Total synthesis of (+)-antimycin A3b on solid supports

Article abstract of DOI:10.1002/ejoc.201402430

A straightforward and convergent total synthesis of (+)-antimycin A _3b is reported. Four fragments were assembled on a solid support and the fully functionalized seco acid was cyclized in the solution phase. This synthetic route minimized the n

Full text of DOI:10.1002/ejoc.201402430

FULL PAPER
DOI: 10.1002/ejoc.201402430
Total Synthesis of (+)-Antimycin A3b on Solid Supports
Yusuke Iijima,[a] Osamu Kimata,[a] Santida Decharin,[a] Hisashi Masui,[b] Yoichiro Hirose,[c]
and Takashi Takahashi*[b]
Keywords: Combinatorial chemistry / Solid-phase synthesis / Natural products / Antimycin / Lactones
A straightforward and convergent total synthesis of (+)-anti-
mycin A3b is reported. Four fragments were assembled on a
solid support and the fully functionalized seco acid was cy-
clized in the solution phase. This synthetic route minimized
the number of manipulations in the solution phase and is
useful for a combinatorial library synthesis.
Introduction
Antimycin A was first isolated from Streptomyces in 1949
and since then more than 25 antimycins have been discov-
ered (Figure 1).[1–12] Antimycins possess several attributes
including antifungal,[1] insecticidal,[13] and nematocidal
bioactivities.[10] These bioactivities originate from specific
inhibition of the electron-transfer activity of ubiquinol-
cytochrome c oxidoreductase in the cellular respiration sys-
tem.[14] In 2001, Hockenbery and co-workers reported that
antimycin A induced cell death of cancer cells.[15] Binding
of antimycin A to Bcl-xL triggers apoptosis in cancer cells,
however the 2Ј-methoxy derivative of antimycin A3b is inac-
tive as an inhibitor of cellular respiration but still binds to
Bcl-xL. This discovery aroused our interest in elucidating
the structure–activity relationship of antimycins in their
binding with Bcl-xL.
Several groups have accomplished the total synthesis of
antimycin A3b.[16] Recently, Tsunoda and co-workers com-
pleted the total synthesis of 12 components of antimy-
cins.[17] In all cases, a dilactone ring between the O-5 and
C-6 position was constructed to avoid γ-lactone forma-
tion.[18] The 3-formamidosalicylate group was introduced
after dilactone ring construction. The introduction of the
C-8 O-acyl group was performed both before and after di-
lactone ring construction, although the presence of the C-8
O-acyl group lowered the cyclization yield. Wu and Yang
reported dilactone ring formation of the seco acid with the
C-8 O-acyl group in a good yield by using Shiina’s
method.[19]
Figure 1. Structures of antimycin A1–A20.
As a part of our studies on solid-support combinatorial
library synthesis of antimycins, here, we report the total
synthesis of (+)-antimycin A3b on solid supports. We set the
side chain of the C-7 position, the C-8 O-acyl group, and
the aromatic ring as diversity points for the combinatorial
library synthesis. Our prerequisite was that all diversities
should be introduced prior to cleavage from the solid sup-
port to minimize the number of treatments in solution
phase. The strategy included performing a macrolacton-
ization in the solution phase after cleavage from the solid
support because the formation of the nine-membered di-
lactone is not reliable by on-resin cyclization or cyclization
release. Therefore, it is desirable to introduce the C-8 O-acyl
group and the N-acyl group before cleavage from the solid
support. Since macrolactonization should be performed on
the fully functionalized seco acid, this synthetic route is very
straightforward.
[a] Department of Applied Chemistry, Tokyo Institute of
Technology,
2-12-1 Ookayama, Meguro, Tokyo 152-8552, Japan
[b] Yokohama College of Pharmacy,
601 Matano-cho, Totsuka-ku, Yokohama 245-0066, Japan
E-mail: ttak@hamayaku.ac.jp
http://www.hamayaku.jp/lab/la_26.html
[c] PRISM BioLab Co., Ltd.,
4259-3, Nagatsuda-cho, Midori-ku, Yokohama,
Kanagawa 226-8510, Japan
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402430.
Eur. J. Org. Chem. 2014, 4725–4732
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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T. Takahashi et al.
FULL PAPER
on the solid support. The consecutive stereogenic centers of
the hydroxy acid 7 could be constructed by utilizing Keck’s
Results and Discussion
Our retrosynthetic route is shown in Scheme 1. (+)-Anti- allylation to a protected d-lactaldehyde with chelation con-
mycin A3b (1) can be synthesized by cleavage of the seco trol.[20] This reaction would give a C-9 epimer that could
acid 2 from the solid support, followed by macrolacton- be corrected by exploiting Mitsunobu inversion with either
ization and deprotection of the phenolic hydroxy group. The threonine coupling or at the protection step. The resultant
seco acid 2 can be synthesized by assembling four fragments alkene would be used as a protected carboxylic acid moiety
Scheme 1. Strategy for the total synthesis of (+)-antimycin A3b on solid supports.
Scheme 2. Synthesis of the model compound.
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Total Synthesis of (+)-Antimycin A3b on Solid Supports
to avoid γ-lactone formation. In a preliminary study, we
In the next stage, we performed the total synthesis of
investigated the macrolactonization of the N- and C-8 O- antimycin A3b on solid support. The PS-2-chlorotrityl resin,
acylated seco acid. d-Lactaldehyde, used immediately after which would avoid undesirable cleavage from the solid sup-
the oxidation of the corresponding alcohol, reacted with port by γ-lactone formation, was selected as the solid sup-
alkenyl stannane 9[21] to obtain product 12 as an analyti- port. The chloroacetyl group was selected as the protecting
cally pure stereoisomer (Scheme 2).[20] The stereochemistry group of the C-9 OH moiety, the alkene was converted into
was checked by converting 12 into known lactone 20.[22] the corresponding carboxylic acid, and the fragment was
After C-8 O-acylation and deprotection of the p-meth- attached to the solid support. However, direct Mitsunobu
oxybenzyl (PMB) group, the threonine derivative 15 was inversion with threonine afforded unsatisfactory results
added to achieve the Mitsunobu reaction, which produced both in the solution phase and on the solid support, proba-
inversion of the stereocenter C-9 in moderate yield. After bly because of steric hindrance. Therefore, the stereochemis-
deprotection of THP, the alkene was converted into the cor- try of C-9 was inverted in advance by the Mitsunobu reac-
responding carboxylic acid by consecutive oxidation. RuO4- tion with chloroacetic acid.
catalyzed oxidation[23] of 16 gave a mixture of diol and alde-
The PMB group of 19 was removed and the chloroacetyl
hyde. This mixture was treated by NaIO4, followed by Pin- group was introduced by Mitsunobu reaction with inversion
nick oxidation[24] to give the N-acylated seco acid 17. of the C-9 stereochemistry to give 22 (Scheme 3). The carb-
Macrolactonization was performed by using Shiina’s oxylic acid 23 was synthesized by oxidative cleavage[23,24] of
method.[19] In the presence of 2-methyl-6-nitrobenzoic an- the alkene of 22. After removal of the Bn group, the com-
hydride (MNBA) and 4-(dimethylamino)pyridine (DMAP), pound was immediately attached to the PS-2-chlorotrityl
macrolactonization did not proceed. However, in the pres- resin. Migration of the C-9 O-chloroacetyl group to 8-OH
ence of 4-(dimethylamino)pyridine N-oxide (DMAPO) and was observed when the loading reaction was performed for
N,N-diisopropylethylamine (DIEA) instead of DMAP, 12 h. We therefore set the reaction time as 3 h and used
macrolactone 18 was obtained in good yield. We confirmed an excess amount of resin to suppress the migration of the
that the macrolactonization proceeded after all diversity protecting group. Isovalerate was introduced and the
points were introduced.
chloroacetate was removed on the solid support. Fmoc-
Scheme 3. Total synthesis of (+)-antimycin A3b on solid supports.
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T. Takahashi et al.
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ter stirring at the same temperature for 30 min, the reaction mixture
was poured into saturated aq. NaHCO3. The aqueous layer was
extracted with two portions of CH2Cl2 and the combined extract
was washed with brine, dried with MgSO4, filtered, and the sol-
vents evaporated in vacuo. The residue was purified by chromatog-
raphy on silica gel (hexane/ethyl acetate, 97:3) to give 12 (534 mg,
1.83 mmol, two steps 61%) as a colorless oil. [α]3D0 = –21.7 (c =
0.910, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.25 (d, J =
8.7 Hz, 2 H), 6.88 (d, J = 8.7 Hz, 2 H), 5.59 (dt, J = 16.9, 9.9 Hz,
1 H), 5.04 (dd, J = 9.9, 1.9 Hz, 1 H), 4.96 (dd, J = 16.9, 1.9 Hz, 1
threonine 26 was esterified and the progress of the reaction
was checked by performing the Fmoc test. After deprotec-
tion of the Fmoc group followed by amidation of the sali-
cylic acid derivative 3, seco acid 2 was cleaved from the
solid support by the application of 1% trifluoroacetic acid
(TFA). After the removal of the volatile compounds, the
crude seco acid 2 was directly exposed to the cyclization
conditions. Thus, the reagents were added to a solution of
crude 2 and the cyclization reaction proceeded without the
formation of detectable amounts of cyclic dimer. This sim- H), 4.56 (d, J = 11.1 Hz, 1 H), 4.33 (d, J = 11.1 Hz, 1 H), 3.80 (s,
3 H), 3.63 (dq, J = 3.6, 6.2 Hz, 1 H), 3.20 (dt, J = 3.6, 6.9 Hz, 1
H), 2.16–2.22 (m, 2 H), 1.64–1.67 (m, 1 H), 1.11–1.31 (m, 8 H),
0.88 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
159.2, 140.2, 130.6, 129.4, 116.2, 113.8, 77.9, 74.5, 70.5, 55.3, 47.8,
plified method to perform efficient and rapid library syn-
thesis minimized the treatment in the solution phase. Fi-
nally, the benzyl group of 29 was removed by hydrogenation
to give (+)-antimycin A3b (1). The structures of antimycin
29.4 (ϫ2), 22.8, 16.4, 14.1 ppm. IR (KBr): ν = 3560, 3074, 2956,
˜
1
A3b (1) were confirmed by H NMR, 13C NMR, IR, and
2931, 2859, 1614, 1514, 1249, 1068, 1037, 998, 913, 822 cm–1.
HRMS (ESI-TOF): m/z calcd. for C18H29O3 [M + H]+ 293.2117;
found 293.2120.
HRMS analyses.[16,25]
Conclusions
(2R,3R,4S)-4-Butyl-2-(4-methoxybenzyloxy)hexa-5-en-3-yl 3-Meth-
ylbutanoate (13): To a stirred mixture of 12 (307 mg, 1.05 mmol,
1.00 equiv.), pyridine (425 μL, 5.25 mmol, 5.00 equiv.), and DMAP
(6.41 mg, 0.0525 mmol, 0.0500 equiv.) in CH2Cl2 (5.30 mL) was
added isovaleric anhydride (629 μL, 3.15 mmol, 3.00 equiv.) at
room temperature. After stirring at the same temperature for 6 h,
the reaction mixture was poured into 1 n aq. NaHCO3. The aque-
ous layer was extracted with two portions of hexane and the com-
bined extract was washed with brine, dried with MgSO4, filtered,
and the solvents evaporated in vacuo. The residue was purified by
chromatography on silica gel (hexane/ethyl acetate, 97:3) to give 13
(313 mg, 0.830 mmol, 79%) as a colorless oil. [α]1D7 = +9.86 (c =
0.950, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.25 (d, J =
8.7 Hz, 2 H), 6.87 (d, J = 8.7 Hz, 2 H), 5.51 (dt, J = 17.2, 10.1 Hz,
1 H), 5.05 (dd, J = 10.1, 1.9 Hz, 1 H), 4.98 (dd, J = 17.2, 1.9 Hz,
1 H), 4.81 (dd, J = 9.2, 2.4 Hz, 1 H), 4.52 (d, J = 11.4 Hz, 1 H),
4.33 (d, J = 11.4 Hz, 1 H), 3.80 (s, 3 H), 3.70 (dq, J = 2.4, 6.3 Hz,
1 H), 2.53–2.59 (m, 1 H), 2.26 (d, J = 6.8 Hz, 2 H), 2.20 (m, 1 H),
1.09–1.37 (m, 9 H), 0.97 (d, J = 6.8 Hz, 6 H), 0.85 (t, J = 7.0 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.1, 159.1, 138.6,
130.7, 129.5, 117.1, 113.6, 78.0, 73.1, 70.5, 55.2, 44.9, 43.4, 29.7,
A straightforward, diversity-oriented total synthesis of
(+)-antimycin A3b (1) was accomplished. The consecutive
stereogenic centers from C-7 to C-9 were synthesized by
Keck’s allylation and Mitsunobu reaction, stereoselectively.
All fragments were assembled on a solid support. The key
macrolactonization step was performed with a simple pro-
cedure to minimize manipulations in the solution phase.
This solid-phase procedure could be valuable for the combi-
natorial synthesis of a library of antimycin analogues.
Experimental Section
General Experimental Methods: NMR spectra were recorded at 270
or 400 MHz for 1H, and 67.5, 100 or 125 MHz for 13C nuclei in
the indicated solvent. Chemical shifts are reported in parts per mil-
lion (ppm) relative to the signal for internal tetramethylsilane (δ =
0 ppm) in CDCl3. 1H NMR spectrum data are reported as follows:
CDCl3 (δ =7.26 ppm). 13C NMR spectrum data are reported as
follows: CDCl3 (δ =77.0 ppm). Multiplicities are reported by using
the following abbreviations: s: singlet, d: doublet, t: triplet, q: quar-
tet, sept: septet, m: multiplet, br: broad, coupling constants (J) are
reported in Hertz. Only the strongest and/or structurally important
IR peaks are reported (in cm–1). Anhydrous CH2Cl2 was obtained
from solvent purification columns.
29.0, 25.5, 22.7, 22.4, 16.0, 14.0 ppm. IR (KBr): ν = 2959, 2935,
˜
1734, 1614, 1515, 1467, 1294, 1250, 1067, 994, 822 cm–1. HRMS
(ESI-TOF): m/z calcd. for C23H37O4 [M + H]+ 377.2692; found
377.2690.
(2R,3R,4S)-4-Butyl-2-hydroxyhexa-5-en-3-yl
3-Methylbutanoate
(14): To a stirred mixture of 13 (313 mg, 0.830 mmol, 1.00 equiv.) in
CH2Cl2 (8.30 mL) and water (8.30 mL), was added DDQ (283 mg,
1.24 mmol, 1.50 equiv.) at 0 °C. After stirring at the same tempera-
ture for 1 h, the reaction mixture was poured into saturated aq.
NaHCO3. The aqueous layer was extracted with two portions of
CH2Cl2 and the combined extract was washed with brine, dried
with MgSO4, filtered, and the solvents evaporated in vacuo. The
residue was purified by chromatography on silica gel (hexane/ethyl
acetate, 95:5) to give 14 (207 mg, 0.807 mmol, 97%) as a colorless
oil. [α]1D8 = +2.02 (c = 1.65, CHCl3). 1H NMR (400 MHz, CDCl3):
δ = 5.63–5.54 (m, 1 H), 5.13–5.17 (m, 2 H), 4.73 (dd, J = 9.2,
2.4 Hz, 1 H), 3.97 (dq, J = 2.4, 6.3 Hz, 1 H), 2.47 (dq, J = 2.9,
9.2 Hz, 1 H), 2.28 (d, J = 6.8 Hz, 2 H), 2.20 (sept, J = 6.8 Hz, 1
H), 1.11–1.41 (m, 9 H), 0.99 (d, J = 6.8 Hz, 6 H), 0.86 (t, J =
(2R,3R,4S)-4-Butyl-2-(4-methoxybenzyloxy)hexa-5-en-3-ol (12): To
a stirred mixture of (R)-2-(4-methoxybenzyloxy)propan-1-ol (11;
591 mg, 3.01 mmol, 1.00 equiv.), KBr (35.8 mg, 0.301 mmol,
0.100 equiv.), and TEMPO (23.5 mg, 0.151 mmol, 0.0500 equiv.) in
CH2Cl2 (23.0 mL) and saturated aq. NaHCO3 (23.0 mL) was
added 10 wt.-% aq. NaClO (4.60 mL, 6.02 mmol. 2.00 equiv.) at
0 °C. After stirring at 0 °C for 30 min, the reaction mixture was
poured into water. The aqueous layer was extracted with two por-
tions of CH2Cl2 and the combined extract was washed with brine,
dried with MgSO4, filtered, and the solvents evaporated in vacuo.
The residue was used for the next reaction without further purifica-
tion.
To a stirred mixture of the residue (3.01 mmol, 1.00 equiv.) and
MgBr2·OEt2 (1.01 g, 3.91 mmol, 1.30 equiv.) in CH2Cl2 (6.00 mL) 7.0 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.9, 138.4,
was added a solution of (E)-tri(n-butyl)(hept-2-en-1-yl)stannane
(5.94 g, 3.91 mmol, 1.30 equiv.) in CH2Cl2 (3.00 mL) at –30 °C. Af-
117.5, 78.4, 66.8, 45.3, 43.4, 29.7, 29.0, 25.6, 22.5, 22.4, 20.2,
13.9 ppm. IR (KBr): ν = 3472, 2960, 2934, 1736, 1467, 1924, 1190,
˜
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Total Synthesis of (+)-Antimycin A3b on Solid Supports
1047, 993, 917 cm–1. HRMS (ESI-TOF): m/z calcd. for C15H29O3
To a stirred mixture of the residue (20.6 μmol, 1.00 equiv.) and
NaH2PO4 (19.9 mg, 111 μmol, 5.40 equiv.) in tBuOH (400 μL), 2-
methyl-2-butene (400 μL) and water (400 μL), was added NaClO2
(7.73 mg, 85.5 μmol, 4.15 equiv.) at 0 °C. After stirring at the same
temperature for 4 h, the reaction mixture was poured into water
and the aqueous layer was extracted with two portions of CHCl3.
The combined extract was washed with brine, dried with MgSO4,
filtered, and the solvents evaporated in vacuo. The residue was
purified by preparative thin-layer chromatography (CHCl3/meth-
anol, 9:1) to give 17 (3.20 mg, 6.67 μmol, three steps 32%) as a
colorless oil. [α]2D0 = –1.24 (c = 0.450, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 7.86 (d, J = 7.2 Hz, 2 H), 7.51 (t, J = 7.2 Hz, 1 H),
7.43 (t, J = 7.2 Hz, 2 H), 7.08 (d, J = 9.2 Hz, 1 H), 5.34 (dd, J =
10.1, 3.9 Hz, 1 H), 5.13 (dq, J = 3.9, 6.3 Hz, 1 H), 4.80 (dd, J =
9.2, 1.9 Hz, 1 H), 4.40 (dq, J = 1.9, 6.8 Hz, 1 H), 2.55 (dt, J = 3.9,
10.1 Hz, 1 H), 2.27 (d, J = 6.8 Hz, 2 H), 2.13 (sp, J = 6.8 Hz, 1
H), 1.48–1.59 (m, 2 H), 1.24–1.29 (m, 10 H), 0.99 (d, J = 6.8 Hz,
6 H), 0.85 (t, J = 6.5 Hz, 3 H) ppm. 13C NMR (67.8 MHz, CDCl3):
δ = 173.3, 170.3, 168.4, 133.7, 131.8, 128.5, 127.4, 73.8, 72.2, 70.5,
67.2, 57.9, 47.5, 43.4, 28.9, 28.5, 25.7, 22.5, 22.4, 22.3, 19.7, 14.2,
[M + H]+ 257.2117; found 257.2110.
(1S,2R,3S)-1-Methyl-2-(3-methylbutyryloxy)-3-vinylheptyl (2S,3R)-
2-Benzoylamino-3-hydroxybutylate (16): To a stirred mixture of 14
(36.1 mg, 0.141 mmol, 1.00 equiv.), N-benzoyl-O-(tetrahydro-2H-
pyran-2-yl)-l-threonine (15; 41.4 mg, 0.306 mmol, 2.17 equiv.), and
triphenylphosphine (40.6 mg, 0.155 mmol, 1.10 equiv.) in THF
(0.700 mL) was added DEAD (ca. 2.2 m in toluene, 76.8 μL,
0.169 mmol, 1.20 equiv.) at 0 °C. After stirring at room temperature
for 12 h, the reaction mixture was poured into water and the aque-
ous layer was extracted with two portions of ethyl acetate. The
combined extract was washed with brine, dried with MgSO4, fil-
tered, and the solvents evaporated in vacuo. The residue was used
for the next reaction without further purification.
To a stirred solution of the residue (0.141 mmol, 1.00 equiv.) in
methanol (1.40 mL) was added CSA (1.64 mg, 0.00705 mmol,
0.0500 equiv.) at 0 °C. After stirring at room temperature for 12 h,
the reaction mixture was poured into saturated aq. NaHCO3. The
aqueous layer was extracted with two portions of ethyl acetate and
the combined extract was washed with brine, dried with MgSO4,
filtered, and the solvents evaporated in vacuo. The residue was
purified by chromatography on silica gel (hexane/ethyl acetate,
70:30) to give 16 (24.1 mg, 0.0522 mmol, two steps 37%) as a color-
less oil. [α]1D8 = –9.87 (c = 0.930, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 8.86 (d, J = 7.2 Hz, 2 H), 7.51 (t, J = 7.2 Hz, 1 H),
7.44 (t, J = 7.2 Hz, 2 H), 6.90 (d, J = 9.7 Hz, 1 H), 5.59 (dt, J =
13.8 ppm. IR: ν = 3363, 2960, 2031, 2873, 1742, 1648, 1531, 1466,
˜
1293, 1188, 1165(KBr) cm–1. HRMS (ESI-TOF): m/z calcd. for
C25H38NO8 [M + H]+ 480.2597; found 480.2609.
(3S,4R,7R,8R,9S)-3-Benzamido-7-butyl-4,9-dimethyl-8-(3-methyl-
butanoyloxy)-2,6-dioxo-1,5-dioxacyclononane (18): To a stirred mix-
ture of MNBA (2.37 mg, 6.89 μmol, 3.00 equiv.), DMAPO
(0.629 mg, 4.59 μmol, 2.00 equiv.) and DIEA (4.79 μL, 27.5 μmol,
16.9, 9.7 Hz, 1 H), 5.08–5.20 (m, 4 H), 4.73 (d, J = 9.7 Hz, 1 H), 12.0 equiv.) in CH2Cl2 (780 μL), was added 17 (1.1 mg, 2.3 μmol,
4.26–4.30 (m, 1 H), 3.49 (d, J = 5.3 Hz, 1 H), 2.31 (d, J = 7.2 Hz, 1.00 equiv.) in CH2Cl2 (160 μL) at room temperature. After stirring
2 H), 2.12–2.19 (m, 2 H), 1.11–1.43 (m, 12 H), 1.02 (d, J = 6.3 Hz, at the same temperature for 3 days, the reaction mixture was evapo-
6 H), 0.85 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 174.6, 170.3, 167.9, 136.8, 134.0, 131.7, 128.5, 127.2, 118.1,
75.4, 72.5, 66.8, 58.0, 46.0, 43.6, 30.5, 28.4, 25.7, 22.5, 22.3, 19.7,
rated in vacuo. The residue was purified by chromatography on
silica gel (toluene/acetone, 90:10) to give 18 (1.0 mg, 2.2 μmol,
95%) as a colorless oil. [α]2D0 = +5.13 (c = 0.150, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.82 (d, J = 7.2 Hz, 2 H), 7.54 (t, J =
7.2 Hz, 1 H), 7.47 (t, J = 7.2 Hz, 2 H), 6.84 (d, J = 7.7 Hz, 1 H),
5.75 (dq, J = 7.2,7.2 Hz, 1 H), 5.34 (t, J = 7.7 Hz, 1 H), 5.09 (t, J
= 10.1 Hz, 1 H), 4.99 (dq, J = 10.1, 6.3 Hz, 1 H), 2.47–2.52 (m, 1
H), 2.25 (d, J = 6.8 Hz, 2 H), 2.13 (t sept, J = 6.8 Hz, 1 H), 1.67–
1.73 (m, 1 H), 1.02–1.44 (m, 11 H), 0.99 (d, J = 6.8 Hz, 6 H), 0.86
(t, J = 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.1,
171.6, 170.6, 133.3, 132.1, 128.8, 127.1, 75.6, 74.5, 71.5, 54.1, 50.2,
13.9, 12.1 ppm. IR (KBr): ν = 3397, 2960, 2935, 1740, 1668, 1527,
˜
1488, 1295, 1165, 920, 714 cm–1. HRMS (ESI-TOF): m/z calcd. for
C26H40NO6 [M + H]+ 462.2856; found 426.2850.
(2R,3R,4S)-4-[(2S,3R)-2-Benzamido-3-hydroxybutanoyloxy]-2-
butyl-3-(3-methylbutanoyloxy)pentanoic Acid (17): To a stirred sus-
pension of NaIO4 (5.28 mg, 24.7 μmol, 1.20 equiv.) in water
(60.0 μL) was added CeCl3·7H2O (0.767 mg, 2.06 μmol,
0.100 equiv.) at room temperature. After stirring at 35 °C for
10 min, acetonitrile (190 μL), ethyl acetate (100 μL), and RuCl3
(0.1 m in water, 10.3 μL, 1.03 μmol, 0.0500 equiv.) was added to the
reaction mixture at 0 °C. After stirring at the same temperature for
2 min, a solution of 16 (9.50 mg, 20.6 μmol, 1.00 equiv.) in ethyl
acetate (90.0 μL) was added to the reaction mixture at 0 °C. After
stirring at the same temperature for 5 min, the reaction mixture
was filtered and poured into 10% aq. Na2S2O3. The aqueous layer
was extracted with two portions of ethyl acetate and the combined
extract was washed with brine, dried with MgSO4, filtered, evapo-
rated in vacuo, and purified by short-pad column chromatography
(CHCl3/methanol, 97:3) to give a mixture of diol and aldehyde.
This mixture was used for the next reaction without further purifi-
cation.
43.3, 29.7, 29.2, 28.2, 25.5, 22.4, 17.9, 15.9, 13.8 ppm. IR (KBr): ν
˜
= 3332, 2959, 2858, 1737, 1644, 1532, 1466, 1370, 1185, 1167 cm–1.
HRMS (ESI-TOF): m/z calcd. for C25H36NO7 [M + H]+ 462.2492;
found 462.2493.
(2R,3R,4S)-3-Benzyloxy-2-(4-methoxybenzyloxy)-4-butylhexa-5-ene
(19): To a stirred mixture of 12 (3.00 g, 10.3 mmol, 1.00 equiv.) and
NaH (63% in oil, 549 mg, 14.4 mmol, 1.40 equiv.) in DMF
(30.0 mL), was added benzyl bromide (1.47 mL, 12.4 mmol,
1.20 equiv.) at 0 °C. After stirring at room temperature for 6 h, the
reaction mixture was poured into 1 n HCl and Et2O. The aqueous
layer was extracted with two portions of Et2O and the combined
extract was washed with 1 n HCl, saturated aq. NaHCO3, and
brine, dried with Na2SO4, filtered, and the solvents evaporated in
vacuo. The residue was purified by chromatography on silica gel
(hexane/ethyl acetate, 95:5) to give 19 (3.42 g, 8.94 mmol, 87%) as
a colorless oil. [α]3D0 = +10.4 (c = 2.23, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.23–7.34 (m, 7 H), 6.84 (d, J = 8.7 Hz, 2
H), 5.70–5.72 (m, 1 H), 4.96–5.02 (m, 2 H), 4.72 (d, J = 11.1 Hz,
1 H), 4.60 (d, J = 11.1 Hz, 1 H), 4.54 (d, J = 11.1 Hz, 1 H), 4.42
(d, J = 11.1 Hz, 1 H), 3.80 (s, 3 H), 3.70 (dq, J = 5.7, 5.7 Hz, 1 H),
3.26 (t, J = 5.7 Hz, 1 H), 2.31–2.39 (m, 1 H), 1.19–1.44 (m, 9 H),
0.87 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
To a stirred solution of the mixture (20.6 μmol, 1.00 equiv.) in THF
(400 μL) and water (100 μL) was added NaIO4 (8.78 mg,
41.2 μmol, 2.00 equiv.) at 0 °C. After stirring at the same tempera-
ture for 12 h, the reaction mixture was poured into water and the
aqueous layer was extracted with two portions of ethyl acetate. The
combined extract was washed with brine, dried with MgSO4, fil-
tered, and the solvents evaporated in vacuo. The residue was used
for the next reaction without further purification.
Eur. J. Org. Chem. 2014, 4725–4732
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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T. Takahashi et al.
FULL PAPER
159.0, 140.7, 139.1, 131.1, 129.2, 128.1, 127.7, 127.3, 115.4, 113.6,
86.2, 76.3, 74.3, 71.0, 55.2, 45.9, 29.5, 28.6, 22.7, 16.5, 14.1 ppm.
fied by chromatography on silica gel (hexane/ethyl acetate, 95:5) to
give 21 (705 mg, 2.69 mmol, quant.) as a colorless oil. [α]3D1 = –5.57
(c = 1.93, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.24–7.35 (m,
5 H), 5.66–5.76 (m, 1 H), 5.06–5.11 (m, 2 H), 4.71 (d, J = 11.1 Hz,
1 H), 4.57 (d, J = 11.1 Hz, 1 H), 3.86 (m, 1 H), 3.14 (dd, J = 4.3,
6.3 Hz, 1 H), 2.34–2.39 (m, 1 H), 2.21 (d, J = 6.8 Hz, 1 H), 1.14–
1.37 (m, 9 H), 0.88 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 140.0, 138.3, 128.4, 127.8, 116.4, 86.7, 74.7, 67.7, 46.4,
IR (KBr): ν = 2956, 2933, 2860, 1613, 1514, 1455, 1091, 1037, 913,
˜
822, 735, 698 cm–1. HRMS (ESI-TOF): m/z calcd. for C25H35O3
[M + H]+ 383.2586; found 383.2589.
(2R,3R,4R)-4-Butyl-3-hydroxy-γ-valerolacone (20): To a stirred sus-
pension of NaIO4 (71.0 mg, 0.332 mmol, 1.50 equiv.) in water
(0.400 mL) was added CeCl3·7H2O (8.20 mg, 22.1 μmol,
0.100 equiv.) at room temperature. After stirring at 35 °C for
10 min, acetonitrile (1.30 mL), ethyl acetate (0.800 mL), and RuCl3
(0.1 m in water, 0.111 mL, 11.1 μmol, 0.0500 equiv.) was added to
the reaction mixture at 0 °C. After stirring at the same temperature
for 2 min, a solution of 19 (84.6 mg, 0.221 mmol, 1.00 equiv.) in
ethyl acetate (0.500 mL) was added to the reaction mixture at 0 °C.
After stirring at the same temperature for 5 min, the reaction mix-
ture was filtered and poured into 10% aq. Na2S2O3. The aqueous
layer was extracted with two portions of ethyl acetate and the com-
bined extract was washed with brine, dried with MgSO4, filtered,
evaporated in vacuo, and purified by short-pad column chromatog-
raphy (hexane/ethyl acetate, 60:40). The residue was used for the
next reaction without further purification.
29.6, 29.3, 22.7, 20.4, 14.0 ppm. IR (KBr): ν = 3454, 3068, 2930,
˜
1639, 1455, 1378, 1068, 914, 734, 698 cm–1. HRMS (ESI-TOF): m/z
calcd. for C17H27O2 [M + H]+ 263.2011; found 263.2055.
(2S,3R,4S)-3-Benzyloxy-4-butylhexa-5-en-2-yl Chloroacetate (22):
To a stirred mixture of 21 (90.1 mg, 0.343 mmol, 1.00 equiv.),
chloroacetic acid (48.7 mg, 0.515 mmol, 1.50 equiv.), and tri-
phenylphosphine (180 mg, 0.687 mmol, 2.00 equiv.) in THF
(1.00 mL), was added DEAD (ca. 2.2 m in toluene, 343 μL,
0.775 mmol, 2.20 equiv.) at 0 °C. After stirring at the same tem-
perature for 6 h, the reaction mixture was poured into water. The
aqueous layer was extracted with two portions of ethyl acetate and
the combined extract was washed with brine, dried with MgSO4,
filtered, and the solvents evaporated in vacuo. The residue was
purified by chromatography on silica gel (hexane/ethyl acetate,
98:2) to give 22 (73.8 mg, 0.218 mmol, 63%) as a yellow oil. [α]2D2
= +2.11 (c = 0.950, CHCl3). 1H NMR (400 MHz, CDCl3): δ =
7.28–7.39 (m, 5 H), 5.58 (dt, J = 16.9, 9.7 Hz, 1 H), 5.19 (dq, J =
2.4, 6.3 Hz, 1 H), 5.11 (dd, J = 9.7, 1.5 Hz, 1 H), 5.05 (dd, J =
16.9, 1.5 Hz, 1 H), 4.79 (d, J = 11.1 Hz, 1 H), 4.59 (d, J = 11.1 Hz,
1 H), 4.02 (d, J = 14.5 Hz, 1 H), 3.98 (d, J = 14.5 Hz, 1 H), 3.47
(dd, J = 2.4, 9.7 Hz, 1 H), 2.10 (dq, J = 2.9, 9.7 Hz, 1 H), 1.78–
1.83 (m, 1 H), 1.11–1.35 (m, 8 H), 0.88 (t, J = 7.2 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 166.5, 138.5, 128.3, 127.9, 127.6,
116.9, 82.9, 75.5, 74.8, 47.9, 41.0, 30.0, 29.0, 22.6, 14.0, 13.1 ppm.
To a stirred solution of the residue (0.221 mmol, 1.00 equiv.) in
MeOH (1.30 mL) and water (0.500 mL) was added NaIO4
(71.0 mg, 0.332 mmol, 1.50 equiv.) at 0 °C. After stirring at the
same temperature for 12 h, the reaction mixture was poured into
water. The aqueous layer was extracted with two portions of ethyl
acetate and the combined extract was washed with brine, dried with
MgSO4, filtered, and the solvents evaporated in vacuo. The residue
was used for the next reaction without further purification.
To a stirred mixture of the residue (0.221 μmol, 1.00 equiv.) and
NaH2PO4 (215 mg, 1.20 mmol, 5.43 equiv.) in tBuOH (2.20 mL),
2-methyl-2-butene (2.20 mL) and water (2.20 mL), was added Na-
ClO2 (83.0 mg, 0.917 mmol, 4.15 equiv.) at 0 °C. After stirring at
the same temperature for 4 h, the reaction mixture was poured into
water. The aqueous layer was extracted with two portions of CHCl3
and the combined extract was washed with brine, dried with
MgSO4, filtered, and the solvents evaporated in vacuo. The residue
was used for the next reaction without further purification.
IR (KBr): ν = 2957, 2933, 2860, 1756, 1733, 1455, 1288, 1189,
˜
1107, 1060, 919, 736, 699 cm–1. HRMS (ESI-TOF): m/z calcd. for
C19H28O3Cl [M + H]+ 339.1727; found 339.1733.
(2R,3R,4S)-3-Benzyloxy-2-butyl-4-(chloroacetoxy)pentanoic Acid
(23): To a stirred suspension of NaIO4 (1.03 g, 4.80 mmol,
1.50 equiv.) in water (8.00 mL) was added CeCl3·7H2O (149 mg,
0.400 mmol, 0.100 equiv.) at room temperature. After stirring at
35 °C for 10 min, acetonitrile (24.0 mL), ethyl acetate (20.0 mL),
and RuCl3 (0.1 m in water, 2.00 mL, 0.200 mmol, 0.0500 equiv.) was
added to the reaction mixture at 0 °C. After stirring at the same
temperature for 2 min, a solution of 22 (1.36 g, 4.00 mmol,
1.00 equiv.) in ethyl acetate (4.00 mL) was added to the reaction
mixture at 0 °C. After stirring at the same temperature for 5 min,
the reaction mixture was filtered and poured into 10% aq.
Na2S2O3. The aqueous layer was extracted with two portions of
ethyl acetate and the combined extract was washed with brine,
dried with MgSO4, filtered, evaporated in vacuo, and purified by
short-pad column chromatography (hexane/ethyl acetate, 60:40) to
give a mixture of diol and aldehyde. This mixture was used for the
next reaction without further purification.
To a stirred solution of a part of the residue (47.0 mmol) in meth-
anol (1.00 mL) was added 10 wt.-% Pd/C (5.00 mg). The reaction
mixture was hydrogenated for 12 h under H2 gas. The reaction mix-
ture was filtered, and the solvents evaporated in vacuo. The residue
was purified by chromatography on silica gel (hexane/ethyl acetate,
85:15) to give 20 (5.00 mg, 29.1 mmol, four steps 20%) as a color-
less oil. 1H NMR (400 MHz, CDCl3): δ = 4.63 (dq, J = 6.6, 4.8 Hz,
1 H), 4.21 (dd, J = 4.8, 3.4 Hz, 1 H), 2.54 (ddd, J = 8.2, 6.3, 3.4 Hz,
1 H), 1.70–1.79 (m, 1 H), 1.25–1.50 (m, 8 H), 0.92 (t, J = 6.7 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 177.7, 78.3, 74.2,
49.3, 29.4, 28.2, 22.6, 14.0, 13.9 ppm {ref.[22] 1H NMR (400 MHz,
CDCl3): δ = 4.65 (dq, J = 6.7, 4.8 Hz, 1 H), 4.21 (ddd, J = 4.8,
4.3, 3.2 Hz, 1 H), 2.63 (d, J = 4.3 Hz, 1 H), 2.55 (ddd, J = 8.2, 6.6,
3.2 Hz, 1 H), 1.65–1.78 (m, 1 H), 1.20–1.63 (m, 8 H), 0.92 (t, J =
7.3 Hz, 3 H) ppm}. 13C NMR (100 MHz, CDCl3): δ = 178.3, 78.6,
73.9, 49.2, 29.3, 28.1, 22.4, 13.9, 13.8 ppm.
To a stirred solution of the mixture (4.00 mmol, 1.00 equiv.) in
THF (80.0 mL) and water (20.0 mL) was added NaIO4 (1.28 mg,
6.00 mmol, 1.50 equiv.) at 0 °C. After stirring at room temperature
for 12 h, the reaction mixture was poured into water. The aqueous
layer was extracted with two portions of ethyl acetate and the com-
bined extract was washed with brine, dried with MgSO4, filtered,
and the solvents evaporated in vacuo. The residue was used for the
next reaction without further purification.
(2R,3R,4S)-3-Benzyloxy-4-butylhexa-5-en-2-ol (21): To a stirred
mixture of 19 (1.03 g, 2.70 mmol, 1.00 equiv.) in CH2Cl2 (14.0 mL)
and water (14.0 mL) was added DDQ (919 mg, 4.05 mmol,
1.50 equiv.) at 0 °C. After stirring at the same temperature for 1 h,
the reaction mixture was poured into saturated aq. NaHCO3. The
aqueous layer was extracted with two portions of CH2Cl2 and the
combined extract was washed with brine, dried with MgSO4, fil-
tered, and the solvents evaporated in vacuo. The residue was puri-
To a stirred mixture of the residue (4.00 mmol, 1.00 equiv.) and
NaH2PO4 (3.88 g, 21.7 mmol, 5.43 equiv.) in tBuOH (40.0 mL), 2-
4730
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 4725–4732

Total Synthesis of (+)-Antimycin A3b on Solid Supports
methyl-2-butene (40.0 mL) and water (40.0 mL), was added Na-
ClO2 (1.50 g, 16.6 mmol, 4.15 equiv.) at 0 °C. After stirring at the
same temperature for 4 h, the reaction mixture was poured into
water. The aqueous layer was extracted with two portions of
CHCl3, and the combined extract was washed with brine, dried
with MgSO4, filtered, and the solvents evaporated in vacuo. The
residue was purified by chromatography on silica gel (hexane/ethyl
acetate, 80:20) to give 23 (767 mg, 2.15 mmol, three steps 54%) as
a colorless oil. [α]2D3 = +13.8 (c = 0.935, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.27–7.38 (m, 5 H), 5.08 (dq, J = 4.4,
6.3 Hz, 1 H), 4.75 (d, J = 11.1 Hz, 1 H), 4.63 (d, J = 11.1 Hz, 1
H), 4.01 (s, 2 H), 3.81 (dd, J = 8.3, 4.4 Hz, 1 H), 2.50–2.55 (m, 1
H), 1.61–1.84 (m, 2 H), 1.21–1.37 (m, 7 H), 0.88 (t, J = 6.8 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 179.0, 166.4, 137.7,
128.4, 128.0, 127.9, 80.9, 74.8, 74.3, 48.2, 40.9, 29.4, 28.1, 22.6,
(2R,3R,4S)-4-{[(2S,3R)-2-(9H-9-Fluoren-9-yl)methoxycarbonyl-
amino-3-(tetrahydro-2H-pyran-2-yloxy)butanoyl]oxy}-2-butyl-3-(3-
methylbutanoyloxy)pentanoic Acid Attached to 2-Chlorotrityl Resin
(27): To 25 attached to 2-chlorotrityl resin packed in MicroKan
was added a mixture of N-(9H-9-fluoren-9-yl)methoxycarbonyl-O-
tetrahydro-2H-pyran-2-yl-l-threonine (26; 203 mg, 0.478 mmol,
0.150 m), DIC (150 μL, 0.956 mmol, 0.300 m), and DMAP
(23.4 mg, 0.191 mmol, 0.0600 m) in CH2Cl2 (2.38 mL) and DMF
(0.790 mL) at room temperature and the reaction mixture was
shaken at the same temperature for 24 h (ϫ2). The resin was fil-
tered and washed with CH2Cl2 (ϫ 5), DMF (ϫ 5), and CH2Cl2
(ϫ5) to give 27 attached to 2-chlorotrityl resin.
(2R,3R,4S)-4-{[(2S,3R)-2-(2-Benzyloxy-3-formamidobenzamido)-3-
(tetrahydro-2H-pyran-2-yloxy)-butanoyl]oxy}-2-butyl-3-(3-methyl-
butanoyloxy)pentanoic Acid Attached to 2-Chlorotrityl Resin (28):
To a 27 attached to 2-chlorotrityl resin packed in MicroKan was
added 20% piperidine in DMF (4.00 mL) at room temperature and
the reaction mixture was shaken at the same temperature for 30 min
(ϫ 3). The resin was filtered and washed with DMF (ϫ 5) and
CH2Cl2 (ϫ5) to give (2R,3R,4S)-4-[(2S,3R)-2-amino-3-(tetrahydro-
2H-pyran-2-yloxy-butanoyl)oxy]-2-butyl-3-(3-methylbutanoyloxy)-
pentanoic acid attached to 2-chlorotrityl resin.
14.8, 13.8 ppm. IR (KBr): ν = 3446, 3152, 2959, 2874, 1739, 1733,
˜
1714, 1456, 1288, 1189, 1108, 1064, 960, 752, 700 cm–1. HRMS
(ESI-TOF): m/z calcd. for C18H26O5Cl [M + H]+ 357.1469; found
357.1467.
(2R,3R,4S)-3-Benzyloxy-2-butyl-4-(chloroacetoxy)pentanoic Acid
Attached to 2-Chlorotrityl Resin (24): To a stirred solution of 23
(28.0 mg, 74.1 μmol) in methanol (1.00 mL) was added 10 wt.-%
Pd/C (0.500 mg). The reaction mixture was hydrogenated for 12 h
under H2 gas, then the reaction mixture was filtered and the sol-
vents evaporated in vacuo. The residue was used for the next reac-
tion without further purification.
To (2R,3R,4S)-4-{[(2S,3R)-2-amino-3-(tetrahydro-2H-pyran-2-
yloxy)butanoyl]oxy}-2-butyl-3-(3-methylbutanoyloxy)pentanoic
acid attached to 2-chlorotrityl resin packed in MicroKan was
added a mixture of 2-benzyloxy-3-formamidobenzoic acid (3;
136 mg, 0.500 mmol, 0.100 m), DIC (77.4 μL, 0.500 mmol,
0.100 m), and HOBt·H2O (76.6 mg, 0.500 mmol, 0.100 m) in
CH2Cl2 (3.75 mL) and DMF (1.25 mL) at room temperature and
the reaction mixture was shaken at the same temperature for 12 h.
The resin was filtered and washed with CH2Cl2 (ϫ5), DMF (ϫ5),
and CH2Cl2 (ϫ5) to give 28 attached to 2-chlorotrityl resin.
To a suspension of 2-chlorotritylchloride resin (260 mg, 1.25 mmol/
g, 0.325 mmol, 2.69 equiv.) in CH2Cl2 (5.40 mL) in a syringe-
shaped vessel (Varian reservoir®) was added acetyl chloride
(0.600 mL) at room temperature. After shaking at the same tem-
perature for 3 h, the resin was filtered and washed with CH2Cl2
(ϫ5). To the resin was added a mixture of the residue (0.121 mmol,
1.00 equiv., 23.3 mm) and DIEA (84.3 μL, 0.484 mmol, 93.1 mm) in
CH2Cl2 (5.20 mL) at room temperature. After shaking at the same
temperature for 3 h, the resin was filtered and washed with CH2Cl2
(ϫ5). To the resin was added a mixture of acetic acid (20.6 mL,
0.363 mmol, 69.8 mm) and DIEA (253 μL, 1.45 mmol, 279 mm) in
CH2Cl2 (5.20 mL) at room temperature and the mixture was
shaken at the same temperature for 3 h. The resin was filtered,
washed with CH2Cl2 (ϫ5), DMF (ϫ5), and CH2Cl2 (ϫ5), and
dried under reduced pressure to give 24 attached to 2-chlorotrityl
resin (0.288 mmol/g).
(+)-Antimycin A3b (1): To 28 attached to 2-chlorotrityl resin packed
in MicroKan was added 1% TFA in CH2Cl (4.00 mL) at room
temperature and the reaction mixture was shaken at the same tem-
perature for 1 h. The reaction mixture was filtered and the resin
was rinsed with CH2Cl2. The filtrate was evaporated in vacuo and
the residue was filtered through a short pad of silica gel (CHCl3/
MeOH, 98:2) and the solvents evaporated. The residue was used
for the next reaction without further purification.
To a solution of a part of the residue (21.9 mg, 0.0348 mmol,
1.00 equiv.) in CH2Cl2 (20.0 mL) was added a mixture of MNBA
(34.9 mg,
0.105 mmol,
3.00 equiv.),
DMAPO
(9.56 mg,
(2R,3R,4S)-2-Butyl-4-hydroxy-3-(3-methylbutanoyloxy)pentanoic
Acid Attached to 2-Chlorotrityl Resin (25): To a 24 attached to 2-
chlorotrityl resin (34.6 mg) in a syringe-shaped vessel (Varian reser-
voir®) was added a mixture of isovaleric anhydride (105 μL,
0.518 mmol, 0.370 m), pyridine (63.4 μL 0.784 mmol, 0.560 m), and
DMAP (1.59 mg, 13.0 μmol, 9.30 mm) in CH2Cl2 (1.40 mL) at
room temperature and the reaction mixture was shaken at the same
temperature for 12 h (ϫ2). The resin was filtered and washed with
CH2Cl2 (ϫ5), DMF (ϫ5), and CH2Cl2 (ϫ5) to give (2R,3R,4S)-
2-butyl-4-(chloroacetoxy)-3-(3-methylbutanoyloxy)pentanoic acid
attached 2-chlorotrityl resin.
0.0697 mmol, 2.00 equiv.), and DIEA (72.8 μL, 0.418 mmol,
12.0 equiv.) in CH2Cl2 (15.0 mL) at room temperature. After stir-
ring at the same temperature for 48 h, the reaction mixture was
evaporated in vacuo. The residue was filtered through a short pad
of silica gel with CHCl3, and the solvents evaporated. The residue
was used for the next reaction without further purification.
To a stirred solution of a part of the residue (2.3 mg, 3.77 mmol)
in methanol (0.200 mL) was added 10 wt.-% Pd/C (1.00 mg). The
reaction mixture was hydrogenated for 12 h under H2 gas. The reac-
tion mixture was filtered, and the solvents evaporated in vacuo.
The residue was purified by preparative reverse-phase HPLC to
give (+)-antimycin A3b (1; 0.8 mg, 1.53 mmol, eight steps 2%) as a
white solid. [α]2D6.2 = +34.8 (c = 0. 035, CHCl3); m.p. 171–172 °C.
1H NMR (400 MHz, CDCl3): δ = 12.62 (s, 1 H), 8.55 (d, J =
8.3 Hz, 1 H), 8.50 (d, J = 1.9 Hz, 1 H), 7.91 (s, 1 H), 7.23 (d, J =
1.5 Hz, 1 H), 7.07 (d, J = 7.3 Hz, 1 H), 6.92 (t, J = 8.0 Hz, 1 H),
5.73 (dq, J = 7.3, 6.7 Hz, 1 H), 5.28 (t, J = 7.5 Hz, 1 H), 5.09 (t, J
= 10.2 Hz, 1 H), 4.99 (dq, J = 9.6, 6.3 Hz, 1 H), 2.51 (dt, J = 10.9,
2.9 Hz, 1 H), 2.25 (d, J = 6.8 Hz, 2 H), 2.21–2.09 (m, 1 H), 1.75–
To a (2R,3R,4S)-2-butyl-4-(chloroacetoxy)-3-(3-methylbutanoyl-
oxy)pentanoic acid attached to 2-chlorotrityl resin packed in
MicroKan, was added a mixture of 2,6-lutidine (304 mg,
4.00 mmol, 0.200 m) and thiourea (595 μL, 4.00 mmol, 0.200 m) in
DMF (20.0 mL) at room temperature and the reaction mixture was
shaken at 80 °C for 6 h (ϫ2). The resin was filtered and washed
with DMF (ϫ5) and CH2Cl2 (ϫ5) to give 25 attached to 2-chlo-
rotrityl resin (25).
Eur. J. Org. Chem. 2014, 4725–4732
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4731

T. Takahashi et al.
FULL PAPER
[10] K. Shiomi, K. Hatae, H. Hatanho, A. Matsumoto, Y. Takah-
ashi, C.-L. Jiang, H. Tomoda, S. Kobayashi, H. Tanaka, S.
Omura, J. Antibiot. 2005, 58, 74–78.
[11] N. Hosotani, K. Kumagai, H. Nakagawa, T. Shimatani, I. Saji,
J. Antibiot. 2005, 58, 460–467.
[12] G. Chen, B. Lin, Y. Lin, F. Xie, W. Lu, W.-F. Fong, J. Antibiot.
2005, 58, 519–522.
[13] G. S. Kido, E. Spyhalski, Science 1950, 112, 172–173.
[14] M. K. F. Wikstrom, J. A. Berden, Biochim. Biophys. Acta Bio-
energ. 1972, 283, 403–420.
1.65 (m, 1 H), 1.43–1.13 (m,5 H), 0.99 (d, J = 6.8 Hz, 6 H), 0.87
(t, J = 7.1 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 172.9,
171.6, 170.0, 169.4, 158.9, 150.6, 127.4, 124.8, 120.0, 119.0, 112.5,
75.4, 74.8, 70.9, 53.7, 50.1, 43.2, 29.2, 28.2, 25.4, 22.4, 22.4, 17.8,
15.0, 13.7 ppm. IR (KBr): ν = 3366, 2959, 2922, 2852, 1749, 1694,
˜
1644, 1532, 1464, 1180, 1162 cm–1. HRMS (ESI-TOF): m/z calcd.
for C26H37N2O9 [M + H]+ 521.2499; found 521. 2486.
Supporting Information (see footnote on the first page of this arti-
cle): Analytical data (1H, 13C NMR and LC-MS charts) for the
compounds are provided.
[15] S.-P. Tzung, K. M. Kim, G. Basañez, C. D. Giedt, J. Simon, J.
Zimmerberg, K. Y. J. Zhang, D. M. Hockenbery, Nat. Cell
Biol. 2001, 3, 183–191.
[16] a) M. Kinoshita, M. Wada, S. Umezawa, J. Antibiot. 1969, 22,
580–582; b) M. Kinoshita, M. Wada, S. Aburagi, S. Umezawa,
J. Antibiot. 1971, 24, 724–726; c) M. Kinoshita, S. Aburaki, M.
Wada, S. Umezawa, Bull. Chem. Soc. Jpn. 1973, 46, 1279–1287;
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Acknowledgments
The authors acknowledge the financial support of this work from
Adaptable and Seamless Technology transfer Program (A-STEP
9372). The authors thank Dr. Haruko Takahashi and Prof. Keisuke
Suzuki for NMR spectroscopic assistance. Dr. Hiroshi Tanaka and
Dr. Shinichiro Fuse are thanked for significant support in the prep-
aration of this manuscript.
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Published Online: March 6, 2014
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