Cytotoxicity and actin-depolymerizing activity of aplyronine A, a potent antitumor macrolide of marine origin, and its analogs

Article abstract of DOI:10.1016/S0040-4020(01)01206-6

Artificial analogs of aplyronine A (1), a potent antitumor macrolide, were synthesized and structure-activity (cytotoxicity and actin-depolymerizing activity) relationships were investigated; the side-chain in 1 was found to play a key role in both biological activities.

Full text of DOI:10.1016/S0040-4020(01)01206-6

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 1075±1102
Cytotoxicity and actin-depolymerizing activity of aplyronine A,
a potent antitumor macrolide of marine origin, and its analogs
Hideo Kigoshi,a,p Kiyotake Suenaga,b Masaki Takagi,b Atsushi Akao,b Kengo Kanematsu,b
Noriyuki Kamei,b Youko Okugawab and Kiyoyuki Yamadab,p
aDepartment of Chemistry, University of Tsukuba, Tsukuba, Ibaraki 305-8571 Japan
bDepartment of Chemistry, Graduate School of Science, Nagoya University, Chikusa, Nagoya 464-8602, Japan
Received 30 October 2001; accepted 3 December 2001
AbstractÐArti®cial analogs of aplyronine A (1), a potent antitumor macrolide, were synthesized and structure±activity (cytotoxicity and
actin-depolymerizing activity) relationships were investigated; the side-chain in 1 was found to play a key role in both biological activities.
q 2002 Elsevier Science Ltd. All rights reserved.
We previously isolated1 aplyronine A (1) as a potent cyto-
toxic and antitumor substance from the sea hare Aplysia
kurodai, and determined its absolute stereostructure,2
which was con®rmed by its total synthesis.3 Subsequently,
we investigated the structure±cytotoxicity relationships of
aplyronine A (1) using its natural and arti®cial analogs,3d
and found that (1) the trimethylserine moiety, two hydroxyl
groups, and the side-chain in 1 are responsible for its strong
cytotoxicity, and (2) the N-formyl enamine part and the
dimethylalanine moiety in 1 do not play an important role
in its strong cytotoxicity.3d
The target biomolecules of aplyronine A (1) were investi-
gated: 1 did not interact with DNA, tubulins, or cell cycle-
regulating enzymes, but inhibited the polymerization of
globular actin (G-actin) to ®brous actin (F-actin) and
depolymerized F-actin to G-actin by severing.4 Actin is
one of the most abundant and common proteins in the cyto-
skeleton and regulates various cell functions, such as muscle
contraction, cell motility, and cell division. To date, a few
antitumor substances that interact with actin have been
reported. Thus, aplyronine A (1) is considered a new type
of antitumor substance from the standpoint of its mode of
Figure 1. Natural aplyronines and the previously synthesized arti®cial analogs.
Keywords: marine metabolites; analogs; synthesis; cytotoxicty; actin-depolymerizing; structure±activity.
Corresponding authors. Fax: 181-298-53-4313; e-mail: kigoshi@chem.tsukuba.ac.jp
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)01206-6

1076
H. Kigoshi et al. / Tetrahedron 58 (2002) 1075±1102
Scheme 1. (a) 10, BuLi, THF, 2788C, then 9, 2788C; (b) Ac2O, DMAP, pyridine, rt; (c) 5% Na±Hg, Na2HPO4, MeOH, 08C; (d) AcOH, H2O, THF, rt; (e)
DMSO, Ac2O, AcOH, rt!408C; (f) HCO2H, Et2O, rt; (g) Dess±Martin periodinane, pyridine, CH2Cl2, rt; (h) 16, BuLi, THF, 2788C, then MgBr2, 15, 2788C;
(i) DIBAL, CH2Cl2, 2788C; (j) LDA, (EtO)2P(O)CH2CHvCHCO2Et, THF, 245!08C; (k) HF´pyridine, pyridine, THF, rt; (l) LiOH, H2O, MeOH, rt; (m)
2,4,6-trichlorobenzoyl chloride, DMAP, Et3N, CH2Cl2, 238C; then Ti(O-i-Pr)4, CH2Cl2, rt; (n) TBSCl, imidazole, DMF, 588C; (o) HCl, H2O, DME, rt; (p)
NaBH(OMe)3, MeOH, 238C; (q) TBSCl, Et3N, DMAP, CH2Cl2, 238C.
action. Among natural products, only cytochalasins and
phalloidin were previously known to interact with actin.5
Recently, some marine macrolides, such as latrunculins,6
scytophycins,7 goniodomin,8 mycalolide B,9 swinholide
A,10 and bistheonellide,11 have been shown to exhibit
actin-depolymerizing activity.
to achieve. Assuming that the C14 methyl group is not
important for the biological activities of aplyronine A (1),
we synthesized four analogs that lack the C14 methyl group,
32, 36, 40, and 43, which were more readily accessible by
organic synthesis than 1.
These analogs were obtained by a synthetic strategy similar
to that for aplyronine A (1) from the intermediate 93d
(Scheme 1). Julia ole®nation14 between 9 and sulfone 103d
afforded trans-ole®n 11 (71%). Removal of the TES group
in 11 gave alcohol 12 (95%), which was converted to MTM
ether 13 (82%). The trityl protecting group in 13 was
removed with formic acid to provide alcohol 14 (84%),
which was oxidized to aldehyde 15 (82%). Julia ole®nation
of 15 with sulfone 163a afforded ole®n 17 (65%). For four-
carbon homologation at C5, removal of the pivaloyl group
in 17 and subsequent oxidation led to aldehyde 19 (91%,
two steps), which was treated with a Horner±Emmons
reagent to afford conjugated diene 20 (88%). Conjugated
diene 20 was transformed into a common intermediate
26 (35%) by (1) removal of two TES groups, (2) basic
hydrolysis of the ester group to give dihydroxy acid 22,
(3) macrolactonization under Yamaguchi conditions15 and
subsequent isomerization from the 26-membered by-
product to 23, (4) protection of the hydroxy group, (5) acidic
hydrolysis of the methyl acetal group followed by reduction
No information is currently available on the structure±actin-
depolymerizing activity relationships of 1, which are inter-
esting with regard to the mode of action of 1. Recently, we
reported the synthesis of arti®cial analogs of aplyronine A
(1) and the structure±bioactivity relationships of 1 con-
cerning cytotoxicity and actin-depolymerizing activity.3d,12
In this article, we describe the synthesis of arti®cial analogs
of 1 and also the updated structure±bioactivity relationships
of 1. Fig. 1 shows natural aplyronines and the previously
synthesized analogs of aplyronine A (1).3d
1. Chemical synthesis
1.1. Synthesis of arti®cial analogs that lackthe C14
methyl group13
In the synthesis of aplyronine A (1), stereoselective
construction of the trisubstituted ole®n at C14 was dif®cult

H. Kigoshi et al. / Tetrahedron 58 (2002) 1075±1102
1077
Scheme 2. (a) Ac2O, DMAP, pyridine, rt; (b) DDQ, CH2Cl2, t-BuOH,
phosphate buffer (pH 6), rt; (c) N,N-dimethylalanine (S/Rˆ3:2), DCC,
CSA, DMAP, CH2Cl2, rt; (d) AgNO3, 2,6-lutidine, H2O, THF, 308C;
(e) N,N,O-trimethylserine (S/Rˆ5:2), DCC, CSA, DMAP, CH2Cl2, 358C;
(f) HF´pyridine, pyridine, THF, rt; (g) TESCl, imidazole, DMF, 238C;
(h) HCl, H2O, dioxane, 508C; (i) N,N-dimethylglycine, DCC, CSA,
DMAP, CH2Cl2, rt.
to afford diol 25, and (6) selective protection of the primary
hydroxy group.
From this intermediate 26, four arti®cial analogs, 32, 36, 40,
and 43, were synthesized (Scheme 2). Acetylation of 26 and
subsequent removal of the [(3,4-dimethoxybenzyl)oxy]-
methyl (DMBOM) group3d,16 afforded alcohol 28 (80%,
two steps), which was acylated with N,N-dimethylalanine
(S/Rˆ3:2) under Keck conditions17 to afford a 3:1 diastereo-
meric mixture of dimethylalanine ester 29 quantitatively.
The R/S ratio of the amino acid moiety in 29 was different
from that of the N,N-dimethylalanine used because dynamic
kinetic resolution18 occurred under the acylation conditions.
The MTM protecting group in 29 was removed (80%), and
the resulting alcohol 30 was acylated with N,N,O-trimethyl-
serine under Keck conditions to give a diastereomeric
mixture of trimethylserine ester 31 (72%, R/Sˆ3:1). Finally,
all of the TBS ether groups were removed with HF´pyridine
to provide analog 32 (80%). Analogs 36, 40, and 43 were
also prepared from compound 26 in overall respective yields
of 40, 29, and 45%, by using a strategy similar to that in the
synthesis of 32.
Scheme 3. (a) Sn(OTf)2, Et3N, CH2Cl2, 2788C, then 3-(benzyloxy)propa-
nal, 2788C!2208C; (b) Me4NBH(OAc)3, MeCN, AcOH, 2208C; (c) H2,
20% Pd(OH)2±C, dioxane, rt; (d) (PhS)2, Bu3P, DMF, 08C!rt; (e) Bu4NF,
THF, rt; (f) TrCl, pyridine, 508C; (g) TESCl, imidazole, DMF, 508C;
(h) mCPBA, NaHCO3, CH2Cl2, 08C!rt; (i) 52, BuLi, THF, 2788C, then
MgBr2, 15, 2788C; (j) Ac2O, DMAP, pyridine, rt; (k) 5% Na±Hg,
Na2HPO4, MeOH, 08C; (l) DIBAL, CH2Cl2, 2788C; (m) Dess±Martin
periodinane, pyridine, CH2Cl2, rt; (n) LDA, (EtO)2P(O)CH2CHvCH-
CO2Et, THF, 240!08C; (o) HF´pyridine, pyridine, THF, rt; (p) LiOH,
MeOH, H2O, rt; (q) 2,4,6-trichlorobenzoyl chloride, DMAP, Et3N,
CH2Cl2, rt; (r) TBSCl, imidazole, DMF, 608C; (s) AgNO3, 2,6-lutidine,
H2O, THF, 308C; (t) N,N,O-trimethylserine (S/Rˆ5:2), DCC, CSA,
DMAP, CH2Cl2, 358C; (u) HCl, H2O, dioxane, 508C; (v) HCO2H,
Et2O, 268C; (w) N,N-dimethylalanine (S/Rˆ3:2), DCC, CSA, DMAP,
CH2Cl2, rt.

1078
H. Kigoshi et al. / Tetrahedron 58 (2002) 1075±1102
Scheme 4. (a) 68, BuLi, THF, 2788C, then MgBr2, 15, 2788C; (b) Ac2O, DMAP, pyridine, rt; (c) 5% Na±Hg, Na2HPO4, MeOH, 08C; (d) TESCl, imidazole,
DMF, 508C; (e) DIBAL, CH2Cl2, 2788C; (f) Dess±Martin periodinane, pyridine, CH2Cl2, rt; (g) LDA, (EtO)2P(O)CH2CHvCHCO2Et, THF, 240!08C;
(h) HF´pyridine, pyridine, THF, rt; (i) LiOH, MeOH, H2O, rt; (j) PPh3, DEAD, toluene, 210!48C; (k) AgNO3, 2,6-lutidine, H2O, THF, 308C; (l) N,N,O-
trimethylserine (S/Rˆ5:2), DCC, CSA, DMAP, CH2Cl2, 358C.
1.2. Synthesis of arti®cial analogs with shorter side-
chains and an arti®cial analog without a side-chain
Julia ole®nation of 52 with aldehyde 15 followed by the
same sequence of reactions that were used to convert 17
into 21 gave diol 57 (50%, seven steps). Hydrolysis of the
ester group in 57 and subsequent macrolactonization under
Yamaguchi conditions afforded lactone 59 (62%, two steps),
which was transformed into analog 64 in ®ve steps (52%).
Analog 67 was prepared from the intermediate 62 in three
steps (52%).
To investigate the relationship between the length of the
side-chain and the biological activities of arti®cial analogs,
three analogs, 64, 67, and 78, were prepared (Schemes 3 and
4).
The analogs with a shorter side-chain, 64 and 67, were
prepared from compounds 15 and 52 by a strategy similar
to that for aplyronine A (1). While compound 52 with four
contiguous syn±anti±anti stereocenters was previously
prepared using the Evans aldol reaction and Sharpless asym-
metric epoxidation as key steps,3a the improved synthesis of
52 has been achieved by using the Paterson aldol reaction19
as a key step. Thus, Paterson aldol reaction of ketone 44 and
3-(benzyloxy)propanal gave aldol 45 (83%), stereoselective
reduction of which with Me4NBH(OAc)320 afforded diol 46,
which has syn±anti±anti stereochemistry (80%).
An arti®cial analog without a side-chain, 78, was synthe-
sized from 15 in 22% overall yield using the same strategy
as for analog 8,3d except for the macrolactonization con-
ditions. Whereas hydroxy acid 74 gave lactone 75 in poor
yield under Yamaguchi lactonization conditions, lactone 75
was obtained from 74 in ca. 70% yield under Mitsunobu
lactonization conditions.21
1.3. Synthesis of a tetrahydro analog
A tetrahydro analog that lacks a conjugated diene group, 85,
was synthesized from the synthetic intermediate 793d of
aplyronine A (1) (Scheme 5). Compound 79 was reduced
with NaBH4±NiCl2 to give lactone 80 (69%), which
was converted into analog 85 in 51% overall yield by the
Hydrogenolysis of the benzyl ether group in 46 followed by
substitution of the resulting hydroxy group with the
phenylthio group gave sul®de 48 (93%, two steps). After
removal of the triisopropylsilyl (TIPS) group in 48, the
primary and secondary hydroxy groups were protected as
the trityl and TES ethers, respectively (85%, three steps).
Oxidation of sul®de group in 51 provided sulfone 52 (98%).
22
same sequence of reactions that was used to convert 27 into
32.
Scheme 5. (a) NaBH4, NiCl2´6H2O, MeOH, CH2Cl2, 08C; (b) DDQ, CH2Cl2, t-BuOH, phosphate buffer (pH 6), rt; (c) N,N-dimethylalanine (S/Rˆ3:2), DCC,
CSA, DMAP, CH2Cl2, rt; (d) AgNO3, 2,6-lutidine, H2O, THF, 308C; (e) N,N,O-trimethylserine (S/Rˆ5:2), DCC, CSA, DMAP, CH2Cl2, 358C; (f) HF´pyridine,
pyridine, THF, rt.

H. Kigoshi et al. / Tetrahedron 58 (2002) 1075±1102
1079
of aplyronines for the biological activities, an acyclic analog
of 40, i.e. 111, was prepared (Scheme 8). Sulfone 104 was
prepared from intermediate 163d in ®ve steps (45%). Julia
ole®nation between 104 and 1123d followed by a six-step
sequence of reactions gave analog 111 (11%).
2. Biological activities and discussion
2.1. Structure±cytotoxicity relationships of natural
aplyronines and arti®cial analogs
The cytotoxicity of natural aplyronines and analogs against
HeLa S3 cells is summarized in Table 1. Previously, the
side-chain of 1 was found to be essential for its strong cyto-
toxicity.3d In the present study, the effect of the side-chain of
1 on cytotoxicity was evaluated in more detail; comparison
of the cytotoxicities of 8, 36, and 64 revealed that not only
the presence of the side-chain but also its length is crucial
for strong cytotoxicity. Comparison of the cytotoxicities of
5 and 85 revealed that the conjugated diene moiety is
responsible for the strong cytotoxicity of 1. Analog 43,
which has two dimethylglycine groups, is about 1000-fold
less cytotoxic than analog 32 that has dimethylalanine and
trimethylserine groups. This indicates that the structures of
the amino acid residues are important for cytotoxicity. One
possible explanation for the extremely weak cytotoxicity of
43 is that the dimethylglycine ester groups in 43 might be
apt to be hydrolyzed by an esterase in cells to give a
compound that is very weakly cytotoxic. The analogs that
lack both an N-formyl enamine group and a dimethylalanine
group, 36 and 40, are less cytotoxic than those with either of
these groups, 5, 6, and 32. This indicates that either of these
groups is necessary for the strong cytotoxicity of aplyronine
analogs. As expected, the C14 methyl group of 1 was shown
to have no signi®cant effect on this activity by comparison
of the activities of 5 and 32.
Scheme 6. (a) Ac2O, DMAP, pyridine, rt; (b) HCl, H2O, DME, rt;
(c) NaBH4, EtOH, 08C; (d) NaOMe, MeOH, rt.
1.4. Synthesis of arti®cial analogs that only consist of a
side-chain
An arti®cial analog that consists of a side-chain having only
hydroxy groups, 89, was prepared from the synthetic inter-
mediate 863d of aplyronine A (1) in four steps in 60% overall
yield (Scheme 6).
Another arti®cial analog that consists of the same side-chain
as aplyronine A (1) has, 102, was also prepared from 86
(Scheme 7). Suitable protecting groups were introduced into
86 to afford compound 93 (85%). By a seven-step sequence
of reactions, compound 93 led to compound 99, which was
further converted into the desired analog 102 (10% from
93).
1.5. Synthesis of the acyclic analog
To investigate the importance of the macrocyclic structure
Scheme 7. (a) TBDPSCl, imidazole, DMF, rt; (b) 3,4-(MeO)2C6H3CH2OCH2Cl (DMBOM±Cl),3d,16 i-Pr2NEt, CH2Cl2, rt; (c) AcOH, H2O, THF, rt;
(d) TBSOTf, 2,6-lutidine, CH2Cl2, 08C; (e) HCl, H2O, DME, rt; (f) NaBH4, EtOH, rt; (g) TrCl, pyridine, 508C; (h) Ac2O, DMAP, pyridine, rt; (i) HCO2H,
Ê
Et2O, rt; (j) Dess±Martin periodinane, pyridine, CH2Cl2, rt; (k) MeNHCHO, PPTS, hydroquinone, MS 3 A, benzene, re¯ux; (l) DDQ, CH2Cl2, t-BuOH,
phosphate buffer (pH 6), rt; (m) N,N-dimethylalanine (S/Rˆ3:2), DCC, CSA, DMAP, CH2Cl2, rt; (n) HF´pyridine, pyridine, THF, rt.

1080
H. Kigoshi et al. / Tetrahedron 58 (2002) 1075±1102
Scheme 8. (a) 1 M HCl, DME, rt; (b) NaBH4, EtOH, rt; (c) 2 M HCl, dioxane, 508C; (d) TBSCl, DMAP, Et3N, CH2Cl2, rt; (e) TESCl, imidazole, DMF, rt;
(f) 104, BuLi, THF, 2788C, then MgBr2, 112, 2788C; (g) Ac2O, DMAP, pyridine, rt; (h) 5% Na±Hg, Na2HPO4, MeOH, 08C; (i) DIBAL, CH2Cl2, 2788C;
(j) Dess±Martin periodinane, pyridine, CH2Cl2, rt; (k) LDA, (EtO)2P(O)CH2CHvCHCO2Et, THF, 240!08C; (l) AgNO3, 2,6-lutidine, H2O, THF, 308C;
(m) N,N,O-trimethylserine (S/Rˆ5:2), DCC, CSA, DMAP, CH2Cl2, 358C; (n) HF´pyridine, pyridine, THF, 08C.
2.2. Structure±actin-depolymerizing activity relation-
ships of natural aplyronines and arti®cial analogs
side-chain, 78, is totally inactive. It is interesting that even
a simple hexaol that mimics the side-chain of aplyronine A
(1), 89, exhibits actin-depolymerizing activity, although this
activity is very weak. More interesting is the ®nding that the
analog that only consists of the side-chain part of aplyronine
A (1), 102, exhibits relatively strong activity considering the
size of the molecule. These results indicate that (1) the side-
chain in 1 plays a key role in its activity, (2) the functional
groups in the side-chain greatly enhance the activity, and (3)
the combination of a side-chain and the macrolide moiety is
essential for the potent activity of 1. In addition, comparison
of the activities of 40 and 111 suggests that the macro-
cyclic structure of 1 is not so important for its actin-
depolymerizing activity. The C14 methyl group and the
The actin-depolymerizing activity of natural aplyronines
and analogs was determined by ¯ow birefringence, as
shown in Table 1. Fibrous particles, such as F-actin, in a
¯owing liquid are oriented by the shearing force. Determi-
nation of the extent of the orientation of actin by ¯ow
birefringence makes it possible to evaluate the extent of
polymerization of actin.23 The natural and arti®cial analogs
with side-chains of the same length as in aplyronine A (1)
exhibit strong activity comparable to that of 1, whereas
those with a shorter side-chain, 64 and 67, are approxi-
mately 100 times less active than 1, and that without a
Table 1. Cytotoxicity and actin-depolymerizing activity of natural aplyronines and arti®cial analogs
Compound
Cytotoxicity against HeLa S3 cells
Actin-depolymerizing activitya
IC50c (mM) Relative potencyb
IC50 (ng/mL)
Relative potencyb
Aplyronine A (1)
Aplyronine B (2)
Aplyronine C (3)
4
5
6
0.48d
3.11d
21.2d
216d
1.72d
1.03d
113d
2100d
2.6
37
83
.2000
.2000
n.d.
100
15
2.3
0.22
28
47
0.42
0.023
18
31
33
32
57
78
35
35
n.d.
38
36
190
49
100
94
97
54
40
86
86
7
8
32
36
40
43
64
67
78
85
89
102
111
82
86
16
63
0.69
1.7
1.3
0.58
,0.02
,0.02
4500e
1800
Inactive
70
n.d.
57
n.d.
n.d.
0.84
44
0.41
7600e
3309.9
4606.7
n.d.
a
Activity was monitored by measuring ¯ow birefringence. For the conditions of the biological assay, see Section 3.
The relative potencies were calculated from the IC50 values of the compounds (aplyronine Aˆ100).
IC50 is the concentration required to depolymerize F-actin (40 mM) to 50% of its control amplitude.
Ref. 3d.
b
c
d
e
An exact IC50 value could not be obtained because of the limited solubility of the test compound.

H. Kigoshi et al. / Tetrahedron 58 (2002) 1075±1102
1081
N-formylenamine part in aplyronine A (1) were also not
important for the strong activity of 1, as in the case of the
cytotoxicity of 1, by comparing the activities of 1, 5, and 32.
Other functional groups, such as amino acid residues, two
hydroxyl groups, and the conjugated diene moiety, had little
effect on the actin-depolymerizing activity of 1, in contrast
to their relation to cytotoxicity.
The acetoxy sulfones were used in the next experiment
without separation of the diastereomers.
To a vigorously stirred solution of the diastereomeric
mixture of acetoxy sulfones (164 mg) in MeOH (2 mL)
cooled at 08C were added Na2HPO4 (323 mg, 2.28 mmol)
and 5% Na±Hg (492 mg, 1.07 mmol). The mixture was
stirred at 08C for 100 min, diluted with saturated aqueous
NH4Cl (5 mL), stirred at room temperature for 1 h, and
extracted with Et2O (3£10mL). The combined extracts
were washed with brine (6 mL), dried (Na2SO4), and
concentrated. The residual oil was puri®ed by column
chromatography on silica gel (14 g, hexane±Et2O 15:1!
10:1!5:1!1:1!1:2) to give a mixture of ole®ns. Further
puri®cation of ole®ns by medium-pressure liquid chroma-
tography (Fuji Silysia, FL-60D, 6.4 g, hexane±t-BuOMe
15:1, 2 mL/min) afforded E-ole®n 11 (73.4 mg, 71% from
9) and Z-ole®n (14 mg, 14% from 9) as a colorless oil,
In conclusion, structure±cytotoxicity relationships and
structure±actin-depolymerizing activity relationships of
aplyronine A (1) were determined to a considerable extent.
The side-chain of aplyronine A (1) proved to play a key role
in both of these biological activities of 1.
3. Experimental
3.1. General
27
respectively. 11: [a]D ˆ118.6 (c 0.95, CHCl3); IR
(CHCl3) 1720, 1600, 1460, 1380, 1285, 1255, 1165,
Optical rotations were recorded on a JASCO DIP-1000
polarimeter. UV spectra were obtained on a JASCO
V-550spectrophotometer and IR spectra were measured
on a JASCO FT/IR-230spectrophotometer. 1H NMR
spectra were recorded on a JEOL EX-270(270MHz),
A-400 (400 MHz), or A-600 (600 MHz) spectrometer with
TMS as an internal reference. FABMS spectra and high-
resolution FABMS analysis were performed in m-nitro-
benzyl alcohol on a JEOL LG-2000 spectrometer. Column
chromatography was carried out on a Fuji Silysia silica gel
BW-820MH unless otherwise noted. All solvents and
chemicals were puri®ed by standard procedures.
1
840cm 21; H NMR (270MHz, CDCl 3) d 7.48±7.45 (m,
6H), 7.33±7.22 (m, 9H), 5.52 (td, Jˆ6.9, 15.2 Hz, 1H),
5.20(dd, Jˆ8.3, 15.2 Hz, 1H), 4.22 (td, Jˆ5.5, 11.0Hz,
1H), 4.04 (td, Jˆ7.3, 11.0Hz, 1H), 3.68 (td, Jˆ4.0,
7.3 Hz, 1H), 3.45±3.32 (m, 3H), 3.42 (s, 3H), 3.19 (s,
3H), 3.11 (d, Jˆ4.3 Hz, 2H), 2.12 (ddd, Jˆ5.5, 7.3,
12.2 Hz, 1H), 1.89±1.72 (m, 2H), 1.72±1.30(m, 9H), 1.19
(s, 9H), 0.96, (t, Jˆ7.9 Hz, 9H), 0.89±0.85 (m, 9H), 0.88 (s,
9H), 0.60 (q, Jˆ7.9 Hz, 6H), 0.03 (s, 6H); MS (FAB) m/z
947 (M1Na)1; HRMS (FAB) calcd for C57H92NaO7Si2
[(M1Na)1] 947.6279, found 947.6279. Z-Ole®n: [a]D
ˆ
20
112.1 (c 1.34, CHCl3); IR (CHCl3) 1720, 1460, 1450, 1285,
1
1250, 835 cm21; H NMR (270MHz, CDCl 3) d 7.49±7.43
3,4-Dimethoxybenzyloxymethyl chloride (DMBOM±Cl)
was prepared from 3,4-dimethoxybenzyl alcohol by the pro-
cedure for CH3OC6H4CH2OCH2Cl.24
(m, 6H), 7.33±7.19 (m, 9H), 5.54 (ddd, Jˆ6.3, 8.6, 11.2 Hz,
1H), 5.25 (dd, Jˆ9.3, 11.2 Hz, 1H), 4.22 (td, Jˆ5.5,
11.0Hz, 1H), 4.04 (td, Jˆ7.3, 11.0Hz, 1H), 3.84 (m, 1H),
3.68 (td, Jˆ4.0, 7.3 Hz, 1H), 3.42 (s, 3H), 3.35 (m, 2H), 3.20
(s, 3H), 3.11 (d, Jˆ4.3 Hz, 2H), 2.10±1.86 (m, 3H), 1.89±
1.40 (m, 10H), 1.19 (s, 9H), 0.95, (t, Jˆ7.9 Hz, 9H), 0.89±
0.84 (m, 9H), 0.88 (s, 9H), 0.60 (q, Jˆ7.9 Hz, 6H), 0.03 (s,
6H); MS (FAB) m/z 967 (M1Na)1; HRMS (FAB) calcd for
C57H92NaO7Si2 [(M1Na)1] 967.6279, found 967.6290.
3.1.1. Julia coupling reaction of aldehyde 9 with sulfone
10. To a stirred solution of sulfone 103d (167 mg, 0.316
mmol) in THF (2 mL) cooled at 2788C was added a
1.58 M solution of BuLi in hexane (0.20 mL, 0.316 mmol)
dropwise. After the mixture was stirred at 2788C for
30min, a solution of aldehyde 93d (75.5 mg, 0.132 mmol)
in THF (1.0mL) was added dropwise, and the resulting
mixture was stirred at 2788C for 135 min. The reaction
was quenched by adding saturated aqueous NH4Cl (5 mL),
and the mixture was extracted with Et2O (3£10mL). The
combined extracts were washed with brine (5 mL), dried
(Na2SO4), and concentrated. The residual oil was puri®ed
by column chromatography on silica gel (50g, hexane±
Et2O 5:1!3:1!2:1!1:1) to give a diastereomeric mixture
of hydroxy sulfones (127 mg) as a colorless oil along with
recovered 10 (83 mg, 50%). The hydroxy sulfones were
used in the next experiment without separation of the
diastereomers.
3.1.2. Alcohol 12. To a stirred solution of E-ole®n 11
(267 mg, 0.283 mmol) in THF (4 mL) was added a 4:1
mixture of AcOH and H2O (5 mL), and the mixture was
stirred at room temperature for 6 h. The mixture was poured
into saturated aqueous NaHCO3 (25 mL) cooled at 08C, and
the aqueous mixture was extracted with Et2O (3£80mL).
The combined extracts were washed with saturated aqueous
NaHCO3 (15 mL) and brine (15 mL), dried (Na2SO4), and
concentrated. The residual oil was puri®ed by column
chromatography on silica gel (16 g, hexane±Et2O 10:1!
5:1!3:1!1:1) to give 12 (223 mg, 95%) as a colorless
26
oil: [a]D ˆ114.7 (c 0.97, CHCl3); IR (CHCl3) 3430(br),
1
1720, 1600, 1450, 1285, 1255, 1165, 840 cm21; H NMR
To a stirred solution of the diastereomeric mixture of
hydroxy sulfones (127 mg) in pyridine (1.2 mL) were
added Ac2O (0.6 mL) and DMAP (6.3 mg, 0.052 mmol) at
room temperature. The mixture was stirred at room
temperature for 2 h and concentrated. The residue was
puri®ed by column chromatography on silica gel (10g,
hexane±Et2O 2:1!1:1!1:2) to give a diastereomeric
mixture of acetoxy sulfones (125 mg) as a colorless oil.
(270MHz, CDCl 3) d 7.48±7.44 (m, 6H), 7.33±7.19 (m,
9H), 5.52 (ddd, Jˆ6.9, 6.9, 15.2 Hz, 1H), 5.20(dd, Jˆ8.3,
15.2 Hz, 1H), 4.33 (ddd, Jˆ5.0, 8.6, 11.4 Hz, 1H), 4.20
(ddd, Jˆ5.3, 5.9, 11.4 Hz, 1H), 3.81 (dd, Jˆ1.7, 5.0Hz,
1H), 3.54 (m, 1H), 3.42 (s, 3H), 3.37 (m, 2H), 3.20(s,
3H), 3.11 (d, Jˆ4.6 Hz, 2H), 3.01 (d, Jˆ4.0Hz, 1H, OH),
2.11 (m, 1H), 1.98±1.75 (m, 2H), 1.68±1.35 (m, 9H), 1.20

1082
H. Kigoshi et al. / Tetrahedron 58 (2002) 1075±1102
(s, 9H), 0.89±0.86 (m, 3H), 0.89 (s, 9H), 0.85 (d, Jˆ6.6 Hz,
6H), 0.83 (d, Jˆ6.6 Hz, 3H), 0.06 (s, 3H), 0.05 (s, 3H); MS
(FAB) m/z 853 (M1Na)1.
extracts were washed with H2O (2 mL) and brine (2 mL),
dried (Na2SO4), and concentrated. The residual oil was puri-
®ed by column chromatography on silica gel (4 g, hexane±
Et2O 5:1!3:1!1:1) to give 15 (72.6 mg, 82%) as a color-
30
3.1.3. MTM ether 13. To a stirred solution of alcohol 12
(203 mg, 0.246 mmol) in DMSO (1 mL) was added a 1:5.6
mixture of AcOH and Ac2O (0.825 mL) at room tempera-
ture. The mixture was stirred at room temperature for 2 h
and at 408C for 5 h. The reaction mixture was poured into
saturated aqueous NaHCO3 (20mL) cooled at 0 8C, and the
aqueous mixture was extracted with Et2O (3£30mL). The
combined extracts were washed with saturated aqueous
less oil: [a]D ˆ163.4 (c 1.22, CHCl3); IR (CHCl3) 2710,
1730, 1460, 1285, 1250, 1165, 835 cm21
;
1H NMR
(270MHz, CDCl 3) d 9.62 (d, Jˆ2.4 Hz, 1H), 5.54 (td, Jˆ
6.9, 15.2 Hz, 1H), 5.25 (dd, Jˆ8.3, 15.2 Hz, 1H), 4.63 (d,
Jˆ11.2 Hz, 1H), 4.57 (d, Jˆ11.2 Hz, 1H), 4.14 (m, 2H),
3.61 (m, 1H), 3.50(t, Jˆ3.9 Hz, 1H), 3.43 (s, 3H), 3.42
(m, 1H), 3.22 (s, 3H), 2.15 (s, 3H), 2.13 (m, 1H), 1.99±
1.36 (m, 13H), 1.19 (s, 9H), 0.93 (d, Jˆ6.8 Hz, 3H), 0.88
(d, Jˆ6.8 Hz, 3H), 0.88 (s, 9H), 0.87 (d, Jˆ6.8 Hz, 3H),
0.05 (s, 3H), 0.04 (s, 3H); MS (FAB) m/z 669 (M1Na)1;
HRMS (FAB) calcd for C34H66NaO7SSi (M1Na)1
669.4196, found 669.4196.
NaHCO3 (10mL) and brine (10mL), dried (Na SO4), and
2
concentrated. The residual oil was puri®ed by column
chromatography on silica gel (30g, hexane±Et 2O 10:1!
7:1!5:1!1:1) to give 13 (182 mg, 82%) as a colorless
26
oil: [a]D ˆ142.4 (c 1.07, CHCl3); IR (CHCl3) 1720,
1600, 1450, 1285, 1255, 1160, 835 cm21
;
1H NMR
3.1.6. Ole®n 17. To a stirred solution of sulfone 163d
(117 mg, 0.198 mmol) in THF (1 mL) cooled at 2788C
was added a 1.57 M solution of BuLi in hexane (0.125
mL, 0.196 mmol) dropwise. After the mixture was stirred
(270MHz, CDCl 3) d 7.48±7.45 (m, 6H), 7.36±7.23 (m,
9H), 5.52 (td, Jˆ6.9, 15.2 Hz, 1H), 5.21 (dd, Jˆ8.3, 15.2
Hz, 1H), 4.64 (d, Jˆ11.9 Hz, 1H), 4.57 (d, Jˆ11.9 Hz, 1H),
4.45 (m, 2H), 3.63 (m, 1H), 3.50(t, Jˆ3.6 Hz, 1H), 3.42 (s,
3H), 3.38 (m, 2H), 3.20(s, 3H), 3.11 (d, Jˆ4.9 Hz, 2H),
2.15 (s, 3H), 2.11 (m, 1H), 1.96 (m, 1H), 1.89±1.68 (m, 2H),
1.65±1.33 (m, 9H), 1.20 (s, 9H), 0.90±0.84 (m, 9H), 0.89 (s,
9H), 0.06 (s, 3H), 0.05 (s, 3H); MS (FAB) m/z 913 (M1
Na)1; HRMS (FAB) calcd for C53H82NaO7SSi [(M1Na)1]
913.5448, found 913.5430.
at 2788C for 30min, a 0.25 M solution of MgBr in THF
2
(0.89 mL, 0.223 mmol) was added and the mixture was
stirred at 2788C for 10min. A solution of aldehyde 15
(74 mg, 0.115 mmol) in THF (1.0 mL) was added dropwise,
and the resulting mixture was stirred at 2788C for 90min.
The reaction was quenched by adding saturated aqueous
NH4Cl (3 mL), and the mixture was extracted with Et2O
(3£10mL). The combined extracts were washed with
brine (4 mL), dried (Na2SO4), and concentrated. The resi-
dual oil was puri®ed by column chromatography on silica
gel (35 g, benzene±EtOAc 20:1!15:1!10:1!5:1) to give
a diastereomeric mixture of hydroxy sulfones (160mg) as a
colorless oil along with recovered 16 (81 mg, 45%). The
hydroxy sulfones were used in the next experiment without
separation of the diastereomers.
3.1.4. Alcohol 14. To a stirred solution of MTM ether 13
(80.6 mg, 0.0906 mmol) in Et2O (0.75 mL) was added
HCOOH (0.5 mL), and the mixture was stirred at 268C for
30min. The mixture was poured into saturated aqueous
NaHCO3 (10mL) cooled at 0 8C, and the resulting mixture
was extracted with Et2O (30mL, 20mL). The combined
extracts were washed with saturated aqueous NaHCO3
(10mL) and brine (10mL), dried (Na SO4), and concen-
2
trated. The residual oil was puri®ed by column chroma-
tography on silica gel (5 g, hexane±Et2O 5:1!1:1!1:2)
To a stirred solution of the diastereomeric mixture of
hydroxy sulfones (160mg) in pyridine (1 mL) were added
Ac2O (0.5 mL) and DMAP (13.3 mg, 0.108 mmol) at room
temperature. The mixture was stirred at room temperature
for 3.5 h and concentrated. The residue was puri®ed by
column chromatography on silica gel (20g, hexane±Et 2O
2:1!1:1!1:2) to give a diastereomeric mixture of acetoxy
sulfones (164 mg) as a colorless oil. The acetoxy sulfones
were used in the next experiment without separation of the
diastereomers.
27
to give 14 (49.0mg, 84%) as a colorless oil: [ a]D
ˆ
131.4 (c 1.00, CHCl3); IR (CHCl3) 3630, 3460 (br), 1720,
1285, 1255, 1165, 840cm 21; 1H NMR (270MHz, CDCl 3) d
5.56 (ddd, Jˆ6.9, 6.9, 15.2 Hz, 1H), 5.25 (dd, Jˆ8.3,
15.2 Hz, 1H), 4.64 (d, Jˆ11.5 Hz, 1H), 4.57 (d, Jˆ
11.5 Hz, 1H), 4.22±4.07 (m, 2H), 3.70 (ddd, Jˆ3.0, 6.9,
11.5 Hz, 1H), 3.62 (ddd, Jˆ2.6, 5.0, 8.3 Hz, 1H), 3.51 (t,
Jˆ3.6 Hz, 1H), 3.48±3.31 (m, 3H), 3.40(s, 3H), 3.23 (s,
3H), 2.17 (s, 3H), 2.11 (m, 1H), 2.00±1.35 (m, 12H),
1.20 (s, 9H), 0.91±0.89 (m, 3H), 0.93 (d, Jˆ6.6 Hz,
3H), 0 .90 (s, 9H), 0 .87 J(ˆd,6.6 Hz, 3H), 0.06 (s,
3H), 0.05 (s, 3H); MS (FAB) m/z 671 (M1Na)1;
HRMS (FAB) calcd for C34H68NaO7SSi [(M1Na)1]
671.4352, found 671.4385.
To a vigorously stirred solution of the diastereomeric
mixture of acetoxy sulfones (164 mg) in MeOH (3 mL)
cooled at 08C were added Na2HPO4 (442 mg, 3.11 mmol)
and 5% Na±Hg (725 mg, 1.56 mmol). The mixture was
stirred at 08C for 35 min, diluted with saturated aqueous
NH4Cl (3 mL), stirred at room temperature for 1 h, and
extracted with Et2O (3£20mL). The combined extracts
were washed with brine (5 mL), dried (Na2SO4), and
concentrated. The residual oil was puri®ed by column
chromatography on silica gel (20g, hexane±Et 2O 5:1!
3:1!2:1!1:1) to give a mixture of ole®ns. Further puri®-
cation of ole®ns by medium-pressure liquid chroma-
tography (Fuji Silysia, FL-60D, 43 g, benzene±EtOAc
(10:1!5:1), 6 mL/min) afforded E-ole®n 17 (105 mg,
66% from 15) and Z-ole®n (11 mg, 7% from 15) as a
3.1.5. C5±C20 Segment 15. To a stirred solution of alcohol
14 (89.4 mg, 0.138 mmol) in CH2Cl2 (0.9 mL) were added
pyridine (0.11 mL, 1.4 mmol) and the Dess±Martin period-
inane, C6H4(COO)I(OAc)3 (71.0mg, 0.167 mmol), at room
temperature. After the mixture was stirred at room tempera-
ture for 15 min, Et2O (1 mL), saturated aqueous NaHCO3
(1 mL), and saturated aqueous Na2S2O3 (1 mL) were added.
The aqueous mixture was stirred at room temperature for
40min and extracted with Et 2O (3£5 mL). The combined

H. Kigoshi et al. / Tetrahedron 58 (2002) 1075±1102
1083
28
colorless oil, respectively. 17: [a]D ˆ131.8 (c 0.904,
1160, 1095, 1030, 970, 830 cm21; H NMR (400 MHz,
0.90 (s, 9H), 0.87 (d, Jˆ6.6 Hz, 3H), 0.78 (d, Jˆ6.9 Hz,
3H), 0.60 (q, Jˆ7.8 Hz, 6H), 0.60 (q, Jˆ7.8 Hz, 6H), 0.05
(s, 3H), 0.05 (s, 3H); MS (FAB) m/z 1321 (M1Na)1;
HRMS (FAB) calcd for C70H134NaO13SSi3 [(M1Na)1]
1321.8750, found 1321.8750.
CHCl3); IR (CHCl3) 1720, 1595, 1515, 1460, 1380, 1260,
1
CDCl3) d 6.92±6.90(m, 2H), 6.82 (d, Jˆ8.3 Hz, 1H),
5.59±5.47 (m, 2H), 5.23 (dd, Jˆ8.3, 14.2 Hz, 1H), 5.23
(dd, Jˆ8.3, 14.2 Hz, 1H), 4.88 (d, Jˆ4.4 Hz, 1H), 4.83 (d,
Jˆ6.8 Hz, 1H), 4.81 (d, Jˆ6.8 Hz, 1H), 4.64 (d, Jˆ11.2 Hz,
1H), 4.60(d, Jˆ11.2 Hz, 1H), 4.58 (d, Jˆ11.2 Hz, 1H), 4.56
(d, Jˆ 11.7 Hz, 1H), 4.20±4.09 (m, 2H), 4.03 (dd, Jˆ6.8,
6.8 Hz, 1H), 3.96 (m, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.63±
3.30(m, 6H), 3.27 (s, 3H), 3.23 (s, 3H), 3.21 (s, 3H), 2.33±
1.36 (m, 25H), 2.16 (s, 3H), 1.20(s, 9H), 1.09 (d, Jˆ6.8 Hz,
3H), 0.97±0.86 (m, 9H), 0.95 (t, Jˆ7.8 Hz, 9H), 0.95 (t, Jˆ
7.8 Hz, 9H), 0.90 (s, 9H), 0.88 (d, Jˆ6.8 Hz, 3H), 0.87 (d,
Jˆ6.8 Hz, 3H), 0.78 (d, Jˆ6.8 Hz, 3H), 0.60 (q, Jˆ7.8 Hz,
6H), 0.59 (q, Jˆ7.8 Hz, 6H), 0.06 (s, 3H), 0.05 (s, 3H);
MS (FAB) m/z 1405 (M1Na)1; HRMS (FAB) calcd
for C75H142NaO14SSi3 [(M1Na)1] 1405.9325, found
3.1.8. Aldehyde 19. The experimental procedure was
similar to that described for compound 15. 19 (91%
30
yield): a colorless oil; [a]D ˆ123.6 (c 1.11, CHCl3); IR
(CHCl3) 2730, 1725, 1595, 1515, 1465, 1380, 1260, 1095,
1030, 970, 835 cm21; 1H NMR (270MHz, CDCl 3) d 9.82 (t,
Jˆ2.3 Hz, 1H), 6.92±6.89 (m, 2H), 6.82 (d, Jˆ7.9 Hz, 1H),
5.61±5.45 (m, 2H), 5.24 (dd, Jˆ8.2, 15.5 Hz, 1H), 5.22 (dd,
Jˆ8.2, 15.5 Hz, 1H), 4.88 (d, Jˆ4.6 Hz, 1H), 4.83 (d, Jˆ
7.3 Hz, 1H), 4.80(d, Jˆ7.3 Hz, 1H), 4.67 (d, Jˆ11.5 Hz,
1H), 4.61 (d, Jˆ11.5 Hz, 1H), 4.60(d, Jˆ11.5 Hz, 1H), 4.55
(d, Jˆ11.5 Hz, 1H), 4.08±3.93 (m, 3H), 3.88 (s, 3H), 3.87
(s, 3H), 3.60±3.40 (m, 5H), 3.27 (s, 3H), 3.24 (s, 3H), 3.21
(s, 3H), 2.59±2.55 (m, 2H), 2.31±1.97 (m, 6H), 2.14 (s, 3H),
1.87 (m, 1H), 1.67±1.34 (m, 15H), 1.10±1.01 (m, 1H), 1.09
(d, Jˆ6.6 Hz, 3H), 0.98±0.86 (m, 12H), 0.95 (t, Jˆ7.9 Hz,
9H), 0.95 (t, Jˆ7.9 Hz, 9H), 0.90 (s, 9H), 0.87 (d, Jˆ6.6 Hz,
3H), 0.78 (d, Jˆ6.9 Hz, 3H), 0.60 (q, Jˆ7.9 Hz, 6H), 0.59
(q, Jˆ7.9 Hz, 6H), 0.05 (s, 6H); MS (FAB) m/z 1319 (M1
Na)1; HRMS (FAB) calcd for C70H132NaO13SSi3 [(M1
Na)1] 1319.8595, found 1319.8590.
30
1405.9270. Z-Ole®n: [a]D ˆ133.0( c 0.656, CHCl3); IR
(CHCl3) 1720, 1595, 1515, 1465, 1380, 1260, 1160, 1095,
1030, 970, 835 cm21; 1H NMR (400 MHz, CDCl3) d 6.92±
6.90(m, 2H), 6.82 (d, Jˆ8.3 Hz, 1H), 5.59±5.47 (m, 2H),
5.23 (dd, Jˆ8.3, 14.2 Hz, 1H), 5.23 (dd, Jˆ8.3, 14.2 Hz,
1H), 4.88 (d, Jˆ4.4 Hz, 1H), 4.83 (d, Jˆ6.8 Hz, 1H), 4.81
(d, Jˆ6.8 Hz, 1H), 4.64 (d, Jˆ11.2 Hz, 1H), 4.60(d, Jˆ
11.2 Hz, 1H), 4.58 (d, Jˆ11.2 Hz, 1H), 4.56 (d, Jˆ11.7 Hz,
1H), 4.20±4.09 (m, 2H), 4.03 (dd, Jˆ6.8, 6.8 Hz, 1H), 3.96
(m, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.63±3.30(m, 6H), 3.27
(s, 3H), 3.23 (s, 3H), 3.21 (s, 3H), 2.33±1.36 (m, 25H), 2.16
(s, 3H), 1.20(s, 9H), 1.09 (d, Jˆ6.8 Hz, 3H), 0.97±0.86 (m,
9H), 0.95 (t, Jˆ7.8 Hz, 9H), 0.95 (t, Jˆ7.8 Hz, 9H), 0.90 (s,
9H), 0.88 (d, Jˆ6.8 Hz, 3H), 0.87 (d, Jˆ6.8 Hz, 3H), 0.78
(d, Jˆ6.8 Hz, 3H), 0.60 (q, Jˆ7.8 Hz, 6H), 0.59 (q, Jˆ
7.8 Hz, 6H), 0.06 (s, 3H), 0.05 (s, 3H); MS (FAB) m/z
1405 (M1Na)1; HRMS (FAB) calcd for C75H142NaO14SSi3
[(M1Na)1] 1405.9325, found 1405.9250.
3.1.9. a,b,g,d-Unsaturated ester 20. To a stirred solution
of triethyl 4-phosphonocrotonate (50.8 mg, 0.203 mmol) in
THF (0.5 mL) cooled at 2488C was added a 0.5 M solution
of LDA (0.35 mL, 0.18 mmol). The mixture was stirred at
2488C for 30min, and a solution of aldehyde 19 (46.0mg,
0.0355 mmol) in THF (0.8 mL) was added dropwise. The
resulting mixture was stirred at 2488C for 10min and at
08C for 15 min. The mixture was diluted with saturated
aqueous NH4Cl (2 mL) and extracted with Et2O (3£
6 mL). The combined extracts were washed with brine
(2 mL), dried (Na2SO4), and concentrated. The residual oil
was puri®ed by column chromatography on silica gel (5 g,
hexane±Et2O 3:1!1:1) to give 20 (4E/4Zˆ16:1) (43.6 mg,
3.1.7. Alcohol 18. To a stirred solution of E-ole®n 17
(106 mg, 0.0767 mmol) in CH2Cl2 (3 mL) cooled at
2788C was added a 1.0M solution of DIBAL in hexane
(0.31 mL, 0.31 mmol) dropwise. The mixture was stirred
at 2788C for 1 h and the reaction was quenched by adding
MeOH (0.5 mL) and saturated aqueous potassium sodium
tartrate (4 mL). The resulting mixture was warmed to room
temperature, stirred for 30min, and extracted with Et 2O
(3£10mL). The combined extracts were washed with
brine (3 mL), dried (Na2SO4), and concentrated. The
residual oil was puri®ed by column chromatography on
silica gel (5 g, hexane±EtOAc 4:1!2:1!1:1) to give 18
31
88%) as a colorless oil: [a]D ˆ16.98 (c 1.15, CHCl3); IR
(CHCl3) 1705, 1645, 1615, 1595, 1515, 1465, 1365, 1260,
1
1095, 1025, 970, 835 cm21; H NMR (270MHz, CDCl 3)
(4E-isomer) d 7.26 (dd, Jˆ10.2, 15.1 Hz, 1H), 6.92±6.89
(m, 2H), 6.82 (d, Jˆ8.3 Hz, 1H), 6.28±6.13 (m, 2H), 5.80
(d, Jˆ15.1 Hz, 1H), 5.59±5.46 (m, 2H), 5.23 (dd, Jˆ8.3,
15.1 Hz, 1H), 5.22 (dd, Jˆ8.3, 15.1 Hz, 1H), 4.88 (d, Jˆ
4.4 Hz, 1H), 4.83 (d, Jˆ6.8 Hz, 1H), 4.80(d, Jˆ6.8 Hz,
1H), 4.62 (d, Jˆ11.7 Hz, 1H), 4.60(d, Jˆ11.7 Hz, 1H),
4.59 (d, Jˆ11.7 Hz, 1H), 4.56 (d, Jˆ11.7 Hz, 1H), 4.20
(q, Jˆ6.8 Hz, 2H), 4.03 (br dd, Jˆ7.3, 7.3 Hz, 1H), 3.96
(m, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.63 (dd, Jˆ3.4, 3.4 Hz,
1H), 3.59±3.47 (m, 4H), 3.41 (m, 1H), 3.27 (s, 3H), 3.24 (s,
3H), 3.21 (s, 3H), 2.47 (m, 1H), 2.34±2.12 (m, 5H), 2.15 (s,
3H), 2.09 (dd, Jˆ7.3, 12.2 Hz, 1H), 1.90±1.83 (m, 2H),
1.68±1.37 (m, 15H), 1.29 (t, Jˆ6.8 Hz, 3H), 1.09 (d, Jˆ
6.8 Hz, 3H), 1.06 (m, 1H), 0.95 (t, Jˆ7.8 Hz, 9H), 0.95 (t,
Jˆ7.8 Hz, 9H), 0.94±0.77 (m, 6H), 0.93 (d, Jˆ6.8 Hz, 3H),
0.90 (s, 9H), 0.87 (d, Jˆ6.8 Hz, 3H), 0.84 (d, Jˆ6.8 Hz,
3H), 0.78 (d, Jˆ6.8 Hz, 3H), 0.60 (q, Jˆ7.8 Hz, 6H), 0.59
(q, Jˆ7.8 Hz, 6H), 0.06 (s, 3H), 0.05 (s, 3H); MS (FAB) m/z
1415 (M1Na)1; HRMS (FAB) calcd for C76H140NaO14SSi3
[(M1Na)1] 1415.9170, found 1415.9170.
32
(99 mg, 99%) as a colorless oil: [a]D ˆ136.8 (c 1.03,
CHCl3); IR (CHCl3) 3480(br), 1595, 1515, 1465, 1380,
1
1260, 1095, 1030, 970, 835 cm21; H NMR (400 MHz,
CDCl3) d 6.92±6.89 (m, 2H), 6.82 (d, Jˆ7.9 Hz, 1H),
5.61±5.45 (m, 2H), 5.24 (dd, Jˆ8.6, 15.1 Hz, 1H), 5.23
(dd, Jˆ8.6, 15.1 Hz, 1H), 4.88 (d, Jˆ5.0Hz, 1H), 4.83 (d,
Jˆ7.3 Hz, 1H), 4.80(d, Jˆ7.3 Hz, 1H), 4.70(d, Jˆ11.6 Hz,
1H), 4.61 (d, Jˆ11.6 Hz, 1H), 4.59 (d, Jˆ11.6 Hz, 1H), 4.56
(d, Jˆ11.6 Hz, 1H), 4.05±3.93 (m, 2H), 3.88 (s, 3H), 3.87
(s, 3H), 3.84±3.67 (m, 3H), 3.60±3.41 (m, 5H), 3.27 (s, 3H),
3.24 (s, 3H), 3.21 (s, 3H), 2.43 (t, Jˆ5.9 Hz, 1H, ±OH),
2.31±1.82 (m, 7H), 2.21 (s, 3H), 1.70±1.37 (m, 17H),
1.10±1.03 (m, 1H), 1.09 (d, Jˆ6.6 Hz, 3H), 0.98±0.86
(m, 12H), 0.95 (t, Jˆ7.8 Hz, 9H), 0.95 (t, Jˆ7.8 Hz, 9H),

1084
H. Kigoshi et al. / Tetrahedron 58 (2002) 1075±1102
3.1.10. Diol 21. A solution of a,b,g,d-unsaturated ester 20
(4E/4Zˆ16:1) (42.0 mg, 0.0302 mmol) in a 5:3:1 mixture of
THF, pyridine, and HF´pyridine (1 mL) was stirred at room
temperature for 1 h. The mixture was diluted with EtOAc
(5 mL) and cooled to 08C, and then saturated aqueous
NaHCO3 (8 mL) was added. The organic layer was sepa-
rated, and the aqueous layer was extracted with EtOAc
(3£10mL). The organic layer and the extracts were
combined, washed with brine (4 mL), dried (Na2SO4), and
concentrated. The residual oil was puri®ed by column
chromatography on silica gel (2 g, hexane±EtOAc 1:1!
2:3!1:2) to give 21 (4E/4Zˆ16:1) (34.6 mg, 99%) as a
1.10(d, Jˆ6.8 Hz, 3H), 0.96 (d, Jˆ6.8 Hz, 3H), 0.91 (m,
9H), 0.89 (s, 9H), 0.87 (d, Jˆ6.8 Hz, 3H), 0.84 (d, Jˆ
6.8 Hz, 3H), 0.06 (s, 3H), 0.05 (s, 3H). Signals of three protons
(COOH, 2£OH) were not observed; MS (FAB) m/z 1181
(M2H12Na)1; HRMS (FAB) calcd for C62H107Na2O14SSi
[(M2H12Na)1] 1181.6947, found 1181.6930.
3.1.12. Macrolactonization of seco-acid 22. To a stirred
solution of seco-acid 22 (4E/4Zˆ16:1) (29.0 mg, 0.0255
mmol) in CH2Cl2 (30mL) were successively added Et 3N
(0.035 mL, 0.25 mmol), DMAP (63.6 mg, 0.52 mmol),
and 2,4,6-trichlorobenzoyl chloride (0.035 mL, 0.22
mmol) at room temperature. The mixture was stirred at
room temperature for 2.5 h and successively washed with
1 M aqueous HCl (5 mL), saturated aqueous NaHCO3
29
colorless oil: [a]D ˆ11.17 (c 1.19, CHCl3); IR (CHCl3)
3490 (br), 1700, 1640, 1615, 1595, 1515, 1465, 1365, 1260,
1
1095, 1025, 970, 835 cm21; H NMR (400 MHz, CDCl3)
(4E-isomer) d 7.26 (dd, Jˆ10.3, 15.6 Hz, 1H), 6.94±6.90
(m, 2H), 6.83 (d, Jˆ8.3 Hz, 1H), 6.28±6.13 (m, 2H), 5.80
(d, Jˆ15.6 Hz, 1H), 5.62 (ddd, Jˆ7.3, 7.3, 15.1 Hz, 1H),
5.54 (ddd, Jˆ7.3, 7.3, 15.1 Hz, 1H), 5.34 (dd, Jˆ8.3,
15.1 Hz, 1H), 5.23 (dd, Jˆ8.3, 15.1 Hz, 1H), 4.90(d, Jˆ
4.9 Hz, 1H), 4.86 (d, Jˆ6.8 Hz, 1H), 4.83 (d, Jˆ6.8 Hz,
1H), 4.63±4.56 (m, 4H), 4.20(q, Jˆ7.3 Hz, 2H), 4.06 (dd,
Jˆ6.3, 6.3 Hz, 1H), 3.97 (m, 1H), 3.89 (s, 3H), 3.87 (s, 3H),
3.63 (dd, Jˆ3.4, 3.4 Hz, 1H), 3.60±3.54 (m, 3H), 3.42 (m,
1H), 3.30(m, 1H), 3.30(s, 3H), 3.23 (s, 3H), 3.23 (s, 3H),
2.77 (d, Jˆ2.9 Hz, 1H, ±OH), 2.72 (d, Jˆ5.4 Hz, 1H,
±OH), 2.44 (m, 1H), 2.34±2.05 (m, 6H), 2.15 (s, 3H),
1.92±1.79 (m, 3H), 1.67±1.38 (m, 14H), 1.29 (t, Jˆ
7.3 Hz, 3H), 1.19±0.87 (m, 13H), 1.10 (d, Jˆ6.3 Hz, 3H),
0.97 (d, Jˆ7.3 Hz, 3H), 0.89 (s, 9H), 0.84 (d, Jˆ6.8 Hz,
3H), 0.06 (s, 3H), 0.05 (s, 3H); MS (FAB) m/z 1187 (M1
Na)1; HRMS (FAB) calcd for C64H112NaO14SSi [(M1
Na)1] 1187.7439, found 1187.7490.
(10mL), and brine (10mL), dried (Na SO4), and concen-
2
trated. The residue was puri®ed by column chromatography
on silica gel (2 g, hexane±EtOAc 2:1!1:1) and preparative
HPLC (Develosil 30-10, 20£250mm, hexane±EtOAc±
MeOH 80:20:1, 6 mL/min) to give the 24-membered
lactone 23 (tRˆ38 min, 10mg, 35%) and the 26-membered
lactone (tRˆ46 min, 8.8 mg, 31%) as a colorless oil, respec-
27
tively. 23: [a]D ˆ142.9 (c 0.968, CHCl3); IR (CHCl3)
3500 (br), 1690, 1640, 1615, 1595, 1515, 1465, 1380,
1
1260, 1095, 1030, 970, 835 cm21; H NMR (400 MHz,
CDCl3) d 7.26 (m, 1H), 6.93±6.91 (m, 2H), 6.83 (d, Jˆ
8.3 Hz, 1H), 6.30±6.17 (m, 2H), 5.82 (d, Jˆ15.6 Hz, 1H),
5.53 (ddd, Jˆ4.4, 10.3, 14.6 Hz, 1H), 5.37 (br d, Jˆ10.7 Hz,
1H), 5.28 (ddd, Jˆ5.9, 8.3, 14.6 Hz, 1H), 5.17±5.08 (m,
2H), 4.89 (d, Jˆ4.9 Hz, 1H), 4.86 (d, Jˆ6.8 Hz, 1H), 4.83
(d, Jˆ6.8 Hz, 1H), 4.61 (d, Jˆ11.7 Hz, 1H), 4.61 (d, Jˆ
11.7 Hz, 1H), 4.56 (d, Jˆ11.7 Hz, 1H), 4.55 (d, Jˆ11.7 Hz,
1H), 4.06 (br dd, Jˆ6.3, 6.3 Hz, 1H), 3.89 (s, 3H), 3.87 (s,
3H), 3.58±3.39 (m, 3H), 3.56 (dd, Jˆ6.8, 10.3 Hz, 1H), 3.41
(ddd, Jˆ3.9, 3.9, 9.8 Hz, 1H), 3.27 (s, 3H), 3.25 (s, 3H),
3.20(s, 3H), 3.17 (d, Jˆ4.9 Hz, 1H), 2.99 (m, 1H), 2.50±
2.32 (m, 2H), 2.26±2.05 (m, 6H), 2.17 (s, 3H), 1.86 (m, 2H),
1.72±1.09 (m, 15H), 1.10 (d, Jˆ6.3 Hz, 3H), 1.01 (d, Jˆ
6.8 Hz, 3H), 0.93 (d, Jˆ6.8 Hz, 3H), 0.89 (s, 9H), 0.89±0.86
(m, 6H), 0.83 (d, Jˆ6.8 Hz, 3H), 0.73 (d, Jˆ5.9 Hz, 3H),
0.05 (s, 3H), 0.04 (s, 3H); MS (FAB) m/z 1141 (M1Na)1;
HRMS (FAB) calcd for C62H106NaO13SSi [(M1Na)1]
1141.7021, found 1141.7010. 26-membered lactone:
3.1.11. seco-Acid 22. To a stirred solution of diol 21 (4E/
4Zˆ16:1) (43.1 mg, 0.0370 mmol) in MeOH (4 mL) was
added 5 M aqueous LiOH (0.5 mL) at room temperature,
and the mixture was stirred at room temperature for
13.5 h. The mixture was diluted with EtOAc (10mL),
cooled to 08C, and acidi®ed (pH 1) with 1 M aqueous HCl
(3 mL). Sodium chloride (2 g) was added to the mixture and
the organic layer was separated. The aqueous layer was
extracted with EtOAc (3£10mL). The organic layer and
the extracts were combined, washed with brine (4 mL),
dried (Na2SO4), and concentrated. The residual oil was
puri®ed by column chromatography on silica gel (4 g,
hexane±EtOAc 1:1!EtOAc) to give 22 (4E/4Zˆ16:1)
27
[a]D ˆ120.3 (c 1.23, CHCl3); IR (CHCl3) 3500 (br),
1690, 1640, 1615, 1595, 1515, 1465, 1380, 1260, 1095,
1
1030, 970, 835 cm21; H NMR (400 MHz, CDCl3) d 7.26
(m, 1H), 6.93±6.91 (m, 2H), 6.83 (d, Jˆ8.3 Hz, 1H), 6.30±
6.17 (m, 2H), 5.82 (d, Jˆ15.6 Hz, 1H), 5.53 (ddd, Jˆ4.4,
10.3, 14.6 Hz, 1H), 5.37 (d, Jˆ10.7 Hz, 1H), 5.17±5.08 (m,
2H), 4.89 (d, Jˆ4.9 Hz, 1H), 4.86 (d, Jˆ6.8 Hz, 1H), 4.83
(d, Jˆ6.8 Hz, 1H), 4.61 (d, Jˆ11.7 Hz, 1H), 4.61 (d, Jˆ
11.7 Hz, 1H), 4.56 (d, Jˆ11.7 Hz, 1H), 4.55 (d, Jˆ11.7 Hz,
1H), 4.06 (br dd, Jˆ6.3, 6.3 Hz, 1H), 3.89 (s, 3H), 3.87 (s,
3H), 3.58±3.39 (m, 4H), 3.56 (dd, Jˆ6.8, 10.3 Hz, 1H), 3.41
(ddd, Jˆ3.9, 3.9, 9.8 Hz, 1H), 3.27 (s, 3H), 3.25 (s, 3H),
3.20(s, 3H), 3.17 (d, Jˆ4.9 Hz, 1H), 2.99 (m, 1H), 2.50±
2.32 (m, 2H), 2.26±2.05 (m, 6H), 2.17 (s, 3H), 1.86 (m, 2H),
1.72±1.09 (m, 15H), 1.10 (d, Jˆ6.3 Hz, 3H), 1.01 (d, Jˆ
6.8 Hz, 3H), 0.93 (d, Jˆ6.8 Hz, 3H), 0.89 (s, 9H), 0.89±0.86
(m, 6H), 0.83 (d, Jˆ6.8 Hz, 3H), 0.73 (d, Jˆ5.9 Hz, 3H),
0.05 (s, 3H), 0.04 (s, 3H); MS (FAB) m/z 1141 (M1Na)1;
HRMS (FAB) calcd for C62H106NaO13SSi [(M1Na)1]
1141.7021, found 1141.6990.
27
(41.8 mg, 99%) as a colorless oil: [a]D ˆ27.7 (c 1.06,
CHCl3); IR (CHCl3) 3600±2400 (br), 1690, 1640, 1615,
1595, 1515, 1465, 1380, 1260, 1095, 1025, 970, 835
1
cm21; H NMR (270MHz, CDCl 3) (4E-isomer) d 7.29
(dd, Jˆ10.7, 15.1 Hz, 1H), 6.94±6.90 (m, 2H), 6.83 (d,
Jˆ7.8 Hz, 1H), 6.30±6.18 (m, 2H), 5.79 (d, Jˆ15.1 Hz,
1H), 5.60(ddd, Jˆ7.3, 7.3, 15.1 Hz, 1H), 5.53 (ddd, Jˆ
7.3, 7.3, 15.1 Hz, 1H), 5.34 (dd, Jˆ8.3, 15.1 Hz, 1H), 5.22
(dd, Jˆ8.3, 15.1 Hz, 1H), 4.91 (d, Jˆ4.9 Hz, 1H), 4.86 (d,
Jˆ6.8 Hz, 1H), 4.83 (d, Jˆ6.8 Hz, 1H), 4.64±4.61 (m, 2H),
4.59 (d, Jˆ11.7 Hz, 1H), 4.58 (d, Jˆ11.7 Hz, 1H), 4.06 (m,
1H), 3.99 (m, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.63 (dd, Jˆ
2.9, 3.4 Hz, 1H), 3.60±3.53 (m, 3H), 3.42 (m, 1H), 3.35 (dd,
Jˆ5.9, 5.9 Hz, 1H), 3.30(s, 3H), 3.24 (s, 3H), 3.23 (s, 3H),
2.47 (ddd, Jˆ4.4, 4.4, 15.6 Hz, 1H), 2.36±2.05 (m, 7H),
2.16 (s, 3H), 1.94±1.78 (m, 3H), 1.67±1.00 (m, 15H),

H. Kigoshi et al. / Tetrahedron 58 (2002) 1075±1102
1085
3.1.13. Isomerization of the 26-membered lactone to the
24-membered lactone 23. To a stirred solution of the
26-membered lactone (42.0 mg, 0.0377 mmol) in CH2Cl2
(1.8 mL) was added Ti(O-i-Pr)4 (0.045 mL, 0.15 mmol) at
room temperature. The solution was stirred at room
temperature for 13 h and diluted with Et2O (5 mL) and
0.5 M aqueous (1)-tartaric acid (5 mL). The mixture was
stirred at room temperature for 30min and extracted with
Et2O (3£5 mL). The combined extracts were washed with
brine (3 mL), dried (Na2SO4), and concentrated. The
residual oil was puri®ed as described above to give 84
(28 mg, 66%) along with the recovered 26-membered
lactone (7.7 mg, 18%).
acetone (0.2 mL) and the resulting mixture was stirred at
room temperature for 10min. Et 2O (2 mL) and saturated
aqueous NH4Cl (1 mL) were added, and the mixture was
stirred for 10min and separated. The aqueous layer was
extracted with Et2O (3£10mL). The organic layer and the
extracts were combined, washed with brine (3 mL), dried
(Na2SO4), and concentrated. The residual oil was puri®ed by
column chromatography on silica gel (2 g, hexane±EtOAc
3:1!3:2!1:1!1:2) to give 25 (19.0mg, 67%) as a color-
29
less oil: [a]D ˆ113.4 (c 1.03, CHCl3); IR (CHCl3) 3420
(br), 1705, 1645, 1615, 1595, 1515, 1465, 1375, 1260, 1030,
1
970, 835 cm21; H NMR (400 MHz, CDCl3) d 7.22 (ddd,
Jˆ4.9, 10.3, 15.1 Hz, 1H), 7.00±6.87 (m, 2H), 6.83 (d, Jˆ
8.8 Hz, 1H), 6.25±6.16 (m, 2H), 5.81 (d, Jˆ15.1 Hz, 1H),
5.53 (ddd, Jˆ3.9, 10.2, 15.1 Hz, 1H), 5.33±5.23 (m, 2H),
5.14±5.07 (m, 2H), 4.82 (d, Jˆ6.8 Hz, 1H), 4.77 (d, Jˆ
6.8 Hz, 1H), 4.65 (d, Jˆ11.7 Hz, 1H), 4.60(d, Jˆ11.7 Hz,
1H), 4.55 (d, Jˆ11.7 Hz, 1H), 4.53 (d, Jˆ11.7 Hz, 1H), 4.06
(br s, 1H, ±OH), 3.89 (s, 3H), 3.89 (m, 1H), 3.88 (s, 3H),
3.72 (ddd, Jˆ5.4, 5.4, 11.7 Hz, 1H), 3.58±3.37 (m, 7H),
3.24 (s, 3H), 3.20(s, 3H), 3.06 (br s, 1H, ±OH), 2.45 (m,
1H), 2.34±2.16 (m, 3H), 2.17 (s, 3H), 1.94±1.69 (m, 6H),
1.67±1.09 (m, 15H), 1.02 (d, Jˆ6.8 Hz, 3H), 0.95±0.88 (m,
6H), 0.95 (d, Jˆ7.3 Hz, 3H), 0.93 (d, Jˆ6.8 Hz, 3H), 0.90
(s, 9H), 0.89 (s, 9H), 0.87 (d, Jˆ5.6 Hz, 3H), 0.77 (d, Jˆ
6.3 Hz, 3H), 0.12 (s, 3H), 0.05 (s, 6H), 0.04 (s, 3H); MS
(FAB) m/z 1243 (M1Na)1; HRMS (FAB) calcd for
3.1.14. Disilyl ether 24. To a stirred solution of the 24-
membered lactone 23 (18.2 mg, 0.0163 mmol) and imida-
zole (131 mg, 1.92 mmol) in DMF (0.16 mL) was added
t-BuMe2SiCl (119 mg, 0.766 mmol) at room temperature,
and the resulting solution was stirred at 608C for 16 h.
The mixture was cooled to room temperature, and ice
water (2 g) was added. The mixture was stirred at room
temperature for 20min and extracted with Et 2O (3£
10mL). The combined extracts were successively washed
with 1 M aqueous HCl (3 mL), saturated aqueous NaHCO3
(4 mL), and brine (3 mL), dried (Na2SO4), and concen-
trated. The residual oil was puri®ed by column chroma-
tography on silica gel (2 g, hexane±EtOAc 5:1!4:1!
3:1!2:1!1:1) to give 24 (17.0mg, 85%) as a colorless
C67H120NaO13SSi2
1243.7880.
[(M1Na)1]
1243.7886,
found
24
oil: [a]D ˆ136.5 (c 1.11, CHCl3); IR (CHCl3) 1705,
1645, 1615, 1595, 1515, 1465, 1375, 1260, 1095, 1030,
1
970, 835 cm21; H NMR (400 MHz, CDCl3) d 7.21 (ddd,
3.1.16. Silyl ether 26. To a stirred solution of diol 25
(9.3 mg, 7.6 mmol) in CH2Cl2 (0.1 mL) was added Et3N
(0.025 mL, 0.18 mmol), DMAP (0.7 mg, 5.7 mmol), and
t-BuMe2SiCl (18.0mg, 0.119 mmol) at room temperature.
The solution was stirred at room temperature for 35 min. Ice
(ca. 1 g) and saturated aqueous NaHCO3 (1 mL) were added
and the mixture was stirred at room temperature for 30min
and extracted with Et2O (3£5 mL). The combined extracts
were washed with brine (2 mL), dried (Na2SO4), and
concentrated. The residual oil was puri®ed by column chro-
matography on silica gel (2 g, hexane±EtOAc 4:1!
3:1!2:1) to give 26 (10.2 mg, 100%) as a colorless oil:
Jˆ4.9, 10.3, 15.1 Hz, 1H), 6.93±6.90 (m, 2H), 6.83 (d,
Jˆ6.8 Hz, 1H), 6.24±6.16 (m, 2H), 5.80(d, Jˆ15.1 Hz,
1H), 5.54 (ddd, Jˆ3.9, 10.3, 14.6 Hz, 1H), 5.30±5.25 (m,
2H), 5.13±5.04 (m, 2H), 4.89 (d, Jˆ4.4 Hz, 1H), 4.84 (d,
Jˆ6.8 Hz, 1H), 4.81 (d, Jˆ6.8 Hz, 1H), 4.56 (d, Jˆ11.2 Hz,
1H), 4.55±4.50(m, 3H), 4.04 (br dd, Jˆ6.8, 6.8 Hz, 1H),
3.89 (s, 3H), 3.88 (s, 3H), 3.56±3.34 (m, 6H), 3.27 (s, 3H),
3.24 (s, 3H), 3.20(s, 3H), 2.42 (m, 1H), 2.35±2.18 (m, 4H),
2.18 (s, 3H), 2.10(dd, Jˆ7.3, 12.2 Hz, 1H), 1.86±1.00 (m,
19H), 1.10(d, Jˆ6.8 Hz, 3H), 0.95 (d, Jˆ7.3 Hz, 3H), 0.93
(d, Jˆ6.8 Hz, 3H), 0.92±0.85 (m, 6H), 0.90 (s, 9H), 0.89 (s,
9H), 0.87 (d, Jˆ6.8 Hz, 3H), 0.77 (d, Jˆ6.4 Hz, 3H), 0.12
(s, 3H), 0.05 (s, 6H), 0.04 (s, 3H); MS (FAB) m/z 1255
(M1Na)1; HRMS (FAB) calcd for C68H120NaO13SSi2
[(M1Na)1] 1255.7887, found 1255.7870.
30
[a]D ˆ115.5 (c 0.55, CHCl3); IR (CHCl3) 3495, 1705,
1640, 1615, 1595, 1515, 1460, 1375, 1260, 1095, 1030,
1
970, 835 cm21; H NMR (400 MHz, CDCl3) d 7.21 (ddd,
Jˆ4.4, 9.8, 15.1 Hz, 1H), 6.89±6.87 (m, 2H), 6.83 (d, Jˆ
8.8 Hz, 1H), 6.25±6.15 (m, 2H), 5.80(d, Jˆ15.1 Hz, 1H),
5.54 (ddd, Jˆ4.4, 10.7, 15.1 Hz, 1H), 5.33±5.25 (m, 2H),
5.14±5.06 (m, 2H), 4.82 (d, Jˆ7.3 Hz, 1H), 4.76 (d, Jˆ
7.3 Hz, 1H), 4.64 (d, Jˆ11.7 Hz, 1H), 4.60(d, Jˆ11.7 Hz,
1H), 4.56 (d, Jˆ11.7 Hz, 1H), 4.53 (d, Jˆ11.7 Hz, 1H), 3.89
(s, 3H), 3.88 (m, 1H), 3.87 (s, 3H), 3.74±3.39 (m, 9H), 3.24
(s, 3H), 3.20(s, 3H), 2.45±2.17 (m, 4H), 2.17 (s, 3H), 1.87±
1.15 (m, 21H), 1.00 (d, Jˆ6.8 Hz, 3H), 0.94 (d, Jˆ6.8 Hz,
3H), 0.92 (d, Jˆ6.3 Hz, 3H), 0.90 (s, 9H), 0.89 (s, 18H),
0.90±0.86 (m, 6H), 0.84 (d, Jˆ6.8 Hz, 3H), 0.77 (d, Jˆ
6.3 Hz, 3H), 0.12 (s, 3H), 0.05 (s, 6H), 0.04 (s, 9H); MS
(FAB) m/z 1357 (M1Na)1; HRMS (FAB) calcd
for C73H134NaO13SSi3 [(M1Na)1] 1357.8751, found
1357.8770.
3.1.15. Diol 25. To a stirred solution of disilyl ether 24
(28.5 mg, 0.0231 mmol) in 1,2-dimethoxyethane (3.2 mL)
was added 1 M aqueous HCl (0.8 mL) at room temperature.
The solution was stirred at room temperature for 6.5 h,
cooled to 08C, and diluted with saturated aqueous
NaHCO3 (2 mL). The mixture was extracted with Et2O
(3£10mL). The combined extracts were washed with
brine (3 mL), dried (Na2SO4), and concentrated. The
residual oil was puri®ed by column chromatography on
silica gel (4 g, hexane±EtOAc 5:1!3:1!3:2) to give a dia-
stereomeric mixture of hemiacetals (19.7 mg) as a colorless
oil along with recovered 24 (3.0mg, 11%). To a stirred
solution of the hemiacetals (19.7 mg) in MeOH (0.5 mL)
cooled at 08C was added sodium trimethoxyborohydride
(22.8 mg, 0.178 mmol). The solution was stirred at room
temperature for 4.5 h. The reaction was quenched by adding
3.1.17. Acetate 27. To a stirred solution of silyl ether 26
(17.0 mg, 0.0124 mmol) in pyridine (0.2 mL) were added

1086
H. Kigoshi et al. / Tetrahedron 58 (2002) 1075±1102
Ac2O (0.1 mL) and DMAP (0.7 mg, 5.7 mmol) at room
temperature. The mixture was stirred at room temperature
for 13 h and concentrated. The residual oil was puri®ed by
column chromatography on silica gel (2 g, hexane±EtOAc
5:1!4:1!3:1) to give 27 (16.7 mg, 95%) as a colorless oil:
temperature for 12 h, and saturated aqueous NaHCO3
(2.5 mL) was added. The mixture was stirred at room
temperature for 30min and extracted with EtOAc
(3£10mL). The combined extracts were washed with
brine (2 mL), dried (Na2SO4), and concentrated. The residue
was puri®ed by column chromatography on silica gel (2 g,
hexane±acetone 10:1!7:1! 5:1) and preparative TLC on
silica gel (200£100£ 0.25 mm3, hexane±acetone 2:1) to
give a diastereomeric mixture of 29 (S/Rˆ3:1) (4.8 mg,
30
[a]D ˆ134 (c 0.20, CHCl3); IR (CHCl3) 1720, 1705, 1640,
1615, 1595, 1515, 1465, 1375, 1255, 1030, 970, 835 cm21
;
1H NMR (400 MHz, CDCl3) d 7.22 (ddd, Jˆ4.4, 10.2,
15.1 Hz, 1H), 6.89±6.87 (m, 2H), 6.82 (d, Jˆ7.8 Hz, 1H),
6.25±6.15 (m, 2H), 5.80(d, Jˆ15.1 Hz, 1H), 5.53 (ddd,
Jˆ4.4, 10.2, 15.1 Hz, 1H), 5.33±5.24 (m, 2H), 5.14±5.06
(m, 2H), 5.00 (dd, Jˆ2.4, 9.8 Hz, 1H), 4.77 (d, Jˆ6.8 Hz,
1H), 4.67 (d, Jˆ6.8 Hz, 1H), 4.62 (d, Jˆ11.7 Hz, 1H), 4.60
(d, Jˆ11.7 Hz, 1H), 4.55 (d, Jˆ11.7 Hz, 1H), 4.49 (d, Jˆ
11.7 Hz, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.69 (m, 1H),
3.60±3.39 (m, 7H), 3.24 (s, 3H), 3.20 (s, 3H), 2.47 (m,
1H), 2.36±2.17 (m, 3H), 2.17 (s, 3H), 2.03 (s, 3H), 2.03±
1.17 (m, 21H), 0.93 (d, Jˆ6.8 Hz, 3H), 0.93±0.86 (m, 12H),
0.90 (s, 9H), 0.89 (s, 9H), 0.89 (s, 9H), 0.87 (d, Jˆ6.3 Hz,
3H), 0.77 (d, Jˆ5.9 Hz, 3H), 0.13 (s, 3H), 0.06 (s, 3H), 0.05
(s, 12H); MS (FAB) m/z 1399 (M1Na)1; HRMS (FAB)
calcd for C75H136NaO14SSi3 [(M1Na)1] 1399.8856, found
1399.8850.
30
100%) as a colorless oil: [a]D ˆ131 (c 0.17, MeOH); IR
(CHCl3) 1725, 1700, 1655, 1465, 1375, 1250, 1080, 1035,
970, 835 cm21; 1H NMR (400 MHz, acetone-d6) d 7.25 (dd,
Jˆ10.7, 15.1 Hz, 1H), 6.44±6.27 (m, 2H), 5.90 (d,
Jˆ15.1 Hz, 1H), 5.56 (ddd, Jˆ4.4, 10.7, 14.6 Hz, 1H),
5.38 (ddd, Jˆ5.4, 8.8, 14.6 Hz, 1H), 5.32 (ddd, Jˆ2.0,
4.9, 10.7 Hz, 1H), 5.09 (dd, Jˆ8.8, 14.6 Hz, 1H), 5.06
(dd, Jˆ8.8, 14.6 Hz, 1H), 4.95 (br dd, Jˆ6.3, 6.3 Hz, 1H),
4.81 (dd, Jˆ2.4, 9.8 Hz, 1H), 4.69 (d, Jˆ11.7 Hz, 1H), 4.65
(d, Jˆ11.7 Hz, 1H), 3.76±3.43 (m, 6H), 3.55 (dd, Jˆ4.9,
4.9 Hz, 1H), 3.18 (m, 3H), 3.18 (s, 3H), 3.12 (s, 3H), 2.51
(m, 1H), 2.41 [2.37] (s, 6H), 2.41±2.25 (m, 3H), 2.18 (s,
3H), 2.02±1.09 (m, 24H), 0.99 (d, Jˆ6.8 Hz, 3H), 0.99 (d,
Jˆ6.8 Hz, 3H), 0.98±0.87 (m, 9H), 0.94 (s, 9H), 0.91 (s,
9H), 0.90 (s, 9H), 0.87 (d, Jˆ6.8 Hz, 3H), 0.78 (d,
Jˆ6.3 Hz, 3H), 0.17 (s, 3H), 0.11 (s, 3H), 0.10 (s, 3H),
0.09 (s, 3H), 0.07 (s, 3H), 0.07 (s, 3H). Signals of three
protons (CH3COO) were overlapped with the solvent signals.
The minor counterparts of doubled signals in the ratio of 3:1
are in brackets; MS (FAB) m/z 1318 (M1Na)1; HRMS
(FAB) calcd for C70H133NNaO12SSi3 [(M1Na)1]
1318.8753, found 1318.8710.
3.1.18. Alcohol 28. To a stirred solution of acetate 27
(8.0mg, 5.8 mmol) in CH2Cl2 (1.8 mL), tert-butyl alcohol
(0.1 mL), and 1 M phosphate buffer (pH 6, 0.1 mL) cooled
at 08C was added 2,3-dichloro-5,6-dicyano-p-benzoquinone
(DDQ) (2.0mg, 8.8 mmol). The mixture was warmed to
room temperature and stirred for 30min. The mixture was
diluted with 1 M phosphate buffer (pH 6, 2 mL), stirred at
room temperature for 40min, and extracted with Et 2O
(10mL, 3 £3 mL). The combined extracts were successively
washed with 1 M phosphate buffer (pH 6, 2 mL), saturated
aqueous NaHCO3 (2 mL), H2O (2 mL), and brine (2 mL),
and then dried (Na2SO4) and concentrated. The residual oil
was puri®ed by preparative TLC on silica gel (200£
100£0.25 mm3, hexane±acetone 3:1) to give 28 (6.0mg,
3.1.20. Alcohol 30. To a stirred solution of dimethylalanine
ester 29 (S/Rˆ3:1) (3.5 mg, 2.7 mmol) in THF (0.20 mL)
and H2O (0.05 mL) were added 2,6-lutidine (0.05 mL,
0.43 mmol) and AgNO3 (69 mg, 0.41 mmol) at room
temperature. The mixture was stirred at 308C for 22 h in
the dark and ®ltered through a pad of Celite, and the residue
was washed with EtOAc (20mL). The ®ltrate and the wash-
ings were combined, washed with H2O (4 mL) and brine
(4 mL), and concentrated. The residual oil was puri®ed by
column chromatography on silica gel (2 g, hexane±acetone
5:1!4:1) to give 30 (S/Rˆ3:1) (2.8 mg, 80%) as a colorless
30
86%) as a colorless oil: [a]D ˆ129 (c 0.21, CHCl3); IR
(CHCl3) 3520 (br), 1705, 1655, 1465, 1375, 1255, 1080,
1
1050, 970, 835 cm21; H NMR (400 MHz, CDCl3) d 7.25
(m, 1H), 6.25±6.16 (m, 2H), 5.81 (d, Jˆ15.1 Hz, 1H), 5.54
(ddd, Jˆ4.4, 10.3, 15.1 Hz, 1H), 5.33±5.26 (m, 2H), 5.14±
5.06 (m, 2H), 4.81 (dd, Jˆ2.4, 10.4 Hz, 1H), 4.61 (d, Jˆ
11.7 Hz, 1H), 4.56 (d, Jˆ11.7 Hz, 1H), 3.71 (ddd, Jˆ3.9,
6.3, 10.2 Hz, 1H), 3.62±3.54 (m, 3H), 3.50 (ddd, Jˆ4.9, 4.9,
8.8 Hz, 1H), 3.45±3.38 (m, 3H), 3.24 (s, 3H), 3.20(s, 3H),
2.62 (d, Jˆ3.4 Hz, 1H), 2.45 (m, 1H), 2.37±2.01 (m, 4H),
2.18 (s, 3H), 2.12 (s, 3H), 1.89±1.17 (m, 20H), 0.97±0.84
(m, 9H), 0.96 (d, Jˆ7.3 Hz, 3H), 0.93 (d, Jˆ6.8 Hz, 3H),
0.90 (s, 9H), 0.90 (s, 9H), 0.89 (s, 9H), 0.85 (d, Jˆ6.8 Hz,
3H), 0.77 (d, Jˆ6.3 Hz, 3H), 0.12 (s, 3H), 0.05 (s, 9H), 0.04
(s, 6H); MS (FAB) m/z 1219 (M1Na)1; HRMS (FAB)
calcd for C65H124NaO11SSi3 [(M1Na)1] 1219.8070, found
1219.8090.
29
oil: [a]D ˆ123 (c 0.13, MeOH); IR (CHCl3) 3450(br),
1725, 1705, 1640, 1460, 1360, 1250, 1080, 1035, 970,
835 cm21 1H NMR (400 MHz, acetone-d6) d 7.24 (m,
;
1H), 6.41±6.32 (m, 2H), 5.87 (d, Jˆ15.1 Hz, 1H), 5.56
(ddd, Jˆ4.4, 10.7, 15.1 Hz, 1H), 5.40 (ddd, Jˆ5.9, 10.7,
15.1 Hz, 1H), 5.31 (ddd, Jˆ2.0, 4.9, 10.7 Hz, 1H), 5.12±
5.04 (m, 2H), 4.94 (m, 1H), 4.80 (dd, Jˆ2.4, 10.3 Hz, 1H),
3.85±3.60(m, 5H), 3.55 (dd, Jˆ4.4, 4.4 Hz, 1H), 3.51±3.44
(m, 2H), 3.18 (m, 1H), 3.17 (s, 3H), 3.12 (s, 3H), 2.52 (m,
1H), 2.40±2.21 (m, 3H), 2.32 [2.30] (s, 6H), 2.00 (s, 3H),
1.95±1.06 (m, 21H), 1.24 [1.20] (d, Jˆ7.8 Hz, 3H), 0.99 (d,
Jˆ6.8 Hz, 3H), 0.99 (d, Jˆ6.8 Hz, 3H), 0.96±0.87 (m, 9H),
0.94 (s, 9H), 0.91 (s, 9H), 0.90 (s, 9H), 0.88 (d, Jˆ6.8 Hz,
3H), 0.78 (d, Jˆ6.3 Hz, 3H), 0.16 (s, 3H), 0.11 (s, 3H), 0.09
(s, 3H), 0.09 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H). Signals of
three protons (CH3COO) were overlapped with the solvent
signals. The minor counterparts of doubled signals in the
ratio of 3:1 are in brackets; MS (FAB) m/z 1258 (M1Na)1;
HRMS (FAB) calcd for C68H129NNaO12Si3 [(M1Na)1]
1258.8721, found 1258.8760.
3.1.19. Dimethylalanine ester 29. To a mixture of alcohol
28 (4.4 mg, 3.7 mmol), l-N,N-dimethylalanine (3.9 mg,
0.033
mmol),
d-N,N-dimethylalanine
(2.8 mg,
0.024 mmol), DMAP (20.9 mg, 0.17 mmol), and (^)-
camphorsulfonic acid (15.2 mg, 0.065 mmol) was added a
0.22 M solution of DCC in CH2Cl2 (0.26 mL, 0.057 mmol)
at room temperature. The mixture was stirred at room

H. Kigoshi et al. / Tetrahedron 58 (2002) 1075±1102
1087
3.1.21. Trimethylserine ester 31. To a mixture of alcohol
30 (S/Rˆ3:1) (2.8 mg, 2.3 mmol), l-N,N,O-trimethylserine
(7.0mg, 0.048 mmol), d-N,N,O-trimethylserine (2.4 mg,
0.018 mmol), DMAP (21.7 mg, 0.178 mmol), and (^)-cam-
phorsulfonic acid (15.4 mg, 0.066 mmol) was added a
0.15 M solution of DCC in CH2Cl2 (0.40 mL, 0.060
mmol) at room temperature. The mixture was stirred at
358C for 1.5 h, cooled to room temperature, and diluted
with saturated aqueous NaHCO3 (2 mL). The mixture was
stirred at room temperature for 40min and extracted with
EtOAc (3£10mL). The combined extracts were washed
with brine (3 mL), dried (Na2SO4), and concentrated. The
residue was puri®ed by column chromatography on silica
gel (2 g, hexane±acetone 5:1!4:1!3:1) and preparative
TLC on silica gel (200£100£0.25 mm3, hexane±EtOAc
1:4; 200£100£0.25 mm3, benzene±EtOAc 1:1) to give a
diastereomeric mixture of 31 (S/Rˆ4:3 as to the trimethyl-
serine part, S/Rˆ3:1 as to the dimethylalanine part) (2.2 mg,
Jˆ15.0Hz, 1H), 5.62 (ddd, Jˆ4.4, 11.0, 15.0 Hz, 1H), 5.47
(br d, Jˆ11.0Hz, 1H), 5.18 (m, 1H), 5.10(ddd, Jˆ5.1, 8.8,
13.9 Hz, 1H), 4.99 (dd, Jˆ8.8, 15.0Hz, 1H), 4.96 (m, 1H),
4.78 (dd, Jˆ2.6, 9.9 Hz, 1H), 4.76 (m, 1H), 3.68 (dd, Jˆ7.7,
9.2 Hz, 1H), 3.64 (m, 1H), 3.60±3.57 (m, 2H), 3.55±3.45
(m, 4H), 3.37 (ddd, Jˆ5.5, 5.5, 7.3 Hz, 1H), 3.33 [3.30]b (s,
3H), 3.30(m, 1H), 3.18 (m, 1H), 3.18 (s, 3H), 3.10(s, 3H),
3.05 (m, 1H), 2.49±2.41 (m, 3H), 2.35 [2.36]b (s, 6H), 2.32
[2.30]a (s, 6H), 2.30(m, 1H), 2.15 (m, 1H), 1.99 [1.97] a (s,
3H), 1.88 (m, 1H), 1.79±1.13 (m, 20H), 1.24 [1.19]a (d,
Jˆ7.0 Hz, 3H), 1.02±0.98 (m, 12H), 0.91 (d, Jˆ7.0Hz,
3H), 0.87 (d, Jˆ7.0 Hz, 3H), 0.73 [0.72]b (d, Jˆ7.0Hz,
3H). The minor counterparts of doubled signals in the ratios
of 3:1 (superscript a), and 4:3 (superscript b) are in brackets;
MS (FAB) m/z 1045 (M1Na)1; HRMS (FAB) calcd for
C56H98N2NaO14 [(M1Na)1] 1045.6916, found 1045.6930.
3.1.23. Alcohol 33. The experimental procedure was similar
to that described for compound 30. 33 (84% yield): a color-
29
72%) as a colorless amorphous powder: [a]D ˆ12.5 (c
27
0.12, MeOH); IR (CHCl3) 1730, 1700 1655, 1460, 1375,
less oil; [a]D ˆ137 (c 0.15, CHCl3); IR (CHCl3) 3450(br),
1
1250, 1095, 970, 835 cm21; H NMR (400 MHz, acetone-
1725, 1705, 1640, 1460, 1375, 1250, 1100, 1035, 970,
d6) d 7.21 [7.22]b (dd, Jˆ10.7, 15.1 Hz, 1H), 6.40 [6.41]b
(dd, Jˆ10.7, 15.1 Hz, 1H), 6.27 (m, 1H), 5.91 (d, Jˆ
15.1 Hz, 1H), 5.56 (ddd, Jˆ4.4, 10.7, 15.1 Hz, 1H), 5.41±
5.30(m, 2H), 5.13 (dd, Jˆ8.8, 15.1 Hz, 1H), 5.07 (dd,
Jˆ8.8, 15.1 Hz, 1H), 4.94 (m, 1H), 4.86 (m, 1H), 4.80
(dd, Jˆ2.4, 10.3 Hz, 1H), 3.78±3.56 (m, 6H), 3.54 (dd,
Jˆ4.4, 4.4 Hz, 1H), 3.51±3.48 (m, 2H), 3.38 (ddd, Jˆ2.4,
5.4, 8.3 Hz, 1H), 3.33 [3.31]b (s, 3H), 3.19 (m, 1H), 3.18 (s,
3H), 3.12 (s, 3H), 2.59±2.52 (m, 2H), 2.39±2.13 (m, 3H),
2.36 [2.36]b (s, 6H), 2.32 [2.29]a (s, 6H), 1.99±1.06 (m,
19H), 1.24 [1.20]a (d, Jˆ7.3 Hz, 3H), 1.00±0.87 (m,
12H), 0.99 (d, Jˆ6.8 Hz, 3H), 0.94 (s, 9H), 0.91 (s, 9H),
0.90 (s, 9H), 0.87 (d, Jˆ6.8 Hz, 3H), 0.78 (d, Jˆ6.8 Hz,
3H), 0.16 (s, 3H), 0.11 (s, 3H), 0.09 (s, 3H), 0.08 (s, 3H),
0.06 (s, 6H). Signals of three protons (CH3COO) were over-
lapped with the solvent signals. The minor counterparts of
doubled signals in the ratios of 3:1 (superscript a) and 4:3
(superscript b) are in brackets; MS (FAB) m/z 1387
(M1Na)1; HRMS (FAB) calcd for C74H140N2NaO14Si3
[(M1Na)1] 1387.9509, found 1387.9510.
835 cm21; H NMR (400 MHz, CDCl3) d 7.25 (dd, Jˆ
1
11.0, 15.0 Hz, 1H), 6.90±6.87 (m, 2H), 6.82 (d, Jˆ7.8 Hz,
1H), 6.31±6.17 (m, 2H), 5.78 (d, Jˆ15.1 Hz, 1H), 5.50
(ddd, Jˆ4.4, 10.3, 15.1 Hz, 1H), 5.40 (ddd, Jˆ6.8, 6.8,
15.1 Hz, 1H), 5.26±5.12 (m, 3H), 5.00 (dd, Jˆ2.4, 9.8 Hz,
1H), 4.77 (d, Jˆ6.8 Hz, 1H), 4.67 (d, Jˆ6.8 Hz, 1H), 4.62
(d, Jˆ11.7 Hz, 1H), 4.49 (d, Jˆ11.7 Hz, 1H), 3.89 (s, 3H),
3.87 (s, 3H), 3.77 (m, 1H), 3.69 (m, 1H), 3.60±3.38 (m, 7H),
3.23 (s, 3H), 3.21 (m, 1H, ±OH), 3.20(s, 3H), 2.48 (m, 1H),
2.35±2.17 (m, 3H), 2.05±1.94 (m, 2H), 2.03 (s, 3H), 1.92±
1.00 (m, 18H), 0.95 (d, Jˆ6.8 Hz, 3H), 0.93 (d, Jˆ6.8 Hz,
3H), 0.93±0.88 (m, 9H), 0.91 (br s, 18H), 0.89 (s, 9H), 0.85
(d, Jˆ6.8 Hz, 3H), 0.76 (d, Jˆ6.3 Hz, 3H), 0.13 (s, 3H),
0.09 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H), 0.05 (s, 6H); MS
(FAB) m/z 1339 (M1Na)1; HRMS (FAB) calcd for
C73H132NaO14Si3 [(M1Na)1] 1339.8823, found 1339.8800.
3.1.24. Trimethylserine ester 34. The experimental pro-
cedure was similar to that described for compound 31. 34
(88% yield, S/Rˆ4:3): a colorless amorphous powder;
29
[a]D ˆ120( c 0.096, MeOH); IR (CHCl3) 1730, 1700,
1
3.1.22. Analog 32. A solution of trimethylserine ester 31
(S/Rˆ4:3 as to the trimethylserine part, S/Rˆ3:1 as to the
dimethylalanine part) (2.0mg, 1.5 mmol) in a 5:3:8 mixture
of HF´pyridine, pyridine, and THF (0.5 mL) was stirred at
room temperature for 22 h. The mixture was diluted with
EtOAc (2 mL) and poured into saturated aqueous NaHCO3
(4 mL) cooled at 08C, and the resulting mixture was
extracted with EtOAc (3£10mL). The combined extracts
were washed with brine (2 mL), dried (Na2SO4), and
concentrated. The residual oil was puri®ed by column
chromatography on silica gel (0.4 g, hexane±EtOAc±
MeOH 4:4:1!1:1:1) and HPLC (Develosil 60-5, 10£
250mm 2, hexane±EtOAc±MeOH 4:4:1, ¯ow rate 2.5 mL/
min) to give 32 (S/Rˆ4:3 as to the trimethylserine part, S/
Rˆ3:1 as to the dimethylalanine part) (1.0mg, 80%) as
1655, 1460, 1375, 1250, 1095, 970, 835 cm21; H NMR
(400 MHz, acetone-d6) d 7.20[7.21] (dd, Jˆ10.7, 15.1
Hz, 1H), 6.94±6.85 (m, 3H), 6.39 [6.39] (dd, Jˆ10.7,
15.1 Hz, 1H), 6.24 (m, 1H), 5.90(d, Jˆ15.1 Hz, 1H), 5.55
(ddd, Jˆ4.4, 10.7, 15.1 Hz, 1H), 5.37 (m, 1H), 5.30 (dd,
Jˆ4.4, 10.7 Hz, 1H), 5.12 (dd, Jˆ8.8, 15.1 Hz, 1H), 5.06
(dd, Jˆ8.8, 15.1 Hz, 1H), 4.99 (dd, Jˆ2.4, 10.3 Hz, 1H),
4.85 [4.86] (dd, Jˆ6.8, 6.8 Hz, 1H), 4.74 (d, Jˆ6.8 Hz, 1H),
4.65 (d, Jˆ6.8 Hz, 1H), 4.60(d, Jˆ11.7 Hz, 1H), 4.45 (d,
Jˆ11.7 Hz, 1H), 3.80(s, 3H), 3.78 (s, 3H), 3.76±3.56 (m,
6H), 3.52 (dd, Jˆ4.9, 4.9 Hz, 1H), 3.51±3.43 (m, 2H), 3.38
(ddd, Jˆ2.0, 5.4, 7.8 Hz, 1H), 3.33 [3.30] (s, 3H), 3.18 (s,
3H), 3.12 (s, 3H), 2.56±2.45 (m, 2H), 2.43±1.03 (m, 23H),
2.36 [2.36] (s, 6H), 2.08 (s, 3H), 0.98±0.89 (m, 12H), 0.97
(d, Jˆ6.8 Hz, 3H), 0.93 (s, 9H), 0.91 (s, 9H), 0.90 (s, 9H),
0.78 (d, Jˆ7.3 Hz, 3H), 0.88 (d, Jˆ6.3 Hz, 3H), 0.16 (s,
3H), 0.11 (s, 3H), 0.09 [0.08] (s, 3H), 0.07 (s, 3H), 0.06
(s, 6H). The minor counterparts of doubled signals in the
ratio of 4:3 are in brackets; MS (FAB) m/z 1468 (M1Na)1;
HRMS (FAB) calcd for C79H143NNaO16Si3 [(M1Na)1]
1468.9612, found 1468.9560.
30
a colorless amorphous powder: [a]D ˆ153 (c 0.051,
MeOH); UV (MeCN) lmax 261 nm (1 29,000); IR
(CHCl3) 3490 (br), 1725, 1700, 1640, 1620, 1600, 1460,
1370, 1245, 1090, 970 cm21; 1H NMR (600 MHz, acetone-
d6) d 7.21 [7.22]b (dd, Jˆ11.0, 15.0 Hz, 1H), 6.44 [6.45]b
(dd, Jˆ11.0, 15.0 Hz, 1H), 6.29 (m, 1H), 5.97 [5.98]b (d,

1088
H. Kigoshi et al. / Tetrahedron 58 (2002) 1075±1102
3.1.25. Alcohol 35. The experimental procedure was similar
to that described for compound 32. 35 (98% yield, S/Rˆ
(s, 2H), 4.61 (d, Jˆ11.7 Hz, 1H), 4.60(d, Jˆ11.7 Hz, 1H),
4.55 (d, Jˆ11.7 Hz, 1H), 4.50(d, Jˆ11.7 Hz, 1H), 3.89 (s,
3H), 3.88 (s, 3H), 3.75 (br dd, Jˆ5.9, 5.9 Hz, 1H), 3.68
(ddd, Jˆ4.4, 6.8, 11.2 Hz, 1H), 3.60±3.39 (m, 7H), 3.24
(s, 3H), 3.20(s, 3H), 2.45 (m, 1H), 2.34±2.17 (m, 3H),
2.17 (s, 3H), 1.89±1.09 (m, 21H), 0.96±0.77 (m, 12H),
0.94 (t, Jˆ7.8 Hz, 9H), 0.90 (s, 9H), 0.89 (s, 9H), 0.89 (s,
9H), 0.87 (d, Jˆ6.8 Hz, 3H), 0.86 (d, Jˆ7.3 Hz, 3H), 0.77
(d, Jˆ6.3 Hz, 3H), 0.61 (q, Jˆ7.8 Hz, 6H), 0.12 (s, 3H),
0.05 (s, 6H), 0.05 (s, 9H); MS (FAB) m/z 1471 (M1Na)1;
HRMS (FAB) calcd for C79H148NaO13SSi4 [(M1Na)1]
1471.9616, found 1471.9650.
28
4:3): a colorless oil; [a]D ˆ152 (c 0.054, MeOH); IR
(CHCl3) 3480 (br), 1730, 1690, 1655, 1455, 1370, 1240,
1
1080, 970 cm21; H NMR (600 MHz, acetone-d6) d 7.21
(dd, Jˆ10.7, 15.1 Hz, 1H), 6.95±6.86 (m, 3H), 6.44 [6.45]
(dd, Jˆ10.7, 15.1 Hz, 1H), 6.29 (m, 1H), 5.97 (d, Jˆ
15.1 Hz, 1H), 5.59 (ddd, Jˆ4.4, 10.7, 15.1 Hz, 1H), 5.45±
5.34 (m, 2H), 5.10(m, 1H), 5.00±4.95 (m, 2H), 4.76 (m,
1H), 4.75 (d, Jˆ6.8 Hz, 1H), 4.67 (d, Jˆ6.8 Hz, 1H), 4.62
(d, Jˆ11.7 Hz, 1H), 4.44 (d, Jˆ11.7 Hz, 1H), 3.80(s, 3H),
3.78 (s, 3H), 3.70±3.45 (m, 9H), 3.39±3.30 (m, 2H), 3.33
[3.30] (s, 3H), 3.18 (s, 3H), 3.10 (s, 3H), 3.03 (m, 1H), 2.50±
2.35 (m, 2H), 2.36 [2.35] (s, 6H), 2.30±1.85 (m, 10H),
1.77±0.97 (m, 26H), 0.90 (d, Jˆ6.8 Hz, 3H), 0.89 (d, Jˆ
6.8 Hz, 3H), 0.87 (d, Jˆ6.8 Hz, 3H), 0.73 [0.71] (d, Jˆ
6.3 Hz, 3H). The minor counterparts of doubled signals in
the ratio of 4:3 are in brackets; MS (FAB) m/z 1126 (M1
Na)1; HRMS (FAB) calcd for C61H101NNaO16 [(M1Na)1]
1126.7018, found 1126.7020.
3.1.28. Alcohol 38. The experimental procedure was similar
to that described for compound 30. 38 (54% yield): a color-
29
less oil; [a]D ˆ147 (c 0.35, CHCl3); IR (CHCl3) 3450(br),
1705, 1640, 1460, 1380, 1260, 1090, 1035, 970, 835 cm21
;
1H NMR (400 MHz, CDCl3) d 7.25 (dd, Jˆ9.8, 15.1 Hz,
1H), 6.89±6.87 (m, 2H), 6.83 (d, Jˆ7.8 Hz, 1H), 6.31±6.17
(m, 2H), 5.88 (d, Jˆ15.1 Hz, 1H), 5.51 (ddd, Jˆ3.9, 10.2,
15.1 Hz, 1H), 5.31 (m, 1H), 5.26±5.18 (m, 2H), 5.14 (dd,
Jˆ8.8, 15.1 Hz, 1H), 4.78 (s, 2H), 4.55 (d, Jˆ11.7 Hz, 1H),
4.45 (d, Jˆ11.7 Hz, 1H), 3.89 (s, 3H), 3.88 (s, 3H), 3.77±
3.43 (m, 9H), 3.23 (s, 3H), 3.20(s, 3H), 3.14 (m, 1H, ±OH),
2.46 (m, 1H), 2.35±2.17 (m, 3H), 2.01 (m, 1H), 1.81±1.05
(m, 20H), 0.96±0.89 (m, 12H), 0.94 (t, Jˆ7.8 Hz, 9H), 0.91
(s, 9H), 0.90 (s, 9H), 0.89 (s, 9H), 0.86 (d, Jˆ6.8 Hz, 3H),
0.85 (d, Jˆ6.8 Hz, 3H), 0.76 (d, Jˆ6.8 Hz, 3H), 0.61 (q,
Jˆ7.8 Hz, 6H), 0.12 (s, 3H), 0.09 (s, 3H), 0.07 (s, 3H), 0.06
(s, 3H), 0.05 (s, 6H); MS (FAB) m/z 1411 (M1Na)1;
HRMS (FAB) calcd for C77H144NaO13Si4 [(M1Na)1]
1411.9581, found 1411.9530.
3.1.26. Analog 36. The experimental procedure was similar
to that described for compound 28. 36 (86% yield,
30
S/Rˆ4:3): a colorless amorphous powder: [a]D ˆ157 (c
0.058, MeOH); UV (MeCN) lmax 262 nm (1 28,000); IR
(CHCl3) 3500 (br), 1710, 1640, 1620, 1560, 1460, 1370,
1260, 1140, 1090, 970 cm21; 1H NMR (600 MHz, acetone-
d6) d 7.21 (dd, Jˆ11.0, 15.0 Hz, 1H), 6.44 [6.45] (dd, Jˆ
11.0, 15.0 Hz, 1H), 6.29 (m, 1H), 5.97 [5.98] (d, Jˆ15.0Hz,
1H), 5.61 (ddd, Jˆ4.0, 11.0, 15.0 Hz, 1H), 5.47 [5.47] (d,
Jˆ11.0Hz, 1H), 5.38 (m, 1H), 5.10[5.10] (ddd, Jˆ5.1, 9.2,
15.0Hz, 1H), 4.99 (dd, Jˆ9.2, 15.0Hz, 1H), 4.86 (dd,
Jˆ2.6, 9.9 Hz, 1H), 4.76 (m, 1H), 3.68 (dd, Jˆ7.7,
8.8 Hz, 1H), 3.66 (m, 1H), 3.58 [3.58] (dd, Jˆ5.5, 9.2 Hz,
1H), 3.54±3.42 (m, 7H), 3.37 (ddd, Jˆ5.5, 5.5, 7.7 Hz, 1H),
3.33 [3.30] (s, 3H), 3.28 (m, 1H), 3.18 [3.18] (s, 3H), 3.10 (s,
3H), 3.04 (m, 1H), 3.00 (d, Jˆ4.4 Hz, 1H), 2.49±2.41 (m,
2H), 2.35 [2.36] (s, 6H), 2.33 (m, 1H), 2.14 (m, 1H), 2.06
[2.08] (s, 3H), 1.99 (m, 1H), 1.90±1.04 (m, 20H), 1.00
[1.02] (d, Jˆ6.6 Hz, 3H), 1.00 (d, Jˆ6.6 Hz, 3H), 0.97 (d,
Jˆ6.6 Hz, 3H), 0.89 (d, Jˆ6.6 Hz, 3H), 0.89 (d, Jˆ6.6 Hz,
3H), 0.85 (d, Jˆ7.0 Hz, 3H), 0.73 [0.72] (d, Jˆ7.0Hz, 3H).
The minor counterparts of doubled signals in the ratio of 4:3
are in brackets; MS (FAB) m/z 946 (M1Na)1; HRMS
(FAB) calcd for C51H89NNaO13 [(M1Na)1] 946.6232,
found 946.6231.
3.1.29. Trimethylserine ester 39. The experimental pro-
cedure was similar to that described for compound 31. 39
30
(88% yield, S/Rˆ4:3): a colorless oil; [a]D ˆ119 (c 0.31,
MeOH); IR (CHCl3) 1730, 1700, 1645, 1460, 1375, 1260,
1
1095, 970, 835 cm21; H NMR (400 MHz, acetone-d6) d
7.21 [7.21] (dd, Jˆ10.7, 15.1 Hz, 1H), 6.94±6.86 (m, 3H),
6.38 [6.39] (dd, Jˆ10.7, 15.1 Hz, 1H), 6.25 (m, 1H), 5.90 (d,
Jˆ15.1 Hz, 1H), 5.55 (ddd, Jˆ4.4, 10.7, 15.1 Hz, 1H), 5.38
(m, 1H), 5.30(m, 1H), 5.12 (dd, Jˆ8.8, 15.1 Hz, 1H), 5.06
(dd, Jˆ8.8, 15.1 Hz, 1H), 4.86 (ddd, Jˆ2.4, 6.8, 6.8 Hz,
1H), 4.80(s, 2H), 4.60(d, Jˆ11.7 Hz, 1H), 4.50(d, Jˆ
11.7 Hz, 1H), 3.80(s, 3H), 3.79 (s, 3H), 3.76±3.52 (m,
8H), 3.48 (m, 2H), 3.38 (ddd, Jˆ2.4, 5.4, 7.8 Hz, 1H),
3.33 [3.30] (s, 3H), 3.18 (s, 3H), 3.12 (s, 3H), 2.52±2.19
(m, 4H), 2.36 [2.36] (s, 6H), 2.00±1.06 (m, 21H), 0.99±0.88
(m, 18H), 0.97 (t, Jˆ7.8 Hz, 9H), 0.93 (s, 9H), 0.91 (s, 9H),
0.90 (s, 9H), 0.78 (d, Jˆ6.3 Hz, 3H), 0.67 (q, Jˆ7.8 Hz, 6H),
0.16 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H), 0.08 (s, 3H), 0.06 (s,
6H). The minor counterparts of doubled signals in the ratio
of 4:3 are in brackets; MS (FAB) m/z 1540(M 1Na)1.
3.1.27. TES ether 37. To a mixture of silyl ether 26 (7.0mg,
5.25 mmol), imidazole (7.6 mg, 0.12 mmol) in DMF
(0.2 mL) was added Et3SiCl (9 mL, 0.054 mmol). After
being stirred at room temperature for 3 h, the mixture was
diluted with ice (1 g) and saturated aqueous NaHCO3 and
extracted with Et2O (3£10mL). The combined extracts
were washed with brine (2 mL), dried (Na2SO4), and
concentrated. The residue was puri®ed by column chroma-
tography on silica gel (2 g, hexane±Et2O 4:1!3:1!
2:1!1:1!1:2) to give 31 (7.7 mg, 100%) as a colorless
3.1.30. Analog 40. A solution of trimethylserine ester 39
(3.0mg, 2.0mmol) in 1,4-dioxane (0.6 mL) and 2 M HCl
(0.2 mL) was stirred at 508C for 2.5 h, diluted with EtOAc
(10mL) and saturated aqueous NaHCO 3 (5 mL), and
extracted with EtOAc (3£10mL). The combined extracts
were washed with brine (2 mL), dried (Na2SO4), and
concentrated. The residue was puri®ed by preparative
TLC on silica gel (200£100£0.25 mm3, hexane±EtOAc±
MeOH 2:2:1) to give 40 (1.0mg, 57%, S/Rˆ4:3) as a
29
oil: [a]D ˆ129 (c 0.41, CHCl3); IR (CHCl3) 1705, 1645,
1615, 1595, 1515, 1465, 1375, 1255, 1095, 1030, 970,
1
835 cm21; H NMR (400 MHz, CDCl3) d 7.22 (m, 1H),
6.89±6.87 (m, 2H), 6.83 (d, Jˆ8.3 Hz, 1H), 6.25±6.14
(m, 2H), 5.80(d, Jˆ15.1 Hz, 1H), 5.54 (ddd, Jˆ4.4, 10.3,
15.1 Hz, 1H), 5.33±5.26 (m, 2H), 5.14±5.06 (m, 2H), 4.78

H. Kigoshi et al. / Tetrahedron 58 (2002) 1075±1102
1089
30
colorless amorphous powder: [a]D ˆ151 (c 0.015,
15.1 Hz, 1H), 5.30(ddd, Jˆ2.0, 4.9, 10.7 Hz, 1H), 5.13
(dd, Jˆ8.8, 15.1 Hz, 1H), 5.06 (dd, Jˆ8.8, 15.1 Hz, 1H),
4.97 (br dd, Jˆ5.9, 5.9 Hz, 1H), 4.83±4.78 (m, 2H), 3.73
(ddd, Jˆ3.9, 6.3, 10.2 Hz, 1H), 3.66±3.60 (m, 2H), 3.55 (dd,
Jˆ4.9, 4.9 Hz, 1H), 3.52±3.45 (m, 2H), 3.19 (s, 2H), 3.18
(s, 3H), 3.12 (s, 3H), 3.10(s, 2H), 2.59±2.28 (m, 6H), 2.32
(s, 6H), 2.30 (s, 6H), 1.98 (s, 3H), 1.90±1.06 (m, 19H), 0.98
(d, Jˆ6.8 Hz, 3H), 0.98±0.90 (m, 12H), 0.94 (s, 9H), 0.90
(s, 9H), 0.90 (s, 9H), 0.87 (d, Jˆ6.8 Hz, 3H), 0.77 (d, Jˆ
6.4 Hz, 3H), 0.16 (s, 3H), 0.11 (s, 3H), 0.07 (s, 6H), 0.06 (s,
6H); MS (FAB) m/z 1329 (M1Na)1; HRMS (FAB) calcd
for C71H134N2NaO13Si3 [(M1Na)1] 1329.9091, found
1329.9110.
MeOH); UV (MeCN) lmax 261 nm (1 26,000); IR
(CHCl3) 3500 (br), 1710, 1640, 1620, 1560, 1460, 1370,
1
1260, 1140, 1090, 970 cm21; H NMR (600 MHz, ace-
tone-d6) d 7.21 [7.21] (dd, Jˆ11.0, 15.4 Hz, 1H), 6.44
[6.45] (dd, Jˆ11.0, 15.4 Hz, 1H), 6.29 (m, 1H), 5.97
[5.98] (d, Jˆ15.4 Hz, 1H), 5.61 (ddd, Jˆ4.0, 11.0,
15.0Hz, 1H), 5.47 [5.47] (d, Jˆ11.0Hz, 1H), 5.38 (m,
1H), 5.09 [5.09] (ddd, Jˆ5.5, 9.2, 15.0Hz, 1H), 4.99 (dd,
Jˆ9.2, 15.0Hz, 1H), 4.76 (m, 1H), 4.37 (d, Jˆ5.5 Hz, 1H),
3.92 (m, 1H), 3.83 (d, Jˆ4.0Hz, 1H), 3.74±3.67 (m, 3H),
3.60±3.45 (m, 5H), 3.58 [3.58] (dd, Jˆ5.5, 9.2 Hz, 1H),
3.39±3.30(m, 3H), 3.33 [3.3]0 (s, 3H), 3.18 [3.18] (s,
3H), 3.10(s, 3H), 3.05 (m, 1H), 2.49±2.29 (m, 3H), 2.35
[2.36] (s, 6H), 2.15 (m, 1H), 2.08±1.06 (m, 21H), 1.00
[1.02] (d, Jˆ7.0Hz, 3H), 1.00(d, Jˆ6.6 Hz, 3H), 0.97 (d,
Jˆ7.0Hz, 3H), 0.91 (d, Jˆ7.0Hz, 3H), 0.91 (d, Jˆ7.0Hz,
3H), 0.90 (d, Jˆ7.0 Hz, 3H), 0.73 [0.72] (d, Jˆ6.6 Hz, 3H).
The minor counterparts of doubled signals in the ratio of
4:3 are in brackets; MS (FAB) m/z 904 (M1Na)1; HRMS
(FAB) calcd for C49H87NNaO12 [(M1Na)1] 904.6126,
found 904.6125.
3.1.33. Analog 43. The experimental procedure was similar
to that described for compound 32. 43 (94% yield): a color-
29
less amorphous powder; [a]D ˆ164 (c 0.028, MeOH); UV
(MeCN) lmax 262 nm (1 31,000); IR (CHCl3) 3480(br),
1730, 1695, 1640, 1620, 1460, 1370, 1245, 1195, 1145,
1
1090, 970 cm21; H NMR (600 MHz, acetone-d6) d 7.23
(dd, Jˆ11.0, 15.0 Hz, 1H), 6.44 (dd, Jˆ11.0, 15.0 Hz,
1H), 6.29 (ddd, Jˆ5.1, 9.9, 15.0Hz, 1H), 5.97 (d, Jˆ
15.0Hz, 1H), 5.61 (ddd, Jˆ4.0, 11.0, 15.0 Hz, 1H), 5.47
(br d, Jˆ11.0Hz, 1H), 5.38 (ddd, Jˆ4.0, 11.0, 15.0 Hz,
1H), 5.10(ddd, Jˆ1.5, 9.2, 15.0Hz, 1H), 5.02±4.97 (m,
2H), 4.78 (dd, Jˆ2.6, 9.9 Hz, 1H), 4.72 (ddd, Jˆ2.6, 3.7,
10.3 Hz, 1H), 3.65 (m, 1H), 3.58 (d, Jˆ5.1 Hz, 1H), 3.55±
3.46 (m, 5H), 3.30(m, 1H), 3.21 (d, Jˆ16.1 Hz, 1H), 3.18
(s, 3H), 3.17 (d, Jˆ16.1 Hz, 1H), 3.10(s, 3H), 3.09 (s, 2H),
3.06 (ddd, Jˆ2.6, 5.1, 9.2 Hz, 1H), 2.48±2.41 (m, 2H), 2.31
(s, 6H), 2.30(s, 6H), 2.30(m, 1H), 2.15 (m, 1H), 2.08±1.12
(m, 21H), 1.97 (s, 3H), 0.99 (d, Jˆ7.0Hz, 3H), 0.99 (d,
Jˆ7.0Hz, 3H), 0.98 (d, Jˆ7.0Hz, 3H), 0.96 (d, Jˆ
7.0Hz, 3H), 0.90 (d, Jˆ7.0Hz, 3H), 0.87 (d, Jˆ7.0Hz,
3H), 0.71 (d, Jˆ6.6 Hz, 3H); MS (FAB) m/z 987 (M1
Na)1; HRMS (FAB) calcd for C59H92N2NaO13 [(M1
Na)1] 987.6497, found 987.6520.
3.1.31. Alcohol 41. The experimental procedure was similar
to that described for compound 30. 41 (74% yield): a color-
29
less oil: [a]D ˆ138 (c 0.29, CHCl3); IR (CHCl3) 3480(br),
1710, 1640, 1460, 1375, 1255, 1100, 1050, 970, 835 cm21
;
1H NMR (400 MHz, CDCl3) d 7.23 (m, 1H), 6.31±6.18 (m,
2H), 5.78 (d, Jˆ15.1 Hz, 1H), 5.51 (ddd, Jˆ4.4, 10.7,
15.1 Hz, 1H), 5.40(m, 1H), 5.28±5.18 (m, 2H), 5.14 (dd,
Jˆ10.7, 15.1 Hz, 1H), 4.81 (dd, Jˆ2.4, 10.7 Hz, 1H), 3.77
(m, 1H), 3.71 (ddd, Jˆ3.9, 6.8, 10.7, Hz, 1H), 3.62±3.43
(m, 6H), 3.23 (s, 3H), 3.20(s, 3H), 3.14 (br s, 1H, ±OH),
2.61 (d, Jˆ3.9 Hz, 1H, ±OH), 2.46 (m, 1H), 2.32±2.21 (m,
3H), 2.12 (s, 3H), 2.05±1.97 (m, 2H), 1.83±1.05 (m, 19H),
0.96 (d, Jˆ6.8 Hz, 3H), 0.95 (d, Jˆ6.8 Hz, 3H), 0.92±0.90
(m, 6H), 0.91 (s, 9H), 0.90 (s, 9H), 0.90 (s, 9H), 0.86 (d,
Jˆ6.8 Hz, 3H), 0.85 (d, Jˆ6.8 Hz, 3H), 0.76 (d, Jˆ6.8 Hz,
3H), 0.12 (s, 3H), 0.09 (s, 3H), 0.07 (s, 3H), 0.05 (s, 9H).;
MS (FAB) m/z 1159 (M1Na)1; HRMS (FAB) calcd for
C63H120NaO11Si3 [(M1Na)1] 1159.8036, found 1159.8040.
3.1.34. Aldol 45. To a mixture of Sn(OTf)2 (8.0g,
18.4 mmol) and Et3N (3.2 mL, 23 mmol) in CH2Cl2
(70mL) was added a solution of ketone 44 (3.85 g,
14.1 mmol) in CH2Cl2 (4 mL) at 2788C, and the mixture
was stirred at the same temperature for 2 h. A solution of
3-(benzyloxy)propanal (4.15 g, 25.3 mmol) in CH2Cl2
(6 mL) was added, and the reaction mixture was stirred at
2788C for 2 h, at 2508C for 2 h, and at 2208C for 12 h. The
reaction mixture was diluted with 0.5 M phosphate buffer
(pH 7.0, 200 mL), and the organic layer was separated.
After the aqueous layer was extracted with Et2O (3£
150mL), the organic layer and the ethereal extracts were
combined, washed with 0.5 M phosphate buffer (pH 7.0,
80mL), dried (Na 2SO4), and concentrated. The residue
was puri®ed by column chromatography on silica gel
(160g, hexane±acetone 25:1 !20:1!18:1) and MPLC
(Develosil Lop 60, 150 g, hexane±acetone 20:1!18:1,
10mL/min) to give 45 (tRˆ63 min, 5.08 g, 83%) as a color-
3.1.32. Bisdimethylglycine ester 42. To a mixture of
alcohol 41 (1.0mg, 0.88 mmol), N,N-dimethylglycine
(2.8 mg, 0.027 mmol), DMAP (8.2 mg, 0.067 mmol), and
(^)-camphorsulfonic acid (7.2 mg, 0.031 mmol) was
added a 0.188 M solution of DCC in CH2Cl2 (0.16 mL,
0.030 mmol) at room temperature. The mixture was stirred
at room temperature for 16.5 h and diluted with saturated
aqueous NaHCO3 (1.5 mL). The mixture was stirred for
30min and extracted with EtOAc (3 £10mL). The
combined extracts were washed with brine (2 mL), dried
(Na2SO4), and concentrated. The residue was puri®ed by
column chromatography on silica gel (1 g, hexane±acetone
5:1!4:1!3:1) and preparative TLC on silica gel (200£
100£0.25 mm3, hexane±EtOAc±MeOH 10:5:1; 200£100£
0.25 mm3, benzene±EtOAc 1:1) to give 42 (0.9 mg, 80%) as
28
less oil: [a]D ˆ126.5 (c 1.26, CHCl3); IR (CHCl3) 3500
29
a colorless oil: [a]D ˆ16.3 (c 0.23, MeOH); IR (CHCl3)
(br), 1700, 1595, 1460, 1365, 1245, 1100, 1000, 880 cm21
;
1740, 1725, 1640, 1460, 1375, 1250, 1095, 970, 835 cm21
;
1H NMR (400 MHz, CDCl3) d 7.36±7.27 (m, 5H), 4.51 (s,
2H), 4.21 (ddd, Jˆ2.9, 6.4, 9.3 Hz, 1H), 3.87 (dd, Jˆ9.3,
9.3 Hz, 1H), 3.68±3.60(m, 3H), 3.27 (d, Jˆ2.4 Hz, 1H,
OH), 3.05 (m, 1H), 2.77 (ddq, Jˆ4.2, 14.1, 6.8 Hz, 1H),
1.80(m, 1H), 1.68 (m, 1H), 1.44 (d, Jˆ6.8 Hz, 3H), 1.00
1H NMR (400 MHz, acetone-d6) d 7.23 (dd, Jˆ10.7,
15.1 Hz, 1H), 6.39 (dd, Jˆ10.7, 15.1 Hz, 1H), 6.24 (ddd,
Jˆ5.9, 8.8, 15.1 Hz, 1H), 5.98 (d, Jˆ15.1 Hz, 1H), 5.55
(ddd, Jˆ4.4, 10.7, 15.1 Hz, 1H), 5.40 (ddd, Jˆ7.2, 7.2,

1090
H. Kigoshi et al. / Tetrahedron 58 (2002) 1075±1102
(d, Jˆ7.2 Hz, 3H), 1.11±1.01 (m, 21H); MS (FAB) m/z 459
(M1Na)1; HRMS (FAB) calcd for C25H44NaO4Si [(M1
Na)1] 459.2906, found 459.2905.
8.4, 13.2 Hz, 1H), 3.00 (ddd, Jˆ7.1, 8.1, 13.2 Hz, 1H), 2.03
(m, 1H), 1.96 (m, 1H), 1.70(m, 1H), 1.59 (m, 1H), 1.19±
1.04 (m, 21H), 1.02 (d, Jˆ7.3 Hz, 3H), 0.81 (d, Jˆ6.9 Hz,
3H); MS (FAB) m/z 463 (M1Na)1; HRMS (FAB) calcd for
C24H44NaO3SSi [(M1Na)1] 463.2678, found 463.2657.
3.1.35. Diol 46. To a solution of Me4NBH(OAc)3 (3.13 g,
11.9 mmol) in CH3CN (9.5 mL) and AcOH (9.5 mL) was
added a solution of aldol 45 (1.12 g, 2.57 mmol) in CH3CN
(3 mL) at 2408C, and the mixture was stirred at 2208C
for 25 h. Since the reaction was not completed, Me4NB-
H(OAc)3 (4.63 g, 17.6 mmol) was added by portions over
44 h and the mixture was further stirred at 2208C for 38 h.
To the mixture was added 1 M aqueous potassium sodium
tartrate (60mL), and the mixture was stirred at room
temperature for 1 h. The mixture was diluted with saturated
aqueous NaHCO3 (10mL) and extracted with CH 2Cl2
(3£70mL). The combined extracts were washed with satu-
rated aqueous NaHCO3 (10mL), dried (Na 2SO4), and
concentrated. The residue was puri®ed by column chroma-
tography on silica gel (100 g, hexane±Et2O 4:1!3:1!2:1
and 50g, hexane±Et 2O 5:1!4:1) to give 46 (0.89 g, 80%)
3.1.38. Triol 49. To a solution of sul®de 48 (0.87 g,
2.0mmol) in THF (4 mL) was added a 1 M solution of
Bu4NF in THF (4 mL, 4 mmol), and the mixture was stirred
at room temperature for 3 h. The mixture was diluted with
saturated aqueous NH4Cl (10mL) and extracted with Et 2O
(3£10mL). The combined extracts were washed with brine
(10mL), dried (Na 2SO4), and concentrated. The residue was
puri®ed by column chromatography on silica gel (25 g,
hexane±Et2O 4:1!2:1!1:2) to give 49 (0.69 g, 100%) as
29
a colorless oil: [a]D ˆ216.0( c 1.09, CHCl3); IR (CHCl3)
1
3400 (br), 1580, 1460, 1090, 1050, 970 cm21; H NMR
(270MHz, CDCl 3) d 7.38±7.27 (m, 4H), 7.19 (m, 1H),
4.69 (br s, 1H), 4.22 (m, 1H), 3.95 (br s, 1H), 3.86 (dd,
Jˆ3.3, 10.6 Hz, 1H), 3.68±3.58 (m, 2H), 3.51 (br s, 1H),
3.12 (ddd, Jˆ5.7, 9.9, 13.0Hz, 1H), 3.01 (td, Jˆ7.3,
13.0 Hz, 1H), 2.08±1.59 (m, 4H), 1.02 (d, Jˆ7.3 Hz, 3H),
0.86 (d, Jˆ6.9 Hz, 3H); MS (FAB) m/z 307 (M1Na)1;
HRMS (FAB) calcd for C15H24NaO3S [(M1Na)1]
307.1344, found 307.1324.
31
as a colorless oil: [a]D ˆ21.65 (c 1.39, CHCl3); IR
(CHCl3) 3420 (br), 1595, 1460, 1360, 1080, 1015, 880
1
cm21; H NMR (270MHz, CDCl 3) d 7.36±7.29 (m, 5H),
4.85 (d, Jˆ1.7 Hz, 1H), 4.52 (s, 2H), 4.18 (m, 1H), 4.02 (d,
Jˆ1.3 Hz, 1H), 3.89 (dd, Jˆ4.1, 9.9 Hz, 1H), 3.70(dd,
Jˆ8.1, 9.9 Hz, 1H), 3.65 (dd, Jˆ6.4, 6.4 Hz, 2H), 3.60
(m, 1H), 2.04 (m, 1H), 1.91 (m, 1H), 1.74 (m, 1H), 1.63
(m, 1H), 1.11±1.03 (m, 24H), 0.81 (d, Jˆ6.9 Hz, 3H); MS
(FAB) m/z 461 (M1Na)1; HRMS (FAB) calcd for
C25H46NaO4Si [(M1Na)1] 461.3063, found 461.3061.
3.1.39. Trityl ether 50. A solution of triol 49 (0.52 g,
1.8 mmol) and trityl chloride (0.88 g, 3.2 mmol) in pyridine
(4 mL) was stirred at 508C for 11.5 h. After ice (2 g) was
added to the reaction mixture, the mixture was stirred for
10min, diluted with H 2O (10mL), and extracted with Et 2O
(3£50mL). The combined extracts were washed with
saturated aqueous NaHCO3 (2£30mL) and brine (30mL),
dried (Na2SO4), and concentrated. The residue was puri®ed
by column chromatography on silica gel (25 g, hexane±
Et2O±Et3N 5:1:0.06!2:1:0!1:2:0) to give 50 (0.92 g,
3.1.36. Triol 47. A mixture of diol 46 (0.87 g, 2.0 mmol)
and 20% Pd(OH)2/C (0.20 g) in 1,4-dioxane (5 mL) was
stirred under hydrogen at room temperature for 15 min.
The mixture was ®ltered through a pad of Celite, and the
residue was washed with EtOAc (200 mL). The ®ltrate and
washings were combined and concentrated. The residue was
puri®ed by column chromatography on silica gel (25 g,
hexane±Et2O 5:1!3:1!1:1) to give 47 (0.69 g, 100%) as
30
96%) as a colorless oil: [a]D ˆ19.88 (c 1.00, CHCl3);
IR (CHCl3) 3440 (br), 1595, 1580, 1450, 1090, 1050, 975,
1
900 cm21; H NMR (270MHz, CDCl 3) d 7.43±7.13 (m,
30
a colorless oil: [a]D ˆ19.82 (c 1.07, CHCl3); IR (CHCl3)
20H), 4.38 (d, Jˆ2.0Hz, 1H), 4.11 (m, 1H), 3.83 (d, Jˆ
1.3 Hz, 1H), 3.46 (m, 1H), 3.39 (dd, Jˆ3.6, 10.6 Hz, 1H),
3.14 (ddd, Jˆ5.8, 8.6, 13.9 Hz, 1H), 3.10(dd, Jˆ8.1,
10.6 Hz, 1H), 2.99 (ddd, Jˆ7.6, 7.6, 13.9 Hz, 1H), 2.13±
2.03 (m, 2H), 2.00±1.86 (m, 2H), 0.94 (d, Jˆ7.3 Hz, 3H),
0.80 (d, Jˆ6.9 Hz, 3H); MS (FAB) m/z 549 (M1Na)1;
HRMS (FAB) calcd for C34H38NaO3S [(M1Na)1]
549.2439, found 549.2429.
1
3410 (br), 1460, 1080, 1055, 1010, 880 cm21; H NMR
(270MHz, CDCl 3) d 5.01 (m, 1H), 4.33 (br s, 1H),4.23
(m, 1H), 3.95 (dd, Jˆ3.6, 9.9 Hz, 1H), 3.84 (m, 2H), 3.69
(dd, Jˆ8.6, 9.9 Hz, 1H), 3.63 (ddd, Jˆ2.0, 3.6, 7.9 Hz, 1H),
2.92 (dd, Jˆ3.3, 6.9 Hz, 1H), 2.06 (m, 1H), 1.92 (m, 1H),
1.70 (m, 1H), 1.45 (m, 1H), 1.18±1.04 (m, 24H), 0.82 (d,
Jˆ6.9 Hz, 3H); MS (FAB) m/z 371 (M1Na)1; HRMS
(FAB) calcd for C18H40NaO4Si [(M1Na)1] 371.2594,
found 371.2599.
3.1.40. Silyl ether 51. To a solution of trityl ether 50
(0.92 g, 1.7 mmol) in DMF (4 mL) were added imidazole
(0.68 g, 10 mmol) and Et3SiCl (0.84 mL, 5.0 mmol). After
the mixture was stirred at 508C for 1.5 h, H2O (2 mL) was
added. The mixture was stirred for 10min, diluted with H 2O
(10mL), and extracted with Et 2O (3£40mL). The
combined extracts were washed with brine (30mL), dried
(Na2SO4), and concentrated. The residue was puri®ed by
3.1.37. Sul®de 48. A solution of triol 47 (0.78 g, 2.2 mmol),
PhSSPh (0.80 g, 3.7 mmol), and PBu3 (0.80 mL, 3.2 mmol)
in DMF (3.5 mL) was stirred at room temperature for 1.5 h.
The mixture was diluted with H2O (1 mL), stirred for
10min, and concentrated in vacuo. The residue was puri®ed
by column chromatography on silica gel (40g, hexane±
Et2O 20:1!10:1!5:1) to give 48 (0.95 g, 93%) as a color-
column chromatography on silica gel (30g, hexane±Et 2O
29
31
less oil: [a]D ˆ216.3 (c 1.36, CHCl3); IR (CHCl3) 3400
40:1) to give 51 (1.22 g, 93%) as a colorless oil: [a]D
ˆ
1
(br), 1585, 1460, 1080, 1055, 1015, 880 cm21; H NMR
216.2 (c 1.01, CHCl3); IR (CHCl3) 1595, 1580, 1450, 1065,
1010, 910 cm21; 1H NMR (270MHz, CDCl 3) d 7.47±7.14
(m, 20H), 3.84 (ddd, Jˆ5.6, 5.6, 5.6 Hz, 1H), 3.55 (dd,
Jˆ2.6, 6.6 Hz, 1H), 3.24 (dd, Jˆ4.8, 9.1 Hz, 1H), 2.84±
2.77 (m, 3H), 2.08 (m, 1H), 1.82±1.73 (m, 2H), 1.60 (m,
(270MHz, CDCl 3) d 7.37±7.32 (m, 2H), 7.30±7.23 (m,
2H), 7.15 (m, 1H), 5.00 (m, 1H), 4.14 (m, 1H), 4.10 (br s,
1H), 3.95 (dd, Jˆ3.6, 9.9 Hz, 1H), 3.68 (dd, Jˆ8.6, 9.9 Hz,
1H), 3.62 (ddd, Jˆ2.0, 3.6, 7.9 Hz, 1H), 3.15 (ddd, Jˆ5.4,

H. Kigoshi et al. / Tetrahedron 58 (2002) 1075±1102
1091
1H), 1.02 (d, Jˆ6.9 Hz, 3H), 0.94 (t, Jˆ7.6 Hz, 9H), 0.85 (t,
Jˆ7.6 Hz, 9H), 0.70 (d, Jˆ6.9 Hz, 3H), 0.57 (q, Jˆ7.6 Hz,
6H), 0.49 (q, Jˆ6.9 Hz, 6H); MS (FAB) m/z 777 (M1Na)1;
HRMS (FAB) calcd for C46H66NaO3SSi2 [(M1Na)1]
777.4169, found 777.4174.
15.4 Hz, 1H), 5.18 (dd, Jˆ8.3, 15.4 Hz, 1H), 4.69 (d, Jˆ
11.7 Hz, 1H), 4.59 (d, Jˆ11.7 Hz, 1H), 3.86 (m, 1H), 3.81±
3.68 (m, 3H), 3.60(dd, Jˆ2.4, 7.3 Hz, 1H), 3.50(dd, Jˆ2.9,
4.4 Hz, 1H), 3.48±3.39 (m, 2H), 3.23 (s, 3H) 3.20(m, 1H),
3.09 (s, 3H), 2.82 (dd, Jˆ8.8, 8.8 Hz, 1H), 2.51 (br s, 1H),
2.28±2.23 (m, 2H), 2.21 (s, 3H), 2.16±2.06 (m, 2H), 1.99
(m, 1H), 1.84 (m, 1H), 1.74±1.33 (m, 10H), 1.11 (m, 1H),
1.03 (d, Jˆ6.8 Hz, 3H), 0.95 (t, Jˆ7.8 Hz, 9H), 0.91±0.86
(m, 6H), 0.90 (s, 9H), 0.85 (d, Jˆ6.8 Hz, 3H), 0.85 (t, Jˆ
7.8 Hz, 9H), 0.65 (d, Jˆ6.8 Hz, 3H), 0.59 (q, Jˆ7.8 Hz,
6H), 0.50 (q, Jˆ7.8 Hz, 6H), 0.05 (s, 3H), 0.05 (s,
3H); MS (FAB) m/z 1191 (M1H)1; HRMS (FAB) calcd
for C69H118NaO8SSi3 [(M1Na)1] 1213.7752, found
1213.7740.
3.1.41. Sulfone 52. To a solution of silyl ether 51 (1.18 g,
1.56 mmol) in CH2Cl2 (10mL) were added NaHCO 3
(0.88 g, 10.4 mmol) and m-chloroperbenzoic acid (0.83 g,
4.8 mmol). After the mixture was stirred at room tempera-
ture for 1.5 h, saturated aqueous Na2S2O3 (2 mL) and H2O
(10mL) were added. The mixture was stirred for 1 h and
extracted with Et2O (3£20mL). The combined extracts
were successively washed with saturated aqueous
NaHCO3 (10mL), H 2O (10mL), and brine (10mL), and
then dried (Na2SO4) and concentrated. The residue was
puri®ed by column chromatography on silica gel (40g,
hexane±Et2O 20:1!10:1) to give 52 (1.20g, 98%) as a
3.1.44. Aldehyde 55. The experimental procedure was
similar to that described for compound 19. 55 (83% yield,
28
20E/20Zˆ10:1): a colorless oil; [a]D ˆ19.61 (c 0.915,
29
colorless oil: [a]D ˆ25.73 (c 1.18, CHCl3); IR (CHCl3)
CHCl3); IR (CHCl3) 2730, 1725, 1595, 1515, 1460, 1380,
1
1
1595, 1585, 1450, 1305, 1150, 1060, 1010, 910 cm21; H
1240, 1110, 1040, 970, 835 cm21; H NMR (400 MHz,
NMR (270MHz, CDCl 3) d 7.87±7.83 (m, 2H), 7.61 (m,
1H), 7.55±7.50(m, 2H), 7.43±7.36 (m, 6H), 7.30±7.21
(m, 9H), 3.71 (ddd, Jˆ5.6, 5.6, 5.6 Hz, 1H), 3.45 (dd, Jˆ
3.0, 6.3 Hz, 1H), 3.15 (dd, Jˆ5.1, 9.0Hz, 1H), 3.10±2.89
(m, 2H), 2.79 (dd, Jˆ9.0, 9.0 Hz, 1H), 1.95 (m, 1H), 1.89±
1.72 (m, 2H), 1.41 (ddd, Jˆ6.9, 6.9, 6.9 Hz, 1H), 0.94 (d,
Jˆ6.9 Hz, 3H), 0.88 (t, Jˆ7.6 Hz, 9H), 0.81 (t, Jˆ7.6 Hz,
9H), 0.66 (d, Jˆ6.9 Hz, 3H), 0.50 (q, Jˆ7.6 Hz, 6H), 0.43
(q, Jˆ6.9 Hz, 6H); MS (FAB) m/z 809 (M1Na)1; HRMS
(FAB) calcd for C46H66NaO5SSi2 [(M1Na)1] 809.4066,
found 809.4057.
CDCl3) (20E-isomer) d 9.82 (dd, Jˆ2.0, 2.9 Hz, 1H),
7.44±7.42 (m, 6H), 7.29±7.18 (m, 9H), 5.54 (ddd, Jˆ7.3,
7.3, 15.1 Hz, 1H), 5.46 (ddd, Jˆ7.3, 7.3, 15.1 Hz, 1H), 5.22
(dd, Jˆ8.3, 15.1 Hz, 1H), 5.18 (dd, Jˆ8.3, 15.1 Hz, 1H),
4.66 (d, Jˆ11.7 Hz, 1H), 4.60(d, Jˆ11.7 Hz, 1H), 4.06 (m,
1H), 3.86 (m, 1H), 3.60(dd, Jˆ3.4, 8.0Hz, 1H), 3.57 (dd,
Jˆ3.4, 3.4 Hz, 1H), 3.23 (s, 3H), 3.47 (ddd, Jˆ6.8, 6.8,
6.8 Hz, 1H), 3.41 (ddd, Jˆ6.8, 6.8, 6.8 Hz, 1H), 3.20(m,
1H), 3.09 (s, 3H), 2.82 (dd, Jˆ9.0, 9.0 Hz, 1H), 2.60 (ddd,
Jˆ2.9, 7.8, 16.6 Hz, 1H), 2.53 (ddd, Jˆ2.0, 3.9, 16.6 Hz,
1H), 2.33±2.21 (m, 2H), 2.13 (s, 3H), 2.10(m, 1H), 2.00(m,
1H), 1.84 (ddd, Jˆ7.1, 7.3, 13.7 Hz, 1H), 1.66±1.33 (m,
9H), 1.10(m, 1H), 1.03 (d, Jˆ6.8 Hz, 3H), 0.95 (t, Jˆ
7.8 Hz, 9H), 0.90 (s, 9H), 0.90 (d, Jˆ6.8 Hz, 3H), 0.88 (d,
Jˆ7.3 Hz, 3H), 0.85 (t, Jˆ7.8 Hz, 9H), 0.85 (d, Jˆ6.8 Hz,
3H), 0.66 (d, Jˆ7.3 Hz, 3H), 0.59 (q, Jˆ7.8 Hz, 6H), 0.50
(q, Jˆ7.8 Hz, 6H), 0.05 (s, 6H); MS (FAB) m/z 1211 (M1
Na)1; HRMS (FAB) calcd for C69H116NaO8SSi3 [(M1
Na)1] 1211.7597, found 1211.7570.
3.1.42. Ole®n 53. The experimental procedure was similar
to that described for compound 17. 53 (73% yield, 20E/
30
20Zˆ10:1): a colorless oil; [a]D ˆ120.3 (c 1.02,
CHCl3); IR (CHCl3) 1720, 1600, 1460, 1160, 1090, 1020,
1
970, 835 cm21; H NMR (270MHz, CDCl 3) (20E-isomer)
d 7.44±7.42 (m, 6H), 7.29±7.25 (m, 6H), 7.22±7.19 (m,
3H), 5.54 (ddd, Jˆ7.3, 7.3, 15.4 Hz, 1H), 5.47 (ddd, Jˆ
7.3, 7.3, 15.4 Hz, 1H), 5.22 (dd, Jˆ7.8, 15.4 Hz, 1H), 5.19
(dd, Jˆ8.3, 15.4 Hz, 1H) 4.64 (d, Jˆ11.5 Hz, 1H), 4.58 (d,
Jˆ11.5 Hz, 1H), 4.21±4.10(m, 2H), 3.87 (m, 1H), 3.65±
3.57 (m, 2H) 3.52 (dd, Jˆ3.4, 3.4 Hz, 1H), 3.47 (ddd, Jˆ
7.3, 7.3, 7.3 Hz, 1H), 3.41 (ddd, Jˆ7.3, 7.3, 7.3 Hz, 1H),
3.23 (s, 3H), 3.20(m, 1H), 3.09 (s, 3H), 2.83 (dd, Jˆ9.0,
9.0Hz, 1H), 2.28±2.24 (m, 2H), 2.16 (s, 3H), 2.16±2.08 (m,
2H), 1.97 (m, 1H), 1.88±1.78 (m, 2H), 1.72 (m, 1H), 1.67±
1.34 (m, 8H), 1.21 (s, 9H), 1.09 (m, 1H), 1.04 (d, Jˆ6.8 Hz,
3H), 0.96 (t, Jˆ7.8 Hz, 9H), 0.91±0.86 (m, 6H), 0.90 (s,
9H), 0.85 (d, Jˆ6.8 Hz, 3H), 0.85 (t, Jˆ7.8 Hz, 9H), 0.66
(d, Jˆ6.8 Hz, 3H), 0.59 (q, Jˆ7.8 Hz, 6H), 0.50 (q, Jˆ
7.8 Hz, 6H), 0.06 (s, 3H), 0.06 (s, 3H); MS (FAB) m/z
1297 (M1Na)1; HRMS (FAB) calcd for C74H126NaO9SSi3
[(M1Na)1] 1297.8328, found 1297.8340.
3.1.45. a,b,g,d-Unsaturated ester 56. The experimental
procedure was similar to that described for compound 20.
56 (94% yield, 4E/4Zˆ30:1, 20E/20Zˆ10:1): a colorless
28
oil; [a]D ˆ25.71 (c 0.947, CHCl3); IR (CHCl3) 1700,
1640, 1615, 1595, 1460, 1370, 1250, 1090, 1045, 975,
1
835 cm21; H NMR (400 MHz, CDCl3) (4E,20E-isomer)
d 7.44±7.42 (m, 6H), 7.29±7.18 (m, 10H), 6.25 (dd, Jˆ
10.2, 15.1 Hz, 1H), 6.17 (ddd, Jˆ6.8, 6.8, 15.1 Hz, 1H),
5.80(d, Jˆ15.1 Hz, 1H), 5.54 (ddd, Jˆ7.3, 7.3, 15.6 Hz,
1H), 5.46 (ddd, Jˆ7.8, 7.8, 15.6 Hz, 1H), 5.22 (dd, Jˆ8.3,
15.6 Hz, 1H), 5.18 (dd, Jˆ8.3, 15.6 Hz, 1H), 4.62 (d, Jˆ
11.7 Hz, 1H), 4.58 (d, Jˆ11.7 Hz, 1H), 4.19 (q, Jˆ7.1 Hz,
2H), 3.86 (m, 1H), 3.63 (dd, Jˆ3.4, 3.4 Hz, 1H), 3.62±3.54
(m, 2H), 3.48 (ddd, Jˆ7.1, 7.1, 7.1 Hz, 1H), 3.41 (ddd,
Jˆ6.1, 6.1, 6.1 Hz, 1H), 3.23 (s, 3H), 3.20(m, 1H), 3.09
(s, 3H), 2.82 (dd, Jˆ9.0, 9.0 Hz, 1H), 2.45 (m, 1H), 2.34±
2.26 (m, 3H), 2.14 (s, 3H), 2.12±2.08 (m, 2H), 1.89±1.80
(m, 2H), 1.63±1.33 (m, 8H), 1.29 (t, Jˆ7.1 Hz, 3H), 1.08
(m, 1H), 1.03 (d, Jˆ6.8 Hz, 3H), 0.95 (t, Jˆ7.8 Hz, 9H),
0.90 (s, 9H), 0.87 (m, 3H), 0.85 (t, Jˆ7.8 Hz, 9H), 0.85 (d,
Jˆ6.8 Hz, 3H), 0.85 (d, Jˆ6.8 Hz, 3H), 0.65 (d, Jˆ6.8 Hz,
3H), 0.59 (q, Jˆ7.8 Hz, 6H), 0.50 (q, Jˆ7.8 Hz, 6H), 0.06
(s, 3H) 0.05 (s, 3H); MS (FAB) m/z 1307 (M1Na)1; HRMS
3.1.43. Alcohol 54. The experimental procedure was similar
to that described for compound 18. 54 (96% yield, 20E/
31
20Zˆ10:1): a colorless oil; [a]D ˆ127.7 (c 1.16,
CHCl3); IR (CHCl3) 3500 (br), 1600, 1460, 1380, 1255,
1
1090, 1035, 975, 835 cm21; H NMR (270MHz, CDCl 3)
(20E-isomer) d 7.44±7.42 (m, 6H), 7.29±7.25 (m, 6H),
7.22±7.19 (m, 3H), 5.54 (ddd, Jˆ7.3, 7.3, 15.4 Hz, 1H),
5.46 (ddd, Jˆ7.3, 7.3, 15.4 Hz, 1H), 5.23 (dd, Jˆ8.3,

1092
H. Kigoshi et al. / Tetrahedron 58 (2002) 1075±1102
(FAB) calcd for C75H124NaO9SSi3 [(M1Na)1] 1307.8171,
found 1307.8170.
2.17 (s, 3H), 2.08 (m, 1H), 2.00±1.88 (m, 2H) 1.84 (m, 1H),
1.75 (m, 1H), 1.66±1.08 (m, 8H), 0.98 (d, Jˆ6.8 Hz, 3H),
0.93 (d, Jˆ6.8 Hz, 3H), 0.90 (s, 9H), 0.88 (m, 3H), 0.87 (d,
Jˆ7.3 Hz, 3H), 0.72 (d, Jˆ6.8 Hz, 3H), 0.06 (s, 3H) 0.05 (s,
3H); MS (FAB) m/z 1033 (M1Na)1; HRMS (FAB)
calcd for C61H90NaO8SSi [(M1Na)1] 1033.6022, found
1033.6040.
3.1.46. Diol 57. The experimental procedure was similar to
that described for compound 21. 57 (91% yield, 4E/
28
4Zˆ30:1, 20E/20Zˆ10:1): a colorless oil; [a]D ˆ18.90
(c 0.963, CHCl3); IR (CHCl3) 3450(br), 1750, 1645,
1615, 1590, 1460, 1375, 1250, 1100, 1045, 975,
1
835 cm21; H NMR (400 MHz, CDCl3) (4E,20E-isomer)
3.1.48. Isomerization of a 26-membered lactone to the
26-membered lactone 59. The experimental procedure
was similar to that described for isomerization of a
26-membered lactone to 23 (78% yield).
d 7.44±7.42 (m, 6H), 7.34±7.23 (m, 10H), 6.25 (dd, Jˆ
10.2, 15.1 Hz, 1H), 6.18 (ddd, Jˆ6.3, 6.3, 15.1 Hz, 1H),
5.80(d, Jˆ15.1 Hz, 1H), 5.63 (ddd, Jˆ7.8, 7.8, 15.1 Hz,
1H), 5.54 (ddd, Jˆ7.5, 7.5, 15.1 Hz, 1H), 5.31 (dd, Jˆ8.3,
15.1 Hz, 1H), 5.23 (dd, Jˆ8.3, 15.1 Hz, 1H), 4.62 (d, Jˆ
11.5 Hz, 1H), 4.58 (d, Jˆ11.5 Hz, 1H), 4.39 (br s, 1H), 4.19
(q, Jˆ7.1 Hz, 2H), 4.01 (m, 1H), 3.83 (br s, 1H), 3.63 (dd,
Jˆ3.4, 3.4 Hz, 1H), 3.59±3.53 (m, 2H), 3.49 (m, 1H), 3.42
(m, 1H), 3.39 (dd, Jˆ3.9, 8.8 Hz, 1H), 3.23 (s, 3H), 3.22 (s,
3H), 3.11 (dd, Jˆ8.8, 8.8 Hz, 1H), 2.45 (m, 1H), 2.37±2.27
(m, 2H), 2.17±2.08 (m, 2H), 2.14 (s, 3H), 1.92±1.82 (m,
2H), 1.64±1.39 (m, 10H), 1.29 (t, Jˆ7.1 Hz, 3H), 1.01 (d,
Jˆ7.3 Hz, 3H), 0.90 (s, 9H), 0.88 (m, 3H), 0.87 (d, Jˆ
6.3 Hz, 3H), 0.85 (d, Jˆ6.8 Hz, 3H), 0.76 (d, Jˆ6.8 Hz,
3H), 0.06 (s, 3H) 0.05 (s, 3H); MS (FAB) m/z 1079 (M1
Na)1; HRMS (FAB) calcd for C63H96NaO9SSi [(M1Na)1]
1079.6442, found 1079.6430.
3.1.49. Silyl ether 60. The experimental procedure was
similar to that described for compound 24. 60 (86%
29
yield): a colorless oil; [a]D ˆ113.5 (c 1.00, CHCl3); IR
(CHCl3) 1705, 1640, 1615, 1595, 1515, 1460, 1360, 1255,
1075, 1045, 970, 835 cm21; 1H NMR (400 MHz, CDCl3) d
7.43±7.41 (m, 6H), 7.29±7.19 (m, 10H), 6.22±6.18 (m,
2H), 5.79 (d, Jˆ15.6 Hz, 1H), 5.52 (ddd, Jˆ4.1, 10.5,
15.1 Hz, 1H), 5.28 (ddd, Jˆ7.3, 7.3, 15.1 Hz, 1H), 5.22
(m, 1H), 5.12 (dd, Jˆ8.8, 15.1 Hz, 1H), 5.09 (dd, Jˆ8.8,
15.1 Hz, 1H), 4.60(d, Jˆ11.7 Hz, 1H), 4.55 (d, Jˆ11.7 Hz,
1H), 3.60±3.54 (m, 3H), 3.49 (ddd, Jˆ4.9, 9.0, 9.0 Hz, 1H),
3.41 (ddd, Jˆ3.7, 9.0, 9.0 Hz, 1H), 3.25 (m, 1H), 3.24 (s,
3H), 3.20(s, 3H), 2.79 (dd, Jˆ9.0, 9.0 Hz, 1H), 2.43±2.07
(m, 5H), 2.17 (s, 3H), 1.90±1.80 (m, 3H), 1.69±1.12 (m,
9H), 1.03 (d, Jˆ6.8 Hz, 3H), 0.93 (d, Jˆ6.8 Hz, 3H), 0.89
(s, 9H), 0.87 (d, Jˆ6.8 Hz, 3H), 0.83 (d, Jˆ7.3 Hz, 3H),
0.77 (d, Jˆ6.3 Hz, 3H), 0.74 (s, 9H), 0.05 (s, 3H), 0.04 (s,
3H), 0.04 (s, 3H), 20.11 (s, 3H); MS (FAB) m/z 1147
(M1Na)1; HRMS (FAB) calcd for C67H104NaO8SSi2
[(M1Na)1] 1147.6889, found 1147.6880.
3.1.47. 24-Membered lactone 59 and a 26-membered
lactone. The experimental procedure was similar to that
described for compound 23 and a 26-membered lactone.
30
59 (49% yield from 57): a colorless oil; [a]D ˆ139.7 (c
1.13, CHCl3); IR (CHCl3) 3500 (br), 1690, 1640, 1615,
1
1590, 1460, 1380, 1260, 1075, 1050, 975, 835 cm21; H
NMR (400 MHz, CDCl3) d 7.44±7.42 (m, 6H), 7.31±7.20
(m, 10H), 6.26±6.15 (m, 2H), 5.80 (d, Jˆ15.1 Hz, 1H), 5.55
(ddd, Jˆ4.4, 10.4, 15.2 Hz, 1H), 5.40 (br d, Jˆ11.2 Hz, 1H),
5.28 (ddd, Jˆ6.3, 8.3, 15.2 Hz, 1H), 5.10(dd, Jˆ8.8,
15.2 Hz, 1H), 5.10(dd, Jˆ8.8, 15.2 Hz, 1H), 4.60(d, Jˆ
11.2 Hz, 1H), 4.58 (d, Jˆ11.2 Hz, 1H), 3.62±3.45 (m, 3H),
3.41 (ddd, Jˆ3.9, 9.3, 9.3 Hz, 1H), 3.06 (ddd, Jˆ3.9, 6.8,
10.2 Hz, 1H), 3.29±3.23 (m, 2H), 3.24 (s, 3H), 3.20 (s, 3H),
3.11 (dd, Jˆ5.4, 9.3 Hz, 1H), 2.44±2.31 (m, 2H), 2.24 (m,
1H), 2.17 (s, 3H), 2.10(m, 1H), 2.00(m, 1H), 1.98±1.80(m,
3H), 1.62±1.11 (m, 9H), 1.13 (d, Jˆ6.8 Hz, 3H), 0.92 (d,
Jˆ6.8 Hz, 3H), 0.89 (s, 9H), 0.88 (m, 3H), 0.80 (d, Jˆ
6.8 Hz, 3H), 0.74 (d, Jˆ5.9 Hz, 3H), 0.05 (s, 3H), 0.04 (s,
3H); MS (FAB) m/z 1033 (M1Na)1; HRMS (FAB)
calcd for C61H90NaO8SSi [(M1Na)1] 1033.6022, found
1033.6030.
3.1.50. Alcohol 61. The experimental procedure was similar
to that described for compound 30. 61 (86% yield): a color-
less oil; [a]D ˆ121.3 (c 1.05, CHCl3); IR (CHCl3) 3460
28
(br), 1705, 1640, 1615, 1595, 1460, 1360, 1265, 1090, 1070,
1035, 970, 835 cm21; 1H NMR (500 MHz, CDCl3) d 7.43±
7.41 (m, 6H), 7.29±7.19 (m, 10H), 6.27 (ddd, Jˆ5.7, 8.1,
15.1 Hz, 1H), 6.21 (dd, Jˆ10.0, 15.1 Hz, 1H), 5.77 (d, Jˆ
15.1 Hz, 1H), 5.49 (ddd, Jˆ4.4, 10.3, 15.2 Hz, 1H), 5.40
(ddd, Jˆ7.3, 7.3, 15.2 Hz, 1H), 5.22 (dd, Jˆ8.8, 15.2 Hz,
1H), 5.22 (m, 1H), 5.14 (dd, Jˆ8.8, 15.2 Hz, 1H), 3.78 (dd,
Jˆ2.9, 2.9 Hz, 1H), 3.59 (ddd, Jˆ3.4, 5.9, 11.7 Hz, 1H),
3.55 (dd, Jˆ4.4, 4.4 Hz, 1H), 3.52±3.46 (m, 2H), 3.25
(dd, Jˆ5.1, 9.0Hz, 1H), 3.23 (s, 3H), 3.20 (s, 3H), 3.09
(br s, 1H), 2.78 (dd, Jˆ9.0, 9.0 Hz, 1H), 2.40 (m, 1H),
2.36±2.27 (m, 2H), 2.17 (ddd, Jˆ10.5, 10.5, 14.1 Hz,
1H), 2.11 (m, 1H), 2.00 (ddd, Jˆ6.8, 6.8, 13.2 Hz, 1H),
1.78 (ddd, Jˆ6.3, 6.3, 13.2 Hz, 1H), 1.73±1.59 (m, 4H),
1.54±1.14 (m, 6H), 1.03 (d, Jˆ6.8 Hz, 3H), 0.95 (d, Jˆ
6.8 Hz, 3H), 0.91 (s, 9H), 0.86 (d, Jˆ6.8 Hz, 3H), 0.82 (d,
Jˆ7.3 Hz, 3H), 0.77 (d, Jˆ6.3 Hz, 3H), 0.74 (s, 9H), 0.09
(s, 3H), 0.07 (s, 3H), 0.03 (s, 3H), 20.11 (s, 3H); MS
(FAB) m/z 1087 (M1Na)1; HRMS (FAB) calcd for
C65H100NaO8Si2 [(M1Na)1] 1087.6854, found 1087.6860.
26-Membered lactone (19% yield from 57): a colorless oil;
29
[a]D ˆ119.0( c 0.977, CHCl3); IR (CHCl3) 3500 (br),
1685, 1640, 1615, 1590, 1460, 1360, 1255, 1090, 1005,
1
975, 835 cm21; H NMR (270MHz, CDCl 3) d 7.46±7.44
(m, 6H), 7.32±7.23 (m, 9H), 7.06 (dd, Jˆ10.7, 15.1 Hz,
1H), 6.25 (dd, Jˆ10.7, 15.1 Hz, 1H), 6.13 (ddd, Jˆ6.8,
7.2, 15.1 Hz, 1H), 5.71 (d, Jˆ15.1 Hz, 1H), 5.47±5.38 (m,
2H), 5.23 (dd, Jˆ8.3, 15.1 Hz, 1H), 5.19 (dd, Jˆ8.3,
15.1 Hz, 1H), 4.87 (dd, Jˆ2.4, 10.7 Hz, 1H), 4.65 (d, Jˆ
11.5 Hz, 1H), 4.61 (d, Jˆ11.5 Hz, 1H), 3.73 (m, 1H), 3.60
(m, 1H), 3.46±3.38 (m, 2H), 3.34 (m, 1H), 3.28 (dd, Jˆ5.6,
9.0Hz, 1H), 3.22 (s, 3H), 3.17 (s, 3H), 3.03 (dd, Jˆ8.3,
9.0Hz, 1H), 2.75 (d, Jˆ3.9 Hz, 1H), 2.49±2.23 (m, 4H),
3.1.51. Trimethylserine ester 62. The experimental pro-
cedure was similar to that described for compound 31. 62
28
(93% yield, S/Rˆ1:1): a colorless oil; [a]D ˆ149 (c 0.40,
MeOH); IR (CHCl3) 1710, 1645, 1620, 1600, 1450, 1360,
1
1245, 1085, 975 cm21; H NMR (500 MHz, acetone-d6) d

H. Kigoshi et al. / Tetrahedron 58 (2002) 1075±1102
1093
7.47±7.44 (m, 6H), 7.34±7.17 (m, 10H), 6.42 [6.45] (dd,
Jˆ10.7, 15.1 Hz, 1H), 6.29 [6.27] (ddd, Jˆ4.9, 10.7,
15.1 Hz, 1H), 5.95 [5.95] (d, Jˆ15.1 Hz, 1H), 5.57 (ddd,
Jˆ4.4, 10.7, 15.1 Hz, 1H), 5.42±5.33 (m, 2H), 5.10 (m,
1H), 4.97 (dd, Jˆ9.3, 15.1 Hz, 1H), 4.76 (m, 1H), 3.68
(m, 1H), 3.58 [3.58] (dd, Jˆ5.4, 9.3 Hz, 1H), 3.53±3.28
(m, 8H), 3.30[3.32] (s, 3H), 3.18 (s, 3H), 3.10(s, 3H),
3.03 (dd, Jˆ6.8, 9.3 Hz, 1H), 2.50±1.85 (m, 10H), 2.36
[2.35] (s, 6H), 1.76±1.28 (m, 7H), 1.07 (d, Jˆ6.8 Hz,
3H), 1.02±0.99 (m, 6H), 0.87 (d, Jˆ6.8 Hz, 3H), 0.72
[0.71] (d, Jˆ6.1 Hz, 3H). The counterparts of doubled
signals in the ratio of 1:1 are in brackets; MS (FAB) m/z
1216 (M1Na)1; HRMS (FAB) calcd for C71H111NNaO10Si2
[(M1Na)1] 1216.7645, found 1216.7680.
4.8 mmol) in 1,4-dioxane (0.6 mL) and 2 M HCl (0.2 mL)
was stirred at 508C for 5 h and poured into ice-cooled satu-
rated aqueous NaHCO3 (5 mL). The aqueous mixture was
extracted with EtOAc (3£10mL). The extracts were
combined, washed with brine (5 mL), dried (Na2SO4), and
concentrated. The residual oil was puri®ed by column
chromatography on silica gel (4 g, hexane±acetone 2:1!
1:1!1:2) to give 64 (1.5 mg, 44%) as a colorless oil.
3.1.54. Alcohol 65. The experimental procedure was similar
to that described for compound 14. 65 (76% yield, S/
29
Rˆ1:1): a colorless oil; [a]D ˆ122 (c 0.75, MeOH); IR
(CHCl3) 3520 (br), 1710 (sh), 1645, 1625, 1480, 1360, 1300,
1
1255, 1035, 1000, 970, 840 cm21; H NMR (400 MHz,
acetone-d6) d 7.21 [7.21] (dd, Jˆ10.7, 15.1 Hz, 1H), 6.39
[6.41] (dd, Jˆ10.7, 15.6 Hz, 1H), 6.25 (m, 1H), 5.90 (d,
Jˆ15.1 Hz, 1H), 5.55 (ddd, Jˆ3.9, 10.2, 14.6 Hz, 1H),
5.38 (m, 1H), 5.29 (m, 1H), 5.12 (dd, Jˆ8.8, 14.6 Hz,
1H), 5.07 (dd, Jˆ8.8, 14.6 Hz, 1H), 4.86 (td, Jˆ6.8,
2.4 Hz, 1H), 3.74 (t, Jˆ4.7 Hz, 1H), 3.69 (dd, Jˆ7.8,
9.3 Hz, 1H), 3.63 (m, 2H), 3.61 [3.58] (dd, Jˆ5.9, 9.3 Hz,
1H), 3.52±3.35 (m, 4H), 3.33 [3.31] (s, 3H), 3.18 (s, 3H),
3.12 (s, 3H), 2.57±2.45 (m, 2H), 2.45±2.24 (m, 4H), 2.36 (s,
3H), 2.36 (s, 3H), 2.10±1.80 (m, 5H), 1.80±1.13 (m, 9H),
1.01 (d, Jˆ6.8 Hz, 3H), 1.00 (d, Jˆ6.8 Hz, 3H), 1.00±0.94
(m, 3H), 0.91 (s, 18H), 0.78 (d, Jˆ6.3 Hz, 3H), 0.14 (s, 3H),
0.11 (s, 3H), 0.09±0.08 (m, 6H). A signal due to OH was not
detected. The counterparts of doubled signals in the ratio of
1:1 are in brackets; MS (FAB) m/z 974 (M1Na)1; HRMS
(FAB) calcd for C52H97NNaO10Si2 [(M1Na)1] 974.6548,
found 974.6539.
3.1.52. Diol 63 and triol 64. A solution of trimethylserine
ester 62 (11.8 mg, 9.89 mmol) in a 8:3:5 mixture of THF,
pyridine, and HF´pyridine (1 mL) was stirred at room
temperature for 20h and at 40 8C for 19 h and poured into
ice-cooled saturated aqueous NaHCO3 (8 mL). The aqueous
mixture was extracted with EtOAc (3£10mL). The extracts
were combined, washed with brine (5 mL), dried (Na2SO4),
and concentrated. The residual oil was puri®ed by column
chromatography on silica gel (3 g, hexane±acetone 1:1!
1:2!1:3!1:4) to give 63 (5.0mg, 52%, S/Rˆ1:1) and 64
(3.1 mg, 43%, S/Rˆ1:1) as a colorless oil, respectively. 63:
28
[a]D ˆ149 (c 0.40, MeOH); IR (CHCl3) 1710, 1645,
1620, 1600, 1450, 1360, 1245, 1085, 975 cm21; H NMR
1
(500 MHz, acetone-d6) d 7.47±7.44 (m, 6H), 7.34±7.17 (m,
10H), 6.42 [6.45] (dd, Jˆ10.7, 15.1 Hz, 1H), 6.29 [6.27]
(ddd, Jˆ4.9, 10.7, 15.1 Hz, 1H), 5.95 [5.95] (d, Jˆ
15.1 Hz, 1H), 5.57 (ddd, Jˆ4.4, 10.7, 15.1 Hz, 1H), 5.42±
5.33 (m, 2H), 5.10(m, 1H), 4.97 (dd, Jˆ9.3, 15.1 Hz, 1H),
4.76 (m, 1H), 3.68 (m, 1H), 3.58 [3.58] (dd, Jˆ5.4, 9.3 Hz,
1H), 3.53±3.28 (m, 8H), 3.30[3.32] (s, 3H), 3.18 (s, 3H),
3.10(s, 3H), 3.03 (dd, Jˆ6.8, 9.3 Hz, 1H), 2.50±1.85 (m,
10H), 2.36 [2.35] (s, 6H), 1.76±1.28 (m, 7H), 1.07 (d, Jˆ
6.8 Hz, 3H), 1.02±0.99 (m, 6H), 0.87 (d, Jˆ6.8 Hz, 3H),
0.72 [0.71] (d, Jˆ6.1 Hz, 3H). The counterparts of doubled
signals in the ratio of 1:1 are in brackets; MS (FAB) m/z 988
(M1Na)1; HRMS (FAB) calcd for C59H83NNaO10 [(M1
3.1.55. Dimethylalanine ester 66. The experimental pro-
cedure was similar to that described for compound 29. 66
(100% yield, S/Rˆ1:1 as to the trimethylserine part, S/
Rˆ2:1 as to the dimethylalanine part): a colorless oil;
30
[a]D ˆ112 (c 0.75, MeOH); IR (CHCl3) 1720, 1700,
1
1645, 1620, 1460, 1280, 840 cm21; H NMR (400 MHz,
acetone-d6) d 7.21 [7.22] (dd, Jˆ10.7, 15.1 Hz, 1H), 6.40
[6.41] (dd, Jˆ10.7, 15.6 Hz, 1H), 6.26 (m, 1H), 5.90 (d,
Jˆ15.1 Hz, 1H), 5.55 (ddd, Jˆ3.9, 10.2, 14.6 Hz, 1H),
5.38 (m, 1H), 5.30(m, 1H), 5.12 (dd, Jˆ8.8, 14.6 Hz,
1H), 5.07 (dd, Jˆ8.8, 14.6 Hz, 1H), 4.86 (td, Jˆ6.8,
2.4 Hz, 1H), 4.32 [4.33] (dd, Jˆ4.4, 11.2 Hz, 1H), 3.88
[3.87] (dd, Jˆ7.8, 11.2 Hz, 1H), 3.74 (t, Jˆ4.7 Hz, 1H),
3.69 (dd, Jˆ7.8, 9.3 Hz, 1H), 3.63 (m, 1H), 3.61 [3.58]
(dd, Jˆ5.9, 9.3 Hz, 1H), 3.48 (m, 2H), 3.37 (ddd, Jˆ3.7,
5.9, 7.8 Hz, 1H), 3.30[3.31] (dd, Jˆ5.9, 7.8 Hz, 3H), 3.27
[3.28] (q, Jˆ6.8 Hz, 1H), 3.18 (s, 3H), 3.12 (s, 3H), 2.56±
2.45 (m, 2H), 2.45±2.18 (m, 3H), 2.36 [2.36] (s, 6H), 2.28
[2.27] (s, 6H), 2.13±1.75 (m, 5H), 1.65±1.13 (m, 7H), 1.19
[1.20] (d, Jˆ6.8 Hz, 3H), 1.04 (d, Jˆ6.8 Hz, 6H), 1.00±0.85
(m, 6H), 0.92 (s, 9H), 0.91 (s, 9H), 0.78 (d, Jˆ6.8 Hz, 3H),
0.16 (s, 3H), 0.11 (s, 3H), 0.09 (s, 3H), 0.07 (s, 3H). The
minor counterparts of doubled signals are in brackets; MS
(FAB) m/z 1073 (M1Na)1; HRMS (FAB) calcd for
C57H106N2NaO11Si2 [(M1Na)1] 1073.7233, found
1073.7230.
Na)1] 988.5915, found 988.5895. 64: [a]D ˆ194 (c
30
0.045, MeOH); UV(MeCN) lmax 261 nm (1 28,000); IR
(CHCl3) 3580 (br), 1730, 1695, 1645, 1615, 1455, 1360,
1
1245, 1090, 970 cm21; H NMR (500 MHz, acetone-d6) d
7.20(dd, Jˆ10.7, 15.1 Hz, 1H), 6.45 [6.42] (dd, Jˆ10.7,
15.1 Hz, 1H), 6.31 [6.27] (ddd, Jˆ4.9, 10.3, 15.1 Hz, 1H),
5.96 [5.96] (d, Jˆ15.1 Hz, 1H), 5.61 (ddd, Jˆ4.2, 10.7,
15.1 Hz, 1H), 5.48 (br d, Jˆ10.3 Hz, 1H), 5.38 (m, 1H),
5.11 (m, 1H), 4.99 (dd, Jˆ8.8, 15.1 Hz, 1H), 4.77 (m,
1H), 3.87 (br d, Jˆ4.9 Hz, 1H), 3.68 [3.68] (dd, Jˆ7.8,
9.3 Hz, 1H), 3.62±3.43 (m, 7H), 3.37 (ddd, Jˆ3.9, 5.9,
9.3 Hz, 1H), 3.30[3.33] (s, 3H), 3.18 (s, 3H), 3.18 (s,
3H), 3.10(m, 1H), 2.50±2.32 (m, 3H), 2.36 [2.35] (s, 6H),
2.16 (m, 1H), 2.06±1.98 (m, 2H), 1.94±1.86 (m, 3H), 1.76±
1.46 (m, 6H), 1.32 (m, 1H), 1.21 (m, 1H), 1.09 (m, 1H),
1.02±0.99 (m, 9H), 0.95 (d, Jˆ6.8 Hz, 3H), 0.74 [0.73] (d,
Jˆ6.3 Hz, 3H). The counterparts of doubled signals in the
ratio of 1:1 are in brackets; MS (FAB) m/z 746 (M1Na)1;
HRMS (FAB) calcd for C40H69NNaO10 [(M1Na)1]
746.4819, found 746.4819.
3.1.56. Diol 67. The experimental procedure was similar to
that described for compounds 63 and 64. 67 (78% yield,
S/Rˆ1:1 as to the trimethylserine part, S/Rˆ2:1 as to the
27
3.1.53. Hydrolysis of diol 63. A solution of diol 63 (4.6 mg,
dimethylalanine part): a colorless oil; [a]D ˆ166 (c 0.10,

1094
H. Kigoshi et al. / Tetrahedron 58 (2002) 1075±1102
MeOH); IR (CHCl3) 3500 (br), 1725, 1695 (sh), 1645, 1620,
1H), 5.55 (td, Jˆ7.6, 15.6 Hz, 1H), 5.27 (dd, Jˆ8.3,
15.6 Hz, 1H), 5.24 (dd, Jˆ8.3, 15.6 Hz, 1H), 4.66 (d, Jˆ
11.7 Hz, 1H), 4.60(d, Jˆ11.7 Hz, 1H), 4.05 (ddd, Jˆ3.9,
5.6, 7.6 Hz, 1H), 3.65 (t, Jˆ6.8 Hz, 2H), 3.57 (dd, Jˆ3.7,
3.7 Hz, 1H), 3.53 (m, 1H), 3.42 (ddd, Jˆ6.8, 6.8, 6.8 Hz,
1H), 3.24 (s, 3H), 3.23 (s, 3H), 2.62±2.52 (m, 2H), 2.59
(ddd, Jˆ2.9, 7.3, 16.6 Hz, 1H), 2.53 (ddd, Jˆ2.0, 3.9,
16.6 Hz, 1H), 2.14 (s, 3H), 2.11 (m, 1H), 2.01 (m, 1H),
1.90(ddd, Jˆ7.3, 7.3, 14.6 Hz, 1H), 1.67±1.38 (m, 7H),
1.05 (m, 1H), 0.96 (t, Jˆ7.8 Hz, 9H), 0.92±0.87 (m, 9H),
0.90 (s, 9H), 0.60 (q, Jˆ7.8 Hz, 6H), 0.05 (s, 3H), 0.05 (s,
3H); MS (FAB) m/z 739 (M1Na)1; HRMS (FAB) calcd for
C38H76NaO6SSi2 [(M1Na)1] 739.4799, found 739.4799.
1
1460, 1380, 1240, 1095, 970 cm21; H NMR (400 MHz,
acetone-d6) d 7.22 [7.22] (dd, Jˆ10.7, 15.1 Hz, 1H), 6.45
[6.46] (dd, Jˆ10.7, 15.6 Hz, 1H), 6.29 [6.30] (td, Jˆ9.8,
15.6 Hz, 1H), 5.98 [5.98] (d, Jˆ15.1 Hz, 1H), 5.62 (ddd,
Jˆ4.4, 10.7, 15.1 Hz, 1H), 5.46 (br d, Jˆ10.3 Hz, 1H),
5.38 (m, 1H), 5.10(m, 1H), 5.0(dd,
Jˆ9.3, 15.1 Hz,
1H), 4.76 (m, 1H), 4.26 (ddd, Jˆ5.4, 7.8, 11.2 Hz, 1H),
3.90(ddd, Jˆ5.9, 8.3, 11.2 Hz, 1H), 3.82 (br s, 1H), 3.68
(dd, Jˆ7.8, 9.3 Hz, 1H), 3.58 [3.58] (dd, Jˆ5.4, 9.3 Hz,
1H), 3.50(m, 3H), 3.37 (dd, Jˆ3.7, 5.4, 7.8 Hz, 1H), 3.33
[3.30] (s, 3H), 3.24 [3.24] (q, Jˆ7.3 Hz, 1H), 3.18 (s, 3H),
3.11 (m, 1H), 3.10(s, 3H), 2.52±2.40(m, 2H), 2.35±2.25
(m, 1H), 2.35 [2.36] (s, 6H), 2.28 (s, 6H), 2.25±1.80(m,
7H), 1.80±1.25 (m, 7H), 1.20 (d, Jˆ6.8 Hz, 3H), 1.04±0.97
(m, 12H), 0.73 [0.72] (d, Jˆ6.3 Hz, 3H). The minor
counterparts of doubled signals are in brackets; MS (FAB)
m/z 845 (M1Na)1; HRMS (FAB) calcd for C45H78N2NaO11
[(M1Na)1] 845.5504, found 845.5487.
3.1.60. a,b,g,d-Unsaturated ester 72. The experimental
procedure was similar to that described for compound 20.
72 (89% yield, 4E/4Zˆ30:1, 20E/20Zˆ10:1): a colorless
26
oil; [a]D ˆ10.14 (c 1.04, CHCl3); IR (CHCl3) 1700,
1
1640, 1620, 1465, 1095, 1045, 970, 835 cm21; H NMR
(500 MHz, CDCl3) (4E,20E-isomer) d 7.26 (dd, Jˆ10.7,
15.1 Hz, 1H), 6.25 (dd, Jˆ10.7, 15.1 Hz, 1H), 6.17 (td,
Jˆ7.2, 15.1 Hz, 1H), 5.80(d, Jˆ15.1 Hz, 1H), 5.62 (td,
Jˆ8.3, 15.6 Hz, 1H), 5.55 (td, Jˆ7.3, 15.6 Hz, 1H), 5.27
(dd, Jˆ8.3, 15.6 Hz, 1H), 5.24 (dd, Jˆ8.3, 15.6 Hz, 1H),
4.62 (d, Jˆ11.5 Hz, 1H), 4.59 (d, Jˆ11.5 Hz, 1H), 4.20(q,
Jˆ7.3 Hz, 2H), 3.65 (t, Jˆ6.8 Hz, 2H), 3.65 (m, 1H), 3.59±
3.52 (m, 2H), 3.42 (ddd, Jˆ6.8, 6.8, 6.8 Hz, 1H), 3.24 (s,
3H), 3.23 (s, 3H), 2.45 (m, 1H), 2.34±2.28 (m, 3H), 2.15 (s,
3H), 2.12 (m, 1H), 1.92±1.83 (m, 2H), 1.68±1.39 (m, 7H),
1.29 (t, Jˆ7.3 Hz, 3H), 1.05 (m, 1H), 0.96 (t, Jˆ7.8 Hz,
9H), 0.90 (s, 9H), 0.88 (d, Jˆ7.3 Hz, 3H), 0.88 (d, Jˆ
6.3 Hz, 3H), 0.85 (d, Jˆ6.8 Hz, 3H), 0.60 (q, Jˆ7.8 Hz,
6H), 0.06 (s, 3H), 0.05 (s, 3H); MS (FAB) m/z 835 (M1
Na)1; HRMS (FAB) calcd for C44H84NaO7SSi2 [(M1Na)1]
835.5374, found 835.5377.
3.1.57. Ole®n 69. The experimental procedure for Julia
ole®nation between 15 and 68 was similar to that described
for compound 17 and that for silylation was similar to that
given for compound 51. 69 (70% yield, 20E/20Zˆ10:1): a
31
colorless oil; [a]D ˆ137.9 (c 0.899, CHCl3); IR (CHCl3)
1720, 1460, 1165, 1090, 1045, 970, 835 cm21; H NMR
1
(400 MHz, CDCl3) (20E-isomer) d 5.62 (td, Jˆ6.8,
15.6 Hz, 1H), 5.55 (td, Jˆ7.3, 15.6 Hz, 1H), 5.27 (dd, Jˆ
8.3, 15.6 Hz, 1H), 5.23 (d, Jˆ8.3, 15.6 Hz, 1H), 4.64 (d,
Jˆ11.5 Hz, 1H), 4.58 (d, Jˆ11.5 Hz, 1H), 4.20±4.10 (m,
2H), 3.65 (dd, Jˆ6.8, 6.8 Hz, 1H), 3.64±3.60(m, 2H),
3.57±3.50(m, 2H), 3.41 (m, 1H), 3.23 (s, 6H), 2.32±2.27
(m, 2H), 2.16 (s, 3H), 2.10 (m, 1H), 2.00±1.38 (m, 10H),
1.21 (s, 9H), 1.05 (m, 1H), 0.96 (t, Jˆ7.8 Hz, 9H), 0.99±
0.87 (m, 10H), 0.90 (s, 9H), 0.60 (q, Jˆ7.8 Hz, 6H), 0.05 (s,
3H), 0.05 (s, 3H); MS (FAB) m/z 825 (M1Na)1; HRMS
(FAB) calcd for C43H86NaO7SSi2 [(M1Na)1] 825.5530,
found 825.5562.
3.1.61. Hydroxy ester 73. The experimental procedure was
similar to that described for compound 21. 73 (99% yield,
28
4E/4Zˆ30:1, 20E/20Zˆ10:1): a colorless oil; [a]D
ˆ
3.1.58. Alcohol 70. The experimental procedure was similar
to that described for compound 18. 70 (93% yield, 20E/
21.99 (c 1.14, CHCl3); IR (CHCl3) 3460 (br), 1700, 1640,
1620, 1460, 1090, 1045, 975, 835 cm21; H NMR (500
1
32
20Zˆ10:1): a colorless oil; [a]D ˆ151.3 (c 1.16,
MHz, CDCl3) (4E,20E-isomer) d 7.26 (dd, Jˆ10.7,
15.4 Hz, 1H), 6.25 (dd, Jˆ10.7, 15.4 Hz, 1H), 6.17 (td,
Jˆ7.3, 15.4 Hz, 1H), 5.80(d, Jˆ15.4 Hz, 1H), 5.62 (td,
Jˆ7.3, 15.6 Hz, 1H), 5.55 (td, Jˆ7.3, 15.6 Hz, 1H), 5.37
(dd, Jˆ8.3, 15.6 Hz, 1H), 5.24 (dd, Jˆ8.3, 15.6 Hz, 1H),
4.62 (d, Jˆ11.7 Hz, 1H), 4.59 (d, Jˆ11.7 Hz, 1H), 4.20(q,
Jˆ7.3 Hz, 2H), 3.69±3.64 (m, 2H), 3.63 (t, Jˆ3.4 Hz, 1H),
3.59±3.55 (m, 2H), 3.42 (m, 1H), 3.24 (s, 3H), 3.24 (s, 3H),
2.45 (m, 1H), 2.38±2.32 (m, 3H), 2.15 (s, 3H), 2.12 (m, 1H),
1.95±1.82 (m, 2H), 1.66±1.39 (m, 8H), 1.29 (t, Jˆ7.3 Hz,
3H), 1.05 (m, 1H), 0.92±0.88 (m, 6H), 0.90 (s, 9H), 0.85 (d,
Jˆ6.8 Hz, 3H), 0.06 (s, 3H), 0.05 (s, 3H); MS (FAB) m/z
721 (M1Na)1; HRMS (FAB) calcd for C38H70NaO7SSi
[(M1Na)1] 721.4509, found 721.4514.
CHCl3); IR (CHCl3) 3470 (br), 1460, 1090, 1050, 970,
1
835 cm21; H NMR (400 MHz, CDCl3) (20E-isomer) d
5.62 (td, Jˆ7.3, 15.1 Hz, 1H), 5.55 (td, Jˆ6.8, 15.6 Hz,
1H), 5.30±5.21 (m, 2H), 4.70 (d, Jˆ11.7 Hz, 1H), 4.59 (d,
Jˆ11.7 Hz, 1H), 3.82±3.68 (m, 3H), 3.65 (t, Jˆ6.8 Hz, 2H),
3.55 (m, 1H), 3.50(dd, Jˆ3.4, 4.4 Hz, 1H), 3.42 (m, 1H),
3.24 (s, 3H), 3.23 (s, 3H), 2.50(br t, Jˆ5.3 Hz, 1H), 2.30(dt,
Jˆ6.8, 6.8 Hz, 2H), 2.21 (s, 3H), 2.11 (m, 1H), 1.98 (m,
1H), 1.90(ddd, Jˆ7.3, 7.3, 14.6 Hz, 1H), 1.74±1.38 (m,
9H), 1.05 (m, 1H), 0.96 (t, Jˆ7.8 Hz, 9H), 0.90 (s, 9H),
0.90±0.87 (m, 9H), 0.60 (q, Jˆ7.8 Hz, 6H), 0.05 (s, 3H),
0.05 (s, 3H); MS (FAB) m/z 741 (M1Na)1; HRMS (FAB)
calcd for C38H78NaO6SSi2 [(M1Na)1] 741.4955, found
741.4968.
3.1.62. Lactone 75. The experimental procedure for
hydrolysis of 73 was similar to that described for compound
22 to give seco-acid 74. To a solution of crude 74 (10.6 mg
obtained from 10.0 mg of 73, 0.014 mmol) in toluene
(20mL) were added PPh 3 (80mg, 0.31 mmol) and
(EtOOCNv)2 (0.05 mL, 0.32 mmol) at 210to 2208C.
The mixture was stirred at 210to 2208C for 4.5 h and at
3.1.59. Aldehyde 71. The experimental procedure was
similar to that described for compound 19. 71 (81% yield,
27
20E/20Zˆ10:1): a colorless oil; [a]D ˆ128.8 (c 0.96,
CHCl3); IR (CHCl3) 2735, 1720, 1460, 1095, 1095, 975,
1
835 cm21; H NMR (500 MHz, CDCl3) (20E-isomer) d
9.82 (dd, Jˆ2.0, 2.9 Hz, 1H), 5.63 (td, Jˆ6.8, 15.6 Hz,

H. Kigoshi et al. / Tetrahedron 58 (2002) 1075±1102
1095
48C for 42 h. The mixture was concentrated, and the residual
(MeCN) lmax 259 nm (1 25,000); IR (CHCl3) 3510(br),
1
oil was puri®ed by column chromatography on silica gel
(5 g, hexane±EtOAc 8:1!6:1!4:1) and preparative TLC
(200£100£0.25 mm3, 2 plates, benzene±EtOAc 6:1) to give
1710, 1650, 1620, 1460, 1380, 1270, 1090, 975 cm21; H
NMR (600 MHz, acetone-d6) d 7.19 (dd, Jˆ10.6, 15.4 Hz,
1H), 6.39 [6.39] (dd, Jˆ10.6, 14.7 Hz, 1H), 6.22 (m, 1H),
5.87 (d, Jˆ15.4 Hz, 1H), 5.60(ddd, Jˆ4.4, 9.7, 15.4 Hz,
1H), 5.44 (m, 1H), 5.15 (m, 1H), 5.09 (br dd, Jˆ9.2,
15.4 Hz, 1H), 4.84 [4.82] (m, 1H), 4.43 [4.44] (ddd, Jˆ
2.6, 8.4, 14.7 Hz, 1H), 4.05 (ddd, Jˆ3.7, 7.3, 14.7 Hz,
1H), 3.67 [3.68] (dd, Jˆ7.5, 7.5 Hz, 1H), 3.57 (ddd, Jˆ
2.2, 5.5, 9.2 Hz, 1H), 3.55±3.49 (m, 2H), 3.44 (dd, Jˆ6.0,
12.2 Hz, 1H), 3.38±3.33 (m, 2H), 3.31 [3.29] (s, 3H), 3.17
[3.17] (s, 3H), 3.12 [3.12] (s, 3H), 2.48±2.34 (m, 3H), 2.23
(m, 1H), 2.34 [2.35] (s, 6H), 1.99 (m, 2H), 1.76±1.55 (m,
5H), 1.49 (m, 1H), 1.39 (m, 1H), 1.31 (m, 1H), 1.18 (m, 1H),
1.01 (d, Jˆ7.0 Hz, 3H), 0.98 [0.99] (d, Jˆ6.6 Hz, 3H), 0.80
[0.79] (d, Jˆ7.0Hz, 3H). The minor counterparts of
doubled signals in the ratio of 1.1:1 are in brackets; MS
(FAB) m/z 630(M 1Na)1; HRMS (FAB) calcd for
C34H57NNaO8 630.3982, found 630.3981.
28
75 (6.0mg, 64% from 73) as a colorless oil: [a]D ˆ147 (c
0.25, CHCl3); IR (CHCl3) 1705, 1645, 1615, 1465, 1255,
1
1045, 970, 835 cm21; H NMR (400 MHz, CDCl3) d 7.20
(dd, Jˆ10.7, 15.4 Hz, 1H), 6.25 (dd, Jˆ10.7, 15.4 Hz, 1H),
6.15 (td, Jˆ6.8, 15.4 Hz, 1H), 5.79 (d, Jˆ15.4 Hz, 1H), 5.60
(td, Jˆ6.8, 15.6 Hz, 1H), 5.38 (td, Jˆ7.4, 15.6 Hz, 1H), 5.25
(dd, Jˆ8.8, 15.6 Hz, 1H), 5.16 (dd, Jˆ8.8, 15.6 Hz, 1H),
4.62 (d, Jˆ11.7 Hz, 1H), 4.58 (d, Jˆ11.7 Hz, 1H), 4.38 (td,
Jˆ6.8, 11.2 Hz, 1H), 4.17 (td, Jˆ11.2, 3.9 Hz, 1H), 3.68±
3.54 (m, 3H), 3.40(td, Jˆ9.0, 4.2 Hz, 1H), 3.24 (s, 3H), 3.23
(s, 3H), 2.45 (m, 2H), 2.34 (m, 2H), 2.17 (s, 3H), 1.97 (m,
2H), 1.82 (m, 1H), 1.68±1.07 (m, 8H), 0.92 (d, Jˆ6.8 Hz,
3H), 0.89 (s, 9H), 0.86 (d, Jˆ6.8 Hz, 3H), 0.83 (d, Jˆ
6.3 Hz, 3H), 0.05 (s, 3H), 0.04 (s, 3H); MS (FAB) m/z
675 (M1Na)1; HRMS (FAB) calcd for C36H64NaO6SSi
[(M1Na)1] 675.4091, found 675.4104.
3.1.66. Lactone 80. To an ice-cooled solution of diene 79
(11.5 mg, 7.56 mmol) in CH2Cl2 (0.4 mL) and MeOH
(0.8 mL) were added NiCl2´6H2O (3 mg, 13 mmol) and
NaBH4 (6.0mg, 0.16 mmol). After the mixture was stirred
at 08C for 15 min, acetone (0.2 mL) was added. The mixture
was stirred at room temperature for 10min, diluted with
saturated aqueous NH4Cl (1 mL) and H2O (1 mL), and
extracted with Et2O (3£10mL). The combined extracts
were washed with brine (2 mL), dried (Na2SO4), and
concentrated. The residue was puri®ed by preparative
3.1.63. Alcohol 76. The experimental procedure was similar
to that described for compound 30. 76 (91% yield): a
28
colorless oil; [a]D ˆ189 (c 0.22, CHCl3); IR (CHCl3)
3450 (br), 1730, 1645, 1615, 1465, 1250, 1045, 975,
1
840cm 21; H NMR (400 MHz, CDCl3) d 7.21 (dd, Jˆ
10.2, 15.4 Hz, 1H), 6.25 (dd, Jˆ10.2, 15.4 Hz, 1H), 6.18
(td, Jˆ7.0, 15.4 Hz, 1H), 5.77 (d, Jˆ15.4 Hz, 1H), 5.59
(td, Jˆ6.8, 15.6 Hz, 1H), 5.44 (ddd, Jˆ6.3, 8.3, 15.6 Hz,
1H), 5.28 (dd, Jˆ8.3, 15.6 Hz, 1H), 5.22 (dd, Jˆ8.3,
15.6 Hz, 1H), 4.34 (ddd, Jˆ5.4, 6.8, 11.2 Hz, 1H), 4.19
(td, Jˆ4.4, 11.2 Hz, 1H), 3.80(t, Jˆ2.7 Hz, 1H), 3.66 (m,
1H), 3.56 (td, Jˆ5.9, 8.3 Hz, 1H), 3.47 (td, Jˆ4.4, 8.3 Hz,
1H), 3.24 (s, 3H), 3.23 (s, 3H), 3.21 (br s, 1H), 2.44 (m, 2H),
2.34 (t, Jˆ5.9 Hz, 2H), 2.04 (ddd, Jˆ6.8, 6.8, 13.7 Hz, 1H),
1.94 (m, 1H), 1.74±1.36 (m, 8H), 1.07 (m, 1H), 0.95 (d,
Jˆ6.8 Hz, 3H), 0.91 (s, 9H), 0.88 (d, Jˆ6.8 Hz, 3H), 0.83
(d, Jˆ6.3 Hz, 3H), 0.10 (s, 3H), 0.08 (s, 3H); MS (FAB) m/z
615 (M1Na)1; HRMS (FAB) calcd for C34H60NaO6Si
[(M1Na)1] 615.4057, found 615.4046.
TLC on silica gel (200£200£0.25 mm3, benzene±Et2O
28
10:1) to give 80 (8.0mg, 69%) as a colorless oil: [ a]D
121 (c 0.43, CHCl3); IR (CHCl3) 1725, 1600, 1595, 1460,
ˆ
1375, 1250, 1170, 1035, 835 cm21; H NMR (400 MHz,
1
CDCl3) d 7.45±7.41 (m, 6H), 7.31±7.20(m, 9H), 6.89±
6.87 (m, 2H), 6.81 (d, Jˆ8.3 Hz, 1H), 5.55 (ddd, Jˆ3.8,
8.4, 15.1 Hz, 1H), 5.24±5.14 (m, 3H), 4.99 (dd, Jˆ2.0,
9.8 Hz, 1H), 4.77 (d, Jˆ7.1 Hz, 1H), 4.67 (d, Jˆ7.1 Hz,
1H), 4.61 (d, Jˆ11.7 Hz, 1H), 4.59 (d, Jˆ11.7 Hz, 1H),
4.55 (d, Jˆ11.7 Hz, 1H), 4.49 (d, Jˆ11.7 Hz, 1H), 3.88
(s, 3H), 3.86 (s, 3H), 3.59±3.38 (m, 6H), 3.23±3.18 (m,
1H), 3.21 (s, 3H), 3.16 (s, 3H), 2.99 (m, 1H), 2.47 (m,
1H), 2.32±2.20(m, 3H), 2.17 (s, 3H), 2.00(s, 3H), 2.20±
1.74 (m, 5H), 1.74±1.05 (m, 21H), 1.05±0.75 (m, 3H), 1.49
(s, 3H), 0.95 (d, Jˆ6.8 Hz, 6H), 0.91 (d, Jˆ6.8 Hz, 6H),
0.92 (s, 9H), 0.89 (s, 9H), 0.87 (d, Jˆ6.8 Hz, 3H), 0.82 (d,
Jˆ6.8 Hz, 3H), 0.70 (d, Jˆ6.8 Hz, 3H), 0.13 (s, 3H), 0.08
(s, 3H), 0.04 (s, 3H), 0.03 (s, 3H); MS (FAB) m/z 1545
(M1Na)1.
3.1.64. Trimethylserine ester 77. The experimental pro-
cedure was similar to that described for compound 31. 77
25
(95% yield, S/Rˆ1.1:1): a colorless oil; [a]D ˆ114 (c
0.081, MeOH); IR (CHCl3) 1710, 1645, 1460, 1260, 1095,
975, 835 cm21; 1H NMR (400 MHz, acetone-d6) d 7.19 (dd,
Jˆ10.7, 15.4 Hz, 1H), 6.39 [6.39] (dd, Jˆ10.7, 15.4 Hz,
1H), 6.22 (m, 1H), 5.85 (d, Jˆ15.4 Hz, 1H), 5.63 (td, Jˆ
7.3, 15.1 Hz, 1H), 5.46 (m, 1H), 5.18±5.13 (m, 2H), 4.90
(m, 1H), 4.36 (m, 1H), 4.11 (m, 1H), 3.71±3.66 (m, 2H),
3.62±3.55 (m, 2H), 3.46 (m, 1H), 3.38 (dd, Jˆ4.9, 7.8 Hz,
1H), 3.31 [3.30] (s, 3H), 3.18 (s, 3H), 3.15 (s, 3H), 2.59±
2.39 (m, 4H), 2.36 [2.35] (s, 6H), 2.08±1.17 (m, 11H), 0.97
(d, Jˆ7.3 Hz, 3H), 0.94 (d, Jˆ7.3 Hz, 3H), 0.91 (s, 9H),
0.83 (d, Jˆ6.8 Hz, 3H), 0.08 (s, 3H), 0.07 (s, 3H). The
minor counterparts of doubled signals in the ratio of
1.1:1 are in brackets; MS (FAB) m/z 744 (M1Na)1;
HRMS (FAB) calcd for C40H71NNaO8Si 744.4847, found
744.4828.
3.1.67. Alcohol 81. The experimental procedure was similar
to that described for compound 28. 81 (79% yield): a
26
colorless oil; [a]D ˆ120( c 0.25, CHCl3); IR (CHCl3)
3520 (br), 1725, 1600, 1460, 1375, 1255, 1180, 1155,
1
835 cm21; H NMR (400 MHz, acetone-d6) d 7.45±7.41
(m, 6H), 7.31±7.21 (m, 9H), 5.54 (ddd, Jˆ5.5, 9.3,
15.1 Hz, 1H), 5.24±5.14 (m, 3H), 4.78 (dd, Jˆ2.4, 9.8 Hz,
1H), 4.59 (d, Jˆ11.7 Hz, 1H), 4.55 (d, Jˆ11.7 Hz, 1H),
3.24±3.19 (m, 1H), 3.21 (s, 3H), 3.16 (s, 3H), 3.00 (td,
Jˆ8.9, 5.9 Hz, 1H), 2.62 (d, Jˆ3.9 Hz, 1H, ±OH), 2.47
(m, 1H), 2.36±2.20(m, 3H), 2.17 (s, 3H), 2.08 (s, 3H),
2.20±1.74 (m, 5H), 1.74±1.05 (m, 21H), 1.49 (s, 3H),
0.94 (d, Jˆ6.8 Hz, 6H), 1.20±0.84 (m, 33H), 0.82 (d, Jˆ
3.1.65. Analog 78. The experimental procedure was similar
to that described for compound 32. 78 (85% yield, S/Rˆ
27
1.1:1): a colorless oil; [a]D ˆ161 (c 0.054, MeOH); UV

1096
H. Kigoshi et al. / Tetrahedron 58 (2002) 1075±1102
6.8 Hz, 3H), 0.82 (d, Jˆ6.8 Hz, 3H), 0.73 (d, Jˆ6.8 Hz,
3H), 0.12±0.02 (m, 12H); MS (FAB) m/z 1365 (M1Na)1.
Jˆ6.8 Hz, 3H), 1.01 (d, Jˆ6.8 Hz, 3H), 0.97 (d, Jˆ
6.8 Hz, 3H), 0.95 (s, 9H), 0.95±0.91 (m, 3H), 0.91 (s,
9H), 0.88 (d, Jˆ6.8 Hz, 3H), 0.70 (d, Jˆ6.8 Hz, 3H), 0.09
(s, 3H), 0.08 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H). The minor
counterparts of doubled signals in the ratios of 3:1 (super-
script a) and 1.2:1 (superscript b) are in brackets.
3.1.68. Dimethylalanine ester 82. The experimental pro-
cedure was similar to that described for compound 29. 82
26
(98% yield, S/Rˆ3:1): a colorless oil; [a]D ˆ112 (c 0.25,
MeOH); IR (CHCl3) 1725, 1600, 1460, 1450, 1375, 1250,
1
1180, 1155, 835 cm21; H NMR (400 MHz, acetone-d6) d
3.1.71. Analog 85. The experimental procedure was similar
to that described for compound 32. 85 (85% yield, S/Rˆ
1.2:1 as to the trimethylserine part, S/Rˆ3:1 as to the
7.49±7.45 (m, 6H), 7.37±7.32 (m, 6H), 7.29±7.24 (m, 3H),
5.59 (ddd, Jˆ5.4, 8.3, 14.6 Hz, 1H), 5.34 (br t, Jˆ6.6 Hz,
1H), 5.27±5.17 (m, 2H), 4.95 (br t, Jˆ6.1 Hz, 1H), 4.80(dd,
Jˆ2.4, 10.5 Hz, 1H), 4.80 (dd, Jˆ2.4, 10.5 Hz, 1H), 4.64 (s,
2H), 3.72 (m, 1H), 3.59±3.50(m, 3H), 3.45 (dd, Jˆ5.4,
9.3 Hz, 1H), 3.29±3.21 (m, 1H), 3.19 (q, Jˆ66.8 Hz, 1H),
3.16 (s, 3H), 3.13 (s, 3H), 3.04 (td, Jˆ9.3, 5.9 Hz, 1H), 2.51
(m, 1H), 2.45±2.26 (m, 3H), 2.33 [2.31] (s, 6H), 2.17 (s,
3H), 1.98 [1.96] (s, 3H), 2.18±1.85 (m, 10H), 1.51 (s, 3H),
1.76±1.44 (m, 13H), 1.44±1.23 (m, 6H), 1.26 [1.21] (d,
Jˆ6.8 Hz, 3H), 1.05 (d, Jˆ6.8 Hz, 3H), 1.02 (d, Jˆ
6.8 Hz, 3H), 0.99 (d, Jˆ6.8 Hz, 3H), 0.96 (s, 9H), 0.94 (d,
Jˆ6.8 Hz, 3H), 0.92 (s, 9H), 0.89 (d, Jˆ6.8 Hz, 3H), 0.87
(d, Jˆ6.8 Hz, 3H), 0.71 (d, Jˆ6.8 Hz, 3H), 0.15 (s, 3H),
0.17 (s, 3H),0.14 (s, 3H), 0.11 (s, 3H), 0.10 (s, 3H). The
minor counterparts of doubled signals in the ratio of 3:1 are
in brackets; MS (FAB) m/z 1464 (M1Na)1.
26
dimethylalanine part): a colorless oil; [a]D ˆ116 (c
0.13, MeOH); IR (CHCl3) 3500 (br), 1725, 1460, 1375,
1
1240, 1090, 970 cm21; H NMR (400 MHz, acetone-d6) d
5.60(td, Jˆ6.8, 14.6 Hz, 1H), 5.43±5.35 (m, 2H), 5.23 (dd,
Jˆ7.3, 14.6 Hz, 1H), 4.97±4.82 (m, 2H), 4.79 (dd, Jˆ2.4,
9.8 Hz, 1H), 3.71±3.43 (m, 8H), 3.35 (m, 1H), 3.30[3.29] a
b
(s, 3H), 3.30[3.29] (s, 3H), 3.11 [3.11]b (s, 3H), 2.51 (m,
1H), 2.38±2.28 (m, 14H), 2.13±1.98 (m, 9H), 2.00 [2.01]a
(s, 3H), 1.98±1.47 (m, 15H), 1.53 [1.51]b (s, 3H), 1.41±1.10
(m, 10H), 1.01±0.85 (m, 21H). Signals of three protons (3£
OH) were not observed. The minor counterparts of doubled
signals in the ratios of 3:1 (superscript a), and 1.2:1 (super-
script b) are in brackets; MS (FAB) m/z 1063 (M1Na)1;
HRMS (FAB) calcd for C57H104N2NaO14 [(M1Na)1]
1063.7385, found 1063.7440.
3.1.69. Alcohol 83. The experimental procedure was similar
to that described for compound 30. 83 (95% yield, S/Rˆ
3.1.72. Diacetate 87. A mixture of diol 86 (5.5 mg,
9.3 mmol), DMAP (1.9 mg, 15 mmol), Ac2O (0.16 mL),
and pyridine (0.16 mL) was stirred at room temperature
for 3 h and concentrated in vacuo. The residue was puri®ed
by column chromatography on silica gel (0.5 g, hexane±
Et2O 4:1!3:1) to give 87 (6.7 mg, 100%) as a colorless
26
3:1): a colorless oil; [a]D ˆ15.7 (c 0.24, MeOH); IR
(CHCl3) 3345 (br), 1725, 1600, 1460, 1450, 1250,
1
840cm 21; H NMR (400 MHz, acetone-d6) d 7.48±7.44
(m, 6H), 7.35±7.31 (m, 6H), 7.28±7.23 (m, 3H), 5.57 (td,
Jˆ6.8, 15.6 Hz, 1H), 5.34 (t, Jˆ7.1 Hz, 1H), 5.27±5.18 (m,
2H), 4.93 (m, 1H), 4.78 (dd, Jˆ2.4, 9.8 Hz, 1H), 3.96 (t,
Jˆ3.4 Hz, 1H), 3.58±3.48 (m, 2H), 3.48±3.40(m, 2H), 3.31
(d, Jˆ4.9 Hz, 1H, ±OH), 3.27±3.14 (m, 2H), 3.17 (s, 3H),
3.10(s, 3H), 3.03 (td, Jˆ8.8, 5.4 Hz, 1H), 2.51±1.85 (m,
6H), 2.32 [2.30] (s, 6H), 1.96 [1.95] (s, 3H), 1.73±1.15 (m,
27H), 1.49 (s, 3H), 1.24 [1.19] (d, Jˆ7.3 Hz, 3H), 1.04 (d,
Jˆ6.8 Hz, 3H), 1.01 (d, Jˆ6.8 Hz, 3H), 0.98 (d, Jˆ6.8 Hz,
3H), 0.95 (s, 9H), 0.92 (d, Jˆ6.8 Hz, 3H), 0.91 (s, 9H), 0.88
(d, Jˆ6.8 Hz, 3H), 0.84 (d, Jˆ6.8 Hz, 3H), 0.70 (d, Jˆ
6.8 Hz, 3H), 0.15 (s, 3H), 0.13 (s, 3H), 0.09 (s, 3H), 0.08
(s, 3H). The minor counterparts of doubled signals in the
ratio of 3:1 are in brackets; MS (FAB) m/z 1404 (M1Na)1.
31
oil: [a]D ˆ17.8 (c 0.34, CHCl3); IR (CHCl3) 1725,
1460, 1370, 1255, 1095, 1080, 1025 cm21 1H NMR
;
(270MHz, CDCl 3) d 5.28 (ddd, Jˆ2.0, 6.9, 7.3 Hz, 1H),
4.91 (d, Jˆ4.6 Hz, 1H), 4.10±3.96 (m, 3H), 3.55 (dd, Jˆ2.6,
7.3 Hz, 1H), 3.35 (dd, Jˆ6.6, 9.6 Hz, 1H), 3.30(s, 3H), 2.23
(m, 1H), 2.08 (dd, Jˆ7.6, 12.9 Hz, 1H), 2.04 (s, 6H), 1.90±
1.36 (m, 10H), 1.09 (d, Jˆ6.6 Hz, 3H), 0.96 (t, Jˆ7.9 Hz,
18H), 0.93 (d, Jˆ6.9 Hz, 3H), 0.90 (d, Jˆ7.3 Hz, 3H), 0.81
(d, Jˆ6.9 Hz, 3H), 0.62 (q, Jˆ7.9 Hz, 6H), 0.60 (q, Jˆ
7.9 Hz, 6H); MS (FAB) m/z 697 (M1Na)1; HRMS (FAB)
calcd for C35H70NaO8Si2 [(M1Na)1] 697.4507, found
697.4512.
3.1.73. Tetraol 88. A solution of diacetate 87 (8.8 mg,
13 mmol) in DME (0.56 mL) and 1 M HCl (0.14 mL) was
stirred at room temperature for 3.5 h. The reaction mixture
was diluted with saturated aqueous NaHCO3 (2 mL) and
extracted with EtOAc (3£2 mL). The combined extracts
were washed with brine (1 mL), dried (Na2SO4), and con-
centrated. The residue was puri®ed by preparative TLC on
silica gel (200£100£0.25 mm3, 2 plates, hexane±acetone
3:2) to give a diastereomeric mixture of hemiacetals
(4.3 mg) as a colorless oil. The mixture was used in the
next experiment without puri®cation.
3.1.70. Trimethylserine ester 84. The experimental pro-
cedure was similar to that described for compound 31. 84
(83% yield, S/Rˆ1.2:1 as to the trimethylserine part, S/Rˆ
25
3:1 as to the dimethylalanine part): a colorless oil; [a]D
18.6 (c 0.19, MeOH); IR (CHCl3) 1730, 1700 (sh), 1655,
ˆ
1460, 1375, 1250, 1095, 970, 835 cm21; H NMR (400
1
MHz, acetone-d6) d 7.48±7.44 (m, 6H), 7.36±7.31 (m,
6H), 7.28±7.23 (m, 3H), 5.56 (m, 1H), 5.34 (t, Jˆ6.6 Hz,
1H), 5.26±5.18 (m, 2H), 4.93 (m, 1H), 4.83 (m, 1H), 4.78
(dd, Jˆ2.4, 10.2 Hz, 1H), 3.68 [3.68]b (dd, Jˆ7.3, 9.3 Hz,
1H), 3.64±3.49 (m, 4H), 3.46 (dd, Jˆ4.9, 10.2 Hz, 1H), 3.36
(ddd, Jˆ3.9, 5.4, 7.3 Hz, 1H), 3.31 [3.30]a (s, 3H), 3.28±
3.14 (m, 2H), 3.17 (s, 3H), 3.11 (s, 3H), 3.03 (td, Jˆ8.8,
To an ice-cooled solution of the mixture of hemiacetals
(1.4 mg) in EtOH (0.2 mL) was added NaBH4 (0.8 mg,
0.02 mmol). The mixture was stirred at 08C for 6 h, diluted
with saturated aqueous NH4Cl (1 mL), and extracted with
EtOAc (4£2 mL). The combined extracts were washed with
brine (1 mL), dried (Na2SO4), and concentrated. The residue
b
5.4 Hz, 1H), 2.50(m, 1H), 2.40±2.15 (m, 4H), 2.37 [2.36]
(s, 6H), 2.32 [2.30]a (s, 3H), 2.15±1.80(m, 10H), 1.96
[1.95]a (s, 3H), 1.80±1.42 (m, 13H), 1.51 (s, 3H), 1.42±
1.10(m, 11H), 1.24 [1.19] (d, Jˆ7.3 Hz, 3H), 1.04 (d,
b

H. Kigoshi et al. / Tetrahedron 58 (2002) 1075±1102
1097
was puri®ed by preparative TLC on silica gel (100£100£
0.25 mm3, 2 plates, hexane±acetone 1:1) to give 88 (1.1 mg,
i-Pr2NEt (0.34 mL, 0.20 mmol) and a 1 M solution of
DMBOM±Cl3d,16 in CH2Cl2 (0.52 mL, 0.52 mmol). After
the mixture was stirred at room temperature for 13 h,
MeOH (2 mL) and NaHCO3 (19 mg) were added. The
mixture was stirred at room temperature for 10h, diluted
with H2O (3 mL), and extracted with hexane (5£3 mL). The
combined extracts were washed successively with saturated
aqueous NaHCO3 (5 mL), H2O (5 mL), and brine (5 mL),
and then dried (Na2SO4) and concentrated. The residue was
puri®ed by column chromatography on alumina (5 g,
hexane±EtOAc 15:1!10:1!7:1) and preparative TLC on
silica gel (200£100£0.25 mm3, 4 plates, hexane±Et2O 1:1)
23
60% from 87) as a colorless oil: [a]D ˆ215.8 (c 0.091,
CHCl3); IR (CHCl3) 3380 (br), 1725, 1455, 1380, 1260,
1020 cm21 1H NMR (400 MHz, CDCl3) d 5.29 (br t,
;
Jˆ8.3 Hz, 1H), 4.75 (d, Jˆ4.9 Hz, 1H, ±OH), 4.60(br s,
1H, ±OH), 4.40(br s, 1H, ±OH), 4.23 (ddd, Jˆ5.9, 8.3,
11.2 Hz, 1H), 4.14 (ddd, Jˆ5.4, 5.4, 11.2 Hz, 1H), 4.04
(m, 1H), 3.71 (dt, Jˆ2.4, 10.2 Hz, 1H), 3.63 (d, Jˆ7.8 Hz,
1H, ±OH), 3.48 (m, 1H), 3.14 (m, 1H), 3.01 (dd, Jˆ2.4,
10.4 Hz, 1H), 2.12 (s, 3H), 2.06 (s, 3H), 2.08±1.95 (m, 2H),
1.90±1.47 (m, 9H), 1.07 (d, Jˆ7.3 Hz, 3H), 1.06 (d, Jˆ
6.8 Hz, 3H), 0.90 (m, 1H), 0.84 (d, Jˆ6.4 Hz, 3H), 0.82
(d, Jˆ6.4 Hz, 3H); MS (FAB) m/z 457 (M1Na)1; HRMS
(FAB) calcd for C22H42NaO8 [(M1Na)1] 457.2777, found
457.2765.
31
to give 91 (37.4 mg, 94%) as a colorless oil: [a]D ˆ17.7 (c
0.87, CHCl3); IR (CHCl3) 1595, 1515, 1465, 1265, 1240,
1
1215, 1095, 1030 cm21; H NMR (270MHz, CDCl 3) d
7.69±7.60(m, 4H), 7.45±7.33 (m, 6H), 6.91 (d, Jˆ
7.9 Hz, 1H), 6.90(s, 1H), 6.81 (d, Jˆ7.9 Hz, 1H), 4.87 (d,
Jˆ4.6 Hz, 1H), 4.82 (s, 2H), 4.61 (d, Jˆ11.2 Hz, 1H), 4.55
(d, Jˆ11.2 Hz, 1H), 4.03 (ddd, Jˆ0.7, 6.6, 6.6 Hz, 1H), 3.91
(m, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.60(t, Jˆ6.9 Hz, 2H),
3.59 (dd, Jˆ3.3, 6.9 Hz, 1H), 3.53 (dd, Jˆ2.0, 7.3 Hz, 1H),
3.22 (s, 3H), 2.25 (m, 1H), 2.09 (dd, Jˆ7.3, 12.5 Hz, 1H),
1.78±1.32 (m, 10H), 1.10 (d, Jˆ6.6 Hz, 3H), 1.04 (s, 9H),
0.93±0.85 (m, 6H), 0.90 (t, Jˆ7.6 Hz, 18H), 0.74 (d, Jˆ
6.9 Hz, 3H), 0.55 (q, Jˆ7.6 Hz, 6H), 0.53 (q, Jˆ7.6 Hz,
6H); MS (FAB) m/z 1031 (M1Na)1.
3.1.74. Analog 89. A solution of tetraol 88 (1.7 mg,
3.9 mmol) in a 0.23 M solution of NaOMe in MeOH
(0.07 mL, 16 mmol) was stirred at room temperature for
1
5 h. Amberlite IRC-50(H form, 20mg) was added, and
the mixture was stirred for 20min and then passed through a
column of Amberlite IRC-50(H 1 form, 100 mg). The resin
was washed with MeOH (10mL), and the eluate and wash-
ings were combined and concentrated. The residue was
puri®ed by preparative TLC on silica gel (130£100£
0.25 mm3, CH2Cl2±acetone±MeOH 4:4:1) to give 89
29
(1.5 mg, 100%) as a colorless oil: [a]D ˆ23.6 (c 0.13,
3.1.77. Diol 92. The experimental procedure was similar to
that described for compound 21. 92 (90% yield): a colorless
MeOH); IR (®lm) 3340, 2930, 1455, 1380, 1260,
1
30
1055 cm21; H NMR (400 MHz, acetone-d6) d 4.39 (d,
oil; [a]D ˆ17.5 (c 1.03, CHCl3); IR (CHCl3) 3470(br),
Jˆ5.2 Hz, 1H), 4.17 (m, 1H), 4.11 (d, Jˆ5.6 Hz, 1H),
4.09 (d, Jˆ3.6 Hz, 1H), 3.94 (m, 1H), 3.85 (d, Jˆ4.4 Hz,
1H), 3.78±3.63 (m, 5H), 3.56 (m, 1H), 3.34 (m, 2H), 2.05±
1.61 (m, 7H), 1.58±1.49 (m, 2H), 1.46±1.36 (m, 2H), 1.08
(m, 1H), 0.92 (d, Jˆ6.8 Hz, 3H), 0.91 (d, Jˆ6.8 Hz, 6H),
0.91 (d, Jˆ6.8 Hz, 3H); MS (FAB) m/z 373 (M1Na)1;
HRMS (FAB) calcd for C18H38NaO6 [(M1Na)1]
373.2566, found 373.2560.
1595, 1515, 1465, 1430, 1380, 1265, 1240, 1210, 1100,
1
1030 cm21; H NMR (400 MHz, CDCl3) d 7.67±7.65 (m,
4H), 7.46±7.38 (m, 6H), 6.94 (s, 1H), 6.92 (d, Jˆ8.3 Hz,
1H), 6.82 (d, Jˆ8.3 Hz, 1H), 4.89 (d, Jˆ4.4 Hz, 1H), 4.87
(d, Jˆ6.8 Hz, 1H), 4.84 (d, Jˆ6.8 Hz, 1H), 4.62 (d, Jˆ
11.2 Hz, 1H), 4.58 (d, Jˆ11.2 Hz, 1H), 4.20(m, 1H), 4.08
(m, 1H), 3.92±3.81 (m, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.81
(br s, 1H, ±OH), 3.57 (dd, Jˆ6.8, 9.8 Hz, 1H), 3.34 (m, 1H),
3.29 (s, 3H), 2.24 (m, 1H), 2.09 (dd, Jˆ7.2, 12.8 Hz, 1H),
1.91 (ddq, Jˆ9.6, 14.8, 4.8 Hz, 1H), 1.80(ddq, Jˆ2.0, 6.8,
6.8 Hz, 1H), 1.70±1.59 (m, 7H), 1.45 (m, 1H), 1.10 (d,
Jˆ6.8 Hz, 3H), 1.04 (s, 9H), 0.94 (d, Jˆ6.0Hz, 3H), 0.90
(d, Jˆ6.8 Hz, 3H), 0.89 (d, Jˆ6.8 Hz, 3H); MS (FAB) m/z
803 (M1Na)1.
3.1.75. TBDPS ether 90. A solution of diol 86 (23.3 mg,
39.5 mmol), TBDPSCl (0.015 mL, 58 mmol), and imidazole
(8.1 mg, 0.13 mmol) in DMF (0.2 mL) was stirred at room
temperature for 50min. After ice (2 g) and H 2O (1 mL)
were added, the mixture was stirred at room temperature
for 1 h and extracted with Et2O (3£3 mL). The combined
extracts were washed with brine (3 mL), dried (Na2SO4),
and concentrated. The residue was puri®ed by column
chromatography on silica gel (2 g, hexane±Et2O 4:1!2:1)
3.1.78. Silyl ether 93. To an ice-cooled solution of diol 92
(20.2 mg, 25.9 mmol) in CH2Cl2 were added 2,6-lutidine
(0.015 mL, 0.12 mmol) and t-BuMe2SiOTf (0.022 mL,
0.097 mmol). After the mixture was stirred at 08C for
1.5 h, 2,6-lutidine (0.015 mL, 0.12 mmol) and t-BuMe2-
SiOTf (0.022 mL, 0.097 mmol) were added. After the
mixture was stirred at 08C for 1 h, the reaction was
quenched by adding ice (3 g), and the mixture was extracted
with Et2O (3£3 mL). The combined extracts were washed
with brine (3 mL), dried (Na2SO4), and concentrated. The
residue was puri®ed by column chromatography on silica gel
(1.5 g, hexane±Et2O 5:1!3:1!1:1) to give 93 (26.2 mg,
31
to give 90 (33.0 mg, 100%) as a colorless oil: [a]D ˆ114.9
(c 1.67, CHCl3); IR (CHCl3) 3500 (br), 1460, 1425, 1415,
1
1380, 1235, 1215, 1110, 1080, 1025, 1010 cm21; H NMR
(270MHz, CDCl 3) d 7.69±7.65 (m, 4H), 7.42±7.33 (m,
6H), 4.91 (d, Jˆ5.0Hz, 1H), 3.94 (m, 1H), 3.84 (m, 1H),
3.64 (t, Jˆ6.9 Hz, 2H), 3.56 (dd, Jˆ6.9, 8.3 Hz, 1H), 3.55
(dd, Jˆ1.3, 7.9 Hz, 1H), 3.33 (s, 3H), 2.67 (m, 1H, ±OH),
2.24 (m, 1H), 2.08 (dd, Jˆ6.9, 12.9 Hz, 1H), 1.91±1.28 (m,
10H), 1.06 (d, Jˆ6.6 Hz, 3H), 1.05 (s, 9H), 1.04 (d,
Jˆ4.6 Hz, 3H), 0.95 (d, Jˆ7.3 Hz, 3H), 0.91 (t, Jˆ7.6 Hz,
18H), 0.78 (d, Jˆ7.3 Hz, 3H), 0.57 (q, Jˆ7.3 Hz, 6H), 0.54
(q, Jˆ7.3 Hz, 6H); MS (FAB) m/z 851 (M1Na)1.
31
100%) as a colorless oil: [a]D ˆ16.3 (c 1.41, CHCl3);
IR (CHCl3) 1595, 1515, 1465, 1425, 1380, 1360, 1255,
1215, 1155, 1140, 1095, 1080, 1030 cm21 1H NMR
;
(270MHz, CDCl 3) d 7.67±7.63 (m, 4H), 7.44±7.33 (m,
6H), 6.91 (d, Jˆ7.9 Hz, 1H), 6.89 (s, 1H), 6.82 (d, Jˆ
7.9 Hz, 1H), 4.88 (d, Jˆ4.6 Hz, 1H), 4.82 (s, 2H), 4.61 (d,
3.1.76. DMBOM ether 91. To a solution of TBDPS ether
90 (33.0mg, 39.5 mmol) in CH2Cl2 (0.34 mL) were added

1098
H. Kigoshi et al. / Tetrahedron 58 (2002) 1075±1102
Jˆ11.6 Hz, 1H), 4.55 (d, Jˆ11.6 Hz, 1H), 4.04 (ddd, Jˆ1.0,
6.3, 6.3 Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.85 (m, 1H),
3.66 (t, Jˆ6.9 Hz, 2H), 3.58 (dd, Jˆ6.6, 9.9 Hz, 1H), 3.52
(dd, Jˆ1.7, 6.9 Hz, 1H), 3.24 (s, 3H), 2.24 (m, 1H), 2.09
(dd, Jˆ7.6, 12.5 Hz, 1H), 1.86±1.71 (m, 2H), 1.66±1.39 (m,
8H), 1.10(d, Jˆ6.6 Hz, 3H), 1.04 (s, 9H), 0.93 (d, Jˆ
6.9 Hz, 3H), 0.87 (d, Jˆ7.3 Hz, 3H), 0.84 (s, 9H), 0.83 (s,
9H), 0.77 (d, Jˆ7.3 Hz, 3H), 0.01 (s, 3H), 0.00 (s, 3H),
20.01 (s, 3H), 20.02 (s, 3H); MS (FAB) m/z 1031
(M1Na)1.
Jˆ11.7 Hz, 1H), 3.88 (m, 1H), 3.87 (s, 3H), 3.86 (s, 3H),
3.66 (t, Jˆ6.8 Hz, 2H), 3.51 (dd, Jˆ2.4, 6.8 Hz, 1H), 3.39
(m, 1H), 3.20(m, 1H), 2.98 (ddd, Jˆ5.9, 8.8, 8.8 Hz, 1H),
1.96 (s, 3H), 2.36±1.40 (m, 12H), 1.04 (s, 9H), 0.95 (d,
Jˆ7.3 Hz, 3H), 0.94 (d, Jˆ6.8 Hz, 3H), 0.86 (s, 9H), 0.83
(s, 9H), 0.79 (d, Jˆ6.8 Hz, 3H), 0.69 (d, Jˆ6.8 Hz, 3H),
0.03 (s, 3H), 0.01 (s, 3H), 20.01 (s, 3H), 20.02 (s, 3H);
MS (FAB) m/z 1303 (M1Na)1.
3.1.82. Alcohol 97. A solution of acetate 96 (21.2 mg,
16.6 mmol) in HCOOH (0.08 mL) and Et2O (0.12 mL)
was stirred at room temperature for 30min. The mixture
was poured into ice-cooled saturated aqueous NaHCO3
(3 mL), and the aqueous mixture was extracted with Et2O
(5£3 mL). The combined extracts were washed with brine
(5 mL), dried (Na2SO4), and concentrated. The residue was
puri®ed by column chromatography on silica gel (1 g, hex-
3.1.79. Diol 94. The experimental procedure was similar to
that described for compound 88. 94 (72% yield): a colorless
30
oil; [a]D ˆ219.3 (c 0.995, CHCl3); IR (CHCl3) 3440(br),
1595, 1520, 1460, 1425, 1395, 1360, 1260, 1215, 1160,
;
1140, 1110, 1080, 1030 cm21 1H NMR (270MHz,
CDCl3) d 7.67±7.63 (m, 4H), 7.44±7.33 (m, 6H), 6.88±
6.80(m, 3H), 4.80(d, Jˆ6.9 Hz, 1H), 4.75 (d, Jˆ6.9 Hz,
1H), 4.64 (d, Jˆ11.9 Hz, 1H), 4.50(d, Jˆ11.9 Hz, 1H), 3.88
(s, 3H), 3.87 (s, 3H), 3.88±3.87 (m, 2H), 3.74±3.53 (m, 4H),
3.66 (t, Jˆ6.9 Hz, 2H), 3.52 (dd, Jˆ1.3, 5.9 Hz, 1H), 3.45
(dd, Jˆ4.0, 8.3 Hz, 1H), 1.96±1.26 (m, 12H), 1.04 (s, 9H),
0.99 (d, Jˆ6.9 Hz, 3H), 0.92 (d, Jˆ6.9 Hz, 3H), 0.90 (s,
9H), 0.87 (d, Jˆ7.3 Hz, 3H), 0.84 (s, 9H), 0.83 (s, 9H),
0.80 (d, Jˆ7.3 Hz, 3H), 0.01 (s, 6H), 20.01 (s, 3H),
20.02 (s, 3H); MS (FAB) m/z 1019 (M1Na)1.
ane±Et2O 3:1!2:1!1:1!1:3) to give 97 (11.8 mg, 68%)
30
as a colorless oil, along with 96 (1.7 mg, 8%). 97: [a]D
13.7 (c 0.82, CHCl3); IR (CHCl3) 3500 (br), 1725, 1595,
ˆ
1520, 1465, 1430, 1385, 1255, 1215, 1160, 1140, 1110,
1
1030 cm21; H NMR (270MHz, CDCl 3) d 7.68±7.63 (m,
4H), 7.44±7.33 (m, 6H), 6.87 (d, Jˆ8.6 Hz, 1H), 6.86 (s,
1H), 6.81 (d, Jˆ8.6 Hz, 1H), 4.98 (dd, Jˆ2.6, 9.6 Hz, 1H),
4.75 (d, Jˆ6.9 Hz, 1H), 4.66 (d, Jˆ6.9 Hz, 1H), 4.59 (d,
Jˆ11.9 Hz, 1H), 4.50(d, Jˆ11.9 Hz, 1H), 3.90±3.86 (m,
2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.80±3.59 (m, 2H), 3.66 (t,
Jˆ6.9 Hz, 2H), 3.50(dd, Jˆ2.6, 6.6 Hz, 1H), 3.49 (m, 1H),
2.01 (s, 1H), 2.03±1.34 (m, 12H), 1.04 (s, 9H), 0.92 (d,
Jˆ6.9 Hz, 3H), 0.90 (d, Jˆ6.9 Hz, 3H), 0.85 (s, 9H), 0.84
(d, Jˆ6.9 Hz, 3H), 0.83 (s, 9H), 0.79 (d, Jˆ6.9 Hz, 3H),
0.02 (s, 3H), 0.01 (s, 3H), 20.02 (s, 6H); MS (FAB) m/z
1061 (M1Na)1.
3.1.80. Trityl ether 95. A solution of diol 94 (16.0mg,
16.1 mmol) and TrCl (18 mg, 64 mmol) in pyridine
(0.17 mL) was stirred at 508C for 13.5 h. The mixture was
diluted with saturated aqueous NaHCO3 (1 mL), stirred at
room temperature for 1.5 h, and extracted with Et2O
(3£2 mL). The combined extracts were washed with brine
(2 mL), dried (Na2SO4), and concentrated. The residue was
puri®ed by column chromatography on silica gel (1.5 g,
hexane±Et2O 5:1!3:1!1:1) to give 95 (18.6 mg, 93%)
3.1.83. Aldehyde 98. To a solution of alcohol 97 (6.2 mg,
6.0 mmol) in CH2Cl2 (0.14 mL) were added pyridine
(0.014 mL, 0.17 mmol) and the Dess±Martin periodinane,
C6H4(COO)I(OAc)3 (6.9 mg, 16 mmol). After the mixture
was stirred at room temperature for 40min, saturated
aqueous NaHCO3 (1 mL) and saturated aqueous Na2S2O3
(1 mL) were added. The aqueous mixture was stirred at
room temperature for 20min and extracted with Et 2O
(3£3 mL). The combined extracts were washed with brine
(3 mL), dried (Na2SO4), and concentrated. The residue was
puri®ed by column chromatography on silica gel (0.3 g,
hexane±EtOAc 5:1!3:1!1:1) to give 98 (5.5 mg, 89%)
30
as a colorless oil: [a]D ˆ23.3 (c 0.36, CHCl3); IR
(CHCl3) 3490 (br), 1595, 1520, 1460, 1450, 1425, 1385,
1360, 1260, 1220, 1210, 1155, 1140, 1110, 1075, 1025,
1
1005 cm21; H NMR (270MHz, CDCl 3) d 7.67±7.63 (m,
4H), 7.46±7.18 (m, 21H), 6.88±6.78 (m, 3H), 4.80(d, Jˆ
6.9 Hz, 1H), 4.74 (d, Jˆ6.9 Hz, 1H), 4.64 (d, Jˆ11.5 Hz,
1H), 4.49 (d, Jˆ11.5 Hz, 1H), 3.91±3.85 (m, 2H), 3.86 (s,
3H), 3.85 (s, 3H), 3.67 (t, Jˆ6.9 Hz, 2H), 3.54 (dd, Jˆ1.7,
6.3 Hz, 1H), 3.44 (m, 1H), 3.44 (br s, 1H, ±OH), 3.24 (m,
1H), 3.00 (m, 1H), 1.90±1.41 (m, 12H), 1.05 (s, 9H), 0.94
(d, Jˆ6.9 Hz, 3H), 0.89 (d, Jˆ6.9 Hz, 3H), 0.84 (s, 9H),
0.83 (d, Jˆ7.3 Hz, 3H), 0.83 (s, 9H), 0.80 (d, Jˆ7.3 Hz,
3H), 0.02 (s, 3H), 0.01 (s, 3H), 0.00 (s, 3H), 20.01 (s,
3H); MS (FAB) m/z 1261 (M1Na)1.
29
as a colorless oil: [a]D ˆ14.3 (c 0.45, CHCl3); IR
(CHCl3) 1725, 1595, 1515, 1460, 1430, 1385, 1250, 1220,
1
1160, 1140, 1110, 1075, 1030 cm21; H NMR (270MHz,
CDCl3) d 9.75 (m, 1H), 7.67±7.63 (m, 4H), 7.43±7.33 (m,
6H), 6.87 (d, Jˆ8.6 Hz, 1H), 6.86 (s, 1H), 6.81 (d,
Jˆ8.6 Hz, 1H), 5.00 (dd, Jˆ3.0, 9.2 Hz, 1H), 4.75 (d, Jˆ
6.9 Hz, 1H), 4.66 (d, Jˆ6.9 Hz, 1H), 4.60(d, Jˆ11.6 Hz,
1H), 4.49 (d, Jˆ11.6 Hz, 1H), 3.87 (m, 1H), 3.87 (s, 3H),
3.86 (s, 3H), 3.66 (t, Jˆ6.9 Hz, 2H), 3.50(dd, Jˆ2.0,
6.3 Hz, 1H), 3.44 (ddd, Jˆ0.8, 7.3, 7.3 Hz, 1H), 2.47±
2.42 (m, 2H), 2.28 (ddd, Jˆ2.3, 9.6, 16.8 Hz, 1H), 2.01 (s,
3H), 1.88±1.40 (m, 9H), 1.04 (s, 9H), 0.96 (d, Jˆ6.6 Hz,
3H), 0.92 (d, Jˆ6.6 Hz, 3H), 0.89 (d, Jˆ6.6 Hz, 3H), 0.85
(s, 9H), 0.83 (s, 9H), 0.79 (d, Jˆ6.9 Hz, 3H), 0.02 (s, 3H),
0.01 (s, 3H),20.01 (s, 6H); MS (FAB) m/z 1059 (M1Na)1.
3.1.81. Acetate 96. A solution of trityl ether 95 (18.6 mg,
15.0 mmol) and DMAP (0.9 mg, 7 mmol) in Ac2O
(0.13 mL) and pyridine (0.26 mL) was stirred at room
temperature for 22 h. The mixture was concentrated in
vacuo and puri®ed by column chromatography on silica
gel (1 g, hexane±Et2O 4:1!2:1) to give 96 (16.7 mg,
30
87%) as a colorless oil: [a]D ˆ15.5 (c 1.0, CHCl3); IR
(CHCl3) 1725, 1595, 1520, 1460, 1385, 1255, 1215, 1160,
1140, 1110, 1070, 1030 cm21; 1H NMR (400 MHz, CDCl3)
d 7.66±7.63 (m, 4H), 7.45±7.20(m, 21H), 6.89±6.79 (m,
3H), 4.98 (dd, Jˆ2.4, 9.8 Hz, 1H), 4.76 (d, Jˆ7.3 Hz, 1H),
4.67 (d, Jˆ7.3 Hz, 1H), 4.61 (d, Jˆ11.7 Hz, 1H), 4.49 (d,
3.1.84. Enamide 99. A solution of aldehyde 98 (4.4 mg,

H. Kigoshi et al. / Tetrahedron 58 (2002) 1075±1102
1099
4.2 mmol), N-methylformamide (0.06 mL, 1.0 mmol),
pyridinium p-toluenesulfonate (2.1 mg, 8.4 mmol), and
hydroquinone (0.9 mg, 8 mmol) in benzene (3.2 mL) was
re¯uxed for 18 h with the continuous removal of water by
(superscript b) are in brackets; MS (FAB) m/z 1018
(M1Na)1.
3.1.87. Analog 102. The experimental procedure was
similar to that described for compound 32. 102 (82%
Ê
use of molecular sieves 3 A. Triethylamine (0.06 mL) and
32
saturated aqueous NaHCO3 (3 mL) were added, and the
aqueous mixture was extracted with Et2O (3£3 mL). The
combined extracts were washed with brine (3 mL), dried
(Na2SO4), and concentrated. The residue was puri®ed by
preparative TLC on silica gel (200£100£0.25 mm3,
hexane±EtOAc 3:2) and by column chromatography on
silica gel (0.3 g, hexane±EtOAc 5:1!3:1!1:1) to give 99
yield, S/Rˆ3:1): a colorless oil; [a]D ˆ227.3 (c 0.038,
CHCl3); IR (®lm) 3400 (br), 3320, 1730, 1690, 1655,
1620, 1580, 1540, 1455, 1435, 1375, 1310, 1235, 1175,
1
1090, 1070, 1045 cm21; H NMR (400 MHz, acetone-d6)
d 8.34 [8.08]a (s, 1H), 6.82 [7.13]a (d, Jˆ14.2 Hz, 1H),
5.18±5.00 (m, 2H), 4.78 [4.79]b (dd, Jˆ2.4, 10.3 Hz, 1H),
4.36 (br s, 1H, ±OH), 4.16 (dd, Jˆ1.0, 9.3 Hz, 1H), 4.11 (br
s, 1H, ±OH), 4.08 (t, Jˆ6.8 Hz, 2H), 3.29 (m, 1H), 3.17 (m,
1H), 2.94 [3.06]a (s, 3H), 2.62 (m, 1H), 2.31 [2.50]a [2.31]b
(s, 6H), 1.76±1.49 (m, 10H), 1.23 [1.24]b (d, Jˆ7.3 Hz, 3H),
0.98 [0.99]b (d, Jˆ7.3 Hz, 6H), 0.89 [0.90]b (d, Jˆ6.8 Hz,
6H). Signals of three protons (CH3COO) were overlapped
with the solvent signals. The minor counterparts of doubled
signals in the ratios of 2:1 (superscript a), and 3:1 (super-
script b) are in brackets; MS (FAB) m/z 553 (M1Na)1;
HRMS (FAB) calcd for C27H50N2NaO8 [(M1Na)1]
553.3465, found 553.3440.
30
(2.3 mg, 51%) as a colorless oil: [a]D ˆ210.9 (c 0.237,
CHCl3); IR (CHCl3) 1725, 1690, 1655, 1595, 1515, 1460,
1430, 1375, 1255, 1220, 1160, 1140, 1110, 1080,
1
1030 cm21; H NMR (400 MHz, CDCl3) d 8.26 [8.03] (s,
1H), 7.66±7.63 (m, 4H), 7.43±7.34 (m, 6H), 7.00±6.80 (m,
3H), 6.47 [7.16] (d, Jˆ14.0Hz, 1H), 5.05±4.98 (m, 2H),
4.75 [4.74] (d, Jˆ6.8 Hz, 1H), 4.64 (d, Jˆ6.8 Hz, 1H), 4.59
(d, Jˆ11.6 Hz, 1H), 4.49 [4.48] (d, Jˆ11.6 Hz, 1H), 3.87 (s,
3H), 3.86 (s, 3H), 3.86 (m, 1H), 3.65 (t, Jˆ6.8 Hz, 2H), 3.49
(dd, Jˆ2.4, 6.4 Hz, 1H), 3.45 (m, 1H), 2.97 (s, 3H), 2.54 (m,
1H), 2.04 (s, 3H), 1.85±1.25 (m, 9H), 1.05±1.01 (m, 3H),
1.04 (s, 9H), 0.91 (d, Jˆ6.8 Hz, 3H), 0.87 (d, Jˆ6.8 Hz,
3H), 0.82 (s, 18H), 0.78 (d, Jˆ6.8 Hz, 3H), 0.00 [20.01]
(s, 6H), 20.02 (s, 6H). The minor counterparts of doubled
signals in the ratio of 2:1 due to the rotamers are in brackets;
MS (FAB) m/z 1100 (M1Na)1.
3.1.88. Sulfone 103. A solution of sulfone 16 (108 mg,
0.126 mmol) in DME (8 mL) and 1 M HCl (2 mL) was
stirred at room temperature for 4 h. The mixture was poured
into ice-cooled saturated aqueous NaHCO3 (6 mL), and the
aqueous mixture was extracted with Et2O (3£10mL). The
combined extracts were washed with brine (10mL), dried
(Na2SO4), and concentrated. The residue was puri®ed by
column chromatography on silica gel (6 g, hexane±acetone
2:1!1:1!1:2) to give a diastereomeric mixture of hemi-
acetals (75.3 mg).
3.1.85. Alcohol 100. The experimental procedure was
similar to that described for compound 28. 100 (86%
30
yield): a colorless oil; [a]D ˆ222.0( c 0.102, CHCl3); IR
(CHCl3) 3500 (br), 1715, 1695, 1655, 1470, 1460, 1425,
1390, 1370, 1255, 1215, 1110, 1080 cm21 1H NMR
;
(270MHz, CDCl 3) d 8.29 [8.06] (s, 1H), 7.67±7.63 (m,
4H), 7.44±7.33 (m, 6H), 6.57 [7.18] (d, Jˆ14.2 Hz, 1H),
5.01 [5.03] (dd, Jˆ9.6, 14.2 Hz, 1H), 4.84 (dd, Jˆ2.6,
9.6 Hz, 1H), 3.88 (m, 1H), 3.65 (t, Jˆ6.9 Hz, 2H), 3.51
(dd, Jˆ2.0, 6.9 Hz, 1H), 3.44 (m, 1H), 3.01 [3.03] (s, 3H),
2.58 (m, 1H), 2.48 (m, 1H, ±OH), 2.13 [2.12] (s, 3H), 1.85±
1.38 (m, 9H), 1.05 (d, Jˆ6.6 Hz, 3H), 1.04 (s, 9H), 0.90 (d,
Jˆ6.6 Hz, 3H), 0.85 (d, Jˆ6.6 Hz, 3H), 0.83 (s, 18H), 0.78
(d, Jˆ6.9 Hz, 3H), 0.01 (s, 3H), 0.00 (s, 3H), 20.02 (s, 6H).
The minor counterparts of doubled signals in the ratio of 2:1
due to the rotamers are in brackets; MS (FAB) m/z 920
(M1Na)1.
A solution of the hemiacetals (75.3 mg) and NaBH4
(9.7 mg, 0.26 mmol) in EtOH (2 mL) was stirred at room
temperature for 45 min. Sodium borohydride (10.5 mg,
0.28 mmol) was added, and the reaction mixture was stirred
for 45 min. Furthermore, NaBH4 (6.5 mg, 0.17 mmol) was
added, and the reaction mixture was stirred for 45 min. The
mixture was diluted with saturated NH4Cl (5 mL) and
extracted with EtOAc (3£10mL). The combined extracts
were washed with brine (2 mL), dried (Na2SO4), and
concentrated. The residue was puri®ed by column chroma-
tography on silica gel (6 g, CH2Cl2±acetone 4:1!
acetone!MeOH) to give a tetraol (80.5 mg).
3.1.86. Dimethylalanine ester 101. The experimental
procedure was similar to that described for compound 29.
101 (76% yield, S/Rˆ3:1): a colorless oil; [a]D ˆ213.4 (c
A solution of the tetraol (76.5 mg) in 1,4-dioxane (4.5 mL)
and 2 M HCl (1.5 mL) was stirred at 508C for 2 h. The
mixture was poured into ice-cooled saturated aqueous
NaHCO3 (6 mL), and the aqueous mixture was extracted
with EtOAc (3£10mL). The combined extracts were
washed with brine (3 mL), dried (Na2SO4), and concen-
trated. The residue was puri®ed by column chromatography
on silica gel (6 g, CHCl3±MeOH 20:1!15:1!10:1) to give
a pentaol (33.0mg).
29
0.118, CHCl3); IR (CHCl3) 1730, 1690, 1655, 1470, 1460,
1250, 1215, 1110, 1080 cm21; 1H NMR (400 MHz, CDCl3)
d 8.27 [8.03]a (s, 1H), 7.66±7.63 (m, 4H), 7.44±7.35 (m,
6H), 6.48 [7.16]a (d, Jˆ14.2 Hz, 1H), 5.01±4.93 (m, 2H),
4.78 (dd, Jˆ3.4, 9.8 Hz, 1H), 3.87 (m, 1H), 3.64 (t, Jˆ
6.8 Hz, 2H), 3.49 (m, 1H), 3.22 (m, 1H), 2.99 [3.00]b (s,
3H), 2.55 (m, 1H), 2.37 [2.34]b (s, 6H), 2.07 [2.06]a (s, 3H),
1.85±1.25 (m, 13H), 1.04 (s, 9H), 1.02 [1.01]b (d, Jˆ6.8 Hz,
3H), 0.93 [0.92]b (d, Jˆ7.3 Hz, 3H), 0.91 [0.89]b (d, Jˆ
7.3 Hz, 3H), 0.83 (s, 9H), 0.82 (s, 9H), 0.76 (d, Jˆ6.8 Hz,
3H), 0.00 (s, 3H), 20.01 [0.00]a (s, 3H), 20.02 (s, 3H),
20.03 [20.02]a (s, 3H). The minor counterparts of
doubled signals in the ratios of 2:1 (superscript a), and 3:1
A solution of the pentaol (31.5 mg), DMAP (2.8 mg,
0.023 mmol), Et3N (0.012 mL, 0.086 mmol), and t-BuMe2-
SiCl (11.1 mg, 0.074 mmol) in CH2Cl2 (0.5 mL) was stirred
at room temperature for 1 h. DMAP (6.8 mg, 0.056 mmol)
and t-BuMe2SiCl (6.2 mg, 0.041 mmol), and Et3N (0.005
mL, 0.036 mmol) were added to the reaction mixture, and

1100
H. Kigoshi et al. / Tetrahedron 58 (2002) 1075±1102
the mixture was stirred at room temperature for 2 h. Further-
more, t-BuMe2SiCl (6.4 mg, 0.042 mmol) and Et3N (0.005
mL, 0.036 mmol) were added, and the mixture was stirred at
room temperature for 30min, diluted with ice water (1 g),
and extracted with EtOAc (3£5 mL). The combined extracts
were washed successively with 1 M HCl (2 mL), saturated
aqueous NaHCO3 (2 mL), and brine (2 mL), and then dried
(Na2SO4) and concentrated. The residue was puri®ed by
column chromatography on silica gel (5 g, CH2Cl2±acetone
4:1!1:1) to give 103 (34.5 mg, 51% from 16) as a colorless
0.05 (s, 3H), 0.04 (s, 6H); MS (FAB) m/z 1569 (M1Na)1.
29
cis-Isomer (7% yield): a colorless oil; [a]D ˆ123 (c 0.24,
CHCl3); IR (CHCl3) 1720, 1460, 1380, 1285, 1255, 1160,
1
1090, 1050, 1035, 970, 835 cm21; H NMR (400 MHz,
CDCl3) d 5.55 (ddd, Jˆ6.8, 6.8, 10.7 Hz, 1H), 5.34 (dd,
Jˆ6.8, 6.8 Hz, 1H), 5.24 (dd, Jˆ9.8, 10.7 Hz, 1H), 4.64
(d, Jˆ11.2 Hz, 1H), 4.58 (d, Jˆ11.2 Hz, 1H), 4.21±4.08
(m, 2H), 4.04±3.95 (m, 2H), 3.85 (m, 1H), 3.71±3.52 (m,
5H), 3.49 (dd, Jˆ3.9, 3.9 Hz, 1H), 3.37 (dd, Jˆ6.8, 6.8 Hz,
1H), 3.26 (s, 3H), 3.15 (s, 3H), 2.44±2.26 (m, 3H), 2.17 (m,
1H), 2.16 (s, 3H), 1.96 (m, 1H), 1.86±1.16 (m, 20H), 1.50 (s,
3H), 1.20 (s, 9H), 0.99±0.87 (m, 15H), 0.97 (t, Jˆ7.8 Hz,
9H), 0.95 (t, Jˆ7.8 Hz, 18H), 0.94 (t, Jˆ7.8 Hz, 9H), 0.89
(s, 18H), 0.80 (d, Jˆ6.8 Hz, 3H), 0.77 (d, Jˆ7.3 Hz, 3H),
0.65±0.55 (m, 24H), 0.05 (s, 3H), 0.04 (s, 9H); MS (FAB)
m/z 1569 (M1Na)1.
30
oil: [a]D ˆ212.7 (c 1.11, CHCl3); IR (CHCl3) 3495±3100,
1460, 1380, 1255, 1150, 1085, 1030, 975, 840 cm21; H
1
NMR (400 MHz, CDCl3) d 7.92 (dd, Jˆ1.5, 6.8 Hz, 2H),
7.66 (tt, Jˆ1.5, 7.3 Hz, 1H), 7.57 (dd, Jˆ6.8, 7.3 Hz, 2H),
4.47 (d, Jˆ3.9 Hz, 1H, ±OH), 3.99 (br d, Jˆ1.5 Hz, 1H,
±OH), 3.94±3.86 (m, 2H), 3.78 (ddd, Jˆ3.4, 7.3, 10.7 Hz,
1H), 3.65 (ddd, Jˆ3.4, 7.3, 10.7 Hz, 1H), 3.64 (d, Jˆ3.9 Hz,
1H, ±OH), 3.40(ddd, Jˆ4.9, 10.7, 14.2 Hz, 1H), 3.44±3.33
(m, 2H), 3.14 (ddd, Jˆ4.9, 10.7, 14.2 Hz, 1H), 3.08 (d, Jˆ
4.4 Hz, 1H, ±OH), 2.01±1.87 (m, 2H), 1.83±1.57 (m, 7H),
1.54±1.41 (m, 2H), 1.16 (m, 1H), 0.97 (d, Jˆ6.8 Hz, 3H),
0.93 (d, Jˆ7.3 Hz, 3H), 0.92±0.90 (m, 3H), 0.90 (s, 9H),
0.88 (d, Jˆ6.8 Hz, 3H), 0.08 (s, 6H); MS (FAB) m/z 611
(M1Na)1.
3.1.91. Alcohol 106. The experimental procedure was
similar to that described for compound 18. 106 (100%
29
yield): a colorless oil; [a]D ˆ129.6 (c 1.04, CHCl3); IR
(CHCl3) 3480 (br), 1595, 1515, 1465, 1380, 1260, 1095,
1
1030, 970, 835 cm21; H NMR (400 MHz, CDCl3) d 5.53
(ddd, Jˆ7.3, 7.3, 15.1 Hz, 1H), 5.34 (dd, Jˆ7.3, 7.3 Hz,
1H), 5.23 (dd, Jˆ8.3, 15.1 Hz, 1H), 4.70(d, Jˆ11.7 Hz,
1H), 4.59 (d, Jˆ11.7 Hz, 1H), 3.97 (m, 1H), 3.87 (m, 1H),
3.82±3.65 (m, 4H), 3.60±3.51 (m, 4H), 3.49 (dd, Jˆ3.4,
4.9 Hz, 1H), 3.38 (dd, Jˆ6.8, 6.8 Hz, 1H), 3.22 (s, 3H),
3.16 (s, 3H), 2.50(br s, 1H, ±OH), 2.31 (m, 2H), 2.21 (s,
3H), 2.14 (m, 1H), 1.98 (m, 1H), 1.88±1.21 (m, 21H), 1.50
(s, 3H), 0.99±0.87 (m, 15H), 0.97 (t, Jˆ7.8 Hz, 9H), 0.96 (t,
Jˆ7.8 Hz, 18H), 0.94 (t, Jˆ7.8 Hz, 9H), 0.89 (s, 9H), 0.89
(s, 9H), 0.80 (d, Jˆ6.8 Hz, 3H), 0.76 (d, Jˆ6.8 Hz, 3H),
0.65±0.58 (m, 24H), 0.05 (s, 3H), 0.04 (s, 9H); MS (FAB)
m/z 1485 (M1Na)1.
3.1.89. TES ether 104. A solution of sulfone 103 (34.5 mg,
0.059 mmol), imidazole (65 mg, 0.96 mmol), and Et3SiCl
(0.080 mL, 0.48 mmol) in DMF (0.5 mL) was stirred at
room temperature for 30min and at 40 8C for 75 min. The
mixture was diluted with ice water (2 g) and extracted with
Et2O (3£5 mL). The combined extracts were washed with
brine (2 mL), dried (Na2SO4), and concentrated. The residue
was puri®ed by column chromatography on silica gel (5 g,
hexane±Et2O 15:1!10:1) to give 104 (54.2 mg, 88%) as a
31
colorless oil: [a]D ˆ20.74 (c 0.41, CHCl3); IR (CHCl3)
1460, 1415, 1380, 1310, 1240, 1145, 1085, 1010, 970,
3.1.92. Aldehyde 107. The experimental procedure was
similar to that described for compound 19. 107 (89%
1
835 cm21; H NMR (400 MHz, CDCl3) d 7.91±7.89 (m,
26
2H), 7.66 (m, 1H), 7.59±7.55 (m, 2H), 3.86±3.78 (m,
2H), 3.68 (ddd, Jˆ4.4, 7.3, 10.3 Hz, 1H), 3.60±3.54 (m,
2H), 3.42 (dd, Jˆ2.4, 6.8 Hz, 1H), 3.12 (ddd, Jˆ5.9, 11.7,
13.7 Hz, 1H), 3.02 (ddd, Jˆ5.9, 10.7, 13.7 Hz, 1H), 1.94±
1.24 (m, 12H), 0.95 (t, Jˆ7.8 Hz, 18H), 0.93 (t, Jˆ7.8 Hz,
9H), 0.93±0.89 (m, 3H), 0.90 (t, Jˆ7.8 Hz, 9H), 0.89 (s,
9H), 0.84 (d, Jˆ6.8 Hz, 3H), 0.77 (d, Jˆ6.8 Hz, 3H), 0.76
(d, Jˆ6.8 Hz, 3H), 0.68±0.49 (m, 24H), 0.04 (s, 6H); MS
(FAB) m/z 1067 (M1Na)1.
yield): a colorless oil; [a]D ˆ113.3 (c 1.03, CHCl3); IR
(CHCl3) 2730, 1720, 1460, 1380, 1360, 1285, 1255, 1165,
1095, 1045, 835 cm21; 1H NMR (400 MHz, CDCl3) d 9.82
(dd, Jˆ2.0, 2.4 Hz, 1H), 5.53 (ddd, Jˆ7.3, 7.3, 15.1 Hz,
1H), 5.34 (dd, Jˆ6.8, 6.8 Hz, 1H), 5.23 (dd, Jˆ8.3,
15.1 Hz, 1H), 4.67 (d, Jˆ11.7 Hz, 1H), 4.60(d, Jˆ
11.7 Hz, 1H), 4.06 (ddd, Jˆ3.9, 5.9, 7.3 Hz, 1H), 3.97
(ddd, Jˆ2.4, 4.9, 7.3 Hz, 1H), 3.87 (m, 1H), 3.68 (ddd,
Jˆ4.4, 7.3, 9.8 Hz, 1H), 3.60±3.50 (m, 5H), 3.38 (dd, Jˆ
6.8, 6.8 Hz, 1H), 3.22 (s, 3H), 3.16 (s, 3H), 2.59 (ddd,
Jˆ2.4, 7.3, 16.6 Hz, 1H), 2.53 (ddd, Jˆ2.0, 3.9, 16.6 Hz,
1H), 2.31 (m, 2H), 2.14 (s, 3H), 2.14 (m, 1H), 2.00 (m, 1H),
1.86±1.21 (m, 20H), 1.50 (s, 3H), 0.99±0.76 (m, 12H), 0.97
(t, Jˆ7.8 Hz, 9H), 0.96 (t, Jˆ7.8 Hz, 19H), 0.94 (t, Jˆ
7.8 Hz, 9H), 0.89 (s, 9H), 0.89 (s, 9H), 0.88 (d, Jˆ7.3 Hz,
3H), 0.80 (d, Jˆ6.8 Hz, 3H), 0.76 (d, Jˆ6.8 Hz, 3H), 0.65±
0.56 (m, 24H), 0.07 (br s, 3H), 0.05 (s, 3H), 0.04 (s, 6H); MS
(FAB) m/z 1483 (M1Na)1.
3.1.90. Ole®n 105 and the cis-isomer. The experimental
procedure was similar to that described for compound 17.
28
105 (70% yield): a colorless oil; [a]D ˆ121.1 (c 1.39,
CHCl3); IR (CHCl3) 1720, 1460, 1380, 1285, 1255, 1165,
1
1090, 1050, 1005, 970, 835 cm21; H NMR (400 MHz,
CDCl3) d 5.52 (ddd, Jˆ7.3, 7.3, 15.1 Hz, 1H), 5.34 (dd,
Jˆ7.3, 7.3 Hz, 1H), 5.23 (dd, Jˆ8.3, 15.1 Hz, 1H), 4.64
(d, Jˆ11.7 Hz, 1H), 4.58 (d, Jˆ11.7 Hz, 1H), 4.20±4.09
(m, 2H), 3.97 (m, 1H), 3.87 (m, 1H), 3.70±3.51 (m, 6H),
3.49 (dd, Jˆ3.9, 3.9 Hz, 1H), 3.37 (dd, Jˆ6.8, 6.8 Hz, 1H),
3.22 (s, 3H), 3.15 (s, 3H), 2.30(m, 2H), 2.16 (s, 3H), 2.15
(m, 1H), 1.96 (m, 1H), 1.87±1.20(m, 21H), 1.49 (s, 3H),
1.20 (s, 9H), 0.99±0.87 (m, 12H), 0.97 (t, Jˆ7.8 Hz, 9H),
0.96 (t, Jˆ7.8 Hz, 18H), 0.94 (t, Jˆ7.8 Hz, 9H), 0.89 (s,
18H), 0.88 (d, Jˆ6.8 Hz, 3H), 0.79 (d, Jˆ6.8 Hz, 3H),
0.76 (d, Jˆ6.8 Hz, 3H), 0.65±0.58 (m, 24H), 0.05 (s, 3H),
3.1.93. a,b,g,d-Unsaturated ester 108. The experimental
procedure was similar to that described for compound 20.
27
108 (89% yield): a colorless oil; [a]D ˆ11.17 (c 0.915,
CHCl3); IR (CHCl3) 1700, 1640, 1620, 1460, 1415, 1370,
1
1300, 1255, 1085, 1045, 970, 835 cm21; H NMR (400
MHz, CDCl3) d 7.27 (dd, Jˆ10.3, 15.1 Hz, 1H), 6.28±
6.13 (m, 2H), 5.80(d, Jˆ15.1 Hz, 1H), 5.52 (ddd, Jˆ7.3,

H. Kigoshi et al. / Tetrahedron 58 (2002) 1075±1102
1101
7.3, 15.1 Hz, 1H), 5.34 (dd, Jˆ7.3, 7.3 Hz, 1H), 5.23 (dd,
Jˆ8.3, 15.1 Hz, 1H), 4.67 (d, Jˆ11.7 Hz, 1H), 4.58 (d, Jˆ
11.7 Hz, 1H), 4.20(q, Jˆ7.3 Hz, 2H), 3.97 (m, 1H), 3.87
(m, 1H), 3.68 (ddd, Jˆ4.4, 7.3, 10.3 Hz, 1H), 3.61 (dd, Jˆ
3.9, 3.9 Hz, 1H), 3.58±3.51 (m, 5H), 3.38 (dd, Jˆ6.8,
6.8 Hz, 1H), 3.22 (s, 3H), 3.16 (s, 3H), 2.45 (ddd, Jˆ3.4,
5.4, 15.6 Hz, 1H), 2.36±2.27 (m, 3H), 2.15 (m, 1H), 2.14 (s,
3H), 1.87±1.26 (m, 18H), 1.50(s, 3H), 1.29 (t, Jˆ7.3 Hz,
3H), 0.99±0.76 (m, 12H), 0.97 (t, Jˆ7.8 Hz, 9H), 0.96 (t,
Jˆ7.8 Hz, 18H), 0.96 (m, 1H), 0.94 (t, Jˆ7.8 Hz, 9H), 0.89
(s, 9H), 0.89 (s, 9H), 0.88 (d, Jˆ7.3 Hz, 3H), 0.80 (d, Jˆ
6.8 Hz, 3H), 0.76 (d, Jˆ6.8 Hz, 3H), 0.65±0.56 (m, 24H),
0.07 (s, 3H), 0.05 (s, 3H), 0.04 (s, 6H); MS (FAB) m/z 1579
(M1Na)1.
(CHCl3) 3615, 3490 (br), 1705, 1645, 1640, 1620, 1460,
1
1370, 1305 1250, 1180, 1090, 975 cm21; H NMR (600
MHz, acetone-d6) d 7.22 (dd, Jˆ10.6, 15.0 Hz, 1H), 6.34
(m, 1H), 6.22 (m, 1H), 5.84 (d, Jˆ15.0Hz, 1H), 5.68 (ddd,
Jˆ7.3, 7.3, 15.0Hz, 1H), 5.36 (dd, Jˆ7.3, 7.3 Hz, 1H), 5.28
(dd, Jˆ8.4, 15.0Hz, 1H), 5.04 (ddd, Jˆ3.7, 3.7, 7.7 Hz,
1H), 4.42 (br s, 1H), 4.13 (q, Jˆ7.3 Hz, 2H), 4.11 (br s,
1H), 4.05 (dd, Jˆ6.6, 6.6 Hz, 1H), 3.97±3.91 (m, 2H),
3.85 (br s, 1H), 3.78 (br s, 1H), 3.69±3.63 (m, 2H), 3.60±
3.54 (m, 3H), 3.41±3.26 (m, 5H), 3.28 [3.29] (s, 3H), 3.19
(br s, 1H), 3.17 (s, 3H), 3.10(s, 3H), 2.67 (m, 1H), 2.47
(ddd, Jˆ7.7, 7.7, 15.4 Hz, 1H), 2.31 [2.33] (s, 6H), 2.28 (m,
1H), 2.20(m, 1H), 2.09 (m, 1H), 1.96±1.74 (m, 8H), 1.66
(m, 2H), 1.57±1.40(m, 8H), 1.49 (s, 3H), 1.23 (t, Jˆ7.3 Hz,
3H), 1.11±0.95 (m, 2H), 0.96 (d, Jˆ7.0Hz, 3H), 0.92±0.88
(m, 3H), 0.91 (d, Jˆ6.2 Hz, 3H), 0.89 (d, Jˆ6.6 Hz, 3H),
0.76 [0.80] (d, Jˆ6.6 Hz, 3H). The counterparts of doubled
signals in the ratios of 1.3:1 are in brackets; MS (FAB) m/z
964 (M1Na)1; HRMS (FAB) calcd for C52H95NNaO13
[(M1Na)1] 964.6701, found 964.6725.
3.1.94. Alcohol 109. The experimental procedure was
similar to that described for compound 30. 109 (80%
28
yield): a colorless oil; [a]D ˆ17.5 (c 0.49, CHCl3); IR
(CHCl3) 3450 (br), 1700, 1640, 1615, 1460, 1415, 1370,
1
1255, 1090, 970, 835 cm21; H NMR (400 MHz, CDCl3)
d 7.28 (dd, Jˆ9.8, 15.1 Hz, 1H), 6.30±6.18 (m, 2H), 5.81
(d, Jˆ15.1 Hz, 1H), 5.52 (ddd, Jˆ7.3, 7.3, 15.1 Hz, 1H),
5.34 (dd, Jˆ6.8, 6.8 Hz, 1H), 5.22 (dd, Jˆ8.3, 15.1 Hz, 1H),
4.20(q, Jˆ7.3 Hz, 2H), 3.97 (ddd, Jˆ2.4, 5.4, 7.8 Hz, 1H),
3.87 (m, 1H), 3.75 (dd, Jˆ2.0, 4.9 Hz, 1H), 3.71±3.63 (m,
2H), 3.60±3.51 (m, 4H), 3.38 (dd, Jˆ6.8, 6.8 Hz, 1H), 3.22
(s, 3H), 3.16 (s, 3H), 3.01 (m, 1H, ±OH), 2.48 (ddd, Jˆ3.9,
5.4, 15.6 Hz, 1H), 2.30(m, 2H), 2.26±2.10(m, 2H), 2.14 (s,
3H), 1.87±1.26 (m, 19H), 1.50(s, 3H), 1.29 (t, Jˆ7.3 Hz,
3H), 0.97 (t, Jˆ7.8 Hz, 9H), 0.96 (t, Jˆ7.8 Hz, 18H), 0.96
(m, 1H), 0.94 (t, Jˆ7.8 Hz, 9H), 0.90±0.87 (m, 9H) 0.90 (s,
9H), 0.89 (s, 9H), 0.88 (d, Jˆ6.8 Hz, 3H), 0.83 (d, Jˆ
6.8 Hz, 3H), 0.79 (d, Jˆ6.8 Hz, 3H), 0.76 (d, Jˆ6.8 Hz,
3H), 0.62 (q, Jˆ7.8 Hz, 6H), 0.61 (q, Jˆ7.8 Hz, 18H),
0.07 (s, 3H), 0.05 (s, 3H), 0.04 (s, 6H); MS (FAB) m/z
1519 (M1Na)1.
3.2. Cytotoxic activity
The cytotoxicity was observed by Dr Hisao Ekimoto and Ms
Mutsuko Kimura (Nippon Kayaku Co., Ltd) using the
reported procedure.25
3.3. Measurement of ¯ow birefringence
Actin was extracted in cold water from the acetone-dried
powder of rabbit skeletal muscle, puri®ed,26 and poly-
merized in 100 mM KCl, 5 mM Tris-HCl (pH 8.0),
0.2 mM ATP, and 1 mM DTT before use. The test com-
pounds were dissolved in DMSO and added to the F-actin
solution (40 mM). The incubated actin solutions (room
temperature, 1 min) were analyzed in a micro FBR-Mark
II apparatus (Wakenyaku Co., Kyoto, Japan) with rotation at
500 rpm. The IC50 values were calculated as the concen-
trations of the test compounds required to reduce the ¯ow
birefringence of the F-actin solution (40 mM) to 50% of its
control amplitude. The ®nal concentration of DMSO added
to the reaction mixtures with the test compounds was 1%
(v/v) except for compounds 64, 67 and 89 (5±10%, v/v).
The IC50 values are mean values of at least three
experiments.
3.1.95. Trimethylserine ester 110. The experimental
procedure was similar to that described for compound 31.
31
110 (86% yield, S/Rˆ1.3:1): a colorless oil; [a]D ˆ28.6 (c
0.45, MeOH); IR (CHCl3) 1710, 1645, 1620, 1460, 1415,
1
1370, 1255, 1090, 1040, 970, 835 cm21; H NMR (400
MHz, CDCl3) d 7.21 (dd, Jˆ10.7, 15.1 Hz, 1H), 6.31 (m,
1H), 6.23 (ddd, Jˆ7.3, 7.3, 15.1 Hz, 1H), 5.95 (d, Jˆ
15.1 Hz, 1H), 5.59 (ddd, Jˆ7.3, 7.3, 15.1 Hz, 1H), 5.39
(dd, Jˆ7.3, 7.3 Hz, 1H), 5.29 (dd, Jˆ7.8, 15.1 Hz, 1H),
4.92 (m, 1H),4.14 (q, Jˆ7.3 Hz, 2H), 4.07 (m, 1H), 4.00
(m, 1H), 3.73 (ddd, Jˆ4.4, 7.3, 10.3 Hz, 1H), 3.68±3.55 (m,
7H), 3.43±3.36 (m, 2H), 3.30(s, 3H), 3.21 (s, 3H), 3.12
[3.12] (s, 3H), 2.64 (m, 1H), 2.49±2.32 (m, 5H), 2.37
[2.33] (s, 6H), 2.16 (m, 1H), 2.08±0.98 (m, 18H), 1.51 (s,
3H), 1.23 (t, Jˆ7.3 Hz, 3H), 1.00 (t, Jˆ7.8 Hz, 27H), 1.00
(t, Jˆ7.8 Hz, 9H), 0.94±0.89 (m, 15H), 0.92 (s, 9H), 0.90 (s,
9H), 0.87 (d, Jˆ7.3 Hz, 3H), 0.83 (d, Jˆ6.8 Hz, 3H), 0.72±
0.62 (m, 24H), 0.16 (s, 3H), 0.11 [0.10] (s, 3H), 0.07 [0.06]
(s, 3H), 0.06 (s, 6H). The counterparts of doubled signals in
the ratios of 1.3:1 are in brackets; MS (FAB) m/z 1648
(M1Na)1.
Acknowledgements
We are grateful to Professor Hirokazu Hotani and Drs
Tomohiko Itoh and Kingo Takiguchi (Department of
Molecular Biology, Graduate School of Science, Nagoya
University) for their donation of actin and their helpful
advice and discussions. We express our gratitude to
Professor Daisuke Uemura (Department of Chemistry,
Graduate School of Science, Nagoya University) for his
interest in this work. We thank Dr Hisao Ekimoto and Ms
Mutsuko Kimura (Nippon Kayaku Co., Ltd) for evaluating
the cytotoxicity of the natural and synthetic compounds.
This work was supported in part by Grants-in-Aid for
Scienti®c Research on Priority Areas (K. Y.), for COE
Research (H. K.), and for the Encouragement of Young
Scientists (K. S.) from the Ministry of Education, Science,
3.1.96. Acyclic analog 111. The experimental procedure
was similar to that described for compound 32. 111 (75%
31
yield, S/Rˆ1.3:1): a colorless oil; [a]D ˆ216 (c 0.428,
MeOH); UV (MeCN) lmax 258 nm (1 29,000); IR

1102
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