Total synthesis of TT-1 (rasfonin), an α-pyrone-containing natural product from a fungus Trichurus terrophilus

Article abstract of DOI:10.1016/j.tet.2004.12.013

Total synthesis of TT-1 (1=rasfonin), an α-pyrone-containing natural product from a Fungi Imperfecti Trichurus terrophilus culture was achieved by a stereoselective method in optically active form, which further provided evidence for the whole structure of TT-1 (1) including the absolute stereochemistry.

Full text of DOI:10.1016/j.tet.2004.12.013

Tetrahedron 61 (2005) 1827–1833
Total synthesis of TT-1 (rasfonin), an a-pyrone-containing natural
product from a fungus Trichurus terrophilus
*
Kohki Akiyama, Shunsuke Yamamoto, Haruhiro Fujimoto and Masami Ishibashi
Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Received 24 November 2004; revised 7 December 2004; accepted 7 December 2004
Available online 22 December 2004
Abstract—Total synthesis of TT-1 (1Zrasfonin), an a-pyrone-containing natural product from a Fungi Imperfecti Trichurus terrophilus
culture was achieved by a stereoselective method in optically active form, which further provided evidence for the whole structure of TT-1
(1) including the absolute stereochemistry.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
In 2000, an a-pyrone-containing natural product, TT-1, was
isolated from the ethyl acetate extract of a Fungi Imperfecti
Trichurus terrophilus culture by Fujimoto and co-workers
in our laboratory.1 Almost at the same time, Hayakawa and
co-workers reported isolation of rasfonin, which had the
same planar structure as TT-1, from the fermented mycelia
of an Ascomycete Talaromyces sp. 3656-A1.2 Rasfonin was
reported as a new apoptosis inducer in ras-dependent cells,
while TT-1 significantly suppressed proliferation (blasto-
genesis) of mouse splenic lymphocytes stimulated with
mitogens, concanavalin A (Con A) and lipopolysaccharide
(LPS), with IC50 values of 0.7 and 0.5 mg/mL, respectively.1
We investigated the absolute stereochemistry of five chiral
centers of 1 on the basis of synthesis of partial structural
units (segments A and B) of 1 in optically active forms and
comparison of their spectral and optical data with those of
natural specimens, and reported in 2003 that 1 had 5R, 6R,
7S, 9R, and 60S-configurations.3 In the synthesis of segment
A of 1, we previously obtained 5-membered lactone (2)
instead of 6-membered lactone (3),3 and we here describe
the stereoselective synthesis of the 6-membered lactone (3)
by a modified procedure and the total synthesis of TT-1 (1)
to provide further unequivocal evidence for the whole
structure of TT-1 (1) including the absolute stereochemistry.
2. Results and discussion
2.1. Synthesis of segment A
Our modified synthesis of segment A (3) (Scheme 1) began
with the known monoacetate (4),4–7 which was converted
into E-unsaturated ester (5, J4,5Z15.6 Hz)8 by a four-step
reaction [(i) protection with t-butyldimethylsilyl (TBS)
ether; (ii) alkaline hydrolysis of the acetate; (iii) Swern
oxidation; (iv) Horner–Emmons reaction]. The asymmetric
dihydroxylation of ester (5) with AD-mix b9 led to the a,b-
dihydroxy ester (6), which was protected with a benzyl
acetal, and the LiAlH4 reduction of the ester moiety afforded
the alcohol (7). Treatment of 7 with borane-methyl sulfide in
the presence of boron trifluoride diethyl etherate10 led to
reductive deprotection of the benzyl acetal to give a 1,2-diol
Keywords: TT-1 (rasfonin); Trichurus terrophilus; a-Pyrone; Total
synthesis.
* Corresponding author. Tel./fax: C81 43 290 2913;
e-mail: mish@p.chiba-u.ac.jp
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.12.013

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K. Akiyama et al. / Tetrahedron 61 (2005) 1827–1833
Scheme 1. Reagents and conditions: (a) (i) TBSCl, imidazole, DMF, rt, 1 h (82%); (ii) NaOH aq, MeOH, rt, 2 h (97%); (iii) (COCl)2, DMSO, Et3N, CH2Cl2,
K78 8C, 2 h; (iv) (EtO)2P(O)CH2CO2Et, NaH, DME, 0 8C 2 h (84% for 2 steps); (b) AD-mix-b, CH3SO2NH2, t-BuOH/H2O (1:1), 0 8C-rt, 45 h (80%);
(c) (i) PhCH(OCH3)2, TsOH, CH2Cl2, rt, 1 h (90%); (ii) LiAlH4, THF, 0 8C, 0.5 h (81%); (d) BH3 SMe2, BF3 OEt2, CH2Cl2, 0 8C, 1 h (70%);
(e) (i) (CH3)2C(OCH3)2, TsOH, acetone, rt, 1 h (91%); (ii) TBAF, THF, rt, 1 h (91%); (iii) I2, Ph3P, imidazole, benzene, rt, 2 h (95%); (f) 2-bromo-cis-2-
butene, Li, THF, 0 8C-rt, 2 h (62%); (g) (i) TsOH, MeOH, rt, 2 h (84%); (ii) PivCl, pyridine, 0 8C-rt, 14 h (93%); (h) (i) TBSCl, imidazole, DMF, rt, 14 h (95%);
(ii) DIBAL, CH2Cl2, K78 8C, 1 h (86%); (iii) Dess-Martin periodinane, CH2Cl2, rt, 1 h; (iv) (CF3CH2O)2P(O)CH2CO2Me, KHMDS, 18-crown-6, THF,
K78 8C, 2 h (80% for 2 steps); (i) (i) DDQ, H2O, CH2Cl2, rt, 2 h (78%); (ii) DIBAL, CH2Cl2, K78 8C, 1 h; (iii) MnO2, CH2Cl2, rt (68% for 2 steps); (j) TBAF,
THF, rt, 2 h (89%).
(8) selectively (formation of 1,3-diol was not detectable).
The 1,2-diol (8) was protected with an acetonide, and
deprotection of the TBS ether and treatment with iodine
and triphenylphosphine gave the iodide (9). The iodide (9)
was treated with the alkenyllithium reagent11 derived from
2-bromo-cis-2-butene to give the alkene (10). Deprotection
of the acetonide group of 10 and selective protection of the
primary hydroxy group with pivaloyl ester afforded 11. The
remaining secondary hydroxy group of 11 was protected by
the TBS ether, which was converted into Z-unsaturated ester
(12, J3,4Z11.7 Hz) through three steps [(i) removal of
the pivaloyl group with DIBAL; (ii) Swern oxidation;
(iii) Still’s variant of the Horner–Emmons reaction12].
Deprotection of the benzyl ether with DDQ, and reduction
2.2. Coupling of segments A and B
Preparation of the ethyl ester of the di-TBS ether of segment
B (14) was described previously,3 and summarized in
Scheme 2 and Section 3. Coupling of segment A (3) with the
acid obtained by alkaline hydrolysis of the ethyl ester (14)
was carried out, as shown in Scheme 3, by treatment with
1,3-dicyclohyxylcarbodiimide (DCC) in the presence of
4-dimethylaminopyridine (DMAP) to give the TT-1 di-TBS
ether (15). The TT-1 di-TBS ether (15) was also prepared
from natural product the TT-1 (1) by treatment with
TBSOTf in the presence of 2,6-lutidine in dichloromethane.
1
The H and 13C NMR and FABMS spectra of synthetic 15
and natural-product-derived 15 proved to be completely
identical and the sign of their optical rotation data were both
levorotatory. The di-TBS ether of 15 was removed by
treatment with p-toluenesulfonic acid to give TT-1 (1) to
complete the total synthesis of TT-1 (1).
13
with DIBAL followed by allylic oxidation with MnO2
afforded the 6-membered lactone (13), whose TBS ether
was removed by treatment with tetrabutylammonium
fluoride to afford segment A (3).
Scheme 2. (a) (i)TBSCl, imidazole, DMF, 0 8C, 2 h (85%); (ii) TsCl, pyridine, rt, 72 h (80%). (b) NaCN, DMSO, 90 8C, 3.5 h (54%). (c) (i) DIBAL, CH2Cl2,
K78 8C, 1 h; (ii) Ph3PZC(CH3)CO2Et, CH2Cl2, rt, 73 h (47% for 2 steps). (d) (i) DIBAL, CH2Cl2, K78 8C, 1 h; (ii) MnO2, CH2Cl2, rt, 14 h;
(iii) (EtO)2P(O)CH2CO2Et, NaH, DME, 0 8C, 1 h (81% for 3 steps).

K. Akiyama et al. / Tetrahedron 61 (2005) 1827–1833
1829
Scheme 3. (a) (i) 2 N NaOH aq, MeOH, rt, 19 h (80%); (ii) segment A (3), DCC, DMAP, CH2Cl2, rt, 17 h (86%); (b) TBSOTf, 2,6-lutidine, CH2Cl2, 0 8C, 4 h
(43%); (c) p-TsOH, MeOH, rt, 1 h (21%).
1
From these results, the total synthesis of TT-1 (1) was
accomplished and the whole structure of 1 has been
unambiguously established by the present study.
1181, 1094, and 1037 cmK1; H NMR (400 MHz, CDCl3)
dH 0.03 (6H, s, SiCH3), 0.85 (3H, d, JZ6.6 Hz, H-9), 0.88
(9H, s, SiC(CH3)3), 1.05 (3H, d, JZ6.6 Hz, H-8), 1.09 (1H,
m, H-5), 1.28 (3H, t, JZ7.1 Hz, OCH2CH3), 1.50 (1H, ddd,
JZ4.6, 9.1, 13.9 Hz, H-5), 1.60 (1H, m, H-6), 2.43 (1H, m,
H-4), 3.38 (2H, dd, JZ4.6, 6.1 Hz, H-7), 4.18 (2H, q, JZ
7.1 Hz, OCH2CH3), 5.78 (1H, dd, JZ1.0, 15.6 Hz, H-2),
and 6.80 (1H, dd, JZ8.3, 15.6 Hz, H-3); 13C NMR
(100 MHz, CDCl3) dC K5.4(2C), 14.3, 16.6, 18.3, 20.5,
25.9(3C), 33.4, 34.2, 39.9, 60.1, 68.4, 119.8, 154.4, and
116.9; FABMS m/z 315 [MCH]C; HRFABMS found m/z
315.2382 (calcd for 315.2355, C17H35O3Si).
3. Experimental
3.1. General procedures
Optical rotations were recorded on a JASCO J-20. IR
spectra were measured on NaCl disks in a Hitachi 260-10
infrared spectrophotometer. NMR spectra were recorded on
JEOL JNM GSX-A400, A500 and ecp600 spectrometers.
High-resolution fast atom bombardment (HRFAB) mass
spectra were acquired on a JMS HX-110 and JMS AX-500
mass spectrometer.
3.1.2. (2R,3R,4S,6R)-Ethyl 7-(t-Butyldimethysilyloxy)-
2,3-dihydroxy-4,6-dimethylheptanoate (6). AD-mix-b
(40.43 g) was dissolved in 60 mL of t-BuOH/H2O (1:1),
and the solution was stirred at room temperature for 1 h. To
this solution, methanesulfonamide (2.79 g) was added and
the mixture was cooled to 0 8C. The ester (5, 8.97 g) was
added to this solution and stirred for 45 h at room
temperature. After addition of sodium sulfite (40 g),
extraction with ethyl acetate (100 mL!6) followed by
purification with silica gel column chromatography (EtOAc/
hexane, 1:1) afforded the diol (6, 7.79 g, 80%): [a]2D6K7.1 (c
2.08, CHCl3); IR n (neat) 3377, 2957, 2929, 2857, 1723,
3.1.1. (2E,4S,6R)-Ethyl 7-(t-Butyldimethysilyloxy)-4,6-
dimethyl-2-heptenoate (5). The known monoacetate4–7
(4, 12.94 g) was dissolved in DMF (100 mL) and treated
with TBSCl (13.66 g) in the presence of imidazole (11.85 g)
at room temperature for 1 h. After addition of water, the
reaction mixture was extracted with ether (100 mL!5),
dried over MgSO4, and purified with silica gel column
chromatography (EtOAc/hexane, 1:19) to afford a TBS
ether (17.42 g, 82%), which was subjected to hydrolysis by
treatment with 2 M NaOH aqueous solution (100 mL) and
MeOH (150 mL) at room temperature for 2 h. The reaction
mixture was extracted with chloroform (150 mL!6), and
dried over MgSO4, and evaporation of the organic phase
under reduced pressure afforded an alcohol (14.49 g, 97%).
This alcohol (6.98 g) was added to the solution of DMSO
(8.1 mL) and oxalyl chloride (7.5 mL) in CH2Cl2 (150 mL)
at K78 8C, and stirred at room temperature for 1 h under
argon atmosphere. After addition of triethylamine
(24.4 mL), the reaction mixture was gradually warmed to
room temperature and stirred for 1 h. After addition of
water, the mixture was extracted with CHCl3 (100 mL!5),
washed with water, dried over MgSO4 to give an aldehyde,
which was without purification subjected to the following
Horner–Emmons reaction. To a solution of sodium hydride
(60% in oil, 1.27 g) in DME (50 mL), triethyl phosphonoa-
cetate (6.3 mL) was added at 0 8C under argon atmosphere
and the mixture was stirred for 1 h. The aldehyde obtained
above was added to this solution and the mixture was stirred
for 1 h additionally. After addition of ammonium chloride
aqueous solution, extraction with ethyl acetate (100 mL!5)
and purification of the organic phase with silica gel column
chromatography (EtOAc/hexane, 1:19) afforded the unsa-
turated ester (5, 7.53 g, 84% for 2 steps): [a]2D6K0.7 (c 2.00,
CHCl3); IR n (neat) 2957, 1703, 1652, 1462, 1369, 1259,
1465, 1387, 1255, 1222, 1136, and 1097 cmK1; H NMR
1
(400 MHz, CDCl3) dH 0.03 (6H, s, SiCH3), 0.88 (9H, s,
SiC(CH3)3), 0.90 (1H, m, H-5), 0.91 (3H, d, JZ6.6 Hz,
H-9), 1.02 (3H, d, JZ6.6 Hz, H-8), 1.31 (3H, t, JZ7.1 Hz,
OCH2CH3), 1.53 (1H, ddd, JZ5.2, 7.3, 13.8 Hz, H-5), 1.71
(1H, m, H-6), 1.78 (1H, m, H-4), 3.03 (1H, brd, JZ4.4 Hz,
H-3), 3.37 (1H, dd, JZ6.1, 9.7 Hz, H-7), 3.45 (1H, dd, JZ
5.4, 9.7 Hz, H-7), 3.56 (1H, brd, JZ5.9 Hz, H-2), and 4.26
(2H, q, JZ7.1 Hz, OCH2CH3); 13C NMR (125 MHz,
CDCl3) dC K5.4(2C), 14.2, 16.1, 18.1, 25.9(3C), 33.3,
34.0, 37.2, 43.4, 62.1, 67.6, 71.4, 76.2, and 174.1; FABMS
m/z 349 [MCH]C; HRFABMS found m/z 349.2402 (calcd
for 349.2411, C17H37O5Si).
3.1.3. (2R,3R,4S,6R)-7-(t-Butyldimethysilyloxy)-2,3-ben-
zylidendioxy-4,6-dimethylheptanol (7). A solution of the
diol (6, 7.79 g) in dichloromethane (40 mL) was treated
with benzaldehyde dimethylacetal (6.8 mL) in the presence
of p-toluenesulfonic acid monohydrate (230 mg) at room
temperature for 1 h. After addition of sodium hydrogen
carbonate aqueous solution, the mixture was extracted with
ethyl acetate (50 mL!6), dried over MgSO4, and purified
with silica gel column chromatography (EtOAc/hexane,
1:19) afforded an ester (8.12 g, 83%). A part of this ester
(7.07 g) in THF solution (10 mL) was added to the solution
of LiAlH4 (952 mg) in THF (40 mL), and the mixture was

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K. Akiyama et al. / Tetrahedron 61 (2005) 1827–1833
stirred at 0 8C for 30 min. After addition of water and
neutralization with 2 M HCl, the mixture was extracted with
ethyl acetate (30 mL!5), dried over MgSO4, and purified
with silica gel column chromatography (EtOAc/hexane,
1:9) to afford the alcohol (7, 5.17 g, 83%): [a]2D6C2.5 (c
2.00, CHCl3); IR (neat) n 3414, 2954, 2928, 2884, 2856,
(3.63 g, 91%). A part of this alcohol (1.50 g) was dissolved
in benzene (40 mL), and treated with imidazole (809 mg),
triphenylphosphine (3.13 g), and iodine (2.38 g) at room
temperature for 2 h. After addition of sodium sulfite
aqueous solution, extraction with EtOAc (3 mL!4) fol-
lowed by purification with silica gel column chroma-
tography (EtOAc/hexane, 1:9) afforded an iodide (9, 1.92 g,
95%): [a]2D7C32.8 (c 2.00, CHCl3); IR n (neat) 2956, 2928,
1459, 1406, 1387, 1219, 1093, 1067 cmK1 1H NMR
;
(400 MHz, CDCl3) dH 0.03 (6H, s, SiCH3), 0.89 (9H, s,
SiCCH3), 0.92 (3H, d, JZ6.6 Hz, H-9), 1.06 (3H, d, JZ
6.8 Hz, H-8), 1.07 (1H, m, H-5), 1.51 (1H, m, H-5), 1.76
(1H, m, H-6), 1.87 (1H, m, H-4), 3.37 (1H, dd, JZ6.1,
9.8 Hz, H-7), 3.48 (1H, dd, JZ4.9, 9.8 Hz, H-7), 3.76 (2H, t,
JZ4.8 Hz, H-1), 3.81 (1H, dd, JZ5.1, 6.8 Hz, H-3), 4.09
(1H, dt, JZ6.8, 4.8 Hz, H-2), 5.97 (1H, s, OCHPh), 7.38–
7.49 (5H, m, Ph); 13C NMR (100 MHz, CDCl3) dC
K5.4(2C), 15.4, 18.2, 25.9(3C), 32.8, 33.1, 37.2, 63.4,
65.4, 67.4, 79.8, 82.2, 103.1, 127.0, 128.4(2C), 129.5(2C),
137.3; FABMS m/z 395 [MCH]C; HRFABMS found m/z
395.2618 (calcd for 395.2618, C22H39O4Si).
1
2857, 1462, 1421, 1388, 1265, 1091, and 1027 cmK1; H
NMR (400 MHz, CDCl3) dH 0.91 (3H, d, JZ6.6 Hz, H-9),
0.93 (3H, d, JZ6.9 Hz, H-8), 1.09 (1H, m, H-5), 1.30 (1H,
m, H-5), 1.42 (3H, s, OCCH3), 1.43 (2H, m, H-4,6), 1.46
(3H, s, OCCH3), 3.00 (1H, dd, JZ5.9, 9.6 Hz, H-7), 3.08
(1H, dd, JZ4.1, 9.6 Hz, H-7), 3.29 (1H, dd, JZ1.0, 7.8 Hz,
H-3), 3.52 (1H, dt, JZ1.0, 7.8 Hz, H-1), 4.00 (1H, dt, JZ
1.0, 7.8, H-1), 4.33 (1H, q, JZ7.8 Hz, H-2), 4.64 (1H, d, JZ
11.2 Hz, OCH2Ph), 4.86 (1H, s, OCH2Ph), and 7.33–7.39
(5H, m, Ph); 13C NMR (100 MHz, CDCl3) dC 14.4, 17.9,
20.8, 25.8, 26.8, 31.3, 32.6, 40.9, 66.5, 73.7, 79.1, 81.8,
109.3, 127.5(2C), 128.0, 128.2(2C), and 139.1; FABMS m/z
433 [MCH]C; HRFABMS found m/z 433.1224 (calcd for
433.1240, C19H30IO3).
3.1.4. (2R,3R,4S,6R)-3-Benzyloxy-7-(t-butyldimethysilyl-
oxy)-4,6-dimethyl-1,2-heptanediol (8). To a solution of the
alcohol (7, 6.68 g) in dichloromethane (80 mL), dimethyl-
sulfide borane (1.8 mL) was slowly added at 0 8C under
argon atmosphere, and the mixture was stirred and gradually
warmed to room temperature over 1 h. This reaction mixture
was cooled again to 0 8C and boron trifluoride ethyl ether
complex (2.15 mL) was added. The mixture was further
stirred for 10 min. After addition of water, extraction with
EtOAc (50 mL!5) followed by purification with silica gel
column chromatography (EtOAc/hexane, 1:1) afforded a
1,2-diol (8, 4.68 g, 70%): [a]2D7K22.9 (c 2.00, CHCl3); IR n
(neat) 3448, 2956, 2928, 2857, 1462, 1421, 1388, 1265,
1091, and 1027 cmK1; 1H NMR (400 MHz, CDCl3) dH 0.03
(6H, s, SiCH3), 0.89 (9H, s, SiCCH3), 0.90 (3H, d, JZ
6.6 Hz, H-9), 0.98 (3H, d, JZ6.9 Hz, H-8), 1.04 (1H, m,
H-5), 1.65 (1H, m, H-5), 1.75 (1H, m, H-6), 1.86 (1H, m,
H-4), 3.35 (1H, dd, JZ4.8, 5.7 Hz, H-3), 3.41 (2H, dd, JZ
5.3, 7.8 Hz, H-7), 3.54 (1H, m, H-1), 3.63 (1H, m, H-1),
3.74 (1H, m, H-2), 4.55 (1H, d, JZ11.2 Hz, OCH2Ph), 4.74
(1H, s, OCH2Ph), and 7.30–7.37 (5H, m, Ph); 13C NMR
(100 MHz, CDCl3) dC K5.4(2C), 15.5, 17.8, 18.3,
25.9(3C), 32.7, 33.2, 37.7, 64.5, 68.0, 72.0, 74.6, 82.2,
127.8(2C), 127.9, 128.5(2C), and 138.2; FABMS m/z 397
[MCH]C; HRFABMS found m/z 397.2747 (calcd for
397.2774, C22H41O4Si).
3.1.6. (2R,3R,4S,6R,8E)-3-Benzyloxy-1,2-isopropyliden-
dioxy-4,6,8-trimethyl-8-heptene (10). To the mixture of
lithium metal (87.1 mg) and anhydrous ether (4 mL) under
argon atmosphere, 2-bromo-cis-2-butene (851 mg) was
added over 30 min, and the mixture was stirred for 2 h at
room temperature. Then, the mixture was cooled to 0 8C and
a solution of the iodide (9, 901 mg) in THF (6 mL) was
added to this mixture, which was gradually warmed to room
temperature and stirred for 2 h. After addition of ammonium
chloride aqueous solution, the mixture was extracted with
ethyl acetate (30 mL!4), dried over MgSO4, and purified
with silica gel column chromatography (EtOAc/hexane,
1:19) to give the alkene (10, 461 mg, 62%): [a]2D7C20.8 (c
2.00, CHCl3); IR n (neat) 2958, 2930, 1654, 1455, 1378,
1
1250, 1214, 1159, and 1068 cmK1; H NMR (400 MHz,
CDCl3) dH 0.77 (3H, d, JZ6.3 Hz, H-12), 0.93 (3H, d, JZ
6.6 Hz, H-11), 0.95 (1H, m, H-5), 1.38 (3H, s, OCCH3), 1.39
(1H, m, H-5), 1.45 (2H, m, H-4,6), 1.54 (3H, d, JZ6.4 Hz,
H-10), 1.55 (3H, s, H-13), 1.57 (1H, m, H-7), 1.61 (1H, m,
H-6), 1.70 (1H, m, H-4), 1.90 (1H, brdd, JZ5.5, 13.0 Hz,
H-7), 3.32 (1H, dd, JZ1.8, 8.1 Hz, H-3), 3.50 (1H, t, JZ
8.1 Hz, H-1), 4.00 (1H, dd, JZ6.2, 8.1 Hz, H-1), 4.29 (1H,
m, H-2), 4.55 (1H, d, JZ11.7 Hz, OCH2Ph), 5.15 (1H, d,
JZ11.7 Hz, OCH2Ph), 5.14 (1H, q, JZ6.4 Hz, H-9), and
7.30–7.38 (5H, m, Ph); 13C NMR (100 MHz, CDCl3) dC
13.3, 14.9, 15.7, 25.8, 26.9, 27.9, 32.7, 41.8, 47.9, 66.5,
73.9, 77.2, 79.4, 120.1, 127.2, 127.6(2C), 128.1(2C), 134.4,
and 139.4; FABMS m/z 361 [MCH]C; HRFABMS found
m/z 361.2736 (calcd for 361.2743, C23H37O3).
3.1.5. (2R,3R,4S,6R)-3-Benzyloxy-7-iodo-1,2-isopropyl-
idendioxy-4,6-dimethylheptane (9). A solution of the
diol (8, 5.35 g) in dichloromethane (40 mL) was treated
with 2,2-dimethoxypropane in the presence of p-toluene-
sulfonic acid monohydrate (120 mg) at room temperature
for 1 h. After addition of sodium hydrogen carbonate
aqueous solution, the mixture was extracted with ethyl
acetate (50 mL!5), dried over MgSO4, and purified with
silica gel column chromatography (EtOAc/hexane, 3:97) to
afford an acetonide (5.38 g, 91%), which was dissolved
in THF (30 mL) and treated with tetrabutylammonium
fluoride, 1.0 M solution in THF (16 mL) at room tempera-
ture for 1 h. After addition of water, the mixture was
extracted with ethyl acetate (50 mL!4), washed with brine,
dried over MgSO4, and purified with silica gel column
chromatography (EtOAc/hexane, 1:4) to give an alcohol
3.1.7. (2R,3R,4S,6R,8E)-3-Benzyloxy-2-hydroxy-4,6,8-
trimethyl-8-decenyl pivaloate (11). A solution of the
alkene (10, 891 mg) in methanol (20 mL) was treated with
p-toluenesulfonic acid monohydrate (86 mg) at room
temperature for 2 h. After addition of water, the mixture
was extracted with ethyl acetate (30 mL!4), dried over
MgSO4, and purified with silica gel column chromatog-
raphy (EtOAc/hexane, 1:4) to give a diol (662 mg, 84%), a
part of which (507 mg) was dissolved in pyridine (1 mL) at
0 8C and treated with pivaloyl chloride (0.32 mL) at room

K. Akiyama et al. / Tetrahedron 61 (2005) 1827–1833
1831
temperature for 14 h. After addition of water and neutral-
ization with 2 M HCl, the mixture was extracted with ethyl
acetate (20 mL!5), dried over MgSO4, and purified with
silica gel column chromatography (EtOAc/hexane, 1:19)
to give the pivaloyl ester (11, 668 mg, 93%): [a]2D7K16.0
(c 2.00, CHCl3); IR n (neat) 3448, 2962, 2929, 1730, 1654,
6.1 Hz, H-14), 0.88 (9H, s, SiCCH3), 0.95 (3H, d, JZ
6.6 Hz, H-13), 0.96 (1H, m, H-7), 1.40 (1H, m, H-7), 1.51
(3H, s, H-15), 1.52 (3H, d, JZ6.6 Hz, H-12), 1.57 (1H, m,
H-9), 1.62 (1H, m, H-8), 1.77 (1H, m, H-6), 1.89 (1H, m,
H-9), 3.27 (1H, dd, JZ3.0, 6.3 Hz, H-5), 3.69 (3H, s,
OCH3), 4.52 (1H, d, JZ11.7, CH2Ph), 4.58 (1H, d, JZ11.7,
CH2Ph), 5.14 (1H, q, JZ6.6 Hz, H-11), 5.58 (1H, dd, JZ
6.3, 9.5 Hz, H-4), 5.80 (1H, d, JZ11.8 Hz, H-2), 6.15 (1H,
dd, JZ9.5, 11.8 Hz, H-3), and 7.29–7.35 (5H, m, Ph); 13C
NMR (100 MHz, CDCl3) dC K4.5(2C), 13.3, 15.5, 15.6,
19.9, 25.9(3C), 28.1, 31.4, 42.2, 47.6, 51.3, 69.9, 74.4, 84.9,
119.4, 119.8, 127.3(2C), 128.0(2C), 134.5, 139.4, 149.6,
and 166.2; FABMS m/z 489 [MCH]C; HRFABMS found
m/z 489.3423 (calcd for 489.3400, C29H49O4Si).
1480, 1457, 1397, 1375, 1283, 1160, 1095, and 1068 cmK1
;
1H NMR (400 MHz, CDCl3) dH 0.83 (3H, d, JZ6.3 Hz,
H-12), 0.98 (3H, d, JZ6.8 Hz, H-11), 1.06 (1H, m, H-5),
1.24 (9H, s, OCCH3), 1.49 (1H, m, H-5), 1.54 (3H, d, JZ
6.6 Hz, H-10), 1.55 (3H, s, H-13), 1.66 (1H, m, H-7), 1.73
(1H, m, H-6), 1.84 (1H, m, H-4), 2.04 (1H, m, H-7), 3.32
(1H, t, JZ4.4 Hz, H-3), 3.88 (1H, dt, JZ5.8, 4.4 Hz, H-2),
4.09 (2H, d, JZ5.8 Hz, H-1), 4.59 (1H, d, JZ11.0 Hz,
CH2Ph), 4.67 (1H, d, JZ11.0 Hz, CH2Ph), 5.17 (1H, q, JZ
6.6 Hz, H-9), and 7.30–7.36 (5H, m, Ph); 13C NMR
(100 MHz, CDCl3) dC 13.3, 15.6, 20.4, 27.2(3C), 28.4,
32.6, 38.8, 42.3, 47.3, 65.6, 70.3, 74.7, 81.8, 120.1,
127.3(2C), 127.8, 128.5(2C), 134.3, 138.1, and 178.3;
FABMS m/z 405 [MCH]C; HRFABMS found m/z
405.2979 (calcd for 405.3005, C25H41O4).
3.1.9. (5R,6R,10S,30R)-5-(tert-Butyl-dimethyl-silanyloxy)-
6-(10,30,50-trimethyl-hept-5-enyl)-5,6-dihydro-pyran-2-
one (13). The unsaturated ester (12, 5.0 mg) was dissolved
in dichloromethane (0.2 mL), and this solution was treated
with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (23.1 mg)
and water (0.013 mL) at room temperature for 2 h. After
addition of water, extraction with chloroform (50 mL!4)
and purification with silica gel column chromatography
(EtOAc/hexane, 1:9) afforded an alcohol (3.0 mg, 78%),
which was dissolved in dichloromethane (0.2 mL) at
K78 8C under argon atmosphere. To this solution, 0.93 M
dichloromethane solution of DIBAL (0.2 mL) was added,
and this mixture was stirred for 1 h. After warming to room
temperature, potassium sodium (C)-tartarate aqueous
solution was added, and the mixture was extracted with
ethyl acetate (10 mL!4), dried over MgSO4, and evapo-
rated under reduced pressure to give a residue, which was
dissolved in dichloromethane (0.3 mL). To this solution,
manganese dioxide (4.2 mg) was added, and this mixture
was stirred at room temperature for 23 h. Filtration through
celite to remove MnO2 followed by purification with silica
gel preparative TLC gave the 6-membered lactone (13,
2.0 mg, 68% for 2 steps): [a]2D1K160 (c 1.50, CHCl3); IR n
(neat) 3053, 2986, 2958, 2929, 2857, 1723, 1654, 1458,
3.1.8. (2Z,4R,5R,6S,8R,10E)-Methyl 5-benzyloxy-4-(t-
butyldimethylsilyloxy)-6,8,10-trimethyl-dodecadienate
(12). The pivaloyl ester (11, 668 mg) was dissolved in DMF
(6 mL) and treated with TBSCl (752 mg) in the presence of
imidazole (1.16 g) at room temperature for 14 h. After
addition of water, the reaction mixture was extracted with
ether (30 mL!4), dried over MgSO4, and purified with
silica gel column chromatography (EtOAc/hexane, 3:97) to
afford a TBS ether (806 mg, 95%), a part of which (771 mg)
was dissolved in dichloromethane (14 mL). To this solution,
0.93 M diisobutylaluminium hydride in hexane solution
(3.6 mL) was added, and the mixture was stirred at K78 8C
under argon atmosphere. After addition of potassium
sodium (C)-tartarate aqueous solution, the mixture was
extracted with ethyl acetate (20 mL!4), dried over MgSO4,
and purified with silica gel column chromatography
(EtOAc/hexane, 3:97) to afford an alcohol (553 mg, 86%).
A part of this alcohol (259 mg) was dissolved in
dichloromethane (4 mL) and treated with Dess-Martin
periodinane (389 mg) at room temperature for 1 h. After
addition of water, the mixture was extracted with ether
(10 mL!3), washed with aqueous solution of sodium
hydrogen carbonate and sodium thiosulfate (1:1), dried
over MgSO4, and evaporated under reduced pressure to
afford an aldehyde, which was used without purification in
the following reaction. A solution of 18-crown-6 (802 mg)
in THF (6 mL) at K78 8C under argon atmosphere, 0.5 M
toluene solution of potassium bis(trimethylsilyl)-amide
(1.4 mL) and bis-(2,2,2-trifluoroethyl)-(methoxycarbonyl
methyl)phosphonate (0.14 mL) were added and the mixture
was stirred at K78 8C for 1 h. To this solution, the aldehyde
obtained above dissolved in THF (3 mL) was added, and
the mixture was further stirred for 2 h. After addition of
ammonium chloride aqueous solution, the mixture was
extracted with ethyl acetate (10 mL!4), dried over MgSO4,
and purified with silica gel column chromatography
(EtOAc/hexane, 1:9) to afford the unsaturated ester (12,
233 mg, 80% for 2 steps): [a]2D6C19.4 (c 2.20, CHCl3); IR n
(neat) 2954, 2928, 2857, 1726, 1653, 1459, 1437, 1254,
1421, 1380.8, 1159, 1126, and 1053 cmK1 1H NMR
;
(500 MHz, CDCl3) dH 0.03 (3H, s, SiCH3), 0.06 (3H, s,
SiCH3), 0.76 (3H, d, JZ6.6 Hz, H-15), 0.88 (9H, s,
SiCCH3), 0.98 (1H, m, H-8), 1.11 (3H, d, JZ6.6 Hz,
H-14), 1.37 (1H, m, H-8), 1.53 (1H, m, H-10), 1.55 (3H, s,
H-16), 1.56 (3H, d, JZ6.6 Hz, H-13), 1.75 (1H, m, H-9),
2.10 (1H, m, H-10), 2.14 (1H, m, H-7), 3.87 (1H, ddd, JZ
2.4, 8.5, 16.1 Hz, H-6), 4.26 (1H, dt, JZ5.6, 2.4 Hz, H-5),
5.17 (1H, q, JZ6.6 Hz, H-12), 6.08 (1H, dd, JZ1.0, 9.7 Hz,
H-3), and 6.87 (1H, dd, JZ5.6, 9.7 Hz); 13C NMR
(125 MHz, CDCl3) dC K4.3 (2C), 13.3, 14.8, 15.2, 15.4,
20.6, 25.7 (3C), 27.6, 30.8, 40.2, 46.1, 61.7, 85.3, 120.0,
122.8, 134.3, 144.6, and 163.9; FABMS m/z 367 [MCH]C;
HRFABMS found m/z 367.2644 (calcd for 367.2668,
C21H39O3Si).
3.1.10. (5R,6R,10S,30R)-5-Hydroxy-6-(10,30,50-trimethyl-
hept-5-enyl)-5,6-dihydro-pyran-2-one (3). The 6-mem-
bered lactone (13, 8.1 mg) was dissolved in THF (0.15 mL)
and treated with 1.0 M solution of tetrabutylammonium
fluoride in THF (0.03 mL) at room temperature for 2 h.
After addition of water, the mixture was extracted with ethyl
acetate (10 mL!3), dried over MgSO4, and purified with
silica gel prepatative TLC (EtOAc/hexane, 1:1) to give an
1
1197, 1179, and 1096 cmK1; H NMR (400 MHz, CDCl3)
dH 0.03 (3H, s, SiCH3), 0.06 (3H, s, SiCH3), 0.75 (3H, d, JZ

1832
K. Akiyama et al. / Tetrahedron 61 (2005) 1827–1833
alcohol (segment A, 3, 5.0 mg, 89%): [a]2D4K72.5 (c 2.00,
CHCl3); IR n (neat) 3385, 2927, 1712, 1381, 1265, and
sodium (C)-tartarate aqueous solution was added, and the
mixture was extracted with CHCl3 (30 mL!4), dried over
MgSO4, and evaporated under reduced pressure to give a
residue, which was dissolved in dichloromethane (0.5 mL).
This solution was treated with (1-carbethoxyethylidene)-
triphenylphosphorane (364.5 mg) under argon atmosphere
at room temperature for 73 h. After evaporation under
reduced pressure, the residue was purified with silica gel
column chromatography (EtOAc/hexane, 3:97) to afford an
ester (19, 100.6 mg, 47% for 2 steps): [a]2D2C21.0 (c 0.11,
CHCl3); IR n (neat) 2954, 2929, 2895, 2858, 1713, 1653,
1
1040 cmK1; H NMR (500 MHz, CDCl3) dH 0.84 (3H, d,
JZ6.8 Hz, H-15), 1.15 (3H, d, JZ6.4 Hz, H-14), 1.65 (6H,
br.s; H-13 and H-16), 3.92 (1H, dd, JZ9.1, 1.9 Hz, H-6),
4.23 (1H, br.s, H-5), 5.20 (1H, q, JZ6.4 Hz, H-12), 6.13
(1H, dd, JZ9.4 Hz, H-3), and 7.01 (1H, dd, JZ9.4 Hz); 13C
NMR (125 MHz, CDCl3) dC 13.4, 15.6, 15.7, 21.0, 27.9,
31.3, 39.8, 46.4, 60.7, 85.2, 120.1, 123.2, 134.5, 144.2, and
163.9; FABMS m/z 253 [MCH]C; HRFABMS found m/z
253.1807 (calcd for 253.1804, C15H25O3).
1
1472, 1388, 1362, and 1255 cmK1; H NMR (400 MHz,
CDCl3) dH 0.08 (6H, s, SiCH3), 0.10 (6H, s, SiCH3), 0.90
(9H, s, SiC(CH3)3), 0.91 (9H, s, SiC(CH3)3), 1.28 (1H, t, JZ
7.2 Hz, –OCH2CH3), 1.45 (1H, m, H-5), 1.81 (1H, m, H-4),
1.86 (3H, d, JZ1.4 Hz, H-7), 2.78 (1H, m, H-4), 3.52 (1H,
m, H-8), 3.54 (2H, dd, JZ4.1, 6.1 Hz, H-6), 3.60 (1H, m,
H-8), 4.18 (2H, q, JZ7.2 Hz, –OCH2CH3), and 6.57 (1H,
dd, JZ1.4, 10.5 Hz, H-3); 13C NMR (125 MHz, CDCl3) dC
K5.4(4C), 12.9, 14.3, 18.3, 25.8(6C), 34.3, 38.4, 60.4, 60.9,
65.9, 129.0, 143.5, and 168.2; FABMS m/z 431 [MCH]C;
HRFABMS found m/z 431.2990 (calcd for 431.3013,
C22H47O4Si2).
3.1.11. Preparation of segment B di-TBS ether (14)
(Scheme 2). The known triol14 (16, 2.968 g) was dissolved
in DMF (30 mL) and treated with TBSCl (9.697 g) in the
presence of imidazole (9.532 g) at room temperature for 2 h
under argon atmosphere. After addition of water, the
reaction mixture was extracted with CHCl3 (100 mL!5),
dried over MgSO4, and purified with silica gel column
chromatography (EtOAc/hexane, 1:1) to afford a TBS ether
(7.954 g, 85%), part of which (2.011 g) was treated with
TsCl (1.711 g) in pyridine (12 mL) at room temperature for
72 h. After addition of water, the reaction mixture was
neutralized with potassium hydrogensulfate, and extracted
with CHCl3 (100 mL!5), dried over MgSO4, and purified
with silica gel column chromatography (EtOAc/hexane,
1:19) to afford a tosylate (17, 2.337 g, 80%): [a]2D2K16.8 (c
0.20, CHCl3); IR n (neat) 2955, 2929, 2885, 2857, 1598,
To the solution of the ester (19, 85.7 mg) in CH2Cl2 under
argon atmosphere at K78 8C, 0.93 M dichloromethane
solution of DIBAL (0.44 mL) was added, and this mixture
was stirred for 1 h. After warming to room temperature,
potassium sodium (C)-tartarate aqueous solution was
added, and the mixture was extracted with CHCl3
(30 mL!4), dried over MgSO4, and evaporated under
reduced pressure to give a residue, which was dissolved in
dichloromethane (10 mL). This solution was treated with
MnO2 (161.2 mg) at room temperature for 13 h. After
evaporation under reduced pressure, the residue (aldehyde)
was used to the next reaction. A mixture of triethyl
phosphonoacetate and sodium hydride (50% in oil, 21 mg)
in dimethoxyethane (2.5 mL) was stirred at 0 8C under
argon atmosphere for 1 h. To this mixture, the aldehyde
obtained as above was added and stirred for 1 h. After
addition of water, the mixture was extracted with ether
(20 mL!5), dried over MgSO4, and purified with silica gel
column chromatography (EtOAc/hexane, 1:49) to afford the
segment B di-TBS ether (14, 74.3 mg, 81% for 3 steps):
[a]2D2C20.2 (c 0.60, CHCl3); IR n (neat) 2954, 2928, 2857,
1
1471, 1462, 1362, 1256, 1177, and 1098 cmK1; H NMR
(400 MHz, CDCl3) dH K0.01(3H, s, SiCH3), 0.00 (3H, s,
SiCH3), 0.01 (6H, s, SiCH3), 0.85 (18H, s, SiC(CH3)3), 1.80
(1H, m, H-3), 1.90 (1H, m, H-3), 2.44 (3H, s, ArCH3), 3.48
(1H, ddd, JZ6.0, 7.1, 10.5 Hz, H-4), 3.56 (1H, dt, JZ10.5,
6.0 Hz, H-4), 3.72 (2H, d, JZ8.0 Hz, H-1), 7.31 (2H, d, JZ
8.0 Hz, Ar), and 7.80 (2H, d, JZ8.0 Hz, Ar); 13C NMR
(100 MHz, CDCl3)dC K5.5, K5.4, 21.6, 25.7(2C),
25.9(2C), 25.9, 34.3, 58.7, 64.3, 81.0, 127.8(2C),
129.7(2C), and 144.8; FABMS m/z 489 [MCH]C;
HRFABMS found m/z 489.2490 (calcd for 489.2526,
C23H45O5SSi2).
To a solution of sodium cyanide (517.8 mg) in DMSO
(52 mL), the tosylate (17, 2.337 g) was added, and the
mixture was stirred at 90 8C for 3.5 h. After cooling to room
temperature and addition of water, the mixture was
extracted with extracted with CHCl3 (50 mL!5), dried
over MgSO4, and purified with silica gel column chroma-
tography (EtOAc/hexane, 1:4) to afford a nitrile (18,
887 mg, 54%): [a]2D2C15.6 (c 0.50, CHCl3); IR n (neat)
1718, 1624, 1471, 1388, 1364, 1300, 1256, and 1169 cmK1
;
1H NMR (500 MHz, CDCl3) dH 0.01 (12H, s, SiCH3), 0.86
(9H, s, SiC(CH3)3), 0.89 (9H, s, SiC(CH3)3), 1.30 (1H, t, JZ
7.2 Hz, –OCH2CH3), 1.41 (1H, ddt, JZ8.5, 13.5, 5.3 Hz,
H-7), 1.80 (3H, d, s, H-9), 1.86 (ddt, JZ8.5, 13.5, 5.3 Hz,
H-7), 2.82 (1H, ddt, JZ4.2, 10.4, 6.2 Hz, H-6), 3.50 (1H,
ddt, JZ5.1, 6.4, 10.1 Hz, H-8), 3.52 (2H, t, JZ6.2 Hz,
H-10), 3.60 (1H, ddt, JZ5.1, 6.4, 10.1 Hz, H-8), 4.52 (2H,
q, JZ7.2 Hz, –OCH2CH3), 5.74 (1H, d, JZ10.1 Hz, H-5),
5.80 (1H, d, JZ15.6 Hz, H-2), and 7.31 (1H, d, JZ15.6 Hz,
H-3); 13C NMR (125 MHz, CDCl3) dC K5.3(4C), 12.7,
14.3, 18.2, 25.8(6C), 34.3, 38.3, 60.2, 60.8, 66.1, 115.9,
134.0, 143.5, 149.6, and 167.6; FABMS m/z 457 [MCH]C;
HRFABMS found m/z 457.3132 (calcd for 457.3169,
C24H49O4Si2).
1
2955, 2930, 2885, 2858, 1472, 1256, and 1103 cmK1; H
NMR (400 MHz, CDCl3) dH K0.08 (6H, s, SiCH3), 0.10
(6H, s, SiCH3), 0.90 (9H, s, SiC(CH3)3), 0.91 (9H, s,
SiC(CH3)3), 1.83 (2H, m, H-3), 2.95 (1H, dq, JZ8.5,
5.8 Hz, H-2), and 3.78 (4H, m, H-1, 4); 13C NMR
(100 MHz, CDCl3) dH K5.4(4C), 18.3, 26.0(6C), 31.8,
59.9, 63.1, and 120.9; FABMS m/z 344 [MCH]C;
HRFABMS found m/z 344.2416 (calcd for 344.2441,
C17H38O2Si2N).
To the solution of the nitrile (18, 171.8 mg) in CH2Cl2 under
argon atmosphere at K78 8C, 0.93 M dichloromethane
solution of DIBAL was added, and this mixture was stirred
for 1 h. After warming to room temperature, potassium
3.1.12. Coupling of segments A and B. Segment B di-TBS
ether (14, 8.0 mg) in methanol (0.5 mL) was treated with

K. Akiyama et al. / Tetrahedron 61 (2005) 1827–1833
1833
2 M sodium hydroxide aqueous solution (0.5 mL) at room
temperature for 19 h. After addition of water, the mixture
was extracted with ethyl acetate (10 mL!4), dried over
MgSO4, and evaporated under reduced pressure to give an
acid (segment B, 6.0 mg, 80%). The alcohol (segment A, 3,
2.0 mg) and the acid (segment B, 4.0 mg) were dissolved in
dichloromethane (0.2 mL), and this mixture was treated
with 1,3-dicyclohyxylcarbodiimide (DCC, 2.0 mg) in the
presence of 4-dimethylaminopyridine (DMAP, 1.2 mg) at
room temperature for 17 h. After addition of water, the
mixture was extracted with ether (10 mL!4), dried over
MgSO4, and silica gel prepatative TLC (EtOAc/hexane, 1:4)
to give TT-1 di-TBS ether (15, 4.5 mg, 86%): [a]2D3K125 (c
2.0, CHCl3); IR n (neat) 1718, 1617, 1256, 1157, and
of water, the mixture was extracted with CHCl3 (10 mL!
4), dried over MgSO4, and purified with HPLC (Develosil
ODS-HG; 10!250 mm; flow rate: 2.0 mL; UV detection
at 251 nm; eluent: CH3CN/H2O, 1:1) to afford TT-1
(1, 0.3 mg, 21%).
Acknowledgements
This work was partly supported by a Grant-in-Aid from
the Ministry of Education, Culture, Sports, Science, and
Technology of Japan.
1
1092 cmK1; H NMR (500 MHz, CDCl3) dH 0.00 (3H, s,
SiCH3), 0.06 (3H, s, SiCH3), 0.78 (3H, d, JZ7.0 Hz, H-15),
0.87 (9H, s, SiCCH3), 0.88 (9H, s, SiCCH3), 1.15 (3H, d,
JZ6.5 Hz, H-14), 1.52 (3H, br.s, H-16), 1.53 (3H, d, JZ
6.2 Hz, H-13), 1.79 (30H, s, H-90), 2.83 (1H, br.s, H-60),
3.48–3.62 (4H, m, H-8 and H-100), 4.13 (1H, dd, JZ8.8,
1.8 Hz, H-6), 5.12 (1H, q, JZ6.2 Hz, H-12), 50.36 (1H, d0d,
JZ6.0, 1.8 Hz, H-5), 5.73–5.85 (2H, m, H-2 and H-5 ),
6.21 (d, JZ9.5 Hz, H-3), 7.05 (1H, dd, JZ9.5, 6 Hz, H-4),
and 7.34 (1H, d, JZ15.5 Hz); 13C NMR (125 MHz, CDCl3)
dC K5.43, K5.40, K5.38, K5.30, 12.7, 13.3, 15.5, 15.9,
18.2, 18.2, 20.6, 25.84, 25.88, 27.9, 31.4, 34.6, 38.4, 40.0,
46.3, 60.7, 61.6, 66.0, 83.3, 114.1, 120.0, 124.9, 134.0,
134.1, 140.7, 145.3, 151.6, 163.3, and 166.4; FABMS m/z
663 [MCH]C; HRFABMS found m/z 663.4480 (calcd for
663.4476, C37H67O6Si2).
References and notes
1. Fujimoto, H.; Sone, E.; Okuyama, E.; Ishibashi, M. 120th
Annual Meeting of the Pharmaceutical Society of Japan,
Abstracts of Papers 2, 2000; p 68.
2. Tomikawa, T.; Shin-ya, K.; Furihata, K.; Kinoshita, T.;
Miyajima, A.; Seto, H.; Hayakawa, Y. J. Antibiot. 2000, 53,
848–850.
3. Akiyama, K.; Kawamoto, S.; Fujimoto, H.; Ishibashi, M.
Tetrahedron Lett. 2003, 44, 8427–8431.
4. Atta-ur-Rahman; Beisler, L. A.; Harlet-Mason, J. Tetrahedron
1980, 36, 1063–1070.
5. Allinger, N. L. J. Am. Chem. Soc. 1959, 81, 232–236.
6. Fujita, K.; Mori, K. Eur. J. Org. Chem. 2001, 493–502.
7. Wang, Y. F.; Chen, C.-S.; Gridaukas, G.; Sih, C. J. J. Am.
Chem. Soc. 1984, 106, 3695–3696.
3.2. Preparation of TT-1 di-TBS ether (15) from TT-1 (1)
To the solution of TT-1 (1, 5.0 mg) in dichloromethane
(0.1 mL), 2,6-lutidine (5.4 mL) was added at 0 8C under
argon atmosphere. To this solution, TBSOTf (7.9 mL) was
added dropwise over 5 min and the mixture was stirred for
4 h at 0 8C. After addition of water (0.5 mL), the reaction
mixture was extracted with CHCl3 (10 mL!4), dried over
MgSO4, and purified with preparative TLC (silica gel,
EtOAc/hexane, 1:4) to afford a TT-1 TBS ether (15, 3.3 mg,
43%), which was completely identical with synthetic 15 on
8. The numberings of the synthetic intermediates also refers to
those of the natural product (1).
9. Sharpless, K. B.; Amberg, W.; Beller, M.; Chen, H.; Hartung,
J.; Kawanami, Y.; Lubben, D.; Manoury, E.; Ogino, Y.;
Shibata, T.; Ukita, T. J. Org. Chem. 1991, 56, 4585–4588.
10. Saito, S.; Kuroda, A.; Tanaka, K.; Kimura, R. Synlett 1996,
231–233.
11. Nivelet, A.; Dechoux, L.; le Gall, T.; Mioskowski, C. Eur.
J. Org. Chem. 1999, 3251–3256.
1
the basis of comparison of H and 13C NMR and FABMS
12. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24,
4405–4408.
spectral data, and the sign of the optical rotation was also the
same ([a]2D4K70 (c 2.0, CHCl3)).
13. We initially expected the formation of the 6-membered lactone
by only deprotection of the benzyl ether, followed by acid
treatment, but it was not obtained. We then used the
reduction and oxidation procedure. Murayama, T.; Sugiyama,
T.; Yamashita, K. Agric. Biol. Chem. 1986, 50, 2351–2374.
14. Hanessian, S.; Ugolini, A.; Dube, D.; Glamyan, A. Can.
J. Chem. 1984, 62, 2146–2147.
3.3. Conversion of TT-1 di-TBS ether (15) into TT-1 (1)
TT-1 TBS ether (15, 2.2 mg) was dissolved in MeOH
(0.55 mL) and treated with p-toluenesulfonic acid mono
hydrate (28 mg) at room temperature for 1 h. After addition