Synthesis and biological activity of the C'D'E'F' ring system of maitotoxin

Article abstract of DOI:10.1021/jo5005235

Stereoselective synthesis of the C'D'E'F' ring system of maitotoxin was achieved starting from the E' ring through successive formation of the D' and C' rings based on SmI₂-mediated reductive cyclization. Construction of the F' ring was accomplished via Suzuki-Miyaura cross-coupling with a side chain fragment and Pd(II)-catalyzed cyclization of an allylic alcohol. The C'D'E'F' ring system inhibited maitotoxin-induced Ca²⁺ influx in rat glioma C6 cells with an IC₅₀ value of 59 μM.

Full text of DOI:10.1021/jo5005235

Article
pubs.acs.org/joc
Synthesis and Biological Activity of the C′D′E′F′ Ring System of
Maitotoxin
†
‡
§
†
†
Masahiro Kunitake, Takahiro Oshima, Keiichi Konoki, Makoto Ebine, Kohei Torikai,
‡
,†
Michio Murata, and Tohru Oishi*
†Department of Chemistry, Faculty and Graduate School of Sciences, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka
12-8581, Japan
8
‡
Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan
§Graduate, School of Agricultural Science, Tohoku University, 1-1 Tsutsumidori Amamiyamachi, Aoba-ku, Sendai 981-8555, Japan
S Supporting Information
*
ABSTRACT: Stereoselective synthesis of the C′D′E′F′ ring system of maitotoxin was achieved starting from the E′ ring through
successive formation of the D′ and C′ rings based on SmI -mediated reductive cyclization. Construction of the F′ ring was
2
accomplished via Suzuki−Miyaura cross-coupling with a side chain fragment and Pd(II)-catalyzed cyclization of an allylic alcohol.
2+
The C′D′E′F′ ring system inhibited maitotoxin-induced Ca influx in rat glioma C6 cells with an IC50 value of 59 μM.
INTRODUCTION
stereoselective synthesis of the C′D′E′F′ ring system (3) and
its inhibitory activity against MTX-induced Ca2+ influx.
■
Maitotoxin (MTX, 1), produced by epiphytic dinoflagellate
Gambierdiscus toxicus, is suspected as one of the causative
toxins associated with seafood poisoning (Figure 1). MTX is
RESULTS AND DISCUSSION
1
■
Although synthesis of the C′D′E′F′ ring system of MTX was
one of the largest molecules among the nonpeptide secondary
6c
2
3
reported by Nakata and that lacking its side chain on the F′
metabolites whose structures have been elucidated. Because
of its unique molecular structure possessing 32 cyclic ethers
7a
ring by Nicolaou, we envisaged an alternative synthetic route
as shown in Scheme 1. The C′D′E′F′ ring system 3 would be
synthesized through Pd(II)-catalyzed cyclization reported by
4
,5
and 98 stereogenic centers, MTX has attracted considerable
attention from the synthetic community. MTX exhibits
remarkable biological activities at extremely low concen-
6
,7
12
Uenishi for the construction of the F′ ring from diol 4,
which was to be derived from trans-iodoolefin 5 and terminal
8
2+
trations, i.e., hemolytic activity at 15 nM and Ca influx
13
olefin 6 via Suzuki-Miyaura cross coupling reaction. For the
9
activity at 0.3 nM. The gigantic molecule can be divided into
construction of the C′D′E′ ring system 7, SmI -mediated
2
14
two parts, the hydrophobic part (the P−F′ ring system) and
reductive cyclization developed by Nakata, was to be utilized
2e
1
5
the hydrophilic part (the A−O ring system). During the
course of structure−activity relationship studies to develop
inhibitors against biological activities induced by MTX, we
have designed and synthesized the W−C′ ring system of
iteratively starting from the known compound 8 corre-
sponding to the E′ ring.
Synthesis of the C′D′E′ ring system is shown in Scheme 2.
1
5
Hydroboration of the known terminal olefin 8 with
disiamylborane gave primary alcohol 11 in 95% yield after
1
0
MTX (2) corresponding to a partial structure of the
hydrophobic part of the molecule, based on the hypothesis
that the hydrophobic portion would be an interacting motif
16
oxidative work up. TEMPO oxidation of 11 gave an
aldehyde, followed by treatment with methylmagnesium
11
17
against its target membrane proteins. We found that
bromide and 2-azaadamantane-N-oxyl (AZADO) oxidation
compound 2 inhibited hemolytic activity induced by MTX
of the resulting secondary alcohol to furnish ketone 12.
Removal of the TBS group of 12 with TBAF at room
temperature for 1 h gave secondary alcohol 13 in 75% yield
10
by 80% at a concentration of 10 μM, while its inhibitory
2
+
activity against MTX-induced Ca influx was comparable to
11
that of brevetoxin B (IC50 = 30 μM). These results
prompted us to examine the biological activities of the rest of
the hydrophobic moiety of MTX. Herein, we describe a
Received: March 4, 2014
©
XXXX American Chemical Society
A
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Figure 1. Structures of maitotoxin (MTX, 1), the W−C′ ring system (2), and the C′D′E′F′ ring system (3).
Scheme 1. Retrosynthetic Analysis of the C′D′E′F′ Ring System (3) of MTX
with recovery of 12 (18%), but prolonged reaction time
reactivity of the tertiary alcohol. After considerable exper-
imentation, we found that desired product 17 was obtained by
adding methyl propiolate (3 equiv) to a solution of 16 and
trimethylphosphine (5 equiv) at room temperature in 83%
18
resulted in the formation of byproducts. Oxa-Michael
addition of the secondary alcohol 13 by treatment with
ethyl propiolate in the presence of N-methylmorpholine
19
(
NMM) resulted in the formation of trans-β-alkoxyacrylate 14
yield. Methanolysis of acetate 17 with K CO gave primary
2 3
in 89% yield, which was subjected to SmI -mediated reductive
alcohol 18 (92%), which was oxidized under Parikh-Doering
2
1
4
20
cyclization to afford the D′E′ ring system 7 in 86% yield as
a single isomer. The structure of 7 was unambiguously
determined by NOE experiments. Treatment of the ester 7
conditions. The resulting aldehyde was subjected to the
14
second SmI -mediated reductive cyclization to afford the
2
C′D′E′ ring system 19 as a single isomer in 77% yield for two
steps, and the structure was confirmed by NOE experiments.
with LiAlH formed diol 15, followed by selective protection
4
of the primary alcohol 15 as an acetate to furnish 16 in 99%
yield over two steps. The second oxa-Michael addition of the
tertiary alcohol 16 was problematic because of the low
Reduction of the ester 19 with LiAlH followed by protection
of the resulting diol 20 as benzyl ethers by treatment with
BnBr and NaH furnished 21 in 77% yield for two steps.
4
B
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a
Scheme 2. Synthesis of the C′D′E′ Ring Fragment (6) of MTX
a
(
a) (Sia) BH, rt, 1 h; then, NaOH, H O , rt, 1 h, 95% (b) TEMPO, KBr, NaOCl, NaHCO , CH Cl , 0 °C, 30 min; (c) MeMgBr, THF, 0 °C, 20
2 2 2 3 2 2
min, 82% (2 steps); (d) AZADO, KBr, NaOCl, NaHCO , CH Cl , 0 °C, 25 min, 92%; (e) TBAF, THF, rt, 1 h, 75%; (f) HCCCO Et, NMM,
3
2
2
2
CH Cl , rt, 5 h 45 min, 89%; (g) SmI , MeOH, THF, 0 °C, 50 min, 86%; (h) LiAlH , THF, −15 °C, 2 h; (i) Ac O, pyridine, rt, 2 h, 99% (2 steps);
2
2
2
4
2
(
j) HCCCO Me, Me P, THF, rt, 40 min, 83%; (k) K CO , MeOH, rt, 4 h 20 min, 92%; (l) SO ·Py, DMSO, Et N, CH Cl , rt, 2 h; (m) SmI ,
2
3
2
3
3
3
2
2
2
MeOH, THF, 0 °C, 40 min, 77% (2 steps); (n) LiAlH , THF, −15 °C, 2 h 15 min; (o) BnBr, NaH, THF, DMF, 20 h, 77% (2 steps); (p) CSA,
THF, MeOH, rt, 3 h 10 min, 89%; (q) TBSCl, imidazole, DMF, rt, 38 h; (r) CSA, CH Cl , MeOH, rt, 3 h, 88% (2 steps); (s) TEMPO, KBr, NaOCl,
4
2
2
NaHCO , CH Cl , 0 °C, 1 h 10 min; (t) Tebbe reagent, THF, 0 °C, 20 min, 80% (2 steps).
3
2
2
6
c,24
Removal of the benzylidene acetal with CSA in methanol gave
diol 22, followed by protection of the resulting diol as TBS
ethers 23. Selective deprotection with CSA in methanol
resulted in the formation of primary alcohol 24 in 88% yield
for two steps. TEMPO oxidation of 24 gave an aldehyde,
which was converted to the terminal olefin 6 by treatment
tively to afford 27 in 99% yield in a > 30:1 ratio.
Reductive removal of the chiral auxiliary with LiBH gave
4
primary alcohol 28 in 77% yield. TEMPO oxidation of 28
followed by treatment of the resulting aldehyde with lithium
trimethylsilylacetylide resulted in the formation of a
propargylic alcohol in 85% yield over two steps as a mixture
of diastereomers, which was converted to ketone 29 by
oxidation with MnO2 in 84% yield. Noyori asymmetric
hydrogen transfer using catalyst 30 afforded alcohol 31 as a
single isomer in 95% yield. The TMS group was removed
with K CO in methanol to give terminal alkyne 32 in 97%
21
with Tebbe reagent in 80% yield for two steps.
Next, synthesis of the trans-iodoolefin 5 commenced with
Horner−Wadsworth−Emmons reaction of the known alde-
25
2
2
hyde 9 derived from diol 25 by oxidative cleavage with
6
c
NaIO4 in an analogous sequence reported by Nakata2
3
(
Scheme 3). Treatment of the known phosphonate 10
2
3
yield. The terminal alkyne was subjected to a hydro-
zirconation-iodination sequence by treatment with Schwartz
reagent prepared from Cp ZrCl and DIBALH in situ
possessing a chiral auxiliary with NaHMDS, followed by
addition of the aldehyde, resulted in the formation of olefin
26
26 in 72% yield over two steps as a single isomer. Subsequent
2
2
conjugate addition of methylcuprate proceeded stereoselec-
followed by iodine to afford iodoolefin 33 in 71% yield.
C
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a
Scheme 3. Synthesis of the trans-Iodoolefin (5)
a
(
a) NaIO , THF, H O, rt, 10 min; (b) NaHMDS, rt, 30 min; then, 9, 0 °C, 16 h, 72%; (c) CuBr·SMe , MeMgBr, Me S, THF, −66 to 0 °C, 65 min;
4
2
2
2
then 26, THF, CH Cl , −65 to −30 °C, 1.5 h, 99%; (d) LiBH , MeOH, Et O, 0 °C, 15 min, 77%; (e) TEMPO, KBr, NaOCl, NaHCO , CH Cl , 0
2
2
4
2
3
2
2
°
C, 40 min; (f) TMS acetylene, n-BuLi, −70 °C, 25 min, 85% (2 steps); (g) MnO , CH Cl , rt, 37 h, 84%; (h) 30, i-PrOH, rt, 100 h, 95%; (i)
2
2
2
K CO , MeOH, rt, 15.5 h, 97%; (j) Cp ZrCl , DIBALH, THF, 0 °C, 35 min; then, 32, THF, rt, 40 min; then, I , THF, −71 to 0 °C, 10 min, 71%;
2
3
2
2
2
(
k) TBSOTf, 2,6-lutidine, CH Cl , 0 °C, 15 min, 98%.
2 2
Protection of the secondary alcohol as a TBS ether furnished
alcohol 38, followed by Wittig olefination of the resulting
aldehyde, gave terminal olefin 39 in 77% yield for two steps.
Finally, removal of the TBS groups of 39 with TBAF afforded
the C′D′E′F′ ring system 3 in quantitative yield. The longest
linear sequence is 29 steps from the E′ ring 8, and the total
yield is 5.9% with 90% average yield.
5
in 98% yield.
Having synthesized the C′D′E′ ring fragment 6 and the
trans-iodoolefin 5, we moved onto the synthesis of the
C′D′E′F′ ring system 3 (Scheme 4). Suzuki-Miyaura
1
3
coupling via hydroboration of the terminal olefin 6 with
9-BBN followed by treatment with the iodoolefin 5 (1.25
Differences in the proton (600 MHz) and carbon (150
equiv) in the presence of PdCl (dppf)·CH Cl and K PO in
2
2
2
3
4
MHz) NMR chemical shifts in 1:1 C D N-CD OD between
5
5
3
THF/DMF at 35 °C for 5 h proceeded smoothly to afford
coupling product 34 in 98% yield. Removal of the TBS
groups with TBAF furnished diol 4 in 96% yield, which is the
precursor for the key reaction for the construction of the F′
ring system. As expected, treatment of the allylic alcohol 4
with PdCl (CH CN) resulted in the formation of 35 in 93%
the synthetic C′D′E′F′ ring system 3 and MTX are shown in
29
1
13
Figure 2. The H and C NMR chemical shifts of 3 were in
good accordance with those of MTX, supporting the
proposed structure, but those at the C′ terminus deviated
since the structure was different from MTX.
2
3
2
1
2
The biological activity of the synthetic C′D′E′F′ ring
system 3 was then evaluated. MTX induced Ca2+ influx in rat
glioma C6 cells at 1 nM, and this value was taken as 100%.
yield as a single isomer.
The structure of 35 was
unambiguously determined by NOE experiments. Stereo-
selective dihydroxylation of the olefin 35 was achieved by
2+
27
The C′D′E′F′ ring system 3 blocked this Ca influx activity
in a dose-dependent manner as shown in Figure 3, and the
IC50 value was estimated to be 59 μM. Although this value is
Sharpless asymmetric dihydroxylation using (DHQD) AQN
2
as a ligand to afford α-diol 36 as a mixture of the β-diol in a
10:1 ratio in 96% yield. It is interesting to note that the use of
10
higher than that of the W−C′ ring system 2 (IC50 = 30
μM), it is interesting to note that the tetracyclic system (3)
elicited inhibitory activity in comparable magnitude with the
t-BuOMe as a cosolvent was essential to obtaining high
5a
diastereoselectivity, and the reaction rate was faster than that
using (DHQD) PHAL. The diol 36 was protected as a TBS
2
3
0−32
ether to give 37 (92%), and the PMB group of 37 was
removed with DDQ to afford primary alcohol 38 (88%),
which was separated from the other diastereomer derived
heptacyclic system (2).
To improve the inhibitory
activity against MTX-induced Ca2+ influx, design and synthesis
of a decacyclic system corresponding to the W−F′ ring
portion of MTX is in progress in our laboratory.
28
from the β-diol. Dess-Martin oxidation of the primary
D
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a
Scheme 4. Synthesis of the C′D′E′F′ Ring System (3) of MTX
a
(
a) 9-BBN, THF, rt, 1.5 h; H O; then 5 (1.25 equiv), Pd(dppf)Cl ·CH Cl , K PO , THF, DMF, 35 °C, 5 h, 98%; (b) TBAF, THF, reflux, 13 h,
2 2 2 2 3 4
9
0
6%; (c) PdCl (CH CN) , THF, 0 °C, 2 h, 93%; (d) K OsO ·2H O, (DHQD) AQN, K CO , MeSO NH ; K Fe(CN) , t-BuOMe, t-BuOH, H O,
2 3 2 2 4 2 2 2 3 2 2 3 6 2
°C, 24 h, 96%; (e) TBSOTf, 2,6-lutidine, CH Cl , 0 °C, 50 min, 92%; (f) DDQ, pH 6.9 buffer, CH Cl , rt, 50 min, 88%; (g) DMP, CH Cl , rt, 2 h;
2
2
2
2
2
2
+
−
(
h) PPh CH Br , NaHMDS, THF, 0 °C, 40 min, 77%; (i) TBAF, THF, 50 °C, 12 h, quant.
3 3
neutral, 100−210 μm) or for flash chromatography (40−50 μm).
CONCLUSION
■
Optical rotations were recorded on a polarimeter. IR spectra were
In conclusion, the stereoselective synthesis of the C′D′E′F′-
1
recorded on a FT/IR equipment. H NMR spectra were recorded at
ring system of MTX containing the side chain was achieved.
13
6
00 or 400 MHz, and C NMR spectra were recorded at 150 or
The key reactions are (i) SmI -mediated reductive cyclization
2
100 MHz. Chemical shifts are reported in ppm from tetramethylsi-
1
for the construction of the C′ and D′ rings, (ii) Suzuki-
lane (TMS) with reference to internal residual solvent [ H NMR,
13
Miyaura cross coupling for introduction of the side chain, and
CHCl (7.26), CD HOD (3.31); C NMR, CDCl (77.16), CD OD
3 2 3 3
(
iii) Pd(II)-catalyzed cyclization for the construction of the F′
(48.94)]. The following abbreviations are used to designate the
multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, brs = broad singlet. High resolution mass spectra (HRMS)
were recorded on ESI-TOF equipment.
2+
ring. The C′D′E′F′ ring system inhibited MTX-induced Ca
influx into rat glioma C6 cells (IC = 59 μM). Further
5
0
structure−activity relationship studies based on the chemical
synthesis of partial structures of MTX are currently in
progress in our laboratory.
2
-((2R,4aR,6S,7R,8aS)-7-((tert-Butyldimethylsilyl)oxy)-4a,6-
dimethyl-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-6-yl)-
ethanol (11). 2-Methyl-2-butene (23.0 mL, 217 mmol) was added
to a solution of BH ·SMe (10.3 mL, 109 mmol) in dry THF (161
3
2
EXPERIMENTAL SECTION
g) at 0 °C. After the mixture was stirred at room temperature for 1
h, a solution of olefin 8 (33.0 g, 81.6 mmol) in dry THF (60.4 g +
5.0 mL × three rinses) was added via cannula to the reaction mixture
at 0 °C. After the mixture was stirred at room temperature for 1 h, a
■
General Methods for Organic Synthesis. All reactions
sensitive to air or moisture were performed under argon atmosphere
with dry glassware unless otherwise noted in particular. The
dehydrated solvents, CH Cl , tetrahydrofuran (THF), toluene, and
solution of NaOH (3 M in H
O, 163 mL, 489 mmol) and H O
2
2
2
2 2
N,N-dimethylformamide (DMF) were used without further dehy-
dration. NMM and BnBr were distilled before using. Molecular
sieves (MS4A) were preactivated by heating in vacuo. All other
chemicals were obtained from local venders and used as supplied
unless otherwise stated. Thin-layer chromatography (TLC) was
performed using precoated TLC glass plates (silica gel 60 F254, 0.25
mm thickness) for the reaction analyses. For column chromatog-
raphy, silica gel was used for column chromatography (spherical,
(30% in H O, 84 mL, 0.82 mol) was added to the reaction mixture.
2
After the mixture was stirred at room temperature for 1 h, the
reaction mixture was quenched with saturated aqueous solution of
Na
S O
2 2 3
and extracted with EtOAc. The organic layer was dried over
anhydrous Na
SO , filtered, and concentrated under reduced
2
4
pressure. The residue was purified by silica gel column chromatog-
raphy (hexane/ethyl acetate = 7/1 → 5/1 → 3/1 → 2/1) to give
primary alcohol 11 (32.8 g, 77.5 mmol, 95%) as colorless solid.
E
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Figure 2. Differences in H- and 13C NMR (150 MHz, 1:1 C D N/CD OD, 25 °C) chemical shifts between MTX and the synthetic fragment 3.
1
5
5
3
The x- and y-axes represent carbon number and Δδ (Δδ = δMTX − δsynthetic 3 in ppm), respectively.
(ddd, J = 11.7, 11.7, 11.6 Hz, 1H), 1.85 (ddd, J = 14.5, 6.2, 2.8 Hz,
1
3
H), 1.75 (ddd, J = 14.5, 8.3, 3.5 Hz, 1H), 1.55 (s, 3H), 1.35 (s,
H), 0.87 (s, 9H), 0.09 (s, 3H), 0.06 (s, 3H); 13C NMR (150 MHz,
CDCl ) δ 137.5, 129.3, 128.5 (2C), 126.4 (2C), 103.2, 81.8, 80.3,
3
7
−
4
6.9, 74.0, 69.7, 59.5, 43.1, 31.0, 25.8 (3C), 22.1, 19.0, 17.9, −3.7,
+
4.9; HRMS (ESI-TOF) m/z: [M + Na] Calcd for C H O SiNa
23 38 5
45.2386; Found 445.2387.
-((2R,4aR,6S,7R,8aS)-7-((tert-Butyldimethylsilyl)oxy)-4a,6-
1
dimethyl-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-6-yl)-
propan-2-one (12). TEMPO (124 mg, 790 μmol) and KBr (0.5 M
in H O, 15.5 mL, 7.75 mmol) were added to a solution of alcohol
2
1
1 (32.8 g, 77.5 mmol) in CH Cl (150 mL) at 0 °C, and then a
2 2
mixture of a solution of NaOCl (1.73 M in H O, 49.5 mL, 85.6
2
2
+
mmol) and saturated aqueous solution of NaHCO (49.5 mL) was
3
Figure 3. Inhibition of MTX-induced Ca influx by the C′D′E′F′
ring (3). The level of Ca2+ influx induced by 1 nM MTX was
added dropwise to the reaction mixture over 6 min. After being
stirred at 0 °C for 30 min, the reaction mixture was quenched with
saturated aqueous solution of Na S O and extracted with EtOAc.
defined as 100%.
2
2
3
α] 24 −27.5 (c 1.33, CHCl ); IR (neat) 3453, 2953, 2857, 1471,
The organic layer was washed with saturated aqueous solution of
[
D
3
−1 1
NaCl, dried over anhydrous Na SO , filtered, and concentrated under
1
7
9
3
374, 1254, 1090, 836, 775 cm ; H NMR (600 MHz, CDCl ) δ
2
4
3
reduced pressure to give crude aldehyde (32.3 g) as pale brown
amorphous. The material was used directly in the next reaction
without further purification.
.48−7.47 (m, 2H), 7.38−7.35 (m, 3H), 5.56 (s, 1H), 3.85 (d, J =
.6 Hz, 1H), 3.84−3.79 (m, 3H), 3.60 (dd, J = 12.4, 3.5 Hz, 1H),
.53 (d, J = 9.6 Hz, 1H), 2.03 (ddd, J = 11.0, 4.1, 3.4 Hz, 1H), 1.97
F
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A solution of MeMgBr (1 M in THF, 92.5 mL, 92.5 mmol) was
added dropwise to a solution of aldehyde described above in dry
THF (200 g) at 0 °C over 17 min. After being stirred at room
temperature for 20 min, the reaction mixture was quenched with a
10/1 → 7/1 → 5/1 → 3/1 → 2/1) to give β-alkoxyacrylate 14 (11.9
g, 28.5 mmol, 89%) as yellow amorphous.
[α]D23 −41.7 (c 1.74, CHCl ); IR (neat) 2983, 2867, 2348, 1706,
3
−1 1
1643, 1624, 1469, 1372, 1126, 1010, 838 cm ; H NMR (400 MHz,
saturated aqueous solution of NH Cl and extracted with EtOAc. The
organic layer was washed with a saturated aqueous solution of NaCl,
CDCl ) δ 7.54 (dd, J = 12.4 Hz, 1H), 7.48−7.45 (m, 2H), 7.40−
4
3
7.35 (m, 3H), 5.55 (s, 1H), 5.36 (d, J = 12.4 Hz, 1H), 4.34 (dd, J =
11.4, 4.6 Hz, 1H), 4.16 (dq, J = 7.3, 1.8 Hz, 2H), 3.85 (d, J = 9.6
Hz, 1H), 3.57 (dd, J = 12.8, 3.6 Hz, 1H), 3.49 (d, J = 11.0 Hz, 1H),
2.74 (d, J = 13.3 Hz, 1H), 2.35 (d, J = 13.3 Hz, 1H), 2.25 (ddd, J =
11.9, 4.2, 4.1 Hz, 1H), 2.18 (s, 3H), 2.01 (d, J = 12.4 Hz, 1H), 1.54
(s, 3H), 1.38 (s, 3H), 1.27 (t, J = 7.3 Hz, 1H); 1 C NMR (100
dried over anhydrous Na SO , filtered, and concentrated under
2
4
reduced pressure. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate = 10/1 → 7/1 → 5/1 → 3/
1) to give secondary alcohol (27.8 g, 63.7 mmol, 82% yield from
3
alcohol 11) as colorless amorphous.
AZADO (1.5 mg, 9.9 μmol) and KBr (0.5 M in H O, 380 μL, 190
MHz, CDCl ) δ 207.7, 167.5, 161.0, 137.3, 129.3, 128.4 (2C), 126.3
2
3
μmol) were added to a solution of the alcohol (737 mg, 1.69 mmol)
in CH Cl (10 mL) at 0 °C, and then a mixture of NaOCl (1.73 M
(2C), 103.0, 99.1, 80.0, 79.5, 77.2, 76.3, 69.5, 59.9, 51.7, 33.6, 27.1,
23.8, 18.8, 14.4; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C H O Na 441.1884; Found 441.1886.
2
2
in H O, 1.17 mL, 2.02 mmol) and saturated aqueous solution of
2
23 30
7
NaHCO (1.17 mL) was added dropwise to the reaction mixture.
Ethyl-2-((2R,4aR,5aS,7R,8S,9aR,10aS)-7-hydroxy-4a,5a,7-tri-
3
After being stirred at 0 °C for 15 min, a mixture of NaOCl (1.73 M
methyl-2-phenyloctahydro-4H-pyrano[2′,3′:5,6]pyrano[3,2-d]-
in H O, 0.585 mL, 1.01 mmol) and saturated aqueous solution of
[1,3]dioxin-8-yl)acetate (7). A solution of freshly prepared SmI
2
2
NaHCO (0.59 mL) was added dropwise to the reaction mixture.
(0.080 M in THF, 634 mL, 50.8 mmol) was added to a solution of
β-alkoxyacrylate 14 (8.55 g, 20.4 mmol) and dry MeOH (3.10 mL,
76.6 mmol) in dry THF (191 g) via cannula at 0 °C. After being
stirred at 0 °C for 50 min, the reaction mixture was quenched with a
3
After being stirred at 0 °C for 10 min, the reaction mixture was
quenched with saturated aqueous solution of Na S O and extracted
2
2
3
with EtOAc. The organic layer was washed with saturated aqueous
solution of NaCl, dried over anhydrous Na SO , filtered, and
1:1 mixture of saturated aqueous solution of Na
S O and saturated
2 2 3
2
4
concentrated under reduced pressure. The residue was purified by
flash silica gel column chromatography (hexane/ethyl acetate = 30/1
aqueous solution of NaHCO , and the resulting cake was removed
3
by filtration through a pad of Celite. The filtrate was concentrated to
a half volume under reduced pressure and extracted with EtOAc.
→
20/1 → 14/1 → 10/1 → 7/1 → 5/1 → 3/1) to give ketone 12
(
677 mg, 1.56 mmol, 92%) as a colorless solid.
The organic layer was dried over anhydrous Na SO , filtered, and
2 4
[
α]D22 −25.6 (c 0.990, CHCl ); IR (neat) 2954, 2929, 2857, 2363,
concentrated under reduced pressure. The residue was purified by
flash silica gel column chromatography (hexane/ethyl acetate = 5/1
→ 3/1 → 2/1 → 1/1 → 1/2 → 1/3) to give ester 7 (7.40 g, 17.6
mmol, 86%) as colorless solid.
3
−1
1
1707, 1471, 1373, 1254, 1093, 837 cm ; H NMR (600 MHz,
CDCl ) δ 7.48−7.46 (m, 2H), 7.38−7.34 (m, 3H), 5.54 (s, 1H),
3
4.13 (dd, J = 11.0, 4.8 Hz, 1H), 3.83 (d, J = 9.6 Hz, 1H), 3.54 (dd, J
24
D
=
12.4, 3.4 Hz, 1H), 3.49 (d, J = 9.6 Hz, 1H), 2.65 (d, J = 13.1 Hz,
[α]
1456, 1124, 1092, 1049, 919 cm ; H NMR (600 MHz, CDCl ) δ
3
−31.5 (c 0.930, CHCl ); IR (neat) 3482, 2957, 2863, 1774,
3
−1 1
1
4
3
H), 2.43 (d, J = 13.0 Hz, 1H), 2.18 (s, 3H), 2.00 (ddd, J = 12.4,
.8, 4.1 Hz, 1H), 1.92 (ddd, J = 11.7, 11.7, 11.7 Hz, 1H), 1.52 (s,
7.48−7.47 (m, 2H), 7.38−7.34 (m, 3H), 5.57 (s, 1H), 4.18 (dq, J =
6.9, 2.1 Hz, 2H), 3.84 (d, J = 9.7 Hz, 1H), 3.82 (dd, J = 8.9, 4.1 Hz,
1H), 3.67 (dd, J = 12.4, 3.4 Hz, 1H), 3.54 (d, J = 9.7 Hz, 1H), 3.36
(dd, J = 11.7, 2.8 Hz, 1H), 2.67 (dd, J = 15.1, 4.1 Hz, 1H), 2.49 (dd,
J = 15.8, 8.9 Hz, 1H), 2.13−2.10 (m, 1H), 2.10 (d, J = 12.4 Hz,
1H), 1.97 (ddd, J = 12.4, 11.7, 11.6, Hz, 1H), 1.83 (brs, 1H), 1.73
(d, J = 12.4 Hz, 1H), 1.61 (s, 3H), 1.40 (s, 3H), 1.33 (s, 3H), 1.27
H), 1.31 (s, 3H), 0.87 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H); 13
C
NMR (150 MHz, CDCl ) δ 208.5, 137.7, 129.3, 128.5 (2C), 126.5
3
(
2
2C), 103.1, 80.2, 79.3, 76.8, 71.8, 69.3, 52.9, 33.6, 31.0, 25.8 (3C)+,
3.3, 19.0, 18.0, −3.9, −4.8; HRMS (ESI-TOF) m/z: [M + Na]
Calcd for C H O SiNa 457.2386; Found 457.2385.
24
38
5
1
-((2R,4aR,6S,7R,8aS)-7-Hydroxy-4a,6-dimethyl-2-phenyl-
(t, J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl ) δ 172.2, 137.5,
hexahydropyrano[3,2-d][1,3]dioxin-6-yl)propan-2-one (13). A
solution of TBAF (1.0 M in THF, 57.0 mL, 57.0 mmol) was added
to a solution of 12 (16.6 g, 38.1 mmol) in dry THF (160 g) at 0 °C.
After being stirred at room temperature for 1 h, the reaction mixture
3
129.3, 128.5 (2C), 126.4 (2C), 103.3, 85.0, 83.5, 83.2, 76.9, 74.4,
70.6, 70.4, 61.0, 55.0, 35.1, 27.3, 25.1, 21.3, 20.6, 14.3; HRMS (ESI-
+
TOF) m/z: [M + Na] Calcd for C H O Na 443.2040; Found
23
32
7
was quenched with saturated aqueous solution of NH Cl and
443.2043.
4
extracted with EtOAc. The organic layer was dried over anhydrous
(2R,4aR,5aS,7R,8S,9aR,10aS)-8-(2-Hydroxyethyl)-4a,5a,7-tri-
Na SO , filtered, and concentrated under reduced pressure. The
methyl-2-phenyloctahydro-4H-pyrano[2′,3′:5,6]pyrano[3,2-d]-
2
4
residue was purified by silica gel column chromatography (hexane/
ethyl acetate = 30/1 → 20/1 → 10/1 → 7/1 → 3/1 → 1/1 → 1/3)
to give alcohol 13 (9.12 g, 28.5 mmol, 75%) as colorless amorphous
and recovery of ketone 12 (2.91 g, 6.70 mmol, 18%).
[1,3]dioxin-7-ol (15). LiAlH (746 mL, 19.7 mmol) was added to a
4
solution of ester 7 (6.31 g, 15.0 mmol) in dry THF (110 g) at −15
°C. After being stirred at −15 °C for 2 h, the reaction mixture was
diluted with Et O (300 mL) and quenched with H O (1.20 mL).
2 2
[
α]D27 +9.83 (c 1.37, CHCl ); IR (neat) 3444, 2960, 2866, 2360,
The reaction mixture was allowed to warm to room temperature, and
H O (8.35 mL) was added to the reaction mixture. The resulting
2
3
−1 1
1
670, 1376, 1112, 1069, 1015, 757, 699 cm ; H NMR (400 MHz,
CDCl ) δ 7.49−7.47 (m, 2H), 7.40−7.34 (m, 3H), 5.55 (s, 1H),
cake was removed by filtration through a pad of Celite. The filtrate
was concentrated under reduced pressure to give crude diol 15 (6.24
g) as colorless amorphous. The material was used directly in the next
3
3
.94 (dd, J = 11.5, 4.3 Hz, 1H), 3.84 (d, J = 9.6 Hz, 1H), 3.80 (d, J
=
3.7 Hz, 1H), 3.55 (dd, J = 12.8, 3.7 Hz, 1H), 3.50 (d, J = 9.6 Hz,
1
3
1
H), 2.85 (d, J = 15.6 Hz, 1H), 2.69 (d, J = 16.0 Hz, 1H), 2.22 (s,
reaction without further purification.
1
H), 2.14 (ddd, J = 12.4, 4.4, 4.3 Hz, 1H), 1.93 (ddd, J = 12.4, 12.4,
H NMR (600 MHz, CDCl ) δ 7.49−7.47 (m, 2H), 7.38−7.36
3
13
1.5 Hz, 1H), 1.53 (s, 3H), 1.36 (s, 3H); C NMR (100 MHz,
(m, 3H), 5.57 (s, 1H), 3.90−3.78 (m, 3H), 3.67 (dd, J = 11.9, 3.2
Hz, 1H), 3.54 (d, J = 11.0 Hz, 1H), 3.51 (dd, J = 9.2, 4.2 Hz, 1H),
3.36 (dd, J = 11.9, 2.3 Hz, 1H), 2.14−1.88 (m, 2H), 1.79−1.70 (m,
2H), 1.62 (s, 3H), 1.42 (s, 3H), 1.36 (s, 3H)
CDCl ) δ 210.2, 137.5, 129.2, 128.5 (2C), 126.4 (2C), 103.0, 80.4,
7
m/z: [M + Na] Calcd for C H O Na 343.1521; Found 343.1520.
3
8.3, 76.7, 72.0, 69.2, 55.5, 32.7, 29.9, 22.2, 18.9; HRMS (ESI-TOF)
+
18
24
5
(
E)-Ethyl-3-(((2R,4aR,6S,7R,8aS)-4a,6-dimethyl-6-(2-oxoprop-
2-((2R,4aR,5aS,7R,8S,9aR,10aS)-7-Hydroxy-4a,5a,7-trimeth-
yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-
yl-2-phenyloctahydro-4H-pyrano[2′,3′:5,6]pyrano[3,2-d][1,3]-
acrylate (14). NMM (10.5 mL, 95.5 mmol) and ethyl propiolate
dioxin-8-yl)ethyl acetate (16). Ac O (14.2 mL, 150 mmol) was
2
(
4.86 mL, 47.9 mmol) were added sequentially to a solution of
added to a solution of the diol 15 described above in pyridine (66.0
mL, 823 mmol) at 0 °C. After being stirred at room temperature for
2 h, the reaction mixture was quenched with saturated aqueous
alcohol 13 (10.2 g, 31.9 mmol) in dry CH Cl (233 g) at 0 °C. After
2
2
being stirred at room temperature for 5 h 45 min, the reaction
mixture was concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (hexane/ethyl acetate =
solution of NaHCO and extracted with EtOAc. The organic layer
3
was washed with saturated aqueous solution of KHSO , saturated
4
G
dx.doi.org/10.1021/jo5005235 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
aqueous solution of NaHCO , and saturated aqueous solution of
(m, 1H), 1.59 (s, 3H), 1.47 (s, 3H), 1.39 (s, 3H); 13C NMR (150
3
NaCl sequentially, dried over anhydrous Na SO , filtered, and
MHz, CDCl ) δ 168.1, 156.4, 137.4, 129.3, 128.5 (2C), 126.3 (2C),
2
4
3
concentrated under reduced pressure. The residue was purified by
flash silica gel column chromatography (hexane/ethyl acetate = 5/1
103.3, 100.4, 85.0, 83.3, 83.0, 80.1, 76.7, 74.0, 70.6, 60.8, 51.5, 51.2+,
31.5, 27.3, 23.0, 21.2, 20.7; HRMS (ESI-TOF) m/z: [M + Na]
→
3/1 → 2/1 → 1/1 → 1/2 → 1/3) to give acetate 16 (6.26 g,
Calcd for C25H O Na 485.2146; Found 485.2145.
34 8
1
4.9 mmol, 99% yield from ester 7) as colorless solid.
Methyl-2-((2R,4aR,5aS,6aR,8S,9R,10aS,11aR,12aS)-9-hy-
droxy-4a,5a,6a,8-tetramethyl-2-phenyldodecahydropyrano-
[2″,3″:5′,6′]pyrano[2′,3′:5,6]pyrano[3,2-d][1,3]dioxin-8-yl)-
[
α]D24 −56.0 (c 1.14, CHCl ); IR (neat) 3479, 2960, 2863, 1737,
3
−1 1
1
7
1
456, 1382, 1247, 1091, 753 cm ; H NMR (600 MHz, CDCl ) δ
3
acetate (19). Dry DMSO (7.26 mL, 102 mmol) and Et N (7.11
3
.48−7.47 (m, 2H), 7.39−7.34 (m, 3H), 5.57 (s, 1H), 4.32 (ddd, J =
1.7, 6.2, 5.5 Hz, 1H), 4.18 (ddd, J = 13.7, 8.2, 5.5 Hz, 1H), 3.84 (d,
mL, 51.2 mmol) and SO ·Py (4.08 g, 25.6 mmol) were added
3
sequentially to a solution of 18 (5.91 g, 12.8 mmol) in dry CH Cl
2
2
J = 9.6 Hz, 1H), 3.67 (dd, J = 12.4, 3.4 Hz, 1H), 3.53 (d, J = 9.6 Hz,
(
100 mL) at 0 °C. After the mixture was stirred at room temperature
1
1
1
1
3
1
7
H), 3.37 (dd, J = 11.0, 2.0 Hz, 1H), 3.29 (dd, J = 11.7, 2.8 Hz,
H), 2.12 (ddd, J = 11.0, 3.5, 3.4 Hz, 1H), 2.08 (d, J = 12.4 Hz,
H), 2.07 (s, 3H), 2.00−1.94 (m, 1H), 1.97 (d, J = 11.7 Hz, 1H),
.74−1.68 (m, 1H), 1.71 (d, J = 13.7 Hz, 1H), 1.61 (s, 3H), 1.41 (s,
for 1 h, Et N (3.55 mL, 25.5 mmol) and SO ·Py (2.06 g, 12.9
3
3
mmol) were added sequentially to the reaction mixture at 0 °C. After
being stirred at room temperature for 1 h, the reaction mixture was
H), 1.33 (s, 3H); 13C NMR (150 MHz, CDCl ) δ 171.3, 137.5,
quenched with saturated aqueous solution of NH
4
Cl and extracted
3
with EtOAc. The organic layer was dried over anhydrous Na SO ,
2
4
29.3, 128.5 (2C), 126.4 (2C), 103.3, 85.4, 83.5, 83.3, 77.0, 74.4,
filtered, and concentrated under reduced pressure. The residue was
roughly purified by silica gel column chromatography to give
aldehyde (5.01 g) as colorless solid. The material was used directly
in the next reaction without further purification.
1.0, 70.4, 62.1, 51.2, 28.4, 27.3, 25.1, 21.3, 21.2, 20.6; HRMS (ESI-
+
TOF) m/z: [M + Na] Calcd for C H O Na 443.2040; Found
4
23
32
7
43.2041.
(
E)-Methyl-3-(((2R,4aR,5aS,7R,8S,9aR,10aS)-8-(2-acetoxyeth-
A solution of freshly prepared SmI (0.096 M in THF, 356 mL,
4.2 mmol) was added to a solution of the aldehyde described above
2
yl)-4a,5a,7-trimethyl-2-phenyloctahydro-4H-pyrano[2′,3′:5,6]-
pyrano[3,2-d][1,3]dioxin-7-yl)oxy)acrylate (17). Methyl propio-
late (3.50 mL, 42.9 mmol) was added dropwise to a mixture of
tertiary alcohol 16 (6.05 g, 14.4 mmol) and a solution of Me P (1.0
M, 71.9 mL, 71.9 mmol) at room temperature over 6 min. After
being stirred at room temperature for 40 min, the reaction mixture
was quenched with H O and extracted with EtOAc. The organic
layer was dried over anhydrous Na SO , filtered, and concentrated
under reduced pressure. The residue was purified by flash silica gel
column chromatography (hexane/ethyl acetate = 10/1 → 7/1 → 5/1
3
and dry MeOH (1.81 mL, 44.7 mmol) in dry THF (52.1 g) via
cannula at 0 °C. After being stirred at 0 °C for 40 min, the reaction
mixture was quenched with a 1:1 mixture of saturated aqueous
solution of Na S O and saturated aqueous solution of NaHCO , and
3
2
2
3
3
the resulting cake was removed by filtration through a pad of Celite.
The filtrate was concentrated to a half volume under reduced
pressure and extracted with EtOAc. The organic layer was dried over
anhydrous Na SO , filtered, and concentrated under reduced
2
2
4
2
4
pressure. The residue was purified by flash silica gel column
chromatography (hexane/ethyl acetate = 3/1 → 2/1 → 1/1 → 1/2
→
3/1 → 2/1 → 1/1 → 1/2 → 1/3) to give β-alkoxyacrylate 17
6.04 g, 12.0 mmol, 83%) as colorless solid and recovery of tertiary
alcohol 16 (974 mg, 2.32 mmol).
(
→
1/3) to give ester 19 (4.58 g, 9.90 mmol, 77% yield from alcohol
2
3
18) as pale yellow solid.
[
α]D −83.1 (c 1.20, CHCl ); IR (neat) 2952, 2857, 1738, 1713,
3
23
−1 1
[α]
D
−55.5 (c 0.755, CHCl ); IR (neat) 3460, 2952, 2858, 1738,
3
1
638, 1385, 1247, 1131, 1042, 837 cm ; H NMR (400 MHz,
−1 1
1
7
6
383, 1112, 1027, 755 cm ; H NMR (600 MHz, CDCl ) δ 7.48−
.47 (m, 2H), 7.39−7.34 (m, 3H), 5.56 (s, 1H), 3.90 (ddd, J = 9.6,
.2, 5.5 Hz, 1H), 3.83 (d, J = 9.6 Hz, 1H), 3.69 (s, 3H), 3.66 (dd, J
3
CDCl ) δ 7.58 (d, J = 11.9 Hz, 1H), 7.49−7.46 (m, 2H), 7.40−7.35
3
(
m, 3H), 5.56 (s, 1H), 5.35 (d, J = 11.9 Hz, 1H), 4.32 (ddd, J =
1.4, 6.9, 5.0 Hz, 1H), 4.17 (ddd, J = 11.0, 8.3, 6.0 Hz, 1H), 3.83 (d,
J = 9.6 Hz, 1H), 3.69 (s, 3H), 3.67 (dd, J = 11.9, 1.4 Hz, 1H), 3.57
dd, J = 10.5, 1.84 Hz, 1H), 3.52 (d, J = 9.6 Hz, 1H), 3.32 (dd, J =
1
=
12.4, 4.1 Hz, 1H), 3.57−3.50 (m, 1H), 3.51 (d, J = 10.3 Hz, 1H),
.38 (dd, J = 12.4, 2.8 Hz, 1H), 3.23 (dd, J = 13.1, 2.8 Hz, 1H), 2.72
dd, J = 15.1, 4.8 Hz, 1H), 2.55 (d, J = 6.2 Hz, 1H), 2.52 (dd, J =
5.1, 6.2 Hz, 1H), 2.23 (ddd, J = 11.7, 5.5, 2.7 Hz, 1H), 2.14 (ddd, J
12.4, 4.1, 4.1 Hz, 1H), 2.03 (dd, J = 12.4, 8.3 Hz, 1H), 2.00 (d, J =
3
(
1
=
(
1
3
1
1
1.9, 3.2 Hz, 1H), 2.26 (d, J = 12.4 Hz, 1H), 2.14 (ddd, J = 11.4,
.6, 3.2 Hz, 1H), 2.07 (s, 3H), 1.97 (ddd, J = 11.9, 11.9, 11.4 Hz,
H), 1.94−1.88 (m, 1H), 1.82 (d, J = 11.9 Hz, 1H), 1.76−1.67 (m,
H), 1.61 (s, 3H), 1.47 (s, 3H), 1.40 (s, 3H); 1 C NMR (100 MHz,
3
12.4 Hz, 1H), 1.73−1.67 (m, 2H), 1.63 (s, 3H), 1.59 (d, J = 12.4
Hz, 1H), 1.48 (s, 3H), 1.37 (s, 3H); 13C NMR (150 MHz, CDCl )
3
CDCl ) δ 171.0, 168.0, 156.3, 137.4, 129.2, 128.4 (2C), 126.3 (2C),
1
5
3
δ 172.7, 137.5, 129.4, 128.5 (2C), 126.4 (2C), 103.4, 86.0, 83.8, 83.5,
03.2, 100.4, 83.3, 82.92, 82.87, 80.0, 76.7, 74.0, 70.5, 61.4, 51.3,
7
2
7.1, 75.4, 73.2, 71.3, 70.8, 70.6, 52.4, 52.0, 38.8, 33.7, 27.5, 22.0,
1.2, 28.4, 27.1, 22.8, 21.2, 21.1, 20.8; HRMS (ESI-TOF) m/z: [M +
1.7, 18.1; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
+
Na] Calcd for C H O Na 527.2257; Found 527.2257.
27
36
9
C H O Na 485.2146; Found 485.2145.
25
34
8
(
E)-Methyl-3-(((2R,4aR,5aS,7R,8S,9aR,10aS)-8-(2-hydroxyeth-
(
2R,4aR,5aS,6aR,8S,9R,10aS,11aR,12aS)-8-(2-Hydroxyethyl)-
yl)-4a,5a,7-trimethyl-2-phenyloctahydro-4H-pyrano[2′,3′:5,6]-
4
[
a,5a,6a,8-tetramethyl-2-phenyldodecahydropyrano-
pyrano[3,2-d][1,3]dioxin-7-yl)oxy)acrylate (18). K CO (793
2
3
2″,3″:5′,6′]pyrano[2′,3′:5,6]pyrano[3,2-d][1,3]dioxin-9-ol (20).
mg, 5.74 mmol) was added to a solution of β-alkoxyacrylate 17
7.22 g, 14.3 mmol) in MeOH (140 mL) at 0 °C. After being stirred
LiAlH (489 mg, 12.9 mmol) was added to a solution of ester 19
4
(
(
4.58 g, 9.90 mmol) in dry THF (100 mL) at −10 °C. After being
at room temperature for 4 h 20 min, the reaction mixture was
quenched with saturated aqueous solution of NH Cl and extracted
with EtOAc. The organic layer was dried over anhydrous Na SO ,
filtered, and concentrated under reduced pressure. The residue was
purified by flash silica gel column chromatography (hexane/ethyl
acetate = 5/1 → 3/1 → 2/1 → 1/1 → 1/2 → 1/3 → 0/1) to give
alcohol 18 (6.08 g, 13.1 mmol, 92%) as colorless solid.
stirred at −10 °C for 2.25 h, the reaction mixture was diluted with
THF (300 mL) and quenched with H O (2.00 mL). The reaction
4
2
2
4
mixture was allowed to warm to room temperature, and H O (7.16
2
mL) was added to the reaction mixture. The resulting cake was
removed by filtration through a pad of Celite. The filtrate was
concentrated under reduced pressure to give crude diol 20 (4.86 g)
as a pale yellow solid. The material was used directly in the next
reaction without further purification.
[
α]D22 −89.1 (c 0.735, CHCl ); IR (neat) 3473, 2951, 2873, 1710,
3
−1
1
1
637, 1385, 1131, 756 cm ; H NMR (600 MHz, CDCl ) δ 7.57
3
(
2R,4aR,5aS,6aR,8S,9R,10aS,11aR,12aS)-9-(Benzyloxy)-8-(2-
(
d, J = 11.7 Hz, 1H), 7.47−7.46 (m, 2H), 7.38−7.33 (m, 3H), 5.54
(
benzyloxy)ethyl)-4a,5a,6a,8-tetramethyl-2-phenyldodeca-
(
s, 1H), 5.35 (d, J = 12.4 Hz, 1H), 3.81 (d, J = 9.6 Hz, 1H), 3.81−
hydropyrano[2″,3″:5′,6′]pyrano[2′,3′:5,6]pyrano[3,2-d][1,3]-
dioxine (21). NaH (60% in mineral oil, 1.28 g, 32.0 mmol) and
BnBr (2.82 mL, 23.8 mmol) were sequentially added to a solution of
20 described above in dry THF (80 mL) and dry DMF (15 mL) at
0 °C. After the mixture was stirred at room temperature for 14 h,
NaH (60% in mineral oil, 0.64 g, 16 mmol) and BnBr (1.41 mL,
3
.75 (m, 2H), 3.69 (dd, J = 11.7, 2.0 Hz, 1H), 3.67 (s, 3H), 3.64
(
dd, J = 11.7, 3.4 Hz, 1H), 3.51 (d, J = 9.6 Hz, 1H), 3.37 (dd, J =
1
1.6, 3.42 Hz, 1H), 2.29−2.26 (m, 1H), 2.25 (d, J = 12.4 Hz, 1H),
2.12 (ddd, J = 11.7, 3.4, 3.4 Hz, 1H), 1.97 (ddd, J = 11.7, 11.7, 11.6
Hz, 1H), 1.81 (d, J = 11.7 Hz, 1H), 1.82−1.78 (m, 1H), 1.72−1.66
H
dx.doi.org/10.1021/jo5005235 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
1.9 mmol) were sequentially added to the reaction mixture. After
tetramethyldecahydro-2H-dipyrano[3,2-b:2′,3′-e]pyran-2-yl)-
methanol (24). CSA (1.87 g, 8.05 mmol) was added to a solution
being stirred at room temperature for 5.5 h, the reaction mixture was
quenched with saturated aqueous solution of NH Cl and extracted
with EtOAc. The organic layer was dried over anhydrous Na SO ,
filtered, and concentrated under reduced pressure. The residue was
purified by flash silica gel column chromatography (hexane/ethyl
acetate = 10/1 → 7/1 → 5/1 → 3/1 → 2/1 → 1/1 → 1/2) to give
benzyl ether 21 (4.66 g, 7.59 mmol, 77% yield from ester 19) as pale
yellow amorphous.
of TBS ether 23 described above in CH Cl (40 mL) and MeOH
4
2 2
(20 mL) at 0 °C. After being stirred at room temperature for 3 h,
the reaction mixture was quenched with saturated aqueous solution
2
4
of NaHCO
washed with saturated aqueous solution of NaCl, dried over
anhydrous Na SO , filtered, and concentrated under reduced
and extracted with EtOAc. The organic layer was
3
2
4
pressure. The residue was purified by flash silica gel column
chromatography (hexane/ethyl acetate = 14/1 → 10/1 → 7/1 → 5/
1 → 3/1 → 2/1) to give alcohol 24 (3.77 g, 5.88 mmol, 88% yield
from diol 22) as colorless amorphous.
[
α]D24 −68.7 (c 1.57, CHCl ); IR (neat) 2952, 2863, 1455, 1382,
3
−1 1
1
7
110, 927 cm ; H NMR (600 MHz, CDCl ) δ 7.52−7.50 (m, 2H),
3
.41−7.29 (m, 13H), 5.58 (s, 1H), 4.66 (d, J = 11.7 Hz, 1H), 4.54
2
2
(
d, J = 11.7 Hz, 1H), 4.49 (d, J = 11.7 Hz, 1H), 4.48 (d, J = 11.6
[α]
D
−42.6 (c 1.07, CHCl ); IR (neat) 3500, 2953, 2928, 2857,
3
Hz, 1H), 3.87 (d, J = 9.7 Hz, 1H), 3.76 (ddd, J = 8.9, 8.9, 3.1 Hz,
H), 3.68 (dd, J = 11.7, 3.4 Hz, 1H), 3.62−3.56 (m, 2H), 3.53 (d, J
9.6 Hz, 1H), 3.39 (dd, J = 12.4, 2.8 Hz, 1H), 3.29 (ddd, J = 9.7,
2366, 2356, 2335, 1728, 1471, 1456, 1386, 1255, 1104, 1049, 864,
837, 776, 736, 697; H NMR (600 MHz, CDCl ) δ 7.35−7.27 (m,
3
1
1
=
10H), 4.62 (d, J = 11.7 Hz, 1H), 4.51 (d, J = 12.4 Hz, 1H), 4.47−
4.44 (m, 2H), 4.02 (dd, J = 11.0, 5.5 Hz, 1H), 3.71 (dt, J = 8.9, 2.8
Hz, 1H), 3.59−3.53 (m, 2H), 3.28−3.22 (m, 3H), 3.44−3.40 (m,
1H), 3.11 (ddd, J = 12.4, 8.9, 3.4 Hz, 1H), 2.35−2.31 (m, 1H),
2.21−2.16 (m, 1H), 2.03 (dd, J = 10.3, 2.8 Hz, 1H), 1.98−0.95 (m,
2H), 1.84 (q, J = 11.6 Hz, 1H), 1.67−1.58 (m, 2H), 1.47 (d, J =
9
1
1
1
.7, 5.5 Hz, 1H), 3.18 (dd, J = 13.1, 2.8 Hz, 1H), 2.39−2.36 (m,
H), 2.24−2.19 (m, 1H), 2.16 (d, J = 11.7 Hz, 1H), 2.07 (dd, J =
1.7, 11.7 Hz, 1H), 2.01 (d, J = 12.4 Hz, 1H), 1.73−1.66 (m, 2H),
.67 (s, 3H), 1.60 (d, J = 12.4 Hz, 1H), 1.51 (s, 3H), 1.36 (s, 3H);
1
3
C NMR (150 MHz, CDCl ) δ 138.8, 138.0, 137.5, 129.3, 128.55,
3
1
0
2.4 Hz, 1H), 1.40 (s, 3H), 1.29 (s, 3H), 1.15 (s, 3H), 0.86 (s, 9H),
1
8
3
28.50, 128.4, 128.0, 127.9, 127.7, 127.5, 126.4, 103.4, 85.9, 83.8,
3.7, 77.4, 77.1, 75.4, 72.9, 72.6, 71.0, 69.2, 67.0, 60.5, 52.6, 33.1,
.09 (s, 3H), 0.07 (s, 3H); 13C NMR (150 MHz, CDCl ) δ 138.7,
3
+
138.0, 128.5 (2C), 128.4 (2C), 128.0 (2C), 127.9, 127.7 (2C), 127.5,
0.2, 27.6, 21.9, 21.7, 18.3; HRMS (ESI-TOF) m/z: [M + Na]
8
3.3, 82.7, 78.7, 77.9, 73.4, 72.9, 72.4, 71.0, 69.2, 68.9, 67.2, 66.9,
Calcd for C H O Na 637.3136; Found 637.3137.
38
46
7
5
2.8, 33.0, 31.1, 30.1, 25.7 (3C), 21.4, 21.1, 17.9, 17.6, −3.9, −5.1;
(
2R,3S,4aR,5aS,7R,8S,9aR,10aS)-7-(Benzyloxy)-8-(2-(benzyl-
+
oxy)ethyl)-2-(hydroxymethyl)-2,8,9a,10a-tetramethyldecahy-
HRMS (ESI-TOF) m/z: [M + Na] Calcd for C37
H
56
O
7
SiNa
dro-2H-dipyrano[3,2-b:2′,3′-e]pyran-3-ol (22). CSA (519 mg,
663.3688; Found 663.3688.
1.61 mmol) was added to a solution of 21 (4.95 g, 8.05 mmol) in
(((2R,3S,4aR,5aS,7R,8S,9aR,10aS)-7-(Benzyloxy)-8-(2-
THF (40 mL) and MeOH (20 mL) at 0 °C. After being stirred at
room temperature for 3 h 10 min, the reaction mixture was
quenched with saturated aqueous solution of NaHCO and extracted
with EtOAc. The organic layer was washed with saturated aqueous
solution of NaCl, dried over anhydrous Na SO , filtered, and
concentrated under reduced pressure. The residue was purified by
flash silica gel column chromatography (hexane/ethyl acetate = 3/1
(benzyloxy)ethyl)-2,8,9a,10a-tetramethyl-2-vinyldecahydro-
2
H-dipyrano[3,2-b:2′,3′-e]pyran-3-yl)oxy)(tert-butyl)-
dimethylsilane (6). TEMPO (42.1 mg, 269 μmol) and KBr (0.5 M
3
in H O, 1.18 mL, 590 μmol) were added to a solution of alcohol 24
2
(
3.75 g, 5.85 mmol) in CH Cl (60 mL) at 0 °C, and then a mixture
2 2
2
4
of NaOCl (1.61 M in H O, 4.15 mL, 6.60 mmol) and saturated
2
aqueous solution of NaHCO (4.15 mL) was added dropwise to the
3
reaction mixture. After the mixture was stirred at 0 °C for 50 min, a
→
2/1 → 1/1 → 1/2 → 1/3 → 0/1) to give alcohol 22 (3.77 g,
mixture of NaOCl (1.61 M in H O, 364 μL, 578 μmol) and
2
7.16 mmol, 89%) as colorless amorphous.
α]D24 −51.5 (c 1.67, CHCl ); IR (neat) 3431, 2952, 2870, 1455,
saturated aqueous solution of NaHCO3 (364 μL) was added
dropwise to the reaction mixture. After being stirred at 0 °C for 20
min, the reaction mixture was quenched with saturated aqueous
solution of Na S O and extracted with EtOAc. The organic layer
[
3
−1 1
1
7
4
1
3
1
2
1
386, 1091, 1041, 838 cm ; H NMR (600 MHz, CDCl ) δ 7.35−
3
.27 (m, 10H), 4.63 (d, J = 11.6 Hz, 1H), 4.52 (d, J = 11.6 Hz, 1H),
.47 (d, J = 12.4 Hz, 1H), 4.46 (d, J = 11.7 Hz, 1H), 4.05−4.01 (m,
H), 3.72 (ddd, J = 8.9, 8.9, 2.0 Hz, 1H), 3.60−3.56 (m, 2H), 3.38−
.31 (m, 2H), 3.25 (ddd, J = 10.3, 10.3, 5.5 Hz, 1H), 3.13 (dd, J =
3.0, 2.0 Hz, 2H), 2.39−2.33 (m, 2H), 2.22−2.17 (m, 1H), 2.07−
.05 (m, 1H), 1.97 (d, J = 11.7 Hz, 1H), 1.84 (ddd, J = 12.4, 11.7,
2
2
3
was washed with saturated aqueous solution of NaCl, dried over
anhydrous Na SO , filtered, and concentrated under reduced
2
4
pressure to give crude aldehyde (3.85 g) as pale brown amorphous.
The material was used directly in the next reaction without further
purification.
1.6 Hz, 1H), 1.69−1.60 (m, 2H), 1.50 (d, J = 12.4 Hz, 1H), 1.41
s, 3H), 1.30 (s, 3H), 1.22 (s, 3H); 1 C NMR (150 MHz, CDCl ) δ
3
A solution of Tebbe reagent (0.5 M in toluene, 14.0 mL, 7.00
mmol) was added dropwise to a solution of the aldehyde described
above in dry THF (93 g) at 0 °C. After being stirred at 0 °C for 20
(
3
1
1
6
38.8, 138.0, 128.5 (2C), 128.4 (2C), 128.0 (2C), 127.9, 127.7 (2C),
27.6, 83.6, 82.8, 77.9 (2C), 73.7, 72.9, 72.5, 71.0, 69.2, 69.1, 68.1,
min, the reaction mixture was diluted with Et O and quenched with
2
6.9, 52.8, 33.1, 30.5, 30.2, 21.1, 20.8, 17.7; HRMS (ESI-TOF) m/z:
+
a solution of NaOH (1.5 M in H O, 5.62 mL). After stirring 1 h 10
2
[
M + Na] Calcd for C H O Na 549.2828; Found 549.2829.
31
42
7
min, and the resulting cake was removed by filtration through a pad
(
((2R,3S,4aR,5aS,7R,8S,9aR,10aS)-7-(Benzyloxy)-8-(2-
of Celite and anhydrous Na SO and concentrated under reduced
(benzyloxy)ethyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-
2
2
4
pressure. The residue was purified by flash silica gel column
chromatography to (hexane/ethyl acetate = 1/0 → 20/1 → 15/1 →
10/1 → 7/1) give olefin 6 (3.00 g, 4.71 mol, 80% yield from alcohol
24) as pale brown amorphous.
,8,9a,10a-tetramethyldecahydro-2H-dipyrano[3,2-b:2′,3′-e]-
pyran-3-yl)oxy)(tert-butyl)dimethylsilane (23). Imidazole (1.64
g, 24.1 mmol) and TBSCl (2.40 g, 15.9 mmol) were added
sequentially to a solution of alcohol 22 (3.52 g, 6.69 mmoL) in dry
DMF (10 mL) at 0 °C. After the mixture was stirred at room
temperature for 15 h, dry DMF (10 mL) was added to the reaction
mixture. After being stirred at room temperature for 22.5 h, the
reaction mixture was quenched with saturated aqueous solution of
2
3
[α]
−42.0 (c 1.04, CHCl ); IR (neat) 2953, 2857, 2341, 1471,
D
3
−1
1
1386, 1255, 1110, 837, 773 cm ; H NMR (600 MHz, CDCl
) δ
3
7.34−7.23 (m, 10H), 5.86 (dd, J = 17.2, 10.3 Hz, 1H), 5.25 (d, J =
17.2 Hz, 1H), 4.99 (d, J = 10.9 Hz, 1H), 4.62 (d, J = 11.7 Hz, 1H),
4.52 (d, J = 11.7 Hz, 1H), 4.46 (d, J = 11.7 Hz, 1H), 4.45 (d, J =
11.6 Hz, 1H), 3.73−3.69 (m, 2H), 3.60−3.53 (m, 2H), 3.34 (dd, J =
12.4, 3.42 Hz, 1H), 3.23 (dt, J = 9.6, 5.52 Hz, 1H), 3.11 (dd, J =
13.1, 3.5 Hz, 1H), 2.32−2.30 (m, 1H), 2.22−2.16 (m, 1H), 2.03−
2.01 (m, 2H), 1.82 (dt, J = 12.4, 8.94 Hz, 1H), 1.67−1.60 (m, 3H),
1.45 (s, 3H), 1.30 (s, 3H), 1.29 (s, 3H), 0.88 (s, 9H), 0.07 (s, 3H),
NaHCO and extracted with a 4:1 mixuture of hexane and EtOAc.
The organic layer was washed with H O and saturated aqueous
solution of NaCl, dried over anhydrous Na SO , filtered, and
concentrated under reduced pressure to give TBS ether 23 (5.36 g)
as colorless amorphous. The material was used directly in the next
reaction without further purification.
3
2
2
4
0.03 (s, 3H); 13C NMR (600 MHz, CDCl
) δ 145.9, 138.8, 138.1,
(
(2R,3S,4aR,5aS,7R,8S,9aR,10aS)-7-(Benzyloxy)-8-(2-
3
(
benzyloxy)ethyl)-3-((tert-butyldimethylsilyl)oxy)-2,8,9a,10a-
128.5 (2C), 128.4 (2C), 128.0 (2C), 127.9, 127.7 (2C), 127.5, 112.1,
I
dx.doi.org/10.1021/jo5005235 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
8
3
2.5, 82.3, 78.2, 77.9, 74.9, 73.1, 72.9, 72.5, 70.9, 69.1, 67.0, 53.2,
16.6, 16.4; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
3.1, 32.0, 30.2, 25.8 (3C), 24.0, 21.6, 18.0, 17.5, −4.1, −4.9; HRMS
C H NO Na 448.2094; Found 448.2096.
25
31
5
+
(
ESI-TOF) m/z: [M + Na] Calcd for C H O SiNa 659.3738;
(3R,4S)-6-((4-Methoxybenzyl)oxy)-3,4-dimethylhexan-1-ol
38
56
6
Found 659.3735.
(28). LiBH (703 mg, 32.3 mmol) was added to a solution of amide
4
(
R)-3-((S,E)-6-((4-Methoxybenzyl)oxy)-4-methylhex-2-enoyl)-
27 (11.3 g, 26.5 mmol) and dry MeOH (1.30 mL, 32.1 mmol) in
4
-phenyloxazolidin-2-one (26). A solution of diol 25 (5.92 g,
dry Et O (250 mL) at 0 °C. After being stirred at 0 °C for 15 min,
2
23.3 mmol) in THF (15 mL + 5.0 mL × three rinses) was added to
the reaction mixture was quenched with a solution of NaOH (3.0 M
a solution of sodium periodate (5.98 g, 28.0 mmol) in THF (30 mL)
in H O). After being stirred at room temperature for 3 h, the
2
and H O (30 mL) at 0 °C. After being stirred at room temperature
reaction mixture was extracted with EtOAc. The organic layer was
washed with saturated aqueous solution of NaCl, dried over
anhydrous Na SO , filtered, and concentrated under reduced
2
for 10 min, the reaction mixture was diluted with EtOAc and
quenched with saturated aqueous solution of Na S O and extracted
2
2
3
2
4
with EtOAc. The organic layer was washed with saturated aqueous
pressure. The residue was purified by silica gel column chromatog-
raphy (hexane/ethyl acetate = 5/1 → 3/1 → 2/1 → 1/1) to give
alcohol 28 (5.44 g, 20.4 mmol, 77%) as pale yellow oil.
solution of NaCl, dried over anhydrous Na SO , filtered, and
2
4
concentrated under reduced pressure to give crude aldehyde 9 (5.50
g) as pale yellow oil. The material was used directly in the next
reaction without further purification.
[α]D21 −3.50 (c 1.06, CHCl ); IR (neat) 3396, 2955, 2871, 1612,
3
−1 1
1513, 1246, 1091, 1036, 821 cm ; H NMR (600 MHz, CDCl ) δ
3
A solution of NaHMDS (1.9 M in THF, 20.8 mL, 39.5 mmol)
was added dropwise to a solution of pohosphonate 10 (15.9 g, 46.6
mmol) in dry THF (180 g) over 2 min at 0 °C. After being stirred
for 30 min, the mixture was cooled to 0 °C, and a solution of
aldehyde 9 described above in dry THF (39.9 g + 3.0 mL × three
rinses) was added via cannula. After being stirred at 0 °C for 15.5 h,
the reaction mixture was quenched with saturated aqueous solution
7.26−7.25 (m, 2H), 6.88−6.87 (m, 2H), 4.44 (d, J = 11.0 Hz, 1H),
4.42 (d, J = 11.7 Hz, 1H), 3.80 (s, 3H), 3.70 (ddd, J = 10.3, 6.8, 5.5
Hz, 1H), 3.62 (ddd, J = 9.6, 6.9, 6.8 Hz, 1H), 3.50 (ddd, J = 9.6, 7.6,
5.5 Hz, 1H), 3.44 (ddd, J = 9.6, 7.6, 6.9 Hz, 1H), 1.71−1.66 (m,
1H), 1.63−1.52 (m, 3H), 1.39−1.30 (m, 2H), 0.86 (d, J = 6.9 Hz,
3H), 0.85 (d, J = 6.2 Hz, 3H); 13C NMR (150 MHz, CDCl ) δ
3
159.2, 130.7, 129.32 (2C), 113.8 (2C), 72.6, 68.9, 61.6, 55.3, 35.9+,
34.5, 34.1, 32.8, 16.41, 16.37; HRMS (ESI-TOF) m/z: [M + Na]
Calcd for C H O Na 289.1774; Found 289.1774.
of NH Cl and extracted with EtOAc. The organic layer was washed
4
with saturated aqueous solution of NaCl, dried over anhydrous
16
26
3
Na SO , filtered and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (hexane/
ethyl acetate =7/1 → 5/1 → 3/1 → 2/1 → 1/1) to give olefin 26
(5R,6S)-8-((4-Methoxybenzyl)oxy)-5,6-dimethyl-1-(trimeth-
2
4
ylsilyl)oct-1-yn-3-one (29). TEMPO (31.5 mg, 202 μmol) and
KBr (0.5 M in H
of alcohol 28 (5.44 g, 20.4 mmol) in CH
then a mixture of NaOCl (1.95 M in H O, 11.5 mL, 22.4 mmol) and
saturated aqueous solution of NaHCO (11.5 mL) was added
dropwise to the reaction mixture over 1.5 min. After being stirred at
0 °C for 20 min, a mixture of NaOCl (1.95 M in H O, 1.05 mL,
2.04 mmol) and saturated aqueous solution of NaHCO (1.05 mL)
O, 4.08 mL, 2.04 mmol) were added to a solution
2
(
6.89 g, 16.8 mmol, 72% yield from alcohol 25) as yellow syrup.
2
Cl (100 mL) at 0 °C, and
2
[
α]D26 −24.2 (c 0.965, CHCl ); IR (neat) 2929, 2859, 2359, 1775,
2
3
−1 1
1
685, 1633, 1513, 1326, 1246, 1194, 1099, 760 cm ; H NMR (600
3
MHz, CDCl ) δ 7.39−7.37 (m, 2H), 7.34−7.31 (m, 3H), 7.24−7.20
3
(
m, 3H), 6.98 (dd, J = 15.1, 7.6 Hz, 1H), 6.88−6.85 (m, 2H), 5.48
2
(
dd, J = 8.22, 3.4 Hz, 1H), 4.70 (t, J = 8.6 Hz, 1H), 4.39 (s, 2H),
3
4
2
.28 (dd, J = 8.9, 3.4 Hz, 1H), 3.80 (s, 3H), 3.45−3.39 (m, 2H),
.62−2.57 (m, 1H), 1.71−1.62 (m, 2H), 1.06 (d, J = 6.9 Hz, 3H);
was added dropwise to the reaction mixture over 2 min. After being
stirred at 0 °C for 20 min, the reaction mixture was quenched with
1
3
C NMR (150 MHz, CDCl ) δ 164.7, 159.1, 156.4, 153.7, 139.2,
saturated aqueous solution of Na
The organic layer was washed with saturated aqueous solution of
NaCl, dried over anhydrous Na SO , filtered, and concentrated under
2 2 3
S O and extracted with EtOAc.
3
1
7
30.5, 129.3 (2C), 129.1 (2C), 128.6, 126.0 (2C), 118.9, 113.8 (2C),
2.6, 69.9, 67.5, 57.7, 55.2, 35.7, 33.8, 19.3; HRMS (ESI-TOF) m/z:
2
4
+
[
M + Na] Calcd for C H NO Na 432.1787; Found 432.1787.
reduced pressure to give crude aldehyde (5.66 g) as pale brown oil.
The material was used directly in the next reaction without further
purification.
A solution of n-BuLi (1.6 M in hexane, 19.0 mL, 30.6 mmol) was
added to a solution of trimethylsilylacetylene (5.41 mL, 38.3 mmol)
in dry THF (91.2 g) at 0 °C. After being stirred for 40 min at 0 °C,
the mixture was cooled to −70 °C, and a solution of the aldehyde
described above in dry THF (15 mL + 3.0 mL x 3 rinse) was added
via cannula over 5 min. After being stirred at −70 °C for 25 min, the
reaction mixture was quenched with saturated aqueous solution of
24
27
5
(
R)-3-((3R,4S)-6-((4-Methoxybenzyl)oxy)-3,4-dimethylhexa-
noyl)-4-phenyloxazolidin-2-one (27). A solution of methylmag-
nesium bromide (1.0 M in THF, 95 mL, 95 mmol) was added
dropwise to a solution of copper(I) bromide dimethyl sulfide
complex (13.8 g, 67.3 mmol) in dry THF (150 g) and dry dimethyl
sulfide (80 mL) over 23 min at −66 °C. After being stirred at −66
°
C for 40 min, the mixture was allowed to warm to 0 °C. After being
stirred for 25 min, the mixture was cooled to −70 °C. The mixture
was added to a solution of olefin 26 (10.9 g, 26.7 mmol) in dry THF
(
128 g) and dry CH Cl (137 g) at −65 °C via cannula over 10 min,
NH Cl and extracted with EtOAc. The organic layer was washed
with saturated aqueous solution of NaCl, dried over anhydrous
2
2
4
and then the reaction mixture was allowed to warm to −30 °C over
6
mixture was quenched with saturated aqueous solution of NH Cl
and extracted with EtOAc. The organic layer was washed with
0 min. After being stirred at −30 °C for 20 min, the reaction
Na SO , filtered, and concentrated under reduced pressure. The
2
4
residue was purified by silica gel column chromatography (hexane/
ethyl acetate = 14/1 → 10/1 → 7/1 → 5/1 → 3/1) to give alcohol
(6.32 g, 17.4 mmol, 85% yield from alcohol 28) as brown oil.
4
saturated aqueous solution of NaCl, dried over anhydrous Na SO ,
2
4
filtered, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (hexane/ethyl acetate =
MnO (44.7 g, 515 mmol) was added to a solution of the alcohol
2
(6.22 g, 17.2 mmol) in dry CH Cl (174 g) at room temperature.
2
2
7/1 → 5/1 → 3/1 → 2/1 → 1/1) to give amide 27 (11.3 g, 26.5
After being stirred at room temperature for 13 h, MnO (7.05 g, 81.1
2
mmol, 99%, dr > 30:1) as colorless solid.
mmol) was added to the reaction mixture. After being stirred at
[
α]D25 −42.1 (c 1.05, CHCl ); IR (neat) 2958, 2872, 1779, 1704,
room temperature for 8.5 h, MnO (16.4 g, 189 mmol) was added to
3
2
−
1
1
1
512, 1384, 1246, 1093, 820, 769 cm ; H NMR (400 MHz,
the reaction mixture. After being stirred at room temperature for
15.5 h, the reaction mixture was filtered through a pad of Celite, and
the filterate was concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (hexane/ethyl
acetate = 50/1 → 30/1 → 20/1 → 14/1 → 10/1) to give alcohol 29
(5.20 g, 14.4 mmol, 84%) as a pale yellow oil.
CDCl ) δ 7.39−7.22 (m, 7H), 6.88−6.85 (m, 2H), 5.38 (dd, J =
3
8
1
.72, 4.12 Hz, 1H), 4.62 (t, J = 8.9 Hz, 1H), 4.42 (d, J = 11.4 Hz,
H), 4.38 (d, J = 11.5 Hz, 1H), 4.24 (dd, J = 8.7, 3.7 Hz, 1H), 3.80
(
(
1
0
1
s, 3H), 3.49−3.37 (m, 2H), 2.91 (dd, J = 16.0, 5.5 Hz, 1H), 2.78
dd, J = 16.0, 8.7 Hz, 1H), 2.08−1.98 (m, 1H), 1.72−1.64 (m, 1H),
.61−1.55 (m, 1H), 1.36−1.26 (m, 1H), 0.85 (d, J = 6.9 Hz, 3H),
[α]D27 −6.43 (c 1.30, CHCl ); IR (neat) 2959, 2366, 1675, 1613,
3
.81 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl ) δ 172.7,
1249, 1092, 846 cm ; H NMR (600 MHz, CDCl ) δ 7.26−7.25
−1
1
3
3
59.2, 153.8, 139.3, 130.9, 129.3 (2C), 129.2 (2C), 128.7, 126.0
(m, 2H), 6.88−6.87 (m, 2H), 4.44 (d, J = 11.7 Hz, 1H), 4.41 (d, J =
11.6 Hz, 1H), 3.80 (s, 3H), 3.50 (ddd, J = 8.94, 7.56, 5.5 Hz, 1H),
(
2C), 113.8 (2C), 72.6, 69.9, 68.7, 57.8, 55.4, 38.9, 34.3, 34.0, 32.7,
J
dx.doi.org/10.1021/jo5005235 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3
1
.44 (ddd, J = 8.94, 6.9, 6.8 Hz, 1H), 2.56 (dd, J = 15.8, 4.8 Hz,
H), 2.32 (dd, J = 15.8, 9.5 Hz, 1H), 2.17−2.11 (m, 1H), 1.70−1.59
anhydrous Na SO , filtered, and concentrated under reduced
2
4
pressure. The residue was purified by flash silica gel column
chromatography (hexane/ethyl acetate = 10/1 → 7/1 → 5/1 → 3/1
→ 2/1) to give iodoolefin 33 (2.44 g, 5.84 mmol, 71%, trans:gem >
20:1) as a brown oil.
(
m, 2H), 1.40−1.34 (m, 1H), 0.90 (d, J = 6.9 Hz, 3H), 0.85 (d, J =
6
1
4
.8 Hz, 3H), 0.24 (s, 9H); 13C NMR (150 MHz, CDCl ) δ 187.8,
3
59.2, 130.7, 129.2 (2C), 113.8 (2C), 102.3, 97.3, 72.6, 68.5, 55.2,
9.0, 34.3, 34.0, 33.2, 16.7, 16.1, −0.7 (3C); HRMS (ESI-TOF) m/z:
[α]22 +15.3 (c 1.37, CHCl ); IR (neat) 3412, 2955, 2871, 2359,
D
2
+
−1 1
[
M + Na] Calcd for C H O SiNa 383.2013; Found 383.2017.
2341, 1611, 1512, 1246, 1083, 1034, 820, 772 cm ; H NMR (600
21
32
3
(
3R,5R,6S)-8-((4-Methoxybenzyl)oxy)-5,6-dimethyl-1-
trimethylsilyl)oct-1-yn-3-ol (31). (R,R)-Ru catalyst 30 (83.7 mg,
40 mmol) was added to a solution of ketone 29 (5.06 g, 14.0
MHz, CDCl ) δ 7.26−7.25 (m, 2H), 6.89−6.87 (m, 2H), 6.57 (dd, J
3
(
1
= 14.5, 6.9 Hz, 1H), 6.31 (dd, J = 14.4, 1.0 Hz, 1H), 4.43 (d, J =
11.6 Hz, 1H), 4.41 (d, J = 11.6 Hz, 1H), 4.14−4.10 (m, 1H), 3.81
(s, 3H), 3.52−3.48 (m, 1H), 3.45−3.41 (m, 1H), 1.80 (d, J = 4.8
Hz, 1H), 1.75−1.69 (m, 1H), 1.69−1.63 (m, 1H), 1.61−1.58 (m,
1H), 1.50 (ddd, J = 13.7, 9.6, 3.4 Hz, 1H), 1.39−1.33 (m, 1H), 1.23
(ddd, J = 14.4, 10.3, 4.1 Hz, 1H), 0.88 (d, J = 6.9 Hz, 3H), 0.82 (d, J
mmol) in i-PrOH (150 mL), and the resulting mixture was stirred at
room temperature for 98.5 h. During the period, additional (R, R)-
Ru catalyst 30 was added portion wise after 48 h (50.6 mg, 84.4
mmol), after 7 h (85.0 mg, 142 mmol), after 15 h (41.3 mg, 68.9
mmol), and after 8.5 h (43.5 mg, 72.5 mmol). The solvent was
evaporated under reduced pressure. The residue was purified by silica
gel column chromatography (hexane/ethyl acetate = 7/1) to give
alcohol 31 (4.81 g, 13.3 mmol, 95%) as a yellow oil.
= 6.9 Hz, 3H); 13C NMR (150 MHz, CDCl ) δ 159.2, 149.5, 130.6,
3
129.4 (2C), 113.8 (2C), 76.6, 72.7 (2C), 68.9, 55.4, 39.8, 35.0, 33.1,
32.9, 16.4, 16.2; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C H IO Na 441.0897, found 441.0888.
18
27
3
[
α]D26 +17.5 (c 1.27, CHCl ); IR (neat) 3425, 2956, 2858, 2170,
tert-Butyl(((3R,5R,6S,E)-1-iodo-8-((4-methoxybenzyl)oxy)-
3
−1
1
1
612, 1513, 1249, 1093, 1037, 841 cm ; H NMR (600 MHz,
CDCl ) δ 7.26−7.25 (m, 2H), 6.88 (d, J = 8.9 Hz, 2H) 4.42 (dd, J =
7.2, 11.7 Hz, 2H), 4.38 (m, 1H), 3.80 (s, 3H), 3.50 (m, 1H), 3.43
m, 1H) 1.79 (d, J = 5.5 Hz, 1H), 1.77−1.72 (m, 2H), 1.68 (m,
H), 1.60 (m, 1H), 1.45 (m, 1H), 1.36 (m, 1H), 0.89 (d, J = 6.9 Hz,
H), 0.84 (d, J = 6.8 Hz, 3H), 0.17 (s, 9H); C NMR (100 MHz,
CDCl ) δ 159.2, 130.7, 129.4 (2C), 113.8 (2C), 107.7, 88.8, 72.6,
8.9, 61.2, 55.4, 41.3, 34.6, 33.5, 32.7, 16.3, 16.2, 0.00 (3C); HRMS
ESI-TOF) m/z: [M + Na] Calcd for C H O SiNa 385.2175;
Found 385.2174.
(
-ol (32). K CO (361 mg, 2.61 mmol) was added to a solution of
1 (4.72 g, 13.0 mmol) in MeOH (65 mL) at 0 °C. After being
stirred at room temperature for 15.5 h, the reaction mixture was
quenched with saturated aqueous NH Cl and extracted with EtOAc.
The organic layer was dried over anhydrous Na SO , filtered and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (hexane/ethyl acetate = 14/1 →
0/1 → 7/1 → 5/1 → 3/1 → 2/1) to give alcohol 32 (3.65 g, 12.6
mmol, 97%) as pale yellow oil.
5,6-dimethyloct-1-en-3-yl)oxy)dimethylsilane (5). 2,6-Lutidine
(1.63 mL, 14.0 mmol) and TBSOTf (1.61 mL, 7.00 mmol) were
added sequentially to a solution of alcohol 33 (2.44 g, 5.84 mmoL)
in dry CH Cl (75.8 g) at 0 °C. After being stirred at 0 °C for 15
3
1
(
2
2
1
3
min, the reaction mixture was quenched with saturated aqueous
13
solution of NaHCO and extracted with EtOAc. The organic layer
3
3
was washed sequentially with saturated aqueous solution of
NaHCO , KHSO , and NaCl, and dried over anhydrous Na SO ,
6
(
3
4
2
4
+
21
34
3
filtered, and concentrated under reduced pressure. The residue was
purified by flash silica gel column chromatography (hexane/ethyl
acetate = 50/1 → 30/1 → 20/1 → 14/1) to give TBS ether 5 (3.50
g, 5.73 mmol, 98%) as a pale yellow oil.
3R,5R,6S)-8-((4-Methoxybenzyl)oxy)-5,6-dimethyloct-1-yn-
3
2
3
2
2
3
[
α] +42.7 (c 1.11, CHCl ); IR (neat) 2953, 2928, 2855, 2359,
D
3
−
1 1
2
341, 1611, 1513, 1247, 1086, 835, 774, 678 cm ; H NMR (600
4
MHz, CDCl ) δ 7.26−7.25 (m, 2H), 6.87 (d, J = 8.9 Hz, 2H), 6.50
3
2
4
(dd, J = 14.4, 6.8 Hz, 1H), 6.19 (d, J = 14.5 Hz, 1H), 4.43 (d, J =
1
(
1
=
1.7 Hz, 1H), 4.41 (d, J = 11.0 Hz, 1H), 4.11−4.08 (m, 1H), 3.80
s, 3H), 3.48−3.42 (m, 2H), 1.65−1.61 (m, 2H), 1.49 (ddd, J =
2.4, 8.9, 3.5 Hz, 1H), 1.39−1.33 (m, 1H), 1.25 (s, 1H), 1.12 (ddd, J
13.7, 10.3, 4.1 Hz, 1H), 0.88 (s, 9H), 0.84 (d, J = 6.9 Hz, 3H),
1
26
[
α]D +17.0 (c 0.995, CHCl ); IR (neat) 3411, 3289, 2956, 2872,
13
3
0.80 (d, J = 6.9 Hz, 3H), 0.03 (s, 3H), 0.01 (s, 3H); C NMR (150
−1
1
2
359, 1612, 1513, 1246, 1034, 821 cm ; H NMR (600 MHz,
CDCl ) δ 7.26−7.25 (m, 2H), 6.88−6.87 (m, 2H), 4.44 (d, J = 11.7
Hz, 1H), 4.41 (d, J = 11.7 Hz, 1H), 4.39 (ddd, J = 10.3, 8.3, 2.7 Hz,
H), 3.81 (s, 3H), 3.50 (ddd, J = 8.9, 6.9, 5.5 Hz, 1H), 3.43 (ddd, J
8.9, 7.6, 6.9 Hz, 1H), 2.45 (d, J = 2.4 Hz, 1H), 1.83 (d, J = 6.2 Hz,
H), 1.80−1.75 (m, 2H), 1.70−1.65 (m, 1H), 1.62−1.58 (m, 1H),
.46 (ddd, J = 14.5, 10.3, 4.1 Hz, 1H), 1.36 (ddd, J = 14.4, 8.9, 6.2
MHz, CDCl ) δ 159.2, 150.1, 130.9, 129.3 (2C), 113.8 (2C), 75.6,
3
3
73.6, 72.7, 68.8, 55.4, 40.8, 34.7, 33.2, 32.8, 26.0 (3C), 18.2, 16.6,
+
1
6.0, −4.2, −4.8; HRMS (ESI-TOF) m/z: [M + Na] Calcd for
1
=
1
C H IO SiNa 555.1762, found 555.1751.
24
41
3
(
((2R,3S,4aR,5aS,7R,8S,9aR,10aS)-7-(Benzyloxy)-8-(2-
(benzyloxy)ethyl)-2-((5R,7R,8S,E)-5-((tert-butyldimethylsilyl)-
oxy)-10-((4-methoxybenzyl)oxy)-7,8-dimethyldec-3-en-1-yl)-
2,9a,10a-trimethyldecahydro-2H-dipyrano[3,2-b:2′,3′-e]pyran-
1
13
Hz, 1H), 0.90 (d, J = 6.2 Hz, 3H), 0.84 (d, J = 6.2 Hz, 3H);
NMR (150 MHz, CDCl ) δ 159.2, 130.7 (2C), 129.4 (2C), 113.9,
C
3-yl)oxy)(tert-butyl)dimethylsilane (34). Olefin 6 (2.32 g, 3.65
3
mmol) was azeotroped with toluene and then dried over MS4A (21
granule) in dry THF (9.04 g) for 40 min. The dried olefin 6 in dry
THF (9.04 g + 1.5 mL × three rinses) was added via cannula to a
suspension of 9-BBN dimer (2.23 g, 9.12 mmol) in dry THF (5.5
8
5.8, 72.6, 72.5, 68.8, 60.5, 55.3, 42.9, 34.5, 33.4, 32.7, 16.3, 16.1;
+
HRMS (ESI-TOF) m/z: [M + Na] Calcd for C H O Na
1
8
26
3
313.1774; Found 313.1779.
(
3R,5R,6S,E)-1-Iodo-8-((4-methoxybenzyl)oxy)-5,6-dimethyl-
oct-1-en-3-ol-(33). A solution of DIBALH (1.0 M in toluene, 18.6
mL, 18.6 mmol) was added dropwise to a solution of zirconocene
dichloride (5.71 g, 19.5 mmol) in dry THF (74.4 g) at 0 °C over 4
min. After stirring at 0 °C for 35 min, a solution of alkyne 32 (2.39
g, 8.21 mmol) in dry THF (12.1 g + 5.0 mL × 2 rinse) was added
via cannula to the reaction mixture at 0 °C over 3 min. The reaction
mixture was allowed to warm to room temperature. After being
stirred at room temperature for 40 min, the reaction mixture was
mL) at 0 °C. After being stirred at room temperature for 1.5 h, H O
2
(987 μL, 54.8 mmol) was added to the reaction mixture at 0 °C.
After being stirred at room temperature for 25 min, the reaction
mixture in THF (9.04 g + 10.0 mL + 2.5 mL × two rinses) was
added via cannula to the 100 mL Schlenk flask in which
PdCl (dppf)·CH Cl (498 mg, 609 μmol) and K PO (2.60 g,
2 2 2 3 4
12.2 mmol) in freshly distilled DMF (17.0 mL) were stirred at 35
°C. Iodoolefin 5 (2.42 g, 4.55 mmol) in freshly distilled DMF (6.0
mL + 2.0 mL rinse) was added via cannula to the reaction mixture at
35 °C. After being stirred at 35 °C for 5 h, the reaction mixture was
quenched with NaBO ·4H O (9.37 g, 60.9 mmol) and H O (15 mL)
cooled to −71 °C, and then a solution I (1.0 M in THF, 22.0 mL,
2
2
2.0 mmol) was added to the reaction mixture at −71 °C over 8
min; the reaction mixture was allowed to warm to 0 °C. After being
stirred at 0 °C for 10 min, the reaction mixture was quenched with
saturated aqueous solution of Na S O and sodium potassium
3
2
2
at room temperature. After being stirred at room temperature for
13.8 h, saturated aqueous solution of Na S O was added to the
2
2
3
2
2
3
tartrate, and the reaction mixture was allowed to warm to room
temperature. After being stirred at room temperature for 2 days 15.5
h, the mixture was extracted with EtOAc. The organic layer was
washed with saturated aqueous solution of NaCl, dried over
reaction mixture. After being stirred at room temperature for 3 h, the
reaction mixture extracted with a 4:1 mixture of hexane and EtOAc.
The organic layer was washed with H O and saturated aqueous
2
solution of NaCl, dried over anhydrous Na SO , filtered, and
2
4
K
dx.doi.org/10.1021/jo5005235 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
concentrated under reduced pressure. The residue was purified by
flash silica gel column chromatography (hexane/ethyl acetate = 20/1
[α]23 −68.4 (c 1.04, CHCl ); IR (neat) 2952, 2930, 2857, 2360,
D
3
−1 1
2340, 2211, 1671, 1612, 1512, 1248, 1105, 775 cm ; H NMR (600
→
14/1 → 10/1 → 7/1 → 5/1) to give coupling product 34 (3.75
MHz, CDCl ) δ 7.35−7.23 (m, 12H), 6.88−6.87 (m, 2H), 5.63 (dt,
3
g, 3.59 mmol, 98%) as yellow amorphous.
J = 15.1, 6.8 Hz, 1H), 5.44 (dd, J = 15.8, 6.8 Hz, 1H), 4.62 (d, J =
11.6 Hz, 1H), 4.51 (d, J = 12.4 Hz, 1H), 4.47−4.40 (m, 4H), 3.92−
3.89 (m, 1H), 3.80 (s, 3H), 3.70 (dd, J = 8.94, 2.8 Hz, 1H), 3.59−
2
2
[
α] −13.5 (c 1.29, CHCl ); IR (neat) 2953, 2928, 2856, 2360,
−1 1
D
3
2
336, 1462, 1613, 1249, 1102, 836 cm ; H NMR (600 MHz,
3
1
3
2
.52 (m, 2H), 3.50−3.46 (m, 1H), 3.44−3.40 (m, 1H), 3.28 (dd, J =
2.4, 3.4 Hz, 1H), 3.25 (dt, J = 15.1, 5.5 Hz, 2H), 3.19 (dd, J = 11.7,
.4 Hz, 1H), 3.13 (dd, J = 13.1, 2.8 Hz, 1H), 2.35−2.32 (m, 1H),
.19−2.15 (m, 1H), 2.11−2.06 (m, 1H), 2.03−2.00 (m, 1H), 1.97
CDCl ) δ 7.34−7.25 (m, 12H), 6.87 (d, J = 8.2 Hz, 2H), 5.59 (dt, J
3
=
15.7, 6.2 Hz, 1H), 5.44 (dd, J = 15.8, 6.8 Hz, 1H), 4.62 (d, J =
1.6 Hz, 1H), 4.51 (d, J = 12.3 Hz, 1H), 4.47−4.42 (m, 4H), 4.08
bs, 1H), 3.80 (s, 3H), 3.72−3.69 (m, 2H), 3.57−3.54 (m, 2H),
.52−3.48 (m, 1H), 3.46−3.42 (m, 1H), 3.25−3.21 (m, 1H), 3.10
1
(
3
(
d, J = 12.4 Hz, 1H), 1.88 (q, J = 12.4 Hz, 1H), 1.81−1.74 (m, 2H),
1
1
.71−1.60 (m, 5H), 1.57−1.51 (m, 2H), 1.50−1.43 (m, 4H), 1.37−
.31 (m, 7H), 0.83 (d, J = 6.8 Hz, 3H), 0.81 (d, J = 7.2 Hz, 3H);
(
ddd, J = 15.8, 13.0, 3.4 Hz, 1H), 2.32−2.30 (m, 1H), 2.20−2.04 (m,
3H), 1.93 (d, J = 12.4 Hz, 1H), 1.81 (q, J = 11.6 Hz, 1H), 1.70−
.60 (m, 5H), 1.52−1.47 (m, 3H), 1.45−1.40 (m, 1H), 1.38−1.33
13
C NMR (150 MHz, CDCl ) δ 159.2, 138.9, 138.1, 132.6, 131.3,
3
1
1
30.9, 129.3 (2C), 128.6 (2C), 128.4 (2C), 128.0 (2C), 127.9, 127.7
(
m, 4H), 1.28 (s, 3H), 1.23 (s, 3H), 1.18 (ddd, J = 13.4, 9.6, 4.1 Hz,
(
2C), 127.6, 113.9 (2C), 86.2, 83.5, 83.3, 80.3, 78.1, 74.6, 73.7, 72.9,
72.69, 72.65, 71.0, 69.2, 69.0, 67.0, 55.4, 53.0, 38.8, 37.9, 36.2, 34.3,
3.2, 32.9, 30.6, 30.2, 28.1, 21.7, 21.5, 18.3, 16.6, 16.2; HRMS (ESI-
1
0
1
1
7
4
2
H), 0.88−0.85 (m, 12H), 0.83 (d, J = 6.8 Hz, 3H), 0.08 (s, 3H),
.05 (s, 3H); 13C NMR (150 MHz, CDCl ) δ 159.2, 138.9, 138.1,
3
3
34.5, 131.0, 130.1, 129.3 (2C), 128.6 (2C), 128.4 (2C), 128.0 (2C),
27.9, 127.8 (2C), 127.6, 113.9 (2C), 83.7, 82.7, 78.0, 77.9, 73.5,
3.0, 72.8, 72.7, 72.6, 72.0, 71.0, 69.2, 69.1, 67.1, 55.4, 53.0, 42.2,
1.7, 34.7, 33.21, 33.18, 32.0, 31.6, 30.2, 26.1 (4C), 25.8 (3C), 24.7,
+
TOF) m/z: [M + Na] Calcd for C H O Na 819.4806, found.
50
68
8
8
19.4808
1S,2R,4R,5S)-1-((2S,4aR,5aS,6aR,8S,9R,10aS,11aR,12aS)-9-
Benzyloxy)-8-(2-(benzyloxy)ethyl)-4a,5a,6a-trimethyltetra-
(
(
1.0, 18.3, 18.0, 17.7, 16.6, 16.2, −3.6, −3.7, −4.6, −4.9; HRMS
decahydropyrano[3,2-b]pyrano[2′,3′:5,6]pyrano[2,3-e]pyran-
2-yl)-7-((4-methoxybenzyl)oxy)-4,5-dimethylheptane-1,2-diol
(36). A mixture of K OsO ·2H O (106 mg, 286 μmol),
(DHQD) AQN (541 mg, 631 μmol), K Fe(CN) (2.83 g, 8.60
mmol), K CO (1.19 g, 8.61 mmol), and MeSO NH (818 mg, 8.60
2 3 2 2
+
(
ESI-TOF) m/z: [M + Na] Calcd for C H O Si 1065.6642,
62
98
9
2
found 1065.6643.
2
4
2
(
2R,3S,4aR,5aS,7R,8S,9aR,10aS)-7-(Benzyloxy)-8-(2-
2
3
6
(
benzyloxy)ethyl)-2-((5R,7R,8S,E)-5-hydroxy-10-((4-methoxy-
benzyl)oxy)-7,8-dimethyldec-3-en-1-yl)-2,9a,10a-trimethylde-
cahydro-2H-dipyrano[3,2-b:2′,3′-e]pyran-3-ol (4). A solution of
TBAF (1.0 M in THF, 11.0 mL, 11.0 mmol) was added dropwise to
a solution TBS ether 34 (4.78 g, 4.58 mmol) in dry THF (34.0 mL)
at room temperature. After being stirred under reflux for 13 h, the
reaction mixture was quenched with saturated aqueous solution of
mmol) in t-BuOH (14.5 mL) and H O (14.5 mL) was stirred at
2
room temperature for 30 min, t-BuOMe (18.0 mL) was added to
this suspension. A solution of olefin 35 (2.28 g, 2.86 mmol) in t-
BuOMe (5.0 mL + 2.0 mL × three rinses) was added to this
suspension at 0 °C. After being stirred at 0 °C for 24 h, the reaction
mixture was quenched with saturated aqueous solution of Na S O
3
2
2
NH Cl at room temperature. The mixture was extracted with EtOAc.
(70 mL) and allowed to warm to room temperature, and EtOAc (30
4
The organic layer was washed with saturated aqueous solution of
mL) and H O (50 mL) were added to the reaction mixture. After
2
NaCl, dried over anhydrous Na SO , filtered, and concentrated under
being stirred at room temperature for 62.5 h, the organic layer was
separated, and the aqueous layer was extracted with EtOAc. The
organic layer was dried over anhydrous Na SO , filtered and
2
4
reduced pressure. The residue was purified by flash silica gel column
chromatography (hexane/ethyl acetate = 3/1 → 2/1 → 1/1 → 1/2
2
4
→
1/3) to give diol 4 (3.57 g, 4.38 mmol, 96%) as pale brown
concentrated under reduced pressure. The residue was purified by
flash silica gel column chromatography (hexane/ethyl acetate = 3/1
→ 2/1 → 1/1 → 1/3) to give diol 36 (2.30 g, 2.76 mmol, 96%, α/β
amorphous.
22
[
α] −31.6 (c 0.93, CHCl ); IR (neat) 3437, 2953, 2928, 2871,
−1 1
D
3
2369, 2328, 1612, 1513, 1248, 1092, 1040, 772 cm ; H NMR (600
= 10:1) as colorless amorphous.
1
MHz, CDCl ) δ 7.33−7.25 (m, 12H), 6.88−6.87 (m, 2H), 5.60 (dt,
J = 14.4, 6.2 Hz, 1H), 5.46 (dd, J = 15.8, 6.8 Hz, 1H), 4.62 (d, J =
H NMR (600 MHz, CDCl ) δ 7.35−7.23 (m, 12H), 6.88−6.87
3
3
(
m, 2H), 4.63 (d, J = 11.7 Hz, 1H), 4.51 (d, J = 11.7 Hz, 1H),
4
1
.47−4.40 (m, 4H), 3.80 (s, 3H), 3.75−3.69 (m, 2H), 3.62 (ddd, J =
1
1.7 Hz, 1H), 4.51 (d, J = 12.4 Hz, 1H), 4.47−4.40 (m, 4H), 4.08
1.6, 3.4, 3.4 Hz, 1H), 3.59−3.42 (m, 4H), 3.28−3.18 (m, 4H), 3.13
(
3
1
bs, 1H), 3.80 (s, 3H), 3.73−3.70 (m, 2H), 3.57−3.53 (m, 2H),
(
dd, J = 12.0, 2.8 Hz, 1H), 2.59 (d, J = 4.8 Hz, 1H), 2.54 (d, J = 6.9
.52−3.48 (m, 1H), 3.45−3.41 (m, 1H), 3.23 (dt, J = 15.1, 4.7 Hz,
H), 3.12 (dt, J = 13.4, 2.8 Hz, 2H), 2.33−2.30 (m, 1H), 2.20−2.16
Hz, 1H), 2.32 (ddd, J = 11.0, 4.8, 3.4 Hz, 1H), 2.17 (dddq, J = 5.5,
5
1
1
0
.5, 2.7, 2.0 Hz, 1H), 2.01−1.94 (m, 2H), 1.89−1.84 (m, 2H), 1.72−
.52 (m, 9H), 1.47 (ddd, J = 13.0, 12.4, 4.8 Hz, 1H), 1.43 (s, 3H),
.40−1.38 (m, 1H), 1.34 (s, 3H), 1.31 (s, 3H), 1.15−1.11 (m, 1H),
(
1
m, 2H), 2.10 (q, J = 6.8 Hz, 2H), 2.07−2.03 (m, 1H), 1.94 (d, J =
2.4 Hz, 1H), 1.82 (q, J = 11.0 Hz, 1H), 1.70−1.47 (m, 6H), 1.38−
1.33 (m, 4H), 1.28 (s, 6H), 1.19 (ddd, J = 6.5, 4.3, 1.7 Hz, 1H), 0.87
1
3
.87 (d, J = 6.9 Hz, 3H), 0.84 (d, J = 6.9 Hz, 3H); C NMR (150
(
d, J = 11.4 Hz, 3H), 0.86 (d, J = 11.0 Hz, 3H), 0.83 (d, J = 1.8 Hz,
H); 1 C NMR (150 MHz, CDCl ) δ 159.2, 138.8, 138.1, 133.7,
3
MHz, CDCl
3
) δ 159.2, 138.8, 138.0, 130.8, 129.4 (2C), 128.5 (2C),
3
1
1
7
3
3
1
8
6
2
28.4 (2C), 128.0 (2C), 127.9, 127.7 (2C), 127.5, 113.9 (2C), 85.9,
3.6, 83.4, 81.3, 78.0, 75.8, 74.7, 73.6, 72.9, 72.7, 72.6, 71.0, 70.4,
9.1, 69.0, 67.0, 55.4, 53.0, 43.5, 38.1, 37.2, 35.0, 33.3, 33.1, 32.9,
31.5, 130.8, 129.4 (2C), 128.6 (2C), 128.4 (2C), 128.0 (2C), 127.9,
27.7 (2C), 127.5, 113.9 (2C), 83.8, 82.8, 78.0, 73.3 (2C), 73.0,
2.9, 72.7, 72.5, 71.1, 71.0, 69.2, 69.1, 67.0, 55.4, 52.9, 42.3, 40.8,
7.9, 25.6, 21.6, 21.2, 18.3, 16.4, 16.1; HRMS (ESI-TOF) m/z: [M +
4.8, 33.5, 33.1, 32.8, 31.1, 30.2, 26.0, 23.7, 21.0, 17.7, 16.38, 16.37;
+
Na] Calcd for C H O Na 853.4861; Found 853.4862.
+
50 70 10
HRMS (ESI-TOF) m/z: [M + Na] Calcd for C H O Na
5
0
70
9
(
5R,6R)-5-((2S,4aR,5aS,6aR,8S,9R,10aS,11aR,12aS)-9-(Benzyl-
837.4912; Found 837.4912.
oxy)-8-(2-(benzyloxy)ethyl)-4a,5a,6a-trimethyltetradecahydro-
(
2S,3R,4aS,5aR,6aS,8S,10aR,11aS,12aR)-3-(Benzyloxy)-2-(2-
pyrano[3,2-b]pyrano[2′,3′:5,6]pyrano[2,3-e]pyran-2-yl)-6-
(
benzyloxy)ethyl)-8-((4R,5S,E)-7-((4-methoxybenzyl)oxy)-4,5-
(
(2R,3S)-5-((4-methoxybenzyl)oxy)-2,3-dimethylpentyl)-
dimethylhept-1-en-1-yl)-10a,11a,12a-trimethyltetradeca-
2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane (37). 2,6-
Lutidine (1.95 mL, 16.8 mmol) and TBSOTf (1.93 mL, 8.40 mmol)
were added sequentially to a solution of alcohol 36 (3.17 g, 3.82
mmoL) in dry CH Cl (87.3 g) at 0 °C. After being stirred at 0 °C
hydropyrano[3,2-b]pyrano[2′,3′:5,6]pyrano[2,3-e]pyran (35).
PdCl (CH CN) (322 mg, 1.24 mmol) was added to a solution of
2
3
2
diol 3 (3.37 g, 4.14 mmol) in dry THF (51.9 g) at 0 °C. After being
stirred at 0 °C for 2 h, the reaction mixture was concentrated under
reduced pressure. The residue was purified by flash silica gel column
chromatography (hexane/ethyl acetate = 7/1 → 5/1 → 3/1 → 2/1
2
2
for 50 min, the reaction mixture was quenched with saturated
aqueous solution of NaHCO3 and extracted with EtOAc. The
organic layer was washed sequentially with saturated aqueous
solution of NaHCO , KHSO , and NaCl, and dried over anhydrous
→
1/1) to give olefin 35 (3.07 g, 3.85 mmol, 93%) as colorless
3
4
amorphous.
Na SO , filtered, and concentrated under reduced pressure. The
2
4
L
dx.doi.org/10.1021/jo5005235 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
residue was purified by flash silica gel column chromatography
colorless amorphous. The material was used directly in the next
reaction without further purification.
(
hexane/ethyl acetate = 15/1 → 10/1 → 7/1 → 5/1) to give TBS
ether 37 (3.73 g, 3.52 mmol, 92%, α/β = 10:1) as colorless
A solution of NaHMDS (0.6 M in toluene, 85 μL, 51 μmol) was
added to a solution methyltriphenylphosphonium bromide (36.5 mg,
102 μmol) in dry THF (0.3 mL) at 0 °C. After the mixture was
stirred at 0 °C for 30 min, a solution of 51 (10.4 mg, 10.2 μmol,
crude) in dry THF (0.2 mL × three rinses) was added to the
reaction mixture via cannula. After being stirred at 0 °C for 40 min,
the reaction mixture was quenched with saturated aqueous solution
amorphous.
1
H NMR (600 MHz, CDCl ) δ 7.35−7.26 (m, 12H), 6.89−6.88
3
(
m, 2H), 4.62 (d, J = 11.7 Hz, 1H), 4.51 (d, J = 11.7 Hz, 1H),
4
1
3
9
.47−4.44 (m, 4H), 3.80 (s, 3H), 3.71 (ddd, J = 8.9, 8.9, 2.0 Hz,
H), 3.67 (ddd, J = 9.6, 3.4, 2.8 Hz, 1H), 3.59−3.54 (m, 2H), 3.50−
.41 (m, 4H), 3.28 (dd, J = 12.4, 2.0 Hz, 1H), 3.24 (ddd, J = 9.6,
.6, 4.8 Hz, 1H), 3.14−3.09 (m, 2H), 2.33 (ddd, J = 11.0, 4.1, 4.1
of NH
with saturated aqueous solution of NaCl, dried over anhydrous
Na SO , and concentrated under reduced pressure. The residue was
Cl and extracted with EtOAc. The organic layer was washed
4
Hz, 1H), 2.17 (dddq, J = 6.2, 4.9, 2.7, 2.0 Hz, 1H), 2.00 (ddd, J =
1
1
1
3
3
3
1
1
7
3
1
1.7, 3.4, 2.8 Hz, 1H), 1.97 (d, J = 12.4 Hz, 1H), 1.83 (ddd, J =
1.7, 11.7, 11.6 Hz, 1H), 1.77 (ddd, J = 12.4, 3.4, 3.4 Hz, 1H),
.71−1.59 (m, 6H), 1.55−1.51 (m, 3H), 1.45−1.34 (m, 4H), 1.43 (s,
H), 1.31 (s, 6H), 0.885 (s, 3H), 0.878 (s, 3H), 0.82 (d, J = 7.6 Hz,
H), 0.81 (d, J = 6.2 Hz, 3H), 0.054 (s, 6H), 0.050 (s, 3H), 0.04 (s,
2
4
purified by flash silica gel column chromatography (hexane/ethyl
acetate = 1/0 → 30/1 → 20/1 → 14/1 → 10/1 → 7/1) to give
olefin 39 (7.4 mg, 7.9 μmol, 77% from alcohol 38) as colorless
amorphous.
H); 13C NMR (150 MHz, CDCl ) δ 159.2, 138.9, 138.1, 130.9,
23
[α]
−19 (c 0.37, CHCl ); IR (neat) 2953, 2857, 2349, 1558,
3
D
3
−1
1
29.4 (2C), 128.6 (2C), 128.4 (2C), 128.0 (2C), 127.9, 127.8 (2C),
27.5, 113.9 (2C), 86.1, 83.4, 83.2, 79.7, 78.1, 77.1, 74.5, 73.8, 73.2,
2.9, 72.74, 72.66, 71.0, 69.18, 69.16, 67.0, 55.4, 53.1, 38.8, 35.4,
4.4, 33.5, 33.4, 33.2, 30.2, 28.0, 27.0, 26.1 (6C), 21.7, 21.5, 18.4,
1457, 1253, 1101, 835, 697 cm ; H NMR (600 MHz, CDCl ) δ
3
7.34−7.25 (m, 10H), 5.82−5.75 (m, 1H), 5.01−4.96 (m, 2H), 4.62
(d, J = 11.6 Hz, 1H), 4.51 (d, J = 12.4 Hz, 1H), 4.46−4.44 (m, 2H),
3.72−3.66 (m, 2H), 3.58−3.54 (m, 2H), 3.52−3.48 (m, 1H), 3.42
(
8
=
(
dd, J = 6.2, 3.4 Hz, 1H), 3.29−3.22 (m, 2H), 3.12 (ddd, J = 12.4,
.9, 2.8 Hz, 2H), 2.35−2.31 (m, 1H), 2.19−2.14 (m, 1H), 2.10 (dt, J
13.0, 5.5 Hz, 1H), 2.00−1.96 (m, 2H), 1.86−1.81 (m, 2H), 1.77
dt, J = 11.7, 3.5 Hz, 1H), 1.66−1.52 (m, 6H), 1.47−1.38 (m, 7H),
8.3, 18.2, 16.2, 16.1, −3.5, −3.9, −4.5, −4.6; HRMS (ESI-TOF) m/
+
z: [M + Na] Calcd for C H O Si Na 1081.6591; Found
6
2
98 10
2
1
081.6590.
3S,4R,6R,7R)-7-((2S,4aR,5aS,6aR,8S,9R,10aS,11aR,12aS)-9-
Benzyloxy)-8-(2-(benzyloxy)ethyl)-4a,5a,6a-trimethyltetra-
(
(
1.33−1.25 (m, 7H), 0.88 (s, 9H), 0.87 (s, 9H), 0.83−0.81 (m, 6H),
13
decahydropyrano[3,2-b]pyrano[2′,3′:5,6]pyrano[2,3-e]pyran-
0.05−0.04 (s, 12H); C NMR (150 MHz, CDCl ) δ 138.9, 138.5,
3
2
1
-yl)-6,7-bis((tert-butyldimethylsilyl)oxy)-3,4-dimethylheptan-
-ol (38). DDQ (15.3 mg, 67.4 μmol) was added to a solution of 37
138.1, 128.6 (2C), 128.4 (2C), 128.0 (2C), 127.9, 127.8 (2C), 127.6,
1
15.4, 86.2, 83.5, 83.2, 79.8, 78.1, 77.21, 74.6, 73.9, 73.1, 72.9, 72.7,
(
50.7 mg, 47.8 μmol) in CH Cl (1.0 mL) and pH 6.86 buffer (0.5
2 2
71.0, 69.2, 67.0, 53.1, 38.8, 38.7, 38.2, 33.2 (2C), 30.2, 28.0, 27.0,
mL) at 0 °C. After the mixture was stirred at room temperature for
2
6.1 (7C), 21.7, 21.5, 18.4, 18.3, 18.2, 16.3, 16.1, −3.5, −3.9, −4.5
+
4
0 min, DDQ (6.0 mg, 26 μmol) was added to the reaction mixture
(2C); HRMS (ESI-TOF) m/z: [M + Na] Calcd for C H O Si Na
55 90 8 2
at 0 °C. After being stirred at room temperature for 10 min, the
reaction mixture was quenched with saturated aqueous solution of
NaHCO and saturated aqueous solution of Na S O . The reaction
9
57.6066; Found 957.6066.
(
1S,2R,4R,5S)-1-((2S,4aR,5aS,6aR,8S,9R,10aS,11aR,12aS)-9-
3
2
2
3
(Benzyloxy)-8-(2-(benzyloxy)ethyl)-4a,5a,6a-trimethyltetra-
mixture was extracted with EtOAc and washed with saturated
decahydropyrano[3,2-b]pyrano[2′,3′:5,6]pyrano[2,3-e]pyran-
2
-yl)-4,5-dimethyloct-7-ene-1,2-diol (3). A solution of TBAF
aqueous solution of NaCl, dried over anhydrous Na SO , filtered,
2
4
(
(
1.0 M in THF, 230 μL, 230 μmol) was added to a solution of 39
21.8 mg, 23.3 μmol) in dry THF (0.8 mL) at room temperature.
and concentrated under reduced pressure. The residue was purified
by flash silica gel column chromatography (hexane/ethyl acetate
The reaction mixture was stirred at 50 °C for 11.5 h. The reaction
mixture was cooled to room temperature and quenched with
=10/1 → 7/1 → 5/1 → 4/1) to give alcohol 38 (39.6 mg, 42.2
μmol, 88%) as colorless amorphous.
2
3
saturated aqueous solution of NH Cl and extracted with EtOAc. The
[
α]
−22 (c 0.48, CHCl ); IR (neat) 3475, 2953, 2856, 2357,
4
D
3
−1
1
organic layer was washed with saturated aqueous solution of NaCl,
dried over anhydrous Na SO , and concentrated under reduced
1
471, 1384, 1252, 1098, 835, 774 cm ; H NMR (600 MHz,
CDCl ) δ 7.34−7.25 (m, 10H), 4.62 (d, J = 11.7 Hz, 1H), 4.51 (d, J
2
4
3
pressure. The residue was purified by flash silica gel column
chromatography (hexane/ethyl acetate = 5/1 → 3/1 → 2/1 → 1/1
=
(
1
12.4 Hz, 1H), 4.46−4.44 (m, 2H), 3.73−3.62 (m, 4H), 3.59−3.48
m, 3H), 3.42 (dd, J = 6.2, 4.1 Hz, 1H), 3.28 (dd, J = 12.4, 2.8 Hz,
H), 3.24 (dt, J = 10.3, 5.5 Hz, 1H), 3.12 (ddd, J = 15.1, 12.4, 3.5
→
1/2) to give C′D′E′F′ ring system 3 (17.0 mg, 23.3 μmol, quant)
as colorless amorphous.
Hz, 2H), 2.35−2.32 (m, 1H), 2.19−2.14 (m, 1H), 2.00−1.96 (m,
23
D
[
α] −45.8 (c 0.82, CHCl ); IR (neat) 3481, 2953, 2871, 2368,
−1 1
2
1
6
H), 1.84 (q, J = 11.7 Hz, 1H), 1.77 (dt, J = 11.7, 3.4 Hz, 1H),
.69−1.59 (m, 6H), 1.55−1.53 (m, 3H), 1.45−1.34 (m, 7H), 1.31 (s,
H), 0.883 (s, 9H), 0.878 (s, 9H), 0.85 (d, J = 6.9 Hz, 3H), 0.82 (d,
3
1
636, 1456, 1384, 1219, 1107, 772, 699 cm ; H NMR (600 MHz,
CDCl ) δ 7.35−7.26 (m, 10H), 5.81−5.74 (m, 1H), 5.02−4.97 (m,
3
13
2H), 4.63 (d, J = 11.6 Hz, 1H), 4.51 (d, J = 12.4 Hz, 1H), 4.46−
J = 6.8 Hz, 3H), 0.06 (s, 6H), 0.05 (s, 6H); C NMR (150 MHz,
4
3
1
2
.44 (m, 2H), 3.75−3.74 (m, 1H), 3.70 (dt, J = 8.9, 2.8 Hz, 1H),
.65 (dt, J = 11.7, 3.4 Hz, 1H), 3.58−3.52 (m, 4H), 3.12 (dd, J =
3.1, 3.4 Hz, 1H), 2.58−2.55 (m, 2H), 2.33−2.30 (m, 1H), 2.20−
.10 (m, 2H), 2.03−1.96 (m, 3H), 1.89−1.84 (m, 3H), 1.76−1.70
CDCl ) δ 138.9, 138.1, 128.6 (2C), 128.4 (2C), 128.0 (2C), 127.9,
3
1
7
3
27.8 (2C), 127.6, 86.2, 83.5, 83.2, 79.6, 78.1, 77.1, 74.6, 73.9, 73.2,
2.9, 72.7, 71.0, 69.2, 67.0, 61.9, 53.1, 38.8, 36.6, 35.2, 34.4, 33.4,
3.2, 30.2, 28.0, 27.0, 26.1 (7C), 21.7, 21.5, 18.4, 18.3, 18.2, 16.2,
+
(m, 2H), 1.68−1.45 (m, 7H), 1.43 (s, 3H), 1.34 (s, 3H), 1.31 (s,
−
3.5, −3.9, −4.49, −4.54; HRMS (ESI-TOF) m/z: [M + Na] Calcd
3
3
1
H), 1.12 (ddd, J = 13.4, 11.0, 3.4 Hz, 1H), 0.89 (d, J = 6.9 Hz,
for C H O Si Na 961.6016; Found 961.6061.
54
90
9
2
H), 0.84 (d, J = 6.8 Hz, 3H); 13C NMR (150 MHz, CDCl ) δ
(
5R,6R)-5-((2S,4aR,5aS,6aR,8S,9R,10aS,11aR,12aS)-9-(Benzyl-
3
38.9, 138.4, 138.1, 128.6 (2C), 128.4 (2C), 128.0 (2C), 128.0,
oxy)-8-(2-(benzyloxy)ethyl)-4a,5a,6a-trimethyltetradecahydro-
pyrano[3,2-b]pyrano[2′,3′:5,6]pyrano[2,3-e]pyran-2-yl)-6-
127.8 (2C), 127.6, 115.5, 85.9, 83.7, 83.5, 81.6, 78.1, 75.8, 74.7, 73.6,
73.0, 72.6, 71.1, 70.5, 69.2, 67.0, 53.0, 38.25, 38.18, 38.0, 37.2, 33.2,
33.0, 30.2, 28.0, 25.6, 21.7, 21.2, 18.3, 16.4, 16.0; HRMS (ESI) calcd.
(
4
(2R,3S)-2,3-dimethylhex-5-en-1-yl)-2,2,3,3,8,8,9,9-octamethyl-
,7-dioxa-3,8-disiladecane (39). DMP (8.6 mg, 20 μmol) was
+
added to a solution of 38 (9.6 mg, 10 μmol) in CH Cl (1.0 mL) at
C H O Na For (M + Na ) 729.4337, found. 729.4336.
2
2
43 62
8
1
0
°C. After being stirred at room temperature for 2 h, the reaction
H NMR (600 MHz, C D N-CD OD = 1:1, ref CHD OD: 3.310
5 5 3 2
mixture was quenched with saturated aqueous solution of NaHCO3
and saturated aqueous solution of Na S O . The reaction mixture
was extracted with EtOAc and washed with saturated aqueous
ppm) δ 7.32−7.31 (m, 2H), 7.28−7.16 (m, 8H), 5.74−5.67 (m,
1H), 4.93−4.90 (m, 1H), 4.89−4.87 (m, 1H), 4.60 (d, J = 11.6 Hz,
1H), 4.41 (d, J = 13.7 Hz, 2H), 4.36 (d, J = 12.4 Hz, 1H), 3.85 (dt,
J = 10.3, 3.4 Hz, 1H), 3.78 (dt, J = 11.7, 3.5 Hz, 1H), 3.73 (dt, J =
8.9, 2.1 Hz, 1H), 3.56−3.50 (m, 2H), 3.36 (d, J = 4.8 Hz, 1H),
2
2
3
solution of NaCl, dried over anhydrous Na SO , filtered, and
2
4
concentrated under reduced pressure to give crude aldehyde as
M
dx.doi.org/10.1021/jo5005235 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3
1
1
1
1
.29−3.21 (m, 3H), 3.10 (dd, J = 13.0, 2.7 Hz, 1H), 2.34−2.30 (m,
H), 2.19−2.15 (m, 1H), 2.09−2.06 (m, 1H), 1.94−1.92 (m, 3H),
.86−1.83 (m, 2H), 1.78−1.71 (m, 3H), 1.65−1.61 (m, 2H), 1.56−
.50 (m, 3H), 1.42−1.38 (m, 1H), 1.34 (s, 3H), 1.30 (s, 3H), 1.27−
.23 (m, 1H), 1.21 (s, 3H), 0.86 (d, J = 6.9 Hz, 3H), 0.75 (d, J = 6.8
(6) (a) Satoh, M.; Koshino, H.; Nakata, T. Org. Lett. 2008, 10,
1683−1685. (b) Morita, M.; Haketa, T.; Koshino, H.; Nakata, T.
Org. Lett. 2008, 10, 1679−1682. (c) Morita, M.; Ishiyama, S.;
Koshino, H.; Nakata, T. Org. Lett. 2008, 10, 1675−1678. (d) Satoh,
M.; Mori, M.; Nakata, T. Heterocycles 2007, 74, 259−263.
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Matsukura, H. Chem. Pharm. Bull. 1996, 44, 627−629.
1
3
Hz, 3H); C NMR (150 MHz, C D N-CD OD = 1:1, ref
CHD OD: 48.94 ppm) δ 140.0, 139.7, 139.3, 129.3 (2C), 129.2
5
5
3
2
(
7
(
1
2C), 128.8 (2C), 128.5 (3C), 128.3, 115.8, 86.8, 84.3 (2C), 81.6,
9.1, 77.8, 75.4, 74.8, 73.5, 73.4, 71.4, 70.2, 69.9, 67.6, 54.1, 39.4
2C), 38.8, 37.8, 34.13, 34.09, 31.0, 28.8, 26.5, 22.2, 21.9, 18.6, 16.7,
6.4.
(7) (a) Nicolaou, K. C.; Seo, J. H.; Nakamura, T.; Aversa, R. J. J.
Am. Chem. Soc. 2011, 133, 214−219. (b) Nicolaou, K. C.; Baker, T.
M.; Nakamura, T. J. Am. Chem. Soc. 2011, 133, 220−226.
(c) Nicolaou, K. C.; Aversa, R. J.; Jin, J.; Rivas, F. J. Am. Chem.
ASSOCIATED CONTENT
■
Soc. 2010, 132, 6855−6861. (d) Nicolaou, K. C.; Gelin, C. F.; Seo, J.
*
S
Supporting Information
H.; Huang, Z.; Umezawa, T. J. Am. Chem. Soc. 2010, 132, 9900−
1
H and 13C NMR spectra of new compounds. This material is
9
907. (e) Nicolaou, K. C.; Frederick, M. O.; Aversa, R. J. Angew.
available free of charge via the Internet at http://pubs.acs.org.
Chem., Int. Ed. 2008, 47, 7182−7225. (f) Nicolaou, K. C.; Frederick,
M. O.; Burtoloso, A. C. B.; Denton, R. M.; Rivas, F.; Cole, K. P.;
Aversa, R. J.; Gibe, R.; Umezawa, T.; Suzuki, T. J. Am. Chem. Soc.
AUTHOR INFORMATION
■
2
008, 130, 7466−7476. (g) Nicolaou, K. C.; Cole, K. P.; Frederick,
Corresponding Author
M. O.; Aversa, R. J.; Denton, R. M. Angew. Chem., Int. Ed. 2007, 46,
*
E-mail: oishi@chem.kyushu-univ.jp
8
875−8879. (h) Nicolaou, K. C.; Frederick, M. O. Angew. Chem., Int.
Ed. 2007, 46, 5278−5282. (i) Nicolaou, K. C.; Postema, M. H. D.;
Notes
Yue, E. W.; Nadin, A. J. Am. Chem. Soc. 1996, 118, 10335−10336.
The authors declare no competing financial interest.
(
8) Igarashi, T.; Aritake, S.; Yasumoto, T. Nat. Toxins 1999, 7, 71−
7
9.
ACKNOWLEDGMENTS
■
(9) Konoki, K.; Hashimoto, M.; Nonomura, T.; Sasaki, M.; Murata,
M.; Tachibana, K. J. Neurochem. 1998, 70, 409−416.
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11) Konoki, K.; Hashimoto, M.; Honda, K.; Tachibana, K.;
Tamate, R.; Hasegawa, F.; Oishi, T.; Murata, M. Heterocycles 2009,
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73−484. (b) Kawai, N.; Lagrange, J.-M.; Uenishi, J. Eur. J. Org.
We are grateful to Prof. Yoshiharu Iwabuchi of Tohoku
University for the generous gift of AZADO. This work was
supported by a Grant-in-Aid for Scientific Research (A) (No.
(
(
2
1350028) from JSPS, a Grant-in-Aid for Scientific Research
on Innovative Areas “Organic Synthesis Based on Research
Integration, Development of New Methods and Creation of
New Substances” (No. 2015) from MEXT, and the Uehara
Memorial Foundation.
7
(
4
Chem. 2007, 2808−2814. (c) Kawai, N.; Lagrange, J.-M.; Ohmi, M.;
Uenishi, J. J. Org. Chem. 2006, 71, 4530−4537. (d) Palimkar, S. S.;
Uenishi, J.; Ii, H. J. Org. Chem. 2012, 77, 388−399. (e) Yokoyama,
H.; Nakayama, S.; Murase, M.; Miyazawa, M.; Yamaguchi, S.; Hirai,
Y. Heterocycles 2009, 77, 211−215.
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