An asymmetric synthesis of (+)-monomorine I

Article abstract of DOI:10.1016/j.tetasy.2017.09.008

The synthesis of (+)-monomorine I, an indolizidine alkaloid isolated from Monomorium pharaonis, has been achieved. The 2,6-cis-piperidine ring moiety of (+)-monomorine I was constructed using diastereoselective aminopalladation. Chain elongation via cross

Full text of DOI:10.1016/j.tetasy.2017.09.008

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
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Tetrahedron: Asymmetry
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An asymmetric synthesis of (+)-monomorine I
Masaki Asai a,y, Yukiko Takemoto b,y, Ayaka Deguchi c, Yasunao Hattori d, Hidefumi Makabe a,b,
⇑
a Graduate School of Science and Technology, Department of Agriculture, Division of Food Science and Biotechnology, Shinshu University, 8304 Minami-minowa, Kami-ina,
Nagano 399-4598, Japan
b Graduate School of Agriculture, Sciences of Functional Foods, Shinshu University, 8304 Minami-minowa, Kami-ina, Nagano 399-4598, Japan
c Department of Bioscience and Biotechnology, Faculty of Agriculture, Shinshu University, 8304 Minami-minowa, Kami-ina, Nagano 399-4598, Japan
d Center for Instrumental Analysis, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of (+)-monomorine I, an indolizidine alkaloid isolated from Monomorium pharaonis, has
been achieved. The 2,6-cis-piperidine ring moiety of (+)-monomorine I was constructed using diastereos-
elective aminopalladation. Chain elongation via cross-metathesis using Hoveyda-Grubbs 2nd catalyst fol-
lowed by deprotection of the Cbz group and cyclic reductive hydroamination afforded (+)-monomorine I.
Ó 2017 Elsevier Ltd. All rights reserved.
Received 12 July 2017
Revised 9 August 2017
Accepted 15 August 2017
Available online xxxx
1. Introduction
piperidine ring 2 via deprotection followed by the formation of
the imine and successive reduction of the double bond. Compound
Indolizidine alkaloids have attracted much attention due to
their unique structures and biological activities.1 Most of them
possess alkyl side chains at the 3- and 5-positions. Due to their
potential biological activities, much effort has been made towards
their total synthesis.2 (+)-Monomorine I 1, which has a 3,5-disub-
stituted indolizidine skeleton, was isolated from the pharaoh’s
ant Monomorium pharaonis.3 To date, several enantioselective syn-
theses of both enantiomers of monomorine I have been reported.4,5
Quite recently, we reported the synthesis of (ꢀ)-isosolenopsin
using diastereoselective aminopalladation.6 Herein, we report a
detailed study of diastereoselective aminopalladation7 and its
application to the synthesis of (+)-monomorine I 1 (Fig. 1).
3 would be synthesized from piperidine ring 4 and 2-octen-4-one
using cross-metathesis8 followed by reduction of the double bond.
Piperidine ring 4 would be prepared from allyl alcohol 5 via
diastereoselective aminopalladation (Scheme 1).
The diastereoselective aminopalladation to afford a 2,6-cis-
piperidine ring has been reported by us before.6 We examined fur-
ther the diastereoselective aminopalladation of 5. At first, we used
the Boc group as a protecting group of the amino group. When the
reaction time was 20 min, the ratio of cis: trans was 67:33. Extend-
ing the reaction time to 5 h gave the 2,6-cis-piperidine ring exclu-
sively. Extraction of the reaction mixture in a thorough manner
improved the isolated yield of piperidine ring 4b up to 63% yield.6
From these observations, this reaction should be reversible and the
Pd p-complex should be present in equilibrium between complex
A and B.9 Complex B suffers from steric hindrance between the
Boc group and the allylic alcohol. On the other hand, complex A
is favorable because it has less steric hindrance and the chelation
effect between Pd and two oxygens of the Boc group and allylic
alcohol. When we used the Cbz group as a cyclization precursor,
the yield of the cyclized products was 77%, however, the selectivity
of cis/trans was 53:47 (Table 1, Fig. 2).
N
n-C4H9
(+)-monomorine I 1
Figure 1. Structure of (+)-monomorine 1.
For the synthesis of (+)-monomorine I 1, we examined the
cross-metathesis of 4a with a side chain.8 At first, we used 4-ben-
zyloxy-2-octene as the side chain. However, the cross-metathesis
reaction did not proceed at all. Thus, we used commercially avail-
able 2-octen-4-one. Using 20 mol % of Grubbs 2nd catalyst afforded
3a in 39% yield. Changing the catalyst to Hoveyda-Grubbs 2nd cat-
alyst gave 3a in high yield (Table 1).
2. Results and discussion
Our synthetic strategy is shown in Scheme 1. The complete car-
bon skeleton of 1 would be constructed from 2,6-cis-substituted
⇑
Corresponding author. Tel.: +81 265 77 1630; fax: +81 265 77 1700.
E-mail address: makabeh@shinshu-u.ac.jp (H. Makabe).
M.A. and Y.T. equally contributed.
y
http://dx.doi.org/10.1016/j.tetasy.2017.09.008
0957-4166/Ó 2017 Elsevier Ltd. All rights reserved.
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2
M. Asai et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
N
N
N
H
:
H2
O
n-C4H9
1
(+)-monomorine I
N
R
N
R
O
O
3
2
cross-metathesis
+
N
R
O
4
2-octen-4-one
diastereoselective aminopalladation
NHR
HO
5
Scheme 1. Synthetic strategy of (+)-monomorine I 1.
Table 1
Diastereoselective aminopalladation
HO
20 mol% of Cl2Pd(MeCN)2
N
+
N
R
NHR
CH2Cl2
R
5
cis-4
trans-4
Entry
R
Time (h)
Yield of cis-4 and trans-4 (%)
cis/trans
1
2
3
Boc
Boc
Cbz
0.33
5
5
49
63
77
67:33
>98:2
53:47
of 3a was hydrogenated using Pearlman’s catalyst to give 2a. Next,
we tried to synthesize (+)-monomorine I 1 via a cyclic imine fol-
lowed by reduction with NaBH4. However, deprotection of the
Boc group of 2a using methanolic HCl followed by reduction with
NaBH4 gave a complex mixture (Scheme 2, Table 2).
Next, we chose hydrogenolysis followed by reductive amination
as reported by Iska et al.4g Reduction of the ketone 2a with NaBH4
gave alcohol 7. Changing the protecting group of the amino group
from a Boc group to a Cbz group followed by oxidation of the
hydroxy group with Dess–Martin periodinane afforded 2b. Finally,
hydrogenolysis of the Cbz group and reductive amination in situ
using Pearlman’s catalyst under a hydrogen atmosphere furnished
(+)-monomorine I 1 in 41% yield. The specific rotation value and
spectroscopic data of synthetic 1 were in good agreement with
the reported values (Scheme 3).5h
OH
Me
Pd
Me
NH
B
Pd
O
O
H
N
H
O
O
OH
H
A
N
N
Boc
Boc
2,6-cis
2,6-trans
4a
4b
Although (+)-monomorine I 1 was synthesized from enone 3a, it
took six steps to synthesize and the yield of transformation from 7
to 2b was 37% in three steps. We thus pursued a more efficient syn-
thesis of 1. As shown in Table 1, a bulky protecting group, such as a
Boc group, was necessary to obtain high selectivity in the Pd(II)-cat-
alyzed stereoselective aminopalladation. Thus, we used piperidine
Figure 2. Proposed transition state forming 2,6-cis-piperidine 4a.
Since the side chain had been successfully introduced, we
focused on the synthesis of (+)-monomorine I 1. The double bond
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M. Asai et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
H2, Pd(OH)2/C
N
1) conc. HCl, MeOH
2) NaBH4
N
Boc
74%
Boc
O
O
2a
3a
+
N
N
N
H
:
n-C4H9
O
H−
(+)-monomorine I 1
Scheme 2. Attempt to synthesize (+)-monomorine I 1 via cyclic imine followed by reduction with NaBH4.
Table 2
Table 3
Cross-metathesis of piperidine ring 4a with side chain
Cross-metathesis of piperidine ring 8a with 2-octen-4-one.
Entry
Catalyst
Time (h)
Yield of 9 (%)
1
2
3
Grubbs 1st
Grubbs 2nd
Hoveyda-Grubbs 2nd
24
20
20
0
32
62
OBn
N
N
Boc
Boc
cross-metathesis
OBn
4a
6
Synthetic studies on other indolizidine alkaloids are currently
underway.
O
N
N
cross-metathesis
Boc
Boc
4. Experimental
4.1. General
O
4a
3a
Entry
Catalyst (mol %)
Time (h)
Yield of 3a (%)
1
2
3
Grubbs 2nd (10)
Grubbs 2nd (20)
Hoveyda-Grubbs 2nd (10)
6
6
7
25
39
94
All reactions were carried out in dry solvents under an argon
atmosphere, unless otherwise noted. Analytical thin-layer chro-
matography (TLC) was performed using E. Merck Silica gel 60
F254 pre-coated plates (0.25 mm). Preparative thin-layer chro-
matography (PTLC) was performed using E. Merck Silica gel 60
F254 pre-coated plates (1.5 mm). Optical rotations were measured
on JASCO DIP-1000 polarimeter at room temperature using the
sodium D line. Infrared (IR) spectra were recorded as a thin film
on a NaCl disk using JASCO FT-IR 480 Plus infrared spectrophotome-
ter. 1H and 13C NMR spectra were recorded on Bruker Avance
500 MHz spectrometer. Chemical shifts were reported in ppm on
the d scale relative to tetramethylsilane (TMS) (d = 0.00 for 1H
NMR), CDCl3 (d = 77.0 for 13C NMR) as internal reference. Signal pat-
terns are indicated as s, singlet; d, doublet; t, triplet; m, multiplet;
br, broaden peak. High resolution mass spectra were measured on
JEOL GC mate II mass spectrometers.
4a as a chiral synthon. As shown in Scheme 3, compound 2b could
be transformed into monomorine I 1 using a one pot-operation.
Thus, we tried to change the Boc group of 4a to a Cbz group. Using
the procedure reported by Lee et al. afforded the Cbz protected
amine 8a from 4a in 78% yield.10 The cross-metathesis of 8a with
2-octen-4-one gave chain elongated product 9. As shown in Table 3,
Hoveyda-Grubbs 2nd catalyst gave 9 in 62% yield. Finally, reduction
of the double bond, hydrogenolysis of the Cbz group, and the reduc-
tive amination in situ using Pearlman’s catalyst under hydrogen
atmosphere furnished (+)-monomorine I 1 in 67% yield as a single
diastereomer through a one-pot procedure.11 The specific rotation
value and spectroscopic data of synthetic 1 were in good agreement
with Scheme 3 (Scheme 4, Table 3).5h
4.1.1. (2S,6S,10E)-N-tert-Butoxycarbonyl-2-methyl-6-(30-oxohept-
10-enyl)piperidine 3a
3. Conclusion
A solution of piperidine ring 4a (40 mg, 0.18 mmol), 2-octen-4-
one (137 lL, 0.92 mmol), and Hoveyda-Grubbs 2nd catalyst
(12.5 mg, 0.015 mmol) in CH2Cl2 (6 mL) was stirred for 7 h at
In conclusion, synthesis of (+)-monomorine I 1 was achieved
using stereoselective aminopalladation and cross-metathesis.
1) HCl, MeOH
2) CbzCl, NaHCO3, dioxane/H2O
NaBH4
N
N
quant.
Boc
Boc
3) Dess-Martin periodinane
OH
O
2a
2b
7
37% (3 steps)
H2, Pd(OH)2/C
41%
N
N
Cbz
n-C4H9
O
1
(+)-monomorine I
Scheme 3. Synthesis of (+)-monomorine I 1.
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4
M. Asai et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
1) 2-chloropyridine, Tf2O
2) BnOH, Et3N
O
N
N
cross-metathesis
catalyst (10 mol%)
Boc
78%
Cbz
4a
8a
Table 3
H2, Pd(OH)2/C
N
N
Cbz
MeOH
67%
O
n-C4H9
9
1
(+)-monomorine I
Scheme 4. Synthesis of (+)-monomorine I (1) from 8a.
reflux. After the reaction had been completed, the solvent was
evaporated and the residue was purified with PTLC (hexane/
over anhydrous MgSO4, filtered, and concentrated. The residue
was dissolved into dioxane–H2O (5:1, 6.0 mL). To this solution,
AcOEt = 5:1) to afford 3a (51 mg, 94%) as
a
colorless oil.
NaHCO3 (109 mg, 1.3 mmol) and benzylchloroformate (91
0.64 mmol) were added. After being stirred for 26 h, benzylchloro-
formate (90 L, 0.64 mmol) was added again and the mixture was
lL,
[a
]
D
20 = ꢀ50 (c 0.59, CHCl3); IR (film) mmax cmꢀ1: 2934, 1687,
1392, 1364, 1174, 1078 cmꢀ1
;
1H NMR (500 MHz, CDCl3) d: 6.81
l
(1H, dd, J = 16.0, 5.0 Hz), 6.15 (1H, dd, J = 16.0, 1.5 Hz), 4.85–4.84
(1H, m), 4.38–4.34 (1H, m), 2.54 (2H, t, J = 7.5 Hz), 1.91–1.89 (1H,
m), 1.74–1.50 (7H, m), 1.45 (9H, s), 1.39–1.30 (2H, m), 1.13 (3H,
d, J = 7.0 Hz), 0.91 (3H, t, J = 7.5 Hz); 13C NMR (125 MHz, CDCl3)
d: 200.7, 155.0, 147.8, 129.3, 79.8, 50.4, 46.1, 40.4, 29.9, 28.4 (C
ꢁ 3), 28.0, 26.3, 22.4, 20.4, 14.5, 13.9 ppm. HREIMS [M]+: found,
309.2306, calcd for C18H31NO3: 309.2304.
further stirred for 24 h. The mixture was extracted with EtOAc
(10 mL ꢁ 3) and the organic layer was washed with brine, dried
over anhydrous MgSO4, filtered and concentrated. This crude pro-
duct was used for the next step without further purification. To a
solution of the crude material was added NaHCO3 (294 mg,
3.5 mmol) and Dess–Martin periodinane (445 mg, 1.1 mmol) in
CH2Cl2 (10 mL) at 0 °C. After being stirred for 20 min, the mixture
was diluted with diethyl ether (12 mL) and saturated aqueous
NaHCO3, after which Na2S2O3 and water (2:2:1, 15 mL) were added
to the mixture. The mixture was extracted with Et2O (10 mL ꢁ 3)
and the organic layer was washed with saturated aqueous NaHCO3,
water, brine, dried over anhydrous MgSO4, filtered, and concen-
trated. The residue was purified with preparative TLC (hexane/
EtOAc = 38:5) afforded 2b as a colorless oil (16.5 mg, 37% in 3
4.1.2. (2S,6S)-N-tert-Butoxycarbonyl-2-methyl-6-(30-oxoheptyl)
piperidine 2a
To a solution of 3a (51 mg, 0.17 mmol) was added Pd(OH)2/C
(4.8 mg) under a hydrogen atmosphere. After stirring for 16 h,
the mixture was filtered. The filtrate was concentrated to afford
2a (47 mg, 88%) as a colorless oil; [
a
]
20 = ꢀ6.8 (c 0.39, CHCl3); IR
D
(film) mmax cmꢀ1: 2936, 2360, 1725, 1684, 1559, 1362, 1175,
steps); [
a
]
D
20 = ꢀ6.6 (c 0.83, CHCl3); IR (film) mmax cmꢀ1: 2936,
1080 cmꢀ1
;
1H NMR (500 MHz, CDCl3) d: 4.32–4.29 (1H, m),
1720, 1684, 1653, 1559, 1409, 1308, 1072, 755 cmꢀ1
;
1H NMR
4.10–4.09 (1H, m), 2.50–2.30 (4H, m), 1.84–1.49 (9H, m), 1.46
(9H, s), 1.34–1.25 (3H, m), 1.18 (3H, d, J = 7.0 Hz), 0.90 (3H, t,
J = 7.5 Hz); 13C NMR (125 MHz, CDCl3) d: 210.9, 155.4, 79.1, 42.6,
40.5, 30.2, 28.7, 28.5 (C ꢁ 2), 28.4 (C ꢁ 3), 28.1, 26.0, 22.3, 20.5,
14.1, 13.8 ppm. HREIMS: m/z [M]+: found, 311.2464, calcd for
(500 MHz, CDCl3) d: 7.37–7.30 (5H, m), 5.13 (2H, s), 4.43–4.41
(1H, m), 4.19–4.18 (1H, m), 2.40–2.39 (1H, m), 2.31–2.28 (3H,
m), 1.88–1.43 (9H, m), 1.31–1.23 (3H, m), 1.20 (3H, d, J = 7.0 Hz),
0.89 (3H, t, J = 7.5 Hz); 13C NMR (125 MHz, CDCl3) d: 210.8, 155.9,
142.3, 137.0, 128.5 (C ꢁ 2), 127.9, 127.8, 66.9, 49.9, 46.1, 42.5,
40.3, 30.1, 28.7, 28.3, 25.9, 22.3, 20.6, 14.0, 13.9 ppm. HREIMS
[M]+: found, 345.2301, calcd for C21H31NO3: 345.2304.
C18H33NO3: 311.2460.
4.1.3. (2S,6S,30RS)-N-tert-Butoxycarbonyl-2-methyl-6-(30-hydro-
xyheptyl)piperidine 7
4.1.5. (+)-Monomorine I 1
To a solution of 2a (47 mg, 0.15 mmol) in MeOH (5 mL) was
added NaBH4 (28 mg, 0.75 mmol) at 0 °C. After being stirred for
1.5 h, the solvent was evaporated and the solid material was
removed by filtration. The filtrate was concentrated to give 7
To a solution of 2b (15 mg, 0.05 mmol) was added Pd(OH)2/C
(1.4 mg) under hydrogen atmosphere. After being stirred for 4 h,
the mixture was filtered. The filtrate was concentrated to afford
1 (4.0 mg, 41%) as a colorless oil; [a]
20 = +32 (c 0.14, n-hexane),
D
(49 mg, quant.) as a colorless oil. [
a
]
20 = ꢀ2.1 (c 0.40, CHCl3); IR
{lit. +33.8 (c 1.00, n-hexane)};4h IR (film) mmax cmꢀ1: 2956, 2927,
2858, 1457, 1378, 1319, 1206, 1169, 1132, 1107, 1056; 1H NMR
(500 MHz, CDCl3) d: 2.48 (1H, brt, J = 8.3 Hz), 2.29–2.17 (1H, m),
2.11–2.05 (1H, m), 1.90–1.50 (6H, m), 1.49–1.15 (10H, m), 1.14
(3H, d, J = 6.0 Hz), 0.89 (3H, t, J = 7.0 Hz); 13C NMR (125 MHz,
CDCl3) d: 67.1, 62.9, 60.2, 39.7, 35.8, 30.9, 30.3, 29.8, 29.4, 24.9,
22.9 (C ꢁ 2), 14.0 ppm. HREIMS [M]+: found, 195.1985, calcd for
D
(film) mmax cmꢀ1: 3441, 2933, 2861, 1684, 1662, 1456, 1405,
1364, 1254, 1178, 1083 cmꢀ1 1H NMR (500 MHz, CDCl3) d: 4.28–
;
4.25 (1H, m), 4.10–4.04 (1H, m), 3.71 (0.4H, m), 3.63 (0.6H, m),
1.75–1.25 (26H, m), 1.15 (3H, d, J = 6.3 Hz), 0.91 (3H, t,
J = 7.0 Hz); 13C NMR (125 MHz, CDCl3) d: 155.6, 79.4, 79.1, 72.3,
37.2, 31.3, 30.2, 28.5 (C ꢁ 3), 28.0, 27.9, 27.6, 22.8, 20.4, 14.1,
13.9, 13.8 ppm. HREIMS [M]+: found, 313.2622, calcd for
C18H35NO3: 313.2617.
C13H25N: 195.1987.
4.1.6. (2S,6S)-N-Benzyloxycarbonyl-2-methyl-6-vinylpiperidine
8a
4.1.4. (2S,6S)-N-Benzyloxycarbonyl-2-methyl-6-(30-oxoheptyl)
piperidine 2b
To a solution of 4a (20 mg, 0.089 mmol) in CH2Cl2 (5.0 mL) were
To a solution of 7 (40 mg, 0.13 mmol) in MeOH (5 mL) was
added ten drops of conc. HCl. After being stirred for 10 min, the sol-
vent was evaporated and saturated aqueous NaHCO3 (5 mL) was
added to the mixture. The mixture was extracted with EtOAc
(10 mL ꢁ 3) and the organic layer was washed with brine, dried
added 2-chloropyridine (25
0.13 mmol). After being stirred for 15 min, BnOH (28
0.27 mmol) and Et3N (37
ture. After the resulting mixture had been stirred for 1 h, the reac-
tion was quenched with water. The mixture was extracted with
l
L, 0.27 mmol) and Tf2O (22
l
l
L,
L,
l
L, 0.27 mmol) were added to the mix-
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M. Asai et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
EtOAc (10 mL ꢁ 3) and the organic layer was washed with
saturated aqueous NaHCO3, water, brine, dried over anhydrous
Na2SO4, filtered and concentrated. The residue was purified with
preparative TLC (hexane/EtOAc = 3:1) afforded 8 a (18 mg, 78%)
being stirred for 18 h, the mixture was filtered through a pad of
Celite. The filtrate was concentrated. The residue was purified with
alumina column chromatography (pH 9.0–11.0, hexane/Et2O = 10:
1) to afford 1 (13 mg, 67%) as a pale yellow oil. The physiochemical
and spectroscopic data were in good accordance with those
described above.
as a colorless oil. [
a
]
19 = ꢀ13.7 (c 1.00, CHCl3); IR (film) mmax
D
cmꢀ1: 3065, 3033, 2940, 2870, 1695, 1497, 1456, 1405, 1381,
1328, 1310, 1271, 1213, 1146, 1096, 1075, 1029, 981, 917,
771 cmꢀ1
;
1H NMR (500 MHz, CDCl3) d: 7.40–7.28 (5H, m),
Acknowledgement
5.97–5.90 (1H, m), 5.15 (2H, s), 5.10 (2H, dd, J = 19.0, 10.5 Hz),
4.79–4.77 (1H, m), 4.45–4.40 (1H, m), 1.90–1.88 (1H, m), 1.77–
1.60 (3H, m), 1.55–1.53 (1H, m), 1.49–1.44 (1H, m), 1.18 (3H, d,
J = 7.0 Hz); 13C NMR (125 MHz, CDCl3) d: 155.8, 140.0, 137.0,
128.4 (C ꢁ 2), 127.8, 127.7 (C ꢁ 2), 114.8, 66.9, 51.8, 46.6, 30.1,
27.9, 20.4, 14.2 ppm. HREIMS [M]+: found, 259.1578, calcd for
This work was supported in part by JSPS KAKENHI Grant Num-
ber 24580160 to H. M.
References
1. Takahata, H.; Momose, T. Alkaloids 1993, 44, 189.
C16H21NO2: 259.1572.
2. Sunil, V. P.; Rakesh, G. T. Targets Heterocycl. Syst. 2013, 17, 57.
3. Ritter, F. J.; Rotgans, I. E. M.; Tulman, E.; Verwiel, P. E. J.; Stein, F. Experientia
1973, 29, 530.
4. Classical syntheses of monomorine I: (a) Stevens, R. V.; Lee, A. W. M. J. Chem.
Soc. Chem. Commun. 1982, 102; (b) Royer, J.; Husson, H. P. J. Org. Chem. 1985, 50,
670.
4.1.7. (2S,6S, 10E)-N-Benzyloxycarbonyl-2-methyl-6-(30-oxohept-
10-enyl)piperidine 9
To a solution of 8 a (45 mg, 0.17 mmol) and 2-octen-4-one
(129 lL, 0.87 mmol) was added Hoveyda-Grubbs 2nd catalyst
(11 mg, 0.017 mmol) in CH2Cl2 (3.0 mL). After being stirred for
20 h at reflux, the solvent was evaporated and the residue was
5. Recent syntheses of monomorine I: (a) Deng, H.-Q.; Qian, X.-Y.; Li, Y.-X.; Zheng,
J.-F.; Xie, L.; Huang, P.-Q. Org. Chem. Front. 2014, 1, 258; (b) Reddy, C. R.; Latha,
B.; Rao, N. N. Tetrahedron 2012, 68, 145; (c) Le, T. Q.; Oliver III, R. M.; Arcari, J. T.;
Mitton-Fly, M. J. Tetrahedron Lett. 2012, 53, 5660; (d) Reddy, C. R.; Latha, B.
Tetrahedron: Asymmetry 1849, 2011, 22; (e) Davis, F. A.; Zhang, J.; Wu, Y.
Tetrahedron Lett. 2011, 52, 2054; (f) Lapointe, G.; Schenk, K.; Renaud, P. Chem.
Eur. J. 2011, 17, 3207; (g) Iska, R. V. B.; Verdolino, V.; Wiest, O.; Helquist, P. J.
Org. Chem. 2010, 75, 1325; (h) Lesma, G.; Colombo, A.; Sacchetti, A.; Silvani, A. J.
Org. Chem. 2009, 74, 590; (i) Pattenden, L. C.; Adams, H.; Smith, S. A.; Harrity, J.
P. A. Tetrahedron 2008, 64, 2951; (j) Kuhakarn, C.; Seehasombat, P.; Jaipetch, T.;
Pomakotr, M.; Reutrakul, V. Tetrahedron 2008, 64, 1663; (k) Toyooka, N.; Zhou,
D.; Nemoto, H. J. Org. Chem. 2008, 73, 4575; (l) Conchon, E.; Gelas-Mialhe, G.;
Remuson, R. Tetrahedron: Asymmetry 2006, 17, 1253; (m) Berry, M. B.; Craig, D.;
Jones, P. S.; Rowlands, G. J. Beilstein J. Org. Chem. 2007, 3, 39; (n) Zhang, S.; Xu,
L.; Miao, L.; Shu, H.; Trudell, M. L. J. Org. Chem. 2007, 72, 3133.
6. Takemoto, Y.; Hattori, Y.; Makabe, H. Heterocycles 2017, 94, 286.
7. (a) Makabe, H.; Looi, K. K.; Hirota, M. Org. Lett. 2003, 5, 27; (b) Kurogome, Y.;
Kogiso, M.; Looi, K. K.; Hattori, Y.; Hirota, M.; Makabe, H. Tetrahedron 2013, 69,
8349; (c) Yokoyama, H.; Otaya, K.; Kobayashi, H.; Miyazawa, M.; Yamaguchi, S.;
Hirai, Y. Org. Lett. 2000, 2, 2427; (d) Katsuyama, M.; Furuta, M.; Kobayashi, K.;
Teruya, K.; Makabe, H.; Akaji, K.; Hattori, Y. Heterocycles 2015, 91, 959.
8. Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
purified with preparative TLC (hexane/EtOAc = 5:1) to afford 9
19
(36 mg, 62%) as a colorless oil. [
a
]
D = ꢀ67.9 (c 0.500, CHCl3); IR
(film) mmax cmꢀ1: 2935, 2871, 1695, 1456, 1405, 1341, 1310,
1272, 1074, 975, 771 cmꢀ1 1H NMR (500 MHz, CDCl3) d:
;
7.40–7.30 (5H, m), 6.81 (1H, dd, J = 16.0, 5.0 Hz), 6.12 (1H, d,
J = 16.0 Hz), 5.18 (1H, d, J = 7.0 Hz), 5.14 (1H, d, J = 7.0 Hz), 4.95–
4.92 (1H, m), 4.47–4.44 (1H, m), 2.50 (2H, t, J = 7.5 Hz), 1.93–1.91
(1H, m), 1.76–1.49 (7H, m), 1.36–1.25 (2H, m), 1.16 (3H, d,
J = 7.0 Hz), 0.91 (3H, t, J = 7.5 Hz); 13C NMR (125 MHz, CDCl3) d:
200.6, 155.6, 147.1, 136.7, 129.5, 128.5 (C ꢁ 2), 128.0, 127.9 (C ꢁ
2), 67.2, 50.6, 46.6, 40.4, 29.9, 27.8, 26.2, 22.4, 20.5, 14.4,
13.9 ppm. HREIMS [M]+: found, 343.2145, calcd for C21H29NO3:
343.2147.
9. Reversible reaction mechanism of oxypalladation was reported by Kawai, N.;
Lagrange, J. M.; Ohmi, M.; Uenishi, J. J. Org. Chem. 2006, 71, 4530.
10. Kim, H.-K.; Lee, A. Tetrahedron Lett. 2016, 57, 4890.
4.1.8. (+)-Monomorine I 1 from 9
To a solution of 9 (36 mg, 0.10 mmol) in MeOH (2.0 mL) was
added Pd(OH)2/C (3.0 mg) under a hydrogen atmosphere. After
11. Amat, M.; Llor, N.; Hidalgo, J.; Escolano, C.; Bosch, J. J. Org. Chem. 2003, 68, 1919.
Please cite this article in press as: Asai, M.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.09.008