Absolute stereochemistry of amphidinolide C: Synthesis of C-1-C-10 and C-17-C-29 segments

Article abstract of DOI:10.1016/S0040-4020(03)00142-X

Two of each diastereomers of the C-1-C-10 and C-17-C-29 segments of amphidinolide C (1) were synthesized. Comparing the ¹H NMR chemical shifts of its MTPA esters with those of linear methyl ester of 1, the absolute configurations at C-7, C-8, C-20, C-23, and C-24 in amphidinolide C (1) were confirmed to be all R.

Full text of DOI:10.1016/S0040-4020(03)00142-X

Tetrahedron 59 (2003) 1613–1625
Absolute stereochemistry of amphidinolide C:
synthesis of C-1–C-10 and C-17–C-29 segments
*
Takaaki Kubota, Masashi Tsuda and Jun’ichi Kobayashi
Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Kita-ku, Sapporo 060-0812, Japan
Received 16 December 2002; revised 27 January 2003; accepted 27 January 2003
Abstract—Two of each diastereomers of the C-1–C-10 and C-17–C-29 segments of amphidinolide C (1) were synthesized. Comparing the
1H NMR chemical shifts of its MTPA esters with those of linear methyl ester of 1, the absolute configurations at C-7, C-8, C-20, C-23, and
C-24 in amphidinolide C (1) were confirmed to be all R. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
method for erythro-glycol proposed by Kusumi et al.8 was
applied.
Amphidinolides are a series of cytotoxic macrolides
possessing unique structural features isolated from labora-
tory-cultured marine dinoflagellates Amphidinium sp.1
Amphidinolide C (1), obtained from the marine dinofla-
gellate Amphidinium sp. (Y-5), is unique 25-membered
macrolides having two tetrahydrofuran rings and vicinally-
located one-carbon branches, of which the gross structure
has been elucidated by 2D NMR data.2 An erythro
relationship for the C-7–C-8 bond was deduced from
analysis of the NOESY spectrum of the 7,8-O-isopropyli-
dene derivative of 1.3 On the other hand, the relative
stereochemistry of H-20/H-23 and H-23/H-24 was assigned
to be anti and threo, respectively, from analysis of the
NOESY spectrum of 1.4 Recently, relatively large amounts
of amphidinolide C (1) have been isolated from three strains
(Y-56, Y-59, and Y-71) of the genus Amphidinium, which
were separated from the inside cells of the marine acoel
flatworms Amphiscolops sp. This sample allowed us to
apply the elucidation of the absolute configurations of 12
chiral centers in 1.5 The absolute configurations at C-12,
C-13, C-20, C-23, and C-29 were assigned as R, S, and S by
J-based configuration analysis6 and the modified Mosher’s
method.7 3S, 4R, 6R, and 16S-configurations were deter-
mined by comparison of the 1H NMR spectra of the C-1–C-
7 and C16–C-18 segments obtained by oxidative degra-
dation of 1 with those of the synthetic segments. For the
absolute stereochemistry of C-7 and C-8, the Mosher’s
Here, we synthesized two of each diastereomers of the C-1–
C-10 (4a and 4b) and C-17–C-29 segments (6a and 6b) of
1
amphidinolide C (1) and compared the H NMR chemical
Keywords: amphidinolide C; a-methoxy-a-trifluoromethylphenylacetyl;
acetonide.
shifts of their a-methoxy-a-trifluoromethylphenylacetyl
(MTPA) esters with those of pentakis- and bis-MTPA
esters (2 and 3, respectively) of the linear methyl ester of 1.
*
Corresponding author. Tel.: þ81-14-706-4985; fax: þ81-14-706-4989;
e-mail: jkobay@pharm.hokudai.ac.jp
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00142-X

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T. Kubota et al. / Tetrahedron 59 (2003) 1613–1625
TES ester 12a, and treatment of the terminal olefin in 12a
with OsO4 and then NaIO4 afforded an aldehyde, which was
subjected to Grignard reaction with isopropenylmagnesium
bromide (isopropenylMgBr) to afford 7,8-erythro and threo
diols (13a and 13b, respectively) (Scheme 2). The absolute
configuration at C-8 in major isomer 13a was determined as
R by a modified Mosher’s method (selective Dd values; H-6:
20.11, H3-10: þ0.14, H2-36:þ0.14 and þ0.08) as well as
NOE data of its 7,8-O-isopropylidene acetal 15a. Two-step
oxidation of 14a and then methylation with trimethylsilyl-
diazomethane (TMSCHN2) afforded methyl ester 15a.
Finally acetonide of 15a was hydrolyzed to afford the
(7R,8R)-C-1–C-10 segment (4a), which was then trans-
formed into the bis-(S)-MTPA ester (5a) with 3S-, 4R-, 6R-,
7S-, and 8R-configurations. The (7S,8S)-C-1–C-10 segment
(4b) and its (S)-MTPA ester 5b were also synthesized from
12b by the same procedures as describe above.
The proton chemical shifts of the two diastereomers 5a and
5b were compared with those of the corresponding portion
in 2. Subtraction of the chemical shift values of synthetic
segments from those of 2 shown in Figure 1. Though they
were similar to each other, differences were observed for the
chemical shifts for signals due to H-5, H-6, and H-7. The 1H
NMR profile of the C-1–C-10 portion in 2 was close to that
of 5a possessing 7S- and 8R-configurations rather than that
of (7R,8S)-5b. Therefore, the absolute configurations at C-7
and C-8 in amphidinolide C (1) were demonstrated to be
both R, corresponding to the previous results.
2. Results and discussion
The C-1–C-10 segments (4a and 4b) were synthesized from
tetrahydrofuran 8,5 which was prepared from D-glutamic
acid. The hydroxyl group of 8 was protected with TBDMS
group, and then the benzyl group in 9 was removed by
hydrogenolysis to afford alcohol 10 (Scheme 1). Oxidation
of 10 with Dess–Martin periodinane9 followed by treatment
of the corresponding aldehyde with vinylmagnesium
bromide (vinylMgBr) afforded 1:1 mixture of 11a and
11b, which was separated by silica gel column chromatog-
raphy. The absolute configurations at C-7 in 11b was
determined as S by a modified Mosher’s method (selective
Dd values; H2-5: þ0.10 and þ0.04, H-6: þ0.07, H-8:
20.08, H2-9: 20.10 and 20.06). Thus, 11a possessed 7R-
configuration. The 7R-alcohol 11a were converted into a
The C-17–C-29 segments of 1 were synthesized from (R)-5-
benzyloxymethyl-g-butyrolactone (16), which was prepared
from D-glutamic acid.5 Two-carbon elongation of 16 with
Wittig reaction afforded E-olefin 17 in two steps (Scheme
3). The unsaturated ester 17 was converted into a
tetrahydrofuran by treatment with TBAF in THF through
Michael addition.10 After the ester carbonyl group was
reduced by DIBAL-H, protection of the hydroxyl group
with TBDMSCl and deprotection of the benzyloxy group by
hydrogenation using palladium–charcoal (Pd–C) in EtOH
afforded a 1:1 mixture of 18a and its 20R-isomer 18b, which
was separated by silica gel column chromatography.
Relative stereochemistry between H-20 and H-23 of 18a
and 18b was elucidated to be anti and syn, respectively, by
NOESY correlations (18a: H2-19/H-23 and H-20/H2-24,
18b: H-20/H-22). The alcohol 18a was then subjected to
Parikh–Doering oxidation11 and the resultant aldehyde was
treated with vinylmagnesium bromide to afford a 1:1
mixture of 19a and 19b, which was separated by silica gel
column chromatography. Absolute configuration at C-24 in
Figure 1. Graphs for differences between proton chemical shifts of
pentakis-(S)-MTPA ester (2) derived from amphidinolide C (1) and those of
synthetic (a) (7S,8R)- and (b) (7R,8S)-C-1–C-10 segments [5a and 5b,
respectively]. The x and y axes represent proton number and Dd
[d(2)2d(synthetic segments) in ppm], respectively.
Scheme 1. Reagents and conditions: (a) TBSCl, imidazole, DMF, rt, 1 h;
(b) H2, Pd–C, EtOH, rt, 6 h; (c) Dess–Martin periodinane, NaHCO3,
CH2Cl2, rt, 30 min; (d) vinylMgBr, THF, 08C, 1 h.

T. Kubota et al. / Tetrahedron 59 (2003) 1613–1625
1615
Scheme 2. Reagents and conditions: (a) TESCl, imidazole, DMF, rt, 3 h; (b) OsO4, NMO, acetone, H2O, rt, 16 h; (c) NaIO4, THF–phosphate buffer (1:1), 08C,
1 h; (d) isopropenylMgBr, THF, 2788C, 30 min; (e) AcOH–H2O–THF (3:1:1), rt, 6 h; (f) 2,2-dimethoxypropane, PPTS, acetone, rt, 1 h; (g) DMSO, SO3–
pyridine, Et3N, CH2Cl2, rt, 1 h; (h) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH–H2O (4:1), 08C, 1 h; (i) TMSCHN2, MeOH, 08C, 1 h; (j) PPTS, MeOH,
558C, 5 h; (k) (R)-MTPACl, DMAP, Et3N, CH2Cl2, rt, 1 h; (l) (S)-MTPACl, DMAP, Et3N, CH2Cl2, rt, 1 h.
19a was determined as R by modified Mosher’s method
(selective Dd values; H2-22: 20.07 and 20.06, H-23:
20.01, H-25: þ0.17, H2-26: þ0.14 and þ0.08). The
hydroxyl group of 19a was converted into 2-(trimethylsi-
lyl)ethoxymethyl (SEM) ethers 20a (Scheme 4). Treatment
of the terminal olefin in 20a with OsO4 and then NaIO4
resulted in generation of an aldehyde, which was condensed
with (3-methyl-2-butene-1-sulfonyl)benzene12 using Julia
coupling13 to afford a diastereomeric mixture of b-hydroxy
sulfones. Protection of the resultant hydroxyl group with
benzoyl chloride (BzCl) converted the mixture of alcohols
into a mixture of b-benzoyloxy sulfones 21a. In this stage,
SEM and TBDMS groups were deprotected by treatment of
21a with trifluoroacetic acid in CH2Cl2 at 08C, and then two
hydroxyl groups were protected by triethylsilyl chloride
(TESCl) to afford a bis-TES ether 22a, since removal of the
SEM group was troublesome in later steps. To form a diene
unit, the resultant bis-TES ether 22a was treated with
sodium amalgam [Na(Hg)] to afford an E-olefin 23a. In this
stage, the Z-isomer of 23a was not obtained. The TES group
on C-18 of 23a was removed selectively by treatment with
AcOH–THF–H2O (1:20:20) at 08C to afford 24a. The
hydroxyl group of 24a was oxidized by Parikh–Doering
procedure and then the resultant aldehyde was treated with
MeMgBr to afford an alcohol with the terminal carbon
elongation, which was oxidized again to afford ketone 25a.
The TES group at C-24 of 25a was carefully deprotected by
treatment with AcOH–THF–H2O (1:10:10) at 08C to afford
the (20R,23R,24R)-C-17–C-29 segment (6a). Finally, the
segment 6a was transformed into (R)- and (S)-MTPA esters
(7a and 7b, respectively). The (20R,23R,24S)-C-17–C-29
segment (6b) and its (R)- and (S)-MTPA esters (7c and 7d,
respectively) were also synthesized by similar procedures
from the 24S-isomer (19b) of 19a.
1
The H NMR profiles of four diastereomers (7a–d) were
compared with that of the corresponding portion in 3, which
was derived by four-step conversion of amphidinolide C (1):
actonization of C-7 and C-8 and protection of C-29,
hydrolysis of a ester carbonyl group, and esterification of
hydroxyl groups at C-13 and C-24 with (R)-MTPACl. The
1H NMR profiles of the C-17–C-29 portion in 3 were close
Scheme 3. Reagents and conditions: (a) DIBAL-H, CH2Cl2, 2788C, 1 h; (b) Ph3PvCHCO2Et, benzene, 558C, 16 h; (c) TBAF, THF, rt, 1 h; (d) DIBAL-H,
CH2Cl2, 2788C, 1 h; (e) TBDMSCl, imidazole, DMF, rt, 3.5 h; (f) H2, Pd–C, EtOH, rt, 6 h; (g) SO3-pyridine, DMSO, Et3N, CH2Cl2, 08C then rt, 20 min;
(h) vinylMgBr, THF, 08C, 1 h.

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T. Kubota et al. / Tetrahedron 59 (2003) 1613–1625
Scheme 4. Reagents and conditions: (a) (i) SEMCl, i-Pr2NEt, CH2Cl2, rt, 4 h; (b) OsO4, NMO, acetone–H2O (8:1), rt, 19 h; (c) NaIO4, THF–phosphate buffer
(1:1), 08C then rt, 1 h; (d) (CH3)2C¼CHCH2SO2Ph, BuLi, THF, 2788C, 2 h, then rt, 1 h; (e) BzCl, DMAP, Et3N, CH2Cl2, rt, 20 h; (f) TFA, CH2Cl2, 08C,
30 min; (g) TESCl, imidazole, DMF, rt, 3 h; (h) Na(Hg), Na2HPO4, THF–MeOH (3:1), 2208C, 1 h; (i) AcOH–H2O–THF (1:20:20), 08C, 1 h; (j) SO3–
pyridine, DMSO, Et3N, CH2Cl2, 08C then rt, 30 min; (k) MeMgBr, THF, 08C, 1 h; (l) SO3-pyridine, DMSO, Et3N, CH2Cl2, rt, 30 min; (m) AcOH–H2O–THF
(1:10:10), 08C, 4 h; (n) (R)-MTPACl, DMAP, Et3N, CH2Cl2, rt, 16 h; (o) (S)-MTPACl, DMAP, Et3N, CH2Cl2, rt, 16 h.
to those of 7a rather than those of 7b–d, suggesting that 3
possessed 20R-, 23R-, and 24R-configurations. Therefore,
the absolute configurations at C-20, C-23 and C-24 in
amphidinolide C (1) were concluded as R, R, and R,
respectively as estimated previously (Fig. 2).
chemical shifts with those of 2a and 2b. As a result, the
absolute configurations at C-7, C-8, C-20, C-23, and C-24 in
amphidinolide C (1) were concluded as all R unambiguously.
3. Experimental
In conclusion, the absolute configurations at C-7, C-8, C-20,
C-23, and C-24 in amphidinolide C (1) were reinvestigated
on the basis of synthesis of the diastereomers corresponding
to the C-1–C-10 and C-17–C-29 portions in the derivatives
(2 and 3, respectively) of 1 and comparison of their 1H NMR
3.1. General experimental procedures
1H, 13C, and 2D NMR spectra were recorded on a Bruker
AMX-500 and 600 spectrometers at 300 K. FABMS spectra
were recorded on a JEOL JMS-HX110 using p-nitrobenzyl
alcohol as matrix in positive mode. Positive mode
electrospray ionization (ESI) mass spectra were measured
on a JEOL JMS-700TZ using samples dissolved in MeOH
with flow rate of 0.1 mL/min. Column chromatography
(CC) was performed on silica gel (Wakogel C-200).
3.1.1. (2S,3R,5R)-2-[2-(tert-Butyldimethylsilyloxy)ethyl]-
5-benzyloxymethyl-3-methyltetrahydrofuran
(9).
(2S,3R,5R)-2-(5-Benzyloxymethyl-3-methyltetrahydro-
furan-2-yl)-ethanol5 (8, 1.20 g, 4.79 mmol) dissolved in dry
DMF (18.5 mL) was treated with TBDMSCl (1.10 g,
7.30 mmol) and imidazole (635 mg, 9.33 mmol) at rt for
1 h. After addition of saturated aqueous NH4Cl, the mixture
was extracted with Et2O. The organic layer was washed
with H2O and brine, dried, and concentrated. The residue
was purified by CC (hexane–EtOAc, 15:1) to afford
compound 9 (1.72 g, 4.73 mmol, 99%) as colorless oil;
[a]2D0¼288 (c 1.0, CHCl3); IR (neat) nmax 3064, 3030, 2955,
2928, 2857, 1496, 1461, 1360, 1095, 734, and 697 cm21; 1H
NMR (500 MHz; CDCl3) dH 0.06 (6H, s), 0.90 (9H, s), 1.02
Figure 2. Graphs for differences between proton chemical shifts of bis-(S)-
MTPA ester (3) derived from amphidinolide C (1) and those of synthetic
(a) (S)- and (b) (R)-MTPA ester of (24S)- and (c) (S)- and (d) (R)-MTPA
ester of (24R)-C-17–C-29 segments [7a–d, respectively]. The x and y axes
represent proton number and Dd [d(3)2d(synthetic segments) in ppm],
respectively.

T. Kubota et al. / Tetrahedron 59 (2003) 1613–1625
1617
(3H, d, J¼6.6 Hz), 1.33 (1H, m), 1.67 (1H, m), 1.80 (1H,
m), 1.90 (1H, m), 2.14 (1H, m), 3.44 (1H, dd, J¼10.0,
4.4 Hz), 3.49 (1H, dd, J¼10.0, 5.6 Hz), 3.53 (1H, m), 3.73
(1H, m), 3.80 (1H, m), 4.17 (1H, m), 4.56 (1H, d,
J¼12.3 Hz), 4.60 (1H, d, J¼12.3 Hz), and 7.25–7.35 (5H,
m); 13C NMR (125 MHz; CDCl3) dC 25.3 (2C, q), 16.4 (q),
18.3 (s), 25.9 (3C, q), 37.3 (t), 37.9 (t), 39.7 (d), 60.5 (t),
73.2 (t), 73.3 (t), 77.0 (d), 82.1 (d), 127.4 (d), 127.6 (2C, d),
128.3 (2C, d), and 138.5 (s); FABMS m/z 365 (MþH)þ;
HRFABMS m/z 365.2483 [(MþH)þ, calcd for C21H37O3Si:
365.2512].
HRFABMS m/z 301.2186 [(MþH)þ, calcd for C16H33O3Si:
301.2199].
Compound 11b. Colorless oil; [a]2D0¼2248 (c 1.0, CHCl3);
IR (neat) nmax 3451, 2954, 2929, 2856, 1458, and 1095 cm21
;
1H NMR (500 MHz; CDCl3) dH 0.03 (6H, s), 0.87 (9H, s),
0.99 (3H, d, J¼6.2 Hz), 1.53 (1H, m), 1.58 (1H, m), 1.77 (1H,
m), 1.83–1.93 (2H, m), 3.53 (1H, m), 3.66–3.78 (2H, m),
3.95 (1H, m), 4.25 (1H, m), 5.14 (1H, m), 5.29 (1H, m), and
5.76 (1H, m); 13C NMR (125 MHz; CDCl3) dC 25.4 (2C, q),
16.1 (q), 18.2 (s), 25.9 (3C, q), 34.5 (t), 37.5 (t), 39.9 (d), 60.3
(t), 73.4 (d), 80.7 (d), 83.0 (d), 116.1 (t), and 136.4 (d);
FABMS m/z 301 (MþH)þ; HRFABMS m/z 301.2211
[(MþH)þ, calcd for C16H33O3Si: 301.2199].
3.1.2. {(2R,4R,5S)-5-[2-(tert-Butyldimethylsilylox-
y)ethyl]-4-methyltetrahydrofuran-2-yl}-methanol (10).
Compound 9 (1.70 g, 4.67 mmol) was treated with 10%
Pd–C (170 mg) in EtOH (47 mL) under hydrogen atmos-
phere at rt for 6 h. After filtration of the catalyst, the filtrate
was evaporated to afford compound 10 (1.26 g, 4.59 mmol,
98%) as colorless oil; [a]2D0¼268 (c 1.0, CHCl3); IR (neat)
3.1.4. (S)-MTPA ester of 11b. To a solution of 11b
(0.5 mg, 1.67 mmol) in CH2Cl2 (60 mL) were added DMAP
(30 mg), Et3N (0.13 mL), and (R)-(2)-MTPACl (0.23 mL)
at rt, and stirring was continued for 18 h. N,N-Dimethyl-1,3-
propanediamine (0.23 mL) was added, and the reaction
mixture was stirred for 10 min. After addition of phosphate
buffer (pH 6.85), the reaction mixture was extracted with
CHCl3, and then the organic layer was evaporated. The
residue was purified by CC (hexane–EtOAc, 1:0 to 2:1) to
afford an (S)-MTPA ester of 11a (0.8 mg, 1.55 mmol, 93%)
n
max 3433, 3063, 3029, 2929, 2872, 1496, 1454, 1378, 1052,
737, and 699 cm21; H NMR (500 MHz; CDCl3) dH 0.04
(6H, s), 0.88 (9H, s), 1.00 (3H, d, J¼6.6 Hz), 1.33 (1H, m),
1.61 (1H, m), 1.79 (1H, m), 1.90 (1H, m), 2.06 (1H, m), 3.46
(1H, dd, J¼11.8, 6.4 Hz), 3.49 (1H, m), 3.60 (1H, dd,
J¼11.8, 2.5 Hz), 3.70 (1H, m), 3.76 (1H, m), and 4.06 (1H,
m); 13C NMR (125 MHz; CDCl3) dC 25.4 (2C, q), 16.3 (q),
18.2 (s), 25.9 (3C, q), 36.6 (t), 37.3 (t), 40.0 (d), 60.4 (t),
65.2 (t), 78.4 (d), and 82.0 (d); FABMS m/z 275 (MþH)þ;
HRFABMS m/z 275.2036 [(MþH)þ, calcd for C14H31O3Si:
275.2042].
1
1
as colorless oil; H NMR (600 MHz; CDCl3) dH 0.05 (6H,
s), 0.89 (9H, s), 0.97 (3H, d, J¼6.2 Hz, H-35), 1.50 (1H, m,
H-5), 1.62 (1H, m, H-2), 1.78 (1H, m, H-2), 1.89 (1H, m, H-
4), 2.03 (1H, m, H-5), 3.46 (1H, brdt, J¼3.1, 8.7 Hz, H-3),
3.56 (3H, s, OMe), 3.67 (1H, m, H-1), 3.77 (1H, m, H-1),
4.12 (1H, m, H-6), 5.27 (1H, brd, J¼10.6 Hz, H-9), 5.31
(1H, brd, J¼16.8 Hz, H-9), 5.57 (1H, dd, J¼6.9, 3.7 Hz, H-
7), 5.74 (1H, ddd, J¼16.8, 10.6, 6.9 Hz, H-8), and 7.35–
7.61 (5H, m, ph); FABMS m/z 517 (MþH)þ; HRFABMS
m/z 517.2603 [(MþH)þ, calcd for C26H40O5F3Si:
517.2597].
3.1.3. (1R)- and (1S)-1-{(2R,4R,5S)-5-[2-(tert-Butyldi-
methylsilyloxy)ethyl]-4-methyltetrahydrofuran-2-yl}-2-
propen-1-ol (11a and 11b). To a solution of 10 (511.2 mg,
1.86 mmol) in CH2Cl2 (30 mL) were added NaHCO3
(950 mg) and Dess–Martin periodinane (950.5 mg,
2.24 mmol), and the mixture was stirred at rt for 30 min.
The reaction was quenched by addition of saturated aqueous
Na2S2O3 (10 mL), and then the mixture was extracted with
Et2O. The organic layer was washed with H2O and brine,
dried, and concentrated. The residue was purified by CC
(hexane–EtOAc, 15:1 to 10:1) to afford an aldehyde
(474 mg, 1.74 mmol, 93%) as colorless oil. To a stirred
solution of the aldehyde (474 mg, 1.74 mmol) in THF
(5.0 mL) was added vinylMgBr (1.06 M, 5.0 mL, 5.3 mmol)
in Et2O at 08C. After stirring for 1 h, the reaction was
quenched by addition of saturated aqueous NH4Cl, and then
the mixture was extracted with Et2O. The organic layer was
washed with H2O and brine, dried, and concentrated. The
residue was purified by CC (hexane–EtOAc, 8:1 to 3:1) to
afford compounds 11a (181.4 mg, 605 mmol, 35%) and 11b
(185.2 mg, 617 mmol, 35%).
3.1.5. (R)-MTPA ester of 11b. The (R)-MTPA ester of 11b
(1.5 mg, 1.5 mmol) was obtained from 11b (0.5 mg,
1.6 mmol) in 92% yield through the same procedure as
described for preparation of the (S)-MTPA ester of 11a. (R)-
1
MTPA ester of 11b. H NMR (600 MHz; CDCl3) dH 0.04
(6H, s), 0.89 (9H, s), 0.94 (3H, d, J¼6.2 Hz, H-35), 1.40
(1H, m, H-5), 1.57 (1H, m, H-2), 1.73 (1H, m, H-2), 1.83
(1H, m, H-4), 1.99 (1H, m, H-5), 3.39 (1H, brdt, J¼3.1,
8.7 Hz, H-3), 3.55 (3H, s, OMe), 3.64 (1H, m, H-1), 3.71
(1H, m, H-1), 4.05 (1H, m, H-6), 5.33 (1H, brd, J¼10.6 Hz,
H-9), 5.41 (1H, brd, J¼16.8 Hz, H-9), 5.55 (1H, dd, J¼6.9,
3.7 Hz, H-7), 5.82 (1H, ddd, J¼16.8, 10.6, 6.9 Hz, H-8), and
7.34–7.57 (5H, m, ph); FABMS m/z 517 (MþH)þ;
HRFABMS m/z 517.2605 [(MþH)þ, calcd for
C26H40O5F3Si: 517.2597].
Compound 11a. Colorless oil; [a]2D0¼2238 (c 1.0, CHCl3);
IR (neat) nmax 3459, 2956, 2930, 2857, 1462, and
3.1.6. (2S,3R,5R)-2-[2-(tert-Butyldimethylsilyloxy)ethyl]-
3-methyl-5-[(1R)-1-(triethylsilyloxy)-2-propenyl]-tetra-
hydrofuran (12a). Compound 11a (176.2 mg, 587 mmol)
dissolved in dry DMF (2.0 mL) was treated with TESCl
(160 mL, 0.9 mmol) and imidazole (82.6 mg, 1.21 mmol) at
rt for 3 h. After evaporation of the solvent, the reaction
mixture was purified by CC (hexane–EtOAc, 15:1) to afford
12a (238.2 mg, 575 mmol, 98%). Colorless oil; [a]2D0¼238
(c 1.0, CHCl3); IR (neat) nmax 2955, 2876, 1457 and
1
1095 cm21; H NMR (500 MHz; CDCl3) dH 0.00 (6H, s),
0.84 (9H, s), 0.96 (3H, d, J¼6.2 Hz), 1.28 (1H, m), 1.56
(1H, m), 1.75 (1H, m), 1.85 (1H, m), 2.01 (1H, m), 3.46 (1H,
m), 3.63–3.74 (2H, m), 3.77 (1H, m), 3.87 (1H, m), 5.12
(1H, m), 5.30 (1H, m), and 5.72 (1H, m); 13C NMR
(125 MHz; CDCl3) dC 25.4 (2C, q), 16.1 (q), 18.2 (s), 25.8
(3C, q), 37.0 (t), 37.2 (t), 40.1 (d), 60.2 (t), 75.9 (d), 80.8 (d),
81.9 (d), 116.6 (t), and 136.6 (d); FABMS m/z 301 (MþH)þ;
1
1095 cm21; H NMR (500 MHz; CDCl3) dH 0.04 (6H, s),

1618
T. Kubota et al. / Tetrahedron 59 (2003) 1613–1625
1
0.60 (6H, q, J¼8.1 Hz), 0.89 (9H, s), 0.94 (9H, t, J¼8.1 Hz),
0.97 (3H, d, J¼6.2 Hz), 1.34 (1H, m), 1.59 (1H, m), 1.73–
1.86 (2H, m), 1.97 (1H, m), 3.41 (1H, m), 3.68 (1H, m), 3.78
(1H, m), 3.89 (1H, m), 4.10 (1H, m), 5.12 (1H, m), 5.27 (1H,
m), and 5.83 (1H, m); 13C NMR (125 MHz; CDCl3) dC
25.3 (2C, q), 5.0 (3C, t), 6.7 (3C, q), 15.9 (q), 18.3 (s), 26.0
(3C, q), 36.7 (t), 37.3 (t), 39.9 (d), 60.7 (t), 76.0 (d), 81.1 (d),
82.0 (d), 115.5 (t), and 137.8 (d); FABMS m/z 415 (MþH)þ;
HRFABMS m/z 415.3069 [(MþH)þ, calcd for
C22H47O3Si2: 415.3064].
1096 cm21; H NMR (500 MHz; CDCl3) dH 0.05 (6H, s),
0.65 (6H, q, J¼8.1 Hz), 0.88 (9H, s), 0.98 (9H, t, J¼8.1 Hz),
1.00 (3H, d, J¼6.2 Hz), 1.53–1.63 (2H, m), 1.74 (3H, s),
1.75–1.84 (2H, m), 1.97 (1H, dt, J¼11.8, 6.5 Hz), 3.54 (1H,
dt, J¼2.4, 9.3 Hz), 3.68 (2H, m), 3.76 (1H, ddd, J¼10.0,
8.1, 5.0 Hz), 4.06 (1H, ddd, J¼9.3, 6.2, 3.1 Hz), 4.14 (1H, d,
J¼3.7 Hz), 4.92 (1H, s), and 5.09 (1H, s); 13C NMR
(125 MHz; CDCl3) dC 5.4 (2C, q), 5.2 (3C, t), 6.9 (3C, q),
15.9 (s), 18.3 (q), 19.4 (q), 25.9 (3C, q), 36.9 (t), 37.3 (t),
39.4 (d), 60.6 (t), 73.9 (d), 78.1 (d), 78.5 (d), 82.9 (d), 112.3
(t), and 145.0 (s); FABMS m/z 459 (MþH)þ; HRFABMS
m/z 459.3346 [(MþH)þ, calcd for C24H51O4S2: 459.3326].
3.1.7. (2S,3R,5R)-2-[2-(tert-Butyldimethylsilyloxy)ethyl]-
3-methyl-5-[(1S)-1-(triethylsilyloxy)-2-propenyl]-tetra-
hydrofuran (12b). Compound 12b (239.5 mg, 577 mmol)
was obtained from 11b (180.1 mg, 600 mmol) in 96% yield
through the same procedure as described for preparation of
12a.
Compound 13b. Colorless oil; [a]2D0¼2108 (c 1.0, CHCl3);
IR (neat) nmax 3484, 2955, 2875, 1453, 1376, and
1
1093 cm21; H NMR (500 MHz; CDCl3) dH 0.05 (6H, s),
0.62 (6H, q, J¼8.1 Hz), 0.89 (9H, s), 0.94 (9H, t, J¼8.1 Hz),
1.02 (3H, d, J¼6.2 Hz), 1.30 (1H, m), 1.53 (1H, m), 1.72
(3H, s), 1.78 (1H, m), 1.88 (1H, m), 1.97 (1H, ddd, J¼12.2,
6.3 Hz), 3.45 (1H, brt, J¼8.9 Hz), 3.58 (1H, brd, J¼6.9 Hz),
3.67 (1H, dt, J¼9.6, 7.3 Hz), 3.80 (1H, ddd, J¼9.9, 9.6,
7.3 Hz), 3.86 (1H, brs), 4.06 (1H, dt, J¼10.0, 6.5 Hz), 4.90
(1H, s), and 5.02 (1H, s); 13C NMR (125 MHz; CDCl3) dC
25.4 (1C, q), 25.3 (1C, q), 5.2 (3C, t), 6.9 (3C, q), 16.0 (s),
18.3 (q), 19.2 (q), 25.9 (3C, q), 37.5 (t), 37.9 (t), 40.0 (d),
60.8 (t), 74.1 (d), 75.9 (d), 80.0 (d), 82.1 (d), 111.2 (t), and
145.1 (s); FABMS m/z 459 (MþH)þ; HRFABMS m/z
459.3308 [(MþH)þ, calcd for C24H51O4S2: 459.3326].
Compound 12b. Colorless oil; [a]2D0¼2218 (c 1.0, CHCl3);
IR (neat) nmax 2956, 2863, 1458, and 1094 cm21; 1H NMR
(500 MHz; CDCl3) dH 0.04 (6H, s), 0.60 (6H, q, J¼8.1 Hz),
0.88 (9H, s), 0.95 (9H, t, J¼8.1 Hz), 0.99 (3H, d, J¼6.2 Hz),
1.35 (1H, m), 1.59 (1H, m), 1.72–1.85 (2H, m), 1.92 (1H,
m), 3.47 (1H, m), 3.67 (1H, m), 3.77 (1H, m), 3.87 (1H, m),
4.23 (1H, m), 5.07 (1H, m), 5.22 (1H, m), and 5.77 (1H, m);
13C NMR (125 MHz; CDCl3) dC 25.4 (2C, q), 4.9 (3C, t),
6.8 (3C, q), 15.9 (q), 18.3 (s), 26.0 (3C, q), 34.9 (t), 37.6 (t),
39.9 (d), 60.8 (t), 75.5 (d), 81.2 (d), 82.6 (d), 114.9 (t), and
138.7 (d); FABMS m/z 415 (MþH)þ; HRFABMS m/z
415.3058 [(MþH)þ, calcd for C22H47O3Si2: 415.3064].
3.1.9. (S)-MTPA ester of 13a. The (S)-MTPA ester of 13a
(0.6 mg, 0.8 mmol) was obtained from 13a (0.5 mg,
1.1 mmol) in 72% yield through the same procedure as
described for preparation of the (S)-MTPA ester of 11b. (S)-
3.1.8. (1R,2R)- and (1R,2S)-1-{(2R,4R,5S)-5-[2-(tert-
Butyldimethylsilyloxy)ethyl]-4-methyltetrahydrofuran-
2-yl}-3-methyl-1-triethylsilyloxy-3-buten-2-ol (13a and
13b). Compound 12a (233.4 mg, 564 mmol) was dissolved
in an 8:1 mixture (6.5 mL) of acetone and H2O, and to this
mixture were added 1% OsO4 in t-BuOH (720 mL, 28 mmol)
and NMO (132.2 mg, 1.13 mmol). After stirring at rt for 16 h,
the reaction was quenched by addition of saturated aqueous
NaHSO3, and then the mixture was extracted with EtOAc. The
organic layer was washed with brine, dried, and concentrated.
The residuewas purifiedbyCC(hexane–EtOAc, 5:1to3:1)to
afford a mixture of diols (245.7 mg, 547 mmol, 97%) as
colorless oil. To a stirring solution of the mixture of diols
(79.5 mg, 177 mmol) in a 1:1 mixture (1.6 mL) of THF and
potassium phosphate buffer (pH 6.8) was added NaIO4
(56.8 mg, 404 mmol) at 08C. After stirring at 08C for 1 h, the
mixture was extracted with Et2O. The organic layer was
washed with brine, dried, and concentrated. The residue was
purified by CC (hexane–EtOAc, 20:1 to 10:1) to afford an
aldehyde (71.3 mg, 171 mmol, 97%) as colorless oil. To a
stirred solution of the aldehyde (71.3 mg, 171 mmol) in THF
(0.8 mL) was added isopropenylMgBr (0.675 M, 1.6 mL,
1.08 mmol) in THF at 2788C. After stirring for 30 min, the
reaction was quenched by addition of saturated aqueous
NH4Cl and then the mixture was extracted with Et2O. The
organic layer was washed with H2O and brine, dried, and
concentrated. The residue was purified by CC (hexane–
EtOAc, 8:1 to 3:1) to afford 13a (40.3 mg, 88.0 mmol, 51%)
and 13b (23.8 mg, 52.0 mmol, 30%).
1
MTPA ester of 13a. Colorless oil; H NMR (600 MHz;
CDCl3) dH 0.05 (6H, s), 0.49 (6H, m), 0.86 (9H, t,
J¼8.1 Hz), 0.89 (9H, s), 0.97 (3H, d, J¼6.9 Hz, H-35),
1.19–1.39 (2H, m), 1.50–1.65 (1H, m), 1.77 (1H, m), 1.84
(3H, s, H-10), 1.90 (1H, m, H-5), 3.37 (1H, brdt, J¼2.5,
9.3 Hz, H-3), 3.56 (3H, s, OMe), 3.63–3.73 (3H, m), 3.78
(1H, m, H-6), 5.04 (1H, brs, H-36), 5.08 (1H, s, H-36), 5.41
(1H, d, J¼4.4 Hz, H-8), and 7.34–7.59 (5H, m, ph);
FABMS m/z 675 (MþH)þ; HRFABMS m/z 675.3722
[(MþH)þ, calcd for C34H58O6F3Si2: 675.3724].
3.1.10. (R)-MTPA ester of 13a. The (R)-MTPA ester of
13a (0.7 mg, 1.0 mmol) was obtained from 13a (0.5 mg,
1.1 mmol) in 95% yield through the same procedure as
described for preparation of the (S)-MTPA ester of 11b. (R)-
1
MTPA ester of 13a. Colorless oil; H NMR (600 MHz;
CDCl3) dH 0.05 (6H, s), 0.58 (6H, m), 0.88 (9H, s), 0.91
(9H, t, J¼8.1 Hz), 0.98 (3H, d, J¼6.2 Hz, H-35), 1.21–1.41
(2H, m), 1.70 (3H, s, H-10), 1.50–1.65 (1H, m), 1.74–1.88
(1H, m), 1.97 (1H, m, H-5), 3.39 (1H, brdt, J¼2.5, 9.3 Hz,
H-3), 3.57 (3H, s, OMe), 3.67 (1H, dt, J¼10.0, 7.5 Hz, H-7),
3.74–3.82 (2H, m), 3.89 (1H, dd, J¼10.0, 5.6 Hz, H-6),
4.93 (1H, s, H-36), 4.96 (1H, brs, H-36), 5.41 (1H, d,
J¼4.4 Hz, H-8), and 7.33–7.63 (5H, m, ph); FABMS m/z
675 (MþH)þ; HRFABMS m/z 675.3726 [(MþH)þ, calcd
for C34H58O6F3Si2: 675.3724].
3.1.11. (1S,2S)- and (1S,2R)-1-{(2R,4R,5S)-5-[2-(tert-
Butyldimethylsilyloxy)ethyl]-4-methyltetrahydrofuran-
2-yl}-3-methyl-1-triethylsilyloxy-3-buten-2-ol (13c and
Compound 13a. Colorless oil; [a]2D0¼2258 (c 1.0, CHCl3);
IR (neat) nmax 3480, 2955, 2877, 1456, 1378, and

T. Kubota et al. / Tetrahedron 59 (2003) 1613–1625
1619
13d). Compound 13c (138.2 mg, 302 mmol) and 13d
(24.6 mg, 53.7 mmol) were obtained from 12b (235.1 mg,
568 mmol) in 60 and 12% yield, respectively, through
the same procedure as described for preparation of 13a and
13b.
FABMS m/z 675 (MþH)þ; HRFABMS m/z 675.3719
[(MþH)þ, calcd for C34H58O6F3Si2: 675.3724].
3.1.14. (1R,2R)-1-[(2R,4R,5S)-5-(2-Hydroxyethyl)-4-
methyltetrahydrofuran-2-yl]-3-methyl-3-butene-1,2-diol
(14a). Compound 13a (36.0 mg, 78.6 mmol) was dissolved
in a 3:1:1 mixture (4.0 mL) of AcOH, H2O, and THF. After
stirring at rt for 6 h, the reaction was quenched by addition
of NaHCO3. After filtration of the insoluble material, the
filtrate was concentrated. The residue was purified by CC
(CHCl3–MeOH, 9:1) to afford a triol 14a (15.5 mg,
67.4 mmol, 86%). Colorless oil; [a]2D0¼2218 (c 1.0,
Compound 13c. Colorless oil; [a]2D0¼2128 (c 1.0, CHCl3);
IR (neat) nmax 3470, 2955, 2930, 2867, 1472 and
1
1095 cm21; H NMR (500 MHz; CDCl3) dH 0.04 (6H, s),
0.64 (6H, q, J¼8.1 Hz), 0.88 (9H, s), 0.97 (9H, t, J¼8.1 Hz),
1.00 (3H, d, J¼6.2 Hz), 1.59 (2H, m), 1.74 (3H, s), 1.71–
1.87 (2H, m), 2.00 (1H, ddd, J¼12.5, 6.2, 5.6 Hz), 3.43 (1H,
ddd, J¼9.0, 9.0, 3.1 Hz), 3.65 (1H, ddd, J¼10.0, 6.9,
6.9 Hz), 3.75 (1H, ddd, J¼10.0, 8.1, 5.0 Hz), 3.90 (1H, ddd,
J¼10.0, 5.6, 3.7 Hz), 3.94 (1H, dd, J¼5.0, 3.7 Hz), 4.08
(1H, d, J¼5.0 Hz), 4.88 (1H, s), and 5.07 (1H, s); 13C NMR
(125 MHz; CDCl3) dC 25.3 (2C, q), 5.1 (3C, t), 6.9 (3C, q),
16.2 (s), 18.3 (q), 19.3 (q), 25.9 (3C, q), 36.4 (t), 37.7 (t),
40.1 (d), 60.7 (t), 74.3 (d), 77.5 (d), 78.4 (d), 82.0 (d), 111.8
(t), and 143.2 (s); FABMS m/z 459 (MþH)þ; HRFABMS
m/z 459.3308 [(MþH)þ, calcd for C24H51O4Si2: 459.3326].
CHCl3); IR (neat) nmax 3420, 2957, 1455, and 1053 cm21
;
1H NMR (500 MHz; CDCl3) dH 1.03 (3H, d, J¼6.2 Hz),
1.62 (1H, m), 1.73 (1H, m), 1.75 (3H, s), 1.83–1.95 (2H, m),
2.03 (1H, ddd, J¼11.8, 6.2, 6.2 Hz), 3.56 (1H, dd, J¼5.0,
2.5 Hz), 3.64 (1H, ddd, J¼9.0, 9.0, 2.5 Hz), 3.72–3.83 (2H,
m), 4.18 (1H, m), 4.97 (1H, brs), and 5.07 (1H, brs); 13C
NMR (125 MHz; CDCl3) dC 15.8 (q), 18.7 (q), 36.7 (t), 36.9
(t), 39.7 (d), 60.9 (t), 72.1 (d), 77.5 (d), 77.5 (d), 85.3 (d),
112.5 (t), and 144.6 (s); FABMS m/z 231 (MþH)þ;
HRFABMS m/z 231.1589 [(MþH)þ, calcd for C12H23O4:
231.1596].
Compound 13d. Colorless oil; [a]2D0¼288 (c 1.0, CHCl3);
1
IR (neat) nmax 3478, 2955, 2872, 1468 and 1093 cm21; H
NMR (500 MHz; CDCl3) dH 0.05 (6H, s), 0.64 (6H, q,
J¼8.1 Hz), 0.89 (9H, s), 0.97 (9H, t, J¼8.1 Hz), 1.02 (3H, d,
J¼6.2 Hz), 1.55–165 (2H, m), 1.75 (3H, s), 1.78 (1H, m),
1.84 (1H, m), 1.97 (1H, m), 3.49 (1H, brt, J¼9.0 Hz), 3.62–
3.70 (2H, m), 3.75 (1H, m), 3.88 (1H, m), 4.13 (1H, m), 4.92
(1H, s), and 5.00 (1H, s); 13C NMR (125 MHz; CDCl3) dC
25.4 (1C, q), 25.3 (1C, q), 5.2 (3C, t), 6.9 (3C, q), 16.0 (s),
16.4 (q), 18.9 (q), 25.9 (3C, q), 36.3 (t), 37.9 (t), 40.0 (d),
60.6 (t), 74.8 (d), 75.9 (d), 79.7 (d), 82.9 (d), 112.5 (t), and
144.6 (s); FABMS m/z 459 (MþH)þ; HRFABMS m/z
459.3313 [(MþH)þ, calcd for C24H51O4S2: 459.3326].
3.1.15. (1S,2S)-1-[(2R,4R,5S)-5-(2-Hydroxyethyl)-4-
methyltetrahydrofuran-2-yl]-3-methyl-3-butene-1,2-diol
(14b). Compound 14b (59.9 mg, 260 mmol) was obtained
from 13b (130.2 mg, 284 mmol) in 92% yield through the
same procedure as described for preparation of 14a.
Compound 14b. Colorless oil; [a]2D0¼248 (c 1.0, CHCl3);
IR (neat) nmax 3425, 2956, 2930, 2860, 1460, and
1
1054 cm21; H NMR (500 MHz; CDCl3) dH 1.05 (3H, d,
J¼6.2 Hz), 1.57–1.70 (2H, m), 1.79 (3H, s), 1.87 (1H, m),
1.93 (1H, m), 2.22 (1H, m), 3.63 (1H, dt, J¼2.5, 9.3 Hz),
3.65 (1H, brt, J¼6.5 Hz), 3.78 (2H, m), 4.07 (1H, dt, J¼9.3,
6.2 Hz), 4.12 (1H, d, J¼6.9 Hz), 5.01 (1H, s), and 5.06 (1H,
s); 13C NMR (125 MHz; CDCl3) dC 16.0 (q), 17.9 (q), 35.7
(t), 37.0 (t), 39.9 (d), 61.3 (t), 72.6 (d), 77.9 (d), 79.9 (d),
85.4 (d), 114.0 (t), and 144.3 (s); FABMS m/z 231 (MþH)þ;
HRFABMS m/z 231.1602 [(MþH)þ, calcd for C12H23O4
231.1596].
3.1.12. (S)-MTPA ester of 13c. The (S)-MTPA ester of 13c
(0.6 mg, 0.8 mmol) was obtained from 13c (0.5 mg,
1.1 mmol) in 72% yield through the same procedure as
described for preparation of the (S)-MTPA ester of 11b. (S)-
1
MTPA ester of 13c. As colorless oil; H NMR (600 MHz;
CDCl3) dH 0.04 (6H, s), 0.61 (6H, q, J¼8.1 Hz), 0.87 (9H,
s), 0.91 (9H, t, J¼8.1 Hz), 0.98 (3H, d, J¼6.2 Hz, H-35),
1.45–1.82 (5H, m), 1.71 (3H, s, H-10), 3.41 (1H, brdt,
J¼2.5, 8.7 Hz, H-3), 3.58 (3H, s, OMe), 3.64 (1H, dt,
J¼10.0, 7.5 Hz, H-1), 3.74 (1H, m, H-1), 3.90 (1H, m, H-6),
4.11 (1H, brt, J¼3.7 Hz, H-7), 4.72 (1H, s, H-36), 4.86 (1H,
brs, H-36), 5.36 (1H, d, J¼4.4 Hz, H-8), and 7.34–7.60 (5H,
m, ph); FABMS m/z 675 (MþH)þ; HRFABMS m/z
675.3712 [(MþH)þ, calcd for C34H58O6F3Si2: 675.3724].
3.1.16. Methyl {(2S,3R,5R)-5-[(1S,2R)-1,2-isopropylide-
nedioxy-3-methyl-3-butenyl]-3-methyltetrahydrofuran-
2-yl}-acetate (15a). Compound 14a (10.3 mg, 44.8 mmol)
was dissolved in acetone (1.5 mL) and treated with 2,2-
dimethoxypropane (0.5 mL) and PPTS (12 mg) at rt for 1 h.
After addition of H2O, the reaction mixture was extracted
with EtOAc. The organic layer was washed with brine,
dried, and evaporated to afford an acetonide (9.7 mg,
1
3.1.13. (R)-MTPA ester of 13c. The (R)-MTPA ester of 13c
(0.7 mg, 1.0 mmol) was obtained from 13c (0.5 mg,
1.1 mmol) in 91% yield through the same procedure as
described for preparation of the (S)-MTPA ester of 11b. (R)-
35.9 mmol, 80%): H NMR (500 MHz; CDCl3) dH 1.01
(3H, d, J¼6.2 Hz), 1.35 (1H, m), 1.39 (3H, s), 1.54 (3H, s),
1.64 (1H, m), 1.77 (3H, s), 1.82–1.93 (2H, m), 2.08 (1H,
ddd, J¼12.5, 6.2, 6.2 Hz), 3.61 (1H, ddd, J¼8.7, 8.7,
3.1 Hz), 3.73–3.83 (2H, m), 4.00 (1H, ddd, J¼9.3, 5.6,
5.6 Hz), 4.09 (1H, dd, J¼6.9, 5.6 Hz), 4.57 (1H, d,
J¼6.9 Hz), 4.98 (1H, s), and 5.09 (1H, s); 13C NMR
(125 MHz; CDCl3) dC 9.1 (q), 13.3 (q), 18.6 (q), 20.0 (q),
28.3 (t), 31.1 (t), 32.9 (d), 54.8 (t), 69.8 (d), 73.4 (d), 73.9
(d), 79.3 (d), 102.0 (s), 106.8 (t), and 134.1 (s); FABMS m/z
271 (MþH)þ; HRFABMS m/z 271.1918 [(MþH)þ, calcd
for C14H24O4 271.1909].
1
MTPA ester of 13c. Colorless oil; H NMR (600 MHz;
CDCl3) dH 0.04 (6H, s), 0.55 (6H, q, J¼8.1 Hz), 0.87 (9H,
s), 0.91 (9H, t, J¼8.1 Hz), 0.98 (3H, d, J¼6.2 Hz, H-35),
1.38 (1H, m), 1.43–1.73 (4H, m), 1.80 (3H, s, H-10), 3.36
(1H, brdt, J¼2.5, 8.7 Hz, H-3), 3.55 (3H, s, OMe), 3.62 (1H,
dt, J¼10.0, 7.5 Hz, H-1), 3.72 (2H, m), 4.01 (1H, dd, J¼5.6,
3.1 Hz, H-7), 5.01 (1H, brs, H-36), 5.06 (1H, s, H-36), 5.31
(1H, d, J¼5.6 Hz, H-8), and 7.34–7.56 (5H, m, ph);

1620
T. Kubota et al. / Tetrahedron 59 (2003) 1613–1625
To a solution of the acetonide (6.0 mg, 22.2 mmol)
dissolved in a mixture of DMSO (74.5 mL), CH2Cl2
(451 mL) and Et3N (25.9 mL) was added SO3-pyridine
complex (20.5 mg, 129 mmol) at 08C. After stirring at rt for
1 h, the solution was poured into H2O and the aqueous layer
was extracted with Et2O. The combined organic layer was
washed with H2O and brine, dried, and concentrated to
afford a crude aldehyde (6.0 mg, 22.2 mmol, quant.). To a
solution of the crude aldehyde (6.0 mg) in a mixture of t-
BuOH (1.56 mL) and H2O (388 mL) were added 2-methyl-
2-butene (2 M, 107.3 mL, 214 mmol) in THF, NaH2PO4
(17.4 mg), and NaClO2, (15.6 mg). After stirring at 08C for
1 h, saturated aqueous NaHSO3 was added, and the mixture
was extracted with EtOAc. The organic layer was washed
with brine, dried, and concentrated to afford a crude
carboxylic acid (5.7 mg, 20.1 mmol, 91%). To a solution
of the crude carboxylic acid in MeOH (1.0 mL) was added
trimethylsilyldiazomethane (TMSCHN2, 2 M, 125 mL,
250 mmol) in hexanes at 08C. After stirring at 08C for 1 h,
the solution was evaporated. The residue was purified by CC
(hexane–EtOAc, 15:1) to afford a methyl ester 15a (4.3 mg,
14.4 mmol, 72%).
m), 1.91 (1H, m), 2.04 (1H, ddd, J¼12.0, 6.6, 6.6 Hz), 2.43
(1H, dd, J¼15.3, 8.6 Hz), 2.55 (1H, dd, J¼15.3, 3.7 Hz),
3.57 (1H, dd, J¼4.8, 2.4 Hz), 3.69 (3H, s), 3.87 (1H, ddd,
J¼8.8, 8.8, 3.7 Hz), 4.15 (1H, ddd, J¼9.7, 6.1, 2.3 Hz), 4.20
(1H, d, J¼4.8 Hz), 4.97 (1H, brs), and 5.07 (1H, s); FABMS
m/z 259 (MþH)þ; HRFABMS m/z 259.1558 [(MþH)þ,
calcd for C13H23O5: 259.1546].
3.1.19. Methyl {(2S,3R,5R)-5-[(1S,2S)-1,2-dihydroxy-3-
methyl-3-butenyl]-3-methyltetrahydrofuran-2-yl}-ace-
tate (4b). Compound 4b (2.1 mg, 8.1 mmol) was obtained
from 15b (3.0 mg, 10.1 mmol) in 80% yield through the
same procedure as described for preparation of 4a.
Compound 4b. Colorless oil; [a]2D0¼268 (c 0.5, CHCl3); IR
1
(neat) nmax 3461, 2957, 2925, 1457, and 1033 cm21; H
NMR (500 MHz; CDCl3) dH 1.06 (3H, d, J¼6.6 Hz), 1.64
(1H, ddd, J¼12.8, 11.2, 9.4 Hz), 1.79 (3H, s), 1.95 (1H, m),
2.30 (1H, ddd, J¼12.8, 6.6, 6.6 Hz), 2.46 (1H, dd, J¼15.4,
8.8 Hz), 2.56 (1H, dd, J¼15.4, 3.5 Hz), 3.55 (1H, brt,
J¼7.08 Hz), 3.69 (3H, s), 3.89 (1H, ddd, J¼8.9, 8.9,
3.5 Hz), 4.03 (1H, ddd, J¼9.4, 6.3, 6.3 Hz), 4.15 (1H, d,
J¼7.5 Hz), 5.02 (1H, brs), and 5.05 (1H, s); FABMS m/z
259 (MþH)þ; HRFABMS m/z 259.1553 [(MþH)þ, calcd
for C13H23O5: 259.1546].
Compound 15a. Colorless oil; [a]2D0¼2218 (c 0.5, CHCl3);
IR (neat) nmax 2956, 2931, 1743, 1456, and 1044 cm21; 1H
NMR (500 MHz; CDCl3) dH 1.01 (3H, d, J¼6.6 Hz), 1.27
(1H, m), 1.39 (3H, s), 1.54 (3H, s), 1.77 (3H, s), 1.97 (1H,
m), 2.15 (1H, ddd, J¼12.3, 6.6, 6.6 Hz), 2.51 (1H, dd,
J¼14.9, 5.7 Hz), 2.60 (1H, dd, J¼14.9, 6.4 Hz), 3.66 (3H,
s), 3.89 (1H, ddd, J¼8.5, 6.1, 6.1 Hz), 3.97 (1H, m), 4.13
(1H, brt, J¼7.2 Hz), 4.54 (1H, d, J¼6.8 Hz), 4.96 (1H, s),
and 4.97 (1H, s); FABMS m/z 299 (MþH)þ; HRFABMS
m/z 299.1860 [(MþH)þ, calcd for C15H27O4: 299.1859].
3.1.20. Bis-(S)-MTPA ester (5a) of 4a. Compound 5a
(1.5 mg, 2.2 mmol) was obtained from 4a (0.7 mg,
2.7 mmol) in 81% yield through the same procedure as
described for preparation of the (S)-MTPA ester of 11a.
1
Compound 5a. Colorless oil; H NMR (600 MHz; CDCl3)
dH 0.86 (3H, d, J¼6.4 Hz, H-35), 1.22 (1H, brdt, J¼9.7,
11.4 Hz, H-5), 1.72 (3H, s, H-10), 1.81 (1H, m, H-4), 1.92
(1H, brdt, J¼12.3, 6.6 Hz, H-5), 2.36 (1H, dd, J¼14.7,
7.9 Hz, H-2), 2.46 (1H, dd, J¼14.7, 4.4 Hz, H-2), 3.40 (3H,
s, OMe), 3.51 (3H, s, OMe), 3.66 (3H, s, OMe), 3.71 (1H,
brdt, J¼4.4, 9.0 Hz, H-3), 3.81 (1H, brdt, J¼9.7, 5.7 Hz, H-
6), 5.04 (1H, brs, H-36), 5.10 (1H, s, H-36), 5.30 (1H, brt,
J¼6.0 Hz and H-7), 5.61 (1H, d, J¼6.8 Hz, H-8), and 7.32–
7.54 (10H, m, Ph); FABMS m/z 691 (MþH)þ; HRFABMS
m/z 691.2353 [(MþH)þ, calcd for C33H37O9F6: 691.2342].
3.1.17. Methyl {(2S,3R,5R)-5-[(1R,2S)-1,2-isopropylide-
nedioxy-3-methyl-3-butenyl]-3-methyltetrahydrofuran-
2-yl}-acetate (15b). Compound 15b (5.3 mg, 17.7 mmol)
was obtained from 14b (5.0 mg, 21.6 mmol) in 82% yield by
4 steps through the same procedure as described for
preparation of 15a.
Compound 15b. Colorless oil; [a]2D0¼þ18 (c 1.0, CHCl3); IR
1
(neat) nmax 2956, 2930, 2857, 1457, and 1055 cm21; H
NMR (500 MHz; CDCl3) dH 1.02 (3H, d, J¼6.4 Hz), 1.36
(3H, S), 1.45 (3H, s), 1.54 (1H, ddd, J¼12.5, 10.9, 9.0 Hz),
1.74 (3H, s), 1.86 (1H, m), 2.17 (1H, ddd, J¼12.7, 6.6,
6.6 Hz), 2.39 (1H, dd, J¼14.7, 8.6 Hz), 2.48 (1H, dd,
J¼14.7, 4.0 Hz), 3.66 (3H, s), 3.81 (1H, ddd, J¼8.6, 4.0,
4.0 Hz), 3.89 (1H, m), 4.05 (1H, dd, J¼7.9, 6.3 Hz), 4.56
(1H, d, J¼6.3 Hz), 4.93 (1H, s), and 5.12 (1H, s); m/z;
FABMS m/z 299 (MþH)þ; HRFABMS m/z 299.1849
[(MþH)þ, calcd for C15H27O4: 299.1859].
3.1.21. Bis-(S)-MTPA ester (5b) of 4b. Compound 5b
(1.2 mg, 1.7 mmol) was obtained from 4b (0.5 mg,
1.9 mmol) in 89% yield through the same procedure as
described for preparation of 11a.
1
Compound 5b. Colorless oil; H NMR (600 MHz; CDCl3)
dH 0.86 (3H, d, J¼6.4 Hz, H-35), 1.22 (1H, brdt, J¼9.7,
11.4 Hz, H-5), 1.72 (3H, s, H-10), 1.81 (1H, m, H-4), 1.92
(1H, brdt, J¼12.3, 6.6 Hz, H-5), 2.36 (1H, dd, J¼14.7,
7.9 Hz, H-2), 2.46 (1H, dd, J¼14.7, 4.4 Hz, H-2), 3.40 (3H,
s, OMe), 3.51 (3H, s, OMe), 3.66 (3H, s, OMe), 3.71 (1H,
brdt, J¼4.4, 9.0 Hz, H-3), 3.81 (1H, brdt, J¼9.7, 5.7 Hz, H-
6), 5.04 (1H, brs, H-36), 5.10 (1H, s, H-36), 5.30 (1H, brt,
J¼6.0 Hz and H-7), 5.61 (1H, d, J¼6.8 Hz, H-8), and 7.32–
7.54 (10H, m, Ph); FABMS m/z 691 (MþH)þ; HRFABMS
m/z 691.2353 [(MþH)þ, calcd for C33H37O9F6: 691.2342].
3.1.18. Methyl {(2S,3R,5R)-5-[(1R,2R)-1,2-dihydroxy-3-
methyl-3-butenyl]-3-methyltetrahydrofuran-2-yl}-acet-
ate (4a). To a solution of 15a (3.3 mg, 11.1 mmol) dissolved
in MeOH (504 mL) was added PPTS (3.75 mg, 0.02 mmol).
After stirring at 558C for 5 h, the solvent was evaporated.
The residue was purified by CC (hexane–EtOAc, 2:1) to
afford 4a (2.4 mg, 9.3 mmol, 84%). Colorless oil;
[a]2D0¼2428 (c 0.5, CHCl3); IR (neat) nmax 3433, 2957,
3.1.22. Ethyl (2E,6R)-7-benzyloxy-6-hydroxy-2-hepteno-
ate (17). To a solution of (R)-5-benzyloxymethyl-g-
butyrolactone (16, 9.27 g, 45.0 mmol) in CH2Cl2
1
2922, 1732, 1456, and 1033 cm21; H NMR (500 MHz;
CDCl3) dH 1.05 (3H, d, J¼6.4 Hz), 1.74 (3H, s), 1.79 (1H,

T. Kubota et al. / Tetrahedron 59 (2003) 1613–1625
1621
(100 mL) was added DIBAL-H (1.01 M, 56 mL,
56.6 mmol) in toluene at 2788C, and the mixture was
stirred for 1 h. After addition of MeOH and saturated
aqueous potassium sodium tartrate, the mixture was allowed
to warm to rt, and stirred vigorously for 1 h. The reaction
mixture was extracted with EtOAc, and the organic layer
was washed with H2O and brine, dried, and evaporated to
afford a crude acetal (9.36 g, 45.0 mmol, quant.). To a
solution of the crude acetal (9.36 g, 45.0 mmol) in benzene
(200 mL) was added (ethoxycarbonylmethylene)triphenyl
phosphorane (22.7 g, 67.5 mmol), and stirring was con-
tinued at 558C for 16 h. After evaporation of the solvent, the
residue was subjected to CC (hexane–EtOAc, 5:1) to afford
17 (11.0 g, 39.6 mmol, 87%). Colorless oil; [a]2D0¼þ0.48 (c
1.0, CHCl3); IR (neat) nmax 3478, 3030, 2981, 2931, 2860,
1716, 1653, 1454, 1368, 1045, 738, and 699 cm21; 1H NMR
(500 MHz; CDCl3) dH 1.25 (3H, t, J¼6.9 Hz), 1.56 (2H, m),
2.25 (1H, m), 2.34 (1H, m), 3.32 (1H, m), 3.44 (1H, m), 3.77
(1H, m), 4.15 (2H, m), 4.51 (2H, m), 5.81 (1H, d,
J¼15.6 Hz), 6.94 (1H, m), and 7.22–7.37 (5H, m); 13C
NMR (125 MHz; CDCl3) dC 14.1 (q), 28.0 (t), 31.3 (t), 60.0
(t), 69.3 (d), 73.1 (t), 74.2 (t), 121.5 (d), 127.5 (2C, d), 127.6
(d), 128.3 (2C, d), 137.7 (s), 148.4 (d), and 166.4 (s);
FABMS m/z 279 (MþH)þ; HRFABMS m/z 279.1602
[(MþH)þ, calcd for C16H23O4: 279.1596].
13C NMR (125 MHz; CDCl3) dC 25.4 (2C, q), 18.3 (s), 25.9
(3C, q), 27.5 (t), 32.2 (t), 38.8 (t), 60.4 (t), 65.1 (t), 76.4 (d),
and 78.7 (d); FABMS m/z 261 (MþH)þ; HRFABMS m/z
261.1894 [(MþH)þ, calcd for C13H29O3Si: 261.1886].
Compound 18b. Colorless oil; [a]2D0¼þ48 (c 1.0, CHCl3); IR
(neat) nmax 3438, 2957, 2929, 2858, 1471, and 1095 cm21
;
1H NMR (500 MHz; CDCl3) dH 0.05 (6H, s), 0.89 (9H, s),
1.55 (1H, m), 1.67–1.77 (2H, m), 1.79 (1H, m), 1.91 (1H,
m), 1.99 (1H, m), 3.46 (1H, dd, J¼11.2, 5.6 Hz), 3.69 (1H,
dd, J¼11.2, 3.1 Hz), 3.72 (2H, t, 6.2), and 3.97–4.04 (2H,
m); 13C NMR (125 MHz; CDCl3) dC 25.4 (2C, q), 18.3 (s),
25.9 (3C, q), 27.0 (t), 31.6 (t), 39.0 (t), 60.6 (t), 65.2 (t), 77.4
(d), and 79.2 (d); FABMS m/z 261 (MþH)þ; HRFABMS
m/z 261.1876 [(MþH)þ, calcd for C13H29O3Si: 261.1886].
3.1.24. (1R)- and (1S)-1-{(2R,5R)-5-[2-(tert-Butyldi-
methylsilyloxy)ethyl]-tetrahydrofuran-2-yl}-2-propen-
1-ol (19a and 19b). To a solution of 18a (1.00 g,
3.85 mmol) in a mixture of DMSO (11 mL), CH2Cl2
(67.1 mL) and Et3N (3.85 mL) was added SO3-pyridine
complex (3.05 g, 19.2 mmol) at 08C. After stirring at rt for
20 min, the solution was poured into H2O and the mixture
was extracted with Et2O. The organic layer was washed
with H2O and brine, dried, and concentrated to afford a
crude aldehyde (832.8 mg), which was used for the
following reaction without purification. To a stirred solution
of the crude aldehyde (832.8 mg) in THF (9.0 mL) was
added vinylMgBr (1.06 M, 12.0 mL, 12.7 mmol) in THF at
08C. After stirring for 1 h, the reaction was quenched by
addition of saturated aqueous NH4Cl and then the mixture
was extracted with Et2O. The organic layer was washed
with H2O and brine, dried, and concentrated. The residue
was purified by CC (CHCl3–acetone, 10:0 to 9:1) to afford
19a (376.1 mg, 1.32 mmol, 41%) and 19b (339.9 mg,
1.19 mmol, 37%).
3.1.23. {(2R,5R)- and {(2S,5R)-5-[2-(tert-Butyldimethyl-
silyloxy)ethyl]-tetrahydrofuran-2-yl}-methanol (18a and
18b). To a solution of 17 (6.82 g, 24.5 mmol) in THF
(100 mL) was added TBAF (1.00 M, 30 mL, 30 mmol) in
THF, and the mixture was stirred at rt for 1 h. After
evaporation of the solvent, the residue was subjected to CC
(hexane–EtOAc, 10:0 to 4:1) to afford a tetrahydrofuran
(6.53 g, 23.5 mmol, 96%). To a solution of the tetrahy-
drofuran (6.48 g, 23.3 mmol) in CH2Cl2 (85 mL) was added
DIBAL-H (1.01 M, 69 mL, 69.7 mmol) in toluene at
2788C, and the mixture was stirred for 1 h. After addition
of MeOH and saturated aqueous potassium sodium tartrate,
the mixture was allowed to warm to rt, and stirred
vigorously for 1 h. The reaction mixture was extracted
with EtOAc, and the organic layer was washed with H2O
and brine, dried, and evaporated to afford a crude alcohol
(5.5 g, 23.3 mmol, 99%). The crude alcohol (5.5 g,
23.3 mmol) in dry DMF (90 mL) was treated with
TBDMSCl (5.2 g, 33.1 mmol) and imidazole (3.1 g,
46.6 mmol) at rt for 3.5 h. After addition of saturated
aqueous NH4Cl, the mixture was extracted with Et2O. The
organic layer was washed with H2O and brine, dried, and
concentrated. The residue was purified by CC (hexane–
EtOAc, 15:1) to afford a TBDMS ether (7.81 g, 22.3 mmol,
96%) as colorless oil. The TBDMS ether (7.81 g,
22.3 mmol) in EtOH (100 mL) was treated with 10% Pd–
C (385 mg) under a hydrogen atmosphere at rt for 6 h. After
filtration of the catalyst, the filtrate was evaporated to afford
18a (2.50 g, 9.61 mmol, 43%) and 18b (2.51 g, 9.65 mmol,
43%).
Compound 19a. [a]2D0¼26.18 (c 1.00, CHCl3); IR (neat)
1
nmax 3446, 2954, 2929, 2857, 1472, and 1092 cm21; H
NMR (500 MHz; CDCl3) dH 0.05 (6H, s), 0.89 (9H, s), 1.58
(1H, m), 1.69 (2H, m), 1.78 (1H, m), 1.96 (1H, m), 2.06 (1H,
m), 3.71 (2H, m), 3.84 (1H, m), 3.91 (1H, m), 4.07 (1H, m),
5.20 (1H, d, J¼10.6 Hz), 5.36 (1H, d, J¼17.4 Hz), and 5.79
(1H, ddd, J¼17.4, 10.6, 6.2 Hz); 13C NMR (125 MHz;
CDCl3) dC 25.4 (2C, q), 18.3 (s), 25.9 (3C, q), 27.9 (t), 32.3
(t), 38.7 (t), 60.4 (t), 75.6 (d), 76.5 (d), 81.4 (d), 117.0 (t),
and 136.8 (d); FABMS m/z 287 (MþH)þ; HRFABMS m/z
287.2044 [(MþH)þ, calcd for C15H31O3Si: 287.2042].
Compound 19b. [a]2D0¼25.78 (c 1.00, CHCl3); IR (neat)
1
nmax 3446, 2954, 2929, 2857, 1472, and 1092 cm21; H
NMR (500 MHz; CDCl3) dH 0.05 (6H, s), 0.89 (9H, s), 1.55
(1H, m), 1.67 (1H, m), 1.78 (1H, m), 1.84 (2H, m), 2.06 (1H,
m), 3.71 (2H, m), 3.99 (1H, m), 4.12 (1H, m), 4.29 (1H, m),
5.19 (1H, d, J¼10.6 Hz), 5.33 (1H, d, J¼17.4 Hz), and 5.81
(1H, ddd, J¼17.4, 10.6, 6.2 Hz); 13C NMR (125 MHz;
CDCl3) dC 25.3 (2C, q), 18.3 (s), 25.5 (t), 25.9 (3C, q), 32.3
(t), 39.0 (t), 60.4 (t), 73.6 (d), 77.4 (d), 81.0 (d), 116.3 (t),
and 136.4 (d); FABMS m/z 287 (MþH)þ; HRFABMS m/z
287.2044 [(MþH)þ, calcd for C15H31O3Si: 287.2042].
Compound 18a. Colorless oil; [a]2D0¼2148 (c 1.0, CHCl3);
IR (neat) nmax 3444, 2954, 2930, 2857, 1463, and
1
1095 cm21; H NMR (500 MHz; CDCl3) dH 0.05 (6H, s),
0.89 (9H, s), 1.52–1.71 (3H, m), 1.78 (1H, m), 1.96 (1H, m),
2.05 (1H, m), 3.47 (1H, dd, J¼11.2, 6.2 Hz), 3.61 (1H, dd,
J¼11.2, 3.1 Hz), 3.71 (2H, t, 6.2), and 4.02–4.14 (2H, m);
3.1.25. (S)-MTPA ester of 19a. The (S)-MTPA ester of 19a
(0.7 mg, 1.4 mmol) was obtained from 19a (0.5 mg,

1622
T. Kubota et al. / Tetrahedron 59 (2003) 1613–1625
1.7 mmol) in 82% yield through the same procedure as
described for preparation of the (S)-MTPA ester of 11a. (S)-
MTPA ester of 19a. Colorless oil; H NMR (600 MHz;
m), 1.93–2.06 (2H, m), 3.54 (1H, m), 3.64–3.78 (3H, m),
4.03 (3H, m), 4.67 (1H, d, J¼6.9 Hz), 4.71 (1H, d,
J¼6.9 Hz), 5.27 (2H, d, J¼17.4 Hz), and 5.75 (1H, m);
13C NMR (125 MHz; CDCl3) dC 25.4 (q), 25.3 (q), 21.4
(3C, q), 18.0 (t), 18.3 (s), 25.9 (3C, q), 27.5 (t), 32.0 (t), 38.8
(t), 60.5 (t), 65.0 (t), 77.2 (d), 79.4 (d), 80.4 (d), 92.4 (t),
118.8 (t), and 135.2 (d); FABMS m/z 417 (MþH)þ;
HRFABMS m/z 417.2863 [(MþH)þ, calcd for
C21H45O4Si2: 417.2856].
1
CDCl3) dH 0.03 (6H, s), 0.88 (9H, s), 1.47 (1H, m), 1.59
(1H, m), 1.63 (1H, m), 1.73 (1H, m), 1.90 (1H, m), 1.93 (1H,
m), 3.55 (3H, s), 3.66 (2H, m), 3.96 (1H, m), 4.07 (1H, m),
5.33 (1H, d, J¼10.6 Hz), 5.42 (1H, d, J¼17.4 Hz), 5.45 (1H,
m), 5.87 (1H, d, J¼17.4, 10.6, 7.5 Hz), 7.36–7.42 (3H, m),
and 7.54–7.60 (2H, m); FABMS m/z 503 (MþH)þ;
HRFABMS m/z 503.2443 [(MþH)þ, calcd for
C25H38O5F3Si: 503.2441].
3.1.29. (2R,5R)-2-[(1R,2E)-5-Methyl-1-(triethylsilyloxy)-
2,4-hexadienyl]-5-[2-(triethylsilyloxy)ethyl]-tetrahydro-
furan (23a). Compound 20a (251.2 mg, 604 mmol) was
dissolved in a 8:1 mixture of acetone and H2O (6.9 mL), and
to this mixture were added OsO4 (1%, 764 mL, 30 mmol) in
t-BuOH and NMO (143.2 mg, 1.22 mmol). After stirring at
rt for 19 h, the reaction was quenched by addition of
saturated aqueous NaHSO3, and then the mixture was
extracted with EtOAc. The organic layer was washed with
brine, dried, and concentrated. The residue was purified by
CC (hexane–EtOAc, 5:1 to 2:1) to afford a mixture of diols
(243.7 mg, 542 mmol, 90%) as colorless oil. To a stirring
solution of the mixture (243.7 mg, 542 mmol) in a 1:1
mixture (5 mL) of THF and phosphate buffer (pH 6.8) was
added NaIO4 (159.3 mg, 1.13 mmol) at 08C. After stirring at
rt for 1 h, the mixture was extracted with Et2O, washed with
brine, dried, and concentrated. The residue was purified by
CC (hexane–EtOAc, 10:0 to 9:1) to afford an aldehyde
(198.8 mg, 476 mmol, 88%) as colorless oil.
3.1.26. (R)-MTPA ester of 19a. The (R)-MTPA ester of
19a (0.8 mg, 1.6 mmol) was obtained from 19a (0.5 mg,
1.7 mmol) in 94% yield through the same procedure as
described for preparation of the (S)-MTPA ester of 11a. (R)-
1
MTPA ester of 19a. Colorless oil; H NMR (600 MHz;
CDCl3) dH 0.02 (6H, s), 0.88 (9H, s), 1.55 (1H, m), 1.65
(1H, m), 1.70 (1H, m), 1.76 (1H, m), 1.97 (1H, m), 2.06 (1H,
m), 3.62 (3H, s), 3.66 (2H, m), 4.04 (1H, m), 4.08 (1H, m),
5.24 (1H, d, J¼10.6 Hz), 5.29 (1H, d, J¼17.4 Hz), 5.41 (1H,
m), 5.70 (1H, d, J¼17.4, 10.6, 6.9 Hz), 7.34–7.42 (3H, m),
and 7.56–7.63 (2H, m); FABMS m/z 503 (MþH)þ;
HRFABMS m/z 503.2445 [(MþH)þ, calcd for
C25H38O5F3Si: 503.2441].
3.1.27. (2R,5R)-2-[2-(tert-Butyldimethylsilyloxy)ethyl]-5-
{(1R)-1-[2-(trimethylsilyl)ethoxymethoxy]-2-propenyl}-
tetrahydrofuran (20a). Compound 19a (335.3 mg,
1.17 mmol) dissolved in dry CH2Cl2 (7.0 mL) was treated
with SEMCl (0.37 mL, 2.32 mmol) and i-Pr2NEt (0.61 mL,
3.48 mmol) at rt for 4 h. The reaction was quenched by
addition of saturated aqueous NaHCO3 and then the mixture
was extracted with Et2O. The organic layer was dried and
concentrated. The residue was purified by CC (hexane–
EtOAc, 10:0 to 8:2) to afford 20a (462.8 mg, 1.11 mmol,
95%).
A solution of BuLi (2.46 M, 830 mL, 2.04 mmol) in hexane
was added to a solution of (3-methyl-2-butene-1-sulfonyl)-
benzene12 (453 mg, 2.16 mmol) in THF (28 mL) at 2788C.
After stirring for 20 min, a solution of the aldehyde
(198.8 mg, 476 mmol) in THF (3.5 mL) was added to the
mixture at 2788C. Stirring was continued at 2788C for 2 h,
and then the reaction mixture was allowed to warm to rt over
1 h. The reaction was quenched by addition of saturated
aqueous NH4Cl, and then the mixture was extracted with
Et2O, washed with brine, dried, and concentrated. The
residue was purified by CC (hexane–EtOAc, 10:0 to 8:2) to
afford a diastereomeric mixture of the b-hydroxy sulfone
(260.8 mg, 415 mmol, 87%) as colorless oil. The b-hydroxy
sulfone (260.8 mg, 415 mmol) in CH2Cl2 (20 mL) was
treated with Et3N (115 mL), DMAP (275 mg), and BzCl
(130 mL), and stirring was continued at rt for 20 h. The
reaction was quenched by addition of saturated aqueous
NH4Cl, and then the mixture was extracted with Et2O. The
organic layer was washed with brine, dried, and concen-
trated. The residue was purified by CC (hexane–EtOAc,
10:0 to 8:2) to afford a diastereomeric mixture of the b-
benzoyloxy sulfone 21a (295.0 mg, 403 mmol, 97%) as
colorless oil.
Compound 20a. Colorless oil; [a]2D0¼2338 (c 1.0, CHCl3);
IR (neat) nmax 2954, 2858, 1716, 1473, and 1096 cm21; 1H
NMR (500 MHz; CDCl3) dH 0.01 (9H, s), 0.04 (6H, s), 0.88
(9H, s), 0.92 (2H, m), 1.52 (1H, m), 1.60 to 1.75 (2H, m),
1.83 (1H, m), 1.91 (1H, m), 2.01 (1H, m), 3.55 (1H, m), 3.69
(2H, m), 3.75 (1H, m), 3.98–4.08 (3H, m), 4.71 (2H, m),
5.25 (1H, d, J¼10.6 Hz), 5.29 (1H, d, J¼17.4 Hz), and 5.72
(1H, ddd, J¼17.4, 10.6, 6.9 Hz); 13C NMR (125 MHz;
CDCl3) dC 25.3 (2C, q), 21.4 (3C, q), 18.1 (t), 18.3 (s),
26.0 (3C, q), 28.1 (t), 32.1 (t), 38.9 (t), 60.6 (t), 65.0 (t), 76.9
(d), 79.5 (d), 80.3 (d), 92.5 (t), 118.6 (t), and 135.1 (d);
FABMS m/z 417 (MþH)þ; HRFABMS m/z 417.2859
[(MþH)þ, calcd for C21H45O4Si2: 417.2856].
3.1.28. (2R,5R)-2-[2-(tert-Butyldimethylsilyloxy)ethyl]-5-
{(1S)-1-[2-(trimethylsilyl)ethoxymethoxy]-2-propenyl}-
tetrahydrofuran (20b). Compound 20b (274.6 mg,
660 mmol) was obtained from 19b (227.0 mg, 794 mmol)
in 81% yield through the same procedure as described for
preparation of 20a.
Compound 21a (198.6 mg, 271 mmol) in CH2Cl2 (12 mL)
was treated with TFA (4 mL) at 08C for 30 min. The
reaction mixture was partitioned between CH2Cl2 and
H2O. The organic layer was washed with brine, dried, and
evaporated. The residue was purified by CC (CH2Cl2–
MeOH, 10:0 to 9:1) to afford a diastereomeric mixture of
18,24-diols (116.4 mg, 238 mmol, 87%) as colorless oil.
The mixture (60.5 mg, 124 mmol) dissolved in dry DMF
(0.4 mL) was treated with TESCl (63.5 mL, 378 mmol) and
Compound 20b. Colorless oil; [a]2D0¼2508 (c 1.0, CHCl3);
IR (neat) nmax 2954, 2868, 1718, 1463, and 1096 cm21; 1H
NMR (500 MHz; CDCl3) dH 0.01 (9H, s), 0.04 (6H, s), 0.88
(9H, s), 0.93 (2H, m), 1.53 (1H, m), 1.64 (1H, m), 1.81 (2H,

T. Kubota et al. / Tetrahedron 59 (2003) 1613–1625
1623
imidazole (50.3 mg, 746 mmol) at rt for 3 h. After
evaporation of the solvent, the reaction mixture was purified
with CC (hexane–EtOAc, 10:0 to 9:1) to afford a
diastereomer mixture (22a) of 18,24-bis-TES ethers
(83.1 mg, 116 mmol, 94%) as colorless oil.
(1H, m), 4.11 (1H, m), 4.14 (1H, m), 5.51 (1H, dd, J¼15.0,
6.2 Hz), 5.81 (1H, d, J¼11.2 Hz), and 6.44 (1H, dd, J¼15.0,
11.2 Hz); 13C NMR (125 MHz; CDCl3) dC 5.0 (3C, t), 6.8
(3C, q), 18.2 (q), 26.0 (q), 27.2 (t), 32.4 (t), 37.2 (t), 61.8 (t),
75.5 (d), 79.8 (d), 82.5 (d), 124.6 (d), 127.8 (d), 129.7 (d),
and 135.3 (s); FABMS m/z 341 (MþH)þ; HRFABMS m/z
341.2515 [(MþH)þ, calcd for C19H36O3Si: 341.2512].
A solution of 22a (83.1 mg, 116 mmol) in a 3:1 mixture
(7.2 mL) of THF and MeOH was treated with Na(Hg)
(700.0 mg) and Na2HPO4 (701.2 mg) at 2208C for 1 h. The
reaction was quenched by addition of H2O, and then the
mixture was extracted with Et2O. The organic layer was
washed with brine, dried, and concentrated. The residue was
subjected to CC (hexane–EtOAc, 10:0 to 4:1) to afford 23a
(35.3 mg, 77.8 mmol, 67%). Colorless oil; [a]2D0¼þ138 (c
1.0, CHCl3); UV (cyclohexane) lmax 240 nm (1 24000); IR
3.1.32. 2-{(2R,5R)-5-[(1S,2E)-5-Methyl-1-(triethylsilyl-
oxy)-2,4-hexadienyl]-tetrahydrofuran-2-yl}-ethanol
(24b). Compound 24b (25.2 mg, 74.1 mmol) was obtained
from 23b (42.3 mg, 93.2 mmol) in 80% yield through the
same procedure as described for preparation of 24a.
Compound 24b. Colorless oil; [a]2D0¼þ38 (c 1.0, CHCl3);
1H NMR (500 MHz; CDCl3) dH 0.59 (6H, q, J¼8.1 Hz),
0.95 (9H, t, J¼8.1 Hz), 1.52 (1H, m), 1.68–1.78 (2H, m),
1.75 (3H, s), 1.76 (3H, s), 1.80–1.94 (2H, m), 2.03 (1H, m),
3.76 (2H, m), 3.94 (1H, m), 4.15 (1H, m), 4.26 (1H, m), 5.45
(1H, dd, J¼15.6, 6.2 Hz), 5.79 (1H, d, J¼11.2 Hz), and 6.40
(1H, dd, J¼15.6, 11.2 Hz); 13C NMR (125 MHz; CDCl3) dC
5.0 (3C, t), 6.8 (3C, q), 18.2 (q), 25.7 (t), 25.9 (q), 32.5 (t),
37.3 (t), 61.9 (t), 75.2 (d), 80.4 (d), 82.6 (d), 124.5 (d), 127.3
(d), 130.4 (d), and 135.3 (s); FABMS m/z 341 (MþH)þ;
HRFABMS m/z 341.2512 [(MþH)þ, calcd for C19H36O3Si:
341.2512].
1
(neat) nmax 2955, 2876, 1457, and 1070 cm21; H NMR
(500 MHz; CDCl3) dH 0.55–0.65 (12H, m), 0.95 (18H, t,
J¼8.1 Hz), 1.46 (1H, m), 1.60–1.74 (2H, m), 1.75 (3H, s),
1.77 (3H, s), 1.78–1.91 (2H, m), 1.95 (1H, m), 3.64–3.76
(2H, m), 3.92 (1H, m), 3.97 (1H, m), 4.17 (1H, brt,
J¼5.6 Hz), 5.53 (1H, dd, J¼15.0, 5.6 Hz), 5.82 (1H, d,
J¼11.2 Hz), and 6.45 (1H, dd, J¼15.0, 11.2 Hz); 13C NMR
(125 MHz; CDCl3) dC 4.4 (3C, t), 5.0 (3C, t), 6.7 (3C, q), 6.8
(3C, q), 18.2 (q), 25.9 (q), 27.3 (t), 32.3 (t), 39.0 (t), 60.4 (t),
75.4 (d), 76.6 (d), 82.0 (d), 124.8 (d), 127.4 (d), 130.0 (d),
and 134.8 (s); FABMS m/z 455 (MþH)þ; HRFABMS m/z
455.3369 [(MþH)þ, calcd for C25H51O3Si2: 455.3377].
3.1.33. 1-{(2R,5R)-5-[(1R,2E)-5-Methyl-1-(triethylsilyl-
oxy)-2,4-hexadienyl]-tetrahydrofuran-2-yl}-propan-2-
one (25a). To a solution of 24a (22.7 mg, 66.8 mmol) in a
mixture of DMSO (197 mL), CH2Cl2 (1.2 mL), and Et3N
(67 mL) was added SO3-pyridine complex (53.7 mg,
338 mmol) at 08C. After stirring at rt for 30 min, the
solution was poured into H2O, and the mixture was
extracted with Et2O. The organic layer was washed with
brine, dried, and concentrated to afford a crude aldehyde
(22.5 mg, 66.6 mmol, 99%). To a stirred solution of the
aldehyde (22.5 mg, 66.6 mmol) in THF (9.0 mL) was added
MeMgBr (0.87 M, 386 mL, 0.34 mmol) in THF at 08C.
After stirring for 1 h, the reaction was quenched by addition
of saturated aqueous NH4Cl, and then the mixture was
extracted with Et2O. The organic layer was washed with
H2O and brine, dried, and concentrated to afford a
diastereomeric mixture of alcohols (17.6 mg, 47.9 mmol,
72%). The diastereomeric mixture (17.6 mg, 47.9 mmol) of
alcohols in a mixture of DMSO (197 mL), CH2Cl2 (1.2 mL)
and Et3N (67 mL) was treated with SO3–pyridine complex
(32.5 mg, 204 mmol) at rt for 30 min. The solution was
poured into H2O, and the mixture was extracted with
Et2O. The organic layer was washed with brine, dried, and
concentrated to afford 25a (11.7 mg, 33.2 mmol, 69%).
Colorless oil; [a]2D0¼þ108 (c 0.5, CHCl3); UV (cyclohex-
ane) lmax 240 nm (1 21000); IR (neat) nmax 2954, 2911,
3.1.30. (2R,5R)-2-[(1S,2E)-5-Methyl-1-(triethylsilyloxy)-
2,4-hexadienyl]-5-[2-(triethylsilyloxy)ethyl]-tetrahydro-
furan (23b). Compound 23b (50.3 mg, 111 mmol) was
obtained from 20b 159.6 mg, 383 mmol) in 29% yield by 7
steps through the same procedure as described for
preparation of 23a.
Compound 23b. Colorless oil; [a]2D0¼þ48 (c 1.0, CHCl3);
UV (cyclohexane) lmax 238 nm (1 23500); IR (neat) nmax
1
2954, 2876, 1463, and 1069 cm21; H NMR (500 MHz;
CDCl3) dH 0.54–0.64 (12H, m), 0.95 (18H, dt, J¼8.1 Hz),
1.46 (1H, m), 1.64 (1H, m), 1.74 (3H, s), 1.76 (3H, s), 1.77–
1.93 (3H, m), 2.00 (1H, m), 3.69 (2H, m), 3.88 (1H, m), 4.04
(1H, m), 4.25 (1H, brt, J¼5.0 Hz), 5.48 (1H, dd, J¼15.6,
6.2 Hz), 5.80 (1H, d, J¼11.2 Hz) and 6.40 (1H, dd, 15.6 and
11.2); 13C NMR (125 MHz; CDCl3) dC 4.4 (3C, t), 5.0 (3C,
t), 6.7 (3C, q), 6.8 (3C, q), 18.2 (q), 25.9 (q), 26.1 (t), 32.3
(t), 39.1 (t), 60.4 (t), 75.4 (d), 77.0 (d), 82.1 (d), 124.7 (d),
127.0 (d), 130.9 (d), and 134.9 (s); FABMS m/z 55
(MþH)þ; HRFABMS m/z 455.3373 [(MþH)þ, calcd for
C25H51O3Si2: 455.3377].
3.1.31. 2-{(2R,5R)-5-[(1R,2E)-5-Methyl-1-(triethylsilyl-
oxy)-2,4-hexadienyl]-tetrahydrofuran-2-yl}-ethanol
(24a). To 23a (32.3 mg, 71.1 mmol) was added a mixture
(8.2 mL) of AcOH–H2O–THF (1:20:20), and the reaction
mixture was stirred at 08C for 1 h. The reaction was
quenched by addition of saturated aqueous NaHCO3 and
then the mixture was extracted with CHCl3. The organic
layer was dried, and evaporated. The residue was purified by
CC (hexane–EtOAc, 10:0 to 9:1) to afford 24a (18.2 mg,
53.5 mmol, 75%). Colorless oil; [a]2D0¼þ88 (c 1.0, CHCl3);
1H NMR (500 MHz; CDCl3) dH 0.60 (6H, q, J¼8.1 Hz),
0.95 (9H, t, J¼8.1 Hz), 1.54 (1H, m), 1.64–1.92 (4H, m),
1.75 (3H, s), 1.77 (3H, s), 1.99 (1H, m), 3.77 (2H, m), 3.97
1
2876, 1718, 1458, and 1085 cm21; H NMR (500 MHz;
CDCl3) dH 0.59 (6H, q, J¼8.1 Hz), 0.94 (9H, t, J¼8.1 Hz),
1.45 (1H, m), 1.68–1.80 (1H, m), 1.75 (3H, s), 1.77 (3H, s),
1.88 (1H, m), 2.06 (1H, m), 2.18 (3H, s), 2.49 (1H, dd,
J¼15.6, 5.6 Hz), 2.72 (1H, dd, J¼15.6, 6.9 Hz), 3.95 (1H,
m), 4.17 (1H, m), 4.28 (1H, m), 5.52 (1H, dd, J¼15.0,
6.2 Hz), 5.82 (1H, d, J¼11.2 Hz) and 6.44 (1H, dd, J¼15.0,
11.2 Hz); 13C NMR (125 MHz; CDCl3) dC 5.0 (3C, t), 6.8
(3C, q), 18.2 (q), 26.0 (q), 27.1 (t), 30.7 (q), 32.3 (t), 49.7 (t),
75.3 (d), 75.4 (d), 82.3 (d), 124.7 (d), 127.7 (d), 129.7 (d),

1624
T. Kubota et al. / Tetrahedron 59 (2003) 1613–1625
135.2 (s), and 207.5 (s); FABMS m/z 353 (MþH)þ;
HRFABMS m/z 353.2502 [(MþH)þ, calcd for
C20H37O3S: 353.2512].
4.01 (1H, m), 4.31 (1H, m), 4.40 (1H, m), 5.47 (1H, dd,
J¼15.0, 6.9 Hz), 5.82 (1H, d, J¼11.2 Hz) and 6.49 (1H, dd,
J¼15.0, 11.2 Hz); 13C NMR (125 MHz; CDCl3) dC 18.3 (q),
25.5 (t), 26.0 (q), 30.7 (q), 32.3 (t), 49.7 (t), 73.6 (t), 76.0 (t),
81.8 (t), 124.4 (d), 127.9 (d), 128.8 (d), 136.3 (s), and 207.1
(s); FABMS m/z 239 (MþH)þ; HRFABMS m/z 239.1649
[(MþH)þ, calcd for C14H23O3: 239.1647].
3.1.34. 1-{(2R,5R)-5-[(1S,2E)-5-Methyl-1-(triethylsilyl-
oxy)-2,4-hexadienyl]-tetrahydrofuran-2-yl}-propan-2-
one (25b). Compound 25b (17.2 mg, 48.9 mmol) was
obtained from 23b (31.6 mg, 92.9 mmol) in 53% yield by
3 steps through the same procedure as described for
preparation of 25a.
3.1.37. (S)-MTPA ester (7a) of 6a. The (S)-MTPA ester 7a
(0.90 mg, 1.98 mmol) was obtained from 6a (0.50 mg,
2.09 mmol) in 95% yield through the same procedure as
described for preparation of the (S)-MTPA ester of 11a.
Compound 25b. Colorless oil; [a]2D0¼þ68 (c 0.5, CHCl3);
UV (cyclohexane) lmax 240 nm (1 22000); IR (neat) nmax
1
1
2954, 2910, 2876, 1720, 1458, and 1085 cm21; H NMR
Compound 7a. Colorless oil; H NMR (600 MHz; CDCl3)
(500 MHz; CDCl3) dH 0.59 (6H, q, J¼8.1 Hz), 0.94 (9H, t,
J¼8.1 Hz), 1.45 (1H, m), 1.74 (3H, s), 1.76 (3H, s), 1.80–
1.97 (2H, m), 2.11 (1H, m), 2.17 (3H, s), 2.49 (1H, dd,
J¼15.6, 6.2 Hz), 2.70 (1H, dd, J¼15.6, 6.9 Hz), 3.91 (1H,
brdt, J¼4.4, 6.9 Hz), 4.23 (1H, m), 4.33 (1H, m), 5.46 (1H,
dd, J¼15.0, 6.2 Hz), 5.79 (1H, d, J¼10.6 Hz), and 6.39 (1H,
dd, J¼15.0, 10.6 Hz); 13C NMR (125 MHz; CDCl3) dC 5.0
(3C, t), 6.8 (3C, q), 18.2 (q), 25.9 (t), 25.9 (q), 30.6 (q), 32.3
(t), 49.9 (t), 75.2 (d), 75.8 (d), 82.5 (d), 124.5 (d), 127.2 (d),
130.6 (d), 135.2 (s), and 207.5 (s); FABMS m/z 353
(MþH)þ; HRFABMS m/z 353.2498 [(MþH)þ, calcd for
C20H37O3Si: 353.2512].
dH 1.44 (1H, m, H-21), 1.60 (1H, m, H-22), 1.76 (3H, s, H-
40), 1.79 (3H, s, H-29), 1.93 (1H, m, H-22), 2.01 (1H, m, H-
21), 2.13 (3H, s, H-17), 2.48 (1H, dd, J¼15.6, 5.7 Hz, H-
19), 2.63 (1H, dd, J¼15.6, 7.2 Hz, H-19), 3.54 (3H, s,
OMe), 4.10 (1H, m, H-23), 4.24 (1H, m, H-20), 5.45 (1H,
brt, J¼8.4 Hz, H-24), 5.51 (1H, dd, J¼14.1, 8.4 Hz, H-25),
5.81 (1H, d, J¼11.1 Hz, H-27), 6.60 (1H, dd, J¼14.1,
11.1 Hz, H-26), and 7.30–7.60 (5H, m, Ph); FABMS m/z
455 (MþH)þ; HRFABMS m/z 455.2039 [(MþH)þ, calcd
for C24H30O5F3: 455.2045].
3.1.38. (R)-MTPA ester (7b) of 6a. The (R)-MTPA ester 7b
(0.88 mg, 1.94 mmol) was obtained from 6a (0.50 mg,
2.09 mmol) in 93% yield through the same procedure as
described for preparation of the (S)-MTPA ester of 11a.
3.1.35. 1-{(2R,5R)-5-[(1R,2E)-1-Hydroxy-5-methyl-2,4-
hexadienyl]-tetrahydrofuran-2-yl}-propan-2-one (6a).
Compound 25a (5.03 mg, 14.3 mmol) was dissolved in the
mixture (1.7 mL) of AcOH–H2O–THF (1:10:10), and the
solution was stirred at 08C for 4 h. The reaction was
quenched by addition of saturated aqueous NaHCO3, and
then the mixture was extracted with CHCl3. The organic
layer was dried, evaporated. The residue was purified with
CC (hexane–EtOAc, 2:1 to 1:1) to afford 6a (3.12 mg,
13.1 mmol, 92%). Colorless oil; [a]2D0¼þ158 (c 1.0,
CHCl3); UV (cyclohexane) lmax 240 nm (1 24000); IR
1
Compound 7b. Colorless oil; H NMR (600 MHz; CDCl3)
dH 1.52 (1H, m, H-21), 1.67 (1H, m, H-22), 1.70 (3H, s, H-
40), 1.77 (3H, s, H-29), 1.99 (1H, m, H-22), 2.14 (3H, s, H-
17), 2.16 (1H, m, H-21), 2.54 (1H, dd, J¼15.6, 5.3 Hz, H-
19), 2.68 (1H, dd, J¼15.6, 7.6 Hz, H-19), 3.59 (3H, s,
OMe), 4.11 (1H, m, H-23), 4.36 (1H, m, H-20), 5.34 (1H,
dd, J¼15.3, 7.6 Hz, H-25), 5.45 (1H, brt, J¼7.8 Hz, H-24),
5.76 (1H, d, J¼11.1 Hz, H-27), 6.50 (1H, dd, J¼14.9,
11.1 Hz, H-26), and 7.30–7.60 (5H, m, Ph); FABMS m/z
455 (MþH)þ; HRFABMS m/z 455.2037 [(MþH)þ, calcd
for C24H30O5F3: 455.2045].
(neat) nmax 3446, 2971, 2926, 1716, 1458, and 1068 cm21
;
1H NMR (500 MHz; CDCl3) dH 1.54 (1H, m), 1.69 (1H, m),
1.76 (3H, s), 1.78 (3H, s), 1.96 (1H, m), 2.15 (1H, m), 2.18
(3H, s), 2.55 (1H, dd, J¼15.6, 5.6 Hz), 2.79 (1H, dd,
J¼15.6, 6.9 Hz), 3.87 (1H, m), 3.96 (1H, brt, J¼7.2 Hz),
4.36 (1H, m), 5.45 (1H, dd, J¼15.0, 6.9 Hz), 5.81 (1H, d,
J¼11.2 Hz), and 6.52 (1H, dd, J¼15.0, 11.2 Hz); 13C NMR
(125 MHz; CDCl3) dC 18.3 (q), 26.0 (t), 27.9 (q), 30.8 (q),
32.2 (t), 49.3 (t), 75.1 (d), 75.5 (d), 82.2 (d), 124.4 (d), 128.0
(d), 129.4 (d), 136.6 (s), and 207.0 (s); FABMS m/z 239
(MþH)þ; HRFABMS m/z 239.1658 [(MþH)þ, calcd for
C14H23O3: 239.1647].
3.1.39. (S)-MTPA ester (7c) of 6b. The (S)-MTPA ester 7c
(0.85 mg, 1.87 mmol) was obtained from 6b (0.52 mg,
2.17 mmol) in 86% yield through the same procedure as
described for preparation of the (S)-MTPA ester of 11a.
1
Compound 7c. Colorless oil; H NMR (600 MHz; CDCl3)
dH 1.50 (1H, m, H-21), 1.85 (1H, m, H-22), 1.73 (3H, s, H-
40), 1.78 (3H, s, H-29), 1.98 (1H, m, H-22), 2.10 (1H, m, H-
21), 2.16 (3H, s, H-17), 2.50 (1H, dd, J¼15.6, 5.7 Hz, H-
19), 2.71 (1H, dd, J¼15.6, 7.2 Hz, H-19), 3.54 (3H, s,
OMe), 4.14 (1H, m, H-23), 4.29 (1H, m, H-20), 5.37 (1H,
dd, J¼15.3, 7.6 Hz, H-25), 5.62 (1H, dd, J¼7.6, 3.8 Hz, H-
24), 5.78 (1H, d, J¼11.1 Hz, H-27), 6.54 (1H, dd, J¼15.3,
11.1 Hz, H-26), and 7.30–7.70 (5H, m, Ph); FABMS m/z
455 (MþH)þ; HRFABMS m/z 455.2042 [(MþH)þ, calcd
for C24H30O5F3: 455.2045].
3.1.36. 1-{(2R,5R)-5-[(1S,2E)-1-Hydroxy-5-methylhexa-
(6b).
2,4-dienyl]-tetrahydrofuran-2-yl}-propan-2-one
Compound 6b (2.93 mg, 12.3 mmol) was obtained from
25b (5.05 mg, 14.3 mmol) in 86% yield through the same
procedure as described for preparation of 6a.
Compound 6b. Colorless oil; [a]2D0¼þ38 (c 1.0, CHCl3); UV
(cyclohexane) lmax 240 nm (1 23000); IR (neat) nmax 3450,
2970, 2925, 1714, 1458, and 1069 cm21
;
1H NMR
3.1.40. (R)-MTPA ester (7d) of 6b. The (R)-MTPA ester
7d (0.89 mg, 1.96 mmol) was obtained from 6b (0.51 mg,
2.13 mmol) in 92% yield through the same procedure as
described for preparation of the (S)-MTPA ester of 11a.
(500 MHz; CDCl3) dH 1.53 (1H, m), 1.76 (3H, s), 1.78
(3H, s), 1.84–1.92 (2H, m), 2.14 (1H, m), 2.18 (3H, s), 2.54
(1H, dd, J¼16.2, 5.2 Hz), 2.75 (1H, dd, J¼16.2, 7.5 Hz),

T. Kubota et al. / Tetrahedron 59 (2003) 1613–1625
1625
1
Compound 7d. Colorless oil; H NMR (600 MHz; CDCl3)
(1H, m, H-3), 3.92 (1H, m, H-6), 4.11 (1H, m, H-23), 4.12
(1H, m, H-7), 4.17 (1H, m, H-20), 4.47 (1H, s, H-29), 4.53
(1H, d, J¼7.0 Hz, H-8), 4.93 (1H, s, H-41b), 4.95 (1H, s, H-
41a), 5.08 (1H, s, H-36b), 5.35 (1H, s, H-36a), 5.48 (1H, brt,
J¼7.2 Hz, H-24), 5.62 (1H, dd, J¼15.3, 7.9 Hz, H-25), 5.73
(1H, m, H-13), 5.81 (1H, s, H-10), 6.10 (1H, d, J¼11.0 Hz,
H-27), 6.61 (1H, dd, J¼15.2, 11.0 Hz, H-26), and 7.32–
7.57 (10H, m, Ph); m/z ESIMS m/z 1313 (MþNa)þ;
HRESIMS m/z 1313.6199 [(MþNa)þ, calcd for
C69H92O16F6Na: 1313.6187].
dH 1.43 (1H, m, H-21), 1.77 (1H, m, H-22), 1.76 (3H, s, H-
40), 1.79 (3H, s, H-29), 1.92 (1H, m, H-22), 2.02 (1H, m, H-
21), 2.12 (3H, s, H-17), 2.44 (1H, dd, J¼15.6, 6.1 Hz, H-
19), 2.64 (1H, dd, J¼15.6, 6.9 Hz, H-19), 3.55 (3H, s,
OMe), 4.07 (1H, m, H-23), 4.10 (1H, m, H-20), 5.45 (1H,
dd, J¼15.3, 8.0 Hz, H-25), 5.62 (1H, dd, J¼8.4, 4.2 Hz, H-
24), 5.82 (1H, d, J¼11.1 Hz, H-27), 6.61 (1H, dd, J¼15.3,
11.1 Hz, H-26), and 7.30–7.70 (5H, m, Ph); FABMS m/z
455 (MþH)þ; HRFABMS m/z 455.2033 [(MþH)þ, calcd
for C24H30O5F3: 455.2045].
3.1.41. Linear methyl ester 3 of amphidinolide C (1).
Amphidinolide C (1, 0.9 mg) dissolved in acetone (30 mL)
was treated with 2,2-dimethoxypropane (10 mL) and PPTS
(0.24 mg) at rt for 1 h. After addition of Et3N (0.24 mL) and
evaporation of the solvent, the residue was subjected to CC
(hexane–EtOAc, 3:1) to0 afford a 7,8-acetonide derivative5
(1.2 mg) and 29-(1 -methoxy)isopropyl-7,08-acetonide
derivative (0.4 mg) of 1. To a solution of 29-(1 -methoxy)-
isopropyl derivative (0.4 mg) in MeOH (30 mL) was added
K2CO3 (0.14 mg), and the mixture was stirred at 48C for
40 h. After filtration and evaporation, a mixture (0.4 mg) of
four diastereomers of linear methyl ester was obtained. The
mixture was subjected to C18 HPLC (Develosil ODS-HG-5,
Nomura Chemical Co., Ltd., 10£250 mm; eluent, CH3CN–
H2O, 65:35; flow rate, 2.5 mL/min; UV detection at
240 nm) to afford two linear methyl esters (0.08 mg, tR
16.0 min; 0.08 mg, tR 17.3 min) and a mixture of two other
diasteromers (0.12 mg, tR 16.6 min).
Acknowledgements
This work was partly supported by a Grant-in-aid from the
Takeda Science Foundation, a Grant-in-Aid from the Naito
Foundation, and a Grant-in-aid for Scientific Research from
the Ministry of Education, Culture, Sports, Science and
Technology of Japan. T. K. thanks Research Fellowships of
the Japan Society for the Promoting of Science for Young
Scientists.
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