Divergent synthesis of trans-fused polycyclic ethers by a convergent oxiranyl anion strategy

Article abstract of DOI:10.1021/jo302267f

Octacyclic polyethers that correspond to the CDEFGHIJ-ring system of yessotoxin as well as G-and/or I-ring-modified analogues were synthesized in a divergent manner, starting from a common intermediate, using an [X + 2 + Y]-type convergent method. Reaction of a triflate with the oxiranyl anion generated from an epoxy sulfone, followed by ring expansion, allowed for the incorporation of medium-sized ring ethers into the key intermediate. Subsequent acetal formation and reductive etherification afforded various octacycles containing seven-and eight-membered ether rings.

Full text of DOI:10.1021/jo302267f

Article
pubs.acs.org/joc
Divergent Synthesis of Trans-Fused Polycyclic Ethers by a
Convergent Oxiranyl Anion Strategy
Takeo Sakai, Ai Sugimoto, Hiroki Tatematsu, and Yuji Mori*
Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan
S
* Supporting Information
ABSTRACT: Octacyclic polyethers that correspond to the
CDEFGHIJ-ring system of yessotoxin as well as G- and/or I-
ring-modified analogues were synthesized in a divergent
manner, starting from a common intermediate, using an [X
+ 2 + Y]-type convergent method. Reaction of a triflate with the oxiranyl anion generated from an epoxy sulfone, followed by
ring expansion, allowed for the incorporation of medium-sized ring ethers into the key intermediate. Subsequent acetal formation
and reductive etherification afforded various octacycles containing seven- and eight-membered ether rings.
of human lymphocytes,18 and enhancement of phosphodies-
INTRODUCTION
■
terase activity.19 An SAR study of YTXs revealed that the C9
terminal chain is important for fragmentation of E-cadherin in
MCF-7 breast cancer cells.20 However, despite extensive
biological studies, the precise mechanism of action of YTX is
not yet fully understood.21 The high structural variability of
YTX, furthermore, demands further chemical and biological
studies.22
Polycyclic ethers are one of the most representative classes of
marine toxins produced by dinoflagellates.1,2 Ingestion of fish
and shellfish contaminated with dinoflagellate toxins causes
serious seafood poisoning such as ciguatera fish poisoning and
diarrhetic shellfish poisoning (DSP).3 The origin of ciguatera
toxins has been identified in the dinoflagellate Gambierdiscus
toxicus, which produces maitotoxin,4 ciguatoxins,5 gambierol,6
and gambieric acids7 (Figure 1). The characteristic trans-fused
ladder-shaped molecular structures and strong biological
activity of these toxins continue to stimulate the development
of new synthetic routes and their application in natural product
synthesis.8 Ciguatoxin (CTX), for example, is a lipophilic
sodium channel activator that binds to site 5 on voltage-
dependent Na+ channels in excitabe cells and induces the
influx of Na+ ions, causing cell depolarization.9 The total
syntheses10 and subsequent structure−activity relationship
(SAR) study of CTXs11 revealed that modification of the
ring size strongly influences the biological activity: two F-ring-
modified CTX3Cs, i.e., an eight-membered and an open-chain
O-linked analogue, showed markedly diminished biological
activity, while the ten-membered F-ring analogue of 51-
hydroxy-CTX3C retained 2% of the cytotoxicity of CTX. A
recent SAR study of an artificial polycyclic ether demonstrated
that a 6/7/6/6/7/6/6 heptacyclic ring system inhibits
maitotoxin-induced Ca2+ influx in rat glioma C6 cells.12
Another intriguing example of polycyclic ethers is yessotoxin
(YTX) (Figure 1), which was first isolated as a diarrheic
polyether toxin from the digestive gland of the scallop
Patinopecten yessoensis13 and later reported to be produced by
the dinoflagellates Protoceratium reticulatum and Lingulodinium
polyedrum.14 Since the discovery of YTX, about 40 derivatives
have been characterized by NMR and LC-MS techniques.15
Although YTX was originally classified among the toxins
responsible for DSP, YTX proved not to be diarrheagenic or
lethal to mice after oral administration.16 YTX has been found
to exhibit multiple biological activities, including in vitro
induction of apoptosis,17 modulation of cellular calcium levels
Marine polycyclic ethers, as mentioned above, vary in
chemical structure and mode of action and exhibit distinct
biological activities, because of which they may find potential
applications in pharmacology. However, their limited avail-
ability, which is due to the extremely low abundance of
standard toxins in natural sources, has hampered SAR studies.
Chemical synthesis offers a powerful alternative to biosynthesis
for supplying standard materials and their analogues. The aim
of this study is to develop a flexible and divergent method for
the synthesis of polycyclic ethers containing medium ring
ethers, which in turn can be applied to the synthesis of natural
toxins as well as their analogues.
The strategy we pursued is a novel [X + 2 + Y] convergent
approach,8a,23 where a nucleophilic substitution reaction of the
oxiranyl anion I24 with triflate II affords the coupling product
III (Scheme 1, step 1).25 Intramolecular hydroxy−epoxide
cyclization affords the six-membered ketone IV (step 2), while
an ensuing ring expansion reaction yields the seven-membered
ketone V (step 3). Finally, reductive etherification of IV and V
yields polycyclic ethers VI and VII, respectively, which feature
new six−six- and six−seven-membered ether rings (step 4).26
The advantage of this strategy is its flexibility, which allows for
the generation of two different ring systems (VI and VII) from
the common ketone intermediate IV. Using this strategy, we
were also interested in deliberately creating new ring-modified
and desmethyl analogues useful for biological studies, because
Received: October 23, 2012
© XXXX American Chemical Society
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Figure 1. Chemical structure of representative polycyclic ethers.
Scheme 1. Convergent Synthetic Strategy for the
Construction of Polycyclic Ethers
Scheme 2. Retrosynthetic Analysis of Octacyclic Polyether 1
ring fragment 10, a precursor of 2, commenced with the
coupling of 426 with 522c (Scheme 3). The reaction proceeded
optimally through the formation of the oxiranyl anion of 4 in
the presence of 5, when carried out using n-BuLi at −100 °C
in THF/HMPA for 30 min, to afford 6 in 85% yield. Removal
of the triethylsilyl (TES) group with TsOH, followed by
exposure of the product to MgBr2·OEt2 in the presence of
LiBr, gave bromo ketone 7 as a mixture of two
diastereoisomers. DBU-mediated cyclization of 7 afforded the
six-membered ketone 8 in good yield, as a single isomer. This
cyclization has the advantage that neither the stereochemistry
of the bromo ketone 7, in turn, nor that of epoxy sulfone 6 is
relevant, because the initial cyclization products undergo facile
DBU-promoted equilibration to afford a thermodynamically
more stable isomer possessing an equatorial side chain. The
ketone was then subjected to the ring expansion reaction with
trimethylsilyldiazomethane (TMS-diazomethane)29 in the
presence of BF3·OEt2, and the TMS group of the resulting
α-trimethylsilyl ketone was removed with PPTS to furnish the
bioactivities of polycyclic ethers are known to be influenced by
the conformation and substituents of the ring systems.27
In this article, we report a convergent−divergent approach
to the synthesis of the octacyclic CDEFGHIJ-ring skeleton 1
of yessotoxin and its G- and I-ring-modified analogues having
different conformations.28 Our convergent strategy was applied
to the construction of the GH-ring of octacyclic ether 1, after
connection of the CDEF-ring triflate 2 and the bicyclic epoxy
sulfone 3 (Scheme 2). Our flexible approach may be readily
applied to octacyclic systems with combinations of different-
sized G- and/or I-rings in 1, by including ring expansion at a
suitable stage of the synthesis. The tetracyclic compound 2 can
then be conveniently synthesized by the same convergent
strategy from epoxy sulfone 4 and monocyclic triflate 5.
RESULTS AND DISSCUSSION
■
Convergent Synthesis of a Tetracyclic Ether Contain-
ing a Seven-Membered Ring. The synthesis of the CDEF-
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Scheme 3. Synthesis of Tetracyclic Ether 10
Scheme 4. Ring Expansion of Seven-Membered Ether Ring
11
Scheme 5. Synthesis of Tetracyclic Ether 18
desired seven-membered ketone 9 in 74% yield over the two
steps. Sequential cleavage of the TBS group and acetalization
was accomplished by the treatment of 9 with TsOH in
CHCl3/MeOH at 55 °C, to give the corresponding methyl
acetal in 94% yield. Finally, reductive etherification of the
methyl acetal with Et3SiH in the presence of trimethylsilyl
triflate (TMSOTf) afforded the tetracyclic ether 10 containing
a seven-membered ether ring, in 92% yield.
Synthesis of a Tetracyclic Ether Containing an Eight-
Membered Ring Ether. Apart from seven-membered ring
ethers, eight-membered ether rings are also commonly
encountered structural units of polycyclic ether marine toxins.
Because we established the synthetic route to seven-membered
ether rings by ring expansion, we anticipated that further
carbon homologation of a seven-membered ring would provide
a concise route to eight-membered ether rings. Hirama and co-
workers recently attempted the AlMe3-mediated ring ex-
pansion reaction with TMS-diazomethane to construct the
eight-membered E-ring of ciguatoxins; the reaction afforded
the desired E-ring ketone and the byproduct, a seven-
membered spiroepoxide, in 1.5:1 ratio.30 Under our conditions
(TMS-diazomethane and BF3·OEt2 at −80 °C), ring expansion
of the seven-membered ketone 1122b afforded the desired
eight-membered ketone 13 in 53% yield, along with 5% of the
regioisomeric ketone 14 and 16% of spiroepoxide 15, after
mild acid treatment (Scheme 4).
Having developed the ring-expansion methodology, we next
examined the BF3-mediated ring expansion reaction of ketone
9 (Scheme 5). In this case, a higher temperature (−40 °C) was
required to achieve the desired conversion to silyl ketone 16.
Removal of the TMS group of 16 with PPTS afforded the
eight-membered ketone 17 in 53% yield over the two steps.
Acid-catalyzed deprotection of the TBS ether, followed by
heating in trimethyl orthoformate at 55 °C (both steps in one
pot), gave the methyl acetal in 82% yield. Reduction with
Et3SiH and TMSOTf afforded tetracyclic ether 18, which
contained an eight-membered ether ring, in 89% yield. An
attempt for simultaneous removal of the TMS and TBS groups
in 16 with TBAF, however, caused concomitant epimerization
at C13a to give an inseparable diastereomeric mixture of
hemiacetal 19, probably because of the basic nature and the
presence of a hydroxide in commercial TBAF. Reductive
etherification, followed by careful separation of the products by
column chromatography, afforded tetracycles 18 and 13a-epi-
18 in 36% and 38% yields, respectively.
Divergent Synthesis of Octacyclic Ring Systems. Our
newly developed [X + 2 + Y]-type convergent approach
allowed for the construction of six-, seven-, and eight-
membered polycyclic ethers from the same intermediate. To
demonstrate the utility of our method, we focused on higher
polycyclic ethers. We therefore implemented our approach in
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the synthesis of the octacyclic framework corresponding to the
CDEFGHIJ-ring 1 of yessotoxin and its G- and/or I-ring-
modified analogues.
Scheme 7. Synthesis of Ketone 28
Monocyclic diol 2031 was selected as the starting material
for the preparation of epoxy sulfone 3 (Scheme 6). One-pot
Scheme 6. Synthesis of Epoxy Sulfone 3
ketone 28, a key intermediate in the present divergent
synthesis, in good overall yield.
Finally, five different octacyclic ethers, including the
CDEFGHIJ-ring skeleton 1 of yessotoxin, were synthesized
from the key intermediate 28 (Scheme 8). First, desilylative
acetalization, followed by reductive etherification of the
resulting methyl acetal 29 with Et3SiH and TMSOTf, gave
octacyclic ether 30 in good yield. To introduce an angular
methyl group at the acetal carbon atom, mixed thioacetal 31
was prepared by removal of the TBS group with TsOH in
aqueous THF at 65 °C, followed by reaction with EtSH in the
presence of Zn(OTf)2. Oxidation of 31 to the corresponding
sulfone with m-CPBA, followed by methylation with AlMe3,34
allowed for the stereoselective introduction of the angular
methyl group, and cyclic ether 32 was obtained as a single
isomer in 73% yield.
In addition, the ring expansion approach enabled access to
octacyclic derivatives containing seven- and eight-membered
ether rings at the center of the molecule. Thus, treatment of
28 with TMS-diazomethane and subsequent removal of the
TMS group gave the seven-membered ketone 33 in 87% yield.
The one-pot removal of the TBS group and cyclic acetal
formation was followed by reductive etherification with Et3SiH
and TMSOTf to afford the seven-membered G-ring analogue
34 in good yield. A second BF3-mediated ring expansion
reaction of 33 with TMS-diazomethane afforded the eight-
membered ketone 35, after removal of the TMS group. Cyclic
acetal formation and subsequent reductive etherification gave
octacyclic ether 1, which corresponds to the CDEFGHIJ-ring
system of yessotoxin.
triflation of the primary hydroxy group and tert-butyldime-
thylsilylation of the secondary hydroxy group of 20, followed
by triflate displacement with 2-lithio-1,3-dithiane, gave
dithioacetal 21. Removal of the TBS group with TBAF,
hetero-Michael addition of the resulting secondary alcohol to
ethyl propiolate in the presence of N-methylmorpholine, and
subsequent alkylative hydrolysis of the dithioacetal with MeI
and NaHCO3 in aqueous acetonitrile afforded β-alkoxyacrylate
aldehyde 22 in high yield. Reductive radical cyclization of 22
32
using SmI2 allowed for the efficient synthesis of the
stereochemically defined bicyclic hydroxy ester 23 as the sole
product in 92% yield. Protection of the hydroxy group as the
TBS ether, followed by reduction of the ester with DIBALH,
gave aldehyde 24, which was then subjected to Peterson
olefination33 using (trimethylsilyl)methyl phenyl sulfone and
n-BuLi to give cis-enriched vinyl sulfone 25 in 93% yield (cis−
trans ratio = 70:30). Subsequent epoxidation with t-BuOOH
and t-BuOK in THF afforded the bicyclic epoxy sulfone 3 in
good yield.26
Toward the convergent synthesis of octacyclic ethers, triflate
2 was prepared from tetracyclic benzyl ether 10 in two steps:
(1) hydrogenolysis of the two benzyl ether protecting groups,
and (2) one-pot triflate and triethylsilyl ether formation
(Scheme 7). The ensuing second convergent synthesis was
achieved by treating a mixture of the tetracyclic triflate 2 and
the bicyclic epoxy sulfone 3 with n-BuLi in THF at −100 °C,
to afford epoxy sulfone 27 as a mixture of diastereoisomers in
95% yield. The same three-step sequence used earlier in this
study (see Scheme 3), which involved deprotection of the TES
ether of 27 with TsOH, epoxide opening with MgBr2·OEt2,
and DBU-mediated cyclization of the resulting hydroxy bromo
ketone, led to the formation of the six-membered ring ether
The utility of the present divergent approach was further
demonstrated by repositioning the carbonyl group in 28 to the
I-ring. Reduction of ketone 28 with NaBH4, followed by
acetylation of the resulting alcohol, gave the G-ring acetate,
where the TBS ether on the I-ring was cleaved by the action of
TBAF in the presence of acetic acid. Oxidation of the resulting
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Scheme 8. Synthesis of Octacyclic Ether 1 and Its Ring-Modified Analogues
alcohol with Dess−Martin periodinane35 gave the I-ring ketone
36. Ring expansion of 36 was then accomplished by using the
same conditions as those employed for ketone 33, giving the
seven-membered ketone 37 in moderate yield. Heating of the
ketone with TsOH in dichloroethane (DCE)/MeOH at 75 °C
led to simultaneous deacetylation and cyclic methyl acetal
formation. Finally, reductive etherification afforded octacyclic
ether 38, a positional isomer of the seven-membered ring of
34.
polyethers. The present method provides a flexible and
divergent synthetic route to polycyclic ethers consisting of
six-, seven-, and eight-membered ether rings, as they can be
synthesized from the same starting material. Further
application of this method to the synthesis of marine
polycyclic ethers and their analogues is in progress.
EXPERIMENTAL SECTION
■
General. All air- and moisture-sensitive reactions were carried out
under an argon atmosphere in dry, freshly distilled solvents under
anhydrous conditions. The term “dried” refers to the drying of an
organic solution over MgSO4 followed by filtration. Flash
chromatography was carried out with silica gel (spherical, neutral,
particle size 40−50 μm). Melting points are uncorrected. Chemical
shifts are reported in ppm relative to internal TMS (δ 0.00 ppm) for
1H NMR spectra and to the solvent signals (δ 77.0 ppm for CDCl3, δ
128.39 ppm for C6D6, and δ 123.87 ppm for pyridine-d5) for 13C
NMR spectra. Coupling constants (J) are reported in hertz. Data are
reported as follows: chemical shift, integration, multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br =
CONCLUSION
■
We have demonstrated a divergent synthesis of trans-fused
polycyclic ethers by a new [X + 2 + Y]-type convergent
method based on an oxiranyl anion strategy. The key feature of
this method is that seven- and eight-membered ether rings can
readily be constructed by introducing ring expansion at the
stage where intermediate ketones are formed. The ensuing
intramolecular acetalization and reductive etherification re-
actions allow for the construction of various types of octacyclic
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1
broad). H and 13C spectra are provided in Supporting Information.
reaction mixture was stirred at room temperature for 1 h. The
reaction was quenched with saturated aqueous NH4Cl solution, and
the reaction mixture was extracted with EtOAc. The extract was
washed with water, dried, and concentrated under reduced pressure.
Purification by flash chromatography (30% EtOAc in hexane) gave
ketone 8 (131 mg, 73% overall yield for the three steps) as a colorless
The low- and high-resolution mass spectra were recorded on
magnetic sector FAB or EI mass spectrometers.
(2S,3R,5S,6R)-5-(Benzyloxy)-6-((benzyloxy)methyl)-2-
(((((2R,3S)-3-((tert-butyldimethylsilyl)oxy)tetrahydro-2H-
pyran-2-yl)methyl)-2-(phenylsulfonyl)oxiran-2-yl)methyl)-3-
((triethylsilyl)oxy)tetrahydropyran (6). To a solution of epoxy
sulfones 426 (214 mg, 0.519 mmol, 64:36 mixture of isomers) and
triflate 522c (209 mg, 0.346 mmol) in THF (6 mL) and HMPA
(0.241 mL, 1.38 mmol) at −100 °C was added dropwise n-BuLi
(0.346 mL of a 1.6 M solution in n-hexane, 0.554 mmol). The
reaction mixture was stirred at −100 °C for 30 min, and then the
reaction was quenched with saturated aqueous NH4Cl solution. The
resulting mixture was allowed to warm to room temperature and
extracted with EtOAc. The extract was washed with water and brine,
dried, and concentrated under reduced pressure. Purification by flash
chromatography (20% EtOAc in hexane) afforded a 58:42 mixture of
oil. [α]23 +50.9 (c 1.00, CHCl3); IR (CHCl3) 1719, 1455, 1364,
D
1
1254, 1098, 839 cm−1; H NMR (400 MHz, CDCl3) δ 7.34−7.20
(10H, m, Ar), 4.62 and 4.55 (each 1H, d, J = 12.2 Hz), 4.59 and 4.42
(each 1H, d, J = 11.2 Hz), 3.99 (1H, dd, J = 6.4, 2.9 Hz), 3.80 (1H,
m), 3.76 (1H, dd, J = 10.7, 1.5 Hz), 3.67 (1H, dd, J = 10.7, 4.9 Hz),
3.58 (1H, ddd, J = 10.7, 9.3, 4.4 Hz), 3.47 (1H, ddd, J = 9.3, 4.9, 1.5
Hz), 3.41 (1H, ddd, J = 10.7, 9.3, 6.3 Hz), 3.36−3.18 (4H, m), 2.98
(1H, dd, J = 17.1, 5.9 Hz), 2.65 (1H, ddd, J = 11.7, 4.4, 4.4 Hz),
2.45−2.37 (2H, m), 1.96 (1H, m), 1.81 (1H, ddd, J = 14.2, 9.3, 3.4
Hz), 1.68−1.57 (2H, m), 1.55 (1H, q, J = 11.2 Hz), 1.39 (1H, m),
0.87 (9H, s), 0.05 (6H, s); 13C NMR (100 MHz, CDCl3) δ 206.8,
138.1, 137.9, 128.4, 128.3, 127.9, 127.8 (×2), 127.6, 79.8, 79.4, 78.5,
75.6, 74.0, 73.5, 72.1, 71.9, 71.1, 69.1, 67.3, 44.2, 35.2, 33.9, 33.5, 25.8,
25.6, 17.9, −4.1, −4.7; HRFABMS m/z calcd for C35H51O7Si (MH+)
611.3404, found 611.3420.
epoxy sulfones 6 (255 mg, 85%) as a pale yellow oil. [α]28 −15.5 (c
D
1.07, CHCl3); IR (CHCl3) 1454, 1324, 1098, 838 cm−1; 1H NMR for
the major isomer (CDCl3, 600 MHz) δ 7.96−7.92 (2H, m), 7.65−
7.60 (1H, m), 7.54−7.51 (2H, m), 7.34−7.20 (10H, m), 4.67 and
4.49 (each 1H, d, J = 12.1 Hz), 4.51 and 4.44 (each 1H, d, J = 11.5
Hz), 3.88 (1H, m), 3.79 (1H, dd, J = 11.0, 3.3 Hz), 3.65−3.51 (4H,
m), 3.40 (1H, ddd, J = 13.2, 8.8, 4.4 Hz), 3.33−3.11 (4H, m), 2.81
(1H, m), 2.48 (1H, dd, J = 15.0, 2.2 Hz), 2.39 (1H, ddd, J = 15.7, 9.5,
7.3 Hz), 2.32−2.26 (1H, m), 2.08−1.99 (1H, m), 1.69−1.59 (2H, m),
1.48−1.38 (2H, m), 1.19 (1H, dd, J = 15.0, 11.0 Hz), 0.91 (9H, s),
0.83 (9H, t, J = 8.0 Hz), 0.439 (3H, dq, J = 15.0, 8.0 Hz), 0.436 (3H,
dq, J = 15.0, 8.9 Hz), 0.14 (3H, s), 0.09 (3H, s); 13C NMR for the
major isomer (CDCl3, 150 MHz) δ 138.5, 138.4, 138.1, 133.8, 129.0
(×2), 128.4 (×2), 127.8 (×2), 127.64, 127.56, 81.9, 79.9, 78.8, 73.6,
72.7, 71.7, 71.4, 71.0, 70.3, 69.0, 67.7, 64.1, 39.6, 35.8, 33.5, 30.5, 25.8,
25.5, 17.9, 6.7, 4.9, −4.2, −4.7; 1H NMR for the minor isomer
(CDCl3, 600 MHz) δ 7.96−7.92 (2H, m), 7.65−7.60 (1H, m), 7.54−
7.51 (2H, m), 7.34−7.20 (10H, m), 4.64 and 4.51 (each 1H, d, J =
12.1 Hz), 4.50 and 4.42 (each 1H, d, J = 11.5 Hz), 3.76 (1H, m), 3.71
(1H, dd, J = 8.4, 2.6 Hz), 3.70 (1H, dd, J = 10.6, 3.7 Hz), 3.65−3.51
(2H, m), 3.33−3.11 (6H, m), 2.93 (1H, ddd, J = 15.0, 8.4, 2.2 Hz),
2.79 (1H, ddd, J = 15.0, 2.6, 2.6 Hz), 2.32−2.26 (1H, m), 2.13 (1H,
dd, J = 15.0, 9.5 Hz), 2.08−1.99 (2H, m), 1.69−1.59 (2H, m), 1.48−
1.38 (2H, m), 1.32 (1H, q, J = 11.7 Hz), 0.91 (9H, s), 0.78 (9H, t, J =
8.0 Hz), 0.36 (1H, dq, J = 15.1, 8.0 Hz), 0.33 (1H, dq, J = 15.1, 8.0
Hz), 0.12 (3H, s), 0.08 (3H, s); 13C NMR for the minor isomer
(CDCl3, 150 MHz) δ 138.5, 138.33, 138.28, 133.7, 129.04, 129.0,
128.3 (×2), 127.8 (×2), 127.7, 127.5, 80.4, 79.8, 77.0, 75.2, 73.4, 71.6,
71.5, 71.4, 69.0, 68.5, 67.4, 62.5, 39.6, 33.4, 31.5, 30.4, 25.8, 25.6, 17.9,
6.7, 4.8, −4.3, −4.7; HRFABMS m/z calcd for C47H71O9SSi2 (MH+)
867.4357, found 867.4356.
(2R,3S,4aR,6S,9aS)-3-(Benzyloxy)-2-((benzyloxy)methyl)-6-
(((2R,3S)-3-((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-
2-yl)methyl)hexahydro-2H-pyrano[3,2-b]oxepin-7(3H)-one (9).
To a suspension of ketone 8 (120 mg, 0.197 mmol) and powdered 4
Å molecular sieves (600 mg) in CH2Cl2 (6 mL) at −80 °C were
added BF3·OEt2 (0.121 mL, 0.983 mmol) and trimethylsilyldiazo-
methane (0.493 mL of a 2.0 M solution in hexanes, 0.986 mmol).
After being stirred at −80 °C for 3 h, the reaction was quenched with
saturated aqueous NaHCO3 solution. The resulting mixture was
allowed to warm to room temperature and extracted with EtOAc. The
extract was washed with water and brine, dried, and concentrated
under reduced pressure to afford 139 mg of the crude TMS ketone,
which was immediately used in the next reaction without further
purification.
A solution of the above TMS ketone (139 mg, 0.197 mmol) and
PPTS (50 mg, 0.199 mmol) in CH2Cl2 (2.5 mL) and MeOH (2.5
mL) was stirred at room temperature for 1 h. The reaction was
quenched with Et3N, and the reaction mixture was concentrated
under reduced pressure. The residue was purified by flash
chromatography (20% EtOAc in hexane) to give ketone 9 (91 mg,
74%) as a colorless oil. [α]24 +10.5 (c 0.16, CHCl3); IR (CHCl3)
D
1
1711, 1454, 1256, 1097 cm−1; H NMR (400 MHz, CDCl3) δ 7.33−
7.20 (10H, m, Ar), 4.60 and 4.54 (each 1H, d, J = 12.2 Hz), 4.58 and
4.39 (each 1H, d, J = 11.2 Hz), 3.96 (1H, dd, J = 6.8, 3.9 Hz), 3.78
(1H, m), 3.74 (1H, dd, J = 10.7, 1.5 Hz), 3.61 (1H, dd, J = 10.7, 4.9
Hz), 3.49−3.39 (2H, m), 3.37−3.19 (4H, m), 3.03 (1H, ddd, J =
11.2, 9.3, 4.4 Hz), 2.87 (1H, ddd, J = 13.7, 12.9, 2.0 Hz), 2.55 (1H,
ddd, J = 11.7, 4.4, 3.9 Hz), 2.32 (1H, dd, J = 11.2, 6.8 Hz), 2.24 (1H,
ddd, J = 9.2, 7.3, 2.4 Hz), 2.19 (1H, m), 1.96 (1H, m), 1.76 (1H, ddd,
J = 13.7, 9.3, 3.9 Hz), 1.67−1.49 (4H, m), 1.40 (1H, m), 0.88 (9H,
s), 0.05 (3H, s), 0.04 (3H, s); 13C NMR (100 MHz, CDCl3) δ 216.0,
138.2, 138.0, 128.4, 128.3, 127.9, 127.7 (×2), 127.6, 83.9, 80.7, 80.3,
80.0, 78.1, 73.5, 72.4, 71.3, 71.0, 69.2, 67.4, 37.1, 36.5, 36.3, 33.5, 29.2,
25.8, 25.5, 17.9, −3.9, −4.7; HRFABMS m/z calcd for C36H53O7Si
(MH+) 625.3561, found 625.3580.
(2S,4aS,6R,7S,8aR)-7-(Benzyloxy)-6-((benzyloxy)methyl)-2-
(((2R,3S)-3-((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-
2-yl)methyl)hexahydropyrano[3,2-b]pyran-3(2H)-one (8). A
solution of the TES ether 6 (255 mg, 0.294 mmol) and TsOH·H2O
(5.6 mg, 0.029 mmol) in CH2Cl2 (2.5 mL) and MeOH (2.5 mL) was
stirred at room temperature for 1 h. The reaction was quenched with
Et3N, and the reaction mixture was concentrated under reduced
pressure. Purification of the residue by flash chromatography (50→
80% EtOAc in hexane) afforded 201 mg of the secondary alcohol as a
colorless oil.
The secondary alcohol (201 mg, 0.267 mmol) prepared in the
previous step was dissolved in CH2Cl2 (5 mL), and the solution was
cooled to −15 °C. LiBr (46 mg, 0.53 mmol) and MgBr2·OEt2 (138
mg, 0.534 mmol) were added and the reaction mixture was stirred at
−15 °C for 30 min. The reaction was quenched with saturated
aqueous NaHCO3 solution, and the resulting mixture was extracted
with EtOAc. The extract was washed with water and brine, dried, and
concentrated under reduced pressure. Purification by flash chroma-
tography (40% EtOAc in hexane) provided bromo ketone 7 (171
mg) as a colorless oil.
(2R,3S,4aR,5aS,6aR,10aS,11aR,13aS)-3-(Benzyloxy)-2-
((benzyloxy)methyl)tetradecahydro-2H-pyrano[3,2-b]pyrano-
[2′,3′:5,6]pyrano[2,3-f ]oxepine (10). i. Acetalization of Ketone 9.
A solution of 9 (438 mg, 0.701 mmol) and TsOH·H2O (2.2 mg,
0.012 mmol) in CHCl3 (10 mL) and MeOH (10 mL) was stirred at
55 °C for 7 h. The reaction mixture was cooled to room temperature,
and the reaction was quenched with Et3N. The reaction mixture was
concentrated under reduced pressure. Purification by flash chroma-
tography (40% EtOAc in hexane) afforded methyl acetal 11a-OMe-10
(347 mg, 94%) as a colorless oil. (2R,3S,4aR,5aS,6aR,10aS,11a-
R,13aS)-3-(Benzyloxy)-2-((benzyloxy)methyl)-11a-methoxytetradeca-
hydro-2H-pyrano[3,2-b]pyrano[2′,3′:5,6]pyrano[2,3-f ]oxepine (11a-
To a solution of bromo ketone 7 (171 mg, 0.248 mmol) in CH2Cl2
(5 mL) was added DBU (0.039 mL, 0.26 mmol) at 0 °C, and the
OMe-10): [α]24 +4.7 (c 0.15, CHCl3); IR (CHCl3) 1454, 1242,
D
1
1067 cm−1; H NMR (400 MHz, CDCl3) δ 7.34−7.18 (10H, m, Ar),
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The Journal of Organic Chemistry
Article
4.61 and 4.54 (each 1H, d, J = 12.2 Hz), 4.57 and 4.37 (each 1H, d, J
= 11.2 Hz), 3.91 (1H, m), 3.73 (1H, dd, J = 10.7, 1.5 Hz), 3.61 (1H,
dd, J = 10.7, 5.4 Hz), 3.46 (1H, ddd, J = 11.2, 9.8, 4.9 Hz), 3.42 (1H,
dd, J = 10.7, 4.9 Hz), 3.41−3.25 (4H, m), 3.25 (3H, s), 3.21 (1H,
ddd, J = 13.2, 9.3, 3.9 Hz), 2.98 (1H, ddd, J = 10.7, 9.3, 4.9 Hz), 2.58
(1H, ddd, J = 11.2, 4.4, 4.4 Hz), 2.14 (1H, m), 2.08−1.70 (8H, m),
1.59 (1H, q, J = 11.2 Hz), 1.41 (1H, m); 13C NMR (100 MHz,
CDCl3) δ 138.2, 138.0, 128.4, 128.3, 127.8, 127.7, 127.7, 127.6, 100.0,
82.0, 81.1, 80.2, 79.1, 77.6, 73.5, 72.5, 70.8, 70.2, 69.3, 67.9, 47.3, 36.9,
32.3, 31.0, 28.9, 27.6, 25.7; HREIMS m/z calcd for C31H40O7 (M+)
524.2774, found 524.2750.
(4aR,6R,10aS)-2,2-Di-tert-butyl-6-(((tert-butyldiphenylsilyl)-
oxy)methyl)hexahydro-[1,3,2]dioxasilino[5,4-b]oxocin-8(9H)-
one (14). Colorless oil; [α]29 +11.2 (c 1.00, CHCl3); IR (CHCl3)
D
1
2961, 2933, 2860, 1697, 1473, 1105 cm−1; H NMR (CDCl3, 400
MHz) δ 7.66−7.64 (4H, m), 7.45−7.36 (6H, m), 4.05 (1H, ddd, J =
9.5, 5.0, 2.9 Hz), 3.98 (1H, dd, J = 10.5, 5.1 Hz), 3.84 (1H, dddd, J =
10.3, 5.6, 5.1, 2.4 Hz), 3.67 (1H, dd, J = 10.5, 10.2 Hz), 3.65 (1H, dd,
J = 10.7, 5.6 Hz), 3.55 (1H, dd, J = 10.7, 5.1 Hz), 3.10 (1H, ddd, J =
10.2, 9.5, 5.1 Hz), 2.95 (1H, dd, J = 10.9, 10.3 Hz), 2.73 (1H, ddd, J
= 16.1, 12.4, 1.9 Hz), 2.57 (1H, dddd, J = 15.1, 12.4, 2.9, 2.2 Hz),
2.43 (1H, dd, J = 10.9, 2.4 Hz), 2.41 (1H, ddd, J = 16.1, 7.1, 2.2 Hz),
2.00 (1H, dddd, J = 15.1, 7.1, 5.0, 1.9 Hz), 1.05 (9H, s), 1.02 (9H, s),
0.98 (9H, s); 13C NMR (CDCl3, 100 MHz) δ 214.6, 135.69, 135.66,
133.28, 133.25, 129.83, 129.81, 127.8 (×2), 82.7, 77.0, 76.2, 67.3,
66.7, 45.0, 39.3, 29.4, 27.4, 27.0, 26.7, 22.5, 20.1, 19.1; HRFABMS m/
z calcd for C33H51O5Si2 (MH+) 583.3275, found 583.3267.
ii. Reductive Etherification of Acetal 11a-OMe-10. To a solution
of 11a-OMe-10 (347 mg, 0.662 mmol) in CH2Cl2 (15 mL) at 0 °C
were added Et3SiH (0.529 mL, 3.312 mmol) and TMSOTf (0.360
mL, 1.986 mmol), and the reaction mixture was stirred at 0 °C for 30
min. The reaction was quenched with saturated aqueous NaHCO3
solution, and the resulting mixture was extracted with EtOAc. The
extract was washed with water and brine, dried, and concentrated
under reduced pressure. Purification by flash chromatography (40%
EtOAc in hexane) afforded the tetracyclic polyether 10 (302 mg,
(4aR,6S,9aS)-2,2-Di-tert-butyl-6-(((tert-butyldiphenylsilyl)-
oxy)methyl)-3′-(trimethylsilyl)hexahydrospiro[[1,3,2]-
dioxasilino[5,4-b]oxepine-7,2′-oxirane] (cis-15 and trans-15).
A 57:43 mixture of cis-15 and trans-15. Colorless oil; [α]29 −39.7 (c
D
1
1.23, CHCl3); IR (CHCl3) 2960, 2933, 2889, 2860, 1115 cm−1; H
92%) as a colorless solid. Mp 144−147 °C; [α]25 +30.9 (c 0.39,
D
NMR of the major cis-15 (CDCl3, 500 MHz) δ 7.74−7.67 (4H, m),
7.42−7.34 (6H, m), 4.06 (1H, dd, J = 10.8, 5.3 Hz), 3.89−3.84 (1H,
m), 3.83 (1H, dd, J = 10.8, 10.3 Hz), 3.78 (2H, d, J = 4.4 Hz), 3.61
(1H, t, J = 4.4 Hz), 3.37 (1H, ddd, J = 10.3, 9.4, 5.3 Hz), 2.53 (1H,
td, J = 13.5, 1.8 Hz), 2.26−2.20 (1H, m), 2.09 (1H, s), 1.43 (1H, tdd,
J = 13.5, 11.5, 1.5 Hz), 1.06 (9H, s), 1.03 (9H, s), 0.98 (9H, s), 1.00−
0.97 (1H, m), 0.13 (9H, s); 13C NMR of the major cis-15 (CDCl3,
125 MHz) δ 135.8, 135.7, 133.9, 133.6, 129.5, 129.53, 129.48, 127.52,
127.50, 79.9, 77.1 (×2), 67.0, 65.5, 64.9, 57.9, 36.3, 31.4, 27.5, 27.1,
1
CHCl3); IR (CHCl3) 1496, 1455, 1338, 1281, 1073 cm−1; H NMR
(400 MHz, C6D6) δ 7.34−7.06 (10H, m, Ar), 4.50 and 4.43 (each
1H, d, J = 12.7 Hz), 4.47 and 4.28 (each 1H, d, J = 12.2 Hz), 3.80
(1H, dd, J = 10.7, 2.0 Hz), 3.74 (1H, dd, J = 10.7, 4.4 Hz), 3.70 (1H,
m), 3.50 (1H, ddd, J = 11.2, 9.3, 4.9 Hz), 3.40 (1H, ddd, J = 9.3, 4.4,
2.0 Hz), 3.15 (1H, ddd, J = 10.7, 9.3, 3.9 Hz), 3.12−3.04 (3H, m),
3.10 (1H, ddd, J = 9.3, 9.3, 4.4 Hz), 2.89 (1H, ddd, J = 11.2, 11.2, 3.9
Hz), 2.84 (1H, ddd, J = 10.2, 10.2, 4.4 Hz), 2.47 (1H, ddd, J = 11.7,
4.4, 4.4 Hz), 2.46 (1H, ddd, J = 11.2, 4.4, 4.4 Hz), 1.95−1.85 (5H,
m), 1.75 (1H, q, J = 11.2 Hz), 1.55 (1H, q, J = 11.2 Hz), 1.49−1.25
(2H, m), 1.19 (1H, m); 13C NMR (100 MHz, CDCl3) δ 138.2, 138.0,
128.4, 128.3, 127.8, 127.7, 127.7, 127.6, 82.1, 81.8, 80.2, 79.5, 78.8,
77.9, 77.2, 73.5, 72.6, 70.9, 69.4, 67.9, 37.5, 37.1, 29.3, 29.3, 29.2,
25.5; HREIMS m/z calcd for C30H38O6 (M+) 494.2668, found
494.2650.
Ring Expansion Reaction of the Seven-Membered Ketone
11. To a suspension of ketone 1122b (357 mg, 0.629 mmol) and
powdered 4 Å molecular sieves (12.9 g) in CH2Cl2 (12 mL) at −80
°C were added BF3·OEt2 (0.232 mL, 1.89 mmol) and trimethylsi-
lyldiazomethane (1.57 mL of a 2.0 M solution in hexanes, 3.14
mmol). The reaction mixture was stirred at −80 °C for 2.3 h. The
reaction was quenched with saturated aqueous NaHCO3 solution.
The resulting mixture was allowed to warm to room temperature and
extracted with EtOAc. The extract was washed with water and brine,
dried, and concentrated under reduced pressure to afford the crude
TMS ketone 12 (441 mg), which was immediately used in the next
reaction without further purification.
1
26.7, 22.6, 19.9, 19.3, −1.9; H NMR of the minor trans-15 (CDCl3,
500 MHz) δ 7.74−7.67 (4H, m), 7.42−7.34 (6H, m), 4.13 (1H, dd, J
= 10.8, 5.3 Hz), 3.89−3.84 (2H, m), 3.74 (1H, dd, J = 11.5, 7.1 Hz),
3.65 (1H, dd, J = 11.5, 2.5 Hz), 3.57 (1H, dd, J = 7.1, 2.5 Hz), 3.30
(1H, ddd, J = 10.1, 9.4, 5.3 Hz), 2.26−2.20 (1H, m), 2.16 (1H, dddd,
J = 13.8, 7.3, 5.2, 1.2 Hz), 1.81 (1H, d, J = 0.9 Hz), 1.46 (1H, tdd, J =
13.5, 11.5, 1.6 Hz), 1.19 (1H, ddd, J = 14.0, 7.3, 1.6 Hz), 1.06 (9H,
s), 1.04 (9H, s), 1.00 (9H, s), 0.12 (9H, s); 13C NMR of the minor
trans-15 (CDCl3, 125 MHz) δ 135.75, 135.72, 134.0, 133.6, 129.6,
129.5, 127.6, 127.5, 85.0, 79.6, 77.4, 67.3, 65.7, 64.1, 58.8, 35.0, 27.5,
27.1, 26.9, 26.8, 22.6, 19.9, 19.2, −2.0; HRFABMS m/z calcd for
C36H58O5Si3Na (MNa+) 677.3490, found 677.3488. The stereo-
chemistry of the epoxides cis- and trans-15 was determined by
difference NOE experiments as shown in Figure 2.
(2R,3S,4aR,6S,10aS)-3-(Benzyloxy)-2-((benzyloxy)methyl)-6-
(((2R,3S)-3-((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-
2-yl)methyl)octahydropyrano[3,2-b]oxocin-7(6H)-one (17). To
a suspension of ketone 9 (29.7 mg, 0.048 mmol) and powdered 4 Å
molecular sieves (148 mg) in CH2Cl2 (2.5 mL) at −80 °C were
A solution of the TMS ketone 12 (441 mg, 0.629 mmol) and
PPTS (152 mg, 0.629 mmol) in CH2Cl2 (3 mL) and MeOH (3 mL)
was stirred at room temperature for 20 h. The reaction was quenched
with Et3N, and the reaction mixture was concentrated under reduced
pressure. Purification by flash chromatography (5→10% EtOAc in n-
hexane) gave ketone 13 (194 mg, 53%), the regioisomer 14 (18 mg,
5%), and a 57:43 mixture of epoxides cis- and trans-15 (69 mg, 16%).
(4aR,6S,10aS)-2,2-Di-tert-butyl-6-(((tert-butyldiphenylsilyl)-
oxy)methyl)hexahydro[1,3,2]dioxasilino[5,4-b]oxocin-7(6H)-
one (13). Colorless oil; [α]27 −85.6 (c 1.28, CHCl3); IR (CHCl3)
D
1
2933, 2860, 1713, 1473, 1110, 1069 cm−1; H NMR (CDCl3, 400
MHz) δ 7.70−7.67 (2H, m), 7.65−7.62 (2H, m), 7.46−7.36 (6H, m),
4.12 (1H, dd, J = 10.7, 4.9 Hz), 4.03 (1H, ddd, J = 9.3, 8.0, 1.5 Hz),
3.89 (1H, dd, J = 10.7, 10.3 Hz), 3.87 (1H, dd, J = 11.2, 5.6 Hz),
3.7943 (1H, dd, J = 11.2, 2.8 Hz), 3.7942 (1H, dd, J = 5.6, 2.8 Hz),
3.22 (1H, ddd, J = 10.3, 9.3, 4.9 Hz), 3.20 (1H, td, J = 11.5, 5.8 Hz),
2.21 (1H, ddd, J = 11.5, 5.6, 4.7 Hz), 2.05 (1H, m), 1.97 (1H, m),
1.87 (1H, m), 1.71 (1H, m), 1.06 (9H, s), 1.02 (9H, s), 0.96 (9H, s);
13C NMR (CDCl3, 100 MHz) δ 217.0, 135.7, 135.6, 133.00, 132.96,
129.8 (×2), 127.8, 127.7, 89.5, 82.3, 77.4, 67.2, 65.9, 38.5, 36.4, 27.4,
27.0, 26.6, 22.6, 22.5, 19.8, 19.1; HRFABMS m/z calcd for
C33H51O5Si2 (MH+) 583.3275, found 583.3280.
Figure 2. Difference NOE experiments of cis-15 and trans-15.
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added BF3·OEt2 (0.029 mL, 0.238 mmol) and trimethylsilyldiazo-
methane (0.238 mL of a 2.0 M solution in hexanes, 0.476 mmol).
After being stirred at −80 °C for 1 h, the reaction mixture was
warmed to −40 °C and stirring was continued for another 3 h. The
reaction was quenched with saturated aqueous NaHCO3 solution.
The resulting mixture was allowed to warm to room temperature and
extracted with EtOAc. The extract was washed with water and brine,
dried, and concentrated under reduced pressure to afford the crude
TMS ketone 16, which was immediately used in the next reaction
without further purification.
under reduced pressure to afford 19.0 mg of a white solid. Purification
by flash chromatography (30% EtOAc in n-hexane) gave 18 (15.9 mg,
89%) as a colorless solid. Mp 117−119 °C; [α]28 +27.8 (c 0.16,
D
CHCl3); IR (CHCl3) 1454, 1085 cm−1; 1H NMR (600 MHz,
C5D5N) δ 7.49−7.29 (10H, m, Ar), 4.74 and 4.55 (each 1H, d, J =
11.7 Hz), 4.66 and 4.61 (each 1H, d, J = 11.7 Hz), 3.98 (1H, br d, J =
11.0 Hz), 3.86 (1H, dd, J = 11.0, 5.1 Hz), 3.85 (1H, m), 3.66 (1H,
ddd, J = 11.0, 9.5, 4.4 Hz), 3.57 (1H, dd, J = 9.4, 5.1 Hz), 3.41 (1H,
ddd, J = 11.7, 10.3, 4.4 Hz), 3.34 (1H, ddd, J = 10.2, 10.2, 4.4 Hz),
3.30 (1H, m), 3.22−3.15 (2H, m), 3.02 (1H, ddd, J = 11.0, 9.5, 4.4
Hz), 2.99 (1H, ddd, J = 11.0, 9.5, 4.4 Hz), 2.70 (1H, ddd, J = 11.0,
11.0, 4.4 Hz), 2.45 (1H, ddd, J = 11.7, 11.0, 4.4 Hz), 2.25−2.19 (2H,
m), 2.03 (1H, m), 1.84 (1H, m), 1.74 (1H, q, J = 11.7 Hz), 1.66 (1H,
q, J = 11.0 Hz), 1.63−1.35 (6H, m); 13C NMR (150 MHz, C5D5N) δ
139.79, 139.76, 129.1, 129.0, 128.5 (×2), 128.3, 128.2, 84.2, 83.6,
82.4, 82.2, 80.8, 78.0, 77.8, 73.8, 74.5, 71.2, 70.8, 67.9, 40.1, 39.6, 37.5,
37.3, 30.1, 26.1, 21.1; HREIMS m/z calcd for C31H40O6 (M+)
508.2825, found 508.2816. The stereochemistry of 18 was determined
based on the NOESY experiments (600 MHz, C5D5N) as shown in
Figure 3.
A solution of the above TMS ketone 16 and PPTS (25 mg, 0.099
mmol) in CH2Cl2 (1.0 mL) and MeOH (1.0 mL) was stirred at room
temperature for 25 h. The reaction was quenched with Et3N (0.1
mL), and the reaction mixture was concentrated under reduced
pressure. The residue was purified by flash chromatography (20%
EtOAc in hexane) to give ketone 17 (16.0 mg, 53%) as a colorless oil.
[α]25 −18.4 (c 0.42, CHCl3); IR (CHCl3) 1709, 1454, 1254, 1099
D
1
cm−1; H NMR (400 MHz, C6D6) δ 7.35−7.07 (10H, m, Ar), 4.49
and 4.42 (each 1H, d, J = 12.2 Hz), 4.41 and 4.24 (each 1H, d, J =
11.7 Hz), 3.90 (1H, dd, J = 7.3, 3.4 Hz), 3.78 (1H, d, J = 10.7 Hz),
3.70 (1H, dd, J = 10.7, 4.4 Hz), 3.61 (1H, m), 3.42−3.35 (3H, m),
3.28 (1H, ddd, J = 9.8, 9.8, 4.4 Hz), 3.17 (1H, ddd, J = 11.2, 11.2, 5.4
Hz), 3.12−3.03 (2H, m), 2.79 (1H, ddd, J = 11.7, 8.8, 4.4 Hz), 2.44
(1H, ddd, J = 12.2, 12.2, 3.9 Hz), 2.40 (1H, ddd, J = 13.7, 7.3, 2.4
Hz), 2.14−2.05 (2H, m), 1.98 (1H, m), 1.83−1.71 (2H, m), 1.67−
1.51 (3H, m), 1.45−1.13 (3H, m), 0.97 (9H, s), 0.44 (3H, s), 0.01
(3H, s); 13C NMR (100 MHz, C6D6) δ 216.0, 139.3, 139.2, 128.7,
128.5, 128.4, 128.1, 127.9, 127.6, 85.5, 82.1, 81.6, 81.0, 78.5, 73.5,
72.8, 71.7, 70.9, 70.1, 67.4, 38.1, 37.6, 35.8, 33.9. 33.5, 26.0, 25.9, 23.7,
18.1, −3.9, −4.6; HRFABMS m/z calcd for C37H55O7Si (MH+)
639.3717, found 639.3691.
Figure 3. NOESY correlation between axial protons of 18.
(2S,3R,4aS,7aR,8aS,12aR,13aS,14aR)-2-(Benzyloxy)-3-
((benzyloxy)methyl)hexadecahydropyrano[3,2-b]pyrano-
[2′,3′:5,6]pyrano[2,3-g]oxocine (18). i. Acetalization of Ketone
17. A solution of 17 (28.0 mg, 0.0439 mmol) and TsOH·H2O (4.2
mg, 0.022 mmol) in 1,2-dichloroethane (1.0 mL) and MeOH (1.0
mL) was stirred at 55 °C for 1.5 h. An additional 4.2 mg of
TsOH·H2O (0.022 mmol) was added, and stirring was continued at
55 °C for another 4 h. Trimethyl orthoformate (0.50 mL, 4.6 mmol)
was then added, and the mixture was stirred at 55 °C for 1 h. The
reaction mixture was cooled to room temperature, and Et3N (0.5 mL)
was added. The resulting mixture was concentrated under reduced
pressure to afford 37 mg of a pale yellow oil. Purification by flash
chromatography (30% EtOAc in n-hexane) gave methyl acetal 7a-
OMe-18 (19.5 mg, 82%) as a colorless oil. (2S,3R,4aS,7aR,8-
aS,12aR,13aS,14aR)-2-(Benzyloxy)-3-((benzyloxy)methyl)-7a-
methoxyhexadecahydropyrano[3,2-b]pyrano[2′,3′:5,6]pyrano[2,3-g]-
(2S,3R,4aS,7aR,8aS,12aR,13aR,14aR)-2-(Benzyloxy)-3-
((benzyloxy)methyl)hexadecahydropyrano[3,2-b]pyrano-
[2′,3′:5,6]pyrano[2,3-g]oxocine (13a-epi-18). To a suspension of
ketone 9 (39.1 mg, 0.063 mmol) and powdered 4 Å molecular sieves
(196 mg) in CH2Cl2 (2.5 mL) at −40 °C were added BF3·OEt2
(0.038 mL, 0.312 mmol) and trimethylsilyldiazomethane (0.314 mL
of a 2.0 M solution in hexanes, 0.628 mmol), and the reaction mixture
was stirred at −40 °C for 2 h. The reaction was quenched with
saturated aqueous NaHCO3 solution. The reaction mixture was
allowed to warm to room temperature and extracted with EtOAc. The
extract was washed with water and brine, dried, and concentrated
under reduced pressure to afford the crude α-silyl ketone 16, which
was immediately used in the next reaction without further
purification.
To a solution of the above silyl ketone 16 in THF (2 mL) was
added TBAF (0.324 mL of a 1 M solution in THF, 0.324 mmol), and
the reaction mixture was stirred at room temperature for 2 h. The
reaction mixture was concentrated under reduced pressure, and the
residue was purified by flash chromatography (60% EtOAc in hexane)
to afford hemiacetal 19 (21.4 mg, 65%).
oxocine (7a-OMe-18): [α]29 −6.8 (c 1.63, CHCl3); IR (CHCl3)
D
3010, 2946, 2867, 1454, 1100, 1082, 1062 cm−1; 1H NMR (600 MHz,
CDCl3) δ 7.34−7.20 (10H, m), 4.59 and 4.54 (each 1H, d, J = 12.4
Hz), 4.56 and 4.37 (each 1H, d, J = 11.3 Hz), 3.90 (1H, m), 3.72
(1H, dd, J = 10.6, 1.8 Hz), 3.58 (1H, dd, J = 10.6, 5.1 Hz), 3.43 (1H,
dd, J = 10.6, 5.5 Hz), 3.42 (1H, ddd, J = 11.0, 9.2, 4.4 Hz), 3.35 (1H,
dd, J = 11.0, 3.3 Hz), 3.34 (1H, ddd, J = 9.2, 5.1, 1.8 Hz), 3.22 (1H,
ddd, J = 11.3, 9.1, 4.4 Hz), 3.19 (3H, s), 3.19−3.17 (2H, m), 2.93
(1H, ddd, J = 10.6, 9.1, 5.1 Hz), 2.44 (1H, ddd, J = 12.1, 4.4, 4.4 Hz),
2.30−2.24 (2H, m), 2.00−1.93 (3H, m), 1.84 (1H, m), 1.75−1.63
(4H, m), 1.45 (1H, m), 1.40−1.35 (2H, m); 13C NMR (150 MHz,
CDCl3) δ 138.3, 138.1, 128.33, 128.26, 127.8, 127.7, 127.6, 127.5,
98.5, 85.3, 84.7, 81.1, 79.7, 77.1, 73.4, 72.6, 70.9, 69.4, 69.3, 67.8, 47.5,
38.4, 37.4, 37.1, 34.3, 28.9, 25.6, 17.7; MS (EI) 538 (M+), 506 (M −
MeOH); HREIMS calcd for C32H42O7 (M+) 538.2931, found
538.2926.
To a solution of hemiacetal 19 (19.3 mg, 0.037 mmol, mixture of
diastereomers) in CH2Cl2 (1 mL) at 0 °C were added Et3SiH (0.059
mL, 0.369 mmol) and TMSOTf (0.330 mL, 0.182 mmol), and the
reaction mixture was stirred at 0 °C for 30 min. The reaction was
quenched with saturated aqueous NaHCO3 solution, and the reaction
mixture was extracted with EtOAc. The extract was washed with
water and brine, dried, and concentrated under reduced pressure.
Purification by flash chromatography (30→40% EtOAc in hexane)
gave the tetracyclic polyethers 18 (7.1 mg, 36%) and 13a-epi-18 (7.1
mg, 38%).
13a-epi-18. [α]28D +29.7 (c 0.16, CHCl3); IR (CHCl3) 1454, 1094
ii. Reductive Etherification of Acetal 7a-OMe-18. To a solution of
7a-OMe-18 (19.0 mg, 0.0353 mmol) and Et3SiH (0.107 mL, 0.670
mmol) in CH2Cl2 (2 mL) at 0 °C was added TMSOTf (0.032 mL,
0.177 mmol), and the reaction mixture was stirred at 0 °C for 1.5 h.
The reaction was quenched with saturated aqueous NaHCO3 solution
(3 mL), and the resulting mixture was extracted with EtOAc. The
extract was washed with water and brine, dried, and concentrated
1
cm−1; H NMR (600 MHz, C6D6) δ 7.34−7.06 (10H, m, Ar), 4.52
and 4.56 (each 1H, d, J = 12.5 Hz), 4.38 and 4.17 (each 1H, d, J =
11.7 Hz), 3.87 (1H, br d, J = 11.0 Hz), 3.74 (1H, m), 3.71 (1H, dd, J
= 10.3, 5.1 Hz), 3.61 (1H, ddd, J = 11.7, 8.8, 3.7 Hz), 3.49−3.44 (2H,
m), 3.35 (1H, ddd, J = 10.3, 10.3, 5.1 Hz), 3.30 (1H, br s), 3.22−3.15
(2H, m), 3.06 (1H, br t, J = 5.1 Hz), 2.99 (1H, ddd, J = 9.5, 9.5, 4.4
H
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The Journal of Organic Chemistry
Article
Hz), 2.29 (1H, ddd, J = 11.7, 3.7, 3.7 Hz), 2.24 (1H, m), 2.05 (1H,
ddd, J = 13.2, 3.7, 3.7 Hz), 2.02−1.94 (3H, m), 1.65 (1H, m), 1.55−
1.49 (3H, m), 1.48 (1H, q, J = 11.0 Hz), 1.38−1.16 (3H, m); 13C
NMR (150 MHz, C6D6) δ 139.7, 139.5, 128.92, 128.87, 128.3, 128.2,
128.1, 127.9, 81.6, 79.0, 78.2 (×2), 76.8, 75.3, 74.0, 73.9, 71.3, 70.8,
69.4, 68.3, 39.0, 35.5, 35.7, 31.9, 30.4, 26.6, 19.1; HREIMS m/z calcd
for C31H40O6 (M+) 508.2825, found 508.2844. The stereochemistry
was determined based on the value of the coupling constant as shown
in Figure 4.
67.9, 66.1, 40.8, 37.4, 29.2, 29.1, 28.9, 25.4, 6.7, 4.9; HREIMS m/z
calcd for C23H39F3O8SSi (M+) 560.2087, found 560.2103.
( 2 R , 4a R , 5 a S , 7a R , 8 a S , 1 2a R , 1 3 a S , 14 a R , 1 5a S ) - 2 -
(((2S,3R,4aS,6R,7S,8aR)-7-(Benzyloxy)-6-((benzyloxy)methyl)-3-
((tert-butyldimethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-
yl)methyl)hexadecahydropyrano[2′,3′:5,6]pyrano[3,2-b]-
pyrano[2′,3′:5,6]pyrano[2,3-f]oxepin-3(2H)-one (28) from tri-
flate 2 and epoxy sulfone 3. i. Coupling Reaction. To a solution
of triflate 2 (249 mg, 0.445 mmol) and epoxy sulfone 326 (618 mg,
0.890 mmol, 29:19:40:12 mixture of diastereomers) in THF (12 mL)
and HMPA (0.310 mL, 1.782 mmol), at −100 °C, was added n-BuLi
(0.584 mL of a 1.6 M solution in hexane, 0.935 mmol) in a dropwise
fashion. After being stirred at −100 °C for 30 min, the reaction was
quenched with saturated aqueous NH4Cl solution. The reaction
mixture was allowed to warm to room temperature and extracted with
EtOAc. The extract was washed with water and brine, dried, and
concentrated under reduced pressure. Purification of the residue by
flash chromatography (6→20% EtOAc in CH2Cl2) afforded the
coupling product 27 (468 mg, 95%) as a pale yellow oil, as well as the
recovered epoxy sulfone 3 (255 mg).
ii. Removal of the Triethylsilyl Group. A solution of the coupling
product 27 (468 mg, 0.418 mmol) and TsOH·H2O (8 mg, 0.042
mmol) in CH2Cl2 (4 mL) and MeOH (4 mL) was stirred at room
temperature for 1 h. The reaction was quenched with Et3N, and the
reaction mixture was concentrated under reduced pressure.
Purification of the residue by flash chromatography (70% EtOAc in
n-hexane) gave hydroxy epoxy sulfone (428 mg, 100%) as a colorless
oil.
iii. Preparation of Bromo Ketone. To a suspension of hydroxy
epoxy sulfone (428 mg, 0.432 mmol) and LiBr (75 mg, 0.864 mmol)
in CH2Cl2 (5 mL) at −15 °C was added MgBr2·OEt2 (223 mg, 0.864
mmol). The reaction mixture was stirred at −15 °C for 30 min and
then at −5 °C for 2 h. The reaction was quenched with saturated
aqueous NaHCO3 solution, and the reaction mixture was extracted
with EtOAc. The extract was washed with water and brine, dried, and
concentrated under reduced pressure. Purification of the residue by
flash chromatography (60% EtOAc in hexane) afforded the bromo
ketone (389 mg, 97%) as a colorless oil.
Figure 4. Coupling constants of 13a-epi-18..
(2R,3S,4aR,5aS,6aR,10aS,11aR,13aS)-2-(Hydroxymethyl)-
tetradecahydro-2H-pyrano[3,2-b]pyrano[2′,3′:5,6]pyrano[2,3-
f]oxepin-3-ol (26). A mixture of benzyl ether 10 (302 mg, 0.611
mmol) and Pd(OH)2/C (60.4 mg) in EtOAc (12 mL) was stirred
vigorously under a hydrogen atmosphere at room temperature for 18
h. The reaction mixture was diluted with MeOH (12 mL) to dissolve
the precipitated product. The catalyst was removed by filtration
through a short pad of Celite, and the pad was washed thoroughly
with MeOH. The combined filtrate and washings were concentrated
under reduced pressure. The residue was purified by flash
chromatography (6→10% MeOH in EtOAc) to afford diol 26 (183
mg, 95%) as a colorless solid. Mp 212−213 °C; [α]29 +3.6 (c 1.02,
D
CHCl3); IR (CHCl3) 3442, 1456, 1345, 1280, 1093 cm−1; H NMR
1
(600 MHz, CDCl3) δ 3.90 (1H, br d, J = 11.7 Hz), 3.83 (1H. ddd, J =
11.4, 6.0, 4.2 Hz), 3.75 (1H, ddd, J = 11.4, 6.0, 4.8 Hz), 3.63 (1H, m),
3.36 (1H, m), 3.32 (1H, ddd, J = 11.0, 11.0, 3.7 Hz), 3.27 (1H, ddd, J
= 11.0, 11.0, 4.4 Hz), 3.21 (2H, m), 3.15 (1H, ddd, J = 8.4, 4.2, 4.2
Hz), 2.96 (2H, m), 2.60 (1H, d, J = 5.4 Hz, OH), 2.40 (1H, ddd, J =
12.0, 4.2, 4.2 Hz), 2.36 (1H, t, J = 6.0 Hz, OH), 2.30 (1H, ddd, J =
11.4, 3.3, 3.3 Hz), 2.06−1.98 (3H, m), 1.91−1.84 (2H, m), 1.75−1.68
(2H, m), 1.52 (2H, q, J = 12.0 Hz), 1.40 (1H, m); 13C NMR (150
MHz, CDCl3) δ 82.0, 81.5, 81.1, 79.5, 78.8, 77.9, 77.2, 67.8, 66.8,
63.0, 40.2, 37.4, 29.2, 29.16, 29.1, 25.4; HREIMS m/z calcd for
C16H26O6 (M+) 314.1729, found 314.1754.
iv. Cyclization with DBU. To a solution of bromo ketone (389 mg,
0.418 mmol) in CH2Cl2 (5 mL) was added DBU (0.066 mL, 0.439
mmol) at room temperature, and the solution was stirred for 30 min.
The reaction was quenched with saturated aqueous NH4Cl solution,
and the reaction mixture was extracted with EtOAc. The extract was
washed with water, dried, and concentrated under reduced pressure.
Purification by flash chromatography (40% EtOAc in hexane) gave
ketone 28 (290 mg, 82%) as a colorless oil. [α]22 −9.2 (c 1.0,
D
1
CHCl3); IR (CHCl3) 1723, 1455, 1344, 1256, 1087, 838 cm−1; H
NMR (400 MHz, CDCl3) δ 7.39−7.19 (10H, m, Ar), 4.61 and 4.54
(each 1H, d, J = 12.2 Hz), 4.53 and 4.40 (each 1H, d, J = 11.7 Hz),
3.99 (1H, dd, J = 5.4, 4.4 Hz), 3.91 (1H, br d, J = 11.2 Hz), 3.74 (1H,
dd, J = 10.7, 1.5 Hz), 3.64 (1H, dd, J = 10.7, 5.4 Hz), 3.52−3.20
(11H, m), 3.04−2.91 (4H, m), 2.88 (1H, dd, J = 16.1, 4.9 Hz), 2.45
(1H, ddd, J = 11.7, 4.4, 4.4 Hz), 2.40−2.28 (5H, m), 2.11−2.00 (3H,
m), 1.94−1.86 (2H, m), 1.78 (1H, ddd, J = 14.2, 8.8, 4.4 Hz), 1.75−
1.68 (2H, m), 1.58 (1H, q, J = 10.7 Hz), 1.53 (1H, q, J = 11.7 Hz),
1.50 (1H, q, J = 11.2 Hz), 1.41 (1H, m), 1.40 (1H, q, J = 11.2 Hz),
0.86 (9H, s), 0.54 (3H, s), 0.04 (3H, s); 13C NMR (100 MHz,
CDCl3) δ 206.1, 138.2, 138.0, 128.4, 128.3, 127.9, 127.8 (×2), 127.6,
82.0, 81.5, 80.1, 79.8, 79.6, 79.0, 78.2, 78.0, 77.2, 76.1, 75.9, 75.7, 75.1,
73.5, 72.6, 71.2, 70.9, 69.3, 67.9, 44.5, 39.2, 37.4, 37.0, 35.0, 32.7, 29.2
(×2), 29.1, 25.7, 25.4, 17.9, −4.1, −4.7; HRFABMS m/z calcd for
C48H69O11Si (MH+) 849.4604, found 849.4624.
(2R,3S,4aR,5aS,6aR,7aS,8aR,9aS,10aR,14aS,15aR,17a-
S,18aR,19aS,20aR,21aS)-3-(Benzyloxy)-2-((benzyloxy)methyl)-
19a-methoxyhexacosahydro-2H-pyrano[2‴′,3‴′:5‴,6‴]-
pyrano[2‴,3‴:5″,6″]pyrano[2″,3″:5′,6′]pyrano[2′,3′:5,6]-
pyrano[3,2-b]pyrano[2′,3′:5,6]pyrano[2,3-f ]oxepine (29). A
solution of ketone 28 (10.0 mg, 0.012 mmol) and TsOH·H2O (2.3
mg, 0.012 mmol) in 1,2-dichloroethane (2 mL) and MeOH (1 mL)
was stirred at 80 °C for 15 h. Trimethyl orthoformate (0.130 mL,
1.19 mmol) was then added, and the reaction mixture was stirred at
((2R,3S,4aR,5aS,6aR,10aS,11aR,13aS)-3-((Triethylsilyl)oxy)-
tetradecahydro-2H-pyrano[3,2-b]pyrano[2′,3′:5,6]pyrano[2,3-
f ]oxepin-2-yl)methyl Trifluoromethanesulfonate (2). To a
solution of diol 26 (183 mg, 0.583 mmol) and 2,6-lutidine (0.405
mL, 3.498 mmol) in THF (12 mL) at −80 °C was added Tf2O
(0.100 mL, 0.595 mmol). After the reaction mixture was stirred at
−80 °C for 30 min, TESOTf (0.158 mL, 0.699 mmol) was added and
the reaction mixture was stirred for another 40 min. The reaction was
quenched with saturated aqueous NaHCO3 solution. The mixture was
allowed to warm to room temperature and extracted with EtOAc. The
extract was washed with water and brine, dried, and concentrated
under reduced pressure. Purification by flash chromatography (10→
20% EtOAc in hexane) gave triflate 2 (249 mg, 76%) as a pale yellow
oil. [α]26 +32.0 (c 1.28, CHCl3); IR (CHCl3) 1456, 1415, 1245,
D
1145, 1090, 945, 822 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.70 (1H,
dd, J = 10.7, 1.5 Hz), 4.52 (1H, dd, J = 10.7, 5.9 Hz), 3.90 (1H, br d,
J = 11.2 Hz), 3.57 (1H, ddd, J = 10.7, 9.9, 4.9 Hz), 3.40−3.28 (3H,
m), 3.27−3.16 (3H, m), 3.00−2.92 (2H, m), 2.35 (1H, ddd, J = 11.7,
4.4, 4.4 Hz), 2.30 (1H, ddd, J = 11.7, 3.9, 3.9 Hz), 2.08−1.97 (3H,
m), 1.92−1.82 (2H, m), 1.75−1.67 (1H, m), 1.55 (1H, q, J = 11.7
Hz), 1.51 (1H, q, J = 11.2 Hz), 1.40 (1H, m), 0.96 (9H, t, J = 7.8
Hz), 0.61 (6H, q, J = 7.8 Hz); 13C NMR (100 MHz, CDCl3) δ 118.6
(q, JC−F = 319 Hz, CF3), 82.0, 81.6, 79.6, 79.1, 78.1, 77.9, 77.2, 75.5,
I
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The Journal of Organic Chemistry
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80 °C for another 3 h. The solution was cooled to room temperature
and the reaction was quenched with Et3N (0.10 mL). The resulting
mixture was concentrated under reduced pressure to afford 29.8 mg
of a white solid. Purification by flash chromatography (25% EtOAc in
CH2Cl2) afforded 29 (6.3 mg, 71%) as a colorless solid. Mp 253−254
10.8, 4.7 Hz), 3.54 (1H, ddd, J = 10.9, 9.5, 4.7 Hz), 3.42 (1H, ddd, J
= 9.5, 4.7, 1.5 Hz), 3.38−3.26 (5H, m), 3.23−3.19 (2H, m), 3.14−
3.08 (3H, m), 3.05 (1H, ddd, J = 11.4, 9.1, 4.0 Hz), 2.98−2.93 (2H,
m), 2.55 (1H, ddd, J = 11.3, 4.7, 4.0 Hz), 2.37 (1H, ddd, J = 11.4, 4.1,
4.1 Hz), 2.31 (1H, brs), 2.30−2.28 (2H, m), 2.19 (1H, dd, J = 12.4,
4.8 Hz), 2.12 (1H, ddd, J = 11.3, 4.0, 4.0 Hz), 2.05−1.99 (3H, m),
1.90−1.85 (2H, m), 1.81 (1H, ddd, J = 11.7, 11.7, 11.7 Hz), 1.72−
1.68 (2H, m), 1.65−1.45 (5H, m), 1.40 (1H, m); 13C NMR (150
MHz, CDCl3) δ 138.2, 137.9, 128.40, 128.35, 127.9, 127.79, 127.76,
127.6, 94.0, 82.3, 81.9, 80.5, 79.7, 79.4, 78.2, 77.9, 77.8, 77.3, 77.0,
76.8, 76.4, 76.3, 73.5, 72.3, 71.0, 69.1, 68.6, 67.9, 41.4, 37.5, 36.8, 35.1,
34.8, 29.9, 29.3 (×2), 29.1, 25.5; MS (FAB) 735 (M + H), 717 (M −
OH); HRFABMS calcd for C42H55O11 (MH+) 735.3744, found
735.3784.
23
°C; [α]D +48.3 (c 0.99, CHCl3); IR (CHCl3) 3010, 2947, 2873,
1
1455, 1078 cm−1; H NMR (400 MHz, CDCl3) δ 7.35−7.19 (10H,
m), 4.62 and 4.54 (each 1H, d, J = 12.2 Hz), 4.56 and 4.38 (each 1H,
d, J = 11.7 Hz), 3.90 (1H, d, J = 10.7 Hz), 3.75 (1H, dd, J = 10.7, 1.5
Hz), 3.66 (1H, d, J = 10.7, 4.9 Hz), 3.54 (1H, ddd, J = 10.7, 9.8, 4.4
Hz), 3.77−3.02 (12H, m), 3.24 (3H, s), 2.96 (2H, m), 2.56 (1H, ddd,
J = 11.7, 4.4, 4.4 Hz), 2.48 (1H, dd, J = 12.9, 3.9 Hz), 2.38−2.29 (3H,
m), 2.08−1.83 (7H, m), 1.73−1.34 (8H, m); 13C NMR (100 MHz,
CDCl3) δ 138.1, 137.8, 128.4, 128.3, 127.9, 127.8 (×2), 127.6, 96.3,
82.2, 81.9, 80.5, 79.7, 79.5, 78.6, 78.1, 77.9, 77.3, 77.1, 76.9, 76.3, 75.4,
73.4, 72.3, 71.0, 69.1, 68.6, 67.8, 47.2, 37.4, 37.4, 36.7, 35.1, 34.7, 34.6,
29.7, 29.2, 29.1, 25.4; MS (FAB) 749 (M + H), 717 (M − OMe);
HRFABMS m/z calcd for C43H57O11 (MH+) 749.3895, found
749.3876.
ii. Thioacetalization of Hemiacetal 19a-OH-31. To a solution of
19a-OH-31 (16.5 mg, 0.0225 mmol) in CH2Cl2 (1 mL) and
nitromethane (1 mL) were added EtSH (0.40 mL, 5.4 mmol) and
Zn(OTf)2 (11 mg, 0.03 mmol), and the reaction mixture was stirred
at room temperature for 2 h. An additional 66 mg of Zn(OTf)2 (0.18
mmol) was added, and stirring was continued for another 10 h. The
reaction was quenched with water (2 mL), and the resulting mixture
was extracted with CH2Cl2. The extract was washed with 10%
aqueous NaOH solution and brine, dried, and concentrated under
reduced pressure. Purification by flash chromatography (0→4%
MeOH in CHCl3) afforded thioacetal 31 (17.4 mg, 94%) as a
colorless solid. Mp 210−212 °C; [α]29D +63.3 (c 1.45, CHCl3); 3010,
(2R,3S,4aR,5aS,6aR,7aS,8aR,9aS,10aR,14aS,15aR,17a-
S,18aR,19aS,20aR,21aS)-3-(Benzyloxy)-2-((benzyloxy)methyl)-
hexacosahydro-2H-pyrano[2‴′,3‴′:5‴,6‴]pyrano-
[2‴,3‴:5″,6″]pyrano[2″,3″:5′,6′]pyrano[2′,3′:5,6]pyrano[3,2-
b]pyrano[2′,3′:5,6]pyrano[2,3-f ]oxepine (30). To a solution of
methyl acetal 29 (6.3 mg, 0.0084 mmol) and Et3SiH (0.030 mL, 0.19
mmol) in CH2Cl2 (0.6 mL) at 0 °C was added TMSOTf (0.010 mL,
0.055 mmol). The reaction mixture was stirred at 0 °C for 1 h, and
then the reaction was quenched with saturated aqueous NaHCO3
solution. The resulting mixture was extracted with CHCl3, and the
extract was washed brine, dried, and concentrated under reduced
pressure to afford 7.2 mg of a white solid. Flash chromatography (2%
MeOH in CHCl3) provided 6.8 mg of a white solid. Further
purification by flash chromatography (0→4% MeOH in CHCl3)
afforded 30 (6.0 mg, 99%) as a colorless solid. Mp 356−357 °C;
1
2938, 2872, 1455, 1075 cm−1; H NMR (500 MHz, CDCl3) δ 7.33−
7.19 (10H, m), 4.62 and 4.55 (each 1H, d, J = 12.4 Hz), 4.56 and
4.39 (each 1H, d, J = 11.5 Hz), 4.04 (1H, ddd, J = 12.4, 8.7, 3.7 Hz),
3.90 (1H, d, J = 11.5 Hz), 3.76−3.70 (2H, m), 3.65 (1H, dd, J = 11.0,
4.8 Hz), 3.53 (1H, ddd, J = 10.8, 9.2, 4.3 Hz), 3.44 (1H, dd, J = 9.2,
4.3 Hz), 3.37−3.29 (4H, m), 3.25−3.11 (5H, m), 3.05 (1H, ddd, J =
11.9, 8.3, 3.9 Hz), 2.97−2.95 (2H, m), 2.58−2.27 (7H, m), 2.10−1.97
(5H, m), 1.90−1.84 (2H, m), 1.72−1.38 (8H, m), 1.25 (3H, t, J = 7.4
Hz); 13C NMR (150 MHz, CDCl3) δ 138.2, 137.9, 128.4, 128.3,
127.9, 127.8 (×2), 127.6, 88.2, 82.3, 81.8, 80.7, 80.5, 79.6, 79.5, 79.2,
77.9, 77.5, 77.2, 76.9, 76.40, 76.37, 73.4, 72.3, 71.0, 69.1, 68.9, 67.8,
40.0, 37.4, 36.9, 35.1, 34.8, 31.0, 29.30, 29.26, 29.2, 25.4, 20.2, 14.5;
MS (FAB) 779 (M + H), 717 (M − SEt); HRFABMS calcd for
C44H59O10S (MH+) 779.3829, found 779.3843.
22
[α]D +24.5 (c 0.11, CHCl3); IR (CHCl3) 3009, 2935, 2873, 1455,
1
1067 cm−1; H NMR (400 MHz, CDCl3) δ 7.34−7.19 (10H, m),
4.62 and 4.55 (each 1H, d, J = 12.2 Hz), 4.56 and 4.39 (each 1H, d, J
= 11.2 Hz), 3.90 (1H, d, J = 11.2 Hz), 3.75 (1H, d, J = 10.7, 1.5 Hz),
3.66 (1H, d, J = 10.7, 4.9 Hz), 3.53 (1H, ddd, J = 10.7, 9.8, 4.9 Hz),
3.43 (1H, ddd, J = 9.8, 4.9, 1.5 Hz), 3.39−3.30 (3H, m), 3.24−3.17
(2H, m), 3.14−2.93 (10H, m), 2.56 (1H, ddd, J = 11.2, 4.4, 4.4 Hz),
2.41−2.28 (5H, m), 2.04−1.99 (3H, m), 1.93−1.88 (2H, m), 1.70−
1.68 (2H, m), 1.55−1.38 (7H, m); 13C NMR (100 MHz, CDCl3) δ
138.2, 137.9, 128.4, 128.3, 127.9, 127.79, 127.76, 127.6, 82.1, 82.0,
80.5, 79.7, 79.3, 77.9, 77.3, 77.1 (×3), 76.9, 76.8, 76.69, 76.66, 76.3,
73.5, 72.3, 71.0, 69.1, 67.9, 37.4, 37.0, 35.1 (×4), 29.3 (×2), 29.2,
25.5; MS (FAB) 719 (M + H); HRFABMS calcd for C42H54O10
(MH+) 719.3790, found 719.3792.
(2R,3S,4aR,5aS,6aR,7aS,8aR,9aS,10aR,14aS,15aR,17a-
S,18aR,19aS,20aR,21aS)-3-(Benzyloxy)-2-((benzyloxy)methyl)-
19a-methylhexacosahydro-2H-pyrano[2‴′,3‴′:5‴,6‴]pyrano-
[2‴,3‴:5″,6″]pyrano[2″,3″:5′,6′]pyrano[2′,3′:5,6]pyrano[3,2-
b]pyrano[2′,3′:5,6]pyrano[2,3-f ]oxepine (32). To a solution of
thioacetal 31 (4.5 mg, 0.0058 mmol) in CH2Cl2 (0.5 mL) at 0 °C was
added m-chloroperbenzoic acid (2.0 mg, 0.0116 mmol). The reaction
mixture was stirred at room temperature for 2 h and then recooled to
0 °C. A 2.0 M solution of AlMe3 in heptane (0.029 mL, 0.058 mmol)
was added, and the reaction mixture was stirred at room temperature
for 0.5 h. An additional 0.10 mL of a 2.0 M solution of AlMe3 in
heptane (0.20 mmol) was added, and stirring was continued for
another 3 h. The reaction was quenched with saturated aqueous
potassium sodium tartrate solution (2 mL), and the resulting mixture
was extracted with CH2Cl2. The extract was washed with brine, dried,
and concentrated under reduced pressure. Purification by flash
chromatography (0→4% MeOH in CHCl3) afforded 32 (3.1 mg,
(2R,3S,4aR,5aS,6aR,7aS,8aR,9aS,10aR,14aS,15aR,17a-
S,18aR,19aR,20aR,21aS)-3-(Benzyloxy)-2-((benzyloxy)methyl)-
19a-(ethylthio)hexacosahydro-2H-pyrano[2‴′,3‴′:5‴,6‴]-
pyrano[2‴,3‴:5″,6″]pyrano[2″,3″:5′,6′]pyrano[2′,3′:5,6]-
pyrano[3,2-b]pyrano[2′,3′:5,6]pyrano[2,3-f ]oxepine (31).
i. Hemiacetalization of Ketone 28. A solution of ketone 28 (10
mg, 0.012 mmol) and TsOH·H2O (2.3 mg, 0.012 mmol) in THF (1
mL) and water (0.1 mL) was stirred at 65 °C for 7 h. The solution
was cooled to room temperature, and the reaction was quenched with
Et3N (1 mL). The resulting mixture was concentrated under reduced
pressure. Purification by flash chromatography (0→10% MeOH in
CHCl3) provided 6.0 mg of a colorless solid. Further purification by
flash chromatography (0→4% MeOH in CHCl3) afforded hemiacetal
19a-OH-31 (5.2 mg, 60%) as a colorless solid. (2R,3S,4aR,5aS,6aR,7-
aS,8aR,9aS,10aR,14aS,15aR,17aS,18aR,19aS,20aR,21aS)-3-(Benzyl-
oxy)-2-((benzyloxy)methyl)hexacosahydro-2H-pyrano-
[2‴′,3‴′:5‴,6‴]pyrano[2‴,3‴:5″,6″]pyrano[2″,3″:5′,6′]pyrano-
[2′,3′:5,6]pyrano[3,2-b]pyrano[2′,3′:5,6]pyrano[2,3-f ]oxepin-19a-ol
73%) as a colorless solid. Mp 209−211 °C; [α]28 +36.8 (c 0.26,
D
1
CHCl3); IR (CHCl3) 3010, 2949, 2873, 1456, 1082 cm−1; H NMR
(600 MHz, CDCl3) δ 7.34−7.20 (10H, m), 4.62 and 4.54 (each 1H,
d, J = 12.4 Hz), 4.56 and 4.39 (each 1H, d, J = 11.3 Hz), 3.90 (1H, d,
J = 11.0 Hz), 3.75 (1H, dd, J = 10.6, 1.4 Hz), 3.66 (1H, dd, J = 10.6,
4.8 Hz), 3.54 (1H, ddd, J = 10.6, 9.5, 4.8 Hz), 3.44−3.40 (2H, m),
3.38−3.30 (3H, m), 3.22−3.03 (8H, m), 2.96−2.95 (2H, m), 2.56
(1H, ddd, J = 11.4, 4.4, 4.4 Hz), 2.37 (1H, ddd, J = 11.7, 4.0, 4.0 Hz),
2.30−2.26 (2H, m), 2.13−2.10 (2H, m), 2.05−1.99 (3H, m), 1.91−
1.85 (2H, m), 1.72−1.69 (2H, m), 1.63 (1H, ddd, J = 11.7, 11.7, 11.7
Hz), 1.55−1.36 (6H, m), 1.27 (3H, s); 13C NMR (150 MHz, CDCl3)
δ 138.2, 137.9, 128.4, 128.3, 127.9, 127.8 (×2), 127.6, 82.4, 81.9, 80.5,
79.9, 79.7, 79.5, 78.9, 78.4, 77.9, 77.3, 77.0, 76.8, 76.5, 73.7, 73.5, 72.4,
(19a−OH-31): mp 290−295 °C (decomp); [α]28 +32.7 (c 0.38,
D
CHCl3); IR (CHCl3) 3691, 3585, 3010, 2947, 2873, 1455, 1080
1
cm−1; H NMR (600 MHz, CDCl3) δ 7.35−7.19 (10H, m), 4.62 and
4.54 (each 1H, d, J = 12.1 Hz), 4.56 and 4.39 (each 1H, d, J = 11.3
Hz), 3.90 (1H, d, J = 10.7 Hz) 3.78−3.74 (2H, m), 3.66 (1H, dd, J =
J
dx.doi.org/10.1021/jo302267f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
71.1, 69.1, 69.0, 67.9, 43.0, 37.5, 37.1, 35.5, 35.2, 30.6, 29.35, 29.28,
29.2, 25.5, 16.2; MS (FAB) 733 (M + H); HRFABMS calcd for
C43H57O10 (MH+) 733.3952, found 733.3919.
82.0, 81.5, 80.8, 80.5, 79.7, 79.6, 79.4, 77.9, 77.3, 77.2, 76.9, 76.2, 73.4,
72.4, 71.0, 69.1, 68.8, 67.9, 47.4, 38.8, 37.4, 35.1, 34.7, 31.9, 30.8,
29.31, 29.28, 29.2, 27.6, 25.5; MS(FAB) 763 (M + H), 731 (M −
OMe); HRFABMS calcd for C44H59O11 (MH+) 763.4052, found
763.4080.
(4aS,5aR,7aS,8aR,12R,13aS,14aR,15aS,16aR)-12-
(((2S,3R,4aS,6R,7S,8aR)-7-(Benzyloxy)-6-((benzyloxy)methyl)-3-
((tert-butyldimethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-
yl)methyl)hexadecahydro-2H-pyrano[2′,3′:5,6]pyrano[2,3-f ]-
pyrano[3,2-b:5,6-b′]bis(oxepine)-11(12H)-one (33). To a sus-
pension of ketone 28 (50.0 mg, 0.0589 mmol) and powdered 4 Å
molecular sieves (287 mg) in CH2Cl2 (6 mL) were added
trimethylsilyldiazomethane (TMSCHN2) (0.148 mL of a 2.0 M
solution in hexanes, 0.295 mmol) and BF3·OEt2 (0.036 mL, 0.30
mmol) at −80 °C, and the reaction mixture was stirred at −80 °C for
3 h. The reaction was quenched with saturated aqueous NaHCO3
solution. The resulting mixture was allowed to warm to room
temperature and extracted with CH2Cl2. The extract was washed with
brine, dried, and concentrated under reduced pressure to afford the
crude α-TMS ketone, which was immediately used in the next step
without further purification.
ii. Reductive Etherification of Acetal 20a-OMe-34. To a solution
of 20a-OMe-34 (4.1 mg, 0.0054 mmol) and Et3SiH (0.019 mL, 0.12
mmol) in CH2Cl2 (0.4 mL) at 0 °C was added TMSOTf (0.0063 mL,
0.035 mmol), and the reaction mixture was stirred at 0 °C for 1 h.
The reaction was quenched with saturated aqueous NaHCO3 (2 mL)
solution, and the resulting mixture was extracted with CH2Cl2. The
extract was washed with brine, dried, and concentrated under reduced
pressure to give 4.1 mg of a white solid. Purification by flash
chromatography (0→2% MeOH in CHCl3) afforded 3.3 mg (84%) of
34 as a colorless solid. Mp 355−362 °C (decomp); [α]22 +23.7 (c
D
1
0.19, CHCl3); IR (CHCl3) 3009, 2936, 2872, 1455, 1076 cm−1; H
NMR (600 MHz, CDCl3) δ 7.34−7.19 (10H, m), 4.61 and 4.54
(each 1H, d, J = 12.5 Hz), 4.56 and 4.39 (each 1H, d, J = 11.7 Hz),
3.90 (1H, d, J = 11.0 Hz), 3.75 (1H, dd, J = 10.6, 1.8 Hz), 3.65 (1H,
dd, J = 10.6, 5.1 Hz), 3.53 (1H, ddd, J = 11.0, 9.5, 4.4 Hz), 3.42 (1H,
ddd, J = 9.5, 5.1, 1.8 Hz), 3.39−3.23 (5H, m), 3.21−3.15 (2H, m),
3.14−3.08 (3H, m), 3.06−2.93 (5H, m), 2.55 (1H, ddd, J = 11.0, 4.4,
4.4 Hz), 2.37−2.33 (2H, m), 2.31−2.26 (2H, m), 2.04−1.98 (5H, m),
1.89−1.83 (4H, m), 1.72−1.69 (2H, m), 1.57−1.39 (6H, m); 13C
NMR (150 MHz, CDCl3) δ 138.2, 137.9, 128.40, 128.35, 127.9, 127.8
(×2), 127.6, 82.12, 82.09, 81.7, 81.6, 80.5, 79.6, 79.44, 79.39, 79.3,
77.9, 77.3, 76.8, 76.7 (×2), 76.1, 73.5, 72.3, 71.0, 69.1, 67.9, 38.9,
37.4, 37.0, 35.2, 35.1, 29.4, 29.3, 29.2 (×3), 25.5; MS (FAB) 733 (M
+ H); HRFABMS calcd for C43H57O10 (MH+) 733.3946, found
733.3939.
A solution of the above α-TMS ketone and PPTS (14.8 mg, 0.0589
mmol) in MeOH (1 mL) and CH2Cl2 (1 mL) was stirred at room
temperature for 1 h. Additional PPTS (50.0 mg, 0.199 mmol) was
added, and the reaction mixture was stirred at room temperature for
another 2.5 h. The reaction was quenched with Et3N (0.1 mL). The
reaction mixture was concentrated under reduced pressure to give 131
mg of colorless oil. Purification by flash chromatography (30% EtOAc
in n-hexane) afforded the seven-membered ketone 33 (44.0 mg, 87%)
as a colorless oil. [α]22 +15.1 (c 0.58, CHCl3); IR (CHCl3) 3009,
D
1
2933, 2860, 1712, 1455, 1085 cm−1; H NMR (400 MHz, CDCl3) δ
7.33−7.18 (10H, m), 4.50 and 4.537 (each 1H, d, J = 12.5 Hz), 4.540
and 4.37 (1H, d, J = 11.4 Hz), 3.98 (1H, dd, J = 4.4, 6.6 Hz), 3.90
(1H, d, J = 11.0 Hz), 3.74 (1H, dd, J = 10.6, 1.5 Hz), 3.63 (1H, dd, J
= 10.6, 5.1 Hz), 3.48 (1H, ddd, J = 10.6, 9.5, 4.4 Hz), 3.42−3.16 (9H,
m), 3.05−2.93 (5H, m), 2.85 (1H, ddd, J = 13.7, 11.9, 1.8 Hz), 2.42−
2.27 (5H, m), 2.21−2.11 (2H, m), 2.05−1.98 (3H, m), 1.91−1.82
(2H, m), 1.78−1.37 (9H, m), 0.85 (9H, s), 0.05 (6H, s); 13C NMR
(150 MHz, CDCl3) δ 215.8, 138.2, 138.0, 128.4, 128.3, 127.9, 127.8,
127.7, 127.6, 84.0, 82.1, 81.5, 81.0, 80.7, 80.2, 79.7, 79.2, 78.0, 77.7,
77.3, 76.0, 75.6, 73.5, 72.6, 71.2, 70.3, 69.4, 67.9, 39.2, 38.8, 37.4, 36.6,
35.6, 34.9, 29.4, 29.3 (×2), 29.2, 25.7, 25.5, 17.9, −4.0, −4.7;
HRFABMS calcd for C49H71O11Si (MH+) 863.4760, found 863.4734.
(2R,3S,4aR,5aS,6aR,7aS,8aR,9aS,10aR,14aS,15aR,17a-
S,18aR,20aS,21aR,22aS)-3-(Benzyloxy)-2-((benzyloxy)methyl)-
octacosahydropyrano[3,2-b]pyrano[2,3-j:6,5-j′]bis(pyrano-
[2′,3′:5,6]pyrano[3,2-b]oxepine) (34). i. Acetalization of Ketone
33. A solution of 33 (7.0 mg, 0.0081 mmol) and TsOH·H2O (1.7
mg, 0.0089 mmol) in 1,2-dichloroethane (2 mL) and MeOH (1 mL)
was stirred at 80 °C for 2 h. An additional 3.4 mg of TsOH·H2O
(0.0179 mmol) was added, and stirring was continued at 80 °C for
another 15 h. Trimethyl orthoformate (0.13 mL) was added, and
heating was continued for 4 h. The reaction mixture was cooled to
room temperature, and the reaction was quenched with Et3N (0.1
mL). The resulting mixture was concentrated under reduced pressure
to give 10.5 mg of a white solid. Purification by flash chromatography
(30→50% EtOAc in benzene) afforded methyl acetal 20a-OMe-34
(4.4 mg, 71%) as a colorless solid. (2R,3S,4aR,5aS,6aR,7aS,8aR,9-
aS,10aR,14aS,15aR,17aS,18aR,20aS,21aR,22aS)-3-(Benzyloxy)-2-
((benzyloxy)methyl)-20a-methoxyoctacosahydropyrano[3,2-b]pyrano-
[2,3-j:6,5-j′]bis(pyrano[2′,3′:5,6]pyrano[3,2-b]oxepine) (20a-OMe-
(4aS,5aR,7aS,8aR,13R,14aS,15aR,16aS,17aR)-13-
(((2S,3R,4aS,6R,7S,8aR)-7-(Benzyloxy)-6-((benzyloxy)methyl)-3-
((tert-butyldimethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-
yl)methyl)octadecahydropyrano[2‴,3‴:5″,6″]pyrano-
[2″,3″:6′,7′]oxepino[2′,3′:5,6]pyrano[3,2-b]oxocin-12(13H)-
one (35). To a suspension of ketone 33 (35.0 mg, 0.0405 mmol) and
powdered 4 Å molecular sieves (196 mg) in CH2Cl2 (4 mL) were
added BF3·OEt2 (0.050 mL, 0.41 mmol) and TMSCHN2 (0.203 mL
of a 2.0 M solution in hexanes, 0.406 mmol) at −40 °C, and the
reaction mixture was stirred at −40 °C for 4 h. The reaction was
quenched with saturated aqueous NaHCO3 solution. The reaction
mixture was allowed to warm to room temperature and extracted with
CH2Cl2. The extract was washed with brine, dried, and concentrated
under reduced pressure to afford the crude α-TMS ketone, which was
immediately used in the next reaction without further purification.
A solution of the above α-TMS ketone and PPTS (30.5 mg, 0.121
mmol) in MeOH (1.0 mL) and CHCl3 (1.0 mL) was stirred at room
temperature for 7 h. Additional PPTS (100 mg, 0.398 mmol) was
added, and the reaction mixture was stirred at room temperature for
another 10 h and then at 60 °C for 6 h. The reaction mixture was
cooled to room temperature, and the reaction was quenched with
saturated aqueous NaHCO3 solution. The resulting mixture was
extracted with CH2Cl2, and the extract was washed with brine, dried,
and concentrated under reduced pressure. The residual pale yellow oil
was purified by flash chromatography (15% EtOAc in benzene) to
afford 19.1 mg of colorless oil. Further purification by flash
chromatography (15% acetone in n-hexane), followed by preparative
TLC (15% acetone in n-hexane), gave the eight-membered ketone 35
(13.4 mg, 38%) as a colorless amorphous solid. Mp 67−69 °C; [α]22
34): mp 266−272 °C (decomp); [α]22 +30.2 (c 0.35, CHCl3); IR
D
D
1
(CHCl3) 3009, 2946, 2872, 1455, 1081 cm−1; H NMR (600 MHz,
+32.8 (c 1.08, CHCl3); IR (CHCl3) 3008, 2933, 2859, 1709, 1455,
1
1083 cm−1; H NMR (600 MHz, CDCl3) δ 7.34−7.19 (10H, m),
CDCl3) δ 7.34−7.19 (10H, m), 4.62 and 4.54 (each 1H, d, J = 12.5
Hz), 4.56 and 4.39 (each 1H, d, J = 11.4 Hz), 3.90 (1H, d, J = 11.0
Hz), 3.75 (1H, dd, J = 11.0, 1.8 Hz), 3.66 (1H, dd, J = 11.0, 4.8 Hz),
3.53 (1H, ddd, J = 11.0, 9.2, 4.4 Hz), 3.43 (1H, ddd, J = 9.5, 4.8, 1.8
Hz), 3.40−3.33 (2H, m), 3.31−3.18 (6H, m), 3.23 (3H, s), 3.15−
3.11 (2H, m), 3.07−3.02 (2H, m), 2.96−2.94 (2H, m), 2.55 (1H,
ddd, J = 11.4, 4.4, 4.4 Hz), 2.35 (1H, ddd, J = 12.1, 4.0, 4.0 Hz),
2.30−2.25 (2H, m), 2.08−1.99 (7H, m), 1.93−1.83 (4H, m), 1.71−
1.68 (2H, m), 1.62−1.40 (5H, m); 13C NMR (150 MHz, CDCl3) δ
138.2, 137.9, 128.4, 128.3, 127.9, 127.81, 127.78, 127.6, 99.9, 82.1,
4.60 and 4.538 (each 1H, d, J = 12.5 Hz), 4.540 and 4.37 (each 1H, d,
J = 11.0 Hz), 3.90 (1H, d, J = 11.0 Hz), 3.80 (1H, dd, J = 7.3, 3.7
Hz), 3.74 (1H, dd, J = 11.0, 1.5 Hz), 3.62 (1H, dd, J = 11.0, 5.1 Hz),
3.48 (1H, ddd, J = 11.0, 9.5, 4.4 Hz), 3.41−3.14 (10H, m), 3.06−2.95
(5H, m), 2.41 (1H, ddd, J = 11.7, 4.4, 4.4 Hz), 2.35 (1H, ddd, J =
12.5, 4.4, 4.4 Hz), 2.31−2.29 (2H, m), 2.17 (1H, ddd, J = 13.9, 7.3,
2.9 Hz), 2.04−1.98 (4H, m), 1.93−1.83 (5H, m), 1.78 (1H, ddd, J =
13.9, 10.3, 3.7 Hz), 1.73−1.69 (2H, m), 1.64 (1H, ddd, J = 11.7, 11.7,
11.7 Hz), 1.57−1.34 (5H, m), 0.86 (9H, s), 0.05 (6H, s); 13C NMR
K
dx.doi.org/10.1021/jo302267f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(150 MHz, CDCl3) δ 218.5, 138.2, 138.0, 128.4, 128.3, 127.9, 127.8,
127.7, 127.6, 85.3, 82.7, 82.2, 81.6, 81.3, 80.1, 79.7, 79.0, 77.9, 77.6,
77.2, 76.1, 75.7, 73.5, 72.7, 71.2, 70.4, 69.4, 67.9, 39.3, 39.2, 37.4, 36.7,
36.1, 34.8, 32.9, 29.4, 29.3 (×2), 25.7, 25.5, 23.7, 17.9, −4.1, −4.7;
MS (FAB) 877 (M + H), 819 (M − t-Bu); HRFABMS calcd for
C50H73O11Si (MH+) 877.4917, found 877.4940.
pyrano[2,3-f ]oxepin-3-yl acetate (36). i. Reduction of Ketone
28. To a solution of 28 (20.0 mg, 0.0236 mmol) in MeOH (1 mL)
and THF (1 mL) was added NaBH4 (5.0 mg, 0.13 mmol), and the
reaction mixture was stirred at room temperature for 80 min. The
reaction was quenched with saturated aqueous NH4Cl solution (2
mL), and the resulting mixture was extracted with CH2Cl2. The
extract was washed with brine, dried, and concentrated under reduced
pressure to give 27.4 mg of a pale yellow oil. Purification by flash
chromatography (50% EtOAc in n-hexane) afforded an 87:13
diastereomixture of alcohol (19.6 mg, 98%) of as a colorless oil.
(2R,3S,4aR,5aS,7aR,8aS,12aR,13aS,14aR,15aS)-2-(((2S,3R,4aS,6R,7-
S,8aR)-7-(benzyloxy)-6-((benzyloxy)methyl)-3-((tert-
butyldimethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-yl)methyl)-
octadecahydropyrano[2′,3′:5,6]pyrano[3,2-b]pyrano[2′,3′:5,6]pyrano-
(2S,3R,4aS,5aR,6aS,9aR,10aS,12aR,13aS,17aR,18aS,19aR,20-
aS,21aR,22aS,23aR)-2-(Benzyloxy)-3-((benzyloxy)methyl)-
octacosahydro-1H-pyrano[2‴,3‴:5″,6″]pyrano[2″,3″:6′,7′]-
oxepino[2′,3′:5,6]pyrano[3,2-b]pyrano[2″,3″:5′,6′]pyrano-
[2′,3′:5,6]pyrano[2,3-g]oxocine (1: CDEFGHIJ-ring polycyclic
skeleton of yessotoxin). i. Acetalization of the Ketone 35. A
solution of 35 (11.7 mg, 0.0133 mmol) and TsOH·H2O (5.0 mg,
0.0263 mmol) in MeOH (0.5 mL) and 1,2-dichloroethane (0.5 mL)
was stirred at 55 °C for 5.5 h. Additional volumes of 1,2-
dichloroethane (0.5 mL) and trimethyl orthoformate (0.20 mL, 1.8
mmol) were added, and the reaction mixture was stirred at 55 °C for
another 2 h. The solution was cooled to room temperature, and the
reaction was quenched with Et3N. The resulting mixture was
concentrated under reduced pressure to give 18.3 mg of a white
solid. Purification by flash chromatography (30→70% EtOAc in n-
hexane) afforded methyl acetal 6a-OMe-1 (9.0 mg, 87%) as a
colorless solid. (2S,3R,4aS,5aR,6aS,9aR,10aS,12aR,13aS,17aR,18a-
S,19aR,20aS,21aR,22aS,23aR)-2-(benzyloxy)-3-((benzyloxy)methyl)-
6a-methoxyoctacosahydro-1H-pyrano[2‴,3‴:5″,6″]pyrano-
[2″,3″:6′,7′]oxepino[2′,3′:5,6]pyrano[3,2-b]pyrano[2″,3″:5′,6′]-
pyrano[2′,3′:5,6]pyrano[2,3-g]oxocine (6a-OMe-1): mp 219−221
[2,3-f ]oxepin-3-ol (alcohol i): [α]29 +2.5 (c 1.63, CHCl3); IR
D
(CHCl3) 3410, 3009, 2952, 2860, 1455, 1083 cm−1; MS (FAB) 851
1
(M + H), 719 (M − OTBS); H NMR for the major isomer (600
MHz, CDCl3) δ 7.33−7.17 (10H, m), 4.60 and 4.54 (each 1H, d, J =
12.1 Hz), 4.56 and 4.54 (each 1H, d, J = 11.3 Hz), 3.90 (1H, dd, J =
11.0 Hz), 3.74 (1H, dd, J = 10.6, 1.5 Hz), 3.63 (1H, dd, J = 10.6, 5.1
Hz), 3.62 (1H, d, J = 3.3 Hz), 3.53−3.30 (8H, m), 3.25−3.18 (3H,
m), 3.12−2.95 (6H, m), 2.55 (1H, ddd, J = 11.3, 4.4, 4.4 Hz), 2.90−
2.26 (4H, m), 2.08 (1H, ddd, J = 15.4, 5.2, 1.9 Hz), 2.05−2.00 (3H,
m), 1.97 (1H, ddd, J = 15.4, 7.0, 3.7 Hz), 1.92−1.86 (2H, m), 1.72−
1.69 (2H, m), 1.60−1.40 (6H, m), 0.87 (9H, s), 0.08 (3H, s), 0.07
(3H, s); 13C NMR for the major isomer (150 MHz, CDCl3) δ 138.1,
137.8, 128.4, 128.3, 127.9, 127.7 (×2), 127.6, 82.00, 81.97, 80.2,
79.63, 79.57, 79.3, 79.2, 77.9, 77.3, 76.8, 76.7, 75.9, 75.8, 73.5, 72.3,
71.0, 69.31, 69.25, 68.9, 67.8, 39.1, 37.5, 37.4, 37.0, 35.0, 34.4, 29.28,
29.26, 29.2, 25.7, 25.5, 17.9, −3.9, −4.9. HRFABMS calcd for
C48H71O11Si (MH+) 851.4687, found 851.4729.
°C; [α]22 +31.6 (c 0.73, CHCl3); IR (CHCl3) 3009, 2947, 2871,
D
1
1455, 1341, 1077 cm−1; H NMR (500 MHz, CDCl3) δ 7.35−7.19
(10H, m), 4.62 and 4.54 (each 1H, d, J = 12.4 Hz), 4.57 and 4.39
(each 1H, d, J = 11.5 Hz), 3.90 (1H, d, J = 11.0 Hz), 3.75 (1H, dd, J
= 10.5, 1.4 Hz), 3.66 (1H, dd, J = 10.5, 5.0 Hz), 3.54 (1H, ddd, J =
11.0, 10.2, 4.4 Hz), 3.44−3.41 (2H, m), 3.38−3.25 (3H, m), 3.23−
3.08 (6H, m), 3.17 (3H, s), 3.06−2.95 (4H, m), 2.55 (1H, ddd, J =
11.5, 4.4, 4.4 Hz), 2.31−2.26 (4H, m), 2.18 (1H, ddd, J = 13.7, 10.5,
3.2 Hz), 2.05−1.91 (5H, m), 1.88−1.81 (3H, m), 1.73−1.62 (4H, m),
1.55−1.44 (3H, m), 1.41−1.34 (3H, m); 13C NMR (100 MHz,
CDCl3) δ 138.2, 137.9, 128.4, 128.3, 127.9, 127.80, 127.77, 127.6,
98.8, 85.7, 85.6, 82.1, 81.3, 81.1, 80.5, 79.6, 79.5, 77.9, 77.3, 76.9, 76.8,
76.1, 73.4, 72.3, 71.0, 69.1, 68.1, 67.9, 47.6, 40.1, 37.5, 37.34, 37.25,
35.1, 34.8, 33.8, 29.3, 29.2 (×2), 25.5, 17.8; MS (FAB) 777 (M + H),
745 (M − OMe); HRFABMS calcd for C45H61O11 (MH+) 777.4208,
found 777.4203.
ii. Acetylation of the Secondary Alcohol. A solution of a 87:13
diastereomixture of alcohol i (19.0 mg, 0.0223 mmol) and DMAP
(1.0 mg, 0.0082 mmol) in pyridine (0.5 mL) and acetic anhydride
(0.1 mL) was stirred at room temperature for 2 h. The reaction was
quenched with saturated aqueous NaHCO3 solution (2 mL), and the
resulting mixture was extracted with EtOAc. The extract was washed
with water and brine, dried, and concentrated under reduced pressure.
Purification by flash chromatography (25% EtOAc in n-hexane)
afforded acetate (15.3 mg, 77%) and its epimer (3.6 mg, 18%, ca. 80%
purity based on NMR analysis) as colorless oils. (2R,3S,4aR,5-
aS,7aR,8aS,12aR,13aS,14aR,15aS)-2-(((2S,3R,4aS,6R,7S,8aR)-7-(Benz-
yloxy)-6-((benzyloxy)methyl)-3-((tert-butyldimethylsilyl)oxy)-
octahydropyrano[3,2-b]pyran-2-yl)methyl)octadecahydropyrano-
[2′,3′:5,6]pyrano[3,2-b]pyrano[2′,3′:5,6]pyrano[2,3-f ]oxepin-3-yl ac-
ii. Reductive Etherification of Acetal 6a-OMe-1. To a solution of
6a-OMe-1 (7.9 mg, 0.010 mmol) and Et3SiH (0.036 mL, 0.22 mmol)
in CH2Cl2 (0.8 mL) at 0 °C was added TMSOTf (0.012 mL, 0.066
mmol), and the reaction mixture was stirred at 0 °C for 1 h. The
reaction was quenched with saturated aqueous NaHCO3 solution, and
the resulting mixture was extracted with CH2Cl2. The extract was
washed with brine, dried, and concentrated under reduced pressure to
give 7.6 mg of a pale yellow solid. Purification by flash
chromatography (CH2Cl2→2% MeOH in CH2Cl2) afforded the
CDEFGHIJ-ring polycyclic ether 1 (6.8 mg, 89%) as a colorless solid.
etate (acetate ii): [α]29 +15.8 (c 1.28, CHCl3); IR (CHCl3) 3008,
D
1
2952, 2860, 1735, 1456, 1248, 1087, 838 cm−1; H NMR (500 MHz,
CDCl3) δ 7.35−7.19 (10H, m), 4.60 and 4.55 (each 1H, d, J = 12.4
Hz), 4.59 (1H, m), 4.58 and 4.37 (each 1H, d, J = 11.5 Hz), 3.90
(1H, d, J = 11.0 Hz), 3.75 (1H, dd, J = 10.6, 1.4 Hz), 3.63 (1H, dd, J
= 10.6, 5.1 Hz), 3.53 (1H, ddd, J = 9.7, 6.4, 4.1 Hz), 3.47−3.41 (3H,
m), 3.39−2.29 (3H, m), 3.26−3.17 (3H, m), 3.07−2.94 (6H, m),
2.56 (1H, ddd, J = 11.5, 4.1, 4.1 Hz), 2.46 (1H, ddd, J = 11.0, 4.1, 4.1
Hz), 2.35−2.28 (3H, m), 2.05−1.99 (4H, m), 2.01 (3H, s), 1.90−
1.84 (2H, m), 1.73−1.68 (2H, m), 1.60−1.46 (4H, m), 1.39 (3H, q, J
= ca. 11.0 Hz, three axial protons), 0.86 (9H, s), 0.06 (3H, s), 0.05
(3H, s); 13C NMR (125 MHz, CDCl3) δ 169.7, 138.2, 138.0, 128.4,
128.3, 127.9, 127.71, 127.68, 127.6, 82.0 (×2), 80.1, 79.7, 79.5, 79.2,
77.9, 77.2, 77.0, 76.8, 76.1, 75.9, 75.6, 73.5, 72.6, 71.4, 71.0, 70.6, 69.4,
67.8, 39.4, 37.5, 37.0, 35.3, 35.1, 34.4, 29.3 (×2), 29.1, 25.8, 25.4,
21.1, 17.9, −4.0, −4.7; MS (FAB) 893 (M + H), 835 (M − t-Bu),
761 (M − OTBS); HRFABMS calcd for C50H73O12Si (MH+)
893.4871, found 893.4849.
iii. Deprotection of the TBS Group. To a solution of acetate ii
(15.0 mg, 0.0168 mmol) and AcOH (0.003 mL, 0.05 mmol) in THF
(0.5 mL) was added Bu4NF (0.034 mL of a 1.0 M solution in THF,
0.034 mmol), and the reaction mixture was stirred at room
temperature. An additional two portions of 0.034 mL of a 1.0 M
solution Bu4NF in THF (0.034 mmol, 2.0 equiv for each portion)
were added after 2 and 7 h. The reaction mixture was stirred for a
Mp 308−310 °C; [α]27 +14.7 (c 0.56, CHCl3); IR (CHCl3) 3066,
D
1
3007, 2935, 1455, 1341, 1084 cm−1; H NMR (600 MHz, CDCl3) δ
7.34−7.19 (10H, m), 4.61 and 4.54 (each 1H, d, J = 12.4 Hz), 4.56
and 4.39 (each 1H, d, J = 11.0 Hz), 3.90 (1H, d, J = 11.0 Hz), 3.75
(1H, dd, J = 11.0, 1.4 Hz), 3.65 (1H, dd, J = 11.0, 5.2 Hz), 3.53 (1H,
ddd, J = 11.0, 9.5, 4.4 Hz), 3.42 (1H, ddd, J = 9.5, 5.2, 1.4 Hz), 3.37−
3.19 (6H, m), 3.12−2.95 (9H, m), 2.54 (1H, ddd, J = 11.0, 4.4, 4.4
Hz), 2.35−2.27 (4H, m), 2.19−2.12 (2H, m), 2.04−1.95 (4H, m),
1.88−1.81 (2H, m), 1.72−1.69 (2H, m), 1.57−1.38 (9H, m); 13C
NMR (150 MHz, CDCl3) δ 138.2, 138.0, 128.4, 128.3, 128.0, 127.79,
127.76, 127.6, 84.2, 83.9, 82.2, 81.9, 81.4, 81.3, 80.5, 79.6, 79.2, 77.9,
77.3, 76.61, 76.56, 76.2, 76.0, 73.5, 72.5, 71.0, 69.1, 67.9, 40.4, 38.5,
37.5, 36.9, 36.7, 35.2, 35.1, 29.3 (×3), 25.5, 20.6; HRFABMS calcd for
C44H58O10 (MH+) 747.4103, found 747.4112.
(2R,3S,4aR,5aS,7aR,8aS,12aR,13aS,14aR,15aS)-2-
(((2S,4aS,6R,7S,8aR)-7-(Benzyloxy)-6-((benzyloxy)methyl)-3-
o x o o c t a h y d r op y r a n o [ 3, 2- b ] py r a n - 2- y l ) m e t h yl ) -
octadecahydropyrano[2′,3′:5,6]pyrano[3,2-b]pyrano[2′,3′:5,6]-
L
dx.doi.org/10.1021/jo302267f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
total of 24 h. After addition of brine (2 mL), the resulting mixture
was extracted with EtOAc. The extract was washed with water and
brine, dried, and concentrated under reduced pressure. Purification by
flash chromatography (70% EtOAc in n-hexane) afforded the
secondary alcohol (13.0 mg, 99%) as a colorless solid. (2R,3S,4aR,5-
aS,7aR,8aS,12aR,13aS,14aR,15aS)-2-(((2S,3R,4aS,6R,7S,8aR)-7-(benz-
yloxy)-6-((benzyloxy)methyl)-3-hydroxyoctahydropyrano[3,2-b]-
pyran-2-yl)methyl)octadecahydropyrano[2′,3′:5,6]pyrano[3,2-b]-
pyrano[2′,3′:5,6]pyrano[2,3-f ]oxepin-3-yl acetate (hydroxy acetate
under reduced pressure to afford the crude α-TMS ketone, which was
immediately used in the next reaction without further purification.
A mixture of the above α-TMS ketone and PPTS (10 mg, 0.040
mmol) in MeOH (0.3 mL) and CH2Cl2 (0.3 mL) was stirred at room
temperature for 9.5 h. An additional 30 mg of PPTS (0.120 mmol)
was added, and stirring was continued at room temperature for 7 h
and then at 55 °C for 1 h. The reaction mixture was cooled to room
temperature, and the reaction was quenched with Et3N (0.5 mL). The
resulting mixture was concentrated under reduced to give 57 mg of a
pale yellow solid. Purification by flash chromatography (0→40%
EtOAc in n-hexane) afforded 37 (6.0 mg, 57%) as a colorless solid.
iii): mp 145−147 °C; [α]28 +43.4 (c 1.08, CHCl3); IR (CHCl3)
D
3515, 3010, 2948, 2872, 1736, 1456, 1244, 1085, 1048 cm−1; 1H
NMR (500 MHz, CDCl3) δ 7.35−7.20 (10H, m), 4.63 (1H, m), 4.61
and 4.55 (1H, d, J = 12.4 Hz), 4.58 and 4.38 (1H, d, J = 11.5 Hz),
3.90 (1H, d, J = 11.0 Hz), 3.76 (1H, dd, J = 11.0, 1.8 Hz), 3.65 (1H,
dd, J = 11.0, 5.1 Hz), 3.58 (1H, ddd, J = 9.6, 7.8, 1.8 Hz), 3.54−3.49
(2H, m), 3.42 (1H, ddd, J = 9.2, 5.1, 1.8 Hz), 3.38−3.28 (3H, m),
3.25 (1H, ddd, J = 9.2, 4.4, 4.4 Hz), 3.22−3.18 (2H, m), 3.13−2.93
(6H, m), 2.72 (1H, brs), 2.53 (1H, ddd, J = 11.5, 4.1, 4.1 Hz), 2.45
(1H, ddd, J = 11.5, 4.1, 4.1 Hz), 2.40 (1H, ddd, J = 11.5, 4.1, 4.1 Hz),
2.36 (1H, ddd, J = 11.5, 4.1, 4.1 Hz), 2.28 (1H, ddd, J = 11.5, 3.7, 3.7
Hz), 2.05 (3H, s), 2.04−1.99 (3H, m), 1.95−1.81 (4H, m), 1.73−
1.68 (2H, m), 1.54−1.39 (6H, m); 13C NMR (125 MHz, CDCl3) δ
169.8, 138.2, 138.0, 128.4, 128.3, 127.9, 127.74, 127.70, 127.6, 81.94,
81.91, 80.3, 79.7, 79.2, 79.0, 77.9, 77.2, 76.69, 76.66, 76.13, 76.11,
75.5, 73.5, 72.5, 71.0, 70.0, 69.3, 68.6, 67.8, 37.6, 37.4, 36.9, 35.2, 35.1,
33.5, 29.2 (×2), 29.1, 25.4, 21.1; MS (FAB) 779 (M + H), 687 (M −
Bn); HRFABMS calcd for C44H59O12 (MH+) 779.4007, found
779.3998.
Mp 145−147 °C; [α]30 +23.5 (c 0.50, CHCl3); IR (CHCl3) 2948,
D
1
2872, 1736, 1714, 1455, 1091 cm−1; H NMR (500 MHz, CDCl3) δ
7.33−7.21 (10H, m), 4.60 and 4.53(each 1H, d, J = 12.1 Hz), 4.594
and 4.40 (each 1H, d, J = 11.5 Hz), 4.54 (1H, m), 3.95 (1H, dd, J =
6.6, 3.7 Hz), 3.90 (1H, d, J = 10.9 Hz), 3.75 (1H, d, J = 10.9 Hz),
3.63 (1H, dd, J = 10.9, 5.2 Hz), 3.53 (1H, ddd, J = 10.3, 10.3, 2.3
Hz), 3.50−3.29 (6H, m), 3.22−3.16 (2H, m), 3.08−2.95 (5H, m),
2.88 (1H, dd, J = 13.7, 12.1 Hz), 2.58 (1H, ddd, J = 12.1, 4.6, 4.6
Hz), 2.42 (1H, ddd, J = 11.5, 4.6, 4.6 Hz), 2.37 (1H, dd, J = 12.1, 6.9
Hz), 2.30−2.19 (3H, m), 2.04 (3H, s), 2.02−1.98 (4H, m), 1.88−
1.83 (3H, m), 1.71−1.69 (2H, m), 1.61−1.38 (6H, m); 13C NMR
(125 MHz, CDCl3) δ 215.1, 169.7, 138.2, 138.0, 128.4, 128.3, 127.9,
127.8, 127.7, 127.6, 83.3, 82.0, 81.9, 80.8, 80.7, 80.0, 79.7, 79.3, 77.9,
77.2, 76.7, 75.6, 74.9, 73.5, 72.3, 71.1, 70.7, 69.2, 67.8, 37.4, 37.1, 36.8,
36.6, 35.5, 35.1, 29.24, 29.22, 29.1, 29.0, 25.4, 21.1; MS (FAB) 791
(M + H), 699 (M − Bn); HRFABMS calcd for C45H59O12 (MH+)
791.4007, found 791.4025.
(2R,3S,4aR,5aS,6aR,7aS,8aR,9aS,10aR,14aS,15aR,17a-
S,18aR,19aS,20aR,22aS)-3-(Benzyloxy)-2-((benzyloxy)methyl)-
octacosahydropyrano[2,3-i]pyrano[3,2-b:5,6-b′]bis(dipyrano-
[3,2-b:2′,3′-f]oxepine) (38). i. Acetalization of Ketone 37. A
solution of 37 (6.0 mg, 0.0076 mmol) and TsOH·H2O (4.3 mg, 0.023
mmol) in MeOH (0.25 mL) and 1,2-dichloroethane (0.25 mL) was
stirred at 75 °C for 24 h. An additional two portions of 0.5 mL of
MeOH were added after 4 and 7 h to prevent the reaction mixture
from drying up. The reaction mixture was cooled to room
temperature. The reaction was quenched with Et3N (0.1 mL), and
the resulting mixture was concentrated under reduced pressure.
Purification by flash chromatography (40→100% EtOAc in n-hexane)
afforded methyl acetal 20a-OMe-38 (4.7 mg, 81%) as a colorless
solid. (2R,3S,4aR,5aS,6aR,7aS,8aR,9aS,10aR,14aS,15aR,17aS,18aR,19a-
S,20aR,22aS)-3-(Benzyloxy)-2-((benzyloxy)methyl)-20a-
methoxyoctacosahydropyrano[2,3-i]pyrano[3,2-b:5,6-b′]bis(dipyrano-
iv. Dess−Martin Oxidation. A mixture of hydroxy acetate iii (12.5
mg, 0.0160 mmol) and Dess−Martin periodinane (10 mg, 0.0236
mmol) in CH2Cl2 (1.0 mL) was stirred at room temperature for 1 h.
An additional 30 mg of Dess−Martin periodinane (0.071 mmol) was
added, and stirring was continued for another 1 h. The reaction was
quenched with saturated aqueous NaHCO3 solution (2 mL) and 10%
aqueous Na2S2O3 solution (2 mL), and the resulting mixture was
extracted with Et2O. The extract was washed with saturated aqueous
NaHCO3 solution and brine, dried, and concentrated under reduced
pressure. Purification by flash chromatography (50% EtOAc−n-
hexane) afforded ketone 36 (10.7 mg, 86%) as a colorless solid. Mp
123−124 °C; [α]28 +46.4 (c 0.89, CHCl3); IR (CHCl3) 3010, 2947,
D
2871, 1732, 1455, 1240, 1089, 1048 cm−1; 1H NMR (500 MHz,
CDCl3) δ 7.34−7.21 (10H, m), 4.62 and 4.55 (each 1H, d, J = 12.4
Hz), 4.61 and 4.42 (each 1H, d, J = 11.5 Hz), 4.60 (1H, m), 3.96
(1H, dd, J = 6.4, 3.7 Hz), 3.90 (1H, d, J = 11.0 Hz), 3.76 (1H, dd, J =
10.6, 1.4 Hz), 3.67 (1H, dd, J = 10.6, 5.1 Hz), 3.62−3.56 (2H, m),
3.48 (1H, ddd, J = 9.2, 5.1, 1.4 Hz), 3.42−3.28 (5H, m), 3.22−3.16
(2H, m), 3.03−2.93 (5H, m), 2.66 (1H, ddd, J = 11.5, 4.1, 4.1 Hz),
2.46 (1H, dd, J = 16.5, 10.6 Hz), 2.43 (1H, ddd, J = 11.5, 4.1, 4.1
Hz), 2.31 (1H, ddd, J = 11.5, 3.7, 3.7 Hz), 2.26 (1H, ddd, J = 11.5,
4.1, 4.1 Hz), 2.18 (1H, ddd, J = 14.7, 6.4, 3.2 Hz), 2.03 (3H, s),
2.02−1.99 (3H, m), 1.89−1.81 (3H, m), 1.73−1.69 (2H, m), 1.55−
1.37 (5H, m); 13C NMR (100 MHz, CDCl3) δ 205.6, 169.8, 138.0,
137.8, 128.41, 128.36, 127.9, 127.80, 127.76, 127.7, 82.0, 81.9, 79.9,
79.7, 79.2, 78.7, 77.9, 77.2, 76.8, 76.0, 75.7, 75.5, 74.4, 73.5, 72.0, 71.1,
70.8, 69.0, 67.8, 44.6, 37.4, 36.8, 35.1, 35.0, 32.1, 29.24, 29.23, 29.1,
25.4, 21.0; MS (FAB) 777 (M + H), 685 (M − Bn); HRFABMS
calcd for C44H57O12 (MH+) 777.3850, found 777.3828.
[3,2-b:2′,3′-f]oxepine) (20a-OMe-38): mp 210−213 °C; [α]28 +3.8
D
(c 0.39, CHCl3); IR (CHCl3) 3009, 2947, 2872, 1455, 1343, 1080
1
cm−1; H NMR (600 MHz, CDCl3) δ 7.34−7.19 (10H, m), 4.60 and
4.54 (each 1H, d, J = 12.4 Hz), 4.57 and 4.37 (each 1H, d, J = 11.5
Hz), 3.90 (1H, d, J = 11.0 Hz), 3.73 (1H, dd, J = 10.6, 1.4 Hz), 3.61
(1H, dd, J = 10.6, 5.2 Hz), 3.46 (1H, ddd, J = 11.7, 9.5, 4.5 Hz), 3.41
(1H, dd, J = 11.7, 4.0 Hz), 3.38−3.18 (9H, m), 3.23 (3H, s), 3.06−
3.01 (3H, m), 2.97−2.95 (2H, m), 2.56 (1H, dt, J = 11.7, 4.5 Hz),
2.34 (1H, dt, J = 11.3, 4.0 Hz), 2.30 (1H, dt, J = 11.3, 3.7 Hz), 2.21
(1H, dt, J = 11.3, 3.7 Hz), 2.12 (1H, dddd, J = 14.6, 11.7, 6.2, 3.7
Hz), 2.06 (5H, m), 1.94 (1H, q, J = 11.7 Hz), 1.91−1.87 (3H, m),
1.79 (1H, dddd, J = 14.6, 7.7, 6.6, 3.7 Hz), 1.72−1.69 (2H, m), 1.58
(1H, q, J = 11.7 Hz), 1.520 (1H, q, J = 11.3 Hz), 1.516 (1H, q, J =
11.3 Hz), 1.43 (1H, q, J = 11.3 Hz), 1.40 (1H, m); 13C NMR (150
MHz, CDCl3) δ 138.3, 138.1, 128.4, 128.3, 127.8, 127.74, 127.69,
127.6, 100.0, 82.1, 82.0, 81.9, 81.1, 80.1, 79.7, 79.4, 79.3, 78.0, 77.31,
77.28, 77.1, 77.0, 73.4, 72.5, 70.8, 69.3, 68.8, 67.8, 47.3, 37.5, 37.0,
36.9, 34.8, 31.9, 30.9, 29.3 (×2), 29.2, 27.6, 25.5; MS (FAB) 763 (M
+ H), 731 (M − OMe); HRFABMS calcd for C44H59O11 (MH+)
763.4057, found 763.4072.
(2R,3S,4aR,5aS,7aR,8aS,12aR,13aS,14aR,15aS)-2-
(((2R,3S,4aR,6S,9aS)-3-(Benzyloxy)-2-((benzyloxy)methyl)-7-
oxooctahydro-2H-pyrano[3,2-b]oxepin-6-yl)methyl)-
octadecahydropyrano[2′,3′:5,6]pyrano[3,2-b]pyrano[2′,3′:5,6]-
pyrano[2,3-f ]oxepin-3-yl Acetate (37). To a suspension of ketone
36 (10.4 mg, 0.0134 mmol) and powdered 4 Å molecular sieves (42
mg) in CH2Cl2 (1 mL) at −80 °C were added BF3·OEt2 (0.0083 mL,
0.067 mmol) and trimethylsilyldiazomethane (0.0335 mL of a 2.0 M
solution in hexanes, 0.067 mmol), and the reaction mixture was
stirred at −80 °C for 1 h. The reaction was quenched with saturated
aqueous NaHCO3 solution (2 mL). The resulting mixture was
allowed to warm to room temperature and extracted with EtOAc. The
extract was washed with water and brine, dried, and concentrated
ii. Reductive Etherification of Acetal 20a-OMe-38. To a solution
of 20a-OMe-38 (4.3 mg, 0.0056 mmol) and Et3SiH (0.017 mL, 0.11
mmol) in CH2Cl2 (0.5 mL) was added TMSOTf (0.0051 mL, 0.028
mmol) at 0 °C, and the reaction mixture was stirred at 0 °C for 1.5 h.
The reaction was quenched with saturated aqueous NaHCO3 solution
(2 mL), and the resulting mixture was extracted with CH2Cl2. The
M
dx.doi.org/10.1021/jo302267f | J. Org. Chem. XXXX, XXX, XXX−XXX

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extract was washed with brine, dried, and concentrated under reduced
pressure. Purification by flush chromatography (0→4% MeOH in
CHCl3) afforded 38 (3.9 mg, 95%) as a colorless solid. Mp 300−325
°C (decomp); [α]27D +19.7 (c 0.33, CHCl3); IR (CHCl3) 3009, 2936,
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1
2872, 1456, 1342, 1076 cm−1; H NMR (600 MHz, CDCl3) δ 7.34−
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7.20 (10H, m), 4.60 and 4.54 (each 1H, d, J = 12.5 Hz), 4.58 and
4.38 (each 1H, d, J = 11.4 Hz), 3.90 (1H, d, J = 11.0 Hz), 3.74 (1H,
dd, J = 10.6, 1.5 Hz), 3.61 (1H, dd, J = 10.6, 5.2 Hz), 3.47 (1H, ddd, J
= 10.6, 9.5, 4.8 Hz), 3.38−3.16 (10H, m), 3.05−2.95 (6H, m), 2.56
(1H, ddd, J = 11.7, 4.4, 4.4 Hz), 2.36−2.28 (4H, m), 2.04−2.00 (5H,
m), 1.95−1.86 (4H, m), 1.73−1.69 (2H, m), 1.54−1.39 (6H, m); 13C
NMR (150 MHz, CDCl3) δ 138.3, 138.0, 128.4, 128.3, 127.9, 127.7
(×2), 127.6, 82.2, 82.1, 82.0, 81.7, 80.2, 79.7, 79.4, 79.3, 78.9, 77.9,
77.3, 77.0 (×2), 76.8 (×2), 73.5, 72.6, 70.9, 69.4, 67.9, 37.5, 37.1, 37.0
(×2), 35.2, 29.3 (×2), 29.21, 29.17 (×2), 25.5; MS (FAB) 733 (M +
H); HRFABMS calcd for C43H57O10 (MH+) 733.3952, found
733.3955.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: mori@meijo-u.ac.jp.
■
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This research was supported by a Grant-in-Aid for Scientific
Research (C) (21590029) and a Grant-in-Aid for Young
Scientists (B) (23790027) from the Japan Society for the
Promotion of Science (JSPS).
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