An improved synthesis of the C42–C52 segment of ciguatoxin 3C

Article abstract of DOI:10.1016/j.tetlet.2018.02.052

In our previously reported method for the construction of the IJKLM-ring of ciguatoxin 3C (CTX3C), the lengthy synthetic process for the intermediate C42–C52 (L-ring) segment was problematic. Therefore, a new and improved procedure for the C42–C52 segment, having modified protecting groups, was developed. The new route includes a chirality transferring Ireland-Claisen rearrangement for the construction of the vicinal dimethyl branching at C47–48, a one-pot cyclization process for the establishment of the stereocenters at C45 and C46 as well as the γ-hydroxy δ-lactone framework corresponding to the L-ring, and Brown's asymmetric crotylboration for the installation of the stereocenters at C43 and C44. The new C42–C52 segment was successfully coupled with the previously reported C32–C41 (I-ring) segment to produce the IJKLM-ring.

Full text of DOI:10.1016/j.tetlet.2018.02.052

Accepted Manuscript
An improved synthesis of the C42-C52 segment of ciguatoxin 3C
Takafumi Saito, Kenshu Fujiwara, Yusuke Sano, Takuto Sato, Yoshihiko
Kondo, Uichi Akiba, Yusuke Ishigaki, Ryo Katoono, Takanori Suzuki
PII:
S0040-4039(18)30241-7
https://doi.org/10.1016/j.tetlet.2018.02.052
TETL 49737
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
3 January 2018
17 February 2018
20 February 2018
Please cite this article as: Saito, T., Fujiwara, K., Sano, Y., Sato, T., Kondo, Y., Akiba, U., Ishigaki, Y., Katoono,
R., Suzuki, T., An improved synthesis of the C42-C52 segment of ciguatoxin 3C, Tetrahedron Letters (2018), doi:
https://doi.org/10.1016/j.tetlet.2018.02.052
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An improved synthesis of the C42-C52
segment of ciguatoxin 3C
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Takafumi Saito, Kenshu Fujiwara,* Yusuke Sano, Takuto Sato, Yoshihiko Kondo, Uichi Akiba, Yusuke
Ishigaki, Ryo Katoono, Takanori Suzuki

1
Tetrahedron Letters
An improved synthesis of the C42-C52 segment of ciguatoxin 3C
Takafumi Saitoa, Kenshu Fujiwarab,  Yusuke Sanoa, Takuto Satoa, Yoshihiko Kondob, Uichi Akibab,
Yusuke Ishigakia, Ryo Katoonoa, Takanori Suzukia
aDepartment of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
bDepartment of Life Science, Graduate School of Engineering Science, Akita University, Akita 010-8502, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
In our previously reported method for the construction of the IJKLM-ring of ciguatoxin 3C
(CTX3C), the lengthy synthetic process for the intermediate C42-C52 (L-ring) segment was
problematic. Therefore, a new and improved procedure for the C42-C52 segment, having
modified protecting groups, was developed. The new route includes a chirality transferring
Ireland-Claisen rearrangement for the construction of the vicinal dimethyl branching at C47-48,
a one-pot cyclization process for the establishment of the stereocenters at C45 and C46 as well
as the γ-hydroxy δ-lactone framework corresponding to the L-ring, and Brown's asymmetric
crotylboration for the installation of the stereocenters at C43 and C44. The new C42-C52
segment was successfully coupled with the previously reported C32-C41 (I-ring) segment to
produce the IJKLM-ring.
Available online
Keywords:
Natural product synthesis
Ireland-Claisen rearrangement
Stereoselective synthesis
Fused polycyclic ethers
One-pot multistep synthesis
2009 Elsevier Ltd. All rights reserved.
Ciguatoxin 3C (CTX3C) (1) (Figure 1) was isolated from
cultured dinoflagellate Gambierdiscus toxicus as one of the
causative toxins of ciguatera fish poisoning, which often breaks
out in tropical and subtropical coral leaf regions causing serious
nervous system disorders in patients.1,2 The ciguatera toxins
including 1 have a ladder-shaped, fused polycyclic ether
framework typically including 13 ether rings with 30 or more
stereocenters. The complex molecular structure and the strong
neurotoxicity of the ciguatera toxins have attracted considerable
attention from synthetic chemists, and, therefore, many studies
toward the total synthesis of 1 and its congeners have been
conducted.3,4,5,6 However, to date, only the Hirama4 and the
Isobe5 groups have achieved the total synthesis of the ciguatera
toxins.
a prototype for the final steps of the total synthesis of 1.6d
However, in the synthesis of the IJKLM-ring, the lengthy
synthetic process (3.9% over 30 steps from tri-O-acetyl-D-glucal)
for the intermediate C42-C52 (L-ring) segment caused difficulty
in large-scale synthesis.6b Therefore, a new pathway for the C42-
C52 segment was explored. Here, we describe the successful
synthesis of a new C42-C52 segment, having modified protecting
groups, with a reduced number of reactions compared to that of
the previous route.
We planned a convergent synthesis of the IJKL-ring 2 from I-
ring 3 and newly designed the C42-C52 segment 4 as shown in
Scheme 1. Due to the expected instability of the LM-ring of 1,
the spiroacetal was intended to be constructed at the final stage of
the total synthesis from an intermediate having a stable cyclic
ether corresponding to the L-ring. Therefore, oxane 4 was
employed as the stable L-ring segment, which would be
connected to I-ring 3 to form IJKL-ring 2 by our previously
developed method. Since the previous C42-C52 segment had
issues of unfavorable detachment of the protecting group at O52
during the formation of the J- and K-rings, we replaced the
protecting group with a stable 4-methoxyphenyl (PMP) group.
For the protecting group of the oxygen atom at C44, a 4-
bromobenzyl (PBB) group was selected based on stability and
removability under specific conditions.7 The PMP and PBB
groups would be removed at the final stage of the total synthesis.
The 4-(methylphenylamino)benzyl (PMPAB) group at O46 was
employed as a temporary protecting group, which would be
removed before the K-ring formation.7 Thus, compound 4 was
designed as the new C42-C52 segment.
Figure 1. The structure of ciguatoxin 3C (1).
During the course of our investigations toward the total
synthesis of 1,6 we have synthesized the ABCDEF-ring and the
IJKLM-ring segments6b,c,g and developed a method for the
construction of the FGHI-ring from the F- and I-ring segments as
———
 Corresponding author. E-mail address: fjwkn@gipc.akita-u.ac.jp (K. Fujiwara).

2
Tetrahedron
was produced in 83% yield with high stereoselectivity (15:epi-15
= 17:1). Interestingly, the enantiomer of 13 (ent-13) gave (R)-
alcohol ent-epi-15 with lower stereoselectivity (ent-15:ent-epi-15
= 1:7) under the same reduction conditions using (S,S)-14,
thereby indicating that the 2,2-dimethyl-1,3-dioxolane moiety of
13 has matched stereochemistry with (S,S)-14 in the Noyori
reduction. Upon treatment with LiAlH4, propargyl alcohol 15 was
converted to (E)-allyl alcohol 16 (95%), which was esterified
with propanoyl chloride to give ester 9 (99%). The (R)-
configuration of the C45 stereocenter of the product was
confirmed by NMR analysis using (R)- and (S)-Mosher esters of
16.16
Scheme 1. Plan for the construction of IJKL-ring 2. PMP: 4-
methoxyphenyl; PBB: 4-bromobenzyl; NAP: 2-naphthylmethyl;
PMPAB: 4-(methylphenylamino)benzyl.
The plan for the construction of 4 is shown in Scheme 2.
Aldehyde 4 would be derived by oxidative cleavage of alkene 5,
in which the C43 and C44 stereocenters would be established by
Brown's asymmetric crotylboration of 6.8 The installation of the
C50-C52 unit and the PBB group to lactone 7 would produce 6.
The construction of the stereocenters at C45 and C46 of 7 would
rely on a process including transformation of the 2,2-dimethyl-
1,3-dioxolane moiety of 8 to a hydroxymethyl group, asymmetric
epoxidation of the double bond at C45 and C46, and 5-exo
cyclization of the resulting epoxy ester to form a γ-lactone. The
resulting γ-lactone was expected to be transformed to stable δ-
lactone 7, in which all the four substituents are equatorial.9
Establishment of the syn-dimethyl group with (47R,48S)-
Scheme 3. Synthesis of ester 9. Reagents and conditions: (a) 2,2-
dimethoxypropane, PTS·H2O (cat.), acetone, 20 °C, 2 h, 98%; (b)
2 mol/L aq. NaOH, 2 mol/L aq. NaClO, RuO2·H2O (cat.), 40 °C, 1
h; (c) MeN(H)OMe·HCl, DCC, DMAP (cat.), CH2Cl2, 25 °C, 3 h,
85% from 11; (d) 1-propynylmagnesium bromide, THF, –20 °C,
30 min, 90%; (e) formic acid, Et3N, (S,S)-14 (cat.), Et2O, 25 °C, 3
h, 83% (15:epi-15 = 17:1); (f) LiAlH4, THF, 40 °C, 5 h, 95%; (g)
propanoyl chloride, pyridine, DMAP (cat.), CH2Cl2, 24 °C, 8 h,
configuration in
8 employed chirality-transferring Ireland-
Claisen rearrangement of ester 9, which would be prepared from
chiral Weinreb amide 10.
99%.
PTS:
p-toluenesulfonic
acid;
DCC:
N,N'-
dicyclohexylcarbodiimide; DMAP: 4-dimethylaminopyridine.
Lactone 7 was constructed from ester 9 as shown in Scheme 4.
First, ester 9 was subjected to Ireland-Claisen rearrangement.
After intensive explorations, we found the following optimized
conditions: treatment of 9 with KDA, prepared by the mixing of
LDA and Tf2NK in THF-HMPA (3:1) at –40 °C for 5 min, and
TMSCl at –78 °C for 30 min followed by warming to ambient
temperature gave a rearranged product, which was esterified with
TMSCHN2 to afford a 6:1 inseparable mixture of 8 and α-epi-8 in
88% combined yield from 9. The standard conditions using LDA
in THF gave 8 and α-epi-8 in 79% yield with low selectivity
(1:1), while the use of sodium bis(trimethylsilyl)amide
(NHMDS) in THF-HMPA (2:1) produced 8 selectively (8:α-epi-8
= >10:1) but in low yield (<30%). The undesired, minor -
epimer could not be separated from the desired major
stereoisomer until the stage of lactone formation. Upon treatment
in one-pot with aqueous HCl followed by NaIO4, the 6:1 mixture
of 8 and α-epi-8 was converted to a diastereomeric mixture of
aldehydes, which was reduced under Luche conditions17 to
produce a 6:1 mixture of 18 and α-epi-18 (98% over 3 steps). The
mixture of allyl alcohols was stereoselectively transformed to a
6:1 mixture of 19 and α-epi-19 by Sharpless asymmetric
epoxidation using L-(+)-DIPT (78%).18 When the mixture of
epoxides was heated in refluxing H2O, the formation of γ-
lactones (20 and α-epi-20) by 5-exo epoxide ring opening was
observed. Next, the reaction solution was basified in situ with
NaOH to produce hydrolyzed 21 and α-epi-21, which were
cyclized in situ by acidification of the solution with HCl to give
Scheme 2. Plan for the synthesis of C42-C52 segment 4. PMP: 4-
methoxyphenyl; PMPAB: 4-(methylphenylamino)benzyl; PBB: 4-
bromobenzyl.
The synthesis of 9 via 10 is illustrated in Scheme 3. Weinreb
amide 10 was prepared from L-ascorbic acid through a three-step
process as follows: (i) formation of isopropylidene ketal 11
(98%),10 (ii) oxidative cleavage of 11 by Carlsen's procedure11
with some modifications12 to give protected glycerate salt 12, and
(iii) amidation of 12 with N,O-dimethylhydroxylamine in the
presence of N,N'-dicyclohexylcarbodiimide (DCC) to produce 10
(85% over 2 steps). Weinreb amide 10 was reacted with 1-
propynylmagnesium bromide to afford ketone 13 (90%).13
Although several successful examples were reported for the
diastereoselective reduction of 2,2-dimethyl-1,3-dioxolan-4-yl
ketones,14,6e ketone 13 was only reduced with low
diastereoselectivity even after intensive exploration of reaction
conditions using achiral reductants. Therefore, the asymmetric
reduction of 13 was examined with ruthenium catalyst (S,S)-14
under Noyori conditions.15 As a result, desired (R)-alcohol 15

3
lactones 7 and α-epi-7. Because lactone 7 was obtained as
crystals, recrystallization was effective to separate 7 from α-epi-7.
The stereostructure of 7 was confirmed by X-ray crystallographic
analysis (Figure 2).19 Thus, lactone 7 was obtained in 66% yield
from the 6:1 mixture of 19 and α-epi-19 through a one-pot three-
step process, achieved by simple heating, basification, and
acidification in aqueous media.
with Dess-Martin periodinane (DMPI)21 followed by Brown's
asymmetric crotylboration using 26 produced 27
stereoselectively (72% over 2 steps).8 The absolute configuration
of 27 was determined by X-ray crystallographic analysis on 3,5-
dinitrobenzoyl ester 29, derived from 27 (Figure 3).22,23 The PBB
group of 27 was converted to the PMPAB group according to the
Buchwald-Seeberger procedure (71%).7 The resulting 28 was
protected with PBBBr to give 5 (75%), the vinyl group of which
was then transformed to a formyl group by a one-pot
dihydroxylation/oxidative cleavage process to afford 4 (93%).24
Thus, L-ring segment 4 was synthesized in 6.6% yield over 26
(or 18 isolation/purification) steps from L-ascorbic acid.
Scheme 4. Synthesis of lactone 7. Reagents and conditions: (a) i-
Pr2NH, Tf2NK, BuLi, –40 °C, THF-HMPA (3:1), 5 min, then 9,
TMSCl, THF-HMPA (2:1), –78 °C, 30 min, then 24 °C, 3.5 h; (b)
TMSCHN2, MeOH-PhH (1:1), 24 °C, 20 min, 88% (an inseparable
6:1 mixture of 8 and α-epi-8) from 9; (c) 2 mol/L aq. HCl, THF, 24
°C, 3 h, then pH 7 buffer, NaIO4, 0 → 24 °C, 1 h; (d) NaBH4,
CeCl3·7H2O, MeOH, –78 °C, 30 min, 98% (an inseparable 6:1
mixture of 18 and α-epi-18) from the above mixture of 8 and α-
epi-8; (e) L-(+)-DIPT, Ti(Oi-Pr)4, TBHP, MS4A, CH2Cl2, –20 °C,
18 h, 78% (an inseparable 6:1 mixture of 19 and α-epi-19); (f)
H2O, reflux, 11 h, then 2 mol/L aq. NaOH, 24 °C, 6 h, then 12
mol/L aq. HCl, 24 °C, 2 h, then recrystallization, 66% (7) from the
above mixture of 19 and α-epi-19. Tf: trifluoromethanesulfonyl;
TMS: trimethylsilyl; HMPA: hexamethylphosphoric triamide;
DIPT: diisopropyl tartrate; TBHP: tert-butyl hydroperoxide.
Scheme 5. Synthesis of C42-C52 segment 5. Reagents and
conditions: (a) 4-bromobenzaldehyde dimethylacetal, CSA (cat.),
CH2Cl2, reflux, 30 min, 100%; (b) 3-(4-methoxyphenyloxy)prop-
1-yne, BuLi, THF, –70 °C, 30 min, then 22, –70 °C, 10 min, 92%;
(c) H2, (Ph3P)3RhCl (cat.), PhH, 25 °C, 19 h, 95%; (d) Et3SiH,
PhBCl2, –78 °C, 40 min, 81%; (e) DMPI, NaHCO3, CH2Cl2, 25
°C, 1 h; (f) 26, THF, –78 °C, 1 h, 72% from 25; (g) PhN(H)Me, t-
BuONa, (2-biphenyl)P(t-Bu)2, Pd(OAc)2 (cat.), THF, 25 °C, 3 d,
71%; (h) t-BuOK, Bu4NI (cat.), PBBBr, THF, 25 °C, 16 h, 75%;
(i) OsO4 (cat.), NMO, pH 7 buffer, 1,4-dioxane, 25 °C, 11.5 h, then
NaIO4, 24 °C, 1 h, 93%. CSA: 10-camphorsulfonic acid; DMPI:
Dess-Martin periodinane; NMO: N-methylmorpholine N-oxide.
Figure 2. ORTEP diagram of 7.
Next, lactone 7 was converted to L-ring segment 4 (Scheme 5).
After protection of 7 as a cyclic 4-bromobenzylidene acetal
(100%), the resulting lactone 22 was reacted with a lithium
acetylide, derived from 3-(4-methoxyphenyloxy)prop-1-yne, to
afford 23 (92%), which was hydrogenated with Wilkinson's
catalyst to produce 24 (95%). Upon treatment of 24 with Et3SiH
in the presence of PhBCl2 as a Lewis acid, the regioselective
reductive cleavage of the cyclic acetal group and the
stereoselective reduction of the hemiacetal group were
simultaneously accomplished to give 25 (81%).20 Oxidation of 25
Figure 3. ORTEP diagram of 3,5-dinitrobenzoyl ester 29.
With L-ring segment 4 in hand, we examined the connection
of 4 with I-ring segment 3B6c followed by JK-ring formation
(Scheme 6). Although the Bn groups of 3B are inappropriate for
further synthesis due to the difficulty in their selective removal in
the presence of the PBB ether after completion of the IJKL-ring
synthesis, we used 3B as a good model compound to demonstrate
the function of the protecting groups of
4 during the

4
Tetrahedron
transformation to the IJKL-ring 2B. First, dithioacetal mono-S-
O52 and the PBB group at O44 would properly function as
protecting groups in the total synthesis of CTX3C.
oxide 3B was deprotonated with LDA, and the resulting anion
was reacted with aldehyde 4 to give adduct 30 (72%).6c,25 Upon
treatment of 30 with p-toluenesulfonic acid (PTS) in MeOH, the
dithioacetal mono-S-oxide moiety and the PMPAB group were
hydrolyzed to give ketodiol 31 (65%). Reductive etherification of
31 with Et3SiH in the presence of TMSOTf afforded tricyclic
ether 32,26 which was subjected to Swern oxidation to produce
ketone 33 as a single diastereomer (87% over 2 steps).27 The
stereochemistry at C41 was determined by NMR analysis, in
which the NOE enhancement between H41 and H46 was
observed. After the NAP group of 33 was removed by DDQ,28 the
resulting 34 was cyclized with Et3SiH and TMSOTf to furnish
tetracyclic 2B (79% over 2 steps).29 The trans-fusion between the
J- and K-rings was confirmed by the presence of NOE
correlations between H38/H42 and between H41/H46 as well as
Scheme 7. Formation of the LM-ring and conversion of the PBB
ether at C44. Reagents and conditions: (a) CAN, MeCN-CH2Cl2-
H2O (2:1:2), 0 °C, 30 min, 86%; (b) PhI(OAc)2, I2, h,
cyclohexane, 23 °C, 3 h, then CSA, MeOH-CH2Cl2 (1:1), 23 °C,
24 h, 78%; (c) BuLi, THF, –78 °C, 1 h, then H2O, –78 → 23 °C, 1
h, 89%; (d) PhN(H)Me, t-BuONa, (2-biphenyl)P(t-Bu)2,
Pd(dba)3·CHCl3 (cat.), PhMe, 80 °C, 16 h; (e) CSA, MeOH-
CH2Cl2 (1:1), 40 °C, 1 h, 69% from 36. CAN: cerium(IV)
ammonium nitrate; dba: dibenzylideneacetone.
3
a large JH41-H42 value (9.2 Hz). Thus, the connection of L-ring 4
with I-ring 3B followed by JK-ring formation smoothly
proceeded in 6 steps to produce 2B in 32% overall yield without
any problem with the protecting groups.
In conclusion, an improved process for the C42-C52 segment
(4) of CTX3C, having modified protecting groups, was
developed. The new route includes chirality transferring Ireland-
Claisen rearrangement for the construction of the vicinal
dimethyl branching at C47-48, a one-pot cyclization process for
the establishment of the stereocenters at C45 and C46 as well as
the γ-hydroxy δ-lactone framework corresponding to the L-ring,
and Brown's asymmetric crotylboration for the installation of the
stereocenters at C43 and C44. The new process, which produced
4 in 6.6% yield over 26 steps from L-ascorbic acid, was also
simplified by the omission of 8 isolation/purification steps,
thereby requiring only 18 isolation/purification steps from L-
ascorbic acid. Thus, the present synthesis of 4 is clearly improved
as compared to the previous synthesis, which provided the same
part in 3.9% yield over 30 (or 26 isolation/purification) steps
from tri-O-acetyl-D-glucal. The new C42-C52 segment (4) was
successfully coupled to the previously reported C32-C41 (I-ring)
segment (3B) to produce the IJKLM-ring. Further studies toward
the total synthesis of ciguatoxin CTX3C are now in progress in
this laboratory.
Acknowledgments
Scheme 6. Synthesis of IJKL-ring 2B. Reagents and conditions:
(a) 3B, LDA, THF, –20 °C, 10 min, then 4, –78 °C, 1.5 h, 72%; (b)
PTS·H2O (cat.), MeOH, CH2Cl2, 24 °C, 13 h, 65%; (c) Et3SiH,
TMSOTf, CH2Cl2, 0 °C, 10 min; (d) (COCl)2, DMSO, CH2Cl2, –
78 °C, 15 min, then Et3N, –78 → 0 °C, 20 min, 87% from 31; (e)
DDQ, H2O-CH2Cl2 (1:10), 25 °C, 1.5 h; (f) Et3SiH, TMSOTf,
CH2Cl2, 0 °C, 10 min, 79% from 33. NOE: nuclear Overhauser
effect.
We thank Dr. Eri Fukushi and Mr. Yusuke Takata (GC-MS
and NMR Laboratory, Faculty of Agriculture, Hokkaido
University) for the measurements of mass spectra. We are also
grateful to Prof. Mitsutoshi Jikei and Prof. Kazuya Matsumoto
(Department of Materials Science, Graduate School of
Engineering Science, Akita University) for the measurements of
NMR spectra and to Prof. Tetsuo Tokiwano (Faculty of
Bioresource Sciences, Akita Prefectural University) for the
measurements of optical rotation. This work was supported by
Grants-in-Aid for Scientific Research from JSPS, Japan.
Finally, formation of the LM-ring and detachment of the PBB
group at O44, which were scheduled for the final stage of our
total synthesis of CTX3C, were demonstrated (Scheme 7). The
PMP group of 2B was removed with cerium(IV) ammonium
nitrate (CAN) to give alcohol 35 (86%).30 Treatment of 35 with
PhI(OAc)2 and iodine under photoirradiation with a 60 W
incandescent lamp afforded a 1:1 mixture of spiroacetal 3631 and
its C49 epimer.32 The epimer was isomerized with 10-
camphorsulfonic acid (CSA) in MeOH to give 36 as a single
stereoisomer (78%).33,6c The stereochemistry of the spiroacetal
moiety was confirmed by the transformation of 36 under basic
conditions to known 37 (89%), which was previously synthesized
by the Hirama group34 and ours.6c The removal of the PBB group
of 36 was also tested. The amination of the PBB group with N-
methylaniline in the presence of a palladium catalyst followed by
the acidic removal of the resulting PMPAB ether produced 3835
(69% over 2 steps).7 This strongly suggests that the PMP group at
References and notes
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5
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19. Crystal data of 7: Crystals were obtained by recrystallizing from
EtOAc. C8H14O4, M = 174.20, colorless platelet, 0.60 × 0.30 × 0.2
mm3, monoclinic P21 (No. 4), a = 6.1339(7) Å, b = 9.462(2) Å, c
= 7.4988(13) Å,  = 90.428(10)°, V = 435.23(14) Å3, Dc (Z = 2) =
1.329 g cm–3. A total 1546 unique data (2max = 52°) were
measured at T = 150 K by Rigaku Mercury 70 apparatus (Mo K
radiation,  = 0.71075 Å). Numerical absorption correction was
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method (SIR2004) and refined by the full-matrix least-squares
method of F2 with anisotropic temperature factors for non-
hydrogen atoms (SHELXL97). All the hydrogen atoms were
located at the positions inferred from neighboring sites, and
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118 parameters. CCDC 1584173.
4. (a) Hirama, M.; Oishi, T.; Uehara, H.; Inoue, M.; Maruyama, M.;
Oguri, H.; Satake, M. Science 2001, 294, 1904. (b) Inoue, M.;
Miyazaki, K.; Uehara, H.; Maruyama, M.; Hirama, M. Proc. Natl.
Acad. Sci. USA 2004, 101, 12013. (c) Hirama, M. Chem. Rec.
2005, 5, 240. (d) Hirama, M. Proc. Jpn. Acad., Ser. B, 2016, 92,
290.
5. (a) Hamajima, A.; Isobe, M. Angew. Chem. Int. Ed. 2009, 48,
2941. (b) Isobe, M.; Hamajima, A. Nat. Prod. Rep. 2010, 27,
1204.
20. Sakagami, M.; Hamana, H. Tetrahedron Lett. 2000, 41, 5547.
21. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b)
Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277
22. Crystal data of 29: Crystals were obtained by recrystallizing from
hexane-EtOAc. C36H41N2O10Br, M = 741.63, orange block, 0.50 ×
0.15 × 0.15 mm3, monoclinic P21 (No. 4), a = 14.190(4) Å, b =
5.9505(15) Å, c = 22.708(6) Å,  = 108.087(4)°, V = 1822.7(9)
6. (a) Fujiwara, K.; Goto, A.; Sato, D.; Ohtaniuchi, Y.; Tanaka, H.;
Murai, A.; Kawai, H.; Suzuki, T. Tetrahedron Lett. 2004, 45, 7011.
(b) Domon, D.; Fujiwara, K.; Ohtaniuchi, Y.; Takezawa, A.;
Takeda, S.; Kawasaki, H.; Murai, A.; Kawai, H.; Suzuki, T.
Tetrahedron Lett. 2005, 46, 8279. (c) Domon, D.; Fujiwara, K.;
Murai, A.; Kawai, H.; Suzuki, T. Tetrahedron Lett. 2005, 46, 8285.
(d) Takizawa, A.; Fujiwara, K.; Doi, E.; Murai, A.; Kawai, H.;
Suzuki, T. Tetrahedron 2006, 62, 7408. (e) Goto, A.; Fujiwara,
K.; Kawai, H.; Suzuki, T. Org. Lett. 2007, 9, 5373. (f) Nogoshi,
K.; Domon, D.; Fujiwara, K.; Kawamura, N.; Katoono, R.; Kawai,
H.; Suzuki, T. Tetrahedron Lett. 2013, 54, 676. (g) Sato, T.;
Fujiwara, K.; Nogoshi, K.; Goto, A.; Domon, D.; Kawamura, N.;
Nomura, Y.; Sato, D.; Tanaka, H.; Murai, A.; Kondo, Y.; Akiba,
U.; Katoono, R.; Kawai, H.; Suzuki T. Tetrahedron 2017, 73, 703.
7. Plante, O. J.; Buchwald, S. L.; Seeberger, P. H. J. Am. Chem. Soc.
2000, 122, 7148.
8. Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1990, 108, 5919.
9. The Hirama group reported a similar γ-hydroxy-δ-lactone
formation in the synthesis of the L-ring of ciguatoxins, in which
the following one-pot process was effectively performed: basic
hydrolysis of a δ-iodo-γ-lactone to form an epoxy carboxylate, 5-
exo cyclization to a δ-hydroxy-γ-lactone, hydrolysis to a γ,δ-
dihydroxy carboxylate, and formation of a γ-hydroxy-δ-lactone by
acidification. See: Uehara, H.; Oishi, T.; Inoue, M.; Shoji, M.;
Nagumo, Y.; Kosaka, M.; Le Brazidec, J.-Y.; Hirama, M.
Tetrahedron 2002, 58, 6493.
Å3, Dc (Z = 2) = 1.351 g cm–3. A total 7600 unique data (2max
=
55°) were measured at T = 150 K by Rigaku Mercury 70 apparatus
(Mo K radiation,  = 0.71075 Å). Numerical absorption
correction was applied ( = 11.89 cm–1). The structure was solved
by the direct method (SIR92) and refined by the full-matrix least-
squares method of F2 with anisotropic temperature factors for non-
hydrogen atoms (SHELXL97). All the hydrogen atoms were
located at the positions inferred from neighboring sites, and
treated by constrained refinement. The final wR value is 0.056 (all
data) for 7600 reflections and 443 parameters. The absolute
structure was deduced based on Flack parameter, 0.000(5), refined
using 3079 Friedel pairs. CCDC 1584171.
23. The absolute stereochemistry of 27 was verified by the Kusumi-
Mosher analysis on (R)- and (S)-MTPA esters of 27,16 which
showed the (S)-configuration of C44.
24. Spectral data of 4: [α]D26 –4.65 (c 1.31, CHCl3); IR (neat)  2967,
2929, 2875, 1721, 1595, 1508, 1466, 1342, 1303, 1231, 1181,
1106, 1071, 1043, 1012, 824, 806, 697 cm–1; 1H NMR (400 MHz,
CDCl3, TMS as 0.00 ppm) δ 0.87 (3H, d, J = 6.5 Hz), 1.10-1.21
(1H, m), 1.12 (3H, d, J = 6.3 Hz), 1.25 (3H, d, J = 7.2 Hz), 1.35-
4.53 (2H, m), 1.74-2.01 (3H, m), 2.83 (1H, brdq, J = 5.3, 7.2 Hz),
2.96 (1H, t, J = 9.8 Hz), 3.01 (1H, brt, J = 9.0 Hz), 3.30 (3H, s),
3.57 (1H, dd, J = 1.2, 9.7 Hz), 3.76 (3H, s), 3.93 (2H, t, J = 6.0
Hz), 4.07 (1H, brdd, J = 1.2, 5.3 Hz), 4.42 (1H, d, J = 12.1 Hz),
4.51 (2H, s), 4.58 (1H, d, J = 12.1 Hz), 6.78-6.85 (4H, m), 6.95
(2H, d, J = 8.4 Hz), 6.98 (1H, brt, J = 7.5 Hz), 7.03 (2H, brd, J =
8.4 Hz), 7.14 (2H, d, J = 8.3 Hz), 7.16 (2H, d, J = 8.4 Hz), 7.27
(2H, brdd, J = 7.5, 8.4 Hz), 7.40 (2H, d, J = 8.3 Hz), 9.72 (1H,
brs); 13C NMR (100 MHz, CDCl3, 13CDCl3 as 77.0 ppm) δ 10.7
(CH3), 14.3 (CH3), 15.5 (CH3), 25.2 (CH2), 29.4 (CH2), 40.2
(CH3), 41.4 (CH), 44.1 (CH), 47.8 (CH), 55.7 (CH3), 68.5 (CH2),
71.2 (CH2), 73.8 (CH2), 78.2 (CH), 80.7 (CH), 81.7 (CH), 82.2
(CH), 114.6 (CH  2), 115.4 (CH  2), 119.8 (CH  2), 121.0 (CH
 2), 121.3 (C), 121.7 (CH), 129.0 (CH  2), 129.22 (CH  2),
129.23 (CH  2), 130.3 (C), 131.4 (CH  2), 137.5 (C), 148.77
(C), 148.84 (C), 153.2 (C), 153.6 (C), 204.1 (CHO); FD-HRMS
(m/z) calcd for C42H5079BrNO6 [M+]: 743.2822, found: 743.2833.
25. (a) Ogura, K.; Tsuchihashi, G. Tetrahedron Lett. 1972, 13, 2681;
(b) Herrmann, J. L.; Richman, J. E.; Wepplo, P. J.; Schlessinger,
R. H. Tetrahedron Lett. 1973, 14, 4707.
10. (a) Jackson, K.; Jones, J. Can. J. Chem. 1969, 47, 2498. (b) Jung,
M. E.; Shaw, T. J. J. Am. Chem. Soc. 1980, 102, 6304.
11. Carlsen, P. H. J.; Misund, K.; Røe, J. Acta Chem. Scand. 1995, 49,
297.
12. Compound 12 was prepared by the following procedure: To an
aqueous solution of NaClO (2 mol/L, 426 mL, 852.95 mmol) was
added RuO2·H2O (114 mg, 0.853 mmol) at 25 °C. To the solution
was added a solution of 11 (18.44 g, 85.30 mmol) in aq. NaOH (2
mol/L, 299 mL, 597.08 mmol) dropwise over 1 h. The reaction
was exothermic, and the reaction temperature was kept at 40 °C
with cooling by water bath. After the addition, an excess amount
of 2-propanol was immediately added as a scavenger of oxidants.
The reaction mixture was filtered through a Celite pad to remove
precipitated Ru species. The filtrate was concentrated under
reduced pressure, and boiling EtOH (300 mL) was added to the
residue. The resulting hot suspension was immediately filtered,
and the filtrate was concentrated under reduced pressure. This
suspension/filtration operation was repeated once more. The
resulting crude mixture of 12 and small amounts of inseparable
byproducts was obtained as colorless solid, which was
immediately used in the next reaction without further purification.
The spectral data of 12 were in good agreement with those of ref.
11.
26. Nicolaou, K. C.; Hwang, C.-K.; Nugiel, D. A. J. Am. Chem. Soc.
1989, 111, 4136.
27. Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43,
2048.
13. Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
14. (a) Pikul, S.; Kozlowska, M.; Jurczak, J. Tetrahedron Lett. 1987,
28, 2627. (b) Yamanoi, T.; Akiyama, T.; Ishida, E.; Abe, H.;
Amemiya, M.; Inazu, T. Chem. Lett. 1989, 335. (c) Dondoni, A.;
Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini, P. J. Org. Chem.
1989, 54, 702. (d) Chikashita, H.; Nikaya, T.; Uemura, H.; Itoh, H.
Bull. Chem. Soc. Jpn. 1989, 62, 2121.
28. (a) Wright, J. A.; Yu, J.; Spencer, J. B. Tetrahedron Lett. 2001,
42, 4033. (b) Inoue, M.; Uehara, H.; Maruyama, M.; Hirama, M.
Org. Lett. 2002, 4, 4551.
29. Spectral data of 2B: [α]D27 –2.35 (c 1.16, CHCl3); IR (neat) 
3063,3030, 2954, 2926, 2869, 1508, 1488, 1453, 1368, 1336,
1287, 1231, 1096, 1073, 1011, 910, 823, 804, 736, 698 cm–1; 1H
NMR (500 MHz, C6D6, C6HD5 as 7.15 ppm)  0.71 (3H, d, J = 6.4
Hz), 1.01 (3H, d, J = 7.0 Hz), 1.02-1.15 (1H, m), 1.13 (3H, d, J =
15. Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J.
Am. Chem. Soc. 1996, 118, 2521.

6
Tetrahedron
7.6 Hz), 1.18 (3H, d, J = 5.9 Hz), 1.16-1.28 (1H, m), 1.40-1.50
(CH2), 40.8 (CH), 42.3 (CH), 44.4 (CH2), 67.5 (CH2), 71.3 (CH2),
71.6 (CH2), 72.6 (CH2), 72.8 (CH2), 73.4 (CH2), 74.8 (CH), 78.4
(CH), 79.6 (CH), 81.1 (CH), 82.6 (CH), 85.5 (CH), 85.6 (CH),
87.5 (CH), 108.6 (C), 121.4 (C), 127.5 (CH), 127.6 (CH), 127.7
(CH × 2), 127.9 (CH × 2), 128.47 (CH × 2), 128.51 (CH × 2),
129.6 (CH × 2), 131.5 (CH × 2), 138.8 (C), 139.2 (C), 139.4 (C);
FD-HRMS (m/z) calcd for C46H5979BrO8 [M+]: 818.3393, found:
818.3384.
(1H, m), 1.54-1.62 (1H, m), 1.70-1.84 (4H, m), 1.85-2.01 (3H, m),
2.04 (1H, brd, J = 13.8 Hz), 2.36-2.44 (1H, m), 2.70-2.77 (1H, m),
2.86 (1H, brdt, J = 1.9, 8.9 Hz), 3.04 (1H, dd, J = 4.7, 9.2 Hz),
3.14-3.20 (1H, m), 3.27 (1H, brd, J = 9.1 Hz), 3.28-3.36 (1H, m),
3.34 (3H, s), 3.32-3.40 (1H, m), 3.46-3.53 (1H, m), 3.55 (1H, brt,
J = 9.3 Hz), 3.60 (1H, brd, J = 2.3 Hz), 3.65-3.72 (2H, m), 3.77
(2H, t, J = 6.2 Hz), 4.07 (1H, brddd, J = 5.2, 9.2, 11.3 Hz), 4.11
(1H, d, J = 11.6 Hz), 4.40 (1H, d, J = 11.6 Hz), 4.40 (2H, s), 4.51
(2H, s), 6.78 (2H, d, J = 9.0 Hz), 6.86 (2H, d, J = 9.0 Hz), 7.07-
7.23 (10H, m), 7.30-7.35 (4H, m); 13C NMR (125 MHz, C6D6,
13CC5D6 as 128.0 ppm)  14.4 (CH3), 15.9 (CH3), 20.2 (CH3), 25.7
(CH2), 26.6 (CH3), 28.6 (CH), 29.9 (CH2), 39.3 (CH2), 40.4 (CH2),
40.8 (CH), 41.5 (CH), 42.7 (CH), 44.4 (CH2), 55.2 (CH3), 68.6
(CH2), 71.3 (CH2), 71.8 (CH2), 72.8 (CH2), 73.3 (CH2), 74.8 (CH),
78.5 (CH), 79.6 (CH), 80.2 (CH), 81.2 (CH), 82.2 (CH), 82.5
(CH), 85.3 (CH), 85.6 (CH), 87.6 (CH), 115.0 (CH  2), 115.7
(CH  2), 121.5 (C), 127.5 (CH), 127.6 (CH), 127.7 (CH  2),
127.9 (CH  2), 128.48 (CH  2), 128.49 (CH  2), 129.7 (CH 
2), 131.6 (CH  2), 138.7 (C), 139.2 (C), 139.4 (C), 153.8 (C),
154.4 (C); FD-HRMS (m/z) calcd for C53H6779BrO9 [M+]:
926.3968, found: 926.3960.
32. (a) Concepción, J. I.; Francisco, C. G.; Hernández, R.; Salazar, J.
A.; Suárez, E. Tetrahedron Lett. 1984, 25, 1953; Reviews
involving the oxidative formation of spiroacetals, see: (b) Perron,
F.; Albizati, K. F. Chem. Rev. 1989, 89, 1617; (c) Brimble, M. A.;
Farès, F. A. Tetrahedron 1999, 55, 7661; See, also: (d) Čeković, Ž.
Tetrahedorn, 2003, 59, 8073.
33. Martín, A.; Salazar, J. A., Suárez, E. J. Org. Chem. 1996, 61,
3999.
34. Uehara, H.; Oishi, T.; Inoue, M.; Shoji, M.; Nagumo, Y.; Kosaka,
M.; Le Brazidec, J.-Y.; Hirama, M. Tetrahedron 2002, 58, 6493.
35. Spectral data of 38: [α]D24 –18.3 (c 0.109, CHCl3); IR (neat) 
3461, 3060, 3029, 2923, 2852, 1730, 1656, 1602, 1515, 1496,
1454, 1374, 1330, 1286, 1261, 1177, 1102, 1073, 1026, 976, 942,
868, 845, 805, 748, 699 cm–1; 1H NMR (500 MHz, C6D6, C6HD5
as 7.15 ppm) δ 0.87 (3H, d, J = 6.7 Hz), 1.00 (3H, d, J = 7.1 Hz),
1.16 (3H, d, J = 6.3 Hz), 1.17 (3H, d, J = 7.5 Hz), 1.30-1.48 (2H,
m), 1.54-1.64 (1H, m), 1.64-1.80 (5H, m), 1.84-1.93 (4H, m), 2.01
(1H, brtd, J = 2.5, 13.9 Hz), 2.32-2.39 (1H, m), 2.72 (1H, brtd, J =
4.8, 12.3 Hz), 2.99 (1H, dd, J = 5.6, 9.3 Hz), 3.12 (1H, dt, J = 2.9,
9.4 Hz), 3.25-3.43 (3H, m), 3.47-3.56 (1H, m), 3.64-3.75 (4H, m),
3.77 (1H, brs), 3.88 (1H, brdd, J = 1.4, 9.4 Hz), 3.93 (1H, ddd, J =
5.1, 9.3, 11.2 Hz), 4.12 (1H, d, J = 11.5 Hz), 4.41 (1H, d, J = 11.5
Hz), 4.42 (2H, s), 7.06-7.25 (8H, m), 7.35 (2H, brd, J = 7.6 Hz);
13C NMR (125 MHz, CDCl3, 13CDCl3 as 77.0 ppm) δ 13.4 (CH3),
15.7 (CH3), 19.7 (CH3), 24.3 (CH2), 26.7 (CH3), 28.1 (CH), 34.9
(CH2), 38.5 (CH), 39.5 (CH2), 39.9 (CH2), 42.1 (CH), 42.2 (CH),
44.2 (CH2), 67.6 (CH2), 71.4 (CH2), 71.7 (CH), 72.1 (CH2), 73.4
(CH2), 75.7 (CH), 77.2 (CH), 78.6 (CH), 79.0 (CH), 80.6 (CH),
82.7 (CH), 85.5 (CH), 86.4 (CH), 108.7 (C), 127.4 (CH), 127.60
(CH), 127.61 (CH × 2), 127.9 (CH × 2), 128.29 (CH × 2), 128.33
(CH × 2), 138.3 (C), 138.5 (C); FD-HRMS (m/z) calcd for
C39H54O8 [M+]: 650.3819, found: 650.3809.
30. Fukuyama, T.; Laud, A. A.; Hotchkiss, L. M. Tetrahedron Lett.
1985, 26, 6291.
31. Spectral data of 36: [α]D27 –16.7 (c 0.700, CHCl3); IR (neat) ν
3063, 3030, 2923, 2854, 1731, 1488, 1455, 1373, 1331, 1263,
1176, 1100, 1072, 1027, 1012, 975, 942, 921, 804, 735, 697 cm–1;
1H NMR (500 MHz, C6D6, C6HD5 as 7.15 ppm) δ 0.88 (3H, d, J =
6.7 Hz), 1.00 (3H, d, J = 7.1 Hz), 1.11 (3H, d, J = 7.6 Hz), 1.19
(3H, d, J = 6.3 Hz), 1.39-1.50 (2H, m), 1.54-1.62 (1H, m), 1.69-
1.82 (5H, m), 1.85-1.98 (3H, m), 2.02 (1H, td, J = 2.4, 14.0 Hz),
2.35-2.43 (1H, m), 2.74 (1H, brtd, J = 4.8, 12.3 Hz), 3.04 (1H, dd,
J = 4.8, 9.3 Hz), 3.14 (1H, dt, J = 2.8, 9.6 Hz), 3.29-3.39 (2H, m),
3.48-3.53 (1H, m), 3.50 (2H, br-d, J = 3.0 Hz), 3.61 (1H, brt, J =
9.7 Hz), 3.65-3.72 (4H, m), 3.95 (1H, br-dd, J = 0.7, 9.5 Hz), 4.07
(1H, ddd, J = 5.1, 9.3, 11.2 Hz), 4.11 (1H, d, J = 11.6 Hz), 4.40
(1H, d, J = 11.6 Hz), 4.41 (2H, s), 4.46 (1H, d, J = 12.6 Hz), 4.50
(1H, d, J = 12.6 Hz), 7.06-7.23 (10H, m), 7.30 (2H, d, J = 8.4 Hz),
7.34 (2H, brd, J = 7.6 Hz); 13C NMR (125 MHz, C6D6, 13CC5D6 as
128.0 ppm) δ 13.6 (CH3), 16.2 (CH3), 20.1 (CH3), 24.7 (CH2),
26.6 (CH3), 28.6 (CH), 35.3 (CH2), 39.0 (CH), 39.3 (CH2), 40.4

7
Development of a practical synthetic route to the
C42-C52 segment of ciguatoxin 3C
Stereoselective construction of the vicinal dimethyl
branching at C47-48 by chirality transferring
Ireland-Claisen rearrangement
Stereoselective formation of a γ-hydroxy δ-lactone
from an epoxy ester by a one-pot, three-step
cyclization process