The first total synthesis of Topsentolide B3

Article abstract of DOI:10.1002/ejoc.201001378

The first total synthesis of the cytotoxic oxylipin Topsentolide B ₃ has been accomplished in 15 steps with an overall yield of 24%. Starting with readily available cis-butene diol as a synthon, the synthesis involved Marouka allylation and Sha

Full text of DOI:10.1002/ejoc.201001378

FULL PAPER
DOI: 10.1002/ejoc.201001378
The First Total Synthesis of Topsentolide B3
Eppakayala Sreedhar,[a] Arramshetti Venkanna,[a] Nagula Chandramouli,[a]
K. Suresh Babu,[a] and Janaswamy Madhusudana Rao*[a]
Keywords: Hydroxylation / Allylation / Metathesis / Asymmetric synthesis / Natural products / Lactones
The first total synthesis of the cytotoxic oxylipin Topsentol- through a selective Grubbs ring-closing metathesis reaction.
ide B3 has been accomplished in 15 steps with an overall
yield of 24%. Starting with readily available cis-butene diol
as a synthon, the synthesis involved Marouka allylation and
Other key steps in the synthesis are CuI-mediated alk-
ynylation and Swern oxidation reactions. This provides a
unique approach to the synthesis of oxylipins and offers the
Sharpless hydroxylation for the construction of three asym- advantages of brevity and relatively high overall yield.
metric centers. The nine-membered lactone ring was built
Introduction
Marine invertebrates and algae have been recognized as
a rich source for a large number of new compounds with
unique structural classes. The topsentolides A1–C2 com-
Figure 1. Structure of topsentolide B3.
prise a novel group of oxylipins that were isolated from the
Topsia sp. off the Korean coast in 2006.[1] The structural
elucidation of these metabolites was achieved by extensive
In this report, a convergent strategy for the stereoselec-
interpretation of their spectroscopic data. The topsentolides
tive synthesis of topsentolide B3 (Scheme 1) makes use of
contain cyclopropane and nine-membered lactone rings to-
Marouka asymmetric allylation, Swern oxidation, and
gether with variable degrees of unsaturation at C-5, C-9,
Grubbs RCM. In the overall sequence, these are the key
and C-17; they are believed to be formed by lipoxygenation
reaction steps for the formation of the lactone ring. Instal-
followed by cyclization of unsaturated fatty acids. De-
lation of the chiral 1,2-diol group was achieved through
pending upon the functional groups at C-11 and C-12, they
Sharpless asymmetric dihydroxylation by using AD-mix
reagent.[3] To the best of our knowledge this is the first total
synthesis of topsentolide B3.
are categorized into three series. Representative members
include those originally assigned the structures of topsento-
lides A, B, and C, respectively.
Because of their important biological properties[1] cou-
pled with the unique stereogenic variations within subfamil-
ies of oxylipins, as well as the limited amounts available
from natural sources, topsentolides have attracted the atten-
tion of a number of synthetic organic chemists worldwide.
Recently, Kobayashi et al.[2] reported the synthesis of
topsentolide A1 and determined the stereochemistry. How-
ever, there are no reports on the synthesis of other topsen-
tolides. These facts coupled with the interesting chiral 1,2-
diol group adjacent to the trans-double bond of topsentol-
ide B3 (1, Figure 1) prompted us to undertake the synthetic
study of topsentolide B3.
Results and Discussion
Recognizing the importance of developing an efficient
synthesis of 1, our synthetic approach to a nine-membered
unsaturated lactone involved a Z-selective ring-closing me-
tathesis (RCM) reaction (Scheme 1). Disconnection of the
C-5–C-6 double bond revealed bis-terminal olefin 2 as a
potential key intermediate. This compound was synthesized
from alcohol 3 by esterification with 5-hexenoic acid. In
designing a unified approach to fragment 3, it was impor-
tant to consider the genesis of the configuration at C-8.
Our goal from the outset was to accomplish this through
stereocontrolled allylation of the corresponding aldehyde
that would leave us with a handle for installing the ste-
reocenter at C-8. In an earlier study from our laboratory,
we demonstrated the versatility of the Marouka allylation
and Grubbs cross-metathesis reactions.[4] Thus, we envi-
sioned that key fragment 3 could be obtained through the
[a] Organic Division-I (NPL),
Indian Institute of Chemical Technology,
Hyderabad 500 607, India
Fax: +91-040-27160512
E-mail: janaswamy@iict.res.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001378.
1078
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1078–1083

The First Total Synthesis of Topsentolide B3
Scheme 1. Retrosynthetic analysis of topsentolide B3 (1).
Marouka asymmetric allylation of aldehyde 4, which in
turn could be realized from compound 5 using Lindlar’s
catalyst, Swern oxidation, and other steps. Alkyne diol 5
in turn was obtained from compound 6 through sequential
condensation with 1-heptyne and Sharpless dihydroxylation
reactions. Thus, our present total synthesis is highlighted by
utilization of a Marouka asymmetric allylation, which di-
rects construction of the stereocenter at C-8, and Grubbs
RCM for the formation of the nine-membered lactone ring.
Furthermore, the simplicity of the precursors made this an
attractive route for the synthesis of a library of compounds
in the oxylipin family, thereby providing ample amounts for
more extensive biological screening.
Commercially available p-methoxybenzyl (PMB) alcohol
was treated with Cl3CCN in the presence of 1,5,7-triazabi-
cyclo[4.4.0]dec-5-ene to give 4-methoxybenzyl-2,2,2-tri-
chloroacetimidate. The synthesis began with commercially
available cis-butenediol (7), which was selectively protected
with freshly prepared 4-methoxybenzyl-2,2,2-trichloroaceti-
midate and a catalytic amount of (–)-camphor-10-sulfonic
acid (CSA) in dichloromethane to give mono-PMB ether
8
[5] (Scheme 2). Resulting allyl alcohol 8 was converted into
Scheme 2. Reagents and conditions: (a) 4-methoxybenzyl-2,2,2-tri-
chloroacetimidate, CSA, 0 °C to r.t., 1 h, 92%; (b) CBr4, Ph3P,
CH2Cl2, 0 °C to r.t., 2 h, 94%; (c) 1-heptyne, CuI, NaI, K2CO3,
N,N-dimethylformamide (DMF), r.t., 8 h, 96%; (d) AD-mix-α,
CH3SO2NH2, (CH3)3COH/H2O (1:1), 0 °C to r.t., 24 h, 97%;
(e) CSA, 2,2-dimethoxypropane, CH2Cl2, r.t., 12 h, 89%; (f) H2/
Lindlar’s catalyst, quinoline, benzene, 10 °C, 2 h, 91%; (g) 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), CH2Cl2/H2O
(9:1), 0 °C to r.t., 1 h, 87%; (h) (COCl)2, dimethyl sulfoxide
(DMSO), Et3N, CH2Cl2, –78 °C, 1 h; then Ph3P=CHCO2Et, C6H6,
92 °C, 2 h, 91% for two steps; (i) diisobutylaluminum hydride (DI-
BAL-H), CH2Cl2, –15 °C, 1 h, 95%; (j) (COCl)2, DMSO, Et3N,
its allyl bromide by using Appel reaction conditions[6,7] to
afford compound 6 in 94% yield, which was further treated
with 1-heptyne by using a CuI-mediated cross-coupling re-
action[7] to give 9 in 96% yield.
When 9 was treated with AD-mix-α in (1:1) aqueous
tBuOH at room temperature, a highly stereoselective dihy-
droxylation[3,8] occurred to give diol 5 in 97% yield, which
was then protected as acetonide 10.[9] Stereospecific hydro-
genation[7] of the triple bond in 10 with Lindlar’s catalyst
and quinoline in benzene resulted in olefin 11. Removal of
the PMB group[10] in compound 11 by using DDQ fur-
nished compound 12. Swern oxidation[3,11] of alcohol 12
followed by Wittig olefination[12] furnished (E)-alkene 13 in
91% overall yield for the two steps. This was converted into
CH2Cl2,
–78 °C,
1 h,
96%;
(k) (S,S)-I
(10 mol-%),
Bu3SnCH2CH=CH2, CH2Cl2, –15 to 0 °C, 24 h, 86%.
With required fragment 3 in hand, we proceeded with the
corresponding allylic alcohol 14 in 95% yield by reduction synthesis of topsentolide B3 (Scheme 3). Thus, condensa-
with DIBAL-H in dichloromethane under standard condi- tion of alcohol 3 with 5-hexenoic acid by using 1-ethyl-3-
tions.[13] Oxidation of the formed primary alcohol under (3-dimethylaminopropyl)carbodiimide (EDCI)/4-(dimeth-
Swern conditions afforded desired aldehyde 4. Marouka al- ylamino)pyridine (DMAP) in pyridine[15,3] afforded ester
lylation[4,14] of 4 by using titanium complex (S,S)-I and al- 15, and subsequent deprotection of the acetonide with (–)-
lyltri-n-butyltin yielded key fragment 3 with excellent camphor-10-sulfonic acid in methanol afforded desired
enantioselectivity of 98%ee (determined by chiral HPLC) product 2. The final step of our synthetic plan involved the
in 86% yield.
generation of the lactone ring by Grubbs RCM. This may
Eur. J. Org. Chem. 2011, 1078–1083
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1079

E. Sreedhar, A. Venkanna, N. Chandramouli, K. S. Babu, J. M. Rao
FULL PAPER
be considered as the most critical step in our synthetic Maruoka asymmetric allylation and Sharpless asymmetric
scheme because the preparation of medium-sized rings by hydroxylation were used for the generation of the chiral cen-
RCM may be difficult in some instances, especially in the ters. Further elaboration by using this sequence of reactions
presence of other reactive sites in the alicyclic chain. Grati- to construct other nine-membered-ring-containing biolo-
fyingly, and in spite of these potential problems, the RCM gically active compounds is underway in our laboratory.
reaction[16] of compound 2 catalyzed by Grubbs second
generation catalyst (10 mol-%) and in dichloromethane
heated to reflux proceeded smoothly and afforded topsento-
lide B3 (1) in 78% yield. Although fragment 2 contained
two other double bonds in the alicyclic chain, only terminal
double bonds were involved selectively to form the nine-
membered lactone ring of 1. This result implied that the
catalyst did not insert into the double bond at the sterically
hindered region and the double bond α to the ester hydroxy
group. In this case, the reaction was highly Z-selective, and
Experimental Section
General: 1H NMR and 13C NMR spectra were recorded at ambient
temperature with a 300, 500, or 75 MHz spectrometer by using
CDCl3 or CD3OD as solvents. The chemical shifts are reported
using TMS as an internal standard, and signal patterns are indi-
cated as follows: s, singlet; d, doublet; dd, doublet of doublet; t,
triplet; m, multiplet; br. s, broad singlet. FTIR spectra were re-
corded as thin films on KBr or as neat films. Optical rotations were
there was no spectroscopic or chromatographic evidence for
the formation of either the E-isomer or other side products.
measured with a digital polarimeter using a 1-mL cell having a 1-
dm path length. For low- (MS) and high- (HRMS) resolution mass
Indeed, to the best of our knowledge, this is the first exam- spectrometry, m/z ratios are reported as values in atomic mass
ple of a selective RCM reaction,[17] demonstrating the for-
units. All reagents and solvents were reagent grade and used with-
out further purification unless otherwise specified. Technical-grade
mation of the lactone ring in the synthesis of the oxylipins
ethyl acetate and hexane were used for column chromatography
class of compounds or any other medium ring lactones. All
and distilled prior to use. When used as a reaction solvent, tetra-
the intermediate products were well characterized using
hydrofuran (THF) was freshly distilled from sodium benzophenone
NMR spectroscopy and mass spectrometry. The data (1H
ketyl. Column chromatography was carried out by using silica gel
(60–120 mesh & 100–200 mesh) packed in glass columns. All reac-
tions were performed under an atmosphere of nitrogen by using
flame- or oven-dried glassware and magnetic stirring.
NMR, 13C NMR, and HRMS) of synthetic topsentolide
was identical and the optical rotation {[α]2D6 = +42 (c = 0.1,
CHCl3)} was comparable to the reported data for the natu-
ral product.
(Z)-4-(4-Methoxybenzyloxy)but-2-en-1-ol (8): To a stirred solution
of 4-methoxybenzyl-2,2,2-trichloroacetimidate (2.82 g, 0.010 mol)
and cis-butenediol (7; 1.0 g, 0.011 mol) in dichloromethane (30 mL)
at 0 °C was added (–)-camphor-10-sulfonic acid (0.12 g,
0.0005 mol). The reaction mixture was warmed to room tempera-
ture and stirred for 1 h. Upon completion (monitored by TLC), the
reaction mixture was quenched with triethylamine (0.5 g,
0.005 mol) and concentrated under reduced pressure to give the
crude product. Purification by flash chromatography (23% ethyl
acetate in hexanes) yielded pure 8 (2.02 g, 92%) as a colorless oil.
1H NMR (300 MHz, CDCl3): δ = 7.22 (d, J = 8.5 Hz 2 H), 6.84
(d, J = 8.5 Hz, 2 H), 5.82–5.63 (m, 2 H), 4.43 (s, 2 H), 4.11 (d, J
= 6.0 Hz, 2 H), 4.02 (d, J = 6.0 Hz, 2 H), 3.79 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 159.1, 132.3,129.7, 129.2 (2 C), 127.6,
113.6 (2 C), 71.8, 65.0, 58.0, 54.9 ppm. HRMS (ESI): calcd. for
C12H16O3Na [M + Na]+ 231.0992; found 231.0991.
(Z)-1-[(4-Bromobut-2-enyloxy)methyl]-4-methoxybenzene (6):
A
solution of 8 (15.0 g, 0.07 mol) and carbon tetrabromide (26.3 g,
0.08 mol) in dichloromethane (75 mL) was cooled to 0 °C. With
vigorous stirring
a solution of triphenylphosphane (22.7 g,
0.85 mol) in dichloromethane (50 mL) was slowly added over
30 min using a syringe. The mixture was warmed to room tempera-
ture and stirred for another 2 h. The reaction mixture was concen-
trated to give a brown oil, which was washed with hexane (500 mL).
The white precipitate was filtered, and the filtrate was concentrated
under reduced pressure to give the crude product. Purification by
flash chromatography (3% ethyl acetate in hexanes) yielded pure 6
(18.23 g, 94%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ
= 7.22 (d, J = 8.7 Hz, 2 H), 6.83 (d, J = 8.3 Hz, 2 H), 5.91–5.80
(m, 1 H), 5.75–5.65 (m, 1 H), 4.43 (s, 2 H), 4.08 (dd, J = 6.0,
1.1 Hz, 2 H), 3.94 (d, J = 8.3 Hz, 2 H), 3.80 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 161.1, 134.4, 133.0, 131.0 (2 C), 129.7,
115.4 (2 C), 73.4, 66.4, 56.4, 28.8 ppm. HRMS (ESI): calcd. for
Scheme 3. Reagents and conditions: (a) 5-hexenoic acid, EDCI,
DMAP, pyridine, r.t., 16 h, 92%; (b) CSA, CH3OH, r.t., 6 h, 83%;
(c) Grubbs second generation catalyst (10 mol-%), CH2Cl2, reflux,
0.5 h, 78%.
Conclusions
In conclusion, we have accomplished the first total syn-
thesis of topsentolide B3, accomplished in 15 steps in a lin-
ear fashion. The key step was a selective RCM reaction. C12H15BrO2Na [M + Na]+ 294.1375; found 294.1377.
1080
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Eur. J. Org. Chem. 2011, 1078–1083

The First Total Synthesis of Topsentolide B3
(Z)-1-Methoxy-4-[(undec-2-en-5-ynyloxy)methyl]benzene (9): Bro-
mide 6 (13.5 g, 0.05 mol) and 1-heptyne (5.7 g, 0.06 mol) were
slowly added to a suspension of the previously dried salts, CuI
(4S,5R,Z)-4-[(4-Methoxybenzyloxy)methyl]-2,2-dimethyl-5-(oct-2-
enyl)-1,3-dioxolane (11): Dry benzene (30 mL) was added to a 250-
mL Erlenmeyer flask with Lindlar’s catalyst (1.25 g). At room tem-
(18.9 g, 0.10 mol), NaI (14.9 g, 0.10 mol), and K2CO3 (10.3 g, perature the mixture was saturated with H2 and cooled to 10 °C.
0.07 mol) in DMF (60 mL). The reaction mixture was stirred at
room temperature for 8 h, quenched with saturated aqueous am-
monium chloride and extracted with diethyl ether. The combined
organic layers were washed with brine and dried with sodium sul-
fate. Removal of the solvent afforded the crude product.
Chromatography on silica gel (2% ethyl acetate in hexanes) gave 9
(13.73 g, 96%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ
= 7.16 (d, J = 8.7 Hz, 2 H), 6.77 (d, J = 8.7 Hz, 2 H), 5.82–5.70
(m, 1 H), 5.66–5.51 (m, 1 H), 4.35 (s, 2 H), 3.90 (dd, J = 5.8,
1.1 Hz, 2 H), 3.73 (s, 3 H), 2.89–2.81 (m, 2 H), 2.14–2.03 (m, 2 H),
Under a stream of N2, a solution of 10 (0.83 g, 0.0023 mol) in ben-
zene (30 mL) and quinoline (1.2 mL) were added. After exchanging
the N2 with H2, the reaction mixture was stirred for 1 h at 10 °C.
The mixture was filtered and washed with 2 m HCl (2ϫ30 mL),
and the solvent was evaporated to afford the crude residue. Purifi-
cation by column chromatography (2% ethyl acetate in hexanes)
gave 11 (0.76 g, 91%) as a colorless oil. [α]2D6 = –10 (c = 1.0, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 7.22 (d, J = 8.5 Hz, 2 H), 6.83
(d, J = 8.5 Hz, 2 H), 5.52–5.30 (m, 2 H), 4.49 (s, 2 H), 3.83–3.72
(m, 2 H), 3.80 (s, 3 H), 3.53–3.46 (m, 2 H), 2.37–2.24 (m, 2 H),
1.48–1.21 (m, 6 H), 0.84 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR 2.04–1.91 (m, 2 H), 1.43–1.20 (m, 12 H), 0.88 (t, J = 6.2 Hz, 3
(75 MHz, CDCl3): δ = 159.0, 130.3, 129.1 (2 C), 128.3, 127.7, 113.5 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 159.1, 132.2, 130.0,
(2 C), 82.5, 76.5, 71.5, 69.7, 54.9, 31.0, 28.6, 22.2, 21.8, 18.7,
14.0 ppm. HRMS (ESI): calcd. for C19H26O2Na [M + Na]+
309.1830; found 309.1827.
129.0 (2 C), 124.3, 113.5 (2 C), 108.3, 79.4, 78.0, 73.0, 70.2, 54.8,
31.4, 30.7, 29.2, 27.3, 27.2, 27.0, 22.5, 14.1 ppm. HRMS (ESI):
calcd. for C22H34O4Na [M + Na]+ 385.2354; found 385.2351.
{(4S,5R)-2,2-Dimethyl-5-[(Z)-oct-2-enyl]-1,3-dioxolan-4-yl}-
methanol (12): To a solution of compound 11 (0.7 g, 0.002 mol) in
dichloromethane/H2O (9:1, 20 mL) at 0 °C was added DDQ
(0.68 g, 0.003 mol). The reaction was warmed to room temperature
and stirred for 1 h. After completion (monitored by TLC), the reac-
tion mixture was filtered through Celite. The filtrate was washed
with saturated sodium hydrogen carbonate (3ϫ20 mL), dried with
sodium sulfate, and concentrated to afford the crude product. Puri-
fication by column chromatography (5% ethyl acetate in hexanes)
gave 12 (0.4 g, 87%) as a colorless oil. [α]2D7 = –9 (c = 1.0, CHCl3).
(2S,3R)-1-(4-Methoxybenzyloxy)undec-5-yne-2,3-diol (5): To a solu-
tion of compound 9 (7.7 g, 0.027 mol) in tert-butyl alcohol/water
(1:1, 308 mL) at 0 °C was added AD-mix-α (37.9 g). The reaction
mixture was stirred for 1 h and CH3SO2NH2 (1.9 g, 0.02 mol) was
added. After stirring for 1 h, the reaction mixture was warmed to
room temperature and allowed to stir for 24 h. The reaction was
quenched with sodium sulfite (38 g) and stirred for an additional
30 min. After extracting with ethyl acetate (3ϫ80 mL), the com-
bined organic layers were dried with sodium sulfate and concen-
trated to afford the crude product. Purification by column
chromatography (15% ethyl acetate in hexanes gave 5 (8.33 g, 97%)
IR (KBr): ν = 3470, 2926, 2861, 1613, 1518, 1460, 1378, 1250, 1166,
˜
1
1062, 841 cm–1. H NMR (300 MHz, CDCl3): δ = 5.58–5.46 (m, 1
as a colorless oil. [α]2D6 = –7 (c = 1.0, CHCl ). IR (KBr): ν = 3290,
˜
3
H), 5.45–5.31 (m, 1 H), 3.95–3.55 (m, 4 H), 2.46–2.21 (m, 2 H),
2.09–1.95 (m, 2 H), 1.44–1.22 (m, 12 H), 0.89 (t, J = 6.2 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 132.7, 124.1, 108.4, 81.3,
76.3, 61.8, 31.6, 30.7, 29.3, 27.5 (2 C), 27.2, 22.7, 14.2 ppm. HRMS
(ESI): calcd. for C14H26O3Na [M + Na]+ 265.1779; found 265.1785.
3217, 2922, 2859, 1612, 1514, 1463, 1253, 1114, 1081, 1040, 992,
1
941, 818, 712 cm–1. H NMR (300 MHz, CDCl3): δ = 7.29 (d, J =
8.5 Hz, 2 H), 6.90 (d, J = 8.7 Hz, 2 H), 4.47 (s, 2 H), 3.90–3.82 (m,
1 H), 3.79 (s, 3 H), 3.76–3.69 (m, 1 H), 3.63–3.48 (m, 2 H), 2.53–
2.41 (m, 1 H), 2.37–2.26 (m, 1 H), 2.16–2.09 (m, 1 H), 2.08–2.04
(m, 1 H), 1.50–1.25 (m, 6 H), 0.88 (t, J = 7.0 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 161.1, 132.6, 130.9 (2 C), 115.4 (2 C),
83.1, 78.8, 74.3, 73.5, 72.5, 72.3, 56.5, 32.7, 30.4, 25.4, 23.8, 20.1,
15.2 ppm. HRMS (ESI): calcd. for C19H28O4Na [M + Na]+
343.1885; found 343.1894.
(E)-Ethyl 3-{(4S,5R)-2,2-Dimethyl-5-[(Z)-oct-2-enyl]-1,3-dioxolan-
4-yl}acrylate (13): Under an inert atmosphere at –78 °C, DMSO
(0.75 g, 0.01 mol) was added dropwise to a solution of oxalyl chlo-
ride (1.7 g, 0.013 mol) in dichloromethane (20 mL). After stirring
for 15 min, a solution of 12 (2.0 g, 0.00877 mol) in dichlorometh-
ane (10 mL) was added dropwise. After stirring for 25 min, triethyl-
amine (6.2 g, 0.06 mol) was added, followed by stirring for an ad-
ditional 20 min. Upon completion, the reaction mixture was
warmed to room temperature and quenched with water (50 mL).
After extracting with dichloromethane, the organic layer was
washed with brine and dried with sodium sulfate. Removal of the
solvent afforded the crude product (1.92 g), which was immediately
utilized for the next step without purification. A solution of
Ph3P=CHCOOEt (3.7 g, 0.01 mol) in benzene (20 mL) was heated
to reflux and a solution of the crude aldehyde in benzene (5 mL)
was added. After stirring for 2 h, the reaction mixture was warmed
to room temperature and concentrated to afford the crude product.
Purification by column chromatography (2% ethyl acetate in hex-
(4S,5R)-4-[(4-Methoxybenzyloxy)methyl]-2,2-dimethyl-5-(oct-2-
ynyl)-1,3-dioxolane (10): To a solution of compound 5 (0.8 g,
0.003 mol) in dichloromethane (15 mL) at 0 °C was added 2,2-di-
methoxypropane (0.8 g, 0.008 mol) and a catalytic amount of (–)-
camphor-10-sulfonic acid. The reaction was warmed to room tem-
perature, and the mixture was stirred for 12 h. After completion
(monitored by TLC), the reaction was quenched with a saturated
solution of sodium hydrogen carbonate and extracted with chloro-
form. The organic layer was dried with sodium sulfate and concen-
trated to afford the crude product. Purification by column
chromatography (5% ethyl acetate in hexane) gave 10 (0.8 g, 89%)
as a colorless oil. [α]2D6 = –4 (c = 2.0, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 7.23 (d, J = 8.5 Hz, 2 H), 6.84 (d, J = 8.7 Hz, 2 H),
4.57–4.45 (m, 2 H), 4.03–3.95 (m, 1 H), 3.88–3.81 (m, 1 H), 3.79
ane) gave 13 (2.21 g, 91% for two steps) as a colorless oil. [α]2D7
–8 (c = 1.0, CHCl3). H NMR (300 MHz, CDCl3): δ = 6.78 (dd, J
=
1
(s, 3 H), 3.66–3.59 (m, 1 H), 3.57–3.50 (m, 1 H), 2.57–2.39 (m, 2 = 5.1, 15.5 Hz, 1 H), 6.08–5.82 (m, 1 H), 5.56–5.20 (m, 2 H), 4.24–
H), 2.10–2.02 (m, 2 H), 1.47–1.24 (m, 6 H), 1.41 (s, 3 H), 1.39 (s, 4.04 (m, 3 H), 3.77–3.58 (m, 1 H), 2.42–2.27 (m, 2 H), 2.10–1.92
3 H), 0.90 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 159.1, 130.1, 129.1 (2 C), 113.6 (2 C), 108.9, 82.5, 79.6, 76.2,
(m, 2 H), 1.42–1.20 (m, 15 H), 0.90 (t, J = 6.0 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 166.0, 145.3, 132.6, 124.5, 123.1,
75.2, 73.0, 70.3, 54.9, 31.1, 28.6, 27.2 (2 C), 23.3, 22.2, 18.7, 109.4, 81.0, 76.0, 60.4, 31.5, 30.1, 29.1, 27.3, 27.0 (2 C), 22.5, 14.2,
14.1 ppm. HRMS (ESI): calcd. for C22H32O4Na [M + Na]+
383.2198; found 383.2195.
14.0 ppm. HRMS (ESI): calcd. for C18H30O4Na [M + Na]+
333.2041; found 333.2049.
Eur. J. Org. Chem. 2011, 1078–1083
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1081

E. Sreedhar, A. Venkanna, N. Chandramouli, K. S. Babu, J. M. Rao
FULL PAPER
(E)-3-{(4S,5R)-2,2-Dimethyl-5-[(Z)-oct-2-enyl]-1,3-dioxolan-4-yl}-
prop-2-en-1-ol (14): Under an inert atmosphere at –15 °C, DIBAL-
H (1 m in toluene, 11.0 mL) was added dropwise to a solution of
ester 13 (1.32 g, 0.0044 mol) in dichloromethane (27 mL). After
stirring for 1 h, the reaction was quenched with a saturated solution
of Rochelle salt, warmed to room temperature, and stirred for an
additional 3 h. The organic phase was separated and the aqueous
phase was extracted with dichloromethane (2ϫ). The combined or-
ganic layers were washed with water, brine, dried with anhydrous
sodium sulfate, and concentrated to afford the crude product. Puri-
fication by column chromatography (11% acetone in hexane) gave
14 (1.13 g, 95%) as a colorless oil. [α]2D8 = –7 (c = 1.2, CHCl3). IR
27.4, 27.1, 26.9, 22.5, 14.0 ppm. HRMS (ESI): calcd. for
C19H32O3Na [M + Na]+ 331.2249; found 331.2251.
(S,E)-1-{(4S,5R)-2,2-Dimethyl-5-[(Z)-oct-2-enyl]-1,3-dioxolan-4-yl}-
hexa-1,5-dien-3-yl Hex-5-enoate (15): To a solution of 5-hexenoic
acid (0.264 g, 0.0023 mol) in pyridine (10 mL) at 0 °C was added
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.296 g,
0.0015 mol) and 4-(dimethylamino)pyridine (0.009 g, 0.00008 mol).
The resulting white cloudy suspension was warmed to room tem-
perature and stirred until a clear solution formed. A solution of 3
(0.12 g, 0.0004 mol) in pyridine (1 mL) was added dropwise. After
stirring for 16 h, the reaction mixture was concentrated to remove
pyridine, aqueous 1 n HCl was added, and the mixture was ex-
tracted with dichloromethane (2ϫ10 mL). The combined organic
layers were washed with brine, dried, and the solvents were evapo-
rated. Purification by column chromatography (2% ethyl acetate in
hexane) gave 15 (0.144 g, 92%) as a colorless oil. [α]2D9 = +3 (c =
0.8, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 5.80–5.58 (m, 4 H),
5.57–5.43 (m, 1 H), 5.42–5.34 (m, 1 H), 5.33–5.27 (m, 1 H), 5.12–
5.03 (m, 2 H), 5.03–4.94 (m, 2 H), 4.01–3.95 (m, 1 H), 3.68–3.59
(m, 1 H), 2.42–2.23 (m, 6 H), 2.15–1.97 (m, 4 H), 1.78–1.68 (m, 2
H), 1.38 (s, 3 H), 1.37 (s, 3 H), 1.42–1.24 (m, 6 H), 0.90 (t, J =
6.8 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 172.5, 137.5,
132.9, 132.6, 131.9, 129.6, 123.7, 118.0, 115.3, 108.6, 81.0, 80.2,
72.3, 38.8, 33.6, 32.9, 31.4, 29.3, 29.1, 27.3, 27.0, 26.8, 24.0, 22.5,
14.0 ppm. HRMS (ESI): calcd. for C25H40O4Na [M + Na]+
427.2824; found 427.2819.
(KBr): ν = 3417, 2926, 2861, 1726, 1459, 1379, 1237, 1164, 1102,
˜
1062, 1005, 970, 855 cm–1. 1H NMR (300 MHz, CDCl3): δ = 5.97–
5.85 (m, 1 H), 5.71–5.60 (m, 1 H), 5.52–5.33 (m, 2 H), 4.14 (d, J
= 4.9 Hz, 2 H), 4.06–3.98 (m, 1 H), 3.72–3.62 (m, 1 H), 2.31 (t, J
= 6.0 Hz, 2 H), 2.01 (q, J = 6.8 Hz, 2 H), 1.39 (s, 3 H), 1.38 (s, 3
H), 1.37–1.23 (m, 6 H), 0.90 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 134.0, 132.6, 127.6, 123.8, 108.5, 81.1, 80.3,
62.5, 31.4, 29.3, 29.1, 27.3, 27.1, 26.9, 22.4, 13.9 ppm. HRMS
(ESI): calcd. for C16H28O3Na [M + Na]+ 291.1936; found 291.1949.
(E)-3-{(4S,5R)-2,2-Dimethyl-5-[(Z)-oct-2-enyl]-1,3-dioxolan-4-yl}-
acrylaldehyde (4): Under an inert atmosphere at –78 °C, DMSO
(0.35 g, 0.0051 mol) was added dropwise to a solution of oxalyl
chloride (0.87 g, 0.0066 mol) in dichloromethane (10 mL). After
stirring for 15 min, a solution of 4 (1.2 g, 0.0045 mol) in dichloro-
methane (5 mL) was added dropwise. After stirring for 25 min, tri-
ethylamine (3.81 g, 0.031 mol) was added, and the reaction was
stirred for an additional 20 min. After completion (monitored by
TLC), the reaction mixture was warmed to room temperature,
quenched with water (25 mL), and extracted with dichloromethane.
The organic layer was washed with brine and dried with sodium
sulfate. Removal of the solvent afforded the crude product (1.15 g).
Purification by column chromatography (3% ethyl acetate in hex-
ane) gave 4 (1.15 g, 96%) as colorless oil. Compound 4 is unstable.
(4S,5E,7S,8R,10Z)-7,8-Dihydroxyhexadeca-1,5,10-trien-4-yl Hex-5-
enoate (2): To a solution of compound 15 (0.12 g, 0.0003 mol) in
methanol (6 mL) at 0 °C was added a catalytic amount of (–)-cam-
phor-10-sulfonic acid. The reaction temperature was warmed to
room temperature and stirred for 6 h. The reaction mixture was
concentrated to remove the methanol and diluted with chloroform.
Saturated sodium hydrogen carbonate solution was added, fol-
lowed by extracting with chloroform, drying the organic layer with
sodium sulfate, and concentrating the mixture to afford the crude
product. Purification by column chromatography (12% ethyl acet-
ate in hexane) gave 2 (0.09 g, 83%) as a colorless oil. [α]2D9 = –8 (c
(S,E)-1-{(4S,5R)-2,2-Dimethyl-5-[(Z)-oct-2-enyl]-1,3-dioxolan-4-yl}-
hexa-1,5-dien-3-ol (3): Dried Ti(OiPr)4 (0.17 mL, 0.0006 mol) was
added to a stirred solution of TiCl4 in (1 m in dichloromethane,
0.2 mL, 0.002 mol) in dichloromethane (5 mL) at 0 °C. The solu-
tion was warmed room temperature. After 1 h, silver(I) oxide
(0.099 g, 0.0004 mol) was added, and the mixture was stirred for
5 h under the exclusion of direct light. The mixture was diluted
with dichloromethane (3 mL), and treated with (S)-binaphthol
(0.235 g, 0.0008 mol) at room temperature for 2 h to furnish chiral
bis-TiIV oxide (S,S)-I. In situ generated (S,S)-I was cooled to
–15 °C and treated sequentially with aldehyde 4 (1.06 g, 0.004 mol)
and allyltributyltin (1.38 mL, 0.0044 mol). The mixture was
warmed to 0 °C and stirred for 4 h. The reaction mixture was
quenched with saturated sodium hydrogen carbonate and extracted
with dichloromethane. The organic extracts were dried with sodium
sulfate and concentrated to afford the crude product. Purification
by column chromatography (7% ethyl acetate in hexane) gave 3
(1.05 g, 86%) as a colorless oil. The absolute configuration of the
product was determined to be S with an enantiomeric purity of
98%ee by analytical HPLC analysis. [α]2D9 = –5 (c = 1.2, CHCl3).
= 0.5, CHCl ). IR (KBr): ν = 3440, 3077, 2925, 2858, 1734, 1642,
˜
3
1459, 1379, 1245, 1170, 1072, 971, 916, 733 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 5.82–5.62 (m, 4 H), 5.59–5.46 (m, 1 H),
5.44–5.32 (m, 1 H), 5.31–5.21 (m, 1 H), 5.12–5.07 (m, 1 H), 5.07–
4.93 (m, 3 H), 3.97–3.90 (m, 1 H), 3.49–3.39 (m, 1 H), 2.44–2.34
(m, 2 H), 2.33–2.16 (m, 4 H), 2.16–1.98 (m, 4 H), 1.77–1.65 (m, 2
H), 1.42–1.22 (m, 6 H), 0.90 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 172.8, 137.6, 133.7, 133.0, 132.0, 130.8,
124.2, 118.1, 115.4, 74.3, 73.9, 72.8, 38.8, 33.7, 32.9, 31.4, 30.9,
29.2, 27.3, 24.0, 22.5, 14.0 ppm. HRMS (ESI): calcd. for
C22H36O4Na [M + Na]+ 387.2511; found 387.2509.
Topsentolide B3 (1): To a solution Grubbs second generation cata-
lyst (0.024 g, 0.000027 mol) in degassed anhydrous dichlorometh-
ane (70 mL) heated to reflux was added compound 2 (0.1 g,
0.00027 mol). After stirring for 0.5 h, the reaction was complete
(monitored by TLC), quenched with ethyl vinyl ether (5 mL),
warmed to room temperature, and concentrated under reduced
pressure. Purification by column chromatography (13% ethyl acet-
ate in hexane) gave 1 (0.072 g, 78%) as a colorless oil. [α]2D6 = +42
IR (KBr): ν = 3458, 2926, 2858, 1726, 1641, 1460, 1379, 1220, 1165,
˜
1110, 1057, 970, 913, 859, 773 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 5.86–5.71 (m, 2 H), 5.70–5.57 (m, 1 H), 5.53–5.33 (m, 2 H), (c = 0.1, CHCl ). IR (KBr): ν = 3283, 1735, 970, 672 cm–1. 1H
˜
3
5.18–5.07 (m, 2 H), 4.23–4.11 (m, 1 H), 4.00 (t, J = 7.5 Hz, 1 H),
NMR (300 MHz, CDCl3): δ = 6.08–5.21 (m, 7 H), 4.45–4.37 (m, 1
3.71–3.60 (m, 1 H), 2.35–2.25 (m, 4 H), 2.01 (q, J = 6.8 Hz, 2 H), H), 3.74–3.64 (m, 1 H), 2.58–2.29 (m, 4 H), 2.24–1.96 (m, 7 H),
1.39 (s, 3 H), 1.38 (s, 3 H), 1.35–1.23 (m, 6 H), 0.90 (t, J = 6.6 Hz,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 136.7, 133.8, 132.6,
127.7, 123.9, 118.5, 108.6, 81.2, 80.3, 70.9, 41.7, 31.5, 29.4, 29.2,
1.80–1.66 (m, 1 H), 1.43–1.23 (m, 6 H), 0.90 (t, J = 6.9 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 173.9, 135.0, 132.1,
132.0, 128.9, 125.0, 124.1, 74.0, 72.1, 66.0, 34.0, 33.5, 32.1, 31.0,
1082
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1078–1083

The First Total Synthesis of Topsentolide B3
Bromination with CBr4 proceeded quickly and was complete
almost as fast as all components could be mixed; b) T. W.
Baughman, J. C. Sworen, K. B. Wagener, Tetrahedron 2004, 60,
10943–10948.
29.1, 27.0, 26.3, 24.9, 22.5, 13.2 ppm. HRMS (ESI): calcd. for
C20H32O4Na [M + Na]+ 359.2356; found 359.2349.
Supporting Information (see footnote on the first page of this arti-
1
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Received: October 7, 2010
Published Online: January 5, 2011
Eur. J. Org. Chem. 2011, 1078–1083
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1083