Total synthesis and revision of the absolute configuration of seimatopolide B

Article abstract of DOI:10.1039/c3ob27518c

The asymmetric total synthesis of natural seimatopolide B along with its enantiomer is described starting from readily available 5-hexen-1-ol and 3-buten-1-ol. The key steps involved are Jacobson hydrolytic kinetic resolution, proline-catalyzed α-hydroxyl

Full text of DOI:10.1039/c3ob27518c

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
Total synthesis and revision of the absolute
configuration of seimatopolide B†
Cite this: Org. Biomol. Chem., 2013, 11,
3355
Chada Raji Reddy,* Uredi Dilipkumar, Motatipally Damoder Reddy and
Nagavaram Narsimha Rao
The asymmetric total synthesis of natural seimatopolide B along with its enantiomer is described starting
from readily available 5-hexen-1-ol and 3-buten-1-ol. The key steps involved are Jacobson hydrolytic
kinetic resolution, proline-catalyzed α-hydroxylation, Yamaguchi esterification and ring-closing meta-
thesis. This asymmetric total synthesis necessitates the revision of the originally assigned (3R, 6S, 9S)-
configuration to (3S, 6R, 9R).
Received 31st December 2012,
Accepted 15th March 2013
DOI: 10.1039/c3ob27518c
www.rsc.org/obc
ester data for 2,2 which revealed that this might be another
Introduction
case of a misassigned natural product.6 To further resolve this
Nonanolides (decanolides or 10-membered macrolides) consti- ambiguity and unequivocally confirm the absolute stereo-
tute an important class of bioactive secondary metabolites due chemistry, we embarked upon the total synthesis of 2 in a
to their notable diverse biological and pharmacological pro- stereoflexible manner, wherein both isomers could be syn-
perties such as anti-bacterial, anti-fungal, anti-malarial, cyto- thesized. In continuation of our interest on the synthesis of
toxic, phytotoxic, anti-microfilament, etc.1 Recently, Lee and macrolides,3,7 we herein report on the asymmetric total syn-
co-workers isolated two new polyhydroxylated 10-membered thesis of seimatopolide B (2) and its enantiomer 2a (Fig. 1)
macrolides, seimatopolide A (1) and B (2, Fig. 1), from an ethyl along with the revision of the absolute configuration of the
acetate extract of Seimatosporium discosioides culture medium.2 natural product.
They were found to act as peroxisome proliferator-activated
As shown in Scheme 1, the synthesis of 2 started from the
receptor (PPAR)-γ activators. The structures of 1 and 2 were alcohol 3 and the acid 4, which could be coupled via Yamagu-
established on the basis of spectroscopic analysis including chi esterification followed by ring-closing metathesis. Alcohol
1D and 2D NMR and the absolute configurations were deter- 3 was to be prepared via proline-catalyzed α-hydroxylation of
mined as 3R, 6R, 7R, 9S for 1 and 3R, 6S, 9S for 2 using the the epoxide 5, which in turn is accessible from commercially
Mosher’s method. These structural features combined with available 5-hexen-1-ol.
their interesting biological profile motivated synthetic organic
chemists to investigate their total synthesis. In this direction,
we have reported the total synthesis of (+)-seimatopolide A (1),
wherein we found that the absolute configuration of the
natural product was misassigned and should be revised as 3S,
6S, 7S, 9R (1a, Fig. 1).3 At the same time, two more total synth-
eses of 1 were published, supporting the originally proposed
configuration for seimatopolide A.4 Very recently, Schmidt and
co-workers have described the synthesis of both enantiomers
of 1, studied the CD spectra of their derivatives and concluded
that the configuration of the natural product should be revised
as 3S, 6S, 7S, 9R,5 which is in agreement with our observation.3
These results prompted us to analyze the reported Mosher
Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical
Technology, Hyderabad 500 007, India. E-mail: rajireddy@iict.res.in;
Fax: +91-40-27160512
†Electronic supplementary information (ESI) available: Copies of 1H NMR and
13C NMR spectra of all the new compounds. See DOI: 10.1039/c3ob27518c
Fig. 1 Structures of seimatopolide A (1), B (2), and their enantiomers 1a
and 2a.
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 3355–3364 | 3355

View Article Online
Paper
Organic & Biomolecular Chemistry
with the diol 7 (47%). Enantiomeric purity (>98% ee) of the
epoxide (−)-5 was determined by chiral HPLC.10 Regioselective
ring opening of the epoxide (−)-5 with trimethylsulfonium
iodide in the presence of n-BuLi as a base in THF at −20 °C
provided the alcohol 8 in 93% yield.11 Subsequent PMB ether
formation using the PMB-trichloroacetimidate (derived from
PMB-OH) in the presence of Sc(OTf)3 in toluene at −20 °C pro-
vided 9 in 76% yield.12 Desilylation of compound 9 using
TBAF in THF gave the alcohol 10 (92% yield). The PMB pro-
tected alcohol 10 was subjected to Dess–Martin periodinane
oxidation to furnish the aldehyde 11 in 87% yield. To establish
the C9-absolute stereochemistry, aldehyde 11 was subjected to
asymmetric α-hydroxylation using L-proline and nitrosoben-
zene in chloroform at 0 °C followed by the in situ reduction of
the resulting anilinoxy aldehyde with NaBH4 in ethanol at 0 °C
and treatment with Zn to obtain the diol 12 in 70% yield.13
The diol 12 was achieved with high diastereoselectivity
(no traces of the other diastereomer were isolated). Treatment
of the diol 12 with tosylimidazole in the presence of NaH in
THF at 0 °C to room temperature furnished the epoxide 13 in
89% yield. Then, to install the nine-carbon side chain, the
epoxide 13 was treated with n-octyl magnesium bromide in the
presence of Li2CuCl4 at −78 °C to give the desired alcohol frag-
ment 3 in 77% yield.
Scheme 1 Retrosynthesis of seimatopolide B (2).
The synthesis of the acid fragment 4 was planned starting
from 3-buten-1-ol through the epoxide 6 using Jacobson
epoxide resolution.
Results and discussion
As presented in Scheme 2, the racemic epoxide 5 was obtained
initially in 83% yield from 5-hexen-1-ol using the literature pro-
tocol.8 Resolution of rac-5 with (S,S)-(salen)CoIII·OAc Jacobson
catalyst9 provided the desired epoxide (−)-5 in 48% yield along
Next, we embarked on the synthesis of acid fragment 4
starting from readily available 3-buten-1-ol (Scheme 3). Conse-
quently, 3-buten-1-ol was converted to (+)-6 via a known three-
step sequence.14 The enantiomeric purity of the epoxide (+)-6
(>99% ee) was determined by chiral HPLC as well as compar-
ing the specific rotation with the reported data.15 The conver-
sion of epoxide (+)-6 to the desired acid 4 was accomplished as
described in our earlier communication in four steps3 invol-
ving (i) epoxide opening to 15, (ii) TBS-protection to obtain 16,
Scheme 2 Synthesis of fragment 3; reagents and conditions: (a) ref. 8; (b) (S,S)-
(salen)CoIII·OAc (0.5 mol%), distd H2O (0.55 equiv.), 0 °C to r.t., 16 h, 48% for
(−)-5, 47% for 7; (c) Me3S+I−, n-BuLi, THF, −20 °C, 2 h, 93%; (d) PMBOC(NH)CCl3,
Sc(OTf)3, −20 °C, toluene, 15 min, 76%; (e) TBAF (1 M in THF), THF, 0 °C to r.t.,
2 h, 92%; (f) Dess–Martin periodinane, CH2Cl2, r.t., 1 h, 87%; (g) PhNO,
L-proline, CHCl3, 0 °C, 2 h then NaBH4, EtOH, 0 °C, 2 h then AcOH, Zn, 12 h,
70%; (h) tosylimidazole, NaH, THF, 0 °C to r.t., 2 h, 89%; (i) 1-bromooctane, Mg,
THF, 0 °C to reflux, 2 h, Li2CuCl4, −78 °C to −20 °C, 2 h, 77%.
Scheme 3 Synthesis of fragment 4; reagents and conditions: (a) (i) PMBCl,
NaH, DMF, 0 °C to r.t., 2 h; (ii) m-CPBA, CH2Cl2, 0 °C to r.t., 4 h, 87% (2 steps); (b)
(R,R)-(salen)CoIII·OAc (0.5 mol%), distd H2O (0.55 equiv.), 0 °C to r.t., 16 h, 44%
for (+)-6, 47% for 14; (c) Me3S+I−, n-BuLi, THF, −20 °C, 2 h, 90%; (d) TBSOTf, 2,6-
lutidine, CH2Cl2, 0 °C, 30 min, 88%; (e) DDQ, CH2Cl2 : pH 7 buffer (9 : 1), 0 °C,
30 min, 93%; (f) TEMPO, BAIB, CH2Cl2 : H2O (1 : 1), 0 °C to r.t., 2 h, 86%.
3356 | Org. Biomol. Chem., 2013, 11, 3355–3364
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
Table 1 Comparison of 1H and 13C NMR (pyridine d5) data for natural seimato-
polide B and synthetic 2 or 2a
1H NMR (δH and J in Hz)
13C NMR (δC)
Natural
seimatopolide B
Synthetic 2
or 2a
Synthetic 2
or 2a
Position
Natural
1
2
—
—
2.88, dd
(3.2, 11.7)
2.74, dd
(3.7, 11.5)
4.95–4.98, m
5.97, dd
(3.0, 16.0)
6.56, dd
(8.5, 16.0)
4.61, dd
170.5
45.7
170.5
45.7
2.89, dd
(3.0, 11.5)
2.72, dd
(3.0, 11.5)
4.96, m
5.98, dd
(3.0, 16.0)
6.56, dd
(8.5, 16.0)
4.62, dd
(7.5, 7.5)
2.30, m
2.00, m
2.00, m
1.72, m
5.06, ddd
(7.0, 7.0, 13.0)
1.62, m
1.51, m
1.22, m
1.22, m
1.22, m
1.22, m
1.22, m
1.22, m
1.22, m
0.86, dd
(7.0, 7.0)
—
—
3
4
67.8
133.4
67.8
133.4
5
133.4
74.9
38.5
31.0
76.5
36.3
133.3
74.7
38.4
31.1
76.4
36.3
6
(7.5, 7.5)
7
2.34–2.23, m
2.06–1.90, m
2.06–1.90, m
1.77–1.41, m
5.06, ddd
(7.0, 7.0, 13.0)
1.77–1.41, m
1.77–1.41, m
1.38–1.14, m
1.38–1.14, m
1.38–1.14, m
1.38–1.14, m
1.38–1.14, m
1.38–1.14, m
1.38–1.14, m
0.84, dd
8
9
10
11
12
13
14
15
16
17
18
26.0
29.9
30.1
30.2
30.1
32.4
23.2
14.6
26.0
29.8
30.1
30.2
30.1
32.3
23.2
14.5
Scheme 4 Coupling of 3 and 4 to (3R, 6S, 9S)-seimatopolide B (2); reagents
and conditions: (a) 4, 2,4,6-trichlorobenzoyl chloride, Et3N, THF, 0 °C to r.t., 2 h,
then 3, DMAP, toluene, 0 °C, 1 h, 82%; (b) Grubbs 2nd generation catalyst (G-II,
10 mol%), CH2Cl2, reflux, 12 h; (c) DDQ, CH2Cl2 : H2O (9 : 1), 0 °C, 30 min, 83%;
(d) TBAF (1 M in THF), THF, 0 °C to r.t., 2 h, 91%; (e) G-II (10 mol%), CH2Cl2,
reflux, 8 h, 62%; (f) DDQ, CH2Cl2 : H2O (9 : 1), 0 °C, 30 min, 73%.
(7.0, 7.0)
(iii) PMB-deprotection to 17 and (iv) oxidation of the alcohol to
the acid 4.
with those reported for the natural product (Table 1). However,
Having both the alcohol 3 and the acid 4 in hand, construc- the specific rotation for synthetic 2 was observed as [α]D20
=
tion of the macrocyclic framework was achieved as shown in +16.6 (c = 0.03, MeOH), whereas for the isolated compound it
Scheme 4. The esterification reaction of 3 with acid 4 was is reported as [α]2D6 = −125.4 (c = 0.03, MeOH).2 The observation
carried out under Yamaguchi conditions (2,4,6-trichloroben- of an opposite sign in optical rotation for synthetic 2 indicates
zoyl chloride, Et3N, THF, DMAP, toluene)16 to furnish the RCM misassignment of the absolute configuration in the isolation
precursor 18 in 82% yield. As a first attempt of ring-closing paper. To further confirm this, based on the observations for
metathesis (RCM),17 18 was treated with the Grubbs second seimatopolide A,3,5 we decided to synthesize the enantiomer
generation catalyst (G-II, 10 mol%). However, the reaction did (2a) of the proposed structure (2).
not progress and the starting material was recovered. In a
The synthetic route to the enantiomer of alcohol subunit 3a
second attempt, the PMB group in compound 18 was depro- is depicted in Scheme 5 from the requisite epoxide (+)-5,
tected using DDQ in CH2Cl2 : H2O (9 : 1) to obtain 19 (83%), obtained from the diol 7. Thus, the treatment of diol 7 with
which was then subjected to the RCM reaction using G-II tosylimidazole/NaH in THF at 0 °C provided (+)-5 in 83% yield
(10 mol%). However, the reaction failed and instead of the with 99% ee.18 The epoxide (+)-5 was then converted to 11a
desired pure product, the formation of an inseparable mixture following the sequence of reactions used for the conversion of
of compounds was observed (path I). Subsequently, desilyla- (−)-5 to 11. Next, C9-absolute stereochemistry was introduced
tion of the TBS group in 18 using TBAF in THF provided the to 11a by asymmetric α-hydroxylation using D-proline to obtain
alcohol 20 in 91% yield. Treatment of the diene 20 with G-II the diol 12a (70% yield). After this, compound 12a was trans-
(10 mol%) lead to the formation of the macrolide 21 in 62% formed to 3a via the epoxide 13a under the conditions
yield and with good E-selectivity (>95%). Finally, the deprotec- described for the conversion of 12 to 3.
tion of the PMB group of 21 with DDQ in CH2Cl2 : H2O (9 : 1)
The enantiomer of the acid fragment (4a) was synthesized
completed the synthesis of the target compound, seimato- from the diol 14 (Scheme 6). Treatment of diol 14 with tosyl-
polide B (2), in 73% yield.
imidazole/NaH in THF at 0 °C provided (−)-6 in 86% yield (98%
All the spectroscopic data (1H, 13C NMR, mass and IR), ee),19 which was transformed to 4a following the sequence of
including NOE analysis for synthetic 2, were in full agreement reactions used for the conversion of (+)-6 to 4.
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 3355–3364 | 3357

View Article Online
Paper
Organic & Biomolecular Chemistry
Scheme 5 Synthesis of the fragment 3a; reagents and conditions: (a) tosylimi-
dazole, NaH, 0 °C to r.t., 2 h, 83%; (b) PhNO, D-proline, CHCl3, 0 °C, 2 h then
NaBH4, EtOH, 0 °C, 2 h then AcOH, Zn, 12 h, 70%; (c) tosylimidazole, NaH, THF,
0 °C, 2 h, 89%; (d) 1-bromooctane, Mg, THF, 0 °C to reflux, 2 h, Li2CuCl4, −78 °C
to −20 °C, 2 h, 77%.
Fig. 2 Energy minimized structure and key NOE correlations for 2a.
represented by structure 2a (enantiomer of 2). Further, NOESY
experiments of 2a show the NOE cross correlations between
H2/H4, H4/H6, H5/H7 and H7/H9 (Fig. 2) as well as the large
coupling constants among H4–H5 (J = 16.0 Hz), H5–H6 (J =
8.5 Hz), which are identical to the natural product data.2 This
clearly supports that the relative stereochemistry at C3, C6 and
C9 of 2a is similar to the natural product and the revision of
absolute configuration.
During the preparation of the manuscript, Kumar et al.
reported the total synthesis of seimatopolide B (2), and sur-
prisingly, they observed a negative specific rotation {[α]D25
=
Scheme 6 Synthesis of the fragment 4a; reagents and conditions: (a) tosylimi-
−212.6 (c = 0.035, MeOH)} for the originally proposed structure
with (3R, 6S, 9S)-configuration,20 which is in contrast to our
observation. On the other hand, at the same time, Lee and co-
workers have revised the initially proposed absolute configur-
ations along with the correction of specific rotations for
natural seimatopolide A and B,21 which are in agreement with
our data (Table 2).
dazole, NaH, 0 °C to r.t., 2 h, 86%.
Conclusions
Scheme 7 Coupling of 3a and 4a to (3S, 6R, 9R)-seimatopolide
B (2a).
Reagents and conditions: (a) 4a, 2,4,6-trichlorobenzoylchloride, Et3N, THF, 0 °C
to r.t., 2 h, then 3a, DMAP, toluene, 0 °C, 1 h, 82%.
In conclusion, we have successfully accomplished the total syn-
thesis of the initially proposed structure of seimatopolide B (2)
from 5-hexen-1-ol in 14 linear steps with 4.2% overall yield.
The next step was the completion of the synthesis of 2a The specific optical rotations of the synthesized compound
from the alcohol 3a and the acid 4a (Scheme 7), which was and the natural product displayed opposite signs. This obser-
successfully attained by following a sequence similar to the vation supports the misassignment of the absolute configur-
reactions used for the synthesis of 2 (from 3 and 4).
ation for the natural product, which was further confirmed
All the spectral data (1H, 13C NMR, mass and IR) of 2a were through the total synthesis of the enantiomer 2a. These results
in full agreement with those reported for the natural product suggest that the absolute configuration of the natural product
(Table 1). The specific rotation for 2a was observed {[α]D20
=
should be 3S, 6R, 9R, which is in accordance with the natural
−13.4 (c = 0.03, MeOH)} with an optical rotation with the same product revised data. Key features of the synthetic approach
sign as the isolated compound {[α]2D6 = −125.4 (c = 0.03, are: (i) generation of the desired absolute stereochemistry
MeOH)}.2 The comparison of spectral data (Table 1), specific through the Jacobson epoxide resolution and proline-catalyzed
rotation values for natural and synthetic seimatopolide B as asymmetric α-hydroxylation, (ii) construction of the macrocyc-
well as the analysis of Mosher ester data reported in the iso- lic framework using Yamaguchi esterification and ring-closing
lation paper, suggests that the absolute configuration of the metathesis reactions, which were readily adapted to obtain the
natural seimatopolide B should be revised as 3S, 6R, 9R natural enantiomer.
3358 | Org. Biomol. Chem., 2013, 11, 3355–3364
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
Table 2 Absolute configurations and specific rotations for natural and synthetic seimatopolide A and B
Seimatopolide A
Seimatopolide B
Reference
Initially proposed for natural product
Through synthesis
(3R, 6R, 7R, 9S)
[α]2D6 = −188.3
(c 0.05, MeOH)
(3R, 6R, 7R, 9S)
[α]2D5 = +30.00
(c 0.05, MeOH)
—
(3R, 6S, 9S)
[α]2D6 = −125.4
(c 0.03, MeOH)
—
2
3a (our earlier work)
This work
Through synthesis
Revised for natural product
(3S, 6S, 7S, 9R)
[α]2D9 = −20.8
(c 0.04, MeOH)
(3S, 6S, 9R)b
[α]2D9 = −12.60
(c 0.03, MeOH)
21b
a The absolute configuration of seimatopolide A has been revised as (3S, 6S, 7S, 9R). b The structure was revised correctly but the absolute
configuration was stated incorrectly.
and diol 7 (740 mg, 47%) as colourless liquids. [α]2D0 = −2.6 (c =
Experimental
General
1.00, CHCl3); IR (KBr): νmax = 3070, 3048, 2934, 2859, 1471,
1428, 1107, 823, 772, 740, 703 cm−1
;
1H NMR (CDCl3,
1H and 13C NMR spectra were recorded in CDCl3 solvent on 500 MHz): δ 7.67–7.65 (m, 4H), 7.43–7.36 (m, 6H), 3.67 (t, J =
Bruker 300 MHz (Avance), Varian Unity 500 MHz (Innova) spec- 6.2 Hz, 2H), 2.90–2.86 (m, 1H), 2.73 (dd, J = 5.1, 3.9 Hz, 1H),
trometers at ambient temperature. Chemical shifts are 2.44 (dd, J = 5.0, 2.7 Hz, 1H), 1.65–1.50 (m, 6H), 1.05 (s, 9H);
reported in ppm relative to TMS as internal standard. FTIR 13C NMR (CDCl3, 75 MHz): δ 135.7, 134.2, 129.7, 127.7, 63.8,
spectra were recorded on a Perkin-Elmer 683 infrared spectro- 52.4, 47.2, 32.4, 32.3, 27.0, 22.5, 19.4; MS (ESI): m/z 377 [M +
photometer; neat or as thin films in KBr. Optical rotations Na]+; HRMS (ESI): calcd for C22H30O2NaSi (M + Na)+ 377.1907;
were measured on an Anton Paar MLP 200 modular circular found 377.1914.
digital polarimeter by using a 2 mL cell with a path length of
(R)-6-(tert-Butyldiphenylsilyloxy)hexane-1,2-diol (7). [α]D20
=
1 dm. Low-resolution MS were recorded on an Agilent Techno- −0.4 (c = 1.00, CHCl3); IR (KBr): νmax = 3374, 2934, 2860, 1467,
1
logies LC-MSD trap SL spectrometer. All the reagents and sol- 1428, 1389, 1361, 1106, 8232, 739, 704 cm−1; H NMR (CDCl3,
vents were of reagent grade and used without further 500 MHz): δ 7.69–7.64 (m, 4H), 7.44–7.39 (m, 6H), 3.71–3.61 (3,
purification unless otherwise stated. Technical-grade EtOAc 4H), 3.41 (dd, J = 11.0, 8.0 Hz, 1H), 1.65–1.38 (m, 6H), 1.05 (s,
and hexanes used for column chromatography were distilled 9H); 13C NMR (CDCl3, 75 MHz): δ 135.5, 133.9, 129.5, 127.6,
before use. THF, when used as solvent for the reactions, was 72.1, 66.6, 63.6, 32.9, 32.4, 26.8, 21.8, 19.2; MS (ESI): m/z 395
freshly distilled from sodium benzophenone ketyl. Column [M + Na]+; HRMS (ESI): calcd for C22H32O3NaSi (M + Na)+
chromatography was carried on silica gel (60–120 mesh) 395.2012; found 395.2014.
packed in glass columns. All the reactions were performed
under N2 in flame or ovendried glassware with magnetic tion of trimethylsulfonium iodide (1.96 g, 9.60 mmol) in THF
stirring. (30 mL) was cooled to −20 °C, n-BuLi (2.5 M solution in
(S)-7-(tert-Butyldiphenylsilyloxy)hept-1-en-3-ol (8). A solu-
(S)-tert-Butyl(4-(oxiran-2-yl)butoxy)diphenylsilane [(−)-5]. A hexane, 2.9 mL, 7.20 mmol) was added dropwise and the
mixture of (S,S)-(−)-N-N′-bis(3,5-di-tert-butylsalicylidine)-1,2- resulting solution stirred for 1 h at −20 °C. A solution of the
cyclohexanediaminocobalt-II (12.7 mg, 0.021 mmol) and acetic epoxide (−)-5 (850 mg, 2.40 mmol) in THF (10 mL) was added
acid (0.012 mL, 0.21 mmol) in toluene (1 mL) was stirred while and stirring continued for another 1 h at −20 °C. The reaction
open to air for 1 h at room temperature. The solvent was mixture was warmed to 0 °C and quenched with saturated
removed under reduced pressure and the brown residue was aqueous NH4Cl (20 mL). The layers were separated and the
dried over high vacuum. The epoxide (1.5 g, 4.2 mmol) was aqueous layer was extracted with diethyl ether (2 × 50 mL). The
added in one portion and the stirred mixture was cooled in an combined organic layers were dried over Na2SO4 and concen-
ice water bath. Water (0.041 mL, 0.23 mmol) was slowly added trated under reduced pressure. Purification of crude com-
and the temperature of the reaction mixture was maintained pound by flash chromatography (silica gel, hexanes : EtOAc =
below 20 °C. After the end of the addition, the ice bath was 90 : 10) gave alcohol 8 (830 mg, 93%) as a pale yellow oil.
removed and the reaction mixture was stirred for 16 h. The [α]2D0 = −3.38 (c = 1.00, CHCl3); IR (KBr): νmax = 3382, 3072,
crude reaction mixture was purified by column chromato- 2933, 2859, 1468, 1428, 1250, 1108, 994, 823, 704 cm−1
;
1H
graphy to afford the chiral epoxide (−)-5 (723 mg, 48% yield) NMR (CDCl3, 500 MHz): δ 7.69–7.64 (m, 4H), 7.44–7.35
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 3355–3364 | 3359

View Article Online
Paper
Organic & Biomolecular Chemistry
(m, 6H), 5.85 (ddd, J = 17.0, 10.0, 7.0 Hz, 1H), 5.21 (d, J = (890 mg, 2.3 mmol) in one portion. The reaction mixture was
17.0 Hz, 1H), 5.10 (d, J = 10.0 Hz, 1H), 4.11–4.03 (m, 1H), 3.67 stirred for 1 h at 0 °C and quenched with saturated aqueous
(t, J = 6.9 Hz, 2H), 1.63–1.36 (m, 6H), 1.05 (s, 9H); 13C NMR Na2S2O3 (5 mL). The layers were separated and the aqueous
(CDCl3, 75 MHz): δ 141.1, 135.5, 134.0, 129.5, 127.5, 114.6, phase was extracted with CH2Cl2 (2 × 5 mL). The combined
73.1, 63.7, 36.6, 32.3, 26.8, 21.6, 19.2; MS (ESI): m/z 391 organic layer was washed with brine (10 mL), dried over
[M + Na]+; HRMS (ESI): calcd for C23H32O2NaSi (M + Na)+ Na2SO4 and concentrated in vacuo. The residue was purified by
391.2063; found 391.2076. 8a: [α]2D0 = +3.2 (c = 1.00, CHCl3).
(S)-tert-Butyl(5-(4-methoxybenzyloxy)hept-6-enyloxy)diphenyl- to give aldehyde 11 (301 mg, 87%) as a colourless oil. [α]D20
silane (9). To a solution of the p-methoxybenzyl trichloroaceti- −25.2 (c = 1.00, CHCl3); IR (KBr): νmax = 3005, 2934, 2835,
midate (600 mg) in toluene (5 mL), at −20 °C was added 1722, 1611, 1512, 1300, 1220, 1175, 927, 772 cm−1 1H NMR
column chromatography (silica gel, hexanes : EtOAc = 90 : 10)
=
;
alcohol 8 (200 mg, 0.54 mmol) in toluene (2.0 mL) followed by (CDCl3, 300 MHz): δ 9.73 (s, 1H), 7.25 (d, J = 8.8 Hz, 2H), 6.87
scandium triflate (13.3 mg, 0.027 mmol), and the reaction (d, J = 8.8 Hz, 2H), 5.73 (ddd, J = 16.8, 10.6, 7.6 Hz, 1H),
mixture was stirred for 15 min at −10 °C. The reaction mixture 5.27–5.18 (m, 2H), 4.53 (d, J = 11.5 Hz, 1H), 4.26 (d, J = 11.5
was then quenched with saturated aqueous NaHCO3 (5 mL) Hz, 1H), 3.80 (s, 3H), 3.72 (q, J = 6.4 Hz, 1H), 2.41 (dt, J = 6.4,
and extracted with EtOAc (2 × 10 mL). The combined organic 1.3 Hz, 2H), 1.83–1.45 (m, 4H); 13C NMR (CDCl3, 75 MHz):
layers were washed with brine (10 mL), dried over Na2SO4 and δ 202.5, 159.0, 138.7, 130.6, 129.3, 117.4, 113.7, 79.6, 69.7,
concentrated in vacuo. The residue was purified by column 55.2, 43.6, 34.8, 18.0; MS (ESI): m/z = 271 [M + Na]+. 11a:
chromatography (silica gel, hexanes : EtOAc = 97 : 03) to give [α]2D0 = +23.5 (c = 1.00, CHCl3).
olefin 9 (200 mg, 76%) as a colourless oil. [α]2D0 = −11.7 (c =
(2R,5S)-5-(4-Methoxybenzyloxy)hept-6-ene-1,2-diol (12). Alde-
1.00, CHCl3); IR (KBr): νmax = 3071, 2933, 2859, 1612, 1512, hyde 11 (200 mg, 0.80 mmol) was added dropwise to a solution
1427, 1247, 1108, 772, 703 cm−1; 1H NMR (CDCl3, 500 MHz): δ of nitrosobenzene (47.4 mg, 0.443 mmol) and L-proline
7.69–7.63 (m, 4H), 7.45–7.32 (m, 6H), 7.27–7.21 (m, 2H), (4.63 mg, 0.0403 mmol) in chloroform (0.5 mL) at 0 °C, and
6.90–6.80 (m, 2H), 5.71 (ddd, J = 17.0, 10.5, 7.4 Hz, 1H), 5.21 the solution was vigorously stirred at 0 °C for 2 h. The reaction
(d, J = 3.8 Hz, 1H), 5.17 (dt, J = 10.9, 1.8 Hz, 1H), 4.51 (d, J = mixture was transferred dropwise to a solution of sodium boro-
11.5 Hz, 1H), 4.27 (d, J = 11.5 Hz, 1H), 3.82–3.76 (m, 4H), 3.64 hydride (30 mg, 0.806 mmol) in ethanol (5.0 mL) at 0 °C and
(t, J = 6.4 Hz, 2H), 1.64–1.36 (m, 6H), 1.04 (s, 9H); 13C NMR the solution stirred at 0 °C for 2 h, then concentrated. Satu-
(CDCl3, 75 MHz): δ 158.9, 139.1, 135.5, 134.0, 130.8, 129.4, rated aqueous sodium bicarbonate solution (5 mL) was added
129.2, 127.5, 116.9, 113.6, 80.2, 69.6, 63.8, 55.2, 35.2, 32.4, and the mixture was extracted with ethyl acetate (3 × 5 mL).
26.8, 21.7, 19.2; MS (ESI): m/z 511 [M + Na]+; HRMS (ESI): calcd The combined organic extracts were dried over Na2SO4 and
for C31H40O3NaSi (M + Na)+ 511.2638; found 511.2641. 9a: concentrated. The residue was dissolved in 3 : 1 ethanol : acetic
[α]2D0 = +10.4 (c = 1.00, CHCl3).
acid (2 mL) and treated with zinc powder (175 mg, 2.68 mmol)
(S)-5-(4-Methoxybenzyloxy)hept-6-en-1-ol (10). A solution of and the reaction mixture was stirred at room temperature for
9 (200 mg, 0.41 mmol) in THF (2 mL) was cooled to 0 °C, TBAF 12 h, then filtered through celite and concentrated. Purifi-
(0.82 mL, 0.82 mmol, 1.0 M solution in THF) was added drop- cation of the residue by flash column chromatography gave
wise and the resulting brown solution was stirred at room the diol 12 (150 mg, 70%) as colourless oil. [α]2D0 = −17.9 (c =
temperature for 2 h. The reaction mixture was then quenched 0.67, CHCl3); IR (KBr): νmax = 3391, 2933, 2864, 1612, 1513,
with saturated aqueous NH4Cl (5 mL) and extracted with 1247, 1065, 1035, 822 cm−1; 1H NMR (CDCl3, 500 MHz): δ 7.24
EtOAc (2 × 5 mL). The combined organic layers were washed (d, J = 8.0 Hz, 2H), 6.87 (d, J = 8.0 Hz, 2H), 5.76 (ddd, J = 17.0,
with brine (15 mL), dried over Na2SO4 and evaporated to 10.0, 8.0 Hz 1H), 5.27–5.20 (m, 2H), 4.54 (d, J = 11.0 Hz, 1H),
dryness under reduced pressure. The residue was purified by 4.28 (d, J = 11.0 Hz, 1H), 1.84–1.74 (m, 1H), 1.76–1.69 (m, 1H),
flash column chromatography (silica gel, hexanes : EtOAc = 1.67–1.56 (m, 1H), 1.53–1.43 (m, 1H), 1.43–1.34 (m, 1H),
80 : 20) to give pure 10 (95 mg, 92%) as a colorless oil. [α]D20
=
1.33–1.21 (m, 4H), 0.89 (t, J = 6.8 Hz, 1H); 13C NMR (CDCl3,
−17.2 (c = 0.5, CHCl3); IR (KBr): νmax = 3399, 2994, 2935, 2863, 75 MHz): δ 159.1, 138.4, 130.2, 129.5, 117.4, 113.7, 80.1, 71.9,
1612, 1585, 1513, 1300, 1246, 1036, 993, 772 cm−1 1H NMR 69.8, 60.6, 55.2, 31.5, 28.9; MS (ESI): m/z 289.2 [M + Na]+;
;
(CDCl3, 500 MHz): δ 7.25 (d, J = 8.9 Hz, 2H), 6.88 (d, J = 8.9 Hz, HRMS (ESI): calcd for C15H22O4Na (M + Na)+ 289.1410; found
2H), 5.74 (ddd, J = 17.0, 10.0, 8.0 Hz, 1H), 5.25–5.18 (m, 2H), 289.1413. 12a: [α]2D0 = +15.38 (c = 0.6, CHCl3).
4.53 (d, J = 12.0 Hz, 1H), 4.28 (d, J = 12.0 Hz, 1H), 3.81 (s, 3H),
(R)-2-((S)-3-(4-Methoxybenzyloxy)pent-4-enyl)oxirane (13). A
3.72 (q, J = 7.0 Hz, 1H), 3.62 (t, J = 6.0 Hz, 2H), 1.71–1.35 (m, solution of the diol 12 (150 mg, 0.57 mmol) in THF (3 mL) was
6H); 13C NMR (CDCl3, 75 MHz): δ 158.9, 138.9, 130.7, 129.3, added to NaH (60 wt% in mineral oil, 55 mg, 2.3 mmol) in
117.1, 113.7, 80.9, 69.6, 62.6, 55.2, 35.1, 32.5, 21.5; MS (ESI): THF (2 mL) at 0 °C. The resulting mixture was then warmed to
m/z 273 [M + Na]+; HRMS (ESI): calcd for C15H22O3Na (M + ambient temperature and stirred for 40 min. The mixture was
Na)+ 273.1461; found 273.1468. 10a: [α]2D0 = +19.0 (c = 1.00, cooled to 0 °C, tosylimidazole (154 mg, 0.67 mmol) was added
CHCl3).
(S)-5-(4-Methoxybenzyloxy)hept-6-enal (11). To
in one portion, the mixture was allowed to warm up to
stirred ambient temperature and stirred for 1 h. The reaction mixture
a
solution of alcohol 10 (350 mg, 1.4 mmol) in dry dichloro- was quenched with water (10 mL) and extracted with EtOAc
methane (3 mL) at 0 °C was added Dess–Martin periodinane (2 × 5 mL). The combined organic layers were washed with
3360 | Org. Biomol. Chem., 2013, 11, 3355–3364
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
brine (10 mL), dried over Na2SO4 and concentrated in vacuo. 2860, 1613, 1514, 1461, 1248, 1094, 755 cm−1; 1H NMR (CDCl3,
The residue was purified by column chromatography (silica 500 MHz): δ 7.27 (d, J = 9.0 Hz, 2H), 6.88 (d, J = 9.0 Hz, 2H),
gel, hexanes : EtOAc = 90 : 10) to give the oxirane 13 (125 mg, 4.46 (s, 2H), 3.81 (s, 3H), 3.64–3.56 (m, 2H), 3.08–3.03 (m, 1H),
89%) as a colourless oil. [α]2D0 = −15.6 (c = 0.9, CHCl3); IR (KBr): 2.78 (dd, J = 4.9, 3.9 Hz, 1H), 2.52 (dd, J = 4.9, 2.9 Hz, 1H),
νmax = 3453, 2926, 2858, 1612, 1513, 1247, 1071, 1035, 1.94–1.85 (m, 1H), 1.82–1.73 (m, 1H); 13C NMR (CDCl3,
824 cm−1
;
1H NMR (CDCl3, 500 MHz): δ 7.24 (d, J = 8.3 Hz, 75 MHz): δ 159.0, 130.1, 129.0, 113.6, 72.5, 66.5, 55.0, 49.9,
2H), 6.87 (d, J = 8.3 Hz, 2H), 5.74 (ddd, J = 16.6, 10.5, 7.5 Hz, 45.9, 32.8; MS (ESI): m/z 231 [M + Na]+.
1H), 5.27–5.18 (m, 2H), 4.53 (d, J = 11.3 Hz, 1H), 4.27 (d, J =
(S)-4-(4-Methoxybenzyloxy)butane-1,2-diol (14). [α]2D0 = +4.0
11.3 Hz, 1H), 3.80 (s, 3H), 3.75 (q, J = 12.8, 7.6 Hz, 1H), (c = 1.00, CHCl3); IR (KBr): νmax = 3364, 2947, 2891, 1456, 1427,
2.94–2.87 (m, 1H), 2.73 (t, J = 4.5 Hz, 1H), 2.48–2.42 (m, 1H), 1349, 1304, 1106, 823, 772, 704 cm−1 1H NMR (CDCl3,
;
1.81–1.47 (m, 4 H); 13C NMR (CDCl3, 75 MHz): δ 159.1, 138.8, 500 MHz): δ 7.24 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H),
130.7, 129.3, 117.3, 113.7, 79.8, 69.8, 69.7, S52.2, 47.1, 31.8, 4.45 (s, 2H), 3.91 (m, 1H), 3.81 (s, 3H), 3.71–3.59 (m, 3H),
28.6; MS (ESI): m/z = 271 [M + Na]+; HRMS (ESI): calcd for 3.56–3.47 (m, 1H), 3.23 (br s, 1H), 2.48 (br s, 1H), 1.89–1.66
C15H20O3Na (M + Na)+ 271.1304; found 271.1312. 13a: [α]2D0
+15.0 (c = 1.00, CHCl3).
=
(m, 2H); 13C NMR (CDCl3, 75 MHz): δ 159.0, 129.8, 129.2,
113.6, 72.5, 70.3, 67.2, 66.255.0, 32.7; MS (ESI): m/z 249
(3S,6S)-3-(4-Methoxybenzyloxy)pentadec-1-en-6-ol (3). A [M + Na]+.
solution of n-octylmagnesium bromide [prepared from n-bromo-
(R)-5-(4-Methoxybenzyloxy)pent-1-en-3-ol (15).3 A solution of
octane (174 mg, 0.108 mmol) and Mg (30 mg, 0.126 mmol) in trimethylsulfonium iodide (1.96 g, 9.61 mmol) in THF (30 mL)
dry THF (3 mL) under nitrogen] was added dropwise to a was cooled to −20 °C, n-BuLi (2.5 M solution in hexane,
stirred solution of 13 (125 mg, 0.504 mmol) in dry THF (3 mL) 2.9 mL, 7.21 mmol) was added dropwise, and the resulting
at −78 °C. Subsequently, a solution of Li2CuCl4 (0.1 M in THF, solution was stirred for 1 h at −20 °C. A solution of the
0.25 mL, 0.025 mmol) was added dropwise to the stirred epoxide 6 (500 mg, 2.40 mmol) in THF (10 mL) was added and
mixture, allowed to warm up to room temperature and stirred a cloudy suspension was formed. The stirring was continued
for 30 min. The reaction was quenched with saturated aqueous for another 1 h at −20 °C. The reaction mixture was warmed to
NH4Cl (10 mL) and extracted with EtOAc (2 × 10 mL). The 0 °C and quenched with saturated aqueous NH4Cl (20 mL).
organic layers were washed with brine (10 mL), dried over The layers were separated and the aqueous layer was extracted
Na2SO4 and concentrated in vacuo. The residue was purified by with diethyl ether (2 × 50 mL). The combined organic layers
column chromatography (silica gel, hexanes : EtOAc = 80 : 20) were dried over Na2SO4 and concentrated under reduced
to give the alcohol 3 (140 mg, 77%) as a colourless oil. [α]D20
−17.1 (c = 1.00, CHCl3); IR (KBr): νmax = 3413, 2926, 2855, graphy (silica gel, hexanes : EtOAc = 90 : 10) gave alcohol 15
1514, 1464, 1248, 1038, 821, 722 cm−1 1H NMR (CDCl3, (480 mg, 90%) as a pale yellow oil. [α]2D0 = −10.1 (c = 0.6,
=
pressure. Purification of crude compound by flash chromato-
;
500 MHz): δ 7.25 (d, J = 7.9 Hz, 2H), 6.87 (d, J = 7.9 Hz, 2H), CHCl3); IR (KBr): νmax = 3414, 2923, 2858, 1612, 1585, 1513,
6.75 (ddd, J = 17.6, 10.6, 7.9 Hz, 1H), 5.25–5.19 (m, 2H), 4.53 1247, 1091, 820 cm−1; 1H NMR (CDCl3, 300 MHz): δ 7.25 (d, J =
(d, J = 11.5 Hz, 1H), 4.29 (d, J = 11.5 Hz, 1H), 3.80 (s, 3H), 3.75 8.3 Hz, 2H), 6.88 (d, J = 8.3 Hz, 2H), 5.87 (ddd, J = 17.3, 10.5,
(q, J = 13.2, 6.2 Hz, 1H), 3.60–3.52 (m, 1H), 1.92 (br s, 1H), 6.0 Hz, 1H), 5.27 (dt, J = 17.3, 1.5 Hz, 1H), 5.10 (dt, J = 10.5,
1.73–1.56 (m, 4H), 1.47–1.36 (m, 3H), 1.34–1.20 (m, 13H), 0.88 1.5 Hz, 1H), 4.45 (s, 2H), 4.38–4.29 (m, 1H), 3.81 (s, 3H),
(t, J = 7.1 Hz, 3H); 13C NMR (CDCl3, 75 MHz): δ 159.1, 138.8, 3.72–3.57 (m, 2H), 1.92–1.74 (m, 2H); 13C NMR (CDCl3,
130.4, 129.4, 117.1, 113.7, 80.3, 71.5, 69.8, 55.2, 37.4, 33.2, 75 MHz): δ 159.3, 140.5, 130.0, 129.3, 114.3, 113.8, 72.9, 71.9,
31.9, 31.6, 29.7, 29.6, 29.5, 29.3, 25.7, 22.6, 14.1; MS (ESI): m/z 68.0, 55.2, 36.2; MS (ESI): m/z 245.2 [M + Na]+.
385 [M + Na]+; HRMS (ESI): calcd for C23H38O3Na (M + Na)+
(R)-tert-Butyl(5-(4-methoxybenzyloxy)pent-1-en-3-yloxy)dimethyl-
silane (16).3 To a 0 °C solution of 15 (450 mg, 2.02 mmol) in
CH2Cl2 (8 mL) was added 2,6-lutidine (0.48 mL, 4.04 mmol)
385.2713; found 385.2730. 3a: [α]2D0 = +16.8 (c = 1.00, CHCl3).
(R)-2-(2-(4-Methoxybenzyloxy)ethyl)oxirane
[(+)-6].3
A
mixture of (R,R)-(−)-N-N′-bis(3,5-di-tert-butylsalicylidine)-1,2- and TBSOTf (0.51 mL, 2.23 mmol). The mixture was stirred at
cyclohexane diaminocobalt-II (46.4 mg, 0.077 mmol) and 0 °C for 30 min and diluted with CH2Cl2 (15 mL). The organic
acetic acid (0.044 mL, 0.77 mmol) in toluene (5 mL) was phase was washed sequentially with a saturated aqueous solu-
stirred while open to air for 1 h at room temperature. The tion of NaHCO3 (20 mL) and brine (15 mL), dried over Na2SO4
solvent was removed under reduced pressure and the brown and evaporated to dryness. The residue was purified by flash
residue was dried over high vacuum. The epoxide (3.2 g, chromatography (silica gel, hexanes : EtOAc = 97 : 03) to give 16
15.38 mmol) was added in one portion, cooled in an ice water (600 mg, 88% yield) as colorless oil. [α]2D0 = −1.9 (c = 1.00,
bath. Water (0.15 mL, 8.46 mmol) was added slowly and the CHCl3); IR (KBr): νmax = 2932, 2857, 1613, 1513, 1249, 1090,
temperature was maintained <20 °C. After the end of the 835 cm−1 1H NMR (CDCl3, 500 MHz): δ 7.25 (d, J = 9.1 Hz,
;
addition, the ice bath was removed and the reaction mixture 2H), 6.87 (d, J = 9.1 Hz, 2H), 5.80 (ddd, J = 17.1, 10.3, 5.7 Hz,
was stirred for 16 h. The crude reaction mixture was purified 1H), 5.14 (d, J = 17.1 Hz, 1H), 5.01 (dt, J = 10.3 Hz, 1H), 4.44 (d,
by column chromatography to afford the chiral epoxide (+)-6 J = 11.4 Hz, 1H), 4.38 (d, J = 11.4 Hz, 1H), 4.29 (q, J = 6.8 Hz,
(1.45 g, 44% yield) and diol 14 (1.63 g, 47%) as colourless 1H), 3.80 (s, 3H), 3.57–3.46 (m, 2H), 1.77 (q, J = 6.8 Hz, 2H),
liquids. [α]2D0 = +12.5 (c = 1.28, CHCl3); IR (KBr): νmax = 2928, 0.89 (s, 9H), 0.05 (s, 3H), 0.03 (s, 3H); 13C NMR (CDCl3,
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 3355–3364 | 3361

View Article Online
Paper
Organic & Biomolecular Chemistry
75 MHz): δ 159.0, 141.5, 130.5, 129.2, 113.7, 113.6, 72.5, 70.7, 1634, 1470, 1249, 844, 766 cm−1; 1H NMR (CDCl3, 300 MHz): δ
66.3, 55.1, 38.0, 25.8, 18.1, −4.4, −5.0; MS (ESI): m/z = 359.2 7.24 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 5.84 (ddd, J =
[M + Na]+.
16.8, 10.3, 6.2 Hz, 1H), 5.70 (ddd, J = 17.2, 10.3, 7.7 Hz, 1H),
4.90–4.80 (m, 1H), 4.57 (q, J = 6.0 Hz, 1H), 4.51 (d, J = 11.3 Hz,
(R)-3-(tert-Butyldimethylsilyloxy)pent-4-en-1-ol (17).3 To
a
solution of 16 (200 mg, 0.60 mmol) in CH2Cl2 (5 mL) and a pH 1H), 4.27 (d, J = 11.3 Hz, 1H), 3.80 (s, 3H), 6.23 (q, J = 6.2 Hz,
buffered solution (1 mL) was added DDQ (162 mg, 1H), 2.48 (ddd, J = 21.0, 14.9, 6.0 Hz, 2H), 1.7–1.4 (m, 6H),
7
0.71 mmol) at 0 °C. The reaction mixture was stirred for 1.36–1.18 (3, 14H), 0.96–0.83 (m, 12H), 0.06 (s, 3H), 0.05 (s,
30 min, and then poured into water. The aqueous phase was 3H); 13C NMR (CDCl3, 75 MHz): δ 170.7, 159.0, 140.3, 138.8,
extracted with CH2Cl2 (2 × 15 mL). The combined organic 130.8, 129.3, 117.4, 114.7, 113.7, 80.2, 74.4, 70.7, 69.7, 55.3,
extracts were washed with aqueous NaHCO3 (10 mL), dried 43.7, 34.0, 31.9, 31.3, 29.9, 29.7, 29.5, 29.3, 25.8, 25.2, 22.7,
over anhydrous Na2SO4 and concentrated in vacuo. Flash 14.1, −4.4, −4.9; MS (ESI): m/z = 597 [M + Na]+; HRMS (ESI):
chromatography (silica gel, hexanes : EtOAc = 90 : 10) afforded calcd for C34H58O5NaSi (M + Na)+ 597.3945; found 597.3971.
alcohol 17 (120 mg, 93%) as a colorless oil. [α]2D0 = +3.9 (c = 18a: [α]D20 = +12.3 (c = 1.00, CHCl3).
1.00, CHCl3); IR (KBr): νmax = 3367, 2932, 2858, 1613, 1514,
(R)-((3S,6S)-3-Hydroxypentadec-1-en-6-yl)3-(tert-butyl-dimethyl-
1
1251, 1089, 773 cm−1; H NMR (CDCl3, 500 MHz): δ 5.86 (ddd, silyloxy)pent-4-enoate (19). To
a
solution of 18 (70 mg,
J = 17.1, 10.3, 5.7 Hz, 1H), 5.22 (d, J = 17.1 Hz, 1H), 5.10 (d, J = 0.12 mmol) in CH2Cl2 (2 mL) and H2O (0.2 mL) was added
10.3 Hz, 1H), 4.41 (q, J = 5.7 Hz, 1H), 3.86–3.79 (m, 1H), DDQ (33 mg, 0.146 mmol) at 0 °C. The reaction mixture was
3.74–3.69 (m, 1H), 2.38 (br s, 1H), 1.90–1.81 (m, 1H), 1.76–1.68 stirred for 30 min, and then poured into water. The aqueous
(m, 1H), 0.91 (s, 9H), 0.10 (s, 3H), 0.07 (s, 3H); 13C NMR phase was extracted with CH2Cl2 (2 × 5 mL). The combined
(CDCl3, 75 MHz): δ 140.5, 114.3, 73.0, 59.9, 39.1, 25.7, 18.0, organic extracts were washed with aqueous NaHCO3 (10 mL),
−4.4, −5.1.
dried over anhydrous Na2SO4 and concentrated in vacuo. Flash
(R)-3-(tert-Butyldimethylsilyloxy)pent-4-enoic acid (4).3 To a chromatography (silica gel, hexanes : EtOAc = 90 : 10) afforded
solution of the above alcohol 17 (250 mg, 1.16 mmol) in H2O– alcohol 19 (45 mg, 83%) as a colorless oil. [α]2D0 = −4.0 (c = 0.5,
CH2Cl2 (1/1, 4 mL) were added TEMPO (52 mg, 0.35 mmol) CHCl3); IR (KBr): νmax = 3454, 2927, 2856, 1733, 1464, 1254,
and BAIB (1.12 g, 3.48 mmol). After stirring at room tempera- 1181, 1082, 923, 835, 774 cm−1; H NMR (CDCl3, 300 MHz): δ
1
ture for 2 h, the reaction mixture was diluted with CH2Cl2 5.86 (dd, J = 10.7, 6.2 Hz, 1H), 5.80 (dd, J = 10.1, 6.2 Hz, 1H),
(5 mL) and washed with saturated aqueous Na2S2O3 (10 mL). 5.20 (d, J = 17.0 Hz, 2H), 5.13–5.03 (m, 2H), 4.91–4.80 (m, 1H),
The organic layer was dried over Na2SO4 and filtered. The fil- 4.56 (q, J = 6.8 Hz, 1H), 4.13–4.03 (m, 1H), 2.53 (dd, J = 14.9,
trate was concentrated under reduced pressure to give the 7.1 Hz, 1H), 2.49 (dd, J = 14.9, 5.6 Hz, 1H), 1.72–1.43 (m, 6H),
crude carboxylic acid, which was further purified by flash 1.36–1.22 (m, 14H), 0.88 (t, J = 6.6 Hz, 3H), 0.87 (s, 9H), 0.06 (s,
column chromatography (silica gel, hexanes : EtOAc = 90 : 10) 3H), 0.04 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ 170.7, 141.0,
to give the acid 4 (230 mg, 86%) as a colorless oil. [α]2D0 = −4.0 140.4, 114.9, 114.7, 74.3, 73.0, 70.78, 43.8, 34.2, 32.8, 32.0,
(c = 1.0, CHCl3); IR (KBr): νmax = 2930, 2858, 1714, 1466, 1254, 30.0, 29.8, 29.6, 29.4, 25.9, 25.4, 22.8, 18.2, 14.2, −4.3, −4.8;
1
1087, 835, 774 cm−1; H NMR (CDCl3, 300 MHz): δ 10.57 (br s, MS (ESI): m/z = 477 [M + Na]+; HRMS (ESI): calcd for
1H), 5.85 (ddd, J = 16.8, 10.3, 6.2 Hz, 1H), 5.25 (d, J = 16.8 Hz, C26H50O4NaSi (M + Na)+ 477.3370; found 477.3375.
1H), 5.10 (d, J = 10.3 Hz, 1H), 4.58 (q, J = 6.2 Hz, 1H), 2.61–2.47
(R)-((3S,6S)-3-(4-Methoxybenzyloxy)pentadec-1-en-6-yl)3-hydroxy-
(m, 2H), 0.88 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H); 13C NMR pent-4-enoate (20). A solution of 18 (145 mg, 0.253 mmol) in
(CDCl3, 75 MHz): δ 176.8, 139.6, 115.0, 70.5, 43.3, 25.7, 18.0, THF (3 mL) was cooled to 0 °C and TBAF (0.38 mL, 0.38 mmol,
−4.4, −5.2; MS (ESI): m/z = 253.1 [M + Na]+.
1.0 M solution in THF) was added dropwise. The resulting
(R)-((3S,6S)-3-(4-Methoxybenzyloxy)pentadec-1-en-6-yl)3-(tert- brown solution was stirred at room temperature for 2 h. The
butyldimethylsilyloxy)pent-4-enoate (18). To a solution of acid reaction was quenched with saturated aqueous NH4Cl (5 mL)
4 (89 mg, 0.386 mmol) in dry THF (7 mL) at 0 °C were added and extracted with EtOAc (2 × 10 mL). The combined organic
Et3N (0.16 mL, 1.16 mmol) and 2,4,6-Cl3C6H2COCl (0.12 mL, layers were washed with brine (10 mL), dried over Na2SO4 and
0.77 mmol), and the resulting mixture was stirred at room evaporated to dryness under reduced pressure. The residue
temperature for 2 h. The solvent was removed under reduced was purified by flash column chromatography (silica gel,
pressure, and the residue was dissolved in toluene (5 mL). To hexanes : EtOAc = 90 : 10) to give 20 (105 mg, 91%) as a color-
this mixture at 0 °C was added a solution of DMAP (141 mg, less oil. [α]2D0 = −14.6 (c = 1.00, CHCl3); IR (KBr): νmax = 3448,
1
1.16 mmol) and alcohol 3 (140 mg, 0.386 mmol) in toluene 2925, 2855, 1725, 1615, 1513, 1247, 1175, 1038, 770 cm−1; H
(2 mL), and the resulting mixture was stirred for 15 min. The NMR (CDCl3, 500 MHz): δ 7.24 (d, J = 9.0 Hz, 2H), 6.87 (d, J =
reaction mixture was diluted with EtOAc (5 mL), washed with 9.0 Hz, 2H), 5.87 (ddd, J = 17.0, 11.0, 6.0 Hz, 1H), 5.71 (ddd, J =
saturated aqueous NH4Cl (5 mL), and then with brine solution 18.0, 10.0, 8.0 Hz, 1H), 5.34–5.12 (m, 4H), 4.94–4.88 (m, 1H),
(10 mL). The organic layer was dried over Na2SO4, filtered, and 4.51 (d, J = 12.0 Hz, 1H), 4.50 (br s, 1H), 4.27 (d, J = 12.0 Hz,
concentrated under reduced pressure. Purification of the 1H), 3.80 (s, 3H), 3.68 (q, J = 7.0 Hz, 1H), 2.58–2.46 (m, 2H),
residue by flash chromatography (silica gel, hexanes : EtOAc = 1.74–1.46 (m, 6H), 1.33–1.21 (m, 14H), 0.88 (t, J = 7.0 Hz, 3H);
97 : 03) gave diene 18 (183 mg, 82%) as a colorless oil. 13C NMR (CDCl3, 75 MHz): δ 172.1, 159.0, 138.8, 138.7, 130.6,
[α]2D0 = −13.2 (c = 0.5, CHCl3); IR (KBr): νmax = 3445, 2925, 2855, 129.4, 117.5, 115.3, 113.7, 79.9, 74.9, 69.7, 68.9, 55.2, 41.3,
3362 | Org. Biomol. Chem., 2013, 11, 3355–3364
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
34.0, 31.9, 31.0, 29.8, 29.7, 29.5, 29.4, 29.3, 25.2, 22.7, 14.1; MS washed with brine (10 mL), dried over Na2SO4 and concen-
(ESI): m/z 483.3 [M + Na]+; HRMS (ESI): calcd for C28H44O5Na trated in vacuo. The residue was purified by column chromato-
(M + Na)+ 483.3081; found 483.3078. 20a: [α]2D0 = +13.2 (c = graphy (silica gel, hexanes : EtOAc = 95 : 05) to give oxirane
1.00, CHCl3).
(4R,7S,10S,E)-4-Hydroxy-7-(4-methoxybenzyloxy)-10-nonyl- CHCl3).
(+)-5 (157 mg, 83%) as a colourless oil. [α]2D0 = +2.8 (c = 1.00,
3,4,7,8,9,10-hexahydro-2H-oxecin-2-one (21). Grubbs second
(S)-2-(2-(4-Methoxybenzyloxy)ethyl)oxirane [(−)-6]. A solu-
generation catalyst (G-II, 8.3 mg, 0.00978 mmol) was dissolved tion of diol 14 (230 mg, 1.01 mmol) in THF (10 mL) was added
in dry, deoxygenated CH2Cl2 (120 mL). After heating the solu- to NaH (60 wt% in mineral oil, 98 mg, 4.07 mmol) in THF
tion to reflux, diene 20 (45 mg, 0.0978 mmol) dissolved in dry, (5 mL) at 0 °C. The resulting mixture was then warmed to
deoxygenated CH2Cl2 (30 mL) was added dropwise over ambient temperature and stirred for 40 min. The mixture was
30 min. The mixture was stirred at reflux for 8 h and cooled to then cooled to 0 °C and tosylimidazole (279 mg, 1.22 mmol)
room temperature, all volatiles were removed under reduced was added in one portion. The reaction mixture was allowed
pressure. The residue was purified by flash column chromato- warm up to ambient temperature and stirred for 1 h. The reac-
graphy (silica gel, hexanes : EtOAc = 85 : 15) to give 21 (26 mg, tion mixture was quenched with water (10 mL) and extracted
62%) as a colourless oil. IR (KBr): νmax = 3431, 2925, 2854, with EtOAc (2 × 15 mL). The combined organic layer was
1737, 1513, 1461, 1245, 1173, 1037, 971, 772 cm−1 1H NMR washed with brine (10 mL), dried over Na2SO4 and concen-
;
(CDCl3, 500 MHz): δ 7.22 (d, J = 8.0 Hz, 2H), 6.86 (d, J = 8.0 Hz, trated in vacuo. The residue was purified by column chromato-
2H), 5.73 (d, J = 15.9 Hz, 1H), 5.66 (dd, J = 15.9, 6.9 Hz, 1H), graphy (silica gel, hexanes : EtOAc = 90 : 10) to give oxirane
4.82 (q, J = 6.0 Hz, 1H), 4.74–4.69 (m, 1H), 4.50 (d, J = 12.0 Hz, (−)-6 (181 mg, 86%) as a colourless oil; [α]2D0 = −11.8 (c = 1.00,
1H), 4.27 (d, J = 12.0 Hz, 1H), 3.91–3.84 (m, 1H), 3.79 (s, 3H), CHCl3).
2.58 (ddd, J = 16.0, 12.0, 4.0 Hz, 2H), 2.06–1.37 (m, 4H),
Seimatopolide B (2a). [α]2D0 = −13.4 (c = 0.03, MeOH), All
1.34–1.18 (m, 14H), 0.87 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, other spectral data are identical to those reported for 2.
75 MHz): δ 171.0, 159.1, 134.3, 130.1, 130.0, 129.4, 113.8, 77.2,
76.8, 69.5, 67.7, 55.3, 44.2, 33.6, 32.0, 31.9, 29.7, 29.5, 29.4,
29.4, 29.2, 25.3, 22.7, 14.1.
Acknowledgements
Seimatopolide
B (2). To a solution of 21 (18 mg,
0.042 mmol) in CH2Cl2 (1 mL) and H2O (0.1 mL) was added UD, MDR and NNR thank the Council of Scientific and Indus-
DDQ (11.5 mg, 0.0508 mmol) at 0 °C. The reaction mixture trial Research (CSIR), New Delhi for research fellowships. The
was stirred for 30 min, and then poured into water. The authors are grateful to the Council of Scientific and Industrial
aqueous phase was extracted with CH2Cl2 (2 × 5 mL). The com- Research (CSIR)-New Delhi for research funding under the
bined organic extracts were washed with aqueous NaHCO3 ORIGIN program of the 12th five year plan. We thank Dr Kiran
(10 mL), dried over anhydrous Na2SO4 and concentrated Kumar Singarapu, CSIR-IICT, for NMR analysis.
in vacuo. Flash chromatography (silica gel, CH2Cl2 : MeOH =
97 : 3) afforded
[α]2D0 = +16.6 (c = 0.03, MeOH); IR (KBr): νmax = 3340, 2915,
2849, 1723, 1459, 1257, 1220, 1167, 979, 772 cm−1 1H NMR
2 (9.5 mg, 73%) as a colourless solid.
Notes and references
;
(pyridine d5, 300 MHz): δ 6.56 (dd, J = 16.0, 8.5 Hz, 1H), 5.97
(dd, J = 16.0, 3.0 Hz, 1H), 5.06 (ddd, J = 13.0, 7.0, 7.0 Hz, 1H),
4.95–4.98 (m, 1H), 4.61 (dd, J = 7.5, 7.5 Hz, 1H), 2.88 (dd, J =
11.7, 3.2 Hz, 1H), 2.71 (dd, J = 11.5, 3.7 Hz, 1H), 2.34–2.23 (m,
1H), 2.06–1.90 (m, 2H), 1.77–1.41 (m, 3H), 1.38–1.14 (m, 14H),
0.84 (dd, J = 6.9, 6.9 Hz, 3H); 13C NMR (pyridine d5, 75 MHz): δ
170.5, 133.4, 133.3, 76.4, 74.7, 67.8, 45.7, 38.4, 36.3, 32.3, 31.1,
30.2, 30.1, 30.1, 29.8, 26.0, 23.2, 14.5; MS (ESI): m/z = 335
[M + Na]+; HRMS (ESI): calcd for C18H32O5Na (M + Na)+
335.2192; found 335.2191.
(R)-tert-Butyl(4-(oxiran-2-yl)butoxy)diphenylsilane [(+)-5]. A
solution of diol 7 (200 mg, 0.53 mmol) in THF (5 mL) was
added to NaH (60 wt% in mineral oil, 54 mg, 2.1 mmol) in
THF (2 mL) at 0 °C. The resulting mixture was then warmed to
ambient temperature and stirred for 40 min. The mixture was
then cooled to 0 °C and tosylimidazole (146 mg, 0.63 mmol)
was added in one portion. The reaction mixture was allowed to
warm up to ambient temperature and stirred for 1 h. The reac-
tion mixture was quenched with water (10 mL) and extracted
with EtOAc (2 × 10 mL). The combined organic layer was
1 For reviews, see: (a) P. Sun, S. Lu, T. V. Ree, K. Krohn, L. Li
and W. Zhang, Curr. Med. Chem., 2012, 19, 3417–3455;
(b) G. Drager, A. Kirschning, R. Thiericke and M. Zerlin,
Nat. Prod. Rep., 1996, 13, 365–375.
2 N. T. Hiep, Y.-h. Choi, N. Kim, S. S. Hong, S.-B. Hong,
B. Y. Hwang, H.-J. Lee, D. S. Jang and D. Lee, J. Nat. Prod.,
2012, 75, 784–788.
3 Ch. R. Reddy, N. N. Rao and M. D. Reddy, Eur. J. Org.
Chem., 2012, 4910–4913.
4 (a) G. Sabitha, A. Y. Reddy and J. S. Yadav, Tetrahedron Lett.,
2012, 53, 5624–5626; (b) B. P. Reddy, T. Pandurangam,
J. S. Yadav and B. V. S. Reddy, Tetrahedron Lett., 2012, 53,
5749–5752.
5 B. Schmidt, O. Kunz and M. H. Petersen, J. Org. Chem.,
2012, 77, 10897–10906.
6 For a review on the misassigned natural products, see:
K. C. Nicolaou and S. A. Snyder, Angew. Chem., Int. Ed.,
2005, 44, 1012–1044.
7 (a) Ch. R. Reddy and N. N. Rao, Eur. J. Org. Chem., 2012,
1819–1824; (b) Ch. R. Reddy, D. Suman and N. N. Rao,
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 3355–3364 | 3363

View Article Online
Paper
Organic & Biomolecular Chemistry
Synlett, 2012, 23, 272–274; (c) Ch. R. Reddy, G. Dharmapuri 16 (a) H. Fuwa, A. Saito and M. Sasaki, Angew. Chem., 2010,
and N. N. Rao, Org. Lett., 2009, 11, 5730–5733; (d) Ch. R. Reddy
and N. N. Rao, Tetrahedron Lett., 2009, 50, 2478–2480.
8 C. Cook, X. Guinchard, F. Liron and E. Roulland, Org. Lett.,
2010, 12, 744–747.
9 M. Tokunaga, J. F. Larrow, F. Kakiuchi and E. N. Jacobsen,
Science, 1997, 277, 936–938.
122, 3105, (Angew. Chem., Int. Ed., 2010, 49, 3041–3044);
(b) J. Inanaga, K. Hirata, H. Sacki, T. Hatsuki and
M. Yamaguchi, Bull. Chem. Soc. Jpn., 1979, 52, 1989–1993.
17 (a) A. G. Giri, M. A. Mondal, V. G. Puranik and
C. V. Ramana, Org. Biomol. Chem., 2010, 8, 398–406 and
references cited therein (b) M. Scholl, S. Ding, C. W. Lee
and R. H. Grubbs, Org. Lett., 1999, 1, 953–956.
10 (a) Enantiomeric excess (ee) of epoxide (−)-5 was deter-
mined by chiral HPLC [Chiralpack-OD-H, 250 × 4.6 mm, 18 (a) Enantiomeric excess (ee) of epoxide (+)-5 was deter-
5 μ, 0.5% iPr-OH in hexanes, flow rate 1.0 mL min−1, reten-
tion time 17.08 (0.56%), 20.84 (99.43%)]; (b) Specific
rotation: observed, [α]2D0 = −2.6 (c = 1.00, CHCl3).
11 L. Alcaraz, J. J. Harnett, C. Mioskowski, J. P. Martel, T. Le
Gall, D.-S. Shin and J. R. Falck, Tetrahedron Lett., 1994, 35,
5449–5452.
mined by chiral HPLC [Chiralpak-OD-H; 250 × 4.6 mm, 5 μ,
0.5% iPr-OH in hexanes, flow rate 1.0 mL min−1, retention
time 16.86 (99.91%), 20.33 (0.08%)] (b) Comparing the
specific rotation with the reported data: observed, [α]D20
=
+2.8 (c = 1.00, CHCl3); reported, [α]D +3.8 (c 1.06, CHCl3),
99.5% ee, see: ref. 6.
12 A. N. Rai and A. Basu, Tetrahedron Lett., 2003, 44, 2267–2269. 19 (a) Enantiomeric excess (ee) of epoxide (−)-6 was deter-
13 (a) T. J. Donohoe, P. J. Lindsay-Scott, J. S. Parker and
C. K. A. Callens, Org. Lett., 2010, 12, 1060–1063; (b) S. P. Brown,
M. P. Brochu, C. J. Sinz and D. W. C. MacMillan, J. Am. Chem.
Soc., 2003, 125, 10808–10809.
14 J. A. Marshall, G. Schaaf and A. Nolting, Org. Lett., 2005, 7,
5331–5333.
15 (a) Enantiomeric excess (ee) of epoxide (+)-6 was deter-
mined by chiral HPLC [Chiralpack-AD-H, 250 × 4.6 mm,
5 μ, 1.0% iPr-OH in hexanes, flow rate 1.2 mL min−1, reten-
tion time 23.74 (99.96%), 27.07 (0.03%)] (b) Specific
rotation: observed, [α]D20 = +12.5 (c 1.28, CHCl3); reported
for (+)-6 formed via kinetic resolution, [α]2D1 +12.7 (c 4.42,
mined by chiral HPLC [Chiralpack-AD-H, 250 × 4.6 mm,
5 μ, 1.0% iPr-OH in hexanes, flow rate 1.2 mL min−1, reten-
tion time 21.41 (0.94%), 22.65 (99.04%)] (b) Specific
rotation: observed, [α]D20 = −11.8 (c = 1.00, CHCl3); reported
for (−)-6 formed via kinetic resolution, [α]2D6 = −13.9 (c 1.0,
CHCl3), see: S. Roy and C. D. Spilling, Org. Lett., 2010, 12,
5326–5329.; for (−)-6 prepared from D-aspartic acid, [α]2D4
=
−14.23 (c 0.66, CHCl3); see: F. Glaus and K.-H. Altmann,
Angew. Chem., Int. Ed., 2012, 51, 3405–3409; for (−)-6 pre-
pared from L-malic acid, [α]D25 = −13.1 (c 0.58, CHCl3), see:
M. J. Gaunt, A. S. Jessiman, P. Orsini, H. R. Tanner,
D. F. Hook and S. V. Ley, Org. Lett., 2003, 5, 4819–4822.
CHCl3), see: K. Mori, Y. Shikichi, S. Shankar and J. Y. Yew, 20 U. Nookaraju, A. Harbindu, A. D. Bhise, B. M. Sharma and
Tetrahedron, 2010, 66, 7161–7168.; for (+)-6 prepared from P. Kumar, RSC Adv., 2012, 2, 11231–11234.
L-aspartic acid, [α]D24 +12.1 (c 0.607, CHCl3), see: 21 N. T. Hiep, Y.-h. Choi, N. Kim, S. S. Hong, S.-B. Hong,
C. W. Wullschleger, J. Gertsch and K.-H. Altmann, Org.
Lett., 2010, 12, 1120–1123.
B. Y. Hwang, H.-J. Lee, D. S. Jang and D. Lee, J. Nat. Prod.,
2012, 75, 2045–2046.
3364 | Org. Biomol. Chem., 2013, 11, 3355–3364
This journal is © The Royal Society of Chemistry 2013