Stereoselective 6-exo radical cyclization using cis-Vinyl sulfoxide: Practical total synthesis of CTX3C

Article abstract of DOI:10.1021/np100729d

Ciguatoxins, the principal causative toxins of ciguatera seafood poisoning, are large ladder-like polycyclic ethers. We report a highly stereoselective 6-exo radical cyclization/ring-closing olefin metathesis sequence to construct the syn/trans-fused poly

Full text of DOI:10.1021/np100729d

ARTICLE
pubs.acs.org/jnp
Stereoselective 6-exo Radical Cyclization Using cis-Vinyl Sulfoxide:
Practical Total Synthesis of CTX3C
Shuji Yamashita,*,‡ Yuuki Ishihara,‡ Hiroyuki Morita,‡ Junichi Uchiyama,‡ Katsutoshi Takeuchi,‡
Masayuki Inoue,‡,§,^ and Masahiro Hirama*,‡,§
‡Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
§Research and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
S Supporting Information
b
ABSTRACT: Ciguatoxins, the principal
causative toxins of ciguatera seafood poi-
soning, are large ladder-like polycyclic
ethers. We report a highly stereoselective
6-exo radical cyclization/ring-closing ole-
fin metathesis sequence to construct the
syn/trans-fused polyether system. The
new method was applied to the practical
synthesis of ciguatoxin CTX3C.
iguatera seafood poisoning is a foodborne illness that afflicts
more than 50000 people annually in tropical and subtropical
prepare sufficient amounts of congeners and analogues are still
required for further detailed studies.
C
areas.1 Ciguatoxins are regarded as the causative toxins of ciguatera
(1-4).2 Yasumoto and co-workers demonstrated that these toxins
are originally produced by an epiphytic dinoflagellate, Gambierdiscus
toxicus, and are transferred to various fish and eventually to humans
by the food chain.3 In 1989, the Yasumoto group successfully
determined the structures of ciguatoxins CTX4B (3) and CTX1B
(4), which were found to be large ladder-like polycyclic ethers 3 nm
in length with 13 rings ranging from five- to nine-membered.4 Sub-
sequently, more than 20 ciguatoxin congeners were structurally
identified, including CTX3C (1) and 51-hydroxyCTX3C (2).5
Ciguatoxins exhibit their potent toxicities (LD50 = 0.25-4 μg/kg,
mice) by binding to the voltage-sensitive sodium channels (VSSC)
of excitable membranes.6-8 However, the very limited supply of
ciguatoxins from natural sources has hampered detailed biological
studies and the development of therapeutic treatments for ciguatera.
The unique bioactivities and intriguing molecular structures of
the ciguatoxins prompted us to investigate their synthesis. We
have successfully achieved the total syntheses of three important
congeners (1, 2, and 4)9 and the analogues (5, 6)10 utilizing a
unified strategy. These synthetic ciguatoxins and their fragments
enabled us to develop anti-ciguatoxin antibodies as well as sand-
wich enzyme-linked immunosorbent assay (ELISA) detection
methods without cross-reactivity against other marine toxins.11
SAR and electrophysiological studies using the synthetic materials
were also performed in order to understand ciguatoxin-VSSC
interactions.10,12 However, more practical and secure methods to
Special Issue: Special Issue in Honor of Koji Nakanishi
Received: October 12, 2010
Published: January 20, 2011
r
Copyright
2011 American Chemical Society and
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dx.doi.org/10.1021/np100729d J. Nat. Prod. 2011, 74, 357–364
American Society of Pharmacognosy
|

Journal of Natural Products
ARTICLE
Scheme 1. Complementary Radical Routes for Construction
of trans-Fused Polyether Systems
unselective hydrogen addition (path b). Attempts to improve the
stereoselectivity of this reaction using (R)-sulfoxide 13b (entry 2),
bulky mesityl sulfoxide 13c (entry 3), and sulfone 13d (entry 4)
led to unfruitful results. The corresponding cis-methylacrylate
(R1 = CO2Me) could not be prepared. After careful screening of
substrates and conditions, we finally found that treatment of 13a
with n-Bu3SnH and Et3B in toluene at low temperature provided
17a almost exclusively in high yield (entry 5).17 Sulfoxide 17a was
successfully converted to 6/7- and 6/8-ring systems (20 and 21,
respectively), both in six steps.18
Having successfully established the new method, we applied it
to the synthesis of CTX3C (1). The modified synthesis of the
E-ring moiety of 1 is shown in Scheme 2. Ester 22 was prepared
from D-glucose according to known procedures.19 Alkylation of
22 with iodide 2320 gave 24 as a 1.2:1 diastereomeric mixture.
DIBAL reduction of ester 24 and nucleophilic addition of allyl-
magnesium bromide to the corresponding aldehyde afforded
alcohol 25 in 56% yield. RCM reaction of 25 using Grubbs’ first-
generation catalyst 2621 provided the eight-membered E-ring 27
(56%) with recovery of the starting material (21%). Diastereo-
meric mixture 27 was oxidized using Dess-Martin periodinane22
and then was isomerized at the C15 position to provide the de-
sired ketone 28 in 86% overall yield. After several experiments, we
found that DIBAL reduction of 28 at low temperature afforded
E-ring alcohol 29 in 87% yield.
The coupling partner of 29 was easily prepared from the
known AB-ring 3013b (Scheme 3). After the protection of se-
condary alcohol 30 as its TES ether, DIBAL reduction of 31 led
to the aldehyde, which was oxidized to carboxylic acid 32 in 79%
overall yield. Efficient condensation of AB-ring carboxylic acid 32
and E-ring alcohol 29 was realized using the Yamaguchi pro-
tocol23 to produce the ester 33 in 95% yield. Following Rych-
novsky’s report,24 acetal 34 was prepared by DIBAL reduction of
ester 33 and subsequent acetylation of the resulting hemiacetal.
Selective O,Se-acetal formation was successfully accomplished by
the action of i-Bu2AlSePh25,16 to provide 35 without destruction
of the p-anisyl (MP) acetal moiety. Treatment of 35 with TBAF
at low temperature gave secondary alcohol 37 along with the
corresponding diol 36, which was selectively protected with
TBDPS chloride to deliver 37 in 92% combined yield from 35.
The reaction of lithium alkoxide, which was generated from
alcohol 37 and MeLi, with acetylene sulfoxide (S)-3826 furnished
the cis-oriented radical acceptor 39. Treatment of 39 under the
optimum radical conditions exclusively constructed the desired
six-membered ring 40 in 86% yield. Pummerer rearrangement27
of sulfoxide 40 and Wittig reaction of the resulting aldehyde
afforded olefin 41. Three-step conversion of 41 to the terminal
diene 42 was conducted in 97% overall yield. Finally, RCM
reaction of 42 and subsequent acid treatment produced the
ABCDE-ring diol 43, which afforded the left wing 44 according
to the previously reported protocol.13b
Recently, we developed two efficient routes for constructing
trans-fused polyethers based on O,S-acetal intermediates: (i) an
acyl radical cyclization/reductive etherification sequence for 6/6-
and 7/6-rings;13 (ii) a 7-exo radical cyclization/ring-closing
olefin metathesis (RCM) sequence for 7/7-, 7/8-, and 7/9-ring
systems (8 f 9 f 10, Scheme 1).9,14 While the former acyl radi-
cal cyclization can create six- and seven-membered rings, the latter
radical reaction affords only seven-membered ethers. To increase
the utility and diversity of the radical cyclization/RCM strategy, a
complementary method for assembling 6/7- and 6/8-membered
ring systems (11 f 12 f 10, Scheme 1), which are inaccessible by
the previous methodologies, was investigated. Herein, we describe
the development of a trans-selective 6-exo radical reaction leading to
such systems and its application to the practical total synthesis of 1.
’ RESULTS AND DISCUSSION
We first investigated the trans-selective radical cyclization
using model compounds (Table 1).15 Previously, the Sasaki and
Tachibana group reported that the 6-exo radical cyclization using a
trans-acrylate selectively provided the undesired cis-substituted
pyran ring.16 With this result in mind, we examined the reac-
tion using cis-olefins as radical acceptors. It was envisioned that
an R-oxy radical, generated from O,Se-acetal 13, would react with
a radical acceptor through the transition state 15 to alleviate the
steric repulsion between bulky R1 and R2O groups in 14, re-
sulting in trans-substituted pyran ring 17 via 16 (path a). Indeed,
when 13a [R1 = p-tolyl (S)-sulfoxide] was treated with n-Bu3SnH
and Et3B in benzene at room temperature (entry 1), we found
that the tetracyclic compound 17a with the desired configura-
tions was obtained in 59% yield. Unfortunately, an isomeric
product was also obtained in 23% yield, which was determined to
be the C15-epimer 18a by NMR experiments. These observa-
tions can be explained by the proposed mechanism (paths a and
b) in Table 1. While the 6-exo cyclization should proceed with
complete stereocontrol at both C9 and C10, the resultant inter-
mediate 16 appeared to undergo, in addition to a direct forma-
tion of 17 (path a), the unexpected 1,5-hydrogen atom transfer
from C15 to C11 to generate tertiary radical 19. The interme-
diacy of 19 would result in the formation of 17 and 18 via
Total synthesis of 1 was completed as shown in Scheme 4. The
left wing 44 was assembled with the right wing R-chlorosulfide
46, generated from sulfide 45,9c by the action of AgOTf and
DTBMP to furnish O,S-acetal 47 in 70% yield.9e,14,28 After the
TIPS group of 47 was removed, the pentafluorophenyl acrylate
was installed to the resulting secondary alcohol 48 and gave 49 in
86% overall yield. We previously demonstrated that the electron-
withdrawing pentafluorophenyl group promoted 7-exo radical
cyclization over the entropically favored 6-exo cyclization by
enhancing SOMO/LUMO interactions.9g Actually, treatment of
49 with AIBN and n-Bu3SnH formed the G-ring stereoselectively
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Journal of Natural Products
ARTICLE
Table 1. Development of 6-exo Radical Cyclization
1
in 74% yield along with a small amount of 6-exo product 51 (7%).
The resulting carboxylic acid 50 was converted to pentaene 52
through a three-step functional group manipulation. Lastly, the
RCM reaction constructed the nine-membered F-ring, and oxi-
dative removal of the three 2-naphthylmethyl (NAP)9b,29 groups
using DDQ provided 1 in 59% yield from 52.
In summary, we have devised an efficient method to construct
polyether systems through a 6-exo radical cyclization of a cis-vinyl
sulfoxide and subsequent RCM reaction. This neutral and re-
liable reaction sequence secures multimilligram quantities of 1.
The strategy developed here will facilitate the practical total syn-
theses of ciguatoxin congeners and other polycyclic ethers.
rotations were recorded on a JASCO P-2200 polarimeter. H NMR
spectra were recorded on Varian INOVA 500 (500 MHz) and Varian
400-MR (400 MHz) spectrometers. Chemical shifts are reported in δ
(ppm) downfield from tetramethylsilane with reference to solvent sig-
nals [1H NMR: CHCl3 (7.26), C6D5H (7.16), C5HD4N (7.56); 13C
NMR: CDCl3 (77.16), C6D6 (128.06), C5D5N (123.5)]. Signal patterns
are indicated as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet;
br, broad peak. MALDI-TOF MS spectra were measured on an Applied
Biosystems Voyager DE STR SI-3 instrument. High-resolution mass
spectra were measured on a Themo Fisher Scientific Orbitrap Discovery
(ESI LTQ Orbitrap).
Vinyl Sulfoxide 39. To a solution of alcohol 37 (47.5 mg, 43.9
μmol) in THF (1.0 mL) at -78 ꢀC was added MeLi (0.96 M in Et2O,
82.3 μL, 79 μmol) and warmed to room temperature. After being stirred
for 1 h, the mixture was slowly added to sulfoxide (S)-38 (21.6 mg,
132 μmol) in THF (0.5 mL). After being stirred for 40 min, the mixture
was quenched with saturated aqueous NH4Cl and extracted with EtOAc.
The organic layer was washed with brine and dried over Na2SO4. Con-
centration and flash column chromatography (hexane/EtOAc, 10:1-
2:1) gave vinyl sulfoxide 39 (45.7 mg, 36.7 μmol) in 84% yield: colorless,
amorphous solid; 1H NMR (400 MHz, C6D6) δ 7.84-7.23 (23H, m,
MP, NAP, SePh, TBDPS, p-Tol), 6.87-6.79 (5H, m, SePh, p-Tol), 6.70
(2H, d, J = 8.0 Hz, MP), 6.26 (1/2H, d, J = 5.6 Hz, H12), 6.14 (1/2H, dd,
J = 11.2, 4.8 Hz, H19), 6.07 (1/2H, d, J = 5.6 Hz, H12), 6.06 (1/2H, m,
H18), 6.02 (1/2H, dd, J = 10.8, 4.4 Hz, H19), 5.87 (1/2H, m, H18), 4.66
’ EXPERIMENTAL SECTION
General Experimental Procedures. All reactions sensitive to
air or moisture were carried out under argon or nitrogen atmosphere in
dry, freshly distilled solvents under anhydrous conditions, unless other-
wise noted. Analytical thin-layer chromatography (TLC) was performed
using E. Merck silica gel 60 F254 precoated plates. Column chroma-
tography was performed using 100-210 μm silica gel 60N (Kanto
Chemical Co., Inc.), and for flash column chromatography 40-50 μm
silica gel 60N (Kanto Chemical Co., Inc.) was used. Melting points were
measured on a Yanaco MP-S3 micro melting point apparatus. Optical
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Journal of Natural Products
ARTICLE
Scheme 2. Synthesis of E-Ringa
3.56 (1H, m, H15), 3.55 (1H, m, H16), 3.53 (1H, m, H11), 3.43 (1H,
dd, J = 10.8, 10.8 Hz, H22), 3.41 (1H, dd, J = 8.4, 8.4 Hz, H6), 3.35 (1H,
m, H13), 3.34 (1H, m, H5), 3.32 (1H, m, H21), 3.19 (1H, ddd, J = 11.6,
8.8, 4.4 Hz, H9), 3.05 (1H, dd, J = 8.8, 8.4 Hz, H8), 3.04 (1H, m, H12),
3.01 (1H, m, H13), 2.66 (1H, m, H4), 2.62 (1H, m, H17), 2.47 (1H,
ddd, J = 11.6, 4.4, 4.4 Hz, H10), 2.35 (1H, m, H4), 2.32 (1H, m, H17),
2.31 (3H, s, p-Tol), 1.95 (1H, m, H14), 1.48 (1H, m, H14), 1.44 (1H,
ddd, J = 11.6, 11.6, 11.6 Hz, H10), 1.06 (9H, s, TBDPS); 13C NMR (100
MHz, CDCl3) δ 160.2 (C, MP), 141.9 (C), 140.4 (C), 136.5 (C),
135.70 (CH, TBDPS), 135.68 (CH, TBDPS), 133.75 (C), 133.68 (C),
133.6 (C), 133.4 (CH, C19), 133.2 (C), 131.4 (CH, C2), 130.3 (C),
130.2 (CHꢀ2, p-Tol), 129.88 (CH), 129.86 (CH), 128.11 (CH),
128.05 (CH), 127.93 (CH), 127.88 (CH), 127.8 (CH), 127.6 (CH),
126.8 (CH), 126.6 (CH), 126.5 (CH), 126.1 (CH), 125.9 (CH), 125.8
(CH), 124.6 (CHꢀ2, p-Tol), 113.8 (CHꢀ2, MP), 100.9 (CH, MP),
87.4 (CH, C6), 83.8 (CH, C15 or C16), 81.9 (CH, C7), 81.4 (CH,
C12), 79.8 (CH, C20), 77.4 (CH, C15 or C16), 77.1 (CH, C5), 76.8
(CH, C8), 75.72 (CH, C21), 75.66 (CH2, NAP), 75.4 (CH, C11), 72.8
(CH, C9), 69.3 (CH2, C22), 68.6 (CH2, C1), 60.7 (CH2, C13), 60.3
(CH2, C140), 55.4 (CH3, MP), 37.4 (CH2, C10), 36.8 (CH2, C14), 34.8
(CH2, C4), 30.5 (CH2, C17), 27.1 (CH3ꢀ3, TBDPS), 21.5 (CH3,
p-Tol), 19.3 (C, TBDPS); HRESIMS m/z 1113.4601 [M þ Na]þ (calcd
for C65H74O11SSiNa 1113.4613).
a Reagents and conditions: (a) 23 (1.3 equiv), lithium diisopropylamide
(LDA), THF/HMPA (4:1), -78 to -50 ꢀC, 80%; (b) DIBAL, CH2Cl2,
-78 ꢀC; (c) allylmagnesium bromide, THF, -78 ꢀC, 56% (2 steps);
(d) 26,CH2Cl2,40ꢀC, 56%; (e) Dess-Martin periodinane, CH2Cl2, RT, 87%;
(f) imidazole, toluene, 70 ꢀC, 99%; (g) DIBAL, CH2Cl2, -95 ꢀC, 87%.
Pentafluorophenylacrylate 49. To a solution of alcohol 48 (31
mg, 18.2 μmol) and pentafluorophenyl propiolate (17.2 mg, 72.8 μmol)
in CH2Cl2 (610 μL) at room temperature was added PMe3 (1.0 M solu-
tion in toluene, 36.4 μL, 36.4 μmol). Further pentafluorophenyl propio-
late (34.4 mg, 145.6 μmol) and PMe3 (1.0 M solution in toluene,
72.8 μL, 72.8 μmol) was added. After 1 h, the reaction mixture was con-
centrated, and column chromatography (hexane/Et2O, 3:1-0:1, con-
taining 1% Et3N) gave pentafluorophenylacrylate 49 (33.3 mg, 17.3
μmol) in 95% yield: colorless, amorphous solid; [R]26D -20.1 (c 0.42,
(1/2H, dd, J = 6.2, 6.2 Hz, H11), 5.56 (1H, m, H2), 5.54 (1/2H, m,
H11), 5.51 (1H, m, H3), 5.31 (1/2H, d, J = 5.6 Hz, H13), 5.31 (1/2H,
m, MP), 5.25 (1/2H, m, MP), 5.21 (1/2H, d, J = 5.6 Hz, H13), 5.08 (1/
2H, d, J = 11.2 Hz, NAP), 5.05 (1/2H, d, J = 11.2 Hz, NAP), 4.76 (1/2H,
d, J = 11.2 Hz, NAP), 4.74 (1/2H, d, J = 11.2 Hz, NAP), 4.28 (1H, m,
H20), 4.24 (1/2H, m, H16), 4.11 (1/2H, dd, J = 11.2, 5.0 Hz, H22), 4.08
(1/2H, m, H1), 4.03 (1/2H, m, H1), 3.99 (1/2H, m, H15), 3.93-3.87
(3/2H, m, H5, H9, H15), 3.85-3.68 (9/2H, m, H1, H7, H140ꢀ2, H16,
H22), 3.63 (1/2H, dd, J = 8.8, 8.8 Hz, H7), 3.57 (1/2H, m, H21), 3.53
(1/2H, m, H9), 3.51-3.43 (1H, m, H6, H22), 3.37 (1/2H, dd, J = 10.4,
10.4 Hz, H22), 3.30 (1/2H, m, H6), 3.29 (3/2H, s, MP), 3.28 (3/2H, s,
MP), 3.28-3.24 (1H, m, H8, H21), 3.24-3.18 (3/2H, m, H5, H8,
H17), 2.77 (1/2H, m, H10), 2.71 (1/2H, m, H17), 2.69-2.62 (1H, m,
H4, H10), 2.59 (1H, m, H17), 2.46 (1/2H, m, H4), 2.43 (1/2H, m,
H14), 2.34 (1/2H, m, H4), 2.30 (1/2H, m, H10), 2.24 (1/2H, m, H4),
2.19 (1/2H, m, H10), 2.09 (1/2H, m, H14), 1.87 (3H, s, p-Tol), 1.64
(1/2H, m, H14), 1.54 (1/2H, m, H14), 1.22 (9/2H, s, TBDPS), 1.15
(9/2H, s, TBDPS); HRESIMS m/z 1269.4081 [M þ Na]þ (calcd for
C71H78O11SSeSiNa 1269.4092).
CH2Cl2); IR (film) ν 3055, 2925, 1752, 1638, 1521, 1087, 1006 cm-1
;
1H NMR (500 MHz, C6D6) δ 7.94-7.00 (33H, m, NAPꢀ4, PhS), 7.75
(1H, d, J = 12.0 Hz, H26), 5.96 (1H, ddt, J = 16.5, 10.5, 7.0 Hz, H23),
5.95 (1H, m, H13), 5.92 (1H, m, H19), 5.80 (1H, m, H18), 5.78 (1H, m,
H14), 5.60 (1H, d, J = 12.0 Hz, H25), 5.54 (1H, dddd, J = 12.0, 5.5, 3.0,
3.0 Hz, H2), 5.47 (1H, m, H3), 5.35 (1H, dd, J = 10.0, 3.5 Hz, H27), 5.22
(1H, d, J = 12.5 Hz, NAP), 5.17 (1H, m, H230), 5.15 (1H, d, J = 12.5 Hz,
NAP), 5.14 (1H, m, H230), 5.02 (1H, d, J = 12.0 Hz, NAP), 4.91 (1H, d,
J = 12.0 Hz, NAP), 4.84 (2H, s, NAP), 4.32 (2H, s, NAP), 4.30 (1H, m,
H20), 4.22 (1H, ddd, J = 11.5, 9.5, 5.0 Hz, H41), 4.12 (1H, dd, J = 16.0,
5.5 Hz, H1), 4.11 (1H, m, H31), 4.07 (1H, m, H15), 4.06 (1H, m, H52),
4.00 (1H, t, J = 10.0 Hz, H29), 3.99 (1H, d, J = 9.5 Hz, H45), 3.81 (1H,
dd, J = 9.5, 9.5 Hz, H46), 3.80 (1H, m, H52), 3.78 (1H, m, H1), 3.74
(1H, dddd, J = 9.0, 2.5, 2.5, 2.5 Hz, H12), 3.65 (1H, dd, J = 9.0, 9.0 Hz,
H7), 3.65 (1H, d, J = 3.0 Hz, H44), 3.46 (1H, dddd, J = 8.5, 2.5, 2.5, 2.5
Hz, H16), 3.39 (1H, m, H21), 3.37 (1H, dd, J = 9.0, 9.0 Hz, H6), 3.26
(1H, ddd, J = 9.0, 9.0, 4.0 Hz, H5), 3.23 (1H, m, H34), 3.19 (1H, dd, J =
9.0, 9.0 Hz, H8), 3.06 (1H, m, H42), 3.05 (1H, m, H11), 3.03 (1H, m,
H38), 2.91 (1H, ddd, J = 12.0, 9.0, 4.5 Hz, H9), 2.87 (1H, m, H39), 2.77
(1H, m, H22), 2.75 (1H, m, H33), 2.63 (1H, m, H28), 2.59 (1H, m,
H17), 2.55 (1H, m, H4), 2.53 (1H, m, H43), 2.34 (1H, m, H40), 2.32
(1H, m, H28), 2.30 (1H, m, H10), 2.29 (1H, m, H22), 2.25 (1H, m, H4),
2.23 (1H, m, H50), 2.22 (1H, m, H50), 2.14 (1H, m, H17), 2.04 (1H, m,
H47), 2.00 (1H, m, H37), 1.99 (1H, m, H51), 1.88 (1H, m, H32), 1.80
(1H, m, H35), 1.75 (1H, m, H36), 1.72 (1H, m, H51), 1.69 (1H, ddd, J =
11.5, 11.5, 11.5 Hz, H40), 1.64 (1H, ddd, J = 12.0, 12.0, 12.0 Hz, H10),
1.57 (1H, m, H32), 1.57 (1H, m, H37), 1.55 (1H, m, H48), 1.38 (1H, m,
H35), 1.24 (3H, d, J = 6.0 Hz, Me56), 1.16 (3H, d, J = 7.5 Hz, Me55),
1.14 (3H, d, J = 7.0 Hz, Me57), 1.07 (3H, s, Me53), 0.92 (3H, d, J = 7.0
Hz, Me54); 13C NMR (125 MHz, C6D6) δ 165.2, 163.5, 142.8, 139.1,
138.3, 137.8, 136.5, 136.4, 135.9, 135.80, 135.76, 134.01, 133.93, 133.91,
133.7, 133.58, 133.56, 133.3, 131.7, 131.2, 129.2, 128.7, 128.6, 128.5,
Sulfoxide 40. To a mixture of 39 (45.7 mg, 36.7 μmol) and
n-Bu3SnH (98.6 μL, 367 μmol) in toluene (12.2 mL) at -78 ꢀC was
added Et3B (1.0 M in THF, 293 μL, 293 μmol). After being stirred for
3 h, the reaction mixture was concentrated and directly subjected to flash
column chromatography (hexane/EtOAc, 4:1-1:1) to give sulfoxide 40
(34.3 mg, 31.4 μmol) in 86% yield: colorless oil; [R]28D -50.2 (c 1.25,
CHCl3); IR (film) ν 2929, 2856, 1616, 1518, 1427, 1387, 1249, 1103
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.90-7.81 (4H, m, NAP),
7.68-7.62 (4H, m, TBDPS), 7.58 (2H, d, J = 8.0 Hz, p-Tol), 7.45 (2H,
d, J = 8.4 Hz, MP), 7.45-7.38 (9H, m, NAP, TBDPS), 7.19 (2H, d, J =
8.0 Hz, p-Tol), 6.89 (2H, d, J = 8.4 Hz, MP), 5.89 (1H, m, H2), 5.79 (1H,
dd, J = 10.8, 4.8 Hz, H19), 5.77 (1H, m, H3), 5.63 (1H, m, H18), 5.36
(1H, s, MP), 5.13 (1H, d, J = 11.6 Hz, NAP), 5.06 (1H, d, J = 11.6 Hz,
NAP), 4.37 (1H, dd, J = 16.0, 5.8 Hz, H1), 4.35 (1H, m, H20), 4.10 (1H,
dd, J = 16.0, 1.6 Hz, H1), 3.91 (1H, dd, J = 10.8, 5.2 Hz, H22), 3.80 (3H,
s, MP), 3.76-3.66 (2H, m, H140), 3.59 (1H, dd, J = 8.4, 8.4 Hz, H7),
360
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Scheme 3. Synthesis of Left Wing of CTX3Ca
a Reagents and conditions: (a) TESCl, imidazole, DMF, 50 ꢀC; (b) DIBAL, CH2Cl2, -78 ꢀC; (c) NaClO2, NaH2PO4 2H2O, 2-methyl-2-butene,
3
t-BuOH/H2O (4:1), RT, 79% (3 steps); (d) 29 (1.1 equiv), 2,4,6-trichlorobenzoyl chloride, Et3N, 4-(dimethylamino)pyridine (DMAP), toluene, RT,
95% from 32; (e) DIBAL, CH2Cl2, -78 ꢀC; Ac2O, DMAP, pyridine, CH2Cl2, -78 to -60 ꢀC; (f) DIBAL, (PhSe)2, CH2Cl2/hexane, 0 ꢀC, 83%
(3 steps); (g) TBAF, THF, -30 ꢀC, 36, 31%; 37, 66%; (h) TDBPSCl, imidazole, DMF, RT, 85%; (i) (S)-38, MeLi, THF, -78 ꢀC to RT, 84%;
(j) n-Bu3SnH, Et3B, toluene, -78 ꢀC, 86%; (k) TFAA, pyridine, MeCN, 0 ꢀC; KOAc, H2O, RT; (l) Ph3PCH3Br, t-BuOK, THF, 0 ꢀC, 73% (2 steps);
(m) TBAF, THF, 40 ꢀC, 99%; (n) PhSeCN, n-Bu3P, THF, RT; (o) H2O2(aq), NaHCO3, THF, RT to 40 ꢀC, 98% (2 steps); (p) 26, CH2Cl2, 40 ꢀC; (q)
CSA, MeOH/CH2Cl2, 65% (2 steps); (r) TsCl, pyridine, 4 Å molecular sieves, RT, 94%; (s) NaCN, DMSO, 45 ꢀC, 97%; (t) DIBAL, CH2Cl2, -80 ꢀC;
(u) Ph3PCH3Br, t-BuOK, THF, 0 ꢀC, 90% (2 steps).
128.4, 128.14, 128.12, 128.0, 127.2, 126.9, 126.6, 126.54, 126.51, 126.47,
126.46, 126.36, 126.26, 126.18, 126.15, 126.09, 125.92, 125.87, 125.84,
125.76, 117.5, 109.5, 95.8, 88.4, 87.8, 87.5, 85.6, 85.5, 84.9, 83.7, 82.4,
81.8, 81.7, 81.6, 81.5, 81.0, 79.5, 79.3, 79.1, 78.6, 78.3, 77.8, 77.3, 75.2,
74.7, 74.4, 73.8, 73.4, 73.0, 72.8, 71.8, 71.3, 68.6, 46.6, 46.1, 43.3, 42.2,
41.2, 40.9, 39.2, 38.0, 37.6, 36.3, 35.2, 34.7, 32.9, 30.5, 30.2, 28.4, 27.9,
27.2, 23.1, 20.2, 16.3, 13.8; MALDI-TOF MS m/z 1785.5879 [M þ
Na]þ (calcd for C114H119F5NaO19S 1785.6101).
Pentaene 52. AIBN (7.6 mg, 46 μmol) was added to a degassed
solution of pentafluorophenylacrylate 49 (8.8 mg, 4.58 μmol) and
n-Bu3SnH (62 μL, 230 μmol) in toluene (4.6 mL). After being stirred
for 3 h at 85 ꢀC, the reaction mixture was concentrated, and column
chromatography (hexane/EtOAc, 10:1-0:1) gave oxepane carboxylic
acid 50 (5.6 mg, 3.4 μmol) in 74% yield and tetrahydropyran 51 (0.6 mg,
0.33 μmol) in 7% yield. To a solution of oxepane carboxylic acid 50
(9.0 mg, 6.04 μmol) in MeOH (400 μL) and benzene (1 mL) at room
temperature was added TMSCHN2 (2.0 M solution in hexane, 6 μL,
12 μmol). After being stirred for 30 min at room temperature, the reac-
tion mixture was quenched with AcOH, diluted with EtOAc and satu-
rated aqueous NaHCO3, and extracted with EtOAc (ꢀ3). The organic
layer was washed with brine and dried over Na2SO4. Concentration and
column chromatography (hexane/EtOAc, 10:1-1:1) gave the oxepane
methyl ester (9.1 mg, 6.04 μmol) in 100% yield.
To a solution of the above methyl ester (4.4 mg, 2.93 μmol) in
CH2Cl2 (1.0 mL) at -90 ꢀC was added DIBAL (15 μL, 14.6 μmol).
After being stirred for 30 min at -90 ꢀC, the reaction mixture was que-
nched with EtOAc and aqueous NH4Cl. The mixture was extracted with
EtOAc (ꢀ3), and the organic layer was washed with brine and dried over
MgSO4. Concentration gave the aldehyde, which was used in the next
reaction without further purification. To a suspension of Ph3PCH3Br
(52 mg, 146 μmol) in THF (1.0 mL) at 0 ꢀC was added t-BuOK (8.2 mg,
73.3 μmol). After 15 min, a solution of the above aldehyde in THF
(300 μL) at 0 ꢀC was added dropwise to the reaction mixture. After
being stirred for 30 min at 0 ꢀC, the reaction mixture was quenched with
aqueous NH4Cl. The mixture was extracted with EtOAc (ꢀ3), and the
organic layer was washed with brine and dried over MgSO4. Concentra-
tion and column chromatography (hexane/EtOAc, 20:1-10:1) gave the
pentaene 52 (4.0 mg, 2.71 μmol) in 92% yield over two steps: white,
amorphous solid; [R]19D -5.1 (c 0.21, CHCl3); IR (film) ν 2927, 2872,
1
1641, 1509, 1456, 1090, 854 cm-1; H NMR (500 MHz, CDCl3) δ
7.85-7.65 (12H, m, NAP), 7.58-7.42 (9H, m, NAP) 5.88 (1H, m, H2),
5.82 (1H, m, H23), 5.79-5.74 (2H, m, H3, H13), 5.69 (1H, m, H24),
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Scheme 4. Practical Total Synthesis of CTX3C (1)a
a Reagents and conditions: (a) N-Chlorosuccinimide (NCS), CCl4/CH2Cl2 (6:1), RT; (b) AgOTf, 2,6-di-tert-butyl-4-methylpyridine (DTBMP),
CH2Cl2/CCl4 (5:1), 4 Å molecular sieves, -70 to 0 ꢀC, 70% from 44; (c) TBAF, THF, 35 ꢀC, 92%; (d) Me3P, pentafluorophenyl propiolate, CH2Cl2,
RT, 93%; (e) n-Bu3SnH, 2,20-azobisisobutyronitrile (AIBN), toluene, 85 ꢀC, 50, 74%; 51, 7%; (f) trimethylsilyl diazomethane (TMSCHN2), benzene/
MeOH (2.5:1), RT, quant; (g) DIBAL, CH2Cl2, -90 ꢀC; (h) Ph3PCH3Br, t-BuOK, THF, 0 ꢀC, 92% (2 steps); (i) 26, CH2Cl2, 40 ꢀC, 90%; (j) 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), CH2Cl2/H2O (10:1), RT, 65%.
5.67-5.61 (2H, m, H14, H18), 5.19 (1H, dd, J = 10.5, 5.5 Hz, H19),
5.11-5.06 (2H, m, H230, H230), 5.05 (1H, d, J = 12.0 Hz, NAP), 5.00
(1H, d, J = 12.0 Hz, NAP), 5.01-4.97 (2H, m, H240, H240), 4.95 (1H, d,
J = 12.5 Hz, NAP), 4.84 (1H, d, J = 12.5 Hz, NAP), 4.81 (1H, d, J = 12.5
Hz, NAP), 4.77 (1H, d, J = 12.5 Hz, NAP), 4.31 (1H, dd, J = 15.5, 5.5 Hz,
H1), 4.05 (1H, m, H1), 3.84-3.88 (2H, m, H41, H52), 3.83-3.77 (2H,
m, H12, H15), 3.75 (1H, m, H52), 3.70 (1H, m, H27), 3.66 (1H, d, J =
10.5 Hz, H45), 3.64 (1H, m, H20), 3.56 (1H, m, H26), 3.53 (1H, m,
H16), 3.49 (1H, d, J = 3.5 Hz, H44), 3.49 (1H, dd, J = 9.5, 9.5 Hz, H7),
3.43-3.34 (4H, m, H6, H29, H34, H46), 3.29 (1H, ddd, J = 9.5, 9.5, 4.0
Hz, H5), 3.21 (1H, dd, J = 11.5, 4.5 Hz, H31), 3.20 (1H, m, H11),
3.16-3.06 (4H, m, H8, H9, H33, H39), 2.99 (1H, ddd, J = 9.5, 9.5, 2.5
Hz, H38), 2.93 (1H, ddd, J = 9.0, 9.0, 3.0 Hz, H21), 2.87 (1H, dd, J = 9.0,
4.5 Hz, H42), 2.65 (1H, ddd, J = 16.5, 7.0, 4.0 Hz, H4), 2.56 (1H, m,
H17), 2.48 (1H, m, H22), 2.35 (1H, m, H4), 2.30-2.25 (2H, m, H10,
H40), 2.20 (1H, m, H17), 2.17 (1H, m, H43), 2.14 (1H, m, H25),
2.02-1.85 (9H, m, H22, H25, H28, H32, H35, H36, H37, H50, H51),
1.84-1.75 (3H, m, H28, H50, H51), 1.64-1.50 (6H, m, H10, H32,
H35, H37, H47, H48), 1.41 (1H, m, H40), 1.26 (3H, s, Me53), 1.11
(3H, d, J = 7.5 Hz, Me55), 1.09 (3H, d, J = 7.0 Hz, Me54), 1.03 (3H, d,
J = 6.0 Hz, Me56), 0.91 (3H, d, J = 6.5 Hz, Me57); 13C NMR (125 MHz,
CDCl3) δ 137.0, 136.9, 136.68, 136.64, 136.62, 135.7, 135.3, 135.2,
134.1, 133.3, 133.28, 133.26, 132.9, 132.1, 131.4, 130.3, 129.0, 128.5,
128.4, 128.2, 127.89, 127.84, 127.82, 127.69, 127.67, 126.8, 126.6, 126.3,
126.10, 126.08, 126.06, 126.03, 125.91, 125.89, 125.70, 125.64, 125.62,
125.60, 117.7, 117.0, 108.3, 87.5, 86.87, 86.85, 84.6, 84.59, 84.55, 83.6,
82.5, 82.0, 80.98, 80.96, 80.92, 80.7, 79.9, 79.7, 78.4, 78.28, 78.27, 78.26,
78.21, 78.1, 77.97, 77.95, 77.94, 77.8, 75.2, 74.4, 73.7, 73.2, 72.2, 72.1,
71.9, 68.4, 67.39, 67.35, 41.9, 40.5, 40.3, 39.6, 35.6, 37.7, 36.9, 35.1, 34.6,
32.4, 29.7, 27.7, 24.4, 20.0, 15.8, 13.5; HRFABMS m/z 1493.7698 [M þ
Na]þ (calcd for C92H110O16Na 1493.7686).
CTX3C. To a solution of tris-NAP CTX3C S18 (3.3 mg, 2.29 μmol)
in CH2Cl2 (1.6 mL) and H2O (800 μL) at room temperature was
added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (5.1 mg,
22.9 μmol). After being stirred for 3 h at room temperature, the mixture
was quenched with saturated aqueous Na2S2O3 at room temperature,
diluted with EtOAc and saturated aqueous NaHCO3, and extracted with
EtOAc (ꢀ6). The organic layer was washed with brine. Concentration
and reversed-phase column chromatography (Shodex Asahipak ODP
50-6D, 6.0 ꢀ 150 mm, UV 210 nm, CH3CN/H2O, 75:25, 1.0 mL/min)
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gave pure synthetic CTX3C (1) (tR = 19.7 min, 1.83 mg, 1.79 μmol) in
65% yield: colorless, amorphous solid; [R]32D -42.6 (c 0.10, MeOH);
1H NMR (600 MHz, C5D5N) δ 6.02 (1H, m, H24), 6.02 (1H, m, H23),
5.96 (1H, dd, J = 10.8, 5.4 Hz, H19), 5.91 (1H, m, H14), 5.86 (1H, m,
H2), 5.83 (1H, m, H13), 5.82 (1H, m, H18), 5.72 (1H, m, H3), 4.44
(1H, m, H41), 4.32 (1H, dd, J = 15.0, 6.0 Hz, H1), 4.19 (1H, m, H44),
4.15 (1H, m, H15), 4.14 (1H, m, H20), 4.12 (1H, m, H29), 4.06 (1H, m,
H12), 4.07 (1H, m, H7), 4.01 (1H, d, J = 9.6 Hz, H45), 4.06 (1H, m,
H1), 3.53 (1H, dd, J = 9.6, 9.6 Hz, H46), 3.86 (1H, m, H52), 3.86 (1H,
m, H52), 3.76 (1H, m, H26), 3.70 (1H, m, H16), 3.58 (1H, m, H27),
3.58 (1H, m, H21), 3.53 (1H, dd, J = 9.0, 9.0 Hz, H6), 3.45 (1H, m, H5),
3.43 (1H, m, H34), 3.41 (1H, m, H11), 3.41 (1H, dd, J = 9.0, 9.0 Hz,
H8), 3.33 (1H, m, H9), 3.32 (1H, m, H39), 3.32 (1H, m, H33), 3.30
(1H, m, H31), 3.18 (1H, m, H38), 3.17 (1H, m, H42), 3.02 (1H, m,
H25), 2.98 (1H, m, H22), 2.83 (1H, m, H17), 2.65 (1H, m, H4), 2.56
(1H, m, H43), 2.54 (1H, m, H40), 2.53 (1H, m, H10), 2.53 (1H, m,
H28), 2.49 (1H, m, H28), 2.42 (1H, m, H4), 2.30 (1H, m, H25), 2.27
(1H, m, H17), 2.23 (1H, m, H22), 2.22 (1H, m, H32), 1.98 (1H, m,
H37), 1.91 (1H, m, H47), 1.90 (1H, m, H50), 1.89 (1H, m, H51), 1.87
(1H, m, H32), 1.85 (1H, m, H36), 1.83 (1H, m, H50), 1.82 (1H, m,
H10), 1.80 (1H, m, H35), 1.75 (1H, ddd, J = 12.0, 12.0, 12.0 Hz, H40),
1.68 (1H, m, H37), 1.66 (1H, m, H51), 1.59 (1H, m, H48), 1.51 (1H, m,
H35), 1.25 (3H, m, Me53), 1.26 (3H, m, Me55), 1.25 (3H, m, Me56),
0.94 (3H, d, J = 6.6 Hz, Me57), 0.88 (3H, d, J = 6.6 Hz, Me54); 13C
NMR (150 MHz, C5D5N) δ 137.9, 136.5, 132.1, 131.0, 128.7, 128.5,
127.1, 125.8, 108.8, 88.7, 87.7, 86.1, 85.3, 84.5, 84.0, 83.8, 83.7, 83.4,
82.5, 81.7, 81.6, 81.1, 80.9, 79.3, 78.6, 78.2, 77.0, 76.9, 74.9, 74.7, 74.3,
73.5, 73.1, 72.6, 68.5, 67.5, 46.6, 46.1, 44.0, 42.3, 41.4, 40.0, 39.0, 37.6,
36.4, 35.1, 34.9, 32.8, 32.7, 32.4, 28.4, 28.0, 24.6, 20.3, 16.2, 13.7, 9.9;
HRESIMS m/z 1045.5496 [M þ Na]þ (calcd for C57H82O16Na
1045.5495).
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S
Supporting Information. Experimental procedures and
b
NMR spectra for new compounds are available free of charge via
the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Tel: þ81-22-795-6564. Fax: þ81-22-795-6566. E-mail:
s-yamashita@m.tohoku.ac.jp; hirama@m.tohoku.ac.jp.
Present Addresses
^Graduate School of Pharmaceutical Sciences, The University of
Tokyo, Tokyo 113-0033, Japan.
’ ACKNOWLEDGMENT
This work was supported financially by a Grant-in-Aid
for Specially Promoted Research from the Ministry of Educa-
tion, Culture, Sports, Science and Technology (MEXT) in
Japan.
(12) (a) Yamaoka, K.; Inoue, M.; Miyahara, H.; Miyazaki, K.;
Hirama, M. Br. J. Pharmacol. 2004, 142, 879–889. (b) Yamaoka, K.;
Inoue, M.; Miyazaki, K.; Hirama, M.; Kondo, C.; Kinoshita, E.; Miyoshi,
H.; Seyama, I. J. Biol. Chem. 2009, 284, 7597–7605.
(13) (a) Inoue, M.; Ishihara, Y.; Yamashita, S.; Hirama, M. Org. Lett.
2006, 8, 5801–5804. (b) Inoue, M.; Yamashita, S.; Ishihara, Y.; Hirama,
M. Org. Lett. 2006, 8, 5805–5808.
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2002, 4, 3439–3442. (b) Inoue, M.; Wang, J.; Wang, G. X.; Ogasawara,
Y.; Hirama, M. Tetrahedron 2003, 59, 5645–5659.
(15) Compounds 13a-d were synthesized from 2-deoxy-D-ribose
according to the known procedures: See Supporting Information.
(16) The Sasaki and Tachibana group reported that 6-exo radical
cyclization of i afforded the undesired cis-substituted pyran ring iii via
’ DEDICATION
This paper is dedicated to Dr. Koji Nakanishi of Columbia
University for his pioneering work on bioactive natural products.
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