2 ꢁ 20 mL), brine (1 ꢁ 50 mL),
SO , and concentrated. The crude residue
2
4
1
3
was purified by column chromatography using hexane/ethylac-
etate (75:25) as eluent to obtain pure aldehyde (285 mg, 87% yield)
as a colorless liquid.
3
(d, J = 6.5 Hz, 3H); C NMR (75 MHz, CDCl ): d 170.4, 169.9,
162.6, 144.6, 132.4, 127.3, 121.4, 110.3, 80.8, 79.1, 78.0, 74.5,
70.6, 26.9, 26.2, 21.1, 21.0, 15.0; ESI/MS (m/z): 405 (M+Na).
To
.796 mmol) in THF (4 mL) was added allyl bromide (0.2 ml,
.388 mmol) and zinc (207 mg, 3.18 mmol). Saturated NH Cl
a cooled (0 °C) solution of the aldehyde (250 mg,
0
2
4.1.16. (2S,3R,6R,7S,E)-6,7-Dihydroxy-7-((R)-6-oxo-3,6-dyhydro-
2H-pyran-2-yl)hept-4-ene-2,3-diyl diacetate 1
4
(
1
1 ml) was then added dropwise to the reaction mixture over
0 min and stirred at the same temperature for 1 h. The reaction
To a cooled (0 °C) solution of compound 21 (15 mg,
0.039 mmol) in MeOH (4 mL) was added PPTS (29 mg,
0.117 mmol) and the resulting mixture was refluxed for 6 h. After
completion of the reaction, the MeOH was evaporated under vac-
mixture was then stirred at room temperature for 8 h. After com-
pletion of the reaction, the reaction was diluted with saturated
NH
etate (3 ꢁ 25). The combined organic layer was washed with brine
1 ꢁ 25 mL), and dried over anhydrous Na SO , and concentrated.
4
Cl (5 ml), poured into water (5 ml), and extracted with ethylac-
3
uum and diluted with ethylacetate (10 ml). Solid NaHCO was
added to the reaction mixture which was stirred for an additional
10 min. The reaction mixture was then filtered through a shot pad
(
2
4
Please cite this article in press as: Ramulu, U.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.07.007

U. Ramulu et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
7
of Celite, and the Celite pad was washed with EtOAC (3 ꢁ 5 ml).
3. (a) Romines, K. R.; Chrusciel, R. A. Curr. Med. Chem. 1995, 2, 825–838;
b) Hagen, S. E.; Vara-Prasad, J. V. N.; Tait, B. D. Adv. Med. Chem. 2000,
159–195.
(
5
The combined organic phase was washed with brine, and dried
,
2 4
over Na SO . After evaporation of the solvent, the crude residue
was purified by column chromatography using (hexane/ethylac-
4.
(a) Huang, Z. W. Chem. Biol. 2002, 9, 1059–1072; (b) Inayat-Hussain, S. H.;
Annuar, B. O.; Din, L. B.; Taniguchi, N. Toxicol. Lett. 2002, 131, 153–159; (c)
Inayat-Hussain, S. H.; Annuar, B. O.; Din, L. B.; Ali, A. M.; Ross, D. Toxicol. In Vitro
etate) (10:90) as eluent to afford the desired product 1 (9.4 mg,
2003, 17, 433–439.
2
5
7
0% yield) as colorless liquid.
[
a
]
D
= +24.8 (c 0.4, CHCl
3
),
5.
Kikuchi, H.; Sasaki, K.; Sekiya, J.; Maeda, Y.; Amagai, A.; Kubohara, Y.; Ohsima,
7
ꢀ1
[
Lit. = +28.8 (c 0.18, CHCl
3
)]. IR (neat, cm ):
853, 1738, 1610, 1383, 1244, 772; H NMR (300 MHz, CDCl
.95 (ddd, J = 9.6, 5.8, 3.0 Hz, 1H), 6.03 (dt, J = 9.7, 1.2 Hz, 1H),
.88 (dd, J = 15.7, 5.2 Hz, 1H), 5.79 (dd, J = 15.6, 6.0 Hz, 1H), 5.32
m
max 3435, 2924,
): d
Y. Bioorg. Med. Chem. 2004, 12, 3203–3214.
1
6. (a) Parker, S. R.; Culter, H. G.; Jacyno, J. M.; Hillf, R. A. J. Agric. Food Chem. 1997,
5, 2774–2776; (b) Suzuki, K.; Kuwahara, A.; Yoshida, H.; Fujita, S.; Nishikiori,
2
6
5
3
4
T. J. Antibiot. 1997, 50, 314–317.
7. Collett, L. A.; Davies-Coleman, M. T.; Rivett, D. E. A. Phytochemistry 1998, 48,
6
51–656.
Pereda-Miranda, R.; Garcia, M.; Delgardo, G. Phytochemistry 1990, 29, 2971–
974.
9. Prasad, K. R.; Phaneendra, G. J. Org. Chem. 2013, 78, 3313–3322.
(
2
m, 1H), 5.07 (m, 1H), 4.52 (m, 1H), 4.49 (m, 1H), 3.70 (m, 1H),
.57 (m, 2H), 2.41 (br s, 1H), 2.08 (s, 3H), 2.04 (s, 3H), 1.21 (d,
8.
2
1
3
J = 6.5 Hz, 3H); C NMR (75 MHz, MeOH-d
4
): d 172.2, 171.9,
10. Sabitha, G.; Shankaraih, K.; Yadav, J. S. Eur. J. Org. Chem. 2013, 22, 4870–
1
2
66.4, 148.7, 136.6, 126.6, 121.1, 78.9, 76.3, 75.8, 72.1, 71.5, 26.4,
1.0, 20.9, 15.1; ESI/MS (m/z): 365 (M+Na) .
+
4878.
11. Saidulu, K.; Bhasker, K.; Lingaiah, N.; Akkewar, D. M. Tetrahedron Lett. 2014, 55,
3087–3089.
Acknowledgements
12. (a) Ramulu, U.; Ramesh, D.; Rajaram, S.; Reddy, S. P.; Venkatesham, K.;
Venkateswarlu, Y. Tetrahedron: Asymmetry 2012, 23, 117–123; (b) Ramulu, U.;
Ramesh, D.; Reddy, S. P.; Rajaram, S.; Suresh Babu, K. Tetrahedron: Asymmetry
The authors thank the director, CSIR-Indian Institute of
Chemical Technology for her encouragement. This work was finan-
cially supported by ORIGIN Project Grant CSE-108 from the Council
of Scientific and Research, New Delhi (India) under the CSIR-
Network program. U.R., S.R. and D.R. are thankful to CSIR-UGC for
providing fellowships.
2014, 25, 1409–1417; (c) Rajaram, S.; Ramulu, U.; Ramesh, D.; Prabhakar, P.;
Venkateswarlu, Y. Helv. Chim. Acta 2013, 96, 2115–2123; (d) Ramesh, D.;
Rajaram, S.; Prabhakar, P.; Ramulu, U.; Reddy, D. K.; Venkateswarlu, Y. Helv.
Chim. Acta 2011, 94, 1226–1233; (e) Ramesh, D.; Shekhar, V.; Chantibabu, D.;
Rajaram, S.; Ramulu, U.; Venkateswarlu, Y. Tetrahedron Lett. 2012, 53, 1258–
1260; (f) Rajaram, S.; Ramesh, D.; Ramulu, U.; Prabhakar, P.; Venkateswarlu, Y.
Helv. Chim. Acta 2014, 97, 112–121.
13. (a) Rao, K. S.; Mukkanti, K.; Reddy, D. S.; Pal, M.; Iqbal, J. Tetrahedron Lett. 2005,
4
6, 2287; (b) Janetzko, J.; Batey, R. A. J. Org. Chem. 2014, 79, 7415–7424.
References
14. (a) Bedke, D. K.; Shibuya, G. M.; Pereira, A. R.; Gerwick, W. H.; Vanderwal, C. D.
J. Am. Chem. Soc. 2010, 132, 2542; (b) Wang, Y.; Gang, S.; Bierstedt, A.; Gruner,
M.; Frohlich, R.; Metz, P. Adv. Synth. Catal. 2007, 349, 2361.
1
.
For reviews, see: (a) Marco, J. A.; Carda, M.; Murga, J.; Falomir, E. Tetrahedron
007, 63, 2929–2958; (b) Boucard, V.; Broustal, G.; Campagne, J. M. Eur. J. Org.
15. Kavitha, N.; Praveen Kumar, V.; Reddy, C. S.; Chandrasekhar, S. Tetrahedron:
2
Asymmetry 2013, 24, 1576.
Chem. 2007, 225–236.
1
1
6. Bartlett, S. L.; Beaudry, C. M. J. Org. Chem. 2011, 76, 9852–9855.
7. (a) Mulzer, J.; Kappert, M.; Hultner, G.; Jibril, I. Angew. Chem., Int. Ed. 2011, 67,
2
.
(a) Perda-Miranda, R.; Fragoso-Serrano, M.; Cerda-Garcia-Rojas, C. M.
Tetrahedron 2001, 57, 47–53; (b) Davis-Coleman, M. T.; Rivett, D. E. A. Prog.
Chem. Org. Nat. Prod. 1989, 55, 1–35; (c) Haffmann, H. M. R.; Rabe, J. Angew.
Chem., Int. Ed. 1985, 24, 94–110; (d) Collett, L. A.; Davies-Coleman, M. T.; Rivett,
D. E. A. Prog. Chem. Org. Nat. Prod. 1998, 75, 181–209; (e) Dickinson, J. M. Nat.
Prod. Rep. 1993, 10, 71–97.
4260; (b) Yadav, J. S.; Srilatha, A.; Shiva Shanker, K.; Saibal, D. Eur. J. Org. Chem.
2013, 30, 6967.
18. Kanada, R. M.; Itoh, D.; Nagai, M.; Niijima, J.; Asai, N.; Mizui, Y.; Abe, S.; Kotake,
Y. Angew. Chem., Int. Ed. 2007, 46, 4350.
Please cite this article in press as: Ramulu, U.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.07.007