Total synthesis of (8S,11R,12R)- and (8R,11R,12R)-topsentolide B 2 diastereomers and assignment of the absolute configuration

Article abstract of DOI:10.1016/j.tetasy.2011.10.020

An improved total synthesis of (8S,11R,12R)- and (8R,11R,12R)-topsentolide B₂ diastereomers has been completed in eight steps with overall yields of 10.2% and 10.4%, respectively. The key steps involve a regioselective asymmetric dihydroxylation, diastereoselective Roush allylation, and ring closing metathesis. The stereochemistry of natural topsentolide B₂ has been determined to be (8S,11R,12R) by comparison of the specific rotation.

Full text of DOI:10.1016/j.tetasy.2011.10.020

Tetrahedron: Asymmetry 22 (2011) 1930–1935
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Total synthesis of (8S,11R,12R)- and (8R,11R,12R)-topsentolide B2
diastereomers and assignment of the absolute configuration
⇑
Rodney A. Fernandes , Pullaiah Kattanguru
Department of Chemistry, Indian Institute of Technology Bombay, Powai, 400 076 Mumbai, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 October 2011
Accepted 28 October 2011
An improved total synthesis of (8S,11R,12R)- and (8R,11R,12R)-topsentolide B2 diastereomers has been
completed in eight steps with overall yields of 10.2% and 10.4%, respectively. The key steps involve a reg-
ioselective asymmetric dihydroxylation, diastereoselective Roush allylation, and ring closing metathesis.
The stereochemistry of natural topsentolide B
the specific rotation.
2
has been determined to be (8S,11R,12R) by comparison of
Ó 2011 Elsevier Ltd. All rights reserved.
1
. Introduction
2
topsentolide B diastereomers and assignment of the absolute
stereochemistry to the natural isolate.
A new class of oxylipins named topsentolides 1–7 (Fig. 1) was re-
1
cently isolated by Jung et al. from the marine sponge Topsentia sp.
(
family Halichondriidae, order Halichondrida). These have similar
structural frames to halicholactone 8 and neohalicholactone 9,
which were isolated from the marine sponge Halichondria oka-
O
2
a,b
dai.
The latter oxylipins have important biological activities such
O
1
1
8
17
as the inhibition of lipoxygenase and farnesyl protein transferase
and hence have attracted considerable attention from synthetic
9
8
3
12
chemists. Topsentolides have been shown to be cytotoxic against
11
1
5
SK-OV-3 and SK-MEL-2 human solid tumor cell lines. The struc-
X
tures of topsentolides were elucidated by exhaustive spectroscopic
studies. Watanabe et al. described the first enantioselective syn-
thesis of (8S,11S,12R)-topsentolide A and its (8S,11R,12S)-diaste-
1
Y
1
Topsentolide A1 1 : X,Y = 11,12-cis-epoxide
Topsentolide A2 2 : X,Y = 11,12-cis-epoxide, 17,18-dihydro
Topsentolide B1 3 : X = Y = OH, (11,12-threo)
reomer and established the absolute stereochemistry of natural
topsentolide A
2R)-topsentolide B
1
1 to be (8R,11R,12S).4 The synthesis of (8S,11S,
Topsentolide B2 4 : X = Y = OH, (11,12-threo), 17,18-dihydro
5
1
3
5 was recently reported. Topsentolide B
2
4
Topsentolide B 5 : X = Y = OH, (11,12-erythro), 17,18-dihydro
3
has three stereocenters, a nine-membered lactone, a vicinal diol
functionality, and three isolated double bonds of which two are
cis and one trans. The relative stereochemistry of the diol function-
Topsentolide C1 6 : X = βOH, Y = OMe
Topsentolide C2 7 : X = βOH, Y = OMe, 17,18-dihydro
1
ality was proposed to be threo by spectroscopic studies. However,
the absolute stereochemistry of three stereocenters is yet to be
determined. The C8 stereochemistry was conventionally assigned
as (8S) by comparing the specific rotation with similar lactones
such as 8 and 9 with the assumption that the optical activity was
modulated by the stereochemistry of the lactone ring. As part of
our research aimed at the enantioselective total synthesis of
O
O
1
H
8
OH
Z
6
5
H
bioactive natural products, we recently completed the total syn-
6c
thesis of (8S,11R,12R)-topsentolide B
2
.
Herein we report a short
OH
and improved synthesis of the (8S,11R,12R)- and (8R,11R,12R)-
halicholactone 8: Z = CH2CH2
neohalicholactone 9: Z = cis CH:CH
⇑
Corresponding author. Fax: +91 22 25767152.
E-mail address: rfernand@chem.iitb.ac.in (R.A. Fernandes).
Figure 1. The structures of topsentolides 1–7 and halicholactones 8 and 9.
0
957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.10.020

R. A. Fernandes, P. Kattanguru / Tetrahedron: Asymmetry 22 (2011) 1930–1935
1931
O
O
1
Roush
O
O
allylation
5
8
RCM
1
1
C5H11
C5H11
1
2
HO
O
1
3
OH
O
(
8S)-isomer 10a
8R)-isomer 10b
(
8S,11R,12R) topsentolide B2 4a
8R,11R,12R)-isomer 4b
(
(
OEt
O
allene-type
regioselective
O rearrangement
asymmetric
dihydroxylation
C5H11
EtO
5 11
C H
O
12
O
1
1
2
Scheme 1. Retrosynthesis of topsentolide B stereoisomers 4a and 4b.
2
. Results and discussion
lactone from intermediate 11. The DIBAL-H reduction of the ester
group in 11 to the corresponding aldehyde, followed by asymmetric
Roush allylation using (R,R)-diisopropyl allylboronate efficiently
7
Our retrosynthetic analysis of 4a and its diastereomer 4b is
shown in Scheme 1. The C5–C6 internal cis-double bond was
planned through the ring closing metathesis of compounds 10a
or 10b to give 4a or 4b, respectively. The terminal olefinic com-
pounds 10a or 10b can be obtained by acylation of homoallylic
alcohol, which in turn can be derived through asymmetric Roush
placed the allyl group and fixed the C8 stereochemistry providing
16a in a 72% yield over two steps. Similarly the C8 epimer 16b was
obtained using (S,S)-diisopropyl allylboronate in a 76% yield. No
trace amounts of other diastereomers were observed in the 1
H
NMR of 16a or 16b. Acylation of 16a and 16b with 5-hexenoic acid
provided the bis-terminal olefin compounds 10a and 10b, each in
a 90% yield. The ring closing metathesis (RCM) reaction using Grub-
bs-II catalyst afforded the nine-membered lactone in lower yields.10
After multiple trials, we found the use of Grubbs-I catalyst
7
allylation on the aldehyde of the key intermediate compound
1
1. An earlier synthesis of 11 involved the asymmetric dihydroxy-
lation and the sequential generation of double bonds or asymmet-
6
c
ric dihydroxylation of a dienoate and Wittig olefination. To
shorten the synthetic sequence and aiming to target other diaste-
reomers in a convenient manner, we envisioned the synthesis of
diene-ester 11 through the regioselective asymmetric dihydroxyla-
tion of trienoate 12 to directly give 11 after acetonide protection of
the precursor diol. The success of this strategy was anticipated
based on the fact that a cis-olefin bond is less reactive and that
1
1
4
(20 mol %) and Ti(O-iPr) (20 mol %) was the best to obtain the lac-
tones 17a and 17b in 52% and 51% yields, respectively. The reaction
was Z-selective while the formation of E-diastereomer was not ob-
served by NMR spectra of 17a or 17b. This was in accordance to sim-
3
b–
ilar literature preparations of Z-olefinic nine-membered lactones.
f,5
Removal of the acetonide group afforded the (8S,11R,12R)-topsen-
tolide B 4a and (8R,11R,12R)-4b in 92% and 90% yields, respectively.
The specific rotation values of 4a and 4b were +8.9 (c 0.27, MeOH)
and +49.4 (c 0.27, MeOH), respectively. Topsentolide B has three
the
a,b-unsaturated double bond would be electron deficient in
2
comparison to
c,d-double bond of trienoate 12.
The synthesis of diene-ester 11 was initiated from the commer-
cially available alcohol 13 as shown in Scheme 2. The Swern oxida-
tion of alcohol 13 to the aldehyde and subsequent addition of
2
stereocenters and so should have four pairs of enantiomers. Since
the C11–C12 diol functionality is expected to be threo, only two
lithiated ethylpropiolate provided alkynoate 14 (75% over two
2
pairs of enantiomers are possible for topsentolide B ; that is
8
steps). The allene-type-rearrangement of 14 with PPh
3
gave the
(8S,11R,12R)- and (8R,11R,12R)- and their enantiomers. We have
completed the synthesis of the above diastereomers. The
(8S,11R,12R)-4a isomer had a specific rotation of +8.9 (c 0.27,
MeOH), and matched well with the natural isolate, +9.8 (c 0.27,
MeOH). On the basis of this and matching the spectroscopic data
(E,E,Z)-trienoate 12 in a 76% yield. The stereo- and regioselective
2
asymmetric dihydroxylation of 12 using the (DHQD) PHAL ligand
over a shorter reaction time of 6 h gave diol 15 in 61% yield and
9
9
4% ee. With a longer reaction time of 10–12 h, the participation
1
13
1
of the isolated cis-double bond was also observed. Acetonide pro-
tection of diol 15 delivered diene-ester 11 in a 95% yield. The over-
all sequence from 13 to 11 was completed in just four steps with
an overall yield of 31% (Scheme 2).
of 4a ( H NMR and C NMR) to that given in literature, we propose
the (8S,11R,12R)-stereochemistry for natural topsentolide B . The
2
(8S) stereochemistry is also in accordance to that predicted earlier
based on comparing the specific rotation with similar lactones such
as halicholactone and neohalicolactone with the assumption that
the optical activity is modulated by the stereochemistry of the lac-
tone ring.
The completion of the synthesis of the two diastereomers of tops-
2
entolide B is shown in Scheme 3. The reaction steps involved the
installation of the C8 stereogenic center and nine-membered

1
932
R. A. Fernandes, P. Kattanguru / Tetrahedron: Asymmetry 22 (2011) 1930–1935
OH
i. (COCl)2, DMSO
C5H11
C5H11
CH2Cl2, Et3N
-78 °C, 2.5 h
HO
EtO2C
ii. Ethylpropiolate
THF, LiHMDS
14
1
3
-
78 °C, 1.5h
75% (over two steps)
(
DHQD)2PHAL, K2CO3
K3Fe(CN)6, MeSO2NH2
PPh3, C6H6
rt, 4 h, 76%
C5H11
EtO2C
K2OsO4.2H2O, t-BuOH/H2O
°C, 6 h, 61%, 94% ee
0
12
OEt
O
(
CH3)2C(OMe)2
OH
p-TsOH
C5H11
5 11
C H
acetone
EtO2C
O
O
OH
rt, 4 h, 95%
15
11
Scheme 2. Synthesis of intermediate diene–ester 11.
O
CO2i-Pr
CO2i-Pr
HO
O
B
O
O
C5H11
(
R,R)-tartrate
O
allylboronate
5
C H
11
O
EtO2C
O
72% 16a
O
10a
hex-5-enoic acid
i. DIBAL-H
CH2Cl2
-78 °C, 45 min
ii. MS 4Å, toluene
C5H11
DCC, DMAP, CH2Cl2
-
78 °C,1 h
0
°C to rt, 12 h
90%
O
O
O
HO
CO2i-Pr
O
11
O
B
C5H11
CO2i-Pr
O
O
O
5
C H
11
(
S,S)-tartrate
O
allylboronate
76% 16b
O
10b
O
O
O
O
10a
O
HO
O
HO
G-I catalyst
52%
(
20 mol%)
TFA, CH2Cl2
0 °C, 2 h
(
8S)-isomer 17a
Ti(Oi-Pr)4 (20 mol%)
92% (8S,11R,12R)-topsentolide B2 4a
CH2Cl2, reflux
12 h
O
O
O
O
1
0b
O
HO
HO
5
1%
O
90%
(8R,11R,12R)-isomer 4b
(
8R)-isomer 17b
Scheme 3. Synthesis of the two diastereomers of topsentolide B
2
4a and 4b.

R. A. Fernandes, P. Kattanguru / Tetrahedron: Asymmetry 22 (2011) 1930–1935
1933
3
. Conclusion
4.1.2. (2E,4E,7Z)-Ethyl tridec-2,4,7-trienoate 12
To a stirred solution of 14 (2.1 g, 8.32 mmol) in dry benzene
(20 mL) was added PPh (2.62 g, 9.98 mmol, 1.2 equiv) at room
In conclusion, we have successfully demonstrated a shorter and
3
improved total synthesis of topsentolide B
2
and its C8 epimer in
temperature and the resulting mixture stirred for 4 h. It was then
diluted with petroleum ether/EtOAc (19:1, 30 mL) and filtered
through a pad of silica gel. The filtrate was concentrated and the
residue purified by silica gel column chromatography using petro-
leum ether/EtOAc (19:1) as eluent to give 12 (1.49 g, 76%). IR
eight steps with overall yields of 10.2% and 10.4%, respectively.
The key steps involve a regioselective asymmetric dihydroxylation,
diastereoselective Roush allylation, and RCM reaction. We have
2
also established the stereochemistry of natural topsentolide B .
This synthetic strategy can be further extended to the synthesis
of other topsentolides and oxylipins. Work in this direction is cur-
rently ongoing in our laboratory.
(CHCl
1369, 1303, 1266, 1178, 1137, 1040, 1002, 868, 758 cm
NMR (400 MHz, CDCl ): d = 7.27 (dd, J = 15.3, 10.7 Hz, 1H), 6.22–
.07 (m, 2H), 5.79 (d, J = 15.3 Hz, 1H), 5.81–5.47 (m, 1H), 5.41–
.34 (m, 1H), 4.19 (q, J = 7.2 Hz, 2H), 2.91 (t, J = 6.7 Hz, 2H), 2.03
3
): m = 2956, 2930, 2873, 2860, 1717, 1641, 1621, 1465,
ꢀ1
1
.
H
3
6
5
4
4
. Experimental
(
q, J = 7.3 Hz, 2H), 1.39–1.20 (m, 9H), 0.89 (t, J = 6.9 Hz, 3H). 13
C
NMR (100 MHz, CDCl
3
): d = 167.2, 144.8, 142.3, 132.2, 128.3,
.1. General information
1
25.0, 119.5, 60.2, 31.4, 30.7, 29.1, 27.1, 22.5, 14.3, 14.0. HRMS
+
(
ESI+) calcd for [C15
24
H O
2
+H] : 237.1855, found: 237.1860.
Flasks were oven or flame dried and cooled in a desiccator. Dry
2
reactions were carried out under an atmosphere of Ar or N . Sol-
vents and reagents were purified by standard methods. Thin-layer
chromatography was performed on EM 250 Kieselgel 60 F254 silica
4
K
.1.3. (4R,5R,2E,7Z)-Ethyl 4,5-dihydroxytrideca-2,7-dienoate 15
To a mixture of K
3
Fe(CN)
6
(4.01 g, 12.18 mmol, 3.0 equiv),
PHAL (32 mg,
2
CO (1.68 g, 12.18 mmol, 3.0 equiv) and (DHQD)
3
2
4
gel plates. The spots were visualized by staining with KMnO or by
1
13
2
0.041 mmol, 1.0 mol %) in t-BuOH–H O (1:1, 40 mL) cooled at
0
lowed by methanesulfonamide (0.386 g, 4.06 mmol, 1.0 equiv).
After stirring for 5 min at 0 °C, olefin 12 (0.96 g, 4.06 mmol) was
added in one portion. The reaction mixture was stirred at 0 °C for
UV lamp. H NMR and C NMR were recorded on Varian Mercury
Plus, AS400 spectrometer and Bruker, AVANCE III 400 and 500
°C, was added K
2
OsO
4
ꢂ2H
2
O (6 mg, 0.016 mmol, 0.4 mol %) fol-
spectrometers. The chemical shifts are based on a TMS peak at d
1
0
.00 ppm for the H NMR and a CDCl
3
peak at d 77.00 ppm (t) in
1
3
C NMR. IR spectra were obtained on Perkin Elmer Spectrum
6
2 3
h and then quenched with solid Na SO (1.0 g). Stirring was con-
One FT-IR spectrometer. Optical rotations were measured with Jas-
co P-2000 digital polarimeter. HRMS was recorded using Micro-
mass: Q-Tof micro (YA-105) spectrometer. HPLC was performed
with JASCO-PU-2080PLUS Pump with UV-2075PLUS Detector.
tinued for an additional 45 min and the solution extracted with
EtOAc (4 ꢁ 20 mL). The combined organic layers were washed with
2 4
aq 2 M KOH, water, brine, dried (Na SO ), and concentrated. The
residue was purified by silica gel column chromatography using
petroleum ether/EtOAc (7:3) as eluent to give 15 (0.665 g, 61%)
4
.1.1. (Z)-Ethyl 4-hydroxytridec-7-en-2-ynoate 14
A solution of DMSO (2.7 mL, 3.0 g, 38.4 mmol, 3.0 equiv) in dry
2
5
as a colorless oil.
½
a
ꢃ
¼ þ23:4 (c 1.0, CHCl
3
). IR (CHCl
3
):
D
m
= 3435, 2957, 2928, 2859, 1716, 1660, 1466, 1369, 1306, 1279,
CH
1.7 mL, 2.44 g, 19.2 mmol, 1.5 equiv) in CH
over a period of 10 min. After stirring for 15 min, a solution of alco-
hol 13 (2.0 g, 12.80 mmol) in CH Cl (10 mL) was added and the
reaction mixture stirred for 45 min. A solution of Et N (7.1 mL,
.18 g, 51.2 mmol, 4.0 equiv) in CH Cl (5 mL) was added and stir-
red for 30 min. After warming to room temperature over 1 h, water
2
Cl
2
(15 mL) was gradually added to a solution of oxalyl chloride
ꢀ1
1
1
179, 1042, 981, 877, 760 cm
.
H NMR (400 MHz, CDCl
3
):
(
2
Cl
2
(45 mL) at ꢀ78 °C
d = 6.93 (dd, J = 15.7, 5.0 Hz, 1H), 6.12 (dd, J = 15.8, 1.7 Hz, 1H),
5
3
.59–5.41 (m, 1H), 5.40–5.37 (m, 1H), 4.20–4.15 (m, 3H), 3.61–
2
2
.56 (m, 1H), 2.76 (br s, 2H, OH), 2.33–2.25 (m, 2H), 2.05–1.99
3
(
(
m, 2H), 1.36–1.23 (m, 9H), 0.86 (t, J = 6.9 Hz, 3H). 13C NMR
5
2
2
100 MHz, CDCl
3
): d = 166.3, 146.8, 134.3, 123.8, 122.4, 73.4, 73.3,
6
0.6, 31.4, 31.2, 29.2, 27.4, 22.5, 14.2, 14.0. HRMS (ESI+) calcd for
(
30 mL) was added. The aqueous layer was extracted with CH
3 ꢁ 30 mL). The combined organic extracts were washed with
SO ), and concentrated to give the crude
aldehyde (1.8 g) which was used directly in the next reaction.
To stirred solution of ethylpropiolate (1.4 mL, 1.37 g,
2 2
Cl
+
[
C
15
H
26
O
4
+H] : 271.1909, found: 271.1905.
(
water, brine, dried (Na
2
4
4
.1.4. (4R,5R,2E,7Z)-Ethyl 4,5-isopropylidenedioxytridec-2,7-
dieneote 11
a
To a solution of diol 15 (0.50 g, 1.85 mmol) in acetone (15 mL)
were added pTsOH (2 mg, catalytic) and 2,2-dimethoxypropane
1
4.0 mmol, 1.2 equiv) in THF (40 mL) at ꢀ78 °C, LiHMDS (1.2 M in
THF, 13.6 mL, 16.34 mmol, 1.4 equiv) was added slowly and the
mixture stirred for 1 h. The aldehyde (1.8 g, 11.67 mmol) in THF
(
0.57 mL, 0.48 g, 4.62 mmol, 2.5 equiv) and the reaction mixture
stirred at room temperature for 4 h. Solid NaHCO (0.2 g) was
3
(
10 mL) was added at ꢀ78 °C and stirring continued for 30 min.
The reaction was quenched with saturated aq NH Cl solution
10 mL) and warmed to room temperature. It was diluted with
water (30 mL) and extracted with EtOAc (3 ꢁ 50 mL). The combined
organic layers were washed with water, brine, dried (Na SO ), and
added and the mixture stirred for an additional 30 min and filtered
through a pad of silica gel. The filtrate was concentrated and the
residue purified by silica gel column chromatography using petro-
leum ether/EtOAc (19:1) as eluent to give 11 (0.548 g, 95%) as a
4
(
2
4
2
D
5
colorless oil. ½
a
ꢃ
¼ þ26:6 (c 0.5, CHCl
3
). IR (CHCl
3
): m = 2927,
concentrated. The residue was purified by silica gel column chro-
matography using petroleum ether/EtOAc (9:1) as eluent to give
2
9
857, 1726, 1662, 1464, 1371, 1303, 1219, 1164, 1113, 1035,
78, 857, 756 cm
ꢀ1
1
.
3
H NMR (400 MHz, CDCl ): d = 6.86 (dd,
1
2
7
5
1
2
4 (2.42 g, 75%) as a colorless oil. IR (CHCl
3
): m = 3416, 2957,
J = 15.6, 5.5 Hz, 1H), 6.11 (dd, J = 15.6, 1.2 Hz, 1H), 5.58–5.52 (m,
1H), 5.43–5.37 (m, 1H), 4.23–4.19 (m, 3H), 3.80 (dt, J = 8.2,
929, 2858, 2237, 1716, 1466, 1368, 1248, 1068, 1029, 970, 861,
ꢀ1 1
3
53 cm . H NMR (400 MHz, CDCl ): d = 5.46–5.41 (m, 1H), 5.37–
6
.0 Hz, 1H), 2.43–2.37 (m, 2H), 2.06–2.0 (m, 2H), 1.44 (s, 3H),
.33 (m, 1H), 4.52–4.48 (m, 1H), 4.24 (q, J = 7.1 Hz, 2H), 2.4 (br s,
H, OH), 2.27–2.21 (m, 2H), 2.05 (q, J = 6.9 Hz, 2H), 1.89–1.79 (m,
H), 1.38–1.26 (m, 9H), 0.89 (t, J = 6.9 Hz, 3H).
): d = 153.5, 131.6, 127.5, 88.0, 76.4, 62.1, 61.4,
6.6, 31.4, 29.2, 27.1, 22.7, 22.4, 13.9, 13.8. HRMS (ESI+) calcd for
1
.41 (s, 3H), 1.37–1.24 (m, 6H), 1.29 (t, J = 6.7 Hz, 3H), 0.88 (t,
1
3
1
3
J = 6.7 Hz, 3H).
3
C NMR (100 MHz, CDCl ): d = 166.0, 144.1,
C
NMR
1
2
33.3, 123.2, 122.5, 109.4, 80.1, 79.7, 60.5, 31.4, 29.7, 29.1, 27.4,
7.1, 26.6, 22.5, 14.1, 14.0. HRMS (ESI+) calcd for [C18H O +H] :
30 4
(
100 MHz, CDCl
3
+
3
+
311.2222, found: 311.2225.
15 24 3
[C H O +Na] : 275.1623, found: 275.1621.

1
934
R. A. Fernandes, P. Kattanguru / Tetrahedron: Asymmetry 22 (2011) 1930–1935
4
1
.1.5. (4S,7R,8R,5E,10Z)-7,8-Isopropylidenedioxyhexadec-1,5,
0-trien-4-ol 16a
3.70 (dt, J = 8.3, 5.8 Hz, 1H), 2.40–2.29 (m, 6H), 2.10–2.05 (m, 2H),
2.04–1.98 (m, 2H), 1.73–1.63 (m, 2H), 1.41 (s, 3H), 1.40 (s, 3H),
1
3
To a solution of 11 (0.13 g, 0.42 mmol) in dry CH
2
Cl
2
(15 mL) at
1.37–1.25 (m, 6H), 0.88 (t, J = 6.9 Hz, 3H). C NMR (100 MHz,
CDCl ): d = 172.6, 137.6, 133.0, 132.7, 132.0, 129.7, 123.8, 118.1,
ꢀ
78 °C under an argon atmosphere, DIBAL-H (0.42 mL, 0.42 mmol,
.0 equiv, 1 M solution in hexane) was added dropwise over a per-
3
1
115.4, 108.7, 81.0, 80.3, 72.3, 38.9, 33.7, 33.0, 31.5, 29.4, 29.2,
iod of 20 min. The reaction mixture was stirred for 45 min and
quenched with a saturated aq sodium potassium tartrate solution
27.4, 27.1, 26.9, 24.0, 22.5, 14.0. HRMS (ESI+) calcd for
+
[C25
H
40
O
4
+Na] : 427.2824, found: 427.2841.
(
2 mL). Stirring was continued for 2 h at room temperature and
the aqueous layer extracted with CH Cl
(3 ꢁ 10 mL). The com-
bined organic layers were washed with water, brine, dried
Na SO ) and concentrated to give the crude aldehyde (0.11 g),
which was used for the next reaction without further purification.
To the mixture of the above aldehyde (0.11 g, 0.41 mmol) and
powdered molecular sieves 4 Å (50 mg) in dry toluene (5 mL) at
2
2
4.1.8. (4R,7R,8R,5E,10Z)-7,8-Isopropylidenedioxyhexadec-1,5,
10-trien-4-yl hex-5-enoate 10b
(
2
4
The title compound was prepared from 16b (150 mg,
0.48 mmol) by a similar procedure as described for 10a, to give
2
D
5
10b (177 mg, 90%) as a colorless oil. ½
IR (CHCl ): = 3090, 2931, 2859, 1738, 1643, 1457, 1379, 1241,
1168, 1105, 1062, 970, 917, 858, 759 cm
CDCl ): d = 5.83–5.66 (m, 4H), 5.53–5.47 (m, 1H), 5.43–5.34 (m,
a
ꢃ
¼ þ24:7 (c 0.8, CHCl
3
).
3
m
ꢀ
1 1
ꢀ
78 °C was added (R,R)-diisopropyl tartrate allylboronate (0.22
mL, 0.23 g, 0.82 mmol, 2.0 equiv) and stirred for 1 h. The reaction
was quenched with a saturated aq NaHCO solution (2.0 mL) and
. H NMR (400 MHz,
3
3
2H), 5.11–4.98 (m, 4H), 4.04 (t, J = 7.5 Hz, 1H), 3.77–3.65 (m, 1H),
stirring continued for 30 min at room temperature. The aqueous
2.43–2.29 (m, 6H), 2.12–1.99 (m, 4H), 1.76–1.68 (m, 2H), 1.42 (s,
phase was extracted with EtOAc (3 ꢁ 10 mL). The combined organic
3H), 1.41 (s, 3H), 1.37–1.26 (m, 6H), 0.89 (t, J = 6.7 Hz, 3H). 13
C
extracts were washed with brine, dried (Na
2
SO
4
), and concentrated.
3
NMR (100 MHz, CDCl ): d = 172.5, 137.6, 132.9, 132.7, 131.9,
The residue purified by silica gel column chromatography using
129.9, 123.8, 118.1, 115.4, 108.7, 81.0, 80.4, 72.4, 38.8, 33.7, 33.0,
petroleum ether/EtOAc (9:1) as eluent to give 16a (93 mg, 72% over
31.5, 29.4, 29.2, 27.4, 27.1, 26.9, 24.1, 22.5, 14.0. HRMS (ESI+) calcd
25
+
two steps) as a colorless oil. ½
a
ꢃ
¼ þ7:9 (c 1.2, CHCl
3
). IR (CHCl
3
):
for [C25H
40
O
4
+Na] : 427.2824, found: 427.2838.
D
m
9
5
1
3
= 3432, 2930, 2859, 1645, 1457, 1379, 1218, 1165, 1106, 1043,
ꢀ1 1
71, 912, 860, 760, 669 cm . H NMR (400 MHz, CDCl
3
): d = 5.88–
4.1.9. 9-(9S,6Z)-[(3R,4R,1E,6Z)-3,4-Isopropylidenedioxydodec-1,
6-dienyl]-4,5,8,9-tetrahydro-(3H)-oxonin-2-one 17a
To a solution of 10a (50 mg, 0.123 mmol) in dry and degassed
2 2 4
CH Cl (150 mL) was added freshly distilled Ti(O-iPr) (7.3 lL,
.75 (m, 2H), 5.74–5.64 (m, 1H), 5.54–5.47 (m, 1H), 5.43–5.37 (m,
H), 5.16–5.12 (m, 2H), 4.29–4.18 (m, 1H), 4.08–4.04 (m, 1H),
.76–3.70 (m, 1H), 2.45–2.26 (m, 4H), 2.02 (q, J = 7.0 Hz, 2H), 1.71
(
br s, 1H, OH), 1.42 (s, 3H), 1.41 (s, 3H), 1.39–1.20 (m, 6H), 0.88 (t,
7.0 mg, 0.0247 mmol, 20 mol %) and the mixture refluxed for
1.5 h under a nitrogen atmosphere. Grubbs-I catalyst (20.3 mg,
0.0247 mmol, 20 mol %) was added and the resulting solution re-
fluxed for 12 h. It was cooled to room temperature, filtered through
a pad of silica gel, and concentrated. The residue was purified by
silica gel column chromatography using petroleum ether/EtOAc
(4:1) as eluent to give 17a (24.2 mg, 52%) as a brown oil.
1
3
J = 6.9 Hz, 3H). C NMR (100 MHz, CDCl
3
): d = 136.8, 133.8, 132.6,
1
2
3
27.7, 123.9, 118.4, 108.6, 81.2, 80.3, 70.9, 41.6, 31.5, 29.3, 29.1,
+
7.4, 27.1, 26.9, 22.5, 14.0. HRMS (ESI+) calcd for [C19
31.2249, found: 331.2254.
32 3
H O +Na] :
4
1
.1.6. (4R,7R,8R,5E,10Z)-7,8-Isopropylidenedioxyhexadec-1,5,
0-trien-4-ol 16b
The title compound was synthesized from 11 (280 mg,
.90 mmol) with (S,S)-diisopropyl tartrate allylboronate by a simi-
2
5
½
a
ꢃ
¼ þ9:5 (c 0.28, CHCl
3
). IR (CHCl
3
): m = 3015, 2930, 2857,
D
1731, 1646, 1453, 1379, 1272, 1218, 1164, 1106, 1054, 969, 896,
ꢀ1
1
0
3
855, 758, 713, 667 cm . H NMR (400 MHz, CDCl ): d = 5.81–
lar procedure as described for 16a, to give 16b (211 mg, 76%) as a
5.65 (m, 2H), 5.55–5.43 (m, 4H), 5.40–5.30 (m, 1H), 4.09–4.02
(m, 1H), 3.74–3.63 (m, 1H), 2.34–2.29 (m, 6H), 2.11–1.94 (m,
2
5
colorless oil. ½
a
ꢃ
¼ ꢀ4:2 (c 1.0, CHCl
3
). IR (CHCl
3
): m = 3438, 3077,
D
2
9
2
5
985, 2930, 2858, 1642, 1458, 1378, 1242, 1165, 1106, 1062, 972,
4H), 1.70–1.60 (m, 2H), 1.40 (s, 6H), 1.37–1.19 (m, 6H), 0.88 (t,
ꢀ1
1
13
16, 857, 728 cm . H NMR (400 MHz, CDCl
H), 5.73–5.67 (m, 1H), 5.55–5.48 (m, 1H), 5.45–5.38 (m, 1H),
.18–5.16 (m, 1H), 5.14–5.13 (m, 1H), 4.24–4.23 (m, 1H), 4.07 (t,
3
): d = 5.88–5.76 (m,
J = 6.7 Hz, 3H).
3
C NMR (100 MHz, CDCl ): d = 172.5, 137.7,
132.7, 132.5, 129.3, 124.5, 123.8, 108.7, 81.0, 80.4, 76.6, 37.8,
33.7, 33.0, 31.5, 29.4, 29.2, 27.4, 27.1, 26.9, 24.1, 22.5, 14.0. HRMS
+
J = 7.7 Hz, 1H), 3.77–3.72 (m, 1H), 2.41–2.34 (m, 3H), 2.31–2.23
m, 1H), 2.03 (q, J = 7.0 Hz, 2H), 1.78 (br s, 1H, OH), 1.42 (s, 3H),
(ESI+) calcd for [C23
H
36
O
4
+Na] : 399.2504, found: 399.2514.
(
1
(
1
2
3
.41 (s, 3H), 1.41–1.26 (m, 6H), 0.89 (t, J = 6.9 Hz, 3H). 1 C NMR
100 MHz, CDCl ): d = 136.7, 133.8, 132.6, 127.4, 123.9, 118.4,
08.5, 81.2, 80.3, 70.5, 41.6, 31.5, 29.4, 29.1, 27.4, 27.1, 26.9,
2.5, 14.0. HRMS (ESI+) calcd for [C19
31.2255.
3
4.1.10. 9-(9R,6Z)-[(3R,4R,1E,6Z)-3,4-Isopropylidenedioxydodec-
1,6-dienyl]-4,5,8,9-tetrahydro-(3H)-oxonin-2-one 17b
3
The title compound was obtained from 10b (0.1 g, 0.247 mmol)
by a similar procedure as described for 17a, to give 17b (47.5 mg,
+
32 3
H O +Na] : 331.2249, found:
2
D
5
51%) as a brown oil. ½
a
ꢃ
¼ þ18:7 (c 0.34, CHCl
3 3
). IR (CHCl ):
m
= 3091, 2930, 2857, 1735, 1645, 1456, 1380, 1218, 1166, 1051,
969, 759 cm . H NMR (400 MHz, CDCl ): d = 5.85–5.70 (m, 2H),
3
ꢀ1 1
4
1
.1.7. (4S,7R,8R,5E,10Z)-7,8-Isopropylidenedioxyhexadec-1,5,
0-trien-4-yl hex-5-enoate 10a
5.49–5.31 (m, 4H), 5.15–5.0 (m, 1H), 4.07–4.04 (m, 1H), 3.75–
3.72 (m, 1H), 2.52–2.27 (m, 6H), 2.10–2.0 (m, 4H), 1.70–1.60 (m,
To a stirred solution of hex-5-enoic acid (50
.42 mmol, 2.0 equiv) in dry CH Cl (10 mL) at 0 °C, DCC (87 mg,
.42 mmol, 2.0 equiv) and DMAP (5 mg, cat.) were added. After
0 min alcohol 16a (65 mg, 0.21 mmol) in dry CH Cl (2 mL) was
lL, 48 mg,
0
0
1
2
2
2H), 1.42 (s, 6H), 1.40–1.25 (m, 6H), 0.89 (t, J = 6.7 Hz, 3H). 13
C
3
NMR (100 MHz, CDCl ): d = 172.7, 137.6, 132.7, 132.9, 129.9,
124.7, 123.8, 108.7, 81.0, 80.4, 76.6, 38.8, 33.7, 33.0, 32.6, 29.4,
2
2
added at 0 °C. The reaction mixture was stirred at room temperature
for 12 h. The solvent was evaporated and the residue purified by sil-
ica gel column chromatography using petroleum ether/EtOAc (9:1)
29.2, 27.4, 27.1, 26.9, 24.1, 22.5, 14.0. HRMS (ESI+) calcd for
+
[C23
H
36
O
4
+Na] : 399.2504, found: 399.2512.
25
as eluent to afford 10a (77 mg, 90%) as a colorless oil. ½
a
ꢃ
¼ þ4:9 (c
4.1.11. (8S,11R,12R)-Topsentolide B
2
4a
D
1
.0, CHCl
3
). IR (CHCl
3
):
m
= 3018, 2930, 2853, 1738, 1620, 1375,
To a stirred solution of 17a (20 mg, 0.053 mmol) in dry CH Cl
2 2
ꢀ1 1
1
219, 1104, 1019, 967, 918, 767 cm . H NMR (400 MHz, CDCl
3
):
(5 mL) at 0 °C was added trifluoroacetic acid (0.01 mL, 15 mg,
d = 5.82–5.62 (m, 4H), 5.52–5.47 (m, 1H), 5.42–5.32 (m, 2H), 5.10–
.03 (m, 3H), 4.98 (dt, J = 10.7, 1.2 Hz, 1H), 4.03 (t, J = 7.6 Hz, 1H),
0.132 mmol) under an argon atmosphere and stirred for 2 h. It
was then quenched with saturated aq NaHCO solution and water
3
5

R. A. Fernandes, P. Kattanguru / Tetrahedron: Asymmetry 22 (2011) 1930–1935
1935
(
(
3 mL) was added. The solution was extracted with CH
4 ꢁ 5 mL). The combined organic layers were washed with brine,
SO ) and concentrated. The residue was purified by silica
gel column chromatography using petroleum ether/EtOAc (1:4) to
2
Cl
2
References
1
.
.
Luo, X.; Li, F.; Hong, J.; Lee, C.-O.; Sim, C. J.; Im, K. S.; Jung, J. H. J. Nat. Prod. 2006,
9, 567–571.
(a) Niwa, H.; Wakamatsu, K.; Yamada, K. Tetrahedron Lett. 1989, 30, 4543–
4546; (b) Kigoshi, H.; Niwa, H.; Yamada, K.; Stout, T. J.; Clardy, J. Tetrahedron
Lett. 1991, 32, 2427–2428.
dried (Na
2
4
6
2
25
furnish 4a (16.4 mg, 92%) as a colorless oil. ½
a
ꢃ
¼ þ8:9 (c 0.27,
D
1
23
D
MeOH), {lit.
½
aꢃ
¼ þ9:8 (c 0.27, MeOH)}. IR (CHCl
3
): m = 3400,
ꢀ1
1
3. (a) Bischop, M.; Doum, V.; Nordschild, C. M. A.; Pietruszka, J.; Sandkuhl, D.
Synthesis 2010, 527–537; (b) Zhu, C.-Y.; Cao, X.-Y.; Zhu, B.-H.; Deng, C.; Sun, X.-
L.; Wang, B.-Q.; Shen, Q.; Tang, Y. Chem. Eur. J. 2009, 15, 11465–11468; (c)
Mohapatra, D. K.; Durugkar, K. A. Arkivoc 2004, 1, 146–155; (d) Takahashi, T.;
Watanabe, H.; Kitahara, T. Heterocycles 2002, 58, 99–104; (e) Baba, Y.; Saha, G.;
Nakao, S.; Iwata, C.; Tanaka, T.; Ibuka, T.; Ohishi, H.; Takemoto, Y. J. Org. Chem.
2
918, 2850, 1712, 1660, 1455, 1217, 1117, 973, 758 cm . H
3
NMR (500 MHz, CD OD): d = 5.85–5.62 (m, 2H), 5.56–5.32, (m,
4
1
1
H), 5.25–5.06 (m, 1H), 3.97 (br d, J = 2.5 Hz, 1H), 3.47–3.42 (m,
H), 2.51–2.25 (m, 6H), 2.31–2.01 (m, 4H), 1.73–1.63 (m, 2H),
.45–1.31 (m, 6H), 0.91 (t, J = 6.5 Hz, 3H). 13C NMR (100 MHz,
2001, 66, 81–88; (f) Takemoto, Y.; Baba, Y.; Saha, G.; Nakao, S.; Iwata, C.;
CD
4.4, 71.5, 34.8, 32.8, 31.7, 30.8, 30.4, 28.5, 26.6, 26.2, 23.6, 13.5.
3
OD): d = 174.7, 136.6, 132.3, 131.5 (2C), 127.1, 126.9, 75.0,
Tanaka, T.; Ibuka, T. Tetrahedron Lett. 2000, 41, 3653–3656; (g) Mohapatra, D.
K.; Datta, A. J. Org. Chem. 1998, 63, 642–646; (h) Critcher, D. J.; Connolly, S.;
Wills, M. J. Org. Chem. 1997, 62, 6638–6657; (i) Critcher, D. J.; Connolly, S.;
Wills, M. Tetrahedron Lett. 1995, 36, 3763–3766; (j) Critcher, D. J.; Connolly, S.;
Mohan, M. F.; Wills, M. J. Chem. Soc., Chem. Commun. 1995, 2, 139–140.
Kobayashi, M.; Ishigami, K.; Watanabe, H. Tetrahedron Lett. 2010, 51, 2762–
7
+
HRMS (ESI+) calcd for [C20
H
32
O
4
+Na] : 359.2356, found: 359.2350.
4.
5.
6.
4
.1.12. (8R,11R,12R)-Topsentolide B 4b
2
2764.
The title compound was prepared from 17b (50 mg,
.133 mmol) by a similar procedure as described for 4a, to give
Sreedhar, E.; Venkanna, A.; Chandramouli, N.; Babu, K. S.; Rao, J. M. Eur. J. Org.
Chem. 2011, 1078–1083.
(a) Fernandes, R. A.; Chowdhury, A. K. Tetrahedron: Asymmetry 2011, 22, 1114–
0
25
4
b (40.2 mg, 90%) as a colorless oil. ½
): = 3446, 2927, 2855, 1733, 1640, 1456, 1378, 1240,
164, 1047, 970, 916, 872, 758 cm . H NMR (400 MHz, CDCl
d = 5.85–5.72 (m, 2H), 5.62–5.56 (m, 1H), 5.49–5.26 (m, 3H),
a
ꢃ
¼ þ49:4 (c 0.27, MeOH).
D
1
1
119; (b) Fernandes, R. A.; Chowdhury, A. K. Eur. J. Org. Chem. 2011, 1106–
112; (c) Fernandes, R. A.; Kattanguru, P. Tetrahedron Lett. 2011, 52, 1788–
IR (CHCl
1
3
m
ꢀ1 1
3
):
1790; (d) Fernandes, R. A.; Ingle, A. B. Tetrahedron Lett. 2011, 52, 458–460; (e)
Fernandes, R. A.; Mulay, S. V. J. Org. Chem. 2010, 75, 7029–7032; (f) Fernandes,
R. A.; Ingle, A. B. Synlett 2010, 158–160; (g) Fernandes, R. A.; Chowdhury, A. K. J.
Org. Chem. 2009, 74, 8826–8829.
5
2
1
.24–5.07 (m, 1H), 4.01 (br d, J = 3.8 Hz, 1H), 3.55–3.47 (m, 1H),
.34–2.24 (m, 6H), 2.11–2.12 (m, 4H), 1.68–1.66 (m, 2H), 1.42–
7. For asymmetric Roush allylations see: (a) Roush, W. R.; Walts, A. E.; Hoong, L. K.
J. Am. Chem. Soc. 1985, 107, 8186–8190; (b) Roush, W. R.; Palkowitz, A. D. J. Am.
Chem. Soc. 1987, 109, 953–955; (c) Roush, W. R.; Hoong, L. K.; Palmer, M. A. J.;
Park, J. C. J. Org. Chem. 1990, 55, 4109–4117.
1
.25 (m, 6H), 0.89 (t, J = 6.8 Hz, 3H). H NMR (400 MHz, CD
3
OD):
d = 5.85–5.71 (m, 2H), 5.55–5.25 (m, 5H), 3.98–3.91 (m, 1H),
3
1
.51–3.42 (m, 1H), 2.41–2.24 (m, 6H), 2.15–1.99 (m, 4H), 1.75–
8. Guo, C.; Lu, X. J. Chem. Soc., Chem. Commun. 1993, 394–395.
1
3
.62 (m, 2H), 1.41–1.25 (m, 6H), 0.89 (t, J = 7.0 Hz, 3H). C NMR
): d = 173.8, 135.2, 132.3, 132.1, 129.0, 124.8,
24.2, 74.2, 72.1, 66.3, 33.9, 33.2, 31.9, 31.0, 29.2, 27.5, 26.4,
9. The formation of other regioisomers was not observed when the reaction time
was 6 h. The enantiomeric excess of 15 was determined by chiral HPLC using
CHIRALCEL OD-H column, Hexane/iPrOH = 95:5, flow rate = 1 mL/min, UV
(
100 MHz, CDCl
3
1
2
detection at 254 nm,
(minor enantiomer), 94% ee. For similar regio- and stereoselective
asymmetric dihydroxylations of a distant olefinic bond of ,b, ,d-unsaturated
R R
t = 10.64 min (major enantiomer), t = 13.70 min
+
32 4
4.9, 22.6, 13.4. HRMS (ESI+) calcd for [C20H O +Na] : 359.2356,
a
c
found: 359.2351.
esters see: (a) Zhang, Y.; O’Doherty, G. A. Tetrahedron 2005, 61, 6337–6351; (b)
Hunter, T. J.; O’Doherty, G. A. Org. Lett. 2001, 3, 1049–1052; (c) Berker, H.; Soler,
M. A.; Sharpless, K. B. Tetrahedron 1995, 51, 1345–1376; (d) Xu, D.; Crispino, G.
A.; Sharpless, K. B. J. Am. Chem. Soc. 1992, 114, 7570–7571.
Acknowledgements
1
0. For a similar low yielding RCM reaction in the synthesis of halicholactone using
Financial support by Industrial Research and Consultancy Cen-
tre (IRCC), Indian Institute of Technology Bombay and Department
of Science and Technology (DST) New Delhi are gratefully acknowl-
edged. P.K. thanks the Council of Scientific and Industrial Research
3b
Grubbs-II catalyst see the literature.
11. For a similar use of Grubbs-I catalyst and Ti(OiPr) (in the synthesis of
4
halicholactone) see the literature.3
b,e
(
CSIR), New Delhi for a senior research fellowship.