Total synthesis of 4-epi-atpenin A5 as a potent nematode complex II inhibitor

Article abstract of DOI:10.1016/j.tet.2019.02.050

It is clear that atpenins and their analogs are useful chemical tools for elucidation of complex II functionality and that they could act as lead compounds for the development of novel helminth complex II-specific inhibitors. Recently, we discovered 4-epi

Full text of DOI:10.1016/j.tet.2019.02.050

Accepted Manuscript
Total synthesis of 4-epi-atpenin A5 as a potent nematode complex II inhibitor
Daiki Lee, Hiroki Kondo, Yui Kuwayama, Kento Takahashi, Shiho Arima, Satoshi
Omura, Masaki Ohtawa, Tohru Nagamitsu
PII:
S0040-4020(19)30210-8
https://doi.org/10.1016/j.tet.2019.02.050
TET 30173
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 30 January 2019
Revised Date: 15 February 2019
Accepted Date: 22 February 2019
Please cite this article as: Lee D, Kondo H, Kuwayama Y, Takahashi K, Arima S, Omura S, Ohtawa M,
Nagamitsu T, Total synthesis of 4-epi-atpenin A5 as a potent nematode complex II inhibitor, Tetrahedron
(2019), doi: https://doi.org/10.1016/j.tet.2019.02.050.
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Total synthesis of 4-epi-atpenin A5 as a
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potent nematode complex II inhibitor.
Daiki Lee, Hiroki Kondo, Yui Kuwayama, Kento Takahashi,
Shiho Arima, Satoshi Omura, Masaki Ohtawa , and Tohru Nagamitsu
OMOM
37% yield
over 6 steps
HO
MeO
OH
N
O
Cl
MeO
MeO
Cl
Cl
N
MeO
N
OMOM
Cl
14% yield
over 10 steps
O
OH
OHC
Cl
HO
OMe
4-epi-Atpenin A5
2.4% yield over 19 steps
(Previous: 0.9% yield over 27 steps)

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Total synthesis of 4-epi-atpenin A5 as a potent nematode complex II inhibitor.
Daiki Leea, Hiroki Kondoa, Yui Kuwayamaa, Kento Takahashia, Shiho Arimaa, Satoshi Omurab, Masaki
Ohtawaa , and Tohru Nagamitsua
aDepartment of Synthetic Natural Products Chemistry and Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5–9–1 Shirokane,
Minato-ku, Tokyo 108–8641, Japan
bKitasato Institute for Life Sciences, Kitasato University, Tokyo, 108-8641, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
It is clear that atpenins and their analogs are useful chemical tools for elucidation of complex II
functionality and that they could act as lead compounds for the development of novel helminth
complex II-specific inhibitors. Recently, we discovered 4-epi-atpenin A5 as a potent nematode
complex II inhibitor during our SAR studies of atpenin A5. This result led us to embark on a
concise total synthesis of 4-epi-atpenin A5. In this study, we describe the total synthesis of 4-
epi-atpenin A5. Importantly, this was more concise and practical synthesis than our previous
total synthesis of atpenin A5.
Available online
Keywords:
Atpenin A5
4-epi-Atpenin A5
Nematode complex II inhibitor
Total synthesis
2009 Elsevier Ltd. All rights reserved
.
Dedicated to Professor Ryan A Shenvi in recognition
of his receipt of the 2019 Tetrahedron Young
Investigator Award.
1. Introduction
as lead compounds for the development of novel helminth
complex II-specific inhibitors. In 2009, we achieved
a
stereoselective total synthesis of atpenin A5 (1)7 by improving
the Quéguiner procedure (Scheme 1). We have also reported the
total synthesis of other natural atpenin A5 analogs (A4 and B
etc.) using this synthetic strategy.8 Moreover, we reported on the
structure–activity relationship of atpenin A5 analogs with
chemical modification of the side chain moiety, including atpenin
A5 stereoisomers,9,10 in which 4-epi-atpenin A5 (2) was shown to
be a more potent nematode complex II inhibitor than 1 (Figure
1). Therefore, a large scale synthesis of 4-epi-atpenin A5 (2) was
suggested for future animal tests and use as a chemical tool.
Unfortunately, our total synthesis of 1 was suitable only for small
scale synthesis of a variety of atpenin A5 analogs; it was
inadequate for large scale synthesis of 2. Herein, we report a
concise total synthesis of 4-epi-atpenin A5.
Atpenin A5 (1) and its analogs, which possess a highly
functionalized pyridine unit, were first isolated in 1988 from a
fermentation broth of the atpenin-producing strain Penicillium sp.
FO-125. They were isolated as growth inhibitors of both fatty
acid synthase deficient (A-1) and acyl-CoA synthase I deficient
(L-7) mutants of Candida lipolytica (Figure 1).1,2 The absolute
configuration of atpenin A5 (1) has been confirmed by X-ray
crystallographic analysis.3,4 The total synthesis of (±)-atpenin B
(5’,6’-dedichloroatpenin A5) was reported by the Quéguiner
group in 1994.5 In 2003, new interest in atpenin A5 (1) developed
when a microbial screening assay showed that the compound
provided high levels of inhibition against mitochondrial complex
II (succinate-ubiquinone oxidoreductase), which is an attractive
target for the treatment of helminthiasis.6 In particular, atpenin
A5 (1) proved to be much more potent against bovine heart
complex II than any known complex II inhibitor, although the
inhibition of
1 was non-selective across helminthes and
mammals. Crystal structure analysis of Escherichia coli complex
II co-crystallized with atpenin A5 (1) has also been achieved.3 It
is clear that atpenins and their analogs are useful chemical tools
for elucidation of complex II functionality and that they could act
Figure 1 Structures of atpenin A5 (1) and 4-epi-atpenin A5 (2).
———
Corresponding author. Tel.: +81-3-5791-6377; fax: +81-3-3444-4742; e-mail: ohtawam@pharm.kitasato-u.ac.jp
Corresponding author. Tel.: +81-3-5791-6376; fax: +81-3-3444-4742; e-mail: nagamitsut@pharm.kitasato-u.ac.jp

2
Tetrahedron
1) I2, K2CO3
1) MeI, NaH
DMF, 98%
2) NaH, MeOH, DMF
80 °C, 86%
ACCEPTED MANUSCRIPT
1) nBuLi, (MeO)3B
THF, –78 °C
then mCPBA, 61%
H2O, rt, 75%
2) MOMCl, NaH
DMF, rt, 90%
OH
OMOM
OMOM
I
HO
Cl
MeO
MeO
MeO
MeO
MeO
3) nBuLi, B(OMe)3, mCPBA
THF, –78 °C, 61%
2) MOMCl, NaH
DMF, rt, 90%
3) LDA, THF
–40 °C, 75 %
N
N
MeO
N
I
N
OMOM
3
4
5
6
14% yield over 8 steps
1) Ph3P=CHCO2Et
benzene, 50 °C
85%
2) DIBAL, CH2Cl2,
0 °C, 86%
1) TIPSCl, imid., DMF, rt
2) DIBAL, CH2Cl2, –78 °C
3) p-TsCl, Et3N, Me3N·HCl
CH2Cl2, 0 °C
1) TrCl, Et3N
CH2Cl2, rt, quant.
O
O
OH
H
HO
OMe
TIPSO
TIPSO
4) KCN, DMSO, 100 °C
4 steps 90%
5) DIBAL, CH2Cl2
–78 °C, 74%
2) Me2CuLi, BF3·Et2O
CH2Cl2, –78 °C
89%
3) (+)-DET, Ti(Oi-Pr)4
TBHP, MS4A
CH2Cl2,–20 °C
85%
O
9
7
8
1) PPh3, p-nitrobenzoic acid
DEAD, benzene, rt
1) NCS, PPh3
THF, 60 °C
2) NaOH, MeOH, THF, rt
2 steps 71%
2) TBAF, THF, rt
2 steps 75%
OH
OH
OH
O
Cl
Cl
OTr
TIPSO
TIPSO
H
3) Li, NH3, tBuOH
THF, –78 °C, 80%
3) TEMPO, PhI(OAc)2
CH2Cl2, rt, 81%
10
11
12
13% yield over 16 steps
1) nBuLi, THF, –78 °C
then 12, 61%
2) DMP, CH2Cl2, rt, 85%
OMOM
I
OH
O
Cl
MeO
MeO
MeO
MeO
4
Cl
0.9% yield over 27 steps
3) TFA, CH2Cl2, 0 °C
quant.
N
OMOM
N
OH
6
4-epi-Atpenin A5 (2)
Scheme 1 Total synthesis of 4-epi-atpenin A5 (2), reported previously by our group.
highly oxygen-functionalized pyridine unit 13 and the aldehyde
12 followed by chemical transformations afford 4-epi-atpenin
A5 (2), according to our previous synthetic procedure. The key
pyridine unit 13, derived easily from 4,6-dihydroxypyridine 14,
could be synthesized from a commercially available pyridinol 3
via 4,6-dihalogenation and substitution reaction of C–X to C-OR
(R = alkyl or H). This synthetic strategy would lead to a concise
synthesis of the key intermediate 13. The aldehyde 12 could be
synthesized via construction of epoxy alcohol 16 from a
commercially available (–)-Roche ester 7 using Sharpless
asymmetric epoxidation, regio- and stereoselective reduction,
and dichlorination.
2. Results and discussion
Our previous total synthesis of 2, in which 2 was synthesized
by a coupling reaction between pyridine unit 6 and aldehyde 12,
corresponding to the side chain moiety, is shown in Scheme 1.7-9
The pyridine unit 6 was constructed by a clockwise introduction
of oxygen functionalities on the pyridine ring from
a
commercially available pyridinol 3 (14% yield over eight steps).
The aldehyde 12 was prepared from a commercially available (–
)-Roche ester (7) via Sharpless asymmetric epoxidation, regio-
and stereoselective epoxide-opening reaction, and Mitsunobu
reaction as the key reactions (13% yield over 16 steps). Our
previous synthetic procedure was developed to synthesize a
variety of atpenin A5 analogs with chemical transformation of
each functional group and its stereoisomers; however, this
required the frequent use of strong bases during synthesis of the
pyridine unit 6, as well as time-consuming steps to obtain each
final product, including 2. Therefore, a new synthetic strategy
only for 4-epi-atpenin A5 (2) was formulated, as shown in
Scheme 2. It is clear that the coupling reaction between the
We undertook a concise synthesis of the key intermediate 13,
which was commenced with dihalogenation of 3-pyridinol
18.11,12 3-Pyridinol 18 was readily synthesized from
a
commercially available 2-chloro-3-pyridinol (3) via O-
benzylation, one-pot SNAr reaction with sodium methoxide, and
debenzylation by hydrogenolysis (Scheme 3).
Scheme 2 Retrosynthesis of 4-epi-atpenin A5 (2).

3
reaction was attempted according to the first catalytic reaction
ACCEPTED MANUSCRIPT
of aliphatic alcohols with aryl halides, as reported by Buchwald
et al.13 Treatment of 15c with benzyl alcohol in the presence of
Cs2CO3 as a base, L1 or L2 as a ligand, and CuI led to no
reaction (Runs 1 and 2). Other reaction conditions using L3 as a
ligand14 and without a ligand15 were also tested; however, the
results were not improved (Runs 3 and 4). This is attributable to
the low reactivity of our substrate dichloropyridine in the
Ullmann-type reaction.
Scheme 3 Synthesis of the 3-pyridinol 18.
Table 1 Dihalogenation of 18.
Table 2 Unsuccessful conversion of 15c to 20 via Ullmann-type
reaction.
Run
1
Conditions
Yield (%)
decomposed
decomposed
decomposed
1) I2, K2CO3, H2O, rt, 3 h
2
1) NIS, K2CO3, THF-H2O (1:1), rt, 1 h
1) NBS, K2CO3, THF-H2O (1:1), rt, 3 h
3
1) Bis(sym-collidine)bromide(I)
hexafluorophosphate, CH2Cl2, rt, 3 h
4
5
decomposed
1) NCS, K2CO3, THF-H2O (1:1), rt, 1 h
2) NaH, MeI, DMF, rt, 1 h
15c (55)
Run
1
Conditions (equiv.)a)
Solvent
toluene
Results
BnOH (4), Cs2CO3 (4),
No reaction
First, we attempted the dihalogenation of 3-pyridinol 18 under
the same conditions as those used in our previous synthesis (o-
iodination of 4 in Scheme 1)7 (Table 1). However, the desired
diiodide 19a was not obtained at all; the reaction led to
decomposition of the substrates (Run 1). Diiodination with NIS
instead of iodine gave the same result (Run 2). Next,
dibromination was investigated under similar conditions using
CuI (0.1), L1 (0.2)
2
3
4
BnOH (4), Cs2CO3 (4),
CuI (0.1), L2 (0.2)
toluene
toluene
DMF
No reaction
No reaction
No reaction
BnOH (4), K3PO4 (4),
CuI (0.1), L3 (1.2)
BnOH (3), K2CO3 (6),
CuI (0.1), Cu (0.3)
NBS
and
Rousseau’s
conditions
with
bis(sym-
collidine)bromide(I);11d however, the desired dibromide 19b was
not observed (Runs 3 and 4). Dichlorination with NCS proceeded
smoothly to afford the corresponding dichloride 19c, which was
subjected to methylation without purification to afford the
desired dichloride 15c in 55% yield over two steps (Run 5).
a) All reactions were carried out under reflux for 18 h.
Third, palladium-catalyzed C–Cl hydroxylation was
a
explored (Table 3). The first set of reaction conditions used
followed the first report of Buchwald et al.16 Although the low
reactivity of dichloropyridine was a continual concern, the C–Cl
hydroxylation of 15c in 1,4-dioxane-H2O (1:1) at 100 °C in the
presence of Pd2(dba)3 as a palladium catalyst, Me4tBuXPhos (L4)
as a ligand, and KOH as a hydroxide salt proceeded smoothly to
afford the desired dihydroxypyridine 14, including an inseparable
by-product and pure mono-hydroxypyridine 24, in 3% yield after
purification by a silica-gel column chromatography. The former
was subjected to MOM protection to give the pure desired
product 13 in 40% yield over two steps (Run 1). Next, the
reaction conditions reported by Stradiotto et al.17 were used, in
which Pd2(dba)3 as a palladium catalyst, Singer’s BippyPhos
(L5)18 as a ligand, and CsOH·H2O as a hydroxide salt were used
in 1,4-dioxane at 100 °C (Run 2). This reaction also provided the
desired product 13 in 45% yield over two steps, accompanied by
24 in 7% yield. To improve the yield of the desired product 13,
optimization of the reaction conditions was conducted. In Runs 3
and 4, L4 as a ligand was used and only the solvent or solvent
and hydroxide salt were changed (unlike Run 1). Consequently,
the yields of 13 in these reactions greatly decreased. In addition,
L5 as a ligand was fixed (like Run 2) and only the hydroxide salt
or hydroxide salt and solvent were changed (Runs 5 and 6).
Fortunately, the reaction using KOH instead of CsOH·H2O (Run
5) in 1,4-dioxane afforded the desired product 13 in 71% yield
With this dichloride 15c, we next explored conversion to 4,6-
dihydroxypyridine 14. First, SNAr reaction of 15c by treatment
with BnONa was attempted, as shown in Scheme 4.
Unfortunately, the desired 20 was not obtained at all; instead, the
undesired SNAr products 21 and 22 was obtained in 69% and
23% yields, respectively.
Scheme 4 SNAr reaction of 15c.
Second, we investigated the conversion of 15c to 20 via an
Ullmann-type reaction (Table 2). Although the copper-promoted
C–O coupling reaction has been widely used in synthetic organic
chemistry, the coupling reactions between halopyridines and
aliphatic alcohols have been hardly reported and no coupling
reaction with dichloropyridine has been reported. The coupling

4
Tetrahedron
ACCEPTED MANUSCRIPT
Table 3 Conversion of 15c to 13 via a palladium-catalyzed C–
Cl hydroxylation.
Scheme 5 Synthesis of 12.
O
Run Ligand
Hydroxide
salt
Solvent
Yield (%)
13a) 23
HO
Cl
HO
OMe
24
N
1
L4
KOHb)
1,4-dioxane
-H2O (1:1)
40
ꢀ
3
3
7
37% yield
14% yield
over 10 steps
over 6 steps
2
3
4
5
6
L5
L4
L4
L5
L5
CsOH·H2O 1,4-dioxane
KOHb)
1,4-dioxane
CsOH·H2O 1,4-dioxane
45
9
ꢀ
ꢀ
ꢀ
7
31
ꢀ
OMOM
Cl
Cl
18
71
45
MeO
MeO
OHC
KOHb)
KOHb)
1,4-dioxane
8
14
6
N
OMOM
13
12
1,4-dioxane
-H2O (1:1)
ꢀ
7
8
L6
L6
KOHb)
KOHb)
1,4-dioxane
27
32
ꢀ
ꢀ
5
1) nBuLi, 13
THF, –78 °C
1,4-dioxane
-H2O (1:1)
ꢀ
then 12, 55%
2) DMP
CH2Cl2, rt
89%
3) TFA
9
L6
CsOH·H2O 1,4-dioxane
54
ꢀ
4
CH2Cl2, 0 °C
93%
a) Over two steps from 15c b) Used as powder by grinding
pellets
over two steps, accompanied by small amounts of 2319 (8%) and
24 (14%). The change of solvent (Run 6) gave similar results to
those of Run 2. The reaction conditions using a new ligand L620
were also screened. As such, the use of KOH as a hydroxide salt,
regardless of solvent, led to a small decrease in the yield of the
desired product 13 and the reaction yield using CsOH·H2O
increased as compared with the reaction using L4. In all reactions
with KOH, the use of powdered KOH was very important. The
formation of diaryl ethers was not observed in Runs 1–9. Another
synthetic procedure using a catalytic amount of RockPhos Pd G3,
Cs2CO3, and benzaldehyde oxime as a hydroxide surrogate for
the palladium-catalyzed C–Cl hydroxylation, as reported by Fier
and Maloney et al.,21 was also attempted; however, the desired 14
was not obtained (not shown in Table 3). We thus determined the
effective reaction conditions for the palladium-catalyzed C–Cl
hydroxylation of dichloropyridine 15c (Table 3, Run 5) and
succeeded to develop a concise synthesis of the key intermediate
13 without using any strong bases (37% yield over six steps).
OH
N
O
Cl
MeO
MeO
Cl
OH
4-epi-Atpenin A5 (2)
2.4% yield over 19 steps
Scheme 6 Completion of the total synthesis of 4-epi-atpenin A5
(2).
We then turned to the synthesis of another key intermediate 12
(Scheme 5). Acetylene 25 was prepared from a commercially
available (–)-Roche ester (7) according to a known procedure.22
Subsequent Negishi carboalumination and treatment with a
paraformaldehyde23 afforded trans-allyl alcohol 26 in 68% yield
stereoselectively, which was subjected to Sharpless epoxidation24
using (–)-DET to give the epoxide 16 in 99% yield
stereoselectively (d.r.
= 15:1). Regio- and stereoselective
reduction of the epoxide 16 with NaBH3CN in the presence of

5
BF3·Et2O25 proceeded to furnish diol 27 in 74% yield. Other
reactions leading to the desired aldehyde 12 were followed
according to our previous synthesis. Finally, concise synthesis of
the key intermediate aldehyde 12 was achieved in 14% yield over
10 steps. The coupling reaction between 12 and 13 (55% yield),
Dess-Martin oxidation (89% yield), and MOM deprotection
under acidic conditions (93% yield) according to our previous
synthesis afforded 4-epi-atpenin A5 (2) (Scheme 6). All
analytical data of the synthetic 2 were identical to those reported
by us previously.9
were carefully added MeOH (110 mL) and NaH (55 %, 16.8 g,
ACCEPTED MANUSCRIPT
386 mmol). The resulting mixture was stirred for 17 h at 80 °C,
quenched with a saturated aqueous NH4Cl solution, and extracted
with EtOAc. The combined organic layers were dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo to afford
the crude 17.
Next, a suspension of the crude 17 and 10% Pd/C (1.7 mg) in
THF/MeOH (1:1, 300 mL) was vigorously stirred under an H2
atmosphere overnight at room temperature. The resulting mixture
was filtered through a pad of Celite and the filtrate was
concentrated in vacuo. The residue was purified by flash silica-
gel column chromatography (8:1 hexanes/EtOAc) to afford 18
(9.10 g, 94%, two steps) as a yellow oil.
In conclusion, we have achieved a concise total synthesis of 4-
epi-atpenin A5 (2). Key features of the synthetic strategy
included dihalogenation of pyridinol 18 and the palladium-
catalyzed C–Cl hydroxylation for the synthesis of the key
pyridine unit 13 and Sharpless epoxidation and regio- and
stereoselective reductive epoxide-opening reaction for the
synthesis of the key aldehyde 12. Our new total synthesis of 2
was provided in 2.4% overall yield over 19 steps (0.9% overall
yield over 27 steps for our previous total synthesis). Future
structure–activity relationship studies of atpenin A5 (1) and 4-
epi-atpenin A5 (2) analogs in our laboratory will allow
substantial progress in this field because the synthesis of the key
pyridine unit 13 was both efficient and practical. Such research is
currently under way and will be reported in due course.
18: IR (KBr): 3403, 3068, 2952, 1609, 1477, 1247, 1107, 789,
754 cm−1; H-NMR (400 MHz, CDCl3) δ 7.69 (dd, 1H, J = 1.6,
1
5.1 Hz), 7.11 (dd, 1H, J = 1.6, 7.6 Hz,), 6.81 (dd, 1H, J = 5.1, 7.6
Hz), 5.53 (s, 1H), 4.02 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ
152.8, 140.5, 137.1, 120.7, 117.7, 53.6; HRMS (EI) [M]+ calcd
for C6H7NO2 428.1862, found 428.1855.
3.3. 4,6-Dichloro-2,3-dimethoxypyridine (15c)
To a solution of 18 (2.08 g, 16.6 mmol) in H2O/THF (1:1, 84
mL) were added K2CO3 (11.5 g, 83.0 mmol) and NCS (11.1 g,
83.0 mmol) at 0 °C. After stirring for 1 h at 0 °C, 2N HCl was
added and the resulting mixture was extracted with EtOAc. The
combined organic layers were dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo to give the crude 19c. Next,
the crude 19c was dissolved in DMF (166 mL) and treated with
NaH (55%, 1.09 g, 33.2 mmol) and MeI (2.07 mL, 33.2 mmol) at
0 °C. The reaction mixture was stirred for 1 h at 0 °C, quenched
with a saturated aqueous NH4Cl solution, and extracted with
EtOAc. The combined organic layers were dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by flash silica-gel column chromatography (hexanes) to
afford 15c (1.90 g, 55%, two steps) as a white solid.
3. Experimental section
3.1. General
The reactions were carried out in flame-dried glassware under
a nitrogen or argon atmosphere employing standard techniques
for handling air-sensitive materials. Commercial reagents were
used without further purification, unless otherwise indicated.
Organic solvents were distilled and dried over 3 or 4Å molecular
sieves. Cold baths were prepared as follows: 0 °C, wet ice/water,
−78 °C, dry ice/acetone. Purifications by flash column
chromatography were performed over silica gel 60N (spherical,
neutral, particle size 40–50 µm). TLC was performed on 0.25 nm
Merck silica gel 60 F254 plates and the effluents were visualized
by UV (254 nm) as well as by phosphomolybdic acid and p-
anisaldehyde TLC stains. Yields refer to chromotographically
and spectroscopically pure compounds, unless otherwise noted.
1H- and 13C-NMR spectra were recorded using an internal
deuterium lock on 400-MR, VNMRS-400, and UNITY-400
spectrometers (Agilent Technologies, Waldbormn, Germany).
All NMR signals were reported in ppm relative to the internal
reference standard provided by chloroform (that is, 7.26 and 77.0
15c: IR (KBr): 2941, 1567, 1474, 1413, 1378, 1293, 1246,
1173, 1113, 1037, 996, 912, 838, 739 cm−1; 1H-NMR (400 MHz,
CDCl3) δ 6.94 (s, 1H), 4.01 (s, 3H), 3.87 (s, 3H); 13C-NMR (100
MHz, CDCl3) δ 157.8, 141.4, 139.4, 138.1, 117.5, 60.6, 54.6;
HRMS (EI) [M]+ calcd for C7H7Cl2NO2 206.9854, found
206.9855.
3.4. 6-(Benzyloxy)-4-chloro-2,3-dimethoxypyridine (21) and
2,4,6-tris(benzyloxy)-3-methoxypyridine (22)
To a solution of 15c (41.4 mg, 0.200 mmol) in DMF (800 µL)
were added NaH (55%, 34.9 mg, 0.800 mmol) and a solution of
BnOH (83.1 µL, 0.800 mmol) in DMF (1.2 mL) at 0 °C. After
stirring for 1 h at room temperature, the reaction mixture was
stirred for 14 h at 80 °C. The resulting mixture was poured into
water and extracted with EtOAc. The combined organic layers
were dried over anhydrous Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by flash silica-gel column
chromatography (30:1 hexanes/EtOAc) to afford 21 (38.8 mg,
69%) as a colorless oil and 22 (19.9 mg, 23%) as a colorless oil.
1
ppm for the H and 13C spectra, respectively). Multiplicity data
were presented as follows: s = singlet, d = doublet, t = triplet, q =
quarted, m = multiplet, br = broad, dd = double doublet, and dt =
double triplet. Coupling constants (J) were reported in Hz. IR
spectra were recorded on a FT/IR460-plus IR spectrometer
(JASCO, Tokyo, Japan). Absorption data were given as
wavenumber (cm−1). Optical rotations were recorded on a
JASCO DIP-1000 polarimeter (JASCO, Tokyo, Japan) and
reported as follows: [α]TD, concentration (g per 100 mL), and
solvent. High-resolution mass spectra were obtained on JEOL
JMS-700 Mstation, JEOL JMS-AX505HA, and JEOL JMS-
T100LP systems (JEOL, Tokyo, Japan) equipped with FAB, EI,
and ESI high-resolution mass spectrometers.
21: IR (KBr): 2931, 2831, 1583, 1484, 1446, 1371, 1235,
1114, 998, 894, 744 cm−1; H-NMR (400 MHz, CDCl3) δ 7.41-
1
7.35 (m, 5H), 6.60 (s, 1H), 5.14 (s, 2H), 3.97 (s, 3H), 3.83 (s,
3H); 13C-NMR (100 MHz, CDCl3) δ 159.3, 157.7, 142.1, 135.4,
131.3, 128.8 (2C), 128.4 (2C), 127.2, 103.9, 71.0, 60.8, 54.4;
HRMS (ESI+) [M+H]+ calcd for C14H15ClNO3, 280.0740, found
280.0731.
3.2. 2-Methoxypyridin-3-ol (18)
To a solution of 3 (10.0 g, 77.2 mmol) in DMF (175 mL) was
added NaH (55 %, 5.05 g, 116 mmol) at 0 °C. After stirring for 5
min at 0 °C, the reaction mixture was treated with BnBr (11.1
mL, 92.6 mmol) and stirred at 0 °C for 15 min. To the mixture
22: IR (KBr): 3031, 2930, 1600, 1485, 1348, 1111, 1062,
1
1028, 906, 801 cm−1; H-NMR (400 MHz, CDCl3) δ 7.42-7.23

6
Tetrahedron
ACCEPTED MANUSCRIPT
(m, 15H), 6.01 (s, 1H), 5.42 (s, 2H), 5.23 (s, 2H), 5.11 (s, 2H),
To a solution of Cp2ZrCl2 (128 mg, 0.440 mmol) in CH2Cl2
3.80 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ 160.9, 157.4, 138.0,
137.6, 136.1, 128.6(2C), 128.4(2C), 128.3(2C), 128.1(2C),
127.8(3C), 127.5(2C), 127.1(2C), 126.8(2C), 88.4, 70.5, 67.7,
67.6, 60.9; HRMS (ESI) [M+H]+ calcd for C27H26NO4, 428.1862,
found 428.1855.
(2.4 mL) was added dropwise Me3Al (1.07 M in n-hexane, 1.23
mL, 1.32 mmol) at 0 °C under argon. After stirring for 0.5 h at 0
°C, a solution of 25 (148 mg, 0.440 mmol) in CH2Cl2 (2.0 mL) at
0 °C was added. The mixture was allowed to warm to room
temperature and was then stirred for 11 h. The resulting mixture
was cooled to 0 °C and treated with (HCHO)n (198 mg). After
stirring for 0.5 h at 0 °C, the mixture was quenched with a
saturated aqueous NH4Cl solution and extracted with CH2Cl2.
The combined organic layers were dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo. The residue was purified by
flash silica-gel column chromatography (10:1 hexanes/EtOAc) to
afford 26 (116 mg, 68%) as a colorless oil.
26: [α]24 −8.41 (c 1.0, CHCl3); IR (KBr): 3313, 2929, 1427,
D
1
1108, 869, 701, 504 cm−1; H-NMR (400 MHz, CDCl3) δ 7.67-
3.5. 2,3-Dimethoxy-4,6-bis(methoxymethoxy)pyridine (13), 6-
chloro-2,3-dimethoxypyridin-4-ol (23), and 2,3-
dimethoxypyridin-4-ol (24) (Table 3, Run 5)
7.64 (m, 4H), 7.43-7.35 (m, 6H), 5.39-5.36 (m, 1H), 4.12-4.09
(m, 2H), 3.47 (dd, 2H, J = 2.0, 6.0 Hz), 2.25-2.21 (m, 1H), 1.84-
1.73 (m, 2H), 1.61 (s, 3H), 1.05 (s, 9H), 0.89 (d, 3H, J = 6.3 Hz);
13C-NMR (100 MHz, CDCl3) δ 138.3, 135.6, 134.0, 129.5, 127.6,
125.0, 68.5, 59.3, 43.6, 33.7, 26.9, 19.3, 16.6, 16.1; HRMS
(ESI+) [M+Na]+ calcd for C24H34NaO2Si, 405.2226, found
405.2220.
To a solution of 15c (100 mg, 0.481 mmol) in 1,4-dioxane
(1.0 mL) were added Pd2(dba)3 (8.8 mg, 9.58 µmol), Bippyphos
(19.4 mg, 38.3 µmol), and KOH (161 mg, 2.87 mmol) at room
temperature. The mixture was stirred for 22 h at 100℃. After
cooling to room temperature, 2N HCl was added and the mixture
was extracted with EtOAc/MeOH (10:1). The combined organic
layers were dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. The residue was semipurified by flash
silica-gel column chromatography (8:1 to 0:1 hexane/EtOAc) to
afford 2319 (7.1 mg, 8%) as a yellow solid, 24 (10.1 mg, 14%) as
a yellow oil, and the crude 14.
3.7. ((2R,3R)-3-((S)-3-((tert-Butyldiphenylsilyl)oxy)-2-
methylpropyl)-3-methyloxiran-2-yl)methanol (16)
To a suspension of 4Å molecular sieves (80 mg) and Ti(Oi-
Pr)4 (182 µL, 0.620 mmol) in CH2Cl2 (1.0 mL) were added
dropwise (–)-DET (126 µL, 0.740 mmol) and a solution of 26
(158 mg, 0.410 mmol) in CH2Cl2 (3.0 mL) at −20 °C. After
stirring for 20 min, TBHP (5.0 M in decane, 224 µL, 1.23 mmol)
was added dropwise to the suspension at −20 °C and the resulting
mixture was stirred for 2 h. The reaction was quenched with 10%
aqueous tartaric acid solution (4.0 mL) and 10% aqueous Na2SO3
solution (1.0 mL) and extracted with EtOAc. The combined
organic layers were dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by flash silica-
gel column chromatography (5:1 hexanes/EtOAc) to afford 16
(162 mg, 99%, d.r. = 15:1) as a colorless oil.
Next, to a solution of the crude 14 (80.1 mg) in DMF (4.8 mL)
were added NaH (55 %, 83.6 mg, 1.92 mmol) and MOMCl (144
µL, 1.92 mmol) at 0 °C. The reaction mixture was stirred for 1 h
at 0 °C, quenched with a saturated aqueous NH4Cl solution, and
extracted with EtOAc. The combined organic layers were dried
over anhydrous Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by flash silica-gel column chromatography
(5:1 hexanes/EtOAc) to afford 13 (88.1 mg, 71%, two steps) as a
colorless oil.
16: [α]24 −4.01 (c 1.0, CHCl3); IR (KBr): 3446, 2958, 2857,
D
1470, 1387, 1109, 862, 797, 702, 650 cm−1; 1H-NMR (400 MHz,
CDCl3) δ 7.67-7.62 (m, 4H), 7.46-7.35 (m, 6H), 3.63-3.57 (m,
2H), 3.52-3.43 (m, 2H), 2.95-2.80 (m, 1H), 2.07-2.03 (m, 1H),
1.89-1.84 (m, 2H), 1.25 (s, 3H), 1.06 (s, 9H), 0.97 (d, 3H, J = 6.8
Hz); 13C-NMR (100 MHz, CDCl3) δ 135.6, 133.8, 133.7, 129.7,
129.6, 127.7, 127.6, 68.0, 62.6, 61.2, 60.3, 42.1, 33.0, 26.9, 19.3,
17.6, 16.6; HRMS (ESI+) [M+Na]+ calcd for C24H34NaO3Si,
421.2175, found 421.2595.
23: IR (KBr): 3358, 2992, 2942, 1587, 1473, 1390, 1254,
1098, 1050, 994, 753 cm−1; HRMS (EI+) [M]+ calcd for
1
C7H8ClNO3, 189.0193, found 189.0199; Major regioisomer: H-
NMR (400 MHz, CDCl3) δ 6.33 (s, 1H), 3.92 (s, 3H), 3.80 (s,
3H); 13C-NMR (100 MHz, CDCl3) δ156.4, 155.8, 140.1, 134.5,
100.8, 60.8, 54.3; Minor regioisomer: 1H-NMR (400 MHz,
CDCl3) δ 6.59 (s, 1H), 3.98 (s, 3H), 3.88 (s, 3H); 13C-NMR (100
MHz, CDCl3) δ156.9, 156.0, 142.0, 129.2, 105.8, 60.8, 54.2.
24: IR (KBr): 3423, 2928, 1599, 1465, 1403, 1102, 709 cm−1;
1H-NMR (400 MHz, CDCl3) δ 7.73 (d, 1H, J = 5.4 Hz), 6.57 (d,
1H, J = 5.4 Hz), 6.16 (s, 1H), 3.99 (s, 3H), 3.90 (s, 3H); 13C-
NMR (100 MHz, CDCl3) δ 157.2, 155.5, 141.5, 130.2, 106.5,
60.7, 53.6; HRMS (ESI+) [M+H]+ calcd for C7H10NO3,
156.0662, found 156.0661.
3.8. (2S,3R,5S)-6-((tert-Butyldiphenylsilyl)oxy)-3,5-
dimethylhexane-1,2-diol (27)
To a solution of 16 (77.1 mg, 0.190 mmol) in Et2O (1.9 mL)
was added NaBH3CN (53.5 mg, 0.890 mmol) at 0 °C. The
resulting mixture was vigorously stirred at 0 °C and treated with
BF3·Et2O (122 µL, 0.970 mmol). After stirring for 0.5 h at 0 °C,
the reaction was quenched with 2 N HCl and extracted with
EtOAc. The combined organic layers were washed with a
saturated aqueous NaHCO3 solution and brine, dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by flash silica-gel column chromatography
(3:1 hexanes/EtOAc) to afford 27 (57.4 mg, 74%) as a colorless
oil.
13: IR (KBr): 2951, 2829, 1603, 1487, 1422, 1381, 1351,
1239, 1154, 1118, 1075, 1025, 999, 924, 904, 814, 794 cm−1; 1H-
NMR (400 MHz, CDCl3) δ 6.23 (s, 1H), 5.43 (s, 2H), 5.24 (s,
2H), 3.94 (s, 3H), 3.52 (s, 3H), 3.50 (s, 3H), 3.79 (s, 3H); 13C-
NMR (100 MHz, CDCl3) δ 159.1, 156.4, 156.0, 127.4, 94.5,
91.9, 89.9, 60.8, 56.9, 56.4, 53.6; HRMS (EI) [M]+ calcd for
C11H17NO6 259.1056, found 259.1052.
27: [α]24 +3.44 (c 1.0, CHCl3); IR (KBr) 3432, 2957, 2857,
3.6. (S,E)-6-((tert-Butyldiphenylsilyl)oxy)-3,5-dimethylhex-2-en-
1-ol (26)
D
1629, 1469, 1388, 1109, 1079 cm−1; 1H-NMR (400 MHz, CDCl3)
δ 7.67-7.64 (m, 4H), 7.45-7.35 (m, 6H), 3.60-3.43 (m, 5H), 1.74-

7
1.52 (m, 4H), 1.05 (s, 9H), 0.94 (d, 3H, J = 8.0 Hz), 0.86 (d, 3H,
J = 8.0 Hz); 13C-NMR (100 MHz, CDCl3) δ 135.6, 133.9, 129.6,
127.7, 127.6, 77.3, 77.0, 76.7, 75.3, 68.4, 65.2, 37.1, 33.0, 26.9,
19.3, 18.0, 14.9; HRMS (ESI+) [M+Na]+ calcd for
C24H36NaO3Si, 423.2331, found 423.2321.
and a saturated aqueous NaHCO3 solution, and extracted with
ACCEPTED MANUSCRIPT
CH2Cl2. The combined organic layers were dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by flash silica-gel column chromatography (10:1
hexanes/EtOAc) to afford the MOM-protected 4-epi-atpenin A5
(48.4 mg, 89%) as a colorless oil.
3.9. (2S,4R,5R) -5,6-Dichloro-2,4-dimethylhexan-1-ol (28)
MOM-protected 4-epi-atpenin A5: [α]27 +19.7 (c 0.1,
D
To a solution of 27 (898 mg, 2.24 mmol) in THF (11.2 mL)
were added NCS (898 mg, 6.73 mmol) and PPh3 (1.76 g, 6.73
mmol) at room temperature. The mixture was stirred for 3 h at 60
°C, quenched with H2O, and extracted with CH2Cl2. The
combined organic layers were dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo. The residue was semipurified
by flash silica-gel column chromatography (hexanes) to afford
the crude dichloride.
CHCl3); IR (KBr) 3401, 3020, 1636, 1589, 1471, 1389, 1213,
787, 754, 671 cm−1; 1H-NMR (400 MHz, CDCl3) δ 5.60 (d, 1H, J
= 5.6, Hz), 5.39 (d, 1H, J = 5.6 Hz), 5.33 (d, 1H, J = 5.2, Hz),
5.26 (d, 1H, J = 5.2 Hz), 4.03 (ddd, 1H, J = 2.4, 6.6, 7.0 Hz),
3.96 (s, 3H), 3.87 (dd, 1H, J = 6.6, 11.6 Hz), 3.76 (dd, 1H, J =
7.0, 11.6 Hz), 3.76 (s, 3H), 3.48 (s, 3H), 3.47 (s, 3H), 3.27-3.19
(m, 1H), 2.25-2.17 (m, 1H), 2.07 (ddd, 1H, J = 3.2, 10.0, 13.5
Hz), 1.28-1.19 (m, 1H), 1.17 (d, 3H, J = 7.2 Hz), 1.10 (d, 3H, J =
6.8 Hz); 13C-NMR (100 MHz, CDCl3) δ 204.5, 157.2, 156.1,
152.8, 129.8, 110.6, 99.0, 91.9, 68.1, 60.8, 57.8, 57.4, 54.0, 46.6,
44.8, 34.6, 33.8, 18.0, 17.7; HRMS (ESI) [M+Na]+ calcd for
C19H29Cl2NNaO7 476.1219, found 476.1223.
A solution of the crude dichloride in THF (22.4 mL) was
treated with TBAF (1.0 M in THF, 4.48 mL, 4.48 mmol) at room
temperature. After stirring for 1.5 h at room temperature, the
reaction mixture was quenched with a saturated aqueous NH4Cl
solution and extracted with EtOAc. The combined organic layers
were dried over anhydrous Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by flash silica-gel column
chromatography (15:1 hexanes/EtOAc) to afford 28 (237 mg,
53%, two steps) as a white solid.
A solution of MOM-protected 4-epi-atpenin A5 (27.8 mg,
0.0612 mmol) in CH2Cl2 (600 µL) was treated with TFA (600
µL) at 0 °C. After stirring for 0.5 h at 0 °C, the reaction mixture
was concentrated in vacuo. The residue was purified by flash
silica-gel column chromatography (1:1 hexanes/EtOAc) to afford
4-epi-atpenin A5 (2) (20.9 mg, 93%) as a white solid.
28: [α]27 +18.3 (c 0.1, CHCl3); IR (KBr) 3020, 1215, 930,
D
1
794, 754, 667, 534, 438, 409 cm−1; H-NMR (400 MHz, CDCl3)
4-epi-Atpenin A5 (2): [α]27 +38.7 (c 1.0, CHCl3); IR (KBr)
D
δ 4.03 (ddd, 1H, J = 2.7, 5.3, 5.3 Hz), 3.76 (dd, 1H, J = 5.3 Hz),
3.76 (dd, 1H, J = 5.3 Hz), 3.57 (dd, 1H, J = 3.3, 7.8 Hz), 3.46
(dd, 1H, J = 4.5, 7.8 Hz), 2.29-2.20 (m, 1H), 1.75-1.70 (m, 1H),
1.53 (ddd, 1H, J = 4.5, 6.6, 9.6 Hz), 1.08 (d, 3H, J = 5.4 Hz),
1.00 (d, 3H, J = 5.1 Hz), 0.95-0.89 (m, 1H); 13C-NMR (100
MHz, CDCl3) δ 67.4, 67.2, 46.0, 34.3, 33.5, 33.1, 18.3, 17.7;
HRMS (EI) [M–CH2OH]+ calcd for C7H13Cl2 167.0394, found
167.0392.
2934, 1646, 1593, 1457, 1325, 1289, 1195, 1163, 994, 956, 592
1
cm−1; H-NMR (400 MHz, CDCl3) δ 4.19 (s, 3H), 4.22-4.12 (m,
1H), 4.00 (ddd, 1H, J = 2.8, 6.6, 7.2 Hz) 3.85 (dd, 1H, J = 7.2,
11.4 Hz), 3.80 (s, 3H), 3.75 (dd, 1H, J = 6.6, 11.4 Hz), 2.10 (ddd,
1H, J = 3.2, 10.2, 12.3 Hz), 2.07-1.98 (m, 1H), 1.27-1.20 (m,
1H), 1.18 (d, 3H, J = 6.8 Hz), 1.03 (d, 3H, J = 6.8 Hz); 13C-NMR
(100 MHz, CDCl3) δ 209.4, 172.1, 161.6, 155.5, 121.4, 100.8,
67.7, 61.6, 57.9, 46.3, 40.2, 34.1, 33.8, 19.1, 17.7; HRMS (ESI)
[M+Na]+ calcd for C15H21Cl2NNaO5 388.0695, found 388.0707.
3.10. 4-epi-Atpenin A5 (2)
To a solution of 28 (56.0 mg, 0.281 mmol) in CH2Cl2 (2.8
mL) were added TEMPO (4.4 mg, 0.0281 mmol) and PhI(OAc)2
(136 mg, 0.422 mmol) at room temperature. The mixture was
stirred for 3.3 h at room temperature, quenched with a saturated
aqueous Na2S2O3 solution, and extracted with CH2Cl2. The
combined organic layers were dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo. The residue was purified by
flash silica-gel column chromatography (20:1 hexanes/EtOAc) to
afford 12 (47.7 mg, 86%) as a colorless oil. All analytical data of
the synthetic 12 were identical to those reported by us
previously.9
Acknowledgments
This work was supported by a Grant-in-Aid for Scientific
Research (C) (S.A., KAKENHI No. 17K08370), a Grant-in-Aid
for Young Scientists (B) (M.O., KAKENHI No. 21790117 and
23790140), a Kitasato University research grant for young
researchers (M.O.), and a Nagai Memorial Research Scholarship
from the Pharmaceutical Society of Japan (D.L.). We also thank
Ms. N. Sato and Dr. K. Nagai (Kitasato University) for kindly
measuring NMR and MS spectra.
References and notes
A solution of 13 (75.3 mg, 0.290 mmol) in THF (2.4 mL) was
added to a solution of nBuLi (1.55 M in hexanes, 225 µL, 0.248
mmol) in THF (1.2 mL) at –78 °C. After stirring for 1.5 h at –78
°C, a solution of 12 (47.7 mg, 0.242 mmol) in THF (1.2 mL) was
added dropwise to the resulting mixture. The reaction mixture
was stirred for 1.5 h at –78 °C, quenched with MeOH, diluted
with H2O, and extracted with EtOAc. The combined organic
layers were dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. The residue was semipurified by flash
silica-gel column chromatography (3:1 hexanes/EtOAc) to afford
the corresponding coupling product (60.2 mg, 55%) as a
diastereomixture.
1. Omura, S.; Tomoda, H.; Kimura, K.; Zhen, D. Z.; Kumagai, H.;
Igarashi, K.; Imamura, N.; Takahashi, Y.; Tanaka, Y.; Iwai, Y. J.
Antibiot. 1988, 41, 1769–1773.
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temperature, quenched with a saturated aqueous Na2S2O3 solution
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8
Tetrahedron
8. Ohtawa, M.; Sugiyama, K.; Hiura, T.; Izawa, S.; Shiomi, K.;
17. Lavery, C. B.; NRotta-Loria, N. L.; McDonald, R.; Stradiotto, M.
ACCEPTED MANUSCRIPT
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novel methodology they developed was achieved and led to the
synthesis of new analogs possessing a similar complex II
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