Synthesis and Structural Implication of the JKLMN-Ring Fragment of Caribbean Ciguatoxin C-CTX-1

Article abstract of DOI:10.1021/acs.joc.0c03031

Synthesis of the JKLMN-ring fragment of Caribbean ciguatoxin C-CTX-1, the causative toxin of ciguatera fish poisoning in the Caribbean Sea and the Northeast Atlantic areas, is described in detail. Key to the synthesis are a [2,3]-sigmatropic rearrangement to construct a seven-membered α-hydroxy exo-enol ether, stereoselective construction of an angular tetrasubstituted stereogenic center on the seven-membered M-ring by a hydrogen atom transfer-based reductive olefin coupling, Suzuki-Miyaura coupling of the KLMN-ring enol phosphate with a highly congested M-ring, and silica gel-mediated epoxide ring opening to form the J-ring. Comparison of the nuclear magnetic resonance spectroscopic data for the synthesized fragment with those for the natural product provided support for the formerly assigned structure of the N-ring in the right-hand terminal of C-CTX-1.

Full text of DOI:10.1021/acs.joc.0c03031

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Synthesis and Structural Implication of the JKLMN-Ring Fragment of
Caribbean Ciguatoxin C‑CTX‑1
Makoto Sasaki,* Kotaro Iwasaki, and Keisuke Arai
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ABSTRACT: Synthesis of the JKLMN-ring fragment of Caribbean
ciguatoxin C-CTX-1, the causative toxin of ciguatera fish poisoning in
the Caribbean Sea and the Northeast Atlantic areas, is described in
detail. Key to the synthesis are a [2,3]-sigmatropic rearrangement to
construct a seven-membered α-hydroxy exo-enol ether, stereoselective
construction of an angular tetrasubstituted stereogenic center on the
seven-membered M-ring by a hydrogen atom transfer-based reductive
olefin coupling, Suzuki−Miyaura coupling of the KLMN-ring enol
phosphate with a highly congested M-ring, and silica gel-mediated
epoxide ring opening to form the J-ring. Comparison of the nuclear
magnetic resonance spectroscopic data for the synthesized fragment
with those for the natural product provided support for the formerly
assigned structure of the N-ring in the right-hand terminal of C-CTX-1.
the typical Pacific ciguatoxins, such as 1, Caribbean ciguatoxins
possess 14 ether rings with a more complicated architecture. In
particular, the sterically congested seven-membered M-ring
with two pseudoaxially oriented angular methyl groups in a
1,3-relationship represents a formidable synthetic challenge.12
Very recently, it has been reported on the basis of LC−MS/
MS analysis that the N-ring of C-CTX-1 (2) is more likely a
seven-membered ring as shown in structure 4 rather than a six-
membered ring.13 Hence, the structure of the N-ring should be
confirmed using synthetic methods.
As part of our synthetic studies toward C-CTX-1 and its
structural fragments as synthetic haptens for the development
of antibody-based immunological detection methods, we have
already developed a synthetic route to the LMN-ring fragment
of C-CTX-1, in which a hydrogen atom transfer (HAT)-based
olefin coupling14 was utilized for an efficient construction of
the M-ring.15 We describe herein in detail an advanced
synthetic route to the JKLMN-ring fragment of C-CTX-1
through Suzuki−Miyaura coupling and 6-exo epoxide opening,
providing support for the originally assigned structure of the
right-hand N-ring.
INTRODUCTION
■
Ciguatera fish poisoning (CFP) is a foodborne disease
prevalent in circumtropical areas of the Pacific Ocean, Indian
Ocean, and Caribbean Sea with more than 20,000−60,000
patients annually, and continues to be a serious public health
problem around the world.1,2 Because of the globalization of
trade, in addition to climate change, the incidence of CFP has
recently been spreading in temperate regions,3 and thus
prevention of CFP is a global issue to be urgently addressed.
Pacific ciguatoxins, the causative toxins for CFP in the Pacific
Ocean, are produced by the epiphytic dinoflagellate
Gambierdiscus toxicus, enter the food chain, and accumulate
in many fish.4 So far, more than 20 Pacific ciguatoxin
congeners, including CTX3C (1)5 (Figure 1), have been
identified from toxic fish and/or G. toxicus.6 Hirama and
colleagues have reported the total synthesis of four Pacific
ciguatoxins, including CTX3C (1),7 and developed a sandwich
enzyme-linked immunosorbent assay utilizing monoclonal
antibodies for their sensitive and specific detection.8
In contrast to the Pacific ciguatoxins, research on Caribbean
ciguatoxins has not made much progress because of the
extremely limited availability of toxins from natural sources. A
major Caribbean ciguatoxin, C-CTX-1, the causative toxin for
CFP in the Caribbean Sea and the Northeast Atlantic areas,
was first isolated in 1995 by Dickey and co-workers from
Caribbean barracuda (Sphyraena barracuda) and horse-eye jack
(Caranx latus).9 In 1997, Vernoux and Lewis isolated C-CTX-
1, along with a minor analogue, C-CTX-2, from horse-eye
jack.10 The structures of C-CTX-1 (2) and C-CTX-2 (3) were
determined from extensive two dimensional nuclear magnetic
resonance (2D NMR) experiments (Figure 1).11 Compared to
Received: December 26, 2020
Published: March 5, 2021
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Figure 1. Structures of CTX3C (1), C-CTX-1 (2), C-CTX-2 (3), and newly proposed structure 4 for C-CTX-1.
contrast, allyltitanation with the Hafner−Duthaler reagent22
provided gram amounts of 17 in high yield (89% in two steps)
and with excellent and reproducible diastereoselectivity (dr >
20:1). The configuration of the C44 stereogenic center was
confirmed using the NOE data after conversion to bis-
acetonide derivative 18 (Figure 2). Protection of alcohol 17 as
its TIPS ether and hydroboration of the terminal olefin using
dicyclohexylborane followed by benzylation provided bis-
benzyl ether 19 in 91% overall yield. Removal of the p-
methoxybenzylidene acetal under acidic conditions afforded
diol 20 in 96% yield. Diol 20 was subjected to one-pot
triflation and triethylsilyl (TES) protection23 provided a
triflate, which was then treated with allylmagnesium bromide
in the presence of CuBr24 to afford elongated olefin 21 in 96%
yield in two steps. Removal of the TES group of 21 with TsOH
(98%), followed by Dess−Martin oxidation25 of the resulting
secondary alcohol 22, provided ketone 23 in 98% yield. Upon
treatment of ketone 23 with excess Me3Al (CH2Cl2, −78 to
−15 °C),26 the requisite tertiary alcohol 24 was obtained in
92% yield along with a small amount of its diastereomer (7%).
The configuration of the C48 stereogenic center of 24 was
determined by NOE. Hydroboration of 24 provided diol 25,
which was oxidized with 2-hydroxy-2-azaadamantane (AZA-
DOL) and PhI(OAc)2 in CH2Cl2/pH 7 buffer (1:1)27 to
afford hydroxy carboxylic acid 26 in 87% yield in two steps.
Yamaguchi lactonization28 of 26 provided seven-membered
lactone 27 in 96% yield. Finally, lactone 27 was converted into
enol phosphate 13 in 97% yield by treatment with KHMDS
and (PhO)2P(O)Cl [HMPA, tetrahydrofuran (THF), −78
°C].
RESULTS AND DISCUSSION
■
Synthesis Plan. Retrosynthetic analysis of the JKLMN-ring
fragment 5 of C-CTX-1 (2) is depicted in Scheme 1. We
envisioned that the J-ring of 5 would be constructed by acid- or
base-catalyzed 6-exo epoxide opening and the precursor
epoxide could be derived from enol ether 6. Compound 6
would be synthesized from enol phosphate 7 and alkylborate 8
through Suzuki−Miyaura coupling,16,17 and enol phosphate 7
in turn would be accessed from compound 9. For the
construction of the C53 tetrasubstituted stereogenic center as
well as installation of a four-carbon unit required for the N-
ring, we planned to use a HAT-based reductive olefin
coupling14,18 of exo-enol ether 10 with vinyl ketone 11. The
exo-enol ether 10 would be derived from allylic selenide 12
through [2,3]-sigmatropic rearrangement.19 The selenide 12
would be available from the corresponding allylic alcohol,
which in turn, would be accessed from enol phosphate 13
through Stille coupling with (tributylstannyl)methanol.
Synthesis of Enol Phosphate 13. The synthesis of enol
phosphate 13 was carried out according to the previous
method15 with some modifications (Scheme 2). Benzylation of
the known alcohol 1412b (93%) and ozonolysis of the derived
benzyl ether 15 provided the corresponding aldehyde, which
was subjected to Brown asymmetric allylboration using (−)-B-
allyldiisopinocamphenylborane.20 The desired homoallylic
alcohol 17 was obtained in 73% yield (two steps) with a
diastereomeric ratio of 10:1. However, during scaleup, we
could not secure reproducibility of the diastereomer ratio of
this allylboration (4.8:1 to 15:1). No conversion of the
aldehyde to 17 was observed under Keck allylation.21 In
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Scheme 1. Retrosynthetic Analysis of JKLMN-Ring
Fragment 5 of C-CTX-1
Figure 2. Configurational assignment of homoallylic alcohol 17.
lation by Stille coupling.29 Thus, Stille coupling of enol
phosphate 13 with (tributylstannyl)methanol30,31 using Pd-
(PPh3)4 and LiCl (THF, reflux) gave allylic alcohol 28 in 85%
yield (Scheme 3). Alcohol 28 was then converted into 2-
nitrophenylselenide 12 in 88% yield according to the Grieco−
Nishizawa protocol.32 The [2,3]-sigmatropic rearrangement19
of selenide 12 was best achieved by treatment with aqueous
H2O2 and 4-dimethylaminopyridine (DMAP) in THF at −44
°C to room temperature, giving α-hydroxy exo-enol ether 29
with the incorrect configuration at C52 in 68% yield. Under
these conditions, the desired alcohol 31 was obtained in only
small amounts (<2%). The C52 configuration of 29 was
confirmed using the NOE data as shown in Figure 3. The
observed stereoselectivity in this [2,3]-sigmatropic rearrange-
ment could be explained by the steric hindrance of the C48
angular methyl group. The C52 hydroxy group of 29 was
inverted by modified Mitsunobu conditions (4-
NO2C6H4CO2H, Ph3P, DEAD, toluene, 0 °C),33 and
subsequent methanolysis of the resulting 4-nitrobenzoate 30
(K2CO3 and MeOH) led to alcohol 31 in 74% yield in two
steps. TES protection of 31 completed the synthesis of exo-
enol ether 10 in 95% yield.
Synthesis of exo-Enol Ether 10. With the desired enol
phosphate 13 in hand, we next attempted the hydroxymethy-
Scheme 2. Synthesis of Enol Phosphate 13
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Scheme 3. Synthesis of exo-Enol Ether 10
33 was improved by increasing the molar amounts of 11 and
Fe(dibm)3 (entry 2). Baran and colleagues reported that olefin
cross-coupling of glucal derivatives required the slow addition
of a large excess of both methyl vinyl ketone and PhSiH3 to
obtain an acceptable yield.14a,b Thus, a solution of vinyl ketone
11 (5 equiv) and Ph(i-PrO)SiH2 (5 equiv) in EtOAc was
slowly added using a syringe pump to a mixture of 10,
Fe(dibm)3 (30 mol %), and Na2HPO4 in i-PrOH to provide
33 in 63% yield (entry 3). Finally, running the reaction in the
degassed solvents further improved the yield of the desired
ketone 33 to 70% (entry 4). The configuration of the newly
generated stereogenic center of C53 was confirmed by an NOE
observed between two methyl groups. The stereochemical
outcome of this radical reaction could be ascribed to the
effective shielding of the α-face of the seven-membered ring by
the C48 angular methyl and C52 triethysilyloxy substituents of
the intermediary radical species 32.
Figure 3. Configurational assignment of alcohol 29.
Synthesis of LMN-Ring Fragment 9. With the key
intermediate 10 in hand, we next investigated the crucial HAT-
based reductive olefin coupling14 with the known vinyl ketone
1134 using a combination of (isopropoxy)phenylsilane Ph(i-
35
PrO)SiH2
and iron(III) diisobutyrylmethanoate (Fe-
(dibm)3)14a,b (Table 1). Thus, slow addition of Ph(i-PrO)SiH2
(3.5 equiv) to exo-enol ether 10 and vinyl ketone 11 (3.5
equiv) in the presence of Fe(dibm)3 (10 mol %) and
Na2HPO4 (1 equiv) in EtOAc/i-PrOH (1:1) at room
temperature led to the desired product 33 in moderate yield
(44%) as a single stereoisomer (Table 1, entry 1). The yield of
Selective removal of the tert-butyldimethylsilyl (TBS) and
TES ethers of 33 under acidic conditions (CSA, CH2Cl2/
MeOH) gave methyl acetal 34 in 85% yield as a single
a
Table 1. Optimization of HAT-Based Reductive Olefin Coupling
entry
Fe(dibm)3 (mol %)
Ph(i-PrO)SiH2 (equiv)
enone 11 (equiv)
yield (%)
b
1
2
3
4
10
15
30
30
3.5
5
5
3.5
5
5
44
57
63
70
b
c
cd
,
5
5
a
b
The reaction was performed in the presence of Na2HPO4 (1 equiv) in EtOAc/i-PrOH (1:1). Silane was added to a solution of exo-olefin, enone,
c
and Fe(dibm)3 in EtOAc/i-PrOH. A solution of enone and silane in EtOAc was slowly added via a syringe pump to a solution of exo-olefin and
Fe(dibm)3 in i-PrOH. The solvents were degassed with argon for 1 h.
d
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diastereomer (Scheme 4). Subsequent treatment of methyl
acetal 34 with scandium(III) triflate12b,36 in acetone provided
the desired LMN-ring fragment 9 of C-CTX-1 in 81% yield.
Scheme 6. Synthesis of Iodide 37
Scheme 4. Synthesis of LMN-Ring Fragment 9
Synthesis of Ketone 43. Suzuki−Miyaura coupling of
enol phosphate 7 with alkylborate 8, in situ generated from
iodide 37 (t-BuLi, B-MeO-9-BBN, Et2O/THF, −78 °C to
room temperature),42 was carried out in the presence of
Pd(PPh3)4 as a catalyst and the aqueous Cs2CO3 solution as a
base in dimethylformamide (DMF) at 50 °C, giving the
desired enol ether 6 in 81% yield (Scheme 7). Hydroboration
Scheme 7. Synthesis of Ketone 43
Synthesis of KLMN-Ring Enol Phosphate 7. Removal of
the benzyl ethers of 9 was carried out with lithium 4,4′-di-tert-
biphenylide (LiDBB)37 to give diol 35 in 99% yield (Scheme
5). Oxidative lactonization of 1,6-diol 35 using a catalytic
Scheme 5. Synthesis of KLMN-Ring Enol Phosphate 7
of 6 with BH3·THF followed by oxidative workup gave alcohol
42 (79%) with the incorrect configuration at C41 because of
the sterically encumbered pseudoaxially oriented tri-
(isopropyl)silyloxy group at the C44 position.43 Dess−Martin
oxidation25 of alcohol 42 (90%), followed by treatment of the
resultant ketone with excess 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU) in toluene under reflux conditions, provided the
desired ketone 43 (86%). The relative configuration at the C41
position of 43 was confirmed using the ROE data.
Synthesis of JKLMN-Ring Fragment 5. With the desired
ketone 43 in hand, the next task was the construction of the J-
ring. To this end, stereoselective reduction of ketone 43 was
next investigated. After some experimentation, it was found
that DIBALH reduction of 43 (CH2Cl2, −78 °C) gave the
desired alcohol 44 albeit in a moderate yield (51%) (Scheme
8). The configuration at the C42 position was confirmed by
amount of TEMPO and PhI(OAc)2 as a stoichiometric oxidant
(CH2Cl2, 0.1 M, room temperature)38 proceeded smoothly to
provide seven-membered lactone 36 in 94% yield. Lactone 36
was converted to the requisite enol phosphate 7 in 97% yield
by the action of KHMDS and (PhO)2P(O)Cl.
Synthesis of Iodide 37. The synthesis of iodide 37, the
precursor of alkylborate 8, commenced with the known alcohol
38,39 which was readily available from (−)-malic acid in three
steps (Scheme 6). Protection of 38 as its PMB ether using 2-
(4-methoxybenzyloxy)-4-methylquinoline 39 in the presence
of CSA (0.1 equiv) (CH2Cl2, room temperature, 4 days)40
provided 40,41 which was reduced with LiAlH4 (THF, −40
°C) to give primary alcohol 41 in 67% yield in two steps.
Iodination of alcohol 41 with I2, PPh3, and imidazole provided
iodide 37 in 84% yield.
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Scheme 8. Synthesis of JKLMN-Ring Fragment 5
derivatization to the corresponding acetate 45 and ROE
experiments. After careful examination of the DIBALH
reduction of 43, its low yield was ascribed to the partial
deprotection of the primary TBS ether under the current
reaction conditions.44 Thus, ketone 43 was treated with excess
DIBALH in CH2Cl2 at −78 °C for 1 h, and then allowed to
warm to −20 °C and stirred for 3 h to complete the
deprotection of the primary hydroxy group by reductive
cleavage of the TBS ether. Under these conditions, diol 46 was
obtained in 76% yield with a diastereomer ratio of >20:1.
Selective tosylation of the primary alcohol within 46 (TsCl,
Et3N, DMAP, CH2Cl2) provided tosylate 47 in 95% yield.
Oxidative removal of the PMB ether of 47 with DDQ, followed
by treatment with K2CO3 in CH2Cl2/MeOH, afforded epoxide
48 in 84% yield in two steps. The final 6-exo cyclization in the
epoxide opening of 48 to form the J-ring proved to be
unexpectedly difficult. Cyclization of 48 under basic conditions
using potassium dimsylate45 in THF provided the desired 49
in only a low yield (32%). An acidic treatment of epoxide 48
using CSA, PPTS, or Sc(OTf)3 also resulted in a low yield of
49 because of the competitive cleavage of the acetonide group.
Upon careful experimentation, it was found that cyclization
product 49 was formed in small amounts during the
experiment on a thin layer chromatography (TLC) plate for
a long time. Accordingly, epoxide 48 was dissolved in a slurry
of silica gel in toluene and stirred at 50 °C for 13 h 40 min to
effect clean cyclization, giving the desired 49 in quantitative
yield.46 Finally, desilylation of 49 with tetra-n-butylammonium
fluoride (TBAF) (THF, 50 °C) completed the synthesis of the
JKLMN-ring fragment 5 in 87% yield. The relative
configuration of the newly generated stereogenic centers
within 5 was determined by NOE experiments.
Scheme 9. Synthesis of Tetrahydroxy JKLMN-Ring
Fragment 50
product.47 As shown in Figure 4, the 1H NMR chemical shifts
in the KLMN-ring region of 50 matched well with those
reported for the natural product within 0.06 ppm, while the
13C NMR chemical shifts for 50 also corresponded to those for
C-CTX-1 within 1.0 ppm except that for C62 (C53-Me).48
Especially, the 1H and 13C NMR signals of the C57
hydroxymethyl group were clearly observed in compound 50,
and their chemical shifts were virtually identical to those
reported for the natural product, but there is no corresponding
partial structure in the revised structure 4. These results
demonstrated that the formerly assigned structure of the right-
hand terminal of C-CTX-1 by the Lewis group is most likely
represented by structure 50, which contains the six-membered
N-ring.
Structural Implication of the N-Ring of Caribbean
Ciguatoxin C-CTX-1. In order to confirm the structure of the
N-ring of C-CTX-1, we decided to synthesize tetrahydroxy
JKLMN-ring fragment 50 and compare its NMR data with
those reported for the natural product. Thus, cleavage of the
acetonide of compound 5 with THF/H2O/TFA (5:1:1) at 50
°C gave tetraol 50 in 94% yield as an approximately 5:1
CONCLUSIONS
■
In conclusion, we have reported an advanced synthetic route to
the JKLMN-ring fragment of Caribbean ciguatoxin C-CTX-1.
Highlights of the synthesis are a [2,3]-sigmatropic rearrange-
ment of allylic selenoxide to form the α-hydroxy exo-enol ether,
a HAT-based reductive olefin coupling for the stereoselective
construction of an angular tetrasubstituted stereogenic center
on the seven-membered M-ring, and silica-gel-promoted 6-exo
epoxide opening to form the J-ring. Additional salient features
1
mixture of anomers at the C56 position (Scheme 9). The H
and 13C NMR data for 50 thus prepared were carefully
compared to those for the corresponding portion of the natural
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Optical rotations were measured on a digital polarimeter at 589 nm.
IR spectra were recorded as a thin film on a KBr disk using an FT-IR
spectrometer and reported in wavenumbers (cm−1). 1H and 13C
NMR spectra were recorded using 600 and 150 MHz NMR
spectrometers, respectively. Chemical shift values are reported in
ppm (δ) downfield from tetramethylsilane with reference to internal
residual solvents [1H NMR, CHCl3 (7.26), C6HD5 (7.16), and
C5HD4N (7.21); 13C NMR, CDCl3 (77.0), C6D6 (128.0), and C5D5N
(123.5)]. Coupling constants (J) are reported in hertz (Hz). The
following abbreviations were used to designate the multiplicities: s =
singlet; d = doublet; t = triplet; q = quartet; m = multiplet or
unresolved; and br = broad. High-resolution mass spectra (HRMS)
were measured on an electron spin ionization-time of flight mass
spectrometer. The diastereomer ratio (dr) and the E/Z isomer ratio
1
were estimated by H NMR spectroscopic analysis, unless otherwise
noted.
Benzyl Ether 15. To a solution of alcohol 14 (20.40 g, 66.59
mmol) in THF (320 mL) at 0 °C was added t-BuOK (17.26 g, 153.8
mmol). The resultant solution was stirred at room temperature for 20
min. To this mixture were added sequentially BnBr (12.0 mL, 101
mmol) and n-Bu4NI (2.47 g, 6.69 mmol), and the resultant solution
was stirred at room temperature for 2 h. The reaction was quenched
with the saturated aqueous NH4Cl solution (100 mL) at 0 °C. The
mixture was extracted with EtOAc (500 mL), and the organic layer
was washed with brine (2 × 100 mL), dried over MgSO4, filtered, and
concentrated under reduced pressure. Purification of the residue by
column chromatography (silica gel, 5 to 10 to 15 to 20% EtOAc/
hexanes) gave benzyl ether 15 (24.68 g, 93%) as a colorless solid: mp
83.0−84.0 °C; [α]2D4.3 −35.9 (c 1.29, CHCl3); IR (neat): 2984, 2940,
1
2863, 1615, 1518, 1250, 1092, 1034, 829, 698 cm−1; H NMR (600
MHz, CDCl3): δ 7.44−7.40 (m, 2H), 7.36−7.27 (m, 5H), 6.92−6.88
(m, 2H), 6.04 (dd, J = 17.4, 11.0 Hz, 1H), 5.48 (s, 1H), 5.34 (dd, J =
17.4, 1.4 Hz, 1H), 5.13 (dd, J = 11.0, 1.4 Hz, 1H), 4.61 (d, J = 11.9
Hz, 1H), 4.50 (d, J = 11.9 Hz, 1H), 4.27 (m, 1H), 3.80 (s, 3H), 3.70−
3.64 (m, 2H), 3.47 (m, 1H), 3.43 (dd, J = 11.5, 4.6 Hz, 1H), 2.41
(ddd, J = 11.9, 4.6, 4.1 Hz, 1H), 1.80 (ddd, J = 11.9, 11.5, 11.5 Hz,
1H), 1.41 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ 160.1,
142.6, 138.1, 130.0, 128.3 (2C), 127.7, 127.5 (2C), 127.4 (2C), 113.7
(2C), 113.5, 101.6, 79.0, 77.32, 77.29, 71.6, 70.0, 66.3, 55.3, 30.9,
15.9; HRMS (FAB) m/z: [M + H]+ calcd for C24H29O5, 397.2010;
found, 397.2013.
Aldehyde S1. Ozone gas was bubbled through a solution of benzyl
ether 15 (6.12 g, 15.4 mmol) in CH2Cl2/MeOH/pyridine (4:4:1, v/
v/v, 153 mL) at −78 °C until a blue color persisted for 34 min. After
passing O2 gas to remove excess O3 for 12 min, Me2S (7.0 mL, 94.6
mmol) was added to the reaction mixture. The resultant solution was
allowed to warm to room temperature and stirred for 3 h. The
mixture was concentrated under reduced pressure. The residue was
diluted with EtOAc (250 mL), washed with H2O (80 mL) and brine
(80 mL), dried over MgSO4, filtered, and concentrated under reduced
pressure. The crude aldehyde S1 (6.29 g) was used in the next step
without further purification.
Preparation of Duthaler−Hafner Reagent 16. To a suspension of
CpTiCl3 (4.49 g, 20.06 mmol) in anhydrous cyclohexane (400 mL)
was added (4R,trans)-2,2-dimethyl-α,α,α′,α′-tetraphenyl-1,3-dioxo-
lane-4,5-dimethanol (9.37 g, 20.08 mmol). The reaction flask was
fitted with a Soxhlet extractor containing 16 g of MgO (activated at
450 °C (heat gun) for 3.5 h under reduced pressure), and the mixture
was stirred under reflux (oil bath) for 19 h 20 min. The resultant
mixture was cooled to room temperature, and the solvent was
evaporated with caution. The residue was twice dissolved in
anhydrous Et2O (200 mL), stirred at room temperature for 10−15
min, and concentrated under reduced pressure. Duthaler−Hafner
reagent 16 thus obtained as a pale yellow solid was used in the next
step without further purification.
Figure 4. Differences in 1H and 13C NMR chemical shifts between C-
CTX-1 and synthetic fragment 50. Δδ = δ (natural product) − δ
(synthetic fragment) in ppm (pyridine-d5).
include a hydroxymethylation by Stille coupling of seven-
membered enol phosphate, TEMPO/PhI(OAc)2-mediated
oxidative lactonization of a 1,6-diol, and Suzuki−Miyaura
coupling of the KLMN-ring enol phosphate containing the
sterically congested M-ring. The present synthesis also
provided support for the formerly assigned structure of the
N-ring of C-CTX-1. The first synthesis of the JKLMN-ring
fragment of C-CTX-1 enabled the preparation of a nontoxic
hapten to generate monoclonal antibodies that specifically
recognize the right-hand structure of C-CTX-1. Further studies
along this line and toward the total synthesis of C-CTX-1 are
underway and will be reported in due course.
EXPERIMENTAL SECTION
■
General Methods. All reactions sensitive to moisture and/or air
were carried out under an atmosphere of argon in dry, freshly distilled
solvents under anhydrous conditions using oven-dried glassware
unless otherwise noted. Anhydrous acetone, acetonitrile (MeCN),
1,2-dichloroethane (DCE), dichloromethane (CH2Cl2), DMF, ethyl
acetate (EtOAc), methanol (MeOH), and 2-propanol (i-PrOH) were
purchased, and anhydrous diethyl ether (Et2O), THF, and toluene
were purified using a Glass Contour solvent purification system. 2,6-
lutidine and triethylamine (Et3N) were distilled from calcium hydride
under an atmosphere of argon. Hexamethylphosphoramide (HMPA)
was distilled from calcium hydride under reduced pressure. All other
chemicals were purchased at the highest commercial grade and used
directly. Analytical TLC was performed using a precoated glass plate
(silica gel 60 F254, 0.25 mm thickness). Flash column chromatography
was carried out using silica gel (spherical, neutral, and 40−100 mesh).
Homoallylic Alcohol 17. To a solution of the above Duthaler−
Hafner reagent 16 in Et2O (300 mL) at 0 °C was added
allylmagnesium chloride (2.0 M solution in THF, 9.6 mL, and 19.2
mmol) dropwise over 5 min, and the resultant orange-brown
suspension was stirred at 0 °C for 1 h 50 min. The resultant
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suspension was cooled to −78 °C, and a solution of the above crude
aldehyde S1 (6.29 g) in THF (25 mL + 2 × 5 mL rinse) was added
dropwise over 10 min. The resultant mixture was stirred at −78 °C for
3.5 h. The reaction was quenched with pH 7.0 phosphate buffer (150
mL). The mixture was allowed to warm to room temperature and
stirred for 4 days. The mixture was filtered through a pad of Celite,
washing with EtOAc (250 mL). The aqueous layer was separated and
extracted with EtOAc (120 mL). The combined organic extracts were
washed with brine (2 × 100 mL), dried over MgSO4, filtered, and
concentrated under reduced pressure. Purification of the residue by
column chromatography (silica gel, 10 to 20 to 30 to 35% EtOAc/
hexanes) gave homoallylic alcohol 17 (6.05 g, 89% in two steps, dr >
20:1) as a colorless solid and (4R,trans)-2,2-dimethyl-α,α,α′,α′-
tetraphenyl-1,3-dioxolane-4,5-dimethanol (9.09 g, 97%) was recov-
ered: data for 17: mp 76.0−77.0 °C; [α]1D9.8 −61.3 (c 1.32, CHCl3);
IR (neat): 3501, 2948, 2865, 2360, 2341, 1615, 1518, 1463, 1386,
7.44−7.40 (m, 2H), 7.36−7.26 (m, 5H), 6.91−6.87 (m, 2H), 5.85
(dddd, J = 17.0, 10.0, 6.9, 6.9 Hz, 1H), 5.44 (s, 1H), 5.02−4.95 (m,
2H), 4.61 (d, J = 11.5 Hz, 1H), 4.51 (d, J = 11.5 Hz, 1H), 4.18 (m,
1H), 4.11 (dd, J = 11.5, 4.6 Hz, 1H), 3.84 (dd, J = 6.9, 4.6 Hz, 1H),
3.80 (s, 3H), 3.65−3.58 (m, 2H), 3.40 (m, 1H), 2.64 (m, 1H), 2.43
(ddd, J = 11.5, 4.6, 4.6 Hz, 1H), 2.33 (m, 1H), 1.73 (ddd, J = 11.9,
11.9, 11.4 Hz, 1H), 1.28 (s, 3H), 1.15−1.08 (m, 21H); 13C{1H}
NMR (150 MHz, CDCl3): δ 160.1, 138.2, 137.6, 130.1, 128.3 (2C),
127.7 (2C), 127.6, 127.4 (2C), 115.9, 113.7 (2C), 101.7, 80.8, 79.0,
76.9, 73.0, 70.7, 69.9, 66.3, 55.3, 39.2, 30.8, 18.5 (3C), 18.4 (3C),
14.3, 13.3 (3C); HRMS (FAB) m/z: [M + H]+ calcd for C35H53O6Si,
597.3608; found, 597.3617.
To a solution of cyclohexene (7.0 mL, 69.1 mmol) in THF (140
mL) at 0 °C was slowly added BH3·THF (0.9 M solution in THF,
34.0 mL, 30.6 mmol), and the resultant solution was stirred at 0 °C
for 1 h. To the resultant white suspension was slowly added a solution
of the above TIPS ether S2 (15.46 g) in THF (25 mL + 2 × 5 mL
rinse) over 12 min. The resultant solution was stirred at room
temperature for 1 h. To this solution at 0 °C were slowly added 3 M
aqueous NaOH solution (34 mL) followed by 30% aqueous H2O2
solution (34 mL). The resultant mixture was stirred at room
temperature for 1.5 h. The organic layer was separated, and the
aqueous layer was extracted with Et2O (2 × 60 mL). The combined
organic layers were washed with brine (2 × 80 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure.
Purification of the residue by flash column chromatography (silica
gel, 10 to 20 to 30% EtOAc/hexanes) gave alcohol S3 (15.03 g) as a
colorless oil: [α]2D1.6 −36.7 (c 1.45, CHCl3); IR (neat): 3433, 2943,
2865, 1615, 1518, 1464, 1384, 1366, 1250, 1173, 1033, 883, 829, 678
1
1367, 1250, 1173, 1094, 1030, 829, 699 cm−1; H NMR (600 MHz,
CDCl3): δ 7.43−7.40 (m, 2H), 7.37−7.33 (m, 2H), 7.32−7.28 (m,
3H), 6.91−6.88 (m, 2H), 5.88 (dddd, J = 17.0, 10.1, 7.3, 6.4 Hz, 1H),
5.48 (s, 1H), 5.12−5.05 (m, 2H), 4.66 (d, J = 11.5 Hz, 1H), 4.45 (d, J
= 11.5 Hz, 1H), 4.21 (m, 1H), 3.80 (s, 3H), 3.79 (dd, J = 11.5, 4.6
Hz, 1H), 3.65−3.59 (m, 3H), 3.42 (m, 1H), 3.03 (m, 1H), 2.54 (ddd,
J = 11.5, 4.6, 4.6 Hz, 1H), 2.38 (m, 1H), 2.14 (m, 1H), 1.79 (ddd, J =
11.9, 11.5, 11.5 Hz, 1H), 1.34 (s, 3H); 13C{1H} NMR (150 MHz,
CDCl3): δ 160.1, 137.3, 136.4, 129.8, 128.5 (2C), 127.9, 127.7 (2C),
127.4 (2C), 116.5, 113.7 (2C), 101.7, 78.5, 77.9, 77.2, 76.9, 70.2,
69.8, 66.2, 55.3, 35.4, 30.0, 12.6; HRMS (FAB) m/z: [M + H]+ calcd
for C26H33O6, 441.2272; found, 441.2274.
Bis-acetonide 18. To a solution of homoallylic alcohol 17 (22.1
mg, 0.0502 mmol) in MeOH (1 mL) was added 10% Pd/C (11 mg),
and the resultant mixture was stirred at room temperature under an
atmosphere of H2 (balloon) for 22 h. The mixture was filtered
through a pad of Celite eluting with EtOAc and MeOH, and the
filtrate was concentrated under reduced pressure to give crude tetraol
(13.5 mg).
To a solution of the above tetraol in CH2Cl2 (1 mL) were added
2,2-dimethoxypropane (0.2 mL, 1.6 mmol) and PPTS (2.8 mg, 0.011
mmol), and the resultant solution was stirred at room temperature for
17 h. The mixture was neutralized with Et3N (0.1 mL) and
concentrated under reduced pressure. Purification of the residue by
flash column chromatography (silica gel, 10% EtOAc/hexanes) gave
bis-acetonide 18 (12.3 mg, 78% in two steps): [α]2D6.4 −6.9 (c 1.26,
CHCl3); IR (neat): 2991, 2958, 2873, 1466, 1269, 1200, 1120, 1104,
1069, 1041, 931, 903, 863, 755 cm−1; 1H NMR (600 MHz, CDCl3): δ
3.79 (dd, J = 10.6, 5.0 Hz, 1H), 3.68 (dd, J = 11.5, 4.1 Hz, 1H), ca.
3.66 (m, 1H, overlapped), 3.65 (dd, J = 10.6, 10.5 Hz, 1H), 3.52 (dd,
J = 9.6, 2.3 Hz, 1H), 3.48 (ddd, J = 10.5, 10.1, 5.0 Hz, 1H), 1.92 (ddd,
J = 11.5, 4.1, 4.1 Hz, 1H), 1.76 (ddd, J = 11.5, 11.5, 11.5 Hz, 1H),
1.56−1.44 (m, 2H, overlapped), 1.49 (s, 3H), 1.47 (s, 3H), 1.41 (s,
3H), 1.40 (s, 3H), 1.32−1.22 (m, 2H, overlapped), 1.24 (s, 3H);
13C{1H} NMR (150 MHz, CDCl3): δ 100.2, 99.4, 77.7, 74.0, 73.0,
70.7, 68.1, 63.5, 30.3, 29.9, 29.6, 29.2, 19.6, 19.3, 19.2, 14.0, 10.6;
HRMS (FAB) m/z: [M + H]+ calcd for C17H31O5 315.2166; found,
315.2166.
1
cm−1; H NMR (600 MHz, CDCl3): δ 7.44−7.39 (m, 2H), 7.35−
7.26 (m, 5H), 6.91−6.87 (m, 2H), 5.43 (s, 1H), 4.61 (d, J = 11.5 Hz,
1H), 4.46 (d, J = 11.5 Hz, 1H), 4.17 (m, 1H), 4.08 (dd, J = 11.5, 4.6
Hz, 1H), 3.80 (s, 3H), 3.72 (m, 1H), 3.65−3.58 (m, 2H), 3.58−3.53
(m, 2H), 3.40 (m 1H), 2.44 (ddd, J = 11.5, 4.6, 4.6 Hz, 1H), 1.85−
1.72 (m, 2H), 1.72 (ddd, J = 11.5, 11.5, 11.5 Hz, 1H), 1.60−1.47 (m,
2H), 1.26 (s, 3H), 1.17−1.06 (m, 21H), one proton missing due to
H/D exchange; 13C{1H} NMR (150 MHz, CDCl3): δ 160.1, 138.3,
130.1, 128.3 (2C), 127.8 (2C), 127.6, 127.4 (2C). 113.7 (2C), 101.7,
80.8, 79.6, 76.9, 73.1, 70.8, 69.9, 66.4, 63.3, 55.3, 31.3, 30.8, 30.6, 18.6
(3C), 18.5 (3C), 14.3, 13.5 (3C); HRMS (FAB) m/z: [M + Na]+
calcd for C35H54O7SiNa, 637.3531; found, 637.3541.
To a solution of the above alcohol S3 (15.03 g) in THF (180 mL)
at 0 °C was added KOt-Bu (8.00 g, 71.3 mmol), and the resultant
solution was stirred at room temperature for 30 min. To this solution
at 0 °C was added benzyl bromide (4.2 mL, 35.1 mmol), and the
resultant solution was stirred at room temperature for 1.5 h.
Additional benzyl bromide (0.4 mL, 3.3 mmol) was added, and the
resultant solution was stirred at room temperature for 40 min. MeOH
(3 mL) was added, and the resultant mixture was stirred at room
temperature for 1 h. The reaction was quenched with the saturated
aqueous NH4Cl solution (50 mL). The resultant mixture was
extracted with EtOAc (200 mL), and the organic layer was washed
with H2O (50 mL) and brine (50 mL), dried over MgSO4, filtered,
and concentrated under reduced pressure. Purification of the residue
by flash column chromatography (silica gel, 5 to 10 to 15% EtOAc/
hexanes) gave benzyl ether 19 (15.20 g, 91% in three steps) as a
colorless oil: [α]2D5.6 −25.7 (c 1.69, CHCl3); IR (neat): 2924, 2863,
1615, 1517, 1462, 1364, 1250, 1092, 1034, 883, 828, 734, 698, 678
Bis-benzyl Ether 19. To a solution of alcohol 17 (10.42 g, 23.65
mmol) in DCE (200 mL) were sequentially added 2,6-lutidine (8.4
mL, 72.1 mmol) and TIPSOTf (7.8 mL, 29.0 mmol). The resultant
solution was heated to 50 °C (oil bath) for 22.5 h. Additional
TIPSOTf (1.9 mL, 7.07 mmol) was added, and the resultant solution
was stirred at 50−60 °C (oil bath) for 5.5 h. The reaction was
quenched with MeOH (3 mL) at room temperature, and the resultant
mixture was stirred at room temperature for 15 min. The mixture was
diluted with CH2Cl2 (200 mL), washed with the saturated aqueous
NaHCO3 solution (150 mL), dried over MgSO4, filtered, and
concentrated under reduced pressure. Purification of the residue by
flash column chromatography (silica gel, 5% EtOAc/hexanes) gave
TIPS ether S2 (15.46 g) as a pale yellow oil, which was contaminated
with a small amount of TIPSOH. Data for S2: [α]2D1.1 −37.6 (c 1.13,
CHCl3); IR (neat): 2943, 2864, 1615, 1463, 1384, 1365, 1250, 1173,
1
cm−1; H NMR (600 MHz, CDCl3): δ 7.44−7.40 (m, 2H), 7.35−
7.23 (m, 10H), 6.91−6.87 (m, 2H), 5.43 (s, 1H), 4.58 (d, J = 11.9
Hz, 1H), 4.51−4.44 (m, 2H, overlapped), 4.48 (d, J = 11.9 Hz, 1H),
4.17 (m, 1H), 4.08 (dd, J = 11.5, 4.6 Hz, 1H), 3.80 (s, 3H), 3.72 (m,
1H), 3.65−3.58 (m, 2H), 3.45−3.36 (m, 3H), 3.42 (m, 1H), 1.93−
1.80 (m, 2H), 1.72 (ddd, J = 11.5, 11.5, 11.5 Hz, 1H), 1.62−1.53 (m,
2H), 1.26 (s, 3H), 1.16−1.06 (m, 21H); 13C{1H} NMR (150 MHz,
CDCl3): δ 160.1, 138.7, 138.3, 130.1, 128.30 (2C), 128.28 (2C),
127.7 (2C), 127.5 (3C), 127.4 (3C), 113.7 (2C), 101.7, 80.8, 79.7,
76.9, 73.0, 72.8, 70.78, 70.71, 69.9, 66.3, 55.3, 31.0, 30.9, 28.4, 18.6
(3C), 18.5 (3C), 14.3, 13.4 (3C); HRMS (FAB) m/z: [M + Na]+
calcd for C42H60O7SiNa, 727.4001; found, 727.4005.
1
1092, 1034, 883, 827, 678 cm−1; H NMR (600 MHz, CDCl3): δ
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Diol 20. To a solution of p-methoxybenzylidene acetal 19 (4.37 g,
6.20 mmol) in CH2Cl2/MeOH (1:1, v/v, 120 mL) at room
temperature was added TsOH·H2O (356.8 mg, 1.876 mmol), and
the resulting solution was stirred at room temperature for 3 h. The
reaction was quenched with Et3N (3 mL). The mixture was
concentrated under reduced pressure. Purification of the residue by
flash column chromatography (silica gel, 20 to 30 to 40 to 50%
EtOAc/hexanes) gave diol 20 (3.50 g, 96%) as a colorless oil: [α]D22.6
−13.9 (c 1.50, CHCl3); IR (neat): 3398, 2943, 2866, 1463, 1455,
chromatography (silica gel, 10 to 20% EtOAc/hexanes) gave alcohol
22 (3.34 g, 98%) as a colorless oil: [α]2D5.4 −2.3 (c 1.54,00, CHCl3);
IR (neat): 3388, 2943, 2865, 1455, 1361, 1102, 1058, 883, 734, 697,
678 cm−1; 1H NMR (600 MHz, CDCl3): δ 7.35−7.23 (m, 10H), 5.80
(dddd, J = 17.0, 10.1, 6.9, 6.4 Hz, 1H), 5.00 (dm, J = 17.0 Hz, 1H),
4.95 (dm, J = 10.1 Hz, 1H), 4.56 (d, J = 11.5 Hz, 1H), 4.48 (d, J =
11.5 Hz, 1H), 4.50−4.45 (m, 2H, overlapped), 3.99 (dd, J = 11.0, 4.6
Hz, 1H), 3.72 (dd, J = 6.9, 3.2 Hz, 1H), 3.44−3.36 (m, 2H), 3.30−
3.24 (m, 2H), 2.31−2.23 (m, 2H), 2.07 (m, 1H), 1.91−1.79 (m, 3H),
1.66−1.52 (m, 3H), 1.38 (m, 1H), 1.17 (s, 3H), 1.15−1.07 (m, 21H),
one proton missing due to H/D exchange; 13C{1H} NMR (150 MHz,
CDCl3): δ 138.8, 138.64, 138.57, 128.3 (4C), 127.7 (2C), 127.50
(2C), 127.46, 127.38, 114.6, 79.5, 79.3, 73.69, 73.66, 72.8, 71.1, 70.8,
70.3, 34.4, 31.4, 31.0, 30.0, 28.3, 18.6 (3C), 18.5 (3C), 13.7, 13.4
(3C); HRMS (ESI) m/z: [M + Na]+ calcd for C37H58O5SiNa,
633.3946; found, 633.3945.
1
1362, 1207, 1109, 1058, 883, 734, 697, 678 cm−1; H NMR (600
MHz, CDCl3): δ 7.35−7.23 (m, 10H), 4.57 (d, J = 11.5 Hz, 1H),
4.50−4.44 (m, 3H), 3.92 (dd, J = 11.0, 4.6 Hz, 1H), 3.78 (ddd, J =
11.0, 6.9, 4.6 Hz, 1H), 3.75 (dd, J = 5.9, 3.2 Hz, 1H), 3.67 (m, 1H),
3.53−3.44 (m, 2H), 3.39 (dd, J = 6.4, 6.0 Hz, 2H), 2.30 (ddd, J =
12.4, 4.6, 4.6 Hz, 1H), 2.26−2.17 (m, 2H), 1.90−1.77 (m, 2H),
1.69−1.54 (m, 3H), 1.23 (s, 3H), 1.12−1.05 (m, 21H); 13C{1H}
NMR (150 MHz, CDCl3): δ 138.6, 138.3, 128.3 (4C), 127.7 (2C),
127.5 (3C), 127.4, 80.1, 78.7, 74.0, 73.5, 72.8, 71.1, 70.6, 67.8, 64.3,
33.8, 30.8, 28.1, 18.5 (3C), 18.4 (3C), 13.8, 13.4 (3C); HRMS (ESI)
m/z: [M + Na]+ calcd for C34H54O6SiNa, 609.3582; found, 609.3582.
Olefin 21. To a solution of diol 20 (3.42 g, 5.83 mmol) and 2,6-
lutidine (2.7 mL, 23.2 mmol) in CH2Cl2 (100 mL) at −80 °C was
slowly added Tf2O (98%, 1.05 mL, 6.27 mmol), and the resultant
solution was stirred at −80 °C for 30 min. To this mixture was slowly
added TESOTf (2.6 mL, 11.5 mmol), and the resultant solution was
stirred at −80 °C for 40 min. The reaction was quenched with the
saturated aqueous NaHCO3 solution (50 mL). The mixture was
extracted with CH2Cl2 (100 mL), washed with brine (50 mL),
washed with brine (50 mL), dried over MgSO4, filtered, and
concentrated under reduced pressure. Purification of the residue by
flash column chromatography (silica gel, 10% EtOAc/hexanes) gave
triflate S4, which was unstable and immediately used in the next
reaction.
Ketone 23. To a suspension of alcohol 22 (3.46 g, 5.66 mmol) and
NaHCO3 (2.41 g, 28.7 mmol) in CH2Cl2 (60 mL) at 0 °C was added
Dess−Martin periodinane (95%, 5.06 g, 11.3 mmol), and the resultant
mixture was stirred at room temperature for 2 h. The reaction was
quenched with a 1:1 mixture of the saturated aqueous NaHCO3
solution and the saturated aqueous Na2S2O3 solution (70 mL) at 0
°C. The resultant mixture was stirred at room temperature for 20 min.
The mixture was extracted with EtOAc (200, 60 mL), and the
combined organic layers were washed with the saturated aqueous
NaHCO3 solution (60 mL) and brine (60 mL), dried over MgSO4,
filtered, and concentrated under reduced pressure. Purification of the
residue by flash column chromatography (silica gel, 5 to 15% EtOAc/
hexanes) gave ketone 23 (3.37 g, 98%) as a colorless oil: [α]2D5.7 +54.3
(c 1.80, CHCl3); IR (neat): 2943, 2866, 1736, 1455, 1097, 1069, 883,
1
735, 697, 680 cm−1; H NMR (600 MHz, CDCl3): δ 7.36−7.24 (m,
10H), 5.77 (dddd, J = 17.4, 10.1, 6.9, 6.4 Hz, 1H), 5.01 (dd, J = 17.4,
1.9 Hz, 1H), 4.96 (dm, J = 10.1 Hz, 1H), 4.54 (d, J = 11.5 Hz, 1H),
4.50 (s, 2H), 4.35 (d, J = 11.5 Hz, 1H), 4.22 (dd, J = 3.7, 2.8 Hz, 1H),
3.97 (dd, J = 9.1, 3.2 Hz, 1H), 3.77 (dd, J = 5.5, 5.0 Hz, 1H), 3.48−
3.41 (m, 2H), 2.83 (dd, J = 15.6, 2.7 Hz, 1H), 2.66 (dd, J = 15.6, 4.1
Hz, 1H), 2.17 (m, 1H), 2.11 (m, 1H), 1.98−1.90 (m, 2H), 1.84−1.74
(m, 2H), 1.63−1.52 (m, 2H), 1.26 (s, 3H), 1.10−1.05 (m, 21H);
13C{1H} NMR (150 MHz, CDCl3): δ 212.2, 138.7, 138.0, 137.9,
128.3 (4C), 127.6, 127.54 (2C), 127.46 (2C), 127.43, 115.2, 82.1,
77.0, 76.5, 75.4, 72.8, 71.4, 70.6, 39.8, 30.7, 29.6, 29.0, 27.8, 18.4
(3C), 18.3 (3C), 13.5, 13.3 (3C); HRMS (FAB) m/z: [M + Na]+
calcd for C37H56O5SiNa, 631.3789; found, 631.3792.
To a suspension of CuBr (838 mg, 5.84 mmol) in Et2O (20 mL) at
0 °C was slowly added allylmagnesium bromide (1.0 M solution in
Et2O, 30 mL, 30 mmol) over 5 min, and the resultant solution was
stirred at 0 °C for 30 min. To the resultant black solution was slowly
added a solution of the above triflate S4 in Et2O (15 mL + 2 × 5 mL
rinse) over 10 min. The resultant solution was stirred at 0 °C for 1 h,
then allowed to warm to room temperature, and stirred for 17.5 h.
The reaction was quenched with the saturated aqueous NH4Cl
solution (30 mL) at 0 °C with caution. The mixture was stirred at
room temperature for 50 min and filtered through a pad of Celite
eluting with Et2O (ca. 100 mL). The organic layer was separated,
washed with brine (50 mL), dried over MgSO4, filtered, and
concentrated under reduced pressure. Purification of the residue by
flash column chromatography (silica gel, 2 to 4 to 6% EtOAc/
hexanes) gave olefin 21 (4.06 g, 96% in two steps) as a colorless oil:
[α]2D5.0 +14.3 (c 1.99, CHCl3); IR (neat): 2946, 2867, 1455, 1361,
Alcohols 24 and 47-epi-24. To a solution of ketone 23 (3.37 g,
5.53 mmol) in CH2Cl2 (55 mL) at −78 °C was slowly added Me3Al
(1.4 M solution in n-hexane, 15.0 mL, 21.0 mmol). The resultant
solution was stirred at −78 °C for 6 h, then allowed to warm to −15
°C and stirred for 16.5 h. The reaction was quenched with MeOH (2
mL). The mixture was diluted with the saturated aqueous potassium
sodium tartrate solution (50 mL) and EtOAc (50 mL), and the
resultant mixture was vigorously stirred at room temperature for 50
min. The mixture was extracted with EtOAc (120, 50 mL), and the
combined organic layers were washed with brine (50 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure.
Purification of the residue by flash column chromatography (silica
gel, 10 to 20 to 30% EtOAc/hexanes) gave alcohol 24 (3.19 g, 92%)
as a colorless oil, along with its diastereomeric alcohol 47-epi-24 (0.24
g, 7%) as a colorless oil. Data for 24: [α]2D4.8 +0.73 (c 1.02, CHCl3);
IR (neat): 3421, 2943, 2865, 2360, 1639, 1455, 1378, 1362, 1098,
1
1240, 1108, 1014, 884, 733, 697, 677 cm−1; H NMR (600 MHz,
CDCl3): δ 7.35−7.22 (m, 10H), 5.79 (dddd, J = 17.4, 10.1, 6.9, 6.4
Hz, 1H), 4.98 (d, J = 17.4 Hz, 1H), 4.93 (dm, J = 10.1 Hz, 1H), 4.53
(d, J = 11.9 Hz, 1H), 4.48 (d, J = 11.9 Hz, 1H), 4.50−4.45 (m, 2H),
3.96 (dd, J = 11.9, 4.6 Hz, 1H), 3.71 (br d, J = 5.9 Hz, 1H), 3.45−
3.36 (m, 2H), 3.25 (dd, J = 9.6, 9.2 Hz, 1H), 3.20 (ddd, J = 10.5, 9.2,
4.6 Hz, 1H), 2.24 (m, 1H), 2.09 (ddd, J = 12.4, 5.0, 4.6 Hz, 1H), 2.02
(m, 1H), 1.90−1.81 (m, 3H), 1.64−1.53 (m, 2H), 1.50 (ddd, J =
11.9, 11.5, 11.5 Hz, 1H), 1.25 (m, 1H), 1.14 (s, 3H), 1.18−1.08 (m,
21H), 0.94 (t, J = 7.8 Hz, 9H), 0.56 (q, J = 7.8 Hz, 6H); 13C{1H}
NMR (150 MHz, CDCl3): δ 138.9, 138.78, 138.76, 128.3 (2C), 128.2
(2C), 127.8 (2C), 127.5 (2C), 127.39, 127.37, 114.2, 79.9, 79.1, 73.7,
72.9, 72.8, 71.0, 70.8, 70.5, 35.6, 31.00, 30.98, 30.2, 28.4, 18.6 (3C),
18.5 (3C), 14.0, 13.4 (3C), 6.8 (3C), 5.0 (3C); HRMS (ESI) m/z:
[M + Na]+ calcd for C43H72O5Si2Na, 747.4810; found, 747.4810.
Alcohol 22. To a solution of olefin 21 (4.03 g, 5.56 mmol) in
CH2Cl2/MeOH (1:1, v/v, 70 mL) at room temperature was added
TsOH·H2O (317.4 mg, 1.669 mmol), and the resulting solution was
stirred at room temperature for 1 h 40 min. The reaction was
quenched with Et3N (2.0 mL). The mixture was concentrated under
reduced pressure. Purification of the residue by flash column
1
1072, 883, 733, 697, 679 cm−1; H NMR (600 MHz, CDCl3): δ
7.35−7.24 (m, 10H), 5.81 (dddd, J = 17.4, 10.1, 7.3, 6.4 Hz, 1H),
5.00 (dd, J = 17.4, 1.9 Hz, 1H), 4.94 (dm, J = 10.1 Hz, 1H), 4.54 (d, J
= 11.5 Hz, 1H), 4.50−4.45 (m, 2H), 4.45 (d, J = 11.5 Hz, 1H), 3.84
(dd, J = 10.1, 4.1 Hz, 1H), 3.72 (dd, J = 5.0, 5.0 Hz, 1H), 3.40 (dd, J
= 6.8, 6.4 Hz, 2H), 3.36 (dd, J = 10.6, 1.8 Hz, 1H), 2.26 (m, 1H),
2.03 (m, 1H), 1.97−1.90 (m, 2H), 1.81 (m, 1H), 1.71 (dd, J = 12.4,
10.1 Hz, 1H), 1.70−1.51 (m, 3H), 1.33 (m, 1H), 1.21 (s, 3H), 1.12
(s, 3H), 1.14−1.07 (m, 21H, overlapped), one proton missing due to
H/D exchange; 13C{1H} NMR (150 MHz, CDCl3): δ 138.9, 138.8,
138.4, 128.32 (2C), 128.28 (2C), 127.7 (2C), 127.6, 127.5 (2C),
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127.4, 114.5, 80.4, 78.1, 75.8, 74.9, 72.7, 71.36, 71.34, 70.8, 40.5,
30.73, 30.71, 28.2, 28.0, 21.6, 18.5 (3C), 18.4 (3C), 13.6 (3C), 13.5;
HRMS (FAB) m/z: [M + Na]+ calcd for C38H60O5SiNa, 647.4102;
found, 647.4110. Data for 47-epi-24: [α]2D4.4 −5.38 (c 1.19, CHCl3);
IR (neat): 3579, 3480, 2944, 2866, 2360, 1639, 1455, 1362, 1097,
H/D exchange; 13C{1H} NMR (150 MHz, CDCl3): δ 178.6, 138.6,
138.3, 128.32 (2C), 128.27 (2C), 127.7 (2C), 127.6, 127.5 (2C),
127.4, 80.5, 77.9, 76.4, 74.8, 72.7, 71.4, 71.3, 70.8, 40.3, 33.9, 30.5,
28.1, 27.7, 22.1, 21.5, 18.4 (3C), 18.3 (3C), 13.5 (3C), 13.4; HRMS
(FAB) m/z: [M + Na]+ calcd for C38H60O7SiNa, 679.4001; found,
679.4012.
1
911, 883, 815, 734, 697, 679 cm−1; H NMR (600 MHz, CDCl3): δ
7.35−7.21 (m, 10H), 5.79 (dddd, J = 17.0, 10.1, 7.3, 5.9 Hz, 1H),
5.00 (dm, J = 17.0 Hz, 1H), 4.96 (dm, J = 10.1 Hz, 1H), 4.56 (d, J =
11.5 Hz, 1H), 4.49−4.44 (m, 2H), 4.42 (d, J = 11.5 Hz, 1H), 4.09
(dd, J = 11.9, 5.3 Hz, 1H), 3.76 (dd, J = 6.2, 4.4 Hz, 1H), 3.40−3.35
(m, 3H), 2.25 (m, 1H), 2.16 (dd, J = 13.1, 5.3 Hz, 1H), 2.03 (m, 1H),
1.94 (m, 1H), 1.84 (m, 1H), 1.65−1.48 (m, 4H), 1.51 (dd, J = 12.8,
11.9 Hz, 1H, overlapped), 1.16 (s, 3H), 1.14−1.08 (m, 24H), one
proton missing due to H/D exchange; 13C{1H} NMR (150 MHz,
CDCl3): δ 138.7, 138.6 (2C), 128.3 (2C), 128.2 (2C), 127.6 (2C),
127.5 (2C), 127.40, 127.38, 114.7, 80.0, 79.6, 74.8, 72.8, 71.4, 71.1,
70.7, 70.5, 39.6, 31.0, 30.2, 28.3, 27.2, 24.2, 18.4 (6C), 13.8 (3C),
13.6; HRMS (ESI) m/z: [M + Na]+ calcd for C38H60O5SiNa,
647.4102; found, 647.4128.
Diol 25. To a solution of cyclohexene (4.0 mL, 39.5 mmol) in THF
(70 mL) at 0 °C was slowly added BH3·THF (0.9 M solution in THF,
20.0 mL, 18.0 mmol), and the resultant solution was stirred at 0 °C
for 1 h. To the resultant white suspension was slowly added a solution
of alcohol 24 (4.46 g, 7.14 mmol) in THF (20 mL + 2 × 5 mL rinse)
over 35 min. The resultant solution was stirred at room temperature
for 1 h. To this solution at 0 °C were slowly added 3 M aqueous
NaOH solution (30 mL) followed by 30% aqueous H2O2 solution (30
mL). The resultant mixture was vigorously stirred at room
temperature for 90 min. The organic layer was separated, and the
aqueous layer was extracted with Et2O (2 × 100 mL). The combined
organic layers were washed with the saturated aqueous Na2S2O3
solution (80 mL) and brine (80 mL), dried over MgSO4, filtered, and
concentrated under reduced pressure. Purification of the residue by
flash column chromatography (silica gel, first round: 40 to 50 to 60%
EtOAc/hexanes, second round: 40 to 70% EtOAc/hexanes) gave diol
25 (4.70 g, quantitative) as a colorless oil: [α]2D4.4 +1.49 (c 1.13,
CHCl3); IR (neat): 3373, 2943, 2865, 1455, 1378, 1362, 1098, 1072,
883, 734, 697, 679 cm−1; 1H NMR (600 MHz, CDCl3): δ 7.35−7.24
(m, 10H), 4.53 (d, J = 11.5 Hz, 1H), 4.47 (s, 2H), 4.44 (d, J = 11.5
Hz, 1H), 3.81 (dd, J = 9.6, 4.1 Hz, 1H), 3.71 (dd, J = 5.0, 5.0 Hz,
1H), 3.64−3.58 (m, 2H), 3.39 (dd, J = 6.9, 6.4 Hz, 2H), 3.33 (d, J =
9.6 Hz, 1H), 1.94 (dd, J = 12.8, 4.1 Hz, 1H), 1.90 (m, 1H), 1.80 (m,
1H), 1.71 (dd, J = 12.8, 9.6 Hz, 1H), 1.70−1.49 (m, 8H), 1.22 (s,
3H), 1.11 (s, 3H), 1.11−1.06 (m, 21H), two protons missing due to
H/D exchange; 13C{1H} NMR (150 MHz, CDCl3): δ 138.7, 138.4,
128.33 (2C), 128.28 (2C), 127.7 (2C), 127.6, 127.5 (2C), 127.4,
80.4, 77.9, 76.6, 74.9, 72.7, 71.4, 71.3, 70.8, 62.9, 40.4, 32.7, 30.6,
28.2, 28.1, 22.9, 21.6, 18.4 (3C), 18.3 (3C), 13.6 (3C), 13.4; HRMS
(FAB) m/z: [M + Na]+ calcd for C38H62O6SiNa, 665.4208; found,
665.4212.
Carboxylic Acid 26. To a solution of the above diol 25 (4.70 g,
7.31 mmol) in CH2Cl2/pH 7.0 phosphate buffer (1:1, v/v, 48 mL) at
0 °C were sequentially added AZADOL (115.4 mg, 0.7532 mmol)
and PhI(OAc)2 (7.07 g, 21.9 mmol). The resultant solution was
stirred at room temperature for 3 h 40 min. The reaction was
quenched with the saturated aqueous Na2S2O3 solution (50 mL) at 0
°C. The mixture was extracted with EtOAc (120 mL, 2 × 60 mL),
washed with brine (50 mL), dried over MgSO4, filtered, and
concentrated under reduced pressure. Purification of the residue by
flash column chromatography (silica gel, 40 to 50 to 60 to 70%
EtOAc/hexanes) gave carboxylic acid 26 (4.11 g, 87% in two steps) as
a colorless oil: [α]2D6.5 −1.91 (c 1.49, CHCl3); IR (neat): 3409, 2943,
2866, 1710, 1455, 1380, 1363, 1252, 1206, 1097, 883, 735, 697, 679
cm−1; 1H NMR (600 MHz, CDCl3): δ 7.35−7.24 (m, 10H), 4.54 (d,
J = 11.5 Hz, 1H), 4.48 (s, 2H), 4.44 (d, J = 11.5 Hz, 1H), 3.81 (dd, J
= 10.1, 4.1 Hz, 1H), 3.72 (dd, J = 5.0, 5.0 Hz, 1H), 3.40 (dd, J = 6.4,
6.4 Hz, 2H), 3.35 (d, J = 10.1 Hz, 1H), 2.40−2.30 (m, 2H), 1.98−
1.87 (m, 2H), 1.86−1.76 (m, 2H), 1.72 (dd, J = 12.4, 10.1 Hz, 1H),
1.70−1.60 (m, 3H), 1.53 (m, 1H), 1.26 (m, 1H), 1.23 (s, 3H), 1.11
(s, 3H), 1.13−1.05 (m, 21H, overlapped), two protons missing due to
Lactone 27. To a solution of carboxylic acid 26 (4.11 g, 6.26
mmol) and Et3N (2.7 mL, 19.4 mmol) in THF (62 mL) at 0 °C was
slowly added 2,4,6-trichlorobenzoyl chloride (1.4 mL, 8.95 mmol),
and the resultant solution was stirred at room temperature for 50 min.
The mixture was filtered through a pad of Celite and washed with
benzene (ca. 50 mL). The filtrate was concentrated under reduced
pressure to give a crude mixed anhydride. To a solution of DMAP
(3.86 g, 31.6 mmol) in toluene (550 mL) at 100 °C (oil bath) was
slowly added a solution of the above mixed anhydride in toluene (150
mL + 2 × 20 mL rinse) over 3 h. The resultant mixture was stirred at
100 °C (oil bath) for further 55 min. The mixture was cooled to room
temperature and transferred to a separatory funnel with EtOAc (140
mL). The mixture was washed with cold 1 M aqueous HCl solution
(100 mL), the saturated aqueous NaHCO3 solution (100 mL), and
brine (100 mL), dried over MgSO4, filtered, and concentrated under
reduced pressure. Purification of the residue by flash column
chromatography (silica gel, 10 to 20 to 30% EtOAc/hexanes) gave
lactone 27 (3.83 g, 96%) as a pale yellow oil: [α]2D4.8 −37.8 (c 1.40,
CHCl3); IR (neat): 2944, 2866, 1728, 1455, 1273, 1201, 1100, 1067,
1
1052, 884, 734, 697, 679 cm−1; H NMR (600 MHz, CDCl3): δ
7.35−7.24 (m, 10H), 4.53 (d, J = 11.5 Hz, 1H), 4.49−4.44 (m, 2H),
4.43 (d, J = 11.5 Hz, 1H), 3.86 (dd, J = 11.9, 4.6 Hz, 1H), 3.73 (dd, J
= 5.9, 4.1 Hz, 1H), 3.60 (dd, J = 11.0, 2.8 Hz, 1H), 3.42−3.35 (m,
2H), 2.78 (m, 1H), 2.51 (m, 1H), 2.19 (dd, J = 12.6, 4.8 Hz, 1H),
1.97−1.77 (m, 5H), 1.71−1.49 (m, 4H), 1.44 (s, 3H), 1.21 (s, 3H),
1.12−1.06 (m, 21H); 13C{1H} NMR (150 MHz, CDCl3): δ 174.0,
138.7, 138.1, 128.30 (2C), 128.28 (2C), 127.9 (2C), 127.6, 127.46
(2C), 127.41, 80.7, 80.0, 78.9, 73.5, 72.8, 72.1, 70.9, 70.7, 40.4, 36.8,
30.9 (2C), 28.3, 20.6, 19.1, 18.5 (3C), 18.4 (3C), 13.7, 13.6 (3C);
HRMS (FAB) m/z: [M + Na]+ calcd for C38H58O6SiNa, 661.3895;
found, 661.3903.
Enol Phosphate 13. To a solution of lactone 27 (3.83 g, 5.99
mmol) in THF (60 mL) were added HMPA (4.2 mL, 24.1 mmol)
and (PhO)2P(O)Cl (3.8 mL, 18.4 mmol). To this solution at −78 °C
was slowly added KHMDS (0.5 M solution in toluene, 36 mL, 18
mmol) dropwise over 15 min, and the resultant solution was stirred at
−78 °C for 1 h. The reaction was quenched with 3% NH4OH (30
mL). The resultant mixture was diluted with Et2O (30 mL) and
vigorously stirred at room temperature for 20 min. The mixture was
extracted with EtOAc (160 mL), and the organic layer was washed
with H2O (60 mL) and brine (60 mL), dried over MgSO4, filtered,
and concentrated under reduced pressure. Purification of the residue
by flash column chromatography (silica gel, 10 to 15 to 20% EtOAc/
hexanes) gave enol phosphate 13 (5.07 g, 97%) as a pale yellow oil,
which was unstable and used immediately in the next reaction without
1
further purification: H NMR (600 MHz, CDCl3): δ 7.37−7.17 (m,
20H), 4.86 (m, 1H), 4.49 (d, J = 11.5 Hz, 1H), 4.48−4.42 (m, 1H),
4.36 (d, J = 11.5 Hz, 1H), 3.82 (dd, J = 11.9, 4.6 Hz, 1H), 3.71 (dd, J
= 5.9, 4.1 Hz, 1H), 3.51 (dd, J = 11.5, 2.8 Hz, 1H), 3.40−3.32 (m,
2H), 2.09 (m 1H), 2.04−1.97 (m, 2H), 1.90 (m, 1H), 1.79 (m, 1H),
1.76 (dd, J = 11.9, 11.9 Hz, 1H), 1.62−1.53 (m, 2H), 1.52−1.41 (m,
2H), 1.31 (s, 3H), 1.21 (s, 3H), 1.11−1.04 (m, 21H).
Allylic Alcohol 28. LiCl (99%, 749.6 mg, 17.5 mmol) was placed in
a flask and dried with a heat gun under reduced pressure for 40 min.
Pd(PPh3)4 (1.01 g, 0.874 mmol) and THF (40 mL) were added to
the flask, and the resultant mixture was stirred at room temperature
for 15 min. To the resultant clear yellow solution were slowly added a
solution of the above enol phosphate 13 (5.07 g, 5.82 mmol) in THF
(20 mL + 2 × 5 mL rinse) followed by a solution of n-Bu3SnCH2OH
(3.85 g, 12.0 mmol) in THF (20 + 10 mL rinse). The resultant
solution was heated to 75 °C (oil bath) for 3 h. The resultant brown
solution was cooled to room temperature and treated with H2O (60
mL). The mixture was extracted with EtOAc (150, 60 mL), and the
combined organic layers were washed with brine (60 mL), dried over
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MgSO4, filtered, and concentrated under reduced pressure.
Purification of the residue by flash column chromatography (10%
w/w anhydrous K2CO3−silica gel, 10 to 20 to 25% EtOAc/hexanes)
gave allylic alcohol 28 (3.22 g, 85%) as a pale yellow oil: [α]2D4.1 −9.53
(c 1.29, CHCl3); IR (neat): 3420, 2943, 2865, 1717, 1454, 1362,
1097, 735, 697, 679 cm−1; 1H NMR (600 MHz, CDCl3): δ 7.35−7.24
(m, 10H), 5.15 (dd, J = 6.9, 5.0 Hz, 1H), 4.57 (d, J = 11.5 Hz, 1H),
4.49−4.43 (m, 2H), 4.43 (d, J = 11.5 Hz, 1H), 3.91−3.83 (m, 3H),
3.75 (dd, J = 6.0, 4.1 Hz, 1H), 3.56 (dd, J = 11.5, 3.2 Hz, 1H), 3.41−
3.34 (m, 2H), 2.15 (dd, J = 11.9, 5.0 Hz, 1H), 2.12−2.03 (m, 2H),
1.94 (m, 1H), 1.86 (dd, J = 11.9, 11.9 Hz, 1H), 1.82 (m, 1H), 1.68−
1.56 (m, 3H), 1.56−1.43 (m, 2H), 1.24 (s, 3H), 1.20 (s, 3H), 1.12−
1.06 (m, 21H); 13C{1H} NMR (150 MHz, CDCl3): δ 152.4, 138.7,
138.4, 128.28 (2C), 128.25 (2C), 127.8 (2C), 127.5 (3C), 127.4,
108.2, 79.9, 79.0, 77.9, 76.7, 72.9, 72.7, 70.8, 70.7, 65.2, 40.2, 30.9,
28.3, 27.1, 21.9, 18.5 (3C), 18.4 (3C), 16.4, 13.9, 13.6 (3C); HRMS
(FAB) m/z: [M + H]+ calcd for C39H61O6Si, 653.4232; found,
653.4233.
4-Nitrobenzoate 30. To a solution of alcohol 29 (1.79 g, 2.74
mmol) and PPh3 (2.16 g, 8.24 mmol) in THF (30 mL) at 0 °C were
sequentially added 4-nitrobenzoic acid (1.37 g, 8.20 mmol) and
DEAD (2.2 M solution in toluene, 3.7 mL, 8.14 mmol). The resultant
solution was stirred at room temperature for 1 h. The reaction was
quenched with the saturated aqueous NaHCO3 solution (30 mL) at 0
°C. The mixture was extracted with EtOAc (160 mL), and the organic
layer was washed with brine (30 mL), dried over Na2SO4, filtered, and
concentrated under reduced pressure. Purification of the residue by
flash column chromatography (silica gel, 5 to 8 to 10% EtOAc/
hexanes) gave 4-nitrobenzoate 30 (1.91 g, 87%) as a bright yellow oil:
[α]2D5.5 −15.8 (c 1.09, CHCl3); IR (neat): 2944, 2865, 1725, 1530,
1
1348, 1270, 1100, 1069, 1014, 883, 719, 697, 679 cm−1; H NMR
(600 MHz, CDCl3): δ 8.31−8.28 (m, 2H), 8.22−8.18 (m, 2H),
7.35−7.24 (m, 10H), 7.58 (m, 1H), 7.48−7.43 (m, 2H), 7.35−7.23
(m, 10H), 5.93 (br d, J = 5.5 Hz, 1H), 4.82 (s, 1H), 4.79 (s, 1H), 4.59
(d, J = 11.5 Hz, 1H), 4.50−4.45 (m, 2H), 4.44 (d, J = 11.5 Hz, 1H),
3.88 (dd, J = 11.5, 5.0 Hz, 1H), 3.77 (dd, J = 5.5, 4.6 Hz, 1H), 3.65
(m, 1H), 3.43−3.36 (m, 2H), 2.17 (dd, J = 11.9, 5.0 Hz, 1H), 2.09
(m, 1H), 1.96 (m, 1H), 1.92−1.79 (m, 4H), 1.72 (m, 1H), 1.61 (m,
1H), 1.53 (m, 1H), 1.40 (s, 3H), 1.25 (s, 3H), 1.16−1.07 (m, 21H);
13C{1H} NMR (150 MHz, CDCl3): δ 163.5, 156.6, 150.5, 138.7,
138.2, 135.7, 130.6 (2C), 128.3 (4C), 127.7 (2C), 127.5, 127.41
(2C), 127.38, 123.6 (2C), 104.6, 80.0, 79.1, 78.9, 74.0, 73.9, 72.9,
72.7, 70.73, 70.66, 40.4, 30.8, 28.3, 27.3, 25.0, 18.5 (3C), 18.4 (3C),
18.0, 14.1, 13.6 (3C); HRMS (FAB) m/z: [M + Na]+ calcd for
C46H63NO9SiNa, 824.4164; found, 824.4173.
Selenide 12. To a solution of allylic alcohol 28 (3.00 g, 4.59 mmol)
and 2-nitrophenyl selenocyanate (98%, 1.33 g, 5.74 mmol) in THF
(50 mL) at 0 °C was slowly added n-Bu3P (1.6 mL, 6.48 mmol), and
the resultant solution was stirred at 0 °C for 70 min. The mixture was
concentrated under reduced pressure, and the residue was directly
purified by flash column chromatography (silica gel, 5 to 10 to 15%
EtOAc/hexanes) to give selenide 12 (3.38 g, 88%) as a bright yellow
oil: [α]2D4.5 −3.14 (c 1.27, CHCl3); IR (neat): 2942, 2865, 1515, 1454,
1
1331, 1303, 1098, 1066, 731, 697, 679 cm−1; H NMR (600 MHz,
CDCl3): δ 8.28 (dd, J = 8.3, 1.4 Hz, 1H), 7.66 (dd, J = 8.2, 0.9 Hz,
1H), 7.48 (ddd, J = 8.3, 8.2, 1.4 Hz, 1H), 7.34−7.22 (m, 11H), 5.24
(dd, J = 6.4, 5.5 Hz, 1H), 4.54 (d, J = 11.5 Hz, 1H), 4.49−4.43 (m,
2H), 4.40 (d, J = 11.5 Hz, 1H), 3.83 (dd, J = 11.9, 5.0 Hz, 1H), 3.73
(dd, J = 5.9, 4.1 Hz, 1H), 3.56−3.47 (m, 3H), 3.40−3.33 (m, 2H),
2.11−2.05 (m, 3H), 1.91 (m, 1H), 1.82 (dd, J = 12.4, 11.9 Hz, 1H),
1.81 (m, 1H), 1.63−1.54 (m, 2H), 1.54−1.42 (m, 2H), 1.22 (s, 3H),
1.21 (s, 3H), 1.11−1.05 (m, 21H); 13C{1H} NMR (150 MHz,
CDCl3): δ 149.2, 146.7, 138.7, 138.4, 134.5, 133.4, 129.5, 128.27
(2C), 128.24 (2C), 127.7 (2C), 127.5 (3C), 127.4, 126.2, 125.4,
110.5, 79.9, 79.0, 78.4, 76.4, 72.82, 72.76, 70.8, 70.6, 39.9, 32.8, 30.8,
28.3, 27.0, 22.6, 18.5 (3C), 18.4 (3C), 16.4, 13.9, 13.6 (3C); HRMS
(ESI) m/z: [M + Na]+ calcd for C45H63NO7SeSiNa, 860.3431; found,
860.3425.
exo-Olefins 29. To a solution of selenide 12 (3.38 g, 4.04 mmol)
and DMAP (2.60 g, 21.3 mmol) in THF (65 mL) at −44 °C was
slowly added 30% aqueous H2O2 solution (5.0 mL, ca. 44 mmol), and
the resultant solution was stirred at −44 °C for 1 h. The mixture was
allowed to warm to room temperature and stirred for 15 h 20 min.
The reaction was quenched with a 1:1 mixture of the saturated
aqueous NaHCO3 solution and the saturated aqueous Na2S2O3
solution (60 mL) at 0 °C. The mixture was extracted with EtOAc
(2 × 80 mL), and the combined organic layers were washed with
brine (60 mL), dried over Na2SO4, filtered, and concentrated under
reduced pressure. Purification of the residue by flash column
chromatography (silica gel, 10 to 15 to 20% EtOAc/hexanes) gave
exo-olefin 29 (1.79 g, 68%) as a pale yellow oil, along with a small
amount of its C52 diastereomeric alcohol 31 (39.4 mg) as a pale
yellow oil. Data for 29: [α]2D6.5 −32.6 (c 0.86, CHCl3); IR (neat):
3427, 2943, 2866, 1715, 1455, 1361, 1097, 1071, 883, 735, 697, 679
cm−1; 1H NMR (600 MHz, CDCl3): δ 7.34−7.22 (m, 10H), 4.77 (d,
J = 0.9 Hz, 1H), 4.63 (s, 1H), 4.56 (d, J = 11.5 Hz, 1H), 4.49−4.43
(m, 2H), 4.41 (d, J = 11.5 Hz, 1H), 4.20 (m, 1H), 3.82 (dd, J = 11.5,
5.0 Hz, 1H), 3.72 (dd, J = 5.5, 4.6 Hz, 1H), 3.61 (dd, J = 10.6, 3.2 Hz,
1H), 3.40−3.33 (m, 2H), 2.13 (dd, J = 12.4, 5.0 Hz, 1H), 1.99−1.89
(m, 2H), 1.83 (dd, J = 11.9, 11.9 Hz, 1H), 1.81 (m, 1H), 1.74−1.54
(m, 4H), 1.50 (m, 1H), 1.21 (s, 3H), 1.20 (s, 3H), 1.12−1.05 (m,
21H), one proton missing due to H/D exchange; 13C{1H} NMR (150
MHz, CDCl3): δ 162.8, 138.7, 138.4, 128.27 (2C), 128.25 (2C),
127.7 (2C), 127.48, 127.45 (2C), 127.38, 97.3, 80.0, 78.9, 78.6, 73.4,
73.0, 72.7 (2C), 70.8, 70.7, 40.1, 32.8, 30.8, 28.3, 26.7, 19.0, 18.5
(3C), 18.4 (3C), 14.1, 13.6 (3C); HRMS (FAB) m/z: [M + H]+
calcd for C39H61O6Si, 653.4232; found, 653.4235.
Alcohol 31. To a solution of 4-nitrobenzoate 30 (1.91 g, 2.38
mmol) in MeOH/THF (1:1, v/v, 40 mL) was added K2CO3 (989.4
mg, 7.159 mmol). The resultant solution was stirred at room
temperature for 50 min. The reaction was quenched with the
saturated aqueous NH4Cl solution (20 mL) at 0 °C. The mixture was
extracted with CH2Cl2 (4 × 40 mL), dried over Na2SO4, filtered, and
concentrated under reduced pressure. Purification of the residue by
flash column chromatography (silica gel, 10 to 20 to 30% EtOAc/
hexanes) gave alcohol 31 (1.32 g, 85%) as a pale yellow oil, which was
unstable under both neutral and acidic conditions and immediately
used in the next reaction without further identification. Data for 31:
[α]2D5.4 −11.7 (c 0.92, CHCl3); IR (neat): 3444, 2943, 2866, 1715,
1
1455, 1380, 1362, 1208, 1097, 1070, 883, 734, 697, 679 cm−1; H
NMR (600 MHz, CDCl3): δ 7.35−7.23 (m, 10H), 4.64 (s, 1H), 4.61
(s, 1H), 4.57 (d, J = 11.5 Hz, 1H), 4.49−4.44 (m, 2H), 4.44 (m, 1H),
4.42 (d, J = 11.5 Hz, 1H), 3.85 (dd, J = 11.5, 5.0 Hz, 1H), 3.74 (dd, J
= 5.5, 4.6 Hz, 1H), 3.55 (dd, J = 11.0, 2.8 Hz, 1H), 3.41−3.34 (m,
2H), 2.15 (dd, J = 11.9, 5.0 Hz, 1H), 1.99−1.78 (m, 4H), 1.81 (dd, J
= 11.9, 11.9 Hz, 1H, overlapped), 1.70−1.47 (m, 4H), 1.35 (s, 3H),
1.20 (s, 3H), 1.12−1.06 (m, 21H), one proton missing due to H/D
exchange; 13C{1H} NMR (150 MHz, CDCl3): δ 161.2, 138.7, 138.4,
128.27 (2C), 128.25 (2C), 127.7 (2C), 127.48, 127.46 (2C), 127.38,
100.9, 79.9, 78.9 (2C), 73.6, 73.1, 72.8, 71.1, 70.8, 70.7, 39.8, 30.83,
30.80, 28.3, 24.5, 18.8, 18.5 (3C), 18.4 (3C), 14.0, 13.6 (3C).
TES Ether 10. To a solution of alcohol 31 (1.32 g, 2.02 mmol) and
imidazole (692.9 mg, 10.18 mmol) in DMF (20 mL) at 0 °C was
slowly added TESCl (1.0 mL, 5.97 mmol), and the resultant solution
was stirred at room temperature for 1 h. The reaction was quenched
with the saturated aqueous NaHCO3 solution (4 mL) at 0 °C. The
mixture was extracted with t-BuOMe (100 mL) and washed with H2O
(50 mL). The aqueous layer was extracted with t-BuOMe (2 × 50
mL), and the combined organic layers were washed with brine (50
mL), dried over Na2SO4, filtered, and concentrated under reduced
pressure. Purification of the residue by flash column chromatography
(silica gel, 3 to 4% EtOAc/hexanes) gave TES ether 10 (1.47 g, 95%)
as a colorless oil: [α]2D5.7 −13.6 (c 1.03, CHCl3); IR (neat): 2946,
2868, 1456, 1379, 1240, 1099, 1069, 1011, 883, 734, 697, 679 cm−1;
1H NMR (600 MHz, CDCl3): δ 7.35−7.22 (m, 10H), 4.56 (d, J =
11.5 Hz, 1H), 4.51 (s, 1H), 4.49−4.44 (m, 2H), 4.43 (dd, J = 5.9, 2.3
Hz, 1H), 4.411 (s, 1H), 4.406 (d, J = 11.5 Hz, 1H), 3.81 (dd, J = 11.9,
5.0 Hz, 1H), 3.73 (dd, J = 5.9, 4.1 Hz, 1H), 3.50 (dd, J = 11.5, 2.8 Hz,
1H), 3.42−3.34 (m, 2H), 2.15 (dd, J = 11.9, 5.0 Hz, 1H), 1.98−1.88
(m, 2H), 1.86−1.72 (m, 3H), 1.67−1.55 (m, 2H), 1.54−1.47 (m,
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2H), 1.38 (s, 3H), 1.20 (s, 3H), 1.14−1.06 (m, 21H), 0.96 (t, J = 8.0
Hz, 9H), 0.61 (q, J = 8.0 Hz, 6H); 13C{1H} NMR (150 MHz,
CDCl3): δ 162.3, 138.7, 138.5, 128.3 (2C), 128.2 (2C), 127.8 (2C),
127.5 (2C), 127.41, 127.36, 98.9, 79.6, 79.0, 78.8, 74.4, 73.0, 72.7,
71.1, 70.8, 70.5, 40.7, 31.7, 30.8, 28.3, 24.7, 18.5 (3C), 18.4 (3C),
18.1, 14.0, 13.6 (3C), 6.8 (3C), 4.8 (3C); HRMS (FAB) m/z: [M +
Na]+ calcd for C45H74O6Si2Na, 789.4916; found, 789.4927.
NMR (600 MHz, CDCl3): δ 7.34−7.21 (m, 10H), 4.54 (d, J = 11.5
Hz, 1H), 4.48−4.43 (m, 2H), 4.37 (d, J = 11.5 Hz, 1H), 3.93 (d, J =
8.3 Hz, 1H), 3.91 (dd, J = 10.6, 5.0 Hz, 1H), 3.78 (dd, J = 11.9, 4.6
Hz, 1H), 3.70 (dd, J = 5.9, 4.1 Hz, 1H), 3.69 (d, J = 8.3 Hz, 1H), 3.67
(dd, J = 11.0, 4.6 Hz, 1H), 3.40−3.33 (m, 2H), 2.06 (dd, J = 12.4, 4.6
Hz, 1H), 1.92−1.85 (m, 2H), 1.84−1.71 (m, 4H), 1.70−1.54 (m,
6H), 1.50 (s, 3H), 1.50 (m, 1H, overlapped), 1.40 (s, 3H), 1.26 (s,
3H), 1.19 (s, 3H), 1.12−1.05 (m, 21H); 13C{1H} NMR (150 MHz,
CDCl3): δ 138.7, 138.6, 128.3 (2C), 128.2 (2C), 127.8 (2C), 127.5
(2C), 127.36, 127.34, 111.1, 103.0, 79.5, 79.0, 77.9, 76.0, 74.6, 73.5,
72.8, 72.7, 72.6, 70.9, 70.4, 41.6, 37.1, 30.9, 30.4, 28.3, 27.2, 26.8,
24.7, 24.5, 20.6, 18.6, 18.5 (3C), 18.4 (3C), 14.0, 13.6 (3C); HRMS
(FAB) m/z: [M + Na]+ calcd for C46H72O8SiNa, 803.4889; found,
803.4893.
Ketone 33. To a suspension of TES ether 10 (480.3 mg, 0.6260
mmol), Na2HPO4 (90.7 mg, 0.639 mmol), and Fe(dibm)3 (99.0 mg,
0.190 mmol) in i-PrOH (degassed with argon for 1 h, 6 mL) was
added a solution of vinyl ketone 11 (669.7 mg, 3.343 mmol) and
Ph(i-PrO)SiH2 (0.60 mL, 3.25 mmol) in EtOAc (degassed with argon
for 1 h, 6 + 1 mL rinse) via a syringe pump over 2.5 h. The resultant
solution was stirred at room temperature for further 2 h. The reaction
was quenched with brine (10 mL). The organic layer was separated,
and the aqueous layer was extracted with EtOAc (4 × 20 mL). The
combined organic layers were dried over MgSO4, filtered, and
concentrated under reduced pressure. Purification of the residue by
flash column chromatography (silica gel, 3 to 4 to 5% EtOAc/
hexanes) gave ketone 33 (427.3 mg, 70%) as a colorless oil: [α]D26.3
−7.6 (c 1.03, CHCl3); IR (neat): 2952, 2866, 1720, 1463, 1378, 1362,
Diol 35. To a solution of bis-benzyl ether 9 (441.1 mg, 0.5647
mmol) in THF (18 mL) at −78 °C was added LiDBB (ca. 0.4 M
solution in THF, 15 mL, 6.0 mmol) dropwise over 5 min. The
resultant solution was stirred at −78 °C for 1 h, then allowed to warm
to −50 °C and stirred for 45 min. The reaction was quenched with
the saturated aqueous NH4Cl solution (15 mL). The resultant
mixture was warmed to room temperature, extracted with EtOAc
(150 mL), and the organic layer was washed with brine (20 mL),
dried over MgSO4, filtered, and concentrated under reduced pressure.
Purification of the residue by column chromatography (silica gel, 30
to 50% EtOAc/hexanes) gave diol 35 (337.3 mg, 99%) as a colorless
amorphous powder: [α]2D2.5 −5.5 (c 0.55, CHCl3); IR (neat): 3477,
1
1254, 1102, 1070, 1005, 839, 735, 697, 678 cm−1; H NMR (600
MHz, CDCl3): δ 7.34−7.21 (m, 10H), 4.54 (d, J = 11.5 Hz, 1H),
4.48−4.43 (m, 2H), 4.37 (d, J = 11.5 Hz, 1H), 4.22−4.15 (m, 2H),
3.79 (dd, J = 11.9, 4.6 Hz, 1H), 3.75 (d, J = 5.9 Hz, 1H), 3.70 (dd, J =
6.4, 4.1 Hz, 1H), 3.40−3.33 (m, 2H), 3.20 (dd, J = 11.5, 3.7 Hz, 1H),
2.78 (ddd, J = 17.9, 10.1, 5.5 Hz, 1H), 2.52 (ddd, J = 17.9, 10.1, 5.0
Hz, 1H), 1.93 (dd, J = 12.4, 4.6 Hz, 1H), ca. 1.92 (m, 1H,
overlapped), 1.89−1.77 (m, 3H), 1.76 (m, 1H), 1.67 (m, 1H), 1.58
(m, 1H), 1.51 (dd, J = 12.4, 11.9 Hz, 1H), ca. 1.47 (m, 1H,
overlapped), 1.41 (s, 3H), 1.42−1.33 (m, 2H), 1.19 (s, 3H), 1.15 (s,
3H), 1.14−1.06 (m, 21H), 0.96 (t, J = 7.8 Hz, 9H), 0.93 (s, 9H), 0.60
(q, J = 7.8 Hz, 6H), 0.093 (s, 3H), 0.090 (s, 3H); 13C{1H} NMR
(150 MHz, CDCl3): δ 211.8, 138.8 (2C), 128.3 (2C), 128.1 (2C),
127.7 (2C), 127.5 (2C), 127.33, 127.26, 80.6, 79.4, 79.3, 77.2, 76.4,
76.3, 72.8, 72.7, 70.9, 70.3, 69.3, 42.0, 37.1, 33.8, 30.9, 28.4, 27.4, 25.8
(3C), 24.0, 23.5, 18.5 (3C), 18.4 (3C), 18.2, 17.6, 14.2, 13.7 (3C),
6.9 (3C), 4.9 (3C), −5.5 (2C); HRMS (FAB) m/z: [M + H]+ calcd
for C55H97O8Si3, 969.6486; found, 969.6493.
Methyl Acetal 34. To a solution of ketone 33 (427.3 mg, 0.4407
mmol) in CH2Cl2/MeOH (1:1, v/v, 44 mL) was added CSA (53.9
mg, 0.232 mmol), and the resultant solution was stirred at room
temperature for 23 h. The reaction was quenched with Et3N (0.3
mL). The mixture was concentrated under reduced pressure.
Purification of the residue by flash column chromatography (silica
gel, 30 to 40% EtOAc/hexanes) gave methyl acetal 34 (282.7 mg,
85%) as a colorless oil: [α]2D5.7 −63.2 (c 0.99, CHCl3); IR (neat):
3464, 2944, 2866, 1456, 1379, 1115, 1071, 883, 735, 697, 679 cm−1;
1H NMR (600 MHz, CDCl3): δ 7.35−7.21 (m, 10H), 4.54 (d, J =
11.5 Hz, 1H), 4.49−4.43 (m, 2H), 4.37 (d, J = 11.5 Hz, 1H), 3.78
(dd, J = 11.9, 5.0 Hz, 1H), 3.71 (dd, J = 6.0, 4.1 Hz, 1H), 3.67−3.62
(m, 2H), 3.51 (dd, J = 11.5, 5.5 Hz, 1H), 3.46 (dd, J = 11.5, 6.4 Hz,
1H), 3.40−3.33 (m, 2H), 3.24 (s, 3H), 2.06 (dd, J = 12.4, 5.0 Hz,
1H), 1.88 (m, 1H), 1.85−1.70 (m, 7H), 1.68−1.55 (m, 5H), 1.50 (m,
1H), 1.29 (s, 3H), 1.25 (s, 3H), 1.19 (s, 3H), 1.12−1.06 (m, 21H);
13C{1H} NMR (150 MHz, CDCl3): δ 138.7, 138.6, 128.26 (2C),
128.18 (2C), 127.8 (2C), 127.5 (2C), 127.36, 127.34, 97.7, 79.5,
78.9, 77.9, 76.1, 72.9, 72.8, 72.7, 72.6, 70.9, 70.4, 64.2, 48.3, 41.6,
35.9, 30.8, 28.9, 28.2, 24.7, 24.3, 20.6, 18.50 (3C), 18.48, 18.43 (3C),
13.9, 13.6 (3C); HRMS (FAB) m/z: [M + Na]+ calcd for
C44H70O8SiNa, 777.4732; found, 777.4736.
1
2947, 2869, 1464, 1382, 1209, 1118, 1065, 1036, 985, 756 cm−1; H
NMR (600 MHz, CDCl3): δ 3.92 (d, J = 8.5 Hz, 1H), 3.90−3.85 (m,
2H), 3.74 (dd, J = 11.9, 5.0 Hz, 1H), 3.69 (d, J = 8.5 Hz, 1H), 3.62
(m, 1H), 3.59 (dd, J = 11.5, 4.6 Hz, 1H), 3.41 (s, 1H), 1.96−1.85 (m,
3H), 1.84−1.59 (m, 10H), 1.56 (M, 1H), 1.51 (s, 3H), 1.40 (s, 3H),
1.30 (s, 3H), 1.25 (s, 3H), 1.23 (s, 3H), 1.15−1.08 (m, 21H), one
proton missing due to H/D exchange; 13C{1H} NMR (150 MHz,
CDCl3): δ 111.1, 103.0, 82.3, 78.5, 77.3, 76.0, 74.5, 73.5, 73.0, 72.6,
63.2, 43.8, 36.9, 31.1, 30.3, 29.9, 27.3, 26.7, 24.7, 24.3, 20.2, 18.5, 18.2
(3C), 18.1 (3C), 13.5 (3C), 10.1; HRMS (ESI) m/z: [M + Na]+
calcd for C32H60O8SiNa, 623.3950; found, 623.3952.
Lactone 36. To a solution of diol 35 (337.3 mg, 0.5613 mmol) in
CH2Cl2 (18 mL) were added sequentially PhI(OAc)2 (549.2 mg,
1.705 mmol) and TEMPO (9.1 mg, 0.058 mmol), and the resultant
solution was stirred at room temperature for 16.5 h. The reaction was
quenched with the saturated aqueous NaHCO3 solution/saturated
aqueous Na2S2O3 solution (1:1, v/v, 20 mL), and the resultant
mixture was stirred at room temperature for 30 min. The mixture was
extracted with EtOAc (100 mL), and the organic layer was washed
with the saturated aqueous NaHCO3 solution (20 mL) and brine (20
mL), dried over MgSO4, filtered, and concentrated under reduced
pressure. Purification of the residue by column chromatography (silica
gel, 10 to 20% EtOAc/hexanes) gave lactone 36 (315.3 mg, 94%) as a
colorless amorphous powder: [α]2D3.1 +15.1 (c 0.52, CHCl3); IR
(neat): 2945, 2868, 1741, 1382, 1262, 1120, 1037, 984, 883, 756
1
cm−1; H NMR (600 MHz, CDCl3): δ 4.68 (dd, J = 12.4, 5.9 Hz,
1H), 3.95 (br d, J = 3.7 Hz, 1H), 3.93 (d, J = 8.7 H, 1H), 3.89 (dd, J =
13.3, 3.7 Hz, 1H), 3.69 (d, J = 8.7 Hz, 1H), 3.61 (dd, J = 10.6, 3.7 Hz,
1H), 3.13 (ddd, J = 14.0, 14.0, 2.3 Hz, 1H), 2.32 (dd, J = 14.0, 5.7 Hz,
1H), 2.03 (dd, J = 12.8, 5.9 Hz, 1H), 1.94 (dd, J = 14.0, 14.0 Hz, 1H),
1.92−1.85 (m, 2H), 1.81 (dd, J = 12.8, 12.4 Hz, 1H), 1.80−1.65 (m,
7H), 1.50 (s, 3H), 1.40 (s, 3H), 1.33 (s, 3H), 1.26 (s, 3H), 1.14 (s,
3H), 1.12−1.06 (m, 21H); 13C{1H} NMR (150 MHz, CDCl3): δ
174.9, 111.0, 102.9, 77.4, 76.1, 74.5, 73.8, 73.6, 73.0, 70.4, 42.4, 36.8,
30.2, 27.9, 27.2, 26.9, 26.7, 24.6, 24.3, 19.9, 18.5, 18.3 (3C), 18.2
(3C), 14.6, 12.9 (3C), one oxygenated quaternary carbon missing due
to overlapping with CDCl3 signals; HRMS (ESI) m/z: [M + H]+
calcd for C32H56O8SiNa, 619.3637; found, 619.3636.
Enol Phosphate 7. To a solution of lactone 36 (171.6 mg, 0.2875
mmol), which was azeotropically dried with toluene (×3), in THF (6
mL) were added HMPA (0.20 mL, 1.15 mmol) and (PhO)2P(O)Cl
(0.18 mL, 0.871 mmol). To this solution at −78 °C was added slowly
KHMDS (0.5 M solution in toluene, 1.8 mL, 0.90 mmol), and the
resultant solution was stirred at −78 °C for 3 h. The reaction was
LMN-Ring Fragment 9. To a solution of methyl acetal 34 (282.7
mg, 0.3744 mmol) in acetone (38 mL) at 0 °C was added Sc(OTf)3
(56.5 mg, 0.115 mmol), the resultant yellow solution was stirred at 0
°C for 1 h 20 min. The reaction was quenched with Et3N (0.3 mL).
The mixture was concentrated under reduced pressure. Purification of
the residue by flash column chromatography (silica gel, 5 to 10 to
20% EtOAc/hexanes) gave LMN-ring fragment 9 (237.5 mg, 81%) as
a colorless oil: [α]2D6.0 −60.4 (c 0.74, CHCl3); IR (neat): 2944, 2866,
1
1455, 1381, 1114, 1067, 1036, 984, 883, 734, 697, 679 cm−1; H
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quenched with 3% aqueous NH4OH solution (8 mL). The mixture
was allowed to warm to room temperature and stirred for 20 min. The
resultant mixture was extracted with EtOAc (60 mL), and the organic
layer was washed with H2O (8 mL) and brine (8 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure.
Purification of the residue by column chromatography (silica gel,
20% EtOAc/hexanes) gave enol phosphate 7 (230.9 mg, 97%) as a
colorless amorphous powder, which was unstable and used
immediately in the next Suzuki−Miyaura reaction without further
purification.
1.95−1.84 (m, 2H), 0.96 (s, 9H), 0.035 (s, 3H), 0.031 (s, 3H);
13C{1H} NMR (150 MHz, C6D6): δ 159.8, 131.4, 129.6 (2C), 114.1
(2C), 79.3, 72.3, 65.0, 54.8, 36.5, 26.0 (3C), 18.4, 3.1, −5.3 (2C);
HRMS (ESI) m/z: [M + Na]+ calcd for C18H31IO3SiNa, 473.0979;
found, 473.0982.
Enol Ether 6. To a solution of iodide 37 (296.5 mg, 0.6583 mmol)
and β-methoxy-9-borabicyclo[3.3.1]nonane (β-MeO-9-BBN) (1.0 M
solution in n-hexane, 1.3 mL, 1.3 mmol) in Et2O (6 mL) at −78 °C
was added t-BuLi (1.62 M solution in pentane, 0.95 mL, 1.54 mmol)
at once. The resultant mixture was stirred at −78 °C for 10 min and
then diluted with THF (6 mL). The mixture was allowed to warm to
room temperature and stirred for 1 h to generate alkylborate 8. The
resultant solution was treated with 3 M aqueous Cs2CO3 solution
(0.65 mL, 1.95 mmol) and stirred at room temperature for 20 min.
To this mixture were sequentially added a solution of the above enol
phosphate 7 (230.9 mg, 0.2785 mmol) in DMF (6 mL + 2 × 1 mL
rinse) and a solution of Pd(PPh3)4 (50.6 mg, 0.0438 mmol) in THF
(1 + 1 mL rinse), and the resultant mixture was stirred at 50 °C (oil
bath) for 17 h 15 min. The reaction was quenched with H2O at room
temperature. The mixture was extracted with EtOAc (50 mL), and the
organic layer was washed with H2O (10 mL) and brine (2 × 10 mL),
dried over MgSO4, filtered, and concentrated under reduced pressure.
Purification of the residue by column chromatography (silica gel, first
round: 5 to 10 to 20% EtOAc/hexanes, second round: 5 to 7 to 10%
EtOAc/hexanes) gave enol ether 6 (203.2 mg, 81%) as a pale yellow
oil: [α]2D5.4 +12.6 (c 1.17, CHCl3); IR (neat): 2948, 2865, 1514, 1464,
Alcohol 40. To a solution of TBS ether 38 (1.57 g, 6.32 mmol)
and 2-(4-methoxybenzyloxy)-4-methylquinoline 39 (3.56 g, 12.7
mmol) in CH2Cl2 (30 mL) was added CSA (147.4 mg, 0.6346
mmol), and the resultant solution was stirred at room temperature for
91 h. The mixture was poured into the saturated aqueous NaHCO3
solution (40 mL) and extracted with EtOAc (160 mL). The organic
layer was washed with 1 M aqueous HCl solution (3 × 30 mL), the
saturated aqueous NaHCO3 solution (30 mL), and brine (30 mL),
dried over MgSO4, filtered, and concentrated under reduced pressure.
The residue was roughly purified by column chromatography (silica
gel, 5 to 10 to 25% EtOAc/hexanes) gave PMB ether 40 (2.30 g) as a
colorless oil, which was contaminated by some impurities and used in
1
the next reaction without further purification: H NMR (600 MHz,
CDCl3): δ 7.26−7.23 (m, 2H), 6.88−6.85 (m, 2H), 4.58 (d, J = 11.0
Hz, 1H), 4.54 (d, J = 11.0 Hz, 1H), 3.94 (m, 1H), 3.81 (s, 3H), 3.70
(dd, J = 10.6, 5.3 Hz, 1H), 3.67 (s, 3H), 3.56 (dd, J = 10.6, 6.2 Hz,
1H), 2.63 (dd, J = 15.5, 4.8 Hz, 1H), 2.51 (dd, J = 15.5, 7.8 Hz, 1H),
0.89 (s, 9H), 0.05 (s, 6H); 13C{1H} NMR (150 MHz, CDCl3): δ
172.2, 159.2, 130.5, 129.4 (2C), 113.8 (2C), 76.4, 72.2, 64.7, 53.3,
51.6, 37.4, 25.9 (3C), 18.3, −5.4, −5.5.
1
1381, 1249, 1119, 1063, 1036, 837, 777, 677 cm−1; H NMR (600
MHz, C6D6): δ 7.36−7.31 (m, 2H), 6.85−6.81 (m, 2H), 4.70 (d, J =
11.5 Hz, 1H), 4.58−4.54 (m, 2H), 4.32−4.24 (m, 2H), 3.96 (d, J =
8.3 Hz, 1H), 3.87 (m, 1H), 3.81−3.74 (m, 2H), 3.64 (dd, J = 10.3, 4.3
Hz, 1H), 3.58 (m, 1H), 3.51 (d, J = 8.3 Hz, 1H), 3.32 (s, 3H), 2.40−
2.21 (m, 5H), 2.14−2.02 (m, 3H), 1.96−1.77 (m, 5H), 1.75 (m, 1H),
1.55 (s, 3H), 1.46 (s, 3H), 1.37 (s, 3H), 1.23 (s, 3H), 1.23−1.18 (m,
21H), 1.17−1.09 (m, 2H), 1.06 (s, 3H), 1.01 (s, 9H), 0.104 (s, 3H),
0.095 (s, 3H); 13C{1H} NMR (150 MHz, C6D6): δ 159.6, 159.3,
132.0, 129.2 (2C), 114.0 (2C), 111.1, 103.5, 101.1, 80.2, 79.2, 78.4,
76.2, 74.9, 74.4, 74.3, 73.5, 72.5, 72.1, 66.2, 54.7, 43.9, 37.6, 32.5,
30.9, 30.6, 29.8, 27.4, 27.1, 26.2 (3C), 25.2, 25.1, 20.7, 18.8, 18.7
(3C), 18.6 (3C), 18.5, 13.7, 13.4 (3C), −5.2 (2C); HRMS (ESI) m/
z: [M + Na]+ calcd for C50H86O10Si2Na, 925.5652; found, 925.5652.
Alcohol 42. To a solution of enol ether 6 (201.2 mg, 0.2227 mmol)
in THF (5 mL) at 0 °C was added BH3·THF (0.9 M solution in THF,
0.75 mL, 0.675 mmol). The resultant solution was stirred at 0 °C for
15 min, then allowed to warm to room temperature and stirred for 2
h. The mixture was cooled to 0 °C and treated with 3 M aqueous
NaOH solution (0.5 mL, 1.5 mmol) followed by 30% aqueous H2O2
solution (0.6 mL, 1.5 mmol). The resultant mixture was stirred at
room temperature for 1 h. The mixture was diluted with t-BuOMe
(40 mL), washed with H2O (6 mL) and brine (6 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure.
Purification of the residue by column chromatography (silica gel, 15
to 20 to 25% EtOAc/hexanes) gave alcohol 42 (162.7 mg, 79%) as a
colorless oil, which was used in the next reaction without further
To a solution of the above PMB ether 40 (2.30 g) in THF (40 mL)
at −40 °C was added LiAlH4 (281.7 mg, 7.423 mmol), and the
resultant solution was stirred at −40 °C for 1 h. The reaction was
quenched with the saturated potassium sodium tartrate solution (20
mL). The resultant mixture was diluted with EtOAc (15 mL) and the
saturated potassium sodium tartrate solution (10 mL), and vigorously
stirred at room temperature for 75 min. The mixture was extracted
with EtOAc (100 mL), and the organic layer was washed with brine
(40 mL), dried over MgSO4, filtered, and concentrated under reduced
pressure. Purification of the residue by column chromatography (silica
gel, 20 to 33% EtOAc/hexanes) gave alcohol 41 (1.44 g, 67% in two
steps) as a colorless oil: [α]2D2.5 −34.2 (c 1.85, CHCl3); IR (neat):
3419, 2953, 2929, 2857, 1613, 1514, 1464, 1302, 1250, 1173, 1090,
1034, 837, 777, 668 cm−1; 1H NMR (600 MHz, CDCl3): δ 7.28−7.25
(m, 2H), 6.90−6.86 (m, 2H), 4.66 (d, J = 11.0 Hz, 1H), 4.51 (d, J =
11.0 Hz, 1H), 3.80 (s, 3H), 3.77 (dd, J = 10.1, 5.0 Hz, 1H), 3.73 (t, J
= 5.5 Hz, 2H), 3.66 (m, 1H), 3.63 (dd, J = 10.1, 5.5 Hz, 1H), 1.91
(br, 1H), 1.85−1.72 (m, 2H), 0.91 (s, 9H), 0.07 (s, 6H); 13C{1H}
NMR (150 MHz, CDCl3): δ 159.3, 130.5, 129.5 (2C), 113.9 (2C),
78.6, 71.9, 65.4, 60.4, 55.3, 34.3, 25.9 (3C), 18.3, −5.41, −5.44;
HRMS (ESI) m/z: [M + Na]+ calcd for C18H32O4SiNa, 363.1962;
found, 363.1962.
Iodide 37. To a solution of imidazole (126.9 mg, 1.864 mmol) in
CH2Cl2 (10 mL) were sequentially added PPh3 (334.2 mg, 1.274
mmol) and I2 (338.7 mg, 1.335 mmol), and the resultant solution was
stirred at room temperature for 20 min. To this solution was added a
solution of alcohol 41 (391.1 mg, 1.148 mmol) in CH2Cl2 (7 + 3 mL
rinse) dropwise over 8 min. The resultant solution was stirred at room
temperature for 40 min. The reaction was quenched with the
saturated aqueous Na2S2O3 solution (20 mL). The mixture was
extracted with EtOAc (80 mL), and the organic layer was washed with
brine (20 mL), dried over MgSO4, filtered, and concentrated under
reduced pressure. Purification of the residue by column chromatog-
raphy (silica gel, 5 to 10% EtOAc/hexanes) gave iodide 37 (436.0 mg,
84%) as a colorless oil: [α]2D2.4 −53.5 (c 1.91, CHCl3); IR (neat):
2953, 2929, 2856, 1613, 1514, 1464, 1302, 1116, 1038, 837, 777
cm−1; 1H NMR (600 MHz, C6D6): δ 7.25−7.22 (m, 2H), 6.82−6.79
(m, 2H), 4.55 (d, J = 11.5 Hz, 1H), 4.39 (d, J = 11.5 Hz, 1H), 3.55
(dd, J = 9.7, 4.1 Hz, 1H), 3.50−3.43 (m, 2H), 3.31 (s, 3H), 3.09
(ddd, J = 9.5, 8.7, 7.3 Hz, 1H), 3.02 (ddd, J = 9.5, 6.9, 5.0 Hz, 1H),
1
purification: H NMR (600 MHz, CDCl3): δ 7.30−7.26 (m, 2H),
6.88−6.84 (m, 2H), 4.62 (d, J = 11.5 Hz, 1H), 4.52 (d, J = 11.5 Hz,
1H), 4.12 (m, 1H), 3.93 (d, J = 8.8 Hz, 1H), 3.88 (dd, J = 10.1, 3.7
Hz, 1H), 3.84 (d, J = 5.9 Hz, 1H), 3.79 (s, 3H), 3.71 (dd, J = 10.5, 5.5
Hz, 1H), 3.60−3.54 (m, 3H), 3.45 (m, 1H), 3.23 (m, 1H), 2.08 (dd, J
= 13.3, 11.0 Hz, 1H), 1.92−1.79 (m, 4H), 1.78−1.62 (m, 8H), 1.62−
1.56 (m, 2H), 1.53 (m, 1H), 1.50 (s, 3H), 1.50−1.44 (m, 2H), 1.40
(s, 3H), 1.26 (s, 3H), 1.24 (s, 3H), 1.16 (s, 3H), 1.12−1.06 (m,
21H), 0.91 (s, 9H), 0.07 (s, 6H); 13C{1H} NMR (150 MHz, CDCl3):
δ 159.1, 131.2, 129.3 (2C), 113.7 (2C), 111.1, 103.0, 82.6, 79.8, 78.4,
77.9, 75.8, 74.6, 73.7, 73.4, 72.9, 71.7, 69.4, 65.5, 64.6, 55.3, 44.5,
39.7, 37.0, 30.3, 28.5, 28.3, 27.2, 26.7, 26.0 (3C), 24.7, 24.6, 120.3,
18.5, 18.4 (6C), 18.3, 15.7, 12.8 (3C), −5.30, −5.34.
Ketone 43. To a suspension of alcohol 42 (162.7 mg, 0.176 mmol)
and NaHCO3 (80.2 mg, 0.955 mmol) in CH2Cl2 (9 mL) at 0 °C was
added Dess−Martin periodinane (95%, 199.9 mg, 0.4477 mmol), and
the resultant mixture was stirred at room temperature for 1 h. The
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reaction was quenched with the saturated aqueous NaHCO3
solution/saturated aqueous Na2S2O3 solution (1:1, v/v, 10 mL).
The mixture was stirred at room temperature for 10 min. The mixture
was extracted with EtOAc (40 mL), and the organic layer was washed
with saturated aqueous NaHCO3 (6 mL) and brine (6 mL), dried
over MgSO4, filtered, and concentrated under reduced pressure.
Purification of the residue by column chromatography (silica gel, 15%
EtOAc/hexanes) gave ketone S5 (146.7 mg, 90%) as a colorless oil,
resultant solution was stirred at room temperature for 1.5 h. The
mixture was diluted with EtOAc (12 mL), washed with the saturated
aqueous NaHCO3 solution (4 mL) and brine (4 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure.
Purification of the residue by column chromatography (silica gel, 10
to 20% EtOAc/hexanes) gave acetate 45 (9.0 mg, 98%) as a colorless
1
oil: H NMR (600 MHz, CDCl3): δ 7.27−7.24 (m, 2H), 6.87−6.83
(m, 2H), 4.77 (ddd, J = 9.2, 9.2, 3.2 Hz, 1H), 4.62 (d, J = 11.3 Hz,
1H), 4.47 (d, J = 11.3 Hz, 1H), 3.94 (dd, J = 4.6, 2.8 Hz, 1H), 3.93
(d, J = 8.8 Hz, 1H), 3.90 (dd, J = 11.0, 3.7 Hz, 1H), 3.87 (dd, J =
13.3, 4.1 Hz, 1H), 3.84 (m, 1H), 3.79 (s, 3H), 3.68 (d, J = 8.8 Hz,
1H), 3.673 (dd, J = 10.6, 6.0 Hz, 1H), 3.669 (dd, J = 11.0, 4.6 Hz,
1H), 3.57 (dd, J = 10.6, 4.8 Hz, 1H), 3.42 (m, 1H), 2.51 (ddd, J =
16.0, 9.2, 2.8 Hz, 1H), 1.96 (s, 3H), 1.91−1.84 (m, 2H), 1.84−1.56
(m, 12H), 1.49 (s, 3H), 1.40 (s, 3H), 1.34 (s, 3H), 1.28 (m, 1H), 1.25
(s, 3H), 1.11 (s, 3H), 1.11−1.07 (m, 21H), 0.91 (s, 9H), 0.061 (s,
3H), 0.058 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ 170.2,
159.0, 131.3, 129.2, (2C), 113.7 (2C), 111.1, 103.1, 81.0, 79.3, 79.2,
78.3, 76.3, 76.0, 74.6, 74.5 (2C), 73.36, 73.34, 71.8, 65.9, 55.3, 42.6,
37.3, 37.1, 30.4, 29.2, 27.7, 27.2, 26.8, 26.0 (3C), 24.5, 24.3, 21.1,
20.8, 18.5, 18.4 (3C), 18.3 (4C), 13.6, 12.8 (3C), −5.3, −5.4; HRMS
(ESI) m/z: [M + Na]+ calcd for C52H90O12Si2Na, 985.5863; found,
985.5861.
1
which was used in the next reaction without further purification: H
NMR (600 MHz, CDCl3): δ 7.28−7.24 (m, 2H), 6.87−6.84 (m, 2H),
4.60 (d, J = 11.0 Hz, 1H), 4.51 (d, J = 11.0 Hz, 1H), 3.93 (d, J = 8.7
Hz, 1H), 3.93−3.89 (m, 3H), 3.82 (dd, J = 12.8, 5.0 Hz, 1H), 3.79 (s,
3H), 3.72−3.66 (m, 3H), 3.56 (dd, J = 10.6, 5.5 Hz, 1H), 3.43 (m,
1H), 3.04 (d, J = 12.8 Hz, 1H), 2.66 (dd, J = 12.8, 6.9 Hz, 1H), 2.15
(m, 1H), 1.93−1.61 (m, 12H), 1.55 (m, 1H), 1.50 (s, 3H), 1.40 (s,
3H), 1.32 (s, 3H), 1.29 (s, 3H), 1.24 (s, 3H), 1.11−1.05 (m, 21H),
0.90 (s, 9H), 0.06 (s, 6H); 13C{1H} NMR (150 MHz, CDCl3): δ
211.5, 159.1, 131.0, 129.3 (2C), 113.7 (2C), 111.1, 103.1, 84.8, 79.7,
78.8, 78.1, 76.0, 74.6, 74.4, 73.5, 73.4, 71.9, 66.0, 65.5, 55.3, 46.5,
43.9, 37.0, 30.3, 28.4, 27.2, 26.7, 26.0 (3C), 24.5, 24.4, 24.3, 20.4,
18.5, 18.3, 18.2 (6C), 14.4, 12.8 (3C), −5.34, −5.30.
To a solution of the above ketone S5 (146.7 mg, 0.1596 mmol) in
toluene (8 mL) was added DBU (0.95 mL, 6.36 mmol), and the
resultant solution was stirred under reflux (oil bath) for 48 h. The
mixture was cooled to room temperature and concentrated under
reduced pressure. Purification of the residue by column chromatog-
raphy (silica gel, 5 to 10 to 20 to 30% EtOAc/hexanes) gave ketone
43 (126.2 mg, 86%) as a colorless oil: [α]2D3.4 −64.7 (c 1.10, CHCl3);
IR (neat): 2948, 2866, 1715, 1514, 1464, 1381, 1249, 1116, 1066,
1036, 837, 756 cm−1; 1H NMR (600 MHz, CDCl3): δ 7.27−7.23 (m,
2H), 6.87−6.84 (m, 2H), 4.59 (d, J = 11.0 Hz, 1H), 4.46 (d, J = 11.0
Hz, 1H), 3.94 (br d, J = 6.9 Hz, 1H), 3.93 (d, J = 8.7 Hz, 1H), 3.91
(m, 1H), 3.79 (s, 3H), 3.72−3.67 (m 3H), 3.652 (dd, J = 10.6, 5.7
Hz, 1H), 3.647 (dd, J = 12.8, 4.6 Hz, 1H), 3.53 (dd, J = 10.6, 5.4 Hz,
1H), 3.42 (m, 1H), 2.97 (d, J = 13.1 Hz, 1H), 2.60 (dd, J = 13.1, 7.1
Hz, 1H), 1.93−1.85 (m, 2H), 1.83−1.54 (m, 12H), 1.50 (s, 3H), 1.40
(s, 3H), 1.31 (s, 3H), 1.29 (s, 3H), 1.25 (s, 3H), 1.10−1.04 (m,
21H), 0.90 (s, 9H), 0.05 (s, 6H); 13C{1H} NMR (150 MHz, CDCl3):
δ 213.6, 131.1, 129.3 (3C), 113.7 (2C), 111.1, 103.1, 101.1, 87.0,
79.0, 78.7, 78.1, 76.0, 74.6, 74.3, 73.5 (2C), 71.8, 65.7, 55.3, 45.7,
43.0, 37.1, 30.3, 29.0, 27.4, 27.2, 26.8, 26.0 (3C), 24.5, 24.4, 20.5,
18.5, 18.3, 18.2 (6C), 14.6, 12.8 (3C), −5.4, −5.3; HRMS (ESI) m/z:
[M + Na]+ calcd for C50H86O11Si2Na, 941.5601; found, 941.5601.
Alcohol 44. To a solution of ketone 43 (17.4 mg, 0.0189 mmol) in
CH2Cl2 (2 mL) at −78 °C was added DIBALH (1.0 M solution in n-
hexane, 0.06 mL, 0.06 mmol), and the resultant solution was stirred at
−78 °C for 50 min. The reaction was quenched with the saturated
aqueous potassium sodium tartrate solution (1 mL). The mixture was
diluted with EtOAc (2 mL) and vigorously stirred at room
temperature for 45 min. The mixture was extracted with EtOAc (15
mL), and the organic layer was washed with brine (4 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure.
Purification of the residue by column chromatography (20%
EtOAc/hexanes) gave alcohol 44 (8.8 mg, 51%) as a colorless oil:
1H NMR (600 MHz, CDCl3): δ 7.27−7.24 (m, 2H), 6.87−6.84 (m,
2H), 4.61 (br d, J = 7.3 Hz, 1H), 4.60 (d, J = 11.2 Hz, 1H), 4.48 (d, J
= 11.2 Hz, 1H), 4.10 (br d, J = 5.0 Hz, 1H), 3.93 (d, J = 8.5 Hz, 1H),
3.89 (m, 1H), 3.86 (dd, J = 12.4, 5.0 Hz, 1H), 3.81−3.77 (m, 4H),
3.69 (d, J = 8.5 Hz, 1H), 3.68−3.62 (m, 3H), 3.55 (dd, J = 10.3, 4.8
Hz, 1H), 3.44 (m, 1H), 2.21 (ddd, J = 15.5, 5.5, 5.5 Hz, 1H), 1.92−
1.84 (m, 3H), 1.82−1.52 (m, 11H), 1.50 (s, 3H), 1.45 (m, 1H), 1.40
(s, 3H), 1.32 (s, 3H), 1.25 (s, 3H), 1.20−1.09 (m, 24H), 0.90 (s,
9H), 0.05 (s, 6H); 13C{1H} NMR (150 MHz, CDCl3): δ 159.0,
131.2, 129.3 (2C), 113.7 (2C), 111.0, 103.1, 86.2, 79.3, 78.6, 78.4,
77.8, 76.5, 75.9, 74.6, 73.5, 73.3, 71.8, 71.6, 65.9, 55.3, 43.6, 37.1,
32.0, 30.7, 30.4, 27.7, 27.2, 26.8, 26.0 (3C), 24.5, 24.4, 20.6, 18.5, 18.4
(4C), 18.3 (3C), 15.4, 12.8 (3C), −5.4, −5.3.
Diol 46. To a solution of ketone 43 (59.7 mg, 0.0649 mmol) in
CH2Cl2 (3 mL) at −78 °C was added DIBALH (1.0 M solution in n-
hexane, 0.4 mL, 0.4 mmol). The resultant solution was stirred at −78
°C for 1 h, and then allowed to warm to −20 °C and stirred for 3 h.
The reaction was quenched with the saturated aqueous potassium
sodium tartrate solution (5 mL). The resultant mixture was diluted
with EtOAc (5 mL) and vigorously stirred at room temperature for 1
h. The mixture was extracted with EtOAc (10 mL, 6 mL), and the
combined organic layers were washed with brine (5 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure.
Purification of the residue by column chromatography (1 to 2 to
4% MeOH/CHCl3) gave diol 46 (39.8 mg, 76%) as a colorless oil:
[α]2D2.6 −18.1 (c 0.39, CHCl3); IR (neat): 3449, 2944, 2867, 1514,
1
1464, 1381, 1248, 1092, 1035, 985, 755, 678 cm−1; H NMR (600
MHz, CDCl3): δ 7.28−7.24 (m, 2H), 6.90−6.86 (m, 2H), 4.54 (d, J =
11.5 Hz, 1H), 4.45 (d, J = 11.5 Hz, 1H), 4.11 (br d, J = 5.0 Hz, 1H),
3.93 (d, J = 8.7 Hz, 1H), 3.92−3.86 (m, 2H), 3.2−3.78 (m, 4H), 3.69
(d, J = 8.7 Hz, 1H), 3.68−3.62 (m, 3H), 3.55−3.48 (m, 2H), 2.22
(ddd, J = 15.4, 5.5, 5.5 Hz, 1H), 1.92−1.85 (m, 3H), 1.82−1.62 (m,
10H), 1.55 (m, 1H), 1.50 (s, 3H), 1.49 (m, 1H), 1.39 (s, 3H), 1.33 (s,
3H), 1.25 (s, 3H), 1.14 (s, 3H), 1.13−1.09 (m, 21H), two protons
missing due to H/D exchange; 13C{1H} NMR (150 MHz, CDCl3): δ
159.3, 130.6, 129.4 (2C), 113.9 (2C), 111.1, 103.1, 86.4, 79.0, 78.5,
78.4, 77.8, 76.5, 76.0, 74.6, 73.5, 73.3, 71.8, 71.1, 64.1, 55.3, 43.5,
37.1, 31.9, 30.6, 30.4, 27.2, 27.0, 26.7, 24.5, 24.4, 20.6, 18.5, 18.4
(3C), 18.3 (3C), 15.4, 12.8 (3C); HRMS (ESI) m/z: [M + Na]+
calcd for C44H74O11SiNa, 829.4893; found, 829.4893.
Tosylate 47. To a solution of diol 46 (38.3 mg, 0.0475 mmol),
Et3N (0.07 mL, 0.50 mmol), and DMAP (6.5 mg, 0.053 mmol) in
CH2Cl2 (2 mL) was added TsCl (27.2 mg, 0.143 mmol), and the
resultant solution was stirred at room temperature for 19.5 h. The
reaction was quenched with the saturated aqueous NaHCO3 solution
(5 mL). The mixture was extracted with EtOAc (15 and 5 mL), and
the combined organic layers were washed with brine (5 mL), dried
over MgSO4, filtered, and concentrated under reduced pressure.
Purification of the residue by column chromatography (25 to 30 to
40% EtOAc/hexanes) gave tosylate 47 (43.3 mg, 95%) as a colorless
oil: [α]2D2.1 −24.0 (c 0.85, CHCl3); IR (neat): 3444, 2945, 2868, 1514,
1
1464, 1368, 1248, 1177, 1095, 1035, 983, 756, 667 cm−1; H NMR
(600 MHz, CDCl3): δ 7.80−7.76 (m, 2H), 7.34−7.30 (m, 2H),
7.19−7.15 (m, 2H), 6.86−6.82 (m, 2H), 4.47 (d, J = 11.5 Hz, 1H),
4.39 (d, J = 11.5 Hz, 1H), 4.09 (br d, J = 4.6 Hz, 1H), 4.03−3.97 (m,
2H), 3.93 (d, J = 8.7 Hz, 1H), 3.90 (dd, J = 8.3, 6.8 Hz, 1H), 3.84
(dd, J = 12.4, 5.0 Hz, 1H), 3.81−3.79 (m, 4H), 3.73 (m, 1H), 3.69 (d,
J = 8.7 Hz, 1H), 3.65 (dd, J = 11.0, 4.1 Hz, 1H), 3.63−3.56 (m, 2H),
2.44 (s, 3H), 2.19 (ddd, J = 15.1, 5.5, 5.5 Hz, 1H), 1.93−1.57 (m,
12H), 1.50 (s, 3H), 1.48 (m, 1H), 1.43−1.32 (m, 2H, overlapped),
Acetate 45. To a solution of alcohol 44 (8.8 mg, 0.0095 mmol),
Et3N (20 μL, 0.144 mmol), and a catalytic amount of DMAP in
CH2Cl2 (1 mL) was added Ac2O (10 μL, 0.106 mmol), and the
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1.40 (s, 3H), 1.32 (s, 3H), 1.26 (s, 3H), 1.20−1.08 (m, 24H);
13C{1H} NMR (150 MHz, CDCl3): δ 159.2, 144.7, 133.0, 130.2,
129.8 (2C), 129.4 (2C), 128.0 (2C), 113.8 (2C), 111.1, 103.1, 85.8,
78.5, 78.4, 77.8, 76.4, 76.0, 75.7, 74.6, 73.5, 73.2, 71.8, 71.7, 71.6,
55.3, 43.6, 37.1, 31.8, 30.40, 30.37, 27.7, 27.2, 26.8, 24.5, 24.4, 21.6,
20.6, 18.5, 18.4 (3C), 18.3 (3C), 15.4, 12.8 (3C); HRMS (ESI) m/z:
[M + Na]+ calcd for C51H80SO13SiNa, 983.4981; found, 983.4984.
Epoxide 48. To a solution of tosylate 47 (41.8 mg, 0.0435 mmol)
in CH2Cl2 (2.5 mL)/pH 7.0 phosphate buffer (5:1, v/v, 3 mL) was
added DDQ (29.6 mg, 0.130 mmol), and the mixture was stirred at
room temperature for 2 h. The reaction was quenched with the
saturated aqueous NaHCO3 solution/saturated aqueous Na2S2O3
solution (1:1, v/v, 10 mL). The mixture was extracted with EtOAc
(20 mL, 10 mL), and the combined organic layers were washed with
the saturated aqueous NaHCO3 solution (6 mL) and brine (6 mL),
dried over MgSO4, filtered, and concentrated under reduced pressure.
Purification of the residue by column chromatography (10 to 30 to
40% EtOAc/hexanes) gave diol S6 (38.1 mg): [α]2D3.3 −15.9 (c 1.50,
CHCl3); IR (neat): 3442, 2945, 1463, 1368, 1177, 1118, 1096, 1035,
7.4 Hz, 1H), 2.05 (dd, J = 12.8, 12.8 Hz, 1H), 1.97−1.90 (m, 2H),
1.90−1.70 (m, 5H), 1.55 (s, 3H), 1.52−1.42 (m, 3H), 1.49−1.39 (m,
2H, overlapped), 1.45 (s, 3H), 1.31 (m, 1H), 1.27−1.10 (m, 26H),
0.96 (s, 3H), one proton missing due to H/D exchange; 13C{1H}
NMR (150 MHz, C6D6): δ 111.2, 103.5, 80.1, 80.0, 78.7, 77.6, 77.3,
76.9, 76.4, 74.9, 74.0, 73.8, 73.2, 65.8, 43.8, 38.7, 37.7, 31.8, 30.8,
27.4, 27.1, 27.0, 25.1, 24.9, 21.2, 18.8, 18.6 (3C), 18.5 (3C), 13.4,
13.2 (3C); HRMS (ESI) m/z: [M + Na]+ calcd for C36H64O9SiNa,
691.4212; found, 691.4213.
JKLMN-Ring Fragment 5. To a solution of alcohol 49 (17.3 mg,
0.0259 mmol) in THF (2 mL) was added TBAF (1.0 M solution in
THF, 0.26 mL, 0.26 mmol), and the resultant solution was stirred at
50 °C (oil bath) for 3.5 h. The reaction was quenched with the
saturated aqueous NH4Cl solution (3 mL) at room temperature. The
mixture was extracted with EtOAc (8 mL, 2 × 4 m L), and the
combined organic layers were washed with brine (4 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure.
Purification of the residue by column chromatography (silica gel,
first round: 2 to 4% MeOH/CHCl3, second round: 15 to 20 to 25 to
30% acetone/benzene) gave JKLMN-ring fragment 5 (11.6 mg, 87%)
as a colorless oil: [α]2D2.0 −44.0 (c 1.13, CHCl3); IR (neat): 3466,
2986, 2948, 2873, 1458, 1382, 1209, 1090, 1036, 984, 909, 865, 756,
666 cm−1; 1H NMR (600 MHz, C6D6): δ 4.20 (dd, J = 11.0, 3.7 Hz,
1H), 3.96 (d, J = 8.5 Hz, 1H), 3.93 (dd, J = 12.8, 1.6 Hz, 1H), 3.75−
3.69 (m, 2H), 3.51 (d, J = 8.5 Hz, 1H), 3.39 (br dd, J = 11.2, 3.2 Hz,
1H), 3.34 (dd, J = 11.2, 6.4 Hz, 1H), 3.28 (ddd, J = 10.6, 9.7, 4.6 Hz,
1H), 3.15 (ddd, J = 9.7, 8.3, 6.9 Hz, 1H), 3.05 (m, 1H), 2.79 (m, 1H),
2.38 (ddd, J = 15.5, 6.9, 6.4 Hz, 1H), 2.18 (ddd, J = 13.7, 13.3, 5.9 Hz,
1H), 2.15 (dd, J = 12.8, 4.6 Hz, 1H), 2.03 (ddd, J = 15.5, 8.3, 4.1 Hz,
1H), 1.96 (dd, J = 12.8, 12.8 Hz, 1H), 1.90−1.75 (m, 4H), 1.71 (ddd,
J = 13.3, 4.6, 2.7 Hz, 1H), 1.55 (s, 3H), 1.52−1.42 (m, 3H), 1.36 (s,
3H), 1.27 (m, 1H), 1.25 (s, 3H), 1.21 (s, 3H), 1.17−1.06 (m, 2H),
0.93 (s, 3H), one proton missing due to H/D exchange; 13C{1H}
NMR (150 MHz, C6D6): δ 111.2, 103.5, 79.3, 79.0, 78.8, 78.1, 77.6,
76.4, 74.9, 74.4, 74.0, 73.5, 72.6, 65.7, 44.0, 37.9, 37.7, 31.2, 30.8,
27.4, 27.0, 26.8, 25.1, 24.8, 20.5, 18.8, 15.2; HRMS (ESI) m/z: [M +
Na]+ calcd for C27H44O9Na, 535.2878; found, 535.2881.
1
983, 756, 667 cm−1; H NMR (600 MHz, CDCl3): δ 7.82−7.99 (m,
2H), 7.38−7.34 (m, 2H), 4.11 (br d, J = 5.5 Hz, 1H), 3.97−3.87 (m,
4H, overlapped), 3.93 (d, J = 8.7 Hz, 1H), 3.81−3.76 (m, 2H), 3.69
(d, J = 8.7 Hz, 1H), 3.67 (m, 1H), 3.64 (dd, J = 10.5, 4.1 Hz, 1H),
2.45 (s, 3H), 2.23 (ddd, J = 15.6, 5.5, 5.5 Hz, 1H), 1.92−1.83 (m,
3H), 1.80−1.58 (m, 11H), 1.49 (s, 3H), 1.48 (m, 1H), 1.39 (s, 3H),
1.39 (m, 1H, overlapped), 1.32 (s, 3H), 1.25 (s, 3H), 1.19−1.08 (m,
25H), one proton missing due to H/D exchange; 13C{1H} NMR (150
MHz, C6D6): δ 144.9, 132.8, 129.9 (2C), 128.0 (2C), 111.0, 103.0,
86.2, 78.4, 78.2, 77.7, 76.3, 76.0, 74.6, 73.7, 73.5, 73.3, 71.7, 69.4,
43.3, 37.0, 31.5, 31.2, 30.4, 29.7, 27.2, 26.7, 24.5, 24.3, 21.6, 20.5,
18.5, 18.34 (3C), 18.28 (3C), 15.4, 12.7 (3C); HRMS (ESI) m/z: [M
+ Na]+ calcd for C43H72SO12SiNa, 863.4406; found, 863.4406.
To a solution of the above diol S6 (38.1 mg) in CH2Cl2/MeOH
(2:1, v/v, 3 mL) was added K2CO3 (30.2 mg, 0.219 mmol), and the
resultant solution was stirred at room temperature for 45 min. To this
mixture was added MeOH (1 mL), and the mixture was stirred for
further 45 min. The reaction was quenched with the saturated
aqueous NH4Cl solution (3 mL). The mixture was extracted with
CH2Cl2 (3 × 6 mL), dried over MgSO4, filtered, and concentrated
under reduced pressure. Purification of the residue by column
chromatography (30 to 40% EtOAc/hexanes) gave epoxide 48 (24.5
mg, 84% in two steps) as a colorless oil: [α]2D1.4 −31.2 (c 0.98,
CHCl3); IR (neat): 3456, 2945, 2868, 1464, 1382, 1247, 1209, 1098,
1065, 1035, 985, 882, 755, 679 cm−1; 1H NMR (600 MHz, CDCl3): δ
4.60 (d, J = 7.8 Hz, 1H), 4.11 (br d, J = 5.5 Hz, 1H), 3.93 (d, J = 8.2
Hz, 1H), 3.91−3.86 (m, 2H), 3.80 (m, 1H), 3.70 (ddd, J = 9.7, 3.7,
3.2 Hz, 1H), 3.69 (d, J = 8.2 Hz, 1H), 3.66 (dd, J = 11.0, 4.6 Hz, 1H),
2.92 (m, 1H), 2.74 (dd, J = 5.0, 4.1 Hz, 1H), 2.47 (dd, J = 5.0, 2.7 Hz,
1H), 2.22 (ddd, J = 15.6, 5.5, 5.5 Hz, 1H), 1.94−1.84 (m, 3H), 1.82−
1.62 (m, 8H), 1.62−1.53 (m, 3H), 1.50 (s, 3H), 1.47 (m, 1H), 1.39
(s, 3H), 1.33 (s, 3H), 1.25 (s, 3H), 1.21−1.09 (m, 21H, overlapped),
1.14 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ 111.1, 103.1,
85.5, 78.6, 78.4, 77.8, 76.5, 76.0, 74.6, 73.5, 73.3, 71.7, 51.9, 47.2,
43.5, 37.1, 32.0, 31.3, 30.4, 28.8, 27.2, 26.7, 24.5, 24.4, 20.6, 18.5, 18.4
(3C), 18.3 (3C), 15.3, 12.8 (3C); HRMS (ESI) m/z: [M + Na]+
calcd for C36H64O9SiNa, 691.4212; found, 691.4212.
Tetrahydroxy JKLMN-Ring Fragment 50. A solution of 5 (3.1
mg, 0.00605 mmol) in THF/H2O/TFA (5:1:1, v/v, 0.8 mL) was
stirred at 50 °C (oil bath) for 15 h 20 min. The reaction was
quenched with 3% aqueous NH4OH solution (1 mL) at 0 °C. The
mixture was extracted with CH2Cl2 (5 × 2 mL), dried over MgSO4,
filtered, and concentrated under reduced pressure. Purification of the
residue by column chromatography (silica gel, 5 to 10% MeOH/
CHCl3) gave tetrahydroxy JKLMN-ring fragment 50 (2.7 mg, 94%)
as a colorless amorphous powder: [α]2D2.1 −23.6 (c 0.59, CHCl3); IR
(neat): 3418, 2950, 2874, 1716, 1456, 1382, 1260, 1217, 1086, 1038,
1
752, 666 cm−1; H NMR (600 MHz, pyridine-d5): δ 6.99 (s, 1H),
6.44 (m, 1H), 6.20 (m, 1H), 5.95 (d, J = 2.5 Hz, 1H), 4.58 (dd, J =
11.5, 2.8 Hz, 1H), 4.44 (dd, J = 13.0, 4.7 Hz, 1H), 4.08 (m, 1H),
3.97−3.88 (m, 4H), 3.88 (m, 1H), 3.81 (m, 1H), 3.63−3.54 (m, 2H),
2.65 (ddd, J = 15.5, 8.1, 5.3 Hz, 1H), 2.47 (ddd, J = 13.5, 13.3, 4.6 Hz,
1H), 2.29−2.21 (m, 2H), 2.16−2.08 (m, 2H), 2.07 (dd, J = 12.6, 12.4
Hz, 1H), 2.04−1.94 (m, 2H), 1.94−1.85 (m, 3 H), 1.80−1.70 (m,
2H), 1.59−1.48 (m, 2H, overlapped), 1.50 (s, 3H), 1.43 (s, 3H), 1.20
(s, 3H); 13C{1H} NMR (150 MHz, pyridine-d5): δ 96.3, 80.1, 79.8,
78.9, 78.6, 78.3, 77.4, 74.8, 73.7, 72.9, 72.5, 69.6, 65.7, 44.2, 38.5,
37.1, 32.0, 29.8, 28.0, 25.5, 25.2, 20.8, 18.9, 14.1; HRMS (ESI) m/z:
[M + Na]+ calcd for C24H40O9Na, 495.2565; found, 495.2565.
Alcohol 49. To a solution of epoxide 48 (16.1 mg, 0.0241 mmol)
in toluene (2 mL) was added silica gel (100 mg), and the resultant
mixture was stirred at 50 °C (oil bath) for 13 h 40 min. The mixture
was filtered through a cotton plug, and the filter cake was washed with
EtOAc. The filtrate was concentrated under reduce pressure to give
alcohol 49 (16.3 mg, quantitative) as a colorless oil: [α]2D8.1 −39.1 (c
0.32, CHCl3); IR (neat): 3465, 2944, 2867, 1464, 1381, 1259, 1209,
ASSOCIATED CONTENT
■
sı
* Supporting Information
1
1092, 1036, 754 cm−1; H NMR (600 MHz, C6D6): δ 4.26 (dd, J =
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c03031.
9.9, 4.8 Hz, 1H), 4.22 (dd, J = 12.8, 4.6 Hz, 1H), 4.00 (dd, J = 3.7, 3.2
Hz, 1H), 3.96 (d, J = 8.5 Hz, 1H), 3.83 (dd, J = 11.0, 4.6 Hz, 1H),
3.77 (ddd, J = 10.1, 9.6, 4.6 Hz, 1H), 3.50 (d, J = 8.5 Hz, 1H), 3.44
(br dd, J = 11.0, 2.7 Hz, 1H), 3.36 (dd, J = 11.0, 6.4 Hz, 1H), 3.29
(ddd, J = 9.6, 9.2, 4.1 Hz, 1H), 3.05 (m, 1H), 2.32 (ddd, J = 16.1, 9.2,
4.1 Hz, 1H), 2.24 (dd, J = 12.8, 4.1 Hz, 1H), 2.20 (ddd, J = 12.4, 11.9,
Comparison of NMR chemical shifts for compound 50
with the data for Caribbean ciguatoxin C-CTX-1 and
copies of 1H and 13C NMR spectra of all new
compounds (PDF)
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Article
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AUTHOR INFORMATION
Corresponding Author
Makoto Sasaki − Graduate School of Life Sciences, Tohoku
University, Sendai, Japan; orcid.org/0000-0003-2964-
7986; Email: masasaki@tohoku.ac.jp
■
Authors
Kotaro Iwasaki − Graduate School of Life Sciences, Tohoku
University, Sendai, Japan
Keisuke Arai − Graduate School of Life Sciences, Tohoku
University, Sendai, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c03031
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by JSPS KAKENHI Grant
Numbers JP16H03278 and JP20H029190. We are grateful to
Dr. Masahiro Hirama (Emeritus Professor of Tohoku
University) for his encouragement. We also thank Daisuke
Unabara and Yuka Taguchi (Tohoku University) for FAB and
ESI-TOF mass measurements.
(8) (a) Tsumuraya, T.; Fujii, I.; Hirama, M. Preparation of Anti-
Ciguatoxin Monoclonal Antibodies Using Synthetic Haptens:
Sandwich ELISA Detection of Ciguatoxins. J. AOAC Int. 2014, 97,
373−379. (b) Tsumuraya, T.; Takeuchi, K.; Yamashita, S.; Fujii, I.;
Hirama, M. Development of a Monoclonal Antibody against the Left
Wing of Ciguatoxin CTX1B: Thiol Strategy and Detection Using a
Sandwich ELISA. Toxicon 2012, 60, 348−357. (c) Tsumuraya, T.;
Fujii, I.; Hirama, M. Production of Monoclonal Antibodies for
Sandwich Immunoassay Detection of Pacific Ciguatoxins. Toxicon
2010, 56, 797−803. (d) Tsumuraya, T.; Fujii, I.; Inoue, M.; Tatami,
A.; Miyazaki, K.; Hirama, M. Production of Monoclonal Antibodies
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yCTX3C. Toxicon 2006, 48, 287−294. (e) Oguri, H.; Hirama, M.;
Tsumuraya, T.; Fujii, I.; Maruyama, M.; Uehara, H.; Nagumo, Y.
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Ciguatoxin CTX3C. J. Am. Chem. Soc. 2003, 125, 7608−7612.
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