Convergent synthesis of the IJKLM-ring part of ciguatoxin CTX3C

Article abstract of DOI:10.1016/j.tetlet.2005.09.164

Convergent synthesis of the IJKLM-ring part (2) of ciguatoxin CTX3C has been achieved from the I-ring and the L-ring parts (4 and 5) in total eight steps in 27% overall yield. The carbanion derived from 4, stabilized by a dimethyldithioacetal S-oxide grou

Full text of DOI:10.1016/j.tetlet.2005.09.164

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8285–8288
Convergent synthesis of the IJKLM-ring part of ciguatoxin CTX3C
Daisuke Domon, Kenshu Fujiwara,* Akio Murai, Hidethoshi Kawai and Takanori Suzuki
Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Received 2 September 2005; revised 22 September 2005; accepted 28 September 2005
Available online 17 October 2005
Abstract—Convergent synthesis of the IJKLM-ring part (2) of ciguatoxin CTX3C has been achieved from the I-ring and the L-ring
parts (4 and 5) in total eight steps in 27% overall yield. The carbanion derived from 4, stabilized by a dimethyldithioacetal S-oxide
group, was readily reacted with aldehyde 5 to give an adduct, which was facilely transformed into the corresponding a,e-dihydroxy
ketone 3. The JK-ring formation from 3 under reductive conditions followed by oxidative M-ring cyclization efficiently led to the
pentacyclic ether 2. Improved synthesis of 6, a synthetic intermediate for 4, was also established.
ꢀ 2005 Elsevier Ltd. All rights reserved.
CTX3C (1)1 was isolated as a congener of ciguatoxin
(CTX)2 from cultured dinoflagellate Gambierdiscus toxi-
cus by the Yasumoto group. It shows potent neurotoxi-
city [ip LD50 (mouse): 1.3 lg/kg] by strong binding to
voltage-sensitive sodium channels.3 Its unique ladder-
shaped polycyclic ether structure and strong bioactivity
have attracted the attention of many synthetic chem-
ists.4,5 In the course of our studies directed toward the
total synthesis of ciguatoxins,6 we have developed a gen-
eral method for the convergent construction of X/6/7/X
ring systems and applied the method to the synthesis of
the ABCDE-ring part of 1.6k Herein, we describe an effi-
cient synthesis of the IJKLM-ring part (2)7 of 1 based on
our established methodology.6g
be a precursor of 4, was previously synthesized from
aldehyde 8 in total 17 steps,6h we also envisioned an
alternative route to 6 from 8 via 7, including a two-step
ring-closing olefin metathesis (RCM)/stereoselective
hydrogenation process, in order to improve the effi-
ciency of the I-ring synthesis.
The synthesis of 4, which includes the improved route to
6 from 8, is shown in Scheme 2. Stereoselective methal-
lylation of 8 by treatment with methallyltributyltin and
dichlorodiisopropoxytitanium afforded homoallyl alco-
hol 9 as a major product (89%) along with a small
amount of 34-epi-9 (11%).11 After deprotection of the
TBS groups of 9 followed by oxidative cleavage, the
resulting dialdehyde was reduced to triol 10 (85% overall
yield). The 1,3-diol part of 10 was selectively protected
as phenyl boronate to give alcohol 11 in quantitative
yield, which was converted to diol 12 by a three-step
process [(i) Dess–Martin oxidation;12 (ii) Wittig reac-
tion; (iii) removal of the phenyl boronate group] (67%
overall yield). The primary hydroxy group of 12 was
selectively protected as its TBDPS ether to give diene
7 in 90% yield. Ring closure of 7 in refluxing 1,2-dichlo-
roethane by GrubbsÕ second-generation ruthenium cata-
lyst13 afforded olefin 13 (82% yield), which was
hydrogenated stereoselectively using CrabtreeÕs cata-
lyst14 to give eight-membered ether 6 in 80% yield
(dr >20:1).6h Thereby, the improved synthesis of 6 from
8 was achieved in 10 steps in overall 34% yield.15 Con-
version of 6 to diol 14 was performed through a three-
step protection/deprotection sequence [(i) removal of
the TBDPS group; (ii) protection of the resulting diol
as the benzyl ether; and (iii) removal of the benzylidene
We planned the synthesis of 2 from the I-ring part 4 and
the L-ring part 56n via the same route as that previously
established in the IJKL-ring model (Scheme 1).6g The
dimethyldithioacetal mono-S-oxide group of 4 would
be deprotonated facilely by an appropriate amide base
to give an acyl anion equivalent,8 which would be read-
ily coupled with aldehyde 5. The resulting adduct would
be transformed to the corresponding a,e-dihydroxy
ketone 3. The subsequent reductive hydroxy-ketone
cyclization reactions9 would construct the JK-ring part.
The M-ring would be constructed through an intramo-
lecular hydrogen abstraction–cyclization process at the
final stage.10 Although the I-ring part 6, which would
Keywords: Ciguatoxin CTX3C; Natural product synthesis; Acyl anion
equivalent; Reductive etherification; Spirocyclic acetal formation.
*
Corresponding author. Tel.: +81 11 706 2701; fax: +81 11 706
4924; e-mail: fjwkn@sci.hokudai.ac.jp
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.164

8286
D. Domon et al. / Tetrahedron Letters 46 (2005) 8285–8288
Me
H
H
Me
RCM and
HO
O
Ph
H
Me
H
Stereoselective
Hydrogenation
O
H
H
Me
L
I
O
H
K
O
H
H
HO
H
O
H
G
J
Me
O
OH
H
H
H
H
H
H
O
O
H
H
32 H
O
B
E
H
H
O
H
O
Ph
F
OTBDPS
7
H
O
D
A
O
C
O
O
O
H
H
H
O
H
OHC
O
O
52
H
HO
O
O
M
Me
H
OH
Ciguatoxin CTX3C (1)
Me
TBSO
O
Ph
OTBDPS
TBSO
6
α,ε-Dihydroxy Ketone
8
Reductive Etherification
Formation
Me
HO
Spirocyclic Acetal
Formation
HO
TBDPSO
Me
Me
Me
NAPO
Me
Me
OBn
H
O
L
OBn
OBn
O
H
H
ONAP
52
O
J
OHC
52
O
M
K
O
L
I
41
42
I
BnO
BnO
BnO
BnO
+
SMe
O
O
O
HO
Me
O
O
H
H
MeS
O
TBSO
H
Me
Me
Reductive Etherification
Scheme 1. Synthetic plan for the IJKLM-ring part (2) of CTX3C (1).
Me
32
BnO
NAP: (2-Naphthyl)methyl
Me
BnO
32
Me
3
4
2
5
acetal group] (91% overall yield). Since diol 14 was
obtained as colorless plates (mp 63–64 ꢁC), the structure
of 14 was established by X-ray crystallographic analysis
(Fig. 1).16 Diol 14 was treated with 2-naphthaldehyde to
produce naphthylmethylene acetal 15 (93% yield), which
was cleaved regioselectively using LiAlH4–AlCl3 to give
primary alcohol 16 exclusively in 85% yield.17 Transfor-
mation of 16 into the corresponding triflate ester and the
subsequent substitution by the carbanion generated
from methylthiomethyl methyl sulfoxide afforded 4 in
84% yield. Thus, the I-ring part 4 was synthesized from
8 in 17 steps in 18% overall yield.
Me
b, c
Me
H
H
H
H
34
O
O
d
a
HO
HO
O
HO
O
8
O
O
Ph
TBSO
O
Ph
HO
10
TBSO
9
OH
H
H
Me
Me
O
Ph
O
Ph
e, f, g
H
H
i
R1O
R2O
O
O
B
O
H
O
H
H
H
Ph
O
12: R1=R2=H
11
h
7: R1=H, R2=TBDPS
Construction of the IJKLM-ring part 2 is depicted in
Scheme 3. Deprotonation of 4 with LDA followed by
the reaction with 56n (0.19 equiv) produced 17 as a mix-
ture of diastereomers (98% yield from 5, 81% recovery
of 4). The TBS, TBDPS, and methylthio methylsulfinyl
acetal groups of 17 were removed under acidic condi-
tions to give 3 (69% yield), which was cyclized by the
treatment with Et3SiH in the presence of TMSOTf into
18 as the sole stereoisomer in 73% yield.9 After the
Me
OH
Me
H
O
Ph
k, l, m
n
j
6
OH
O
BnO
HO
O
O
H
BnO
OTBDPS
13
14
Me
Me
H
H
O
Np
ONAP
o
p, q
O
OH
O
4
BnO
BnO
BnO
BnO
O
Np: 2-Naphthyl
15
16
Scheme 2. Synthesis of the I-ring part 4. Reagents and conditions: (a)
Bu3SnCH2C(CH3)CH2, TiCl2(OiPr)2, CH2Cl2, ꢀ78 ꢁC, 2 h, 9: 89%, 34-
epi-9: 11%; (b) TBAF, THF, 23 ꢁC, 12 h; (c) NaIO4, 1,4-dioxane–H2O
(3:1), 23 ꢁC, 1 h, then NaBH4, MeOH, 0 ꢁC, 1 h, 85% from 8; (d)
PhB(OH)2, PhH, 23 ꢁC, 30 min, 100%; (e) DMPI, CH2Cl2, 23 ꢁC, 21 h;
(f) Ph3PCH3Br, NHMDS, THF, 23 ꢁC, 1 h, ꢀ78 ! 23 ꢁC, 2 h; (g)
H2O2, EtOAc, 23 ꢁC, 1 h, 67% from 10; (h) TBDPSCl, imidazole,
DMF, 23 ꢁC, 30 min, 90%; (i) (H2IMes)(PCy3)Cl2RuCHPh, (CH2Cl)2,
reflux, 82%; (j) H2, [(cod)(py)(Cy3P)Ir]PF6, CH2Cl2, 0 ꢁC, 5 h, 80%; (k)
TBAF, THF, 23 ꢁC, 30 min; (l) BnBr, tBuOK, TBAI, THF, 23 ꢁC,
30 min; (m) ethanedithiol, BF3Et2O, CH2Cl2, ꢀ20 ꢁC, 30 min, 91%
from 6; (n) 2-naphthaldehyde, PPTS, benzene, reflux, 12 h, 93%; (o)
LiAlH4, AlCl3, CH2Cl2–Et2O (1:1), 23 ꢁC, 2 h, 85%; (p) Tf2O, 2,6-
lutidine, CH2Cl2, ꢀ20 ꢁC, 30 min; (q) MeSCH2S(O)Me, NHMDS,
THF, ꢀ20 ꢁC, 15 min, 84% from 16.
Figure 1. ORTEP diagram of 14.

D. Domon et al. / Tetrahedron Letters 46 (2005) 8285–8288
8287
TBDPSO
OBn
HO
HO
Me
Me
HO
Me
HO
NAPO
Me
NAPO
Me
NAPO
O
Me
OBn
O
OBn
H
HO
41
a
b
c
42
O
O
4
41
46
46
SMe
BnO
BnO
BnO
BnO
5
BnO
BnO
O
HO
O
O
O
H
H
H
MeS
TBSO
Me
Me
Me
Me
Me
Me
O
17
3
18
d
NOE
TBDPSO
OBn
H
TBDPSO
OBn
H
HO
Me
HO
Me
NAPO
Me
Me
HO
Me
Me
OBn
H
H
H
O
O
h
g
e, f
38
42
38
42
38
42
O
O
O
2
41
BnO
BnO
49
46
BnO
BnO
BnO
BnO
O
O
O
O
H
O
O
H
H
H
H
H
H
NOE
H
Me
H
Me
Me
Me
Me
Me
21
19
20
Scheme 3. Synthesis of the IJKLM-ring part 2. Reagents and conditions: (a) 4, LDA, THF, ꢀ20 ꢁC, 15 min, then 5, ꢀ78 ꢁC, 30 min, 98%; (b) PTS,
MeOH, 23 ꢁC, 30 min, 69%; (c) TMSOTf, Et3SiH, CH2Cl2, 0 ꢁC, 30 min, 73%; (d) TBDPSCl, imidazole, DMF, 23 ꢁC, 30 min, 87%; (e) (COCl)2,
DMSO, Et3N, CH2Cl2, ꢀ78 ꢁC, 10 min; (f) DDQ, CH2Cl2—pH 7 buffer (10:1), 23 ꢁC, 10 min; (g) TMSOTf, Et3SiH, CH2Cl2, 0 ꢁC, 30 min, 86% from
19; (h) PhI(OAc)2, I2, hm, cyclohexane, 23 ꢁC, 3 h, then CSA, MeOH, 23 ꢁC, 5 h, 73%.
protection of the primary hydroxy group of 18 as its
TBDPS ether (87% yield), oxidation and the subsequent
deprotection of the NAP group with DDQ afforded
hydroxy-ketone 20. Reductive cyclization of 20 with the
concomitant detachment of the TBDPS group produced
tetracyclic ether 2118 (86% overall yield). The presence
of NOE (H41/H46 and H38/H42) in 21 confirmed that
the newly formed stereocenters at the C41 and C42 posi-
tions had the desired stereochemistry. With the IJKL-
ring part 21 in hand, oxidative radical cyclization of
the M-ring was performed. Irradiation of a mixture of
21, PhI(OAc)2, and iodine in cyclohexane with a 60 W
incandescent lamp successfully produced a 1:1 mixture
of spirocyclic acetal 2 and its C49 epimer.10 When the
diastereomeric mixture was exposed to CSA in MeOH
in order to perform isomerization, the spirocyclic acetal
2 was given as the sole product in 73% yield. The spec-
tral data (1H NMR and 13C NMR) and optical rotation
graphic Data Center as supplementary publication num-
ber CCDC 282748. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK [fax: +44 (0)1223
336033 or e-mail: deposit@ccdc.cam.ac.uk].
Acknowledgements
We are grateful to Professor Masahiro Hirama and Pro-
fessor Masayuki Inoue (Tohoku University), for kindly
1
providing H NMR, 13C NMR spectra of compound 2.
We also thank Mr. Kenji Watanabe and Dr. Eri Fuku-
shi (GC–MS and NMR Laboratory, Graduate School
of Agriculture, Hokkaido University), for the measure-
ments of mass spectra. This work was supported by a
Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science, and Technology
of Japanese Government.
23
29
{½aꢁD ꢀ39.0 (c 0.070, CHCl3); Lit.: ½aꢁD ꢀ41.2 (c 0.807,
CHCl3)4d} of 2 agreed well with those of the literature.4d
Thus, the I- and L-ring parts (4 and 5) were conver-
gently assembled into the IJKLM-ring part 2 in eight
steps in 27% overall yield.
References and notes
1. Satake, M.; Murata, M.; Yasumoto, T. Tetrahedron Lett.
1993, 34, 1975.
In conclusion, convergent synthesis of the IJKLM-ring
part (2) of ciguatoxin CTX3C has been achieved from
the I-ring and the L-ring parts (4 and 5). The carbanion
derived from 4, stabilized by a dimethyldithioacetal S-
oxide group, was readily reacted with the aldehyde
group of 5. The resulting adduct 17 was facilely trans-
formed to the corresponding a,e-dihydroxy ketone 3,
which was efficiently transformed into the pentacyclic
ether 2 by reductive etherification constructing the
JK-ring part and the subsequent oxidative M-ring cycli-
zation. Further studies toward the total synthesis of
ciguatoxin CTX3C are now in progress in this laboratory.
2. (a) Scheuer, P. J.; Takahashi, W.; Tsutsumi, J.; Yoshida,
T. Science 1967, 155, 1267; (b) Murata, M.; Legrand, A.
M.; Ishibashi, Y.; Fukui, M.; Yasumoto, T. J. Am. Chem.
Soc. 1990, 112, 4380; (c) Satake, M.; Morohashi, A.;
Oguri, H.; Oishi, T.; Hirama, M.; Harada, N.; Yasumoto,
T. J. Am. Chem. Soc. 1997, 119, 11325; (d) Yasumoto, T.
Chem. Rec. 2001, 1, 228.
3. (a) Anger, T.; Madge, D. J.; Mulla, M.; Riddal, D. J. Med.
Chem. 2001, 44, 115; (b) Catterall, W. A. Neuron 2000, 26,
13; (c) Dechraoui, M.-Y.; Naar, J.; Pauillac, S.; Legrand,
A.-M. Toxicon 1999, 37, 125; (d) Lombet, A.; Bidard, J.-N.;
Lazdunski, M. FEBS Lett. 1987, 219, 355.
4. Total synthesis of CTX3C: (a) Hirama, M.; Oishi, T.;
Uehara, H.; Inoue, M.; Maruyama, M.; Oguri, H.; Satake,
M. Science 2001, 294, 1904; (b) Inoue, M.; Uehara, H.;
Maruyama, M.; Hirama, M. Org. Lett. 2002, 4, 4551; (c)
Maruyama, M.; Inoue, M.; Oishi, T.; Oguri, H.; Ogasa-
wara, Y.; Shindo, Y.; Hirama, M. Tetrahedron 2002, 58,
Supplementary data
Crystallographic data (excluding structure factors) of 14
have been deposited with the Cambridge Crystallo-

8288
D. Domon et al. / Tetrahedron Letters 46 (2005) 8285–8288
´
´
1835; (d) Uehara, H.; Oishi, T.; Inoue, M.; Shoji, M.;
Nagumo, Y.; Kosaka, M.; Le Brazidec, J.-Y.; Hirama, M.
Tetrahedron 2002, 58, 6493; (e) Kobayashi, S.; Takahashi,
Y.; Komano, K.; Alizadeh, B. H.; Kawada, Y.; Oishi, T.;
Tanaka, S.-i.; Ogasawara, Y.; Sasaki, S.-y.; Hirama, M.
Tetrahedron 2004, 60, 8375; (f) Inoue, M.; Yamashita, S.;
Tatami, A.; Miyazaki, K.; Hirama, M. J. Org. Chem.
2004, 69, 2797; Reviews: (g) Inoue, M.; Hirama, M.
Synlett 2004, 57; (h) Inoue, M.; Miyazaki, K.; Uehara, H.;
Maruyama, M.; Hirama, M. Proc. Natl. Sci. Acad. U.S.A.
2004, 101, 12013; (i) Inoue, M.; Hirama, M. Acc. Chem.
Res. 2004, 37, 961.
10. Martın, A.; Salazar, J. A.; Suarez, E. J. Org. Chem. 1996,
61, 3999.
11. When this reaction was performed using the chiral Lewis
acid prepared in situ from Cl2Ti(OiPr)2 and (R)-BINOL,
no reaction occurred probably due to steric hindrance.
Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem.
Soc. 1993, 115, 8467.
12. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48,
4155.
13. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953.
14. (a) Crabtree, R. H.; Felkin, H.; Morris, G. E. J. Chem.
Soc., Chem. Commun. 1976, 716; (b) Crabtree, R. H.;
Felkin, H.; Fellebeen-Khan, T.; Morris, G. E. J. Organo-
met. Chem. 1979, 168, 183; (c) Crabtree, R. H.; Davis, M.
W. Organometallics 1983, 2, 681; (d) Stork, G.; Kahne, D.
E. J. Am. Chem. Soc. 1983, 105, 1072.
5. Recent synthetic studies on ciguatoxins by other groups:
(a) Kobayashi, S.; Alizadeh, B. H.; Sasaki, S.-y.; Oguri,
H.; Hirama, M. Org. Lett. 2004, 6, 751; (b) Baba, T.;
Takai, S.; Sawada, N.; Isobe, M. Synlett 2004, 603; (c)
Baba, T.; Huang, G.; Isobe, M. Tetrahedron 2003, 59,
6851; (d) Fuwa, H.; Fujikawa, S.; Tachibana, K.; Taka-
kura, H.; Sasaki, M. Tetrahedron Lett. 2004, 45, 4795;
(e) Takakura, H.; Sasaki, M.; Honda, S.; Tachibana, K.
Org. Lett. 2002, 4, 2771; (f) Bond, S.; Perlmutter, P.
Tetrahedron 2002, 58, 1779; (g) Candenas, M. L.; Pinto,
15. In our previous route,6h cyclic ether 6 was synthesized
from 8 in 17 steps in 34% overall yield. Although the
overall yields of both new and old routes were equal, this
new route, seven steps shorter than the previous route,
saved time and labor.
´
F. J.; Cintada, C. G.; Morales, E. Q.; Brouard, I.; Dıaz,
16. Crystal data of 14: C24H34O6, M 418.53, monoclinic P21
˚
˚
˚
´
´
M. T.; Rico, M.; Rodrıguez, E.; Rodrıguez, R. M.;
Perez, R.; Perez, R. L.; Martın, J. D. Tetrahedron 2002,
(No. 4), a = 12.785(6) A, b = 4.685(2) A, c = 19.814(9) A,
3
˚
´
´
´
b = 103.620(3), U = 1153.4(9) A , Dc (Z = 2) = 1.205 g/
58, 1921.
cm3, T = 153 K, l = 0.85 cmꢀ1. The final R value is 0.052
for 2616 independent reflections with I > 2rI and 271
parameters.
6. (a) Oka, T.; Fujiwara, K.; Murai, A. Tetrahedron 1996, 52,
12091; (b) Atsuta, H.; Fujiwara, K.; Murai, A. Synlett
1997, 307; (c) Oka, T.; Murai, A. Tetrahedron 1998, 54, 1;
(d) Oka, T.; Fujiwara, K.; Murai, A. Tetrahedron 1998, 54,
21; (e) Fujiwara, K.; Saka, K.; Takaoka, D.; Murai, A.
Synlett 1999, 1037; (f) Fujiwara, K.; Tanaka, H.; Murai,
A. Chem. Lett. 2000, 610; (g) Fujiwara, K.; Takaoka, D.;
Kusumi, K.; Kawai, K.; Murai, A. Synlett 2001, 691; (h)
Fujiwara, K.; Koyama, Y.; Doi, E.; Shimawaki, K.;
Ohtaniuchi, Y.; Takemura, A.; Souma, S.; Murai, A.
Synlett 2002, 1496; (i) Fujiwara, K.; Koyama, Y.; Kawai,
K.; Tanaka, H.; Murai, A. Synlett 2002, 1835; (j) Tanaka,
H.; Kawai, K.; Fujiwara, K.; Murai, A. Tetrahedron 2002,
58, 10017; (k) Fujiwara, K.; Goto, A.; Sato, D.; Ohtan-
iuchi, Y.; Tanaka, H.; Murai, A.; Kawai, H.; Suzuki, T.
Tetrahedron Lett. 2004, 45, 7011; (l) Takemura, A.;
Fujiwara, K.; Murai, A.; Kawai, H.; Suzuki, T. Tetrahe-
dron Lett. 2004, 45, 7567; (m) Takemura, A.; Fujiwara, K.;
Shimawaki, K.; Murai, A.; Kawai, H.; Suzuki, T. Tetra-
hedron 2005, 61, 7392; (n) Fujiwara, K; Domon, D.;
Ohtaniuchi, Y.; Takeda, S.; Takezawa, A.; Kawasaki, H.;
Murai, A.; Kawai, H.; Suzuki, T., preceding paper,
Tetrahedron Lett. 2005, 46, doi:10.1016/j.tetlet.2005.09.
163.
´
´
´
´
17. (a) Borbas, A.; Szabo, Z. B.; Szilagyi, L.; Beneyi, A.;
´
´
Liptak, A. Tetrahedron 2002, 58, 5723; (b) Liptak, A.;
´
´
´
Borbas, A.; Janossy, L.; Szilagyi, L. Tetrahedron Lett.
2000, 41, 4949.
23
18. Selected spectral data of 21: ½aꢁD ꢀ9.6 (c 0.13, CHCl3); 1H
NMR (400 MHz, C6D6, C6HD5 as 7.15 ppm): d 0.65 (3H,
d, J = 6.1 Hz), 1.01 (3H, d, J = 6.8 Hz), 1.11–1.14 (6H,
m), 1.14–1.23 (2H, m), 1.35–1.44 (1H, m), 1.55–1.81 (5H,
m), 1.87–1.95 (2H, m), 2.05 (1H, br d, J = 10.3 Hz), 2.48
(1H, m), 2.68 (1H, dt, J = 9.1, 3.3 Hz), 2.85 (1H, br t,
J = 4.0), 3.05 (1H, dd, J = 4.8, 9.2 Hz), 3.16 (1H, dt,
J = 1.5, 7.5 Hz), 3.28 (1H, m), 3.30 (1H, br d, J = 9.6 Hz),
3.37 (1H, dt, J = 1.5, 6.3 Hz), 3.59 (1H, t, J = 9.6 Hz),
3.48–3.74 (5H, m), 4.09 (1H, m), 4.12 (1H, d, J = 11.8 Hz),
4.35–4.46 (3H, m), 4.67 (1H, d, J = 12.0 Hz), 4.72 (1H, d,
J = 12.0 Hz), 7.04–7.65 (15H, m); 13C NMR (75 MHz,
C6D6, 13CC5D6 as 128.0 ppm): d 14.4 (CH3), 15.8 (CH3),
20.2 (CH3), 26.7 (CH3), 28.6 (CH), 28.8 (CH2), 30.0
(CH2), 39.5 (CH2), 40.3 (CH), 40.4 (CH2), 40.8 (CH), 42.7
(CH), 44.5 (CH2), 62.9 (CH2), 71.3 (CH2), 72.6 (CH2),
72.8 (CH2), 73.4 (CH2), 74.8 (CH), 78.4 (CH), 79.6 (CH),
80.3 (CH), 81.1 (CH), 82.5 (CH), 82.6 (CH), 85.2 (CH),
85.6 (CH), 87.6 (CH), 127.5 (CH), 127.61 (CH), 127.64
(CH), 127.7 (CH) · 4, 127.9 (CH) · 2, 128.3 (CH) · 4,
128.5 (CH) · 2, 139.2 (C), 139.5 (C), 139.6 (C); IR (film)
7. The IJKLM-ring part 2 was first reported by Hirama, see:
Ref. 4d.
8. (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.
9. Nicolaou, K. C.; Hwang, C.-K.; Nugiel, D. A. J. Am.
Chem. Soc. 1989, 111, 4136.
mmax 3447, 3061, 3029, 2922, 2853, 1496, 1453, 1436, 1375,
1336, 1285, 1274, 1259, 1071, 1028, 734, 697, 677; LR-
FDMS, m/z 743 ([M+], bp); HR-FDMS, calcd for
C46H62O8 [M+]: 742.4445, found: 742.4453.