Total synthesis of marine eicosanoid (-)-hybridalactone

Article abstract of DOI:10.1002/chem.201200210

(-)-Hybridalactone (1) is a marine eicosanoid isolated from the red alga Laurencia hybrida. This natural product contains cyclopropane, cyclopentane, 13-membered macrolactone and epoxide ring systems incorporating seven stereogenic centers. Moreover, this compound has an acid-labile skipped Z,Z-diene motif. In this paper, we report on the total synthesis of (-)-hybridalactone (1). The unique eicosanoid (-)-hybridalactone (1) was synthesized starting from optically active γ-butyrolactone 2 in a linear sequence comprising 21 steps with an overall yield of 21.9 %. A key step in the synthesis of (-)-hybridalactone (1) is the methyl phenylsulfonylacetate-mediated one-pot synthesis of the cis-cyclopropane-γ-lactone derivative. This reaction provided an efficient and stereoselective access to cis-cyclopropane-γ-lactone 12. Further elaboration of the latter compounds through desulfonylation, epoxidation, oxidation, Wittig olefination and Shiina macrolactonization afforded (-)-hybridalactone.

Full text of DOI:10.1002/chem.201200210

FULL PAPER
DOI: 10.1002/chem.201200210
Total Synthesis of Marine Eicosanoid (À)-Hybridalactone
Koichiro Ota, Naoto Sugata, Yoshihiko Ohshiro, Etsuko Kawashima, and
[
a]
Hiroaki Miyaoka*
Abstract: (À)-Hybridalactone (1) is a
marine eicosanoid isolated from the
red alga Laurencia hybrida. This natu-
ral product contains cyclopropane, cy-
clopentane, 13-membered macrolac-
tone and epoxide ring systems incorpo-
rating seven stereogenic centers. More-
over, this compound has an acid-labile
skipped Z,Z-diene motif. In this paper,
we report on the total synthesis of (À)-
hybridalactone (1). The unique eicosa-
noid (À)-hybridalactone (1) was syn-
thesized starting from optically active
g-butyrolactone 2 in a linear sequence
comprising 21 steps with an overall
yield of 21.9%. A key step in the syn-
thesis of (À)-hybridalactone (1) is the
methyl phenylsulfonylacetate-mediated
one-pot synthesis of the cis-cyclopro-
pane-g-lactone derivative. This reaction
provided an efficient and stereoselec-
tive access to cis-cyclopropane-g-lac-
tone 12. Further elaboration of the
latter compounds through desulfonyla-
tion, epoxidation, oxidation, Wittig ole-
fination and Shiina macrolactonization
afforded (À)-hybridalactone.
Keywords: hybridalactone · macro-
lactone · natural products · one-pot
synthesis · total synthesis
Introduction
Hybridalactone possesses a tetracyclic ring system compris-
ing cyclopropane, cyclopentane, 13-membered lactone and
epoxide moieties, contains seven contiguous stereogenic
centers and a skipped Z,Z-configured 1,4-diene motif, the
overall composition of which makes it a challenging synthet-
ic target. Recently, the protecting group-free total synthesis
of 1 using molybdenum alkylidene-catalyzed ring-closing
alkyne metathesis as a key step was reported by Fꢁrstnerꢀs
Hybridalactone (1) is a structur-
ally unique eicosanoid first iso-
lated in 1981 from antibacterial
extracts of the red alga Lauren-
cia hybrida by Higgs and co-
workers (Figure 1). The over-
all structure of hybridalactone
[1]
[4]
group.
was demonstrated on the basis
Figure 1. Structure and num- of spectral analysis and chemi-
Our synthetic strategy for (À)-hybridalactone (1) features
the stereocontrolled one-pot synthesis of the cyclopropane
derivative employing alkyl phenyl sulfone and epoxide de-
veloped by the authors. Our retrosynthetic analysis is
briefly outlined in Scheme 1. We envisioned that the skipped
Z,Z-configured 1,4-diene motif on the macrolactone ring
should be constructed in the latter stages of the synthesis
due to sensitivity of the 1,4-diene moiety to both acidic and
oxidative conditions. Therefore, we set aldehyde A for fur-
bering of (À)-hybridalactone.
cal conversion. Although the
relative configurations of the
cyclopentane (C-10 to C-14)
[5]
and cyclopropane (C-16 to C-18) moieties were assigned by
1
the coupling constants obtained from the H NMR spec-
trum, the relative configuration at C-15 and the absolute
structure of this compound were not elaborated. The com-
plete stereochemistry was then determined based on consid-
eration of a combined analysis of molecular mechanic calcu-
1
lations and the reported H NMR data in 1984 by Corey
and co-workers. Moreover, the absolute configuration of hy-
bridalactone was determined by X-ray crystallographic anal-
ysis of a saturated lactone bromohydrin derived from an au-
[2]
thentic sample. The first total synthesis of hybridalactone
[3]
was achieved based on the above results by Coreyꢀs group.
[
a] K. Ota, N. Sugata, Y. Ohshiro, Dr. E. Kawashima, Dr. H. Miyaoka
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences
432-1 Horinouchi, Hachioji, Tokyo 192-0392 (Japan)
1
Fax : (+81)42-676-3073
E-mail: miyaokah@toyaku.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200210.
Scheme 1. Retrosynthetic analysis of (À)-hybridalactone (1).
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ther elaboration toward 1. Aldehyde A was expected to be
generated from cyclopentene B through desulfonylation, va-
nadium-catalyzed epoxidation and oxidation of the primary
hydroxy group. Key intermediate B would be constructed
by our developed stereocontrolled one-pot synthesis of cy-
clopropane derivative using epoxy tosylate C and phenyl
propyl sulfone. The cyclopentene ring in epoxy tosylate C
was surmised to be constructed by the ring-closing metathe-
sis of epoxy alcohol D. Epoxy alcohol D could easily be pre-
sylate 7 is a substrate of the one-pot synthesis of the cyclo-
propane derivative.
The sulfonyl carbanion prepared from phenyl propyl sul-
[10]
fone
(2.3 equiv) and nBuLi (2.2 equiv) was treated with
epoxy tosylate 7 at À788C to room temperature over 12 h to
give b-sulfone 9a and a-sulfone 9b as a diastereomeric mix-
[11]
ture at C-18 in a ratio of 7:1 in 96% yield (Scheme 3).
[6]
pared from known optically active g-butyrolactone 2.
Results and Discussion
The synthesis of (À)-hybridalactone (1) commenced with al-
lylation at the a-position of optically active g-butyrolactone
[
6]
2
(>99.5% ee). g-Butyrolactone 2 was treated with lithium
diisopropylamide (LDA) in tetrahydrofuran (THF) at
À788C and then with 3-iodopropene to give the trans-lac-
[7]
tone in a stereoselective manner (Scheme 2). Subsequent
Scheme 3. One-pot synthesis of cyclopropanes 9a and 9b.
These cyclopropanes were easily separated by silica gel
chromatography, and the relative configurations of 9a and
9
b were determined by NOESY analysis (Figure 2). The cis
configuration of the cyclopropane in 9a was determined by
NOE correlation between the methine proton at C-15 and
Scheme 2. Synthesis of epoxy tosylate 7. a) LDA, 3-iodopropene, THF,
À788C; b) DIBAH, CH
2
Cl
, reflux, 88%; d) TBSCl, Et
, À788C, 96% (2 steps); f) TBHP, d-(À)-DIPT, Ti
Cl Cl , RT, 93%; h) TsCl,
, À208C, 93%; g) Grubbs 1st cat., CH
N, CH Cl , reflux, 86%.
2
, À788C, 85% (2 steps); c) Ph
N, DMAP, CH Cl , RT; e) DIBAH,
(OiPr) , 4 ꢃ
3 2
P=CHCO Et,
CH
CH
2
Cl
Cl
2
3
2
2
2
2
A
H
U
G
R
N
U
G
4
MS, CH
Et
2
2
2
2
3
2
2
reduction of the trans-lactone by diisobutylaluminum hy-
dride (DIBAH) afforded the hemiacetal as a mixture of dia-
stereomers (d.r. 3:2) in 85% yield for two steps from 2. The
resulting hemiacetal was then treated with Ph P=CHCO Et
Figure 2. Selected NOE correlations of 9a and 9b.
3
2
in CH Cl under reflux to afford (E)-a,b-unsaturated ester 3
the methylene protons at C-19. In the same way, the trans
configuration of the cyclopropane in 9b was determined by
NOE correlation between the methine proton at C-15 and
2
2
in 88% yield as a single compound. In this reaction, when
the reaction temperature was raised further, the oxy-Mi-
chael adduct was predominantly obtained. Protection of the
primary hydroxy group in 3, and subsequent reduction of
the ester moiety with DIBAH, cleanly generated allylic al-
cohol 4 in 96% yield for two steps from 3. Asymmetric ep-
oxidation of allylic alcohol 4 according to the Sharpless pro-
2
the sp -methine proton at the ortho position of the sulfonyl
group. The diastereoselectivity of this reaction was presuma-
bly derived from steric hindrance between the phenylsulfon-
yl group and the cyclopentene ring (8a and 8b), which
might favor attack of the sulfonylcarbanion on the epoxide
from the less hindered side.
[8]
cedure gave epoxy alcohol 5 in 93% yield as a sole prod-
uct. Ring-closing metathesis of epoxy alcohol 5 using
The phenylsulfonyl group in b-sulfone 9a was removed by
treatment with Na(Hg) and Na HPO to give cyclopropane
[9]
Grubbs first-generation catalyst afforded cyclopentene 6 in
3% yield. Tosylation of the primary hydroxy group in cy-
clopentene 6 gave epoxy tosylate 7 in 86% yield. Epoxy to-
2
4
9
as a sole product (Scheme 4). However, the relative configu-
ration at C-18 could not be determined. Determination of
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Natural Products
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Scheme 4. Desulfonylation of 9a and ORTEP drawing of trans-cyclopro-
pane 10. a) Na(Hg), Na
2 4 2
HPO , MeOH, RT; b) TBHP, VO ACHTNUTGREUNNNG( acac) ,
CH Cl , RT; c) TBAF, THF, RT, 86% (3 steps).
2
2
the cyclopropane stereochemistry was performed in a later
step. The aforementioned desulfonylated product was treat-
[12]
2
ed with TBHP in the presence of catalytic VO
A
H
U
G
R
N
U
G
to
give the a-epoxide, and deprotection of the TBS group with
TBAF furnished diol 10 as crystalline solid in 86% yield for
three steps from 9a. The structure of diol 10 was determined
by single-crystal X-ray diffraction, and unfortunately the C-
18 stereochemistry of the cyclopropane moiety is the result
of epimerization under the desulfonylation conditions em-
ployed. With respect to this unanticipated epimerization, we
hypothesized that repulsion between the side chains of cy-
clopropane is the main factor driving for conversion to the
trans configuration. In order to avoid the inversion of C-18,
it is necessary to modify the initial synthetic plans for (À)-
hybridalactone (1).
We envisioned that the cyclopropane moiety could be as-
sembled in a cis-fused manner using a methyl phenylsulfony-
lacetate-mediated one-pot synthesis of the cis-cyclopropane-
g-lactone derivative. To implement this strategy, cyclopen-
Scheme 6. A plausible mechanism for the formation of cis-cyclopropane-
g-lactone 12.
tene 6 was treated with MsCl and Et N to give the corre-
3
sponding mesylate (Scheme 5). The resulting mesylate was
to form the epoxy sulfone, which is rapidly converted into
the corresponding sulfonylcarbanions 13a and 13b. Intramo-
lecular alkylation of sulfonylcarbanions 13a and 13b gave
diastereomeric cyclopropanes 14a and 14b, respectively.
These intramolecular alkylations are reversible reactions.
Therefore, an equilibrium is established between cyclopro-
panes 14a and 14b via epoxides 13a and 13b. However,
only cyclopropane 14a can further cyclize to an ester moiety
to give cis-cyclopropane-g-lactone 12. In order to confirm
this hypothesis, we performed the following investigation.
Epoxy iodide 11 was treated with methyl phenylsulfonylace-
tate and K CO in DMF at room temperature for a shorter
Scheme 5. Synthesis of cis-cyclopropane-g-lactone 12. a) MsCl, Et
CH Cl , 08C; b) NaI, NaHCO , acetone, 408C, 85% (2 steps); c) methyl
phenylsulfonylacetate, K CO , DMF, RT, 93%.
3
N,
2
2
3
2
3
2
3
reaction time to afford cis-cyclopropane-g-lactone 12 togeth-
er with cyclopropane 15 derived from sulfonylcarbanion
14b. The relative configuration of cyclopropane 15 was de-
termined by NOESY analysis (Figure 3). The trans configu-
ration of the cyclopropane in 15 was determined by NOE
converted to epoxy iodide 11 by treatment with NaI and
NaHCO in 85% yield for two steps from 6. Epoxy iodide
3
11 is the substance generated for the one-pot synthesis of
the cis-cyclopropane-g-lactone derivative. Thus, under opti-
mized conditions, epoxy iodide 11 was treated with methyl
2
correlation between the methine proton at C-15 and the sp -
[13]
phenylsulfonylacetate and K CO in dry N,N-dimethylfor-
methine proton at the ortho position of the sulfonyl group.
Cyclopropane 15 was treated with K CO in DMF for 36 h
2
3
mamide (DMF) at room temperature for 36 h to afford the
desired cis-cyclopropane-g-lactone 12 in 93% yield as a
single isomer.
A plausible mechanism for the formation of cis-cyclopro-
pane-g-lactone 12 is given in Scheme 6. The carbanion of
methyl phenylsulfonylacetate reacted with epoxy iodide 11
2
3
again to give cis-cyclopropane-g-lactone 12 in 92% yield as
a sole product. This result clearly supports our proposed re-
action mechanism.
[14]
Reductive desulfonylation of 12 with Mg in MeOH at
508C afforded the g-lactone (Scheme 7). The resulting g-lac-
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H. Miyaoka et al.
was performed using palladium catalyst, cleavage of the cy-
clopropane ring was observed. Protection of the secondary
hydroxy group in 17 with methoxyacetyl chloride
(
MeOAcCl) and pyridine, followed by deprotection of TBS
with tetrabutylammonium fluoride (TBAF), furnished pri-
mary alcohol 18 in 94% yield for two steps from 17. Initial
attempts to protect the secondary hydroxy group using a va-
riety of ether protecting groups resulted in decomposition of
the 1,4-skipped diene moiety during deprotection. There-
fore, an ester protecting group was selected, although use of
an acetyl group led to decomposition of the epoxide moiety
owing to the strongly basic conditions for deprotection, and
a formyl group was not tolerated in the following oxidation.
Eventually, the methoxyacetyl group was found to be an ef-
ficient protecting group due to its moderate stability. Subse-
quent attempts to oxidize the primary hydroxy group in 18
under various conditions were met with limited success due
to instability of the generated aldehyde. This transformation
was best achieved by oxidation with 2-iodoxybenzoic acid
Figure 3. Selected NOE correlations of 15.
[16]
(
IBX ) in dimethylsulfoxide (DMSO)/THF to give the al-
dehyde. The aldehyde was then treated with phosphonium
ylide derived from (Z)-(8-methoxy-8-oxooct-3-enyl)triphe-
[17]
nylphosphonium bromide
and lithium hexamethyldisila-
zide (LiHMDS) in the presence of HMPA to give the skip-
ped Z,Z-configured 1,4-diene 19 as a sole product. To com-
plete the total synthesis, hydrolysis of the methyl ester and
methoxyacetyl group using aqueous LiOH gave the corre-
sponding hydroxycarboxylic acid. Finally, macrolactoniza-
tion of hydroxycarboxylic acid with 2-methyl-6-nitrobenzoic
[
18]
anhydride (MNBA ) and 4-N,N-dimethylaminopyridine
(DMAP) furnished (À)-hybridalactone (1) in 68% yield for
four steps from 18. Physical data of synthetic (À)-hybrida-
Scheme 7. Total synthesis of (À)-hybridalactone (1). a) Mg, MeOH,
5
08C; b) DIBAH, CH
2
Cl
2
, À788C; c) Ph
3
PCH
, CH
CN, RT, 81% (2 steps); f) MeOAcCl,
3
Br, tBuOK, THF/toluene,
RT, 86% (3 steps): d) TBHP, VO
, riboflavin tetrabutyrate, CH
A
H
U
G
R
N
U
G
2
2 2 2 2 2
Cl , RT; e) H NNH ·H O,
O
2
3
[1–3]
lactone (1) were consistent with that of reported data.
Py, RT; g) TBAF, AcOH, THF, RT, 94% (2 steps); h) IBX, DMSO/THF,
RT; i) (Z)-(8-methoxy-8-oxooct-3-enyl)triphenylphosphonium bromide,
LiHMDS, HMPA, THF, À788C; j) 0.2m LiOH aq., THF, RT; k) MNBA,
DMAP, CH
2
Cl
2
, RT, 68% (4 steps).
Conclusion
In summary, we have achieved the enantioselective total
synthesis of (À)-hybridalactone (1) in 21.9% overall yield
via a 21-step linear sequence from inexpensive g-butyrolac-
tone 2. Essential to the development of this route was ex-
ploitation of the one-pot synthesis of the cis-cyclopropane-g-
lactone derivative sequence to furnish cis-cyclopropane-g-
lactone 12.
tone was reduced with DIBAH to the hemiacetal, which
was then treated with Wittig reagent (Ph P=CH ) to afford
3
2
diene 16 in 86% yield for three steps from 12. Diene 16 was
treated with TBHP in the presence of a catalytic amount of
VO ACHTUNGTRENNUNG( acac) to give the a-epoxide as a sole product. The re-
2
gioselectivity of this epoxidation can be explained by differ-
ences in the electron density of the two double bonds. That
is, since the reaction proceeds in preference to a more elec-
tron-rich endocyclic alkene, the desired product was ob-
tained. Furthermore, the stereoselectivity may be accounted
for by invoking a process involving coordination of the hy-
droxy group at C-15 to the reagent. The terminal olefin
moiety in a-epoxide was hydrogenated by a flavin-catalyzed
aerobic reduction according to the method developed by
Experimental Section
General: All reagents (Aldrich, Kanto, TCI and Wako) and solvents
were of commercial quality and were used as received. Reactions were
monitored by thin layer chromatography on glass plates coated with a
fluorescent indicator with a 254 nm excitation wavelength (Merck-5554-
7). Flash column chromatography was performed using Kanto Chemical
Silica Gel 60N (spherical, natural) 40–50 mm. Melting points (m.p.) were
measured using the Yanaco melting point apparatus MP-S3 and are un-
corrected. Optical rotations were measured with a JASCO P-1030 polar-
imeter. IR spectra were recorded with a JASCO FT-IR/620 spectrometer.
UV spectra were recorded using a JASCO V-550 spectrophotometer. X-
[15]
Naota and co-workers. Thus, treatment of the a-epoxide
with riboflavin tetrabutyrate and hydrazine monohydrate in
dry acetonitrile using a balloon of O at room temperature
2
furnished the desired secondary alcohol 17 in 81% yield for
two steps from 16. In this reduction, when hydrogenation
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Natural Products
FULL PAPER
ray diffraction data were collected on a Bruker SMART APEX II Ultra
diffractometer with APEX II CCD area detector, comprising a Bruker
TXS fine-focus rotating anode and Bruker Helios multilayer confocal
mirror. The data collection, cell refinement, and data reduction were per-
225.1494; elemental analysis calcd (%) for C13
found: C 69.55, H 8.86.
20 3
H O : C 69.61, H 8.99;
Allylic alcohol 4: To a stirred solution of (E)-a,b-unsaturated ester 3
3.54 g, 15.8 mmol) in CH Cl (15.8 mL) were added Et N (2.70 mL,
9.4 mmol), DMAP (1.93 g, 15.8 mmol) and TBSCl (3.33 g, 22.1 mmol) at
(
2
2
3
[
19]
formed using Bruker Suite software package.
solved by the direct method and refined on F by using SHELX-97.
The structures were
1
2
[20]
room temperature. After stirring for 15 min, the reaction mixture was di-
luted with Et O, washed with saturated aqueous NaHCO , H O and
1
13
The non-hydrogen atoms were refined anisotropically. H- and C NMR
spectra were recorded on a Bruker DRX-400 or Bruker Biospin AV-600
spectrometer. Chemical shifts are given on the d (ppm) scale using tetra-
methylsilane (TMS) as the internal standard (s, singlet; d, doublet; t, trip-
let; q, quartet; quint., quintet; m, multiplet; br, broad). High resolution
ESIMS (HRESIMS) spectra were obtained using a Micromass LCT spec-
trometer. Elemental analysis data were obtained using an Elementar
Vario EL.
2
3
2
brine, and then concentrated in vacuo. The residue was passed through a
pad of silica gel (hexane/AcOEt 6:1) and then concentrated in vacuo to
give a crude product.
To a stirred solution of the crude product in CH
DIBAH (1.04m solution in hexane, 38.0 mL, 39.5 mmol) over 15 min at
SO ·10H O (30.0 g) was slowly
2 2
Cl (158 mL) was added
À788C. After stirring for 15 min, Na
2
4
2
added. The mixture was then allowed to warm to room temperature.
After stirring for 12 h, the mixture was passed through a pad of Na SO
CCDC-858852 (10) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
2
4
and then concentrated in vacuo. The residue was purified with flash
column chromatography on silica gel (hexane/AcOEt 6:1) to give allylic
alcohol 4 (4.50 g, 96% over two steps) as a colorless oil. R
f
=0.38
); H NMR
3
, 278C): d = 5.76–5.60 (m, 3H), 5.48 (ddd, J=15.4, 8.8,
2
D
5
1
(
(
hexane/AcOEt 3:1); [a] = +2.29 (c=1.44 in CHCl
400 MHz, CDCl
3
(
E)-a,b-Unsaturated ester 3: nBuLi (1.56m solution in hexane, 0.660 mL,
1
1
.03 mmol) was added to a solution of diisopropylamine (0.156 mL,
.11 mmol) in THF (9.00 mL) at À788C and the resulting mixture was
1
9
2
.6 Hz, 1H), 5.10–4.95 (m, 4H), 4.10 (d, J=5.8 Hz, 2H), 3.61 (dt, J=5.1,
.9 Hz, 1H), 3.58 (dt, J=5.8, 9.9 Hz, 1H), 3.53 (brs, 1H), 2.32–2.25 (m,
H), 2.14 (m, 1H), 1.97 (m, 1H), 0.88 (s, 9H), 0.01 ppm (s, 6H);
stirred at 08C for 30 min. After cooling to À788C, a solution of g-butyro-
lactone 2 (96.4 mg, 0.860 mmol) in THF (2.30 mL) was introduced and
stirring continued at this temperature for 30 min prior to addition of 3-io-
dopropene (0.120 mL, 1.31 mmol). After an additional 20 min, the reac-
1
3
3
C NMR (100 MHz, CDCl , 278C): d = 138.7 (t), 137.1 (t), 134.7 (t),
1
2
2
30.4 (t), 116.7 (d), 115.7 (d), 64.4 (d), 63.7 (d), 50.4 (t), 42.6 (t), 36.3 (d),
5.9ꢄ3 (s), 18.3 (q), À5.4 (s), À5.4 ppm (s); IR (neat): n˜ = 3348, 3076,
tion mixture was diluted with Et
2
O, washed with saturated aqueous
SO , and then concen-
À1
954, 2929, 2858, 1641 cm ; HRMS (ESI): m/z: calcd for C17
32 2
H O Si+
NH Cl, H O and brine, dried over anhydrous Na
4
2
2
4
+
+
Na : 319.2069 [M+Na ]; found: 319.2082; elemental analysis calcd (%)
for C17 Si: C 68.86, H 10.88; found: C 68.58, H 10.66.
Epoxy alcohol 5: To a cold (À208C) suspension of 4 ꢃ molecular sieves
3.86 g) in CH Cl
(12.7 mL) were added d-(À)-DIPT (0.164 mL,
.784 mmol), Ti(OiPr) (0.193 mL, 0.653 mmol) and TBHP (6.54m solu-
tion in CH Cl , 2.99 mL, 19.6 mmol). After stirring for 10 min at the
same temperature, a solution of allylic alcohol 4 (1.93 g, 6.53 mmol) in
CH Cl
(20.0 mL) was added over 1 h. After stirring at À208C for 2 h,
NaOH (30% solution in brine, 0.446 mL) was added. The mixture was di-
luted with Et O, warmed to room temperature, and stirred for 10 min.
trated in vacuo to give a crude product which was used for the next step
without further purification.
32 2
H O
2 2
To a stirred solution of the crude product in CH Cl (8.23 mL) was added
(
0
2
2
DIBAH (1.04m solution in hexane, 0.870 mL, 0.905 mmol) over 5 min at
À788C. After stirring for 20 min, the reaction mixture was diluted with
A
H
U
G
R
N
U
G
4
2
2
2 2 4 2
Et O and Na SO ·10H O (1.00 g) was slowly added. The mixture was
then allowed to warm to room temperature. After stirring for 12 h, the
mixture was diluted with AcOEt, passed through a pad of Na SO , and
2
2
2
4
then concentrated in vacuo. The residue was purified with flash column
chromatography on silica gel (hexane/AcOEt 3:1) to give a diastereomer-
2
Magnesium sulfate (408 mg) and Celite (41.0 mg) were then added, and
after stirring for 15 min the mixture was passed through a pad of Celite
and then concentrated in vacuo. The residue was purified with flash
column chromatography on silica gel (hexane/AcOEt 5:1) to give epoxy
ic mixture of the hemiacetal (3:2, 113 mg, 85% over two steps) as a col-
1
orless oil. R
f
=0.25 (hexane/AcOEt 2:1); H NMR (400 MHz, CDCl
3
,
2
0
0
8
0
78C): d = 5.90–5.73 (m, 1.6H), 5.66–5.57 (m, 0.4H), 5.39 (t, J=3.8 Hz,
.4H), 5.21 (t, J=3.4 Hz, 0.6H), 5.14–4.98 (m, 4H), 4.20 (t, J=8.6 Hz,
.4H), 3.99 (t, J=8.5 Hz, 0.6H), 3.81 (t, J=8.5 Hz, 0.6H), 3.59 (t, J=
.6 Hz, 0.4H), 2.93 (brs, 1H), 2.80–2.71 (m, 0.6H), 2.53 (quint, J=8.6 Hz,
.4H), 2.31–2.12 (m, 2H), 2.00–1.93 (m, 0.6H), 1.91–1.83 ppm (m, 0.4H);
alcohol 5 (1.90 g, 93%) as a colorless oil. R
f
=0.20 (hexane/AcOEt 4:1);
); H NMR (400 MHz, CDCl , 278C): d =
.74 (m, 1H), 5.69 (dt, J=17.9, 9.4 Hz, 1H), 5.17–4.99 (m, 4H), 3.87 (d,
25
1
[
a]D = +11.8 (c=0.29 in CHCl
3
3
5
J=12.4 Hz, 1H), 3.73 (dd, J=10.2, 7.2 Hz, 1H), 3.63 (dd, J=10.2, 6.5 Hz,
1
3
C NMR (100 MHz, CDCl
3
, 278C): d = 137.7 (t), 137.7 (t), 136.8 (t),
1
1
1
H), 3.59 (m, 1H), 2.91 (dt, J=4.3, 2.5 Hz, 1H), 2.80 (dd, J=9.0, 2.5 Hz,
1
35.9 (t), 117.3 (d), 116.7 (d), 116.6 (d), 115.8 (d), 103.3 (t), 98.7 (t), 72.0
H), 2.52 (m, 1H), 2.33 (m, 1H), 1.99 (m, 1H), 1.60 (brs, 1H), 1.52 (m,
(
(
d), 71.3 (d), 52.2 (t), 49.9 (t), 49.7 (t), 46.8 (t), 35.5 (d), 31.2 ppm (d); IR
13
H), 0.88 (s, 9H), 0.04 ppm (s, 6H); C NMR (100 MHz, CDCl
3
, 278C):
À1
neat): n˜ = 3408, 3078, 2978, 2937, 1642 cm ; HRMS (ESI): m/z: calcd
d = 137.0 (t), 136.7 (t), 117.9 (d), 116.3 (d), 64.1 (d), 61.7 (d), 59.0 (t),
+
+
for C
9
H
14
O
2
+Na : 177.0891 [M+Na ]; found: 177.0890; elemental anal-
: C 70.10, H 9.15; found: C 69.89, H 8.98.
To a stirred solution of the above hemiacetal (226 mg, 1.47 mmol) in
CH Cl (7.40 mL) was added Ph P=CHCO Et (2.56 g, 7.35 mmol) at
5
7.7 (t), 48.6 (t), 41.5 (t), 32.4 (d), 25.9ꢄ 3 (s), 18.3 (q), À5.3 (s),
ysis calcd (%) for C
9
H
14
O
2
À1
À5.4 ppm (s); IR (neat): n˜ = 3442, 3077, 2928, 2858, 1641 cm ; HRMS
+
+
(ESI): m/z: calcd for C H O Si+H : 313.2199 [M+H ]; found:
1
7
32
3
2
2
3
2
17 32 3
313.2199; elemental analysis calcd (%) for C H O Si: C 65.33, H 10.32;
room temperature. The mixture was then refluxed for 96 hr. After cool-
ing to room temperature, the mixture was passed through a pad of silica
gel and then concentrated in vacuo. The residue was purified with flash
column chromatography on silica gel (hexane/AcOEt 1:1) to give 3
found: C 65.07, H 10.18.
Cyclopentene 6: To a stirred solution of 5 (1.14 g, 3.65 mmol) in CH
2
Cl
730 mL) was added Grubbs 1st catalyst (300 mg, 0.365 mmol). After stir-
2
(
2
ring for 2 hr, the reaction mixture was diluted with Et O, passed through
a pad of silica gel, and then concentrated in vacuo. The residue was puri-
fied with flash column chromatography on silica gel (hexane/AcOEt 3:1)
2
5
(
291 mg, 88%) as a colorless oil. R
f
=0.22 (hexane/AcOEt 2:1); [a]
=
D
1
+
27.6 (c=1.20 in CHCl
3
); H NMR (400 MHz, CDCl
3
, 278C): d = 6.75
(
5
dd, J=15.6, 9.2 Hz, 1H), 5.80 (d, J=15.6 Hz, 1H), 5.71–5.60 (m, 2H),
.28 (dd, J=10.3, 1.7 Hz, 1H), 5.20 (dd, J=17.1, 1.7 Hz, 1H), 5.02–4.98
to give cyclopentene 6 (969 mg, 93%) as a colorless oil. R =0.33
f
2
5
1
(hexane/AcOEt 2:1); [a] =À65.5 (c=0.20 in CHCl ); H NMR
3
D
(
m, 2H), 4.19 (q, J=7.1 Hz, 2H), 3.63 (m, 1H), 3.41 (m, 1H), 2.37–2.23
m, 3H), 2.08 (m, 1H), 1.43 (m, 1H), 1.29 ppm (t, J=7.1 Hz, 3H);
(400 MHz, CDCl , 278C): d = 5.70 (ddt, J=5.8, 4.0, 1.9 Hz, 1H), 5.63
3
(
(ddt, J=5.8, 4.0, 2.0 Hz, 1H), 3.90 (m, 1H), 3.62 (m, 1H), 3.56 (dt, J=
1
3
C NMR (100 MHz, CDCl
3
, 278C): d = 166.2 (q), 149.8 (t), 137.4 (t),
6.0, 9.7 Hz, 1H), 3.53 (dt, J=6.4, 9.7 Hz, 1H), 3.02–2.96 (m, 2H), 2.80
(m, 1H), 2.50 (ddq, J=16.8, 8.9, 2.3 Hz, 1H), 2.14 (m, 1H), 2.06 (m, 1H),
1
3
35.4 (t), 122.8 (t), 119.4 (d), 117.0 (d), 63.6 (d), 60.3 (d), 50.2 (t), 43.5 (t),
À1
13
6.2 (d), 14.2 ppm (s); IR (neat): n˜ = 3442, 3077, 2979, 1714, 1651 cm
;
1.76 (brs, 1H), 0.88 (s, 9H), 0.04 ppm (s, 6H); C NMR (100 MHz,
À1
3
À1
UV/Vis (MeOH):
HRMS (ESI): m/z: calcd for C13
l
max (e)=209 nm (3900) (200000 mol m cm );
CDCl , 278C): d = 131.6 (t), 130.2 (t), 66.2 (d), 61.7 (d), 58.7 (t), 57.1 (t),
3
+
+
H
20
O
3
+H : 225.1491 [M+H ]; found:
52.3 (t), 41.1 (t), 34.5 (d), 25.9ꢄ3 (s), 18.3 (q), À5.4 (s), À5.4 ppm (s); IR
Chem. Eur. J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
5
&
ÞÞ
These are not the final page numbers!

H. Miyaoka et al.
À1
(
neat): n˜ = 3433, 3054, 2930, 2856, 1620 cm ; HRMS (ESI): m/z: calcd
140.8 (q), 133.6 (t), 131.4 (t), 130.4 (t), 128.9ꢄ2 (t), 128.7ꢄ2 (t), 69.5 (t),
67.6 (d), 52.8 (t), 52.4 (s), 49.7 (t), 49.7 (q), 39.1 (t), 35.9 (d), 26.0ꢄ3 (s),
+
+
for C15
H
28
O
3
Si+H : 285.1886 [M+H ]; found: 285.1885; elemental anal-
Si: C 63.33, H 9.92; found: C 63.12, H 9.89.
stirred solution of cyclopentene (2.45 g,
(86.1 mL) were added Et N (3.60 mL, 25.8 mmol)
and MsCl (0.800 mL, 10.3 mmol) at 08C. After stirring for 15 min, the re-
action mixture was diluted with Et O, washed with saturated aqueous
NaHCO , H O and brine, dried over anhydrous Na SO , and then con-
ysis calcd (%) for C15
Epoxy iodide 11: To
.61 mmol) in CH Cl
H
28
O
3
20.6 (d), 18.4 (q), À5.4 (s), À5.4 ppm (s); IR (neat): n˜ = 3528, 3406, 3058,
À1
2
953, 2929, 2856, 1735 cm ; HRMS (ESI): m/z: calcd for C24
H
36
O
6
SSi+
a
6
+
+
Na : 503.1900 [M+Na ]; found: 503.1882; elemental analysis calcd (%)
for C24 SSi: C 59.97, H 7.55; found: C 60.01, H 7.39.
cis-Cyclopropane-g-lactone 12: To a stirred solution of cyclopropane 15
(1.4 mg, 0.00290 mmol) in DMF (0.0970 mL) was added K CO (1.2 mg,
0.00868 mmol) at room temperature. After stirring for 36 h, the reaction
mixture was diluted with Et O, washed with H O and brine, dried over
anhydrous Na SO , and then concentrated in vacuo. The residue was pu-
rified with flash column chromatography on silica gel (hexane/AcOEt
:1) to give cis-cyclopropane-g-lactone 12 (1.2 mg, 92%).
8
2
2
3
36 6
H O
2
3
2
2
4
2
3
centrated in vacuo to give a crude product which was used for the next
step without further purification.
2
2
To a stirred solution of the crude product in acetone (86.1 mL) were
2
4
added NaHCO
temperature. The resulting mixture was then heated to 408C. After stir-
ring for 13 h, the reaction mixture was diluted with Et O, filtered through
3
(3.60 g, 43.1 mmol) and NaI (6.50 g, 43.1 mmol) at room
8
Diene 16: To a stirred solution of cis-cyclopropane-g-lactone 12 (101 mg,
0.226 mmol) in MeOH (11.3 mL) was added Mg (565 mg, 23.2 mmol) at
room temperature. The resulting mixture was then heated to 508C. After
2
silica gel, and then concentrated in vacuo. The residue was purified with
flash column chromatography on silica gel (hexane/AcOEt 15:1) to give
epoxy iodide 11 (2.89 g, 85% over two steps) as a colorless oil. R
f
=0.65
stirring for 30 min, the reaction mixture was diluted with Et
tracted by centrifugation. The combined organic extracts were washed
with H O and brine, dried over anhydrous Na SO , and then concentrat-
ed in vacuo. The residue was passed through a pad of silica gel (hexane/
AcOEt 5:1) and then concentrated in vacuo to give a crude product.
2
O and ex-
2
5
1
(
(
(
hexane/AcOEt 6:1); [a] =À110.3 (c=0.11 in CHCl
3
); H NMR
D
400 MHz, CDCl
3
, 278C): d = 5.71 (ddt, J=5.8, 2.1, 2.1 Hz, 1H), 5.64
2
2
4
ddt, J=5.8, 2.1, 2.1 Hz, 1H), 3.54 (dt, J=6.4, 9.7 Hz, 1H), 3.52 (dt, J=
6
2
2
1
.2, 9.7 Hz, 1H), 3.28 (dd, J=9.1, 5.0 Hz, 1H), 3.04 (ddd, J=6.8, 5.0,
.1 Hz, 1H), 3.01 (dd, J=9.0, 7.2 Hz, 1H), 2.84 (dd, J=6.8, 1.8 Hz, 1H),
.81 (m, 1H), 2.51 (ddq, J=16.9, 8.0, 2.4 Hz, 1H), 2.18 (m, 1H), 2.03 (m,
To a stirred solution of the crude product in CH Cl (4.50 mL) was added
2
2
DIBAH (1.03m solution in hexane, 0.260 mL, 0.268 mmol) over 5 min at
À788C. After stirring for 5 min, Na SO ·10H O (1.00 g) was slowly added
1
3
3
H), 0.89 (s, 9H), 0.34 ppm (s, 6H); C NMR (100 MHz, CDCl , 278C):
2
4
2
d = 131.5 (t), 130.3 (t), 66.1 (d), 65.4 (t), 57.1 (t), 52.5 (t), 41.4 (t), 34.5
to the reaction mixture. The mixture was allowed to warm to room tem-
perature. After stirring for 1.5 h, the mixture was passed through a pad
of anhydrous Na SO , and then concentrated in vacuo to give a crude
(
3
d), 25.9ꢄ3 (s), 18.3 (q), 5.0 (d), À5.3 (s), À5.4 ppm (s); IR (neat): n˜ =
À1
054, 2953, 2929, 2855 cm ; HRMS (ESI): m/z: calcd for C15
H
27IO
2
Si+
2
4
+
+
H : 395.0903 [M+H ]; found: 395.0903; elemental analysis calcd (%)
for C15 Si: C 45.68, H 6.90; found: C 45.53, H 6.91.
cis-Cyclopropane-g-lactone 12: To a stirred solution of epoxy iodide 11
915 mg, 2.32 mmol) and methyl phenylsulfonylacetate (1.99 g,
.28 mmol) in DMF (23.2 mL) was added K CO (3.21 g, 23.2 mmol) at
room temperature. After stirring for 36 hr, the reaction mixture was di-
luted with Et O, washed with H O and brine, dried over anhydrous
Na SO , and then concentrated in vacuo. The residue was purified with
product which was used for the next step without further purification.
H
27IO
2
To a stirred suspension of Ph PCH Br (323 mg, 0.903 mmol) in toluene
3
3
(4.50 mL) was added tBuOK (88.7 mg, 0.791 mmol) at room temperature.
After stirring for 1.5 h, a solution of the above crude product in THF
(4.50 mL) was added to the mixture. After stirring for 15 min at room
(
9
2
3
temperature, the reaction mixture was diluted with Et O, washed with sa-
2
2
2
4 2 2 4
turated aqueous NH Cl, H O and brine, dried over anhydrous Na SO ,
and then concentrated in vacuo. The residue was purified with flash
column chromatography on silica gel (hexane/AcOEt 5:1) to give diene
2
4
flash column chromatography on silica gel (hexane/AcOEt 7:1) to give
cis-cyclopropane-g-lactone 12 (1.04 g, 93%) as a white needle-like crys-
16 (60.0 mg, 86% over three steps) as a colorless oil. R
f
=0.55 (hexane/
2
5
25
1
talline solid. R
À145.1 (c=0.76 in CHCl
f
=0.47 (hexane/AcOEt 3:1); m.p. 185–1868C; [a]
=
AcOEt 3:1); [a]D =À69.3 (c=0.49 in CHCl
3
); H NMR (400 MHz,
CDCl , 278C): d = 5.73 (m, 1H), 5.61 (dt, J=17.0, 10.1 Hz, 1H), 5.44 (m,
3
D
1
3
); H NMR (400 MHz, CDCl
3
, 278C): d = 8.08–
8.04 (m, 2H), 7.69 (m, 1H), 7.62–7.56 (m, 2H), 5.69 (ddt, J=5.8, 2.0,
1.9 Hz, 1H), 5.65 (ddt, J=5.8, 2.0, 1.9 Hz, 1H), 4.46 (dd, J=10.4, 4.4 Hz,
1H), 3.58 (dd, J=9.9, 4.9 Hz, 1H), 3.41 (dd, J=9.9, 6.3 Hz, 1H), 3.14 (dt,
1H), 5.10 (dd, J=17.0, 1.6 Hz, 1H), 4.96 (dd, J=10.1, 1.6 Hz, 1H), 3.83
(ddd, J=9.6, 4.4, 1.9 Hz, 1H), 3.76 (d, J=1.9 Hz, 1H), 3.34 (t, J=9.6 Hz,
1H), 3.21 (dt, J=8.7, 9.6 Hz, 1H), 2.83 (m, 1H), 2.54 (m, 1H), 2.30 (m,
1H), 2.16 (m, 1H), 1.61 (m, 1H), 1.11 (dq, J=8.5, 6.2 Hz, 1H), 0.99 (dt,
J=4.9, 8.5 Hz, 1H), 0.92 (s, 9H), 0.66 (dd J=10.9, 5.2 Hz, 1H), 0.10 ppm
J=7.7, 5.4 Hz, 1H), 2.80 (m, 1H), 2.60 (m, 1H), 2.10–2.04 (m, 3H), 1.53
1
3
(
t, J=5.4 Hz, 1H), 0.84 (s, 9H), 0.02 ppm (s, 6H); C NMR (100 MHz,
CDCl , 278C): d = 167.1 (q), 138.3 (q), 134.3 (t), 132.3 (t), 129.2 (t),
29.1ꢄ2 (t), 129.1ꢄ2 (t), 80.6 (t), 65.2 (d), 52.4 (t), 47.2 (q), 41.4 (t), 34.3
1
3
3
(s, 6H); C NMR (100 MHz, CDCl , 278C): d = 139.1 (t), 131.7 (t), 129.8
3
1
(t), 114.1 (d), 73.9 (t), 67.9 (d), 53.2 (t), 51.6 (t), 36.2 (d), 26.0ꢄ3 (s), 24.8
(
d), 29.7 (t), 25.8ꢄ3 (s), 18.2 (q), 16.4 (d), À5.4 (s), À5.4 ppm (s); IR
(t), 21.1 (t), 18.4 (q), 9.9 (d), À5.5ꢄ2 ppm (s); IR (neat): n˜ = 3437, 3052,
À1
À1
+
(
KBr): n˜ = 3073, 2930, 2857, 1782 cm ; HRMS (ESI): m/z: calcd for
2929, 2857, 1633 cm ; HRMS (ESI): m/z: calcd for C18
H
32
O
2
Si+H :
+
+
+
C
23
H
32
O
5
SSi+H : 449.1818 [M+H ]; found: 449.1832; elemental analy-
SSi: C 61.57, H 7.19; found: C 61.58, H 7.08.
309.2250 [M+H ]; found: 309.2260; elemental analysis calcd (%) for
sis calcd (%) for C23
H
32
O
5
C
18
H
32
O
2
Si: C 70.07, H 10.45; found: C 69.99, H 10.46.
Secondary alcohol 17: To stirred solution of diene 16 (121 mg,
0.392 mmol) in CH Cl (7.80 mL) were added VO
0.0392 mmol) and TBHP (5.26m solution in CH
cis-Cyclopropane-g-lactone 12 and cyclopropane 15: To a stirred solution
of epoxy iodide 11 (9.7 mg, 0.0247 mmol) and methyl phenylsulfonylace-
a
2
2
A
H
U
G
R
N
U
G
2
(10.4 mg,
2
, 0.370 mL,
tate (15.9 mg, 0.0742 mmol) in DMF (0.494 mL) was added K
17.1 mg, 0.124 mmol) at room temperature. After stirring for 12 h, the
reaction mixture was diluted with Et O, washed with H O and brine,
dried over anhydrous Na SO , and then concentrated in vacuo. The resi-
due was purified with flash column chromatography on silica gel
hexane/AcOEt 7:1) to give cis-cyclopropane-g-lactone 12 (9.6 mg, 87%)
as a white needle-like crystalline solid and cyclopropane 15 (1.4 mg,
2%) as a colorless oil. cyclopropane 15: R =0.13 (hexane/AcOEt 3:1);
); H NMR (400 MHz, CDCl , 278C): d =
2
CO
3
2
(
1.95 mmol) at room temperature. After stirring for 3 h, dimethylsulfide
was added to the reaction mixture. The mixture was filtered through
silica gel and then concentrated in vacuo. The residue was passed through
a pad of silica gel (hexane/AcOEt 5:1) and then concentrated in vacuo to
give a crude product.
2
2
2
4
(
To a stirred solution of the crude product in CH CN (3.90 mL) were
3
1
f
added riboflavin tetrabutyrate (5.2 mg, 0.00790 mmol) and hydrazine
2
D
5
1
[
a] =À11.1 (c=1.05 in CHCl
3
3
monohydrate (0.0380 mL, 0.783 mmol) under an oxygen atmosphere at
room temperature. After stirring for 12 h, the reaction mixture was con-
centrated in vacuo. The residue was purified with flash column chroma-
tography on silica gel (hexane/AcOEt 5:1) to give secondary alcohol 17
(104 mg, 81% over two steps) as a white needle-like crystalline solid.
7
2
6
.96–7.93 (m, 2H), 7.61 (m, 1H), 7.54–7.50 (m, 2H), 5.74 (ddt, J=5.7,
.3, 2.1 Hz, 1H), 5.52 (ddt, J=5.7, 2.3, 2.1 Hz, 1H), 4.34 (ddd, J=0.8, 2.1,
.8 Hz, 1H), 4.06 (d, J=2.1 Hz, 1H), 3.73 (dd, J=9.6, 5.3 Hz, 1H), 3.55
s, 3H), 3.43 (dd, J=9.6, 8.8 Hz, 1H), 2.92 (m, 1H), 2.56–2.52 (m, 2H),
.33 (dd, J=8.8, 4.9 Hz, 1H), 2.24 (m, 1H), 2.16 (ddd, J=10.0, 8.8,
(
2
D
5
2
6
0
R =0.33 (hexane/AcOEt 4:1); m.p. 68–698C; [a] =À30.1 (c=0.48 in
f
1
.1 Hz, 1H), 1.96 (dd, J=10.0, 4.9 Hz, 1H), 0.89 (s, 9H), 0.07 (s, 3H),
CHCl ); H NMR (400 MHz, CDCl , 278C): d = 3.72 (dd, J=10.0,
3
3
1
3
.07 ppm (s, 3H); C NMR (100 MHz, CDCl
3
, 278C): d = 167.1 (q),
4.9 Hz, 1H), 3.60 (dd, J=10.0, 6.6 Hz, 1H), 3.57 (m, 1H), 3.53 (m, 1H),
&
6
&
www.chemeurj.org
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Natural Products
FULL PAPER
3
(
.49 (d, J=2.7 Hz, 1H), 3.10 (m, 1H), 2.68 (m, 1H), 2.21 (m, 1H), 2.17
m, 1H), 1.99 (d, J=13.9 Hz, 1H), 1.55 (m, 1H), 1.10 (m, 1H), 0.99 (t,
J=7.1 Hz, 3H), 0.90 (s, 9H), 0.83–0.68 (m, 3H), 0.14 (m, 1H), 0.06 ppm
To a stirred solution of MNBA (22.7 mg, 0.0660 mmol) and DMAP
(16.2 mg, 0.132 mmol) in CH
above crude product in CH Cl
perature. The mixture was cooled to 08C, and then saturated aqueous
NaHCO was added. After stirring for 5 min, the reaction mixture was di-
luted with Et O, washed with H O and brine, dried over anhydrous
Na SO , and then concentrated in vacuo. The residue was purified with
2
Cl
2
(2.40 mL) was added a solution of the
2
2
(23.0 mL) dropwise over 4 h at room tem-
1
3
(
3
s, 6H); C NMR (100 MHz, CDCl , 278C): d = 74.2 (t), 64.4 (d), 61.7
(
t), 59.3 (t), 45.6 (t), 43.1 (t), 32.9 (d), 25.8ꢄ3 (s), 22.4 (d), 21.7 (t), 18.2
3
(
2
:
q), 18.0 (t), 14.5 (s), 9.2 (d), À5.5 (s), À5.6 ppm (s); IR (KBr): n˜ = 3422,
2
2
À1
+
962, 2932, 2900, 2864 cm ; HRMS (ESI): m/z calcd for C18
H
34
O
3
Si+H
2
4
+
327.2355 [M+H ]; found: 327.2369; elemental analysis calcd (%) for
flash column chromatography on silica gel (hexane/AcOEt 15:1) to give
C
18
H
34
O
3
Si: C 66.21, H 10.49; found: C 66.23, H 10.46.
(À)-hybridalactone (1) (13.3 mg, 68% over four steps) as a white semi-
2
D
5
solid. R
f
=0.23 (hexane/AcOEt 10:1); [a] =À55.3 (c=0.20 in MeOH);
Primary alcohol 18: To a stirred solution of secondary alcohol 17
29.7 mg, 0.0910 mmol) in pyridine (0.460 mL) was added methoxyacetyl
chloride (0.0130 mL, 0.137 mmol) at room temperature. After stirring for
5 min, the reaction mixture was diluted with Et O, washed with saturat-
ed aqueous NaHCO , H O and brine, dried over anhydrous Na SO , and
1
3
H NMR (400 MHz, CDCl , 278C): d = 5.51 (dt, J=4.6, 10.8 Hz, 1H),
(
5
5
1
.47 (ddd, J=10.8, 3.9, 1.2 Hz, 1H), 5.27 (ddt, J=3.2, 1.7, 10.8 Hz, 1H),
.07 (dt, J=2.0, 10.8 Hz, 1H), 4.72 (t, J=10.2 Hz, 1H), 3.51 (d, J=
.8 Hz, 1H), 3.37 (dt, J=14.7, 10.8 Hz, 1H), 3.17 (d, J=1.8 Hz, 1H), 2.96
4
2
3
2
2
4
(
d, J=10.5 Hz, 1H), 2.40–2.20 (m, 5H), 2.05 (t, J=10.2 Hz, 1H), 2.02–
then concentrated in vacuo to give a crude product. The residue was
passed through a pad of silica gel (hexane/AcOEt 7:1) and then concen-
trated in vacuo to give a crude product.
1
7
0
.90 (m, 3H), 1.72 (m, 1H), 1.48 (m, 1H), 1.17 (m, 1H), 1.03 (t, J=
.1 Hz, 3H), 0.89 (m, 1H), 0.76 (m, 1H), 0.57 (dt, J=4.7, 8.5 Hz, 1H),
1
3
.05 ppm (dd, J=8.5, 4.7 Hz, 1H); C NMR (100 MHz, CDCl
3
, 278C): d
To a stirred solution of the crude product in THF (1.80 mL) were added
acetic acid (0.0520 mL, 0.910 mmol) and TBAF (1.00m solution in THF,
=
173.2 (q), 129.0 (t), 128.5 (t), 128.2 (t), 127.1 (t), 79.0 (t), 60.9 (t), 58.2
(
(
1
t), 49.0 (t), 41.6 (t), 32.8 (d), 28.6 (d), 26.4 (d), 25.8 (d), 24.0 (d), 23.2
0
.460 mL, 0.460 mmol). After stirring for 4 h, the reaction mixture was di-
luted with Et O, washed with saturated aqueous NaHCO , H O and
brine, dried over anhydrous Na SO , and then concentrated in vacuo.
The residue was purified with flash column chromatography on silica gel
d), 21.2 (t), 20.4 (t), 14.2 (s), 8.5 ppm (d); IR (KBr): n˜ = 2954, 2926,
2
3
2
À1
+
725 cm
;
HRMS (ESI): m/z calcd for
C
20
H
28
O
3
+Na : 339.1936
: C
2
4
+
[
M+Na ]; found: 339.1934; elemental analysis calcd (%) for C20
28 3
H O
7
5.91, H 8.92; found: C 76.18, H 8.93.
(
hexane/AcOEt 1:4) to give primary alcohol 18 (24.2 mg, 94% over two
25
D
steps) as a colorless oil. R
f
=0.23 (hexane/AcOEt 1:2); [a] =À2.37 (c=
1
0
9
3
1
.46 in CHCl
3
); H NMR (400 MHz, CDCl
3
, 278C): d = 4.65 (t, J=
[
[
1] M. D. Higgs, L. J. Mulheirn, Tetrahedron 1981, 37, 4259–4262.
2] E. J. Corey, B. De, J. W. Ponder, J. M. Berg, Tetrahedron Lett. 1984,
5, 1015–1018.
[3] E. J. Corey, B. De, J. Am. Chem. Soc. 1984, 106, 2735–2736.
.2 Hz, 1H), 4.02 (s, 2H), 3.60–3.56 (m, 2H), 3.47 (m, 1H), 3.44 (s, 3H),
.41 (d, J=2.3 Hz, 1H), 2.24–2.12 (m, 3H), 2.00–1.82 (m, 2H), 1.68 (m,
H), 1.12 (m, 1H), 1.02 (t, J=7.2 Hz, 3H), 0.92–0.82 (m, 2H), 0.61 (dt,
2
1
3
J=5.6, 8.3 Hz, 1H), 0.10 ppm (dd, J=10.5, 5.6 Hz, 1H); C NMR
[
4] V. Hickmann, A. Kondoh, B. Gabor, M. Alcarazo, A. Fꢁrstner, J.
Am. Chem. Soc. 2011, 133, 13471–13480.
(
(
3
100 MHz, CDCl , 278C): d = 170.1 (q), 79.8 (t), 70.1 (d), 63.4 (d), 59.6
t), 59.3 (s), 58.0 (t), 45.3 (t), 45.0 (t), 29.3 (d), 23.0 (d), 20.8 (t), 20.2 (t),
À1
[5] H. Miyaoka, T. Shigemoto, I. Shinohara, A. Suzuki, Y. Yamada, Tet-
rahedron 2000, 56, 8077–8081.
1
4.1 (s), 9.0 ppm (d); IR (neat): n˜ = 3458, 2930, 2873, 1743 cm ; HRMS
+
+
(
ESI): m/z: calcd for
C
15
H
24
O
5
+Na : 307.1521 [M+Na ]; found:
[
6] F. Ishibashi, E. Taniguchi, Bull. Chem. Soc. Jpn. 1988, 61, 4361–
366.
3
07.1520; elemental analysis calcd (%) for C15 : C 63.36, H 8.51;
24 5
H O
4
found: C 63.27, H 8.48.
À)-Hybridalactone (1): To a solution of IBX (34.5 mg, 0.123 mmol) in
DMSO (1.20 mL) was added a solution of primary alcohol 18 (17.6 mg,
.0619 mmol) in THF (1.20 mL). After stirring for 13 h at room tempera-
ture, H O was added to the mixture. The mixture was filtered through
Celite, washed with H O and brine, dried over anhydrous Na SO , and
[
7] a) H. Miyaoka, Y. Hara, I. Shinohara, T. Kurokawa, Y. Yamada, Tet-
rahedron Lett. 2005, 46, 7945–7949; b) H. Miyaoka, Y. Hara, I. Shi-
nohara, T. Kurokawa, E. Kawashima, Y. Yamada, Heterocycles 2009,
(
0
7
7, 1185–1208.
2
[
[
8] T. Katsuki, K. B. Sharpless, J. Am. Chem. Soc. 1980, 102, 5974–5976.
9] P. Schwab, M. B. France, J. W. Ziller, R. H. Grubbs, Angew. Chem.
2
2
4
then concentrated in vacuo. The residue was passed through a pad of
silica gel (hexane/AcOEt 1:4) and then concentrated in vacuo to give a
crude product.
1
995, 107, 2179–2181; Angew. Chem. Int. Ed. Engl. 1995, 34, 2039–
2
041.
[
[
10] K. Jeyakumar, D. K. Chand, Tetrahedron Lett. 2006, 47, 4573–4576.
11] The position number of all compounds is in accordance with that for
hybridalactone in this paper.
To a stirred suspension of (Z)-(8-methoxy-8-oxooct-3-enyl)triphenylphos-
phonium bromide (122 mg, 0.246 mmol) in THF (1.10 mL) were added
LiHMDS (1.00m solution in THF, 0.220 mL, 0.220 mmol) and HMPA
[
[
12] a) K. A. Jørgensen, Chem. Rev. 1989, 89, 431; b) W. Adam, T. Wirth,
Acc. Chem. Res. 1999, 32, 703.
13] T. M. C. Tan, Y. Chen, K. H. Kong, J. Bai, Y. Li, S. G. Lim, T. H.
Ang, Y. Lam, Antiviral Res. 2006, 71, 7–14.
(
0.110 mL, 0.615 mmol) dropwise at 08C and the resulting mixture was
stirred for 30 min at same temperature. The mixture was cooled to
À788C. A solution of the above crude product in THF (1.00 mL) was
then added to the mixture. After stirring for 10 min at room temperature,
[
[
14] A. C. Brown, L. A. Carpino, J. Org. Chem. 1985, 50, 1749–1750.
15] Y. Imada, H. Iida, T. Kitagawa, T. Naota, Chem. Eur. J. 2011, 17,
the reaction mixture was diluted with Et
ous NH Cl, H O and brine, dried over anhydrous Na
centrated in vacuo. The residue was passed through a pad of silica gel
hexane/AcOEt 4:1) and then concentrated in vacuo to give a crude
2
O, washed with saturated aque-
4
2
2
SO , and then con-
4
5
908–5920.
[16] R. E. Ireland, L. Liu, J. Org. Chem. 1993, 58, 2899–2899.
[17] J. Sandri, J. Viala, J. Org. Chem. 1995, 60, 6627–6630.
[18] I. Shiina, R. Ibuka, M. Kubota, Chem. Lett. 2002, 286–287.
(
product.
To a stirred solution of the crude ester in THF (1.30 mL) was added
[19] Bruker Suite, Bruker AXS Inc., Madison, USA, 2008.
[20] G. M. Sheldrick, Program for the Solution for Crystal Structures,
University of Gçttingen, Germany, 1997.
LiOH (0.20m solution in H
After stirring for 1.5 h, the mixture was diluted with Et
washed with saturated aqueous NH Cl, H O and brine, dried over anhy-
drous Na SO , and then concentrated in vacuo. The residue was passed
2
O, 15.4 mL, 3.08 mmol) at room temperature.
2
O/CHCl (3:1),
3
4
2
2
4
Received: January 19, 2012
Revised: April 26, 2012
Published online: && &&, 0000
through a pad of silica gel (hexane/AcOEt 1:1) and then concentrated in
vacuo to give a crude product.
Chem. Eur. J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
7
&
ÞÞ
These are not the final page numbers!

H. Miyaoka et al.
Natural Products
K. Ota, N. Sugata, Y. Ohshiro,
E. Kawashima,
H. Miyaoka* .................. &&&& — &&&&
Total Synthesis of Marine Eicosanoid
(
À)-Hybridalactone
Natural product synthesis: The asym-
metric total synthesis of a marine eico-
sanoid (À)-hybridalactone) was ach-
ieved with the methyl phenylsulfonyla-
cetate-mediated one-pot synthesis of
cis-cyclopropane-g-lactone derivative
as a key reaction for the construction
of cis-cyclopropane moiety.
&
8
&
www.chemeurj.org
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!