Convergent synthesis of the HIJKLM ring fragment of ciguatoxin CTX3C

Article abstract of DOI:10.1016/S0040-4020(02)00660-9

Ciguatoxin CTX3C is a representative congener of the ciguatoxins, which are known to be the principal causative agents of ciguatera food poisoning. The structure of CTX3C spans more than 3nm and is characterized by 13 ether rings. To attain a practical construction of this molecule, efficient supplies of the structural fragments are crucial. Herein we report the convergent synthesis of the HIJKLM ring fragment and present a new carbonyl olefination protocol to cyclize the J ring using low-valent titanium.

Full text of DOI:10.1016/S0040-4020(02)00660-9

Tetrahedron 58 (2002) 6493–6512
Convergent synthesis of the HIJKLM ring fragment
of ciguatoxin CTX3C
Hisatoshi Uehara, Tohru Oishi,† Masayuki Inoue, Mitsuru Shoji, Yoko Nagumo, Masashi Kosaka,
*
Jean-Yves Le Brazidec and Masahiro Hirama
Department of Chemistry, Graduate School of Science, Tohoku University, and CREST, Japan Science and Technology Corporation (JST),
Sendai 980-8578, Japan
Received 27 March 2002; accepted 23 April 2002
In honor of Professor Yoshito Kishi on the occasion of his award of the prestigious Tetrahedron Prize
Abstract—Ciguatoxin CTX3C is a representative congener of the ciguatoxins, which are known to be the principal causative agents of
ciguatera food poisoning. The structure of CTX3C spans more than 3 nm and is characterized by 13 ether rings. To attain a practical
construction of this molecule, efficient supplies of the structural fragments are crucial. Herein we report the convergent synthesis of the
HIJKLM ring fragment and present a new carbonyl olefination protocol to cyclize the J ring using low-valent titanium. q 2002 Elsevier
Science Ltd. All rights reserved.
1. Introduction
the toxins and their biologically important activities.9–11
We planned a flexible and convergent synthetic route to
construct the highly complex polycyclic structure, in which
the final stage of the total synthesis would involve the
coupling of the ABCDE ring fragment 39e,f and the
HIJKLM ring fragment 4 with the simultaneous construc-
tion of the central FG ring system (Scheme 1).8,9d This
strategy is particularly suitable for the synthesis of various
ciguatoxins because the FG ring system is a common
structure to all ciguatoxins. In this full account, we report
the development of our synthetic route to the right half of
CTX3C (2), the HIJKLM ring moiety 4, useful for the total
synthesis of 2.8,12
Ciguatera is a major source of food poisoning in tropical and
subtropical regions, and often causes long-lasting health
problems with diverse symptoms.1 The causative toxins,
such as ciguatoxin (CTX, 1)2 and CTX3C (2),3 are produced
by the marine dinoflagellate Gambierdiscus toxicus and
accumulate in fish of many species through the food chain
(Scheme 1).4 More than 20 congeners of ciguatoxin have
been identified to date,5 and most exhibit potent toxicity
against mice (LD50¼0.25–4 mg/kg). Since ciguateric fish
look, taste, and smell normal, immunochemical methods for
detecting ciguatoxins prior to consumption have been in
demand for a long time.6 Biological studies have revealed
that ciguatoxins exert their toxicity through the activation of
voltage-sensitive sodium channels (VSSC).7 However,
detailed biological studies at the molecular level as well
as the preparation of anti-ciguatoxin antibodies have been
hampered by the extremely low availability of the causative
agents. Chemical synthesis is therefore the only plausible
solution. Here, we choose CTX3C (2) as the prime target for
total synthesis, which has very recently been achieved.8
2. Results and discussion
Retrosynthetically, the tetrahydropyran ring H in 4 should
be readily constructed by a 6-endo selective cyclization as
we have previously demonstrated for the HIJ ring system of
ciguatoxin (Scheme 1).13 The IJKLM ring system 5 can be
dissected into two parts, the I ring 6 and the LM ring 7,
which may be assembled back into 5 by construction of the
JK ring moiety. The J ring is expected to be built through the
ring-closing olefin metathesis reaction (RCM),14,15 provid-
ing for the subsequent reductive etherification of the K
ring.16 The 8-membered ring of 6 may be constructed by
RCM, deriving the C36–C40 carbons from D-2-deoxy-
ribose. It is expected that the stereocenters of C43 and C44
of 7 can be installed using a stereoselective crotylmetal
addition method.17 Retrosynthetic removal of the ketal M
ring of 7 further simplifies the intermediate to lactone 8. The
The chemical construction of ciguatoxins that possess 13
ether rings and 30 stereogenic centers has received
considerable attention due to the interesting structure of
Keywords: intramolecular carbonyl olefination; low-valent titanium
complex; ring-closing metathesis; polyether; ciguatoxin; CTX3C.
*
Corresponding author. Tel.: þ81-22-217-6563; fax: þ81-22-217-6566;
e-mail: hirama@ykbsc.chem.tohoku.ac.jp
Present address: Department of Chemistry, Graduate School of Science,
Osaka University, Osaka 560-0043, Japan.
†
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00660-9

6494
H. Uehara et al. / Tetrahedron 58 (2002) 6493–6512
Me
H
HO
H
J
Me
O
O
Me
I
H
O
H
H
H
G
OH
H
H
(
)
n
O
O
H
H
H
H
H
H
H
H
K
O
E
O
B
H
F
H O
H
O
D
C
O
O
O
M
A
L
H
H
H
O
H
Me
R1
Ciguatoxin (1) : R1 =
OH
Me
R2
, R2 = OH, n = 0
HO
OH
coupling?
Me
CTX3C (2) : R1, R2 = H, n = 1
36
H
H
J
Me
O
Me
43
H
I
O
H
H
H
H
H
H
O
H
H
OBOM
O
O
E
O
B
TIPDS
H
H
H
32
K
40 H O
HO
A
C
O
D
O
O
O
H
H
O
47L
H
O
49M
H
OBn
4
Me
3
Me
RCM
crotyl addition
Me
Me
RCM
Me
esterification
38 OH
HO
OBn
H
O
L
H
H
H
Me OBn
O
J
H
O
43
O
M
coupling?
K
44
BnO
BnO
O
I
M
I
BnO
BnO
L
O
39
O
H
O
O
H
H
Me
H
H
MOMO
Me
Me
reductive
6
7
5
Me
etherification
Ireland-Claisen
rearrengement
Me
O
H
O
OH
O
L
O
OR
48
BnO
HO
39
MeO
38
BnO
48
Me
HO
BnO
Me
47
47
Me
OH
Me
10: R=COEt
11: R=H
D-2-deoxyribose
8
9
Scheme 1. Structure of ciguatoxins and synthetic strategy for the total synthesis of CTX3C. Bn¼benzyl; BOM¼benzyloxy methyl; MP¼p-methoxyphenyl;
MPM¼p-methoxybenzyl; RCM¼ring closing olefin metathesis; TIPDS¼tetraisopropyl disiloxyl.
contiguous dimethyl groups of 8 will then correspond to the
product of the Ireland–Claisen rearrangement (10!9).18 In
the synthetic direction, successive intramolecular reactions
to 9 are expected to reliably introduce the stereocenters into
8. Thus, the known allylic alcohol 1119 was chosen as an
appropriate starting material for the synthesis of the LM ring
portion.
chromatographically separated from other 3 diastereomers
(62% yield).21 Conversion of iodolactone 13 to d-lactone 8
was achieved through saponification of 13 followed by
treatment with acetic acid at 608C, affording the desired
product in 72% yield along with g-lactone 16 in 18% yield.
The isolated g-lactone 16 was equilibrated under the same
conditions to provide a mixture of 8 (41%) and 16 (51%).
For large-scale synthesis (100 g), it was more convenient to
prepare 8 without the separation of the mixture of 13–15
(39% yield from 9 and 12). The structure of 8 was
determined with the NOEs and the coupling constants
indicated in Scheme 2.
2.1. Synthesis of the LM ring fragment12a
As shown in Scheme 2, synthesis of the L ring lactone 8
started from a glycidol derivative. The allylic ether 11,
prepared from benzyl-(S )-glycidol20 according to the
protocol of Ogasawara et al.,19 was converted to propionate
10 in 90% yield. Enol silyl ether formation from 10 at
2788C and subsequent warming to room temperature
resulted in the Ireland–Claisen rearrangement product,18
which was directly treated with diazomethane to yield a
mixture of the desired ester 9 and its C48-epimer 12 (3:1,
88% combined yield). Iodolactonization of this mixture
gave the desired lactone 13 as the major product, which was
The mechanism of conversion of iodolactone 13 to the L
ring lactone 8 is shown in Scheme 2. Hydroxy carboxylate
17, formed by saponification of 13, transforms to epoxide
18,22 which undergoes intramolecular attack by the
carboxylate group to give g-lactone 16 with the stereo-
chemical inversion of the C46 center. A second saponifica-
tion affords the dihydroxy carboxylate 19, acidic treatment
of which leads to g-lactone 16 and d-lactone 8. Since it was

H. Uehara et al. / Tetrahedron 58 (2002) 6493–6512
6495
Scheme 2. Reagents and conditions: (a) propionyl chloride, pyridine, 08C to rt, 90%; (b) LDA, TMSCl, THF-HMPA, 2808C to rt; (c) CH2N2, 88% (2 steps);
(d) I2, CH3CN, rt, 62%; (e) NaOH aq., EtOH, rt, then AcOH, 608C, 1 h. Bn¼benzyl; HMPA¼hexamethylphosphoramide; LDA¼lithium diisopropylamide;
TMS¼trimethylsilyl.
found that 8 isomerizes into its g-form 16 after extended
exposure to acid, 8 appears to be a kinetic product under
these conditions.
submitted to the RCM reaction with Grubbs catalyst14 to
provide the 8-membered cyclic ether 31 in 75% yield. The
ester of 31 was reduced by LiAlH4, and the newly formed
primary alcohol was protected selectively as its TBDPS
ether to give 32 (74%, 2 steps). The secondary alcohol of 32
was converted to ketone 33 by Swern oxidation. Stereo-
selective introduction of the C36-methyl group was
successfully achieved by conjugate addition of Me2-
Cu(CN)Li2 to enone 33, resulting in a single isomer 34 in
69% yield (2 steps). As shown in Fig. 1, the stereoselectivity
can be explained by examining the three-dimensional
structure of 33, where one face of the olefin is blocked by
the projecting H38. Removal of the TBDPS ether from 34
using TBAF buffered with AcOH, followed by stereoselec-
tive reduction with NaBH(OAc)3,26 led to diol 35 with the
correct stereochemistry (92% yield). Through these syn-
thetic procedures, over 10 g of 35 was provided.
The synthesis of the LM ring fragment 7 was continued as
illustrated in Scheme 3. After protection of the C46-alcohol
of 8 as its MOM ether, the addition of allyl magnesium
bromide to 20 introduced the carbon chain corresponding to
the M ring, to yield ketal 21. A hydroboration–oxidation
sequence on the terminal olefin of 21 followed by acid
treatment afforded the thermodynamically stable spiroketal
22 in 75% overall yield from 20. The liberation of the
primary alcohol of 22 by hydrogenolysis and subsequent
oxidation under Swern conditions led to the aldehyde 24.
Then, treatment of 24 with (R,R )-diisopropyl tartrate (Z)-
crotylboronate 2523 resulted in the stereoselective introduc-
tion of both the C43-methyl and C44-hydroxyl groups. After
benzylation of the newly formed secondary alcohol, 26 was
isolated as a single isomer in 52% yield over the 3 steps.
Finally, oxidative cleavage of the olefin of 26 and
subsequent oxidation provided the LM carboxylic acid 7
quantitatively.
Functional group manipulations of 35 were performed in
order to couple 35 with the LM ring fragment 7 (Scheme 4).
Benzyl protection of 35 and removal of the p-methoxy-
benzylidene acetal provided diol 37 in 83% overall yield (2
steps). The one-carbon homologation of 37 via two-step
sequence led to cyanide 39 in 84% yield. Finally, DIBAL-
reduction of nitrile 39 and Wittig olefination gave olefin 6
(Z/E¼4:1, 76%, 2 steps).
2.2. Synthesis of the I ring fragment12c
Synthesis of the 8-membered I ring moiety is illustrated in
Scheme 4. Although we have previously prepared the I ring
based on a ring-expansion method,24 a more practical route
has been developed based on an aldol–RCM strategy.9e,f,25
The Wittig reaction of D-2-deoxyribose and subsequent
protection of the 1,3-diol gave the p-methoxybenzylidene
acetal 27, which was converted to glycolate 28 by
O-alkylation with t-butyl bromoacetate. Aldol reaction of
the ester 28 with acrolein gave the adduct 29 as an epimeric
mixture of C34-alcohols (44%) along with 33S-diastereo-
mers 30 (44%). The chromatographically isolated 29 was
2.3. Construction of the J ring12b,c
Having synthesized both fragments, the I ring (6) and the
LM ring (7), we examined the coupling reaction and the
ensuing construction of the J ring (Scheme 5). We initially
planned to construct the J ring by cyclization using an ester
olefination–RCM sequence through the action of Tebbe
reagent,27 according to the method developed by Nicolaou
and co-workers.28 We coupled the I ring alcohol 6 with LM

6496
H. Uehara et al. / Tetrahedron 58 (2002) 6493–6512
OH
H
H
O
L
O
O
BnO
BnO
b
R1O
Me
46
MOMO
Me
Me
Me
21
8: R1=H
20: R1=MOM
a
c, d
H
O
H
O
OHC
O
O
R2O
f
MOMO
Me
MOMO
Me
Figure 1. Energy-minimized structure of 33 (MM2p, MacroModel Ver.
6.0). Protecting groups are replaced by methyl groups for clarity.
Me
Me
Me
24
22: R2=Bn
23: R2=H
e
CO2i-Pr
CO2i-Pr
O
O
significant amounts of the exo-enol ethers 43–45 were
produced. Despite extensive investigations, reproducible
conditions to form 42 could not be secured. Treatment of the
obtained mixture of exo-enol ethers (43, 44) with 41, the
Schrock catalyst (46),29 the Grubbs catalyst (47)14 or the N-
heterocyclic carbene (NHC)-Grubbs catalyst (48),30 did not
give the cyclized product 42,31 indicating that these RCM
catalysts could not induce the cyclization, presumably
because of steric hindrance around the exo-enol ether.
B
g, h
25
Me
OBn
H
Me
OBn
O
H
O
O
O
L
M
43 44
i, j
HO
O
Me
Me
MOMO
MOMO
Me
Me
26
7
Scheme 3. Reagents and conditions: (a) MOMCl, i-Pr2NEt, (CH2Cl)2,
508C, 95%; (b) CH2vCHCH2MgBr, THF, 2708C; (c) (Sia)2BH, THF, 08C,
then NaHCO3, H2O2; (d) CSA, (CH2Cl)2, rt, 75% (3 steps); (e) H2, 20%
Pd(OH)2/C, AcOEt, rt, 100%; (f) (COCl)2, DMSO, Et3N, CH2Cl2, 280 to
2608C; (g) 25, toluene, 280 to 2708C; (h) BnBr, NaH, DMF, THF, rt, 52%
(3 steps); (i) OsO4, NMO, t-BuOH, H2O, rt, then NaIO4, rt; (j) NaClO2,
NaH2PO4·2H2O, 2-methyl-2-butene, t-BuOH, H2O, rt, 99% (2 steps).
Bn¼benzyl; CSA¼10-camphorsulfonic acid; MOM¼methoxymethyl;
NMO¼4-methylmorpholine N-oxide; Sia¼1,2-dimethylpropyl.
The unsuccessful cyclizations of diene 44 suggested that the
intermediate for the 6-membered ring formation of our
substrate might not be the titanium alkylidene complex 49,
in contrast to the literature precedents (49!50!42, Scheme
6).28,31 There is the possibility that the desired product 42
may be obtained directly by carbonyl olefination of 51,
formed through the addition of the Tebbe reagent to the
olefin before exo-enol ether formation. In this mechanism,
the strong affinity between the titanium and the carbonyl
oxygen could favorably drive the reaction to give the
oxatitanacyclobutane 52, despite the steric hindrance,
leading to the product 42. From these considerations, it
carboxylic acid 7 by esterification to afford the olefinic ester
40 in 75% yield, followed by treatment with Tebbe reagent
(41) to produce the cyclic enol ether 42. The yield of 42
varied from 0 to 63%, and in the low-yield reactions,
O
OH
H
O
H
H
O
a, b
e
d
X
O
MP
HO
34
MP
HO
33R
MP
MP
O
R2
O
O
R1O
27: R1=H
O
OH
H
H
O
29
t-BuO2C
H
H
D-2-deoxyribose
31: R2=CO2t-Bu, X=H, OH
32: R2=CH2OTBDPS, X=H, OH
33: R2=CH2OTBDPS, X=O
f, g
h
c
28: R1=CH2CO2t-Bu
H
HO
34
O
33S
O
O
30
i
t-BuO2C
H
H
NOE
MeH
Me
Me
Me
O
H
36
H
BnO
BnO
R3O
R3O
O
BnO
OH
O
O
p, q
j, k
OH
I
m
MP
MP
O
O
O
R4
TBDPSO
BnO
O
O
H
H
H
H
H
H
H
H
37: R4=OH
38: R4=I
39: R4=CN
35: R3=H
36: R3=Bn
34
6: Z:E = 4:1
n
o
l
Scheme 4. Reagents and conditions: (a) Ph3PMeBr, t-BuOK, THF, 0–358C; (b) MPCH(OMe)2, CSA, CH2Cl2, reflux, 76% (2 steps); (c) t-BuO2CCH2Br, NaH,
THF, DMF, 08C to rt, 82%; (d) LDA, acrolein, THF, 2708C, 29: 44%, 30: 44%; (e) (PCy3)2Cl2RuvCHPh (10 mol%), CH2Cl2 (0.01 M), reflux, 24 h, 75%; (f)
LiAlH4, THF, 08C to rt; (g) TBDPSCl, Et3N, CH2Cl2, rt, 74% (2 steps); (h) (COCl)2, DMSO, Et3N, CH2Cl2, 280 to 2508C; (i) Me2Cu(CN)Li2, Et2O, 2808C,
69% (2 steps); (j) TBAF, AcOH, THF, rt, 90%; (k) NaBH(OAc)3, AcOH, CH3CN, 2408C to rt, 92%; (l) BnBr, NaH, THF, DMF, 08C to rt, quant.; (m)
TsOH·H2O, MeOH, H2O, rt, 83%; (n) I2, PPh3, imidazole, THF, 08C to rt, 87%; (o) NaCN, DMSO, 408C, 97%; (p) DIBAL, CH2Cl2, 280 to 2608C; (q)
Ph3PEtBr, t-BuOK, THF, 08C to rt, 76% (2 steps, Z/E¼4:1). Bn¼benzyl; CSA¼10-camphorsulfonic acid; Cy¼cyclohexyl; LDA¼lithium diisopropylamide;
MP¼p-methoxyphenyl; TBAF¼tetrabutylammonium fluoride; TBDPS¼t-butyldiphenylsilyl; TsOH¼p-toluenesulfonic acid.

H. Uehara et al. / Tetrahedron 58 (2002) 6493–6512
6497
Me
OBn
H
Me
Me
OBn
H
Me
H
H
O
H
H
O
AlMe2
Cp2Ti
O
O
O
J
O
Cl
41
a
6 + 7
O
BnO
BnO
BnO
Me
Me
b
O
H
O
H
MOMO
MOMO
Me
Me
BnO
42
40: Z:E = 4:1
Me
OBn
Me
41, 46,
H
H
H
O
O
O
47 or 48
i-Pr
CH3
i-Pr
Ph
PCy3
Mes
Cl
Mes
N
N
Ph
N
Cl
BnO
Me
Ph
O
H
F3C
F3C
Ru
MOMO
R
O
Ru
PCy3
Mo
Cl
Me
Cl
PCy3
47
BnO
O
43: R=H
F3C
F3C
44: R=Me
46
48
CH3
Me
Me
H
H
O
BnO
O
H
45
BnO
Scheme 5. Reagents and conditions: (a) DCC, DMAP, CSA, CH2Cl2, 358C, 1 d, 75%; (b) 41, THF, 608C, 42: trace–63%, 43–45: 18–70%.
Cp¼cyclopentadienyl; CSA¼10-camphorsulfonic acid; Cy¼cyclohexyl; DCC¼1,3-dicyclohexylcarbodiimide; DMAP¼p-(dimethylamino)pyridine;
Mes¼2,4,6-trimethylphenyl.
was anticipated that selective formation of the intermediate
51 would increase both the yield and reproducibility of the
cyclization. Very recently, Takeda et al. reported the
carbonyl olefination reaction of titanium carbenes, which
were selectively generated from bis(phenylthio)acetals by
the action of a low-valent titanium complex Cp2-
Ti[P(OEt)3]2 (see 53!51).32 In light of this, we modified
our initial strategy such that the dithioacetal 53 acts as the
precursor for 42.
generated the desired enol ether 42 in a reproducible
manner (52–67%).34 This novel methodology based on
intramolecular carbonyl olefination routinely supplies
multi-gram quantities of 42, and can be applied to a wide
variety of complex substrates.
2.4. Construction of the K ring12b,c
The next task in the synthesis was the stereocontrolled
construction of the K ring by reductive etherification
(Scheme 7).16 Hydroboration of 42 followed by Swern
oxidation produced the C42-epimeric ketones 57 and 58
(2–3:1), which were subsequently separated by silica gel
chromatography. Isomerization of the undesired ketone 57
was realized by using DBU in dichloromethane (57/
58¼1:1). After three cycles of isomerization, the desired
ketone 58 was obtained in 64% combined yield. The
subsequent step, transformation of ketone 58 to the 7-
membered methylketal 60, was found to be problematic. For
The modified synthetic route to 42 is shown in Scheme 7.
The secondary alcohol of 39 was protected as its TES ether
to afford 54. DIBAL reduction of the nitrile of 54 to the
aldehyde, followed by treatment with PhSSPh and Bu3P,33
gave rise to the dithioacetal 55 in 73% yield over 3 steps.
After removal of the TES group of 55, 56 was coupled with
the carboxylic acid 7 to give ester 53 in 76% yield. Fulfilling
our expectations, treatment of 53 with the low-valent
titanium complex Cp2Ti[P(OEt)3]2 in refluxing THF
Me
Me
Me
Me
H
H
Ti-carbene
formation
O
O
RCM
TiCp2
BnO
BnO
BnO
44
O
O
H
H
H
H
methylenation
TiCp2
BnO
49
50
Me
O
OBn
H
Me
Me
Me
OBn
H
H
O
H
H
O
O
O
O
O
BnO
BnO
BnO
BnO
Me
Me
O
O
H
MOMO
MOMO
H
H
Me
Me
40
42
Me
Me
Me
Me
H
H
Ti-carbene
formation
O
O
carbonyl
olefination
O
Me
Me
O
TiCp2
BnO
BnO
BnO
BnO
H
H
O
H
O
H
O
H
H
TiCp2
Cp2Ti[P(OEt)3]2?
51
52
O
BnO
BnO
O
H
SPh
53
PhS
Scheme 6. Mechanistic considerations of the J ring cyclization.

6498
H. Uehara et al. / Tetrahedron 58 (2002) 6493–6512
Me
Me
Me OBn
Me OBn
H
H
O
H
H
O
O
L
M
HO
O
O
OR1
R2
BnO
BnO
e
BnO
BnO
I
+
O
O
O
O
Me
MOMO
Me
H
H
H
H
MOMO
Me
Me
39: R1=H, R2=CN
7
PhS
SPh
a
b, c
d
53
54: R1=TES, R2=CN
55: R1=TES, R2=CH(SPh)2
56: R1=H, R2=CH(SPh)2
f
Me
Me OBn
H
H
H
H
O
O
O
42
Me
Me OBn
H
BnO
BnO
O
Me
57
O
H
H
O
MOMO
O
J
O
Me
g,h
i
BnO
Me
O
H
MOMO
H
Me
Me OBn
Me
Me OBn
Me
BnO
H
H
H
H
O
H
H
H
H
O
O
O
O
O
42
j
45
46
42
O
O
BnO
BnO
BnO
Me
59
Me
58
O
H
O
H
HO
MOMO
Me
Me
BnO
k
l
Me
Me
Me
Me
OR4
H
O
O
L
Me
Me
H
OBn
H
H
H
H
H
H
H
H
H
O
O
O
OBn
H
44
45
45
K
O
I
K
J
H
O
m
O
O
46
R3O
R3O
BnO
BnO
48
BnO
BnO
M
O
O
H
46
O
O
O
H
O
H
49
H
H
H
H
MeO
H
O
Me
Me
Me
Me
Me
Me
5: R3,R4=Bn
63: R3=p-BrBz, R4=H
Me
H
61
60
NOE
44,45=10.2 Hz
n,o
OH
45
46
O
49
J
HO
H
Me 62
Me
Scheme 7. Reagents and conditions: (a) TESOTf, 2,6-lutidine, CH2Cl2, 230 to 2208C, 86%; (b) DIBAL, CH2Cl2, 2708C; (c) PhSSPh, Bu3P, rt, 73% (2 steps);
(d) TBAF, THF, rt, 95%; (e) EDC·HCl, DMAP, CSA, 408C, 2 d, 76%; (f) Cp2Ti[P(OEt)3]2, THF, rt to reflux, 1 h, 52–67%; (g) BH3·THF, THF, 08C to rt,
NaOH, H2O2, 75%; (h) (COCl)2, DMSO, Et3N, CH2Cl2, 270 to 2408C, 58: 31%, 57: 57%; (i) DBU, CH2Cl2, rt (3 cycles), 58: 58%, 57: 12%; (j) TMSBr,
CH2Cl2, 270 to 2508C; (k) TfOH, CH(OMe)3, benzene, rt, 3 h, 60: ,50%, 61: ,40%; (l) TfOH, CH(OMe)3, hexane, rt, 20 h, 60: 84%; (m) Et3SiH, BF3·OEt2,
CH2Cl2, 250 to 2208C, 1 h, 71%; (n) H2, Pd(OH)2/C, AcOEt, MeOH, AcOH, rt, 99%; (o) p-BrBzCl, DMAP, Et3N, CH2Cl2, rt, 65%. Bn¼benzyl;
BOM¼benzyloxymethyl; Bz¼benzoyl; Cp¼cyclopentadienyl; DBU¼1,8-diazabicyclo[5.4.0]undec-7-ene; DIBAL¼diisobutylaluminum hydride; DMAP¼p-
(dimethylamino)pyridine; EDC¼1-(3-dimethylaminopropyl)-3-ethylcarbodiimide; TBAF¼tetrabutylammonium fluoride; TES¼triethylsilyl; Tf¼
trifluoromethanesulfonyl; TMS¼trimethylsilyl.
example, removal of the MOM group of 58 using TMSBr
provided the C46-alcohol 59, which when treated with
trimethyl orthoformate in the presence of TfOH gave 60
(,50%) along with a considerable amount of the 6-
membered methylketal 61 (,40%). The structure of 61
was determined from NOE experiments and coupling values
(Scheme 7), and it was revealed that the LM spiroketal
partially isomerized into the 5-5 spiroketal under acidic
conditions (59!62), with subsequent methyl ketal for-
mation affording 61. As it was anticipated that the spiroketal
isomerization could be suppressed without liberation of
C46–OH, direct methyl ketalization from the MOM-
protected 58 was pursued. This approach proved successful,
with the 7-membered ketal 60 obtained in good yield (84%)
by treatment of 58 with trimethyl orthoformate and TfOH in
hexane. The final reductive etherification of the methylketal
60 was realized by treatment with BF3·OEt2 (2 equiv.) in the
presence of Et3SiH at 2608C to 2208C. In this way, the
IJKLM ring fragment 5 was isolated in 71% yield. This
reductive etherification is particularly sensitive to the
reaction conditions: at higher reaction temperature
(.2108C) or with excess BF3·OEt2, reductive opening of
the C49-spiroketal occurred.
The stereochemistry of the IJKLM ring system 5 was
confirmed unambiguously by X-ray crystallography of the
bis-p-bromobenzoate 63 (Fig. 2),35 which was prepared by
debenzylation of 5 followed by acylation with p-bromo-
benzoyl chloride (Scheme 7).
2.5. Construction of the H ring12c
The final task in our synthesis of the HIJKLM ring system
was the attachment of the H ring to 5 using the acid-
catalyzed epoxide opening reaction as the key step (Scheme
8).13,36 All of the benzyl groups of 5 were first removed by
hydrogenolysis, and the resulting 1,3-diol was protected as
its p-methoxybenzylidene acetal 64 (76%, 2 steps). After
conversion of the remaining C44-alcohol of 64 to the BOM
ether 65, reductive cleavage of the benzylidene acetal with
DIBAL regioselectively afforded the MPM ether 66 (100%,
2 steps) without affecting other acetal functionality, such as
the C44-BOM ether or the C49-spiroketal. Mesylation of the
C32-primary alcohol of 66 and subsequent displacement
with cyanide yielded nitrile 67 in 91% over 2 steps. DIBAL
reduction of 67 gave an aldehyde, which was subsequently
treated with (carbethoxyethylene)triphenylphosphorane to

H. Uehara et al. / Tetrahedron 58 (2002) 6493–6512
6499
accomplished in 41% overall yield over 13 steps from the
IJKLM ring fragment 5.
3. Conclusion
Firstly, we established concise routes to the I ring fragment
56 and the LM ring fragment 7: the I ring 56 was constructed
via an aldol–RCM sequence, while the LM ring 7 was
prepared via Ireland–Claisen rearrangement followed by
successive emplacement of its requisite stereocenters. These
fragments were then coupled by esterification, and the JK
rings were built through a novel intramolecular carbonyl
olefination using the Takeda reagent Cp2Ti[P(OEt)3]2 to
give the J ring, followed by a reductive etherification
sequence to give the K ring. Finally, the synthesis of the full
HIJKLM ring system 4 was achieved by constructing the H
ring through a 6-endo-selective epoxide-opening reaction.
The longest linear sequence of this synthesis involves 37
steps from the known allylic alcohol 11, and the route
presented here is highly practical to supply material not only
for the total synthesis of CTX3C, but also for the
preparation of anti-ciguatoxin antibodies. Further studies
in the chemistry and biology of ciguatoxins are currently
underway in our laboratory.
Figure 2. ORTEP drawing of bis-p-bromobenzoate 63.
provide the a,b-unsaturated ester 68 (84% yield, 2 steps).
The ester 68 was then reduced to alcohol 69 in 95% yield.
Katsuki–Sharpless epoxidation37 of 69 at 2208C for 17 h
generated only 13% of the epoxy alcohol 70, while the
major product was the 6-membered diol 71 (52%), produced
via the 6-endo cyclization of 70 with simultaneous removal
of the MPM group. Interestingly, the 6-endo cyclization was
preferred over the 5-exo mode, presumably due to the
cation-stabilizing ability of the C30-tertiary carbon.38 In
contrast, similar epoxidation at 250 to 2408C gave epoxide
70 in 97% yield without the subsequent cyclization step.
The latter epoxidation procedure was therefore employed
for production of 70 for further transformation because of
the excellent chemical yield. Oxidation of 70 to its aldehyde
and subsequent Wittig methylenation gave 72 in 86% yield
(2 steps). Finally, treatment of 72 with DDQ in CH2Cl2–
H2O (20:1) led to the cleavage of the MPM ether, and in situ
cyclization of the resulting epoxy alcohol under the mild
acidic reaction conditions afforded the hexacyclic product 4
in 88% yield. Thus, the construction of the H ring was
4. Experimental
All reactions sensitive to air or moisture were carried out
under argon or nitrogen atmosphere in dry, freshly distilled
solvents under anhydrous conditions, unless otherwise
noted. THF was distilled sodium/benzophenone, diethyl
ether (Et2O) from LiAlH4, acetonitrile, benzene, dichloro-
ethane (CH2Cl)2, dichloromethane (CH2Cl2), diisopropyl-
amine, diisopropylethylamine (i-Pr2NEt), hexane, pyridine,
Me
Me
Me
Me
Me
Me
OR1
H
O
OBn
H
O
OBOM
H
H
H
H
H
H
H
H
O
O
O
H
O
44
a, b
d
H
O
O
O
O
49
MPMO
R2
49
BnO
BnO
O
O
O
H
O
O
H
O
H
H
H
H
MP
H
H
H
H
O
32
Me
Me
Me
Me
Me
Me
5
66: R2=OH
67: R2=CN
64: R1=H
65: R1=BOM
c
e,f
g,h
Me
Me
Me
Me
Me
OBOM
OBOM
H
H
H
H
H
Me
H
O
O
H
O
H
OBOM
O
J
H
O
O
H
O
j or k
O
n
I
MPMO
MPMO
R3
O
Me
K
O
H
Me
O
O
O
H
O
O
H
H
H
H
H
H
O
H
H
H
M
L
H
H
O
X
Me
Me
Me
Me
30
HO
Me
4
Me
l, m
Me
H
O
68: R3=CO2Et
69: R3=CH2OH
70: X=H, OH
72: X=CH2
Me
HO
i
30
H
HO
71
Scheme 8. Reagents and conditions: (a) Pd(OH)2/C, H2, AcOEt, MeOH, AcOH, rt; (b) MPCH(OMe)2, CSA, THF, rt, 76% (2 steps); (c) BOMCl, i-Pr2NEt,
(CH2Cl)2, 408C; (d) DIBAL, CH2Cl2, 280 to 2408C, 100% (2 steps); (e) MsCl, Et3N, (CH2Cl)2, 08C; (f) NaCN, 18-crown-6, DMF, 508C, 91% (2 steps); (g)
DIBAL, CH2Cl2, 280 to 2708C; (h) Ph3PvCMeCO2Et, toluene, rt, 84% (2 steps); (i) DIBAL, CH2Cl2, 2608C, 95%; (j) (2)-DET, Ti(Oi-Pr)4, TBHP, MS4 A,
CH2Cl2, 2208C, 17 h, 70: 13%, 71: 52%; (k) (2)-DET, Ti(Oi-Pr)4, TBHP, MS4A, CH2Cl2, 250 to 2408C, 3 h, 70: 97%; (l) SO3·Py, Et3N, DMSO, (CH2Cl)2,
rt; (m) Ph3PCH3Br, NaHMDS, THF, 08C, 86% (2 steps); (n) DDQ, CH2Cl2–H2O (20:1), rt, 7 h, 88%. Bn¼benzyl; BOM¼benzyloxymethyl; DET¼diethyl
tartrate; DDQ¼2,3-dichloro-5.6-dicyano-1,4-benzoquinone; DIBAL¼diisobutylaluminum hydride; HMDS¼bis(trimethylsilyl)amide; MP¼p-methoxyphe-
nyl; MPM¼p-methoxybenzyl; Ms¼methanesulfonyl; MS¼molecular sieves; TBHP¼t-butylhydroperoxide.

6500
H. Uehara et al. / Tetrahedron 58 (2002) 6493–6512
triethylamine (Et3N), and toluene from calcium hydride,
and DMF, DMSO and HMPA from calcium hydride under
reduced pressure. All other reagents were used as supplied
unless otherwise stated.
contained rearranged carboxylate, was acidified by 2 M
H2SO4, and extracted with EtOAc. To the solution of
rearranged carboxylic acid was added diazomethane at 08C
until the carboxylic acid was consumed. The mixture was
stirred overnight at rt, concentrated, and subjected to flash
column chromatography (hexane/EtOAc 1:0–5:1) to give a
mixture of the methyl esters 9 and 12 (3:1, 24.8 g,
94.5 mmol, 88% combined yield).
Analytical thin-layer chromatography (TLC) was per-
formed using E. Merck Silica gel 60 F254 pre-coated
plates. Column chromatography was performed using 100–
210 mm Silica Gel 60N (Kanto Chemical Co., Inc.), and for
flash column chromatography 40–50 mm Silica Gel 60N
(Kanto Chemical Co., Inc.) was used.
4.1.3. Iodolactone 13. A solution of the methyl esters 9 and
12 (3:1, 994 mg, 3.79 mmol) in CH3CN (25 ml) was added
to a solution of I2 (2.88 g, 11.4 mmol) in CH3CN (40 ml) at
08C. After being stirred for 30 min at rt, the mixture was
quenched with aqueous Na2S2O3 and extracted with
Et2O. The organic layer was washed with brine and dried
over MgSO4. Concentration and flash column chromato-
graphy (hexane/EtOAc 1:0–4:1) afforded iodolactone 13
(876 mg, 2.34 mmol, 62% yield) and a mixture of the other
diastereomers 14 and 15 (153 mg, 0.41 mmol, 11% yield).
13: IR (neat) n 3032, 2972, 2936, 2876, 1781, 1547, 1456,
1H and 13C NMR spectra were recorded on a Varian
Mercury 200 (200 MHz), a Varian INOVA 500 (500 MHz),
or Bruker AM-600 (600 MHz) spectrometer. Chemical
shifts are reported in d (ppm) using residual CHCl3 as an
internal standard of d 7.26 and d 77.00 for 1H and 13C NMR,
respectively. Signal patterns are indicated as s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet; br, broad peak. IR
spectra were recorded on a Perkin–Elmer Spectrum BX FT-
IR spectrometer. Low- and high-resolution mass spectra
(MS, HRMS) were recorded on a HITACHI M-2500-S
instrument. Time of flight mass spectra (MALDI-TOF MS)
were recorded on a PerSeptive Biosystem Voyager DE STR
SI-3 instrument. Elemental analysis was conducted with a
Yanaco CHN corder MT-5. Optical rotations were recorded
on a JASCO DIP-370 polarimeter. Melting points were
measured on a Yanaco MP-S3 micro melting point
apparatus.
1367, 1317, 1251, 1181, 1075, 1019, 982, 913, 818 cm21
;
1H NMR (500 MHz, CDCl3) d 1.25 (3H, d, J¼6.5 Hz), 1.26
(3H, d, J¼7.0 Hz), 2.12 (1H, ddq, J¼10.5, 8.2, 6.5 Hz), 2.27
(1H, dq, J¼10.5, 7.0 Hz), 3.79 (1H, dd, J¼10.5, 8.0 Hz),
3.86 (1H, dd, J¼10.5, 5.5 Hz), 4.03 (1H, dd, J¼8.2, 4.8 Hz),
4.50 (1H, ddd, J¼8.0, 5.5, 4.8 Hz), 4.54 (1H, d, J¼12.0 Hz),
4.57 (1H, d, J¼12.0 Hz), 4.55 (2H, s), 7.28–7.38 (5H, m);
13C NMR (125 MHz, CDCl3) d 13.7, 17.9, 32.4, 43.1, 43.2,
71.9, 73.2, 83.4, 127.8, 128.0, 128.5, 137.3, 177.5.
4.1. Synthesis of the LM ring fragment
4.1.4. L ring lactone 8. To a solution of iodolactone 13
(1.62 g, 4.32 mmol) in EtOH (10 ml) at rt was added 15%
NaOH (5.1 ml, 4.2 M in H2O, 22 mmol). After being stirred
for 2 h at rt, AcOH (3.5 ml, 60 mmol) was added at 608C.
After additional 1 h at 608C, the mixture was quenched with
saturated aqueous NaHCO3 at rt and extracted with Et2O
(£2). The organic layer was washed with brine and dried
over MgSO4. Concentration and flash column chromato-
graphy (hexane/EtOAc 10:1–4:1) afforded L ring lactone 8
(824 mg, 3.12 mmol, 72% yield) and g-lactone 16 (206 mg,
0.78 mmol, 18% yield). 8: white needles; mp 108–1108C;
Rf¼0.40 (hexane/EtOAc 1:1); [a ]2D8¼211.1 (c 0.59,
CHCl3); IR (neat) n 3428, 2982, 2930, 1734, 1456, 1369,
1243, 1197, 1077, 1054 cm21; 1H NMR (500 MHz, CDCl3)
d 1.12 (3H, d, J¼6.5 Hz), 1.32 (3H, d, J¼7.0 Hz), 1.67 (1H,
ddq, J¼11.2, 10.5, 6.5 Hz), 2.13 (1H, dq, J¼11.2, 7.0 Hz),
2.93 (1H, d, J¼3.5 Hz), 3.60 (1H, ddd, J¼10.5, 9.0, 3.5 Hz),
3.69 (1H, dd, J¼10.2, 5.5 Hz), 3.85 (1H, dd, J¼10.2,
3.5 Hz), 4.17 (1H, ddd, J¼9.0, 5.5, 3.5 Hz), 4.56 (1H, d,
J¼11.7 Hz), 4.60 (1H, d, J¼11.7 Hz), 7.29–7.38 (5H, m);
13C NMR (125 MHz, CDCl3) d 14.9, 15.6, 39.9, 40.8, 70.4,
71.1, 73.9, 80.2, 127.8, 128.1, 128.5, 137.2, 172.7; HRMS
(EI), calcd for C15H20O4 264.1362 (Mþ), found 264.1373;
Anal. calcd for C, 68.16; H, 7.63, found: C, 68.25; H, 7.69.
4.1.1. Propionate 10. To a solution of allyl alcohol 11
(228 g, 1.19 mol) in pyridine (300 ml, 3.7 mol) at 08C were
added propionyl chloride (115 ml, 1.32 mol) over 20 min.
After 40 min, MeOH (10 ml) was added to the mixture,
which was concentrated and subjected to open column
chromatography (hexane/EtOAc 1:0–30:1) to give the
propionate 10 (266 g, 1.07 mol, 90% yield). Rf¼0.70
(hexane/EtOAc 3:1); [a]2D9¼216.6 (c 1.12, CHCl3); IR
(neat) n 2982, 2944, 2922, 2864, 1738, 1456, 1367, 1274,
1189, 1102, 1029, 967 cm21; 1H NMR (200 MHz, CDCl3) d
1.14 (3H, t, J¼7.5 Hz), 1.70 (3H, dd, J¼6.0, 0.9 Hz), 2.35
(2H, q, J¼7.5 Hz), 3.45–3.60 (2H, m), 4.54 (1H, d,
J¼12.0 Hz), 4.57 (1H, d, J¼12.0 Hz), 5.40–5.55 (2H, m),
5.65–5.90 (1H, m), 7.23–7.38 (5H, m); 13C NMR (50 MHz,
CDCl3) d 8.8, 17.7, 27.7, 71.3, 71.5, 72.9, 73.0, 126.3,
127.4, 128.2, 130.4, 138.0, 173.6; MALDI-TOF MS, calcd
for C15H20O3Na (MþNaþ) 271.131, found 271.135.
4.1.2. Methyl esters 9 and 12. n-BuLi (103 ml, 1.56 M in
hexane, 0.16 mol) was added to a solution of diisopropyl-
amine (30 ml, 0.22 mol) in hexane (100 ml) at 08C over
15 min, and the solution was concentrated to remove
hexane, and dissolved in THF (140 ml). To a solution of
propionate 10 (26.7 g, 108 mmol) in THF (280 ml) and
HMPA (140 ml) at 2808C was added TMSCl (41 ml,
0.32 mol). The LDA solution was introduced to the reaction
mixture over 30 min at 2808C. The solution was allowed to
warm to rt over 10 h, and then quenched with saturated
aqueous NH4Cl and 2N HCl at 08C. The mixture was
extracted with Et2O (£2), and the combined organic layer
was extracted with 5% NaOH. The aqueous layer, which
4.1.5. Large scale preparation of L ring lactone 8. n-BuLi
(500 ml, 1.56 M in hexane, 0.78 mol) was added to
diisopropylamine (120 ml, 0.86 mol) at 08C, and the
solution was concentrated to remove hexane, and dissolved
in THF (600 ml). To a solution of propionate 10 (135 g,
0.54 mol) in THF (1000 ml) and HMPA (680 ml) at 2808C
was added TMSCl (215 ml, 1.69 mol). The LDA solution
was introduced to the reaction mixture over 30 min at

H. Uehara et al. / Tetrahedron 58 (2002) 6493–6512
6501
2808C. The solution was allowed to warm to rt overnight,
and then quenched with water (20 ml) at 08C. The mixture
was extracted with hexane (£4), and the combined organic
layer was extracted with 15% NaOH (£2). The combined
aqueous layer, which contained rearranged carboxylate, was
acidified by 9 M H2SO4 and extracted with hexane (£3), and
the combined organic layer was washed with 1 M HCl and
brine. The same reaction was carried out with the same
amount of the propionate 10 (132 g, 0.53 mol), and the
crude material was combined. To the solution of rearranged
carboxylic acid was added diazomethane (,1200 ml, ,1 M
in Et2O, ,1.2 mol) at 08C. The mixture was stirred
overnight at rt, and then concentrated to give a mixture of
the methyl esters 9 and 12 (3:1), which was subjected to the
next reaction without further purification.
3.76 (1H, dd, J¼11.0, 3.0 Hz, H44), 4.29 (1H, dd, J¼7.0,
3.0 Hz, H45), 4.53 (1H, d, J¼12.5 Hz, Bn), 4.59 (1H, d,
J¼12.0 Hz, Bn), 4.62 (1H, d, J¼7.0 Hz, MOM), 4.71 (1H,
d, J¼6.5 Hz, MOM), 7.26–7.36 (5H, m, Bn); 13C NMR
(125 MHz, CDCl3) d 14.4, 16.3, 38.8, 39.9, 56.2, 69.3, 73.6,
77.5, 81.6, 97.9, 127.74, 127.76, 128.4, 137.6, 173.6; HRMS
(EI), calcd for C17H24O5 308.1624 (Mþ), found 308.1628;
Anal. calcd for C, 66.21; H, 7.84, found C, 66.04; H, 7.95.
4.1.7. Spiroketal 22. To a solution of the MOM ether 20
(44.3 g, 144 mmol) in THF (700 ml) at 2708C was added
allylmagnesium bromide (190 ml, 0.74 M in THF,
140 mmol) over 1 h. After 10 min, additional allylmagne-
sium bromide (20 ml, 0.74 M in THF, 15 mmol) was
introduced to complete the reaction, and the mixture was
quenched with aqueous saturated NH4Cl at 2708C. The
mixture was extracted with hexane/EtOAc (£2), and the
organic layer was washed with brine, dried over MgSO4,
and concentrated. The crude hemiacetal 21 was subjected to
the next step without further purification.
To a solution of the methyl esters 9 and 12 in CH3CN
(900 ml) at 08C was added I2 (341 g, 1.34 mol). After being
stirred for 18 h at rt, the additional I2 (125 g, 0.49 mol) was
introduced. After being stirred for 2 d, the additional I2
(246 g, 1.00 mol) was introduced, again. After 4 h, the
mixture was quenched with aqueous Na2S2O3 and extracted
with hexane/EtOAc (£4). The organic layer was washed
with saturated aqueous Na2S2O3 and brine, and concen-
trated to give a mixture of the iodolactones 13–15, which
was subjected to the next reaction without further
purification.
To a solution of the hemiacetal 21 in THF (140 ml) at 08C
was added disiamylborane [(Sia)2BH, 300 ml, 1 M in THF,
300 mmol] dropwise over 1 h. After 10 min, additional
(Sia)2BH (30 ml, 1 M in THF, 30 mmol) was introduced to
complete the reaction. MeOH (10 ml) was carefully poured
into the reaction mixture, followed by addition of aqueous
saturated NaHCO3 (470 ml) and 30% aqueous H2O2
(130 ml), while the internal reaction temperature was kept
below at 208C with ice bath. After being stirred overnight at
rt, the mixture was treated with aqueous saturated Na2S2O3
(30 ml), and extracted with EtOAc (£3). The organic layer
was washed with brine, dried over MgSO4, and concen-
trated. The crude alcohol was subjected to the next step
without further purification.
To a solution of the iodolactones 13–15 in H2O (600 ml)
and EtOH (120 ml) was added 15% NaOH (520 ml, 4.2 M
in H2O, 2.2 mol) at rt. After stirring for 2 d at rt, HCl
(290 ml, 6 M in H2O, 1.7 mol) was added at 08C. After 1 h,
the mixture was quenched with saturated aqueous NaHCO3
and extracted with hexane/EtOAc. The organic layer was
washed with saturated aqueous NaHCO3 and brine,
concentrated, and recrystalized from hexane/EtOAc (2.5:1,
900 ml) to give the L ring lactone 8. The mother liquor was
concentrated and subjected to flash column chromatography
(hexane/EtOAc 10:1–4:1) to afford the products (8, 16, and
other diastereomers). A mixture of the g-lactones was
subjected to the saponification–acid treatment sequence,
followed by recrystalization and flash column chromato-
graphy, to furnish the L ring lactone 8 (total 96.1 g,
0.36 mol, 34%, 4 steps).
To a solution of the alcohol in (CH2Cl)2 (140 ml) at rt was
added CSA (1.0 g, 4.3 mmol). After 3 h, the mixture was
quenched with aqueous saturated NaHCO3 and extracted
with EtOAc (£3). The organic layer was washed with brine
and dried over MgSO4. Concentration and flash column
chromatography (hexane/EtOAc 25:1–4:1) afforded the
desired spiroketal 22 (37.5 g, 107 mmol, 75% yield for 3
steps) and its C49-epimer (7.3 g, 21 mmol, 15% yield for 3
steps). 22: colorless oil; Rf¼0.60 (hexane/EtOAc 3:1);
[a ]3D1¼235.3 (c 0.956, CHCl3); IR (film) n 2973, 2888,
1454, 1364, 1145, 1097, 1041, 921, 870, 734, 699 cm21; 1H
NMR (500 MHz, CDCl3) d 0.91 (3H, d, J¼6.5 Hz), 1.03
(3H, d, J¼6.5 Hz), 1.54–1.70 (2H, m), 1.72–1.83 (1H, m),
1.84–2.06 (3H, m), 3.19 (1H, t, J¼9.8 Hz), 3.34 (3H, s),
3.60 (1H, dd, J¼11.0, 2.0 Hz), 3.64 (1H, dd, J¼11.0,
4.0 Hz), 3.74–3.78 (1H, m), 3.81–3.92 (2H, m), 4.54 (1H,
d, J¼6.0 Hz), 4.55 (1H, d, J¼12.5 Hz), 4.61 (1H, d,
J¼12.5 Hz), 4.68 (1H, d, J¼6.5 Hz), 7.25–7.35 (5H, m);
13C NMR (125 MHz, CDCl3) d 13.5, 15.7, 24.3, 34.8, 39.3,
41.9, 56.1, 67.4, 69.6, 72.2, 73.2, 79.5, 98.0, 108.1, 127.4,
127.8, 128.2, 138.3; MALDI-TOF MS, calcd for
C20H30O5Na 373.199 (MþNaþ), found 373.196.
4.1.6. MOM ether 20. To a solution of lactone 8 (44.5 g,
169 mmol) and i-Pr2NEt (38 ml, 220 mmol) in (CH2Cl)2
(80 ml) at rt was added MOMCl (15 ml, 200 mmol), and the
reaction mixture was heated to 508C for 1 d. The mixture
was cooled to 08C and quenched with MeOH (10 ml). The
mixture was extracted with hexane/EtOAc (£2), and the
organic layer was washed with aqueous saturated NH4Cl
(£2), brine, and dried over MgSO4. Concentration and open
column chromatography (hexane/EtOAc 8:1) afforded the
MOM ether 20 (49.6 g, 161 mmol) in 95% yield. 20: white
needles; mp 62–638C; Rf¼0.60 (hexane/EtOAc 1:1);
[a]2D1¼227.7 (c 0.598, CHCl3); IR (film) n 2933, 1731,
1496, 1455, 1383, 1361, 1299, 1236, 1186, 1147, 1074,
1
1029, 961, 920, 793, 738, 699 cm21; H NMR (500 MHz,
CDCl3) d 1.10 (3H, d, J¼6.5 Hz, Me56), 1.29 (3H, d,
J¼7.5 Hz, Me57), 1.71–1.80 (1H, m, H47), 2.22 (1H, dq,
J¼11.5, 7.5 Hz, H48), 3.36 (3H, s, MOM), 3.63 (1H, dd,
J¼10.5, 7.5 Hz, H46), 3.71 (1H, dd, J¼10.5, 2.5 Hz, H44),
4.1.8. Alcohol 23. To a solution of benzyl ether 22 (20.4 g,
58.2 mmol) in EtOAc (60 ml) at rt was added 20%
Pd(OH)2/C (0.93 g, 1.3 mmol), and the mixture was stirred
under hydrogen. After 1 d, the catalyst was filtered off, and

6502
H. Uehara et al. / Tetrahedron 58 (2002) 6493–6512
the solvent was removed under reduced pressure to give the
alcohol 23 (15.1 g, 58.1 mmol) in 100% yield. 23: colorless
oil; Rf¼0.40 (hexane/EtOAc 1:1); [a ]3D0¼296.6 (c 1.044,
CHCl3); IR (film) n 3479, 2973, 2887, 1461, 1381, 1302,
the benzyl ether 26 (3.79 g, 9.36 mmol) in 52% yield over 3
steps. 26: pale yellow oil; Rf¼0.75 (hexane/EtOAc 3:1);
[a ]3D0¼250.2 (c 1.158, CHCl3); IR (film) n 3030, 2974,
2930, 2881, 1497, 1455, 1363, 1097, 1070, 1029, 920, 736,
1214, 1143, 1098, 1038, 921, 868 cm21
;
1H NMR
697 cm21 1H NMR (500 MHz, CDCl3) d 0.91 (3H, d,
;
(500 MHz, CDCl3) d 0.91 (3H, d, J¼7.0 Hz), 1.01 (3H, d,
J¼6.0 Hz), 1.54 (1H, dq, J¼11.0, 6.5 Hz), 1.63–1.71 (1H,
m), 1.73–1.87 (2H, m), 1.90–2.03 (2H, m), 2.56 (1H, bs),
3.16 (1H, t, J¼9.8 Hz), 3.42 (3H, s), 3.59–3.72 (2H, m),
3.76–3.91 (3H, m), 4.68 (1H, d, J¼6.5 Hz), 4.71 (1H, d,
J¼6.5 Hz); 13C NMR (50 MHz, CDCl3) d 13.5, 15.5, 24.3,
34.9, 39.6, 42.1, 56.3, 62.5, 67.6, 72.7, 79.9, 98.8, 108.3;
HRMS (EI), calcd for C13H24O5 260.1624 (Mþ), found
260.1625.
J¼6.5 Hz, Me57), 1.04 (3H, d, J¼6.5 Hz, Me56), 1.09 (3H,
d, J¼6.5 Hz, Me55), 1.51 (1H, dq, J¼11.0, 7.0 Hz, H48),
1.62–1.70 (1H, m, H47), 1.74–1.81 (2H, m, H50, 51),
1.90–1.94 (1H, m, H50), 1.97–2.04 (1H, m, H51), 2.60
(1H, sextet, J¼7.5 Hz, H43), 3.25 (1H, t, J¼10.0 Hz, H46),
3.33 (1H, dd, J¼8.5, 1.0 Hz, H44), 3.38 (3H, s, MOM), 3.80
(1H, q, J¼7.5 Hz, H52), 4.02 (1H, dd, J¼10.0, 1.0 Hz,
H45), 4.50 (1H, d, J¼11.5 Hz, Bn), 4.63 (1H, d, J¼6.0 Hz,
MOM), 4.76 (1H, d, J¼11.5 Hz, Bn), 4.79 (1H, d,
J¼6.0 Hz, MOM), 4.99 (1H, bd, J¼10.5 Hz, H41), 5.05
(1H, bd, J¼17.0 Hz, H41), 5.78 (1H, ddd, J¼17.0, 10.5,
8.5 Hz, H42), 7.31–7.34 (5H, m, Bn); 13C NMR (50 MHz,
CDCl3) d 13.6, 15.8, 17.5, 24.3, 35.0, 40.0, 40.2, 42.1, 56.3,
67.3, 72.9, 73.0, 80.7, 83.6, 98.4, 107.8, 114.5, 127.2, 127.8,
128.1, 139.2, 142.3; MALDI-TOF MS, calcd for
C24H36O5Na 427.246 (MþNaþ), found 427.231.
4.1.9. Benzyl ether 26. A solution of alcohol 23 (4.68 g,
18.0 mmol) in CH2Cl2 (40 ml) was added to a solution of
DMSO (2.6 ml, 36 mmol) and (COCl)2 (2.4 ml, 27 mmol)
in CH2Cl2 (150 ml) at 2808C. After 15 min at the same
temperature, Et3N (10.0 ml, 72 mmol) was added, and the
mixture was allowed to warm to 2608C over 2 h, and then
quenched with aqueous NH4Cl at 2608C. The mixture was
extracted with Et2O (£2), and the organic layer was washed
with aqueous saturated NH4Cl and brine, and dried over
MgSO4. Concentration and florisil column chromatography
afforded aldehyde 24, which was subjected to the next
reaction immediately.
4.1.10. Carboxylic acid 7. To a solution of olefin 26
(420 mg, 1.04 mmol) and NMO (0.65 ml, 50% aqueous
solution, 3.12 mmol) in t-BuOH (2.5 ml) and H2O (2.5 ml)
at rt was added OsO4 (550 ml, 19 mM in t-BuOH,
10.4 mmol). After 1 d, NaIO4 (440 mg, 2.06 mmol) was
added, and the reaction mixture was stirred for additional
1 h, and then diluted with aqueous NaHCO3. The mixture
was extracted with Et2O (£3), and the organic layer was
washed with brine, dried over MgSO4, and concentrated to
give crude aldehyde, which was immediately subjected to
the next reaction without further purification.
To a solution of aldehyde 24 in toluene (90 ml) at 2808C
was added (R,R )-diisopropyl tartrate (Z )-crotylboronate
(27 ml, ,0.7 M in toluene, ,19 mmol) dropwise over
20 min. After 15 min at 2708C, NaBH4 (150 mg) and EtOH
(25 ml) were added to reduce unreacted aldehyde, and the
mixture was allowed to warm to rt. To this solution was
introduced 15% aqueous NaOH (10 ml), and the mixture
was stirred for 3 d to saponify the tartrate of the reagent, and
then extracted with Et2O (£2). The organic layer was
washed with brine, and dried over MgSO4. Concentration
and flash column chromatography (hexane/EtOAc 15:1–
10:1) afforded the homoallyl alcohol (4.8 g), which was
subjected to the next reaction without further purification.
Rf¼0.70 (hexane/EtOAc 1:1); 1H NMR (500 MHz, CDCl3)
d 0.89 (3H, d, J¼7.0 Hz), 1.00 (3H, d, J¼7.0 Hz), 1.03 (3H,
d, J¼7.0 Hz), 1.53 (1H, dq, J¼13.5, 6.5 Hz), 1.67–1.83
(3H, m), 1.88–2.03 (2H, m), 2.59–2.67 (1H, m), 3.19 (1H,
t, J¼9.8 Hz), 3.28 (1H, d, J¼4.5 Hz), 3.41 (3H, s), 3.66 (1H,
dt, J¼6.0, 4.5 Hz), 3.73 (1H, dd, J¼9.5, 6.5 Hz), 3.85–3.91
(1H, m), 4.70 (1H, d, J¼6.0 Hz), 4.79 (1H, d, J¼6.0 Hz),
5.03 (1H, bd, J¼11.0 Hz), 5.07 (1H, bd, J¼17.5 Hz), 5.93
(1H, ddd, J¼17.0, 10.5, 7.5 Hz); 13C NMR (50 MHz,
CDCl3) d 12.7, 13.5, 15.5, 24.5, 35.1, 38.9, 40.3, 42.2, 56.2,
68.2, 71.5, 76.8, 84.8, 98.9, 107.9, 113.8, 142.8; MALDI-
TOF MS, calcd for C17H30O5Na 337.199 (MþNaþ), found
337.192.
To a solution of the aldehyde in t-BuOH (8.0 ml) and H2O
(2.0 ml) at rt were added NaH2PO4 (600 mg, 3.8 mmol), 2-
methyl-2-butene (1.1 ml, 10.4 mmol), and NaClO2
(670 mg, 17.4 mmol). After being stirred for 3 h at rt, the
mixture was extracted with EtOAc (£2), and the organic
layer was washed with brine and dried over MgSO4.
Concentration and flash column chromatography (hex-
ane/EtOAc 10:1–1:1) gave the carboxylic acid 7 (437 mg,
1.03 mmol) in 99% yield over 2 steps. 7: [a ]3D1¼257.1 (c
1.02, CHCl3); IR (film) n 3400–2800, 2975, 2938, 2888,
1731, 1704, 1497, 1455, 1380, 1097, 1069, 1028, 921, 736,
698 cm21 1H NMR (500 MHz, CDCl3) d 0.89 (3H, d,
;
J¼6.5 Hz), 1.02 (3H, d, J¼6.5 Hz), 1.30 (3H, d, J¼6.5 Hz),
1.52 (1H, dq, J¼11.0, 6.5 Hz), 1.68 (1H, tq, J¼10.5,
6.5 Hz), 1.72–1.84 (2H, m), 1.90 (1H, ddd, J¼13.0, 9.5,
7.0 Hz), 2.01–2.10 (1H, m), 2.86 (1H, quint., J¼6.5 Hz),
3.09 (1H, t, J¼10.0 Hz), 3.34 (3H, s), 3.81–3.90 (2H, m),
3.98–4.04 (2H, m), 4.58 (1H, d, J¼11.5 Hz), 4.65 (1H, d,
J¼6.5 Hz), 4.73 (1H, d, J¼6.5 Hz), 4.76 (1H, d,
J¼11.5 Hz), 7.25–7.37 (5H, m); 13C NMR (50 MHz,
CDCl3) d 13.5, 13.7, 15.7, 24.1, 34.6, 40.0, 41.2, 41.7,
56.2, 67.5, 72.3, 73.5, 79.4, 81.3, 98.5, 108.0, 127.6, 127.7,
128.3, 138.2, 179.3; MALDI-TOF MS, calcd for
C23H34O7Na 445.220 (MþNaþ), found 445.232.
To a solution of the homoallyl alcohol (4.8 g) in THF (5 ml)
and DMF (5 ml) at 08C were added NaH (1.3 g, 60% oil
suspension, 32 mmol) and BnBr (2.8 ml, 23 mmol). After
7 h at rt, MeOH was added to the mixture, and the resultant
solution was extracted with hexane/EtOAc (£2). The
organic layer was washed with aqueous saturated NH4Cl
and brine, and dried over MgSO4. Concentration and flash
column chromatography (hexane/EtOAc 1:0–20:1) gave
4.2. Synthesis of the I ring fragment
4.2.1. p-Methoxybenzylidene acetal 27. A mixture of
triphenylphosphonium bromide (166 g, 466 mmol) in THF

H. Uehara et al. / Tetrahedron 58 (2002) 6493–6512
6503
(1900 ml) was treated with t-BuOK (50 g, 447 mmol) at 08C
for 30 min. To the resulting yellow suspension at 08C was
added D-2-deoxyribose (25.0 g, 186 mmol). The mixture
was stirred at 358C for 1 d, and quenched with NH4Cl (25 g)
at 08C. After 12 h, insoluble salts in the suspension was
filtered off, and the resulting solution was concentrated to
give a triol, which was subjected to the next reaction without
further purification.
extracted with hexane/EtOAc (£2). The organic layer was
washed with saturated aqueous NH4Cl and brine, and dried
over MgSO4. Concentration and flash column chromato-
graphy (hexane/EtOAc 20:1–5:1) gave diene 29 with 33R-
stereochemisty as an epimeric mixture of C34-alcohols
(5.08 g, 12.1 mmol, 44% yield) and 33S-diastereomers 30
(5.12 g, 12.2 mmol, 44% yield).
4.2.4. Eight-membered ring 31. To a solution of diene 29
(23.7 g, 56.4 mmol) in CH2Cl2 (1600 ml) at rt was added
(PCy3)2Cl2RuvCHPh (920 mg, 1.13 mmol), and the sol-
ution was heated to reflux. The additional catalyst (total
3.22 g, 3.91 mmol) was introduced over 4 d. Et3N (100 ml)
was added to this mixture at rt, and the solution was stirred
overnight, concentrated, and subjected to flash column
chromatography (hexane/EtOAc 19:1–8:1) to afford a C34-
epimeric mixture of 8-membered ring 31 (16.6 g,
42.3 mmol) in 75% yield. 31a: white solid; mp 118–
1228C; Rf¼0.56 (hexane/EtOAc 1:1); [a ]2D6¼þ89.2 (c 1.08,
CHCl3); IR (KBr) n 3388, 2974, 2846, 1732, 1614, 1517,
To a solution of the triol and anisaldehyde dimethylacetal
[MPCH(OMe)2, 52 ml, 280 mmol] in CH2Cl2 (370 ml) at rt
was added CSA (8.6 g, 37 mmol), and the solution was
heated to reflux for 1 d. The reaction mixture was quenched
with saturated aqueous NaHCO3 at 08C and extracted with
hexane/EtOAc. The organic layer was washed with brine,
concentrated, and subjected to open column chromato-
graphy (hexane/EtOAc 1:0–3:1) to afford p-methoxyben-
zylidene acetal 27 (35.6 g, 142 mmol) in 76% yield over 2
steps. 27: white solid; mp 38–408C; Rf¼0.48 (hexane/
EtOAc 1:1); [a]2D2¼223.5 (c 0.70, CHCl3); IR (KBr) n
3417, 3071, 2932, 2845, 1614, 1518, 1429, 1395,
1396, 1367, 1249, 1162, 1102, 1039, 974, 824, 672 cm21
;
1303, 1251, 1080, 1032, 931, 828, 563 cm21; H NMR
1H NMR (500 MHz, CDCl3) d 1.50 (9H, s), 2.46 (1H, ddd,
J¼14.0, 7.0, 2.0 Hz), 2.61 (1H, d, J¼4.0 Hz), 2.81 (1H, ddd,
J¼14.0, 9.5, 5.0 Hz), 3.66 (1H, t, J¼10.0 Hz), 3.74 (1H,
ddd, J¼10.0, 9.0, 4.5 Hz), 3.76 (1H, d, J¼9.0 Hz), 3.79 (3H,
s), 3.88 (1H, ddd, J¼9.0, 5.0, 2.0 Hz), 4.20 (1H, dd, J¼10.0,
4.5 Hz), 4.63 (1H, m), 5.39 (1H, s), 5.81 (1H, dd, J¼11.0,
5.5 Hz), 5.88 (1H, m), 6.86–6.88 (2H, m), 7.37–7.39 (2H,
m); 13C NMR (125 MHz, CDCl3) d 27.9, 30.3, 55.2, 69.1,
70.1, 72.8, 82.1, 82.5, 83.0, 101.6, 113.6, 127.3, 127.4,
129.9, 135.6, 160.0, 169.5; MALDI-TOF MS, calcd for
C21H28O7Na (MþNaþ) 415.173, found 415.168. 31b: white
solid; mp 158–1608C; Rf¼0.50 (silica, 1:1, hexane/EtOAc);
[a ]2D6¼þ18.7 (c 0.63, CHCl3); IR (KBr) n 3446, 2978,
2845, 1733, 1614, 1516, 1394, 1369, 1303, 1248, 1173,
1118, 1052, 824, 722 cm21; 1H NMR (500 MHz, CDCl3) d
1.50 (9H, s), 2.45 (1H, m), 2.60 (1H, ddd, J¼14.0, 9.5,
3.0 Hz), 2.83 (1H, d, J¼7.5 Hz), 3.55 (1H, ddd, J¼10.5, 9.5,
3.0 Hz), 3.67 (1H, d, J¼10.5 Hz), 3.68 (1H, td, J¼9.5,
3.0 Hz), 3.79 (3H, s), 4.21 (1H, d, J¼5.0 Hz), 4.23 (1H, dd,
J¼10.5, 5.0 Hz), 4.79 (1H, m), 5.41 (1H, s), 5.67 (1H, ddd,
J¼10.5, 8.0, 1.5 Hz), 5.92 (1H, tdd, J¼10.0, 8.0, 1.5 Hz),
6.87–6.89 (2H, m), 7.38–7.40 (2H, m); 13C NMR
(125 MHz, CDCl3) d 28.0, 32.9, 55.3, 68.6, 69.3, 74.7,
79.4, 79.9, 82.9, 101.0, 113.6, 127.0, 127.4, 130.0, 132.0,
160.0, 168.3; MALDI-TOF MS, calcd for C21H28O7Na
(MþNaþ) 415.173, found 415.155.
1
(200 MHz, CDCl3) d 2.40–2.51 (1H, m), 2.58–2.67 (1H,
m), 3.54–3.66 (2H, m), 3.81 (1H, s), 4.03–4.25 (2H, m),
5.14 (1H, dd, J¼10.0, 2.0 Hz), 5.21 (1H, dd, J¼16.5,
2.0 Hz), 5.45 (1H, s), 5.96–6.05 (1H, m), 6.89–6.91 (2H,
m), 7.41–7.43 (2H, m); 13C NMR (50 MHz, CDCl3) d 36.5,
55.2, 65.5, 70.9, 80.9, 100.8, 113.6, 117.4, 127.3, 130.3,
134.3, 159.9.
4.2.2. Glycolate 28. To a solution of the p-methoxybenzyl-
idene acetal 27 (12.0 g, 47.9 mmol) and BrCH2CO2t-Bu
(9.2 ml, 62 mmol) in THF (160 ml) and DMF (16 ml) at 08C
was added NaH (2.3 g, 60% oil suspension, 58 mmol). After
18 h at rt, saturated aqueous NaHCO3 was then added to the
mixture, and the resultant solution was extracted with
Et2O. The organic layer was washed with saturated aqueous
NaHCO3 and brine, and dried over MgSO4. Concentration
and flash column chromatography (hexane/EtOAc 13:1–
5:1) gave glycolate 28 (14.3 g, 39.2 mmol) in 82% yield. 28:
white solid; Rf¼0.52 (hexane/EtOAc 3:1); 1H NMR
(500 MHz, CDCl3) d 1.48 (9H, s), 2.43 (1H, dtt, J¼14.5,
7.5, 1.5 Hz), 2.73 (1H, dddt, J¼14.5, 7.0, 3.5, 1.7 Hz), 3.37
(1H, ddd, J¼10.5, 9.5, 5.0 Hz), 3.64 (1H, t, J¼10.5 Hz),
3.72 (1H, ddd, J¼9.5, 7.0, 3.5 Hz), 3.78 (3H, s), 4.00 (1H, d,
J¼16.0 Hz), 4.07 (1H, d, J¼16.0 Hz), 4.43 (1H, dd, J¼10.5,
5.0 Hz), 5.10 (1H, ddt, J¼10.0, 3.3, 1.6 Hz), 5.16 (1H, ddt,
J¼17.0, 3.3, 1.7 Hz), 5.42 (1H, s), 5.98 (1H, ddt, J¼17.0,
10.0, 7.0 Hz), 6.86–6.88 (2H, m), 7.38–7.40 (2H, m); 13C
NMR (125 MHz, CDCl3) d 28.0, 36.1, 68.3, 69.0, 73.7,
79.8, 81.5, 81.8, 100.6, 100.7, 113.4, 117.1, 127.3, 130.2,
134.2, 159.9, 169.1; MALDI-TOF MS, calcd for
C20H28O6Na (MþNaþ) 387.178, found 387.176.
4.2.5. TBPS ether 32. To a solution of ester 31 (29.2 g,
80.4 mmol) in Et2O (350 ml) at 08C was added a suspension
of LiAlH4 (3.66 g, 96.5 mmol) in Et2O (30 ml) over 10 min.
The mixture was allowed to warm to rt over 3 h, then
quenched with saturated aqueous NaHCO3 (80 ml) at 08C,
and diluted with EtOAc. The aqueous layer was adjusted to
pH 7 by the addition of 2 M HCl (,50 ml), and extracted
with EtOAc. The organic layer was concentrated to afford
diol (23.7 g), which was subjected to the next reaction
without further purification. The diol: white solid; mp 146–
1478C; Rf¼0.52 (EtOAc); IR (KBr) n 3330, 2935, 2855,
4.2.3. Diene 29. n-BuLi (26 ml, 1.56 M in hexane,
41 mmol) was added to diisopropylamine (6.3 ml,
45 mmol) in THF (75 ml) at 2708C, and the solution was
stirred for 20 min. A solution of glycolate 28 (10.0 g,
27.4 mmol) in THF (36 ml) was added dropwise to the LDA
solution at 2708C over 30 min. After 20 min, acrolein
(2.1 ml, 32 mmol) was introduced to the reaction mixture
over 20 min at 2708C. After 30 min, the mixture was
quenched with saturated aqueous NH4Cl at 2708C, and
1614, 1586, 1515, 1249, 1101, 1057, 1032, 826, 770 cm21
;
1H NMR (500 MHz, CDCl3) d 2.19 (1H, brt, J¼6.0 Hz),
2.26 (1H, brd, J¼4.0 Hz), 2.46 (1H, ddd, J¼14.5, 6.3,
2.0 Hz), 2.78 (1H, ddd, J¼14.5, 8.2, 5.0 Hz), 3.47 (1H, ddd,

6504
H. Uehara et al. / Tetrahedron 58 (2002) 6493–6512
J¼8.5, 5.2, 4.0 Hz), 3.61 (1H, t, J¼10.0 Hz), 3.74–3.83
(2H, m), 3.76 (1H, dd, J¼10.0, 5.2 Hz), 3.79 (3H, s), 3.88
(1H, ddd, J¼10.5, 6.8, 4.0 Hz), 4.17 (1H, dd, J¼10.0,
5.0 Hz), 4.47 (1H, dd, J¼8.5, 4.0 Hz), 5.39 (1H, s), 5.80–
5.88 (2H, m), 6.86–6.89 (2H, m), 7.36–7.39 (2H, m); 13C
NMR (125 MHz, CDCl3) d 30.4, 55.3, 64.2, 69.4, 70.4,
72.3, 82.0, 83.1, 101.6, 113.7, 126.8, 127.5, 130.0, 136.9,
160.1; MALDI-TOF MS, calcd for C17H22O6Na (MþNaþ)
345.131, found 345.123; Anal. calcd for C17H22O6 C, 63.34;
H, 6.88, found C, 63.05; H, 6.72.
MALDI-TOF MS, calcd for C33H38O6SiNa (MþNaþ)
581.234, found 581.183.
CuCN (3.66 g, 40.8 mmol) was dried using heat gun under
vacuo, and suspended in Et2O (150 ml). To this suspension
was added MeLi (68 ml, 1.14 M in Et2O, 78 mmol) over
15 min at 2708C. The mixture was warmed to 08C for
15 min before being cooled to 2808C. A solution of enone
33 in Et2O (100 ml) was added to the Me2Cu(CN)Li2
solution over 20 min at 2808C. The mixture was allowed to
warm to 2608C over 1 h, quenched with saturated aqueous
NH4Cl/concentrated NH3 (5:1, 30 ml), and extracted with
hexane/EtOAc (£2). The organic layer was washed with
saturated aqueous NH4Cl–concentrated NH3 (5:1) and
brine, and dried over MgSO4. Concentration and flash
column chromatography (hexane/EtOAc 18:1–7:1)
afforded ketone 34 (9.71 g, 17.0 mmol) in 69% yield over
2 steps. 34: colorless viscous oil; Rf¼0.45 (hexane/EtOAc
3:1); [a]2D9¼2102 (c 1.01, CHCl3); IR (KBr) n 2931, 2857,
2359, 2341, 1715, 1615, 1588, 1517, 1458, 1427, 1373,
1296, 1249, 1172, 1136, 1112, 1035, 976, 941, 824, 795,
738 cm21; 1H NMR (500 MHz, CDCl3) d 1.04 (9H, s), 1.11
(3H, d, J¼6.5 Hz), 1.53 (1H, ddd, J¼15.5, 13.0, 9.0 Hz),
1.96 (1H, brd, J¼11.0 Hz), 2.01 (1H, dd, J¼15.5, 5.0 Hz),
2.29–2.36 (1H, m), 3.33 (1H, td, J¼9.0, 4.5 Hz), 3.62 (1H,
dd, J¼11.0, 6.5 Hz), 3.76 (1H, dd, J¼4.5, 2.5 Hz), 3.77 (1H,
t, J¼10.5 Hz), 3.81 (3H, s), 3.82 (1H, t, J¼9.0 Hz), 3.85
(1H, dd, J¼10.5, 2.5 Hz), 3.93 (1H, dd, J¼10.5, 4.5 Hz),
4.30 (1H, dd, J¼10.5, 4.5 Hz), 5.46 (1H, s), 6.90–6.92 (2H,
m), 7.39–7.46 (8H, m), 7.65–7.67 (2H, m), 7.71–7.73 (2H,
m); 13C NMR (125 MHz, CDCl3) d 19.2, 21.8, 26.7, 30.7,
41.8, 42.3, 55.3, 66.6, 69.6, 79.3, 81.2, 89.9, 101.1, 113.7,
127.4, 127.65, 127.71, 129.8, 130.0, 133.0, 133.1, 135.6,
135.7, 160.1, 215.4; MALDI-TOF MS, calcd for C34H42-
O6SiNa (MþNaþ) 597.265, found 597.265.
To a solution of the diol (23.7 g) and Et3N (30.8 ml,
221 mmol) in CH2Cl2 (74 ml) at rt was added TBPSCl
(12.9 ml, 73.5 mmol). After 11 h at rt, additional TBPSCl
(2.6 ml, 14.7 mmol) was introduced. After 19 h, the mixture
was quenched with MeOH and extracted with EtOAc (£2).
The organic layer was washed with brine, and dried over
MgSO4. Concentration and flash column chromatography
(hexane/EtOAc 1:0–10:1) afforded TBPS ether 32 (33.57 g,
60.0 mmol) in 74% yield over 2 steps. 32: viscous oil;
Rf¼0.30 (hexane/EtOAc 3:1); IR (KBr) n 3469, 3014, 2932,
2857, 1615, 1517, 1463, 1428, 1391, 1302, 1250, 1172,
1105, 1085, 1036, 972, 826, 759, 704, 610 cm21; 1H NMR
(500 MHz, CDCl3) d 1.08 (9H, s), 2.46 (1H, ddd, J¼14.0,
5.0, 1.5 Hz), 2.78 (1H, ddd, J¼14.0, 8.0, 5.0 Hz), 3.09 (1H,
d, J¼2.5 Hz), 3.44 (1H, dt, J¼9.0, 5.0 Hz), 3.51 (1H, t,
J¼9.5 Hz), 3.71 (1H, td, J¼9.5, 5.0 Hz), 3.75 (1H, ddd,
J¼9.5, 5.0, 1.5 Hz), 3.80 (3H, s), 3.91 (2H, dd, J¼10.5,
5.0 Hz), 4.06 (1H, dd, J¼9.5, 5.0 Hz), 4.60 (1H, dt, J¼9.0,
2.5 Hz), 5.38 (1H, s), 5.82–5.84 (2H, m), 6.87–6.91 (2H,
m), 7.37–7.47 (8H, m), 7.68–7.72 (4H, m); 13C NMR
(125 MHz, CDCl3) d 19.2, 26.8, 30.4, 55.2, 66.3, 69.5, 71.4,
72.0, 82.1, 82.3, 101.5, 113.6, 126.3, 127.4, 127.67, 127.75,
129.83, 129.9, 130.1, 132.7, 132.9, 135.5, 135.6, 136.9,
160.0; MALDI-TOF MS, calcd for C33H40O6SiNa
(MþNaþ) 583.249, found 583.218.
4.2.7. Diol 35. To a solution of TBPS ether 34 (50.5 g,
87.8 mmol) in THF (100 ml) at 08C was added a solution of
TBAF (131 ml, 1 M in THF, 131 mmol) and AcOH
(7.53 ml, 131 mmol). After being stirred for 1 d at rt, the
solution was concentrated, and the residue was subjected to
flash column chromatography (hexane/EtOAc 3:1–1:2) to
afford the hydroxy ketone (26.8 g, 79.6 mmol) in 90% yield.
The hydroxy ketone: white solid; mp 157–1588C; Rf¼0.40
(hexane/EtOAc 1:1); [a ]2D4¼2186 (c 0.93, CHCl3); IR
(KBr) n 3372, 2969, 2851, 1709, 1613, 1521, 1455, 1285,
1252, 1172, 1132, 1098, 1009, 972, 846, 817, 553 cm21; 1H
NMR (500 MHz, CDCl3) d 1.07 (3H, d, J¼7.0 Hz), 1.93
(1H, brd, J¼11.0 Hz), 2.01 (1H, dd, J¼15.0, 4.5 Hz), 2.19
(1H, brs), 2.26–2.32 (1H, m), 3.35 (1H, ddd, J¼11.0, 10.0,
5.5 Hz), 3.47 (1H, dd, J¼11.0, 6.8 Hz), 3.70 (1H, t,
J¼11.0 Hz), 3.69–3.79 (4H, m), 3.79 (3H, s), 4.28 (1H,
dd, J¼11.0, 5.5 Hz), 5.42 (1H, s), 6.87–6.89 (2H, m), 7.38–
7.40 (2H, m); 13C NMR (125 MHz, CDCl3) d 21.5, 30.6,
41.6, 41.9, 55.2, 64.2, 69.3, 79.3, 81.0, 89.3, 101.1, 113.6,
127.4, 129.8, 160.1, 215.0; MALDI-TOF MS, calcd for
C18H24O6Na (MþNaþ) 359.147, found 359.155; Anal.
calcd for C18H24O6 C, 64.27; H, 7.19, found C, 64.45; H,
7.08.
4.2.6. Ketone 34. A solution of allyl alcohol 32 (13.9 g,
24.7 mmol) in CH2Cl2 (100 ml) was added to a solution of
DMSO (5.3 ml, 74 mmol) and (COCl)2 (4.4 ml, 49 mmol)
in CH2Cl2 (150 ml) at 2808C. After 1 h at the same
temperature, Et3N (20 ml, 140 mmol) was added, and the
mixture was allowed to warm to 2508C over 1 h, and then
quenched with aqueous NH4Cl at 2508C. The mixture was
extracted with hexane2EtOAc (£3), and the organic layer
was washed with aqueous saturated NH4Cl and brine, and
dried over MgSO4. Concentration and florisil column
chromatography (hexane/EtOAc 12:1–4:1) afforded enone
33, which was used in the next reaction without further
purification. 33: colorless viscous oil; Rf¼0.50 (hexane/
EtOAc 3:1); IR (KBr) n 2931, 1673, 1615, 1517, 1428,
1392, 1251, 1112, 1034, 910, 825, 737, 704, 614 cm21; 1H
NMR (500 MHz, CDCl3) d 1.09 (9H, s), 2.62 (1H, dd,
J¼13.5, 10.0 Hz), 2.87 (1H, dddd, J¼13.5, 10.0, 8.5,
1.5 Hz), 3.70–3.74 (2H, m), 3.78 (1H, td, J¼9.0, 4.5 Hz),
3.82 (3H, s), 3.87 (1H, dd, J¼11.0, 7.5 Hz), 4.06 (1H, dd,
J¼11.0, 3.3 Hz), 4.35 (1H, dd, J¼11.0, 4.5 Hz), 4.38 (1H,
dd, J¼7.5, 3.3 Hz), 5.49 (1H, s), 5.89 (1H, brd, J¼12.0 Hz),
6.48 (1H, ddd, J¼12.0, 10.0, 8.5 Hz), 6.91–6.93 (2H, m),
7.40–7.46 (8H, m), 7.69–7.72 (4H, m); 13C NMR
(125 MHz, CDCl3) d 19.1, 26.7, 33.9, 55.1, 65.0, 69.5,
77.7, 88.2, 101.3, 113.6, 127.3, 127.6, 127.7, 129.65,
129.73, 130.8, 133.0, 135.4, 135.5, 136.0, 160.0, 201.5;
A solution of the hydroxy ketone (26.8 g, 79.6 mmol) in
CH3CN (100 ml) was added to a solution of NaBH(OAc)3
(84.3 g, 398 mmol) and AcOH (68.4 ml, 1.19 mol) in

H. Uehara et al. / Tetrahedron 58 (2002) 6493–6512
6505
CH3CN (600 ml) at 2408C, which was allowed to warm to
rt over 4 h. K2CO3 (150 g) was added to the mixture, and the
resultant solution was extracted with EtOAc (£2). The
organic layer was washed with saturated aqueous K2CO3
and brine, dried over MgSO4, and concentrated. Recrystal-
ization and open column chromatography (hexane/EtOAc
5:1–0:1) afforded diol 35 (24.7 g, 73.1 mmol) in 92% yield.
35: white solid; mp 1698C; Rf¼0.10 (hexane/EtOAc 1:1);
[a]2D4¼26.56 (c 1.01, CHCl3); IR (KBr) n 3292, 2920,
2853, 1617, 1521, 1450, 1399, 1255, 1118, 1089, 1029, 977,
832, 818 cm21; 1H NMR (500 MHz, CDCl3) d 1.11 (3H, d,
J¼7.0 Hz), 1.75 (1H, dt, J¼14.0, 10.0 Hz), 1.80–1.88 (2H,
m), 1.93–1.98 (1H, m), 1.98 (1H, ddd, J¼14.0, 4.0, 1.5 Hz),
2.08 (1H, m), 3.40 (1H, dt, J¼9.5, 4.0 Hz), 3.53 (1H, t,
J¼9.5 Hz), 3.53–3.58 (1H, m), 3.63 (1H, td, J¼10.0,
4.0 Hz), 3.67–3.72 (2H, m), 3.80 (3H, s), 3.82 (1H, dd,
J¼11.0, 4.0 Hz), 4.25 (1H, dd, J¼9.5, 4.0 Hz), 5.39 (1H, s),
6.87–6.89 (2H, m), 7.38–7.40 (2H, m); 13C NMR
(125 MHz, CDCl3) d 27.8, 45.1, 47.7, 55.3, 65.2, 69.8,
73.0, 78.5, 80.7, 87.8, 100.7, 100.8, 113.7, 127.4, 130.2,
160.0; MALDI-TOF MS, calcd for C18H26O6Na (MþNaþ)
361.163, found 361.164; Anal. calcd for C18H26O6 C, 63.89;
H, 7.74, found C, 63.94; H, 7.65.
and I2 (0.34 g, 1.3 mmol)] were introduced twice. After
21 h, aqueous NH4Cl was added to the mixture, and the
resultant mixture was extracted with hexane/EtOAc (£2).
The organic layer was washed with brine, and dried over
MgSO4. Concentration and flash column chromatography
(hexane/EtOAc 1:0–5:1) gave iodide 38 (5.97 g,
11.7 mmol) in 87% yield. 38: pale yellow oil; Rf¼0.70
(hexane/EtOAc 1:1); [a ]2D9¼244.3 (c 0.974, CHCl3); IR
(neat) n 3445, 3063, 3030, 2921, 1496, 1454, 1371, 1304,
1
1096, 909, 736, 697 cm21; H NMR (500 MHz, CDCl3) d
1.04 (3H, d, J¼7.0 Hz), 1.49 (1H, bs), 1.64 (1H, ddd,
J¼15.0, 9.0, 7.5 Hz), 1.78–1.86 (2H, m), 1.91–2.01 (2H,
m), 3.23 (1H, ddd, J¼8.5, 5.0, 3.0 Hz), 3.42 (1H, dd,
J¼10.0, 4.5 Hz), 3.48 (1H, td, J¼8.5, 3.0 Hz), 3.55 (1H, dd,
J¼10.0, 6.5 Hz), 3.58–3.65 (1H, m), 3.64 (1H, dd, J¼10.5,
3.0 Hz), 3.72 (1H, ddd, J¼9.0, 6.0, 2.5 Hz), 3.80 (1H, dd,
J¼10.0, 3.0 Hz), 4.37 (1H, d, J¼11.0 Hz), 4.56 (1H, d,
J¼11.5 Hz), 4.58 (2H, s), 7.20–7.40 (10H, m); 13C NMR
(50 MHz, CDCl3) d 12.5, 27.3, 27.6, 41.4, 46.8, 71.4, 71.5,
73.6, 74.0, 78.5, 84.8, 85.6, 127.5, 127.6, 127.8, 128.3,
128.4, 138.1, 138.4; MALDI-TOF MS, calcd for
C24H31IO4Na 533.117 (MþNaþ), found 533.116.
4.2.10. Nitrile 39. To a solution of iodide 38 (1.64 g,
3.21 mmol) in DMSO (6.4 ml) at rt was added NaCN
(0.31 g, 6.4 mmol). After 19 h at 408C, H2O was then added
to the mixture, the resultant mixture was extracted with
EtOAc (£2). The organic layer was washed with brine, and
dried over MgSO4. Concentration and open column
chromatography (hexane/EtOAc 10:0–3:1) gave nitrile 39
(1.27 g, 3.10 mmol) in 97% yield. 39: colorless oil; Rf¼0.50
(hexane/EtOAc 1:1); [a ]2D9¼261.7 (c 0.920, CHCl3); IR
(neat) n 3467, 3064, 3031, 2924, 2866, 2251, 1496, 1455,
4.2.8. Diol 37. To a solution of diol 35 (208 mg, 613 mmol)
in THF (3.0 ml) and DMF (0.6 ml) at 08C were added NaH
(147 mg, 60% oil suspension, 3.7 mmol) and BnBr
(0.29 ml, 2.5 mmol). After 10 h at rt, MeOH was added to
the mixture, and the mixture was diluted with Et2O and
aqueous NH4Cl, and extracted with Et2O (£2). The organic
layer was washed with brine, and dried over MgSO4.
Concentration and flash column chromatography (hex-
ane/EtOAc 10:0–8:1) gave the benzyl ether 36 (378 mg,
quant.).
1
1362, 1295, 1208, 1112, 1068, 1027, 738, 698 cm21; H
NMR (500 MHz, CDCl3) d 1.04 (3H, d, J¼7.5 Hz), 1.40
(1H, d, J¼5.0 Hz), 1.61 (1H, ddd, J¼14.5, 10.0, 7.5 Hz),
1.72–1.80 (1H, m), 1.81–1.85 (1H, m), 1.92–2.01 (2H, m),
2.65 (1H, dd, J¼16.5, 5.0 Hz), 2.85 (1H, dd, J¼16.5,
3.5 Hz), 3.44 (1H, td, J¼9.0, 3.5 Hz), 3.52 (1H, dd, J¼10.0,
6.5 Hz), 3.63–3.71 (3H, m), 3.78 (1H, dd, J¼9.5, 2.5 Hz),
4.35 (1H, d, J¼11.5 Hz), 4.54 (1H, d, J¼11.5 Hz), 4.55 (1H,
d, J¼11.5 Hz), 4.58 (1H, d, J¼11.5 Hz), 7.21–7.35 (10H,
m); 13C NMR (50 MHz, CDCl3) d 22.7, 27.4, 27.5, 41.7,
47.6, 71.5 (£2), 72.6, 73.5, 78.5, 82.7, 86.3, 118.3, 127.6,
127.7, 127.8 (£4), 128.3 (£4), 138.0, 138.2; MALDI-TOF
MS, calcd for C25H31NO4Na 432.215 (MþNaþ), found
432.180.
To a solution of the benzyl ether 36 (834 mg, 1.61 mmol) in
MeOH (8 ml) and H2O (10 drops) at rt was added p-
TsOH·H2O (31 mg, 0.16 mmol). After 3 h at rt, Et3N was
added, and the mixture was concentrated and subjected to
flash column chromatography (hexane/EtOAc 3:0–0:1) to
give diol 37 (533 mg, 1.33 mmol) in 83% yield. 37: white
solid; mp 96–978C; Rf¼0.35 (hexane/EtOAc 1:1);
[a]2D8¼240.3 (c 1.04, CHCl3); IR (film) n 3429, 3030,
2923, 2866, 1496, 1454, 1208, 1122, 1097, 1071, 1028, 738,
698 cm21 1H NMR (500 MHz, CDCl3) d 1.04 (3H, d,
;
J¼6.5 Hz), 1.62 (1H, dt, J¼14.0, 10.5 Hz), 1.69 (1H, ddd,
J¼15.0, 11.0, 6.5 Hz), 1.79–1.95 (3H, m), 3.13–3.19 (1H,
m), 3.39 (1H, t, J¼9.5 Hz), 3.49 (1H, td, J¼10.0, 4.0 Hz),
3.53–3.60 (2H, m), 3.76 (1H, td, J¼9.5, 2.0 Hz), 3.83 (1H,
dd, J¼9.5, 2.5 Hz), 3.89–3.95 (1H, m), 4.29 (1H, d,
J¼11.0 Hz), 4.55 (1H, d, J¼11.0 Hz), 4.56 (1H, d,
J¼11.5 Hz), 4.59 (1H, d, J¼11.5 Hz), 7.18–7.39 (10H,
m); 13C NMR (50 MHz, CDCl3) d 27.3, 27.6, 42.3, 48.7,
65.6, 71.0, 71.9, 72.5, 73.4, 79.4, 85.7, 88.5, 127.7, 127.8,
127.9, 128.0, 128.36, 128.44, 137.1, 137.8; MALDI-TOF
MS, calcd for C24H32O5Na 423.215 (MþNaþ), found
423.200.
4.2.11. TES ether 54. To a solution of nitrile 39 (1.27 g,
3.10 mmol) and 2,6-lutidine (0.54 ml, 4.7 mmol) in CH2Cl2
(6.2 ml) at 2308C was added TESOTf (0.77 ml, 3.4 mmol).
After being stirred for 1.5 h at 2208C, the mixture was
quenched with aqueous saturated NH4Cl and extracted with
hexane/EtOAc (£2). The organic layer was washed with
brine, and dried over MgSO4. Concentration and flash
column chromatography (hexane/EtOAc 1:0–10:1) gave
TES ether 54 (1.40 g, 2.67 mmol) in 86% yield. 54:
colorless oil; Rf¼0.70 (hexane/EtOAc 1:1); [a ]2D8¼232.1
(c 1.034, CHCl3); IR (neat) n 3064, 3031, 2953, 2875, 2249,
1496, 1454, 1415, 1373, 1302, 1239, 1092, 1009, 811, 735,
4.2.9. Iodide 38. To a solution of diol 37 (5.35 g,
13.4 mmol) in THF (70 ml) at 08C were added imidazole
(1.83 g, 26.7 mmol), PPh3 (3.51 g, 13.4 mmol), and I2
(3.04 g, 12.0 mmol). The stirred mixture was allowed to
warm to rt, and additional reagents [PPh3 (0.35 g, 1.4 mmol)
698 cm21 1H NMR (500 MHz, CDCl3) d 0.61 (6H, q,
;
J¼8.0 Hz), 0.95 (9H, t, J¼8.0 Hz), 1.03 (3H, d, J¼7.5 Hz),
1.56–1.64 (1H, m), 1.71 (1H, dt, J¼14.0, 9.0 Hz), 1.77–

6506
H. Uehara et al. / Tetrahedron 58 (2002) 6493–6512
1.82 (1H, m), 1.90–1.97 (2H, m), 2.55 (1H, dd, J¼16.5,
4.5 Hz), 2.79 (1H, dd, J¼16.5, 3.5 Hz), 3.44 (1H, td, J¼9.5,
3.5 Hz), 3.53 (1H, dd, J¼9.5, 6.0 Hz), 3.61–3.69 (3H, m),
3.80 (1H, dd, J¼9.5, 2.0 Hz), 4.34 (1H, d, J¼11.0 Hz), 4.53
(1H, d, J¼12.0 Hz), 4.55 (1H, d, J¼11.0 Hz), 4.58 (1H, d,
J¼12.0 Hz), 7.21–7.35 (10H, m); 13C NMR (50 MHz,
CDCl3) d 4.9, 6.8, 22.5, 27.2, 27.6, 42.0, 47.5, 71.36, 71.40,
73.37, 73.41, 78.2, 83.5, 86.3, 118.3, 127.5, 127.56, 127.68,
127.73, 128.3, 138.0, 138.2; MALDI-TOF MS, calcd for
C31H45NO4SiNa 546.302 (MþNaþ), found 546.297.
m); 13C NMR (125 MHz, CDCl3) d 26.5, 27.9, 39.2, 41.0,
45.4, 52.3, 71.17, 71.19, 73.0, 74.3, 78.6, 82.7, 83.3, 126.8,
127.40, 127.43, 127.6, 128.18, 128.21, 128.6, 128.7, 131.3,
132.6, 133.1, 134.7, 138.0, 138.2; MALDI-TOF MS, calcd
for C37H42O4S2Na 637.242 (MþNaþ), found 637.266.
4.3. Construction of the J ring
4.3.1. Ester 53. To a mixture of alcohol 56 (1.54 g,
2.50 mmol) and carboxylic acid 7 (768 mg, 1.82 mmol) at rt
were added EDC·HCl (540 mg, 2.8 mmol), DMAP (22 mg,
0.18 mmol), and CSA (44 mg, 0.18 mmol). After being
stirred 2 d at 408C, the reaction mixture was directly
subjected to flash column chromatography (deactivated with
1% Et3N/hexane, hexane/EtOAc 20:1–10:1) gave ester 53
(1.41 g, 1.38 mmol) in 76% yield. 53: colorless oil; Rf¼0.65
(hexane/EtOAc 3:1); [a ]2D7¼269.2 (c 1.040, CHCl3); IR
(film) n 3062, 3030, 2929, 1731, 1583, 1496, 1455, 1373,
4.2.12. Dithioacetal 55. To a solution of nitrile 54 (4.78 g,
9.13 mmol) in CH2Cl2 (32 ml) at 2708C was added DIBAL
(18.5 ml, 0.95 M in hexane, 17.6 mmol) over 10 min. After
being stirred for 40 min, the reaction mixture was quenched
with EtOAc at 2708C, diluted with EtOAc, and stirred with
saturated Rochelle’s salt (20 ml) at rt for 2 h. The mixture
was extracted with hexane/EtOAc (£3), and the organic
layer was washed with brine and dried over MgSO4.
Concentration and purification through a pad of florisil
column afforded the aldehyde, which was used
immediately.
1
1175, 1097, 1069, 1028, 920, 737, 696 cm21; H NMR
(500 MHz, CDCl3) d 0.89 (3H, d, J¼6.5 Hz), 1.02 (6H, d,
J¼7.0 Hz), 1.20 (3H, d, J¼7.0 Hz), 1.45–2.09 (13H, m),
2.79 (1H, quint., J¼7.5 Hz), 3.06 (1H, t, J¼10.0 Hz), 3.36
(3H, s), 3.43–3.53 (3H, m), 3.79–3.89 (4H, m), 3.90–3.95
(1H, m), 4.24–4.30 (1H, m), 4.33 (1H, d, J¼12.5 Hz), 4.34
(1H, d, J¼11.5 Hz), 4.36 (1H, d, J¼12.5 Hz), 4.52 (1H, d,
J¼12.5 Hz), 4.54 (1H, d, J¼11.5 Hz), 4.61 (1H, d,
J¼7.0 Hz), 4.59–4.65 (1H, m), 4.72 (1H, d, J¼12.0 Hz),
4.75 (1H, d, J¼6.0 Hz), 5.10 (1H, dd, J¼9.5, 4.5 Hz), 7.17–
7.36 (21H, m), 7.36–7.39 (2H, m), 7.52–7.55 (2H, m); 13C
NMR (50 MHz, CDCl3) d 13.6, 14.6, 15.8, 24.4, 25.9, 28.1,
35.1, 38.0, 39.8, 40.3, 40.4, 41.6, 42.1, 52.1, 56.5, 67.5,
71.3, 72.6, 73.1, 73.7, 75.7, 78.7, 79.9, 80.0, 81.0, 83.1,
98.5, 107.9, 126.8, 127.3, 127.5, 127.65, 127.71, 128.19,
128.29, 128.33, 128.75, 128.80, 131.2, 132.5, 133.4, 136.3,
138.3, 139.0, 174.5; MALDI-TOF MS, calcd for
C60H74O10S2 1041.462 (MþNaþ), found 1041.441.
To the aldehyde and PhSSPh (2.20 g, 10.0 mmol) at rt was
added Bu3P (3.0 ml, 12.0 mmol) over 5 min. After being
stirred for 1 d at rt, the mixture was directly subjected to
flash column chromatography (deactivated with 1% Et3N/
hexane, hexane/EtOAc 50:1–30:1) gave dithioacetal 55
(4.83 g, 6.63 mmol) in 73% yield for 2 steps. 55: colorless
oil; Rf¼0.70 (hexane/EtOAc 3:1); [a ]2D8¼222.0 (c 1.00,
CHCl3); IR (neat) n 3061, 3030, 2953, 2875, 1583, 1481,
1454, 1438, 1362, 1239, 1090, 1006, 809, 736, 694 cm21
;
1H NMR (500 MHz, CDCl3) d 0.47–0.53 (6H, m), 0.89
(9H, t, J¼8.0 Hz), 1.02 (3H, d, J¼7.0 Hz), 1.64–1.98 (6H,
m), 2.15–2.22 (1H, m), 3.42–3.52 (3H, m), 3.55 (1H, dd,
J¼10.0, 1.5 Hz), 3.87–3.91 (1H, m), 3.95–4.00 (1H, m),
4.34 (1H, d, J¼11.0 Hz), 4.36 (1H, d, J¼12.5 Hz), 4.41 (1H,
d, J¼12.5 Hz), 4.53 (1H, d, J¼11.5 Hz), 5.07 (1H, dd,
J¼12.0, 2.5 Hz), 7.16–7.32 (16H, m), 7.43–7.46 (2H, m),
7.50–7.53 (2H, m); 13C NMR (50 MHz, CDCl3) d 4.9, 6.9,
26.6, 28.0, 39.5, 41.1, 45.3, 52.6, 71.1, 71.2, 73.1, 75.4,
78.5, 83.2, 83.3, 127.1, 127.37, 127.41, 127.5, 127.66,
127.71, 128.2, 128.3, 128.61, 128.64, 132.2, 132.7, 133.2,
134.4, 138.2, 138.6; MALDI-TOF MS, calcd for C43H56-
O4S2SiNa 751.329 (MþNaþ), found 751.337.
4.3.2. Cyclic enol ether 42. Mg turnings (58 mg,
2.4 mmol), powdered MS4A (200 mg), and Cp2TiCl2
(500 mg, 2.0 mmol) were placed in a flask and dried with
a heat gun under reduced pressure. THF (4.0 ml) and
P(OEt)3 (0.69 ml, 4.0 mmol) were added to this flask
successively under argon at rt, and the reaction mixture
was stirred for 3 h. Then a solution of ester 53 (504 mg,
494 mmol) in THF (6 ml) was added dropwise at rt. After
being heated to reflux for 1 h, the reaction mixture was
quenched with 1 M NaOH (15 ml) at rt and the resulting
insoluble materials were filtered off. The mixture was
extracted with Et2O (£2), and the organic layer was washed
with brine. The violet organic layer was left overnight to
give a colorless solution, which was dried over K2CO3.
Concentration and flash column chromatography (deacti-
vated with 1% Et3N/hexane, hexane/EtOAc 20:1–10:1)
afforded the cyclic enol ether 42 (260 mg, 331 mmol) in
67% yield. 42: colorless oil; Rf¼0.40 (hexane/EtOAc 6:1);
IR (film) n 2928, 1728, 1497, 1454, 1374, 1098, 1028, 736,
4.2.13. Alcohol 56. To dithioacetal 55 (5.73 g, 7.86 mmol)
at rt was added TBAF (8.7 ml, 1 M in THF, 8.7 mmol).
After being stirred for 3 h at rt, the mixture was
concentrated and subjected to flash column chromatography
(deactivated with 1% Et3N/hexane, hexane/EtOAc 10:1–
4:1) gave alcohol 56 (4.61 g, 7.01 mmol) in 95% yield. 56:
colorless oil; Rf¼0.45 (hexane/EtOAc 3:1); [a ]2D4¼268.6
(c 1.25, CHCl3); IR (film) n 3448, 3060, 3029, 2922, 2864,
1582, 1481, 1453, 1438, 1090, 1069, 1026, 738, 695 cm21
;
1H NMR (500 MHz, CDCl3) d 1.04 (3H, d, J¼7.0 Hz), 1.22
(1H, d, J¼6.0 Hz), 1.71 (1H, dt, J¼15.0, 8.0 Hz), 1.76–1.94
(3H, m), 1.95–2.02 (1H, m), 2.08 (1H, ddd, J¼14.0, 9.0,
3.0 Hz), 2.28 (1H, ddd, J¼14.0, 11.5, 2.5 Hz), 3.42–3.50
(3H, m), 3.54 (1H, dd, J¼10.0, 2.5 Hz), 3.85–3.90 (1H, m),
3.94–3.99 (1H, m), 4.35 (1H, d, J¼11.5 Hz), 4.40 (2H, s),
4.54 (1H, d, J¼11.0 Hz), 5.09 (1H, dd, J¼10.5, 4.0 Hz),
7.18–7.32 (16H, m), 7.41–7.44 (2H, m), 7.51–7.54 (2H,
697 cm21 1H NMR (500 MHz, CDCl3) d 0.88 (3H, d,
;
J¼6.0 Hz, Me57), 0.94 (3H, t, J¼7.5 Hz, Me41), 1.02 (3H,
d, J¼6.5 Hz, Me56), 1.03 (3H, d, J¼7.0 Hz, Me54), 1.23
(3H, d, J¼7.5 Hz, Me55), 1.39 (1H, dq, J¼14.0, 7.0 Hz,
H40), 1.47 (1H, dq, J¼11.0, 6.5 Hz, H48), 1.60–2.01 (10H,
m, H35£2, 37£2, 40, 47, 50£2, 51£2), 2.02–2.10 (1H, m,
H36), 2.82 (1H, dq, J¼8.0, 7.0 Hz, H43), 3.12 (1H, t,

H. Uehara et al. / Tetrahedron 58 (2002) 6493–6512
6507
J¼10.0 Hz, H46), 3.36 (3H, s, MOM), 3.50–3.57 (2H, m,
H34, 39), 3.57 (1H, dd, J¼9.5, 5.0 Hz, H32), 3.65 (1H, dd,
J¼9.5, 2.5 Hz, H32), 3.71 (1H, ddd, J¼8.5, 5.0, 2.5 Hz,
H33), 3.77–3.87 (4H, m, H44, 45, 52£2), 4.36 (1H, d,
J¼11.5 Hz, Bn), 4.51 (1H, d, J¼11.5 Hz, Bn), 4.52 (1H, d,
J¼12.5 Hz, Bn), 4.56 (1H, d, J¼12.0 Hz, Bn), 4.58 (1H, d,
J¼11.0 Hz, Bn), 4.63 (1H, d, J¼6.0 Hz, MOM), 4.69–4.75
(1H, m, H38), 4.74 (1H, d, J¼12.0 Hz, Bn), 4.78 (1H, d,
J¼6.5 Hz, MOM), 7.20–7.36 (15H, m, Bn£3); MALDI-
TOF MS, calcd for C48H66O10Na 825.455 (MþNaþ), found
825.369.
1454, 1379, 1324, 1099, 1069, 1028, 943, 921, 736, 698,
607 cm21 1H NMR (500 MHz, CDCl3) d 0.91 (6H, d,
;
J¼6.5 Hz, Me55, 57), 1.05 (3H, d, J¼6.2 Hz, Me56), 1.10
(3H, d, J¼7.0 Hz, Me54), 1.50–2.07 (11H, m, H35£2, 36,
37£2, 47, 48, 50£2, 51£2), 2.36–2.46 (1H, m, H52), 2.41
(1H, dd, J¼17.0, 9.5 Hz, H40), 2.93 (1H, dd, J¼17.0,
6.0 Hz, H40), 3.23 (1H, t, J¼10.0 Hz, H46), 3.35 (3H, s,
MOM), 3.35–4.00 (10H, m, H32£2, 33, 34, 38, 39, 44, 45,
52£2), 3.51 (1H, d, J¼9.0 Hz, H42), 4.32 (1H, d,
J¼11.0 Hz, Bn), 4.49 (1H, d, J¼11.5 Hz, Bn), 4.53 (2H,
s, Bn£2), 4.60 (1H, d, J¼11.0 Hz, Bn), 4.60 (1H, d,
J¼6.9 Hz, MOM), 4.81 (1H, d, J¼11.5 Hz, Bn), 4.85 (1H,
d, J¼6.9 Hz, MOM), 7.20–7.36 (15H, m, Bn£3); 13C NMR
(50 MHz, CDCl3) d 12.2, 13.6, 15.8, 24.3, 26.3, 28.4, 35.0,
36.1, 38.8, 39.9, 42.1, 43.3, 46.8, 56.2, 67.2, 71.4, 71.8,
72.8, 73.3, 73.5, 78.9, 79.9, 80.8, 81.8, 82.8, 84.1, 84.9,
98.8, 107.9, 127.1, 127.4, 127.5, 127.6, 127.7, 128.1, 128.3,
138.1, 138.3, 139.3, 207.5; HRMS (EI, 70 eV), calcd for
C48H64O10 800.4500 (Mþ), found 800.4504. 57: colorless
oil; Rf¼0.50 (pentane/Et2O 3:2); [a ]2D8¼297.4 (c 1.007,
CHCl3); IR (film) n 3030, 2927, 1721, 1496, 1454, 1380,
4.4. Construction of the K ring
4.4.1. Ketone 58. To a solution of the cyclic enol ether 42
(1.24 g, 1.58 mmol) in THF (16 ml) at 08C was added
BH3·THF complex (1.75 ml, 1 M in THF, 1.75 mmol).
After 2.5 h at rt, additional BH3·THF complex (0.16 ml, 1 M
in THF, 0.16 mmol) was introduced at 08C to complete the
hydroboration reaction. After additional 1 h at rt, 15%
aqueous NaOH (1.9 ml, 7.9 mmol) was added to the
reaction mixture at 08C, followed by addition of 30%
aqueous H2O2 (1.8 ml, 16 mmol). After being stirred
overnight at rt, the mixture was diluted with aqueous
saturated NH4Cl, extracted with EtOAc (£2), and the
organic layer was washed with brine, and dried over
MgSO4. Concentration and flash column chromatography
(hexane/EtOAc 10:1–3:1) afforded a diastereomer mixture
of the alcohols (950 mg, 1.18 mmol) in 75% combined
yield.
1
1323, 1099, 1069, 1028, 921, 751, 698 cm21; H NMR
(500 MHz, CDCl3) d 0.88 (3H, d, J¼6.7 Hz, Me55), 0.93
(3H, d, J¼6.2 Hz, Me57), 1.07 (3H, d, J¼6.2 Hz, Me56),
1.10 (3H, d, J¼7.0 Hz, Me54), 1.50–2.06 (11H, m, H35£2,
36, 37£2, 47, 48, 50£2, 51£2), 2.45–2.60 (1H, m, H43),
2.53 (1H, dd, J¼14.3, 11.4 Hz, H40), 2.87 (1H, dd, J¼14.3,
5.0 Hz, H40), 3.12 (1H, t, J¼10.0 Hz, H46), 3.37 (3H, s,
MOM), 3.37–3.93 (10H, m, H32£2, 33, 34, 38, 39, 42, 44,
52£2), 4.15 (1H, dd, J¼10.0, 2.5 Hz, H45), 4.31 (1H, d,
J¼11.0 Hz, Bn), 4.50 (1H, d, J¼11.5 Hz, Bn), 4.50–4.60
(2H, m, MOM), 4.57 (1H, d, J¼11.0 Hz, Bn), 4.64 (2H, s,
Bn£2), 4.73 (1H, J¼11.5 Hz, Bn), 7.20–7.36 (15H, m,
Bn£3); 13C NMR (50 MHz, CDCl3) d 10.6, 13.6, 16.0, 24.3,
26.7, 28.0, 32.4, 35.0, 38.4, 40.2, 42.4, 43.7, 45.7, 56.2,
67.7, 71.4, 71.5, 72.0, 72.5, 73.0, 73.3, 78.0, 78.6, 80.7,
83.2, 83.8, 85.7, 95.9, 107.7, 127.2, 127.48, 127.55, 127.64,
127.8, 128.1, 128.3, 138.1, 138.2, 139.0, 206.9; HRMS (EI,
70 eV), calcd for C48H64O10 800.4500 (Mþ), found
800.4487.
The mixture of the alcohols (1.11 g, 1.39 mmol) in CH2Cl2
(6 ml) was added to a solution of DMSO (0.49 ml,
6.9 mmol) and (COCl)2 (0.38 ml, 4.2 mmol) in CH2Cl2
(10 ml) at 2708C. After 30 min at the same temperature,
Et3N (2.0 ml, 14 mmol) was added, and the reaction mixture
was allowed to warm to 2408C over 1 h, and then quenched
with aqueous NH4Cl at 2408C. The mixture was extracted
with hexane/EtOAc (£2), and the organic layer was washed
with aqueous saturated NH4Cl and brine, dried over MgSO4,
and concentrated. The residue was purified through a pad of
silica gel and the resulting ketones were separated by
medium pressure column chromatography (MPLC, Ultra
Pack SI-40B, Yamazen, hexane/Et2O 10:1–5:1) to give the
desired ketone 58 (346 mg, 432 mmol, 31%) and the C42-
epimer 57 (628 mg, 784 mmol, 57%).
4.4.2. Methyl ketal 60. To a solution of ketone 58 (281 mg,
295 mmol) and CH(OMe)3 (0.35 ml) in hexane (3.5 ml) at rt
was added TfOH (42 ml, 0.25 M in CH2Cl2, 11 mmol). After
being stirred for 19 h at rt, the mixture was quenched with
aqueous saturated NaHCO3, extracted with hexane/EtOAc
(£2). The organic layer was washed with brine, and dried
over MgSO4. Concentration and flash column chromato-
graphy (hexane/EtOAc 1:0–15:1) afforded the methyl ketal
60 (227 mg, 295 mmol) in 84% yield. 60: colorless oil;
Rf¼0.70 (pentane/Et2O 3:2); [a ]2D9¼225.8 (c 0.752,
CHCl3); IR (film) n 3064, 3030, 2926, 1496, 1462, 1455,
To a solution of the C-42 epimeric ketone 57 (628 mg,
784 mmol) in CH2Cl2 (5 ml) at rt was added DBU (0.25 ml).
After being stirred for 4 h, the mixture was diluted with
EtOAc and aqueous saturated NH4Cl and then extracted
with hexane/EtOAc (£2). The organic layer was washed
with aqueous saturated NH4Cl and brine, dried over MgSO4,
and concentrated. The residue was purified through a pad of
flash column and the resulting ketones were separated by
MPLC to give the desired ketone 58 and the C42-epimer 57.
The undesired C42-epimer 57 was subjected to additional
two cycles of the isomerization–separation sequence to
afford the desired ketone 58 (367 mg, 458 mmol, 58% yield
for 3 cycles) and the C42-epimer 57 (75 mg, 94 mmol, 12%
yield for 3 cycles). 58: colorless oil; Rf¼0.45 (pentane/Et2O
3:2); [a]2D8¼231.4 (c 0.876, CHCl3); IR (film) n 3088,
3063, 3030, 2926, 2061, 1723, 1641, 1605, 1548, 1496,
1
1360, 1206, 1069, 1028, 972, 752, 697 cm21; H NMR
(500 MHz, CDCl3) d 0.90 (3H, d, J¼6.2 Hz, Me57), 1.05
(3H, d, J¼7.0 Hz, Me55), 1.06 (3H, d, J¼6.0 Hz, Me56),
1.08 (3H, d, J¼7.0 Hz, Me54), 1.40–2.40 (13H, m, H35£2,
36, 37£2, 40, 43, 47, 48, 50£2, 51£2), 2.57 (1H, dd,
J¼14.0, 4.0 Hz, H40), 2.89 (1H, d, J¼9.2 Hz, H42), 3.04–
3.12 (1H, m, H38), 3.09 (3H, s, OMe), 3.25–3.32 (2H, m,
H39, 44), 3.38 (1H, td, J¼9.0, 3.0 Hz, H34), 3.43 (1H, dd,
J¼10.0, 7.0 Hz, H32), 3.52–3.58 (2H, m, H45, 46), 3.60–
3.65 (1H, m, H33), 3.74 (1H, dd, J¼10.0, 3.0 Hz, H32), 3.82
(1H, bq, J¼7.0 Hz, H52), 3.86–3.92 (1H, m, H52), 4.31

6508
H. Uehara et al. / Tetrahedron 58 (2002) 6493–6512
(1H, d, J¼11.2 Hz, Bn), 4.51 (1H, d, J¼11.5 Hz, Bn), 4.54
(1H, d, J¼11.5 Hz, Bn), 4.58 (1H, d, J¼11.2 Hz, Bn), 4.63
(2H, s, Bn£2), 7.20–7.36 (15H, m, Bn£3); 13C NMR
(50 MHz, CDCl3) d 13.5, 16.6, 20.2, 24.6, 26.8, 28.1, 35.0,
37.2, 38.5, 39.0, 40.2, 40.7, 43.9, 48.3, 67.6, 68.7, 71.4,
72.4, 72.6, 72.9, 73.4, 79.0, 80.8, 81.5, 83.9, 85.4, 85.9,
98.9, 107.7, 126.8, 127.26, 127.31, 127.39, 127.46, 127.50,
127.59, 127.7, 127.9, 128.2, 128.3, 138.2, 138.5, 140.0;
HRMS (EI, 70 eV), calcd for C47H62O9 770.4394 (Mþ),
found 770.4399.
(0.4 ml) and Et3N (0.1 ml) at rt were added DMAP (0.7 mg,
6 mmol) and p-BrBzCl (6.8 mg, 31 mmol). Additional p-
BrBzCl (6.8 mg, 31 mmol) was introduced to complete the
reaction. MeOH was added to the mixture, and the resultant
solution was diluted with EtOAc and aqueous saturated
NH4Cl, and extracted with hexane/EtOAc (£2). The organic
layer was washed with brine, and dried over MgSO4.
Concentration and flash column chromatography (hex-
ane/EtOAc 1:0–6:1) gave bis-p-bromobenzoate 63
(3.8 mg, 4.5 mmol, 65% yield), which was recrystallized
from hexane/CH2Cl2 and subjected to X-ray crystallogra-
phy. 63: prisms; Rf¼0.70 (hexane/EtOAc 1:1); IR (film) n
3440, 2959, 2924, 1727, 1715, 1591, 1455, 1398, 1264,
4.4.3. IJKLM ring fragment 5. To a solution of the methyl
ketal 60 (104 mg, 134 mmol) and Et3SiH (0.48 ml,
3.0 mmol) in CH2Cl2 (1.1 ml) at 2508C was added
BF3·OEt2 (0.33 ml, 10% solution in CH2Cl2, 0.27 mmol).
The reaction was allowed to warm to 2208C over 1 h, and
then quenched with 1% Et3N/hexane and aqueous NaHCO3
at 2208C. The mixture was extracted with hexane/EtOAc
(£2), and the organic layer was washed with brine, and dried
over MgSO4. Concentration and flash column chromato-
graphy (hexane/EtOAc 1:0–15:1) gave the IJKLM ring
fragment 5 (70.9 mg, 95.7 mmol) in 71% yield. 5: colorless
oil; Rf¼0.75 (pentane/Et2O 3:2); [a ]2D9¼241.2 (c 0.807,
CHCl3); IR (film) n 2954, 2925, 2854, 1454, 1377, 1260,
1
1175, 1116, 1069, 1013, 976, 847, 755 cm21; H NMR
(500 MHz, CDCl3) d 0.88–0.91 (6H, m), 1.07 (3H, d,
J¼7.0 Hz), 1.15 (3H, d, J¼7.5 Hz), 1.40 (1H, q,
J¼11.5 Hz), 1.46–2.07 (12H, m), 2.16 (1H, bs), 2.24 (1H,
dt, J¼12.5, 4.5 Hz), 2.87 (1H, dd, J¼9.5, 4.5 Hz), 3.07–
3.13 (1H, m), 3.15 (1H, t, J¼9.5 Hz), 3.32 (1H, ddd,
J¼11.5, 8.5, 4.5 Hz), 3.61–3.67 (2H, m), 3.72 (1H, bs), 3.79
(1H, q, J¼7.0 Hz), 3.88 (1H, td, J¼8.0, 4.0 Hz), 4.00–4.05
(1H, m), 4.24 (1H, dd, J¼11.5, 8.0 Hz), 4.42 (1H, dd,
J¼11.5, 3.0 Hz), 5.07 (1H, td, J¼9.5, 2.5 Hz), 7.53–7.58
(4H, m), 7.83–7.90 (4H, m); 13C NMR (50 MHz, CDCl3) d
13.4, 15.5, 19.8, 24.3, 26.9, 27.9, 34.9, 38.4, 39.4, 41.7,
42.0, 42.2, 44.3, 66.4, 67.6, 71.6, 74.2, 75.4, 77.3, 78.7,
80.2, 82.7, 83.3, 86.4, 108.7, 128.2, 128.4, 128.8 (£2),
131.06 (£2), 131.11 (£2), 131.79 (£2), 131.81 (£2), 164.7,
165.5; MALDI-TOF MS, calcd for C39H48Br2O10Na
857.151 (MþNaþ), found 857.134.
1098, 1072, 1027, 974, 803, 733, 697 cm21 1H NMR
;
(600 MHz, CDCl3) d 0.89 (3H, d, J¼6.3 Hz, Me57), 1.02
(3H, d, J¼6.0 Hz, Me56), 1.08 (3H, d, J¼7.1 Hz, Me54),
1.11 (3H, d, J¼7.7 Hz, Me55), 1.41 (1H, q, J¼11.7 Hz,
H40), 1.50–1.57 (2H, m, H47, 48), 1.63 (1H, bdt, J¼14.2,
10.2 Hz, H37), 1.68 (1H, bddd, J¼15.2, 9.5, 6.4 Hz, H35),
1.73–1.81 (2H, m, H50, 51), 1.83–1.88 (1H, m, H37),
1.90–1.98 (4H, m, H35, 36, 50, 51), 2.15 (1H, qdd, J¼7.7,
4.6, 3.5 Hz, H43), 2.40 (1H, bdt, J¼12.0, 4.8 Hz, H40), 2.87
(1H, dd, J¼9.3, 4.6 Hz, H42), 3.06 (1H, btd, J¼9.6, 3.0 Hz,
H38), 3.23 (1H, ddd, J¼11.3, 9.0, 4.4 Hz, H39), 3.35 (1H, t,
J¼9.5 Hz, H46), 3.41 (1H, btd, J¼9.2, 2.8 Hz, H34), 3.43
(1H, bdd, J¼3.5, 1.0 Hz, H41), 3.44 (1H, dd, J¼10.0,
6.5 Hz, H32), 3.60 (1H, bddd, J¼9.3, 6.5, 2.1 Hz, H33),
3.64 (1H, dd, J¼9.5, 1.0 Hz, H45), 3.68 (1H, dd, J¼10.0,
2.1 Hz, H32), 3.75 (1H, bq, J¼7.5 Hz, H52), 3.82 (1H, ddd,
J¼11.2, 9.3, 5.0 Hz, H41), 3.87 (1H, btd, J¼7.8, 4.5 Hz,
H52), 4.32 (1H, d, J¼11.1 Hz, Bn), 4.55 (2H, s, Bn£2), 4.58
(1H, d, J¼11.1 Hz, Bn), 4.63 (1H, d, J¼12.2 Hz, Bn), 4.68
(1H, d, J¼12.2 Hz, Bn), 7.20–7.40 (15H, m, Bn£3); 13C
NMR (125 MHz, CDCl3) d 13.4, 15.8, 20.0, 22.7, 24.4,
28.2, 29.7, 30.3, 35.0, 38.6, 39.6, 40.3, 41.8, 71.4, 71.9,
72.0, 72.1, 73.4, 74.3, 77.2, 77.5, 78.1, 79.0, 80.3, 82.7,
84.7, 86.9, 108.3, 127.1, 127.4, 127.58, 127.63, 127.9,
128.1, 128.29, 128.33, 138.6; HRMS (EI, 70 eV), calcd for
C46H60O8 740.4288 (Mþ), found 740.4304.
4.5. Construction of the H ring
4.5.1. p-Methoxybenzylidene acetal 64. To a solution of
the tribenzyl ethers 5 (290 mg, 390 mmol) in EtOAc (1 ml),
MeOH (1 ml), and AcOH (30 ml) at rt was added 20%
Pd(OH)2/C (37 mg, 53 mmol), and the mixture was stirred
under hydrogen. After 1 d, additional 20% Pd(OH)2/C
(11 mg, 16 mmol) was introduced to the reaction mixture.
After 1.5 d, the catalyst was filtered off, and the solvent was
removed under reduced pressure to give the triol, which was
used in the next reaction without further purification. The
triol: white solid; Rf¼0.30 (hexane/EtOAc 1:3); IR (film) n
3452, 2957, 2926, 1455, 1379, 1274, 1072, 1027, 976,
759 cm21 1H NMR (500 MHz, CDCl3) d 0.89 (3H, d,
;
J¼6.5 Hz), 1.03 (3H, d, J¼6.5 Hz), 1.06 (3H, d, J¼7.0 Hz),
1.15 (3H, d, J¼7.5 Hz), 1.41 (1H, q, J¼11.5 Hz), 1.46–2.06
(14H, m), 2.19 (1H, bs), 2.33 (1H, dt, J¼12.0, 5.0 Hz), 2.87
(1H, dd, J¼9.5, 4.5 Hz), 2.99–3.06 (1H, m), 3.24 (1H, t,
J¼9.5 Hz), 3.22–3.29 (1H, m), 3.36 (1H, dt, J¼9.5,
5.0 Hz), 3.60–3.75 (5H, m), 3.79 (1H, q, J¼7.5 Hz),
3.78–3.82 (1H, m), 3.88 (1H, td, J¼7.5, 4.5 Hz); 13C
NMR (50 MHz, CDCl3) d 13.4, 15.7, 19.7, 24.3, 27.7, 27.8,
35.0, 38.5, 39.9, 42.1, 42.2, 44.9, 47.6, 65.1, 67.6, 71.7,
72.9, 75.5, 77.2, 78.6, 80.7, 82.9, 86.3, 87.3, 108.7; MALDI-
TOF MS, calcd for C25H42O8Na 493.278 (MþNaþ), found
493.259.
4.4.4. Bis-p-bromobenzoate 63. To a solution of the
tribenzyl ethers 5 (11.3 mg, 15.3 mmol) in EtOAc (1 ml),
MeOH (1 ml), and AcOH (30 ml) at rt was added 20%
Pd(OH)2/C (4.3 mg, 8 mmol), and the mixture was stirred
under hydrogen. After 2 d, additional 20% Pd(OH)2/C
(4.3 mg, 8 mmol) was introduced to the reaction mixture.
After 1 d, the catalyst was filtered off, and the solvent was
removed under reduced pressure and the residue was
subjected to flash column chromatography (hexane/EtOAc
3:1–0:1) to give the triol (7.1 mg, 15.1 mmol) in 99% yield.
To a solution of the triol and anisaldehyde dimethylacetal
(100 ml, 540 mmol) in THF (2 ml) at rt was added CSA
(4.2 mg, 18 mmol). After being stirred for 1 h, the mixture
was quenched with aqueous saturated NaHCO3 and
extracted with hexane/EtOAc (£3). The organic layer was
To a solution of the triol (3.3 mg, 7.0 mmol) in CH2Cl2

H. Uehara et al. / Tetrahedron 58 (2002) 6493–6512
6509
washed with brine, and dried over MgSO4. Concentration
and flash column chromatography (hexane/EtOAc 20:1–
3:1) gave the p-methoxybenzylidene acetal 64 (174 mg,
296 mmol) in 76% yield. 64: white solid; Rf¼0.30
4.5 Hz), 4.29 (1H, d, J¼11.0 Hz), 4.55 (1H, d, J¼11.0 Hz),
4.62 (1H, d, J¼11.0 Hz), 4.68 (1H, d, J¼11.0 Hz), 4.81 (1H,
d, J¼7.0 Hz), 4.84 (1H, d, J¼7.0 Hz), 6.84–6.89 (2H, m),
7.19–7.23 (2H, m), 7.26–7.38 (5H, m); MALDI-TOF MS,
calcd for C41H58O10Na 733.393 (MþNaþ), found 733.605.
1
(hexane/EtOAc 3:1); H NMR (500 MHz, CDCl3) d 0.90
(3H, d, J¼7.0 Hz), 1.04 (3H, d, J¼6.5 Hz), 1.07 (3H, d,
J¼7.5 Hz), 1.16 (3H, d, J¼7.5 Hz), 1.42 (1H, q,
J¼12.0 Hz), 1.46–2.07 (12H, m), 2.16 (1H, d, J¼2.0 Hz),
2.25 (1H, dt, J¼12.0, 5.0 Hz), 2.87 (1H, dd, J¼9.5, 5.0 Hz),
2.97–3.03 (1H, m), 3.19 (1H, ddd, J¼12.0, 8.5, 5.0 Hz),
3.25 (1H, t, J¼10.0 Hz), 3.43 (1H, td, J¼9.0, 5.0 Hz), 3.50
(1H, t, J¼10.5 Hz), 3.56–3.62 (1H, m), 3.65 (1H, dd,
J¼9.5, 1.0 Hz), 3.69–3.76 (2H, m), 3.79 (3H, s), 3.79 (1H,
q, J¼7.5 Hz), 3.89 (1H, td, J¼7.5, 5.0 Hz), 4.16 (1H, td,
J¼10.5, 5.0 Hz), 5.36 (1H, s), 6.85–6.88 (2H, m), 7.36–
7.39 (2H, m).
4.5.3. Nitrile 67. To a solution of alcohol 66 (220 mg,
309 mmol) in (CH2Cl)2 (3.0 ml) and Et3N (0.18 ml,
1.3 mmol) at 08C was added MsCl (50 ml, 0.62 mmol).
After 40 min, aqueous NH4Cl was added to the mixture,
which was extracted with hexane/EtOAc (£2). The organic
layer was washed with brine, and dried over MgSO4.
Concentration and flash column chromatography (hex-
ane/EtOAc 3:1) gave a mesylate, which was used in the
next reaction without further purification.
To a solution of the mesylate and 18-crown-6 (25 mg,
95 mmol) in DMF (1.0 ml) at rt was added NaCN (90 mg,
1.84 mmol). After 2 d at 508C, aqueous NaHCO3 was added
to the mixture, which was extracted with EtOAc (£2). The
organic layer was washed with brine, and dried over
MgSO4. Concentration and flash column chromatography
(hexane/EtOAc 1:0–3:1) gave nitrile 67 (202 mg,
280 mmol) in 91% over 2 steps. 67: colorless oil; Rf¼0.40
4.5.2. Alcohol 66. To a solution of alcohol 64 (182 mg,
309 mmol) and i-Pr2NEt (0.54 ml, 3.1 mmol) in (CH2Cl)2
(1 ml) at rt was added BOMCl (0.13 ml, 0.93 mmol), and
the reaction mixture was heated to 408C for 14 h. The
reaction mixture was cooled to rt, and quenched with Et3N
(0.5 ml) and MeOH (0.3 ml). The solution was diluted with
aqueous NH4Cl and extracted with EtOAc (£3), and the
organic layer was washed with brine and dried over MgSO4.
Concentration and flash column chromatography (hex-
ane/EtOAc 1:0–5:1) afforded the BOM ether 65
(222.5 mg), which was used in the next reaction without
further purification. 65: colorless viscous oil; Rf¼0.60
1
(hexane/EtOAc 3:1); H NMR (500 MHz, CDCl3) d 0.87
(3H, d, J¼6.0 Hz), 1.03 (3H, d, J¼6.0 Hz), 1.11 (3H, d,
J¼7.5 Hz), 1.14 (3H, d, J¼7.5 Hz), 1.41 (1H, q,
J¼11.5 Hz), 1.45–1.77 (6H, m), 1.84–2.01 (5H, m),
2.07–2.13 (1H, m), 2.31 (1H, dd, J¼16.5, 8.5 Hz), 2.50
(1H, dt, J¼12.5, 5.0 Hz), 2.71 (1H, dd, J¼16.5, 2.5 Hz),
2.87 (1H, dd, J¼9.5, 4.5 Hz), 2.99–3.04 (1H, m), 3.21–3.28
(2H, m), 3.32 (1H, t, J¼9.5 Hz), 3.65 (1H, d, J¼10.0 Hz),
3.67 (1H, td, J¼9.0, 3.0 Hz), 3.73 (1H, d, J¼3.5 Hz), 3.76
(1H, q, J¼7.5 Hz), 3.80 (3H, s), 3.78–3.84 (1H, m), 3.86
(1H, td, J¼7.5, 4.5 Hz), 4.26 (1H, d, J¼11.5 Hz), 4.57 (1H,
d, J¼11.5 Hz), 4.62 (1H, d, J¼11.0 Hz), 4.67 (1H, d,
J¼11.0 Hz), 4.81 (1H, d, J¼7.0 Hz), 4.84 (1H, d,
J¼7.0 Hz), 6.85–6.89 (2H, m), 7.18–7.21 (2H, m), 7.25–
7.38 (5H, m); MALDI-TOF MS, calcd for C42H57NO9Na
742.3931 (MþNaþ), found 742.4296.
1
(hexane/EtOAc 3:1); H NMR (500 MHz, CDCl3) d 0.88
(3H, d, J¼6.0 Hz), 1.05 (3H, d, J¼5.5 Hz), 1.07 (3H, d,
J¼7.5 Hz), 1.16 (3H, d, J¼7.5 Hz), 1.42 (1H, q,
J¼11.5 Hz), 1.46–1.98 (11H, m), 2.09–2.15 (1H, m),
2.25 (1H, dt, J¼12.5, 4.5 Hz), 2.88 (1H, dd, J¼9.5, 4.5 Hz),
2.97–3.02 (1H, m), 3.13–3.20 (1H, m), 3.32 (1H, t,
J¼9.5 Hz), 3.44 (1H, td, J¼9.0, 5.0 Hz), 3.50 (1H, t,
J¼10.5 Hz), 3.56–3.62 (1H, m), 3.66 (1H, d, J¼9.0 Hz),
3.73–3.83 (2H, m), 3.77 (1H, q, J¼7.5 Hz), 3.79 (3H, s),
3.87 (1H, td, J¼7.5, 5.0 Hz), 4.17 (1H, td, J¼10.5, 5.5 Hz),
4.63 (1H, d, J¼11.5 Hz), 4.69 (1H, d, J¼11.5 Hz), 4.82 (1H,
d, J¼7.0 Hz), 4.85 (1H, d, J¼7.0 Hz), 5.37 (1H, s), 6.85–
6.88 (2H, m), 7.26–7.41 (7H, m).
4.5.4. a,b-Unsaturated ester 68. To a solution of nitrile 67
(80.8 mg, 112 mmol) in CH2Cl2 (1.1 ml) at 2808C was
added DIBAL (0.36 ml, 0.95 M in hexane, 0.34 mmol)
dropwise. After 30 min, the reaction mixture was quenched
with EtOAc at 2708C, diluted with EtOAc and aqueous
saturated NH4Cl, and stirred with aqueous saturated
Rochelle’s salt at rt for 30 min. The mixture was extracted
with EtOAc (£2), and the organic layer was washed with
brine, dried over MgSO4, and concentrated to afford an
aldehyde, which was used in the next reaction immediately.
To a solution of the BOM ether 65 (222.5 mg) in CH2Cl2
(6.0 ml) at 2808C was added DIBAL (8.5 ml, 0.93 M in
hexane, 7.7 mmol) over 5 min. The solution was allowed to
warm to 2408C over 1.5 h, and then the mixture was
quenched with aqueous saturated NH4Cl at 2408C, diluted
with EtOAc, and stirred with saturated Rochelle’s salt for
2 h. The mixture was extracted with EtOAc (£2), and the
organic layer was washed with brine and dried over MgSO4.
Concentration and flash column chromatography (hex-
ane/EtOAc 10:1–3:1) afforded alcohol 66 (220 mg,
309 mmol) in 100% yield over 2 steps. 66: colorless oil;
Rf¼0.30 (hexane/EtOAc 3:1); 1H NMR (500 MHz, CDCl3)
d 0.88 (3H, d, J¼6.0 Hz), 1.03 (3H, d, J¼6.0 Hz), 1.08 (3H,
d, J¼7.0 Hz), 1.15 (3H, d, J¼7.5 Hz), 1.39 (1H, q,
J¼11.5 Hz), 1.45–1.77 (6H, m), 1.84–1.96 (5H, m),
2.00–2.17 (2H, m), 2.33 (1H, dd, J¼12.0, 4.5 Hz), 2.87
(1H, dd, J¼9.5, 4.5 Hz), 3.00–3.06 (1H, m), 3.25 (1H, ddd,
J¼11.0, 9.5, 5.0 Hz), 3.31 (1H, t, J¼9.5 Hz), 3.34 (1H, td,
J¼9.0, 2.5 Hz), 3.42–3.51 (2H, m), 3.56 (1H, d, J¼9.0 Hz),
3.72–3.81 (4H, m), 3.79 (3H, s), 3.87 (1H, td, J¼7.5,
To a solution of the aldehyde in toluene (1.2 ml) at rt was
added (carbethoxyethylene)triphenylphosphorane (123 mg,
0.34 mmol). After being stirred for 3 h, the mixture was
subjected directly to flash column chromatography (hex-
ane/EtOAc 20:1–10:1) to give the a,b-unsaturated ester 68
(75.7 mg, 93.8 mmol) in 84% over 2 steps. 68: colorless oil;
Rf¼0.60 (hexane/EtOAc 3:1); 1H NMR (500 MHz, CDCl3)
d 0.87 (3H, d, J¼6.0 Hz), 1.02 (3H, d, J¼6.0 Hz), 1.07 (3H,
d, J¼7.0 Hz), 1.14 (3H, d, J¼7.0 Hz), 1.28 (3H, t,
J¼7.5 Hz), 1.44–1.77 (6H, m), 1.82 (3H, s), 1.81–1.95
(6H, m), 2.07–2.14 (1H, m), 2.18 (1H, dt, J¼15.0, 8.5 Hz),

6510
H. Uehara et al. / Tetrahedron 58 (2002) 6493–6512
2.27 (1H, dt, J¼12.0, 5.0 Hz), 2.58–2.64 (1H, m), 2.85 (1H,
dd, J¼9.5, 4.5 Hz), 2.98–3.04 (1H, m), 3.17 (1H, ddd,
J¼11.0, 9.0, 5.0 Hz), 3.23 (1H, dd, J¼9.0, 3.0 Hz), 3.29
(1H, t, J¼9.5 Hz), 3.45 (1H, td, J¼9.0, 3.0 Hz), 3.65 (1H, d,
J¼10.0 Hz), 3.69–3.76 (2H, m), 3.76 (1H, q, J¼8.0 Hz),
3.79 (3H, s), 3.86 (1H, td, J¼8.0, 5.0 Hz), 4.14–4.21 (2H,
m), 4.29 (1H, d, J¼11.0 Hz), 4.55 (1H, d, J¼11.0 Hz), 4.62
(1H, d, J¼11.5 Hz), 4.68 (1H, d, J¼11.5 Hz), 4.81 (1H, d,
J¼6.5 Hz), 4.84 (1H, d, J¼6.5 Hz), 6.81–6.88 (3H, m),
7.20–7.24 (2H, m), 7.25–7.38 (5H, m); MALDI-TOF MS,
calcd for C47H66O11Na 829.450 (MþNaþ), found 829.459.
chromatography (hexane/EtOAc 12:1–3:1) gave the epoxy
alcohol 70 (174 mg, 223 mmol) in 97% yield. 70: colorless
oil; Rf¼0.70 (hexane/EtOAc 1:1); [a]2D9¼231.6 (c 0.994,
CHCl3); IR (film) n 3479, 2929, 2873, 1613, 1514, 1455,
1
1380, 1249, 1176, 1101, 1073, 1037, 822, 735 cm21; H
NMR (500 MHz, CDCl3) d 0.87 (3H, d, J¼6.5 Hz, Me57),
1.03 (3H, d, J¼6.0 Hz, Me56), 1.08 (3H, d, J¼7.0 Hz,
Me54), 1.14 (3H, d, J¼7.5 Hz, Me55), 1.27 (3H, s, Me53),
1.39 (1H, q, J¼11.5 Hz, H40), 1.45–1.61 (3H, m, H37, 47,
48), 1.64–1.99 (10H, m, H32£2, 35£2, 36, 37, 50£2,
51£2), 2.09–2.14 (1H, m, H43), 2.32 (1H, dt, J¼12.0,
5.0 Hz, H40), 2.87 (1H, dd, J¼9.5, 4.5 Hz, H42), 3.06 (1H,
td, J¼9.5, 4.5 Hz, H38), 3.20 (1H, t, J¼6.0 Hz, H31), 3.22–
3.28 (1H, m, H39), 3.31 (1H, t, J¼9.5 Hz, H46), 3.30–3.35
(1H, m, H34), 3.49–3.54 (1H, m, H33), 3.56 (1H, dd,
J¼12.5, 8.0 Hz, H29), 3.65 (1H, d, J¼9.5 Hz, H45), 3.68
(1H, dd, J¼12.5, 4.0 Hz, H29), 3.72–3.81 (3H, m, H41, 44,
52), 3.79 (3H, s, MPM), 3.86 (1H, td, J¼8.0, 4.5 Hz, H52),
4.31 (1H, d, J¼11.0 Hz, MPM), 4.54 (1H, d, J¼11.0 Hz,
MPM), 4.62 (1H, d, J¼11.5 Hz, BOM), 4.68 (1H, d,
J¼11.5 Hz, BOM), 4.81 (1H, d, J¼7.0 Hz, BOM), 4.85 (1H,
d, J¼7.0 Hz, BOM), 6.84–6.87 (2H, m, MPM), 7.20–7.38
(7H, m, MPM, BOM); 13C NMR (125 MHz, CDCl3) d 13.3,
14.2, 15.6, 19.9, 24.2, 26.2, 27.9, 33.2, 34.8, 38.4, 38.7,
39.5, 40.5, 41.7, 44.0, 55.1, 57.6, 59.9, 65.5, 67.2, 69.0,
70.9, 71.1, 74.2, 78.2, 80.0, 81.7, 81.8, 81.9, 83.6, 86.7,
93.4, 108.2, 113.6, 127.4, 127.9, 128.2, 129.5, 130.3, 138.0,
159.1; MALDI-TOF MS, calcd for C45H64O11Na 803.435
(MþNaþ), found 803.439.
4.5.5. Allyl alcohol 69. To a solution of the a,b-unsaturated
ester 68 (194 mg, 240 mmol) in CH2Cl2 (2.4 ml) at 2608C
was added DIBAL (0.8 ml, 0.93 M in hexane, 0.74 mmol)
over 10 min. After being stirred for 20 min at 2608C, the
reaction mixture was quenched with EtOAc at 2608C,
diluted with EtOAc, and stirred with aqueous saturated
Rochelle’s salt for 2 h. The mixture was extracted with
EtOAc (£3), and the combined organic layer was washed
with brine and dried over MgSO4. Concentration and flash
column chromatography (hexane/EtOAc 1:0–5:1) afforded
the allyl alcohol 69 (175 mg, 229 mmol) in 95% yield. 69:
colorless oil; Rf¼0.25 (hexane/EtOAc 3:1); [a ]3D0¼236.0
(c 0.985, CHCl3); IR (film) n 3469, 2927, 2873, 1612, 1514,
1
1454, 1249, 1178, 1101, 1074, 1038, 754 cm21; H NMR
(500 MHz, CDCl3) d 0.88 (3H, d, J¼6.5 Hz, Me57), 1.03
(3H, d, J¼6.0 Hz, Me56), 1.07 (3H, d, J¼7.5 Hz, Me54),
1.14 (3H, d, J¼7.0 Hz, Me55), 1.30 (1H, q, J¼11.5 Hz,
H40), 1.66 (3H, s, Me53), 1.45–1.95 (11H, m, H35£2, 36,
37£2, 47, 48, 50£2, 51£2), 2.03–2.14 (2H, m, H32, 43),
2.26 (1H, dt, J¼12.0, 5.0 Hz, H40), 2.45–2.51 (1H, m,
H32), 2.85 (1H, dd, J¼9.0, 4.5 Hz, H42), 3.01 (1H, td,
J¼9.5, 3.5 Hz, H38), 3.16 (1H, ddd, J¼11.5, 9.0, 5.0 Hz,
H39), 3.23 (1H, td, J¼9.0, 2.0 Hz, H34), 3.31 (1H, t,
J¼9.5 Hz, H46), 3.37 (1H, td, J¼9.0, 2.5 Hz, H33), 3.65
(1H, d, J¼9.0 Hz, H45), 3.69–3.75 (2H, m, H41, 44), 3.76
(1H, q, J¼7.5 Hz, H52), 3.79 (3H, s, MPM), 3.86 (1H, td,
J¼7.5, 4.5 Hz, H52), 3.98–4.04 (2H, m, H29£2), 4.29 (1H,
d, J¼11.0 Hz, MPM), 4.55 (1H, d, J¼11.0 Hz, MPM), 4.62
(1H, d, J¼11.5 Hz, BOM), 4.68 (1H, d, J¼11.5 Hz, BOM),
4.81 (1H, d, J¼6.5 Hz, BOM), 4.84 (1H, d, J¼6.5 Hz,
BOM), 5.48 (1H, t, J¼7.0 Hz, H31), 6.84–6.87 (2H, m,
MPM), 7.20–7.38 (7H, m, MPM, BOM); 13C NMR
(125 MHz, CDCl3) d 13.4, 14.0, 15.7, 20.0, 24.2, 26.5,
28.1, 32.6, 34.9, 38.5, 39.3, 39.5, 40.5, 41.8, 44.2, 55.2,
67.3, 68.9, 69.0, 70.9, 71.2, 74.4, 78.3, 80.3, 81.8, 81.9,
82.0, 86.0, 86.7, 93.5, 108.3, 113.7, 122.9, 127.5, 128.0,
128.2, 129.5, 130.4, 136.5, 138.1, 159.1; MALDI-TOF MS,
calcd for C45H64O10Na 787.440 (MþNaþ), found 787.445.
4.5.7. Vinyl epoxide 72. To a solution of epoxy alcohol 70
(174 mg, 223 mmol) and Et3N (0.6 ml, 4.4 mmol) in
(CH2Cl)2 (0.6 ml) and DMSO (0.6 ml) at 08C was added
SO3·pyridine complex (220 mg, 1.4 mmol). After being
stirred for 40 min at rt, the mixture was diluted with
EtOAc and aqueous NH4Cl, and extracted with EtOAc
(£3). The organic layer was washed with brine and dried
over MgSO4, and concentrated. The residue was purified
by florisil column chromatography to afford the aldehyde,
which was subjected to the next reaction without further
purification. A mixture of triphenylphosphonium bromide
(394 mg, 1.10 mmol) in THF (0.6 ml) was treated with
NaHMDS (0.9 ml, 1 M in THF, 0.9 mmol) at 08C for
15 min. To the resultant yellow suspension at 08C was
added dropwise a solution of the aldehyde in THF
(2.3 ml). The reaction mixture was stirred at 08C for
45 min, quenched with aqueous saturated NH4Cl, and
extracted with EtOAc (£3). The organic layer was
washed with brine and dried over MgSO4. Concentration
and flash column chromatography (hexane/EtOAc 1:0–
10:1) gave the vinyl epoxide 72 (148 mg, 191 mmol) in
86% yield over 2 steps. 72: colorless oil; Rf¼0.60
(hexane/EtOAc 3:1); [a ]2D9¼245.0 (c 1.070, CHCl3); IR
(film) n 2929, 2874, 1612, 1514, 1455, 1249, 1176, 1102,
4.5.6. Epoxy alcohol 70. To a solution of allyl alcohol 69
(175 mg, 229 mmol), D-(2)-DET (40 ml, 230 mmol), and
activated powdered MS4 A (100 mg) in CH2Cl2 (3.0 ml) at
2508C was added Ti(Oi-Pr)4 (50 ml, 170 mmol). After
10 min, TBHP (0.8 ml, 3 M in CH2Cl2, 2.4 mmol) was
added to the mixture, and the reaction temperature kept
below 2408C for 3 h. The mixture was diluted with Et2O
(8 ml), and 30% aqueous NaOH saturated with NaCl (4 ml)
were added. The mixture was stirred overnight at rt, and
then diluted with aqueous saturated NH4Cl and extracted
with EtOAc (£3). The organic layer was washed with brine
and dried over MgSO4. Concentration and flash column
1074, 1038, 755 cm21 1H NMR (500 MHz, CDCl3) d
;
0.87 (3H, d, J¼6.5 Hz, Me57), 1.03 (3H, d, J¼6.0 Hz,
Me56), 1.06 (3H, d, J¼6.5 Hz, Me54), 1.14 (3H, d,
J¼7.0 Hz, Me55), 1.35 (1H, q, J¼11.5 Hz, H40), 1.39
(3H, s, Me53), 1.45–1.97 (13H, m, H32£2, 35£2, 36,
37£2, 47, 48, 50£2, 51£2), 2.10–2.14 (1H, m, H43),
2.30 (1H, dt, J¼12.5, 5.0 Hz, H40), 2.87 (1H, dd, J¼9.0,
4.5 Hz, H42), 3.02 (1H, t, J¼6.5 Hz, H31), 3.03–3.08
(1H, m, H38), 3.23 (1H, ddd, J¼9.0, 7.0, 4.5 Hz, H39),

H. Uehara et al. / Tetrahedron 58 (2002) 6493–6512
6511
3.29 (1H, t, J¼9.5 Hz, H46), 3.27–3.32 (1H, m, H34),
References
3.47 (1H, td, J¼8.0, 3.5 Hz, H33), 3.65 (1H, d,
J¼10.0 Hz, H45), 3.69–3.75 (2H, m, H41, 44), 3.76
(1H, q, J¼8.0 Hz, H52), 3.79 (3H, s, MPM), 3.87 (1H, td,
J¼8.0, 5.0 Hz, H52), 4.31 (1H, d, J¼11.0 Hz, MPM),
4.53 (1H, d, J¼11.0 Hz, MPM), 4.62 (1H, d, J¼11.5 Hz,
BOM), 4.68 (1H, d, J¼11.5 Hz, BOM), 4.81 (1H, d,
J¼6.5 Hz, BOM), 4.85 (1H, d, J¼6.5 Hz, BOM), 5.18
(1H, dd, J¼11.0, 1.0 Hz, H28), 5.33 (1H, dd, J¼17.5,
1.0 Hz, H28), 5.66 (1H, dd, J¼17.5, 11.0 Hz, H29),
6.84–6.87 (2H, m, MPM), 7.20–7.38 (7H, m, MPM,
BOM); 13C NMR (125 MHz, CDCl3) d 13.4, 14.9, 15.7,
20.0, 24.3, 26.5, 27.8, 33.7, 34.9, 38.5, 39.48, 39.53, 40.5,
41.8, 44.4, 55.2, 58.5, 62.7, 67.3, 69.1, 71.0, 71.2, 74.3,
78.4, 80.0, 81.9, 82.0, 82.0, 83.9, 86.7, 93.6, 108.3, 113.7,
115.9, 127.5, 128.0, 128.3, 129.6, 130.3, 138.1, 141.0,
159.2; MALDI-TOF MS, calcd for C46H64O10Na 799.440
(MþNaþ), found 799.439.
1. For recent reviews, see: (a) Scheuer, P. J. Tetrahedron 1994,
50, 3. (b) Lewis, R. J. Toxicon 2001, 39, 97. (c) Yasumoto, T.;
Murata, M. Chem. Rev. 1993, 93, 1897. (d) Yasumoto, T.
Chem. Rec. 2001, 1, 228.
2. (a) Murata, M.; Legrand, A. M.; Ishibashi, Y.; Yasumoto, T.
J. Am. Chem. Soc. 1989, 111, 8929. (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.
3. Satake, M.; Murata, M.; Yasumoto, T. Tetrahedron Lett. 1993,
34, 1975.
4. Bagnis, R.; Chanteau, S.; Chungue, E.; Hurtel, J. M.;
Yasumoto, T.; Inoue, A. Toxicon 1980, 18, 199.
5. Yasumoto, T.; Igarashi, T.; Legrand, A.-M.; Cruchet, P.;
Chinain, M.; Fujita, T.; Naoki, H. J. Am. Chem. Soc. 2000,
122, 4988.
4.5.8. HIJKLM ring system 4. To a solution of vinyl
epoxide 72 (148 mg, 191 mmol) in CH2Cl2 (4.0 ml) and
H2O (0.2 ml) at rt was added DDQ (42 mg, 0.19 mmol).
After 3.5 h, additional DDQ (4 mg, 18 mmol) was intro-
duced to complete the reaction. After additional 3.5 h, the
mixture was diluted with EtOAc and aqueous saturated
NaHCO3, and extracted with EtOAc (£3). The organic layer
was washed with brine, and dried over MgSO4. Concen-
tration and flash column chromatography (hexane/EtOAc
20:1–3:1) gave the HIJKLM ring system 4 (110 mg,
167 mmol) in 88% yield. 4: colorless oil; Rf¼0.40
(hexane/EtOAc 3:1); [a ]2D8¼24.9 (c 0.612, CHCl3); IR
(film) n 3470, 2929, 2883, 1454, 1379, 1103, 1071, 1038,
6. For attempts toward the preparation of anti-CTX antibodies,
see: (a) Oguri, H.; Tanaka, S.-i.; Hishiyama, S.; Oishi, T.;
Hirama, M.; Tsumuraya, T.; Tomioka, Y.; Mizugaki, M.
Synthesis 1999, 1431. (b) Nagumo, Y.; Oguri, H.; Shindo, Y.;
Sasaki, S.-Y.; Oishi, T.; Hirama, M.; Tomioka, Y.; Mizugaki,
M.; Tsumuraya, T. Bioorg. Med. Chem. Lett. 2001, 11, 2037.
(c) Hokama, Y.; Takenaka, W. E.; Nishimura, K. L.; Ebesu,
J. S. M.; Bourke, R.; Sullivan, P. K. J. AOAC Int. 1998, 81,
727. (d) Pauillac, S.; Sasaki, M.; Inoue, M.; Naar, J.; Branaa,
P.; Chinain, M.; Tachibana, K.; Legrand, A.-M. Toxicon 2000,
38, 669.
7. (a) Lombet, A.; Bidard, J.-N.; Lazdunski, M. FEBS Lett. 1987,
219, 355. (b) Dechraoui, M.-Y.; Naar, J.; Pauillac, S.; Legrand,
A.-M. Toxicon 1999, 37, 125.
1
921, 753, 698 cm21; H NMR (500 MHz, CDCl3) d 0.88
(3H, d, J¼6.0 Hz, Me57), 1.04 (3H, d, J¼7.0 Hz, Me54),
1.04 (3H, d, J¼6.0 Hz, Me56), 1.14 (3H, d, J¼8.0 Hz,
Me55), 1.26 (3H, s, Me53), 1.43 (1H, q, J¼12.0 Hz, H40),
1.47–1.96 (12H, m, H32, 35£2, 36, 37£2, 47, 48, 50£2,
51£2), 2.09–2.15 (1H, m, H43), 2.17 (1H, dt, J¼12.5,
5.0 Hz, H32), 2.28 (1H, dt, J¼12.0, 5.0 Hz, H40), 2.87 (1H,
dd, J¼9.5, 4.5 Hz, H42), 2.97–3.02 (1H, m, H38), 3.14 (1H,
ddd, J¼11.5, 9.0, 4.5 Hz, H39), 3.22 (1H, td, J¼10.0,
4.5 Hz, H33), 3.31 (1H, t, J¼9.5 Hz, H46), 3.41 (1H, td,
J¼10.0, 3.5 Hz, H34), 3.44 (1H, dd, J¼12.0, 4.0 Hz, H31),
3.66 (1H, d, J¼9.0 Hz, H45), 3.72–3.80 (3H, m, H41, 44,
52), 3.87 (1H, td, J¼8.0, 4.5 Hz, H52), 4.63 (1H, d,
J¼11.5 Hz, BOM), 4.68 (1H, d, J¼11.5 Hz, BOM), 4.81
(1H, d, J¼7.0 Hz, BOM), 4.85 (1H, d, J¼7.0 Hz, BOM),
5.17 (1H, bd, J¼10.5 Hz, H28), 5.29 (1H, bd, J¼17.5 Hz,
H28), 5.89 (1H, dd, J¼17.5, 10.5 Hz, H29), 7.27–7.38 (5H,
m, BOM); 13C NMR (50 MHz, CDCl3) d 13.4, 13.5, 15.8,
20.0, 24.3, 27.7, 28.2, 34.9, 36.6, 38.5, 40.48, 40.54, 41.8,
45.6, 46.3, 67.4, 69.1, 71.0, 71.2, 73.3, 74.5, 76.5, 78.4,
81.0, 81.9, 83.6, 83.8, 86.8, 93.6, 108.3, 114.5, 127.5, 128.0,
128.3, 138.1, 143.0; HRMS (EI, 70 eV), calcd for C38H56O9
656.3924 (Mþ), found 656.3922.
8. Hirama, M.; Oishi, T.; Uehara, H.; Inoue, M.; Maruyama, M.;
Oguri, H.; Satake, M. Science 2001, 294, 1904.
9. For recent synthetic studies from our laboratory, see: (a)
Oguri, H.; Sasaki, S.-y.; Oishi, T.; Hirama, M. Tetrahedron
Lett. 1999, 40, 5405. (b) Oguri, H.; Tanaka, S.-i.; Oishi, T.;
Hirama, M. Tetrahedron Lett. 2000, 41, 975. (c) Oishi, T.;
Tanaka, S.-i.; Ogasawara, Y.; Maeda, K.; Oguri, H.; Hirama,
M. Synlett 2001, 952. (d) Imai, H.; Uehara, H.; Inoue, M.;
Oguri, H.; Oishi, T.; Hirama, M. Tetrahedron Lett. 2001, 42,
6219. (e) Maruyama, M.; Maeda, K.; Oishi, T.; Oguri, H.;
Hirama, M. Heterocycles 2001, 54, 93. (f) Maruyama, M.;
Inoue, M.; Oishi, T.; Oguri, H.; Ogasawara, Y.; Shindo, Y.;
Hirama, M. Tetrahedron 2002, 58, 1835.
10. For recent synthetic studies of ciguatoxins from other groups,
see: (a) Sasaki, M.; Noguchi, K.; Fuwa, H.; Tachibana, K.
Tetrahedron Lett. 2000, 41, 1425. (b) Takakura, H.; Noguchi,
K.; Sasaki, M.; Tachibana, K. Angew. Chem., Int. Ed. Engl.
2001, 40, 1090. (c) Sasaki, M.; Ishikawa, M.; Fuwa, H.;
Tachibana, K. Tetrahedron 2002, 58, 1889. (d) Fujiwara, K.;
Tanaka, H.; Murai, A. Chem. Lett. 2000, 610. (e) Fujiwara, K.;
Takaoka, D.; Kusumi, K.; Kawai, K.; Murai, A. Synlett 2001,
691. (f) Kira, K.; Isobe, M. Tetrahedron Lett. 2000, 41, 5951.
(g) Kira, K.; Isobe, M. Tetrahedron Lett. 2001, 42, 2821. (h)
Takai, S.; Isobe, M. Org. Lett. 2002, 4, 1183. (i) Eriksson, L.;
Guy, S.; Perlmutter, P. J. Org. Chem. 1999, 64, 8396. (j)
Leeuwenburgh, M. A.; Kulker, C.; Overkleeft, H. S.; van der
Marel, G. A.; van Boom, J. H. Synlett 1999, 1945. (k) Clark,
J. S.; Hamelin, O. Angew. Chem., Int. Ed. Engl. 2000, 39, 372.
and references therein.
Acknowledgments
Fellowships to Y. N. and J.-Y. L. B. from the Japanese
Society for the Promotion of Science are gratefully
acknowledged.
´
11. For reviews, see: (a) Alvarez, E.; Candenas, M.-L.; Perez, R.;