Chiral approach to total synthesis of phytotoxic and related nonenolides: (Z)-isomer of (6S,7R,9R)-6,7-dihydroxy-9-propylnon-4-eno-9-lactone, herbarumin-III and their C-9 epimers

Article abstract of DOI:10.1016/j.tet.2016.09.052

A new and efficient strategy has been developed for the stereoselective total synthesis of nonenolides: (Z)-isomer of (6S,7R,9R)-6,7-dihydroxy-9-propylnon-4-eno-9-lactone, herbarumin-III and their C-9 epimers starting from D (?) ribose. The synthesis includes the coupling of the alcohol and acid fragments of the molecules, employing Yamaguchi esterification protocol followed by intramolecular ring closure metathesis. The method has efficiently constructed the 10-membered lactone skeleton of the compounds with proper stereogenic centers containing appropriate functionalities.

Full text of DOI:10.1016/j.tet.2016.09.052

Accepted Manuscript
Chiral approach to total synthesis of phytotoxic and related nonenolides: (Z)-isomer of
(6S,7R,9R)-6,7-dihydroxy-9-propylnon-4-eno-9-lactone, herbarumin-III and their C-9
epimers
Lingaiah Maram, Raghavendar Reddy Parigi, Biswanath Das
PII:
S0040-4020(16)30968-1
10.1016/j.tet.2016.09.052
TET 28123
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 14 June 2016
Revised Date: 20 September 2016
Accepted Date: 22 September 2016
Please cite this article as: Maram L, Parigi RR, Das B, Chiral approach to total synthesis of phytotoxic
and related nonenolides: (Z)-isomer of (6S,7R,9R)-6,7-dihydroxy-9-propylnon-4-eno-9-lactone,
herbarumin-III and their C-9 epimers, Tetrahedron (2016), doi: 10.1016/j.tet.2016.09.052.
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Chiral approach to total synthesis of phytotoxic and related nonenolides: (Z)-isomer of
(6S,7R,9R)-6,7-dihydroxy-9-propylnon-4-eno-9-lactone, herbarumin-III and their C-9
epimers.
Lingaiah Maram[a], Raghavendar Reddy Parigi[a] and Biswanath Das*[a]

ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Chiral approach to total synthesis of phytotoxic and related nonenolides: (Z)-isomer
of (6S,7R,9R)-6,7-dihydroxy-9-propylnon-4-eno-9-lactone, herbarumin-III and their
C-9 epimers†
Lingaiah Maram[a], Raghavendar Reddy Parigi[a], Biswanath Das*[a]
[
a] Natural Products Chemistry Division, CSIR- Indian Institute of Chemical Technology, Hyderabad -500 007, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A new and efficient strategy has been developed for the stereoselective total synthesis of
nonenolides: (Z)-isomer of (6S,7R,9R)-6,7-dihydroxy-9-propylnon-4-eno-9-lactone, herbarumin-
III and their C-9 epimers starting from D (-) ribose. The synthesis includes the coupling of the
alcohol and acid fragments of the molecules, employing Yamaguchi esterification protocol
followed by intramolecular ring closure metathesis. The method has efficiently constructed the
ten-membered lactone skeleton of the compounds with proper stereogenic centers containing
appropriate functionalities.
Available online
Keywords:
Nonenolides, Phytotoxic activity, Total synthesis,
(Z)-isomer of (6S,7R,9R)-6,7-dihydroxy-9-propylnon-
4-eno-9-lactone, herbarumin-III, C-9 epimers,
2015 Elsevier Ltd. All rights reserved.
stereoselective
synthesis,
Mosher’s
method,
Yamaguchi esterification, Ring closing metathesis
1. Introduction
The novel phytotoxic nonenolide, (6S,7R,9R)-6,7-dihydroxy-9-
propylnon-4-eno-9-lactone (1) (Figure 1) was obtained from
Natural nonenolides are 10-membered lactonic compounds
interesting structural features and important
solid cultures of the endophytic fungus Phomopsis sp.
HCCB03520, together with three known compounds.4 The
compound 1 showed activity on germination and radicle growth
of Medicago sativa, Trifoliumhybridum, and Buchloe dactyloides.
The IC50 values of 1 on germination of Medicago sativa,
Trifolium hybridum, and Buchloe dactyloides were 15.8, 24.2,
and 31.2 µg/ml, and for radicle growth of these plants were 31.9,
63.3, 130.9 µg/ml, respectively, and the compound is less active
then positive control [2-(2, 4-dichlorophenoxy) acetic acid (IC50:
1.5, 1.6, and 1.2 µg/ml for germination, and 3.7, 7.4, 1.5 µg/ml
for radicle growth)]. Earlier the synthesis of the (Z)-isomer of
(6R,7R,9R)-6,7-dihydroxy-9-propylnon-4-eno-9-lactone (3) was
accomplished.5 We have now planned for the synthesis of 1, but
we have achieved the synthesis of its Z-isomer 3 and also for the
first time the synthesis of the C-9 epimer (3a) of 3 through a
common route.
with
pharmacological activities. They have been discovered as the
common chemical constituents of several fungi.1 These
compounds are found to contain various functionalities in
different stereoconfigurations and to exhibit impressive
biological properties such as anticancer, antifungal, antimalarial,
antibacterial and phytotoxic activities.2 The term phytotoxicity
refers to the toxic effect of compounds on plant growth and the
nonenolides with phytotoxic activity have been isolated from
various sources.3
OH
4
6
4
HO
HO
HO
12
5
HO
12
5
3
3
6
9
7
7
1
9
2
1
O
O
2
8
8
O
O
10
10
O
O
11
11
Another phytotoxic nonenolide, namely (7R,9R)-7-hydroxy-9-
propyl-5-nonen-9-olide which was designated with the trivial
name herbarumin-III (2) (Figure 1) was isolated from
reinvestigation of the fermentation broth and mycelium of the
fungus Phoma herbarum.6 The compound 2 interacted with
bovine-brain calmodulin and inhibited the activation of the
calmodulin dependent enzyme cAMP phosphodiesterase. It
showed relevant phytotoxic effects (IC50: 2 x 10-5 M) and
inhibited radicle growth with higher potency than 2, 2-
dichlorophenoxyacetic acid (IC50: 2 x 10-4 M), used as positive
control. Some syntheses of the herbarumin-III have been
achieved but our approach is effective and different from earlier
3
2
1
OH
HO
HO
HO
HO
O
O
O
O
O
O
3a
2a
1a
Figure 1. Structures of phyotoxic nonenolides and their C-9 epimers
.
________________________
*Corresponding author. Tel.: +91-40-2719-1625; Fax: +91-40-
27193198. E-mail address: biswanathdas@yahoo.com

2
reports.7 However, for the first time we have accomplished the
synthesis of C-9 epimer (2a) of herbarumin-III (2).
Scheme 2. Synthesis of alcohol 8 and its diastereomer 8a
ACCEPTED MANUSCRIPT
Reagents and conditions: (a) acetone, Cat. H2SO4, r.t., 4 h,
96%; (b) Ph3P, Iodine, Imidazole, toluene, reflux, 2 h, 94% ; (c) Zn,
MeOH, AcOH (cat.), reflux, 2 h then NaBH4, MeOH, 0 oC-r.t., 4 h,
86% (for two steps); (d) TBS-Cl, imidazole, CH2Cl2, 0 C-r.t., 2 h,
96%; (e) (c-Hex)2BH, THF, 0 C-r.t., 2 h, then 30% aq. H2O2, 20%
2. Results and Discussions
In continuation of our work8 on the stereoselective
construction of bioactive natural products we have realized that 1,
2 and their C-9 epimers 1a, 2a can be synthesized from the
dienes 4, 5 and 4a, 5a respectively (Scheme 1). The dienes 4, 4a
and 5, 5a in turn, can be prepared from the esters 6, 6a and 7, 7a
while the esters 6, 6a and 7, 7a from the diastereoisomeric
alcohols 8 and 8a. Both the alcohols 8, 8a can be generated from
the D (-) ribose which is commercially available.
o
o
o
aq. NaOH, 0 C-r.t., 8 h, 84%; (f) SO3.Py, CH2Cl2, DMSO (3:1),
Et3N, 0 oC, 1 h then C3H7MgBr in THF, THF, 0 oC-r.t., 4 h, 96% (for
two steps).
The absolute stereochemistry of the newly generated
stereogenic center in compound 8a bearing the hydroxyl group
was determined by preparing the S and R-MTPA (α-Methoxy-α-
trifluoromethylphenyl acetic acid) esters by a modified Mosher’s
method13 and found to have (S)- configuration at C-5 (Figure 2).
The negative chemical shift difference to the left side of the
MTPA plane and the positive chemical shift differences to the
right side of the MTPA plane indicated that the hydroxyl
stereochemistry has (S)-configuration (Figure 2). Consequently,
the stereochemistry of the same group in 8 is of R-configuration.
These configurations of both 8 and 8a were further confirmed by
their subsequent transformations by coupling with the acid
fragments into the target molecules.
Figure 2: Determination of absolute configuration and ꢀδ values for
the (S) and (R)-MTPA ester derivatives of 8a (ꢀδ =δS-δR).
Scheme 1
2a
. Retrosynthesis of 1, 2 and their C-9 epimers 1a and
After successful achievement of the diastereomeric alcohols 8
and 8a, they were individually esterified with 4-pentenoic acid
under Yamaguchi esterification protocol14 to afford the esters 6
and 6a (Scheme 3). The TBS ether group of esters 6 and 6a was
separately cleaved with TBAF to form the alcohols 14 and 14a
respectively. The alcohols 14 and 14a were oxidized with
SO3.Py12 and the generated corresponding aldehydes were
subjected to C-1 Wittig olefination with Ph3PCH3Br in the
presence of NaHMDS to yield the dienes 4 and 4a required for
the synthesis of the nonenolide 1. The dienes 4 and 4a were
individually, subjected to intramolecular ring closing metathesis
using Grubbs’ II-generation catalyst15 (A) and it was observed
that both the dienes 4 and 4a afforded the cyclization products 15
and 15a respectively in high yields. Finally, deprotection of the
acetonide group of 15 and 15a was carried out with 4 N HCl in
CH3CN to furnish the (Z)-isomer (3) of the nonenolide 1 (from
15) and also the (Z)-isomer (3a) of the C-9 epimer 1a (from 15a).
The present synthesis was initiated by converting D (-)
ribose (Scheme 2) into the iodo compound 10 via the
formation of the primary alcohol
9 following reported
methods.9 The iodo compound 10 was reacted with Zn and
AcOH (cat.) in MeOH under reflux to generate the olefinic
aldehyde, which was not isolated but simultaneously reacted
with NaBH4 in MeOH to afford the alcohol 11 10
The
.
hydroxyl group in 11 was protected as TBS to afford the 12
.
The TBS ether 12 on treatment with (c-Hex)2BH11 in THF
followed by oxidation with H2O2/NaOH afforded the alcohol
13. The alcohol 13 was oxidized with SO3.Py12 to generate
the corresponding aldehyde and the crude aldehyde was
immediately treated with the Grignard reagent, C3H7MgBr
to produce the diastereoisomeric alcohols
Both the alcohols were separated by column
chromatography and utilized for subsequent steps.
8 and 8a (dr: 2:3).
In the present synthesis compounds 15 and 15a were formed
with an olefinic double bond having Z-stereochemistry. These
two compounds, 15 and 15a were subsequently converted into 3
and 3a respectively. The compound 15 is a known molecule,
previously synthesized by our group5b and also by another
group.5a Its structure was settled earlier from its spectral (1H, 13C
and 2D NMR) studies. We have now established the structures of
our presently synthesized compounds, 15 and 15a by comparison
of the spectral (1H and 13C NMR) values with those reported for
1
the former.5 In the H NMR spectra of both the compounds the
coupling constant between two olefinic protons was around 10.0
Hz (for 15, 10.2 Hz and for 15a, 10.5 Hz) indicating clearly the
Z- configuration of the double bond present in these compounds.

3. Conclusion
ACCEPTED MANUSCRIPT
O
O
O
O
O
O
In conclusion, we have described the stereoselective total
OH
O
O
b
a
O
O
C3H7
C3H7
synthesis of (Z)-isomer of a novel phytotoxic nonenolide,
C3H7
OH
(6S,7R,9R)-6,7-dihydroxy-9-propylnon-4-eno-9-lactone
and
OTBS
OTBS
14 : 5R
14a: 5S
6 : 5R
6a: 5S
8 : 5R
8a: 5S
herbarumin-III along with their C-9 epimers through a common
route. The C-9 epimers have been synthesized here for the first
time. The inexpensive and commonly available D (-) ribose has
been used as the starting material. The Grignard addition,
Yamaguchi esterification and intramolecular ring-closing
metathesis are important steps involved in the present synthesis.
HO
HO
O
O
O
O
O
e
c
d
O
C3H7
O
O
O
O
4 : 5R
4a: 5S
15 : 5R
15a: 5S
3 : 9R
3a: 9S
4. Experimental Section
4. 1. General methods
1H NMR and 13C NMR spectra were recorded in CDCl3
solvent on Bruker (Avance) 300 MHz (1H) and 75 MHz (13C) and
Varian Unity (Innova) 500 MHz (1H) and 125 MHz (13C)
spectrometers at ambient temperature. Chemical shifts are
reported in ppm relative to TMS as internal standard. IR spectra
Scheme 3. Synthesis of (Z) isomer of (6S, 7R, 9R)-6,7-dihydroxy-9-
propylnon-4-eno-9-lactone (3) and its C-9 epimer (3a)
Reagents and conditions: (a) 4-pentenoic acid, 2,4,6-
trichlorobenzoyl chloride, Et3N, DMAP, toluene, 0 °C to r.t., 6 h,
96%; (b) TBAF (1 M in THF), THF, 0 °C to r.t., 4 h, 94%; (c)
SO3.Py, CH2Cl2, DMSO (3:1), Et3N, 0 oC, 1 h then Ph3PCH3Br,
NaHMDS, THF, 0 C-r.t., 8 h, 84% (for two steps); (d) Grubbs’ II
(cat.), CH2Cl2, reflux, 12 h, 92%; (e) CH3CN, 4 N HCl, 0 °C to r.t., 2
o
were
recorded
using
a
Perkin-Elmer
Infrared-683
spectrophotometer with KBr optics. ESI-MS were obtained on a
VG-Autospec Micro mass instrument and HRMS (ESI) on an
Exactive Orbitrap mass spectrometer (Thermo Scientific, USA).
Optical rotations were measured on a Jasco Dip 360 digital Polari
meter. Silica gel F254 plates were used for thin-layer
chromatography (TLC) in which the spots were examined under
UV light and then developed using Iodine vapor. All the reagents
and solvents were of reagent grade and used without further
purification unless otherwise stated. Column chromatography
was carried on silica gel (60–120 mesh) packed in glass columns.
h, 90%.
The diastereomeric alcohols 8 and 8a were successfully
utilized for synthesis of herbarumin-III and its C-9 epimer
(Scheme 4). The alcohols were individually esterified with 5-
hexenoic acid under Yamaguchi esterification protocol14 to afford
the esters 7 and 7a respectively. The TBS ether group of the
esters 7 and 7a was separately cleaved with TBAF to form the
alcohols 16 and 16a which were converted into the iodo
compounds 17 and 17a by treatment with iodine, Ph3P and
imidazole in THF.16 Next, the iodo compounds 17 and 17a were
reacted17 with Zn in EtOH under reflux to produce the dienes 5
(from 17) and 5a (from 17a). The intramolecular ring-closing
metathesis (RCM)16a of 5 and 5a individually by using Grubbs’
II-generation catalyst (A) afforded the herbarumin-III (2)18 and
its C-9 epimer (2a) respectively.
4.1.1. tert-Butyl (((4S, 5R)-2, 2-Dimethyl-5-vinyl-1, 3-dioxolan-4-
yl) methoxy) dimethylsilane (12): To a stirred solution of alcohol
11 (6.0 g, 37.97 mmol) and imidazole (7.74 g, 113.92) in CH2Cl2
o
at 0 C was added the TBS-Cl (6.3 g, 41.72 mmol) and stirring
was continued at room temperature for 2 h. After completion of
the reaction as monitored by TLC, reaction was quenched with
H2O (5 mL) and worked up with CH2Cl2 (2 x 15 mL). The
organic layer was dried over anhydrous Na2SO4 and concentrated
in vacuo, the crude product was purified by a silica gel column
chromatography (60–120 mesh) using hexane/AcOEt (98:2) to
obtain pure compound 12 (9.91 g, 98%) as colorless oil; IR
(KBr): 2931, 2858, 1468, 1253, 1098, 838, 777 cm-1; [α]D27
-
1
12.00 (c 1.0, CHCl3); H NMR (500 MHz, CDCl3): δ 5.96-5.80
(1H, m), 5.34 (1H, d, J = 16.9 Hz), 5.21 (1H, d, J = 10.3 Hz),
4.61 (1H, t, J = 6.7 Hz), 4.19 (1H, q, J = 6.7 Hz), 3.60 (2H, d, J =
6.0 Hz), 1.47 (3H, s), 1.36 (3H, s), 0.88 (9H, s), 0.04 (6H, s); 13
C
NMR (125 MHz, CDCl3): δ 133.6, 117.7, 108.5, 78.6, 78.4, 62.2,
27.8, 25.8, 25.3, 18.2, -5.4; MS (ESI): m/z = 295 [M+Na]+;
HRMS (ESI): calcd for C14H29O3Si [M+H]+: 273.3839; found:
273.3832.
Scheme 3: Synthesis of herbarumin-III (2) and its C-9 epimer (2a)
Reagents and conditions: (a) 5-hexenoic acid, 2,4,6-
trichlorobenzoyl chloride, Et3N, DMAP, toluene, 0 °C to r.t., 6 h,
94%; (b) TBAF (1 M in THF), THF, 0 °C to r.t., 4 h, 96%; (c) Ph3P,
I2, imidazole, THF, 0 C-r.t., 2 h, then Zn, EtOH, reflux, 4 h, 94%
(for two steps) (d) Grubbs’ II (cat.), CH2Cl2, reflux, 12 h, 90%.
4.1.2. 2-((4R, 5S)-5-(((tert-Butyldimethylsilyl) oxy) me-thyl)-2, 2-
dimethyl-1, 3-dioxolan-4-yl) ethanol (13): To a stirred solution of
o
alkene 12 (6.0 g, 22.05 mmol) in dry THF (20 mL) at 0 C, [c-
o
Hex)2BH] dicyclohexylborane (17.64 mL, 26.47 mmol, 1.5 M in
THF) was added slowly. The mixture was stirred at room
temperature for 12 h. Then it was cooled to 0 oC and treated with
aq. NaOH (11.2 mL, 110.25 mmol, 10 M aqueous solution)
followed by H2O2 (4.2 mL, 110.30 mmol, 50% aqueous solution).
The reaction mixture was stirred for 2 h at room temperature. Aq.
NH4Cl was added and the reaction mixture was extracted with
AcOEt (2 x 30 mL). The combined organic layers were dried
over anhydrous Na2SO4 and concentrated in vacuo. The residue
was purified by silica gel column chromatography (60–120

4
o
mesh) using hexane/AcOEt (90:10) to afford compound 13 (5.43
g, 85%) as a colorless liquid; IR (KBr): 3454, 2931, 2858, 1467,
1253, 1099, 839 cm-1; [α]D27 -2.10 (c 1.0, CHCl3); 1H NMR (500
MHz, CDCl3): δ 4.35 (1H, m), 4.17-4.09 (1H, m), 3.88-3.82 (1H,
m), 3.85 (1H, m), 3.67 (1H, dd, J =12.0, 10.0 Hz ), 3.0 (1H, dd, J
= 12.0, 5.0 Hz), 2.58 (1H, brs), 1.96-1.84 (2H, m), 1.42 (3H, s),
1.35 (3H, s), 0.89 (9H, s), 0.07 (6H, s); 13C NMR (125 MHz,
CDCl3): δ 107.8, 77.7 (2C), 61.7, 61.2, 31.1, 28.1, 25.8, 25.4,
18.3, -5.4, -5.5; MS (ESI): m/z = 313 [M+Na]+; HRMS (ESI):
calcd for C14H31O4Si [M+H]+: 291. 8353; found: 291. 8349.
(5.0 mL) were then added to the above solution at 0 C. The
ACCEPTED MANUSCRIPT
resulting mixture was stirred at room temperature for 8 h. After
completion of the reaction as monitored by TLC, the reaction
mixture was quenched with saturated aq. NaHCO3 at 0 oC and the
reaction mixture was extracted with AcOEt (3 x 10 mL), washed
with brine, dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The crude product was purified by flash
chromatography (60-120 mesh) using hexane/AcOEt (90:10) to
give compound 6 (1.00 g, 96%) as a colorless oil; IR (KBr): 2957,
2859, 1734, 1466, 1254, 1100, 839, 778 cm-1; [α]D27 +10.55 (c
1
1.0, CHCl3); H NMR (500 MHz, CDCl3): δ 5.92-5.75 (1H, m),
4.1.3. (R)-1-((4R, 5S)-5-(((tert-Butyldimethylsilyl) oxy) methyl)-2,
2-dimethyl-1, 3-dioxolan-4-yl) pentan-2-ol (8): To a stirred
solution of compound 13 (5.0 g, 17.24 mmol) in a mixture of
5.19-4.96 (3H, m), 4.24-4.15 (1H, m), 4.10-4.02 (1H, m), 3.68-
3.53 (2H, m), 2.40 (4H, s), 1.96-1.79 (2H, m), 1.61-1.52 (2H, m),
1.44-1.32 (4H, m), 1.32-1.24 (4H, m), 0.96-0.83 (12H, m), 0.06
(6H, s); 13C NMR (125 MHz, CDCl3): δ 172.6, 136.8, 115.2,
107.9, 77.6, 74.7, 72.0, 61.7, 36.7, 33.8, 33.6, 28.9, 28.1, 25.4,
25.8, 18.3, 13.9, -5.4, -5.5; MS (ESI): m/z = 437 [M+Na]+;
HRMS (ESI): calcd for C22H43O5Si [M+H]+: 415.2635;
found:415.2629.
o
CH2Cl2/DMSO (3:1, 40 mL) at 0 C, Et3N (12.0 mL, 86.13
mmol) and SO3.Py (13.79 g, 86.20 mmol) were added
simultaneously under N2 condition. The resulting solution was
stirred at same temperature for 1 h. After completion of the
reaction monitored by TLC, the reaction mixture was diluted
with cold H2O (15 mL) and the organic layer was extracted with
Et2O (3 x 20 mL). The combined organic layers were dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo. The
crude aldehyde was used directly after flash chromatography for
the next reaction.
4.1.5. (S)-1-((4R, 5S)-5-(((tert-Butyldimethylsilyl) oxy) methyl)-2,
2-dimethyl-1, 3-dioxolan-4-yl) pentan-2-yl pent-4-enoate (6a):
To a stirred solution of 4-pentenoic acid (0.22 g, 2.24 mmol) in
toluene (3 mL) were added Et3N (0.39 mL, 2.80 mmol) and 2, 4,
6- Cl3C6H2COCl (0.38 mL, 2.42 mmol) at 0 C. The reaction
mixture was stirred for 0.5 h at 0 C and a solution of alcohol 8a
o
To a stirred solution of aldehyde (4.96 g, 17.22 mmol) in dry
THF (10 mL) was added n-propyl magnesium bromide (1.5 M
solution in THF) at 0 oC and stirred for 6 h at the same
temperature. After completion of the reaction as monitored by
TLC, the reaction was quenched with saturated aq. NH4Cl (15
mL) at 0 oC. The reaction mixture was worked up with AcOEt (3
x 20 mL), washed with brine, dried over Na2SO4 and
concentrated under reduced pressure. The crude product was
purified by a silica gel column chromatography (60–120 mesh)
using hexane/AcOEt (97:3) to obtain pure compounds 8 (2.52 g,
7.59 mmol) and 8a (3.08 g, 9.27 mmol) as colourless liquids
(5.60 g, 16.86 mmol, dr = 2:3, 98% (for two steps)).
o
(0.62 g, 1.86 mmol) and DMAP (100 mg, 1.86 mmol) in toluene
(5.0 mL) were then added to the above solution at 0 C. The
o
resulting mixture was stirred at room temperature for 8 h. After
completion of the reaction as monitored by TLC, the reaction
mixture was quenched with sat. NaHCO3 at 0 oC and the reaction
mixture was extracted with AcOEt (2 x 10 mL), washed with
brine, dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The crude product was purified by flash
chromatography (60-120 mesh) using hexane/AcOEt (90:10) to
give compound 6a (0.76 g, 98%) as a colorless oil; IR (KBr):
2932, 2860, 1736, 1645, 1374, 1252, 1097, 840, 777 cm-1; [α]D27
1
+22.00 (c 1.0, CHCl3); H NMR (500 MHz, CDCl3): δ 5.91-5.74
Spectral data of compound (8): IR (KBr): 3453, 2931, 2859,
1463, 1254, 1095, 837, 776 cm-1; [α]D27 -5.62 (c 1.0, CHCl3); 1H
NMR (300 MHz, CDCl3): δ 4.39-4.34 (1H, m), 4.15-4.10 (1H,
m), 3.86-3.80 (1H, m), 3.67-3.59 (2H, m), 3.36 (1H, brs), 1.82
(1H, dt, J = 15.0, 6.0 Hz), 1.67-1.58 (2H, m), 1.56-1.49 (1H, m),
1.48-1.37 (4H, m), 1.34 (3H, s), 1.25 (1H, brs), 0.93 (3H, t, J =
7.1 Hz), 0.88 (9H, s), 0.06 (6H, s); 13C NMR (75 MHz, CDCl3): δ
108.3, 77.8, 71.3, 68.2, 61.6, 39.5, 35.6, 30.3, 28.0, 25.8, 18.7,
14.1, -5.4, -5.5; MS (ESI): m/z = 355 [M+Na]+; HRMS (ESI):
calcd for C17H37O4Si [M+H]+: 333. 1992; found: 333. 1987.
(1H, m), 5.16-4.96 (3H, m), 4.20-4.12 (1H, m), 4.04 (1H, q, J =
5.6 Hz), 3.68-3.55 (2H, m), 2.44-2.32 (4H, brs), 1.92-1.81 (1H,
m), 1.80-1.67 (1H, m), 1.66-1.47 (3H, m), 1.39 (3H, s), 1.36-1.23
(4H, m), 0.95-0.84 (12H, m), 0.06 (6H, s); 13C NMR (125 MHz,
CDCl3): δ 172.5, 136.7, 115.3, 107.9, 77.5, 73.7, 71.8, 61.7, 37.1,
33.8, 29.0, 28.1, 25.8, 25.4, 18.3, 13.9, -5.4, -5.5; MS (ESI): m/z
= 437 [M+Na]+; HRMS (ESI): calcd for C22H43O5Si [M+H]+:
415.2635; found: 415.2627.
4.1.6. (R)-1-((4R, 5S)-5-(Hydroxymethyl)-2, 2-dimethyl-1, 3-
dioxolan-4-yl) pentan-2-yl pent-4-enoate (14): To a stirred
solution of ester 6 (0.9 g, 2.17 mmol) in THF was added TBAF
(2.6 mL, 1.2 equv) (1M in THF) at 0 oC and stirring was
continued for 4 h at room temperature until TLC showed
complete conversion of the starting material. The reaction
mixture was quenched with water and the organic layer was
extracted with AcOEt (3 x 10 mL). The organic extract was dried
over anhydrous Na2SO4, and evaporated. The crude reaction
mixture was purified by silica gel column chromatography (60-
120 mesh) using hexane/AcOEt (80:20) as an eluent to provide
the compound 14 (0.64 g, 98%) as a clear oil; IR (KBr): 3457,
2932, 2874, 1731, 1375, 1217, 1044, 916 cm-1; [α]D27 -2.66 (c
Spectral data of compound (8a): IR (KBr): 3460, 2931, 2957,
2859, 1463, 1380, 1254, 1094, 838, 775 cm-1; [α]D27 -4.16 (c 1.0,
CHCl3); 1H NMR (300 MHz, CDCl3): δ 4.43 (1H, q, J = 7.0 Hz),
4.20-4.16 (1H, m), 3.80-3.73 (1H, m), 3.67 (1H, dd, J = 12.0,
10.0 Hz), 3.56 (1H, dd, J = 12.0, 6.0 Hz), 2.73 (1H, brs), 1.91-
1.84 (1H, m), 1.80-1.71 (1H, m), 1.53-1.42 (2H, m), 1.40 (4H, m),
1.35 (4H, m), 0.93 (3H, t, J = 7.0 Hz), 0.90 (9H, s), 0.09 (6H, s) ;
13C NMR (75 MHz, CDCl3): δ 107.2, 77.7, 75.2, 69.2, 61.8, 40.5,
35.5, 28.1, 25.9, 25.4, 18.9, 14.0, -5.5; MS (ESI): m/z = 355
[M+Na]+; HRMS (ESI): calcd for C17H36O4Si [M+H]+: 333.1992;
found:333.1985.
1
4.1.4. (R)-1-((4R, 5S)-5-(((tert-Butyldimethylsilyl) oxy) methyl)-2,
2-dimethyl-1, 3-dioxolan-4-yl) pentan-2-yl pent-4-enoate (6): To
a stirred solution of 4-pentenoic acid (0.30 g, 3.03 mmol) in
toluene (5 mL) were added Et3N (0.52 mL, 3.79 mmol) and 2, 4,
1.0, CHCl3); H NMR (500 MHz, CDCl3): δ 5.88-5.78 (1H, m),
5.11-5.04 (2H, m), 5.01 (1H, dd, J = 1.2, 10.2 Hz), 4.25-4.20 (1H,
m), 4.15 (1H, q, J = 6.0 Hz), 3.61 (2H, d, J = 6.0 Hz), 2.44-2.34
(4H, m), 1.93-1.84 (1H, m), 1.79-1.73 (1H, m), 1.63-1.54 (2H,
m), 1.46 (3H, s), 1.40-1.23 (6H, m), 0.91 (3H, t, J = 7.3 Hz); 13C
NMR (125 MHz, CDCl3): δ 172.7, 136.6, 115.3, 77.7, 74.0, 71.6,
61.3, 36.1, 33.7, 33.5, 28.7, 28.0, 25.3, 18.3, 13.7; MS (ESI): m/z
o
6- Cl3C6H2COCl (0.51 mL, 3.28 mmol) at 0 C. The reaction
o
mixture was stirred for 1 h at 0 C and a solution of alcohol 8
(0.84 g, 2.53 mmol) and DMAP (227 mg, 1.86 mmol) in toluene

= 323 [M+Na]+; HRMS (ESI): calcd for C16H29O5 [M+H]+:
300.1145; found: 300.1139.
(1.06 g, 6.62 mmol) were added simultaneously under N2
condition. The resulting reaction mixture was stirred at same
temperature for 1 h. After completion of the reaction as
monitored by TLC, the reaction mixture was diluted with cold
water (5 mL) and the organic layer was extracted with Et2O (3 x
15 mL). The combined organic layers were dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. The crude aldehyde
(0.36 g, 96%) was used directly after flash chromatography for
the next reaction.
ACCEPTED MANUSCRIPT
4.1.7. (S)-1-((4R, 5S)-5-(Hydroxymethyl)-2, 2-dimethyl-1, 3-
dioxolan-4-yl) pentan-2-yl pent-4-enoate (14a): To a stirred
solution of ester 6a (0.7 g, 1.69 mmol) in THF was added TBAF
(2.0 mL, 1.2 equv) (1M in THF) at 0 oC and stirring was
continued for 6 h at room temperature until TLC showed
complete conversion of the starting material. The reaction
mixture was quenched with water and the organic layer was
extracted with AcOEt (3 x 10 mL). The organic extract was dried
over anhydrous Na2SO4, and evaporated. The crude reaction
mixture was purified by silica gel column chromatography (60-
120 mesh) using hexane/AcOEt (80:20) as an eluent to provide
the compound 14a (0.49 g, 96%) as a clear oil; IR (KBr): 3420,
Methyltriphenylphosphonium bromide (0.96 g, 2.68 mmol) was
thoroughly flame dried and anhydrous THF (10 mL) was added
and the resulting suspension was cooled to 0 °C prior to the drop
wise addition of NaHMDS in THF (1.6 M) (3.5 mL, 2.75 mmol).
The resulting gold suspension was warmed to 25 °C for 30 min
and re-cooled to -10 °C prior to the addition of above aldehyde
(0.36 g, 1.20 mmol) solution in anhydrous THF (5 mL). The
reaction was stirred at room temperature for 12 h, as judged by
TLC, and quenched by the addition of saturated aq. NH4Cl (10
ml). The mixture was then extracted with Et2O (2 x 10 mL),
washed sequentially with H2O (15 mL) and saturated aq. NaCl (3
x 5 mL) and then dried over anhydrous Na2SO4. Removal of
solvents under reduced pressure followed by flash column
chromatography (60-120 mesh) using hexane/AcOEt (90:10)
gave compound 4a (0.33 g, 86%) as a colorless oil; IR (KBr):
2961, 2930, 1734, 1639, 1376, 1172, 1048, 922, 769 cm-1; [α]D27
2928, 2873, 1728, 1376, 1376, 1180, 1066, 916 cm-1; [α]D27
-
1
1.42 (c 1.0, CHCl3); H NMR (500 MHz, CDCl3): δ 5.87-5.77
(1H, m), 5.10-5.02 (2H, m), 5.01 (1H, dd, J = 1.2, 10.2 Hz), 4.20-
4.15 (1H, m), 4.13-4.08 (1H, m), 3.66-3.56 (2H, m), 2.42-2.34
(4H, m), 2.01 (1H, brs), 1.85-1.78 (1H, m), 1.75-1.68 (1H, m),
1.63-1.50 (2H, m), 1.44 (3H, s), 1.39-1.24 (5H, m), 0.90 (3H, t, J
= 7.4 Hz); 13C NMR (125 MHz, CDCl3): δ 172.6, 136.6, 115.5,
108.1, 77.6, 73.5, 71.8, 61.6, 37.0, 33.7, 28.9. 28.0, 25.6, 18.3,
13.9; MS (ESI): m/z = 323 [M+Na]+; HRMS (ESI): calcd for
C16H29O5 [M+H]+: 301.1145; found: 301.1141.
4.1.8. (R)-1-((4R, 5S)-2, 2-Dimethyl-5-vinyl-1, 3-dioxolan-4-yl)
pentan-2-yl pent-4-enoate (4): To a stirred solution of compound
14 (0.6 g, 2.0 mmol) in a mixture of CH2Cl2/DMSO (3:1, 15 mL)
1
-17.53 (c 1.0, CHCl3); H NMR (500 MHz, CDCl3): δ 5.95-5.71
(2H, m), 5.38-5.22 (2H, m), 5.14-4.96 (3H, m), 4.48 (1H, t, J =
6.4 Hz), 4.22-4.10 (1H, m), 2.39 (4H, s), 1.73-1.51 (3H, m), 1.47
(3H, s), 1.41-1.20 (6H, m), 0.91 (3H, t, J = 7.1 Hz); 13C NMR
(125 MHz, CDCl3): δ 172.5, 136.7, 134.2, 118.3, 115.4, 108.3,
79.5, 74.6, 71.7, 37.0, 35.1, 33.7, 29.0, 28.2, 25.6, 18.3, 13.9; MS
(ESI): m/z = 319 [M+Na]+; HRMS (ESI): calcd for C17H29O4
[M+H]+: 297. 3833; found: 297. 3825.
o
at 0 C, Et3N (1.39 mL, 10.0 mmol) and SO3.Py (1.6 g, 10.0
mmol) were added simultaneously under N2 atm. The resulting
reaction mixture was stirred at same temperature for 1 h. After
completion of the reaction as monitored by TLC, the reaction
mixture was diluted with cold water (5 mL) and the organic layer
was extracted with Et2O (3 x 15 mL). The combined organic
layers were dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. The crude aldehyde (0.56 g, 96%) was
used directly after flash chromatography for the next reaction.
4.1.10. (3aR, 5R, 11aS, Z)-2, 2-Dimethyl-5-propyl-4, 5, 8, 9-
tetrahydro-3aH-[1, 3]dioxolo[4, 5d]oxecin-7(11aH)-one (15):
Grubbs’ II generation catalyst (45 mg, 0.05 mmol) was dissolved
in dry, deoxygenated CH2Cl2 (120 mL). After heating the
solution to reflux, diene 4 (0.08 g, 0.27 mmol) dissolved in dry,
deoxygenated CH2Cl2 (80 mL) was added drop wise over 30 min.
Methyltriphenylphosphonium bromide (1.43 g, 4.0 mmol) was
thoroughly flame dried and anhydrous THF (15 mL) was added
and the resulting suspension was cooled to 0 °C prior to the drop
wise addition of NaHMDS in THF (1.6 M in THF) (5.0 mL, 4.10
mmol). The resulting gold suspension was warmed to 25 °C for
30 min and re-cooled to -10 °C prior to the addition of above
aldehyde (0.56 g, 1.87 mmol) in anhydrous THF (5 mL). The
reaction was stirred at room temperature for 10 h, as judged by
TLC, and quenched by the addition of saturated aq. NH4Cl (10
ml). The mixture was then extracted with Et2O (4 x 10 mL),
washed sequentially with H2O (15 mL) and saturated aq. NaCl (3
x 10 mL) and then dried over anhydrous Na2SO4. Removal of
solvents under reduced pressure followed by flash column
chromatography (60-120 mesh) using hexane/AcOEt (90:10)
gave compound 4 (0.49 g, 84%) as a colorless oil; IR (KBr):
o
The reaction mixture was refluxed for 12 h at 50 C. After
completion of the reaction (by TLC), the mixture was
concentrated in vacuo, and the residue was purified by column
chromatography (60-120 mesh) using hexane/AcOEt (80:20) to
afford pure 15 (0.059 g, 82%) as a white solid; IR (KBr): 2958,
2932, 1736, 1245, 1067, 976, 878, 762 cm-1; [α]D27 -33.12 (c 1.0,
1
CHCl3); H NMR (500 MHz, CDCl3): δ 5.60 (1H, td, J = 10.2,
5.1 Hz), 5.48 (1H, t, J = 10.2 Hz), 5.19-5.14 (1H, m), 5.04-4.99
(1H, m), 4.41 (1H, m), 2.77-2.67 (1H, m), 2.64-2.58 (1H, m),
2.34-2.24 (1H, m), 2.10-1.99 (2H, m), 1.90-1.84 (1H, m), 1.78-
1.69 (1H, m), 1.66-1.51 (2H, m), 1.49 (3H, s), 1.40 (3H, s), 1.38-
1.24 (1H, m), 0.94 (3H, t, J = 7.0 Hz); 13C NMR (125 MHz,
CDCl3): δ 171.2, 129.5, 129.4, 107.2, 74.6, 74.0, 70.3, 34.0, 33.4,
31.5, 28.5, 26.1, 22.5, 19.3, 13.7; MS (ESI): m/z = 291 [M+Na]+;
HRMS (ESI): calcd for C15H25O4 [M+H]+: 269.2435; found:
269.2429.
2959, 2932, 1732, 1380, 1243, 1174, 1051, 926 cm-1; [α]D27
-
1
13.33 (c 1.0, CHCl3); H NMR (300 MHz, CDCl3): δ 5.90-5.72
(2H, m), 5.38-5.21 (2H, m), 5.10-4.98 (3H, m), 4.49 (1H, t, J =
7.0 Hz), 4.19 (1H, t, J = 7.0 Hz), 2.40 (4H, s), 1.80 (1H, m),
1.68-1.51 (2H, m), 1.48 (3H, s), 1.41-1.20 (6H, m), 0.90 (3H, t, J
= 7.0 Hz); 13C NMR (75 MHz, CDCl3): δ 172.7, 136.7, 134.2,
118.7, 115.4, 108.3, 79.8, 75.0, 71.4, 36.4, 35.0, 28.9, 28.2, 25.6,
18.4, 13.8; MS (ESI): m/z = 319 [M+Na]+; HRMS (ESI): calcd
for C17H29O4 [M+H]+: 297. 3833; found: 297. 3828.
4.1.11. (3aR, 5S, 11aS, Z)-2, 2-Dimethyl-5-propyl-4, 5, 8, 9-
tetrahydro-3aH-[1, 3]dioxolo[4, 5 d]oxecin-7(11aH)-one (15a):
Grubbs’ II generation catalyst (34 mg, 0.04 mmol) was dissolved
in dry, deoxygenated CH2Cl2 (100 mL). After heating the
solution to reflux, diene 4a (0.08 g, 0.27 mmol) dissolved in dry,
deoxygenated CH2Cl2 (60 mL) was added dropwise over 30 min.
The reaction mixture was refluxed for 9 h at 50 oC. After
completion of the reaction (by TLC), the mixture was
concentrated in vacuo, and the residue was purified by column
4.1.9. (S)-1-((4R, 5S)-2, 2-Dimethyl-5-vinyl-1, 3-dioxolan-4-yl)
pentan-2-yl pent-4-enoate (4a): To a stirred solution of
compound 14a (0.4 g, 1.33 mmol) in a mixture of CH2Cl2/DMSO
o
(3:1, 15 mL) at 0 C, Et3N (0.93 mL, 6.62 mmol) and SO3.Py

6
chromatography (60-120 mesh) using hexane/AcOEt (80:20) to
reduced pressure. The crude product was purified by flash
ACCEPTED MANUSCRIPT
afford pure 15a (0.06 g, 84%) as a yellow oil; IR (KBr): 2958,
chromatography (60-120 mesh) using hexane/AcOEt (90:10) to
give compound 7 (0.86 g, 96%) as a colorless oil; IR (KBr): 2957,
2929, 1733, 1464, 1251, 1100, 840, 778 cm-1; [α]D27 +10.00 (c
2930, 1735, 1379, 1245, 1169, 1067, 878, 769 cm-1; [α]D27
-
50.83 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3): δ 5.72 (1H, td,
J = 10.5, 7.0 Hz), 5.60 (1H, t, J = 10.5 Hz), 5.10 (1H, m), 4.71
(1H, dd, J = 10.5, 7.0 Hz), 4.31 (1H, q, J = 7.0 Hz), 2.71-2.56
(1H, m), 2.44-2.20 (3H, m), 2.19-2.07 (1H, m), 1.99-1.90 (2H,
m), 1.72-1.54 (2H, m), 1.47 (3H, s), 1.40-1.19 (4H, m), 0.91 (3H,
t, J = 7.1 Hz); 13C NMR (125 MHz, CDCl3): δ 172.9, 131.1,
129.0, 107.2, 77.9, 72.9, 71.5, 37.4, 36.0, 34.2, 28.1, 25.3, 24.1,
18.5, 13.7; MS (ESI): m/z = 291 [M+Na]+; HRMS (ESI): calcd
for C15H25O4 [M+H]+: 269.2435; found: 269.2430.
1
1.0, CHCl3); H NMR (500 MHz, CDCl3): δ 5.79 (1H, m), 5.12
(1H, m), 5.04 (1H, m), 5.01 (1H, m), 4.20 (1H, m), 4.06 (1H, m),
3.62 (1H, dd, J = 12.0, 10.0 Hz), 3.58 (1H, dd, J = 12.0, 5.0 Hz),
2.38 (1H, t, J = 7.0 Hz), 2.31 (1H, t, J = 7.0 Hz), 2.14-2.08 (2H,
m), 1.94-1.81 (2H, m), 1.78-1.70 (2H, m), 1.59-1.52 (2H, m),
1.40 (3H, s), 1.38-1.24 (4H, m), 0.93-0.86 (12H, m), 0.06 (6H, s);
13C NMR (125 MHz, CDCl3): δ 173.3, 137.7, 115.2, 107.9, 77.6,
74.7, 71.9, 61.7, 36.2, 33.9, 33.6, 33.1, 28.1, 25.8, 25.4, 25.1,
18.4, 13.9, -5.4, -5.5; MS (ESI): m/z = 451 [M+Na]+; HRMS
(ESI): calcd for C23H45O5Si [M+H]+: 429.1798; found: 429.1792.
4.1.12. (4Z, 6S, 7R, 9R)-6, 7-Dihydroxy-9-propylnon-4-eno-9-
lactone (3): To a solution of compound 15 (0.045 g, 0.17 mmol)
in CH3CN (5 mL) was added aq. HCl (4N, 0.5 mL) at 0 ºC. The
resulting mixture was stirred for 6 h at room temperature and
then added solid NaHCO3. The reaction mixture was filtered
through a pad of Celite and washed with AcOEt (10 mL). The
filtrate was dried over anhydrous Na2SO4 and concentrated. The
product was purified by silica gel column chromatography (60-
120 mesh) using hexane/AcOEt (70:30) to afford the pure
compound 3 (0.034 g, 91%) as a yellow oil; IR (KBr): 3400,
2958, 2927, 1728, 1452, 1250, 1163, 1066, 911, 722 cm-1; [α]D27
4.1.15. (S)-1-((4R, 5S)-5-(((tert-Butyldimethylsilyl) oxy) methyl)-
2, 2-dimethyl-1, 3-dioxolan-4 yl) pentan-2-yl hex-5-enoate (7a):
To a stirred solution of 5-hexenoic acid (0.26 g, 2.26 mmol) in
toluene (5 mL) were added Et3N (0.31 mL, 2.26 mmol) and
2,4,6-Cl3C6H2COCl (0.35 mL, 2.25 mmol) at 0 C. The reaction
mixture was stirred for 1 h at 0 C and a solution of alcohol 8a
o
o
(0.50 g, 1.50 mmol) and DMAP (200 mg, 1.86 mmol) in toluene
(5.0 mL) was then added to the above solution at 0 C and the
o
resulting mixture was stirred at room temperature for 8 h. After
completion of the reaction as monitored by TLC, the reaction
mixture was quenched with saturated aq. NaHCO3 at 0 oC and the
reaction mixture was extracted with AcOEt (3 x 10 mL), washed
with brine, dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The crude product was purified by flash
chromatography (60-120 mesh) using hexane/AcOEt (90:10) to
give compound 7a (0.63 g, 96%) as a colorless oil; IR (KBr):
2957, 2932, 1736, 1639, 1376, 1250, 1098, 839, 776 cm-1; [α]D27
1
+10.00 (c 1.0, CHCl3); H NMR (500 MHz, CDCl3): δ 5.73-5.64
(2H, m), 5.02-4.95 (1H, m), 4.80 (1H, dd, J = 6.4, 2.4 Hz), 4.19
(1H, td, J = 11.2, 3.5 Hz), 2.86-2.74 (1H, m), 2.61 (1H, qd, J =
14.9, 3.5, 1.3 Hz), 2.31-2.22 (1H, m), 2.13-2.06 (1H, m), 1.89-
1.75 (2H, m), 1.73-1.63 (1H, m), 1.59-1.50 (1H, m), 1.47-1.18
(5H, m), 0.94 (3H, t, J = 7.3 Hz); 13C NMR (125 MHz, CDCl3): δ
171.4, 130.7, 128.3, 71.3, 69.8, 68.3, 35.2, 33.7, 29.6, 23.2, 19.2,
13.6; MS (ESI): m/z = 251 [M+Na]+; HRMS (ESI): calcd for
C12H21O4 [M+H]+: 229.0968; found: 229. 0965.
1
+7.85 (c 1.0, CHCl3); H NMR (500 MHz, CDCl3): δ 5.86-5.70
(1H, m), 5.14-5.03 (1H, m), 5.02-4.95 (1H, m), 4.20-4.17 (1H,
m), 4.05 (1H, q, J = 5.6 Hz), 3.65-3.57 (2H, m), 2.30 (2H, t, J =
7.0 Hz), 2.09 (2H, q, J = 7.0 Hz), 1.92-1.81 (1H, m), 1.80-1.66
(3H, m), 1.65-1.52 (4H, m), 1.39 (3H, s), 1.36-1.24 (4H, m),
0.96-0.85 (12H, m), 0.06 (6H, s); 13C NMR (125 MHz, CDCl3): δ
173.1, 137.5, 115.0, 107.6, 77.4, 74.5, 71.6, 61.5, 36.0, 33.7, 32.9,
28.0, 25.6, 25.2, 23.9, 18.2, 13.7, -5.5; MS (ESI): m/z = 451
[M+Na]+; HRMS (ESI): calcd for C23H45O5Si [M+H]+: 429.1798;
found: 429.1790.
4.1.13. (4Z, 6S, 7R, 9S)-6, 7-Dihydroxy-9-propylnon-4-eno-9-
lactone (3a): To a solution of compound 15a (0.05 g, 0.19 mmol)
in CH3CN (5 mL) was added aq. HCl (4N, 0.5 mL) at 0 ºC. The
resulting mixture was stirred for 4 h at room temperature and
then added solid NaHCO3. The reaction mixture was filtered
through a pad of Celite and washed with AcOEt (15 mL). The
filtrate was dried over anhydrous Na2SO4 and concentrated. The
product was purified by silica gel column chromatography (60-
120 mesh) using hexane/AcOEt (70:30) to afford the pure
compound 3a (0.038 g, 89%) as a yellow oil; IR (KBr): 3421,
2929, 2874, 1723, 1263, 1152, 1026, 770 cm-1; [α]D27 -26.66 (c
4.1.16. (R)-1-((4R, 5S)-5-(Hydroxymethyl)-2, 2-dimethyl-1, 3-
dioxolan-4-yl) pentan-2-yl hex-5-enoate (16): To a stirred
solution of compound 7 (0.80 g, 1.86 mmol) in anhydrous THF
was added 5 mL of TBAF (2.24 mL, 1.0 M solution in THF) at 0
oC and the reaction mixture was stirred at room temperature for 1
h. The solvent was then concentrated in vacuo. The crude residue
was purified by column chromatography (60-120 mesh) using
hexane/AcOEt (80:20) to afford the primary alcohol 16 (0.54 g,
92%) as a pale yellow oil; IR (KBr): 3445, 2960, 2935, 1731,
1380, 1220, 1046, 913, 773 cm-1; [α]D27 -12.00 (c 1.0, CHCl3);
1H NMR (300 MHz, CDCl3): δ 5.86-5.70 (1H, m), 5.13-4.95 (3H,
m), 4.27-4.08 (2H, m), 3.61 (2H, d, J = 5.4 Hz), 2.31 (2H, t, J =
7.5 Hz), 2.10 (2H, q, J = 7.0 Hz), 1.95-1.82 (1H, m), 1.81-1.67
(3H, m), 1.62-1.51 (2H, m), 1.46 (3H, s), 1.42-1.22 (6H, m), 0.91
(3H, t, J = 6.9 Hz); 13C NMR (75 MHz, CDCl3): δ 173.3, 137.6,
115.3, 108.1, 77.7, 74.0, 71.5, 61.5, 36.2, 33.8, 33.6, 33.0, 28.1,
25.3, 24.0, 18.5, 13.8; MS (ESI): m/z = 337 [M+Na]+; HRMS
(ESI): calcd for C17H31O5 [M+H]+: 315.2459; found: 315.2451.
1
1.0, CHCl3); H NMR (500 MHz, CDCl3): δ 5.93-5.72 (2H, m),
4.85-4.71 (1H, m), 4.30 (1H, dd, J = 9.8, 3.0 Hz), 4.09-3.97 (1H,
m), 2.69-2.53 (1H, m), 2.46-2.23 (2H, m), 2.21-1.99 (1H, m),
1.96-1.82 (1H, m), 1.78-1.63 (1H, m), 1.60-1.46 (2H, m), 1.43-
1.20 (4H, m), 0.91 (3H, t, J = 7.5 Hz); 13C NMR (125 MHz,
CDCl3): δ 172.9, 130.7, 129.1, 72.5, 72.4, 67.8, 37.8, 37.7, 34.1,
24.3, 18.5, 13.8; MS (ESI): m/z = 251 [M+Na]+; HRMS (ESI):
calcd for C12H21O4 [M+H]+: 229.0968; found: 229.0961.
4.1.14. (R)-1-((4R, 5S)-5-(((tert-Butyldimethylsilyl) oxy) methyl)-
2, 2-dimethyl-1, 3-dioxolan-4-yl) pentan-2-yl hex-5-enoate (7):
To a stirred solution of 5-hexenoic acid (0.36 g, 3.12 mmol) in
toluene (5 mL) were added Et3N (0.43 mL, 3.12 mmol) and 2, 4,
o
6- Cl3C6H2COCl (0.48 mL, 3.12 mmol) at 0 C. The reaction
o
mixture was stirred for 1 h at 0 C and a solution of alcohol 8
(0.70 g, 2.08 mmol) and DMAP (220 mg, 1.86 mmol) in toluene
o
(5.0 mL) was then added to the above solution at 0 C. The
resulting mixture was stirred at room temperature for 8 h. After
completion of the reaction as monitored by TLC, the reaction
mixture was quenched with saturated aq. NaHCO3 at 0 oC and the
reaction mixture was extracted with AcOEt (3 x 10 mL), washed
with brine, dried over anhydrous Na2SO4 and concentrated under
4.1.17. (S)-1-((4R, 5S)-5-(Hydroxymethyl)-2, 2-dimethyl-1, 3-
dioxolan-4-yl) pentan-2-yl hex-5-enoate (16a): To a stirred
solution of compound 7a (0.60 g, 1.40 mmol) in anhydrous THF
was added 5 mL of TBAF (1.7 mL, 1.0 M solution in THF) at 0
oC and the reaction mixture was stirred at room temperature for 1

the mixture was stirred at 80 °C for 3 h (TLC monitoring). When
h. The solvent was then removed in vacuo. TheAcrCudCe rEesPidTueEwDas MANUSCRIPT
purified by column chromatography (60-120 mesh) using
hexane/AcOEt (80:20) to afford the primary alcohol 16a (0.42 g,
96 %) as a pale yellow oil; IR (KBr): 3455, 2959, 2931, 1733,
1459, 1376, 1219, 1048, 994 cm-1; [α]D27 -3.75 (c 1.0, CHCl3);
1H NMR (300 MHz, CDCl3): δ 5.83-5.72 (1H, m), 5.03-4.97 (3H,
m), 4.21-4.16 (1H, m), 4.13-4.09 (1H, m), 3.68-3.57 (2H, m),
2.31 (2H, t, J = 7.3 Hz), 2.10 (2H, q, J = 7.1 Hz), 1.86-1.79 (1H,
m), 1.77-1.69 (3H, m), 1.67-1.51 (3H, m), 1.45 (3H, s), 1.41-1.28
(4H, m), 1.25 (1H, brs), 0.91 (3H, t, J = 7.3 Hz); 13C NMR (75
MHz, CDCl3): δ 173.1, 137.6, 115.3, 108.0, 77.6, 73.5, 71.6, 61.6,
37.0, 33.7, 33.6, 33.0, 28.1, 25.4, 24.1, 18.4, 13.9; MS (ESI): m/z
= 337 [M+Na]+; HRMS (ESI): calcd for C17H30O5 [M+H]+:
315.2459; found: 315.2453.
the reaction was complete, the reaction mixture was allowed to
keep at room temperature and filtered through a short pad of
Celite and the Celite pad was washed with AcOEt (2 x 15 mL)
and the solvent was evaporated. Column chromatography of the
residue (60-120 mesh) using hexane/AcOEt (70:30) furnished 5
(0.31 g, 92%) as a colorless oil; IR (KBr): 3445, 2959, 2930,
1732, 1458, 1248, 1175, 997, 916, 760 cm-1; [α]D27 +1.28 (c 1.0,
1
CHCl3); H NMR (500 MHz, CDCl3): δ 5.90-5.73 (2H, m), 5.23
(1H, d, J = 17.2 Hz), 5.11 (1H, d, J = 10.3 Hz), 5.06-4.97 (3H,
m), 4.26-4.16 (1H, m), 2.37-2.25 (2H, m), 2.09 (2H, q, J = 7.1
Hz), 2.01 (1H, brs), 1.90-1.78 (1H, m), 1.77-1.69 (2H, m), 1.68-
1.63 (1H, brs), 1.62-1.50 (1H, m), 1.47-1.40 (1H, m), 1.40-1.28
(1H, m), 1.25 (1H, brs), 0.91 (3H, t, J = 7.3 Hz); 13C NMR (125
MHz, CDCl3): δ 173.5, 140.5, 137.6, 115.3, 114.9, 71.5, 70.5,
41.5, 36.7, 33.8, 33.0, 24.0, 13.8; MS (ESI): m/z = 263 [M+Na]+;
HRMS (ESI): calcd for C14H25O3 [M+H]+: 241.3839; found:
241.3831.
4.1.18. (R)-1-((4R, 5R)-5-(Iodomethyl)-2, 2-dimethyl-1, 3-
dioxolan-4-yl) pentan-2-yl hex-5-enoate (17): To a solution of 16
(0.5 g, 1.59 mmol) in anhydrous THF (10 mL) were added Ph3P
(0.52 g, 1.99 mmol), imidazole (0.16 g, 2.38 mmol), and iodine
o
(0.48 g, 1.91 mmol) simultaneously at 0 C. The mixture was
4.1.21. (4S, 6R)-6-Hydroxyoct-7-en-4-yl hex-5-enoate (5a): To a
solution of iodide 17a (0.50 g, 1.18 mmol) in 95% EtOH (15 mL)
was added Zn dust (0.38 g, 5.90 mmol) at room temperature and
the mixture was stirred at 80 °C for 3 h (TLC monitoring). When
the reaction was complete, the reaction mixture was allowed to
keep at room temperature and filtered through a short pad of
Celite washed with AcOEt (2 x 15 mL) and the solvent was
evaporated. Column chromatography of the residue (60-120
mesh) using hexane/AcOEt (70:30) furnished pure compound 5a
(0.26 g, 94%) as a colorless oil; IR (KBr): 3450, 2959, 2929,
1729, 1642, 1178, 994, 754 cm-1; [α]D27 -6.66 (c 1.0, CHCl3); 1H
NMR (500 MHz, CDCl3): δ 5.90-5.74 (2H, m), 5.27 (1H, dt, J =
17.2, 3.0 Hz), 5.13-5.07 (2H, m), 5.06-4.98 (2H, m), 4.05 (1H,
m), 2.36 (2H, t, J = 7.3 Hz), 2.11 (2H, q, J = 7.1 Hz), 1.76 (2H, q,
J = 7.6 Hz), 1.73-1.65 (1H, m), 1.65-1.58 (3H, m), 1.56-1.47 (1H,
m), 1.39-1.24 (2H, m), 0.91 (3H, t, J = 7.3 Hz); 13C NMR (125
MHz, CDCl3): δ 174.7, 139.9, 137.5, 115.5, 114.4, 71.0, 68.4,
42.4, 36.9, 33.7, 33.0, 24.1, 18.6, 13.8; MS (ESI): m/z = 263
[M+Na]+; HRMS (ESI): calcd for C14H25O3 [M+H]+: 241.3839;
found: 241.3834.
stirred at room temperature for 3 h. When the reaction was
complete as monitored by TLC, the mixture was diluted with
H2O (10 mL), and extracted with Et2O (3 x 20 mL). The
combined organic layers were washed with brine (20 mL) and
saturated aq. Na2S2O3 (10 mL), dried over anhydrous Na2SO4 and
the organic layer was concentrated in vacuo. Column
chromatography of the residue (60-120 mesh) using
hexane/AcOEt (96:4) gave the iodide 17 (0.36 g, 0.65 mmol,
96%) as a colorless oil; IR (KBr): 2958, 1732, 1458, 1458, 1376,
1
1220, 1170, 1057, 913 cm-1; [α]D27 +5.83 (c 1.0, CHCl3); H
NMR (500 MHz, CDCl3): δ 5.86-5.71 (1H, m), 5.16-5.04 (2H,
m), 5.03-4.96 (1H, m), 4.33 (1H, q, J = 6.4 Hz), 4.24-4.15 (1H,
m), 3.19-3.06 (2H, m), 2.31 (2H, t, J = 7.3 Hz), 2.10 (2H, q, J =
6.9 Hz), 1.92-1.67 (3H, m), 1.65-1.54 (3H, m), 1.47 (3H, s),
1.44-1.24 (5H, m), 0.92 (3H, t, J = 7.3 Hz); 13C NMR (125 MHz,
CDCl3): δ 173.2, 137.6, 115.3, 108.7, 78.2, 74.9, 71.3, 35.8, 33.8,
33.6, 33.1, 28.4, 25.7, 24.0, 18.4, 13.9, 3.4; MS (ESI): m/z = 447
[M+Na]+; HRMS (ESI): calcd for C17H30IO4 [M+H]+: 425.1753;
found: 425.1748.
4.1.19. (S)-1-((4R, 5R)-5-(Iodomethyl)-2, 2-dimethyl-1, 3-
dioxolan-4-yl) pentan-2-yl hex-5 enoate (17a): To a solution of
16a (0.4 g, 1.27 mmol) in anhydrous THF (10 mL) were added
Ph3P (0.42 g, 1.59 mmol), imidazole (0.130 g, 1.91 mmol), and
4.1.22.
(7R,9R)-7-Hydroxy-9-propyl-5-nonen-9-olide
(Herbarumin-III) (2): Grubbs’ II generation catalyst (45 mg, 0.05
mmol) was dissolved in dry, deoxygenated CH2Cl2 (120 mL).
After heating the solution to reflux, diene 5 (0.08 g, 0.33 mmol)
dissolved in dry, deoxygenated CH2Cl2 (80 mL) was added drop
wise over 30 min. The reaction mixture was refluxed for 12 h at
o
iodine (0.39 g, 1.52 mmol) simultaneously at 0 C. The mixture
was stirred at room temperature for 3 h. When the reaction was
complete as monitored by TLC, the mixture was diluted with
H2O (10 mL), and extracted with Et2O (3 x 20 mL). The
combined organic layers were washed with brine (20 mL) and
saturated aq. Na2S2O3 (10 mL), dried over anhydrous Na2SO4 and
the organic layer was concentrated in vacuo. Column
chromatography of the crude residue (60-120 mesh) using
hexane/ AcOEt (96:4) afforded the pure iodide 17a (0.53 g, 98%)
as a colorless oil; IR (KBr): 2958, 2827, 1731, 1375, 1169, 1056,
o
50 C. After completion of the reaction (monitored by TLC), the
mixture was concentrated in vacuo, and the residue was purified
by column chromatography (60-120 mesh) using hexane/AcOEt
(70:30) to afford the pure compound 2 (0.059 g, 84%) as a light
yellow oil. IR (KBr): 3461, 2927, 2855, 1728, 1440, 1203, 1094,
986, 771 cm-1; [α]D27 +28.00 (c 1.0, CHCl3); 1H NMR (300 MHz,
CDCl3): δ 5.63 (1H, dt, J = 17.0, 1.5 Hz), 5.50-5.41 (1H, m),
5.29-5.22 (1H, m), 4.41 (1H, m), 2.44-2.34 (1H, m), 2.32-2.25
(1H, m), 2.17-2.06 (1H, m), 2.05-1.92 (3H, m), 1.89-1.69 (3H,
m), 1.58-1.49 (1H, m), 1.45-1.37 (1H, m), 1.36-1.23 (2H, m),
0.89 (3H, t, J = 7.3 Hz); 13C NMR (75 MHz, CDCl3): δ 176.8,
134.5, 124.7, 67.9, 67.7, 40.5, 37.3, 34.5, 33.6, 25.9, 18.3, 13.7;
MS (ESI): m/z = 235 [M+Na]+; HRMS (ESI): calcd for C12H21O3
[M+H]+: 213.3003; found: 213.2994.
1
913 cm-1; [α]D27 -25.12 (c 1.0, CHCl3); H NMR (500 MHz,
CDCl3): δ 5.83-5.74 (1H, m), 5.11-4.97 (3H, m), 4.31-4.25 (1H,
m), 4.15-4.10 (1H, m), 3.21-3.11 (2H, m), 2.33-2.28 (2H, m),
2.10 (2H, q, J = 7.0 Hz), 1.84-1.69 (3H, m), 1.66-1.51 (3H, m),
1.45 (3H, s), 1.40-1.24 (4H, m), 1.25 (1H, brs), 0.92 (3H, t, J =
7.3 Hz); 13C NMR (125 MHz, CDCl3): δ 173.0, 137.6, 115.4,
108.5, 78.2, 74.5, 71.2, 37.0, 33.7, 33.0, 28.4, 25.7, 24.1, 18.4,
13.9, 3.8; MS (ESI): m/z = 447 [M+Na]+; HRMS (ESI): calcd for
C17H30IO4 [M+H]+: 425.1753; found: 425.1746.
4.1.23. (7R,9S)-7-Hydroxy-9-propyl-5-nonen-9-olide (C-9 epimer
of Herbarumin-III) (2a): Grubbs’ II generation catalyst (45 mg,
0.05 mmol) was dissolved in dry, deoxygenated CH2Cl2 (120
mL). After heating the solution to reflux, diene 5a (0.08 g, 0.33
mmol) dissolved in dry, deoxygenated CH2Cl2 (80 mL) was
added drop wise over 30 min. The reaction mixture was refluxed
4.1.20. (4R, 6R)-6-Hydroxyoct-7-en-4-yl hex-5-enoate (5): To a
solution of iodide 17 (0.60 g, 1.41 mmol) in 95% EtOH (15 mL)
was added Zn dust (0.46 g, 7.07 mmol) at room temperature and

8
for 12 h at 50 oC. After completion of the reaction (monitored by
TLC), the mixture was concentrated in vacuo, and the residue
was purified by column chromatography (60-120 mesh) using
hexane, AcOEt (70:30) to afford the pure compound 2a (0.056 g,
80%) as a light yellow oil; IR (KBr): 3444, 2958, 2930, 1727,
1364, 1211, 1113, 1029, 974, 932 cm-1; [α]D27 -14.20 (c 1.0,
CHCl3); 1H NMR (500 MHz, CDCl3): δ 5.52-5.42 (1H, m), 5.08-
5.02 (1H, m), 4.11-4.05 (1H, m), 2.36-2.29 (2H, m), 2.07-1.92
(2H, m), 1.91-1.84 (1H, m), 1.84-1.77 (1H, m), 1.77-1.68 (1H,
m), 1.64-1.50 (4H, m), 1.49-1.41 (1H, m), 1.38-1.23 (2H, m),
0.90 (3H, t, J = 7.3 Hz); 13C NMR (125 MHz, CDCl3): δ 175.5,
135.8, 131.2, 72.7, 70.9, 41.4, 37.7, 34.6, 33.4, 29.7, 26.3, 18.3,
13.8; MS (ESI): m/z = 235 [M+Na]+; HRMS (ESI): calcd for
C12H21O3 [M+H]+: 213.3003; found: 213.2998.
Tetrahedron:Asymmetry 2009, 20, 2315; (d) Lingaiah, M.; Das, B.
Synlett, 2014, 25, 2327.
ACCEPTED MANUSCRIPT
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Acknowledgments
The authors thank CSIR and UGC, New Delhi for financial
assistance. They are also thankful to NMR, Mass and IR
divisions of CSIR-IICT for spectral recording.
Supporting Information
Supplementary data associated with this article can be found, in
the online version.
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