Asymmetric Total Synthesis of (+)-Coprophilin

Article abstract of DOI:10.1055/s-0036-1591866

In this paper, we report the first total synthesis of (+)-coprophilin, an anticoccidial agent, by constructing the chiral linear precursor via a Mukaiyama-Evans aldol reaction and a stereoselective intramolecular Diels-Alder reaction. The proposed method can be used to provide large amounts of (+)-coprophilin, which exhibits a 3,4,5,6,7-pentasubstituted Δ ^1,2 -octalin core structure.

Full text of DOI:10.1055/s-0036-1591866

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
©
Georg Thieme Verlag Stuttgart · New York
2017, 49, A–F
paper
A
en
Synthesis
I. Shiina et al.
Paper
Asymmetric Total Synthesis of (+)-Coprophilin
Isamu Shiina*
Yuma Umezaki
Takatsugu Murata
Kyohei Suzuki
Takayuki Tonoi
Bn
N
O
O
O
H
OEt
O
TBSO
O
Department of Applied Chemistry, Faculty of Science,
Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku,
Tokyo 162-8601, Japan
MeO
O
intramolecular
Diels–Alder
shiina@rs.kagu.tus.ac.jp
reaction (IMDA)
–
Parikh−Doering oxidation followed by
boron-mediated aldol reaction
H
H
HO
–
–
diastereoselective IMDA reaction
25% overall yield in 11 steps
from the key intermediate
(+)-coprophilin
Received: 13.10.2017
Accepted after revision: 21.11.2017
Published online: 21.12.2017
Scheme 1 describes the proposed asymmetric synthesis
of 1, including the following two notable methodologies:
(a) a sequential Parikh–Doering oxidation of alcohol 8 and
boron-mediated aldol reaction with the chiral oxazolidi-
DOI: 10.1055/s-0036-1591866; Art ID: ss-2017-f0667-op
Abstract In this paper, we report the first total synthesis of (+)-copro-
philin, an anticoccidial agent, by constructing the chiral linear precursor
via a Mukaiyama–Evans aldol reaction and a stereoselective intramolec-
ular Diels–Alder reaction. The proposed method can be used to provide
large amounts of (+)-coprophilin, which exhibits a 3,4,5,6,7-penta-
substituted Δ1 -octalin core structure.
3
none 6 and (b) a diastereoselective IMDA reaction of the
chiral linear ester 4 to form octahydronaphthalene 3, from
which we have successfully accomplished the total synthe-
sis of the antitumor agent AMF-26 (M-COPA).4 Although 3
had been prepared as a key intermediate of the synthesis of
AMF-26 by using a chiral Sn(II)-complex-mediated reac-
tion,6 the asymmetric aldol reaction could not be per-
formed in a sequential manner in the total synthesis of
AMF-26.4 Additionally, the Horner–Wadsworth–Emmons
(HWE) reaction using aldehyde 3 with phosphonate 2 was
effectively performed to obtain the corresponding ester for
the preparation of the basic skeleton of the target molecule
1 in this research.
,5
,2
Key words total synthesis, stereoselective synthesis, antibiotics,
Diels–Alder reaction, aldol reaction
(+)-Coprophilin (1) was first isolated from an unidenti-
fied, nonsporulating fungus (MF 5773) by Merck Research
Laboratories in 1998 (Figure 1). It was revealed that 1 in-
1
hibited the growth of Eimeria tenella in MDBK 441 cells and
exhibited an MIC value of less than 1.5 μM without the for-
mation of schizonts. This biologically active compound has
an unusual structure consisting of a pentadienoic methyl
ester part and a 3,4,5,6,7-pentasubstituted Δ -octalin moi-
ety. In this research, we report the first total synthesis of 1
by using an asymmetric aldol reaction to construct the chi-
ral linear precursor and a stereoselective intramolecular
Diels–Alder (IMDA) reaction to provide the core structure of
Alcohol 8 was prepared by using (2E,4E)-hexa-2,4-dien-
1-ol as a starting material by a previously reported proce-
4
dure (Scheme 2). After preparation of (E,E)-diene aldehyde
1
,2
7 by using a pyridine–sulfur trioxide complex in situ, the
7,8
boron-mediated stereoselective aldol reaction of 7 with
9
the chiral oxazolidinone 6 took place directly to exclusively
provide the desired α,β,γ-trisubstituted aldol 5 in a succes-
sive manner (Scheme 2). Complete 2,3-syn and 3,4-syn
asymmetric induction was observed in this boron-mediat-
ed aldol reaction similar to the tin(II)-promoted stereo-
2
the multisubstituted octahydronaphthalene.
MeO
O
4
selective aldol addition formerly reported by our group.
Chiral aldehyde 11 was afforded by transformation of oxaz-
olidinone 5 into Weinreb amide 9, protection of the free hy-
droxyl group in 9, and reduction of the resulting TBS ether
H
H
HO
10 with DIBAL-H. Subsequent treatment of 11 with a Wittig
reagent provided α,β-unsaturated ester 4 as the key syn-
thetic intermediate.
Figure 1 Structure of (+)-coprophilin (1)
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

B
Synthesis
I. Shiina et al.
Paper
MeO
O
MeO
O
H
H
O
HWE
reaction
Diels–Alder
reaction
TBSO
+
H
HO
(EtO)2P
H
3
O
H
2
(
+)-coprophilin (1)
Bn
N
OEt
O
TBSO
O
HO
O
O
4
5
Bn
+
N
6
O
O
O
H
OH
O
7
8
Parikh–Doering oxidation followed by
boron-mediated aldol reaction
Scheme 1 Retrosynthetic analysis of (+)-coprophilin (1)
Bn
N
O
6
(
1.2 equiv)
O
O
(
a) SO3⋅Py (3.0 equiv)
Et3N (1.8 equiv)
DMSO (3.6 equiv)
(b) nBu2BOTf (1.2 equiv)
Et3N (1.2 equiv)
OH
H
CH2Cl2 (0.2 M)
r.t., 1 h
2 2
CH Cl (0.2 M)
O
–78 to 0 °C, 2 h
8
7
94%
successive operation
Bn
(c) MeNHOMe·HCl (2.3 equiv)
Me
N
Me3Al (2.3 equiv)
N
O
OMe
THF (0.1 M)
HO
O
O
HO
9
O
0
°C, 15 min, 95%
5
(
2
d) TBSOTf (1.5 equiv)
,6-lutidine (4.0 equiv)
Me
(e) DIBAL-H (2.1 equiv)
N
OMe
CH2Cl2 (0.1 M)
°C, 30 min, 99%
THF (0.1 M)
–78 °C, 2.5 h
TBSO
O
0
10
(
f) Ph3P=CHCO2Et (2.5 equiv)
toluene (0.1 M)
H
O
OEt
TBSO
TBSO
4
O
110 °C, 1.5 h
81% (from 10)
11
Scheme 2 Preparation of the key chiral linear ester intermediate 4
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

C
Synthesis
I. Shiina et al.
Paper
O
H
OEt
OH
H
(
a) Et2AlCl (4.0 equiv)
CH2Cl2 (0.02 M)
TBSO
(b) DIBAL-H (2.0 equiv)
TBSO
4
CH2Cl2 (0.05 M)
0 °C, 20 min
H
H
–78 °C to r.t., 16 h
62% (2 steps)
12
13
MeO
O
MeO
O
(
(
c) TPAP (0.1 equiv)
NMO (3.0 equiv)
4
Å MS
CH2Cl2 (0.05 M)
°C, 30 min
H
H
H
H
0
TBSO
(e) 12 M HCl
HO
d) phosphonate 2 (3.1 equiv)
LHMDS (3.0 equiv)
THF (0.05 M)
MeOH/THF
r.t., 10 h
92%
coprophilin (1)
14
–
6
78 °C to r.t., 3 h
1% (from 13)
Scheme 3 Completion of total synthesis of coprophilin (1)
The IMDA reaction was examined according to the es-
tablished procedure for the synthesis of AMF-26 in order to
prepare the desired bicyclic compound (Scheme 3).4 The
stereoselective Diels–Alder reaction of 4 in the presence of
(R)-4-Benzyl-3-[(2R,3S,4R,6E,8E)-3-hydroxy-2,4-dimethyldeca-
,8-dienoyl]oxazolidin-2-one (5)
Preparation of aldehyde 7: Sulfur trioxide–pyridine complex (374 mg,
.35 mmol) was added to a solution of alcohol 8 (110 mg, 0.784
mmol), Et N (0.20 mL, 1.43 mmol), and DMSO (0.20 mL, 2.82 mmol)
6
2
3
Et AlCl took place smoothly to afford the desired endo-type
2
in CH Cl (3.93 mL) at 0 °C. After the mixture had stirred for 1 h at r.t.,
1,2
2
2
(
9R,10R)-Δ -octalin derivative 12 in good yield. Next, the
aldehyde 7 was obtained and used in the next step without further
installation of the α,β,γ,δ-bis-unsaturated ester moiety of
the targeted molecules in the (9R,10R)-Δ1,2-octalin deriva-
tive 13 was attempted. The oxidation of 13 by using TPAP
with NMO was performed in order to provide the corre-
sponding aldehyde 3, and the subsequent HWE olefination
of the resulting aldehyde 3 with phosphonate 2 smoothly
proceeded to afford the desired triene 14. Deprotection of
the silyl ether group at the C-6 position of triene 14 was
eventually examined by using 12 M hydrochloric acid, and
the desired product 1 was readily prepared in excellent
yield by this facile procedure. All the spectroscopic data, in-
cluding the optical rotation of the completely synthetic 1,
correspond to those reported for naturally occurring copro-
purification.
Preparation of the boron enolate: A 1.00 M solution of dibutylboron
triflate in CH Cl (0.940 mL, 0.940 mmol) and Et N (0.130 mL, 0.943
mmol) were added to a solution of oxazolidinone 6 (220 mg, 0.943
mmol) in CH Cl (3.93 mL) at 0 °C. After stirring for 10 min at 0 °C, the
mixture was used in the following reaction without further purifica-
tion.
2
2
3
2
2
Preparation of 5: The mixture of aldehyde 7 was added via a cannula
to a solution of the boron enolate at –78 °C. After the reaction mix-
ture had stirred for 1 h at –78 °C and for 1 h at 0 °C, MeOH, phosphate
buffer solution (pH 7), and 35% aq H O were added at 0 °C. After the
reaction mixture had stirred for 30 min at 0 °C, sat. aq Na S O was
added. The mixture was extracted with EtOAc, and the organic layer
was washed with brine and dried over Na SO . After filtration of the
2
2
2
2
3
2
4
24
philin [our synthetic sample: [α]
+96.6 (c 0.170, MeOH);
mixture and evaporation of the solvent, the crude product was puri-
fied twice by TLC (silica gel, hexane–EtOAc, 2:1) to afford aldol 5.
D
1
22
Lit. [α] +96 (c 0.92, MeOH)].
D
24
In summary, we have developed a convenient method
for the preparation of 1. This total synthesis was performed
in 11 steps to afford 1 from 8 and the overall yield was 25%.
Yield: 273 mg (94%); colorless oil; [α]
IR (neat): 3471, 1782 cm–1
D
–39.9 (c 1.01, CHCl ).
3
.
1
H NMR (500 MHz, CDCl ): δ = 7.40–7.10 (m, 5 H, Ph), 6.10–5.90 (m, 2
3
H, 7′-H, 8′-H), 5.60 (qd, J = 7.0, 13.0 Hz, 1 H, 9′-H), 5.51 (td, J = 7.0, 14.5
Hz, 1 H, 6′-H), 4.73–4.60 (m, 1 H, 4′-H), 4.21 (dd, J = 8.5, 12.5 Hz, 1 H,
Bn), 4.19 (dd, J = 2.5, 12.5 Hz, 1 H, Bn), 3.99 (dq, J = 3.5, 6.0 Hz, 1 H, 2′-
H), 3.71 (ddd, J = 3.5, 4.0, 7.5 Hz, 1 H, 3′-H), 3.25 (dd, J = 2.5, 13.5 Hz, 1
H, 5-H), 2.78 (dd, J = 8.5, 13.5 Hz, 1 H, 5-H), 2.59 (d, J = 3.5 Hz, 1 H,
OH), 2.20 (ddd, J = 6.0, 7.0, 13.0 Hz, 1 H, 5′-H), 1.94 (ddd, J = 7.5, 8.5,
All melting points are uncorrected. 1H and 13C NMR spectra were re-
corded with chloroform (in CDCl ) as internal standard. TLC was per-
3
formed on Wakogel B5F. All reactions were carried out under argon
atmosphere in dried glassware. CH Cl2 was distilled from P O , then
2
2
5
1
1
3.0 Hz, 1 H, 5′-H), 1.80–1.63 (m, 1 H, 4′-H), 1.73 (d, J = 7.0 Hz, 3 H,
0′-H), 1.28 (d, J = 6.0 Hz, 3 H, 2′-Me), 0.98 (d, J = 7.5 Hz, 3 H, 4′-Me).
CaH , and dried over 4 Å MS; benzene and toluene were distilled from
2
P O , and dried over 4 Å MS; THF and Et O were distilled from sodi-
2
5
2
13
um/benzophenone immediately prior to use. All reagents were pur-
chased from Tokyo Kasei Kogyo Co., Ltd., Kanto Chemical Co., Inc. or
Aldrich Chemical Co., Inc., and used without further purification un-
less otherwise noted.
C NMR (125 MHz, CDCl ): δ = 177.3 (1′), 152.8 (2), 135.0 (Ph), 132.2
3
(7′), 131.5 (8′), 129.4 (Ph), 129.0 (6′), 128.9 (Ph), 127.4 (Ph), 127.3 (9′),
74.7 (3′), 66.1 (Bn), 55.1 (4′), 39.9 (2′), 37.7 (5), 36.5 (5′), 35.9 (4′), 17.9
(10′), 15.0 (4′-Me), 11.5 (2′-Me).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

D
Synthesis
I. Shiina et al.
Paper
HRMS: m/z [M + Na]+ calcd for C22H29O NNa: 394.1989; found:
Ethyl (2E,4S,5S,6R,8E,10E)-5-(tert-Butyldimethylsiloxy)-4,6-di-
4
394.1981.
methyldodeca-2,8,10-trienoate (4)
A 1.00 M solution of DIBAL-H in hexane (8.32 mL, 8.32 mmol) was
added to a solution of TBS ether 10 (1.23 g, 3.96 mmol) in THF (33.3
mL) at –78 °C. After the mixture had stirred for 2.5 h at –78 °C, MeOH
and sat. aq Rochelle salt was added. The mixture was extracted with
EtOAc, and the organic layer was washed with brine and dried over
(
2R,3S,4R,6E,8E)-3-Hydroxy-N-methoxy-N,2,4-trimethyldeca-6,8-
dienamide (9)
A 1.00 M solution of Me Al in hexane (16.7 mL, 16.7 mmol) was add-
ed to a solution of N,O-dimethylhydroxylamine hydrochloride (1.63 g,
1
1
mmol) in THF (10.0 mL) was added at 0 °C. After the mixture had
stirred for 15 min at 0 °C, 1.0 M aq HCl was added at 0 °C. The acidi-
fied mixture (pH 4) was extracted with CH Cl , and the organic layer
3
Na SO . After evaporation of the solvent, the residue was dried under
6.7 mmol) in THF (45.7 mL) at 0 °C. After the mixture had stirred for
5 min at 0 °C and for 15 min at r.t., a solution of aldol 5 (2.68 g, 7.21
2
4
reduced pressure to afford aldehyde 11. The crude aldehyde 11 prod-
uct was used in the following reaction without further purification.
Ethyl (triphenylphosphoranylidene)acetate (3.48 g, 9.99 mmol) was
added to a solution of aldehyde 11 in toluene (33.3 mL) at r.t. The
mixture was stirred for 1.5 h at 110 °C. After evaporation of the sol-
vent, the crude product was purified by column chromatography (sil-
ica gel, hexane–EtOAc, 40:1) to afford ester 4.
2
2
was washed with brine and dried over Na SO . After filtration of the
2
4
mixture and evaporation of the solvent, the crude product was puri-
fied by column chromatography (silica gel, hexane–EtOAc, 5:1 to 3:1)
to afford amide 9.
Yield: 1.75 g (95%); colorless oil; [α]D27 +1.9 (c 1.28, CHCl3).
IR (neat): 3433, 1643 cm–1
1
Yield: 1.22 g (81%, 2 steps); colorless oil; [α]D25 –23.0 (c 1.01, CHCl3).
IR (neat): 1720 cm–1
.
.
1
H NMR (500 MHz, CDCl ): δ = 6.99 (dd, J = 8.5, 15.5 Hz, 1 H, 3-H), 6.01
3
H NMR (500 MHz, CDCl ): δ = 6.10–5.93 (m, 2 H, 7-H, 8-H), 5.65–5.45
(dd, J = 10.0, 13.5 Hz, 1 H, 10-H), 5.99 (dd, J = 10.0, 14.5 Hz, 1 H, 9-H),
5.77 (d, J = 15.5 Hz, 1 H, 2-H), 5.58 (qd, J = 7.0, 13.5 Hz, 1 H, 11-H),
5.46 (ddd, J = 7.0, 7.5, 14.5 Hz, 1 H, 8-H), 4.19 (q, J = 7.0 Hz, 2 H, OEt),
3.51 (dd, J = 4.0, 6.5 Hz, 1 H, 5-H), 2.51 (dqd, J = 6.5, 7.5, 8.5 Hz, 1 H, 4-
H), 2.14 (ddd, J = 6.5, 7.0, 13.5 Hz, 1 H, 7-H), 1.90 (ddd, J = 6.0, 7.5, 13.5
Hz, 1 H, 7-H), 1.73 (d, J = 7.0 Hz, 3 H, 12-H), 1.68–1.54 (m, 1 H, 6-H),
1.29 (t, J = 7.0 Hz, 3 H, OEt), 1.04 (d, J = 7.5 Hz, 3 H, 4-Me), 0.91 (s, 9 H,
TBS), 0.82 (d, J = 7.5 Hz, 3 H, 6-Me), 0.06 (s, 3 H, TBS), 0.05 (s, 3 H,
TBS).
3
(m, 2 H, 6-H, 9-H), 3.70 (d, J = 5.0 Hz, 3 H, OMe), 3.64–3.56 (m, 1 H, 3-
H), 3.52–3.44 (m, 1 H, OH), 3.20 (d, J = 4.0 Hz, 3 H, NMe), 3.20–3.08
m, 1 H, 2-H), 2.25–2.10 (m, 1 H, 5-H), 2.00–1.90 (m, 1 H, 5-H), 1.80–
.63 (m, 1 H, 4-H), 1.72 (d, J = 6.0 Hz, 3 H, 10-H), 1.17 (d, J = 7.0 Hz, 3
H, 2-Me), 1.00 (d, J = 6.5 Hz, 3 H, 4-Me).
(
1
1
3
C NMR (125 MHz, CDCl ): δ = 178.0 (1), 132.1 (8), 131.4 (7), 129.1
3
(
(
9), 127.2 (6), 75.0 (3), 61.5 (OMe), 36.6 (4), 36.2 (2), 35.4 (5), 31.9
NMe), 17.9 (10), 15.2 (2-Me), 11.1 (4-Me).
13
HRMS: m/z [M + Na]+ calcd for C14H25O NNa: 278.1727; found:
2
C NMR (125 MHz, CDCl ): δ = 166.7 (1), 152.4 (3), 131.8 (9), 131.6
3
3
(
(
10), 130.3 (8), 127.1 (11), 120.2 (2), 78.4 (5), 60.1 (OEt), 41.3 (4), 37.7
7), 37.4 (6), 26.1 (TBS), 18.4 (TBS), 18.0 (12), 15.6 (4-Me), 14.3 (6-
78.1735.
Me), 14.3 (OEt), –3.78 (TBS), –3.80 (TBS).
HRMS: m/z [M + Na]+ calcd for C22
03.2651.
(
2R,3S,4R,6E,8E)-3-(tert-Butyldimethylsiloxy)-N-methoxy-N,2,4-
trimethyldeca-6,8-dienamide (10)
H O SiNa: 403.2639; found:
40 3
4
tert-Butyldimethylsilyl trifluoromethanesulfonate (2.77 mL, 10.3
mmol) was added to a solution of amide 9 (1.75 g, 6.86 mmol) and
2
,6-lutidine (3.16 mL, 27.4 mmol) in CH Cl (68.6 mL) at 0 °C. After
[(1S,2S,4aR,6R,7S,8S,8aS)-7-(tert-Butyldimethylsiloxy)-2,6,8-
trimethyl-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl]methanol
(13)
2
2
the reaction mixture had stirred for 30 min at 0 °C, sat. aq NH Cl was
added. The mixture was extracted with Et O, and the organic layer
4
2
was washed with brine and dried over Na SO . After filtration of the
A 1.00 M solution of Et AlCl in hexane (0.210 mL, 0.210 mmol) was
2
4
2
mixture and evaporation of the solvent, the crude product was puri-
fied by column chromatography (silica gel, hexane–EtOAc, 5:1) to af-
ford TBS ether 10.
added to a solution of ester 4 (20.0 mg, 0.0525 mmol) in CH Cl (2.6
mL) at –78 °C. After the mixture had stirred for 16 h at r.t., 1.0 M aq
HCl was added at 0 °C. The acidified mixture (pH = 4) was extracted
2
2
Yield: 2.53 g (99%); colorless oil; [α]D25 +5.6 (c 0.720, CHCl3).
with Et O and dried over Na SO . After filtration of the mixture and
2
2
4
evaporation of the solvent, the residue was dried under reduced pres-
sure to afford crude octalin 12, which was used in the following reac-
tion without further purification.
IR (neat): 1666 cm–1
.
1
H NMR (500 MHz, CDCl ): δ = 6.08–5.90 (m, 2 H, 7-H, 8-H), 5.56 (qd,
3
J = 7.0, 21.0 Hz, 1 H, 9-H), 5.48 (td, J = 7.5, 14.5 Hz, 1 H, 6-H), 3.89 (d,
J = 7.5, 8.5 Hz, 1 H, 3-H), 3.69 (s, 3 H, OMe), 3.16 (s, 3 H, NMe), 3.30–
A 1.00 M solution of DIBAL-H in hexane (0.110 mL, 0.110 mmol) was
added to a solution of the crude octalin 12 in CH Cl (1.0 mL) at 0 °C.
2
2
2.95 (m, 1 H, 3-H), 2.33–2.15 (m, 1 H, 5-H), 2.00–1.80 (m, 1 H, 5-H),
After the mixture had stirred for 20 min at 0 °C, MeOH and sat. aq
Rochelle salt were added. The mixture was extracted with CH Cl , and
1.72 (d, J = 7.5 Hz, 3 H, 10-H), 1.63–1.44 (m, 1 H, 4-H), 1.14 (d, J = 7.0
2
2
Hz, 3 H, 2-Me), 0.92 (s, 9 H, TBS), 0.81 (d, J = 6.0 Hz, 3 H, 4-Me), 0.10 (s,
H, TBS), 0.08 (s, 3 H, TBS).
the organic layer was washed with water and brine and dried over
Na SO . After filtration of the mixture and evaporation of the solvent,
3
2
4
13
C NMR (125 MHz, CDCl ): δ = 177.0 (1), 131.7 (8), 131.5 (7), 130.8
3
the crude product was purified by TLC (silica gel, hexane–EtOAc–
MeOH, 100:10:1) to afford alcohol 13.
(
(
9), 126.7 (6), 77.0 (3), 61.4 (OMe), 38.9 (2), 38.6 (4), 37.2 (5), 32.2
NMe), 26.2 (TBS), 18.4 (TBS), 18.0 (10), 15.8 (2-Me), 13.5 (4-Me),
Yield: 11.0 mg (62%, 2 steps); colorless oil.
–3.69 (TBS), –3.72 (TBS).
HRMS: m/z [M + Na]+ calcd for C20H39O NNa: 392.2591; found:
3
392.2607.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

E
Synthesis
I. Shiina et al.
Paper
Ethyl (1S,2S,4aR,6R,7S,8S,8aR)-7-(tert-Butyldimethylsiloxy)-2,6,8-
over Na SO . After filtration of the mixture and evaporation of the sol-
2
4
trimethyl-1,2,4a,5,6,7,8,8a-octahydronaphthalene-1-carboxylate
vent, the crude product was purified by TLC (silica gel, hexane–EtOAc,
(12)
10:1) to afford ester 14.
Yield: 18.9 mg (61%, 2 steps); colorless oil; [α]D24 +2.3 (c 0.720, CHCl3).
An analytical sample of 12 was prepared as a colorless oil by purifica-
tion of the crude product by using TLC (silica gel, hexane–EtOAc,
IR (neat): 1720, 1643 cm–1
.
25
20:1); [α]D –9.1 (c 0.973, CHCl3).
1
H NMR (500 MHz, CDCl ): δ = 7.28 (dd, J = 14.5, 15.5 Hz, 1 H, 3-H),
3
IR (neat): 1736 cm–1
.
6
.13 (dd, J = 9.5, 16.0 Hz, 1 H, 5-H), 6.09 (dd, J = 9.5, 14.5 Hz, 1 H, 4-H),
5.79 (d, J = 15.5 Hz, 1 H, 2-H), 5.61–5.52 (m, 1 H, 3′-H), 5.50–5.47 (m,
1 H, 4′-H), 3.74 (s, 3 H, OMe), 2.85 (dd, J = 8.5, 10.0 Hz, 1 H, 7′-H),
2.48–2.39 (m, 1 H, 1′-H), 2.28–2.13 (m, 1 H, 2′-H), 1.90–1.79 (m, 1 H,
4′a-H), 1.75 (ddd, J = 3.5, 3.5, 13.5 Hz, 1 H, 5′-H), 1.60–1.44 (m, 1 H, 6′-
H), 1.44–1.28 (m, 1 H, 8′-H), 1.05–0.80 (m, 2 H, 8′a-H, 5′-H), 0.98 (d,
J = 6.0 Hz, 3 H, 8′-Me), 0.97 (d, J = 6.0 Hz, 3 H, 6′-Me), 0.94 (d, J = 7.5
Hz, 3 H, 2′-Me), 0.90 (s, 9 H, TBS), 0.06 (s, 6 H, TBS).
1
H NMR (500 MHz, CDCl ): δ = 5.64 (ddd, J = 2.5, 3.0, 9.0 Hz, 1 H, 3′-H),
3
5.58 (ddd, J = 3.0, 3.5, 9.0 Hz, 1 H, 4′-H), 4.12 (qd, J = 7.5, 10.5 Hz, 1 H,
OEt), 4.10 (qd, J = 7.5, 10.5 Hz, 1 H, OEt), 2.88 (dd, J = 9.0, 9.0 Hz, 1 H,
7
(
1
′-H), 2.57 (dd, J = 8.0, 8.0 Hz, 1 H, 1′-H), 2.45–2.28 (m, 1 H, 2′-H), 1.88
ddd, J = 3.5, 4.5, 13.5 Hz, 1 H, 5′-H), 1.80–1.70 (m, 1 H, 4′a-H), 1.58–
.45 (m, 1 H, 6′-H), 1.40–1.20 (m, 2 H, 8′a-H, 8′-H), 1.26 (t, J = 7.5 Hz, 3
H, OEt), 1.08 (ddd, J = 12.5, 13.0, 13.5 Hz, 1 H, 5′-H), 1.04 (d, J = 7.5 Hz,
H, 2′-Me), 0.97 (d, J = 7.0 Hz, 3 H, 6′-Me), 0.93 (d, J = 6.5 Hz, 3 H, 8′-
Me), 0.91 (s, 9 H, TBS), 0.06 (s, 3 H, TBS), 0.05 (s, 3 H, TBS).
3
13
C NMR (125 MHz, CDCl ): δ = 167.8 (1), 150.0 (5), 145.3 (3), 132.7
3
(3′), 132.1 (4′), 126.7 (4), 118.6 (2), 83.8 (7′), 51.4 (OMe), 49.4 (1′),
13
C NMR (125 MHz, CDCl ): δ = 176.2 (1), 133.7 (3′), 132.3 (4′), 82.6
46.7 (8′a), 44.5 (8′), 41.4 (4′a), 39.8 (6′), 39.6 (5′), 36.0 (2′), 26.3 (TBS),
20.4 (8′-Me), 18.6 (5′-Me), 16.7 (2′-Me), –2.6 (TBS), –2.8 (TBS).
HRMS: m/z [M + Na]+ calcd for C25H42O SiNa: 441.2795; found:
3
(7′), 59.9 (OEt), 50.3 (1′), 47.2 (8′a), 46.0 (8′), 39.8 (6′), 39.3 (5′), 38.9
(4′a), 31.3 (2′), 26.3 (TBS), 20.2 (6′-Me), 18.5 (TBS), 17.4 (2′-Me), 16.4
(8′-Me), 14.2 (OEt), –2.8 (TBS), –2.9 (TBS).
3
441.2808.
HRMS: m/z [M + Na]+ calcd for C22H40O SiNa: 403.2639; found:
3
4
03.2645.
Methyl (2E,4E)-5-[(1S,2S,4aR,6R,7S,8S,8aS)-7-Hydroxy-2,6,8-
trimethyl-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl]penta-2,4-
dienoate [(+)-Coprophilin; 1]
Alcohol 13
α]D23 –29.8 (c 1.03, CHCl3).
[
A 12.0 M aq HCl solution (0.100 mL, 1.20 mmol) was added to a solu-
tion of ester 14 (12.7 mg, 0.030 mmol) in MeOH (0.5 mL) and THF (0.5
mL) at 0 °C. The mixture was stirred for 10 h at r.t. and then sat. aq
NaHCO3 was added at 0 °C. The mixture was extracted with EtOAc
and dried over Na SO . After filtration of the mixture and evaporation
IR (neat): 3348 cm–1
.
1
H NMR (500 MHz, CDCl ): δ = 5.72 (ddd, J = 3.0, 3.5, 9.0 Hz, 1 H, 3′-H),
3
5.60 (ddd, J = 2.5, 2.5, 9.0 Hz, 1 H, 4′-H), 3.80 (ddd, J = 4.0, 7.5, 11.0 Hz,
2
4
1
H, 1-H), 3.52 (ddd, J = 5.0, 5.5, 11.0 Hz, 1 H, 1-H), 2.88 (dd, J = 9.0, 9.5
of the solvent, the crude product was purified by TLC (silica gel, hex-
ane–EtOAc, 3:1) to afford coprophilin (1).
Hz, 1 H, 7′-H), 2.43–2.32 (m, 1 H, 2′-H), 1.88–1.74 (m, 3 H, 1′-H, 5′-H,
4
7
3
′a-H), 1.59–1.49 (m, 1 H, 6′-H), 1.49–1.38 (m, 1 H, 8′-H), 1.12 (d, J =
.0 Hz, 3 H, 2′-Me), 1.09–1.00 (m, 2 H, 4′a-H, 5′-H), 1.02 (d, J = 6.0 Hz,
H, 8′-Me), 0.98 (d, J = 6.0 Hz, 3 H, 6′-Me), 0.92 (s, 9 H, TBS), 0.08 (s, 6
1
Yield: 8.5 mg (92%); white solid; mp 81.5–82.5 °C (Lit. 82–83 °C);
24
1
22
[
α]D +96.6 (c 0.170, MeOH) [Lit. [α]D +96 (c 0.92, MeOH)].
IR (neat): 3417, 1720, 1635 cm–1
.
H, TBS).
13
1
C NMR (125 MHz, CDCl ): δ = 134.6 (3′), 134.3 (4′), 84.0 (7′), 64.8 (1),
H NMR (500 MHz, CDCl ): δ = 7.29 (dd, J = 11.0, 15.5 Hz, 1 H, 3-H),
3
3
4
3
6.5 (8′a), 46.0 (1′), 44.3 (8′), 40.5 (5′ or 4′a), 39.6 (6′), 39.0 (4′a or 5′),
1.7 (2′), 26.3 (TBS), 20.3 (6′-Me), 18.5 (TBS), 17.6 (8′-Me), 16.2 (2′-
6.19 (dd, J = 11.0, 14.5 Hz, 1 H, 5-H), 6.10 (dd, J = 11.0, 14.5 Hz, 1 H, 4-
H), 5.79 (d, J = 15.5 Hz, 1 H, 2-H), 5.60–5.56 (m, 1 H, 3′-H), 5.47–5.44
(m, 1 H, 4′-H), 3.74 (s, 3 H, OMe), 2.76–2.70 (m, 1 H, 7′-H), 2.45 (ddd,
J = 4.5, 8.5, 11.0 Hz, 1 H, 1′-H), 2.28–2.13 (m, 1 H, 2′-H), 1.92–1.82 (m,
Me), –2.6 (TBS), –2.8 (TBS).
HRMS: m/z [M + Na]+ calcd for C20H38O SiNa: 361.2533; found:
2
1
H, 4′a-H), 1.76 (ddd, J = 3.5, 4.0, 13.5 Hz, 1 H, 5′-H), 1.60–1.38 (m, 1
361.2520.
H, 6′-H), 1.38–1.18 (m, 1 H, 8′-H), 1.13–1.00 (m, 1 H, 8′a-H), 1.07 (d,
J = 6.0 Hz, 3 H, 8′-Me), 1.04 (d, J = 6.0 Hz, 3 H, 6′-Me), 1.00–0.88 (m, 1
H, 5′-H), 0.95 (d, J = 7.0 Hz, 3 H, 2′-Me).
Methyl (2E,4E)-5-[(1S,2S,4aR,6R,7S,8S,8aS)-7-(tert-Butyldimethyl-
siloxy)-2,6,8-trimethyl-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-
yl]penta-2,4-dienoate (14)
13C NMR (125 MHz, CDCl
(
): δ = 167.8 (1), 149.6 (5), 145.2 (3), 132.7
3′), 131.6 (4′), 126.8 (4), 118.8 (2), 82.1 (7′), 51.5 (OMe), 49.4 (1′),
3
Tetrapropylammonium perruthenate (TPAP) (2.6 mg, 0.0074 mmol)
was added to a suspension of 4 Å MS (44.6 mg), alcohol 13 (25.1 mg,
46.0 (8′a), 43.9 (8′), 41.7 (4′a), 39.6 (6′), 39.2 (5′), 36.3 (2′), 19.0 (8′-
Me), 17.9 (6′-Me), 16.5 (2′-Me).
0
.0741 mmol), and NMO (26.0 mg, 0.222 mmol) in CH Cl (1.5 mL) at
2 2
0
°C. The mixture was stirred for 30 min at 0 °C and then it was fil-
HRMS: m/z [M + Na]+ calcd for C19H28O Na: 327.1931; found:
3
tered through a short pad of silica with EtOAc. After evaporation of
the solvent, the residue was dried under reduced pressure to afford
crude aldehyde 3, which was used in the following reaction without
further purification.
327.1939.
Methyl (E)-4-(Diethoxyphosphoryl)but-2-enoate (2)
Triethyl phosphite (0.190 mL, 1.10 mmol) was added to methyl (E)-4-
bromobut-2-enoate (179 mg, 1.00 mmol) at r.t. The mixture was
stirred for 3 h at 130 °C and the crude product was purified by col-
umn chromatography (silica gel, hexane–EtOAc, 10:1 to CHCl3–
MeOH, 9:1) to afford phosphonate 2.
A 1.00 M solution of LHMDS in THF (0.220 mL, 0.220 mmol) was add-
ed to a solution of phosphonate 2 (57.6 mg, 0.230 mmol) in THF (0.5
mL) at –78 °C. The mixture was stirred for 20 min at –78 °C and then a
solution of crude aldehyde 3 in THF (1.0 mL) was added. After the
mixture had stirred for 3 h at r.t., sat. aq NH Cl was added at 0 °C. The
mixture was extracted with EtOAc, and the organic layer was dried
4
Yield: 231 mg (92%); colorless oil.
IR (neat): 1720, 1658 cm–1
.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

F
Synthesis
I. Shiina et al.
Paper
1
H NMR (500 MHz, CDCl ): δ = 6.88 (m, 1 H, 3-H), 5.96 (m, 1 H, 2-H),
.12 (m, 4 H, OEt), 3.74 (s, 3 H, OMe), 2.74 (dd, J = 8.0, 23.0 Hz, 2 H, 3-
Mohammad, S.; Nguyen Van Buu, O.; Galvani, G.; Meyer, Y.;
Lannou, M.-I.; Sorin, G.; Ardisson, J. Nat. Prod. Rep. 2015, 32,
841.
3
4
H), 1.32 (t, J = 7.2 Hz, 6 H, OEt).
1
3
(4) Shiina, I.; Umezaki, Y.; Ohashi, Y.; Yamazaki, Y.; Dan, S.; Yamori,
T. J. Med. Chem. 2013, 56, 150.
C NMR (125 MHz, CDCl ): δ = 166.1 (1), 137.8 (d, J = 43.0 Hz, 3),
3
PC
1
25.3 (d, JPC = 57.5 Hz, 2), 62.3 (OEt), 62.2 (OEt), 51.6 (OMe), 30.6 (d,
(
5) For related biological studies using synthetic AMF-26 (M-COPA),
see: (a) Ohashi, Y.; Okamura, M.; Hirosawa, A.; Tamaki, N.;
Akatsuka, A.; Wu, K.-M.; Choi, H.-W.; Yoshimatsu, K.; Shiina, I.;
Yamori, T.; Dan, S. Cancer Res. 2016, 76, 3895. (b) Hattori, T.;
Watanabe-Takahashi, M.; Shiina, I.; Ohashi, Y.; Dan, S.;
Nishikawa, K.; Yamori, T.; Naito, M. Genes Cells 2016, 21, 901.
JPC = 554 Hz, 4), 16.4 (OEt), 16.4 (OEt).
HRMS: m/z [M + Na]+ calcd for C H O PNa: 259.0706; found:
2
9
17
5
59.0715.
Acknowledgement
(
c) Hara, Y.; Obata, Y.; Horikawa, K.; Tasaki, Y.; Suzuki, K.;
Murata, T.; Shiina, I.; Abe, R. PLoS One 2017, 12, e0175514.
d) Benabdi, S.; Peurois, F.; Nawrotek, A.; Chikireddy, J.;
The authors thank Messrs. Masaki Honda, Teppei Kuboki, and Naoki
Egashira, and Ms. Anna Tanaka for their efforts in the preparation of
intermediate 13.
(
Cañeque, T.; Yamori, T.; Shiina, I.; Ohashi, Y.; Dan, S.; Rodriguez,
R.; Cherfils, J.; Zeghouf, M. Biochemistry 2017, 56, 5125.
(e) Ignashkova, T. I.; Gendarme, M.; Peschk, K.; Eggenweiler, H.-
M.; Lindemann, R. K.; Reiling, J. H. Traffic 2017, 18, 530.
6) (a) Mukaiyama, T.; Kobayashi, S.; Uchiro, H.; Shiina, I. Chem.
Lett. 1990, 19, 129. (b) Kobayashi, S.; Uchiro, H.; Fujishita, Y.;
Shiina, I.; Mukaiyama, T. J. Am. Chem. Soc. 1991, 113, 4247.
Supporting Information
(
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591866.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
(
c) Shiina, I. Chem. Rec. 2014, 14, 144.
7) (a) Mukaiyama, T.; Inoue, T. Chem. Lett. 1976, 5, 559.
b) Mukaiyama, T.; Saigo, K.; Takazawa, O. Chem. Lett. 1976, 5,
(
(
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©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F