Synthesis of the C-14-C-26 segment of amphidinolide B

Article abstract of DOI:10.1039/a900938h

The C-14-C-26 segment 2 of amphidinolide B 1, a potent cytotoxic 26-membered macrolide, has been synthesized.

Full text of DOI:10.1039/a900938h

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Synthesis of the C-14–C-26 segment of amphidinolide B
Haruaki Ishiyama, Takahiro Takemura, Masashi Tsuda and Jun’ichi Kobayashi*
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
Received (in Cambridge) 3rd February 1999, Accepted 19th March 1999
The C-14–C-26 segment 2 of amphidinolide B 1, a potent cytotoxic 26-membered macrolide, has been synthesized.
Amphidinolide B1,2 1, isolated from the culture of a symbiotic
marine dinoflagellate Amphidinium sp. (strain Y-5), is a potent
cytotoxic 26-membered macrolide possessing nine chiral cen-
ters as well as unique partial structures such as an allyl epoxide
and an s-cis diene. Since the absolute stereochemistry of nine
chiral centers in 1 was determined by X-ray crystal analysis3
and synthesis of the C-22–C-26 segment,4 this macrolide has
attracted great interest as one of the challenging targets for
total synthesis.5–8 Here we describe the stereoselective synthesis
of the C-14–C-26 segment 2 of amphidinolide B 1.
be derived from commercially available 3-methylbut-3-en-1-ol 5
via asymmetric dihydroxylation using hydroquinidine pyrid-
azine-1,4-diyl diether [(DHQD)2PYDZ]ؒOsO4 catalyst9,10
followed by C1-homologation using carbon tetrabromide.11 On
the other hand, unit 4 could be synthesized from (2S,4S)-
pentane-2,4-diol 6 through a Horner–Wadsworth–Emmons
reaction and Sharpless asymmetric dihydroxylation.12 Triiso-
propylsilyl (TIPS) ether was selected as a protective group
for the hydroxy groups at C-16, C-18, C-21 and C-22, while
the hydroxy group at C-25 was protected with a tert-butyl-
dimethylsilyl (TBS) ether.
Protection of the primary hydroxy group in the chiral diol
7 (91% ee),10 derived from 3-methylbut-3-en-1-ol through
asymmetric dihydroxylation, afforded a pivaloyl ester (94%).
The tertiary hydroxy group was converted into a TIPS ether
(93%), and then the pivaloyl ester was deprotected using
DIBAL-H reduction to afford the primary alcohol 8 in 81%
yield (Scheme 2). Swern oxidation of 8 followed by treatment of
31
OH
18
O
20
OH
30
OH
21
23
16
14
32
26
29
22
HO
13
11
28
25
27
6
8
O
1
3
OH
9
O
a,b,c
71 %
ref. 10
18
O
OH
MPO
HO
16
Amphidinolide B (1)
16
7
5
(91 % ee)
Results and discussion
We planned to synthesize the C-14–C-26 segment 2 by a con-
vergent strategy through an aldol coupling reaction between the
C-14–C-18 3 and C-19–C-26 4 units (Scheme 1). Unit 3 could
OTIPS
16
OTIPS
OH
16
18
18
d,e,f
MPO
MPO
87 %
8
9
OTIPS
g,h
65 %
18
OHC
OTIPS
31
O
OTIPS
23
TIPSO
16
3
14
26
21
25
16
18
14
Scheme 2 Reagents and conditions: a PivCl, pyridine–CH2Cl2 (1:1),
rt, 12 h; b TIPSOTf, 2,6-lutidine, CH2Cl2, rt, 12 h; c DIBAL-H, CH2Cl2,
Ϫ78 ЊC, 30 min; d (COCl)2, DMSO, CH2Cl2, Ϫ78 ЊC, 45 min, then
Et3N, Ϫ50 ЊC, 30 min; e CBr4, Ph3P, Et3N, CH2Cl2, 50 ЊC, 1 h;
f EtMgBr, THF, 0 ЊC, 1 h; g CAN, CH3CN–water (4:1), rt, 5 min;
h Dess–Martin periodinane, pyridine–CH2Cl2 (1:1), rt, 2 h.
TIPSO
OTBS
32
C-14–C-26 2
top-half
the corresponding aldehyde with carbon tetrabromide gave the
dibromoolefin in 90% yield,11 which was treated with 4.1
equivalents of ethylmagnesium bromide in THF at 0 ЊC to
afford the acetylene 9 in 97% yield. The p-methoxyphenyl (MP)
group of 9 was removed by ceric ammonium nitrate (CAN) and
then the hydroxy group at C-18 was oxidized by Dess–Martin
periodinane13 in CH2Cl2–pyridine (1:1) to afford the aldehyde
3, corresponding to the C-14–C-18 segment, in 65% yield in two
steps.
O
OTIPS
23
31
TIPSO
26
18
25
21
+
CHO
16
19
14
TIPSO
OTBS
32
C-14 – C-18 3
C-19 – C-26 4
32
26
31
23
HO
On the other hand, cyanide14 10, prepared from (2S,4S)-
pentane-2,4-diol 6 in three steps, was converted into the
α,β-unsaturated ketone 11 by DIBAL-H reduction and then
Horner–Wadsworth–Emmons reaction with diethyl (2-oxo-
propyl)phosphonate in 49% yield (Scheme 3). Sharpless asym-
25
18
16
OH
OH
14
6
5
Scheme 1
J. Chem. Soc., Perkin Trans. 1, 1999, 1163–1166
1163

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Table 1
22
CN
25
a,b
ref. 14
Yield (%)
49 %
HO
OH
TBSO
Reagent
Temperature/ ЊC
Time/h
14
15
6
10
KHMDS
NaHMDS
LiHMDS, ZnCl2
Ϫ78
Ϫ78
Ϫ50
0.5
0.5
1
30
25
9
20
27
26
O
HO
O
d
c
25
21
25
22
22
90 %
79 %
19
19
O
TBSO
TBSO
OH
OTIPS
31
11
12
TIPSO
22
O
OTIPS
TIPSO
TIPSOTf
S
26
OTBS
14
18
22
32
TIPSO
22
OTIPS
19
70 %
14
e
TIPSO
25
25
TBSO
93 %
19
2
OTIPS
TBSO
OTIPS
4
13
S-configuration, since 18R-configuration of 15 was assigned by
the modified Mosher method.‡ Finally, treatment of 14 with
TIPSOTf afforded the C-14–C-26 segment 2 in 70% yield.
Thus the synthesis of the C-14–C-26 segment 2 lacking C-30
of amphidinolide B 1 has been completed. The synthesis of the
C-1–C-13 segment and total synthesis of amphidinolide B 1 are
under investigation.
Scheme 3 Reagents and conditions: a DIBAL-H, CH2Cl2, Ϫ20 ЊC, 30
min, then aq. NH4Cl, rt, 20 min; b (EtO)2P(O)CHCOCH3, NaH, 0 ЊC,
20 min, and then rt, 8.5 h; c AD-mix-α, K2OsO4ؒ2H2O, NaHCO3,
CH3SO2NH2, t-BuOH–H2O, (1:1), rt, 10 h; d TIPSOTf, 2,6-lutidine,
CH2Cl2, rt, 9 h; e PPTS, CH2Cl2, rt, 10 h.
metric dihydroxylation of 11 with AD-mix-α12 in t-BuOH–H2O
(1:1) followed by silica gel column chromatography (hexane–
CHCl3–acetone–MeOH, 45:46:5:4) gave a 21,22-diol 12 in
90% yield. The absolute configurations at C-21 and C-22 of 12
were assigned as R and S, respectively, on the basis of the
modified Mosher method15 using 22-(S)- and 22-(R)-α-
methoxy-α-(trifluoromethyl)phenylacetyl (MTPA) esters of
12.† Although protection of the two hydroxy groups of 12
using TIPSCl and (i-Pr)2NEt failed, treatment with triisopro-
pylsilyl trifluoromethanesulfonate (TIPSOTf) and 2,6-lutidine
(2,6-dimethylpyridine) in CH2Cl2 led to the protection of the
hydroxy groups as a bis-TIPS ether and the 20-ketone carbonyl
as a TIPS enol ether. The silyl enol ether 13 was transformed
into the methyl ketone (4, 93% yield), corresponding to the C-
19–C-26 unit, by treatment with pyridinium toluene-p-sulfonate
(PPTS) in 93% yield.
Experimental
General methods
All moisture and air sensitive reactions were performed in
flamed dried glassware equipped with rubber septa under a
positive pressure of nitrogen or argon. Et2O and THF were
distilled from sodium benzophenone ketyl prior to use. CH2Cl2,
toluene, benzene, and pyridine were distilled from CaH2, while
DMSO was dried over molecular sieves (4 Å). All yields
reported refer to isolated material judged to be homogeneous
by TLC and NMR spectroscopy. The work-up procedure
involved extraction with EtOAc or ether or CHCl3, washing of
the organic extract with water and brine, drying (anhydrous
Na2SO4), and evaporation of the solvent at aspirator pressure.
Optical rotations were measured on a JASCO DIP-370 polar-
imeter and [α]D values are given in 10Ϫ1 deg cm2 gϪ1. IR spectra
were recorded on a JASCO FT/IR-5300 spectrophotometer. 1H
and 13C NMR spectra were measured on Bruker ARX-500 or
JEOL EX-400 spectrometers in CDCl3; 1H NMR spectra were
recorded in ppm in relation to the residual CHCl3 signal (δ 7.26)
as an internal standard, while 13C NMR spectra were recorded
in ppm relative to the CDCl3 signal (δ 77.0). Multiplicity of
each carbon signal was assigned on the basis of DEPT spectra.
EI and FAB mass spectra were obtained on JEOL DX-303 and
JMX-HX110 spectrometers, respectively.
The coupling reactions between the C-14–C-18 3 and the
C-19–C-26 4 units (Scheme 4) are summarized in Table 1. The
31
OH
S
O
OTIPS
TIPSO
Table 1
26
OTBS
+
4
3
22
32
18
14
TIPSO
14
+
31
OH
R
O
OTIPS
TIPSO
26
OTBS
(2R)-4-(4-Methoxyphenoxy)-2-methyl-2-(triisopropylsilyloxy)-
butan-1-ol (8)
22
32
18
14
TIPSO
15
To a solution of the diol 710 (517 mg, 2.28 mmol) in pyridine–
CH2Cl2 (1:1, 5 mL) was slowly added pivaloyl chloride (337
mL, 2.74 mmol) at 0 ЊC, and stirring was continued at room
temp. for 12 h. After addition of 2 M HCl (20 mL), the reaction
mixture was worked-up with EtOAc (40 mL × 3). The residue
was purified by silica gel column chromatography (hexane–
acetone, 8:1→4:1) to yield a pivaloyl ester (667 mg, 2.15 mmol,
94%). A solution of the pivaloyl ester in CH2Cl2 (2 mL) was
treated with 2,6-lutidine (501 mg, 4.3 mmol) and TIPSOTf (867
µL, 3.2 mmol) at room temp. for 12 h. After addition of satur-
ated aqueous NH4Cl (10 mL), the reaction mixture was worked-
up with ether (20 mL × 3). The residue was purified by silica gel
Scheme 4
aldol reaction between aldehyde 3 and the enolate generated
from potassium hexamethyldisilazane (KHMDS) and the
ketone 4 afforded the desired product 14 and its diastereomer
15 in 30 and 20% yields, respectively. On the other hand, alde-
hyde 3 was added to a THF solution of the zinc enolate of 4,
which was generated using LiHMDS and zinc chloride at
Ϫ50 ЊC to give compounds 14 and 15 in 9 and 26% yields,
respectively, while the aldol reaction using NaHMDS gave
14 and 15 in 25 and 27% yields, respectively. The stereo-
chemistry at C-18 of compound 14 is believed to be the desired
‡ ∆δ value [∆δ (in ppm) = δS Ϫ δR] obtained for 22-(S)- and 22-(R)-
MTPA esters of 15 are as follows: H-14, ϩ0.09; H2-17, ϩ0.01 and
ϩ0.01; H-18, ϩ0.07; H2-19, Ϫ0.07 and Ϫ0.05; H-21, Ϫ0.01; H-22, 0.01;
H-25, Ϫ0.01; H3-26, Ϫ0.03.
† ∆δ value [∆δ (in ppm) = δS Ϫ δR] obtained for 22-(S)- and 22-(R)-
MTPA esters of 12 are as follows: H3-19, ϩ0.03; H-21, ϩ0.03; H-22,
Ϫ0.04; H-25, Ϫ0.05; H3-26, Ϫ0.07; H3-32, Ϫ0.12.
1164
J. Chem. Soc., Perkin Trans. 1, 1999, 1163–1166

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column chromatography (hexane–EtOAc, 20:1→15:1) to
afford a TIPS ether (931 mg, 1.99 mmol, 93%). The TIPS ether
(882 mg, 1.89 mmol) in CH2Cl2 (5 mL) was treated with 0.95 M
DIBAL-H solution in hexane (4.5 mL, 4.3 mmol) at Ϫ78 ЊC for
30 min. After addition of saturated aqueous potassium sodium
tartrate (10 mL) and Et2O (20 mL) to the mixture, the reaction
mixture was stirred vigorously at room temp. for 1 h. The
reaction mixture was worked-up with EtOAc (20 mL × 3). The
residue was eluted through a silica gel column (hexane–EtOAc,
10:1→8.1) to give a primary alcohol 8 (590 mg, 1.54 mmol,
81%) as a colorless oil; [α]D26 Ϫ11 (c 1.07, CHCl3); νmax/cmϪ1
3480, 1590, 1230, 1040 and 825; δH(CDCl3) 1.05, (21H, m), 1.33
(3H, s), 2.05 (2H, m), 3.42 (1H, dd, J = 9.0 and 10.9 Hz), 3.51
(1H, dd, J = 5.0 and 10.9 Hz), 3.75 (3H, s), 3.97 (1H, m), 4.09
(1H, m) and 6.81 (4H, m); δC(CDCl3) 13.4 (3C, d), 18.3 (6C, q),
25.8 (q), 39.3 (t), 55.7 (q), 65.0 (t), 70.0 (t), 75.2 (s), 114.7 (2C,
d), 115.4 (2C, d), 152.7 (s) and 154.0 (s); m/z (FABMS) 383
(M ϩ H)ϩ; m/z (HRFABMS) 383.2629 [(M ϩ H)ϩ. Calc. for
C21H39O4Si: 383.2617].
µmol, 74%) as a colorless oil; δH(CDCl3) 1.07 (18H, m), 1.17
(3H, m), 1.64 (3H, s), 2.56 (1H, s), 2.69 (2H, m) and 9.93 (1H,
br s); δC(CDCl3) 12.9 (3C, d), 18.2 (3C, q), 18.3 (3C, q), 31.3 (q),
57.5 (t), 66.5 (d), 73.5 (s), 86.6 (s) and 201.3 (d); mz (FABMS)
269 (M ϩ H)ϩ; m/z (HRFABMS) 269.1913 [(M ϩ H)ϩ. Calc.
for C15H29O2Si: 269.1889].
(3E,5R,7S)-7-(tert-Butyldimethylsilyloxy)-5-methyloct-3-en-2-
one (11)
To a solution of the cyanide 10 (6.69 g, 29.4 mmol) in CH2Cl2
(150 mL) was added a 0.95 M hexane solution of DIBAL-H (41
mL, 39 mmol) at Ϫ20 ЊC, and the mixture was stirred at Ϫ20 ЊC
for 30 min. MeOH (380 µL) was added to the reaction mixture,
and stirring was continued at 0 ЊC for 10 min. After addition of
saturated aqueous NH4Cl (34 mL), the mixture was stirred at
room temp. for 20 min. After addition of saturated aqueous
potassium sodium tartrate (60 mL) and then Et2O (120 mL),
the reaction mixture was stirred vigorously at room temp. for
1 h. The reaction mixture was worked-up with Et2O (400
mL × 3) to afford a crude aldehyde (6.64 g), which was used for
the following reaction without separation. To a suspension of
NaH (3.0 g, 74 mmol) in THF (100 mL) was added diethyl (2-
oxopropyl)phosphonate (14.2 g, 74 mmol) in THF (100 mL) at
0 ЊC, and the mixture was stirred at room temp. for 1 h. To this
mixture was added a solution of the crude aldehyde (6.64 g) in
THF (50 mL) at 0 ЊC, and stirring was continued at room temp.
for 8.5 h. After addition of saturated aqueous NH4Cl (120 mL),
the mixture was worked-up with ether (250 mL × 3). The resi-
due was purified by silica gel column chromatography (hexane–
Et2O, 8:1–5:1) to give an α,β-unsaturated ketone 11 (3.89 g,
14.4 mmol, 49% in two steps) as a colorless oil; [α]D26 Ϫ7.7 (c
1.00, CHCl3); νmax/cmϪ1 1700, 1680, 1255 and 835; δH(CDCl3)
0.02 (3H, s), 0.03 (3H, s), 0.86 (9H, s), 1.04 (3H, d, J = 6.6 Hz),
1.11 (3H, d, J = 6.1 Hz), 1.31 (1H, m), 1.58 (1H, m), 2.22 (3H,
s), 2.47 (1H, m), 3.81 (1H, m), 6.01 (1H, d, J = 15.9 Hz) and
6.70 (1H, dd, J = 7.3 and 15.9 Hz); δC(CDCl3) Ϫ5.01 (q), Ϫ4.36
(q), 17.8 (s), 18.6 (q), 23.8 (q), 25.6 (3C, q), 26.6 (d), 32.9 (q),
45.6 (t), 65.8 (d), 128.8 (d), 153.6 (d) and 198.5 (s); m/z (EIMS)
270 (Mϩ); m/z (HREIMS) 270.2020 (Mϩ. Calc. for C15H30-
O2Si: 270.2025).
(3R)-5-(4-Methoxyphenoxy)-3-methyl-3-(triisopropylsilyloxy)-
pent-1-yne (9)
To a solution of oxalyl chloride (224 µL, 2.56 mmol) and
DMSO (275 µL, 3.87 mmol) in CH2Cl2 (5 mL) was added
dropwise a solution of the alcohol 8 (490 mg, 1.34 mmol) in
CH2Cl2 (3 mL) at Ϫ78 ЊC. After being stirred at Ϫ78 ЊC for 45
min, the mixture was treated with triethylamine (915 µL, 6.41
mmol) and allowed to warm to Ϫ50 ЊC, and stirring was con-
tinued for 30 min. After addition of saturated aqueous NH4Cl
(20 mL), the reaction mixture was worked-up with Et2O (40
mL × 3) to afford a crude aldehyde (500 mg), which was used
for the following reaction without separation. To a solution of
the crude aldehyde (600 mg) in toluene (20 mL) were added
triethylamine (1.8 mL, 12 mmol), carbon tetrabromide (2.05 g,
6.2 mmol), and triphenylphosphine (3.14 g, 12 mmol), the mix-
ture was stirred at 50 ЊC for 1 h. After addition of water (20
mL), the reaction mixture was worked-up with CHCl3 (40
mL × 3). The residue was eluted through a silica gel column
(hexane–CHCl3, 8:1) to yield a dibrominated olefin (739 mg,
1.38 mmol, 90%). A solution of the olefin (1.04 g, 1.93 mmol) in
THF (10 mL) was treated with 1 M THF solution of EtMgBr
(8 mL, 8 mmol) at 0 ЊC for 1 h. After addition of saturated
aqueous NH4Cl (20 mL), the reaction mixture was worked-up
with EtOAc (40 mL × 3). The residue was purified by silica gel
column chromatography (hexane–EtOAc, 8:1) to afford acetyl-
ene 9 (709 mg, 1.88 mmol, 97%) as a colorless oil; [α]D25 Ϫ0.66 (c
1.06, CHCl3); νmax/cmϪ1 1590, 1230, 1045 and 825; δH(CDCl3)
1.07, (21H, m), 1.57 (3H, s), 2.19 (2H, m), 2.42 (1H, s), 3.75
(3H, s), 4.16 (2H, m) and 6.82 (4H, m); δC(CDCl3) 13.1 (3C, d),
18.4 (6C, q), 31.3 (q), 44.3 (t), 55.7 (q), 65.1 (t), 67.6 (d), 72.1 (s),
87.6 (s), 114.5 (2C, d), 115.2 (2C, d), 152.9 (s) and 153.6 (s);
m/z (FABMS) 361 (M ϩ H)ϩ; m/z (HRFABMS) 361.2579
[(M ϩ H)ϩ. Calc. for C22H37O2Si: 361.2563].
(3R,4S,5R,7S)-7-(tert-Butyldimethylsilyloxy)-3,4-dihydroxy-5-
methyloctan-2-one (12)
To a suspension of AD-mix-α (21 g) in t-BuOH–water (1:1, 100
mL) were added potassium osmate dihydrate (44 mg, 120
µmol), NaHCO3 (2.52 g, 30 mmol), and methanesulfonanide
(3.6 g, 38 mmol) at room temp., and the mixture was stirred for
10 min. To the mixture was added a solution of compound 11
(2.707 g, 10.0 mmol) in t-BuOH–water (1:1, 20 mL) at 4 ЊC,
and stirring was continued at 4 ЊC for 13 h. After addition of
Na2SO3 (3.78 g, 30 mmol), stirring was further continued at
room temp. for 1 h. The mixture was worked-up with EtOAc
(300 mL × 3). The residue was eluted on a silica gel column
(hexane–CHCl3–acetone–MeOH, 45:46:5:4) to yield a diol 12
(2.74 g, 9.00 mmol, 90%) as a colorless oil; [α]D26 Ϫ2.1 (c 1.01,
CHCl3); νmax/cmϪ1 3445, 1715 and 835; δH(CDCl3) 0.07 (6H, s),
0.89 (9H, s), 1.04 (3H, d, J = 6.6 Hz), 1.14 (3H, d, J = 6.1 Hz),
1.23 (1H, m), 1.64 (1H, m), 2.10 (1H, m), 2.27 (3H, s), 3.66 (1H,
m), 3.93 (1H, m) and 4.23 (1H, s); δC(CDCl3) Ϫ4.30 (q), Ϫ3.73
(q), 15.8 (s), 18.4 (q), 24.8 (q), 25.2 (q), 25.6 (3C, q), 33.7 (d),
43.6 (t), 66.5 (d), 76.0 (d), 78.0 (d) and 212.0 (s); m/z (FABMS)
305 (M ϩ H)ϩ; m/z (HRFABMS) 305.2173 [(M ϩ H)ϩ. Calc.
for C15H33O4Si: 305.2148].
C-14–C-18 unit: (3R)-3-(triisopropylsilyloxy)-3-methylpent-4-
ynal (3)
Acetylene 9 (70.5 mg, 187 µmol) in acetonitrile–water (4:1, 2.5
mL) was treated with ceric ammonium nitrate (260 mg, 474
µmol) at room temp. for 5 min. After addition of saturated
aqueous NaHCO3 (5 mL), the reaction mixture was worked-up
with EtOAc (50 mL × 3). The residue was purified by silica gel
column chromatography (hexane–EtOAc, 6:1) to give an alco-
hol (44.7 mg, 165 mmol, 88%). To a solution of the alcohol (45
mg, 166 µmol) in pyridine–CH2Cl2 (1:1, 1.6 mL) was added
Dess–Martin periodinane (106 mg, 248 µmol), and stirring was
continued at room temp. for 2 h. After addition of saturated
aqueous Na2SO3 (4 mL), the mixture was worked-up with
EtOAc (15 mL × 3). The residue was subjected to a silica gel
column (hexane–EtOAc, 10:1) to yield aldehyde 3 (33 mg, 123
(3R,4S,5R,7S)-7-(tert-Butyldimethylsilyloxy)-5-methyl-2,3,4-
tris(triisopropylsilyloxy)oct-1-ene (13)
To a solution of the diol 12 (49.5 mg, 242 µmol) in CH2Cl2 (0.4
mL) were added 2,6-lutidine (0.18 mL, 2.18 mmol) and triiso-
J. Chem. Soc., Perkin Trans. 1, 1999, 1163–1166
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propylsilyl trifluoromethanesulfonate (0.27 mL, 1.45 mmol) at
0 ЊC, and the reaction mixture was stirred at room temperature
for 9 h. After addition of aqueous saturated NH4Cl (3 mL), the
mixture was worked-up with Et2O (5 mL × 3). The residue was
purified by silica gel column chromatography (hexane) to afford
a silyl enol ether 13 (147 mg, 191 µmol, 79%) as a colorless oil;
[α]D26 Ϫ0.48 (c 1.03, CHCl3); νmax/cmϪ1 1625, 1465, 885 and 835;
δH(CDCl3) 0.02 (3H, s), 0.22 (3H, s), 0.85 (9H, s), 1.07 (57H,
m), 1.14 (3H, d, J = 6.1 Hz), 1.23 (9H, m), 1.24 (1H, m), 1.74
(1H, m), 2.08 (1H, m), 3.78 (1H, br s), 3.87 (1H, m), 4.13 (1H,
br s), 4.20 (1H, s) and 4.50 (1H, s); δC(CDCl3) Ϫ4.51 (q), Ϫ4.18
(q), 12.9 (3C, d), 13.0 (3C, d), 13.6 (3C, d), 15.3 (s), 18.3
(12C, q), 18.5 (6C, q), 22.7 (q), 26.0 (3C, q), 32.7 (d), 44.0 (t),
66.2 (d), 75.4 (d), 78.8 (d), 90.1 (t) and 159.4 (s); m/z (FABMS)
773 (Mϩ); m/z (HRFABMS) 773.5365 (Mϩ. Calc. for
C42H92O4Si4: 773.5321).
(1H, dd, J = 9.5 and 14.2 Hz), 2.11 (1H, m), 2.45 (1H, s), 2.80
(2H, m), 3.52 (1H, m), 3.83 (1H, m), 3.96 (1H, m) and 4.49 (2H,
m); m/z (FABMS) 907 (M ϩ Na)ϩ; m/z (HRFABMS) 907.6497
[(M ϩ Na)ϩ. Calc. for C48H100O6Si4Na, 907.6494].
C-14–C-26 segment: (3S,5S,8R,9S,10R,12S)-12-(tert-butyl-
dimethylsilyloxy)-3,10-dimethyl-3,5,8,9-tetrakis(triisopropyl-
silyloxy)tridec-1-yn-7-one (2)
A solution of compound 14 (18 mg, 20.4 µmol) in CH2Cl2 was
treated with triisopropylsilyl trifluoromethanesulfonate (40 µL,
215 µmol) and 2,6-lutidine (35 µL, 300 µmol) at room temp. for
36 h. After addition of H2O (1 mL), the mixture was worked-up
with EtOAc (2 mL × 3). The residue was purified by silica gel
column chromatography (hexane) to give the C-14–C-26 seg-
ment 2 (15 mg, 14.4 µmol, 70%) as a colorless oil; [α]D27 Ϫ9.2 (c
1.00, CHCl3); νmax/cmϪ1 3310, 1725 and 835; δH(CDCl3) 0.03
(3H, s), 0.04 (3H, s), 0.81 (12H, d, J = 6.8 Hz), 0.87 (9H, s), 1.12
(79H, m), 1.58 (3H, s), 1.60 (1H, m), 1.80 (1H, dd, J = 5.6 and
13.5 Hz), 2.07 (1H, dd, J = 5.6 and 13.5 Hz), 2.14 (1H, m), 2.43
(1H, s), 3.02 (2H, m), 3.84 (1H, m), 3.92 (1H, m), 4.35 (1H, d,
J = 4.7 Hz) and 4.66 (1H, m); δC(CDCl3) Ϫ4.23 (q), Ϫ4.18 (q),
12.5 (6C, d), 13.1 (3C, d), 13.8 (3C, d), 15.0 (s), 17.9 (q), 18.1
(3C, q), 18.2 (6C, q), 18.3 (3C, q), 18.4 (6C, q), 18.5 (6C, s), 24.6
(q), 26.0 (3C, q), 30.4 (d), 30.5 (q), 45.2 (t), 50.0 (t), 52.5 (t),
66.2 (d), 68.3 (d), 73.2 (s), 80.1 (d), 88.1 (s) and 206.9 (s);
m/z (FABMS) 1041 (M ϩ H)ϩ; m/z (HRFABMS) 1041.7990
[(M ϩ H)ϩ. Calc. for C57H121O6Si5: 1041.8010].
C-19–C-26 unit: (3R,4S, 5R,7S)-3,4-bis(triisopropylsilyloxy)-
7-(tert-butyldimethylsilyloxy)-5-methyloctan-2-one (4)
Compound 13 (155.3 mg, 201 µmol) in CH2Cl2 (2 mL) was
treated with pyridinium toluene-p-sulfonate (53 mg, 207 µmol)
at room temp. for 10 h. After addition of water (10 mL), the
reaction mixture was worked-up with Et2O (15 mL × 3). The
residue was purified by silica gel column chromatography
(hexane–Et2O, 8:1–5:1) to give a ketone 4 (114.7 mg, 186 µmol,
93%) as a colorless oil; [α]D24 Ϫ34.4 (c 1.07, CHCl3); νmax/cmϪ1
1725 and 835; δH(CDCl3) 0.00 (3H, s), 0.01 (3H, s), 0.79 (6H, d,
J = 5.6 Hz), 0.85 (9H, s), 1.06 (21H, m), 1.15 (21H, m), 1.22
(1H, m), 1.60 (1H, m), 2.12 (1H, m), 2.24 (3H, s), 3.83 (1H, m),
3.90 (1H, m) and 4.34 (1H, d, J = 4.6 Hz); δC(CDCl3) Ϫ4.7 (q),
Ϫ4.1 (q), 12.5 (3C, d), 13.0 (3C, d), 14.5 (s), 17.8 (q), 18.15 (6C,
q), 18.18 (4C, q), 18.4 (2C, q), 24.7 (q), 25.9 (3C, q), 29.2
(q), 31.0 (d), 44.9 (d), 66.0 (d), 80.0 (d), 81.7 (d) and 208.6 (s);
m/z (FABMS) 617 (M ϩ H)ϩ; m/z (HRFABMS) 617.4832
[(M ϩ H)ϩ. Calc. for C33H73O4Si: 617.4817].
Acknowledgements
We are grateful to Professor M. Ishibashi, Chiba University, for
helpful discussions. This work was partly supported by a
Grant-in-Aid for Scientific Research from the Ministry of
Education, Science, Sports, and Culture of Japan. H. I. thanks
Research Fellowships of the Japanese Society for the Promo-
tion of Science for Young Scientists.
Aldol coupling between C-14–C18 (3) and C-19–C-26 (4) units
References
To a stirring solution of the ketone 4 (120.6 mg, 196 µmol) in
THF (2 mL) was added 0.5 M potassium hexamethyldisilazide
in THF (570 µL, 285 µmol) at Ϫ78 ЊC. After being stirred at
Ϫ78 ЊC for 30 min, the mixture was added to a solution of
aldehyde 3 (43.7 mg, 163 µmol) in THF (2 mL) at Ϫ78 ЊC, and
the mixture was stirred at Ϫ78 ЊC for 30 min. After addition
of 1 M phosphate buffer (pH 7.3, 2 mL), the reaction mixture
was worked-up with EtOAc (10 mL × 3). The residue was
eluted on a silica gel column (hexane–CHCl3, 2:1) to yield
(3S,5S,8R,9S,10R,12S)-12-(tert-butyldimethylsilyloxy)-3,10-
dimethyl-5-hydroxy-3,8,9-tris(triisopropylsilyoxy)tridec-1-yn-7-
one 14 (43.3 mg, 48.9 µmol, 30%) and its 5R-isomer 15 (28.9
mg, 32.6 µmol, 20%), and the ketone 4 (55.4 mg, 89.8 µmol,
46%). 14: a colorless oil; [α]D25 Ϫ15 (c 0.93, CHCl3); νmax/cmϪ1
1720 and 835; δH(CDCl3) 0.02 (3H, s), 0.03 (3H, s), 0.79 (9H, d,
J = 5.6 Hz), 0.87 (9H, s), 1.11 (61H, m), 1.59 (1H, m), 1.80 (1H,
dd, J = 1.7 and 14.1 Hz), 1.95 (1H, dd, J = 8.9 and 14.1 Hz),
1.63 (3H, s), 2.17 (1H, m), 2.43 (1H, s), 2.69 (1H, dd, J = 2.5
and 18.4 Hz), 3.00 (1H, dd, J = 8.1 and 18.4 Hz), 3.46 (1H, d,
J = 1.9 Hz), 3.84 (1H, m), 3.97 (1H, m) and 4.41 (2H, m);
δC(CDCl3) Ϫ4.6 (q), Ϫ4.1 (q), 12.5 (6C, d), 13.1 (3C, d), 14.5 (s),
18.1 (4C, q), 18.2 (6C, q), 18.3 (3C, q), 18.4 (6C, q), 24.7 (q),
25.9 (3C, q), 30.5 (d), 30.6 (q), 45.3 (t), 49.0 (t), 51.1 (t), 64.6 (d),
66.0 (d), 69.0 (d), 72.4 (s), 80.0 (d), 81.2 (d), 88.0 (s) and 210.7
(s); m/z (FABMS) 907 (M ϩ Na)ϩ; m/z (HRFABMS) 907.6491
[(M ϩ Na)ϩ. Calc. for C48H100O6Si4Na: 907.6494]. 15: a color-
less oil; [α]D27 Ϫ45 (c 1.00, CHCl3); νmax/cmϪ1 3530, 1720 and 835;
δH(CDCl3) 0.02 (3H, s), 0.03 (3H, s), 0.78 (9H, m), 0.86 (9H, s),
1.12 (61H, m), 1.59 (1H, m), 1.60 (3H, s), 1.77 (1H, m), 1.89
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J. Chem. Soc., Perkin Trans. 1, 1999, 1163–1166