Stereoselective synthesis of (-)-blepharocalyxin D

Article abstract of DOI:10.1016/j.tet.2007.02.028

The Prins cyclization strategy was successfully applied in the stereoselective synthesis of (-)-blepharocalyxin D (1), a cytotoxic dimeric diarylheptanoid isolated from Alpinia blepharocalyx.

Full text of DOI:10.1016/j.tet.2007.02.028

Tetrahedron 63 (2007) 5797–5805
Stereoselective synthesis of (L)-blepharocalyxin D
Haye Min Ko,a Dong Gil Lee,a Min Ah Kim,a Hak Joong Kim,a Jaejoon Park,b
Myoung Soo Lahb and Eun Leea,
*
aDepartment of Chemistry, College of Natural Sciences, Seoul National University NS60, Seoul 151-747, Republic of Korea
bDepartment of Chemistry and Applied Chemistry, Hanyang University, 1271 Sa-1-dong, Ansan, Kyunggi-do 426-791,
Republic of Korea
Received 9 January 2007; revised 8 February 2007; accepted 8 February 2007
Available online 13 February 2007
Abstract—The Prins cyclization strategy was successfully applied in the stereoselective synthesis of (ꢀ)-blepharocalyxin D (1), a cytotoxic
dimeric diarylheptanoid isolated from Alpinia blepharocalyx.
Ó 2007 Elsevier Ltd. All rights reserved.
HO
OH
1. Introduction
O
H
A large number of bioactive diarylheptanoid natural prod-
ucts were isolated recently by Kadota and co-workers
from the seeds of Alpinia blepharocalyx K. Schum, a mem-
ber of Zingiberaceae family found in China.1,2 Plants of this
family are known to have antihepatotoxic, anti-inflamma-
tory, and stomachic properties. More recently, synthetic in-
vestigations3 by Rychnovsky and co-workers led to revised
structures of some of the diarylheptanoids such as calyxins
L, F, M, and G (Fig. 1).
HO
OH
OH
OMe O
Calyxin L
OH
HO
MeO
O
H
Blepharocalyxin D (1)1e,h is a unique member of dimeric di-
arylheptanoid natural products isolated from the seeds of A.
blepharocalyx (Fig. 2). It is an antiproliferative agent (ED50
3.61 mM) against murine colon 26-L5 carcinoma cells. The
most characteristic feature of blepharocalyxin D (1) is
a rare 2,8-dioxabicyclo[4.4.0]decane core, to which four
p-hydroxyphenyl groups are appended.4 No general strategy
has evolved for generation of this dioxabicyclodecane sys-
tem, and there have been no advances made toward synthesis
of this interesting natural product.5 Herein, we describe
a concise stereoselective synthesis of 1 employing two dis-
tinctive Prins cyclization reactions.6
O
OH
OH
OH
HO
OH
O
H
Calyxin F
OH
H
HO
O
OH
MeO
O
O
H
OMe O
Calyxin M
Epicalyxin M
H
O
OH
OH
In our retrosynthetic analysis, the oxane derivative A was
considered as a pivotal intermediate in the synthesis of ble-
pharocalyxin D (1). A number of different synthetic routes
may be considered for the efficient conversion from A to
OH
Calyxin G
Epicalyxin G
* Corresponding author. Tel.: +82 2 880 6646; fax: +82 2 889 1568; e-mail:
eunlee@snu.ac.kr
Figure 1. Some diarylheptanoid natural products from Alpinia blepharo-
calyx.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.02.028

5798
H. M. Ko et al. / Tetrahedron 63 (2007) 5797–5805
HO
OH
O
O
3
1
O
O
OH
Oi-Pr
O
Ti
H
O
i-PrO
Ti
O
5'
H
3
1'
MeO
Ar
OH
1) SO3.pyr, TEA, DMSO
OH
2) 10 mol% 3
CH2CHCH2SnBu3
90%
2
4
OH
1 Blepharocalyxin D
R*COCl
pyridine
Ar=Ph(p-OMe)
Figure 2. Structure of blepharocalyxin D (1).
R*COCl=(O)-acetyl-(S)-mandeloyl chloride
Ar
O2CR*
H
S
1. Intermediate A may be prepared from homoallylic alcohol
B and aldehyde C. This type of Prins cyclization has already
been reported by Willis and co-workers.7 (Scheme 1).
5
MeO
H
MeO
O
O
Ph vs
OAc
Ph
S
R
H
6
OAc
H
O
O
2. Results and discussion
5
δ 5.42, 4.81, 4.78
(24:1)
δ 5.72, 5.07, 5.06
Sulfur trioxide–DMSO oxidation of 3-(p-methoxyphenyl)-
propan-1-ol (2) yielded the corresponding aldehyde, which
was converted into homoallylic alcohol 4 (92% ee) via reac-
tion with allyltributylstannane in the presence of 10 mol %
catalyst 3 following the Maruoka protocol.8 The (S)-config-
uration of homoallylic alcohol 4 was confirmed by NMR
analysis of the ester derivatives, which were produced via re-
action with (O)-acetyl-(S)-mandeloyl chloride.9 The NMR
spectra of the major product 5 exhibited vinylic proton sig-
nals at d 5.42, 4.81, and 4.78, compared to the signals of
the minor isomer 6 at d 5.72, 5.07, and 5.06 (Scheme 2).
Scheme 2. Synthesis of homoallylic alcohol 4.
TES derivative could also be converted into oxane triacetate
9 under similar conditions, but the malonate derivative 7 did
not serve as a viable precursor for Prins cyclization yielding
a complex reaction mixture.
1) TIPSOTf
2) (Sia)2BH; H2O2
3) SO3.pyr, DMSO
Ar
OTIPS
4
CO2Et
CO2Et
4) CH2(CO2Et)2
piperidine
5) LDA
TIPS-protection of 4, hydroboration–oxidation, and sulfur
trioxide–DMSO oxidation produced the corresponding
aldehyde. The aldehyde was converted into the malonate de-
rivative 7 after Knoevenagel condensation and LDA-medi-
ated deconjugation. Lithium aluminum hydride reduction
of 7 and acetylation of the resulting diol produced the homo-
allylic alcohol diacetate derivative 8. Reaction of 8 with
p-anisaldehyde in the presence of boron trifluoride diethyl
etherate and trimethylsilyl acetate in acetic acid10 resulted
in the formation of the oxane triacetate product 9 in 35%
yield accompanied by diacetate 10 in 60% yield (Scheme 3).
Diacetate 10 could be recycled under the same reaction
conditions producing 9 in 35% yield. The corresponding
7
1) LAH
2) Ac2O
65%
36%
Ar
OTIPS
OAc
OAc
8
1.2 equiv ArCHO, 4.0 equiv BF3.OEt2
1.0 equiv TMSOAc, 40 equiv AcOH
r.t. 90 min
Ar
O
Ar
Ar
OH
OAc
OAc
OAc
OAc
H
OAc
35%
HO
OH
60%
10
9
O
O
OH
Ar
H
Scheme 3. Synthesis of homoallylic alcohol derivative 8 and Prins
cyclization.
H
Ar
H
OH
O
C
The efficacy of olefin cross metathesis reaction was then ex-
amined for potential alternative for the laborious route to the
pivotal oxane intermediate 9 described above. The required
olefin 14 was prepared starting from triol 11. Cyclic acetal
formation and sulfur trioxide–DMSO oxidation yielded al-
dehyde 12.11 Wittig olefination and oxidative deprotection
produced diol 13, from which diacetate 14 was obtained
via acetylation. Cross metathesis reaction of 4 with 2 equiv
of olefin 14 in the presence of the second generation Hov-
eyda–Grubbs catalyst (15)12 proceeded smoothly producing
OR
OR
B
Ar
O
Ar
OH
1 Blepharocalyxin D
OR
OR
H
HO
A
Scheme 1. Retrosynthetic analysis.

H. M. Ko et al. / Tetrahedron 63 (2007) 5797–5805
5799
1.2 equiv ArCHO
4.0 equiv TESOTf
1.0 equiv TMSOAc
homoallylic alcohol 10 in 67% yield (Scheme 4). Use of the
second generation Grubbs catalyst under the identical reac-
tion conditions provided the product 10 in 48% yield. Use
of alternative olefin partners, for example, diol 13 or its
bis(TBS) ether, led to more sluggish reactions producing
the corresponding products in 10–20% yield in the presence
of the second generation Grubbs catalyst.
Ar
O
Ar
1) K2CO3
10
9
40 equiv AcOH
r.t. 1 h
60%
2) CBr4,Ph3P
TEA
48%
Br
H
OH
16
Br
ArCOCCH, NMM
89%
Ar
O
Ar
Ar
H
1) p-MeOPhCH(OMe)2
(TMS)3SiH
or Bu3SnH
CSA
O
O
HO
Br
OH
OH
Complex
product
mixture
H
O
2) SO3.pyridine, TEA
O
Br
O
AIBN
DMSO
11
88%
OMe
12
17
1) Ph3PMe+Br-, n-BuLi
2) CAN, H2O
46%
Scheme 5. Improved Prins cyclization of 10 and radical cyclization
attempted.
Ac2O, TEA
OAc
OAc
OH
OH
DMAP
83%
elimination was carried out in hot diphenyl ether to provide
the seven-membered cyclic acetal 20.16 The second Prins re-
action proceeded smoothly in the presence of boron trifluor-
ide diethyl etherate producing a mixture of the axial
aldehyde 21 (83%) and the equatorial aldehyde 22 (2%).
As far as we know, this type of Prins cyclization using meth-
ylidene-substituted seven-membered cyclic acetals is un-
precedented. The high stereoselectivity is surprising, as the
Prins-pinacol sequence on related diol substrates is known
to yield mainly equatorial aldehydes.17,18 The kinetic prefer-
ence in our case may be explained by the conformational
constraints originating from the steric crowding.
14
13
N
N
Mes
Mes
Cl
2.0 equiv 14
5 mol% 15
67%
Ru
O
4
10
Cl
15
Scheme 4. Improved synthesis of homoallylic alcohol diacetate 10.
For the crucial Prins cyclization of homoallylic alcohol 10
with p-anisaldehyde, reaction conditions of Willis and co-
workers7,10 were modified for maximum efficiency: in our
hands, use of 4 equiv of triethylsilyl triflate and 1 equiv of
trimethylsilyl acetate in 40 equiv of acetic acid worked
best producing the oxane product 9 stereoselectively in
60% yield. No sign of racemization was noticed originating
from oxonia-Cope rearrangement.13 Use of 2 equiv of boron
trifluoride diethyl etherate, 4 equiv of trimethylsilyl acetate,
and 4 equiv of acetic acid in cyclohexane produced 9 in 18–
26% yield. No oxane product was formed in the presence of
4 equiv of trifluoroacetic acid in trifluoromethylbenzene.
Under basic conditions, aldehyde 21 was converted into
a product mixture favoring the equatorial aldehyde 22 (22,
52%; 21, 25%). Epimerization at C50 (from 21 to 22) was ac-
companied by the diagnostic upfield shift of the aldehyde
proton signals in the 1H NMR spectra: the aldehyde proton
of 21 exhibits a singlet at d 9.68 compared to a doublet at
d 8.38 (J¼4.7 Hz) for the same proton of 22. The axial alde-
hyde 21 recovered could be recycled to produce an addi-
tional amount of 22. Julia–Julia reaction19 of the lithiated
sulfone 23 with aldehyde 22 proceeded smoothly, and
a 77% yield of the (E)-olefin 24 was obtained stereoselec-
tively (50:1). Crystals of 24 were obtained from carbon
tetrachloride–pentane solution and the crystallographic data
confirmed the assigned structure (Fig. 3).
At this point, radical cyclization routes toward the required
dioxabicyclodecane system were investigated. The triol ob-
tained via exhaustive hydrolysis of triacetate 9 was converted
into dibromide 16 in the presence of carbon tetrabromide and
triphenylphosphine. Reaction of 16 with (p-methoxyphe-
nyl)propynone in the presence of N-methylmorpholine pro-
duced b-alkoxyvinyl ketone 17. These type of vinyl ethers
are known to be viable precursors for radical cyclization.14
Unfortunately, reaction of 17 with tris(trimethylsilyl)silane
or tributylstannane in the presence of AIBN resulted in the
formation of complex product mixtures, and it was not pos-
sible to obtain the desired bicyclic product (Scheme 5).
Global demethylation of 24 was not possible under various
reaction conditions using Lewis acids: presumably, oxygen
atoms in the dioxabicyclodecane system presented more
basic sites. Eventually, blepharocalyxin D (1) was obtained
in acceptable yield using lithium propanethiolate in hot
HMPA20,21 (Scheme 6).
The synthetic sample of blepharocalyxin D (1) exhibited
variable specific rotation values, particularly in methanol.
Some values are [a]D22 ꢀ88.1 (c 0.43, MeOH), [a]2D2 ꢀ77.1
(c 0.11, MeOH), [a]2D2 ꢀ89.9 (c 0.027, MeOH), [a]2D3
ꢀ72.9 (c 0.32, acetone), and [a]2D4 ꢀ85.0 (c 0.31, MeOH–
DCM (1:1)). These values are at odds with the value reported
by Kadota and co-workers:1e,h [a]2D5 +18.5 (c 0.025, MeOH).
The synthetic sample has (3S)-configuration, but at this
point, determination of the absolute stereochemistry of the
Alternative ways for preparation of the dioxabicyclodecane
system were examined and a prominent possibility appeared
to be a second Prins cyclization. Exhaustive deacetylation of
9 led to the corresponding triol, which was converted into
thionocarbonate 18 in 67% yield. Cyclic acetal formation
of 18 with 3-(p-methoxyphenyl)propanal was accomplished
using ionic liquid [SOClMIm]Cl (19),15 and thermal

5800
H. M. Ko et al. / Tetrahedron 63 (2007) 5797–5805
original sample ([a]D14 ꢀ90.4 (c 0.32, CHCl3)) of 24,
which confirms the structure of the synthetic sample of
1 beyond any doubt.
In this synthesis, two oxane rings in blepharocalyxin D (1)
were constructed via two different types of Prins cyclization
reaction. The synthetic scheme adopts a highly modular
approach and the strategy may easily be adapted to library
synthesis.
3. Experimental
3.1. General
1H and 13C NMR spectra were obtained on Bruker DPX-300
(300 MHz), Bruker Avance-600 (600 MHz), and JEOL
ECX-400 (400 MHz). Chemical shift values were recorded
as parts per million relative to tetramethylsilane as an
internal standard unless otherwise indicated, and coupling
constants in Hertz. Mass spectra were recorded on a JEOL
JMS 600W spectrometer using electron impact (EI) or
chemical ionization (CI), and JEOL JMS AX505WA spec-
trometer using fast atom bombardment (FAB) method.
Significant fragments are reported in the following fashion:
m/z (relative intensity). Optical rotation data were obtained
on a Jasco P-1030 automatic polarimeter.
Figure 3. Crystal structure of 24. (One of the phenyl groups was statistically
disordered: the minor part of the disordered phenyl group is shown in broken
lines.)
Ar
O
Ar
1) K2CO3
S
9
2) PhOCSCl
pyridine
67%
O
OPh
H
OH
18
OH
O
S
Cl-
1) ArCH2CH2CHO
19
+
N
N
Cl
2) NaHCO3
diphenyl ether
reflux
The progress of the reaction was checked on TLC plates
(Merck 5554 Kiesel gel 60 F254), and the spots were visual-
ized under 254 nm UV light and/or by charring after dipping
the TLC plate into vanillin solution (9.0 g of vanillin and
1.5 mL of concentrated sulfuric acid in 300 mL of metha-
nol), KMnO4 solution (3 g of KMnO4, 20 g of K2CO3, and
5 mL of 5% NaOH solution in 300 mL of water), or phos-
phomolybdic acid solution (250 mg phosphomolybdic acid
in 50 mL ethanol). Column chromatography was performed
on silica gel (Merck 9385 Kiesel gel 60) using hexane–
EtOAc (v/v) or hexane–acetone (v/v). The solvents were
simple distilled unless otherwise noted.
19 [SOClMIm]Cl
55%
Ar
O
Ar
Ar
O
O
Ar
Ar
O
H
H
1.2 equiv BF3.OEt2, DCM
H
H
O
-55 ~ -20 °C, 3 h
O
83%
21
20
Ar
NaOH
52% (25% s.m.)
Ar
O
Ar
H
Ar
O
O
Ar
Ar
H
O
Unless otherwise specified, all reactions were conducted
under a slight positive pressure of dry nitrogen. The usual
work-up refers to washing the quenched reaction mixture
with brine, drying the organic extracts over anhydrous
MgSO4 or Na2SO4, and evaporating under reduced pressure
using a rotary evaporator.
23, LiHMDS
77%
Ar
H
H
H
O
(E:Z=50:1)
24
22
Ar
OMe
O2
MeI, K2CO3
acetone, reflux
91%
n-PrSLi, HMPA
160 ~ 170 °C
56%
N
S
All solvents used in reactions were dried under nitrogen at-
mosphere. THF was distilled from Na-benzophenone and
CH2Cl2 was distilled from P2O5. Et2O was distilled from
LAH. CH3CN was distilled from CaH2 and stored over
S
23
1
Scheme 6. Synthesis of blepharocalyxin D (1) via the second Prins cycliza-
tion of 20.
˚
4 A molecular sieves. Pyridine and TEA were distilled
˚
over KOH and stored over 4 A molecular sieves.
natural product is not possible. Examples of unreliable opti-
cal rotation values of related polyphenols have already been
reported by Rychnovsky and co-workers.3
Enantiomeric excesses were calculated from chiral HPLC
using a chiralcel OD-H column (flow rate 0.5 mL/min), or
from 1H NMR spectra of the (O)-acetyl-(S)-mandelate
derivatives.
A synthetic sample of blepharocalyxin D (1) was con-
verted back into the tetramethyl ether derivative 24 using
iodomethane and potassium carbonate in hot acetone. The
specific rotation of this sample ([a]2D3 ꢀ87.8 (c 0.065,
CHCl3)) was almost identical with the value of the
3.1.1. Homoallylic alcohol 4. Triethylamine (14.7 mL,
105 mmol) and SO3$pyridine (8.38 g, 52.6 mmol) were
added to a solution of alcohol 2 (4.37 g, 26.3 mmol) in

H. M. Ko et al. / Tetrahedron 63 (2007) 5797–5805
5801
DMSO–CH2Cl2 (1:1, 50 mL) at 0 ꢁC. The reaction mixture
was allowed to warm to room temperature and stirred for
20 min at this temperature. The reaction was quenched by
addition of saturated NH4Cl solution (40 mL) at 0 ꢁC. The
reaction mixture was extracted with CH2Cl2 (3ꢂ40 mL).
The organic extracts were washed with brine (40 mL), dried
over MgSO4, filtered, and concentrated. Purification of the
residue by flash column chromatography (Hex–EtOAc,
2:1) gave 3-(p-methoxyphenyl)propanal (4.14 g, 96%). Rf
0.68 (Hex–EtOAc, 2:1). 1H NMR (300 MHz, CDCl3):
d 9.82 (s, 1H), 7.12 (d, 2H, J¼8.5 Hz), 6.84 (d, 2H,
J¼8.5 Hz), 3.79 (s, 3H), 2.91 (t, 2H, J¼7.3 Hz), 2.75 (t,
2H, J¼7.3 Hz). 13C NMR (75 MHz, CDCl3): d 201.7,
157.9, 132.2, 129.1, 113.8, 55.0, 45.3, 27.1. IR (neat):
nmax¼3001, 2935, 2835, 2725, 1724, 1612, 1583, 1514,
1466, 1408, 1389, 1248, 1034 cmꢀ1. MS m/z (CI, relative in-
tensity): 165 (M++1, 15), 149 (23), 141 (34), 121 (100), 85
(9), 71 (8). HRMS (CI) calcd for C10H13O2 (M++1)
165.0915, found 165.0915.
(0.018 mL, 0.22 mmol) were then added. The reaction mix-
ture was stirred for 10 min and concentrated. Flash column
chromatography (Hex–EtOAc, 2:1) gave (O)-acetyl-(S)-
mandelate 5. Rf 0.61 (Hex–EtOAc, 2:1). 1H NMR
(300 MHz, CDCl3): d 7.48–7.36 (m, 6H), 7.06 (d, 2H,
J¼8.4 Hz), 6.81 (d, 2H, J¼8.4 Hz), 5.94–5.89 (m, 1H),
5.42 (ddt, 1H, J¼16.4, 10, 7.2 Hz), 4.98–4.92 (m, 1H),
4.81 (d, 1H, J¼9.5 Hz), 4.78 (d, 1H, J¼17.2 Hz), 3.78 (s,
3H), 3.72 (s, 1H), 2.65–2.51 (m, 2H), 2.20 (s, 6H), 1.92–
1.79 (m, 2H).
3.1.3. Alcohol 10. Olefin 14 (20 mg, 0.11 mmol) and homo-
allylic alcohol 4 (11 mg, 0.053 mmol) were added to a solu-
tion of the Hoveyda–Grubbs second generation catalyst 15
(2 mg, 5 mol %) in CH2Cl2 (1 mL) at room temperature un-
der Ar. The reaction mixture was stirred for 24 h at this tem-
perature. Concentration and purification of the residue by
flash column chromatography (Hex–EtOAc, 2:1) gave alco-
1
hol 10 (13 mg, 67%). Rf 0.22 (Hex–EtOAc, 2:1). H NMR
(300 MHz, CDCl3): d 7.12 (d, 2H, J¼8.5 Hz), 6.83 (d, 2H,
J¼8.6 Hz), 5.70–5.56 (m, 1H), 5.42 (dd, 1H, J¼15.5,
8.0 Hz), 4.15–4.02 (m, 4H), 3.79 (s, 3H), 3.62 (br, 1H),
2.79–2.58 (m, 3H), 2.27 and 2.15 (ABX2, 2H, JAB¼13.5,
JAX¼6.3, JBX¼7.1 Hz), 2.04 (s, 6H), 1.77–1.69 (m, 3H).
13C NMR (75 MHz, CDCl3): d 170.94, 170.92, 157.7,
133.9, 130.1, 130.0, 129.2, 113.7, 69.8, 64.15, 64.11, 55.2,
41.2, 40.8, 38.6, 31.0, 20.8. IR (neat): nmax¼3464, 2935,
1739, 1612, 1583, 1514, 1466, 1367, 1246, 1178,
1038 cmꢀ1. MS m/z (CI, relative intensity): 365 (M++1, 5),
305 (29), 287 (49), 227 (100), 147 (18), 140 (18), 121
(61). HRMS (CI) calcd for C20H29O6 (M++1) 365.1964,
found 365.1964. [a]2D7 ꢀ4.6 (c 0.78, CHCl3).
A solution of TiCl4 (0.099 mL, 0.90 mmol) in CH2Cl2
(18 mL) at 0 ꢁC was treated with Ti(OiPr)4 (0.804 mL,
2.70 mmol) under Ar. The mixture was allowed to warm to
room temperature and stirred for 1 h at this temperature. Sil-
ver oxide (Ag2O, 0.417 g, 1.80 mmol) was added at room
temperature and the whole reaction mixture was stirred for
5 h with exclusion of direct light. The reaction mixture
was diluted with CH2Cl2 (36 mL) and treated with (R)-
BINOL (1.03 g, 3.60 mmol) at room temperature for 2 h to
furnish catalyst 3. The catalyst 3 thus generated was cooled
to ꢀ15 ꢁC and treated with 3-(p-methoxyphenyl)-propanal
(2.96 g, 18.0 mmol) in CH2Cl2 (1 mL) and allyltributylstan-
nane (11 mL, 36 mmol). The reaction mixture was allowed
to warm to 0 ꢁC and stirred for 7 h. The reaction was
quenched with saturated NaHCO3 (40 mL) and the reaction
mixture was extracted with ether (3ꢂ40 mL). The organic
extracts were dried over Na2SO4 and concentrated. Flash
chromatography of the residue on silica gel (Hex–EtOAc,
2:1) gave homoallylic alcohol 4 (3.5 g, 94%, 92% ee). Rf
0.44 (Hex–EtOAc, 2:1). The enantiomeric excess was deter-
mined by chiral HPLC (Chiralcel OD-H, 10% isopropanol/
hexane, 0.5 mL/min): tR¼10.0 min (S-isomer), 10.9 min
3.1.4. Aldehyde 12. Anisaldehyde dimethylacetal (0.77 mL,
4.5 mmol) and CSA (44 mg, 0.19 mmol) were added to a so-
lution of triol 11 (401 mg, 3.78 mmol) in CH2Cl2 (20 mL) at
room temperature. The reaction mixture was stirred for 2 h.
The reaction was quenched by addition of TEA (0.6 mL).
Concentration and purification by flash column chromato-
graphy (Hex–EtOAc, 1:1) gave the cyclic acetal alcohol
(835 mg, 98%). Rf 0.22 (Hex–EtOAc, 1:1).
1
(R-isomer). H NMR (300 MHz, CDCl3): d 7.12 (d, 2H,
Triethylamine (4.37 mL, 31.3 mmol) and SO3$pyridine
(2.5 g, 16 mmol) were added to a solution of cyclic acetal al-
cohol (1.76 g, 7.84 mmol) in DMSO–CH2Cl2 (1:1, 18 mL)
at 0 ꢁC. The reaction mixture was allowed to warm to
room temperature and stirred for 20 min. The reaction was
quenched by addition of saturated NH4Cl solution (15 mL)
at 0 ꢁC. The reaction mixture was extracted with CH2Cl2
(3ꢂ15 mL). The organic extracts were washed with brine
(15 mL), dried over MgSO4, filtered, and concentrated. Pu-
rification of the residue by flash chromatography (Hex–
EtOAc, 1:1) gave aldehyde 12 (1.58 g, 91%). Rf 0.37
(Hex–EtOAc, 1:1).
J¼8.4 Hz), 6.83 (d, 2H, J¼8.4 Hz), 5.82 (ddt, 1H, J¼16.9,
10.1, 7.1 Hz), 5.14 (d, 2H, J¼12.6 Hz), 3.78 (s, 3H), 3.71–
3.62 (m, 1H), 2.80–2.58 (m, 2H), 2.30 and 2.19 (ABX2,
2H, JAB¼13.3, JAX¼7.0, JBX¼7.2 Hz), 1.79–1.67 (m, 2H),
1.57 (d, 1H, J¼4.2 Hz). 13C NMR (75 MHz, CDCl3):
d 157.7, 134.6, 134.0, 129.3, 118.3, 113.8, 69.8, 55.2,
42.0, 38.6, 31.1. IR (neat): nmax¼3348, 3072, 3032, 3003,
2927, 1612, 1514, 1469, 1454, 1335, 1300, 1246,
1034 cmꢀ1. MS m/z (EI, relative intensity): 206 (M+, 22),
188 (5), 147 (20), 122 (11), 121 (100), 91 (4), 70 (4).
HRMS (EI) calcd for C13H18O2 (M+) 206.1307, found
206.1307. [a]1D1 ꢀ19.5 (c 0.55, CHCl3).
3.1.5. Diol 13. A solution of n-BuLi (2.5 M in hexane,
1.46 mL) was added dropwise to a solution of PPh3Me+Brꢀ
(1.45 g, 4.07 mmol) in THF (6 mL) at ꢀ78 ꢁC under Ar. The
reaction mixture was stirred for 20 min at this temperature.
The ylide thus generated was treated with aldehyde 12
(452 mg, 2.03 mmol) in THF (4 mL). The reaction mixture
was stirred for 1 h at ꢀ78 ꢁC and warmed to 0 ꢁC over
30 min. The reaction mixture was diluted with ether
3.1.2. (O)-Acetyl-(S)-mandelate 5. Oxalyl chloride
(0.634 mL, 7.30 mmol) was added to a solution of (S)-(+)-
(O)-acetylmandelic acid (141 mg, 0.730 mmol) in CH2Cl2
(0.5 mL) at room temperature. The reaction mixture was
stirred for 1.5 h and the residual oxalyl chloride was thor-
oughly evaporated in vacuo. Homoallylic alcohol 4
(15 mg, 0.073 mmol) in CH2Cl2 (0.5 mL) and pyridine

5802
H. M. Ko et al. / Tetrahedron 63 (2007) 5797–5805
(10 mL) and treated with acetone (10 mL). The reaction
mixture was filtered through a short pad of silica gel. Con-
centration of the filtrate and purification of the residue by
flash chromatography (Hex–EtOAc, 4:1) gave a mixture of
the cyclic acetal olefins (isomer-1 (cis), 86 mg, 19%; iso-
mer-2 (trans), 172 mg, 39%). Isomer-1, Rf 0.65 (Hex–
3.1.7. Oxane 9. Anisaldehyde (0.0053 mL, 0.047 mmol)
and TMSOAc (0.0060 mL, 0.039 mmol) were added to a so-
lution of homoallylic alcohol 10 (14 mg, 0.039 mmol) in
AcOH (0.090 mL, 1.6 mmol) at room temperature. TESOTf
(0.040 mL, 0.16 mmol) was added dropwise to the resulting
solution at the same temperature. The reaction mixture was
stirred for 1 h, diluted with CH2Cl2 (2 mL), and treated with
TEA (0.1 mL). Concentration and purification of the residue
by flash column chromatography (Hex–EtOAc, 1:1) gave
oxane 9 (13 mg, 60%). Rf 0.57 (Hex–EtOAc, 1:1). 1H
NMR (300 MHz, CDCl3): d 7.27 (d, 2H, J¼9.3 Hz), 7.03
(d, 2H, J¼8.6 Hz), 6.91 (d, 2H, J¼8.6 Hz), 6.80 (d, 2H,
J¼8.6 Hz), 5.02 (dt, 1H, J¼10.8, 4.7 Hz), 4.24 (d, 1H, J¼
10.5 Hz), 4.10 (dd, 1H, J¼11, 7.9 Hz), 3.96 (dd, 1H,
J¼11, 7.0 Hz), 3.87 (d, 2H, J¼6.0 Hz), 3.82 (s, 3H), 3.78
(s, 3H), 3.51–3.41 (m, 1H), 2.69–2.52 (m, 2H), 2.25–2.20
(m, 1H), 2.14 (t, 1H, J¼11.3 Hz), 2.08 (s, 3H), 2.03 (s,
3H), 1.97 (s, 3H), 1.94–1.89 (m, 1H), 1.87–1.80 (m, 1H),
1.75–1.64 (m, 1H), 1.43 (q, 1H, J¼11.4 Hz). 13C NMR
(75 MHz, CDCl3): d 170.5, 170.0, 159.7, 157.8, 133.8,
131.8, 129.3, 129.0, 114.1, 113.7, 81.1, 74.3, 72.3, 64.4,
62.0, 55.3, 55.2, 45.8, 37.8, 37.3, 36.2, 30.4, 21.4, 20.8. IR
(neat): nmax¼2952, 2837, 1739, 1612, 1585, 1514, 1464,
1367, 1246, 1178, 1036 cmꢀ1. MS m/z (FAB, relative inten-
sity): 542 (M+, 4), 483 (10), 282 (11), 154 (60), 121 (100), 69
(64), 55 (76), 43 (61). HRMS (FAB) calcd for C30H38O9
(M+) 542.2516, found 542.2523. [a]1D3 ꢀ22.6 (c 0.55,
CHCl3).
1
EtOAc, 4:1). H NMR (300 MHz, CDCl3): d 7.41 (d, 2H,
J¼8.6 Hz), 6.89 (d, 2H, J¼8.6 Hz), 5.53 (ddd, 1H, J¼
17.5, 10.3, 7.4 Hz), 5.39 (s, 1H), 5.17 (d, 1H, J¼18.8 Hz),
5.15 (d, 1H, J¼9.5 Hz), 4.21 (dd, 2H, J¼11.5, 4.7 Hz),
3.80 (s, 3H), 3.70 (t, 2H, J¼11.4 Hz), 2.86–2.80 (m, 1H).
13C NMR (75 MHz, CDCl3): d 160.0, 133.6, 130.9, 127.4,
118.0, 113.7, 101.2, 71.3, 55.3, 38.9. Isomer-2, Rf 0.57
1
(Hex–EtOAc, 4:1). H NMR (300 MHz, CDCl3): d 7.41
(d, 2H, J¼8.6 Hz), 6.89 (d, 2H, J¼8.6 Hz), 6.38 (ddd, 1H,
J¼17.6, 10.2, 7.6 Hz), 5.50 (s, 1H), 5.28 (d, 1H, J¼
17.4 Hz), 5.21 (d, 1H, J¼10.5 Hz), 4.19–4.10 (m, 4H),
3.80 (s, 3H), 2.19–2.17 (m, 1H). 13C NMR (75 MHz,
CDCl3): d 160.0, 138.3, 131.1, 127.4, 116.0, 113.6, 101.7,
71.0, 55.3, 38.5. IR (neat): nmax¼3070, 2964, 2910, 2850,
1614, 1518, 1464, 1387, 1304, 1248, 1171, 1032 cmꢀ1
.
MS m/z (CI, relative intensity): 221 (M++1, 100), 220 (17),
219 (14), 137 (31), 113 (61), 67 (13). HRMS (CI) calcd
for C13H17O3 (M++1) 221.1178, found 221.1178.
Ceric ammonium nitrate (6.8 g, 12 mmol) was added to a
solution of the olefin isomers (544 mg, 2.47 mmol) in
CH3CN–H2O (9:1, 56 mL) at 0 ꢁC. The reaction mixture
was allowed to warm to room temperature and stirred for
20 min. The reaction mixture was diluted with EtOAc and
treated with saturated NaHCO3 (40 mL) at 0 ꢁC. The mix-
ture was extracted with EtOAc (3ꢂ40 mL) and the organic
extracts were dried over Na2SO4, filtered, and concentrated.
Purification of the residue by flash chromatography (Hex–
EtOAc, 1:1) gave diol 13 (205 mg, 81%). Rf 0.11 (Hex–
EtOAc, 1:1). 1H NMR (300 MHz, CDCl3): d 5.77–5.65
(m, 1H), 5.21 (dd, 1H, J¼11, 0.7 Hz), 5.20 (d, 1H, J¼
16.9 Hz), 3.76 (d, 4H, J¼6.2 Hz), 2.54 (dq, 1H, J¼6.4,
6.4 Hz), 2.21 (br, 2H). 13C NMR (75 MHz, CDCl3):
d 135.6, 118.1, 64.7, 47.5. IR (neat): nmax¼3400, 2927,
1643, 1425, 1032 cmꢀ1. MS m/z (CI, relative intensity):
103 (M++1, 16), 89 (21), 85 (69), 67 (100), 57 (58), 55
(46), 54 (20). HRMS (CI) calcd for C5H11O2 (M++1)
103.0759, found 103.0759.
3.1.8. Thionocarbonate 18. Potassium carbonate (1.53 g,
11.1 mmol) was added to a solution of oxane 9 (602 mg,
1.11 mmol) in MeOH (30 mL) at room temperature. The re-
action mixture was stirred for 3 h, concentrated, and diluted
with H2O (20 mL). The reaction mixture was extracted with
ether (3ꢂ20 mL), the organic extracts were dried over
MgSO4, and filtered. Concentration and purification of the
residue by flash chromatography (Hex–acetone, 1:1) gave
the corresponding triol (392 mg, 85%). Rf 0.26 (Hex–ace-
1
tone, 1:1). H NMR (300 MHz, CDCl3): d 7.24 (d, 2H,
J¼8.0 Hz), 7.04 (d, 2H, J¼8.6 Hz), 6.87 (d, 2H,
J¼8.6 Hz), 6.79 (d, 2H, J¼8.6 Hz), 4.98 (br, 1H), 4.31 (br,
1H), 4.11 (d, 1H, J¼10.4 Hz), 3.78 (s, 3H), 3.76 (s, 3H),
3.69 (br, 2H), 3.60 (d, 1H, J¼8.3 Hz), 3.41–3.34 (m, 2H),
3.20 (br, 1H), 2.68–2.52 (m, 2H), 2.02 (dd, 1H, J¼12.0,
3.6 Hz), 1.93–1.81 (m, 1H), 1.77–1.65 (m, 2H), 15.9–1.58
(m, 1H), 1.42 (q, 1H, J¼11.5 Hz). 13C NMR (75 MHz,
CDCl3): d 159.4, 157.7, 134.0, 132.7, 129.3, 129.0, 114.0,
113.7, 81.6, 74.5, 68.2, 64.0, 60.2, 55.22, 55.20, 51.5,
41.1, 40.8, 37.4, 30.4. IR (neat): nmax¼3334, 2937, 1612,
3.1.6. Olefin 14. Acetic anhydride (0.16 mL, 1.7 mmol),
TEA (0.38 mL, 2.8 mmol), and DMAP (4.2 mg,
0.035 mmol) were added to a solution of diol 13 (70.6 mg,
0.690 mmol) in CH2Cl2 (7 mL) at room temperature. The re-
action mixture was stirred for 1 h, quenched with saturated
NH4Cl (10 mL), and extracted with CH2Cl2 (3ꢂ10 mL).
The organic extracts were dried over MgSO4 and concen-
trated. Flash column chromatography (Hex–EtOAc, 2:1)
gave olefin 14 (107 mg, 83%). Rf 0.57 (Hex–EtOAc, 2:1).
1H NMR (300 MHz, CDCl3): d 5.72 (ddd, 1H, J¼17.6, 10,
7.7 Hz), 5.193 (d, 1H, J¼16 Hz), 5.186 (d, 1H, J¼
11.8 Hz), 4.18–4.07 (m, 4H), 2.75 (dq, 1H, J¼6.5, 6.5 Hz),
2.06 (s, 6H). 13C NMR (75 MHz, CDCl3): d 170.9, 134.6,
118.2, 63.9, 41.8, 20.8. IR (neat): nmax¼3084, 2958, 1745,
1645, 1427, 1381, 1367, 1227, 1039 cmꢀ1. MS m/z (CI, rel-
ative intensity): 187 (M++1, 2), 127 (100), 89 (6), 85 (4), 67
(12), 61 (4). HRMS (CI) calcd for C9H15O4 (M++1)
187.0970, found 187.0970.
1585, 1514, 1464, 1369, 1300, 1248, 1178, 1034 cmꢀ1
.
MS m/z (FAB, relative intensity): 417 (M++1, 6), 399 (10),
191 (12), 154 (25), 121 (100), 55 (24), 43 (17). HRMS
(FAB) calcd for C24H33O6 (M++1) 417.2277, found
417.2290. [a]1D3 ꢀ50.9 (c 0.56, CHCl3).
Phenyl chlorothionoformate (0.0061 mL, 0.044 mmol) and
pyridine (0.0060 mL, 0.073 mmol) were added to a solution
of triol (15 mg, 0.037 mmol) in CH2Cl2 (3 mL) at 0 ꢁC. The
reaction mixture was allowed to warm to room temperature
and stirred for 20 min. Concentration and purification of
the residue by flash chromatography (Hex–acetone, 1:1)
gave thionocarbonate 18 (16 mg, 80%). Rf 0.42 (Hex–
1
acetone, 1:1). H NMR (300 MHz, CDCl3): d 7.40 (t, 2H,

H. M. Ko et al. / Tetrahedron 63 (2007) 5797–5805
5803
J¼7.7 Hz), 7.29 (d, 1H, J¼7.0 Hz), 7.27 (d, 2H, J¼6.8 Hz),
7.07 (d, 2H, J¼8.4 Hz), 7.04 (d, 2H, J¼7.5 Hz), 6.90 (d, 2H,
J¼8.6 Hz), 6.81 (d, 2H, J¼8.5 Hz), 4.81–4.70 (m, 1H), 4.42
(dd, 1H, J¼10.9, 5.9 Hz), 4.13 (d, 1H, J¼10.4 Hz), 4.04–
3.99 (m, 1H), 3.84–3.76 (m, 8H), 3.48–3.41 (m, 1H), 3.03
(br, 1H), 2.63 (t, 2H, J¼7.5 Hz), 2.17 (br, 1H), 2.09–2.02
(m, 2H), 1.97–1.84 (m, 1H), 1.81–1.69 (m, 2H), 1.52 (q,
1H, J¼11.9 Hz).
The reaction mixture was stirred for 3 h at the same temper-
ature, allowed to warm to ꢀ20 ꢁC, and stirred for 15 min.
The reaction was quenched with saturated NH4Cl (20 mL)
and the reaction mixture was extracted with CH2Cl2
(3ꢂ20 mL). The organic extracts were dried over Na2SO4.
Purification by flash chromatography (Hex–EtOAc, 2:1)
gave aldehyde 21 (526 mg, 83%). Rf 0.51 (Hex–EtOAc,
1
2:1). H NMR (300 MHz, CDCl3): d 9.68 (s, 1H), 7.23 (d,
2H, J¼7.1 Hz), 7.07 (d, 4H, J¼8.5 Hz), 6.87 (d, 2H,
J¼6.8 Hz), 6.81 (d, 4H, J¼8.6 Hz), 4.65 (d, 1H, J¼
10.5 Hz), 3.84–3.75 (m, 10H), 3.60–3.53 (m, 1H), 3.44–
3.35 (m, 1H), 2.76–2.53 (m, 4H), 2.32 (t, 1H, J¼4.2 Hz),
2.06–2.01 (m, 1H), 1.99–1.94 (m, 1H), 1.91–1.80 (m, 1H),
1.78–1.73 (m, 3H), 1.66–1.62 (m, 1H), 1.55–1.43 (m, 2H).
13C NMR (75 MHz, CDCl3): d 203.3, 159.5, 157.8, 157.7,
134.1, 134.0, 131.7, 129.33, 129.26, 128.5, 114.0, 113.80,
113.76, 78.5, 75.0, 74.3, 72.7, 55.3, 55.2, 49.1, 45.7, 38.6,
38.0, 37.8, 31.8, 30.7, 30.5. IR (neat): nmax¼2935, 2835,
1720, 1612, 1583, 1514, 1464, 1300, 1246, 1178, 1068,
1036 cmꢀ1. MS m/z (FAB, relative intensity): 545 (M++1,
11), 307 (25), 289 (12), 154 (100), 121 (70), 107 (21), 89
(16). HRMS (FAB) calcd for C34H41O6 (M++1) 545.2903,
found 545.2894. [a]1D6 ꢀ32.1 (c 0.23, CHCl3).
3.1.9. Acetal 20. A solution of thionyl chloride (0.123 mL,
1.72 mmol) in CH3CN (0.2 mL) was treated dropwise
with 1-methylimidazole (0.134 mL, 1.72 mmol) at room
temperature. The reaction mixture was stirred for 12 h and
concentrated. Residual CH3CN, thionyl chloride, and 1-
methylimidazole were removed in vacuo at 150 ꢁC. The
ionic liquid 19 generated was diluted with CH2Cl2 (3 mL).
The resulting solution was treated with 3-(p-methoxyphe-
nyl)propanal (24 mg, 0.15 mmol) and thionocarbonate 18
(68 mg, 0.12 mmol) in CH2Cl2 (3 mL). The mixture was
heated under reflux for 90 min and treated with H2O
(6 mL). The reaction mixture was extracted with ether
(3ꢂ6 mL) and the organic extracts were dried over
Na2SO4. Concentration and purification of the residue by
flash chromatography (Hex–EtOAc, 2:1) gave the corre-
sponding cyclic acetal (60 mg, 69%). Rf 0.44 (Hex–EtOAc,
2:1). 1H NMR (300 MHz, CDCl3): d 7.38 (t, 2H, J¼7.8 Hz),
7.30–7.23 (m, 3H), 7.12–7.00 (m, 6H), 6.89 (d, 2H,
J¼8.5 Hz), 6.83 (d, 2H, J¼8.3 Hz), 6.81 (d, 2H, J¼
8.4 Hz), 4.50 (t, 1H, J¼5.1 Hz), 4.31 (t, 1H, J¼10.4 Hz),
4.07 (dd, 1H, J¼13.3, 2.8 Hz), 3.97 (d, 1H, J¼10.2 Hz),
3.86–3.78 (m, 11H), 3.63 (dd, 1H, J¼10.3, 4.5 Hz), 3.44–
3.37 (m, 1H), 2.70–2.62 (m, 4H), 2.07–2.00 (m, 1H),
1.96–1.87 (m, 3H), 1.82–1.73 (m, 2H), 1.66–1.52 (m, 2H).
13C NMR (75 MHz, CDCl3): d 194.2, 159.7, 157.8, 157.7,
153.3, 133.9, 133.7, 131.8, 129.4, 129.3, 129.0, 126.4,
121.9, 114.1, 113.8, 113.7, 105.9, 82.7, 79.0, 74.6, 73.9,
66.9, 55.3, 55.2, 50.2, 39.3, 39.1, 37.4, 36.4, 30.4, 29.9. IR
(neat): nmax¼2951, 2835, 1612, 1585, 1512, 1464, 1379,
1298, 1246, 1201, 1136, 1036 cmꢀ1. MS m/z (FAB, relative
intensity): 698 (M+, 2), 535 (9), 399 (8), 173 (15), 121 (100),
55 (20), 43 (13). HRMS (FAB) calcd for C41H46O8S (M+)
698.2913, found 698.2928.
3.1.11. Aldehyde 22. A solution of aldehyde 21 (526 mg,
0.970 mmol) in THF (15 mL) was treated with NaOH solu-
tion (2 N, 15 mL). The reaction mixture was heated under re-
flux for 4 h and treated with saturated NH4Cl (20 mL). The
mixture was extracted with ether (3ꢂ20 mL), the organic ex-
tracts were washed with brine (20 mL), dried over MgSO4,
filtered, and concentrated. Purification of the residue by
flash chromatography (Hex–EtOAc, 2:1) gave aldehyde 22
(272 mg, 52%). Rf 0.37 (Hex–EtOAc, 2:1). Aldehyde 21
1
(133 mg, 25%) was also recovered. H NMR (300 MHz,
CDCl3): d 8.38 (d, 1H, J¼4.7 Hz), 7.21 (br, 2H), 7.10–
7.06 (m, 4H), 6.86–6.80 (m, 6H), 3.91 (d, 1H, J¼9.6 Hz),
3.79 (s, 9H), 3.58–3.51 (m, 1H), 3.36–3.28 (m, 2H), 2.75–
2.57 (m, 4H), 2.24–2.13 (m, 1H), 2.06 (dd, 1H, J¼12.2,
2.1 Hz), 2.01–1.87 (m, 2H), 1.85–1.77 (m, 2H), 1.74–1.61
(m, 2H), 1.50–1.41 (m, 1H), 1.31 (q, 1H, J¼11.6 Hz). 13C
NMR (75 MHz, CDCl3): d 200.0, 160.1, 157.83, 157.75,
134.0, 133.7, 131.0, 129.33, 129.30, 113.8, 113.7, 82.0,
77.9, 75.2, 74.7, 55.25, 55.21, 49.7, 47.6, 37.9, 37.73,
37.65, 32.2, 30.5, 30.4. IR (neat): nmax¼2937, 2837, 1720,
1612, 1583, 1512, 1464, 1300, 1246, 1176, 1132,
1034 cmꢀ1. MS m/z (EI, relative intensity): 544 (M+, 20),
526 (14), 366 (24), 323 (11), 147 (14), 121 (100). HRMS
(EI) calcd for C34H40O6 (M+) 544.2825, found 544.2825.
[a]1D6 ꢀ30.0 (c 0.34, CHCl3).
A solution of the cyclic acetal (1.01 g, 1.44 mmol) in di-
phenyl ether (20 mL) was treated with NaHCO3 (0.61 g,
7.2 mmol). The reaction mixture was heated under reflux
for 3 h. Flash chromatography (Hex–EtOAc, 2:1) gave the
methylidene-substituted cyclic acetal 20 (619 mg, 79%). Rf
0.49 (Hex–EtOAc, 2:1). 1H NMR (300 MHz, CDCl3):
d 7.24 (d, 2H, J¼8.3 Hz), 7.08 (d, 4H, J¼8.2 Hz), 6.83 (t,
6H, J¼8.2 Hz), 4.96 (s, 1H), 4.77 (s, 1H), 4.63 (t, 1H,
J¼5.5 Hz), 4.39 (d, 1H, J¼10.7 Hz), 4.21 and 4.07 (ABq,
2H, J¼12.6 Hz), 3.78 (s, 9H), 3.54–3.41 (m, 2H), 2.71–
2.62 (m, 5H), 2.08 (dd, 1H, J¼12.8, 3.1 Hz), 1.99–1.87
(m, 3H), 1.80–1.69 (m, 1H), 1.56 (q, 1H, J¼11.8 Hz). 13C
NMR (75 MHz, CDCl3): d 159.2, 157.8, 157.7, 145.4,
134.0, 133.7, 132.4, 129.4, 129.3, 129.2, 116.6, 113.84,
113.79, 113.74, 113.65, 100.2, 80.7, 79.9, 74.8, 74.6,
55.24, 55.19, 51.9, 38.3, 37.5, 37.4, 30.5, 30.0.
3.1.12. Sulfone 23. A solution of 2-mercaptobenzothiazole
(3.03 g, 18.1 mmol) and diethyl azodicarboxylate
(2.85 mL, 18.1 mmol) in THF (20 mL) was added to a solu-
tion of p-methoxybenzyl alcohol (1.81 mL, 14.5 mmol) and
PPh3 (4.75 g, 18.1 mmol) in THF (20 mL) at 0 ꢁC. The mix-
ture was warmed to room temperature and stirred for 6 h.
The reaction mixture was concentrated and purified by flash
chromatography (Hex–EtOAc, 2:1) to give the correspond-
1
ing sulfide (4.16 g, 100%). Rf 0.71 (Hex–EtOAc, 2:1). H
NMR (300 MHz, CDCl3): d 7.89 (d, 1H, J¼8.1 Hz), 7.72
(dd, 1H, J¼8.0, 0.6 Hz), 7.43–7.33 (m, 3H), 7.30–7.23 (m,
1H), 6.86–6.82 (m, 2H), 4.54 (s, 1H), 3.76 (s, 3H). 13C
NMR (75 MHz, CDCl3): d 166.5, 159.1, 153.1, 135.2,
3.1.10. Aldehyde 21. A solution of acetal 20 (619 mg,
1.14 mmol) in CH2Cl2 (20 mL) was cooled to ꢀ55 ꢁC and
treated dropwise with BF3$OEt2 (0.173 mL, 1.36 mmol).

5804
H. M. Ko et al. / Tetrahedron 63 (2007) 5797–5805
130.3, 127.9, 126.0, 124.2, 121.4, 120.9, 114.0, 55.2, 37.2.
IR (neat): nmax¼3047, 2962, 2927, 2837, 1614, 1516,
1456, 1427, 1309, 1257, 1037 cmꢀ1. MS m/z (CI, relative in-
tensity): 288 (M++1, 34), 410 (12), 409 (27), 408 (100), 289
(8), 287 (21), 121 (44). HRMS (CI) calcd for C15H14NOS2
(M++1) 288.0517, found 288.0517.
was quenched with saturated aqueous NH4Cl solution (3 mL)
and H2O (2 mL), and the mixture was extracted with EtOAc
(3ꢂ5 mL). The organic extracts were dried over Na2SO4.
Concentration and purification of the residue by flash chro-
matography (CHCl3–MeOH, 10:1) gave blepharocalyxin D
1
(1, 17 mg, 56%). Rf 0.2 (CHCl3–MeOH, 10:1). H NMR
(300 MHz, CD3OD): d 7.08 (br, 2H), 6.98 (t, 4H,
J¼7.8 Hz), 6.70–6.52 (m, 10H), 5.75 (d, 1H, J¼15.8 Hz),
5.00 (dd, 1H, J¼15.7, 8.6 Hz), 3.97 (d, 1H, J¼9.8 Hz),
3.53–3.48 (m, 2H), 3.41–3.34 (m, 1H), 2.70–2.52 (m, 4H),
2.20–2.11 (m, 1H), 2.01–1.97 (m, 1H), 1.88–1.78 (m, 1H),
1.75–1.66 (m, 2H), 1.63–1.56 (m, 2H), 1.54–1.46 (m, 2H),
1.26 (q, 1H, J¼12.1 Hz). 13C NMR (75 MHz, CD3OD):
d 158.2, 157.0, 156.38, 156.35, 134.23, 134.19, 133.5,
132.7, 131.0, 130.4, 130.3, 128.6, 128.0, 116.1, 116.0,
115.7, 84.4, 80.6, 77.3, 76.4, 52.2, 43.1, 41.8, 39.4, 39.2,
31.8, 31.6. IR (neat): nmax¼3375, 3022, 2976, 2931, 1660,
1614, 1514, 1446, 1383, 1230, 1101 cmꢀ1. MS m/z (FAB,
relative intensity): 591 (Mꢀꢀ1, 3), 306 (57), 266 (56), 199
(35), 153 (100), 113 (73), 46 (32). HRMS (FAB) calcd for
C38H39O6 (Mꢀꢀ1) 591.2747, found 591.2734.
A solution of the sulfide (3.32 g, 11.0 mmol) in CH2Cl2
(40 mL) was treated with m-CPBA (9.45 g, 54.8 mmol)
and NaHCO3 (9.20 g, 110 mmol) at room temperature.
The reaction mixture was stirred for 5 h and treated with
the aqueous solution saturated with NaHCO3 and Na2S2O3
(30 mL). The reaction mixture was extracted with EtOAc
(3ꢂ40 mL). The organic extracts were washed with brine
(40 mL), dried over Na2SO4, filtered, and concentrated.
Purification of the residue by flash chromatography (Hex–
EtOAc, 2:1) gave sulfone 23 (3.50 g, quant.). Rf 0.43 (Hex–
1
EtOAc, 2:1). H NMR (300 MHz, CDCl3): d 8.25 (d, 1H,
J¼7.9 Hz), 7.96–7.93 (m, 1H), 7.67–7.55 (m, 2H), 7.18 (d,
2H, J¼8.7 Hz), 6.79 (d, 2H, J¼8.7 Hz), 4.70 (s, 2H), 3.76
(s, 3H). 13C NMR (75 MHz, CDCl3): d 165.5, 160.3,
152.6, 137.1, 132.3, 127.9, 127.6, 125.4, 122.3, 118.1,
114.4, 60.4, 55.2. IR (neat): nmax¼3020, 2974, 2927, 2843,
1610, 1514, 1466, 1325, 1257, 1147, 1026 cmꢀ1. MS m/z
(CI, relative intensity): 320 (M++1, 14), 440 (32), 257
(13), 256 (77), 122 (9), 121 (100). HRMS (CI) calcd for
C15H14NO3S2 (M++1) 320.0415, found 320.0415.
3.1.15. Tetramethyl blepharocalyxin D (24) from 1. A
mixture of blepharocalyxin D (1, 1.3 mg, 0.0022 mmol),
K2CO3 (3.0 mg, 0.022 mmol), and MeI (0.01 mL,
0.022 mmol) in acetone (2 mL) was heated under reflux
for 4 h. The reaction mixture was filtered to remove
K2CO3 and concentrated. The residue was dissolved in
EtOAc and washed with water. The organic layer was dried
over Na2SO4 and evaporated under reduced pressure. Purifi-
cation by flash chromatography (Hex–EtOAc, 2:1) gave
tetramethyl blepharocalyxin D (24, 1.3 mg, 91%). [a]D23
ꢀ87.8 (c 0.065, CHCl3).
3.1.13. Tetramethyl blepharocalyxin D (24). A solution of
sulfone 23 (248 mg, 0.780 mmol) in THF (10 mL) was
cooled to ꢀ78 ꢁC and treated dropwise with LiHMDS
(1.0 M in THF, 1.62 mL) under Ar. The reaction mixture
was stirred for 20 min and treated with aldehyde 22
(353 mg, 0.650 mmol) in THF (10 mL). The reaction mix-
ture was stirred for 3 h at the same temperature and allowed
to warm to room temperature, stirred for 3 h, and treated
with H2O (15 mL). The reaction mixture was extracted
with ether (3ꢂ20 mL), the organic extracts were dried
over MgSO4, and concentrated. Purification of the residue
by flash chromatography (Hex–EtOAc, 2:1) gave tetra-
methyl blepharocalyxin D (24, 323 mg, 77%). Rf 0.57
Acknowledgements
This work was supported by a grant from the Korea Research
Foundation (MOEHRD) (KRF-2005-070-C00073) and a
grant from Center for Bioactive Molecular Hybrids (Yonsei
University and KOSEF). Brain Korea 21 graduate fellowship
grants to H.M.K., D.G.L., M.A.K., and H.J.K. are gratefully
acknowledged. The authors thank Prof. Kadota of Toyama
Medical and Pharmaceutical University for providing
spectroscopic data of the natural sample of blepharo-
calyxin D (1).
1
(Hex–EtOAc, 2:1). H NMR (300 MHz, CDCl3): d 7.14
(br, 1H), 7.08 (t, 5H, J¼8.8 Hz), 6.81 (t, 4H, J¼7.5 Hz),
6.72–6.65 (m, 6H), 5.70 (d, 1H, J¼15.8 Hz), 4.98 (dd, 1H,
J¼15.8, 8.8 Hz), 3.94 (d, 1H, J¼9.7 Hz), 3.78 (d, 6H,
J¼2.2 Hz), 3.75 (s, 3H), 3.52–3.42 (m, 5H), 3.37–3.29 (m,
1H), 2.75–2.57 (m, 4H), 2.16–2.02 (m, 2H), 1.98–1.86
(m, 1H), 1.84–1.75 (m, 2H), 1.73–1.57 (m, 3H), 1.54–1.50
(m, 1H), 1.29 (q, 1H, J¼12.5 Hz). 13C NMR (75 MHz,
CDCl3): d 159.0, 158.3, 157.62, 157.57, 134.11, 134.08,
133.2, 132.2, 130.4, 129.33, 129.31, 126.9, 126.7, 113.7,
113.6, 113.2, 82.7, 79.1, 75.6, 74.8, 55.2, 54.8, 51.0, 41.9,
40.3, 38.1, 37.8, 37.6, 30.6, 30.4. IR (neat): nmax¼2997,
2933, 2835, 1738, 1707, 1610, 1583, 1512, 1464, 1360,
1300, 1246, 1176, 1036 cmꢀ1. MS m/z (EI, relative inten-
sity): 648 (M+, 67), 338 (9), 308 (9), 174 (16), 147 (15),
121 (100). HRMS (EI) calcd for C42H48O6 (M+) 648.3451,
found 648.3451. [a]1D4 ꢀ90.4 (c 0.32, CHCl3).
Supplementary data
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.tet.2007.02.028.
References and notes
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