Enantioselective Synthesis of Aspergillide B

Article abstract of DOI:10.1271/bbb.90221

The enantioselective synthesis of aspergillide B, a 14-membered macrocyclic cytotoxin, was achieved in a 49% yield via 7 steps from a synthetic intermediate of aspergillide C. The spectroscopic data and specific rotation value for the synthetic material m

Full text of DOI:10.1271/bbb.90221

Biosci. Biotechnol. Biochem., 73 (8), 1893–1894, 2009
Note
Enantioselective Synthesis of Aspergillide B
y
Tomohiro NAGASAWA and Shigefumi KUWAHARA
Laboratory of Applied Bioorganic Chemistry, Graduate School of Agricultural Science, Tohoku University,
Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai 981-8555, Japan
Received April 1, 2009; Accepted April 14, 2009; Online Publication, August 7, 2009
[doi:10.1271/bbb.90221]
The enantioselective synthesis of aspergillide B, a
14-membered macrocyclic cytotoxin, was achieved in a
49% yield via 7 steps from a synthetic intermediate of
aspergillide C. The spectroscopic data and specific
rotation value for the synthetic material matched those
of natural aspergillide B.
was then selectively hydrolyzed by directly adding water
to the reaction mixture to afford 8 in an 89% yield from
7.3) Oxidative deprotection of the PMB group with DDQ
gave hydroxy carboxylic acid 9 in a 77% yield. Finally,
seco acid 9 was subjected to the known two-step
sequence involving Yamaguchi lactonization and TBS
deprotection to afford aspergillide B (1) in an 80%
1
Key words: aspergillide; cytotoxic; macrolide; enantio-
selective synthesis
yield.2) The H- and 13C-NMR spectra of 1, obtained as
a microcrystalline solid (mp 82.5–83.5 ꢀC), were iden-
tical with those reported for natural aspergillide B, and
25
Aspergillides A–C, which exhibit significant cytotox-
icity against mouse lymphocytic leukemica cells
(L1210), were recently isolated by Kusumi and co-
workers from a bromine-modified 1/2PD (potato-
dextrose) culture medium of the marine-derived fungus,
Aspergillus ostianus strain 01F313, and their structures
were proposed to be heptaketidic 14-membered macro-
lides based on extensive spectroscopic analyses.1) The
structural proposal for aspergillides A and B was,
however, revealed to be incorrect by the synthesis of the
proposed structures by Uenishi and co-workers.2) They
concluded that the genuine structure of aspergillide B
must be represented by structure 1 (Fig. 1), and the real
structure of aspergillide A should be reinvestigated.2)
We also took an interest in the unique structures of
aspergillides A–C proposed by Kusumi et al., which
featured a 14-membered macrolide structure incorporat-
ing a 2,6-trans-substituted tetrahydro- or dihydropyran
ring,3) and embarked on their total synthesis. We
recently completed the enantioselective total synthesis
of the proposed structure of aspergillide C (2), and
confirmed its structure.3) In this note, we describe a
new synthesis for aspergillide B (1) from a synthetic
intermediate of 2.
As shown in Scheme 1, our synthesis of 1 began with
the saponification of 5 and subsequent in-situ iodolacto-
nization of the resulting carboxylate salt to give 6;
olefinic ester 5 in turn was prepared according to our
previously reported procedure, using 3 and 4 as chiral
sources.3) Reductive elimination of iodolactone 6 pro-
ceeded smoothly, affording 7 in a 90% yield from 5.
Hydrolysis of the lactone moiety of 7 with lithium
hydroxide in aqueous THF gave a mixture containing
the corresponding hydroxy carboxylate. The mixture
was concentrated to dryness, dissolved in DMF, and
treated with TBSOTf, imidazole and DMAP to give a
bis-silylated intermediate, the TBS ester group of which
the specific rotation of 1 {½ꢀꢁ
ꢂ108 (c 0.175,
D
MeOH)} showed good agreement with reported data
20
31
{½ꢀꢁ
ꢂ97:2 (c 0.27, MeOH),1) ½ꢀꢁ
ꢂ90:0 (c 0.10,
D
D
MeOH)2)}.
Experimental
IR spectra were recorded by a Jasco FT/IR-4100 spectrometer,
using an ATR (ZnSe) attachment. NMR spectra were recorded with
TMS as an internal standard in CDCl3 by a Varian Gemini 2000
spectrometer (300 MHz for 1H and 75 MHz for 13C), unless otherwise
stated. Optical rotation values were measured with a Horiba Septa-300
polarimeter, and mass spectra were obtained with a Jeol JMS-700
spectrometer. Merck silica gel 60 (70–230 mesh) was used for column
chromatography.
(3aS,5R,7aS)-5-[(1E,6S)-6-(4-Methoxybenzyloxy)-1-heptenyl]hexa-
hydrofuro[3,2-b]pyran-2-one (7). To a stirred solution of 5 (30.7 mg,
79.0 mmol) in THF (0.15 ml) was added a solution of NaOH (9.7 mg,
0.23 mmol) in water (50 ml) at room temperature. The mixture was
stirred at 40 ꢀC for 5 h and then cooled to room temperature. To the
mixture were successively added a solution of NaHCO3 (67.9 mg,
0.808 mmol) in water (1 ml) and a solution of I2 (26.8 mg, 0.106 mmol)
and KI (67.8 mg, 0.408 mmol) in water (1 ml). After being stirred
overnight in the dark, the mixture was quenched with satd. Na2S2O3
aq. and extracted with CHCl3. The resulting extract was washed with
brine, dried (MgSO4), and concentrated in vacuo to give 6 (42.5 mg) as
a yellow oil which was then taken up in toluene (2.0 ml). To the
solution was successively added Bu3SnH (30.0 ml, 0.108 mmol) and a
solution of Et3B (1 M in hexane, 45.0 ml, 45 mmol) at ꢂ30 ꢀC. After
being stirred at ꢂ30 ꢀC for 30 min under an oxygen atmosphere, the
mixture was quenched with satd. NaHCO3 aq. and extracted with
EtOAc. The resulting extract was washed with brine, dried (MgSO4),
and concentrated in vacuo. The residue was purified by silica gel
column chromatography (hexane/EtOAc = 3:1) to give 26.6 mg
23
(90%) of 7 as a pale yellow oil. ½ꢀꢁ
ꢂ34:5 (c 1.18, CHCl3); IR
D
ꢁ
max: 1782 (vs), 1612 (m), 1513 (s), 1246 (s), 1034 (s); 1H-NMR ꢂ:
1.18 (3H, d, J ¼ 6:0 Hz, 70-H3), 1.37–1.61 (5H, m), 1.97–2.11 (5H, m),
2.50 (1H. dd, J ¼ 17:3, 1.1 Hz, 3-H), 2.65 (1H, dd, J ¼ 17:3, 4.4 Hz,
3-H), 3.46–3.55 (1H, m, 60-H), 3.80 (3H, s, OCH3), 4.33–4.40 (3H, m,
3a-H, 7a-H, 5-H), 4.37 (1H, d, J ¼ 11:3 Hz, Ar–CH), 4.51 (1H, d,
J ¼ 11:3 Hz, Ar–CH), 5.57 (1H, ddt, J ¼ 15:7, 4.9, 1.4 Hz, 10-H), 5.71
(1H, ddt, J ¼ 15:7, 1.4, 6.6 Hz, 20-H), 6.84–6.90 (2H, m, Ar–H), 7.23–
y
To whom correspondence should be addressed. Fax: +81-22-717-8783; E-mail: skuwahar@biochem.tohoku.ac.jp
Abbreviations: PMB, p-methoxybenzyl; TBS, tert-butyldimethylsilyl; TBSOTf, tert-butyldimethylsilyl trifluoromethanesulfonate; imid, imidazole;
DMAP, 4-(dimethylamino)pyridine; DDQ, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone

1894
T. NAGASAWA and S. KUWAHARA
700-H3), 1.32–1.68 (6H, m), 1.72–1.83 (1H, m), 1.85–1.96 (1H, m), 2.01
(2H, br q, J ¼ 6:6 Hz), 2.61 (1H, dd, J ¼ 15:7, 4.9 Hz, 2-H), 2.73 (1H,
dd, J ¼ 15:7, 8.8 Hz, 2-H), 3.43–3.53 (1H, m, 600-H), 3.76–3.86 (1H,
m, 30-H), 3.80 (3H, s, OCH3), 4.13–4.20 (1H, m, 20-H), 4.22–4.29 (1H,
m, 60-H), 4.37 (1H, d, J ¼ 11:4 Hz, Ar–CH), 4.49 (1H, d, J ¼ 11:4 Hz,
Ar–CH), 5.45 (1H, br dd, J ¼ 15:7, 5.5 Hz, 10-H), 5.66 (1H, ddt,
J ¼ 15:7, 1.1, 6.6 Hz, 200-H), 6.84–6.90 (2H, m, Ar–H), 7.23–7.29 (2H,
m, Ar–H); 13C-NMR ꢂ: ꢂ5:1, ꢂ4:9, 17.9, 19.5, 24.8, 25.7 (3C), 27.2,
27.3, 32.3, 33.4, 36.0, 55.2, 67.6, 69.9, 70.9, 72.2, 74.3, 113.8 (2C),
129.3 (2C), 129.4, 131.2, 133.3, 159.2, 176.4; HRMS (EI) m=z: calcd.
for C28H46O6Si, 506.3064; found, 506.3069 (Mþ).
O
O
H
O
O
H
O
O
H
H
HO
aspergillide B
HO
aspergillide C
1
2
Fig. 1. Structures of Aspergillides B and C.
{(2S,3S,6R)-3-(tert-Butyldimethylsilyloxy)-6-[(1E,6S)-6-hydroxy-1-
heptenyl]-tetrahydropyran-2-yl}acetic acid (9). To a stirred mixture of
8 (22.5 mg, 44.4 mmol) in CH2Cl2 (0.4 ml)/1 M phosphate buffer
(pH 7.0, 0.2 ml) was added DDQ (22.2 mg, 94.9 mmol) at room
temperature. After 12 h, additional DDQ (15.9 mg, 67.9 mmol) was
added, and the mixture was stirred for 4 h. The mixture was extracted
with CH2Cl2, and the extract was washed with brine, dried (MgSO4),
and concentrated in vacuo. The residue was purified by silica gel
CO2Me
OPMB
NaOH
PMBO
H
ref. 3
3
aq. THF
O
OTBS
then KI3
NaHCO3
MeO2C
H
O
O
5
4
column chromatography (hexane/EtOAc = 2:1–1:0) to give 13.2 mg
22
(77%) of 9 as a pale yellow oil. ½ꢀꢁ
ꢂ27:9 (c 0.815, CHCl3); IR
D
Bu3SnH, Et3B
O2, toluene
PMBO
H
PMBO
H
ꢁ
max: 3402 (br w), 3000 (br w), 1713 (s), 1104 (s), 836 (s); 1H-NMR ꢂ:
0.05 (3H, s, SiCH3), 0.06 (3H, s, SiCH3), 0.89 (9H, s, SiC(CH3)3), 1.18
(3H, d, J ¼ 6:0 Hz, 700-H3), 1.36–1.52 (5H, m), 1.57–1.69 (1H, m),
1.74–1.84 (1H, m), 1.88–1.97 (1H, m), 2.00–2.10 (2H, m, 300-H2), 2.56
(1H, dd, J ¼ 15:6, 4.4 Hz, 2-H), 2.72 (1H, dd, J ¼ 15:6, 9.3 Hz, 2-H),
3.75–3.85 (2H, m, 30-H, 600-H), 4.17–4.29 (2H, m, 20-H, 60-H), 5.48
(1H, br dd, J ¼ 15:7, 5.8 Hz, 100-H), 5.68 (1H, ddt, J ¼ 15:7, 1.1,
6.6 Hz, 200-H); 13C-NMR ꢂ: ꢂ5:1, ꢂ4:8, 17.9, 23.2, 24.9, 25.7 (3C),
27.0, 27.2, 32.1, 33.8, 38.4, 67.7, 68.0, 70.9, 72.1, 129.5, 133.3, 176.3;
HRMS (FAB) m=z: calcd. for C20H39O5Si, 387.2566; found, 387.2564
(½M þ Hꢁþ).
O
I
O
90% from 5
H
H
O
O
O
6
7
1) aq. LiOH/THF
DDQ
PMBO
2) TBSOTf, imid
DMAP, DMF
then H2O
CH2Cl2
77%
H
O
HO2C
H
89%
TBSO
(1S,5S,9E,11R,14S)-14-Hydroxy-5-methyl-4,15-dioxabicyclo[9.3.1]-
pentadec-9-en-3-one (1). Compound 1 was prepared from 9 in an 80%
yield via 2 steps according to the procedure reported in ref. 2. Mp
8
25
82.5–83.5 ꢀC; ½ꢀꢁ
ꢂ108 (c 0.175, MeOH); IR ꢁmax: 3437 (br m),
OH
O
O
H
ref. 2
D
2930 (s), 1724 (vs), 1183 (m), 1023 (s); 1H-NMR (C6D6) ꢂ: 0.99 (1H,
dddd, J ¼ 14:0, 4.9. 2.5, 1.2 Hz, 6-H), 1.06 (3H, d, J ¼ 6:3 Hz,
5-CH3), 1.27–1.44 (3H, m), 1.46–1.68 (3H, m), 1.68–1.91 (2H, m),
1.86–1.96 (1H, br, OH), 1.98–2.09 (1H, m, 8-H), 2.12 (1H, dd,
J ¼ 13:7, 1.9 Hz, 2-H), 2.72 (1H, dd, J ¼ 13:7, 11.5 Hz, 2-H), 3.21
(1H, br s, 14-H), 4.08 (1H, br d, J ¼ 11:5 Hz, 1-H), 4.28–4.34 (1H, m,
11-H), 5.04–5.14 (1H, m, 5-H), 5.39 (1H, br dd, J ¼ 15:7, 4.4 Hz,
10-H), 6.19 (1H, dddd, J ¼ 15:7, 10.9, 4.9, 1.9 Hz, 9-H); 13C-NMR
(C6D6) ꢂ: 19.0, 22.4, 25.1, 27.6, 30.6, 31.9, 39.7, 67.2, 69.5, 69.7, 71.4,
129.0, 138.2, 169.9; HRMS (EI) m=z: calcd. for C14H22O4, 254.1518;
found, 254.1520 (Mþ).
H
O
2 steps
80%
O
HO2C
H
H
TBSO
HO
9
1
Scheme 1. Synthesis of Aspergillide B.
7.29 (2H, m, Ar–H); 13C-NMR ꢂ: 19.5, 20.6, 22.1, 24.9, 32.4, 36.1,
38.0, 55.2, 67.2, 69.9, 71.7, 74.2, 76.9, 113.8 (2C), 127.4, 129.2 (2C),
131.2, 134.4, 159.2, 176.2; HRMS (EI) m=z: calcd. for C22H30O5,
374.2093; found, 374.2095 (Mþ).
{(2S,3S,6R)-3-(tert-Butyldimethylsilyloxy)-6-[(1E,6S)-6-(4-methoxy-
benzyloxy)-1-heptenyl]tetrahydropyran-2-yl}acetic acid (8). To a stirred
solution of 7 (26.2 mg, 70.0 mmol) in THF (0.10 ml) was added a
Acknowledgments
.
solution of LiOH H2O (3.4 mg, 77 mmol) in water (30 ml) at room
This work was supported, in part, by grant-aid for
scientific research (B) from the Ministry of Education,
Culture, Sports, Science and Technology of Japan
(no. 19380065). We thank Ms. Yamada (Tohoku
University) for measuring the NMR and MS data.
temperature. After 2 h, the mixture was concentrated in vacuo to give a
lithium carboxylate salt as a pale yellow solid which was then
dissolved in DMF (0.2 ml). To the solution were successively added a
solution of imidazole (26.7 mg, 0.392 mmol) and DMAP (6.0 mg,
49 mmol) in DMF (0.25 ml) and TBSOTf (68 ml, 0.290 mmol) at room
temperature. After 2 h, water (2.0 ml) was added, and the mixture was
stirred for 1 h. The mixture was diluted with water and extracted with
CH2Cl2. The extract was washed with brine, dried (MgSO4), and
concentrated in vacuo. The residue was purified by silica gel column
References
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T, Org. Lett., 10, 225–228 (2008).
chromatography (hexane/EtOAc = 2:1) to give 31.5 mg (89%) of 8 as
23
a pale yellow oil. ½ꢀꢁ
ꢂ11:3 (c 0.780, CHCl3); IR ꢁmax: 3000 (br m),
2) Hande SM and Uenishi J, Tetrahedron Lett., 50, 189–192 (2009).
3) Nagasawa T and Kuwahara S, Org. Lett., 11, 761–764 (2009).
D
1711 (s), 1513 (m), 1248 (s), 835 (s); 1H-NMR ꢂ: 0.05 (3H, s, SiCH3),
0.06 (3H, s, SiCH3), 0.89 (9H, s, SiC(CH3)3), 1.17 (3H, d, J ¼ 6:3 Hz,